CHAPTER 1
ELECTROPHILIC AMINATION OF CARBANIONS, ENOLATES,AND THEIR SURROGATES
ENGELBERT CIGANEK
121 Spring House Way, Kennett Square, PA, 19348, USA
CONTENTSPAGE
ACKNOWLEDGEMENTS . . . . . . . . . . . . . 4INTRODUCTION . . . . . . . . . . . . . . 5REAGENTS AND MECHANISMS . . . . . . . . . . . 6
Preparation of Carbanions, Enolates, and Their Surrogates . . . . . 6Aminating Reagents . . . . . . . . . . . . 6
Metal Amides . . . . . . . . . . . . . 6Haloamines . . . . . . . . . . . . . 7Hydroxylamines . . . . . . . . . . . . 8
N-Unsubstituted O-Alkylhydroxylamines . . . . . . . 8N-Unsubstituted O-Arylhydroxylamines . . . . . . . . 8N-Monosubstituted O-Alkylhydroxylamines . . . . . . . 8N,N-Disubstituted O-Alkylhydroxylamines . . . . . . . 9O-Acyl Hydroxylamines . . . . . . . . . . 10N-Unsubstituted O-Sulfonylhydroxylamines . . . . . . . 10N-Monosubstituted O-Sulfonylhydroxylamines . . . . . . 10N,N-Disubstituted O-Sulfonylhydroxylamines . . . . . . 11O-Phosphinoylhydroxylamines . . . . . . . . . 11
Oxaziridines . . . . . . . . . . . . . 12Imines . . . . . . . . . . . . . . 13(N -Arenesulfonylimino)phenyliodinanes . . . . . . . . 14Oximes . . . . . . . . . . . . . . 15Diazonium Salts . . . . . . . . . . . . 15Diazo Compounds . . . . . . . . . . . . 16Azo Compounds . . . . . . . . . . . . 16
Alkyl Azo Compounds . . . . . . . . . . . 16Aryl Azo Compounds . . . . . . . . . . . 16Esters of Azodicarboxylic Acid . . . . . . . . . 16Other Acyl Azo Compounds . . . . . . . . . . 18Sulfonyl Azo Compounds . . . . . . . . . . 18
Azides . . . . . . . . . . . . . . 18Alkyl Azides . . . . . . . . . . . . . 18
[email protected] Reactions, Vol. 72, Edited by Scott E. Denmark et al. 2008 Organic Reactions, Inc. Published by John Wiley & Sons, Inc.
1
COPYRIG
HTED M
ATERIAL
2 ORGANIC REACTIONS
Vinyl Azides . . . . . . . . . . . . . 20Aryl Azides . . . . . . . . . . . . . 20Acyl Azides . . . . . . . . . . . . . 21Sulfonyl Azides . . . . . . . . . . . . 21Sodium Azide/Ammonium Cerium(IV) Nitrate . . . . . . 23Diphenyl Phosphorazidate . . . . . . . . . . 23Miscellaneous Azides . . . . . . . . . . . 23
Miscellaneous Reagents . . . . . . . . . . . 24Chloramine-T/Osmium Tetroxide . . . . . . . . . 24N -Chlorocarbamate/Chromium(II) Chloride . . . . . . . 24Bis[N -p-Toluenesulfonyl)]selenodiimide . . . . . . . 24Nitridomanganese Complexes . . . . . . . . . 24
SCOPE AND LIMITATIONS . . . . . . . . . . . . 24Amination of Aliphatic Carbanions . . . . . . . . . 24
Preparation of Alkyl Amines . . . . . . . . . . 24Preparation of Alkyl Hydrazines . . . . . . . . . 26Preparation of Alkyl Azides . . . . . . . . . . 28
Amination of Allylic and Propargylic Carbanions . . . . . . . 28Amination of Arylmethyl and Heteroarylmethyl Carbanions . . . . . 28Amination of Vinyl and Allenyl Carbanions . . . . . . . . 29Amination of Ethynyl Carbanions . . . . . . . . . . 30Amination of Aryl Carbanions . . . . . . . . . . 30
Preparation of Arylamines . . . . . . . . . . . 30Preparation of Aryl Hydrazines . . . . . . . . . . 32Preparation of Aryl Azides . . . . . . . . . . 32
Amination of Heterocyclic Carbanions . . . . . . . . . 32Amination of Aldehyde Enolates, Enol Ethers, and Enamines . . . . 33Amination of Ketone Enolates, Enol Ethers, and Enamines . . . . . 35Amination of Imine and Hydrazone Anions . . . . . . . . 39Amination of Carboxylic Acid Dianions . . . . . . . . 40Amination of Ester Enolates and Ketene Acetals . . . . . . . 41Amination of Thioester Enolates and Ketene Thioacetals . . . . . 44Amination of Lactone Enolates . . . . . . . . . . 44Amination of Amide Enolates and Ketene Aminals . . . . . . 45Amination of N -Acyloxazolidinone Enolates . . . . . . . . 46Amination of Lactam Enolates . . . . . . . . . . 50Amination of Nitrile-Stabilized Carbanions . . . . . . . . 51Amination of Nitronates . . . . . . . . . . . 52Amination of Sulfone-Stabilized Carbanions . . . . . . . . 52Amination of Phosphorus-Stabilized Carbanions . . . . . . . 52Amination of Enolates of α,β-Unsaturated Carbonyl Compounds . . . . 54Amination of Enolates of α-Cyanocarbonyl and β-Dicarbonyl Compounds . . 56Intramolecular Aminations . . . . . . . . . . . 58
Formation of Aziridines . . . . . . . . . . . 58Formation of Higher-Membered Rings . . . . . . . . 59
COMPARISON WITH OTHER METHODS . . . . . . . . . . 60Amination with Nitrogen Oxides . . . . . . . . . . 60Amination with Nitrosyl Chloride, Nitryl Chloride, and Nitronium Tetrafluoroborate 60Amination with Alkyl Nitrites . . . . . . . . . . 61Amination with Alkyl Nitrates . . . . . . . . . . 61Amination with Nitroso Compounds . . . . . . . . . 62Amination With Nitro Compounds . . . . . . . . . 63Amination of Enolates with Diazonium Salts . . . . . . . . 65
ELECTROPHILIC AMINATION OF CARBANIONS 3
The Diazo Transfer Reaction . . . . . . . . . . . 65Amination of Boranes . . . . . . . . . . . . 65The Neber Rearrangement . . . . . . . . . . . 66
EXPERIMENTAL CONDITIONS . . . . . . . . . . . 66Preparation of Electrophilic Aminating Reagents . . . . . . . 66Conversions of Amination Products . . . . . . . . . 66
EXPERIMENTAL PROCEDURES . . . . . . . . . . . 68N ,N -Diisopropylaniline (Amination of an Arylcopper Reagent with a Lithium
Dialkylamide) . . . . . . . . . . . . . 69Diethyl Aminomalonate (Amination of a β-Dicarbonyl Compound with
Chloramine) . . . . . . . . . . . . . 70N -tert-Butylbenzylamine (Amination of an Alkyllithium Compound with a Lithium
Nitrenoid) . . . . . . . . . . . . . . 71tert-Butyl 4-Fluorophenylcarbamate (Amination of an Arylcopper Reagent with
Lithium tert-Butyl N -Tosyloxycarbamate) . . . . . . . . 72N -Phenylmorpholine (Amination of an Arylzinc Derivative with an
O-Acylhydroxylamine) . . . . . . . . . . . 72N ,N -Diethyl-5,10-dihydroindeno[1,2-b]indol-10-amine (Amination of a Benzylic
Anion with an N ,N -Disubstituted O-Arenesulfonylhydroxylamine) . . . 73Ethyl (N -Acetylamino)phenylacetate (Amination of an Ester Enolate with an
O-Phosphinoylhydroxylamine) . . . . . . . . . . 73Diamino-N ,N ′-diphenylmalonamide and Imino-N ,N ′-diphenylmalonamide
(Diamination of a Malonamide with 1-Oxa-2-azaspiro[2.5]octane and Conversion ofthe Product into an Imine) . . . . . . . . . . 74
Ethyl tert-Butoxycarbonylamino(cyano)phenylacetate (Amination of a CyanoaceticEster Enolate with an N -Acyloxaziridine) . . . . . . . . 74
N -Isopropyl-p-anisidine (Amination of a Grignard Reagent with an Imine) . 752-[N -(p-Toluenesulfonyl)amino]acetophenone (Amination of a Ketone Silyl Enol Ether
with [N -(p-tolylsulfonyl)imino] phenyliodinane) . . . . . . 751-Aminoadamantane Hydrochloride (Amination of a Grignard Reagent with an
O-Arenesulfonyloxime) . . . . . . . . . . . 75E-(tert-Butyl)(4-chlorophenyl)diazene (Reaction of a Grignard Reagent with an
Aryldiazonium Salt) . . . . . . . . . . . . 761,2-Diphenyl-1-(1-p-tolylpentyl)hydrazine (Amination of a Benzotriazolylmethyl
Anion with an Azo Compound Followed by Displacement of the BenzotriazoleFunctionality by a Grignard Reagent) . . . . . . . . 76
tert-Butyl N -(3-Bromo-1-methylpropyl)-N ′-(tert-butoxycarbonyl)hydrazinecarboxylicAcid (Catalyzed Hydrohydrazination of an Olefin with an Azo Ester) . . 77
2-[N ,N ′-bis(tert-Butoxycarbonyl)hydrazino]thiophene (Amination of a HeterocyclicZinc Reagent with an Azo Ester) . . . . . . . . . 77
(R)-Dibenzyl 1-(1-Hydroxyhexan-2-yl)hydrazine-1,2-dicarboxylate (CatalyticAsymmetric Amination of an Aldehyde with an Azo Ester) . . . . 78
(S)-Dibenzyl 1-(1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)hydrazine-1,2-dicarboxylate(Catalyzed Asymmetric Amination of a Ketone Silyl Enol Ether with anAzo Ester) . . . . . . . . . . . . . 78
Methyl 2-(Naphthalen-2-ylamino)methylacrylate (Amination of an Allylindium Specieswith an Azide) . . . . . . . . . . . . . 79
N -Ethylaniline (Preparation of an N -Substituted Aniline by Reaction of a GrignardReagent with an Aromatic Azide) . . . . . . . . . 79
2,4-Dimethylaniline (Preparation of Trimethylsilylmethyl Azide and Its Reaction withan Arylmagnesium Reagent to Give an Aniline) . . . . . . 80
2-Aminobenzothiazole (Preparation of Azidomethyl Phenyl Sulfide and Its Reactionwith a Heterocyclic Grignard Reagent to Give a Heterocyclic Amine) . . 80
4 ORGANIC REACTIONS
(4R)-3{(Z,2R)-2-Azido-6-[(4R)-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidin-4-yl]-1-oxohex-5-enyl}-4-phenylmethyl-1,3-oxazolidinone and(4R)-4[(1Z,5R)-5-Azido-5-carboxypent-1-enyl]-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidine (Diastereoselective Azidation of an N -Acyloxazolidinone with TrisylAzide and Removal of the Chiral Auxiliary) . . . . . . . 81
2-Azido-1,3,5-trimethylbenzene (Preparation of an Azide from a Grignard Reagent andTosyl Azide) . . . . . . . . . . . . . 82
α-[(tert-Butoxycarbonyl)amino]-N -methyl-N -phenyl-2-thiopheneacetamide (Aminationof an Amide Enolate with Diphenyl Phosphorazidate) . . . . . 83
2-Azido-2-methylcyclohexanone (Preparation of an α-Azido Ketone by Reaction of aKetone Triisopropylsilyl Enol Ether with Sodium Azide and Ammonium Cerium(IV)Nitrate) . . . . . . . . . . . . . . 83
2,2,2-Trichloroethyl 2-Oxocyclohexylcarbamate (Amination of a Ketone Enol Etherwith the Chromium(II) Chloride/Chlorocarbamate Reagent) . . . . 83
TABULAR SURVEY . . . . . . . . . . . . . 84Chart 1. Structures of Reagents and Catalysts . . . . . . . 87Table 1A. Acyclic Aliphatic Carbanions . . . . . . . . 88Table 1B. Cyclic Aliphatic Carbanions . . . . . . . . . 118Table 1C. Allylic and Propargylic Carbanions . . . . . . . 126Table 1D. Arylmethyl and Heteroarylmethyl Carbanions . . . . . 132Table 2. Vinyl and Allenyl Carbanions . . . . . . . . . 143Table 3. Ethynyl Carbanions . . . . . . . . . . . 146Table 4. Aryl Carbanions . . . . . . . . . . . 147Table 5. Heterocyclic Carbanions . . . . . . . . . . 186Table 6. Aldehyde Enolates . . . . . . . . . . . 194Table 7A. Acyclic Ketone Enolates . . . . . . . . . 207Table 7B. Cyclic Ketone Enolates . . . . . . . . . . 216Table 8. Imine and Hydrazone Anions . . . . . . . . . 235Table 9. Carboxylic Acid Dianions . . . . . . . . . 238Table 10A. Ester Enolates . . . . . . . . . . . 240Table 10B. Thioester Enolates . . . . . . . . . . 258Table 11. Lactone Enolates . . . . . . . . . . . 260Table 12. Amide Enolates . . . . . . . . . . . 264Table 13. N -Acyloxazolidinone Enolates . . . . . . . . 267Table 14. Lactam Enolates . . . . . . . . . . . 286Table 15. Cyano-Stabilized Carbanions . . . . . . . . . 290Table 16. Nitronates . . . . . . . . . . . . 295Table 17. Sulfone-Stabilized Carbanions . . . . . . . . 296Table 18. Phoshorus-Stabilized Carbanions . . . . . . . . 297Table 19. Enolates of α,β-Unsaturated Carbonyl Compounds . . . . . 303Table 20. Enolates of α-Cyanocarbonyl and β-Dicarbonyl Compounds . . . 307Table 21. Intramolecular Aminations . . . . . . . . . 336
REFERENCES . . . . . . . . . . . . . . 345
ACKNOWLEDGEMENTS
I am indebted to E. I. du Pont de Nemours & Co., Inc. and Dr. Pat Confalonefor permission to use the company libraries and especially to Ms. Susan Titterof the Agricultural Products Department for valuable assistance. Professor ScottDenmark and Ms. Donna Whitehill of the University of Illinois and Professor
ELECTROPHILIC AMINATION OF CARBANIONS 5
Peter Wipf and Ms. Michelle Woodring of the University of Pittsburgh graciouslyprovided copies of less common journals. I also thank the many colleagues whoanswered questions or provided copies of their papers. My editor, Dr. StuartMcCombie, is thanked for his guidance and advice and for painstakingly proof-reading the manuscript. Last, but not least, I owe a large debt of gratitude toDr. Linda Press for valuable help during the preparation of this chapter andfor patiently answering my many questions regarding the mysteries of computersoftware.
INTRODUCTION
Nitrogen-containing organic compounds are ubiquitous in nature and essentialto life. They are also important intermediates and products of the chemical andpharmaceutical industries. As a consequence, chemists have developed a plethoraof methods for their generation, starting with the first organic synthesis, Wohler’spreparation of urea from ammonium cyanate in 1828.1 There are many reports ofthe formation of carbon-nitrogen bonds by electrophilic amination of carbanionsand enolates in the early literature, but development of this method as a usefulsynthetic tool, especially for asymmetric synthesis, is of more recent date.
Most electrophilic aminations can be divided into two types: substitutions(e.g. Eq. 1) and additions (e.g. Eq. 2) to give products that in many cases arenot amines. A detailed discussion of the conversion of these intermediates intoamines is beyond the scope of this chapter, but references to relevant methodsare given in the section on Experimental Conditions.
R1M + (R2)2NX
R1M = Grignard or organolithium reagent, etc.
R1N(R2)2 + MX (Eq. 1)
MO
R1 R3
R21. R4N=NR5
2. H2O R1 NO
NHR2 R3
R4
R5
M = metal
(Eq. 2)
The initial intent to cover the subject exhaustively had to be abandoned becauseof the overwhelming amount of relevant literature. The following reactions arenot covered but are briefly discussed, with references to reviews and seminalpapers, in the section on Comparison with Other Methods: reactions of carbanionsand enolates and their surrogates with nitrogen oxides, nitrite and nitrate esters,and nitroso and nitro compounds; reactions of enolates with diazonium salts,including the Japp-Klingemann reaction; the diazo transfer reaction except as itinterferes with the synthesis of azides; the amination of boranes; and the Neberrearrangement.
The large number of reagents that are available for amination necessitated adeviation from the standard Organic Reactions format. The section on Reagentsand Mechanisms includes discussion and exemplification of each reagent orreagent class as well as comments on mechanism, particularly in context ofreagent-substrate combinations that can lead to more than one product. Stereo-chemistry is discussed in the relevant sections of Scope and Limitations.
6 ORGANIC REACTIONS
There is only one previous comprehensive review of the electrophilicamination of carbanions;2 shorter reviews3 – 9 and reviews limited to particularreagents, substrates, or products have appeared: amination with haloamines,10
sulfonylhydroxylamines,11 oxaziridines,12 oximes,13 diazonium salts,14,15 diazocompounds,16 activated azo compounds,17 azides,18 – 23 and nitridomanganese(V)reagents;24,25 amination of enolates;26 – 30 and the preparation of α-amino acidsby electrophilic amination.31 – 34
REAGENTS AND MECHANISMS
Preparation of Carbanions, Enolates, and Their Surrogates
The preparation of carbanions,35 organolithium reagents,36,37 Grignardreagents,38,39 and organozinc reagents40,41 has been reviewed. For reviews onthe generation of enolates see refs. 42–45. The synthesis of silyl enol ethersis reviewed in refs. 46–49, that of silyl ketene acetals in ref. 50. The term“carbanion” is used loosely without regard to aggregation or solvation.
Aminating Reagents
All aminating reagents dealt with in this chapter are listed here; references totheir preparation are found in the section on Experimental Conditions. Stereo-chemistry is discussed in the relevant sections of Scope and Limitations. Theterm amination refers to the formation of a carbon-nitrogen bond, not just to theintroduction of an amine group. For a quantum Monte Carlo study of electrophilicamination reagents see ref. 51.
Metal Amides. Amidocuprates, when treated with molecular oxygen at lowtemperatures, give secondary or tertiary amines (Eq. 3). The substrates may begenerated from disubstituted lithium cuprates and a primary or secondary amine(method A);52 one equivalent of the cuprate may be used but yields are higherwith three to five equivalents. Only one of the two R1 groups enters into theproduct; it may be, among others, an aryl or tert-butyl group. Acyl and hydroxygroups in the amine are tolerated. Method B involves the reaction of an organo-lithium reagent with an excess of a copper amide, which in turn is generated froma lithium amide with copper(II) iodide.52 The copper amide may be replaced byan anilido cuprate ArN(R3)Cu(X)Li where X is Cl or CN.53 The third method(C) employs a lower-order cuprate and a lithium amide. R1 may be alkyl, aryl,heteroaryl, or styryl. Yields in the three methods are moderate to good. Sub-stituted hydrazines are obtained by replacing the lithium amides in method Cwith a lithium hydrazide, but yields are only in the 20–40% range.54 THF is thepreferred solvent in these reactions, which fail with Grignard or organolithiumreagents. An eight-membered planar complex has been suggested54 as the inter-mediate, which reacts with oxygen to give the product via an aminyl radical.
ELECTROPHILIC AMINATION OF CARBANIONS 7
Yields are improved in method C when zinc cyanocuprates and co-oxidants (o-dinitrobenzene or copper(II) nitrate) are employed.55
R1Cu(CN)Li + R2R3NLi
O2
A
B
C
(R1)2CuLi + R2R3NH
R1Li + R2R3NCu amidocuprate R1NR2R3 (Eq. 3)
Haloamines. Chloramine was one of the earliest reagents investigated for theamination of Grignard reagents and organolithium compounds.56 – 59 An excessof the latter is usually required because of the acidic nature of the haloaminehydrogens. Replacement of one of these by lithium to give a nitrenoid hasbeen suggested as the first step (Eq. 4).60 Bromamine offers no advantage overchloramine.61 In the reactions of haloamines with Grignard reagents, yieldsdecrease in the order of RMgCl > RMgBr > RMgI.61 Chloramine aminates sodiomalonates.62 – 64 With sodium phenolates, ring-expanded products are obtained.65
The mechanism of these reactions is unknown62 but a nitrenoid intermediateis unlikely because of the lower basicity of the substrates. No reaction occursbetween 2-lithio N -methylimidazole and chloramine.66
H2O RLi
–LiClRLi + ClNH2 ClNHLi RNHLi RNH2
(Eq. 4)
Monosubstituted chloramines have not received much attention. The reactionof N -chloro-tert-butylamine with di(tert-butyl)magnesium gives di(tert-butyl)amine in 10% yield.67 Butylmagnesium chloride and N -chloromethylamine pro-duce mostly methylamine by reduction and only 14% of N -methylbutylamine.68
Disubstituted chloramines are claimed to not react with phenylmagnesiumbromide69 and with only very poor yields with n-butyl- or benzylmagnesiumchloride.68 N -Chlorodiisopropylamine reacts with isopropylpotassium to give tri-isopropylamine in 3% yield.70 Similar low yields are obtained in the reactionsof phenylethynyllithium,71 phenylethynylmagnesium bromide,71 or diethylzinc72
with N -chlorodiethylamine. Chloramines of type ClNRCHRAr, prepared fromthe secondary amines with N -chlorosuccinimide, react with arylmagnesium chlo-rides to give the corresponding tertiary amines (see Eq. 62).73 N,N-DisubstitutedN -chloroamines react with enamines to give mixtures of α-amino aldehydesin moderate to excellent yields where the α-amino group is derived from thechloro amine in one product and from the enamine in the other (see Eq. 86). Amechanism involving aziridinium intermediates has been suggested.74
N ,N -Dibromoamine,75 N ,N -dichloroalkylamines,68,72,76 and even trichloro-amine58,77 react with Grignard or dialkylzinc reagents to give amines by reductionof the excess halogen. Yields are low and these reagents are currently of no valuein synthesis.
Chloramine-T, the sodium salt of N -chloro-p-toluenesulfonamide, tosylami-nates a number of in situ generated enamines of α-substituted propionaldehydes(see Eq. 78), α-substituted arylacetaldehydes, and methyl arylmethyl ketones.78
8 ORGANIC REACTIONS
Hydroxylamines. A number of O-substituted hydroxylamines are electrophi-lic aminating reagents for introduction of unsubstituted as well as mono- anddisubstituted amino groups.
N-Unsubstituted O-Alkylhydroxylamines. The most widely used in this cat-egory are O-methylhydroxylamine, and, to a lesser extent, O-benzylhydroxyl-amine. In the amination of the dianion of 3-methylbutanoic acid with RONH2,79
yields decrease in the order R = Me > Et = i-Pr > t-Bu > Bn and range from34% for MeONH2 to a trace for BnONH2. However, the latter aminates organo-lithium and Grignard reagents (two equivalents) in fair to good yields.80 Themechanism of the amination of organolithium reagents with O-alkylhydroxylami-nes involves the nitrenoid intermediate 1 (Eq. 5) and eventual displacement ofthe methoxy group by R in a counterintuitive reaction between two negativelycharged species that is sterically akin to an SN2 reaction. The mechanism is basedon extensive experimental81 – 85 and computational work60,86 – 90 and also appliesto Grignard, organozinc, and organocopper reagents.91 However, it should be keptin mind that other mechanisms are, at least in principle, available, in view of thefact that N,N-disusbstituted O-alkylhydroxylamines are also aminating reagentseven though a process involving a nitrenoid is impossible with these reagents.By generating the nitrenoid 1 with methyllithium only one equivalent of RLi isrequired. Application of this method to aminations with O-alkylhydroxylaminesreported in the earlier literature should increase the efficiency of these reactions.An excess of the nitrenoid MeONHLi is recommended; in the reaction with n-butyllithium the yields of n-butylamine are 51% with one equivalent, 71% withtwo (see also Eq. 63), and 85% with four.92
MeLi + MeONH2
RLi
1
R OMeNH
2–
RNHLi– LiOMe
RNH2
H2O
RLi
NLi H
OMeMeONHLi
2 Li+
(Eq. 5)
N-Unsubstituted O-Arylhydroxylamines. Amination of malonic and cyano-acetic ester enolates93 and of methyl 9-fluorenecarboxylate94 may be carried outin fair to good yields with O-(2,4-dinitrophenyl)hydroxylamine. Yields are lowwith the more basic phenylacetic ester enolates and the anion of phenylacetoni-trile, both of which partially decompose the reagent with formation of diimide.93
This reagent provides much poorer yields than Ph2P(O)ONH2 in the aminationof the anion of tetraethyl methylenebis(phosphonate).95 The corresponding N -methyl derivative is unreactive in an N-amination.94 Various analogs of the highlyexplosive O-(2,4-dinitrophenyl)hydroxylamine have been tested in N-aminationsonly 94,96 and O-(4-nitrophenyl)hydroxylamine was found to provide the highestyields and to have the highest onset temperature of explosive decomposition.96
N-Monosubstituted O-Alkylhydroxylamines. Various O-methylhydroxyl-amine derivatives (MeONHR) aminate aliphatic and aromatic organolithium com-pounds: R = Me,82,83,97 n-Pr and i-Pr,83 benzyl,83,85 α-methylbenzyl,82,83,85,97
ELECTROPHILIC AMINATION OF CARBANIONS 9
and 2-phenylethyl.83 The order of reactivity of BnNLiOMe toward butyl-lithium reagents is n-Bu < s-Bu < t-Bu.85 BnNLiOMe reacts much morerapidly with these three alkyllithium reagents than its α-methyl derivativePhCHMeNLiOMe;85 the latter is about equal in reactivity to MeNLiOMe.97
Reagents of type RCH2NLiOBn may be prepared by addition of an organolithiumreagent RLi to formaldehyde O-benzyl oxime (Eq. 6).98 A nitrenoid of this classis also formed in the reaction of phenyllithium with nitrosobenzene (Eq. 7),99 butit reacts so rapidly with unreacted phenyllithium that the possibility of trappingit with another organolithium reagent seems remote.
CH2 NOBn n-BuLi, THF
–40°
1. PhLi, 0-40°
2. 4-PhC6H4COCl
(47%)
n-Bu NOBn
Lin-Bu N
PhPh
O
(Eq. 6)
PhNOPhLi (1.1 eq), THF
–100°, 70 minPhN(Li)OPh Ph2NLi + PhOLi
H2OPh2NH + PhOH(41%) (41%)
PhLi
(Eq. 7)
O-Trimethylsilylhydroxylamine reagents (RNHOTMS where R is TMS oralkyl), aminate organocuprates of type R1
2Cu(CN)Li2 (see Eqs. 64 and 73), butnot organolithium reagents.100 – 102 Small amounts of alcohols R1OH are formedin some reactions as a consequence of the nitrenoid 2/oxenoid 3 equilibrium(Eq. 8), with the latter acting as a hydroxylating agent.60,103
TMSNOTMS
2 3
(TMS)2NO– M+
M+–
(Eq. 8)
Amination with an N-monosubstituted cyclic hydroxylamine is shown inEq. 9.104
NHO
O
O NHPhOH
O
OPhMgBr (3 eq), –78° to 0°, 1 h
(~100%)
(Eq. 9)
N,N-Disubstituted O-Alkylhydroxylamines. In the amination with a series ofN,N-disubstituted O-methylhydroxylamines, more bulky alkyllithium compoundsreact more readily (product 4, Eq. 10).85 The small amounts of products 5 are theresult of elimination of methanol from the substrate to give the imine followedby addition of R1Li to the latter. Reagents where R2, R2 is H, Me or Me, Medo not react. A single-electron-transfer process involving a nitrogen radical has
10 ORGANIC REACTIONS
been proposed,85 but no cyclized product is formed when R3 is a dimethylvinylgroup.
BnNOMe
R3
R2 R2R1Li, –78°, 3 h
rt, 1-2 dBn
NH
R3
R2 R2
+R1
5
R1
n-Bus-But-But-Bu
BnNR1
R3
R2 R2
R2
HHHH
R3
PhPhPhCH=CMe2
4
4(5%)
(47%)(72%)(67%)
5(5%)(5%)(5%)(—)
(Eq. 10)
Silyl ketene acetals are aminated by the ethoxycarbonylnitrene precursorEtO2CN(TMS)OTMS to give α-ethoxycarbonylamino esters via aziridines in fairto good yields (see Eq. 124).105
O-Acyl Hydroxylamines. O-Acyl N-unsubstituted hydroxylamines have beenused occasionally in the amination of enolates.79,106 In the amination of thesodium salt of diethyl phenylmalonate, O-(4-nitrobenzoyl)hydroxylamine issomewhat more efficient than (4-MeOC6H4)2P(O)ONH2 (99% vs 92% yields).106
This reagent also gives the highest yield in the N-amination of oxazolidinoneanions.107 A series of N,N-disubstituted O-benzoylhydroxylamines is used in theamination of alkyl- and arylzinc chlorides in the presence of a catalytic amountof (Ph3P)2NiCl2108 and of dialkyl-, diaryl-, and di(heteroaryl)zinc reagents inthe presence of a catalytic amount of a copper(II) salt (see Eq. 36).109 – 112 Thedisubstituted zinc reagents may be prepared in situ by reaction of Grignardreagents with a catalytic amount of zinc chloride because transmetalation isfaster than the reaction of the Grignard reagent with O-benzoylhydroxylamine.Functional groups on the aryl ring, such as NO2, CO2R, and CN are toleratedand 0.6 equivalent of the disubstituted zinc reagent may be employed with aslight reduction of the yield. Arylmagnesium reagents may be aminated in thisway without the intervention of the corresponding zinc reagents.113 An SN2mechanism has been advanced.113
N-Unsubstituted O-Sulfonylhydroxylamines. The acidic nature of hydroxy-lamine O-sulfonic acid makes it essentially useless in electrophilic aminations ofcarbanions. One of the few exceptions is shown in Eq. 161. The explosive114,115
O-(mesitylenesulfonyl)hydroxylamine aminates alkylzirconium complexes (seeEqs. 41 and 51),116 acid dianions,115 and ester enolates.117 O-Arenesulfonylhy-droxylamines with no ortho substituents are thermally unstable at room tempe-rature.11
N-Monosubstituted O-Sulfonylhydroxylamines. N -Ethoxycarbonyl-O-(p-tol-uenesulfonyl)hydroxylamine (6) is used in the amination of enamines.118,119
The more reactive N -ethoxycarbonyl-O-(4-nitrobenzenesulfonyl)hydroxylamine
ELECTROPHILIC AMINATION OF CARBANIONS 11
(7) aminates enamines120,121 and enol ethers122 derived from ketones (seeEq. 96), as well as metalloimines,123 enolates of β-dicarbonyl compounds,124
and enamines derived from β-dicarbonyl compounds.125 The lithium saltof N -(tert-butoxycarbonyl)-O-(p-toluenesulfonyl)hydroxylamine (8) aminatesalkyl- and aryllithium and -copper reagents (see Eq. 69),126 – 128 estersand N -acyloxazolidinone enolates,126 and α-alkylphosphonamides.129 Theallyloxycarbonyl analogs 10 and 11 are similarly used.130 The structure ofthe mesityl analog 9 (dimer, crystallizing with three molecules of THF) hasbeen determined by single crystal X-ray crystallography.131 Because this classof reagents offers a much better leaving group, the possibility exists thatthe nitrenoids lose the elements of ArSO3M to give nitrenes NCO2R.60 Theinvolvement of these reactive intermediates has been proposed in a number ofexamples.
6 R = Me7 R = O2N
10 R = Me11 R = 4-MeC6H4
8 R1 = Me R2 = H9 R1, R2 = Me
R
O2S
O
LiN O
O
O2S
O
R2
R1 R2R
O2S
O
HN
CO2EtLiN
CO2Bu-t
N,N-Disubstituted O-Sulfonylhydroxylamines. Compounds of typeR1SO2ON(R2)2 (R1 = Me, Ph, p-tolyl, mesityl; R2 = Me, Et) are versatile ami-nating reagents for a wide variety of substrates: aliphatic (see Eq. 35),132,133
allylic,133,134 olefinic (see Eq. 56),133 acetylenic (see Eq. 60),135 benzylic(see Eq. 53),133,136 and aromatic132,133 metal derivatives and enolates (seeEq. 89).133,134 Reactions of MeSO2ONMe2 (and probably other similar reagents)with RMgI should be avoided because iodide reduces the reagent.137 Both anelectron-transfer and an SN2-type substitution mechanism have been consideredfor these transformations.136
O-Phosphinoylhydroxylamines. The non-explosive138 O-diphenylphosphi-noylhydroxylamine, Ph2P(O)ONH2, aminates alkyl,139,140 aryl,139 ethynyl (seeEq. 60),135 cyanomethyl, and phosphinoylmethyl (see Eq. 152)95,141 metalderivatives and enolates of esters,139,142 lactams (see Eq. 137),143 α,β-unsaturatedcarbonyl compounds (see Eq. 153),144 and β-dicarbonyl compounds.139
The equally stable methoxy analog (4-MeOC6H4)2P(O)ONH2 has beenrecommended106 as a better reagent because of its increased solubility in organicsolvents at low temperatures but there is a report of a low yield and formation ofa hydroxylation product in the amination of a malonic ester enolate.145 Aminationwith the disubstituted analog Ph2P(O)ONMe2
146 and the chiral, non-racemiccyclic derivative 12 (see Eqs. 109 and 143)147 has also been reported. Thereappear to be no mechanistic studies of these reagents but it is relevant thatequimolar amounts of the substrate and the reagent or a slight excess of the latterare usually employed.
12 ORGANIC REACTIONS
NMe
POPh
ONMe2
12
O
HN
13a
ONCOY
ArY = t-Bu, NEt2, (–)-menthoxide
14
O
Oxaziridines. The readily synthesized 1-oxa-2-azaspiro[2,5]octane (13a)148
aminates12 enolates of β-dicarbonyl compounds,149,150 α-cyano carbonylcompounds,149,150 and anions derived from cyanomethyl derivatives furtheractivated by aryl or heteroaryl groups.150 The products are either amines, N -cyclohexylidene derivatives, or more complex structures (see Eq. 162). Thecamphor-derived oxaziridine 13b aminates enolates of esters, β-dicarbonyl andα-cyano carbonyl compounds,151 and anions derived from various cyanomethylcompounds.151 Esters are aminated only if they carry an additional aryl group.151
The products resulting from β-dicarbonyl and α-cyano carbonyl compounds arecamphorimines that have lost the ester group by hydrolysis and decarboxylation.Camphorimines derived from aminations of esters retain the ester group. Thecyano group in all substrates is converted into an amide group and the mechanismshown in Eq. 11 has been proposed. The first step is analogous to that of themechanistically fairly well-established hydroxylation of enolates with N -sulfonyloxaziridines152 except that attack by the anion is on nitrogen rather than oxygen.When R is methyl or ethyl, only rearrangement products of the aminating reagentare isolated.151
13bO
NHR
CNO–
HN
R
N
ONH
R
N–
N–O
NHR
NO
NH2
R
H2O
–
R = CH=CH2, Ar (45-80%)
R = Me, Et (0%)
(Eq. 11)
Oxaziridines 14 transfer the NCOY group to enolates of ketones (seeEq. 90),153 – 156 esters (see Eq. 110),153,155,157,158 amides,158 N -acyloxazolidino-nes,153,157 and β-dicarbonyl compounds,155 anions stabilized by cyano (seeEq. 141),155 sulfonyl (see Eq. 145),158 and phosphinoyl154 groups, and ketoneenol ethers.155 Yields are in the 20–60% range. The first step in these reactions ispresumably attack of the enolate on nitrogen as in Eq. 11, followed by eliminationof an aldehyde ArCHO and formation of the amination product. With esters,
ELECTROPHILIC AMINATION OF CARBANIONS 13
the aldehyde may undergo an aldol reaction with the substrate enolate whenLiHMDS, KHMDS, LDA, or t-BuLi are used as the bases to generate theenolates. This undesired side reaction is not observed with NaHMDS providedthat two equivalents of the reagent are used, but yields are low.155
Imines. Organometallic compounds normally attack imines at the carbonatom. Predominant or exclusive attack on nitrogen may be forced by attachingone or two electron-withdrawing groups to the imine carbon atom.159 – 167 Inthe examples of Eq. 12161 involving a substrate with a fairly bulky group onnitrogen, the ratios of product 15 to 16 demonstrate that only the tert-butyl andallyl Grignard reagents attack on carbon, the former presumably for steric reasons.All cadmium reagents RCdX tested (R = Me, n-Pr, i-Pr, Bn) add normally oncarbon.
N CO2R1
PhH
R2MX (X not specified)
Et2O
R1 =
NR2
CO2R1
PhH
NH
CO2R1
PhH
R2
+
15 16
MMgMgMgMgMgMgMgCd
15 + 16(45-55%)(44-55%)(44-55%)(45-55%)(45-55%)(45-55%)(45-55%)(55-70%)
15:1695:596:4
60:400:10096:4
0:100100:00:100
R2
Etn-Pri-PrCH2CH=CH2
i-But-BuBnBn
(Eq. 12)
A second method of favoring attack on nitrogen involves systems where theimine carbon is surrounded by fairly bulky substituents and where placing anegative charge on this carbon is favored by formation of a cyclopentadienylanion (Eq. 13).168 A phenyl group on nitrogen reverses this trend, with product18 now predominating over 17.
NR1
R2Li, THF, hexane
–78°, 2 h; to rt
R1R2N H R1NH R2
+
R1
Men-BuPh
R2
n-BuEtn-Bu
17(71%)(65%)(15%)
17 18
18(0%)(5%)(50%)
(Eq. 13)
Attack of isopropylmagnesium bromide on the hindered imine in Eq. 14 sur-prisingly occurs on nitrogen whereas the less bulky ethylmagnesium bromide addsto the carbonyl group.169 Organozinc reagents react with anthranil under Ni(acac)2
catalysis to give α-aminobenzaldehyde derivatives by a proposed single-electron
14 ORGANIC REACTIONS
transfer mechanism (Eq. 15).170 Diethyl zinc adds to 1,4-diaza-1,3-butadienes ina net 1,4-fashion (Eq. 16).171
HN O
t-Bu
t-Bu
i-PrNH O
t-Bu
t-Bu
i-PrMgBr, Et2O
(35%)
(Eq. 14)
RZnCl +N
ONi(acac)2, THF, 0° to rt, 2 h CHO
NHRR = Me, 2-thienyl, Ph, 2-, 3-, and 4-MeOC6H4
(4-86%)
(Eq. 15)
NN
Bu-tt-Bu Et2Zn, toluene
–70° NBu-t
ZnEt2
Bu-tN –50°
NBu-t
ZnEtN
t-Bu Et
t-BuOH, pentane, rtN NHBu-t
t-BuEt N NBu-t
t-BuEt+
(76%) (12%)
(Eq. 16)
(N -Arenesulfonylimino)phenyliodinanes. [N -(p-tolylsulfonyl)imino]phe-nyliodinane (TsN=IPh) and its pentafluoro analog C6F5SO2N=IPh react read-ily on warming in acetonitrile with silyl enol ethers derived from acetophe-nones to give the α-tosylamino derivatives in high yields. The reaction isless efficient in methylene chloride, gives low yields with the trimethylsilylether of 3-pentanone and with 1-trimethylsilyloxybutadiene, and fails com-pletely with 1-trimethylsilyloxycyclohexene and a ketene acetal, 1-phenoxy-1-(trimethylsilyloxy)ethylene.172 The latter two types of substrates do reactwhen a copper catalyst is employed, but yields do not exceed 50% (see alsoEq. 92).173 With chiral (ligand 19 or 20) copper catalysts, modest to fair enan-tiomeric excesses are achieved (Eq. 17).174 The proposed mechanism involves aslightly favored front-side attack of the enol derivative on the initially formedligand–copper nitrene complex with formation of an aziridine, which is con-verted directly into the α-tosylamino product during isolation when methyl ortrimethylsilyl enol ethers are used.
Ph
AcO+ TsN=IPh
[Cu(MeCN)4]PF6, 19 or 20
CH2Cl2, –40° Ph
AcONTs
HCl, MeOH
PhNHTs
O
Ligand1920
Conversion a
(>95%)(61%)
ee28% R52% RN N
Ar Ar19 Ar = C6H3Cl2-2,6
N
O
N
O
Ph Ph20
a based on TsN=IPh reacted
(Eq. 17)
ELECTROPHILIC AMINATION OF CARBANIONS 15
Oximes. Reaction of alkyl- or arylmagnesium reagents with two equivalentsof acetone oxime in toluene gives alkyl or arylamines, respectively, in low yields.The yields are improved by converting the oxime into the salt with ethylmagne-sium halide followed by addition of the desired Grignard reagent. A mechanisminvolving a four-membered cyclic transition state is postulated (Eq. 18).174a Sim-ilar reactions with the lithium salt or methyl ether of benzaldoxime have alsobeen reported.175 Among the O-sulfonyloxime derivatives 21176 – 178 (see Eq. 61),22178,179 (see Eq. 40), 23,180 24,181 and 25,181,182 the dioxolane 25b combinesthe advantages of high product yields in reactions with alkyl-, vinyl-, aryl-, andheteroarylmagnesium reagents with ease of hydrolysis of the initially formedimine to the amine (see Eq. 37).182 Reactions with other types of anions donot seem to have been investigated except that phenolates (Eq. 176) and eno-lates of β-dicarbonyl (Eq. 175) and α-sulfonyl carbonyl compounds undergo anintramolecular version of this amination reaction. The mechanism is believed toinvolve direct SN2 substitution on the sp2 nitrogen of the oxime13,183 rather thanaddition/elimination or electron transfer.
EtMgX Ph(CH2)2MgX (2 eq)
N
CH2
MgX
MgXO
Bn
NOH NO– MgX+
N
Ph
H2N
Ph
(48%)
(Eq. 18)
NR OSO2C6H2Me3-2,4,6
21 R = Me, Ph
N
PhPh
PhPh23
EtO
EtON
OTs
OSO2Ph
Z
YN
OSO2Ph
24
25a25b25c25d25e
YOONMeONMe
ZOOONMeNMe
R1
R1
R1
R1
R1
HMeHHH
NAr
Ar OSO2R
22 Ar = Ph, 4-CF3C6H4, 3,5-(CF3)2C6H3
R = Me, 4-MeC6H4
Diazonium Salts. Diazonium salts are potentially explosive. See the caution-ary note in Experimental Conditions. Aryldiazonium salts 26 react with alkyl- andarylmagnesium reagents,184 – 191 arylzinc,190,192,193 and aryltin reagents194 to giveazo compounds. Yields vary considerably; the best are achieved with the diazo-nium salt 26e191 (see Eq. 48). Aryldiazonium salts also react with enolates, enolderivatives, or enamines of aldehydes (see Eq. 85),195 ketones (see Eq. 95),185
and with silyl ketene acetals (see Eq. 121).196,197
16 ORGANIC REACTIONS
ArN2+ X–
26a26b26c26d
26e X =SO2
N
O2S
XClZnCl3BF4
Zn(BF4)Cl2
Diazo Compounds.198 Alkyl- and arylmagnesium199 – 204 and alkyllithiumreagents205 add to diazo compounds in a little-used reaction to give hydrazones.Diazo compounds add to enolates to give azines.206 With enamines, diazo com-pounds give hydrazones of α-diketones.207
Azo Compounds. Alkyl Azo Compounds. The only aminations with alkylazo compounds found in the literature involve the cyclic derivatives 27,208 28,209
and 29.210 Reaction of 29 with phenyllithium followed by in situ arylation of theanion (Eq. 19)210 is one of the few examples of tandem reactions in aminationsreported thus far. Azo compounds 27 add to cyclohexyl- and phenylmagnesiumreagents at −78◦ with fair to excellent yields,208 and the bicyclic azo compound28 gives an adduct with t-BuLi at −78◦ in almost quantitative yield.209 Reliefof strain no doubt is one of the driving forces for these reactions but the lowtemperatures involved may indicate that they could be extended to acyclic alkylazo compounds.
NNR
R
R, RMe, Men-Pr, n-Pr—(CH2)5—27
NN
28
NN
29
1. PhLi, MeO(CH2)2OMe, Et2O, –35° to –20°
NC6H4NO2-4
NPh
(34%)
2. 4-FC6H4NO2, –20° to rt (Eq. 19)
Aryl Azo Compounds. Alkyl- (including tert-butyl) and aryllithium reagentsadd to azo benzene to give trisubstituted hydrazines in fair to excellent yields(see Eqs. 44 and 45); alkylation of the intermediate anion in situ leads to tetra-substituted hydrazines.211 Benzyl and heteroarylmethyl (see Eq. 54) anions andthe enolate of phenylacetamide add to azo benzene in fair to excellent yields.212
Aromatic Grignard reagents are reported to reduce azo benzene and its deriva-tives to the hydrazo compounds (cf. also Eq. 20).213 The only other aryl azocompound investigated in aminations appears to be benzo[c]cinnoline.214
Esters of Azodicarboxylic Acid. These compounds are versatile aminatingreagents for alkyl- (see Eq. 46), allenyl- (see Eq. 59), aryl- and heteroarylmetal(see Eq. 75) derivatives, and especially enolates (see Eqs. 87, 88, 115–117, and
ELECTROPHILIC AMINATION OF CARBANIONS 17
119) and metalloimines (see Eqs. 104–106). An important new reaction involvesaddition of azo esters to alkenes,215 dienes,216 and enynes216 in the presence ofsilanes catalyzed by cobalt and manganese complexes to give the more highlysubstituted hydrazino esters (see Eqs. 49, 52, and 55). Based on preliminarymechanistic studies of this hydrohydrazination reaction, rate-limiting addition ofa metal hydride species to the double bond is followed by a fast amination step.215
Benzyl and tert-butyl esters are widely used because of their ready conver-sion into the hydrazines after the amination step and the presence of an aromaticchromophore in the former. Addition of the organometallic species to the estercarbonyl group does not appear to be a problem, although tert-butyl esters oftenprovide higher yields. Formation of substantial amounts of an α,β-unsaturatedcarbonyl compound by elimination of the hydrazino ester from the desired prod-uct has been reported in the reaction of dibenzyl azodicarboxylate with the enolateof a sugar ketone.217 Esters derived from azodicarboxylic acid and chiral alcoholshave been prepared218,219 and a chiral amide has been used in the amination of anachiral enolate (see Eq. 134).219 The failure of a secondary Grignard reagent toadd to diisopropyl azodicarboxylate is shown in Eq. 20.220 The asymmetric ami-nation of aldehydes (see Eqs. 76 and 77)221 – 227 and ketones (see Eq. 91)228,229 byazo esters is catalyzed by proline and its derivatives. The proposed mechanisminvolving a hydrogen bond from the catalyst to the N=N double bond in the tran-sition structure is shown in Eq. 21221 (see also ref. 224). The amination of β-ketoesters by azo esters proceeds at room temperature neat or in polar solvents suchas alcohols230,231 or, as with β-aminocrotonic ester, even in petroleum ether.230
The former reaction may be carried out enantioselectively with catalysts such ascinchona alkaloids (see Eq. 163),231,232 chiral urea and thiourea derivatives,233
chiral copper(bis)oxazoline complexes234 (see Eqs. 103, 151, and 164),235 – 237
and chiral palladium BINAP complexes (see Eqs. 150 and 165).238,239
PhMgCl
Ph
(82%)(82%)
i-PrO2CN
NCO2Pr-i+ i-PrO2C
HN
NH
CO2Pr-i+
(Eq. 20)
R1 CHONH
CO2HN CO2H
OH–N CO2H
R1 R1
R2O2CN=NCO2R2
N CO2–
NH
CO2H+N
R1
O
OHN
N
R2O2C
CO2R2R1 N
H
NHCO2R2
CO2R2
CHO
R1 N
H
NHCO2R2
CO2R2
(Eq. 21)
18 ORGANIC REACTIONS
Azo esters also aminate enol ethers (see Eq. 82),240 – 245 enamines (seeEq. 147),118,246 – 250 ketene acetals (see Eqs. 112 and 113),251 ketene aminals (seeEqs. 125 and 126),251,252 and ketene thioacetals.253
Other Acyl Azo Compounds. Various azo derivatives [R1N=NCOR2: R1 =aryl, R2 = CO2R, CONR2, or COAryl; and R1CON=NCOR2: R1 = R3O, (R3)2 N,Ar, R2 = (R3)2N, Ar] have been used as aminating agents. The site selectivityis governed by the degree to which a substituent stabilizes the negative chargeon nitrogen, which increases in the order Aryl < CONR2 < CO2R < COAr.N -Phenyltriazolinedione has been used to aminate acetone254 and a silyl enolether.245
Sulfonyl Azo Compounds. Aryl and cyclopropyl Grignard reagents add toArN=NTs to give diaryl or cyclopropylarylamines after allylation and reduction(Eq. 22).255 For a similar reaction involving organozinc reagents see Eq. 38.
Ar1Ii-PrMgCl, THF
–20°Ar1MgI
1. Ar2N=NTs, THF, –20°
2. ICH2CH=CH2, N-methylpyrrolidinone, rt, 2 h
Ar1
NN
Ar2
Ts1. Remove solvents
2. Zn, HOAc, CF3CO2H, 75°Ar1NHAr2
(63-86%)
(Eq. 22)
Azides. Alkyl Azides. A variety of alkyl azides react with alkyl- and aryl-metal species to give triazenes (Eq. 23) (see cautionary note with regard to bothazides and triazenes in Experimental Conditions): methyl azide,256 – 258 ethylazide,258 isopropyl azide,259 n-butyl azide,260 – 262 cyclopropylmethyl azide,262
allyl azide,263 trimethylsilylmethyl azide,264 – 267 a protected 2-hydroxyethylazide,268 n-hexyl and cyclohexyl azide,269 benzyl azide,261,269,270 and polymethy-lene diazides N3(CH2)nN3 (n = 2,3).271,272 Protolysis of the intermediate metalsalts of the triazenes may give rise to two different triazenes (Eq. 23) and theirstructures have not always been determined with certainty. The product of thereaction of benzyl azide with phenylmagnesium bromide is identical to thatobtained from phenyl azide and benzylmagnesium chloride and was assignedstructure 30 with the extended conjugation (Eq. 24)270 on the basis of the prod-uct obtained with phenyl cyanate. Protolysis of triazene 30 with 1 N HCl givesaniline hydrochloride and benzyl chloride (Eq. 24);270 similarly, N -methyl- andN -ethyl-N ′-phenyltriazenes, on treatment with HCl, give aniline hydrochlorideand methyl or ethyl chloride, respectively.270 The intermediate triazenes obtainedfrom trimethylsilylmethyl azide and aryllithium or arylmagnesium reagents de-compose to arylamines on aqueous workup.264 Triazenes are also not isolatedfrom the reaction of allylindium species, generated in situ from the bromides andindium metal, with alkyl and aryl azides in DMF; however, N -alkyl and N -arylallylamines, respectively, are obtained (Eq. 25).269 This example appears to beone of only two instances where, in a reaction of an organometallic species withan azide, both substituents on the intermediate triazene appear in the product. Theother is the addition of alkylmagnesium species to aryl azides mentioned below.
ELECTROPHILIC AMINATION OF CARBANIONS 19
By contrast, allyl azide, and aryllithium or arylmagnesium species react to givearylamines after acidic workup (Eq. 26).263 The triazene intermediate should bethe same, except for the counter ion and the solvent, as the one in Eq. 25. Noexplanation for these differing results has been advanced.
R1M + R2N3H2O R1
NH
NN
R2 R1
NN
NH
R2
and/orNN
NR1 R2 M+
(Eq. 23)
BnMgCl + PhN3
PhMgBr + BnN3
HClBnCl + PhNH3
+ Cl– + N2(—) (—)
30 ("good yield")
BnNH
NN
Ph(Eq. 24)
N3Br+
In, NaI, DMF
rt, 2 h
NN
N NH4Cl
H2O
HN
(90%)
N
(5-8%)
+
(Eq. 25)
MgBrN3+
Et2O
–78° to rt
H3O+ NH2
(83%)
NN
N
(Eq. 26)
Both N ,N ′-di(n-butyl) and N ,N ′-di(cyclopropylmethyl)triazenes react differ-ently with dilute HCl (0.1% in acetone) to give nitrogen gas and nitrogen-freeproducts (n-BuOH, s-BuOH, 1-butene, and 2-butene with the former triazene)via alkyldiazonium species.262
Reaction of the α-heteroatom-substituted azides 31 and 32 with 2-phenethyl-magnesium bromide proceeds with equal rates at −78◦; analog 33 only reacts at0◦, whereas both azides 34 and 35 are essentially unreactive at this temperature.273
Both aliphatic (see Eq. 40) and aromatic Grignard reagents, but not aromaticlithium reagents, may be used with azide 32, which has a low steric requirement asevidenced by its reaction with the exo and endo isomers of 2-norbornylmagnesiumbromide at about equal rates274 (see also Eq. 39).
31 R = MeO
32 R = H
TMSO N3
i-Pr
33 3435
MeS N3 MeO N3S
R
N3
Hydrolysis of the triazenes so obtained from aromatic Grignard reagents togive aromatic amines may be carried out with either aqueous formic acid or
20 ORGANIC REACTIONS
aqueous potassium hydroxide.275 Triazene anions derived from aliphatic Grignardreagents are quenched with acetic anhydride (or benzoyl chloride) and the acetates36 are then converted into the aliphatic amines using the conditions shown inEq. 27.273 The scope of this method is somewhat limited, however: the unstabletriazenes, obtained in almost quantitative yields from tert-butylmagnesium chlo-ride and n-octylmagnesium bromide, could not be converted into the amines andquenching the triazene anion obtained from azide 32 and 1-octenylmagnesiumbromide with acetic anhydride gives the regioisomer of acetate 36, which isunsuitable for further manipulation.274 The 2-anions of furan, thiophene, N -methylpyrrole, and N -methylindole do not react with azide 32.274
MgBr+Ac2O
–60° to –30°, 1.5 h
RNAc
NN SPh
n-Bu4NH+ HCO2–, DMF, 45°
or: KOH, Me2SO, 0°RNH2
36
RN
NN
CH2SPh
(Eq. 27)
Azide 32 aminates ester enolates (see Eq. 114)275 and a sugar-derived azideaminates the anion derived from cyanoacetamide276 (see Eq. 167).
Vinyl Azides. Vinyl azides such as 37 or 38 react with alkyl-, aryl-, andheteroaryllithium reagents like other azides to give the corresponding triazenes.Hydrolysis of the latter leads to nitrogen-free carbonyl compounds when aliphaticlithium reagents are used (path A, Eq. 28),277 but when benzyl, aromatic, andheteroaromatic lithium reagents are used, amines are formed in fair to good yields(path B).278
Ph
N3 N3
Bu-t37
1. RLi, THF –78°
2. H2OR N
N NH
Bu-t
HClA
BRNH2
38 (45-70%)
t-Bu CHO
R
or
(Eq. 28)
Aryl Azides. The triazenes formed by addition of alkylmagnesium halidesto aryl azides lose nitrogen and give N -alkylaniline derivatives on workup withaqueous ammonium chloride (Eq. 29).279 This is unusual in two respects: earlierreports270,280 – 283 state that triazenes are isolated under these conditions (see alsoEq. 58) and that anilines, rather than N -alkylanilines, are formed on treatmentwith acid at room temperature (see discussion under Alkyl Azides, above).
F
N3 c-C6H11MgBr
Et2O, rt, 1 h
NH4Cl, H2O
F
NHC6H11-c
(85%)
F
NC6H11-c
MgBr+
– N2NN
NC6H11-c
F
MgBr+–
(Eq. 29)
ELECTROPHILIC AMINATION OF CARBANIONS 21
Aromatic Grignard reagents react normally with aryl azides to givetriazenes280,281,284,285 as do vinylmagnesium halides.286 – 288 Grignard reagentsalso add to a variety of aromatic diazides to give the correspondingbis(triazenes).272,289,290 Phenylmagnesium bromide adds preferentially to anazide group in the presence of a diaryl azo group.290 Addition of N-protectedimidazole anions to phenyl azide gives the corresponding 2-amino derivativesafter acid hydrolysis.66 Addition of phenyl azide to ketene dimethyl acetalsand decomposition of the intermediate triazolines gives α-anilino esters in lowyields.291 The formation of diazomalonamide in addition to aniline from theenolate of malonamide and phenyl azide is the earliest example of a diazotransfer reaction.292 Aryl azides undergo net reduction to arylamines and N -formyl arylamines on reaction with the enolate of acetaldehyde.293
Acyl Azides. The only additions of a Grignard reagent to acyl azides appear tobe those of phenylmagnesium bromide to carbonyl azide (N3CON3) and methyland ethyl azidoformates (N3CO2R) to give triazenes in low or unstated yieldswith retention of the carbonyl group.284 However, the same Grignard reagentreacts faster with the carbonyl than the azide group in azido acetone.294 Ethyland tert-butyl azidoformates aminate tetrahydropyrans,295 ketone silyl enol ethers(see Eq. 98),296,297 ketene acetals,298 – 301 and enamines.302,303 A camphorsulfone-derived acyl azide has also been used.304 Either irradiation or thermolysis or acombination of the two is used and the reactions proceed either via the triazolineand aziridine or directly via the latter. Yields vary widely from poor to good.
Sulfonyl Azides. Alkyl- and arylmagnesium halides,305,306 as well as alkyl-307,aryl- (see Eq. 70),308 – 312 and heteroaryllithium313 reagents add to sulfonyl azidesto give triazene salts which may be reduced to amines 305,310 – 312 or convertedinto azides. The latter reaction has been accomplished by an aqueous workup withthe highly hindered 2,6-dimesitylphenyl azide,314 whereas quenching with aque-ous potassium hydroxide (see Eq. 72)305,315 sodium bicarbonate,313 or sodiumpyrophosphate305,316 (see Eqs. 67 and 74) is necessary with other arenesulfonylazide adducts. Thermolysis of the dry triazene salts also leads to azides,307,308
but because of the hazards involved, this procedure is not recommended.Azidations of certain phosphorus-stabilized anions with 2,4,6-triisopropylben-
zenesulfonyl azide (“trisyl azide,” 41a) may be reversible.317
The most widely used application of sulfonyl azides is in the azidation ofenolates and other stabilized carbanions. The main challenge here is the avoid-ance of the diazo transfer reaction, which leads to diazo compounds and thusmakes a diastereoselective amination impossible. Addition of the enolates to thesulfonyl azide proceeds rapidly at low temperatures (−78◦ or lower) to give themesomeric ion 42 (Eq. 30).318 Reagents 41, the counter ion M+, the solvent,and the quenching reagent all influence the subsequent partition between azideand diazo compound. For enolates of esters (39) and N -acyloxazolidinones (40)the preferred reagent is trisyl azide (41a); 4-nitrobenzenesulfonyl azide (41c)promotes diazo transfer, and tosyl azide (41b) usually leads to mixtures of thetwo types of products. For ester enolates 39, either lithium or potassium as the
22 ORGANIC REACTIONS
counter ion in combination with trisyl azide favors azidation (see Eqs. 118, 120,122, and 123), whereas for N -acyloxazolidinone enolates 40 the potassium eno-lates are usually employed. Diazidation may occur with ester enolates (but notwith N -acyloxazolidinone enolates) as a consequence of proton transfer from theinitial adduct 42 to the enolate 39 (see Eq. 122); it can be avoided or minimizedby use of the lithium enolate or by inverse addition of the enolate to the sulfonylazide. Quenching agents are added after short reaction times (about one minute).Acetic acid is the reagent of choice for azidation, whereas trifluoroacetic acidpromotes diazo transfer.318 In the triethylamine-promoted reaction of a β-ketoester with trisyl azide, use of THF or acetonitrile as the solvent leads to the azideexclusively, whereas in methylene chloride only diazo transfer and other prod-ucts are formed.319 The use of TMSCl as the quenching agent gives considerablyhigher yields than acetic acid in the azidation of a lactone enolate.320 The reasonsfor the above experimental observations do not appear to be clear. In the azida-tion of cyclic β-keto esters, where trisyl azide also promotes azidation,319,321 thebulky and less electrophilic trisyl azide may inhibit formation of the triazolineprecursor to the diazo compound. However, trisyl azide is the only reagent thatpromotes diazo transfer to a number of simple ketone enolates, which do not nor-mally react with sulfonyl azides.322 – 324 One of the few exceptions is the azidationof a taxane-derived ketone enolate where reaction with tosyl azide followed byquenching with acetic acid gives the diazo compound, whereas quenching withaqueous ammonium chloride leads to the azide.325 In another example, a lactonelithium enolate reacts with 4-nitrobenzenesulfonyl azide (41c) to give exclu-sively the azide.326 These examples underscore the fact that exceptions exist tothe above-mentioned rules. Other factors that affect yields and azide/diazo com-pound partitioning in specific reactions are discussed in the relevant sections ofScope and Limitations. A reaction in which the N -arenesulfonylamide rather thanthe azide is obtained on quenching with aqueous ammonium chloride is shownin Eq. 106.327
R1
R2
O–M+
39 R2 = OR3
40 R2 = ON
O
R4
ArSO2N3
R1
R2
O
NNN
SO2Ar41a Ar = 2,4,6-(i-Pr)3C6H2
41b Ar = 4-MeC6H4
41c Ar = 4-O2NC6H4
R1
R2
O
NNN
SO2ArM+ M+
42
R1
R2
O
N3
R1
R2
O
N2
A
B
+ ArSO2H
+ ArSO2NH2
quench
(Eq. 30)
ELECTROPHILIC AMINATION OF CARBANIONS 23
Trifluoromethanesulfonyl azide, prepared in situ from trifluoromethanesulfonylchloride and sodium azide in dimethylformamide, is reported to azidate phospho-noacetic esters and β-dicarbonyl compounds in the presence of triethylamine,309
whereas the same, but preformed, reagent gives the diazo compounds with α-nitro328 and α-cyano329 carbonyl compounds in the presence of pyridine. Thereason for this dichotomy is not clear but because the former reaction was car-ried out under typical diazo transfer conditions the products may have beenmisidentified.330
Sodium Azide/Ammonium Cerium(IV) Nitrate. Silyl enol ethers give α-azidoketones on treament with sodium azide and anhydrous ammonium cerium(IV)nitrate in anhydrous acetonitrile (see Eq. 97).297,325,331 With a glycal, the 2-azido-1-hydroxy nitrate derivative is formed.332 Low yields due to hydrolysis of the silylenol ether may be improved by use of the triisopropylsilyl (TIPS) derivatives,331
although with a sterically encumbered taxane-derived enol ether the TMS deriva-tive gives higher yields than the TIPS derivative.325 The mechanism is believedto involve addition of an azide radical to the double bond.
Diphenyl Phosphorazidate. (PhO)2P(O)N3, reacts with aromatic Grignardand lithium reagents to give aromatic amines after in situ reduction of the initiallyformed triazene salt.333,334 Reaction of a lithiated poly(phenylsulfone) with thisreagent is not as clean as the corresponding reaction with tosyl azide.335 Addi-tion of lithium amide enolates to (PhO)2P(O)N3 at low temperature and trappingthe triazene salt with di-tert-butyl dicarbonate gives protected α-amino amides inhigh yields (Eq. 31).336 When the initial addition is carried out at 0◦, the α-diazoamides are formed exclusively.337 Similarly, reaction of (PhO)2P(O)N3 with anester enolate gives exclusively the diazo ester whereas azidation only occurs withtrisyl azide.338
RN(Me)Ph
O
NNN
(PhO)2PO– Li+
RN(Me)Ph
O
N– Li+NN
(PhO)2P
(t-BuO2C)2O
–78°
RN(Me)Ph
O
NCO2Bu-tNN
(PhO)2P
RN(Me)Ph
O
NCO2Bu-tNN
(PhO)2POHO H
H2O RN(Me)Ph
O
NHCO2Bu-t
OO(Eq. 31)
Miscellaneous Azides. Ethyl (N -methanesulfonyl)azidoformimidate[N3C (OEt)=NSO2Me] has been used to aminate chiral cyclopentanone enaminesbut the yields are low and the reaction could not be extended to the correspond-ing cyclohexanone enamines.303 Trimethylsilyl azide (TMSN3) transfers the TMSrather than the azide group to a lactam enolate.339
24 ORGANIC REACTIONS
Miscellaneous Reagents. Chloramine-T/Osmium Tetroxide. The Sharplessasymmetric aminohydroxylation system for olefins (4-MeC6H4SO2N(Na)Cl/OsO4/cinchona alkaloid derived catalysts)340,341 converts silyl enol ethers intoα-(p-tosylamino) ketones in 34–40% yield and 76–92% ee (see Eq. 99).342
N-Chlorocarbamate/Chromium(II) Chloride. Enol ethers (see Eq. 80) andglycals (see Eq. 84) react with N-chlorocarbamates in the presence of chromouschloride to produce α-amino carbonyl derivatives.343 Trimethylsilyl enol ethersgive low yields because of their ease of hydrolysis. A radical chain mechanismhas been proposed with the N-haloamide acting as the transfer agent (Eq. 32).344
OR1
R2R4
R3
ClNHCOR5 + CrCl2 NHCOR5 + CrCl3
NHCOR5 +OR1
R2R4
R3
R5CONH
OR1
R2R4
R3
R5CONH ClNHCOR5+OR1
R2R4
R3
R5CONH Cl NHCOR5+
R2R4
R3
R5CONHOOR1
R2R4
R3
R5CONH ClH3O+
(Eq. 32)
Bis[N-(p-Toluenesulfonyl)]selenodiimide. The reagent obtained from thereaction of chloramine-T with selenium metal, proposed to have structureTsN=Se=NTs, reacts with TIPS enol ethers in an ene-like reaction to give thecorresponding α-tosylamino enol ethers (see Eq. 100).345 – 349
Nitridomanganese Complexes. Stoichiometric amounts of chiral complexesof type 43 react with silyl enol ethers in the presence of trifluoroacetic orp-toluenesulfonic anhydride to give α-(N -trifluroacetyl)amino- and α-(N -p-tosylamino) ketones, respectively (see Eq. 160).350 – 353 With glycals, the 1-hydroxy-2-(N -trifluoroacetyl)amino derivatives are formed (see Eq. 83).354 Amechanism involving approach of the enol ether from the least hindered sideof the 43•TFA complex has been proposed.353
N N
O O
R2
R1
R2
R1
R3R3
43
N
Mn
SCOPE AND LIMITATIONS
Amination of Aliphatic CarbanionsPreparation of Alkyl Amines. The main application of the electrophilic
amination of aliphatic carbanions is in the preparation of hindered amines. These
ELECTROPHILIC AMINATION OF CARBANIONS 25
are not usually accessible by nucleophilic displacement involving an alkyl halideand ammonia or an amine and have been prepared by alternate methods such asthe Curtius rearrangement or the Ritter reaction. Examples are shown in Eqs. 10,12, 33,52 34,355 35,133 36,112 37,182 and 38.356
t-BuCuMeLi +
NH21. Et2O, –20°, 2 h
2. O2, –20°
NHBu-t
(35%) (Eq. 33)
ClNH2, Et2O, sonication(67%)
Ph
PhPh Li
Ph
PhPh NH2 (Eq. 34)
Li2,4,6-Me3C6H2SO2ONMe2, Et2O
–10° to –15°; to rt, 15 h
NMe2
(54%) (Eq. 35)
(t-Bu)2Zn + Bn2NOBzTHF, (CuOTf)2•C6H6 (1 mol%)
15-60 mint-BuNBn2 (98%) (Eq. 36)
O O
NOSO2Ph
+1. Et2O, CH2Cl2, 0°, 30 min
2. HCl, EtOH, H2O, reflux, 10 hMgBr NH2(89%)
(Eq. 37)
Zn2
EtO2C
N=NTs
+1. THF, –20°, 30 min
2. RaNi, EtOH, reflux, 90 min NH
CO2Et
(50%)
(Eq. 38)
Preparation of N -alkylanilines from aliphatic Grignard reagents and aryl azideswas discussed previously (Eq. 29). The net insertion of a methylene groupbetween the alkyl or aryl group of an organolithium reagent and the nitrogenas part of an amination was also mentioned earlier (Eq. 6).
Both lithium and Grignard reagents are aminated with retention of configu-ration (Eqs. 39274 and 40220). On the other hand, preparation of an organozincreagent from a chiral, non-racemic bromide with highly reactive zinc, subse-quent amination with an azo ester, and reduction of the adduct gives the racemicamine; racemization is believed to have occurred during preparation of the zincreagent.357
NH2
H
1. t-BuLi (2 eq), pentane, –78°, 30 min; to rt2. PhSCH2N3, THF, pentane, –78°; to rt, 1.5 h
(45%)Br
H
H
H
H
H3. NH4Cl, H2O4. KOH, DMSO, rt, 1 h
(Eq. 39)
26 ORGANIC REACTIONS
PhS
Cl
PhNHAc
A: 1. [3,5-(CF3)2C6H3]2C=NOTs, toluene, Et2O, –70°, 10 d 2. Ac2O, Et3NB: 1. PhSCH2N3, THF, –78°, 1 h 2. Ac2O, –60° to –30° 3. KOH, DMSO, 0° to rt, 3 h
(25%) 90% ee
(82%) 92-95% ee
O
Cl
THF, –78° to –30° PhMgCl A or BEtMgCl (5 eq)
(Eq. 40)
Zirconium complexes, generated in situ by addition of HZrCp2Cl to alkenes,can be aminated with O-(mesitylenesulfonyl)hydroxylamine; an example isshown in Eq. 41.116 When the initial hydrozirconation is not regioselective, aswith styrene, mixtures of amines are formed. A reaction that permits aminationat the tertiary carbon in a similar substrate is discussed below (Eq. 49).
1. HZrCp2Cl (inverse addition), THF, rt
2. 2,4,6-Me3C6H2SO2ONH2, 0°, 10 minNH2
(88%) (Eq. 41)
Chiral ligands of type 44 may be prepared from chiral amines via ami-docuprates (Eq. 42).54
n-BuCu(CN)Li +1. THF, –40°, 15 min
2. O2, –78°, 20 min; to rt
NHLi NHBu-n
44 (60%)
(Eq. 42)
Preparation of Alkyl Hydrazines. As mentioned previously (Eq. 19), addi-tions of aliphatic carbanions to unactivated azo compounds are rare. Anotherexample is shown in Eq. 43.208 On the other hand, additions to diaryl azocompounds (Eq. 44)211 and esters of azodicarboxylic acids (Eq. 46)358 are welldocumented. The intermediate anion in Eq. 44 can be trapped with alkyl halidesto give tetrasubstituted hydrazines. An extension of the reaction of Eq. 44 exploitsthe ready displacement of the benzotriazole functionality by Grignard reagents(Eq. 45).359 Because of the instability of the intermediate 45, the Grignard reagentis added before the azobenzene in the actual experiments.
MgBr NN
+Et2O, 0° to rt, 1 h
HNN
(86%) (Eq. 43)
t-BuLi + PhN
NPh
hexane, THF, –78°, 2 h
rt, 10 h
PhN
HN
Pht-Bu
(47%) (Eq. 44)
ELECTROPHILIC AMINATION OF CARBANIONS 27
NNN
1. n-BuLi, THF, –78°
2. PhN=NPh NHNn-BuPh
PhNLi
NNPh
Ph
NN
2. NH4Cl
(54%)45Ph PhPh
1. n-BuMgBr, –78° to rt
(Eq. 45)
ZnBr
+ t-BuO2CN
NCO2Bu-t THF, 0°, 1 h t-BuO2C
HN
NCO2Bu-t
(75%)
(Eq. 46)
Hydrazines may also be obtained via amidocuprates (Eq. 47)54 but the yieldsare low. Addition of Grignard reagents to diazonium salts provides azo com-pounds, which may be reduced to hydrazines. Yields in the former reaction areoften low and the requirement to use dry diazonium salts adds a potential hazard.The best yields are obtained with o-benzenedisulfonimide salts (Eq. 48).191
t-BuCu(CN)Li1. Ph2NNHLi, THF, –40°, 30 min
2. O2, –78°, 30 mint-Bu
NH
NPh
Ph
(30%) (Eq. 47)
Cl
N2+ O2
SN
SO2
–t-BuMgX +THF, –78°, 1 h
to rtCl
NN
Bu-t
(83%)
(Eq. 48)
A wide variety of N -alkyl hydrazinedicarboxylic esters may be obtained inexcellent yields by the hydrohydrazination reaction depicted in Eq. 49.215 Useof cobalt complexes results in more highly regioselective reactions at the cost oflower reaction rates as compared to additions where manganese complexes areemployed. Di(tert-butyl) azodicarboxylate is the preferred azo ester; reduction ofthe N=N double bond becomes more prominent when less hindered azo esters areused. Alcoholic solvents are essential; the reaction fails when methylene chlorideor THF is used.
PhSiH3, t-BuO2CN=NCO2Bu-t
cobalt complex (5 mol%), EtOH, rt, 5 h
L = MeOH
NCO2Bu-t
NHCO2Bu-t(90%)
NCo
O
OO
O
NH2O
L
cobalt complex
(Eq. 49)
28 ORGANIC REACTIONS
Preparation of Alkyl Azides. A hydroazidation reaction similar to the reac-tion of Eq. 49 permits preparation of alkyl azides (Eq. 50).215
3. TsN3, t-BuO2H, rt, 5 min4. (Me2SiH)2O, rt, 10 h
t-Bu OH
N
PhPh
OK
O
ligandBu-t
BnO
OBnO
O
N3
(77%)
1. Co(BF4)3•6 H2O (6 mol%), ligand (6 mol%), EtOH, rt, 10 min2. Substrate
(Eq. 50)
Amination of Allylic and Propargylic CarbanionsThe literature in this area is fairly sparse, presumably because of the ease of
preparation of allyl- and propargylamines by nucleophilic amination. The reactionof allylindium species with aryl azides to give N -allylarylamines was mentionedearlier (Eq. 25). It has also been applied to the indium species derived frommethyl 2-(bromomethyl)acrylate.269 The amination of alkylzirconium speciesmentioned above (Eq. 41) can also be applied to allenes (Eq. 51).116
1. HZrCp2Cl (inverse addition), THF, rt
2. 2,4,6-Me3C6H2SO2ONH2, 0°, 10 min•
NH2(62%) (Eq. 51)
Application of the hydrohydrazination mentioned above (Eq. 49) to dienes andenynes gives N -allyl- and N -propargyl- (Eq. 52)216 hydrazinedicarboxylic estersin generally good yields. Serious competition from the Diels-Alder reaction is aproblem only with very reactive dienes such as cyclopentadiene.
PhPh(Me2SiH)2O, t-BuO2CN=NCO2Bu-t
cobalt complex (5 mol%), EtOH, rt, 2 hNNHCO2Bu-t
CO2Bu-t(56%)
L = MeOH
NCo
O
OO
O
NH2O
L
cobalt complex
(Eq. 52)
Amination of Arylmethyl and Heteroarylmethyl CarbanionsArylmethyl carbanions such as benzyl carbanions in general undergo most of
the amination reactions discussed for aliphatic carbanions. The difference is that
ELECTROPHILIC AMINATION OF CARBANIONS 29
they may often be generated directly by metalation of the arylmethyl compoundsas shown in Eq. 53.136 Heteroarylmethyl carbanions frequently are also accessibleby direct metalation but they have been used in electrophilic aminations muchless frequently, although the method shown in Eq. 54212 should be applicable toother aminating reagents.
HN 1. n-BuLi (2.1 eq), THF, hexane, 0°
HN
NEt2
(43%)2. 2,4,6-Me3C6H2SO2ONEt2, –78°, to rt; rt, overnight
(Eq. 53)
NN
1. LDA (2 eq), THF, hexane, 1 h
2. PhN=NPh, –78°, 10 min(77%)
PhN
NH
Ph
(Eq. 54)
Catalytic hydrohydrazination of vinylarenes and vinylheteroarenes proceedsregioselectively and with often excellent yields (Eq. 55).215
3. substrate, 0°, 5 h
N
NMe
N
NMe
NNHCO2Bu-t
CO2Bu-t
1. manganese complex (1 mol%), i-PrOH, rt to 0°2. PhSiH3, t-BuO2CN=NCO2Bu-t, 0°
(88%)
manganese complex
Mn
OO
O
O
OO
Bu-t
t-But-Bu
t-But-Bu
Bu-t(Eq. 55)
Amination of Vinyl and Allenyl CarbanionsAmination of vinyl carbanions gives enamines (Eqs. 56133 and 5755) or their
derivatives (Eq. 58).286 Only arylamines are isolated when products of type 46are hydrolyzed with acid.
Li2,4,6-Me3C6H2SO2ONEt2, Et2O or Et2O/THF
–10° to –20°; to rt, 14 h(28%)NEt2 (Eq. 56)
1. (i-Pr)2NLi, THF, –78° to –40°, 40 min2. 1,2-(O2N)2C6H4, THF, –78°
PhN(Pr-i)2
(60%)
PhCu(CN)ZnCl 3. O2, –78°, 30 min
(Eq. 57)
PhMgBr
Ph
N3
OMe
+THF, rt, 2 h
Ph
PhN
N
HN
OMe46 (55%)
(Eq. 58)
30 ORGANIC REACTIONS
In situ generated allenyltitanium complexes of type 47 are aminated byazodicarboxylic esters and the products may be degraded to α-hydrazino acids(Eq. 59).360 High α-symmetric induction is achieved only when R is a methylgroup; when it is n-butyl or isobutyl, the enantiomeric excess in the productdecreases to 55% and 27%, respectively.
TMSOP(O)(OEt)2
R+ Ti(OPr-i)4
i-PrMgBr (3 eq), Et2O
–50°, 2 h•
TMS
(i-PrO)2TiOP(O)(OEt)2
R
t-BuO2CN=NCO2Bu-t
–78°; to 0°, 1 h
TMSNCO2Bu-t
R
(77%) 81% ee
R = Me (94% ee)47
HNCO2Bu-t
HO2CNCO2Bu-t
R
HNCO2Bu-t
(80-83%)
RuCl3
NaIO4
(Eq. 59)
Amination of Ethynyl Carbanions
Amination of alkynylcuprates gives ynamines (Eq. 60);135 the yields are basedon two of the three ethynyl groups reacting. Yields are very low with organo-lithium and Grignard reagents.135 Amination of lithium bis(phenylethynyl)cupratewith Ph2P(O)ONH2 gives phenylacetonitrile by rearrangement of the initiallyformed primary ynamine.139 Imines of primary ynamines, however, can be iso-lated (Eq. 61).178 Phenylethynylsodium and tosyl azide react to give the triazolineby cycloaddition rather than the ethynyl azide.361
(RC C)3CuLi2Me2NX, Et2O
RC CNMe2
Rt-BuPh
XPh2P(O)OMsO
(71%)(52%)
(Eq. 60)
(PhC C)3CuLi2 NOSO2PhPh
Et2O, rt, 20 hN
Ph(39%)Ph+ (Eq. 61)
Amination of Aryl Carbanions
Preparation of Arylamines. Many methods to prepare arylamines by elec-trophilic amination are available. Some have been mentioned previously (Eqs. 13,15, 22, 24, 25, 26, 28, and 29) and some of the methods described for thepreparation of alkylamines (Eqs. 33, 35–37) can also be used to synthesize ary-lamines. Additional methods are shown in Eqs. 62,73 63,82 64,101 65264 66,333,334
and 67.305 The recently developed direct catalytic amination of aryl halides andaryl sulfonates,362 – 373 and arylboronic acids,374 however, has the advantage overthese methods of requiring one or more fewer steps. The approach that meritsconsideration will need to be decided based on each individual objective.
ELECTROPHILIC AMINATION OF CARBANIONS 31
NC MgCl•LiClNMe
Br
Cl
THF, –45°, 15 minNC
MeN
Br
(70%)(Eq. 62)
MeONHLi (2 eq)Li
+1. Et2O, hexane, –78° to –15°, 2 h
2. BzCl
NHBz
(96%)
(Eq. 63)
Cu(CN)Li2+
F
2t-BuNHOTMS
THF, –50° to rt, 2 h
F
NHBu-t
(45%)
(Eq. 64)
MgBr+ TMSCH2N3
1. Et2O, rt, 3 h
2. H2O
NH2(79%) (Eq. 65)
MgBr+ (PhO)2P(O)N3
1. Et2O, –73° to –69°, 2 h NH2
(67%)
2. NaAlH2(OCH2CH2OMe)2, toluene, –70° to 0°, 1 h
(Eq. 66)
MgBr
Bn
1. TsN3, THF, 0°
2. Na4P2O7, H2O
2. RaNi, NaOH
3. HCl
N3
Bn
NH3+ Cl–
Bn
(49%)
(71%)
(Eq. 67)
The situation is more favorable when the aryl carbanion can be prepareddirectly from the arene by ortho lithiation. Examples are shown in Eqs. 68,53
69 (the copper reagent gives higher yields than the lithium reagent),128 and70.311 Phenylthiomethyl azide (32) does not react with aryllithium reagentsbut this failure can be remedied by converting them into magnesium reagents(Eq. 71).274,275,375 Trimethylsilylmethyl azide (Eq. 65) aminates aryllithiumreagents but the yields are lower than for Grignard reagents. On the other hand,the reactions of diphenyl phosphorazidate, illustrated in Eq. 66, work equallywell with organolithium reagents.
OMeCONEt2
1. s-BuLi, TMEDA, THF, –78°, 50 min2. PhNHCu(CN)Li, –78°, 2 h
OMeCONEt2
NHPh
(63%)3. O2, –78°, 30 min
(Eq. 68)
O
O1. n-BuLi, THF, Et2O, 0°, 2 h; rt, 22 h2. CuI, 0°, 15 min
O
O
NHCO2Bu-t
(45%)
3. TsON(Li)CO2Bu-t, –78°, 30 min; 0°, 2 h(Eq. 69)
32 ORGANIC REACTIONS
O
N1. s-BuLi, TMEDA, THF, –78°, 1 h2. TsN3
O
N
NH2(50%)
3. NaBH4, n-Bu4N+ HSO4– (Eq. 70)
O
O
CONEt2
1. s-BuLi, THF, hexane2. MgBr2
3. PhSCH2N3, –78° to 0°; 0°, 1 hO
O
CONEt2
NH2
(71%)
4. NH4Cl, H2O5. 50% KOH in H2O, MeOH, THF, rt, 16 h
(Eq. 71)
The direct amination of arenes with chloramines in the presence of redoxcatalysts is another alternative that usually proceeds with good yields.376
Preparation of Aryl Hydrazines. All methods mentioned above for thehydrazination of alkyl carbanions may also be applied to aryl carbanions. Addi-tion of phenyllithium to a cyclic azo compound followed by in situ arylationto give a tetrasubstituted hydrazine was mentioned earlier (Eq. 19). An alternatehydrazination method, not involving aryl anions, is the reaction of electron-richarenes with azodicarboxylic esters and aroylazocarboxylic esters under the influ-ence of various catalysts.230,377 – 384
Preparation of Aryl Azides. Aryl azides may be prepared by reaction ofaryl carbanions with tosyl azide followed by treatment of the triazene salt withsodium pyrophosphate (Eq. 67)305 or aqueous base (Eq. 72).315
1. n-BuLi (5.4 eq), Et2O, rt, 5 h2. TsN3, rt, overnight
(28%) (6%)
Fe Fe FeN3 N3
N3
+3. 10% KOH in H2O
(Eq. 72)
Amination of Heterocyclic Carbanions
Aminations in this area involve anions of both π-excessive and π-deficientheterocycles, which are generated from the halo compounds or by directmetalation. Most of the aminating reagents seem to be applicable except thatphenylthiomethyl azide (32) fails with the 2-lithium or 2-copper derivatives offuran, thiophene, N -methylpyrrole, and N -methylindole.274 Similarly, chloramineand O-methylhydroxylamine, but not phenyl azide, fail to aminate 2-lithio-1-methylimidazole 66 and the MeN(Li)OMe nitrenoid does not react with 2-lithiothiophene.97 The reactions that appear to be most widely applicable toheterocyclic carbanions are shown in Eqs. 73,100,101 74,316 and 75.358
ELECTROPHILIC AMINATION OF CARBANIONS 33
1. CuCN, THF, –40°, 20 min
2. R2NHOTMS, –50° to rt, 2 hR1Li R1NHR2
R1
2-thienyl3-pyridyl2-benzo[b]thienyl
R2
i-PrTMSTMS
(65%)(58%)(58%)
R2 = H after hydrolytic workup
(Eq. 73)
S
Li
O
O1. TsN3, Et2O, –78°
2. Na4P2O7, H2O, rt, overnight S
N3
O
O (65%) (Eq. 74)
S ZnBr
t-BuO2CN=NCO2Bu-t
THF, 0°, 1 h S NCO2Bu-t
NHCO2Bu-t(80%) (Eq. 75)
Amination of Aldehyde Enolates, Enol Ethers, and Enamines
There appear to be no reports of aminations of aldehyde enolates in the lit-erature, presumably because of their instability and their tendency to undergoaldol self-condensations. Since electrophilic hydroxylations of sterically hinderedaldehyde enolates have been reported,152 these should also be amenable to elec-trophilic amination. α-Amino aldehydes or their derivatives, however, can be gen-erated by the use of aldehyde enol ethers or enamines, either as substrates, or as insitu generated intermediates. An example of the latter is shown in Eq. 76223 wherethe aldehyde product is isolated.222,226,229,385 The mechanism of this reactionwas discussed earlier (Eq. 21). D-Proline gives the enantiomeric product.224,227
Derivatives of proline385,386 and L-azetidinecarboxylic acid222,223,229 are also usedas catalysts. In other applications of this method the products are reduced in situ tothe α-amino alcohols221,223,227 or their cyclization products.222 – 225,386 An exampleof the latter reaction sequence involves a diastereoselctive Michael addition to anα,β-unsaturated aldehyde to generate the precursor aldehyde enolate (Eq. 77).225
L-Proline in this reaction gives lower diastereo- and enantioselectivities. Reactionof α-branched aldehydes with chloramine-T in the presence of L-proline gives theracemic α-tosylamino aldehydes in high yield (Eq. 78).78 A similar reaction withsulfonyl azides also produces α-tosylamino aldehydes, but with modest yieldsand enantioselectivities (Eq. 79).386a
CHO
1. L-proline (0.5 eq), CH2Cl2, 0°; rt, 1 h2. EtO2CN=NCO2Et, rt, 2.5 d
CHO
N NHCO2EtCO2Et
(54%) 86% ee
3. H2O
(Eq. 76)
34 ORGANIC REACTIONS
CHO
(1.5 eq)+ BnSH
NH
ArAr
OTMS(0.1 eq)
BzOH, toluene, –15°, 16 h CHOSBn
EtO2CN=NCO2Et
–15°, 16 h
CHOSBn
NHN
CO2EtCO2Et
1. NaBH4, MeOH, 0°, 10 min
2. NaOH ON
ONH
EtO2C
SBn
(63%) 90% de, >99% ee
Ar = 3,5-(CF3)2C6H3
(Eq. 77)
TsN(Cl)Na•x H2O, L-proline (2 mol%),
MeCN, rt, 2 d
CHO CHO
NHTs (86%) (Eq. 78)
CHO
CHO
NHSO2C6H4NO2-44-O2NC6H4SO2N3, L-proline (1 eq),
EtOH, rt, 1 d
OMe OMe (49%) 69% ee
(Eq. 79)
Examples where enol ethers of aldehydes are used as starting materials areshown in Eqs. 80,343 81,387 and 82.241 Glycals may also serve as substrates(Eqs. 83354 and 84343).
OEt + ClNHCO2Bn
1. CHCl3, MeOH, –78°2. CrCl2, –78°
OEt
OMeBnO2CHN
(81%)3. NaOMe, –78° to rt
(Eq. 80)
OBu-nO2N
N3
+ CHCl3, 40°, 70 h
n-BuO
OAc HN
NO2
NNN
OBu-n
NO2
(96%)
AcOH, PhH
50°, 10 minN
OBu-n
NO2
H
+(88%)
(Eq. 81)
O1. MeO2CN=NCO2Me
2. HCl, MeOH
O
OMeN
MeO2CNH
MeO2C
(85%) (Eq. 82)
ELECTROPHILIC AMINATION OF CARBANIONS 35
+1. 2,6-(t-Bu)2-4-Me-pyridine, CH2Cl2
2. (CF3CO)2O, –78° to rt, 5-6 h(2 eq)
(80%) C2 de 86%
O
BnO
BnO
O
BnO
BnO
OHNHCOCF3
2
N N
O O
N
Mn
(Eq. 83)
O
AcO
OAc
AcO 1. ClNHCO2CH2CH2Cl, CHCl3, MeOH, –78°
(55%)O
AcO
OAc
AcO
NHCO2CH2CH2Cl
OMe
2. CrCl23. MeOH, AgNO3
(Eq. 84)
Enamines may serve as precursors as well (Eqs. 85195 and 8674). The latterreaction is of interest for the formation of rearrangement product 48, whichapparently has not been followed up as a means of preparing α-amino aldehydes.A mechanism involving an aziridinium intermediate has been proposed.74
PhNEt2
HO2C
N2+ Cl–
+NaOAc, H2O
pH 5-6
Ph CHO
NNH
CO2H
(89%)
(Eq. 85)
NMe2NCl+
dioxane, Et2O, 0°, 2 h
rt, overnight; reflux, 5 h NMe2
CHO NCHO
+
(53%) 48 (24%)
(Eq. 86)
Amination of Ketone Enolates, Enol Ethers, and EnaminesWith ketone enolates, issues of site selectivity arise. Generation of enolates
under conditions of kinetic control results in preferential amination at the less sub-stituted α-carbon (product 49, Eq. 87;388 Eq. 88217) unless one of the α-positionsis benzylic (Eq. 89).134 Trialkylsilyl groups may also be used to direct aminations(Eq. 90).156 On the other hand, in reactions involving ketone enamine interme-diates under thermodynamic control, amination at the more highly substitutedα-carbon predominates, but as the bulk at that position increases, reaction timesincrease and selectivity decreases (products 51 and 52, Eq. 91).228 A potentialsolution to this problem that apparently has not been explored extensively is toselectively generate silyl enol ethers and treat them with one of the reagents thatare known to aminate these derivatives. The lone example of this approach isshown in Eq. 92.173
36 ORGANIC REACTIONS
R1 R2O
1. Ph(n-Bu)NMnMe•4 LiBr,THF, rt, 1 h
2. R4O2CN=NCO2R4, –30°; rt, 2.5 h
E = N(CO2R4)NHCO2R4
R1
Hn-C5H11
Et
R2
HMeEt
R3
MeMeBn
R4
Ett-BuEt
49
49 + 50(50%)(60%)(93%)
49:501:1
98:298:2
R3
R1 R2O
R3E
R1 R2O
R3 E
50
49 dr——3:1
+
(Eq. 87)
O
TBSO
OOBu-t
O
TBSO
OOBu-tNBnO2CN
H CO2Bn
1. LDA, THF, –78°
2. BnO2CN=NCO2Bn, –78°
(74%)
(Eq. 88)
O 1. unspecified Li base, Et2O or THF
2. Me2NOMs, –30° to 0°
O
NMe2
(52%) (Eq. 89)
OPr-i
i-Pr
OPr-i
i-PrNHCO2Bu-tNCO2Bu-t
O
4-O2NC6H4
1. LDA, THF, 0°
2. , –100° to rt
(29%) 88% de
t-BuMe2Si t-BuMe2Si
(Eq. 90)
OR
EtO2CN=NCO2Et, L-proline (0.1 eq)
MeCN, rt, time
OR
OR+
E = N(CO2Et)NHCO2Et
51 52Time10 h20 h95 h
51 + 52(80%)(77%)(69%)
51:5210:14:13:1
51 ee95%98%99%
RMeEti-Pr
EE(Eq. 91)
OTMS TsN=IPh (0.67 eq),
CuClO4 (8 mol%)
MeCN, 0°, 1.5 h
ONHTs
(53%)
(Eq. 92)
Ketone silyl enol ethers react with derivatives of diacyl azo compounds atroom temperature245 or on heating242,243 (see also Eq. 82) as well as enantio-selectively under the influence of silver trifluoromethanesulfonate and BINAP(Eq. 93)244 or copper bis(oxazoline) complexes (Eq. 94). The latter is proposed toproceed via a formal hetero Diels-Alder adduct.252 Ketones themselves react withazodicarboxylic esters either thermally246,389,390 or in the presence of potassiumcarbonate390 but yields are low. Higher yields can be achieved with LDA,391 – 394
(see also Eq. 88), LiHMDS,395,396 or KOBu-t325 as the bases. Aryl diazonium
ELECTROPHILIC AMINATION OF CARBANIONS 37
salts also aminate lithium enolates (Eq. 95) but yields can be low.185 Better yieldscould potentially be achieved with arenediazonium o-benzenedisulfonimides(26d), which are very efficient in the amination of Grignard reagents (seeEq. 48).191
OTMS1. BnO2CN=NCO2Bn, AgOTf, (R)-BINAP (12 mol%), THF, 2,4,6-Me3C6H3, –45°, 1 h
O
NNH CO2Bn
(95%) 86% ee
2. HF, THFBnO2C (Eq. 93)
copper complex (10 mol%),CF3CH2OH (1 eq), THF, –78°, overnight
(94%) 99% ee
TMSO
ON NH
CO2CH2CCl3
ON
OO
N
OO
N
t-Bu t-BuCu
(OTf)2
NNN
Cl3CCH2O2C
O
OO
2+
N
NN CO2CH2CCl3
O
O
OCuL2
TMSO
CF3CH2OH
copper complex (Eq. 94)
OLi
+ PhN2+ BF4
–THF, –78°
O
N NPh
(72%) (Eq. 95)
Hypervalent iodine reagents aminate ketone enol ethers.172 – 174 Yields areoften high but enantioselectivities in catalyzed reactions are generally consid-erably lower than the 52% achieved in Eq. 17.174 Other reagents that aminateketone enol ethers include N -arenesulfonyloxy carbamates119,122,397 (Eq. 96),122
the sodium azide/ammonium cerium(IV) nitrate reagent297,331 (Eq. 97),297 ethylazidoformate,296,397 (Eq. 98),296 the N -chlorocarbamate/chromium(II) chloridereagent (Eq. 32),343 the chloramine-T/osmium tetroxide system (Eq. 99),342 andbis[N -(p-toluenesulfonyl)]selenodiimide (Eq. 100).345 Nitridomanganese comp-lexes (cf. Eq. 83) can also be applied to the amination of silyl enol ethers.352,353,398
OTMS
+ 4-O2NC6H4SO2ONHCO2EtCH2Cl2, CaO
rt, 3.5 h
ONHCO2Et
(67%)
(Eq. 96)
38 ORGANIC REACTIONS
OO
OOTBS
NaN3, Ce(NH4)2(NO3)6
MeCN, –15°, 2 h; to rt
OO
OO
N3
H
(70%) (Eq. 97)
OTMS
+ EtO2CN3
1. 100°, 15 h
2. SiO2
O
NHCO2Et (40%) (Eq. 98)
OTMS
t-Bu
rt, 15 min
a see List of Abbreviations
O
t-Bu
NHTs
+ TsN(Cl)Na
(34%) 76% ee
(DHQD)2CLBa (0.008 eq),OsO4 (0.004 eq), t-BuOH/H2O (1:1)
(Eq. 99)
OSi(Pr-i)3
+ "TsN=Se=NTs"CH2Cl2, 0°
OSi(Pr-i)3
TsNH(62%) (Eq. 100)
Enamines derived from ketones undergo some of the same reactionsdescribed for enol ethers, for example with arenesulfonyloxy carbamates as inEq. 96120,121,399 and with ethyl azidoformate as in Eq. 98.302,303 The reactionwith activated azo compounds occurs readily at room temperature or belowand diamination often cannot be avoided with the more electrophilic reagents(Eq. 101).400,401 The proline-catalyzed reaction of ketones with azodicarboxylicesters, which proceeds by way of the enamines, has been mentioned above(Eq. 91).
N
1. PhN=NCOPh, Et2O, 0°, 15 min
2. HCl, Me2CO, 0°, few min
O
N
1. PhCON=NCO2Me (1 eq), Et2O, –30°, 3 h
2. HCl, Me2CO, 5°, 48 h
O
E
O
EE+
E = C(CO2Me)NHCOPh
(20%) (26%)
(55%)NHCOPh
Ph
(Eq. 101)
In the Morita-Baylis-Hillman reaction, enolate intermediates are formed byaddition of a nucleophilic catalyst to an α,β-unsaturated carbonyl compound.These intermediates can be trapped with a variety of electrophiles,402 includingazodicarboxylic esters (Eq. 102).403 The reaction fails with ethyl acrylate.
ELECTROPHILIC AMINATION OF CARBANIONS 39
C7H13-n
OC7H13-n
O
NNHCO2EtEtO2C
1,4-diazabicyclo[2.2.2]octane (cat)
THF, rt, 8 h
(61%)
EtO2CN
NCO2Et+
(Eq. 102)
α-Keto esters can be aminated enantioselectively with azodicarboxylic estersunder the influence of copper bis(oxazoline) catalysts (Eq. 103);404 the initialproducts were not isolated but were reduced and cyclized to give derivatives ofsyn-β-amino-α-hydroxy esters.
CO2Et
O
N
OO
NCu
(OTf)2Ph Ph
Ph Ph
BnO2CN
NCO2Bn
CO2Et
O
NBnO2C NHCO2Bn
L-selectride, THF
–78°, 1 h; to rtCO2Et
NBnO2C NHCO2Bn
OH
1. NaOH, H2O, rt, 2 h
2. TMSCH2N2, MeOH, 15 minON
O
CO2Me
BnO2CNH(62%) 93% ee
(10 mol%)
CH2Cl2, rt, 16 h+
(Eq. 103)
Enamines derived from cyclohexane-1,2-dione react readily with azodicar-boxylic esters but the enamine products are very resistant to hydrolysis.249
Amination of Imine and Hydrazone Anions
Imines have the advantage over ketones of permitting the introduction of achiral auxiliary on the imine nitrogen, which is then removed when the imine ishydrolyzed to the ketone. An example involving a manganese enamine is shownin Eq. 104.388 Amination occurs selectively at the less substituted α-carbon, asshown by the distribution of products 53 and 54; the configuration at the newlycreated stereogenic center was not reported. Reaction of imines with azodi-carboxylic esters proceeds slowly at room temperature (Eq. 105a), and yieldsand diastereoselectivities are comparable to those achieved via the aza enolate(Eq. 105b).405
40 ORGANIC REACTIONS
R1 R3N
t-BuS(O)
R2
R1 R3NMnN(Me)Ph
t-BuS(O)
R2
Ph(Me)NMnMe•4 LiBr
THF, rt, 1 h
1. R4O2CN=NCO2R4, –30°; rt, 2.5 h
2. HClR1 R3
O
R2
R1 R3O
R2EE
+
53 54
E = N(CO2R4)NHCO2R4
R1
Men-C5H11
Et
R2
MeMeEt
R3
MeMeBn
R4
Ett-But-Bu
53 + 54(50%)(65%)(50%)
*
*RRR,S
53 ee40%68%—
53:5490:1098:299:1
*
(Eq. 104)
N
MeO Bu-i
H
1. LDA, hexane, THF, –45°, 75 min
2. t-BuO2CN=NCO2Bu-t, –78°, 5 min
t-BuO2CN=NCO2Bu-t, rt, 24 h
(85%) 64% eeN
MeO Bu-i
HE
E = N(CO2Bu-t)NHCO2Bu-t(82%) 76% ee
(Eq. 105a)
(Eq. 105b)
Hydrazone anions have also been subjected to electrophilic amination. Theyreact very rapidly at −78◦ but the overall yields of the α-aminated ketones areonly fair (Eq. 106).327 Interestingly, the N -arylsulfonamides rather than the azidesare obtained in the attempted azidations.
Ph
NMe2N
1. LDA, THF
0°, 4-6 h
Ph
NMe2N
2. t-BuO2CN=NCO2Bu-t
–78°, 2-5 min
2. 2,4,6-(i-Pr)3C6H2SO2N3
Ph
NMe2N
Ph
O
Ph
O
O3, CH2Cl2
–30°
O3, CH2Cl2
–30°
(66%) (65%)E = N(CO2Bu-t)NHCO2Bu-t
(69%) (48%)R = SO2C6H2(Pr-i)3-2,4,6
E E
NHR NHR–78°, 2-5 min
3. NH4Cl, H2O
(Eq. 106)
Amination of Carboxylic Acid Dianions406
Although electrophilic amination of carboxylic acid dianions is potentiallya very short route to α-amino acids and their derivatives, little work has beenpublished and yields achieved so far, with few exceptions (Eq. 107),407 are low.Aminations of the dianions of α,β-unsaturated acids are discussed in the sectionon α,β-unsaturated carbonyl compounds (see below).
ELECTROPHILIC AMINATION OF CARBANIONS 41
Ph CO2H1. LDA (2.2 eq), THF, HMPA
2. MeONH2, –15° to –10°, 2 h, rt, overnight Ph CO2H
NH2(55%) (Eq. 107)
Amination of Ester Enolates and Ketene AcetalsEfforts to introduce the amino or substituted amino group directly into
ester enolates by electrophilic amination have met with limited success. O-[Di(p-methoxyphenyl)]phosphinoylhydroxylamine aminates the enolate of ethylphenylacetate (Eq.108),106 but the reaction has not been applied to enolatesthat do not contain a second activating group such as phenyl or carbonyl. Thechiral phosphinoyl reagent 12 also has been applied only to phenylacetatesand the products are obtained with low diastereoselectivities (Eq. 109).147 O-Mesitylenesulfonylhydroxylamine aminates a simple ester in low yield117 andN ,N -dimethyl-O-methanesulfonylhydroxylamine converts the lithium enolate ofethyl phenylacetate into ethyl (α-dimethylamino)phenylacetate in 48% yield.134
The amination with oxaziridines,151,154,155,157,158 including chiral, non-racemicones such as 55 (Eq. 110),154 is often plagued by low yields and generally poordiastereoselectivities and sometimes154 side reactions involving the aldehyde thatis a product of the reaction.
Ph CO2Et
1. KOBu-t, –78°, 15 min2. (4-MeOC6H4)2P(O)ONH2, –78°, 6 h; to rt
Ph CO2Et
NHAc(76%)
3. Ac2O, Et3N
(Eq. 108)
Ph CO2Et
PPh
ONMe2
Ph CO2Et
NMe2(50%) 23% ee
O
Li 12
THF, –15°
(Eq. 109)
CO2Et
ON
NC
O
O
i-Pr
1. LDA, THF, –78°, 1 h
2. 55, –78°; to rt, 2-3 h
CO2Et
HN O
O
i-Pr
+
NC
CHO
(49%) 17% de
55
(Eq. 110)
Silyl ketene acetals are aminated by the hypervalent iodine reagent TsN=IPh(Eq. 111),173 and by EtO2CN(TMS)(OTMS) (see Eq. 124 in the section on ami-nation of lactones).105
+ TsN=IPh (0.67 eq)MeCN, –20°
OTMS
OPhOPh
O
NHTs(50%)
(Eq. 111)
42 ORGANIC REACTIONS
Aminations of ester enolates with azodicarboxylic esters and arenesulfonylazides are more successful but the most widely used method for the prepara-tion of chiral, non-racemic α-amino acids involves N -acyloxazolidinones whichare discussed in a separate section (see below). Ester enolates in general reactrapidly with azodicarboxylic esters at low temperature as illustrated below inconnection with β-substituted ester enolates (Eqs. 115–117 and 119). Esters ofazodicarboxylic acid derived from borneol, menthol, and isoborneol aminateester enolates with no or low diastereoselectivity.408 Similarly, an ester eno-late where the alcohol portion is derived from a camphorsulfonamide reactswith di(tert-butyl) azodicarboxylate with only moderate diastereoselectivity.409
Ketene acetals react with azodicarboxylic esters either slowly at room temperature(Eq. 112),251 or at low temperatures catalyzed by TiCl4,410,411 Ti(OPr-i)4,409,412
AgOTf,244 or AgClO4. The latter catalyst together with (R)-BINAP furnishes theamination product with moderate enantioselectivity.244 Much higher diastereos-electivities are achieved with enol ethers derived from chiral alcohols409,411,412
(Eq. 113).409,412
OMe
OMePh+ EtO2CN=NCO2Et
PhH, rt, 6 dOMe
OMePh
NEtO2CNHCO2Et
(86%)
(Eq. 112)
O
OTMsSO2N(C6H11-c)2
1. Ti(OPr-i)4, CH2Cl2, –78°2. t-BuO2CN=NCO2Bu-t, –78°, 5 min O
OSO2N(C6H11-c)2
NH
NHCO2Bu-t
CO2Bu-t
(65%) >99.5% de
3. TiCl44. Add substrate, –78°, 1 h
(Eq. 113)
Reaction of ester enolates with trisyl azide and short reaction times at −78◦
gives the α-azido esters in 50–70% yields;318,413,414 with 4-nitrobenzenesulfonylazide, the diazo esters are formed almost exclusively.318 Azidomethyl phenylsulfide and ester enolates give α-amino amides274,275 (Eq. 114),274 but the scopeof this reaction has not been determined.
CO2Me
NN
NOSPh
NH2
ONH
SPh1. LDA, THF, –78° 1. NH4Cl, H2O
(79%)
2. PhSCH2N3, –78° to –20°, 45 min
2. NH4OH, THF, rt, 12-24 h
(Eq. 114)
Ketene dimethyl acetals react with phenyl azide to give α-anilido esters afteracid hydrolysis of the intermediate triazolines, but yields are low.291 The reac-tion of ketene acetals with arenesulfonyl azides does not appear to have beeninvestigated.
ELECTROPHILIC AMINATION OF CARBANIONS 43
A considerable amount of work has been carried out on the amination withazodicarboxylic esters of β-hydroxy esters, a class of compounds where bothenantiomers are readily available by asymmetric reduction of β-keto esters. Yieldsare in the range of 50-70% for lithium115,415 – 417 (Eq. 115),417 magnesium,416
zinc,416,418 – 424 and titanium enolates,416 but diastereoselectivities are highest withzinc enolates (Eq. 116).416 Attack from the less hindered side of zinc enolate 57accounts for the observed anti selectivity. Similar results are obtained with theother enantiomer.416 The lithium enolate of the rigidized derivative of ester 56gives higher yields with a somewhat reduced anti selectivity (Eq. 117). 416
MeO
MeOCO2Et
OH 1. LDA (4 eq), THF, –78°
2. t-BuO2CN=NCO2Bu-tMeO
MeOCO2Et
OH
Nt-BuO2C NHCO2Bu-t
(55%) 89% de (Eq. 115)
OEt
OH O1. MeZnBr (1.1 eq), THF, Et2O, 0°
OEt
O OZn
1. t-BuO2CN=NCO2Bu-t –78°, 10 min
OEt
OH O
Nt-BuO2C NHCO2Bu-t
(63%) >90% de
57562. LDA (2.2 eq), –78°, 1 h 2. NH4Cl, H2O
(Eq. 116)
OO
O
1. LDA
2. t-BuO2CN=NCO2Bu-t, –78°
OO
ON
NHCO2Bu-tt-BuO2C
(90%), 90% de
(Eq. 117)
Reaction of the lithium enolate of ethyl β-hydroxybutyrate with trisyl azidefurnishes the azide in 77% yield but with only 64% anti diastereomeric excess;the diazo ester (10%) and the diazide (1%) are also formed.318
Other β-substituents also promote anti selectivity with both azo esters andtrisyl azide. Examples are given in Eqs. 118,425 and 119.426 Use of trisyl azidein the latter reaction gives the two diastereomeric azides as a 1 : 1 mixture in 90%yield.426 More remote substituents, however, may reverse the trend (Eq. 120).427
CO2MeSiMe2Ph
CO2MeSiMe2Ph
1. LDA, THF, –78°
2. 2,4,6-(i-Pr)3C6H2SO2N3,
–78° to rt, 10 h
N3
(73%) 95% de
(Eq. 118)
44 ORGANIC REACTIONS
PhHN
CO2EtEtO2C 1. LiHMDS (1.2 eq), THF,
HMPA, –78°; –55°, 1 hPhHN
CO2EtEtO2C
Nt-BuO2CNH CO2Bu-t
(80%) 93.5% de
2. t-BuO2CN=NCO2Bu-t, –78°, 4.5 min3. HOAc
(Eq. 119)
TBDPSOCO2Me
BOMO1. KHMDS, THF, –78°, 30 min
TBDPSOCO2Me
BOMO N3
(70%)
2. 2,4,6-(i-Pr)3C6H2SO2N3, –78°, 20 min
(Eq. 120)
Reaction of silyl ketene acetals with aryldiazonium salts produces α-ketoester hydrazones196,197 by rearrangement of the initially formed azo compounds(Eq. 121). The latter are obtained with disubstituted ketene acetals.197
Ph
OMe
OTMS
PhN2+ BF4
–, pyridine
0°, 2 hCO2Me
Ph
NCO2Me
Ph
NPhNHPhN
(70%)
(Eq. 121)
Amination of Thioester Enolates and Ketene Thioacetals
Only a few examples in this category were found in the literature and azodi-carboxylic esters are the only aminating reagents that have been used. Thereactivities appear to be similar to those described above for ester enolates andketene acetals. The catalyzed enantioselective amination of ketone silyl enolethers described in Eq. 94 has also been applied to ketene thioacetals.252
Amination of Lactone Enolates
Lactone enolates behave similarly to ester enolates in electrophilic aminations.Examples are shown in Eqs. 122428 and 123;429 attack on the less-hindered sideto give the equatorial azide is illustrated by the distribution of products 58 and59 in Eq. 123.
O
O
OO
1. KHMDS, THF, –80°; rt, 50 min
O
O
OO O
O
OO
H
N3
N3
N3+
(79%) (6%)
2. 2,4,6-(i-Pr)3C6H2SO2N3, –80°, 10 min
(Eq. 122)
ELECTROPHILIC AMINATION OF CARBANIONS 45
OO
BnO
R1
R2
OBnO
O
BnO
R1
R2
OBnO
O
BnO
R1
R2
OBnN3
N3
58 59
1. KHMDS, toluene, THF, –90°, 15 min
2. 2,4,6-(i-Pr)3C6H3SO2N3, –90°, 2 min
O
BnOBnO
OBn
R1
BnO
H
H
R2
H
BnO
58
(0%)
(50%)
(0%)
59
(70%)
(0%)
(60%)OBn
+
(Eq. 123)
Ester- and lactone-derived silyl enol ethers are aminated by theEt2OCN(TMS) OTMS reagent (Eq. 124).105
O
OTMS90°, 5 d
O
O
NHCO2EtEtO2C NTMS
OTMS+ (44%) (Eq. 124)
Amination of Amide Enolates and Ketene Aminals
Amide enolates mirror ester enolates in their amination reactions. Secondaryamides can be used by employing two equivalents of the base, but yields inthe only example found in the literature are low to fair.212 Ketene aminals reactwith azodicarboxylic esters at room temperature, but yields are low (Eq. 125).251
Eq. 126 shows the application of the copper-catalyzed enantioselective additionof mixed ketene acetal/aminals to azodicarboxylic esters previously described forsilyl enol ethers in Eq. 94.252 Increasing bulk of the R substituent in the substratecauses partial or complete amination on the pyrrole, as evidenced by the yieldsof products 60 and 61 as R is varied.
N
N
Y
Y
+ RO2CN
NCO2R PhH, rt, 3 d
RO2CN
NH
CO2R
YOCH2
(18%)(41%)
REtMe
NO
Y
(Eq. 125)
46 ORGANIC REACTIONS
copper complex (5 mol%),THF, CF3CH2OH
NNN
Cl3CCH2O2C
O
OOR OTMS
N
R
N
O
E
R
N
O
E
+
RMet-Bu
60 61
NNH
NE = Cl3CCH2O2C
O
OO
Temp–78°–20°
Time30 min5 min
60(96%) 99% ee
(0%)
61(0%)(80%)
N
OO
N
t-Bu t-BuCu
(OTf)2
copper complex
(Eq. 126)
Amination of N -Acyloxazolidinone Enolates
This reaction is arguably the most useful and certainly the most widely usedapplication of the electrophilic C-amination of enolates in organic synthesis. Anumber of 4- and 4,5-substituted 2-oxazolidinones are commercially available inboth enantiomeric forms and the chiral auxiliary is easily recovered.430 Reactionsof N -acyloxazolidinone enolates with azo esters431,432 and arenesulfonyl azides433
are rapid even at very low temperatures (−100◦) and the diastereochemical out-
come is reliably predictable. The facile removal of the chiral auxiliary and readyconversion of the azide or hydrazino ester functionalities into amines makes thesereactions a standard method for the preparation of D- and L-α-amino acids.
The optimum conditions have been thoroughly worked out,318,431 although adirect comparison of the diastereodirecting efficiency of various oxazolidinonesdoes not appear to have been made for aminations. However, they all direct theincoming electrophile to the less hindered side of the Z-enolate as illustratedin Eqs. 127431 and 128.434 The diastereomer with the opposite configuration atthe amination site can be obtained using the enantiomeric chiral auxiliary orfrom the same N -acyloxazolidinone by a bromination/SN2 displacement sequence(Eq. 129)431 or a hydroxylation/Mitsunobu reaction protocol.427
Ph N
O
O
O
Bn
LDA, THF, –78°
30 min Ph N
O
O
O
Bn
Li
t-BuO2CN=NCO2Bu-t
CH2Cl2, –78°, 0.5 to 3 min
Ph N
O
O
O
BnNR
NCO2Bu-t
Li+ –
HOAc Ph N
O
O
O
BnNR
HNCO2Bu-t
62 R = CO2Bu-t
(91%) 94% de
(Eq. 127)
ELECTROPHILIC AMINATION OF CARBANIONS 47
N
O
O
O
Ph
i-Pr
MeO2. 2,4,6-(i-Pr)3C6H2SO2N3, –78°, 15 min3. HOAc
N
O
O
Oi-Pr
MeON3
Ph
(85%) >90% de
1. KHMDS, THF, –78°, 30 min
(Eq. 128)
Ph N
O
O
O
Bn
1. i-Pr2NEt, CH2Cl2, rt2. (n-Bu)2BOTf, –78°; to rt, 1 h
Ph N
O
O
O
BnBr
(98%) 80% deMe2N
Me2NNH2
+ N3–1. , CH2Cl2, 0°, 3 h
2. NaHCO3, H2OPh N
O
O
O
BnN3
(85%) >98% de
3. Add to NBS, CH2Cl2, –78°, 3 h4. NaHSO3, H2O
(Eq. 129)
Lithium diisopropylamide (LDA) or KHMDS is used as the base althoughthe former seems to be preferred for reactions with azodicarboxylic esters andthe latter with trisyl azide. In one report435 a mixture of KHMDS and sodiumhydride (one equivalent of each) gave much-improved yields in an azidation.As little as 5 mol% of sodium tert-butoxide, lanthanum tri(tert-butoxide), or theconjugate base 62 (Eq. 127) effect the amination, indicating that the externalbase serves as initiator whereas anion 62 is the base in the catalytic cycle.436 Noyields were reported in this investigation. Most procedures call for slightly morethan one equivalent of the base except when other acidic protons are present inthe molecule (see below). In one azidation, 1.2 equivalents of KHMDS gave amixture of the diazo compound and the azide in low yields, whereas the latterwas formed exclusively in 78% yield with 1.5 equivalents of the base.437 Trisylazide is the electrophile of choice for the azidation; 4-nitrobenzenesulfonyl azideand tosyl azide lead to the diazo compounds either exclusively or in admixturewith the azides. The benzyl and tert-butyl esters of azodicarboxylic acid are themost widely used members of that class of electrophiles because the products areeasily cleaved to the hydrazines and the former has an aromatic chromophore forUV detection in chromatography. Azo esters and trisyl azide usually work equallywell although there is one report where the former gives a cleaner product,438
and one instance involving an N -acyloxazolidinone with a sugar attached tothe γ-position where di(tert-butyl) azodicarboxylate reacted (Eq. 135), but trisylazide did not.439 Addition of the pre-cooled electrophile solution to the enolate(or vice versa) is often carried out by means of a cooled or insulated cannulaalthough one report finds that addition of the solid trisyl azide to the cold enolatesolution gives the highest yield.440 The reaction is usually quenched with aceticacid after a short period. The effect of other quenching reagents was discussedin the section on Reagents and Mechanisms.
The following functional groups are tolerated in electrophilic aminations of N -acyloxazolidinones: Br 441 – 443 (but see below), CH2CO2Bu-t (with one equivalent
48 ORGANIC REACTIONS
of base),444 NH (with two equivalents of base),445,446 NRCO2Bu-t (with twoequivalents of base when R = H),440,447 – 452 NHAc (with two equivalents ofbase),453 RNCO2Bn,454 aliphatic alcohols protected by trialkylsilyl or tosyl,455
protected phenols, phenylselenyl,456 (t-BuO)2P(O)CH2 (with one equivalent ofbase),457 and Ph2P(S)CH2 (the amount of base was not reported).458
A few problems have been reported. Cleavage of the N -acyloxazolidinoneoccurs to a considerable extent in the reaction of Eq. 130.445,446 A bromine atomat a distance of five carbons from the carbonyl group causes the enolate to cyclizeunder normal procedures (product 64, Eq. 131); azide 63 (n = 3) is obtainedin 40% yield only by adding an excess of trisyl azide early in the enolizationstep.443 The α,β-unsaturated N -acyloxazolidinone 65 does not undergo aminationunder conditions where its isomer 66 does (Eq. 132).453 However, product 67epimerized on attempted removal of the auxiliary.
HN
N5
O
O
O
Bn
1. KHMDS (2.3 eq), THF, –78°, 30 min2. 2,4,6-(i-Pr)3C6H2SO2N3, –78°, 3 min
HN
N5
O
O
O
Bn(34%)
HN
NH25
O
(24%)
+N3 N3
3. HOAc, –78° to rt, overnight4. NaHCO3, H2O
(Eq. 130)
BrN
O
OO
Bn
n1. KHMDS, THF, –78°, 30 min
2. 2,4,6-(i-Pr)3C6H2SO2N3
BrN
O
OO
Bn
NO
OO
Bn
+N3
63 64
n234
63(60-70%)
(0%)(60-70%)
64(—)
only product(—)
n
(Eq. 131)
N
O
O
O
AcNH Bn65
N
O
O
O
AcNH Bn
66
1. KHMDS, THF, –78°, 30 min
N
O
O
O
AcNH Bn
67 (53%) E = N(CO2Bu-t)NHCO2Bu-t
E2. t-BuO2CN=NCO2Bu-t, CH2Cl2, –78°, 3 min
(Eq. 132)
ELECTROPHILIC AMINATION OF CARBANIONS 49
In the attempted double diastereoselection shown in Eq. 133, amination of apair of enantiomeric N -acyloxazolidinones with (−)-diisobornyl azodicarboxy-late furnishes a single product for each. The same reactions with dibenzyl azodi-carboxylate as the electrophile proceed with only 9:1 diasteromeric ratio. Theseexperiments indicate that the only effect of the bulky isobornyl group is toenhance the diastereoselectivity, which is controlled by the enolate geometry.408
N
O
O
O
i-Pr
1. LDA, THF, –78°, 40 min
2. RO2CN=NCO2R, –78°, 4 minN
O
O
O
i-PrE
RBn(–)-isobornylBn(–)-isobornyl
Yield(—)
(56%)(—)
(88%)
% de80 (S)
100 (S)80 (R)
100 (R)
E = N(CO2R)NHCO2R
C4 Config.SSRR
4 4
(Eq. 133)
Alternate routes to chiral α-amino acids and α-amino alcohols that apparentlyproceed with somewhat higher diasteroselectivity involve the reactions of achi-ral α-chloronitroso compounds with chiral enolates or of chiral α-chloronitrosocompounds with achiral enolates (see section on the amination with nitroso com-pounds in Comparison with Other Methods), but they have not been appliednearly as frequently as the aminations described above.
Chiral azo amide 68 reacts with an achiral oxazolidinone enolate to givea single product with the configuration indicated in Eq. 134, but the hydrazinoamide could not be hydrolyzed.219 A remote chiral group attached to an achiral N -acyloxazolidinone directs a diastereoselctive amination as shown in Eq. 135.459
HNN
MeN
NMe
O
O
N
O
O
O
NN
MeN
NMe
O
O
N
O
O
O 1. LDA, THF, –78°, 20 min
2. 68, CH2Cl2, –78°, 7 min
(85%)
68 (Eq. 134)
O
RR
R R
O
N O
O
O
RR
R R
O
N O
O
R = OBn
1. LDA, THF, –78°, 30 minN
CO2Bu-tHNCO2Bu-t
(70%) 73% de
2. t-BuO2CN=NCO2Bu-t, –78°, 5 min
(Eq. 135)
50 ORGANIC REACTIONS
The amination of an achiral N -acyloxazolidinone with azo esters may also becarried out catalytically with magnesium complex 69 as the base (Eq. 136).436
The role of N -methyl-p-toluenesulfonamide, which accelerates the reaction, isnot clear. Enantiomeric excesses are in the range of 82–90% but the catalyticamination has only been carried out with N -arylmethylcarbonyloxazolidinones.
N -acyloxazolidinones are cleaved to the acid salts by lithium hydroxide/hydro-gen peroxide.318 The chiral auxiliary is recovered by extraction into an organicsolvent; the acid is obtained by acidification of the aqueous phase.
O
N O
OF
N N
PhPh
SO2O2SMg
69
t-BuO2CN=NCO2Bu-t, 69 (10 mol%), TsNHMe (20 mol%)
O
N O
OF
Nt-BuO2C NHCO2Bu-t
(97%) 90% ee
Et2O, CH2Cl2, –65°, 2 d
(Eq. 136)
Amination of Lactam Enolates
O-(Diphenylphosphinoyl)hydroxylamine (Eq. 137),143 azo esters (Eq. 138),460
and arenesulfonyl azides (Eq. 139)339 have been used to aminate lactam enolates.In the azidation of the lactam 70,461 the diazo compound 73 predominates overazide 72 even though trisyl azide is used as the aminating agent; amination withdi(tert-butyl) azodicarboxylate was unsuccessful. The closely related lactam 71462
reacts normally with trisyl azide (Eq. 140).
Nt-BuO2C
H
O
1. LiHMDS, THF, –78°
2. (Ph2P(O)ONH2
Nt-BuO2C
H
O
NH2
(47%) >82% de
(Eq. 137)
MeN
MeN
O1. LDA, THF, hexane, –78°, 2 h MeN
MeN
ON
(67%) >98% de
2. t-BuO2CN=NCO2Bu-t, –78°, 6 h; to rt, 3-6 h
CO2Bu-t
NHCO2Bu-t(Eq. 138)
N
S
MeO2C CO2MeO
1. LiHMDS, THF, –78°, 4 h2. TsN3, –70°
N
S
MeO2C CO2MeO
H N3
(68%)3. TMSCl
(Eq. 139)
ELECTROPHILIC AMINATION OF CARBANIONS 51
N
H
RO
mn
O
1. LDA, THF, –78°, 20 minN
H
RO
mn
O
N
H
RO
mn
O
R = TBDPS70 or 71
N3 N2+
m21
n12
72 73
72(20%)(43%)
73(64%)(0%)
Time10 min3 h
7071
2. 2,4,6-(i-Pr)3C6H2SO2N3, –78°, time
(Eq. 140)
Amination of Nitrile-Stabilized CarbanionsLittle work could be found on the electrophilic amination of simple nitrile-
stabilized carbanions. The lithium anion of propionitrile reacts normally with anN-substituted oxaziridine (Eq. 141).158 The amination of nitriles with a camphor-derived N-unsubstituted oxaziridine was discussed earlier (Eq. 11).151 Aminoma-lononitrile is formed from malononitrile anion and O-(mesitylenesulfonyl)hydro-xylamine (Eq. 142).463
CN
1. n-BuLi, hexane, THF, 0°, 30 min
NCONEt2 ,O
2-NCC6H4
CN
NHCONEt2(56%)
2.
–78°, 3 h; to rt, 1.5 h
(Eq. 141)
NC CN2. 2,4,6-Me3C6H2SO2ONH2, THF, 0°, 2.5 h3. TsOH
NC CN
NH3+ TsO–
(55%)1. unspecified Na base
(Eq. 142)
The anion of phenylacetonitrile has been aminated with a variety of reagents;examples are shown in Eq. 143.106,147 In the reaction involving the chiral O-phosphinoylhydroxylamine, epimerization is believed to have occurred duringisolation of the product.
Ph CN
2. (4-MeOC6H4)2P(O)NH2, –78° to rt; rt, overnight3. Ac2O, Et3N
Ph CN
NMe2NMe
POPh
ONMe2
1. unspecified Li base, THF
2. , –15°
Ph CN
NHAc(67%)
(62%) 8% ee
O
1. KOBu-t, THF, –78°, 15 min
3. H3O+ (pH 4.5)(Eq. 143)
52 ORGANIC REACTIONS
Amination of NitronatesOnly one example involving a number of substituted nitromethane anions was
found in the literature and the reaction with p-toluenesulfonyl azide proceedswith loss of the nitro group (Eq. 144). Nitromethane itself failed to react underthese conditions.464
NO2
1. KH, THF, rt; 40°, 15 min
2. TsN3, –10° to 0°; 0°, 1 h
Ts N3
(56%)(Eq. 144)
Amination of Sulfone-Stabilized CarbanionsThe few examples indicate that sulfone-stabilized carbanions should react nor-
mally with electrophilic aminating reagents (Eqs. 145158 and 146465) with thecaveat that free α-amino sulfones are unstable.158,465 The β,γ-unsaturated sulfone74 is aminated at the γ-position (Eq. 147),250 presumably by an ene reaction. Thepreparation of α-tosyl azides from nitronates was shown above in Eq. 144. Thescope of this reaction does not seem to have been determined. Reaction of theanions of nitrobenzyl aryl sulfones with 1-oxa-2-azaspiro[2.5]octane (13a) givesnitrobenzaldehydes by cleavage of the initially formed amination products.466
Similarly, reaction of the lithium salt of benzyl phenyl sulfone with phenyl azidegives benzilydeneaniline and phenyl sulfinate.467 No reports on aminations ofsulfoxide-stabilized carbanions were found.
O2S
Me
O2S1. n-BuLi, THF, hexane, 0°, 30 min NHCONEt2
(43%)
NCONEt2 ,O
2-NCC6H42.
–78°, 3 h; to rt, 1.5 h
(Eq. 145)
SO2
N
H
BnOR
SO2
N
H
OR
1. n-BuLi, THF, pentane, –78°, 55 min
Bn
N3
R = TBDPS
SO2
N
H
OR
N3
Bn+
(24%)(40%)
2. 2,4,6-Me3C6H2SO2N3, –78°, 6 h
(Eq. 146)
SO2
NHBu-n
EtO2CN=NCO2Et, MeCN
reflux, 3 h
SO2
NHBu-nN
EtO2CNH
EtO2C
(65%)
74
(Eq. 147)
Amination of Phosphorus-Stabilized CarbanionsOnly one report on the amination of a phosphine oxide anion (Eq. 148) is
known;467 the product is claimed to have the structure shown but no spectral
ELECTROPHILIC AMINATION OF CARBANIONS 53
data excluding the isomer where the N=N double bond is conjugated with thephenyl group were provided.
PP
1. LiNEt2, PhH, rt, 1 h2. PhN3, rt, 18 h
NNNHPh
(26%)O
O
3. H2O(Eq. 148)
All other reactions involve derivatives of methanephosphonic acid and a rangeof aminating reagents has been applied, including hydroxylamine derivatives,oxaziridines, azo esters, and sulfonyl azides. The products are α-amino phospho-nic acids or derivatives that can be converted into these biologically interestinganalogs of α-amino acids. The best results with methanephosphonic acid deriva-tives not containing an additional activating group have been obtained so farwith phosphorinanes of type 75 (Eq. 149).317 The diastereoselectivity using thestandard acetic acid quench to generate the azide is disappointing, and yieldsfrom analogous compounds are low, possibly because here the addition of trisylazide is reversible. Trapping the triazene salt with acetic anhydride resolves theproblem. Cleavage of the product and removal of the chiral auxiliary gives thephosphono analog of (S)-phenylglycine.
NPO Ph
t-Bu
O
75 (2S,6S)
1. LDA, Et2O, –78°, 30 min2. 2,4,6-Me3C6H2SO2N3, –78°, 5 h N
PO Ph
t-Bu
O
AcNNN
C6H2(Pr-i)3-2,4,6
(75%) 86% de
3. Ac2O
(Eq. 149)
Two catalytic enantioselective methods have been developed for β-keto phos-phonic acid derivatives (Eqs. 150238 and 151468).
O
P(O)(OEt)2
P(C6H3Me2-3,5)2
P(C6H3Me2-3,5)2
P
P
P
PPd
O
OPd
+2
EtO2CN=NCO2Et
2 BF4– (2.5 mol%),
Me2CO, rt, 20 h
O
P(O)(OEt)2
N CO2EtNHCO2Et
(91%) 99% ee
P
P=
(Eq. 150)
54 ORGANIC REACTIONS
1. (10 mol%), CH2Cl2
2. add substrate, then BnO2CN=NCO2Bn, rt, 140 h
OP(O)(OEt)2
OP(O)(OEt)2
N CO2Bn
NHCO2Bn
(85%) 98% ee
NZn
N
OO
Ph Ph(OTf)2
(Eq. 151)
Standard amination methods may be used for the synthesis of racemic α-phosphono α-amino carboxylic esters (Eq. 152).141 No diastereo- or enantiose-lective syntheses appear to have been reported.
1. NaH, THF, rt, 1 h2. Ph2P(O)ONH2, THF, –78°, 2 h
(60%)
(EtO)2P CO2Bn
O
(EtO)2P CO2Bn
O NH3+ –O2CCO2H
3. HO2CCO2H(Eq. 152)
Amination of Enolates of α,β-Unsaturated Carbonyl Compounds
Enolates of α,β-unsaturated carbonyl compounds can react at either the α- orγ-position and α,β-unsaturated ketones can react at the α′-position as well. On thebasis of limited evidence, NH2
+ synthons react at the α-position,64,144 whereasazo esters aminate preferentially at the γ-position144,469 (Eq. 153),144 both bykinetic control, although there are exceptions (product 77 vs. 76, Eq. 154).469
With an α,β-unsaturated N -acyloxazolidinone, the two constitutiona isomers areformed in equal amounts (Eq. 155).431 The catalytic method shown in Eq. 156470
is believed to involve a hetero Diels-Alder reaction of the intermediate dienamine.Allyltin and allylgermanium reagents give mostly or exclusively the productsof an SE2′ reaction (Eqs. 157 and 158).469 The substrates for these reactionsare prepared by addition of tin tetrachloride and trimethylgermanium chloride,respectively, to the lithium enolates of the corresponding α,β-unsaturated esters.The generation of the tin substrate can be carried out in situ. Silyl ketene acetal78, the only example of this type of derivative whose amination was found inthe literature, reacts predominantly at the γ-position (Eq. 159).469
CO2H
1. LiNEt2 (2.0 eq), THF, –70°, 15 min
2. Ph2P(O)ONH2, –70°, 25 min; rt, 2 h
1. LiNEt2 (2.2 eq), THF, –70°, 30 min
2. EtO2CN=NCO2Et, –70°, 55 min
CO2HNH2
(64%)
CO2H
N(50%)
EtO2CNHCO2Et
(Eq. 153)
ELECTROPHILIC AMINATION OF CARBANIONS 55
CO2Et
1. LDA, HMPA, THF, –78°, 70 min2. EtO2CN=NCO2Et, –78°, 3 min
CO2EtCO2Et
EE
n n n+
76 77
n12
76(22%)(55%)
77(65%)(14%)
77 E:Z1:2
1:1.5
E = N(CO2Et)NHCO2Et
3. MeOH
(Eq. 154)
NO
OO
Bn
1. LDA, THF, –78°, 30 minN
O
OO
Bn
NO
OO
Bn
E
E+
(51%) 96% de(42%) E:Z = 3:2
E = N(CO2Bu-t)NHCO2Bu-t
2. t-BuO2CN=NCO2Bu-t, CH2Cl2, –78°, 0.5 to 3 min
(Eq. 155)
CHOCHO
NEtO2C NHCO2Et
MeSMeS
(43%), 88% ee
1. (10 mol%),
toluene, rt, 15 min
NH
OTMSAr
Ar
2. EtO2CN=NCO2Et, 1.5 h
(Eq. 156)
Cl3Sn CO2Me
1. EtO2CN=NCO2Et, THF, –10°, 30 min
CO2MeE CO2Me
E+
(53%) (5%)
E = N(CO2Et)NHCO2Et
2. to –78°; MeOH, –78° to rt
(Eq. 157)
CO2Me
GeMe31. EtO2CN=NCO2Et, ZnCl2, CH2Cl2, –78°
CO2Me
NEtO2C NHCO2Et
(55%) E:Z = 6:1
2. add substrate, –78° to 0°, 30 min3. MeOH
(Eq. 158)
OMe
OTMS
1. EtO2CN=NCO2Et, TiCl4, CH2Cl2, –78°
E CO2MeCO2Me
E+
(68%) (17%)
E = N(CO2Et)NHCO2Et78
2. add substrate, –78°, 30 min3. MeOH
(Eq. 159)
The dianion of trans,trans-hepta-2,4-dienoic acid (sorbic acid) is aminated inthe α-position by Ph2P(O)ONH2 and in the γ-position by diethyl azodicarbo-xylate.144
The amination of the only derivative of an α,β-unsaturated ketone is shownin Eq. 160.471
56 ORGANIC REACTIONS
OTMS
CH2Cl2, TFAA, pyridine, –78° to rt, 3-4 h
ONHCOCF3
(50%)
N N
O O
N
Mn(Eq. 160)
Amination of Enolates of α-Cyanocarbonyl and β-Dicarbonyl CompoundsThe electrophilic amination of the sodium salts of α-unsubstituted β-dicarbonyl compounds is one of the few examples of an amination wherehydroxylamine O-sulfonic acid gives useful yields (Eq. 161);472 with twoequivalents of the substrate, pyrroles are formed.472,473 Chloramine,62,64 O-arylhydroxylamines,93,124,474 O-sulfonylhydroxylamines,134 and O-(diarylphos-phinoyl)hydroxylamines106,139,475 have also been employed, although a low yieldand formation of the hydroxylation product as a side product have been reportedin one instance with (4-MeOC6H4)2P(O)ONH2.145 Some of these aminations usechiral auxiliaries in the substrates with modest diastereoselectivities,124,475,476 butthese have been superseded by the catalytic methods discussed below.
OO
NH2OSO3H, NaOH, H2O
rt, few minutesOO
NH2
(100%) (Eq. 161)
The oxaziridine 13a reacts with a variety of β-dicarbonyl and α-cyanocarbonylcompounds under base catalysis (Eq. 162).149
O
HN
13a
NCN
O
OR+
R = H; toluene, NaOH
H2O, 0°, 10 min
R = C6H4OMe-4
N
O
ONH2
NHHN
OR
NO
O
+
(48%) (39%)
N
O
OR NH2
(56%)
EtOH, reflux, 5 min
(95%)
H2N
O
O
H2N
toluene, NaOH, H2O, rt, 12 h
(Eq. 162)
Lithium477 and potassium478 enolates of β-dicarbonyl compounds are aminatedby azodicarboxylic esters in good to excellent yields. Diethyl malonate, ethylacetoacetate, N ,N -diethyl acetoacetamide, and acetylacetone have also been ami-nated with diethyl azodicarboxylate under nickel acetylacetonate catalysis,479 andnickel salicylideneimine complexes catalyze the analogous amination of acetyl-acetone and its 2-methyl derivative.480
ELECTROPHILIC AMINATION OF CARBANIONS 57
A number of catalytic, enantioselective reactions of azodicarboxylic esterswith β-dicarbonyl and α-cyanocarbonyl compounds have been recently devel-oped, using cinchona alkaloids or their derivatives,231,232,481 BINAP-derived pal-ladium complexes,239 chiral copper bis(oxazoline) complexes,235,237 and chiralamidines and amines233 as catalysts. With cinchona alkaloid-derived catalysts,cyanoacetic esters carrying aryl substituents in the α-position give higher selec-tivities than those with alkyl groups in that position232,481 (Eq. 163).232 Withthe quinidine-derived catalyst 79, the newly created stereogenic center has theS-configuration; the quinine-derived enantiomer furnishes the R-isomer. Cin-chonine and cinchonidine catalyze the reaction of dibenzyl azodicarboxylatewith ethyl α-ethylacetoacetate but the enantioselectivity is low (47 and 27%ee, respectively).231 However, α-fluoro-237 and α-alkyl 235 acyl and aroylacetatesrespond well to catalysis by chiral copper bis(oxazoline) complexes (Eq. 164).235
The reaction of ethyl α-methylacetoacetate with dibenzyl azodicarboxylate is alsocatalyzed by a BINAP-derived palladium complex (95% ee).239 This catalystalso induces good enantioselectivity in the amination of two cyclic β-dicarbonylcompounds (Eq. 165).239
NC CO2Et
RBnO2C
NN
CO2Bn+
N
NC CO2Et
R NNHCO2Bn
CO2Bn
RMe4-BrC6H4
Time30 min1 min
(75%)(86%)
ee35%91%
N
OH
BnO
79 (10 mol%)
toluene, –78°
79
(Eq. 163)
CO2Bu-tO
t-BuO2CN
NCO2Bu-t
+
CH2Cl2, rt, 16 h
CO2Bu-tO
N CO2Bu-tNHCO2Bu-t
(89%) 98% ee
NCu
N
OO
Ph Ph(OTf)2
(0.5 mol %)
(Eq. 164)
PPh2
PPh2
P
PPd
OH2
NCMe
+2
i-PrO2CN=NCO2Pr-i
2 PF6– (5 mol%), MeOH, rt
P
P
=
Y O
COR
Y O
RMeOEt
YOCH2
Time9 h
31 h(93%)(89%)
ee93%97%
CORN
CO2Pr-i
NHCO2Pr-i
(Eq. 165)
58 ORGANIC REACTIONS
Enolates of β-dicarbonyl and α-cyanocarbonyl compounds have a strongtendency to form diazo compounds with arenesulfonyl azides. α-Substitutedsubstrates react normally to give azides482,483 but even then a diazo transfer(Eq. 166)484 or other transformations319,321,484 may occur as side reactions.
O TsN3, Et3N, Et2O
rt, 140 h
OCO2Et
N3
NHTsO
CO2EtN2
+
(74%)
(20%)
CO2Et (Eq. 166)
An interesting addition of a sugar azide to the enolate of cyanoacetamide isshown in Eq. 167.276
OR
R
R
N3
R = OBn
OR
R
R
N+ NC CONH2
KOH, DMF, H2O, rt
NN
NH2
CONH2(85%)
(Eq. 167)
Intramolecular AminationsFormation of Aziridines. The addition of O-methylhydroxylamine to α,β-
unsaturated carbonyl compounds gives β-methoxyamino derivatives which ontreatment with sodium methoxide at elevated temperatures give aziridines(Eq. 168).485,486 The products were initially considered to be the isomeric primaryenamines.485 The reaction has been carried out with other leaving groups:benzyloxy,487 – 489 OCOBu-t ,490 TMSO,491 arenesulfonyloxy492,493 (Eq. 169),492
and trimethylammonium (with formation of an azirine; Eq. 170).494 An exampleinvolving a chiral auxiliary is shown in Eq. 171.487,488
Ph Ph
OMeONH2, EtOH
80°, 3 h Ph Ph
O
Ph
O
MeONHNaOMe, MeOH
60°, 10 min
HN
(64%)
(94%)Ph
ONHMeO
Ph Ph
(Eq. 168)
MeO2CCO2Me
CO2Me 2,4,6-Me3C6H2SO2ONH2
BF3•Et2O, Et2O, rt, 48 hMeO2C
CO2Me
CO2Me
NHOSO2C6H2Me3-2,4,6
Et3N, CH2Cl2, rt
MeO2CCO2Me
CO2MeNH
(50%)
(100%)(Eq. 169)
ELECTROPHILIC AMINATION OF CARBANIONS 59
NNMe3 I–+
NaOPr-i, i-PrOH, 40°, 1 h
Ph(80%)
N
Ph (Eq. 170)
N NMe
O O
Ph
N NMe
O O
Ph
HN1. AlMe2Cl, CH2Cl2
(71%)
BnONH
2. add to Et3N (2 eq), CH2Cl2, rt, 30 min
(Eq. 171)
Hydroxylamine derivatives add to activated double bonds in the presence of abase to give aziridines where intermediates of the type illustrated above have notbeen isolated or observed. These reactions may proceed via stereospecific additionof nitrenoid intermediates to the double bonds. However, in some instances,both isomeric aziridines are produced and these are included in Table 21 of theTabular Survey since the possibility exists that they are formed by a Michaeladdition/cyclization process. An example is shown in Eq. 172.495
O
H
O
4-O2NC6H4SO2ONHCO2Et (3 eq)
CaO, CH2Cl2, rtO
H
O
EtO2CN
O
H
O
EtO2CH2N+
(42%) (39%)
(Eq. 172)
Formation of Higher-Membered Rings. Intramolecular displacement of amethoxy group by an aryl carbanion by way of a nitrenoid intermediate (Eq. 5)produces 4- (Eq. 173),83 5-,82 6-,83 and 7-membered83 benzannulated ring sys-tems. The 8-membered benzazocine cannot be prepared by this method.83 Thediphenylphosphinoyloxy functionality has also been employed as the leavinggroup (Eq. 174).496 Five-, 6-, and 7-membered unsaturated nitrogen-containingrings are obtained from substituted oximes (Eqs. 175497 and 176498,499). The for-mer reaction is postulated to proceed by an SN2 displacement on sp2 nitrogenrather than an addition/elimination process. The intermediate 80 in the latter reac-tion is air sensitive and is either reduced to the tetrahydroquinoline or oxidized tothe quinoline. The cyclization in this case is believed to involve a single-electrontransfer.
Br
NHOMe1. MeLi, hexane, –78°2. n-BuLi, –78°, 30 min; to –15°
NAc(21%)
3. AcCl
(Eq. 173)
NCO2Et
CO2EtPh2P(O)O Me
t-BuOKNMe
CO2Et
CO2Et (95%) (Eq. 174)
NOSO2Me
CO2BnCO2Bn
N
CO2BnCO2Bn
DBU, CH2Cl2, 0°, 30 min(87%) (Eq. 175)
60 ORGANIC REACTIONS
OHNOC6H3(NO2)2-2,4
OHNH
OHN
OHN
NaH
dioxane
Na(CN)BH3
50°, 10 h(78%)
(70%)DDQ, HOAc
reflux, 2 h80
(Eq. 176)
COMPARISON WITH OTHER METHODS
The number of methods for the formation of carbon-nitrogen bonds500 – 505
is too large to permit a meaningful comparison. A few other methods werementioned where appropriate in Scope and Limitations. The following is a briefdiscussion of the reagents for electrophilic amination that were excluded fromthe scope of this chapter.
Amination with Nitrogen Oxides
Nitrous oxide (N2O) reacts with phenyllithium to give complex mixturescontaining azobenzene, hydrazobenzene, and biphenyl, among others.506 With 9-fluorenyllithium, fluorenone azine is formed in 60% yield; the analogous productis obtained with the sodium salt of phenylacetonitrile.506 With n-butyllithium, theN -butylhydrazone of butyraldehyde is formed in low yield.507 Nitric oxide (NO)reacts with alkyl- and arylmagnesium reagents to give N -nitrosohydroxylaminesin low to fair yields.508,509 α,β-Unsaturated amides react with nitric oxide andtriethylsilane in the presence of cobalt complexes to give α-nitroso amides.510
Dinitrogen tetroxide (N2O4) and ethylmagnesium bromide511 or triethylaluminumetherate512 give N ,N -diethylhydroxylamine.
Amination with Nitrosyl Chloride, Nitryl Chloride, and NitroniumTetrafluoroborate
Combination of arylmagnesium halides and nitrosyl chloride (NOCl) givesmixtures of arylnitroso compounds and diarylamines.513 – 515 With alkylmagne-sium halides, N -nitrosohydroxylamines509 or dialkylhydroxylamines516,517 areformed. Aldehyde and ketone trimethylsilyl enol ethers and ketene acetals reactwith nitrosyl chloride to give the α-oximino aldehydes, ketones, or esters, respec-tively, by rearrangement of the intermediate nitroso compounds (Eq. 177).518 Thelatter are isolated from enol ethers of α, α-disubstituted aldehydes. α-Nitro alde-hydes and α-nitro ketones are formed in low yields by reaction of enol acetateswith nitryl chloride (NO2Cl).519 Alkyl- and allylsilanes react with nitroniumtetrafluoroborate (NO2
+ BF4−) to give the corresponding nitro compounds.520
The reaction of ketone enol ethers with nitronium tetrafluoroborate gives α-nitroketones.521,522
ELECTROPHILIC AMINATION OF CARBANIONS 61
OTMS 1. NOCl (excess), CH2Cl2, –10° to –15°, 30 s
O
NO
O
NOH
(82%)
2. 0°, vacuum(Eq. 177)
Amination with Alkyl Nitrites
Alkyl nitrites, of which the most commonly used representative is isopentylnitrite,523 react with a wide variety of compounds containing active methylenegroups to give oximes.524 – 526 Activating functionalities include carbonyl, cyano,nitro, and aryl. For the latter, the presence of two aryl groups is usually requiredbut by using chromium-complexed arenes, one aryl group suffices (Eq. 178).527
The oximes can then be reduced to hydroxylamines or amines.528,529 Alkyl nitritesreact with dialkylzinc530 and alkylmagnesium516 reagents to give dialkylhydrox-ylamines, whereas with arylmagnesium reagents, diarylnitroxyls are formed.531
Activated olefins react with triphenylsilane and n-butyl nitrite in the presence ofcobalt complexes to give the corresponding α-hydroxyimino derivatives.532,533 Asimilar reaction of unactivated olefins in the presence of iron complexes givesnitrosoalkane dimers.534
MeO
(CO)3Cr1. t-BuONO, DMSO, rt
2. KOBu-t, 30 minMeO
(CO)3CrNOH
(60%) (Eq. 178)
Amination with Alkyl Nitrates
Alkyl nitrates535 give N ,N -dialkylhydroxylamines with alkylmagnesium rea-gents.536,537 The reaction of 9-fluorenylpotassium with isopentyl nitrate forms the9-nitro derivative in unspecified yield.538 The main application of alkyl nitrates,however, has been in the nitration of ketone enolates539 – 544 to give mono- ordinitro ketones. Many steroid nitro ketones have been prepared in this waybut yields are variable.542,545 – 548 α-Nitro amides,549 α-nitro lactams,540 and α-nitro nitriles550 may also be prepared in this manner. Aza enolates give nitroenamines551,552 (Eq. 179).552 Acetyl nitrate, prepared in situ from acetic anhy-dride and nitric acid, nitrates enol acetates.522,553 – 555 Similarly, α-nitro ketonesare formed from the reaction of enol ethers and esters with trifluoroacetyl nitrate,prepared in situ from ammonium nitrate and trifluoroacetic anhydride.522,548,556,557
Cyclohexanone triisopropylsilyl enol ethers and a mixture of tetra-n-butylammo-nium nitrate and trifluoroacetic anhydride give α-nitro enol ethers.558
N 1. KNH2, NH3 (liq), –33°, 1 h
2. n-PrONO2, <–40°; –33°, 25 min
HN
NO2
(50%)
(Eq. 179)
62 ORGANIC REACTIONS
Amination with Nitroso CompoundsNitroso compounds559 – 561 are versatile electrophiles that undergo a num-
ber of different amination reactions. Arylnitroso compounds and aryl Grig-nard reagents are variously reported to give diarylhydroxylamines,99,562 – 568
diarylamines,99,514,569 or diaryl azo compounds.567 The reaction has beendeveloped into a general diarylamine synthesis (Eq. 180).570 Nitrosotrifluo-romethane undergoes a nitroso aldol reaction with the anions of pentane-2,4-dione(Eq. 181)571 and bis(trifluoromethyl)acetonitrile572 as does nitrosobenzene withketone lithium and tin enolates573 and with aldehydes in the presence of a proline-derived catalyst.574 The reaction of tin enolates with nitrosobenzene catalyzed byLewis acids gives mostly the hydroxylation products.575 Ketone trimethylsilylenol ethers react with nitrosobenzene to give adducts of type 81,242,243,576,577
which on reaction with triethylamine give imines of α-keto aldehydes.576 Oxi-dation of intermediates 81 leads to nitrones,577 and reduction to amino alco-hol derivatives (Eq. 182).578 Similarly, ketene bis(trimethylsilyl)acetals give N -phenyl α-amino acids on reduction of the intermediate adducts.578 Enamines reactwith nitroso arenes to give α-(N -arylhydroxylamino) ketones.579,580
Me2N
NO ClMg
CO2Et
+1. THF, –20°, 1 h
2. FeCl2, NaBH4, rt, 2 h
HN
CO2EtMe2N
(72%)
(Eq. 180)
O OO O
+ CF3NOEt3N, Et2O
–10°
NCF3 OH
(65%) (Eq. 181)
TMSO
Ph PhNO, CHCl3
rt, 4-6 h PhN
O OTMS
PhN
O
Ph
Et3N, CHCl3
rt, 1 d
81 (80%)
(100%)
PhN
O
Ph(80%)
1. HCl, THF, rt
2. Ag2O, C6H6, rt
Ph
HN
Ph(75-78%)
OHLiAlH4, Et2O, rt
or Pd/C, H2, THF, rt
Ph
O
(Eq. 182)
α-Chloronitroso compounds581 react with alkyl- and arylmagnesium rea-gents582,583 and with trialkylaluminum reagents584 to give nitrones. In
ELECTROPHILIC AMINATION OF CARBANIONS 63
contrast, allylzinc reagents and α-chloronitroso compounds furnish mostly O-allyloximes.585 An important application of these reagents is in the aminationof enolates586 – 594 (Eqs. 183587 and 184595). Using these methods, the reactionsapparently proceed with somewhat higher diastereoselectivity than aminationsof N -acyloxazolidinones. However, amination of a β-lactam enolate withchloronitroso reagent 82, while completely trans selective, occurs with poordiscrimination between the two enantiomers of the enolate (products 83 and 84,Eq. 185).592 A mannose-derived α-chloronitroso compound has been prepared596
but apparently not yet applied in amination reactions.
N
SO2
1. KHMDS, THF, –78°, 30 min
2. , –78°, 30 minCl NO
O
N
SO2
O
NO
+
–
Ph Ph
N
SO2
O
PhNHOHHCl, H2O
rtO
PhNH2
1. Zn, HCl, HOAc, rt
2. LiOH
(78%) >99% de(87%) >99% ee
HO
(Eq. 183)
R
Cl
NO
Ph
O1. LiHMDS2. ZnCl2
Ph
O
NO
+–
R
82 R = SO2N(C6H11-c)2
1. HCl2. NaBH4, MeOH
Ph
OH
NH2
(68%) 90% de, 96% ee
3. 82 3. Zn, HCl, HOAc
(Eq. 184)
NO Ar
HPh
1. LDA, –78°, 10 min2. 82, –78° to –30°, 2 h
NO Ar
NO Ar
+
Ar = C6H4OMe-483 84(58%) 83:84 = 3:2
HONH PhPh HONH
3. HCl (Eq. 185)
Amination With Nitro CompoundsThe reaction of Grignard reagents with nitro compounds is complex and the
products depend on the nature of both reactants, but a number of useful syn-thetic schemes have been developed in recent years. Alkylmagnesium reagentsundergo 1,2- or 1,4-addition to aromatic nitro compounds to give ring-alkylatedintermediates that may be converted into ring-alkylated arylnitro compounds oranilines.597 The less basic organocerium reagents react with nitroalkanes to giveN,N-disusbstituted hydroxylamines.598 N -Allyl-599 and N -allenylmagnesium600
64 ORGANIC REACTIONS
halides react with nitroalkanes and nitroarenes to give N -allyl- and N -propargyl-,N -alkyl- and N -arylhydroxylamines after reduction of the intermediate hydrox-ylamine N -oxides. Nitrones can be isolated from the reaction of allyl- andbenzylmagnesium reagents with nitroalkanes601 – 603 (Eq. 186).603 Arylmagnesiumreagents react with nitroarenes to give nitroso arenes which rapidly react withanother molecule of the arylmagnesium halide to give diarylhydroxylamines inlow to good yields;604 the formation of diarylamines has also been reported.605 Byreducing the unstable diarylhydroxylamines in situ, diarylamines are accessiblein good yields (compare to Eq. 180).606
O2NTHF, –78°
20 min
Ph NO–
+Ph N
O–
++
Ph MgCl +
(29%) (46%)
Ph N–O OMgCl
+
(Eq. 186)
Reactions of nitroarenes with vinylmagnesium halides give indoles (the Bartolireaction).607 Site selectivity problems may be avoided by temporarily installinga bromine ortho to the nitro group (Eq. 187).608
BrNO2
MgBr+
3 eq
THF, –40°, 1 h
BrNO
BrN
O
MgBr BrNMgBr
O
Br
N OMgBr
Br
NH
(67%)NH
(91%) Bu3SnH, AIBN
toluene, 110°, 12 h
(Eq. 187)
Reaction of the highly explosive fluorotrinitromethane with the anion of 2,4,6-trinitrotoluene, prepared with potassium hydroxide, gives the highly explosiveα,2,4,6-tetranitrotoluene in 89% yield.609 Ketone enol silyl ethers and the equallyhighly explosive tetranitromethane react to give α-nitro ketones in low to veryhigh yields (Eq. 188).610
OTMS
Ph
1. C(NO2)4, pentane, –30°, 6 h
2. KF, H2O, 30 min
O
PhNO2
(55%)
(Eq. 188)
ELECTROPHILIC AMINATION OF CARBANIONS 65
N,N-Disubstituted nitroxides are formed in the reaction of tert-butylmagnesiumchloride with 1,1-dimethylnitroethane611 and nitroarenes,612,613 and by reactionof 1,1-dimethylnitroethane with arylsodium or aryllithium reagents.614
Amination of Enolates with Diazonium Salts
Enolates of β-dicarbonyl and similar doubly activated compounds are aminatedby aryldiazonium salts to give hydrazones by rearrangement of the intermediateazo compounds.14,15,615,616 The Japp-Klingemann reaction617,618 is a variation inwhich either acyl cleavage or decarboxylation occurs in situ after the amination.The hydrazones may be reduced to amines.619
The Diazo Transfer Reaction
Stabilized carbanions react with certain azides to give diazo compounds(Eq. 30, path A)620 – 624 Substrates include enolates with one additional activatinggroup and cyclopentadienide anions.625 Simple ketones only rarely322,324 undergothe diazo transfer reaction unless a formyl group is installed temporarily in theα-position. Only one example of an alkylcarbanion leading to a diazo compoundwas found in the literature.626 The most widely used azide is tosyl azide but lessdangerous sulfonyl azides have been proposed as alternatives.627 – 629 The vastmajority of diazo compounds preparared in this manner is used as precursors tocarbenes or carbenoids although methods exist for their reduction to hydrazones,hydrazines, or amines.198,205,630 Diastereo- or enantioselective reductions of thiskind do not seem to have been reported although the carbenoid NH insertion631
reaction shown in Eq. 189632 indicates that they may be feasible.
NMe
POPh O
N2
PhBnOCONH2, Rh2(OAc)4 (cat)
toluene, 80°, 5 h NMe
POPh O
Ph
NHCO2Bn
(56%) 15% de
(Eq. 189)
Amination of Boranes
Organoboranes, which are readily accessible by hydroboration of olefins,633
undergo many of the amination reactions also observed with alkyl carbanions butoften afford higher yields with fewer complications.634 Thus organoboranes giveamines by reaction with chloramine635 and its dialkyl derivatives, N -chloro O-(2,4-dinitrophenyl)hydroxylamine,636 hydroxylamine O-sulfonic acid,635,637,638
O-(2,4-dinitrophenyl)hydroxylamine,639 the lithium or potassium salts of tert-butyl N -tosyloxycarbamate,640 chloramine-T,641 and azides.642 – 644 Enantiomer-ically enriched amines are formed using chiral, non-racemic borane645,646 orboronic esters.220,647,648 Reaction of triphenylborane with hydroxylamine O-sulfonic acid gives aniline.649
66 ORGANIC REACTIONS
The Neber RearrangementThe Neber rearrangement650 – 653 is a method for preparing α-amino ketones
by base-catalyzed intramolecular rearrangement of ketoxime O-sulfonates. Theintermediate azirine,654 – 656 which can be isolated, can also lead to aziridinederivatives when the base is lithium aluminum hydride657 or a Grignard reagent(the Hoch-Campbell reaction)658,659 (Eq. 190).
R1 R2N
OY– HOY
pyridine
or RO–
LiAlH4
R3MgX
R1 R2O
NH2
N
R1
R2
NH
R1
R2
NH
R1
R2
R3
(Eq. 190)
EXPERIMENTAL CONDITIONS
A number of reagent and product classes discussed in this chapterrequire special handling. Haloamines are toxic and explosive; the exper-imental hazards are eliminated or greatly reduced by using solutionsin inert solvents.10 Some O-sulfonylhydroxylamines are explosive: O-(2,4-dinitrobenzenesulfonyl)hydroxylamine is flammable, highly toxic, and highlyexplosive; an explosion occurred when brought in contact with potassiumhydride.93 An explosion of O-mesitylenesulfonylhydroxylamine occurred on stor-age below 0 ◦.114 Dry aryldiazonium salts are explosive. Hydrazoic acid and itssalts are toxic. Organic azides are explosive. Distillation should be avoided or car-ried out at low temperatures behind a shield. Tosyl azide has the exposive powerof TNT.627,660,661 Triazenes, the products of the reaction of azides with carbanions,are potent chemical carcinogens 258 and vesicants.259 Low-molecular-weight tri-azenes have high vapor pressures. Some are explosive and cause headaches.662
Chromium and cadmium salts are toxic.The great variey of reagents and substrates dealt with in this chapter does
not permit a detailed discussion of conditions for each experiment. Most ofthe reactions require flame-dried glassware, anhydrous solvents, and an inertatmosphere of nitrogen or argon.
Preparation of Electrophilic Aminating ReagentsReferences to the preparation of electrophilic aminating reagents are given in
Table A.
ELECTROPHILIC AMINATION OF CARBANIONS 67
Table A
References to the Preparation of Amination Reagents
1. Haloamines. Reviews: refs.10, 663. ClNH2: refs. 664-668; method of analysis: ref. 64. BrNH2: ref. 669. Cl2NH: refs. 663, 667. Cl3N: ref. 670. RNHCl, R2NCl, RNCl2; R = alkyl: ref. 68. R2NCl from R2NH and N-chlorosuccinimide: refs. 671-673. ClNHCO2R: ref. 674.2. O-Substituted Hydroxylamines: review ref. 675. a. O-Alkyl-Substituted Hydroxylamines: refs. 676-680. MeONH2: refs. 681-683. EtONH2: ref. 682. BnONH2: refs. 85, 680, 684, 685. MeONHR [R = Bn, 2-MeC6H4, Ph(CH2)3]: ref. 85. MeONR2 (R = alkyl): ref. 85. RONMe2 (R = alkyl): ref. 677. b. O-Arylhydroxylamines PhONH2: ref. 686. 2-O2NC6H4ONH2: ref. 94. 4-O2NC6H4ONH2: refs. 94, 96, 107. 2,4-(O2N)2C6H3ONH2: refs. 93, 94, 96, 687-689. various substituted 2-O2NC6H3ONH2 and 5-O2NC6H3ONH2: ref. 96. 2,4,6-(O2N)3C6H4ONH2: ref. 94. c. O-Acylhydroxylamines: refs. 679, 699. Me3CCO2NH2: ref. 690. BzONH2: refs. 690, 691. 3-ClC6H4CO2NH2: ref. 690. 4-O2NC6H4CO2NH2: ref. 690. 2,4,6-Me3C6H2CO2NH2: refs. 690, 692, 693. BzONHR ( R = alkyl): ref. 694. RCO2NHCO2Bu-t (R = t-Bu, aryl: ref. 690. BzONR2: refs. 109, 695.
d. O-Sulfonylhydroxylamines HSO3ONH2: refs. 696-698. MeSO2ONH2: ref. 137. PhSO2ONH2: ref. 133. 4-MeC6H4SO2ONH2: refs. 132, 699. 2,4,6-Me2C6H2SO2ONH : refs. 700 (review), 116, 133, 693, 699-703. 2
Hazards: refs. 114, 116, 395, 703, 704. 2-O2NC6H4SO2ONH2: ref. 705. 2,4-(O2N)2C6H3SO2ONH2: ref. 705. 2,4,6-(O2N)3C6H2SO2ONH2: ref. 705. ArSO2ONEt2 (Ar = Ph, 2,4,6-Me3C6H2): ref. 133. ArSO2ONR2 (Ar = Ph, 2,4,6-Me3C6H2; NR2 = 1-piperidinyl): ref. 134. TsONHCO2Et: ref. 119. TsON(M)CO2Bu-t (M = Li, MgCl): refs. 127. ArSO2ON(Li)CO2CH2CH=CH2 (Ar = 4-MeC6H4; 2,4,6-Me3C6H2): ref. 130. 4-O2NC6H4SO2ONHP(O)NHSO2C6H4NO2-4: ref. 706.
68 ORGANIC REACTIONS
SO2ONH2O
Brref. 534
NP
O O
ONMe2
Ph
ref. 147
O
O
NHOSO2C6H4-NO2-4
NC6H3Me2-3,5
SO2Ph
ref. 707
NOSO2CF3
ref. 708
e. OSi-Substituted Hydroxylamines TMSONHOTMS: refs. 699, 709. TMSONHR (R = alkyl): refs. 101, 709. TMSONHBn: ref. 709.f. O-Phosphinylhydroxylamines Ph2P(O)ONH2: refs 138, 141, 710-713. (4-MeOC6H4)2P(O)ONH2: refs. 106, 141, 712, 713. (4-MeC6H4)2P(O)ONH2: refs. 141, 712, 713. Ph2P(O)ONMe2: refs. 85, 714. Ph2P(O)ONR1R2 (R1 = alkyl; R2 = alkyl, allyl, Bn): ref. 715. Ph2P(O)ONR1R2 (R1R2 = (CH2)4, CH=CH-CH=CH): ref. 715. Ph2P(O)ONR2 (R = alkyl, c-C6H11, Bn): ref. 716.
3. Oxaziridines
O
HN
ONH N
H
O
ref. 718 ref. 718ref. 148
O
HN
ref. 717
ONR3R1
R2
R2
HMeCO2EtPhCF3
HHHH
HPh
R3
CO2Bu-tCOMe (chiral)CO2Bu-tCO2Bu-tCO2Bu-tCO2MeCO2Bu-tCONEt2
CONHCH(Me)CH(ODBDPS)Ph (derived from pseudoephedrine) 9-fluorenylmethoxycarbonylCO2Me
Refs.719717155155155153
157, 720158155
720153
R1
CCl3MeCO2EtCO2MePhArArArAr
ArPh
4. Imines
NEtO2C
EtO2C
C6H4OMe-4
ref. 167
NArCF3
EtO2C
ref. 721
5. (N-Arylsulfonylimino)phenyliodinanes TsN=IPh: ref. 722.
ELECTROPHILIC AMINATION OF CARBANIONS 69
6. OximesN
R1
R2
OR3
R1
HMePh4-CF3C6H4
4-CF3C6H4
3,5-(CF3)2C6H3
R2
HMeMe, Ph4-CF3C6H4
4-CF3C6H4
3,5-(CF3)2C6H3
R3
Bn (see Eq. 6)SO2C6H2Me3-2,4,6SO2Ph, 4-BrC6H4SO2, 4-MeC6H4SO2
SO2MeSO2C6H4Me-4SO2C6H4Me-4
Refs.723724725179, 726179179
7. Diazonium Salts
SO2
–N
O2S
ref. 728
8. Azo Compounds
R1
PhPhArArArNHCO
R2
CO2RCOPhSO2C6H4Me-4COArCO2R
Refs.401, 729, 730729255389, 729383, 731
R1N=NR2
Z
YN
OSO2Ar
YOONMeONMe
ZOOONMeNMe
R1
R1
R1
R1
R1
HMeHHH
refs. 181, 182 NTsO
Ph
PhPh
Ph
ref. 727
ArN2+
R1
EtCl3CCH2
Cl3CCH2
allylt-BuPhBn(+)-menthyl(–)-menthyl(–)-bornyl(–)-isobornyl
R2
EtCl3CCH2
(CH2)2TMSallylt-But-BuBn(+)-menthyl(–)-menthyl(–)-bornyl(–)-isobornyl
Refs.732733, 734380735736410737408218406408
R1O2CN=NCO2R2
O
O
N
O
(CH2)n N
OO
n = 1, 2 ref. 738
NN
MeN
NMe
O
O
ref. 219
70 ORGANIC REACTIONS
10. "TSN=Se=NTs": refs. 348, 349, 754.11. Nitridomanganese complexes reviews: 24, 25
refs. 471, 755, 756
RSO2N3
RTMSTMSCH2
EtO2Ct-BuCH=CHPhSCH2
(PhO)2P(O)
Refs.739see Experimental Procedures302, 740741see Experimental Procedures742
RN3
RMeCF3
4-MeC6H4
RPh R = H, 2-I, 2-NO2
2,4,6-(i-Pr)3C6H2
4-AcNHCOC6H4
polymer-bound
Refs.743309, 744, 745335, 746, 747hazards: 627, 660, 661safer analogs: 627-629, 748 448, 748-750751752, 753NCON3
SO2
ref. 304
9. Azides
N N
O O
R2
R1
R2
R1
N
Mn
R3 R3
Conversions of Amination ProductsThe following is a selection of procedures for the conversion of non-amine
amination products into amines and other nitrogen-containing compounds. Rele-vant information may also be found in reviews of protecting groups.757,758
N -Tosylamines into Amines: Bu3SnH,349 Na/liquid ammonia.348
N -Tosylamines into N -Tosylimines: SeO2.345
Azo Compounds into Hydrazines: Al/Hg.205
Azo Compounds into Amines:759 H2/Pd.196,197,415
Hydrazides into Amides or Amines:759 TFA-SmI2;233,481,760 peracids;761
Raney nickel;405,432,460,762−765 sodium in liquid ammonia;762,766 N2O3 orNaNO2/HOAc;767,768 H2/Pt.411,769,770
Triazene Salts into Amines: NaBH4;311 Ac2O-Al/Hg;317 sodium bis(2-methoxyethoxy)aluminum hydride.333
Azides into Amines:20,23,771,772 H2/Pd or H2/Pt;317,318,339,450,773 H2/Pd-(Boc)2Oin N -acyloxazolidinones to prevent reaction of the amine with the chiralauxiliary;774 Raney nickel;444 SnCl2;444,450,458,775,776 Zn;777 Al/Hg;777 sodiumborohydride under phase-transfer conditions;778 lithium aluminum hydride;779
H2S;780 triphenylphosphine.325,781,782
Azides into Imines: base.783 – 785
Azides into Enamines: NaReO4.331
ELECTROPHILIC AMINATION OF CARBANIONS 71
EXPERIMENTAL PROCEDURES
Procedures are listed by type of reagent in the same order as in the section onReagents and Mechanisms.
+ CuCNTHF, –40°
PhCu(CN)Li1. i-Pr2NLi, –40°
2. O2, –78°, 20 min
Li N(Pr-i)2
(60%)
N ,N -Diisopropylaniline (Amination of an Arylcopper Reagent with a Li-thium Dialkylamide).54 Copper(I) cyanide (2 mmol) was added at −40◦ to asolution of phenyllithium (2 mmol) in THF (10 mL) and the mixture was stirredfor 20 minutes. A THF solution of LDA was added and after 15 minutes at −40◦
the mixture was cooled to −78◦ and a vigorous stream of oxygen was introducedfor 20 minutes. The mixture was allowed to warm to room temperature andpassed through a pad of celite. Concentration and kugelrohr distillation of theresidue (100◦ bath temperature, 20 mmHg) gave 0.21 g (60%) of the title productas an oil: 1H NMR (CDCl3) δ 7.69–7.33 (m, 5H), 3.80 (m. 2H) and 1.24 (d,J = 6.8 Hz, 12H). Anal. Calcd for C12H19N: C, 81.29; H, 10.81; N, 7.90. Found:C, 82.00; H, 10.81; N, 8.92.
EtO2C CO2Et1. NaH, benzene EtO2C CO2Et
NH2(89%)
2. ClNH2, morpholine, Et2O, rt, overnight; reflux, 5 h
Diethyl Aminomalonate (Amination of a β-Dicarbonyl Compound withChloramine).62 Diethyl malonate was converted into the sodium salt withsodium hydride in benzene and the solvent was removed. To a suspension ofthe salt (11.3 g, 0.06 mol) in Et2O (100 mL) was added with cooling a solutionof chloramine in Et2O (0.12 mol) followed by morpholine (5.22 g, 0.06 mol).The mixture was stirred with cooling for 2 hours and at room temperature overnight and then refluxed for 5 hours. The filtered mixture was concentrated and theresidue was distilled to give 10.9 g (89%) of the title compound, bp 116–117◦
(18 mmHg). The product gave the correct elemental analysis and the physicalproperties were those reported in the literature.
MeLi +
HN
MeO ether, hexanes
–78°
LiN
MeO t-BuLi, pentane
–78° to –10°
HN
t-Bu(99%)
N-tert-Butylbenzylamine (Amination of an Alkyllithium Compound witha Lithium Nitrenoid).85 To a solution of MeLi in Et2O (1.40 mL, 1.54 mmol)was added at −78◦ a solution of N -benzyl-O-methylhydroxylamine (0.21 g,1.53 mmol) in hexanes (5 mL). After stirring for 5 minutes, a solution of t-BuLiin pentane (1.2 mL, 1.28 M, 1.53 mmol) was added, the mixture was allowed towarm to −10◦ and kept at that temperature for 2 hours. Water and Et2O were
72 ORGANIC REACTIONS
added and the dried (Na2SO4) Et2O solution was concentrated. The residue wasdistilled (kugelrohr) to give 0.28 g (99%) of the title product, bp 70◦ (0.5 mmHg):1H NMR (CDCl3) δ 7.33 (s, 5H), 3.73 (s, 2H) and 1.18 (s, 9H); 13C NMR δ
141.4, 128.4, 128.2, 126.7, 50.6, 47.2, 29.1. Anal. Calcd for C11H17N: C, 80.93;H, 10.50; N, 8.58. Found: C, 80.59; H, 10.91; N. 8.67.
Br
F
1. n-BuLi, hexanes, –78°2. CuBr•Me2S
NHCO2Bu-t
F
(50%)3. TsON(Li)CO2Bu-t, THF, –78°
tert-Butyl 4-Fluorophenylcarbamate (Amination of an Arylcopper Rea-gent with Lithium tert-Butyl N -Tosyloxycarbamate).127 A solution of n-BuLiin hexane (0.4 mL, 2.5 M, 1 mmol) was added dropwise at −78◦ to a solutionof tert-butyl N -tosyloxycarbamate (0.287 g, 1 mmol) in THF. The mixture wasstirred at −78◦ for one hour. In a separate vessel, a solution of 4-fluoro-1-bromobenzene (1 mmol) was treated with one equivalent of n-BuLi in hexaneat −78◦ for 30 minutes and then cannulated into a suspension of CuBr•Me2S(1 mmol) in THF (2 mL). The mixture was stirred at −60◦ to −78◦ for onehour, cooled to −78◦, treated dropwise with the solution of lithium tert-butylN -tosyloxycarbamate, and stirred at −78◦ for 30 minutes. A saturated aqueoussolution of NH4Cl and ammonia (5 mL) was added and the aqueous phase wasextracted with Et2O. The combined organic phases were washed with brine,dried (MgSO4), and concentrated. Flash chromatography of the residue (1:5EtOAc/cyclohexane) gave 0.105 g (50%) of the title product, mp. 111◦: IR (KBr)2255, 1690 cm−1; 1H NMR (CDCl3) δ 7.31 (m, 2H), 6.97 (m, 2H), 6.6 (s, 1H);1.51 (s, 9H); 13C NMR δ 158.6, 156.2, 134.2, 120.2, 115.4, 80.5, 28.2. Anal.Calcd for C11H14FO2N: C, 62.55; H, 6.68; N, 6.62. Found: C, 62.45; H, 6.69;N, 6.47.
Ph2Zn +
O
NO
Bz
CuCl2 (2.5 mol%)
THF, 0-5°, 90 minO
NPh
(67%)
N -Phenylmorpholine (Amination of an Arylzinc Derivative with an O-Acylhydroxylamine). This procedure is found in Organic Syntheses.111
NH
1. n-BuLi (2.1 eq), THF, hexane, TMEDA, 0°
NH
Et2N
(43%)2. 2,4,6-Me3C6H2SO2ONEt2, –78°; to rt, overnight
ELECTROPHILIC AMINATION OF CARBANIONS 73
N,N-Diethyl-5,10-dihydroindeno[1,2-b]indol-10-amine (Amination of aBenzylic Anion with an N,N-Disubstituted O-Arenesulfonylhydroxyl-amine).136 A solution of n-BuLi (30 mL, 2.25 M in hexane, 67.5 mmol) wasadded with ice cooling to a solution of 5,10-dihydroindeno[1,2-b]indol (6.6 g,32.1 mmol) and TMEDA (20 mL) in THF (200 mL), the mixture was stirredat room temperature for 45 minutes, and cooled to −78◦. Solid N,N-diethyl O-mesitylenesulfonylhydroxylamine (8.7 g, 39.7 mmol) (caution, the N,N-unsubsti-tuted analog is explosive) was added in one portion and the mixture was leftto warm to room temperature and stirred overnight. Et2O (150 mL) was addedand the organic phase was washed with water (2 × 100 mL) and then extractedwith 2 N HCl (2 × 60 mL). The precipitate that formed in the acid extracts wascollected by filtration and suspended in 2 N NaOH solution (100 mL). The mix-ture was extracted with Et2O (150 mL), which was then washed with water (3 ×100 mL). Concentration of the dried (MgSO4) Et2O solution gave 3.8 g (43%)of the title product as a brownish-pink solid, mp 126.0−126.5◦, unchanged oncrystallization from petrol ether: 1H NMR (CDCl3) δ 8.2 (br s, 1H), 7.91–7.03(m, 8H), 4.87 (s, 1H), 2.58 (q, J = 7 Hz, 4H), 1.08 (t, J = 7 Hz, 6H). Anal.Calcd for C19H20N2: C, 82.56; H, 7.28; N, 10.13. Found: C, 82.81; H, 7.29;N, 9.93.
CO2Et
1. KOBu-t, THF, –78°2. (4-MeOC6H4)2P(O)ONH2, –78° to rt
CO2Et
NHAc
(67%)3. Ac2O, Et3N
Ethyl (N -Acetylamino)phenylacetate (Amination of an Ester Enolate withan O-Phosphinoylhydroxylamine).106 A freshly prepared solution of KOBu-t(31 mg, 0.28 mmol) in THF (2 mL) was added slowly to a solution of ethylphenylacetate (41 mg; 0.25 mmol) in THF (3 mL) cooled to −78◦ and the mix-ture was stirred at −78◦ for 15 minutes. O-[Di(p-methoxyphenyl)]phosphinoyl-hydroxylamine (caution, related hydroxylamine derivatives are explosive) (81 mg,0.28 mmol) was added as a solid in one portion, and the mixture was left to warmto room temperature and stirred overnight. Acetic anhydride (71 µL, 0.75 mmol)and triethylamine (210 µL, 1.5 mmol) were added and the mixture was stirredat room temperature for one hour. Et2O (20 mL) and saturated aqueous NH4Clsolution (30 mL) were added, and the aqueous layer was extracted with Et2O (2x 30 mL). The dried (MgSO4) extracts were concentrated and the residue waspurified by flash chromatography (1:1 EtOAc:cyclohexane) to give 37 mg (67%)of the title product as a colorless oil, Rf 0.20 (1:1 EtOAc:cyclohexane). No otherdata were reported.
NH (2.5 eq)O
DABCO, toluene,rt, 12 h
CONHPh
CONHPh
CONHPh
CONHPh
H2N
H2N
CONHPh
CONHPh
EtOH, refluxHN
(91%) (96%)
74 ORGANIC REACTIONS
Diamino-N ,N ′-diphenylmalonamide and Imino-N ,N ′-diphenylmalona-mide (Diamination of a Malonamide with 1-Oxa-2-azaspiro[2.5]octane andConversion of the Product into an Imine).149 A suspension of N ,N ′-diphen-ylmalonamide in a mixture of toluene and 2.2–2.5 equivalents of 1-oxa-2-azaspi-ro[2.5]octane was treated with a solution of 1,4-diazabicyclo[2.2.2]octane (5–10mol%) in toluene (1 mL). The solid was collected by filtration after 12 hoursat room temperature, washed with a small amount of EtOH, and air dried togive diamino-N ,N ′-diphenylmalonamide in 91% yield, mp 130−132◦: 1H NMR(DMSO-d6) δ 6.9-7.9 (m, 10H), 3.2–3.6 (br, 6H); 13C NMR (DMSO-d6) δ 170.6,138.3, 128.6, 123.6, 119.4, 73.9. Anal. Calcd for C15H16N4O2: C, 63.37; H, 5.67;N, 19.71. Found: C, 62.60; H, 5.85; N, 19.74.
A 10% solution of diamino-N ,N ′-diphenylmalonamide in EtOH was heatedunder reflux for 15 minutes. The solid was collected after 12 hours at roomtemperature and air-dried to give imino-N ,N ′-diphenylmalonamide in 96% yield,mp 158−162◦. 1H NMR (DMSO-d6) δ 12.33 (br, 1H), 10.5 (br, 2H), 6.9–7.9 (m,10H); 13C NMR (DMSO-d6) δ 159.8, 162.3, 164.1, 137.3, 137.3, 119.7, 120.4,128.6, 128.9, 124.3, 124.4. Anal. Calcd. for C15H13N3O2: C, 67.40; H, 4.90; N,15.72. Found: C, 66.70; H, 5.05; N, 16.34.
CO2Et
CN
ONCO2Bu-t
EtO2C
EtO2C
1. LiHMDS, THF, –78°CN
CO2EtNHCO2Bu-t
(70%)2. , –78°, 20 h
Ethyl tert-Butoxycarbonylamino(cyano)phenylacetate (Amination of aCyanoacetic Ester Enolate with an N -Acyloxaziridine).155 Ethyl phenyl-cyanoacetate (0.22 mmol) was added to a solution of LiHMDS (0.22 mL, 1.0M in hexane, 0.22 mmol) at −78◦. After 30 minutes, a solution of N-tert-butoxycarbonyl-3,3-bis(ethoxycarbonyl)oxaziridine (95 mg, 0.33 mmol) in THF(1 mL) was added, the mixture was stirred at −78◦ for 12 hours and then left towarm to room temperature. CH2Cl2 and saturated aqueous NH4Cl were added,and the organic layer was washed twice with saturated NH4Cl. Removal ofthe solvent from the dried (Na2SO4) solution and flash chromatography of theresidue (10:1 petrol ether/EtOAc) gave 47 mg (70%) of the title product as anoil: IR (film) 2253, 1754, 1721 cm−1; 1H NMR (CDCl3) δ 7.67 (br 2H), 7.46-7.45 (m, 3H), 5.75 (br, 1H), 4.25 (q, J = 7.2 Hz, 2H), 1.46 (s, 9H), 1.25 (d,J = 7.2 Hz, 3H). MS-CI (m/z): [M + H]+ calcd for C16H20N2O4: 305.1501;found: 305.1511.
i-PrMgBrN
MeO
CO2Me
CO2Me
THF, –95°Pr-iN
MeO
CO2Me
CO2Me
KOH, EtOH
air, rt, 48 h
NHPr-i
MeO(57%)
+
ELECTROPHILIC AMINATION OF CARBANIONS 75
N -Isopropyl-p-anisidine (Amination of a Grignard Reagent with anImine).167 Isopropylmagnesium bromide (0.83 M in THF, 0.54 mL, 0.45 mmol)was added slowly to a solution of diethyl 2-[N -(p-methoxyphenyl)imino]malo-nate (84 mg, 0.30 mmol) in THF (5 mL) at −95◦. After 30 minutes saturatedaqueous NaHCO3 was added and the mixture was extracted with EtOAc (3 ×10 mL). The combined extracts were washed with brine, dried (Na2SO4), and thesolvent was removed. The residue was stirred vigorously with 1 M aqueous KOH(0.11 mL) and EtOH (3.3 mL) at room temperature for 48 hours. The EtOH wasremoved after addition of aqueous Na2SO3 and the residue was extracted withEtOAc (3 × 10 mL). The extracts were washed with brine, dried (Na2SO4),and the solvent was removed. Preparative TLC of the residue (silica gel, 1:15EtOAc:hexane) gave 28 mg (57%) of the title product: 1H NMR (CDCl3) δ 6.57(d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 1.19 (d, J = 6.3 Hz, 6H), 3.74(s, 3H), 3.61–3.48 (m, 1H); 13C NMR (CDCl3) δ 23.07, 45.24, 55.79, 114.93,141.73, 151.95.
OTMS
+ TsN=IPhMeCN, warm
ONHTs
(95%)
2-[N -(p-Toluenesulfonyl)amino]acetophenone (Amination of a Ketone SilylEnol Ether with [N -(p-tolylsulfonyl)imino] phenyliodinane).172 A solution of1-(trimethylsilyloxy)styrene (0.5 mmol) in dry MeCN (7 mL) was treated withTsN=IPh (0.6 mmol). The mixture was warmed and the solvent was removedafter the reagent had dissolved. The residue was purified by chromatography onsilica gel followed by crystallization from Et2O to give the title product in 95%yield. No analytical or spectroscopic data were reported.
MgBrOO
NO
SO2Ph
+N
O O
PhCl, 0° HCl, EtOH
reflux, 6 h NH3+ Cl–
(89%)
1-Aminoadamantane Hydrochloride (Amination of a Grignard Reagentwith an O-Arenesulfonyloxime).182 To a solution of 4,4,5,5-tetramethyl-1,3-dioxolane-2-one O-benzenesulfonyloxime (602 mg, 2.01 mmol) in chloroben-zene (14 mL) was added dropwise at 0◦ 1-adamantylmagnesium bromide (0.63M in Et2O, 3.5 mL, 2.2 mmol) and the mixture was stirred at 0◦ for 30 minutes.The reaction was quenched with pH 9 buffer at 0◦ and the mixture was extractedthree times with EtOAc. The combined extracts were washed with brine, dried(Na2SO4), and concentrated. The crude imine was refluxed with 10 mL of EtOHand 1.3 mL of 6 M HCl for 10 hours. The ethanol was removed, the residue wasmade basic with 5 mL of 5 M NaOH, and the mixture was extracted three timeswith CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4),
76 ORGANIC REACTIONS
and concentrated. The residue was dissolved in MeOH, HCl in Et2O was added,and all volatiles were removed under vacuum. The residue was stirred with Et2Oand the solids were collected by filtration and dried to give 334 mg (89%) of thetitle product: 1H NMR (DMSO-d6) δ 8.18 (br, 3H), 2.05 (s, 3H), 1.79 (s, 6H),1.62 (d, J = 12.2 Hz, 3H), 1.54 (d, J = 12.2 Hz, 3H); 13C NMR (DMSO-d6)δ 51.1, 40.1, 35.4, 28.5.
t-BuMgCl +
O2S
NSO2
–N2
+
Cl
N
Cl
NBu-tTHF, –78°(86%)
E -(tert-Butyl)(4-chlorophenyl)diazene (Reaction of a Grignard Reagentwith an Aryldiazonium Salt).191 A suspension of 4-chlorobenzenediazoniumo-benzenedisulfonimide (1.77 g, 5 mmol) in anhydrous THF (15 mL) was stirredvigorously at −78◦, a solution of t-BuMgCl (5 mmol) was added over a periodof 10 minutes, and stirring at −78◦ was continued for one hour. The mixture waspoured into 30 mL of water and extracted with Et2O (2 × 30 mL). The washed(H2O, 30 mL) and dried (Na2SO4) extracts were heated in a 70◦ water bath toremove the Et2O and heating was continued for 1 hour to ensure conversionof any Z into the E isomer. Purification by column chromatography gave thetitle product in 83% yield, bp 57–58◦/0.25 mm: 1H NMR (CDCl3) δ 7.60 (d,J = 8.9 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H), 1.32 (s, 9H); 13C NMR (CDCl3)δ 150.5, 135.5, 128.8, 122.9, 67.5, 26.4.
NN
N
1. n-BuLi, THF, –78°
2. PhN=NPh
NHNn-BuPh
PhNLi
NNPh
Ph
NN
1. n-BuMgBr, –78° to rt
(57%)
2. NH4Cl
1,2-Diphenyl-1-(1-p-tolylpentyl)hydrazine (Amination of a Benzotriazolyl-methyl Anion with an Azo Compound Followed by Displacement of theBenzotriazole Functionality by a Grignard Reagent).359 To a solution of1-(4-methylbenzyl)benzotriazole (2 mmol) in THF (7 mL) was added n-BuLi(2 mmol) at −78◦ and the mixture was stirred at −78◦ for 10 minutes. n-BuMgBr(4 mmol) in Et2O was added followed by the azobenzene (2 mmol), and the mix-ture was left to warm to room temperature overnight. It was washed with 30 mLof 10% NH4Cl solution and the washing was extracted with EtOAc (2 × 10 mL).Removal of the solvents from the dried (MgSO4) organic phase and column chro-matography of the residue (SiO2, 1:1 toluene/hexane) gave the title product in57% yield, mp 97–99◦: 1H NMR δ 7.20–7.04 (m, 8H), 6.93 (d, J = 8 Hz,2H), 6.81–6.68 (m, 4H), 5.07 (br, s, 1H), 4.94 (t, J = 7 Hz, 1H), 2.28 (s, 3H),2.18–2.06 (m, 1H), 2.01–1.86 (m, 1H), 1.57–1.26 (m, 4H), 0.88 (t, J = 7 Hz,
ELECTROPHILIC AMINATION OF CARBANIONS 77
3H); 13C NMR δ 150.3, 148.5, 137.1, 129.1, 128.9, 128.1, 119.5, 115.2, 112.2,66.0, 31.2, 29.4, 22.7, 21.1, 14.1. Anal. Calcd for C24H28N2: C, 83.68; H, 7.93;N, 8.48. Found: C, 83.68; H, 8.06; N, 8.48.
PhSiH3, t-BuO2CN=NCO2Bu-t,
cobalt complex, EtOH, rt, 5 hBr
Br
NNHCO2Bu-tt-BuO2C
(90%)
L = MeOH
NCo
O
OO
O
NH2O
L
cobalt complex
tert-Butyl N -(3-Bromo-1-methylpropyl)-N ′-(tert-butoxycarbonyl)hydra-zinecarboxylic Acid (Catalyzed Hydrohydrazination of an Olefin with anAzo Ester).215 The Co catalyst (10 mg, 0.025 mmol) was dissolved in EtOH(2.5 mL) at room temperature under argon. To the brown-red solution were added4-bromo-1-butene (68 mg, 0.50 mmol) and phenylsilane (65 µL, 0.52 mmol),followed by di(tert-butyl) azodicarboxylate (0.17 g, 0.75 mmol) in one portion.The resulting solution was stirred at room temperature for 5 hours. Water (1 mL)and brine (5 mL) were added and the reaction mixture was extracted with EtOAc(3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, andthe solvents were removed under reduced pressure. The residue was purified bycolumn chromatography (1:15 EtOAc:hexane) to give 166 mg (90%) of the titleproduct, mp 88−90◦: 1H NMR (CDCl3, 300 MHz, 52◦
) δ 6.06 (br s, 1H), 4.38(m, 1H), 3.45 (m, 2H), 2.13 (m, 1H), 1.82 (m, 1H), 1.46 (s, 18H), 1.12 (d,J = 6.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz, 52◦
) δ 156.0, 154.7, 81.3, 52.2,37.5, 30.5, 28.3, 28.2, 18.0. Anal. Calcd for C14H27N2O4Br: C, 45.78; H, 7.41;N, 7.63. Found: C, 45.98; H, 7.48; N, 7.63.
S Br1. Zn*, THF, rt
2. t-BuO2CN=NCO2Bu-t, 0° to rt S NNHCO2Bu-t
CO2Bu-t(80%)
2-[N ,N ′-bis(tert-Butoxycarbonyl)hydrazino]thiophene (Amination of aHeterocyclic Zinc Reagent with an Azo Ester).358 To 1.5 equivalents of activezinc in THF, contained in a 50-mL centrifuge tube, was added 2-bromothiophene(0.163 g, 1 mmol) with stirring at room temperature. The mixture was stirred for30 minutes, then centrifuged. The supernatant was cannulated into another flaskand di(tert-butyl) azodicarboxylate (1 mmol in THF) was added over 5 minutes at0◦. After stirring for one hour the reaction was quenched with saturated aqueousNaHCO3, the mixture was extracted with Et2O, the solvent was removed, andthe residue was purified by flash chromatography (silica, hexanes/EtOAc) to give
78 ORGANIC REACTIONS
1.2 g (80%) of the title product, mp. 82–84◦ (Et2O): 1H NMR (DMSO-d6, 100◦)δ 9.54 (br s, 1H), 7.03 (dd, J = 5.5, 1.6 Hz, 1H), 6.82 (dd, J = 5.5, 3.8 Hz,1H), 6.70 (dd, J = 3.8, 1.6 Hz, 1H), 1.47 (s, 9H), 1.44 (s, 9H). Anal. Calcd forC14H22N2O4S: C, 53.43; H, 7.05; N, 8.91; S, 10.20. Found: C, 53.8; H, 7.0; N,8.7; S, 10.2.
1. BnO2CN=NCO2Bn, L-proline, MeCN, 0° to rt, 3 h
BnO2CNH
NOH
CO2Bn
CHO
(94%) 97% ee
2. NaBH4, EtOH3. NaOH
(R)-Dibenzyl 1-(1-Hydroxyhexan-2-yl)hydrazine-1,2-dicarboxylate (Cata-lytic Asymmetric Amination of an Aldehyde with an Azo Ester).221 Hex-anal (1.5 mmol) was added to a solution of dibenzyl azodicarboxylate (330 mg,1 mmol) and L-proline (12 mg, 0.1 mmol) in MeCN (10 mL) at 0◦. The mixturewas stirred at 0◦ for 2 hours, warmed to room temperature during one hour, andcooled back to 0◦. EtOH (10 mL) and NaBH4 (40 mg) were added and the mix-ture was stirred at 0◦ for 5 minutes. Addition of aqueous NH4Cl and EtOAc andremoval of the solvent from the dried (MgSO4) organic phase gave the crude titleproduct, which was purified by column chromatography (EtOAc/hexanes) to give376 mg (94%) of the title compound as a colorless solid: 1H NMR (CDCl3) δ 7.35(m, 10H), 6.45 (s, 1H), 5.10 (m, 4H), 4.60–3.90 (m, 2H), 3.34 (m, 2H), 1.25(m, 6H), 0.83 (m, 3H); 13C NMR (CDCl3) δ 136.2, 135.8, 129.5, 129.1, 128.7,128.5, 69.1, 68.9, 62.9, 61.2, 28.8, 28.2, 22.3, 14.3; HRMS-MALDI (m/z): [M +Na]+ calcd for C22H28N2O5, 423.1890; found 423.1889. The enantiomeric excess(97%) was determined by conversion into the oxazolidinone (K2CO3, toluene,reflux, 1 hour) and HPLC on a Chiralpak AD-RH column.
OSiMe3 ON
NHCO2Bn
CO2Bn1. AgClO4, (R)-BINAP, BnO2CN=NCO2Bn, THF, –45°
(82%) 65% ee
2. add substrate, –45°, 5 h
(S )-Dibenzyl 1-(1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)hydrazine-1,2-dicarboxylate (Catalyzed Asymmetric Amination of a Ketone Silyl EnolEther with an Azo Ester).244 A solution of silver perchlorate (0.040 mmol)and (R)-BINAP (0.048 mmol, 12 mol%) in THF (1 mL) was stirred at roomtemperature for 30 minutes, cooled to −45◦, and treated with dibenzyl azodicar-boxylate (0.44 mmol). After stirring for 10 minutes, (3,4-dihydronaphthalen-1-yloxy)trimethylsilane (0.4 mmol) in THF (0.5 mL) was added and the mixturewas stirred at −45◦ for 5 hours. Aqueous HF (20%) and THF (1:1) were addedand the mixture was stirred at room temperature for one hour after which timeit was made basic with aqueous NaHCO3 solution and extracted with CH2Cl2.
ELECTROPHILIC AMINATION OF CARBANIONS 79
Removal of the solvent from the dried (MgSO4) extracts and preparative thin-layer chromatography of the residue gave the title product in 82% yield, mp141◦. 1H NMR (DMSO-d6, 70◦) δ 2.2–2.4 (m, 2 H), 2.9–3.5 (m, 2 H), 4.92 (brs, 1 H), 5.09 (s, 2 H), 5.13 (s, 2 H), 7.2–7.5 (m, 12 H), 7.56 (t, J = 7.5 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1 H), 9.35 (br s, 1 H). Anal. Calcd for C26H24N2O5:C, 70.26; H, 5.44; N, 6.30. Found: C, 70.52; H, 5.57; N, 6.13. The enantiomericexcess (65%) was determined by HPLC analysis (DAICEL, CHIRALCEL ODor AS).
N3
CO2Me
Br+
In, NaI, DMF
rt, 3.5 h
HN
CO2Me (75%)
Methyl 2-(Naphthalen-2-ylamino)methylacrylate (Amination of an Allylin-dium Species with an Azide).269 A mixture of 2-azidonaphthalene (5 mmol),methyl 2-(bromomethyl)acrylate (7.5 mmol), indium powder (7.5 mmol), sodiumiodide, (7.5 mmol), and DMF (15 mL) was stirred at room temperature for3.5 hours. Saturated aqueous NH4Cl (15 mL) was added and the mixture wasextracted with Et2O (2 × 15 mL). The solvent was removed from the extractsand the residue was purified by silica gel chromatography (0.5:9.5 EtOAc/hexane)to give the title product in 75% yield: IR (KBr) 1605 cm−1; NMR (CDCl3)δ 7.87–7.80 (m, 2H), 7.50–7.43 (m, 2H), 7.30 (d, J = 8 Hz, 1H), 7.25 (d,J = 8.0 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.35 (s, 1H), 5.85 (s, 1H), 4.25 (s,2H), 3.83 (s, 3H); EIMS (m/z): 241 (M+), 209, 180.
N3
+ EtMgBrEt2O, rt, 30 min NHEt
(90%)
N -Ethylaniline (Preparation of an N -Substituted Aniline by Reaction ofa Grignard Reagent with an Aromatic Azide).279 A solution of ethylmag-nesium bromide (15 mmol) in Et2O (20 mL) was added to a solution of phenylazide (1.19 g, 10 mmol) in Et2O (5 mL) at room temperature and the mixturewas stirred another 30 minutes. Saturated aqueous NH4Cl (15 mL) was addedand the mixture was extracted with ethyl acetate (2 × 25 mL). The extracts werewashed with water and brine, dried (Na2SO4), and concentrated. The residuewas purified by column chromatography (silica, 1:9 EtOAc:hexane) to give 1.09g (90%) of the title product as a pale yellow liquid. 1H NMR δ 6.8-6.5 (m, 5H),3.25 (br s, 1H), 3.15 (q, J = 8.0 Hz, 2H), 1.25 (t, J = 8.0 Hz, 3H); 13C NMRδ 148.2, 128.9, 116.8, 112.5, 38.1, 14.5; MS (m/z): 121 (M+), 106, 77, 51.
MgBr
TMS ClNaN3, DMF
80°, 44 hTMS N3 Et2O, rt, 3 h
NH2
(98%)(79%)
80 ORGANIC REACTIONS
2,4-Dimethylaniline (Preparation of Trimethylsilylmethyl Azide and ItsReaction with an Arylmagnesium Reagent to Give an Aniline).264 A mix-ture of trimethylsilylmethyl chloride (0.2 mol), sodium azide (0.24 mol), and dryDMF was heated at 80◦ for 44 hours. Distillation gave trimethylsilylmethyl azide,bp 43◦ (43 mmHg) in 97% yield. 1H NMR δ 2.75 (s, 2H), 0.12 (s, 9H). Theproduct is stable and can be stored in a refrigerator for at least 6 months but likeall azides it is potentially explosive and should be handled with care.
Trimethylsilylmethyl azide (1.2 eq) was added dropwise at room temperatureto a solution of 2,4-dimethylphenylmagnesium bromide (1 eq) in ether and themixture was stirred at room temperature for 3 hours. After conventional workupthe low-boiling substances were removed under reduced pressure, leaving thetitle product in 79% yield. It was identified by comparison of its properties withthose of an authentic sample.
S Cl NaN3, NaI (cat)
MeCN, reflux, 4.4 h
S N3(99%)
S
N1. n-BuLi, –75°2. MgBr, CuI, 0°
S
NNH2 (59%)
3. PhSCH2N3, 0° to rt4. KOH, MeOH, rt
2-Aminobenzothiazole (Preparation of Azidomethyl Phenyl Sulfide andIts Reaction with a Heterocyclic Grignard Reagent to Give a HeterocyclicAmine).274 A mixture of chloromethyl phenyl sulfide (40.0 g, 0.25 mol),sodium azide (32.5 g, 0.50 mol), dry MeCN (167 mL), and sodium iodide (100mg) was stirred and heated under reflux for 4.4 hours, cooled, diluted with Et2O,and filtered through celite. Removal of the solvents and distillation of the residuegave 40.8 g (99%) of azidomethyl phenyl sulfide as a colorless oil, bp 55–58◦
(0.23 mmHg): 1H NMR (CDCl3) δ 7.64–7.34 (m, 5H), 4.58 (s, 2H); 13C NMR(acetone-d6) δ 134.5, 131.2, 129.8, 128.0, 55.9.
A solution of benzothiazole (75 mg, 0.55 mmol) in Et2O (0.75 mL) was addedto a solution of n-BuLi in hexane (0.32 mL, 1.75 M, 0.55 mmol) and Et2O(0.75 mL) at −75◦. After 10 minutes, a solution of MgBr2 (0.26 mL, 2.24 M inbenzene/Et2O, 0.58 mmol) was added, followed by THF (0.75 mL). Azidomethylphenyl sulfide (96 mg, 0.58 mmol) was added and the solution was warmedto 0◦. Cuprous iodide (5.0 mg, 0.026 mmol) was added and after 1 hour themixture was warmed to room temperature, stirred for another 2 hours, and pouredinto saturated aqueous NH4Cl. The mixture was extracted twice with Et2O, theextracts were washed with brine, dried (Na2SO4), and concentrated. The residuewas stirred with THF (1 mL), methanol (1 mL), and 50% KOH in H2O (0.25 mL)at room temperature for 3 hours and the mixture was poured into water andextracted three times with Et2O. Acid-base purification and crystallization ofthe crude product from water gave 49 mg (59%) of 2-aminobenzothiazole, mp129–131◦ (lit. mp 129◦
): 1H NMR (CDCl3) δ 7.55 (t, J = 9.0 Hz, 2H), 7.30 (dt,J = 7.6, 1.2 Hz, 1H), 7.11 (dt, J = 7.6, 1.2 Hz), 5.35 (br s, 2H).
ELECTROPHILIC AMINATION OF CARBANIONS 81
NO
O
Bn
O
O
NBoc
1. KHMDS, THF, –78°2. 2,4,6-(i-Pr)3C6H4SO2N3, N
O
O
Bn
O
O
NBocN3
LiOH, rt
O
O
NBocN3
OH
(92%)
(97%)
–78°, 3 min3. HOAc
(4R)-3{(Z ,2R)-2-Azido-6-[(4R)-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidin-4-yl]-1-oxohex-5-enyl}-4-phenylmethyl-1,3-oxazolidinone and(4R)-4[(1Z ,5R)-5-Azido-5-carboxypent-1-enyl]-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidine (Diastereoselective Azidation of an N -Acyloxazoli-dinone with Trisyl Azide and Removal of the Chiral Auxiliary).440 KHMDSin toluene (2.85 mL, 0.5 M, 1.43 mmol) was added at −78◦ to THF (7.5 mL)followed by a pre-cooled (−78◦
) solution of the substrate (601 mg, 1.27 mmol;E/Z = 1:13) in THF (9.5 mL) by insulated steel cannula. The mixture was stirredat −78◦ for 80 minutes. Solid 2,4,6-triisopropylbenzenesulfonyl azide (591 mg,1.91 mmol) was added in one portion with vigorous stirring and the reaction wasquenched with AcOH/THF (1:1, 0.7 mL) after 3 minutes. The flask was imme-diately placed in a 28◦ water bath, the mixture was stirred for 30 minutes, andthen partitioned between 50 mL of half-saturated aqueous NH4Cl and 50 mLof EtOAc, and the aqueous phase was extracted with 2 × 50 mL of EtOAc.The combined extracts were dried (MgSO4) and concentrated, and the residuewas purified by flash chromatography (EtOAc/hexane) to give 602 mg (92%)of the title product as an oil, E/Z = 1:13. Crystallization (Et2O/hexane) gavethe pure Z-isomer, mp 87–88◦: [α]22
D −6.3◦ (c 1.15, CHCl3); IR (CHCl3)2108,1783, 1690 cm−1; 1H NMR (CDCl3) δ 7.12-6.82 (m, 5H), 5.51 (ddt, J = 10.7,9.2, 1.4 Hz, 1H), 5.38 (br dt, J = 10.7, 7.5 Hz, 1H), 5.18 (br q, 1H), 4.62 (m,1H), 4.15 (ddt, J = 9.2, 8.2, 3.2 Hz, 1H), 3.85 (dd, J = 8.6, 6.3 Hz, 1H), 3.54(dd, J = 8.6, 3.1 Hz, 1H), 3.35 (t, J = 9.1 Hz, 1H), 2.93 (dd, J = 13.6, 3.2 Hz,1H), 2.44–2.28 (m, 2H), 2.33 (dd, J = 13.6, 9.2 Hz, 1H), 2.08–1.94 (m, 1H),1.92–1.78 (m, 1H), 1.67 (s, 3H), 1.56 (s, 3H), 1.43 (s, 9H). Anal. Calcd forC26H35N5O6: C, 60.80; H, 6.87; N, 13.64. Found: C, 60.8; H, 6.9; N. 13.0.
A solution of the above product (150 mg, 0.29 mmol) in 3:1 THF/water wastreated at 0◦ with lithium hydroxide hydrate (25 mg, 0.59 mmol) and the mixturewas stirred at 0−2◦ for 45 minutes. Aqueous NaHCO3 (2 mL, 0.5 M) was addedat 0−2◦ and the THF was removed under reduced pressure. The aqueous phasewas extracted with CH2Cl2 (4 × 30 mL) to recover the chiral auxiliary (51 mg,98%). The aqueous phase and aqueous back-extracts were acidified (2 mL of2 N HCl) and the product was extracted into EtOAc (4 × 40 mL). The dried(MgSO4) extracts were concentrated to give 101 mg (97%) of the title acid, mp95.5–96.5◦: [α]22
D + 54.5◦ (c 0.53, CHCl3); IR (CHCl3) 2109, 1719, 1698 cm−1;
82 ORGANIC REACTIONS
1H NMR (C6D6) δ 1.3–1.9 (m, 2 H), 1.41 (s, 9 H), 1.53 (s, 3 H), 1.63 (s, 3H), 2.07–2.33 (m, 2 H), 3.48 (dd, J = 8.7, 3.3 Hz, 1 H), 3.80 (br m, 1 H), 5.22(dt, J = 10.2, 7.5 Hz, 1 H), 5.45 (dd, J = 10.7, 9.2 Hz, 1 H), 8.49 (br s 1 H).Anal. Calcd for C16H26N4O5: C, 54.22; H, 7.39; N, 15.81. Found, C, 54.0; H,7.3; N, 15.8.
MgBr
4-MeC6H4SO2N3
Et2O, 0°
NN N
SO2C6H4Me-4 – MgBr+
Na4P2O7, H2O
Et2O, rt, overnight
N3
(63%)
2-Azido-1,3,5-trimethylbenzene (Preparation of an Azide from a GrignardReagent and Tosyl Azide).305 A solution of 2,4,6-trimethylphenylmagnesiumbromide in Et2O, prepared from 39.8 g (0.2 mol) of 2-bromo-1,3,5-trimethylben-zene, was added with ice cooling to a solution of 19.7 g (0.1 mol) of tosylazide (caution; tosyl azide has the explosive power of TNT ) in Et2O (500 mL).The mixture was stirred for 30 minutes and the tan precipitate was collected byfiltration, washed with Et2O and petrol ether, and dried to give 50.8 g of thetriazene salt (caution: triazenes are potential carcinogens). It was suspended in250 mL of Et2O and a solution of tetrasodium pyrophosphate decahydrate (44.6g) in H2O (500 mL) was added dropwise with ice cooling. The mixture wasstirred overnight, the layers were separated, and the aqueous layer was extractedwith petrol ether (2 × 100 mL). The solvents were removed from the dried(CaCl2) organic phases to leave 16.7 g of a red oil, which was passed through acolumn of 300 g of alumina and eluted with petrol ether to give 10.16 g (63%)of the title product as a colorless oil. An analytical sample was distilled at 65◦
(0.2 mm): IR (neat) 2130 cm−1; 1H NMR (CCl4) δ 6.60 (s, 2H), 2.21 (s, 6H),2.17 (s, 3H). Anal. Calcd for C9H11N3: C, 67.05; H, 6.88; N, 26.07. Found: C,66.98; H, 6.82; N, 26.03.
S NMePh
O1. LDA, THF, –78°, 1 h2. (PhO)2P(O)N3, –78°, 5 min
S NMePh
O
NHCO2Bu-t
(70%)3. (t-BuO2C)2O, –78° to rt, 6 h
α-[(tert-Butoxycarbonyl)amino]-N -methyl-N -phenyl-2-thiopheneaceta-mide (Amination of an Amide Enolate with Diphenyl Phosphorazidate).336
To a solution of N -methyl-N -phenyl-2-thiopheneacetamide (3 mmol) in THF(6 mL) was added LDA (1.5 M in cyclohexane, 3.3 mmol) at −78◦ and the mix-ture was stirred at −78◦ for one hour. Diphenyl phosphorazidate (3.3 mmol) wasadded, the mixture was stirred for 5 minutes, (t-BuO2C)2O (6 mmol) in THF
ELECTROPHILIC AMINATION OF CARBANIONS 83
(3 mL) was added, and the mixture left to warm to room temperature during6 hours. The solvents were removed and the residue was purified by chromatog-raphy (SiO2, hexane/EtOAc) to give 725 mg (70%) of the title product as yellowcrystals, mp 104−106◦: IR 1705, 1655 cm−1; 1H NMR δ 7.45−7.40 (m, 3H),7.35–7.25 (d-like, 1H), 7.20–7.00 (m, 2H), 6.85–6.80 (t-like, 1H), 6.70-6.65(d-like, 1H), 5.74 (d, J = 8 Hz, 1H), 3.30 (s, 3H), 1.40 (s, 3H); MS–CI (m/z):[M + 1]+ 293.
OSi(Pr-i)3NaN3, (NH4)2Ce(NO2)6
MeCN, –20°
ON3
(49%)
2-Azido-2-methylcyclohexanone (Preparation of an α-Azido Ketone byReaction of a Ketone Triisopropylsilyl Enol Ether with Sodium Azide andAmmonium Cerium(IV) Nitrate).331 To a solution of 1-methyl-2-(triisopro-pylsilyloxy)cyclohexene in MeCN (0.4M, 1.99 mmol) was added at −20◦ sodiumazide (8.86 mmol, 4.5 eq) followed dropwise by a solution of ammonium cerium-(IV) nitrate in MeCN (0.4M, 5.90 mmol, 3 eq). When the reaction was complete(TLC), ice-cold water was added and the mixture was extracted with ice-coldEt2O. The combined extracts were washed with ice-cold water, dried (Na2SO4),and concentrated. The residue was purified by silica gel chromatography (1:3ether/pentanes) to give the title product in 49% yield as a pale yellow oil: IR(CHCl3) 2102, 1722 cm−1; 1H NMR (CDCl3) δ 2.61–2.51 (m, 1H); 2.37–2.28(m, 1H), 1.91-1.56 (m, 6H), 1.35 (s, 3H); 13C NMR δ 207.7, 67.9, 39.1, 36.2,26.9, 21.1, 20.2; HRMS (m/z): calcd for C7H11NO, 153.090; found, 153.090.
OMe 1. ClNHCO2CH2CCl3 (inverse addition), CHCl3, MeOH, –78°
ONHCO2CH2CCl3 (86%)
2. CrO2, MeOH, –78° to rt
2,2,2-Trichloroethyl 2-Oxocyclohexylcarbamate (Amination of a KetoneEnol Ether with the Chromium(II) Chloride/Chlorocarbamate Reagent).343
A solution of N -chloro 2,2,2-trichloroethyl carbamate (1.33 g, 5.74 mmol) inCHCl3 (4 mL) and MeOH (1 mL) was cooled to −78◦ and treated with a pre-cooled solution of 1-methoxycyclohexene (1.5 mL, 12 mmol) in CHCl3 (2 mL).During 1 hour, a 1 M solution of CrCl2 (about 5 mL, 5 mmol) in MeOH wasadded dropwise until a starch-iodide paper test was negative. The cooling bathwas removed and air was admitted. Sulfuric acid (1 mL of a 1 N solution) wasadded and the mixture was stirred at room temperature for 4 hours, poured into50 mL of water, and extracted with CH2Cl2 (3 × 100 mL). The combined extractswere washed twice with water, dried, and concentrated. The residue was sepa-rated by chromatography (1:4 ether/hexane) into 2,2,2-trichloroethyl carbamate
84 ORGANIC REACTIONS
(0.185 g) and the less polar title product (1.302 g, 86%), mp 75−78◦. Crystal-lization from hexane gave an analytical sample, mp 80−80.5◦: IR (CCl4)1745,1720 cm−1; 1H NMR (CCl4) δ 5.92 (m, 1H), 4.63 (s, 2H), 4.22 (dt, J = 6, 12 Hz;dd, J = 6, 11.5 Hz after D2O exchange, 1H). Anal. Calcd for C9H12Cl3NO3: C,37.44; H, 4.19; Cl, 36.89; N, 4.85. Found: C, 37.43, H, 4.17; Cl, 37.10; N, 5.02.
TABULAR SURVEY
An effort was made to include all relevant reactions that appeared in the liter-ature up to the middle of 2007. However, in view of the difficulties in searchingthe subject, omissions are inevitable. The tables are arranged according to sub-strates and follow the organization of the section on Scope and Limitations. Thetitles of the individual tables are listed in the Table of Contents and are notrepeated here.
Substrates are listed in the order of increasing carbon count. To group similarsubstrates together, protecting groups and chiral auxiliaries are not counted norare groups on heteroatoms such as N, O, S, and P. This includes alcohol por-tions of esters and groups such as methyl or ethyl in ethers, amides, and amines.Ligands in metal complexes are excluded from the count but ferrocene is listedin Table 4 (Aromatic Carbanions) under C10. However, all ring carbons in hete-rocycles are included in the carbon count. Within each carbon count or range ofcarbon counts entries are listed in the order in which reagents are discussed inthe section on Reagents and Mechanisms: amines, haloamines, hydroxylamines,oxaziridines, imines, oximes, diazonium salts, diazo compounds, azo compounds,azides, and miscellaneous other reagents. This order is not followed in Table 5(Heterocyclic Anions) where like heterocycles are grouped together. Only sub-strates where the carbanionic center is in the heterocyclic ring are listed here.Heterocyclic substrates where the carbanionic center is on a side chain are listedin Table 1A (Arylmethyl and Heteroarylmethyl Carbanions). Substrates wherethe carbanionic center is on an aromatic ring fused to, or attached to, a hetero-cycle are listed Table 4 (Aryl Carbanions). Table 10A (Esters) does not includelactones and Table 12 (amides) does not include lactams which are in separatetables (11 and 14, respectively) and which are not listed in Table 5 (HeterocyclicCarbanions). Surrogates of carbonyl compounds, such as enol ethers or enamines,are listed together with their parent carbonyl compounds.
A dash enclosed in parentheses [(−)] next to a product signifies that theproduct was isolated but no yield was reported. When a reaction involving thesame aminating reagent has been reported in more than one publication, theconditions producing the highest yield are shown and the reference to that paperis given first. Extensive variations of catalysts, solvents, and conditions are notincluded in the tables; instead, one or two sets of conditions that produce thehighest yield and best selectivity are given.
ELECTROPHILIC AMINATION OF CARBANIONS 85
The following abbreviations are used in the tables:
Ac acetylacac 2,4-pentadionato (acetylacetonato)BINAP 2,2-bis(diphenylphosphino)-1-binaphthyl[bmim][BF4] N -butyl-N ′-methylimidazolium tetrafluoroborateBn benzylBoc tert-butoxycarbonylBOM benzyloxymethylBu butylBz benzoyl[capemim][BF4] N -5-carboxypentyl-N ′-methylimidazolium
tetrafluoroborateCbz benzyloxycarbonylCp η5-cyclopentadienylDABCO 1,4-diazabicyclo[2.2.2]octaneDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDDQ 2,3-dichloro-5,6-dicyanobenzoquinone(DHQD)2CLB dihydroquinidinyl p-chlorobenzoate (see Chart 1)(DHQD)2PYR dihydroquinidinyl pyrimidine (see Chart 1)DMF dimethylformamideDME dimethoxyethaneDMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneDMSO dimethylsulfoxideEt ethylFmoc 9-fluorenylmethoxycarbonylHMPA hexamethylphosphoric triamideia inverse additionKHMDS potassium hexamethyldisilazideLDA lithium diisopropylamideLiHMDS lithium hexamethyldisilazideMe methylMEM (2-methoxyethoxy)methylMs methanesulfonylNaHMDS sodium hexamethyldisilazidePh phenylPiv pivaloylPMB p-methoxybenzylPr propylPy pyridine(saltmen)Mn(N) nitrido[N ,N ′-(1,1,2,2-tetramethyl)
bis(salicylideneaminato)]manganese (see Chart 1)TMS trimethylsilylTBS tert-butyldimethylsilylTBDPS tert-butyldiphenylsilyl
86 ORGANIC REACTIONS
TEMPO 2,2,6,6-tetramethylpiperidinyl-1-oxylTf trifluoromethanesulfonylTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTMEDA tetramethylethylenediamineTr triphenylmethylTs tosyl; 4-methylbenzenesulfonyl
NN
OO
N Mn
CH
AR
T 1
. ST
RU
CT
UR
ES
OF
RE
AG
EN
TS
AN
D C
AT
AL
YST
S
(sal
tmen
)Mn(
N)
Nitr
ido[
N,N
'-(1,
1,2,
2-te
tram
ethy
l)bi
s(sa
licyl
iden
eam
inat
o)]m
anga
nese N
N
OO
NN
OM
eM
eOH
H
N
H
Et
NE
t
(DH
QD
) 2PY
R
N
MeO
HO
O
Cl
Et
H
(DH
QD
) 2C
LB
cata
lyst
A
L =
MeO
H, 2
:1 m
ixtu
re o
f is
omer
s
cata
lyst
B
N
Co
O
OO
O
NH
2O
LM
n
OO O
O
OO
Bu-
t
t-B
u
t-B
u
t-B
u
t-B
u
Bu-
t
87
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S
R1 M
(1-
5 eq
)1.
R2 R
3 NH
, sol
vent
, tem
p 1,
2 h
2. O
2, te
mp
2, ti
me
R1 N
R2 R
352
R1
Me
Me
Me
Me
Me
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
M CuM
eLi
Cu
CuM
eLi
Cu
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
CuM
eLi
R2
Ph Ph n-C
7H15
n-C
7H15
(CH
2)2P
h
Ph Ph n-C
7H15
c-C
6H11
(CH
2)2P
h
Ph 3-A
cC6H
4
3-(M
eCH
OH
)C6H
4
1-na
phth
yl
n-C
10H
21
(CH
2)2P
h
R3
Me
Me
n-B
u
n-B
u
(CH
2)2P
h
Me
(CH
2)2O
H
n-B
u
c-C
6H11
(CH
2)2P
h
H H H H H (CH
2)2P
h
Solv
ent
tolu
ene
TH
F, H
MPA
Et 2
O
TH
F
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
TH
F
Et 2
O
Et 2
O
TH
F
TH
F
TH
F
Tem
p 1
0° rt rt rt rt
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
Tem
p 2
–78° rt rt rt rt
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
Tim
e
— — — — — — —
3 m
in
— — — — — — — —
(33)
(46)
(39)
(52)
(76)
(57)
(37)
(73)
(38)
(62)
(46)
(32)
(39)
(35)
(23)
(26)
C1-
4
R1 C
u(C
N)L
iR
1 NR
2 R3
54
R1
Me
n-B
u
n-B
u
n-B
u
n-B
u
R2
Ph Me
i-Pr
Ph (R)-
1-(1
-nap
hthy
l)et
hyl
R3
Bn
Bn
i-Pr
H H
(50)
(45)
(50)
(62)
(60)
1. R
2 R3 N
Li,
TH
F, –
40°,
15 m
in
2. O
2, –
78°.
20 m
in; t
o rt
88
R1 C
u(C
N)X
1. R
2 R3 N
Li,
TH
F, te
mp,
tim
e
2. A
dden
d, T
HF,
–78
°3.
O2,
–78
°, 30
min
R1 N
R2 R
3
R1
Me
n-B
u
n-B
u
n-B
u
n-B
u
R2
Ph H Me
i-Pr
Ph
R2
Bn
Ph Bn
i-Pr
Ph
Add
end
1,2-
(O2N
) 2C
6H4
none
1,2-
(O2N
) 2C
6H4
none
Cu(
NO
3)2
Tem
p
–78°
to –
40°
–78°
to –
40°
–78°
to –
40°
–78°
to –
40°
–40°
Tim
e
40 m
in
40 m
in
40 m
in
40 m
in
20 m
in
(60)
(70)
(57)
(85)
(60)
55
C1-
4
RM
(x
eq)
See
tabl
e.R
NH
2 +
R2N
H
C1-
8
R Me
Me
Et
Et
Et
Et
n-Pr
n-Pr
n-Pr
i-Pr
i-Pr
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
s-B
u
s-B
u
M Li
MgB
r
MgC
l
MgC
l
ZnE
t
ZnE
t
MgC
l
ZnP
r-n
ZnP
r-n
MgC
l
MgC
l
Li
MgC
l
MgB
u-n
MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
x 1
exce
ss
exce
ss
4
exce
ss
exce
ss
exce
ss
exce
ss
exce
ss
exce
ss
4 3 1
3 or
mor
e
4
exce
ss
exce
ss
exce
ss
4
Rea
gent
NH
2Cl
NH
2Cl
NH
2Cl
NC
l 3
NH
2Cl
NC
l 3
NH
2Cl
NH
2Cl
NC
l 3
NH
2Cl
NC
l 3
NH
2Cl
NH
2Cl
NH
2Cl
NC
l 3
NH
2Br
NH
Br 2
NH
2Cl
NC
l 3
Con
ditio
ns
Et 2
O, 0
°E
t 2O
, 0°
Et 2
O, 0
°E
t 2O
petr
ol e
ther
, –30
°; r
t, ov
erni
ght
petr
ol e
ther
, –30
°; r
t, ov
erni
ght
Et 2
O, 0
°pe
trol
eth
er, –
30°;
rt,
over
nigh
t
petr
ol e
ther
, –30
°; r
t, ov
erni
ght
Et 2
O, 0
°E
t 2O
Et 2
O, –
50°
petr
ol e
ther
, 0°;
rt,
over
nigh
t
Et 2
O, d
ioxa
ne, –
60°
Et 2
O
E2O
, 2-3
°E
t 2O
, 0°
Et 2
O, 0
°E
t 2O
(4)
(26)
(57)
(29)
(46)
(17)
(58)
(57)
(8)
(66)
(23)
(39)
(57)
(97)
(37)
(29)
(15)
(70)
(23)
(—)
(—)
(—)
(6)
(—)
(—)
(—)
(—)
(—)
(—)
(2)
(—)
(—)
(—)
(5)
(—)
(5)
(—)
(3)
58 56 56, 5
8
77, 5
8
58 58 58,5
6
58
58 57 77 58 59, 5
6, 5
8
59 77, 5
8
61 75 57 77
X ZnC
l
ZnC
l
ZnC
l
ZnC
l
Li
89
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
R s-B
u
s-B
u
t-B
u
t-B
u
t-B
u
n-C
5H11
i-C
5H11
s-C
5H11
t-C
5H11
Ph(C
H2)
2
Ph(C
H2)
2
Ph(C
H2)
2
M MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
MgC
l
x
exce
ss
exce
ss
exce
ss
4
exce
ss
4
exce
ss
exce
ss
exce
ss
exce
ss
4
exce
ss
Rea
gent
NH
2Br
NH
Br 2
NH
2Cl
NC
l 3
NH
2Br
NC
l 3
NH
2Cl
NH
2Cl
NH
2Cl
NH
2Cl
NC
l 3
NH
Br 2
Con
ditio
ns
Et 2
O, 2-
3°E
t 2O
, 2-3
°E
t 2O
, 0°
Et 2
O
Et 2
O, 2
-3°
Et 2
O
Et 2
O, 0
°E
t 2O
, 0°
Et 2
O, 0
°E
t 2O
, 0°
Et 2
O
Et 2
O, 2
-3°
(46)
(21)
(60)
(30)
(45)
(21)
(55)
(72)
(66)
(74)
(20)
(18)
(—)
(5)
(—)
(2)
(—)
(5)
(—)
(—)
(—)
(—)
(2)
(3)
61 75 57 77 61 77 56 57 57 56 77 75
R1 N
HB
zR
1 M1.
R2 O
NH
Li (
2 eq
, ia)
, Et 2
O, –
78° t
o –1
5°, 2
h
2. B
zCl
R1
Me
Et
n-B
u
n-B
u
n-B
u
i-B
u
s-B
u
s-B
u
s-B
u
s-B
u
t-B
u
(80)
(78)
(77)
a
(95)
(16)
(67)
(71)
(19)
(58)
(18)
(80)
82, 7
86
82, 7
86
82, 7
86
82 83, 7
86
82, 7
86
82, 8
3
83 83 83 82, 7
86
M Li
Li
Li
Li
MgB
r
Li
Li
MgB
r
CuL
i
Me 2
ZnL
i
Li
R2
Me
Me
Me
CH
2CH
=C
H2
Me
Me
Me
Me
Me
Me
Me
C1-
8
C1-
4
RM
x e
q
See
tabl
e.R
NH
2 +
R2N
H
90
C1-
4
RM
1T
sON
CO
2Bu-
t (M
2 )+R
NH
CO
2Bu-
t
R Me
n-B
u
n-B
u
n-B
u
s-B
u
s-B
u
s-B
u
M2
Li
Li
Li
MgC
l
Li
Li
MgC
l
M1
Li
Li
(CuL
i)0.
5
(CuL
i)0.
5
Li
(CuL
i)0.
5
(CuL
i)0.
5
Tim
e
2 h
3 h
1.5
h
1.5
h
3 h
1.5
h
1.5
h
Tem
p
–78°
to –
30°
–78°
to –
40°
–78°
–78° 0° –78°
–78°
(60)
(71)
(62)
(70)
(42)
(32)
(57)
126
127,
126
127
127
127,
126
127
127
R1 M
2 SO2O
N(R
R3 ) 2
(ia)
, Et 2
O o
r E
t 2O
/TH
FR
1 N(R
3 ) 2
R1
Me
Me
n-B
u
Ph(C
H2)
2
R3
Me
Et
Me
Me
R2
2,4,
6-M
e 3C
6H2
Ph Ph Me
RM
X
X n
ot s
peci
fied
(ia)
, Et 2
OC
O2
R Me
Et
n-Pr
n-Pr
i-Pr
i-Pr
i-B
u
t-B
u
M Cd
Mg
Mg
Cd
Mg
Cd
Mg
MgC
O2
N
PhH
RC
O2
N H
PhH
R
III
+16
1
I +
II
(55-
70)
(45-
55)
(45-
55)
(55-
70)
(45-
55)
(55-
70)
(45-
55)
(45-
55)
I:II
0:10
0b
95:5
96:4
0:10
0b
60:4
0
0:1
00b
96:4
0:10
0
(45)
(39)
(47)
(70)
M Li
Li
Li
MgB
r
Tem
p, T
ime
–10°
to –
20°;
to r
t, 15
h
–10°
to –
20°;
to r
t, 15
h
–10°
to –
20°;
to r
t, 15
h
–30°
to 0
°
133
133
133
134
C1-
8
C1-
4
– N
PhH
Pr-i
91
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
C1-
14
RM
gBr
4-M
eOC
6H4N
(R)C
H(C
O2E
t)2
I
4-M
eOC
6H4N
HR
II
167,
166
R Me
Et
n-Pr
i-Pr
n-B
u
t-B
u
c-C
6H11
CH
2
Ph(C
H2)
2
n-C
10H
21
n-C
12H
25
n-C
14H
29
Tem
p
–78°
–78°
–78°
–95°
–78°
–95°
–78°
–78°
–78°
–78°
–78°
I
(98)
c
(91)
c
(81)
c
(86)
c
(98)
c
(56)
(93)
c
(86)
c
(78)
c
(94)
c
(79)
c
IId
(63)
(93)
(79)
(68)
(98)
(0)
(91)
(89)
(79)
(84)
(71)
R1 M
gIR
2 R3 C
=N
2, E
t 2O
R1
Me
Me
Me
Me
Et
R2
EtO
2C
CN
Ph Ph EtO
2C
R3
H CN
Ph Bz
H
(30)
(60)
(84)
(—)
(—)
C1-
2
R2 R
3 C=
NN
HR
1
C1
MeL
i1.
ZnC
l 2, T
HF,
0° t
o rt
2.
(ia
), N
i(ac
ac) 2
(ca
t), 2
h
NO
CH
O
NH
Me
(70)
170
199
203
202
201
199
1. 4
-MeO
C6H
4N=
C(C
O2E
t)2,
TH
F, te
mp,
30
min
(fo
rms
I)
2. A
ir, K
OH
, H2O
, EtO
H (
form
s II
)
92
Fe
MeL
iN
2
O
, Et 2
O, c
oolin
gN
NH
Me
O
(—)
201
C1
MeL
i
N2
1.
(
ia),
Et 2
O
2. F
eCl 3
N=
NM
e
N=
NM
e
787
(—)
RM
X1
ArN
2+ (X
2 )–Ph
N=
NR
C1-
6
X1
I I I Br
Br
Br
Cl
— — — Cl
Br
Solv
ent
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
E2O
TH
F
TH
F
TH
F
TH
F
TH
F
Tem
p
refl
ux
refl
ux
refl
ux
refl
ux
refl
ux
refl
ux
–10°
–78°
–78°
–78°
–78° 0°
(15)
e
(7)e
(5)e
(15)
e
(5)e
(10)
e
(40)
(71)
(83)
(78)
(40)
(0)
184
184
184
184
184
184
192
191
191
191
185
190
X2
Cl
Cl
Cl
Cl
Cl
Cl
BF 4
f f f BF 4
BF 4
M Mg
Mg
Mg
Mg
Mg
Mg
Zn
Mg
Mg
Mg
Mg
Zn(
C6H
11-n
) 2
Ar
Ph 1-na
phth
yl
2-na
phth
yl
Ph 1-na
phth
yl
2-na
phth
yl
Ph Ph 4-C
lC6H
4
4-M
eOC
6H4
Ph Ph
R Me
Me
Me
Et
Et
Et
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
n-C
6H11
Tim
e
15 m
in
15 m
in
15 m
in
15 m
in
15 m
in
15 m
in
22 h
1 hg
1 hg
1 hg
— 1 h
93
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
R1 M
N3
R1 N
HN
=N
R2
an
d/or
h R
1 N=
N-N
HR
2
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
M Li
MgC
l
MgB
r
MgI
MgB
r
Li
MgI
MgI
MgI
MgI
R2
R2
Me
Me
Me
Me
n-B
u
(CH
2)2O
TB
DM
S (i
a)
4-B
rC6H
4
Ph 4-M
eC6H
4
4-E
tC6H
4
Solv
ent
pent
ane
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Tem
p, T
ime
0°, 1
h
–40°
; –10
°, 30
min
; to
rt
–40°
; 0°,
30 m
in; t
o rt
–20°
; to
rt; r
eflu
x, 2
0 m
in
0° to
rt,
2 h
–20°
; to
rt, 2
h
refl
ux, 0
.5 h
refl
ux, 0
.5 h
refl
ux, 3
0 m
in
refl
ux, 3
0 m
in
(60)
(—)
(—)
(—)
(85)
(70)
(—)
(75)
(—)
(—)
258,
256
257
257
257
261
268
280
270,
285
280
280
C1-
10
94
R1
Me
Me
Me
Et
Et
Et
Et
Et
n-Pr
i-Pr
n-B
u
n-B
u
n-B
u
t-B
u
t-B
u
c-C
3H5C
H2
i-C
5H11
i-C
5H11
n-C
6H13
4-cy
cloh
exen
ylm
ethy
l
n-C
8H17
Ph(C
H2)
2
Ph(C
H2)
2
Ph(C
H2)
2
Ph(C
H2)
2
4-M
eOC
6H4(
CH
2)2
PhC
(Me)
2CH
2
M MgB
r
MgB
r
MgI
MgB
r
Al 1
/3
Al 1
/3
MgI
MgB
r
MgB
r
MgB
r
Li
Li
MgB
r
MgC
l
MgC
l
Li
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
R2
Bn
1-na
phth
yl
PhSO
2 (i
a)
Et
n-B
u
Ph Ph 1-na
phth
yl
1-na
phth
yl
i-Pr
n-B
u
Bn
1-na
phth
yl
PhSO
2 (i
a)
PhSC
H2
(ia)
c-C
3H5C
H2
(ia)
Ph 1-na
phth
yl
PhSO
2 (i
a)
PhSC
H2
(ia)
PhSC
H2
(ia)
MeS
CH
2 (i
a)
PhSC
H2
(ia)
4-M
eOC
6H4S
CH
2 (i
a)
4-M
eC6H
4SO
2
PhSC
H2
4-M
eC6H
4SO
2
Solv
ent
Et 2
O
Et 2
O
Et 2
O
Et 2
O
petr
ol e
ther
petr
ol e
ther
Et 2
O
Et 2
O
Et 2
O
pent
ane
TH
F
pent
ane
Et 2
O
Et 2
O
TH
F
pent
ane
Et 2
O
Et 2
O
Et 2
O
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
Et 2
O
TH
F
Tem
p, T
ime
refl
ux, 2
5 m
in
0° to
rt,
2 h
—
0°, 1
h
40°,
10 h
rt, 1
d
refl
ux, 3
0 m
in
refl
ux, 2
5 m
in
refl
ux, 2
5 m
in
0° to
rt,
2 h
0°, 1
h
0° to
rt,
2 h
refl
ux, 2
5 m
in
—
–78°
; to
–20°
, 2.5
h
–70°
, 30
min
refl
ux, 2
5 m
in
refl
ux, 2
5 m
in
— –78°
–78°
, 1 h
; to
rt
0°, 2
h
–78°
, 1.7
5 h;
to 0
°, 30
min
–78°
, 1.7
5 h;
to 0
°, 30
min
0°–7
8°, 2
h
0°
(95)
(80)
(—)
(45)
(60)
(50)
(55)
(53)
(54)
(12)
(>88
)
(91)
(65)
(—)
(96)
(>55
)
(—)
(50-
55)
(—)
(86)
(100
)
(>86
)
(>90
)
(90)
(25)
i
(>73
)j
(25)
i
261,
270
281
306
258
260
260
270
281
281
259
262
261
281
306
274
262
281
281
306
273
274
274
274,
273
274
305
274,
273
305
95
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
C1
SS
Li
N3
Ph1.
,
TH
F, –
78°;
rt,
2 h
2. H
Cl
SS
NH
2(6
4)27
8
RL
i27
7N
3B
u-t
RH
NN
NB
u-t
R Me
Et
n-B
u
t-B
u
(91)
(—)
(—)
(—)
, E
t 2O
, –78
°; to
rt,
2-12
h
C1-
4
RM
gX X
= C
l or
Br
N
YN
N3
N3
N3
N
YN
N=
NN
HR
N=
NN
HR
RN
HN
=N
, Et 2
O, 1
h
R Me
Et
n-B
u
n-B
u
(60)
(70)
(52)
(—)
788
RM
gBr
PhC
OC
H2N
3, E
t 2O
789
RN
NN
HR
PhH
OR M
e
Et
n-B
u
(93)
(95)
(64)
C1
MeL
iY
N3
N3
, Et 2
OY
RR
Y =
O, C
H2
; R =
N=
NN
HM
e
(—)
290
Y CH
CH
CH
N
96
C1-
5
RM
gXN
3–Y
–N3,
Et 2
O27
2
R Me
Me
Et
Et
n-Pr
n-Pr
i-Pr
i-Pr
n-B
u
n-B
u
n-B
u
n-B
u
i-C
5H11
i-C
5H11
Y (CH
2)2
(CH
2)2
(CH
2)2
(CH
2)2
CH
2CH
Me
(CH
2)3
(CH
2)2
X I I Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
(92)
(80)
(41)
(80)
(—)
(76)
(72)
(70)
(71)
(87)
(65)
(72)
(61)
(78)
NY
NN
NH
Rh
NR
HN
97
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
RM
gX
X
not
spe
cifi
edNS
N3
NSR
HN
N=
N
, Et 2
O, 1
0-12
h
R Me
Et
n-Pr
i-Pr
n-B
u
i-B
u
n-C
5H11
i-C
5H11
(78)
(68)
(23)
(57)
(28)
(40)
(38)
(62)
790
C1-
5
C2-
3
(R1 ) 2
Zn
R2 N
Cl 2
, pet
rol e
ther
, col
d
R2
Me
Et
n-B
u
i-C
5H11
n-B
u
(46)
(42)
(43)
(42)
(24)
R2 N
H2
+
R
2 NH
R1
R1
Et
Et
Et
Et
n-Pr
72
(44)
(49)
(57)
(52)
(61)
C2
Et 2
Zn
EtN
Cl 2
, Et 2
O, 0
°E
t
Et3N
(35
)
+
EtN
H2
(—)
76
Et 2
NC
l, pe
trol
eth
er, c
old
2NH
(70
)
+
Et 3
N (
2)72
98
R1 M
gX1
1. R
2 ON
H2,
sol
vent
, tem
p (f
orm
s I)
2. H
X2
(for
ms
II)
R1 N
H2
I
R1 N
H3X
2 II
R1
Et
Et
n-Pr
n-B
u
n-B
u
i-B
u
s-B
u
t-B
u
n-C
5H11
i-C
5H11
i-C
5H11
i-C
5H11
i-C
5H11
t-C
5H11
4-(1
-pen
teny
l)
Ph(C
H2)
2
X1
Br
Br
Br
Cl
Br
Br
Cl
Cl
Br
Cl
Br
I Br
Br
Cl
Cl
R2
Me
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Me
Me
Me
X2
Cl
Cl
Cl
— — — Cl
Cl
— Cl
Cl
Cl
Cl
— — —
I
(—)
(—)
(—)
(58)
(63)
(90)
(—)
(—)
(65)
(—)
(—)
(—)
(—)
(48)
(—)
(68)
II (81)
(46)
(85)
(—)
(—)
(—)
(73)
(74)
(—)
(80)
(71)
(5)
(61)
(—)
(—)
(—)
791,
792
80 791
791
791
791
792
791,
792
791
791
791
792
80 791
793
791
C2-
8
Solv
ent
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
— Et 2
O
Tem
p
–10
° to
–15°
–10
° to
–15°
–10
° to
–15°
–10
° to
–15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
—
–10°
to –
15°
R1
ZrC
pCl
k2,
4,6-
Me 3
C6H
2SO
2ON
H2,
Et 2
O, 0
°, 10
min
116
C2-
10
R1
TM
S
TM
SCH
2
Cl(
CH
2)3
Et
n-C
6H13
Ph Ph(C
H2)
2
R2
R1
NH
2
R2
R2
H H H i-Pr
H H H
(81)
(76)
(78)
(85)
(77)
(60)
l
(80)
99
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
Bn 2
NO
Bz
+ C
uCl 2
(2.
5 m
ol%
, ia,
slo
w a
dditi
on),
TH
F, r
t, 15
min
RN
Bn 2
113
R Et
t-B
u
C2-
4
(95)
(88)
X Br
Cl
RM
gX
(R1 ) 2
Zn
1.1
eq
R2 R
3 NO
Bz,
cat
alys
t, T
HF,
rt
R1 R
2 R3 N
R1
Et
i-Pr
t-B
u
t-B
u
t-B
u
R2
Bn
Bn
t-B
uCH
2CM
e 2
Bn
Bn
Cat
alys
t
(CuO
Tf)
2•Ph
H
(CuO
Tf)
2•Ph
H
CuC
l 2
CuC
l 2
(CuO
Tf)
2•Ph
H
R3
Bn
Bn
H Bn
Bn
Tim
e
1 h
1 h
15-6
0 m
in
15 m
in
1 h
(91)
(77)
(43)
(99)
(98)
109,
112
109,
112
112
109
109,
112
C2
Et 2
Zn
R1 N
=C
HC
O2R
2 , pen
tane
, –80
° to
rt
R1 =
i-Pr
, t-B
u; R
2 = M
e, E
tN
R1
NC
O2R
2
OR1
Et
(80-
90)
163
1. t-
BuN
=C
HC
OM
e, h
exan
e, –
100°
2. C
H2C
l 2, H
2Ot-
Bu
NC
OM
e
Et
(80)
162
R1 N
NR
1R
2
R3
1.
, hex
ane,
rt
2. t-
BuO
H
NE
tR1
R1 E
tN R2
R3
171
R1
i-Pr
i-Pr
t-B
u
t-B
uCH
2
c-C
6H11
c-C
6H11
(i-P
r)2C
H
R2
H H H H H Me
H
R3
H Me
H H H Me
H
(—)
(—)
(88)
(—)
(—)
(—)
(—)
100
C2-
4
R1 M
165
R2 C
F 2N
R3
CO
2Et
NR
1 R3
CO
2Et
R2
FC
F 3
CO
2Et
NH
R3
R1
NR
1 R3
CO
2Et
+
R1
Et
Et
Et
Et
Et
Et
Et
Et
n-B
u
M MgB
r
ZnE
t
ZnE
t
ZnE
t
ZnE
t
ZnE
t
ZnE
t
ZnE
t
Li
R2
F F F F F F F C2F
5
F
R3
4-M
eOC
6H4
4-M
eOC
6H4
Ph 4-C
lC6H
4
2-E
tC6H
4
2,6-
Me 2
C6H
3
PhC
HM
e
4-M
eOC
6H4
4-M
eOC
6H4
Solv
ent
Et 2
O
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
Tim
e
30 s
30 s
30 s
30 s
30 s
30 s
30 s
2 m
in
30 s
R1
F
+
III
III
I
(50)
(88)
(80)
(84)
(65)
(1)
(85)
(77)
(0)
II (0)
(1)
(—)
(—)
(—)
(—)
(—)
(—)
(80)
III
(15)
(0)
(—)
(—)
(—)
(—)
(—)
(—)
(0)
R1 L
i, T
HF,
hex
ane,
–78
°, 2
h; to
rt
168
NR
2
R3
R3
R3
R2 H
NR
1R
1 R2 N
H
+
R1
Et
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
R2
n-B
u
Me
n-B
u
n-B
u
i-B
u
Ph 4-M
eC6H
4
4-M
eOC
6H4
Ph(C
H2)
2
Ph(C
H2)
4
R3
H H H Me
H H H H H H
(65)
(71)
(70)
(0)
(41)
(15)
(17)
(19)
(80)
(62)
(5)
(0)
(0)
(—)
(16)
(50)
(52)
(47)
(5)
(15)
Tem
p
rt rt rt rt rt rt rt
100°
80°
101
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
RM
gX
1. [
3,5-
(CF 3
) 2C
6H3]
2C=
NO
Ts
(ia)
, Et 2
O, t
olue
ne, r
t, 0.
5 h
2. H
Cl,
Me 2
CO
3. B
zCl,
Et 3
N
RN
HB
z17
9
R Et
t-B
u
Ph(C
H2)
3
X Br
Cl
Br
(87)
(35)
(96)
m
C2-
9
R1 M
Br
R2 C
ON
=N
R3
NN
R1
R3
H
R2 C
O
R1
Et
Et
n-Pr
i-Pr
i-B
u
t-B
u
i-C
5H11
Me 2
(Et)
C
MeC
O2(
CH
2)4
5-C
l(C
H2)
2
4-N
C(C
H2)
4
EtO
2C(C
H2)
5
2-oc
tyl
M Mg
Mg
Mg
Mg
Mg
Mgn
Mg
Zn
Mg
Zn
Zn
Zn
Zn
Zn
R2
Ph Ph Ph Ph Ph t-B
uO
Ph t-B
uO
CH
2=C
HC
H2O
t-B
uO
t-B
uO
t-B
uO
t-B
uO
t-B
uO
R3
Ph Bz
Bz
Bz
Bz
CO
2Bu-
t (ia
)
Bz
CO
2Bu-
t
CO
2CH
2CH
=C
H2
(ia)
CO
2Bu-
t
CO
2Bu-
t
CO
2Bu-
t
CO
2Bu-
t
CO
2Bu-
t
(25)
(—)
(—)
(poo
r)
(—)
(26)
(40)
(75)
(55)
(90)
(81)
(90)
(90)
(94)
Solv
ent
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
794
794
794
794
794
795
794
358
735
358
358
358
358
358
Tem
p, T
ime
rt rt rt rt rt
0°, 1
5 m
in; r
t, 10
h
rt
rt, 3
0 m
in
–78°
to r
t
rt, 3
h
rt, 3
h
rt, 1
h
rt, 3
h
rt, 3
h
C2-
8
TM
SCC
(CH
2)2
RM
t-B
uO2C
NN
CO
NN
NH
CO
N
t-B
uO2C
NH
N
R
t-B
uO2C
I
+
II
410
CO
R
N
C2-
4
, –78
°, so
lven
t, 1
h
102
RM
Et 2
AlC
l
Et 2
Zn•
TiC
l 4
n-B
uLi
Solv
ent
CH
2Cl 2
CH
2Cl 2
Et 2
O
I
(100
)
(—)
(65)
II (0)
(64)
(23)
RM
gX
X n
ot s
peci
fied
ArN
3 (i
a), E
t 2O
, rt
ArN
HR
279
R Et
Et
n-Pr
n-Pr
i-Pr
i-Pr
i-Pr
i-Pr
n-B
u
n-C
5H11
n-C
7H15
n-C
8H17
n-C
10H
21
n-C
12H
25
Ar
Ph MeC
6H4
4-FC
6H4
(3-O
CH
2-4)
C6H
3
3,4-
Cl 2
C6H
3
4-M
eOC
6H4
3,4-
(MeO
) 2C
6H3
2-na
phth
yl
MeC
6H4
2-na
phth
yl
4-C
lC6H
4
4-M
eOC
6H4
2-na
phth
yl
4-C
lC6H
4
(90)
(89)
(82)
(88)
(85)
(88)
(87)
(88)
(87)
(87)
(84)
(90)
(88)
(85)
C2-
12
Tim
e
30 m
in
30 m
in
1 h
30 m
in
1 h
1 h
30 m
in
1 h
30 m
in
1 h
1 h
30 m
in
1 h
1.5
h
EtM
gBr
4-N
3C6H
4CO
Me,
Et 2
O(—
)28
3
N3
N3 , E
t 2O
, –20
°(5
8)
EtN
HN
=N
N=
NN
HE
th
289
C2
OH
Et
EtN
HN
=N
103
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
R1 M
gCl
R1 R
2 NH
+ (
R1 ) 2
NR
2 + R
2 NH
2
R1
n-Pr
n-B
u
n-B
u
n-C
5H11
R2
Et
Me
Et
Et
(12)
(22)
(11)
(12)
(8)
(5)
(9)
(8)
(52)
(43)
(36)
(34)
68R
2 NC
l 2, E
t 2O
, 5°,
1 h
C3-
5
C3-
4
R1 M
(R2 ) 2
NC
l(R
2 ) 2N
H +
R1 (R
2 ) 2N
+ (
R2 ) 2
NN
(R2 ) 2
R1
i-Pr
n-B
u
R2
i-Pr
n-B
u
(—)
(85)
Solv
ent
petr
ol e
ther
Et 2
O
(3)
(4)
(4.5
)
(0)
70 68
C3-
8
Ph2P
(O)O
NH
2, T
HF
RN
H2
C3
i-Pr
MgC
l
NH
O
t-B
ut-
Bu
, Et 2
O
NPr
-i
O
t-B
ut-
Bu
(35)
169
R i-Pr
n-B
u
Ph(C
H2)
2
X Cl o
r B
r
Cl o
r B
r
Br
RM
gX
Tem
p
–78°
; to
rt
–78°
; to
rt
–20°
; rt,
12 h
(36)
m
(50)
m
(40)
140
140
139
Tem
p
rt,
then
ref
lux
5°
M K MgC
l
Tim
e
— 1 h
104
C3-
10
RZ
nX1.
ArN
=N
Ts,
TH
F, –
20°
2. R
aney
Ni,
EtO
H, r
eflu
x
ArN
HR
356
R EtO
2C(C
H2)
2
n-C
5H11
n-C
8H17
PhC
(Me)
2CH
2
PhC
(Me)
2CH
2
X EtO
2C(C
H2)
2
I I Br
Br
(45)
(55)
(52)
(79)
(0)q
Ar
4-M
eOC
6H4
4-E
tO2C
C6H
4
4-E
tO2C
C6H
4
4-E
tO2C
C6H
4
3,5-
(CF 3
) 2C
6H3
C3-
8
RM
gX
1. (
4-C
F 3C
6H4)
2C=
NO
Ms
+ C
uCN
•2 L
iCl (
ia),
TH
F, H
MPA
, 0°,
30 m
in
2. H
3O+
RN
H2
179,
726
R i-Pr
n-B
u
t-B
u
3,4-
(TB
SO) 2
C6H
3(C
H2)
2
(93)
o
(96)
o
(61)
o
(87)
p
X Br
Cl
Cl
Br
105
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
R2
R1
R3
R2
R1
R3 E
R5
R4
R4
R5
R2
R1
R3
R4
R5
E+
III
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
HH
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2
. Sub
stra
te, t
hen
PhSi
H3
3
. t-B
uO2C
N=
NC
O2B
u-t,
rt, t
ime
Con
ditio
ns 2
: 1. C
atal
yst B
(se
e C
hart
1; 2
mol
%),
i-Pr
OH
, 0°
2
. Sub
stra
te, t
hen
PhSi
H3,
0°
3
. t-B
uO2C
N=
NC
O2B
u-t,
0°, t
ime
C3-
10
R1
H H H H H Me
H H Me
Et
Et
H Me
Me
H H H
R2
H H H H H H H H Me
H H H Me
Me
H H H
R3
H H H H H H H H H H H Me
Me
Me
H H H
R4
OH
OB
n
OM
e
CH
2OH
CH
2OH
OH
OH
CH
2Br
OH
Me
Me
Et
H H CH
2CO
Me
CH
2Ph
CH
2Ph
R5
H H OM
e
H H H Me
H H H H H H H H H H
Con
ditio
ns
1 1 1 1 2 2 1 1 1 1 2 1 1 2 1 1 2
I
(78)
(76)
(70)
(22)
(72)
(32)
(73)
dr
1:1
(90)
(—)
(16)
(66)
(88)
(14)
(78)
(76)
(85)
(76)
215
215
215
796
215
215
215
215
215
796
215
215
215
215
215
215
215
II (—)
(—)
(—)
(—)
(—)
(58)
(—)
(—)
(70)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(18)
Tim
e
3 h
3 h
7 h
12 h
2.5
h
2 h
5 h
5 h
8 h
10 h
3 h
5 h
10 h
3 h
3 h
4 h
2.5
106
R2
R1
R3
R4
R1
H H H H H H H H H H H H H H H H H CH
2OT
BD
PS
CH
2OT
BD
PS
CH
2OT
BD
PS
CH
2OT
BD
PS
R2
H H H H H H H H H H H H H H H H H H H H H
R5
4-M
eC6H
4
4-M
eC6H
4
2-M
eO-5
-MeC
6H3
2-M
eO2C
C6H
4
4-M
eC6H
4
4-M
eC6H
4
2-M
eO-5
-MeC
6H3
2-M
eO2C
C6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
2-M
eO-5
-MeC
6H3
2-M
eO2C
C6H
4
4-M
eC6H
4
2-M
eO-5
-MeC
6H3
2-M
eO2C
C6H
4
4-M
eC6H
4
4-M
eC6H
4
2-M
eO-5
-MeC
6H3
2-M
eO2C
C6H
4
Sila
ne
PhSi
H3
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
Tim
e
48 h
48 h
— 48 h
2 h
18 h
18 h
18 h
3 h
3 h
— — — — — — — — — — —
I
(35)
(39)
(<20
)
(28)
(55)
(67)
(19)
(44)
(73)
(85)
(73)
(58)
(89)
(91)
(40)
(64)
(76)
(63)
(48)
(83)
(79)
I:II — — — — — — — — — — — — — — — — — — — —
89:1
1
R3
H H H H H H H H H H Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
C3-
14
1. C
o(B
F 4) 3
•6 H
2O (
6 m
ol%
), li
gand
(6
mol
%),
EtO
H, r
t, 10
min
2. S
ubst
rate
3. R
5 SO2N
3, t-
BuO
2H, r
t, 5
min
4. S
ilane
, rt,
time
t-B
uO
H
N
PhPh
OK
O
Lig
and:
215
Bu-
t
R4
CH
2OB
n
CH
2OB
n
CH
2OB
n
CH
2OB
n
CH
2OT
BD
PS
CH
2OT
BD
PS
CH
2OT
BD
PS
CH
2OT
BD
PS
(CH
2)2O
TB
DPS
(CH
2)2O
TB
DPS
CH
2OT
BD
PS
CH
2OT
BD
PS
CH
2OT
BD
PS
CH
2OT
BD
PS
CH
2OB
n
CH
2OB
n
CH
2OB
n
Me
Me
Me
Me
+
III
R2
N3
R1
R4R
3
R2
R1
R4
R3
107
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
R2
R1
R3
R4
C3-
14
R1
H H H H H H H H H H H H H H Me
Me
H H
R2
H H H H H H H H H H H H H H H H H H
R5
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
2-M
eO-5
-MeC
6H3
2-M
eO2C
C6H
4
Et
Ph 4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
R4
(CH
2)2C
O2B
n
(CH
2)2C
O2B
n
CH
2C6H
3-3-
CH
2OC
H2-
4
CH
2C6H
3-3-
CH
2OC
H2-
4
(CH
2)2P
h
(CH
2)2P
h
(CH
2)2P
h
(CH
2)2P
h
(CH
2)2P
h
(CH
2)2P
h
(CH
2)2P
h
(CH
2)2P
h
(CH
2)2C
OPh
(CH
2)2C
OPh
(CH
2)2P
h
(CH
2)2P
h
(CH
2)2-
2-na
phth
yl
(CH
2)2-
2-na
phth
yl
Sila
ne
PhSi
H3
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
(Me 2
SiH
) 2O
PhSi
H3
PhSi
H3
PhSi
H3
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
PhSi
H3
(Me 2
SiH
) 2O
Tim
e
10 h
10 h
20 h
20 h
2 h
3 h
5 h
4 h
2 h
10 h
3 h
12 h
24 h
24 h
30 h
30 h
8 h
12 h
I
(75)
(77)
(65)
(62)
(90)
(86)
(94)
(91)
(>75
)
(90)
(86)
(90)
(49)
(46)
(66)
(48)
(72)
(69)
I:II
96:4
— — —
89:1
1
— — —
77:2
3
90:1
0
— — — — — — — —
R3
H H H H H H H H H H Me
Me
H H Me
Me
H H
(Tab
le c
onti
nued
from
pre
viou
s pa
ge.)
+
III
215
n-B
uMgC
lM
eNH
Cl,
Et 2
O, 5
°, 1
hn-
BuN
HM
e (1
4) +
MeN
H2
(72
)68
(t-B
u)2M
gt-
BuN
HC
l, di
oxan
e, E
t 2O
, 5°,
2 h;
rt o
vern
ight
(t-B
u)2N
H (
10)
67
C4
R2
N3
R1
R4R
3
R2
R1
R4
R3
108
RL
i
R n-B
u
s-B
u
t-B
u
(0)
(35.
5)
(29.
2)
(71)
(25)
(7.3
)
PhN L
i
OM
e (
ia),
hex
ane,
–78
°; to
rt,
2 h
PhN H
RPh
NH
2
R+
85C
4
R1 L
i1.
R2 N
(Li)
OR
3 (ia
), te
mp,
tim
e
2. A
rCO
Cl
R1 R
2 NC
OA
r
R1
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
n-B
u
s-B
u
s-B
u
s-B
u
t-B
u
t-B
u
t-B
u
R2
Me
n-Pr
i-Pr
n-C
5H11
i-C
5H11
Bn
PhC
HM
es
Ph(C
H2)
2
Me
Bn
Ph(C
H2)
3
Me
Bn
Ph(C
H2)
3
Ar
Ph Ph Ph Phr
4-M
eOC
6H4r
— — Ph Ph Ph — Ph — —
Solv
ent(
s)
Et 2
O, h
exan
e
Et 2
O, h
exan
e
Et 2
O, h
exan
e
TH
F
TH
F
hexa
ne
Et 2
O, h
exan
e
Et 2
O, h
exan
e
— hexa
ne
hexa
ne
— hexa
ne
hexa
ne
R3
Me
Me
Me
Bn
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
(63)
(64)
(47)
(70)
(50)
(68)
t
(68)
t
(68)
(62)
(60)
(66)
t
(30)
(99)
t
(61)
t
83, 8
2, 9
7
83 83 98 98 85 82, 9
7
83 97, 8
2
85, 8
3
85 82 85 85
Tem
p, T
ime
–78
°; to
rt,
3 h
–78
°; to
–15
°, 3
h
–78
°; to
rt,
18 h
0° t
o 40
°, 1-
3 h
0° t
o 40
°, 1-
3 h
–78
°; to
–10
°, 2
h
rt t
o 40
°, 2
h
–78
°; to
rt
—
–78
°; to
–10
°, 2
h
–78
°; to
–10
°, 2
h
—
–78
°; to
–10
°, 2
h
–78
°; to
–10
°, 2
h
RL
i R
= n
-Bu,
s-B
u, t-
Bu
BnN
(Li)
OM
e +
PhC
HM
eN(L
i)O
Me
(1:1
9, ia
), h
exan
e, –
78° t
o –1
0°R
NH
Bn
(—)
85
R1 L
i +
R2 L
iB
nN(L
i)O
Me
(ia)
, hex
ane,
–78
° to
–10°
, 2 h
R1 N
HB
n +
R
2 NH
Bn
85
R1
s-B
u
t-B
u
t-B
u
R2
n-B
u
n-B
u
s-B
u
R1 L
i:R2 L
i
1:9.
8
1:12
.3
1:11
.7
(27)
(29)
(19)
(47)
(50)
(60)
109
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
R1 L
i(i
a), h
exan
e, –
78°,
3 h;
rt,
1-2
dR
2N O
Me
R3
R4
R5
R2
N R1
R3
R4
R5
R2
N H
R3
R4
R5
+II
85
R1
n-B
u
s-B
u
s-B
u
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
R2
Ph Ph c-C
6H11
Ph Ph c-C
6H11
Ph Ph
R3
H H H H H H Me
Me
R4
H H H H H H H Me
R5
Ph Ph c-C
6H11
CH
=C
Me 2
Ph c-C
6H11
Ph Ph
I (5)
(47)
(9.5
)
(67)
(72)
(45)
(tra
ce)
(tra
ce)
II
III(5
)
(5)
(—)
(—)
(5)
(—)
(—)
(—)
R1
R2C
u(C
N)L
i 21.
TM
SNH
OT
MS,
TH
F, –
50° t
o rt
, 1 h
2. B
zCl,
pyri
dine
RN
HB
z I
+ R
OH
II
100
(48)
(60)
(80)
(18)
(5)
(10)
R n-B
u
s-B
u
t-B
u
C4
I
RM
gX (
x eq
)
X
not
spe
cifi
ed
Me 2
C=
NO
M, t
olue
neR
NH
217
4a
R n-B
u
Ph(C
H2)
2
Ph(C
H2)
2
(15)
(25)
(48)
x 2 2 1
M H H MgB
ru
C4-
10
RM
gBr
(ia)
, tol
uene
, Et 2
O, –
78°,
15 m
in18
1N
Me
MeN
NO
Ts
NM
eM
eN
NR
vR t-
Bu
Ph(C
H2)
2
Ph(C
H2)
2CH
Me
(<8)
(94)
(96)
110
C4
"4-C
l(C
H2)
4Zn
reag
ents
"M
e 2C
=N
OSO
2C6H
3Me 3
-2,4
,6, C
uCN
(ca
t), T
HF,
rt,
3 h
4-C
l(C
H2)
4NH
2(0
)17
7
RC
u1.
(4-
CF 3
C6H
4)2C
=N
OM
s, T
HF,
HM
PA, t
emp,
tim
e
2. B
zCl,
Et 3
N
RN
HB
z17
9
R n-B
u
s-B
u
t-B
u
Tem
p
–23°
–45°
–23°
(92)
(79)
(60)
Tim
e
30 m
in
1 h
1 h
Bn
RO
2CN
2
Bn
RO
2CN
NH
Bu-
n1.
, T
HF,
–78
°, 20
min
(fo
rms
I)
2. M
eI, –
78°,
3 h;
to r
t, 18
h (
form
s II
)
N=
NB
u-n
Bn
RO
2C
205
III
R Me
Bu
I
(56)
(—)
II (—)
(52)
n-B
uLi
CH
2=N
2, E
t 2O
, rt
(53)
202
1. Z
nCl 2
, TH
F, –
78°,
10 m
in
2. C
uCN
, –30
°3.
Ph 2
NN
HL
i, 30
min
4. O
2, –
78°
(18)
54
t-B
uLi
NN
(ia)
, TH
F, –
78°
N H
NB
u-t
(>90
)20
9
RL
iPh
N=
NPh
, hex
ane
or c
yclo
hexa
ne/T
HF,
–78
°, 2
h; r
t, 10
h
R n-B
u
s-B
u
t-B
u
(88)
(73)
(47)
211,
797
211
211,
798
Me
H NN H
Bu-
n
n-B
u
H NN
Ph2
Ph
R NN H
Ph
111
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
R1 M
2 O2C
N=
NC
O2R
2
R1
CH
2=C
H(C
H2)
2
CH
2=C
H(C
H2)
3
t-C
5H11
MeC
O2(
CH
2)4
(Z)-
TM
SCH
2CH
=C
H(C
H2)
2
(Z)-
EtC
H=
CH
(CH
2)2
Cl(
CH
2)5
NC
(CH
2)4
EtO
2C(C
H2)
5
2-oc
tyl
M MgX
w
MgX
w
MgX
w
ZnB
r
ZnB
r
MgX
w
MgX
w
ZnB
r
ZnB
r
ZnB
r
ZnB
r
Solv
ent
Et 2
O o
r T
HF
Et 2
O o
r T
HF
Et 2
O o
r T
HF
TH
F
TH
F
Et 2
O o
r T
HF
Et 2
O o
r T
HF
TH
F
TH
F
TH
F
TH
F
Tem
p
–78°
–78°
–78° rt rt
–78°
–78° 0° rt rt rt
(>47
)
(>42
)
(>46
)
(75)
(90)
(>23
)
(>35
)
(81)
(90)
(90)
(94)
799
799
799
358
358
799
799
358
358
358
358
R2
Me
Me
Me
t-B
u
t-B
u
Me
Me
t-B
u
t-B
u
t-B
u
t-B
u
Tim
e
— — —
30 m
in
3 h
— — 3 h
1 h
3 h
3 h
C4-
8
C4
R1 C
u(C
N)M
1. (
R2 ) 2
NN
HL
i, T
HF,
tem
p 1,
tim
e 1
2. A
dden
d
3. O
2, te
mp
2, 3
0 m
in
R1 N
HN
(R2 ) 2
R1
n-B
u
n-B
u
t-B
u
t-B
u
M ZnC
l
ZnC
l
ZnC
l
Li
R2
Me
Ph Ph Ph
Tem
p 1
–78°
to –
40°
–78°
to –
40°
–78°
to –
40°
–40°
Tim
e 1
— — —
30 m
in
Add
end
1,2-
(O2N
) 2C
6H4
1,2-
(O2N
) 2C
6H4
1,2-
(O2N
) 2C
6H4
—
Tem
p 2
— — — –78°
(50)
(34)
(60)
(30)
55 55 55 55, 5
4
n-B
uMgB
r80
0NS
Cl
N3
NS
Cl
NH
2(9
5)1.
,
Et 2
O, r
t, 30
min
2. N
H4C
l, H
2O
CH
C(C
H) 2
R2 O
2CN
N H
CO
2R2
R1
R
112
C5-
10
BrM
g(C
H2)
nMgB
rM
eON
H2,
Et 2
O, –
10° t
o –1
5°, 3
0 m
in2N
(CH
2)nN
H2
791
n 5 6 10
(68)
(51)
(53)
n-B
uM(i
a)80
0NS
PhN
NNNS
PhM L
i
MgB
r
Solv
ent
PhH
Et 2
O
Con
ditio
ns
–10°
to r
t, 1
h; th
en H
2O
rt, 3
0 m
in; r
eflu
x, 3
0 m
in;
then
NH
4Cl,
H2
H
O, N
H3
(—)
(54)
N=
NN
HB
u-n
NN
N CH
2Li
n-B
uMgB
r1.
(ia)
, TH
F, –
78°
2. P
hN=
NPh
, –78
°; to
rt
Ph(n
-C5H
11)N
NH
Ph(3
4)35
9
C5
C6
Mg,
Me 2
NO
SO2C
6H2M
e 3-2
,4,6
, Mg,
TH
F, r
t, 2
h80
1
1. M
g, M
e 2C
=N
OSO
2C6H
2Me 3
-2,4
,6, T
HF,
ref
lux,
3 h
2. B
zCl
(<15
)80
2
E+
1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2. S
ubst
rate
, the
n Ph
SiH
3
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 5 h
(59%
)(<
5%)
215
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
E
Br
NM
e 2(5
4)
NH
Bz
113
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
RM
gBr
OO
NO
SO2P
h
1.
,
Et 2
O, C
H2C
l 2, t
emp,
tim
e
2. H
Cl,
EtO
H, H
2O, r
eflu
x, 2
-6 h
RN
H3+
Cl–
182
(90)
(89)
(92)
R Ph(C
H2)
2
PhC
H2C
HM
e
PhC
HM
eCH
2
C8-
9
C8
NO
Bz
O, (
Ph3P
) 2N
iCl 2
(ca
t), T
HF,
rt,
10 m
in to
6 h
(58)
108
Tim
e
15 m
in
1 h
30 m
in
Tem
p
rt 0° 0°
C6-
9
YY
E
Y
EE
Y
E
+
+E
= N
(CO
2Bu-
t)N
HC
O2B
u-t
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2
. Sub
stra
te, t
hen
PhSi
H3
3
. t-B
uO2C
N=
NC
O2B
u-t,
rt, t
ime
Con
ditio
ns 2
: 1. C
atal
yst B
(se
e C
hart
1; 2
mol
%),
i-Pr
OH
, 0°
2
. Sub
stra
te, t
hen
PhSi
H3,
0°
3
. t-B
uO2C
N=
NC
O2B
u-t,
0°, t
ime
III
III
215
Y O O CH
2
CH
2
C(C
O2E
t)2
C(C
O2E
t)2
Con
ditio
ns
1 2 1 2 1 2
Tim
e
15 h
24 h
20 h
15 h
15 h
4 h
I
(<5)
(<5)
(40)
(34)
(<5)
(<5)
II (—)
(—)
(24)
(30)
(—)
(—)
III
(68)
(88)
(8)
(6)
(62)
(93)
III
dr
1.6:
1
2.5:
1
1.4:
1
5:1
7:1
9:1
ZnC
l4
N4
O
114
C8
1. P
hSC
H2N
3 (i
a), T
HF,
–78
°, 1-
4 h
2. A
cyla
ting
reag
ent,
tem
p, 1
h
3. N
H4C
l, H
2O
4. H
ydro
lysi
s
274
Acy
latin
g R
eage
nt
Ac 2
O
BzC
l
Hyd
roly
sis
n-B
u 4N
+ H
CO
2– , DM
F,
45°
, 4 h
50%
KO
H in
H2O
, TH
F,
MeO
H, 0
°, 40
min
(82)
R =
Me
(75)
R =
Ph
1. R
SCH
2N3
(ia)
, TH
F, te
mp,
tim
e
2. N
H4C
l, H
2O
274
R Me
Ph 4-M
eOC
6H4
Tem
p, T
ime
0°, 2
hx
–78°
, 1.7
5 h;
to 0
°, 30
min
–78°
, 2 h
(>86
)
(>90
)
(90)
C10
MgC
l
i-Pr
O2C
N=
NC
O2P
r-iaa
Ph+
i-P
rO2C
NH
NH
CO
2Pr-
i
(82)
(82)
220
1. [
3,5-
(CF 3
) 2C
6H3]
C=
NO
Ts,
tolu
ene,
Et 2
O, –
70°,
10 d
2. A
c 2O
, Et 3
NPh
NH
Ac
220
(25)
90%
ee
1. Z
n, T
HF,
0°
2. t-
BuO
2CN
=N
CO
2Bu-
t, 0°
(94)
z35
7
Ph
2,4,
6-M
e 3C
6H2S
O2O
NH
2, E
t 2O
, 0°,
10 m
in(8
8)11
6
1. P
hSC
H2N
3, T
HF,
–60
°, 1
h
2. A
c 2O
, –60
° to
–30°
3. K
OH
, DM
SO, 0
° to
rt, 3
hPh
NH
Ac
220
(82)
92-
95%
ee
PhM
gBr
PhN
HC
OR
Tem
p
–78°
to –
20°
–78°
to 0
°
Ph
H NN
NR
h
n-C
8H17
Br
n-C
8H17
Nt-
BuO
2CN
HC
O2B
u-t
ZrC
p 2C
l yN
H2
115
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
A. A
CY
CL
IC A
LIP
HA
TIC
CA
RB
AN
ION
S (C
onti
nued
)
C10
1. Z
nCl 2
, TH
F, –
78°,
80 m
in
2. B
n 2N
OB
z, C
uCl 2
(ca
t), –
78° t
o rt
, 2 h
3. H
2, P
d
3. A
c 2O
, Et 3
N
Ph
NH
Ac
(18)
75%
ee
113
MgC
l
Ph(c
a. 8
4% e
e)
aA
fter
30
min
utes
at –
15° t
he m
ixtu
re w
as r
eflu
xed
for
one
hour
.b
The
rea
ctio
n w
as c
arri
ed o
ut w
ith b
oth
R a
nd S
ena
ntio
mer
s (C
MeP
h); t
he o
ptic
al y
ield
s w
ere
5-46
%.
cT
he p
rodu
ct is
uns
tabl
e; th
e yi
eld
was
det
erm
ined
by
NM
R s
pect
rosc
opy.
d T
reat
men
t of
prod
ucts
II
with
BnO
CO
Cl f
ollo
wed
by
ceri
um a
mm
oniu
m n
itrat
e ga
ve R
NH
CO
2Bn.
eT
he y
ield
was
est
imat
ed b
y re
duct
ion
with
Zn/
HC
l and
titr
atio
n w
ith N
aNO
2.f X
2 was
.
gH
eatin
g to
70°
con
vert
ed a
ny Z
-azo
com
poun
ds in
to th
e E
isom
ers.
hSo
me
of th
e tr
iaze
nes
are
isol
ated
as
mix
ture
s of
dou
ble-
bond
isom
ers.
iT
he y
ield
is th
at o
f th
e am
ine
hydr
ochl
orid
e af
ter
redu
ctio
n of
the
tria
zene
with
RaN
i.J
The
pro
duct
was
con
vert
ed in
situ
into
the
(N-4
-met
hoxy
phen
ylet
hyl)
pipe
rony
lcar
boxa
mid
e.k
The
sub
stra
te w
as p
repa
red
in s
itu b
y re
actio
n of
the
alke
neR
1 R2 C
=C
H2
with
HZ
rCp 2
Cl i
n T
HF
at r
oom
tem
pera
ture
.l
PhC
HM
eNH
2(2
1%)
was
als
o fo
rmed
by
addi
tion
of th
e zi
rcon
ium
rea
gent
toC
1 of
sty
rene
.m
The
yie
ld is
that
of
the
hydr
ochl
orid
e.n
The
sub
stra
te w
as t-
BuM
gCl.
oT
he y
ield
is th
at o
f th
e N
-ben
zoyl
der
ivat
ive.
pT
he y
ield
is th
at o
f th
e fu
mar
ate.
qT
he in
itial
unc
leav
ed a
dduc
t was
isol
ated
in 4
1% y
ield
.r
The
rea
gent
R2 C
H2N
(Li)
OB
n w
as p
repa
red
in s
itu b
y ad
ditio
n of
R2 L
i to
CH
2=N
OB
n.s
The
rea
gent
was
pre
pare
d ei
ther
by
reac
tion
of P
hCH
MeN
HO
Me
with
MeL
i or
of P
hCH
MeN
(OM
e)C
O2(
CH
2)2B
r w
ith tw
o eq
uiva
lent
s of
t-B
uLi.
The
yie
ld in
the
latte
r re
actio
n w
as 6
4%.
tT
he y
ield
is th
at o
f th
e un
benz
oyla
ted
amin
e.u
The
rea
gent
was
pre
pare
d in
situ
by
reac
tion
of th
e ox
ime
with
one
equ
ival
ent o
f E
tMgB
r.
S O2N
O2
S
116
v T
he p
rodu
cts
wer
e co
nver
ted
into
RN
H2
with
CsO
H in
eth
ylen
e gl
ycol
at 1
50° o
r in
to R
NH
Me
with
LiA
lH4.
w X
was
not
spe
cifi
ed.
x N
o re
actio
n oc
curr
ed a
t –7
8°.
y T
he s
ubst
rate
was
pre
pare
d in
situ
by
reac
tion
of (
1S)-
(–)-
β-pi
nene
with
HZ
rCp 2
Cl i
n T
HF
at r
oom
tem
pera
ture
.
z T
reat
men
t with
TFA
fol
low
ed b
y re
duct
ion
with
RaN
i/H2
gave
the
race
mic
am
ine.
Rac
emiz
atio
n m
ost l
ikel
y oc
curr
ed d
urin
g fo
rmat
ion
of th
e or
gano
zinc
rea
gent
.aa
The
sub
stra
te w
as r
acem
ic.
117
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
B. C
YC
LIC
AL
IPH
AT
IC C
AR
BA
NIO
NS
R1 M
gBr
(R2 ) 2
NO
Bz
+ C
uCl 2
(x
mol
%, i
a, s
low
add
ition
), T
HF,
rt,
15 m
inR
1 N(R
2 ) 211
3
R1
c-C
3H5
c-C
6H11
c-C
6H11
C3-
6R
2
Bn
CH
2CH
=C
H2
Bn
x 15 2.5
2.5
(59)
(84)
(88)
C5-
10
RZ
nX1.
ArN
=N
Ts,
TH
F, –
20°,
30 m
in
2. R
aney
Ni,
EtO
H, r
eflu
x, 1
.5 h
ArN
HR
356
R c-C
5H9
c-C
5H9
c-C
6H11
c-C
6H11
exo-
1-no
rbor
nyl
exo-
1-no
rbor
nyl
X I I I c-C
6H11
exo-
1-no
rbor
nyl
exo-
1-no
rbor
nyl
Ar
4-E
tO2C
C6H
4
3,5-
Me 2
C6H
3
4-FC
6H4
4-E
tO2C
C6H
4
4-M
eOC
6H4
3-qu
inol
yl
4-M
eOC
6H4
4-E
tO2C
C6H
4
(71)
(76)
(75)
(62)
(71)
exo
:end
o =
4:1
(62)
exo
:end
o =
4:1
(67)
(50)
C3
1. 4
-RC
6H4N
=N
Ts,
TH
F, –
28°,
1 h
2. C
H2=
CH
CH
2I, N
-met
hylp
yrro
lidin
one,
rt,
3 h
3. Z
n, A
cOH
, TFA
, 75°
, 10
min
255
R Br
CO
2Et
(67)
(62)
MgB
rN
HC
6H4R
-4
C5-
12
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2
. Sub
stra
te, t
hen
PhSi
H3
3
. t-B
uO2C
N=
NC
O2B
u-t,
rt, t
ime
Con
ditio
ns 2
: 1. C
atal
yst B
(se
e C
hart
1; 2
mol
%),
i-Pr
OH
, 0°
2
. Sub
stra
te, t
hen
PhSi
H3,
0°
3
. t-B
uO2C
N=
NC
O2B
u-t,
0°, t
ime
n
R1
R2
n
R1
R2
NC
O2B
u-t
NH
CO
2Bu-
t
215
118
R1
H H H H H H Me
—(C
H2)
4—
—(C
H2)
4—
H
n 1 1 2 2 4 4 2 2 2 2
R2
H H H H H H Me
Ph
Con
ditio
ns
1 2 1 2 1 2 2 1 2 1
(74)
(94)
(24)
(90)
(62)
(95)
(79)
, dr
= 1
:1
(78)
(74)
(80)
Tim
e
8 h
2 h
24 h
2 h
24 h
2.5
h
3 h
18 h
18 h
8 h
C6
1. B
nON
H2,
Et 2
O, –
10° t
o –1
5°2.
HC
l
X Cl
Br
(79)
(62)
80
2,4,
6-M
e 3C
6H2S
O2O
NH
2, E
t 2O
, 0°,
10 m
in11
6(7
5)
1. T
sON
Me 2
, Et 2
O, r
t, 10
min
2. H
Cl
(13)
132
1. P
h 2P(
O)O
NH
2, T
HF,
–78
°; to
rt
2. H
O2C
CO
2H
(24)
140
Me 2
C=
NO
H, t
olue
ne(1
2)17
4a
MgX
NH
3+ C
l–
ZrC
p 2C
laN
H2
MgX
NM
e 2
exce
ss
X =
Br
NH
3+ H
O2C
CO
2–
X =
Cl o
r B
r
MgX
b
2 eq
NH
2
1. M
g, M
e 2C
=N
OSO
2C6H
2Me 3
-2,4
,6, T
HF,
ref
lux,
3 h
2. B
zCl
(<15
)80
2
NH
Bz
Br
119
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
B. C
YC
LIC
AL
IPH
AT
IC C
AR
BA
NIO
NS
(Con
tinu
ed)
1.M
e 2C
=N
OSO
2C6H
2Me 3
-2,4
,6, E
t 2O
, tol
uene
, 0°,
2 h
2. H
ydro
lysi
s
(40)
c80
3
C6
MgB
rN
H2
RM
gBr
1.
, E
t 2O
, CH
2Cl 2
, tem
p, ti
me
1
2. H
Cl,
EtO
H, H
2O, r
eflu
x, ti
me
2
OO
NO
SO2P
h
RN
H3+
Cl–
182
R c-C
6H11
1-no
rbor
nyl
1-ad
aman
tyl
C6-
10
Tem
p
0° rt 0°
Tim
e 1
30 m
in
12 m
in
30 m
in
Tim
e 2
6 h
10 h
10 h
(92)
d
(64)
(89)
1. M
e 2C
=N
OSO
2C6H
2Me 3
-2,4
,6, C
uCN
(0.
2 eq
), T
HF,
rt,
3 h
2. H
Cl
(20)
177
[Ar 2
C=
NO
R2
+ a
dden
d] (
ia),
30
min
R1 N
H2
R1
c-C
6H11
c-C
6H11
1-no
rbor
nyl
1-ad
aman
tyl
Ar
4-C
F 3C
6H4
3,5-
(CF 3
) 2C
6H3
4-C
F 3C
6H4
4-C
F 3C
6H4
R2
Ms
Ts
Ms
Ms
Add
end
CuC
N +
2 L
iCl (
0.2
eq)
— CuC
N +
2 L
iCl (
0.2
eq)
CuC
N +
2 L
iCl (
0.2
eq)
Solv
ent
TH
F, H
MPA
Et 2
O, t
olue
ne
TH
F, H
MPA
TH
F, H
MPA
Tem
p
0° rt 0° 0°
(80)
d
(87)
d
(96)
e
(82)
e
X Cl
Cl
Cl
Br
179,
726
179
179
179,
726
R1 M
gX
ZnC
l
exce
ss
NH
3+C
l–
C6
(EtO
2C) 2
C=
NC
6H4O
Me-
4 (i
a), T
HF,
–95
°, 30
min
(48)
167
PhN
2+ B
F 4– , T
HF,
0°,
1 h
(0)
190
MgB
rN
OM
e
C6H
11-c
EtO
2C EtO
2C
PhN
N
ZnM
gBr
3
120
, Et 2
O, 0
° to
rt, 1
hN
H
NC
6H11
-cR
1
R2
208
R1
Me
i-Pr
—(C
H2)
5—R2
Me
i-Pr
(62)
(40)
f
(86)
NNR
1
R2
MgB
r
RM
gX
1. P
hSC
H2N
3, T
HF,
Et 2
O, –
78°
2. A
c 2O
, –78
°3.
n-B
u 4N
+ H
CO
2– , DM
F, r
t, 1.
5 h;
45°
, 2 h
RN
HA
c27
3, 2
74,
275
R c-C
6H11
2-no
rbor
nylg
(93)
(70)
C6-
7
PhSO
2N3
(ia)
, Et 2
O30
6
N3
N3
, Et 2
O(7
9)27
2
2
4-FC
6H4N
3 (i
a), E
t 2O
, rt,
1 h
(85)
279
(—)
C6
C7
MgB
r
MgX
b
MgC
lH N
NN
SO2P
h
H N
FH N
NN
MgB
rN
Bn 2
1. Z
nCl 2
(50
mol
%),
Et 2
O, T
HF,
rt,
1 h
2. B
n 2N
OB
z, C
uCl 2
(ca
t), T
HF,
rt,
2 h
(57)
, end
o:ex
o =
65:
3511
3
exo:
endo
= 6
0:40
MgB
rN
Bn 2
1. Z
nCl 2
(50
mol
%),
Et 2
O, T
HF,
–78
°, 1
h
2. B
n 2N
OB
z, C
uCl 2
(ca
t), T
HF,
–78
° to
rt, 2
h
(56)
, end
o:ex
o >
95:
511
3H
H
Li
NM
e 2
2,4,
6-M
e 3C
6H2S
O2O
NM
e 2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–15°
; to
rt, 1
5 h
(54)
133
121
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
B. C
YC
LIC
AL
IPH
AT
IC C
AR
BA
NIO
NS
(Con
tinu
ed)
Li
NH
2
(39)
355
ClN
H2,
Et 2
O, s
onic
atio
n
NCO
2Bu-
t
NH
CO
2Bu-
t21
5
Con
ditio
ns
1 2
(66)
(98)
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2
. Sub
stra
te, t
hen
PhSi
H3
3
. t-B
uO2C
N=
NC
O2B
u-t,
rt, 7
h
Con
ditio
ns 2
: 1. C
atal
yst B
(se
e C
hart
1; 2
mol
%),
i-Pr
OH
, 0°
2
. Sub
stra
te, t
hen
PhSi
H3,
0°
3
. t-B
uO2C
N=
NC
O2B
u-t,
0°, 7
h
C7
NC
O2B
u-t
NH
CO
2Bu-
t
1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2. S
ubst
rate
, the
n Ph
SiH
3
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 5 h
(90)
215
(27)
307
Cl
H2N
1. L
i, cy
cloh
exan
e, 9
0°2.
TsN
3, E
t 2O
, pen
tane
, –15
°, 30
min
3. I
sola
te tr
iaze
ne s
alt a
nd h
eat t
o 75
°/0.
1 m
m f
or 5
hh
N3
1. C
o(B
F 4) 3
•6H
2O, l
igan
d, E
tOH
, rt,
10 m
in
2. S
ubst
rate
3. 4
-MeC
6H4S
O2N
3, t-
BuO
2H, r
t, 5
min
4. P
hSiH
3, r
t, 12
h
t-B
uO
H
t-B
uN
PhPh
OK
O
Lig
and:
(56)
215
C8
122
Li
H
NH
2
H
1. P
hSC
H2N
3, T
HF,
pen
tane
, –78
°; to
rt,
1.5
h
2. N
H4C
l, H
2O
3. K
OH
, DM
SO, r
t, 1
h
C9
(45)
274
H H
H H
C10
-12
R
Br
1. L
i, E
t 2O
, son
icat
ion
2. C
lNH
2, E
t 2O
, son
icat
ion
R H Me
(54)
(48)
355
R
R
NH
2
R
1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2. S
ubst
rate
, the
n Ph
SiH
3
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 4 h
215
(94)
NCO
2Bu-
t
NH
CO
2Bu-
t
PhN
2+ B
F 4– , T
HF,
–78
°N
(low
)18
5N
Ph
MgB
rN
NM
e
MeN
NM
eM
eN
NO
Ts
(ia)
, tol
uene
, Et 2
O, 0
°, 15
min
(55)
i18
1
NN
HC
O2B
u-t
NH
CO
2Bu-
t
1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2. S
ubst
rate
, the
n Ph
SiH
3
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 5 h
(70)
, dr
= 5
:121
5
C10
1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2. S
ubst
rate
, the
n Ph
SiH
3
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 5 h
N NH
CO
2Bu-
t
CO
2Bu-
t(8
4), d
r =
1:2
-1:3
215
123
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
B. C
YC
LIC
AL
IPH
AT
IC C
AR
BA
NIO
NS
(Con
tinu
ed)
C11
OM
e
ZnP
r-i
OM
e
NH
C6H
4CO
2Et-
4
1. 4
-EtO
2CC
6H4N
=N
Ts,
TH
F, –
20°
2. R
aney
Ni,
EtO
H, r
eflu
x, 1
2 h
(40)
88%
ee;
tran
s:ci
s =
98:
235
6
chir
al n
on-r
acem
ic
N3
1. C
o(B
F 4) 3
•6H
2O, l
igan
d, E
tOH
, rt,
10 m
in
2. S
ubst
rate
3. 4
-MeC
6H4S
O2N
3, t-
BuO
2H, r
t, 5
min
4. S
ilane
, rt,
12 h
t-B
uO
H
t-B
uN
PhPh
OK
O
Lig
and:
Sila
ne
PhSi
H3
(Me 2
SiH
) 2O
(89)
(76)
dr 4:1
4:1
215
C10
C15
Ph
Ph
MgB
r
2,4,
6-M
e 3C
6H2S
O2O
NM
e 2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–15°
; to
rt, 1
5 h
Ph
Ph
NM
e 213
3, 1
34(4
7)
C20
Li
ClN
H2,
Et 2
O, s
onic
atio
n
NH
2
(41)
355
124
N
(48)
CO
2Bu-
t
t-B
uO2C
N=
NC
O2B
u-t,
Et 2
O, s
onic
atio
n35
5
a The
sub
stra
te w
as p
repa
red
in s
itu b
y ad
ditio
n of
HZ
rCp 2
Cl t
o cy
cloh
exen
e.b X
was
not
spe
cifi
ed.
c The
yie
ld w
as d
eter
min
ed b
y ga
s ch
rom
atog
raph
y.d T
he p
rodu
ct w
as is
olat
ed a
s th
e N
-ben
zoyl
der
ivat
ive.
e T
he p
rodu
ct w
as is
olat
ed a
s th
e hy
droc
hlor
ide.
f The
pro
duct
was
isol
ated
as
the
oxal
ate.
g T
he s
ubst
rate
was
a m
ixtu
re o
f ex
o an
d en
do is
omer
s.
h C
auti
on!
Exp
losi
ons
and
spon
tane
ous
igni
tion
wer
e en
coun
tere
d in
this
ste
p.
i The
pro
duct
was
con
vert
ed in
to a
min
oada
man
tane
with
CsO
H in
eth
ylen
e gl
ycol
at 1
50° (
71%
yie
ld)
or
into
N-m
ethy
lam
inoa
dam
anta
ne w
ith L
iAlH
4 (5
5% y
ield
).
NH
t-B
uO2C
125
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
C. A
LL
YL
IC A
ND
PR
OPA
RG
YL
IC C
AR
BA
NIO
NS
C3
Li
1. M
eON
HL
i (2
eq, i
a), E
t 2O
, –78
° to
rt, 2
h
2. B
zCl
NH
Bz
82(7
8)
NC
O2
PhH
N HC
O2
PhH
(0)
(44-
55)
+16
1M
gX
MgX
R
C3-
4
N
RM
eO2C
N=
NC
O2M
e, E
t 2O
or
TH
F, –
78°
R H Me
(>23
)
(>60
)
799
MgX
RN
3, E
t 2O
NH
N=
NR
R Ph PhSO
2
1-na
phth
yl
Tem
p
— —
refl
ux
(48)
(—)a
(60)
282
306
281
In b
R1
R2 N
3, D
MF,
rt
NH
R2
R1
269
NR
2
R1
+2
C3
C3-
4
MeO
NH
2, E
t 2O
, –10
° to
–15°
, 30
min
791
(40)
MgB
rN
H2
X Br
Cl
Br
III
X n
ot s
peci
fied
2 eq
X n
ot s
peci
fied
Tim
e
— —
25 m
in
(ia)
, Et 2
ON
CO
2
PhH
CO
2Me
NH
CO
2Me
i-Pr
i-Pr
126
R1
H H H H H H CO
2Me
CO
2Me
CO
2Me
CO
2Me
CO
2Me
CO
2Me
CO
2Me
CO
2Me
CO
2Me
CO
2Me
R2
Ph c-C
6H11
n-C
6H11
4-C
lC6H
4
4-M
eC6H
4
Bn
Ph 3-C
lC6H
4
3,4-
Cl 2
C6H
3
4-M
eOC
6H4
4-C
l-2-
MeO
C6H
3
3,4-
(MeO
) 2C
6H3
2-M
eC6H
4
2-B
r-4-
MeC
6H3
Bn
2-na
phth
yl
Tim
e
2.0
h
2.5
h
3.0
h
3.0
h
1.5
h
2.0
h
1.5
h
2.5
h
2.5
h
1.0
h
2.5
h
3.0
h
3.0
h
2.0
h
2.5
h
3.5
h
I
(90)
(73)
(70)
(85)
(88)
(80)
(80)
(81)
(80)
(87)
(80)
(89)
(84)
(85)
(84)
(75)
II
(5-8
)
(5-8
)
(5-8
)
(5-8
)
(5-8
)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
C4
2t-
BuO
2CN
(M)O
Ts,
TH
F, –
78°,
1.5
hN
HC
O2B
u-t
127
M Li
MgC
l
(66)
(72)
CN
1. L
iHM
DS
(ia)
, TH
F, –
78°
2.
(
+),
–78
°; to
rt,
26.5
h
N H
ON
CO
NH
2
151
(45)
CuM
gCl
SnB
u 3t-
BuO
2CN
NC
ON
ZnC
l 2•O
Et 2
, CH
2Cl 2
, –78
° to
rt, 2
hN
CO
N
(73)
410
t-B
uO2C
NH
Nt-
BuO
2CH
NC
ON
+
(7)
,
127
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
C. A
LL
YL
IC A
ND
PR
OPA
RG
YL
IC C
AR
BA
NIO
NS
(Con
tinu
ed)
C4-
10
R1
R3
R4
R1
R3
R4
NN
HC
O2R
5R
5 O2C
1. C
atal
yst A
(1-
5 m
ol%
), E
tOH
, rt
2. S
ubst
rate
, the
n si
lane
3. R
5 O2C
N=
NC
O2R
5 , rt,
time
R1
TM
S
TM
S
TM
S
TM
S
TM
S
TM
S
TM
S
TM
S
TM
S
TM
S
TM
S
n-B
u
n-B
u
Ph Ph (4-M
eOC
6H4C
O2)
CM
e 2
(4-M
eOC
6H4C
O2)
CM
e 2
R2
H H H H Me
Me
H H H Me
Me
H H H H H H
R2
R2
R3
H H Me
(H)
Me
(H)
H H CH
2OH
CH
2OT
BD
MS
CO
2Me
H H H H H H H H
R4
H H H (
Me)
H (
Me)
H H H H H CH
2OH
CH
2OH
H H H H H H
R5
Et
t-B
u
Et
t-B
u
Et
t-B
u
t-B
u
t-B
u
t-B
u
Et
t-B
u
Et
t-B
u
Et
t-B
u
Et
t-B
u
Sila
ne
PhSi
H3
PhSi
H3
PhSi
H3
PhSi
H3
PhSi
H3
PhSi
H3
PhSi
H3
PhSi
H3
PhSi
H3
PhSi
H3
(Me 2
SiH
) 2O
PhSi
H3
PhSi
H3
PhSi
H3
(Me 2
SiH
) 2O
PhSi
H3
PhSi
H3
Tim
e
1 h
2 h
1.5
h
3 h
2 h
4 h
2 h
2 h
4 h
3 h
4 h
1.5
h
45 m
in
1.5
2 h
1 h
1.5
h
(73)
(83)
(45)
(55)
(67)
(42)
(77)
(63)
(47)
(66)
(27)
(72)
(78)
(46)
(56)
(75)
(61)
216
C5
Me 2
N
Me 2
NO
Ms,
TH
F, –
20°,
30 m
in(4
7)80
4L
i+
ZrC
p 2C
l cN
H2
2,4,
6-M
e 3C
6H2S
O2O
NH
2, E
t 2O
, 0°,
10 m
in(6
2)d
116
128
C6
EE
+
III
I +
II
(60)
, I:I
I =
4:1
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. (
Me 2
SiH
) 2O
, the
n su
bstr
ate
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 12
h
216
C5-
8
n
N
NC
O2B
u-t
CO
2Bu-
t
n
+
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. (
Me 2
SiH
) 2O
, the
n su
bstr
ate
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, tim
e
n 1 2 3 4
Tim
e
12 h
12 h
12 h
6 h
I
(45)
(73)
(84)
(81)
II (23)
(0)
(0)
(0)
216
NN
HC
O2B
u-t
CO
2Bu-
t
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. (
Me 2
SiH
) 2O
, the
n su
bstr
ate
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 12
h
(83)
216
C5
Y
C6-
9
Y
E
Y
+
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. (
Me 2
SiH
) 2O
, the
n su
bstr
ate
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, tim
eI
IIE
= N
(CO
2Bu-
t)N
HC
O2B
u-t
Y NT
s
C(C
O2E
t)2
I
(90)
(60)
II (0)
(15)
216
Tim
e
7 h
2 h
NN
N CH
(Li)
CH
=C
H2
n-B
uMgB
r
1.
(
ia),
TH
F, –
78°
2. P
hN=
NPh
, –78
°; to
rt
359
C7
n-B
uN
(32)
E
NC
O2B
u-t
NH
CO
2Bu-
t
n
NH
Ph
Ph
129
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
C. A
LL
YL
IC A
ND
PR
OPA
RG
YL
IC C
AR
BA
NIO
NS
(Con
tinu
ed)
C8
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. (
Me 2
SiH
) 2O
, the
n su
bstr
ate
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 12
hE
E
+I
II
E =
N(C
O2B
u- t)N
HC
O2B
u- t
I +
II
(71)
, I:I
I =
7:1
216
C9
NH
2Ph
MgC
lPh
ClN
H2,
Et 2
O, –
20°
(14)
805
(PhO
) 2P(
O)O
NM
e 2, T
HF,
–30
° to
0°(—
)14
6
Li+
(PhO
) 2P(
O)O
NM
e 2, T
HF,
–30
° to
0°(4
0)14
6
H H
NM
e 2
H
HN
Me 2
Li+
2,4,
6-M
e 3C
6H2S
O2O
NM
e 2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–15°
; to
rt, 1
5 h
NM
e 2
(69)
133
Li
2,4,
6-M
e 3C
6H2S
O2O
NM
e 2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–15°
; to
rt, 1
5 h
NM
e 2
133
+
NM
e 2
III
I +
II
(57)
, I:I
I —
Li+
C10
(37)
NH
2
Ph2P
(O)O
NH
2, T
HF,
–20
°; r
t, 12
h13
9
130
ON
Ph
Li
MeO
C11
t-B
uO2C
N=
NC
O2B
u-t,
TH
F, –
78°;
to r
t, 15
h
ON
Ph
MeO
(34)
806
C15
-21
PhPh
Li
C15
PhPh
Ph2P
(O)O
NH
2, T
HF,
–20
°; r
t, 12
hO
(31)
139
a Pyr
olys
is o
f th
e tr
iaze
ne s
alt g
ave
ally
l azi
de in
13%
yie
ld.
b The
sub
stra
tes
wer
e pr
epar
ed c
oncu
rren
tly f
rom
the
brom
ide
with
indi
um m
etal
in th
e pr
esen
ce o
f on
e eq
uiva
lent
of
NaI
.c T
he s
ubst
rate
was
pre
pare
d in
situ
by
addi
tion
of H
ZrC
p 2C
l to
3-m
ethy
l-1,
2-bu
tadi
ene.
d The
pro
duct
was
cha
ract
eriz
ed a
s th
e N
-ben
zoyl
der
ivat
ive.
PhPh
R1
Li
PhPh
R1
2,4,
6-M
e 3C
6H2S
O2O
N(R
2 ) 2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–15°
; to
rt, 1
5 h
R1
H t-B
u
Ph Ph
(37)
(31)
(38)
(39)
133
R2
Me
Me
Me
Et
(R2 ) 2
N
C10
1. C
atal
yst A
(se
e C
hart
1; 1
.5 m
ol%
), E
tOH
, rt
2. (
Me 2
SiH
) 2O
, the
n su
bstr
ate
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 12
h
NC
O2B
u-t
NH
CO
2Bu-
t
(65)
216
NN
CO
2Bu-
t
CO
2Bu-
t
+
(3)
NN
HC
O2B
u-t
t-B
uO2C
131
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
D. A
RY
LM
ET
HY
L A
ND
HE
TE
RO
AR
YL
ME
TH
YL
CA
RB
AN
ION
S
C5
NN
NN
1. K
NH
2, N
H3
(liq
uid)
, Et 2
O
2. P
hN=
NPh
(39)
212
N1.
Bas
e (x
eq)
, TH
F, h
exan
e, c
ondi
tions
2. A
rN=
NA
r, –
78°,
10 m
in
212
R H H 4-M
e
6-M
e
4,6-
Me 2
Bas
e
LD
A
LD
A
n-B
uLi
LD
A
n-B
uLi
Con
ditio
ns
rt, 1
h
rt, 1
h
—
rt, 1
h
—
(69)
(36)
(47)
(83)
(63)
Ar
Ph 4-C
lC6H
4
Ph Ph Ph
x 2 1 1 2 1
C6-
8
R
C5-
6
Y
N R
Y
N R
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2
. PhS
iH3,
t-B
uO2C
N=
NC
O2B
u-t,
rt
3
. Sub
stra
te, r
t, tim
e
Con
ditio
ns 2
: 1. C
atal
yst B
(se
e C
hart
1; 1
mol
%),
i-Pr
OH
, rt t
o 0°
2
. PhS
iH3,
t-B
uO2C
N=
NC
O2B
u-t,
0°
3. S
ubst
rate
, 0°,
time
215
Y N N CH
CH
CH
R Me
Me
H Boc
Ts
Con
ditio
ns
1 2 1 1 1
(60)
(88)
(<5)
(67)
(74)
Tim
e
8 h
5 h
— 11 h
11 h
Nt-
BuO
2CN
HC
O2B
u-t
N
RNA
r
NH
Ar
NN
HPh
Ph
132
C6-
7
YR
Y
Y O S S
R H H Me
(68)
(84)
(58)
215
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. P
hSiH
3, t-
BuO
2CN
=N
CO
2Bu-
t, rt
3. S
ubst
rate
, rt,
time
Tim
e
12 h
18 h
7 h
Nt-
BuO
2CN
HC
O2B
u-t
R
C6
O
O
Nt-
BuO
2CN
HC
O2B
u-t (7
5)21
5
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. P
hSiH
3, t-
BuO
2CN
=N
CO
2Bu-
t, rt
3. S
ubst
rate
, rt,
18 h
C6-
8
NY
NY
Nt-
BuO
2CN
HC
O2B
u-t
R1
R2
R2
R1 Y N C
H
CH
CH
R1
H H Me
H
R2
H H H Me
(63)
(77)
(60)
(54)
215
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. P
hSiH
3, t-
BuO
2CN
=N
CO
2Bu-
t, rt
3. S
ubst
rate
, rt,
time
Tim
e
24 h
4 h
5 h
5 h
N
1. L
DA
(2
eq),
TH
F, h
exan
e, 1
h
2. A
rN=
NA
r, –
78°,
10 m
in
Ar
Ph 2-C
lC6H
4
4-C
lC6H
4
Ph Ph
(97)
(53)
(44)
(82)
(77)
R21
2
212
212
212
212,
807
R H H H 2-M
e
2,6-
Me 2
N
R
NA
r
NH
Ar
133
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
D. A
RY
LM
ET
HY
L A
ND
HE
TE
RO
AR
YL
ME
TH
YL
CA
RB
AN
ION
S (C
onti
nued
)
C7
NC
l 3, E
t 2O
77
Br 2
NH
, Et 2
O, 2
-3°
75
RN
HC
l, E
t 2O
, 5°,
1 h
68
R Me
Et
I
(14)
(12)
II (70)
(75)
NH
2Cl,
Et 2
O, 0
°(9
2)80
5, 5
6
RN
Cl 2
, Et 2
O, 5
°, 1
h68
2 eq
1. B
nON
H2,
Et 2
O, –
10° t
o –1
5°2.
HC
l
80
1. M
eON
HL
i (2
eq, i
a), E
t 2O
2. B
zCl
(97)
82, 7
86
I
(25)
(19)
III
(3)
(6)
II (43)
(28)
R Me
Et
III
R2N
Cl,
Et 2
O, 5
°, 1
hR
2NH
III
R Me
Et
n-Pr
I (5)
(5)
(5)
II (95)
(89)
(78)
68
PhM
gCl
exce
ss
4 eq
exce
ss
PhN
H2
PhN H
PhI
(32)
+
II (
7)
I (3
4) +
II
(6)
PhN
HR
+R
NH
2
I III
I +
II
+Ph
N RPh
PhN
R2
+
PhL
iPh
N HPh
O
PhN
H3+
Cl–
(79)
134
Me 2
NO
Ms,
Et 2
O o
r T
HF,
–30
° to
0°13
4
Mg,
Me 2
NO
SO2C
6H2M
e 3-2
,4,6
, Mg,
TH
F, r
t, 2
h80
1
R1 R
2 NO
Bz,
(Ph
3P) 2
NiC
l 2 (
cat)
, TH
F, r
t, 10
min
to 6
h10
8
R1
—
(CH
2)5—
—(C
H2)
2O(C
H2)
2—R2
(68)
(85)
R1 R
2 NO
Bz,
(C
uOT
f)2•
PhH
(ca
t), T
HF,
rt,
1 h
R1
Bn
—(C
H2)
2O(C
H2)
2—
R2
Bn
109
112,
109
(91)
(80)
PhM
gCl
PhN
Me 2
(43)
I
I (1
0)Ph
Br
PhZ
nCl
PhN
R1 R
2
PhZ
n
I
IPh
Ph2P
(O)O
NH
2, T
HF,
–20
°; r
t, 12
h13
9
M Li
MgC
l
MgB
r
(30)
(70)
(51)
, TH
F, –
78°;
to r
t, ov
erni
ght
PhN
CO
2Bu-
n
PhN
BnC
O2B
u-n
M MgC
l
MgC
l•E
t 3A
l
Cu
Cu•
BF 3
Ti(
OPr
-i) 3
(95)
(78)
(22)
(50)
(55)
164
PhM
PhN
H2
X n
ot s
peci
fied
M Mg
CdN
CO
2
PhH
Bn
N HC
O2
PhH
Bn
I
II
+
161
I +
II
(45-
55)
(55-
70)
I:II
100:
0
0:10
0a
PhM
X(i
a), E
t 2O
NC
O2
PhH
i-Pr
i-Pr
135
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
D. A
RY
LM
ET
HY
L A
ND
HE
TE
RO
AR
YL
ME
TH
YL
CA
RB
AN
ION
S (C
onti
nued
)
4-M
eOC
6H4N
CO
2Et
CO
2Et
(80)
167,
166
Me 2
C=
NO
SO2C
6H2M
e 3-2
,4,6
, CuC
N (
cat)
, TH
F, r
t, 3
h(5
6)17
7
1. C
H2=
N2,
Et 2
O, r
t
2. H
Cl
202,
199
(ia)
, TH
F, –
95°,
30 m
inPh
MgB
r
PhZ
nPh
exce
ssPh
NH
2
PhM
gCl
Me
H NN H
Bn
•HC
l(4
1)
C7
NC
O2E
t
CO
2Et
Bn
MeO
Ph2C
=N
2, E
t 2O
, rt
(73)
202
(0)
PhN
2+ B
F 4– , T
HF,
0°,
1 h
190
RC
ON
=N
CO
R
R MeO
t-B
uO
Ph
Solv
ent
Et 2
O o
r T
HF
TH
F
Et 2
O
(>70
)
(90)
(30)
Tim
e
—
30 m
in
—
M MgX
b
ZnB
r
MgB
r
799
358
794
Tem
p
–78° rt rt
RN
3, E
t 2O
R Ph PhSO
2 (i
a)
Tem
p
refl
ux
—
(goo
d)
(98)
270
306
PhM
gBr
PhN
H NB
n
Ph
PhM
PhN
NPh
RN
H N
O
Bn
R
O
PhM
gCl
Tim
e
30 m
in
—
N
H NN H
Bn
cR
N
136
N3
Ph
1.
, TH
F, –
78°;
to r
t, 2
h
2. H
Cl,
then
bas
e
278
790
NSN
3
(43)
, Et 2
O, 1
0-12
h
PhL
iPh
NH
2(6
0) NSN
BnH
NN
PhM
gXb
C8
, TH
F, –
15°
N MeP
O
ON
Me 2
Ph
147
X Cl
Br
(63)
30%
ee
(40)
44%
ee
O
1. L
DA
, TH
F, h
exan
e, 1
h
2. A
rN=
NA
r, –
78°,
5 m
in21
2
Ar
Ph 2-C
lC6H
4
(73)
(68)
PhM
gXPh
NM
e 2
NC
NC
N
H N
Ar
Ar
NN
N CH
(R2 )L
i
R1 M
gBr
1.
(ia)
, TH
F, –
78°
2. A
rN=
NA
r, –
78°;
to r
t
359
C8-
13
R1
Ar
NN
HA
r
R2 R
1
Me
n-B
u
n-B
u
n-B
u
n-B
u
Ph
R2
Ph Ph Ph Ph 4-M
eC6H
4
Ph
Ar
Ph Ph 4-C
lC6H
4
4-M
eC6H
4
Ph Ph
(40)
(54)
(51)
(48)
(57)
(52)
137
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
D. A
RY
LM
ET
HY
L A
ND
HE
TE
RO
AR
YL
ME
TH
YL
CA
RB
AN
ION
S (C
onti
nued
)
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2
. Sub
stra
te a
nd P
hSiH
3
3
. t-B
uO2C
N=
NC
O2B
u-t,
rt, t
ime
Con
ditio
ns 2
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2
. PhS
iH3,
t-B
uO2C
N=
NC
O2B
u-t,
rt
3
. Sub
stra
te, r
t, tim
e
Con
ditio
ns 3
: 1. C
atal
yst B
(se
e C
hart
1; 5
mol
%),
i-
PrO
H, r
t to
0°
2. S
ubst
rate
, PhS
iH3
3
. t-B
uO2C
N=
NC
O2B
u-t,
0°, t
ime
Con
ditio
ns 4
: 1. C
atal
yst B
(se
e C
hart
1; 1
mol
%),
i-
PrO
H, r
t to
0°
2
. PhS
iH3,
t-B
uO2C
N=
NC
O2B
u-t,
0°
3. S
ubst
rate
, 0°,
time
C8-
15
R1
Ar
R3
R2
R3
R2
N
Ar
R1
t-B
uO2C
NH
CO
2Bu-
t
Ar
Ph 4-H
2NC
6H4
4-H
2NC
6H4
4-Fm
ocN
HC
6H4
Ph Ph Ph Ph Ph
R1
H H H H Me
H H Me
Me
R2
H H H H H Me
CH
2OH
Me
Me
R1
H H H H H H H H Me
Con
ditio
ns
2 2 4 2 2 1 1 1 3
(86)
(20-
40)
(66)
(98)
(88)
(88)
(91)
(13)
(51)
215
Tim
e
5 h
20 h
4 h
4 h
2 h
3 h
1 h
20 h
4 h
C8
N
1. B
uLi,
hexa
ne, T
HF,
–78
°2.
PhN
=N
Ph(6
5-77
)21
2
N
NN
HPh
Ph
138
Li
2,4,
6-M
e 3C
6H2S
O2O
NM
e 2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–15°
; to
rt, 1
5 h
NM
e 2
133
NM
e 2
+(5
7)
C10
NN
212
1. B
ase,
sol
vent
, tem
p, ti
me
2. A
rN=
NA
r Bas
e
KN
H2,
NH
3 (l
iq)
LD
A
Solv
ent
Et 2
O
TH
F, h
exan
e
Tem
p, T
ime
30 m
in
rt, 1
h, t
hen
–78°
Ar
Ph 2-C
lC6H
4
(50)
(7)
C9
1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2. S
ubst
rate
, the
n Ph
SiH
3
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 4 h
215
(94)
NCO
2Bu-
t
NH
CO
2Bu-
t
NS1.
Cat
alys
t A (
see
Cha
rt 1
; 5 m
ol%
), E
tOH
, rt
2. S
ubst
rate
, the
n Ph
SiH
3
3. R
O2C
N=
NC
O2R
, rt,
4 h
215
NS
N CO
2RNH
CO
2RR E
t
t-B
u
(54)
(<14
)
N HN H
N NH
CO
2Bu-
t
CO
2Bu-
t1.
Cat
alys
t A (
see
Cha
rt 1
; 2.5
mol
%),
EtO
H, r
t
2. P
hSiH
3, t-
BuO
2CN
=N
CO
2Bu-
t
3. S
ubst
rate
, rt,
5 h
(82)
215
N RN RN
t-B
uO2C
NH
CO
2Bu-
t
1. C
atal
yst A
(se
e C
hart
1; 2
.5 m
ol%
), E
tOH
, rt
2. P
hSiH
3, t-
BuO
2CN
=N
CO
2Bu-
t
3. S
ubst
rate
, rt,
11 h
R Boc
Ts
(76)
(85)
215
NAr
NH
Ar
139
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
D. A
RY
LM
ET
HY
L A
ND
HE
TE
RO
AR
YL
ME
TH
YL
CA
RB
AN
ION
S (C
onti
nued
)
C11
NH
2
ClN
H2
(47)
805
MgC
l
MsO
NM
e 2, E
t 2O
or
TH
F, –
30° t
o 0°
(84)
134
R Me
2,4,
6-M
e 3C
6H2
Solv
ent(
s)
Et 2
O o
r T
HF
Et 2
O o
r E
t 2O
/TH
F
(61)
(95)
134
133
C13
RSO
2ON
Me 2
Tem
p, T
ime
–30°
to 0
°–1
0° to
–20
° to
rt; r
t, 15
h
Li
NM
e 2
PhPh
N NH
CO
2Bu-
t
CO
2Bu-
t
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
EtO
H, r
t
2
. Sub
stra
te, t
hen
PhSi
H3
3
. t-B
uO2C
N=
NC
O2B
u-t,
rt, 5
h
Con
ditio
ns 2
: 1. C
atal
yst B
(se
e C
hart
1; 2
mol
%),
i-Pr
OH
, 0°
2
. Sub
stra
te, t
hen
PhSi
H3,
0°
3
. t-B
uO2C
N=
NC
O2B
u-t,
0°, 4
h
Con
ditio
ns
1 2
(48)
(60)
215
C12
PhPh N N
HC
O2B
u-t
CO
2Bu-
t1.
Cat
alys
t A (
see
Cha
rt 1
; 5 m
ol%
), E
tOH
, rt
2. S
ubst
rate
, the
n Ph
SiH
3
3. t-
BuO
2CN
=N
CO
2Bu-
t, rt
, 4 h
(80)
215
PhL
i
Ph
PhN
Me 2
Ph
140
Ph2P
(O)O
NH
2, T
HF,
–20
°; r
t, 12
h(4
1)13
9
NH
2
Ph2P
(O)O
NH
2, T
HF,
–20
°; r
t, 12
h13
9(3
0)
1. L
DA
, TH
F, h
exan
e, 1
h
2. A
rN=
NA
r, –
78°,
10 m
in
212
Ar
Ph 2-C
lC6H
4
(92)
(20)
PhL
i
Ph
PhN
H2
Ph
PhN
Ph
Ar
NH
Ar
PhPh
R1
Li
C15
-21
PhPh
R1
2,4,
6-M
e 3C
6H2S
O2O
N(R
2 ) 2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–15°
; to
rt, 1
5 h
R1
H t-B
u
Ph Ph
(37)
(31)
(38)
(39)
133
R2
Me
Me
Me
Et
(R2 ) 2
N
H N
H N Et 2
N
(43)
1. n
-BuL
i (2.
1 eq
), T
HF,
hex
ane,
0°
2. 2
,4,6
-Me 3
C6H
2SO
2ON
Et 2
, –78
° to
rt; r
t, ov
erni
ght
136
C15
O PhOC
14
1. K
NH
2, N
H3
(liq
), E
t 2O
2. P
hN=
NPh
OO
PhN
(30)
212
NH
Ph
Ph
141
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
D. A
RY
LM
ET
HY
L A
ND
HE
TE
RO
AR
YL
ME
TH
YL
CA
RB
AN
ION
S (C
onti
nued
)
C19
ClN
H2,
Et 2
O, s
onic
atio
n
(67)
355
R Me
2,4,
6-M
e 3C
6H2
Solv
ent(
s)
Et 2
O o
r T
HF
Et 2
O o
r E
t 2O
/TH
F
(60)
(30)
134
133
Tem
p, T
ime
–30°
to 0
°–1
0° to
–20
°; r
t, 15
h
RSO
2ON
Me 2
Cn
Ph Li
n
Ph NH
2n
1. M
eON
HL
i, T
HF,
Et 2
O, h
exan
e, –
78° t
o –1
5°, 2
h
2. M
eOH
(93)
808
d
a The
rea
ctio
n w
as c
arri
ed o
ut w
ith b
oth
R a
nd S
ena
ntio
mer
s (C
MeP
h); t
he o
ptic
al y
ield
s w
ere
5-46
%.
b X w
as n
ot s
peci
fied
.c S
ome
of th
e tr
iaze
nes
are
isol
ated
as
mix
ture
s of
dou
ble-
bond
isom
ers.
d The
sub
stra
te w
as p
repa
red
by a
dditi
on o
f se
c-bu
tylli
thiu
m to
sty
rene
in b
enze
ne/T
HF
at r
oom
tem
pera
ture
.
PhL
i
PhPh
PhN
H2
PhPh
PhN
Me 2
PhPh
142
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
. VIN
YL
AN
D A
LL
EN
YL
CA
RB
AN
ION
S
C2-
3
R
MgB
rR
= H
, Me
PhN
2+ B
F 4– , T
HF
R
N(0
)18
5
C3
2,4,
6-M
e 3C
6H2S
O2O
NE
t 2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–20°
; to
rt, 1
4 h
(28)
133
C3-
8
OO
NO
SO2P
h
1.
,
Et 2
O, P
hCl,
0°; r
t 2 h
2. p
H 9
buf
fer
N
R2
R1
OO18
2
R1
H Ph
R2
Me
H
(93)
a
(100
)
MgB
rN
(0)
185
C6
MgB
r
R2
R1
PhN
2+ B
F 4– , T
HF
E:Z — 1:1
NPh
NPh
Li
NE
t 2
R2
MgB
r
R1
C4-
14
ArN
3, T
HF,
2 h
R2
N
R1
NN
HA
r
R1
Me
H H H Ph Ph Ph Ph
Ar
Ph Ph 4-M
eC6H
4
2-na
phth
yl
Ph 4-B
rC6H
4
4-M
eC6H
4
4-M
eOC
6H4
(—)
(55)
(72)
(48)
(63)
(31)
(56)
(55)
286
R2
Me
Ph Ph Ph Ph Ph Ph Ph
143
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
. VIN
YL
AN
D A
LL
EN
YL
CA
RB
AN
ION
S (C
onti
nued
)
C8
1. R
1 R2 N
Li,
TH
F, –
78° t
o –
40°,
40 m
in
2. 1
,2-(
O2N
) 2C
6H4,
TH
F, –
78°
3. O
2, –
78°,
30 m
in; t
o rt
55, 5
4
n-C
6H13
MgB
r1.
PhS
CH
2N3
(ia)
, pen
tane
, ben
zene
, TH
F, E
t 2O
,
–
75° t
o 0°
, 1 h
; 0°,
1 h
2. A
c 2O
, 30
min
n-C
6H13
NN
Ac
NSP
h(4
1)27
4
R1 Ti
•R
2
R3
X(i
-PrO
) 2R
4 O2C
N=
NC
O2R
4 , Et 2
O, –
78° t
o rt
, 1 h
b
R1
R2
R3
R4 O
2CN
NH
CO
2R4
360
R1
TM
S
n-C
5H11
TM
S
TM
S
Me
n-B
u
TM
S
TM
S
TM
S
TM
S
TM
S
R2
H H i-B
u
i-B
u
i-B
u
Me
Me
Me
Me
n-B
u
i-B
u
R3
H H H H H H (CH
2)3P
r-i
(CH
2)3P
r-i
H H H
R4
t-B
u
t-B
u
t-B
u
Et
t-B
u
t-B
u
t-B
u
Et
t-B
u (S
) 94
% e
e
t-B
uc 9
6% e
e
t-B
uc 96
% e
e
(49)
(51)
(75)
(52)
(62)
(61)
(61)
(50)
(77)
81%
ee
(S)
(73)
53%
eea
(74)
27%
eea
X =
OC
O2E
t or
OP(
O)(
OE
t)2
C7-
12
R1
i-Pr
i-Pr
R2
Me
Bn
(60)
(56)
PhC
u(C
N)L
iPh
NR
1 R2
144
Ar
MgB
rA
r
Ar
C20
Ar
N=
NN
HPh
Ar
Ar
PhN
3
(59)
(50
)d
(35)
d
287,
288
288
Ar
Ph 4-M
eOC
6H4
Solv
ent
Et 2
O
TH
F
a The
con
figu
ratio
n w
as n
ot r
epor
ted.
b T
he s
ubst
rate
was
pre
pare
d by
rea
ctio
n of
[X
= O
CO
2Et o
r O
P(O
)(O
Et)
2] w
ith T
i(O
Pr-i
)4
and
two
equi
vale
nts
of i-
PrM
gBr.
c T
he s
ubst
rate
was
a s
ingl
e en
antio
mer
of
unsp
ecif
ied
conf
igur
atio
n.
d The
sub
stra
te h
ad 14
C in
the
2-po
sitio
n.
R1 C
CC
R2 R
3 X
Tem
p
rt 0°
Tim
e
3 h
1 h
145
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 3
. ET
HY
NY
L C
AR
BA
NIO
NS
C2-
8
Me 2
NX
, Et 2
O
R TM
S
n-Pr
n-B
u
t-B
u
c-C
6H11
Phc
PhS
X Ph2P
(O)O
Ph2P
(O)O
Ph2P
(O)O
Ph2P
(O)O
Ph2P
(O)O
MsO
Ph2P
(O)O
(67)
(87)
b
(78)
(71)
(75)
(52)
(45)
PhN
3, E
t 2O
, 10
d28
9, 8
09C
2
C2-
81.
TsN
3, E
t 2O
, 0°
2. 2
-C10
H7O
H, r
t
3. H
+N
NN
H
RN
=NH
O
R H n-B
u
Ph
(tra
ce)
(31)
(10)
810
135
C3
N3
N3, E
t 2O
(90)
272
C8
ClN
Et 2
M Li
MgB
r
Solv
ent
diox
ane
Et 2
O
(2.3
)e
(1.7
)
71
Ph2P
(O)O
NH
2, T
HF,
–20
°; r
t, 12
h13
9
Ph RN
OSO
2Ar,
Et 2
O, 2
0°, 2
0 h
PhN
R Me
Ph
Ar
Ph 4-M
eC6H
4
(39)
(45)
178
R
MgB
rB
rMg
R3
RN
Me 2
a
NH
N=
NPh
d (1
-2)
PhN
=N
HN
Li
R
MgB
rN
HN
=N
2
PhM
PhN
Et 2
Ph2
Ph3
CuL
i 2Ph
a The
yie
lds
of th
is p
rodu
ct a
re b
ased
on
two
of th
e th
ree
acet
ylen
ic g
roup
s re
actin
g.b T
he y
ield
was
det
erm
ined
by
NM
R s
pect
rosc
opy.
c (Ph
enyl
ethy
nyl)
lithi
um u
nder
thes
e co
nditi
ons
prod
uced
no
ethy
nyla
min
e; th
e co
rres
pond
ing
Gri
gnar
d re
agen
t gav
e on
ly tr
aces
.
d The
pro
duct
was
a m
ixtu
re o
f tw
o is
omer
s.e T
he y
ield
rep
orte
d is
that
of
the
crud
e pr
oduc
t.f 2
-Phe
nyle
thyn
amin
e w
as f
orm
ed a
s an
inte
rmed
iate
.
CuL
i 2
CuL
iPh
CN
f(3
8)
Tem
p
50°;
rt
rt
Tim
e
—; 3
d
12 h
146
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S
PhM
gCl
PhN
H2
58, 5
6(2
7)
ArL
i (3
eq)
ClN
H2,
Et 2
OA
rNH
258
PhC
u(C
N)Z
nCl
1. R
1 R2 N
Li,
TH
F, –
78° t
o –9
0°, 4
0 m
in
2. 1
,2-(
O2N
) 2C
6H4,
TH
F, –
78°
3. O
2, –
78°,
30 m
in
PhN
R1 R
255
R1
H i-Pr
Ph Ph
R2
Ph i-Pr
Ph Bn
(69)
(70)
(76)
(68)
OE
t
Li
OE
t
Ph2C
uLi
1. R
1 R2 N
H, s
olve
nt, r
eflu
x, 6
h
2. O
2, –
78°
PhN
R1 R
252
R1
Me
n-B
u
Ph
R2
Ph n-C
7H15
Ph
(72)
(64)
(94)
1.
(
5 eq
), T
HF,
hex
ane,
ref
lux,
2 h
2. O
2
OE
t
N OE
t
(51)
52
C6
NC
u
ClN
H2,
pet
rol e
ther
, 0°;
rt,
over
nigh
t
Solv
ent
TH
F
Et 2
O
Et 2
O
ArC
u(C
N)L
i
NH
Li
R
1.
,
TH
F, –
40°,
15 m
in
2. O
2, –
78°,
20 m
in; t
o rt
NH
Ar
Ar
Ph 2-M
eOC
6H4
2-B
nOC
6H4
(48)
(55)
(46)
54
Ar
Ph 4-M
eC6H
4
Tem
p
–50° 0°
(33)
(16)
147
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
Ar1 M
gCl•
LiC
l, T
HF,
–45
°, 15
min
73C
lN
Ar2
R1
R2
Ar1
NA
r2
R1
R2
Ar1
Ph 4-IC
6H4
3-N
CC
6H4
3-N
CC
6H4
4-N
CC
6H4
2-E
tO2C
C6H
4
2-E
tO2C
C6H
4
4-M
eO2C
C6H
4
4-M
eO2C
C6H
4
4-M
eO2C
C6H
4
1-na
phth
yl
Ar2
Ph Ph 4-B
rC6H
4
1-na
phth
yl
Ph Ph Ph Ph 4-B
rC6H
4
Ph Ph
R1
H H H Me
Me
(R)
H Me
(R)
H H Me
(S)
H
R2
Me
Et
Me
Me
Me
Et
Me
Me
Me
n-C
6H13
Me
(57)
(33)
(70)
(65)
(70)
99%
ee
(67)
(67)
99%
ee
(64)
(73)
(34)
98%
ee
(56)
C6-
7
PhM
gBr
R1 R
2 NC
l, E
t 2O
, 0°;
rt,
12 h
R1 , R
2 = M
e, M
e; E
t, E
t; —
(CH
2)5—
PhN
R1 R
2 (0)
69
PhM
gBr
H2N
OH
, Et 2
O, 0
°, 30
min
; rt,
15 m
inPh
NH
2 (
4)81
1
M =
MgB
r, (
CuM
gBr)
0.5,
Zn 0
.5C
uCN
Ar
= P
h, 3
-BrC
6H4,
4-B
rC6H
4, 3
-MeC
6H4,
4-M
eC6H
4, 3
-MeO
C6H
4, 4
-MeO
C6H
4H2N
OM
e (2
eq)
, TH
F, –
15°
ArN
H2
(—
)a91
PhM
gCl (
4 eq
)N
Cl 3
, Et 2
OPh
NH
2 (4
) +
Ph 2
NH
(1)
77
C6
ArM
148
C6-
10
ArM
RO
NH
2A
rNH
2
M Li
Li
MgB
r
MgI
MgB
r
MgI
Zn 0
.5
ZnC
l
Ph2Z
nLi
MgB
r
MgB
r
ZnC
l
Zn(
C6H
4OM
e-4)
MgB
r
R Me
Bn
Me
Me
Bn
Bn
Me
Me
Me
Me
Bn
Me
Me
Bn
Add
end
— — — — — — — CuC
N
CuC
N
— — CuC
N
CuC
N
—
Solv
ent
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
TH
F
TH
F
TH
F
Et 2
O
Et 2
O
TH
F
TH
F
Et 2
O
Tem
p
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
–10°
to –
15°
rt rt rt
–10°
to –
15°
–10°
to –
15°
rt rt
–10°
to –
15°
Ar
Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-B
rC6H
4
4-B
rC6H
4
4-M
eC6H
4
4-M
eOC
6H4
1-na
phth
yl
792
80 792
792
80 80 177
176
176
792
80 176
176
80
(63)
b
(72)
b
(67)
b
(0.3
)b
(57)
b
(7)b
(41)
c
(70)
(92)
(73)
b
(58)
b
(65)
c
(65)
c
(25)
b
Tim
e
— — — — — — 3 h
3 h
3 h
— — 3 h
3 h
—
C6-
8
ArL
i
1. M
eON
HL
i (2
eq, i
a), E
t 2O
, hex
ane,
–7
8° to
–15
°, 2
h
2. B
zCl
ArN
HB
z(9
0)d
(46)
(98)
(73)
(28)
(96)
(93)
(14)
e
(78)
82, 8
3,
177,
786
83 83, 7
86
83 83 82 83 82 83
Ar
Ph 3-C
lC6H
4
2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
2-M
eC6H
4
4-M
eC6H
4
2-(i
-Pr)
2NC
OC
6H4
2-E
tC6H
4
149
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
Ar1 L
i1.
R1 N
(Li)
OR
2 (ia
), s
olve
nt(s
), te
mp,
tim
e
2. A
r2 CO
Cl
Ar1 N
R1 C
OA
r2
Ar1
Ph Ph Ph Ph 2-(i
-Pr)
2NC
OC
6H4
R1
Me
n-C
5H11
f
Bnf
PhC
HM
e
Me
Solv
ent(
s)
Et 2
O, h
exan
e
TH
F
TH
F
Et 2
O, h
exan
e
Et 2
O, h
exan
e
Tem
p, T
ime
–78°
to –
15°,
3 h
0° to
40°
, 1-3
h
0° to
40°
, 1-3
h
78° t
o –1
5°, 3
h; t
o 40
°78
° to
–15°
, 3 h
Ar2
Ph 4-Ph
C6H
4
4-M
eOC
6H4
Ph Ph
(67)
(47)
(37)
(44)
(0)
97, 8
2
98 98 97 97
R2
Me
Bn
Bn
Me
Me
C6
Ar
Ph Ph Ph Ph 4-FC
6H4
4-FC
6H4
3-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
R TM
S
Me
i-Pr
t-B
u
i-Pr
t-B
u
Me
t-B
u
TM
S
Me
i-Pr
Me
i-Pr
t-B
u
100
101
101
101
101
101
101
101
100
101
101
101
101
101
C6-
7
Tem
p
–50°
–50°
to r
t
–50°
to r
t
–50°
to r
t
–50°
to r
t
–50°
to r
t
–50°
to r
t
–50°
to r
t
–50°
–50°
to r
t
–50°
to r
t
–50°
to r
t
–50°
to r
t
–50°
to r
t
Ar 2
Cu(
CN
)Li 2
1. R
NH
OT
MS,
TH
F, te
mp,
tim
e
2. H
Cl,
then
bas
e
ArN
HR
(90)
R =
Hb
(58)
(64)
(53)
(45)
(45)
(59)
(73)
(70)
R =
Hb
(88)
(73)
(57)
(67)
(65)
Tim
e
1 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
1 h
2 h
2 h
2 h
2 h
2 h
150
C6
PhM
gBr
1. M
e 2N
OT
s, E
t 2O
, rt,
10 m
in
2. H
Cl
PhN
HM
e 2+ C
l– (50
)13
2
ArC
uC
H2=
CH
CH
2O2C
N(L
i)O
R,
TH
F, –
78°
130
Ar
Ph Ph 3-FC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
1-na
phth
yl
R Ms
Ts
Ts
Ms
Ts
Ts
Tim
e
1 h
1 h
3 h
3 h
3 h
4 h
(51)
(51)
(44)
(52)
(68)
(57)
C6-
10
ArM
t-B
uO2C
N(L
i)O
Ts,
TH
F
Ar
Ph Ph 4-FC
6H4
2-M
eOC
6H4
M Li
Cu
Cu
Cu
Tem
p
–78°
to 0
°0° –78°
–78°
to 0
°
Tim
e
2 h
2 h
30 m
in
2 h
(10)
(51)
(50)
(73)
127
127,
126
127
127
C6
OO1.
n-B
uLi,
TH
F, E
t 2O
, hex
ane,
0°,
2 h;
rt,
22 h
2. C
uI, 0
°, 15
min
3. t-
BuO
2CN
(Li)
OT
s, –
78°,
30 m
in; 0
°, 2
hOO
NH
CO
2Bu-
t
(45)
128
PhM
gBr
1. M
e 2N
OT
s, E
t 2O
, rt,
10 m
in
2. H
Cl
PhN
HM
e 2+ C
l– (50
)13
2
C6-
10
2,4,
6-M
e 3C
6H2S
O2O
NR
2, E
t 2O
or
Et 2
O/T
HF,
–10
° to
–15°
; to
rt, 1
5 h
ArM
gBr
ArN
R2
133
Ar
Ph 1-na
phth
yl
R Et
Me
(42)
(69)
OH N
O
Ar
OB
u-t
H N
O
Ar
151
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
C6-
7A
rBr
ArN
Me 2
801
Mg,
Me 2
NO
SO2C
6H2M
e 3-2
,4,6
,
Mg,
TH
F, r
t, 2
h
Ar
Ph 2-M
eC6H
4
3-M
eC6H
4
4-M
eC6H
4
3-M
eOC
6H4
4-M
eOC
6H4
(81)
(60)
(83)
(79)
(78)
(80)
C6-
9
ArM
gBr
R1 R
2 NO
Bz
+ C
uCl 2
(x
mol
%, i
a, s
low
add
ition
),
T
HF,
rt,
15 m
in
ArN
R1 R
211
3
Ar
Ph Ph Ph Ph Ph Ph Ph 4-FC
6H4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
2,4,
6-M
e 3C
6H2
2,4,
6-M
e 3C
6H2
R1
s-B
u
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
—
(CH
2)5—
—
(CH
2)5—
Bn
Bn
Bn
Et
—(C
H2)
2O(C
H2)
2—
—
(CH
2)5—
Et
Et
Et
Et
Et
—
(CH
2)5—
R2
H Bn
Bn
Bn
Et
Et
Et
Et
Et
Et
Et
x 5 2.5
10 2.5
10 5 10 10 2.5
2.5
2.5 5 10 25 50 2.5
2.5
(tra
ce)
(37)
(68)
(52)
(64)
(20)
(92)
(58)
(61)
(7)
(75)
(65)
(75)
(26)
(8)
(80)
(61)
152
PhM
gBr
x e
q
Et 2
NO
CO
R (
slow
ia d
urin
g 7
min
),
CuC
l 2 (
3 m
ol%
), Z
nCl 2
(y
eq),
TH
F, r
t; rt
, 15
min
PhN
Et 2
R EtO
t-B
u
Ph Ph Ph 4-M
eOC
6H4
4-M
eOC
6H4
4-M
e 2N
C6H
4
4-M
e 2N
C6H
4
2-M
eC6H
4
2-M
eC6H
4
2,4,
6-M
e 3C
6H2
2,4,
6-M
e 3C
6H2
(27)
(83)
(89)
(87)
(84)
(79)
(62)
(79)
(81)
(89)
(74)
(82)
(75)
x 2.2
2.2
1.1
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
y 0 0 0 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1
113
N OB
zN Ph
(ia)
, CuC
l 2 (
2.5
mol
%),
TH
F, r
t(0
)11
3
ArZ
nCl
R1 R
2 NO
Bz,
(Ph
3P) 2
NiC
l 2 (
cat)
,
TH
F, r
t, 10
min
to 6
h
ArN
R1 R
210
8
Ar
Ph Ph Ph 4-C
lC6H
4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
2-M
eC6H
4
4-C
F 3C
6H4
4-N
CC
6H4
4-E
tO2C
C6H
4
R1
Et
—(C
H2)
5—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
Et
—(C
H2)
5—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—R2
Et
Et
(71)
(77)
(89)
(84)
(92)
(92)
(89)
(73)
(82)
(56)
(59)
C6-
7
153
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
Ph2Z
n1.
(67)
111
2. S
ubst
rate
, TH
F, 0
-5°,
1.5
hO
NPh
C6
NO
Bz,
CuC
l 2 (
2.5
mol
%),
TH
F, 0
-5°
O
PhM
x e
q
NO
Bz,
Cu
sour
ce (
y eq
), T
HF
NPh
113
M Li
Li
Li
MgB
r
MgB
r
ZnB
r
ZnB
r
ZnP
h
x 1 2 2 1 1 2 2 1.1
y 1 1 1 1 1 1 1
0.05
Cu
sour
ce
CuB
r•M
e 2S
CuB
r•M
e 2S
Li 2
CuC
l 3
CuB
r•M
e 2S
Li 2
CuC
l 3
CuB
r•M
e 2S
Li 2
CuC
l 3
CuC
l
(55)
(68)
(72)
(56)
(68)
(68)
(78)
(88)
Et 2
NO
CO
R, T
HF
PhN
Et 2
113
M MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
Li
Li
Li
x 2.2
2.2
2.2
2.2
1.1
1.1
1.1
1.1
1.1
2.2
2.2
2.2
R EtO
t-B
u
t-B
u
t-B
u
Ph 2-M
eC6H
4
4-M
eOC
6H4
4-M
e 2N
C6H
4
2,4,
6-M
e 3C
6H2
2,4,
6-M
e 3C
6H2
2,4,
6-M
e 3C
6H2
2,4,
6-M
e 3C
6H2
Tem
p
rt 0° rt 44°
rt rt rt rt rt
–30° 0° rt
(14)
(37)
(54)
(57)
(9)
(18)
(17)
(21)
(85)
(50)
(46)
(36)
154
Ar 2
Zn
1.1
eqg
R1 R
2 NO
Bz
(ia)
, (C
uOT
f)2•
PhH
(ca
t),
TH
F, r
t, 15
to 6
0 m
in
ArN
R1 R
2
Ar
Ph Ph Ph Ph Ph Ph Ph Ph Ph 2-M
eOC
H2O
C6H
4h
2-E
t 2N
CO
C6H
4h
3-FC
6H4
4-FC
6H4
4-C
lC6H
4
4-C
lC6H
4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
4-A
cOC
6H4
4-T
fOC
6H4
2-O
2NC
6H4
2-O
2NC
6H4
2,4-
(O2N
) 2C
6H3
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
3-C
F 3C
6H4
R1
s-B
u
i-B
u
Et
—(C
H2)
2O(C
H2)
2—
—
(CH
2)5—
i-Pr
CH
2CH
=C
H2
t-B
uCH
2CM
e 2
Bn
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
Bn
—(C
H2)
2O(C
H2)
2—
—
(CH
2)5—
Bn
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
Bn
—(C
H2)
2O(C
H2)
2—
Et
—(C
H2)
2O(C
H2)
2—
—
(CH
2)5—
i-Pr
—(C
H2)
2O(C
H2)
2—R2
H H Et
i-Pr
CH
2CH
=C
H2
H Bn
Bn
Bn
Bn
Et
i-Pr
(80)
(71)
(69)
(91)
(91)
(72)
(96)
(74)
(94)
(95)
(62)
(74)
(71)
(74
)i
(93)
(88)
(93)
(71
)i
(95)
(87)
(76)
(95)
(83
)i
(83)
(97)
(59)
(70)
(94)
(86)
i
(62)
(74)
C6-
10
112,
109
,
111
155
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
Ar 2
Zn
1.1
eqg
(T
able
con
tinu
ed fr
om p
revi
ous
page
.)
ArN
R1 R
2
Ar
2-(4
,4-d
imet
hyl-
4,5
-dih
ydro
oxaz
ol-2
-yl)
]phe
nylh
4-N
CC
6H4
4-N
CC
6H4
4-E
tO2C
C6H
4
4-E
tO2C
C6H
4
4-(i
-Pr)
2NC
OC
6H4h
4-(2
-met
hyl-
1,3
-dio
xola
n-2-
yl)p
heny
l
2,4,
6-M
e 3C
6H2
1-na
phth
yl
R1
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
Bn
—(C
H2)
2O(C
H2)
2—
Bn
—(C
H2)
2O(C
H2)
2—
—(C
H2)
2O(C
H2)
2—
i-Pr
—(C
H2)
2O(C
H2)
2—
R2
Bn
Bn
i-Pr
(55)
(76)
(74
)i
(95)
(77)
(99)
(88)
(79)
(76)
(90)
C6-
10
112,
109
,
111
X Cl
Br
Br
(35)
(22)
(31)
ArM
gXPh
2P(O
)ON
H2,
TH
F, –
20°;
rt,
12 h
ArN
H2
139
Ar
Ph Ph 1-na
phth
yl
PhM
gBr
4-M
eOC
6H4N
=C
(CO
2Et)
2 (i
a),
TH
F, –
95°,
30 m
in
167,
166
PhN
CH
(CO
2Et)
2
4-M
eOC
6H4
(59)
PhM
gBr
2
eq
1. P
hCH
=N
OR
, Et 2
O,
heat
2. H
Cl
175
R H Me
Bn
(—)
(—)
(68)
PhM
gBr
3
eqN
HOO
O, –
78° t
o 0°
, 1 h
NH
Ph
OH
O
O(~
100)
C6
104
PhN H
Ph
Ph •HC
l
156
C6-
7
ArM
gXj
x
eqM
e 2C
=N
OR
, tol
uene
ArN
H2
174a
Ar
Ph Ph 4-C
lC6H
4
2-M
eOC
6H4
4-M
eOC
6H4
4-M
eC6H
4
4-M
eC6H
4
x 1 2 2 2 2 1 2
(62)
(35)
(20)
(18)
(12)
(70)
(31)
C6
PhL
i
3
eq
Me 2
C=
NO
HI
+
P
hNH
2 I
I
I +
II
(—),
I:I
I =
4:1
174a
ArL
i
NO
1. Z
nCl 2
, TH
F, 0
°; to
rt
2.
, N
i(ac
ac) 2
(ca
t), 2
h
CH
O
NH
Ar
Ar
Ph 2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
(86)
(61)
(70)
(79)
170
R MgB
r
H H H H MgB
r
H
PhN
HPh
ArM
gBr
NM
eM
eN
NO
Ts
(ia)
, tol
uene
, Et 2
O
NM
eM
eN
NA
r18
1
Ar
Ph 2-M
eOC
6H4
2,4-
(MeO
) 2C
6H3
2-M
eC6H
4
4-C
F 3C
6H4
2,6-
Me 2
C6H
3
1-na
phth
yl
Tem
p
0°0°
to r
t
0° to
rt
0° 0°0°
to r
t
0°
Tim
e
15 m
in
30 m
in
30 m
in
15 m
in
15 m
in
30 m
in
30 m
in
(98)
k
(99)
k
(96)
k
(96)
k
(88)
l
(85)
m
(>99
)k
C6-
10
157
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
PhM
gBr
181
R1
—
O(C
H2)
2O—
EtO
—N
Me(
CH
2)2O
—
—O
(CH
2)2N
Me—
—N
Me(
CH
2)2N
Me—R2
EtO
Solv
ent
tolu
ene
tolu
ene
tolu
ene
CH
2Cl 2
tolu
ene
(66)
(<10
)
(97)
(0)n
(98)
R1
R2
NO
Ts
R1
R2
NPh
(ia)
Tem
p
0°–3
0° to
rt
rt 0° 0°
ArM
gBr
R2C
=N
OSO
2C6H
2Me 3
-2,4
,6 (
0.6-
0.8
eq),
cat
alys
t, E
t 2O
, tol
uene
, 60°
ArN
H2p
803
Ar
Ph Ph Ph Ph 4-M
eC6H
4
4-M
eC6H
4
1-na
phth
yl
(58)
(59)
(56)
(59)
(36)
(58)
(0)
R Me
Me
Me
Ph Me
Me
Me
Cat
alys
t
— CuI
MgC
l 2
CuI
— MgC
l 2
—
Tim
e
40 h
11 h
22h
2.5
h
46 h
20 h
—
C6
Tim
e
1 h
12 h
30 m
in
30 m
in
15 m
in
C6-
10
ArN
H3+
Cl–
182
OO
NO
SO2R
1.
(i
a), E
t 2O
, cos
olve
nt, t
emp,
tim
e 1
2. M
etho
d A
: HC
l, M
eOH
, Et 2
O, r
t, tim
e 2
or
M
etho
d B
: HC
l, E
tOH
, H2O
, ref
lux,
tim
e 2
158
Ar
Ph 4-FC
6H4
2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
2,4-
(MeO
) 2C
6H3
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-C
F 3C
6H4
2,6-
Me 2
C6H
3
1-na
phth
yl
R Ph Ph Ph Ph Ph Ph Meo
Ph 4-M
eC6H
4
2,4,
6-M
e 3C
6H2
Ph Ph Ph
Cos
olve
nt
PhC
l
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
PhC
l
CH
2Cl 2
CH
2Cl 2
PhC
l
CH
2Cl 2
CH
2Cl 2
PhC
l
PhC
l
CH
2Cl 2
Tem
p
0° rt rt rt 0° rt — 0° — — 0° 0° rt
Tim
e 1
0.5
h
1 h
0.5
h
0.5
h
0.5
h
1 h
— 0.5
h
— — 1 h
1 h
0.5
h
Met
hod
A A A A A A A A A A A B A
Tim
e 2
1.5
h
1.5
h
2 h
2.5
h
2.5
h
6.5
h
— 1.5
h
— — 0.5
h
3 h
1 h
(93)
(90)
(96)
(90)
(96)
(91)
(86)
(97)
(90)
(80)
(94)
(90)
(93)
ArZ
nCl
1. M
e 2C
=N
OSO
2C6H
2Me 3
-2,4
,6 (
2 eq
),
C
uCN
(10
mol
%),
DM
PU (
2 eq
), r
t, 3
h
2. c
onc.
HC
l, th
en b
ase
3. B
zCl
ArN
HB
z81
2
Ar
Ph 3-B
rC6H
4
4-M
eOC
6H4
4-M
eC6H
4
1-na
phth
yl
(78)
(70)
(75)
(72)
(79)
159
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
ArM
Me 2
C=
NO
SO2C
6H2M
e 3-2
,4,6
,
CuC
N (
cat)
, TH
F
ArN
H2
R Ph Ph Ph Ph Ph Ph 4-B
rC6H
4
4-M
eOC
6H4
4-M
eC6H
4
4-E
tO2C
C6H
4
M ZnC
l
Ph2Z
nLi
PhZ
n
Cu(
CN
)Li
Cu(
CN
)ZnC
l
Ph2Z
nMgB
r
ZnC
l
ZnC
l
ZnC
l
ZnC
l
Tem
p
rt rt rt rt 0° rt rt rt rt rt
Tim
e
3 h
3 h
3 h
3 h
1 h
3 h
3 h
3 h
3 h
3 h
(70)
(79)
(44)
(76)
c
(57)
(85)
(33)
(54)
c
(49)
c
(51)
176,
177
176
176
177
176
177
177
176,
177
176,
177
177
C6-
7
Me 2
C=
NO
SO2C
6H2M
e 3-2
,4,6
,
TH
F, r
eflu
x, 1
-2 h
ArN
H2
(—)a
183
ArB
r
1. M
g, M
e 2C
=N
OSO
2C6H
4Me 3
-2,4
,6,
T
HF,
ref
lux,
3 h
2. B
zCl
ArN
HB
z80
2
Ar
Ph 4-M
eOC
6H4
4-M
eC6H
4
1-na
phth
yl
(52)
(40)
(53)
(40)
ArM
gBr
1. [
3,5-
(CF 3
) 2C
6H3]
2C=
NO
Ts
(ia)
,
E
t 2O
, tol
uene
, rt,
30 m
in
2. B
zCl,
Et 3
N
ArN
HB
z17
9
Ar
Ph 4-FC
6H4
2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
4-C
F 3C
6H4
2,4-
Me 2
C6H
3
1-na
phth
yl
(96)
(86)
(72)
(94)
(98)
(71)
b
(98)
(91)
C6-
10
ArM A
r =
Ph,
3-B
rC6H
4, 4
-BrC
6H4,
4-M
eOC
6H4,
3-M
eC6H
4, 4
-MeC
6H4;
M =
MgB
r or
Cu(
CN
)ZnC
l
160
C6-
14
ArM
gBr
NO
Ts
Ph
PhPh
Ph(i
a), T
HF,
–78
°, 45
-90
min
NA
r
Ph
PhPh
Ph18
0
Ar
Ph 2,3,
5,6-
Me 4
C6H
1-na
phth
yl
2-na
phth
yl
9-ph
enan
thry
l
(95)
(65-
68)
(70)
(78)
(83)
PhM
gBr
N2
PhL
i, F
eCl 3
(—)
787
CH
2=N
2, E
t 2O
, 0°
(8)
200
CH
2=N
2, E
t 2O
, rt
(48)
b20
2
EtO
2CC
H=
N2,
Et 2
O, c
oolin
g(—
)19
9
(NC
) 2C
=N
2, E
t 2O
, coo
ling
(66)
203
PhC
u(C
N)L
i1.
Me 2
NN
HL
i, T
HF,
–40
°, 40
min
2. O
2, –
78°,
30 m
in
(40)
54
C6
Ph2C
=N
2, E
t 2O
, rt,
30 m
in(7
0)20
2
(PhS
O2)
2C=
N2
(ia)
, Et 2
O, 3
0 m
in(5
4)20
4
PhM
gBr
O
N2
O
NN
HPh
, Et 2
O, c
oolin
g20
1(—
)
Ph
H NN
Me 2
NN
HPh
Ph
H NN
HPh
Ph
NN
HPh
Ph Ph
OH
NC
NN
HPh
CN
Fe
NN
Ph
NN
Ph
NN
HPh
Ph
Ph
NN
HPh
PhSO
2 PhSO
2
161
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
C6-
7
Ar 3
ZnM
gBr
PhN
2+ B
F 4– , T
HF,
0°,
1 h
190
Ar
Ph 4-B
rC6H
4
4-M
eOC
6H4
4-M
eC6H
4
(87)
(74)
(72)
(88)
ArM
1. P
hN2+
BF 4
– , TH
F, a
dden
d, te
mp,
tim
e
2. H
Cl
3. N
aBH
4, N
iCl 3
•6 H
2O, M
eOH
, 0°,
1 h
ArN
H2
190
Ar
Ph Ph (4-M
eC6H
4)3
M MgB
r
MgB
r
ZnB
r
Add
end
— TM
ED
A (
0.3
eq)
—
Tem
p
–78°
–15°
–15°
Tim
e
3 h
3 h
1 h
(53)
p
(57)
p
(67)
p
Ar1 M
gBr
Ar2 N
2+ Z
nCl 3
– (i
a), E
t 2O
, ref
lux;
rt,
60 m
inC
6-10
Ar1
Ph Ph Ph Ph Ph 2-B
rC6H
4
2-B
rC6H
4
3-B
rC6H
4
3-B
rC6H
4
3-B
rC6H
4
4-B
rC6H
4
4-B
rC6H
4
Ar2
2-E
tO2C
C6H
4
3-E
tO2C
C6H
4
4-E
tO2C
C6H
4
1-na
phth
yl
2-na
phth
yl
1-na
phth
yl
2-na
phth
yl
3-M
eOC
6H4
1-na
phth
yl
2-na
phth
yl
1-na
phth
yl
2-na
phth
yl
(poo
r)
(43)
(42)
(22)
(11)
(3.5
)
(12)
(17)
(4)
(12)
(11)
(13)
187
187
187
188
188
188
188
189
188
188
188
188
Ar
NN
Ph
Ar1
NN
Ar2
162
2-M
eOC
6H4
2-M
eOC
6H4
2-M
eOC
6H4
2-M
eOC
6H4
2-M
eOC
6H4
3-M
eOC
6H4
3-M
eOC
6H4
3-M
eOC
6H4
3-M
eOC
6H4
3-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
2-M
eC6H
4
3-M
eC6H
4
3-M
eC6H
4
3-M
eC6H
4
3-M
eC6H
4
4-B
rC6H
4
2-M
eOC
6H4
3-B
rC6H
4
1-na
phth
yl
2-na
phth
yl
4-B
rC6H
4
2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
1-na
phth
yl
2-na
phth
yl
3-B
rC6H
4
4-B
rC6H
4
2-M
eOC
6H4
4-M
eOC
6H4
1-na
phth
yl
2-na
phth
yl
2-B
rC6H
4
3-B
rC6H
4
4-B
rC6H
4
2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
2-E
tO2C
C6H
4
3-E
tO2C
C6H
4
4-E
tO2C
C6H
4
1-na
phth
yl
2-na
phth
yl
2-B
rC6H
4
3-B
rC6H
4
4-B
rC6H
4
2-M
eOC
6H4
(2)
(1.4
)
(9)
(12)
(11)
(1)
(11)
(8)
(34)
(12)
(6)
(10)
(14)
(7)
(7)
(9)
(11)
(64)
(61)
(42)
(18)
(29)
(9)
(36)
(56)
(63)
(7)
(12)
(40)
(52)
(68)
(11)
189
189
189
188
188
189
189
189
189
188
188
189
189
189
189
188
188
186
186
186
189
189
189
187
187
187
188
188
186
186
186
189
163
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
Ar1
3-M
eC6H
4
3-M
eC6H
4
3-M
eC6H
4
3-M
eC6H
4
3-M
eC6H
4
3-M
eC6H
4
3-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
1-na
phth
yl
1-na
phth
yl
1-na
phth
yl
2-na
phth
yl
2-na
phth
yl
2-na
phth
yl
Ar2
3-M
eOC
6H4
4-M
eOC
6H4
2-E
tO2C
C6H
4
3-E
tO2C
C6H
4
4-E
tO2C
C6H
4
1-na
phth
yl
2-na
phth
yl
2-B
rC6H
4
3-B
rC6H
4
4-B
rC6H
4
2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
2-E
tO2C
C6H
4
3-E
tO2C
C6H
4
4-E
tO2C
C6H
4
1-na
phth
yl
2-na
phth
yl
2-E
tO2C
C6H
4
3-E
tO2C
C6H
4
4-E
tO2C
C6H
4
2-E
tO2C
C6H
4
3-E
tO2C
C6H
4
4-E
tO2C
C6H
4
(20)
(4)
(45)
(53)
(42)
(23)
(6)
(60)
(68)
(68)
(11)
(14)
(13)
(49)
(48)
(45)
(20)
(7)
(tra
ce)
(25)
(4)
(1)
(1)
(tra
ce)
189
189
187
187
187
188
188
186
186
186
189
189
189
187
187
187
188
188
188
188
188
188
188
188
Ar1 M
gBr
(T
able
con
tinu
ed fr
om p
revi
ous
page
.)
C6-
10
Ar1
NN
Ar2
164
Ar1 Z
nCl
Ar2 N
2+ B
F 4– , E
t 2O
, –10
°19
2
Ar1
Ph Ph Ph 4-C
lC6H
4
4-M
eOC
6H4
2,4,
6-M
e 3C
6H2
Ar2
4-C
lC6H
4
4-M
eOC
6H4
2,4,
6-M
e 3C
6H2
Ph Ph Ph
Tim
e
18 h
22 h
24 h
6 h
18 h
22 h
(10)
(2)
(0)
(35)
(20)
(8)
C6-
9
Ar1
NN
Ar2
165
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
Ar1 M
gX1
Ar2 N
2+ (
X2 )– (
ia)
Ar1
Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-C
lC6H
4
4-C
lC6H
4
4-C
lC6H
4
4-C
lC6H
4
4-C
lC6H
4
4-C
lC6H
4
4-C
lC6H
4
4-M
eOC
6H4
2-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
X1
— Br
— — — — — — Br
— — — — — — — Br
Br
— — — — — — —
Ar2
Ph Ph 2-C
lC6H
4
4-C
lC6H
4
3-B
rC6H
4
4-B
rC6H
4
3-M
eOC
6H4
4-M
eOC
6H4
1-na
phth
yl
Ph 2-C
lC6H
4
4-C
lC6H
4
3-B
rC6H
4
4-B
rC6H
4
3-M
eOC
6H4
4-M
eOC
6H4
Ph Ph Ph 2-C
lC6H
4
4-C
lC6H
4
3-B
rC6H
4
4-B
rC6H
4
3-M
eOC
6H4
4-M
eOC
6H4
X2
q BF 4
q q q q q q Cl
q q q q q q q BF 4
BF 4
q q q q q q q
Solv
ent
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
Et 2
O
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
(71)
(66)
(52)
(80)
(82)
(85)
(81)
(91)
(5)
(69)
(45)
(79)
(80)
(86)
(86)
(85)
(74)
(87)
(66)
(45)
(84)
(89)
(83)
(84)
(84)
191
185,
184
191
191
191
191
191
191
184
191
191
191
191
191
191
191
185
185
191
191
191
191
191
191
191
Con
ditio
ns
–78°
, 1 h
; 70°
, 1 h
r
–78°
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
ZnC
l 2, r
eflu
x, 1
5 m
in
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
–78°
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
–78°
, 1 h
; 70°
, 1 h
r
C6-
7
Ar1
NN
Ar2
166
C6
Ph2Z
nA
rN2+
BF 4
– , DM
F, 0
°19
3
Ar
Ph 4-C
lC6H
4
4-O
2NC
6H4
4-M
eOC
6H4
Tim
e
2.5
h
15 m
in
15 m
in
15 m
in
(95)
(96)
(57)
(72)
ArS
n(R
1 ) 3(i
a), M
eCN
, rt
N2+
BF 4
–
O2N
R2
N=
NA
r
O2N
R2
813
Ar
Ph 4-C
lC6H
4
2-M
eOC
6H4
2-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
3-C
H2O
CH
2-4-
C6H
3
4-T
MSC
6H4
2-M
eC6H
4
3-M
eC6H
4
4-M
eC6H
4
4-E
tC6H
4
2,4,
6-M
e 3C
6H2
R2
NO
2
NO
2
H NO
2
H NO
2
NO
2
NO
2
NO
2
NO
2
NO
2
NO
2
NO
2
R1
n-B
u
Me
Me
n-B
u
Me
Me
Me
Me
Me
Me
Me
Me
n-B
u
Tim
e
18 h
18 h
27 h
1.5
h
7 h
2 m
in
2 m
in
20 h
16 h
16 h
16 h
18 h
6 h
(31)
(14)
(16)
(66)
(57)
(83)
(78)
(36)
(53)
(67)
(62)
(54)
(65)
C6-
9
C6
PhM
gBr
PhN
HN
(62)
s20
8, E
t 2O
, 0°;
to r
t, 1
h
PhL
iN
N
4-O
2NC
6H4NPh
N(3
4)21
01.
,
DM
E, E
t 2O
, –35
° to
–20°
2. F
C6H
4NO
2-4,
–20
° to
rt
N N
PhN
NA
r
167
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
PhM
PhN
=N
Ph
NN
, Et 2
O, 1
5 m
in
PhN
NH
(—)
214
PhL
i
M Li
K CaI
Solv
ent(
s)
hexa
ne o
r cy
cloh
exan
e, T
HF
PhH
Et 2
O
Tem
p
–78°
; rt
0°re
flux
(90)
(38)
(18)
211,
214
,
506,
814
815
815
C6
ArM
gBr
C6-
9
NN
Ts
R1.
, T
HF,
–20
°, 1
h
NH
Ar
R25
5
Ar
4-IC
6H4
3-T
fOC
6H4
3-T
fOC
6H4
3-T
fOC
6H4
R 4-E
tO2C
t
4-B
r
4-M
eO
3-T
fO
(63)
(70)
(81)
(76)
3-T
fOC
6H4
2-E
tO2C
C6H
4
4-E
tO2C
C6H
4
4-E
tO2C
C6H
4
4-E
tO2C
C6H
4
4-E
tO2C
C6H
4
2,4,
6-M
e 2C
6H2
2,4,
6-M
e 2C
6H2
4-E
tO2C
t
4-B
r
2-B
r
4-B
r
4-I
4-N
C
4-B
r
4-M
eO
(80)
(80)
(65)
(83)
(71)
(64)
(69)
(83)
Ph
H NN
Ph2
2. C
H2=
CH
CH
2I, N
-met
hylp
yrro
lidin
one,
rt,
3 h
3. Z
n, A
cOH
, TFA
, 75°
, 2.5
h
Tim
e
2 h;
10
h
8 h
12 h
168
ArM
R1 O
CN
=N
R2
C6-
10
Ar
Ph Ph Ph Ph Ph Ph 4-M
eOC
6H4
4-M
eSC
6H4
3,4-
(MeO
) 2C
6H3
4-(n
-C5H
11O
)C6H
4
4-(C
F 3C
H2O
)C6H
4
2-C
F 3C
6H4
4-N
CC
6H4
4-E
tO2C
C6H
4
6-M
eO-2
-nap
hthy
l
R1
EtO
t-B
uO
MeO
EtO
Ph Ph t-B
uO
t-B
uO
Et
t-B
uO
t-B
uO
t-B
uO
t-B
uO
t-B
uO
t-B
uO
M Li
Li
MgB
r
MgB
r
MgB
r
MgB
r
ZnI
MgB
r
MgB
r
MgB
r
Li
MgB
r
ZnB
r
ZnB
r
MgB
r
R2
CO
2Et
CO
2Bu-
t
CO
2Me
CO
2Et
Ph CO
Ph
CO
2Bu-
t
CO
2Bu-
t
CO
2Et
CO
2Bu-
t
CO
2Bu-
t
CO
2Bu-
t
CO
2Bu-
t
CO
2Bu-
t
CO
2Bu-
t
Solv
ent
TH
F
TH
F
— TH
F
Et 2
O
Et 2
O
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
Tem
p
–78°
–78° — –78° rt rt rt
–78°
–78°
–78°
–78°
–78°
70°
70°
–78°
(100
)
(60)
(poo
r)
(100
)
(50)
(30)
(55)
u
(>75
)
(96)
(>60
)
(61)
(81)
(66)
(40)
(47)
816
816
794
816
794
794
358
816
816
816
816
816
358
358
816
ArM
TM
SCH
2N3
ArN
H2
Ar
Ph 4-C
lC6H
4
2-M
eOC
6H4
2-M
eOC
6H4
4-M
eOC
6H4
2-M
e 2N
CH
2C6H
4
2,3-
(MeO
) 2C
6H3
2,6-
Me 2
C6H
3
M MgB
r
MgB
r
Li
MgB
r
MgB
r
Li
Li
MgB
r
Solv
ent
Et 2
O
Et 2
O
— Et 2
O
Et 2
O
— Et 2
O
Et 2
O
Con
ditio
ns
rt, 3
h, t
hen
H2O
rt, 3
h, t
hen
H2O
—
rt, 3
h, t
hen
H2O
rt, 3
h, t
hen
H2O
—
0° to
rt,
then
HC
l, N
aOH
rt, 3
h, t
hen
H2O
(72)
(92)
(35)
(73)
(69)
(41)
(78)
(79)
264
264
264
264
264
264
265
264
C6-
7
C6
PhM
gBr
2
eq
N3(
CH
2)nN
3, E
t 2O
n 2 5
(72)
(—)
271
290
Tim
e
— — — — — — 3 h
310
min
— — — — 3 h
3 h
—
PhN
N
H NH N
NN
Phn
Tem
p
rt —
Tim
e
10 m
in
—
NN
HR
2
O
R1
Ar
169
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
C6-
10A
rMC
H2=
CH
CH
2N3,
sol
vent
, –78
° to
rt; t
hen
H3O
+A
rNH
226
3
Ar
Ph Ph 3-C
lC6H
4
4-C
lC6H
4
2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
2-M
e-5 -
FC6H
3
2-na
phth
yl
M Li
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
MgB
r
Solv
ent
n-he
xane
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
Et 2
O
(61)
(76)
(68)
(52)
(71)
(55)
(75)
(66)
(77)
ArL
i1.
CH
2=C
(N3)
R1 , T
HF,
–78
°; to
rt,
2 h
2. K
OH
ArN
H2
278
Ar
Ph 2,3-
(MeO
) 2C
6H3
2,6-
(MeO
) 2C
6H3
2-R
2 NH
CO
C6H
4w
(68)
(60)
(70)
(52)
R1
—v
Ph —v
—v
C6-
7
Ar1 M
gBr
Ar2 N
3, E
t 2O
Ar1
Ph Ph Ph Ph Ph 4-E
tOC
6H4
4-M
eC6H
4
1-na
phth
yl
Ar2
Ph 4-E
tOC
6H4
4-M
eC6H
4
Bn
1-na
phth
yl
Ph Ph Ph
Tem
p
0°re
flux
refl
ux
refl
ux
refl
ux
refl
ux
refl
ux
refl
ux
(71)
(—)
(—)
("go
od")
(64)
(—)
(—)
(—)
285,
284
280
280
270
281,
280
280
280
280
C6-
10
Ar1
H NN
NA
r2 x
Tim
e
—
30 m
in
30 m
in
30 m
in
25 m
in
30 m
in
30 m
in
30 m
in
170
1. P
hSC
H2N
3, T
HF,
hex
ane,
tem
p, ti
me
1
2. N
H4C
l, H
2O
3. 5
0% K
OH
in H
2O, M
eOH
, TH
F, r
t, tim
e 2
275,
274
R H 2-M
eO
4-M
eO
2,6-
(MeO
) 2
2-M
e 2N
CH
2
2-(t
-BuO
2CN
H)-
5
-5
-5
-Cl
2-(E
t 2N
CO
)-(
OC
H2)
-6
2-M
eO-P
h
MgB
r
R
Me
N N Me
2-C
H2
Tem
p, T
ime
1
–78°
, 3 h
; rt,
2 h
–78°
, 1.5
h; 0
°, 2
h
–78°
, 2 h
; 0°,
1 h
–78°
, 45
min
; to
0°, 3
h
–78°
, 15
min
; 0°,
3 h
–78°
, 1.5
h; 0
°, 2
h
–78°
to 0
°; 0
°, 1
h
–78°
, 1.5
h; t
o 0°
, 1.5
h
0°, 2
h
Tim
e 2
3 h
2 h
24 h
3 h
2 h
19 m
in
over
nigh
t
36 h
24 h
(66)
(78)
(50)
(67)
y
(85)
(66)
(71)
(60)
z
(84)
C6-
12N
H2
R
PhM
gBr
RC
OC
H2N
3, E
t 2O
, coo
ling;
rt,
over
nigh
t81
7
R Me
Ph
(40)
(50)
C6
C6-
7
ArM
gBr
PhC
OC
H2N
3, E
t 2O
789
Ar
4-M
eOC
6H4
4-M
eC6H
4
(71)
(35)
PhM
gBr
4-N
3C6H
4CO
Me,
Et 2
O(8
4)28
3
ArN
=N
C6H
4N3-
4, E
t 2O
Ar
Ph 4-M
eC6H
4
(91)
(—)
290
C6
Ph
H NN
NPh
RO
H
Ph
H NN
NA
rA
rO
H
NA
rN
NN
NH
Ph
N H
N
Ph
PhN
OH
171
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
PhM
gXj
2
eq
, Et 2
O, 1
0-12
h79
0(7
8)x
NSN
3
NSPh
NH
N=
NC
6
PhM
800
NSN
3
Cl
(ia)
NSN
HN
=N
Phx
Cl
M Li
MgB
r
Solv
ent
— Et 2
O
Tem
p
–10°
to r
t
rt
(63)
(100
)
PhM
gBr
NS
NNN
, tol
uene
, 100
°, 30
min
NSN
=N
NH
Ph x
(70)
818
, Et 2
O, 0
°28
9N
3N
3Ph
NH
N=
NN
=N
NH
Ph x
(65)
N
YN
N3
N3
N3
, Et 2
O, 1
h
N
YN
PhN
HN
=N
N=
NN
HPh
N=
NN
HPh
788
Y CH
N
(47)
(90)
PhM
gX(i
a)NS
NNN
NSN
HN
=N
Ph x
X Br
Cl
Br
Br
Br
Solv
ent
tolu
ene
tolu
ene
tolu
ene
tolu
ene
Et 2
O
RR
R H 6-C
l
6-M
eO
6-M
e
4-Ph
(80)
(—)
(85)
(—)
(65)
818
819
818
818
800
4
6
x
Tim
e
1 h
10 h
Tem
p
100°
100°
100°
100°
rt; r
eflu
x
Tim
e
30 m
in
30 m
in
30 m
in
30 m
in
30 m
in; 3
0 m
in
172
(CH
2)n
N3
N3, E
t 2O
(CH
2)n
RR
R =
PhN
HN
=N
— x
n 0 1
PhM
gBr
(79)
(—)
272
290
RC
ON
3, E
t 2O
, coo
ling;
ref
lux,
15
min
R H2N
MeO
EtO
Ph PhN
H
(14-
18)
(11-
14)
(—)
(8)
(0)
N3C
ON
3, E
t 2O
, coo
ling
284
820
820,
284
820
820
820
(18)
aa
ArM
gBr
1. P
h 3Si
N3,
sol
vent
, tem
p, ti
me
2. H
Cl,
refl
ux
ArN
H2
821
Ar
Ph 2,4,
6-M
e 3C
6H2
Solv
ent
Et 2
O
tolu
ene
Tim
e
6 h
4 h
(56)
(26)
PhM
Ph3S
iN3,
Et 2
O, 1
00°,
24 h
821
M MgB
r
MgP
h
(61)
(—)
ArM
gBr
1. (
PhO
) 2P(
O)N
3 (i
a), E
t 2O
, –73
° to
–69°
, 2 h
2. 1
0% H
Cl,
MeO
H, r
t, 20
0 m
in
ArN
H3+
Cl–
334
Ar
Ph 4-C
lC6H
4
2-M
eC6H
4
4-M
eC6H
4
1-na
phth
yl
(51)
(63)
(33)
(33)
(28)
e
C6-
9
C6
C6-
10
RN
NN
HPh
O
NH
2N H
NPh
N
O
PhSi
NPhPh
M
Ph
Tem
p
100°
120°
173
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
ArM
1. (
PhO
) 2P(
O)N
3 (i
a), s
olve
nt, –
73° t
o –6
9°, 2
h
2. N
aAlH
2(O
CH
2CH
2OM
e)2,
tolu
ene,
–7
0°; t
o 0°
, 1 h
ArN
H2
Ar
Ph 4-C
lC6H
4
4-M
eOC
6H4
2,6-
(MeO
) 2C
6H3
2,5-
(MeO
CH
2O) 2
C6H
3
4-M
eC6H
4
2,4,
6-M
e 3C
6H2
1-na
phth
yl
M MgB
r
MgB
r
Li
Li
Li
MgB
r
MgB
r
MgB
r
Solv
ent
Et 2
O
Et 2
O
TH
F
TH
F
TH
F
Et 2
O
Et 2
O
Et 2
O
(73)
b
(79)
b
(84)
(72)
(47)
(88)
b
(67)
(89)
333,
334
C6-
10
PhM
gBr
1. T
sN3
(ia)
, Et 2
O, –
18° t
o –1
5°, 3
0 m
in
2. I
sola
te P
hN=
NN
(MgB
r)T
s
3. 1
20-1
30° (
0.1-
3.0
mm
Hg)
PhN
330
8(8
2)
ArM
gBr
1. T
sN3,
TH
F, 0
°2.
Rea
gent
s
ArN
330
5
Ar
Ph 4-C
lC6H
4
4-M
eOC
6H4
4-M
eC6H
4
2,4,
6-M
e 3C
6H2
2-t-
BuC
6H4
4-Ph
C6H
4
2-B
nC6H
4
Rea
gent
s
NaO
H, H
2O
Na 4
P 2O
7, K
OH
, H2O
Na 4
P 2O
7, H
2O
Na 4
P 2O
7, K
OH
, H2O
Na 4
P 2O
7, H
2O
Na 4
P 2O
7, H
2O
NH
4Cl,
H2O
Na 4
P 2O
7, H
2O
(50)
(70)
(55)
(73)
(63)
(42)
(68-
79)
(49)
C6-
13
174
ArM
gBr
1. T
sN3,
TH
F, 0
°2.
RaN
i, N
aOH
3. H
Cl
ArN
H3+
Cl–
305
(41)
(49)
(63)
(51)
(82)
(79)
(66)
(76)
(19)
(62)
e
(71)
C6-
13
R1
Li
R2
R1
NH
2
R2
1. T
sN3,
Et 2
O, 0
°2.
RaN
i, 50
% K
OH
, 0° t
o rt
, 2 h
310
R1
H MeO
CH
2NM
e 2
CO
NH
Me
CO
NH
Me
R2
H H H H MeO
(80-
85)
(75-
80)
(52-
55)
(37-
40)
(34-
38)
C6-
7
Ar
3-C
lC6H
4
4-C
lC6H
4
2-M
eOC
6H4
4-M
eOC
6H4
2-M
eC6H
4
3-M
eC6H
4
4-M
eC6H
4
2,4-
Me 2
C6H
3
2-t-
BuC
6H4
4-Ph
C6H
4
2-B
nC6H
4
175
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
OM
e
CO
NM
e 2
Li
OM
e
CO
NM
e 2
N
NC
u(C
N)L
i1.
(
5 eq
), T
HF,
78°
, 2 h
2. O
2, –
78°
(33)
53
C7
R1
Li
R2
R1
NH
2
R2
1. T
sN3
(ia)
, Et 2
O, –
70°;
–70
°, 5
h; to
–10
°2.
NaB
H4,
Bn 4
N+
HSO
4– , H2O
C6-
8
3
R1
OC
H2O
Me
OC
H2O
Me
OC
ON
Et 2
CO
NE
t 2
CO
NE
t 2
CO
NE
t 2
CO
NE
t 2
CO
NE
t 2
CO
NE
t 2
CO
NE
t 2
CO
NE
t 2
CO
NE
t 2
ON
R2
H 3-M
e
H H H 3-C
l
3-M
eO
4-M
eO
6-M
eO
5-M
eO-6
-TM
S
5-M
eO-6
-CH
(TM
S)2
4-M
e
3-M
eO-4
-Me
(67)
(72)
bb
(94)
(50)
(40)
(31)
(55)
(34)
(66)
(69)
(47)
(82)
(69)
311
312
311
311
311
311
311
311
311
311
311
311
311
176
CO
N(R
2 ) 2
Li
R1
NR
4 Cu(
X)L
iR
31.
(5
eq)
, TH
F, –
78°,
2 h
2. O
2, –
78°
CO
N(R
2 ) 2
N
R1
R4
R3
53
C7-
11
R1
H H 3-M
eO
3-M
eO
3-M
eO
3-M
eO
6-M
eO
3,5-
(MeO
) 2
3-M
eO-4
-OC
H2O
-5
3-(C
H=
CH
) 2-4
3
R2
Et
Et
Et
Me
Et
Me
Me
Me
Me
Et
R3
H 2-M
eO
H H H 3-M
eO
H H H H
R4
Me
H H Me
TM
S
H Me
Me
Me
Me
X Cl
CN
CN
CN
CN
CN
CN
Cl
Cl
CN
(46)
(50)
(63)
(33)
(54)
(R
4 = H
)
(36)
(26)
(43)
(48)
(61)
1. M
eLi,
t-B
uLi
2. A
cCl
C7-
9
ON
HM
e
Li
n
OA
c
NM
eAc
n
n 1 2 3
(13)
cc
(7)cc
(12)
cc
81 82 83
C7
MgC
l
CO
2Me
NB
n 2
CO
2Me
1. Z
nCl 2
, TH
F, –
78°,
15 m
in
2. B
n 2N
OB
z, C
uCl 2
(ca
t), T
HF,
–35
° to
rt, 1
h
(81)
113
CO
2N(C
H2A
r)2
MgC
l
CO
2Me
N(C
H2A
r)2
1:1
mix
ture
of
Ar
= P
h, R
= H
and
and
Ar
= C
6D5,
R =
D
1. Z
nCl 2
(1
eq),
TH
F, –
78°,
–3
5°, 4
0 m
in
2. C
uCl 2
(0.
0015
mol
%),
–35
° to
rt
3. T
MSC
HN
2, M
eOH
, Et 2
O
(50)
d0:
d 4:d
10:d
14 =
100
:100
:97:
94cc
R R
R
R
113
177
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
1. T
MSC
H2N
3
2. H
3O+
(39)
267
C10
RO
NH
2, E
t 2O
R Me
Bn
Con
ditio
ns
–20°
to r
t, 4
h
–18°
to –
20°,
15 m
in; t
o rt
, 30
min
(8)
(21)
822
823,
684
,
822
RR
RLi
RR
RNH
2
R =
CH
(TM
S)2
C9
R1
R2
C10
-11
R1
R2
1.
, t-
BuO
K, D
MSO
, rt,
4 h
2. A
c 2O
, pyr
idin
e
NN
NH
2NN
HA
c
R1
H H Cl
R2
H CN
Cl
(38)
(64)
(60)
824
C10
MgB
rN
H2
PhC
H=
NO
H o
r Ph
CH
=N
OM
e, E
t 2O
, ref
lux
(15)
175
(2 e
q)
ArM
gBr
Ar
= 1
-nap
hthy
lB
zCH
=N
2, E
t 2O
, rt,
seve
ral h
Ar
N H
NO
H
Ar
Ph
Ar
N H
NPh
O
+82
5
(7)
(8-1
6)
Fe
Li
Fe
NH
2
178
SnR
3N
=N
C6H
3(N
O2)
2-2,
4
2,4-
(O2N
) 2C
6H3N
2+ B
F 4– , M
eCN
, rt
R Me
n-B
u
Tim
e
6 h
1 h
(55)
(71)
813
2,4-
(O2N
) 2C
6H3N
2+ B
F 4– , M
eCN
, rt
SnM
e 3N
=N
C6H
3(N
O2)
2-2,
4
(76)
813
1. 4
-BrC
6H4N
=N
Ts,
TH
F, –
20°,
1 h
2. C
H2=
CH
CH
2I, N
-met
hylp
yrro
lidin
one,
rt,
3 h
3. Z
n, A
cOH
, TFA
, 75°
, 15
min
(58)
255
R1
R2
R2
OH
R1
R2
R2
OH
NC
O2B
u-t
t-B
uO2C
N=
NC
O2B
u-t,
cata
lyst
(20
mol
%)
N
Et
HH
OE
CO
2Bu-
t
826
HO
Cat
alys
t
IA IB IC
E H N(C
O2B
u-t)
NH
N(C
O2B
u-t)
NH
CO
2Bu-
t
I
N
Et
HH
O
HO II
t-B
uO2C
NH
Fe
MgB
r
Fe
NH
C6H
4Br-
4
179
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
R1
R2
R2
OH
(Ent
ry c
onti
nued
from
pre
viou
s pa
ge.)
C10
1. n
-BuL
i (5.
4 eq
), E
t 2O
, rt,
5 h
2. T
sN3
(ia)
, rt,
30 m
in; r
t, ov
erni
ght
3. 1
0% K
OH
in H
2O
+(2
8)(6
)31
5
1. n
-BuL
i (1.
3 eq
), T
HF,
pen
tane
, rt,
2 h
2. T
sN3,
0°;
rt,
4 h
3. N
aBH
4, n
-Bu 4
+ I
– , H2O
, rt,
48 h
(64)
, >
98%
de
(R,R
)82
7
(85)
(90)
(85)
(87)
(91)
(95)
(91)
(94)
(98)
(95)
(98)
(98)
(98)
(80)
(96)
(85)
(95)
% e
edd
16 88 –61
87 –96
33 93 –96
78 94 –94
48 92 –98
80 98 –96
R1
NH
2
NH
2
NH
2
NH
2
NH
2
NH
Me
NH
Me
NH
Me
NH
C5H
11-n
NH
C5H
11-n
NH
C5H
11-n
NH
Bn
NH
Bn
NH
Bn
NH
2
NH
2
NH
2
R2
H H H H H H H H H H H H H H Br
Br
Br
Cat
alys
t
quin
ine
IA II IB IC IA IB IC IA IB IC IA IB IC IA IB IC
Solv
ent
tolu
ene
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
ClC
H2C
H2C
l
Tem
p
rt
–20° rt
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
Fe Fe
SR
O
t-B
u
Fe
N3
N3
Fe
N3
Fe
SO
t-B
u
NH
2
180
C10
SS Y
YB
rMg
SS Y
YH
2N
1. P
hSC
H2N
3, E
t 2O
, TH
F, h
exan
e, –
78° t
o 0°
, 1 h
2. 5
0% K
OH
in H
2O, M
eOH
, TH
F, 3
0 m
in
Y O NM
e
(88)
(—)ee
274
C11
MeO
Li
OL
i
MeO
NH
2O
H
1. P
hSC
H2N
3, T
HF,
pen
tane
, –78
° to
rt, 1
.5 h
2. K
OH
, DM
SO, r
t, 1
h
("po
or")
274
1. L
DA
, TH
F, –
78°,
40 m
in
2. T
sN3,
–78
°, 4
h; to
rt
3. N
aBH
4, n
-Bu 4
+ I
– , H2O
, rt,
48 h
(67)
>99
% d
e (S
,S)
827
OM
e
MgB
r
OM
e
OM
e
MO
MO
375
1. P
hSC
H2N
3 (i
a), T
HF,
hex
ane,
–7
8°; t
o 0°
; 0°,
1h; r
t, 1
h
2. N
H4C
l, H
2O
3. 5
0% a
q. K
OH
, MeO
H, T
HF,
rt,
2.5
h
OM
e
NH
2
OM
e
OM
e
MO
MO
(71)
TM
SNH
OT
MS,
Et 2
O, T
HF,
–50
°, 1
h;
to
rt, o
vern
ight
R =
2-t
hien
yl
(56)
102
C12
SL
iS
NH
2
MeO
NH
Li,
Et 2
O, h
exan
e, –
15°,
30
min
; ref
lux
1 h
(55)
786
Fe
SS
C6H
4Me-
2
O
Fe
SC
6H4M
e-2
O
NH
2
Fe
O
O
OM
e
CuR
Li
Fe
O
O
OM
e
NH
2
181
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
YL
iY
NH
2
NH
2OM
e, –
20°,
2 h
Y O S
(78)
(28)
828,
829
830
1. (
PhO
) 2P(
O)N
3, T
HF,
–78
°, 2
h; to
–20
°, 30
min
2. N
aAlH
2(O
CH
2CH
2OM
e)2,
tolu
ene,
–7
8°; 0
°, 1
h; r
t, 30
min
I
I33
3, 3
34
Y O S
(58)
(62)
O S
(58)
(62)
OO
OM
e
NH
2OM
e, E
t 2O
, 0°,
then
HC
l(2
4)83
1
BrM
gO
Me
H3N
Cl–
SS
MeO
NH
Li (
ia),
Et 2
O, –
78° t
o –1
5°, 2
h(5
5)82
OO
NH
2OM
e(3
3)82
8
OO
Li
NH
21.
(Ph
O) 2
P(O
)N3,
TH
F, –
78°,
2 h;
to –
20°,
30 m
in
2. N
aAlH
2(O
CH
2CH
2OM
e)2,
tolu
ene,
–7
8°; 0
°, 1
h; r
t, 30
min
(71)
333,
334
MgB
rN
H2
Li
NH
2
YS
Li
YS
NH
2
NH
2OM
e, E
t 2O
Y O S
832
833,
834
(59)
(26)
Tem
p
–20°
; ref
lux
0-5°
; rt
Tim
e
—; "
seve
ral"
h
15 m
in; 1
h
C12
182
C24
R!
R!
R2
Li
R1
R1
R2
N3
TsN
3
R1
2,4,
6-M
e 3C
6H2
2,4,
6-M
e 3C
6H2
R2
H Me
Solv
ent(
s)
Et 2
O, h
exan
es
TH
F
(96)
(95)
314
835
Cn
Poly
sulf
oneff
1. n
-BuL
i, T
HF,
hex
ane,
–70
°2.
MeO
NH
2
Am
inat
ed p
olys
ulfo
ne(—
)83
6
OO
2S
On
1. n
-BuL
i (2.
15 e
q), T
HF,
–78
°
15
min
2. T
sN3
(3 e
q), t
o –5
0°, 1
h
335
OO
2S
On
N3
N3
(95)
gg
OO
2S
O
n
1. n
-BuL
i (1.
2 eq
), T
HF,
–78
°2.
MeO
NH
Li,
–78°
OO
2S
O
n
NH
2
(17)
837
OO
2S
O
n
N3
1. n
-BuL
i (2.
5 eq
), T
HF,
–78
°2.
TsN
3 (3
eq)
, –78
°, 15
min
;
t
o –5
0°, 9
0 m
in
335
Tem
p
0° —
Tim
e
2 h
—
(95)
N3
183
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 4
. AR
YL
CA
RB
AN
ION
S (C
onti
nued
)
OO
2S
YO
n
1. n
-BuL
i (2.
1 eq
), T
HF,
–65
°2.
4-A
cNH
C6H
4SO
2N3,
to –
50°,
15 m
in
3. H
2O, E
tOH
OO
2S
YO
n
(—)
837
N3
N3
Y =
bon
d or
CM
e 2
a Thi
s is
a c
ompe
titiv
e ki
netic
stu
dy. N
o yi
elds
wer
e re
port
ed.
b The
pro
duct
was
isol
ated
as
the
hydr
ochl
orid
e.c T
he p
rodu
ct w
as is
olat
ed a
s th
e N
-ben
zoyl
der
ivat
ive.
d With
PhM
gBr
at r
eflu
x th
e yi
eld
was
37%
and
with
PhC
uLi t
he y
ield
was
83%
.e T
he y
ield
is th
at o
f th
e am
ine.
f The
rea
gent
was
pre
pare
d in
situ
by
addi
tion
of n
-BuL
i or
PhL
i, re
spec
tivel
y, to
CH
2=N
OB
n.g U
nles
s ot
herw
ise
note
d, th
e su
bstr
ates
wer
e pr
epar
ed f
rom
the
Gri
gnar
d re
agen
ts a
nd Z
nCl 2
.h T
he s
ubst
rate
was
pre
pare
d by
ort
holit
hiat
ion
follo
wed
by
reac
tion
with
ZnC
l 2. T
he c
atal
yst i
n th
e su
bseq
uent
am
inat
ion
was
CuC
l 2.
i Thi
s w
as th
e yi
eld
whe
n 0.
6 eq
uiva
lent
s of
Ar 2
Zn
wer
e us
ed.
j X w
as n
ot s
peci
fied
.k T
he p
rodu
ct w
as c
onve
rted
into
the
aryl
amin
e w
ith C
sOH
in e
thyl
ene
glyc
ol a
t 150
° or
into
the
N-m
ethy
lary
lam
ine
with
LiA
lH4.
l Hyd
roly
sis
with
CsO
H in
eth
ylen
e gl
ycol
at 1
50° g
ave
met
hyl 4
-am
inob
enzo
ate;
with
LiA
lH4,
par
tial l
oss
of th
e fl
uori
ne a
nd th
e m
ethy
l gro
up w
as o
bser
ved.
m N
o re
actio
n oc
curr
ed u
nder
the
cond
ition
s of
foo
tnot
e k.
n PhC
(=N
Ts)
NM
e(C
H2)
2OH
was
for
med
in 7
0% y
ield
.o T
his
reag
ent i
s hy
gros
copi
c an
d re
prod
ucib
le r
esul
ts w
ere
obta
ined
onl
y w
ith f
resh
ly p
repa
red
mat
eria
l.p T
he y
ield
s w
ere
dete
rmin
ed b
y ga
s ch
rom
atog
raph
y.
q X2 w
as
.
S O2N
O2
S
Cn
184
r Hea
ting
to 7
0° f
or o
ne h
our
conv
erte
d an
y Z
-azo
com
poun
d in
to th
e E
isom
er.
s The
yie
ld w
as d
eter
min
ed b
y io
dom
etry
.t T
hese
are
cor
rect
ed e
ntri
es; K
noch
el, P
.; K
ofin
k, C
. Uni
vers
ity o
f M
unic
h, G
erm
any.
Per
sona
l com
mun
icat
ion,
200
5.u T
he y
ield
was
det
erm
ined
by
NM
R s
pect
rosc
opy.
v R1 w
as n
ot s
peci
fied
but
it w
as e
ither
Ph
or t-
Bu.
w R
2 was
not
spe
cifi
ed.
x So
me
of th
e tr
iaze
nes
are
isol
ated
as
mix
ture
s of
dou
ble-
bond
isom
ers.
y 2,6
-Dim
etho
xy-4
-(ph
enyl
thio
met
hyl)
anili
ne w
as a
lso
form
ed in
16%
yie
ld.
z The
pro
duct
was
indo
le a
fter
trea
tmen
t of
the
amin
e w
ith o
xalic
aci
d.aa
A la
ter
publ
icat
ion
(ref
. 820
) re
port
ed a
0%
yie
ld f
or th
is r
eact
ion.
bb T
he p
rodu
ct w
as is
olat
ed a
s th
e N
-ter
t-bu
toxy
carb
onyl
der
ivat
ive.
cc D
eute
rium
labe
ling
indi
cate
s th
at th
e re
actio
n is
inte
rmol
ecul
ar.
dd C
atal
ysts
IA
, IB
, and
IC
, II
gave
atr
opis
omer
s w
ith th
e op
posi
te a
bsol
ute
conf
igur
atio
ns.
ee A
mix
ture
of
tria
zene
s w
as o
btai
ned
in lo
w y
ield
.ff T
he ty
pe o
f po
lysu
lfon
e w
as n
ot s
peci
fied
.gg
A m
ono-
azid
e w
as o
btai
ned
in 9
5% y
ield
with
1.1
eq
of n
-BuL
i and
1.5
eq
of T
sN3.
The
cor
resp
ondi
ng r
eact
ions
with
(Ph
O) 2
P(O
)N3
wer
e no
t as
clea
n.
185
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 5
. HE
TE
RO
CY
CL
IC C
AR
BA
NIO
NS
C3
N
N Me
Li
N
N Me
NH
2C
lNH
2 or
MeO
NH
2(0
)66
PhN3
1.
o
r
, T
HF,
–78
° to
rt, 2
h
2. H
Cl,
then
bas
e
I (
45)
278
N3
Bu-
t
N
N R
Li
N
N R
NH
3+ C
l–
1. P
hN3,
rt,
1.5
h
2. H
OA
c, H
2O
3. H
Cl,
80-9
0°
R Me
Ph Bn
(70)
(43)
(64)
66
C4
NN B
nO
HO
NN B
nO
HO
NH
2
NN B
nO
HO
H N
(90)
+
(4)
149
O
H N, t
olue
ne, N
aOH
, H2O
, 0°,
10 m
in
1. P
hSC
H2N
3 (i
a), T
HF,
–75
° to
0°2.
CuI
, 0°,
1 h
3. K
OH
(50
% a
q.),
MeO
H, T
HF,
rt,
3 h
N RL
iN R
NH
2R
= M
e or
SO
2Ph
(0)
274
NN Ph
ON
N Ph
OC
(CN
) 2, p
yrid
ine,
0°,
1 h
TsO
N
NC
(CN
) 2
PyH
+(5
0)83
8
N
N
HO
OH
OH
N
N
HO
OH
O
C(C
N) 2
, pyr
idin
e, –
30° t
o rt
TsO
NN
C(C
N) 2
PyH
+(5
0)83
8
I
N
186
OO
MgB
rN
PhPh Ph
PhN
OT
s
PhPh
PhPh
180
(ia)
, TH
F, –
78°,
10 m
in(8
1)
1. P
hSC
H2N
3 (i
a), T
HF,
–75
° to
0°2.
CuI
, 0°,
1 h
3. K
OH
(50
% a
q.),
MeO
H, T
HF,
rt,
3 h
OM
ON
H2
M =
Li o
r M
gBr
(0)
274
C4
O
ON
OT
s
PhPh
PhPh
180
(ia)
, TH
F, –
78°,
10 m
in(7
8)
MgB
r
NPh Ph
Ph
Ph
SC
u(C
N)M
SN
PhR
1. P
hRN
Li,
TH
F, te
mp
1, ti
me
1
2. A
dden
d, T
HF,
–78
°3.
O2,
tem
p 2,
tim
e 2
M Li
Li
ZnC
l
R Me
Me
Bn
Add
end
— Cu(
NO
3)2
1,2-
(O2N
) 2C
6H4
(52)
(70)
(75)
54 55 55
OO
t-B
uO2C
N(L
i)O
Ts,
TH
F,
–78
° to
–40°
, 2 h
(48)
127
Cu
NH
CO
2Bu-
t
SL
iS
NH
Me
MeN
(Li)
OM
e, E
t 2O
, hex
ane,
–78
° to
–15°
, 3 h
(0)
97
OO
Nt-
BuO
2CN
HC
O2B
u-t
1. C
atal
yst B
(se
e C
hart
1; 2
mol
%),
i-
PrO
H, r
t to
0°2.
Add
sub
stra
te, t
hen
PhSi
H3,
0°
3. t-
BuO
2CN
=N
CO
2Bu-
t, 0°
, 4 h
(81)
215
Tem
p 1
–40°
–40°
–78°
to –
40°
Tem
p 2
–78°
; to
rt
–78°
–78°
Tim
e 1
15 m
in
20 m
in
40 m
in
Tim
e 2
—
30 m
in
30 m
in
187
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 5
. HE
TE
RO
CY
CL
IC C
AR
BA
NIO
NS
(Con
tinu
ed)
SC
u(C
N)L
i 2S
NH
RR
NH
OT
MS,
TH
F2
R TM
S
Me
i-Pr
Tim
e
1 h;
—
2 h
2 h
(72)
(60)
(65)
100
101
101
SM
gBr
SN
N Me
MeN
NM
eM
eN
NO
Ts
(ia)
, tol
uene
, Et 2
O,
(84)
a18
1
SL
i
NO
1. Z
nCl 2
, TH
F, 0
°; to
rt
2.
(ia
), N
i(ac
ac) 2
(ca
t), T
HF,
2 h
SN H
OH
C
(4-1
5)17
0
SZ
nBr
(80)
358
t-B
uO2C
N=
NC
O2B
u-t,
TH
F, r
t, 30
min
1. T
sN3,
Et 2
O, –
70°
2. N
a 4P 2
O7,
H2O
, rt,
over
nigh
tS
Li
SN
3
316
R H 1,3-
diox
olan
-2-y
l
C4-
5
(10)
(0)
S
R
S
R1.
TsN
3, E
t 2O
, –70
°2.
Na 4
P 2O
7, H
2O, r
t, ov
erni
ght
Li
N3
316
R H 2-M
e
4-M
e
2-(1
,3-d
ioxo
lan-
2-yl
)
4-(1
,3-d
ioxo
lan-
2-yl
)
(85)
(68)
(70)
(65)
(70)
RR
SC
uS
NH
CO
2Bu-
tt-
BuO
2CN
(Li)
Ts,
TH
F, –
78° t
o –4
0°, 2
h12
7(5
2)
C4
0°, 1
5 m
in
Tem
p
–50°
; to
rt
–50°
to r
t
–50°
to r
t
SN
H N
CO
2Bu-
t
CO
2Bu-
t
188
SS
Li
N3
Ph1.
, T
HF,
–78
°; r
t, 2
h
2. H
Cl
SS
NH
2(6
4)27
8
NZ
n2
NN
O
ON
OB
z (i
a), (
CuO
Tf)
2•Ph
H (
cat)
,(7
1)11
2, 1
09
N
C4
C5
Cu
NN
HC
O2B
u-t
t-B
uO2C
N(L
i)O
Ts,
TH
F, 0
°, 2.
5 h
(53)
127
RN
HO
TM
S, T
HF
NC
u(C
N)L
i 22
NN
HR
R TM
S
Me
i-Pr
t-B
u
Tim
e
— 2 h
2 h
2 h
(60)
R =
H b
(65)
(68)
(70)
100
101
101
101
NC
uN
N H
TsO
N(L
i)C
O2C
H2C
H=
CH
2, T
HF,
–78
°, 3
h(2
6)13
0
NL
iN
NH
2
N3
PhB
u-t
N3
o
r
, T
HF,
–78
°;
to
rt, 2
h, t
hen
HC
l, or
KO
H
(45)
278
1. P
hN3,
Et 2
O
2. H
OA
c, H
2O
3. H
Cl,
80-9
0°N
NH
3+ C
l–(3
8)66
1. P
hSC
H2N
3 (i
a), T
HF,
–75
° to
0°2.
CuI
, 0°,
1 h
3. K
OH
(50
% a
q.),
MeO
H, T
HF,
rt,
3 h
SL
iS
NH
2(0
)27
4
TH
F, r
t, 15
-60
min
Tem
p
–60°
to r
t
–50°
to r
t
–50°
to r
t
–50°
to r
t
O
O
189
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 5
. HE
TE
RO
CY
CL
IC C
AR
BA
NIO
NS
(Con
tinu
ed)
NN
N RN
NN
N RNN
3
NN
N RN
2
1. L
DA
, tol
uene
, TH
F, –
78°,
20 m
in
2. A
rSO
2N3,
–78
°; to
rt,
1-2
h
3. N
aHC
O3,
H2O
R MeO
CH
2
BnO
CH
2
—
Ar
4-M
eC6H
4
4-M
eC6H
4
2,4,
6-M
e 2C
6H2
(57)
(69)
(0)
(16)
c
(11)
(—)
313
SN
H2
SL
i(5
8)27
8
N
N Me
NH
CO
2Bu-
t
N
N Me
NH
CO
2Bu-
t
C5
N3
1. n
-BuL
i (2.
1 eq
), T
HF,
–75
°2.
TsN
3, 1
0 m
in
(60)
840
SNM
gBr
SNN
H2
1. P
hSC
H2N
3 (i
a), T
HF,
–75
° to
0°2.
CuI
, 0°,
1 h
3. K
OH
(50
% a
q.),
MeO
H, T
HF,
rt,
3 h
(59)
274
SNL
iSN
NH
2(5
3)27
8
1. P
hN3,
Et 2
O
2. H
OA
c, H
2O
3. H
Cl,
80-9
0°SN
NH
3+ C
l–66
(52)
C7
Boc
NS
MeO
2CN
=N
CO
2Me,
105
°, 2
d83
9
MeO
2C
Boc
NS
MeO
2CN
(CO
2Me)
NH
CO
2Me
(—)
1. T
MSN
HO
TM
S, T
HF,
–60
° to
rt
2. "
Hyd
roly
tic w
orku
p" b
N2
N
Cu(
CN
)Li 2
NH
2
(58)
100
N3
PhB
u-t
N3
o
r
, T
HF,
–78
°; to
rt,
2 h
N3
PhB
u-t
N3
o
r
, T
HF,
–78
°; to
rt,
2 h
C6
190
N HN H
N H
NE
750
4-R
C6H
4SO
2N3
R O2N
MeO
Me
Solv
ent
EtO
H
diox
ane
diox
ane
Tem
p
refl
ux
80°
75-8
0°
I +
II
(61)
(22)
(46)N
HE
E =
SO
2C6H
4R-4
N Me
N Me
N Me
NE
NH
ER
C6H
4SO
2N3,
dio
xane
, 75-
80°,
18-2
4 h
750
+
III
R H 4-C
l
4-B
r
3,4-
Cl 2
4-A
cNH
2-O
2N
3-O
2N
4-O
2N
3-O
2N,4
-Cl
4-M
eO
4-M
e
2,4,
6-M
e 3
2,4,
6-(i
-Pr)
3
I
(54)
(60)
(49)
(63)
(67)
(75)
(74)
(72)
(82)
(44)
(47)
(34)
(32)
II (22)
(16)
(12)
(14)
(5)
(14)
(6)
(21)
(8)
(22)
(24)
(15)
(24)
E =
SO
2C6H
4R
NN
Et
Li
NN
Et
NH
N=
NPh
PhN
3, E
t 2O
, –20
°, 1
h(6
1)84
1
C8
+
III Tim
e
6 h
26 h
48 h
d
191
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 5
. HE
TE
RO
CY
CL
IC C
AR
BA
NIO
NS
(Con
tinu
ed)
O2
Cu(
CN
)Li 2
ON
TM
S1.
TM
SNH
OT
MS,
TH
F, –
30° t
o rt
, 18
h
2. T
MSC
l
(70)
100
S2
Cu(
CN
)Li 2
ST
MSN
HO
TM
S, T
HF,
–50
°, 1
h; to
rt
(58)
100
NH
2
OC
u(C
N)L
iO
NM
ePh
1. P
hMeN
Li,
TH
F, –
40°,
20 m
in
2. C
u(N
O3)
2, T
HF,
–78
°3.
O2,
–78
°, 30
min
(76)
55, 5
4
SL
iS
N3
1. T
sN3,
Et 2
O, –
70°,
5 h
2. N
a 4P 2
O7,
H2O
(7)
316
SS
1. T
sN3,
Et 2
O, –
70°,
5 h
2. N
a 4P 2
O7,
H2O
(83)
316
Li
N3
SL
i
R
SN
3
R
TsN
3, E
t 2O
, hex
ane,
–70
°, 5
h; to
–10
°R 2-
thie
nyl
3-th
ieny
l
(33)
(41)
779
SR
Li
SR
N3
TsN
3, E
t 2O
, hex
ane,
–70
°, 5
h; to
–10
°R 2-
thie
nyl
3-th
ieny
l
(72)
(73)
779
S
Li
S
N3
TsN
3, E
t 2O
, hex
ane,
–70
°, 5
h; to
–10
°R 2-
thie
nyl
3-th
ieny
l
(75)
(77)
779
RR
N R
MgB
rN R
NH
2
1. P
hSC
H2N
3 (i
a), T
HF,
–75
° to
0°2.
CuI
, 0°,
1 h
3. K
OH
(50
% a
q.),
MeO
H, T
HF,
rt,
3 h
(0)
274
R =
Me,
PhS
O2
C8
192
O PhO
1. K
NH
2, N
H3
(liq
), E
t 2O
2. P
hN=
NPh
OO
PhN
(Ph)
NH
Ph
(30)
212
C14
a The
pro
duct
was
con
vert
ed in
to N
-met
hyl-
2-th
ieny
lam
ine
with
LiA
lH4
but i
t cou
ld n
ot b
e hy
drol
yzed
to th
e am
ine.
b A
hyd
roly
tic w
orku
p w
as m
entio
ned
in th
e te
xt b
ut n
o de
tails
wer
e gi
ven
in th
e E
xper
imen
tal S
ectio
n.
c With
KH
MD
S, o
nly
the
dim
er I
I w
as o
btai
ned
in 7
0% y
ield
.d I
som
ers
I an
d II
exi
st in
equ
ilibr
ium
.
C9
N Bn
CO
2Et
MgC
l
N Bn
CO
2Et
NH
C6H
4R-4
1. 4
-RC
6H4N
=N
Ts,
TH
F, –
20°,
1 h
2. C
H2=
CH
CH
2I, N
-met
hylp
yrro
ldin
one,
rt
, 3 h
3. Z
n, A
cOH
, TFA
, 75°
, 2.5
h
R Br
CO
2Et
(58)
(71)
255
193
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 6
. AL
DE
HY
DE
EN
OL
AT
ES
C2
OE
t1.
ClN
HC
O2B
n, C
HC
l 3, M
eOH
, –78
°2.
CrC
l 2
3. M
eON
aB
nO2C
NH
OE
t
OM
e(8
1)34
3
4-O
2NC
6H4N
2+ C
l– , H2O
, 0-1
0°(—
)84
2
OR
1. M
eO2C
N=
NC
O2M
e, r
t
2. H
Cl (
3% in
MeO
H),
rt
MeO
2CN
HN
OM
e
OM
eM
eO2C
(—)
843
R =
Et,
i-B
u, n
-C18
H37
SR
R =
Et,
Ph, 4
-ClC
6H4
1. E
tO2C
N=
NC
O2E
t, Ph
H, r
t
2. M
eOH
EtO
2CN
HN
SR
OM
eE
tO2C
(—)
844
OB
u-n
1. 4
-O2N
C6H
4N3,
CH
Cl 3
, 40°
, 7 h
2. A
cOH
, PhH
, 50°
, 10
min
4-O
2NC
6H4N
HO
Ac
OB
u-n
(84)
387
N1.
MeO
2CN
=N
CO
2Me,
Et 2
O,
rt
2. H
Cl (
3% in
MeO
H),
rt
MeO
2CN
HN
N
OM
eM
eO2C
(—)
843
OO
OPh
1. R
CO
N=
NC
OR
, rt
2. H
Cl,
MeO
H
RC
ON
HN
OPh
OM
e(—
)R
CO
240
OA
r1.
MeO
2CN
=N
CO
2Me,
rt
2. H
Cl,
MeO
H
MeO
2CN
HN
OA
r
OM
eM
eO2C
240
Ar
4-C
lC6H
4
4-M
eOC
6H4
4-M
eC6H
4
(56)
(82)
(85)
4-O
2NC
6H4N
2+ C
l– , H2O
, 0-1
0°84
2O
Et
(—)
C3
N H
NC
HO
O2N
N H
NC
HO
O2N
R =
MeO
, EtO
, Cl 3
CC
H2O
, Ph
194
1. R
2 O2C
N=
NC
O2R
2 ,
L
-pro
line
(0.1
eq)
, MeC
N
2. N
aBH
4, E
tOH
221
CO
2R2
NO
H
R1
R2 O
2CN
H
R1
Me
n-Pr
i-Pr
i-Pr
n-B
u
Bn
(97)
(93)
(97)
(99)
(94)
(95)
R2
Bn
Bn
t-B
u
Bn
Bn
Bn
Tem
p
0° to
rt
0° to
rt
20°
0° to
rt
0° to
rt
0° to
rt
Tim
e
3 h
3 h
— 3 h
3 h
3 h
% e
e
>95
>95 92 96 97 >95
1. E
tO2C
N=
NC
O2E
t, D
-pro
line
, 5°
2. N
aBH
4
OE
tO2C
NH
N
C3
O
224
(—)
92-9
3% e
e
C3-
9
C3-
7
R2 O
2CN
=N
CO
2R2 , c
atal
yst (
x eq
), r
t
CO
2R2
NC
HO
R2 O
2CN
H
R1
Me
Me
Me
Me
Me
Me
Me
Et
i-Pr
n-C
5H11
n-C
5H11
R2
Et
— Et
i-Pr
t-B
u
Bn
t-B
u
Et
Bn
Bn
Bn
x 0.5
— 0.02 0.1
0.1
0.2
0.2
0,1
0.1
0.2
0.2
Solv
ent
CH
2Cl 2
neat
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
Tim
e
45 m
in
2 m
in
5 h
105
min
205
min
3.5
h
22 h
2 h
4 h
1.25
h
15 h
(93)
(100
)
(92)
(91)
(99)
(62)
(60)
(77)
(>90
)
(62)
(69)
% e
e
92 77 84 88 89 54 74 90 >90 91 72
R1
Cat
alys
t
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-a
zetid
inec
arbo
xylic
aci
d
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-a
zetid
inec
arbo
xylic
aci
d
222
222
222
222
222
229
229
222
229
229
229
HR
1
O
1.5
eq H
O
195
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 6
. AL
DE
HY
DE
EN
OL
AT
ES
(Con
tinu
ed)
1. R
2 O2C
N=
NC
O2R
2 ,
L
-pro
line
(0.1
eq)
, CH
2Cl 2
, rt
2. N
aBH
4, M
eOH
, the
n 0.
5 N
NaO
HO
R2 O
2CN
HN
O
R1
R1
Me
Et
CH
2=C
HC
H2
i-Pr
i-Pr
t-B
u
Bn
R2
Et
Et
Et
Et
Bn
Et
Et
(67)
(77)
(92)
(83)
(70)
(57)
(68)
% e
e
93 95 93 93 91 91 89C
4
222,
224
,
845
222
222
222
222
222
222
C3-
9
NR
1 R2
NR
3 R4
CH
O
NR
1 R2
CH
O+
R3 R
4 NC
l, O
2, d
ioxa
ne,
0°, 2
h;
rt,
over
nigh
t; re
flux
, 5 h
74
R1
Me
Me
Et
—(C
H2)
4—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
5—
—(C
H2)
5—
t-B
u
R2
Me
Me
Et
MgB
r
R3
Me
Me
Et
Me
Me
Me
—(C
H2)
5—
Me
R4
Me
Me
Et
Me
Me
Me
Me
R1
CH
O
R2
R1
R2
CH
O
NH
Ts
4-M
eC6H
4SO
2N(C
l)N
a•x
H2O
,
L-p
rolin
e (2
mol
%),
MeC
N, r
t
78
R1
Me
Me
Et
H —(C
H2)
5—R2
Me
Et
Et
i-Pr
Tim
e
1 d
1 d
1 d
1 d
2 d
(83)
(81)
(78)
(86)
(86)
% e
e
0 0 0 0 0
C4-
7
R1
CH
O
III
I
(—)
(7)
(32)
(53)
(42)
(53)
(—)
(88)
I +
II
(61)
(—)
(—)
(—)
(—)
(—)
(42)
(—)
II (—)
(32)
(7)
(36)
(15)
(24)
(—)
(0)
196
C4
1. [
BnO
2CN
=N
CO
2Bn,
D-p
rolin
e, M
eCN
] (i
a),
0°
, 2 h
; to
rt, 1
h; r
t
2. N
aBH
4, E
tOH
, 0°,
5 m
in
CO
2Bn
NO
HB
nO2C
NH
Et
(92)
, 96%
ee
227
OT
MS
CH
O
NH
Ts
PhI=
NT
s, M
eCN
172
(52)
4-O
2NC
6H4N
2+ C
l– , H2O
, 0-1
0°84
2(—
)O
ArN
HN
R1
CH
O
ArN
2+ C
l– , H2O
, NaO
Ac,
pH
5-6
195
R1
Et
Et
Et
Ph Ph Ph Ph
C4-
8
R2
—(C
H2)
5—
—(C
H2)
5—
—(C
H2)
5—
Et
Et
Et
Et
R3
Et
Et
Et
Et
Ar
4-C
lC6H
4
4-O
2NC
6H4
4-H
O2C
C6H
4
4-C
lC6H
4
4-O
2NC
6H4
4-M
eOC
6H4
4-H
O2C
C6H
4
(65)
(41)
(53)
(90)
(94)
(76)
(89)
C4
S
S
i-Pr
4-O
2NC
6H4N
2+ B
F 4– , C
H2C
l 2, r
t, 1
h(8
5)84
6
C4-
6
1.
(10
mol
%),
R
2 O2C
N=
NC
O2R
2 , CH
2Cl 2
, rt,
15 m
inO
N
O
NH
CO
2R2
R1
R1
Et
i-Pr
i-Pr
ally
l
t-B
u
R2
Et
Et
i-Pr
Et
Et
(79)
(88)
(73)
(81)
(83)
% e
e
90 97 92 92 97
386
CH
O
Ar
= 3
,5-(
CF 3
) 2C
6H3
S
S
i-Pr
NN
O2N
R1
NR
2 R3
HO
CH
O
N
H N
NO
2
N H
Ar A
rO
TM
S
2. N
aBH
4, M
eOH
, 0°
O
R1
H
197
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 6
. AL
DE
HY
DE
EN
OL
AT
ES
(Con
tinu
ed)
C4-
15Fo
r I:
1. C
atal
yst (
0.5
eq),
sol
vent
, rt,
30 m
in
2. S
ubst
rate
, 0°;
rt,
1 h
3. R
3 O2C
N=
NC
O2R
3 , rt,
time
For
II f
rom
I:
NaB
H4,
CH
2Cl 2
, EtO
H, 0
°, 30
min
CH
O
R2
R1
R2
R1
N NH
CO
2R3
O
OR
2
R1
CH
O
E
R1
Me
Me
Me
Me
Me
Me
Et
Et
—(C
H2)
5—
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
R2
Me
Me
Et
Et
n-Pr
n-Pr
Et
Et
n-B
u
2-th
ieny
l
Ph Ph Ph Ph Ph 4-FC
6H4
4-FC
6H4
4-C
lC6H
4
4-B
rC6H
4
4-O
2NC
6H4
Cat
alys
t
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-2
-aze
tidin
ecar
boxy
lic a
cid
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-2
-aze
tidin
ecar
boxy
lic a
cid
L-p
rolin
e
L-2
-aze
tidin
ecar
boxy
lic a
cid
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
R3
Et
Bn
Et
Et
Et
Bn
Et
Bn
Et
Et
Bn
Et
Et
Et
Bn
Bn
Et
Bn
Bn
Bn
Et
Tim
e
3 d
3 d
— — 3 d
3d 4 d
4 d
4 d
9 d
3 d
3 d
3 d
— 3 d
— 5 d
5 d
3 d
3 d
2 d
I
(83)
(85)
(—)
(—)
(60)
(60)
(55)
(51)
(—)
(—)
(60)
(62)
(—)
(—)
(—)
(—)
(26)
(29)
(86)
(70)
(85)
223
223
847,
223
847
223
223
223
223
847,
223
847,
223
223
223,
847
847
847
847,
223
847
223
223
223
223
223
% e
e
— — 28 6 — — — — — 4 — — 81 51 81 52 — — — — —
II (—)
(—)
(52)
(—)
(—)
(—)
(—)
(—)
(26)
(35)
(—)
(—)
(17)
(—)
(83)
(—)
(—)
(—)
(—)
(—)
(—)
% e
e
— — — — — 39 — — — — 70 80 — — — — 68 35 61 79 36
III
E: N
(CO
2R3 )N
HC
O2R
3
198
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Me
Me
4-O
2NC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
3,5-
(MeO
) 2C
6H3
3,4-
(BnO
) 2C
6H3
4-N
CC
6H4
4-C
F 3C
6H4
4-C
F 3C
6H4
4-M
eO2C
C6H
4
4-Ph
C6H
4
Ph Ph 2-na
phth
yl
2-na
phth
yl
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-2
-aze
tidin
ecar
boxy
lic a
cid
L-p
rolin
e
L-2
-aze
tidin
ecar
boxy
lic a
cid
Bn
Et
Et
Et
Bn
Bn
Et
Bn
Et
Bn
Et
Et
Et
Et
2 d
3 d
5 d
6 d
7 d
3 d
5 d
3 d
6 d
3 d
3 d
— 2.5
d
—
(99)
(62)
(87)
(63)
(58)
(62)
(19)
(40)
(50)
(53)
(59)
(—)
(54)
(—)
223
223
223,
847
223,
847
223
223
223
223
223,
847
223
223,
847
847
223,
847
847
— — — — — — — — — — — — — —
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
56 83 76 85 73 53 — — 82 84 80 49 86 56
R1
CH
OR
2 SO
R3 O
2CN
HN
R1
O
225
1.5
eq
C4-
5
R1
Me
Me
Me
Et
Et
R2
Et
Bn
Bn
Bn
Et
R3
Bn
Et
Bn
Et
Bn
Tim
e
16 h
3.5
h
16 h
16 h
16 h
(51)
(57)
(44)
(42)
(38)
dr
88:1
2
95:5
89:1
1
96:4
95:5
ee %
>99
>99
a
>99
>99 97
1.
(cat
), R
2 SH (
1 eq
),
to
luen
e
Ar
= 3
,5-(
CF 3
) 2C
6H3
N H
Ar A
rO
TM
S
2. R
3 O2C
N=
NC
O2R
3 (1.
3 eq
), ti
me
3. N
aBH
4
4. N
aOH
199
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 6
. AL
DE
HY
DE
EN
OL
AT
ES
(Con
tinu
ed)
CH
O
R1
R2
CH
O
NH
SO2R
3
R1
R2
R3 SO
2N3,
(1
eq),
rt
N H
R4
386a
C4-
14
R2
Ph Me
Et
n-Pr
Et
n-B
u
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
R3
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
2-O
2NC
6H4
Me
n-C
4F9
5-ch
loro
-3-t
hien
yl
2,5-
dich
loro
-3-t
hien
yl
6-ch
loro
-5-b
rom
o-2-
pyri
dyl
2-O
2NC
6H4
4-O
2NC
6H4
2,4-
(O2N
) 2C
6H3
3,4-
(MeO
) 2C
6H3
4-M
eC6H
4
2-M
eO2C
C6H
4
1-na
phth
yl
2-na
phth
yl
2,4,
6-(i
-Pr)
3C6H
2
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
R4
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
H tetr
azol
yl
CO
NH
Ts
Solv
ent
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
DM
SO
Tim
e
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
(26)
(42)
(49)
(51)
(47)
(52)
(54)
(33)
(24)
(36)
(27)
(24)
(44)
(52)
(27)
(43)
(35)
(39)
(36)
(42)
(33)
(36)
(24)
(25)
% e
e
— — 5 12 — — 28 71 29 54 47 46 56 82 45 67 59 8 65 63 50 — 66 66
R1
H Me
Me
Me
Et
—(C
H2)
5—
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
200
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 2-M
eOC
6H4
2-M
eOC
6H4
3-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
2,4-
(MeO
) 2C
6H3
2,5-
(MeO
) 2)C
6H3
3,5-
(BnO
) 2C
6H3
4-(t
-Bu)
C6H
4
Ph
4-M
eC6H
4
2-O
2NC
6H4
4-M
eC6H
4
4-M
eC6H
4
2-O
2NC
6H4
2-O
2NC
6H4
2-O
2NC
6H4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
2-O
2NC
6H4
4-M
eC6H
4
2-O
2NC
6H4
4-O
2NC
6H4
2-O
2NC
6H4
4-O
2NC
6H4
2-O
2NC
6H4
4-O
2NC
6H4
2-O
2NC
6H4
2-O
2NC
6H4
2-O
2NC
6H4
2-O
2NC
6H4
4-M
eC6H
4
(1-p
yrro
lidin
yl)m
ethy
l•C
F 3C
O2H
(1-p
yrro
lidin
yl)m
ethy
l•C
F 3C
O2H
CH
2OH
C(P
h)2O
H
C(P
h)2O
TM
S
C(C
10H
7)2O
TM
S
C(P
h)2C
Me
CO
2Hc
CO
2Hc
CO
2Hc
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
CO
2H
DM
SO
DM
SO
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
TH
F
MeC
N
CH
2Cl 2
t-B
uOH
DM
SO
[bm
im][
BF 4
]
[bm
im][
BF 4
]
[cap
emim
][B
F 4]
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
EtO
H
70 m
in
1 d
4 d
1 d
1 d
1 d
1 d
7d 4d 4d 1 d
2 h
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
1 d
(23)
(26)
(<10
)
(0)
(26)
b
(38)
b
(52)
(21)
(14)
(0)
(25)
(28)
(38)
(55)
(53)
(21)
(21)
(47)
(49)
(53)
(44)
(34)
(32)
(31)
(55)
(36)
45 57 — — — 64 55 53 54 — 54 60 72 66 20 72 59 84 69 86 76 45 54 72 61 —
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
C5
OO
OM
e
NH
CO
2Et
1. C
lNH
CO
2Et,
CH
Cl 3
, MeO
H, –
78°
2. C
rCl 3
3. H
2SO
4
(77)
343
201
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 6
. AL
DE
HY
DE
EN
OL
AT
ES
(Con
tinu
ed)
C5-
6
O
R1 R2
EtO
2CN
3, R
3 OH
, hν
O
R1 R2
NH
CO
2Et
OR
3O
R1 R2
NH
CO
2Et
OR
3
O
R1 R2
NH
CO
2Et
OR
3O
R1 R2
NH
CO
2Et
OR
3
III
III
IV
R1
H H AcO
CH
2
AcO
CH
2
H
R2
H H H H MeO
R3
Me
t-B
u
Me
t-B
u
t-B
u
I (0)
(0)
(31)
(36)
(51)
II (53)
(69)
(25)
(20)
(0)
III
(0)
(0)
(0)
(0)
(18)
IV (10)
(7)
(11)
(tra
ce)
(11)
295
1. (
Saltm
en)M
n(N
) (2
eq)
,
2,
6-(t
-Bu)
2,4-
Me-
pyri
dine
, CH
2Cl 2
2. T
FFA
, –78
°; to
rt,
5-6
h
(80)
, C2
de 8
6%35
4
1. (
Saltm
en)M
n(N
) (2
eq)
,
2,
6-(t
-Bu)
2,4-
Me-
pyri
dine
, CH
2Cl 2
2. T
FFA
, –78
°; to
rt,
5-6
h
(80)
, C2
de 8
2%35
4
O
BnO
OB
n
OH
NH
CO
CF 3
O
BnO
OB
n2
OO
DPT
PS
OO
OO
DPT
PS
OO
NH
CO
CF 3
OH
2
C5
202
C6
OO
Ac
AcO R
1 R2
OO
Ac
AcO R
1 R2
OM
e
NH
CO
2Et
OO
Ac
AcO R
1 R2
NH
CO
2Et
OM
e
OO
Ac
AcO R
1
III
III
R1
H AcO
R2
AcO
H
I (5)
(4)
II (26)
(4)
III
(11)
(34)
N3C
O2E
t, M
eOH
, hν
295
R2
OM
eN
HC
O2E
t
OO
Ac
AcO
AcO
NaN
3, C
e(N
H4)
2(N
O3)
6,
MeC
N, c
oolin
g, 8
-10
h
OO
Ac
AcO
AcO
N3
ON
O2
OO
Ac
AcO
AcO
N3
OO
Ac
AcO
AcO
OO
Ac
AcO
AcO
ON
O2
ON
O2
N3
NH
Ac
(53)
(22)
(8)
(10)
332
N3
O
O
OA
c
OO
O
OA
c
OO
Me
NH
CO
2Et(1
2)34
3
1. C
lNH
CO
2Et,
CH
Cl 3
,
M
eOH
, –78
°2.
CrC
l 2
3. M
eOH
, AgN
O3
O
AcO
OA
cO
AcO
OA
c NH
CO
2CH
2CH
2Cl
OM
e
AcO
AcO
1. C
lNH
CO
2CH
2CH
2Cl,
C
HC
l 3, M
eOH
, –78
°2.
CrC
l 2
3. M
eOH
, AgN
O3
(55)
343
PhPh
203
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 6
. AL
DE
HY
DE
EN
OL
AT
ES
(Con
tinu
ed)
O
OO
O
AcO
1. C
lNH
CO
2CH
2CC
l 3,
C
HC
l 3, M
eOH
, –78
°2.
CrC
l 2
3. M
eOH
, AgN
O3
4. A
cOH
, the
n A
c 2O
(65)
343
OA
cO
Ac
NH
CO
2CH
2CC
l 3
AcO
OM
e
Ph
1. T
FAA
, CH
2Cl 2
2. (
Saltm
en)M
n(N
) (1
eq)
, CH
2Cl 2
;
ad
ditio
n ov
er 7
h
O
OO
PhO
OO
PhO
H
NH
CO
CF 3
2(7
0), C
2 de
0%
354
1. T
FAA
, CH
2Cl 2
2. (
Saltm
en)M
n(N
) (1
eq)
, CH
2Cl 2
;
ad
ditio
n ov
er 7
h
O
O
OR
O
R =
TB
S
O
O
OR
O
PhO
H
NH
CO
CF 3
2(7
5), C
2 de
75%
354
Ph
O
PMB
O
PMB
O1.
TFA
A, C
H2C
l 2
2. (
Saltm
en)M
n(N
) (1
eq)
, CH
2Cl 2
;
ad
ditio
n ov
er 7
h
O
PMB
O
PMB
ON
HC
OC
F 3O
H(6
0), C
2 de
75%
354
2
O
OO
OPM
B
1. T
FAA
, CH
2Cl 2
2. (
Saltm
en)M
n(N
) (1
eq)
, CH
2Cl 2
;
ad
ditio
n ov
er 7
h
O
OO
OPM
B
NH
CO
CF 3
OH
235
4Ph
PhR PM
B
TB
S
(66)
(68)C
2 %
de
71
75
C6
1. T
FAA
, CH
2Cl 2
2. (
Saltm
en)M
n(N
) (1
eq)
, CH
2Cl 2
;
ad
ditio
n ov
er 7
h
354
R Bn
TB
DPS
(62)
(64)
C2
de %
87.5
87.5
O
OO
RO
O
OO
RO
NH
CO
CF 3
HO
(Sal
tmen
)Mn(
N),
TFA
A,
2,
6-(t
-Bu)
2,4-
Me-
pyri
dine
, –78
° to
rt
O
OO
O
OO
NH
CO
CF 3
HO
(69)
351
2
2
204
SSH H
PhSS
H H
N Ph
SSH H
N Ph
4-O
2NC
6H4N
2+ B
F 4– , C
H2C
l 2, r
t
EtO
2CN
=N
CO
2Et,
CH
2Cl 2
, rt,
6 h
(79)(5
8)84
6
846
PhN
PhC
HO
N1.
MeO
2CN
=N
CO
2Me
2. H
3O+, H
2O(—
)24
7
C8
PhC
HO
Ph
NH
Ts
CH
O
4-M
eC6H
4SO
2N(C
l)N
a•x
H2O
,
pyr
rolid
ine
(10
mol
%),
PhN
Me 3
+ B
r 3– (
10 m
ol%
), M
eCN
, rt,
1 d
(70)
78
C9
NC
6H4N
O2-
4
NH C
O2E
t
CO
2Et
NH
CO
2Me
MeO
2C
R1
CH
O
R2
R1
R2
CH
O
NH
Ts
4-M
eC6H
4SO
2N(C
l)N
a•x
H2O
,
L-p
rolin
e (2
mol
%),
MeC
N, m
icro
wav
e ir
radi
atio
n (y
W)
0% e
e78
R2
Ph Ph Ph Ph 4-FC
6H4
4-O
2NC
6H4
4-M
eC6H
4
4-C
F 3C
6H4
4-N
CC
6H4
Ph naph
thyl
4-(i
-Pr)
C6H
4CH
2
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph Me
Me
Tem
p
90°
50°
50°
60°
60°
60°
60°
60°
60°
60°
60°
rt
Tim
e
30 m
in
30 m
in
40 m
in
30 m
in
30 m
in
30 m
in
30 m
in
30 m
in
30 m
in
30 m
in
30 m
in
1 d
(50)
(66)
(90)
(90)
(85)
(89)
(73)
(79)
(86)
(88)
(91)
(83)
C9-
13
y 100
150
200
200
200
200
200
200
200
200
200
200
205
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 6
. AL
DE
HY
DE
EN
OL
AT
ES
(Con
tinu
ed)
CH
O
R
OH
CN
BnO
2CN
=N
CO
2Bn,
L-p
rolin
e (3
0 m
ol%
),
MeC
N, r
t, 1
h
226
(99%
), >
99%
ee
Br
C10
N HH
NNN
N1.
(
15 m
ol%
), M
eCN
2. A
dd B
nO2C
N=
NC
O2B
n,
th
en s
ubst
rate
, rt,
3 h
(95)
, 80
% e
e38
5
OH
C
Br
OH
CN
CH
O
R
C10
-11
R
EC
HO
R Br
CO
2Me
(75)
(96)
% e
e
>99
>99
1. D
-Pro
line
(15
mol
%),
MeC
N,
B
nO2C
N=
NC
O2B
n
2. A
dd s
ubst
rate
, rt,
4 h
226
E =
N(C
O2B
n)N
HC
O2B
n
a With
L-p
rolin
e as
the
cata
lyst
, bot
h dr
and
ee
valu
es w
ere
cons
ider
ably
low
er.
b The
pro
duct
was
red
uced
with
NaB
H4
prio
r to
isol
atio
n.c T
he c
atal
yst l
oadi
ng w
as 4
0 m
ol%
.
NH
CO
2Bn
CO
2BnN
HC
O2B
n
CO
2Bn
206
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
A. A
CY
CL
IC K
ET
ON
E E
NO
LA
TE
S
C3
OE
t4-
O2N
C6H
4N2+
Cl– , H
2O, 0
–10°
(—)
842
N
N Ph
N
OO
, ref
lux
HN
N Ph
NC
H2C
OM
e
OO
(~10
0)25
4
C4-
14
R2
O
R3
R1
R2
O
R3
R1
R2
O
R3
R1
1. P
hR4 N
MnM
e•4
LiB
r (i
a), T
HF,
rt,
1 h
2. R
5 O2C
N=
NC
O2R
5 , –30
°; r
t, 2.
5 h
NI
IIR
1
H Me
Et
n-Pr
n-Pr
n-C
5H11
Et
Et
R2
H Me
H H H Me
Et
Et
R3
Me
Me
Et
n-Pr
n-Pr
Me
Bn
Bn
R4
n-B
u
n-B
u
Me
Me
Me
n-B
u
n-B
u
n-B
u
R5
Et
Et
t-B
u
Et
t-B
u
t-B
u
Et
t-B
u
I +
II
(50)
(72)
(60)
(90)
(60)
(60)
(93)
(75)
I:II
50:5
0
90:1
0
— — — 98:2
98:2
90:1
0
I dr
— — — — — — 3:1
3:1
388
R1
O40
3R
2 O2C
N=
NC
O2R
2 , DA
BC
O (
cat)
, TH
F
R1
Me
Me
Et
Et
n-C
6H13
n-C
7H15
PhC
H=
CH
PhC
H=
CH
C4-
11
R2
Et
t-B
u
Et
t-B
u
Et
Et
Et
t-B
u
Tem
p
rt 40°
rt 40°
rt rt rt 40°
Tim
e
8 h
24 h
24 h
24 h
24 h
8 h
8 h
24 h
(83)
(63)
(78)
(34)
(79)
(61)
(90)
(52)
O
H NN
Ac
O2N
E =
CO
2R5
NN H
EE
E
NH
E
+
R1
O
NR
2 O2C
NH
CO
2R2
207
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
A. A
CY
CL
IC K
ET
ON
E E
NO
LA
TE
S (C
onti
nued
)
C4-
10O
R1
R2
O
R1
R3 O
2CN
=N
CO
2R3 , c
atal
yst (
x eq
), r
t
O
R1
N
R2
R2
I
R1
H H H H H Me
H H H
R2
Me
Me
Me
Me
Me
Me
Et
i-Pr
Bn
R3
Et
Et
Et
t-B
u
t-B
u
Et
Et
Et
Et
x 0.2
0.05 0.1
0.2
0.1
0.1
0.1
0.1
0.1
Tim
e
52 h
65 h
10 h
114
h
114
h
60 h
20 h
96 h
24 h
I
(—)
(—)
(73)
(49)
(54)
(79)
(62)
(52)
(75)
I %
eea
96 93 95 94 90 94 98 99 98
II
(<10
)
(<10
)
(7)
— — — (15)
(17)
(17)
Cat
alys
t
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-a
zetid
inec
arbo
xylic
aci
d
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
228
228
228
229
229
228
228
228
228
Solv
ent
MeC
N
neat
MeC
N
CH
2Cl 2
CH
2Cl 2
MeC
N
MeC
N
MeC
N
MeC
N
R1
CO
2Et
O
N
OO
NR3
R3
R4
R5
R4
R5
Cu
(OT
f)2
1.
(
10 m
ol%
), s
olve
ntN
OO
NH
CO
2R2
MeO
2C
R1
404
R1
Me
Me
i-Pr
i-Pr
CH
2CH
=C
H2
CH
2CH
=C
H2
i-B
u
i-B
u
(CH
2)2C
H=
CH
2
(CH
2)2C
H=
CH
2
R2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
R3
H Me
H H H H H H H H
R4
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
R5
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
Solv
ent
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
(45)
(44)
(78)
(60)
(62)
(38)
(53)
(51)
(52)
(36)
% e
e
90 92 95 95 93 90 96 95 92 94
E =
CO
2R3
NH
E
E
II
+
NE
EH
N
2. A
dd s
ubst
rate
, the
n R
2 O2C
N=
NC
O2R
2 ,
rt
, 16
h
3. L
-Sel
ectr
ide,
TH
F, –
78°,
1 h;
to r
t
4. N
aOH
, H2O
, rt,
2 h
5. T
MSC
HN
2, M
eOH
, tol
uene
, hex
ane,
15
min
208
n-C
5H11
n-C
5H11
c-C
6H11
CH
2
c-C
6H11
CH
2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Et
Et
Bn
Bn
Bn
Bn
Bn
H H H H Me
Me
Me
Me
Me
H Me
Ph Ph Ph Ph H H H H H Ph Ph
Ph Ph Ph Ph Ph Ph Ph Ph t-B
u
Ph Ph
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
TH
F
TH
F
TH
F
(63)
(48)
(54)
(72)
(55)
(47)
(39)
(60)
(31)
(57)
(58)
93 97 96 96 68 35 90 82 7 89 88
OT
MS
O
NH
Ts
PhI=
NT
s, M
eCN
(53)
172
C5
R1
R2
R3 M
e 2Si
R1
R2
R3 M
e 2Si
NH
CO
2Bu-
t
1. L
DA
, TH
F, 0
°2.
, tem
p; to
rt
R1
Me
Et
n-Pr
Me
Bn
R2
Me
Et
n-Pr
Bn
Me
R3
t-B
u
t-B
u
t-B
u
t-B
u
t-C
6H13
Tem
p
–100
°–1
00°
–100
°–7
8°–7
8°
(27)
(37)
(29)
(19)
(20)
% d
e
80 87 88 41 83
156
OO
ON
4-O
2NC
6H4
CO
2Bu-
t
C5-
11
209
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
A. A
CY
CL
IC K
ET
ON
E E
NO
LA
TE
S (C
onti
nued
)
S
SR
1
R2
OC
5-12
OS
SR
1
R2
OO
S
SR
1
R2
OO
NC
O2B
u-t
NC
O2B
u-t
NH
CO
2Bu-
tN
HC
O2B
u-t
III
R1
Me
Et
Et
Et
Et
Ph Et
Et
R2
Me
H Me
i-Pr
t-B
u
Me
Ph Bn
Ena
ntio
mer
+/–
+/–
+/– + + +/– + +
1. L
iHM
DS,
TH
F, –
78°
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
5 m
in
3. H
OA
c, –
78° b
I +
II
(69)
(72)
(48)
(89)
(91)
(37)
(85)
(93)
I:II
2:1
—
>99
:1
— — 2:1
— —
% d
e
— — — 72c
— — — 69c
848
S
SR
1
R2
O
C5-
6
OS
SR
1
R2
OO
S
SR
1
R2
OO
NC
O2B
u-t
NC
O2B
u-t
NH
CO
2Bu-
tN
HC
O2B
u-t
III
1. L
iHM
DS,
TH
F, –
78°
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
5 m
in
3. H
OA
c, –
78° b
848
(+/–
)
R1
Me
Et
Et
R2
Me
H Me
I +
II
(76)
(89)
(42)
I:II
3:1
— 12:1
C5
OSi
(Pr-
i)3
O
N3
NaN
3, C
e(N
H4)
2(N
O3)
6, M
eCN
, –20
°(3
0)33
1
+ +
210
C6-
9
R1
R2
OT
MS
R1
NH
Ts
O
R2
PhI=
NT
s (0
.67
eq),
CuC
lO4
(3-6
mol
%),
MeC
N
173
R1
n-B
u
Ph Ph
R2
H H Me
Tem
p
0° –20° 0°
Tim
e
1.5
h
3 h
15 m
in
(53)
(76)
(58)
OO
TM
S
C6
EtO
2CN
=N
CO
2Et,
PhH
, 80°
, 8 h
(73)
243,
242
R1
OT
MS
R1
NH
CO
2Et
O
R2
1. E
tO2N
3, 1
00°
2. S
iO2
296
R2
R1
t-B
u
n-Pr
Ph
C6-
8
R2
H Et
H
(65)
(56)
(35)
C7
OL
iO
N=
NPh
PhN
2+ B
F 4– (
ia),
TH
F, –
78°
(72)
185
1. L
iHM
DS
(ia)
, TH
F, –
78°,
30 m
in
2.
,
–78°
, 20
h; to
rt
ON
CO
2Bu-
tE
tO2C
EtO
2C
R H Me
Ph
(21)
(31)
(15)
155
C8-
14
C8-
9
C8
OM
eN
HC
O2E
t
O1.
ClN
HC
O2E
t, C
HC
l 3, M
eOH
, –78
°2.
CrC
l 2
3. H
2SO
4
(59)
343
ON
CO
2R2
4-N
CC
6H4
i-Pr
1. L
DA
(ia
), T
HF,
–78
°, 1
h
2.
, –
78°;
to r
t, 2-
3 h
NH
O
OR
2Ph
O
154
R1
R1
H Me
(59)
(62)
% d
e
— 5
R2 =
OO
NN
HC
O2E
t
CO
2Et
Ph
H NC
O2B
u-t
R
O
Ph
R
O
Ph
R1
O
211
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
A. A
CY
CL
IC K
ET
ON
E E
NO
LA
TE
S (C
onti
nued
)
C8-
9
Ar
OT
MS
Ar
O
PhI=
NT
s, M
eCN
, rt
172
Ar
Ph 4-C
lC6H
4
4-O
2NC
6H4
4-M
eOC
6H4
2-M
eC6H
4
3-M
eC6H
4
4-M
eC6H
4
Ph
Tim
e
4.5
h
>24
h
6 h
3.5
h
18 h
11 h
1 h
—
(95)
(99)
(85)
(97)
(51)
(96)
(97)
(94)
Ph
OT
MS
C8
ON
CO
NE
t 2,
4-C
lC6H
4
155
TsN
H
H NPh
O
Et 2
N
OPh
O
HO
III
+I
+ I
I (—
), I
:II
= 1
:5
RR
R H H H H H H H Me
RPh
OT
MS
C8-
9
RPh
O
N
1. B
nO2C
N=
NC
O2B
n +
AgO
Tf
(ia)
,
C
H2C
l 2, –
45°,
30 m
in
2. H
F, T
HF
244
R H Me
(91)
(84)
Ph
O1.
BnO
2CN
=N
CO
2Bn
+ A
gOT
f +
(R
)-B
INA
P (i
a),
T
HF,
cos
olve
nt, –
45°,
time
2. H
F, T
HF
244
N
BnO
2CR M
e
Et
Cos
olve
nt
2,4,
6-M
e 3C
6H3
—
(95)
(93)
% e
e
86 59R
Ph
OT
MS
Ph
O
N
EtO
2C
N H
1. E
tO2C
N=
NC
O2E
t, C
H2C
l 2,
0-
5°, 3
h; r
t, 2
h
2. H
2O, r
t, 2
h
(56)
245
C8
Tim
e
18 h
3 h
1.
, C
H2C
l 2,
0-
5°, 3
h; r
t, 2
h
N
N Ph
N
OO
HN
N Ph
N
OO
PhO
(50)
245
EtO
H, H
2O (
3:1)
, rt,
44 h
2. H
2O, r
t, 2
h
EtO
2C
NH
CO
2Bn
BnO
2C
BnO
2CH
N
212
Ph
OT
MS
C8
(Sal
tmen
)Mn(
N),
CH
2Cl 2
, pyr
idin
e,
TFF
A, –
78° t
o rt
, 3-4
hPh
O
CF 3
CO
NH
(69)
471
1. L
i bas
e, E
t 2O
or
TH
F
2. M
e 2N
OM
s, –
30° t
o 0°
(52)
134
C9
Ph
OR
Ph
O
PhI=
NT
s, C
uPF 6
, lig
and
(5.5
-6 m
ol%
),
C
H2C
l 2, –
40°
NN
2,6-
Cl 2
C6H
4C
6H3C
l 2-2
,6
R Me
Me
Ac
Ac
TM
S
TM
S
TB
DM
S
TB
DM
S
Tim
e
3 h
3 h
5 h
5 h
5 h
4 h
3 h
16 h
(87)
(76)
(>95
)
(61)
(>95
)
(90)
(>95
)
(92)
% e
e
9 (R
)
10 (
S)
28 (
R)
52 (
R)
18 (
S)
16 (
S)
12 (
S)
13 (
S)
174
Lig
and
1 2 1 2 1 2 1 2N
OO
N
PhPh
1 2
NH
Ts
1. L
DA
(ia
), T
HF,
–78
°, 1
h
2.
,
ON
CO
NE
t 22-
NC
C6H
415
8
1. L
iHM
DS,
TH
F, –
78°,
30 m
in
2.
, –78
°, 30
min
153,
157
ON
CO
2Bu-
t4-
NC
C6H
4Ph
O
Ph
O
NH
CO
2Bu-
tPh
OO
H
C6H
4CN
-4+
(36)
(25)
Ph
O
NH
CO
NE
t 2
(60)
Ar
O
Ar
O
NH
Ts
4-M
eC6H
4SO
2N(C
l)N
a•x
H2O
,
L-p
rolin
e (2
mol
%),
MeC
N, r
t
0% e
e
Ar
Ph 4-FC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
3-C
F 3C
6H4
Tim
e
1 d
2 d
1 d
1 d
2 d
(83)
(82)
(74)
(71)
(83)
78
Ph
OPh
O
NM
e 2
–78°
, 3 h
; to
rt, 1
.5 h
213
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
A. A
CY
CL
IC K
ET
ON
E E
NO
LA
TE
S (C
onti
nued
)
(43)
849
EtO
2CN
=N
CO
2Et,
AlC
l 3, d
ioxa
ne, r
t, 48
hPh
O
PhN
OC
O2E
t
NH
CO
2Et
Ph
OR
Ph
O
NH
Ts
PhI=
NT
s, C
uPF 6
, 1 o
r 2
(str
uctu
res
on
pre
viou
s pa
ge, 6
mol
%),
CH
2Cl 2
, –40
°, 4
h
R TM
S
TB
DM
S
TM
S
TB
DM
S
(89)
(91)
(92)
(>95
)
174
Lig
and
1 1 2 2
% e
e
20 (
R)
27 (
R)
19 (
S)
21 (
S)
Ar
R
OT
MS
Ar
R
O
Cl 3
CC
H2O
2CN
N HN
OOO
252
Ar
Ph 4-M
eOC
6H4
Ph Ph Ph Ph 4-M
eOC
6H4
6-M
eO-2
-nap
hthy
l
4-M
eOC
6H4
4-M
eOC
6H4
R Me
Me
Et
CH
2CH
=C
H2
i-Pr
i-B
u
t-B
u
Me
Ph Bn
Tem
p
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–20°
–50°
–78°
(95)
(96)
(93)
(92)
(86)
(92)
(84)
(96)
(94)
(94)
% e
e
99 99 98 97 99 98 98 99 97
99
Tim
e
2 m
in
<1
min
30 m
in
2 h
3 h
2 h
6 h
1 m
in
13 h
12 h
Ph
OT
MS
TsN
(Cl)
Na
+ O
sO4
(0.0
04 e
q) +
(D
HQ
D) 2
PYR
(0.
008
eq)
(ia)
,
t-B
uOH
/H2O
(1:
1), r
t, 2
hPh
O
NH
Ts
(45)
, 85%
ee
342
C9-
13
C9
C9
ON
Cl 3
CC
H2O
2CN
=N
OO
CF 3
CH
2OH
(1
eq),
3 (
5 m
ol%
), T
HF
,
NC
u(O
Tf)
2
N
OO
t-B
uB
u-t
3
214
a The
ee
valu
es a
re th
ose
of th
e cr
ude
prod
ucts
; som
e ra
cem
izat
ion
occu
rred
on
silic
a ch
rom
atog
raph
y.b S
ome
equi
libra
tion
appe
ars
to o
ccur
eve
n at
–78
°.c T
he e
e va
lue
was
det
erm
ined
in a
deg
rada
tion
prod
uct.
OT
MS
PhI=
NT
s, M
eCN
O
NH
Ts
(70)
172
C15
215
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
C5
NN
NC
O2E
tN N
HC
O2E
t(1
2)
(10)
(8)
4-O
2NC
6H4S
O2O
NH
CO
2Et,
Et 3
N, C
H2C
l 2, r
t, 2
h
399
C5-
10O
Si(P
r-i)
3
R1
R2
R1
R2
OSi
(Pr-
i)3
N3
N3
nn
PhIO
(1.
5 eq
), T
MSN
3 (3
eq)
,
TE
MPO
a (0.
1 eq
), s
olve
nt, –
45°,
16 h
R1
H H —
OC
H2O
—
t-B
u
R2
H H H
n 0 1 1 1 1
Solv
ent
tolu
ene
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
(60)
sin
gle
isom
er
(91)
sin
gle
isom
er
(82)
3:1
mix
ture
of
isom
ers
(71)
sin
gle
isom
er
(67)
4:2
:1 m
ixtu
re o
f is
omer
s
850
C5
NO
O
NN
HC
H2C
O2M
e1.
MeO
2CC
H=
N2,
rt,
7 d
2. S
iO2,
H2O
(—)
207
(MeO
2C) 2
C=
N2,
Et 2
O, –
30°
207
NO
NN
HC
H(C
O2M
e)2
(65)
OO
EtO
2CC
O2E
t
O
NH
CO
2Et
++
216
OT
MS n
O
N1.
EtO
2CN
=N
CO
2Et,
Et 2
O, 0
-5°,
3 h;
rt,
2 h
2. H
2O, r
t, 2
h
245
n 0 1
(68)
(>72
)
C5-
6C
O2E
t
NH
CO
2Et
NYC
5
O
NH
PhNY
NPh
NH
CO
2Me
1. P
hN=
NC
O2M
e, E
t 2O
, dar
k,
rt
, 96
h (f
orm
s I)
2. H
Cl (
5% in
Me 2
CO
), 5
°, 48
h (
form
s II
)
III
401
Y — CH
2
NPh
O
I
(—)
(—)
(—)
(46)
II (70)
(71)
(40)
(71)
1. B
zN=
NC
O2M
e (1
eq)
, Et 2
O,
–3
0°, 3
h (
form
s I,
II,
and
III
)
2. H
Cl (
10%
in M
e 2C
O),
5°,
48 h
(f
orm
s IV
fro
m I
and
II;
V f
rom
III
)
NY
NY
EE
NY
EE
III
O
E
O
EE
E =
N(C
O2M
e)N
HB
z
IVV
Y — CH
2
NPh
O
I
(—)
(—)
(—)
(—)
II (—)
(—)
(—)
(40)
III
(—)
(—)
(—)
(—)
IV (20)
(30)
(32)
(40)
V (26)
(23)
(8)
(23)
401
N
N Ph
N
O, C
H2C
l 2, 0
-5°,
4 h;
O
O
nNN
PhH
N
O
n 0 1
(62)
(60)
245
n
rt,
over
nigh
t
III
++
+
O
217
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
NO
NO
NN
PhNH
HN
N
O
O
+Ph
N=
NC
ON
H2,
MeO
H, 0
°; 5
°, 2
h85
1
NH
CO
NH
2
Ph
C5
(25)
(25-
35)
1. A
r1 N=
NC
OA
r2 , sol
vent
, 0°,
time
1
2. 1
0% H
Cl,
Me 2
CO
, tem
p, ti
me
2
400
Ar1
Ph 4-O
2NC
6H4
Ph
Ar2
Ph Ph C6H
4NO
2-4
Solv
ent
Et 2
O
PhH
PhH
Tim
e 1
10-1
5 m
in
2 d
2 d
Tem
p
0° rt rt
Tim
e 2
few
min
24-4
8 h
24-4
8 h
(55)
(64)
(63)
O2S
NO
1. E
tO2C
N=
NC
O2E
t, Ph
H, r
t, 72
h
2. H
Cl,
EtO
H, H
2O, r
t, 24
h
(86)
248
O2S
NH
Bu-
n
O2S
n-B
uHN
NE
tO2C
N=
NC
OR
, MeC
N, r
eflu
x, 3
h25
0
R OE
t
Ph
(65)
(65)
YOT
MS
n1.
EtO
2CN
3, 1
00°,
15 h
2. S
iO2
296
Y CH
2
CH
2
CH
Bu-
t
n 0 1 1
(40)
(49)
(36)
C5-
9
YO nN
HC
O2E
t
O
NN
HC
OA
r2
Ar1
O2S
O
NN
HC
O2E
t
CO
2Et
NH
CO
R
CO
2Et
218
YOT
MS
YO
N3
NaN
3, C
e(N
H4)
2(N
O3)
6, M
eCN
, –20
°Y — O
(65)
(47)
331
C5
NM
eOO
NH
CO
2Et
1. E
tO2C
N3,
CH
2Cl 2
, ref
lux
2. h
ν, rt
, 4 h
(18)
, 24%
ee
303
OH N
, C
H2C
l 2, r
t, 30
min
(25)
, 18%
ee
303
MsN EtO
N3
NM
s
OE
t
NM
eOO
Me
, C
H2C
l 2, r
t, 30
min
MsN EtO
N3
NM
eOO
Me
H NN
Ms
OE
t
OH N
NM
e
OE
t
I (
18),
>95
% d
eII
20%
ee
303
NO
NH
CO
R
NSO
2
RC
ON
3, C
H2C
l 2, 3
0 m
in
R =
NC
OR
N(5
), 4
5% d
e(2
2), >
95%
de
304
1. 2. r
t ; I
con
vert
s sl
owly
into
II
+
C6
OM
eO
NH
CO
2CH
2CC
l 31.
ClN
HC
O2C
H2C
Cl 3
, CH
Cl 3
, MeO
H, –
78°
2. C
rCl 2
3. M
eON
a
(86)
343
OR
1O
NH
CO
2Et
4-R
2 C6H
4SO
2ON
HC
O2E
t, ad
dend
,
C
H2C
l 2, r
t
R1
TM
S
TM
S
O(C
H2)
2OT
MS
Tim
e
24 h
3.5
h
2 h
(51)
(67)
(33)
R2
Me
O2N
O2N
Add
end
Cs 2
CO
3
CaO
CaO
119
122
122
219
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
NR
O
NH
CO
2Et
4-O
2NC
6H4S
O2O
NH
CO
2Et,
Et 3
N,
C
H2C
l 2, r
t, 3
hN N
HC
O2E
t
R
III
(—)
R CO
2Bu-
t (S)
CH
2OT
MS
(S)
CH
2OM
e (S
)
CH
2OM
e (R
)
I
(14)
(12)
(18)
(21)
% e
e
5 52 77 50
121
C6
NR
1R
1O
NH
CO
2Et
N NH
CO
2Et
III
ArS
O2O
NH
CO
2Et,
adde
nd,
C
H2C
l 2, r
t
R2
R2
R1
H H H Me
H H
R2
H H H H Me
t-B
u
Add
end
— Cs 2
CO
3
Cs 2
CO
3
Et 3
N
Et 3
N
Et 3
N
Tim
e
2 h
24 h
24 h
3 h
3 h
3 h
I
(—)
(38)
(35)
(15)
(19)
(24)
II (—)
(0)
(34)
(0)
(0)
(0)
I:II
49:5
1
— — — — —
399
118
118
120
120
120
OO
TM
S
RR
O
NH
CH
O2E
t4-
O2N
C6H
4SO
2ON
HC
O2E
t, E
t 3N
,
C
H2C
l 2, r
t, 3
h
ON
CO
2Et
OT
MS
R
R
III
R Me
(R,R
)
MeO
CH
2 (R
,R)
Ph (
S,S)
BnO
CH
2 (S
,S)
I
(24)
(27)
(36)
(28)
% e
e
68 63 75 60
II (0)
(0)
(19)
(0)
% d
e
— — >95 —
397
Ar
4-O
2NC
6H4
4-M
eC6H
4
4-O
2NC
6H4
4-O
2NC
6H4
4-O
2NC
6H4
4-O
2NC
6H4
NN
CO
2Et
III
III
(0)
(tra
ce)
(31)
(0)
(0)
(0)
+
+
++
220
OR
O
NH
Ts
PhI=
NT
s (0
.67
eq),
MeC
N, –
20°,
1.5
h(6
4-65
)R
= T
MS,
TB
S17
2, 1
73
NN
2,6-
Cl 2
C6H
4C
6H3C
l 2-2
,6
OT
MS
PhI=
NT
s, C
uPF 6
, 1 (
cat)
,
CH
2Cl 2
, –40
°, 5
h
O
NH
Ts
(45)
, 19%
ee
174
OL
i
PhN
2+ B
F 4– (
ia),
TH
F, –
78°
O
N=
NPh
(10-
30)
com
plex
mix
ture
185
N
O
N-N
HA
r1.
ArN
2+ C
l– , con
c. H
Cl,
H2O
, –3°
to 0
°2.
NaO
Ac
to p
H 5
-6
852
Ar
Ph 2-O
2NC
6H4
4-O
2NC
6H4
2-M
eOC
6H4
4-M
eOC
6H4
2-M
eC6H
4
4-M
eC6H
4
(75)
(74)
(77)
(61)
(55)
(82)
(85)
C6-
10
RNY
RO
N1.
ArN
=N
CO
2Et,
0°2.
HC
l, H
2O, E
tOH
R H H H H t-B
u
Y — — O O —
Ar
Ph 4-O
2NC
6H4
Ph 4-O
2NC
6H4
Ph
(45)
(50)
(10)
(45)
(39)
853
NH
CO
2Et
Ar
1
221
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
C6-
10
RNY
RO
N
1. E
tO2C
N=
NC
OA
r, E
t 2O
, 0°,
48 h
2. H
Cl,
Me 2
CO
, H2O
, 48
h
R H H t-B
u
t-B
u
t-B
u
t-B
u
Y O O O O — —
Ar
Ph 4-O
2NC
6H4
Ph 4-O
2NC
6H4
Ph 4-O
2NC
6H4
(84)
b
(36)
b
(41)
b
(55)
b
(50)
b
(37)
b
853
R1
NO
R1
NO
N
R1
H H H t-B
u
t-B
u
t-B
u
R2
H H O2N
H H O2N
R3
H O2N
H H O2N
H
Solv
ent
Et 2
O
PhH
PhH
Et 2
O
PhH
PhH
(23)
(20)
(80)
(41)
(21)
(74)
4-(R
2 )C6H
4N=
NC
OC
6H4(
R3 )-
4,
sol
vent
, 0°,
48 h
854
NC
OC
6H4(
R3 )-
4
C6H
4(R
2 )-4
RO
RO
N
BzN
=N
Bz,
100
-110
°, 20
hR
= H
, t-B
u(2
0-25
)38
9
RNY
Y — CH
2
O O O
R H H H H t-B
u
Ar
Ph Ph Ph 4-M
eC6H
4
Ph
(79)
(87)
(80)
(81)
(74)
389,
855
ArC
ON
=N
CO
Ar,
PhH
, 7-8
°; r
t, 24
h
NH
CO
Ar
CO
2Et
NH
Bz
Bz
RO
NN
HC
OA
r
CO
Ar
222
O
EtO
2CN
=N
CO
2Et,
K2C
O3
or K
OA
c, 1
00°,
4 h
(28-
32)
390
RO
2CN
=N
CO
2R, 1
00°,
24 h
R Me
Et
(20)
(48)
246
390,
246
OT
MS
1. B
nO2C
N=
NC
O2B
n +
AgO
Tf
(ia)
,
C
H2C
l 2, 0
°, 30
min
2. H
F, T
HF
(91)
244
C6
O
NN
HC
O2E
t
CO
2Et
O
NN
HC
O2R
CO
2R
O
NN
HC
O2B
n
CO
2Bn
RO
2CN
=N
CO
2R, c
atal
yst (
x eq
)
O
E
R Et
Et
Et
i-Pr
t-B
u
Bn
Bn
Bn
Bn
x 0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Solv
ent
Cl(
CH
2)2C
l
Cl(
CH
2)2C
l
CH
2Cl 2
MeC
N
MeC
N
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
Tim
e
23 h
44 h
— 6 h
52 h
24 h
24 h
— 24 h
I
(67)
(—)
(46)
(—)
(—)
(—)
(56)
(—)
60)
% e
ec
84 84 — 59 59 — 61 6 90
O
EE
II (0)
(0)
— (10)
(10)
(—)
(—)
(—)
(—)
E =
N(C
O2R
)NH
CO
2R
228
228
229
228
228
229
229
229
229
Cat
alys
t
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
L-p
rolin
e
DL
-pro
line
L-p
rolin
e
L-a
zetid
inec
arbo
xylic
aci
d
L-a
zetid
inec
arbo
xylic
aci
d
Tem
p
rt rt rt rt rt rt rt 40°
rt
III
O
+
223
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
NY
R1
NY
R1
E
O
R1
ENY
EE
EE
O
III
III
IV
1. R
2 O2C
N=
NC
O2R
2 (1
eq),
sol
vent
,
te
mp,
tim
e
2. H
Cl R
1
H H H H Me
H H
R2
Me
Et
Me
Et
Et
Me
Et
Y — — O O O CH
2
CH
2
Solv
ent
Et 2
O
Et 2
O
Et 2
O
Et 2
O
PhH
Et 2
O
Et 2
O
Tem
p, T
ime
rt, 2
0 h
rt, 1
5 h
rt, 4
8 h
ice
bath
, the
n rt
, 24
h
refl
ux, 4
h
ice
bath
, the
n rt
, 15
h
ice
bath
, the
n rt
, 15
h
I (0)
(0)
(0)
(45)
(0)
(56)
(0)
II (53)
(38)
(67)
(18)
(79)
(35)
(86)
e
dd
III
(12)
(48)
(0)
(0)
(0)
(0)
(0)
IV (16)
(0)
(19)
(28)
(0)
(0)
(0)
E =
N(C
O2R
2 )NH
CO
2R2
246
C6-
7
++
+
1. P
hR2 N
MnM
e (i
a), T
HF,
rt,
time
2. t-
BuO
2CN
=N
CO
2Bu-
t
O
R1
O
E
O
E
R1
E
R1
H Me
Me
Me
Mee
R2
Me
Me
n-B
u
n-B
u
—
Tim
e
1 h
1 h
0.5
h
1 h
—
I +
II
(25)
(52)
(96)
(84)
(52)
I:II —
40:6
0
88:1
2
91:9
12:8
8
I
388
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
II
I dr — 3:1
3:1
3:1
3:1
O
Nt-
BuO
2CN
=N
CO
2Bu-
t, Ph
H, r
t, 24
h(6
6),
38%
ee
(S)
NM
eO
+
NH
CO
2Bu-
t
CO
2Bu-
t
224
O
NH
R1
O
NH
R1
N
O
N
N
ON
NH
CO
R2
R1 N
O
III
III
EtO
2CN
=N
CO
R2 , E
t 2O
, –20
°
R1
n-B
u
n-B
u
t-B
u
t-B
u
Ph Ph
R2
EtO
Ph EtO
Ph EtO
Ph
Tim
e
2 h
2 h
2 h
48 h
2 h
15 m
in
I
(—)
(—)
(90)
(—)
(90)
(25)
II (35)
(35)
(0)
(60)
(—)
(—)
III
(30)
(35)
(0)
(—)
(—)
(—)
856
NH
CO
R2
CO
2Et
CO
2Et
R1
CO
2Et
NH
CO
R2
+
+
C6
O
NY
O
NY
NR
1 N=
NC
OR
2 , PhH
Y — — O O O O
(100
)f
(58)
f
(100
)f
(100
)f
(100
)f
(95)
R2
OE
t
Ph OE
t
Ph C6H
4NO
2-4
C6H
4NO
2-4
R1
EtO
2C
EtO
2C
EtO
2C
EtO
2C
EtO
2C
4-O
2NC
6H4
249
249
249
249
249
857
Tem
p, T
ime
0°, 4
8-72
h; t
o rt
0°, 4
8-72
h; t
o rt
0°, 4
8-72
h; t
o rt
0°, 4
8-72
h; t
o rt
0°, 4
8-72
h; t
o rt
refl
ux
NH
CO
R2
R1
225
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
R4
R5
R2
OR
1
R3
R4
R5
R2
OR
3 N3
R1
SiM
e 3
Si(P
r-i)
3
Si(P
r-i)
3
Si(P
r-i)
3
Si(P
r-i)
3
Si(P
r-i)
3
Si(P
r-i)
3
R2
H H Me
H H H H
R3
H H H Me
H H t-B
u
R4
H H H H Me
—O
(CH
2)2O
—
H
R5
H H H H H H
(38)
(72)
(56)
g
(49)
(81)
g
(59)
(65)
g
NaN
3, C
e(N
H4)
2(N
O3)
6, M
eCN
, –20
°33
1
OO
OO
TB
S
C6-
10
C6
OO
OO
N3
NaN
3, C
e(N
H4)
2(N
O3)
6,
MeC
N, –
15°,
2 h;
to r
t
(70)
297
H
NR
O
NH
CO
2Et
1. E
tO2C
N3,
CH
2Cl 2
, ref
lux
2. h
ν3.
SiO
2
R CO
2Bu-
t
CH
2OT
MS
CH
2OM
e
(48)
(51)
(40)
% e
e
3 (S
)
35 (
S)
18 (
S)
302
302
302,
303
OO
O
OO
O
1. t-
BuO
2CN
3, 6
0°, 3
6 h
(for
ms
I)
For
II f
rom
I:
1. h
ν, M
eCN
, 0°,
30 m
in
2. A
cOH
, the
n n-
Bu 4
N+ F
–
297
N N CO
2Bu-
t
N
OT
BS
OT
BS
OO
O
O
NH
CO
2Bu-
t
I (
85)
II (
88)
OO
TM
S
RR
O
NH
CO
2Et
EtO
2CN
3, C
H2C
l 2, 1
20°,
4 h
III
397
OO
NH
CO
2Et
RR
+
226
R Me
(R,R
)
CH
2OM
e (R
,R)
CH
2OB
n (S
,S)
Ph (
S,S)
I
(—)
(—)
(10)
(—)
% e
e
— — 76 —
II (14)
(14)
(—)
(13)
% d
e
69 63 — 62
OR
NC
ON
3
S O2
, CH
2Cl 2
, hν,
7 h
NC
ON
S O2
HO
R TM
S
Me
(61)
(53)
% d
e
60 60
304
OT
MS
C6-
10
R
O R
NH
Ts
[TsN
(Cl)
Na
+ O
sO4
(0.0
04 e
q) +
cat
alys
t (0.
008
eq)]
(ia)
,
t-B
uOH
/H2O
(1:
1), r
t, 15
min
342
R H Me
t-B
u
Cat
alys
t
(DH
QD
) 2C
LB
(DH
QD
) 2PY
R
(DH
QD
) 2C
LB
(35)
(40)
(34)
% e
e
92 86 76
OSi
(Pr-
i)3
h
R
OR N
HT
s"T
sN=
Se=
NT
s"(i
a), C
H2C
l 2, 0
° to
rt, 3
h
nn
n 0 1 1
R Me
Me
Ph
(23)
(39)
(36)
348,
347
C6-
8O
Si(P
r-i)
3 h
R1
R2
R3
OSi
(Pr-
i)3
R1
R3
R4
"TsN
=Se
=N
Ts"
(ia)
, CH
2Cl 2
, 0° t
o rt
, 3 h
n
R1
Me
H Me
H H
n 0 1 1 1 1
R2
H H H H Me
R3
H H H Me
Me
NH
Ts
OSi
(Pr-
i)3
TsN
H I
(38)
(39)
(49)
(51)
(37)
II (0)
(11)
(0)
(0)
(0)
348,
347
III
n+
C6-
12
227
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
C7
OT
MS
O
NH
CO
2Bn
1. C
lNH
CO
2Bn,
MeO
H, C
HC
l 3, –
78°
2. C
rCl 2
3. M
eOH
(19)
343
OT
MS
ON
=N
PhPh
N2+
BF 4
– (ia
), T
HF,
–78
°(6
1)18
5
Me
N
O
Me
N
O
1. L
DA
, TH
F, –
78°,
45 m
in
2. E
tO2C
N=
NC
O2E
t, –7
8°, 3
0 m
in
(80)
391
N H
O
O
O
O
O
O
O
O
N1.
LD
A, T
HF,
hex
ane,
–78
°, 1
h
2. t-
BuO
2CN
=N
CO
2Bu-
t,
C
H2C
l 2, –
78°,
30 m
in
(66)
349
H
OO
O
O
O
O
O
NH
Ts
"TsN
=Se
=N
Ts"
, CH
2Cl 2
, rt,
2 h
(81)
349
OSi
(Pr-
i)3
H
NH
CO
2Et
CO
2Et
NH
CO
2Bu-
t
CO
2Bu-
t
O
TB
SO
O
OB
u-t
O
TB
SO
O
OB
u-t
NB
nO2C
N HC
O2B
n
1. L
DA
, TH
F, –
78°
2. B
nO2C
N=
NC
O2B
n, –
78°
(74)
217
O
TB
SO
O
OB
u-t
O
TB
SO
O
OB
u-t
NB
nO2C
N HC
O2B
n
1. L
DA
, TH
F, –
78°
2. B
nO2C
N=
NC
O2B
n, –
78°
(—)
217
O
TB
SO
O
OB
u-t
("su
bsta
ntia
l am
ount
s")
+
228
O
TB
SO
OB
u-t
O
O
TB
SO
OB
u-t
O
E1.
t-B
uOK
,i TH
F, –
78° t
o 0°
2. B
nO2C
N=
NC
O2B
n, –
78°,
10 m
in
(94)
E =
N(C
O2B
n)N
HC
O2B
n85
8, 2
17
PivO
PivO
ON R
NN
HO
1. L
DA
(ia
), T
HF,
–78
°, 1
h
2. R
N3,
–78
°, 30
min
; to
rt
859
R n-C
6H11
c-C
6H11
Bn
(93)
(69)
(67)
j
OSi
(Pr-
i)3
R1
R2
R3
OSi
(Pr-
i)3
R1
R2
R3
TsN
H
"TsN
=Se
=N
Ts"
345
R1
H Me
R2
H CH
2=C
(Me)
R3
Me
H
Solv
ent
— CH
2Cl 2
Tem
p
rt 0°
C7-
10
(51)
(62)
C8-
10
ClN
H2,
2,6
-(R
1 ) 2-4
-R2 C
6H2O
H, 1
00-1
40°;
rt
, ove
rnig
ht
R1
Me
Me
Et
R2
H Me
H
(55)
(51)
(33)
65
O– N
a+ R1
R1
R2
NH
OR
1
R2
R1
C9
OOT
MS
OO
NH
Ts
NN
2,6-
Cl 2
C6H
3C
6H3C
l 2-2
,6
PhI=
NT
s, C
uPF 6
, 1 (
cat)
, CH
2Cl 2
, –40
°, 3
h(1
6), 6
% e
e17
4
1
k
229
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
n
R
OT
MS
C9-
11
nO
N
R H Me
H H
n 1 1 2 3
Tem
p
–78°
–78°
–20°
–78°
(90)
(88)
(51)
(94)
% e
e
21 96 90 99
CO
2CH
2CC
l 3
H N
O N
O
O
ON
Cl 3
CC
H2O
2CN
=N
OO
CF 3
CH
2OH
(1
eq),
2 (
10 m
ol%
), T
HF
252
C10
OO
NH
CO
NE
t 2
O
NC
ON
Et 2
2-N
CC
6H4
1. n
-BuL
i, he
xane
, TH
F, 0
°, 30
min
2.
, –78
°, 3
h;
to
rt,
1.5
h
(59)
158
OT
MS
O
NH
Ts
PhI=
NT
s (0
.67
eq),
CuC
lO4
(3-6
mol
%),
M
eCN
, 0°,
90 m
in
(53)
173
R
O
R
O
R1.
LD
A, T
HF,
hex
ane,
–78
°2.
BnO
2CN
=N
CO
2Bn,
–78
°, 3
min
393,
392
R H MeO
(87)
(57)
N
,
NH
CO
2Bn
CO
2Bn
O
NB
n 2
O
NB
n 2
EO
H
E1.
LD
A, T
HF,
HM
PA, –
78°,
30 m
in
2. B
nO2C
N=
NC
O2B
n, –
78°,
1 h;
rt,
24 h
(45-
60)
(11-
28)
860
E =
N(C
O2B
n)N
HC
O2B
n
+
NC
u(O
Tf)
2
N
OO
t-B
uB
u-t
2
Tim
e
12 h
6 h
0.5
h
over
nigh
t
230
OT
MS
O
N1.
BnO
2CN
=N
CO
2Bn
+ A
gClO
4 +
(R
) -B
INA
P +
TH
F (i
a), –
45°,
5 h
2. H
F, T
HF
(82)
, 65%
ee
244
NN
O
NN
O
N
1. L
iHM
DS,
TH
F, –
78°,
30 m
in
2. B
nO2C
N=
NC
O2B
n, –
78°,
3 m
in
(52)
395,
396
OSi
(Pr-
i)3
N3
N3
Si(P
r-i)
3
PhIO
(1.
5 eq
), T
MSN
3 (3
eq)
, TE
MPO
a ,
CH
2Cl 2
, –45
°, 16
h
(41)
, 4:1
mix
ture
of
isom
ers
850
OT
MS
O
NH
Ts
TsN
(Cl)
Na,
(D
HQ
D) 2
CL
B (
0.00
8 eq
),
OsO
4 (0
.004
eq)
, t-B
uOH
/H2O
(1:
1), 1
0 m
in
(28)
, 76%
ee
342
OSi
(Pr-
i) 3
R
C10
-13
OSi
(Pr-
i)3
R
NH
Ts
TsN
=Se
=N
Ts,
CH
2Cl 2
, 0° t
o rt
, 40
h34
8, 3
46
R H CH
2=C
HC
H2
(71)
(59)
OT
MS
C10
(Sal
tmen
)Mn(
N),
CH
2Cl 2
, pyr
idin
e, T
FFA
,
–78
° to
rt, 3
-4 h
O
NH
CO
CF 3
(78)
471
OM
eO
Me
NH
CO
2Bn
CO
2Bn
BnO
2CN
HC
O2B
n
231
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
C10
OT
MS
R1
R1
O
NH
CO
CF 3
235
3
R1
H H MeO
MeO
R2
—(C
H2)
4—
Ph —(C
H2)
4—
Ph
Mn
NN
OO
N
R3
Ph Ph
(R,R
)
(S,S
)
(R,R
)
(S,S
)
R4
H t-B
u
H H
(83)
(74)
(58)
(55)
% e
e C
2
75 (
R)
65 (
S)
62 (
R)
41 (
S)
OT
MS
H
4 (y
eq)
, R2O
, pyr
idin
e, C
H2C
l 2, a
dden
d
x eq
O
NH
R
x 10 1
y 1 2
R Ts
CF 3
CO
Add
end
pyri
dine
N-o
xide
—
Tim
e
6 h
3 h
(76)
(58)
% e
e
48 79
352
Mn
NN
OO
NO
TM
S
1. 5
(2
eq)
+ p
yrid
ine
(ia)
, CH
2Cl 2
, –78
°2.
TFF
A, –
78° t
o rt
, 3-4
hO
NH
CO
CF 3
H(5
5)47
1
C11
O
OH
OSi
(Pr-
i)3
O
OH
O
N3
NaN
3, C
e(N
H4)
2(N
O3)
6, M
eCN
, –20
°(6
0)33
1
H
Mn
NN
OO
NR
2R
3
R4
R4
1. 3
(2.
2 eq
), p
yrid
ine,
CH
2Cl 2
, –78
°2.
TFF
A, –
78°,
6 h;
to r
t
3 4
Tem
p
0°–7
8° to
rt
5
232
C12
O
Ph
OPh N
Me 2
1. L
i bas
e, E
t 2O
or
TH
F
2. M
e 2N
OSO
2Me,
–30
° to
0°(5
0)13
4
OSi
(Pr-
i)3
Ph(i
-Pr)
3SiO
N3
N3
PhPh
IO, T
MSN
3 (3
eq)
, TE
MPO
a ,
CH
2Cl 2
, –45
°, 16
h
(59)
, 67%
de
850
N
O
O
CH
(OE
t)2
CH
(OE
t)2
N
O
O
CH
(OE
t)2
CH
(OE
t)2
N(C
O2B
n)N
HC
O2B
n
1. L
DA
, TH
F, –
78°
2. B
nO2C
N=
NC
O2B
n, –
78°,
3 m
in
(75)
394,
392
O
OA
cOO
R1
OH
OA
cH
OB
zO
C20
O
OA
cOO
R1
OH
OA
cH
OB
zO
1. K
OB
u-t (
ia),
TH
F, D
MPU
, –72
°, tim
e 1
2. R
2 O2C
N=
NC
O2R
2 , tem
p, ti
me
2
325
R1
SiE
t 3
CO
2Bu-
t
CO
2Bu-
t
R2
Bn
Bn
t-B
u
Tim
e 1
45 m
in
15 m
in
15 m
in
Tem
p
–65°
–68°
to –
50°
–68°
Tim
e 2
3 h
3 h
1 h
(76)
(65)
(72)
R2 O
2CN
HN C
O2R
2
O
OA
cOO
R
OH
OA
cH
OB
zO
O
OA
cOO
R
OH
OA
cH
OB
zO
1. K
OB
u-t (
ia),
TH
F, D
MPU
, –72
°, 10
min
2. T
sN3,
–72
° to
–50°
, 2 h
3. N
H4C
l, H
2Ol
325
N3
R SiE
t 3
CO
2Bu-
t
(92)
(85)
233
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 7
B. C
YC
LIC
KE
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
OA
cOO
SiE
t 3 OH
OA
cH
OB
zO
O
OA
cOO
SiE
t 3 OH
OA
cH
OB
zO
NaN
3, C
e(N
H4)
2(N
O3)
6, M
eCN
, 0°
N3
RO
325
R Me 3
Si
(i-P
r)3S
i
(95)
(55)
a TE
MPO
was
add
ed to
sup
pres
s fo
rmat
ion
of th
e β-
azid
o en
ol e
ther
by
a ra
dica
l mec
hani
sm.
b T
he y
ield
is th
at o
f th
e pr
oduc
t bef
ore
acid
hyd
roly
sis;
the
latte
r is
rep
orte
d to
pro
ceed
in a
lmos
t qua
ntita
tive
yiel
d.c
The
ee
valu
es a
re th
ose
of th
e cr
ude
prod
ucts
; som
e ra
cem
izat
ion
occu
rred
dur
ing
chro
mat
ogra
phy
on s
ilica
.d
Thi
s pr
oduc
t was
isol
ated
bef
ore
acid
trea
tmen
t. e
The
sub
stra
te w
as th
e lit
hium
eno
late
pre
pare
d w
ith L
DA
at 0
° to
roo
m te
mpe
ratu
re f
or o
ne h
our.
f The
pro
duct
is v
ery
resi
stan
t to
acid
hyd
roly
sis.
g The
pro
duct
is a
mix
ture
of
cis
and
tran
s is
omer
s.h T
MS
and
TB
DM
S en
ol e
ther
s ga
ve n
eglig
ible
am
ount
s of
pro
duct
s.i W
ith L
DA
, lith
ium
tetr
amet
hylp
iper
idid
e, o
r L
iHM
DS,
red
uctio
n of
the
keto
ne o
ccur
red.
j With
die
thyl
ket
one,
cyc
lohe
xano
ne, a
nd v
ario
us c
yclo
hexe
none
s, e
limin
atio
n of
wat
er o
ccur
red
to g
ive
the
tria
zole
der
ivat
ives
.k T
he in
term
edia
te a
min
atio
n pr
oduc
t rin
g ex
pand
s to
the
trop
olon
e pr
oduc
t und
er th
e re
actio
n co
nditi
ons.
l The
dia
zo c
ompo
unds
wer
e fo
rmed
whe
n th
e re
actio
ns w
ere
quen
ched
with
ace
tic a
cid.
Tim
e
1 h
1 d
C20
234
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 8
. IM
INE
AN
D H
YD
RA
ZO
NE
AN
ION
S
C5-
15
R1
R2
NR
1R
2
N
N
1. L
DA
, TH
F, 0
°, 4-
6 h
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 2
-5 m
in
R1
Et
n-Pr
—(C
H2)
4—
Ph Bn
R2
Me
Et
Me
Ph
(85)
(75)
(78)
(66)
(63)
327
R1
R2
N
NH
SO2C
6H2(
Pr-i
) 3-2
,4,6
1. L
DA
, TH
F, 0
°, 4-
6 h
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–
78°,
2-5
min
3. N
H4C
l, H
2O
R1
Et
n-Pr
—(C
H2)
4—
Ph Bn
R2
Me
Et
Me
Ph
(84)
(78)
(66)
(69)
(65)
327
C6
NR1
H a
R2
O1.
Uns
peci
fied
K b
ase,
DM
E,
C
H2C
l 2, r
t, 1.
5 h
2. 4
-O2N
C6H
4SO
2ON
HC
O2E
t (3
eq),
L
iOH
(10
eq)
, –70
°, 3
h; to
rt
3. H
3O+
NH
CO
2Et
O
NCO
2Et
123
R1
Ph Me
MeO
CH
2
I
(32)
(25)
(10)
% e
e
— 34 36
II — (10)
(5)
% e
e
— 8 9
III
R2
H Ph Bn
1. t-
BuO
2CN
=N
CO
2Bu-
t, to
luen
e,
re
flux
, 2-
5 h
2. H
O2C
CO
2H
O
NR
1
Ph Me
MeO
CH
2
R2
H Ph Bn
(45)
(30)
(—)
% e
e
— — 5
123
Me 2
NM
e 2N
Me 2
N
+
NH
CO
2Bu-
tt-
BuO
2C
NH
CO
2Bu-
t
CO
2Bu-
t
NH
CO
2Et
235
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 8
. IM
INE
AN
D H
YD
RA
ZO
NE
AN
ION
S (C
onti
nued
)
C6-
13
R1
R3
R2
Nt-
BuS
(O)
R1
R3
R2
O
N
R1
R3
R2
O
N
1. P
hMeN
MnM
e•4
LiB
r, T
HF,
rt,
1 h
2. R
4 O2C
N=
NC
O2R
4 , –30
°; r
t, 2.
5 h
3. H
Cl
388
R1
Me
n-Pr
n-C
5H11
n-C
5H11
Et
R2
Me
H Me
Me
Et
R3
Me
n-Pr
Me
Me
Bn
R4
Et
Et
t-B
u
t-B
u
t-B
u
* R R R,S
R R,S
*
III
I
(50)
(50)
(65)
(65)
(50)
I:II
90:1
0
— 98:2
98:2
99:1
I %
ee
40 65 — 68 —
C6
NR1
H a
R2
O1.
LD
A, H
MPA
, TH
F, 0
°, 90
min
2. t-
BuO
2CN
=N
CO
2Bu-
t, 0°
; to
rt, t
ime
3. H
O2C
CO
2H
N12
3
R1
Ph Me
MeO
CH
2
R2
H Ph Bn
Tim
e
3 h
4 h
8 h
(23)
(19)
(28)
% d
e
— 29 33
C9-
10
PhR
1
NR
2
PhR
1
NR
2 N
EtO
2CN
=N
CO
2Et,
hexa
ne, r
t, 2
h84
9
R1
Me
Me
Et
Et
Et
R2
Ph 4-M
eC6H
4
Ph 2-M
eC6H
4
4-M
eC6H
4
(59)
(—)
(—)
(—)
(—)
NH
CO
2Bu-
t
CO
2Bu-
t
R4 O
2C
NH
CO
2R4
NH
CO
2R4
R4 O
2C
+
NH
CO
2Et
EtO
2C
236
C10
N
MeO
R2
HR
1
N
MeO
R2
HR
1E
N
MeO
R2
HR
1E
III
E =
N(C
O2R
3 )NH
CO
2R3
R1
H H MeO
H
R2
Bn
i-B
u
i-Pr
Bn
1. L
DA
, TH
F, h
exan
e, –
45°,
1.25
h
2. R
3 O2C
N=
NC
O2R
3 , –78
°, 3
min
R3
t-B
u
t-B
u
t-B
u
Bn
I +
II
(86)
(82)
(—)
(65)
I %
de
72 76 38 40
405
R3 O
2CN
=N
CO
2R3 , T
HF
I +
II
R1
H H H H MeO
H
R2
Bn
i-B
u
i-Pr
t-B
u
i-Pr
Bn
R3
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
Bn
Tem
p
rt rt rt rt rt 0°
Tim
e
24 h
24 h
24 h
48 h
20 h
1 h
I +
II
(84)
(85)
(85)
(85)
(77)
(72)
I %
de
74 64 58 74 — 40
405
a Thi
s is
a c
orre
cted
str
uctu
re; p
erso
nal c
omm
unic
atio
n fr
om L
. Pel
laca
ni, D
ipar
timen
to d
i Chi
mic
a, U
nive
rsitá
"L
a Sa
pien
za",
Rom
e, I
taly
.
+
237
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 9
. CA
RB
OX
YL
IC A
CID
DIA
NIO
NS
C4-
101.
LD
A (
2.2
eq),
TH
F, 0
°2.
R2 N
H2,
–10
° to
rt, 1
h; r
t to
30°,
2-5
h
R1
MeS
CH
2CH
2
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-B
u
Ph Ph(C
H2)
2
R2
MeO
Cl
HO
SO2O
MeO
EtO
i-Pr
O
t-B
uO
BnO
2,4,
6-M
e 3C
6H2C
O2
2,4,
6-M
e 3-3
,5-(
O2N
)C6C
O2
MeO
MeO
MeO
(—)
(8)
(tra
ce)
(34)
(22)
(25)
(13)
(tra
ce)
(4)
(5)
(—)
(56)
(24)
861
79 79 79 79 79 79 79 79 79 861
79, 8
61
861
1. L
DA
(2.
2 eq
), T
HF,
HM
PA, –
15°,
15 m
in
2. M
eON
H2a
(3 e
q), t
emp,
tim
e
R1
MeS
CH
2CH
2
i-Pr
CH
2Pr-
i
Ph Bn
407
Tim
e
2 h;
ove
rnig
ht
2 h;
ove
rnig
ht
2 h;
ove
rnig
ht
2 h
2 h;
ove
rnig
ht
(9)b
(27)
(11)
b
(55)
(70b
C4-
11
R1
CO
2HR
1C
O2H
NH
2
R1
CO
2H
NH
2
Tem
p
–15°
to –
10°;
rt
–15°
to –
10°;
rt
–15°
to –
10°;
rt
–15°
to –
10°
–15°
to –
10°;
rt
238
HO
2CC
O2H
R
HO
2CC
O2H
R
1. n
-BuL
i (3
eq),
TH
F, h
exan
e, te
mp
1, ti
me
1
2. C
lNH
2, E
t 2O
, tem
p 2,
tim
e 2
668
R H PhS
Tim
e 2
—; 1
h
—; 4
5 m
in
(8)
(3.7
)
NH
2
C6
a Oth
er a
min
atin
g ag
ents
gav
e lo
wer
yie
lds.
b The
yie
ld w
as d
eter
min
ed b
y an
am
ino
acid
ana
lyze
r.
C7
1. L
DA
(2.
4 eq
), T
HF,
–10
°, 30
min
2. H
MPA
, –5°
, 30
min
3. 2
,4,6
-Me 3
C6H
2SO
2ON
H2,
–5°
; 0°,
3 h
(27)
668
1. n
-BuL
i (3.
3 eq
), T
HF,
hex
ane,
–5
0° to
0°,
1 h
2. C
lNH
2, E
t 2O
, –50
° to
–10°
; 0°,
45 m
in
+66
8
III
I +
II
(19)
, I:I
I =
1:3
NO
MeO
CO
2HN
O
MeO
CO
2H
H2N
(19)
115
1. n
-BuL
i (3.
3 eq
), T
HF,
hex
ane,
–5
0° to
0°,
1 h
2. C
lNH
2, E
t 2O
, –50
° to
–10°
; 0°,
45 m
in
HO
2CC
O2H
HO
2CC
O2H
HO
2CC
O2H
NH
2
HO
2CN
H2
CO
2HH
O2C
NH
2
CO
2H
Tem
p 1
–50°
; –40
°; 0
°–5
0° to
0°
Tim
e 1
—; 0
.5 h
; 1.5
h
1 h
Tem
p 2
–50°
; to
rt
–50°
to –
10°;
0°
239
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S
C2
(0)
932,
4-(O
2N) 2
C6H
3ON
H2,
TH
F
153,
157
1. L
iHM
DS,
TH
F, –
78°,
30 m
in
2.
, –7
8°, 3
0 m
in
O
NC
O2B
u-t
4-N
CC
6H4
1. B
ase
(ia)
, TH
F, –
78°,
1 h
2.
,
–78
°, 3
h; to
rt,
1.5
h
O
NC
ON
Et 2
Ar
Ar
2-C
lC6H
4
4-C
lC6H
4
4-C
lC6H
4
2,6-
Cl 2
C6H
3
2-N
CC
6H4
2-N
CC
6H4
4-N
CC
6H4
I (0)
(31)
(30)
(0)
(55)
(33)
(39)
Bas
e
LD
A
LD
A
NaH
MD
Sa
LD
A
LD
A
NaH
MD
S
LD
A
II (0)
(10)
(0)
(0)
(7)
(23)
(20)
158
158
155
158
158
155
158
R1
CO
2R2
R1
CO
2R2
HN
Oi-
Pr
1. L
DA
(ia
), T
HF,
–78
°, 1
h
2. 1
, –78
° to
rt, 2
-3 h
C2-
5
ON
4-N
CC
6H4
O
O
i-Pr
R1
H Me
Me
Me
i-Pr
R2
Bu-
t
Me
Et
t-B
u
Et
(60)
(57)
(52)
(51)
(49)
% d
e
— 5 8 7 17
154
O
OB
u-t
O
OB
u-t
OH N
t-B
uO2C
(35)
OB
u-t
OH N
Et 2
NC
OO
Bu-
t
O
Ar
OH
+
III
BrZ
nC
O2E
tH
2NC
O2E
t
1
240
C2-
81.
LiH
MD
S, T
HF,
–78
°
2.
, –78
°, 3-
7 h;
to r
t
ON
H
RC
O2E
t
NC
O2E
t
RH
NC
O2E
t
RH
R H n-Pr
PhI
II
151
I (0)
(0)
(25)
II (0)
(0)
(25)
+
OPh
OT
MS
PhI=
NT
s, M
eCN
(0)
172
OM
e
OM
eR
O2C
N=
NC
O2R
, PhH
, rt
251
C2
R Me
Et
Tim
e
2 d
shor
t
(74)
(52)
C3-
4
OT
MS
OR
3
R1
R2
CO
2R3
NH
CO
2Et
R2
R1
EtO
2CN
(OT
MS)
(TM
S), 9
0°, 5
d
R1
Me
H H
R2
Me
Me
Et
R3
Me
Et
Et
(25)
(70)
(48)
105
C3
CO
2Et
CO
2Et
NH
CO
NE
t 2O
NC
ON
Et 2
Ar
1. L
DA
2.(<
10)
155
R2C
HC
O2E
t
R2C
HC
O2E
t
HN
1. L
DA
(ia
), T
HF,
–78
°2.
2,
–78°
, 4 h
; to
rt
155
C3-
5
R H Me
(low
)
(<10
)
dr —
5:1
(S:R
)
TsH
NC
O2P
h
RO
2CN
CO
2Me
NH
CO
2R+
tw
o 2:
1 ad
duct
s (—
)
Na
CO
2Et
NC
O2E
t
Pn
EtO
2CN
H
PhN
=N
CO
2Et
(—)
159
Ar
= 2
-NC
C6H
4 or
4-N
CC
6H4
ON
4-C
lC6H
4
O
NM
e
OT
BD
PS
Ph
2
O
Me
N
Ph
OT
BD
PS
241
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S (C
onti
nued
)
C3
OL
i
OB
u-t
PhN
2+ B
F 4– (
ia),
TH
F, –
78°
PhN
=N
CO
2Bu-
t(1
0-30
) co
mpl
ex m
ixtu
re18
5
OM
e
OT
MS
RR
CO
2Me
NPh
NH
RC
O2M
e
NN
HPh
PhN
2+ B
F 4– ,
pyri
dine
, 0°,
2 h
R Me
2-th
ieny
l
Ph Bn
I +
II
(59)
(72)
(83)
(76)
I:II
100:
0
90:1
0
88:1
2
100:
0
197,
196
C3-
9
C3
CO
2Me
CO
2Me
EtO
2CN
NH
CO
2Et
EtO
2CN
=N
CO
2Et,
DA
BC
O, T
HF,
rt,
120
h40
3
R1
R2
OR
3
OM
e
1. B
nO2C
N=
NC
O2B
n +
AgO
Tf
(ia)
,
C
H2C
l 2, –
45°,
0.5
h
2. H
F, T
HF
R1
H Me
Me
R2
Meb
Me
Me
R3
TM
S
TM
S
TB
DM
S
(91)
(97)
(95)
244
C3-
4
OT
MS
OPh
NC
O2P
h
CO
2Bn
1. B
nO2C
N=
NC
O2B
n +
AgC
lO4
+
(
R)-
BIN
AP
(cat
) (i
a), t
olue
ne, T
HF,
–
45°,
3 h
2. H
F, T
HF
(73)
, 51%
ee
244
C3
C3-
9
OR
2R
1
OT
MS
R2 =
Ph
NM
e 2
HH
R1
Me
Et
i-Pr
n-B
u
i-B
u
Bn
(70)
(65)
(35)
(45)
(70)
(45)
% d
e
90 84 — 78 81 91
t-B
uO2C
N=
NC
O2B
u-t,
TiC
l 4, C
H2C
l 2, –
80°
411
(0)
+
R2
NN
HC
O2B
nR
1C
O2M
e
CO
2Bn
BnO
2CH
N
t-B
uO2C
HN
NC
O2R
2
CO
2Bu-
t
HR
1
242
O
OT
MS
SO2N
(C6H
11-c
) 2
C3-
13
O
OSO
2N(C
6H11
-c) 2
RE
H
R1.
Ti(
OPr
-i) 4
, CH
2Cl 2
, –78
°2.
t-B
uO2C
N=
NC
O2B
u-t,
–78°
, 5 m
in
3. T
iCl 4
4. S
ubst
rate
, –78
°, 1
h
R Me
Et
n-Pr
i-Pr
n-B
uc
i-B
u
n-C
6H11
Bn
1-ad
aman
tylm
ethy
l
(81)
(84)
(72)
(73)
(85)
(71)
(69)
(76)
(65)
% d
ed
93.8
96.2
96.4
95.2
92.6
93.2
96.0
96.4
64.0
412,
409
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
C3
R1
R2
OT
MS
OR
3
C3-
4
EtO
2CN
3R
2C
O2R
3
R1
NH
CO
2Et
R2
CO
2R3
R1
O
NT
MS
OE
tR
2C
ON
HC
O2E
t
R1
OR
3
III
III
R1
H H Me
Me
H H H
R2
Me
Me
Me
Me
Et
Et
Et
R3
Et
Et
Me
Me
Et
Et
Et
Con
ditio
ns
110°
, 30
min
hν, 0
°, 5
h
110°
, 30
min
hν, r
t, 5
h
110°
, 30
min
hν, 0
°, 5
h
CH
2Cl 2
, hν,
0°,
5 h
I (1)
(21)
(7)
(30)
(4)
(38)
(82)
II (42)
(1)
(9)
(1)
(42)
(2)
(—)
III
(4)
(4)
(35)
(7)
(13)
(4)
(—)
299
299
299
299
299
299
300
O
OSi
Me 2
RSO
2N(C
6H11
-c) 2
O
OSO
2N(C
6H11
-c) 2
NH
CO
2Et
HE
tO2C
N3,
pen
tane
, hν,
Ar
R Me
(1S,
2R)
Me
(1R
,2S)
t-B
u (1
S,2R
)
(14)
(38)
(77)
% d
e
50 (
S)
53 (
R)
70 (
S)
300
++
243
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S (C
onti
nued
)
OE
t
OT
MS
TM
SOC
O2E
t
TM
SO
N=
NPh
PhN
2+ B
F 4– , p
yrid
ine,
–35
°, 18
h(2
2), d
r >
95:5
415
OM
e
OT
MS
N=
NPhCO
2Me
PhN
2+ B
F 4– , p
yrid
ine,
0°,
2 h
(90)
196
C4-
10
OR
3
OT
MS
R1
R2
R1
N=
NA
r
R2
CO
2R3
ArN
2+ B
F 4– , p
yrid
ine,
0°,
2 h
197
R1
Me
Me
Me
Et
Ph
R2
Me
Me
Me
Ph Et
R3
Me
Me
Me
Ph Me
Ar
Ph 4-C
lC6H
4
4-M
eOC
6H4
Ph Ph
(90-
92)
(72)
(84)
(90)
(90)
C4
R1
CO
2R2
R1
CO
2R2
Nt-
BuO
2CN
HC
O2B
u-t
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
E
tOH
, rt
2
. Sub
stra
te, t
hen
PhSi
H3
3
. t-B
uO2C
N=
NC
O2B
u-t,
rt,
tim
e
Con
ditio
ns 2
: 1. C
atal
yst B
(se
e C
hart
1; 2
mol
%),
i-
PrO
H, 0
°
2. S
ubst
rate
, the
n Ph
SiH
3, 0
°
3. t
-BuO
2CN
=N
CO
2Bu-
t, 0°
, tim
e
R1
Me
Me
Me
Me
OOR
2
Et
Et
Con
ditio
ns
1 2 1 2
Tim
e
12 h
6 h
20 h
3 h
(66)
(88)
(75)
(74)
dr — — 78:2
61:9
215
215
215
215
PhE
t1
—(8
7)9:
179
6
C4-
9
EtO
2CC
O2E
tE
tO2C
CO
2Et
N1.
LiH
MD
S, T
HF,
–78
°, 15
min
2. R
O2C
N=
NC
O2R
, –78
°, 7
min
408
R (–)-
men
thyl
(–)-
born
yl
(–)-
isob
orny
l
(13)
(49)
(41)
2S:2
R
1:1
1:1
1:1
C4
NH
CO
2RR
O2C
244
R1
CO
2R2
OH
R1
CO
2R2
OH
N
1. L
DA
(x
eq),
TH
F, h
exan
e, te
mp
1, ti
me
1
2. t-
BuO
2CN
=N
CO
2Bu-
t, te
mp
2, ti
me
2
x 4.2
4.2
2.5
4.2 3 4.2
4.2
Tim
e 2
1 h
10 m
in
15 m
in
3 m
in
—
3 m
in
3 m
in
R1
Me
Me
Me
CF 3
Ph3C
OC
H2
n-C
6H13
c-C
6H11
R1
CO
2R2
OH
N
III
I +
II
(56)
(75)
(62-
66)
(62)
(48)
(74)
(81)
I:II
94:6
84:1
6
—
87:1
3
96:4
90:1
0
85:1
5
415
415
769
415,
862
769
415
415
R2
Et
Et
t-B
u
Et
t-B
u
Et
Et
C4-
9
RC
O2M
e
NB
n 2
RC
O2M
e
NB
n 2
E
RC
O2M
e
NB
n 2 E
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
+
III
R CH
2OB
n
Ph Bn
I +
II
(90)
(92)
(90)
I:II
94:6
93:7
97:3
863
C4-
10
1. K
HM
DS,
TH
F, to
luen
e, –
78°,
1 h
2. t-
BuO
2CN
=N
CO
2Bu-
t (so
lid),
–78
°, 1
h
R1
CO
2Me
OH
R1
CO
2Me
OH
N
1. M
eZnB
r, T
HF,
0°,
time
1
2. L
DA
(2
eq),
–78
°, 1
h
3. R
2 O2C
N=
NC
O2R
2 (2 e
q), –
78°,
time
3
C4-
8
R1
CH
(OM
e)2
Et
n-C
5H11
Tim
e 1
30 m
in
1 h
1 h
R2
Bn
t-B
u
t-B
u
Tim
e 3
—
10 m
in
10 m
in
(66)
(60)
(63)
% d
e
>95
>90
>90
421
416
416
Tem
p 1
–60°
; –20
°–6
0°; –
20°
–60°
to –
20°
–60°
; –20
°–4
0°; 0
°–6
0°; –
20°
–60°
; –20
°
Tim
e 1
—; 3
0 m
in
—; 3
0 m
in
30 m
in
—; 3
0 m
in
5 m
in; 3
0 m
in
—; 3
0 m
in
—; 3
0 m
in
Tem
p 2
–25°
–50°
–50°
–78°
–20°
to 0
°–7
8°–7
8°
+
NH
CO
2R2
R2 O
2C
NH
CO
2Bu-
tt-
BuO
2CN
HC
O2B
u-t
t-B
uO2C
245
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S (C
onti
nued
)
R1
Me
(MeO
) 2C
H
(i-P
r)3S
iOC
H2
Et
n-C
5H11
Ph
R2
Et
Me
Me
Me
Me
Et
R3
t-B
u
Bn
Bn
t-B
u
t-B
u
t-B
u
Tim
e 1
1 h
30 m
in
1 h
1 h
1 h
1 h
Tim
e 3
10 m
in
30 m
in
90 m
in
10 m
in
10 m
in
10 m
in
(63)
(66)
(52)
(58)
(66)
(69)
416
422
423
416
416
416
% d
e
>90
>95
>95
>90
>90
>90
C4-
9
R1
CO
2R2
OH
R1
CO
2R2
OH
N
1. M
eZnB
r, T
HF,
0°,
time
1
2. L
DA
(2
eq),
–78
°, 1
h
3. R
3 O2C
N=
NC
O2R
3 (2
eq)
, –78
°, tim
e 3
R1
CO
2R2
OH
R1
CO
2R2
OH
N1.
LD
A (
2 eq
), T
HF
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 3
min
R1
H H
R2
Me
Et
(58)
(57)
% d
e
(64)
(54)
864
C4
NH
CO
2R3
R3 O
2C
NH
CO
2Bu-
tt-
BuO
2C
OO
OR
OO
OR
N
1. L
DA
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°
R Me
n-C
5H11
(74)
(66)
% d
e
>90
>90
416
NH
CO
2Bu-
tt-
BuO
2C
OO
O
R3
R2 R1
OO
O
R3
R2 R1
N
1. B
ase,
TH
F, te
mp
1
2. t-
BuO
2CN
=N
CO
2Bu-
t, te
mp
2, ti
me
2
C4-
14
NH
CO
2Bu-
tt-
BuO
2C
246
R1
Me
Me
CF 3
CF 3
CF 3
CF 3
R2
H H H Me
n-B
u
Ph
R3
H (CH
2)2P
h
t-B
u
t-B
u
t-B
u
t-B
u
Tem
p 1
— — –75°
–75°
–75°
–75°
Tem
p 2
–78°
–78°
–75°
–75°
–75°
–75°
Bas
e
LD
A
LD
A
t-B
uLi
t-B
uLi
t-B
uLi
t-B
uLi
(90)
(95)
(97)
(86)
(80)
(71)
% d
e
90 99 >96
>96
>96
>96
416
864
865,
866
865
865
865
C4
NH
O OC
O2E
t
NH
O OC
O2E
t
Ni-
PrO
2C
NH
CO
2Pr-
i
1. U
nspe
cifi
ed b
ase
2. i-
PrO
2CN
=N
CO
2Pr-
i
(52)
sin
gle
isom
er86
7
HN
Ph
CO
2Et
EtO
2C
HN
Ph
CO
2Et
EtO
2C1.
LiH
MD
S (1
.2 e
q, ia
), T
HF,
HM
PA,
–7
8°; –
55°,
1 h
2. R
O2C
N=
NC
O2R
, –78
°, 4.
5 m
in
HN
Ph
CO
2Et
EtO
2C
N
III
R t-B
u
Bn
I +
II
(80)
(75)
I:II
e
30:1
18:1
N
426
Tim
e 2
—
3 m
in
40 m
in
40 m
in
40 m
in
40 m
in
+
OM
e
OM
e
R1
R2
C4-
6
R1
NH
CO
2Et
R2
CO
2Me
1. E
tO2C
N3
(0.5
eq)
, 35°
, tim
e
2. H
Cl,
Me 2
CO
, 30
min
R1
Me
—(C
H2)
4—R2
Me
(10)
(34)
298
Tim
e
14 d
4 d
RO
2CN
HC
O2R
RO
2CN
HC
O2R
247
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S (C
onti
nued
)
R1
CO
2Me
R2
NNN
R3
R1
R2
O
R2
R1
NH
2CO
NH
R3
For
I:
1. L
DA
, TH
F, –
78°
2. R
3 N3
(ia)
, tem
p, ti
me
For
II f
rom
I:
1. N
H4C
l, H
2O
2. N
H4O
H, T
HF,
rt,
12-2
4 h
R1
Me
Me
—
(CH
2)5—
—C
H2C
H=
CH
(CH
2)2—R
2
Me
Me
R3
PhSC
H2
1-ad
aman
tyl
PhSC
H2
PhSC
H2
Tem
p, T
ime
–78°
, 20
min
; to
–10°
, 90
min
–78°
; rt,
3 h
–78°
to –
20°,
45 m
in
–78°
; rt,
3 h
I
(85)
(70)
(—)
(—)
II (78)
(—)
(79)
(83)
274,
275
867a
274
274,
275
C4-
7
III
RC
O2E
t
SiM
e 2Ph
RC
O2E
t
SiM
e 2Ph
N3
1. L
DA
, –78
°2.
2,4
,6-(
i-Pr
)C6H
2SO
2N3,
–78
°, 2
h
R Me
Ph
(58)
(64)
% d
e
>96
>96
868
C4-
9
C4-
6
R1
R2
OM
e
OM
e
PhN
NN
OM
e OM
eR
1
R2
R1
NH
Ph
R2
CO
2Me
1. P
hN3
(0.6
eq)
, 70°
, 4 h
; 100
°, 20
h (
form
s I)
2. H
OA
c, M
e 2C
O, r
t, 24
h (
form
s II
)
III
291
R1
Me
—(C
H2)
4—R2
Me
I
(44)
(38)
II (11)
f
(7)f
CO
2Bu-
t
NB
nPh
CO
2Bu-
t
NB
nPh
N3
CO
2Bu-
t
NB
nPh
N2
1. L
DA
(ia
), T
HF,
–78
°, 1
h
2. R
eage
nt, –
78°,
2 m
in
Rea
gent
2,4,
6-(i
-Pr)
3C6H
2SO
2N3
Ph2P
(O)N
3
III
I
(32)
(0)
% d
e
>95 —
II (9)
(64)
338
+
C4
248
NH
O OC
O2E
t
NH
O OC
O2E
tN
3
NH
O OC
O2E
tN
3
1. M
HM
DS
(2 e
q), T
HF,
–78
°2.
ArS
O2N
3
III
M Li
Li
Na
Na
K K
Ar
4-M
eC6H
4
2,4,
6-(i
-Pr)
3C6H
2
4-M
eC6H
4
2,4,
6-(i
-Pr)
3C6H
2
4-M
eC6H
4
2,4,
6-(i
-Pr)
3C6H
2
I +
II
(90)
(80)
(86)
(89)
(84)
(84)
I:II
5:1
3:1
7:1
7:1
5:1
4:1
867
HN
Ph
CO
2Et
EtO
2C
HN
Ph
CO
2Et
EtO
2C
HN
Ph
CO
2Et
EtO
2C
N3
N3
+1.
KH
MD
S (1
.3 e
q, ia
), T
HF,
–78
°; –
55°,
1 h
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 6
min
(45)
426
(45)
CO
2Et
OH
CO
2Et
OH
1. L
DA
(2.
2 eq
), T
HF,
–78
° to
–20°
, 10
min
2. H
MPA
3. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 30
s
318
N3
(77)
, 64%
de
CO
2Et
1. N
aHM
DS,
TH
F, –
80°,
5 m
in
2. t-
BuO
2CN
=N
CO
2Bu-
t, –8
0°, 3
min
869
O
O
CO
2Et
O
O
N
(87)
CO
2Et
OH
MeOM
eO
CO
2Et
OH
MeOM
eO1.
LD
A (
4 eq
), T
HF,
–78
°2.
t-B
uO2C
N=
NC
O2B
u-t
(55)
, 89%
de
417
C5
+
NH
CO
2Bu-
tt-
BuO
2C
249
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S (C
onti
nued
)
CO
2Me
OH
MeOM
eOC
O2M
e
OH
MeOM
eO
N
1. L
DA
, MeZ
nBr
2. B
nO2C
N=
NC
O2B
n, –
78°
(66)
, >98
% d
e42
4
N H
H N
O
CO
2Bu-
i
C5
1. L
DA
, TH
F
2. B
nO2C
N=
NC
O2B
n, –
78°
870
O
O
CO
2Bu-
i
O
O
N
(61)
, 89%
de
OH
OH
CO
2Et
3N H
H N
O
CO
2Et
3N3
1. L
DA
, TH
F, –
30°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
HM
PA, –
78°
(70)
414
C6
OR
1
OR
2n-
Bu
PhI=
NT
s (0
.8 e
q), C
u(M
eCN
) 4C
lO4
(cat
)
R1
TM
S
TM
S
TB
DM
S
PhM
e 2Si
R2
Me
Ph Ph Ph
Tim
e
— — 1 h
—
(27)
(50)
(50)
(0)
173
O
SO2N
(C6H
11-c
) 2
O
OSO
2N(C
6H11
-c) 2
E
Bu
1. L
DA
, TH
F, –
78°,
adde
nd
2. t-
BuO
2CN
=N
CO
2Bu-
t
409
O
Bu
E =
N(C
O2B
u-t)
NH
CO
2Bu-
tO
OSO
2N(C
6H11
-c) 2
E
Bu
+
I (—
)II
(—
)A
dden
d
— HM
PA
I:II
81:1
9
27:7
3
OT
MS
OM
et-
Bu
t-B
uC
O2M
e
–78;
to r
t, 12
.5 h
NN
HC
O2B
u-t
CO
N(1
5)41
0N
CO
N=
NC
O2B
u-t,
TiC
l 4, C
H2C
l 2,
Tem
p
rt
–20°
–20° rt
n-B
uN
HT
s
CO
2R2
BnO
2CN
HC
O2B
n
BnO
2CN
HC
O2B
n
250
SiM
e 2Ph
SiM
e 2PhC
O2M
eC
O2M
e
N3
1. L
DA
, TH
F, –
78°
2. 2
,4,6
-Me 3
C6H
2SO
2N3,
–78
° to
rt, 1
0 h
(73)
, 95%
de
425
1. L
iHM
DS,
g T
HF,
–78
°2.
2,4
,6-M
e 3C
6H2S
O2N
3, –
78°
R Me
Et
MeO
CH
2
BnO
CH
2
(66)
, (71
)h
(74)
, (85
)h
(83)
, (65
h)h
(84)
, (61
)h
dr
>19
:1
>19
:1
>19
:1
>19
:1
784
TB
DPS
OC
O2M
e
OB
OM
TB
DPS
OC
O2M
e
BO
MO
N3
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-Me 3
C6H
2SO
2N3,
–78
°, 20
min
(70)
427
CO
2Me
NO
CO
2Bu-
t
CO
2Me
NO
CO
2Bu-
t
CO
2Me
NO
CO
2Bu-
tN
3N
3+
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-Me 3
C6H
2SO
2N3,
–78
°, 20
min
427
III
I +
II
(72)
, I:I
I=
6:1
C6
C6-
7
NC
O2M
e
O
O
Ph
Ph
R
N3
NC
O2M
e
O
O
Ph
Ph
R
EtO
2CC
O2E
tE
tO2C
CO
2Et
NH
2
1. B
ase
2. P
h 2P(
O)N
3
(0)
668
C7
i-Pr
O2C
CO
2Et
HO
2CC
O2H
NH
2
1. L
DA
, TH
F, –
40° t
o –5
°2.
ClN
H2,
Et 2
O, –
40°;
to r
t
3. H
Cl,
HO
Ac,
ref
lux,
2.4
h
HO
2CH
2C
O2H
NH
2
+
III
I +
II
(27)
, I:I
I =
1:2
668
O
OO
MeO
CO
2Me
O
OO
MeO
CO
2Me
R1
R1
R2
R2
R1
OH
H
R2
H OH
(56)
(59)
1. M
eZnB
r, T
HF,
0°,
30 m
in
2. L
DA
(2.
2 eq
), –
78°,
1 h
3. B
nO2C
N=
NC
O2B
n (2
eq)
, –78
°42
1R
4R
3
R3
H E
R4
E H
% d
e
>95
>95
E =
N(C
O2B
n)N
HC
O2B
n
251
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S (C
onti
nued
)
N R
TB
SO
CO
2Me
N R
TB
SO
N R
TB
SO
1. K
HM
DS,
tolu
ene,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-Me 3
C6H
2SO
2N3,
–78
°, 3
min
III
R Cbz
CO
2Me
I +
II
(>80
)
(91)
I:II
90:1
0
>95
:5
872
873
N R1
R2
CO
2Me
N R1
R2
N R1
R2
1. K
HM
DS,
tolu
ene,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-Me 3
C6H
2SO
2N3,
–78
°, 3-
5 m
in
R1
H Cbz
Cbz
R2
H H TB
S
III
I +
II
(—)
(>80
)
(>80
)
I:II
90:1
0
80:2
0
95:5
871
872,
454
872
C8
1. n
-BuL
i, T
HF,
–70
°2.
MeO
NH
2, –
20° t
o –1
5°, 2
h; r
t, ov
erni
ght
(0)
874
PhC
O2E
t
R1.
NaH
, –70
° to
0°, 2
5 m
in
2. 2
,4-(
O2N
) 2C
6H3O
NH
2, 0
°, 35
min
R H Me
(8)
(31)
93
Me 2
NO
SO2M
e, E
t 2O
or
TH
F, –
30° t
o 0°
(48)
134
C8-
9
PhO
TM
S
OE
t
C8
2,4-
(O2N
) 2C
6H3O
NH
2, T
HF,
ref
lux,
4 h
(0)
93H
2NC
O2E
t
PhNH
2
CO
2Et
Ph
R
PhC
O2E
t
NM
e 2
PhC
O2B
u-t
NH
2
PhC
O2E
t
Li
PhC
O2B
u-t
+
+
N3
CO
2Me
CO
2Me
N3
N3
CO
2Me
CO
2Me
N3
HH
HH
252
PhC
HO
ZnM
e
OPr
-i
PhC
O2P
r-i
NH
CO
2Bu-
tT
sON
(Li)
CO
2Bu-
t, T
HF,
–78
° to
0°, 3
h(3
5)12
6
C8
PhC
HO
Li
OE
t
PhC
O2E
t
NH
2
Ph2P
(O)O
NH
2, T
HF,
–20
°; r
t, 12
h (
45)
139
1. B
ase,
TH
F, –
78°,
15 m
in
2. (
4-M
eOC
6H4)
2P(O
)ON
H2,
tem
p, ti
me
3. A
c 2O
, Et 3
N
PhC
O2E
t
NH
Ac
106
PhC
O2E
t
R
PhC
O2E
t
RN
Me 2
1. L
i bas
e
2.
, T
HF,
–15
°
N MeP
OPh
ON
Me 2
R H Me
(50)
(56)
% e
e
23 21
147
PhC
O2B
u-t
NH
CO
NE
t 2O
NC
ON
Et 2
4-C
lC6H
4
1. N
aHM
DS
2.(t
race
)15
5
C8
C8-
9
Bas
e
LiH
MD
S
LD
A
NaH
MD
S
KO
Bu-
t
KO
Bu-
t
(22)
i
(31)
i
(46)
i
(67)
i
(76)
i
(25)
i
Tim
e
over
nigh
t
over
nigh
t
over
nigh
t
over
nigh
t
6 h;
—
over
nigh
t
PhC
HO
Li
OPr
-iT
sON
(Li)
CO
2Bu-
t, T
HF,
–78
° to
rt, 1
6 h
126
PhC
O2P
r-i
NH
2
(0)
+
t-B
uO2C
NH
2 (3
5)
O
PhC
O2E
t
PhC
O2B
u-t
Tem
p
–78°
to r
t
–78°
to r
t
–78°
to r
t
–78°
to r
t
–78°
; to
rt
–78°
to r
t
MeS
CO
2Me
MeS
CO
2Me
NH
2
1. L
DA
(ia
), T
HF,
HM
PA, –
78°,
3 h
2. 2
,4,6
-Me 3
C6H
2SO
2ON
H2,
–78
°, 2
h;
r
t, ov
erni
ght
(38)
117
(Me 2
N) 3
PN P(
NM
e 2) 2
t-B
uN
253
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S (C
onti
nued
)
1. L
iHM
DS
(ia)
, TH
F, –
78°,
15 m
in
2. R
O2C
N=
NC
O2R
, –78
°, 7
min
PhC
O2E
t
N
R (–)-
men
thyl
(–)-
born
yl
(–)-
isob
orny
l
(59)
(57)
(42)
22S
:2R
2:1
1:1
1:1
408
CO
2Me
OH
Et
CO
2Me
OH
Et
N
1. M
eZnB
r, T
HF,
0°,
1 h
2. L
DA
, TH
F, –
78°,
1 h
3. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
0 m
in
(53)
, >98
% d
e41
8
PhO
R1
OR
2R
3 O2C
N=
NC
O2R
3 , PhH
, rt
PhO
R1
OR
2R
3 O2C
NH
N CO
2R3
R1
Me
Me
—(C
H2)
2—R1
Me
Me
R3
Me
Et
Et
(42)
(86)
(42)
251
C9
PhC
O2B
nPh
CO
2Bn
N1.
LD
A, T
HF,
–78
°, 30
min
2. t-
BuO
2CN
=N
CO
2Bu-
t, C
H2C
l 2, –
70°
(60)
431,
848
BnOC
lC
O2M
e
OH
420
1. M
eZnB
r, 0
°2.
LD
A (
2 eq
), –
78°
3. t-
BuO
2CN
=N
CO
2Bu-
t (2
eq),
–78
°B
nOCl
CO
2Me
OH
N(6
5),
>98
% d
e
CO
2Bn
1. M
eZnB
r
2. L
DA
3. t-
BuO
2CN
=N
CO
2Bu-
t
875
MeO
OH
CO
2Bn
MeO
OH
N(5
0), >
95%
de
CO
2Me
OH
CO
2Me
OH
N
1. M
eZnB
r, T
HF,
0°,
1 h
2. L
DA
(2.
2 eq
), –
78°,
1 h
3. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 3
0 m
in
(66)
, >95
% d
e87
6, 4
19
C8
PhC
O2E
t
Tim
e
4 d
6 d
2 d
t-B
uO2C
NH
CO
2Bu-
t
t-B
uO2C
NH
CO
2Bu-
t
t-B
uO2C
NH
CO
2Bu-
t
t-B
uO2C
NH
CO
2Bu-
t
t-B
uO2C
NH
CO
2Bu-
t
RO
2CN
HC
O2R
BnO
BnO
254
CO
2Me
OH
CO
2Me
OH
N
1. M
eZnB
r, 0
°2.
LD
A (
2 eq
), –
78°
3. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°(5
5), >
98%
de
419
PhC
O2B
nPh
CO
2Bn
PhC
O2B
nPh
CO
2Bn
N3
N3
N3
N2
1. B
ase,
TH
F, –
78°,
30 m
in
2. A
rSO
2N3,
TH
F, –
78°,
time
III
III
Bas
e
LD
A
LD
A
LD
A
KH
MD
S
KH
MD
S
Ar
2,4,
6-(i
-Pr)
3C6H
2
4-M
eC6H
4
4-O
2NC
6H4
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
Tim
e
2 m
in
0.5
min
15 m
in
1 m
in
1 m
in j
I
(73)
(48)
(5)
(48)
(72)
II (—)
(—)
(—)
(20)
(8)
III
(1)
(24)
(68)
(—)
(—)
318
++
R1
R2
CO
2Et
413
R1
R2
CO
2Et
N3
1. L
DA
(ia
), T
HF,
–78
° to
–30°
, 1 h
2. H
MPA
, –78
°3.
2,4
,6-(
i-Pr
) 3C
6H2S
O2N
3, –
78°,
1 h
R1
H H H —C
H2O
CH
2—R2
H MeO
MO
MO
(60)
(58)
(51)
(52)
t-B
uO2C
NH
CO
2Bu-
t
PhC
O2B
u-t
NB
nPh
PhC
O2B
u-t
NB
nPh
PhC
O2B
u-t
NB
nPh
N3
1. B
ase
(ia)
, TH
F, –
78°,
1 h
2. 2
,4,6
-Me 3
C6H
2SO
2N3,
–78
°, 2
min
III
338
Bas
e
LD
A
KN
(Pr-
i)2
I
(57)
(64)
de 85 55
II (17)
(<2)
N2
+
255
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0A. E
STE
R E
NO
LA
TE
S (C
onti
nued
)
NB
ocO
CO
2Me
OR
NB
ocO
CO
2Me
OR
N3
R =
MO
M
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-Me 3
C6H
2SO
2N3,
–78
°, 20
min
(65)
427
C9
SO2N
R2
O
O
OT
BS
Ph
Ph
OT
BS
SO2N
R2
EtO
2CN
3, p
enta
ne, h
ν, 0
°, 8
h
SO2N
R2
O
O
NH
CO
2Et
Ph
SO2N
R2
O
O
NH
CO
2Et
Ph
III
301
I +
II
(84)
, I:I
I =
88:
12
EtO
2CN
3, p
enta
ne, h
ν, 0
°, 8
h30
1O
SO2N
R2
O
NH
CO
2Et
Ph
O
SO2N
R2
O
NH
CO
2Et
Ph
III
I +
II
(89)
, I:I
I =
77:
23
R =
c-C
6H11
R =
c-C
6H11
C10
OT
BS
OM
e
HPh
EtO
2CN
3, p
enta
ne, h
ν, 0
°, 8
h
III
I +
II
(61)
, I:I
I =
7:3
301
C12
FC
O2B
u-t
Bn
F
FC
O2B
u-t
Bn
NH
2
F
1. L
DA
, TH
F, –
78°,
30 m
in
2. P
h 2P(
O)O
NH
2, –
78°,
30 m
in
142
(20)
FC
O2B
u-t
Bn
N
F
1. L
DA
, TH
F, –
78°,
30 m
in
2. E
tO2C
N=
NC
O2E
, –78
°, 3
min
142
(44)
CO
2Me
Ph
NH
CO
2Et
CO
2Me
Ph
NH
CO
2Et
+
+ +
EtO
2C
NH
CO
2Et
C14
(34)
134
Me 2
NO
SO2M
e, E
t 2O
or
TH
F, –
30° t
o 0°
PhC
O2E
t
PhL
i
PhC
O2E
t
PhN
Me 2
256
CO
2Me
H2N
CO
2Me
1. K
OM
e, M
eOH
, PhH
2. 2
,4-(
O2N
) 2C
6H3O
NH
2, r
t, ov
erni
ght
(50
)
Me 2
NC
O2M
eN
aC
O2M
e
Me 2
NO
SO2M
e, E
t 2O
or
TH
F, –
30° t
o 0°
(54)
134
94,8
77
1. L
i bas
e
2. P
h 2P(
O)O
NH
2, T
HF,
–20
°; r
t, ov
erni
ght
139
CO
2RH
2NC
O2R
R Me
Bu-
t
(47)
(78)
1. N
aH, g
lym
e, r
t
2. T
sN3,
rt;
35-4
0°, 1
h
483
CO
2Me
N3
CO
2R
(57)
CO
2Me
OH
11
CO
2Me
OH
11
N
1. M
eZnB
r, 0
°, 1
h
2. L
DA
(2
eq),
–78
°, 1
h
3. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 2
h
(72)
, >95
% d
e87
8
C17
t-B
uO2C
NH
CO
2Bu-
t
a Am
ong
a ra
nge
of b
ases
(L
iHM
DS,
NaH
MD
S, K
HM
DS,
BuL
i, N
aH, a
nd N
aOB
u-t)
, NaH
MD
S ga
ve th
e hi
ghes
t yie
ld.
b The
sub
stra
te c
onta
ined
6%
of
the
Z is
omer
.c R
eact
ion
of th
e ki
netic
lith
ium
eno
late
with
t-B
uO2C
N=
NC
O2B
u-t g
ave
the
prod
uct i
n 62
% y
ield
and
62%
de.
d T
he v
alue
s ar
e fo
r th
e cr
ude
prod
ucts
.e
Use
of
LiH
MD
S w
ithou
t HM
PA, n
-BuL
i-L
iHM
DS,
or
KH
MD
S re
sulte
d in
I:I
I ra
tios
of 1
:1 to
2.5
:1.
f The
num
ber
is th
e ov
er-a
ll yi
eld
from
the
subs
trat
e ke
tene
ace
tal.
g With
KH
MD
S as
the
base
, the
yie
lds
wer
e hi
gher
but
the
dias
tere
omer
ic r
atio
s w
ere
low
er.
h The
yie
lds
are
from
the
two
dias
tere
omer
s of
the
subs
trat
e, r
espe
ctiv
ely.
i The
num
ber
is th
e pe
rcen
t con
vers
ion.
j The
eno
late
was
add
ed to
the
azid
e.
257
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
0B. T
HIO
EST
ER
EN
OL
AT
ES
OT
MS
SEt
1. t-
BuO
2CN
=N
CO
2Bu-
t + A
gOT
f (i
a),
C
H2C
l 2, 0
°, 3
h
2. H
F, T
HF
(92)
244
R1
YR
2
S
C2-
8
R1
YR
2
S
N
1. B
uLi (
ia),
TH
F, –
70°,
20 m
in
2. R
3 O2C
N=
NC
O2R
3 , –70°
‚ to
rt
R1
H H H H Ph
R2
Me
Me
Et
Et
Et
R3
Et
t-B
u
Et
Et
Et
Y S S O S S
(54)
(57)
(57)
(57)
(0)
477
RSE
t
SEt
RSE
t
SEt
MeO
2CN
=N
CO
2Me,
PhH
, rt,
time
N NH
CO
2Me
R H Ph
Tim
e
3 d
2 d
(56)
(90)
251
R1
STM
S
SMe
R2
1. t-
BuO
2CN
=N
CO
2Bu-
t, C
H2C
l 2, r
t, tim
e
2. H
OA
c, H
2O
R1
H Me
Me
n-C
5H11
Ph Bn
n-C
8H17
R2
H H Me
H H H H
Tim
e
3 h
1 h
3 h
1 h
2 h
1 h
1 h
(37)
(72)
(90)
(75)
(69)
(76)
(80)
253
C3
R3 O
2CN
HC
O2R
3
MeO
2C
R1
SMe
S
R2
N
t-B
uO2C
NH
CO
2Bu-
t
CO
SEt
Nt-
BuO
2CN
HC
O2B
u-t
258
OT
MS
SBu-
t25
2
ON
O
NN
Cl 3
CC
H2O
CO
O
1, 2
(0.
1 m
ol%
), T
HF,
CF 3
CH
2OH
,
–78
°, ov
erni
ght
ON
O
N H
O(8
9), 8
4% e
eN
CO
SBu-
t
Cl 3
CC
H2O
O
NC
u(O
Tf)
2
N
OO
t-B
uB
u-t
21
252
ON
O
N H
O
(85)
, 96%
ee
N
CO
SBu-
t
Cl 3
CC
H2O
O
1, 2
(0.
1 m
ol%
), T
HF,
CF 3
CH
2OH
,
–20
°, 20
h
OT
MS
SBu-
t
259
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
1. L
AC
TO
NE
EN
OL
AT
ES
OO
OR
OO
OR
N
1. L
DA
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°
R Me
n-C
5H11
(74)
(66)
% d
e
>90
>90
416
C5
OO
O
R3
R2 R1
OO
O
R3
R2 R1
N
1. B
ase,
TH
F, te
mp
1
2. t-
BuO
2CN
=N
CO
2Bu-
t,
te
mp
2, ti
me
2
R1
Me
Me
CF 3
CF 3
CF 3
CF 3
R2
H H H Me
n-B
u
Ph
R3
H (CH
2)2P
h
t-B
u
t-B
u
t-B
u
t-B
u
Tem
p 1
— — –75°
–75°
–75°
–75°
Tem
p 2
–78°
–78°
–75°
–75°
–75°
–75°
Bas
e
LD
A
LD
A
t-B
uLi
t-B
uLi
t-B
uLi
t-B
uLi
(90)
(95)
(97)
(86)
(80)
(71)
% d
e
90 99 >96
>96
>96
>96
416
864
865,
866
865
865
865
Boc
NH
OO
Boc
NH
N3
1. L
DA
(2.
1 eq
), T
HF,
–7
8° to
–20
°, 1
h
2. T
sN3,
–78
°, 1
h
3. T
MSC
l, –7
8° to
0°
(58)
, 100
% d
e87
9
OO
RN
H
OO
RN
HN
31.
LiH
MD
S (2
eq,
ia),
TH
F,
–7
8°, 3
0 m
in
2. T
sN3,
TH
F, –
78°,
5 m
in
(55)
a88
0
R =
Boc
or
Cbz
OO
C4
OO
TM
SE
tO2C
N(T
MS)
OT
MS,
90°
, 5 d
(44)
OO
NH
CO
2Et
105
Tim
e 2
—
3 m
in
40 m
in
40 m
in
40 m
in
40 m
in
t-B
uO2C
NH
CO
2Bu-
t
t-B
uO2C
NH
CO
2Bu-
t
260
O
O
OO
C7
O
O
OO
O
O
OO
N3
N3 N
3+
1. K
HM
DS
(ia)
, TH
F, –
80°;
to r
t, 50
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–80
°, 10
min
86%
ee
(79)
(6)
428
H
OO
1. B
ase,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
3SO
2N3
882
Bas
e
LiH
MD
S
NaH
MD
S
KH
MD
S
I
(45)
(20)
(26)
SMe
OO
SMe
OO
SMe
OO
SMe
N2
N3
N3
II (7)
(4)
(4)
III
(0)
(9)
(28)
III
III
OO
BnO
R1
R2
OB
n
C6
OO
BnO
R1
R2
OB
nO
O
BnO
R1
R2
OB
nN
3
N3
III
1. K
HM
DS,
tolu
ene,
TH
F, –
90°,
15 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
3SO
2N3,
–90
°, 2
min
R1
BnO
H
R2
H BnO
429,
881
I (0)
(50)
II (70)
(0)
C5
OO
RO
OO
RO
OO
RO
N3
N3
+
III
1. B
ase,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 30
min
3. Q
uenc
hing
age
nt
320
R TB
DPS
TB
DPS
Tr
Tr
Tr
Bas
e
LiH
MD
S
LiH
MD
S
LiH
MD
S
NaH
MD
S
KH
MD
S
Que
nchi
ng A
gent
HO
Ac
TM
SCl
HO
Ac
HO
Ac
HO
Ac
I
(33)
(53)
(37)
(25)
(11)
II (13)
(28)
(12)
(tra
ce)
(tra
ce)
+
++
261
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
1. L
AC
TO
NE
EN
OL
AT
ES
(Con
tinu
ed)
C9
O
O OT
BS
O
O OT
BS
N3
1. K
HM
DS
(ia)
, tol
uene
, TH
F,
–7
8°, 3
0 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1-
2 m
in
(63)
883
OO
i-B
u
OO
i-B
u
OO
i-B
uN
3N
3
+(6
9)(2
6)1.
LiH
MD
S (i
a), T
HF,
–78
°, 60
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 30
min
884
TB
DPS
OT
BD
PSO
TB
DPS
O
OO
Ar
ArC
H2O
OO
Ar
ArC
H2O
OO
Ar
ArC
H2O
N3
N2
C11
1. L
DA
2. 4
-O2N
C6H
4SO
2N3
3. p
H 7
buf
fer
1. L
iHM
DS,
TH
F, –
78°,
45 m
in
2. 4
-O2N
C6H
4SO
2N3,
–78
°, 10
min
3. Q
uenc
h co
nditi
ons
III
Ar
Ph 3,4-
(OC
H2O
)C6H
3
Que
nch
cond
ition
s
AcO
H, t
o rt
AcC
l, to
rt;
then
DM
AP,
TH
F, r
t, 16
h
I
(58)
(27)
II (0)
(40)
OO
Ph
BnO
OO
Ph
BnO
OO
Ph
BnO
N3
N2
326
(45)
(6)
O
O
OT
BS
O
O
OT
BS
N3
1. L
DA
(ia
), T
HF,
–78
°, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 15
min
(89)
885
326,
886
326
++
262
1. L
iHM
DS,
TH
F, –
78°,
45 m
in
2. 4
-O2N
C6H
4SO
2N3,
–78
°, 10
min
3. A
cCl,
–78°
; to
rt
OO
Ph
BnO
N
OO
Ph
BnO
N+
326
III
Ar
= C
6H4N
O2-
4
I +
II
(100
)b
R =
TB
DPS
1. n
-BuL
i, T
HF
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°(7
2)88
7
C18
OO
BnO
R
OB
nO
O
BnO
R
OB
nO
O
BnO
R
OB
nN
3
N2
1. K
HM
DS,
tolu
ene,
TH
F, –
78°,
15 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
429
(60)
(15)
O
BnO BnO
R =
C12
OB
n
a The
use
of
KH
MD
S or
2,4
,6-(
i-Pr
) 3C
6H2S
O2N
3 ga
ve lo
wer
yie
lds.
b The
rat
io I
:II
was
not
rep
orte
d. O
n tr
eatm
ent w
ith D
MA
P in
TH
F, th
e 3-
R a
zide
and
the
diaz
o co
mpo
und
wer
e ob
tain
ed in
48%
and
51%
yie
lds,
res
pect
ivel
y.
C22
N Boc
OPh Ph
Bn
O1.
KH
MD
S, T
HF,
–78
° to
rt
2. B
nO2C
N=
NC
O2B
n or
2,
4,6-
(i-P
r)3C
6H2S
O2N
3, –
78°,
30 m
inN B
oc
OPh Ph
O Bn
E =
N(C
O2B
n)N
HC
O2B
n or
N3
(0)
888
E
+
N Boc
HEt
OR
O
H
ON B
ocHE
t
OR
O
H
ON3
N
N
Ac
SO2A
rN
Ac
NA
r
OB
n
263
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
2. A
MID
E E
NO
LA
TE
S
C2
1. L
DA
(ia
), T
HF,
–78
°, 1
h
2. 1
, –78
°; to
rt,
2-3
h
ON
4-N
CC
6H4
O
Oi-
Pr
i-Pr
ON H
O(5
6)15
4, 1
58
N N
Y Y
1. L
DA
, TH
F, h
exan
e, –
78°,
40 m
in
2. R
2 O2C
N=
NC
O2R
2 , –78
°, 4
min
Y CH
2
O
R Me
Et
(41)
(18)
251
C3-
9
RN
O
O
RN
O
Ot-
BuO
2CN
H
1. n
-BuL
i, T
HF,
–78
°2.
CuC
N, –
78° t
o –5
°3.
TsO
N(L
i)C
O2B
u-t,
–78°
, 30
min
889
R Me
i-Pr
n-B
u
i-B
u
t-B
u
Ph Bn
(63)
(67)
(68)
(72)
(52)
(51)
(77)
% d
e
99 99 96 99 99 99 99
R1
CO
NM
e 2
C3-
5
R1
CO
NM
e 2
N40
8
R1
Me
i-Pr
(72)
(87)
% d
e
(0)
(0)
RC
ON
MeP
hR
CO
NM
ePh
NH
CO
2Bu-
t
1. L
DA
, TH
F, –
78°,
60 m
in
2. (
PhO
) 2P(
O)N
3, –
78°,
5 m
in
3. (
t-B
uO2C
) 2O
, –78
° to
rt, 6
h
C3-
8
336
R Me
Et
2-th
ieny
l
Ph
(74)
(76)
(70)
(80)
RO
2CN
=N
CO
2R, P
hH, r
t, 3
dN O
Y
NR
O2C
HN
CO
2R
1
NM
e 2
O
NM
e 2
O
NH
CO
2R2
R2 O
2C R
2 = is
obor
nyl
264
R1
O
R2
R1
O
R2
N
1. T
ris(
dipi
valo
ylm
etha
nato
)man
gane
se(I
II)
(
5 m
ol%
) +
i-Pr
OH
(ia
), 0
°2.
R3 O
2CN
=N
CO
2R3 , i
-PrO
H
3. P
h 3Si
H, 0
°, tim
e
890
R1
H Me
MeS
(CH
2)2
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
n-C
7H15
Ph(C
H2)
2
R2
III
III
III
I II III
III
III
III
III
III
R3
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
Et
i-Pr
t-B
u
t-B
u
t-B
u
t-B
u
Tim
e
1 h
1 h
1 h
1.5
h
1.5
h
1.5
h
1.5
h
1.5
h
1.5
h
1.5
h
1.5
h
(56)
(84)
(72)
(—)a
(78)
(—)a
(47)
(81)
(78)
(80)
(68)
dr 91:1
98:2
96:4
—
89:1
1
—
90:1
0
96:4
99:1
96:4
97:3
I R
2 =N
Ph
Ph
II R
2 =N
Ph
Ph
NS O
2
III
R2 =
C3-
11
OT
MS
NR
N
O
E
RN
O E
R Me
CH
2=C
H-C
H2
i-Pr
t-B
u
Tem
p
–78°
–20°
–20°
–20°
I
(96)
(73)
(65)
(0)
% e
e
(99)
(98)
(99)
(—)
II (0)
(18)
(23)
(80)
III
252
C3-
6
NH
CO
2R3
R3 O
2C
ON
O
NN
Cl 3
CC
H2O
CO
O
1, 2
(5
mol
%),
TH
F, C
F 3C
H2O
H
1
+
ON
O
N H
NC
l 3C
CH
2OC
O
OE
=
Tim
e
30 m
in
5 m
in
5 m
in
5 m
in
NC
u(O
Tf)
2
N
OO
t-B
uB
u-t
2
C5-
9
NS O
2
R
Ot-
Bu
NS O
2
R
Ot-
Bu
N3
1. N
aHM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
891
R CH
2CH
=C
H2
Bn
(96)
(85)
% d
e
>96 98
265
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
2. A
MID
E E
NO
LA
TE
S (C
onti
nued
)
C7
N S O2
O
R
R =
O
R
N3
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1-
2 m
in
(78)
776
Bn 2
N
O
Bn 2
N
O
PhN
R1 R
2
OPh
NR
1 R2
O
NH
2
1. B
ase
(x e
q), T
HF,
–70
°2.
MeO
NH
2, te
mp,
2 h
;
rt
, ove
rnig
ht
874
R1
H H Et
R2
H t-B
u
Et
Bas
e
n-B
uLi
LD
A
LD
A
x 2 2 1
(0)
(49)
(15)
Tem
p
–20°
to –
15°
–20°
to –
15°
–20°
C8
PhN
HR
OPh
NH
R
O
N
1. B
ase
(2 e
q), T
HF,
1 h
2. A
rN=
NA
r, –
78°,
5 m
in
R H Ph Ph
Ar
Ph Ph 2-C
lC6H
4
Bas
e
NaN
H2
NaN
H2
LD
A
(29)
(49)
(6)
212
R1
R2
R3
Me
N
O
Ph
OH
R1
R2
R3
Me
N
O
Ph
OH
1. L
DA
(2
eq),
TH
F, 7
8°, 1
h;
0°
, 15
min
; rt,
5 m
in
2. t-
BuO
2CN
=N
CO
2Bu-
t, –1
05°,
1 h;
to r
t
NR
1
MeO
—O
CH
2O—
MeO
BnO
R2
MeO
MeO
MeO
R3
H H MeO
BnO
(89)
(91)
(90)
(86)
% d
e
>90
>90
>90
>90
764,
892
,
765
NH
Ar
Ar
t-B
uO2C
NH
CO
2Bu-
t
a The
rea
ctio
n pr
oduc
ts w
ere
a co
mpl
ex m
ixtu
re.
C8-
12
S O2N
R
t-B
uO
S O2N
R
t-B
uO
N3
1. N
aHM
DS
(ia)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2N3,
–78
°, 2
min
R 3-T
MSO
C6H
4
1-na
phth
yl
(92)
(96)
893
266
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S
C3-
9
NO
OO
R1.
LD
A, T
HF,
–78
°, 20
min
2. 1
, C
H2C
l 2, –
78°,
7 m
in
R Me
Bn
(85)
a
(92)
a
219
HN N
Me
N N Me
O OR
N
O
O
O
N N
Me
N N Me
O O
NO
OO
R1
i-Pr
NO
OO
i-Pr
1. L
DA
, TH
F, –
78°,
15-4
0 m
in
2. R
2 O2C
N=
NC
O2R
2 , –78
°3.
HC
l, tim
e (q
uenc
h; f
or
R
2 = is
obor
nyl:
HO
Ac)
R1
Me
Me
Me
t-B
u
Bn
R2
t-B
u
Bn
(–)-
isob
orny
l
Bn
Bn
Tim
e
0 m
in
0 m
in
4 m
in
0 m
in
0 m
in
(92)
(91)
(56)
(85)
(90)
% d
e
— 80b
100
94b
88b
432
432,
408
408
432
432
NO
OO
i-Pr
C3
1. L
DA
, TH
F, –
78°,
40 m
in
2. R
O2C
N=
NC
O2R
, –78
°, 4
min
R Bn
(–)-
isob
orny
l
(—)
(88)
% d
e
80 100
408
1
E =
N(C
O2R
2 )NH
CO
2R2
R1
E
NO
OO
i-Pr
E
E =
N(C
O2R
)NH
CO
2R
267
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
NO
OO
R
Bn
1. L
DA
, TH
F, –
78°,
30 m
in
2. t-
BuO
2CN
=N
CO
2Bu-
t, C
H2C
l 2,
3
0-18
0 s
R Me
i-Pr
CH
2CH
=C
H2
t-B
u
MeO
2C(C
H2)
2c
Ph Bn
(92)
(95)
(94)
(96)
(51)
(96)
(91)
2S:2
R
98:2
98:2
98:2
>99
:1
>95
:5
97:3
97:3
431
C3-
8
NO
OO
R
Bn N
O
OO
R
Bn
1. B
ase,
TH
F, –
78°,
30 m
in
2. A
rSO
2N3,
–78
°, tim
e 2
3. A
cid,
tem
p 3,
tim
e 3
(que
nch)
C3-
9
N3
NO
OO
R
Bn
N2
+
III
R Me
i-Pr
CH
2CH
=C
H2
t-B
u
Ph Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ar
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
4-O
2NC
6H4
4-O
2NC
6H4
4-M
eC6H
4
4-M
eC6H
4
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
Bas
e
KH
MD
S
KH
MD
S
KH
MD
S
KH
MD
S
KH
MD
S
NaH
MD
S
KH
MD
S
KH
MD
S
KH
MD
S
LD
A
NaH
MD
S
KH
MD
S
Tim
e 2
1-2
min
1-2
min
1-2
min
1-2
min
1-2
min
1 h
— — —
1 m
in
30 s
1-2
min
I
(74)
d
(77)
d
(78)
d
(90)
d
(82)
d
(0)
(15)
(51)
(0)
(74)
(59)
(92)
I %
de
94 96 94 >98 82 — — — — — — 94
II (0)
(0)
(0)
(0)
(0)
(85)
(70)
(26)
(57)
(0)
(0)
(0)
318,
433
Aci
d
HO
Ac
HO
Ac
HO
Ac
HO
Ac
HO
Ac
TM
SCl
HO
Ac
HO
Ac
TFA
HO
Ac
HO
Ac
HO
Ac
Tem
p 3
— — — — — –78° — — —
–78°
to r
t
–78°
to r
t
–78°
to r
t
Tim
e 3
— — — — — 1 h
— — — 12 h
3 h
3 h
E
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
268
C3-
4
NO
OO
(EtO
) 2P(
O)
1. N
aHM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
T
HF
(pre
cool
ed),
–78
°, 30
min
894
n 1 2
(66)
(64)
de
>98
%
—
nN
O
OO
(EtO
) 2P(
O)
n N3
NO
OO
Bn
Ph2P
(S)
NO
OO
Bn
Ph2P
(S)
N3
1. K
HM
DS
(ia)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
458
(85)
, 94%
de
C3
1. N
aHM
DS,
TH
F, –
78°,
30 m
in
2. H
MPA
, –78
°, 15
min
3. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
h
I (
61)
+
II
(21
)89
5
C4
NO
OO
Bn
NO
OO
Bn
NO
OO
Bn
NO
OO
Bn
1. L
DA
, TH
F, –
78°,
30 m
in
2. H
MPA
, –78
°, 15
min
3. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
hE
E
E
I (
44)
+
+
II (
18)
(7)
(i-P
r)2N
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
895
269
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
C4-
5
C4
N
OO
R1
N
OO
N
OO
ER
1R
1E
+
E =
N(C
O2R
2 )NH
CO
2R2
R2 O
2CN
=N
CO
2R2 , c
atal
yst (
10 m
ol%
),
ClC
H2C
H2C
l
896
R1
H H H H H H Me
R2
Et
Et
Bn
Bn
Bn
Bn
Et
Cat
alys
t
A B A B B B B
Tem
p
rt rt 0° rt 0° 50°
50°
Tim
e
18 h
12 h
4 d
17 h
72 h
17 h
—
I +
II
(94)
(97)
(100
)
(100
)
(100
)
(100
)
(0)
I:II
73:2
7
74:2
6
89:1
1
70:3
0
69:3
1
63:2
7
—
ON
iO
OO
ON
iO
OO
Cat
alys
t A
III
O
O
Bn
OO
OO
Bn
Bn
NO
OO
Bn
RO
NO
OO
Bn
RO
R =
TB
DM
SE
(71)
, 80%
de
1. N
aHM
DS,
TH
F. –
78°,
30 m
in
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
h
895
Cat
alys
t B
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
NO
OO
Bn
1. L
DA
, TH
F, –
78°,
30 m
in
2. A
dden
d
3. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
h
NO
OO
Bn
E
NO
OO
Bn
E+
III
Add
end
— HM
PA (
1 eq
)
HM
PA (
5 eq
)
I
(51)
(61)
(52)
II (33)
(21)
(11)
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
895
270
NO
OO
R2
R1
Bn
NO
OO
R2
Bn
1. B
ase,
TH
F, te
mp
1, ti
me
1
2. t-
BuO
2CN
=N
CO
2Bu-
t,
te
mp
2, ti
me
2
R1
MeO
—O
(CH
2)2O
—R2
MeO
Bas
e
LD
A
NaH
MD
S
(93)
(67)
897
896,
898
NO
OO B
n
Br
1. L
DA
(ia
), T
HF,
–78
°, 45
min
2. t-
BuO
2CN
=N
CO
2Bu-
t, C
H2C
l 2,
–
78°,
15 m
in
NO
OO
Br
Bn
(84)
441
R1
NO
OO
Bn
NO
OO
Bn
1. L
DA
, TH
F, –
78°,
30 m
in
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 3
min
E
(86)
, 98%
de
895
C5
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
NO
OO
Br
Ph
NO
OO
PhN
Boc
N Boc
(70)
441
1. L
DA
(ia
), T
HF,
hex
ane,
–78
°, 80
min
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
h
3. D
MPU
, –78
° to
rt
E E
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
Tem
p 1
–78°
–80°
Tim
e 1
—
30 m
in
Tem
p 2
–78°
–80°
Tim
e 2
—
3 m
in
NO
OO B
n
Br
1. L
DA
(ia
), T
HF,
–78
°, 2
h
2. t-
BuO
2CN
=N
CO
2Bu-
t, C
H2C
l 2,
< –
70°,
15 m
in
3. B
u 4N
I (0
.15
eq),
e –78
°, 15
min
;
–
20°,
18 h
NO
OO B
n
(91)
, 94%
de
442,
441
NB
ocN B
oc
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
NO
OO B
n
Br
C5-
7
N
OO B
n
Br
O
N3
n 2 3 4
(60-
70)
(40)
f
(60-
70)
% d
e
95 95 95
443
nn
271
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
NO
OO
N3
Bn
R1
R2
NO
OO
N3
Bn
R1
R2
N3
1. K
HM
DS
(ia)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
TH
F,
–
78°,
1-2
min
(46)
, 82.
5% d
e89
9
mix
ture
of
R1 =
T; R
2 = H
and
R1 =
H a
nd R
2 = T
C5
PhSe
NO
OO B
n
PhSe
NO
OO B
n
1. K
HM
DS
(ia)
, tol
uene
, TH
F,
–
78°,
40 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
TH
F,
–
78°,
4 m
in
N3
(80)
456
NO
OO B
n
OT
BD
PS
MeN
CO
2Bu-
t
NO
OO B
n
OT
BD
PS
MeN
CO
2Bu-
tN
3
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1
min
(>40
), 9
3% d
e44
7
1. T
ris(
dipi
valo
ylm
etha
nato
)man
gane
se(I
II)
(
5 m
ol%
), i-
PrO
H (
ia),
0°
2. t-
BuO
2CN
=N
CO
2Bu-
t, i-
PrO
H
3. P
h 3Si
H, 0
°, 90
min
NOO
RR
O Ph
NOO
RR
O PhE
C6
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
R H Ph
(75)
(51)
dr
68:3
2
65:3
5
890,
900
NO
OO
R2
NO
OO
R2
N3
1. B
ase
(x e
q), T
HF,
–78
°2.
2,4
,6-(
i-Pr
) 3C
6H2S
O2N
3, –
78°,
time
R1
R1
C6-
7
NO
OO
R1
N2
+
III
272
R1
TB
DPS
O
BzO
Me
Me
R2
Ph Bn
Bn
Bn
Bas
e
KH
MD
S
NaH
MD
S
KH
MD
S
KH
MD
S
x — 1.2
1.2
1.5
I
(82)
(73)
(10)
(76)
II (—)
(—)
(20)
(—)
901,
902
903
437
437
C6
Tim
e
2 m
in
3 m
in
— —
TB
DPS
ON
O
OO B
n
TB
DPS
ON
O
OO B
n
*1.
KH
MD
S, T
HF,
–78
°, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
* C
onfi
g.
R S
(86)
(80)
904
NO
OO B
n
O
NO
OO B
n
O
N3
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
(84)
905
NO
OO i-
Pr
RN
O
OO i-
Pr
R
N3
1. K
HM
DS
(ia)
, TH
F, –
78°,
45 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
min
R CM
e 2C
O2B
n
1-ad
aman
tyl
(55)
(27)
906
C6-
12
C7
NO
OO
Bn
NO
OO
Bn
N3
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°(6
7)90
7
N3
NO
OO
Bn
NO
OO
Bn
N3
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°(—
)90
8
*
273
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
NO
OO
Bn
R1
NR
2 CO
2Bu-
t
NO
OO
Bn
R1
NR
2 CO
2Bu-
t
N3
R1 , R
2 = H
, H; H
, Me;
Me,
H; M
e,M
e
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°(4
0-50
), d
e >
95%
451
NO
OO
Ph
N N Bn
NO
OO
Ph
N N Bn
1. K
HM
DS
(ia)
, TH
F, –
50°,
45 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
° 2 m
inN
3
(72)
909
NO
OO
R1
N Cbz
H
R2
NO
OO
R1
N Cbz
H
R2
N3
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
min
R1
H Me
R2
H Ph
(—)
(68)
thre
o:er
ythr
o
1:2
100:
0
871
454
NO
Bn
O
N
O
O
Bn
OO
NO
Bn
O
N
O
O
Bn
OO
1. K
HM
DS
(2 e
q, ia
), T
HF,
–78
°, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
(2 e
q),
–
78°,
30 m
inN
3N
3
OO
N3
N3
+
(35)
(8)
910
NO
Bn
O
N
O
O
Bn
OO
1. K
HM
DS
(2 e
q, ia
), T
HF,
–78
°, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
(2 e
q),
–
78°,
30 m
in
N
O
O
Bn
O
2,4,
6-(i
-Pr)
3C6H
2SO
2NH
O
(—)
910
C7-
8
C7
H
274
NO
OO
Ar
C8-
12
NO
OO
Ar
t-B
uO2C
N=
NC
O2B
u-t,
TsN
HM
e (0
.2 e
q), C
H2C
l 2
RN
MgN
R
PhPh
(0.1
eq)
,
Ar
Ph 4-FC
6H4
4-M
eOC
6H4
3,4-
(OC
H2O
)C6H
3
3-C
l-4 -
MeO
C6H
3
2-na
phth
yl
Tem
p
–75°
–65°
–65°
–75°
–75°
–65°
Tim
e
48 h
48 h
48 h
72 h
60 h
48 h
(92)
d
(97)
d
(93)
d
(85)
d
(84)
d
(87)
d
% e
e
86 90 86 82 80 82
436
R =
SO
2C6H
3Me 2
-2,5
E
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
NO
OO
Bn
Ph
C8
1. B
ase
(x e
q)
2. t-
BuO
2CN
=N
CO
2Bu-
tN
O
OO
Bn
Ph(—
)
Bas
e
LiN
Et 2
NaO
Bu-
t
La(
OB
u-t)
3
1
x 1.0
0.05
0.05
0.05
436
2S:2
R
97:3
95:5
97:3
95:5
NO
OO
Ar
Bn
1. K
HM
DS,
TH
F, –
78°,
time
1
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, tim
e 2
NO
OO
Ar
Bn
N3
Ar
3,5-
(MeO
) 2C
6H3
4-(M
eO)-3
,5-(
i-Pr
O) 2
C6H
2
4-(M
eO)-
3,5-
(BnO
) 2C
6H2
Tim
e 1
—
30 m
in
30 m
in
Tim
e 2
—
5 m
in
2 m
in
(—)
(71)
(82)
% d
e
>60
>85 80
911
892,
912
913
E =
N(C
O2B
u-t)
NH
CO
2Bu-
tE
E =
N(C
O2B
u-t)
NC
O2B
u-t
NO
OO B
n
Ph
E
–Na+
1
275
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
NO
OO
Ar
Ph
NO
OO
Ar
PhN
3
C8-
9
1. K
HM
DS,
TH
F, –
78°,
time
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
Ar
3-B
nOC
6H4
3-B
nO-4
-MeO
C6H
3
4-C
lC6H
4CH
2
Tim
e
30 m
in
23 m
in
30 m
in
(30-
50)
(90)
(68)
% d
e
— 92 >98
914
915
914
C8
NO
OO B
n
O
O
H
HN
O
OO B
n
O
O
H
HN
O
OO B
n
O
O
H
HN
3N
3
+1.
KH
MD
S, T
HF,
–78
°, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
(26)
(26)
916
NO
OO
Ar
Bn
NO
OO
Ar
Bn
N3
1. K
HM
DS,
TH
F, –
78°,
time
1
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, tim
e 2
Ar
Ph 4-FC
6H4
4-C
lC6H
4
3,5-
(MeO
) 2C
6H3
3-T
BSO
-4-M
eOC
6H3
3,5-
(BnO
) 2C
6H3
3,5-
(BnO
) 2-4
-MeC
6H2
3-(C
H2=
CH
CH
2O)-
4-M
e-5-
BnO
C6H
2
3,5-
(3,4
-Cl 2
C6H
3CH
2)2C
6H3
Tim
e 1
15-4
5 m
in
30 m
in
20 m
in
15-4
5 m
in
20 m
in
—
15-4
5 m
in
15-4
5 m
in
15-4
5 m
in
Tim
e 2
1-2
min
2 m
in
5 m
in
1-2
min
5 m
in
—
1-2
min
1-2
min
1-2
min
(82)
(67)
(—)
(78)
(75)
(81)
(81)
(75)
(76)
% d
e
82 — — 80 — — 76 80 76
450
917
918
450
918
919
450
450
450
C8-
22
276
NO
OO B
n
NR
CO
2Bu-
t
NO
OO B
n
NR
CO
2Bu-
t
N3
1. K
HM
DS
(2 e
q), T
HF,
–78
°, 20
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1
min
R H Me
(54)
(51)
452
NO
OO B
n
R
C8-
11
NO
OO B
n
R
N3
1. K
HM
DS
(ia)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1-
2 m
in
R i-Pr
(R
,S)
Ph (
R)
Ph (
S)
920
(63)
(68)
(68)
NO
OO B
n
NO
OO B
n
R
N3
1. K
HM
DS
(ia)
, TH
F, –
78°,
60 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 60
min
R c-C
5H9
c-C
6H11
CH
2
c-C
8H15
t-B
u
(—)
(61)
(—)
(—)
(—)
R
C8-
13
438
C8
NO
OO B
nO
NB
oc
NO
OO B
nO
NB
ocN
3
1. K
HM
DS
(ia)
, TH
F, –
78°,
80 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
(m
ode
of a
dditi
on),
tem
p, ti
me
Mod
e of
Add
ition
azid
e so
lutio
n pr
ecoo
led
to –
78°
azid
e so
lutio
n pr
ecoo
led
to –
95°,
ins
ulat
ed c
annu
la
azid
e ad
ded
as a
sol
id
Tem
p
–78°
–95°
to –
100°
–78°
Tim
e
220
sec
220
sec
200
sec
(20-
40)
(45-
82)
(75-
95)
440
277
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
C9
NO
OO
Bn
NO
OO
Bn
1. L
i bas
e, C
uI, T
HF
2. T
osO
N(L
i)C
O2B
u-t,
–50°
, 1 h
NH
2
(55)
126
O
NC
O2B
u-t,
4-N
CC
6H4
1. L
iHM
DS
(ia)
, TH
F, –
78°,
60 m
in
2.
–
78°,
30 m
in
NO
OO
Bn
(33)
153,
157
14C
NO
OO B
n
Bn
14C
NO
OO B
n
Bn
1. L
DA
(ia
), T
HF,
–78
°, 1.
5 h
2. t-
BuO
2CN
=N
CO
2Bu-
t, T
HF,
–
78°,
30 m
in
(46)
921
NO
OO B
nA
cNH
NO
OO B
nA
cNH
1. K
HM
DS
(1.9
eq)
, TH
F, –
78°,
30 m
in
2. t-
BuO
2CN
=N
CO
2Bu-
t (ia
),
C
H2C
l 2, –
78°,
3 m
in
(53)
h45
3
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
E
EE
= N
(CO
2Bu-
t)N
HC
O2B
u-t
NH
t-B
uO2C
NO
OO B
n
Ar
NO
OO B
n
Ar
N3
1. K
HM
DS,
TH
F, –
78°,
time
1
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, tim
e 2
Ar
Ph 3-B
nOC
6H4
3-(i
-PrO
)-4-
MeO
C6H
3
Tim
e 1
15 m
in
—
30 m
in
Tim
e 2
2 m
in
—
2 m
in
(—)
(59)
(83)
dr — 95:5
—
444
774,
922
923
278
NO
OO i-
Pr
Ph
C6H
4Me-
4
C6H
4Me-
4
1. K
HM
DS
(ia)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
NO
OO i-
Pr
Ph
C6H
4Me-
4
C6H
4Me-
4
N3
924
(65)
, 92%
de
NO
OO
R2
O
OR
1O
R1
R1 O
OR
1N
O
OO
R2
E
1. B
ase,
TH
F, –
78°,
30 m
in
2. t-
BuO
2CN
=N
CO
2Bu-
t (ia
),
–
78°,
5 m
in*
R1
Me
Bn
Bn
Bn
Bn
* α β α β β
n 1 1 1 1 2
Bas
e
KH
MD
S
LD
A
KH
MD
S
KH
MD
S
LD
A
(61)
(70)
(72)
(68)
(65)
C10
-11
% d
e
92 73i
72 98 98
R2
i-Pr
H i-Pr
i-Pr
i-Pr
439
459
439
439
459
NO
OO B
n
C10
N
O
O
O
Bn
NO
OO B
n
N
O
O
O
Bn
N3
N3
1. K
HM
DS
(2.1
eq)
(ia
), T
HF,
–
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
(2.2
eq)
,
–
78°,
10 m
in
Con
nect
ion
1,3
1,4
(73)
(65)
% d
e
>95 60
925
NO
OO B
n
BnN
N CO
2Bn
NH
CO
2Bu-
t
NO
OO B
n
BnN
N CO
2Bn
NH
CO
2Bu-
tN3
1. K
HM
DS
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
(>62
), 5
2% d
e44
9
nn
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
279
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
NO
OO B
n
OO
OT
s
NO
OO B
n
OO
OT
s
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 3
min
N3
(73)
455
C11
NO
OO
PhPM
BO
TM
S
NO
OO
PhPM
BO
TM
S N3
1. K
HM
DS,
TH
F, –
100°
, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
(3 e
q),
–
78°,
5 m
in
(50)
, 80%
de
782
NO
OO Ph
N R
NO
OO Ph
N R
N3
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
min
R CO
2Bu-
t
2,4,
6-M
e 3C
6H2S
O2
(40)
(59)
928
929,
930
C12
NO
OO Ph
N R
NO
OO Ph
N R
N3
1. K
HM
DS
(ia)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
(ia)
, –78
°, 5
min
R =
2,4
,6-M
e 3C
6H2S
O2
(62)
929,
930
C10
C11
-13
NO
OO Ph
1. K
HM
DS,
TH
F
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°
R
Ar
NO
OO Ph
R
Ar
Ar
2,6-
Me 2
-4-M
eOC
6H2
2-na
phth
yl
R i-Pr
Me
(80)
(94)
% d
e
>95
>95
N3
926
927
280
NO
OO B
n
RO
NO
OO Ph
RO
1. K
HM
DS
(ia)
, TH
F, –
78°,
40 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
N3
R TB
S
Bn
(95)
(73)
931
O
NO
O
Bn
O
NO
O
Bn
E1.
LD
A, T
HF,
–78
°, 30
min
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
h
(82)
C13
438
NO
OO i-
PrN M
e
NO
OO i-
PrN M
e
N3
1. K
HM
DS
(ia)
, TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1
min
(70)
, >
98%
de
932
NO
OO B
n
TB
SO
R
NO
OO B
n
TB
SO
R
1. K
HM
DS
(1.2
eq,
ia),
TH
F, –
78°,
40 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
N3
(35)
457
C15
NO
OO
Ph
Ph
Ph
NO
OO
Ph
Ph
Ph
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°N
3
(94)
933
R =
(t-
BuO
) 2P(
O)
NO
OO Ph
MeO
i-Pr
NO
OO Ph
MeO
i-Pr
N3
1. K
HM
DS
(ia)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 15
min
(85)
, >
90 d
e43
4
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
NO
OO
Ph
Ph
NO
OO
Ph
Ph
Ph1.
KH
MD
S, T
HF,
–78
°2.
2,4
,6-(
i-Pr
) 3C
6H2S
O2N
3, –
78°
N3
(—)
933
Ph
R =
P(O
)(O
Bu-
t)2
281
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
NO
OO i-
Pr
N
N
OE
t
OE
t
i-Pr
NO
OO i-
Pr
N
N
OE
t
OE
t
i-Pr
N3
1. K
HM
DS
(ia)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
(84)
934
NO
OO
Ph
NO
OO
Ph
C17
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°N
3
(85)
935
C15
NO
OO
Ph
NO
OO
Ph
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°N
3
(—)
935
NO
OO B
n
NH N
NO
OO B
n
NH N
N3
O
N3
NH
2
1. K
HM
DS
(2.3
eq)
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 3
min
3. H
OA
c, –
78° t
o rt
, ove
rnig
ht
4. N
aHC
O3,
H2O
+44
5, 4
46
(34)
(24)
NO
OO B
n
R
Cl
R
R
NO
OO B
n
R
Cl
R
R
R =
BnO
N3
1. K
HM
DS,
TH
F, –
78°,
15-4
5 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1-
2 m
in
(77)
, >90
% d
e45
0
55
5
55
282
C17
NO
OO B
nO
NO
OO B
nO
N3
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
(85)
448
OBoc
N
OBoc
N
NO
Bn
(83-
86),
d 95%
deg
OO
O
MeO
CO
2Bu-
t
C18
NO
Bn
OO
O
MeO
CO
2Bu-
tN3
1. K
HM
DS,
TH
F, –
78°,
15 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 2
min
444
NO
Bn
(85)
OO
1. K
HM
DS
(2.2
eq)
, TH
F, –
78°,
15 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1-
2 m
in
433
MeO
O
CO
2Bn
NH
Boc
NO
Bn
OO
MeO
O
CO
2Bn
NH
Boc
N3
NO
Bn
OO
BnO
OB
n
BnO
R
NH
Boc
NO
Bn
OO
BnO
OB
n
BnO
R
NH
Boc
R =
TM
S(C
H2)
2O2C
1:1
mix
ture
of
2 at
ropi
som
ers
N3
1. K
HM
DS
(2.2
eq)
, TH
F, –
78°,
15 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1
min
(60)
, 86%
dej
450
283
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
3. N
-AC
YL
OX
AZ
OL
IDIN
ON
E E
NO
LA
TE
S (C
onti
nued
)
NO
PhOO
R
1. K
HM
DS
(1 e
q), N
aH (
1 eq
), T
HF,
–
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 15
min
NO
PhOO
R
R t-B
u
Ph
(54)
(73)
435,
936
NO
PhOO
R
1. K
HM
DS
(1 e
q), N
aH (
1 eq
), T
HF,
–
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 15
min
NO
PhOO
R
R t-B
u
Ph
(51)
(60)
435,
936
N3
N3
ME
MO
ME
MO
ME
MO
ME
MO
C19
-21
NO
Bn
OO
BnO
O
O CN
NO
Bn
OO
BnO
O
O CN
N3
1. K
HM
DS
(2.2
eq)
, TH
F, –
78°,
15
-45
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1-
2 m
in
(61)
, 84%
de
450
C24
284
a The
chi
ral a
uxili
ary
coul
d no
t be
clea
ved
to g
ive
the
hydr
azin
e de
riva
tive.
b Rea
gent
s w
here
R1 =
Me
or E
t gav
e pr
oduc
ts w
ith p
oore
r dr
val
ues.
c The
trea
tmen
t tim
e w
ith L
DA
was
5 m
inut
es.
d The
num
ber
is th
e yi
eld
of p
ure
maj
or p
rodu
ct.
e Add
ition
of
Bu 4
NI
prev
ents
the
reve
rse
reac
tion
of th
e in
itial
ly f
orm
ed a
dduc
t; oc
curr
ence
of
a re
vers
e re
actio
n ha
s be
en d
ispu
ted
(Ref
. 441
).f E
xces
s 2,
4,6-
(i-P
r)3C
6H2S
O2N
3 w
as a
dded
ear
ly in
the
enol
izat
ion
step
to p
artia
lly c
ount
erac
t cyc
lizat
ion
of th
e en
olat
e.g T
he v
alue
s ar
e th
ose
of th
e cr
ude
prod
uct.
h The
pro
duct
epi
mer
ized
on
atte
mpt
ed r
emov
al o
f th
e ch
iral
aux
iliar
y.i N
o co
nfig
urat
ions
wer
e as
sign
ed to
the
two
dias
tere
omer
s.j T
he n
umbe
rs a
re th
e fo
r th
e tw
o at
ropi
som
ers.
285
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
4. L
AC
TA
M E
NO
LA
TE
S
C3-
4
MeN
O
R
MeN
O
R1.
LD
A, E
t 2O
, –70
°2.
TsN
3, –
78° t
o –5
0°, 1
h
3. T
MSC
l, re
flux
, 6 h
N3
R EtS
Me
(52)
(39)
339
TB
SNO
PhS
H
TB
SNO
PhS
H
1. L
DA
2. 2
-C10
H7S
O2N
3
(66)
780
TB
SNO
PhS
H
TB
SNO
PhS
HN
31.
LD
A
2. 2
-C10
H7S
O2N
3
3. T
MSC
l
(56)
780
N3
C4-
10
NN
O
R
Me
Bn
NN
OM
e
Bn
N R1.
LD
A, T
HF,
hex
ane,
–78
°, 2
h
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 6
h; r
t, 3-
6 h
R Me
Et
Bn
(45)
(67)
(73)
% d
e
>98
>98
>98
460
NNO
R
Me Bn
NNO
Me
Bn
N R1.
LD
A, T
HF,
hex
ane,
–78
°, 2
h
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 6
h; r
t, 3-
6 h
R Me
Et
Bn
(41)
(37)
(25)
% d
e
>98
>98
>98
460
RN
OR
NON
31.
LD
A, T
HF,
–78
°, 2
h
2. T
sN3,
–78
°, 1
h
3. T
MSC
l, rt
. 1 h
R =
C(C
O2M
e)2C
6H4O
Bn-
4
(76)
777
MeN
OM
eNO
1. L
DA
, Et 2
O, –
70°
2. T
MSN
3, –
78° t
o –5
0°, 1
h
3. T
MSC
l, re
flux
, 6 h
TM
S
339
(64)
C4
C3
CO
2Bu-
t
NH
CO
2Bu-
t
CO
2Bu-
t
NH
CO
2Bu-
t
286
Nt-
BuO
2CO
H
C7
1. L
iHM
DS,
TH
F, –
78°
2. P
h 2P(
O)O
NH
2
Nt-
BuO
2CO
H
NH
2(4
7)14
3
C9
N Boc
ON B
oc
ON3
1. K
HM
DS
(ia)
, TH
F, –
78°,
80 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3
(pre
cool
ed to
–9
5°, i
nsul
ated
can
nula
)
(36)
, 17%
de
440
N
S
MeO
2CC
O2M
eON
S
MeO
2CC
O2M
eON3
H1.
LiH
MD
S, T
HF,
–70
°, 4
h
2. T
sN3,
–70
°3.
TM
SCl,
to r
t
(68)
339
N
O
H
TB
DPS
O
N
O
H
TB
DPS
O
1. L
DA
(ia
), T
HF,
–78
°, 20
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 3
hN
3
(65)
, 72%
de
462
NH
TB
DPS
OO
NH
TB
DPS
OO
1. L
DA
(ia
), T
HF,
–78
°, 20
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
a –78
°, 10
min
N3
NH
TB
DPS
OO
N2
(20)
(64)
461
Boc
OB
ocO
C8
1. K
OB
u-t,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
TH
F, –
78°,
30 m
inN
R N
Cl
O
N
R N
Cl
O
N3
R Me
PMB
(57)
(92)
938
+
C5
Cbz
NO
t-B
uO2C
Cbz
NO
t-B
uO2C
Cbz
NO
t-B
uO2C
EE
1. L
iHM
DS,
–78
°2.
t-B
uO2C
N=
NC
O2B
u-t
I+
II
I +
II
(76)
, I:I
I =
10:
1
937
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
287
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
4. L
AC
TA
M E
NO
LA
TE
S (C
onti
nued
)
N
O
H
TB
DPS
O
N
O
H
TB
DPS
O
1. t-
BuL
i, T
HF,
–78
°, 1
h
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 3
h
(63)
940
OM
e
N3
OM
eC
10
C9
NM
e
NPr
-i
O
O
NM
e
NPr
-i
O
ON
3
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°(—
)93
9
C10
N N
O
OHN N
O
OHN N
O
ON3
R
HN
3N
3
RR
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°
R H OT
BD
MS
I
(42)
(22)
II (0)
(22)
941
C11
-21
N
N R2
OR
1
N
N R2
OR
1
N3
R1
Me
Me
Me
Me
Me
CH
2CF 3
CH
2CF 3
CH
2CF 3
i-Pr
4-M
eOC
6H4C
H2
4-M
eOC
6H4C
H2
R2
Et
n-Pr
i-Pr
MeO
(CH
2)2O
CM
e 2
Ph i-Pr
i-Pr
Ph Ph i-Pr
Ph
(83)
(76)
(86)
(81)
(88)
(50)
(94)
b
(77)
(89)
(84)
(89)
942
1. K
HM
DS,
TH
F, –
78°,
5 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
min
III
+
288
N N
O
OHN N
O
ON3
MeO
2CM
eO2C
1. K
HM
DS,
TH
F, –
78°
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°94
1(7
9)
C11
C12
NO
ON(B
n)O
Bn
H
Ph
NO
ON(B
n)O
Bn
H
Ph
1. L
DA
(ia
), T
HF,
–78
°, 30
min
2. R
O2C
N=
NC
O2R
, –78
°, 8
h
NR t-
Bu
Bn
(70)
(85)
943,
944
C15
-18
N
OOM
eH
TB
DPS
O
Et
RN
OOM
eH
TB
DPS
O
Et
1. t-
BuL
i, T
HF
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°88
7N
3
R
R CM
e=C
H2
1-cy
cloh
exen
yl
Ph
(72)
(78)
(60)
N
O
H
Bn
TB
DPS
O
N
O
H
TB
DPS
O
N
O
H
TB
DPS
O
Bn
N3
N3
Bn
1. t-
BuL
i, T
HF,
pen
tane
, –78
°, 50
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 6
h
C16
(27)
(15)
462
NN
N
MeO
O
Ph
NN
N
MeO
O
Ph
N3
1. t-
BuO
K, T
HF
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°
(26)
945
N
O4-
MeO
C6H
4
R
TB
SO
N
O4-
MeO
C6H
4
R
TB
SO
N3
N
O4-
MeO
C6H
4
R
TB
SO
N3
1. L
DA
(ia
), T
HF,
–78
°; to
0°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
min
C18
(59)
(24)
946
R =
OSi
Et 3
a No
reac
tion
occu
rred
with
t-B
uO2C
N=
NC
O2B
u-t.
b The
bas
e w
as K
OB
u-t (
2 eq
).
+ +
NH
CO
2R
CO
2R
289
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
5. C
YA
NO
-ST
AB
ILIZ
ED
CA
RB
AN
ION
S
C3
NC
NC
Na+
1. 2
,4,6
-Me 3
C6H
2SO
2ON
H2,
TH
F, 0
°, 2.
5 h
2. T
sOH
NC
NC
NH
3+ T
sO–
(55)
463
CN
NC
ON
Et 2
O
2-N
CC
6H4
1. n
-BuL
i, he
xane
, TH
F, 0
°, 30
min
2.
,
–78°
, 3 h
; to
rt, 1
.5 h
CN
NH
CO
NE
t 2(5
6)15
8
NC
NC
HN
O
1. L
iHM
DS
(ia)
, TH
F, –
78°,
1 h
2.
(–)
, –78
°, 7
h; to
rt
N
CN C
ON
H2(5
7), 2
3% d
e15
1
N
CN C
ON
H2
(82)
, dr
1:1
151
(NC
) 2C
=N
OT
s, p
yrid
ine,
Et 2
O, 0
°N
C
NC
NC
N
CN
(55)
838
C3-
4
RC
N
1. L
iHM
DS
(ia)
, TH
F, –
78°,
1 h
2.
(
+)
, –78
°, tim
e; to
rt
ON
H
CO
NH
2
N
OI
II
R Me
Et
Tim
e
4.5
h
6.5
h
I
(36)
(83)
II (0)
(17)
151
C3
H
1. L
iHM
DS
(ia)
, TH
F, –
78°,
1 h
2.
(
+)
, –78
°, 6
h; to
rt
ON
H
+
C4
CN
NC
ON
H2
(45)
151
1. L
iHM
DS
(ia)
, TH
F, –
78°,
1 h
2.
(
+)
, –78
°, 26
.5 h
; to
rt
ON
H
PyH
+
290
Con
ditio
ns 1
: 1. C
atal
yst A
(se
e C
hart
1; 5
mol
%),
E
tOH
, rt
2
. Sub
stra
te, t
hen
PhSi
H3
3
. t-B
uO2C
N=
NC
O2B
u-t,
rt, t
ime
Con
ditio
ns 2
: 1. C
atal
yst B
(se
e C
hart
1; 2
mol
%),
i-
PrO
H, 0
°
2. S
ubst
rate
, the
n Ph
SiH
3, 0
°
3. t
-BuO
2CN
=N
CO
2Bu-
t, 0°
, tim
e
CN
CN
NN
HC
O2B
u-t
t-B
uO2C
Con
ditio
ns
1 2
Tim
e
18 h
2.5
h
(46)
(45)
215
TM
SO NC
R1.
LD
A
2. P
h 2P(
O)O
NM
e 2, –
78° t
o 20
°, 5
h
947
C6-
15
R 2-fu
ryl
2-th
ieny
l
2-(1
-met
hylp
yrro
lyl)
2-py
ridi
nyl
Ph 2-C
lC6H
4
4-C
lC6H
4
4-B
rC6H
4
4-M
eOC
6H4
4-M
e 2N
C6H
4
2,4-
(HO
) 2C
6H3
E-P
hCH
=C
H
1-na
phth
yl
2-na
phth
yl
4-B
zC6H
4
(77)
(80)
(68)
(96)
(76)
(92)
(95)
(91)
(75)
(98)
(67)
(35)
(80)
(90)
(51)
RN
Me 2
O
Ph NC
1. n
-BuL
i
2. 2
,4-(
O2N
) 2C
6H4O
NH
2
Ph NC
NH
2 (
7)93
C8
1. B
ase,
TH
F, –
78°,
15 m
in
2. (
4-M
eOC
6H4)
2P(O
)ON
H2,
–78
° to
rt;
rt
, ove
rnig
ht
3. A
c 2O
, Et 3
N
Ph NC
NH
Ac
106
Bas
e
LiH
MD
S
NaH
MD
S
KO
Bu-
t
(59)
(64)
(67)
291
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
5. C
YA
NO
-ST
AB
ILIZ
ED
CA
RB
AN
ION
S (C
onti
nued
)
Ph NC
C8
1. L
i bas
e, T
HF
or e
ther
2. M
eSO
2ON
Me 2
, –30
° to
0°
Ph NC
NM
e 2
I (
69)
134
LD
A, P
h 2P(
O18
)ON
Me 2
84
NPO
PhO
NM
e 2
Me
I (6
5)
I (6
2), 8
% e
ea14
7O
NC
ON
H2
151
Ar
NC
ON
H2
Ar
+
CO
NH
2
III
III
+
Ar
Ph 4-C
lC6H
4
4-O
2NC
6H4
4-M
eOC
6H4
1-na
phth
yl
2-na
phth
yl
Tim
e
4.5
h
5 h
6 h
9 h
4.5
h
4.5
h
I +
II
(78)
b
(80)
(0)
(75)
(80)
(73)
% d
e
25 16 — 5 33 33
III
(0)
(0)
(21)
(0)
(0)
(0)
C8-
12
Ar
NC
1. L
iHM
DS
(ia)
, TH
F, –
78°,
1 h
2.
(
+)
, –78
°, tim
e; to
rt
ON
H
1. L
i bas
e, T
HF
2.
, –15
°
NA
r
CO
NH
2
Ar
Ph 1-na
phth
yl
2-na
phth
yl
(55)
(48)
(31)
% d
e
50 33 52
151
HN
O
1. L
iHM
DS
(ia)
, TH
F, –
78°,
1 h
2.
(–)
, –78
°; to
rt
292
1. L
iHM
DS
(ia)
, TH
F, –
78°
2.
,
–78°
, 20
h; to
rt
ON
CO
2Bu-
tE
tO2C
EtO
2C
Ar
NC
NH
CO
2Bu-
t
Ar
Ph 4-C
lC6H
4
4-M
eOC
6H4
(45)
(46)
(20)
155
N HNC
N
NH
O, D
AB
CO
(ca
t), t
olue
ne, r
tN HN
CO
NH
2
N(—
)15
0
C14
Ph PhC
N1.
Li b
ase,
TH
F
2. P
h 2P(
O)O
NH
2, –
20°,
rt, 2
0 h
Ph Ph
CN
NH
2
I (
67)
139
4-O
2NC
6H4
NC
4-O
2NC
6H4
NC
N
CN
CN
–Py
H+ (
85)
NC
NC
NT
s, p
yrid
ine,
rt,
1 h
838
C8
C9
CN
TM
SO
C10
OT
MS
NC
Me 2
N
NM
e 2O
O
1. L
DA
2. P
h 2P(
O)N
Me 2
, –78
° to
rt, 5
h
(36)
947
1. N
aH, T
HF,
rt,
15 m
in
2. R
eage
nt, r
t, ov
erni
ght
106
Rea
gent
Ph2P
(O)O
NH
2c
(4-M
eOC
6H4)
2P(O
)ON
H2
4-O
2NC
6H4C
O2N
H2
(67)
(85)
(66)
I
293
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
5. C
YA
NO
-ST
AB
ILIZ
ED
CA
RB
AN
ION
S (C
onti
nued
)
N H
HN
Ph Ph
O
(82)
150
1. L
i bas
e, E
t 2O
or
TH
F
2. M
eSO
2ON
Me 2
, –30
° to
0°
Ph Ph
CN
NM
e 2(6
7)13
4
1. N
aH, g
lym
e, r
t
2. T
sN3,
rt;
35-4
0°, 1
h
Ph Ph
CN
N3
(18)
d48
3
a R
acem
izat
ion
prob
ably
occ
urre
d du
ring
isol
atio
n by
trea
tmen
t with
aci
d (p
H 4
.5).
b I is
the
maj
or is
omer
.c L
iHM
DS
was
use
d as
the
base
.d T
he r
epor
ted
yiel
d is
that
of
the
crud
e pr
oduc
t.
C14
Ph PhC
NN
HO
, DA
BC
O (
cat)
, tol
uene
, rt
294
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
6. N
ITR
ON
AT
ES
C1-
6
R1
R2
NO
2
R1
R2
N3
Ts
1. K
H, T
HF,
rt;
40°,
15 m
in
2. T
sN3,
–10
° to
0°; 0
°, 1
h
464
R1
H Me
Me
—(C
H2)
5—
Me
R2
H H Me
(0)
(37)
(49)
(56)
(35)
OO
(CH
2)2
295
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
7. S
UL
FON
E-S
TA
BIL
IZE
D C
AR
BA
NIO
NS
PhSO
2C
uLi
PhSO
2N
Me 2
Me 2
NO
SO2R
, Et 2
O o
r T
HF,
0°
R =
Me,
Ph,
4-M
eC6H
4, o
r 2,
4,6-
Me 3
C6H
2
134
(22)
PhO
2SC
uLi
PhO
2S13
4(2
8)
C7
PhPh
Ph
NM
e 2
PhO
2SN
Me 2
PhC
13
PhSO
2Me
ON
CO
NE
t 2,
2-N
CC
6H4
1. n
-BuL
i, T
HF,
hex
ane,
0°,
30 m
in
2.
–
78°,
3 h;
to r
t, 90
min
(43)
158
C15
S O2
NH
OT
BD
PSB
nS O
2
NH
OT
BD
PSS O
2
NH
OT
BD
PS
Bn
N3
N3
Bn
(40)
(33)
1. t-
BuL
i, T
HF,
pen
tane
, –78
°, 55
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 6
h
465
PhO
2SC
uLi
Ph
SO2
NH
Bu-
n
C5
SO2
NH
Bu-
n
EtO
2CN
RC
ON
H
EtO
2CN
=N
CO
R, M
eCN
, ref
lux,
3 h
(60)
(60)
R OE
t
Ph
250
1. M
e 2N
OSO
2R, E
t 2O
or
TH
F, 0
° (fo
rms
I as
inte
rm.)
2.
(fo
rms
II)
R =
Me,
Ph,
4-M
eC6H
4, o
r 2,
4,6-
Me 3
C6H
2I
II
(—)
+
H NC
ON
Et 2
PhSO
2
296
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%)
TA
BL
E 1
8. P
HO
SPH
OR
US-
STA
BIL
IZE
D C
AR
BA
NIO
NS
C1
1. N
aH, T
HF,
rt,
15 m
in
2. S
ee ta
ble.
95
Rea
gent
2,4-
(O2N
) 2C
6H3O
NH
2
Ph2P
(O)O
NH
2
Tem
p
rt
–70°
; rt
(15)
(50)
(51)
158
C1-
8R H M
e
i-Pr
t-B
u
Ph Bn
(53)
(65)
(65)
(71)
(75)
(50)
770
C2
1. N
aH, D
ME
2. 2
,4,6
-Me 3
C6H
2SO
2ON
H2,
30°
, 30
min
(47)
704
1. N
aH, T
HF,
rt,
1 h
2. P
h 2P(
O)O
NH
2, T
HF,
–78
°, 2
h
3. H
O2C
CO
2H
(60)
141
MsO
N(L
i)C
O2C
H2C
H=
CH
2, T
HF,
–78
° to
–60°
, 1.5
h
(58)
130
1. n
-BuL
i, T
HF,
–78
°2.
t-B
uO2C
N=
NC
O2B
u-t,
–78°
, few
min
EtO
PP
O
EtO
O
OE
tO
Et
EtO
PM
e
O
EtO
EtO
PO
EtO
R
EtO
PO
EtO
CO
2Me
EtO
PO
EtO
CO
2Bn
EtO
PO
EtO
–C
u+
EtO
PP
O
EtO
O
OE
tO
Et
NH
2
Tim
e
12 h
2 h;
10
h
ON
CO
NE
t 2,
2-N
CC
6H4
1. n
-BuL
i, T
HF,
hex
ane,
0°,
30 m
in
2.
–
78°,
3 h;
to r
t, 1.
5 h
EtO
PO
EtO
H NC
ON
Et 2
EtO
PO
EtO
R
Nt-
BuO
2CN
HC
O2B
u-t
EtO
PO
EtO
CO
2Me
NH
2
EtO
PO
EtO
CO
2Bn
NH
3+ H
O2C
CO
2–
EtO
PO
EtO
HN
O
O
297
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
8. P
HO
SPH
OR
US-
STA
BIL
IZE
D C
AR
BA
NIO
NS
(Con
tinu
ed)
TsO
N(L
i)C
O2B
u-t
R Me
Ph
(80)
(50)
126
EtO
PO
EtO
R–
Cu+
C2-
7
EtO
PO
EtO
R
NH
CO
2Bu-
t
Me
N N MeP
Ph Ph
C2-
8M
eN N M
eP
Ph PhN
HC
O2B
u-t
1. n
-BuL
i, T
HF,
–78
°2.
CuB
r. Me 2
S
3. T
sON
(Li)
CO
2Bu-
t, T
HF,
–78
°
R Me
Ph
(59)
(49)
% d
e
30 35
129
1. n
-BuL
i, T
HF,
–78
°2.
t-B
uO2C
N=
NC
O2B
u-t,
–78°
, few
min
Me
N N MeP
Me
N N Me
(33)
mix
ture
of
two
dias
tere
omer
s
770
Me
N N MeP
Ph Bn
Me
N N MeP
Ph Bn
N
1. L
DA
, TH
F, –
30°
2. t-
BuO
2CN
=N
CO
2Bu-
t, –3
0°, 5
min
(41)
, 52%
de
948
Me
N N MeP
Ph Bn
Me
N N MeP
Ph Bn
1. L
DA
, TH
F, –
30°
2. t-
BuO
2CN
=N
CO
2Bu-
t, –3
0°, 5
min
(46)
, 83%
de
948
R N OP
R2
R1
C2
1. L
DA
, TH
F, –
78°
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 3
0 m
in
R1
H Ph Ph
R2
Ph H H
R3
Me
Me
i-Pr
(55)
(58)
(65)
dr 2:1
1.5:
1
1:4
949
OO
OO
OO
OO
O
RR
PN
NH
CO
2Bu-
t
CO
2Bu-
t
t-B
uO2C
NH
CO
2Bu-
t
Nt-
BuO
2CN
HC
O2B
u-t
3R N O
P
R2
R1
O Nt-
BuO
2CN
HC
O2B
u-t
3
298
N OP
R2
R1
1. L
DA
, TH
F, –
78°
2. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 3
0 m
in
R1
H Ph Ph
R2
Ph H H
R3
R3
Me
Me
i-Pr
(50)
(54)
(62)
dr 1:1
1.5:
1
1:3
949
O
R N OP
R2
R1
O Nt-
BuO
2CN
HC
O2B
u-t
3
C2-
9
1. n
-BuL
i, he
xane
, cos
olve
nt,
–7
8°, 3
0 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
h
3. A
c 2O
, –78
° to
rtR
1
H H H Me
H H Me
Me
R2
Bu-
t
Bu-
t
Bu-
t
Bu-
t
Bu-
t
CE
t 3Ph
CH
Me
(S)
isob
orny
l
R3
Me
Ph Ph Ph Bn
Ph Phc
Phd
(72)
(56-
79)
(75)
(70-
93)
(63)
(79)
(52)
(74)
dra
4:1
11:1
13:1
b
>20
:1
2:1
3:1
>20
:1
5.3:
1
317
N R2P
O
R1
R3
N R2P
O
R1
R3
NN
NSO
2C6H
2(Pr
-i) 3
-2,4
,6
Ac
OO
Cos
olve
nt
TH
F
TH
F
Et 2
O
TH
F
TH
F
TH
F
TH
F
TH
FC
3
PO
OE
t1.
LD
A, T
HF,
–78
°2.
2,4
,6-(
i-Pr
) 3C
6H4S
O2N
3, –
78°
Com
plex
mix
ture
895
C4-
13
R1
P(O
)(O
R3 ) 2
O
R2
R1
P(O
)(O
R3 ) 2
O R2
N
1. 1
(10
mol
%),
CH
2Cl 2
2. S
ubst
rate
,
th
en B
nO2C
N=
NC
O2B
n, r
t, tim
e
R1
Me
—
(CH
2)3—
—
(CH
2)4—
Ph Ph Bn
Ph 2-na
phth
yl
R2
Me
Me
Me
Me
CH
2CH
=C
H2
Me
R3
Et
Et
Et
Me
Et
Et
Et
Et
Tim
e
48 h
48 h
48 h
48 h
48 h
48 h
140
h
48 h
(75)
(98)
(98)
(97)
(85)
(60)
(85)
(93)
% e
e
85 95 94 94 92 95 98 92
468
NZ
n(O
Tf)
2
N
OO
PhPh
1
NH
CO
2Bn
CO
2Bn
299
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
8. P
HO
SPH
OR
US-
STA
BIL
IZE
D C
AR
BA
NIO
NS
(Con
tinu
ed)
C4-
6
1. n
-BuL
i, T
HF,
–78
°, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 1
h
n 1 1 2 2 3 3
R Et
i-Pr
Et
i-Pr
Et
i-Pr
(74)
(77)
(76)
(69)
(69)
(72)
773
C7
N MeP
Me
NPh
N MeP
Me
NPh
NH
CO
2Bu-
t
1. n
-BuL
i, T
HF,
–78
°2.
CuB
r•M
e 2S
3. T
sNO
(Li)
CO
2Bu-
t, T
HF,
–78
°(4
9), 5
2% d
e12
9
1. L
iN(E
t)2,
PhH
, rt,
1 h
2. P
hN3,
rt,
18 h
(26)
467
OO
NP(O
)(O
Pr-i
) 21.
n-B
uLi o
r L
DA
, TH
F, –
78°
2. E
tO2C
N=
NC
O2E
t
(35)
773
C4
P(O
)(O
R) 2
nn
P(O
)(O
R) 2
N3
N MeP
OPh
PhN M
ePO
Ph
Ph
N3
N MeP
OPh
Ph
N2
1. L
DA
, TH
F, –
78°,
30 m
in
2. 4
-O2N
C6H
4SO
2N3,
–78
°; to
rt
(—)
(19)
632
+
OO
O
N MeP
Me
N
Ph
O
N MeP
Me
N
Ph
O
N MeP
Me
N
Ph
O
N3
+(—
)(3
3)1.
n-B
uLi,
TH
F, –
78°,
30 m
in
2. 4
-O2N
C6H
4SO
2N3,
–78
°, 4
h
632
NH
CO
2Et
CO
2Et
P(O
)(O
Pr-i
) 2
PhP
PhPh
OPh
PPh
PhO
NN
NH
Ph
N2
300
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 3
h
3. A
cOH
(34-
53),
dr
>20
:1a
317
N Bu-
t
PO
Ph
N Bu-
t
PO
PhN
3H
H
OO
R1
H Me
Me
R2
Bu-
t
Bu-
t
PhC
HM
e (S
)
(52-
70)
(52-
68)
(70)
dra
1.3:
1
>20
:1
2:1
317
1. n
-BuL
i, he
xane
, sol
vent
, –78
°, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
h
3. A
c 2O
, –78
° to
rt
R1
H Me
R2
H Me
(47-
60)
(56)
dra
3:1
>20
:1
317
ON
PPh
ON
PPh
t-B
u
N3
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 3
h
3. A
cOH
(30)
, dr
>20
:1a
317
Solv
ent
TH
F
Et 2
O
N R2P
O
R1
1. K
HM
DS,
TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 3
h
3. A
cOH
N Bu-
t
PO
R1
Ph
R2
H
PhN R
2PO
R1
Ph
N3
O
OO
O
N Bu-
t
PO
R1
Ph
R2
H
O
AcNN
NSO2C
6H2(
Pr-i
) 3-2
,4,6
1. n
-BuL
i, he
xane
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
h
3. A
c 2O
, –78
° to
rt
ON
PPh
N(6
2), d
r 2.
5:1a
317
O
t-B
u
t-B
u
NN
SO2C
6H2(
Pr-i
) 3-2
,4,6
Ac
ON
P
Ph
ON
P
Ph
N
1. n
-BuL
i, he
xane
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
h
3. A
c 2O
, –78
° to
rt
(81)
, dr
4.3:
1a31
7O
O
N
Ac
N
SO2C
6H2(
Pr-i
) 3-2
,4,6
t-B
u
t-B
u
301
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
8. P
HO
SPH
OR
US-
STA
BIL
IZE
D C
AR
BA
NIO
NS
(Con
tinu
ed)
Bu-
tN
P
R
PhB
u-t
NP
R
Ph
N1.
n-B
uLi,
hexa
ne, T
HF,
–78
°, 30
min
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 5
h
3. A
c 2O
, –78
° to
rt
R H Me
(70)
(85)
dra
6:1
9:1
317
HO
HO
OO
NA
cN
SO2C
6H2(
Pr-i
) 3-2
,4,6
C7
N Pr-iP
Pr-i
NPh Ph
PhN Pr
-iP
Pr-i
NPh Ph
Ph
N3
1. n
-BuL
i, he
xane
, TH
F, –
78°,
30 m
in
2. 2
,4,6
-(i-
Pr) 3
C6H
2SO
2N3,
–78
°, 3
h
3. H
2O
(100
)e , dr
2:1a
317
C9
O
P(O
)(O
R) 2
O
N(C
O2E
t)N
HC
O2E
t
P(O
)(O
R) 2
H OPd
O H
PdP P
P P=
P(C
6H3M
e 2-3
,5) 2
P(C
6H3M
e 2-3
,5) 2
EtO
2CN
=N
CO
2Et,
2 (2
.5 m
ol%
),
Me 2
CO
, rt
R Me
Et
i-Pr
Tim
e
35 h
20 h
60 h
(81)
(92)
(68)
% e
e
99 99 99
238
2+
OO
2
P P
2 B
F 4–
a The
val
ues
are
for
the
dias
tere
omer
ic r
atio
s in
the
crud
e pr
oduc
ts.
b Cle
avag
e of
the
prod
uct f
ollo
wed
by
hydr
olys
is g
ave
(S)-
phos
phon
o gl
ycin
e.c T
he c
onfi
gura
tion
on p
hosp
horu
s w
as n
ot e
stab
lishe
d.d T
he s
ubst
rate
was
a m
ixtu
re o
f ci
s an
d tr
ans
isom
ers.
e The
rep
orte
d yi
eld
is th
at o
f cr
ude
prod
uct.
302
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
9. E
NO
LA
TE
S O
F α,
β-U
NSA
TU
RA
TE
D C
AR
BO
NY
L C
OM
POU
ND
S
C4-
10
R3
CO
2H
R2
R1
R3
CO
2H
R2
R1
NH
2
1. L
iNE
t 2 (
2.2
eq,a ia
),
T
HF,
–70
°; 0
°, 15
min
2. P
h 2P(
O)O
NH
2, –
70°,
25 m
in; r
t, 2
h
R1
H Me
Me
H H
R2
H H H t-B
u
Ph
R3
H H Me
H H
(14)
(45)
(64)
(28)
(45)
144
1. L
iNE
t 2 (
2.2
eq,a ia
),
T
HF,
–70
°, 30
min
2. E
tO2C
N=
NC
O2E
t, –7
0°, 1
5 m
in
R3
CO
2H
R2
R1
N
R3
CO
2H
R2
R1
NN
HC
O2E
tI
R1
H Me
H H Me
H H
R2
H H Me
H H H Ph
R3
H H H Me
Me
Et
H
I
(69)
(65)
(68)
(51)
(50)
(62)
(74)
II
II
(0)
(3)
(0)
(0)
(0)
(0)
(0)
144
C4-
11
CO
2R3
R1
R2
CO
2R3
I
R1
R2
N
CO
2R3
II
R1
R2
N1.
LD
A, T
HF,
add
end,
–78
°, 70
min
2. E
tO2C
N=
NC
O2E
t, –7
8°‚
3 m
in
3. M
eOH
, –78
°; to
rt
469,
950
R1
H H H H Bn
R3
Me
Et
Et
Et
Me
R2
H Me
Me
Me
H
Add
end
HM
PA
HM
PA
— ZnC
l 2b
HM
PA
I
(64)
(63)
(71)
(61)
(71)
I E
:Z
>99
:1
2:1
1:1
1:1
>99
:1
II (0)
(12)
(7)
(25)
(0)
EtO
2CN
HC
O2E
t
NH
CO
2Et
EtO
2CE
tO2C
NH
CO
2Et
EtO
2C
+ +
303
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
9. E
NO
LA
TE
S O
F α,
β-U
NSA
TU
RA
TE
D C
AR
BO
NY
L C
OM
POU
ND
S (C
onti
nued
)
OM
e
OT
MS
CO
2Me
NNH
CO
2Et
CO
2Me
N(6
8)(1
7)
1. E
tO2C
N=
NC
O2E
t, T
iCl 4
,
C
H2C
l 2, –
78°
2. S
ubst
rate
, –78
°, 30
min
469,
950
C4-
5
RC
O2E
t c
Cl 3
Sn
CO
2Et
E
R1.
EtO
2CN
=N
CO
2Et,
TH
F,
–
10°,
time;
to –
78°
2. M
eOH
, –78
° to
rt
RC
O2E
t
E
R H Me
II (5)
(3)
Tim
e
30 m
in
100
min
I
(53)
(26)
E =
N(C
O2E
t)N
HC
O2E
t
469
III
C5
CO
2Et
Bu 3
Sn
CO
2Et
CO
2Et
NN
(75)
(5)
469,
950
R1
CO
2R3
GeM
e 3 d
R2
1. E
tO2C
N=
NC
O2E
t, Z
nCl 2
,
C
H2C
l 2, –
78°
2. S
ubst
rate
, –78
° to
tem
p, ti
me
R1
CO
2R3
R2
N
469
R1
H —(C
H2)
3—
—(C
H2)
4—R2
Me
R3
Et
Et
Me
Tem
p
rt 5° 0°
(71)
(88)
(55)
E:Z
3:1
8:1
6:1
1. E
tO2C
N=
NC
O2E
t, Z
nCl 2
,
C
H2C
l 2, –
78°
2. S
ubst
rate
, –78
° to
0°, 4
0 m
in
NO
OO
Bn
1. L
DA
, TH
F, –
78°,
30 m
in
2. A
dden
d
3. t-
BuO
2CN
=N
CO
2Bu-
t, –7
8°, 1
h
NO
OO
Bn
E
NO
OO
Bn
E+
I
Add
end
— HM
PA (
1 eq
)
HM
PA (
5 eq
)
I
I
(51)
(61)
(52)
II
II
(33)
(21)
(11)
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
895
C4
Tim
e
2 h
40 m
in
30 m
in
+
+
+
EtO
2CN
HC
O2E
tE
tO2C
EtO
2CN
HC
O2E
t
NH
CO
2Et
CO
2Et
EtO
2CN
HC
O2E
t
304
ON
O Bn
O
ON
O Bn
O
EO
N
O Bn
OE
+
1. L
DA
, TH
F, –
78°,
30 m
in
2. t-
BuO
2CN
=N
CO
2Bu-
t, C
H2C
l 2, –
78°‚
30
-180
s
431
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t(5
1), >
96%
de
(42)
, E:Z
= 3
:2
1. N
aH, E
t 2O
, 0°,
3 h
2. C
lNH
2, –
78°;
to 0
°
C6
CO
2Et
CO
2Et
EtO
2C2
(74)
+
(1.5
)64
C5-
11
RC
HO
RC
HO
NE
tO2C
NH
CO
2Et
1.
(10
mol
%),
s
olve
nt, r
t, 15
min
2. E
tO2C
N=
NC
O2E
t, tim
e
Ar
= 3
,5-(
CF 3
) 2C
6H3
N H
OT
MS
Ar
Ar
R Me
Me
Et
MeS
CH
2
n-Pr
i-Pr
CH
2CH
=C
HE
t
n-C
6H13
Bn
% e
e
97 89 89 88 88 89 89 88 93
(46)
(56)
(58)
(43)
(56)
(40)
(54)
(49)
(52)
Tim
e
— 3 h
6 h
1.5
h
5 h
56 h
4.5
h
8 h
4 h
Solv
ent
CH
2Cl 2
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
470
CO
2H1.
LiN
Et 2
(2.
2 eq
,a ia),
TH
F, –
70°;
0°
, 15
min
2. P
h 2P(
O)O
NH
2, –
70°,
25 m
in; r
t, 2
h
CO
2H
NH
2
(50)
144
1. L
iNE
t 2 (
ia),
TH
F, –
70°,
30 m
in
2. E
tO2C
N=
NC
O2E
t, –7
0°, 1
5 m
inC
O2H
(81)
144
NE
tO2C
NH
CO
2Et
EtO
2CN
H2
EtO
2CC
O2E
t
EtO
2CN
H
EtO
2CC
O2E
t
305
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 1
9. E
NO
LA
TE
S O
F α,
β-U
NSA
TU
RA
TE
D C
AR
BO
NY
L C
OM
POU
ND
S (C
onti
nued
)
CO
2Rn
CO
2Rn
CO
2Rn
1. L
DA
, HM
PA, T
HF,
–78
°, 70
min
2. E
tO2C
N=
NC
O2E
t, –7
8°, 3
min
3. M
eOH
, –78
°
EE
III
R Et
Me
Me
n 1 2 2E
= N
(CO
2Et)
NH
CO
2Et
I
(65)
(14)
(13)
E:Z 1:2
1:1.
5
10:1
II (22)
(55)
(38)
e
469
C7-
8
NOO
O Bn
NOO
O Bn
E1.
LiH
MD
S, T
HF,
78°
2. t-
BuO
2CN
=N
CO
2Bu-
t
(0)
453
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
C8
OT
MS
O
NH
CO
CF 3
(50)
471
RR
R =
NH
Ac
(Sal
tmen
)Mn(
N),
CH
2Cl 2
, pyr
idin
e,
TFF
A, –
78° t
o rt
, 3-4
h
C8-
10
ClN
H2,
2,6
-(R
1 ) 2-4
-R2 C
6H2O
H,
100
-140
°; r
t, ov
erni
ght
R1
Me
Me
Et
R2
H Me
H
(55)
(51)
(33)
65
Na+
O
R1
R1
R2
NH
OR
1
R2
R1
+
a T
his
is a
cor
rect
ed v
alue
; per
sona
l com
mun
icat
ion
from
R. M
estr
es, D
epar
tmen
t of
Che
mis
try,
Uni
vers
ity o
f V
alen
cia,
Spa
in, 2
006.
b
The
ZnC
l 2 w
as a
dded
aft
er th
e fo
rmat
ion
of th
e lit
hium
die
nola
te.
c The
sub
stra
te w
as g
ener
ated
in s
itu f
rom
the
lithi
um d
ieno
late
and
SnC
l 4.
d The
sub
stra
te w
as g
ener
ated
in s
itu f
rom
the
lithi
um d
ieno
late
and
ClG
eMe 3
.e P
roto
natio
n w
as c
arri
ed o
ut a
t 0°.
f The
inte
rmed
iate
for
med
upo
n am
inat
ion
of th
e en
olat
e un
derg
oes
subs
eque
nt r
ing
expa
nsio
n to
giv
e th
e pr
oduc
t sho
wn.
f
306
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
C3-
10
ClN
H2
(ia)
, Et 2
O, m
orph
olin
e, 0
°, 2
h;
rt,
over
nigh
t; re
flux
, 5 h
62
R H Me
Et
i-Pr
s-B
u
Ph Bn
(92)
(85)
(89)
(71)
(83)
(70)
(72)
1. N
aH, T
HF,
rt,
25 m
in
2. 2
,4-(
O2N
) 2C
6H3O
NH
2, r
t, ov
erni
ght
3. 6
N H
Cl,
refl
ux
4. E
t 3N
R Me
Et
Et 2
OC
CH
2
n-B
u
Bn
(98)
(74)
(61)
(46-
57)
(73)
93
1. N
aH, T
HF,
rt,
25 m
in
2. 2
,4-(
O2N
) 2C
6H3O
NH
2, r
t, ov
erni
ght
C3-
10
C3-
9R H M
e
Ph
(55)
a
(31)
b
(65)
93
C3-
9
1. N
aH, T
HF,
rt,
15 m
in
2. R
eage
nt, r
t, ov
erni
ght
R H H H Ph Ph Ph
Rea
gent
Ph2P
(O)O
NH
2
(4-M
eOC
6H4)
2P(O
)ON
H2
4-O
2NC
6H4C
O2N
H2
Ph2P
(O)O
NH
2
(4-M
eOC
6H4)
2P(O
)ON
H2
4-O
2NC
6H4C
O2N
H2
(57)
b
(41)
(52)
(31)
b
(92)
(99)
106
RC
O2E
t
CO
2Et
RC
O2E
t
CO
2Et
RC
O2E
t
CO
2Et
R
CO
2Et
EtO
2C
NH
2
R
CO
2Et
EtO
2C
NH
2
RN
H2
CO
2H
CO
2Et
CO
2Et
RN
a+
–
R
CO
2Et
EtO
2C
NH
2
307
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
C3
NH
HN
Y
OO
NH
HN
Y
OO
NH
2
150
Y O S
(78)
(82)
NH
HN
O
OO
HN
HN
N
NH
NH
O O
O
OO
O– N
H4+
(88)
149
NH
HN
OO
HN
HN
N
O O
(79)
149
NC
NR
1 R2
O
NR
1 R2
O
NH
2
NH
O
, NaO
H, t
olue
ne
NH
O
, tol
uene
, H2O
, N
H4O
H, r
t, 30
min
NH
O
, tol
uene
, DA
BC
O, r
t, 12
h
NH
O
, tol
uene
, NaO
H, H
2O, 0
°, 10
min
O
H2N
NR
1 R2
OO
H2N
H2N
NH
2I
R1
H Me
H
—(C
H2)
4—
—(C
H2)
2O(C
H2)
2—
—(C
H2)
5—
H
R2
Me
Me
n-Pr
Bn
I
I
(62)
(81)
(18)
(59)
(56)
(61)
(17)
II
II
III(0
)
(0)
(0)
(0)
(0)
(0)
(74)
149
+
NH
R
O
NH
O
NH
R
OO
RH
N H2N
NH
2
149
O
RH
NN
HR
OO
RH
N
NH I
1.(2
eq)
, tol
uene
, DA
BC
O, r
t, 12
h (
form
s I)
2.E
tOH
, ref
lux,
15
min
; rt,
12 h
(fo
rms
II)
308
R n-Pr
Ph 3-C
lC6H
4
4-B
rC6H
4
2-E
tO2C
C6H
4
Bn
n-C
8H17
I
(47)
(91)
(73)
(52)
(93)
(83)
(39)
II (—)
(96)
(—)
(73)
(90)
(—)
(—)
I
NC
O2E
t
R2
NC
O2E
t
R2
ON
H
151
C3-
9
1. L
iHM
DS
(ia)
, TH
F, –
78°,
30 m
in
2.
,
78°,
20 h
; to
rt
R1
EtO
Me
EtO
EtO
EtO
R2
H H Me
Bu
Ph
I +
II
(50)
(43)
(20)
(14)
(0)
Tim
e
6 h
48 h
56 h
49 h
60 h
NC
O2B
u-t
EtO
2CR
1
H H Ph
R2
Et
Bu-
t
Et
(33)
(20)
(50)
155
1. L
iHM
DS
(1.1
eq,
ia),
TH
F, –
78°,
1 h
2.
, –
78° t
o rt
, 2 h
; rt,
time
OE
tO2C
R1
CO
2Et
R2
O
NC
CO
2R2
R1
C3-
4
NC
O2E
t
R
NC
O2E
t
R
ON
H1.
NaO
Et (
2.9
eq),
, E
tOH
, rt
2. S
ubst
rate
, rt,
time
R H Me
Tim
e
3 h
4 h
I
I
(—)
(45)
II (—)
(45)
151
EtO
2CC
O2E
t
R
NC
NH
CO
2Bu-
t
R1
CO
2R2
+ +
I +
II
II
III(6
8)
(—)
309
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
NO
Ts
NC
NC
, pyr
idin
e, E
t 2O
NC
NC
N
CN
CO
R
PyH
+R N
H2
OM
e
OE
t
Tem
p
refl
ux
— —
(45)
(51)
(46)
838
C3
NC
CO
R
Tim
e
10 h
— —C
3-4
1. N
a ba
se
2. P
hNH
N=
C(C
O2E
t)2
PhN
HN
CO
2Et
R
CH
(CO
2Et)
2
159
RC
O2E
t
C3-
5
1. N
a ba
se
2. R
3 N=
NC
O2E
t
R1
NC
NC
Ac
Ac
R2
EtO
EtO
EtO
Me
159
R2 O
2CN
=N
CO
2R2 , K
OA
c
R1
NC
EtO
2C
EtO
2C
R2
Et
Me
Et
Tem
p
60°
rt rt
(25)
(>90
)
(80-
90)
478
C3
R3
EtO
2C
Ph Ph Ph
R1
CO
R2
R1
CO
R2
NR
3N
HC
O2E
t
R1
CO
2Et
N NH
HNN
R2 O
2CC
O2R
2
R1
CO
2Et
R2 O
2CC
O2R
2
R =
CN
, CO
2Et,
Ac
(—)
("ve
ry p
oor"
)
R1
R1
YY
R1
R1
YY
N
1. n
-BuL
i (ia
), T
HF,
–70
°, 20
min
2. R
2 CO
N=
NC
OR
2 , –78
°; to
rt
R1
MeO
MeO
MeO
MeO
MeO
Me 2
N
Me 2
N
Me 2
N
Me 2
N
Me 2
N
Y O O O S S O O O O S
R2
EtO
i-Pr
O
t-B
uO
EtO
t-B
uO
EtO
i-Pr
O
t-B
uO
N-m
orph
olin
yl
t-B
uO
(88)
(83)
(80)
(62)
(54)
(85)
(76)
(82)
(76)
(57)
b
477
R2 O
CN
HC
OR
2
310
Me 2
NN
Me 2
SS
Me 2
NN
Me 2
SS
1. L
DA
, TH
F, –
70°,
1 h
2. E
tO2C
N=
NC
O2E
t, –7
8°; t
o rt
, 2 h
NC
O2E
t
(52)
477
R2
EtO
EtO
NE
t 2
Me
Tem
p
rt rt rt 50°
Tim
e
2 h
2 h
17 h
1 h
EtO
2CN
=N
CO
2Et,
Ni(
acac
) 2, C
H2C
l 2R
1R
2
O
N47
9
R1
EtO
Me
Me
Me
(71)
(87)
(95)
(78)
R1
R2
OO
C3-
5
R MeO
EtO
Me
(34)
(30)
(28)
C3
O
RN
3
R
R
R =
BnO
, KO
H, D
MF,
H2O
, rt
O
RN
R
RN N
CO
NH
2
NH
2
O
R
R
R
NN
NC
ON
H2
NH
2+
(5)
O
R
R
R
R =
BnO
, KO
H, D
MF,
H2O
, rt
N3
I (
85)
276
276
C4-
5
1. H
2NSO
3H, K
2CO
3, H
2O, r
t, ov
erni
ght
2. A
cCH
2CO
RN H
CO
R
RC
O47
3
C4-
9
1. L
i bas
e
2. M
e 2N
OSO
2Me,
Et 2
O o
r T
HF,
–30
° to
0°
R Me
Ph
(50)
(52)
134
NC
CO
NH
2
Ac
CO
R
RC
O2E
t
CO
2Et
EtO
2CN
HC
O2E
t
I
(72)
RN
Me 2
EtO
2CC
O2E
t
C4-
5
N
S O2
OO
R
N
S O2
OO
4-O
2NC
6H4S
O2O
NH
CO
2Et,
CaO
,
CH
2Cl 2
, rt,
6 h
RN
HC
O2E
t
124
R H Me
(54)
(0)
% d
e
40 —
O
c
311
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
C4-
7
4-O
2NC
6H4S
O2O
NH
CO
2Et (
y eq
), C
aO (
z eq
),
CH
2Cl 2
, rt
124
R H H Me
i-Pr
x — 5 5 1
y — 1 1 3
z 3 2 1 6d
III
III
I (2)
(58)
(58)
(28)
II (41)
(8)
(0)
(0)
III
(0)
(0)
(4)
(5)
Tim
e
3 h
— 1 h
5 h
C4-
6
N
CO
2Et
R1
R2
R1
R2
NH
CO
2Et
CO
2Et
O
4-O
2NC
6H4S
O2O
NH
CO
2Et,
CH
2Cl 2
, rt
R1
H H CH
2OM
e
R2
H Me
H
Tim
e
45 h
2 h
2 h
(40)
(33)
(36)
% d
e
—
— (
R)
80 (
S)
125
C4-
10
R1
CO
2R2
CN
SO2N
(C6H
11-c
) 2
OR
2 =
1. L
iHM
DS,
TH
F, h
exan
e, –
78°,
1 h
2. P
h 2P(
O)O
NH
2, –
78°;
rt,
12 h
CN
H2N
CO
2R2
R1
R1
Me
n-Pr
i-Pr
i-B
u
Bn
(87)
(84)
(78)
(84)
(91)
% d
e
56 52 40 44 60
475
NN B
nO
HO
C4
NN B
nO
HO
NH
2
NN B
nO
HO
NH
N
(90)
+(4
)14
9O
H N, t
olue
ne, N
aOH
, H2O
, 0°,
10 m
in
RO
2CC
O2R
RO
2CC
O2R
NH
CO
2Bu-
t1.
LiH
MD
S (i
a), T
HF,
–78
°, 30
min
2.
,
–78°
, 20
h; to
rt
ON
CO
2Bu-
tE
tO2C
EtO
2C
R Me
Et
(30)
(22)
155
Ac
CO
2Et
R
Ac
CO
2Et
R
NH
CO
2Et
EtO
2CH
N
CO
2Et
Ac
NH
CO
2Et
Ac
CO
2Et
R
NC
O2E
t
NH
CO
2Et
++
x eq
312
N
OH
N
OH
Et
EtO
2CC
O2P
ht-
BuO
2CN
=N
CO
2Bu-
t, 1
(5 m
ol%
),
tol
uene
, rt,
16 h
EtO
2CC
O2P
h
N(C
O2B
u-t)
NH
CO
2Bu-
t(9
9), 9
0% e
e (R
)48
1
C4
C4-
6
R3
O
R1
O
R2
R3
O
R1
O
N
Ar Ar
NH
NH
2
t-B
uO2C
N=
NC
O2B
u-t,
2 (
2 m
ol%
), T
HF,
–60
°
2
Bu-
t
Bu-
t
951
R1
H Me
Me
Me
Et
R2
Me
Me
Me
Et
Me
R3
OB
u-t
OE
t
OB
u-t
OB
u-t
OB
u-t
Tim
e
0.5
h
0.5
h
3 h
24 h
24 h
(99)
(99)
(>99
)
(54)
(90)
% e
e
83
85 (
S)
88 62 86
R2
NC
O2B
u-t
NH
CO
2Bu-
t
Ar
=
1
313
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
R2
OO
R1
R2
OO
R2
OO
ER
1R
1E
+
E =
N(C
O2R
3 )NH
CO
2R3
R3 O
2CN
=N
CO
2R3 , c
atal
yst (
10 m
ol%
),
ClC
H2C
H2C
l89
6
R1
H H H H H H Me
Me
Me
NO
Bn
O
R2
Y Y Y Y Y Y Me
OE
t
Y
R3
Et
Et
Bn
Bn
Bn
Bn
Et
Et
Et
Cat
alys
t
A B A B B B B B B
Tem
p
rt rt 0° rt 0° 50°
50°
50°
50°
Tim
e
18 h
12 h
4 d
17 h
72 h
17 h
20 h
23 h
—
I +
II
(94)
(97)
(100
)
(100
)
(100
)
(100
)
(96)
(73)
(0)
I:II
73:2
7
74:2
6
89:1
1
70:3
0
69:3
1
63:2
7
— — —
Y =
ON
iO
OO
ON
iO
OO
Cat
alys
t A
III
Cat
alys
t B
C4-
6
C4-
13
NC
CO
2Bu-
t
R1
NC
CO
2Bu-
t
R1
N48
1
N
OH
N
OH
Et
R2 O
2CN
=N
CO
2R2 , 1
(5
mol
%),
tolu
ene
1
NH
CO
2R2
R2 O
2C
314
R1
Me
i-B
u
2-th
ieny
l
Ph Ph Ph Ph Ph 2-FC
6H4
4-C
lC6H
4
4-O
2NC
6H4
4-M
eOC
6H4
3-M
eC6H
4
2-na
phth
yl
R2
t-B
u
t-B
u
t-B
u
Et
Cl 3
CC
H2
t-B
u
t-B
u
Bn
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
Tem
p
— — –78°
–78°
–78°
–78° rt
–78°
–50°
–78°
–50°
–78°
–78°
–78°
Tim
e
— —
16-2
0 h
30 s
30 s
4 h
45 m
in
30 s
16-2
0 h
16-2
0 h
16-2
0 h
16-2
0 h
16-2
0 h
16-2
0 h
("ex
celle
nt")
("ex
celle
nt")
(99)
(>95
)
(>95
)
(>95
)
(>95
)
(>95
)
(99)
(99)
(99)
(95)
(99)
(99)
% e
e
("lo
wer
")
("lo
wer
")
97 84 7 >98 90 64 98
98 (
S)
91 89 97 98C
4
BnO
2CN
=N
CO
2Bn,
cat
alys
t (10
mol
%),
tol
uene
, –78
°, 30
min N
NOH
BnO
N
OB
n
NOH
Cat
alys
t AC
atal
yst B
NC
CO
2Et
NC
CO
2Et
NC
atal
yst
A B
(75)
(74)
% e
e
35 23
232
NH
CO
2Bn
BnO
2C
315
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
C4-
9
R1 C
OC
OR
2
F
R1 C
OC
OR
2
FN
1.
[S
,S (
A)
or R
,R (
B),
5 m
ol%
],N
OO
N
PhPh
237
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
t-B
u
t-B
u
Ph Ph
R2
OM
e
OM
e
OM
e
OE
t
OE
t
OE
t
OE
t
OE
t
OE
t
(2S,
3R)-
men
thyl
oxy
(2S,
3R)-
men
thyl
oxy
(2S,
3R)-
men
thyl
oxy
NPh
2
OE
t
OE
t
OE
t
OE
t
R3
Et
Et
Bn
Et
Et
Et
Et
Bn
Bn
Bn
Bn
Bn
Bn
Et
Bn
Et
Bn
Solv
ent
CH
2Cl 2
hexa
ne
CH
2Cl 2
CH
2Cl 2
hexa
ne
tolu
ene
MeC
N
CH
2Cl 2
hexa
ne
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
(94)
(90)
(95)
(90)
(84)
(95)
(82)
(73)
(—)
(31)
(75)
(95)
(88)
(84)
(84)
(85)
(78)
% e
e or
dr
94 86 92 93 90 85 20 91 88
43:5
7
87.5
:12.
5
1.5:
98.5
92 93 93 87 81
Cat
alys
t or
Add
end
A A A A A A A A A
TM
ED
A
A B A A A A A
CO
2Et
NH
2N
NH
2CO
2Et
RO
2CN
=N
CO
2R, s
olve
nt23
0
R Me
Et
(—)
(96)
e
Solv
ent
Et 2
O
MeO
H
C4
NH
CO
2R3
CO
2R3
C
u(O
Tf)
2 (5
mol
%),
sol
vent
, rt,
3 h
2. S
ubst
rate
and
R3 O
2CN
=N
CO
2R3 , r
t, 2
d
CO
2R
NH
CO
2R
316
C4
N
S O2
OO
N
S O2
OO
N
S O2
OO
HE
HE
BnO
2CN
=N
CO
2Bn,
cat
alys
t (0.
06 e
q), M
eCN
,
ref
lux,
24
h
+
I m
ajor
pro
duct
II
476
Cat
alys
t
RuH
2(PP
h 3) 4
RuC
l 2(P
Ph3)
3
PPh 3
I +
II
(100
)
(100
)
(86)
% d
e
81 79 22
C5-
7
R1
R2
OO
R1
R2
OO
NH
2
1. H
2NSO
3H, N
aOH
, H2O
, rt,
few
min
utes
(f
orm
s I)
2. R
1 C(O
)CH
2C(O
)R2 (
form
s II
)
472
x eq
N H
R2 O
C
CO
R2
R1
R1
III
I
(100
)
(—)
(—)
(—)
(—)
II (0)
(—)
(—)
(30)
(47)
OO
R
C5-
6
OO
RN
1.
(
cat)
, tol
uene
, BrC
8F17
, 60°
2.E
tO2C
N=
NC
O2E
t, re
flux
, 3 d
480
R H Me
(96)
(40)
f
E =
N(C
O2B
n)N
HC
O2B
n
R1
Me
Me
Et
Me
Me
R2
Me
Me
Et
OE
t
NH
Ph
x 1 2 2 2 2
Ar
= 4
- (n-
C10
F 21)
C6H
4
NN
i/ 2O
Ar
NH
CO
2Et
CO
2Et
317
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
C5-
15
R1
R2
OO
R1
R2
OO
N
R3 N
HC
ON
=N
CO
2R4 , Z
nCl 2
, CH
2Cl 2
(fo
rms
I, th
en I
I)N N
HC
O2R
4
NR
3
O
R1
R2 C
OI
952
R1
Me
Me
Me
Me
Me
Me
Me
Me
Ph Ph Ph Ph Ph Ph Ph
R2
Me
Me
Me
OE
t
Ph Ph Ph Ph OE
t
OE
t
OE
t
Ph Ph Ph Ph
R3
Cl(
CH
2)2
c-C
6H11
4-M
eOC
6H4
Cl(
CH
2)2
Cl(
CH
2)2
Ph 2,4-
F 2C
6H3
4-FC
6H4
Cl(
CH
2)2
4-FC
6H4
c-C
6H11
Cl(
CH
2)2
c-C
6H11
2,4-
F 2C
6H3
3-C
lC6H
4
R4
Me
Me
Me
Me
Me
Et
Et
Et
Me
Et
Me
Me
Me
Et
Et
Tem
p
rt rt 0° rt rt 0° 0° 0° rt 0° rt rt rt 0° 0°
Tim
e
4 h
4 h
5 h
4 h
23 h
2.5
h
5 h
2 h
3 h
2 h
2 h
10 h
4 h
5 h
2 h
I
I
>73
>86
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(>92
)
(—)
(>90
)
(—)
(—)
II
II
(—)
(—)
(47)
(69)
(68)
(77)
(90)
(86)
(65)
(88)
(—)
(93)
(—)
(57)
(72)
CO
2Et
OC
5
CO
2Et
ON
(57)
, 95%
ee
(R)
239
OH
2Pd
NC
Me
P P=
PPh 2
PPh 2
2+
3
P P
2 PF
6–
BnO
2CN
=N
CO
2Bn,
3 (
5 m
ol%
),
MeO
H, r
t, 62
h
NH
CO
2R4
R3 H
NO
C
NH
CO
2Bn
CO
2Bn
318
CO
2Et
O
Ar
N HN H
S
NM
e 2
tol
uene
, rt,
"slo
w"
(10
mol
%),
t-B
uO2C
N=
NC
O2B
u-t,
N(7
6) 1
5% e
e23
3C
O2E
t
O
C5
R1
CO
2R3
O
R2
C5-
11
R1
N
O R2
CO
2R3
1.
(S,
S) (
x m
ol%
),N
OO
N
PhPh
235
R1
Me
Me
Me
—(C
H2)
3—
—(C
H2)
3—
Et
—(C
H2)
4—
Me
i-Pr
i-Pr
—(C
H2)
5—
Ph Ph Bn
Bn
R2
Me
Me
Me
Me
CH
2CH
=C
H2
Me
Me
Me
Me
Me
Me
R3
Et
Et
t-B
u
Et
Et
Et
Et
t-B
u
t-B
u
t-B
u
Et
Et
Et
t-B
u
t-B
u
x 0.2
10 10 0.5
10 0.5
0.5
0.5
0.5
10 0.5
0.5
10 0.5
10
(91)
(98)
(86)
(96)
(98)
(98)
(96)
(80)
(89)
(96)
(70)
(81)
(85)
(79)
(84)
% e
e
96 98 98 99 99 98 99 98 98 98 99 87 95 98 98
Ar
= 3
,5-(
CF 3
) 2C
6H3
t-B
uO2C
NH
CO
2Bu-
t
NH
CO
2Bn
CO
2Bn
C
u(O
Tf)
2, C
H2C
l 2
2. S
ubst
rate
, the
n B
nO2C
N=
NC
O2B
n, r
t, 16
h
319
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
O
OO
O
OO
OO
OO
O
OO
O
EO
OO
E
+
I m
ajor
isom
erII
E =
N(C
O2R
)NH
CO
2R
RO
2CN
=N
CO
2R, c
atal
yst (
x eq
),
MeC
N, r
t, 24
h
R Et
Et
Et
i-Pr
t-B
u
t-B
u
Bn
Bn
Bn
Cat
alys
t
RuC
l 2(P
Ph3)
3
RuH
2(PP
h 3) 4
PPh 3
RuH
2(PP
h 3) 4
RuC
l 3(P
Ph3)
3
RuH
2(PP
h 3) 4
RuC
l 2(P
Ph3)
3
RuH
2(PP
h 3) 4
PPh 3
x
0.03
0.03
0.09
0.03
0.09
0.09
0.03
0.03
0.09
I +
II
(92)
(72)
(83)
(69)
(75)
(55)
(98)
(64)
(65)
% d
e
13 33 48 40 0 19 5 34 0
476
C5
CO
2Et
EtO
2C
CO
2Et
C6
1. N
aH, E
t 2O
, 0°,
3 h
2. N
H2C
l, –7
8°; t
o 0°
(74)
+
(1.5
)
CO
2Et
EtO
2C
CO
2Et
1. N
aH, E
t 2O
, 0°,
3 h
2. N
H2C
l, –7
8°; t
o 0°
64(—
)
64
CO
2Et
EtO
2C
CO
2Et
1. N
aH, P
hH, 0
°; r
t, 1
h
2. A
dd s
uspe
nsio
n of
Na
salt
in E
t 2O
to C
lNH
2
at
0°;
rt,
2 h
I (
65)
63
EtO
2CN
H2
EtO
2CC
O2E
t
EtO
2CN
H2
EtO
2CC
O2E
t
I
EtO
2C
H N
EE
CO
2Et
EE
E =
CO
2Et
320
C6-
10
NC
NH
R2
O
R1
NH
HN
OR
1
CO
NH
R2
NR
2
N HO
R1
H2N
CH
2ON
H, t
olue
ne, N
aOH
, H2O
, rt,
12 h
O
149
R1
i-Pr
c-C
6H11
4-C
lC6H
4CH
2
4-O
2NC
6H4C
H2
2-M
eOC
6H4C
H2
4-M
eOC
6H4C
H2
4-M
eOC
6H4C
H2
4-M
eOC
6H4C
H2
4-M
e 2N
C6H
4CH
2
R2
2,6-
Me 2
C6H
3
PhC
H2C
H2
Me
3,4-
(MeO
) 2C
6H3(
CH
2)2
Me
i-Pr
Ph 2,6-
Me 2
C6H
3
i-Pr
I
(—)
(62)
(47)
(35)
(81)
(—)
(—)
(52)
II (81)
(—)
(—)
(—)
(—)
(58)
(98)
(—)
CO
2Et
Et
OC
O2E
t
O
BnO
2CN
=N
CO
2Bn,
cat
alys
t, C
H2C
l 2, –
25°,
7 d
Et
N
Cat
alys
t
cinc
honi
ne
cinc
honi
dine
(72)
(72)
% e
e
47g
27g
231
C6
O
CO
2Et
O
CO
2Et
NR i-
Pr
Bn
Tim
e
31 h
1 h
(89)
(73)
% e
e
97
93 (
R)
239
RO
2CN
=N
CO
2R, 3
(5
mol
%),
MeO
H, r
t
+
I +
II
(54)
NH
CO
2Bn
CO
2Bn
CO
2R NH
CO
2R
C6-
7O
CO
2Et
O
CO
2Et
O
CO
2Et
NC
O2E
tN
HC
O2E
t4-
O2N
C6H
4SO
2ON
HC
O2E
t (1
eq),
CaO
(2
eq),
CH
2Cl 2
, rt
5 eq
n 1 2
Tim
e
1 h
3 h
I
(49)
(40)
II (4)
(10)
+12
4
nn
nI
I
II
II
OH
2Pd
NC
Me
P P=
PPh 2
PPh 2
2+
3
P P
2 PF
6–
321
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
O
CO
2Et
EtO
2CN
=N
CO
2Et,
4 (c
at),
tolu
ene,
rt
OC
uO
OOt-
Bu
Bu-
t
(95)
953
O
CO
2Et
N
C6
O
CO
2R1
O
CO
2R1
N
1. 5
(12
.5 m
ol%
), M
(OT
f)3
(9 m
ol%
), 4
Å M
S,
so
lven
t, rt
, ove
rnig
ht
2. S
ubst
rate
3. t-
BuO
2CN
=N
CO
2Bu-
t, te
mp
NN
OO
N
R2
R2
954
4
5
CO
2Bu-
t
NH
CO
2Bu-
t
CO
2Et
NH
CO
2Et
322
R1
Et
Et
Et
Et
Et
Et
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
1-ad
aman
tyl
1-ad
aman
tyl
1-ad
aman
tyl
1-ad
aman
tyl
1-ad
aman
tyl
1-ad
aman
tyl
1-ad
aman
tyl
1-ad
aman
tyl
1-ad
aman
tyl
1-ad
aman
tyl
R2
i-Pr
1-ad
aman
tyl
i-Pr
1-ad
aman
tyl
i-Pr
1-ad
aman
tyl
i-Pr
i-Pr
1-ad
aman
tyl
i-Pr
i-Pr
1-ad
aman
tyl
i-Pr
1-ad
aman
tyl
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
M Yb
Yb
Eu
Eu
La
La
Sc Yb
Yb
Eu
Eu
Eu
La
La
Yb
La
Eu
Eu
Eu
Eu
Eu
Eu
Eu
Eu
Solv
ent
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
MeC
N
MeC
N
MeC
N
MeC
N
ClC
H2C
H2C
l
CH
2Cl 2
DM
E
TH
F
cycl
ohex
ane
Tem
p
rt rt 0° 0° 0° 0° rt
–41°
to 0
°rt rt
–41°
to 0
°–4
1° 0° –41°
0° rt rt 0° –41° 0° 0° 0° 0° 0°
(85)
(74)
(82)
(88)
(84)
(79)
(0)
(70)
(31)
(55)
(81)
(66)
(78)
(71)
(62)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
(—)
% e
e
68 0 62 12 52 18 — 70 66 67 >95 86 22 84 55 89 93 95 100
73 71 30 50 0
Con
fig.
R — R S R R — R S R R S R S R R R R R R R R R —
323
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
n 1 1 1 1 1 1 1 2 2
R Et
Et
Et
Et
Et
Bn
Bn
Et
Et
Cat
alys
t
KO
Ac
quin
ine
quin
idin
e
cinc
honi
ne
cinc
honi
dine
cinc
honi
ne
cinc
honi
dine
cinc
honi
ne
cinc
honi
dine
Tim
e
15 m
in
2 m
in
1 m
in
5 m
in
5 m
in
2 m
in
10 m
in
48 h
24 h
% e
e
— 26h
38h
88 (
R)
87 (
S)
54i
76i
84 (
R)
77 (
S)
C6-
7O
CO
2R
O
CO
R
NB
nO2C
N=
NC
O2B
n, C
H2C
l 2, c
atal
yst,
–25°
231
nn
(>80
)
(—)
(—)
(95)
(95)
(99)
(99)
(92)
(81)
NH
CO
2Bn
CO
2Bn
t-B
uO2C
N=
NC
O2B
u-t,
2 (
x m
ol%
), T
HF,
–60
°95
1
n 1 1 2
x
0.05 2 2
Tim
e
4 h
5 m
in
24 h
(100
)
(100
)
(>99
)
% e
e
97 (
R)
97 (
R)
98
O
CO
2Et
n
O
CO
2Et
nN N
HC
O2B
u-t
CO
2Bu-
t
N
Ar Ar
NH
NH
2
2
Bu-
t
Bu-
t
Ar
=
Con
fig.
— — — R S — — R S
Con
fig.
R R —
324
YO
CO
Me
YON
CO
2Bu-
t
NH
CO
2Bu-
tt-
BuO
2CN
=N
CO
2Bu-
t, 2
(cat
, 2 m
ol%
), T
HF,
–60
°Y O C
H2
Tim
e
24 h
5 h
(>99
)
(99)
% e
e
15 91
951
CO
Me
N
Ar Ar
NH
NH
2
2
Bu-
t
Bu-
t
Ar
=
C6-
7
C6-
11
R OB
u-t
Et
CH
2Bu-
t
Tem
p
–52° rt
–50°
(99)
(86)
(90)
Tim
e
66 h
143
h
91 h
% e
e
89 83 83
481
n 1 2 1
O
CO
Me
O
C6
O
CO
Me
OE(9
3), 9
3% e
e23
9
O
CO
R
n
OC
OR
nN N
HC
O2B
u-t
CO
2Bu-
t
E =
N(C
O2P
r-i)
NH
CO
2Pr-
i
N
OH
N
OH
Et
t-B
uO2C
N=
NC
O2B
u-t,
1 (5
mol
%),
tolu
ene
1
i-Pr
O2C
N=
NC
O2P
r-i,
3 (5
mol
%),
MeO
H, r
t, 9
h
OH
2Pd
NC
Me
P P=
PPh 2
PPh 2
2+
3
P P
2 B
F 4–
325
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
O
NY
O
NY
E
OE
OH
1. E
tO2C
N=
NC
OA
r, P
hH, 0
°, 2-
3 d
(for
ms
I)
2. H
3O+, r
t, 30
d (
form
s II
)
249
I
(59)
(50)
(67)
(65)
II (40)
(45)
(—)
(—)
Ar
Ph 4-O
2NC
6H4
Ph 4-O
2NC
6H4
Y — — O O
III
E =
N(C
O2E
t)N
HC
OA
r
C6
NH
R1
O
NH
R1
ONR
2 CO
N=
NC
OR
2 , MeC
N, r
eflu
x, 3
h
R1
n-B
u
n-B
u
t-B
u
t-B
u
Ph Ph
250
R2
EtO
Ph EtO
Ph EtO
Ph
(46)
(67)
(50)
(40)
(65)
(65)
CO
R2
NH
CO
R2
O
CO
R OO
CO
R
ONB
nO2C
N=
NC
O2B
n, C
H2C
l 2, c
atal
yst,
–25°
Cat
alys
t
cinc
honi
ne
cinc
honi
dine
cinc
honi
ne
cinc
honi
dine
cinc
honi
ne
cinc
honi
dine
Tim
e
2 m
in
2 m
in
25 m
in
40 m
in
4 d
4 d
(91)
(96)
(91)
(91)
(68)
(51)
% e
ei
49 42 60 64 51 57
R Me
Me
i-Pr
i-Pr
t-B
u
t-B
u
231
NY
OR
R
NY
OR
R
N95
5
R H H Me
Me
Y — O — O
(100
)
(100
)
(—)
(—)
EtO
2CN
=N
CO
2Et
CO
2Bn
NH
CO
2Bn
CO
2Et
NH
CO
2Et
C6-
9
C6-
8
326
C7
CO
2Et
NH
ON
HC
O2E
t
CO
2Et
4-O
2NC
6H4S
O2O
NH
CO
2Et,
CH
2Cl 2
, rt
(49)
, 60%
de
125
Ph
BnO
2CN
=N
CO
2Bn,
CH
2Cl 2
(100
)23
6•
Ac
CO
2Et
•A
c
EtO
2CN
NH
CO
2Bn
CO
2Bn
C7-
8
CO
R1
OO
N
CO
R1
R2 O
2CN
=N
CO
2R2 , c
atal
yst (
10 m
ol%
), to
luen
e
3,5-
(CF 3
) 2C
6H3
N HN H
Y
NM
e 2ca
taly
st A
: Y =
S B
: Y =
O
NM
e 2
BzN
H
cata
lyst
C
233
R1
OM
e
OM
e
OM
e
OM
e
OM
e
OM
e
OPr
-i
OB
u-t
Me
OM
e
OB
u-t
R2
Et
i-Pr
t-B
u
t-B
u
t-B
u
Bn
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
Cat
alys
t
B B A B C B B B B B B
Tem
p
–78°
–78° rt
–78°
–78°
–78°
–78°
–78°
–78° rt
–40°
Tim
e
2 h
2.5
h
1 h
3 h
15 h
2 h
10 h
15 h
3 h
96 h
48 h
n 1 1 1 1 1 1 1 1 1 2 3
(96)
(94)
(91)
(96)
(90)
(92)
(98)
(96)
(97)
(52)
(90)
% d
e
51 72 75 83 60 50 91 91 80 87 90
nn
CO
2R2
NH
CO
2R2
C8-
11
CN
H2N
O
HN
NH
O
R
CO
NH
2
R14
9
R c-C
5H9
2-fu
rylm
ethy
l
4-(1
-ben
zyl)
pipe
ridy
l
c-C
6H11
n-C
8H17
(94)
(87)
(81)
(99)
(76)
NH
, DA
BC
O (
cat)
, tol
uene
, rt,
12 h
O
327
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
NHC
O2E
t
ONH
CO
2Et
N3
O
1. L
DA
, TH
F
2. T
sN3
3. T
MSC
l
(—)
482
C9
(53)
1. N
aH, D
MF
2. 2
,4-(
O2N
) 2C
6H3O
NH
287
7
1. L
i bas
e, T
HF
2. P
h 2P(
O)O
NH
2, –
20°;
rt,
12 h
I (
31)
139
Ph
CO
2Et
CO
2Et
Ph
CO
2Et
CO
2Et
H2N
I
C8
O
CO
R1
n
O nNC
OR
2
NH
CO
2R2
n 1 1 2 2 2 2 2 2 2 2 3 3
R1
s-B
u
s-B
u
Me
Me
Et
i-Pr
s-B
u
s-B
u
Ph Ph s-B
u
s-B
u
R2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Et
Bn
Bn
Bn
x 10 10 1 10 10 10 1 10 10 10 10 10
Tem
p
rt
–24° rt rt rt rt rt rt rt rt rt
–24°
Tim
e
18 h
18 h
18 h
18 h
18 h
18 h
18 h
18 h
40 h
18 h
18 h
18 h
(60)
(60)
(94)
(82)
(83)
(86)
(76)
(76)
(74)
(87)
(90)
(89)
% e
e
89 94 80 84 94 94 94 95 77 91 83 85
956
C8-
13
1.
(S,
S) (
x m
ol%
),N
OO
N
PhPh
C
u(O
Tf)
2 (x
mol
%),
CH
2Cl 2
, rt,
2 h
2. S
ubst
rate
, the
n R
2 O2C
N=
NC
O2R
2 ,
te
mp,
tim
e
CO
2R2
328
1. N
aH, T
HF,
rt,
15 m
in
2. R
eage
nt, r
t, ov
erni
ght
Rea
gent
Ph2P
(O)O
NH
2
(4-M
eOC
6H4)
2P(O
)ON
H2
4-O
2NC
6H4C
O2N
H2
(96)
b
(75)
(85)
106
1. L
iHM
DS
or N
aHM
DS
2.(0
)15
5
1. L
i bas
e, T
HF
2. P
h 2P(
O)O
NH
2, –
20°;
rt,
12 h
139
I (
>96
)
O
NC
ON
Et 2
4-C
lC6H
4
CO
NH
Ph
CO
NH
PhN
H, D
AB
CO
, tol
uene
, rt,
12 h
O(7
2)14
9Ph
CO
2Et
CN
1. L
iHM
DS
(ia)
, TH
F, –
78°,
1 h
2.
(+
), –
78°,
31 h
; to
rt
ON
HN
NN
PhH
HPh
CN
CN
CO
NH
2
Ph
(34)
(34)
(9)
151
Ph+
+
1. L
i bas
e
2. 2
,4,6
-Me 3
C6H
2SO
2ON
Me 2
, Et 2
O o
r T
HF,
–10°
to –
20° ;
rt,
15 h
(95)
133
Ar
N HN H
S
NM
e 2(10
mol
%),
tolu
ene,
–78
°
t-B
uO2C
N=
NC
O2B
u-t,
233
(93)
, 73%
ee
CO
2Et
CN
Ph
Ph
CNCO
2Et
Me 2
N
Ar
= 3
,5-(
CF 3
) 2C
6H3
Ph
CNCO
2Et
H2N
I
Ph
NH
CO
NE
t 2
CO
2Et
NC
Ph
CO
NH
Ph
CO
NH
Ph
NH
2
Ph
NCO
2Et
NC
NH
CO
2Bu-
t
CO
2Bu-
t
PhC
O2E
t
CN
1. N
aH, T
HF
2. 2
,4-(
O2N
) 2C
6H3O
NH
2
(54)
93Ph
CNCO
2Et
H2N
329
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
C9-
13A
rC
O2E
t
CN
RO
2CN
=N
CO
2R, c
atal
yst (
x m
ol%
),
so
lven
t, –7
8°
N
NOH
BnO
N
OB
n
NOH
cata
lyst
A
cata
lyst
B
232
Ar
Ph Ph Ph Ph Ph Ph Ph Ph 4-FC
6H4
4-FC
6H4
4-C
lC6H
4
4-C
lC6H
4
4-B
rC6H
4
4-B
rC6H
4
4-B
rC6H
4
4-B
rC6H
4
4-M
eOC
6H4
4-M
eOC
6H4
2-M
eC6H
4
2-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
1-na
phth
yl
1-na
phth
yl
R Et
i-Pr
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
Bn
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
Bn
Bn
t-B
u
t-B
u
Bn
Bn
t-B
u
t-B
u
t-B
u
t-B
u
Cat
alys
t
A A A A A A B A A B A B A B A B A B A B A B A B
x 10 10 10 10 10 5 5 10 5 5 5 5 5 5 5 5 10 10 5 5 5 5 10 10
Solv
ent
tolu
ene
tolu
ene
Et 2
O
TH
F
CH
2Cl 2
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
tolu
ene
Tim
e
1 m
in
45 m
in
3 h
12 h
11 h
2 h
4 h
1 m
in
1 h
2 h
30 m
in
30 m
in
1 h
2 h
1 m
in
1 m
in
5 m
in
10 m
in
1 h
3.5
h
8 h
8 h
8 h
12 h
(—)
(—)
(—)
(—)
(—)
(92)
(92)
(—)
(97)
(95)
(96)
(94)
(99)
(97)
(86)
(83)
(96)
(96)
(71)
(72)
(96)
(96)
(99)
(98)
% e
e
85 44 70 10 77 95 97 89 94 96
93 (
S)
97 93 96 91 92 94 97 82 87 94 96 93 99
Ar
NCO
2Et
NC
NH
CO
2R
CO
2R
330
C9-
10R
CO
2Et
CO
2Et
1. N
aH, g
lym
e, r
t
2. T
sN3,
rt;
35° t
o 40
°, 1
h
483
R Ph 7-cy
cloh
epta
trie
nyl
(71)
j
(65)
j
4-B
nOC
6H4
CO
2Et
CO
2Et
1. N
aH, T
HF,
HM
PA, r
t, 2
h
2. T
sN3,
50°
, 2.5
h
(76)
777,
957
C9
O CO
2Et
O CO
2Et
N3
TsN
HC
O2E
t
N2
O
TsN
3, E
t 3N
, Et 2
O, r
t, 14
0 h
+
(74)
k(2
0)
NC
NR
2 R3
O
R1
NH
HN
OR
1 CO
NR
2 R3
H2N
CH
2ON
R2 R
3
O
R1
N
III
NH
, NaO
H, t
olue
ne, H
2O, r
t, 12
hO
149
+
H2N
OC
NR
2 R3
O
R1
H2N
III
R1
4-M
eOC
6H4C
H2
4-C
lC6H
4CH
2
2-M
eOC
6H4C
H2
4-M
eOC
6H4C
H2
R2
—(C
H2)
2O(C
H2)
2—
—(C
H2)
5—
—(C
H2)
5—
Ph
R3
Me
I
(48)
+ 3
9% I
II
(62)
I +
III
(—)
(—)
II (—)
(—)
(32)
(43)
Add
end
— — HC
l
HC
l
III
(95)
(82)
(90)
a
(98)
a
C10
O
CO
2R
C10
-11
O
CO
2R
E23
3
n 1 2
R t-B
u
Me
Tem
p
–78°
–40°
Tim
e
4 h
5 h
(93)
(99)
% e
e
90 97
E =
N(C
O2B
u-t)
NH
CO
2Bu-
t
319
n
(for
ms
I +
II)
1. 2. I
or
II, E
tOH
, add
end,
ref
lux,
5 m
in
(f
orm
s II
I)
R
CO
2Et
CO
2Et
N3
4-B
nOC
6H4
CO
2Et
CO
2Et
N3
Ar
N HN H
S
NM
e 2(10
mol
%),
tolu
ene
t-B
uO2C
N=
NC
O2B
u-t,
Ar
= 3
,5-(
CF 3
) 2C
6H3
n
331
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
O
CO
2R3
O
CO
2R3
E
R1
R2
n 1 1 1 1 2 2 2
R1
H H H MeO
H H H
R2
H H H MeO
H H MeO
R3
Et
Et
Bn
Et
Me
Et
Et
R4
Et
i-Pr
i-Pr
i-Pr
t-B
u
Et
t-B
u
X PF6
PF6
PF6
PF6
BF 4
PF6
SbF 6
Solv
ent
MeO
H
MeO
H
MeO
H
Me 2
CO
MeO
H
MeO
H
MeO
H
Tim
e
30 m
in
30 m
in
30 m
in
170
h
106
h
1 h
144
h
(94)
(98)
(99)
(71)
(56)
(75)
(66)
% e
e
94 97 94 95 95 91 91
239
C10
-11
O
CO
2Et
RO
2CN
=N
CO
2R, 3
(5
mol
%),
ion
ic li
quid
[bm
im]Y
, rt
O
CO
2Et
E
239
C10
R Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
i-Pr
X BF 4
PF6
SbF 6
PF6
SbF 6
PF6
SbF 6
PF6
SbF 6
Y BF 4
BF 4
SbF 6
SbF 6
PF6
PF6
PF6
PF6
SbF 6
Tim
e
30 m
in
1 h
30 m
in
1 h
1 h
1 h
12 h
18 h
12 h
(88)
(90)
(91)
(89)
(96)
(93)
(96)
(81)
(92)
% e
e
0 0 87 79 97 85 91 71 89
OH
2Pd
NC
Me
P P=
PPh 2
PPh 2
2+
3
P P
2 X
–
E =
N(C
O2R
)NH
CO
2R
R4 O
2CN
=N
CO
2R4 , 3
(as
abo
ve, 5
mol
%),
sol
vent
, rt
E =
N(C
O2R
4 )NH
CO
2R4
nn
332
C10
S
NOC
O2M
e
EtO
2CC
O2E
t
1. L
iHM
DS,
TH
F, –
70°,
5 m
in
2. T
sN3,
–70
°3.
TM
SCl,
–70°
; to
rt,
2 h
S
NO
EtO
2CC
O2E
tN3
CO
2Me
339
(43)
C10
-12
O
CO
2Et
O
CO
2Et
N3
RSO
2N3,
Et 3
N, s
olve
nt
+
prod
ucts
of
diaz
o tr
ansf
er I
II
I
n 1 1 2 2 3 3 3 3 3 3 3 3 3
R 4-O
2NC
6H4
4-M
eC6H
4
4-O
2NC
6H4
4-M
eC6H
4
4-O
2NC
6H4
4-M
eC6H
4
4-M
eC6H
4
4-M
eC6H
4
Me
Me
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
2,4,
6-(i
-Pr)
3C6H
2
Solv
ent
TH
F
TH
F
TH
F
TH
F
TH
F
TH
F
MeC
N
DM
F
TH
F
MeC
N
TH
F
MeC
N
CH
2Cl 2
Tim
e
30 m
in; 2
h
6 d
20 h
4 d
6 d
5 d
1 d
10 h
3 d
15 h
10 d
4 d
1 h
I (0)
(16)
(21)
(75)
(31)
(31)
(20)
(32)
(24)
(19)
(72)
(80)
(0)
II (0)
(0)
(47)
(0)
(34)
(0)
(56)
(18)
(30)
(60)
(0)
(0)
(71)
EtO
2CC
ON
HSO
2R
II
III
(94)
(80)
(0)
(tra
ce)
(14)
(66)
(18)
(10)
(28)
(8)
(0)
(0)
(15)
321
321
321
321
319
321
319
319
319
319
319
319
319
TsN
3, E
t 3N
, Et 2
O, r
t, 19
0 h
O
CO
2Me
O
CO
2Me
CO
NH
Ts
N2
CO
2Me
+(2
0)(5
6)31
9
C11
N3
nn
n−1
+
Tem
p
0°; r
t
rt rt rt rt rt rt rt rt rt rt rt 0°
333
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
0. E
NO
LA
TE
S O
F α−
CY
AN
O C
AR
BO
NY
L A
ND
β−D
ICA
RB
ON
YL
CO
MPO
UN
DS
(Con
tinu
ed)
C17
PhC
O2E
t
CO
2Et
Ph
CO
2Et
CO
2Et
NH
21.
NaH
, TH
F, r
t, 25
min
2. 2
,4-(
O2N
) 2C
6H3O
NH
2, r
t, 20
h(6
2)47
4
PhPh
OO
Et
C13
PhPh
OO
Et
NE
tO2C
N=
NC
O2E
t, ca
taly
st (
x eq
), M
eCN
,
rt
, 24
h
476
N CO
2EtC
O2M
e
CO
2Me
i-Pr
N CO
2EtCO
2Me
CO
2Me
i-Pr
1. N
aH, T
HF,
HM
PA, r
t, 2
h
2. T
sN3,
rt;
refl
ux, 2
h
(62)
958
N3Cat
alys
t
Ph3P
RuC
l 2(P
Ph3)
3
x 1
0.06
(100
)
(83)
C11
O
CO
2Et
OC
O2E
t
N NH
CO
2Bu-
t
(>99
), 9
7% e
e95
1
N
Ar Ar
NH
NH
2
t-B
uO2C
N=
NC
O2B
u-t,
2 (
2 m
ol%
), T
HF,
–60
°, 1
h
2
Bu-
t
Bu-
t
Ar
=
CO
2Bu-
t
NH
CO
2Et
CO
2Et
334
C19
(4-M
eOC
6H4)
2P(O
)ON
H2,
NaH
, TH
F, r
t14
5
CO
2Et
CO
2Et
n-C
6H13 N
O2
CO
2Et
CO
2Et
n-C
6H13 N
O2
+
NH
2
CO
2Et
CO
2Et
n-C
6H13 N
O2 O
H
(31)
(15)
a The
pro
duct
was
isol
ated
as
the
hydr
ochl
orid
e.b
The
bas
e us
ed w
as L
DA
.c T
he a
min
ated
pro
duct
is f
orm
ed a
s an
inte
rmed
iate
, whi
ch th
en r
eact
s w
ith a
noth
er m
olec
ule
of th
e st
artin
g di
keto
ne to
yie
ld th
e py
rrol
e de
riva
tive.
d Lith
ium
hyd
roxi
de (
6 eq
) w
as a
lso
adde
d.e T
he n
umbe
r is
the
yiel
d of
cru
de p
rodu
ct.
f With
cat
alys
t rec
over
ed f
rom
the
BrC
8F17
pha
se, t
he y
ield
was
92%
.g T
he a
bsol
ute
conf
igur
atio
n w
as n
ot d
eter
min
ed b
ut it
was
opp
osite
to th
at o
btai
ned
with
the
othe
r ca
taly
st.
h Qui
nine
and
qui
nidi
ne g
ave
the
oppo
site
ena
ntio
mer
s as
the
maj
or p
rodu
cts.
i In e
ach
exam
ple,
cin
chon
ine
and
cinc
honi
dine
gav
e th
e op
posi
te e
nant
iom
ers
as th
e m
ajor
pro
duct
s.j T
he n
umbe
r is
the
yiel
d of
unp
urif
ied
prod
uct.
k With
the
corr
espo
ndin
g 5-
, 6-,
and
7-m
embe
red
keto
est
ers,
onl
y th
e ri
ng-o
pene
d di
azo
este
rs w
ere
obta
ined
.l T
he is
omer
ic 1
-car
beth
oxy-
2-ke
to a
nalo
gs (
n =
1, 2
) on
ly g
ave
the
prod
ucts
of
diaz
o tr
ansf
er a
nd/o
r ri
ng c
ontr
actio
n.
335
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
1. I
NT
RA
MO
LE
CU
LA
R A
MIN
AT
ION
S
NC
O2M
ePh
OC
OB
u-t
C3
NaH
, KH
, or
LD
A, T
HF,
–80
° to
15°
(0)
490
NN
Me
OO
Ph
NN
Me
OO
Ph
NH
1. T
iCl 4
, CH
2Cl 2
, rt,
15 m
in
2. A
dd to
Et 3
N (
2 eq
), C
H2C
l 2, r
t, 30
min
488
NN
Me
OO
Ph
NH
+
NN
Me
O
R
O
Ph
NN
Me
O
R
O
Ph
NH
1. M
X, C
H2C
l 22.
Add
to E
t 3N
(2
eq),
CH
2Cl 2
, rt,
30 m
in
487,
488
BnO
NH
C4-
6R M
e
Me
Et
n-Pr
MX
TiC
l 4
AlM
e 2C
l
AlM
e 2C
l
AlM
e 2C
l
(97)
(80)
(67)
(70)
C4-
12
R2
NO
2
R1
R2NO
2
R1
NO
2
R2
R1
CO
2Et
NC
O2E
tN
+4-
O2N
C6H
4SO
2ON
HC
O2E
t,
CaO
, nea
t, rt
, 20
min
III
959
R1
Me
Et
i-Pr
—
(CH
2)4—
c-C
6H11
n-C
6H13
Z-E
tCH
=C
H(C
H2)
2
Ph(C
H2)
2
Ph(C
H2)
2
R2
Me
Me
Me
Me
(CH
2)2C
H=
CH
2
Me
Me
Et
I
(38)
(58)
(63)
(89)
(70)
(71)
(70)
(70)
(72)
II (5)
(6)
(12)
(0)
(8)
(4)
(7)
(16)
(13)
NPh
CO
2Me
BnO
NH
(81)
(14)
336
C4
F F
CF 3
CF 3
F F
CF 3
CF 3
NCO
Ph
Y NH
Cl
NH
OK
NN
Me 3
Pyri
dine
, DM
F, 0
° to
rt; r
t, 1
h
MeC
N, 0
°; r
t, 14
h
MeC
N, h
eat
(66)
(62)
(5)
960
F F
CF 3
R1
F F
CF 3
R1
NR2
R2 N
HO
SO2C
6H4N
O2-
4, E
t 3N
, sol
vent
R1
CF 3
CF 3
CO
2Me
CO
NM
e 2
R2
CO
2Et
SO2P
h
CO
2Et
CO
2Et
Solv
ent
Et 2
O
MeC
N
Et 2
O
CH
2Cl 2
961
NN
Me
O
R
O
Ph
NN
Me
O
R
O
Ph
NH
1. M
X, C
H2C
l 22.
Add
to E
t 3N
(2
eq),
CH
2Cl 2
, rt,
30 m
in
487,
488
BnO
NH
R Me
Me
Et
n-Pr
MX
TiC
l 4
AlM
e 2C
l
AlM
e 2C
l
AlM
e 2C
l
(96)
(77)
(71)
(70)
C4-
6
Ar1
NC
O2R
CF 3
Et 2
OC
NaH
, TH
F49
3
R Et
Bn
Ph
NA
r2
NA
r2
PhO
2S
(67)
(47)
(88)
(52)
PhC
OY
CF 3
CO
2R
NCO
2Et
Ar1 =
4-O
2NC
6H4S
O2O
(100
)
(100
)
(100
)
(100
)
(—)
— —
de 1
8-19
%
de 6
8-72
%
sing
le d
iast
ereo
mer
Ar2 =
3,5
-Me 2
C6H
3— — —
mix
ture
of
dias
tere
omer
s
sing
le d
iast
ereo
mer
PhO
2S
337
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
1. I
NT
RA
MO
LE
CU
LA
R A
MIN
AT
ION
S (C
onti
nued
)
4-O
2NC
6H4S
O2O
NH
CO
2Et (
5-6
eq),
CaO
, CH
2Cl 2
495
R1
H H MeO
R2
H Me
H
(tra
ce)
(30)
(tra
ce)
C4-
5
OO
R1
R2
OO
R1
R2
N
R4
R3
R2
R1
C5-
10
Et 3
N, E
t 2O
, rt
N H
R2
R1
R4
R3
R1
H H H Me
H
R2
CO
2Me
CO
2Me
CN
CO
2Me
4-O
2NC
6H4
R3
CO
2Me
CN
CO
2Et
CN
CO
2Me
R4
CO
2Me
CO
2Me
CO
2Et
CO
2Me
CN
(100
)a
(80)
b
(90)
b
(76)
b
(32)
b
492
OOR
2R
1
C5-
11
4-O
2NC
6H4S
O2O
NH
CO
2Et (
x eq
), C
aO, C
H2C
l 2,
w
ater
bat
h
OOR
2R
1
OOR
1R
2
EtO
2CN
EtO
2CN
+
III
R1
H Me
H Me
n-C
5H11
H Ph
R2
H H Me
Me
H n-C
5H11
H
x 2 3 3 3 5 5 5
I
(39)
(45)
(42)
(52)
(47)
(28)
(60)
II (0)
(0)
(39)
(0)
(0)
(24)
(0)
495
Ar
= 2
,4,6
-Me 3
C6H
2SO
2O
NH
Ar
CO
2Et
338
N
CO
2Et
R2
Ph2P
(O)O
R1
C6-
13
N H
CO
2Et
R2
Bas
e
R1
Me
Me
CH
2CH
=C
H2
Bn
Bn
CH
MeP
h
CM
e 2Ph
R2
H CO
2Et
H H CO
2Et
H H
Bas
e
LD
A
t-B
uOK
LD
A
LD
A
t-B
uOK
LD
A
LD
A
I
(75)
(95)
(20)
(47)
(81)
(10)
(0)
YN
+
III
II (0)
(0)
(0)
(40)
(0)
("al
mos
t exc
lusi
vely
")
(0)
496
C7-
10
CO
2Me
R
TM
SON
CO
2Me
t-B
uOK
(0.
25 e
q), C
H2C
l 2, T
HF,
rt,
4 h
N HH
RC
O2M
e
CO
2Me
R n-Pr
i-Pr
i-B
u
Ph n-C
7H15
(57)
(78)
(65)
(0)
(54)
491
•
CF 3
CF 3
CF 3
CF 3
EtO
2CN
HO
SO2C
6H4N
O2-
4, E
t 3N
, CH
2Cl 2
,
Fr
eon®
113
, rt,
3 h
CF 3
CF 3
CF 3CF 3
CO
2Et
N(7
0)96
1
C7
CO
2Et
C7-
11
Br
NH
OM
eN C
OM
e
1. M
eLi,
adde
nd, E
t 2O
, –78
°, 30
min
;
to
–15
°, 3
h
2. A
cCl,
pyri
dine
n 0 1 2 3 4
Add
end
n-B
uLi
n-B
uLi
t-B
uLi
t-B
uLi
—
(21)
(43)
(64)
(24)
(0)
n83 82
, 97
83 83 83
n
Y — — — PhC
H
— PhM
eC
—
339
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
1. I
NT
RA
MO
LE
CU
LA
R A
MIN
AT
ION
S (C
onti
nued
)
R1 O
2CR
4
NO
R5
R3
R2
R1 O
2C
DB
U, C
H2C
l 2, 0
°, 30
min
NR4
R1 O
2CC
O2R
1
R2R
3
R1
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
R2
H H i-Pr
n-C
5H11
Ph Ph Ph
R3
H Me
H H H H H H H
R4
Me
Me
Me
Me
H Me
Me
Me
CO
2Me
Ph Ph Ph
R5
Ms
Ms
Ms
Ms
Ms
Ac
CO
CF 3
Ms
Ms
(87)
(96
)c
(87)
(79
)c
(96)
(79
)c
(83)
(0)d
(0)
(57)
(99)
(83)
(80
)c
497
C8
NO
Ms
BnO
2C
CO
2Bn
DB
U, D
MF,
rt,
5 d
N
BnO
2CC
O2B
n
(83)
497
NM
eN
Ph
O
Ph
NH
OB
nO
NM
eN
Ph
O
Ph
OH N
C9
AlM
e 2C
l, E
t 3N
, CH
2Cl 2
, 0°
489
NM
eN
Ph
O
Ph
NH
OB
nO
NM
eN
Ph
OO
H N
AlM
e 2C
l, E
t 3N
, CH
2Cl 2
, 0°
489
(75)
, 100
% d
e
(75)
, 100
% d
ePh
C7-
11
340
N
PhPh
NN
Me 3
I–
C9-
10R
1R
1R
1
H Me
Tem
p
50°
—
(29%
)
(85%
)
494
962
R3
N
R1
OH
OC
6H3(
NO
2)2-
2,4
R2
R4
R3
N H
R1
OH
R2
R4
NaH
+ N
a(C
N)B
H3
(ia)
, dio
xane
, rt;
50°
, 10
h
R1
H Br
H H H H H
R2
H H H Me
H H H
R3
H H H H H Me
H
R4
H Me
Me
Me
i-Pr
Et
CH
=C
HPh
(0)
(92)
(78)
(83)
(83)
(70)
(64)
C9-
17
498
499
499
499
499
499
499
C10
-17
R3
N
R1
OH
OC
6H3(
NO
2)2-
2,4
R2
R4
R3
N
R1
OH
R2
R4
1. N
aH, d
ioxa
ne, 5
0°, 2
0 h
2. D
DQ
, HO
Ac,
ref
lux,
2 h
499
R1
Br
H H H H H H H
R2
H H H Me
H H H H
R3
H H H H H Me
—O
CM
e 2O
—
H
R4
Me
Me
Et
Me
i-Pr
Et
CH
=C
HPh
(90)
(80)
(75)
(74)
(84)
(72)
(62)
(60)
cis:
tran
s
— — — 5:1
— 5:1
—
NaO
R2 , R
2 OH
Tim
e
1 h
—
R2
t-B
u
i-Pr
+
341
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
1. I
NT
RA
MO
LE
CU
LA
R A
MIN
AT
ION
S (C
onti
nued
)
C10
O
OC
ON
3
OH N
O
O
OH
(20)
, 95%
de
963
1. h
ν, C
H2C
l 2, r
t, 4
h
2. B
F 3•E
t 2O
, MeO
H, r
eflu
x, 2
h
N
OH
OSO
2Me
OH
N
OH
N
+(2
0)(6
)N
aH, d
ioxa
ne, r
eflu
x49
8
NPh
O2S
CO
2Et
OM
s
C12
N H
EtO
2CD
BU
, CH
2Cl 2
, 0°,
30 m
in(4
8)49
7
C12
-14
N H
NO
H
R2
R3
R1
N CO
C6F
5
N
R1
R2
R3
OH
R1
H Me
H
R2
H H Me
R3
H H Me
(63)
sin
gle
dias
tere
omer
(72)
mix
ture
of
two
dias
tere
omer
s
(74)
sin
gle
dias
tere
omer
1. M
sCl,
Et 3
N, C
H2C
l 2, 0
°, 1
h
2. C
6F5C
OC
l, rt
, 4 h
3. N
aHC
O3,
H2O
, Me 2
CO
, rt,
20 h
964
Ph
NN
Me 3
I–
NaO
Pr-i
, i-P
rOH
, 40°
, 1 h
(80)
494
C13
N
Ph
+
342
N HN
NM
sCl,
Et 3
N, C
H2C
l 2, 0
°96
4
R1
NO
HR
2R
2
R1
R1
H CO
2Bu-
t
R2
Me
H
Tim
e
1 h
6 h
(95)
(68)
mix
ture
of
two
isom
ers
C13
NPh
CO
CO
2Et
OM
sN H
DB
U, C
H2C
l 2, 0
°, 30
min
(80)
497
PhC
O
EtO
2C
C13
Y N OC
6H3(
NO
2)2-
2,4
R
OH
nY N H
R
OH
nH
H
H
HN
aH, N
a(C
N)B
H3,
dio
xane
, rt,
5 h
Y CH
2
CH
2
NB
oc
R Me
Me
n-B
u
n 1 2 1
Y N HR
OH
nH
H+
III
I
(65)
(80)
(93)
II (28)
(0)
(0)
499
C13
-16
N OC
6H3(
NO
2)2-
2,4
OH
H
H
N HO
H
H
H
N
OH
NaH
, Na(
CN
)BH
3, d
ioxa
ne, r
t, 17
h+
(52)
(12)
499
C14
343
Subs
trat
eR
efs.
Con
ditio
nsPr
oduc
t(s)
and
Yie
ld(s
) (%
)
TA
BL
E 2
1. I
NT
RA
MO
LE
CU
LA
R A
MIN
AT
ION
S (C
onti
nued
)
N OC
6H3(
NO
2)2-
2,4
OH
NaH
, dio
xane
, rt,
4 h
N
OH
(98)
499,
498
C15
-16
4-R
1 C6H
4C
6H4R
2 -4
ON
HO
Me
4-R
1 C6H
4C
6H4R
2 -4
ON
NaO
Me,
MeO
H, 6
0°, 1
0 m
in; r
t, ov
erni
ght
R1
H H Cl
Br
H Me
R2
H Cl
H H Br
H
(94)
(80)
(66)
(83)
(90)
(64)
485e
485e
485e
485e
485e
485e , 4
86
C20
O
PO
NM
e 2O
Ph
1. L
DA
, TH
F, –
10°,
1 h;
rt,
36 h
2. C
H2N
2
85(7
)f
a The
rea
ctio
n w
as c
arri
ed o
ut in
CH
2Cl 2
.b T
he y
ield
incl
udes
that
of
the
prep
arat
ion
of th
e su
bstr
ate.
c The
yie
ld is
that
of
the
one-
pot r
eact
ion
of th
e ox
ime
with
MsC
l and
Et 3
N f
ollo
wed
by
addi
tion
of D
BU
.d B
eckm
ann
frag
men
tatio
n oc
curr
ed e
xclu
sive
ly.
e The
pro
duct
s w
ere
initi
ally
con
side
red
to b
e th
e pr
imar
y en
amin
es. T
he c
orre
ct a
ssig
nmen
t was
mad
e in
a la
ter
publ
icat
ion.
486
f The
yie
ld w
as 1
0% w
ith th
e su
bstr
ate
labe
led
with
13C
at t
he c
yano
car
bon
and
one
deut
eriu
m in
one
of
the
met
hyl g
roup
s. T
he is
otop
ic la
belin
g co
nfir
med
the
intr
amol
ecul
arity
of
the
reac
tion.
H
O3
CN
O
PO
Me
OPh
O3
CN
Me 2
N
MeO
H, r
eflu
x, 1
5 m
in(6
5)96
54-
MeO
C6H
4Ph
ON
HO
Me
4-M
eOC
6H4
Ph
ONH
C14
C16
344
ELECTROPHILIC AMINATION OF CARBANIONS 345
REFERENCES
1 Wohler, F. Ann. Physik 1828, 12, 253.2 Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947.3 Schmitz, E. Uspekhi Khim. 1976, 45, 54; Russ. Chem. Rev. 1976, 45, 16.4 Kron, K. Nachr. Chem., Tech. Lab. 1987, 35, 1047.5 Mulzer, J.; Altenbach, H. J.; Brown, M.; Krohn, K.; Reissig, H.-U. In Organic Synthesis High-
lights; VCH: Weinheim, Germany, 1991; p 43.6 Boche, G. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1995; Vol. E21e, p 5133.7 Greck, G.; Genet, J.-P. Synlett 1997, 741.8 Modern Amination Methods; Ricci, A., Ed.: Wiley-VCH: Weinheim 2000.9 Dembech, P.; Seconi, C.; Ricci, A. Chem. Eur. J. 2000, 6, 1281.
10 Kovacic, P.; Lowery, M. K.; Field, K. W. Chem. Rev. 1970, 70, 639.11 Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1.12 Andreae, S.; Schmitz, E. Synthesis 1991, 327.13 Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 4505.14 Parmerter, S. M. Org. React. 1959, 10, 1.15 Lang-Fugmann, S.; Lang-Fugmann, S. In Methoden der organischen Chemie (Houben-Weyl);
Georg Thieme Verlag: Stuttgart, New York 1992; Vol. E16d/1 p 99.16 Enders, E. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1967; Vol. 10/2, p 456.17 Fahr, E.; Lind, H. Angew. Chem., Int. Ed. Engl. 1966, 5, 372.18 Suling, C. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1965; Vol. 10/3, p 721.19 L’Abbe, G. Ind. Chim. Belge 1989, 34, 519.20 Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 298.21 Engel, A. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1990; Vol. 16a/2, p 1182.22 Hassner, A. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
New York, 1992; Vol. E16d/2, p 1283.23 Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188.24 Du Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. Acc. Chem. Res. 1997, 30, 364.25 Tomooka, C. S.; Iikura, H.; Carreira, E. M. In Modern Amination Methods; Ricci, A., Ed.:
Wiley-VCH: Weinheim 2000, chapter 5.26 List, B. Tetrahedron 2002, 58, 5573.27 Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975.28 Erdik, E. Tetrahedron 2004, 60, 8747.29 Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem. 2004, 1377.30 Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292.31 Duthaler, R. O. Tetrahedron 1994, 50, 1539.32 Calmes, M.; Daunis, J. Amino Acids, 1999, 16, 215.33 Vogt, H.; Brase, S. Org. Biomol. Chem. 2007, 406.34 Kruger, G. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1992; Vol. 16d/1, p 618.35 Backes, J.; Braun, M.; Maercker, A.; von Rague-Schleyer, P.; Bransdma, L.; Lambert, C.; Saal-
frank, R. W.; Subramanian, L. R. In Methoden der organischen Chemie (Houben-Weyl); GeorgThieme Verlag: Stuttgart, New York, 1992; Vol. E19d, p 1.
36 Leroux, F.; Schlosser, M.; Zohar, E.; Marek, I. In The Chemistry of Organolithium Compounds;Patai, Z.; Marek, I., Eds.; John Wiley & Sons: Chichester, 2004, p 435.
37 Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1.38 Nutzel, K. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1973; Vol. 13/2a, p 47.39 Wakefield, B. J. Organomagnesium Methods in Organic Synthesis; Academic Press: New York
NY, 1995.
346 ORGANIC REACTIONS
40 Nutzel, K. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,1973; Vol. 13/2a, p 553.
41 Knochel, P.; Millot, N.; Rodriguez, A. L. Org. React. 2001, 58, 417.42 Arya, P.; Qin, H. Tetrahedron 2000, 56, 917.43 Klar, G.; Kramolowski, R. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme
Verlag: Stuttgart, 1993; Vol. E15a, p 463.44 Heathcock, C. H. Modern Enolate Chemistry ; VCH: Weinheim, Germany, 1992.45 Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984;
Vol. 3, p 1.46 Rasmussen, J. K. Synthesis 1977, 91.47 Pawlenko, S. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag:
Stuttgart, 1980; Vol. E13/5, p 1.48 Pawlenko, S. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag:
Stuttgart, 1980; Vol. E15/1, p 404.49 Brownbridge, P. Synthesis 1983, 1.50 Pawlenko, S. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag:
Stuttgart, 1993; Vol. E15/2, p 1742.51 Amado-Bedolla, C.; Salmon-Ferrer, R.; Lester, W. A., Jr.; Vazquez-Martınez, J. A.; Aspuru-
Guzik, A. J. Chem. Phys. 2007, 126, 204308.52 Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739.53 Iwao, M.; Reed, J. N.; Snieckus, V. J. Am. Chem. Soc. 1982, 104, 5531.54 Alberti, A.; Cane, F.; Dembech, P.; Lazzari. D.; Ricci, A.; Seconi, G. J. Org. Chem. 1996,
61, 1677.55 Cane, F.; Brancaleoni, D.; Dembech, P.; Ricci, A.; Seconi, G. Synthesis 1997, 545.56 Coleman, G. H.; Hauser, C. R. J. Am. Chem. Soc. 1928, 50, 1193.57 Coleman, G. H.; Yager, C. B. J. Am. Chem. Soc. 1929, 51, 567.58 Coleman, G. H.; Hermanson, J. L.; Johnson, H. L. J. Am. Chem. Soc. 1937, 59, 1896.59 Coleman, G. H.; Blomquist, R. F. J. Am. Chem. Soc. 1941, 63, 1692.60 Boche, G.; Lohrenz, J. C. W. Chem. Rev. 2001, 101, 697.61 Coleman, G. H.; Soroos, H.; Yager, C. B. J. Am. Chem. Soc. 1933, 55, 2075.62 Horiike, M.; Oda, J.; Inouye, Y.; Ohno, M. Agr. Biol. Chem. 1969, 33, 292.63 Dowd, P.; Kaufman, C. J. Org. Chem. 1979, 44, 3956.64 Hand, E. S.; Baker, D. C. Int. J. Pept. Protein Res. 1984, 23, 420.65 Paquette, L. A. J. Am. Chem. Soc. 1963, 85, 3288.66 Tortov, G. A.; Burykin, V. V.; Koblik, A. V. Khim. Geterotsikl. Soedin. 1972, 11, 1552; Engl.
Transl. p 1403.67 Klages, F.; Nober, G.; Kircher, F.; Bock, M. Liebigs Ann. Chem. 1941, 547, 1.68 Coleman, G. H. J. Am. Chem. Soc. 1933, 55, 3001.69 Le Fevre, R. J. W. J. Chem. Soc. 1932, 1745.70 Kuffner, F.; Seifried, W. Monatsh. Chem. 1952, 83, 748.71 Wolf, V.; Kowitz, F. Liebigs Ann. Chem. 1960, 638, 33.72 Coleman, G. H.; Andersen, H. P.; Hermanson, J. L. J. Am. Chem. Soc. 1934, 56, 1381.73 Sinha, P.; Knochel, P. Synlett 2006, 3304.74 Wada, T.; Oda, J.-i.; Inouye, Y. Agr. Biol. Chem. 1972, 36, 799.75 Coleman, G. H.; Yager, C. B.; Soroos, H. J. Am. Chem. Soc. 1934, 56, 965.76 Tcherniak, M. J. Bull. Soc. Chim. Fr. 1876, 25, 160.77 Coleman, G. H.; Buchanan, M. A.; Paxson, W. L. J. Am. Chem. Soc. 1933, 55, 3669.78 Baumann, T.; Bachle, M.; Brase, S. Org. Lett. 2006, 8, 3797.79 Yamada, S.-i.; Oguri, T.; Shioiri, T. J. Chem. Soc., Chem. Commun. 1972, 623.80 Shverdina, N. I.; Kocheshkov, K. A. Izv. Akad. Nauk SSSR, Ser. Khim. 1941, 75; Chem. Abstr.
1943, 37, 3006.81 Beak, P,; Basha, A.; Kokko, B. J. Am. Chem. Soc. 1984, 106, 1511.82 Beak, P.; Basha, A.; Kokko, B.: Loo, D. K. J. Am. Chem. Soc. 1986, 108, 6016.83 Beak, P.; Selling, G. W. J. Org. Chem. 1989, 54, 5574.
ELECTROPHILIC AMINATION OF CARBANIONS 347
84 Beak, P.; Li, J. J. Am. Chem. Soc. 1991, 113, 2796.85 Beak, P.; Conser Basu, K.; Li, J. J. J. Org. Chem. 1999, 64, 5218.86 Boche, G.; Wagner, H.-U. J. Chem. Soc., Chem. Commun. 1984, 1591.87 Armstrong, D. R.; Snaith, R.; Walker, G. T. J. Chem. Soc., Chem. Commun. 1985, 789.88 McKee, M. L. J. Am. Chem. Soc. 1985, 107, 859.89 Buhl, M.; Schaefer, H. F., III J. Am. Chem. Soc. 1993, 115, 364.90 Glukhovtsev, M. N.; Pross, A.; Radom, L. J. Am. Chem. Soc. 1995, 117, 9012.91 Erdik, E.; Eroglu, F.; Kahya, D. J. Phys. Org. Chem. 2005, 18, 950.92 Kokko, B. PhD. Dissertation, University of Illinois at Champaign-Urbana, 1983.93 Radhakrishna, A. S.; Loudon, G. M.; Miller, M. J. J. Org. Chem. 1979, 44, 4836.94 Sheradsky, T.; Salemnick, G.; Nir, Z. Tetrahedron 1972, 28, 3833.95 Sturtz, G.; Couthon, H. C. R. Hebd. Sceances Acad. Sci. 1993, 316/II, 181.96 Boyles, D. C.; Curran, T. T.; Partlett, R. V., IV Org. Proc. Res. Dev. 2002, 6, 230.97 Kokko, B. J.; Beak, P. Tetrahedron Lett. 1983, 24, 561.98 Basha, A.; Brooks, D. W. J. Chem. Soc., Chem. Commun. 1987, 305.99 Buck, P.; Kobrich, G. Tetrahedron Lett. 1967, 1563.
100 Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato, G.; Ricci, A.; Seconi, G. J. Org.Chem. 1993, 58, 5620.
101 Bernardi, P.; Dembech, P.; Fabbri, G.; Ricci, A.; Seconi, G. J. Org. Chem. 1999, 64, 641.102 Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B. J. Org. Chem. 1997, 62, 6733.103 West, R.; Boudjouk, P. J. Am. Chem. Soc. 1973, 95, 3987.104 Lin, C.-C.; Wang, Y.-C.; Hsu, J.-L.; Chiang, C.-C.; Su, D.-W.; Yan, T.-H. J. Org. Chem. 1997,
62, 3806.105 Loreto, M. A.; Pellacani, L.; Tardella, P. A. J. Chem. Res. (S) 1988, 304.106 Smulik, J. A.; Vedejs, E. Org. Lett. 2003, 5, 4187.107 Shen, Y.; Friestad, G. K. J. Org. Chem. 2002, 67, 6236.108 Berman, A. M.; Johnson, J. S. Synlett 2005, 1799.109 Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680.110 Berman, A. M.; Johnson, J. S. J. Org. Chem. 2005, 70, 364.111 Berman, A. M.; Johnson, J. S. Org. Synth. 2006, 83, 31.112 Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219.113 Campbell, M. J.; Johnson, J. S. Org. Lett. 2007, 9, 1521.114 Ning, R. Y. Chem. Eng. News 1973, 51, 36.115 Hansen, J. J.; Krogsgaard-Larsen, P. J. Chem. Soc., Perkin Trans. 1 1980, 1826.116 Zheng, B.; Srebnik, M. J. Org. Chem. 1995, 60, 1912.117 Glass, R. S.; Hojjatie, M.; Sabahi, M.; Steffen, L. K.; Wilson, G. S. J. Org. Chem. 1990, 55, 3797.118 Fioravanti, S.; Pellacani, L.; Tardella, P. A. Gazz. Chim. Ital. 1997, 127, 41.119 Barani, M,; Fioravanti, S.; Peliciani, L.; Tardella, P. A. Tetrahedron 1994, 50, 11235.120 Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. J. Org. Chem. 1985, 50, 5365.121 Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. J. Chem. Res. (S) 1987, 310.122 Barani, M.; Fioravanti, S.; Loreto, A. M.; Pellacani, L.; Tardella, P. A. Tetrahedron 1994,
50, 3829.123 Fioravanti, S.; Olivieri, L.; Pellacani, L.; Tardella, P. A. J. Chem. Res. (S) 1998, 338.124 Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 2001, 42, 1171.125 Felice, E.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 1999, 40, 4413.126 Genet, J.-P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron Lett. 1991, 32, 2359.127 Greck, C.; Bischoff, L.; Girard, A.; Hajicek, J.; Genet, J.-P. Bull. Soc. Chim. Fr. 1994, 131, 429.128 Shopova, M.; Vassileva, E.; Fugier, C.; Henry-Basch, E. Synth. Commun. 1997, 27, 1661.129 Ferreira, F. Ph. D. Dissertation, Universite P. & M. Curie, Paris, France, 1996; Lavergne, D.,
Ecole Nationale Superieure de Chimie, Paris, France, unpublished work; both cited (references11a and 11b on p 101) by Genet, J. P.; Greck, C.; Lavergne, D, in Modern Amination Methods;Ricci, A., Ed.: Wiley-VCH: Weinheim 2000.
130 Greck, C.; Bischoff, L.; Ferreira, F.; Genet, J.-P. J. Org. Chem. 1995, 60, 7010.
348 ORGANIC REACTIONS
131 Boche, G.; Boie, C.; Bosold, F.; Harms, K.; Marsch, M. Angew. Chem., Int. Ed. Engl. 1994,33, 115.
132 Barton, D. H. R.; Bould, L.; Clive, D. L. J.; Magnus, P. D.; Hase, T. J. Chem. Soc. C 1971, 2204.133 Boche, G.; Mayer, N.; Bernheim, M.; Wagner, K. Angew. Chem., Int. Ed. Engl. 1978, 17, 687.134 Bernheim, M. Ph. D. Dissertation, University of Munich, Germany, 1981; quoted in ref. 137,
ref. 2b.135 Boche, G.; Bernheim, M.; Niessner, M. Angew. Chem., Int. Ed. Engl. 1983, 22, 53.136 Abraham, T.; Curran, T. Tetrahedron 1982, 38, 1019.137 Boche, G. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 2100.138 Klotzer, W.; Stadlwieser, J.; Raneburger, J. Org. Synth. Coll. Vol. 7 1986, 8.139 Boche, G.; Bernheim, M.; Schrott, W. Tetrahedron Lett. 1982, 23, 5399.140 Sosnovsky, G.; Purgstaller, K. Z. Naturforsch. 1989, 44b, 582.141 Colvin, E. W.; Kirby, G. W.; Wilson, A. C. Tetrahedron Lett. 1982, 23, 3835.142 Kendrick, D. A.; Kolb, M. J. Fluorine Chem. 1989, 45, 265.143 Baldwin, J. E.; Adlington, R. M.; Jones. R. H.; Schofield, C. J.; Zarocostas, C.; Greengrass,
C. W. J. Chem. Soc., Chem. Commun. 1985, 194.144 Aurell, M. J.; Gil, S.; Martınez, P. V.; Parra, M.; Tortajada, A.; Mestres, R. Synth. Commun.
1991, 21, 1833.145 Sun, C.; Bittman, R. J. Org. Chem. 2006, 71, 2200.146 Boche, G.; Bernheim, M.; Lawaldt, D.; Ruisinger, B. Tetrahedron Lett. 1979, 4285.147 Boche, G.; Schrott, W. Tetrahedron Lett. 1982, 23, 5403.148 Andreae, S.; Schmitz, E. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.;
Wiley: New York, 1995; p 3810.149 Andreae, S.; Schmitz, E.; Wulf, J.-P.; Schulz, B. Liebigs Ann. Chem. 1992, 239.150 Wulff, J.-P.; Andreae, S. unpublished results quoted in Andreae, S.; Schmitz, E. Synthesis 1991,
327 (ref. 58).151 Page, P. C. B.; Limousin, C.; Murrell, V. L. J. Org. Chem. 2002, 67, 7787.152 Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React. 2003, 62, 1.153 Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J.-C.; Aubry, A.; Collet, A. Chem. Eur. J. 1997,
3, 1691.154 Armstrong, A.; Atkin, M. A.; Swallow, S. Tetrahedron: Asymmetry 2001, 12, 535.155 Armstrong, A.; Edmonds, I. D.; Swarbrick, M. E.; Treweeke, N. R. Tetrahedron 2005, 61, 8423.156 Enders, D.; Poiesz, C.; Joseph, R. Tetrahedron: Asymmetry 1998, 9, 3709.157 Vidal, J.; Guy, L.; Sterin, S.; Collet, A. J. Org. Chem. 1993, 58, 4791.158 Armstrong, A.; Atkin, M. A.; Swallow, S. Tetrahedron Lett. 2000, 41, 2247.159 Ghosh, T. N.; Guha, P. C. J. Indian Inst. Sci. 1933, 16A, 103; Chem. Abstr. 1934, 28, 2691.160 Fiaud, J.-C.; Kagan, H. B. Tetrahedron Lett. 1970, 1813.161 Fiaud, J.-C.; Kagan, H. B. Tetrahedron Lett. 1971, 1019.162 van Vliet, M. R. P.; Jastrzebski, J. T. B. H.; van Koten, G.; Vrieze, K. J. Organomet. Chem.
1983, 251, C17.163 van Vliet, M. R. P.; Jastrzebski, J. T. B. H.; Klaver, W. J.; Goubitz, K.; van Koten, G. Recl.
Trav. Chim. Pays-Bas 1987, 106, 132.164 Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415.165 Uneyama, K.; Yan, F.; Hirama, S.; Katagiri, T. Tetrahedron Lett. 1996, 37, 2045.166 Niwa, Y.; Takayama, K.; Shimizu, M. Tetrahedron Lett. 2001, 42, 5473.167 Niwa, Y.; Takayama, K.; Shimizu, M. Bull. Chem. Soc. Jpn. 2002, 75, 1819.168 Dai, W.; Srinivasan, R.; Katzenellenbogen, J. A. J. Org. Chem. 1989, 54, 2204.169 Bracht, J.; Rieker, A. Synthesis 1977, 708.170 Baum, J. S.; Condon, M. E.; Shook, D. A. J. Org. Chem. 1987, 52, 2983.171 Klerks, J. M.; Jastrzebski, J. T. B. H.; van Koten, G.; Vrieze, K. J. Organomet. Chem. 1982,
224, 107.172 Lim, B.-W.; Ahn, K.-H. Synth. Commun. 1996, 26, 3407.173 Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742.
ELECTROPHILIC AMINATION OF CARBANIONS 349
174 Adam, W.; Roschmann, K. J.; Saha-Moller, C. R. Eur. J. Org. Chem. 2000, 557.174 a. Alvernhe, G.; Laurent, A. Tetrahedron Lett. 1972, 1007.175 Busch, M.; Hobein, R. Chem. Ber. 1907, 40, 2096.176 Erdik, E.; Daskapan, T. Synth. Commun. 1999, 29, 3989.177 Erdik, E.; Daskapan, T. J. Chem. Soc., Perkin Trans. 1 1999, 3139.178 Wurthwein, E.-U.; Weigmann, R. Angew. Chem., Int. Ed. Engl. 1987, 26, 923.179 Tsutsui, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 1869.180 Hagopian, R. A.; Therien, M. J.; Murdoch, J. R. J. Am. Chem. Soc. 1984, 106, 5753.181 Kitamura, M.; Chiba, S.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003, 76, 1063.182 Kitamura, M.; Suga, T.; Chiba, S.; Narasaka, K. Org. Lett. 2004, 6, 4619.183 Erdik, E.; Omur, O. Appl. Organomet. Chem. 2005, 19, 887.184 Hodgson, H. H.; Marsden, E. J. Chem. Soc. 1945, 274.185 Garst, M. E.; Lukton, D. Synth. Commun. 1980, 10, 155.186 Nomura, Y. Bull. Chem. Soc. Jpn. 1961, 34, 1648.187 Nomura, Y.; Anzai, H. Bull. Chem. Soc. Jpn. 1962, 35, 111.188 Nomura, Y.; Anzai, H. Bull. Chem. Soc. Jpn. 1964, 37, 970.189 Nomura, Y.; Anzai, H.; Tarao, R.; Shiomi, K. Bull. Chem. Soc. Jpn. 1964, 37, 967.190 Erdik, E.; Kocuglu, M. Main Group Metal Chem. 2002, 25, 621.191 Barbero, M.; Degani, I.; Dughera, S.; Fochi, R.; Perracino, P. Synthesis 1998, 1235.192 Curtin, D. Y.; Ursprung, J. A. J. Org. Chem. 1956, 21, 1221.193 Curtin, D. Y.; Tveten, J. L. J. Org. Chem. 1961, 26, 1764.194 Neumann, W. P.; Wicenec, C. Chem. Ber. 1991, 124, 2297.195 Crary, J. W.; Quayle, O. R.; Lester, C. T. J. Am. Chem. Soc. 1956, 78, 5584.196 Sakakura, T.; Tanaka, M. J. Chem. Soc., Chem. Commun. 1985, 1309.197 Sakakura, T.; Hara, M.; Tanaka, M. J. Chem. Soc., Perkin Trans. 1 1994, 289.198 Eistert, B.; Regitz, M.; Heck, G.; Schwall, H. In Methoden der organischen Chemie (Houben-
Weyl); Georg Thieme Verlag: Stuttgart, 1968; Vol. 10/4, p 709.199 Zerner, E. Monatsh. Chem. 1913, 34, 1609.200 Zerner, E. Monatsh. Chem. 1913, 34, 1631.201 Forster, M. O.; Cardwell, D. J. Chem. Soc. 1913, 861.202 Coleman, G. H.; Gilman, H.; Adams, C. E.; Pratt, P. E. J. Org. Chem. 1938, 3, 99.203 Ciganek, E. J. Org. Chem. 1965. 30, 4198.204 Diekmann, J. J. Org. Chem. 1965, 30, 2272.205 Takamura, N.; Yamada, S.-i. Chem. Pharm. Bull. 1976, 24, 800.206 Balli, H.; Gipp, R. Liebigs Ann. Chem. 1966, 699, 133.207 Huisgen, R.; Bihlmeier, W.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1979, 18, 331.208 Schmitz, E.; Ohme, R. Chem. Ber. 1961, 94, 2166.209 Nelsen, S. F.; Landis, R. T., II J. Am. Chem. Soc. 1973, 95, 2719.210 Neugebauer, F. A.; Weger, H. Chem. Ber. 1979, 112, 1076.211 Katritzky, A. R.; Wu, J.; Verin, S. V. Synthesis 1995, 651.212 Kaiser, E. M.; Bartling, G. J. J. Org. Chem. 1972, 37, 490.213 Bozzini, S.; Stener, A. Ann. Chim. (Rome) 1968, 58, 169.214 Wittig, G.; Schuhmacher, A. Chem. Ber. 1955, 88, 234.215 Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693.216 Waser, J.; Gonzales-Gomez, J. C.; Nambu, H.; Huber, P.; Carreira, E. M. Org. Lett. 2005, 7, 4249.217 Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1988, 53, 2132.218 Brimble, M. A.; Heathcock, C. H.; Nobin, G. N. Tetrahedron: Asymmetry 1996, 7, 2007.219 Harris, J. M.; McDonald, R.; Vederas, J. C. J. Chem. Soc., Perkin Trans. 1 1996, 2669.220 Hoffmann, R. W.; Holzer, B.; Knopff, O. Org. Lett. 2001, 3, 1945.221 List, B. J. Am. Chem. Soc. 2002, 124, 5656.222 Bøgevig, A.; Juhl, K.; Kumuragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2002, 41, 1790.223 Baumann, T.; Vogt, H.; Brase, S. Eur. J. Org. Chem. 2007, 266.224 Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770.
350 ORGANIC REACTIONS
225 Marigo, M.; Schulte, T.; Franzen, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710.226 Suri, J. T.; Steiner, D. D.; Barbas, C. F., III Org. Lett. 2005, 7, 3885.227 Kotkar, S. P.; Sudalai, A. Tetrahedron: Asymmetry 2006, 17, 1738.228 Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc.
2002, 124, 6254.229 Thomassigny, C.; Prim, D.; Greck, C. Tetrahedron Lett. 2006, 47, 1117.230 Diels, O. Liebigs Ann. Chem. 1922, 429, 1.231 Pihko, P. M.; Pohjakallio, A. Synlett 2004, 2115.232 Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167.233 Xu, X.; Yabuta, T.; Yuan, P.; Takemoto, Y. Synlett 2006, 137.234 Ghosh, A. K.; Mathivanan, P.; Capiello, J. Tetrahedron: Asymmetry 1998, 9, 1.235 Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1367.236 Ma, S.; Jiao, N.; Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.; Deng, Y.; Chen, G. Org. Lett. 2004, 6, 2193.237 Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron: Asymmetry 2006, 17, 658.238 Kim, S. M.; Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7, 2309.239 Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565.240 Firl, J.; Sommer, S. Tetrahedron Lett. 1970, 1925.241 Firl, J.; Sommer, S. Tetrahedron Lett. 1970, 1929.242 Sasaki, T.; Ishibashi, Y.; Ohno, M. Heterocycles 1983, 20, 1933.243 Sasaki, T.; Ishibashi, Y.; Ohno, M. J. Chem. Res. (M) 1984, 1972.244 Yamashita, Y.; Ishitani, H.; Kobayashi, S. Can. J. Chem. 2000, 78, 666; Kobayashi, S.; Yamashita,
Y.; Ishitani, H. Chem. Lett. 1999, 307.245 Moriarty, R. M.; Prakash, I. Synth. Commun. 1985, 15, 649.246 Risaliti, A.; Marchetti, L. Ann. Chim. (Rome) 1963, 53, 718.247 Firl, J.; Sommer, S. Tetrahedron Lett. 1969, 1137.248 Fatutta, S.; Pitacco, G.; Russo, C.; Valentin, E. J. Chem. Soc., Perkin Trans. 1 1992, 2045.249 Forchiassin, M.; Pitacco, G.; Risalti, A.; Russo, C.; Valentin, E. J. Heterocycl. Chem. 1983,
20, 305.250 Benedetti, F.; Bozzini, S.; Fatutta, S.; Forchiassin, M.; Nitti, P.; Pitacco, G.; Russo, C. Gazz.
Chim. Ital. 1991, 121, 401.251 Hall, J. H.; Woiciechowska, M. J. Org. Chem. 1978, 43, 3348.252 Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595.253 Beslin, P.; Marion, P. Tetrahedron Lett. 1992, 33, 935.254 Cookson, R. C.; Gilani, S. S. H.; Stevens, I. D. R. J. Chem. Soc. C. 1967, 1905.255 Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 897.256 Dimroth, O. Chem. Ber. 1906, 39, 3905.257 Brinckman, F. E.; Haiss, H. S.; Robb, R. A. Inorg. Chem. 1965, 4, 936.258 Smith, R. H., Jr.; Michejda, C. J. Synthesis 1983, 476.259 Smith, R. H., Jr.; Denlinger, C. L.; Kupper, R.; Mehl, A. F.; Michejda, C. J. J. Am. Chem. Soc.
1986, 108, 3726.260 Danilov, S. N.; Yastrebov, L. N.; Burova, L. N. Zh. Obshch. Khim. 1970, 40, 2248; Engl. Transl.
p 2235.261 Sieh, D. H.; Wilbur, D. J.; Michejda, C. J. J. Am. Chem. Soc. 1980, 102, 3883.262 Sieh, D. H.; Michejda, C. J. J. Am. Chem. Soc. 1981, 103, 442.263 Kabalka, G. W.; Li, G. Tetrahedron Lett. 1997, 38, 5777.264 Nishiyama, K.; Tanaka, N. J. Chem. Soc., Chem. Commun. 1983, 1322.265 Kelly, T. R.; Maguire, M. P. Tetrahedron 1985, 41, 3033.266 Perrin, P.; Aubert, F.; Lellouche, J. P.; Beaucourt, J. P. Tetrahedron Lett. 1986, 27, 6193.267 Okazaki, R.; Unno, M.; Inamoto, N. Chem. Lett. 1987, 2293.268 Smith, R. H., Jr.; Mehl, A. F.; Shantz, D. L., Jr.; Chmurny, G. N.; Michejda, C. J. J. Org. Chem.
1988, 53, 1467.269 Yadav, J. S.; Madhuri, C.; Reddy, B. V. S.; Reddy, G. S. K. K.; Sabitha, G. Synth. Commun.
2002, 32, 2771.270 Dimroth, O. Chem. Ber. 1905, 38, 670.
ELECTROPHILIC AMINATION OF CARBANIONS 351
271 Forster, M. O.; Fierz, H. E.; Joshua, W. P. J. Chem. Soc. 1908, 1070.272 Pochinok, V. Ya.; Shrobovich, V. A.; Portnyagina, V. A.; Polyanskaya, A.L. Ukr. Khim. Zh.
1959, 25, 774; Chem. Abstr. 1960, 54. 13034i.273 Trost, B. M.; Pearson, W. H. J. Am. Chem. Soc. 1983, 105, 1054.274 Pearson, W. H. Ph. D. Dissertation, University of Wisconsin, Madison, 1982; Univ. Mictofilms
Int., Order No. 8301883T.275 Trost, B. M.; Pearson, W. H. J. Am. Chem. Soc. 1981, 103, 2483.276 Tolman, R. L.; Smith, C. W.; Robins, R. K. J. Am. Chem. Soc. 1972, 94, 2530.277 Hassner, A.; Belinka, B. A., Jr. J. Am. Chem. Soc. 1980, 102, 6185.278 Hassner, A.; Munger, P.; Belinka, B. A., Jr. Tetrahedron Lett. 1982, 23, 699.279 Kumar, S. H. M.; Reddy, S. B. V.; Anjaneyulu, S.; Yadav, J. S. Tetrahedron Lett. 1999, 40, 8305.280 Dimroth, O.; Eble, M.; Gruhl. W. Chem. Ber. 1907, 40, 2390.281 Pochinok, V. Ya.; El’gort, R. G. Ukr. Khim. Zh. 1949, 15, 311; Chem. Abstr. 1951, 48, 3320c.282 Pochinok, V. Ya. Zh. Obshch. Khim. 1946, 16, 1303; Chem. Abstr. 1947, 41, 3066h. 283. Pochi-
nok, V. Ya.; Kalashnikova, E. S. Ukr. Khim. Zh. 1951, 17, 517; Chem. Abstr. 1951, 48, 10640d.284 Bertho, A. J. Prakt. Chem. 1901, 63, 101.285 Dimroth, O. Chem. Ber. 1903, 36, 909.286 Akimova, G. S.; Kolokol’tseva, I. G.; Chistokletov, V. N.; Petrov, A. A. Zh. Org. Khim. 1968,
4, 954; Engl. Transl. p 927.287 Jones, W. M.; Maness, D. D. J. Am. Chem. Soc. 1970, 92, 5457.288 Lee, C. C.; Ko, E. C. F. Can. J. Chem. 1976, 54, 3041.289 Kleinfeller, H. J. Prakt. Chem. 1928, 119, 61; Kleinfeller, H.; Bonig, G. J. Prakt. Chem. 1931,
132, 175.290 Pochinok. A. V.; Pochinok, V. Ya.; Kondratenko, P. A. Ukr. Khim. Zh. 1984, 50, 884; Chem.
Abstr. 1985, 102, 61876m.291 Scarpati, R.; Sica, D. Gazz. Chim. Ital. 1963, 93, 942.292 Dimroth, O. Liebigs Ann. Chem. 1910, 373, 336.293 Babudri, F.; Di Nunno, L.; Florio, S.; Valzano, S. Tetrahedron 1984, 40, 1731.294 Pochinok, V. Ya. Ukr. Khim. Zh. 1949, 15, 302; Chem. Abstr. 1954, 48, 3285d.295 Kozlowska-Gramsz, E.; Descotes, G. Tetrahedron Lett. 1981, 22, 563.296 Lociuro, S.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 1983, 24, 593.297 Auberson, Y.; Vogel, P. Tetrahedron 1990, 46, 7019.298 Scarpati, R.; Graziano, M. L.; Nicolaus, R. A. Gazz. Chim. Ital. 1970, 100, 665.299 Cipollone, A.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. J. Org. Chem. 1987, 52, 2584.300 Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 1989, 30, 2975.301 Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Sabbatini, F.; Tardella, P. A. Tetrahedron: Asymmetry
1994, 5, 473.302 Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron: Asymmetry 1990, 1, 931.303 Fioravanti, S.; Pellacani, L.; Ricci, D.; Tardella, P. A. Tetrahedron: Asymmetry 1997, 8, 2261.304 Del Signore, G.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Tetrahedron 2001, 57, 4623.305 Smith, P. A. S.; Rowe, C. D.; Bruner, L. B. J. Org. Chem. 1969, 34, 3430.306 Ito, S.; Hirabayashi, T.; Matsumoto, K. Bull. Chem. Soc. Jpn. 1970, 43, 2254.307 Reed, J. O.; Lwowski, W. J. Org. Chem. 1971, 36, 2864.308 Ito, S. Bull. Chem. Soc. Jpn. 1966, 39, 635.309 Hakimelahi, G. H.; Just, G. Synth. Commun. 1980, 10, 429.310 Narasimhan, N. S.; Ammanamanchi, R. Tetrahedron Lett. 1983, 23, 4733.311 Reed, J. N.; Snieckus, V. Tetrahedron Lett. 1983, 24, 3795.312 Reed, J. N.; Snieckus, V. Tetrahedron Lett. 1984, 25, 5505.313 Wan, Z.-K.; Woo, G. H. C.; Snyder, J. K. Tetrahedron 2001, 57, 5497.314 Gavenonis, J.; Tilley, T. D. Organometallics 2002, 21, 5549.315 Nesmeyanov, A. N.; Drozd, V. N.; Sazonova, V. A. Dokl. Akad. Nauk SSSR 1963, 150, 321;
Engl. Transl. p 416.316 Spagnolo, P.; Zanirato, P. J. Org. Chem. 1978, 43, 3539.317 Denmark, S.; Chatani, N.; Pansare, S. V. Tetrahedron 1992, 48, 2191.
352 ORGANIC REACTIONS
318 Evans, D. A.; Britton, T. C.; Ellman, J. A. Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011.319 Benati, L.; Nanni, D.; Spagnolo, P. J. Org. Chem. 1999, 64, 5132.320 Shiro, Y.; Kato, K.; Fujii, M.; Ida, Y.; Akita, H. Tetrahedron 2006, 62, 8687.321 Benati, L.; Calestani, G.; Nanni, D.; Spagnolo, P. J. Org. Chem. 1998, 63, 4679.322 Lombardo, L.; Mander, L. N. Synthesis 1980, 368.323 Coates, R. M.; Kang, H.-Y. J. Org. Chem. 1987, 52, 2065.324 Uyehara, T.; Takehara, N.; Ueno, M.; Sato, T. Bull. Chem. Soc. Jpn. 1995, 68, 2687.325 Battaglia, A.; Baldelli, E.; Bombardelli, E.; Carenzi, G.; Fontana, G.; Gelmi, M. L.; Guerrini,
A.; Pocar, D. Tetrahedron 2005, 61, 7737.326 Brown, R. C. D.; Bataille, C. J. R.; Bruton, G.; Hinks, J. D.; Swain, N. A. J. Org. Chem. 1994,
66, 6719.327 Enders, D.; Joseph, R.; Poiesz, C. Tetrahedron 1998, 54, 10069.328 Charette, A. B.; Wurz, R. P.; Ollevier, T. Helv. Chim. Acta 2002, 85, 4468.329 Wurz, R. P.; Lin, W.; Charette, A. B. Tetrahedron Lett. 2003, 44, 8845.330 A repetition of the reaction of triethyl phosphonoacetate with trifluoromethanesulfonyl azide gave
exclusively the diazo transfer product rather than the azide as reported in reference 309. Charette,A. B.; Marcoux, D. Department de Chimie, Universite de Montreal, Montreal, Canada. Personalcommunication, 2007.
331 Magnus, P.; Barth, L. Tetrahedron 1995, 51, 11075.332 Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57, 1244.333 Mori, S.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1984, 25, 429.334 Mori, S.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1986, 34, 1524.335 Guiver, M. D.; Robertson, G. P. Macromolecules 1995, 28, 294.336 Villalgordo, J. M.; Linden. A.; Heimgartner, H. Helv. Chim. Acta 1996, 79, 213.337 Villalgordo, J. M; Enderli, A.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 1995, 78, 1983.338 Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.;
Smith, A. D. Org. Biomol. Chem. 2003, 3708.339 Kuhlein, K.; Jensen, H. Liebigs Ann. Chem. 1974, 369.340 Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451.341 Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207.342 Phukan, P.; Sudelai, A. Tetrahedron: Asymmetry 1998, 9, 1001.343 Driguez, H.; Vermes, J.-P.; Lessard, J. Can. J. Chem. 1978, 56, 119.344 Driguez, H.; Lessard, J. Can. J. Chem. 1977, 55, 720.345 Magnus, P.; Mugrage, B. J. Am. Chem. Soc. 1990, 112, 462.346 Magnus, P.; Coldham, I. J. Am. Chem. Soc. 1991, 113, 672.347 Magnus, P.; Lacour, J.; Bauta, W.; Mugrage, B.; Lynch, V. J. Chem. Soc., Chem. Commun.
1991, 1362.348 Magnus, P.; Lacour. J.; Coldham, I.; Mugrage, B.; Bauta, W. B. Tetrahedron 1995, 51, 11087.349 Gethin, D. M.; Simpkins, N. S. Tetrahedron 1997, 53, 14417.350 Du Bois, J.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1996, 118, 915.351 Carreira, E. M.; Hong, J.; Du Bois, J.; Tomooka, C. S. Pure Appl. Chem. 1998, 70, 1097.352 Minakata, S.; Ando, T.; Nishimura, M.; Ryu, I.; Komatsu, M. Angew. Chem., Int. Ed. Engl. 1998,
37, 3392.353 Svenstrup, N.; Bøgevig, A.; Hazell, R. G.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1
1999, 1559.354 Du Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179.355 Kraus, G. A. U. S. Patent 5,599,998 (1997).356 Sinha, P.; Kofink, C. C.; Knochel, P. Org. Lett. 2006. 8, 3741.357 Guijarro, A.; Rieke, R. D. Angew. Chem., Int. Ed. Engl. 1998, 37, 1679.358 Velarde-Ortiz, R.; Guijarro, A.; Rieke, R. D. Tetrahedron Lett. 1998, 39, 9157.359 Katritzky, A. R.; Verin, S. V.; Yang, B. Org. Prep. Proc. Int. 1996, 28, 97.360 An, D. K.; Hirakawa, K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1999, 40, 3737.361 Boyer, J. H.; Mack, C. H.; Goebel, N.; Morgan, L. R., Jr. J. Org. Chem. 1958, 23, 1051.362 Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
ELECTROPHILIC AMINATION OF CARBANIONS 353
363 Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046.364 Wolfe, J. P.; Wagah, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.365 Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.: Wiley-VCH: Weinheim, 2000,
Chapter 7.366 Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I.,
Ed.; Wiley: New York, 2002, Vol. 1, p1051.367 Lipshutz, B. H.; Ueda, H. Angew. Chem., Int. Ed. 2000, 39, 4492.368 Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.369 Wolfe, J. P.; Buchwald, S. L. Org. Synth. 2002, 78, 23.370 Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 2987.371 Tasler, S.; Lipshutz, B. H. J. Org. Chem. 2003, 68, 1190.372 Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599.373 Christensen, H.; Kiil, S.; Dam-Johansen, K.; Nielsen, O.; Sommer, M. B. Org. Process Res. Dev.
2006, 10, 762.374 Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.375 Trost, B. M.; Pearson, W. H. Tetrahedron Lett. 1983, 24, 263.376 Minisci, F. Top. Curr. Chem. 1976, 62, 1.377 Stolle, R.; Adam, G. J. Prakt. Chem. 1925, 111, 167.378 Stolle, R.; Reichert, W. J. Prakt. Chem. 1929, 123, 75.379 Zaltsgendler, I.; Leblanc, Y.; Bernstein, M. A. Tetrahedron Lett. 1993, 34, 2441.380 Mitchell, H.; Leblanc, Y. J. Org. Chem. 1994, 59, 682.381 Leblanc, Y.; Boudreault, N. J. Org. Chem. 1995, 60, 4268.382 Dufresne, C.; Leblanc, Y.; Berthelette, C.; McCooeye, C. Synth. Commun. 1997, 27, 3613.383 Lenarsic, R.; Kocevar, M.; Polanc, S. J. Org. Chem. 1999, 64, 2558.384 Bombek, S.; Pozgan, F.; Kocevar, M.; Polanc, S. J. Org. Chem. 2004, 69, 2224.385 Chowdari, N. S.; Barbas, C. F., III Org Lett 2005, 7, 867.386 Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T.C.; Kjaersgaard, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296.386 a. Vogt, H.; Baumann, T.; Nieger, M.; Brase, S. Eur. J. Org. Chem. 2006, 5315.387 Huisgen, R.; Mobius, L.; Szeimies, G. Chem. Ber. 1965, 98, 1138.388 Dessole, G.; Bernardi, L.; Bonini, B. F.; Capito, E.; Fochi, M.; Herrera, R. P.; Ricci, A.; Cahiez,
G. J. Org. Chem. 2004, 69, 8525.389 Marchetti, L. J. Chem. Soc., Perkin Trans. 2 1978, 382.390 Huisgen, R.; Jakob, F. Liebigs Ann. Chem. 1954, 590, 37.391 Majewski, M.; Zheng, G.-Z. Can. J. Chem. 1992, 70, 2618.392 Gmeiner, P.; Bollinger, B. Tetrahedron Lett. 1991, 32, 5927.393 Gmeiner, P.; Bollinger, B. Liebigs Ann. Chem. 1992, 273.394 Gmeiner, P.; Bollinger, B.; Mierau, J.; Hofner, G. Arch. Pharm. (Weinheim, Ger.) 1995, 328, 609.395 Gmeiner, P.; Sommer, J. Arch. Pharm. (Weinheim, Ger.) 1994, 327, 435.396 Gmeiner, P.; Sommer, J.; Mierau, J.; Hofner, G. Bioorg. Med. Chem. Lett. 1993, 3, 1477.397 Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron 1991, 47, 5877.398 Du Bois, J.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1996, 118, 915.399 Pellacani, L.; Pulcini, P.; Tardella, P. A. J. Org. Chem. 1982, 47, 5023.400 Benedetti, F.; Forchiassin, M.; Russo, C. Risaliti, A. Gazz. Chim. Ital. 1985, 115, 663.401 Ballaben, E.; Forchiassin, M.; Nitti, P.; Russo, C. Gazz. Chim. Ital. 1993, 123, 387.402 Ciganek, E. Org. React. 1997, 51, 201.403 Kamimura, A.; Gunjigake, Y.; Mitsudera, H.; Yokoyama, S. Tetrahedron Lett. 1998, 39, 7323.404 Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 2420.405 Gmeiner, P.; Bollinger, B. Tetrahedron 1994, 50, 10909.406 Green, J. R. Science in Synthesis 2006, 8a, 427.407 Oguri. T.; Shioiri, T.; Yamada, S.-i. Chem. Pharm. Bull. 1975, 23, 167.408 Harris, J. M.; Bolessa, E. A.; Mendonca, A. J.; Feng, S.-C.; Vederas, J. C. J. Chem. Soc., Perkin
Trans. 1 1995, 1945.409 Oppolzer, W.; Moretti, R. Helv. Chim. Acta 1986, 69, 1923.
354 ORGANIC REACTIONS
410 Yamamoto, Y.; Yumoto, M.; Yamada, J.-i. Tetrahedron Lett. 1991, 32, 3079.411 Gennari, C.; Colombo, L.; Bertolini, G. J. Am. Chem. Soc. 1986, 108, 6394.412 Oppolzer, W.; Moretti, R. Tetrahedron 1988, 44, 5541.413 Molina, P.; Fresneda, P. M.; Sanz, M. J. Org. Chem. 1999, 64, 2540.414 Fresneda, P. M.; Molina, P.; Sanz, M. A. Tetrahedron Lett. 2001, 42, 851.415 Guenti, G.; Banfi, L.; Narisano, E. Tetrahedron 1988, 44, 5553.416 Greck, C.; Bischoff, L.; Ferreira, F.; Pinel, C.; Piveteau, E.; Genet, J.-P. Synlett, 1993, 475.417 Ciufolini, M. A.; Xi, N. J. Chem. Soc., Chem. Commun. 1994, 1867.418 Greck, C.; Bischoff, L.; Genet, J.-P. Tetrahedron: Asymmetry 1995, 6, 1989.419 Greck, C.; Ferreira, F.; Genet, J.-P. Tetrahedron Lett. 1996, 37, 2031.420 Girard, A.; Greck, C.; Ferroud, D.; Genet, J.-P. Tetrahedron Lett. 1996, 37, 7967.421 Drouillat, B.; Poupardin, O.; Bourdreux, Y.; Greck, C. Tetrahedron Lett. 2003, 44, 2781.422 Poupardin, O.; Greck, C.; Genet, J.-P. Tetrahedron Lett. 2000, 41, 8795.423 Bourdreux, Y.; Drouillat, B.; Greck, C. Synlett 2005, 2086.424 Poupardin, O.; Greck, C.; Genet, J.-P. Synlett 1998, 1279.425 Panek, J. S.; Beresis, R.; Xu, F.; Yang, M. J. Org. Chem. 1991, 56, 7341.426 Fernandez-Megıa, E.; Paz, M. M.; Sardina, F. J. J. Org. Chem. 1994, 59, 7643.427 Hanessian, S.; Wang, W.; Gai, Y. Tetrahedron Lett. 1996, 37, 7477.428 Kapeller, H.; Griengl, H. Tetrahedron 1997, 53, 14635.429 Kumar, J. S. D.; Dupradeau, F.-Y.; Strouse, M. J.; Phelps, M. E.; Toyokuni, T. J. Org. Chem.
2001, 66, 3220.430 Ager, D. J. Chem. Rev. 1996, 96, 835.431 Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr. Tetrahedron 1988, 44, 5525.432 Trimble, L. A.; Vederas, J. C. J. Am. Chem. Soc. 1986, 108, 6397.433 Evans, D. A.; Britton, T. C. J. Am. Chem. Soc. 1987, 109, 6881.434 Lin, J.; Liao, S.; Han, Y.; Qiu, W.; Hruby, V. Tetrahedron: Asymmetry 1997, 8, 3213.435 Lin, J.; Liao, S.; Hruby, V. J. J. Peptide Res. 2005, 65, 105.436 Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452.437 Nishida, A.; Fuwa, M.; Fujikawa, Y.; Nakahata, E.; Furuno, A.; Nakagawa, M. Tetrahedron Lett.
1998, 39, 5983.438 Tilley, J. W.; Danho, W.; Shiuey, S.-J.; Kulesha, I.; Sarabu, R.; Swistok, J.; Makofske, R.; Olsen,
G. L.; Chiang, E.; Rusiecki, V. K.; Wagner, R.; Michalewski, J.; Triscari, J.; Nelsen, D.; Chiruzzo,F. Y.; Weatherford. S. Int. J. Pept. Protein Res. 1992, 39, 322.
439 Ben, R. N.; Orellana, A.; Arya, P. J. Org. Chem. 1998, 63, 4817.440 Derrer, S.; Davies, J. E.; Holmes, A. B. J. Chem. Soc., Perkin Trans. 1 2000, 2943.441 Hale, K. J.; Cai, J.; Delisser, V.; Manaviazar, S.; Peak, S. A.; Bhatia, G. S.; Collins, T. C.;
Jogiya, N. Tetrahedron 1996, 52, 1047.442 Decicco, C. P.; Leathers, T. Synlett 1995, 615.443 Lundquist, J. T.; Dix, T. A. Tetrahedron Lett. 1998, 39, 775.444 Evans, D. A.; Ellman, J. A. J. Chem. Soc., Perkin Trans. 1 1989, 111, 1063.445 Whitman, D. B.; Askew, B. C.; Duong, L. T.; Fernandez-Metzler, C.; Halczenko, W.; Hartman,
G. D.; Hutchinson, J. H.; Leu, C.-T.; Prueksaritanont, T.; Rodan, G. A.; Rodan, S. B.; Duggan,M. E. Bioorg. Med. Chem. Lett. 2004, 14, 4411.
446 Whitman, D. B., Merck Research Laboratories, West Point, PA. Personal communication, 2005.447 Broka, C. A.; Ehrler, J. Tetrahedron Lett. 1991, 32, 5907.448 Stone, M. J.; van Dyk, M. S.; Booth, P. M.; Williams, D. H. J. Chem. Soc., Perkin Trans. 1
1991, 1629.449 Evans, D. A.; Lundy, K. M. J. Am. Chem. Soc. 1992, 114, 1495.450 Evans, D. A.; Evrard, D. A.; Rychnovsky, S. D.; Fruh, T.; Whittingham, W. G.; DeVries, K. M.
Tetrahedron Lett. 1992, 33, 1189.451 Kennedy, K. J.; Lundquist, J. T., IV; Simandan, T. L.; Beeson, C. C.; Dix, T. A. Bioorg. Med.
Chem. Lett. 1997, 7, 1937.452 Kennedy, K. J.; Lundquist, J. T., IV; Simandan, T. L.; Kokko, K. P.; Beeson, C. C.; Dix, T. A.
J. Peptide Res. 2000, 55, 348.
ELECTROPHILIC AMINATION OF CARBANIONS 355
453 Noguchi, H.; Aoyama, T.; Shioiri, T. Heterocycles 2002, 58, 471.454 Chung, H.-K.; Kim, H.-W.; Chung, K.-H. Heterocycles 1999, 51, 2983.455 Taunton, J.; Collins, J. L.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 10412.456 Woiwode, T. F.; Wandless, T. J. J. Org, Chem. 1999, 64, 7670.457 Liu, D.-G.; Wang, X.-Z.; Gao, Y.; Li, B.; Yang, D.; Burke, T. R., Jr. Tetrahedron 2002, 58, 10423.458 Gilbertson, S. R.; Chen, G.; McLoughlin, M. J. Am. Chem. Soc. 1994, 116, 4481.459 Arya, P.; Ben, R. N.; Qin, H. Tetrahedron Lett. 1998, 39, 6131.460 Castellanos, E.; Reyes-Rangel, G.; Juaristi, E. Helv. Chim. Acta 2004, 87, 1016.461 Shimizu, M.; Nemoto, H.; Kakuda, H.; Takahata, H. Heterocycles 2003, 59, 245.462 Hanessian, S.; Sailes, H.; Munro, A.; Therrien, E. J. Org. Chem. 2003, 68, 7219.463 Taylor, E. C.; Sun, J.-H. Synthesis 1980, 801.464 Koft, E. R. J. Org. Chem. 1987, 52, 3466.465 Hanessian, S.; Sailes, H.; Therrien, E. Tetrahedron 2003, 59, 7047.466 Wulf, J.-P,; Sienkewicz, K.; Makosza, M.; Schmitz, E. Liebigs Ann. Chem. 1991, 537.467 Hoffmann, H. Chem. Ber. 1962, 95, 2563.468 Bernardi, L.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 5772.469 Yamamoto, Y.; Hatsuya, S.; Yamada, J.-i. J. Org. Chem. 1990, 55, 3113.470 Bertelsen, S.; Marigo, M.; Brandes, S.; Diner, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006,
128, 12973.471 Du Bois, J.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1996, 118, 915.472 Schmitz, E.; Janisch, K. Z. Chem. 1971, 11, 458.473 Tamura, Y.; Kato, S.; Ikeda, M. Chem. Ind. (London) 1971, 767.474 Sofia, M. J.; Katzenellenbogen, J. A. J. Org. Chem. 1985, 50, 2331.475 Badorrey, R.; Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron: Asymmetry 1995,
6, 2787.476 Lumbierres, M.; Marchi, C.; Moreno-Manas, M.; Sebastian, R. M.; Vallribera, A.; Lago, E.;
Molins, E. Eur. J. Org. Chem. 2001, 2321.477 Hartke, K.; Brutsche, A.; Gerber, H.-D. Liebigs Ann. Chem. 1992, 927.478 Diels, O.; Behncke, H. Chem. Ber. 1924, 57, 653.479 Nelson, J. H.; Howells, P. N.; DeLullo, G. C.; Landen, G. L.; Henry, R. A. J. Org. Chem. 1980,
45, 1246.480 Meseguer, M.; Mareno-Manas, M.; Vallribera, A. Tetrahedron Lett. 2000, 41, 4093.481 Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120.482 Golding, B. T.; Smith, A. J. J. Chem. Soc., Chem. Commun. 1980, 702.483 Weininger, S. J.; Kohen, S.; Mataka, S.; Koga, G.; Anselme, J.-P. J. Org. Chem. 1974, 39, 1591.484 Benati, L.; Nanni, D.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1997, 457.485 Blatt, A. H. J. Am. Chem. Soc. 1939, 61, 3494.486 Cromwell, N. H.; Barker, N. G.; Wankel, R. A.; Vanderhorst, P. J.; Olson, F. W.; Anglin, J. H.,
Jr. J. Am. Chem. Soc. 1951, 73, 1044.487 Cardillo, G.; Casolari, S.; Gentilucci, L.; Tomasini, C. Angew. Chem., Int. Ed. Engl. 1996,
35, 1848.488 Bongini, A.; Cardillo, G.; Gentilucci, L.; Tomasini, C. J. Org. Chem. 1997, 62, 9148.489 Cardillo, G.; Gentilucci, L.; Tolomelli, A. Tetrahedron Lett. 1999, 40, 8261.490 Pereira, M. M.; Santos, P. P. O.; Reis, L. V.; Lobo, A. M.; Prabhakar, S. J. Chem. Soc., Chem.
Commun. 1993, 38.491 Cardillo, G.; Gentilucci, L.; Gianotti, M.; Perciaccante, R.; Tolomelli, A. J. Org. Chem. 2001,
66, 8657.492 Metra, P.; Hamelin, J. J. Chem. Soc., Chem. Commun. 1980, 1038.493 Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Org. Lett. 2004, 6, 197.494 Sato, S. Bull. Chem. Soc. Jpn. 1968, 41, 1440.495 Gasperi, T.; Loreto, M. A.; Tardella, P. A.; Veri, E. Tetrahedron Lett. 2003, 44, 4953.496 Sheradsky, T.; Yusupova, L. Tetrahedron Lett. 1995, 36, 7701.497 Yoshida, M.; Uchiyama, K.; Narasaka, K. Heterocycles 2000, 52, 681.498 Uchiyama, K.; Hayashi, Y.; Narasaka, K. Synlett 1997, 445.
356 ORGANIC REACTIONS
499 Uchiyama, K.; Ono, A.; Hayashi, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1998, 71, 2945.500 Glaser, H.; Moller, F.; Pieper, G.; Schroter, R.; Spielberger, G.; Soll, H. In Methoden der organ-
ischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart, 1957; Vol. 11/1, p 3.501 Chemistry of the Amino Group; Patai, S. Ed.; Wiley: New York, 1968.502 Mitsunobu, O. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 6, p 65.503 Hemmer, R.; Lurken, W. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme
Verlag: Stuttgart, New York, 1992; Vol. 16d/2, p 646.504 Chemistry of the Amino, Nitroso, Nitro, and Related Groups, Part 2 ; Patai, S. Ed.; Wiley: Chich-
ester, 1996.505 Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675.506 Meier, R. Chem. Ber. 1953, 86, 1483.507 Beringer, F. M.; Farr, J. A., Jr.; Sands, S. J. Am. Chem. Soc. 1953, 75, 3984.508 Sand, J.; Singer, F. Liebigs Ann. Chem. 1903, 329, 190.509 Muller, E.; Metzger, H. Chem. Ber. 1956, 89, 396.510 Kato, K.; Mukaiyama, T. Chem. Lett. 1990, 1395.511 Wieland, H. Chem. Ber. 1903, 36, 2315.512 Baker, E. B.; Sisler, H. H. J. Am. Chem. Soc. 1953, 75, 5193.513 Oddo, B. Gazz. Chim. Ital. 1909, 39, 659.514 Waters, W. L.; Marsh, P. G. J. Org. Chem. 1975, 40, 3344.515 Waters, W. L.; Marsh, P. G. J. Org. Chem. 1975, 40, 3349.516 Klages, F.; Sitz, H.; Heinle, R. Chem. Ber. 1959, 92, 2606.517 Klages, F.; Heinle, R.; Sitz, H.; Specht, E. Chem. Ber. 1963, 96, 2387.518 Rasmussen, J. K.; Hassner, A. J. Org. Chem. 1974, 39, 2558.519 Bachman, G. B.; Hokama, T. J. Org. Chem. 1960, 25, 178.520 Olah, G. A.; Rochin, C. J. Org. Chem. 1987, 52, 701.521 Elfehail, F.; Dampawan, P.; Zajac, W., Jr. Synth. Commun. 1980, 10, 929.522 Dampawan, P.; Zajac, W. W., Jr. J. Org. Chem. 1982, 47, 1176.523 Detty, M. R.; Logan, M. E. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette,
Ed.; Wiley: New York, 1995; p 2908.524 Touster, O. Org. React. 1953, 7, 327.525 Metzger, H. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag:
Stuttgart, 1968; Vol. 10/4, p 17.526 Unterhalt, B. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag:
Stuttgart, New York 1990; Vol. E14b, p 295.527 Senechal-Tocquer, M.-C.; Senechal, D.; Le Bihan, J.-Y.; Gentric, D.; Caro, B.; Gruselle, M.;
Jaouen, G. J. Organomet. Chem. 1992, 433, 261.528 Metzger, H. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag:
Stuttgart, 1968; Vol. 10/4, p 236.529 Hemmer, R.; Lurken, W. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme
Verlag: Stuttgart, New York, 1992; Vol. 16d/2, p 878.530 Bewad, I. J. Prakt. Chem. 1901, 63, 94.531 Berti, C. Synthesis 1983, 793.532 Kato, K.; Mukaiyama, T. Chem. Lett. 1990, 1917.533 Kato, K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1991, 64, 2948.534 Kato, K.; Mukaiyama, T. Chem. Lett. 1990, 1137.535 Boschan, R.; Merrow, R. T.; Van Dolah, R. W. Chem. Rev. 1955, 55, 485.536 Moureu, C. C. R. Hebd. Sceances Acad. Sci. 1901, 132, 837.537 Hepworth, H. J. Chem. Soc. 1921, 251.538 Wislicenus, W.; Waldmuller, M. Chem. Ber. 1908, 41, 3334.539 Kornblum, N. Org. React. 1962, 12, 101.540 Feuer, H.; Blecker, L. R.; Jans, R. W., Jr.; Frost, J. W. J. Heterocycl. Chem. 1979, 16, 481 and
earlier papers in this series.541 Elfehail, F. E.; Zajac, W. W., Jr. J. Org. Chem. 1981, 46, 5151.
ELECTROPHILIC AMINATION OF CARBANIONS 357
542 Hassner, A.; Larkin, J. M.; Dowd, J. E. J. Org. Chem. 1968, 33, 1733.543 Cushman, M.; Mathew, J. Synthesis 1982, 397.544 Kobayashi, Y. Bull. Chem. Soc. Jpn. 1973, 46, 3462.545 Schaub, R. E.; Fulmor, W.; Weiss, M. J. Tetrahedron 1964, 20, 373.546 Chadwick, D. J.; Cottrell, W. R. T.; Meakins, G. D. J. Chem. Soc., Perkin Trans. 1 1972, 655.547 Suginome, H.; Kurokawa, Y. Bull. Chem. Soc. Jpn. 1989, 62, 1343.548 Curran, T. T.; Flynn, G. A.; Rudisill, D. E.; Weintraub, P. M. Tetrahedron Lett. 1995, 36, 4761.549 Feuer, H.; Vincent, B. F., Jr. J. Org. Chem. 1964, 29, 939.550 Feuer, H.; Savides, C. J. Am. Chem. Soc. 1959, 81, 5826.551 Feuer, H.; Spinicelli, L. F. J. Org. Chem. 1976, 41, 2981.552 Fetell, A. I.; Feuer, H. J. Org. Chem. 1978, 43, 497.553 Griswold, A. A.; Starcher, P. S. J. Org. Chem. 1966, 31, 357.554 Sheehan, D.; Vellturo, A. F. South African Patent 67 05,789 (1968); Chem. Abstr. 1969, 70,
57261k.555 Ozbal, H.; Zajac, W. W., Jr. J. Org. Chem. 1981, 46, 3082.556 Dampawan, P.; Zajac, W. W., Jr. Synthesis 1983, 545.557 Rank, W. Tetrahedron Lett. 1991, 32, 5353.558 Evans, P. A.; Longmire, J. M. Tetrahedron Lett. 1994, 35, 8345.559 Zuman, P.; Shah, B. Chem. Rev. 1994, 94, 1621.560 Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317.561 Joghyuk, L.; Li, C.; Ann, H. W.; George, B. R. Chem. Rev. 2002, 102, 1019.562 Wieland, H.; Roseeu, A. Chem. Ber. 1912, 45, 494.563 Wieland, H.; Offenbacher, M. Chem. Ber. 1914, 47, 2111.564 Wieland, H.; Reverdy, A. Chem. Ber. 1915, 48, 1117.565 Wieland, H.; Reverdy, A. Chem. Ber. 1915, 48, 1112.566 Wieland, H.; Roth, K. Chem. Ber. 1920, 53, 210.567 Wieland, H.; Kogl, F. Chem. Ber. 1922, 55, 1798.568 Maruyama, K. Bull. Chem. Soc. Jpn. 1964, 37, 1013.569 Gilman, H.; McCracken, R. J. Am. Chem. Soc. 1927, 49, 1052.570 Kopp, F.; Sapountzis, I.; Knochel, P. Synlett 2003, 885.571 Belousova, S. P.; Vasil’ev, N. V.; Kolomiets, A. F.; Nikolaev, K. M.; Sokol’skii, G. A.; Fokin,
A. V. Izv. Akad. Nauk, Ser. Khim. 1984, 1198; Engl. Transl. p 1103.572 Vasil’ev, N. V.; Kolomiets, A. F.; Sokol’skii, G. A. Zh. Org. Khim. 1981, 17, 1321; Engl. Transl.
p 1171.573 Momiyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579.574 Guo, H.-M.; Cheng, L.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem. Commun.
2006, 429.575 Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038.576 Sasaki, T.; Ishibashi, Y.; Ohno. M. Chem. Lett. 1983, 863.577 Sasaki, T.; Mori, K.; Ohno, M. Synthesis 1985, 279.578 Sasaki, T.; Mori, K.; Ohno, M. Synthesis 1985, 280.579 Lewis, J. W.; Myers, P. L.; Ormerod, J. A. J. Chem. Soc., Perkin Trans. 1 1972, 2521.580 Abramovitch, R. A.; Challand, S. R.; Yamada, Y. J. Org. Chem. 1975, 40, 1541.581 Kresze, G.; Ascherl, B.; Braun, H. Org. Prep. Proc. Int. 1987, 19, 329.582 Schenk, C.; Beekes, M. L.; van der Drift, J. A. M.; de Boer, T. J. Recl. Trav. Chim. Pays-Bas
1980, 99, 278.583 Schlenk, C.; Beekes, M. L.; de Boer, T. J. Recl. Trav. Chim. Pays-Bas 1980, 99, 246.584 Lub, J.; Beekes, M. L.; de Boer, T. J. Recl. Trav. Chim. Pays-Bas 1986, 105, 22.585 Filip, S. V.; Seewald, N. Synthesis 2005, 3565.586 Oppolzer, W.; Tamura, O. Tetrahedron Lett. 1990. 31, 991.587 Oppolzer, W.; Tamura, O.; Deerberg, J. Helv. Chim. Acta 1992, 75, 1965.588 Oppolzer, W.; Merifield, E. Helv. Chim. Acta 1993, 76, 957.589 Oppolzer, W.; Cintas-Moreno, P.; Tamura, O. Helv. Chim. Acta 1993, 76, 187.590 Oppolzer, W.; Bochet, C. G.; Merifield, E. Tetrahedron Lett. 1994, 35, 7015.
358 ORGANIC REACTIONS
591 Ludwig, S. N.; Unkefer, C. J. J. Labeled Comp. Radiopharm. 1996, 38, 239.592 Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Scolaro, A. Gazz. Chim. Ital. 1995,
125, 65.593 Otaka, A.; Mitsuyama, E.; Kinoshita, T.; Tamamura, H.; Fujii, N. J. Org. Chem. 2000, 65, 4888.594 Davison, E. C.; Fox, M. E.; Holmes, A. B.; Roughley, S. D.; Smith, C. J.; Williams, G. M.;
Davies, J. E.; Raithby, P. R.; Adams, J. P.; Forbes, I. T.; Press, N. J.; Thompson, M. J. J. Chem.Soc., Perkin Trans. 1 2002, 1494.
595 Oppolzer, W.; Tamura, O.; Sundarababu, G.; Signer, M. J. Am. Chem. Soc. 1992, 114, 5900.596 Felber, H.; Kresze, G.; Braun, H.; Vasella, A. Tetrahedron Lett. 1984, 25, 5381.597 Bartoli, G. Acc. Chem. Res. 1984, 17, 109.598 Bartoli, G.; Marcantoni, E.; Petrini, M. J. Chem. Soc., Chem. Commun. 1993, 1373.599 Barboni, L.; Bartoli, G.; Marcantoni, E.; Petrini, M.; Dalpozzo, R. J. Chem. Soc., Perkin Trans.
1 1990, 2133.600 Bartoli, G.; Palmieri, G.; Petrini, M.; Bosco, M.; Dalpozzo, R. Gazz. Chim. Ital. 1990, 120, 247.601 Bartoli, G.; Marcantoni, E.; Petrini, M.; Dalpozzo, R. J. Org. Chem. 1990, 55, 4456.602 Bartoli, G.; Marcantoni, E.; Petrini, M. J. Chem. Soc., Chem. Commun. 1991, 793.603 Bartoli, G.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57, 5834.604 Yost, Y.; Gutmann, H. R.; Muscoplat, C. C. J. Chem. Soc. (C) 1971, 2119.605 Gilman, H.; McCracken, R. J. Am. Chem. Soc. 1929, 51, 821.606 Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124, 9390.607 Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163.608 Dobbs, A. J. Org. Chem. 2001, 66, 638.609 Sitzmann, M. E.; Kaplan, L. A.; Angres, I. J. Org. Chem. 1977, 42, 563.610 Rathore, R.; Lin, Z.; Kochi, J. K. Tetrahedron Lett. 1993, 34, 1859.611 Briere, R.; Rassat, A. Bull. Soc. Chim. Fr. 1965, 378.612 Chapelet-Letourneux, G.; Lemaire, H.; Rassat, A. Bull. Soc. Chim. Fr. 1965, 444.613 Lemaire, H.; Marechal, Y.; Ramasseul, R.; Rassat, A. Bull. Soc. Chim. Fr. 1965, 372.614 Hoffmann, A. K.; Feldman, A. M.; Gelblum, E. J. Am. Chem. Soc. 1964, 86, 646.615 Enders, E. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1965; Vol. 10/3, p 490.616 Dumic, M; Kuruncev, D.; Kovacevic, K.; Polak, L.; Kolbah, D. In Methoden der organischen
Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart, New York, 1990; Vol. E14b/1, p 450.617 Phillips, R. R. Org. React. 1959, 10, 143.618 Enders, E. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1965; Vol. 10/3, p 522.619 Schroter, R. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag:
Stuttgart, 1957; Vol. 11/1 p 531.620 Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733.621 Regitz, M. Synthesis 1972, 351.622 Regitz, M.; Maas, G. Diazo Compounds; Academic Press: Orlando, 1986.623 Bohshar, M.; Fink, J.; Heydt, H.; Wagner, O.; Regitz, M. In Methoden der organischen Chemie
(Houben-Weyl); Georg Thieme Verlag: Stuttgart, 1990; Vol. E14b/2, p 961.624 Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.625 Doering, W. von E.; DePuy, C. H. J. Am. Chem. Soc. 1953, 75, 5955.626 Ando, W.; Tanikawa, H.; Sekiguchi, A. Tetrahedron Lett. 1983, 39, 4245.627 Hazen, G. G.; Weinstock, L. M.; Connell, R.; Bollinger, F. W. Synth. Commun. 1981, 11, 947.628 Hazen, G. G.; Bollinger, F. W.; Roberts, F. E.; Russ, W. K.; Seman, J. J.; Staskiewicz, S. Org.
Synth. 1996, 75, 144.629 Tuma, L. D. Thermochim. Acta 1994, 243, 161.630 Gisin, B.; Brenner, M. Helv. Chim. Acta 1970, 53, 1030.631 Davis, F. A.; Yang, B.; Deng, J. J. Org. Chem. 2003, 68, 5147.632 Moody, C. J.; Morfitt, C. N.; Slawin, A. M. Z. Tetrahedron: Asymmetry 2001, 12. 1657.633 Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M. Organic Synthesis via Boranes;
Wiley: New York, 1975.
ELECTROPHILIC AMINATION OF CARBANIONS 359
634 Carboni, B.; Vaultier, M. Bull. Soc. Chim. Fr. 1995, 132, 1003.635 Brown, H. C.; Kim, K.-W.; Srebnik, M.; Singaram, B. Tetrahedron 1987, 43, 4071.636 Mueller, R. H. Tetrahedron Lett. 1976, 2925.637 Brown, H. C.; Heydkamp, W. R.; Breuer, E.; Murphy, W. S. J. Am. Chem. Soc. 1964, 86, 3565.638 Rathke, M. W.; Millard, A. A. Org. Synth. Coll. Vol. 6, 1988, 943.639 Mikhailov, B. M.; Shagova, E. A.; Etinger, M. Yu. J. Organomet. Chem. 1981, 220, 1.640 Genet, J.-P.; Hajicek, J.; Bischoff, L.; Greck, C. Tetrahedron Lett. 1992, 33, 2677.641 Jigajinni, V. B.; Pelter, A.; Smith, K. Tetrahedron Lett. 1978, 181.642 Brown, H. C.; Midland, M. M.; Levy, A. B. Tetrahedron 1987, 43, 4079.643 Kabalka, G. W.; Goudgaon, N. M.; Liang, Y. Synth. Commun. 1988, 18, 1363.644 Carboni, B; Vaultier, M.; Courgeon, T.; Carrie, R. Bull. Soc. Chim. Fr. 1989, 844.645 Brown, H. C.; Salunkhe, A. M.; Singaram, B. J. Org. Chem. 1991, 56, 1170.646 Fernandez, E.; Hooper, M. W.; Knight, F. I.; Brown, J. J. Chem. Soc., Chem. Commun. 1997, 173.647 Brown, H. C.; Kim, K.-W.; Cole, T. E.; Singaram, B. J. Am. Chem. Soc. 1986, 108, 6761.648 Matheson, D. S. Acc. Chem. Res. 1988, 21, 294.649 Kabalka, G. W.; Ferrell, J. W. Synth. Commun. 1979, 9, 443.650 O’Brien, C. Chem. Rev. 1964, 64, 81.651 Mayer, D. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1977; Vol. 7/2c, p 2272 and references cited therein.652 Fisher, L. E.; Muchowski, J. M. Org. Prep. Proced. Int. 1990, 22, 399.653 Maruoka, K.; Yamamoto, H. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.,
Eds., 1991, Vol. 6, p 763.654 Cram, D. J.; Hatch, M. J. J. Am. Chem. Soc. 1953, 75, 33.655 Egushi, S.; Ishii, Y. Bull. Chem. Soc. Jpn. 1963, 36, 1434.656 Alvernhe, G.; Laurent, A. J. Chem. Res. (S) 1978, 28; J. Chem. Res. (M) 1978. 501.657 Ricart, G.; Couturier, D. C. R. Hebd. Sceances Acad. Sci. 1977, 284, 191 and references cited
therein.658 Hoch, J. C. R. Hebd. Sceances Acad. Sci. 1934, 198, 1865.659 Campbell, K. N.; Campbell, B. K.; McKenna, J. F.; Chaput, E. P. J. Org. Chem. 1943, 8, 103
and references cited therein.660 Rewicki, D.; Tuchscherer, C. Angew. Chem., Int. Ed. Engl. 1972, 11, 44.661 Spencer, H. Chem. Britain 1981, 17.662 Muller, E. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1967; Vol. 10/4, p 827.663 Andree, R.; Kluth, J. F.; Hanefeld, W. In Methoden der organischen Chemie (Houben-Weyl);
Georg Thieme Verlag: Stuttgart, New York, 1990; Vol. 16a/2, p 856.664 Goehring, R, R. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley:
New York, 1995; p 1052.665 Sisler, H. H.; Omietanski, G. Inorg. Synth. 1957, 5, 91.666 Coleman, G. H.; Johnson, H. L. Inorg. Synth. 1939, I , 59.667 Schmitz, E.; Schramm, S.; Flamme, W.; Bricker, U. Z. Anorg. Allgem. Chem. 1973, 396, 178.668 Allan, R. D.; Duke, R. K.; Hambley, T. W.; Johnston, G. A. R.; Mewett, K. N.; Quickert, N.;
Tran, W. Aust. J. Chem. 1997, 49, 785.669 Coleman, G. H.; Goheen, G. E. Inorg. Synth. 1939, I , 62.670 Noyes, W. A. Inorg. Synth. 1939, 1, 65.671 Bartsch, R. A.; Cho, B. R.. J. Am. Chem. Soc. 1979, 101, 3587.672 Cho, B. R,; Namgoong, S. K.; Kim, T. R. J. Chem. Soc., Perkin Trans. 2 1987, 853.673 Noack, M.; Gottlich, R. Eur. J. Org. Chem. 2002, 3171.674 Bachand, C.; Driguez, H.; Paton, J. M.; Touchard, D.; Lessard, J. J. Org. Chem. 1974, 39, 3136.675 Andree, R.; Kluth, J. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag:
Stuttgart, 1990; Vol. 16a/1, p 214.676 Theilacker, W.; Ebke, K. Angew. Chem. 1956, 68, 303.677 Palazzo, G.; Rogers, E. F.; Marini-Bettolo, G. B. Gazz. Chim. Ital. 1954, 84, 915.678 Choong, I. C.; Ellman, J. A. J. Org. Chem. 1999, 64, 6528.
360 ORGANIC REACTIONS
679 Foot, O. F.; Knight, D. W. Chem. Commun. 2000, 975.680 Chimiak, A.; Kolasa, T. Bull. Acad. Pol. Sci. Chim. 1974, 22, 195; Chem. Abstr. 1974, 80,
132725b.681 Kokko, B. J. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley:
New York, 1995; p 3511.682 Hjeds, H. Acta Chem. Scand. 1965, 19, 1764.683 Traube, W.; Ohlendorf, H.; Zander, H. Chem. Ber. 1920, 53, 1477.684 Knox, G. R.; Pauson, P. L.; Willison, D.; Solcanova, E.; Toma, S. Organometallics 1990, 9, 301.685 Rees, D. C.; Hamilton, N. M. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette,
Ed.; Wiley: New York, 1995; p 332.686 Bumgardner, C. L.; Lilly, R. L. Chem. Ind. (London) 1962, 559.687 Bellettini, J. R.; Olsen, E. R.; Teng, M.; Miller, M. J. In Encyclopedia of Reagents for Organic
Synthesis; L. A. Paquette, Ed.; Wiley: New York, 1995; p 2189.688 Sheradsky, T. J. Heterocycl. Chem. 1967, 4, 413.689 Legault, C.; Charette, A. J. Org. Chem. 2003, 68, 7119.690 Marmer, W. N.; Maerker, G. J. Org. Chem. 1972, 37, 3520.691 Carpino, L. A.; Giza, C. A.; Carpino, B. A. J. Am. Chem. Soc. 1959, 81, 955.692 Boche, G. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 3270.693 Carpino, L. A. J. Am. Chem. Soc. 1960, 82, 3133.694 Psiorz, M.; Zinner, G. Synthesis 1984, 217.695 Biloski, A. J.; Ganem, B. Synthesis 1983, 537.696 Erdik, E. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 2764.697 Wallace, R. G. Aldrichimica Acta 1980, 13, 3.698 Wallace, R. G. Org. Prep. Proced. Int. 1982, 14, 265.699 King, F. D.; Walton, D. R. M. Synthesis 1975, 788.700 Tamura, Y.; Ikeda, M. Yuki Gosei Kagaku Kyokai Shi 1974, 32, 136.701 Boche, G. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 3277.702 Krause, J. G. Synthesis 1972, 140.703 Johnson, C. R.; Kirchhoff, R. A.; Corkins, H. G. J. Org. Chem. 1974, 39, 3458.704 Scopes, D. I. C.; Kluge, A. F.; Edwards, J. A. J. Org. Chem. 1977, 42, 376.705 Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii. S.; Ikeda, M. J. Org. Chem. 1973, 38, 1239.706 Koziara, A.; Novalinska, M.; Zwierzak, A. Synth. Commun. 1993, 23, 2127.707 Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 2003, 44, 3031.708 Chapman, T. M.; Freedman, E. A. Synthesis 1971, 591.709 Knight, F. I.; Brown, J. M.; Lazzari, D.; Ricci, A.; Blacker, A. J. Tetrahedron 1997, 53, 11411.710 Boche, G. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 2240.711 Klotzer, W.; Baldinger, H.; Karpitschka, E. M.; Knoflach, J. Synthesis 1982, 592.712 Harger, M. J. P. J. Chem. Soc., Chem. Commun. 1979, 768.713 Harger, M. J. P. J. Chem. Soc., Perkin Trans. 1 1981, 3284.714 Boche, G. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 2066.715 Boche, G.; Sommerlade, R. H. Tetrahedron 1986, 42, 2703.716 Yaquanc, J. J.; Masse, G.; Sturtz, G. Synthesis 1985, 807.717 Shustov, G. V.; Kadorkina, G. K.; Varlamov, S. V.; Kachanov, A. V.; Kostyanovsky, R. G.;
Rauk, A. J. Am. Chem. Soc. 1992, 114, 1616.718 Page, P. C. B.; Murrell, V. L.; Limousin, C.; Laffan, D. D. P.; Bethell, D.; Slawin, A. M. Z.;
Smith, T. A. D. J. Org. Chem. 2000, 65, 4204.719 Vidal, J.; Hannachi, J.-C.; Hourdin, G.; Mulatier, J.-C.; Collet, A. Tetrahedron Lett. 1998,
39, 8845.720 Vidal, J.; Damestoy, S.; Collet, A. Tetrahedron Lett. 1995, 36, 1439.
ELECTROPHILIC AMINATION OF CARBANIONS 361
721 Watanabe, H.; Hashizume, Y.; Uneyama, K. Tetrahedron Lett. 1992, 33, 4333.722 Evans, D. A.; Barnes, D. M. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette,
Ed.; Wiley: New York, 1995; p 4958.723 Hellmann, H.; Teichmann, K. Chem. Ber. 1956, 89, 1134.724 Erdik, E. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 41.725 Oxley, P.; Short, W. F. J. Chem. Soc. 1948, 1514.726 Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1997, 317.727 Erdik, E. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 4826.728 Barbero, M.; Crisma, M.; Degani, I.; Fochi, R.; Perracino, P. Synthesis 1998, 1171.729 Cohen, S. G.; Nicholson, J. J. Org. Chem. 1965, 30, 1162.730 Bock, H.; Baltin, E.; Kroner, J. Chem. Ber. 1966, 99, 3337.731 Knight, G. T.; Loadman, M. J. R.; Saville, B.; Wildgoose, J. J. Chem. Soc., Chem. Commun.
1974, 193.732 Stoner, E. J. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 1790.733 Mackay, D.; Pilger, C. W.; Wong, L. L. J. Org. Chem. 1973, 38, 2043.734 Little, R. D.; Bregant, T. M. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette,
Ed.; Wiley: New York, 1995; p 572.735 Rutjes, F. P. J. T.; Paz, M. M.; Hiemstra, H.; Speckamp, N. Tetrahedron Lett. 1991, 32, 6629.736 Klinge, M.; Vederas, J. C. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette,
Ed.; Wiley: New York, 1995; p 1586.737 Leblanc, Y. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 1532.738 Harris, J. M.; Bolessa, E. A.; Vederas, J. C. J. Chem. Soc., Perkin Trans. 1 1995, 1951.739 Vorbruggen, H.; Krolikiewicz, K. Synthesis 1979, 35.740 Pearson, W. J.; Ramamoorthy, P. S. In Encyclopedia of Reagents for Organic Synthesis; L. A.
Paquette, Ed.; Wiley: New York, 1995; p 2393.741 Hassner, A. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley: New
York, 1995; p 219.742 Thomas, A. V. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley:
New York, 1995; p 2242.743 Nikolaev, V. A. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley:
New York, 1995; p 3306.744 Cavender, C. J.; Shiner, V. J., Jr. J. Org. Chem. 1972, 37, 3567.745 Fritschi, S.; Vasella, A. Helv. Chim. Acta 1991, 74, 2024.746 Heydt, H.; Regitz, M. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.;
Wiley: New York, 1995; p 4943.747 Regitz, M.; Hocker, J.; Liedhegener, A. Org. Synth., Coll. Vol. 5, 1973, 179.748 Leffler, J. E.; Tsuno, Y. J. Org. Chem. 1963, 28, 902.749 Mander, L. N. In Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, Ed.; Wiley:
New York, 1995; p 5174.750 Harmon, R. E.; Wellman, G.; Gupta, S. K. J. Org. Chem. 1973, 38, 11.751 Davies, H. M. L.; Cantrell, W. R., Jr.; Romines, K. R.; Baum, J. S. Org. Synth. 1992, 70, 93.752 Durr, H.; Hauck, G.; Bruck, W.; Kober, H. Z. Naturforsch. 1981, 86b, 1149.753 Roush, W. R.; Feitler, D.; Rebek, J. Tetrahedron Lett. 1974, 1391.754 Weinreb, S. M.; Heintzelman, G. R. In Encyclopedia of Reagents for Organic Synthesis; L. A.
Paquette, Ed.; Wiley: New York, 1995; p 562.755 Du Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M.; Day, M. W. Angew. Chem., Int. Ed. Engl.
1997, 36, 1645.756 Jepsen, A. S.; Roberson, M.; Hazell, R. G.; Jørgensen, K. A. Chem. Commun. 1998, 1599.757 Theodoridis, G. Tetrahedron 2000, 56, 2339 and references cited therein.758 Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 2005.
362 ORGANIC REACTIONS
759 Marshalkin, M. F.; Yakhontov, L. N. Uspekhi Khim. 1986, 55, 1785; Russian Chem. Rev. 1986,55, 1016.
760 Ding, H.; Fristad, G. K. Org. Lett. 2004, 6, 637.761 Fernandez, R.; Ferrete, A.; Llera, J. M.; Magriz, A.; Martın-Zamora, E.; Dıez, E.; Lassaletta,
J. M. Chem. Eur. J. 2004, 10, 737.762 Robinson, F. P.; Brown, R. K. Can. J. Chem. 1961, 39, 1171.763 Alexakis, A.; Lensen, N.; Mangeney, P. Synlett 1991, 625.764 Anakabe, E.; Vicario, J. L.; Badıa, D.; Carrillo, L.; Yoldi, V. Eur. J. Org. Chem. 2001, 4343.765 Vicario, J. L.; Badıa, D.; Domınguez, E.; Crespo, A.; Carillo, L.; Anakabe, E. Tetrahedron Lett.
1999, 40, 7123.766 Gilchrist, T. L.; Hughes, D.; Wasson, R. Tetrahedron Lett. 1987, 28, 1573.767 LiBassi, G.; Ventura, P.; Monguzzi, R.; Pifferi, G. Gazz. Chim. Ital. 1977, 107, 253.768 Milcent, R.; Guevrekian-Soghomoniantz, M.; Barbier, G. J. Heterocycl. Chem. 1986, 23, 1845.769 Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Narisano, E.; Riva, R. Tetrahedron 1994,
50, 11967.770 Maffre, D.; Dumy, P.; Vidal, J.-P.; Escale, R.; Girard, J.-P. J. Chem. Res. (S) 1994, 30.771 Hassner, A. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1990; Vol. 16a/2, p 1275.772 Hemmer, R.; Lurken, W. In Methoden der organischen Chemie (Houben-Weyl); Georg Thieme
Verlag: Stuttgart, New York, 1992; Vol. 16d/2, p 956.773 Gueguen, C.; About-Jaudet, E.; Collignon, N.; Savignac, P. Synth. Commun. 1996, 26, 4131.774 Banteli, R.; Brun, I.; Hall, P.; Metternich, R. Tetrahedron Lett. 1999, 40, 2109.775 Maiti, S. N.; Singh, M. P.; Micetich, R. G. Tetrahedron Lett. 1986, 27, 1423.776 Liang, B.; Carroll, P. J.; Joullie, M. M. Org. Lett. 2000, 2, 4157.777 Wasserman, H. H.; Hlasta, D. J.; Tremper, A. W.; Wu, J. S. J. Org. Chem. 1981, 46, 2999.778 Rolla, F. J. Org. Chem. 1982, 47, 4327.779 Spagnolo, P.; Zanirato, P.; Gronowitz, S. J. Org. Chem. 1982, 47, 3177.780 Nishida, A.; Shibasaki, M.; Ikegami, S. Tetrahedron Lett. 1984, 25, 765.781 Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983, 24, 763.782 Shaw, A. N.; Dolle, R. E.; Kruse, L. I. Tetrahedron Lett. 1990, 31, 5081.783 Manis, P. A.; Rathke, M. W. J. Org. Chem. 1980, 45, 4952.784 Es-Sayed, M.; Gratkowski, C.; Krass, N.; Meyers, A. I.; de Meijere, A. Synlett 1992, 962.785 Patonay, T.; Hoffman, R. V. J. Org. Chem. 1995, 60, 2368.786 Beak, P.; Kokko, B. J. J. Org. Chem. 1982, 47, 2823.787 Knox, G. R. Proc. Chem. Soc. 1959, 56.788 Pochinok, V. Ya.; Avramenko, L. F.; Grigorenko, T. F.; Pochinok, A. V.; Sidorenko, I, A.;
Bovchaljuk, L. N. Ukr. Khim. Zh. 1979, 45, 975; Chem. Abstr. 1980, 92, 76464z.789 Pochinok, V. Ya.; Mikhailyuchenko, N. K. Ukr. Khim. Zh. 1955, 21, 625; Chem. Abstr. 1955,
50, 14599i.790 Skripnik, L. I.; Pochinok, V. Ya. Khim. Geterotsikl. Soedin. 1967, 3, 292; Engl. Transl. p 221.791 Brown, R.; Jones, W. E. J. Chem. Soc. 1946, 781.792 Shverdina, N. I.; Kocheshkov, K. A. Zh. Obshch, Khim. 1938, 8, 1825; Chem. Abstr. 1939,
33, 5804.793 Silver, M. S.; Shafer, P. R.; Nordlander, J. E.; Ruchardt, C.; Roberts, J. D. J. Am. Chem. Soc.
1960, 82, 2646.794 Stolle, R.; Reichert, W. J. Prakt. Chem. 1929, 122, 344.795 Carpino, L. A.; Terry, P. H.; Crowley, P. J. J. Org. Chem. 1961, 26, 4336.796 Waser, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 4099.797 Kaiser, E. M.; Bartling, G. J. Tetrahedron Lett. 1969, 4357.798 Yeung, D. W. K.; Warkentin, J. Can. J. Chem. 1976, 54, 1345.799 Rutjes, F. P. J. T.; Hiemstra, H.; Mooiweer, H. H.; Speckamp, W. N. Tetrahedron Lett. 1988,
29, 6975.800 Skripnik, L. I.; Pochinok, V. Ya. Khim. Geterotsikl. Soedin. 1968, 4, 474; Engl. Transl. p 353.801 Erdik, E.; Ates, S. Synth. Commun. 2006, 36, 2813.
ELECTROPHILIC AMINATION OF CARBANIONS 363
802 Erdik, E.; Daskapan, T. Tetrahedron Lett. 2002, 43, 6237.803 Erdik, E.; Ay, M. Synth. React. Inorg. Met.-Org. Chem. 1989, 19, 663.804 Bernheim, M.; Boche, G. Angew. Chem., Int Ed. Engl. 1980, 19, 1010.805 Coleman, G. H.; Forrester, R. A. J. Am. Chem. Soc. 1936, 58, 27.806 Unger, C.; Zimmer, R.; Reissig, H.-U.; Wurthwein, E.-U. Chem. Ber. 1991, 124, 2279.807 Kaiser, E. M.; Bartling, G. J.; Foy, T. Org. Syn. 1973, 53, 1829 [sic]; Chem. Abstr. 1974,
81, 105213x.808 Quirk, R. P.; Cheng, P. L. Macromolecules 1986, 19, 1291.809 Kleinfeller, H.; Bonig, G. J. Prakt. Chem. 1931, 132, 175.810 Robson, E.; Tedder, J. M.; Webster, B. J. Chem. Soc. 1963, 1863.811 Weißberger, A.; Fasold, K.; Bach, H. J. Prakt. Chem. 1930, 124, 29.812 Daskapan, T. Tetrahedron Lett. 2006, 47, 2879.813 Neumann W. P.; Wicenec, C. Chem. Ber. 1991, 124, 2297.814 Holt, P. F.; Hughes, B. P. J. Chem. Soc. 1954, 764.815 Gilman, H.; Bailie, J. C. J. Org. Chem. 1937, 2, 84.816 Demers, J. P.; Klaubert, D. H. Tetrahedron Lett. 1987, 28, 4933.817 Pochinok, V. Ya. Zh. Obshch. Khim. 1946, 16, 1306; Chem. Abstr. 1947, 41, 3066f.818 Pochinok, V. Ya.; Zaitseva, S. D.; El’gort, R. G. Ukr. Khim. Zh. 1951, 17, 509; Chem. Abstr.
1954, 48, 11392i.819 Pochinok, V. Ya.; Zaitseva, S. D. Ukr. Khim. Zh. 1960, 26, 351; Chem. Abstr. 1961, 55, 4485i.820 Bertho A. J. Prakt. Chem. 1927, 116, 101.821 Wiberg, N.; Joo, W.-C. J. Organomet. Chem. 1970, 22, 333.822 Acton, E. M.; Silverstein, R. M. J. Org. Chem. 1959, 24, 1487.823 Nesmeyanov, A. N.; Perevalova, E. G.; Golovaya, R. V.; Shilovtseva, L. S. Dokl. Akad. Nauk
SSSR 1955, 102, 535.824 Makosza, M.; Podraza, R. Eur. J. Org. Chem. 2000, 193.825 Canonica, L.; Tedeschi, C. Gazz. Chim. Ital. 1951, 84, 175.826 Brandes, S.; Bella, M.; Kjoersgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 1147.827 Priego, J.; Mancheno, O. G.; Cabrera, S.; Carretero, J. C. J. Org. Chem. 2002, 67, 1346.828 Willis, H. B. Iowa State Coll. J. Sci. 1943, 18, 98; Chem. Abstr. 1944, 38, 739.829 Gilman, H.; Ingham, R. K. J. Am. Chem. Soc. 1953, 75, 4843.830 Gilman, H.; Avakian, S. J. Am. Chem. Soc. 1946, 68, 1514.831 Gilman, H.; Avakian, S. J. Am. Chem. Soc. 1946, 68, 580.832 Gilman, H.; Van Ess, M. W.; Willis, H. B.; Stuckwish, C. G. J. Am. Chem. Soc. 1940, 62, 2606.833 Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1957, 79, 208.834 Gilman, H.; Stuckwisch, C. G. J. Am. Chem. Soc. 1943, 65, 1461.835 Sasaki, S.; Hatsushiba, H.; Yoshifuji, M. Chem. Commun. 1998, 2221.836 Hinke, E.; Staude, E. J. Appl. Polym. Sci. 1991, 42, 2951.837 Guiver, M. D.; Robertson, G. P.; Foley, S. Macromolecules 1995, 28, 7612.838 Perchais, J.; Fleury, J.-P. Tetrahedron 1974, 30, 999.839 Woodward. R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan,
S.; Vorbruggen, H. J. Am. Chem. Soc. 1966, 68, 852.840 Lindel, T.; Hochgurtel, M. Tetrahedron Lett. 1998, 39, 2541.841 Tertov, B. A.; Onishchenko, P. P. Zh. Obshch. Khim. 1971, 41, 1594; Engl. Transl. p 1601.842 Seefelder, M.; Eilingsfeld, H. Angew. Chem., Int. Ed. Engl. 1963, 2, 484.843 Firl, J.; Sommer, S. Tetrahedron Lett. 1969, 1133.844 Firl, J.; Sommer, S. Tetrahedron Lett. 1972, 4713.845 Iwamura, H.; Wells, D. H., Jr.; Mathew, S. P.; Klussmann, M.; Armstrong, A.; Blackmond, D.
G. J. Am. Chem. Soc. 2004, 126, 16312.846 Carey, F. A.; Neergaard, J. R. J. Org. Chem. 1971, 36, 2731.847 Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Commun. 2003, 2448.848 Page, P. C. B.; McKenzie, M. J.; Allin, S. M.; Buckle, D. R. Tetrahedron 2000, 56, 9683.848 a. Page, P. C. B.; Allin, S. M,; Collington, E. W.; Carr, R. A. E. Tetrahedron Lett. 1994, 35, 2427.849 Barluenga, J.; Gomez, N.; Palacios, F.; Gotor, V. Synthesis 1981, 563.
364 ORGANIC REACTIONS
850 Magnus, P.; Ros, M. B.; Hulme, C. J. Chem. Soc., Chem. Commun. 1995, 263.851 Benedetti, F.; Forchiassin, M.; Russo, C.; Nitti, P. Gazz. Chim. Ital. 1988, 118, 695.852 Shvedov, V. I.; Altukhova, L. B.; Grinev, A. N. Zh. Org. Khim. 1965, 1, 879; Engl. Transl. p 882.853 Forchiassin, M.; Risaliti, A.; Russo, C. Tetrahedron 1981, 37, 2921.854 Bigotto, A.; Forchiassin, M.; Risaliti, A.; Russo, C. Tetrahedron Lett. 1979, 4761.855 Marchetti, L.; Tosi, G. Tetrahedron Lett. 1971, 3071.856 Benedetti, F.; Forchiassin, M.; Pispisa, G.; Nitti, P.; Pitacco, G.; Russo, C.; Valentin, E. Gazz.
Chim. Ital. 1990, 120, 327.857 Forchiassin, M.; Pitacco, G.; Russo, C.; Valentin, E. Gazz. Chim. Ital. 1982, 112, 335.858 Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103.859 Yao, L.; Smith, B. T.; Aube, J. J. Org. Chem. 2004, 69, 1720.860 Gmeiner, P.; Hummel, E. Synthesis 1994, 1026.861 Yamada, S.; Oguri, T.; Shioiri, T. Japanese Patent 74 00217 (1974); Chem. Abstr. 1974, 80,
121321r.862 Shimizu, M.; Yokota, T.; Fujimori, K.; Fujisawa, T. Tetrahedron: Asymmetry 1993, 4, 835.863 Capone, S.; Guaragna, A.; Pulumbo, G.; Pedarella, S. Tetrahedron 2005, 61, 6575.864 Genet, J.-P.; Juge, S.; Mallart, S. Tetrahedron Lett. 1985, 29, 6765.865 Sting, R. A.; Seebach, D. Tetrahedron 1996, 52, 279.866 Gautschi, M.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1992, 31, 1083.867 Kim, K. H.; Kil, K.-e.; Ko, D. H. Bull. Korean Chem. Soc. 2002, 23, 655.867 a. Quast, H.; Seiferling, B. Tetrahedron Lett. 1982, 23, 4681.868 Chabaud, L.; Landais, Y. Tetrahederon Lett. 2003, 44. 6995.869 Schmidt, U.; Riedl, B. Synthesis 1993, 809.870 Ciufolini, M. A.; Xi, N. J. Org. Chem. 1997, 62, 2320.871 Chung, K.-H.; An, S.-O. J. Korean Chem. Soc. 1995, 39, 431.872 Chung, H.-K.; Kim, H.-W.; Chung, K.-H. Bull. Korean Chem. Soc. 1999, 20, 325.873 Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenlander, F. Tetrahedron 1996, 52, 6409.874 Oguri. T.; Shioiri, T.; Yamada, S.-i. Chem. Pharm. Bull. 1975, 23, 173.875 Poupardin, O.; Ferreira, F.; Genet, J.-P.; Greck, C. Tetrahedron Lett. 2001, 42, 1523.876 Ferreira, F.; Greck, C.; Genet, J. P. Bull. Soc. Chim. Fr. 1997, 134, 615.877 Sheradsky, T.; Nir, Z. Tetrahedron Lett. 1969, 77.878 Lebeeuw, O.; Phansavath, P.; Genet, J.-P. Tetrahedron Lett. 2003, 44, 6383.879 Nitta, H.; Hatanaka, M.; Ishimaru, T. J. Chem. Soc., Chem. Commun. 1987, 51.880 Hanessian, S.; Vanasse, B.; Yang, H.; Alpegiani, M. Can. J. Chem. 1993, 71, 1407.881 Dupradeau, F.-Y.; Hakomori, S.-I.; Toyokuni, T. J. Chem. Soc., Chem. Commun. 1995, 221.882 Lee, C.-S.; Lee, K.-I; Hamilton, A. D. Tetrahedron Lett. 2001, 42, 211.883 Tarver, J. E., Jr.; Joullie, M. J. Org. Chem. 2004, 69, 815.884 Hanessian, S.; Moitessier, N.; Wilmouth, S. Tetrahedron 2000, 56, 7643.885 Eipert, M.; Maichle-Mossmer, C.; Maier, M. E. Tetrahedron 2003, 59, 7949.886 Brown, R. C. D.; Hinks, J. D. Chem. Commun. 1998, 1895.887 Hanessian, S.; Therrien, E.; Granberg, K.; Nilsson, I. Bioorg. Med. Chem. Lett. 2002, 12, 2907.888 Clark, C. Ph. D. Dissertation, Louisiana State University, 2005.889 Zheng, N.; Armstrong, J. D., III; McWilliams, J. C.; Volante, R. P. Tetrahedron Lett. 1997,
38, 2817.890 Sato, M.; Gunji, Y.; Ikeno, T.; Yamada, T. Chem. Lett. 2005, 34, 316.891 Ahn, K. H.; Kim, S.-K.; Ham, C. Tetrahedron Lett. 1998, 39, 6321.892 Vergne, C.; Bouillon, J.-P.; Chastanet, J.; Bois-Choussy, M.; Zhu, J. Tetrahedron: Asymmetry
1998, 9, 3095893 Ku, H.-Y.; Jung, J.; Kim, S.-H.; Kim, H. Y; Ahn, K. H.; Kim, S.-G. Tetrahedron: Asymmetry
2006, 17.1111.894 Reyes-Rangel, G.; Maranon, V.; Avila-Ortiz, G.; Anaya de Parrodi, C.; Quintero, L.; Juaristi,
E. Tetrahedron 2006, 62, 8404.895 Zhang, P. J. Ph. D. Dissertation, Universite Catholique de Louvain, Belgium, 2003.
ELECTROPHILIC AMINATION OF CARBANIONS 365
896 Clariana, J.; Galvez, N.; Marchi, C.; Moreno-Manas, M.; Vallribera, A.; Molins, E. Tetrahedron1999, 55, 7331.
897 Nakamura, Y.; Shin, C.-g. Chem. Lett. 1991, 1953.898 Schmidt, U.; Riedl, B. J. Chem. Soc., Chem. Commun. 1992, 1186.899 Parry, R. J.; Ju. S.; Baker, B. J. J. Labeled Compd. Radiopharm. 1991, 29, 633.900 The configuration of the oxazolidinones is R as shown in Table 1 of ref. 890 and not S as
specified in the text. Tohru Yamada, Department of Chemistry, Keio University, Yokohama,Japan. Personal communication, 2007.
901 Sugiyama, H.; Shioiri, T.; Yokokawa, F. Tetrahedron Lett. 2002, 43, 3489.902 Arda, A.; Jimenez, C.; Rodrıguez, J. Eur. J. Org. Chem. 2006, 3645.903 Wen, S.-J.; Yao, Z.-J. Org. Lett. 2004, 6, 2721.904 Sabol, J. S.; Flynn, G. A.; Friedrich, D.; Huber, E. W. Tetrahedron Lett. 1997, 38, 3687.905 Thompson, W. J.; Ghosh, A. K.; Holloway, M. K.; Lee, H. Y.; Munson, P. M.; Schwering, J. E.;
Wai, J.; Darke, P. L.; Zugay, J.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. J. Am.Chem. Soc. 1993, 115, 801.
906 Ogilvie, W.; Bailey, M.; Poupart, M.-A.; Abraham, A.; Bhavsar, A.; Bonneau, P.; Bordeleau,J.; Bousquet, Y.; Chabot, C.; Duceppe, J.-S.; Fazal, G.; Goulet, S.; Grand Maitre, C.; Guse, I.;Halmos, T.; Lavallee, P.; Leach, M.; Malenfant, E.; O’Meara, J.; Plante, R.; Plouffe, C.; Poirier,M.; Soucy, F.; Yoakim, C.; Deziel, R. J. Med. Chem. 1997, 40, 4113.
907 Ripka, A. S.; Bohacek, R. S.; Rich, D. H. Bioorg. Med. Chem. Lett. 1998, 8, 357.908 Belshaw, P. J.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 1805.909 Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134.910 Neset, S.; Hope, H.; Undheim, K. Tetrahedron 1997, 53, 10459.911 Stone, M. J.; Maplestone, R. A.; Rahman, S. K.; Williams, D. H. Tetrahedron Lett. 1991, 32, 2663.912 Beugelmans, R.; Bois-Choussy, M.; Vergne, C.; Bouillon, J.-P.; Zhu, J. J. Chem. Soc., Chem.
Commun. 1996, 1029.913 Pearson, A. J.; Chelliah, M. V.; Bignan, G. C. Synthesis 1997, 536.914 Pearson, A. J.; Park, J. G. J. Org. Chem. 1992, 57, 1744.915 Pearson, A. J.; Shin, H. Tetrahedron 1992, 48, 7527.916 Ami, E.; Rajesh, S.; Wang, J.; Kimura, T.; Hayashi, Y.; Kiso, Y.; Ishida, T. Tetrahedron Lett.
2002, 43, 2931.917 Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.;
Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak,N. M. J.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J. Med. Chem. 1998,41, 4607.
918 Pearson, A. J.; Zhang, P.; Lee, K. J. Org. Chem. 1996, 61, 6581.919 Freund, E.; Vitali, F.; Linden, A.; Robinson, J. A. Helv. Chim. Acta 2000, 83, 2572.920 Evans, M. C.; Johnson, R. L. Tetrahedron 2000, 56, 9801.921 Lee, H. T.; Hicks, J. L.; Johnson, D. R. J. Labeled Compd. Radiopharm. 1991, 29, 1065.922 Lee, H.-Y.; Sohn, J.-H.; Kwon, B.-M. Bioorg. Med. Chem. Lett. 2002, 12, 1599.923 Bigot, A.; Dau, M. E. T. H.; Zhu, J. J. Org. Chem. 1999, 64, 6283.924 Alexander, K.; Cook, S.; Gibson, C. L.; Kennedy, A. R. J. Chem. Soc., Perkin Trans. 1 2001,
1538.925 Falck-Pedersen, M. L.; Undheim, K. Tetrahedron 1996, 52, 7761.926 Han, Y.; Liao, S.; Qiu, W.; Cai, C.; Hruby, V. J. Tetrahedron Lett. 1997, 38, 5135.927 Yuan, W.; Hruby, V. J. Tetrahedron Lett. 1997, 38, 3853.928 Moore, S. B.; Grant, M.; Rew, Y.; Bosa, E.; Fabbri, M.; Kumar, U.; Goodman, M. J. Peptide
Res. 2005, 66, 404.929 Boteju, L. W.; Wegner, K.; Qian, X.; Hruby, V. J. Tetrahedron 1994, 50, 2391.930 Boteju, L. W.; Wegner, K.; Hruby, V. J. Tetrahedron Lett. 1992, 33, 7494.931 Liu, D.-G.; Gao, Y.; Wang, X.; Kelly, J. A.; Burke, T. R., Jr J. Org. Chem. 2002, 67, 1448.932 Andersen, R. J.; Coleman, J. E.; Piers, E.; Wallace, D. J. Tetrahedron Lett. 1997, 38, 317.933 Chen, H. G.; Beylin, V. G.; Marlatt, M.; Leja, B.; Goel, O. P. Tetrahedron Lett. 1992, 33, 3293.
366 ORGANIC REACTIONS
934 McNamara, L. M. A.; Andrews, M. J. I.; Mitzel, F.; Siligardi, G.; Tabor, A. B. J. Org. Chem.2001, 66, 4585.
935 Beylin, V. G.; Chen, H. G.; Dunbar, J.; Goel, O. P.; Harter, W.; Marlatt, M.; Topliss, J. G.Tetrahedron Lett. 1993, 34, 953.
936 Lin, J.; Liao, S.; Hruby, V. J. Tetrahedron Lett. 1998, 39, 3117.937 Kaczmarek, K.; Zabrocki, J.; Lachwa, M.; Lipkowski, A. W. In Peptides 1998 ; Bajusz, S.,
Hudecz, F., Eds.; Akademiai Kiado: Budapest, 1999; p 668.938 Nadin, A.; Sanchez Lopez, J. M.; Owens, A. P.; Howells, D. M.; Talbot, A. C.; Harrison, T. J.
Org. Chem. 2003, 68, 2844.939 Prasad, C. V. C.; Vig, S.; Smith, D. W.; Gao, Q.; Polson, C. T.; Corsa, J. A.; Guss, V. L.; Loo,
A.; Barten, D. M.; Zheng, M.; Felsenstein, K. M.; Roberts, S. B. Bioorg. Med. Chem. Lett. 2004,14, 3535.
940 Hanessian, S.; Papeo, G.; Fettis, K.; Therrien, E.; Viet, M. P. T. J. Org. Chem. 2004, 69, 4891.941 Poullenec, K. G.; Kelly, A. T.; Romo, D. Org. Lett. 2002, 4, 2645.942 Butcher, J. W.; Liverton, N. J.; Selnick, H. G.; Elliot, J. M.; Smith, G. R.; Tebben, A. J.; Pribush,
D. A.; Wai, J. S.; Claremon, D. A. Tetrahedron Lett. 1996, 37, 6685.943 Chan, P. W. H.; Cottrell, I. F.; Moloney, M. G. J. Chem. Soc., Perkin Trans. 1 2001, 3007.944 Chan, P. W. H.; Cottrell, I. F.; Moloney, M. F. Tetrahedron: Asymmetry 1999, 10, 3887.945 Devillers, I.; Pevet, I.; Jacobelli, H.; Durand, C.; Fasquelle, V.; Puaud, J.; Gaudilliere, B.; Idrissi,
M.; Moreu, F.; Wigglesworth, R. Bioorg. Med. Chem. Lett. 2004, 14, 3303.946 Maeng, J.-H.; Funk, R. L. Org. Lett. 2001, 3, 1125.947 Boche, G.; Bosold, F.; Niessner, M. Tetrahedron Lett. 1982, 23, 3255.948 Pagliarin, R.; Papeo, G.; Sello, G.; Sisti, M.; Paleari, L. Tetrahedron 1996, 52, 13783.949 Jommi, G.; Miglierini, G.; Pagliarin, R.; Sello, G.; Sisti, M. Tetrahedron 1992, 48, 7275.950 Yamamoto, Y.; Hatsuya, S.; Yamada, J.-i. Tetrahedron Lett. 1989, 30, 3445.951 Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044.952 Bumbek, S.; Lenarsic, R.; Kocevar, M.; Polanc, S. Synlett 2001, 1237.953 Comelles, J.; Moreno-Manas, M.; Perez, E.; Roglans, A.; Sebastian, R. M.; Vallribera, A. J. Org.
Chem. 2004, 69, 6834.954 Comelles, J.; Pericas, A.; Moreno-Manas, M.; Vallribera, A.; Drudis-Sole, G.; Lledos, A.; Parella,
T.; Roglans, A.; Garcıa-Granda, S.; Roces-Fernandez, L. J. Org. Chem. 2007, 72, 2077.955 Colonna, F. P.; Pitacco, G.; Valentin, E. J. Chem. Soc., Chem. Commun. 1975, 71.956 Marigo, M.; Kumuragurubaran, N.; Jørgensen, K. A. Synthesis 2005, 957.957 Winkler, F. J.; Stahl, D. J. Am. Chem. Soc. 1978, 100, 6780.958 Kozikowski, A. P.; Greco, M. N. J. Org. Chem. 1984, 49, 2310.959 Fioravanti, S.; Pellacani, L.; Stabile, S.; Tardella, P. A.; Ballini, R. Tetrahedron 1998, 54, 6169.960 Zeifman, Yu. V.; Koshtoyan, S. O.; Knunyants, I. L. Dokl. Akad. Nauk SSSR 1970, 195, 93; Engl.
Transl. p 783.961 Zeifman, Yu. V.; Rokhlin, E. M.; Utebaev, U.; Knunyants, I. L. Dokl. Akad. Nauk SSSR 1976,
226, 1337; Engl. Transl. p 149.962 Parcell, R. F. Chem. Ind. (London) 1963, 1396.963 de Santis, M.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Eur. J. Org. Chem. 1999, 2709.964 Tanaka, K.; Mori, Y.; Narasaka, K. Chem. Lett. 2004, 26.965 Drefahl, G.; Ponsold, K.; Schonecker, B. Chem. Ber. 1964, 97, 2014.