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Name Reactions
Fourth Expanded Edition
Jie Jack Li
Name Reactions
A Collection of Detailed Mechanismsand Synthetic Applications
Fourth Expanded Edition
123
Jie Jack Li, Ph.D.Discovery ChemistryBristol-Myers Squibb Company5 Research ParkwayWallingford, CT 06492USAjack.li@bms.com
ISBN 978-3-642-01052-1 e-ISBN 978-3-642-01053-8DOI 10.1007/978-3-642-01053-8Springer Dordrecht Heidelberg London New York
c© Springer-Verlag Berlin Heidelberg 2009This work is subject to copyright. All rights are reserved, whether the whole or part of the material isconcerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publicationor parts thereof is permitted only under the provisions of the German Copyright Law of September 9,1965, in its current version, and permission for use must always be obtained from Springer. Violationsare liable to prosecution under the German Copyright Law.The use of general descriptive names, registered names, trademarks, etc. in this publication does notimply, even in the absence of a specific statement, that such names are exempt from the relevant protectivelaws and regulations and therefore free for general use.
Cover design: KunkelLopka GmbH
Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)
Library of Congress Control Number: 2009931220
To Vivien
Foreword
I don't have my name on anything that I don't really do. –Heidi Klum
Can the organic chemists associated with so-called “Named Reactions” make the same claim as supermodel Heidi Klum? Many scholars of chemistry do not hesitate to point out that the names associated with “name reactions” are often not the actual inventors. For instance, the Arndt–Eistert reaction has nothing to do with either Arndt or Eistert, Pummerer did not discover the “Pummerer” rearrangement, and even the famous Birch reduction owes its initial discovery to someone named Charles Wooster (first reported in a DuPont patent). The list goes on and on…
But does that mean we should ignore, boycott, or outlaw “named reactions”? Absolutely not. The above examples are merely exceptions to the rule. In fact, the chemists associated with name reactions are typically the original discoverers, contribute greatly to its general use, and/or are the first to popularize the transformation. Regardless of the controversial history underlying certain named reactions, it is the students of organic chemistry who benefit the most from the cataloging of reactions by name. Indeed, it is with education in mind that Dr. Jack Li has masterfully brought the chemical community the latest edition of Name Reactions.
It is clear why this beautiful treatise has rapidly become a bestseller within the chemical community. The quintessence of hundreds of named reactions is encapsulated in a concise format that is ideal for students and seasoned chemists alike. Detailed mechanistic and occasionally even historical details are given for hundreds of reactions along with key references. This “must-have” book will undoubtedly find a place on the bookshelves of all serious practitioners and students of the art and science of synthesis.
Phil S. Baran May 2009
La Jolla, California
Preface
The first three editions of this book have been warmly embraced by the organic chemistry community. Many readers have indicated that while they like the detailed mechanisms, they prefer to have more real case applications in synthesis. For this edition, we have revolutionized the format, which finally liberated more space to accomodate many more synthetic examples. As a consequence, the subtitle of the book has been changed to A Collection of Detailed Mechanisms and Synthetic Applications. When putting together the 4th edition, I also strived to cap-ture the latest references, up to 2009 whenever possible. Coincidentally, my daughter Vivien, a sophomore at the University of Michigan, will take soon Or-ganic Chemistry. I hope she finds this book useful in preparing for her exams.
I am very much indebted to the readers who have kindly written to me with suggestions, which helped transform this book into a useful reference book for senior undergrate and graduate students around the world—the second edition was translated to both Chinese and Russian. I am grateful to my good friend Derek A. Pflum at Ash Stevens Inc. who kindly proofead the entire manuscript and provided many invaluable suggestions. Prof. Derrick L. J. Clive at University of Alberta also proofread the first half of the manuscript and offered helpful comments. I also wish to thank Prof. Phil S. Baran at Scripps Research Institute and his students, Tanja Gulder, Yoshi Ishihara, Chad A. Lewis, Jonathan Lockner, Jun Cindy Shi, and Ian B. Seiple for proofreading the final draft of the manuscript. Their knowledge and time have tremendously enhanced the quality of this book. Any remaining errors are, of course, solely my own responsibility.
As always, I welcome your critique!
Jie Jack Li May 2009
Killingworth, Connecticut
Alder ene reaction ..................................................................................................... 1 Aldol condensation.................................................................................................... 3 Algar–Flynn–Oyamada reaction ............................................................................... 6 Allan–Robinson reaction........................................................................................... 8 Arndt–Eistert homologation.................................................................................... 10 Baeyer–Villiger oxidation....................................................................................... 12 Baker–Venkataraman rearrangement...................................................................... 14 Bamford–Stevens reaction ...................................................................................... 16 Barbier coupling reaction ........................................................................................ 18 Bartoli indole synthesis ........................................................................................... 20 Barton radical decarboxylation ............................................................................... 22 Barton–McCombie deoxygenation ......................................................................... 24 Barton nitrite photolysis .......................................................................................... 26 Batcho–Leimgruber indole synthesis...................................................................... 28 Baylis–Hillman reaction.......................................................................................... 30 Beckmann rearrangement........................................................................................ 33 Abnormal Beckmann rearrangement ............................................................ 34 Benzilic acid rearrangement.................................................................................... 36 Benzoin condensation.............................................................................................. 38 Bergman cyclization................................................................................................ 40 Biginelli pyrimidone synthesis................................................................................ 42 Birch reduction ........................................................................................................ 44 Bischler–Möhlau indole synthesis .......................................................................... 46 Bischler–Napieralski reaction ................................................................................. 48 Blaise reaction ........................................................................................................ 50 Blum–Ittah aziridine synthesis ............................................................................... 52 Boekelheide reaction ............................................................................................... 54 Boger pyridine synthesis ......................................................................................... 56 Borch reductive amination ...................................................................................... 58 Borsche–Drechsel cyclization................................................................................. 60 Boulton–Katritzky rearrangement........................................................................... 62 Bouveault aldehyde synthesis ................................................................................. 64 Bouveault–Blanc reduction..................................................................................... 65 Bradsher reaction..................................................................................................... 66 Brook rearrangement............................................................................................... 68 Brown hydroboration .............................................................................................. 70 Bucherer carbazole synthesis .................................................................................. 72
Table of Contents
Foreword............................................................................................................... VIIPreface ................................................................................................................Abbreviations .......................................................................................................XIX
IX..
XII
Buchwald–Hartwig amination ................................................................................ 80 Burgess dehydrating reagent................................................................................... 84 Burke boronates....................................................................................................... 87 Cadiot–Chodkiewicz coupling................................................................................ 90 Camps quinoline synthesis...................................................................................... 92 Cannizzaro reaction................................................................................................. 94 Carroll rearrangement ............................................................................................. 96 Castro–Stephens coupling....................................................................................... 98 Chan alkyne reduction........................................................................................... 100 Chan–Lam C–X coupling reaction ....................................................................... 102 Chapman rearrangement ....................................................................................... 105 Chichibabin pyridine synthesis ............................................................................. 107 Chugaev reaction................................................................................................... 110 Ciamician–Dennsted rearrangement..................................................................... 112 Claisen condensation............................................................................................. 113 Claisen isoxazole synthesis................................................................................... 115 Claisen rearrangement........................................................................................... 117 para-Claisen rearrangement ....................................................................... 119 Abnormal Claisen rearrangement ................................................................ 121 Eschenmoser–Claisen amide acetal rearrangement .................................... 123 Ireland–Claisen (silyl ketene acetal) rearrangement ................................... 125 Johnson–Claisen (orthoester) rearrangement .............................................. 127 Clemmensen reduction.......................................................................................... 129 Combes quinoline synthesis.................................................................................. 131 Conrad–Limpach reaction..................................................................................... 133 Cope elimination reaction ..................................................................................... 135 Cope rearrangement .............................................................................................. 137 Anionic oxy-Cope rearrangement................................................................. 138 Oxy-Cope rearrangement.............................................................................. 140 Siloxy-Cope rearrangement .......................................................................... 141 Corey–Bakshi–Shibata (CBS) reagent ................................................................. 143 Corey−Chaykovsky reaction................................................................................. 146 Corey–Fuchs reaction............................................................................................ 148 Corey–Kim oxidation............................................................................................ 150 Corey–Nicolaou macrolactonization .................................................................... 152 Corey–Seebach reaction........................................................................................ 154 Corey–Winter olefin synthesis.............................................................................. 156 Criegee glycol cleavage ........................................................................................ 159 Criegee mechanism of ozonolysis ........................................................................ 161 Curtius rearrangement........................................................................................... 162 Dakin oxidation ..................................................................................................... 165 Dakin–West reaction............................................................................................. 167 Darzens condensation............................................................................................ 169
Bucherer reaction..................................................................................................... 74 Bucherer–Bergs reaction ......................................................................................... 76 Büchner ring expansion........................................................................................... 78
XIII
Tiffeneau–Demjanov rearrangement ............................................................ 177 Dess–Martin periodinane oxidation ...................................................................... 179 Dieckmann condensation ...................................................................................... 182 Diels–Alder reaction.............................................................................................. 184 Inverse electronic demand Diels–Alder reaction ......................................... 186 Hetero-Diels–Alder reaction ........................................................................ 187 Dienone–phenol rearrangement ............................................................................ 190 Di-π-methane rearrangement ................................................................................ 192 Doebner quinoline synthesis ................................................................................. 194 Doebner–von Miller reaction ................................................................................ 196 Dötz reaction.......................................................................................................... 198 Dowd–Beckwith ring expansion........................................................................... 200 Dudley reagent....................................................................................................... 202 Erlenmeyer−Plöchl azlactone synthesis................................................................ 204 Eschenmoser’s salt ................................................................................................ 206 Eschenmoser–Tanabe fragmentation .................................................................... 208 Eschweiler–Clarke reductive alkylation of amines .............................................. 210 Evans aldol reaction .............................................................................................. 212 Favorskii rearrangement........................................................................................ 214 Quasi-Favorskii rearrangement..................................................................... 217 Feist–Bénary furan synthesis ................................................................................ 218 Ferrier carbocyclization......................................................................................... 220 Ferrier glycal allylic rearrangement...................................................................... 222 Fiesselmann thiophene synthesis .......................................................................... 225 Fischer indole synthesis ........................................................................................ 227 Fischer oxazole synthesis ...................................................................................... 229 Fleming–Kumada oxidation ................................................................................. 231 Tamao−Kumada oxidation............................................................................ 233 Friedel–Crafts reaction.......................................................................................... 234 Friedel–Crafts acylation reaction.................................................................. 234 Friedel–Crafts alkylation reaction................................................................. 236 Friedländer quinoline synthesis ............................................................................ 238 Fries rearrangement............................................................................................... 240 Fukuyama amine synthesis ................................................................................... 243 Fukuyama reduction .............................................................................................. 245 Gabriel synthesis ................................................................................................... 246 Ing–Manske procedure.................................................................................. 249 Gabriel–Colman rearrangement ............................................................................ 250 Gassman indole synthesis...................................................................................... 251 Gattermann–Koch reaction ................................................................................... 253 Gewald aminothiophene synthesis........................................................................ 254 Glaser coupling...................................................................................................... 257 Eglinton coupling .......................................................................................... 259
Delépine amine synthesis...................................................................................... 171 de Mayo reaction................................................................................................... 173 Demjanov rearrangement ...................................................................................... 175
XIV
Grob fragmentation ............................................................................................... 268 Guareschi–Thorpe condensation........................................................................... 270 Hajos–Wiechert reaction....................................................................................... 271 Haller–Bauer reaction ........................................................................................... 273 Hantzsch dihydropyridine synthesis ..................................................................... 274 Hantzsch pyrrole synthesis.................................................................................... 276 Heck reaction......................................................................................................... 277 Heteroaryl Heck reaction .............................................................................. 280 Hegedus indole synthesis ...................................................................................... 281 Hell–Volhard–Zelinsky reaction........................................................................... 282 Henry nitroaldol reaction ...................................................................................... 284 Hinsberg synthesis of thiophene derivatives ........................................................ 286 Hiyama cross-coupling reaction ........................................................................... 288 Hofmann rearrangement ....................................................................................... 290 Hofmann–Löffler–Freytag reaction...................................................................... 292 Horner–Wadsworth–Emmons reaction ................................................................ 294 Houben–Hoesch synthesis .................................................................................... 296 Hunsdiecker–Borodin reaction ............................................................................. 298 Jacobsen–Katsuki epoxidation.............................................................................. 300 Japp–Klingemann hydrazone synthesis................................................................ 302 Jones oxidation...................................................................................................... 304 Collins–Sarett oxidation................................................................................ 305 PCC oxidation ............................................................................................... 306 PDC oxidation............................................................................................... 307 Julia–Kocienski olefination................................................................................... 309 Julia–Lythgoe olefination ..................................................................................... 311 Kahne glycosidation.............................................................................................. 313 Knoevenagel condensation ................................................................................... 315 Knorr pyrazole synthesis....................................................................................... 317 Koch–Haaf carbonylation ..................................................................................... 319 Koenig–Knorr glycosidation................................................................................. 320 Kostanecki reaction............................................................................................... 322 Kröhnke pyridine synthesis................................................................................... 323 Kumada cross-coupling reaction........................................................................... 325 Lawesson’s reagent ............................................................................................... 328 Leuckart–Wallach reaction ................................................................................... 330 Lossen rearrangement ........................................................................................... 332 McFadyen–Stevens reduction............................................................................... 334 McMurry coupling ................................................................................................ 335 Mannich reaction................................................................................................... 337 Martin’s sulfurane dehydrating reagent................................................................ 339 Masamune–Roush conditions ............................................................................... 341 Meerwein’s salt ..................................................................................................... 343
Gomberg–Bachmann reaction............................................................................... 262 Gould–Jacobs reaction .......................................................................................... 263 Grignard reaction................................................................................................... 266
XV
[2,3]-Meisenheimer rearrangement....................................................................... 350 Meyers oxazoline method ..................................................................................... 351 Meyer–Schuster rearrangement ............................................................................ 353 Michael addition.................................................................................................... 355 Michaelis–Arbuzov phosphonate synthesis.......................................................... 357 Midland reduction ................................................................................................. 359 Minisci reaction ..................................................................................................... 361 Mislow–Evans rearrangement............................................................................... 363 Mitsunobu reaction................................................................................................ 365 Miyaura borylation ................................................................................................ 368 Moffatt oxidation................................................................................................... 370 Morgan–Walls reaction ........................................................................................ 371 Mori–Ban indole synthesis.................................................................................... 373 Mukaiyama aldol reaction..................................................................................... 375 Mukaiyama Michael addition ............................................................................... 377 Mukaiyama reagent ............................................................................................... 379 Myers−Saito cyclization........................................................................................ 382 Nazarov cyclization............................................................................................... 383 Neber rearrangement ............................................................................................. 385 Nef reaction ........................................................................................................... 387 Negishi cross-coupling reaction............................................................................ 389 Nenitzescu indole synthesis .................................................................................. 391 Newman−Kwart reaction ...................................................................................... 393 Nicholas reaction................................................................................................... 395 Nicolaou dehydrogenation .................................................................................... 397 Noyori asymmetric hydrogenation........................................................................ 399 Nozaki–Hiyama–Kishi reaction............................................................................ 401 Nysted reagent ....................................................................................................... 403 Oppenauer oxidation ............................................................................................. 404 Overman rearrangement........................................................................................ 406 Paal thiophene synthesis........................................................................................ 408 Paal–Knorr furan synthesis ................................................................................... 409 Paal–Knorr pyrrole synthesis ................................................................................ 411 Parham cyclization ................................................................................................ 413 Passerini reaction................................................................................................... 415 Paternò–Büchi reaction ......................................................................................... 417 Pauson–Khand reaction......................................................................................... 419 Payne rearrangement ............................................................................................. 421 Pechmann coumarin synthesis .............................................................................. 423 Perkin reaction....................................................................................................... 424 Petasis reaction ...................................................................................................... 426 Petasis reagent ....................................................................................................... 428 Peterson olefination............................................................................................... 430
Meerwein–Ponndorf–Verley reduction ................................................................ 345 Meisenheimer complex ......................................................................................... 347 [1,2]-Meisenheimer rearrangement ...................................................................... 349
XVI
Pinner reaction....................................................................................................... 438 Polonovski reaction............................................................................................... 440 Polonovski–Potier rearrangement......................................................................... 442 Pomeranz–Fritsch reaction.................................................................................... 444 Schlittler–Müller modification ..................................................................... 446 Prévost trans-dihydroxylation .............................................................................. 447 Prins reaction......................................................................................................... 448 Pschorr cyclization ................................................................................................ 450 Pummerer rearrangement ...................................................................................... 452 Ramberg–Bäcklund reaction................................................................................. 454 Reformatsky reaction ............................................................................................ 456 Regitz diazo synthesis ........................................................................................... 458 Reimer–Tiemann reaction..................................................................................... 460 Reissert reaction.................................................................................................... 461 Reissert indole synthesis ....................................................................................... 463 Ring-closing metathesis (RCM)........................................................................... 465 Ritter reaction ........................................................................................................ 468 Robinson annulation.............................................................................................. 470 Robinson–Gabriel synthesis.................................................................................. 472 Robinson–Schöpf reaction .................................................................................... 474 Rosenmund reduction............................................................................................ 476 Rubottom oxidation............................................................................................... 478 Rupe rearrangement .............................................................................................. 480 Saegusa oxidation.................................................................................................. 482 Sakurai allylation reaction .................................................................................... 484 Sandmeyer reaction............................................................................................... 486 Schiemann reaction ............................................................................................... 488 Schmidt rearrangement ......................................................................................... 490 Schmidt’s trichloroacetimidate glycosidation reaction ........................................ 492 Shapiro reaction..................................................................................................... 494 Sharpless asymmetric amino hydroxylation......................................................... 496 Sharpless asymmetric dihydroxylation................................................................. 499 Sharpless asymmetric epoxidation ....................................................................... 502 Sharpless olefin synthesis ..................................................................................... 505 Simmons–Smith reaction ..................................................................................... 507 Skraup quinoline synthesis.................................................................................... 509 Smiles rearrangement............................................................................................ 511
Truce−Smile rearrangement ......................................................................... 513 Sommelet reaction................................................................................................. 515 Sommelet–Hauser rearrangement......................................................................... 517 Sonogashira reaction ............................................................................................. 519 Staudinger ketene cycloaddition ........................................................................... 521 Staudinger reduction ............................................................................................. 523
Pictet–Gams isoquinoline synthesis...................................................................... 432 Pictet–Spengler tetrahydroisoquinoline synthesis ................................................ 434 Pinacol rearrangement........................................................................................... 436
XVII
Stille–Kelly reaction.............................................................................................. 531 Stobbe condensation.............................................................................................. 532 Strecker amino acid synthesis ............................................................................... 534 Suzuki–Miyaura coupling ..................................................................................... 536 Swern oxidation..................................................................................................... 538 Takai reaction ........................................................................................................ 540 Tebbe olefination................................................................................................... 542 TEMPO oxidation ................................................................................................. 544 Thorpe−Ziegler reaction........................................................................................ 546 Tsuji–Trost allylation ............................................................................................ 548 Ugi reaction ........................................................................................................... 551 Ullmann coupling .................................................................................................. 554 van Leusen oxazole synthesis ............................................................................... 556 Vilsmeier–Haack reaction..................................................................................... 558 Vinylcyclopropane−cyclopentene rearrangement ................................................ 560 von Braun reaction ................................................................................................ 562 Wacker oxidation .................................................................................................. 564 Wagner–Meerwein rearrangement........................................................................ 566 Weiss–Cook reaction............................................................................................. 568 Wharton reaction ................................................................................................... 570 White reagent......................................................................................................... 572 Willgerodt–Kindler reaction ................................................................................. 576 Wittig reaction ....................................................................................................... 578 Schlosser modification of the Wittig reaction ............................................. 580 [1,2]-Wittig rearrangement ................................................................................... 582 [2,3]-Wittig rearrangement ................................................................................... 584 Wohl–Ziegler reaction........................................................................................... 586 Wolff rearrangement ............................................................................................. 588 Wolff–Kishner reduction....................................................................................... 590 Woodward cis-dihydroxylation............................................................................. 592 Yamaguchi esterification....................................................................................... 594 Zincke reaction ...................................................................................................... 596
Subject Index ......................................................................................................... 599
Stetter reaction....................................................................................................... 525 Still–Gennari phosphonate reaction...................................................................... 527 Stille coupling........................................................................................................ 529
Abbreviations and Acronyms
polymer support 3CC three-component condensation 4CC four-component condensation 9-BBN 9-borabicyclo[3.3.1]nonane A adenosine Ac acetyl ADDP 1,1'-(azodicarbonyl)dipiperidine AIBN 2,2 -azobisisobutyronitrile Alpine-borane® B-isopinocampheyl-9-borabicyclo[3.3.1]-nonane AOM p-Anisyloxymethyl = p-MeOC6H4OCH2- Ar aryl B: generic base [bimim]Cl•2AlCl3 1-butyl-3-methylimidazolium chloroaluminuminate BINAP 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl Bn benzyl Boc tert-butyloxycarbonyl BT benzothiazole Bz benzoyl Cbz benzyloxycarbonyl CuTC copper thiophene-2-carboxylate DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC 1,3-dicyclohexylcarbodiimide DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereoselctive excess DEAD diethyl azodicarboxylate (DHQ)2-PHAL 1,4-bis(9-O-dihydroquinine)-phthalazine (DHQD)2-PHAL 1,4-bis(9-O-dihydroquinidine)-phthalazine DIAD diisopropyl azodidicarboxylate DIBAL diisobutylaluminum hydride DIPEA diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMFDMA N,N-dimethylformamide dimethyl acetal DMS dimethylsulfide DMSO dimethylsulfoxide DMSY dimethylsulfoxonium methylide DMT dimethoxytrityl DPPA diphenylphosphoryl azide dppb 1,4-bis(diphenylphosphino)butane
XX
dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1 -bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane dr diastereoselctive ratio DTBAD di-tert-butylazodicarbonate DTBMP 2,6-di-tert-butyl-4-methylpyridine E1 unimolecular elimination E1cB 2-step, base-induced β-elimination via carbanion E2 bimolecular elimination EAN ethylammonium nitrate EDDA ethylenediamine diacetate ee enantiomeric excess Ei two groups leave at about the same time and bond to
each other as they are doing so. Eq equivalent Et ethyl EtOAc ethyl acetate HMDS hexamethyldisilazane HMPA hexamethylphosphoramide HMTTA 1,1,4,7,10,10-hexamethyltriethylenetetramine IBX o-iodoxybenzoic acid Imd imidazole KHMDS potassium hexamethyldisilazide LAH lithium aluminum hydride LDA lithium diisopropylamide LHMDS lithium hexamethyldisilazide LTMP lithium 2,2,6,6-tetramethylpiperidide M metal m-CPBA m-chloroperoxybenzoic acid MCRs multicomponent reactions Mes mesityl MPS morpholine-polysulfide Ms methanesulfonyl MWI microwave irradiation MVK methyl vinyl ketone NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMP 1-methyl-2-pyrrolidinone Nos nosylate (4-nitrobenzenesulfonyl) N-PSP N-phenylselenophthalimide N-PSS N-phenylselenosuccinimide Nu nucleophile PCC pyridinium chlorochromate PDC pyridinium dichromate Piv pivaloyl
XXI
PMB para-methoxybenzyl PPA polyphosphoric acid PPTS pyridinium p-toluenesulfonate PT phenyltetrazolyl PyPh2P diphenyl 2-pyridylphosphine Pyr pyridine Red-Al sodium bis(methoxy-ethoxy)aluminum hydride Red-Al sodium bis(methoxy-ethoxy)aluminum hydride (SMEAH) Salen N,N´-disalicylidene-ethylenediamine SET single electron transfer SIBX Stabilized IBX SM starting material SMEAH sodium bis(methoxy-ethoxy)aluminum hydride SN1 unimolecular nucleophilic substitution SN2 bimolecular nucleophilic substitution SNAr nucleophilic substitution on an aromatic ring TBABB tetra-n-butylammonium bibenzoate TBAF tetra-n-butylammonium fluoride TBAO 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl t-Bu tert-butyl TDS thexyldimethylsilyl TEA triethylamine TEOC trimethysilylethoxycarbonyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFP tri-2-furylphosphine THF tetrahydrofuran TIPS triisopropylsilyl TMEDA N,N,N ,N -tetramethylethylenediamine TMG 1,1,3,3-tetramethylguanidine TMP tetramethylpiperidine TMS trimethylsilyl TMSCl trimethylsilyl chloride TMSCN trimethylsilyl cyanide TMSI trimethylsilyl iodide TMSOTf trimethylsilyl triflate Tol toluene or tolyl Tol-BINAP 2,2 -bis(di-p-tolylphosphino)-1,1 -binaphthyl TosMIC (p-tolylsulfonyl)methyl isocyanide Ts tosyl TsO tosylate
XXII
UHP urea-hydrogen peroxide Δ solvent heated under reflux
Alder ene reaction The Alder ene reaction, also known as the hydro-allyl addition, is addition of an enophile to an alkene (ene) via allylic transposition. The four-electron system in-cluding an alkene -bond and an allylic C–H -bond can participate in a pericyclic reaction in which the double bond shifts and new C–H and C–C -bonds are formed.
H
XY
ene enophile
Δ, or
Lewis acid HYX
HYX‡ HOMO
LUMOH
‡
X=Y: C=C, C C, C=O, C=N, N=N, N=O, S=O, etc.
Example 15
O
O
O
OO
O 6-membered
transition stateH
xylene
reflux, 31%
‡
ene enophile
O
O
O
Alder ene
reaction
OO
O
H
‡
Example 27
OH
NH2NKOH, Pt/Clay, 35%
(Kishner reduction)
O
H
OH
O
O
0 oC, CH2Cl2, 89%(Alder ene reaction)
O
OOH
O
Example 3, Intramolecular Alder-ene reaction8
NO
O
NO H
toluene, reflux
5 h, 95%O
H
1
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_1, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Cobalt-catalyzed Alder-ene reaction9
Et
Ph
OTMS[Co(dppp)Br2], Zn, ZnI2, CH2Cl2
25 oC, 8 h, 95% (GC yield)Ph OTMS
Et
Example 5, Nitrile-Alder-ene reaction10
CN
CH3 sealed ampule
120−130 oC, 5 h70%
CN
CH3
NC
H3C
CN
CH3
CH3NC
CH3
H
CN
CH3
CH3NC
H
HCN
H3CCN
Example 611
C6H13
OAc
SiEt3
CpRu(CH3CN)3•PF6
acetone, rt, 81%SiEt3
C6H13OAc
References 1. Alder, K.; Pascher, F.; Schmitz, A. Ber. 1943, 76, 27−53. Kurt Alder (Germany,
1902−1958) shared the Nobel Prize in Chemistry in 1950 with his teacher Otto Diels (Germany, 1876−1954) for the development of the diene synthesis.
2. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181−1201. (Review). 3. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325−335. (Review). 4. Mikami, K.; Nakai, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., ed.;
Wiley−VCH: New York, 2000, 543−568. (Review). 5. Sulikowski, G. A.; Sulikowski, M. M. e-EROS Encyclopedia of Reagents for Organic
Synthesis (2001), John Wiley & Sons, Ltd., Chichester, UK. 6. Brummond, K. M.; McCabe, J. M. The Rhodium(I)-Catalyzed Alder-ene Reaction. In
Modern Rhodium-Catalyzed Organic Reactions 2005, 151−172. (Review). 7. Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G. J. Org. Chem. 2005, 70,
2862−2865. 8. Pedrosa, R.; Andres, C.; Martin, L.; Nieto, J.; Roson, C. J. Org. Chem. 2005, 70,
4332−4337. 9. Hilt, G.; Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8500−8502. 10. Ashirov, R. V.; Shamov, G. A.; Lodochnikova, O. A.; Litvynov, I. A.; Appolonova, S.
A.; Plemenkov, V. V. J. Org. Chem. 2008, 73, 5985−5988. 11. Cho, E. J.; Lee, D. Org. Lett. 2008, 10, 257−259. 12. Curran, T. T. Alder ene reaction. In Name Reactions for Homologations-Part II; Li, J.
J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review).
2
Aldol condensation The Aldol condensation is the coupling of an enolate ion with a carbonyl compound to form a -hydroxycarbonyl, and sometimes, followed by dehydration to give a conjugated enone. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol.
R2 R3
OR1
OR
1. Base
R1
O
RR3
OHR2
2.
ΔR1
O
RR3
R2
R2R3
O
R1
OR R1
OR
H
B:
deprotonation condensation
R1
O
RR3
OR2
R1
O
RR3
OHR2acidic
workup
Example 13
OTMSO
LDA, THF, thenMgBr2, −110 oC, then
CHOOBnO
BnO OOTMS
OH O
85% yield
Example 28
CO2HO OTBS
LDA, THF, −78 to −40 oC, then aldehyde, 1 h, 43%, 3:2 dr
H
O
CO2HO OTBS
HO
22% of of 6S,7R-diastereomerand 10% recovered SM
6
7
3
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_2, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Enantioselective Mukaiyama-aldol reaction10
Ph
OTMS
CO2CHPh2
O
Sc(OTf)3, 4 Å MS, CH2Cl2, −40 oCPh CO2CHPh2
O OH
NO
N N
OPh
OSii-Pr3
Ph
OSii-Pr3
83% yield, 98% ee
cat.
Example 4, Intermolecular aldol reaction using organocatalyst12
H
OO
Cl
NH
O NH
O
N
H
DMSO, 10 equiv H2O, rt72 h, 57%, 46% ee, 95% de
OHO
Cl
Example 5, Transannular aldol reaction13
MeOMeO
OMe
OMe O
O
OMeO
OMeO
1. LiN(SiMe2Ph)2, THF −105 oC, 74%, 10:1, dr
2. MgI2, Et2O, 57%
MeOMeO
OH
OH O
O
OMe
OMe
CH3
O
OHCH3
References 1. Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436−442. Charles Adolphe Wurtz
(1817−1884) was born in Strasbourg, France. After his doctoral training, he spent a year under Liebig in 1843. In 1874, Wurtz became the Chair of Organic Chemistry at the Sorbonne, where he educated many illustrous chemists such as Crafts, Fittig, Friedel, and van’t Hoff. The Wurtz reaction, where two alkyl halides are treacted with sodium to form a new carbon−carbon bond, is no longer considered synthetically useful, although the Aldol reaction that Wurtz discovered in 1872 has become a staple in organic synthesis. Alexander P. Borodin is also credited with the discovery of the Aldol reaction together with Wurtz. In 1872 he announced to the Russian Chemical Society the discovery of a new byproduct in aldehyde reactions with properties like that of an alcohol, and he noted similarities with compounds already discussed in publications by Wurtz from the same year.
2. Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1−438. (Review). 3. Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031−1034.
4
4. Mukaiyama, T. Org. React. 1982, 28, 203−331. (Review). 5. Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1−103. (Review on Tin(II)
enolates). 6. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325−335. (Review). 7. Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432−440. (Review). 8. (a) Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.; Kim, S.-H.; DiMarco,
J. D.; Fairchild, C. R.; Gougoutas, J. Z.; Lee, F. Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem. Soc. 2000, 122, 8890–8897. (b) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed. 1997, 36, 166−168. (c) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960–7973.
9. Mahrwald, R. (ed.) Modern Aldol Reactions, Wiley−VCH: Weinheim, Germany, 2004. (Book).
10. Desimoni, G.; Faita, G.; Piccinini, F.; Toscanini, M. Eur. J. Org. Chem. 2006, 5228−5230.
11. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249−2293. (Review on enantioselective direct aldol reaction using organocatalysis.)
12. Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.; Clegg, W. Eur. J. Org. Chem. 2008, 1759−1766.
13. O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int. Ed. 2008, 47, 6877−6880.
14. Trost, B. M.; Maulide, N.; Rudd, M. T. J. Am. Chem. Soc. 2009, 131, 420−421.
5
Algar−Flynn−Oyamada Reaction Conversion of 2 -hydroxychalcones to 2-aryl-3-hydroxy-4H-1benzopyran-4-ones (flavonols) by an oxidative cyclization.
OH
O
ArR1
R2
H2O2, NaOHO
O
R1
R2
Ar
OH
O
O
R1
R2
Ar
OH
OH
O
HO
H2O2
O
OO
αβ
O OH
OH
O OOH
β-attackO
OHO
O O
OHO
flavonol A side reaction:
O
OO
α-attack
then dehydration
O
O aurone
α β
Example 15
O
1. PhCHO, NaOH, EtOH, rt
2. H2O2, 15 to 50 oC, 54%
O Ph
OOH
OH
Example 25
OH
O
O
1.
OMe
CHO
, aq. NaOH, EtOH
2. aq. NaOH, 30% H2O2 47% for two steps
O O
OOH
OMe
6
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_3, © Springer-Verlag Berlin Heidelberg 2009
Example 3, The side reaction dominated to give the aurone derivative:9
OHMeO
OMe OOMe
Phaq. NaOH
H2O2, 80%
O
O
MeO
OMe
OMePh
OHH
Example 412
O
OHBnO NaOH
EtOH, 54%
CHO
OMeO
OHBnO OMe
O
OOH
OMe
BnOH2O2, NaOH
EtOH, dioxane76%
References 1. Algar, J.; Flynn, J. P. Proc. Roy. Irish. Acad. 1934, B42, 1−8. 2. Oyamada, T. J. Chem. Soc. Jpn 1934, 55, 1256−1261. 3. Oyamada, T. Bull. Chem. Soc. Jpn. 1935, 10, 182−186. 4. Wheeler, T. S. Record Chem. Progr. 1957, 18, 133−161. (Review) 5. Smith, M. A.; Neumann, R. M.; Webb, R. A. J. Heterocycl. Chem. 1968, 5, 425−426. 6. Wagner, H.; Farkas, L. In The Flavonoids; Harborne, J. B.; Mabry, T. J.; Mabry H.,
Eds.; Academic Press: New York, 1975, 1, pp 127−213. (Review). 7. Wollenweber, E. In The Flavonoids: Advances in Research; Harborne, J. B.; Mabry,
T. J., Eds; Chapman and Hall: New York, 1982; pp 189−259. (Review). 8. Wollenweber, E. In The Flavonoids: Advances in Research Since 1986; Harborne, J.
B., Ed.; Chapman and Hall: New York, 1994, pp 259−335. (Review). 9. Bennett, M.; Burke, A. J.; O’Sullivan, W. I. Tetrahedron 1996, 52, 7163−7178. 10. Bohm, B. A.; Stuessy, T. F. Flavonoids of the Sunflower Family (Asteraceae);
Springer-Verlag: New York, 2000. (Review). 11. Limberakis, C. Algar−Flynn−Oyamada Reaction. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 496−503. (Review).
12. Li, Z.; Ngojeh, G.; DeWitt, P.; Zheng, Z.; Chen, M.; Lainhart, B.; Li, V.; Felpo, P. Tetrahedron Lett. 2008, 49, 7243−7245.
7
Allan–Robinson reaction Synthesis of flavones or isoflavones by the treatment of of o-hydroxyaryl ketones with aromatic aldehydes. Cf. Kostanecki reaction on page 322.
R1 O R1
O O
R1CO2Na, Δ
O
OR
R1OH
OR
OH
OR
enolization
OH
OR
H
R1
O
R1
O
O acylation
R1CO2
OR
OHR1
OCOR1
O− O2CR1
OH
OHR1
O
RO2CR1
enolization
O
OR
OHR1
OHR
O: R1O
H
H
O2CR1
O
OR
R1
Example 16
OH
OOMe
OMeHO
OMe
O
O O
MeO OMe
O
OOMe
OMeHO
OMe
OMe
PhCO2Na, 170−180 oC
8 h, 45%
Example 29
OH
O pyr., 40 oC, 72 h, 85%N
S
Me
O OO O
O N
S
Me
CO2H
8
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_4, © Springer-Verlag Berlin Heidelberg 2009
Example 310
O
O
OH
O O
OMe
O
OMeO
O O
Et3N, reflux, 12 h, 87%
References 1. Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192–2195. Robert Robinson
(United Kingdom, 1886−1975) won the Nobel Prize in Chemistry in 1947 for his stud-ies on alkaloids. However, Robinson himself considered his greatest contribution to science was that he founded the qualitative theory of electronic mechanisms in organic chemistry. Robinson, along with Lapworth (a friend) and Ingold (a rival), pioneered the arrow pushing approach to organic reaction mechanism. Robinson was also an ac-complished pianist. James Allan, his student, also coauthored another important paper with Robinson on the relative directive powers of groups for aromatic substitution.
2. Széll, T.; Dózsai, L.; Zarándy, M.; Menyhárth, K. Tetrahedron 1969, 25, 715–724. 3. Wagner, H.; Maurer, I.; Farkas, L.; Strelisky, J. Tetrahedron 1977, 33, 1405–1409. 4. Dutta, P. K.; Bagchi, D.; Pakrashi, S. C. Indian J. Chem., Sect. B 1982, 21B, 1037–
1038. 5. Patwardhan, S. A.; Gupta, A. S. J. Chem. Res., (S) 1984, 395. 6. Horie, T.; Tsukayama, M.; Kawamura, Y.; Seno, M. J. Org. Chem. 1987, 52, 4702–
4709. 7. Horie, T.; Tsukayama, M.; Kawamura, Y.; Yamamoto, S. Chem. Pharm. Bull. 1987,
35, 4465–4472. 8. Horie, T.; Kawamura, Y.; Tsukayama, M.; Yoshizaki, S. Chem. Pharm. Bull. 1989,
37, 1216–1220. 9. Poyarkov, A. A.; Frasinyuk, M. S.; Kibirev, V. K.; Poyarkova, S. A. Russ. J. Bioorg.
Chem. 2006, 32, 277–279. 10. Peng, C.-C.; Rushmore, T.; Crouch, G. J.; Jones, J. P. Bioorg. Med. Chem. Lett. 2008,
16, 4064–4074.
9
Arndt–Eistert homologation One-carbon homologation of carboxylic acids using diazomethane.
R OH
O SOCl2
R Cl
O 1. CH2N2
OH
OR
2. Ag+, H2O, hv
R Cl
OR Cl
O
NN
R
ON
N
H H
ClH2C N N
R
ON
NR
ON
N
H H
− CH3N2 − N2↑
hv
CH
R OH
OH
OH
OR
:OH2
C C OH
RR
O
:H
α-ketocarbene intermediate ketene intermediate Example 17
CO2HBnO
BnOHN
Boc
1. ClCO2Et, Et3N, THF, −10 oC, 15 min
2. CH2N2, Et2O, 0 oC to rt, 18 h, 78%
BnO
BnOHN
Boc
ON2
PhCO2Ag, Et3N, MeOH/THF, dark
−25 oC to rt, 3 h, 61%
BnO
BnOHN
Boc
CO2Me
Example 2, An interesting variation9
PhCO2H
OH
1. Fmoc-Cl, pyridine, 0 oC2. isobutylchloroformate, Et3N
then CH2N2, 0 oC, 39%Ph
OFmoc
ON2
Ph
CONH2
NH2
PhCO2Ag, dioxane15 min., 50 oC, 72%
PhHN
OCONH2
Ph
10
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_5, © Springer-Verlag Berlin Heidelberg 2009
Example 310
NOTBDPS
CbzMeO2C
H
H H
1. LiOH, MeOH/H2O, reflux2. ClCO2Et, Et3N, THF, 0 oC
3. CH2N2, Et2O4. PhCO2Ag, Et3N, MeOH, rt 69% for 4 steps
NOTBDPS
Cbz
H
H HMeO2C
References 1. Arndt, F.; Eistert, B. Ber. 1935, 68, 200−208. Fritz Arndt (1885−1969) was born in
Hamburg, Germany. He discovered the Arndt−Eistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its re-actions with aldehydes, ketones, and acid chlorides. Fritz Arndt’s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bernd Eistert (1902−1978), born in Ohlau, Silesia, was Arndt’s Ph.D. student. Eistert later joined I. G. Farbenindustrie, which became BASF after the Allies broke up the con-glomerate after WWII.
2. Podlech, J.; Seebach, D. Angew. Chem., Int. Ed. 1995, 34, 471−472. 3. Matthews, J. L.; Braun, C.; Guibourdenche, C.; Overhand, M.; Seebach, D. In Enanti-
oselective Synthesis of β-Amino Acids Juaristi, E. ed.; Wiley-VCH: New York, N. Y. 1997, pp 105−126. (Review).
4. Katritzky, A. R.; Zhang, S.; Fang, Y. Org. Lett. 2000, 2, 3789−3791. 5. Vasanthakumar, G.-R.; Babu, V. V. S. Synth. Commun. 2002, 32, 651−657. 6. Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden, C.; Kuo, H.;
Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W. L.; Schmatz, D. M.; Wy-vratt, M. J.; Fisher, M. H.; Meinke, P. T. Bioorg. Med. Chem. Lett. 2003, 13, 147−150.
7. Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M.; Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2005, 16, 857−864.
8. Podlech, J. In Enantioselective Synthesis of β-Amino Acids (2nd Edn.) John Wiley & Sons: Hoboken, NJ, 2005, pp 93−106. (Review).
9. Spengler, J.; Ruiz-Rodriguez, J.; Burger, K.; Albericio, F. Tetrahedron Lett. 2006, 47, 4557−4560.
10. Toyooka, N.; Kobayashi, S.; Zhou, D.; Tsuneki, H.; Wada, T.; Sakai, H.; Nemoto, H.; Sasaoka, T.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Bioorg. Med. Chem. Lett. 2007, 17, 5872−5875.
11. Fuchter, M. J. Arndt–Eistert Homologation. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 336−349. (Review).
11
Baeyer–Villiger oxidation General scheme:
R1 R2
O HO
O R3
O
R1 O
OR2
HO R3
O
or H2O2
The most electron-rich alkyl group (more substituted carbon) migrates first. The general migration order: tertiary alkyl > cyclohexyl > secondary alkyl > benzyl > phenyl > primary alkyl > methyl >> H.
For substituted aryls: p-MeO-Ar > p-Me-Ar > p-Cl-Ar > p-Br-Ar > p-MeOAr > p-O2N-Ar
Example 1:
O
O
OCl
O
OH
H
:HOAc
AcO
HO
OClalkyl
migration
O
OO
OH O
O
Cl
Example 24
O
Ph N N
O OPhPh
Zr
Zr-salen:UHP,
Zr-salen (5 mol%)
CH2Cl2, rt68%, 87% ee
O
O
Ph
OUHP,
Zr-salen (5 mol%)
PhCl, rt
OO O
O
normal product26%, 82% ee
abnormal product12%, > 99% ee
Y
Y
UHP = Urea-hydrogen peroxide complex
Example 35
NH
OH O
O
m-CPBA
CH2Cl2, rtquant.
NHO
OH O
O 100% 0%NH
OH
O
O
O
12
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_6, © Springer-Verlag Berlin Heidelberg 2009
Example 46
H
O
O
O
O
m-CPBA, NaHCO3
CH2Cl2, 0 °C, 4 h60%
H
O
O
O
AcO
Example 58
OOAc m-CPBA, CF3SO3H
CH2Cl2, 45 min., 90%
O
OAcO
References 1. v. Baeyer, A.; Villiger, V. Ber. 1899, 32, 3625−3633. Adolf von Baeyer (1835−1917)
was one of the most illustrious organic chemists in history. He contributed to many areas of the field. The Baeyer−Drewson indigo synthesis made possible the commer-cialization of synthetic indigo. Another Baeyer’s claim of fame is his synthesis of barbituric acid, named after his then girlfriend, Barbara. Baeyer’s real joy was in his laboratory and he deplored any outside work that took him away from his bench. When a visitor expressed envy that fortune had blessed so much of Baeyer’s work with success, Baeyer retorted dryly: “Herr Kollege, I experiment more than you.” As a scientist, Baeyer was free of vanity. Unlike other scholastic masters of his time (Liebig for instance), he was always ready to acknowledge ungrudgingly the merits of others. Baeyer’s famous greenish-black hat was a part of his perpetual wardrobe and he had a ritual of tipping his hat when he admired novel compounds. Adolf von Baeyer received the Nobel Prize in Chemistry in 1905 at age seventy. His apprentice, Emil Fischer, won it in 1902 when he was fifty, three years before his teacher. Victor Villiger (1868−1934), born in Switzerland, went to Munich and worked with Adolf von Baeyer for eleven years.
2. Krow, G. R. Org. React. 1993, 43, 251−798. (Review). 3. Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 4, 737−750. (Review). 4. Wantanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43,
4481−4485. 5. Laurent, M.; Ceresiat, M.; Marchand-Brynaert, J. J. Org. Chem. 2004, 69, 3194−3197. 6. Brady, T. P.; Kim, S. H.; Wen, K.; Kim, C.; Theodorakis, E. A. Chem. Eur. J. 2005,
11, 7175−7190. 7. Curran, T. T. Baeye−Villiger oxidation. In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 160−182. (Review).
8. Demir, A. S.; Aybey, A. Tetrahedron 2008, 64, 11256−11261. 9. Baj, S.; Chrobok, A. Synth. Commun. 2008, 38, 2385−2391. 10. Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M. E.; Kocovsky, P. J. Org. Chem.
2008, 73, 3996−4003.
13
Baker–Venkataraman rearrangement Base-catalyzed acyl transfer reaction that converts α-acyloxyketones to β-diketones.
OOPh
O
baseOOH
Ph
O
OOPh
O
H
:B
O
OO
Ph
O
O
OPh
OO
Ph
O OOH
Ph
Oacyl
transfer
H3O
workup
Example 1, Carbamoyl Baker−Venkataraman rearrangement5
NaH, THF
reflux, 2 h, 84%
O
O
NEt2OOH
O
NEt2
O
Example 2, Carbamoyl Baker−Venkataraman rearrangement6
2.5 eq. NaH, PhMe, reflux, 2 h
then 6 equiv TFA, reflux, 1 h, 93%
O
MeOO
NEt2OO O
MeOOH
14
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_7, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Ester Baker−Venkataraman rearrangement9
O
O
O
CH3
O
CH3
OO
O
OH
CH3
O
LiH, THF
reflux, 12 h, 50%
O
Example 4, Ester Baker−Venkataraman rearrangement10
OOH O
OH
O Cl
Cl
Cl
O2 equiv DBU
pyridine, 80 oC90% OH
Cl
Cl References 1. Baker, W. J. Chem. Soc. 1933, 1381−1389. Wilson Baker (1900−2002) was born in
Runcorn, England. He studied chemistry at Manchester under Arthur Lapworth and at Oxford under Robinson. In 1943, Baker was the first one who confirmed that penicil-lin contained sulfur, of which Robinson commented: “This is a feather in your cap, Baker.” Baker began his independent academic career at University of Bristol. He re-tired in 1965 as the Head of the School of Chemistry. Baker was a well-known chem-ist centenarian, spending 47 years in retirement!
2. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934, 1767−1771. K. Venkataraman studied under Robert Robinson Manchester. He returned to India and later arose to be the Director of the National Chemical Laboratory at Poona.
3. Kraus, G. A.; Fulton, B. S.; Wood, S. H. J. Org. Chem. 1984, 49, 3212−3214. 4. Reddy, B. P.; Krupadanam, G. L. D. J. Heterocycl. Chem. 1996, 33, 1561−1565. 5. Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V. Tetrahe-
dron Lett. 1998, 39, 4995−4998. 6. Kalinin, A. V.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4999−5002. 7. Thasana, N.; Ruchirawat, S. Tetrahedron Lett. 2002, 43, 4515−4517. 8. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2003, 4575–
4585. 9. Krohn, K.; Vidal, A.; Vitz, J.; Westermann, B.; Abbas, M.; Green, I. Tetrahedron:
Asymmetry 2006, 17, 3051–3057. 10. Abdel Ghani, S. B.; Weaver, L.; Zidan, Z. H.; Ali, H. M.; Keevil, C. W.; Brown, R. C.
D. Bioorg. Med. Chem. Lett. 2008, 18, 518–522.
15
Bamford–Stevens reaction The Bamford−Stevens reaction and the Shapiro reaction share a similar mechanis-tic pathway. The former uses a base such as Na, NaOMe, LiH, NaH, NaNH2, heat, etc., whereas the latter employs bases such as alkyllithiums and Grignard re-agents. As a result, the Bamford−Stevens reaction furnishes more-substituted ole-fins as the thermodynamic products, while the Shapiro reaction generally affords less-substituted olefins as the kinetic products.
R2N
HN
TsR3
R1
R2
R3
R1
H
NaOMe
R2N
NTs
R3
R1 H
H
MeO
R2N
NTs
R3
R1
H :
R2N
R3
R1
H N
In protic solvent (S–H):
− N2R2N
R3
R1
H NR2
NR3
R1
H N
HHS
R2
R3
R1
HR2H
R3
R1
H
S
SHR3
R2
R1
H
In aprotic solvent:
− N2R2N
R3
R1
H NR2
NR3
R1
H N
R2
R3
R1
HR3
R2
R1
HR2
R3
R1
H:
1,2-hydride
shift
Example 1, Tandem Bamford–Stevens/thermal aliphatic Claisen rearrangement sequence2
Ph
NO Ph
N
Ph Rh2(OAc)4ClCH2CH2Cl
130 oC87% (> 20:1)
H
O
Ph
Ph
The starting material N-aziridinyl imine is also known as Eschenmoser hydrazone.
16
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_8, © Springer-Verlag Berlin Heidelberg 2009
Example 2, Thermal Bamford–Stevens6
Me3Si Ph
NN Ph Tol., 145 oC
sealed tube, 65%
Me3Si Ph
E : Z = 90 : 10
Example 37
ON NHTs t-BuOK, t-BuOH
reflux, 83% OOt-Bu
Example 48
R2
O
H
O
R2
R1
R1 NN
Ts
NaRh2(OAc)4
tetrahydrothiophene
BnEt3N+Cl−, MeCN, 40 oC, 3 h, 59−97%
References 1. Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735−4740. Thomas Stevens
(1900−2000), another chemist centenarian, was born in Renfrew, Scotland. He and his student W. R. Bamford published this paper at the University of Sheffield, UK. Ste-vens also contributed to another name reaction, the McFadyen−Stevens reaction (page 334).
2. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276−1319.
3. Shapiro, R. H. Org. React. 1976, 23, 405−507. (Review). 4. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55−59. (Review on the
Shapiro reaction). 5. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1−83. (Review). 6. Sarkar, T. K.; Ghorai, B. K. J. Chem. Soc., Chem. Commun. 1992, 17, 1184−1185. 7. Chandrasekhar, S.; Rajaiah, G.; Chandraiah, L.; Swamy, D. N. Synlett 2001,
1779−1780. 8. Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.;
Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430−1433. 9. May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426−12427. 10. Zhu, S.; Liao, Y.; Zhu, S. Org. Lett. 2004, 6, 377−380. 11. Baldwin, J. E.; Bogdan, A. R.; Leber, P. A.; Powers, D. C. Org. Lett. 2005, 7,
5195−5197. 12. Paul Humphries, P. Bamford−Stevens reaction. In Name Reactions for Homologa-
tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 642−652. (Review).
17
Barbier coupling reaction In essence, the Barbier coupling reaction is a Grignard reaction carried out in situ although its discovery preceded that of the Grignard reaction by a year. Cf. Grig-nard reaction (Page 266).
R1 R2
O R3X, MR1 R2
OH
RR M
According to conventional wisdom,3 the organometallic intermediate (M = Mg, Li, Sm, Zn, La, etc.) is generated in situ, which is intermediately trapped by the carbonyl compound. However, recent experimental and theoretical studies seem to suggest that the Barbier coupling reaction goes through a single electron trans-fer pathway. Generation of the Grignard reagent,
R3 XSET-1
R X MMX
R R MSET-2
R M
Ionic mechanism,
R MgX
O
R OMgX
R2R1R2
R1δ δ
δδ
R OH
R2R1H3O
Single electron transfer mechanism,
H3O
R MgX
OR2
R1 OR2
R1MgX
R R OMgX
R2R1
R OH
R2R1
Example 16
O
O BrSm, THF, rt
20 min., 70%
OHO
18
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_9, © Springer-Verlag Berlin Heidelberg 2009
Example 29
MePh
NHCO2Et
O
BrZn, THF, aq. NH4Cl
0 oC, 82%, 95% de
Me
NHCO2Et
OHPh
Example 310
n-C4H9Br H3C Cl
Mg20 mol% CuCN
THF, rt, 1.5 h, 86%H3C n-C4H9 H3C
n-C4H9
10 : 90
Example 411
O
MeO
I
H OOBn
n-BuLi, THF
−78 oC, 96%
O
MeOH OH
OBn
References 1. Barbier, P. C. R. Hebd. Séances Acad. Sci. 1899, 128, 110–111. Phillippe Barbier
(1848−1922) was born in Luzy, Nièvre, France. He studied terpenoids using zinc and magnesium. Barbier suggested the use of magnesium to his student, Victor Grignard, who later discovered the Grignard reagent and won the Nobel Prize in 1912.
2. Grignard, V. C. R. Hebd. Seanes Acad. Sci. 1900, 130, 1322–1324. 3. Moyano, A.; Pericás, M. A.; Riera, A.; Luche, J.-L. Tetrahedron Lett. 1990, 31, 7619–
7622. (Theoretical study). 4. Alonso, F.; Yus, M. Rec. Res. Dev. Org. Chem. 1997, 1, 397–436. (Review). 5. Russo, D. A. Chem. Ind. 1996, 64, 405–409. (Review). 6. Basu, M. K.; Banik, B. Tetrahedron Lett. 2001, 42, 187–189. 7. Sinha, P.; Roy, S. Chem. Commun. 2001, 1798–1799. 8. Lombardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60, 11725–
11732. 9. Resende, G. O.; Aguiar, L. C. S.; Antunes, O. A. C. Synlett 2005, 119–120. 10. Erdik, E.; Kocoglu, M. Tetrahedron Lett. 2007, 48, 4211–4214. 11. Takeuchi, T.; Matsuhashi, M.; Nakata, T. Tetrahedron Lett. 2008, 49, 6462–6465.
19
Bartoli indole synthesis 7-Substituted indoles from the reaction of ortho-substituted nitroarenes and vinyl Grignard reagents.
NH
RNO2
1.
2. H2O
MgBr
R
RN
O
O
BrMg
RN
O
OMgBr
OMgBr
RN
O
BrMg
nitroso intermediate
[3,3]-sigmatropic
rearrangementR
NO
MgBr RNMgBr
O
H
N
R
OMgBrH3O
workup
H
BrMg
NH
RNH
R
OH2
H
Example 13
NO2NH
1.
2. aq. NH4Cl, 67%
−40 oC, THFMgBr (3 eq)
Example 26
BrNO2
Me
MgCl
THF, −40 oC67%
NH
Me
Br
20
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_10, © Springer-Verlag Berlin Heidelberg 2009
Example 310
BrNO2
MgCl
THF, 66%NH
Br
MeO
MeO
4 equivMeO
MeO
BrNO2
MgCl
THF, 38%NH
Br
MeO
MeO
4 equivMeO
MeO
Br Br
Example 411
BrNO2
MgCl
THF, −40 oC52%
NH
Br
2 equiv
Br Br
References 1. Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. J. Chem. Soc., Perkin Trans. 1 1978,
692−696. Giuseppe Bartoli is a professor at the Università di Bologna, Italy. 2. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, P. E. J. Chem. Soc., Chem. Commun.
1988, 807−805. 3. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30,
2129−2132. 4. Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J. Chem. Soc., Perkin
Trans. 2 1991, 657−663. Mechanistic studies. 5. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc.,
Perkin Trans. 1 1991, 2757−2761. 6. Dobbs, A. J. Org. Chem. 2001, 66, 638−641. 7. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179−13184. 8. Li, J.; Cook, J. M. Bartoli indole synthesis. In Name Reactions in Heterocyclic Chem-
istry; Li, J. J., Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 100−103. (Re-view).
9. Dalpozzo, R.; Bartoli, G. Current Org. Chem. 2005, 9, 163−178. (Review). 10. Huleatt, P. B.; Choo, S. S.; Chua, S.; Chai, C. L. L. Tetrahedron Lett. 2008, 49,
5309−5311. 11. Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201−204.
21
Barton radical decarboxylation Radical decarboxylation via the corresponding thiocarbonyl derivatives of the car-boxylic acids.
R Cl
ON
HOS
R O
ON
SAIBN, Δ R
Hn-Bu3SnH
Barton ester
N N CNNCΔ
CNN2↑ 2homolyticcleavage
AIBN = 2,2 -azobisisobutyronitrile
n-Bu3Sn H CN n-Bu3Sn CNH
R O
ON
S
SnBu3
N
SBu3Sn
R O
O
Bu3SnR HCO2↑ SnBu3HR
Example 13
CO2H
OAc
OAc
1. (COCl)2
2.
NNaO
S
OO
NS
H
H
Δ
S
OAc
N98%
1. m-CPBA, −78 oC
2. 100 oC, 78%
OAc
HH
22
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_11, © Springer-Verlag Berlin Heidelberg 2009
Example 26
HO2C OTBDPS
Ph N
S
O
2
Bu3P, THF, PhH
OTBDPS
Ph
OO
N
SOTBDPS
Me3SiH, AIBN
PhH, 80 oC, 75% Ph
Example 39
NHO
S
O
ON
SMeO2C
CO2HDCC, CH2Cl2
rt, 2 hMeO2C
PhNO O
hv15 oC, 30 min, 82%
5 equiv
MeO2C
NPh
S
O
O
N
1. m-CPBA, CH2Cl2, 0 oC
2. toluene, 110 oC, 1 h, 90%
MeO2C
NPhO
O
References 1. Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983,
939−941. Derek Barton (United Kingdom, 1918−1998) studied under Ian Heilbron at Imperial College in his youth. He taught in England, France and the US. Barton won the Nobel Prize in Chemistry in 1969 for development of the concept of conformation. He passed away in his office at the University of Texas A&M in 1998.
2. Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675−684. (Review). 3. Cochane, E. J.; Lazer, S. W.; Pinhey, J. T.; Whitby, J. D. Tetrahedron Lett. 1989, 30,
7111−7114. 4. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). 5. Crich, D.; Hwang, J.-T.; Yuan, H. J. Org. Chem. 1996, 61, 6189−6198. 6. Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68,
9255−9262. 7. Zard, S. Z. Radical Reactions in Organic Synthesis Oxford University Press: Oxford,
UK, 2003. (Book). 8. Carry, J.-C.; Evers, M.; Barriere, J.-C.; Bashiardes, G.; Bensoussan, C.; Gueguen, J.-
C.; Dereu, N.; Filoche, B.; Sable, S.; Vuilhorgne, M.; Mignani, S. Synlett 2004, 316−320.
9. Brault, L.; Denance, M.; Banaszak, E.; El Maadidi, S.; Battaglia, E.; Bagrel, D.; Samadi, M. Eur. J. Org. Chem. 2007, 42, 243−247.
10. Guthrie, D. B.; Curran, D. P. Org. Lett. 2009, 11, 249−251.
23
Barton–McCombie deoxygenation Deoxygenation of alcohols by means of radical scission of their corresponding thiocarbonyl derivatives.
O S
S n-Bu3SnH, AIBN
PhH, refluxR2
R1
HR2
R1
n-Bu3SnSMe C S↑O
N N CNNCΔ
CNN2↑ 2homolyticcleavage
AIBN = 2,2 -azobisisobutyronitrile
n-Bu3Sn CN n-Bu3Sn CNHH
O S
S
n-Bu3Sn
O S
S
R2
R1
R2
SnBu3R1
O S
Sn-Bu3Snβ-scission
R2
R1
HR2
R1
n-Bu3Sn H n-Bu3Snhydrogen atom
abstractionR2
R1
n-Bu3SnSMeO S
Sn-Bu3Sn
C S↑O
Example 12
OH
SiH2
H2Si
10 mol% AIBNnonane, 80 °C
2 h, 85%
S
PhO
(1.5 equiv)
H
24
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_12, © Springer-Verlag Berlin Heidelberg 2009
Example 26
OO
O
O
O
O
AIBN, Δ, 74%
(CH2)4Bu2SnH
SOPh
OO
O
O
O
Example 310
O
O
O O
OH
OBn 1. NaH, CS2, MeI, 80%
2. Bu3SnH, AIBN, 70%
O
O
O O
OBn
Example 411
N
ONBoc
MeO2C
Ts OHH NaH, CS2
MeI, THFrt
N
ONBoc
MeO2C
Ts OH
SS
N
ONBoc
MeO2C
TsHBu3SnH, AIBN
Toluene, reflux72% 2 steps
References 1. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–1585.
Stuart McCombie, a Barton student, now works at Schering−Plough. 2. Gimisis, T.; Ballestri, M.; Ferreri, C.; Chatgilialoglu, C.; Boukherroub, R.; Manuel, G.
Tetrahedron Lett. 1995, 36, 3897–3900. 3. Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 673–685. 4. Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949–6950. 5. Hansen, H. I.; Kehler, J. Synthesis 1999, 1925–1930. 6. Boussaguet, P.; Delmond, B.; Dumartin, G.; Pereyre, M. Tetrahedron Lett. 2000, 41,
3377–3380. 7. Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 763–766. 8. Clive, D. L. J.; Wang, J. J. Org. Chem. 2002, 67, 1192–1198. 9. Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 1492–1493. 10. Gómez, A. M.; Moreno, E.; Valverde, S.; López, J. C. Eur. J. Org. Chem. 2004, 1830–
1840. 11. Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791–1793. 12. Mancuso, J. Barton–McCombie deoxygenation. In Name Reactions for Homologa-
tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 614−632. (Review).
25
Barton nitrite photolysis Photolysis of a nitrite ester to a γ-oximino alcohol.
O
OO
OAc
NOCl
O
HOO
OAcNO
hν
O
O
OAc
NHO OH
H
O N Cl
O
HOO
OAc
− HCl
O
OO
OAcNO
hν
homolyticcleavage
− ON•
1,5-hydrogen
abstraction
O
OO
OAc
H
O N
O
HOO
OAc
Nitric oxide radical is a stable and therefore, long-lived radical
O
O
OAc
NO OHH
O
O
OAc
NHO OHH
tautomerization
nitroso intermediate
Example 12
H O
NO
H OHNOH
hυPyrex, 250-W Hg lamp
PhH, reflux, 2 h, 67%
26
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_13, © Springer-Verlag Berlin Heidelberg 2009
Example 26
HO
NO
H
HO
H
H
NOH
hν
PhH, 6 oC46%
Example 37
O
OAcH
HO1. NOCl, CH2Cl2, −20 oC, 100%
2. Irradiation at 350 nM 5 h, PhH, 0 oC, 50%
O
OAcH
NHO HO
References 1. (a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am. Chem. Soc.
1960, 82, 2640−2641. In 1960, Derek Barton took a “vacation” in Cambridge, Massa-chusetts; he worked in a small research institute called the Research Institute for Medicine and Chemistry. In order to make the adrenocortical hormone aldosterol, Barton invented the Barton nitrite photolysis by simply writing down on a piece of pa-per what he thought would be an ideal process. His skilled collaborator, Dr. John Bea-ton, was able to reduce it to practice. They were able to make 40 to 50 g of aldosterol at a time when the total world supply was only about 10 mg. Barton considered it his most satisfying piece of work. (b) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1960, 82, 2641−2641. (c) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083−4089. (d) Barton, D. H. R.; Lier, E. F.; McGhie, J. M. J. Chem. Soc., (C) 1968, 1031−1040.
2. Nickon, A; Iwadare, T.; McGuire, F. J.; Mahajan, J. R; Narang, S. A.; Umezawa, B. J. Am. Chem. Soc. 1970 92, 1688–1696.
3. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Smith, L. C. J. Chem. Soc., Perkin Trans. 1 1979, 1159−1165.
4. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3−10. (Review). 5. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (Review). 6. Sicinski, R. R.; Perlman, K. L.; Prahl, J.; Smith, C.; DeLuca, H. F. J. Med. Chem.
1996, 22, 4497–4506. 7. Anikin, A.; Maslov, M.; Sieler, J.; Blaurock, S.; Baldamus, J.; Hennig, L.; Findeisen,
M.; Reinhardt, G.; Oehme, R.; Welzel, P. Tetrahedron 2003, 59, 5295−5305. 8. Suginome, H. CRC Handbook of Organic Photochemistry and Photobiology 2nd edn.;
2004, 102/1−102/16. (Review). 9. Hagan, T. J. Barton nitrite photolysis. In Name Reactions for Homologations-Part I;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 633−647. (Review).
27
Batcho–Leimgruber indole synthesis Condensation of o-nitrotoluene derivatives with formamide acetals, followed by reduction of the trans-β-dimethylamino-2-nitrostyrene to furnish indole deriva-tives.
NO2
R
DMF, 130 oC, 86% NO2
RN
NR1
R2CH
OR3OR3
R1R2 1. Pd/C, H2
2. 5% HCl 82% N
H
R
Example 14
NO2 DMF, Δ NO2
NMe2DMFDMA Pd/C, H2
NH
DMFDMA = N,N-dimethylformamide dimethyl acetal, Me2NCH(OMe)2
NMeO
MeON
MeOOMe
CH2
N
HCH2
NO
OO
O
NMeO
OMe
NO2
NMe2MeO
H
NO2
NMe2MeOH
NH2
NMe2[H]
reduction
:
NH
NMe2
NH
NH
H
NMe2
− NHMe2
Example 24
NO2 NO2
NMe2
CO2H CO2Me1. MeI, NaHCO3
2. Me2NCH(OMe)2 DMF, Δ 80%, 2 steps
NH
CO2Me
Pd/C, H2
PhH, 82%
28
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_14, © Springer-Verlag Berlin Heidelberg 2009
Example 35
NO2NO2
NMe2
OBn OBnMe2NCH(OMe)2pyrrolidine
DMF, 110 oC3 h, 95%
NO2
OBn
15 : 1
NH
OBn
Ra-Ni, NH2NH2
THF, MeOH96%NO2
NMe2
OBn
Example 410
NO2 NO2
NMe2
NO2 NO2
MeO2C
Me2NCH(OMe)2, CuI, DMF
microwave, 180 oC, 10 min.76%
MeO2C
NH
NH2Pd/C, H2
MeOH, 3 d89% MeO2C
References 1. Leimgruber, W.; Batcho, A. D. Third International Congress of Heterocyclic Chemis-
try: Japan, 1971. Andrew D. Batcho and Willy Leimgruber were both chemists at HoffmannLa Roche in Nutley, NJ, USA.
2. Leimgruber, W.; Batcho, A. D. USP 3732245 1973. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York & London,
1970. (Review). 4. Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45, 3350–3352. 5. Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214–225. 6. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195–221. (Review). 7. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106–5110. 8. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2, 160–167. 9. Li, J.; Cook, J. M. Batcho–Leimgruber Indole Synthesis. In Name Reactions in Het-
erocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 104–109. (Review).
10. Braun, H. A.; Zall, A.; Brockhaus, M.; Schütz, M.; Meusinger, R.; Schmidt, B. Tetra-hedron Lett. 2007, 48, 7990–7993.
11. Leze, M.-P.; Palusczak, A.; Hartmann, R. W.; Le Borgne, M. Bioorg. Med. Chem. Lett. 2008, 18, 4713–4715.
29
Baylis–Hillman reaction
30
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_15, © Springer-Verlag Berlin Heidelberg 2009
Also known as Morita–Baylis–Hillman reaction. It is a carbon−carbon bond-forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be alde-hydes, α-alkoxycarbonyl ketones, aldimines, and Michael acceptors. General scheme:
R1 R2
X EWG catalytic
tertiary amineR2 EWG
XHR1
X = O, NR2, EWG = CO2R, COR, CHO, CN, SO2R, SO3R, PO(OEt)2, CONR2, CH2=CHCO2Me Alternative catalytic tertiary amines:
NN
N N
Example 1:
PhPh H
O ON
N OOH
Ph H
OO
NN
:N
N
Oconjugate
addition
aldol
NN
O
Ph
O
H
NN
O
Ph
OH
Ph
OOHN
N
E2 (bimolecular elimination) mechanism is also operative here:
NN
O
PhE2
OH
HPh
OOHN
NN
N
:
2
Example 2, Intramolecular Baylis–Hillman reaction6
CO2Me
O
NOPMB
OBn
N
DME, 0 oC, 7 d90% (dr = 9:1)
CO2Me
OBnN
O
PMB
OHmajor
CO2Me
OBnN
O
PMB
OH
minor
Example 37
CHO
OO O
OEt
DABCO
dioxane:water (1:1)24 h, 72%, de 80%
OO
HO
OOEt
Example 48
OO
OCH(CH3)2
O TiCl4, TBAIOO
OCH(CH3)2
O
HHO
O O O2NO
H ,
CH2Cl2, −78 to −30 oC85%, dr > 99:1
NO2
O O
Example 59
H
O O
OMeCl
NN
OMe
OOH
ClMeOH, rt, 8 h, 79%
31
Example 610
O
H R
NTs
OHOH
NN
(10 mol%)
cyclopentyl methyl ether/toluene, −15 oC
R
O NHTs
87−100%, 88−95% ee
R = p-Cl-C6H5R = p-OMe-C6H5R = p-NO2-C6H5R = 2-furylR = 2-naphthyl
References 1. Baylis, A. B.; Hillman, M. E. D. Ger. Pat. 2,155,113, (1972). Both Anthony B. Baylis
and Melville E. D. Hillman were chemists at Celanese Corp. USA. 2. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001−8062. (Review). 3. Ciganek, E. Org. React. 1997, 51, 201−350. (Review). 4. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc.
2002, 124, 2402−2403. 5. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404−2405. 6. Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230−6231. 7. Krishna, P. R.; Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773−4775. 8. Sagar, R,; Pant, C. S.; Pathak, R.; Shaw, A. K. Tetrahedron 2004, 60, 11399−11406. 9. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338−2341. 10. Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680−3681. 11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7,
147−150. A novel mechanism involving a hemiacetal intermediate is proposed. 12. Limberakis, C. Morita–Baylis–Hillman reaction. In Name Reactions for Homologa-
tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 350−380. (Review).
32
Beckmann rearrangement Acid-mediated isomerization of oximes to amides. In protic acid:
R1 R2
NOH
NH
R2
OR1
H3O
H3O
R1 R2
NOH
R1 R2
NOH2
:OH2
N
R2
R1
NR1
R2
:
the substituent trans to the leaving group migrates
N
R2 O
R1
H
H
N
R2 OH
R1HN
R2 O
R1− H tautomerization
With PCl5:
R1 R2
NOH
NH
R2
OR1PCl5
R1 R2
NO
H
PCl4Cl
R1 R2
NOPCl4− HCl:
:OH2
N
R2
R1
NR1
R2
:
Again, the substituent trans to the leaving group migrates
N
R2 O
R1
H
H
N
R2 OH
R1
HN
R2 O
R1− H tautomerization
Example 1, Microwave (MW) reaction3
NOH
NH
OBiCl3
MW, 90%
33
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_16, © Springer-Verlag Berlin Heidelberg 2009
Example 24
NOH HN
OFeCl3
Solvent free81%
Example 36
NHO
NOH
PPA
21%PPA
72%
HN O
NH
O
PPA = polyphosphoric acid
Example 48
N
OEt
OH
syn
HN
O
OEt
p-TsCl/Et3N
THF, 10% K2CO380%
Abnormal Beckmann rearrangement is when the migrating substituent fragment (e.g., R1) departs from the intermediate, leaving a nitrile as a stable product.
NR2 R1 NR2 R1
R1 R2
NOH
H
Example 19
NOHH3C
H
H
H
AcO
HC(OMe)3F3CCOOH
THF, 60 oC40 min., 79%
NH3C
H
H
H
AcO
OH2
34
H
H
H
AcO
CN
H
H
H
AcO
CN
H HH
References 1. Beckmann, E. Chem. Ber. 1886, 89, 988. Ernst Otto Beckmann (1853−1923) was
born in Solingen, Germany. He studied chemistry and pharmacy at Leipzig. In addi-tion to the Beckmann rearrangement of oximes to amides, his name is associated with the Beckmann thermometer, used to measure freezing and boiling point depressions to determine the molecular weights.
2. Gawley, R. E. Org. React. 1988, 35, 1−420. (Review). 3. Thakur, A. J.; Boruah, A.; Prajapati, D.; Sandhu, J. S. Synth. Commun. 2000, 30,
2105−2011. 4. Khodaei, M. M.; Meybodi, F. A.; Rezai, N.; Salehi, P. Synth. Commun. 2001, 31,
2047−2050. 5. Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Bioorg. Med. Chem. Lett. 2002, 12,
387−390. 6. Hilmey, D. G.; Paquette, L. A. Org. Lett. 2005, 7, 2067−2069. 7. Fernández, A. B.; Boronat, M.; Blasco, T.; Corma, A. Angew. Chem., Int. Ed. 2005,
44, 2370−2373. 8. Collison, C. G.; Chen, J.; Walvoord, R. Synthesis 2006, 2319−2322. 9. Wang, C.; Rath, N. P.; Covey, D. F. Tetrahedron 2007, 63, 7977−7984. 10. Kumar, R. R.; Vanitha, K. A.; Balasubramanian, M. Beckmann rearrangement. In
Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 274−292. (Review).
35
Benzilic acid rearrangement Rearrangement of benzil to benzylic acid via aryl migration.
ArAr
O
O KOHAr
OHOH
O
Ar
benzil benzylic acid
ArAr
O
O
OH
ArO
O
ArOH Ar
OHO
O
Armigration
ArOH
OH
O
Ar
ArO
OH
O
ArH
workup
benzilate anionOH
Final deprotonation of the carboxylic acid drives the reaction forward.
Example 13
O
H3C
H3C
H
H
H
OO
KOH, MeOH/H2O
130−140 oC, 3 h, 32%O
H3C
H3C
H
H
H
CO2HOH
Example 26
OO
HO COOH
KOH, dioxane
30 min., rt, 74%
Example 3, Retro-benzilic acid rearrangement7
NH
O
O OMe
OTBS
NBoc
Boc
H
K2CO3, MeOH
rt, 2 h, 98%
NH
O
O OMe
O
NBoc
Boc
H
NH
O
NBoc
Boc
H
O OH
36
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_17, © Springer-Verlag Berlin Heidelberg 2009
References 1. Liebig, J. Justus Liebigs Ann. Chem. 1838, 27. Justus von Liebig (1803−1873) pur-
sued his Ph.D. In organic chemistry in Paris under the tutelage of Joseph Louis Gay-Lussac (1778−1850). He was appointed the Chair of Chemistry at Giessen University, which incited a furious jealousy amongst several of the professors already working there because he was so young. Fortunately, time would prove the choice was a wise one for the department. Liebig would soon transform Giessen from a sleepy university to the Mecca of organic chemistry in Europe. Liebig is now considered the father of organic chemistry. Many classic name reactions were published in the journal that still bears his name, Justus Liebigs Annalen der Chemie.2
2. Zinin, N. Justus Liebigs Ann. Chem. 1839, 31, 329. 3. Georgian, V.; Kundu, N. Tetrahedron 1963, 19, 1037−1049. 4. Robinson, J. M.; Flynn, E. T.; McMahan, T. L.; Simpson, S. L.; Trisler, J. C.; Conn,
K. B. J. Org. Chem. 1991, 56, 6709−6712. 5. Fohlisch, B.; Radl, A.; Schwetzler-Raschke, R.; Henkel, S. Eur. J. Org. Chem. 2001,
4357−4365. 6. Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 15, 2556−2562. 7. Selig, P.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 5082−5084. 8. Kumar, R. R.; Balasubramanian, M. Benzilic Acid Rearrangement. In Name Reactions
for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 395−405. (Review).
37
Benzoin condensation Cyanide-catalyzed condensation of aryl aldehyde to benzoin. Now cyanide is mostly replaced by a thiazolium salt. Cf. Stetter reaction.
Ar H
O
CN ArAr
O
OHcat.
Ar H
O
Ar H
O
CNAr
OH
CN
Ar
H Oproton
transfer
CN
NCO
OH
Ar
Ar
HNC
OHO
Ar
Ar
HAr
ArO
OHproton
transferCN
Example 12
H
OCl
H
OEtO
MeO
OEtO
MeOOH Cl
NaCN, EtOH
81%
Example 27
CHO
CH3
O
N
S
CH3
HO Br
Et3N, t-BuOH, 60 oC, 24 h, 40%
O
OHCH3
Example 37
OO
Et3N, DMF, 60 oC, 96 h, 69%
OO
OOH
O2
(air)
N
S
CH3
HO Br
H3C
38
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_18, © Springer-Verlag Berlin Heidelberg 2009
Example 49
SiEt3
O O
H
O
OSiEt3
87% yield; 91% ee
OMe
OMe
20% n-BuLiTHF
O
OP
O
H
O
O
ArAr
ArAr
MeMe5%
Ar = 2-FPh Example 510
CHO
N
NN Ph
OTMSPh Ph
BF4
10 mol%
10 mol% KHMDStoluene, rt, 16 h
O
OH
66% yield, 95% ee References 1. Lapworth, A. J. J. Chem. Soc. 1903, 83, 995−1005. Arthur Lapworth (1872−1941)
was born in Scotland. He was one of the great figures in the development of the mod-ern view of the mechanism of organic reactions. Lapworth investigated the benzoin condensation at the Chemical Department, The Goldsmiths’ Institute, New Cross, UK.
2. Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1932, 54, 3302−3309. 3. Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269−304. (Review). 4. Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407−496. (Review). 5. White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124−5131. 6. Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432−8433. 7. Enders, D.; Niemeier, O. Synlett 2004, 2111−2114. 8. Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326−1328. (Review). 9. Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 3070−3071. 10. Enders, D.; Han, J. Tetrahedron: Asymmetry 2008, 19, 1367−1371. 11. Cee, V. J. Benzoin condensation. In Name Reactions for Homologations-Part I; Li, J.
J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp381−392. (Review).
39
Bergman cyclization 1,4-Benzenediyl diradical formation from enediyne via electrocyclization.
hydrogen donor
Δ or
hv2
Helectrocyclization
reversibleH
enediyne 1,4-benzenediyl diradical
Example 16
S
S
DMSO, 180 oC, 24 h, 60% S
SS
S Ph
Ph S
S Ph
Ph
Example 27
N
N
H3Chv
THF, 45%
N
N
H3C
Example 3, Wolff rearrangement followed by the Bergman cyclization8
O
N2
Ohv or Δ, ROH
OHCO2R
CO2ROH
7 : 4
40
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_19, © Springer-Verlag Berlin Heidelberg 2009
Example 410
O
TMS
142 oC, t1/2 = 14.4 h
OTMS
References 1. Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660−661. Robert G. Berg-
man (1942−) is a professor at the University of California, Berkeley. His discovery of the Bergman cyclization was completed far in advance of the discovery of ene-diyne’s anti-cancer properties.
2. Bergman, R. G. Acc. Chem. Res. 1973, 6, 25−31. (Review). 3. Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212−7214. 4. Yus, M.; Foubelo, F. Rec. Res. Dev. Org. Chem. 2002, 6, 205−280. (Review). 5. Basak, A.; Mandal, S.; Bag, S. S. Chem. Rev. 2003, 103, 4077−4094. (Review). 6. Bhattacharyya, S.; Pink, M.; Baik, M.-H.; Zaleski, J. M. Angew. Chem., Int. Ed. 2005,
44, 592−595. 7. Zhao, Z.; Peacock, J. G.; Gubler, D. A.; Peterson, M. A. Tetrahedron Lett. 2005, 46,
1373−1375. 8. Karpov, G. V.; Popik, V. V. J. Am. Chem. Soc. 2007, 129, 3792−3793. 9. Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861−2890. (Review). 10. Lavy, S.; Pérez-Luna, A.; Kündig, E. P. Synlett 2008, 2621−2624. 11. Pandithavidana, D. R.; Poloukhtine, A.; Popik, V. V. J. Am. Chem. Soc. 2009, 131,
351−356.
41
Biginelli pyrimidone synthesis One-pot condensation of an aromatic aldehyde, urea, and β-dicarbonyl compound in the acidic ethanolic solution and expansion of such a condensation thereof. It belongs to a class of transformations called multicomponent reactions (MCRs).
Ar CHOO
O O
H2N NH2
O Δ
NHHN
OO
O
Ar
HCl, EtOH
ArO
O O
HO
aldol
addition
H
O
O OH
H
enolization
H
O
O O
Ar OH
HH
O
O O
Ar OH
H
O
O O
Ar OH2
H
conjugate
additionNH2H2N
O
O
O O
Ar :
H
H
OH
O
O
HN Ar
O NH2
:
O
O
O
NH
ArO
H2N
H
HN NH
O
HO Ar
O OH
H
HN NH
O
H2O Ar
O OH
− H2O
NHHN
OO
O
ArH
42
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_20, © Springer-Verlag Berlin Heidelberg 2009
Example 14
O
OF CHO
H2N NH2
S
NH
NH
O
S
F
HCl
EtOH, Δ81%
Example 25
O O
O H
H2N
O
NH2MeO
OMe
NH
NH
O
OMe
MeOOCCeCl3 •7H2O
EtOH, Δ, 2.5 h95%
Example 3, Microwave-induced Biginelli condensation (MWI = microwave irra-diation)9
O O
O H
H2N
O
NH2EtO
OMe
NH
NH
O
OMe
EtOOCBi(NO3)3, MWI
EtOH, Δ, 5 h80%
References 1. Biginelli, P. Ber. 1891, 24, 1317. Pietro Biginelli was at Lab. chim. della Sanita
pubbl. In Roma, Italy. 2. Kappe, C. O. Tetrahedron 1993, 49, 6937−6963. (Review). 3. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879−888. (Review). 4. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043−1052. (Review). 5. Ghorab, M. M.; Abdel-Gawad, S. M.; El-Gaby, M. S. A. Farmaco 2000, 55, 249−255. 6. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587−590. 7. Kappe, C. O.; Stadler, A. Org. React. 2004, 68, 1−116. (Review). 8. Limberakis, C. Biginelli Pyrimidone Synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 509−520. (Review).
9. Banik, B. K.; Reddy, A. T.; Datta, A.; Mukhopadhyay, C. Tetrahedron Lett. 2007, 48, 7392−7394.
43
Birch reduction The Birch reduction is the 1,4-reduction of aromatics to their corresponding cyclohexadienes by alkali metals (Li, K, Na) dissolved in liquid ammonia in the presence of an alcohol. Benzene ring bearing an electron-donating substituent:
ONa, liq. NH3
ROH
O
O O
H
H
H OR
single electron
transfer (SET)
O
radical anion
OO
H
HH e
O
H
HH
H OR
Benzene ring with an electron-withdrawing substituent:
CO2HNa, liq. NH3
CO2H
H
CO2CO2H CO2e e
radical anion
H NH2H
CO2 CO2HCO2
H H
H
44
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_21, © Springer-Verlag Berlin Heidelberg 2009
Example 14
ON
O
OMe
OMe
1. Na, NH3, THF, −78 oC
2. MeI, 98%, 30:1 dr ON
O
OMe
OMe Example 27
N
Na, NH3, THF
−78 oC, quant.N
Example 38
Ph
PhPh
Na, NH3THF, EtOH
−33 oC, 1 h16.3% H
Ph
H
H
H
H
Ph
H
H
Ph
H
H
HPh
H
H
H
Ph
H
H
H
Ph
H
H
References 1. Birch, A. J. J. Chem. Soc. 1944, 430−436. Arthur Birch (1915−1995), an Australian,
developed the “Birch reduction” at Oxford University during WWII in Robert Robin-son’s laboratory. The Birch reduction was instrumental to the discovery of the birth control pill and many other drugs.
2. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1−334. (Review). 3. Birch, A. J. Pure Appl. Chem. 1996, 68, 553−556. (Review). 4. Donohoe, T. J.; Guillermin, J.-B.; Calabrese, A. A.; Walter, D. S. Tetrahedron Lett.
2001, 42, 5841−5844. 5. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2002, 34, 611−642. (Review). 6. Subba Rao, G. S. R. Pure Appl. Chem. 2003, 75, 1443−1451. (Review). 7. Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054−2059. 8. Gealis, J. P.; Müller-Bunz, H.; Ortin, Y.; Condell, M.; Casey, M.; McGlinchey, M. J.
Chem. Eur. J. 2008, 14, 1552−1560.
45
Bischler–Möhlau indole synthesis The Bischler–Möhlau indole synthesis, also known as the Bischler indole synthesis, refers to the synthesis of 3-arylindoles from the cyclization of -arylamino-ketones and excess anilines.
OH2NBr
Δ
ONH N
H
O
H2N
BrO
NH
: :
H
SN2
NHO
H
H
H
dehydration
N
H
HNH
Example 15
NH2
OO
BrNaHCO3, EtOH
reflux, 4 h
NH O
O230−250 oC
silicone oil, 10−15 min35−80%
NH
O
Example 29
N
OTBS
O
F
NH2N NH2
OMe
DME, H2SO4
reflux, 53%NH2N
OMe
NH
N
F
46
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_22, © Springer-Verlag Berlin Heidelberg 2009
Example 310
OH2NBr N
H
LiBr, NaHCO3
EtOH, reflux6 h, 74%
OMe
OMe
MeO
OMe
Example 4, Microwave-assisted, solvent-free Bischler indole synthesis11
OH2NBr
Cl
ONH
ClneatNaHCO3
rt, 3 h
NH
Cl
H3NBr
cat. DMF, microwave, 540 W60 s, 52%
References 1. Möhlau, R. Ber. 1881, 14, 171–175. 2. Bischler, A.; Fireman, P. Ber. 1893, 26, 1346–1349. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970, pp 164.
(Book). 4. Buu-Hoï, N. P.; Saint-Ruf, G.; Deschamps, D.; Bigot, P. J. Chem. Soc. (C) 1971,
2606–2609. 5. Houlihan, W. J., Ed.; The Chemistry of Heterocyclic Compounds, Indoles (Part 1),
Wiley & Sons: New York, 1972. (Book). 6. Bigot, P.; Saint-Ruf, G.; Buu-Hoï, N. P. J. Chem. Soc., Perkin 1 1972, 2573–2576. 7. Bancroft, K. C. C.; Ward, T. J. J. Chem. Soc., Perkin 1 1974, 1852–1858. 8. Coïc, J. P.; Saint-Ruf, G.; Brown, K. J. Heterocycl. Chem. 1978, 15, 1367–1371. 9. Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998, 39, 8763–8764. 10. Pchalek, K.; Jones, A. W.; Wekking, M. M. T.; Black, D. S. C. Tetrahedron 2005, 61,
77–82. 11. Sridharan, V.; Perumal, S.; Avendaño, C.; Menéndez, J. C. Synlett 2006, 91–95.
47
Bischler–Napieralski reaction Dihydroisoquinolines from β-phenethylamides in refluxing phosphorus oxychlo-ride.
HN O
R
POCl3N
R
HN O
R
PCl
OClCl
HN O
RPOCl2
− ClNH
OPOCl2R
N
R OPOCl2
HH
Cl
N
R OH NH
RPOCl
Cl
POCl
OHCl HCl
Example 12
NH
NO
CO2Me
NH
N1. POCl3
2. NaBH4
H
H
CO2Me
NH
N
CO2MeH
H
H
H
H
H60% 23%
Example 24
NCO2Me
BnMeO N
OBn
MeOPOCl3, P2O5
96%
Example 36
O
O N
H
H
H
MeO2C
O
O N
H
H
H
O
POCl3
80 oC, 81%
48
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_23, © Springer-Verlag Berlin Heidelberg 2009
Example 47
O
OHN O
MeOOMe
OMe
O
ON
MeOOMe
OMe
POCl3
toluene, 95%
Example 59
NH
NO
H H
AcO OAc
H H
HO OH
NH
NH
POCl3, PhH, reflux, 3 h
then LiAlH4, THF, 1.5 h 64%
References 1. Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903–1908. Augustus Bischler
(1865−1957) was born in Southern Russia. He studied in Zurich with Arthur Hantzsch. He discovered the Bischler–Napieralski reaction while studying alkaloids at Basel Chemical Works, Switzerland with his coworker, B. Napieralski.
2. Aubé, J.; Ghosh, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009–9018. 3. Sotomayor, N.; Domínguez, E.; Lete, E. J. Org. Chem. 1996, 61, 4062–4072. 4. Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39, 6609–6612. 5. Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.; Yama-
zaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org. Chem. 2000, 65, 9143–9151. 6. Banwell, M. G.; Harvey, J. E.; Hockless, D. C. R., Wu, A. W. J. Org. Chem. 2000, 65,
4241–4250. 7. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron
2001, 57, 8297–8303. 8. Wolfe, J. P. Bischler–Napieralski Reaction. In Name Reactions in Heterocyclic Chem-
istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 376−385. (Review).
9. Ho, T.-L.; Lin, Q.-x. Tetrahedron 2008, 64, 10401–10405. 10. Csomós, P.; Fodor, L.; Bernáth, G.; Csámpai, A.; Sohár, P. Tetrahedron 2009, 65,
1475–1480.
49
Blaise reaction β-Ketoesters from nitriles, α-haloesters and Zn. Cf. Reformatsky reaction.
R CNBr CO2R2
R1
1. Zn, THF, reflux
2. H3O+CO2R2
R1R
O
R
Br CO2R2
R1
Zn(0)
R1
N
nucleophilic
addition
OR2
O
workupCO2R2
R1R
NZnBr
H2O H
BrZn
The Zn enolate itself is a C-enolate (in the crystal form), but for the reaction to oc-cur, it equilibrates back into an O-enolate
CO2R2
R1R
NHH
H2O:
CO2R2
R1R
O
CO2R2
R1R
OH2N HH2O H
Example 1, Preparation of the statin side chain5
Cl CNOTMS
Br CO2t-Bu1. cat. Zn, THF, reflux
2. H3O+, 85%Cl
OH OCO2t-Bu
Example 26
Zn, MeSO3H
THF, reflux, 2.5 hN
F CN
Cl ClBr CO2Et
HCl, 72%
N
F
Cl Cl
HN
OEt
OZnBr
N
F
Cl Cl
O
OEt
O
50
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_24, © Springer-Verlag Berlin Heidelberg 2009
Example 37
NC OBnOH
MeOMe
O
Br
3 equiv Zn, 1 mol% MeSO3HTHF, reflux, 78%
OBnOHO
MeO2C
Example 4, The first chemoselective tandem acylation of the Blaise reaction in-termediate9
Ph CN
Zn*
BrCH2CO2Et
THF, reflux, 1 h
ZnHN O
OEtPh
Br
n-BuLi, Ac2O
rt, 3 h, 82%
NH2 O
OEtPh
O CH3
References 1. (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478–480. (b) Blaise, E. E.
C. R. Hebd. Seances Acad. Sci. 1901, 132, 978–980. Blaise was at Institut Chimique de Nancy, France.
2. Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091–2096. 3. Deutsch, H. M.; Ye, X.; Shi, Q.; Liu, Z.; Schweri, M. M. Eur. J. Med. Chem. 2001, 36,
303–311. 4. Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324–6334. 5. Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-w.; Chang, J. H.; Lee, K. W.; Nam, D. H.;
Kim, N.-S. Synthesis 2004, 2629–2632. 6. Choi, B. S.; Chang, J. H.; Choi, H.-w.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.;
Heo, T.; Nam, D. H.; Shin, H. Org. Proc. Res. Dev. 2005, 9, 311–313. 7. Pospíšil, J.; Markó, I. E. J. Am. Chem. Soc. 2007, 129, 3516–3517. 8. Rao, H. S. P.; Rafi, S.; Padmavathy, K. Tetrahedron 2008, 64, 8037–8043. (Review). 9. Chun, Y. S.; Lee, S.-g.; Ko, Y. O.; Shin, H. Chem. Commun. 2008, 5098–5100.
51
Blum–Ittah aziridine synthesis Ring opening of oxiranes using azide followed by PPh3-reduction of the interme-diate azido-alcohol to give the corresponding aziridines.
R2R1
O NaN3 R1R2
N3
OH R2R1
HNPPh3
R2R1
OSN2 R1
R2
N3
OHN3 Regardless of the regioselectivity of the SN2 reaction of the azide, the ultimate stereochemical outcome for the aziridine is the same.
R1
R2
HON N N :PPh3
R1
R2
HON N N PPh3 N N N PR3
R1
R2
HO
PR3NN N
X
N2
NPR3
R1R2
OH
NPR3
HOR2
R1
NHR3P:O
R1
R2
R2R1
HNproton
transfer R2O
NHR1
PPh3 Example 13
OTrO
1. NaN3, NH4Cl, MeOH, reflux, 4 h
2. Ph3P, CH3CN, reflux, 30 min. 60−75%
HN OTr
Example 25
OTBSO NaN3, NH4Cl, MeOH
reflux, 4 h, 50%
52
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_25, © Springer-Verlag Berlin Heidelberg 2009
OTBSOH
N3
OTBSN3
OH
Ph3P, CH3CN
reflux, 99% OTBSNH
Example 37
OHN
Cbz 1. NaN3, NH4Cl, MeOH, 3 h, 64 oC
2. PPh3, MeCN, 1 h, reflux 66%
HNH
NCbz
Example 48
O NaN3, NH4Cl
microwave, 15 min.93%
OHN3
PPh3
CH3CN, reflux2 h, 95%
HN
References 1. Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43, 4271–
4273. Jochanan Blum is a professor at The Hebrew University in Jerusalem, Israel. 2. Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211–1214. 3. Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995, 36, 3639–3642. 4. Fürmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649–659. 5. Oh, K.; Parsons, P. J.; Cheshire, D. Synlett 2004, 2771–2775. 6. Serafin, S. V.; Zhang, K.; Aurelio, L.; Hughes, A. B.; Morton, T. H. Org. Lett. 2004,
6, 1561–1564. 7. Torrado, A. Tetrahedron Lett. 2006, 47, 7097–7100. 8. Pulipaka, A. B.; Bergmeier, S. C. J. Org. Chem. 2008, 73, 1462–1467.
53
Boekelheide reaction Treatment of 2-methylpyridine N-oxide with trifluoroacetic anhydride, or acetic, anhydride gives rise to 2-hydroxymethylpyridine.
NO
TFAA
NOH
TFAA, trifluoroacetic anhydride
NO
F3C O CF3
O O
acyl
transferNO
CF3
O
H
O2CCF3
NO
CF3
O
NOHN
O CF3
O
hydrolysis
Example 14
NN
Ac2O, CH2Cl2
reflux, 1 h, 90% NNOAcO
Example 26
NO
Ot-Bu
N
Ot-Bu
OH
1. TFAA, CH2Cl2
2. Na2CO3, 3 h 89%
Example 38
N N
OTBDPS1. Ac2O, 100 oC, 18 h
2. K2CO3, MeOH−H2O, rt, 2 h 63%
N N
OTBDPS
HO OHO O
54
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_26, © Springer-Verlag Berlin Heidelberg 2009
Example 49
N
NO2
O
N
NO2
OH
Ac2O, HOAc, 90 oC, 3 h
then HCl, 79%
References 1. Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286−1291. Virgil Boekel-
heide (1919−2003) was a professor at the University of Oregon. 2. Boekelheide, V.; Harrington, D. L. Chem. Ind. 1955, 1423−1424. 3. Katritzky, A. R.; Lagowski, J. M. Chemistry of the Heterocylic N-Oxides, Academic
Press: NY, 1971. (Review). 4. Newkome, G. R.; Theriot, K. J.; Gupta, V. K.; Fronczek, F. R.; Baker, G. R. J. Org.
Chem. 1989, 54, 1766−1769. 5. Katritzky, A. R.; Lam, J. N. Heterocycles 1992, 33, 1011−1049. (Review). 6. Fontenas, C.; Bejan, E.; Haddou, H. A.; Balavoine, G. G. A. Synth. Commun. 1995,
25, 629−633. 7. Galatsis, P. Boekelheide Reaction. In Name Reactions in Heterocyclic Chemistry; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 340−349. (Review). 8. Havas, F.; Danel, M.; Galaup, C.; Tisnès, P.; Picard, C. Tetrahedron Lett. 2007, 48,
999−1002. 9. Dai, L.; Fan, D.; Wang, X.; Chen, Y. Synth. Commun. 2008, 38, 576−582.
55
Boger pyridine synthesis Pyridine synthesis via hetero-Diels−Alder reaction of 1,2,4-triazines and dieno-philes (e.g., enamine) followed by extrusion of N2.
O
NHN N
N
N
O
HN
: NOH
HH2O
NNN
N
hetero-Diels-Alder
reaction
enamine
NN
NN
:B
N
retro-Diels-Alder
reaction, − N2 NNH
Example 13
NN
NEtO2C
EtO2C
CO2EtN O
NEtO2C
EtO2C
CO2EtCHCl3, 60 oC
26 h, 92%
Example 2, Intramolecular Boger pyridine synthesis8
triisopropylbenzene
232 oC, 36 h
NN N
CH3
N
N
Ph
PhPh N
NCH3
Ph
Ph
70%
N
N
Ph
Ph
27%
56
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_27, © Springer-Verlag Berlin Heidelberg 2009
Example 310
OH3C
HO
H
H H
NNN
1. pyrrolidine, xylene, Δ 10 h, sealed tube2. silica, 5 h, 67%
H3C
HO
H
H H
N
N
N
Example 411
NN
N NN
N
S SN N
S Sp-cumene, 30 h, 150 oC67%
References 1. Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179−2182. Dale Boger obtained
his Ph.D. under Elias J. Corey at Harvard University in 1980. He started his independent career at the University of Kansas, moving onto Purdue University, and currently he is a professor at The Scripps Research Institute.
2. Boger, D. L. Tetrahedron 1983, 39, 2869−2939. (Review). 3. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1988, 66, 142−150. 4. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon, 1991, Vol. 5, 451−512. (Review). 5. Behforouz, M.; Ahmadian, M.Tetrahedron 2000, 56, 5259−5288. (Review). 6. Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099−6138. (Review). 7. Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379−471.
(Review). 8. Lahue, B. R.; Lo, S.-M.; Wan, Z.-K.; Woo, G. H. C.; Snyder, J. K. J. Org. Chem.
2006, 69, 7171−7182. 9. Galatsis, P. Boger Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 323−339. (Review). 10. Catozzi, N.; Bromley, W. J.; Wasnaire, P.; Gibson, M.; Taylor, R. J. K. Synlett 2007,
2217−2221. 11. Lawecka, J.; Bujnicki, B.; Drabowicz, J.; Rykowski, A. Tetrahedron Lett. 2008, 49,
719−722.
57
Borch reductive amination Reduction (often using NaCNBH3) of the imine, formed by an amine and a car-bonyl, to afford the corresponding amine—basically, reductive amination.
H
R1 R2
O
R3
HN
R4 N
R1 R2
R4R3
H
HR1 R2
O
R3
HN
R4
R1 R2
OH
N:R4
R3N
R1 R2
R4R3N
R1 R2
R4R3
H
Example 14
CH3
O
NH2
1. TiCl4, Et3N, CH2Cl2, rt, 18 h
2. NaCNBH3, MeOH, rt, 15 min. 94% CH3
HN
Example 25
5 N HCl, NaCNBH3
MeOH, rt, 72 h, 75%O O
NH2N
Example 38
H
O
NH •HCl
0.3 equiv InCl3
2 equiv Et3SiHMeOH, rt, 48 h, 66%
N
58
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_28, © Springer-Verlag Berlin Heidelberg 2009
Example 49
OHOH
NO
O
O
OBn
1. NaIO4, 8:2 acetone−H2O, rt
2. BnNH2, MeOH, HOAc NaCNBH3, 3 Å MS, −78 oC to rt 64%
NO
O
O
OBn
NBn
References 1. Borch, R. F., Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996–3997. Richard F. Borch,
born in Cleveland, Ohio, was a professor at the University of Minnesota. 2. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. 3. Borch, R. F.; Ho, B. C. J. Org. Chem. 1977, 42, 1225–1227. 4. Barney, C. L.; Huber, E. W.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547–5550. 5. Mehta, G.; Prabhakar, C. J. Org. Chem. 1995, 60, 4638–4640. 6. Lewin, G.; Schaeffer, C. Heterocycles 1998, 48, 171–174. 7. Lewin, G.; Schaeffer, C.; Hocquemiller, R.; Jacoby, E.; Léonce, S.; Pierré, A.; Atassi,
G. Heterocycles 2000, 53, 2353–2356. 8. Lee, O.-Y.; Law, K.-L.; Ho, C.-Y.; Yang, D. J. Org. Chem. 2008, 73, 8829–8837. 9. Sullivan, B.; Hudlicky, T. Tetrahedron Lett. 2008, 49, 5211–5213. 10. Koszelewski, D.; Lavandera, I.; Clay, D.; Guebitz, G. M.; Rozzell, D.; Kroutil, W.
Angew. Chem., Int. Ed. 2008, 47, 9337–9340.
59
Borsche–Drechsel cyclization Tetrahydrocarbazole synthesis from cyclohexanone phenylhydrazone. Cf. Fischer indole synthesis.
NH
N
HCl
NH
[3,3]-sigmatropic
rearrangementNH
N
H
HNH
NHNH
NH
H
NHNH2
H
NH
NH2
H
NH
H
Example 16
NH2
H3CO
O
HO
CH3HCl, NaNO2, NaOAc
H2O, MeOH, 54%
NH
NH
N
H3COO
CH3
HOAc, HCl, reflux
10 min., 44% O
CH3
H3CO
Example 210
OCO2Et
NO
NN
KOAc, H2O
− 4 oC to rt
retro-Claisen condensation
followed by Japp-Klingemann hydrazone synthesis
60
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_29, © Springer-Verlag Berlin Heidelberg 2009
NO
NHN
CO2H
EtO2C
H3O , 100 oC
68% 2 steps NH
NO
CO2Et
CO2H
Example 310
NH
N
CO2Et
CO2H
conc. HCl, EtOH
reflux, 85% NH
CO2Et
CO2Et
References 1. Drechsel, E. J. Prakt. Chem. 1858, 38, 69. 2. Borsche, W.; Feise, M. Ann. 1908, 359, 49–80. Walther Borsche was a professor at
Chemischen Institut, Universität Göttingen, Germany when this paper was published. Borsche was completely devoid of the arrogance shown by many of his contemporar-ies. Both Borsche and his colleague at Frankfurt, Julius von Braun, suffered under the Nazi regime for their independent minds.
3. Bruck, P. J. Org. Chem. 1970, 35, 2222–2227. 4. Gazengel, J.-M.; Lancelot, J.-C.; Rault, S.; Robba, M. J. Heterocycl. Chem. 1990, 27,
1947–1951. 5. Abramovitch, R. A.; Bulman, A. Synlett 1992, 795–796. 6. Lin, G.; Zhang, A. Tetrahedron 2000, 56, 7163–7171. 7. Ergun, Y.; Bayraktar, N.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2000, 37, 11–14. 8. Rebeiro, G. L.; Khadilkar, B. M. Synthesis 2001, 370–372. 9. Takahashi, K.; Kasai, M.; Ohta, M.; Shoji, Y.; Kunishiro, K.; Kanda, M.; Kurahashi,
K.; Shirahase, H. J. Med. Chem. 2008, 51, 4823–4833. 10. Pete, B. Tetrahedron Lett. 2008, 49, 2835–2838.
61
Boulton–Katritzky rearrangement Rearrangement of one five-membered heterocycle into another under thermolysis.
NA
BD
XY
ZH
YX
NZ
ABD
H
Example 14
N:H
NO
N
Ph
N
NO
N
Ph
150 oC H HN
N NH Ph
O
Example 2, Hydrazinolysis7
NN
OF3C
Ph
ONH2NH2, DMF
rt, 1 h NN
OF3C
N
Ph
NH2
NNNH
PhNHF3C
O
5%
N
NH
NF3C
PhN
HO
92%
Example 43
NN
O
NHN
NH
CH3H3C
CF3
Ot-BuOK, DMF
reflux, 2 h, 75%CF3
ONH
O
62
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_30, © Springer-Verlag Berlin Heidelberg 2009
References 1. Boulton, A. J.; Katritzky, A. R.; Majid Hamid, A. J. Chem. Soc. (C) 1967, 2005–2007.
Alan Katritzky, a professor at the University of Florida, is best known for his series Advances of Heterocyclic Chemistry, now in its 93rd volume.
2. Ruccia, M.; Vivona, N.; Spinelli, D. Adv. Heterocycl. Chem. 1981, 29, 141–169. (Re-view).
3. Vivona, N.; Buscemi, S.; Frenna, V.; Gusmano, C. Adv. Heterocyl. Chem. 1993, 56, 49–154. (Review).
4. Katayama, H.; Takatsu, N.; Sakurada, M.; Kawada, Y. Heterocycles 1993, 35, 453–459.
5. Rauhut, G. J. Org. Chem. 2001, 66, 5444–5448. 6. Crampton, M. R.; Pearce, L. M.; Rabbitt, L. C. J. Chem. Soc., Perkin Trans. 2 2002,
257–261. 7. Buscemi, S.; Pace, A.; Piccionello, A. P.; Macaluso, G.; Vivona, N.; Spinelli, D.;
Giorgi, G. J. Org. Chem. 2005, 70, 3288–3291. 8. Pace, A.; Pibiri, I.; Piccionello, A. P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org.
Chem. 2007, 64, 7656–7666. 9. Piccionello, A. P.; Pace, A.; Buscemi, S.; Vivona, N.; Pani, M. Tetrahedron 2008, 64,
4004–4010. 10. Pace, A.; Pierro, P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2009, 74,
351–358.
63
Bouveault aldehyde synthesis Formylation of an alkyl or aryl halide to the homologous aldehyde by transformation to the corresponding organometallic reagent then addition of DMF (M = Li, Mg, Na, and K).
R X
1. M2. DMF
3. HR CHO
R XM
R MMe2N
R
O MH
R CHOMe2N H
O
Comins modification:4
H
ON NLi LiO N
H
N
n-BuLi
ortho-lithiation
N
LiO
N
1. RX, X = Br, I
2. H3OH
O
R
Example3
BrLi, DMF, THF, 10 oC
ultrasound 5 min., 85%
CHO
References 1. Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306−1322, 1322−1327. Louis Bou-
veault (1864−1909) was born in Nevers, France. He devoted his short yet very pro-ductive life to teaching and to working in science.
2. Sicé, J. J. Am. Chem. Soc. 1953, 75, 3697−3700. 3. Pétrier, C.; Gemal, A. L.; Luche, J.-L. Tetrahedron Lett. 1982, 23, 3361−3364. 4. Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078−1083. 5. Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1986, 27, 1793−1796. 6. Meier, H.; Aust, H. J. Prakt. Chem. 1999, 341, 466−471.
64
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_31, © Springer-Verlag Berlin Heidelberg 2009
Bouveault–Blanc reduction Reduction of esters to the corresponding alcohols using sodium in an alcoholic solvent.
R OEt
O Na, EtOHR OH
R OEt
OOEtsingle-electron
transfer (SET) R OEt
O HR OEt
OH
e ketyl (radical anion)
R OEt
OH
R OEt
OH
OEtH
OEt
eR H
O e
OEt
R H
O H
R H
OHR H
OH
OEtHR OH
e
Example2
OEt
OOH
Na, Al2O3t-BuOH, Tol.
reflux, 6 h, 66%
References 1. Bouveault, L.; Blanc, G. Compt. Rend. Hebd. Seances Acad. Sci. 1903, 136,
1676−1678. 2. Bouveault, L.; Blanc, G. Bull. Soc. Chim. 1904, 31, 666−672. 3. Rühlmann, K.; Seefluth, H.; Kiriakidis, T.; Michael, G.; Jancke, H.; Kriegsmann, H. J.
Organomet. Chem. 1971, 27, 327−332. 4. Seo, B.-I.; Wall, L. K.; Lee, H.; Buttrum, J. W.; Lewis, D. E. Synth. Commun. 1993,
23, 15−22. 5. Singh, S.; Dev, S. Tetrahedron 1993, 49, 10959−10964. 6. Schopohl, M. C.; Bergander, K.; Kataeva, O.; Föehlich, R.; Waldvogel, S. R. Synthesis
2003, 2689−2694.
65
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_32, © Springer-Verlag Berlin Heidelberg 2009
Bradsher reaction The intramolecular Bradsher cyclization refers to the acid-catalyzed aromatic cyclodehydration of ortho-acyl diarylmethanes to form anthracenes. On the other hand, the intermolecular Bradsher cycloaddition often involves the Diels–Alder reaction of a pyridium with a vinyl ether or vinyl sulfide.
R
O R
HBr
CH3CO2H
anthracene
R
O
H R
OH
R HO
H
R
− H
OH RR OH2
H
H
Example 1, Intramolecular Bradsher reaction2
Br
O
Br
HBr, CH3CO2H
150 oC, 7 h, 21%
Example 2, Intramolecular Bradsher reaction5
S SClCl
AcOH
PPA S SClCl
O
H3C
S SClCl
CH3
CH3O
66
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_33, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Intermolecular Bradsher cycloaddition (DNP = dinitrophenyl)8
NDNP
OCO2Et
Cl
H OEt CaCO3, MeOH
rt, 2 d
CHO
NHDNP
EtO2COOEt
66%19%N
O
DNP
EtO
Example 4, Intermolecular Bradsher cycloaddition10
H SPh CaCO3, MeOHNDNP
NHAc NHAc
DNPN
PhS
Cl
Cl
H3O
DNPHN SPh
NOH
Ac
80%
References 1. (a) Bradsher, C. K. J. Am. Chem. Soc. 1940, 62, 486–488. Charles K. Bradsher was
born in Petersburg, VA in 1912. After his Ph.D. under Louis F. Fieser at Harvard and postdoctoral training with R. C. Fuson, he became a professor at Duke University. (b) Bradsher, C. K.; Smith, E. S. J. Am. Chem. Soc. 1943, 65, 451–452. (c) Bradsher, C. K.; Vingiello, F. A. J. Org. Chem. 1948, 13, 786–789. (d) Bradsher, C. K.; Sinclair, E. F. J. Org. Chem. 1957, 22, 79–81.
2. Vingiello, F. A.; Spangler, M. O. L.; Bondurant, J. E. J. Org. Chem. 1960, 25, 2091–2094.
3. Brice, L. K.; Katstra, R. D. J. Am. Chem. Soc. 1960, 82, 2669–2670. 4. Saraf, S. D.; Vingiello, F. A. Synthesis 1970, 655. 5. Ahmed, M.; Ashby, J.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1970, 1094–
1095. 6. Ashby, J.; Ayad, M.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1 1974, 1744–1747. 7. Bradsher, C. K. Chem. Rev. 1987, 87, 1277–1297. (Review). 8. Nicolas, T. E.; Franck, R. W. J. Org. Chem. 1995, 60, 6904–6911. 9. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837–840. 10. Soll, C. E.; Franck, R. W. Heterocycles 2006, 70, 531–540.
67
Brook rearrangement Rearrangement of α-silyl oxyanions to α-silyloxy carbanions via a reversible process involving a pentacoordinate silicon intermediate is known as the [1,2]-Brook rearrangement, or [1,2]-silyl migration.
[1,2]-Brook rearrangement
SiR3
OHR1
R2
RLi
Li
OR1
R2
SiR3
SiR3
OR1
R2
R
HSiR3
OR1
R2
R1R2
SiR3
O
pentacoordinate silicon intermediate
H
OPh
Ph
SiPh3OPh
Ph
SiPh3
H OH
workup
[1,3]-Brook rearrangement
OLi
R1
O
R1
SiR3
R2
SiR3OSiR3
R2R1
Li
R2
[1,4]-Brook rearrangement
OLi
R1 R1
O
R2
SiR3OSiR3
R2R1
Li
R2
R3Si
Example 16
t-BuMe2SiCN
O
Ph
1. 4 eq. NaHMDS, −30 to 15 oC
2. PhCH2Br, −10 oC, 75%t-BuMe2SiO
CN
Ph Ph
68
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_34, © Springer-Verlag Berlin Heidelberg 2009
Example 2, [1,2]-Brook rearrangement followed by a retro-[1,5]-Brook rear-rangement8
PhBrt-BuLi, Et2O
−78 oCPhLi
Me3Si Ph
O
−78 oC to rt, 30 min.then NH4Cl, H2O, 44%
Ph
OPh
SiMe3
Example 3, [1,5]-Brook rearrangement9
TMSBu
SS
OH
KHMDS, THF
− 78 oC, 1 h, 93%H
BuSS
OTMS
Example 4, Retro-[1,4]-Brook rearrangement10
Me SnBu3
TESO OTMSn-BuLi, THF
− 78 oC, 30 min.91%
Me TMS
TESO OH
11% [1,2]-BrookMe TES
OH OTMS
89% [1,4]-Brook
References 1. Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886−1889. Adrian G. Brook (1924−) was
born in Toronto, Canada. He was a professor in Lash Miller Chemical Laboratories, University of Toronto, Canada.
2. Brook, A. G. Acc. Chem. Res. 1974, 7, 77−84. (Review). 3. Bulman Page, P. C.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147−195.
(Review). 4. Fleming, I.; Ghosh, U. J. Chem. Soc., Perkin Trans. 1 1994, 257−262. 5. Moser, W. H. Tetrahedron 2001, 57, 2065−2084. (Review). 6. Okugawa, S.; Takeda, K. Org. Lett. 2004, 6, 2973−2975. 7. Matsumoto, T.; Masu, H.; Yamaguchi, K.; Takeda, K. Org. Lett. 2004, 6, 4367−4369. 8. Clayden, J.; Watson, D. W.; Chambers, M. Tetrahedron 2005, 61, 3195−3203. 9. Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem. Soc. 2006, 128,
12368–12369. 10. Mori, Y.; Futamura, Y.; Horisaki, K. Angew. Chem., Int. Ed. 2008, 47, 1091–1093. 11. Greszler, S. N.; Johnson, J. S. Org. Lett. 2009, 11, 827–830.
69
Brown hydroboration Addition of boranes to olefins followed by alkalinic oxidation of the organoborane adducts to afford alcohols.
R1. R'2BH
2. H2O2, NaOHR
OH
RB
HR'
R' syn-
addition RB
H
R'
R'
O OHR
BH
R'R'
RB
H
O
R'OH
R'
alkyl migrationR
OB
R'
R'
O OHR
OB
OR'
OR'
ROHOH B(OH)3
Example 12
H
H
H
H
1. BH3•SMe2, LiAlH4, Et2O
2. NaOOH
H
H
H
H 35% 40%
H
H
H
H
OH HO
Example 27
OMe
OMeNO2
MeO
OBn
HO
Me
BH3•SMe2, NaOOH
THF, 85%, dr 8:1~11:1
OMe
OMeNO2
MeO
OBn
HO
Me
HO
70
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_35, © Springer-Verlag Berlin Heidelberg 2009
Example 38
Ph1. Pyridine•BH3, I2, CH2Cl2, 2 h
2. H2O2, NaOH, MeOH, 92% Ph
OH PhOH
15:1
Example 4, Asymmetric hydroboration10
PhNH
CH3
O
PhNH
O
CH3
O
OP N
Ph
CH3
0.5 mol% Rh(nbd)2•BF41.1% cat., 2 equiv PinBH
THF, 40 oC, 2 h
cat. =
PhNH
CH3
O B(OCMe2)2 H2O2, aq. NaOH
80%
PhNH
CH3
O OH
99% ee
Example 511
NHSi
Ph
HPh
H
t-But-Bu
BH3•SM2, THF;
NaOH, H2O285%
HPh
(t-Bu)2Si
Ph
NH2
OH
OH
References 1. Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1958, 80, 1552−1558. Herbert C.
Brown (USA, 1912−2004) began his academic career at Wayne State University and moved on to Purdue University where he shared the Nobel Prize in Chemistry in 1981 with Georg Wittig (Germany, 1897−1987) for their development of organic boron and phosphorous compounds.
2. Nussim, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1120−1131. 3. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents, Academic Press: New York,
1972. (Book). 4. Brewster, J. H.; Negishi, E. Science 1980, 207, 44−46. (Review). 5. Fu, G. C.; Evans, D. A.; Muci, A. R. Advances in Catalytic Processes 1995, 1,
95−121. (Review). 6. Hayashi, T. Comprehensive Asymmetric Catalysis I−III 1995, 1, 351−364. (Review). 7. Carter K. D.; Panek J. S. Org. Lett. 2004, 6, 55−57. 8. Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766−5767. 9. Clay, J. M. Brown hydroboration reaction. In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 183−188. (Review).
10. Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734−3735. 11. Anderson, L. L.; Woerpel, K. A. Org. Lett. 2009, 11, 425−428.
71
Bucherer carbazole synthesis Carbazole formation from naphthols and aryl hydrazines promoted by sodium bi-sulfite. Another variant of the Fischer indole synthesis.
OH
NHNH2
NaHSO3
NH
OHH O
HH
OSO2H
OHHH
OSO2H
OHH
OSO2H
:NH2NHPh
H H
OSO2H
NHNHPh
H:B
HH
OSO2H
NHNHPhOH
NHNH
H
[3,3]-sigmatropicrearrangement
thenNHNH2H NH
NH2HNH
H
H
Example 12
OH
NHNH2CO2H NH
NaHSO3, NaOHΔ, 130 oC
several days, 46%
Example 23
H2NHN
1. aq. NaHSO3, ΔOH
NH
2. H
72
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_36, © Springer-Verlag Berlin Heidelberg 2009
Example 37
H2NHN NH
Na2S2O5BrOH
Br
HCl, Δ
Example 34
H2NHN
OHHO HNNH
1. NaHSO3, Δ
2. H0.5% yield!
References 1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49−91. Hans Th. Bucherer (1869−1949)
was born in Ehrenfeld, Germany. He shuttled between industry and academia all through his career.
2. Bucherer, H. T.; Schmidt, M. J. Prakt. Chem. 1909, 79, 369−417. 3. Bucherer, H. T.; Sonnenburg, E. F. J. Prakt. Chem. 1909, 81, 1−48. 4. Drake, N. L. Org. React. 1942, 1, 105−128. (Review). 5. Seeboth, H. Angew. Chem., Int. Ed. 1967, 6, 307−317. (Review). 6. Robinson, B. The Fischer Indole Synthesis, Wiley-Interscience, New York, 1982.
(Book). 7. Hill, J. A.; Eaddy, J. F. J. Labelled Compd. Radiopharm. 1994, 34, 697−706. 8. Pischel, I.; Grimme, S.; Kotila, S.; Nieger, M.; Vögtle, F. Tetrahedron: Asymmetry
1996, 7, 109−116. 9. Moore, A. J. Bucherer carbazole synthesis. In Name Reactions in Heterocyclic Chem-
istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 110−115. (Review).
73
Bucherer reaction Transformation of β-naphthols to β-naphthylamines using ammonium sulfite.
OH NH2(NH4)2SO3•NH3
H2O, 150 oC
OH O
HH
OSO2NH4
OHH
OSO2NH4
HH
H
O
OSO2NH4
:NH3
OSO2NH4
NH2
OHtautomerization H
OSO2NH4
NH2
H
NH2
OSO2NH4
NH2
OH2
:
H
Example 1, Although the classic Bucherer reaction requires high temperatures, it may be carried out at room temperature with the aid of microwave (150 watts):7
OH NH2NH3, (NH4)2SO3, H2O, rt
microwave 30 min. 93% Example 2, Retro-Bucherer reaction7
N
N
OOMe
OH
5 mol% Na2S2O5H2O, reflux, 4 h;
10 mol% NaOHreflux, 24 h
46%N
N
OOMe
NH2
74
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_37, © Springer-Verlag Berlin Heidelberg 2009
Example 38
(NH4)2SO3NH3, H2O
200 oC, 5 d, 91%OHOH
OHNH2
References 1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49−91. 2. Drake, N. L. Org. React. 1942, 1, 105−128. (Review). 3. Gilbert, E. E. Sulfonation and Related Reactions Wiley: New York, 1965, p 166. (Re-
view). 4. Seeboth, H. Angew. Chem., Int. Ed. 1967, 6, 307−317. 5. Gruszecka, E.; Shine, H. J. J. Labelled Compd. Radiopharm. 1983, 20, 1257–1264. 6. Belica, P. S.; Manchand, P. S. Synthesis 1990, 539−540. 7. Deady, L. W.; Devine, S. M. Tetrahedron 2006, 62, 2313−2320. 8. Körber, K.; Tang, W.; Hu, X.; Zhang, X. Tetrahedron Lett. 2002, 43, 7163–7165. 9. Budzikiewicz, H. Mini-Reviews Org. Chem. 2006, 3, 93–97. (Review).
75
Bucherer–Bergs reaction Formation of hydantoins from carbonyl compounds with potassium cyanide (KCN) and ammonium carbonate [(NH4)2CO3] or from cyanohydrins and ammo-nium carbonate. It belongs to the category of multiple component reactions (MCRs).
R1
R2O
KCN
(NH4)2CO3NH
HNR1
R2
O
O
(NH4)2CO3 = 2 NH3 + CO2 + H2O
NC
R2H2NOH
R1H3N
R1
R2O :
R1NH2
R2N
C O
:
O
:
R1 R2
NH2
O
NR1
R2
O
HN
H
NH
HNR1
R2
O
O
:
NH2
NR1
R2
O
COOHRH
NR1
R2
OH
O
N
:
isocyanate intermediate
Example 15
N
CH3O
CH3O
O
KCN, (NH4)2CO3
48 h, 60 oC, 83%
N
CH3O
CH3ON
CH3O
CH3OH H
HNNH HN
NHO
O
O
O
Example 26
O
O
O
H
HHCO2Et
KCN, (NH4)2CO3
EtOH/H2O, 70 oC, 50%O
O
H
HHCO2Et
NHHN
O
O
76
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_38, © Springer-Verlag Berlin Heidelberg 2009
Example 37
B(OH)2
CH3
O
KCN, (NH4)2CO3
EtOH/H2O (1:1)60 oC, 4 h, 83%
B(OH)2
CH3
NHHN
O
O
Example 49
EtO2C
F
H
O
O 1. 1 M NaOH, EtOH, rt, 30 min.
2. KCN, (NH4)2CO3, 60 oC, 5 days 77%
HO2CF
H OHN
NH
OO
References 1. Bergs, H. Ger. Pat. 566, 094, 1929. Hermann Bergs worked at I. G. Farben in Ger-
many. 2. Bucherer, H. T., Steiner, W. J. Prakt. Chem. 1934, 140, 291–316. (Mechanism). 3. Ware, E. Chem. Rev. 1950, 46, 403–470. (Review). 4. Wieland, H. In Houben−Weyl’s Methoden der organischen Chemie, Vol. XI/2, 1958, p
371. (Review). 5. Menéndez, J. C.; Díaz, M. P.; Bellver, C.; Söllhuber, M. M. Eur. J. Med. Chem. 1992,
27, 61–66. 6. Domínguez, C.; Ezquerra, A.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron:
Asymmetry 1997, 8, 511–514. 7. Zaidlewicz, M.; Cytarska, J.; Dzielendziak, A.; Ziegler-Borowska, M. ARKIVOC
2004, iii, 11−21. 8. Li, J. J. Bucherer–Bergs Reaction. In Name Reactions in Heterocyclic Chemistry, Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 266−274. (Review). 9. Sakagami, K.; Yasuhara, A.; Chaki, S.; Yoshikawa, R.; Kawakita, Y.; Saito, A.; Ta-
guchi, T.; Nakazato, A. Bioorg. Med. Chem. 2008, 16, 4359–4366. 10. Wuts, P. G. M.; Ashford, S. W.; Conway, B.; Havens, J. L.; Taylor, B.; Hritzko, B.;
Xiang, Y.; Zakarias, P. S. Org. Proc. Res. Dev. 2009, 13, 331–335.
77
Büchner ring expansion Reaction of a phenyl ring with diazoacetic esters to give cyclohepta-2,4,6-trienecarboxylic acid esters. Intramolecular Büchner reaction is more useful in synthesis. Cf. Pfau−Platter azulene synthesis.
N2 CO2CH3
[Rh]CO2CH3
N2 CO2CH3[Rh]
[Rh] CO2CH3N2↑ rhodium carbenoid
[Rh]
CO2CH3
[Rh]
CO2CH3[2 + 2]
cycloaddition
reductive
elimination
CO2CH3electrocyclic
ring openingCO2CH3
Example 1, Intramolecular Büchner reaction7
H O
Rh2(OAc)4
CH2Cl2
ON2
Example 2, Intramolecular Büchner reaction8
Br
ON2
Icat. Rh2(OCOt-Bu)4, DMAP
Ac2O, CH2Cl2, 73%
I
OAc
Example 3, An intramolecular Büchner reaction within the Grubbs’ catalyst!9
NN
RuPh
PCy3
Cl
Cl
1 atm CO
CH2Cl2, 90%
NN
Ru CO
PCy3
Cl
Cl
PhOC
78
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_39, © Springer-Verlag Berlin Heidelberg 2009
Example 410
Ar0.5 mol%
CH2Cl2, −78 oC, 49−66%
ORh Rh
O
CPh3
4
EtO2C
N2
[Rh]CO2Et
Ar
[Rh]
CO2EtAr CO2EtAr
CO2Et
Ar
References 1. Büchner, E. Ber. 1896, 29, 106–109. 2. von E. Doering, W.; Knox, L. H. J. Am. Chem. Soc. 1957, 79, 352–356. 3. Marchard, A. P.; Brockway, N. M. Chem. Rev. 1974, 74, 431–469. (Review). 4. Anciaux, A. J.; Demoncean, A.; Noels, A. F.; Hubert, A. J.; Warin, R.; Teyssié, P. J.
Org. Chem. 1981, 46, 873–876. 5. Duddeck, H.; Ferguson, G.; Kaitner, B.; Kennedy, M.; McKervey, M. A.; Maguire, A.
R. J. Chem. Soc., Perkin Trans. 1 1990, 1055–1063. 6. Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933–935. 7. Manitto, P.; Monti, D.; Speranza, G. J. Org. Chem. 1995, 60, 484–485. 8. Crombie, A. L; Kane, J. L., Jr.; Shea, K. M.; Danheiser, R. L. J. Org. Chem. 2004, 69,
8652–8667. 9. Galan, B. R.; Gembicky, M.; Dominiak, P. M.; Keister, J. B.; Diver, S. T. J. Am.
Chem. Soc. 2005, 127, 15702–15703. 10. Panne, P.; Fox, J. M. J. Am. Chem. Soc. 2007, 129, 22–23. 11. Gomes, A. T. P. C.; Leão, R. A. C.; Alonso, C. M. A.; Neves, M. G. P. M. S.;
Faustino, M. A. F.; Tomé, A. C.; Silva, A.M. S.; Pinheiro, S.; de Souza, M. C. B. V.; Ferreira, V. F.; Cavaleiro, J. A. S. Helv. Chim. Acta 2008, 91, 2270–2283.
79
Buchwald–Hartwig amination The Buchwald–Hartwig amination is an exceedingly general method for generat-ing an aromatic amine from an aryl halide or an aryl sulfonates. The key feature of this methodology is the use of catalytic palladium modulated by various electron-rich ligands. Strong bases, such as sodium tert-butoxide, are essential for catalyst turnover.
R1X+ HN
R2
R3
X = I, Br, Cl, OSO2R
cat. LnPd(0)
NaOt-Bu R1NR2
R3
Mechanism:
Br
NH
NPd(OAc)2, dppf
NaOt-Bu, Tol., Δ
BrPd(0)
oxidative addition
Pd(II) Br NH
ligandexchange
− HBr
NPd(II) N reductive
elimination− Pd(0)
The catalytic cycle is shown on the next page.
Example 13
R1I+ HN
R2
R3
0.5 mol% Pd2(dba)32 mol% P(o-tol)3
NaOt-Bu, dioxane65–100 °C, 2–24 h
18–79% yield
R1NR2
R3
R1 = EWG or EDGamine = 2° cyclic or acyclicamine = 1° aliphatic: low yield, unless R1 ortho
80
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_40, © Springer-Verlag Berlin Heidelberg 2009
Catalytic cycle:
LnPd(0)
LnPdX
Ar
HNR2
R3+ NaOt-Bu+ HOt-BuNaX
LnPdNR2(R3)
Ar
NR2
R3Ar ArX
Ln+1Pd(0)
k1k-1
k2
k3
k4
NR2
R3' H
LnPdH
Ar
Ar H
Ln-1Pd(0)
–d[ArX]
dt=
k1k2
k–1[L][ArX][Pd]
Pd(BINAP)2 catalyzed
Example 24
R1X+ HN
R2
R3
5 mol% (DPPF)PdCl215 mol% DPPF
NaOt-Bu, THF100 °C (sealed), 3 h
80–96% yield(11 examples)
R1NR2
R3
X = Br or IR1 = EWG or EDGamine = 2° acyclic (one example)amine = 1° aliphatic or aromatic
FePPh2
PPh2
DPPF
Example 3, Room temperature Buchwald–Hartwig amination9
R1Br+
1–2 mol% Pd(dba)2(t-Bu)3P (P/Pd = 0.8/1)
NaOt-Bu, tol.22 °C, 1–6 h81–99% yield
R1 = EDG or EWGamine = 2° cyclic or acyclic: aromatic, aliphatic, or azolesamine = 1° anilines: no aliphatic
HNR2
R3R1
NR2
R3
81
Example 410
BrMe
MeOn-HexNH2
0.25 mol% Pd2(dba)30.75 mol% rac-BINAP
NaOt-Bu (1.4 equiv)tol., 80 °C, 18–23 h
94%
HN
Me
MeO
n-Hex
Example 511
O Cl HN O
0.5 mol% Pd2(dba)21 mol% ligand
1.4 eq. NaOt-Bu, Tol.100 oC, 24 h, 92%
O N O
ligand =P
N
N
Ni-Bu
i-Bu
Ni-Bu
Example 612
CO2MeI
NH2Pd(OAc)2, Cs2CO3
DPE-Phos, Tol., 95 oC95%
OCF3
MeO2C HN
OCF3
DPE-Phos =O
PPh2 PPh2
Example 7, Amination of volatile amines14
NXNO
O
X = N, CH2
Br
5 equiv R1NHR25 mol% Pd(OAc)2
10 mol% dppp2 equiv NaOt-Bu
80 oC, 14 h, sealed tube55−98%
NXNO
O
NR2
R1
Example 815
MeO NH2 NCl Cl
O Ot-Bu1 mol% Pd(OAc)2
2 mol% XPhos
1.4 equiv NaOt-Butoluene, rt, 4 d, 67% NN
HCl
O Ot-Bu
MeO
82
PXPhos =
References 1. (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969−5970. John
Hartwig earned his Ph.D. at the University of California-Berkeley in 1990 under the guidance of Robert Bergman and Richard Anderson. He moved from Yale University to the University of Illinois at Urbana-Champaign in 2006. Hartwig and Buchwald in-dependently discovered this chemistry. (b) Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413−5418. (c) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005−8008.
2. (a) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901−7902. Stephen Buchwald received his Ph.D. in 1982 under Jeremy Knowles at Harvard University. He is currently a professor at MIT. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333−10334.
3. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133−1135. 4. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217−7218. 5. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805−818. (Review). 6. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852−860. (Review). 7. Frost, C. G.; Mendonça, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615−2624. (Re-
view). 8. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125−146. (Review). 9. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L.
M. J. Org. Chem. 1999, 64, 5575−5580. 10. Wolfe, J. P.; Buchwald, S. L. Org. Syn. 2002, 78, 23−30. 11. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135−9142. 12. Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737−5750. 13. Janey, J. M. Buchwald–Hartwig amination, In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 564−609. (Review).
14. Li, J. J.; Wang, Z.; Mitchell, L. H. J. Org. Chem. 2007, 72, 3606−3607. 15. Lorimer, A. V.; O’Connor, P. D.; Brimble, M. A. Synthesis 2008, 2764−2770. 16. Nodwell, M.; Pereira, A.; Riffell, J. L.; Zimmerman, C.; Patrick, B. O.; Roberge, M.;
Andersen, R. J. J. Org. Chem. 2009, 74, 995−1006.
83
Burgess reagent
CH3O2C N S NEt3O
O
The Burgess reagent [(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt], a neutral, white crystalline solid, is efficient at generating olefins from secondary and tertiary alcohols where the first-order thermolytic Ei (during the elimination takes place—the two groups leave at about the same time and bond to each other concurrently) mechanism prevails. Preparation2
N S ClO
OO
H3C OH
MeOH, PhH
rt, 88−92%
CH3O2CN S Cl
O
O
H
NEt3, PhH
rt, 84−86%
CH3O2C N S NEt3O
O:NEt3
CH3O2CN S Cl
O
O
H
:NEt3
Mechanism5
MeO2C N S NEt3O
O
Ph
HO DH Ph
Ph
O D
HH
S NCO2Me
OO
HNEt3slow
SN2
H
Ph
Ph
O D
HH
S NCO2Me
OO
HNEt3Ph
fast
Ei Ph H
H Ph OD
S NCO2Me
O
O
HNEt3
84
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_41, © Springer-Verlag Berlin Heidelberg 2009
Example 1, On primary alcohols, the hydroxyl group does not eliminate but rather undergoes substitution3
O NH
OHOMe
H
H
Burgess reagent
THF, 21 oC, 9 h, 71%
O N
OMe
H
H Example 26
OSi
NOH
1.5 eq. Burgess, THF
reflux, 1 h, 97% OSi
N
Example 37
OHO
OBn
NCH O
OBn
NCHBurgess reagent
toluene, 50 oC, 60%
Example 48
2.5 equiv Burgess reagent
THF/CH2Cl2 (4:1)reflux, 6 h, 86%
O OH
OHBnOOBn
OBnO
BnOOBn
OBn
OS
N OO
CO2Me
α/β = (8:1)
Example 510
O
NNHBoc 2.5 equiv Burgess reagent
THF, reflux, 30 min., 86% N NHBoc
O
OHN
O2S
85
References 1 (a) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744–4745. (b)
Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A., Jr. J. Am. Chem. Soc. 1970, 92, 5224–5226. (c) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135–6141. (d) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973, 38, 26–31.
2 (a) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A.; Williams, W. M. Org. Synth. Coll. Edn. 1987, 6, 788–791. (b) Duncan, J. A.; Hendricks, R. T.; Kwong, K. S. J. Am. Chem. Soc. 1990, 112, 8433–8442.
3 Wipf, P.; Xu, W. J. Org. Chem. 1996, 61, 6556–6562. 4 Lamberth, C. J. Prakt. Chem. 2000, 342, 518–522. (Review). 5 Khapli, S.; Dey, S.; Mal, D. J. Indian Inst. Sci. 2001, 81, 461–476. (Review). 6 Miller, C. P.; Kaufman, D. H. Synlett 2000, 8, 1169–1171. 7 Keller, L.; Dumas, F.; D’Angelo, J. Eur. J. Org. Chem. 2003, 2488–2497. 8 Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Huang, X.
Chem. Eur. J. 2004, 10, 5581–5606. 9 Holsworth, D. D. The Burgess Dehydrating Reagent. In Name Reactions for Func-
tional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 189−206. (Review).
10 Li, J. J.; Li, J. J.; Li, J.; Trehan, A. K.; Wong, H. S.; Krishnananthan, S.; Kennedy, L. J.; Gao, Q.; Ng, A.; Robl, J. A.; Balasubramanian, B.; Chen, B.-C. Org. Lett. 2008, 10, 2897−2900.
86
Burke boronates
MeN
OOB
OO
Br
MeN
OOB
OO
B-protected haloboronic acids
HO
MeN
OOB
OO
MeN
OOB
OO
Stable boronic acid surrogates
SBr
Burke boronates can serve as B-protected haloboronic acids for a wide variety of applications in iterative cross-coupling.1–6 The corresponding boronic acids can be liberated using mild aqueous bases such as NaOH or NaHCO3.1–4 Burke boronates are also compatible with many synthetic reagents, enabling the synthesis of complex boronic acids from simple B-containing starting materials.3,6 They can also serve as stable building blocks for cross-coupling, i.e., under aqueous basic conditions, the corresponding boronic acid is released and coupled in situ.2,3,7 Moreover, Burke boronates are highly crystalline, monomeric, free-flowing solids that are indefinitely stable to benchtop storage under air and compatible with silica gel chromatography.1–3,6 Preparation:1,2,4,6
MeN
OOB
OOSBr
B(OH)2SBrHO2C CO2H
NMe
PhH:DMSO 10:1Dean-Stark
99%Burke boronate
MeN
OOB
OOTMS
BBr3 BBr2NaO2C CO2Na
NMe
CH2Cl2 CH3CN86%
30 mmol scale Burke boronate
Burke boronates can be conveniently prepared from the corresponding boronic ac-ids via complexation with N-methyliminodiacetic acid (MIDA)1,4 or from dibromoboranes via complexation with MIDA2−Na+
22,6 Alternatively, many of
these building blocks are now commercially available.
87
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_42, © Springer-Verlag Berlin Heidelberg 2009
Example 12
A wide range of selective couplings can be performed at the halide terminus of a B-protected haloboronic acid.
Pd(OAc)2, PPh3Et3N, DMF, 45 °C
90%
Pd2dba3, Fur3PDMF, 45 °C, 91%
piperidineTHF
23 °C, 73%
Pd(PPh3)4, CuI
MeN
OOB
OO
Br
MeN
OOB
OO
BO
O
MeMeMe
Me
MeN
OOB
OO
Ph
MeN
OOB
OO
Bu3Sn
MeN
OOB
OO
MeN
OOB
OO
TMS
MeN
OOB
OOMeO
O
SnBu3
ZnClBu3Sn
MeO
O
TMSB(OH)2Ph
Pd(OAc)2, SPhosTHF, 0 °C
66%
PdCl2(CH3CN)2SPhos, KOAc
PhMe45 °C, 71%
Pd(OAc)2
OB
OMe
Me
MeMe
2
SPhos, KFPhMe, 23°C
92 %Suzuki coupling Sonogashira coupling
Miyaura coupling
Negishi coupling
Stille coupling
Heck reaction
Example 22 Small molecule natural products can be prepared via iterative cross-coupling with B-protected haloboronic acids.
Me Me
Me
MeB(OH)2
MeN
OOB
OO
BrMe Me
Me
Me MeN
OOB
OO
Pd(OAc)2, SPhosK3PO4,Toluene
23 °C, 78%
Br
Me
O
H
1. aq. NaOH, THF, 23 °C2.
Me Me
Me
Me Me
O
H
all-trans-retinalK3PO4, THF, 23 °C66% over two steps
Pd(OAc)2 SPhos
88
Example 33
Burke boronates are stable to a wide range of synthetic reagents, including acids, non-aqueous bases, oxidants, reductants, electrophiles, and soft nucleophiles. This reagent compatibility enables multistep synthesis of complex boranes from simple boron-containing starting materials.
HO
MeN
OOB
OO
MeN
OOB
OO
PMBO
TfOH, THF0→23 °C , 5 h, 64%
PMBOC(NH)CCl3
23 °C, 1.5 h, 79%DDQ, DCM
TBSCl, Imid, THF
HF•Py, THF23 °C, 20 min
83%
23 °C, 9 h, 98%
CrO3, H2SO4Acetone
23 °C, 30 min90%
MeN
OOB
OO
TBSO
MeN
OOB
OO
O
HO
MeN
OOB
OO
OH
Me
O
NO
Bn
O
MeN
OOB
OO
O
EtO
MeN
OOB
OO
NO
morpholine NaBH(OAc)3
DCE, 23 °C, 8 h, 76%
O(EtO)2P
OEt
O
NaH, DMF23 °C, 30 min, 71%
Me
O
N O
Bn
O
H2O2, MeOHpH 6.0 buffer, 79%
n-BuOTf Et3N, DCM−78→0 °C, 2 h;
Swern and then
Example 42 Burke boronates can be hydrolyzed in situ under aqueous basic coupling condi-tions, as evidenced by this synthesis of the complex polyene skeleton of ampho-tericin B.
OAcMe
ClMe
TESOMe OAc
Me
Me
Me
TESONMe
OO B
OO
Me
Pd(OAc)2, XPhos1 N aq. NaOH
THF, 45 °C, 48%
Me
5
References
1. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716–6717. 2. Lee, S. J., Gray, K. C., Paek, J. S., Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466–
468. 3. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084–14085. 4. Ballmer, S. G.; Gillis, E. P.; Burke, M. D. Org. Synth. 2009, in press. 5. Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, in press. 6. Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron 2009, 65, 3130–3138. 7. Knapp, D. M.; Gillis, E. P., Burke, M. D. J. Am. Chem. Soc. 2009, 131, ASAP.
89
Cadiot–Chodkiewicz coupling Bis-acetylene synthesis from alkynyl halides and alkynyl copper reagents. Cf. Castro−Stephens reaction.
X Cu R2R1 R1 R2
X Cu R2oxidative
addition
XCu R2R1 R1
Cu(III) intermediate
reductive
eliminationCuX R1 R2
Example 13
OHBr
OH
cat. CuCl, NH2OH•HCl
EtNH2, MeOH30−40 oC, 70−80%
Example 27
TBS Br OH TBS OHcat. CuCl, NH2OH•HCl
30% n-BuNH2, H2O, 92%
Example 39
OMeMeO
HH
MeO OMe
Br Br
CuBr, NH2OH•HCl
piperidine, MeOHrt, 3.5 h, 80%
OMeMeO
MeO OMe n
n = 1 to 7
n = 1, 8%n = 2, 11%n = 3, 32%n = 4, 8%n = 5, 13%n = 6, 3%n = 7, 8%
Example 4, Cadiot–Chodkiewicz active template synthesis of rotaxanes and switchable molecular shuttles with weak intercomponent interactions10
90
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_43, © Springer-Verlag Berlin Heidelberg 2009
OH
1
1. 1 equiv n-BuLi THF, −78 oC
2. 1 equiv CuI, 0 oC3. 1 equiv 3 1 equiv 2
OO
N N
O O
O O
N N
O O
O O
trapping molecule 3 =O Br
2
References 1. Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci. 1955, 241, 1055−1057.
Both Paul Cadiot (1923−) and Wladyslav Chodkiewicz (1921−) are French chemists. 2. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., ed.; Dekker:
New York, 1969, 597−647. (Review). 3. Gotteland, J.-P.; Brunel, I.; Gendre, F.; Désiré, J.; Delhon, A.; Junquéro, A.; Oms, P.;
Halazy, S. J. Med. Chem. 1995, 38, 3207−3216. 4. Bartik, B.; Dembinski, R.; Bartik, T.; Arif, A. M.; Gladysz, J. A. New J. Chem. 1997,
21, 739−750. 5. Montierth, J. M.; DeMario, D. R.; Kurth, M. J.; Schore, N. E. Tetrahedron 1998, 54,
11741−11748. 6. Negishi, E.-i.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687−3689. 7. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841−6844. 8. Utesch, N. F.; Diederich, F.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M. Helv. Chim.
Acta 2004, 87, 698−718. 9. Bandyopadhyay, A.; Varghese, B.; Sankararaman, S. J. Org. Chem. 2006, 71, 4544–
4548−4548. 10. Berna, J.; Goldup, S. M.; Lee, A.-L.; Leigh, D. A.; Symes, M. D.; Teobaldi, G.; Zer-
betto, F. Angew. Chem., Int. Ed. 2008, 47, 4392−4396.
91
Camps quinoline synthesis Base-catalyzed intramolecular condensation of a 2-acetamido acetophenone (1) to a 2-(and possibly 3)-substituted-quinolin-4-ol (2), a 4-(and possibly 3)-substituted-quinolin-2-ol (3), or a mixture.
R1O
NH
OR2
R1
N
1 2
OH
R2NaOR
ROH
R2
N
3
OH
R1
Pathway A:
R1O
NH
OR2
1
R1
NH
O
O
R2H
OR
2R1
NH
O
R2
OH
H
H2O
Pathway B:
OR
R1O
NH
OR2
1
R2
NH
O
OR1
H
3R2
NH
O
R1
HOH
H2O
Example 11
69%
N OH
20%
N
OH
NH
O
NaOH, H2O
104 °C
O
92
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_44, © Springer-Verlag Berlin Heidelberg 2009
Example 26
HN
O
O
N
Me
MeN
NOH
Me
MeNaOH
H2O, 90%
References 1. (a) Camps, R. Chem. Ber. 1899, 32, 3228−3234. Rudolf Camps worked under Profes-
sor Engler from 1899 to 1902 at the Technische Hochschule in Karlsruhe, Germany. (b) Camps, R. Arch. Pharm. 1899, 237, 659−691.
2. Elderfield, R. C.; Todd, W. H.; Gerber, S. Heterocyclic Compounds Vol. 6, Elderfield, R. C., ed.; Wiley and Sons, New York, 1957, 576. (Review).
3. Clemence, F.; LeMartret, O.; Collard, J. J. Heterocycl. Chem. 1984, 21, 1345−1353. 4. Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm.
Bull. 1989, 37, 110−115. 5. Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc. 1951, 73, 2641−2647. 6. Barret, R.; Ortillon, S.; Mulamba, M.; Laronze, J. Y.; Trentesaux, C.; Lévy, J. J. Hete-
rocycl. Chem. 2000, 37, 241−244. 7. Pflum, D. A. Camps Quinolinol Synthesis. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 386−389. (Re-view).
93
Cannizzaro reaction Redox reaction between aromatic aldehydes, formaldehyde or other aliphatic al-dehydes without α-hydrogen. Base is used to afford the corresponding alcohols and carboxylic acids.
R H
O OH
R OH
OR OH2
R H
O
OH
OH
R H
OHO
R H
OO
Pathway A:
hydride
transfer R O
OR OR H
O
R OH
OH H R OH R O
O
Final deprotonation of the carboxylic acid drives the reaction forward.
Pathway B:
hydride
transfer R O
OR O
R H
O
R O
OH R OH
OR OH
acidic
workup
Example 14
CHO KOH powder
100 oC, 5 minsolvent-free
CO2HOH
41% 38%
Example 26
CHOOH
NNa
H
THF, 0 oC, 5 h, 76%
OHN
81% 76%
94
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_45, © Springer-Verlag Berlin Heidelberg 2009
Example 38
CHO 1 equiv TMG
H2O, rt, 10 h
CO2HOH
42% 43%
O2N O2N O2N
TMG = 1,1,3,3-tetramethylguanidine
Example 4, Desymmetrization by intramolecular Cannizzaro reaction9
CHO
O
O
O
CHO
2
1 M BaCl2
H2O, refluxquant.
CH2OH
O
O
O
CO2H
2
References 1. Cannizzaro, S. Ann. 1853, 88, 129−130. Stanislao Cannizzaro (1826−1910) was born
in Palermo, Sicily, Italy. In 1847, he had to escape to Paris for participating in the Si-cilian Rebellion. Upon his return to Italy, he discovered benzyl alcohol synthesis by the action of potassium hydroxide on benzaldehyde. Political interests brought Can-nizzaro to the Italian Senate and he later became its vice president.
2. Geissman, T. A. Org. React. 1944, 1, 94−113. (Review). 3. Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem. 2000, 65, 8381−8383. 4. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983−7985. 5. Reddy, B. V. S.; Srinvas, R.; Yadav, J. S.; Ramalingam, T. Synth. Commun. 2002, 32,
219−223. 6. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983−1986. 7. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.; Rosati, O. Org. Lett. 2005,
7, 1331−1333. 8. Basavaiah, D.; Sharada, D. S.; Veerendhar, A. Tetrahedron Lett. 2006, 47,
5771−5774. 9. Ruiz-Sanchez, A. J.; Vida, Y.; Suau, R.; Perez-Inestrosa, E. Tetrahedron 2008, 64,
11661−11665. 10. Yamabe, S.; Yamazaki, S. Org. Biomol. Chem. 2009, 7, 951−961.
95
Carroll rearrangement Thermal rearrangement of β-ketoesters followed by decarboxylation to yield γ-unsaturated ketones via anion-assisted Claisen rearrangement. It is a variant of the Claisen rearrangement (page 117).
O
O O OΔ
O
O O
O
O OH
O
O OH
Δ [3,3]-sigmatropic
rearrangement
O O
– CO2 α
βδ
γ
H
keto–enol
tautomerization
Example 1, Asymmetric Carroll rearrangement4,5
NN
OMe
O
ON
O
OLiOMe
LiN
N
OMe
CO2H
2.4 equiv LiTMP
toluene–100 °C to rt
de > 96%
Example 2, Hetero-Carroll rearrangement6
N
CH3
OH3C
OO
CH3
O 110 °Ctoluene
NH
CH3
H3C
O
O
CH3
N
CH3
H3C
O
CH3
O
OHO
82%
Example 37
H
H3C
HTESO
H3C
O
OS
OPh
OH NaH, xylenes, 140 °C, 82%H3C
HTESO
H3C
SO2PhTESO
H3C
H O
Me HSO2Ph
H
ONa
96
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_46, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Similar to Example 37
TESOH
O
O O2 eq. NaH, xylene
reflux, 96%
TESOH
O O
O
Carroll
rearrangement
TESOH
O
CO2H
CO2
TESOH
O
Example 58
O
OO
OMeMeO
LDA, THF
−78 oC to rt
CCl4
reflux, 86%
OMeMeO
Me
O
HO2C
OMeMeO
Me
O
References 1. (a) Carroll, M. F. J. Chem. Soc. 1940, 704−706. Michael F. Carroll worked at A.
Boake, Roberts and Co. Ltd., in London, UK. (b) Carroll, M. F. J. Chem. Soc. 1941, 507−511.
2. Ziegler, F. E. Chem. Rev. 1988, 88, 1423−1452. (Review). 3. Echavarren, A. M.; Mendosa, J.; Prados, P.; Zapata, A. Tetrahedron Lett. 1991, 32,
6421–6424. 4. Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed. 1995, 34,
2278−2280. 5. Enders, D.; Knopp, M. Tetrahedron 1996, 52, 5805–5818. 6. Coates, R. M.; Said, I. M. J. Am. Chem. Soc. 1977, 99, 2355−2357. 7. Hatcher, M. A.; Posner, G. H. Tetrahedron Lett. 2002, 43, 5009−5012. 8. Jung, M. E.; Duclos, B. A. Tetrahedron Lett. 2004, 45, 107−109. 9. Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. 2004, 69,
4626−4647. 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions
for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−87. (Review).
97
Castro–Stephens coupling Aryl–acetylene synthesis, Cf. Cadiot–Chodkiewicz coupling and Sonogashira coupling. The Castro–Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper.
+CuR1
1: copper acetylide
pyridine, Δ
3: disubstituted alkyne
R1 R2
R2 = aryl, vinyl, X = I, Br
R2X
2: sp2 halideor:
DMF, base, Δ
R1 = alkyl or aryl
CuII
Cu
LL
L
CC
R1
Cu
IL
L
C C R1
R2
I
CCR1
R2
Cu
LL
I
CC
R1
R1 C C Cu
+ ligands (solvent)
R2
R2
An alternative mechanism similar to that of the Cadiot–Chodkiewicz coupling:
Ar X Cu Roxidative
additionAr
XCu R Ar R
reductive
eliminationCuX
Cu(III) intermediate
Example 1, A variant, also known as the Rosenmund–von Braun synthesis of aryl nitriles2
N N
OBr CuCN
1-methyl-2-pyrrolininone
170 oC, 3 h, 55% N N
ONC
Example 24
H
CuSO4, NH2OH•HClaq. NH3, EtOH
ca. 95%Cu
N
OH
I
N
O
pyridine, Δ75%
98
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_47, © Springer-Verlag Berlin Heidelberg 2009
Example 35
N
N
OMeI
MeO
OO
Cu
pyridine, Δ
87% N
N
OMe
MeO
O
O
Example 48
O
I
Ocat. CuI, Ph3P, K2CO3
DMF, 120 oC, 37%
O
O
Example 5, In situ Castro–Stephens reaction10
MeO2C
O
MeO2C I
OH
MeO2C
OO
CO2Me
Cu2O, pyridine
100 oC, 43% References 1. (a) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163. Castro and Stephens
worked in the Department of Nematology and Chemistry at University of California, Riverside. (b) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313–3315.
2. Clark, R. L.; Pessolano, A. A.; Witzel, B.; Lanza, T.; Shen, T. Y.; Van Arman, C. G.; Risley, E. A. J. Med. Chem. 1978, 21, 1158–1162.
3. Staab, H. A.; Neunhoeffer, K. Synthesis 1974, 424. 4. Owsley, D.; Castro, C. Org. Synth. 1988, 52, 128–131. 5. Kundu, N. G.; Chaudhuri, L. N. J. Chem. Soc., Perkin Trans 1 1991, 1677–1682. 6. Kabbara, J.; Hoffmann, C.; Schinzer, D. Synthesis 1995, 299–302. 7. White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc.
2001, 123, 5407–5413. 8. Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487–3490. 9. Rawat, D. S.; Zaleski, J. M. Synth. Commun. 2002, 32, 1489–1494. 10. Bakunova, A.; Bakunov, S.; Wenzler, T.; Barszcz, T.; Werbovetz, K.; Brun, R.; Hall,
J.; Tidwell, R. J. Med. Chem. 2007, 50, 5807–5823. 11. Gray, D. L. Castro–Stephens coupling. In Name Reactions for Homologations-Part I;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 212−235. (Review).
99
Chan alkyne reduction Stereoselective reduction of acetylenic alcohols to E-allylic alcohols using sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH, also known as Red-Al) or Li-AlH4.
R1R
OHNaAlH2(OCH2CH2OCH3)2 in PhH
Et2O, heat R R1
OH
R1R
OHAlH2R2
R1
R
OH2↑
AlRR
H
R1
OAl
RR
R
Hworkup
R R1
OH
Example 13
OHLiAlH4
77%
OH
Example 24
Ph
OH
CO2Me
1.5 eq. Red-Al, −72 oC, 25 min.
then 5 eq. I2, −72 to −10 oC, THF, 2 h78%
Ph
OH
CO2Me
I
Example 36
OH
OTBDPS
OHOTBDPS
Cl
1. Red-Al, THF/PhMe −78 oC to rt, 4 h
2. NCS, −78 oC to rt 65%
Example 47
OO
O
OMeOMeMeO
Me
BnOOH
Me
Red-Al, Et2O
0 oC, 80%
OO
O
OMeOMeMeO
Me
BnOOH
Me
100
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_48, © Springer-Verlag Berlin Heidelberg 2009
References 1. Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem.
1976, 41, 3497−3505. Ka-Kong Chan was a chemist at Hoffmann−La Roche, Inc. in Nutley, NJ, USA.
2. Blunt, J. W.; Hartshorn, M. P.; Munro, M. H. G.; Soong, L. T.; Thompson, R. S.; Vaughan, J. J. Chem. Soc., Chem. Commun. 1980, 820−821.
3. Midland, M. M.; Gabriel, J. J. Org. Chem. 1985, 50, 1143−1144. 4. Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785−1787. 5. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073−4076. 6. Xu, S.; Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed. 2007, 46, 5746−5749. 7. Chakraborty, T. K.; Reddy, V. R.; Gajula, P. K. Tetrahedron 2008, 64, 5162−5167.
101
Chan–Lam C–X coupling reaction Arylation of a wide range of NH/OH/SH substrates by oxidative cross-coupling with boronic acids in the presence of catalytic cupric acetate and either triethyl-amine or pyridine at room temperature in air. The reaction works for amides, amines, anilines, azides, hydantoins, hydrazines, imides, imines, nitroso, pyrazi-nones, pyridones, purines, pyrimidines, sulfonamides, sulfinates, sulfoximines, ureas, alcohols, phenols, and thiols. It is also the mildest method for N/O-vinylation. The boronic acids can be replaced with siloxanes or stannanes. The mild condition of this reaction is an advantage over Buchwald–Hartwig’s Pd-catalyzed cross-coupling. The Chan–Lam C–X bond cross-coupling reaction is complementary to Suzuki–Miyaura’s C–C bond cross-coupling reaction.
M = B(OH)2, B(OR)2, B(OR)3−, BF3
−, SnMe3, Si(OMe)3.X = N, O, S, Se, Te.
Ar M H XRcat. Cu(AcO)2
airAr XR
N
NR
cat. Cu(AcO)2
air, > 90%
N
HNB(OH)2
R
Example 11a,d
NH
B(OH)2
Cu(OAc)2, pyridinert, 48 h, air
74%
H3C
N CH3
Mechanism:1c,d,17
NHCu(OAc)2, pyridine
coordination anddeprotonation
CuIIL L
N OAc
Ph
pyridinium acetate
B(OH)2H3C
transmetallation
CuIIL L
N
PhCH3
AcOB(OH)2+ [CuII]
– [CuI]
N CH3reductive
elimination
CuIIIL L
N
PhCH3
102
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_49, © Springer-Verlag Berlin Heidelberg 2009
Example 24
OH B(OH)2
1.1 eq Cu(OAc)2, TEArt, 24 h, air
52%
O
Example 35
t-BuO2C NH
CO2Me
O
B(OH)2OMe
Cu(OAc)2TEA, air
54%
OH
t-BuO2C NH
CO2Me
OMe
O
O
Example 413
BnO
ONH
O
O N(HO)2B
Cu(OAc)2/Et3N/Py93% (α-ester assistance, acetal lower yield,e.g., dimethyl acetal, 23%)
BnO
ON
O
O
N
1eq/3 eq/ 3 eq4 Å MS, air
Example 514
NH
CO2Me
N
CO2MeB(OH)2
NaHMDS, Cu(AcO)2DMAP, air, 95 oC
93% Example 615
B(OH)2NH2
0.1 eq Cu2OMeOH, air, rt
92%NH4OH
References 1. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett.
1998, 39, 2933–2936. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Win-ters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2949. Dominic Chan is a chemist at DuPont Crop Protection, Wilmington, DE, USA. He did his PhD research with Prof. Barry Trost at the University of Wisconson, Madison. Pat-rick Lam is a research director at Bristol–Myers Squibb, Princeton, NJ, USA. He was formerly with DuPont Pharmaceuticals Company. He did his PhD research with Prof. Louis Friedrich at the Univeristy of Rochester and Postdoc research with Prof. Mi-
103
chael Jung and the late Prof. Donald Cram at UCLA. (c) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937–2940. Prof. Evans’ group found out about the discovery of this reaction on a National Organic Symposium poster and be-came interested in the O-arylation because of his long interest in vancomycin total synthesis. (d) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674–676. (e) Lam, P. Y. S.; Bonne, D.; Vin-cent, G.; Clark, C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44, 1691–1694.
2. Reviews: (a) Chan, D. M. T.; Lam, P. Y. S., Book chapter in Boronic Acids Hall, ed. 2005, Wiley–VCH, 205–240. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
3. Catalytic copper: (a) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. (b) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–2079. (c) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397–4400. (d) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236. (e) Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett 2004, 1095–1097.
4. Vinyl boronic acids: Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003, 44, 4927–4931.
5. Intramolecular: Decicco, C. P.; Song, Y.; Evans, D.A. Org. Lett. 2001, 3, 1029–1032. 6. Solid phase: (a) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S. Tetrahedron
Lett. 1999, 40, 1623–1626. (b) Combs, A. P.; Tadesse, S.; Rafalski, M.; Haque, T. S.; Lam, P. Y. S. J. Comb. Chem. 2002, 4, 179–182.
7. Boronates/borates: (a) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863–3865. (b) Yu, X. Q.; Yamamoto, Y.; Miyuara, N. Chem. Asian J. 2008, 3, 1517–1522.
8. Siloxanes: (a) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600–7601. (b) Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429.
9. Stannanes: Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2002, 43, 3091–3094.
10. Thiols: (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019–2022. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. . Org. Lett. 2002, 4, 4309–4312.
11. Sulfinates: (a) Beaulieu, C.; Guay. D.; Wang, C.; Evans, D. A. Tetrahedron Lett. 2004, 45, 3233–3236. (b) Huang, H.; Batey, R. A. Tetrahedron. 2007, 63, 7667–7672. (c) Kar, A.; Sayyed, L. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.; Tse, M. K. Org. Lett. 2007, 9, 3405–3408.
12. Sulfoximines: Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667–2669. 13. β-Lactam: Wang, W.; Devsathale, P.; et al. Bio. Med. Chem. Lett. 2008, 18, 1939–
1944. 14. Cyclopropyl boronic acid: Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki,
M.; Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653–1655. 15. Ammonia: Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Ang. Chem., Int. Ed. 2009, 48, 1114–
1116. 16. Alcohol: Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381–1384. 17. Mechanism: (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196–
9197. (b) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
104
Chapman rearrangement Thermal aryl rearrangement of O-aryliminoethers to amides.
Ar OPh
NAr1 Δ
Ar NAr1
O
Ph
Ar O
N:Ar1
Ar NAr1
O
Ph
NO
Ar1
Ar
SNAr
oxazete intermediate
Example 12
ClMeO2C
NaO
MeO
N Ph
ClNaOEt, EtOH/Et2O
0 oC to rt, 48 hMeO
N Ph
O
MeO2CCl
210−215 oC, 70 min
28% for 2 steps
MeO
N
PhO
ClMeO2C
MeO
NH
ClHO2C
Example 24
Ph
O
N
Ph
Ph
300 oC
30 min., 87%
PhN
Ph
Ph O
105
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_50, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Double Chapman rearrangement10
OO
MeO2C CO2MeNMe2
N
Me2N
N
C12H25 C12H25
110−140 oC
70−74%
MeO2C CO2Me
NN
C12H25 C12H25
O
NMe2
O
Me2N
Example 4, Chapman-like thermal rearrangement11
SN
OR
OO
Δ
SNR
O
OO
References 1. Chapman, A. W. J. Chem. Soc. 1925, 127, 1992−1998. Arthur William Chapman was
born in 1898 in London, England. He was a Lecturer in Organic Chemistry and later became Registrar of the University of Sheffield from 1944 to 1963.
2. Dauben, W. G.; Hodgson, R. L. J. Am. Chem. Soc. 1950, 72, 3479−3480. 3. Schulenberg, J. W.; Archer, S. Org. React. 1965, 14, 1−51. (Review). 4. Relles, H. M. J. Org. Chem. 1968, 33, 2245−2253. 5. Shawali, A. S.; Hassaneen, H. M. Tetrahedron 1972, 28, 5903−5909. 6. Kimura, M.; Okabayashi, I.; Isogai, K. J. Heterocycl. Chem. 1988, 25, 315−320. 7. Farouz, F.; Miller, M. J. Tetrahedron Lett. 1991, 32, 3305−3308. 8. Dessolin, M.; Eisenstein, O.; Golfier, M.; Prange, T.; Sautet, P. J. Chem. Soc., Chem.
Commun. 1992, 132−134. 9. Shohda, K.-I.; Wada, T.; Sekine, M. Nucleosides Nucleotides 1998, 17, 2199−2210. 10. Marsh, A.; Nolen, E. G.; Gardinier, K. M.; Lehn, J. M. Tetrahedron Lett. 1994, 35,
397−400. 11. Almeida, R.; Gomez-Zavaglia, A.; Kaczor, A.; Cristiano, M. L. S.; Eusebio, M. E. S.;
Maria, T. M. R.; Fausto, R. Tetrahedron 2008, 64, 3296−3305.
106
Chichibabin pyridine synthesis Condensation of aldehydes with ammonia to afford pyridines.
3 R CHO NH3N
RR
R
H3N:
RO
HR
NH2
H
H3N:
ROH
NH2
HR
NH
H
enamine imine
:NH3
RO
H
RO
H
HR
O
H
Aldol
condensation
RO
H
RH
OH
H− H2O R
O
H
R
HN
R
:
Michael
addition
RO
RN
RH
RH
O
RN
R: N
RR
R
OHH
H
H3N H
H
N
RR
R
OHH
HN
RR
R
H
H
autoxidation
[O] N
RR
R
Example 14
CHOO
NH4OAc, HOAc
reflux, 1 h, 68%N
107
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_51, © Springer-Verlag Berlin Heidelberg 2009
Example 28
N
HO
MeTroc
CH2 CHO N
1. AcOH, rt, 1 d, 49%
2. Zn, HCl, MeOH, 65 oC, 72%
N
HO
MeTroc
CH2N
Cl10
CH210
N
HO
MeTroc
Example 39
OO2NO
CF3OHCCH3CO2NH4, MeOH
reflux, 4 h, 45%
OO2NN
O NO2
CF3
Example 4, An abnormal Chichibabin reaction10
H
OBr 1 equiv BnNH3Cl
0.5 equiv Yb(OTf)3
H2O/dioxane, rt, 65%
N
ArAr
ArBn
N
Ar Ar
Bn
dehydration
6πN
Ar Ar
Bn Ar
[O]benzaldehyde
TfO
References 1. Chichibabin, A. E. J. Russ. Phys. Chem. Soc. 1906, 37, 1229. Alexei E. Chichibabin
(1871−1945) was born in Kuzemino, Russia. He was Markovnikov’s favorite student. Markovnikov’s successor, Zelinsky (of Hell–Volhard–Zelinsky reaction fame) did not
108
want to cooperate with the pupil and gave Chichibabin a negative judgment on his Ph.D. work, earning Chichibabin the nickname “the self-educated man.”
2. Sprung, M. M. Chem. Rev. 1940, 40, 297−338. (Review). 3. Frank, R. L.; Riener, E. F. J. Am. Chem. Soc. 1950, 72, 4182−4183. 4. Weiss, M. J. Am. Chem. Soc. 1952, 74, 200−202. 5. Kessar, S. V.; Nadir, U. K.; Singh, M. Indian J. Chem. 1973, 11, 825−826. 6. Shimizu, S.; Abe, N.; Iguchi, A.; Dohba, M.; Sato, H.; Hirose, K.-I. Microporous
Mesoporous Materials 1998, 21, 447−451. 7. Galatasis, P. Chichibabin (Tschitschibabin) Pyridine Synthesis. In Name Reactions in
Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 308−309. (Review).
8. Snider, B. B.; Neubert, B. J. Org. Lett. 2005, 7, 2715−2718. 9. Wang, X.-L.; Li, Y.-F.; Gong, C.-L.; Ma, T.; Yang, F.-C. J. Fluorine Chem. 2008,
129, 56−63. 10. Burns, N. Z.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 205−208. 11. Liaw, D.-J.; Wang, K.-L.; Kang, E.-T.; Pujari, S. Pu.; Chen, M.-H.; Huang, Y.-C.;
Tao, B.-C.; Lee, K.-R.; Lai, J.-Y. J. Polymer Sci., A: Polymer Chem. 2009, 47, 991−1002.
109
Chugaev elimination Thermal elimination of xanthates to olefins.
ROH R
O S
S
1. CS2, NaOH
2. CH3I
ΔR OCS CH3SH
xanthate
RO S
S
Δ HS
O
S
R
CH3SH↑R SO
SC S↑O
H
Example 14
OH
OH OH
1. NaH, CS2; MeI, 90%
2. HMPA, 230 oC, 90%
Example 25
OOHO
H
O
OHH
CS2, MeI, NaH
THF, rt, 2 h, 51%
OOO
H
O
OHH
S
S
dodecane
reflux (216 oC)48 h, 74%
OO
H
O
OHH
Example 3, Chugaev syn-elimination is followed by an intramolecular ene reac-tion6
O
O N
OH
Cbz
CS2, MeI, NaH
THF, 92%
O
O N
O
Cbz
S
S
110
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_52, © Springer-Verlag Berlin Heidelberg 2009
NaHCO3, Ph2O
280 oC, 25 minChugaev
NCbz
OOH N
CbzO
O72%
Alder ene
References 1. Chugaev, L. Ber. 1899, 32, 3332. Lev A. Chugaev (1873−1922) was born in Moscow,
Russia. He was a Professor of Chemistry at Petrograd, a position once held by Dimitri Mendeleyev and Paul Walden. In addition to terpenoids, Chugaev also investigated nickel and platinum chemistry. He completely devoted his life to science. The light in Chugaev’s study would invariably burn until 4 or 5 a.m.
2. Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1975, 23, 467−472. 3. Ho, T.-L.; Liu, S.-H. J. Chem. Soc., Perkin Trans. 1 1984, 615−617. 4. Fu, X.; Cook, J. M. Tetrahedron Lett. 1990, 31, 3409−3412. 5. Meulemans, T. M.; Stork, G. A.; Macaev, F. Z.; Jansen, B. J. M.; de Groot, A. J. Org.
Chem. 1999, 64, 9178−9188. 6. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181−3183. 7. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4523−4526. 8. Fuchter, M. J. Chugaev elimination. In Name Reactions for Functional Group Trans-
formations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 334−342. (Review).
9. Ahmed, S.; Baker, L. A.; Grainger, R. S.; Innocenti, P.; Quevedo, C. E. J. Org. Chem. 2008, 73, 8116−8119.
111
Ciamician–Dennsted rearrangement Cyclopropanation of a pyrrole with dichlorocarbene generated from CHCl3 and NaOH. Subsequent rearrangement takes place to give 3-chloropyridine.
NH N
ClCHCl3
NaOH
Cl3C HOH
CCl2H2OCl
− Cl:CCl2
carbene
NH N
ClCCl2 NCl
Cl
H
HO Example 14
N
Cl2 eq. PhHgCCl3
PhH, Δ, 54%N
H Example 25
NH
NH
HNHN
N
N
N
N
Cla Clb
Cla
Clb
ClaClb
Cla
Clb
NaO2CCl3
26%
References 1. Ciamician, G. L.; Dennsted, M. Ber. 1881, 14, 1153. Giacomo Luigi Ciamician
(1857−1922) was born in Trieste, Italy. Ciamician is considered the father of modern organic photochemistry.
2. Wynberg, H. Chem. Rev. 1960, 60, 169−184. (Review). 3. Wynberg, H. and Meijer, E. W. Org. React. 1982, 28, 1−36. (Review). 4. Parham, W. E.; Davenport, R. W.; Biasotti, J. B. J. Org. Chem. 1970, 35, 3775−3779. 5. Král, V.; Gale, P. A.; Anzenbacher, P. Jr.; K. Jursíková; Lynch, V.; Sessler, J. L. J.
Chem. Soc., Chem. Comm. 1998, 9−10. 6. Pflum, D. A. Ciamician–Dennsted Rearrangement. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 350−354. (Review).
112
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_53, © Springer-Verlag Berlin Heidelberg 2009
Claisen condensation Base-catalyzed condensation of esters to afford β-keto esters.
OR1
OR
base OR1
O
RR2R2 OR3
OO
OR3R2
O
OR1
OR
OR1
OR
H
B:
deprotonation condensation
OR1
O
RR3O
OR2
OR1
O
RR2
O
Example 14
O Ph
O t-BuOK, solvent-free
90 oC, 20 min., 84%O Ph
OPh
O
Ph
Ph
Example 26
CbzHN CO2Me
PhO
t-BuO
CbzHN
Ph
O
O
Ot-Bu
3.5 eq. LDA, THF −45 to −50 oC
then H+, 97%
Example 3, Retro-Claisen condensation9
O O5 equiv H2O
5 mol% In(OTf)3
neat, 80 oC, 24 h85%
OH
O O
O OIn HH2O:
O OHO
In
113
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_54, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Solvent-free Claisen condensation10
OBn
O= 13CKOt-Bu, 100 oC, 30 min.
solvent-free, 51%
O
OBn
O
References 1 Claisen, R. L.; Lowman, O. Ber. 1887, 20, 651. Rainer Ludwig Claisen (1851−1930),
born in Cologne, Germany, probably had the best pedigree in the history of organic chemistry. He apprenticed under Kekulé, Wöhler, von Baeyer, and Fischer before embarking on his own independent research.
2 Hauser, C. R.; Hudson, B. E. Org. React. 1942, 1, 266−302. (Review). 3 Schäfer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1−203. (Review). 4 Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983−7985. 5 Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581−596. (Review). 6 Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett. 2002, 4,
447−449. 7 Mogilaiah, K.; Reddy, N. V. Synth. Commun. 2003, 33, 73−78. 8 Linderberg, M. T.; Moge, M.; Sivadasan, S. Org. Pro. Res. Dev. 2004, 8, 838−845. 9 Kawata, A.; Takata, K.; Kuninobu, Y.; Takai, K. Angew. Chem., Int. Ed. 2007, 46,
7793−7795. 10 Iida, K.; Ohtaka, K.; Komatsu, T.; Makino, T.; Kajiwara, M. J. Labelled Compd. Ra-
diopharm. 2008, 51, 167−169.
114
Claisen isoxazole synthesis Cyclization of β-keto esters with hydroxylamine to provide 3-hydroxy-isoxazoles (3-isoxazolols).
O O
R1R2
OR
ON
R2 OH
R1
NH2OH
− H2O
O O
R1R2
OR
:NH2OH
O O
R1R2
NH
OH
O
R1R2
NH
OHORO
ON
R2 OH
R1ONH
R2 O
R1
HO ONH
R2 O
R1
− H2O
3-isoxazolol
A side reaction:
HON O
R1R2
OR
OHO O
R1R2
OR NH2OH
:NH2OH
H
− H2O:
N O
R1R2
OR
ON
R2
R1 O
O:H
ON
R1
R2
ORO H
5-isoxazolone
Example 1, A thio-analog6
SH O
NH2NMeO
O
1. aqueous NH3, 67%
2. H2S, HCl, EtOH, 53%
O O
OEtNMeO
O
115
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_55, © Springer-Verlag Berlin Heidelberg 2009
SN
R OH
I2, K2CO3, 59%
NMeO
O Example 27
O
OO
O
HO
RO
OO
O53−91%
HN OBoc
Boc
O
ClR , pyr., 0 oC
74−100%For R = Ph:(PhCO)2O, DMF
Meldrum’s acid
O O
R NO
N
OH
ROBoc
Boc
HCl
76−99%
R = Me, Et, i-Pr, cyclopropyl,cyclohexyl, Ph, Bn, neopentyl
Example 38
O O
OMe
ON
OHNH2OH•HCl, NaOH
MeOH, −50 oC, 2 hthen 85 oC, 1 h, 65%
References 1. (a) Claisen, L; Lowman, O. E. Ber. 1888, 21, 784. (b) Claisen, L.; Zedel, W. Ber.
1891, 24, 140. (c) Hantzsch, A. Ber. 1891, 24, 495−506. 2. Barnes, R. A. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York,
1957; Vol. 5, p 474ff. (Review). 3. Loudon, J. D. In Chemistry of Carbon Compounds; Rodd, E. H., Ed.; Elsevier: Am-
sterdam, 1957; Vol. 4a, p. 345ff. (Review). 4. McNab, H. Chem. Soc. Rev. 1978, 7, 345−358. (Review). 5. Chen, B.-C. Heterocycles 1991, 32, 529−597. (Review). 6. Frølund, B.; Kristiansen, U.; Brehm, L.; Hansen, A. B.; Krogsgaard-Larsen, K.; Falch,
E. J. Med. Chem. 1995, 38, 3287−3296. 7. Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, K. J. Org. Chem. 2000, 65,
1003−1007. 8. Madsen, U.; Bräuner-Osborne, H.; Frydenvang, K.; Hvene, L.; Johansen, T.N.; Niel-
sen, B.; Sánchez, C.; Stensbøl, T.B.; Bischoff, F.; Krogsgaard-Larsen, K. J. Med. Chem. 2001, 44, 1051−1059.
9. Brooks, D. A. Claisen Isoxazole Synthesis. In Name Reactions in Heterocyclic Chem-istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 220−224. (Review).
116
Claisen rearrangements The Claisen, para-Claisen rearrangements, Belluš–Claisen rearrangement; Corey–Claisen, Eschenmoser–Claisen rearrangement, Ireland–Claisen, Kazmaier–Claisen, Saucy–Claisen; orthoester Johnson–Claisen, along with the Carroll rear-rangement, belong to the category of [3,3]-sigmatropic rearrangements. The Claisen rearrangement is a concerted process and the arrow pushing here is merely illustrative.
O
R
O
R
O
RΔ, [3,3]-sigmatropic
rearrangement
1 23
1 23
1 23
1 23
π2S
π2S
σ2S3
4
σ2S
π2S
π2S 4
O O O1 1 12
45
6
2 2
4 45
66
5
3
chair-like boat-like
Example 17
O
BnO
BnO O
BnO
BnOO
O O
n-decane/toluene 5:1
180 oC, 70%
O
OBn
BnOO
OBnBnO
O
O
O
Example 28
O
O
Et2AlCl, hexanes
−78 oC, 81%
O
OH
Example 39
O
Et Ph
SiMe3OHC
Et Ph
SiMe31 mol% Ir(PCy3)3
+
PPh3, Δ, 50% yieldsyn:anti 95:85, 91% ee
117
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_56, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Asymmetric Claisen rearrangement10
MeO CH3
O
O
OBn
N N
OO
t-Bu t-BuCu
H2O OH2
2+
2 SbF6−
CH2Cl2, rt, 12 hOMe
CH3
O
O
BnO
98%, > 90% de, 99% eecat. =
CF3CH2OHcat, 7.5 mol%
Example 5, Asymmetric Claisen rearrangement11
MeO CH3
O
O
H3C
MeO
O
O
CH3 CH3
73%, 96% eeNH
NH
NH2
N NPh PhB
CF3
CF3
4
–
20 mol%, hexane, 8 days, 35 °C
References 1. Claisen, L. Ber. 1912, 45, 3157−3166. 2. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1−252. (Review). 3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-
mon, 1991, Vol. 5, 827−873. (Review). 4. Ganem, B. Angew. Chem., Int. Ed. 1996, 35, 937−945. (Review). 5. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43−50. (Review). 6. Castro, A. M. M. Chem. Rev. 2004, 104, 2939−3002. (Review). 7. Jürs, S.; Thiem, J. Tetrahedron: Asymmetry 2005, 16, 1631−1638. 8. Vyvyan, J. R.; Oaksmith, J. M.; Parks, B. W.; Peterson, E. M. Tetrahedron Lett. 2005,
46, 2457−2460. 9. Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232–4233. 10. Körner, M.; Hiersemann, M. Org. Lett. 2007, 9, 4979–4982. 11. Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–9229. 12. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions
for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−43. (Review).
118
para-Claisen rearrangement Further rearrangement of the normal ortho-Claisen rearrangement product gives the para-Claisen rearrangement product.
ORR
OHRR
Δ
Mechanism 1:
ORR
OHRR
ortho-
Claisen
ORR
dienone
Cope
rearrangement
Mechanism 2:
ORR
OHRR
ORR
Dewar intermediate
H2C CH2
Mechanism 3:
ORR
OHRRO
RR[3,3]-sigmatropic
rearrangement
ORR
H
119
Example 16
OHO CHO
160−170 oC
OHHO CHO
58%
OHHO
25.5%CHO
OHHO CHO
4.6%
Example 27
HO O
MeMe
CO2Me
PhNEt2
reflux O OHO
Me
Me
80%O OHO
12%
Me
Me
Example 38
O
OTBSO220 oC
xylene, 70%O
O
OTBSO
OH Example 410
OO
MOMO OMOMPhNMe2, reflux
200 oC, 64%
OOH
MOMO OMOM
References 1. Alexander, E. R.; Kluiber, R. W. J. Am. Chem. Soc. 1951, 73, 4304–4306. 2. Rhoads, S. J.; Raulins, R.; Reynolds, R. D. J. Am. Chem. Soc. 1953, 75, 2531–2532. 3. Dyer, A.; Jefferson, A.; Scheinmann, F. J. Org. Chem. 1968, 33, 1259–1261. 4. Murray, R. D. H.; Lawrie, K. W. M. Tetrahedron 1979, 35, 697–699. 5. Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Chem. Commun. 1986, 1264–
1266. 6. Kilényi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591–2594. 7. Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Perkin Trans. 1 1994, 3101–
3107. 8. Pettus, T. R. R.; Inoue, M.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc. 2000,
122, 6160–6168. 9. Al-Maharik, N.; Botting, N. P. Tetrahedron 2003, 59, 4177–4181. 10. Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2007, 70, 1507–1509.
120
Abnormal Claisen rearrangement Further rearrangement of the normal Claisen rearrangement product with the β-carbon becoming attached to the ring.
OHα
β δ
α
β δ
O
δ
αβ
Δ
O [3,3]-sigmatropicrearrangement
"normal Claisen"
O
H
tautomerization δ
αβ
δ
βα
OHOH
OH
ene
reaction
[1,5]-H-atom
shift δ
βα
δ α
βα
β δ
Example 13
O
Me
PhNEt2, 230 oC
5.5 h, 63%
OH
Menormal, 58%
OH
Meabnormal, 42%
O
Me
10 equiv HSi(NMe2)2PhNEt2, 230 oC
8.0 h, 70%
OH
Menormal, > 99%
OH
Meabnormal, < 1%
Example 2, Enantioselective aromatic Claisen rearrangement4
OHO
Et3N, −23 oC, 2 d 92%, 95% ee
OHOH
NB
N
Ph Ph
Br
SO2
SO2
121
Example 35
OMeMeO
O
CHOMeOPhNEt2
180 oC40%
OMeO
MeO
CHO
OMe
kodsurenin M Example 46
OO
O
Tol., 180 oC
24 h, 65%
OO
O
= 13C
Example 57
OAlM3, CH2Cl2
OH
OH50% 50%
References 1. Hansen, H.-J. In Mechanisms of Molecular Migrations; vol. 3, Thyagarajan, B.
S., ed.; Wiley-Interscience: New York, 1971, pp 177−236. (Review). 2. Kilényi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56,
2591−2594. 3. Fukuyama, T.; Li, T.; Peng, G. Tetrahedron Lett. 1994, 35, 2145−2148. 4. Ito, H.; Sato, A.; Taguchi, T. Tetrahedron Lett. 1997, 38, 4815−4818. 5. Yi, W. M.; Xin, W. A.; Fu, P. X. J. Chem. Soc., (S), 1998, 168. 6. Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.; Nieuwenhuyzen, M. Tet-
rahedron Lett. 2001, 42, 4561−4564. 7. Wipf, P.; Rodriguez, S. Ad. Synth. Catal. 2002, 344, 434−440. 8. Puranik, R.; Rao, Y. J.; Krupadanam, G. L. D. Indian J. Chem., Sect. B 2002,
41B, 868−870. 9. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reac-
tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Ho-boken, NJ, 2009, pp 33−87. (Review).
122
Eschenmoser–Claisen amide acetal rearrangement [3,3]-Sigmatropic rearrangement of N,O-ketene acetals to yield γ,δ-unsaturated amides. Since Eschenmoser was inspired by Meerwein’s observations on the interchange of amide, the Eschenmoser–Claisen rearrangement is sometimes known as the Meerwein–Eschenmoser–Claisen rearrangement.
NMe2
OMeMeO
R R1
OH
R R1
CONMe2Δ
NMe2
OMeMeO
NMe2
OMeOMe
:
R R1
O:
R R1
OH
OMeMe2NH
R R1
OH
NMe2: OMeH NMe2
OMe
R R1
O
NMe2
R R1
[3,3]-sigmatropic
rearrangement
CONMe2
Example 14
O PhF3C
OH
CH3C(OMe)2NMe2
PhH, 100 oC, 2 h, 75%O
NMe2Ph
CF3 O
Example 25
O
H3C CH3
N
HH
OLi
CH3
O
N
CH3
CH3
OMe CH3
CH3
*ArHN
O
LiNEt2, THF
–78 °C to rt5 h, 78 %
(dr 97:3)
123
Example 36
HO
H OTBS
O
OTBS
TBS
H OTBS
O
OTBS
TBS
HH
NMe2
O
NMe2
MeO OMe
xylene, 150 °C18 h, 91%
OPMB OPMB
Example 48
HO CO2Me
5 eq. CH3C(OMe)2NMe2
xylene, reflux, 48 h, 50%
CO2Me
NMe2
O
References 1. Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. Ann. 1961, 641, 1−39. 2. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47,
2425−2429. Albert Eschenmoser (Switzerland, 1925−) is known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Wood-ward in 1973. He now holds dual appointments at both ETH Zürich and the Scripps Research Institute in La Jolla, CA.
3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-mon, 1991, Vol. 5, 827−873. (Review).
4. Konno, T.; Nakano, H.; Kitazume, T. J. Fluorine Chem. 1997, 86, 81−87. 5. Metz, P.; Hungerhoff, B. J. Org. Chem.1997, 62, 4442–4448. 6. Kwon, O. Y.; Su, D. S.; Meng, D. F.; Deng, W.; D’Amico, D. C.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 1998, 37, 1877–1880. 7. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43−50. (Review). 8. Loh, T.-P.; Hu, Q.-Y. Org. Lett. 2001, 3, 279−281. 9. Castro, A. M. M. Chem. Rev. 2004, 104, 2939−3002. (Review). 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions
for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 60−68. (Review).
124
Ireland–Claisen (silyl ketene acetal) rearrangement Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of allylic ester enolates with trimethylsilyl chloride, to yield γ,δ-unsaturated carboxylic acids. The Ireland–Claisen rearrangement seems to be advantageous to the other variants of the Claisen rearrangement in terms of E/Z geometry control and mild conditions.
O
OLDA, then
Me3SiCl
CO2H
O
OLDA, then
Me3SiClO
OSiMe3
O
OSiMe3H CO2HΔ, [3,3]-sigmatropic
rearrangement
Example 12
O
O
OO
SS SS
OO
CO2TBS
S
SH O
HOTBSH
OO
LDA, TBSCl
THF, reflux77%
Example 23
O
N
O
Bn
TIPSOTf, Et3N
PhH, rt, 62%NBn
CO2TIPS
Example 3, Enantioselective ester enolate-Claisen Rearrangement6
O
CH3
O
H3C
CO2H
H3CNB
N
PhPh
Br
SO2
SO2
CF3
CF3
F3C
F3C
pentaisopropylguanidine, –94 to 4 °C86%, dr > 98:2, > 98% ee
110 mol%
125
Example 4, A modified Ireland–Claisen rearrangement8
O
F
FO
F
HOF
F
O
F
BBr3, Et3N, PhMechiral ligand
−78 to rt, 63%, > 99% ee
Example 59
O
OO
OPMP
KHMDS, TMSCl, THF
−78 to 25 oC, 1 h, 81% O
CO2HPMPO
References 1. Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897−5898. Also J. Am.
Chem. Soc. 1976, 98, 2868−2877. Robert E. Ireland obtained his Ph.D. from William S. Johnson before becoming a professor at the University of Virginia and later at the California Institute of Technology. He is now retired.
2. Begley, M. J.; Cameron, A. G.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1986, 1933–1938.
3. Angle, S. R.; Breitenbucher, J. G. Tetrahedron Lett. 1993, 34, 3985−3988. 4. Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17−29. (Review). 5. Ganem, B. Angew. Chem., Int. Ed. 1996, 35, 936−945. (Review). 6. Corey, E.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229−1230. 7. Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron
2002, 58, 2905−2928. (Review). 8. Churcher, I.; Williams, S.; Kerrad, S.; Harrison, T.; Castro, J. L.; Shearman, M. S.;
Lewis, H. D.; Clarke, E. E.; Wrigley, J. D. J.; Beher, D.; Tang, Y. S.; Liu, W. J. Med. Chem. 2003, 46, 2275−2278.
9. Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 3465−3468.
10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 45−51. (Review).
126
Johnson–Claisen orthoester rearrangement Heating of an allylic alcohol with an excess of trialkyl orthoacetate in the presence of trace amounts of a weak acid gives a mixed orthoester. Mechanistically, the or-thoester loses alcohol to generate the ketene acetal, which undergoes [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated ester.
R R1
OH CH(OR2)3
H+ R R1
CO2R2
R R1
OH CH(OR2)3
H+
R R1
OH
OR2R2OH
R R1
OH
OR2:B:
R R1
O
OR2
[3,3]-sigmatropic
rearrangement R R1
CO2R2
Example 12
OH
CH3
CO2Et
OOEt
H
H3C
CH3C(OEt)3EtCO2H (cat.)
xylene, Δ, 3 h 72%
Example 23
TBSO
THPO
H
OPh
HO
THPO
TBSO
THPO
OPhTHPO
•H
CO2EtMeCO2H (cat.)CH3C(OEt)3
170 °C, 30 min 77%
Example 34
ClOH
ClOTBS
CH3C(OCH3)3, TsOH
170 oC, 55%OMe
Cl
OTBS
ClO
127
Example 49
N
OMe
OH
CH3C(OCH3)3cat. CH3CH2CO2H
reflux, 77%
N
OMe
OMe
O
Example 510
O
OOTBS
OOO
OHH
(EtO)3CCH3
pivalic acidxylene, 140 °C
54%, E:Z > 95:5
O
TBSOOTBS
OOO
OHH
EtO2C
E
TBSOH
References 1. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-t.; Faulkner,
D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741–743. William S. Johnson (1913−1995) was born in New Rochelle, New York. He earned his Ph.D. in only two years at Harvard under Louis Fieser. He was a professor at the University of Wiscon-sin for 20 years before moving to Stanford University, where he was credited with building the modern-day Stanford Chemistry Department.
2. Paquette, L.; Ham, W. H. J. Am. Chem. Soc. 1987, 109, 3025–3036. 3. Cooper, G. F.; Wren, D. L.; Jackson, D. Y.; Beard, C. C.; Galeazzi, E.; Van Horn, A.
R.; Li, T. T. J. Org. Chem. 1993, 58, 4280–4286. 4. Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A.; Falck, J. R.; Mioskowski, C.
Angew. Chem., Int. Ed. 1998, 37, 2085–2087. 5. Giardiná, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001, 713–
718. 6. Funabiki, K.; Hara, N.; Nagamori, M.; Shibata, K.; Matsui, M. J. Fluorine Chem.
2003, 122, 237–242. 7. Montero, A.; Mann, E.; Herradón, B. Eur. J. Org. Chem. 2004, 3063–3073. 8. Scaglione, J. B.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2005, 70, 1089–1092. 9. Zartman, A. E.; Duong, L. T.; Fernandez-Metzler, C.; Hartman, G. D.; Leu, C.-T.;
Prueksaritanont, T.; Rodan, G. A.; Rodan, S. B.; Duggan, M. E.; Meissner, R. S. Bio-org. Med. Chem. Lett. 2005, 15, 1647–1650.
10. Hicks, J. D.; Roush, W. R. Org. Lett. 2008, 10, 681–684. 11. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions
for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 68−72. (Review).
128
Clemmensen reduction Reduction of aldehydes and ketones to the corresponding methylene compounds using amalgamated zinc in hydrochloric acid.
R R1
O Zn(Hg)
HCl R R1
HH
The zinc-carbenoid mechanism:3
Ph CH3
O Zn(Hg), HCl
SET Ph CH3
O ZnCl
radical anion
Ph CH3
Zn
Ph CH3
OZnCl
ZnPh CH3
HH
H zinc-carbenoid
The radical anion mechanism:
Ph CH3
O e ; HPh CH3
OZnCl
H
Zn(Hg), HCl
SET Ph CH3
O ZnCl H Ph CH3
OZnCl
H
H
Cl radical anion
Ph CH3
H
Cl
SN2Ph CH3
H
Ph CH3
HHe ; He
Example 15
Zn(Hg), HCl
MeOH, reflux, 1 hOH
OHO OH
O
OH18% 67%
129
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_57, © Springer-Verlag Berlin Heidelberg 2009
Example 26
Zn(Hg), HCl
Et2O, −5 oC, 57%N
OH
HPh
N
H
HPhO O
Example 38
H3CH3C
CH3
HO
H3C H
H H
HOH
OH
H3C
HO
H3C H
H H
O
OZn dust
37% HCl, EtOH
reflux, 15 min.50%diosgenin
References 1. Clemmensen, E. Ber. 1913, 46, 1837−1843. Erik C. Clemmensen (1876−1941) was
born in Odense, Denmark. He received the M.S. degree from the Royal Polytechnic Institute in Copenhagen. In 1900, Clemmensen immigrated to the United States, and worked at Parke, Davis and Company in Detroit as a research chemist for 14 years, where he discovered the reduction of carbonyl compounds with amalgamated zinc. Clemmensen later founded a few chemical companies and was the president of one of them, the Clemmensen Chemical Corporation in Newark, New Jersey.
2. Martin, E. L. Org. React. 1942, 1, 155−209. (Review). 3. Vedejs, E. Org. React. 1975, 22, 401−422. (Review). 4. Talpatra, S. K.; Chakrabarti, S.; Mallik, A. K.; Talapatra, B. Tetrahedron 1990, 46,
6047−6052. 5. Martins, F. J. C.; Viljoen, A. M.; Coetzee, M.; Fourie, L.; Wessels, P. L. Tetrahedron
1991, 47, 9215−9224. 6. Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Chem. Soc., Perkin Trans. 1 1996,
1113−1124. 7. Kappe, T.; Aigner, R.; Roschger, P.; Schnell, B.; Stadlbauer, W. Tetrahedron 1995,
51, 12923−12928. 8. Alessandrini, L.; Ciuffreda, P.; Santaniello, E.; Terraneo, G. Steroids 2004, 69,
789−794. 9. Dey, S. P.; Dey, D. K.; Dhara, M. G.; Mallik, A. K. J. Indian Chem. Soc. 2008, 85,
717−720.
130
Combes quinoline synthesis Acid-catalyzed condensation of anilines and β-diketones to assemble quinolines. Cf. Conrad–Limpach reaction.
NH2 R1 R2
O O H
ΔN R1
R2
NH2:
O
R1
HR2
ONH2
OHR1
O
R2 proton
transfer NH
OH2
:
R1
O
R2
N R1
O
R2
NH
R1
O
R2 H
NH
R1
R2
OH
imine enamine
NH
R1
R2
OH
:
NH
R1
R2OH
N R1
H R2OH
H
H
H
N R1
R2
NH
R1
R2OH H
:
HN R1
R2
H
An electrocyclization mechanism is also possible:
:
NH
R1
R2
OH
N R1
R2
OH
6π-electrocyclization
H
131
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_58, © Springer-Verlag Berlin Heidelberg 2009
N R1
R2HO
N R1
R2
H
proton
transferN R1
HOH2
R2 H2O
Example 16
NH
NH2
MeOO O
PPA, 110 °C
NH
MeO
N
35%
Example 27
NH
NH2
CO2Et
O
Ph
O
cat. p-TsOH, 220 °Cneat, 38%
NH
CO2Et
N
Ph
References 1. Combes, A. Bull. Soc. Chim. Fr. 1888, 49, 89. Alphonse-Edmond Combes
(1858−1896) was born in St. Hippolyte-du-Fort, France. He apprenticed with Wurtz at Paris. He also collaborated with Charles Friedel of the Friedel−Crafts reaction fame. He became the president of the French Chemical Society in 1893 at the age of 35. His sudden death shortly after his 38th birthday was a great loss to organic chemistry.
2. Roberts, E. and Turner, E. J. Chem Soc. 1927, 1832−1857. (Review). 3. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed.; Wiley & Sons:
New York, 1952, vol. 4, 36–38. (Review). 4. Popp, F. D. and McEwen, W. E. Chem. Rev. 1958, 58, 321–401. (Review). 5. Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; Wiley & Sons,
New York, 1977, Quinolines Vol. 32, pp 119–125. (Review). 6. Alunni-Bistocchi, G.; Orvietani, P., Bittoun, P., Ricci, A.; Lescot, E. Pharmazie 1993,
48, 817−820. 7. El Ouar, M.; Knouzi, N.; Hamelin, J. J. Chem. Res. (S) 1998, 92−93. 8. Curran, T. T. Combes Quinoline Synthesis. In Name Reactions in Heterocyclic Chem-
istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 390−397. (Review).
132
Conrad–Limpach reaction Thermal or acid-catalyzed condensation of anilines with β-ketoesters leads to qui-nolin-4-ones. Cf. Combes quinoline synthesis.
NH2 NH
OEt
O O Ph2O
260 oC
O
NH2
EtO2C
O
NH
CO2Et
OH
: :
H2Oproton
transfer
N
CO2Et
N
OEtHO 6π electron
electrocyclizationtautomerize
N
H OEtO
H
Schiff base
− HOEt
N
HO
H OEtNH
Oproton
transfer N
OH
Example 13
N
NH2 CHCl3, HCl (cat.)
60%OEt
O O
N
HNCO2Et
N
N
OH
Ph2O, reflux
60%
133
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_59, © Springer-Verlag Berlin Heidelberg 2009
Example 27
N NH2
EtO2CO
CO2Et3
PPA,
120 °C25%
N N
OCO2Et3
+
paraffin,
280 °C75% N N
HCO2Et3
O
Example 38
NH2
NO2
CO2MeHO
OMeO2C
2 HCl, MeOH
64%
O2N
NH
CO2Me
NHPhNO2MeO2C
Dowtherm A
250 °C, 55% NH
HN
CO2Me
O2NO
NO2
References 1. Conrad, M.; Limpach, L. Ber. 1887, 20, 944. Max Conrad (1848−1920), born in Mu-
nich, Germany, was a professor of the University of Würzburg, where he collaborated with Leonhard Limpach (1852−1933) on the synthesis of quinoline derivatives.
2. Manske, R. F. Chem Rev. 1942, 30, 113–114. (Review). 3. Misani, F.; Bogert, M. T. J. Org. Chem. 1945, 10, 347–365 4. Reitsema, R. H. Chem. Rev. 1948, 43, 43–68. (Review). 5. Elderfield, R. C. In Chemistry of Heterocyclic Compounds, Elderfield, R. C., Wiley &
Sons, New York, 1952, vol. 4, 31–36. (Review). 6. Jones, G. In Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, New York,
1977, Quinolines, Vol 32, 137–151. (Review). 7. Deady, L. W.; Werden, D. M. Synth. Commun. 1987, 17, 319−328. 8. Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077−5080. 9. Curran, T. T. Conrad–Limpach Reaction. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 398−406. (Re-view).
10. Chan, B. K.; Ciufolini, M. A. J. Org. Chem. 2008, 72, 8489−8495.
134
Cope elimination reaction Thermal elimination of N-oxides to olefins and N-hydroxyl amines.
NO
H
R2R3RR1
Δ
R2
R3
R1
R
NOH
Ei
Example 1, Solid-phase Cope elimination5
OO
N
OH
m-CPBA, CHCl3
rt, 67%
OO
N
OH
OH
OO
HON
OH
Example 26
OBn
BnO
BnO
N(CH3)2
OTBDPS
O
OBn
BnO
BnO
N(CH3)2
OTBDPSm-CPBA
CH2Cl2, 0 oC83%
OBn
BnO
BnOOTBDPS
145 oC
63%
Example 38
N
CN
O m-CPBA, CH2Cl2
rt, 100%
NOO
NC H
NOH O
CN
135
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_60, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Retro-Cope elimination9
OMe
PhN
MeOHNC
Cope
elimination
OTBDPSO
MePh
NMe
HNC
OTBDPS m-CPBA, K2CO3
−78 oC, 3 h, then rt
OMe
PhN
MeHO
OTBDPS
MeOH, Δ, 5 d 67%, 2 steps
retro-Copeelimination
O
N
Ph
MeMe
OOTBDPS
O
N
Ph
MeMe
OOTBDPS
5 : 2
References 1. Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949, 71, 3929−3934. Ar-
thur Clay Cope (1909−1966) was born in Dunreith, Indiana. He was a professor at MIT when he discovered the Cope elimination reaction and the Cope rearrangement. The Arthur Cope Award is a prestigious award in organic chemistry from the Ameri-can Chemical Society.
2. Cope, A. C.; Trumbull, E. R. Org. React. 1960, 11, 317−493. (Review). 3. DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431−457. (Review). 4. Gallagher, B. M.; Pearson, W. H. Chemtracts: Org. Chem. 1996, 9, 126−130. (Re-
view). 5. Sammelson, R. E.; Kurth, M. J. Tetrahedron Lett. 2001, 42, 3419−3422. 6. Vasella, A.; Remen, L. Helv. Chim. Acta. 2002, 85, 1118−1127. 7. Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Moya Cerero, S.; Lora
Maroto, B. Tetrahedron: Asymmetry 2002, 13, 17−19. 8. O’Neil, I. A.; Ramos, V. E.; Ellis, G. L.; Cleator, E.; Chorlton, A. P.; Tapolczay, D. J.;
Kalindjian, S. B. Tetrahedron Lett. 2004, 45, 3659−3661. 9. Henry, N.; O’Meil, I. A. Tetrahedron Lett. 2007, 48, 1691−1694. 10. Fuchter, M. J. Cope elimination reaction. In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 342−353. (Review).
11. Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874−875.
136
Cope rearrangement The Cope, oxy-Cope, and anionic oxy-Cope rearrangements belong to the cate-gory of [3,3]-sigmatropic rearrangements. Since it is a concerted process, the ar-row pushing here is only illustrative. This reaction is an equilibrium process. Cf. Claisen rearrangement.
R R RΔ, [3,3]-sigmatropic
rearrangement
Example 14
CO2CH3
OTMS
BrCO2CH3
OTMS
H
BrO
H
Br
160 °C
tolueneCope
NaCl
wet DMSOreflux
Krapcho 71%
Example 26
O OTMS
CO2Me 100 oC, 12 h
84%
CO2Me
TMS
Example 39
CO2Me
CO2MeO
dioxane, Et3N, 60 oC
22 h, 1 bar, 92%O
CO2Me
CO2Me
Example 410
140 °C
benzene
OH
OH
HH
H
H3CO
H
OH
OH
OH
H3COH
94%OH
Example 511
O
OMOMO
OMOMOTBDPS
1,2-dichlorobenzene
reflux, 95% O
O OMOM
OMOMTBDPSO
137
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_61, © Springer-Verlag Berlin Heidelberg 2009
Example 612
H3CO1. HCl, MeOH
2. 1,2-dichloro- benzene reflux, 80%
N
O
OCH3
OCH3H3CO H3CO
N
O
O
OCH3H3CO
References 1. Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441−444. 2. Frey, H. M.; Walsh, R. Chem. Rev. 1969, 69, 103−124. (Review). 3. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1−252. (Review). 4. Wender, P. A.; Schaus, J. M. White, A. W. J. Am. Chem. Soc. 1980, 102, 6159–6161. 5. Hill, R. K. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds.; Per-
gamon, 1991, Vol. 5, 785−826. (Review). 6. Chou, W.-N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114, 4658−4667. 7. Davies, H. M. L. Tetrahedron 1993, 49, 5203−5223. (Review). 8. Miyashi, T.; Ikeda, H.; Takahashi, Y. Acc. Chem. Res. 1999, 32, 815−824. (Review). 9. Von Zezschwitz, P.; Voigt, K.; Lansky, A.; Noltemeyer, M.; De Meijere, A. J. Org.
Chem. 1999, 64, 3806–3812. 10. Lo, P. C.-K.; Snapper, M. L. Org. Lett. 2001, 3, 2819–2821. 11. Clive, D. L. J.; Ou, L. Tetrahedron Lett. 2002, 43, 4559–4563. 12. Malachowski, W. P.; Paul, T.; Phounsavath, S. J. Org. Chem. 2007, 72, 6792–6796. 13. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac-
tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).
Anionic oxy-Cope rearrangement
ROH KH
THF R
O
ROH
ROKKH
THF
Δ, [3,3]-sigmatropic
rearrangementR
OK
ROK H2O
ROH
R
Otautomerize
Example 11
OH KH, THF, rt
then H2O, 88%
O
138
Example 24
OH
CH3
OHKH, THF
70% OH
H3C
H
H3COHC
Example 35
OH
H3CCH3
H3CCH3
O
X = OCH2CH2TMS 0 °C; 71%
OMOM
X
BnOOPMB
OPMB
OTBS
OMOM
X
OTBS
OPMB
OPMBBnO
H
H
KHMDS18-crown-6, THF
temperature;
then NH4Cl, H2O
−78 °C; 85%X = SPh
Example 48
OHNaH, THF, reflux
22 h, 88%
O
Example 59
MeO
MeO
OMeMeO OMe
HO
MeO
MeO
OMeMeO OMe
O
KOt-Bu18-crown-6
THF, −10°C74%
References 1. Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37,
3967–3975. 2. Wender, P. A.; Ternansky, R. J.; Sieburth, S. M. Tetrahedron Lett. 1985, 26, 4319–
4322. 3. Paquette, L. A. Tetrahedron 1997, 53, 13971−14020. (Review). 4. Corey, E. J.; Kania, R. S. Tetrahedron Lett. 1998, 39, 741–744. 5. Paquette, L. A.; Reddy, Y. R.; Haeffner, F.; Houk, K. N. J. Am. Chem. Soc. 2000, 122,
740–741. 6. Voigt, B.; Wartchow, R.; Butenschon, H. Eur. J. Org. Chem. 2001, 2519–2527.
139
7. Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetrahedron Lett. 2002, 43, 3633–3636.
8. Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631–3634. 9. Jones, S. B.; He, L.; Castle, S. L. Org. Lett. 2006, 8, 3757–3760. 10. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac-
tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).
Oxy-Cope rearrangement
While the anionic oxy-Cope rearrangements work at low temperature, the oxy-Cope rearrangements require high temperature but provide a thermodynamic sink.
ROH
ROHΔ, [3,3]-sigmatropic
rearrangement ROH
R
Otautomerize
Example 12
H
Me
Me HO
TMSH
O
Me
Me
OPMBH
Me
Me
Me
OPMBO
H
HO H
OMe
1. 230−240 °C DMF, 19 h
2. CsF, DMF 210 °C, 65%
Example 23
OH
CO2Et reflux
o-dichloro-benzene
O H
EtO2C
ene
EtO2C
OH90%
H
Example 34
PhMe2Si
PhMe2SiO O
O
t-Bu
O
1. 170 oC
2. p-TsOH•H2O 65−75%
O
O
t-Bu
O
PhMe2SiOOHC
Example 46
OH Oxylene, Ace® tube
225 oC, 24 h, 49%
140
References 1. Paquette, L. A. Angew. Chem., Int. Ed. 1990, 29, 609−626. (Review). 2. Paquette, L. A.; Backhaus, D.; Braun, R. J. Am. Chem. Soc. 1996, 118, 11990–11991. 3. Srinivasan, R.; Rajagopalan, K. Tetrahedron Lett. 1998, 39, 4133–4136. 4. Schneider, C.; Rehfeuter, M. Chem. Eur. J. 1999, 5, 2850−2858. 5. Schneider, C. Synlett 2001, 1079−1091. (Review on siloxy-Cope rearrangement). 6. DiMartino, G.; Hursthouse, M. B.; Light, M. E.; Percy, J. M.; Spencer, N. S.; Tolley,
M. Org. Biomol. Chem. 2003, 1, 4423−4434. 7. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac-
tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).
Siloxy-Cope rearrangement
R'OSiR3 Δ, [3,3]-sigmatropic
rearrangement R'
OSiR3
Example 11
OTMSCH3
H
OTMSOTBS
HH3C
OTMS
OTMSOTBSHsealed tube
high vacuum
310 °C, 1 h> 79%
Example 22
O
N
O
BnTDSO
O
180 °C
toluene, 3 h63%
O
N
O
Bn
O
TDSO
> 97:3 dr TDS = thexyldimethylsilyl
Example 33
Et3SiO
AOM
OO
OTBDPS OSiEt3O
OOAOMTBDPSO
chlorobenzene
reflux, 3 h, 99%
AOM = p-Anisyloxymethyl = p-MeOC6H4OCH2-
141
Example 44
OHH3C
4H3C
TESO
OO O
OH
4H3C
TESO
OO O115 °C
toluene, reflux95%
OTBDPS TBDPSO
H3C
References 1. Askin, D.; Angst, C.; Danishefsky, D. J. J. Org. Chem. 1987, 52, 622–635. 2. Schneider, C. Eur. J. Org. Chem. 1998, 1661–1663. 3. Clive, D. L. J.; Sun, S.; Gagliardini, V.; Sano, M. K. Tetrahedron Lett. 2000, 41,
6259–6263. 4. Bio, M. M.; Leighton, J. L. J. Org. Chem. 2003, 68, 1693–1700. 5. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac-
tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).
142
Corey–Bakshi–Shibata (CBS) reagent
N BO
PhPhH
Me
The CBS (Corey–Bakshi–Shibata) reagent is a chiral catalyst derived from proline. Also known as Corey’s oxazaborolidine, it is used in enantioselective bo-rane reduction of ketones, asymmetric Diels–Alder reactions and [3 + 2] cycloadditions. Preparation1,3
NH
O
OH
H
O
MeOH
H3ONH
O
O
H
O
1. PhMgCl2. BH3•THF
50% 3 steps
N BO
PhPhH
MeNH
OH
PhPhH MeB(OH)2, toluene
reflux, 3 h, 86%
The mechanism and catalytic cycle:1,3
O OHcat.
BH3, THF, rt, 97% ee
N BO
PhPhH
Me
CH3
O
N BO
PhPhH
R
N BO
PhPhH
R
BH3•THF
H3B
N BO
PhPhH
OH2B R
B Ph
CH3
::
HHH H
ON B
Ph
Ph H2B OCH3
PhH
RON B
Ph
Ph BH2
OCH3
Ph
R
H
CH3
HH2BO
HCl, MeOH
CH3
HHO
BH3
143
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_62, © Springer-Verlag Berlin Heidelberg 2009
Example 16
SO2C6H4CH3-pO
O
0.1 eq. (S)-CBS1.0 eq. i-Pr(Et)NPh•BH3
THF, rt, syringe pump1.5 h, 98%, 97% ee
SO2C6H4CH3-pOH
O
N BO
PhPhH
CH3
(S)-Me-CBS =
Example 29
O
O
OO BH3•SMe2
cat. (R)-Me-CBS
CH2Cl2, 30 oC84%, > 99% ee
HO
O
OO
Example 311
> 97% eeCO2CH2CF3
NB
O
H
H
PhPh
o-Tol
10 mol%, neat23 oC, 30 h, 97%
OCH2CF3
OTf2N
CO2Et
O
H3N
HN
Ac
H2PO4
oseltamivir (Tamiflu®)
Example 4, Asymmetric [3 + 2]-cycloaddition10
NB
O
H
H
PhPh
o-Tol
Tf2NOMeO
O
O CH3CN−CH2Cl265%
OH
OO
MeO
H
H92% ee99% ee recryst.
References 1. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553.
(b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925–7926. (c) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861–2863.
2. Reviews: (a) Corey, E. J. Pure Appl. Chem. 1990, 62, 1209–1216. (b) Wallbaum, S.; Martens, J. Tetrahedron: Asymm. 1992, 3, 1475–1504. (c) Singh, V. K. Synthesis
144
1992, 605–617. (d) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784. (e) Taraba, M.; Palecek, J. Chem. Listy 1997, 91, 9–22. (f) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986–2012. g) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667. (h) Itsuno, S. Org. React. 1998, 52, 395–576. (i) Cho, B. T. Aldrichimica Acta 2002, 35, 3–16. (j) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2004, 73, 581–608. (k) Cho, B .T. Tetrahedron 2006, 62, 7621–7643.
3. (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880–2888. (b) Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.; Carroll, J. D.; Corley, E. G.; Des-mond, R. Org. Synth. 1997, 74, 50–71.
4. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837–4840. 5. Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.;
Mills, R. J.; Lantos, I.; Baine, N. H. J. Am. Chem. Soc. 1998, 120, 4550–4551. 6. Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043–2047. 7. Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 8086–
8089. 8. Degni, S.; Wilen, C.-E.; Rosling, A. Tetrahedron: Asymmetry 2004, 15, 1495–1499. 9. Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652–4658. 10. Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958–11959. 11. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310–6311. 12. Patti, A.; Pedotti, S. Tetrahedron: Asymmetry 2008, 19, 1891–1897.
145
Corey−Chaykovsky reaction
The Corey−Chaykovsky reaction entails the reaction of a sulfur ylide, either di-methylsulfoxonium methylide 1 (Corey’s ylide) or dimethylsulfonium methylide 2, with electrophile 3 such as carbonyl, olefin, imine, or thiocarbonyl, to offer 4 as the corresponding epoxide, cyclopropane, aziridine, or thiirane.
R R1
X
R R1
X
X = O, CH2, NR2, S, CHCOR3,CHCO2R3, CHCONR2, CHCN
3H3C
SCH3
CH2
1 2
H3CSCH3
CH2
O
4
1 or 2
Preparation1
H3CS
CH3CH3
O
INaH
DMSO H3CSCH3
CH2
O
Mechanism1
H3CS
CH2CH3
O R R1
O
H3CS
H3C
O R
OR1
H3CS
CH3
O
O R1
R
Example 111
N
O
O
ClF
N
O
O
ClF
Me3S(O)+I−
NaH, DMSO
60 oC, 3.5 h79%
Example 29
OOEt
OAcMe2S CO2Et O
OEt
OAc
CO2Et
PhH, rt, 8 h, 62%
Example 310
H
N
Me3SCl50% aq. NaOH
Bu4NHSO4
CH2Cl2, 84%
O
O
H
N
O
O
146
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_63, © Springer-Verlag Berlin Heidelberg 2009
Example 414
Me2S
H
SiEt3BrCHO
2.5 equiv t-Bu3Ga
PhCl, rt, 3 h, 66%Z:E = 94:6
O
SiEt3 Example 515
O
Ph
OH
4 equiv(CH3)3SOI
n-BuLi, THF60 oC, 4 h
O
O
PhS
OO
Ph
OHO
Ph
50% 20%
References 1 (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867−868. (b) Corey, E.
J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 3782. (c) Corey, E. J.; Chaykovsky, M. Tetrahedron Lett. 1963, 169−171. (d) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86, 1639−1640. (e) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353−1364.
2 Okazaki, R.; Tokitoh, N. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 2139−2141. (Review).
3 Ng, J. S.; Liu, C. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 2159−2165. (Review).
4 Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides; Academic Press: New York, 1975. (Re-view).
5 Block, E. Reactions of Organosulfur Compounds Academic Press: New York, 1978. (Review).
6 Gololobov, Y. G.; Nesmeyanov, A. N. Tetrahedron 1987, 43, 2609−2651. (Review). 7 Aubé, J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Ed.; Perga-
mon: Oxford, 1991, Vol. 1, pp 820−825. (Review). 8 Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341−2372. (Review). 9 Rosenberger, M.; Jackson, W.; Saucy, G. Helv. Chim. Acta 1980, 63, 1665−1674. 10 Tewari, R. S.; Awatsthi, A. K.; Awasthi, A. Synthesis 1983, 330−331. 11 Vacher, B.; Bonnaud, B. Funes, P.; Jubault, N.; Koek, W.; Assie, M.-B.; Cosi, C.;
Kleven, M. J. Med. Chem. 1999, 42, 1648−1660. 12 Chandrasekhar, S.; Narasihmulu, Ch.; Jagadeshwar, V.; Reddy, K. V. Tetrahedron
Lett. 2003, 44, 3629−3630. 13 Li, J. J. Corey−Chaykovsky Reaction. In Name Reactions in Heterocyclic Chemistry;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 1−14. (Review). 14 Nishimura, Y.; Shiraishi, T.; Yamaguchi, M. Tetrahedron Lett. 2008, 49, 3492−3495. 15 Chittimalla, S. K.; Chang, T.-C.; Liu, T.-C.; Hsieh, H.-P.; Liao, C.-C. Tetrahedron
2008, 64, 2586−2595.
147
Corey−Fuchs reaction One-carbon homologation of an aldehyde to dibromoolefin, which is then treated with n-BuLi to produce a terminal alkyne.
R CHOCBr4, PPh3
Zn Br
Br
H
R n-BuLiR H
:PPh3Br3C Br CBr3 Br PPh3
SN2
CBr3
Br PPh3
Br
PPh3
BrBr
Br
SN2SN2
Br
Br
H
RO PPh3
R H
O
Br2 PPh3
Br
Br Wittig reaction (see page 578 for the mechanism)
Br2 Zn ZnBr2
Br
Br
H
R
Bu
R Br
BuR HR
acidic
workup
Example 13
OHC
OMe
OTBS
OO
CBr4, Ph3P, CH2Cl2
rt, 35 min., 90%
OMe
OTBS
OO
Br
Br
3.0 eq. n-BuLi/hexanes, THF
−78 oC, 1 h; rt, 1 h, 99%
OMe
OTBS
OO
OH
148
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_64, © Springer-Verlag Berlin Heidelberg 2009
Example 27
Fe
O
HFe H
BrBr
CBr4, Zn
PPh3, quant.
n-BuLi
75%Fe
H
Example 38
CHOOTBS
1. CBr4, Ph3P, Zn, CH2Cl2
2. n-BuLi, then NH4Cl, 90% OTBS
Example 410
CHO
CHO
4 equiv CBr48 equiv PPh3
8 equiv Zn
CH2Cl2, 0 oC to rt3 h, 94%
HH
Br Br
Br Br
n-BuLi, n-hexane
−78 oC to rt, 1 h, 96%
H
H
References 1 Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769−3772. Phil Fuchs is a pro-
fessor at Purdue University. 2 For the synthesis of 1-bromalkynes see Grandjean, D.; Pale, P.; Chuche, J. Tetrahe-
dron Lett. 1994, 35, 3529−3530. 3 Gilbert, A. M.; Miller, R.; Wulff, W. D. Tetrahedron 1999, 55, 1607−1630. 4 Muller, T. J. J. Tetrahedron Lett. 1999, 40, 6563−6566. 5 Serrat, X.; Cabarrocas, G.; Rafel, S.; Ventura, M.; Linden, A.; Villalgordo, J. M.
Tetrahedron: Asymmetry 1999, 10, 3417−3430. 6 Okamura, W. H.; Zhu, G.-D.; Hill, D. K.; Thomas, R. J.; Ringe, K.; Borchardt, D. B.;
Norman, A. W.; Mueller, L. J. J. Org. Chem. 2002, 67, 1637−1650. 7 Tsuboya, N.; Hamasaki, R.; Ito, M.; Mitsuishi, M.; Miyashita, T. Yamamoto, Y. J.
Mater. Chem. 2003, 13, 511–513 8 Zeng, X.; Zeng, F.; Negishi, E.-i. Org. Lett. 2004, 6, 3245−3248. 9 Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4527−4531. 10 Sahu, B.; Muruganantham, R.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2007, 2477–
2489. 11 Han, X. Corey−Fuchs reaction. In Name Reactions for Homologations-Part I; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 393−403. (Review).
149
Corey–Kim oxidation Oxidation of alcohol to the corresponding aldehyde or ketone using NCS/DMS, followed by treatment with a base. Cf. Swern oxidation.
R1 R2
OH
R1 R2
ONCS, DMS
then NEt3
NCS = N-Chlorosuccinimide; DMS = Dimethylsulfide.
SN
O
O
Cl:
ClSN
O
O R1 R2
:OHN
O
O
S
Cl
NH
O
O
R1 R2
OS H
H:NEt3
Cl
R1 R2
O
R1
OS
(CH3)2S↑
HR2
Et3N·HCl
Example 1, Fluorous Corey−Kim reaction5
NO2
OHC6F13
S
NCS, toluene, −25 oC, 2 hthen Et3N, 86%
NO2CHO
Example 2, Odorless Corey−Kim reaction7
NO
0.5 eq. NCS, CH2Cl2, −40 oC, 2 hthen Et3N, −40 oC to rt, 8 h
OH
D
S
O
NO
S D
45%86%
150
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_65, © Springer-Verlag Berlin Heidelberg 2009
Example 39
NH
OH
HH
HH
NCS, Me2S
Et3N, CH2Cl2−78 oC to rt, 90%
NH
CHOHH
HH
Example 410
O
O
O
OH
O
OOBzO
N
N
HN
OO
NCS, DMS
Et3N, CH2Cl2> 300 Kg scale
O
O
O
O
O
OOBzO
N
N
HN
OO
References 1 Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586−7587. Choung U. Kim
now works at Gilead Sciences Inc., a company specialized in antiviral drugs in Foster City, California, where he co-discovered oseltamivir (Tamiflu).
2 Katayama, S.; Fukuda, K.; Watanabe, T.; Yamauchi, M. Synthesis 1988, 178−183. 3 Shapiro, G.; Lavi, Y. Heterocycles 1990, 31, 2099−2102. 4 Pulkkinen, J. T.; Vepsäläinen, J. J. J. Org. Chem. 1996, 61, 8604−8609. 5 Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865−3870. 6 Ohsugi, S.-I.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama, S.; Node,
M. Tetrahedron 2003, 59, 8393−8398. 7 Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green
Chem. 2004, 6, 142−146. 8 Iula, D. M. Corey−Kim Oxidation. In Name Reactions for Functional Group Trans-
formations; Li, J. J., Corey, E. J. (eds), John Wiley & Sons: Hoboken, NJ, 2007, pp 207−217. (Review).
9 Yin, W.; Ma, J.; Rivas, F. M.; Cook, M. Org. Lett. 2007, 9, 295−298. 10 Cink, R. D.; Chambournier, G.; Surjono, H.; Xiao, Z.; Richter, S.; Naris, M.; Bhatia,
A. V. Org. Pro. Res. Dev. 2007, 11, 270−274.
151
Corey–Nicolaou macrolactonization Macrolactonization of ω-hydroxyl-acid using 2,2 -dipyridyl disulfide. Also known as the Corey–Nicolaou double activation method.
OH
OH
O
n
SS
NN
Ph3P On
O
SS
NN
Ph3P:
H
OH
O
O
n
SPPh3
N
HNH
S
S
OH
O
O
n
PPh3
NH
OH
O
O
n
PPh3
S
N
O PPh3NH
S
O n
OH
NH
S
ONH
S
O
On
O
n
2-pyridinethione
Example 13
N
OHOO
HO2C
PhPh H (2-pyr-S)2, PPh3
CHCl3, Δ, 75%
N
HOO
O
O
PhPh
152
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_66, © Springer-Verlag Berlin Heidelberg 2009
Example 26
OH
OH OMOM
O
O O(2-pyr-S)2, PPh3
AgClO4, Δ, 33%
O
O
HOO
O
Example 39
(PyS)2, PPh3
toluene, reflux7 d, 69%
O
HO OH
O
BnO
O
O O
OC5H11
HO2C
O
HO O
O
BnO
O
O O
OC5H11
O
O
O OH
O
BnO
O
O O
OC5H11
O 58% 11%
References 1. Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614–5616. 2. Nicolaou, K. C. Tetrahedron 1977, 33, 683–710. (Review). 3. Devlin, J. A.; Robins, D. J.; Sakdarat, S. J. Chem. Soc., Perkin Trans. 1 1982, 1117–
1121. 4. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1985, 2475–2478. 5. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1988, 1169–1172. 6. Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780–8785. 7. Lu, S.-F.; O’yang, Q. Q.; Guo, Z.-W.; Yu, B.; Hui, Y.-Z. J. Org. Chem. 1997, 62,
8400–8405. 8. Sasaki, T.; Inoue, M.; Hirama, M. Tetrahedron Lett. 2001, 42, 5299–5303. 9. Zhu, X.-M.; He, L.-L.; Yang, G.-L.; Lei, M.; Chen, S.-S.; Yang, J.-S. Synlett 2006,
3510–3512.
153
Corey–Seebach reaction Dithiane as a nucleophile, serving as a masked carbonyl equivalent. This is an ex-ample of umpolung.
SH
SH
CH2(OMe)2
Et2O•BF3 S
S 1. BuLi
2. Cl-(CH2)4-I 80%
S
S
Cl
HgCl2, 50 oC
50%
OHC
Cl
S
S
HH
Bu
S
S
ClI
S
S
Cl
Example 12
CHOS
S
Ph
n-BuLi, THF
0 oC, 30 min., 99%
S S
PhHOPh
PhI(O2CCCl3)2
CH3CN, H2O, rt, 5 min., 95% Ph Ph
HO O
Example 24
O CHO SSPh
n-BuLi, THF, −78 to 0 oC
OOH
SS
Ph
Example 3, Ethyl is infinitely different from methyl6
OMeOS
SLi
MeOH
S
SS
SMe Me
OMeO S
S
Et
CO2H
n-BuLi, THFrt, overnight
80−90%
HO2C
S SO
Et S
SEt
154
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_67, © Springer-Verlag Berlin Heidelberg 2009
HO2C
O
S
SEt
SS
EtSET
HO2C
O
S
SEt
HO2C
S SO
Et S
SEt
S S
Et
HO2C
S SO
Et
Example 48
SO
OBn
OBn
OBn
NHTfa
S n-BuLi, THF
−10 oC, 78%
SSNHTfa
BnOOBn
OBn
HO
54%
S
S
BnO NHTfa
HO
BnO
BnO
23% Tfa = Trifluoroacetyl
S
S
BnO NHTfa
HO
BnO
BnO
Ra-Ni, EtOH
reflux, 71%BnO NHTfa
HO
BnO
BnO
References 1. (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1075–1077. Dieter See-
bach is a professor at ETH in Zürich, Switzerland. (b) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097–4099. (c) Seebach, D.; Jones, N. R.; Corey, E. J. J. Org. Chem. 1968, 33, 300–305. (d) Seebach, D.; Corey, E. J. Org. Synth. 1968, 50, 72. (e) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231–237.
2. Stowell, M. H. B.; Rock, R. S.; Rees, D. C.; Chan, S. I. Tetrahedron Lett. 1996, 37, 307–310.
3. Hassan, H. H. A. M.; Tamm, C. Helv. Chim. Acta 1996, 79, 518–526. 4. Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454–3460. 5. Bräuer, M.; Weston, J.; Anders, E. J. Org. Chem. 2000, 65, 1193–1199. 6. Valiulin, R. A.; Kottani, R.; Kutateladze, A. G. J. Org. Chem. 2006, 71, 5047–5049. 7. Chen, Y.-L.; Leguijt, R.; Redlich, H. J. Carbohydrate Chem. 2007, 26, 279–303. 8. Chen, Y.-L.; Redlich, H.; Bergander, K.; Froehlich, R. Org. Biomol. Chem. 2007, 5,
3330–3339.
155
Corey–Winter olefin synthesis Transformation of diols to the corresponding olefins by sequential treatment with 1,1 -thiocarbonyldiimidazole (TCDI) and trimethylphosphite. Also known as Corey–Winter reductive elimination, or Corey–Winter reductive olefination.
R
R1
OH
OHN N
S
NN
R
R1 O
OS
P(OMe)3 R
R1
H
H
TCDI = Thiocarbonyldiimidazole
R
R1
OH
OH
N N
S
NN
: R
R1
O
OH
NS
N
NN
H R
R1 OH
OImd
S R
R1 O
O
ImdS H
R
R1 O
OS
:P(OMe)3R
R1 O
OS
P(OMe)3
1,3-dioxolane-2-thione (cyclic thiocarbonate)
S P(OMe)3
R
R1 O
OP(OMe)3
R
R1 O
O
P(OMe)3S
:P(OMe)3
R
R1
H
H O
OP(OMe)3 C O↑O P(OMe)3
A mechanism involving a carbene intermediate can also be drawn and is supported by pyrolysis studies:
:P(OMe)3R
R1 O
OS
R
R1 O
OS P(OMe)3
S P(OMe)3R
R1 O
O:P(OMe)3
R
R1 O
OP(OMe)3
156
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_68, © Springer-Verlag Berlin Heidelberg 2009
R
R1
H
H O
OP(OMe)3 :P(OMe)3 C O↑O
Example 12
OO
O
OOH
OH
Cl Cl
S
CH2Cl2, DMAP0 oC, 1 h, 93%
O
O
OO
OO
S
NP
N
Ph
H3C CH3
OO
O
O
40 °C, 88%
Example 24
O
OMOM
HO
HO CF3
N OMe Imd2CS, toluene
reflux, 79%
O
OMOMCF3
N OMeO
OS
P(OMe)3
92%
O
OMOM
N OMeF3C
Single olefin isomer
Example 38
HO
HO
TBSOH
H
OMe
OAc CSCl2, DMAP
CH2Cl2, rt, 96%O
O
TBSOH
H
OMe
OAcS
P(OEt)3, reflux
76%
TBSOH
H
OMe
OAc
157
Example 49
N
OO
CH3O
O
O
CH3H3CO
SO
CH3
P(OMe)3
120 °C, 66%N
OO
CH3
CH3O
O
H3C OCH3
Example 510
AcO OH
OHOAc
Cl
S
OAr(F)5
AcO
OAc
O
O
S
NP
N
PhH3C CH3
AcO
OAc
pyridine, DMAP23 °C, 5 h, 78%
THF, 40 °C 4 h, 65%
Example 611
CbzHNNHCbz
OH
OHPh
PhTCDI, THF
70 oCCbzHN
NHCbz
O
OPh
PhS
CbzHNNHCbz
Ph
Ph
P(OEt)3, 160 oC
77%, 2 steps References 1. Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677−2678. Roland A. E.
Winter works at Ciba Specialty Chemicals Corporation, USA. 2. Corey, E. J.; Carey, F. A.; Winter, R. A. E. J. Am. Chem. Soc. 1965, 87, 934−935. 3. Block, E. Org. React. 1984, 30, 457−566. (Review). 4. Kaneko, S.; Nakajima, N.; Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron 1998,
54, 5485−5506. 5. Crich, D.; Pavlovic, A. B.; Wink, D. J. Synth. Commun. 1999, 29, 359−377. 6. Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden, A. J. Org. Chem. 2001, 66,
4180−4186. 7. Saito, Y.; Zevaco, T. A.; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593−9603. 8. Araki, H.; Inoue, M.; Katoh, T. Synlett 2003, 2401−2403. 9. Brüggermann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.;
Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284−15285. 10. Freiría, M.; Whitehead, A. J.; Motherwell, W. B. Synthesis 2005, 3079−3084. 11. Mergott, D. J. Corey−Winter olefin synthesis. In Name Reactions for Functional
Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 354−362. (Review).
12. Xu, L.; Desai, M. C.; Liu, H. Tetrahedron Lett. 2009, 50, 552−554.
158
Criegee glycol cleavage Vicinal diol is oxidized to the two corresponding carbonyl compounds using Pb(OAc)4, (lead tetraacetate, LTA).
R2 R4
OHHOR1 R3 Pb(OAc)4
R1 R2
O
R3 R4
OPb(OAc)2 2 HOAc
Pb(OAc)3AcO
R2 R4
OHHOR1 R3
HOAc
R2 R4
OHOR1 R3
(AcO)2PbOAc
R2 R4R1 R3
OPb
O
OAcAcO
R1 R2
O
R3 R4
OPb(OAc)2HOAc
An acyclic mechanism is possible as well. It is much slower than the cyclic mechanism, but is operative when the cyclic intermediate can not form:3
O:
OH
H Pb(OAc)3O
O HOAc
O
O
Pb(OAc)2
O
O
AcO
H
H
PbII(OAc)2
O
O
HOAc
Example 17
N
OPh
CO2Et
OH
OH Pb(OAc)4, K2CO3
PhH, 0 oC, 80%
N
O
CO2Et
O
H
159
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_69, © Springer-Verlag Berlin Heidelberg 2009
Example 29
HPhO2S
OHHOH Pb(OAc)4, CH2Cl2, K2CO3
−15 oC to rt, 1 h, then
Ph3P=CHCO2Me, CH3CN, 80% HPhO2S
CO2MeH
E:Z = 10:1
Example 310
OO
ArAr
HO
HO
Pb(OAc)4, PhH
rt, 1.5 h, quant. OHC O ArH H
Example 411
HOMe
Me
OMe
Me Me
OH
Me
OH
Me OHHO
Me
OMe
Me Me
OH
MeH
OPb(OAc)4, EtOAc
0 oC, 5 min., 99%
References 1 Criegee, R. Ber. 1931, 64, 260–266. Rudolf Criegee (1902−1975) was born in Düssel-
dorf, Germany. He earned his Ph.D. at age 23 under K. Dimroth at Würzburg. Criegee became a professor at Technical Institute at Karlsruhe in 1937, a chair in 1947. He was known for his modesty, mater-of-factness, and his breadth of interests.
2 Mihailovici, M. L.; Cekovik, Z. Synthesis 1970, 209–224. (Review). 3 March, J. Advanced Organic Chemistry, 5th ed., Wiley & Sons: Hoboken, NJ, 2003.
(Review). 4 Danielmeier, K.; Steckhan, E. Tetrahedron: Asymmetry 1995, 6, 1181–1190. 5 Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1, 941–944. 6 Lautens, M.; Stammers, T. A. Synthesis 2002, 1993–2012. 7 Hartung, I. V.; Eggert, U.; Haustedt, L. O.; Niess, B.; Schäfer, P. M.; Hoffmann, H. M.
R. Synthesis 2003, 1844–1850. 8 Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042–
6043. 9 Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem. 2004, 783–799. 10 Prasad, K. R.; Anbarasan, P. Tetrahedron 2006, 63, 1089–1092. 11 Perez, L. J.; Micalizio, G. C. Synthesis 2008, 627–648.
160
Criegee mechanism of ozonolysis
O3OO
O
OO
O OO
O:1,3-dipolar
cycloaddition
primary ozonide (1,2,3-trioxolane)
OO
O
OO
O
1,3-dipolar
cycloaddition
zwitterionic peroxide secondary ozonide (1,2,4-trioxolane) (Criegee zwitterion)
also known as “carbonyl oxide” Example 17
HO
HO
O3, EtOAc, −78 oC, then
Ac2O, Et3N, DMAP, −78 oC to rt, 75%
O
OH
H
O OAc
Example 28
O3, CH2Cl2
−70 oC
OO
O
O
MeOH
quant. CO2Me
CO2Me
OMe
H References 1. (a) Criegee, R.; Wenner, G. Ann. 1949, 564, 9−15. (b) Criegee, R. Rec. Chem. Prog.
1957, 18, 111−120. (c) Criegee, R. Angew. Chem. 1975, 87, 765−771. 2. Bunnelle, W. H. Chem. Rev. 1991, 91, 335−362. (Review). 3. Kuczkowski, R. L. Chem. Soc. Rev. 1992, 21, 79−83. (Review). 4. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675−3680. 5. Ponec, R.; Yuzhakov, G.; Haas, Y.; Samuni, U. J. Org. Chem. 1997, 62, 2757−2762. 6. Dussault, P. H.; Raible, J. M. Org. Lett. 2000, 2, 3377−3379. 7. Jiang, L.; Martinelli, J. R.; Burke, S. D. J. Org. Chem. 2003, 68, 1150−1153. 8. Schank, K.; Beck, H.; Pistorius, S. Helv. Chim. Acta 2004, 87, 2025−2049.
161
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_70, © Springer-Verlag Berlin Heidelberg 2009
Curtius rearrangement Alkyl-, vinyl-, and aryl-substituted acyl azides undergo thermal 1,2-carbon-to-nitrogen migration with extrusion of dinitrogen — the Curtius rearrangement — producing isocyantes. Reaction of the isocyanate products with nucleophiles, of-ten in situ, provides carbamates, ureas, and other N-acyl derivatives. Alterna-tively, hydrolysis of the isocyanates leads to primary amines.
R N3
O Heat
R
Nu–H NH
Nu
O
R
NH2RCurtius
RearrangementN
CO
H2O–CO2
The thermal rearrangement:
R Cl
O NaN3
R N3
O ΔR N C ON2↑
H2OR NH3 CO2↑
R Cl
O
R N
O
N3N NR N3
O
R Cl
N3O
R N
O
N N
Δ N2↑ R N C O
:OH2
H
R NH2 CO2↑RHN O
OH
:B
isocyanate intermediate
The photochemical rearrangement:
R N
O
N NN2↑
hν
R N:
O
Nitrene
R N C O R NH2 CO2↑R N:
O
162
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_71, © Springer-Verlag Berlin Heidelberg 2009
Example 1, The Shioiri–Ninomiya–Yamada modification2
NO2H
HO
O
O
NO2H
O21
NH
OMe
O
21
DPPA, Et3NPhH, Δ
then MeOH, Δ89%
DPPA = diphenylphosphoryl azide
Example 23
O
O O
CO2MeHO2C DPPA, Et3N, t-BuOH
80 oC, 16 h, 64%
O
O O
CO2MeBocHN
Example 34
OOCO2H EtO(CO)Cl, then NaN3
EtOH, PhH, reflux, 55% OONHCO2Et
Example 4, The Weinstock variant of the Curtius rearrangement6
NMe
NH
NCOOH
H
H
Cl OEt
O
i-PrNEt2, acetone, 0 °C
then NaN3, rt, 12 h75% N
Me
NH
NHN
H
H
OEt
O
Example 57
PhO
Cl
1. n-Bu3SnN3 PhBr, 0 °C to RT 30 min., 97%
2. t-BuOH/o-xylene Δ, 6 h, 77%
Ph NHBoc
163
Example 6, The Lebel modification8
O
BnOOBn
OBn
CO2HOMPM 2 equiv DPPA
0.1 equiv Ag2CO32 equivK2CO3
PhH, Δ, 16 h, 81%(2 equiv)
O
BnOOBn
OBn
OMeHO O
BnOOBn
OBn
HN
OMPMO
BnOOBn
OBn
OMeO
O
References 1. Curtius, T. Ber. 1890, 23, 3033−3041. Theodor Curtius (1857−1928) was born in Du-
isburg, Germany. He studied music before switching to chemistry under Bunsen, Kolbe, and von Baeyer before succeeding Victor Meyer as a Professor of Chemistry at Heidelberg. He discovered diazoacetic ester, hydrazine, pyrazoline derivatives, and many nitrogen-heterocycles. Curtius also sang in concerts and composed music.
2. Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812–9824. 3. van Well, R. M.; Overkleeft, H. S.; van Boom, J. H.; Coop, A.; Wang, J. B.; Wang, H.;
van der Marel, G. A.; Overhand, M. Eur. J. Org. Chem. 2003, 1704–1710. 4. Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455–7457. 5. Holt, J.; Andreassen, T.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl. Chem. 2005, 42,
259–264. 6. Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995–3998. 7. Tada, T.; Ishida, Y.; Saigo, K. Synlett 2007, 235–238. 8. Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Eur. J. Org. Chem. 2007, 1064–
1068. 9. Rojas, C. M. Curtius Rearrangements. In Name Reactions for Homologations-Part II;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 136−163. (Review).
164
Dakin oxidation Oxidation of aryl aldehydes or aryl ketones to phenols using basic hydrogen per-oxide conditions. Cf. A variant of Baeyer–Villiger oxidation.
HCO2HO CHOH2O2, NaOH
45−50 oCHO OH
OO
H
HOH
OHO
OH
O
HO
aryl
migration
OHO
H OHOhydrolysisHO O
HO
OH
HO OHHO O
H workup
Example 16
OBn
CHO
NHCO2t-Bu
CO2H
2.5 eq. 30% H2O2
4% (PhSe)2CH2Cl2, 18 h
OBnO
NHCO2t-Bu
CO2H
CHONH3, MeOH
1 h, 78%
OBnOH
NHCO2t-Bu
CO2H
Example 27
HO
CHO urea-hydrogen peroxide (UHP)
solvent-free, 55 oC, 3 h, 83% HO
OH
Example 3, Improved solvent-free Dakin oxidation protocol9
MeO
BnO
CHO 1.5 equiv m-CPBA, neat, 5 min.
then10% aq. NaOH 85%
MeO
BnO
OH
165
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_72, © Springer-Verlag Berlin Heidelberg 2009
Example 410
NH
OMe
MeOCHO
H2O2, HCl
MeOH, THF50%
NH
O
MeOO
References: 1. Dakin, H. D. Am. Chem. J. 1909, 42, 477−498. Henry D. Dakin (1880−1952) was
born in London, England. During WWI, he invented his hypochlorite solution (Da-kin’s solution), which became a popular antiseptic for the treatment of wounds. After the Great War, he emmigrated to New York, where he investigated the B vitamins.
2. Hocking, M. B.; Bhandari, K.; Shell, B.; Smyth, T. A. J. Org. Chem. 1982, 47, 4208−4215.
3. Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49, 4740−4741. 4. Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M. Tetrahedron Lett.
1993, 34, 7401−7404. 5. Guzmán, J. A.; Mendoza, V.; García, E.; Garibay, C. F.; Olivares, L. Z.; Maldonado,
L. A. Synth. Commun. 1995, 25, 2121−2133. 6. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553−1555. 7. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189−191. 8. Lawrence, N. J.; Rennison, D.; Woo, M.; McGown, A. T.; Hadfield, J. A. Bioorg.
Med. Chem. Lett. 2001, 11, 51−54. 9. Teixeira da Silva, E.; Camara, C. A.; Antunes, O. A. C.; Barreiro, E. J.; Fraga, C. A.
M. Synth. Commun. 2008, 38, 784−788. 10. Alamgir, M.; Mitchell, P. S. R.; Bowyer, P. K.; Kumar, N.; Black, D. St. C. Tetrahe-
dron 2008, 64, 7136−7142.
166
Dakin−West reaction
The direct conversion of an α-amino acid into the corresponding α-acetylamino-alkyl methyl ketone, via oxazoline (azalactone) intermediates. The reaction pro-ceeds in the presence of acetic anhydride and a base, such as pyridine, with the evolution of CO2.
R CO2H
NH2
Ac2O R
NHAc
O
CO2↑
R CO2H
NH2
O
OO
R
HN
O
OH
O
OO
AcO
R
NH
OOH
OH
:
H
NO
R OHO
H
NO
RO OH
O
NO
RO
H
O
OH
AcO H
H
oxazolone (azalactone) intermediate
HN O
RO
O
O
H N OH
RO
H
R
NHAc
O− CO2 tautomerization
Example 16
Me CO2H
NH2
Me
NHAcMe
OAc2O, AcOH, Et3N
DMAP, 50 oC, 14 h, > 90%
Example 27
NH
OBn
O OOHO
Ac2O, pyr.
90 oC, 2 h, 58% NH
OBn
O OO Me
167
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_73, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Green Dakin–West reaction using the heteropoly acid catalyst, ace-tonitrile is a reactant9
CHO
NC
OPh
CH3CN, H3PW12O40
CH3COClrt, 60 min., 75% NHAc
Ph
O
CN
Example 4, Acetonitrile is a reactant10
CHO
R1
O
R2
CH3CN10 mol% Ln(OTf)3
CH3COCl, reflux78−87% NHAc O
R2R1
References: 1. Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 91, 745, and 757. In 1928, Henry Da-
kin and Rudolf West, a clinician, reported on the reaction of α-amino acids with acetic anhydride to give α-acetamido ketones via azalactone intermediates. Interestingly, one year before this paper by Dakin and West, Levene and Steiger had observed both tyrosine and α-phenylananine gave “abnormal” products when acetylated under these conditions.2,3 Unfortunately, they were slow to identify the products and lost an op-portunity to be immortalized by a name reaction.
2. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91–109. (Review). 3. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553–1555. 4. Kawase, M.; Hirabayashi, M.; Koiwai, H.; Yamamoto, K.; Miyamae, H. Chem. Com-
mun. 1998, 641–642. 5. Kawase, M.; Hirabayashi, M.; Saito, S. Recent Res. Dev. Org. Chem. 2001, 4,
283−293. (Review). 6. Fischer, R. W.; Misun, M. Org. Proc. Res. Dev. 2001, 5, 581–588. 7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J.
Org. Chem. 2003, 68, 2623–2632. 8. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105–
2108. 9. Rafiee, E.; Tork, F.; Joshaghani, M. Bioorg. Med. Chem. Lett. 2006, 16, 1221–1226. 10. Tiwari, A. K.; Kumbhare, R. M.; Agawane, S. B.; Ali, A. Z.; Kumar, K. V. Bioorg.
Med. Chem. Lett. 2008, 18, 4130–4132.
168
Darzens condensation α,β-Epoxy esters (glycidic esters) from base-catalyzed condensation of α-haloesters with carbonyl compounds.
R CO2Et
X
R1 R2
O OEt OR1
R2 CO2EtR
R
XH
OEt
R
X R1 R2
O
OEt
OOEt
O
R2 RO
R1
XCO2Et
OR1
R2 CO2EtR
intramolecular
SN2
Example 14
O
Cl CO2EtO
CO2Ett-BuOK, t-BuOH
10 °C, 85–95% Example 26
H3C Br
t-BuMe2Si
O LDA, THF, –78 °C then H3C
t-BuMe2Si
O OPh
H
H
66%, 90% dePhCHO, –90 °C
Example 39
XNPh2
X = Cl, Br, I
O
Ar H
O
Solid MOH, M = Na, K, RbCH2Cl2, 4−24 h, rt
O
Ar CONPh2
O
Ar CONPh2
N
O O
NCo
OMeMeO 2 mol%
ee up to 50%
ee up to 43%
169
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_74, © Springer-Verlag Berlin Heidelberg 2009
Example 4, the phenyl ring substituting for the carbonyl to acidify the protons10
Br PO(OMe)2
OBr
MeODBU, CH3CN
6 h, 48%
O PO(OMe)2
BrOMe
References 1 Darzens, G. A. Compt. Rend. Acad. Sci. 1904, 139, 1214–1217. George Auguste Dar-
zens (1867−1954), born in Moscow, Russia, studied at École Polytechnique in Paris and stayed there as a professor.
2 Newman, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413–441. (Review). 3 Ballester, M. Chem. Rev. 1955, 55, 283–300. (Review). 4 Hunt, R. H.; Chinn, L. J.; Johnson, W. S. Org. Syn. Coll. IV, 1963, 459. 5 Rosen, T. Darzens Glycidic Ester Condensation In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, pp 409–439. (Re-view).
6 Enders, D.; Hett, R. Synlett 1998, 961−962. 7 Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68,
2410−2419. 8 Myers, B. J. Darzens Glycidic Ester Condensation. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 15−21. (Review).
9 Achard, T. J. R.; Belokon, Y. N.; Ilyin, M.; Moskalenko, M.; North, M.; Pizzato, F. Tetrahedron Lett. 2007, 48, 2965−2969.
10 Demir, A. S.; Emrullahoglu, M.; Pirkin, E.; Akca, N. J. Org. Chem. 2008, 73, 8992−8997.
170
Delépine amine synthesis The reaction between alkyl halides and hexamethylenetetramine, followed by cleavage of the resulting salt with ethanolic HCl to yield primary amines. Cf. Gabriel synthesis, where the product is also an amine and Sommelet reaction, where the product is an aldehyde. The Delépine works well for active halides such as benzyl, allyl halides, and α-halo-ketones.
Ar X NN
N
N
NN
N
NAr
XAr NH3 X
hexamethylenetetramine
[ArCH2C6H12N4]+X− + 3 HCl + 6 H2O
ArCH2NH2•HX + 6 CH2O + 3 NH4Cl
NN
N:
N
NN
N
NAr
Ar X
SN2
X
:
NN
N
NAr
H2O:
NN
N
NAr
HO H
OCH2
NN
N
NAr
H
Ar NH3
X
Example 13
Br OH
O1. (CH2)6N4, NaHCO3 15 h, EtOH, H2O
2. HCl, EtOH, reflux, 15 h, 85% H2N OH
O
Example 27
NN
BrBr
hexamethylenetetramine
CH2Cl2, refux, 5 h, then−30 oC
171
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_75, © Springer-Verlag Berlin Heidelberg 2009
NN
BrN4C6H12
+Br−
conc. HCl, EtOH
reflux, 1 d78%, 2 steps
NN
BrNH2
Example 38
1. hexamethylenetetramine CHCl3, reflux, 6 h
2. 2 N HCl, EtOH, 100 oC, 15 min.
O O
Br
O
OO O O
OOO
O
O O
NH2
O
OO O O
OOO
O
Example 49
BrO
NO2
hexamethylenetetramine
CHCl3, rt, 18 h
O
NO2
NN
N
N
Br
NH3O
NO2
Br48% HBr
CH3OH, rt, 5 d
89% 2 steps
References 1. (a) Delépine, M. Bull. Soc. Chim. Paris 1895, 13, 352−355; (b) Delépine, M. Bull.
Soc. Chim. Paris 1897, 17, 292−295. Stephe Marcel Delépine (1871−1965) was born in St. Martin le Gaillard, France. He was a professor at the Collège de France after working for M. Bertholet at that institute. Delépine’s long and fruitful career in sci-ence encompassed organic chemistry, inorganic chemistry, and pharmacy.
2. Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585−3586. 3. Wendler, N. L. J. Am. Chem. Soc. 1949, 71, 375−384. 4. Quessy, S. N.; Williams, L. R.; Baddeley, V. G. J. Chem. Soc., Perkin Trans. 1 1979,
512−516. 5. Blažzevi , N.; Kolnah, D.; Belin, B.; Šunji , V.; Kafjež, F. Synthesis 1979, 161−176.
(Review). 6. Henry, R. A.; Hollins, R. A.; Lowe-Ma, C.; Moore, D. W.; Nissan, R. A. J. Org.
Chem. 1990, 55, 1796−1801. 7. Charbonnière, L. J.; Weibel, N.; Ziessel, R. Synthesis 2002, 1101−1109. 8. Xie, L.; Yu, D.; Wild, C.; Allaway, G.; Turpin, J.; Smith, P. C.; Lee, K.-H. J. Med.
Chem. 2004, 47, 756−760. 9. Loughlin, W. A.; Henderson, L. C.; Elson, K. E.; Murphy, M. E. Synthesis 2006,
1975−1980.
172
de Mayo reaction [2 + 2]-Photochemical cyclization of enones with olefins is followed by a retro-aldol reaction to give 1,5-diketones.
O
OH
CO2Me hνO
OH
O
O CO2MeCO2Me
Head-to-tail alignment gives the major product:
O
OH
hν, [2 + 2]
cycloadditionCO2Me
O
OHCO2Meδ
δ
δ
δ
retro-aldol
cyclobutane cleavage
O
O CO2Me
H O
O CO2Me
O
OH
CO2Me
Head-to-head alignment gives the minor regioisomer:
OCO2Me
OH
hν, [2 + 2]
cycloaddition
O
OH
CO2Me
retro-aldol
cyclobutane cleavage
O
O
H O
O
CO2Me CO2Me
O
O
CO2Me
H
Example 13
OPh
O
O
1. hν, cyclohexane, 83%
2. H2 (3 atm), Pd/C (10%) HOAc, rt, 18 h, 83%
O
O
173
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_76, © Springer-Verlag Berlin Heidelberg 2009
Example 26
O
OH
hν, MeOH
> 90%
O
HO
O
O
H
H
H
H
Example 39
N
O
O
HO
hv, Pyrex filter
CH3CN, rt, 1.5 h, 72% N
O
OH
O
N
O
O
O
HH
Example 410
O
R
O
O hv
Et2O
O
O
H
OR
H
H
O
O
H
OR
H
H
R = H 70% 100 : 0R = Me 58% 50 : 50R = t-Bu 72% 0 : 100
References 1. (a) de Mayo, P.; Takeshita, H.; Sattar, A. B. M. A. Proc. Chem. Soc., London 1962,
119. Paul de Mayo received his doctorate from Sir Derek Barton at Birkbeck College, University of London. He later became a professor at the University of Western On-tario in London, Ontario, Canada, where he discovered the de Mayo reaction. (b) Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P. J. Org. Chem. 1969, 34, 794−806.
2. de Mayo, P. Acc. Chem. Res. 1971, 4, 41−48. (Review). 3. Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583−2584. 4. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181−1201. (Review). 5. Kaczmarek, R.; Blechert, S. Tetrahedron Lett. 1986, 27, 2845−2848. 6. Disanayaka, B. W.; Weedon, A. C. J. Org. Chem. 1987, 52, 2905−2910. 7. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297−588. (Review). 8. Quevillon, T. M.; Weedon, A. C. Tetrahedron Lett. 1996, 37, 3939−3942. 9. Minter, D. E.; Winslow, C. D. J. Org. Chem. 2004, 69, 1603−1606. 10. Kemmler, M.; Herdtweck, E.; Bach, T. Eur. J. Org. Chem. 2004, 4582−4595.
174
Demjanov rearrangement Carbocation rearrangement of primary amines via diazotization to give alcohols through C−C bond migration.
NH2
HNO2
OHOH
2 HON
OH
H2ON
O
− H2OON
OH
ON
ON
O
ON
ON
O
N N O− HNO2
NH2
:
H
N N OH2
H
:
− H2ON NN N OH
− N2
N OH
N
OH
H
: − H
− N2
OH
OH
H
NN
:
− Hor
Example 13
NPh
NH2 NOH
Ph NPh
NaNO2, HOAc
100 oC, 2 h30% 16%
Example 26
HNH2 NaNO2, AcOH/H2O
100−110 oC, 2 h, 61%
H OH
175
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_77, © Springer-Verlag Berlin Heidelberg 2009
Example 37
O
NH2
NaNO2, 0−4 oC
0.25 M H2SO4/H2O
O
HO
O
OH
Example 48
MeO
OO
H
H
H2N
5 equiv NaNO25 equiv AcOH
H2O/THF (1:1)0 oC, 2 h, 61%
O
O
H
HO
MeOH
References 1. Demjanov, N. J.; Lushnikov, M. J. Russ. Phys. Chem. Soc. 1903, 35, 26−42. Nikolai
J. Demjanov (1861−1938) was a Russian chemist. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157−188. (Review). 3. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840−184. 4. Kotani, R. J. Org. Chem. 1965, 30, 350−354. 5. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840−1844. 6. Nakazaki, M.; Naemura, K.; Hashimoto, M. J. Org. Chem. 1983, 48, 2289−2291. 7. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649−1664. 8. Kürti, L.; Czakó, B.; Corey, E. J. Org. Lett. 2008, 10, 5247−5250. 9. Curran, T. T. Demjanov and Tiffeneau–Demjanov Rearrangement. In Name Reactions
for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review).
176
Tiffeneau–Demjanov rearrangement Carbocation rearrangement of β-aminoalcohols via diazotization to afford car-bonyl compounds through C−C bond migration.
OH
NH2
NaNO2
H
O
Step 1, Generation of N2O3
HON
OH
H2ON
O
− H2OON
OH
ON
ON
O− H
Step 2, Transformation of amine to diazonium salt
ON
ON
OOH
NH2
OH
N:
HN OHONO
HOH
N N OH2:
− H2O OH
NN
OH
N N OH
Step 3, Ring-expansion via rearrangement
O
− N2OH − H
ON
N H:
Example 15
HO
H2NO
ONaNO2, H2O
AcOH, 0 oC,then rt−60 oC 76% yield 90 : 6
177
Example 26
NOMe
OH
AcOH•H2N CONEt2
NaNO2, AcOH
H2O, 0−5 oC60%
O N2
ONEt2H
NOMe
OCONEt2
Example 37
NH2
OHNaNO2, AcOH/H2O, 0 oC, 1 h
then reflux 1 h, 98%O
Example 49
SiMe3
HO NH2 NaNO2
AcOH
O O
SiMe3
SiMe3
72% 28% References 1. Tiffeneau, M.; Weill, P.; Tehoubar, B. Compt. Rend. 1937, 205, 54−56. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157−188. (Review). 3. Parham, W. E.; Roosevelt, C. S. J. Org. Chem. 1972, 37, 1975−1979. 4. Jones, J. B.; Price, P. Tetrahedron 1973, 29, 1941−1947. 5. Miyashita, M.; Yoshikoshi, A. J. Am. Chem Soc. 1974, 96, 1917–1925. 6. Steinberg, N. G.; Rasmusson, G. H.; Reynolds, G. F.; Hirshfield, J. H.; Arison, B. H.
J. Org. Chem. 1984, 49, 4731–4733. 7. Stern, A. G.; Nickon, A. J. Org. Chem. 1992, 57, 5342−5352. 8. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649–1664. 9. Chow, L.; McClure, M.; White, J. Org. Biomol. Chem. 2004, 2, 648−650. 10. Curran, T. T. Demjanov and Tiffeneau–Demjanov Rearrangement. In Name Reactions
for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 293−304. (Review).
178
Dess−Martin periodinane oxidation Oxidation of alcohols to the corresponding carbonyl compounds using triace-toxyperiodinane. The Dess–Martin periodinane, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, is one of the most useful oxidant for the conversion of primary and secondary alcohols to their corresponding aldehyde or ketone prod-ucts, respectively.
R1 R2
OHO
I
O
AcO OAcOAc
R1 R2
O
Preparation,1,2 The oxone preparation is much safer and easier than KBrO3. The IBX intermediate that comes out of it has proven to be far less explosive12
ICO2H
KBrO3, H2SO4, 93%
or 1.3 equiv OxoneH2O, 70 oC, 3 h
79-81%
OI
O
HO O Ac2O, 0.5% TsOH
80 oC, 2 h, 91%O
I
O
AcOOAc
OAc
IBX
However, The Dess–Martin periodinane is hydrolyzed by moisture to o-iodoxybenzoic acid (IBX), which is a more powerful oxidating agent3
OI
O
HO O
OI
O
AcOOAc
OAc
IBX
H2O
CH2Cl2
Mechanism1
OI
O
AcOO
OAc
OI
O
AcOOAc
OAc:O
H
R1
H
R1R2
R2 OAcSN2
OI
O
OAc
R1 R2
OAcOH
179
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_78, © Springer-Verlag Berlin Heidelberg 2009
Example 16
OI
O
AcO OAcOAc
O
OOOH
OCH2Cl2, 2 h, 67% O
OOO
O
Example 2, An atypical Dess–Martin periodinane reactivity7
OI
O
AcO OAcOAc
NaN3, CH2Cl20 oC, 3 h, 86%
N
CHO
N
N3
O
Example 310
t-BuO2CNH
NH
HN
NHBoc
O
O CO2t-Bu
SS N
HOH
O
Dess−Martin periodinane
CH2Cl2, rt, 1 h, 70%
t-BuO2CNH
NH
HN
NHBoc
O
O CO2t-Bu
SS N
HO
O
Example 411
O
OHBnO
BnO OBnO
O
NHAcAllO OTDS
PMBO Dess−Martin periodinane
CH2Cl2, rt, 2 h, 90%
O
OBnO
BnO OBnO
O
NHAcAllO OTDS
PMBO
TDS = Thexyldimethylsilyl
180
References 1. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−4156. James Cullen (J.
C.) Martin (1928−1999) had a distinguished career spanning 36 years both at the Uni-versity of Illinois at Urbana-Champaign and Vanderbilt University. J. C.’s formal training in physical organic chemistry with Don Pearson at Vanderbilt and P. D. Bart-lett at Harvard prepared him well for his early studies on carbocations and radicals. However, it was his interest in understanding the limits of chemical bonding that lead to his landmark investigations into hypervalent compounds of the main group ele-ments. Over a 20-year period the Martin laboratories successfully prepared unprece-dented chemical structures from sulfur, phosphorus, silicon and bromine while the ul-timate “Holy Grail” of stable pentacoordinate carbon remained elusive. Although most of these studies were driven by J. C.’s fascination with unusual bonding schemes, they were not without practical value. Two hypervalent compounds, Martin’s sulfu-rane (for dehydration, page 365) and the Dess−Martin periodinane have found wide-spread application in synthetic organic chemistry. J. C. Martin and his student Daniel Dess developed this methodology at the University of Illinois at Urbana. (Martin’s bi-ography was kindly supplied by Prof. Scott E. Denmark). (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−7287.
2. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. 3. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549−7552. 4. Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996, 338, 588−590. (Review). 5. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39,
622−625. 6. Bach, T.; Kirsch, S. Synlett 2001, 1974−1976. 7. Bose, D. S.; Reddy, A. V. N. Tetrahedron 2003, 44, 3543−3545. 8. Tohma, H.; Kita, Y. Adv. Synth. Cat. 2004, 346, 111−124. (Review). 9. Holsworth, D. D. Dess−Martin oxidation. In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ; 2007, pp 218−236. (Review).
10. More, S. S.; Vince, R. J. Med. Chem. 2008, 51, 4581−4588. 11. Crich, D.; Li, M.; Jayalath, P. Carbohydrate Res. 2009, 344, 140−144. 12. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537−4538.
181
Dieckmann condensation The Dieckmann condensation is the intramolecular version of the Claisen conden-sation.
CO2EtCO2Et NaOEt O
CO2Et
CO2Et O
OEtH O OEt
OOEt
enolate
formation
5-exo-trig
ring closure
OEt
CO2Et
OEtO O
CO2Et
Example 16
N
H OBn
OTBSO
MeO2CNMeO2C
H OBn
OTBS
MeO2C
NaHMDS, THF
−78 oC, 58%
Example 28
O
ON
1. t-BuOK, Tol., reflux, 5 min.
2. 18 N H2SO4, THF, 4 h 61% for two steps
MeO2C
ON
EtO2C
Example 39
Ar1 OCH2CF3O
OAr2
O
3 equiv KOt-Bu, DMF
0 oC, 30−90 min., 75−88%
Ar1O
O
Ar2
OH
182
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_79, © Springer-Verlag Berlin Heidelberg 2009
Example 410
HN
CO2MeO
NCO2Me
1. K2CO3, DMSO, 24 h2. 60 oC, 48 h
3. 5 oC, 2 M HCl, 1 h 63%
NH
O N
CO2Me
O
OMe
HN
N
O
O CO2Me
HN
N
O
HO CO2Me
References 1. Dieckmann, W. Ber. 1894, 27, 102. Walter Dieckman (1869−1925), born in Ham-
burg, Germany, studied with E. Bamberger at Munich. After serving as an assistant to von Baeyer in his private laboratory, he became a professor at Munich. At age 56, he died while working in his chemical laboratory at the Barvarian Academy of Science.
2. Davis, B. R.; Garratt, P. J. Comp. Org. Synth. 1991, 2, 795−863. (Review). 3. Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121, 6507−6508. 4. Balo, C.; Fernández, F.; García-Mera, X.; López, C. Org. Prep. Proced. Int. 2000, 32,
563−566. 5. Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403−1405. 6. Rabiczko, J.; Urba czyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58,
1433−1441. 7. Ho, J. Z.; Mohareb, R. M.; Ahn, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003,
68, 109-114. 8. de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617−1617. 9. Bernier, D.; Brueckner, R. Synthesis 2007, 2249−2272. 10. Koriatopoulou, K.; Karousis, N.; Varvounis, G. Tetrahedron 2008, 64, 10009−10013. 11. Takao, K.-i.; Kojima, Y.; Miyashita, T.; Yashiro, K.; Yamada, T.; Tadano, K.-i.
Heterocycles 2009, 77, 167−172.
183
Diels–Alder reaction The Diels–Alder reaction, inverse electronic demand Diels–Alder reaction, as well as the hetero-Diels–Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illus-trative.
HOMO‡
EDGEWG Δ
EDGEWG
EDGEWG
LUMO
‡
diene dienophile adduct
EDG = electron-donating group; EWG = electron-withdrawing group
Example 16
OMeCO2Et
Me3SiO
OMe
CO2EtH
Me3SiO
AcO
OAc
hydroquinone
180 oC, 1.5 h, 62%
‡
The Danishefsky diene Alder’s endo rule
OMe
AcO
OMe
CO2Et
Me3SiO AcOOSiMe3
EtO2C
4:1 α-OMe : β-OMe
Example 2, Intramolecular Diels–Alder reaction7
O
O
FBr4-BIPOL, AlMe3
CH2Cl2, rt, 8 h, 65%
O
OF
H
184
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_80, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Asymmetric Diels–Alder reaction5,8
94% ee90:10 endo:exo
CO2CH2CF3
NB
O
H
Br3Al
PhPh
4 mol%, CH2Cl2−78 oC, 12 h, 99%
OCH2CF3
OCH3O
O
Example 4, Retro-Diels–Alder reaction4,9
MeO2C
OH
H
MeAlCl2, maleic anhydride
CH2Cl2, μ-wave, 110 oC1 min., 74−84%
MeO2C
O
Example 5, Intramolecular Diels–Alder reaction11
O
OH
Me
HO
OOO
Me
Me2AlCl, CH2Cl2
−78 to −30 oC, 71%
References 1. Diels, O.; Alder, K. Ann. 1928, 460, 98−122. Otto Diels (Germany, 1876−1954) and
his student, Kurt Alder (Germany, 1902−1958), shared the Nobel Prize in Chemistry in 1950 for development of the diene synthesis. In this article they claimed their terri-tory in applying the Diels–Alder reaction in total synthesis: “We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such prob-lems.”
2. Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 315−399. (Review).
3. Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 401−449. (Review).
4. (a) Rickborn, B. The retro-Diels−Alder reaction. Part I. C−C dienophiles in Org. Re-act. John Wiley & Sons, 1998, 52. (b) Rickborn, B. The retro-Diels−Alder reaction. Part II. Dienophiles with one or more heteroatom in Org. React. John Wiley & Sons, 1998, 53.
5. Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650−1667. (Review).
185
6. Wang, J.; Morral, J.; Hendrix, C.; Herdewijn, P. J. Org. Chem. 2001, 66, 8478−8482. 7. Saito, A.; Yanai, H.; Sakamoto, W.; Takahashi, K.; Taguchi, T. J. Fluorine Chem.
2005, 126, 709−714. 8. Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498−1499. 9. Iqbal, M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.; Lledo, A.; Verdaguer, X.;
Riera, A. Org. Biomol. Chem. 2008, 6, 4649−4661. 10. Ibrahim-Ouali, M. Steroids 2009, 74, 133−162. 11. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412.
Inverse electronic demand Diels–Alder reaction
HOMO
‡EWG
EDG
LUMOEWGEDG Δ
EWGEDG
‡
Diene dienophile adduct
Example 12
O
BOO
EtO
3 mol% Cat., BaO, rt, 5 h
O
BOO
OEt
Me
NCr
OClO
Cat. =
OHCCO2Et
O OEtOH
HEtO2C
110 oC, 48 h76% 2 steps 98% dr, 95% ee
Example 23
H R1
O
ClR2 R3
O
N
O
NN
Mes
Cl
5 mol%
1.5 equiv NEt3, EtOAc, rt, 6 h
O
O
R1
R3R2
70−90% yield95−99% ee
186
Example 3, Catalytic asymmetric inverse-electron-demand Diels–Alder reaction4
NO2S
N
Ph
Ph5 equiv10 mol% Ni(ClO4)2•6H2O10 mol% DBFOX-Ph
CH2Cl2, rt, 73% yield
OEtOEt
Ph
SO2ArPh
97:3 endo/exo88% ee
DBFOX-Ph =O
ON N
O
Ph Ph
Example 45
O
OEWG
EWG = CONEt2, CO2Et,COR, SO2Ph, CN, Aryl
OMe
MeO OMe
MeO
1.solvent, 135 oC
2. Et2O•BF3, CH2Cl2, rt
O
OEWG
OMeOMe
O
OEWG
EWG = CONEt2, CO2Et,COR, SO2Ph, CN, Aryl
MeO NR2
MeO
PhH, Δ O
OEWG
OMe
References 1. Boger, D. L.; Patel, M. Prog. Heterocycl. Chem. 1989, 1, 30–64. (Review). 2. Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 1628–1629. 3. He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088–15089. 4. Esquivias, J.; Gomez Arrayas, R.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 1480–
1481. 5. Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org. Lett. 2008, 10, 233–236.
Hetero-Diels–Alder reaction Heterodiene addition to dienophile or heterodienophile addition to diene. Typical hetero-Diels–Alder reactions are aza-Diels–Alder reaction and oxo-Diels–Alder reaction.
187
YYX X
X XXYY
X
e.g.:
NSO2Ph
OEt
Ph
NSO2Ph
Ph OEtH
EtO2CEtO2C
NSO2Ph
Ph
EtO2C OEt
‡
Example 1, Heterodienophile addition to diene1
CO2Et
O
MeO
O
CO2EtMeOtoluene
110 oC, 60%
Example 2, Similar to the Boger pyridine synthesis (see page 59)2
MeO
OMe
OMeMeO N
N NN
CO2Me
CO2Me
CHCl3, reflux
5 days, 65%
NN
N N
CO2Me
MeO2C
MeOMeO
MeO2C CO2Me
Example 3, Using the Rawal diene4
OTBS
O
CO2MeMe
NMe2 CHCl3, −40 oC
71%
O
OMe
MeO2C
Rawal diene Example 4, Also similar to the Boger pyridine synthesis6
N
N
N
OSCH3
N
n
Δ or MW
NO
SCH3
n n = 1, 75%n = 2, 65%n = 3, 54%n = 4, 30%
188
Example 57
EtO
Me
OEt
OO
NCu
N
OOMeMe
Me3C CMe3
OTfH2O OH2
OTf
2 mol%
3 Å MS, THF, 0 oC, 87%
OEtOOEt
O
Me24:1 endo/exo97% ee
References 1. Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 109, 4390–4392. 2. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon, 1991, Vol. 5, 451−512. (Review). 3. Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418−11425. 4. Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321−3323. 5. Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093−2102. (Review). 6. Lipi ska, T. M. Tetrahedron 2006, 62, 5736−5747. 7. Evans, D. A.; Kvaerno, L.; Dunn, T. B.; Beauchemin, A.; Raymer, B.; Mulder, J. A.;
Olhava, E. J.; Juhl, M.; Kagechika, K.; Favor, D. A. J. Am. Chem. Soc. 2008, 130, 16295−16309.
189
Dienone–phenol rearrangement Acid-promoted rearrangement of 4,4-disubstituted cyclohexadienones to 3,4-disubstituted phenols.
O
R R
H
OH
RR
H
O
R R
OH
R
O
R R
H OH
RRH R
H−
:1,2-alkyl
shift
H
Example 14
O
O
O
50% aq. H2SO4
reflux, 80%
O
O
OH
Example 25
O OH
HO conc. H2SO4
Et2O, 95%
HO
Example 39
O
NBoc
O
O
conc. HCl, CH3CN
1.5 h, rt, 73%
OH
NHO
O
190
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_81, © Springer-Verlag Berlin Heidelberg 2009
Example 410
O
O
Ac2OH2SO4
0 oC to rt62%
AcO
OAc
OAc(1:1)
References 1. Shine, H. J. In Aromatic Rearrangements; Elsevier: New York, 1967, pp 55−68. (Re-
view). 2. Schultz, A. G.; Hardinger, S. A. J. Org. Chem. 1991, 56, 1105−1111. 3. Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114, 1824−1829. 4. Hart, D. J.; Kim, A.; Krishnamurthy, R.; Merriman, G. H.; Waltos, A.-M. Tetrahedron
1992, 48, 8179−8188. 5. Frimer, A. A.; Marks, V.; Sprecher, M.; Gilinsky-Sharon, P. J. Org. Chem. 1994, 59,
1831−1834. 6. Oshima, T.; Nakajima, Y.-i.; Nagai, T. Heterocycles 1996, 43, 619−624. 7. Draper, R. W.; Puar, M. S.; Vater, E. J.; Mcphail, A. T. Steroids 1998, 63, 135−140. 8. Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K.; Node, M. Tetrahedron 2004, 60,
4901−4907. 9. Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043−9048. 10. Sauer, A. M.; Crowe, W. E.; Henderson, G.; Laine, R. A. Tetrahedron Lett. 2007, 48,
6590−6593.
191
Di-π-methane rearrangement Conversion of 1,4-dienes to vinylcyclopropanes under photolysis. Also known as the Zimmerman rearrangement.
R1R
R4 R3
R2 hν R1RR2
R4R3
1,4-diene vinylcyclopropane
R1R
R4 R3
R2 hνR1R
R4 R3
R2R1R
R2
R4R3
R1R
R4 R3
R2
diradical diradical
Example 1, Aza-π-methane rearrangement2
hν, acetophenone
benzene, 86%Ph
N OAcPh
Ph
PhN
OAc
Example 24
CN
CNhν, acetone
90%
CN
CN
Example 38
SO2 X S
O2
X
X = CH3, CH2Ph, COCMe3, CO2CH2Ph SiMe3, SnBu3, SePh,
hv, 300 nMCH3COCH3
23−64%
(CH2)3CH3
192
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_82, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Oxa-π-methane rearrangement8
MeO Me
hv, acetone
Pyrex, 76% OMe
Me H
H
References 1. (a) Zimmerman, H. E.; Grunewald, G. L. J. Am. Chem. Soc. 1966, 88, 183–184.
Known for the Traxler–Zimmerman trasition state for the asymmetric synthesis, How-ard E. Zimmerman is a professor at the University of Wisconsin at Madison. (b) Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065–3112. (Review). (c) Zimmerman, H. E.; Církva, V. Org. Lett. 2000, 2, 2365–2367.
2. Armesto, D.; Horspool, W. M.; Langa, F.; Ramos, A. J. Chem. Soc., Perkin Trans. I 1991, 223–228.
3. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Chem. Commun. 2000, 2341–2342. 4. Ünaldi, N. S.; Balci, M. Tetrahedron Lett. 2001, 42, 8365–8367. 5. Altundas, R.; Dastan, A.; Ünaldi, N. S.; Güven, K.; Uzun, O.; Balci, M. Eur. J. Org.
Chem. 2002, 526–533. 6. Zimmerman, H. E.; Chen, W. Org. Lett. 2002, 4, 1155–1158. 7. Tanifuji, N.; Huang, H.; Shinagawa, Y.; Kobayashi, K. Tetrahedron Lett. 2003, 44,
751–754. 8. Dura, R. D.; Paquette, L. A. J. Org. Chem. 2006, 71, 2456–2459. 9. Singh, V.; Chandra, G.; Mobin, S. M. Synlett 2008, 2267–2270.
193
Doebner quinoline synthesis Three-component coupling of an aniline, pyruvic acid, and an aldehyde to provide a quinoline-4-carboxylic acid.
NH2 OHC N
CO2H
CO2H
O
NH2:
NH
OH2O
HH
:− H2O CO2H
OH
NH
H
NH
O CO2H
N
CO2HHOH
HNH
CO2HH2OH
B:
H
N
CO2H
NH
CO2H
air oxidation
− 2 H
− H2O
Example 12
MeO
NH2
O
HO
CO2H
NO2MeO
N
CO2H
NO2
EtOH
Δ, 95%
Example 26
NH2 CO2H
OH
ON
CO2H
EtOH, reflux
3 h, 20%
194
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_83, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Combinatorial Doebner reaction7
NH
HN
O
R3 O
O
NH2R1 OHC
R2 PhH
reflux, 8 h
R1
N
R2
O NH O
HN
R3
References 1. Doebner, O. G. Ann. 1887, 242, 265. Oscar Gustav Doebner (1850−1907) was born in
Meininggen, Germany. After studying under Liebig, he actively took part in the Franco-Prussian War. He apprenticed with Otto and Hofmann for a few years after the war, then began his independent researches at the University at Halle.
2. Mathur, F. C.; Robinson, R. J. Chem. Soc. 1934, 1520−1523. 3. Elderfield, R. C. Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley & Sons,
Inc.: New York, 1952, Vol. 4, Quinoline, Isoquinoline and Their Benzo Derivatives, pp. 25−29. (Review).
4. Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, Inc.: New York, 1977, Vol. 32; Quinolines, pp. 125−131. (Review).
5. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396−401. 6. Herbert, R. B.; Kattah, A. E.; Knagg, E. Tetrahedron 1990, 46, 7119−7138. 7. Gopalsamy, A.; Pallai, P. V. Tetrahedron Lett. 1997, 38, 907−910. 8. Pflum, D. A. Doebner quinoline synthesis. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 407−410. (Re-view).
195
Doebner–von Miller reaction Doebner–von Miller reaction is a variant of the Skraup quinoline synthesis (page 509). Therefore, the mechanism for the Skraup reaction is also operative for the Doebner–von Miller reaction. The following mechanism is favored by Denmark’s mechnistic study using 13C-labelled α,β-unsaturated ketones.9
NH2
O
NH
HCl or
ZnCl2
NH2
Oreversible
conjugate additionNH
O
irreversible
fragmentationN
Ocondensation
N
NH2
conjugate additionN
NH
cyclization
rearomatization NH NH2
Example 15
N CO2Me
NH2
MeO2C CO2Me
O TsOH, CH2Cl2
reflux, 24 h
CO2Me
Example 26
NHAc
FH
ON
FF F
Me
6 N HCl, Tol.
100 °C, 2 h, 70%
196
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_84, © Springer-Verlag Berlin Heidelberg 2009
Example 3, A novel variant10
B(OH)2
NH22 equiv
R3 OR2
R1
3% [RhCl(cod)]2KOH, rt, 24 h
then 10% Pd/Cair, reflux, 4 h
42−96%N
R3R2
R1
References 1. Doebner, O.; von Miller, W. Ber. 1883, 16, 2464. 2. Corey, E. J.; Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599−5600. 3. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269−1274. 4. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Tetrahedron Lett. 1998, 39,
5133−5134. 5. Carrigan, C. N.; Esslinger, C. S.; Bartlett, R. D.; Bridges, R. J. Bioorg. Med. Chem.
Lett. 1999, 9, 2607−2712. 6. Sprecher, A.-v.; Gerspacher, M.; Beck, A.; Kimmel, S.; Wiestner, H.; Anderson, G. P.;
Niederhauser, U.; Subramanian, N.; Bray, M. A. Bioorg. Med. Chem. Lett. 1998, 8, 965−970.
7. Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731−3734. 8. Moore, A. Skraup Doebner–von Miller Reaction. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 488−494. (Review).
9. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668−1676. Mechanistic study using 13C-labelled α,β-unsaturated ketones.
10. Horn, J.; Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117−4120.
197
Dötz reaction Cr(CO)3-coordinated hydroquinone from vinylic alkoxy pentacarbonyl chromium carbene (Fischer carbene) complex and alkynes.
R1 R2
(OC)5CrOR
RL RS
Δ RL
RSOR
R1
OH
Cr(CO)3
R2
R1 R2
(OC)5CrOR
−COOR
R1 R2
(OC)4Cr alkyne
coordination
RL RS
R1 R2
(OC)4CrOR
R3
RSRL
OR
COOCOC CO
Cr
R2R1
alkyne insertion
Cr
R2R1
RSRL
OR
COOC CO
COCO insertion
electrocyclic
ring closureCr(CO)3
ORL
RSOR
R1
RL
RSOR
R1
OH
Cr(CO)3
tautomerizationR2
R2
Example 15
SeNO2
(OC)5CrOMe
1. THF, reflux
2. CAN, 22%
O
O
SeNO2
Example 38
MOMO
MOMO
OMe
Cr(CO)5
O O
H
MOMO OH
MOMO OMe
OO
ClCH2CH2Cl
70 oC, 1 h, 76%
198
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_85, © Springer-Verlag Berlin Heidelberg 2009
Example 38
BnO
MOMO MeO
Cr(CO)5
OMe
THF, 50 oC, 61%OH
MeOOMe
OMOM
BnO
Example 39
O
OMeFMeO
MeO
1. 1.5 equiv t-BuLi, THF, −78 oC2. 1.02 equiv Cr(CO)6, THF −78 oC to rt
3. 1.02 equiv Et3O•FB4, rt 29%
O
OMeFMeO
MeO OEt
Cr(CO)5
5 equiv
THF, 80 oC
Ph H CAN−HNO3
84%, 2 steps
O
MeOMeO
MeO
F
OEt
Ph
Cr(CO)n O
MeOMeO
MeO
O
Ph
O O
References 1. Dötz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644−645. Karl H. Dötz (1943−) was a
professor at the University of Munich in Germany. 2. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI
Press, Greenwich, CT; 1989; Vol. 1. (Review). 3. Wulff, W. D. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F.
G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 12. (Review). 4. Torrent, M.; Solá, M.; Frenking, G. Chem. Rev. 2000, 100, 439−494. (Review). 5. Caldwell, J. J.; Colman, R.; Kerr, W. J.; Magennis, E. J. Synlett 2001, 1428−1430. 6. Solá, M.; Duran, M.; Torrent, M. The Dötz reaction: A chromium Fischer carbene-
mediated benzannulation reaction. In Computational Modeling of Homogeneous Ca-talysis Maseras, F.; Lledós, eds.; Kluwer Academic: Boston; 2002, 269−287. (Re-view).
7. Pulley, S. R.; Czakó, B. Tetrahedron Lett. 2004, 45, 5511−5514. 8. White, J. D.; Smits, H. Org. Lett. 2005, 7, 235−238. 9. Boyd, E.; Jones, R. V. H.; Quayle, P.; Waring, A. J. Tetrahedron Lett. 2005, 47,
7983−7986.
199
Dowd−Beckwith ring expansion Radical-mediated ring expansion of 2-halomethyl cycloalkanones.
OBr
CO2CH3
Bu3SnH, AIBN
PhH, reflux
O
CO2CH3
N N CNNCΔ
CNN2↑ 2homolyticcleavage
2,2 -azobisisobutyronitrile (AIBN)
n-Bu3Sn H CN n-Bu3Sn CNH
SnBu3
OBr
CO2CH3
O
CO2CH3Bu3SnBr
O
CO2CH3
O
CHO2CH3
SnBu3H Bu3Sn
O
CO2CH3
Example 14
1.2 eq. Bu3SnHcat. AIBN
Tol., reflux, 23 h
H
CO2EtH
I
O
H
H
H
CO2EtH
H
O
CO2Et86% 13%
O
Example 29
OCO2Me
I
AIBN, Bu3SnD
PhH, 80 oC
O
CO2MeD77%
OCO2Me
H
D
OCO2Me
D
8% 15%
200
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_86, © Springer-Verlag Berlin Heidelberg 2009
References 1. Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493−3494. Paul Dowd
(1936−1996) was a professor at the University of Pittsburgh. 2. (a) Beckwith, A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc.,
Chem. Commun. 1987, 666−667. Athelstan L. J. Beckwith is a professor at University of Adelaide, Adelaide, Australia. (b) Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565−2575. (c) Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77−90. (d) Dowd, P.; Choi, S.-C. Tetrahedron Lett. 1989, 30, 6129−6132. (e) Dowd, P.; Choi, S.-C. Tetrahedron 1991, 47, 4847−4860.
3. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091−2115. (Review). 4. Banwell, M. G.; Cameron, J. M. Tetrahedron Lett. 1996, 37, 525−526. 5. Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080−3082. 6. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317−4353. (Review). 7. Sugi, M.; Togo, H. Tetrahedron 2002, 58, 3171−3177. 8. Ardura, D.; Sordo, T. L. Tetrahedron Lett. 2004, 45, 8691−8694. 9. Ardura, D.; Sordo, T. L. J. Org. Chem. 2005, 70, 9417−9423.
201
Dudley reagent
NCH3
OOTf
Dudley benzyl reagent
NO
Dudley PMB reagentH3CO
CH3
The Dudley reagents are employed for the protection of alcohols as benzyl1 or PMB2 ethers, respectively, under mild conditions. Carboxylic acids are readily protected as well.3 Activation of the appropriate Dudley reagent in the presence of an alcohol furnishes the desired arylmethyl ether. The benzyl reagent is activated upon warming to approximately 80–85 °C, whereas activation of the PMB reagent occurs at room temperature upon treatment with methyl triflate (CH3OTf) or protic acid.4 Aromatic solvents, most commonly trifluorotoluene, often provide the best results. Magnesium oxide (MgO) is typically included in the reaction mixture as an acid scavenger.5 For benzylation of carboxylic acids, triethylamine (Et3N) is used in place of MgO.3 Preparation:1–3
NO
CH3OTf, toluene
0 °C to rt, 1 h, 99%NCH3
OOTf
Dudley benzyl reagent
NO
Dudley PMB reagentH3CO
CH3
OH
H3CONCl
CH3KOH, 18-crown-6
toluene, reflux (–H2O)90–93%
The Dudley reagents are conveniently prepared from readily available starting ma-terials and are indefinitely stable to storage and handling under standard laboratory conditions. Alternatively, both reagents are commercially available.
Example 16
OHOAc
Dudley benzyl reagent, MgO
PhCF3, 85 °C, 24 h, 96%
OBnOAc
202
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_87, © Springer-Verlag Berlin Heidelberg 2009
Benzylation of a monoacetylated diol is shown in Example 1.6 The Dudley benzyl reagent was uniquely effective for protection of the free alcohol without loss and/or migration of the labile acetyl group. Example 22
PhSi(CH3)3
OHDudley PMB reagent
CH3OTf, MgO
PhCF3, rt, 1 h, 80% PhSi(CH3)3
OPMB
PMB-protection of a β-hydroxysilane can be accomplished without competition from the Peterson elimination (Example 2),2 which would occur under the basic or acidic conditions required for many other alkylation reactions.
Example 34
O
O OOH
O
O
O OOPMB
O
Dudley PMB reagent, CSA
CH2Cl2, rt, 72 h, 85%
The Dudley PMB reagent can also be activated under mildly acidic conditions us-ing catalytic camphorsulfonic acid (CSA) in lieu of CH3OTf (Example 3).4
Example 4, In situ-formation of the Dudley benzyl reagent is achieved by treating a mixture of an alcohol and 2-benzyloxypyridine with CH3OTf 7
O NH
OCH3
O
O
OHCH3OTf, MgO, toluene
0 to 85 °C, 24 h, 84% O NH
OCH3
O
O
OBn
O N
References 1. Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923–3927. 2. Nwoye, E. O.; Dudley, G. B. Chem. Commun. 2007, 1436–1437. 3. Tummatorn, J.; Albiniak, P. A.; Dudley, G. B. J. Org. Chem. 2007, 72, 8962–8964. 4. Stewart, C. A.; Peng, X.; Paquette, L. A. Synthesis 2008, 433–437. 5. Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Org. Synth. 2007, 84, 295–305. 6. Schmidt, J. P.; Beltrân-Rodil, S.; Cox, R. J.; McAllister, G. D.; Reid, M.; Taylor, R. J.
K. Org. Lett. 2007, 9, 4041–4044. 7. Lopez, S. S.; Dudley, G. B. Beilstein J. Org. Chem. 2008, 4, No. 44.
203
Erlenmeyer−Plöchl azlactone synthesis Formation of 5-oxazolones (or “azlactones”) by intramolecular condensation of acylglycines in the presence of acetic anhydride.
O
HN
R1 O
NOR1
Ac2OCO2H
O
HN
R1
OO
H
O
O O
O
N
R1
OO
H
O
mixed anhydride
AcO
O
NOR1
2 AcOH
Example 12
O
HN
PhCO2H
OO
H
O
O
NOPh
O
O
NaOAc, Ac2O
110 oC, 69−73%
Example 28
O
HN
PhCO2H
OH
OH
OO
OO
Pb(OAc)4, Ac2O
THF, reflux, 15 h
NO
O
Ph
BuNH2
67%
OO
H
HNNH-Bu
O
Ph
OO
H
O
5.5:1 Z/E
Example 39
O
HN
PhCO2H H
O
FF
OBnN
O
O
Ph
BnONaOAc, Ac2O
95%
204
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_88, © Springer-Verlag Berlin Heidelberg 2009
References 1. (a) Plöchl, J. Ber. 1884, 17, 1616−1624. (b) Erlenmeyer, E., Jr. Ann. 1893, 275, 1−3.
Emil Erlenmeyer, Jr. (1864−1921) was born in Heidelberg, Germany to Emil Erlen-meyer (1825−1909), a famous chemistry professor at the University of Heidelberg. He investigated the Erlenmeyer−Plöchl azlactone synthesis while he was a Professor of Chemistry at Strasburg. The Erlenmeyer flasks “ ” are ubiquitous in organic chemistry laboratories.
2. Buck, J. S.; Ide, W.S. Org. Synth. Coll. II, 1943, 55. 3. Carter, H. E. Org. React. 1946, 3, 198−239. (Review). 4. Baltazzi, E. Quart. Rev. Chem. Soc. 1955, 9, 150−173. (Review). 5. Filler, R.; Rao, Y. S. New Development in the Chemistry of Oxazolines, In Adv. Het-
erocyclic Chem; Katritzky, A. R.; Boulton, A. J., Eds; Academic Press, Inc: New York, 1977, Vol. 21, pp 175−206. (Review).
6. Mukerjee, A. K.; Kumar, P. Heterocycles 1981, 16, 1995−2034. (Review). 7. Mukerjee, A. K. Heterocycles 1987, 26, 1077−1097. (Review). 8. Combs, A. P.; Armstrong, R. W. Tetrahedron Lett. 1992, 33, 6419−6422. 9. Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L. J. Fluorine Chem. 2002, 115,
27−32. 10. Brooks, D. A. Erlenmeyer−Plöchl Azlactone Synthesis. In Name Reactions in Hetero-
cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 229−233. (Review).
205
Eschenmoser’s salt
NCH2
H3C CH3
I
Eschenmoser’s salt, dimethylmethylideneammonium iodide, is a strong dimethylaminomethylating agent, used to prepare derivatives of the type RCH2N(CH3)2. Enolates, enolsilylethers, and even more acidic ketones undergo efficient dimethylaminomethylation—employed in the Mannich reaction.
Mechanism
LDA
THFR1R2
O
R1R2
OLi NCH2
H3C CH3
I
R1R2
O
NCH2
H3C CH3
R1
O
R2
NCH3
CH3
Li
Example 13 Once prepared, the resulting tertiary amines can be further methylated and then
subjected to base-induced elimination to afford methylenated ketones.
OH
CH3TBSO
O
O
O
H3C H
HH H
OTBS
CO2Me
1. 15 equiv NaN(SiMe3)2, THF −78 oC, 45 min. then 15 equiv of Me2(CH2)N+I−
0 oC, 15 min.
2. 20 equiv MeI, MeOH, 0.5 h3. 10 equiv DBU, PhH, rt, 1 h 51% 3 steps
OH
CH3TBSO
O
O
O
H3C H
HH H
OTBS
CO2Me
206
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_89, © Springer-Verlag Berlin Heidelberg 2009
Example 24
NCH2
H3C CH3
IHN
NH
NO S
OO
OEt3NH Et3N, DMF, rt
12 h, 64%
HN
NN
O SO
OO
NCH3
CH3
: Et3NH
HN
NH
NO S
OO
OEt3NH
HN
NNN
CH3
CH3
HN
NH
NO S
OO
O
Example 35
O
O
NH
OO
NCH2
H3C CH3
I
DMF, 90 oC, 62% N
O
O H
O
O
References 1. Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem., Int. Ed.
1971, 10, 330–331. 2. Kleinman, E. F. Dimethylmethyleneammonium Iodide and Chloride. In Encyclopedia
of Reagents for Organic Synthesis (Ed: Paquette, L. A.) 2004, John Wiley & Sons, New York. (Review).
3. Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X. Y.; Hwang, C. K. J. Am. Chem. Soc. 1993, 115, 3558–3575.
4. Saczewski, J.; Gdaniec, M. Tetrahedron Lett. 2007, 48, 7624–7627. 5. Hong, A.-W.; Cheng, T.-H.; Raghukumar, V.; Sha, C.-K. J. Org. Chem. 2008, 73,
7580–7585. 6. Cesario, C.; Miller, M. J. Org. Lett. 2009, 11, 449–452.
207
Eschenmoser−Tanabe fragmentation
Fragmentation of α,β-epoxyketones via the intermediacy of α,β-epoxy sulfonyl-hydrazones.
O
1. H2O2, −OH
2. H2NNHSO2Ar, H+
3. −OH
O
O
O OH
O
OOH
O
O
N
O
NH
SO2Ar
H2NNHSO2Ar
H
NN SO2Ar
O
SO2Ar N2↑
O
OH
N
O
N SHO2Ar
Example 14
O
OAcO
Tol-SO2NHNH2CHCl3-AcOH (1:1)
rt, 5 h, 73%AcO
O
Example 27
Me
MeOO
1. TsNHNH2, rt
2. 55 oC, 2 h, 50% O
Me
Me
208
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_90, © Springer-Verlag Berlin Heidelberg 2009
Example 39
OO
OAcOMe
H
O
NNs
1. NsNHNH2, AcOH, THF; evaporation, 60 oC, NaBH4, AcOH, THF, 0 oC
2. TESOTf, 2,6-lutidine CH2Cl2, rt 60%, 2 steps
O
OAcOMe
H
NNsTESO
References 1. Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708−713. Albert
Eschenmoser (Switzerland, 1925−) is best known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Woodward in 1973. He now holds appointments at ETH Zürich and Scripps Research Institute, La Jolla.
2. Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943−3946. 3. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv.
Chim. Acta 1972, 55, 1276−1319. 4. Batzold, F. H.; Robinson, C. H. J. Org. Chem. 1976, 41, 313−317. 5. Covey, D. F.; Parikh, V. D. J. Org. Chem. 1982, 47, 5315−5318. 6. Chinn, L. J.; Lenz, G. R.; Choudary, J. B.; Nutting, E. F.; Papaioannou, S. E.; Metcalf,
L. E.; Yang, P. C.; Federici, C.; Gauthier, M. Eur. J. Med. Chem. 1985, 20, 235−240. 7. Dai, W.; Katzenellenbogen, J. A. J. Org. Chem. 1993, 58, 1900−1908. 8. Mück-Lichtenfeld, C. J. Org. Chem. 2000, 65, 1366−1375. 9. Kita, Y.; Toma, T.; Kan, T.; Fukuyama, T. Org. Lett. 2008, 10, 3251−3253.
209
Eschweiler–Clarke reductive alkylation of amines Reductive methylation of primary or secondary amines using formaldehyde and formic acid. Cf. Leuckart–Wallach reaction.
R NH2 CH2O HCO2H R N
formic acid is the hydride source as a reducing agent
R NH2
O
: R NOH2
H
H
HH
R NOH
H
H
R NH O
HO C O↑O
R NH
:
OH
HH
R NOH2:H
R NH O
HO R NC O↑O H R N
− H
Example 17
H3C
ONHCH3
DCOD, DCO2D, DMSO
microwave (120 W)1−3 min.
d3-tamoxifen
H3C
ON
CD3
CH3
Example 29
HN
OH
1.2 equiv 37% CH2O in H2O5 equiv 85% HCO2H in H2O
steam bath, 84%
N
OH
CH3
210
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_91, © Springer-Verlag Berlin Heidelberg 2009
Example 310
N
NNH
CHO
varenicline (Chantix)
N
NN
OH
:
N
NN
H O
ON
NN
References 1 (a) Eschweiler, W. Chem. Ber. 1905, 38, 880–892. Wilhelm Eschweiler (1860−1936)
was born in Euskirchen, Germany. (b) Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571–4587. Hans T. Clarke (1887−1927) was born in Harrow, England.
2 Moore, M. L. Org. React. 1949, 5, 301–330. (Review). 3 Pine, S. H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829–832. 4 Bobowski, G. J. Org. Chem. 1985, 50, 929–931. 5 Alder, R. W.; Colclough, D.; Mowlam, R. W. Tetrahedron Lett. 1991, 32, 7755–7758. 6 Bulman Page, P. C.; Heaney, H.; Rassias, G. A.; Reignier, S.; Sampler, E. P.; Talib, S.
Synlett 2000, 104–106. 7 Harding, J. R.; Jones, J. R.; Lu, S.-Y.; Wood, R. Tetrahedron Lett. 2002, 43, 9487–
9488. 8 Brewer, A. R. E. Eschweiler–Clarke reductive alkylation of amine. In Name Reactions
for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 86−111. (Review).
9 Weis, R.; Faist, J.; di Vora, U.; Schweiger, K.; Brandner, B.; Kungl, A. J.; Seebacher, W. Eur. J. Med. Chem. 2008, 43, 872–879.
10 Waterman, K. C.; Arikpo, W. B.; Fergione, M. B.; Graul, T. W.; Johnson, B. A.; Mac-donald, B. C.; Roy, M. C.; Timpano, R. J. J. Pharm. Sci. 2008, 97, 1499–1507.
211
Evans aldol reaction Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary.
O
R* +H
O
R' base
chiral auxiliary
R*
O
MeMeR'
OH
R* = NO
O
Bn
NO
O
Me
NO
O
Ph Ph
Evans syn
Lewis acid
NO
O
t-Bu
NO
O
i-Pr
Example 12
ON
OO1. Bu2BOTf, R3N
2. PhCHO, − 78 oC79%, 80:20 de
ON
OO
Ph
OH
ON
OO
HR3N:
Bu2B OTf
Z-(O)-boron enolate
formationON
OOB
BuBu
PhCHO
OBO Bu
Bu
Ph
HN
O
OH
H
ON
OO
Ph
Oaldol
condensation
BBuBu
ON
OO
Ph
OHworkup
Example 25
ON
OOMeO
N OMeCO2Me
TiCl4, DIPEACH2Cl2, −78 oC, 1.5 h
then rt, overnight, 52%
ON
OO
NMeO2C
OMe
212
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_92, © Springer-Verlag Berlin Heidelberg 2009
Example 39
OTES
ONO
S
Bn
O
OBn
1 eq. Bu2BOTf1.1 eq. Et3N
PhMe, 0.15 M− 50 to − 30 oC
2 h, 72%
NO
S
Bn
O
OBn
OTESOH
Example 4, Crimmins procedure10
N O
Bn
OO
TBDPSOCHO
TiCl4(−)-sparteine
96%, 96% deN O
Bn
OOOH
TBDPSO
References 1. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127−2129.
David Evans is a professor at Harvard University. (b) Evans, D. A.; McGee, L. R. J. Am. Chem. Soc. 1981, 103, 2876−2878.
2. Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55, 173−181. 3. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3−12. (Review). 4. Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000, 11, 3591−3607. 5. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56,
7411−7422. 6. Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem. 2001, 66, 8463−8469. 7. Guerlavais, V.; Carroll, P. J.; Joullié, M. M. Tetrahedron: Asymmetry 2002, 13,
675−680. 8. Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D. Org. Lett.
2003, 5, 329−331. 9. Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004, 69, 2569−2572. 10. Ghosh, S.; Kumar, S. U.; Shashidhar, J. J. Org. Chem. 2008, 73, 1582−1585. 11. Zhang, J. Evans aldol reaction. In Name Reactions for Homologations-Part II; Li, J.
J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 532−553. (Review).
213
Favorskii rearrangement Transformation of enolizable α-haloketones to esters, carboxylic acids, or amides via alkoxide-, hydroxide-, or amine-catalyzed rearrangements, respectively.
O
R2 R4
R3R1X H
X = Cl, Br, INuc-HNuc = OH, OR, NRR'
O
Nuc
H
R2
R1
R4R3base
The intramolecular Favorskii Rearrangement:
OR2R1
X HNuc-H
( )n
O
NucR1
HR2
( )n
n = 0−5base
ORO
Cl
O OR
enolizable α-haloketone
ORO
ClO
ClHHOR
O
Cl
OR
cyclopropanone intermediate
ORO O ORH OR HOR
O OR
OR
Example 12
O O
Br Br
CO2HHBr2, CH3CO2H
50 oC, 1 h, 97%
KOH, DMSO
100 oC, 1 h47%
214
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_93, © Springer-Verlag Berlin Heidelberg 2009
Example 2, Homo-Favorskii rearrangement3
OTsO 1.96 eq. NaOH
dioxane/H2O90 oC, 3 h, 86%
H
O
51 : 40 : 9
O O
Example 36
OCO2Me
OCO2Me
BrBrBr2
Et2O
O
MeO
O
MeO
NaOMe, MeOH
37% 2 steps
Example 4, Photo-Favorskii Rearrangement7
O
H H
Cl electron
transfer
hν
homolysis
OCl
300 nm light
5% aq. CH3CNpropylene oxide
4 h, 81%
O
H H
ClH H
1,2-aryl
migration O
OH
OH2O
Cl
Example 58
Br
O
Br
Br
O
BrNC
KCN, α-cyclodextrin
MeCN, H2O10−15 oC, 12 h
80%
Br
O
NC
NC
215
HH
NC O
NCH
H
HO O
NC HH
HO O
NC
9 : 1Ratio
Example 610
O
ClTHPO
OMeO
THPO
NaOMe
MeOH0 oC, 15 min.
96%
References 1. (a) Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533−563. Aleksei E. Favorskii
(1860−1945), born in Selo Pavlova, Russia, studied at St. Petersburg State University, where he became a professor since 1900. (b) Favorskii, A. E. J. Prakt. Chem. 1913, 88, 658.
2. Wagner, R. B.; Moore, J. A. J. Am. Chem. Soc. 1950, 72, 3655−3658. 3. Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht, C. L.; Schenk, H. P. J. Am. Chem.
Soc. 1971, 93, 3208−3216. 4. Chenier, P. J. J. Chem. Ed. 1978, 55, 286−291. (Review). 5. Barreta, A.; Waegell, B. In Reactive Intermediates; Abramovitch, R. A., ed.; Plenum
Press: New York, 1982, 2, pp 527−585. (Review). 6. White, J. D.; Dillon, M. P.; Butlin, R. J. J. Am. Chem. Soc. 1992, 114, 9673−9674. 7. Dhavale, D. D.; Mali, V. P.; Sudrik, S. G.; Sonawane, H. R. Tetrahedron 1997, 53,
16789−16794. 8. Kitayama, T.; Okamoto, T. J. Org. Chem. 1999, 64, 2667−2672. 9. Mamedov, V. A.; Tsuboi, S.; Mustakimova, L. V.; Hamamoto, H.; Gubaidullin, A. T.;
Litvinov, I. A.; Levin, Y. A. Chem. Heterocyclic Compd. 2001, 36, 911. (Review). 10. Pogrebnoi, S.; Saraber, F. C. E.; Jansen, B. J. M.; de Groot, A. Tetrahedron 2006, 62,
1743−1748. 11. Filipski, K.J.; Pfefferkorn, J. A. Favorskii rearrangement. In Name Reactions for Ho-
mologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 238−252. (Review).
216
Quasi-Favorskii rearrangement
If there are no enolizable hydrogens present, the classical Favorskii rearrange-ment is not possible. Instead, a semi-benzylic mechanism can lead to a rear-rangement referred to as quasi-Favorskii.
O
R2 R5
R3R1X R4
X = Cl, Br, INuc
Nuc = OH, OR, NRR'
O
Nuc
R5
R3
R4
R1R2 R3,4,5 = H
Example 1, Arthur C. Cope’s initial discovery1
Br
O OEt
Br
OEtO
CO2Et
Hg(OAc)2
EtOH, reflux4 h, 71%
non-enolizable ketone
Example 25
O
Br
NHLi O
NH
Et2O, hexane25 oC, 67%
Example 36
Br
O
Li
THF, −78 to −30 oC, 90% O
References 1. Cope, A. C.; Graham, E. S. J. Am. Chem. Soc. 1951, 73, 4702−4706. 2. Smissman, E. E.; Diebold, J. L. J. Org. Chem. 1965, 30, 4005−4007. 3. Sasaki, T.; Eguchi, S.; Toru, T. J. Am. Chem. Soc. 1969, 91, 3390−3391. 4. Baudry, D.; Begue, J. P.; Charpentier-Morize, M. Tetrahedron Lett. 1970, 2147−2150. 5. Stevens, C. L.; Pillai, P. M.; Taylor, K. G. J. Org. Chem. 1974, 39, 3158−3161. 6. Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563−2565. 7. Harmata, M.; Wacharasindhu, S. J. Org. Chem. 2005, 70, 725−728. 8. Filipski, K.J.; Pfefferkorn, J. A. Favorskii rearrangement. In Name Reactions for Ho-
mologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 438−452. (Review).
9. Harmata, M.; Wacharasindhu, S. Synthesis 2007, 2365−2369.
217
Feist–Bénary furan synthesis α-Haloketones react with β-ketoesters in the presence of base to fashion furans.
OEt
O OCl
OO
CO2Et
Et3N, 0 °C, 52 h
54−57%
ClOCO2Et
O
HCO2Et
O
Et3N Hrate-determining
step
Et3N:
O
OHCl
HCO2Et
:NEt3
O
CO2EtHOEt3N H
O
CO2EtH2O
:
O
CO2Et
O
CO2Et
H
Et3N:
Example 12,3
O
OOEt
O O
ClOCH3
OH3CO2C
O H3CO
KOH, MeOH
57%
Example 24
OEt
O O
HCl
O O
CO2Et
pyridine, rt to 50 °C, 4 h
then rt, overnight, 86%
Example 3, Ionic liquid-promoted interrupted Feist–Benary reaction10
R1 R2
O OR3 OEt
Br O
O
[bmim]OH
rt O
R1OC
R1
HOCO2Et
R3
interrupted Feist−Benary
products
[pmim]Br
70−75 oC O
R1OC
R1
CO2Et
R3
Feist−Benary products
R1 = CH3, Et, Ph, n-Pr, etc.R2 = CH3, OCH3, PEtR3 = H, n-Bu, CO2Et [bmim]OH = N N C4H9
OH[pmim]Br = N N C4H9
Br
218
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_94, © Springer-Verlag Berlin Heidelberg 2009
References 1. (a) Feist, F. Ber. 1902, 35, 1537−1544. (b) Bénary, E. Ber. 1911, 44, 489−492. 2. Gopalan, A.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 1756−1757. 3. Gopalan, A.; Magnus, P. J. Org. Chem. 1984, 49, 2317−2321. 4. Padwa, A.; Gasdaska, J. R. Tetrahedron 1988, 44, 4147−4160. 5. Dean, F. M. Recent Advances in Furan Chemistry. Part I. In Advances in Heterocyclic
Chemistry, Katritzky, A. R., Ed.; Academic Press: New York, 1982; Vol. 30, 167−238. (Review).
6. Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Synth. Commun. 1990, 20, 1923−1929.
7. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.; Bird, C. V. Eds.; Pergamon: New York, 1996; Vol. 2, 351−393. (Review).
8. König, B. Product Class 9: Furans. In Science of Synthesis: Houben−Weyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183−278. (Review).
9. Shea, K. M. Feist–Bénary Furan Synthesis. In Name Reactions in Heterocyclic Chem-istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 160−167. (Review).
10. Ranu, B. C.; Adak, L.; Banerjee, S. Tetrahedron Lett. 2008, 49, 4613−4617.
219
Ferrier carbocyclization This process (also known as the “Ferrier II Reaction”) has proved to be of consid-erable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex com-pounds of interest in biological and medicinal chemistry.1,2
General examples:3
O
OMe
BzOBzO
TsO
O
OMe
BzOBzO
TsO
HgCl
OBzOBzO
HgCl
HO
1
2
HgCl2, Me2CO, H2O
reflux, 4.5 h, 83%
OMeOTs
BzOBzO
O
HgCl
OTs O OH
BzOBzO
TsO
O
43
BzOBzO
O
BzO OH
OBzO
BzOO
OBzBzO
BzO OBzOBz
OMe
BzOBzO
O
OH
OBz
OBzO
OMeBzOBzO
BzOO
OHOBz83%6
93%480%6
More complex products:
O
OMe
BzO
OBzO
O
OMe
BzO
AcOAcO
OH
OBzO
AcOAcO
75%7
O
OMeO
OC6H4OMe(p)O
OC6H4OMe(p)
OH
86% (2:1)8
OAcOAc
OH
AcOAcO
83%7
O
O
O
Complex bioactive compounds made following the application of the reaction:
O
OH
O NH
O
O
OH O
HOH
OHHOH
OH
NHHOHO
HOHO
Paniculide A9 Pancratistatin10 Calystegine B211
O
220
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_95, © Springer-Verlag Berlin Heidelberg 2009
Modified hex-5-enopyranosides and reactions
OH
BnOBnO
BnO
HOOAca,b
85%14
O
OMe
BnOBnO
BnO
OAc
O
OMe
BnOBnO
BnO
OMe
BnOBnO
OMe
BnOBnO
BnO
HO OBn
O
Hc
d
79%13
98%13
a, Hg(OCOCF3)2, Me2CO, H2O, 0 oC; b, NaBH(OAc)3, AcOH, MeCN, rt; c, i-Bu3Al, PhMe, 40 °C; d, Ti(Oi-Pr)Cl3, CH2Cl2, –78 °C, 15 min. (Note: The aglycon is retained in the Al- and Ti-induced reactions). References 1. Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779−2831. (Review). 2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 277−291 (Review). 3. Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455−1458. The discovery (1977)
was made in the Pharmacology Department, University of Edinburgh, while R. J. Fer-rier was on leave from Victoria University of Wellington, New Zealand where he was Professor of Organic Chemistry. He is now a consultant with Industrial Research Ltd., Lower Hutt, New Zealand.
4. Blattner, R.; Ferrier, R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. 1, 1985, 2413−2416.
5. Chida, N.; Ohtsuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2118−2121.
6. Machado, A. S.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1985, 135, 231−239. 7. Sato, K.-i.; Sakuma, S.; Nakamura, Y.; Yoshimura, J.; Hashimoto, H. Chem. Lett.
1991, 17−20. 8. Ermolenko, M. S.; Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 711−714. 9. Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tetrahedron 1999, 55,
3855−3870. 10. Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36, 195−196. 11. Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443−10458. 12. Das, S. K.; Mallet, J.-M.; Sinaÿ, P. Angew. Chem., Int. Ed. 1997, 36, 493−496. 13. Sollogoub, M.; Mallet, J.-M.; Sinaÿ, P. Tetrahedron Lett. 1998, 39, 3471−3472. 14. Bender, S. L.; Budhu, R. J. J. Am. Chem. Soc. 1991, 113, 9883−9884. 15. Estevez, V. A.; Prestwich, E. D. J. Am. Chem. Soc. 1991, 113, 9885−9887. 16. Yadav, J. S.; Reddy, B. V. S.; Narasimha Chary, D.; Madavi, C.; Kunwar, A. C.
Tetrahedron Lett. 2009, 50, 81−84.
221
Ferrier glycal allylic rearrangement In the presence of Lewis acid catalysts O-substituted glycal derivatives can react with O-, S-, C- and, less frequently, N-, P- and halide nucleophiles to give 2,3-unsaturated glycosyl products.1,2 This allylic transformation has been termed the “Ferrier Reaction” or, to avoid complications, the “Ferrier I Reaction” or the “Fer-rier Rearrangement”. However, the reaction was first noted by Emil Fischer when he heated tri-O-acetyl-D-glucal in water.3 When carbon nucleophiles are involved, the term “Carbon Ferrier Reaction” has been used,4 although the only contribution the Ferrier group made in this area was to find that tri-O-acetyl-D-glucal dimerizes under acid catalysis to give a C-glycosidic product.5 The general reaction is illus-trated by the separate conversions of tri-O-acetyl-D-glucal with O-, S- and C-nucleophiles to the corresponding 2,3-unsaturated glycosyl derivatives. Normally, Lewis acids are used as catalysts, boron trifluoride etherate being the most com-mon. Allyloxycarbenium ions are involved as intermediates, high yields of prod-ucts are obtained, and glycosidic compounds with quasi-axial bonds (as illus-trated) predominate (commonly in the , -ratio of about 7:1). The examples illustrated4,6,7 are typical of a very large number of literature reports.1
OAcO
AcO
AcOO
OAc
AcO
i) HOCH2CCH6
ii) HSPh7
iii)
+ Lewis acid
4
O
RAcO
R = i) OCH2CCH6
ii) SPh7
iii) 4
OAc
General examples4
OAcOAcO
OAc SnBr4, C6H14, EtOAc
rt, 5 min, 94%
OAcO
OAc
H
More complex products made directly from the corresponding glycols:
OH
O
O
OH
OH O
O
O
AcO
O
Ph
AcOOAc
EtOO O
O
OMe
In PhCOCH2CO2Et,BF3.OEt2,
rt, 15 min, (81% α-anomer).9
OO NHC(O)CCl3
In benzene, BF3•OEt2,5 oC, 10 min, (67%, α-anomer).8
By spontaneous sigmatropic rearrangement of the glycal3-trichloroacetimidate made with NaH, Cl3CCN, (78% α-anomer).10
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_96, © Springer-Verlag Berlin Heidelberg 2009
Products formed without acid catalysts
OHO O OMe OAcO O
DDQ DEAD, Ph3P(80%, α-anomer)11 (88%, mainly α)12
C-3 leaving group of glycal:
Promoter:
hydroxy acetoxy
OO
O
O
OO
OO
O
N-iodonium dicollidine perchlorate
(65%, mainly α)13
pent-4-enoyloxy
Modified glycals and their reactions:
OOBn
BnOOAc
OBn
OOBn
BnOO
O
O
O
Ph
O
O
O
PhN
NH N
N
ClI
N
NH N
N
Me
, reflux MeNO2,AgNO3, Na2CO36 h (58%, α,β 1:1).15
++
OH
BF3•OEt2, CH2Cl2, 0 oC
(70%, mainly α)14
References 1. Ferrier, R. J.; Zubkov, O. A. Transformation of glycals into 2,3-unsaturated glycosyl
derivatives, In Org. React. 2003, 62, 569−736. (Review). It was almost 50 years after Fischer’s seminal finding that water took part in the reaction3 that Ann Ryan, working in George Overend’s Department in Birkbeck College, University of London, found, by chance, that p-nitrophenol likewise participates.16 Robin Ferrier, her immediate su-pervisor, who suggested her experiment, then found that simple alcohols at high tem-peratures also take part,17 and with other students, notably Nagendra Prasad and George Sankey, he explored the reaction extensively. They did not apply it to make the very important C-glycosides.
2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153−175. (Review). 3. Fischer, E. Chem. Ber. 1914, 47, 196−210. 4. Herscovici, J.; Muleka, K.; Boumaïza, L.; Antonakis, K. J. Chem. Soc., Perkin Trans.
1 1990, 1995−2009. 5. Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C) 1969, 581−586. 6. Moufid, N.; Chapleur, Y.; Mayon, P. J. Chem. Soc., Perkin Trans. 1 1992, 999−1007. 7. Whittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.; Vyas, D. J. Org.
Chem. 1990, 55, 1979−1981. 8. Klaffke, W.; Pudlo, P.; Springer, D.; Thiem, J. Ann. 1991, 509−512. 9. Yougai, S.; Miwa, T. J. Chem. Soc., Chem. Commun. 1983, 68−69. 10. Armstrong, P. L.; Coull, I. C.; Hewson, A. T.; Slater, M. J. Tetrahedron Lett. 1995, 36,
4311−4314.
223
11. Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1994, 35, 3661−3664. 12. Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.; Kinoshita, M. J. Chem. Soc.,
Chem. Commun. 1993, 704−705. 13. López, J. C.; Gómez, A. M.; Valverde, S.; Fraser-Reid, B. J. Org. Chem. 1995, 60,
3851−3858. 14. Booma, C.; Balasubramanian, K. K. Tetrahedron Lett. 1993, 34, 6757−6760. 15. Tam, S. Y.-K.; Fraser-Reid, B. Can. J. Chem. 1977, 55, 3996−4001. 16. Ferrier, R. J.; Overend, W. G.; Ryan, A. E. J. Chem. Soc. (C) 1962, 3667−3670. 17. Ferrier, R. J. J. Chem. Soc. 1964, 5443−5449. 18. De, K.; Legros, J.; Crousse, Be.; Bonnet-Delpon, D. Tetrahedron 2008, 64,
10497−10500.
224
Fiesselmann thiophene synthesis Condensation reaction of thioglycolic acid derivatives with , -acetylenic esters, which upon treatment with base result in the formation of 3-hydroxy-2-thiophenecarboxylic acid derivatives.
CO2MeO
OMeHSMeO2C S
CO2Me
OH
MeO2C
NaOMe
MeO2C
O
OMeS
OCH3
O
O
OMeS
OH3CO
O
OMeSH
S
MeO2C
MeO2C O
OMeS
OOMe
SS
CO2Me
MeO2C
MeO2C
OMe
O
O
OMeSH
SS
CO2MeMeO2C
OMe
O NaOMe
O
MeOH
OMe
SS
CO2Me
O
OMe
MeO2C
OMe
OS
MeO2C
OMe
CO2MeO
SCO2Me
S
MeO2C
CO2Me
SCO2Me
H
H
O HOMe
OMeS
MeO2C
CO2Me
OHS
MeO2C
CO2MeH
O
MeO
Example 15
O
CO2R3
12 equiv HSCH2CO2H
R3OH, HCl (g), −10 oC, 1 h
S
CO2R3
CO2R3 NaOR3, R3OH
rt, 24 h, 46−98%
SCO2R3
OH
225
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_97, © Springer-Verlag Berlin Heidelberg 2009
Example 26
OO
NCH3 CH3
O
OS
NCH3 CH3
O
CO2CH3O
NCH3
S
CH3
O
OCH3HSCH2CO2H
HCl, MeOH
NaOMe
MeOH
Example 37
N Cl
CN
O
OEtHS N S
NH2
CO2Et
NaH, DMSO, 89%
Example 49
CN
S CO2Me
NH2
HSCH2CO2Me
NaOMe, 68%
References 1. Fiesselmann, H.; Schipprak, P. Ber. 1954, 87, 835−841; Fiesselmann, H.; Schipprak,
P.; Zeitler, L. Ber. 1954, 87, 841−848; Fiesselmann, H.; Pfeiffer, G. Ber. 1954, 87, 848; Fiesselmann, H.; Thoma, F. Ber. 1956, 89, 1907−1912; Fiesselmann, H.; Schip-prak, P. Ber. 1956, 89, 1897−1902.
2. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., Ed.; Wiley & Sons: New York, 1985, 88−125. (Review).
3. Nicolaou, K. C.; Skokotas, G.; Furuya, S.; Suemune, H.; Nicolaou, D. C. Angew. Chem., Int. Ed. 1990, 29, 1064−1068.
4. Mullican, M. D.; Sorenson, R. J.; Connor, D. T.; Thueson, D. O.; Kennedy, J. A.; Con-roy, M. C. J. Med. Chem. 1991, 34, 2186−2194.
5. Donoso, R.; Jordan de Urries, P.; Lissavetzky, J. Synthesis 1992, 526−528. 6. Ram, V. J.; Goel, A.; Shukla, P. K.; Kapil, A. Bioorg. Med. Chem. Lett. 1997, 7,
3101−3106. 7. Showalter, H. D. H.; Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D.
W. J. Med. Chem. 1999, 42, 5464−5474. 8. Shkinyova, T. K.; Dalinger, I. L.; Molotov, S. I.; Shevelev, S. A. Tetrahedron Lett.
2000, 41, 4973−4975. 9. Redman, A. M.; Johnson, J. S.; Dally, R.; Swartz, S.; Wild, H.; Paulsen, H.; Caringal,
Y.; Gunn, D.; Renick, J.; Osterhout, M. Bioorg. Med. Chem. Lett. 2001, 11, 9−12. 10. Migianu, E.; Kirsch, G. Synthesis, 2002, 1096. 11. Mullins, R. J.; Williams, D. R. Fiesselmann Thiophene Synthesis. In Name Reactions
in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 184−192. (Review).
226
Fischer indole synthesis Cyclization of arylhydrazones to indoles.
NH
N
R2R1
NH
NH3
O
R2R1
NH
R2
R1
NH3
H
phenylhydrazine phenylhydrazone
NH
N
R2R1
H
HNH
NH2
R2R1
[3,3]-sigmatropic
rearrangement N H
NH2
R2R1
H
H
tautomerization
protonation ene-hydrazine double imine
N H2
NH2
R2R1
N
H
H H
R2R1
NH2 NH
R2
R1
NH3
NH
H
R2R1
NH3
Example 13
NH
N
OPh
ON N
HNH2
NH
N
HN
N
1. neat, 160 oC, 24 h
2. NH2NH2, 120 oC, 12 h 71%
Example 213
NHNH2
O
CNCO2Et
AcOH, Δ, 5 h
57%NH
CNCO2Et
Example 4 (Severe racemization)9
O N
H
H
CO2Me
PhO N
H
H
CO2Me
Ph
or1. PhNHNH2
2. AcOH
227
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_98, © Springer-Verlag Berlin Heidelberg 2009
N
H
H
CO2Me
PhNH
22%NH
NPh
H
H
CO2Me
16%NH
NPh
H
H
CO2Me
6%
N
H
H
CO2Me
PhNH
4%
N
H
H
CO2Me
PhNH
5%
N
H
H
CO2Me
PhNH
4%
References 1. (a) Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241−2245. H. Emil Fischer (1852−1919)
is arguably the greatest organic chemist ever. He was born in Euskirchen, near Bonn, Germany. When he was a boy, his father, Lorenz, said about him: “The boy is too stupid to go in to business; so in God’s name, let him study.” Fischer studied at Bonn and then Strassburg under Adolf von Baeyer. Fischer won the Nobel Prize in Chemis-try in 1902 (three years ahead of his master, von Baeyer) for his synthetic studies in the area of sugar and purine groups. (b) Fischer, E.; Hess, O. Ber. 1884, 17, 559.
2. Robinson, B. The Fisher Indole Synthesis, John Wiley & Sons: New York, NY, 1982. (Book).
3. Martin, M. J.; Trudell, M. L.; Arauzo, H. D.; Allen, M. S.; LaLoggia, A. J.; Deng, L.; Schultz, C. A.; Tan, Y.; Bi, Y.; Narayanan, K.; Dorn, L. J.; Koehler, K. F.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1992, 35, 4105−4117.
4. Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607−632. (Review). 5. Bosch, J.; Roca, T.; Armengol, M.; Fernández-Forner, D. Tetrahedron 2001, 57,
1041−1048. 6. Ergün, Y.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2002, 39, 315−317. 7. Pete, B.; Parlagh, G. Tetrahedron Lett. 2003, 44, 2537−2539. 8. Li, J.; Cook, J. M. Fischer Indole Synthesis. In Name Reactions in Heterocyclic Chem-
istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 116−127. (Review).
9. Borregán, M.; Bradshaw, B.; Valls, N.; Bonjoch, J. Tetrahedron: Asymmetry 2008, 19, 2130−2134.
10. Donald, J. R.; Taylor, R. J. K. Synlett 2009, 59−62.
228
Fischer oxazole synthesis Oxazoles from the condensation of equimolar amounts of aldehyde cyanohydrins and aromatic aldehydes in dry ether in the presence of dry hydrochloric acid.
N
OR2
R1
etherH2O HCl
HClR1 CN
OHR2CHO
O R2
H
:NH
Cl
R1
OH
NHR1
OH
Cl
NHO
R1
Cl
R2OH
NH2O
R1
Cl
R2OH
HCl
ON
Cl
R2
R1
HSN2 isomerization
ON
Cl
R2
R1
H elimination ON
R2
R1HCl
Example 14
H3CNH2
OH
O CHO
TsOH, Tol.
reflux
N
OCH3HN
OCH3
O
POCl3, 80−85 oC
15 min., 40%
Example 28
SOCl2, ether
dry HCl gas
HO
CN
OH
HO
ClNH
Cl
229
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_99, © Springer-Verlag Berlin Heidelberg 2009
N
O
dry HCl gas, 16.5%
N
OH
N
CHO
halfordinal
References 1. Fischer, E. Ber. 1896, 29, 205. 2. Ladenburg, K.; Folkers, K.; Major, R. T. J. Am. Chem. Soc. 1936, 58, 1292−1294. 3. Wiley, R. H. Chem. Rev. 1945, 37, 401−442. (Review). 4. Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1949, 1028-1030. 5. Cornforth, J. W. In Heterocyclic Compounds 5; Elderfield, R. C. Ed.; Wiley & Sons:
New York, 1957, 5, 309−312. (Review). 6. Crow, W. D.; Hodgkin, J. H. Tetrahedron Lett. 1963, 2, 85−89. 7. Brossi, A.; Wenis, E. J. Heterocycl. Chem. 1965, 2, 310−312. 8. Onaka, T. Tetrahedron Lett. 1971, 4393−4394. 9. Brooks, D. A. Fisher Oxazole Synthesis. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 234−236. (Re-view).
230
Fleming−Kumada oxidation Stereoselective oxidation of alkyl-silanes into the corresponding alkyl-alcohols us-ing peracids.
R R1
SiMe2Ph1. HX2. ArCO3H, base
3. hydrolysis R R1
OH
retention of configuration
R R1
SiH
R R1
SiX
Hipso
substitution R R1
SiX H
:OO
Ar
O
the β-carbocation is stabilized by the silicon group
R R1
SiO
O
Ar
OHX ArCO2
R R1
OSiO
O Ar
O
R R1
OSi
HO
O Ar
O
:
R R1
OSiO
HO
O Ar
O
:− ArCO2
R R1
OSi
O
OO
O
Ar
R R1
OSiO
O Ar
OO
R R1
OSiO
OO
Ar
OHO
R R1
OSiO
OO
O
Ar hydrolysis
OH R R1
OR R1
OHHO
O
Ar
Example 14
NBoc
OO O
HO
OH
OTBS
C8H18
NBoc
OO O
(EtO)2PhSi
OH
OTBS
C8H18 m-CPBA, KHF2, DMF
0 to 25 oC, 55−70%
231
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_100, © Springer-Verlag Berlin Heidelberg 2009
Example 25
O NO
OSii-Pri-Pr
H
O
TBSO
HTsO
PhH2O2, KHCO3
THF, H2O55 oC, 90%
O NO
OHOH
O
TBSO
HTsO
PhH
Example 38
O
H3CCH3
CH3H
H3C
H3C
BnO
Si
H2O2, KF, KHCO3
DMF, 93%
HO
H3CCH3
CH3H
H3C
H3C
BnO
HOH3C CH3
Example 49
SiMe2(OMe)MeO2C
CO2Me
KF, KHCO3THF/MeOH
30% H2O2, 77%
OHMeO2C
CO2Me
References 1. (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984, 29−31.
(b) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229−4232. (c) Flem-ing, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57−576. (Review).
2. Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112−1124. 3. Knölker, H.-J.; Jones, P. G.; Wanzl, G. Synlett 1997, 613−616. 4. Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.; White, A. J. P.; Williams, D. J.
J. Org. Chem. 1999, 64, 6005−6018. 5. Denmark, S.; Cottell, J. J. Org. Chem. 2001, 66, 4276−4284. 6. Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337−3339. 7. Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68, 2572−2582. 8. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2003, 125, 1567−1574. 9. Clive, D. L. J.; Cheng, H.; Gangopadhyay, P.; Huang, X.; Prabhudas, B. Tetrahedron
2004, 60, 4205−4221. 10. Mullins, R. J.; Jolley, S. L.; and Knapp, A. R. Tamao–Kumada–Fleming Oxidation. In
Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 237−247. (Review).
232
Tamao−Kumada oxidation Oxidation of alkyl fluorosilanes to the corresponding alcohols. A variant of the Fleming−Kumada oxidation.
RSi
R
FF KF, H2O2
KHCO3, DMF2 ROH
RSi
R
FF
F
R SiR
FF
F
HO
OH
R SiR
FF
FO
HOH
SiR
FF
FO
HOH
R
:
O SiR
FF
FRO Si
OF
F
FRR
2 ROH
Example 13
O
Me2FSi
O
CO2Me
NaCO3, CH3CO3H
3 h, 64%O
HO
O
CO2Me
Example 24
SiO
R
EtEt
OSiMe3
H2O2, KF, KHCO3
THF−MeOH51−85%
R
OH SiEt2F
OHR
OH OH
OH
References 1. Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120−2122. 2. Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57−576. (Review). 3. Kim, S.; Emeric, G.; Fuchs, P. L. J. Org. Chem. 1992, 57, 7362−7364. 4. Mullins, R. J.; Jolley, S. L.; Knapp, A. R. Tamao–Kumada–Fleming Oxidation. In
Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 237−247. (Review).
5. Beignet, J.; Jervis, P. J.; Cox, L. R. J. Org. Chem. 2008, 73, 5462−5475. 6. Cardona, F.; Parmeggiani, C.; Faggi, E.; Bonaccini, C.; Gratteri, P.; Sim, L.; Gloster,
T. M.; Roberts, S.; Davies, G. J.; Rose, D. R.; Goti, A. Chem. Eur. J. 2009, 15, 1627–1636.
233
Friedel–Crafts reaction
Friedel–Crafts acylation reaction Introduction of an acyl group onto an aromatic substrate by treating the substrate with an acyl halide or anhydride in the presence of a Lewis acid.
R Cl
O
AlCl3R
O
HCl
AlCl3complexation
R Cl:
O
R Cl
O:AlCl3 AlCl4
OR
R
O
acylium ion
electrophilic
substitutionR
OH
aromatizationR
OClAlClCl
ClAlCl3HCl
Example 1, Intermolecular Friedel–Crafts acylation6
F
AlCl3, CH2Cl288%
OF
FN NCl
OF
CHOCHO
Example 2, Intramolecular Friedel–Crafts acylation7
OHO
OMeOMe (COCl)2, DMF
then AlCl3, 84%O
OMeOMe
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_101, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Intramolecular Friedel–Crafts acylation8
HN
CO2CH3
CO2HPPSE, CH3NO2
reflux, 10 min., 44% NH
CO2CH3
O
PPSE = Trimethylsilyl polyphosphate
Example 4, Intramolecular Friedel–Crafts acylation9
NH
CONMe2POCl3, K2CO3
CH3CN, 60 oC74%
NH
O
NH
MeOCO2H
PPA, 80 oC
35% NH
O
MeO
N
20 mol% BF3OEt2
MeNO2, 100 oC15 min., 98%
Ns
O
O
O
O
NNs
O
References 1. Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392−1395. Charles Friedel
(1832−1899) was born in Strasbourg, France. He earned his Ph.D. In 1869 under Wurtz at Sorbonne and became a professor and later chair (1884) of organic chemistry at Sorbonne. Friedel was one of the founders of the French Chemical Society and served as its president for four terms. James Mason Crafts (1839−1917) was born in Boston, Massachusetts. He studied under Bunsen and Wurtz in his youth and became a professor at Cornell and MIT. From 1874 to 1891, Crafts collaborated with Friedel at École de Mines in Paris, where they discovered the Friedel–Crafts reaction. He re-turned to MIT in 1892 and later served as its president. The discovery of the Friedel–Crafts reaction was the fruit of serendipity and keen observation. In 1877, both Friedel and Crafts were working in Charles A. Wurtz’s laboratory. In order to prepare amyl iodide, they treated amyl chloride with aluminum and iodide using benzene as the solvent. Instead of amyl iodide, they ended up with amylbenzene! Unlike others before them who may have simply discarded the reaction, they thoroughly investigated
235
the Lewis acid-catalyzed alkylations and acylations and published more than 50 papers and patents on the Friedel–Crafts reaction, which has become one of the most useful organic reactions.
2. Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533−542. (Review). 3. Hermecz, I.; Mészáros, Z. Adv. Heterocyclic Chem. 1983, 33, 241−330. (Review). 4. Metivier, P. Friedel-Crafts Acylation. In Friedel-Crafts Reaction Sheldon, R. A.; Bek-
kum, H., eds.; Wiley-VCH: New York. 2001, pp 161−172. (Review). 5. Basappa; Mantelingu, K.; Sadashira, M. P.; Rangappa, K. S. Indian J. Chem. B. 2004,
43B, 1954−1957. 6. Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. Rev. 2006, 106, 1077−1104. (Re-
view). 7. Simmons, E.M.; Sarpong, R. Org. Lett. 2006, 8, 2883−2886. 8. Bourderioux, A.; Routier, S.; Beneteau, V.; Merour, J.-Y. Tetrahedron 2007, 63,
9465−9475. 9. Fillion, E.; Dumas, A. M. J. Org. Chem. 2008, 73, 2920−2923. 10. de Noronha, R. G.; Fernandes, A. C.; Romao, C. C. Tetrahedron Lett. 2009, 50,
1407−1410.
Friedel–Crafts alkylation reaction Introduction of an alkyl group onto an aromatic substrate by treating the substrate with an alkylating agent such as alkyl halide, alkene, alkyne and alcohol in the presence of a Lewis acid.
AlCl3RCl:
RCl
AlCl3 AlCl4 R
R
RH
aromatization
ClAlClCl
Cl
HCl
alkyl cation
Example 11
O O
O Br
OSnCl4, CH2Cl2
0 oC, 1 h, 84%
O
OO
O
Example 24
NR
R1
R2 R3
O
OH
R3 = aryl, alkyl
NCu
N
OOMeMe
Me3C CMe3TfO OTf10 mol%
NR
R1
R2
R3
O OHH
32−96% yield, 83−98% ee
236
NMe
R3
O
OH
R3 = aryl, alkyl
NCu
N
OOMeMe
Me3C CMe3TfO OTf10 mol%
R3
O
OH
H
80−95% yield, 68−97% ee
NMe
Example 35
OB(OH)2 Me O 20 mol%
DME, rt, 36 h1 equiv HF
O O
Me51% yield, 92% ee
N
NH•HCl
O Me
Me
MeMe
NBu
References 1. Patil, M. L.; Borate, H. B.; Ponde, D. E.; Bhawal, B. M.; Deshpande, V. H. Tetrahe-
dron Lett. 1999, 40, 4437−4438. 2. Meima, G. R.; Lee, G. S.; Garces, J. M. Friedel-Crafts Alkylation. In Friedel−Crafts
Reaction Sheldon, R. A.; Bekkum, H., eds.; Wiley-VCH: New York. 2001, pp 550−556. (Review).
3. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550−556. (Review).
4. Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154−4155.
5. Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438−15439. 6. Poulsen, T. B.; Jorgensen, K. A. Chem. Rev. 2008, 108, 2903−2915. (Review). 7. Silvanus, A. C.; Heffernan, S. J.; Liptrot, D. J.; Kociok-Kohn, G.; Andrews, B. I.; Car-
bery, D. R. Org. Lett. 2009, 11, 1175−1178.
237
Friedländer quinoline synthesis The Friedländer quinoline synthesis combines an α-amino aldehyde or ketone with another aldehyde or ketone with at least one methylene α adjacent to the car-bonyl to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat.
CHO
NH2R
R1
O OH
N
R
R1
NH2
RR1
O
H
HO
RR1
O
H
O Aldol
condensation NH2
R
COR1
OH
HOH
R
NH2
R1
O
:
N
R
N
R
R1R1OH
H
HO
Example 15
CHO
NH2 O N
NBn NBnNaOMe, EtOH
reflux, 3 h, 90%
Example 27
NHBoc
O
HO N
N O
OBn
N
OBn
OAcOH, 100 °C
88%
238
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_102, © Springer-Verlag Berlin Heidelberg 2009
Example 38
N
CHO
NH2 O N N
Me
Me Me N N Me
Me
ConditionsNaOH, rt
pyrrolidine, 5% H2SO4, rtTBAO, 5% H2SO4, rt
TBAO, 5% H2SO4, slow addition, 65 °C
Conversion> 99%97%
> 99%> 99%
Ratio37:6386:1487:1394:6
TBAO = 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane
HN
Me
Me
Me
Example 410
OH
NH2
R2 R1
O 1 mol%
KOH, 1,4-dioxane80 oC, 1 h
N
R2
R1
N NMes Mes
RuClCl PhPCy3
References 1. Friedländer, P. Ber. 1882, 15, 2572−2575. Paul Friedländer (1857−1923), born in
Königsberg, Prussia, apprenticed under Carl Graebe and Adolf von Baeyer. He was interested in music and was an accomplished pianist.
2. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed.; Wiley & Sons,: New York, 1952, 4, Quinoline, Isoquinoline and Their Benzo Derivatives, 45–47. (Review).
3. Jones, G. In Heterocyclic Compounds, Quinolines, vol. 32, 1977; Wiley & Sons: New York, pp 181–191. (Review).
4. Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37−201. (Review). 5. Shiozawa, A.; Ichikawa, Y.-I.; Komuro, C.; Kurashige, S.; Miyazaki, H.; Yamanaka,
H.; Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522−2529. 6. Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.-A.; Thummel, R. P. J. Org.
Chem. 2001, 66, 400−405. 7. Henegar, K. E.; Baughman, T. A. J. Heterocycl. Chem. 2003, 40, 601−605. 8. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider,
P. J.; Sager, J. W.; and Volante, R. P. J. Org. Chem. 2003, 68, 467−477. 9. Pflum, D. A. Friedländer Quinoline Synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 411−415. (Review).
10. Vander Mierde, H.; Van Der Voot, P.; De Vos, D.; Verpoort, F. Eur. J. Org. Chem. 2008, 1625−1631.
239
Fries rearrangement Lewis acid-catalyzed rearrangement of phenol esters and lactams to 2- or 4-ketophenols. Also known as the Fries−Finck rearrangement.
O R
O
AlCl3
OHOH
O R
R
O
and/or
O R
O:
AlCl3
complexation O R
OCl3Al
OAlCl3
C−O bond
fragmentation
O
R
aluminum phenolate, acylium ion
O
R
OOAlCl3
O
R
HH OH
R
O
OAlCl3
O R
OH
O R
O
HR
O
H
Example 15
OMe
O
O
Br
Br
ZrCl4, PhCl
160 oC, 3 h, 63%
OH O OH
Br Br
240
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_103, © Springer-Verlag Berlin Heidelberg 2009
Example 26
OAc
O
O
10% Bi(OTf)3, PhMe
110 oC, 15 h, 64%
OAc
OH O
Example 3, Photo-Fries rearrangement7
HN
OPh
Low-pressure Hg lamp
254 nM, MeCN, 36 h, 65%
NH2 OPh
Example 4, ortho-Fries rearrangement8
MeO OMe
OCONEt2
O 2.1 equiv LTMP
−78 oC to rt, 97%
MeO OMe
O
OCONEt2
Example 5, Thia-Fries rearrangement9
Cl
H
OSO
OCF3
LDA, THF, −78 oC
then H3O+, 80%Cl
OH
SO
O
CF3
References 1. Fries, K.; Finck, G. Ber. 1908, 41, 4271−4284. Karl Theophil Fries (1875−1962) was
born in Kiedrich near Wiesbaden on the Rhine. He earned his doctorate under Theo-dor Zincke. Although G. Finck co-discovered the rearrangement of phenolic esters, somehow his name has been forgotten by history. In all fairness, the Fries rearrange-ment should really be the Fries−Finck rearrangement.
2. Martin, R. Org. Prep. Proced. Int. 1992, 24, 369−435. (Review). 3. Boyer, J. L.; Krum, J. E.; Myers, M. C.; Fazal, A. N.; Wigal, C. T. J. Org. Chem.
2000, 65, 4712−4714. 4. Guisnet, M.; Perot, G. The Fries rearrangement. In Fine Chemicals through Hetero-
geneous Catalysis 2001, 211−216. (Review). 5. Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem. 2004, 69,
8982−8983. 6. Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004, 2794−2796.
241
7. Ferrini, Serena; Ponticelli, Fabio; Taddei, Maurizio. Org. Lett. 2007, 9, 69−72. 8. Macklin, T. K.; Panteleev, J.; Snieckus, V. Angew. Chem., Int. Ed. 2008, 47,
2097−2101. 9. Dyke, A. M.; Gill, D. M.; Harvey, J. N.; Hester, A. J.; Lloyd-Jones, G.C.; Munoz, M.
P.; Shepperson, I. R. Angew. Chem., Int. Ed. 2008, 47, 5067−5070.
242
Fukuyama amine synthesis Transformation of a primary amine to a secondary amine using 2,4-dinitro-benzenesulfonyl chloride and an alcohol. Also known as the Fuku-yama−Mitsunobu procedure.
SO2Cl
NO2
NO2
R1HN
R2
S
NO2
NO2
CO2H1. R1NH2, pyr.2. R2OH, PPh3, DEAD
3. HSCH2CO2HSO2
R1NH2
SO2
NO2
NO2
ClSO2NHR1
NO2
NO2 R2OH, PPh3
DEAD
:
HSO2NR1R2
NO2
NO2
S CO2HH
:
See page 365 for mechanism of the Mitsunobu reaction.
SNAr
NO2
NO2
SO2SHO2C
H
NR1R2
R1HN
R2
S
NO2
NO2
CO2H
SO2
Meisenheimer complex Example 16
Ns NH2
DEAD, PPh3
NsHNBr
Cs2CO3
n-Bu4NI
NsN
n nfor n = 1–367–74% 62–66%
HOBr
n
Example 27
NBocMsO
OH
NsNH2
DEAD, PPh3
O Et
NBocMsO
NsHNO Et
CO2MeOTBDPS
243
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_104, © Springer-Verlag Berlin Heidelberg 2009
K2CO3
DMF NBocMsO
NsNOH
Et
CO2MeOTBDPS
Example 38
OHSO2
NO2
H2NPyPh2P, DTBAD
CH2Cl2, 84%
SO2NO2
HN K2CO3, PhSH
CH3CN, 80% NH2
PyPh2P = diphenyl 2-pyridylphosphine; DTBAD = di-tert-butylazodicarbonate References 1. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373−6374.
Tohru Fukuyama moved to the University of Tokyo from Rice University in 1995. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831−5834.
2. Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett. 1998, 39, 2667−2670. 3. Bolton, G. L.; Hodges, J. C. J. Comb. Chem. 1999, 1, 130−133. 4. Lin, X.; Dorr, H.; Nuss, J. M. Tetrahedron Lett. 2000, 41, 3309−3313. 5. Olsen, C. A.; JØrgensen, M. R.; Witt, M.; Mellor, I. R.; Usherwood, P. N. R.;
Jaroszewski, J. W.; Franzyk, H. Eur. J. Org. Chem. 2003, 3288-3299. 6. Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Tetrahedron 2002, 58,
6267−6276. 7. Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fu-
kuyama, T. Pure Appl. Chem. 2003, 75, 29−38. 8. Guisado, C.; Waterhouse, J. E.; Price, W. S.; JØrgensen, M. R.; Miller, A. D. Org.
Biomol. Chem. 2005, 3, 1049−1057. 9. Olsen, C. A.; Witt, M.; Hansen, S. H.; Jaroszewski, J. W.; Franzyk, H. Tetrahedron
2005, 61, 6046−6055. 10. Janey, J. M. Fukuyama amine synthesis. In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 424−437. (Review).
244
Fukuyama reduction Aldehyde synthesis through reduction of thiol esters with Et3SiH in the presence of Pd/C catalyst.
R SEt
O Et3SiH, Pd/C
THF, rt R H
O
Path A:
Pd(0)
oxidativeaddition
R PdSEt
O
R SEt
O Et3SiH
Et3Si SEtR H
Oreductive
eliminationPd(0)
R PdH
O
Path B: Et3SiH Pd(0) Et3SiPdH
R SEt
O Et3SiPdHR SEt
OSiEt3
PdH Pd(0) R H
O
Et3Si SEtR SEt
OSiEt3
Example 11
CO2Me
COSEtO O
OEt3SiH, 10% Pd/C
acetone, rt, 92%
CO2Me
CHOO O
O
Example 23
HO2C CO2MeNHBoc
EtSH, DCC, DMAP
CH3CN, rt, 1 h, > 70%CO2Me
NHBoc
EtS
O
Et3SiH, 10% Pd/C
acetone, rt, 30 min., >74%CO2Me
NHBoc
H
O Example 38
MeO
COSEt 0.5 mol% Pd/C
2 equiv Et3SiHrt, 2 h, 92% MeO
CHO
245
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_105, © Springer-Verlag Berlin Heidelberg 2009
References 1. Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050–7051. 2. Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451–8452. 3. Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 1667–1673. 4. Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 1121–
1123. 5. Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569–
4573. 6. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048–4049. 7. Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 3219–3223. (Possible mechanisms
were proposed in this paper). 8. Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett 2004, 477–480.
246
Gabriel synthesis Synthesis of primary amines using potassium phthalimide and alkyl halides.
N
O
O
K1. R⎯X
2. Nu or R'OHH2N R
CO2H
CO2H
R X
SN2 N
O
O
Rhydrolysis
OH
N
O
R
OHO
N
O
O
K
HN
OR
OO
H
CO2HN
RO OH
H2N RCO2
CO2
OH
OH
Example 12
O
O
Br
BrO
OO
O
NPhth
NPhthO
OKNPhth, DMF
90 oC, 40 min.90%
O
O
NH2
NH2
O
OH2NNH2, CH3OH
reflux, 1 h, 80%
Example 26
R1
R2 OHR3
R1
R2 NPhthR3
DIAD, PPh3phthalimide
THF, rt, 4 h76−98%
R1
R2 NH2R3
NH2H2 or CH3NH2CH3OH
76−88%
247
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_106, © Springer-Verlag Berlin Heidelberg 2009
Example 38
NK
O
O
Br CO2Et
DMF, 90 oC, 3 h, 77%N
O
O
CO2Et
N
O
O
O OO
6 M HCl, reflux
14 h, 93% HCl•H2N
O OHO
= 13C
Example 49
OH
OH
phthalimide, PPh3
DEAD, THF
NPht
NPht54%
NH2
NH2
1. NH2NH2•H2O, THF, reflux, 8 h
2. Pd/C, H2, THF, 95%, 2 steps
References 1. Gabriel, S. Ber. 1887, 20, 2224−2226. Siegmund Gabriel (1851−1924), born in Ber-
lin, Germany, studied under Hofmann at Berlin and Bunsen in Heidelberg. He taught at Berlin, where he discovered the Gabriel synthesis of amines. Gabriel, a good friend of Emil Fischer, often substituted for Fischer in his lectures.
2. Sheehan, J. C.; Bolhofer, V. A. J. Am. Chem. Soc. 1950, 72, 2786−2788. 3. Han, Y.; Hu, H. Synthesis 1990, 122−124. 4. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285–289. (Review). 5. Toda, F.; Soda, S.; Goldberg, I. J. Chem. Soc., Perkin Trans. 1 1993, 2357−2361. 6. Sen, S. E.; Roach, S. L. Synthesis, 1995, 756−758. 7. Khan, M. N. J. Org. Chem. 1996, 61, 8063−8068. 8. Iida, K.; Tokiwa, S.; Ishii, T.; Kajiwara, M. J. Labelled. Compd. Radiopharm. 2002,
45, 569−570. 9. Tanyeli, C.; Özçubukçu, S. Tetrahedron Asymmetry 2003, 14, 1167−1170. 10. Ahmad, N. M. Gabriel synthesis. In Name Reactions for Functional Group Transfor-
mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 438−450. (Review).
11. Al-Mousawi, S. M.; El-Apasery, M. A.; Al-Kanderi, N. H. ARKIVOC 2008, (16), 268−278.
248
Ing–Manske procedure A variant of Gabriel amine synthesis where hydrazine is used to release the amine from the corresponding phthalimide:
N
O
O
K1. RX
2. NH2NH2H2N R NH
NH
O
O
R X
N
O
O
K SN2N
O
O
R
:NH2NH2
N
O
R
NHNH2O
NHNH2
O
NHRO
:NHNH
O
O NH
H2N R NHNH
O
OR
Example 16
N
O
O
Br P(OEt)3
ΔN
O
O
PO(OEt)2H2NNH2, EtOH
rt, 18 h, 97% H2NPO(OEt)2
References 1. Ing, H. R.; Manske, R. H. F. J. Chem. Soc. 1926, 2348–2351. H. R. Ing was a profes-
sor of pharmacological chemistry at Oxford. R. H. F. Manske, Ing’s collaborator at Oxford, was of German origin but trained in Canada before studying at Oxford. Man-ske left England to return to Canada, eventually to become Director of Research in the Union Rubber Company, Guelph, Ontario, Canada.
2. Ueda, T.; Ishizaki, K. Chem. Pharm. Bull. 1967, 15, 228–237. 3. Khan, M. N. J. Org. Chem. 1995, 60, 4536–4541. 4. Hearn, M. J.; Lucas, L. E. J. Heterocycl. Chem. 1984, 21, 615–622. 5. Khan, M. N. J. Org. Chem. 1996, 61, 8063–8063. 6. Tanyeli, C.; Özçubukçu, S. Tetrahedron: Asymmetry 2003, 14, 1167–1170. 7. Ariffin, A.; Khan, M. N.; Lan, L. C.; May, F. Y.; Yun, C. S. Synth. Commun. 2004, 34,
4439–4445. 8. Ali, M. M.; Woods, M.; Caravan, P.; Opina, A. C. L.; Spiller, M.; Fettinger, J. C.;
Sherry, A. D. Chem. Eur. J. 2008, 14, 7250–7258.
249
Gabriel–Colman rearrangement
250
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_107, © Springer-Verlag Berlin Heidelberg 2009
Reaction of the enolate of a maleimidyl acetate to provide isoquinoline 1,4-diol.
GN
ROO
G = CO, SO2
ArNaOR
ROHG
NH
OH O
RAr
N
O
O
OMe
N
OOR
OR
OMeO
NOMe
O
OR
O
HN
O
OO
OMe
NH
O
O
R
O
N
OH
OH
R
O
NH
O
R
OOOMe
Example 16
SN
Oi-PrOO
OO S
NH
OO
OH O
Oi-Pr4 equiv i-PrONa
i-PrOH, reflux5 min., 85%
Example 29
N
O
OCO2Et NH
OH
O
CO2EtNaOMe, MeOH
reflux, 24 h91%
References 1. (a) Gabriel, S.; Colman, J. Ber. 1900, 33, 980−995. (b) Gabriel, S.; Colman, J. Ber.
1900, 33, 2630−2634. (c) Gabriel, S.; Colman, J. Ber. 1902, 35, 1358−1368. 2. Allen, C. F. H. Chem. Rev. 1950, 47, 275−305. (Review). 3. Gensler, W. J. Heterocyclic Compounds, Vol. 4, R. C. Elderfield, Ed., Wiley & Sons.,
New York, N.Y., 1952, 378. (Review). 4. Hill, J. H. M. J. Org. Chem. 1965, 30, 620−622. (Mechanism). 5. Lombardino, J. G.; Wiseman, E. H.; McLamore, W. M. J. Med. Chem. 1971, 14,
1171−1175. 6. Schapira, C. B.; Perillo, I. A.; Lamdan, S. J. Heterocycl. Chem. 1980, 17, 1281−1288. 7. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; et al. J. Med. Chem. 1997, 40, 980−989. 8. Pflum, D. A. Gabriel−Colman Rearrangement. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 416−422. (Review).
9. Kapatsina, E.; Lordon, M.; Baro, A.; Laschat, S. Synthesis 2008, 2551−2560.
Gassman indole synthesis The Gassman indole synthesis involves a one-pot process in which a hypohalite, a
-carbonyl sulfide derivative, and a base are added sequentially to an aniline or a substituted aniline to provide 3-thioalkoxyindoles. The sulfur can be easily re-moved by hydrogenolysis or Raney nickel.
NHCl
SR
O
Et3N
NH
R
S
NH2
t-BuOCl
NHCl
SR
OSN2
Et3N
NH
S
O
RH
:
:
sulfonium ion
NH
OS
R
HEt3N:
H
NH
S
O
R[2,3]-sigmatropic
rearrangement(Sommelet−Hauser)
NEt3
NH
S
NH
R
S
OHR
N
SHEt3N:
: R
H Example 11
NH2
1. t-BuOCl
S CH3
O3. Et3N, 69%
NH
Me
S
2.
NH2
1. t-BuOCl
3. Et3N
N2.
SCH3
OSCH3
LiAlH4, Et2O
NH
0 oC, 48% overall
251
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_108, © Springer-Verlag Berlin Heidelberg 2009
Example 22
O
OO
MeSt-BuOCl, PhNH2
Et3N, 93%
O
OO
MeS
NH2
Ra-Ni
EtOH
O
OONH2
p-TsOH, PhH, reflux
71% 2 steps
O
ONH
References 1. (a) Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr. J. Am. Chem. Soc.
1974, 96, 5495−5508. Paul G. Gassman (1935−1993) was a professor at the Univer-sity of Minnesota (1974−1993). (b) Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5508−5512. (c) Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5512−5517.
2. Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621−5623. 3. Ishikawa, H.; Uno, T.; Miyamoto, H.; Ueda, H.; Tamaoka, H.; Tominaga, M.; Naka-
gawa, K. Chem. Pharm. Bull. 1990, 38, 2459−2462. 4. Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc.
1990, 112, 8197−8198. 5. Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am.
Chem. Soc. 1992, 114, 1438−1449. 6. Savall, B. M.; McWhorter, W. W.; Walker, E. A. J. Org. Chem. 1996, 61, 8696−8697. 7. Li, J.; Cook, J. M. Gassman Indole Synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 128−131. (Review).
252
Gattermann–Koch reaction Formylation of arenes using carbon monoxide and hydrogen chloride in the pres-ence of aluminum chloride under high pressure.
HClCOAlCl3
Cu2Cl2
CHO
:C O
:::C O:
AlCl3 :C OAlCl3
:
HCl Cl:C O
AlCl3
: C OAlCl3
:Cl
H
Cl H
OAlCl3 O
HAlCl4
Cl H
OCl3Al
: :O
H
acylium ion
CHOHCHO CHO
HCl AlCl3
Cl
AlCl4 AlCl4
Example, A more practical variant4
OH
HO
Zn(CN)2, AlCl3
HCl (g), 0 oC
OH
HO
NH2
Clorcinol
H2O0 to 100 oC
95%
OH
HO
CHO
References 1. Gattermann, L.; Koch, J. A. Ber.1897, 30, 1622−1624. Ludwig Gattermann
(1860−1920) was born in Freiburg, Germany. His textbook, “Die Praxis de or-ganischen Chemie” (1894) was one of his major contributions to organic chemistry.
2. Crounse, N. N. Org. React. 1949, 5, 290−300. (Review). 3. Truce, W. E. Org. React. 1957, 9, 37−72. (Review). 4. Solladié, G.; Rubio, A.; Carreño, M. C.; García Ruano, J. L. Tetrahedron: Asymmetry
1990, 1, 187−198. 5. (a) Tanaka, M.; Fujiwara, M.; Ando, H. J. Org. Chem. 1995, 60, 2106−2111. (b)
Tanaka, M.; Fujiwara, M.; Ando, H.; Souma, Y. Chem. Commun. 1996, 159−160. (c) Tanaka, M.; Fujiwara, M.; Xu, Q.; Souma, Y.; Ando, H.; Laali, K. K. J. Am. Chem. Soc. 1997, 119, 5100−5105. (d) Tanaka, M.; Fujiwara, M.; Xu, Q.; Ando, H.; Raeker, T. J. J. Org. Chem. 1998, 63, 4408−4412.
6. Kantlehner, W.; Vettel, M.; Gissel, A; Haug, E.; Ziegler, G.; Ciesielski, M.; Scherr, O.; Haas, R. J. Prakt. Chem. 2000, 342, 297−310.
253
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Gewald aminothiophene synthesis Base-promoted aminothiophene formation from ketone, α-active methylene nitrile and elemental sulfur.
R
R1
O CO2R2
CNS8
Base
S
CO2R2
NH2R1
R
O
R1
R
CN
OOR2
HB: CN
OOR2 Knoevenagel
condensationBH NC
O
OR2
RR1
HO
H
:B
R
R1
CN
O OR2
H
:B
BH
NC
O
OR2
RR1
HO
R
R1
CN
O OR2
SSS
S SSS
S
R
R1
O OR2
S S S
N
6
:
BHH
S
CO2R2
NH2R1
RS7S
R2O2CNH
R1
R
HSS
S SS
SSB
Ylidene-sulfur adduct
Example 14
N
NH3C CH3
CO2Et
CNS
CO2Et
NH2
N
S8
morpholine
82%
Example 27
O
O O CO2Et
CN St-BuO2C NH2
CO2EtMeS8, EtOH, morpholine
60 oC, 5 h, 74%
254
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_110, © Springer-Verlag Berlin Heidelberg 2009
Example 39
Me
O
O2N
NC CN
HN(TMS)3, HOActoluene, 65 oC, 90%
Knoevenagelcondensation
Me
O2N
NC CN 1.2 atom equiv S81 equiv NaHCO3
THF, H2O, 80−85%O2N
NC
S
NH2
Example 410
O
OO
OO
S
NH2
O O3 equiv morpholine
1 equiv S8, 55 oC, 24 h
85% conversion64% yield
NCO
O
Example 511
ON
NO
O
S
OO
NH2
N
3 equiv morpholine2 equiv S8, MeOH
20−45 oC, 24 h72%
S
OO
NH2
N
Condensation
MPS = morpholine-polysulfide
OO
NN
Addition
of sulfurS
OO
NN
SxS
Cyclization
NH2NC
CN
CO2CH3
CN
dimer
Re-cyclization
Dimerization
ylidene ylidene-sulfuradduct
255
References 1. (a) Gewald, K. Z. Chem. 1962, 2, 305−306. (b) Gewald, K.; Schinke, E.; Böttcher, H.
Chem. Ber. 1966, 99, 94−100. (c) Gewald, K.; Neumann, G.; Böttcher, H. Z. Chem. 1966, 6, 261. (d) Gewald, K.; Schinke, E. Chem. Ber. 1966, 99, 271−275.
2. Mayer, R.; Gewald, K. Angew. Chem., Int. Ed. 1967, 6, 294−306. (Review). 3. Gewald, K. Chimia 1980, 34, 101−110. (Review). 4. Bacon, E. R.; Daum, S. J. J. Heterocycl. Chem. 1991, 28, 1953-1955. 5. Sabnis, R. W. Sulfur Reports 1994, 16, 1−17. (Review). 6. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36,
333−345. (Review). 7. Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger,
K. J. Med. Chem. 1999, 42, 5437. 8. Tinsley, J. M. Gewald Aminothiophene Synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 193−198. (Review).
9. Barnes, D. M.; Haight, A. R.; Hameury, T.; McLaughlin, M. A.; Mei, J.; Tedrow, J. S.; Dalla Riva Toma, J. Tetrahedron 2006, 62, 11311−11319.
10. Tormyshev, V. M.; Trukhin, D. V.; Rogozhnikova, O. Yu.; Mikhalina, T. V.; Troit-skaya, T. I.; Flinn, A. Synlett 2006, 2559−2564.
11. Puterová, Z.; Andicsová, A.; Végh, D. Tetrahedron 2008, 64, 11262−11269.
256
Glaser coupling Oxidative homo-coupling of terminal alkynes using copper catalyst in the pres-ence of oxygen.
CuCl
NH4OH, EtOHC CHR C CR C C R
Cu
Cu+
Cu
XCu
X
L L
L L
+2
L = AmineX = Cl, OAc
Cu+2
2 Cu
Cu
Cu
L L
L L
+2
R
R
Cu
Cu
L L
L L
+2
XR
R R
R
R :
or
Cu
R
Alternatively, the radical mechanism is also operative:
H CuClBase
Cu(I)
O2
Cu(II) Cu(I)
dimerization
Example 11
Cu2O2
NH4OH, EtOH90%
257
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_111, © Springer-Verlag Berlin Heidelberg 2009
Example 2, Homo-coupling2
HO
Cu, NH4Cl
O2, 90% HO OH Example 37
S
SS
SR
R CuCl
TMEDA
O2, CH2Cl2, 0°C
47%
S
S
S
S
SS
S
SS
S
SS
R
R R
R
R R
R = n-Hexyl
References 1. Glaser, C. Ber. 1869, 2, 422–424. 2. Bowden, K.; Heilbron, I.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1947, 1583–
1590. 3. Hoeger, S.; Meckenstock, A.-D.; Pellen, H. J. Org. Chem. 1997, 62, 4556–4557. 4. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632–
2657. (Review). 5. Youngblood, W. J.; Gryko, D. T.; Lammi, R. K.; Bocian, D. F.; Holten, D.; Lindsey, J.
S. J. Org. Chem. 2002, 67, 2111–2117. 6. Moriarty, R. M.; Pavlovic, D. J. Org. Chem. 2004, 69, 5501–5504. 7. Andersson, A. S.; Kilsa, K.; Hassenkam, T.; Gisselbrecht, J.-P.; Boudon, C.; Gross,
M.; Nielsen, M. B.; Diederich, F. Chem. Eur. J. 2006, 12, 8451–8459. 8. Gribble, G. W. Glaser Coupling. In Name Reactions for Homologations-Part I; Li, J.
J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 236−257. (Review).
258
Eglinton coupling Oxidative homo-coupling of terminal alkynes mediated by stoichiometric (or often excess) Cu(OAc)2. A variant of the Glaser coupling reaction.
R HCu(OAc)2
pyridine/MeOHR R
RR Hpyridine
NH
CuAcO OAc
R Cu OAc
R RR
dimerizationR
Example 12
Cu(OAc)2
pyr., 25 °C
20%
Example 2, Cross-coupling3
Ph
SPh
CO2Me
Cu(OAc)2pyridine/MeOH (1:1)
rt, 72%Ph
SPh
CO2Me
Example 3, Homo-coupling4
Cu(OAc)2, pyridine
MeOH, 1.5 h, 68%
NNC
Cl
NNC
Cl
NCN
Cl
259
Example 45
TMS
TIPSR = H, t-Bu
Cu(OAc)2
K2CO3pyr., MeOH
61–70%
R
TIPS
TIPS
R
1. TBAF
2. CuCl, Cu(OAc)2 pyr.
R
R
R
51–64%R
R
Example 511
Fe
CNO
2 equiv Cu(OAc)2•H2O
1 : 1 Pyr : MeOH 70 oC, 12 h, 41%
Fe
CNO Fe
CNO
Example 612
Cu(OAc)2
Pyr./MeOH/Et2O62%
260
References 1. (a) Eglinton, G.; Galbraith, A. R. Chem. Ind. 1956, 737−738. Geoffrey Eglinton
(1927−) was born in Cardiff, Wales. (b) Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem. Soc. 1960, 3614−3625. (c) Eglinton, G.; McRae, W. Adv. Org. Chem. 1963, 4, 225−328. (Review).
2. McQuilkin, R. M.; Garratt, P. J.; Sondheimer, F. J. Am. Chem. Soc. 1970, 92, 6682–6683.
3. Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5558−5560.
4. Srinivasan, R.; Devan, B.; Shanmugam, P.; Rajagopalan, K. Indian J. Chem., Sect. B 1997, 36B, 123−125.
5. Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.; Pak, J. J.; Wan, W. B. Tetra-hedron Lett. 1997, 38, 7483–7486.
6. Nakanishi, H.; Sumi, N.; Aso, Y.; Otsubo, T. J. Org. Chem. 1998, 63, 8632-8633. 7. Kaigtti-Fabian, K. H. H.; Lindner, H.-J.; Nimmerfroh, N.; Hafner, K. Angew. Chem.,
Int. Ed. 2001, 40, 3402−3405. 8. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39,
2632−2657. (Review). 9. Inouchi, K.; Kabashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. Org. Lett. 2002, 4,
2533−2536. 10. Xu, G.-L.; Zou, G.; Ni, Y.-H.; DeRosa, M. C.; Crutchley, R. J.; Ren, T. J. Am. Chem.
Soc. 2003, 125, 10057−10065. 11. Shanmugam, P.; Vaithiyananthan, V.; Viswambharan, B.; Madhavan, S. Tetrahedron
Lett. 2007, 48, 9190−9194. 12. Miljanic, O. S.; Dichtel, W. R.; Khan, S. I.; Mortezaei, S.; Heath, J. R.; Stoddart, J. F.
J. Am. Chem. Soc. 2007, 129, 8236−8246.
261
Gomberg–Bachmann reaction Base-promoted radical coupling between an aryl diazonium salt and an arene to form a diaryl compound.
N2O
O
OH
OHN N
N N
N NOH
Ph
: N NPh
ONN
PhN2↑
ONN
Ph
O
O
OH
ONN
Ph
OHNN
Ph
Example 14
N2O
O
O
O
BF4 KOAc, 18-C-6
rt, 55%O
O Example 25
N
N N
N
NH2
MeOONO
PhH, TFAA, reflux2 d, 33%
N
N N
N
MeO
References 1. Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339−2343. Moses
Gomberg (1866−1947) was born in Elizabetgrad, Russia. He discovered the triphenyl-methyl stable radical at the University of Michigan in Ann Arbor, Michigan. In this article, Gomberg declared that he had reserved the field of radical chemistry for him-self! Werner Bachmann (1901−1951), Gomberg’s Ph.D. student, was born in Detroit, Michigan. After his postdoctoral trainings in Europe Bachmann returned to the Uni-versity of Michigan as the Moses Gomberg Professor of Chemistry.
2. Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49, 1594−1603.
3. McKenzie, T. C.; Rolfes, S. M. J. Heterocycl. Chem. 1987, 24, 859−861. 4. Lai, Y.-H.; Jiang, J. J. Org. Chem. 1997, 62, 4412−4417.
262
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_112, © Springer-Verlag Berlin Heidelberg 2009
Gould–Jacobs reaction The Gould–Jacobs reaction is a sequence of the following reactions: a. Substitution of an aniline with either alkoxy methylenemalonic ester or acyl malonic ester providing the anilinomethylenemalonic ester; b. Cyclization of to the 4-hydroxy-3-carboalkoxyquinoline (4-hydroxyquinolines exist predominantly in 4-oxoform); c. Saponification to form acid; d. Decarboxylation to give the 4-hydroxyquinoline. Extension could lead to unsubstituted parent heterocycles with fused pyridine ring of Skraup type.
NH2
CO2RRO2C
OR''R' NH
R'
CO2Rheat
− R''OH
ΔRO2C
N
CO2ROH
R' N
CO2HOH
R'
HO− Δ
NH
O
R'
R = alkyl; R' = alkyl, aryl, or H; R'' = alkyl or H
NH2
EtO2C
OEt NH2
substitutionEtO2C
OEt
O
OEt
OEt
O
− EtOH
NH
CO2EtOEtO
:
N
CO2EtO
Hcyclization tautomerization
N
CO2EtOH
NH
CO2EtO
Example 13
O
NH
EtO2C CO2EtPh2O, reflux
75%, 10:1NH N
H
OO CO2EtO
OCO2Et
263
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_113, © Springer-Verlag Berlin Heidelberg 2009
Example 28
EtO2C CO2Et
EtO H
N
H2N
RN
HN
R
H
CO2EtEtO2CEtOH, reflux
PhOPh
250 oC
N R
NH
OEtO2C N R
N
ClEtO2CPOCl3
70 oC
Example 3, Microwave-assisted Gould–Jacobs reaction9
N
N CO2EtEtO2C
OEtHNR1
R NH2
Ph−O−Ph
130−140 oC N
N
NR1
R HNCO2Et
CO2Et
Ph−O−Ph250 oC
N
N
NR1
R N
O
CO2Et
Microwave, neat
10−12 min., 64−75%
Example 410
CO2EtEtO2C
OEtH
Ph-O-Ph
heat
NNPh
NH2
Ar
NNPh
NH
ArEtOH
reflux H
EtO2C CO2Et
NN
PhNH
ArCO2Et
O
NN
PhN
ArCO2Et
Cl
POCl3
reflux
POCl3reflux
References 1. Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890−2895. R. Gordon
Gould was born in Chicago in 1909. He earned his Ph.D. at Harvard University in 1933. After serving as an instructor at Harvard and Iowa, Gould worked at Rockefel-
264
ler Institute for Medical Research where he discovered the Gould–Jacobs reaction with his colleague Walter A. Jacobs.
2. Reitsema, R. H. Chem. Rev. 1948, 53, 43−68. (Review). 3. Cruickshank, P. A., Lee, F. T., Lupichuk, A. J. Med. Chem. 1970, 13, 1110−1114. 4. Elguero J., Marzin C., Katritzky A. R., Linda P., The Tautomerism of Heterocycles,
Academic Press, New York, 1976, pp 87−102. (Review). 5. Wang, C. G., Langer, T., Kiamath, P. G., Gu, Z. Q., Skolnick, P., Fryer, R. I. J. Med.
Chem. 1995, 38, 950−957. 6. Milata, V.; Claramunt, R. M.; Elguero, J.; Zálupský, P. Targets in Heterocyclic Sys-
tems 2000, 4, 167–203. (Review). 7. Curran, T. T. Gould–Jacobs Reaction. In Name Reactions in Heterocyclic Chemistry;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 423−436. (Review). 8. Ferlin, M. G.; Chiarelotto, G.; Dall’Acqua, S.; Maciocco, E.; Mascia, M. P.; Pisu, M.
G.; Biggio, G. Bioorg. Med. Chem. 2005, 13, 3531−3541. 9. Desai, N. D. J. Heterocycl. Chem. 2006, 43, 1343−1348. 10. Kendre, D. B.; Toche, R. B.; Jachak, M. N. J. Heterocycl. Chem. 2008, 45,
1281−1286.
265
Grignard reaction Addition of organomagnesium compounds (Grignard reagents), generated from organohalides and magnesium metal, to electrophiles.
R XMg(0)
R MgX R1 R2
O
R OH
R2R1
Formation of the Grignard reagent:
Mg Mg
R X
Mg Mg
R X
single electron
transfer
Mg Mg
R MgXR MgX
Grignard reaction, ionic mechanism:
R OMgX
R2R1R2
R1
R MgX
OR2
R1δ δ
δδ
R MgXO
‡
Radical mechanism,
R MgX
OR2
R1
OR2
R1MgX
R
R OMgX
R2R1
R OH
R2R1H
Example 14
EtMgBr
reflux, tol./ether, 76%NOH
NH
H
This reaction is known as the Hoch–Campbell aziridine synthesis, which entails treatment of ketoximes with excess Grignard reagents and subsequent hydrolysis of the organometallic complex to produce aziridines.
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_114, © Springer-Verlag Berlin Heidelberg 2009
Example 25
OMeMeO
MeOOMe
N
OPh
OMe
OO
Br
OO
MeO
MeOOMe
N
O Ph
MeO
OO
OOMg
65%
Example 510
Garner's aldehydeCHO
OO MgBr
THF
0 oC to rt, 91% OO
OH
Example 611
O
OH
HO
OH
HO
HOO
O
52% 28% 5%
3 equiv BrMg
THF, 55 oC, 1 h, 85%
References 1. Grignard, V. C. R. Acad. Sci. 1900, 130, 1322−1324. Victor Grignard (France,
1871−1935) won the Nobel Prize in Chemistry in 1912 for his discovery of the Grig-nard reagent.
2. Ashby, E. C.; Laemmle, J. T.; Neumann, H. M. Acc. Chem. Res. 1974, 7, 272−280. (Review).
3. Ashby, E. C.; Laemmle, J. T. Chem. Rev. 1975, 75, 521−546. (Review). 4. Sasaki, T.; Eguchi, S.; Hattori, S. Heterocycles 1978, 11, 235−242. 5. Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc. 1987, 109, 5446−5452. 6. Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000. (Book). 7. Holm, T.; Crossland, I. In Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New
York, 2000, Chapter 1, pp 1−26. (Review). 8. Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081−2091. (Review). 9. Graden, H.; Kann, N. Cur. Org. Chem. 2005, 9, 733−763. (Review). 10. Babu, B. N.; Chauhan, K. R. Tetrahedron Lett. 2008, 50, 66−67. 11. Mlinaric-Majerski, K.; Kragol, G.; Ramljak, T. S. Synlett 2008, 405−409. 12. Chen, D.; Yang, C.; Xie, Y.; Ding, J. Heterocycles 2009, 77, 273−277.
267
Grob fragmentation The C−C bond cleavage primarily via a concerted process involving a five atom system. General scheme:
D L
:
D L
D = O−, NR2; L = OH2
+, OTs, I, Br, Cl
Example 12
OMOM
OH
MsO
OMOM
O
MsONaH
15-crown-5
0 oC to rt, 95%O
OMOM
Example 2, Aza-Grob fragmentation3
N O
S
15 eq. NaBH4, THF
70 oC, 31 h, 53% NH
OHSH
Example 37
OH
OTs
NaH, DMSO, 40 oC, 1 h;
then tosylate, 40 oC, 1 h52%MeO
OMeO
Example 48
OH
H
OMsH
H H1.1 equiv KHMDS
THF, 0 oC, 15 min.93%
OH H
H
268
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_115, © Springer-Verlag Berlin Heidelberg 2009
References 1. (a) Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594−603. (b) Grob, C. A.;
Schiess, P. W. Angew. Chem., Int. Ed. 1967, 6, 1−15. Cyril A. Grob (1917−2003) was born in London (UK) to Swiss parents, studied chemistry at ETH Zürich and com-pleted his PhD in 1943 under the guidance of Leopold Ruzicka (A Nobel laureate) on artificial steroidal antigens. He then moved to Basel to work with Taddeus Reichstein (another Nobel laureate) first at the pharmaceutical institute and from 1947 at the or-ganic chemistry institute of the university, where he moved up the academic career ladder to become the director of the institute and holder of the chair there as Reich-stein’s successor in 1960. An investigation of the reductive elimination of bromine from 1,4-dibromides in the presence of zinc led in 1955 to the recognition of hetero-lytic fragmentation as a general reaction principle. The heterolytic fragmentation has now entered textbooks under his name. Experimental evidence for vinyl cations as dis-crete reactive intermediates was also first provided by Grob. Cyril Grob never acted impulsively, but always calmly and deliberately. He never sought attention in public, but fulfilled his social duties efficiently, reliably, and without a fuss. He died in his home in Basel (Switzerland) on December 15, 2003 at the age of 86. (Schiess, P. Angew. Chem., Int. Ed. 2004, 43, 4392.)
2. Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 5215−5218. 3. Hu, W.-P.; Wang, J.-J.; Tsai, P.-C. J. Org. Chem. 2000, 65, 4208−4029. 4. Molander, G. A.; Le Huerou, Y.; Brown, G. A. J. Org. Chem. 2001, 66, 4511−4516. 5. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542−6543. 6. Barluenga, J.; Alvarez-Perez, M.; Wuerth, K.; Rodriguez, F.; Fananas, F. J. Org. Lett.
2003, 5, 905−908. 7. Khripach, V. A.; Zhabinskii, V. N.; Fando, G. P.; et al. Steroids 2004, 69, 495−499. 8. Maimone, T. J.; Voica, A.-F.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47,
3054−3056. 9. Yuan, D.-Y.; Tu, Y.-Q.; Fan, C.-A. J. Org. Chem. 2008, 73, 7797−7799. 10. Barbe, G.; St-Onge, M.; Charette, A. B. Org. Lett. 2008, 10, 5497−5499.
269
Guareschi–Thorpe condensation 2-Pyridone formation from the condensation of cyanoacetic ester with diketone in the presence of ammonia.
O
O
R
R
CN
OR1O
NH3
NH
RCN
R O
CN
OR1O
H3N: CN
OR1O
H2NCN
OH2N
HH3N:
H
R1OHCN
OH2NO
R
O
R
H3N H
CN
R ONH2O
OHR
H :NH3OH
NH
RCN
R O
CN
R ONH2O
R
: NH
RCN
R OOH
HH3N:
H3N H
H2O
Example6
O CO2Et
CN NH3
NH
CNNC
O O
Guareschi imide
75%
References 1. (a) Guareschi, I. Mem. R. Accad. Sci. Torino 1896, II, 7, 11, 25. (b) Baron, H.; Renfry,
F. G. P.; Thorpe, J. F. J. Chem. Soc. 1904, 85, 1726−1961. Jocelyn F. Thorpe spent two years in Germany where he worked in the laboratory of a dyestuff manufacturer before taking a post as a lecturer at Manchester. Thorpe later became FRS (Fellow of the Royal Society) and professor of organic chemistry at Imperial College.
2. Vogel, A. I. J. Chem. Soc. 1934, 1758−1765. 3. McElvain, S. M.; Lyle, R. E. Jr. J. Am. Chem. Soc. 1950, 72, 384−389. 4. Brunskill, J. S. A. J. Chem. Soc. (C) 1968, 960−966. 5. Brunskill, J. S. A. J. Chem. Soc., Perkin Trans. 1 1972, 2946−2950. 6. Holder, R. W.; Daub, J. P.; Baker, W. E.; Gilbert, R. H. III; Graf, N. A. J. Org. Chem.
1982, 47, 1445−1451. 7. Krstic, V.; Misic-Vukovic, M.; Radojkovic-Velickovic, M. J. Chem. Res. (S) 1991, 82. 8. Galatsis, P. Guareschi−Thorpe Pyridine Synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 307−308. (Review).
270
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_116, © Springer-Verlag Berlin Heidelberg 2009
Hajos–Wiechert reaction Asymmetric Robinson annulation catalyzed by (S)-(−)-proline.
O
OO
cat. NH
HO2CH
O
O CH3CN
O
O
O
H
Michael
addition
O
OO
NH
HO2CH
enamine formation
O
ON
HCO2
catalyticasymmetric
enamine aldol
O
ON
CO2 NH H
CO2
:
O
NOH
CO2
H2O: hydrolysis
of iminium salt
O
NOH
CO2
HO
:
O
O
O
OOH
H
B:
O
OOH
E1cB
Example 11a
O
OO
3 mol% (S)-proline
CH3CN, 100%, 93.4% ee
O
O
Example 23
O
1 equiv L−phenylalanine
D-CSA, DMF, rt, 24 h,then increase temperature
10 oC every 24 h for 5 days.79%, 91% ee
OO
O
O
271
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_117, © Springer-Verlag Berlin Heidelberg 2009
Example 38
O
OO
O
O
L-phenylalanine, PPTS
DMSO, 50 oC, 24 hsonication, 94%, 73% ee
OBn OBn
Example 49
O
1 equiv L-phenylalanine0.5 equiv 1 N HClO4
DMSO, 90 oC86%, 48% ee
O
O
OO
References 1. (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615−1621. Hajos and Parrish
were chemists at Hoffmann−La Roche. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496−497.
2. Brown, K. L.; Dann, L.; Duntz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108−3135.
3. Hagiwara, H.; Uda, H. J. Org.Chem. 1998, 53, 2308–2311. 4. Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357−389. 5. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395−2396. 6. List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573−576. 7. Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16−17. 8. Shigehisa, H.; Mizutani, T.; Tosaki, S.-y.; Ohshima, T.; Shibasaki, M. Tetrahedron
2005, 61, 5057−5065. 9. Nagamine, T.; Inomata, K.; Endo, Y.; Paquette, L. A. J. Org. Chem. 2007, 72, 123–
131. 10. Kennedy, J. W. J.; Vietrich, S.; Weinmann, H.; Brittain, D. E. A. J. Org. Chem. 2009,
73, 5151−5154. 11. Christen, D. P. Hajos–Wiechert Reaction. In Name Reactions for Homologations-Part
II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 554−582. (Re-view).
12. Zhu, H.; Clemente, F. R.; Houk, K. N.; Meyer, M. P. J. Am. Chem. Soc. 2009, 131, 1632−1633.
272
Haller–Bauer reaction Base-induced cleavage of non-enolizable ketones leading to carboxylic amide de-rivative and a neutral fragment in which the carbonyl group is replaced by a hy-drogen.
R R5O
R2 R3R1 R4
NaNH2
PhH, reflux
RNH2
O
R2R1
H R5
R3 R4
non-enolizable ketone
R R5O
R2 R3R1 R4
NH2
R R5
R2 R3R1 R4
NH2OR
NH3
O
R2R1
R5
R3R4H R5
R3R4
Example 14
O
t-BuOK, t-BuOH
43%
CO2H
Example 29
O
OOMe
OMe
1. KOH, dioxane
2. CH2N2 77% 2 steps
OO
OMeOMe
OMe
Example 3, Racemization10
H
H
OLiNHC6H11
PhH, 80 oC46%
H
H
O NHC6H11
References 1. Haller, A.; Bauer, E. Compt. Rend. 1908, 147, 824−829. 2. Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989, 54, 1399−1408. 3. Paquette, L. A.; Gilday, J. P.; Maynard, G. D. J. Org. Chem. 1989, 54, 5044−5053. 4. Paquette, L. A.; Gilday, J. P. Org. Prep. Proc. Int. 1990, 22, 167−201. 5. Mehta, G.; Praveen, M. J. Org. Chem. 1995, 60, 279−280. 6. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 1399−1422. (Review). 7. Arjona, O.; Medel, R.; Plumet, J. Tetrahedron Lett. 2001, 42, 1287−1288. 8. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983−1986. 9. Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 2556−2562. 10. Braun, I.; Rudroff, F.; Mihovilovic, M. D.; Bach, T. Synthesis 2007, 24, 3896−3906.
273
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Hantzsch dihydropyridine synthesis 1,4-Dihydropyridine from the condensation of aldehyde, β-ketoester and ammo-nia. Hantzsch 1,4-dihydropyridines are popular reducing reagents in organocata-lysis.
R H
O CO2Et
R1O
NH3
NH
RCO2EtEtO2C
R1 R1
R H
O
CO2Et
R1O
enolate
formationCO2Et
R1OHH3N:
HH3N:
aldol
condensation
R1O
R
OH
CO2EtR1O
RCO2Et
R1O
R
OH
CO2EtH
:NH3
CO2Et
R1O
:NH3enamine
formation
CO2Et
R1HOH2N :
− H2O
H3N:CO2Et
R1
H
H2N
CO2Et
R1H2N
:
Michael
addition
EtO2C
R1
R
O
CO2Et
R1N
REtO2C
OR1
H
H2N HH
:NH3
tautomerizationCO2Et
R1NH2
REtO2C
O R1H2N H N
RCO2EtEtO2C
R1HOR1
H
H
H3N:
NH
RCO2EtEtO2C
R1 R1
Example 12
H
OCO2Et
O
NH3
NH
CO2EtEtO2C
NO2
NO2
nifedipine
274
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_119, © Springer-Verlag Berlin Heidelberg 2009
Example 29
R' H
O O
NH
RCO2R2R1O2C
CO2R2 NH4OAc
SiO2O
OOHO3S
(SiO2-SO3H), solvent-free60 oC, 83−95%
H
Example 3, Hantzsch 1,4-dihydropyridine as a hydrogen donor10
N R
O
OP
O
OH
NH
CO2EtEtO2C
NH
R
84−99% ee
References 1. Hantzsch, A. Ann. 1882, 215, 1−83. 2. Bossert, F.; Vater, W. Naturwissinschaften 1971, 58, 578−585. 3. Balogh, M.; Hermecz, I.; Naray-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem. Soc.,
Perkin Trans. 1 1986, 753−757. 4. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171−5187. 5. Menconi, I.; Angeles, E.; Martinez, L.; Posada, M. E.; Toscano, R. A.; Martinez, R. J.
Heterocycl. Chem. 1995, 32, 831−833. 6. Raboin, J.-C.; Kirsch, G.; Beley, M. J. Heterocycl. Chem. 2000, 37, 1077−1080. 7. Sambongi, Y.; Nitta, H.; Ichihashi, K.; Futai, M.; Ueda, I. J. Org. Chem. 2002, 67,
3499−3501. 8. Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 304−307. (Review).
9. Gupta, R.; Gupta, R.; Paul, S.; Loupy, A. Synthesis 2007, 2835−2838. 10. Metallinos, C.; Barrett, F. B.; Xu, S. Synlett 2008, 720−724.
275
Hantzsch pyrrole synthesis Reaction of α-chloromethyl ketones with β-ketoesters and ammonia to assemble pyrroles.
O
Cl
CO2Et
O NH
CO2EtNH3
CO2Et
O:NH3
enamine
formation
CO2Et
HOH2N:
H3N:CO2EtH
H2N
CO2Et
H2N
− H2O
CO2Et
H2N
ClO
HN
OHCl
HCO2Et
:NH:
− H2OH3N H
N
CO2Et
HN
Cl CO2Et:
H
HH3N: NH
CO2Et
Example 14
O
Br
F3C
CO2MeH2N NH
CO2Me
DME, 87−140 oC
2.5 h, 60% F3C
Example 27
OCl
CO2Et
O NH
CO2EtNH3, EtOH
48 h, 48%
References 1. Hantzsch, A. Ber. 1890, 23, 1474−1483. 2. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171−5186. 3. Kirschke, K.; Costisella, B.; Ramm, M.; Schulz, B. J. Prakt. Chem. 1990, 332,
143−147. 4. Kameswaran, V.; Jiang, B. Synthesis 1997, 530−532. 5. Trautwein, A. W.; Sü muth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8,
2381−2384. 6. Ferreira, V. F.; De Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L.
G. Org. Prep. Proced. Int. 2001, 33, 411−454. (Review). 7. Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk, Yu. V.; Pidlypnyi, N. I.
Chem. Heterocycl. Compounds 2004, 40, 1218−1219.
276
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Heck reaction The palladium-catalyzed alkenylation or arylation of olefins.
R1 XR3
H R2
R4 R3
R1 R2
R4
Pd(0) (catalytic)
base
R1 = aryl, alkenyl, alkyl (with no β-hydrogen)X = Cl, Br, I, OTf, OTs, N2
+
The catalytic cycle:
A
R1 X
R3
H R2
R4
R3
R1 R2
R4
LnPd(II)R1
X
LnPd(0)
Pd(II)LnXR1
H R4R3 R2
Pd(II)LnXH
R3 R4R1 R2
LnPd(II)H
X
base
base•HX
Pd(0) or Pd(II) precatalysts
B
C
D
E
A: Oxidative additionB: Migratory insertion (syn)C: C−C bond rotation
D: syn-β-eliminationE: Reductive elimination
Example 1, Asymmetric intermolecular Heck reaction6
NCO2Me
CO2Et
OTfNCO2Me
EtO2C
*
Pd[(R)-BINAP]23 mol%
proton spongePhH, 60 oC
95%, > 99% ee
277
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_121, © Springer-Verlag Berlin Heidelberg 2009
Example 2, Intramolecular Heck7
N
N
HO
I
OTBS
HN
N
OH
OTBS
0.3 eq. Pd(OAc)2
Bu4NCl, DMF, K2CO370 oC, 3 h, 74%
Example 38
Cl
MeO
O
O
MeO
O
O
1.5% Pd2(dba)3, 6% P(t-Bu)31.1. eq. Cs2CO3, dioxane
120 oC, 24 h, 82%
Example 4, Intramolecular Heck9
N
N Cl
NH N
N
NH
10 mol% Pd(OAc)2
Bu4NCl, K2CO3DMF, 100 oC, 67%
Example 5, Intramolecular Heck13
HN
MeNH
NMeNH H
NBn
ONTsMe
TfO
TsNMe
BnN
O
OTf Pd(OAc)2(R)-Tol-BINAPMeCN, 80 oC
(62%, 90% ee)
NMe
MeMe
MeMe
HN
MeNH
NMeNH H
BnN
NBn
TsNMe
NTsMe
O
O
Example 6, Reductive Heck reaction17
HMe
O
NH
Me
Br
H Me
NH
MeMe
O
5 mol% Pd(P(o-tol)3(OAc)2
NaOCHO, TBAB, Et3NDMF, 80 oC, 65%
278
References 1. Heck, R. F.; Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518−5526. Richard Heck
discovered the Heck reaction when he was an assistant professor at the University of Delaware. Despite having discovered a novel methodology that would see ubiquitous utility in organic chemistry and having published a popular book,4 Heck had difficul-ties in securing funding for his research, he left chemistry and moved to Asia. Now he is retired in Florida.
2. Heck, R. F. Acc. Chem. Res. 1979, 12, 146−151. (Review). 3. Heck, R. F. Org. React. 1982, 27, 345−390. (Review). 4. Heck, R. F. Palladium Reagents in Organic Synthesis, Academic Press, London, 1985.
(Book). 5. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994,
University Science Books: Mill Valley, CA, pp 103−113. (Book). 6. Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett. 1993, 34, 2505−2508. 7. Rawal V. H.; Iwasa, H. J. Org. Chem. 1994, 59, 2685−2686. 8. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10−11. 9. Li, J. J. J. Org. Chem. 1999, 64, 8425−8427. 10. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009−3066. (Review). 11. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314−321. (Review). 12. Link, J. T. Org. React. 2002, 60, 157−534. (Review). 13. Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002,
124, 9008−9009. 14. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945−2963. (Review). 15. Beller, M.; Zapf, A.; Riermeier, T. H. Transition Metals for Organic Synthesis (2nd
edn.) 2004, 1, 271−305. (Review). 16. Oestreich, M. Eur. J. Org. Chem. 2005, 783−792. (Review). 17. Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404−406. 18. Fuchter, M. J. Heck Reaction. In Name Reactions for Homologations-Part I; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review). 19. The Mizoroki-Heck Reaction; Oestreich, M., Ed.; Wiley & Sons: Hoboken, NJ, 2009.
279
Heteroaryl Heck reaction Intermolecular or intramolecular Heck reaction that occurs onto a heteroaryl re-cipient.
N
SI
Pd(Ph3P)4, Ph3P, CuI
Cs2CO3, DMF, 140 oCN
S
N
SI
Pd(0)
oxidative additionPd(II)I
insertion
NS
Pd(II)H
B:I
NSCs2CO3
CsI CsCHO3Pd(0)
Example 12
O
Br
NN
N
BuN
NN
BuO
Pd(OAc)2, NaHCO3
n-Bu4NCl, DMA 150 oC, 24 h, 83%
Example 23
N
N Cl
N
O
N
NN
OPd(Ph3P)4, KOAcDMA, reflux, 65%
References 1. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaka, R.; Miyafuji, A.; Nakata, T.;
Tani, N. Aoyagi, Y. Heterocycles 1990, 31, 1951−1958. 2. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915−6918. 3. Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.; Koma-
tsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J. Honma, R. Akita, Y.; Ohta, A. Heterocy-cles 1992, 33, 257−272.
4. Proudfoot, J. R.; Patel, U. R.; Kapadia, S. R.; Hargrave, K. D. J. Med. Chem. 1995, 38, 1406−1410.
5. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467−473.
6. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry; 2nd ed.; 2007, El-sevier: Oxford, UK. (Review).
280
Hegedus indole synthesis Stoichiometric Pd(II)-mediated oxidative cyclization of alkenyl anilines to in-doles. Cf. Wacker oxidation.
NH2
PdCl2(CH3CN)2, THF
then, Et3N, 84%MeO2C NHMeO2C
CH3
NH2MeO2C PdNH2MeO2C Cl
ClPdCl2(CH3CN)2
palladation
Et3N
precipitate
NH2MeO2C
PdCl
Et3NCl
:
NH2
PdEt3N
Cl
Cl
MeO2C
– HCl
– "PdH"
H
NHMeO2C
"PdH"
NHMeO2C
PdLn
H
NHMeO2C
CH3β-elimination
CH3
Example 11a
NH2
10 mol% (CH3CN)2PdCl2100 mol% benzoquinone
10 eq. Et3N, THF, reflux, 84% NH
CH3
Example 21d
10 mol % (CH3CN)2PdCl2100 mol% benzoquinone
10 eq. LiCl, THF, reflux, 77%NHTs N
Br
Ts
Br
References 1. (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98,
2674−2676. Lou Hegedus is a professor at Colorado State University. (b) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800−5807. (c) Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215−2221. (d) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657−2662. (e) Hegedus, L. S. Angew. Chem., Int. Ed. 1988, 27, 1113−1126. (Review).
2. Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur. J. 1997, 3, 70−74. 3. Osanai, Y. Y.; Kondo, K.; Murakami, Y. Chem. Pharm. Bull. 1999, 47, 1587−1590. 4. Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186−187. A ruthe-
nium variant. 5. Johnston, J. N. Hegedus Indole Synthesis. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 135−139. (Re-view).
281
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Hell–Volhard–Zelinsky reaction α-Halogenation of carboxylic acids using X2/PBr3.
ROH
OR
Br
O
Br
H2OR
OH
O
Br
PBr3
Br2
α-bromoacid
RO
O
P BrBr
Br
RO
OP
Br
Br
Br
RO
OP
Br
Br
BrH
RBr
O
O P Br H
Br
enolization RBr
O
Br Br
H
:OH2
ROH
O
BrR
Br
O
Br
RBr
O
OH
H
Br
HB:
hydrolysis
Example 15
CO2H Cl2, cat. PCl3
97 oC, 6 h, 77%
CO2HCl
Example 26
CO2H
PBr3
Br2, 57%Br
CO2H
CO2HBr
H
References 1. (a) Hell, C. Ber. 1881, 14, 891−893. Carl M. von Hell (1849−1926) was born in Stutt-
gart, Germany. He studied under Fehling and Erlenmeyer. After serving in the war of 1870, he became very ill. Hell became a professor at Stuttgart in 1883 where he dis-covered the Hell–Volhard–Zelinsky reaction. (b) Volhard, J. Ann. 1887, 242, 141−163. Jacob Volhard (1849−1909) was born in Darmstadt, Germany. He appren-ticed under Liebig, Will, Bunsen, Hofmann, Kolbe, and von Baeyer. He improved Hell’s original procedure in preparing α-bromo-acid during his research in thiophenes. (c) Zelinsky, N. D. Ber. 1887, 20, 2026. Nikolai D. Zelinsky (1861−1953) was born in
282
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_123, © Springer-Verlag Berlin Heidelberg 2009
Tyaspol, Russia. He studied at Göttingen under Victor Meyer, receiving his Ph.D. In 1889. Zelinsky returned to Russia and became a professor at the University of Mos-cow. On his ninetieth birthday in 1951, he was awarded the Order of Lenin.
2. Watson, H. B. Chem. Rev. 1930, 7, 173−201. (Review). 3. Sonntag, N. O. V. Chem. Rev. 1953, 52, 237−246. (Review). 4. Harwood, H. J. Chem. Rev. 1962, 62, 99−154. (Review). 5. Jason, E. F.; Fields, E. K. US Patent 3,148,209 (1964). 6. Chow, A. W.; Jakas, D. R.; Hoover, J. R. E. Tetrahedron Lett. 1966, 5427−5431. 7. Liu, H.-J.; Luo, W. Synth. Commun. 1991, 21, 2097−2102. 8. Zhang, L. H.; Duan, J.; Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39,
9621−9622. 9. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1999, 64, 8059−8062. 10. Stack, D. E.; Hill, A. L.; Diffendaffer, C. B.; Burns, N. M. Org. Lett. 2002, 4,
4487−4490.
283
Henry nitroaldol reaction The nitroaldol condensation reaction involving aldehydes and nitronates, derived from deprotonation of nitroalkanes by bases.
R1 R2
O
R4 NO2
BaseR3
R4R2
R1HOR3 H NO2
2-nitroalcohols
NO2
HR1
R2
B
HBnitroalkanes
NO2R2
R1N
R2
R1 O
O
HB
BN
R2
R1
OH
nitronic acidsor aci-nitroalkanes
R3
O
H
NO2
R2
R1
R3
O
NO2
R2
R1
R3
OHHBB
2-nitroalcohols
O
nitronates
Example 14
NO2
CHO
Amberlyst A-21 (basic)rt, 62%
NO2HO
Example 2, Retro-Henry reaction5
OHNO2 NO2
OCuSO4, SiO2
PhH, reflux67%
Example 3, Aza-Henry reaction8
N
Ph
PO
PhPh
NO2Ph
5 mol% TMG, 100 oC
0.1 mBar, 26 h95%, anti:syn = 98:2
HN
Ph
PO
PhPh
NO2
Ph
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Example 4, Intramolecular Henry reaction10
N O
NO2
ON
O
H
O2N
HODBU, MeCN
62%
References 1. Henry, L. Compt. Rend. 1895, 120, 1265–1268. 2. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. J. Org. Chem. 1989, 54, 1233–1234. 3. Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Per-
gamon, 1991, 2, 321−340. (Review). 4. Chen, Y.-J.; Lin, W.-Y. Tetrahedron Lett. 1992, 33, 1749–1750. 5. Saikia, A. K.; Hazarika, M. J.; Barua, N. C.; Bezbarua, M. S.; Sharma, R. P.; Ghosh,
A. C. Synthesis 1996, 981–985. 6. Luzzio, F. A. Tetrahedron 2001, 57, 915–945. (Review). 7. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151–153. (Review on aza-Henry re-
action). 8. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.;
Ricci, A. J. Org. Chem. 2004, 69, 8168–8171. 9. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881–3884. 10. Kamimura, A.; Nagata, Y.; Kadowaki, A.; Uchidaa, K.; Uno, H. Tetrahedron 2007,
63, 11856–11861. 11. Wang, A. X. Henry Reaction. In Name Reactions for Homologations-Part I; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 404−419. (Review).
285
Hinsberg synthesis of thiophene derivatives Condensation of diethyl thiodiglycolate and α-diketones under basic conditions, which provides 3,4-disubstituted thiophene-2,5-dicarbonyls upon hydrolysis of the crude ester product with aqueous acid.
O
O SO
EtO
O
OEt S
PhPh
O
OH
HO
O1.
NaOEt, EtOH2. H3O+
O
Ph
O
Ph
S
CO2Et
CO2Et
O
Ph
O
CO2EtS
EtO
O
Ph S
OO
CO2Et
Ph
O
H
Ph
EtO
O2C
S CO2Et
Ph
OPh
S
Ph Ph
CO2EtHO2C S
Ph Ph
HO2C CO2H
H+, H2O
reflux
Example 12
O
S
O
CH3
CH3
O
H3CO
CH3
O
PhO
Ph
NaOMe
NaOMe
O
ArS
O
Ar
O
ArS
O
Ar
HO OH
HO OH
H3C CH3
Ph Ph
90%
81%
SOCl2, pyr.
SOCl2, pyr.
O
ArS
O
Ar
O
ArS
O
Ar
Ph Ph
H3C CH3
95%
89%
Example 24
S
O
O
S
O
O
(CHO)3, NaOMe
MeOH, 42%
286
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_125, © Springer-Verlag Berlin Heidelberg 2009
Example 35
O
Ph SO
Ph1.
KOH
2. SOCl2, pyr.9% yield, 2 steps
O
OS
O
Ph
OPh Example 46
S CNNCO
H3C
O
CH3
S
CH3H3C
NH2
ONC
NaOH, MeOH
94%
Example 5, Polymer-support Hinsberg thiophene synthesis9
OS R1
O
R2 R2
OO KOt-Bu
R1 = CO2i-Pr CONEt2 PPh3
+
O SR1
O
R2 R2
10% TFA
CH2Cl2
HO SR1
O
R2 R2
References 1. Hinsberg, O. Ber. 1910, 43, 901−906. 2. Miyahara, Y.; Inazu, T.; Yoshino, T. Bull. Chem. Soc. Jpn. 1980, 53, 1187−1188. 3. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., ed.; Wiley-
Interscience: New York, 1985, pp 34−41. (Review). 4. Miyahara, Y.; Inazu, T.; Yoshino, T. J. Org. Chem. 1984, 49, 1177−1182. 5. Christl, M.; Krimm, S.; Kraft, A. Angew. Chem., Int. Ed. 1990, 29, 675−677. 6. Beye, N.; Cava, M. P. J. Org. Chem. 1994, 59, 2223−2226. 7. Vogel, E.; Pohl, M.; Herrmann, A.; Wiss, T.; König, C.; Lex, J.; Gross, M.; Gissel-
brecht, J. P. Angew. Chem., Int. Ed. 1996, 35, 1520−1525. 8. Mullins, R. J.; Williams, D. R. Hinsberg Synthesis of Thiophene Derivatives. In Name
Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Ho-boken, NJ, 2005, pp 199−206. (Review).
9. Traversone, A.; Brill, W. K.-D. Tetrahedron Lett. 2007, 48, 3535−3538.
287
Hiyama cross-coupling reaction Palladium-catalyzed cross-coupling reaction of organosilicons with organic hal-ides, triflates, etc. In the presence of an activating agent such as fluoride or hy-droxide (transmetallation is reluctant to occur without the effect of an activating agent). For the catalytic cycle, see the Kumada coupling on page 325.
R1 SiY R2 XPd catalystactivator
R1 R2
R1 = alkenyl, aryl, alkynyl, alkylR2 = aryl, alkyl, alkenylY = (OR)3, Me3, Me2OH, Me(3-n)F(n+3)X = Cl, Br, I, OTfactivator = TBAF, base
Pd(0)
Ar1 Pd(II) XAr1 Pd(II) Ar2
Ar1 Ar2
R3SiF X
SiR
Ar2
F
R
RBu4N
Ar1 Xoxidativeaddition
trans"metal"lation
reductiveelimination
Example 11a
S Si(Et)F2
S
I
MeO2C S
SMeO2C(η3-C3H5PdCl)2
DMF, KF, 100 oC82%
Example 22
C5H11 Si(OMe)3N
Br
Bu4NF, Pd(OAc)2, Ph3P DMF, reflux, 72%
C5H11N
288
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_126, © Springer-Verlag Berlin Heidelberg 2009
Example 37
SiO
O
OPMB
IMe
Me
CH3
[allylPdCl]2 (7.5 mol%)
TBAF, THF, 25 °C, 60 h61%
OHO
PMBOMe
Example 49
I
CO2Me
OMe
Me
MOMO
Me
O O
H3CO
Ph
Me3Si H
O O
Ph
HMe
Me
CO2Me
O
MOMO
MeMe
O
[allylPdCl]2 TBAF (12 mol%)
THF, 60 °C, 20 h20%
References 1. (a) Hatanaka, Y.; Fukushima, S.; Hiyama, T. Heterocycles 1990, 30, 303−306. (b)
Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471−1478. (c) Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1994, 35, 6507−6510.
2. Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309−1310. 3. Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; 1998, Diederich, F.; Stang,
P. J., Eds.; Wiley–VCH: Weinheim, Germany, pp 421–53. (Review). 4. Denmark, S. E.; Wang, Z. J. Organomet. Chem. 2001, 624, 372−375. 5. Hiyama, T. J. Organomet. Chem. 2002, 653, 58−61. 6. Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697−700. 7. Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2004, 126, 12432−12440. 8. Domin, D.; Benito-Garagorri, D.; Mereiter, K.; Froehlich, J.; Kirchner, K. Or-
ganometallics 2005, 24, 3957−3965. 9. Anzo, T.; Suzuki, A.; Sawamura, K.; Motozaki, T.; Hatta, M.; Takao, K.-i.; Tadano,
K.-i. Tetrahedron Lett. 2007, 48, 8442−8448. 10. Yet L. Hiyama Cross-Coupling Reaction. In Name Reactions for Homologations-Part
I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−416. (Re-view).
289
Hofmann rearrangement Upon treatment of primary amides with hypohalites, primary amines with one less carbon are obtained via the intermediacy of isocyanate. Also know as the Hof-mann degradation reaction.
R NH2
OR N C O
H2OR NH2 CO2↑
Br2
NaOH
R NH
O
OH
Br BrH
R NH
O R N
O
H
Br
R N
OBr
OH
R NH2 CO2↑N C O
RHN O
OH
R
OH OH isocyanate intermediate Example 1, NBS variant2
NH2
O2N
ONBS, DBU, MeOH
reflux, 25 min., 70%
HN
O2N
O
O
Example 2, Iodosobenzene diacetate5
NH2
O
OH
IOCOCF3
OCOCF3
CH3CN/H2O, 4.5 h, 100%NH
O
OH
IO CF3
OPh
:
N
OH
CO
:
H
O
HN
O
Example 3, Bromine and alkoxide6
NH
AcOH
H H HOH
H H
HN
O
O
O
Br2, NaOMe
MeOH, rt → reflux75%
290
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_127, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Sodium hypochlorite7
O
CONH2
OHHO
HOO
NH2
OHHO
HO
NaOCl
aq. NaOH50 °C, 81%
Example 5, The original conditions, bromine and hydroxide9
NN
NN
NNPh Ph
Me
CONH2N
NN
N
NNPh Ph
Me
NH2
Br2, aq. KOH
0 °C to reflux80%
Example 6, Lead tetraacetate10
NO2
O
CONH2
NO2
O
NHBocPb(OAc)4
t-BuOH, Et3Nreflux, 75%
References 1. Hofmann, A. W. Ber. 1881, 14, 2725–2736. 2. Jew, S.-s.; Kang, M.-h. Arch. Pharmacol Res. 1994, 17, 490–491. 3. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62, 7495–7496. 4. Togo, H.; Nabana, T.; Yamaguchi, K. J. Org. Chem. 2000, 65, 8391–8394. 5. Yu, C.; Jiang, Y.; Liu, B.; Hu, L. Tetrahedron Lett. 2001, 42, 1449–1452. 6. Jiang, X.; Wang, J.; Hu, J.; Ge, Z.; Hu, Y.; Hu, H.; Covey, D. F. Steroids 2001, 66,
655–662. 7. Stick, R. V.; Stubbs, K. A. J. Carbohydr. Chem. 2005, 24, 529–547. 8. Moriarty, R. M. J. Org. Chem. 2005, 70, 2893−2903. (Review). 9. El-Mariah, F.; Hosney, M.; Deeb, A. Phosphorus, Sulfur Silicon Relat. Elem. 2006,
181, 2505–2517. 10. Jia, Y.-M.; Liang, X.-M.; Chang, L.; Wang, D.-Q. Synthesis 2007, 744–748. 11. Gribble, G. W. Hofmann rearrangement. In Name Reactions for Homologations-Part
II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 164−199. (Re-view).
291
Hofmann–Löffler–Freytag reaction Formation of pyrrolidines or piperidines by thermal or photochemical decomposi-tion of protonated N-haloamines.
R1 NR2
Cl 1. H+, ΔNR1
R22. −OH
R1 NR2
Cl H
R1 NR2
ClH
Δ
homolyticcleavage
R1 NR2
HClH
chloroammonium salt nitrogen radical cation
HN
R1R2
H1,5-hydrogen
atom transfer
NH2R1
R1 NR2
ClH
R1N
R2H
R2
NH2R1 ClR2
NR1
R2NH
Cl R2R1:
SN2NR1
R2H
OH OH
Example 12
HO
H
H H
NH1. NaOCl, 95%
2. TFA, hv, 87%3. NaOH, MeOH, 76%
HO
H
H H
N
O O
Example 24
84% H2SO465 oC, 30 min.
25% N
N Ph
N
N PhBr
N
O
Example 35
N NNH N
NCS, ether, Et3Nthen hv, (Hg0 lamp)
0 oC, 3.5 h in N2100%
292
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_128, © Springer-Verlag Berlin Heidelberg 2009
Example 47
AcOH
HN P(O)(OEt)2
PhI(OAc)2or Pb(OAc)4
I2, hv, 99%
AcOH
N P(O)(OEt)2
Example 512
Me Me
Me NBr
O
Me
O CF3 1.0 equiv CBr4, hv0.05 M PhCF3
100 W flood lamprt, 7 min. Me Me
Me NH
O
Me
O CF3
Br
1.25 equiv Ag2CO3
CH2Cl2, rt, 1 h
then AcOH, 15 min.> 69% overall
Me Me
Me OO
Me
O
References 1. (a) Hofmann, A. W. Ber. 1883, 16, 558−560. (b) Löffler, K.; Freytag, C. Ber. 1909,
42, 3727. 2. Wolff, M. E.; Kerwin, J. F.; Owings, F. F.; Lewis, B. B.; Blank, B.; Magnani, A.;
Karash, C.; Georgian, V. J. Am. Chem. Soc. 1960, 82, 4117−4118. 3. Wolff, M. E. Chem. Rev. 1963, 63, 55−64. (Review). 4. Dupeyre, R.-M.; Rassat, A. Tetrahedron Lett. 1973, 2699−2701. 5. Kimura, M.; Ban, Y. Synthesis 1976, 201−202. 6. Stella, L. Angew. Chem., Int. Ed. 1983, 22, 337−422. (Review). 7. Betancor, C.; Concepcion, J. I.; Hernandez, R.; Salazar, J. A.; Suarez, E. J. Org.
Chem. 1983, 48, 4430−4432. 8. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (Review). 9. Togo, H.; Katohgi, M. Synlett 2001, 565−581. (Review). 10. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2001, 33, 455−476. (Review). 11. Li, J. J. Hofmann–Löffler–Freytag Reaction. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 89−97. (Review).
12. Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17247−17249.
293
Horner–Wadsworth–Emmons reaction Olefin formation from aldehydes and phosphonates. Workup is more advanta-geous than the corresponding Wittig reaction because the phosphate by-product can be washed away with water. Typically gives the trans- rather than the cis-olefins.
EtOP
OEt
OEtO
O NaH, then
RCHO
CO2Et
R EtOP
ONa
OEtO
EtOP
OEt
OEtO
O
H
HO R
HEtOP
OEt
OEtO
O
EtOP
OEt
OEtO
O
O R
The stereochemical outcome: erythro (kinetic) or threo (thermodynamic)
PO
HR CO2Et
H
O
OEtOEt
HR CO2Et
HPO OEt
OEtO
R CO2Et
erythro, kinetic adduct
PO
HR H
CO2Et
O
OEtOEt CO2Et
RHR H
CO2EtPO OEt
OEtO
threo, thermodynamic adduct Example 13
OCHO
OMe
EtOP
OEt
OEtO
O
NaH, THF, 95%
O
OMe
CO2Et
Example 24
CHOEtO
POEt
OEtO
O
KOH, THF, 95%
CO2Et
BnO BnO Example 37
OH
OTBDPS
OMOMO
NaH, THF92%
N
O
OMe
PEtO
OEtO O
H
OTBDPS
OMOMN
O
OMe
294
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_129, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Intramolecular Horner–Wadsworth–Emmons9
O O
O
ON
N
O
O
OMe
Br
O
O POEtO
OEt
OTBS
MeO
MeOOTIPS
K2CO318-crown-6
Toluene −20 oC
67%Z/E = 5:1
2
3
O
OO
N
N
OO
MeO
Br
O
TBSO
MeO
MeO
OTIPS
O
23
References 1. (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499–
2505. (b) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733–1738. (c) Wadsworth, D. H.; Schupp, O. E.; Seus, E. J.; Ford, J. A., Jr. J. Org. Chem. 1965, 30, 680–685.
2. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863−927. (Review). 3. Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem.
Soc. 1996, 118, 9509–9525. 4. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R. J.; Natarajan, S.;
Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602–2621.
5. Comins, D. L.; Ollinger, C. G. Tetrahedron Lett. 2001, 42, 4115–4118. 6. Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.; Iannece, P.; Scettri, A. Tetrahedron
Lett. 2003, 44, 1333–1337. 7. Ahmed, A.; Hoegenauer. E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig, H.; Öhler, E.;
Mulzer, J. J. Org. Chem. 2003, 68, 3026–3042. 8. Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281–4283. 9. Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.;
Zhou, W.-S.; Lin, G.-Q. Chem. Eur. J. 2006, 12, 1185–1204. 10. Rong, F. Horner–Wadsworth–Emmons reaction in. In Name Reactions for Homologa-
tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 420−466. (Review).
295
Houben−Hoesch reaction Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles.
OH
OH
RCN
HCl, AlCl3
OH
OH
R NH•HCl
OH
OH
R O
H2O
OH
OHR N:AlCl3 complexation
R N AlCl3
:
electrophilic
substitution
O
OH
R NHH
H
OH
OH
R NH•HCl
H2O:
OH
OH
R O
hydrolysis
OH
OH
R ONH2
H
H
Example 1, Intramolecular Houben−Hoesch reaction3
O
CN
OMe
OMe
1. ZnCl2, HCl(g), Et2O
2. H2O, reflux, 89%
O OMe
OMeO Example 26
FPivO CN
OMe
OH
MeO
CO2Me
OH
SbCl5, 2-chloropropane
CH2Cl2, rt, 2 h, 95%
OPiv
MeO FOMe
OCO2Me
OH
NH
Example 38
NH2•HCl14Cu
NC ClBCl3•CH2Cl2, ZnCl2
then aq. HCl
NH214Cu
OCl
14Cu = 14C-labelled
296
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_130, © Springer-Verlag Berlin Heidelberg 2009
Example 49
NH
OMe
MeO
ClNC
NH
OMe
MeO
Cl
O
HCl (g), THF, overnight
then 2% aq. HClreflux, 3 h, 43%
References 1. (a) Hoesch, K. Ber. 1915, 48, 1122−1133. Kurt Hoesch (1882−1932) was born in
Krezau, Germany. He studied at Berlin under Emil Fischer. During WWI, Hoesch was Professor of Chemistry at the University of Istanbul, Turkey. After the war he gave up his scientific activities to devote himself to the management of a family busi-ness. (b) Houben, J. Ber. 1926, 59, 2878−2891.
2. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691−692. 3. Rao, A. V. R.; Gaitonde, A. S.; Prakash, K. R. C.; Rao, S. P. Tetrahedron Lett. 1994,
35, 6347−6350. 4. Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117,
3037−3043. 5. Kawecki, R.; Mazurek, A. P.; Kozerski, L.; Maurin, J. K. Synthesis 1999, 751−753. 6. Udwary, D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124,
5294−5303. 7. Sanchez-Viesca, F.; Gomez, M. R.; Berros, M. Org. Prep. Proc. Int. 2004, 36,
135−140. 8. Wager, C. A. B.; Miller, S. A. J. Labelled Compd. Radiopharm. 2006, 49, 615−622. 9. Black, D. St. C.; Kumar, N.; Wahyuningsih, T. D. ARKIVOC 2008, (6), 42−51.
297
Hunsdiecker−Borodin reaction Conversion of silver carboxylate to halide by treatment with halogen.
R O
OAg
X2R X CO2↑ AgX
R O
OAg
X X
AgX R O
OX
homolytic
cleavage
R XCO2↑XR O
OR
R O
OX
R O
O
Example 15
Cl CO2H Cl BrHgO, Br2, Δ
CCl4, dark, 35−46% Example 26
NBS, n-Bu4N+CF3CO2−
ClCH2CH2Cl, 96%
CO2H
MeO
Br
MeO
Example 38
CO2H
HO
N
N
Cl
2 BF4
KBr, CH3CN, 82%
Br
HO
F"Select fluor"
Example 4, One-pot microwave-Hunsdiecker−Borodin followed by Suzuki10
BnOOMe
CO2HNBS, LiOAc
CH3CN−H2O 9:1MW 1 min.
BnOOMe
Br
298
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_131, © Springer-Verlag Berlin Heidelberg 2009
BnOOMe
PhB(OH)2, K2CO3Pd(PPh3)4
CH3CN/H2O 2:1microwave, 5 min.
64% 2 steps
References 1. (a) Borodin, A. Ann. 1861, 119, 121−123. Aleksandr Porfirevi Borodin (1833−1887)
was born in St Petersburg, the illegitimate son of a prince. He prepared methyl bro-mide from silver acetate in 1861, but another eighty years elapsed before Heinz and Cläre Hunsdiecker converted Borodin’s synthesis into a general method, the Huns-diecker or Hunsdiecker−Borodin reaction. Borodin was also an accomplished com-poser and is now best known for his musical masterpiece, opera Prince Egor. He kept a piano outside his laboratory. (b) Hunsdiecker, H.; Hunsdiecker, C. Ber. 1942, 75, 291−297. Cläre Hunsdiecker was born in 1903 and educated in Cologne. She devel-oped the bromination of silver carboxylate alongside her husband, Heinz.
2. Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 326−421. (Review). 3. Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24,
4979−4982. 4. Crich, D. In Comprehensive Organic Synthesis; Trost, B. M.; Steven, V. L., Eds.; Per-
gamon, 1991, Vol. 7, pp 723−734. (Review). 5. Lampman, G. M.; Aumiller, J. C. Org. Synth. 1988, Coll. Vol. 6, 179. 6. Naskar, D.; Chowdhury, S.; Roy, S. Tetrahedron Lett. 1998, 39, 699−702. 7. Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861−7864. 8. Ye, C.; Shreeve, J. M. J. Org. Chem. 2004, 69, 8561−8563. 9. Li, J. J. Hunsdiecker reaction. In Name Reactions for Functional Group Transforma-
tions; Li, J. J., Corey, E. J., Eds., John Wiley & Sons: Hoboken, NJ, 2007, pp 623−629. (Review).
10. Bazin, M.-A.; El Kihel, L.; Lancelot, J.-C.; Rault, S. Tetrahedron Lett. 2007, 48, 4347−4351.
299
Jacobsen–Katsuki epoxidation Mn(III)salen-catalyzed asymmetric epoxidation of (Z)-olefins.
O
N
O
N
R1
R2 R2
R1Mn
R R
Cl
terminal oxidant, solvent
R3
R4
R5
R6
R3
R4
R5
R6
O
* *
1. Concerted oxygen transfer (cis-epoxide):
R1R OMn(V)
R1R
OMn(V)
R1R
OMn(V)
R1R
O
2. Oxygen transfer via radical intermediate (trans-epoxide):
R1R OMn(V)
R1R
OMn(V)
R1R
O
R1R
OMn(V)
3. Oxygen transfer via manganaoxetane intermediate (cis-epoxide):
R1R OMn(V)
R1
R
OMn(V)
R1R
O
[2 + 2]
cycloaddition
R1
RMn(V)O
Example 12
cat, 4-phenylpyridine-N-oxide
NaOCl, CH2Cl2, 4 oC, 12 h56%, 95−97% ee
CO2EtCO2Et
O
O
N
O
N
t-Bu
t-Bu t-Bu
t-BuMn
Clcat. =
H H
300
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_132, © Springer-Verlag Berlin Heidelberg 2009
Example 25
Ph
OOMe
N
Ph
OOMe
NO
cat., NaOCl
58% yield, 89% ee
Example 26
O88% ee
N
NN
HN
OHOHPh
O NHt-BuCrixivan
cat. NaOCl
88%
References 1. (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990,
112, 2801–2903. (b) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahe-dron Lett. 1990, 31, 7345–7348. (c) Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahe-dron Lett. 1991, 32, 1055–1058. (d) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320–4323. (e) Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457–5460.
2. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296–2298. 3. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim,
New York, 1993, Ch. 4.2. (Review). 4. Jacobsen, E. N. In Comprehensive Organometallic Chemistry II, Eds. G. W. Wilkin-
son, G. W.; Stone, F. G. A.; Abel, E. W.; Hegedus, L. S., Pergamon, New York, 1995, vol 12, Chapter 11.1. (Review).
5. Lynch, J. E.; Choi, W.-B.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.; Ball, R. G. J. Org. Chem. 1997, 62, 9223–9228.
6. Senananyake, C. H. Aldrichimica Acta 1998, 31, 3–15. (Review). 7. Jacobsen, E. N.; Wu, M. H. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H. Eds.; Springer: New York; 1999, Chapter 18.2. (Review). 8. Katsuki, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000, 287. (Review). 9. Katsuki, T. Synlett 2003, 281–297. (Review). 10. Palucki, M. Jacobsen–Katsuki epoxidation. In Name Reactions in Heterocyclic Chem-
istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 29−43. (Re-view).
11. Engelhardt, U.; Linker, T. Chem. Commun. 2005, 1152–1154. 12. Fernandez de la Pradilla, R.; Castellanos, A.; Osante, I.; Colomer, I.; Sanchez, M. I. J.
Org. Chem. 2009, 74, 170–181.
301
Japp–Klingemann hydrazone synthesis Hydrazones from β-ketoesters and diazonium salts with the acid or base.
KOHArN2 Cl CO2R
O N CO2RHN
Ar OH
O
Diazonium salt β-keto-ester hydrazone
CO2RO
HCO2R
O
OHdeprotonation
N N Arcoupling
CO2RO
NN
Ar
HO
CO2RNN
Ar
O OH
N CO2RHN
ArOH
O
N CO2RN
Ar
H
Example 14
SN
OONH2
Me
CO2Et
SN
OON
Me
CO2Et
N
ClNaNO2
conc. HCl, H2O0 oC
SN
OONH
N
CO2Et
NMe2Me NMe2
O
CO2Et
NaOAc (pH 3−4)0 to 50 oC
72%
Me
CO2Et
Example 26
OBnN2
+Cl
NH
OHO2C
0.5 N KOH, THF, rt, 1 h
thenNH
ON
HN
OBn
62% yield
302
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_133, © Springer-Verlag Berlin Heidelberg 2009
Example 310
O
OEt
O
NR1R2
NN
KOAc, H2O
−4 oC to rt60−85%
NR1R2
HNN
O
OEt
H+, 100 oC
70−85%NH
NR1R2
CO2EtHO2C
CO2H
References 1. (a) Japp, F. R.; Klingemann, F. Ber. 1887, 20, 2942−2944. (b) Japp, F. R.; Klinge-
mann, F. Ber. 1887, 21, 2934−2936. (c) Japp, F. R.; Klingemann, F. Ber. 1887, 20, 3398−3401. (d) Japp, F. R.; Klingemann, F. Ann. 1888, 247, 190−225. (e) Japp, F. R.; Klingemann, F. J. Chem. Soc. 1888, 53, 519−544.
2. Phillips, R. R. Org. React. 1959; 10, 143−178. (Review). 3. Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler, T. J. Org. Chem. 1995, 60,
953−959. 4. Pete, B.; Bitter, I.; Harsanyi, K.; Toke, L. Heterocycles 2000, 53, 665−673. 5. Atlan, V.; Kaim, L. E.; Supiot, C. Chem. Commun. 2000, 1385−1386. 6. Dubash, N. P.; Mangu, N. K.; Satyam, A. Synth. Commun. 2004, 34, 1791−1799. 7. He, W.; Zhang, B.-L.; Li, Z.-J.; Zhang, S.-Y. Synth. Commun. 2005, 35, 1359−1368. 8. Li, J. Japp–Klingemann hydrazone synthesis. In Name Reactions for Functional
Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 630−634. (Review).
9. Chen, Y.; Shibata, M.; Rajeswaran, M.; Srikrishnan, T.; Dugar, S.; Pandey, R. K. Tet-rahedron Lett. 2007, 48, 2353−2356.
10. Pete, B. Tetrahedron Lett. 2008, 49, 2835−2838.
303
Jones oxidation The Collins/Sarett oxidation (chromium trioxide-pyridine complex), and Corey´s PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate) oxidations follow a similar pathway as the Jones oxidation (chromium trioxide and sulfuric acid in acetone). All these oxidants have a chromium (VI), normally black or yellow, which is reduced to Cr(IV), often green.
N 2CrO3
Collins/Sarett
N 2Cr2O7
H
CrO3ClNH
PCC PDC
CrO3/H2SO4
Jones
Jones oxidation By the Jones oxidation, the primary alcohols are oxidized to the corresponding aldehyde or carboxylic acids, whereas the secondary alcohols are oxidized to the corresponding ketones.
R1 R2
OH CrO3
H2SO4, acetone R1 R2
O
CrO3 + H2O H2CrO4
R1 R2
OH :
CrO O
R1
OCr
R2H
OH
OH2O
H
:BR1 R2
OCr
O OHCr(VI)
black
Cr(III)
green
O
The intramolecular mechanism is also operative:
R1
OCr
R2H
O
OHO
R1 R2
OCr
O OH
OH
Example 16
CO2t-Bu
OO
O
OO
OH
OH
1. Jones reagent acetone, 20 min.
2. HCO2H, rt, 1 h 96% 2 steps
CO2H
OO
O
OO
OH
O
(−)-CP-263114
304
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_134, © Springer-Verlag Berlin Heidelberg 2009
Example 27
HHO
OCO2Me
H
CrO3, H2SO4acetone/H2O
rt, 74%
HO
OCO2Me
H Example 319
HO
CrO3, H2SO4
acetone, 0 oC1−2 h, 86%
OO
References 1. Bowden, K.; Heilbron, I. M., Jones, E. R. H.; Weedon, B. C. L. J. Chem. Soc. 1946,
39−45. Ewart R. H. (Tim) Jones worked with Ian M. Heilbron at Imperial College. Jones later succeeded Robert Robinson to become the prestigious Chair of Organic Chemistry at Manchester. The recipe for the Jones reagent: 25 g CrO3, 25 mL conc. H2SO4, and 70 mL H2O.
2. Ratcliffe, R. W. Org. Synth. 1973, 53, 1852. 3. Vanmaele, L.; De Clerq, P.; Vandewalle, M. Tetrahedron Lett. 1982, 23, 995−998. 4. Luzzio, F. A. Org. React. 1998, 53, 1−222. (Review). 5. Zhao, M.; Li, J.; Song, Z.; Desmond, R. J.; Tschaen, D. M.; Grabowski, E. J. J.; Rei-
der, P. J. Tetrahedron Lett. 1998, 39, 5323−5326. (Catalytic CrO3 oxidation). 6. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825−7826. 7. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M. Org. Lett.
2001, 3, 251−254. 8. Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44, 1275−1278. 9. Hunter, A. C.; Priest, S.-M. Steroids 2006, 71, 30−33. 10. Dong, J.; Chen, W.; Wang, S.; Zhang, J. J. Chromatogr., B 2007, 858, 239−246.
Collins–Sarett oxidation
Different from the Jones oxidation, the Collins–Sarett oxidation converts primary alcohols to the corresponding aldehydes.
Example 15
O
O
OH
Ph
O
O8 eq CrO3•2Pyr
CH2Cl2, 15 min., 86%
O
O
CHO
Ph
O
O
305
Example 27
MeO2C
Me
OMe
OHMe
7 equiv CrO3•Py2
CH2Cl2, 30 min., 75%
MeO2C
Me
OMe
CHO
Me
Example 39
NPhO2S
R1 R2 R3
R4
CrO3, Pyr.
50−60 oC, 48 h50−65%
NPhO2S
R1 R2 R3
R4O
References 1. Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422–
429. 2. Collins, J. C; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968, 3363–3366. J. C.
Collins was a chemist at Sterling-Winthrop in Resselaer, New York. 3. Collins, J. C; Hess, W. W. Org. Synth. 1972, Coll. Vol. V, 310. 4. Hill, R. K.; Fracheboud, M. G.; Sawada, S.; Carlson, R. M.; Yan, S.-J. Tetrahedron
Lett. 1978, 945–948. 5. Krow, G. R.; Shaw, D. A.; Szczepanski, S.; Ramjit, H. Synth. Commun. 1984, 14,
429–433. 6. Li, M.; Johnson, M. E. Synth. Commun. 1995, 25, 533–537. 7. Harris, P. W. R.; Woodgate, P. D. Tetrahedron 2000, 56, 4001–4015. 8. Nguyen-Trung, N. Q.; Botta, O.; Terenzi, S.; Strazewski, P. J. Org. Chem. 2003, 68,
2038–2041. 9. Arumugam, N.; Srinivasan, P. C. Synth. Commun. 2003, 33, 2313–2320.
PCC oxidation
Example 1, One-pot PCC–Wittig reactions2
SiOH
t-Bu PCC, Celite, CH2Cl2, rt, 3 h
then Ph3P=CHCO2CH380%
Sit-Bu
O
O
95 : 5 E : Z
306
Example 23
NEtO2C
OH 1.5 eq PCC, CH2Cl2
rt, 3 h, 75%N
EtO2CO
Example 34
O
OAcPh
OAc
OAc
PCC, pyr.
CH2Cl2, reflux8 h, 64%
O
OAcPh
OAc
OAc
O
Example 45
O
HO
Cl
PCC, CH2Cl2
75%, 93:7 er
O
O
Cl
References 1. Corey, E. J.; Suggs, W. Tetrahedron Lett. 1975, 16, 2647–2650. 2. Bressette, A. R.; Glover, L. C., IV Synlett 2004, 738–740. 3. Breining, S. R.; Bhatti, B. S.; Hawkins, G. D.; Miao, L.; Mazurov, A.; Phillips, T. Y.;
Miller, C. H. WO2005037832 (2005). 4. Srikanth, G. S. C.; Krishna, U. M.; Trivedi, G. K.; Cannon, J. F. Tetrahedron 2006,
62, 11165–11171. 5. Kim, S.-G. Tetrahedron Lett. 2008, 49, 6148–6151.
PDC oxidation
Example 12
S
S
OH
O
PDC, CH2Cl2
24 h, 68%
SCHO
SO
307
Example 2, Cleavage of primary carbon–boron bond3
B(OH)2PDC, DMF
rt, 24 h75%
CO2H
Example 34
OH
OH OTBDMS
PDC, DMF
rt, 24 h, 56%O
OTBDMS
O References 1 Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399–402. 2 Terpstra, J. W.; Van Leusen, A. M. J. Org. Chem. 1986, 51, 230–208. 3 Brown, H. C.; Kulkarni, S. V.; Khanna, V. V.; Patil, V. D.; Racherla, U. S. J. Org.
Chem. 1992, 57, 6173–6177. 4 Chênevert, R. Courchene, G.; Caron, D. Tetrahedron: Asymmmetry 2003, 2567–2571. 5 Jordão, A. K Synlett 2006, 3364–3365. (Review).
308
Julia–Kocienski olefination Modified one-pot Julia olefination to give predominantly (E)-olefins from het-eroarylsulfones and aldehydes. A sulfone reduction step is not required.
NNN N
SO2R1
Ph
1. KHMDS
2. R2CHOR1
R2
NNN N
Ph
OH SO2
NNN N
SO2R1
Ph
HNN
N NSO2
R1
Ph
R2 H
O
NNN N
SO2R1
Ph
R2O
N(TMS)2
NNN N
Ph
K
SO2
OR2
R1
NN
N NPh
O R2
SR1O
O
R1R2
NNN N
Ph
OH SO2
Alternatives to tetrazole:
S
N NNN
N
N NN N
N F3C
F3Ct-BuPh
PYRBTPT TBT BTFP
The use of larger counterion (such as K+) and polar solvents (such as DME) favors an open transition state (PT = phenyltetrazolyl):
R1R2
SO2PT
OK
O
R2H
HR1
SO2PT Example 1, (BT = benzothiazole)2
SO2BT OHC OTIPSOTIPSNaHMDS, DMF
−78 oC to rt, 90% E:Z (78:22) Example 23
O
O
OPiv
S S
N
O O
OOMe
OTBS
KHMDS, THF, −78 oC, 85%
309
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_135, © Springer-Verlag Berlin Heidelberg 2009
O
O
OPiv
OMe
OTBS
Example 37
CHO
KHMDS, toluene
25 oC, 64%SO
O
NOTIPS
88 : 12
OTIPS TIPSO
Example 48
S
F3C
F3CO
OOMe
MeO
MeO
CHO
MeO
1) P4−t-Bu, THF, −78 oC
2)74%, yieldE/Z = 98/2
OMe
OMe
References 1. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32,
1175−1178. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336−357. (c) Baudin, J. B.; Hareau, G.; Julia, S. A.; Loene, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856−878. (d) Blakemore, P. R.; Cole, W. J.; Kocien-ski, P. J.; Morely, A. Synlett 1998, 26−28.
2. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327−10328. 3. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans.
1 1999, 955−968. 4. Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121,
4924−4925. 5. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365−366. 6. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772−10773. 7. Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42, 5149–5153. 8. Alonso, D. A.; Najera, C.; Varea, M. Tetrahedron Lett. 2004, 45, 573–577. 9. Alonso, D. A.; Fuensanta, M.; Najera, C.; Varea, M. J. Org. Chem. 2005, 70, 6404. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 447−473. (Review).
310
Julia–Lythgoe olefination (E)-Olefins from sulfones and aldehydes.
R SAr
OO
1. n-BuLi2. R1CHO
RR1
SO2Ar
OAc
Na(Hg)
CH3OHR
R1
3. Ac2O
R SAr
OO
H
n-Buα-deprotonation
R
SO2Ar
H O
R1 coupling
RR1
SO2Ar
O
O
O O
acetylation
RR1
SO2Ar
OAc
RR1
SO2Ar
O O
O O
Na(Hg)
single electrontransfer (SET)
RR1
SO2ArOAc
4 possible diastereomers
Na(Hg)
single electrontransfer (SET)
RR1R
R1
OAcOAc
Example 12
SO2Ph
OHC
1. n-BuLi, THF, −78 oC
2.
3. Ac2O
4. Na(Hg) 43% E:Z (99:1)
Example 23
NTEOC H
CHO
OTBSO
SO2PhLi
1. THF, −78 oC2. Ac2O3. 5% Na(Hg), 77%
NTEOC H
OTBSO
Example 37
S
HO
Ph
CH3S
Ph
OHC CH3
n-BuLi, THF, 0 oC to rt61−75% SO2
OH
Ph CH3m-CPBA, CH2Cl2
0 oC, 80−98%
311
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_136, © Springer-Verlag Berlin Heidelberg 2009
SO2
OAc
Ph CH3
H3C
Na/HgTHF, MeOH
−20 oC, 53%
Ac2O, DMPA, CH2Cl2
0 oC to rt, 60−95%
Example 48
1. LDA, THF, −78 oC 2. BzCl, −78 oC to rt3. Me2N(CH2)3OH
Ph SPh
PhCHO
O
PhPh
PhPh
SmI2, THFHMPA, −78 oC
67%, E/Z = > 95:1S
OBzO
Ph
References 1. (a) Julia, M.; Paris, J. M. Tetrahedron. Lett. 1973, 4833–4836. (b) Lythgoe, B. J.
Chem. Soc., Perkin Trans. 1 1978, 834–837. 2. Kocienski, P. J.; Lythgoe, B.; Waterhause, I. J. Chem. Soc., Perkin Trans. 1 1980,
1045–1050. 3. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003–
2005. 4. Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194–3204. 5. Breit, B. Angew. Chem., Int. Ed. 1998, 37, 453–456. 6. Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am.
Chem. Soc. 2002, 124, 1664–1668. 7. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Synlett 2004, 6, 1064–1068. 8. Pospíšil, J.; Pospíšil, T, Markó, I. E. Org. Lett. 2005, 7, 2373–2376. 9. Gollner, A.; Mulzer, J. Org. Lett. 2008, 10, 4701−4704. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 447−473. (Review).
312
Kahne glycosidation Diastereoselective glycosidation of a sulfoxide at the anomeric center as the gly-cosyl acceptor. The sulfoxide activation is achieved using Tf2O.
OPivO
PivOPivO
S
OPiv
Ph
OO
HOO
OPh
SPhN3
N
CH3
t-But-Bu
Tf2O, CH2Cl2, −78 to −30 oC
OOOPh
SPhN3
OPivO
PivOPivO
OPiv
O
OPivO
PivOPivO
S
OPiv
Ph
O
S O SF
F F
FFF
O
O
O
OTfO O:
PivO
PivOPivO
S
OPiv
Ph
OTfSN1
PhS
OTf OHO
OOPh
SPhN3
OPivO
PivOPivO
OPiv
OOOPh
SPhN3
OPivO
PivOPivO
OPiv
O
oxonium ion
Example 11d
O OMOMOMOM
OMe OHBzO
O S(O)PhOBn
OBnOBn
Tf2O, DTBMP, CH2Cl2
−70 to −50 oC, 38% OOBn
OBnOBn
O OMOMOMOM
OMe OBzO
Example 24
OO
O OTBS
SPh
OPMBPh
OO
MeO
OTIPS
OHOTBS
313
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_137, © Springer-Verlag Berlin Heidelberg 2009
Tf2O, DTBMP, CH2Cl2
−78 to 0 oC, 67%O
O
O
O
O
Ph
PMBOOTBS
MeO
OTIPSOTBS
Example 3, Reverse Kahne-type glycosylation6
O
OO
S
O
MeO OMeOCbz
O Et
Tf2O, CH2Cl2
−78 oC, NuH
O
OO
Nu
O
MeO OMeOCbz
NuH = ROH, ArOH, ArNH2, CH2=CHCH2TMS
References 1. (a) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111,
6881−6882. (b) Yan, L.; Taylor, C. M.; Goodnow, R., Jr.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953−6954. (c) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239−9248. (d) Gildersleeve, J.; Pascal, R. A.; Kahne, D. J. Am. Chem. Soc. 1998, 120, 5961−5969. Daniel Kahne now teaches at Harvard University.
2. Boeckman, R. K., Jr.; Liu, Y. J. Org. Chem. 1996, 61, 7984−7985. 3. Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435−436. 4. Crich, D.; Li, H. J. Org. Chem. 2000, 65, 801−805. 5. Nicolaou, K. C.; Rodríguez, R. M.; Mitchell, H. J.; Suzuki, H.; Fylaktakidou, K. C.;
Baudoin, O.; van Delft, F. L. Chem. Eur. J. 2000, 6, 3095−3115. 6. Berkowitz, D. B.; Choi, S.; Bhuniya, D.; Shoemaker, R. K. Org. Lett. 2000, 2,
1149−1152. 7. Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem.
Soc. 2001, 123, 5826−5828. 8. Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115−251. (Review).
314
Knoevenagel condensation Condensation between carbonyl compounds and activated methylene compounds catalyzed by amines.
R CHO CH2(CO2R1)2NH R
CO2R1
CO2R1
OHR
CO2H
CH(CO2R1)2
NHH deprotonation
NH2 CH(CO2R1)2:
NH
(CO2R1)2CH
R O
H iminium ion
formationR
H
NOH
:R N
H:
NH2
R
OHN
R
CO2R1
HCO2R1
NH
O OR1
hydrolysisO
OR1
OH:
HR
O O
O
O
R
OR1O
HO
OR1
OHO
R
O O
O
OH
HHworkup
decarboxylationR
CO2HCO2↑ R • O
OHH
H
Example 13
N NO
H
O
NH
S
OO
piperidine, AcOH
toluene, refluxDean−Stark trap
95%
N NO N
H
S
OO
Example 2, EDDA = Ethylenediamine diacetate5
NBoc
NCbzH
CHO O O
O OEDDA, PhH, 60 oC
12 h, 84%
NBoc
NCbzHO O
O O
Meldrum's acid
315
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_138, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Using ionic liquid ethylammonium nitrate (EAN) as solvent8
CHO
CO2Et
CN ethylammonium nitrate
rt, 10 h, 87%
CN
CO2Et
Example 49
N
SO2Me
O
H
NN
O
MeO2S
piperidineN
SO2Me
H
NN
O
MeO2S
2-propanol, reflux89%
References 1. Knoevenagel, E. Ber. 1898, 31, 2596−2619. Emil Knoevenagel (1865−1921) was
born in Hannover, Germany. He studied at Göttingen under Victor Meyer and Gat-termann, receiving a Ph.D. In 1889. He became a full professor at Heidelberg in 1900. When WWI broke out in 1914, Knoevenagel was one of the first to enlist and rose to the rank of staff officer. After the war, he returned to his academic work until his sud-den death during an appendectomy.
2. Jones, G. Org. React. 1967, 15, 204−599. (Review). 3. Cantello, B. C. C.; Cawthornre, M. A.; Cottam, G. P.; Duff, P. T.; Haigh, D.; Hindley,
R. M.; Lister, C. A.; Smith, S. A. Thurlby, P. L. J. Med. Chem. 1994, 37, 3977−3985. 4. Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40,
4129−4132. 5. Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38, 2045−2047. 6. Pearson, A. J.; Mesaros, E. F. Org. Lett. 2002, 4, 2001−2004. 7. Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67,
4615−4618. 8. Hu, Y.; Chen, J.; Le, Z.-G.; Zheng, Q.-G. Synth. Commun. 2005, 35, 739−744. 9. Conlon, D. A.; Drahus-Paone, A.; Ho, G.-J.; Pipik, B.; Helmy, R.; McNamara, J. M.;
Shi, Y.-J.; Williams, J. M.; MacDonald, D. Org. Process Res. Dev. 2006, 10, 36−45. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 474−501. (Review).
316
Knorr pyrazole synthesis Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal–Knorr pyrrole synthesis (page 411).
NHNH3
O
R1
R NN
R2
OR3
R
R1 R3
R2
NN
R1 R3
R2R
R = H, Alkyl, Aryl, Het-aryl, Acyl, etc.
NHNH2
O
R1
R NN
OR2
OR3
R
R1 R3
OH NN
R
R1 R3
O
RO
RO NH
NH
R
R
OH
OH
NH2NH2
NHN
R
RNHN
R
ROH
Alternatively,
RO
RO
NR
R
NH2O
NH2NH2
NHN
R
RNHN
R
ROH
Example 12
MeO Me
OMe O MeNHNH2 NN
Me
MeHCl, H2O
68%
Example 28
Me
O
Me
EtO2CCF3, NaH, THF
−5 to 0 oC, 30 min.,rt, 5 h, 95%
O
Me
CF3
O
317
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_139, © Springer-Verlag Berlin Heidelberg 2009
HNSH2N
O
ONH2•HCl N N
SH2N O
O
Me
CF3
EtOH, reflux, 46%
Celebrex
References 1 (a) Knorr, L. Ber 1883, 16, 2597. Ludwig Knorr (1859−1921) was born near Munich,
Germany. After studying under Volhard, Emil Fischer, and Bunsen, he was appointed professor of chemistry at Jena. Knorr made tremendous contributions in the synthesis of heterocycles in addition to discovering the important pyrazolone drug, pyrine. (b) Knorr, L. Ber 1884, 17, 546, 2032. (c) Knorr, L. Ber. 1885, 18, 311. (d) Knorr, L. Ann. 1887, 238, 137.
2 Burness, D. M. J. Org. Chem. 1956, 21, 97−101. 3 Jacobs, T. L. in Heterocyclic Compounds, Elderfield, R. C., Ed.; Wiley: New York,
1957, 5, 45. (Review). 4 Houben−Weyl, 1967, 10/2, 539, 587, 589, 590. (Review). 5 Elguero, J., In Comprehensive Heterocyclic Chemistry II, Katrizky, A. R.; Rees, C.
W.: Scriven, E. F. V., Eds; Elsevier: Oxford, 1996, 3, 1. (Review). 6 Stanovnik, E.; Svete, J. In Science of Synthesis, 2002, 12, 15; Neier, R., Ed.; Thieme.
(Review). 7 Sakya, S. M. Knorr Pyrazole Synthesis. In Name Reactions in Heterocyclic Chemistry;
Li, J. J., Corey, E. J., Eds, Wiley & Sons: Hoboken, NJ, 2005, pp 292−300. (Review). 8 Ahlstroem, M. M.; Ridderstroem, M.; Zamora, I.; Luthman, K. J. Med. Chem. 2007,
50, 4444−4452.
318
Koch–Haaf carbonylation
319
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_140, © Springer-Verlag Berlin Heidelberg 2009
Strong acid-catalyzed tertiary carboxylic acid formation from alcohols or olefins and CO.
R OHCO, H2O
H
CO2HR
R O:H
protonationR O
H
HH
CH2R
alkyl
migration
R :C O: RO
The tertiary carbocation is thermodynamically favored
R OH2
OR
O
:OH2
R OH
O
H
acylium ion Example 13
OHHCO2H, H2SO4
rt, 66%
CO2H
Example 25
HCO2H, H2SO4
CCl4, 5 oC, 95%
OH CO2H
References
1. Koch, H.; Haaf, W. Ann. 1958, 618, 251–266. 2. Hiraoka, K.; Kebarle, P. J. Am. Chem. Soc. 1977, 99, 366–370. 3. Langhals, H.; Mergelsberg, I.; Rüchardt, C. Tetrahedron Lett. 1981, 22, 2365–2366. 4. Takeuchi, K.; Akiyama, F.; Miyazaki, T.; Kitagawa, I.; Okamoto, K. Tetrahedron
1987, 43, 701–709. 5. Takahashi, Y.; Yoneda, N. Synth. Commun. 1989, 19, 1945–1954. 6. Stepanov, A. G.; Luzgin, M. V.; Romannikov, V. N.; Zamaraev, K. I. J. Am. Chem.
Soc. 1995, 117, 3615–3616. 7. Olah, G. A.; Prakash, G. K. S.; Mathew, T.; Marinez, E. R. Angew. Chem., Int. Ed.
2000, 39, 2547–2548. 8. Li, T.; Tsumori, N.; Souma, Y.; Xu, Q. Chem. Commun. 2003, 2070–2071. 9. Davis, M. C.; Liu, S. Synth. Commun. 2006, 36, 3509–3514.
Koenig–Knorr glycosidation Formation of the β-glycoside from α-halocarbohydrate under the influence of sil-ver salt.
O
HAcO Br
OHH
AcO
Ac
AcO ROH
Ag2CO3
O
HAcO H
OHOR
AcO
Ac
AcO AgBr CO2↑ H2O
O:
HAcO Br
OHH
AcO
Ac
AcO
Ag
O
HAcO OH
AcO
AcOO:
oxonium ion
O
HAcO H
OHOR
AcO
Ac
AcOβ-anomer is
favored
HO
R
:
O
HAcO OH
AcO
AcOO
β-anomer
Example 17
OMeO2C
PivO
Br
OPivOPiv
NO2HO
NN CF3
Ag2O, 10 eq. HMTTA
CH3CN, rt, 6 h, 41%
OMeO2C
PivO
O
OPivOPiv
NO2
NN CF3
Example 28
O
HAcO Br
OHH
AcO
Ac
AcO
OMe
OH
OMe
Cd2CO3, Tol.
reflux, 6 h, 84%O
HAcO OH
O
AcO
Ac
AcO
320
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_141, © Springer-Verlag Berlin Heidelberg 2009
Example 39
HOH
H
Hcholesterol
HO
HPivO Br
OHH
PivO
Piv
PivO
AgOTf, TMU, CH2Cl2
4 Å MS, −20 oC to rt16 h, 58%
OH
H
H
H
O
HPivO OH
PivO
Piv
PivO
References 1. Koenig, W.; Knorr, E. Ber. 1901, 34, 957−981. 2. Igarashi, K. Adv. Carbohydr. Chem. Biochem. 1977, 34, 243−83. (Review). 3. Schmidt, R. R. Angew. Chem. 1986, 98, 213−236. 4. Smith, A. B., III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991,
113, 2092−2112. 5. Fürstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott, R. J. Org. Chem. 2000,
65, 8758−8762. 6. Yashunsky, D. V.; Tsvetkov, Y. E.; Ferguson, M. A. J.; Nikolaev, A. V. J. Chem. Soc.,
Perkin Trans. 1 2002, 242−256. 7. Stazi, F.; Palmisano, G.; Turconi, M.; Clini, S.; Santagostino, M. J. Org. Chem. 2004,
69, 1097−1103. 8. Wimmer, Z.; Pechova, L.; Saman, D. Molecules 2004, 9, 902−912. 9. Presser, A.; Kunert, O.; Pötschger, I. Monat. Chem. 2006, 137, 365−374. 10. Steinmann, A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 5506−5513. 11. Schoettner, E.; Simon, K.; Friedel, M.; Jones, P. G.; Lindel, T. Tetrahedron Lett. 2008,
49, 5580−5582.
321
Kostanecki reaction Also known as Kostanecki−Robinson reaction. Transformation 1→2 represents an Allan−Robinson reaction (see page 8), whereas 1→3 is a Kostanecki (acyla-tion) reaction:
O
O OOH
O
O
O
R R R O O
R1 2 3
O
O
O
O
O
O
O
R
R
OO
R
OR H
acyl
transferH
: O
O
O
R enolization
O
O
O
R
H
6-exo-trig
ring closure
O O
R
O O
OH
− H2OO O
OHHR
:BR
Example 12
H O
O OOH
O O
OEt
O
O O
OEtHCO2Na, rt, 15 h, 76%
Example 23
O O
O
HO
O
O O
O
O
O
NaOAc, Ac2O, reflux
62 %
References 1. von Kostanecki, S.; Rozycki, A. Ber. 1901, 34, 102−109. 2. Pardanani, N. H.; Trivedi, K. N. J. Indian Chem. Soc. 1972, 49, 599−604. 3. Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; et al. J. Med. Chem. 1996, 39, 1303−1313. 4. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Y. A.
Chemistry of Heterocyclic Compounds 2003, 39, 96−100. 5. Limberakis, C. Kostanecki−Robinson Reaction. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 521−535. (Review).
322
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_142, © Springer-Verlag Berlin Heidelberg 2009
Kröhnke pyridine synthesis Pyridines from α-pyridinium methyl ketone salts and α,β-unsaturated ketones.
RN
O BrR1 R2
O
NH4OAc, HOAc NR R2
R1
RN
O
R1 R2
OH
H
enolizationR
NO
HMichael
additionO
NR
R2
O R1
H
Br
Br
Br
AcOH
ON
RBr
R2
O HR1
O
R
R2
O R1
:NH3
O
R
R2
R1HOH2N:
The ketone is more reactive than the enone
O
R
R2
HN R1
HOAc
NR2
R1
OHR
H H
AcO
NR2 R
R1
Example 11b
N
Ph O O
Ph
Ph NPh Ph
PhNH4OAcAcOH
90%
Example 24
N
N
N
N
NN
N
N
N
N
N
O
O
O
N
NH4OAcAcOH
81%
323
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_143, © Springer-Verlag Berlin Heidelberg 2009
Example 36
NH4OAc, AcOH
115 oC, overnightO
N
OX
NX
X = H, 65%X = F, 83%X = Br, 82%X = OMe, 40%
References 1. (a) Zecher, W.; Kröhnke, F. Ber. 1961, 94, 690−697. (b) Kröhnke, F.; Zecher, W.
Angew. Chem. 1962, 74, 811−817. (c) Kröhnke, F. Synthesis 1976, 1−24. (Review). 2. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103,
3584−3585, 3585−3586. 3. Newkome, G. R.; Hager, D. C.; Kiefer, G. E. J. Org. Chem. 1986, 51, 850−853. 4. Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774−2781. 5. Bark, T.; Von Zelewsky, A. Chimia 2000, 54, 589−592. 6. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 2001, 42,
3045−3048. 7. Cave, G. W. V.; Raston, C. L. J. Chem. Soc., Perkin Trans. 1 2001, 3258−3264. 8. Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kocovsky, P. J. Mol. Cat. A: Chem.
2003, 196, 179−186. 9. Galatsis, P. Kröhnke Pyridine Synthesis. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 311−313. (Re-view).
10. Yan, C.-G.; Wang, Q.-F.; Cai, X.-M.; Sun, J. Central Eur. J. Chem. 2008, 6, 188−198.
324
Kumada cross-coupling reaction
325
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_144, © Springer-Verlag Berlin Heidelberg 2009
The Kumada cross-coupling reaction (also occasionally known as the Kharasch cross-coupling reaction) was originally reported as the nickel-catalyzed cross-coupling of Grignard reagents with aryl- or alkenyl halides. It has subsequently been developed to encompass the coupling of organolithium or organomagnesium compounds with aryl-, alkenyl or alkyl halides, catalyzed by nickel or palladium. The Kumada cross-coupling reaction, as well as the Negishi, Stille, Hiyama, and Suzuki cross-coupling reactions, belong to the same category of Pd-catalyzed cross-coupling reactions of organic halides, triflates and other electrophiles with organometallic reagents. These reactions follow a general mechanistic catalytic cycle as shown below. There are slight variations for the Hiyama and Suzuki re-actions, for which an additional activation step is required for the transmetallation to occur.
R XPd(0)
R R1R1 MgX MgX2
PdL
L X
R R1 MgXR X L2Pd(0)
transmetallationisomerization
oxidative
addition
MgX2 PdL
R R1
LR1R
reductive
eliminationL2Pd(0)
The catalytic cycle:
LnPd(II) R1Mtransmetallation
R1
LnPd(II)R1
LnPd(0)R1R1reductive
elimination
L2Pd(0)
PdL
L X
PdL
R R1
R
L
XR
R1R
transmetallation and isomerization
reductiveelimination
oxidativeaddition
R1M
MX
Example 12
O SBr MgBr
Pd(dppf)Cl2, Et2O
–30 oC to rt, 5 h, 98%O
S Example 23
MgBrMe
BrMe
MeMe
FePh2PMeO
H Me
Ligand
Ni/Ligand
(2−5 mol%)69%
95% ee
Example 35
N Br PdCl2•(dppb)THF, rt, 87%
Br N MgBrN
NBr
S MgBr
PdCl2•(dppb)THF, reflux, 98%
NN
S Example 48
OTBS
I
S
NOTBS
S
N
23 mol% PdCl2(dppf)Et2O, rt, 12 h, 75%
MgBr3 equiv
Example 59
MeO
MeO
C5H11
TESO
OPO
EtOEtO
MeO
MeO
C5H11
TESO
Me
2.5 equiv MeMgCl
10 mol% Ni(acac)2THF, 0 oC, 10 min.
90%
326
1. Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodma, S.-i.; Naka-jima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958−1969.
2. Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919−1929. 3. Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110,
8153−8156. 4. Kalinin, V. N. Synthesis 1992, 413−432. (Review). 5. Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998, 3737−3746. 6. Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (Review). 7. Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889−9890. 8. Rivkin, A.; Njardarson, J. T.; Biswas, K.; Chou, T.-C.; Danishefsky, S. J. J. Org.
Chem. 2002, 67, 7737−7740. 9. William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771−8782. 10. Fuchter, M. J. Kumada cross-coupling reaction. In Name Reactions for Homologa-
tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 47−69. (Review).
327
References
Lawesson’s reagent 2,4-Bis(4-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide transforms the carbonyl groups of aldehydes, ketones, amides, lactams, esters and lactones into the corresponding thiocarbonyl compounds. Cf. Knorr thiophene synthesis.
R1 R2
O
SPS P
OO
S
S
Lawesson's reagent R1 R2
S
R1,R2 = H, R, OR, NHR
NH
O
SPS P
OO
S
SNH
SLawesson's reagent
NHO
SPS P
OO
S
S
2 O PS
S
:
O PO
S
NHS
NH
SO PO
SS H
N O PS
O
Example 14
Lawesson's reagent(Me2N)2C=S
xylene, 160 oC, 47%O
OH
HO
OMe
OO
OH
HS
OMe
S
Example 25
NO
MeO2C H Lawesson's
reagent, quant.
NS
MeO2C H
328
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_145, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Thiophene from dione8
Lawesson's reagent
toluene, reflux88−99%
N N
O O
SO2Ph SO2Ph
R R
N NSO2Ph SO2Ph
SR R R = H
R = MeR = OMeR = ClR = Br
Example 410
N
O
O
O
Me
Me
MeO
O N
O
O
O
Me
Me
MeO
S
Lawesson's reagent
toluene, reflux, 100%
References 1. Scheibye, S.; Shabana, R.; Lawesson, S. O.; Rømming, C. Tetrahedron 1982, 38, 993–
1001. 2. Navech, J.; Majoral, J. P.; Kraemer, R. Tetrahedron Lett. 1983, 24, 5885–5886. 3. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061–5087. (Review). 4. Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel, D. A.; Abe, Y.; Bal Reddy,
K.; DeFrees, S. A.; Reddy, D. R.; Awartani, R. A.; Conley, S. R.; Rutjes, F. P. J. T.; Theodorakis, E. A. J. Am. Chem. Soc. 1995, 117, 10227–10238.
5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003–2005.
6. Luheshi, A.-B. N.; Smalley, R. K.; Kennewell, P. D.; Westwood, R. Tetrahedron Lett. 1990, 31, 123–127.
7. Ishii, A.; Yamashita, R.; Saito, M.; Nakayama, J. J. Org. Chem. 2003, 68, 1555–1558. 8. Diana, P.; Carbone, A.; Barraja, P.; Montalbano, A.; Martorana, A.; Dattolo, G.; Gia,
O.; Dalla Via, L.; Cirrincione, G. Bioorg. Med. Chem. Lett. 2007, 17, 2342–2346. 9. Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210–5278. (Review). 10. Taniguchi, T.; Ishibashi, H. Tetrahedron 2008, 64, 8773–8779. 11. de Moreira, D. R. M. Synlett 2008, 463–464. (Review).
329
Leuckart–Wallach reaction Amine synthesis from reductive amination of a ketone and an amine in the pres-ence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes the Eschweiler–Clarke reductive alkylation of amines on page 210.
R1
R2O
R4HN
R3HCO2H
NR2
R1
R4
R3
CO2↑ H2O
R1
R2O:N
R3H
NHO
R1
R2R3
R4
R4
H NHO
R1
R2R3
R4
:
HH
NR2
R1
R4
R3− H2O
gem-aminoalcohol; iminium ion intermediate
HCO2H NR1 R3
HHO
R4
O
R2 NR2
R1
R4
R3
NH
R1
H
R3
R4R2− CO2 H
reduction
Example 14
HCO2H
60 oC, 57%CHO
HN
ON
O
Example 26
O
OHCN
HCO2H, H2O190 oC, autoclave
16 h, 75%
N
Example 37
HCO2H, reflux
7 h, 45%S
O
H
N
NH2N S
HNN
N
330
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_146, © Springer-Verlag Berlin Heidelberg 2009
Example 48
O NHCOCH3 OHCHN NHCOCH3
H2NCHO
HCO2H150oC
An unexpected intramolecular transamidation via a Wagner–Meerwein shift after the Leuckart–Wallach reaction
O NHCOCH3CH3COHN NHCHO
H2NCHO, HCO2H
150 oC
References 1. Leuckart, R. Ber. 1885, 18, 2341−2344. Carl L. R. A. Leuckart (1854−1889) was born
in Giessen, Germany. After studying under Bunsen, Kolbe, and von Baeyer, he be-came an assistant professor at Göttingen. Unfortunately, chemistry lost a brilliant con-tributor by his sudden death at age 35 as a result of a fall in his parent’s house.
2. Wallach, O. Ann. 1892, 272, 99. Otto Wallach (1847−1931), born in Königsberg, Prussia, studied under Wöhler and Hofmann. He was the director of the Chemical In-stitute at Göttingen from 1889 to 1915. His book “Terpene und Kampfer” served as the foundation for future work in terpene chemistry. Wallach was awarded the Nobel Prize in Chemistry in 1910 for his work on alicyclic compounds.
3. Moore, M. L. Org. React. 1949, 5, 301−330. (Review). 4. DeBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3073−3075. 5. Lukasiewicz, A. Tetrahedron 1963, 19, 1789−1799. (Mechanism). 6. Bach, R. D. J. Org. Chem. 1968, 33, 1647−1649. 7. Musumarra, G.; Sergi, C. Heterocycles 1994, 37, 1033−1039. 8. Martínez, A. G.; Vilar, E. T.; Fraile, A. G.; Ruiz, P. M.; San Antonio, R. M.; Alcazar,
M. P. M. Tetrahedron: Asymmetry 1999, 10, 1499−1505. 9. Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002,
67, 8685−8687. 10. Brewer, A. R. E. Leuckart–Wallach reaction. In Name Reactions for Functional
Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 451−455. (Review).
11. Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe, G. J. Fluorine Chem. 2008, 129, 1052−1055.
331
Lossen rearrangement The Lossen rearrangement involves the generation of an isocyanate via thermal or base-mediated rearrangement of an activated hydroxamate which can be generated from the corresponding hydroxamic acid. Activation of the hydroxamic acid can be achieved through O-acylation, O-arylation, chlorination, or O-sulfonylation. Such hydroxamic acids can also be activated using polyphosphoric acid, car-bodiimide, Mitsunobu conditions, or silyation. The product of the Lossen rear-rangement, an isocyanate can be subsequently converted to an urea or an amine resulting in the net loss of one carbon atom relative to the starting hydroxamic acid.
R1 NH
O R2O
O
OHR1 N C O
H2OR1 NH2 CO2↑
R1 NO R2
O
O
OH
R1 NO R2
O
OH
R1 N C O
:OH2
R2CO2
HO H
isocyanate intermediate
R1 NH2CO2↑R1
HN O
OH
:B
decarboxylation
Example 16
O
NMsO
O
O
N
NHO
O
BnOH, CH3CN, 85 oC, 78%
Example 27
Br
Cl
OEtO2C
HN
OCO2Et
Et3N, H2OBr
NC
OEtOH, H2O
50% Br
NH2
332
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_147, © Springer-Verlag Berlin Heidelberg 2009
Example 38
N
O
O
OS
OO
H3C NH2
PhH, rt, 6 h, 54%
NHCONHAr
CONHArArNH2:
N
O
OSO2Ph
O NH2
Ar
O
HN
O Ar
N OSO2Ph N
HN
O Ar
C OLossen
ArNH2
Example 49
N
NHN
OAcO
OOMeMeO
DBU, THF, H2O
reflux, 1 h
N
NN
OOMeMeO
CO
N
NH2N
OOMeMeO
References 1. Lossen, W. Ann. 1872, 161, 347. Wilhelm C. Lossen (1838−1906) was born in
Kreuznach, Germany. After his Ph.D. studies at Göttingen in 1862, he embarked on his independent academic career, and his interests centered on hydroxyamines.
2. Bauer, L.; Exner, O. Angew. Chem., Int. Ed. 1974, 13, 376. 3. Lipczynska-Kochany, E. Wiad. Chem. 1982, 36, 735−756. 4. Casteel, D. A.; Gephart, R. S.; Morgan, T. Heterocycles 1993, 36, 485−495. 5. Zalipsky, S. Chem. Commun. 1998, 69−70. 6. Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.; Feldman, P. L. J. Org
Chem. 1998, 63, 10040–10044. 7. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41,
5291−5293. 8. Abbady, M. S.; Kandeel, M. M.; Youssef, M. S. K. Phosphorous, Sulfur and Silicon
2000, 163, 55–64. 9. Ohmoto, K.; Yamamoto, T.; Horiuchi, T.; Kojima, T.; Hachiya, K.; Hashimoto, S.;
Kawamura, M.; Nakai, H.; Toda, M. Synlett 2001, 299−301. 10. Choi, C.; Pfefferkorn, J. A. Lossen rearrangement. In Name Reactions for Homologa-
tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 200−209. (Review).
333
McFadyen–Stevens reduction Treatment of acylbenzenesulfonylhydrazines with base delivers the corresponding aldehydes.
R NH
HN
SO2Ar
OBase
R H
O
R NHN
SO2Ar
O
R NN
O
H
B:
H N2↑ R
Ohomolytic
cleavage R H
O
H
Example 18
K2CO3, MeOH
reflux, 1 h, 75%H
OO2N
NHHN
SO2
OO2N
Example 210
NH
NO
NHNHTs
ONa2CO3, glass powder
ethylene glycol
microwave (450 W)90% N
H
NO
H
O
References 1. McFadyen, J. S.; Stevens, T. S. J. Chem. Soc. 1936, 584−587. Thomas S. Stevens
(1900−2000) was born in Renfrew, Scotland. After earning his Ph.D. under W. H. Perkin at Oxford University, he became a reader at the University of Sheffield. J. S. McFadyen (1908−?) was born in Toronto, Canada. After studying under Stevens at the University of Glasgow, he worked for ICI for 15 years before returning to Canada where he worked for the Canadian Industries, Ltd., Montreal.
2. Newman, M. S.; Caflisch, E. G., Jr. J. Am. Chem. Soc. 1958, 80, 862−864. 3. Sprecher, M.; Feldkimel, M.; Wilchek, M. J. Org. Chem. 1961, 26, 3664−3666. 4. Babad, H.; Herbert, W.; Stiles, A. W. Tetrahedron Lett. 1966, 7, 2927−2931. 5. Graboyes, H.; Anderson, E. L.; Levinson, S. H.; Resnick, T. M. J. Heterocycl. Chem.
1975, 12, 1225−1231. 6. Eichler, E.; Rooney, C. S.; Williams, H. W. R. J. Heterocycl. Chem. 1976, 13,
841−844. 7. Nair, M.; Shechter, H. J. Chem. Soc., Chem. Commun. 1978, 793−796. 8. Dudman, C. C.; Grice, P.; Reese, C. B. Tetrahedron Lett. 1980, 21, 4645−4648. 9. Manna, R. K.; Jaisankar, P.; Giri, V. S. Synth. Commun. 1998, 28, 9−16. 10. Jaisankar, P.; Pal, B.; Giri, V. S. Synth. Commun. 2002, 32, 2569−2573.
334
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_148, © Springer-Verlag Berlin Heidelberg 2009
McMurry coupling Olefination of carbonyls with low-valent titanium such as Ti(0) derived from TiCl3/LiAlH4. A single-electron process.
R1
R2O
R2
R1
R2
R11. TiCl3, LiAlH4
2. H2OTiO
Ti(III)Cl3 LiAlH4 Ti(0)
R1
R2O :Ti(0)
single electron
transfer
homocouplingR1
R2 R2R1
O OTi Ti
radical anion intermediate
R2
R1
R2
R1
O OTi Ti
R1
R2 R2R1
O OTi Ti
R1
R2 R2R1
O OTi Ti
oxide-coated titanium surface
Example 1, Cross-McMurry coupling7
MeO2S
O
OZn, TiCl4, reflux
4.5 h, 75%, > 99% Z
OH OHMeO2S
Example 2, Homo-McMurry coupling8
CHOSZn, TiCl4, THF,110 oC
microwave (10 W), 10 min.87%
SS
335
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_149, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Cross-McMurry coupling9
OMe
NOO
N
O O
N
Zn, TiCl4
THF, 78%
N
N
OON
OMe
Example 4, Cross-McMurry coupling10
CHO
OHBnO
OHC
MeO O
OZn−TiCl4, THF
−5 to 0 oC thenreflux, 2.5 h, 77% BnO
O
O
OH
MeO
References 1. (a) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708−4712. (b)
McMurry, J. E. Chem. Rev. 1989, 89, 1513−1524. (Review). 2. Hirao, T. Synlett 1999, 175−181. 3. Sabelle, S.; Hydrio, J.; Leclerc, E.; Mioskowski, C.; Renard, P.-Y. Tetrahedron Lett.
2002, 43, 3645−3648. 4. Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843−1850. 5. Honda, T.; Namiki, H.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44,
3035−3038. 6. Ephritikhine, M.; Villiers, C. In Modern Carbonyl Olefination Takeda, T., Ed.; Wiley-
VCH: Weinheim, Germany, 2004, 223−285. (Review). 7. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Synlett 2004, 1513−1516. 8. Stuhr-Hansen, N. Tetrahedron Lett. 2005, 46, 5491−5494. 9. Zeng, D. X.; Chen, Y. Synlett 2006, 490−492. 10. Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem. 2007, 72, 10283−10286. 11. Debroy, P.; Lindeman, S. V.; Rathore, R. J. Org. Chem. 2009, 74, 2080−2087.
336
Mannich reaction Three-component aminomethylation from amine, aldehyde and a compound with an acidic methylene moiety.
H H
O
RNHR
R1R2
O HN R2R
R R1
O
H H
O
RHN
R
N HR
R
OH
N HR
R
OH2:N
R
R
H
:
H
When R = Me, the +Me2N=CH2 salt is known as Eschenmoser’s salt (page 206)
R1R2
O
enolization N R2R
R R1
O
NR
R
R1R2
OH
H
The Mannich reaction can also operate under basic conditions:
R1R2
O
H
B:
enolate
formationN R2R
R R1
O
NR
R
R1R2
O
Mannich Base
Example 1, Asymmetric Mannich reaction2
O
NH2
O
OHC
NO2
35 mol% L-proline
DMSO, rt, 50%, 94% ee
HN
O
O
NO2
Example 2, Asymmetric Mannich-type reaction9
No-Ts
OHN
O
O
In(Oi-Pr)3, ligand
5 Å MS, THF, rt, 80%
NHo-Ts
OHN
O
O
337
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_150, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Asymmetric Mannich reaction10
R1
O
R2 O
R3
O
NH
ArO2S R4
10 mol %
Na2CO3, NaCl, −15 ºC 72−98%, 99:1 er
R1
O
R2 O
HN
R4
O
R3N
H
H
HO
N
Example 411
EtO2C H
NPMP
OL-proline, DMSO
rt, 81%EtO2C
NHPMP
O
syn
ON
PhPh
O
OL-proline, DMSO
rt, 81%
NH OO
PhPh
O
References 1. Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647–667. Carl U. F. Mannich
(1877−1947) was born in Breslau, Germany. After receiving a Ph.D. at Basel in 1903, he served on the faculties of Göttingen, Frankfurt and Berlin. Mannich synthesized many esters of p-aminobenzoic acid as local anesthetics.
2. List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337. 3. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023–10030. 4. Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221–3242. (Review). 5. Martin, S. F. Acc. Chem. Res. 2002, 35, 895−904. (Review). 6. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851−862.
(Review). 7. Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580−591. (Re-
view). 8. Córdova, A. Acc. Chem. Res. 2004, 37, 102−112. (Review). 9. Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44,
4365–4368. 10. Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72, 9998–10008. 11. Hahn, B. T.; Fröhlich, R.; Harms, K.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47,
9985−9988. 12. Galatsis, P. Mannich reaction. In Name Reactions for Homologations-Part II; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 653−670. (Review).
338
Martin’s sulfurane dehydrating reagent Dehydrates secondary and tertiary alcohols to give olefins, but forms ethers with primary alcohols. Cf. Burgess dehydrating reagent.
OHHOC(CF3)2PhPh2S[OC(CF3)2Ph]2 Ph2S O
Ph2SOC(CF3)2Ph
OC(CF3)2Ph
H Ot-Bu
HOC(CF3)2Ph O
Ph2SO−C(CF3)2Ph
:
The alcohol is acidic
OPh2S
OC(CF3)2Ph protonation
:
H OC(CF3)2Ph
OC(CF3)2Ph OPh2S
O−C(CF3)2PhH
OH
Ph2S OC(CF3)2Ph β-elimination
E1cBHOC(CF3)2PhPh2S O
Example 15
O
OMeO
O
O
O
O
OMe
BzOOBn
OBn OH
OPMB
Martin's sulfurane
Et3N, CHCl3, 50 oC85%
O
OMeO
O
O
O
O
OMe
BzOOBn
OBn
OPMB
Example 26
Martin'ssulfurane
PhH, reflux88%
OBnOH
OBnOO
OBn
OBn
OBnOO
BnO
339
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_151, © Springer-Verlag Berlin Heidelberg 2009
Example 37
OO
OMe
MeO
CO2MeHO
TBSO
1.5 eq. Martin's sulfurane
CH2Cl2, rt, 24 h, 84%O
OOMe
MeO
TBSO
CO2Me
Example 49
HN
O
OMOMi-PrO
H3COOCH3
O
ON
OOH
Cl
TESO O
OTIPS
HN
O
OMOMi-PrO
H3COOCH3
O
ON
O
Cl
TESO O
OTIPS
Martin'ssulfurane
PhH, rt83%
References 1. (a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339–2341; (b0 Martin, J.
C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2341–2342; (c) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327–4329. (d) Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1977, 57, 22–26.
2. Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347–3353. 3. Tse, B.; Kishi, Y. J. Org. Chem. 1994, 59, 7807–7814. 4. Winkler, J. D.; Stelmach, J. E.; Axten, J. Tetrahedron Lett. 1996, 37, 4317–4320. 5. Nicolaou, K. C.; Rodríguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Mitchell, H. J.
Angew. Chem., Int. Ed. 1999, 38, 3340–3345. 6. Kok, S. H. L.; Lee, C. C.; Shing, T. K. M. J. Org. Chem. 2001, 66, 7184–7190. 7. Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; White-
head, R. C. Synlett 2002, 358–360. 8. Myers, A. G.; Glatthar, R.; Hammond, M.; Harrington, P. M.; Kuo, E. Y.; Liang, J.;
Schaus, S. E.; Wu, Y.; Xiang, J.-N. J. Am. Chem. Soc. 2002, 124, 5380–5401. 9. Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem., Int. Ed.
2002, 41, 1062–1067. 10. Shea, K. M. Martin’s sulfurane dehydrating reagent. In Name Reactions for Func-
tional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hobo-ken, NJ, 2007, pp 248−264. (Review).
11. Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org. Lett. 2008, 10, 1291−1294.
340
Masamune–Roush conditions for the Horner–Emmons reaction Applicable to base-sensitive aldehydes and phosphonates for the Horner–Wadsworth–Emmons reaction. α-Keto or α-alkoxycarbonyl phosphonate re-quired.
(EtO)2POEt
O OCHO
AcO
N
N
LiCl, CH3CN, 70%AcO
CO2EtDBU
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene
(EtO)2POEt
O O
N
N
H
:
deprotonation(EtO)2P
OEt
O O LiCl
chelation
AcO
(EtO)2POEt
O OLi
O
HAcO O
EtO2C PO
OEtOEt
AcOCO2Et
AcO
EtO2C
OP(OEt)2
O
Example 15
NH
P(OEt)2
OORCHO
LiBr, Et3NNH
R
O TFAH2N R
O
75−95%
Example 26
OOOMe
MeO
MOMO
OHOO
7
(EtO)2(O)POO
OMe
MeO
MOMO
OO7
LiCl, Hunig base
MeCN, rt, 14 h, 58%
341
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_152, © Springer-Verlag Berlin Heidelberg 2009
Example 37
CHOBocNO
PhN
O
O
O
Ph
(EtO)2(O)P
LiBr, DBU, CH3CN, rt, 67%
NBocN
O
Ph
O
O
O
Ph
Example 48
OP
(EtO)2CO2Et Ph
O NH
N
N
THF, 92%
CO2EtPh
Example 510
(MeO)2PNH
CO2Me
O O Ph MeO CHO
DBU, LiCl, THF, rt90%
NH
CO2Me
O Ph
NH
CO2Me
O Ph
MeO
OMe
98 : 2
References 1. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W.
R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186. 2. Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624–2636. 3. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035–1039, and 6389–6391. 4. Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703–1708. 5. Johnson, C. R.; Zhang, B. Tetrahedron Lett. 1995, 36, 9253–9256. 6. Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058–2059. 7. Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123–125. 8. Simoni, D.; Rossi, M.; Rondannin, R.; Mazzali, A.; Baruchello, R.; Malagutti, C.;
Roberti, M.; Invidiata, F. P. Org. Lett. 2000, 2, 3765–3768. 9. Crackett, P.; Demont, E.; Eatherton, A.; Frampton, C. S.; Gilbert, J.; Kahn, I.; Red-
shaw, S.; Watson, W. Synlett 2004, 679–683. 10. Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.; Bautista, R.; Bustos, P.;
Rojas-Cabrera, H.; Fernandez-Zertuche, M.; Garcia-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427–2436.
11. Zanato, C.; Pignataro, L.; Hao, Z.; Gennari, C. Synthesis 2008, 2158–2162.
342
Meerwein’s salt
343
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_153, © Springer-Verlag Berlin Heidelberg 2009
Meerwein’s salts, also known as the Meerwein reagent, refer to trimethyloxonium tetrafluoroborate (Me3O+BF4
−) and triethyloxonium tetrafluoroborate (Et3O+BF4−).
Named after the inventor Hans Meerwein,1 these trialkyloxonium salts are power-ful alkylating agents.
O
BFF
F F
O
BFF
F F
Preparation:2
4 BF3•OEt2 + 6 Me2O
ClO
+ 3
3 Me3O+BF4− + 4 Et2O
+
Cl
OO Me
3
B
4 BF3•OEt2 + 2 Et2O
ClO
+ 3
3 Et3O+BF4−
+
Cl
OO Et
3
B
Example 1, The Meerwein reagent is an excellent O-alkylating agent:5
Cl
NH
OEt3O•BF4, NaHPO4
CH3CN, rt, 6 h Cl
O
OEt
Cl
N
OEt
H3O
81%
Transforming an amide into its corresponding ethyl or methyl esters
Example 2, Metal-methylation4
Co(CO)6
1. PhLi, Et2O, 0 oC
2. Me3O•BF4
t-Bu, t-BuOMe
45 oC, 79%Dötz reaction
OHt-Bu
OMe
OMe
PhCo(OC)5
Example 3, N-Alkylation, the product is an ionic liquid8
Me3O•BF4
Et2O, 94%N N N N CH3
H3CBF4
Example 4, N-Methylation9
N N
I
SO2NMe2
SPh1. Me3O•BF4, slow addition CH2Cl2, rt
2. BuMeNH, CH3CN, Δ, quant.
N N
I
SPhMe
References 1. (a) Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E. J. Prakt. Chem. 1937,
147, 257–285. (b) Meerwein, H.; Bettenberg, E.; Pfeil, E.; Willfang, G. J. Prakt. Chem. 1939, 154, 83–156.
2. (a) Meerwein, H. Org. Synth.; Coll. Vol. V, 1973, 1080. Triethyloxonium tetra-fluoroborate. (b) Curphey, T. J. Org. Synth.; Coll. Vol. VI, 1988, 1019. Trimethy-loxonium tetrafluoroborate.
3. Chen, F. M. F.; Benoiton, N. L. Can. J. Chem. 1977, 55, 1433–1534. 4. Dötz, K. H.; Möhlemeier, J.; Schubert, U.; Orama, O. J. Organomet. Chem. 1983, 247,
187–201. 5. Downie, I. M.; Heaney, H.; Kemp, G.; King, D.; Wosley, M. Tetrahedron 1992, 48,
4005–4016. 6. Kiessling, A. J.; McClure, C. K. Synth. Commun. 1997, 27, 923–937. 7. Pichlmair, S. Synlett 2004, 195−196. (Review). 8. Egashira, M.; Yamamoto, Y.; Fukutake, T.; Yoshimoto, N.; Morita, M. J. Fluorine
Chem. 2006, 127, 1261–1264. 9. Delest, B.; Nshimyumukiza, P.; Fasbender, O.; Tinant, B.; Marchand-Brynaert, J.;
Darro, F.; Robiette, R. J. Org. Chem. 2008, 73, 6816–6823. 10. Perst, H.; Seapy, D. G. Triethyloxonium Tetrafluoroborate In Encyclopedia of
Reagents for Organic Synthesis John Wiley & Sons, New York, 2008, (Review).
344
Meerwein–Ponndorf–Verley reduction Reduction of ketones to the corresponding alcohols using Al(Oi-Pr)3 in isopropanol. Reverse of the Oppernauer oxidation.
R1 R2
O
R1 R2
OH OAl(Oi-Pr)3
HOi-Pr
R1 R2
O
Al(Oi-Pr)3
coordination
H OAlO
Oi-Pr
Oi-Pr
R1
R2
: O
R1R2 H
OAl
Oi-Pri-PrO‡‡
cyclic transition state
hydride
transfer
H
R1 R2
OO Al(Oi-Pr)2
R1 R2
OH
Example 12
O
OH
H
MeO2CH
Al(Oi-Pr)3
HOi-Pr, 90%
OHH
O
O H
H
H
Example 24
O
R R
OH
*43−99% yield30−80% ee
(R)-BINOL (0.1 eq)AlMe3 (0.1 eq)
i-PrOH (4 eq)toluene
Example 37
O
MeO O
OTBDPS
MeMe
4 equiv Me3Al, i-PrOH
0 oC to rt, 24 hO
MeO OH
OTBDPS
MeMe
84%
O
MeO OH
OTBDPS
MeMe
15%
345
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_154, © Springer-Verlag Berlin Heidelberg 2009
Example 49
O OMeO OMe
O O
3 equiv AlMe39 equiv HOCH(Ph)2
CH2Cl2
O OMeO OMe
OH OH
O OMeO OMe
OH OH73% 12%
References 1. Meerwein, H.; Schmidt, R. Ann. 1925, 444, 221−238. Hans L. Meerwein, born in
Hamburg Germany in 1879, received his Ph.D. at Bonn in 1903. In his long and pro-ductive academic career, Meerwein made many notable contributions in organic chem-istry.
2. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. Tetrahedron 1958, 2, 1−57.
3. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007−1017. (Review).
4. Campbell, E. J.; Zhou, H.; Nguyen, S. T. Angew. Chem., Int. Ed. 2002, 41, 1020−1022.
5. Sominsky, L.; Rozental, E.; Gottlieb, H.; Gedanken, A.; Hoz, S. J. Org. Chem. 2004, 69, 1492−1496.
6. Cha, J. S. Org. Proc. Res. Dev. 2006, 10, 1032−1053. 7. Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.; Aliev, A. E.; Hale,
K. J. Org. Lett. 2006, 8, 4477−4480. 8. Clay, J. M. Meerwein–Ponndorf–Verley reduction. In Name Reactions for Functional
Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 123−128. (Review).
9. Dilger, A. K.; Gopalsamuthiram, V.; Burke, S. D. J. Am. Chem. Soc. 2007, 129, 16273−16277.
346
Meisenheimer complex Also known as the Meisenheimer−Jackson salt, the stable intermediate for cer-tain SNAr reactions.
FNO2
NO2
:R NH2
NO2
NO2SNAr, slow,
rate-determining step
FHNR
NHNO2
NO2
R
NO2
NO2
Ffast
FNHR
Meisenheimer complex
Sanger’s reagent, ipso attack ipso substitution
Example 17
Ph CN
NO2CO2Et
t-BuOK, DMF/THF
−70 oC, argon
NCO2Et
O O
HNC
Phnitronate
Example 29
OH
NO2O2N
NO2
N C NCH2Cl2
argon, rt, 3 h2
NOO
O2N NO2N
N
N
O Ni-Pri-Pr
H
15.5%
NO2N
NO2
NH
O
15.8%
NO2
The reaction using Sanger’s reagent is faster than using the corresponding chloro-, bromo-, and iododinitrobenzene—the fluoro-Meisenheimer complex is the most stabilized because F is the most electron-withdrawing. The reaction rate does not depend upon the capacity of the leaving group.
347
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_155, © Springer-Verlag Berlin Heidelberg 2009
Example 310
FNO2
NO2
NHNO2
NO2
R
HNR'
R
NO2
NO2FNHR
R'R'
NNO2
NO2
R R'
F
H
NO2
NO2FNR
R'
H
F
References 1. Meisenheimer, J. Ann. 1902, 323, 205–214. 2. Strauss, M. J. Acc. Chem. Res. 1974, 7, 181–188. (Review). 3. Bernasconi, C. F. Acc. Chem. Res. 1978, 11, 147–152. (Review). 4. Terrier, F. Chem. Rev. 1982, 82, 77–152. (Review). 5. Manderville, R. A.; Buncel, E. J. Org. Chem. 1997, 62, 7614–7620. 6. Hoshino, K.; Ozawa, N.; Kokado, H.; Seki, H.; Tokunaga, T.; Ishikawa, T. J. Org.
Chem. 1999, 64, 4572–4573. 7. Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. J. Org. Chem. 2000, 65, 1099–
1101. 8. Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548–2555. 9. Al-Kaysi, R. O.; Guirado, G.; Valente, E. J. Eur. J. Org. Chem. 2004, 3408–3411. 10. Um, I.-H.; Min, S.-W.; Dust, J. M. J. Org. Chem. 2007, 72, 8797–8803. 11. Han, T. Y.-J.; Pagoria, P. F.; Gash, A. E.; Maiti, A.; Orme, C. A.; Mitchell, A. R.;
Fried, L. E. New J. Chem. 2009, 33, 50–56.
348
[1,2]-Meisenheimer rearrangement [1,2]-Sigmatropic rearrangement of tertiary amine N-oxides to substituted hy-droxylamines.
R2N
OR1 Δ
R2N
OR
R1RR2
NO
RR1
Example 17
O
O N35% H2O2, CHCl3/MeOH, rt, 15 h
then PtO2, rt, 4.5 h
O
O NO
O
O
NO
THF, reflux, 1 h
64%, 2 steps
References 1. Meisenheimer, J. Ber. 1919, 52, 1667–1677. 2. Castagnoli, N., Jr.; Craig, J. C.; Melikian, A. P.; Roy, S. K. Tetrahedron 1970, 26,
4319–4327. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266. (Review). 4. Kurihara, T.; Sakamoto, Y.; Tsukamoto, K.; Ohishi, H.; Harusawa, S.; Yoneda, R. J.
Chem. Soc., Perkin Trans. 1, 1993, 81–87. 5. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Minami, K.; Harusawa, S.; Kurihara, T. Tetra-
hedron Lett. 1994, 35, 3749–3752. 6. Kurihara, T.; Sakamoto, Y.; Takai, M.; Ohishi, H.; Harusawa, S.; Yoneda, R. Chem.
Pharm. Bull. 1995, 43, 1089–1095. 7. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996,
52, 14563–14576. 8. Yoneda, R.; Araki, L.; Harusawa, S.; Kurihara, T. Chem. Pharm. Bull. 1998, 46, 853–
856.
349
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_156, © Springer-Verlag Berlin Heidelberg 2009
[2,3]-Meisenheimer rearrangement [2,3]-Sigmatropic rearrangement of allylic tertiary amine-N-oxides to give O-allyl hydroxylamines:
ΔN
O
RR R
NO
R1
23
1'2'
1'
2'
1
23
Example 17
N
ON
PhSO2
Ph
Et2O, rt, 48 h48%, 61% de
NO
*
Example 28
NO
OHO
Bn
m-CPBA
CH2Cl2, 100%
NO
OHO
BnHO Al2O3 (alumina)
MeOH
NO
OHO
BnO CDCl3, rt
67%, 65% deN
OO*
OHO
Bn
References 1. Meisenheimer, J. Ber. 1919, 52, 1667–1677. 2. Yamamoto, Y.; Oda, J.; Inouye, Y. J. Org. Chem. 1976, 41, 303–306. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266. (Review). 4. Kurihara, T.; Sakamoto, Y.; Matsumoto, H.; Kawabata, N.; Harusawa, S.; Yoneda, R.
Chem. Pharm. Bull. 1994, 42, 475–480. 5. Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 8279–
8283. 6. Enders, D.; Kempen, H. Synlett 1994, 969–971. 7. Buston, J. E. H.; Coldham, I.; Mulholland, K. R. Synlett 1997, 322–324. 8. Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van Sterkenburg, M. Tet-
rahedron: Asymmetry 2000, 11, 4227–4238. 9. Mucsi, Z.; Szabó, A.; Hermecz, I.; Kucsman, Á.; Csizmadia, I. G. J. Am. Chem. Soc.
2005, 127, 7615–7621. 10. Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.; Beauchemin, A.
M. J. Am. Chem. Soc. 2009, 131, 874–875.
350
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_157, © Springer-Verlag Berlin Heidelberg 2009
Meyers oxazoline method Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nu-cleophilic addition and substitution reactions that lead to the asymmetric construc-tion of carbon–carbon bonds.
N
O Ph
OMe N
O Ph
OMeR
1. LDA
2. R-X
N
O Ph
OMe
H
N(i-Pr)2
ONLi
Ph
OMe
H3C
H ONLi
Ph
OMe
H
H3C
XR
ON
Ph
OMe
H
H3C
R
Example 12
N
O Ph
OMe
TMSO Br1. LDA2.
3. LDA 4. Me2SO4
N
O Ph
OMe
H
TMSO
H3OO
O
66% yield70% ee
Example 25
NO
PhOMe
Li
IOO
NO
Ph OMeOO
1.
2.
99% yield
Example 39
NO 3 equiv n-BuLi3 equiv (−)-sparteine
Et2O, −78 oC, 4 h
NO
n-BuLi MeOH
79%
NO
n-Bu
er (S:R) = 86:14
351
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_158, © Springer-Verlag Berlin Heidelberg 2009
References 1. (a) Meyers, A. I.; Knaus, G.; Kamata, K. J. Am. Chem. Soc. 1974, 96, 268–270. While
Albert I. Meyers was an assistant professor at Wayne State University, neighboring pharmaceutical firm Parke–Davis (Drs. George Moersch and Harry Crooks) donated several kilograms of (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (Meyers referred to it as the Parke–Davis diol), from which his chemistry with chiral oxazolines began. He taught at Colorado State University since 1972. Meyers passed away in 2007. (b) Meyers, A. I.; Knaus, G. J. Am. Chem. Soc. 1974, 96, 6508–6510. (c) Meyers, A. I.; Knaus, G. Tetrahedron Lett. 1974, 15, 1333–1336. (d) Meyers, A. I.; Whitten, C. E. J. Am. Chem. Soc. 1975, 97, 6266–6267. (e) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 1186–1187. (f) Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. 1976, 15, 270–271. (Review). (g) Meyers, A. I. Acc. Chem. Res. 1978, 11, 375–381. (Review).
2. Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. J. Org. Chem. 1980, 45, 2792–2796.
3. Meyers, A. I., Lutomski, K. A. In Asymmetric Synthesis, Morrison, J. D. Ed.; Vol III, Part B, Chapter 3, Academic Press, 1983. (Review).
4. Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837–860. (Review). 5. Robichaud, A. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2607–2609. 6. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360. (Review). 7. Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991–1002. (Review). 8. Wolfe, J. P. Meyers Oxazoline Method. In Name Reactions in Heterocycl. Chemistry;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 237–248. (Review). 9. Hogan, A.-M. L.; Tricotet, T.; Meek, A.; Khokhar, S. S.; O’Shea, D. F. J. Org. Chem.
2008, 73, 6041–6044.
352
Meyer–Schuster rearrangement The isomerization of secondary and tertiary α-acetylenic alcohols to α,β-unsaturated carbonyl compounds via 1,3-shift. When the acetylenic group is ter-minal, the products are aldehydes, whereas the internal acetylenes give ketones. Cf. Rupe rearrangement.
R
OHR
R1
H , H2OR R1
R O
R
OHR
R1
HR
OH2R
R1
RR
R1
:OH2
R •
R
R1 R •
R
R1
OHR R1
R OtautomerizationH
Example 16
O
NOH
Br 98% H2SO4
50% N
H H
OBr
O
Example 27
POP
OPO
O
TMSO
O O
O PO
OTMSOTMS
PhSOH
ClCH2CH2Cl, 83 oC, 30 min.PhS
6%
PhS
O
54%
Example 38
OO
O
HOOEt
10% H2SO4
THF, rt, 1.5 h
OO
O
CO2Et
OO
O
CO2EtHO
70%21%
353
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_159, © Springer-Verlag Berlin Heidelberg 2009
Example 49
EtO2C
CO2EtPMBN
OH
BF3·Et2O
TFA, 89% EtO2C
CO2EtPMBN
O
OMe
OMeOMe
OMe
References 1. Meyer, K. H.; Schuster, K. Ber. 1922, 55, 819–823. 2. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429–438. (Review). 3. Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli, M. D. J. Org. Chem. 1977,
42, 3403–3408. 4. Andres, J.; Cardenas, R.; Silla, E.; Tapia, O. J. Am. Chem. Soc. 1988, 110, 666–674. 5. Tapia, O.; Lluch, J. M.; Cardenas, R.; Andres, J. J. Am. Chem. Soc. 1989, 111, 829–
835. 6. Brown, G. R.; Hollinshead, D. M.; Stokes, E. S.; Clarke, D. S.; Eakin, M. A.; Foubis-
ter, A. J.; Glossop, S. C.; Griffiths, D.; Johnson, M. C.; McTaggart, F.; Mirrlees, D. J.; Smith, G. J.; Wood, R. J. Med. Chem. 1999, 42, 1306–1311.
7. Yoshimatsu, M.; Naito, M.; Kawahigashi, M.; Shimizu, H.; Kataoka, T. J. Org. Chem. 1995, 60, 4798–4802.
8. Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139–7158. 9. Williams, C. M.; Heim, R.; Bernhardt, P. V. Tetrahedron 2005, 61, 3771–3779. 10. Mullins, R. J.; Collins, N. R. Meyer–Schuster Rearrangement. In Name Reactions for
Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 305−318. (Review).
354
Michael addition Also known as conjugate addition, Michael addition is the 1,4-addition of a nu-cleophile to an α,β-unsaturated system.
R2 Y
OR1
R3
Nuc:R2 Y
OR1
R3
Nuc
H
R2 Y
OR1
R3
Nuc:R2 Y
OR1
R3
Nuc
H
conjugate
additionR2 Y
OR1
R3
Nuc
H
enolate
workup
Example 1, Asymmetric Michael addition2
N Si(Me)2Ph
O
OCPh3
O
N Si(Me)2Ph
O
OCPh3
O PhPhMgBr, CuBr•DMS
ether, THF, −55 oC92%, 92% de
Example 2, Thia-Michael addition3
ON
OH2S, NaOMe
MeOH, 75%O
N
OHS
Example 3, Phospha-Michael addition7
MeO R
O (EtO)2P(O)H
MeO P
O ROEt
O OEt
R = H, 71%R = Me, 51%cat.
Me2N NMe2
NH
Example 4, Asymmetric aza-Michael addition9
MeO2CCl
Ph NH2
NaI, Na2CO3, Bu4NBrCH3CN, 82%
NMeO2C
Ph
NMeO2C
Ph2 : 1
355
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_160, © Springer-Verlag Berlin Heidelberg 2009
Example 5, Intramolecular Michael addition10
O OMeBocN
CO2Me
LiHMDS, DMF
−60 oC, 20 min.95%
OO
NBoc
CO2MeMe
H H
H
H
References
1. Michael, A. J. Prakt. Chem. 1887, 35, 349. Arthur Michael (1853−1942) was born in
Buffalo, New York. He studied under Robert Bunsen, August Hofmann, Adolphe Wurtz, and Dimitri Mendeleev, but never bothered to take a degree. Back to the United States, Michael became a Professor of Chemistry at Tufts University, where he married one of his most brilliant students, Helen Abbott, one of the few female organic chemists in this period. Since he failed miserably as an administrator, Michael and his wife set up their own private laboratory at Newton Center, Massachusetts, where the Michael addition was discovered.
2. Hunt, D. A. Org. Prep. Proced. Int. 1989, 21, 705−749. 3. D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992,
3, 459−505. 4. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135−631. (Review). 5. Hoz, S. Acc. Chem. Res. 1993, 26, 69−73. (Review). 6. Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. 1993, 32, 1010−1022. (Review). 7. Simoni, D.; Invidiata, F. P.; Manferdini, M.; Lampronti, I.; Rondanin, R.; Roberti, M.;
Pollini, G. P. Tetrahedron Lett. 1998, 39, 7615−7618. 8. Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006,
29−49. (Review on the phospha-Michael addition). 9. Chen, L.-J.; Hou, D.-R. Tetrahedron: Asymmetry 2008, 19, 715−720. 10. Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2008, 10, 1711−1714. 11. Thaler, T.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 645−648.
356
Michaelis−Arbuzov phosphonate synthesis Phosphonate synthesis from the reaction of alkyl halides with phosphites. General scheme:
(R1O)3P R2 XΔ
R2 PO
OR1
OR1R1 X
R1 = alkyl, etc.; R2 = alkyl, acyl, etc.; X = Cl, Br, I
For instance:
ΔBr
O
O(CH3O)3P
BrO
CH3
O
(CH3O)3P:
SN2
Br
PO
CH3OCH3O
O
OCH3
CH3
PO
CH3OCH3O
O
OCH3Br↑
SN2
Example 12
Br
Br (EtO)3P, Tol.
145 oC, 4 h, 70%
P(OEt)2O
Example 26
PO
BnOBnO
Cl (BnO)3P140 oC
8 h, 92%PO
BnOBnO
PO
OBn
OBn
Example 37
O
FF
F Br (EtO)3P, NiCl2
100 oC, 72 h, 10%
O
FF
F PO
OEtOEt
Example 49
BrN Ph
O
Bn
Me (MeO)3P
105−110 oC92−98%
(MeO)2PN Ph
O
Bn
MeO
357
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_161, © Springer-Verlag Berlin Heidelberg 2009
Example 510
O
BnO OSCN
BnO
Bn
BnO
TMSO−P(OEt)2
50 oC, 1 h, 82%
O
BnO OS
BnO
Bn
BnO P(OEt)2O
References 1. (a) Michaelis, A.; Kaehne, R. Ber. 1898, 31, 1048−1055. (b) Arbuzov, A. E. J. Russ.
Phys. Chem. Soc. 1906, 38, 687. 2. Surmatis, J. D.; Thommen, R. J. Org. Chem. 1969, 34, 559−560. 3. Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem., Int. Ed. 1973, 12,
91−119. (Review). 4. Waschb sch, R.; Carran, J.; Marinetti, A.; Savignac, P. Synthesis 1997, 727−743. 5. Bhattacharya, A. K.; Stolz, F.; Schmidt, R. R. Tetrahedron Lett. 2001, 42, 5393−5395. 6. Erker, T.; Handler, N. Synthesis 2004, 668−670. 7. Souzy, R.; Ameduri, B.; Boutevin, B.; Virieux, D. J. Fluorine Chem. 2004, 125,
1317−1324. 8. Kadyrov, A. A.; Silaev, D. V.; Makarov, K. N.; Gervits, L. L.; Röschenthaler, G.-V. J.
Fluorine Chem. 2004, 125, 1407−1410. 9. Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.; Bautista, R.; Bustos, P.;
Rojas-Cabrera, H.; Fernandez-Zertuche, M.; Garcia-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427−2436.
10. Piekutowska, M.; Pakulski, Z. Carbohydrate Res. 2008, 343, 785−792.
358
Midland reduction Asymmetric reduction of ketones using Alpine-borane®. Alpine-borane® = B-isopinocampheyl-9-borabicyclo[3.3.1]nonane.
R1
O
R
Alpine-borane
neat R1
OH
R
BH
THF
reflux
B
(1R)-(+)-α-pinene 9-BBN (R)-Alpine-borane
9-BBN = 9-borabicyclo[3.3.1]nonane
R1
O
R
BH
OR1
R
B
R1
O
R
B H2O2, NaOH
workupR1
OH
R
hydride
transfer
Example 16
BnOO
H
(R)-Alpine-borane, THF
−10 oC to rt, 95%, 88% ee
BnOOH
H
Example 27
TBSO
O
OPMB(R)-Alpine-borane
22 oC, 6 kbar, 82%80% de
TBSO
OH
OPMB
359
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_162, © Springer-Verlag Berlin Heidelberg 2009
Example 38
TBSO
O
TBSO
OH
(R)-Alpine-borane (neat)
rt, 74%, 93% ee
References 1. Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc. 1979,
101, 2352−2355. M. Mark Midland was a professor at the University of California, Riverside.
2. Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867−869.
3. Brown, H. C.; Pai, G. G. J. Org. Chem. 1982, 47, 1606−1608. 4. Brown, H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984, 106, 1531−1533. 5. Singh, V. K. Synthesis 1992, 605−617. (Review). 6. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721−2724. 7. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891−898. 8. Kiewel, K.; Luo, Z.; Sulikowski, G. A. Org. Lett. 2005, 7, 5163−5165. 9. Clay, J. M. Midland reduction. In Name Reactions for Functional Group Transforma-
tions; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007, pp 40−45. (Re-view).
360
Minisci reaction Radical-based carbon–carbon bond formation with electron-deficient heteroaro-matics. The reaction entails an intermolecular addition of a nucleophilic radical to protonated heteroaromatic nucleus.
R CO2HN RN
2 AgNO3(NH4)2S2O8
H2SO4
R CO2H
N2 AgNO3, (NH4)2S2O8, H2SO4
silver-catalyzed oxidative decarboxylation
CO2 R HH2SO4
NH
R
Example 14
S2O8 CH3OH •CH2OH H+ SO4 SO4•
N
CN
OCH3
BF4(NH4)2S2O8MeOH, H2O
reflux, 1 h, 40% N
CN
OH
Example 25
N
1.6 equiv m-CPBA
acetone, rt, 1.5 h75%
NO
(CH3)3O•BF4
CH2Cl2, rt90 min.
Meerwein’s reagent
NOCH3
BF4
(NH4)2S2O8MeOH, H2O
reflux, 1 h40%, 2 steps
NOH
N
1.6 equiv m-CPBA
acetone, rt, 1.5 h78%
NO
361
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_163, © Springer-Verlag Berlin Heidelberg 2009
NOCH3
BF4(CH3)3O•BF4
CH2Cl2, rt90 min., 85%
(NH4)2S2O8MeOH, H2O
reflux, 1 h, 41%N
OH
Example 3, Intramolecular Minisci reaction6
NH
O
O
OHN
EtO2C
AgNO3, (NH4)2S2O8
CH2Cl2, H2O, AcOH, TFArt, 1 h, 46%
NH
ON
CO2Et
Example 47
NN
Me
Cl
(NH4)2S2O8, AgNO3
TFA, H2O, 75 °C53%
NN
Me
Cl
BzNH
NN
Me
Cl
BzNH
90 : 10
CO2HBzNH
Example 510
CO2H
CO2HHO2C1 equiv
N
N 10 equiv FeSO4•7H2OH2O2, H2O, H2SO4
CH2Cl2, 0 oC, 15 min.24%10 equiv
NN
N
NN
N References 1. Minisci, F, Bernardi. R, Bertini, F, Galli, R, Perchinummo, M. Tetrahedron 1971, 27,
3575–3579. 2. Minisci, F. Synthesis 1973, 1–24. (Review). 3. Minisci, F. Acc. Chem. Res. 1983, 16, 27–32. (Review). 4. Katz, R. B.; Mistry, J.; Mitchell, M. B. Synth. Commun. 1989, 19, 317–325. 5. Biyouki, M. A. A.; Smith, R. A. J.; Bedford, J. J.; Leader, J. P. Synth. Commun. 1998,
28, 3817–3825. 6. Doll, M. K. H. J. Org. Chem. 1999, 64, 1372–1374. 7. Cowden, C. J. Org. Lett. 2003, 5, 4497–4499. 8. Kast, O.; Bracher, F. Synth. Commun. 2003, 33, 3843–3850. 9. Benaglia, M.; Puglisi, A.; Holczknecht, O.; Quici, S.; Pozzi, G. Tetrahedron 2005, 61,
12058–12064. 10. Palde, P. B.; McNaughton, B. R.; Ross, N. T.; Gareiss, P. C.; Mace, C. R.; Spitale, R.
C.; Miller, B. L. Synthesis 2007, 2287–2290. 11. Brebion, F.; Nàjera, F.; Delouvrié, B.; Lacôte, E.; Fensterbank, L.; Malacria, M. J.
Heterocycl. Chem. 2008, 45, 527–532.
362
Mislow–Evans rearrangement [2,3]-Sigmatropic rearrangement of allylic sulfoxide to allylic alcohol.
R SAr
O Δ ArS
O
R
P(OCH3)3 HO
R
SAr
OAr
SO
R
:P(OCH3)3
R [2,3]-sigmatropic
rearrangement1
2
31
21
12
2
3
O
R
SN2Ar
SP(OCH3)3
H HO
R
Example 12
O
TBSOCHO
O
TBSOOMePhS
NaIO4dioxane/H2O
50%
Example 27
OO
OMe
MeOOTBS
SPh
O
(EtO)3P, EtOH
reflux, 16 h, 98%
OO
OMe
MeOOTBS
OH
Example 3, Seleno-Mislow-Evans8
OHH
HO
OTBSPMBO
TBDPSO
1. PhSeCN, Bu3P, THF
2. H2O2, pyr., THF, −30 oC 62%
O
OH
HH
OTBSPMBO
TBDPSO
363
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References 1. (a) Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100–2104. (b) Evans, D. A.;
Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956–4957. (c) Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672–3674. (d) Evans, D. A.; An-drews, G. C. Acc. Chem. Res. 1974, 7, 147–155. (Review).
2. Sato, T.; Shima, H.; Otera, J. J. Org. Chem. 1995, 60, 3936–3937. 3. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc. 1995, 117, 9077–9078. 4. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Org. Chem. 1995, 60, 6682–6683. 5. Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23–27. 6. Zhou, Z. S.; Flohr, A.; Hilvert, D. J. Org. Chem. 1999, 64, 8334–8341. 7. Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341–1343. 8. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485–
3499. 9. Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128,
2792–2793. 10. Pelc, M. J.; Zakarian, A. Tetrahedron Lett. 2006, 47, 7519–7523. 11. Brebion, F.; Najera, F.; Delouvrie, B.; Lacote, E.; Fensterbank, L.; Malacria, M. Syn-
thesis 2007, 2273–2278.
364
Mitsunobu reaction SN2 inversion of an alcohol by a nucleophile using disubstituted azodicarboxylates (originally, diethyl diazodicarboxylate, or DEAD) and trisubstituted phosphines (originally, triphenylphosphine).
R1 R2
OH
HNuc
1o or 20 alcohol
NNEtO2C
CO2Et
PPh3R1 R2
NucPPh3O N
EtO2C
CO2EtHN
H
:PPh3
N NCO2Et
EtO2C N NEtO2C
CO2Et
Ph3P
adduct
formation
H Nuc
R1 R2
:OH
N NEtO2C
CO2Et
Ph3P
H
Diethyl azodicarboxylate (DEAD)
N NCO2Et
HEtO2C
H
alcohol
activation R1 R2
O PPh3
R1 R2
NucO PPh3
Nuc
SN2
reaction
Example 12
O
OAcOAc
OAc
CH2OAc
OH
PhCO2HDIAD, PPh3, THF
−50 oC to rt, 2 h, 80%
O
OAcOAc
OAc
CH2OAc
O2CPh
2:1 β:α
Example 23
OHO
O CO2HO2NDEAD, PPh3, Tol.
−30 to 0 oC, 1 h, 90%
4-O2NPhCOOO
O
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_165, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Ether formation6
PBu3, ADDP, THF,0 oC to rt, overnight
100%
NO
OMe
OHOBnO2C
OBn
OH
BnO OBn
NO
OMe
OO
OBn
CO2Bn
OBn
BnO
ADDP = 1,1'-(azodicarbonyl)dipiperidine
Example 47
TMSHN
OOH
PhN
TMSPh
OPPh3, DIAD, PhCH3
reflux, 60%
Example 58
N
H
H
CH3
HO
H3CCH3
n-BuLi
then Ph2PClN
H
H
CH3
Ph2PO
H3CCH3
N
H
H
CH3
H3CCH3
O
O
O2NOH
O
O2N
OO
80%
Example 6, Intramolecular Mitsunobu reaction9
DEAD, PPh3
PhH, 92 %NBocMeO
OMe
NHNs
R CO2Et
OH
R=CH(OMe)2NBocMeO
OMe
NsHN
R CO2Et
366
References 1. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380−2382. (b) Mit-
sunobu, O. Synthesis 1981, 1−28. (Review). 2. Smith, A. B., III; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986, 27, 5813−5816. 3. Kocie ski, P. J.; Yeates, C.; Street, D. A.; Campbell, S. F. J. Chem. Soc., Perkin
Trans. 1, 1987, 2183−2187. 4. Hughes, D. L. Org. React. 1992, 42, 335−656. (Review). 5. Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127−164. (Review). 6. Vaccaro, W. D.; Sher, R.; Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 35–40. 7. Cevallos, A.; Rios, R.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron: Asymmetry
2000, 11, 4407–4416. 8. Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem. Soc. 2003, 125, 10538–
10539. 9. Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59, 8571–
8587. 10. Christen, D. P. Mitsunobu reaction. In Name Reactions for Homologations-Part II; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 671−748. (Review).
367
Miyaura borylation Palladium-catalyzed reaction of aryl halides with diboron reagents to produce arylboronates. Also known as Hosomi−Miyaura borylation.
Ar XO
BOO
BO Pd(0)
base
OB
OAr
X = I, Br, Cl, OTf.
Ar X L2Pd(0)oxidative
additionPd
L
L X
Ar
O
BOO
BO base O
BOO
BO
base
PdL
L I
transmetallation
Ar
OB
OI
reductive
elimination
PdL
Ar B
L
O
O OB
OAr L2Pd(0)
Example 17
OB
OOB
OPh
BO
OPh
OAc O
CuCl, LiCl, KOAc, DMF, 92%
O
Example 28
O
BOO
BO
NCbz
3% (Ph3P)2PdCl2, 6% Ph3P1.5 eq. K2CO3, dioxane, 90 oC
85%
NCbzOTf
BO
O
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_166, © Springer-Verlag Berlin Heidelberg 2009
Example 39
I
BnO
CO2BnCbzHN
B
BnO
CO2BnCbzHNO
O
OB
OOB
O
Pd(dppf)Cl2, KOAcDMSO, 80 oC, 24 h
85%
I
BnO
CO2BnCbzHN
OBn
BnO2C NHCbz
BnO
CO2BnCbzHN
Pd(dppf)Cl2, K2CO3DMSO, 80 oC, 24 h
85%
Example 4, One-pot synthesis of biindolyl10
NH
MeO
MeOBr
1. 1 mol% Pd2(dba)3, 4 mol% XPhos 3 equiv HB(pin), 3 equiv Et3N dioxane, 100 oC
2. 1 mol% Pd2(dba)3, 3 equiv K3PO4•H2O dioxane/H2O (10 : 1), 100 oC
NH
MeO
MeO
Br NH
MeO
MeO
NH
MeO
MeO
References 1. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508−7510. 2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483. (Review). 3. Suzuki, A. J. Organomet. Chem. 1995, 576, 147−168. (Review). 4. Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477−3480. 5. Giroux, A. Tetrahedron Lett. 2003, 44, 233−235. 6. Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 7885−7887. 7. Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Srivastava, A.; Reddy, M. V. R. Org.
Lett. 2004, 6, 481−484. 8. Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324−7330. 9. Skaff, O.; Jolliffe, K. A.; Hutton, C. A. J. Org. Chem. 2005, 70, 7353−7363. 10. Duong, H. A.; Chua, S.; Huleatt, P. B.; Chai, C. L. L. J. Org. Chem. 2008, 73,
9177−9180. 11. Jo, T. S.; Kim, S. H.; Shin, J.; Bae, C. J. Am. Chem. Soc. 2009, 131, 1656−1657.
369
Moffatt oxidation Oxidation of alcohols using DCC and DMSO, aka “Pfitzner−Moffatt oxidation”.
R1 R2
OH
R1 R2
ODCC
DMSO, HX
DCC, 1,3-dicyclohexylcarbodiimide
N C N N C N
OS
HH
R1 R2
:OH
HN C NO
S
H
NH
NH
O
R1 R2
OS H
HH X
R1 R2
OS
H R1 R2
O
(CH3)2S
1,3-dicyclohexylurea Example 12
OH
OH
DCC, DMSO, C5H5NH+CF3CO2
PhH, rt, 70%
O
O Example 28
O
O O
A OH
DCC, DMSO, Cl2CHCO2H
rt, 90 min., 90%
O
O O
A CHO
A = adenosine
References 1. Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027−3028. 2. Schobert, R. Synthesis 1987, 741−742. 3. Liu, H. J.; Nyangulu, J. M. Tetrahedron Lett. 1988, 29, 3167–3170. 4. Tidwell, T. T. Org. React. 1990, 39, 297−572. (Review). 5. Gordon, J. F.; Hanson, J. R.; Jarvis, A. G.; Ratcliffe, A. H. J. Chem. Soc., Perkin
Trans. 1, 1992, 3019−3022. 6. Krysan, D. J.; Haight, A. R.; Lallaman, J. E. Org. Prep. Proced. Int. 1993, 25,
437−443. 7. Adak, A. K. Synlett 2004, 1651−1652. 8. Wang, M.; Zhang, J.; Andrei, D.; Kuczera, K.; Borchardt, R. T.; Wnuk, S. F. J. Med.
Chem. 2005, 48, 3649−3653. 9. van der Linden, J. J. M.; Hilberink, P. W.; Kronenburg, C. M. P.; Kemperman, G. J.
Org. Proc. Res. Dev. 2008, 12, 911–920.
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Morgan–Walls reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls with phosphorus oxychloride in boiling nitrobenzene.
R1
NHRO
POCl3
R1
NR
R1
NHOR
PCl ClCl
O
:
R1
NHOR
POCl2
R1
NHOPOCl2R
:
R1
NR
H HOPOCl2
Example 16
O2N NO2
HNO
CN
nitrobenzene, POCl3
SnCl4, 98%
O2N NO2
N
CN
Pictet–Hubert reaction
The Morgan-Walls reaction is a variant of the Pictet-Hubert reaction where the phenanthridine cyclization was accomplished by dehydrative ring closure of acyl-o-aminobiphenyls on heating with zinc chloride at 250−300 °C.
R1
NHRO
R1
NR
ZnCl2
250−300 oC
Example 24
N
OH
N
ZnCl2, 250−300 oC
80%
371
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_168, © Springer-Verlag Berlin Heidelberg 2009
References 1. (a) Pictet, A.; Hubert, A. Ber. 1896, 29, 1182−1189. (b) Morgan, C. T.; Walls, L. P. J.
Chem. Soc. 1931, 2447−2456. (c) Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1932, 2225−2231.
2. Gilman, H.; Eisch, J. J. Am. Chem. Soc. 1957, 79, 4423−4426. 3. Hollingsworth, B. L.; Petrow, V. J. Chem. Soc. 1961, 3664−3667. 4. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300. 5. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1988, 31, 774−779. 6. Peytou, V.; Condom, R.; Patino, N.; Guedj, R.; Aubertin, A.-M.; Gelus, N.; Bailly, C.;
Terreux, R.; Cabrol-Bass, D. J. Med. Chem. 1999, 42, 4042−4043. 7. Holsworth, D. D. Pictet–Hubert Reaction. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 465−468. (Re-view).
372
Mori−Ban indole synthesis Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare in-dole.
N
Br
Ac
CO2MePd(OAc)2, Ph3P
NaHCO3, DMF, 130 oC N
CO2Me
Ac
Reduction of Pd(OAc)2 to Pd(0) using Ph3P:
Pd OAcAcOPd OAcPh3P
:PPh3AcO
Pd(0) O PPh3
OO PPh3
O
O O
AcO Mori−Ban indole synthesis:
N
Br
Ac
CO2MePd(0)
NAc
CO2MePdLn
Br
oxidativeaddition
insertion
N
PdBrLn
Ac
MeO2C
H
PdBrLnHNAc
CO2Meβ-hydride
eliminationaddition
of PdH
HNAc
CO2MePdBrLn
N
CO2Me
Ac
β-hydride
elimination N
CO2Me
Ac
Regeneration of Pd(0):
H PdBrLn NaHCO3 Pd(0) NaBr H2O CO2↑ Example 11a
I
NH
NH
MePd(OAc)2
Et3N, MeCNsealed tube
110 °C, 87%
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_169, © Springer-Verlag Berlin Heidelberg 2009
Example 24
N
N Cl
NN
N
N
10 mol% Pd(OAc)2
Bu4NBr, K2CO3,DMF, 100 oC
67%
Example 37
Br
NCOCF3
SO2NHMe
Br
NCbz N
HBr
NSO2NHMe
Cbz
Pd(OAc)2, Bu4NCl
Et3N, DMF heat, DME, 76%
References 1. Mori−Ban indole synthesis, (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977,
18, 1037−1040; (b) Ban, Y.; Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711−1715.
2. Reduction of Pd(OAc)2 to Pd(0), (a) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.; Meyer, G. Organometallics 1995, 14, 5605−5614; (b) Amatore, C.; Carre, E.; M’Barki, M. A. Organometallics 1995, 14, 1818−1826; (c) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11, 3009−3013; (d) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375−8384.
3. Macor, J. E.; Ogilvie, R. J.; Wythes, M. J. Tetrahedron Lett. 1996, 37, 4289−4293. 4. Li, J. J. J. Org. Chem. 1999, 64, 8425−8427. 5. Gelpke, A. E. S.; Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.; van Leuwen, P.
W. N. M.; Hiemstra, H. Tetrahedron 1999, 55, 6657−6670. 6. Sparks, S. M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721−6724. 7. Bosch, J.; Roca, T.; Armengol, M.; Fernandez-Forner, D. Tetrahedron 2001, 57,
1041−1048. 8. Ma, J.; Yin, W.; Zhou, H.; Liao, X.; Cook, J. M. J. Org. Chem. 2009, 74, 264−273.
374
Mukaiyama aldol reaction Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether.
R CHO R1OSiMe3
R2 Lewis
acidR R2
OH
R1
O
R1O
R2 R R2
OH
R1
O
R H
O
SiMe3
X SiMe3
LAX
R R2
Me3SiO
R1
O
Example 1, Intramolecular Mukaiyama aldol reaction3
O
CH(OMe)2
EtO2CEtO2C
1. LDA, THF, −78 oC, 10 min.
2. 1.8 equiv TMSCl, −78 oC, 4 h 92%
OTMS
CH(OMe)2
EtO2CEtO2C
TiCl4, CH2Cl2
−78 oC to rt, 15 h
HOMe
12%
CO2EtEtO2C
OOMe
H
40%
CO2EtEtO2C
O
Example 2, Mukaiyama aldol reaction7
N
O
Bn
OTBDMS
N
O
OHCBoc
BF3•OEt2, DTBMP
CH2Cl2, −78 to −50 oC, 73%NBn
OH
N
O
BocO
O
Example 3, Vinylogous Mukaiyama aldol reaction8
OSiMe3
OO
CHO
CN
1. PhCO2H, rt
2. TFA, 60% O
OO
NC
OH
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_170, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Asymmetric Mukaiyama aldol reaction10
Bu3SnCHO
cat. NBH
O
O
TsOTMS
OMe
Bu3Sn
OTMS
Bu3Sn
HO OMe
O
38% 50%
Example 5, Mukaiyama aldol reaction12
MeBr
CHO
OTBS
O OTIPS
MeMe
Br
OTBS
OH
OO
Me10 mol% Bi(OTf)3CH2Cl2, −40 oC76% out of 56%
conversion
References 1. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011−1014. (b) Mu-
kaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503−7509. 2. Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125−9128. 3. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.-E.; Kelsey, R. D.; Mortlock, A.
A. J. Chem. Soc., Perkin Trans. 1 2002, 1344−1350. 4. Clézio, I. L.; Escudier, J.-M.; Vigroux, A. Org. Lett. 2003, 5, 161−164. 5. Ishihara, K.; Yamamoto, H. Boron and Silicon Lewis Acids for Mukaiyama Aldol Re-
actions. In Modern Aldol Reactions Mahrwald, R., Ed.; 2004, 25−68. (Review). 6. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590−5614. (Review). 7. Adhikari, S.; Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7,
2795−2797. 8. Acocella, M. R.; Massa, A.; Palombi, L.; Villano, R.; Scettri, A. Tetrahedron Lett.
2005, 46, 6141−6144. 9. Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc. 2007, 129,
6386−6387. 10. Webb, M. R.; Addie, M. S.; Crawforth, C. M.; Dale, J. W.; Franci, X.; Pizzonero, M.;
Donald, C.; Taylor, R. J. K. Tetrahedron 2008, 64, 4778−4791. 11. Frings, M.; Atodiresei, I.; Runsink, J.; Raabe, G.; Bolm, C. Chem. Eur. J. 2009, 15,
1566−1569. 12. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412.
376
Mukaiyama Michael addition Lewis acid-catalyzed Michael addition of silyl enol ether to an α,β-unsaturated system.
R1OSiMe3
R2 Lewis
acidR
O
R
OR1
R2
O
Example 12
OOMe
OSiMe3 1. 0.1 mol% TBABB, THF, 3 h
2. 1 N HCl, THF, 0 oC, 0.5 h 87%
O
O
O
TBABB = tetra-n-butylammonium bibenzoate
Example 25
OMe
OSiMe3O1. neat DBU, rt, 24 h
2. 1 N HCl, THF, 68%
O
O
O
Example 38
TBSOOMe
OMeO
O
OMeOMe 10 mol% Sc(OTf)3
CH2Cl2, −78 oC to rt
10% HF/CH3CN quench85%, 20 : 1 (syn/anti)
O
O
OMeOMe
MeOOMe
O
H
Example 49
R3
R1
O
R2
CO2Me
N2
OTBS 0.5 mol% Zn(OTf)2
CH2Cl2, 0−25 oC78−81%
CO2Me
N2
O
OTBS
R1R2
R3
CO2Me
N2
O
O
R1R2
R3
4 N HCl
THF
377
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_171, © Springer-Verlag Berlin Heidelberg 2009
References 1. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011−1014. (b)
Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503−7509. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590−5614. (Review).
2. Gnaneshwar, R.; Wadgaonkar, P. P.; Sivaram, S. Tetrahedron Lett. 2003, 44, 6047−6049.
3. Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046−10057.
4. Jaber, N.; Assie, M.; Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075−3083. 5. Shen, Z.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 507−508. 6. Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7, 1637−1639. 7. Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921−1924. 8. Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2007, 46, 6502−6504. 9. Liu, Y.; Zhang, Y.; Jee, N.; Doyle, M. P. Org. Lett. 2008, 10, 1605−1608. 10. Takahashi, A.; Yanai, H.; Taguchi, T. Chem. Commun. 2008, 2385−2387.
378
Mukaiyama reagent Mukaiyama reagent such as 2-chloro-1-methyl-pyridinium iodide for esterification or amide formation. General scheme:
R1CO2H R2OH
NXR3
Y
R1 OR2
O
NOR3base
X = F, Cl, Br
Example 11c
O CO2HHO BF4
N Br
O
OOBu3N, CH2Cl2
NON
BF4BrO
O BrO
O
O
:
H
SNAr
− H
NBu3
− Br
HO
NO
O
O
Bn
: BF4
NO
O
O OBn
NOBn
OO O
:
H
NHO
BF4
BF4
Amide formation using the Mukaiyama reagent follows a similar mechanistic pathway.1d
Example 2, Polymer-supported Mukaiyama reagent5
OOH
N Cl
Tf2O, CH2Cl2, 16 h, rt
ON
Cl
1.25 mmol/g
TfO
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_172, © Springer-Verlag Berlin Heidelberg 2009
NH
CO2H
NHBoc ONH2
O
polymer-supportedMukaiyama reagent
Et3N, CH2Cl2, rt16 h, 88%
NH
NHBoc
OO
NH
O
Example 39
NS
N S
O
HO
NHBoc
St-BuS
O
NHFmoc
CO2TMSE
Mukaiyama reagent
DIPEA, CH2Cl2, 91% St-BuS
O
NH
CO2TMSE
NS
N S
O
NHBoc
Example 4, Fluorous Mukaiyama reagent10
RCO2H R1NH2 or R2OH
1. Fluorous Mukaiyama reagent 1 equiv DMAP, 3 equiv Et3N dry DMF, rt, 1h
2. H2O, rt, 5 min., 87−100%RCONHR1 or RCO2R2
N
C10F21
ClFluorous Mukaiyama reagent
TfO
References 1. (a) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045–1048.
(b) Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. Chem. Lett. 1977, 635–636. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707–708. (d) For am-ide formation, see: Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 1465–1466.
2. Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402–8403. 3. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540–1542. 4. Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H. J. Org. Chem. 1998, 63, 8170–8182. 5. Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579–4582.
380
6. Mashraqui, S. H.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 34, 3129–3134. 7. Donati, D.; Morelli, C.; Taddei, M. Tetrahedron Lett. 2005, 46, 2817–2819. 8. Vandromme, L.; Monchaud, D.; Teulade-Fichou, M.-P. Synlett 2006, 3423–3426. 9. Ren, Q.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z.; Ye, T. Synlett 2008, 2379–2383. 10. Matsugi, M.; Suganuma, M.; Yoshida, S.; Hasebe, S.; Kunda, Y.; Hagihara, K.; Oka,
S. Tetrahedron Lett. 2008, 49, 6573–6574.
381
Myers−Saito cyclization Cf. Bergman cyclization and Schmittel cyclization.
hydrogen atom donor
Δ or
hv•
•
HreversibleH
allenyl enyne diradical
Example 13
Ph
Ph
H
PhH, reflux
96 h, 40%
Ph Ph
Example 2, Aza-Myers−Saito reaction8
Ph
N CDCl3
10 oC, 12 h
NCHO
Ph
N
Ph
MeOH
0 oC, 14 h
OMe
References 1. (a) Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212–
7214. (b) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369–9386.
2. Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975–4978. 3. Schmittel, M.; Steffen, J.-P.; Auer, D.; Maywald, M. Tetrahedron Lett. 1997, 38,
6177–6180. 4. Bruckner, R; Suffert, J. Synlett 1999, 657−679. (Review). 5. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem.
2002, 67, 1453–1461. 6. Musch, P. W; Remenyi, C.; Helten, H.; Engels, B. J. Am. Chem. Soc. 2002, 124,
1823–1828. 7. Bui, B. H.; Schreiner, P. R. Org. Lett. 2003, 5, 4871–4874. 8. Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M. Org. Lett. 2004, 6, 2059–2062. 9. Schmittel, M.; Mahajan, A. A.; Bucher, G. J. Am. Chem. Soc. 2005, 127, 5324–5325. 10. Karpov, G.; Kuzmin, A.; Popik, V. V. J. Am. Chem. Soc. 2008, 130, 11771–11777.
382
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_173, © Springer-Verlag Berlin Heidelberg 2009
Nazarov cyclization Acid-catalyzed electrocyclic formation of cyclopentenone from di-vinyl ketone.
O
HO
H
OO
protonation
H HO
H
Otautomerization
OH
Example 12
NCO2Me
O
SiMe3
ZrCl4, (CH2Cl)2
60 oC, 36 h, 76% NCO2Me
H O
H
Example 26
O
O
PhHClO4 (10−2 M)
Ac2O (1 M)
EtOAc, 9 h, 75%
OAc
O
Ph
H
Example 39
OTIPS
OTIPSO
MeO2C
MePh
5 mol% Cu(ClO4)2
DCE, 45 oC, 8 h, 80%
OTIPS
OTIPSO
MeO2CMe Ph
383
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_174, © Springer-Verlag Berlin Heidelberg 2009
Example 410
NTs
OAc
MeOO
O
NTs
OAc
MeO
OO
10 mol% Sc(OTf)3LiClO4, 80 oC
ClCH2CH2Cl (0.3 M)65%
Example 511
1. hν (350 nm), CH3CN, rt
2. i-Pr2NH, MeOH, 50 oC 60%, 2 steps
MeCl
OMe
Br
O OO
Me
OTBS
ClO
O
Me
Me
O Me
HH
Me
Br
OO
OMeMe
ClCl
OTBS
OO
Me9
References 1. Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I.
N. Nazarov (1900−1957), a Soviet Union Scientist, discovered this reaction in 1942. It was said that almost as many young synthetic chemists have been lost in the pursuit of an asymmetric Nazarov cyclization as of the Bayliss−Hillman reaction.
2. Denmark, S. E.; Habermas, K. L.; Hite, G. A. Helv. Chim. Acta 1988, 71, 168−194; 195−208.
3. Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1−158. (Review). 4. Kim, S.-H.; Cha, J. K. Synthesis 2000, 2113−2116. 5. Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221−10228. 6. Mateos, A. F.; de la Nava, E. M. M.; González, R. R. Tetrahedron 2001, 57,
1049−1057. 7. Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328−14329. 8. Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171−1174. 9. Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.; Sarpong, R. Angew. Chem., Int.
Ed. 2008, 47, 6379−6383. 10. Bitar, A. Y.; Frontier, A. J. Org. Lett. 2009, 11, 49−52. 11. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412.
384
Neber rearrangement α-Aminoketone from tosyl ketoxime and base. The net conversion of a ketone into an α-aminoketone via the oxime.
R1R2
NOTs 1. KOEt
2. H2OR1 R2
NH2
O
TsOH
ketoxime α-aminoketone
deprotonation
R2
NOTs
cyclizationH
R2
NOTs
R1EtOR1
TsO N
R2R1
:OH2 hydrolysisHR1 R2
NH2
O
HN
R2R1
O H
azirine intermediate Example 13
N
Me
O1. NH2OH•HCl
2. TsCl, Pyr. 93%
N
Me
NOTs
1. KOEt
2. HCl 82% N
NH2
EtO OEt
Example 2, A variant using iminochloride5
Ph
OEt
NH•HCl
PhOEt
NCl
PhOH
O
NH2HOCl
100%
1. KOt-Bu
2. HCl 71%
Example 38
N
N
N
TsON
MeO
OSEM
OMe
N
Br
Ts
1. KOH, H2O, EtOH, 0 oC, 3 h
2. 6 N HCl, 60 oC, 10 h3. K2CO3, THF, H2O, 10 min. 96%
385
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_175, © Springer-Verlag Berlin Heidelberg 2009
N
N
HN
O
MeO
O
OMe
N
Br
Ts
H2N
Example 49
R1
O
R 1. H2NOH
2. MsCl, Et3N; DBU, Bu3P 70–91%
R1N N
H
R1R
Rheat
41–89%
References 1. Neber, P. W.; v. Friedolsheim, A. Ann. 1926, 449, 109–134. 2. O’Brien, C. Chem. Rev. 1964, 64, 81–89. (Review). 3. LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329–330. 4. Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996,
118, 8491–8492. 5. Oldfield, M. F.; Botting, N. P. J. Labelled Cpd. Radiopharm. 1998, 16, 29–36. 6. Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2002, 41, 5363-–
5366. 7. Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640–
7641. 8. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970–5978. 9. Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058–1059. 10. Richter, J. M. Neber rearrangement. In Name Reactions for Homologations-Part I; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 464−473. (Review).
386
Nef reaction Conversion of a primary or secondary nitroalkane into the corresponding carbonyl compound.
R1 R2
NO2
R1 R2
O1/2 N2O 1/2 H2O
1. NaOH
2. H2SO4
R1 R2
NO O
H R1 R2
NO O
HO
H2O
nitronate
R1 R2
NHO O
OH
H− H2O
R1 R2
NHO OH
:OH2
nitronic acid
H H
R1 R2
O1/2 N2O 1/2 H2O
R1 R2
NO
OH
H
R1 R2
OHNO
R1 R2
NHO
OH
Example 14
O
NO2
1. NaOH, EtOH, 0 oC, 30 min.
2. 3 M HCl, 0 to 20 oC, 12 h, 68%
O
O
Example 27
H
HONO2
1. 2 M NaOH, MeOH
2. ice-cooled KMnO4 45% H
HOO
Example 39
OTBS
NO2
OO
SSt-Bu
t-Bu
2.2 equiv PMe3, THF, rt, 30 min.
OTBS
NH
OO H2O, rt, 5 min.
94%, 2 steps
OTBS
O
OO
387
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_176, © Springer-Verlag Berlin Heidelberg 2009
Example 410
*
NO2
CO2HR *
CO2HCO2H
RHOAc, HCl
reflux, 2 h
References 1. Nef, J. U. Ann. 1894, 280, 263−342. John Ulrich Nef (1862−1915) was born in Swit-
zerland and emigrated to the US at the age of four with his parents. He went to Mu-nich, Germany to study with Adolf von Baeyer, earning a Ph.D. In 1886. Back to the States, he served as a professor at Purdue University, Clark University, and the Uni-versity of Chicago. The Nef reaction was discovered at Clark University in Worcester, Massachusetts. Nef was temperamental and impulsive, suffering from a couple of mental breakdowns. He was also highly individualistic, and had never published with a coworker save for three early articles.
2. Pinnick, H. W. Org. React. 1990, 38, 655−792. (Review). 3. Adam, W.; Makosza, M.; Saha-Moeller, C. R.; Zhao, C.-G. Synlett 1998, 1335–1336. 4. Thominiaux, C.; Rousse, S.; Desmaele, D.; d’Angelo, J.; Riche, C. Tetrahedron:
Asymmetry 1999, 10, 2015–2021. 5. Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000,
2681–2688. 6. Ballini, R.; Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Lett. 2002, 43, 5233–5235. 7. Chung, W. K.; Chiu, P. Synlett 2005, 55–58. 8. Wolfe, J. P. Nef reaction. In Name Reactions for Functional Group Transformations;
Li, J. J., Corey, E. J., Eds; John Wiley & Sons: Hoboken, NJ, 2007, pp 645−652. (Re-view).
9. Burés, J.; Vilarrasa, J. Tetrahedron Lett. 2008, 49, 441–444. 10. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C. D. Tetrahedron: Asymmetry 2008,
19, 945–955.
388
Negishi cross-coupling reaction The Negishi cross-coupling reaction is the nickel- or palladium-catalyzed coupling of organozinc compounds with various halides or triflates (aryl, alkenyl, alkynyl, and acyl).
R1 X
R1 = aryl, alkenyl, alkynyl, acylR2 = aryl, heteroaryl, alkenyl, allyl, Bn, homoallyl, homopropargylX = Cl, Br, I, OTfY = Cl, Br, ILn = PPh3, dba, dppe
+ R2Zn Y R2R1NiLn or PdLn
solvent
Pd(0)Ln
R2ZnXZnX2
R1 R2
Pd(II)
R1
Ln
XZnX
R2
Pd(II)R2
Pd(0) or Pd(II) complexes (precatalysts)
R1 X
oxidative addition
LnPd(II)R1
X
reductive elimination
transmetallation/trans/cis isomerization
1
2
3Ln
R1
Example 13
N
I
OHO
OOO
Ph
Ph
N
CH2CO2Et
OHO
OOO
Ph
Ph
BrZnCH2CO2Et, Pd(Ph3P)4
HMPA/(CH2OCH3)2 (1:1)3.5 h, 40%
Example 24
BnOZnI
O
NHTrBnO
IO
NHTr
activated
Zn/Cu couple
389
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_177, © Springer-Verlag Berlin Heidelberg 2009
N
N
I
Boc
CO2t-Bu
NHBoc
NHTrN
NBoc
CO2t-Bu
NHBoc
BnO
O
PdCl2(Ph3P)2, DMA40 oC, 79%
Example 38
NBoc I1. Zn, DMA, TMSCl, BrCH2CH2Br, 65 °C
2. ArX (X = Br, OTf), PdCl2(dppf) (3 mol%) CuI (6 mol%), DMA, 80 °C 41–97%
NBoc Ar
Example 49
I OTBSMe Me
1. t-BuLi, ZnCl2, Et2O, –78 °C2.
Pd(PPh3)4, THF, 0 °C 85%
PivO I
Me Me
OTBSMe Me
PivO
MeMe
References 1. (a) Negishi, E.-I.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596−597. (b) Negi-
shi, E.-I.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821−1823. (c) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340−348. (Review).
2. Erdik, E. Tetrahedron 1992, 48, 9577−9648. (Review). 3. De Vos, E.; Esmans, E. L.; Alderweireldt, F. C.; Balzarini, J.; De Clercq, E. J. Hetero-
cycl. Chem. 1993, 30, 1245−1252. 4. Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. 1993, 32, 1326−1327. 5. Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley–VCH: Weinheim, Germany, 1998, pp 1–47. (Review). 6. Arvanitis, A. G.; Arnold, C. R.; Fitzgerald, L. W.; Frietze, W. E.; Olson, R. E.; Gilli-
gan, P. J.; Robertson, D. W. Bioorg. Med. Chem. Lett. 2003, 13, 289−291. 7. Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817−4830. 8. Corley, E. G.; Conrad, K.; Murry, J. A.; Savarin, C.; Holko, J.; Boice, G. J. Org.
Chem. 2004, 69, 5120−5123. 9. Inoue, M.; Yokota, W.; Katoh, T. Synthesis 2007, 622−637. 10. Yet, L. Negishi cross-coupling reaction. In Name Reactions for Homologations-Part I;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 70−99. (Review).
390
Nenitzescu indole synthesis 5-Hydroxylindole from condensation of p-benzoquinone and β-aminocrotonate.
N
CO2R3
O
O
H
HN
CO2R3
R2R2
R1
HO
R1
Δ
O
O
H
HN
CO2R3
R2R1
:
HO
OR1
conjugate
addition NR2
CO2R3
H
H
N
CO2R3
R2
HO
R1 N
CO2R3
R2
HO
R1
H
OH
H
Example 15
NH
HNBn
O
O
O1. acetone, rt, 48 h2. 20% TFA, CH2Cl2 86%
N
ONH2
Bn
HO
Example 26
N
CO2CH3
O
O
H
HN
CO2CH3 HOCH3NO2, rt
95%
Example 37
R2R1
O R4-NH2
rt R2R1
NHR4 O O
HOAc, rt
391
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_178, © Springer-Verlag Berlin Heidelberg 2009
N
HO
R4
R2
R1HCHO, HNMe2
ethanol, 50 oC N
HO
R4
R2
R1
NMe
Me
Example 410
O
O
OEt
ONH
NH
OEt
O
ZnCl2, CH2Cl2
reflux, 80%
N
N
HOO
OEt
HOO
OEt
References 1. Nenitzescu, C. D. Bull. Soc. Chim. Romania 1929, 11, 37−43. 2. Allen, G. R., Jr. Org. React. 1973, 20, 337−454. (Review). 3. Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.; Tomioka, S.; Kasai,
M. J. Chem. Soc., Perkin Trans. 1 1995, 2677−2681. 4. Mukhanova, T. I.; Panisheva, E. K.; Lyubchanskaya, V. M.; Alekseeva, L. M.;
Sheinker, Y. N.; Granik, V. G. Tetrahedron 1997, 53, 177−184. 5. Ketcha, D. M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2000, 41, 6253−6257. 6. Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415−2418. 7. Böhme, T. M.; Augelli-Szafran, C. E.; Hallak, H.; Pugsley, T.; Serpa, K.; Schwarz, R.
D. J. Med. Chem. 2002, 45, 3094−3102. 8. Schenck, L. W.; Sippel, A.; Kuna, K.; Frank, W.; Albert, A.; Kucklaender, U. Tetra-
hedron 2005, 61, 9129−9139. 9. Li, J.; Cook, J. M. Nenitzescu indole synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 145−153. (Review).
10. Velezheva, V. S.; Sokolov, A. I.; Kornienko, A. G.; Lyssenko, K. A.; Nelyubina, Y. V.; Godovikov, I. A.; Peregudov, A. S.; Mironov, A. F. Tetrahedron Lett. 2008, 49, 7106−7109.
392
Newman−Kwart rearrangement Transformation of phenol to the corresponding thiophenol, a variant of the Smile reaction (page 513).
OHCl NMe2
S
O NMe2
S
Δ
SHS NMe2
O
hydrolysis
O S
NMe2
S NMe2
O
O
SMe2N
The Newman−Kwart rearrangement is a member of a series of related rearrange-ments, such as the Schönberg rearrangement and the Chapman rearrangement (page 105), in which aryl groups migrate intramolecularly between nonadjacent atoms. The Schönberg rearrangement is the most similar and involves the 1,3-migration of an aryl group from oxygen to sulfur in a diarylthioncarbonate. The Chapman rearrangement involves an analogous migration but to nitrogen.
O OAr
S
Δ S OAr
O
O Ar
NAr
Δ N Ar
OAr
Schönberg rearrangement Chapman rearrangement
Example 15
OH
NaH, DMF, 78%
N Cl
SO NMe2
SPh2O, 208 oC
50 h, 55% S NMe2
O
393
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_179, © Springer-Verlag Berlin Heidelberg 2009
Example 26
OHOH
Cl NMe2
S
NaH, DMF85 oC, 1 h, 45%
OOH
NMe2
S275 oC
0.8 mmHg
55%
SOH
NMe2
O
Example 37
O
OH
1. Br2, CH2Cl2, 5 to 20 oC, 90 min.
2. CH2Cl2, 20 oC, 16 h, 37.4%
Cl NMe2
S
O
OBr
Me2N
S
dimethylaniline
218 oC, 7 h, 65.7%
O
SBr
Me2N
O
1. KOH, MeOH, reflux, 2 h
2. MeI, K2CO3, 90%
O
SBr
References 1. (a) Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410–413. (b) Newman, M. S.;
Karnes, H. A. J. Org. Chem. 1966, 31, 3980–3984. (c) Newman, M. S.; Hetzel, F. W. J. Org. Chem. 1969, 34, 3604–3606.
2. Cossu, S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith, R. A. J. Tetra-hedron 1997, 53, 6073–6084.
3. Lin, S.; Moon, B.; Porter, K. T.; Rossman, C. A.; Zennie, T.; Wemple, J. Org. Prep. Proc. Int. 2000, 32, 547–555.
4. Ponaras, A. A.; Zain, Ö. In Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A., Ed.; Wiley & Sons: New York, 1995, 2174–2176. (Review).
5. Kane, V. V.; Gerdes, A.; Grahn, W.; Ernst, L.; Dix, I.; Jones, P. G.; Hopf, H. Tetrahe-dron Lett. 2001, 42, 373–376.
6. Albrow, V.; Biswas, K.; Crane, A.; Chaplin, N.; Easun, T.; Gladiali, S.; Lygo, B.; Woodward, S. Tetrahedron: Asymmetry 2003, 14, 2813–2819.
7. Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley, J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J.; Young, M. J. Org. Proc. Res. Dev. 2004, 8, 33–44.
8. Nicholson, G.; Silversides, J. D.; Archibald, S. J. Tetrahedron Lett. 2006, 47, 6541–6544.
9. Gilday, J. P.; Lenden, P.; Moseley, J. D.; Cox, B. G. J. Org. Chem. 2008, 73, 3130–3134.
10. Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J. S. Synthesis 2008, 661–689. 11. Tilstam, U.; Defrance, T.; Giard, T.; Johnson, M. D. Org. Proc. Res. Dev. 2009, 13,
321–323.
394
Nicholas reaction Hexacarbonyldicobalt-stabilized propargyl cation is captured by a nucleophile. Subsequent oxidative demetallation then gives the propargylated product.
R1
R4
OR2
R31. Co2(CO)8
2. H+ or Lewis acid
1. NuH
2. [O]R1
R4
NuR3
R1
R4
OR2
R3
(CO)4Co Co(CO)3
CO
− CO
R1
R3OR2
Co(CO)3(CO)3CoCO
R4
− COR1
R3OR2
Co(CO)3(CO)3Co
R4
+ H
R1
R3O
Co(CO)3(CO)3Co
R4 R2H SN1
R1
R3
Co(CO)3(CO)3Co
R4R1
R3
Co(CO)3(CO)3Co
R4Nu
NuH
propargyl cation intermediate (stabilized by the hexacarbonyldicobalt com-
plex).
[O]
demetallationC O↑O R1
R3
Co(CO)2(CO)3Co
R4Nu R1
R4
NuR3
Example 1, A chromium variant of the Nicholas reaction3
1. HBF4·Et2O, CH2Cl2, −60 oC2. 5 eq. X, CH2Cl2, −60 oC, 86%
HN NO
CO2n-Bu
OH
ClCr(CO)3
X =
N N
Cl
OCO2n-Bu
Cr(CO)3
N N
Cl
OCO2H
2HCl
Zyrtec
Example 2, A Nicholas-Pauson–Khand sequence4
Me3Si
OEt
O
H
HO
Co(CO)3
(CO)3CoH
H
1. Co2(CO)8
2. Et2AlCl, 82% O
O
H
H
H
H
NMO
70%
395
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_180, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Intramolecular Nicholas reaction using chromium7
OAc
Cr(CO)3BF3•OEt2, CH2Cl2
0 oC, 3.5 h, 49% Cr(CO)3
Example 49
R
OH OH
O
O
O O
H HMe
H
OHMe
HOH H H
Me
OTIPS
1. Co2(CO)8, 100%
2. BF3•OEt2, 75%
O
O
O O
H HMe
H
OHMeH H H
Me
OTIPS
OR
OH
H
(OC)3Co
(OC)3Co
References 1. Nicholas, K. M.; Pettit, R. J. Organomet. Chem. 1972, 44, C21–C24. 2. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214. (Review). 3. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837–4840. 4. Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc.
1997, 119, 4353–4363. 5. Teobald, B. J. Tetrahedron 2002, 58, 4133−4170. (Review). 6. Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org. Lett. 2003, 5, 625–628. 7. Ding, Y.; Green, J. R. Synlett 2005, 271–274. 8. Pinacho Crisóstomo, F. R.; Carrillo, R.; Martin, T.; Martin, V. S. Tetrahedron Lett.
2005, 46, 2829–2832. 9. Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205–1208. 10. Shea, K. M. Nicholas reaction. In Name Reactions for Homologations-Part I; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 284−298. (Review).
396
Nicolaou IBX dehydrogenation α,β-Unsaturation of aldehydes and ketones mediated by stoichiometric amounts of o-iodoxybenzoic acid (IBX), alternative to the Saegusa oxidation (page 482).
R1
O
R3
R2
IO
O
OHO
IBX = o-iodoxybenzoic acid R1
O
R3
R2
A SET mechanism has also been proposed. Additionally, silyl enol ethers are also viable substrates.
R1
O
R3
R2
R1
HO
R3
R2 IO
O
O
HOtautomerization
R1
O
R3
R2IOHO
O OH
H
R1
O
R3
R2
Example 11a
H
OH
H H
H
OH
H H
IBXfluorobenzene
DMSO
65 °C, 24 h80%
Example 23
O
OH
H
TBSO
MeO2C CO2Me
O
OH
H
TBSO
MeO2C CO2Me
IBX
DMSO, Tol.80 °C, 3 h, 52%
397
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_181, © Springer-Verlag Berlin Heidelberg 2009
Example 37
NMe
NO
MeO
H
H
H
HO
IBX
Tol., DMSO70 °C
NMe
NO
MeO
H
H
H
HO
Example 4, o-Methyl-IBX (Me-IBX)9
OI
OMeO
Me OHO
R1S
R2CH3CN, reflux
40−90%
R1S
R2
O
Example 5, Stabilized IBX (SIBX)10
OH
MeO OMe
O
O
MeO OMe
O
OHO
MeO OMe
O
OH
1 : 1
SIBX, THF
rt, 98%
References 1. (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596–
7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 993–996. (c) Nicolaou, K. C.; Gray, D. L.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996–1000.
2. Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737–1740. 3. Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755–767. 4. Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839–9846. 5. Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem.,
Int. Ed. 2004, 43, 1559–1562. 6. Smith, N. D.; Hayashida. J.; Rawal, V. H. Org. Lett. 2005, 7, 4309–4312. 7. Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339–3342. 8. Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342–5344. 9. Moorthy, J. N.; Singhal, N.; Senapati, K. Tetrahedron Lett. 2008, 49, 80–84. 10. Pouységu, L.; Marguerit, M.; Gagnepain, J.; Lyvinec, G.; Eatherton, A. J.; Quideau, S.
Org. Lett. 2008, 10, 5211–5214.
398
Noyori asymmetric hydrogenation Asymmetric reduction of carbonyls and alkenes via hydrogenation, catalyzed by a ruthenium(II) BINAP complex.
O
R R1
R3 R4
R2 R3
OH
R R1
R4 R5
R2 R3
*
*
*
H2, (R)- or (S)-BINAP
Metal [Ru(II) or Rh(I)]
PPh2
PPh2
RuCl2L2(R)-BINAP-Ru =
[RuCl2(binap)(solv)2]
H2
− HCl[RuHCl(binap)(solv)2]
The catalytic cycle:
R
OR1
O
O
[RuHCl(binap)(solv)2]
(binap)ClHRu
R
OR1
O
O(binap)ClRu
H+
[RuCl(binap)(solv)2]+
R OR1
OH O
solv
R OR1
O O
solv
H2
H+, solv
HH
Example 11b
OH
Ru[(S)-BINAP](CF3CO2)2
30 atm H2, rt, 96% ee OH
399
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_182, © Springer-Verlag Berlin Heidelberg 2009
Example 21c
O
Br
Ru[(R)-BINAP]Cl2
100 atm H2, rt, 92% eeOH
Br Example 39
OO
H HOMe8
O O5 bar H2
3.2 mol% Ru(II)-(+)-(R)-BINAP
MeOH, 70 oC, 24 h, 90%
OO
H HOMe8
OH O
Example 410
C5H11 OMe
O O100 atm H2
Ru[(S)-BINAP]Cl2
EtOH, rt, 75%98% ee
C5H11 OMe
OH O
References
1. (a) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117−7119. Ryoji Noyori (Japan, 1938−) and William S. Knowles (USA, 1917−) shared half of the Nobel Prize in Chemistry in 2001 for their work on chirally catalyzed hydrogenation reactions. K. Barry Sharpless (USA, 1941−) shared the other half for his work on chirally catalyzed oxidation reactions. (b) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R.; J. Am. Chem. Soc. 1987, 109, 1596−1598. (c) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629−631. (d) Noyori, R.; Ohkuma, T.; Kitamura, H.; Ta-kaya, H.; Sayo, H.; Kumobayashi, S.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856−5858. (e) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40−73. (Review). (f) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008−2022. (Review, No-bel Prize Address).
2. Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Ojima, I., ed.; Wiley: New York, 1994, Chapter 2. (Review).
3. Chung, J. Y. L.; Zhao, D.; Hughes, D. L.; McNamara, J. M.; Grabowski, E. J. J.; Rei-der, P. J. Tetrahedron Lett. 1995, 36, 7379−7382.
4. Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry 1998, 9, 2015−2018.
5. Berkessel, A.; Schubert, T. J. S.; Mueller, T. N. J. Am. Chem. Soc. 2002, 124, 8693−8698.
6. Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733−736. 7. Ishibashi, Y.; Bessho, Y.; Yoshimura, M.; Tsukamoto, M.; Kitamura, M. Angew.
Chem., Int. Ed. 2005, 44, 7287−7290. 8. Lall, M. S. Noyori asymmetric hydrogenation. In Name Reactions for Functional
Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 46−66. (Review).
9. Bouillon, M. E.; Meyer, H. H. Tetrahedron 2007, 63, 2712−2723. 10. Case-Green, S. C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Tetra-
hedron: Asymmetry 2008, 19, 2620−2631.
400
Nozaki–Hiyama–Kishi reaction Cr−Ni bimetallic catalyst-promoted redox addition of vinyl halides to aldehydes.
R1 X
R1 = alkenyl, aryl, allyl, vinyl, propargyl, alkynyl, allenylR2 = R3 = aryl, alkyl, alkenyl, HX = Cl, Br, I, OTfSolvent = DMF, DMSO, THF
Cr(II)Cl2aprotic solvent R1 Cr(III)ClX
organochromium(III)reagent
R2 R3
O
allylic orhomoallylic
alcohols
R1 R3
OH
R2
The catalytic cycle:2
R1 X
R1 R3
OCr(III)X2
R2
R2 R3
O
R1 Ni(II) X
Ni(II)Cl2
Ni(0)
R1 Cr(III)Cl2
Cr(III)Cl3
oxidativeadditiontransmetallation
2Cr(II)Cl2
2Cr(III)Cl3
Example 13
AcOCHO
OTHPI OTBDPS
AcOOTBDPS
OTHP
OH
10 eq CrCl2, cat. NiCl2
DMSO, 25 oC, 12 h, 80%
Example 25
4 eq CrCl20.008 eq NiCl2
DMF, rt, 15 h35%
O
OOHC
O
OTf
O
O
OOH
401
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_183, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Intramolecular Nozaki–Hiyama–Kishi reaction8
I
CHOOTBDMS
5 equiv CrCl2, NiCl2
THF, 84%
OH
OTBDMS
Example 4, Intramolecular Nozaki–Hiyama–Kishi reaction9
I
O
O
1. HCl, THF, 0.003 M dark
2. CrCl2, NiCl2, DMSO 0.0025 M, 50 oC 37%, 2 steps
HO
References 1. (a) Okude, C. T.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99,
3179−3181. Hitosi Nozaki and T. Hiyama are professors at the Japanese Academy. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281−5284. Kazuhiko Takai was Prof. Nozaki’s student during the discovery of the reaction and is a professor at Okayama University. (c) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644−5646. Yoshito Kishi at Harvard independently discovered the catalytic effect of nickel during his total synthesis of polytoxin. (d) Takai, K.; Tagahira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048−6050. (e) Kress, M. H.; Ruel, R.; Miller, L. W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999−6002.
2. Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349−12357. (The catalytic cy-cle).
3. Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565−566. 4. Fürstner, A. Chem. Rev. 1999, 99, 991−1046. (Review). 5. Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen, J. H.; Hiem-
stra, H. J. Chem. Soc., Perkin Trans. 1 2001, 2250−2256. 6. Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson, I. Angew. Chem.,
Int. Ed. 2003, 42, 1032−1035. 7. Takai, K. Org. React. 2004, 64, 253−612. (Review). 8. Karpov, G. V.; Popik, V. V. J. Am. Chem. Soc. 2007, 129, 3792−3793. 9. Valente, C.; Organ, M. G. Chem. Eur. J. 2008, 14, 8239−8245. 10. Yet, L. Nozaki–Hiyama–Kishi reaction. In Name Reactions for Homologations-Part I;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 299−318. (Review).
402
Nysted reagent
403
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_184, © Springer-Verlag Berlin Heidelberg 2009
The Nysted reagent, cyclo-dibromodi- -methylene( -tetrahydrofuran)trizinc, is used for the olefination of ketones and aldehydes.
OZn
Zn
ZnBrBr
Example 1, The Wittig reagent opened the lactone:6
O
OMOMTBDPSO
O
O
O
O
OMOMTBDPSO
O
CH2
O
excessZn(CH2ZnBr)2•THF
TiCl4, THFreflux, 64%
Example 28
1.5 equivZn(CH2ZnBr)2•THF
1.5 equiv TiCl4THF, reflux
O
OH
OTBS
CH2
OH
OTBS
OH
CH2
OTBS
42% 14%
Example 39
2 equivZn(CH2ZnBr)2•THF
2 equiv TiCl4THF, 0 oC to rt
1 h, 74%
O
OHTBDPSO
BnO
H
CH2
OHTBDPSO
BnO
H
References 1. Nysted, L. N. US Patent 3,865,848 (1975). 2. Tochtermann, W.; Bruhn, S.; Meints, M.; Wolff, C.; Peters, E.-M.; Peters, K.;
von Schnering, H. G. Tetrahedron 1995, 51, 1623 1630. 3. Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313 315. 4. Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.;
Wu, X. M.; Funakoshi, K.; Sakai, K.; Suemune, H. J. Org. Chem. 2000, 65, 5806 5816.
5. Tarraga, A.; Molina, P.; Lopez, J. L.; Velasco, M. D. Tetrahedron Lett. 2001, 42, 8989 8992.
6. Aïssa, C.; Riveiros, R.; Ragot, J.; Fürstner, A. J. Am. Chem. Soc. 2003, 125, 15512 15520.
7. Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org. Lett. 2003, 5, 89 92. 8. Paquette, L. A. Hartung, R. E., Hofferberth, J. E., Vilotijevic, I., Yang, J. J. Org.
Chem. 2004, 69, 2454 2460. 9. Hanessian, S.; Mainetti, E.; Lecomte, F. Org. Lett. 2006, 8, 4047 4049.
Oppenauer oxidation Alkoxide-catalyzed oxidation of secondary alcohols. Reverse of the Meerwein–Ponndorf–Verley reduction.
OR1 R2
OH Al(Oi-Pr)3
R1 R2
O OH
O
R1 R2
OH
Al(Oi-Pr)2
coordinationR1 R2
OOHAl(Oi-Pr)2
Oi-Pr
:
O
H
OAl
R1R2
Oi-Pri-PrO
H OAlO
Oi-Pr
Oi-PrR1
R2
hydride
transfer R1 R2
O OH
cyclic transition state
Example 1, Mg-Oppenauer oxidation3
OOH 1. EtMgBr, i-Pr2O
2. PhCHO, 60%
Example 26
(i-PrO)2AlO2CCF3p-O2N-Ph-CHO
PhH, rt, 24 h, 70%
OH
OH
O
OH
Example 3, Mg-Oppenauer oxidation8
RMgCl•LiCl
−20 oC R'CHO
OMgClR
R'
PhCHO
0 oC to rtO
R
R'PhCH2OMgCl
H O
MgO
H
Ph
R
R'
ClH O
MgO
H
Ph
R
R'
Cl
404
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_185, © Springer-Verlag Berlin Heidelberg 2009
Example 410
O
CF3H3C
AlOR
R1 H
H
R
OH
R1
O
CF3H3C2 equiv
EtOAlEt2
CH2Cl2, rt, 1 h
O
R1R
H
H2C
OH
CF3
References 1. Oppenauer, R. V. Rec. Trav. Chim. 1937, 56, 137−144. Rupert V. Oppenauer
(1910−), born in Burgstall, Italy, studied at ETH in Zurich under Ruzicka and Reich-stei, both Nobel laureates. After a string of academic appointments around Europe and a stint at Hoffman−La Roche, Oppenauer worked for the Ministry of Public Health in Buenos Aires, Argentina.
2. Djerassi, C. Org. React. 1951, 6, 207−235. (Review). 3. Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769−772. 4. Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4,
2669−2672. 5. Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org. Chem. 2003, 68, 1601−1602. 6. Auge, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003, 44, 819−822. 7. Hon, Y.-S.; Chang, C.-P.; Wong, Y.-C. Byrne, B.; Karras, M. Tetrahedron Lett. 2004,
45, 3313−3315. 8. Kloetzing, R. J.; Krasovskiy, A.; Knochel, P. Chem. Eur. J. 2006, 13, 215−227. 9. Fuchter, M. J. Oppenauer oxidation. In Name Reactions for Functional Group Trans-
formations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 265−373. (Review).
10. Mello, R.; Martinez-Ferrer, J.; Asensio, G.; Gonzalez-Nunez, M. E. J. Org. Chem. 2008, 72, 9376−9378.
11. Borzatta, V.; Capparella, E.; Chiappino, R.; Impala, D.; Poluzzi, E.; Vaccari, A. Cat. Today 2009, 140, 112−116.
405
Overman rearrangement Stereoselective transformation of allylic alcohol to allylic trichloroacetamide via trichloroacetimidate intermediate.
R R1
OH cat. NaH
Cl3CCNR R1
O
CCl3
HNΔ
R R1
HN O
CCl3
or Hg(II) or Pd(II)
trichloroacetimidate
R R1
OH
HH2↑
R R1
O
N CCl3
R R1
OH
R R1
O
CCl3
N
OHN
CCl3
R
R1
H
R R1
O
CCl3
HNR R1
HN O
CCl3Δ, [3,3]-sigmatropic
rearrangement
Example 15
O
O
O
O
OH
HO
Cl3CCN, DBU
CH2Cl2, −78 oC
O
O
O
O
OH
OCl3C
HN
K2CO3, p-xylene
reflux, 90%, 2 steps
O
O
O
O
OH
HN
O
Cl3C
Example 26
K2CO3, p-xylene
reflux, 77%
O
TBDMSO
OCl3C
NHO
O
TBDMSO
ONHCl3C
O
406
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_186, © Springer-Verlag Berlin Heidelberg 2009
Example 37
O
OO
OOBn
OHO
OO
OOBn
HN CF3
O
CF3CN, n-BuLi;toluene, 120 °C
30%
Example 49
DBU, CCl3CN
toluene, reflux51%
NMe F
(CH2)3OTBDPS
O O OH
Bn
NMe F
(CH2)3OTBDPS
O O
Bn
NHC(O)CCl3
References 1. (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597−599. (b) Overman, L. E. J. Am.
Chem. Soc. 1976, 98, 2901−2910. (c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218–224. (Review).
2. Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863−866. 3. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4,
151−154. 4. Reilly, M.; Anthony, D. R.; Gallagher, C. Tetrahedron Lett. 2003, 44, 2927−2930. 5. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433−436. 6. Montero, A.; Mann, E.; Herradon, B. Tetrahedron Lett. 2005, 46, 401−405. 7. Hakansson, A. E.; Palmelund, A.; Holm, H.; Madsen, R. Chem. Eur. J. 2006, 12,
3243−3253. 8. Bøjstrup, M.; Fanejord, M.; Lundt, I. Org. Biomol. Chem. 2007, 5, 3164−3171. 9. Lamy, C.; Hifmann, J.; Parrot-Lopez, H.; Goekjian, P. Tetrahedron Lett. 2007, 48,
6177−6180. 10. Wu, Y.-J. Overman rearrangement. In Name Reactions for Homologations-Part II; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 210−225. (Review).
407
Paal thiophene synthesis Thiophene synthesis from addition of a sulfur atom to 1,4-diketones and subse-quent dehydration.
H3C CH3
O O SH3CCH3
P2S5, tetralin
reflux
The reaction now is frequently carried out using the Lawesson’s reagent. For the mechanism of carbonyl to thiocarbonyl transformation, see Lawesson’s reagent on page 328.
O
H3CCH3
O
S
H3CCH3
XX = O or S
P2S5 tautomerization
SH
H3CCH3
X
S
CH3
XHH3C
H
SCH3
H3C− H2X
Example 12
O
PhO
NLawesson's reagent
110 ºC, 10 min, 82%
S NPh
Example 23
PhO
O
PhPh
O Ph
O
SS
Ph
Ph Ph
Ph
Lawesson's reagentchlorobenzene, reflux, 36 h
69%
References 1. (a) Paal, C. Ber. 1885, 18, 2251−2254. (b) Paal, C. Ber. 1885, 18, 367−371. 2. Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T. P.; Lawesson, S.-
O. Chem. Lett. 1983, 809−810. 3. Parakka, J. P.; Sadannandan, E. V.; Cava, M. P. J. Org. Chem. 1994, 59, 4308−4310. 4. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.;
Nagai, M. J. Med. Chem. 2000, 43, 409−423. 5. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J. J. Org. Chem. 2001, 66,
7283−7286. 6. Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925−7929. 7. Mullins, R. J.; Williams, D. R. Paal Thiophene Synthesis. In Name Reactions in Het-
erocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 207−217. (Review).
8. Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008, xii, 17−29.
408
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_187, © Springer-Verlag Berlin Heidelberg 2009
Paal–Knorr furan synthesis Acid-catalyzed cyclization of 1,4-diketones to form furans.
RR3
O
O OR R3
cat. HR2
R1
R1 R2
or P2O5
RR3
O
OR1
H
:
R2
O R3
R1 R2
RHO
: H3O
OR R3
R1 R2
OR R3
R2R1H
H
Example 13
O
O
OTsOH
toluene, reflux
Cl
N
F
ClF
N
Example 26
O
n-Bu98%
n-Bu
O
O
OMe
MeO
OMe
p-TsOH
toluene
MeO OMe
MeO
Example 39
CH3O
O
NH
phosphoric acid
130−140 oC, 4−6 hNH
O CH3
409
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_188, © Springer-Verlag Berlin Heidelberg 2009
Example 410
RO
CH CSMe
OR
SnCl2, H
72−89% O
SMe
R R O
SMe
R R
BrBr2, CHCl3
88−92%
30% HBr−HOAc, CHCl3, 58−64%
References 1. (a) Paal, C. Ber. 1884, 17, 2756−2767. (b) Knorr, L. Ber. 1885, 17, 2863−2870. (c)
Paal, C. Ber. 1885, 18, 367−371. 2. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Per-gamon: New York, 1996; Vol. 2, 351−393. (Review).
3. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689−2694.
4. Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry, Springer: New York, 1999; Vol. 2, 83−84. (Review).
5. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge, 2000; 308−309. (Review).
6. Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838−3848.
7. König, B. Product Class 9: Furans. In Science of Synthesis: Houben−Weyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183−278. (Review).
8. Shea, K. M. Paal–Knorr Furan Synthesis. In Name Reactions in Heterocyclic Chemis-try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 168−181. (Re-view).
9. Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008, xii, 17−29. 10. Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y. J. Org. Chem. 2008, 73,
3377−3383.
410
Paal–Knorr pyrrole synthesis Reaction between 1,4-diketones and primary amines (or ammonia) to give pyr-roles. A variation of the Knorr pyrazole synthesis (page 317).
RR1
O
O
R2 NH2
NR2
R R1
RR1
O
OHHNRR1
O
O
R2H2N:
R2
slowN
HO
R
OH
R1
R2
:
NR2
R1HO
R
H H
NR2
R R1
NR2
R1
H H
NR2
R1HO
R
H
:
R
Example 14
NF
CONHPh
OEtEtO
O
OF
CONHPh
H2N OEt
OEt
1 eq. pivalic acidTHF, reflux, 43%
N
CO2
F
HO
HO
Ca2+
2
O
HN
Lipitor
411
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_189, © Springer-Verlag Berlin Heidelberg 2009
Example 25
O
N
OCl
F
NH4OAc
NH
N
F Cl
HOAc110 °C
90%
Example 39
OOOMeOOMeO
NH
NH4OAc, CSA
MeOH, 50 oC93%
Example 410
HO
O
NH
NH
NR
RNH2, AcOH, MeOH, 40 oC; orRNH2, AcOH, NaOAc, toluene, 60 oC; or
NH4OAc, 28% NH4OH, EtOH, 40 oC30−96%
References 1. (a) Paal, C. Ber. 1885, 18, 367−371. (b) Paal, C. Ber. 1885, 18, 2251−2254. (c) Knorr,
L. Ber. 1885, 18, 299−311. 2. Corwin, A. H. Heterocyclic Compounds Vol. 1, Wiley, NY, 1950; Chapter 6. (Re-
view). 3. Jones, R. A.; Bean, G. P. The Chemistry of Pyrroles, Academic Press, London, 1977,
pp 51−57, 74−79. (Review). 4. (a) Brower, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.;
Roth, B. D. Tetrahedron Lett. 1992, 33, 2279-2282. (b) Baumann, K. L.; Butler, D. E.; Deering, C. F.; Mennen, K. E.; Millar, A.; Nanninga, T. N.; Palmer, C. W.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2279, 2283−2284.
5. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689−2694.
6. Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2001, 3, 3297−3300. 7. Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, Z. Synlett 2003, 75−78. 8. Gribble, G. W. Knorr and Paal−Knorr Pyrrole Syntheses. In Name Reactions in Het-
erocyclic Chemistry; Li, J. J., Corey, E. J., Eds, Wiley & Sons: Hoboken, NJ, 2005, 77−88. (Review).
9. Salamone, S. G.; Dudley, G. B. Org. Lett. 2005, 7, 4443−4445. 10. Fu, L.; Gribble, G. W. Tetrahedron Lett. 2008, 49, 7352−7354.
412
Parham cyclization The Parham cyclization is the generation by halogen–lithium exchange of aryllith-iums and heteroaryllithiums, and their subsequent intramolecular cyclization onto an electrophilic site.
E
X
E
LiRLi
E.g.
ICH3O
CH3ON
ONEt2
2.2 eq. t-BuLi
THF, −78 oC→rt
ICH3O
CH3ON
ONEt2
halogen-metal
exchange I
LiCH3O
CH3ON
Et2N OCH3O
CH3ON
CH3O
CH3ON
OOEt2N
cyclization
The fate of the second equivalent of t-BuLi:
I
H I
Example 12
O O
OBr
MeO
MeO OMe MeO OMe
O
MeOO NMe2
Ot-BuLi
THF, –95 °C92%
Example 24
O
O Br
O
O
O
OPMB
O
n-BuLi
Et2O, –78 °C64%
O
O
OPMBO
OO
OHH
413
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_190, © Springer-Verlag Berlin Heidelberg 2009
Example 35
2 eq. n-BuLi
THF, −78 oC2.5 h, 83%
I
MeOOMe
N
O
ON
MeO
MeOO
Example 49
O Br
N OMe
O
PMB
t-BuLi, THF, −100 oC
Ar, 30 min., 55%
ON
O
PMB
References 1. (a) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1975, 40, 2394−2399. Wil-
liam E. Parham was a professor at Duke University. (b) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1976, 41, 1184−1186. (c) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300−305. (Review).
2. Paleo, M. R.; Lamas, C.; Castedo, L.; Domínguez, D. J. Org. Chem. 1992, 57, 2029–2033.
3. Gray, M.; Tinkl, M.; Snieckus, V. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Exeter, 1995; Vol. 11; p 66. (Review).
4. Gauthier, D. R., Jr.; Bender, S. L. Tetrahedron Lett. 1996, 37, 13–16. 5. Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E. J. Org. Chem. 1997,
62, 2080−2092. 6. Mealy, M. M.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59−67. (Review). 7. Sotomayor, N.; Lete, E. Current Org. Chem. 2003, 7, 275−300. (Review). 8. González-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69,
3875−3885. 9. Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Org. Biomol.
Chem. 2005, 3, 2305−2309. 10. Gribble, G. W. Parham cyclization. In Name Reactions for Homologations-Part II; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 749−764. (Review).
414
Passerini reaction Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford α-acyloxycarboxamides. Cf. Ugi reaction.
R1 N CR2 R3
OR4 CO2H R1
HN
O R4O
R3R2 O
isocyanide
O
R4 O
OH
CN
R1
OO
ON
R1
R4R3R2
HR2
R3
R2 R3
OR4 CO2H
R1
HN
O R4
O
R3R2 OO
ON
R1
R3R2O
R4
H
H
acyl
transfer
Example 13
MeO
MeO
OMe
OMe
OMeOMe
Ts
CNTFA, PhH
rt, 2 h, 93%
MeO
MeO
OMe HN
O
Ts
OMe
OMe Example 25
CHO
CN
HOAc, THF
rt, 93% HNO
EtAcO
Example 36
BocNH CO2HCN CO2Bn
Me
Me
FmocNH
Me
CHO
CbzNH
415
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_191, © Springer-Verlag Berlin Heidelberg 2009
FmocNH
Me
O
O
NH
CO2Bn
Me
Me
O
NHBocCbzNH
CH2Cl2, 0 °C → rt
3–5 days, 80%
Example 47
CNNH
O
CO2Me
Ph
OBn(Cl2)
BocHN CHO
NH
NH2NNO2
NAlloc
OH
O
CH2Cl2, 0 °C → rt
2 days, 59% BocHNO
O
NH
HN
CO2MeO
Ph
O
NAlloc
OBn(Cl2)NH
NH2NNO2
References 1. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126−129. (b) Passerini, M. Gazz. Chim. Ital.
1921, 51, 181−188. Mario Passerini (b, 1891) was born in Scandicci, Italy. He obtained his Ph.D. In chemistry and pharmacy at the University of Florence, where he was a professor for most of his career.
2. Ferosie, I. Aldrichimica Acta 1971, 4, 21. (Review). 3. Barrett, A. G. M.; Barton, D. H. R.; Falck, J. R.; Papaioannou, D.; Widdowson, D. A.
J. Chem. Soc., Perkin Trans. 1 1979, 652−661. 4. Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, p.1083. (Review). 5. Bock, H.; Ugi, I. J. Prakt. Chem. 1997, 339, 385−389. 6. Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985–986. 7. Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301–3304. 8. Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631−1634. 9. Banfi, L.; Riva, R. Org. React. 2005, 65, 1−140. (Review). 10. Klein, J. C.; Williams, D. R. Passerini reaction. In Name Reactions for Homologa-
tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 765−785. (Review).
416
Paternó–Büchi reaction Photoinduced electrocyclization of a carbonyl with an alkene to form polysubsti-tuted oxetane ring systems
R R1
O hv O
RR1
oxetane
R R1
O hv
R R1
O
n, π* triplet
O
RR1
O
RR1
O
RR1
triplet diradical singlet diradical Example 12
Me
PhO
O
O
PhMe
O
O
O
O
OH
*ROOChν, C6H6, 99%Ph H
Example 24
O
Ph Ph
i-Pr
SMe
(E/Z = 6/1)
hν, C6H6
73%
OPh
Ph
i-Pr
SMe
Example 36
H
O
hv, MeCN
82%H
O
417
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_192, © Springer-Verlag Berlin Heidelberg 2009
Example 48
OH
OO
solvent
hv
100%O
O
PhPh
HO
References 1. (a) Paternó, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39, 341−361. Emaubuele Paternó
(1847−1935) was born in Palermo, Sicily, Italy. (b) Büchi, G.; Inman, C. G.; Lipin-sky, E. S. J. Am. Chem. Soc. 1954, 76, 4327−4331. George H. Büchi (1921−1998) was born in Baden, Switzerland. He was a professor at MIT when he elucidated the structure of oxetanes, the products from the light-catalyzed addition of carbonyl com-pounds to olefins, which had been observed by E. Paternó in 1909. Büchi died of heart failure while hiking with his wife in his native Switzerland.
2. Koch, H.; Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983, 24, 3217−3220. 3. Carless, H. A. J. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum
Press: New York, 1984, 425. (Review). 4. Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem. Soc., Chem. Commun. 1987, 964−965. 5. Porco, J. A., Jr.; Schreiber, S. L. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 5, 151−192. (Review). 6. de la Torre, M. C.; Garcia, I.; Sierra, M. A. J. Org. Chem. 2003, 68, 6611−6618. 7. Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70−75. (Re-
view). 8. D’Auria, M.; Emanuele, L.; Racioppi, R. Tetrahedron Lett. 2004, 45, 3877−3880. 9. Liu, C. M. Paternó–Büchi Reaction. In Name Reactions in Heterocyclic Chemistry; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 44−49. (Review). 10. Cho, D. W.; Lee, H.-Y.; Oh, S. W.; Choi, J. H.; Park, H. J.; Mariano, P. S.; Yoon, U.
C. J. Org. Chem. 2008, 73, 4539−4547.
418
Pauson−Khand reaction Formal [2 + 2 +1] cycloaddition of an alkene, alkyne, and carbon monoxide medi-ated by octacarbonyl dicobalt to form cyclopentenones.
O
toluene, 60−80 oC4−6 d, 60%
O
O
Co(CO)3Co(CO)3
HCo2(CO)8
Co(CO)3Co(CO)3
H
H(CO)4Co Co(CO)3
CO
− COCo(CO)3
Co(CO)3
H
OC
− COO
hexacarbonyldicobalt complex
Co(CO)3Co(CO)2
H
− CO OO+ CO
insertiontoward CH (CO)3Co
(CO)3Co H
HH
+ CO
insertion
exo complex sterically-favored isomer
O(CO)3Co H
(CO)3Co
OO
(CO)3Co HO
(CO)3Co
reductive elimination
− Co2(CO)6
O
O
reductive
elimination
Example 13
benzene, 65 oC16 h, 23%
Co2(CO)8OO
O
O
O
Example 2, A catalytic version6
NTs
5 mol% Co2(CO)820 mol% P(OPh)3
3 atm CO, DME120 oC, 48 h, 94%
NTs O
419
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_193, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Intramolecular Pauson−Khand reaction9
NH
N CbzCo2(CO)8, DMSO
THF, 65 oC, 94% NH
NCbz
O
H
Example 4, Intramolecular Pauson−Khand reaction10
Co2(CO)8
5 equiv Me3NO•2H2O
THF/H2O (3:1), 0 oC to rt7 h, 71%
NS
NO2O ON
SNH2O O
O
H
References 1. (a) Pauson, P. L.; Khand, I. U.; Knox, G. R.; Watts, W. E. J. Chem. Soc., Chem. Com-
mun. 1971, 36. Ihsan U. Khand and Peter L. Pauson were at the University of Strath-clyde, Glasgow in Scotland. (b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 975−977. (c) Bladon, P.; Khand, I. U.; Pauson, P. L. J. Chem. Res. (S), 1977, 9. (d) Pauson, P. L. Tetrahedron 1985, 41, 5855−5860. (Review).
2. Schore, N. E. Chem. Rev. 1988, 88, 1081−1119. (Review). 3. Billington, D. C.; Kerr, W. J.; Pauson, P. L.; Farnocchi, C. F. J. Organomet. Chem.
1988, 356, 213−219. 4. Schore, N. E. In Comprehensive Organic Synthesis; Paquette, L. A.; Fleming, I.; Trost,
B. M., Eds.; Pergamon: Oxford, 1991, Vol. 5, p.1037. (Review). 5. Schore, N. E. Org. React. 1991, 40, 1−90. (Review). 6. Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, J. J. Am. Chem. Soc. 1994, 116, 3159−3160. 7. Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263−3283. (Review). 8. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433−436. 9. Miller, K. A.; Martin, S. F. Org. Lett. 2007, 9, 1113−1116. 10. Kaneda, K.; Honda, T. Tetrahedron 2008, 64, 11589−11593. 11. Gao, P.; Xu, P.-F.; Zhai, H. J. Org. Chem. 2009, 74, 2592−2593.
420
Payne rearrangement The isomerization of 2,3-epoxy alcohol under the influence of a base to 1,2-epoxy-3-ol is referred to as the Payne rearrangement. Also known as epoxide mi-gration.
OHO
aq. NaOHR
OH
O
R
OO
HOH
OOR R
R
O
O
SN2 H
workup R
OH
O Example 12
TrOHO
O
HOOTr
NaOMe, MeOH
reflux, 1 h, 84%TrO
HOOTr
OOH
Example 23
BzOCO2Me
OBzOTs K2CO3, MeOH
rt, 2 h, 98% CO2Me
OH
O
Example 3, Aza-Payne rearrangement8
N
HO H
H
Ts
NaOH, t-BuOH/H2O
rt, 4 h, 98%
O
HTsHN
H
Example 4, Aza-Payne rearrangement9
N
H
Me
H
OHBoc
0.28 M NaOH, t-BuOH/H2O/THF (4:5:1),
rt, 30%, or
NaH, THF/HMPA (10:1),
rt, 80%
OCH3
OCH3
OH
NHBoc
MeOCH3
OCH3
421
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_194, © Springer-Verlag Berlin Heidelberg 2009
References 1. Payne, G. B. J. Org. Chem. 1962, 27, 3819−3822. George B. Payne was a chemist at
Shell Development Co. in Emeryville, CA. 2. Buchanan, J. G.; Edgar, A. R. Carbohydr. Res. 1970, 10, 295−302. 3. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.;
Hammerstrom, S. J. Am. Chem. Soc. 1980, 102, 1436−1439, and 3663−3665. 4. Ibuka, T. Chem. Soc. Rev. 1998, 27, 145−154. (Review). 5. Hanson, R. M. Org. React. 2002, 60, 1−156. (Review). 6. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073−4076. 7. Bilke, J. L.; Dzuganova, M.; Froehlich, R.; Wuerthwein, E.-U. Org. Lett. 2005, 7,
3267−3270. 8. Feng, X.; Qiu, G.; Liang, S.; Su, J.; Teng, H.; Wu, L.; Hu, X. Russ. J. Org. Chem.
2006, 42, 514−500. 9. Feng, X.; Qiu, G.; Liang, S.; Teng, H.; Wu, L.; Hu, X. Tetrahedron: Asymmetry 2006,
17, 1394−1401. 10. Kumar, R. R.; Perumal, S. Payne rearrangement. In Name Reactions for Homologa-
tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 474−488. (Review).
422
Pechmann coumarin synthesis Lewis acid-mediated condensation of phenol with β-ketoester to produce cou-marin.
OH
R OEt
O O AlCl3O
R
O
O:H EtO
R
O
OAlCl3 O O
ROH
:
O O
O
RH
H
EtO
R
O
O
AlCl3
O
Michael
addition
O OO
R
O
R OH2
HO O
R OH
H
H
Example 16
OH
OEt
O O
[bimim]Cl•2AlCl3130 oC, 35 min., 90% O OHO HO
Example 28
OH
OH
OEt
O O
BiCl3, 75 oC, 2 h, 66%
OH
O O
O O
References 1. von Pechmann, H.; Duisberg, C. Ber. 1883, 16, 2119. Hans von Pechmann
(1850−1902) was born in Nürnberg, Germany. After his doctorate, he worked with Frankland and von Baeyer. Pechmann taught at Munich and Tübingen. He committed suicide by taking cyanide.
2. Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1990, 2151–2997. 3. Hua, D. H.; Saha, S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J. Org. Chem.
1992, 57, 399–403. 4. Li, T.-S.; Zhang, Z.-H.; Yang, F.; Fu, C.-G. J. Chem. Res., (S) 1998, 38–39. 5. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285–9287. 6. Khandekar, A. C.; Khandilkar, B. M. Synlett. 2002, 152–154. 7. Smitha, G.; Sanjeeva Reddy, C. Synth. Commun. 2004, 34, 3997–4003. 8. De, S. K.; Gibbs, R. A. Synthesis 2005, 1231–1233. 9. Manhas, M. S.; Ganguly, S. N.; Mukherjee, S.; Jain, A. K.; Bose, A. K. Tetrahedron
Lett. 2006, 47, 2423–2425. 10. Rodriguez-Dominguez, J. C.; Kirsch, G. Synthesis 2006, 1895–1897.
423
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_195, © Springer-Verlag Berlin Heidelberg 2009
Perkin reaction Cinnamic acid synthesis from aryl aldehyde and acetic anhydride.
Ar CHO Ac2OAcONa
Ar O
OAc O O OH
H2O Ar OH
O
cinnamic acid
O
O OH
OAcenolate
formationO
O O
H Ar
O
aldol
condensation Ar O
O O
O
intramolecular
acyl transfer Ar O
O O
O
Ar O
O O
O
H
O
O O
Ar O
O O O
O
H
OH
acyl
transferAr O
OE2
elimination
O
OH
AcOH
Ar O
O
O
OHOO
Ar Ar OH
OHOAc
Example 17
CHO
MeO
MeO
MeOCO2H
Ac2O, Et3N, 90 oC
5 h, 66%
MeO
MeO
H
CO2H
MeO
Example 29
ClF2C
PhO
Ac2O, Δ
AcONa, 46%
ClF2C
Ph CO2H
424
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_196, © Springer-Verlag Berlin Heidelberg 2009
References 1. Perkin, W. H. J. Chem. Soc. 1868, 21, 53. William Henry Perkin (1838−1907), born
in London, England, studied under A. W. von Hofmann at the Royal College of Chem-istry. In an attempt to synthesize quinine in his home laboratory in 1856, Perkin syn-thesized mauve, the purple dye. He then started a factory to manufacture mauve and later other dyes including alizarin. Perkin was the first person to show that organic chemistry was not just mere intellectual curiosity but could be profitable, which cata-pulted the discipline into a higher level. In addition, Perkin was also an exceptionally talented pianist.
2. Gaset, A.; Gorrichon, J. P. Synth. Commun. 1982, 12, 71−79. 3. Kinastowski, S.; Nowacki, A. Tetrahedron Lett. 1982, 23, 3723−3724. 4. Koepp, E.; Vögtle, F. Synthesis 1987, 177−179. 5. Brady, W. T.; Gu, Y.-Q. J. Heterocycl. Chem. 1988, 25, 969−971. 6. Pálinkó, I.; Kukovecz, A.; Török, B.; Körtvélyesi, T. Monatsh. Chem. 2001, 131,
1097−1104. 7. Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.; McGown, A. T. J.
Org. Chem. 2001, 66, 8135−8138. 8. Solladié, G.; Pasturel-Jacopé, Y.; Maignan, J. Tetrahedron 2003, 59, 3315−3321. 9. Sevenard, D. V. Tetrahedron Lett. 2003, 44, 7119−7126. 10. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2006, 47, 2249−2251. 11. Lacova, M.; Stankovicova, H.; Bohac, A.; Kotzianova, B. Tetrahedron 2008, 64,
9646−9653.
425
Petasis reaction Allylic amine from the three-component reaction of a vinyl boronic acid, a car-bonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction.
H
OR1 B(OH)2
R2 NH
R3
OH R1OH
NR2 R3
R3
NHR2
H
O
R1 B(OH)2
OH R1OH
NR2 R3N
R2 R3
:OH
NR2 R3
OB
HOR1
OH
Example 12
PhB
OH
OHO
C5H11
OHPh N
H
EtOH, rt
84%, 99% de PhC5H11
NPh
OH
Example 24
HO
HO
CHO
OMe
(HO)2BMeNHBn, EtOH, rt
24 h, 72%, 99% de
HO N
OMe
HO
MeBn
Example 39
N
NBnS R1
HN
R2
R3OHC−CO2H, PhB(OH)2
50−94% N
NBnS R1
N
R2
R3
Ph CO2H
Example 4, Asymmetric Petasis reaction10
H CO2Et
O
R2
HN
R3B(OEt)2R1 15 mol% (S)-VAPOL
3 A MS, −15 oC, Tol.R1 CO2Et
NR3R2
R1 = aryl, alkyl R2 = Bn, allylR3 = alkyl
70−92% yield89:11 to 98:2 er
426
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_197, © Springer-Verlag Berlin Heidelberg 2009
References 1. (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583–586. (b) Petasis,
N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–446. (c) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463–16470. (d) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–11799.
2. Koolmeister, T.; Södergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969–5970. 3. Orru, R. V. A.; deGreef, M. Synthesis 2003, 1471–1499. (Review). 4. Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15, 3149–3153. 5. Chang, Y. M.; Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon, C. M. Tetrahe-
dron Lett. 2005, 46, 3053–3056. 6. Follmann, M.; Graul, F.; Schaefer, T.; Kopec, S.; Hamley, P. Synlett 2005, 1009–
1011. 7. Danieli, E.; Trabocchi, A.; Menchi, G.; Guarna, A. Eur. J. Org. Chem. 2007, 1659–
1668. 8. Konev, A. S.; Stas, S.; Novikov, M. S.; Khlebnikov, A. F.; Abbaspour Tehrani, K. Tet-
rahedron 2007, 64, 117–123. 9. Font, D.; Heras, M.; Villalgordo, J. M. Tetrahedron 2007, 64, 5226–5235. 10. Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922–6923. 11. Abbaspour Tehrani, K.; Stas, S.; Lucas, B.; De Kimpe, N. Tetrahedron 2009, 65,
1957–1966.
427
Petasis reagent
428
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_198, © Springer-Verlag Berlin Heidelberg 2009
The Petasis reagent (Cp2TiMe2, dimethyltitanocene) undergoes similar olefination reactions with ketones and aldehydes as does the Tebbe’s reagent. The originally proposed mechanism5 was very different from that of Tebbe olefination. How-ever, later experimental data seem to suggest that both Petasis and Tebbe olefina-tion share the same mechanism, i.e., the carbene mechanism involving a four-membered titanium oxide ring intermediate.9 Petasis reagent is easier to make than the Tebbe reagent.
TiCl
ClCp
Cp
MeLi or
MeMgCl
heat TiC
CHH
H
HH H
TiCH3
CH3Ti
Cp
CpCH2
− CH4
OR2
R1Ti
H
H
OR2
R1
− Cp2Ti=O
R2
R1Ti
H2C
O R2
R1
Example 12
Cp2TiMe2
THF, 65 °C 8 h, 52%
O
NO Ph
MeO2CCHO
CH3
O
NO Ph
MeO2C CH3
Example 23
TiCp Cp
O O OPhMe, 50 °C, 67%
Example 35
CF3
CF3O
O
O
N
F
2.4 eq MeLi
6 mol% Cp2TiCl2PhMe, 80 °C, 6.5 h
91%
CF3
CF3OO
N
F250 kg(474 mol) 227 kg
O
O Ph0.75 eq
Example 48
R2 N
R3 R1 1.8 equiv Cp2TiMe2
Tol., THF, microwave, 65 oC3−10 min., ~ 50−60%
O
OMe
R2 N
R3 R1 OMe
References 1. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392−6394. 2. Colson, P. J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918−5924. 3. Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34, 943–946. 4. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Synth.
2002, 79, 19. 5. Payack, J. F.; Huffman, M. A.; Cai, D. W.; Hughes, D. L.; Collins, P. C.; Johnson, B.
K.; Cottrell, I. F.; Tuma, L. D. Org. Pro. Res. Dev. 2004, 8, 256−259. 6. Cook, M. J.; Fleming, E. I. Tetrahedron Lett. 2005, 46, 297−300. 7. Morency, L.; Barriault, L. J. Org. Chem. 2005, 70, 8841−8853. 8. Adriaenssens, L. V.; Hartley, R. C. J. Org. Chem. 2007, 72, 10287−10290. 9. Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762−6764. 10. Zhang, J. Tebbe reagent. In Name Reactions for Homologations-Part I, Li, J. J. Ed.,
Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review).
429
Peterson olefination Alkenes from α-silyl carbanions and carbonyl compounds. Also known as the sila-Wittig reaction.
R1 R2
O
R3
HSiR3M
R1
HO
R3
SiR3R2 H
acid or
base R2
R1
R3
H
Basic conditions:
R3
HSiR3
M
R1 R2
O
R2
O
R3
SiR3R1 H
R2 R3R1 H
SiR3O
R2
R1
R3
Hsyn-
elimination
β-silylalkoxide intermediate
Acidic conditions:
R2
HO
R3
SiR3R1 H
rotation
R2
HO
SiR3
R3
R1 HH
R2
R1
H
R3
R2
H2O
SiR3
R3
R1 H E2 anti-
elimination:OH2
β-hydroxysilane
Example 16
OBnHO
HOSiMe2Ph
OH
OBn
OBnHO
HO
OBn
KHMDS,18-C-6, THF
−78 oC, 1 h99%, > 20:1 dr
OBnHO
OH
OBn
H2SO4, THF
23 oC, 24 h95%
Example 27
PhO2S TBS
F 1. n-BuLi, Et2O, −78 oC
2. benzophenone, 63%PhO2S
FPh
Ph
Example 38
N
(t-BuO)Ph2Si CN1. KHMDS, THF, −78 oC
2. N88% yield92:8 Z:ECHO
CN
430
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_199, © Springer-Verlag Berlin Heidelberg 2009
Example 410
O
OMe
OMOM O
OMe
OMOM
1. LiCH2TMS, THF 0 oC, 15 min.2. KHMDS, 0 oC to rt, 1.5 h
3. HCl, MeOH/Et2O, 5 min. 74%
References 1. Peterson, D. J. J. Org. Chem. 1968, 33, 780−784. 2. Ager, D. J. Org. React. 1990, 38, 1−223. (Review). 3. Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A. Synlett 1991, 764−770.
(Review). 4. van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195−200.
(Review). 5. Ager, D. J. Science of Synthesis 2002, 4, 789−809. (Review). 6. Heo, J.-N.; Holson, E. B.; Roush, W. R. Org. Lett. 2003, 5, 1697−1700. 7. Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81−84. 8. Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004, 6, 3917−3920. 9. Kano, N.; Kawashima, T. The Peterson and Related Reactions in Modern Carbonyl
Olefination; Takeda, T., Ed.; Wiley-VCH: Weinheim, Germany, 2004, 18−103. (Re-view).
10. Huang, J.; Wu, C.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 13366. 11. Ahmad, N. M. Peterson olefination. In Name Reactions for Homologations-Part I; Li,
J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 521−538. (Review).
431
Pictet–Gams isoquinoline synthesis The isoquinoline framework is derived from the corresponding acyl derivatives of β-hydroxy-β-phenylethylamines. Upon exposure to a dehydrating agent such as phosphorus pentoxide, or phosphorus oxychloride, under reflux and in an inert solvent such as decalin, isoquinoline frameworks are formed.
P2O5, decalin
reflux4
3
1HN
OH
O
RN
R
1
34
P2O5 actually exists as P4O10, an adamantane-like structure.
HN
OH
R
O
P O PO
O O
O
: HN
OH
R
OP
O
O
NH
R OPO2
OH
:H
N
R
OH : P O P
O
O O
O
N
RN
R
OPO2H
Example 14
O NH
O
HN
O
HN
HO
OHOH
POCl3, P4O10, decalin
180 oC, 6 h, 14%
N
N
N
Example 27
N O
OH
ClH
P2O5
o-dichlorobenzene 80%
N
Cl
432
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_200, © Springer-Verlag Berlin Heidelberg 2009
Reference 1. (a) Pictet, A.; Kay, F. W. Ber. 1909, 42, 1973−1979. (b) Pictet, A.; Gams, A. Ber.
1909, 42, 2943−2952. Amé Pictet (1857−1937), born in Geneva, Switzerland, carried out a tremendous amount of work on alkaloids.
2. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. Tetrahedron Lett. 1977, 18, 4107−4110.
3. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. K.; Hadi, A. H. A.; Sharif, A. M. J. Chem. Soc., Perkin Trans. 1 1979, 539−543.
4. Dyker, G.; Gabler, M.; Nouroozian, M.; Schulz, P. Tetrahedron Lett. 1994, 35, 9697−9700.
5. Poszávácz, L.; Simig, G. J. Heterocycl. Chem. 2000, 37, 343−348. 6. Poszávácz, L.; Simig, G. Tetrahedron 2001, 57, 8573−8580. 7. Manning, H. C.; Goebel, T.; Marx, J. N.; Bornhop, D. J. Org. Lett. 2002, 4,
1075−1081. 8. Holsworth, D. D. Pictet–Gams Isoquinoline Synthesis. In Name Reactions in Hetero-
cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 457−465. (Review).
433
Pictet–Spengler tetrahydroisoquinoline synthesis Tetrahydroisoquinolines from condensation of β-arylethylamines and carbonyl compounds followed by cyclization.
NH2NHR2 H
O HCl
R2
R1O
R1O
R1O
R1O
NH2H
R2
OR1O
R1O : N
R1O
R1O HOH
R2
+ HH
N
R1O
R1O HR2
N:
R1O
R1O HOH2
R2
− H2O
NH
R2
R1O
R1OH
NH
R2
R1O
R1OH
NH
R2
R1O
R1O
Example 14
NO
O
S
O
O
OAcOMe
HO
MeONH2
NO
O
S
O
OAcOMe
NH
HO
MeOsilica gel
dry EtOH80%
Example 27
NHMe
i-PrO
i-PrOMeO
i-PrO
i-PrOMeO
NMe
(CH2O)n
aq. HCl, EtOH
75%
434
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_201, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Asymmetric acyl Pictet–Spengler9
NH
NH2
OHCOTBDPS
CH2Cl2/Et2O (3 : 1)Na2SO4, 23 oC, 2 h
NH
N
OTBDPS
i-Bu2NNH
NHO
t-Bu S
N Ph
AcCl, 2,6-lutidine, Et2O−78 oC to −60 oC, 23 h
NH
NAc
OTBDPS81% 2 steps
94% ee
Example 4, Oxa-Pictet–Spengler10
O
O O
OH
O
CHO
BF3•OEt2, CH2Cl20 oC to rt, 88%, 88% de
O
O O
O
O
References 1. Pictet, A.; Spengler, T. Ber. 1911, 44, 2030−2036. 2. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797−1842. (Review). 3. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202−9203. 4. Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43−46. 5. Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543−547. 6. Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177−180. 7. Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron: Asymmetry 2003,
14, 1309−1320. 8. Tinsley, J. M. Pictet–Spengler Isoquinoline Synthesis. In Name Reactions in Hetero-
cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 469−479. (Review).
9. Mergott, D. J.; Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745−748. 10. Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem. 2009, 74, 423−426.
435
Pinacol rearrangement Acid-catalyzed rearrangement of vicinal diols (pinacols) to carbonyl compounds.
R1
HO
R3
OHR R2 H
RR2
O
R1R3
The most electron-rich alkyl group (more substituted carbon) migrates first. The general migration order:
tertiary alkyl > cyclohexyl > secondary alkyl > benzyl > phenyl > primary alkyl > methyl >> H.
For substituted aryls: p-MeO-Ar > p-Me-Ar > p-Cl-Ar > p-Br-Ar > p-MeOAr > p-O2N-Ar
R1
HO
R3
OHR R2
R1
HO
R3
OH2R R2
− H2OH
H RR2
O
R1R3RR2
O
R1R3
Halkyl
migration
HO
R3R R2
R1
Example 14
OH
OH
OMeMeO
MeO
OTBDMSOTBDMS
OMe
BF3•OEt2
THF, 68%
OMeMeO
MeOOTBDMS
OTBDMSOMe
CHOH
Example 25
Ph
OH
OH
NSO2Ph
1. MsCl, Et3N, CH2Cl2 0 oC, 10 min.
2. Et3Al, CH2Cl2, −78 oC 10 min., 90% N
SO2Ph
OPh
436
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_202, © Springer-Verlag Berlin Heidelberg 2009
Example 37
Ph OHOHPh
cat. TsOH
CDCl3
Ph PhO O
PhPh
3 : 1 Example 49
N O
OHR
HO
OBnBF3•OEt2
CH2Cl2, 0 oC
N O
RO
OBn R = vinyl, 92%R = allyl, 95%R = furyl, 90%R = prenyl, 94%
98% ee
References 1. Fittig, R. Ann. 1860, 114, 54−63. 2. Magnus, P.; Diorazio, L.; Donohoe, T. J.; Giles, M.; Pye, P.; Tarrant, J.; Thom, S. Tet-
rahedron 1996, 52, 14147−14176. 3. Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693−5706. 4. Pettit, G. R.; Lippert III, J. W.; Herald, D. L. J. Org. Chem. 2000, 65, 7438–7444. 5. Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937−6940. 6. Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143−7157. (Review). 7. Mladenova, G.; Singh, G.; Acton, A.; Chen, L.; Rinco, O.; Johnston, L. J.; Lee-Ruff,
E. J. Org. Chem. 2004, 69, 2017−2023. 8. Birsa, M. L.; Jones, P. G.; Hopf, H. Eur. J. Org. Chem. 2005, 3263−3270. 9. Suzuki, K.; Takikawa, H.; Hachisu, Y.; Bode, J. W. Angew. Chem., Int. Ed. 2007, 46,
3252–3254. 10. Goes, B. Pinacol rearrangement. In Name Reactions for Homologations-Part I; Li, J.
J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review).
437
Pinner reaction Transformation of a nitrile into an imino ether, which can be converted to either an ester or an amidine.
R CN R1 OHHCl (g)
R OR1
NH2 ClH+, H2O
NH3, EtOH
R OR1
O
R NH2•HCl
NH2
R1 O R OR1
NH2 ClR N:
HR NH nucleophilic
addition
protonation
H
:
common intermediate
R OR1
NH2 Cl
R OR1
Ohydrolysis
H2O: R OR1
OH2N HH
R OR1
NH2 Cl
R NH2•HCl
NH2
H3N:R NH2
OR1HCl•H2Nnucleophilic
addition
H
H
Example 12
Ph NH
O Ph
N
EtSH, HCl, CH2Cl2
0 oC, 10 min., 95%N O
NHPh
Ph
pyr., H2S
4 h, 0 oC, 42%N O
NH2Ph
Ph Example 22
Ph NH
O
N
EtSH, HCl, CH2Cl2
0 oC, 1 h, 85%
pyr., H2S
2 h, 0 oC, 40%Ph N
H
OSEt
NHPh N
H
OSEt
S Example 36
O2S
OPh
N
MeOH, HCl
Et2O, 0 oC90%
O2S
OPh
HCl•HN OMe
NaHCO3, Et2O
−5 oC, 87−92%
O2S
OPh
HN OMe
438
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_203, © Springer-Verlag Berlin Heidelberg 2009
O2S
OPh
H2N OMe
O2S
OPh
MeO NH2
Ph
NH2
Me
EtOH, rt36 h, 78%
O2S
OPh
HN NH2
Me Ph Example 410
S
N
NC
HCl
EtOH95%
S
N
H2N
OEt
Cl
NaHCO3S
N
HN
OEt
NH4Cl
65%S
N
H2N
NH2Cl
References 1. (a) Pinner, A.; Klein, F. Ber. 1877, 10, 1889–1897. (b) Pinner, A.; Klein, F. Ber.
1878, 11, 1825. 2. Poupaert, J.; Bruylants, A.; Crooy, P. Synthesis 1972, 622–624. 3. Lee, Y. B.; Goo, Y. M.; Lee, Y. Y.; Lee, J. K. Tetrahedron Lett. 1990, 31, 1169–1170. 4. Cheng, C. C. Org. Prep. Proced. Int. 1990, 22, 643–645. 5. Siskos, A. P.; Hill, A. M. Tetrahedron Lett. 2003, 44, 789–794. 6. Fischer, M.; Troschuetz, R. Synthesis 2003, 1603–1609. 7. Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331–2334. 8. Cushion, M. T.; Walzer, P. D.; Collins, M. S.; Rebholz, S.; Vanden Eynde, J. J.; May-
ence, A.; Huang, T. L. Antimicrob. Agents Chemoth. 2004, 48, 4209–4216. 9. Li, J.; Zhang, L.; Shi, D.; Li, Q.; Wang, D.; Wang, C.; Zhang, Q.; Zhang, L.; Fan, Y.
Synlett 2008, 233–236. 10. Racané, L.; Tralic-Kulenovic, V.; Mihalic, Z.; Pavlovic, G.; Karminski-Zamola, G.
Tetrahedron 2008, 64, 11594–11602.
439
Polonovski reaction Treatment of a tertiary N-oxide with an activating agent such as acetic anhydride, resulting in rearrangement where an N,N-disubstituted acetamide and an aldehyde are generated.
(CH3CO)2O
pyr., CH2Cl2R2 N
O
R1
RR
NR1
OR2 H
O
R2 NO
R1
R
O
O O
acylationR2 N
O
R1
RH
O
CH3CO2
R2 NR1
R HOAc
CH3CO2 iminium ion
R2 N:R1
RO O
O
O O
RNR1
OR2 H
OR2 NR
O
OR1
O
OAc
Ac2O
The intramolecular pathway is also operative:
R2 NR
O O
R1
:
RNR1
OR2 H
O
ON
R2
R
R1
O
Example 11
N(CH3CO)2O
100 oCN
OO
Example 22
(CH3CO)2O
< 30 oC, 98%
N N
OO
440
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_204, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Iron salt-mediated Polonovski reaction9
OMe
O
HO H
codeine
NMe
H2O2 then
2 M HCl
OMe
O
HO H NMe
OH
ClFeSO4
87%, 2 steps
OMe
O
HO H NH
References 1. Polonovski, M.; Polonovski, M. Bull. Soc. Chim. Fr. 1927, 41, 1190–1208. 2. Michelot, R. Bull. Soc. Chim. Fr. 1969, 4377–4385. 3. Lounasmaa, M.; Karvinen, E.; Koskinen, A.; Jokela, R. Tetrahedron 1987, 43, 2135–
2146. 4. Tamminen, T.; Jokela, R.; Tirkkonen, B.; Lounasmaa, M. Tetrahedron 1989, 45,
2683–2692. 5. Grierson, D. Org. React. 1990, 39, 85–295. (Review). 6. Morita, H.; Kobayashi, J. J. Org. Chem. 2002, 67, 5378–5381. 7. McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P. J. J. Org. Chem. 2003, 68,
9847–9850. 8. Nakahara, S.; Kubo, A. Heterocycles 2004, 63, 1849–1854. 9. Thavaneswaran, S.; Scammells, P. J. Bioorg. Med. Chem. Lett. 2006, 16, 2868–2871. 10. Volz, H.; Gartner, H. Eur. J. Org. Chem. 2007, 2791–2801.
441
Polonovski–Potier reaction A modification of the Polonovski reaction where trifluoroacetic anhydride is used in place of acetic anhydride. Because the reaction conditions for the Polonovski–Potier reaction are mild, it has largely replaced the Polonovski reaction.
N O (CF3CO)2O
pyr., CH2Cl2
N
O CF3
tertiary N-oxide
N O
F3C O CF3
O O
acylationN O
CF3OH
CF3CO2
N
H
CF3CO2 iminium ion
N:
CF3OF3C
OO
N
O CF3
N
O CF3
HCF3CO2
enamine
Example 12
NH
NNH
NH
(CF3CO)2O, CH2Cl2, 0 oC
then, HCl, heat, 30%HOHO
O
Example 25
N
HN O
O
H
H
OH
N
HN O
O
H
H
OH
OF3C
(CF3CO)2O, pyr.
CH2Cl2, 0 oC, 65%O
442
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_205, © Springer-Verlag Berlin Heidelberg 2009
Example 38
NBoc
N
OHH
Me 1.3 equiv m-CPBA
CH2Cl2, 0 oC, 94% NBoc
N
OHH
Me
O
1. TFAA, CH2Cl2, rt, 3 h
2. KCN, H2O, pH 4 0 oC, 30 min., then rt, 3 h
NBoc
N
OHH
Me
NBoc
N
H
CN O
OHH
HO
25%22% Example 410
HN
HN
CH3
O OH
H
HN
HN
CH3
O H
H 1. m-CPBA, DMF, 0 oC, 0.5 h, 80%
2. Ac2O, Et3N, DMF, 0 oC, 1 h
References 1. Ahond, A.; Cavé, A.; Kan-Fan, C.; Husson, H.-P.; de Rostolan, J.; Potier, P. J. Am.
Chem. Soc. 1968, 90, 5622–5623. 2. Husson, H.-P.; Chevolot, L.; Langlois, Y.; Thal, C.; Potier, P. J. Chem. Soc., Chem.
Commun. 1972, 930–931. 3. Grierson, D. Org. React. 1990, 39, 85–295. (Review). 4. Sundberg, R. J.; Gadamasetti, K. G.; Hunt, P. J. Tetrahedron 1992, 48, 277–296. 5. Kende, A. S.; Liu, K.; Brands, J. K. M. J. Am. Chem. Soc. 1995, 117, 10597–10598. 6. Renko, D.; Mary, A.; Guillou, C.; Potier, P.; Thal, C. Tetrahedron Lett. 1998, 39,
4251–4254. 7. Suau, R.; Nájera, F.; Rico, R. Tetrahedron 2000, 56, 9713–9720. 8. Thomas, O. P.; Zaparucha, A.; Husson, H.-P. Tetrahedron Lett. 2001, 42, 3291–3293. 9. Lim, K.-H.; Low, Y.-Y.; Kam, T.-S. Tetrahedron Lett. 2006, 47, 5037–5039. 10. Gazak, R.; Kren, V.; Sedmera, P.; Passarella, D.; Novotna, M.; Danieli, B.
Tetrahedron 2007, 63, 10466–10478. 11. Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2009, 65, 1608–
1617.
443
Pomeranz–Fritsch reaction Isoquinoline synthesis via acid-mediated cyclization of the appropriate ami-noacetal intermediate.
CHOH2N
OEt
OEt
NOEt
OEtH
N
H2NOEt
OEt
H
O
:
NOEt
OEt
OH2
H
condensation:
imine
formation
H
NOEt
OEtH
:
NOEt
OEt:
N
OEtHOEt
N
OEt
NN
OEtH
H
H
Example 13
N
EtO OEt
N
MeO
MeO
MeO
MeO
BF3•AcOH, (CF3CO)2O
60−82 %
Example 24
N
O
OMeH
Me
TiCl4, CH2Cl2
N
O Me
MeO OMe
−78 oC, 69 %
444
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_206, © Springer-Verlag Berlin Heidelberg 2009
Example 39
N
OMe
OMe
Ns
MeO
MeON
Ns
MeO
MeO6 N HCl, EtOH, dioxane
reflux, 30 min., 68%
Example 4, Bobbitt modification10
MeO
MeOHN
H
BrOEt
OEt
NaH, DMF
MeO
MeON
H
OEtEtO
MeO
MeON
H1. 5 M HCl, 12 h, rt
2. NaBH4, TFA, CH2Cl2 38% overall
References 1. (a) Pomeranz, C. Monatsh. 1893, 14, 116−119. Cesar Pomeranz (1860−1926) re-
ceived his Ph.D. degree at Vienna, where he was employed as an associate professor of chemistry. (b) Fritsch, P. Ber. 1893, 26, 419−422. Paul Fritsch (1859−1913) was born in Oels, Silesia. He studied at Munich where he received his doctorate in 1884. Fritsch eventually became a professor at Marburg after several junior positions.
2. Gensler, W. J. Org. React. 1951, 6, 191−206. (Review). 3. Bevis, M. J.; Forbes, E. J.; Naik, N. N.; Uff, B. C. Tetrahedron 1971, 27, 1253−1259. 4. Ishii, H.; Ishida, T. Chem. Pharm. Bull. 1984, 32, 3248−3251. 5. Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601−616. (Review). 6. Gluszy ska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2000, 11, 2359−2368. 7. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron
2001, 57, 8297−8303. 8. Hudson, A. Pomeranz–Fritsch Reaction. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480−486. (Re-view).
9. Bracca, A. B. J.; Kaufman, T. S. Eur. J. Org. Chem. 2007, 5284−5293. 10. Grajewska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2007, 18, 2910−2914.
445
Schlittler–Müller modification Simple permutation where the amine and the aldehyde switch places for the two reactants in comparison to the Pomeranz–Fritsch reaction.
OHC OEt
OEtNH2
R
NOEt
OEt
HN
R R
Example 13
X
R
HN
OMe
OMe
TsR
NTs
OMe
OMe
RN
Ts
H
Example 24
NH2H2N
EtOO
H
OEt
1.
2. oleum, 30%NN
References 1. Schlittler, E.; Müller, J. Helv. Chim. Acta 1948, 31, 914−924, 1119−1132. 2. Guthrie, D. A.; Frank, A. W.; Purves, C. B. Can. J. Chem. 1955, 33, 729−742. 3. Boger, D. L.; Brotherton, C. E.; Kelley, M. D. Tetrahedron 1981, 37, 3977−3980. 4. Gill, E. W.; Bracher, A. W. J. Heterocycl. Chem. 1983, 20, 1107−1109. 5. Hudson, A. Pomeranz–Fritsch Reaction. In Name Reactions in Heterocyclic Chemis-
try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480−486. (Re-view).
446
Prévost trans-dihydroxylation Cf. Woodward cis-dihydroxylation.
I2
AgO2CPh
O2CPh
O2CPh
hydrolysisOH
OH
I I I
O2CHPh
SN2I
O
SN2
O
Ph cyclic iodonium ion intermediate neighboring group assistance
O O
Ph
O2CPh
SN2O2CPh
O2CPh
hydrolysis OH
OH
Example 15
FFO
OO
Ph
AgOCOPh, I2
PhH, rt, 2 h, reflux, 10 h, 46%
Ph
O
Example 29
AgOCOPh, I2
CCl4, 74%
O2C-C6H4-p-OMe
O
O2C-C6H4-p-OMe
O
OHI 1. KOH, H2O
2. Ac2O, pyr.
OAc
O
OAcAcO
References 1. Prévost, C. Compt. Rend. 1933, 196, 1129–1131. 2. Campbell, M. M.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 5063–5070. 3. Ciganek, E.; Calabrese, J. C. J. Org. Chem. 1995, 60, 4439–4443. 4. Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801–4805. 5. Zajc, B. J. Org. Chem. 1999, 64, 1902–1907. 6. Hamm, S.; Hennig, L.; Findeisen, M.; Muller, D. Tetrahedron 2000, 56, 1345–1348. 7. Ray, J. K.; Gupta, S.; Kar, G. K.; Roy, B. C.; Lin, J.-M. J. Org. Chem. 2000, 65,
8134–8138. 8. Sabat, M.; Johnson, C. R. Tetrahedron Lett. 2001, 42, 1209–1212. 9. Hodgson, R.; Nelson, A. Org. Biomol. Chem. 2004, 2, 373–386.
447
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_207, © Springer-Verlag Berlin Heidelberg 2009
Prins reaction The Prins reaction is the acid-catalyzed addition of aldehydes to alkenes and gives different products depending on the reaction conditions.
HR
H H
O
H2O R OH
OH
R OHor or
O O
R
H
RH H
O H2O
R OH
OHH H
OH
R OH
the common intermediate
R OHR OH
H
:B
H
O O
RH H
O
R O
OR OH
H
H
H
H
Example 15
O
TsO
OAc
OBn
SnBr4, CH2Cl2
−78 oC, 84%O
TsO
Br
OBn
Example 27
AcO
(CH2O)n, Bi(OTf)3
CH3CN, rt, 10 h, 77% AcO
OO
448
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_208, © Springer-Verlag Berlin Heidelberg 2009
Example 39
TMSEO2CO
OBn OTBS
O HO
O
O
O
TMSEO2CO
OBn OH
O
O
O
O
In(OTf)3, TMSCl, CH2Cl2
−78 to −40 ºC, 4 h, 42%
Cl
Example 410
OH
O
OHC
PhO2SO OCH3
AcOH, BF3•OEt2
0 oC, CH2Cl2X = OAc, 33%
X = F, 48%
O O
OOCH3
X
PhO2S
References 1. Prins, H. J. Chem. Weekblad 1919, 16, 1072−1023. Born in Zaandam, The Nether-
lands, Hendrik J. Prins (1889−1958) was not even an organic chemist per se. After obtaining a doctorate in chemical engineering, Prins worked for an essential oil com-pany and then a company dealing with the rendering of condemned meats and car-casses. But he had a small laboratory near his house where he carried out his experi-ments in his spare time, which obviously was not a big distraction—for he rose to be the president-director of the firm he worked for.
2. Adam, D. R.; Bhatnagar, S. P. Synthesis 1977, 661−672. (Review). 3. Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle, W. G.;
Wurster, J. A. Org. Lett. 2000, 2, 223−226. 4. Davis, C. E.; Coates, R. M. Angew. Chem., Int. Ed. 2002, 41, 491−493. 5. Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4,
3919−3922. 6. Braddock, D. C.; Badine, D. M.; Gottschalk, T.; Matsuno, A.; Rodriguez-Lens, M.
Synlett 2003, 345−348. 7. Sreedhar, B.; Swapna, V.; Sridhar, Ch.; Saileela, D.; Sunitha, A. Synth. Commun.
2005, 35, 1177−1182. 8. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44,
3485−3488. 9. Chan, K.-P.; Ling, Y. H.; Loh, T.-P. Chem. Commun. 2007, 939−941. 10. Bahnck, K. B.; Rychnovsky, S. D. J. Am. Chem. Soc. 2008, 130, 13177−13181.
449
Pschorr cyclization The intramolecular version of the Gomberg−Bachmann reaction.
NH2
CO2HNaNO2, HCl
Cu
CO2H
HON
OH2O
NO
ON
OH
− H2O
ON
ON
O
− NO2NH2
CO2H
:H
NH
CO2H
N O
N:
CO2H
NOH2
N
CO2H
NOH
H HH
− H2O
N2
CO2HCu(0)
CO2H
Cu(I)
H
N2↑
CO2H
6-exo-trig
radical cyclization H
Cu(I)Cu(0)
CO2H
H
Example 17
O
NH2S
OO
1. NaNO2, HCl−H2O−HOAc 0 to 5 oC, 2 h
2. CuSO4, HOAc, reflux 2 h, 86%
O
S
OOO
S
OO
6 : 1
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J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_209, © Springer-Verlag Berlin Heidelberg 2009
Example 28
NN
O
NH2 NaNO2, HCl
5 to 20 oC, 64%
NN
O
Example 310
O
Br
hv (350 nM)
MeCN, N2
O
OO
34% 62%
References
1. Pschorr, R. Ber. 1896, 29, 496−501. Robert Pschorr (1868−1930), born in Munich,
Germany, studied under von Baeyer, Bamberger, Knorr, and Fischer. He became an assistant professor in 1899 at Berlin where he discovered the phenanthrene synthesis. During WWI, Pschorr served as a major in the German Army.
2. Kupchan, S. M.; Kameswaran, V.; Findlay, J. W. A. J. Org. Chem. 1973, 38, 405−406. 3. Wassmundt, F. W.; Kiesman, W. F. J. Org. Chem. 1995, 60, 196−201. 4. Qian, X.; Cui, J.; Zhang, R. Chem. Commun. 2001, 2656−2657. 5. Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359−1469. (Review). 6. Karady, S.; Cummins, J. M.; Dannenberg, J. J.; del Rio, E.; Dormer, P. G.; Marcune,
B. F.; Reamer, R. A.; Sordo, T. L. Org. Lett. 2003, 5, 1175−1178. 7. Xu, Y.; Qian, X.; Yao, W.; Mao, P.; Cui, J. Bioorg. Med. Chem. 2003, 11, 5427−5433. 8. Tapolcsányi, P.; Maes, B. U. W.; Monsieurs, K.; Lemière, G. L. F.; Riedl, Z.; Hajós,
G.; Van der Driessche, B.; Dommisse, R. A.; Mátyus, P. Tetrahedron 2003, 59, 5919−5926.
9. Mátyus, P.; Maes, B. U. W.; Riedl, Z.; Hajós, G.; Lemière, G. L. F.; Tapolc anyi, P.; Monsieurs, K.; Éliás, O.; Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 1123−1139. (Review).
10. Moorthy, J. N.; Samanta, S. J. Org. Chem. 2007, 72, 9786−9789.
451
Pummerer rearrangement The transformation of sulfoxides into α-acyloxythioethers using acetic anhydride.
R1 S R2O Ac2O R1 S R2
OAc
R1 S R2O
O
OO
R1 S R2O
O
HR1 S R2
O
OOO
acyl
transfer
AcO
AcO
R1 S R2
OAcR1 S R2 R1 S R2
AcO
HOAc
Example 12
BnOSPh
OH
OH
1. Me2C(OMe)2, H+
2. m-CPBA, CH2Cl2, −20 oC
3. Ac2O, NaOAc, reflux, 6 h 81%
BnOSPh
O
O
OAc
Example 27
MeO
MeO
N
N N
CO2Et
SOPh O
N
NN
CO2EtPhS
MeO
MeO
OBn Bn
TMSOTf, DIPEA
CH2Cl2, −20 oC88%, dr = 2:1
Example 38
N
OSEtO
MeO
MeOCO2Me
Br
N
MeO2CSEt
HO
Br
MeO
MeOCSA, PhMe
reflux, 88%
452
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_210, © Springer-Verlag Berlin Heidelberg 2009
Example 49
BnN SBn
Ph
O OAc2O, pyr., DMAP
CH2Cl2, rt, 91%Bn
N SBn O
OAcPh
References 1. Pummerer, R. Ber. 1910, 43, 1401−1412. Rudolf Pummerer, born in Austria in 1882,
studied under von Baeyer, Willstätter, and Wieland. He worked for BASF for a few years and in 1921 he was appointed head of the organic division of the Munich Labo-ratory, fulfilling his long-desired ambition.
2. Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J. J. Org. Chem. 1982, 47, 1373−1378.
3. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157−406. (Review). 4. Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis 1997, 1353−1378. (Review). 5. Padwa, A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175−203. (Review). 6. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851−862.
(Review). 7. Gámez Montaño, R.; Zhu, J. Chem. Commun. 2002, 2448−2449. 8. Padwa, A.; Danca, M. D.; Hardcastle, K.; McClure, M. J. Org. Chem. 2003, 68, 929. 9. Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J. Org. Chem. 2005, 70, 7317. 10. Ahmad, N. M. Pummerer rearrangement. In Name Reactions for Homologations-Part
II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 334−352. (Re-view).
453
Ramberg–Bäcklund reaction Olefin synthesis via α-halosulfone extrusion.
SO O
R R1
X Base
R
R1
S O↑O
SO O
R R1
X HS
O OX R1
Rbackside
displacement
:B
R
R1
S O↑OS
O O
SO2
extrusion
R R1
episulfone intermediate Example 14
SO2
H
HBr
KOt-Bu, THF
−15 oC to rt, 71%
H
Example 25
HSO2CH2Br
Br KOt-Bu, THF/HOt-Bu
0 oC to rt, 0.5 h, 65%
Example 36
OO
O
O
O
O2S
Cl
H
1. 2.2 eq. KOt-Bu, 10 eq. HMPADME, 70 oC, 5 min., 82%
2. 6 N HCl/THF (1:10, v/v), rt, 4 h, 85%
O O
O
O
O
OH
H
454
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_211, © Springer-Verlag Berlin Heidelberg 2009
Example 4, in situ chlorination7
O2S O
TMSO
TMSO
1. t-BuOK, t-BuOH CCl4, rt, 65%
2. TsOH, H2O, EtOH rt, 95%
O
HO
HO
References 1. Ramberg, L.; Bäcklund, B. Arkiv. Kemi, Mineral Geol. 1940, 13A, 1−50. 2. Paquette, L. A. Acc. Chem. Res. 1968, 1, 209−216. (Review). 3. Paquette, L. A. Org. React. 1977, 25, 1−71. (Review). 4. Becker, K. B.; Labhart, M. P. Helv. Chim. Acta 1983, 66, 1090−1100. 5. Block, E.; Aslam, M.; Eswarakrishnan, V.; Gebreyes, K.; Hutchinson, J.; Iyer, R.; Laf-
fitte, J. A.; Wall, A. J. Am. Chem. Soc. 1986, 108, 4568−4580. 6. Boeckman, R. K., Jr.; Yoon, S. K.; Heckendorn, D. K. J. Am. Chem. Soc. 1991, 113,
9682−9784. 7. Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 7459−7460. 8. Taylor, R. J. K. Chem. Commun. 1999, 217−227. (Review). 9. Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357−475. (Review). 10. Li, J. J. Ramberg–Bäcklund olefin synthesis. In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 386−404. (Review).
11. Pal, T. K.; Pathak, T. Carbohydrate Res. 2008, 343, 2826−2829. 12. Baird, L. J.; Timmer, M. S. M.; Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem.
2009, 74, 2271−2277.
455
Reformatsky reaction Nucleophilic addition of organozinc reagents generated from α-haloesters to car-bonyls.
R R1
OBr
OR2
O
Zn OR2
O
HO
R1R
R R1
OBr
OR2
O
Zn(0)
oxidative addition orelectron transfer
OR2
O
nucleophilic
additionZnBr
OR2
O
BrZnO
R1R
H2O, hydrolysis
during workup
OR2
O
HO
R1R
Example 14
NS
Boc
Ph
OTBDMSBrCH2CO2Me
Zn, THF, reflux, 71% NBoc
Ph
OTBDMS
MeO2C
Example 26
MeO
O
OBr
OZn, THF
60 oC
MeO
HO O
OMeO
O
OHCl
THF, rt, 10 h92%
456
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_212, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Boron-mediated Reformatsky reaction8
O
I
OO
OP
P = TBS
Me
H
H
OBEt3, tol.
−78 oC, quant.
O
OO
OP
Me
H
H
OH
single diastereomer
H
Example 4, SmI2-mediated Reformatsky reaction9
O
BrOSiEt3
OTBDPS
OH
Me
MeO
n-Bu CHOOSiEt3
1. SmI2, THF, −78 oC
2. Martin sulfurane, CH2Cl2 72%, 2 steps
O
O
OSiEt3
OTBDPS
OH
Me
n-Bu
Me
OSiEt3
References 1. Reformatsky, S. Ber. 1887, 20, 1210−1211. Sergei Reformatsky (1860−1934) was
born in Russia. He studied at the University of Kazan in Russia, the cradle of Russian chemistry professors, where he found competent guidance of a distinguished chemist, Alexander M. Za tsev. Reformatsky then studied at Göttingen, Heidelberg, and Leip-zig in Germany. After returning to Russia, Reformatsky became the Chair of Organic Chemistry at the University of Kiev.
2. Rathke, M. W. Org. React. 1975, 22, 423−460. (Review). 3. Fürstner, A. Synthesis 1989, 571−590. (Review). 4. Lee, H. K.; Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173−2174. 5. Fürstner, A. In Organozinc Reagents Knochel, P., Jones, P., Eds.; Oxford University
Press: New York, 1999, pp 287−305. (Review). 6. Zhang, M.; Zhu, L.; Ma, X. Tetrahedron: Asymmetry 2003, 14, 3447−3453. 7. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325−9374. (Review). 8. Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 426−427. 9. Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 15106−15107. 10. Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568−2571. (Review). 11. Ke, Y.-Y.; Li, Y.-J.; Jia, J.-H.; Sheng, W.-J.; Han, L.; Gao, J.-R. Tetrahedron Lett.
2009, 50, 1389−1391.
457
Regitz diazo synthesis Synthesis of 2-diazo-1,3-diketones or 2-diazo-3-oxoesters using sulfonyl azides.
R OR1
O O
TsN3, Et3N
MeCNR OR1
O O
N2
Ts NH2
R OR1
O O
H enolate
formation R OR1
O O
SNNNO
O
:NEt3
R OR1
O O
HNN
NSO2Tol
proton
transferSH2NO
OR OR1
O O
NN
R OR1
O O
NN
HN
SO2Tol:
tosyl amide is the by-product
When only one carbonyl is present, ethylformate can be used as an activating aux-iliary:6−9
O
NaH, HCO2Et
Et2O
O
OHMsN3
Et2O
ON2
:NEt3O
OH
O
O
MeSNNNO
OO
NN
NSO2Me
H
O
ON2MeSHN
O
OOH
ON
NO
NNN
SO2Me
H O
Alternatively, the triazole intermediate may be assembled via a 1,3-dipolar cycloaddition of the enol and mesyl azide:
458
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_213, © Springer-Verlag Berlin Heidelberg 2009
O
NNN
SO2Me
H OH
O
OH
MeSNNNO
O1,3-dipolar
cycloaddition
ON2MeSHN
O
OOH
Example 15
O H
N
OSO2N3O
Ot-Bu
O
Et3N, CH3CN
0 oC, 5 h, 45%
O
O
Ot-Bu
O
N2
Example 210
N NH
OTIPSO O O O
N
CH3SO2N3
CH3CN, 84%
N NH
OTIPSO O O O
NN2
References 1. (a) Regitz, M. Angew. Chem., Int. Ed. 1967, 6, 733–741. (b) Regitz, M.; Anschütz,
W.; Bartz, W.; Liedhegener, A. Tetrahedron Lett. 1968, 9, 3171–3174. (c) Regitz, M. Synthesis 1972, 351–373. (Review).
2. Pudleiner, H.; Laatsch, H. Ann. 1990, 423–426. 3. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112,
4011–4030. 4. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2000, 65, 9252–9254. 5. Hodgson, D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Expésito Castro, M. A. J. Org.
Chem. 2003, 68, 6153–6159. 6. Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 13624–13628. 7. Mejía-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241–3244. 8. Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609–2614. 9. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967–3977. 10. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47–50.
459
Reimer–Tiemann reaction Synthesis of o-formylphenol from phenols and chloroform in alkaline medium.
OH
CHCl3
OH
3 KClCHO3 KOH 2 H2O
a. Carbene generation:
Cl3C HOH
CCl2H2OCl α-elimination
− Cl−, slow:CCl2
fast
b. Addition of dichlorocarbene and hydrolysis:
OH
H2O CCl2
KOHO O
CCl2
HO
CHClCl
OHO Cl
H
O Cl
HOH
OHCHO
O O
H
H
Example 1, Photo-Reimer–Tiemann reaction without base7
CN
OH
hv (Hg lamp)
CHCl3, 5 h, 48%CN
OCHCl2
Example 28
OH
NHBoc
CO2H
CHCl3, 6 eq. NaOH
2 eq. H2O, reflux4 h, 64%
OH
NHBoc
CO2H
CHO
References 1. Reimer, K.; Tiemann, F. Ber. 1876, 9, 824–828. 2. Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 1–36. (Review). 3. Bird, C. W.; Brown, A. L.; Chan, C. C. Tetrahedron 1985, 41, 4685–4690. 4. Neumann, R.; Sasson, Y. Synthesis 1986, 569–570. 5. Cochran, J. C.; Melville, M. G. Synth. Commun. 1990, 20, 609–616. 6. Langlois, B. R. Tetrahedron Lett. 1991, 32, 3691–3694. 7. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Tetrahedron 1995, 51, 5825–5828. 8. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553–1555.
460
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_214, © Springer-Verlag Berlin Heidelberg 2009
Reissert reaction Treatment of quinoline or isoquinoline with acid chloride and KCN gives qui-naldic acid, aldehyde, and KCN.
R Cl
O N
KCN
N
O RCN
H H2SO4
R H
O
N CO2HNH3
Reissert Compound
N N
O RCN
H
:
R O
Cl N
O R
H
CN
N
R O
H
NH
H
Reissert compound
N:O
R
NHH
:
HNO
R
NH
H
HO
H
NO
R
NHH
H
NO
R H
NH2
OHN
OR H
NH2
O HR H
ON
O
NH2
H
NO
NH2
H
H2O:
NH3N CO2H
NO
NH2HO
H
Example 13
Cl
O
MeO
MeO
OMeN
NaCN, H2O, CH2Cl2
4.5 h, 95%
461
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_215, © Springer-Verlag Berlin Heidelberg 2009
H
O
MeO
MeO
OMe
N CN
OMeO
OMeMeO
30% H2SO4
reflux, 1 h, 95%
Example 2, Reissert compound from isoquinoline7
N
Br
chiral Al catalystTMSCN, CH2=CHOCOCl
CH2Cl2, −40 oC, 72 h, 53%
N
Br
CN
O
O
73% ee
Example 3, Reissert compound fron isoquinoline10
N
OCl
O
TMS-CN, CH2Cl248 h, rt, 96%
N
CN O
O N
CN O
O
1 : 1
Reissert compounds References 1. (a) Reissert, A. Ber. 1905, 38, 1603–1614. (b) Reissert, A. Ber. 1905, 38, 3415–3435.
Carl Arnold Reissert was born in 1860 in Powayen, Germany. He received his Ph.D. In 1884 at Berlin, where he became an assistant professor. He collaborated with Tie-mann. Reissert later joined the faculty at Marburg in 1902.
2. Popp, F. D. Adv. Heterocycl. Chem. 1979, 24, 187–214. (Review). 3. Schwartz, A. J. Org. Chem. 1982, 47, 2213–2215. 4. Lorsbach, B. A.; Bagdanoff, J. T.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 1998, 63,
2244–2250. 5. Perrin, S.; Monnier, K.; Laude, B.; Kubicki, M.; Blacque, O. Eur. J. Org. Chem. 1999,
297–303. 6. Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
6801–6808. 7. Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989–1999. 8. Sieck, O.; Schaller, S.; Grimme, S.; Liebscher, J. Synlett 2003, 337–340. 9. Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491–1508. (Review). 10. Gibson, H. W.; Berg, M. A. G.; Clifton Dickson, J.; Lecavalier, P. R.; Wang, H.; Mer-
ola, J. S. J. Org. Chem. 2007, 72, 5759–5770. 11. Fuchs, C.; Bender, C.; Ziemer, B.; Liebscher, J. J. Heterocycl. Chem. 2008, 45, 1651–
1658.
462
Reissert indole synthesis The Reissert indole synthesis involves base-catalyzed condensation of an o-nitrotoluene derivative with an ethyl oxalate, which is followed by reductive cy-clization to an indole-2-carboxylic acid derivative.
NO2
CO2EtCO2Et
NO2
CO2Et
O
BR R
NH
CO2HHR H
CH2
NO2
EtO
OEtO
OCH3
NO2 NO2
OHOEt
CO2Et
B H
NO2CO2Et
Ohydrolysis
NO2CO2H
O H
NH2CO2H
O
NH
CO2H
H
NH
CO2H H
NH
CO2H
OH
Example 12
N
MeO
NO2
CO2EtCO2Et
KOEt
93% N
MeO
NO2
N
MeO
NH
CO2EtH2, Pd/C
EtOH, 85%
CO2EtO
Example 23
NO2
CO2EtCO2Et
KOEt, EtOH
Et2O NO2
CO2Et
OKH2 (30 psi), PtO2
HOAc, 41−44% NH
CO2Et
463
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_216, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Furan ring as the masked carbonyl10
O
O
NHMs
PhO
HCl, EtOH
reflux, 84%
O
O
N
Ph
Ms
O
References 1. Reissert, A. Ber. 1897, 30, 1030−1053. 2. Frydman, B.; Despuy, M. E.; Rapoport, H. J. Am. Chem. Soc. 1965, 87, 3530−3531. 3. Noland, W. E.; Baude, F. J. Org. Synth. 1973; Coll. Vol. 567−571. 4. Leadbetter, G.; Fost, D. L.; Ekwuribe, N. N.; Remers, W. A. J. Org. Chem. 1974, 39,
3580−3583. 5. Cannon, J. G.; Lee, T.; Ilhan, M.; Koons, J.; Long, J. P. J. Med. Chem. 1984, 27,
386−389. 6. Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba, M.; Sato, Y.; Yamada, H.; Murakami,
Y. Synlett 2000, 1196−1198. 7. Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron Lett. 2001,
42, 2031−2036. 8. Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66, 3474−3483. 9. Li, J.; Cook, J. M. Reissert Indole Synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 154−158. (Review).
10. Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.; Bender, W.; Krapivin, G. D. Tetrahe-dron 2006, 63, 474−491.
464
Ring-closing metathesis (RCM)
NMoO
O Ph
F3CF3C
F3CF3C
PhRu
ClCl
Cy3P
N NMes Mes
PhRu
ClCl
Cy3P
PCy3
Grubbs’ catalysts Schrock’s catalyst Mes = mesityl All three catalysts are illustrated as “LnM=CHR” in the mechanism below.
Generation of the real catalyst from the precatalysts:
CHRLnM LnMR
the active catalyst
CHRLnM
[2 + 2]
cycloaddition
LnM CHRcycloreversion
CHRMLn
[2 + 2]
cycloadditionMLn
cycloreversionLnM
Catalytic cycle:
LnM
LnM[2 + 2]
cycloaddition
LnMcycloreversion MLn
[2 + 2]
cycloaddition
MLn cycloreversionLnM
465
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_217, © Springer-Verlag Berlin Heidelberg 2009
Example 13
OO C11H23OO C11H23
10 mol% (PCy3)2Cl2Ru=CHPh
0.3 eq. Ti(Oi-Pr)4CH2Cl2, 40 oC, 93%
Example 25
PhRu
ClCl
Cy3P
N NMes MesEE
45 oC, 60 min., 100%
EE
E = CO2Et
Example 37
O
OO
OBn
1. cat. PhH (0.07 mM) 80 oC, then air
2. 10% Pd/C, H2, EtOAc, rt 80−85%
O
OO
OBn
MesN NMes
Ru
OCl
Clcat. =
Example 49
O
OBzO
H
HCH2Cl2, rt, 73%
5.4 mol%
PhRu
ClCl
Cy3P
N NMes Mes
O
OH
OBz
CH2Cl2, rt, 93%, > 10:1 E:Z
5 mol%
PhRu
ClCl
Cy3P
N NMes Mes
O
OH
OBz
466
Example 510
O
O O O
OTBSO
TES
15 mol% Grubbs II
toluene, 110 oC, 78%
O OTES
OO
TBSO O
singleisomer
Example 612
NH
N
NH
N
NMo
O
N Ph
Cl
TBSO
Cl
1. 1 mol%
PhH, rt, 1 h
2. H2, Pd/C, 81%, 96% ee
References 1. Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J.
Am. Chem. Soc. 1990, 112, 3875–3886. Richard Schrock is a professor at MIT. He shared the 2005 Nobel Prize in Chemistry with Robert Grubbs of Caltech and Yves Chauvin of Institut Français du Pétrole in France for their contributions to metathesis.
2. Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452. (Review). 3. Scholl, M.; Tunka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,
2247–2250. 4. Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781–
10787. 5. Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 2000, 41, 8635–8638. 6. Thiel, O. R. Alkene and alkyne metathesis in organic synthesis. In Transition Metals
for Organic Synthesis (2nd Edn.), 2004, 1, pp 321–333. (Review). 7. Smith, A. B., III; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129, 14872–14874. 8. Hoveyda, A.H.; Zhugralin, A. R. Nature 2007, 450, 243–251. (Review). 9. Marvin, C. C.; Clemens, A. J. L.; Burke, S. D. Org. Lett. 2007, 9, 5353–5356. 10. Keck, G. E.; Giles, R. L.; Cee, V. J.; Wager, C. A.; Yu, T.; Kraft, M. B. J. Org. Chem.
2008, 73, 9675–9691. 11. Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem. Eur. J. 2008, 14, 5716–5726.
(Review). 12. Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2009, 131, 943–953.
467
Ritter reaction Amides from nitriles and alcohols in strong acids. General scheme:
R1 OH R2 CNH
R1NH
R2
O
e.g.:
H3C CNOHH2SO4
H2ONH
O
HOH OH2
:NH2OE1
N
nitrilium ion
N
:OH2
NH
O
N
OH2
N
OHH
Similarly:
H3C CNH2SO4
H2O NH
O
Example 13
CrCO
COOC
HOH
CrCO
COOC
MeOCHNH
H2SO4
MeCN89%
Example 24
N
CH3
CN
t-BuOH, conc. H2SO4
70−75 oC, 75 min., 97%N
CH3
O
HN
468
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_218, © Springer-Verlag Berlin Heidelberg 2009
Example 35
OO2N
NO2
O2N
NO2
OHNH
OPt electrode, E = 2.5 V
CH3CN, LiClO4
H2O, 56%, dr 8:2
Example 46
O
fuming H2SO4, CH3CN, rt, 30 min.,
then H2O, 100 oC, 2 h, 77%
OH
NH2
References 1. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045−4048. (b) Ritter, J. J.;
Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048−4050. 2. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. (Review). 3. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78−82. 4. Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem.
1989, 54, 2242−2244. 5. Le Goanvic, D; Lallemond, M.-C.; Tillequin, F.; Martens, T. Tetrahedron Lett. 2001,
42, 5175−5176. 6. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69,
5906−5925. 7. Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575−1577. 8. Concellón, J. M.; Riego, E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett.
2004, 6, 4499−4501. 9. Penner, M.; Taylor, D.; Desautels, D.; Marat, K.; Schweizer, F. Synlett 2005,
212−216. 10. Brewer, A. R. E. Ritter reaction. In Name Reactions for Functional Group Transfor-
mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 471−476. (Review).
11. Baum, J. C.; Milne, J. E.; Murry, J. A.; Thiel, O. R. J. Org. Chem. 2009, 74, 2207−2209.
469
Robinson annulation Michael addition of cyclohexanones to methyl vinyl ketone followed by in-tramolecular aldol condensation to afford six-membered α,β-unsaturated ketones.
O
R
O baseO
R
methyl vinyl ketone (MVK)
O
R
O
H
B:
O
R
enolate
formation
Michael
additionisomerization
O
RO
O
RO
aldol
addition
H B O
R
− H2O
dehydrationO
R
HOH
:B
Example 1, Homo-Robinson7
TMSOO
MVK, AcOH, BF3•OEt2
−20 oC, 97% OO
NaOMe
98%
2.5 equiv LDA, TMSCl
THF, −78 oC TMSO
1.5 equiv Et2Zn1.1 equiv CH2I2
Et2O, 0 oC
TMSO
1. 2.5 equiv FeCl3, 0 oC2. NaOAc, reflux
40% for 4 steps O Example 28
O O 3 equiv TfOH, P4O10
CH2Cl2, microwave40 oC, 8 h, 57%
O
470
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_219, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Double Robinson-type cyclopentene annulation9
CO2R
RO2C
OH
OH
O10 equiv
0.1 equiv FeCl3•6H2OCH2Cl2, 60 oC, 2 d
O
O
O
O
CO2RRO2C
conc. H2SO40 oC, 1 h
then rt, 16 h
O
O
CO2R
RO2C
Example 410
O
CN
O
DBU, tol., reflux, 20 h,16% NC
O
References 1. Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935, 1285–1288. Robert Robinson used
the Robinson annulaton in his total synthesis of cholesterol. Here is a story told by Derek Barton about Robinson and Woodward: “By pure chance, the two great men met early in a Monday morning on an Oxford train station platform in 1951. Robinson politely asked Woodward what kind of research he was doing these days; Woodward replied that he thought that Robinson would be interested in his recent total synthesis of cholesterol. Robinson, incensed and shouting ‘Why do you always steal my re-search topic?’, hit Woodward with his umbrella.”—An excerpt from Barton, Derek, H. R. Some Recollections of Gap Jumping, American Chemical Society, Washington, D.C., 1991.
2. Gawley, R. E. Synthesis 1976, 777–794. (Review). 3. Guarna, A.; Lombardi, E.; Machetti, F.; Occhiato, E. G.; Scarpi, D. J. Org. Chem.
2000, 65, 8093–8096. 4. Tai, C.-L.; Ly, T. W.; Wu, J.-D.; Shia, K.-S.; Liu, H.-J. Synlett 2001, 214–217. 5. Jung, M. E.; Piizzi, G. Org. Lett. 2003, 5, 137–140. 6. Singletary, J. A.; Lam, H.; Dudley, G. B. J. Org. Chem. 2005, 70, 739–741. 7. Yun, H.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 3879–3882. 8. Jung, M. E.; Maderna, A. Tetrahedron Lett. 2005, 46, 5057–5061. 9. Zhang, Y.; Christoffers, J. Synthesis 2007, 3061–3067. 10. Jahnke, A.; Burschka, C.; Tacke, R.; Kraft, P. Synthesis 2009, 62–68.
471
Robinson–Gabriel synthesis Cyclodehydration of 2-acylamidoketones to give 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles.
HNR3R1
R2
O
NR3R1
R2
O O
− H2O
R1, R2, R3 = alkyl, aryl, heteroaryl
O
N R3
R1
R2
OH
NR3R1
R2
O O
H H
O
NR3R1
R2− H2O
Example 13
O
N
O
O
CbzHN
H
O
HN
O
O
O
CbzHN
HH
Ph3P, I2, Et3N
55%
Example 24
O
OTIPS
MeO
H
HN
OMe
HOO
N
O
O
OH
OMe H
NOMe
N
OR
O
1. Dess−Martin, CH2Cl22. Ph3P, BrCCl2CCl2Br
3. DBU, CH3CN4. TBAF, THF 42% (+)-hennoxazole A
Example 3, Halogen effect9
HN
NHO
O 2 equiv PPh3
CCl4, MeCNreflux, 97% N N
O
472
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_220, © Springer-Verlag Berlin Heidelberg 2009
HN
NHO
O 2 equiv PPh3
CBr4, MeCNreflux, 68% N N
OBr
Example 410
NH
OTBSN
OTBDPSO
O CHO
1. PPh3, C2Br2Cl4, CH2Cl2 2,6-di-tert-butylpyridine NaHCO3, CH2Cl2, 0 oC
2. Et3N, MeCN, 0 oC to rt 89% for 2 steps
N
OTBDPSO
N
OOTBS
References 1. (a) Robinson, R. J. Chem. Soc. 1909, 95, 2167−2174. (b) Gabriel, S. Ber. 1910, 43,
134−138. (c) Gabriel, S. Ber. 1910, 43, 1283−1287. 2. Turchi, I. J. In The Chemistry of Heterocyclic Compounds, 45; Wiley: New York,
1986; pp 1−342. (Review). 3. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604−3606. 4. Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558−559. 5. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org. Lett. 2002, 4, 2665−2668. 6. Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang, X.; Chen, D.
Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42, 1753−1758. 7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J.
Org. Chem. 2003, 68, 2623−2632. 8. Brooks, D. A. Robinson–Gabriel Synthesis. In Name Reactions in Heterocyclic Chem-
istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 249−253. (Re-view).
9. Yang, Y.-H.; Shi, M. Tetrahedron Lett. 2005, 46, 6285–6288. 10. Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, Martin; Ley, Steven V. Angew.
Chem., Int. Ed. 2006, 45, 6714−6718.
473
Robinson−Schöpf reaction 1,4-Diketone condensations with primary amines to give tropinones.
CHO
CHONH2
CO2H
CO2H
O
N
O
2 CO2↑ 2 H2O
CHO
O
HNH2:
CHO
OH
HN:
CHO
N
HO2C CO2HO
H
imine
formation
− H2O
HO2C CO2HO
NHH
O
:
HO2C CO2HO
N
OH
:
HO2C CO2HO
N
H
− H2O
hemiaminal
CO2↑
N
OHHO2C
decarboxylationN
OHO2C
OO
H
N
OOO
H
N
OH
N
O
CO2↑
Example 15
OHNH2
HPh O OMeMeO
KCN, citric acid, H2O, rt, 24−48 h
then EtOH, reflux, 96 h
N O
Ph
NC
474
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_221, © Springer-Verlag Berlin Heidelberg 2009
Example 29
CO2H
CO2H
ONH2
CHO
OH
CHOTHF, rt
72 h, 51%
OH
O
N
References 1. Robinson, R. J. Chem. Soc. 1917, 111, 762–768. 2. Paquette, L. A.; Heimaster, J. W. J. Am. Chem. Soc. 1966, 88, 763–768. 3. Büchi, G.; Fliri, H.; Shapiro, R. J. Org. Chem. 1978, 43, 4765–4769. 4. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem. Soc. 1983, 105,
7754–7755. 5. Royer, J.; Husson, H. P. Tetrahedron Lett. 1987, 28, 6175–6178. 6. Villacampa, M.; Martínez, M.; González-Trigo, G.; Söllhuber, M. M. J. Heterocycl.
Chem. 1992, 29, 1541–1544. 7. Bermudez, J.; Gregory, J. A.; King, F. D.; Starr, S.; Summersell, R. J. Bioorg. Med.
Chem. Lett. 1992, 2, 519–522. 8. Langlois, M.; Yang, D.; Soulier, J. L.; Florac, C. Synth. Commun. 1992, 22, 3115–
3116. 9. Jarevång, T.; Anke, H.; Anke, T.; Erkel, G.; Sterner, O. Acta Chem. Scand. 1998, 52,
1350–1352. 10. Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004, 45, 5175–5177.
475
Rosenmund reduction Hydrogenation reduction of acid chloride to aldehyde using BaSO4-poisoned pal-ladium catalyst. Without this poisoning, the resulting aldehyde may be further re-duced to the corresponding alcohol.
R Cl
O H2
Pd−BaSO4 R H
O
Pd Pd
H HH HPd Pd
H HPd Pd
Pd HH
R Cl
O Pd(0)
oxidativeaddition
R Pd
OCl
Pd HH
ligand exchange
R H
OPd(0)R Pd
OH
reductive
elimination
Example 14
R Cl
O
R H
OH2/Pd or Pd/BaSO42,6-dimethylpyridine, THF
or H2/Pd−C/quinoline−S, PhH74−97%
Example 26
HOCO2t-Bu
O
NBoc2
Cl
Me2NCl
CO2t-BuO
NBoc2
H2, 5% Pd/C2,6-lutidine
THF, 2 h, 78%
HCO2t-Bu
O
NBoc2
Example 39
OH
O 1. SOCl2, cat. DMF, reflux, 4 h
2. H2, 5% Pd/C, EtOAc, 53%
476
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_222, © Springer-Verlag Berlin Heidelberg 2009
H
O
References 1. Rosenmund, K. W. Ber. 1918, 51, 585–594. Karl Wilhelm Rosenmund was born in
Berlin, Germany in 1884. He was a student of Otto Diels and received his Ph.D. In 1906. Rosenmund became professor and director of the Pharmaceutical Institute in Kiel in 1925.
2. Mosettig, E.; Mozingo, R. Org. React. 1948, 4, 362–377. (Review). 3. Tsuji, J.; Ono, K.; Kajimoto, T. Tetrahedron Lett. 1965, 6, 4565–4568. 4. Burgstahler, A. W.; Weigel, L. O.; Schäfer, C. G. Synthesis 1976, 767–768. 5. McEwen, A. B.; Guttieri, M. J.; Maier, W. F.; Laine, R. M.; Shvo, Y. J. Org. Chem.
1983, 48, 4436–4438. 6. Bold, V. G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta 1990, 73, 405–
410. 7. Yadav, V. G.; Chandalia, S. B. Org. Proc. Res. Dev. 1997, 1, 226–232. 8. Chandnani, K. H.; Chandalia, S. B. Org. Proc. Res. Dev. 1999, 3, 416–424. 9. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron 2002, 58, 4851–4858. 10. Ancliff, R. A.; Russell, A. T.; Sanderson, A. J. Chem. Commun. 2006, 3243–3245.
477
Rubottom oxidation α-Hydroxylation of enolsilanes.
OSiR31. m-CPBA
2. K2CO3, H2O
OOH
R3SiO O HOO
Ar
Prilezhaev
epoxidationO
R3SiOH
OO
ArO
OR3Si
H
‡
The “butterfly” transition state
OO
R3Si H OOH
SiR3 OOHK2CO3, H2O
hydrolysis
:
Example 12
N
OSiMe3CO2Me
2.5 eq m-CPBAClCH2CH2Cl
0 oC to rt, 1 h, 80%
N
OOH
CO2Me
Example 23
O
TMSCl, NaI
Et3N, rt, 91%OTMS
1. m-CPBA, NaHCO3, pentane, 0 oC
2. aq. K2CO3, 0 oC, 20 h, 80%O
OH
Example 34
TMSO
TMSO
OTBSO
TMSO
OTBS
TMSO SiO2
O
TMSO
OTBS
HOm-CPBA
63%
478
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_223, © Springer-Verlag Berlin Heidelberg 2009
Example 45
Me
H
H
H
Me
MeO
Me
H
H
H
Me
MeO
HO
1. LDA, TMSCl2. m-CPBA, NaHCO3
3. K2CO3, MeOH 72%
References 1. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 15,
4319−4322. George Rubottom discovered the Rubottom oxidation when he was an assistant professor at the University of Puerto Rico. He is now a grant officer at the National Science Foundation.
2. Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. Tetrahedron Lett. 1985, 26, 3563−2366.
3. Jauch, J. Tetrahedron 1994, 50, 12903−12912. 4. Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; Hollis, W. G., Jr.; O’Mahoney, R.;
Lever, J. G.; Bankaitis-Davis, D. M. J. Am. Chem. Soc. 1996, 118, 7513–7528. 5. Paquette, L. A.; Sun, L.-Q.; Friedrich, D.; Savage, P. B. Tetrahedron Lett. 1997, 38,
195–198. 6. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. J. Org.
Chem. 2004, 69, 2454−2460. 7. Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Cat. 2004, 346, 143−151. (Review). 8. He, J.; Tchabanenko, K.; Adlington, R. M.; Cowley, A. R.; Baldwin, J. E. Eur. J. Org.
Chem. 2006, 4003−4013. 9. Wolfe, J. P. Rubottom oxidation. In Name Reactions for Functional Group Transfor-
mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 282−290. (Review).
10. Wang, H.; Andemichael, Y. W.; Vogt, F. G. J. Org. Chem. 2009, 74, 478−481.
479
Rupe rearrangement Acid-catalyzed rearrangement of tertiary α-acetylenic (terminal) alcohols, leading to the formation of α,β-unsaturated ketones rather than the corresponding α,β-unsaturated aldehydes. Cf. Meyer−Schuster rearrangement.
H+, H2OOH O
HOH OH2 − H2O
dehydration H
− H
H
protonation H
H
H2O:
tautomerizationO
H
H
OH:
H
Example 14
OH
conc. H2SO4
CHCl3, HOAc, reflux, 1 h
O
Example 28
Me
OH
MeCH3
O
HCO2H, reflux
15 min., 42%
Example 39
O
H3C
H
H
H
OHA-252C H+ resin
EtOAc, reflux
4 h, 78%O
H3C
H
H
O
480
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_224, © Springer-Verlag Berlin Heidelberg 2009
References 1. Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9, 672. 2. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429−438. (Review). 3. Hasbrouck, R. W.; Anderson Kiessling, A. D. J. Org. Chem. 1973, 38, 2103−2106. 4. Baran, J.; Klein, H.; Schade, C.; Will, E.; Koschinsky, R.; Bäuml, E.; Mayr, H. Tetra-
hedron 1988, 44, 2181−2184. 5. Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389–7392. 6. An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997,
62, 2505–2511. 7. Yadav, J. S.; Prahlad, V.; Muralidhar, B. Synth. Commun. 1997, 27, 3415−3418. 8. Takeda, K.; Nakane, D.; Takeda, M. Org. Lett. 2000, 2, 1903–1905. 9. Weinmann, H.; Harre, M.; Neh, H.; Nickisch, K.; Skötsch, C.; Tilstam, U. Org. Proc.
Res. Dev. 2002, 6, 216−219. 10. Mullins, R. J.; Collins, N. R. Meyer–Schuster Rearrangement. In Name Reactions for
Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 305−318. (Review).
481
Saegusa oxidation Palladium-catalyzed conversion of enol silanes to enones, also known as the Saegusa enone synthesis.
O
Me
O
Me
Me3Si0.5 Pd(OAc)2
0.5 p-benzoquinonebenzene, rt, 3 h, 91%
The mechanism is similar to that of the Wacker oxidation (page 564).
O:
Me
Me3Si O
Me
Me3Si
Pd(II)
AcO
Me OSiMe3
OPd(II)AcO OAc
OAc
O
MeH
Pd(II) β-hydride
elimination
O
Me
Pd
H
OAc
O
Me
Pd(0) HOAcOAc
Regenerating the Pd(II) oxidant:
Pd(0) 2 HOAc
O
O
OH
OH
Pd(OAc)2
Larock reported regeneration of the Pd(II) oxidant using oxygen:4
Pd(0) O2O
PdO
HOAcHOOPdOAc
OSiMe3
O
HOOSiMe3 Pd(II)(OAc)2 Example 13
OMeO
OO
H
HO O
Me3SiCl, Et3N
CH3OCH2CH2OCH3rt, 3 h, 74%
OMeO
OTMSO
H
HO O
482
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_225, © Springer-Verlag Berlin Heidelberg 2009
Pd(OAc)2, p-benzoquinone
CH3CN, rt, 60 oC, 53%
OMeO
OO
H
HO O
Example 28
O
O
O
O
O
OTBS
LDA, TBSCl
HMPA−THF−78 to 0 oC, 93%
O
O
O
Pd(OAc)2, O2
DMSO, 80 oC48 h, 77%
Example 310
H
OTES
MeO
MeO
MeO
MePd(OAc)2, DMSO
0 oC to rt, 12 h, 81%
References 1. Ito, Y.; Hirao, T.; Saegusa, T.; J. Org. Chem. 1978, 43, 1011–1013. 2. Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54,
5350–5356. 3. Kim, M.; Applegate, L. A.; Park, O.-S.; Vasudevan, S.; Watt, D. S. Synth. Commun.
1990, 20, 989–997. 4. Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett.
1995, 36, 2423–2426. 5. Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem., Int. Ed.
1999, 38, 2015–2016. The authors proposed a sandwiched Pd(II) as a possible alterna-tive pathway.
6. Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217–3220. 7. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596–7597. 8. Kadota, K.; Kurusu, T.; Taniguchi, T.; Ogasawara, K. Adv. Synth. Catal. 2001, 343,
618–623. 9. Sha, C.-K.; Huang, S.-J.; Zhan, Z.-P. J. Org. Chem. 2002, 67, 831–836. 10. Angeles A. R; Waters, S. P.; Danishefsky S. J. J. Am. Chem. Soc. 2008, 130, 13765–
13770.
483
Sakurai allylation reaction Lewis acid-mediated addition of allylsilanes to carbon nucleophiles. Also known as the Hosomi–Sakurai reaction. The allylsilane will add to the carbonyl com-pound directly if the electrophile (carbonyl group) is not part of an α,β-unsaturated system (Example 2), giving rise to an alcohol.
OSiMe3
TiCl4O
O
SiMe3
TiCl4
complexation OTiCl3:
Cl
SiMe3
OTiCl3
Cl
Michael
addition
The β-carbocation is stabilized by the β-silicon effect
silicon
cleavage
OOTiCl3
H2O
workupMe3Si Cl
Example 12
O
EtAlCl2, Tol.
0 oC, 50%O
TMS
Example 26
OBr
OTIPS
CHOSiMe3
TiCl4, CH2Cl2
rt, 10 min., 67%
OBr
OTIPS
OH
9:1 dr
484
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_226, © Springer-Verlag Berlin Heidelberg 2009
Example 39
SiMe3
H3C OPMB
OHC
H
OC(O)CO2Me
CO2Et
BF3•OEt2
−78 oC, 4 h
Ba(OH)2•8H2O
0 oC, 2 h, 62%CO2Et
H
H
H OH
OC(O)CO2Me
HOPMB
Me
OO
Me OPMB
HH CHO
H
Example 410
BnN NBn
O
OHO
HHO HSiMe3
BF3•OEt2, CH2Cl2rt, 64%
BnN NBn
O
O
HH
References 1. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295–1298. 2. Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985, 50, 3615–3618. 3. Tori, M.; Makino, C.; Hisazumi, K.; Sono, M.; Nakashima, K. Tetrahedron: Asymme-
try 2001, 12, 301–307. 4. Leroy, B.; Markó, I. E. J. Org. Chem. 2002, 67, 8744–8752. 5. Itsuno, S.; Kumagai, T. Helv. Chim. Acta 2002, 85, 3185–3196. 6. Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155–13164. 7. Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60, 8591–8603. 8. Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem. Commun. 2005, 394–396. 9. Kalidindi, S.; Jeong, W. B.; Schall, A.; Bandichhor, R.; Nosse, B.; Reiser, O. Angew.
Chem., Int. Ed. 2007, 46, 6361–6363. 10. Norcross, N. R.; Melbardis, J. P.; Solera, M. F.; Sephton, M. A.; Kilner, C.; Zakharov,
L. N.; Astles, P. C.; Warriner, S. L.; Blakemore, P. R. J. Org. Chem. 2008, 73, 7939–7951.
485
Sandmeyer reaction Haloarenes from the reaction of a diazonium salt with CuX.
ArN2 YCuX
Ar X
X = Cl, Br, CN
e.g.:
ArN2 ClCuCl
Ar ClCuCl2ArN2↑ CuCl
Example 14
N2
Cl
Cl1. FeCl3
2. CuCl2 81%
N2
Cl
CuCl4
2
DMSO, rt
97%Cl
Cl
Cl Cl Cl
Example 27
CF3
ClNH2
1. H2SO4
2. NaNO2
CF3
ClN
NCuCN, NaCN
Na2CO3, 50%
CF3
ClCN
Example 38
OH
OMe
H2N
NaNO2, CuBr
55%
OH
OMe
Br
Example 49
N
O
O
NO2
NH
O
1. HOAc, H2O, H2SO4 reflux, 2 h
2. NaNO2, 0 oC3. CuCN, 50 oC 50−58%
N
O
O
NO2
NC
486
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_227, © Springer-Verlag Berlin Heidelberg 2009
References 1. Sandmeyer, T. Ber. 1884, 17, 1633. Traugott Sandmeyer (1854−1922) was born in
Wettingen, Switzerland. He apprenticed under Victor Meyer and Arthur Hantzsch al-though he never took a doctorate. He later spent 31 years at the company J. R. Geigy, which is now part of Novartis.
2. Suzuki, N.; Azuma, T.; Kaneko, Y.; Izawa, Y.; Tomioka, H.; Nomoto, T. J. Chem. Soc., Perkin Trans. 1 1987, 645–647.
3. Merkushev, E. B. Synthesis 1988, 923–937. (Review). 4. Obushak, M. D.; Lyakhovych, M. B.; Ganushchak, M. I. Tetrahedron Lett. 1998, 39,
9567–9570. 5. Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc.,
Perkin Trans. 2 2002, 1135–1150. 6. Daab, J. C.; Bracher, F. Monatsh. Chem. 2003, 134, 573–583. 7. Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Org. Proc. Res. Dev. 2004, 8, 1059–
1064. 8. Kim, S.-G.; Kim, J.; Jung, H. Tetrahedron Lett. 2005, 46, 2437–2439. 9. LaBarbera, D. V.; Bugni, T. S.; Ireland, C. M. J. Org. Chem. 2007, 72, 8501–8505. 10. Gehanne, K.; Lancelot, J.-C.; Lemaitre, S.; El-Kashef, H.; Rault, S. Heterocycles
2008, 75, 3015–3024.
487
Schiemann reaction Fluoroarene formation from arylamines. Also known as the Balz−Schiemann re-action.
ArN2 BF4
Ar NH2 HNO2 HBF4
ΔAr F N2↑ BF3
HBF4HO
NO H2O
NO: H2O N O
HON
OO
NO
NO
ArNH2
ArHN
NO Ar
NN
OH:ON
ON
O: ArN
NOH2
H :
H2O Ar N N ArN2 BF4ArN2↑
Δ Ar F BF3F BF3
Example 14
N
N N
N
F
NH2NaNO2, HBF4, H2O
−10 to 0 oC, 25%
N
N N
N
F
F
R R
R = 2,3-5-tri-O-acetyl-β-D-ribofuranose
Example 2, Photo-Schiemann reaction6
HN N
F NHBoc 1. HBF42. NaNO2
3. hvHN N
F F
HN N
F
36% 8%
Example 3, Photo-Schiemann reaction8
HN N
CO2EtH2N NO+BF4−
[bmim][BF4] HN N
CO2EtBF4−N2
+ hv
[bmim][BF4]0 oC, 24 h, 56%
HN N
CO2EtF
488
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_228, © Springer-Verlag Berlin Heidelberg 2009
Example 410
S
NH2
CO2Me
NaNO2
HBF493% S
N2+BF4
−
CO2Me
160−200 oC
sand, 67% S
F
CO2Me
References 1. Balz, G.; Schiemann. G. Ber. 1927, 60, 1186−1190. Günther Schiemann was born in
Breslau, Germany in 1899. In 1925, he received his doctorate at Breslau, where he became an assistant professor. In 1950, he became the Chair of Technical Chemistry at Istanbul, where he extensively studied aromatic fluorine compounds.
2. Roe, A. Org. React. 1949, 5, 193−228. (Review). 3. Sharts, C. M. J. Chem. Educ. 1968, 45, 185−192. (Review). 4. Montgomery, J. A.; Hewson, K. J. Org. Chem. 1969, 34, 1396−1399. 5. Laali, K. K.; Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31−34. 6. Dolensky, B.; Takeuchi, Y.; Cohen, L. A.; Kirk, K. L. J. Fluorine Chem. 2001, 107,
147−152. 7. Gronheid, R.; Lodder, G.; Okuyama, T. J. Org. Chem. 2002, 67, 693−720. 8. Heredia-Moya, J.; Kirk, K. L. J. Fluorine Chem. 2007, 128, 674−678. 9. Gribble, G. W. Balz-Schiemann reaction. In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 552−563. (Review).
10. Pomerantz, M.; Turkman, N. Synthesis 2008, 2333−2336.
489
Schmidt rearrangement The Schmidt reactions refer to the acid-catalyzed reactions of hydrazoic acid with electrophiles, such as carbonyl compounds, tertiary alcohols and alkenes. These substrates undergo rearrangement and extrusion of nitrogen to furnish amines, ni-triles, amides or imines.
R1 R2
ON2↑
R2 NH
OR1
HN3
H+
R1 R2
O H
R1 R2
OH HN3
R1 R2
N3HO
R1 R2
NHON
N
R1 R2
NH2ON
N
H
azido-alcohol
NR2
R1
N N− H2O
migration
:
R1 NR1
N2↑
H2O
:
R2
nitrilium ion intermediate (Cf. Ritter intermediate)
NR2
R1HO
R2 NH
OR1tautomerization
H
Example 1, A classic example3
CO2EtO
NaN3
MeSO3H21%
HN CO2Et
O
Example 25
O H
NO
NaN3, H2SO4
CHCl3, 92%
490
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_229, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Intramolecular Schmidt rearrangement6
OH
O
N3
TfOH, CH2Cl2
0 oC, 79%N
O
OH
Example 4, Intramolecular Schmidt rearrangement8
H
Et
TiCl482%
OO
N3
Et
O N OH
H
Example 5, Intermolecular Schmidt rearrangement9
OMe
N
ONC
NaN3, CHCl3
conc. H2SO4
OMe
N
NH
OHO2C
OMe
N
HNHO2C O
84%0%
References 1. (a) Schmidt, K. F. Angew. Chem. 1923, 36, 511. Karl Friedrich Schmidt (1887−1971)
collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry after 1923. (b) Schmidt, K. F. Ber. 1924, 57, 704−706.
2. Wolff, H. Org. React. 1946, 3, 307−336. (Review). 3. Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667−2573. 4. Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316−4318. 5. Johnson, P. D.; Aristoff, P. A.; Zurenko, G. E.; Schaadt, R. D.; Yagi, B. H.; Ford, C.
W.; Hamel, J. C.; Stapert, D.; Moerman, J. K. Bioorg. Med. Chem. Lett. 2003, 13, 4197−4200.
6. Wrobleski, A.; Sahasrabudhe, K.; Aubé, J. J. Am. Chem. Soc. 2004, 126, 5475−5481. 7. Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260−11261. 8. Iyengar, R.; Schidknegt, K.; Morton, M..; Aubé, J. J. Org. Chem. 2005, 70,
10645−10652. 9. Amer, F. A.; Hammouda, M.; El-Ahl, A. A. S.; Abdel-Wahab, B. F. Synth. Commun.
2009, 39, 416−425. 10. Wu, Y.-J. Schmidt reactions. In Name Reactions for Homologations-Part II; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 353−372. (Review).
491
Schmidt’s trichloroacetimidate glycosidation reaction Lewis acid-promoted glycosidation of trichloroacetimidates with alcohols or phe-nols.
O
OAcOCH3
AcO
OHO
OAcOCH3
AcO
O
HN CCl3
cat. NaH
Cl3CCN
HO Ar
BF3•OEt2
O
OAcOCH3
AcO
OAr
trichloroacetimidate
O
OAcOCH3
AcO
OH
HO
OAcOCH3
AcO
O
N CCl3
H2↑deprotonation BF3•OEt2
O
OCH3O
AcO
O
HN CCl3
BF3•OEt2
Oneighboring
group assistance
O
NH2Cl3C
O
CH3OAcO O
OO
OAcOCH3
AcO
OArO Ar
H:
Example 15
O
OAcOCH3
AcO
O
HN CCl3
I CO2Me
OMeOMe
HO
O
OAcOCH3
AcO
OBF3•OEt2, 4 Å MS
CH2Cl2, −50 oC, 95%
I CO2Me
OMeOMe
492
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_230, © Springer-Verlag Berlin Heidelberg 2009
Example 27
O
BnO AcO
BnO
BnOO
CCl3
NH
OH
BF3•OEt2CH2Cl2/hexane
−20 oC, 68%
OO
BnO AcO
BnO
BnO
Example 39
O
AcO
AcO
AcOO
CCl3
NH
OAc
0.2 equiv TMSOTf, CH2Cl2, −15 oC, 5 min.
HONH2
PF6
O
AcO
AcO
AcO
ONH2
t-BuPF6
O
AcO
AcO
AcOO
OAc
NH2
t-BuPF6
40%
O
O
30%
References 1. (a) Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203−218. (b) Schmidt,
R. R. Angew. Chem., Int. Ed. 1986, 25, 212−235. (Review). 2. Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am.
Chem. Soc. 1992, 114, 3134−3136. 3. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503−1531. (Review). 4. Nicolaou, K. C. Angew. Chem., Int. Ed. 1993, 32, 1377−1385. (Review). 5. Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl, W.;
Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7593−611.
6. Fürstner, A.; Jeanjean, F.; Razon, P. Angew. Chem., Int. Ed. 2002, 41, 2097−2101. 7. Yan, L. Z.; Mayer, J. P. J. Org. Chem. 2003, 68, 1161−1162. 8. Harding, J. R.; King, C. D.; Perrie, J. A.; Sinnott, D.; Stachulski, A. V. Org. Biomol.
Chem. 2005, 3, 1501−1507. 9. Steinmann, A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 66, 5506−5513. 10. Coutrot, F.; Busseron, E.; Montero, J.-L. Org. Lett. 2008, 10, 753−756.
493
Shapiro reaction The Shapiro reaction is a variant of the Bamford−Stevens reaction. The former uses bases such as alkyl lithium and Grignard reagents whereas the latter employs bases such as Na, NaOMe, LiH, NaH, NaNH2, etc. Consequently, the Shapiro re-action generally affords the less-substituted olefins (the kinetic products), while the Bamford−Stevens reaction delivers the more-substituted olefins (the thermo-dynamic products).
R2
R3
R1
ER2N
HN
TsR3
R12 n-BuLi
then E
R2N
NTs
R3
R1 H
H
BuR2
NN
TsR3
R1
H
Bu
R2
R3
R1
R2N
N
R3
R1− N2 E
R2
R3
R1
E
Example 12
NNHTs MeLi, Et2O
98% 2%
Example 23
NNHTsMeLi, Et2O−PhH
75−80%
Example 37
O
O
MeO
HOMe
H
H H
OTBDPS 1. TsNHNH2, MeOH, THF
2. n-BuLi, THF, –78 °C to rtO
MeO
HOMe
H
H H
OTBDPS
3. aqueous workup69%
494
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_231, © Springer-Verlag Berlin Heidelberg 2009
Example 48
Me
H
Me
NNHTris
1. n-BuLi
2. MgBr2•OEt2
3.
PhO
Me
Me
O
O
Me
H
Me HO PhO
Me
Me
O
55% yieldone diastereomer
References
1. Shapiro, R. H.; Duncan, J. H.; Clopton, J. C. J. Am. Chem. Soc. 1967, 89, 471–472.
Robert H. Shapiro was an assistant professor at the University of Colorado. He was not given tenure despite getting a reaction named after him.
2. Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734–5735. 3. Dauben, W. G.; Lorber, M. E.; Vietmeyer, N. D.; Shapiro, R. H.; Duncan, J. H.;
Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762−4763. 4. Shapiro, R. H. Org. React. 1976, 23, 405−507. (Review). 5. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55–59. (Review). 6. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1−83. (Review). 7. Grieco, P. A.; Collins, J. L.; Moher, E. D.; Fleck, T. J.; Gross, R. S. J. Am. Chem. Soc.
1993, 115, 6078–6093. 8. Tamiya, J.; Sorensen, E. J. Tetrahedron 2003, 59, 6921–6932. 9. Wolfe, J. P. Shapiro reaction. In Name Reactions for Functional Group Transforma-
tions; Li, J. J., Corey, E. J., eds, John Wiley & Sons: Hoboken, NJ, 2007, pp 405−413. 10. Bettinger, H. F.; Mondal, R.; Toenshoff, C. Org. Biomol. Chem. 2008, 6, 3000–3004.
495
Sharpless asymmetric amino-hydroxylation Osmium-mediated cis-addition of nitrogen and oxygen to olefins. Regioselectiv-ity may be controlled by ligand. Nitrogen sources (X−NClNa) include:
SNClNa
R O
O
R = p-Tol; MeEtO NClNa
OBnO NClNa
O
NClNa
OTMS NBrLi
O
R1
R
chiral ligandK2OsO2(OH)4
ClNaN−Xt-BuOH, H2O
R1
HO
R
NHX
The catalytic cycle:
R1
R
R1
HO
R
NHX
OsO4 ClN−X
OsO
OO
N X
OsO
OO
N XL*
OsO
OO
NL*
X
R
R1OsO
OO
NL*
X
R
R1
OsO
OO
NN X
R
R1
X
L*
ClN−X
L*
H2O
Example 11b
5 mol% (DHQD)2PHAL4 mol% K2OsO2(OH)4
n-PrOH/H2O (1:1), 63% ee51%
BnO NClNa
O NH OHBnO
O
496
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_232, © Springer-Verlag Berlin Heidelberg 2009
(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine:
N
HO
N
O
NNO
N
N
O
Example 22
CO2Et
BnO
CO2Et
BnO
OH
NHCbz
BnOCONH2NaOH, t-BuOCl(DHQD)2AQN
K2OsO2(OH)4n-PrOH/H2O (1:1)
rt, 12 h, 45%, 87% ee
Example 36
NaOH, urethaneK2OsO2(OH)4(DHQD)2PHAL
1,3-dichloro-5,5-di-methyl hydantoin
n-PrOH/H2O
F
Me
F
OH
Me
HNOEt
O
F
NH
Me
HO
OEtO
1. Cs2CO2, MeOH
2. H2SO4
F
HN O
O
References 1. (a) Herranz, E.; Sharpless, K. B. J. Org. Chem. 1978, 43, 2544−2548. K. Barry Shar-
pless (USA, 1941−) shared the Nobel Prize in Chemistry in 2001 with Herbert Wil-liam S. Knowles (USA, 1917−) and Ryoji Noyori (Japan, 1938−) for his work on chirally catalyzed oxidation reactions. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 2813−2817. (c) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997, 36, 2637−2640. (d) Kolb, H. C.; Sharpless, K. B. Tran-sition Met. Org. Synth. 1998, 2, 243−260. (Review). (e) Thomas, A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379−8385. (f) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783−786.
497
2. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Braese, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602−2621.
3. Lohr, B.; Orlich, S.; Kunz, H. Synlett 1999, 1139−1141. 4. Boger, D. L.; Lee, R. J.; Bounaud, P.-Y.; Meier, P. J. Org. Chem. 2000, 65,
6770−6772. 5. Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221−2223. 6. Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman, S. A.; Larsen, R. D.; Reider,
P. J. Org. Lett. 2000, 2, 2821−2824. 7. Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic Asymmetric Synthesis; 2nd edn.,
Ojima, I., Ed.; Wiley−VCH: New York, 2000, 399. (Review). 8. Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin 1 2002, 2733−2746. (Review). 9. Rahman, N. A.; Landais, Y. Cur. Org. Chem. 2000, 6, 1369−1395. (Review). 10. Nilov, D.; Reiser, O. Recent Advances on the Sharpless Asymmetric Aminohydroxyla-
tion. In Organic Synthesis Highlights Schmalz, H.-G.; Wirth, T., eds.; Wiley−VCH: Weinheim, Germany 2003, 118−124. (Review).
11. Bodkin, J. A.; Bacskay, G. B.; McLeod, M. D. Org. Biomol. Chem. 2008, 2544−2553. 12. Wong, D.; Taylor, C. M. Tetrahedron Lett. 2009, 50, 1273−1275.
498
Sharpless asymmetric dihydroxylation Enantioselective cis-dihydroxylation of olefins using osmium catalyst in the pres-ence of cinchona alkaloid ligands.
RL
RMRS
H
AD-mix-β
AD-mix-α
K2OsO2(OH)4
K2CO3, K3Fe(CN)6
(DHQD)2-PHAL
(DHQ)2-PHAL
OHHO
RS RL HRM
HO OH
HRMRSRL
(DHQ)2-PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine:
NO
N
O
NNO
N
N
O
The concerted [3 + 2] cycloaddition mechanism:5
LOs
O
OO
OOsO
OO
LO
OsO
OO
LO
[3 + 2]-like
cycloadditionOsO
OO
LO
hydrolysis HO
HO
Example 12
EtO2CO
OH
N3
K2OsO2(OH)4(DHQD)2PHAL
K2CO3, MeSO2NH2t-BuOH/H2O (1:1)rt, 12 h, 90% de
EtO2CO
OH
N3
OH
OH
Example 24
CO2Et
BnO
1. AD-mix-β, MeSO2NH2 t-BuOH/H2O (1:1), rt, 12 h
2. NosCl, Et3N, CH2Cl2 0 oC, 54%, 92% ee
CO2Et
BnO
OH
ONos
Nos = nosylate = 4-nitrobenzenesulfonyl
499
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_233, © Springer-Verlag Berlin Heidelberg 2009
The catalytic cycle: (the secondary cycle is shut off by maintaining a low concen-tration of olefin):
R
R
LH2O
OHR
OHR
low ee
OsO
OR
R
LO O
LR
R
OsOO
OO
OsOO
OO O
RR
H2O
OHR
OHR
high ee
OsOO
OO O
RR
R R
NMONMM
L
Secondary cyclelow ee
Primary cyclehigh ee
Example 39
CO2EtOMe
Me
OO
CO2EtOMe
Me
OO
OH
OHAD-mix-α
t-BuOH/H2O (1:1)93%, 97% ee
500
Example 410
K2OsO2(OH)4(DHQD)2PHAL
NMOacetone/H2O
89%
OH
OH 70% ee
References 1. (a) Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. J. Am.
Chem. Soc. 1988, 110, 1968−1970. (b) Wai, J. S. M.; Markó, I.; Svenden, J. S.; Finn, M. G.; Jacobsen, E. N.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 1123−1125.
2. Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993, 58, 7096−7699. 3. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483−2547. (Review). 4. Rao, A. V. R.; Chakraborty, T. K.; Reddy, K. L.; Rao, A. S. Tetrahedron Lett. 1994,
35, 5043−5046. 5. Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319−329. (Mechanism). 6. DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner,
T.; Thomas, A. A. J. Am. Chem. Soc. 1997, 119, 9907−9908. (Mechanism). 7. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024−2032. (Review, Nobel Prize
Address). 8. Zhang, Y.; O’Doherty, G. A. Tetrahedron 2005, 61, 6337−6351. 9. Chandrasekhar, S.; Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62, 12098−12107. 10. Ferreira, F. C.; Branco, L. C.; Verma, K. K.; Crespo, J. G.; Afonso, C. A. M.
Tetrahedron: Asymmetry 2007, 18, 1637−1641. 11. Ramon, R.; Alonso, M.; Riera, A. Tetrahedron: Asymmetry 2007, 18, 2797−2802. 12. Krishna, P. R.; Reddy, P. S. Synlett 2009, 209−212.
501
Sharpless asymmetric epoxidation Enantioselective epoxidation of allylic alcohols using t-butyl peroxide, titanium tetra-iso-propoxide, and optically pure diethyl tartrate.
R1 R
R2OH
t-Bu−O−OH, Ti(Oi--Pr)4
L-(+)-diethyl tartrate
R1 R
R2OH
O
R1 R
R2OH
t-Bu−O−OH, Ti(Oi-Pr)4
D-(−)-diethyl tartrate
R1 R
R2OH
O
The catalytic cycle:
LnTiOi-Pr
Oi-Pr
OH t-Bu−O−OH
LnTiO
O
Ot-Bu
LnTiO *
t-Bu
O
LnTi OO
Ot-Bu
LnTi OO
Ot-Bu
*
**
***
LnTiO
O
t-Bu
O
*
*
OHO
502
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_234, © Springer-Verlag Berlin Heidelberg 2009
The putative active catalyst and the transition state:
O
Ti
O
Tii-PrO
i-PrO
Oi-PrO
OEt
O
EtO2C
O
CO2EtOEtO
Oi-Pr
OOTi
OO
EtO2C CO2Et
t-Bu
O
Example 13
OHMeTi(Oi-Pr)4, 4 Å MS, (+)-DET
t-BuOOH, CH2Cl2 −20 °C
OHO
Mecrude: 88% yield, 92.3 % ee
recrystallization: 73% yield, > 98% ee
Example 23
OH(−)-DIPT, Ti(Oi-Pr)4
TBHP, 3 Å MS50−60%, 88−92% ee
OHO
Example 311
L-(+)-DIPT, Ti(Oi-Pr)4
TBHP, EtOAc89%, 98% ee
OH OHO
(R,R)O
NHH
HOEt
(S,S)-reboxetine
Example 412
O
BnO BnO
BnO
BnO
OH
D-(−)-DIPT, Ti(Oi-Pr)4
TBHP, 4 Å MS70%, > 95% ee
O
BnO BnO
BnO
BnO
OHO
503
References 1. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974−5976. (b) Wil-
liams, I. D.; Pedersen, S. F.; Sharpless, K. B.; Lippard, S. J. J. Am. Chem. Soc. 1984, 106, 6430−6433. (c) Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 106−113.
2. Pfenninger, A. Synthesis 1986, 89−116. (Review). 3. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765−5780. 4. Corey, E. J. J. Org. Chem. 1990, 55, 1693−1694. (Review). 5. Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed,; Pergamon Press: New York, 1991; Vol. 7, Chapter 3.2. (Review). 6. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., ed,;
VCH: New York, 1993; Chapter 4.1, pp 103−158. (Review). 7. Schinzer, D. Org. Synth. Highlights II 1995, 3. (Review). 8. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1−299. (Review). 9. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; 2nd ed., Ojima, I.,
ed.; Wiley-VCH: New York, 2000, 231−285. (Review). 10. Palucki, M. Sharpless−Katsuki Epoxidation. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 50−62. (Review).
11. Henegar, K. E.; Cebula, M. Org. Proc. Res. Dev. 2007, 11, 354−358. 12. Pu, J.; Franck, R. W. Tetrahedron 2008, 64, 8618−8629. 13. Knight, D. W.; Morgan, I. R. Tetrahedron Lett. 2009, 50, 35−38.
504
Sharpless olefin synthesis Olefin synthesis from the syn-oxidative elimination of o-nitrophenyl selenides, which may be prepared using o-nitrophenyl selenocyanate and Bu3P, among other methods.
OHR
SeCNNO2
Bu3P, THF, rtSe
R
NO2
OR
O
R
SeNO2
CN
H
:
SeNO2
PBu3CN
Bu3P:
SN2
SeR
NO2
SeNO2
OR PBu3 O PBu3
OSe
R
NO2H OR
SeNO2
syn-elimination OH
Example 13
OHOH H
H
N
MeO
1. Bu3P, o-O2NPhSeCN, THF, rt2. CSA, PhH, rt to 70 oC
3. m-CPBA, 2,4,6-collidine CH2Cl2, 0 oC, 42%
OH
H
NH
Example 26
1. Bu3P, o-O2NPhSeCN THF, rt, 6 h, 97%
2. m-CPBA, Et3N, CH2Cl2, −78 oC 86%
OOO
MeO
OH
OH
OH OOO
MeO
OH
OH
505
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_235, © Springer-Verlag Berlin Heidelberg 2009
Example 39
O
H
OH
O
H
OO
HOOMe
OH
SeCNNO2
n-Bu3P, THF, rt, 78%
2. aq. H2O2, THF, pyr. −40 oC to rt, 90%
1.
O
HO
H
OO
HOOMe
Example 410
OH
H O
HOSeCN
NO2
n-Bu3P, THF, rt
2. aq. H2O2, THF, 40 oC 90% 2 steps
1.
OH
H O
References 1. (a) Sharpless, K. B.; Young, M. Y.; Lauer, R. F. Tetrahedron Lett. 1973, 1979−1982.
(b) Sharpless, K. B.; Young, M. Y. J. Org. Chem. 1975, 40, 947−949. 2. (a) Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120−122. (b) Grieco, P. A.;
Miyashita, M. Tetrahedron Lett. 1974, 1869−1871. (c) Grieco, P. A.; Masaki, Y.; Boxler, D. J. Am. Chem. Soc. 1977, 97, 1597−1599. (d) Grieco, P. A.; Gilman, S.; Ni-shizawa, M. J. Org. Chem. 1976, 41, 1485−1486. (e) Grieco, P. A.; Yokoyama, Y. J. Am. Chem. Soc. 1977, 99, 5210−5219.
3. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431−2449. 4. Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1−296. (Review). 5. Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741−4743. 6. Meilert, K.; Pettit, G. R.; Vogel, P. Helv. Chim. Acta 2004, 87, 1493−1507. 7. Siebum, A. H. G.; Woo, W. S.; Raap, J.; Lugtenburg, J. Eur. J. Org. Chem. 2004,
2905−2916. 8. Blay, G.; Cardona, L.; Collado, A. M.; Garcia, B.; Morcillo, V.; Pedro, J. R. J. Org.
Chem. 2004, 69, 7294−7302. The authors observed the concurrent epoxidation of a tri-subsituted olefin, possibly by the o-nitrophenylselenic acid via an intramolecular process.
9. Paquette, L. A.; Dong, S.; Parker, G. D. J. Org. Chem. 2007, 72, 7135−7147. 10. Yokoe, H.; Yoshida, M.; Shishido, K. Tetrahedron Lett. 2008, 49, 3504−3506.
506
Simmons–Smith reaction Cyclopropanation of olefins using CH2I2 and Zn(Cu).
CH2I2 Zn(Cu) ICH2ZnI
CH2 ICH2ZnII IZn
Oxidativeaddition
Simmons−Smith reagent
2 ICH2ZnI (ICH2)2Zn ZnI2
ZnI2CH2
ZnII ZnII
Example 12
O
Zn/Cu [from Zn and Cu(SO4)2]
CH2I2, Et2O, reflux, 36 h, 90%
O
Example 2, An asymmetric version3
MeO
OH
CONEt2
OHOH
CONEt2
(1 eq)
6 eq Zn/Cu, 3 eq CH2I2 CH2Cl2, 0 oC, 15 h
78%, 94% ee
MeO
OH
Example 3, Diastereoselective Simmons−Smith cyclopropanations of allylic amines and carbamates9
NBn2Et2Zn, CH2I2, TFA
CH2Cl2, rt, 1 h92%, > 98% de
NBn2
N
Ph
ZnI
Ph
I
507
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_236, © Springer-Verlag Berlin Heidelberg 2009
Example 410
O
OO
1. PhMe2SiH, RhCl(PPh3)3, 60 oC2. Et2Zn, CH2I2, 0 oC
3. TsOH, MeOH 83%, 3 steps
OO
HOH
OO
HOH
References 1. Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323−5324. Howard E.
Simmons (1929−1997) was born in Norfolk, Virginia. He carried out his graduate studies at MIT under John D. Roberts and Arthur Cope. After obtaining his Ph.D. In 1954, he joined the Chemical Department of the DuPont Company, where he discov-ered the Simmons–Smith reaction with his colleague, R. D. Smith. Simmons rose to be the vice president of the Central Research at DuPont in 1979. His views on physi-cal exercise were the same as those of Alexander Woollcot’s: “If I think about exer-cise, I know if I wait long enough, the thought will go away.”
2. Limasset, J.-C.; Amice, P.; Conia, J.-M. Bull. Soc. Chim. Fr. 1969, 3981−3990. 3. Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn. 1997, 70, 207−217. 4. Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844−5845. 5. Loeppky, R. N.; Elomari, S. J. Org. Chem. 2000, 65, 96−103. 6. Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1−415. (Review). 7. Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341−2350. 8. Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737−2740. 9. Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Chem. Com-
mun. 2007, 4029−4031. 10. Shan, M.; O’Doherty, G. A. Synthesis 2008, 3171−3179. 11. Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131,
954−962.
508
Skraup quinoline synthesis Quinoline from aniline, glycerol, sulfuric acid and oxidizing agent (e.g. PhNO2).
NH2
HO OHOH
H2SO4
PhNO2 N
HO OHOH
H HO OHOH2
Hdehydration
HO OH HOCHO
glycerol
H2OCHO
H
dehydration
H2N
:
O
Hconjugate
additionNH
OH
H
HH
acrolein
NH
O
NH
OH
intramolecular
additionNH
OHH
NH
OH
:
Htautomerization
N
dehydration
NH
OH2H
NH
oxidation by
PhNO2, − H2
H
For an alternative mechanism, see that of the Doebner−von Miller reaction (page 196). Example 15
OHHO OH
F
F
F
NH2
F
F
F
N
NO2
SO3H
H2SO4, FeSO4H3BO3, 80 %
509
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_237, © Springer-Verlag Berlin Heidelberg 2009
Example 26
N O
O
NH2
OHHO OH
N O
O
N
H2SO4, H3BO3FeSO4•7H2O
75 %
Example 3, A modified Skraup quinoline synthesis8
H
MeS
O
SMe
H
NH2MeONMeO SMe
HOAc, reflux
8−10 h, 78%
References 1. (a) Skraup, Z. H. Monatsh. Chem. 1880, 1, 316. Zdenko Hans Skraup (1850−1910)
was born in Prague, Czechoslovakia. He apprenticed under Lieben at the University of Vienna. (b) Skraup, Z. H. Ber. 1880, 13, 2086.
2. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 80−99. (Review). 3. Bergstrom, F. W. Chem. Rev. 1944, 35, 77−277. (Review). 4. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269−1274. 5. Oleynik, I. I.; Shteingarts, V. D. J. Fluorine Chem. 1998, 91, 25−26. 6. Fujiwara, H.; Kitagawa, K. Heterocycles 2000, 53, 409−418. 7. Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U. Tetrahedron 2003, 59, 813−819. 8. Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004, 449−452. 9. Moore, A. Skraup Doebner–von Miller Reaction. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 488−494. (Review).
10. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668−1676. Mechanistic study using 13C-labelled α,β-unsaturated ketones.
11. Vora, J. J.; Vasava, S. B.; Patel, Asha D.; Parmar, K. C.; Chauhan, S. K.; Sharma, S. S. E-J. Chem. 2009, 6, 201−206.
510
Smiles rearrangement Intramolecular nucleophilic aromatic rearrangement. General scheme:
X
YH
Z
Y
XZ
strong
base
X = S, SO, SO2, O, CO2 YH = OH, NHR, SH, CH2R, CONHR Z = NO2, SO2R e.g.:
O2S
OH
OHNO2 O2
S
O
NO2
SNAr
O
NO2O2S
O
O2S
NO2
spirocyclic anion intermediate (Meisenheimer complex)
Example 17
O
HO NaOH, DMA
BrNH2
O O
OH2N
O
NaOH, H2O
50 oC
O
NH
HO
O
H2O, reflux
59%, 3 steps
O
H2N
Example 2, Microwave Smiles rearrangement9
N
N O
NH2
K2CO3, 200 oC
μW, NMP, 30 min.90%
N
HN O
NH
511
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_238, © Springer-Verlag Berlin Heidelberg 2009
Example 310
OMOMO
OHOMe
OI(OAc)2
BnO
2 equiv Na2CO3H2O, rt, 2 h
OMOMO
OHOMe
O
I
OBn
AcO
DMF, 150 oC
87% overall
OMOMO
OOMe
O
OBnI
References 1. Evans, W. J.; Smiles, S. J. Chem. Soc. 1935, 181−188. Samuel Smiles began his ca-
reer at King’s College London as an assistant professor. He later became professor and chair there. He was elected Fellow of the Royal Society (FRS) in 1918.
2. Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React. 1970, 18, 99−215. (Review). 3. Gerasimova, T. N.; Kolchina, E. F. J. Fluorine Chem. 1994, 66, 69−74. (Review). 4. Boschi, D.; Sorba, G.; Bertinaria, M.; Fruttero, R.; Calvino, R.; Gasco, A. J. Chem.
Soc., Perkin Trans. 1 2001, 1751−1757. 5. Hirota, T.; Tomita, K.-I.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S.
Heterocycles 2001, 55, 741−752. 6. Selvakumar, N.; Srinivas, D.; Azhagan, A. M. Synthesis 2002, 2421−2425. 7. Mizuno, M.; Yamano, M. Org. Lett. 2005, 7, 3629−3631. 8. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2005, 7, 3817−3820. 9. Bi, C. F.; Aspnes, G. E.; Guzman-Perez, A.; Walker, D. P. Tetrahedron Lett. 2008, 49,
1832−1835. 10. Jin, Y. L.; Kim, S.; Kim, Y. S.; Kim, S.-A.; Kim, H. S. Tetrahedron Lett. 2008, 49,
6835−6837.
512
Truce−Smile rearrangement A variant of the Smiles rearrangement where Y is carbon:
XL
Zbase
YH
YL
Z
XH
Example 16
N
O
CF3
CO2Me
KH or NaH
N
O
CF3
OMeMO
N
CF3
OM
O
OMe
OO
N
CF3
OOH
N
CF3
Example 27
N
O2S
ONO2
NaOH, H2O
EtOH, reflux
N
O2SNO2
O2S H
N
NO2
41% 46%
Example 38
F
O2N K2CO3, DMF
reflux, 73%HO
O
O
O2NO OH
O2N O
513
Example 410
HOO
OF
NO21. K2CO3, DMSO, rt, 85%
2. PTSA, acetone/H2O 50 oC, 98%
O2NO
O
K2CO3, DMSO
rt, 93% O2NO
OHO O
NO2
References 1. Truce, W. E.; Ray, W. J. Jr.; Norman, O. L.; Eickemeyer, D. B. J. Am. Chem. Soc.
1958, 80, 3625–3629. 2. Truce, W. E.; Hampton, D. C. J. Org. Chem. 1963, 28, 2276–2279. 3. Bayne, D. W; Nicol, A. J.; Tennant, G. J. Chem. Soc., Chem. Comm. 1975, 19, 782–
783. 4. Fukazawa, Y.; Kato, N.; Ito, S.; Tetrahedron Lett. 1982, 23, 437–438. 5. Hoffman, R. V.; Jankowski, B. C.; Carr, C. S.; Düsler, E. N J. Org. Chem. 1986, 51,
130–135. 6. Erickson, W. R.; McKennon, M. J. Tetrahedron Lett. 2000, 41, 4541–4544. 7. Kimbaris, A.; Cobb, J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807–
8815. 8. Mitchell, L. H.; Barvian, N. C. Tetrahedron Lett. 2004, 45, 5669–5672. 9. Snape, T. J. Chem. Soc. Rev. 2008, 37, 2452–2458. (Review). 10. Snape, T. J. Synlett 2008, 2689–2691.
514
Sommelet reaction Transformation of benzyl halides to the corresponding benzaldehydes with the aide of hexamethylenetetramine. Cf. Delépine amine synthesis (page 171).
Ar X NN
N
N
NN
N
NAr
XAr
CHOΔ
H2O
Δ
CHCl3
hexamethylenetetramine
NN
N:
N
NN
N
NAr
X
Ar X
SN2N
NN
N CH2 H
Ar
: hydride
transfer
NN
N
N CH3 Ar
:OH2
NN
N
N CH3 Ar
O H
H ArCHO
NN
NH
N CH3
hemiaminal The hydride transfer and the ring-opening of hexamethylenetetramine may occur in a synchronized fashion:
NN
N
NH
X
Ar
NN
N
N CH3 Ar
Example 13
S
BrBnO 1. HMTA, CHCl3, reflux, 6 h
2. 50% HOAc/H2O, reflux, 3 h 40%
S
CHOBnO
Example 24
NH2
OH
HMTA, HOAc/H2O (11:3)reflux, 4 h
then 4.5 HCl, reflux, 1.5 h68%
CHO
OH
515
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_239, © Springer-Verlag Berlin Heidelberg 2009
Example 37
NN
N
NCl
F
F
HOAc, H2O
Δ, 62%
CHOF
F
Example 48
NBS, BPO
CCl4, reflux, 15 h
38% 62%
Br Br Br
CHO
HMTA, H2O/EtOH (1:1)
reflux, 4 h, 75%
References 1. Sommelet, M. Compt. Rend. 1913, 157, 852−854. Marcel Sommelet (1877−1952) was
born in Langes, France. He received his Ph.D. In 1906 at Paris where he joined the Faculté de Pharmacie after WWI and became the chair of organic chemistry in 1934.
2. Angyal, S. J. Org. React. 1954, 8, 197–217. (Review). 3. Campaigne, E.; Bosin, T.; Neiss, E. S. J. Med. Chem. 1967, 10, 270−271. 4. Stokker, G. E.; Schultz, E. M. Synth. Commun. 1982, 12, 847−853. 5. Armesto, D.; Horspool, W. M.; Martin, J. A. F.; Perez-Ossorio, R. Tetrahedron Lett.
1985, 26, 5217−5220. 6. Kilenyi, S. N., in Encyclopedia of Reagents of Organic Synthesis, ed. Paquette, L. A.,
Wiley: Hoboken, NJ, 1995, Vol. 3, p. 2666. (Review). 7. Malykhin, E. V.; Shteingart, V. D. J. Fluorine Chem. 1998, 91, 19−20. 8. Karamé, I.; Jahjah, M.; Messaoudi, A.; Tommasino, M. L.; Lemaire, M. Tetrahedron:
Asymmetry 2004, 15, 1569−1581. 9. Göker, H.; Boykin, D. W.; Yildiz, S. Bioorg. Med. Chem. 2005, 13, 1707−1714. 10. Li, J. J. Sommelet reaction. In Name Reactions for Functional Group Transformations;
Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 689−695. (Re-view).
516
Sommelet–Hauser rearrangement [2,3]-Wittig rearrangement of benzylic quaternary ammonium salts upon treatment with alkali metal amides via the ammonium ylide intermediates.
NNH2
NH3N
NNH3
H
N [2,3]-sigmatropic
rearrangement
NH2 ammonium ylide
NNH
aromatization
H NH2
Example 13
Ph N SiMe3 IDMF, reflux
18 h, 94%N SiMe3
ICsF, HMPA
rt, 23 h, 86% N
Example 24
N SiMe3
Br CsF, HMPA
10 oC, 0.5 h, 32%AcO
NAcOAcO
N
46:54
Example 38
N
Br
t-BuOK, THF
−15 oC, 50% N
517
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_240, © Springer-Verlag Berlin Heidelberg 2009
Example 410
N CO2R*
CO2Me R* = (−)-8-phenylmenthyl
Br
t-BuOK, THF
−60 oC, 4 h57%, > 20:1 de
CO2Me
N CO2R*
References 1. Sommelet, M. Compt. Rend. 1937, 205, 56–58. 2. Shirai, N.; Sato, Y. J. Org. Chem. 1988, 53, 194–196. 3. Shirai, N.; Watanabe, Y.; Sato, Y. J. Org. Chem. 1990, 55, 2767–2770. 4. Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992, 57, 5034–5036. 5. Klunder, J. M. J. Heterocycl. Chem. 1995, 32, 1687–1691. 6. Maeda, Y.; Sato, Y. J. Org. Chem. 1996, 61, 5188–5190. 7. Endo, Y.; Uchida, T.; Shudo, K. Tetrahedron Lett. 1997, 38, 2113–2116. 8. Hanessian, S.; Talbot, C.; Saravanan, P. Synthesis 2006, 723–734. 9. Liao, M.; Peng, L.; Wang, J. Org. Lett. 2008, 10, 693–696. 10. Tayama, E.; Orihara, K.; Kimura, H. Org. Biomol. Chem. 2008, 6, 3673–3680.
518
Sonogashira reaction Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Cadiot–Chodkiewicz coupling and Castro−Stephens reaction. The Castro–Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper.
R X R'PdCl2•(PPh3)2
CuI, Et3N, rtR R'
II
PdPh3P
Ph3P
Cl
Cl
R'C CCuII
R'C CH
PdPh3P
Ph3P
X
RRX
CuXCuX R'C CH
IIIIPd
Ph3P
Ph3P
C
C
CR'
CR' PdPh3P
Ph3P
C
R
CR'
R'C CC CR'
RC CR'
HX-amine
Pd0(PPh3)2
HX-amine
Cycle A
Cycle BCycle B'ii
iii
iii
iiii. oxidative additionii. transmetallationiii. reductive elimination
CuC CR'
Note that Et3N may reduce Pd(II) to Pd(0) as well, where Et3N is oxidized to the iminium ion at the same time:
NEt3PdCl2
NEt2HH
PdCl2
NEt2
PdH Cl
Cl
NEt2 ClCl Pd H
reductive
eliminationHCl Pd(0)
Example 12
NH
I
CO2Et
PdCl2•(Ph3P)2
CuI, Et3N60 oC, 89% N
HCO2Et
519
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_241, © Springer-Verlag Berlin Heidelberg 2009
Example 23
N Br
SiMe3
NSiMe3
BrBr
PdCl2•(Ph3P)2, CuIEt3N, rt, 65–74%
Example 38
OMeOMe
I
Pd(PPh3)4, CuI, [bmim][BF4] Et3N, 80 °C, 12 h, 11%
N N
[bmim][BF4]MeO
OMeMeO
MeOOMe
OMe
OMe
OMeOMe
MeO
BF4
Example 49
OTf
OO TMSCl
MeOOMOM
OTBDPS
OO
PMPO
OTBS
OHO
OPMPO
OTBS
OH OO TMSCl
MeOOMOM
OTBDPSPd(PPh3)4, CuI,
i-PrNEt2:DMF (1:1)> 83%
References 1. (a) Sonogashira K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467−4470.
Richard Heck also discovered the same transformation using palladium but without the use of copper: J. Organomet. Chem. 1975, 93, 259−263.
2. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 2248−2252.
3. Ernst, A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959−7962. 4. Hundermark, T.; Littke, A.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729−1731. 5. Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411−1414. 6. Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; de Mei-
jere, A., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, 319. (Review). 7. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9839−9847. 8. Li, Y.; Zhang, J.; Wang, W.; Miao, Q.; She, X.; Pan, X. J. Org. Chem. 2005, 70,
3285−3287. 9. Komano, K.; Shimamura, S.; Inoue, M.; Hirama, M. J. Am. Chem. Soc. 2007, 129,
14184−11186. 10. Gray, D. L. Sonogashira Reaction. In Name Reactions for Homologations-Part II; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 100−133. (Review).
520
Staudinger ketene cycloaddition [2 + 2]-Cycloaddition of ketene and imine to form β-lactam. Other coupling part-ners for ketenes include: olefin to give cyclobutanone and carbonyl to give β-lactone.
O
R1 R2
X
R4R3
XO
R1R2R3
R4
X = NR; O; CHR
O
R1 R2
XO
R1R2R3
R4
XR4
R3
puckered transition state:
Example 16
p-TolN
NOt-Bu
OPhO
Cl
O
Et3N, CH2Cl210 oC to rt, 24 h
88%
N
PhOO Ot-Bu
O N p-Tol
Example 27
AcOCl
O
Et3N, CH2Cl2−78 oC to rt, 60%
N N
AcO
O
Example 39
O
O
CO2Et
COCl
PMPN CHPMP
Et3N, CH2Cl2−40 oC to rt15 h, 70%
O
OCO2Et
N
O
PMPH
PMPO
OCO2Et
NPMP
O
PMP H
major minor
521
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_242, © Springer-Verlag Berlin Heidelberg 2009
Example 410
S
NCO2H
CO2t-BuMeO2C NMe
Cl I
CH2Cl2, Et3N S
NC
CO2t-BuMeO2C
O
CH
N CH2Ph PMP
62% SN
CO2t-BuMeO2C
NO CH2PMP
PhH S
NCO2t-Bu
MeO2C
NCH2PMP
O
PhH
56 : 44
References 1. Staudinger, H. Ber. 1907, 40, 1145−1146. Hermann Staudinger (Germany,
1881−1965) won the Nobel Prize in Chemistry in 1953 for his discoveries in the area of macromolecular chemistry.
2. Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. Pure Appl. Chem. 1987, 59, 485−492. (Review).
3. Snider, B. B. Chem. Rev. 1988, 88, 793−811. (Review). 4. Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159−646. (Review). 5. Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545−3565. (Review). 6. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.; San-
cassan, F.; Tavani, C. Tetrahedron 2003, 59, 10195−10201. 7. Banik, I.; Becker, F. F.; Banik, B. K. J. Med. Chem. 2003, 46, 12−15. 8. Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem. Lett. 2005, 13, 3611−3622. 9. Chincholkar, P. M.; Puranik, V. G.; Rakeeb, A.; Deshmukh, A. S. Synlett 2007,
2242−2246. 10. Cremonesi, G.; Dalla Croce, P.; Fontana, F.; La Rosa, C. Tetrahedron: Asymmetry
2008, 19, 554−561.
522
Staudinger reduction Phosphazo compounds (e.g., iminophosphoranes) from the reaction of tertiary phosphine (e.g., Ph3P) with organic azides.
N3XPR3
X N N N PR3N2 X N PR3
phosphazide
NX N N :PR3X N N N PR3X N N N PH2R3
PR3NN N
X phosphazide
PR3NN N
X
PR3NN N
XN2 X N PR3
H2O X NH2 O PR3
‡
4-membered ring transition state
Example 12
N
OMeO
OTBDMS
N3Ph3P, THF
Δ, 81%
N
OMe
OTBDMS
N
Example 23
N3
CO2CH3
O
MeOO
H
H
O
1. PPh3, THF
2. NaBH4, MeOH
60%
CO2CH3OO
H
NHMeO
H
Example 34
NBr NH
Br
HN
O
O
N3
Ts
523
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_243, © Springer-Verlag Berlin Heidelberg 2009
NBr
N
HN O
NH
BrTs
PBu3, toluene
reflux, 20 h, 82%
Example 48
O
N3
BnOBnO
N3O
N3
AcOOAc
N3
1.1 eq. PMe3, 2.4 eq. Boc-ON
Tol., −78 to 10 oC
O
N3
BnOBnO
N3O
N3
AcOOAc
NHBoc
37% O
N3
BnOBnO
N3O
NHBoc
AcOOAc
N3
42%
Example 59
PPh3, H2O
THF, 45 °C78%
NN
F
R2NC
O
O
N3NN
F
R2NC
O
O
NH2
References 1. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635−646. 2. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G.
R. J. Am. Chem. Soc. 2001, 123, 3239−3242. 3. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721−2722. 4. Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1369−1371. 5. Venturini, A.; Gonzalez, J. J. Org. Chem. 2002, 67, 9089−9092. 6. Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281−1283. 7. Fresneda, P. M.; Castaneda, M.; Sanz, M. A.; Molina, P. Tetrahedron Lett. 2004, 45,
1655−1657. 8. Li, J.; Chen, H.-N.; Chang, H.; Wang, J.; Chang, C.-W. T. Org. Lett. 2005, 7,
3061−3064. 9. Takhi, M.; Murugan, C.; Munikumar, M.; Bhaskarreddy, K. M.; Singh, G.; Sreenivas,
K.; Sitaramkumar, M.; Selvakumar, N.; Das, J.; Trehan, S.; Iqbal, J. Bioorg. Med. Chem. Lett. 2006, 16, 2391−2395.
10. Iula, D. M. Staudinger reaction. In Name Reactions for Functional Group Transfor-mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 129−151. (Review).
524
Stetter reaction 1,4-Dicarbonyl derivatives from aldehydes and α,β-unsaturated ketones and es-ters. The thiazolium catalyst serves as a safe surrogate for −CN. Also known as the Michael−Stetter reaction. Cf. Benzoin condensation.
R CHOO
N
S
PhHO
NH3
R
O
O
Cl
N
S
PhHO
H
:NH3
deprotonation N
S
Bn
R1
R
OHR1 = HOCH2CH2CH2-
O
N
S
Bn
R1 OH
RH
N
S
Bn
R1 OH
R
Michael
addition
:NH3
N
S
Bn
R1
R
OH
O
tautomerization N
S
Bn
R1
R
O
O
R
O
O
N
S
PhHO N
S
PhHO
NH4
Example 1, Intramolecular Stetter reaction2
CN
MeO2C
O
CN
MeO2C
OHC
S
NMe
MeI
HO2.3 equiv
TEA, i-PrOH, 80 oC67%
Example 23
O CHOOHC O
(cat.)
Et3N, EtOH, 80 oC, 56%O
OO
OOS
NMe
MeI
HO
525
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_244, © Springer-Verlag Berlin Heidelberg 2009
Example 35
N
NO
H
O
CO2Me
N
S
Ph
HOCl
Et3N, DMF, 100 ºC, 75%
(cat.)
N
NO
O
CO2Me
Example 4, Sila-Stetter reaction9
Ph
OPh
O
Ph Si
O
PhPh
OPh
S
NEt
MeBr
HOMe
MeMe
30 mol%
4 equiv i-PrOH, DBU, THF, 77%
References 1. (a) Stetter, H.; Schreckenberg, H. Angew. Chem. 1973, 85, 89. Hermann Stetter
(1917−1993), born in Bonn, Germany, was a chemist at Technische Hochschule Aachen in West Germany. (b) Stetter, H. Angew. Chem. 1976, 88, 695−704. (Re-view). (c) Stetter, H.; Kuhlmann, H.; Haese, W. Org. Synth. 1987, 65, 26.
2. Trost, B. M.; Shuey, C. D.; DiNinno, F., Jr.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1284−1285.
3. El-Haji, T.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1983, 20, 233−235. 4. Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649−651. 5. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.;
Nagai, M. J. Med. Chem. 2000, 43, 409−419. 6. Kobayashi, N.; Kaku, Y.; Higurashi, K. Bioorg. Med. Chem. Lett. 2002, 12,
1747−1750. 7. Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284−6289. 8. Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368−6378. 9. Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71,
5715−5724. 10. Cee, V. J. Stetter Reaction. In Name Reactions for Homologations-Part I; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 576−587. (Review).
526
Still–Gennari phosphonate reaction A variant of the Horner−Emmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins.
(CF3CH2O)2P CO2CH3
O KN(SiMe3)2, 18-Crown-6
then PhCH2CHOCO2CH3Ph
CF3CH2OP
OMe
OCF3CH2O
O
H CF3CH2OP
OMe
OCF3CH2O
O
O
H
NSiMe3
SiMe3 Ph
PO
HCO2CH3
H
O
OCH2CF3
OCH2CF3
PhH
CO2CH3
HPO OCH2CF3
OCH2CF3O
Ph
CO2CH3Ph
erythro isomer, kinetic adduct
Example 12
(CF3CH2O)2P CO2CH3
OKN(SiMe3)2, 18-Crown-6
−78 oC, THF, 30 min.
then PhCH2CHO, 87%
CO2CH3Ph
Example 23
F3CH2COP
OEt
OF3CH2COO
F Sn(OSO2CF3)2, N-methylpiperidineCH2Cl2, 70%, E:Z = 96:4
CO2Et
MeF
NNMe
NNO
Example 34
S
NCH3
O
OTBS
F3CH2COP
OEt
OF3CH2COO
527
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_245, © Springer-Verlag Berlin Heidelberg 2009
KHMDS, THF18-crown-6, −78 oC, 1 h
89%, (Z)-isomer onlyS
NCH3EtO
O
OTBS
Example 49
MeOP(OCH2CF3)2
O O OTBS TBS
O O
OTBS
CHOOTBS
OPMB
NaH, THF
73%, Z:E 5:1
OTBS
OTBS
OPMB
MeO
O O OTBS TBS
O
References 1. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405−4408. W. Clark Still
(1946−) was born in Augusta, Georgia. He was a professor at Columbia University. 2. Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; LaGreca, S.; Tsuri, T.; Yue, E. W.; Yang,
Z. Chem. Eur. J. 1995, 1, 467−494. 3. Sano, S. Yokoyama, K.; Shiro, M.; Nagao, Y. Chem. Pharm. Bull. 2002, 50, 706–709. 4. Mulzer, J.; Mantoulidis, A.; Öhler, E. Tetrahedron Lett. 1998, 39, 8633–8636. 5. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc.
2001, 123, 9535−9544. 6. Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. 2001, 40, 3842−3846. 7. Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221−2224. 8. Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812−6815. 9. Paterson, I.; Lyothier, I. J. Org. Chem. 2005, 70, 5494−5507. 10. Rong, F. Horner–Wadsworth–Emmons reaction. In Name Reactions for Homologa-
tions-Part I; Li, J. J., Corey, E. J.; Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 420−466. (Review).
528
Stille coupling Palladium-catalyzed cross-coupling reaction of organostannanes with organic hal-ides, triflates, etc. For the catalytic cycle, see Kumada coupling on page 325.
R X R1 Sn(R2)3Pd(0)
R R1 X Sn(R2)3
R XR1 Sn(R2)3
L2Pd(0) transmetallationisomerization
oxidative
additionPd
L
L X
R
X Sn(R2)3 PdL
R R1
LR1R
reductive
eliminationL2Pd(0)
Example 14
N
N
NH2
Cl
ClN
N
NH2
BrCl
Cl PdCl2•(Ph3P)2, CuITHF, reflux, 92%
NSnBu3
SO2Ph
NPhO2S
Example 25
TBDPSO Br
(MeCN)2PdCl2
AsPh3, NMP80 oC, 1.5 h, 55%
Me3Sn Cl
Cl
TBDPSO Cl
Cl HCl
HN Cl
Cl
Zoloft
Example 3, π-Allyl Stille coupling8
OTBDPSSnMe3
OAc
Me
MeO
MeMe
Me
MeO
MeMe
OTBDPSPd2(dba)3, LiCli-Pr2NEt, NMP
35 °C, 1.5 h, 96%
529
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_246, © Springer-Verlag Berlin Heidelberg 2009
Example 49
I
OH
O
Me
OMe
NS
OMeHN
O
MeOMe
OTBS SnMe3
Pd(PPh3)4, CuTC
DMF, 32%
OH
O
Me
OMe
NS
OMeHN
O
MeOMe
OTBS
18
References 1. (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636−3638. John Kenneth
Stille (1930−1989) was born in Tucson, Arizona. He developed the reaction bearing his name at Colorado State University. At the height of his career, Stille unfortunately died of an airplane accident returning from an ACS meeting. (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992−4998. (c) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508−524.
2. Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50, 1–652. (Review). 3. Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235−1249.
(Review on the intramolecular Stille reaction). 4. Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507−4510. 5. Lautens, M.; Rovis, T. Tetrahedron, 1999, 55, 8967−8976. 6. Mitchell, T. N. Organotin Reagents in Cross-Coupling Reactions. In Metal-Catalyzed
Cross-Coupling Reactions (2nd edn.) De Meijere, A.; Diederich, F. eds., 2004, 1, 125−161. Wiley-VCH: Weinheim, Germany. (Review).
7. Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245−2267. (Review). 8. Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740−742. 9. Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am. Chem. Soc. 2007, 129, 8960−8961. 10. Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part I; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 133−162. (Review).
530
Stille− Kelly reaction Palladium-catalyzed intramolecular cross-coupling reaction of bis-aryl halides us-ing ditin reagents.
OHOH
Br
Br Me3Sn SnMe3
Pd(Ph3P)4OH
OH
OHOH
Br
Br
OHOH
Br
BrPd
Me3Sn SnMe3Pd(0)
oxidativeaddition
transmetalation
OHOH
Br
PdMe3Sn
OHOH
Br
Me3Sn
reductive
eliminationPd(0)
Pd(0)
oxidativeaddition
OHOH
PdBr
Me3Sn
transmetallation
OHOH
OHOH
Pdreductive
eliminationPd(0)
Example 16
N
Cl
I HO
I
N
O
I I
NaH, DMF, reflux, 89%
Me3Sn SnMe3
PdCl2•(Ph3P)2xylene, reflux, 92%
N
O
References 1. Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161−164. 2. Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859−3862. 3. Iyoda, M.; Miura, M.; Sasaki, S.; Kabir, S. M. H.; Kuwatani, Y.; Yoshida, M. Hetero-
cycles 1997, 38, 4581−4582. 4. Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40,
105−108. 5. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999,
1505−1510. 6. Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201−2203. 7. Olivera, R.; SanMartin, R.; Tellitu, I.; Dominguez, E. Tetrahedron 2002, 58,
3021−3037. 8. Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part I; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 133−162. (Review).
531
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_247, © Springer-Verlag Berlin Heidelberg 2009
Stobbe condensation Condensation of diethyl succinate and its derivatives with carbonyl compounds in the presence of bases.
R R1
O
CO2Et
CO2Et R
R1
CO2EtCO2HKOt-Bu
HOt-Bu
R
R1
OCO2Et
enolate
formation
aldol
addition
O
OEtH
t-BuO
CO2Et
O
OEt O
CO2EtRR1
OEtO
lactonization
O
RR1
EtO O
CO2Et
O
RR1 CO2Et
O
H
Ot-Bu
R
R1
CO2EtCO2
H R
R1
CO2EtCO2H
ring
opening
Example 1, Stobbe condensation and cyclization5
CO2Me
CO2Me
1. t-BuOK, t-BuOH, reflux
2. Ac2O, NaOAc, reflux 84%
OCHO
OO
O
OO
CO2Me
OAc
Example 2, Stobbe condensation6
O
O
CHOO
O
O
aq. NaOH, EtOH
−10 oC, 5 h, 80−95%
O
O
O
O
OH
Example 3, Cyclization of the Stobbe product7
BnO2C
CO2Et
CO2H
BnO2C
CO2Et
OAc
NaOAc, Ac2O
reflux, 57%
532
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_248, © Springer-Verlag Berlin Heidelberg 2009
Example 4, Two sequential Stobbe condensations9
F CHO
1. (CH2CO2Et)2, NaOMe, MeOH then aq. NaOH, 36%
2. MeOH, H2O4, 94% FCO2Me
CO2Me
NaOMe, MeOH, 74%
CHO
IO
O
F CO2H
CO2Me
IO
O
References 1. Stobbe, H. Ber. 1893, 26, 2312. Hans Stobbe (1860−1938) was born in Tiehenhof,
Germany. He earned his Ph.D. In 1889 at the University of Leipzig where he became a professor in 1894.
2. Zerrer, R.; Simchen, G. Synthesis 1992, 922–924. 3. Yvon, B. L.; Datta, P. K.; Le, T. N.; Charlton, J. L. Synthesis 2001, 1556–1560. 4. Liu, J.; Brooks, N. R. Org. Lett. 2002, 4, 3521–3524. 5. Giles, R. G. F.; Green, I. R.; van Eeden, N. Eur. J. Org. Chem. 2004, 4416–4423. 6. Mahajan, V. A.; Shinde, P. D.; Borate, H. B.; Wakharkar, R. D. Tetrahedron Lett.
2005, 46, 1009–1012. 7. Sato, A.; Scott, A.; Asao, T.; Lee, M. J. Org. Chem. 2006, 71, 4692–4695. 8. Kapferer, T.; Brückner, R. Eur. J. Org. Chem. 2006, 2119–2133. 9. Mizufune, H.; Nakamura, M.; Mitsudera, H. Tetrahedron 2006, 62, 8539–8549. 10. Lowell, A. N.; Fennie, M. W.; Kozlowski, M. C. J. Org. Chem. 2008, 73, 1911–1918.
533
Strecker amino acid synthesis Sodium cyanide-promoted condensation of aldehyde, or ketone, with amine to af-ford α-amino nitrile, which may be hydrolyzed to α-amino acid.
R1 H
OH2N
R2
R1 CN
HNR2
H
R1 CO2H
HNR2
NaCN
AcOH
:
R1 H
O
H2NR2 NC
:
R1
HNH
R1 NH
H
R2O
R2
HH
H2O:
R1
HNR2
N R1
HNR2
NH
OHH
iminium ion
R1
HNR2
NH2
O
:OH2
acidic amide
hydrolysis R1
HNR2
NH2
HO OHR1
HNR2
NH3
HO OH
R1 CO2H
HNR2
H
H
Example 1, Soluble cyanide source2
C8H17
H
H
HO
C8H17
H
H
HN
NC
(EtO)2P CNO
pyrrolidine, THF, 62%
Example 23
NH
S acetone cyanohydrinMgSO4, 45 oCtoluene, 31%
OHCCl
N
S
ClCN
N
S
ClO O
Plavix
Example 38
Ph
O NaCN, NH4Cl
i-PrOH, NH4OH
PhNH2
CNH
PhCN
NH2H34% 35%
534
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_249, © Springer-Verlag Berlin Heidelberg 2009
Example 49
O
O
Ph
CF3
F3C OPh
CF3
F3CCN
HN Bn
NaCN, BnNH2AcOH, MeOH
98%
References 1. Strecker, A. Ann. 1850, 75, 27−45. 2. Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1979, 20, 4663–4666. 3. Burgos, A.; Herbert, J. M.; Simpson, I. J. Labelled. Compd. Radiopharm. 2000, 43,
891–898. 4. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 762–766. 5. Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions, in Or-
ganic Synthesis Highlights V, Schmalz, H.-G.; Wirth, T. eds.; Wiley−VCH: Wein-heim, Germany, 2003, pp 187−193. (Review).
6. Meyer, U.; Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15, 2029–2037.
7. Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027–5029. 8. Cativiela, C.; Lasa, M.; Lopez, P. Tetrahedron: Asymmetry 2005, 16, 2613–2523. 9. Wrobleski, M. L.; Reichard, G. A.; Paliwal, S.; Shah, S.; Tsui, H-C.; Duffy, R. A.; La-
chowicz, J. E.; Morgan, C. A.; Varty, G. B.; Shih, N-Y. Bioorg. Med. Chem. Lett. 2006, 16, 3859–3863.
10. Galatsis, P. Strecker amino acid synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 477−499. (Review).
11. Belokon, Y. N.; Hunt, J.; North, M. Tetrahedron: Asymmetry 2008, 19, 2804−2815.
535
Suzuki–Miyaura coupling Palladium-catalyzed cross-coupling reaction of organoboranes with organic hal-ides, triflates, etc. In the presence of a base (transmetallation is reluctant to occur without the activating effect of a base). For the catalytic cycle, see Kumada cou-pling on page 325.
R X R1 B(R2)2 R1RL2Pd(0)
NaOR3
R X L2Pd(0)oxidative
additionPd
L
L X
R NaOR3
baseR1 B(R2)2 R1 B(R2)2
OR3
PdL
L X
R
transmetallation
isomerizationPd
L
R R1
LR1R
reductive
eliminationL2Pd(0)R3O B(R2)2
Example 12
N
CO2Me
CO2Me
I
CO2Et
OB
O
Pd(OAc)2Ph3P, K2CO3
THF, MeOH70 °C, 15 h, 80% N
CO2Me
CO2Me
CO2Et
Example 24
N
N
I
ISEM
NTBS
N
N
I
I
SEM
I
N
B(OH)2
TBS
Pd(Ph3P)4, Na2CO3, 45%
Example 3, Intramolecular Suzuki–Miyaura coupling8
TBDMSO
O
O
OBn
Br
OMOM
1.BH
2
2. H2O, CH2O3. KHF2
99%
TBDMSO
O
O
OBn
Br
OMOM
BF3K
536
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_250, © Springer-Verlag Berlin Heidelberg 2009
O
O OMOM
BnO
OHcat. Pd(PPh3)4, Cs2CO3
THF/H2O, reflux, 42%
Example 49
SnBu3BO
OBO
Ocat. Pd2(dba)3, Ph3AsDMF, 84%
3
O
NH
OMeI
3NH
OOMe
cat. PdCl2(dppf), Ph3AsK3PO4 (aq), DMF, 71%
OHI O
NH
OMeHO
References 1. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437−3440. (b)
Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866–867. 2. Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164–7168. 3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483. (Review). 4. (a) Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles
1998, 48, 1887–1901. (b) Kawaski, I.; Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 44, 1831–1839.
5. Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley−VCH: Weinhein, Germany, 1998, 49–97. (Review).
6. Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (Review). 7. Zapf, A. Coupling of Aryl and Alkyl Halides with Organoboron Reagents (Suzuki Re-
action). In Transition Metals for Organic Synthesis (2nd edn.); Beller, M.; Bolm, C. eds., 2004, 1, 211−229. Wiley−VCH: Weinheim, Germany. (Review).
8. Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313–10318. 9. Coleman, R. S.; Lu, X.; Modolo, I. J. Am. Chem. Soc. 2007, 129, 3826–3827. 10. Wolfe, J. P.; Nakhla, J. S. Suzuki coupling. In Name Reactions for Homologations-
Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 163−184. (Review).
537
Swern oxidation Oxidation of alcohols to the corresponding carbonyl compounds using (COCl)2, DMSO, and quenching with Et3N.
R1 R2
OH
R1 R2
O(COCl)2, DMSOCH2Cl2, −78 oC
then Et3N
ClCl
O
O
OS
ClO
O
OS
ClCl
OO
SCl O
CO2↑ CO↑
SCl
R1 R2
:OH
Cl
R1 R2
OS H
H
:NEt3
R1 R2
OEt3N•HCl↓ (CH3)2S↑
OHCH2
S
R1
R2
sulfur ylide
Example 12
OMe
OMeOMe OHOH
HOH 1. (COCl)2, DMSO, −60 oC, 45 min
2. Et3N, −60 oC, 15 min. then rt 81%
OMe
OMeOMe OOH
HO
Example 23
O
OHO
TMSCH2CH2O2C
NC
Swernconditions
80%O
OO
TMSCH2CH2O2C
NC
Cl
Example 35
C6H13
OSiMe2t-Bu
OHC11H23 (COCl)2, DMSO
then Et3N, 89%
C6H13
OSiMe2t-Bu
OC11H23
538
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_251, © Springer-Verlag Berlin Heidelberg 2009
Example 47
N
OMeO
OTBDPS
N3
N
OMeHO
OTBDPS
N3 (COCl)2, DMSO
then Et3N, 85%
References 1. (a) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329−3331. (b)
Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 4, 297−299. (c) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480−2482.
2. Ghera, E.; Ben-David, Y. J. Org. Chem. 1988, 53, 2972−2979. 3. Smith, A. B., III; Leenay, T. L.; Liu, H. J.; Nelson, L. A. K.; Ball, R. G. Tetrahedron
Lett. 1988, 29, 49−52. 4. Tidwell, T. T. Org. React. 1990, 39, 297−572. (Review). 5. Chadka, N. K.; Batcho, A. D.; Tang P. C.; Courtney, L. F.; Cook C. M.; Wovliulich, P.
M.; Uskovi , M. R. J. Org. Chem. 1991, 56, 4714−4718. 6. Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem. 1998,
63, 2407−2409. (Odorless protocols). 7. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G.
R. J. Am. Chem. Soc. 2001, 123, 3239−3242. 8. Nishide, K.; Ohsugi, S.-i.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett.
2002, 43, 5177−5179. (Another odorless protocols). 9. Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J.-i. Angew. Chem., Int. Ed.
2005, 44, 2413−2416. 10. Ahmad, N. M. Swern oxidation. In Name Reactions for Functional Group Transfor-
mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 291−308. (Review).
11. Lopez-Alvarado, P; Steinhoff, J; Miranda, S; Avendano, C; Menendez, J. C. Tetrahedron 2009, 65, 1660−1672.
539
Takai reaction Stereoselective conversion of an aldehyde to the corresponding E-vinyl iodide us-ing CHI3 and CrCl2.
R H
OR
ICHI3, CrCl2
THF
CrCl2HI
II H
I
CrIIICl2I CrCl2
R
HO
HCrIIICl2
CrIIICl2I
Cl2CrIII
I
ROCrIIICl2 R
I
A radical mechanism was recently proposed10
I
I
H
I
CrIICrIIII
I
H
I
CrII
R H
O
HI
CrIIII
RI
OCrIII
I
CrII
H RIR
IOCrIII
CrII
HR
IOCrIII
CrIII
Example 12
CHI3, CrCl2
THF, 70%Ph
OTBSCHO Ph
OTBSI
20: 1 E:Z
Example 23
N
N N
NEt
EtEt
Et
Et
Et Et
Et
CHONiN
N N
NEt
EtEt
Et
Et
Et Et
Et
Ni25 equiv CrCl26 equiv CHI3
THF, rt, 3 h75%
I
540
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_252, © Springer-Verlag Berlin Heidelberg 2009
Example 34
CO2MeOHC
OTES CHI3, CrCl2, 0 oC
THF, 50% CO2Me
OTES
I
Example 4, A Br/Cl variant9
OOTHP
6 equiv CrCl2, 2 equiv CHBr3
THF, 0 oC, 2.5 h, 67%
OTHPBr OTHPCl
1 : 1
Example 510
CO2Me
CHOMOMO
H
H CO2MeMOMO
H
H
I
5.8 equiv anhydrous CrCl22 equiv CHI3
1,4-dioxane−THF (6:1)20 oC, 72 h, 88%
References 1. Takai, K.; Nitta, Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410. 2. Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc. 1997, 119, 12159–
12169. 3. Arnold, D. P.; Hartnell, R. D. Tetrahedron 2001, 57, 1335–1345. 4. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717–8724. 5. Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043–2046. 6. Lipomi, D. J.; Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6, 3533–3536. 7. Paterson, I.; Mackay, A. C. Synlett 2004, 1359–1362. 8. Concellón, J. M.; Bernad, P. L.; Méjica, C. Tetrahedron Lett. 2005, 46, 569–571. 9. Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2005, 16, 3107–3114. 10. Legrand, F.; Archambaud, S.; Collet, S.; Aphecetche-Julienne, K.; Guingant, A.;
Evain, M. Synlett 2008, 389–393.
541
Tebbe’s reagent The Tebbe’s reagent, -chlorobis(cyclopentadienyl)(dimethylaluminium)- -methylenetitanium, transforms a carbonyl compound to the corresponding exo-olefin.
Ti
H2C
Cl
AlCH3
CH3
Preparation:2,6
Cp2TiCl2 + 2 Al(CH3)3 Cp2TiCl
Al(CH3)2CH4↑ + Al(CH3)2Cl +
Mechanism:3
Cp2Ti CH2
Cl Al(CH3)2Cp2Ti
ClAl(CH3)2
O
dissociation
RR1
R R1Cp2Ti O
[2 + 2]
cycloaddition
Cp2Ti CH2
OR
R1retro-[2 + 2]
cycloaddition
oxatitanacyclobutane formation of the strong Ti=O is the driving force.
Example 1, Ketone2
Tebbe's reagent, Tol.
then the ketone substrate,THF, 0 oC to rt, 30 min., 67%
O
CO2Et CO2Et
Example 2, Double Tebbe4
O
H2.5 eq
O
H
O THF, CH2Cl2−40 to 25 °C, 69%HO
Ti
Cl
AlCp
Cp
542
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_253, © Springer-Verlag Berlin Heidelberg 2009
Example 3, Double Tebbe5
OHC
TBSO
O
OBn
OBn
OTBS
OTBS
CHO
3 equiv Tebbe's reagent in Tol.pyr., Tol./THF
−78 oC to −15 oC, 2 h86%
TBSO
O
OBn
OBn
OTBS
OTBS
TBSTBS
Example 4, N-Oxide6
NO
Ti
Cl
AlCp
Cp
NTHF, 0 oC to rt, 90%
Example 5, Amide11
N O
N
O
CF3CF3
O
N O
N
O
CF3CF3
OH1. Tebbe's reagent
2. BH3, THF, H2O2, NaOH 75−95%
References 1. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611−3613. 2. Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R.
D. J. Org. Chem. 1985, 50, 1212–1216. 3. Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386–2387. 4. Philippo, C. M. G.; Vo, N. H.; Paquette, L. A. J. Am. Chem. Soc. 1991, 113,
2762−2764. 5. Ikemoto, N.; Schreiber, L. S. J. Am. Chem. Soc. 1992, 114, 2524–2536. 6. Pine, S. H. Org. React. 1993, 43, 1−98. (Review). 7. Nicolaou, K. C.; Koumbis, A. E.; Snyder, S. A.; Simonsen, K. B. Angew. Chem., Int.
Ed. 2000, 39, 2529–2533. 8. Straus, D. A. Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons,
2000. (Review). 9. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Syn., Coll.
Vol. 10, 2004, p 355. 10. Beadham, I.; Micklefield, J. Curr. Org. Synth. 2005, 2, 231−250. (Review). 11. Long, Y. O.; Higuchi, R. I.; Caferro, T.s R.; Lau, T. L. S.; Wu, M.; Cummings, M. L.;
Martinborough, E. A.; Marschke, K. B.; Chang, W. Y.; Lopez, F. J.; Karanewsky, D. S.; Zhi, L. Bioorg. Med. Chem. Lett. 2008, 18, 2967−2971.
12. Zhang, J. Tebbe reagent. In Name Reactions for Homolotions-Part I; Li, J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review).
543
TEMPO oxidation TEMPO = Tetramethyl pentahydropyridine oxide. 2,2,6,6-Tetramethylpiperi-dinyloxy is a stable nitroxyl radical, which serves in oxidations as catalyst
R OHNaOCl, cat. TEMPO
KBr, NaHCO3, CH2Cl2 R OH
O
1/2 NaOClNO
NO
OCl
::
:
NO
HO R
:
NO O
H RH
N O
N
NHAc
OH
R H
O
OCl
:B
R
OH
OCl R O
O
R O
OH
Example 14
NaOCl, cat. TEMPO
KBr, NaHCO3, CH2Cl255%
HO OHO
OHOMe
OH
HOO
HOOH
OMe
HO2C
544
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_254, © Springer-Verlag Berlin Heidelberg 2009
Example 2, Trichloroisocyanuric/TEMPO Oxidation5
R OH0.01 mol equiv TEMPO
0.05 mol equiv NaBracetone, aq. NaHCO3, rt
1−24 h, 75−100%
N
N N
OO
OCl
Cl
Cl
R OH
O
Example 38
cat. TEMPO, 2 eq. 2,6-lutidine
electrolysis in CH3CN/H2O (95:5)95%
O
Example 410
Ormosil-TEMPO, NaOCl
CH3CN, NaHCO3, 5%0 oC, 80%Cl
OHOH
Cl
CO2H
OH
“Ormosil-TEMPO” is a sol-gel hydrophobized nanostructured silica matrix
doped with TEMPO
References 1. Garapon, J.; Sillion, B.; Bonnier, J. M. Tetrahedron Lett. 1970, 11, 4905–4908. 2. de Nooy, A. E.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153–1174. (Re-
view). 3. Rychnovsky, S. D.; Vaidyanathan, R. J. Org. Chem. 1999, 64, 310–312. 4. Fabbrini, M.; Galli, C.; Gentili, P.; Macchitella, D. Tetrahedron Lett. 2001, 42, 7551–
7553. 5. De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem. 2003, 45, 4999–
5001. 6. Ciriminna, R.; Pagliaro, M. Tetrahedron Lett. 2004, 45, 6381–6383. 7. Tashino, Y.; Togo, H. Synlett 2004, 2010–2012. 8. Breton, T.; Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46, 2487–2490. 9. Chauvin, A.-L.; Nepogodiev, S. A.; Field, R. A. J. Org. Chem. 2005, 47, 960–966. 10. Gancitano, P.; Ciriminna, R.; Testa, M. L.; Fidalgo, A.; Ilharco, L. M.; Pagliaro, M.
Org. Biomol. Chem. 2005, 3, 2389–2392. 11. Zhang, M.; Chen, C.; Ma, W.; Zhao, J. Angew. Chem., Int. Ed. 2008, 47, 9730–9733.
545
Thorpe−Ziegler reaction The intramolecular version of the Thorpe reaction, which is base-catalyzed self-condensation of nitriles to yield imines that tautomerize to enamine.
CNCN OEt
CN
NH2HOEt
N
HEtO
N
N
NH OEt H
H OEt
OEt
CN
NH
CN
NH2
H
H OEt
EtO
Example 1, A radical Thorpe−Ziegler reaction2
Br
CN
NC
Bu3SnH, AIBNsyringe pump
PhH, 80 oC, 56%
CNH2N
Example 25
N CNPh
CNLDA, THF
−78 oC to rt
2 h, 80%NPh
CNNH2
Example 38
NH
O
N
SHN
O
PhKOH, EtOH
reflux, 5 min., 80% NH
O
NH2
S
HN
O
Ph
546
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_255, © Springer-Verlag Berlin Heidelberg 2009
Example 49
OMe
NH
NC CN
OMe
N
NC CN
CN
OMe
N
NC
CNCl CN
NH2
Et3N, reflux15 min., 91%
References 1. (a) Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726–1761. (b)
Ziegler, K. et al. Ann. 1933, 504, 94–130. Karl Ziegler (1898−1973), born in Helsa, Germany, received his Ph.D. In 1920 from von Auwers at the University of Marburg. He became the director of the Max-Planck-Institut für Kohlenforschung at Mül-heim/Ruhr in 1943. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (1903−1979) for their work in polymer chemistry. The Ziegler−Natta catalyst is widely used in polymerization.
2. Curran, D. P.; Liu, W. Synlett 1999, 117–119. 3. Dansou, B.; Pichon, C.; Dhal, R.; Brown, E.; Mille, S. Eur. J. Org. Chem. 2000, 1527–
1531. 4. Keller, L.; Dumas, F.; Pizzonero, M.; d’Angelo, J.; Morgant, G.; Nguyen-Huy, D. Tet-
rahedron Lett. 2002, 43, 3225–3228. 5. Malassene, R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 895–898. 6. Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44, 7517–7520. 7. Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245–1256. 8. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P. Monatsh. Chem. 2008, 139,
271–275. 9. Salaheldin, A. M.; Oliveira-Campos, A. M. F.; Rodrigues, L. M. ARKIVOC 2008,
180–190. 10. Miszke, A.; Foks, H.; Brozewicz, K.; Kedzia, A.; Kwapisz, E.; Zwolska, Z.
Heterocycles 2008, 75, 2723–2734.
547
Tsuji−Trost reaction The Tsuji–Trost reaction is the palladium-catalyzed substitution of allylic leaving groups by carbon nucleophiles. These reactions proceed via π-allylpalladium in-termediates.
XR1 NuR1R1
Pd(II)
X
Pd(0) (catalytic)
base
Nu
π-allyl complex2
R2R1
X
R2R1
X
R2R1
NuOR
R1 >> R2
Hard Nu
Pd(0)
Inversion ofconfiguration
Retention ofconfiguration
Soft Nu
Pd(0)
X = OCOR, OCO2R, OCONHR, OP(O)(OR)2, OPh, Cl, NO2, SO2Ph, NR3X, SR2X, OH
R2R1
Nu
The catalytic cycle:
A
LnPd(0)
Pd(0) or Pd(II) precatalysts
B
C
D
A: CoordinationB: Oxidative addition (Ionization)
C: Ligand exchangeD: Substitution then reductive elimination
R1 X
R1 Nu
Nu
R1 X
LnPd(0)
R1
Pd(II)X
+ L
− XL
R1
Pd(II)LL
R1 Nu
LnPd(0)
π-allyl complex
548
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_256, © Springer-Verlag Berlin Heidelberg 2009
Example 1, Allylic ether3
O
BnO OPh
BnON
NH
O
BnO N
BnO
N
Pd2(dba)3, dppb
THF, 60–70 oC72%
α:β = 90:10
Example 2, Allylic acetate3
OAcAcO
N
NH
NaH, Pd(Ph3P)4, DMF60 oC, 18 h, 79%
NAcO
NN
N
NH2
NN
NH2
Example 3, Allylic epoxide5
N
NHO NHO
N
Pd(Ph3P)4, THFrt, 64 h, 35%
Example 4, Intramolecular Tsuji–Trost reaction6
S
N OCO2Me
CO2Me
Bn
ONH2
SCO2Me
NHBnN
O10 mol% Pd(OAc)210 mol% n-Bu4NCl
P(OEt)3, NaHCO3DMF, 100 oC, 77%
Example 5, Intramolecular Tsuji–Trost reaction7
t-BuO
O
Me
O
O
OMe
TMSO
Me
O O
Ot-Bu
TESO OTESMe
Me
TESO
OTES
Me
O
OTMSMe
10 mol% Pd2(dba)3
THF (0.005 M)40 oC, 80%
549
Example 6, Asymmetric Tsuji–Trost reaction8
2.5 mol% (dba)3Pd2•CHCl37.5 mol% ent-cat
30 mol% Bu4NClCH2Cl2
O
O
EtO2CI
OHMeO
O
O
EtO2CI
OMeO OH
O
89% yield, 95% ee
O OBocO
NH HNO O
PPh2 Ph2Pent-cat =
References 1. (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387−4388. (b)
Tsuji, J. Acc. Chem. Res. 1969, 2, 144−152. (Review). 2. Godleski, S. A. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., eds.;
Vol. 4. Chapter 3.3. Pergamon: Oxford, 1991. (Review). 3. Bolitt, V.; Chaguir, B.; Sinou, D. Tetrahedron Lett. 1992, 33, 2481–2484. 4. Moreno-Mañas, M.; Pleixats, R. In Advances in Heterocyclic Chemistry; Katritzky, A.
R., ed.; Academic Press: San Diego, 1996, 66, 73. (Review). 5. Arnau, N.; Cortes, J.; Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. J. Heterocycl.
Chem. 1997, 34, 233−239. 6. Seki, M.; Mori, Y.; Hatsuda, M.; Yamada, S. J. Org. Chem. 2002, 67, 5527−5536. 7. Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorenson, E. J. J. Am. Chem. Soc. 2003,
125, 5393−5407. 8. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090−3100. 9. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044−15045. 10. Fuchter, M. J. Tsuji–Trost Reaction. In Name Reactions for Homologations-Part I; Li,
J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 185−211. (Review).
550
Ugi reaction Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction.
R3 N CR CO2H R1 NH2 R2 CHO R NHN
O
R1
R2
OR3
isocyanide
R1 NH2
R2
H
O
: R2
H
HN
HOR1:
R2
H
N R1 R CO2H R
OO
R3
NC
R2
H
N R1H
imine
R OHN
O N
R1
R3
:
R2
R NHN
O
R1
R2
OR3
O
NO
R
NR3
R2
R1
H
Example 12
OO
NH2
OTBDPS
OMOMOMe
BnO
IBocHN
CO2H
H
O
O
NC
OO
N
OMOM NHPMP
ONHBoc
OMe
OBnI
MeOH, Δ
1 h, 90%
TBDPSOO
551
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_257, © Springer-Verlag Berlin Heidelberg 2009
Example 25
HN
OCO2H
OTBS
N
CHO
O2SO2N NH2
OMe
NC
HN
O
OTBS
NO2SO2N
ON
NHt-Bu
OMeOH, Δ
61%
OMe
Example 37
O
OO
HO
O CH3
CH3
CH3H3CO
N
OCH3
OCH3C
NH2
O
ON
H3C H
O
PMB O NHOCH3
OCH3
CH3
CH3
TFE, rt
78%
Example 48
TBSO
OTBSH
TBSO
HH3C
CH3
H3CH
OHO
H2NO
NH2N
O
OH
C(CH2O)n2
552
HO
OHH
HO
HH3C
CH3
H3CH
NO
NO
O
O
HN
O
Cy
1. MeOH, rt.
2. TBAF, THF 54%, 2 Steps
ONH
Cy
References 1. (a) Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8 21; (b) Ugi, I.; Offermann, K.; Herlin-
ger, H.; Marquarding, D. Liebigs Ann. Chem. 1967, 709, 1–10.; (c) Ugi, I.; Kaufhold, G. Ann. 1967, 709, 11–28; (d) Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Or-ganic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, 1083. (Review); (e) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (Re-view); (f) Ugi, I. Pure Appl. Chem. 2001, 73, 187 191. (Review).
2. Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552−6554.
3. Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596 597. 4. Multicomponent Reactions J. Zhu, H. Bienaymé, Eds.; Wiley-VCH, Weinheim, 2005. 5. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47 50. 6. Dömling, A. Chem. Rev. 2006, 106, 17 89. 7. Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631 3634. 8. Rivera, D. G.; Pando, O.; Bosch, R.; Wessjohann, L. A. J. Org. Chem. 2008, 73,
6229 6238. 9. Bonger, K. M.; Wennekes, T.; Filippov, D. V.; Lodder, G.; van der Marel, G. A.;
Overkleeft, H. S. Eur. J. Org. Chem. 2008, 3678 3688. 10. Williams, D. R.; Walsh, M. J. Ugi Reaction. In Name Reactions for Homologations-
Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 786−805. (Review).
553
Ullmann coupling Homocoupling of aryl halides in the presence of Cu or Ni or Pd to afford biaryls.
I2Cu
CuI2
I Cu(I)ICu(II)ICu, single
electron transfer SET
Cu(II)II
CuI2
The overall transformation of PhI to PhCuI is an oxidative addition process.
Example 13
N
NO2
Cl
Cu powder, DMF
100−105 oC, 4 h, 63%N
NO2
N
O2N
Example 2, CuTC-catalyzed Ullmann coupling4
I
N
I
OSCu
O
NMP, rt, 88%
N
Example 35
OMe
OEt
OI
MeO
OMe
O
OEt
MeO OMeMeO
O
OEt
Cu-bronze210−220 οC
72%
554
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_258, © Springer-Verlag Berlin Heidelberg 2009
Example 48
IO
OI
P(O)Ph2
P(O)Ph2
O P(O)Ph2
O P(O)Ph2
O P(O)Ph2
O P(O)Ph2
Cu, DMF
140 οC, 88%
70% 18%
Example 59
MeO
MOMOI NCy
MeO
MOMOO
N
PhHNOCN
IO
PhHNCu0, Pd(PPh3)4
DMF, 100 οC39%
References 1. (a) Ullmann, F.; Bielecki, J. Ber. 1901, 34, 2174−2185. Fritz Ullmann (1875−1939),
born in Fürth, Bavaria, studied under Graebe at Geneva. He taught at the Technische Hochschule in Berlin and the University of Geneva. (b) Ullmann, F. Ann. 1904, 332, 38−81.
2. Fanta, P. E. Synthesis 1974, 9−21. (Review). 3. Kaczmarek, L.; Nowak, B.; Zukowski, J.; Borowicz, P.; Sepiol, J.; Grabowska, A. J.
Mol. Struct. 1991, 248, 189−200. 4. Zhang, S.; Zhang, D.; Liebskind, L. S. J. Org. Chem. 1997, 62, 2312−2313. 5. Hauser, F. M.; Gauuan, P. J. F. Org. Lett. 1999, 1, 671−672. 6. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org.
Lett. 2002, 4, 1623−1626. 7. Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265−556. (Review). 8. Qui, L.; Kwong, F. Y.; Wu, J.; Wai, H. L.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.;
Zhou, Z.; Chan, A. S. C. J Am. Chem. Soc. 2006, 128, 5955−5965. 9. Markey, M. D.; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255−3257. 10. Ahmad, N. M. Ullman coupling. In Name Reactions for Homologations-Part I; Li, J.
J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 255−267. (Review).
555
van Leusen oxazole synthesis 5-Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC, also known as the van Leusen reagent) with aldehydes in protic solvents at refluxing temperatures.
H
O
MeOH, refluxO
NS NC
O OK2CO3
S NO O
CH
B
S NO O
C
O R
S NO O
C
OR
O
NTos
R
+ HO
NH H
RO
NTos H
R H
H
B
− TosH
Example 13
S NCO O
HO
HN
NPr
PrH
MeOH, reflux81%
HN
NPr
PrH
NO
NaOMe
Example 25
OH
OEtO
O N
OEtOS
NCO OK2CO3
DMF, 80%
556
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_259, © Springer-Verlag Berlin Heidelberg 2009
Example 39
CHO
CHOOHC
TosMIC, K2CO3
MeOH, reflux81%
NO
N
ON
O
Example 410
TosMIC, K2CO3
MeOH, reflux4 h, 91%
N
OCHOO
O
O
O
References 1. (a) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 13,
2369–2381. (b) Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77–80. (c) Sai-kachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem. Pharm. Bull. 1979, 27, 793–796. (d) van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 21, 3723–3726.
2. van Leusen, A. M.; van Leusen, D. In Encyclopedia of Reagents of Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, 4973−4979. (Review).
3. Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harn, N. K.; Kress, T. J.; Varie, D. L.; Wepsiec, J. P. J. Org. Chem. 1997, 62, 8634–8639.
4. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5633–5636. 5. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org.
Chem. 2000, 65, 1516–1524. 6. Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P. A.; Roberts, R. S.
Org. Lett. 2001, 3, 271–273. 7. Herr, R. J.; Fairfax, D. J., Meckler, H.; Wilson, J. D. Org. Process Res. Dev. 2002, 6,
677–681. 8. Brooks, D. A. van Leusen Oxazole Synthesis. In Name Reactions in Heterocyclic
Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 254–259. (Review).
9. Kotha, S.; Shah, V. R. Synthesis 2007, 3653–3658. 10. Besselièvre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. Org. Chem. 2008,
73, 3278–3280.
557
Vilsmeier−Haack reaction The Vilsmeier–Haack reagent, a chloroiminium salt, is a weak electrophile. There-fore, the Vilsmeier–Haack reaction works better with electron-rich carbocycles and heterocycles.
O DMF, POCl3
100 oC, 24 h
OO
CHO
CHO
34% 4%
N O
H
PO
ClClCl:
N O
H
PCl2
O
Cl
N O
Cl
PCl2
O
H
: N H
Cl O PCl2
O
Vilsmeier–Haack reagent
O:
N H
Cl
O
Cl HN
H
O
Cl HN:
B
:
aqueous
workup
O
HO HN
O
CHO
O
H N
HO
H
:
H
Example 12
DMF, POCl3
100 oC, 14 h, 98%OH
OMeMeO
OMeMeO
OHC
Example 23
N
NDMF, POCl3
100 oC, 83%N
N
CHOCl Cl
558
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_260, © Springer-Verlag Berlin Heidelberg 2009
Example 39
POCl3/DMF
100 oC, 20 hN
CH3
CH3
CH3
OH
N
CH3
CH3
ClCHO
N
CH3
CH3
CH3
Cl
N
CH3
CH3
CH3
OHCHO
OH65% 10%
15%
Example 410
OR
12 equiv POCl3/DMF
80−100 oC, 31−71%R
O
OCl
OR
12 equiv POCl3/DMF
120−135 oC, 39−78%R
CHOCl
Cl
References 1. Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119–122. 2. Reddy, M. P.; Rao, G. S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2662–2665. 3. Lancelot, J.-C.; Ladureé, D.; Robba, M. Chem. Pharm. Bull. 1985, 33, 3122–3128. 4. Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994.
(Book). 5. Seybold, G. J. Prakt. Chem. 1996, 338, 392−396 (Review). 6. Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1–330. (Review). 7. Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355–659. (Review). 8. Tasneem, Synlett 2003, 138–139. (Review of the Vilsmeier–Haack reagent). 9. Nandhakumar, R.; Suresh, T.; Jude, A. L. C.; Kannan, V. R.; Mohan, P. S. Eur. J.
Med. Chem. 2007, 42, 1128–1136. 10. Tang, X.-Y.; Shi, M. J. Org. Chem. 2008, 73, 8317–8320. 11. Pundeer, R.; Ranjan, P.; Pannu, K.; Prakash, O. Synth. Commun. 2009, 39, 316–324.
559
Vinylcyclopropane−cyclopentene rearrangement Transformation of vinylcyclopropane to cyclopentene via a diradical intermediate.
R1
R2
R1
R2Δ
R1
R2
R1
R2
R1
R2
R1
R2
Example 11
O
CO2Me
340 oC, 2 h
50%
O CO2Me
Example 22
SO2Ph
1. n-BuLi, THF−HMPT −78 to −30 oC2. PhCH2Br
3. desulfonylation 77% overall yield
Ph
Example 39
O
HH
H
N
NOMOM
OMOM
O
HH
H
NN
O
MOMO
MOM
AlCl3, CH2Cl2
0 oC, 88%
N
NOMOM
OMOM O
O
N
NO
MOM
OMOM
H
H
560
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_261, © Springer-Verlag Berlin Heidelberg 2009
Example 410
O
MeMe
CO2MeMe
H
150 mol% MgI2 (0.2 M)
CH3CN, 40 oC, 6 h, 75%
OMe
MeCO2Me
H
Me
References 1. Brule, D.; Chalchat, J. C.; Garry, R. P.; Lacroix, B.; Michet, A.; Vessier, R. Bull. Soc.
Chim. Fr. 1981, 1−2, 57−64. 2. Danheiser, R. L.; Bronson, J. J.; Okano, K. J. Am. Chem. Soc. 1985, 107, 4579−4581. 3. Hudlický, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247−335. (Review). 4. Goldschmidt, Z.; Crammer, B. Chem. Soc. Rev. 1988, 17, 229−267. (Review). 5. Sonawane, H. R.; Bellur, N. S.; Kulkarni, D. G.; Ahuja, J. R. Synlett 1993, 875−884.
(Review). 6. Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153−156. 7. Baldwin, J. E. Chem. Rev. 2003, 103, 1197−1212. (Review). 8. Wang, S. C.; Tantillo, D. J. J. Organomet. Chem. 2006, 691, 4386−4392. 9. Zhang, F.; Kulesza, A.; Rani, S.; Bernet, B.; Vasella, A. Helv. Chim. Acta 2008, 91,
1201−1218. 10. Coscia, R. W.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 2496−2498.
561
von Braun reaction Different from the von Braun degradation reaction (amide to nitrile), the von Braun reaction refers to the treatment of tertiary amines with cyanogen bromide, resulting in a substituted cyanamide.
R1 NR2
R Br CNR1 N
R2
CNBr R
R1N
R2
RNC Br
:R1
NR2
RCN
BrSN2
R1N
R2
CNBr R
Example 14
O
CF3
N CNO
CF3
N
Br-CN
Tol.
O
CF3
NH
KOH
MeOH/H2O
Prozac
Example 25
N
CO2Me
CO2Me
Br-CN, THF, H2O
75% NCN
CO2Me
CO2Me
Br
Example 39
N
OTBS
Ph
BrCN, CH2Cl2
reflux, 98% N
OTBS
PhCN
Br NCN
TBSO
Ph
Br
References 1. von Braun, J. Ber. 1907, 40, 3914−3933. Julius von Braun (1875−1940) was born in
Warsaw, Poland. He was a Professor of Chemistry at Frankfurt.
562
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_262, © Springer-Verlag Berlin Heidelberg 2009
2. Hageman, H. A. Org. React. 1953, 7, 198−262. (Review). 3. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300. (Review). 4. Mody, S. B.; Mehta, B. P.; Udani, K. L.; Patel, M. V.; Mahajan, Rajendra N.. Indian
Patent IN177159 (1996). 5. McLean, S.; Reynolds, W. F.; Zhu, X. Can. J. Chem. 1987, 65, 200−204. 6. Chambert, S.; Thomasson, F.; Décout, J.-L. J. Org. Chem. 2002, 67, 1898−1904. 7. Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908−9917. 8. Thavaneswaran, S.; McCamley, K.; Scammells, P. J. Nat. Prod. Commun. 2006, 1,
885−897. (Review). 9. McCall, W. S.; Abad Grillo, T.; Comins, D. L. Org. Lett. 2008, 10, 3255−3257.
563
Wacker oxidation Palladium-catalyzed oxidation of olefins to ketones, and aldehydes in certain cases.
R
OR
cat. PdCl2, H2O
CuCl2, O2
LnPdCl2
reductiveelimination
complexation
R
O
R
RLnClPdCl
HO
H: :
HCl
L = ligand or solvent
LnClPd
HR
OH
::
hydride shift
LnPdHCl
HClLnPd
2 CuCl
2 CuCl2
2 HCl+
0.5 O2
H2O
hydroxypalladation
Example 15
CO2HO2, 5% Pd(OAc)2
NaOAc, DMSO, 80%
O
O
Example 27
O
H
H H
O
H 10% Pd(OAc)2, HClO4
0.5 equiv benzoquinoneCH3CN
O
H
H H
O
H
45%
O
H
H H
CHOO
H
35%
O
564
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_263, © Springer-Verlag Berlin Heidelberg 2009
Example 39
O2, 20 mol% Cu(OAc)210 mol% PdCl2
DMA/H2O (7:1)
84%O O O O O
Example 410
O
O
HOO
O
O O 5 eq. PdCl2, air
DMF/H2O (7:1)81%
O
O
HOO
O
O O
O
O
HOO
O CHO
O O
O
12 : 1
References 1. Smidt, J.; Sieber, R. Angew. Chem., Int. Ed. 1962, 1, 80−88. 2. Tsuji, J. Synthesis 1984, 369−384. (Review). 3. Hegedus, L. S. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991,
Vol. 4, 552. (Review). 4. Tsuji, J. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 7,
449. (Review). 5. Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298−5300. 6. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994,
University Science Books: Mill Valley, CA, pp 199−208. (Review). 7. Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron 1997, 53, 10733−10742. 8. Feringa, B. L. Wacker oxidation. In Transition Met. Org. Synth. Beller, M.; Bolm, C.,
eds.; Wiley−VCH: Weinheim, Germany. 1998, 2, 307−315. (Review). 9. Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima,
M.; Qiu, Y.; Salvatore, B. A.; Spoors, P. G.; Duan, J. J.-W. J. Am. Chem. Soc. 1999, 121, 10468−10477.
10. Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381−4384. 11. Hintermann, L. Wacker-type Oxidations in Transition Met. Org. Synth. (2nd edn.) Bel-
ler, M.; Bolm, C., eds., Wiley−VCH: Weinheim, Germany. 2004, 2, pp 379−388. (Re-view).
12. Li, J. J. Wacker−Tsuji oxidation. In Name Reactions for Functional Group Transfor-mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 309−326. (Review).
13. Okamoto, M.; Taniguchi, Y. J. Cat. 2009, 261, 195−200.
565
Wagner–Meerwein rearrangement Acid-catalyzed alkyl group migration of alcohols to give more substituted olefins.
R2 HR
R3
R1
OH H
R3
R
R2
R1
HR2 H
R
R3
R1
OHR2 H
R
R3
R1
OH2
− H2OR2 H
R
R3
R1
1,2-shift
−R2 H
R1
R3R R3
R
R2
R1 H
Example 13
H3CNN O
OHN
N
H3C OH
Br
HNO
OCH3
OCH3H3CO
H3CO2C
CH3SO3H
ClCH2CH2Cl50 oC, 86%
H3CNN O
OHN
N
H3C CO2CH3
Br
HNO
OCH3
OCH3H3CO
Example 2, Double Wagner–Meerwein rearrangement6
O
OEt
O
HOTFA, CH2Cl2
72 h, 76%
O
OEt
O
566
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_264, © Springer-Verlag Berlin Heidelberg 2009
Example 37
HO
OH
CH3 OTBSO
MsOBzO H
O
OH
CH3 OTBS
O
BzO HH
Et2AlCl,CH2Cl2
−78 oC → rt52%
Example 49
O
H
OBzH3C
CH3
H
O
H
OBzCH3
H
H3C H
BzOBzO
BF3•Et2O
benzene, 40%
References 1. Wagner, G. J. Russ. Phys. Chem. Soc. 1899, 31, 690. 2. Hogeveen, H.; Van Kruchten, E. M. G. A. Top. Curr. Chem. 1979, 80, 89–124. (Re-
view). 3. Kinugawa, M.; Nagamura, S.; Sakaguchi, A.; Masuda, Y.; Saito, H.; Ogasa, T.; Kasai,
M. Org. Proc. Res. Dev. 1998, 2, 344–350. 4. Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162–7163. 5. Guizzardi, B.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2003, 68, 1067–1074. 6. Bose, G.; Ullah, E.; Langer, P. Chem. Eur. J. 2004, 10, 6015–6028. 7. Guo, X.; Paquette, L. A. J. Org. Chem. 2005, 70, 315–320. 8. Li, W.-D. Z.; Yang, Y.-R. Org. Lett. 2005, 7, 3107–3110. 9. Michalak, K.; Michalak, M.; Wicha, J. Molecules 2005, 10, 1084–1100. 10. Mullins, R. J.; Grote, A. L. Wagner–Meerwein rearrangement. In Name Reactions for
Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 373−394. (Review).
567
Weiss–Cook reaction Synthesis of cis-bicyclo[3.3.0]octane-3,7-dione. The product is frequently decar-boxylated.
EtO2C
EtO2C
OR1
RO
O
aq. bufferR
R1
OO
EtO2C
EtO2C
CO2Et
CO2Et
EtO2C
EtO2C
O O
OR
R1
EtO2C
EtO2C
OH
EtO2C
EtO2C
O OR1
OHR
HEtO2C
EtO2C
O OR1
OHR
H
OO
EtO2C
EtO2C
CO2Et
CO2Et
OOH
R
R1OH
EtO2CH
HEtO2C
H
R
R1HHO
EtO2C
EtO2C R1
R CO2Et
O
CO2Et
O
EtO2C
EtO2CR1
R CO2Et
O
CO2Et
HH
R
R1
OHO
EtO2C
EtO2C
CO2Et
CO2Et
R
R1
OHHO
EtO2C
EtO2C
CO2Et
CO2Et
Example 12
MeO2C
MeO2C
O
O O
pH 5.6
86%
O
CO2MeMeO2C O
MeO2C CO2Me
Example 23
O CHO
1. pH = 8.32. HOAc/HCl, Δ
90% O O
H
CO2CH3
CO2CH3
O
568
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_265, © Springer-Verlag Berlin Heidelberg 2009
Example 34
O
O
CO2CH3
CO2CH3
O
1. pH = 6.82. HOAc/HCl
80%O O
Example 49
EtO2C
EtO2C
OEt
Me O
O NaHCO3
H2O/MeOHrt, 24 h, 86%
CO2Et
CO2Et
O
Et
Me
OO
EtO2C
EtO2C
CO2Et
CO2Et
Et
Me
OHHO
EtO2C
EtO2C
CO2Et
CO2Et
Et
Me
OHHO
EtO2C
EtO2C
CO2Et
CO2Et
References 1. Weiss, U.; Edwards, J. M. Tetrahedron Lett. 1968, 9, 4885–4887. 2. Bertz, S. H.; Cook, J. M.; Gawish, A.; Weiss, U. Orga. Synth. 1986, 64, 27–38. 3. Kubiak, G.; Fu, X.; Gupta, A. K.; Cook, J. M. Tetrahedron Lett. 1990, 31, 4285–4288. 4. Wrobel, J.; Takahashi, K.; Honkan, V.; Lannoye, G.; Bertz, S. H.; Cook, J. M. J. Org
Chem. 1983, 48, 139–141. 5. Gupta, A. K.; Fu, X.; Snyder, J. P.; Cook, J. M. Tetrahedron 1991, 47, 3665–3710. 6. Paquette, L. A.; Kesselmayer, M. A.; Underiner, G. E.; House, S. D.; Rogers, R. D.;
Meerholz, K.; Heinze, J. J. Am. Chem. Soc. 1992, 114, 2644–2652. 7. Fu, X.; Cook, J. M. Aldrichimica Acta 1992, 25, 43–54. (Review). 8. Fu, X.; Kubiak, G.; Zhang, W.; Han, W.; Gupta, A. K.; Cook, J. M. Tetrahedron 1993,
49, 1511–1518. 9. Williams, R. V.; Gadgil, V. R.; Vij, As.; Cook, J. M.; Kubiak, G.; Huang, Q. J. Chem.
Soc., Perkin Trans. 1 1997, 1425–1428. 10. van Ornum, S. G.; Li, J.; Kubiak, G. G.; Cook, J. M. J. Chem. Soc., Perkin Trans. 1
1997, 3471–3478.
569
Wharton reaction Reduction of α,β-epoxy ketones by hydrazine to allylic alcohols.
R1
R2
OO
NH2NH2
Δ HO
R2 N2↑ H2OR1
R1
R2
OO:NH2NH2
R1
R2
O NHOH
NH2:
H2OHR1
R2
ON
NH
H
hydrazone
tautomerizationR1
R2
ON
N
H:OH2
H
diazene
N2↑HO
R2R1
Example 15
O
NTEOC
O
H
NH2NH2•H2O, MeOH
HOAc, rt, 52%N
TEOC H
OH
Example 26
CO2CH3TBDMSO
OO
NH2NH2•HCl, Et3N
(dimethylamino)ethanol32%
CO2CH3TBDMSO
OH
Example 37
O
O
NH2NH2, KOH
THF, reflux, 64%HO
OH
570
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_266, © Springer-Verlag Berlin Heidelberg 2009
HOOH
OH
HOOH
OH
91 : 9
Example 48
NH2NH2•H2O, MeOH
HOAc, rt, 59%
O
OTESO
O
O
OTESO
O
OH
References 1. (a) Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615−3616. (b) Wharton,
P. S. J. Org. Chem. 1961, 26, 4781−4782. 2. Caine, D. Org. Prep. Proced. Int. 1988, 20, 1−51. (Review). 3. Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 3437−3444. (Review). 4. Thomas, A. F.; Di Giorgio, R.; Guntern, O. Helv. Chim. Acta 1989, 72, 767−773. 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112,
2003−2004. 6. Yamada, K.-i.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63, 3666−3672. 7. Di Filippo, M.; Fezza, F.; Izzo, I.; De Riccardis, F.; Sodano, G. Eur. J. Org. Chem.
2000, 3247−3249. 8. Takagi, R.; Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem. 2005, 3, 2031−2036. 9. Li, J. J. Wharton reaction. In Name Reactions for Functional Group Transformations;
Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 152−158. (Re-view).
571
White Reagent
S SPh PhOO
Pd(OAc)2
·
White Reagent
The White Reagent 1 is a highly versatile, commercially-available catalyst for allylic C–H oxidation which allows for the construction of useful C–O, C–N, and C–C bonds directly from relatively inert allylic C–H bonds (Figure 1).1–11 The White Reagent enables novel and predictable disconnections for the synthesis of complex molecules which can streamline their synthesis.2,4,7,8 Widely available α-olefins undergo intra- and intermolecular C–H oxidation with remarkably high levels of chemo-, regio-, and stereoselectivity. Mechanistic studies provide evidence that the White Reagent promotes allylic C–H cleavage to generate π-allylpalladium intermediate 2 which can then be functionalized with an oxygen, nitrogen or carbon nucleophile (Figure 1).3 Figure 1
R
Pd(II)Ln
R
H
S SPh PhOO
Pd(OAc)2(10 mol%)
·
R
OC(O)R1
R NR'2 R
OC(O)R1
Ar
O
O
White Reagent
2
RNR'2
OH
RCO2Me
NO2
1
C−C
C−N
C−O
Common organic functionality such as Lewis basic phenol 3,3 acid-labile acetal 4,8 highly reactive aryl triflate 6,11 and depsipeptide 55 are well-tolerated under the mild reaction conditions (Figure 2). In all cases the products are isolated as one regioisomer and olefin isomer after column purification.
Current state-of-the-art methods for constructing C–N bonds rely on functional group interconversions or C–C bond forming reactions using preoxidized materials. Allylic amination using the White Reagent can streamline the synthesis of nitrogen-containing molecules by reducing the functional group manipulations necessary for working with oxygenated intermediates. Allylic C–H amination was used to synthesize (–)-8, an intermediate in the synthesis of L-acosamine derivative 9 (Figure 3A).7 The C–H amination route to (–)-8 proceeded in half the total number of steps, no functional group manipulations, and
572
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_267, © Springer-Verlag Berlin Heidelberg 2009
comparable overall yield to the alternative C–O to C–N bond-forming route. Intermolecular C–H amination has also led to the construction of (+)-deoxynegamycin analogue 12 in five less steps and improved overall yield compared to the alternative route relying on C–O substitution (Figure 3B).8
Figure 2
R
CO2Me
NO2
H
MeO2C
TfOOMe
S SPh PhOO
Pd(OAc)2·
RR
linear allylic C-H amination
linear allylic C-H alkylation
branched allylic C-H oxidation
branched macrolactonization
linear product (L)
Nu
branched product (B)
or(10 mol%)
6, 64% yield, > 20:1 E:Z, > 20:1 L:B
HNNH
O
NO
OO
O
Ph
5, 61% yield, 3:1 dr
NTs
CO2MeO
O
OBn(+)-4, 63%, > 20:1 E:Z, > 20:1 L:B
conditions
pro-nucleophile (NuH)(1.5−2.0 equiv)
+
OH
O
O
p-BrPhO2C
3, 65% yield, > 20:1 B:L
BQ (2 equiv),dioxane, 43 oC
BQ (2 equiv)CH2Cl2, 45 oC
DMBQ (1.5 equiv),AcOH (0.5 equiv),
dioxane:DMSO (4:1)
Cr(salen)Cl (6 mol%),BQ (2 equiv), TBME,
45 oC
1Nu
Figure 3
TBSO
O
O
NHTsNTs
O
TBSO
O
PhBQ (1.05 equiv)THF, 50 oC, 72 h
S SPh PhOO
Pd(OAc)2·
(10 mol%) O
Me NHAc
OMe
OH78%, 9:1 dr crude(−)-N-acetyl-O-methyl
acosamine 9(+)-7 (−)-8
H(70% yield, 1 isomer)
OTMSE
O
NTsCBz
BocNH
(−)-10 (+)-11
NH
O
NH2
BocNHN
CO2H2 HBr(+)-deoxynegamycin
analogue 12BQ (2 equiv.), TBME
S SPh PhOO
Pd(OAc)2·
(10 mol%)
54%, 1 isomer
Cr(salen)Cl (6 mol%)
CbzNHTs (2 equiv)
BocNH
TMSEO2C
A.
B.
1
1
steps
steps
Similarly, allylic C–H oxidation can streamline the construction of oxygenated compounds by reducing functional group manipulations necessary for working with bisoxygenated intermediates. For example, a chiral allylic C–H oxidation/enzymatic resolution sequence furnished bisoxygenated compound 14 in 97% ee and in 42% overall yield in just 3 steps from a commercially available
573
monooxygenated precursor, 11-undecenoic acid (Figure 4).10 Alternative routes to similar molecules require protection/deprotection sequences and use a kinetic resolution giving a maximum of 50% yield. Figure 4
undecenoic acid
1. (MeO)NMeNMe
O
7
OAcMeO
42% overall yield> 20:1 B:L, 97% ee
AcOH (1.1 equiv)BQ (2 equiv)
4 Å MS, EtOAc, rt
1 (10 mol%)(R,R)-Cr(salen)F
(10 mol%)
2)
3) Novazyme 435
NMe
O H
7MeO
1314CDI, DCMHO
O H
7
In addition to allylic C–H oxidation, the White Reagent also catalyzes intermolecular Heck arylations.6 Notably, the arylation uses electronically unbiased α-olefins and aryl boronic acids and occurs under acidic, oxidative conditions. A one-pot allylic C–H oxidation/vinylic C–H arylation reaction furnishes E-arylated allylic esters with high regio- and stereoselectivities (Figure 5). This three-component coupling can be used to rapidly synthesize densely functionalized products from inexpensive hydrocarbon feedstocks. N-Boc glylcine allylic ester 9 was synthesized in one step using commercially available olefin, amino acid, and boronic acid reagents. Compounds similar to 15 have been transformed into medicinally relevant dipeptidyl peptidase IV inhibitors.6 Figure 5
Me7
Me7
O
O
Br
S SPh PhOO
Pd(OAc)2·
(10 mol%)
NHBoc
N-Boc-Gly (2 equiv)BQ (2 equiv) Me
7
O
ONHBoc
dioxane, 45 oC
(4-Br)PhB(OH)2(1.5 equiv), 45 oC
15, 75%> 20:1 E:Z
> 20:1 internal:terminal
H
1-undecene
Branched allylic C−H esterification Oxidative Heck
1
Besides the one-pot process described above, the White Reagent catalyzes a chelate-controlled oxidative Heck arylation between a wide range of α-olefins and organoborane compounds in good yields and with excellent regio- and stereoselectivities (Figure 6).9 Unlike other Heck arylation methods, no Pd–H isomerization is observed under the mild reaction conditions. Aryl boronic acids, styrenylpinacol boronic esters, and aryl potassium trifluoroborates (activated with boric acid) are all compatible with the general reaction conditions.
574
Figure 6
S SPh PhOO
Pd(OAc)2·
(10 mol%)AcOH (4 equiv)
quinone (2 equiv)dioxane, rt, 4 h
R
X
n = 0−2
M
ArBpin
M = B(OH)2 = BF3K
or R
X
Ar
R'
> 20:1 E:Z> 20:1 internal:terminal
1
Ph
NHBoc
NBoc
HO
18, 83% (+)-19, 81%
OPh
Bn
BocHN
(+)-17, 62%
HN
CO2MeO
F
F(+)-16, 60% Br
allylic amine
α,β-unsaturated carbonyls
free alcohols
amino acids
References 1. Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346–1347. 2. Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223–226. 3. Chen. M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005,
127, 6970–6971. 4. Covell, D. J.; Vermeulen, N. A.; White, M. C. Angew. Chem. Int. Ed. 2006, 45, 8217–
8220. 5. Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am. Chem. Soc. 2006,
128, 9032–9033. 6. Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076–15077. 7. Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274–7276. 8. Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 129, 3316–3318. 9. Delcamp, J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc. 2008, 129, 11270–
11271. 10. Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448–6451. 11. Young, A. J.; White, M. C. J. Am. Chem. Soc. 2008, 129, 14090–14091.
575
Willgerodt–Kindler reaction Conversion of a ketone to thioamide, with functional group migration.
TsOH, S8, Δ thioamideAr
MeO
n
HNR2 Ar n NR2
S
In Carmack’s mechanism,2 the most unusual movement of a carbonyl group from methylene carbon to methylene carbon was proposed to go through an intricate pathway via a highly reactive intermediate with a sulfur-containing heterocyclic ring. The sulfenamide serves as the isomerization catalyst. e.g.:
OHN O
TsOH, S8, Δ
N
S
Othioamide
SSS
S SSS
S
NHO
SS S
SS
SSH
SNO
NHOsulfenamide
HS SSS
SSH
SNO
SNO
N
O
:
SN
O
NO
SN
O
N
O
SN
O
NO
H thiirene
:
:
:
H
HNO
SN
O
SN
O
N
O
N
O
SN
O:
SN
O
N
O
:H H
H
N
O
N
O
N
S
O
S8N OS
576
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_268, © Springer-Verlag Berlin Heidelberg 2009
Example 1, The Willgerodt–Kindler reaction was a key operation in the initial synthesis of racemic Naproxen:3
O
OHN O
S8 O
N
S
O
O
OH
O
1. H+
2. CH3OH, H2SO4
3. NaH, CH3I4. NaOH Naproxen
Example 25
O HN ON
S
OS8, microwave4 min., 40%
Example 3, A domino annulation reaction under Willgerodt–Kindler conditions:10
N
Cl O HN O
S8, 130 oC, 6 h, 15%N
SS
NO
46%N
SS
N
O
26%
References 1. (a) Willgerodt, C. Ber. 1887, 20, 2467−2470. Conrad Willgerodt (1841−1930), born
in Harlingerode, Germany, was a son of a farmer. He worked to accumulate enough money to support his study toward his doctorate, which he received from Claus. He became a professor at Freiburg, where he taught for 37 years. (b) Kindler, K. Arch. Pharm. 1927, 265, 389−415.
2. Carmack, M.; Spielman, M. A. Org. React. 1946, 3, 83−107. (Review). 3. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roskowski, A.; Tomolonis, A.;
Fried, J. H. J. Med. Chem. 1970, 13, 203−205. 4. Carmack, M. J. Heterocycl. Chem. 1989, 26, 1319−1323. 5. Nooshabadi, M.; Aghapoor, K.; Darabi, H. R.; Mojtahedi, M. M. Tetrahedron Lett.
1999, 40, 7549−7552. 6. Alam, M. M.; Adapa, S. R. Synth. Commun. 2003, 33, 59−63. 7. Reza Darabi, H.; Aghapoor, K.; Tajbakhsh, M. Tetrahedron Lett. 2004, 45,
4167−4169. 8. Purrello, G. Heterocycles 2005, 65, 411−449. (Review). 9. Okamoto, K.; Yamamoto, T.; Kanbara, T. Synlett 2007, 2687−2690. 10. Kadzimirsz, D.; Kramer, D.; Sripanom, L.; Oppel, I. M.; Rodziewicz, P.; Doltsinis, N.
L.; Dyker, G. J. Org. Chem. 2008, 73, 4644−4649.
577
Wittig reaction Olefination of carbonyls using phosphorus ylides, typically the Z-olefin is ob-tained.
R1 R2
OPh3P
R3
R4 R2
R1 R3
R4
Ph3P O
R X
R1Ph3P: SN2
:B R
R1
Ph3PR
HR1X
PPh3
R2 O
R3 Ph3P O
R2R1
R3 R
O
PPh3
betaine
[2 + 2]
cycloaddition
RR1
R2
R3
“puckered” transition state, irreversible and concerted
R2
R3R1
R
Ph3P O
RR1 R2
R3 OPPh3
oxaphosphetane Example 13
CHO
NHTs
NaH, Et2O; then addCH2=CHPPh3
+Br−
DMF, reflux, 48 h, 50% NTs
Example 24
PPh3Cl
OHO O
1.8 N NaOEt, EtOH
−30 oC to rt
CO2H
2-cis-4-cis-vitamin A acid
CO2H
Accutane
578
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_269, © Springer-Verlag Berlin Heidelberg 2009
Example 35
N
HN S
Ot-BuO2C
PPh3
OO
PhOTol., 70 oC
70%N
HN
O
O
PhOS
CO2t-Bu
Example 49
O
O
O
O
O
O
O
H H H
H HH H H
OTMS
PPh3
I
O
O
O
EtS
EtS
OH H H
OTBSH
OTPS 1. n-BuLi, HMPA
2. PPTS, 75%
O
O
OEtS
EtS
HH
H
TBSO
H
OTPS
O
O
O
O
O
O
O
H H H
H HH H H
OTMS
References
1. Wittig, G.; Schöllkopf, U. Ber. 1954, 87, 1318−1330. Georg Wittig (Germany, 1897−1987), born in Berlin, Germany, received his Ph.D. from K. von Auwers. He shared the Nobel Prize in Chemistry in 1981 with Herbert C. Brown (USA, 1912−2004) for their development of organic boron and phosphorous compounds.
2. Maercker, A. Org. React. 1965, 14, 270−490. (Review). 3. Schweizer, E. E.; Smucker, L. D. J. Org. Chem. 1966, 31, 3146–3149. 4. Garbers, C. F.; Schneider, D. F.; van der Merwe, J. P. J. Chem. Soc. (C) 1968, 1982–
1983. 5. Ernest, I.; Gosteli, J.; Greengrass, C. W.; Holick, W.; Jackman, D. E.; Pfaendler, H.
R.; Woodward, R. B. J. Am. Chem. Soc. 1978, 100, 8214–8222. 6. Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 1−30. (Review). 7. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1988, 89, 863−927. (Review). 8. Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1–157. (Review). 9. Nicolaou, K. C. Angew. Chem., Int. Ed. 1996, 35, 589–607. 10. Rong, F. Wittig reaction in. In Name Reactions for Homologations-Part I; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 588−612. (Review).
579
Schlosser modification of the Wittig reaction
The normal Wittig reaction of nonstabilized ylides with aldehydes gives Z-olefins. The Schlosser modification of the Wittig reaction of nonstabilized ylides furnishes E-olefins instead.
R1 CHOBr PhLi PhLi t-BuOH
R1
R
t-BuOKR
Ph3P
RPh3P
Ph3PR
HH
Ph3PR
Ph
R1 O
HBr
phosphorus ylide
Ph
BrPh3P OLi
R R1H
t-BuOHBrPh3P OLi
R R1Li
LiBr complex of β-oxo ylide
These conditions allow for the erythreo betaine to interconvert to the threo betaine
Br
R1
RLiBr
R1H
H
PPh3
RLiO t-BuOH
t-BuOKPh3P O
LiBr complex of threo betaine
Example 16
NO
EtO2C
O
N
Ph HMe
O
PhMe
NO
EtO2C
O
NI 5 equiv Et3P, DMF, rt, 30 min.
then 0 oC, LDA, then
66%
580
Example 210
O PPh3Br
PhLi, Bu2O/THF66%
References
1. (a) Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. 1966, 5, 126. (b) Schlosser, M.; Christmann, K. F. Ann. 1967, 708, 1−35. (c) Schlosser, M.; Christ-mann, K. F.; Piskala, A.; Coffinet, D. Synthesis 1971, 29−31.
2. van Tamelen, E. E.; Leiden, T. M. J. Am. Chem. Soc. 1982, 104, 2061−2062. 3. Parziale, P. A.; Berson, J. A. J. Am. Chem. Soc. 1991, 113, 4595−606. 4. Sarkar, T. K.; Ghosh, S. K.; Rao, P. S.; Satapathi, T. K.; Mamdapur, V. R. Tetrahe-
dron 1992, 48, 6897−6908. 5. Deagostino, A.; Prandi, C.; Tonachini, G.; Venturello, P. Trends Org. Chem. 1995, 5,
103−113. (Review). 6. Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449−5452. 7. Panek, J. S.; Liu, P. J. Am. Chem. Soc. 2000, 122 11090−11097. 8. Duffield, J. J.; Pettit, G. R. J. Nat. Prod. 2001, 64, 472−479. 9. Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2004, 4995−5002. 10. Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2008, 4806−4814.
581
[1,2]-Wittig rearrangement Treatment of ethers with bases, such as alkyl lithium, results in alcohols.
R OR1
R OH
R1
12
12
R2Li
The [1,2]-Wittig rearrangement is believed to proceed via a radical mechanism:
R OR1
H deprotonationR O
R1R2 homolytic
cleavage
Li
R O R1
Li
R OLi
R1
R OLi
R1
R OH
R1workup
Example 1, Aza [1,2]-Wittig rearrangement2
Ph N SnBu3CH3
n-BuLi Ph N LiCH3
PhHN
CH3
workup
83%
Example 23
OO
t-BuLi
58% O OH
Example 34
O
OTBDPS
O
OTBDPS
OH H
OH
TMS TMSn-BuLi, THF, ether
0 °C, 60%, > 98:2 dr
Example 46
O
O
NOMe2 eq. LDA, THF
−78 oC, 82% O
NOMe
OH
Example 58
582
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_270, © Springer-Verlag Berlin Heidelberg 2009
TBSO O PhOTBS n-BuLi, THF
−20 to 0 oC, 32%TBSO
Ph
TBSO OH
Example 69
O PhO
NOMe
LDA, THF
−40 oC, 94%
PhO
NOMe
OH
References 1 Wittig, G.; Löhmann, L. Ann. 1942, 550, 260–268. 2 Peterson, D. J.; Ward, J. F. J. Organomet. Chem. 1974, 66, 209–217. 3 Tsubuki, M.; Okita, H.; Honda, T. J. Chem. Soc., Chem. Commun. 1995, 2135–2136. 4 Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118, 3317–3318. 5 Maleczka, R. E., Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551–8552. 6 Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915–1916. 7 Katritzky, A. R.; Fang, Y. Heterocycles 2000, 53, 1783–1788. 8 Tomooka, K.; Kikuchi, M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew.
Chem., Int. Ed. 2000, 39, 4502–4505. 9 Miyata, O.; Asai, H.; Naito, T. Chem. Pharm. Bull. 2005, 53, 355–360. 10 Wolfe, J. P.; Guthrie, N. J. [1,2]-Wittig Rearrangement. In Name Reactions for Ho-
mologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 226−240. (Review).
583
[2,3]-Wittig rearrangement Transformation of allyl ethers into homoallylic alcohols by treatment with base. Also known as the Still−Wittig rearrangement. Cf. Sommelet−Hauser rearrange-ment.
XY
1
231
2X
Y[2,3]-sigmatropic
rearrangement1
231
2
R2LiO R1
R
HO
R
R1
R2
R1 = alkynyl, alkenyl, Ph, COR, CN.
[2,3]-sigmatropic
rearrangementworkup
R
O R1
R
HO R1
Example 12
OO
KOt-Bu, HOt-Bu, THF
0 oC, 26 h, 22% HOO
Example 23
O CO2H
LDA, THF, −78 oC;
then TsCl, 87%TsO CO2H
> 95% E
Example 35
NO
O
O
H1.5 equiv LiHMDS
5 equiv HMPA, THF
−78 to −10 οC67%
H
H ON
O
HO
H
ON
O
HO
H
94 : 6
HHH
H
584
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_271, © Springer-Verlag Berlin Heidelberg 2009
Example 46
O
Me
O
Me
HO
Me
MeO
OSEM
Me
n-BuLi
THF-pentane97%
OSEM
Me
References 1. Cast, J.; Stevens, T. S.; Holmes, J. J. Chem. Soc. 1960, 3521−3527. 2. Thomas, A. F.; Dubini, R. Helv. Chim. Acta 1974, 57, 2084−2087. 3. Nakai, T.; Mikami, K.; Taya, S.; Kimura, Y.; Mimura, T. Tetrahedron Lett. 1981, 22,
69−72. 4. Nakai, T.; Mikami, K. Org. React. 1994, 46, 105−209. (Review). 5. Kress, M. H.; Yang, C.; Yasuda, N.; Grabowski, E. J. J. Tetrahedron Lett. 1997, 38,
2633−2636. 6. Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962−5970. 7. Maleczka, R. E., Jr.; Geng, F. Org. Lett. 1999, 1, 1111−1113. 8. Tsubuki, M.; Kamata, T.; Nakatani, M.; Yamazaki, K.; Matsui, T.; Honda, T. Tetrahe-
dron: Asymmetry 2000, 11, 4725−4736. 9. Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913−2920. 10. Ahmad, N. M. [2,3]-Wittig Rearrangement. In Name Reactions for Homologations-
Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 241−256. (Review).
585
Wohl–Ziegler reaction The Wohl–Ziegler reaction is the reaction of an allylic or benzylic substrate with N-bromosuccinimide (NBS) under radical initiating conditions to provide the cor-responding allylic or benzylic bromide. Conditions used to promote the radical reaction are typically radical initiators, light and/or heat; carbon tetrachloride (CCl4) is typically utilized as the solvent.
R N
O
O
BrCCl4, reflux
initiatorR
Br
HN
O
O
Initiation:
N N CNNCΔ
CNN2↑ 2homolyticcleavage
2,2 -azobisisobutyronitrile (AIBN)
N Br
O
O
N
O
O
CN CNBr
Propagation:
N
O
O
HH abstraction
NH
O
O
N Br
O
O
N
O
O
Br
The succinimidyl radical is now available for the next cycle of the radical chain reaction.
Example 13
AcO
OAc OAc
NBS, CCl4
reflux, 30 min., 48%AcO
OAc O
AcO
OAc O
OBr
:
586
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_272, © Springer-Verlag Berlin Heidelberg 2009
Example 27
CO2Me 1.2 eq. NBS, 0.1 eq. AIBN
solvent free, 60 to 65 oC89%
CO2Me
Br
Example 38
N
N NBS, CCl4
reflux, 71% N
N
Br
Br
Example 49
BocNO
NBS, AIBN (cat)
CCl4, reflux, 2 h,95%
BocNO
Br
References 1. Wohl, A. Ber. 1919, 52, 51−63. Alfred Wohl (1863−1939), born in Graudenz, Ger-
many, received his Ph.D. from A. W. Hofmann. In 1904, he was appointed Professor of Chemistry at the Technische Hochschule in Danzig.
2. Ziegler, K.; Spath, A.; Schaaf, E.; Schumann, W.; Winkelmann, E. Ann. 1942, 551, 80−119. Karl Ziegler (1898−1973), born in Helsa, Germany, received Ph.D. in 1920 from von Auwers at the University of Marburg. He became the director of the Max-Planck-Institut für Kohlenforschung at Mülheim/Ruhr in 1943 and stayed there until 1969. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (1903−1979) for their work in polymer chemistry. The Ziegler−Natta catalyst is widely used in po-lymerization.
3. Djerassi, C.; Scholz, C. R. J. Org. Chem. 1949, 14, 660−663. 4. Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351−352. 5. Detterbeck, R.; Hesse, M. Tetrahedron Lett. 2002, 43, 4609−4612. 6. Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De Kimpe, N.; Verhe, R.
Synlett 2002, 1089−1092. 7. Togo, H.; Hirai, T. Synlett 2003, 702−704. 8. Marjo, C. E.; Bishop, R.; Craig, D. C.; Scudder, M. L. Mendeleev Commun. 2004,
278−279. 9. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310−6311. 10. Curran, T. T. Wohl–Ziegler reaction. In Name Reactions for Homologations-Part I;
Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 661−674. (Review).
587
Wolff rearrangement Conversion of an α-diazoketone into a ketene.
R2
N2O
R1 N2C
R1
R2O
H2O R1
R2 OH
O CO2 R2 R1Δ
α-diazoketone ketene intermediate
Step-wise mechanism:
R1
O N
R2
N
R1
O N
R2
NN2
R1 R2
OC
R2
R1
O
α-ketocarbene
Treatment of the ketene with water would give the corresponding homologated carboxylic acid.
Concerted mechanism:
R1
O N
R2
NN2 C
R2
R1
O
Example 12
H
O
N2
OΔ or hv
EtOH, dioxane (1:1)> 90%
OEt
O O
Example 23
N
O
MeO
N2 hv, MeOH
90% NMe
O
CO2Me
588
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_273, © Springer-Verlag Berlin Heidelberg 2009
Example 34
O ON2
1. LiHMDS, TFEA
2. MsN3, Et3NO
OMe
hυ
CH3OH
Example 49
NBoc
OEtO2C
N2
Rh2Oct4
C5H11CONH2NBoc
CO2EtO
55%
HNO
C5H11
NBoc
OEtO2C
39%
HNO
C5H11
Wolff rearrangement N-H insertion
References 1. Wolff, L. Ann. 1912, 394, 23−108. Johann Ludwig Wolff (1857−1919) earned his
doctorate in 1882 under Fittig at Strasbourg, where he later became an instructor. In 1891, Wolff joined the faculty of Jena, where he collaborated with Knorr for 27 years.
2. Zeller, K.-P.; Meier, H.; Müller, E. Tetrahedron 1972, 28, 5831−5838. 3. Kappe, C.; Fäber, G.; Wentrup, C.; Kappe, T. Ber. 1993, 126, 2357−2360. 4. Taber, D. F.; Kong, S.; Malcolm, S. C. J. Org. Chem. 1998, 63, 7953−7956. 5. Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts, E. Org. Lett. 2000, 2,
2177−2179. 6. Kirmse, W. “100 years of the Wolff Rearrangement” Eur. J. Org. Chem. 2002,
2193−2256. (Review). 7. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003,
125, 4478−4486. 8. Zeller, K.-P.; Blocher, A.; Haiss, P. Mini-Reviews Org. Chem. 2004, 1, 291−308. (Re-
view). 9. Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 70,
5840−5851. 10. Kumar, R. R.; Balasubramanian, M. Wolff Rearrangement. In Name Reactions for
Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 257−273. (Review).
589
Wolff–Kishner reduction Carbonyl reduction to methylene using basic hydrazine.
R R1
O NH2NH2
NaOH, refluxR R1
R R1
O
NH2NH2
R R1
NHONH2
R R1
NN
H
HHO
HO
H
:
:
H
R R1
R R1
HO
HH
NN R1
R
− N2HO
Example 1, Huang Minlon modification, with loss of ethylene here5
O
NH2NH2•H2ONH2NH2•2HCl
130 oC
KOH, 210 oC
36%
Example 27
O
MeO2C
80% NH2NH2•H2O
toluene, microwave20 min., 75%
N
MeO2C
H2N
KOH, microwave
30 min., 40% MeO2C
Example 38
OOH
OH
HO
85% NH2NH2•H2O, KOH
H2O, 30 min., 165 oC, 87%
590
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_274, © Springer-Verlag Berlin Heidelberg 2009
OHOH
HO
H
O
1,5-hydride shift
OHOH
HO
H
HH
Example 4, Huang Minlon modification10
OMeHO
NOH
OMeHO
MeNH2NH2•H2O
diethylene glycolreflux, 4.75 h, 75%
References 1. (a) Kishner, N. J. Russ. Phys. Chem. Soc. 1911, 43, 582−595. (b) Wolff, L. Ann. 1912,
394, 86. (c) Huang, Minlon J. Am. Chem. Soc. 1946, 68, 2487−2488. (d) Huang, Minlon J. Am. Chem. Soc. 1949, 71, 3301−3303. (The Huang-Minlon modification).
2. Todd, D. Org. React. 1948, 4, 378−422. (Review). 3. Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc. 1962, 84, 1734−1735. 4. Murray, R. K., Jr.; Babiak, K. A. J. Org. Chem. 1973, 38, 2556−2557. 5. Lemieux, R. P.; Beak, P. Tetrahedron Lett. 1989, 30, 1353−1356. 6. Taber, D. F.; Stachel, S. J. Tetrahedron Lett. 1992, 33, 903−906. 7. Gadhwal, S.; Baruah, M.; Sandhu, J. S. Synlett 1999, 1573−1592. 8. Szendi, Z.; Forgó, P.; Tasi, G.; Böcskei, Z.; Nyerges, L.; Sweet, F. Steroids 2002, 67,
31−38. 9. Bashore, C. G.; Samardjiev, I. J.; Bordner, J.; Coe, J. W. J. Am. Chem. Soc. 2003, 125,
3268−3272. 10. Pasha, M. A. Synth. Commun. 2006, 36, 2183−2187. 11. Song, Y.-H.; Seo, J. J. Heterocycl. Chem. 2007, 44, 1439−1443. 12. Shibahara, M.; Watanabe, M.; Aso, K.; Shinmyozu, T. Synthesis 2008, 3749−3754.
591
Woodward cis-dihydroxylation
Cf. Prévost trans-dihydroxylation.
1. I2, AgOAc
2. H2O, H+ OHHO
I I I
OAc
SN2 SN2I
OO:
cyclic iodonium ion intermediate neighboring group assistance
O O
H2O:
O O
OH
− H OHO
O
protonation
OHO
O
:OH2
H
OHO
HO OOHHO
hydrolysis
H Example 11
CH3
O
H3C
H H
CH3
O
H3C
H H
OR1
OR2R1 = Ac, R2 = HR1 = H, R2 = Ac
I2, AgOAcHOAc, H2O
23 → 95 °C3.5 h
CH3
O
H3C
H H
OH
OHKOH, MeOH
23 °C, 71% overall
Example 26
H3C
H
CH3
MeO2CHO
OH
HNBA, AgOAc, HOAc
23 °C, 75%
592
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_275, © Springer-Verlag Berlin Heidelberg 2009
H3C
H
CH3
MeO2CHO
OH
H3C
H
CH3
MeO2CHO
OH
BrOAc
H H
OO
MeBr
References 1. Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958, 80, 209−211. Robert
Burns Woodward (USA, 1917−1979) won the Nobel Prize in Chemistry in 1953 for his synthesis of natural products.
2. Kirschning, A.; Plumeier, C.; Rose, L. Chem. Commun. 1998, 33−34. 3. Monenschein, H.; Sourkouni-Argirusi, G.; Schubothe, K. M.; O’Hare, T.; Kirschning,
A. Org. Lett. 1999, 1, 2101−2104. 4. Kirschning, A.; Jesberger, M.; Monenschein, H. Tetrahedron Lett. 1999, 40,
8999−9002. 5. Muraki, T.; Yokoyama, M.; Togo, H. J. Org. Chem. 2000, 65, 4679−4684. 6. Germain, J.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5269−5278. 7. Myint, Y. Y.; Pasha, M. A. J. Chem. Res. 2004, 333−335. 8. Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A. Org. Lett. 2005, 7, 5071−5074. 9. Mergott, D. J. Woodward cis-dihydroxylation. In Name Reactions for Functional
Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 327−332. (Review).
10. Burlingham, B. T.; Rettig, J. C. J. Chem. Ed. 2008, 85, 959−961.
593
Yamaguchi esterification Esterification using 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent).
R OH
OCl
OCl
Cl
Cl
Et3N, CH2Cl2
R O
O O Cl
Cl Cl
R1HO
DMAP, Tol., reflux R O
OR1
R O
OCl
OCl
Cl
Cl
H
:NEt3R O
O Cl
Cl Cl
ClOR O
O O Cl
Cl ClN
N
:
DMAP (dimethylaminopyridine)
O
O Cl
Cl Cl
OR
N
N
O
O Cl
Cl Cl
R N
O
NO:R1H
Steric hindrance of the chloro substituents blocks attack of the other carbonyl of the mixed anhydride intermediate.
O N
N
ORR1
R O
OR1
Example 1, Intermolecular coupling5
ICO2H
OTES
OMen-Bu3Sn
ODMTOMe
OH
2,4,6-trichlorobenzoyl chlorideDMAP, Tol., Et3N
rt, 24 h, 89%
I
OTES
OMe
n-Bu3SnODMT
OMe
O
O
594
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_276, © Springer-Verlag Berlin Heidelberg 2009
Example 2, Intramolecular coupling7
O O O
CO2H
O
HO
2,4,6-trichlorobenzoyl chlorideEt3N, THF
then DMAP, toluene, 62%
O O O
O
O
O
Example 3, Dimerization8
O
OH
O
BnO
OH
H H
Yamaguchi reagent
125 oC, 6 h, 66%
O
HH H
O
BnO
O
O
H
H H
OO
References 1. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.
Jpn. 1979, 52, 1989−1993. (b) Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943−944.
2. Richardson, T. I.; Rychnovsky, S. D. Tetrahedron 1999, 55, 8977−8996. 3. Paterson, I.; Chen, D. Y.-K.; Aceña, J. L.; Franklin, A. S. Org. Lett. 2000, 2,
1513−1516. 4. Hamelin, O.; Wang, Y.; Deprés, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000, 39,
4314−4316. 5. Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4533−4537. 6. Mlynarski, J.; Ruiz-Caro, J.; Fürstner, A. Chem., Eur. J. 2004, 10, 2214−2222. 7. Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 15970−15971. 8. Smith, A. B. III.; Simov, V. Org. Lett. 2006, 8, 3315−3318. 9. Ahmad, N. M. Yamaguchi esterification. In Name Reactions for Functional Group
Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 545−550. (Review).
10. Wender, P. A.; Verma, V. A. Org. Lett. 2008, 10, 3331−3334. 11. Carrick, J. D.; Jennings, M. P. Org. Lett. 2009, 11, 769−772.
595
Zincke reaction The Zincke reaction is an overall amine exchange process that converts N-(2,4-dinitrophenyl)pyridinium salts, known as Zincke salts, to N-aryl or N-alkyl pyridiniums upon treatment with the appropriate aniline or alkyl amine.
NO2N
NO2
Cl R NH2
RN Cl
NH2O2N
NO2Zincke salt
NO2N
NO2
ClH2N R:
NO2N
NO2
NH
RH
NO2N
NO2
NR
H ring-
opening
NHO2N
NO2
NR
HNH
O2N
NO2
NH
RNH2R :
1,6-addition/elimination
NHO2N
NO2
NH
RNH
R NH2O2N
NO2
:
HR
HN
HN
R RN
HN
Rcis-trans
inversion
RN N
HR
6π
electrocyclizationRN N
HR
RN N
H2
R:
RN Cl
H
596
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_277, © Springer-Verlag Berlin Heidelberg 2009
Example 15
NO2N
NO2
Cl
ClNO2
NO2N
Et Acetone, Δ
overnight (79%)
NH2
PhOH
Et
Cl
n-BuOH, Δ
20 h, 86%N
Et
OHPh
Example 26
N N
ClNO2
NO2
OH OH
NH2
N N
ClH2O, Δ, 16 h
OH
OH
OEt
N
H
O
HO
N
EtO
CaCO3, H2O/THF (4:1)20 oC, 3 days25%, 2 steps
Example 39
NCO2t-Bu
NBoc
11
ClNO2
NO2
MeOH, reflux
89%
Cl
NCO2t-Bu
NBoc
11
NO2
O2N
NH2
N11
n-BuOH, heat, 61%
Cl
NCO2t-Bu
NBoc
11
11
N
597
Example 410
NO2N
NO2
Cl
ClNO2
NO2N
Zincke salt
Me2NHthen NaOH
58%
Me2NCHO Bu3Sn
CHOLiSnBu3
50−55%Zincke aldehyde
References 1. (a) Zincke, Th. Ann. 1903, 330, 361−374. (b) Zincke, Th.; Heuser, G.; Möller, W.
Ann. 1904, 333, 296−345. (c) Zincke, Th.; Würker, W. Ann. 1905, 338, 107−141. (d) Zincke, Th.; Würker, W. Ann. 1905, 341, 365−379. (e) Zincke, Th.; Weisspfenning, G. Ann. 1913, 396, 103−131.
2. Epszju, J.; Lunt, E.; Katritzky, A. R. Tetrahedron 1970, 26, 1665−1673. (Review). 3. Becher, J. Synthesis 1980, 589−612. (Review). 4. Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423−3454. (Re-
view). 5. Wong, Y.-S.; Marazano, C.; Gnecco, D.; Génisson, Y.; Chiaroni, A.; Das, B. C. J.
Org. Chem. 1997, 62, 729−735. 6. Urban, D.; Duval, E.; Langlois, Y. Tetrahedron Lett. 2000, 41, 9251−9256. 7. Cheng, W.-C.; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 585−588. (Review). 8. Rojas, C. M. Zincke Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J.,
Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 355−375. (Review). 9. Shorey, B. J.; Lee, V.; Baldwin, J. E. Tetrahedron 2007, 63, 5587−5592. 10. Michels, T. D.; Rhee, J. U.; Vanderwal, C. D. Org. Lett. 2008, 10, 4787−4790.
598
Subject Index A abnormal Beckmann rearrangement, 34 abnormal Chichibabin reaction, 108 abnormal Claisen rearrangement, 121 acetic anhydride, 54, 167, 204, 424, 440, 442, 452 2-acetamido acetophenone, 92 acetone cyanohydrin, 534 acetonitrile as a reactant, 168 α-acetylamino-alkyl methyl ketone, 167 acetylation, 311 acetylenic alcohols, 100
, -acetylenic esters, 225 acid chloride, 11, 461, 476 acid scavenger, 202 acid-catalyzed acylation, 296 acid-catalyzed alkyl group migration, 566 acid-catalyzed condensation, 131, 133 acid-catalyzed cyclization, 409 acid-catalyzed electrocyclic formation of cyclopentenone, 383 acid-catalyzed reaction, 490 acid-catalyzed rearrangement, 436, 480 acidic alcohol, 339 acidic amide hydrolysis, 534 acidic methylene moiety, 337 acid-labile acetal, 572 acid-mediated cyclization, 444 acid-promoted rearrangement, 190 acrolein, 30, 509 acrylic ester, 30 acrylonitrile, 30 activated hydroxamate, 332 activated methylene compounds, 315 activating agent, 440 activating auxiliary, 458 activating effect of a base, 536 activating group, 288, 351, 440 activation of the hydroxamic acid, 332 activation step, 325 α-active methylene nitrile, 254 acyclic mechanism, 159 acyl anhydride, 234 acyl azides, 162 acyl derivative, 432 N-acyl derivative, 162 ortho-acyl diarylmethanes, 66 acyl group, 234
acyl halide, 234 acyl malonic ester, 263 acyl transfer, 14, 322, 424, 452 2-acylamidoketones, 472 acylation, 8, 51, 234, 235, 296, 322, 332, 440 O-acylation, 332 acylbenzenesulfonylhydrazines, 334 acylglycine, 205 acylium ion, 234, 240, 253, 319 acyl-o-aminobiphenyls, 371 α-acyloxycarboxamide, 415 α-acyloxyketone, 14 α-acyloxythioether, 452 adamantane-like structure, 432 1,4-addition of a nucleophile, 355 addition of Pd-H, 373 cis-addition, 496 1,6-addition/elimination, 596 ADDP, 366 adduct formation, 365 adenosine, 370 aglycon, 221 AIBN, 22, 23, 24, 25, 200, 546, 586, 587 air oxidation, 194 Al(Oi-Pr)3, 345 alcohol activation, 365 aldehyde cyanohydrin, 229 Alder ene reaction, 1, 2, 111 Alder’s endo rule, 184 aldol addition, 470 aldol condensation, 3, 42, 107, 212, 238, 274, 284, 375, 424, 470 Algar–Flynn–Oyamada reaction, 6 alkali metal amide, 517 alkali metal, 44, 517 alkaline medium, 460 alkene, 1, 30, 236, 399, 417, 419, 430, 448, 490 alkenyl anilines, 281 alkenylation, 277 alkoxide-catalyzed oxidation, 404 alkoxide-catalyzed rearrangements, 214 alkoxy methylenemalonic ester, 263 α-alkoxycarbonyl phosphonate, 341 alkyl alcohol, 231 alkyl amine, 596 alkyl cation, 236 alkyl fluorosilane, 233 alkyl group migration, 566
599
J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_BM2, © Springer-Verlag Berlin Heidelberg 2009
alkyl halide, 171, 236, 247, 325, 357 O-allyl hydroxylamines, 350 alkyl lithium, 494, 582 alkyl migration, 319, 436 N-alkyl pyridinium, 596 O-alkylating agent, 343 alkylating agent, 236, 343 N-alkylation, 343 alkylation reaction, 203 alkyl-silane, 231 alkyne coordination, 198 alkyne insertion, 198 alkyne, 98, 100, 148, 198, 236, 257, 259, 419, 519 alkynyl copper reagent, 90, 98, 257, 519 alkynyl halide, 90 Allan–Robinson reaction, 8, 322 allenyl enyne, 382 all-trans-retinal, 88 allyl ether, 584 π-allyl Stille coupling, 529 allyl trimethylsilyl ketene acetal, 125 allylic acetate, 549 allylic alcohol, 100, 127, 363, 401, 406, 502, 570 allylic amination, 572 allylic amine, 426, 507 allylic bromide, 586 allylic carbamate, 507 allylic C–H amination, 572 allylic C–H cleavage, 572 allylic C–H oxidation, 572, 573, 574 allylic epoxide, 549 allylic ester enolate, 125 allylic ether, 549 allylic leaving group, 548 allylic substrate, 586 allylic sulfoxide, 363 allylic tertiary amine-N-oxides, 350 allylic transformation, 222 allylic transposition, 1 allylic trichloroacetamide, 406 allyloxycarbenium ions, 222 π-allylpalladium intermediate, 548, 572 allylsilane, 484 (R)-alpine-borane, 359, 360 aluminum chloride, 253 aluminum hydride, 100, 235 aluminum phenolate, 240 amalgamated zinc, 129
amide, 33, 102, 105, 123, 328, 379, 468, 490, 543562 amidine, 438 amination, 58, 80-82, 330, 572, 573 amine exchange, 596 amine-catalyzed rearrangements, 214 amino acid, 167, 534, 574, 575 α-amino acid, 167, 534 α-amino ketone, 238, 385 α-amino nitrile, 534 aminoacetal intermediate, 444 β-aminoalcohol, 177 gem-aminoalcohol, 330 o-aminobiphenyls, 371 β-aminocrotonate, 391 aminothiophene synthesis, 254 ammonia, 107, 270, 274, 276, 411 ammonium carbonate, 76 ammonium sulfite, 74 ammonium ylide intermediate, 517 amphotericin B, 89 aniline, 46, 81, 102, 131, 133, 194, 251, 263, 281, 373, 394, 509, 596 anilinomethylenemalonic ester, 263 anion-assisted Claisen rearrangement, 96 anionic oxy-Cope rearrangement, 138 p-anisyloxymethyl, 141 α-anomer, 222, 223 β-anomer, 320 anomeric center, 313 anthracenes, 66 AOM, 141 aprotic solvent, 16, 401 aralkyloxazole, 472 Arndt–Eistert homologation, 10 aromatic aldehyde, 229 aromatic solvent, 202 aromatization, 196, 234, 236, 517 Arthur C. Cope, 217 aryl aldehyde, 424 aryl boronic acid, 87, 102, 574 aryl diazonium salt, 262 aryl groups migrate intramolecularly, 393 aryl halide, 64, 80, 368, 531, 554 aryl hydrazine, 72 aryl migration, 36, 165 1,2-aryl migration, 215 aryl potassium trifluoroborate, 574 N-aryl pyridinium, 596
600
aryl–acetylene, 98 -arylamino-ketone, 46
arylation, 102, 277, 332, 574 O-arylation, 332 arylboronates, 368 β-arylethylamine, 434 2-aryl-3-hydroxy-4H-1benzopyran-4-ones, 6 arylhydrazone, 227 O-aryliminoethers, 105 3-arylindole, 46 aryllithium, 413 arylmethyl ether, 202 asymmetric [3+2]-cycloaddition, 144 asymmetric acyl Pictet–Spengler, 434 asymmetric aldol condensation, 212 asymmetric amino-hydroxylation, 496 asymmetric aza-Michael addition, 355 asymmetric Carroll rearrangement, 96 asymmetric Claisen rearrangement, 118 asymmetric construction of carbon–carbon bond, 351 asymmetric Diels–Alder reactions, 143 asymmetric dihydroxylation, 499 asymmetric epoxidation, 300, 502 asymmetric hydroboration, 71 asymmetric hydrogenation, 399 asymmetric intermolecular Heck reac-tion, 277 asymmetric Mannich reaction, 337, 338 asymmetric Mannich-type reaction, 337, 338 asymmetric Michael addition, 355 asymmetric Mukaiyama aldol reaction, 376 asymmetric Petasis reaction, 426 asymmetric reduction of ketones, 359 asymmetric reduction, 359, 399 asymmetric Robinson annulation, 271 asymmetric Simmons−Smith, 507 asymmetric Tsuji–Trost reaction, 550 α-attack, 6 β-attack, 6 aurone derivative, 7 aza [1,2]-Wittig rearrangement, 582 aza-Diels–Alder reaction, 187 aza-Grob fragmentation, 268 aza-Henry reaction, 284 azalactone, 167 aza-Myers−Saito reaction, 382 aza-Payne rearrangement, 421
aza-π-methane rearrangement, 192 azide, 52, 102, 162, 163, 458, 523 azido-alcohol, 52, 490 aziridine, 52, 146, 266 azirine intermediate, 385 N-aziridinyl imine, 16 azlactone, 204 2,2 -azobisisobutyronitrile, 22, 24, 200, 586 1,1'-(azodicarbonyl)dipiperidine, 366 B backside displacement, 454 Baeyer–Villiger oxidation, 12, 70, 165 Baker–Venkataraman rearrangement, 14 Balz−Schiemann reaction, 488 Bamford–Stevens reaction, 16, 494 Barbier coupling reaction, 18 Bartoli indole synthesis, 20 Barton ester, 22 Barton nitrite photolysis, 26 Barton radical decarboxylation, 22 Barton–McCombie deoxygenation, 24 base-catalyzed condensation, 169, 463 base-catalyzed self-condensation, 546 base-induced cleavage, 273 base-mediated rearrangement, 332 base-promoted radical coupling, 262 base-sensitive aldehyde, 341 basic condition, 203, 337, 430 basic hydrogen peroxide conditions, 165 basic oxidation, 70 BaSO4-poisoned palladium catalyst, 476 Batcho–Leimgruber indole synthesis, 28 Baylis–Hillman reaction, 30 9-BBN, 359 Beckmann rearrangement, 33 Belluš–Claisen rearrangement, 117 benzaldehyde, 95, 108, 515 1,4-benzenediyl diradical formation, 40 benzil, 36 benzilate, 36 benzilic acid rearrangement, 36 benzoin condensation, 38, 525 p-benzoquinone, 391 benzothiazole, 309 benzyl halide, 171, 515, 586 benzyl reagent, 202 benzylation, 202, 203 benzylic bromide, 586 benzylic quaternary ammonium salt, 517
601
benzylic substrate, 586 Bergman cyclization, 40, 382 betaine, 578, 580 biaryl, 554 cis-bicyclo[3.3.0]octane-3,7-dione, 568 Biginelli pyrimidone synthesis, 42 biindolyl, 369 bimolecular elimination, 30 Birch reduction, 44 2,4-bis(4-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide, 328 bis(trifluoroethyl)phosphonate, 527 bis-acetylene, 90 bis-aryl halide, 531 1,4-bis(9-O-dihydroquinidine)-phthalazine, 496, 499 Bischler indole synthesis, 46 Bischler–Möhlau indole synthesis, 46 Bischler–Napieralski reaction, 48 B-isopinocampheyl-9-borabicyclo-[3.3.1]-nonane, 359 bisoxygenated intermediate, 573 Blaise reaction , 50 Blum–Ittah aziridine synthesis, 52 boat-like, 117 Bobbitt modification, 445 N-Boc glylcine allylic ester, 574 Boekelheide reaction, 54 Boger pyridine synthesis, 56, 188 9-borabicyclo[3.3.1]nonane, 359, see also 9-BBN borane, 70, 87, 89, 143, 359, 360, 536, 574 Borch reductive amination, 58 boric acid, 574 Z-(O)-boron-enolate, 212 boron trifluoride etherate, 222 boronate, 87, 368 boronic acid-Mannich, 426 boronic acid, 87, 88, 102,426, 574 boron-mediated Reformatsky reaction, 457 boron-protected haloboronic acid, 87, 88 Borsche–Drechsel cyclization, 60 Boulton–Katritzky rearrangement, 62 Bouveault aldehyde synthesis, 64 Bouveault–Blanc reduction, 65 Br/Cl variant of the Takai reaction, 541 Bradsher reaction, 66 bromine/alkoxide for Hofmann rear-rangement, 290
α-bromoacid, 282 bromodinitrobenzene, 347 N-bromosuccinimide, 586, see also NBS Brook rearrangement, 68 [1,2]-Brook rearrangement, 68, 69 [1,3]-Brook rearrangement, 68 [1,4]-Brook rearrangement, 68 [1,5]-Brook rearrangement, 69 Brown hydroboration, 70 BT, 309 Bu3P, 505 Bucherer carbazole synthesis, 72 Bucherer reaction, 74 Bucherer–Bergs reaction, 76 Büchner ring expansion, 78 Buchwald–Hartwig amination, 80, 102 t-BuLi, 69, 199, 390, 413, 414, 582 Burgess dehydrating reagent, 84, 339 Burke boronates, 87 butterfly transition state, 478 t-butyl peroxide, 502 C 13C-labelled α,β-unsaturated ketone, 196 Cadiot–Chodkiewicz coupling, 90, 98, 519 calystegine, 220 camphorsulfonic acid, 203, see also CSA Camps quinoline synthesis, 92 Cannizzaro reaction, 94 carbazole, 60, 70, 72 carbene generation, 460 carbene mechanism, 428 carbene, 10, 112, 156, 198, 428, 460, 588 carbocation rearrangement, 176, 177 β-carbocation stabilization by the silicon group, 231 β-carbocation stabilizationby the β-silicon effect, 484 carbocyclization, 220 carbodiimide, 332, 370 carbon Ferrier reaction, 222 carbon monoxide, 253, 419 carbon nucleophile, 222, 484, 548, 572, see also C- nucleophile carbon tetrachloride, 586, see also CCl4 carbon–boron bond, 306, 328, 387, 430, 434, 436 carbonyl oxide, 161
602
carbonyl, 335, 399, 456, 484, 490, 542 -carbonyl sulfide derivative, 251
1,2-carbon-to-nitrogen migration, 162 carboxylic acid, 10, 22, 94, 202, 214, 282, 304, 415, 551 carboxylic amide derivative, 273 Carroll rearrangement, 96 Castro–Stephens coupling, 90, 98, 519
in situ Castro–Stephens reaction, 99 catalytic asymmetric enamine aldol, 271 catalytic asymmetric inverse-electron-demand Diels–Alder reaction, 187 catalytic cycle, 81, 143, 277, 288, 325, 399, 401, 465, 496, 500, 502, 529, 536, 548, 564 catalytic Pauson−Khand reaction, 419 CBS reagent, 143 3CC, 415 4CC, 551 C–C bond rotation, 277 CCl4, 97, 298, 319, 447, 455, 473, 516, 586, 587 Celebrex, 318 CH2I2, 470, 507, 508 CH3OTf, 202 chair-like, 117 Chan alkyne reduction, 100 Chan–Lam C–X coupling reaction, 102 Chantix, 211 Chapman rearrangement, 105, 393 Chapman-like thermal rearrangement, 106 chelate-controlled oxidative Heck arylation, 574 chemoselective tandem acylation of the Blaise reaction intermediate, 51 chemoselectivity, 572 CHI3, 540 Chichibabin pyridine synthesis, 107 chiral allylic C–H oxidation, 573 chiral auxiliary, 212, 351 chiral ligand, 496 chiral oxazoline, 351 chlorination, 332
in situ chlorination, 455 chloro substituent, 594 chloroammonium salt, 292
-chlorobis-(cyclopentadienyl)-(dimethylaluminium)- -methylenetitanium, 542 chlorodinitrobenzene, 347
chloroiminium salt, 558 α-chloromethyl ketones, 276 2-chloro-1-methyl-pyridinium iodide, 379 3-chloropyridine, 112 N-chlorosuccinimide, 150, see also NCS cholesterol, 321 chromium (VI), 304 chromium trioxide, 304 chromium trioxide-pyridine complex, 304 chromium variant of the Nicholas reac-tion, 395 Chugaev reaction, 110 Chugaev syn-elimination, 110 Ciamician–Dennsted rearrangement, 112 cinchona alkaloid ligand, 499 cinnamic acid synthesis, 424 Claisen condensation, 113, 182 Claisen isoxazole synthesis, 115 Claisen rearrangement, 16, 96, 117 para-Claisen rearrangement, 119 ortho-Claisen rearrangement product, 119 classical Favorskii rearrangement, 217 cleavage of primary carbon–boron bond, 308 Clemmensen reduction, 129 C–O bond fragmentation, 240 CO insertion, 198 CO, 198, 319 cobalt-catalyzed Alder-ene reaction, 2 Collins oxidation, 304 Collins–Sarett oxidation, 305 Combes quinoline synthesis, 131, 133 combinatorial Doebner reaction, 195 Comins modification, 64 complexation, 87, 234, 240, 296, 484, 564 concerted oxygen transfer, 300 concerted process, 113, 117, 137, 184, 268, 499, 578, 588 condensation, 3, 28, 38, 42, 43, 60, 92, 107, 113, 131, 133, 169, 182, 196, 204, 212, 225, 229, 238, 254, 255, 270, 274, 284, 286, 315, 375, 423, 434, 444, 463, 470, 474, 525, 532, 534, 546, 551
Aldol, 3, 424 Benzoin, 38 Claisen, 113 Darzens, 169
603
Dieckmann, 182 Guareschi–Thorpe, 270 Knoevenagel, 254, 255, 315 Stobbe, 532
conjugate addition, 42, 196, 355, 391, 509, see also Michael addition Conrad–Limpach reaction, 131, 133 coordination and deprotonation, 102, 345 coordination, 102, 198, 345, 404, 548 Cope elimination reaction, 135, 136 Cope rearrangement, 119, 137 copper catalyst, 257 Corey’s PCC, 304 Corey’s oxazaborolidine, 143 Corey’s ylide, 146 Corey–Bakshi–Shibata (CBS) reagent, 143 Corey–Claisen, 117 Corey–Fuchs reaction, 148 Corey–Kim oxidation, 150 Corey–Nicolaou double activation, 152 Corey–Nicolaou macrolactonization, 152 Corey–Seebach dithiane reaction, 154 Corey–Winter olefin synthesis, 156 Corey–Winter reductive elimination, 156 Corey−Chaykovsky reaction, 146 coumarin, 423 (−)-CP-263114, 304 Cp2TiMe2, 428 Cr(CO)3-coordinated hydroquinone, 198 Cr(IV), 304 CrCl2, 540 Criegee glycol cleavage, 159 Criegee mechanism of ozonolysis, 161 Criegee zwitterion, 161 Crimmins procedure for Evans aldol, 212 Crixivan, 301 cross-coupling, 87, 88, 102, 259, 288, 289, 299, 325, 389, 519, 529, 531, 536 cross-McMurry coupling, 335, 336 Cr−Ni bimetallic catalyst, 401 CSA, 203, 271, 412, 453, 505 Cu(III) intermediate, 90, 98 Cu(OAc)2, 102, 103, 259, 260, 299, 565 cupric acetate, 102 Curtius rearrangement, 162 CuTC-catalyzed Ullmann coupling, 554
cyanamide, 562 cyanide, 38 cyanoacetic ester, 270 cyanogen bromide, 562 cyanohydrins, 76 cyclic intermediate, 159 cyclic iodonium ion intermediate, 447, 592 cyclic mechanism, 159 cyclic thiocarbonate, 156 cyclic transition state, 345, 404 cyclization of the Stobbe product, 532 cyclization, 6, 40, 46, 60, 66, 115, 131, 133, 173, 196, 220, 227, 255, 263, 281, 371, 382, 383, 385, 400, 413, 417, 423, 434, 444, 450, 463, 532, 596
Bergman, 40 Borsche–Drechsel, 60 Ferrier carbocyclization, 220 Myers−Saito, 382 Nazarov, 383 Parham, 423 Pshorr, 450
[2+2] cycloaddition, 78, 300, 465, 521, 542, 578 [2+2+1] cycloaddition, 419 [3+2]-cycloaddition, 143, 499 [4+2]-cycloaddition reactions, 184 cyclobutane cleavage, 173 cyclobutanone, 521 cyclodehydration, 472 cyclo-dibromodi- -methylene( -tetrahydrofuran)trizinc, 403 cyclohepta-2,4,6-trienecarboxylic acid ester, 78 cyclohexadiene, 44 cyclohexanone phenylhydrazone, 60 cyclohexanone, 60, 220, 383, 419, 470 cyclopentene, 560 cyclopropanation, 112, 507 cyclopropane, 146, 192, 560 cyclopropanone intermediate, 214 cycloreversion, 465 C−C bond cleavage, 268 C−C bond migration, 176, 177 D Dakin oxidation, 165 Dakin–West reaction, 167 Danishefsky diene, 184 Darzens condensation, 169
604
DBU, 15, 170, 206, 285, 290, 333, 341, 342, 377, 386, 406, 407, 471, 472, 526, DCC, 23, 245, 370 de Mayo reaction, 173 DEAD, 223, 243, 248, 365, 366 decalin, 432 decarboxylation, 96, 263, 315, 332, 474, 568 dehydrating reagent, 339, 432 dehydration, 46, 108, 408, 470, 480, 509 dehydrative ring closure, 371 Delépine amine synthesis, 171, 515 demetallation, 395 Demjanov rearrangement, 175 deoxygenation, 24 (+)-deoxynegamycin, 573 deprotonation of nitroalkanes, 284 depsipeptide, 572 Dess–Martin oxidation, 179, 180, 472 desulfonylation, 560 desymmetrization, 95 Dewar intermediate, 119 (DHQ)2-PHAL, 499 (DHQD)2-PHAL, 496 diamide, 551 diaryl compound, 262 diastereomer, 311, 451, 495 diastereoselective glycosidation, 313 diastereoselective Simmons−Smith cyclopro-panation, 507 1,8-diazabicyclo[5.4.0]undec-7-ene, 341, see also DBU diazoacetic esters, 78 2-diazo-1,3-diketone, 458 α-diazoketone, 588 2-diazo-3-oxoester, 458 diazomethane, 10 diazonium salt, 177, 262, 302, 486 diazotization, 176, 177 diboron reagents, 368 dibromoolefin, 148 1,3-dicarbonyl compounds, 317 1,4-dicarbonyl derivative, 525 1,3-dicyclohexylurea, 370 dichlorocarbene, 112, 460 Dieckmann condensation, 182 Diels–Alder adduct, 184 Diels–Alder reaction, 56, 66, 143, 184, 185, 186, 187 diene, 44, 184, 186, 188, 192
1,4-diene, 192
dienone, 119 Dienone–phenol rearrangement, 190 dienophile, 56, 184, 186, 187 diethyl diazodicarboxylate, 365, see also DEAD diethyl succinate, 532 diethyl tartrate, 502 diethyl thiodiglycolate, 286 dihydroisoquinolines, 48 cis-dihydroxylation, 499 1,4-dihydropyridine, 274 diketone, 14, 131, 173, 270, 286, 408,
409, 411, 458, 474 α-diketone, 286 β-diketones, 14, 131 1,4-diketone, 408, 409, 411 1,4-diketone condensation, 474 1,5-diketone, 173
dimerization, 255, 257, 299 dimethylaminomethylating agent, 206 dimethylaminomethylation, 206 dimethylaminopyridine, 594, see also DMAP N,N-dimethylformamide dimethyl acetal, 28 dimethylmethylideneammonium iodide, 206 dimethylsulfide, 150 dimethylsulfonium methylide, 146 dimethylsulfoxonium methylide, 146 dimethyltitanocene, 428 dinitrophenyl, 67 diol, 156, 159, 203, 250, 436, diosgenin, 130 1,3-dioxolane-2-thione, 156 dipeptidyl peptidase IV inhibitor, 574 diphenyl 2-pyridylphosphine, 244 diphenylphosphoryl azide, 163, see also DPPA DIPT, 503 1,3-dipolar cycloaddition, 161, 458, 459 2,2 -dipyridyl disulfide, 152 diradical, 40, 192, 382, 417, 560 N,N-disubstituted acetamide, 440 disubstituted azodicarboxylate, 365 3,4-disubstituted phenols, 190 4,4-disubstituted cyclohexadienone, 190 3,4-disubstituted thiophene-2,5-dicarbonyl, 42, 286, 317, 525 di-tert-butylazodicarbonate, 244 dithiane, 154
605
ditin reagent, 531 di-vinyl ketone, 383 di-π-methane rearrangement, 192 2,4-dinitro-benzenesulfonyl chloride, 243 DMAP, 78, 103, 157, 158, 161, 167, 245, 380, 453, 594, 595 DMFDMA, 28 DMS, 150 DNP, 67 Doebner quinoline synthesis, 194 Doebner–von Miller reaction, 196, 509 domino annulation reaction under Willgerodt–Kindler conditions, 577 Dötz reaction, 198 double Chapman rearrangement, 106 double imine, 227 double Robinson-type cyclopentene annulation, 471 double Tebbe, 542, 543 double Wagner–Meerwein rearrangement, 566 Dowd–Beckwith ring expansion, 200 Dowtherm A, 134 DPE-Phos, 82 DPPA, 163, 164 DTBAD, 244 Dudley reagent, 202 E E/Z geometry control, 125 E1cB, 271, 339 E2, 30, 31, 424, 430 E2 anti-elimination, 430 E2 elimination, 424 E-allylic alcohols, 100 EAN, 316 E-arylated allylic ester, 574 EDDA, 315 EDG, 184 Eglinton coupling, 259 Ei, 84 electrocyclic formation, 383 electrocyclic ring closure, 198 electrocyclic ring opening, 78 electrocyclization, 40, 131, 133, 417, 596 electron transfer, 18, 44, 215, 266, 311, 335, 456, 554 electron-deficient heteroaromatics, 361 electron-donating substituent, 44, 184
electronically unbiased α-olefin, 574 electron-rich alkyl group, 436 electron-rich carbocycle, 558, 558 electron-rich ligands, 80 electron-withdrawing substituent, 44, 184, 347 electrophile, 30, 89, 146, 266, 325, 484, 490, 558 electrophilic site, 413 electrophilic substitution, 234, 296 elemental sulfur, 254, 408 elimination, 30, 80, 84, 90, 98, 102, 110, 135, 136, 156, 229
α-elimination, 460 β-elimination, 281, 339, 519 syn-elimination, 505 syn-β-elimination, 277
Emil Fischer, 222 enamine formation, 271, 274 enamine, 56, 107, 131, 442, 546 enantioselective aromatic Claisen rear-rangement, 121 enantioselective borane reduction, 143 enantioselective cis-dihydroxylation, 499 enantioselective epoxidation, 502 enantioselective ester enolate-Claisen rear-rangement, 125 enantioselective Mukaiyama-aldol reaction, 4 enantiospecific Baker−Venkataraman rear-rangement, 14 ene reaction, 1, 110, 121, 140 enediyne, 40 ene-hydrazine, 227 enol, 96, 458 enol ether, 355, 377, 397 enol silane, 482 enolate, 3, 125, 182, 206, 212, 250, 274, 282, 355, 424, 458, 470, 532 enolates, enolsilylethers, 206 enolizable hydrogens for ketones, 217 enolizable α-haloketones, 214 enolization, 8, 42, 282, 322, 323, 337 enolsilane, 478 enone, 173, 323, 482 enophile, 1 enzymatic resolution, 573 episulfone intermediate, 454 epoxidation
Corey−Chaykovsky, 146
606
Jacobsen–Katsuki, 300 Payne, 421 Prilezhaev, 478 Sharpless, 502
epoxide migration, 421 epoxide, 146, 300, 421, 478, 502 549
cis-epoxide, 300 trans-epoxide, 300
2,3-epoxy alcohol, 421 α,β-epoxy esters, 169 α,β-epoxy ketone, 570 α,β-epoxy sulfonylhydrazones, 208 1,2-epoxy-3-ol, 421 α,β-epoxyketones, 208 Erlenmeyer−Plöchl azlactone synthesis, 204 erythreo betaine, 580 erythro (kinetic adduct), Horner–Wadsworth–Emmons reaction, 294 erythro isomer, 527 Eschenmoser hydrazone, 16 Eschenmoser’s salt, 206, 337 Eschenmoser–Claisen amide acetal rear-rangement, 123 Eschenmoser–Tanabe fragmentation, 208 Eschweiler–Clarke reductive alkylation of amines, 210, 330 6π-electrocyclization, 131, 133, 596 ester, 22, 26, 30, 50, 65, 78, 96, 103, 113, 115, 117, 125, 127, 133, 169, 214, 225, 240, 245, 263, 270, 286, 328, 343, 438, 525 esterification, 379, 574, 594 Et3O+BF4
−, 343 Et3SiH, 245 ether formation, 202, 339, 366, 584 ethyl oxalate, 463 ethylammonium nitrate, 316 ethylenediamine diacetate, 315 ethylformate, 458 Evans aldol reaction, 212 Evans syn, 212 evolution of CO2, 167 EWG, 184 exo complex, 419 extrusion of dinitrogen, 162 extrusion of nitrogen, 56, 490 F Favorskii rearrangement, 214
Feist–Bénary furan synthesis, 218 Ferrier carbocyclization, 220 Ferrier glycal allylic rearrangement, 222 Ferrier I reaction, 222 Ferrier II Reaction, 220 Ferrier reaction, 222 Ferrier rearrangement, 222 Fiesselmann thiophene synthesis, 225 Fischer carbene, 198 Fischer indole synthesis, 60, 72, 227 Fischer oxazole synthesis, 229 flavone, 8 flavonol, 6 Fleming–Tamao oxidation, 231 Fleming−Kumada oxidation, 233 fluoride, 288 fluoroarene, 488 fluoro-Meisenheimer complex, 347 fluorous Corey−Kim reaction, 150 fluorous Mukaiyama reagent, 380 formal [2+2+1] cycloaddition, 419 formaldehyde, 210, 330 formamide acetal, 28 formic acid, 210, 330 o-formylphenol, 460 formylation, 64, 253 four-component condensation, 551 four-electron system, 1 four-membered titanium oxide ring in-termediate, 428 fragmentation, 196, 208, 240, 268 Friedel–Crafts acylation reaction, 234 Friedel–Crafts alkylation reaction, 236 Friedel–Crafts reaction, 234 Friedländer quinoline synthesis, 238 Fries rearrangement, 240 ortho-Fries rearrangement, 241 Fries−Finck rearrangement, 240 Fukuyama amine synthesis, 243 Fukuyama reduction, 245 Fukuyama−Mitsunobu procedure, 243 functional group interconversion, 572 functional group migration, 576 furan ring as the masked carbonyl, 464 furan synthesis, 218, 409 fused pyridine ring, 263 G Gabriel amine synthesis, 249 Gabriel synthesis, 171, 246 Gabriel–Colman rearrangement, 250
607
Garner’s aldehyde, 266 Gassman indole synthesis, 251 Gattermann–Koch reaction, 253 Gewald aminothiophene synthesis, 254 Glaser coupling, 257, 299 glycerol, 509 glycidic ester, 169 glycol, 159, 222, 223, 225, 334, 591 glycosidation, 313, 320, 492 β-glycoside, 320 C-glycosidic product, 222 glycosyl acceptor, 313 Gomberg–Bachmann reaction, 262, 450 Gould–Jacobs reaction, 263 green Dakin–West reaction, 168 Grignard reaction, 18, 266 Grignard reagent, 16, 20, 266, 325, 490, 494 Grob fragmentation, 268 Grubbs’ catalyst, 78, 465, 467 Grubbs’ catalyst, intramolecular Buchner rea-ction, 78 Guareschi imide, 270 Guareschi–Thorpe condensation, 270 H [1,5]-H-atom shift, 121 Hajos–Wiechert reaction, 271 halfordinal, 230 Haller–Bauer reaction, 273 N-haloamines, protonated, 292 o-halo-aniline, 373 haloarene, 486 α-halocarbohydrate, 320 α-haloesters, 50, 169, 456 halogen effect, 472 α-halogenation, 282 halogen–lithium exchange, 413 α-haloketones, 171, 218 2-halomethyl cycloalkanones, 200 α-halosulfone, 454 Hantzsch 1,4-dihydropyridines, 274, 275 Hantzsch dihydropyridine synthesis, 274 Hantzsch pyrrole synthesis, 276 head-to-head alignment, 173 head-to-tail alignment, 173 Heck arylation, 574 Heck reaction, 277, 278, 280, 373, 574 Hegedus indole synthesis, 281 Hell–Volhard–Zelinsky reaction, 282 hemiaminal, 474, 515
(+)-hennoxazole, 472 Henry nitroaldol reaction, 284 heteroaryl Heck reaction, 280 heteroaryl recipient, 280 heteroaryllithium, 413 heteroarylsulfones, 309 hetero-Carroll rearrangemen, 96 hetero-Diels–Alder reaction , 56, 187 heterodiene addition, 187 heterodienophile addition, 187, 188 heteropoly acid catalyst, 168 hex-5-enopyranosides, 221 hexacarbonyldicobalt complex, 395, 419 hexacarbonyldicobalt-stabilized proper-gyl cation, 395 hexamethylenetetramine, 171, 172, 515 Hinsberg synthesis of thiophene deriva-tive, 286 Hiyama cross-coupling reaction, 288 Hoch–Campbell aziridine synthesis, 266 Hofmann degradation, 290 Hofmann rearrangement, 290 Hofmann–Löffler–Freytag reaction, 292 homoallylic alcohol, 584 homocoupling, 258, 299, 335, 554 homo-Favorskii rearrangement, 215 homologated carboxylic acid, 588 homolysis, 215 homolytic cleavage, 22, 24, 26, 200, 292, 298, 334, 582, 586 homo-McMurry coupling, 335 homo-Robinson, 470 Horner–Wadsworth–Emmons reaction, 294, 341 Horner−Emmons reaction, 527 Hosomi–Sakurai reaction, 484 Hosomi−Miyaura borylation, 368 Houben–Hoesch synthesis, 296 Huang Minlon modification, 590, 591 Hunsdiecker–Borodin reaction, 298 hydantoin, 76, 102, 497 hydrazine, 72, 102, 227, 249, 317, 334, 570, 590 hydrazoic acid, 490 hydrazone, 16, 60, 208, 227, 302, 570 hydride, 94, 100, 210, 330, 345, 359, 373, 404, 482, 515, 564, 591 β-hydride elimination, 373, 482 hydride shift, 564, 591 hydride source, 210 hydride transfer, 94, 345, 359, 404, 515
608
hydro-allyl addition, 1 o-hydroxyaryl ketones, 8 hydrogen atom abstraction, 24 1,5-hydrogen abstraction, 26 1,5-hydrogen atom transfer, 292 hydrogen donor, 40, 274 hydrogenation, 399, 476 hydrogenolysis, 251 hydrolysis of iminium salt, 271 hydrolysis, 54, 162, 165, 231, 247, 266, 271, 282, 286, 296, 315, 385, 393, 438, 447, 456, 460, 463, 478, 499, 534, 592 hydropalladation, 564 hydroxamic acid, 332 hydroxide-catalyzed rearrangements, 214 ω-hydroxyl-acid, 152 hydroxylamine, 115, 349 N-hydroxyl amines, 135 α-hydroxylation, 478 4-hydroxy-3-carboalkoxyquinoline, 263
-hydroxycarbonyl, 3 2 -hydroxychalcones, 6 5-hydroxylindole, 391 3-hydroxy-isoxazoles, 115 2-hydroxymethylpyridine, 54 β-hydroxy-β-phenylethylamine, 432 4-hydroxyquinoline, 263 β-hydroxysilane, 203, 430 3-hydroxy-2-thiophenecarboxylic acid deri-vatives, 225 hydrozinolysis, 62 hypohalite, 251, 290 I IBX, 179, 397 imide, 102, 270, 444, 474 imine, 58, 102, 107, 131, 490, 521, 546, 551 iminium formationhydrolysis, 315 iminium ion, 315, 330, 440, 442, 519, 534 imino ether, 438 iminochloride, 385 iminophosphorane, 523 indole, 20, 28, 46, 60, 72, 227, 251, 281, 373, 391, 463 indole synthesis, 227, 251, 281, 373, 391, 463 Bartoli, 20 Batcho–Leimgruber, 28
Bischler–Möhlau, 46 Fischer, 227 Gassman, 251 Hegedus, 281 Mori–Ban, 373 Nenitzescu, 391 Reissert, 463 indole-2-carboxylic acid, 463 Ing–Manske procedure, 249 Initiation, radical, 586 inositol, 220 insertion toward CH, 419 insertion, 198, 277, 280, 373, 419, 589 intercomponent interactions, 90 intermolecular addition, 361, 509 intermolecular aldol, 4 intermolecular Bradsher cycloaddition, 66, 67 intermolecular C–H amination, 573 intermolecular C–H oxidation, 572 intermolecular Friedel–Crafts acylation, 234 intermolecular Heck arylation, 280, 574 intermolecular Yamaguchi coupling, 594 internal acetylenes, 353 intramolecular acyl transfer, 424 intramolecular Alder-ene reaction, 1 intramolecular aldol condensation, 470 intramolecular Baylis–Hillman reaction, 31 intramolecular Boger pyridine synthesis, 56 intramolecular Bradsher cyclization, 66 intramolecular Büchner reaction, 78 intramolecular Cannizzaro reaction, 95 intramolecular C–H oxidation, 572 intramolecular condensation, 205 intramolecular cross-coupling, 531 intramolecular cyclization, 413 intramolecular Diels–Alder reaction, 184, 185 intramolecular ene reaction, 110 intramolecular Favorskii Rearrange-ment, 214 intramolecular Friedel–Crafts acylation, 234, 235 intramolecular Heck reaction, 278, 280, 285, 280, 373 intramolecular Horner–Wadsworth–Emmons, 295
609
intramolecular Houben−Hoesch reac-tion, 296 intramolecular mechanism, 304 intramolecular Michael addition, 356 intramolecular Minisci reaction, 362 intramolecular Mitsunobu reaction, 366 intramolecular Mukaiyama aldol reac-tion, 375 intramolecular Nicholas reaction using chromium, 396 intramolecular Nozaki–Hiyama–Kishi reaction, 401 intramolecular nucleophilic aromatic re-arrangement, 511 intramolecular pathway, 440 intramolecular Pauson−Khand reaction, 419 intramolecular Schmidt rearrangement, 491 intramolecular SN2, 169 intramolecular Stetter reaction, 525 intramolecular Suzuki–Miyaura cou-pling, 536 intramolecular Thorpe reaction, 546 intramolecular transamidation, 331 intramolecular Tsuji–Trost reaction, 549 intramolecular Yamaguchi coupling, 594 inverse electronic demand Diels–Alder reaction, 186 cis-trans inversion, 596 inversion of configuration, 548 iododinitrobenzene, 347 iodosobenzene diacetate for Hofmann rear-rangement, 290 O-iodoxybenzoic acid, 179, 397 ionic liquid, 316, 343 ionic liquid-promoted interrupted Feist–Benary reaction, 218
ionic mechanism, 266 ipso attack, 347 ipso substitution, 231, 347 Ireland–Claisen (silyl ketene acetal) rearrangement, 125 iron salt-mediated Polonovski reaction, 441 irreversible fragmentation, 196 C-isocyanide, 415, 551 isocyanate intermediate, 76, 162, 290, 332 isoflavone, 8
isomerization, 229, 353, 421, 470 isoquinoline 1,4-diol, 250 isoquinoline, 48, 250, 432, 434, 444, 461, 462 3-isoxazolol, 115 5-isoxazolol, 115 J Jacobsen–Katsuki epoxidation, 300 Japp–Klingemann hydrazone synthesis, 60, 302 Johnson–Claisen (orthoester) rearrange-ment, 127 Jones oxidation, 304, 305 Julia olefination, 309 Julia–Kocienski olefination, 309, 311 K Kahne glycosidation, 313 Kazmaier–Claisen, 117 ketene, 10, 123, 125, 127, 521, 588 ketene acetal, 123, 125, 127 ketene cycloaddition, 521 N,O-ketene acetals, 123 α-ketocarbene, 588 α-ketocarbene intermediate, 10 keto-enol tautomerization, 96 β-ketoester, 50, 96, 113, 115, 133, 218, 274, 276, 302, 423 2-ketophenols, 240 4-ketophenols, 240 α-keto-phosphonate, 341 ketoximes, 266 ketyl, 65 Kharasch cross-coupling reaction, 325 kinetic product, 16, 294, 494, 527 kinetic resolution, 574 Kishner reduction, 1 Knoevenagel condensation, 254, 255, 315 Knorr pyrazole synthesis, 317, 411 Knorr thiophene synthesis, 328 Koch–Haaf carbonylation, 319 Koenig–Knorr glycosidation, 320 Kostanecki acylation reaction, 322 Kostanecki reaction, 8, 322 Kostanecki−Robinson reaction, 322 Kröhnke pyridine synthesis, 333 Kumada coupling, 288, 325, 529, 536
610
L lactam, 240, 328, 521 β-lactam, 521 lactone, 204, 328, 403, 521
azalactone, 167, 204 β-lactone, 521 lactonization, 532 larger counterion, 309 Lawesson’s reagent, 328, 408 lead tetraacetate for Hofmann rear-rangement, 291 lead tetraacetate, 159 Lebel modification of the Curtius rear-rangement, 164 less-substituted olefin, 494 Leuckart–Wallach reaction, 210, 330, 331 Lewis acid catalyst, 222 Lewis acid, 1, 212, 222, 234, 236, 240, 375, 377, 395, 423, 484, 492 Lewis acid-catalyzed aldol condensa-tion, 375 Lewis acid-catalyzed Michael addition, 377 Lewis basic phenol, 572 LiBr complex, 580 ligand exchange, 80, 476, 548 Lipitor, 411 liquid ammonia, 44 long-lived radical, 26 Lossen rearrangement, 332 low-valent titanium, 335 L-phenylalanine, 271, 272 proline, 143, 271, 337, 338 LTA, 159 M macrolactonization, 152, 573 magnesium metal, 266 magnesium oxide, 202 maleimidyl acetate, 250 manganaoxetane intermediate, 300 Mannich base, 337 Mannich reaction, 206, 337, 426 Martin’s sulfurane dehydrating reagent, 339, 457 Masamune–Roush conditions, 341 masked carbonyl equivalent, 154 McFadyen–Stevens reduction, 334 McMurry coupling, 335 MCR, 42, 76
Me3O+BF4−, 343
Meerwein reagent, 343, 361 Meerwein’s salt, 343 Meerwein–Eschenmoser–Claisen rear-rangement, 123 Meerwein–Ponndorf–Verley reduction, 345, 404 Me-IBX, 397 Meisenheimer complex, 243, 347, 511 [1,2]-Meisenheimer rearrangement, 349 [2,3]-Meisenheimer rearrangement, 350 Meisenheimer−Jackson salt, 347 Meldrum’s acid, 116 4-membered ring transition state, 523 Mes, 465 mesityl, 465 mesyl azide, 458 metal-methylation, 343 methoxycarbonylsulfamoyl-triethylammonium hydroxide inner salt, 84 o-methyl-IBX, 397 methyl triflate, 202 methyl vinyl ketone, 470 methylenated ketones, 206 N-methylation, 344 N-methyliminodiacetic acid, 87 2-methylpyridine N-oxide, 54 Meyers oxazoline method, 351 Meyer–Schuster rearrangement, 353, 480 MgO, 202 Mg-Oppenauer oxidation, 404 Michael addition, 107, 271, 274, 323, 355, 377, 423, 470, 484, 525, see also conjugate addition Michaelis–Arbuzov phosphonate syn-thesis, 357 Michael−Stetter reaction, 525 microwave, 29, 33, 43, 47, 74, 210, 264, 298, 299, 334, 335, 356, 429, 470, 511, 577, 590 microwave Smiles rearrangement, 511 microwave-assisted Gould–Jacobs reac-tion, 264 microwave-assisted, solvent-free
Bischler-indole synthesis, 47 microwave-Hunsdiecker−Borodin, 298 microwave-indued Biginelli condensation, 43 MIDA, 87
611
Midland reduction, 359 migration order, 12, 436 migration, 12, 36, 68, 162, 165, 175, 177, 203, 215, 319, 393, 421, 436, 490, 566, 576 1,3-migration of an aryl group from oxygen to sulfur, 393 migratory insertion, 277 Minisci reaction, 361 Mislow–Evans rearrangement, 363 Mitsunobu reaction, 243, 332, 365, 366 mixed anhydride, 205, 594 mixed orthoester, 127 Miyaura borylation, 368 Mn(III)salen, 300 Mn(III)salen-catalyzed asymmetric ep-oxidation, 300 modified Ireland–Claisen rearrangement, 126 modified Skraup quinoline synthesis, 509 Moffatt oxidation, 370 monooxygenated precursor, 574 more-substituted olefin, 494 Morgan–Walls reaction , 371 Mori–Ban indole synthesis, 373 Morita–Baylis–Hillman reaction, 30 morpholine-polysulfide, 255 MPS, 255 Mukaiyama aldol reaction, 4, 375, 375, 376 Mukaiyama Michael addition, 377 Mukaiyama reagent, 379, 380 multicomponent reactions, 42, 62 MVK, 470 MWI, 43 Myers−Saito cyclization, 382 N-(2,4-dinitrophenyl)pyridinium salt, 596 N naphthol, 72 β-naphthol, 74 β-naphthylamines, 74 Naproxen, 577 Nazarov cyclization, 383 NBS variant of Hofmann rearrangement, 290 NBS, 290, 298, 516, 586, 587 NCS, 100, 150, 151, 292 Neber rearrangement, 385
Nef reaction, 387 Negishi cross-coupling reaction, 325, 389 neighboring group assistance, 447, 492, 592 Nenitzescu indole synthesis, 391 Newman−Kwart reaction, 393 Nicholas reaction, 395 Nicholas-Pauson–Khand sequence, 395 nickel-catalyzed cross-coupling, 325, 389 Nicolaou dehydrogenation, 397 nifedipine, 274 nitrene, 162 nitrile, 2, 34, 50, 98, 254, 296, 438, 468,, 490, 534, 546, 562 nitrile-Alder-ene reaction, 2 nitrilium ion intermediate, 468, 490 nitrite ester, 26 2-nitroalcohol, 284 nitroaldol condensation, 284 nitroalkanes, 284 nitroarenes, 20 nitrobenzene, 371 4-nitrobenzenesulfonyl, 499 nitrogen nucleophile, 572 nitrogen radical cation, 292 nitrogen source, 496 nitronate, 284, 347, 387 nitronic acid, 284, 387 o-nitrophenyl selenide, 505 o-nitrophenyl selenocyanate, 505 nitroso intermediate, 20, 26, 102 o-nitrotoluene derivatives, 28, 463 non-enolizable ketone, 217, 273 nonstabilized ylide, 580 Nos, 499 nosylate, 499 Noyori asymmetric hydrogenation, 399 Nozaki–Hiyama–Kishi reaction, 401 nucleophile, 89, 154, 162, 222, 355, 365, 395, 484, 548, 572, 573 C-nucleophile, 222, see also carbon nu-cleophile O-nucleophile, 222 S-nucleophile, 222 nucleophilic addition, 50, 351, 438, 456, 456 nucleophilic radical, 361 Nysted reagent, 403
612
O octacarbonyl dicobalt, 419 odorless Corey−Kim reaction, 150 olefin, 16, 66, 70, 84, 110, 135, 146, 148, 156, 157, 173, 277, 294, 309, 319, 335, 339, 373, 454, 494, 499, 500, 505, 507, 521, 564, 566, 572, 574, 578, 580
α-olefin, 572, 574 cis-olefin, 294 E-olefin, 300, 309, 311, 580 exo-olefin, 542 trans-olefin, 294 (Z)-olefin, 300, 527, 578, 580
olefin ether, 66 olefin formation, 294, 454, 505 olefin silfide, 66 olefination, 156, 309, 311, 335, 403, 428, 430, 578 olefination of ketones and aldehydes, 403 oleum, 446 one-carbon homologation, 10 , 148 one-pot PCC–Wittig reactions, 306 Oppenauer oxidation, 404, 345 optically pure diethyl tartrate, 502 organic azide, 523 organoborane, 70, 536, 574 organocatalyst, 4, 274 organohalide, 266, 288, 325, 519, 529, 536 organolithium, 325 organomagnesium compounds, 266, 325, see also Grignard reagent organosilicon, 288 organostannane, 529 organozinc, 389, 456 Ormosil-TEMPO, 545 osmium catalyst, 499 osmium-mediated, 496, 499 O-substituted glycal derivatives, 222 O-sulfonylation, 332 Overman rearrangement, 406 oxaphosphetane, 578 oxa-Pictet–Spengler, 434 oxatitanacyclobutane, 542 oxazete intermediate, 105 oxazole, 229, 472, 556 5-oxazolone, 205 oxazoline intermediate, 167 oxa-π-methane rearrangement, 193 oxetane, 417
manganaoxetane, 300 γ-oximino alcohol, 26 oxidation, 70, 107, 194, 572
Baeyer–Villiger, 12 Collins–Sarett, 305 Corey–Kim, 150 Dakin, 165 Dess−Martin, 179 Étard, 129 Fleming–Tamao, 231 Hooker, 196 Jacobsen–Katsuki, 300 Jones, 304 Moffatt, 370 Oppenauer, 404 PCC, 306 PDC, 307 Prilezhaev, 323 Riley, 336 Rubottom, 378 Saegusa, 482 Sarett, 538 Swern, 402 Tamao−Kumada, 233 TEMPO, 544 Wacker, 564
oxidative addition, 80, 90, 98, 245, 277, 280, 288, 325, 368, 373, 389, 401, 456, 476, 507, 519, 529, 531, 536, 548, 554 syn-oxidative elimination, 505 oxidative cyclization, 6, 281 oxidative demetallation, 395 oxidative homo-coupling, 257, 299 N-oxide, 54, 135, 300, 349, 350, 440, 442, 543 oxide-coated titanium surface, 335 oxime, 33, 266, 385 oxirane, 52 oxo-Diels–Alder reaction, 187 4-oxoform, 263 oxonium ion, 313, 320, 343 β-oxo ylide, 580 oxy-Cope rearrangement, 137, 138, 140 oxygen nucleophile, 572 oxygen transfer, 300 oxygenated compound, 572, 573 P P2O5, 432 P4O10, 432 P4–t-Bu, 311
613
Paal thiophene synthesis, 408 Paal–Knorr furan synthesis, 409 Paal–Knorr pyrrole synthesis, 317, 411 palladation, 281, 564 palladium, 80, 98, 277, 288, 325, 368, 389, 476, 482, 519, 529, 531, 536, 548, 564, 572 palladium-catalyzed alkenylation, 277 palladium-catalyzed arylation, 277 palladium-catalyzed oxidation, 564 palladium-promoted reaction
Buchwald–Hartwig amination, 80 Heck, 277 heteroaryl Heck, 280 Hiyama, 288 Kumada, 325 Miyaura borylation, 368 Mori–Ban indole, 373 Negishi, 389 Rosenmund reduction, 476 Saegusa, 482 Sonogashira, 519 Stille, 529 Stille–Kelly, 531 Suzuki–Miyaura, 536 Tsuji–Trost, 548 Wacker, 564
palladium-catalyzed substitution, 548 pancratistatin, 220 paniculide A, 220 paraffin, 134 Parham cyclization, 413, 415 Passerini reaction, 551 Paternò–Büchi reaction, 417 Pauson–Khand reaction, 395, 419, 420 Payne rearrangement, 421 Pb(OAc)4, 159 PCC oxidation, 304, 306 Pd(II) oxidant, 482 Pd(II) reduction to Pd(0), 519 Pd/C catalyst, 245 Pd/Cu-catalyzed cross-coupling, 519 PDC, 304, 307 Pd–H isomerization, 574 Pechmann coumarin synthesis, 423 pentacoordinate silicon intermediate, 68 peracid, 231 pericyclic reaction, 1 periodinane oxidation, 179, 180
Perkin reaction, 424
Petasis boronic acid-Mannich reaction, 426 Petasis reaction, 426 Petasis reagent, 428 Peterson elimination, 203 Peterson olefination, 430 Pfau−Platter azulene synthesis, 78 Pfitzner−Moffatt oxidation, 370 Ph3P, 52, 53, 99, 148, 149, 152, 223, 280, 288, 360, 365, 368, 373, 472, 519, 523, 536, 578 PhCuI, 554 phenanthridine cyclization, 371 β-phenethylamides, 48 phenol esters, 240 phenol, 102, 165, 190, 240, 296, 393, 423, 460, 492, 572 phenolic ether, 296 phenylhydrazine, 227 4-phenylpyridine N-oxide, 300 phenyltetrazolyl, 309 PhNO2, 509 phospha-Michael addition, 355 phosphate ester, 220 phosphazide, 523 phosphazo compound, 523 phosphite, 357 phosphonate synthesis, 357 phosphonate, 294, 341, 357, 527 phosphoric acid, 409 phosphorus oxychloride, 48, 49, 229, 235, 264, 371, 432, 558, 559, phosphorus pentoxide, 432 phosphorus ylide, 578, 580 [2+2]-photochemical cyclization, 173 photochemical decomposition, 292 photochemical rearrangement, 162 photo-Favorskii Rearrangement, 215 photo-Fries rearrangement, 241 photoinduced electrocyclization, 417 photolysis, 26, 192 photo-Reimer–Tiemann reaction without base, 460 photo-Schiemann reaction, 488 phthalimide, 247, 248, 249 Pictet–Gams isoquinoline synthesis, 432 Pictet–Spengler tetrahydroisoquinoline synthesis, 434 pinacol, 436, 574 pinacol rearrangement, 436 (1R)-(+)-α-pinene, 359
614
Pinner reaction, 438 piperidine, 292 pivalic acid, 411 PMB ethers, 202 PMB reagent, 202 PMB-protection, 203 Polonovski reaction, 440, 442 Polonovski–Potier rearrangement, 442 polyene skeleton, 89 polymer-support Hinsberg thiophene synthesis, 287 polymer-supported Mukaiyama reagent, 379 polyphosphoric acid, 34, 66, 332, see also PPA polysubstituted oxetane ring system, 417 Pomeranz–Fritsch reaction, 444, 446 potassium phthalimide, 247 PPA, 34, 66, 132, 134, 163, 164, 235, PPSE, 235 precatalyst, 465, 548 preoxidized material, 572 Prévost trans-dihydroxylation, 447, 592 Prilezhaev epoxidation, 478 primary alcohol, 304, 305, 339 primary amides, 290 primary amine, 171, 178, , 210, 243, 247, 290, 411, 474 primary cycle, 500 primary nitroalkane, 387 primary ozonide, 161 Prins reaction, 448 proline, 143, 271 (S)-(−)-proline, 271 propagation, 586 propargylated product, 395 protic acid, 33, 202, protic solvent, 16, 556 proton transfer, 38, 52, 131, 132, 133, 458 protonated heteroaromatic nucleus, 361 Pschorr cyclization, 450 PT, 309 puckered transition state, 521, 578 Pummerer rearrangement, 452 purine, 102 putative active catalyst, 502 PyPh2P, 244 PYR, 309 pyrazinone, 102 pyrazole, 317, 411
pyrazolone, 317 2-pyridinethione, 152 2-pyridone, 270 pyridinium chlorochromate, 304, see also PCC pyridinium dichromate, 304, see also PDC pyridium, 66 pyridone, 102 pyrimidine, 102 α-pyridinium methyl ketone salts, 323 pyrolysis, 156 pyrrole, 112, 276, 317, 411 pyrrolidine, 292 pyruvic acid, 194 Q quasi-axial bonds, 222 quasi-Favorskii rearrangement, 217 quinaldic acid, 461 quinoline, 92, 131, 133, 194, 196, 238, 263, 394, 461, 509, 510 quinolin-4-ones, 133 quinoline-4-carboxylic acid, 194 R racemization, 227, 273 radical, 22, 24, 26, 40, 44, 65, 129, 192, 200, 257, 262, 266, 292, 300, 335, 361, 382, 417, 450, 540, 544, 546, 560, 582, 586 radical anion, 44, 65, 129, 335 radical cation, 292 radical chain reaction, 586 radical coupling, 262 6-exo-trig radical cyclization, 450 5-exo-trig-ring closure, 182 radical decarboxylation, 22 radical initiating conditions, 586 radical intermediate, 300 radical mechanism, 257, 266, 540, 582 radical reactions
Barton radical decarboxylation, 22 Barton–McCombie, 240 Barton nitrite photolysis, 26 Dowd–Beckwith ring expansion, 200 Gomberg–Bachmann, 262 McFadyen–Stevens reduction, 334 McMurry coupling, 335 TEMPO-mediated oxidation, 544
radical Thorpe−Ziegler reaction, 546
615
radical-based carbon–carbon bond for-mation, 361 radical-mediated ring expansion, 200 Ramberg–Bäcklund reaction, 454 Raney nickel, 251 Ra-Ni, 29, 155 rate-limiting step, 218 Rawal diene, 188
RCM, 465 real catalyst, 465 rearomatization, 196 rearrangement
abnormal Claisen, 121 anionic oxy–Cope, 138 Baker–Venkataraman, 14 Beckmann, 33 Benzilic acid, 36 Boulton–Katritzky, 62 Brook, 68 Carrol, 96 Chapman, 105 Ciamician–Dennsted, 112 Claisen, 117 para-Claisen Cope, 119 Cope, 137 Curtius, 162 Demjanov, 175 Dienone–phenol, 190 Di-π-methane, 192 Eschenmoser–Claisen, 123 Favorskii, 214 Ferrier glycal allylic, 222 Fries, 240 Gabriel–Colman, 250 Hofmann, 290 Ireland–Claisen, 125 Johnson–Claisen, 127 Lossen, 332 [1,2]-Meisenheimer, 349 [2,3]-Meisenheimer, 350 Meyer–Schuster, 353 Mislow–Evans, 363 Neber, 385 Overman, 406 oxy-Cope, 140 Payne, 421 Pinacol, 436 Polonovski–Potier, 442 Pummerer, 452 Rupe, 480 quasi-Favorskii, 217
Schmidt, 490 siloxy-Cope, 141 Smiles, 511 Sommelet–Hauser, 513 Tiffeneau–Demjanov, 177 Truce−Smile, 513 Vinylcyclopropane−cyclopentene, 560 Wagner–Meerwein, 566 [1,2]-Wittig, 582 [2,3]-Wittig, 584 Wolff, 588
(S,S)-reboxetine, 503 Red-Al, 100 redox reaction, 94, 401 reducing agent, 210, 330, 274 reduction
Birch, 44 Bouveault–Blanc, 65 CBS, 143 Chan alkyne, 100 Clemmensen, 129 Fukuyama, 245 ketones, 345 McFadyen–Stevens, 334 Meerwein–Ponndorf–Verley, 345 Midland, 359 Rosenmund, 476 Staudinger, 532 Wolff–Kishner, 590
1,4-reduction, 44 reduction of Pd(OAc)2 to Pd(0) using Ph3P, 373 reductive amination, 58, 330 reductive cyclization, 463 reductive elimination, 58, 80, 90, 98, 102, 156, 245, 277, 288, 325, 330, 368, 389, 419, 476, 519, 529, 531, 536, 548, 564 reductive Heck reaction, 278 reductive methylation, 210 Reformatsky reaction, 456 regeneration of Pd(0), 373 regioisomer, 173, 572 regioselectivity, 52, 496, 572 Regitz diazo synthesis, 458 Reimer–Tiemann reaction, 460 Reissert aldehyde synthesis, 461 Reissert compound from isoquinoline, 462 Reissert compound, 461
616
Reissert indole synthesis, 463 retention of configuration, 231, 548 retro-[1,4]-Brook rearrangement, 69 retro-[2+2] cycloaddition, 542 retro-aldol reaction, 173 retro-benzilic acid rearrangement, 36 retro-Bucherer reaction, 74 retro-Claisen condensation, 60, 113 retro-Cope elimination, 136 retro-Diels−Alder reaction, 56, 185 retro-Henry reaction, 284 reverse Kahne-type glycosylation, 314 reversible conjugate addition, 196 rhodium carbenoid, 78 ring expansion, 200 ring opening, 532, 596 6-oxo-trig ring formation, 322 ring-closing metathesis, 465 trisubstituted phosphine, 365 Ritter intermediate, 490 Ritter reaction, 468 Robinson annulation, 271, 470 Robinson–Gabriel synthesis, 472 Robinson–Schöpf reaction, 474 room temperature Buchwald–Hartwig amination, 81 Rosenmund reduction, 476 Rosenmund–von Braun synthesis of aryl nitrile, 98 rotation, 277, 430 rotaxane, 90 Rubottom oxidation, 478 Rupe rearrangement, 353, 480 ruthenium(II) BINAP-complex, 399 S Saegusa enone synthesis, 482 Saegusa oxidation, 397, 482 safe surrogate for cyanide, 525 Sakurai allylation reaction, 484 Sandmeyer reaction, 486 Sanger’s reagent, 347 saponification, 263 Sarett oxidation, 304, 305 Saucy–Claisen, 117 Schiemann reaction, 488 Schiff base, 133 Schlittler–Müller modification, 446 Schlosser modification of the Wittig reaction, 580 Schmidt rearrangement, 490
Schmidt’s trichloroacetimidate glycosi-dation reaction, 492 Schmittel cyclization, 382 Schönberg rearrangement, 393 Schrock’s catalyst, 465 secondary alcohol, 179, 304, 339, 404 secondary amine, 210, 243 secondary cycle, 500 secondary nitroalkane, 387 secondary ozonide, 161 secondary α-acetylenic alcohol, 353 seleno-Mislow-Evans, 363 semi-benzylic mechanism, 217 SET, 18, 44, 65, 129, 155, 266, 311, 554, 335, 397, 554 Shapiro reaction, 16, 494 Sharpless asymmetric amino hydroxyla-tion, 496 Sharpless asymmetric dihydroxylation, 499 Sharpless asymmetric epoxidation , 502 Sharpless olefin synthesis, 505 1,3-shift, 353 Shioiri–Ninomiya–Yamada modification of Curtius rearrangement, 163 SIBX, 397 [1,2]-sigmatropic rearrangement, 349 [2,3]-sigmatropic rearranegment, 20, 251, 350, 363, 584 [3,3]-sigmatropic rearranegment, 60, 72, 96, 117, 119, 121, 123, 125, 127, 137, 138, 140, 141, 227, 406 sila-Stetter reaction, 525 sila-Wittig reaction, 430 silicon cleavage, 484 β-silicon effect, 484 siloxane, 102 α-silyloxy carbanions, 68 siloxy-Cope rearrangement, 141 silver carboxylate, 298 silver salt, 320 silver-catalyzed oxidative decarboxyla-tion, 361 silyation, 332 α-silyl carbanion, 430 silyl enol ether, 375, 377, 397 α-silyl oxyanions, 68 [1,2]-silyl migration, 68 β-silylalkoxide intermediate Simmons–Smith reaction , 507 Simmons−Smith reagent, 507
617
single electron transfer, 18, 44, 65, 129, 155, 266, 311, 554, 335, see also SET single-electron process, 335 singlet diradical, 417 six-membered α,β-unsaturated ketone, 470 Skraup quinoline synthesis, 196, 509 Skraup type, 263 SMEAH, 100 SmI2-mediated Reformatsky reaction, 457 Smile reaction, 393 Smiles rearrangement, 511, 513 SN1, 313 SN2 inversion, 365 SN2 reaction, 52, 129, 148, 179, 229, 247, 249, 240, 292, 357, 363, 365, 578, 592 SNAr, 243, 347, 379 sodium amalgam, 311 sodium bis(2-methoxyethoxy)aluminum hydride, 100 sodium bisulfite, 72 sodium cyanide, 534 sodium hypochlorite for Hofmann rear-rangement, 291 sodium tert-butoxide, 80 sodium, 65 solid-phase Cope elimination, 135 soluble cyanide source, 534 solvent-free Claisen condensation, 114 solvent-free Dakin oxidation, 165 Sommelet reaction, 171, 515 Sommelet–Hauser rearrangement, 251, 517, 584 Sonogashira reaction, 98, 519 (−)-sparteine, 213, 351 spirocyclic anion intermediate, 511 stabilized IBX, 397 stable nitroxyl radical, 544 stannane, 20, 102, 529, 531 statin side chain, 50 Staudinger ketene cycloaddition, 521 Staudinger reduction, 523 step-wise mechanism, 588 stereoselective conversion, 540 stereoselective oxidation, 231 stereoselective reduction, 100 stereoselectivity, 572 steric hindrance, 594 sterically-favored isomer, 419
Stetter reaction, 38, 525 Stille coupling, 529 Stille–Kelly reaction, 531 Still–Gennari phosphonate reaction, 527 Still−Wittig rearrangement, 584 Stobbe condensation and cyclization, 532 Stobbe condensation, 532 stoichiometric copper, 519 stoichiometric Pd(II), 281 Strecker amino acid synthesis, 534 strong acid, 319, 468, 598 styrenylpinacol boronic ester, 574 substituted hydrazine, 317 7-substituted indoles, 20 5-substituted oxazole, 556 2-substituted-quinolin-4-ol, 92 4-substituted-quinolin-2-ol, 92 substitution reactions, 351 succinimidyl radical, 586 sulfenamide, 576 sulfinate, 102 sulfonamides, 102 sulfone reduction, 309 sulfone, 30, 309, 311, 454 sulfonium ion, 251 sulfonyl azide, 458 sulfoxide activation, 313 sulfoxide, 313, 363, 452 sulfoximines, 102 sulfur ylide, 146, 538 sulfurane dehydrating reagent, 339, 340, 457 sulfur-containing heterocyclic ring, 576 sulfuric acid, 304 Suzuki, 298 Suzuki–Miyaura coupling, 102, 536 Swern oxidation, 150, 538 switchable molecular shuttles, 90 syn/anti, 377 syn-addition, 70 synchronized fashion, 515 T Takai reaction, 540 Tamao−Kumada oxidation, 233 d3-tamoxifen, 210 tautomerization, 74, 121, 133, 140, 167, 198, 227, 274, 353, 383, 408, 490, 509, 525, 570 TBABB, 377
618
TBAO, 239 TBTBTFP, 309 TDS, 141, 180 Tebbe olefination, 428, 542 Tebbe’s reagent, 428 TEMPO oxidation, 544 terminal acetylenic group, 353 terminal alkyne, 148, 299, 257, 519 tertiary alcohol, 84, 339, 490 tertiary amine, 30, 206, 349, 350, 562 tertiary amine N-oxide, 349 tertiary carbocation, 319 tertiary carboxylic acid formation, 319 tertiary N-oxide, 440, 442 tertiary phosphine, 523 tertiary α-acetylenic (terminal) alcohol, 480 tertiary α-acetylenic alcohols, 353 tetrahydrocarbazole, 60 tetrahydroisoquinoline, 434 tetramethyl pentahydropyridine oxide, 544 tetra-n-butylammonium bibenzoate, 377 1,1,3,3-tetramethylguanidine, 95 2,2,6,6-tetramethylpiperi-dinyloxy, 544 tetrazole, 309 Tf2O, 313, 314, 379 TFA, 14, 54, 287, 292, 354, 362, 375, 391, 415, 445, 507, 566 TFAA, 54, 262, 443 thermal aliphatic Claisen rearrangement, 16 thermal aryl rearrangement, 105 thermal Bamford–Stevens, 17 thermal decomposition, 292 thermal elimination, 110, 135 thermal rearrangement, 96, 162 thermal-catalyzed condensation, 133 thermal-mediated rearrangement, 332 thermodynamic adduct, 294 thermodynamic product, 16, 494 thermodynamic sink, 140 thermodynamically favored, 319 thermolysis, 62 thexyldimethylsilyl, 141, 180 thia-Fries rearrangement, 241 thia-Michael addition, 355 thiazolium catalyst, 525 thiazolium salt, 38 thiirane, 146 3-thioalkoxyindoles, 251
thioamide, 576 thiocarbonyl derivatives, 24, 328, 408 1,1 -thiocarbonyldiimidazole, 156 thioglycolic acid derivatives, 225 thiol, 102, 245 thiophene, 17, 225, 254, 286, 287, 328, 329, 408 thiophene from dione, 328 thiophene synthesis, 225, 408 thiophene-2,5-dicarbonyls, 286 thiophenol, 393 Thorpe−Ziegler reaction, 546 three-component aminomethylation, 337 three-component condensation, 415 three-component coupling, 194, 426, 574 threo (thermodynamic adduct), Horner–Wadsworth–Emmons reaction, 294 threo betaine, 580 Ti(0), 335 Ti=O, 542 TiCl3/LiAlH4, 335 Tiffeneau–Demjanov rearrangement, 177 titanium tetra-iso-propoxide, 502 TMG, 95 TMSO-P(OEt)2, 358 p-tolylsulfonylmethyl isocyanide, 556 tosyl amide, 458 tosyl ketoxime, 385 trans-β-dimethylamino-2-nitrostyrene, 28 transannular aldol reaction, 4 transition state, 1, 309, 345, 404, 478, 503, 521, 523, 578, transmetallation, 102, 288, 325, 368, 389, 401, 519, 529, 531, 536, 536 trapping molecule, 90 Traxler–Zimmerman trasition state, 193 triacetoxyperiodinane, 179 trialkyl orthoacetate, 127 trialkyloxonium salts, 343 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 179 1,2,4-triazine, 56 triazole intermediate, 458 trichloroacetimidate intermediate, 406, 492 2,4,6-trichlorobenzoyl chloride, 594 trichloroisocyanuric/TEMPO oxidation, 545
619
triethyloxonium tetrafluoroborate, 343 triflate, 202, 288, 325, 389, 529, 536, 572 trifluoroacetic anhydride, 54, 442, see also TFAA trifluorotoluene, 202 1,3,3-trimethyl-6-azabicyclo[3.2.1]-octane, 239 trimethyloxonium tetrafluoroborate, 343 trimethylphosphite, 156 trimethylsilyl chloride, 125 trimethylsilyl polyphosphate, 235 tri-O-acetyl-D-glucal, 222 1, 1,2,3-trioxolane, 161 2,4-trioxolane, 161 triphenylphosphine, 365, see also Ph3P triplet diradical, 417 n, π* triplet, 417 tropinone, 474 Truce−Smile rearrangement, 513 Tsuji–Trost allylation, 548 Two sequential Stobbe condensations, 532 U Ugi reaction, 415, 551 UHP, 12, 165 Ullmann coupling, 554 umpolung, 154 11-undecenoic acid, 574 α,β-unsaturation of aldehydes, 397 α,β-unsaturation of ketones, 397 α,β-unsaturated aldehyde, 480 γ,δ-unsaturated amides, 123 α,β-unsaturated carbonyl compounds, 353 γ,δ-unsaturated carboxylic acids, 125 α,β-unsaturated ester, 525 γ,δ-unsaturated ester, 127 2,3-unsaturated glycosyl derivatives, 222 5,6-unsaturated hexopyranose deriva-tives, 220 α,β-unsaturated ketone, 323, 480, 525 γ-unsaturated ketones, 96 α,β-unsaturated system, 355, 377, 484 urea, 12, 42, 102, 162, 165, 332, 370 urea-hydrogen peroxide complex, 12, 165
V van Leusen oxazole synthesis, 556 van Leusen reagent, 556 varenicine, 211 vicinal diol, 159, 436 Vilsmeier–Haack reaction, 558, 558 Vinyl azide, 162 vinyl boronic acid, 426 vinyl Grignard, 20 vinyl halide, 401 E-vinyl iodide, 540 vinyl ketones, 30, 470 vinyl sulfones, 30 N,O-vinylation, 102 vinylcyclopropane, 192, 560 vinylcyclopropane−cyclopentene rearrangement, 560 vinylic alkoxy pentacarbonyl chromium carbene, 198 vinylic C–H arylation, 574 vinylogous Mukaiyama aldol reaction, 375 2-cis-vitamin A acid, 578 von Braun degradation, 562 von Braun reaction, 562 W Wacker oxidation, 281, 482, 564 Wagner–Meerwein rearrangement, 566 Wagner–Meerwein shift, 331 Weinstock variant of the Curtius rear-rangement, 163 Weiss–Cook reaction, 568 Wharton reaction, 570 White reagent, 572 Willgerodt–Kindler reaction, 576 Wittig reaction, 148, 294, 306, 430, 578, 580 Wittig reagent, 403 [1,2]-Wittig rearrangement, 582 [2,3]-Wittig rearrangement, 517, 584 Wohl–Ziegler reaction, 586 Wolff rearrangement, 40, 588 Wolff–Kishner reduction, 590 Woodward cis-dihydroxylation, 447, 592
X xanthate, 110 Xphos, 82, 83, 89, 369
620
Y Yamaguchi esterification, 594, 595 Yamaguchi reagent, 594, 595 ylidene-sulfur adduct, 254, 255 Z Zimmerman rearrangement, 192 zinc amalgam, 129 zinc-carbenoid, 129 zinc chloride, 371 zinc reagent, 389, 403, 456 Zincke anhydride, 598 Zincke reaction, 596 Zincke salt, 596, 598 Zn(Cu), 507 zwitterionic peroxide, 161
621
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