ALDRICH CONGRATULATES THE 2007 ACS AWARD WINNERS

VOL. 40 , NO. 2 • 2007

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Recent Advances in Intermolecular Direct Arylation Reactions

Evolution and Applications of Second-GenerationRuthenium Olefin Metathesis Catalysts

L E A D E R S H I P I N L I F E S C I E N C E , H I G H T E C H N O L O G Y A N D S E R V I C EALDRICH • BOX 355 • MILWAUKEE • WISCONSIN • USA

New Products from Aldrich R&DAldrich Is Pleased to Offer Cutting-Edge Tools for Organic Synthesis

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Lipshutz DCAD Coupling ReagentThe Mitsunobu reaction is one of the most extensively used coupling reactions in organic synthesis and typically employs azodicarboxylate reagents such as DEAD or DIAD. However, these reagents have drawbacks such as low room-temperature stability and difficulty in removing the hydrazine byproducts. Professor Bruce Lipshutz and co-workers have developed an attractive alternative to the existing reagents: di(4-chlorobenzyl) azodicarboxylate (DCAD). DCAD is a stable solid that has an activity comparable to those of DEAD and DIAD in typical Mitsunobu reactions such as substitutions, esterifications, and etherifications. However, unlike the standard reagents, the hydrazine byproduct can be removed by simple precipitation directly from the reaction mixture, and is easily recycled in high yield to regenerate DCAD.Lipshutz, B. H. et al. Org. Lett. 2006, 8, 5069.

Di(4-chlorobenzyl) azodicarboxylate DCAD680850

N NOO

O O

Cl Cl

1 gC16H12Cl2N2O4 10 gFW: 367.18

Hoveyda–Snapper Silylation CatalystBecause of the ease of preparation of meso-diols, synthetic methods that can desymmetrize these substrates are critically important. Professors Marc Snapper and Amir Hoveyda at Boston College have reported the first practical enantioselective silylation of meso-1,2- and 1,3-diols relying on an amino acid derived organocatalyst. The reactions do not require the rigorous exclusion of air or moisture, and the catalyst can be nearly quantitatively recovered by an aqueous wash. This catalyst greatly increases the efficiency with which optically enriched molecules can be prepared.

Zhao, Y. et al. Nature 2006, 443, 67.

(S)-N-((R)-3,3-Dimethylbutan-2-yl)-3,3-dimethyl-2-((1-methyl-1H-imidazol-2-yl)methylamino)butanamide, 97%680826

NH

HN

O

CH3N

N

H3C1 g

C17H32N4O

FW: 308.46

Trichloroacetimidate ReagentsTrichloroacetimidates are useful reagents for protection of alcohols as their allyl and benzyl ethers. We are delighted to offer two new reagents, allyl 2,2,2-trichloroacetimidate and 4-methoxybenzyl 2,2,2-trichloroacetimidate, that have been extensively employed in organic synthesis. These reagents are particularly attractive in applications where base-sensitive functional groups are present that would not tolerate the standard alkoxide alkylation method of alcohol protection.

Clark, J. S. et al. Tetrahedron 2006, 62, 73.

O-Allyl 2,2,2-trichloroacetimidate, 96%678414

O

NHCl

ClCl

5 gC5H6Cl3NOFW: 202.47

4-Methoxybenzyl 2,2,2-trichloroacetimidate679585

O

NHCl

ClCl

H3CO

5 gC10H10Cl3NO2 25 gFW: 282.55

Potassium CyclopropyltrifluoroborateCyclopropyl groups are found in a variety of natural products and are increasingly incorporated into pharmaceuticals such as the broad-spectrum antibiotic ciprofloxacin. Both the Charette1 and Deng2 groups have reported success in the cross-coupling of potassium cyclopropyltrifluoroborates with aryl bromides in the presence of common palladium catalysts. The trifluoroborate salts exhibit enhanced stability and more certain stoichiometry relative to their boronic acid counterparts. However, like boronic acids, post-reaction byproducts are easily removed. We are pleased to add this useful reagent to our ever-growing arsenal of organoboron compounds.

(1) Charette, A. B. et al. Synlett 2005, 11, 1779. (2) Fang, G.-H. et al. Org. Lett. 2004, 6, 357.

Potassium cyclopropyltrifluoroborate662984

BF3K

1 gC3H5BF3K 5 gFW: 147.98

OCH3

CO2H

OCH3

+BnOH

azodicarboxylate reagent

hydrazine byproduct

PPh3 O=PPh3

CH2Cl2, rt

OCH3

CO2Bn

OCH3

92%

+ +

DEAD:DIAD:

94%89%

DCAD:

HO OH

OHHO

TBSO OH

OHTBSO

NH

HN

O

CH3N

N

H3C

20−30 mol %

TBSCl, DIPEAup to 96% yield, up to 96% ee BF3K

R1

R2

Ar Br

[Pd], baseAr

R1

R2

H3C OEt

OOH

H3C OEt

OO

O

NHCl

ClCl

CH2Cl2−hexane, TfOH

82%

33

VO

L. 4

0, N

O. 2

• 2

007

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VOL. 40, NO. 2 • 2007

“PLEASE BOTHER US.”

Professor Gregory B. Dudley of Florida State University kindly suggested that we make 2-benzyloxy-1-methylpyridinium triflate. This crystalline, neutral, and stable organic salt is an excellent reagent for the protection of an alcohol as a benzyl ether under mild conditions. Reaction with this reagent can be performed under near-neutral pH, unlike other benzylation protocols, which require strongly acidic or basic reaction media (e.g., the use of benzyl trichloroacetimidate or benzyl halides).1,2

(1) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923. (2) Poon, K. W. C.; House, S. E.; Dudley, G. B. Synlett 2005, 3142.

NCH3

O CF3SO3–

679674 2-Benzyloxy-1-methylpyridinium triflate 1 g 5 g

Naturally, we made this useful reagent. It was no bother at all, just a pleasure to be able to help.

Do you have a compound that you wish Aldrich could list, and that would help you in your research by saving you time and money? If so, please send us your suggestion; we will be delighted to give it careful consideration. You can contact us in any one of the ways shown on this page and on the inside back cover.

TABLE OF CONTENTSRecent Advances in Intermolecular Direct Arylation Reactions .....................................................................35Louis-Charles Campeau, David R. Stuart, and Keith Fagnou,* University of Ottawa

Evolution and Applications of Second-Generation Ruthenium Olefin Metathesis Catalysts ..........................................................................................................................................................................................................................................45Yann Schrodi* and Richard L. Pederson, Materia, Inc.

ABOUT OUR COVERPanoramic Landscape with Hunters (oil on canvas, 105 × 135 cm) was painted in the mid-1660s by Philips Koninck (1619–1688), one of the great Baroque landscape artists of the Golden Age of Dutch Art (ca. 1600–1680). Although a contemporary of Rembrandt, Koninck is not believed to have studied with him. However, Koninck knew the master and some of his pupils and was certainly familiar with Rembrandt’s paintings, which had some influence on him.

This painting illustrates Koninck’s method of bringing together details of real-life scenes to create fictional but convincing sweeping landscapes featuring streams, fields, abundant flora, and rural dwellings. The translucent colors of the sky, the receding diagonal lines, and the horizontal striations denoting successive planes that recede into the distance add to the great allure of this landscape.

This painting is in the private collection of Isabel and Alfred Bader. Dr. Bader is a perennial ”chemist collector” and a former Aldrich and Sigma-Aldrich president.

Joe Porwoll, President Aldrich Chemical Co., Inc.

Photograph © Alfred Bader.

Reagents for Direct Arylation

BA

N

C

O

[Pd] cat.

XH

X = Cl, Br, I

BA

N

C

ORR

A, B, C = CH or N

NO

80%

OCH3

NO

CO2CH3

74%

NO

88%

N

N

OOCH3

82%

N

N

O

72%

CH3

N

N

ON

80%

NNO

92%

N

NO

OCH3

62%

L E A D E R S H I P I N L I F E S C I E N C E , H I G H T E C H N O L O G Y A N D S E R V I C EALDRICH • BOX 355 • MILWAUKEE • WISCONSIN • USA

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For more information on these and other new products from Sigma-Aldrich, visit sigma-aldrich.com/gochem.

N

N

O

8681350

N

N

O

8678260

NO

NO

Ph

NO

131652

NO

CH3

P42401

NO

CN

142352 183490

NO

CH3

P42606

NO

192694122327

NO

Cl

232408

NO

OBn

410608

NO

NO2

346659

NO

OCH3

349461

• H2O

Pd-catalyzed cross-coupling of organometallic nucleophiles with aryl halides has become the most commonly used method for biaryl synthesis. However, the range of biaryls that can be prepared is limited to those organometallic reagents that are commercially available or easily made. Nitrogen-containing heterocyclic organometallic reagents are often difficult to prepare and success of their coupling reactions can be sporadic. Professor Keith Fagnou and co-workers at the University of Ottawa have developed a novel method for biaryl synthesis by the direct arylation of heterocyclic N-oxides.1–3 Yields are typically very good, and the oxide residue is easily reduced to give the free azine or diazine.

References

(1) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781. (2) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,127, 18020. (3) Campeau, L.-C.; Stuart, D.R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35.

35

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O. 2

• 2

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Outline1. Introduction2. ArylationsofHeterocycles3. ArylationsofSimpleArenes 3.1.DirectedReactions 3.2.NondirectedReactions4. Conclusions5. Acknowledgements6. References

1. IntroductionBiarylmoleculesareimportantbuildingblocksinbothmaterialsandmedicinalchemistry,andhaveattractedtheattentionofthesyntheticorganicchemistrycommunityforover100years.1Thepastquartercenturyhaswitnessedthedevelopmentoftransition-metal-catalyzed biaryl cross-coupling reactions that can beperformedwithanumberoforganometallics(boron,tin,silicon,magnesium)andawiderangeofarylhalides.2Whilehighyieldsandselectivitiescanbeobtained,therequisitearenepreactivationinvolves several manipulations prior to the cross-coupling,generating waste from reagents, solvents, and purifications.Furthermore,astoichiometricamountofmetalwasteisproducedfromthearene-activatinggroupsuponcompletionofthecross-coupling.Insomecases,notallregioisomersoftheorganometallicreagentsarereadilyavailableand,intheworstcases,theymaybeinsufficientlystabletoparticipateinthecouplingreaction.Forthesereasons,thereisacompellingneedtocontinuethesearchformoreefficientmethodsforthepreparationofunsymmetricalbiarylmolecules.

Inrecentyears,directarylationreactionshaveemergedasattractivealternatives to traditionalcross-couplingmethods.3These reactions substitute one of the preactivated couplingpartners with a simple arene. In most cases, the more-difficult-to-prepare organometallic component is replaced,whichalso reduces themetalwastegenerated in theoverallprocess(Scheme 1). In thepast fewyears, thefieldofdirectarylationhasundergonerapidgrowthandcontinuestogarnerworldwideattention.This reviewwilldiscussonly themostrecent advances in the field, with an emphasis on reports

from2005–2006.Furthermore,onlyreactions leading to theformationofbiarylcompoundswillbeaddressed.Forreportsprior to these dates, and for catalytic arylation reactionsleading to theformationofotherproductclasses, thereaderisdirected tootherexcellent reviewsof thefield.3Exampleshavebeenchosenfortheirsyntheticvalueandtheirconceptualadvances. The first section outlines recent advances in thedirectarylationofheterocyclicsubstrates.Subsequentsectionspresent advances in reactionswith simplearenes, includingdirectedandnondirectedreactions.

2. Arylations of HeterocyclesOne of the first examples of heterocycles used in the directarylation was reported by Ohta and co-workers in 1989.4N-Alkylindoleswerearylatedatthe2or3position,dependingon thenatureof theN-substituent (eq 1). Itwassubsequentlydemonstratedthatthesereactionscouldbeextendedtoanumberof π-rich heterocycles using similar reaction conditions.3d,5Itiscommonly accepted that, in direct arylation reactions, π-electron-rich substrates can reactvia an electrophilicpalladation stepandthatthearylationsarefacilitatedbythehighlynucleophilicnatureofthesearenes.6Inrecentyears,researchershavesoughttodevelopnovelstrategiesthatmightallowformilderreactionconditionsaswellasbroadenthesubstratescope.

In2005,Samesandco-workersreported thedevelopmentofC-2selectiveindolearylationreactionswithpalladiumandrhodiumcatalysts.Ofnote, the rhodium-catalyzed reactionsarecompatiblewithunprotectedindolesandaryl iodidesandaffordmoderate-to-goodyieldsof2-arylindoles (eq 2).7TheproposedcatalyticcycleisoutlinedinScheme 2.Therhodiumcatalystfirstinsertsintothearyliodidetoaffordarhodium(III)intermediate. This species was isolated and found to be acompetent catalyst for the reactions, further validating thisas thefirststep in thecatalyticcycle.Thisarylrhodium(III)intermediate can then bind and metallate the indole toafford thediarylrhodium(III)species,whichcanreductivelyeliminate theproductandregenerate therhodium(I)catalyst.Theuseofcesiumpivalateasthebaseiskeytoobtaininghighyields.Whilenoinsightintotheintimatedetailsoftheindole

Recent Advances in Intermolecular Direct Arylation Reactions

Louis-Charles Campeau, David R. Stuart, and Keith Fagnou*Department of ChemistryUniversity of Ottawa10 Marie CurieOttawa, ON K1N 6N5, CanadaEmail: kfagnou@uottawa.ca

Mr.Louis-CharlesCampeau Mr.DavidR.Stuart ProfessorKeithFagnou

36

Rece

nt A

dvan

ces

in In

term

olec

ular

Dire

ct A

ryla

tion

Reac

tions

VO

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O. 2

• 2

007

Scheme 1. Direct Arylation vs Cross-Coupling Reactions.

M

X

M = Sn(R1)3, B(OR2)2, MgX, etc.

X = Cl, Br, I, OSO2R3

R4 R5 R4

R5

M Xcatalyst

Contemporary Cross-Coupling Reactions

H

XR4 R5 R4

R5

H Xcatalyst

Catalytic Direct Arylation

X = Cl, Br, I, OSO2R3

+

+

+

+

metallationstepcouldbeprovided,theauthorspostulatedthatthepivalatemaybeservingasanintramolecularbase.

Samesalsoreportedfurtherstudiesdealingwithpalladium-catalyzedindolearylationreactions thatenableawiderangeofN-substituted indolesubstrates tobeemployed.6,8MostofthesereactionsareselectivetypicallyforC-2oftheindole,butaremarkablebaseeffecthasbeenobservedwithN–HindoleswheretheproperselectionofthebasecounterionallowsfortheselectiveformationofeithertheC-2(eq 3)ortheC-3arylationisomer(eq 4).

Theauthorshavepostulated that theobservedselectivityarises fromamigrationofpalladiumduring themetallationevent(Scheme 3).6KineticdataandisotopeeffectssupportaninitialelectrophilicpalladationatC-3followedbydeprotonationtogivetheC-3isomer.IfmigrationofthearylpalladiummoietytoC-2takesplacepriortodeprotonation,theC-2regioisomerisobtainedinstead.

Sanford and co-workers have established an alternativestrategy to the site-selective arylation of indoles at the C-2position.9 Instead of exploiting the Pd(0)/Pd(II) catalyticmanifold,theydevelopedreactionsfunctioningunderaPd(II)/Pd(IV)redoxcouple.Inthesereactions,aninitialmetallationof indole by a palladium(II) salt is followed by oxidationwithadiaryliodoniumsalt togenerateadiarylpalladium(IV)intermediate, which can reductively eliminate the biarylproductandregenerate thecatalyticallyactivepalladium(II)species(seetherelatedcatalyticcycleinScheme5ofSection3.1).Unlikepriorstudies,whichcommonlyreportedheatingthe reactants to very elevated temperatures, Sanford’sarylationscanbecarriedoutunderremarkablymildconditionsinaceticacidat25ºC(eq 5).9Anumberofsubstitutedindolesparticipate in thereactionand, if theC-2positionisblocked,reaction at the indole C-3 position occurs in lower yields.It is alsopossible toperform the reactionwith anumberoffunctionalizeddiaryliodoniumsalts.

Azoles are another class of heterocycles that have beenstudiedassubstratesforthedirectarylationreaction.Bergman,Ellman,andco-workers found that rhodiumcompoundscanformcarbenecomplexeswithazoles,10whichhasprovidedavaluablemechanisticentrypointfor thefurtherdevelopmentofrhodium-catalyzeddirectarylationreactions.Therhodium–carbeneintermediates,1,havebeenisolatedandarepostulatedto be crucial to the reactivity (Scheme  4).10 Following theformationoftherhodium–carbenecomplex,oxidativeadditionofthearyliodideleadstotheformationofadiarylrhodium(III)species,whichcanundergoreductiveelimination togive thecorrespondingarylazole. In2006,BergmanandEllmanalsodescribedstudiesleadingtothedevelopmentofanewcatalyticsystemforthearylationofazoles.11Thenewreactionconditionsemployarylbromides,whichhadbeenuntilthenrarelyutilizedin thedirectarylationofazoles.Undermicrowaveheatingat250°C,anumberofdifferentazolesubstrateswereusedwithvariousarylbromides togive thearylazoles inmoderate-to-highyields(eq 6).11

Another rhodium-catalyzed transformation of π-rich heterocycles was reported by Itami and co-workers.l2 Thereaction employed an electron-deficient rhodium complexbearing strong π-accepting perf luoroalkylphosphite ligands, which were postulated to favor the electrophilic rhodationof theelectron-richheterocycle.Aryl iodidesparticipated inthe reaction with various heterocycles such as thiophenes,furans,pyrroles,andindoles(eq 7).12Simpleareneswerealsosuccessfullyemployed(seeSection3.2).

eq 1

NMe

N

NCl

Et

Et

+NMe

N

NEt

Et

48%

Pd(PPh3)4

KOAc, DMAreflux, 12 h

Ref. 4

eq 2

NH

+ PhI

[Rh(coe)2Cl]2(4-F3CC6H4)3P

CsOPiv, dioxane120 oC, 18–36 h

RNH

R Ph

R

H4-TsHN

5-BocHN

Yield

82%65%59%

Ref. 7

Scheme 2. C-2 Selective Rhodium-Catalyzed Arylation of Indoles.

RhLn(OPiv)

RhLn

Ar

PivO OPiv

RhLn

Ar

PivO OPiv

NH

RhLn

Ar

OPivNH

PivOHNH

NH

Ar

ArI+

CsOPiv

Ref. 7

eq 3

N+ PhI

Pd(OAc)2PPh3

CsOAc, DMA125 oC, 24 h

NPh

Me Me

88%

eq 4

N

NH

Mg 125 °C, 24 h

PhIPd(OAc)2, PPh3

61%C-3:C-2 (14:1)

Me2N

Me2N

Cl

Ph

NH

dioxane65 °C, 0.5 h

MeMgClTMEDA

Ref. 6,8

Ref. 6

37

Loui

s-C

harle

s C

ampe

au, D

avid

R. S

tuar

t, a

nd K

eith

Fag

nou*

VO

L. 4

0, N

O. 2

• 2

007

In contrast to thenumberof reportsof theutilizationofπ-rich heterocycles in the direct arylation reaction, the use π-deficient heterocycles, such as azines and diazines, is rare. In2005,Campeau,Rousseaux,andFagnoureportedahigh-yieldingandsite-selectivemethodforthearylationofpyridineN-oxides.13 The reaction is broadly applicable to a numberofarylbromidesandpyridinesubstrates,anddeoxygenationof the2-arylpyridineN-oxideproductsgivesrapidaccess to2-arylpyridines.ThemethodologywasalsoextendedtootherazineN-oxidesincludingquinolinesandisoquinolines,aswellas todiazineN-oxides including theN-oxidesofpyrazines,pyridazines,andpyrimidines(eq 8).14CompetitionexperimentsaswellasDFTcalculationswereconsistentwithaconcertedpalladation–deprotonation pathway, which is described indetailinSection3.2.15

Recently,Zhuravlevreportedaverymilddirectarylationreactionbetweenarylhalidesandoxazolo[4,5-b]pyridines.16The arylations were carried out with Pd(OAc)2/PPh3 inacetoneat30 ºC,and led to thecorrespondingC-2productsinmoderate-to-goodyields(eq 9).Thesuperiorreactivityofthesesubstratesisattributedtothehighacidityofthehydrogenthatisreplacedbythearylgroup.

Aclear indicationof thegrowingacceptanceof thedirectarylationmethodologybythesyntheticcommunityisitsuseinindustry.Forexample,researchersatMerck&Co.reportedin2005that thedirectarylationof imidazo[1,2-b][1,2,4]triazinecanbesuccessfullyemployedasanalternative to theSuzukicross-couplingreactioninakeyfragmentcouplingreactionforthepreparationofaselectiveGABAagonist(eq 10).17

3. Arylations of Simple Arenes3.1. Directed ReactionsThecatalyticdirectarylationofsimplearenes ischallengingduetotheattenuatednucleophilicityofthearomaticrings.Topromote thenecessarysubstrate–catalyst interactions,Lewisbasicdirectinggroupshavebeenused;thesegroupsenablethemetallationbybringingthemetal intocloseproximity to thereactivecenter.

Sanfordandco-workershavereported theuseofpyridinemoietiesasefficientdirectinggroupsinthePd-catalyzeddirectarylationof2-arylpyridineswitharyliodoniumsalts(eq 11).18Theyhavealsodemonstratedthatawidevarietyofotherdirectinggroups, includingquinolines,pyrrolidinones,oxazolidinones,andacetanilidesarecompatible.Adiversefunctionalityonthepyridineorthearylmoietyisalsotolerated,andthereactionscanbecarriedoutinambientairandmoistureanddonotrequireexpensiveligandsorstrongbases.Mechanistic investigationssuggest that the arylationproceedsvia a cyclopalladated2-arylpyridinethatisoxidizedbythearyliodoniumsalttogenerateaveryreactivePd(IV)intermediate.ReductiveeliminationofthearylatedproductregeneratesthecatalyticallyactivePd(II)species(Scheme 5).18

Aryl iodides have also been utilized in direct arylationreactionsofsimplearenesbyDaugulisandZaitsev,whoreportedthesuccessfulPd(II)-catalyzeddiarylationofacylanilideswitharyliodides.19StoichiometricamountsofAgOAcwererequiredforeachequivalentofaryl iodideconsumed.Itwasobservedthat the reaction is faster for electron-rich aryl iodides,contrastingthetypicaltrendobservedinPd(0)/Pd(II)catalyticcycles.Acylanilideswithelectron-donatingsubstituentsreactfasterthantheirelectron-neutralorelectron-poorcounterparts,whichisconsistentwithanelectrophilicaromaticmetallationpathway.Amechanisticproposalhasbeenadvancedinvolving

Scheme 3. Mechanistic Rationale for the Observed Regioselec-tivity in the Arylation of Indoles.

PdLn

N NR

HPdLn X

migration

NR

PdLn

NR

Ar

NR

+ PdLn

PdLnNR

H ArPdLn

H

Ar

X– HX

NR

Ar

C-2 arylationproduct

C-3 arylationproduct

+

– HX

+ PdLn

R

X

Ar

Ar Ar–

–

Ref. 6

eq 5

NR'

+

IMesPd(OAc)2(5 mol %)

NR'

RAcOH

25 oC, 15–24 h

RAr2I+ BF4–

1–3 equiv

R

H5-NO2

5-MeO3-Me5-Br2-Me

HHHHHH

R'

HMeH

MeH

MeMeMeMeMeMeMe

Ar

2-Ph2-Pha

2-Ph2-Ph2-Pha

3-Ph2-(3-F3CC6H4)2-(4-MeC6H4)2-(4-FC6H4)2-(4-ClC6H4)

2-(4-MeOC6H4)a

2-(2-MeC6H4)

Yield

81%70%58%89%74%29%64%70%80%90%80%62%

Ar

a The reaction was carried out at 60 oC.

Ref. 9

Scheme 4. Proposed Catalytic Cycle for the Rhodium-Catalyzed Arylation of Azoles.

N

NRhLnCl

NH

NRh

PCy3

PCy3

ClNH

NRhLn

I

Ph

Cl

N

NPh

+ HI

Ph–I

1

MeMe

MeMe

[Rh(coe)2Cl]2PCy3

I

+N

NMe

N

NMe

51%

NEt3, THF105–150 °C

13 h

Ref. 10

eq 6

X

N[Rh(coe)2Cl]2ligand 2, DCBBr

R+X

N R

O

NN

N

HN

PhNH

N Ph

PhPh N

HN

Ph

Ph

MeO

NH

NPh

NH

N

NH

NOMeCN

80% 90% 54%

50% 63% 45% 75%

PCy

2 (i-Pr)2(i-Bu)N (3 equiv)

µw (250 °C), 40 min

Ref. 11

38

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O. 2

• 2

007

acyclopalladatedcomplexthatundergoesoxidativeadditionofthearyliodidetoproduceaPd(IV)intermediate.Pyridines,20

benzamides,21andbenzylamines22haveallbeensuccessfullyusedasdirectinggroups(eq 12).19–22

AckermannhasalsoreportedtheuseofpyridinesandotherLewis basic groups as directing groups in direct arylationreactions. Importantly, these reactions were carried outsuccessfully with aryl chlorides and tosylates by using theappropriate ruthenium catalyst.23 While such reactivity isnowcommonwithother traditionalcross-couplingreactions,achievingdirectarylationwitharylchloridesandtosylates isexceedingly rare. Both electron-rich and electron-poor arylchlorides are compatible and afford diarylated products of2-arylpyridines in good yields (eq  13).23a It is also possibleto achieve monoarylation with the ruthenium catalyst ifiminesderivedfromacetophenonesareutilizedassubstrates.Conveniently, the products are then isolated as the ketonesafterhydrolysisoftheimines(eq 14).23

Imineshavealsobeenutilizedinrhodium-catalyzeddirectarylationreactions.Ina2005reportonthedevelopmentofarhodium-catalyzedSuzuki-typecoupling,Ueuraetal.observedthat, with arenonitriles, benzophenone imines were formedthatweresubsequentlyarylatedorthoto the imine(eq  15).24Whensimilarreactionconditionswereapplieddirectlytotheimine, itwaspossible to isolateamixtureof themono-anddiarylatedproducts(eq 16).24

Çetinkaya and co-workers reported the direct or thoarylationofbenzaldehydederivativeswitharylchloridesandbromides(eq 17).25GoodyieldswereobtainedthroughtheuseofPd(OAc)2,animidazoliumsaltasacarbeneligandprecursor,andCs2CO3indioxaneat80ºC.Theauthorspostulatedthatthealdehydeoxygenwasactingasanortho-directinggroup.Whenarylbromideswereemployed,diarylationtookplaceandledto2,6-diarylbenzaldehydederivatives.

3.2. Nondirected ReactionsIna2006article focusingpredominantlyon thearylationofheterocycles,Itamiandco-workersdescribeddirectarylationreactions with anisole and 1,3-dimethoxybenzene.12 In bothcases, the observed regioselectivity was consistent with anelectrophilicmetallationmechanismoccurringpreferentiallyattheparaandorthopositionsrelativetotheelectron-donatingmethoxy groups (Scheme  6). Given the small number ofnondirectedreactionsofsimplearenesindirectarylation,thisresultshowssignificantpromisefor thedevelopmentofotherrhodium-catalyzeddirectarylationswithsimplearenes.

Thesameyear,Fagnouandco-workersexploredthedirectarylation of perf luorinated arenes. While the π deficiency of these arenes prohibited their use in an electrophilicmetallation process, their direct arylation occurred in highyieldwith1–5mol%palladiumcatalyst in thepresenceofP(t-Bu)2Me•HBF4 (eq  18).26 It was even possible to achievereaction with f luorobenzene, albeit in 8% yield. Based onmechanisticstudiesbyMaseras,Echavarren,andco-workers,whodescribedaconcertedpalladation–deprotonationpathwayin intramolecular direct arylation reactions,27 experimentalandcomputationalmechanisticstudieswereperformed,whichledtotheformulationoftwopossiblepathways(Scheme 7).26PathwayAinvolvesaconcertedpalladationand lossofHBrtoafford thediarylpalladium(II) intermediate.Alternatively,an exchange of the bromide ligand with a carbonate anionallowsforarelatedpalladation–deprotonationprocessthroughtransition state 4  (pathway B). Although pathway B was

eq 7

XR

X = S, O, NR

IR'+

RhCl

CO[(CF3)2CHO]3P P[OHC(CF3)2]3

Ag2CO3, DME, m-xyleneµw, 150–200 oC, 0.5 h

XR

S

OMe

73%

O

Me

Me

Ac

64%

NMe

Ac

80%, C-3/C-2 = 2:1

NPh

Ac

58%

SS

Ac

64%

S

OMe

S

52%

R'

Ref. 12

eq 8

BA

N

C

O

R

Pd(OAc)2 (5 mol %)R3P–HBF4, K2CO3

BA

N

C

O

RAr

NO

p-Tol NO

p-Tol NO

p-Tol

NO2OMe

91% 80% 78%

NO

o-Tol

80%

N

p-Tol

O

94% (14:1)

N

N

p-TolO

N

N

p-TolO

NN PhO

68%75% 76%

PhMe or dioxanereflux, 16 h

+ Ar–Br

Ref. 14

eq 9

Pd(OAc)2 (5 mol %)Ph3P (20 mol %)

N N

O

N N

OAr

O

ONHBoc

NNH2

+ Ar–X

X = Cl, Br, ICs2CO3, acetone

30 °C, 24 h

Ar =

X = Cl33%

X = I74%

X = I48%

Ref. 16

eq 10

NN

N NHO

•HCl•H2O

Pd(OAc)2 (1 mol %)PPh3 (1 mol %)

NN

N NHO

Ar

KOAc, DMAc130 °C, 4 h

86%

Ar =

FF

CN

+ Ar–Br

Ref. 17b

eq 11

N

Ph

88%

N

Ph

O

91%

N

Ph

58%

Pd(OAc)2 (5 mol %)+

(1.1–2.5 equiv)

DGR

DGR

Ph

N

Ph

O

N

Ph

O

Br N

Ph

OO

HN

Ph

O

75% 78% 83% 67%

[Ph2I]BF4 solvent, 100 °C8–24 h

Cl

Ref. 18

39

Loui

s-C

harle

s C

ampe

au, D

avid

R. S

tuar

t, a

nd K

eith

Fag

nou*

VO

L. 4

0, N

O. 2

• 2

007

Scheme 5. Catalytic Cycle of Oxidative Direct Arylation with Diaryliodonium Salts.

Pd(OAc)2

N

N

Pd

AcO

2

N

Ph

N

PdIVLn

Ph

Ph2I+ BF4–Ph–I

eq 12

NHCOt-Bu

73% 68%

62%

Me

R Pd(OAc)2 (cat.)AgOAc (2 equiv)

R

Ar

BB

N

AcBr

NHCOCF3

Ph

Ph

t-Bu

O

NHi-PrMe

Me

79%

solvent, ∆42–165 h

+ ArI(excess)

Ref. 19–22

Ref. 18

eq 13

N

[RuCl2(p-cymene)]2 (2.5 mol %)ligand 3 (10 mol %)

N

Ar

Ar

+ ArCl(2.2 equiv)

POH

3

K2CO3 (3 equiv)NMP (0.5 M)120 °C, 24 h

Ar

Ph4-EtO2CC6H44-MeOC6H4

Yield

95%85%87%

Ref. 23a

eq 14

R

Ar'N 1. [RuCl2(p-cymene)]2 (2.5 mol %) ligand 3 (10 mol %) K2CO3 (3 equiv), NMP (0.5 M) 120 °C, 16–24 h

+

R

O

Ar

2. 1 N HCl(aq), 3 hArCl

(1.2–2.2 equiv)

R

MeHH

Ar

4-AcC6H44-MeOC6H4

4-EtO2CC6H4

Yield

77%74%72%

Ref. 23a

eq 15

CN

NaBPh4 +

[RhCl(cod)]2dppp, NH4Cl

0.5 mmol 2 mmol

PhNH

PhNH

Ph

0.18 mmol71%

0.11 mmol63%

o-xylene, 120 °C44 h

+

dppp = 1,3-bis(diphenylphosphino)propane

Ref. 24

eq 16

Ph Ph

NH

NaBPh4 +

[RhCl(cod)]2NH4Cl

0.5 mmol 2 mmol

PhNH

PhNH

Ph

0.51 mmol25.5%

0.39 mmol19.5%

o-xylene, 120 °C44 h

+

Ref. 24

eq 17

CHO

Cl

Ac

+

Pd(OAc)2 (1 mol %)SIMes•HCl (2 mol %)

CHO

Ac

92%

N N

Cl–

SIMes•HCl

Cs2CO3, dioxane80 oC, 16 h

Ref. 25

Scheme 6. Nondirected Reactions of Simple Arenes in the Direct Arylation Reaction.

OMe

MeO NO2

NO2

OMe

76%

51% (p:o = 2.4:1)[Rh]

Ag2CO3, DMEm-xylene

PhOMe(27 equiv)

1,3-(MeO)2C6H3(27 equiv)

[Rh] = {[OHC(F3C)2]3P}2Rh(CO)Cl

I

NO2

Ref. 12

eq 18

X

FF

RF

F

+ ArBr

Pd(OAc)2 (1–5 mol %)P(t-Bu)2Me•HBF4 (2–10 mol %) X

FF

RF

F

Ar

1.1–1.5 equiv

K2CO3 (1.1 equiv)DMA, 120 °C

4–18 h

H

X

CCCCCN

R

FFF

MeMeO

---

Ar

4-MeC6H44-MeOC6H4

3-Py4-MeC6H44-MeC6H44-MeC6H4

Yield

98%76%78%86%92%86%

Ref. 26

Scheme 7. Proposed Catalytic Cycle for the Direct Arylation of Pentafluorobenzene.

PdLn(Ar)Br

LnPd(0) ArBr

K2CO3

KBr

KHCO3

H

PdLnAr

Ar

PdO

Ar OPR3

O– K+PdR3P

O

–O

O

F

FF

F

FH

F

FF

FF

FF

F

FF

FF

F

FF

PdR3PF

FF

F

F

HBr

HBr

K2CO3

KHCO3 + KBr

4

Pathway B

Pathway A

Ar

Ar

Ref. 26

40

Rece

nt A

dvan

ces

in In

term

olec

ular

Dire

ct A

ryla

tion

Reac

tions

VO

L. 4

0, N

O. 2

• 2

007

deemedlowerinenergybyDFTcalculations(9.9kcal/molvs23.7kcal/mol),thenear-completeinsolubilityofK2CO3underthereactionconditionspreventedpathwayAfrombeingruledoutandprovidedanenticingclueintohowthereactionmightbeimproved.

With thegoalof favoringpathwayBinmorechallengingarylationsofbenzenes,theuseofsolubleacidco-catalystswasinvestigatedinconjunctionwithastoichiometricandinsolublepotassiumcarbonatebase.Theproperchoiceofthecarboxylicacidwascrucial, and theuseof30mol%PivOHproved tobeoptimal.28Using thisprotocol,anumberofarylbromideswere reacted with benzene to afford the biaryl products inhighyields (eq 19).Thecarboxylicacidadditive isbelievedtofacilitate theexchangeof thebromideiononthemetalfora carboxylate ligand that can undergo a similar concertedpalladation–deprotonation(Scheme 8).28

4. ConclusionsDirectarylationreactionsaregaininganincreasinglyconvincingtrack record in the construction of biaryl compounds. Themanyrecentreportshaveallowedfortheuseofmilderreactionconditions and equimolar amounts of coupling partners. Thenumber of diverse catalysts and mechanisms by which directarylationreactionscanbeperformedshowpromiseforamorefrequentuseineverydayorganicsynthesisandshouldstimulate

eq 19

Pd(OAc)2 (2–3 mol %)DavePhos (2–3 mol %)t-BuCO2H (30 mol %)

Ar

PCy2

Me2N

DavePhos

+ ArBrK2CO3

PhH–DMA (1:1.2)120 oC, 10–15 h

Ar

o-Tolm-Tolp-Tol1-Np2-Npm-An

3-ClC6H42-Me-4-NO2C6H3

Yield

85%84%81%80%55%69%63%81%

Ref. 28

Scheme 8. Role of Pivalic Acid Co-Catalyst in the Direct Aryla-tion of Benzene.

PdLn(Ar)Br

ArBr

PdR3P

O

t-Bu

OH

LnPd(0)

t-Bu OH

O

t-Bu O–

O

PdAr(PR3)

Ar

K

K2CO3 KHCO3

KBr

Pd

O

R3P

Ar

t-BuOH

Pd

O

Ar O

PR3

t-Bu

PhH

Ar

+

Ref. 28

thedevelopmentofnovelprocesseswith expanded scope andefficacy.Thisshouldmakethesemethodsincreasinglyattractiveforthepreparationofbiarylmoleculesinanindustrialsetting.

5. AcknowledgementsWethankNSERC, theResearchCorporation(CottrellScholarAward; K. F.), the Ontario government (Premier’s ResearchExcellence Award; K. F.), and the University of Ottawa forfinancialsupportofthiswork.BoehringerIngelheimandMerckFrosst are thanked forunrestricted research support.L.-C.C.andD.R.S.thanktheCanadiangovernmentforNSERC-PGSDscholarships.

6. References(1) Hassan,J.;Sévignon,M.;Gozzi,C.;Schulz,E.;Lemaire,M.Chem.

Rev. 2002,102,1359.(2) For reviews on this topic, see Metal-Catalyzed Cross-Coupling

Reactions, 2nded.;deMeijere,A.,Diederich,F.,Eds.;Wiley-VCH:Weinheim,2004;Vols.1and2.

(3) Forrecentreviews,see:(a)Kakiuchi,F.;Chatani,N.Adv. Synth. Catal.2003, 345,1077.(b)Kakiuchi,F.;Murai,S.Acc. Chem. Res.2002,35,826.(c)Ritleng,V.;SirlinC.;Pfeffer,M.Chem. Rev.2002,102,1731.(d)Miura,M.;Nomura,M.Top. Curr. Chem.2002,219,211.(e)Handbook of C–H Transformations;Dyker,G.,Ed.;Wiley-VCH:Weinheim,2005;Vols.1and2.(f)Daugulis,O.;Zaitsev,V.G.; Shabashov,D.; Pham,Q.-N.; Lazareva,A. Synlett 2006, 20,3382.(g)Campeau,L.-C.;Fagnou,K.Chem. Commun.2006,1253.(h)Duringthepreparationofthismanuscript,ageneralreviewondirectarylationwaspublished:Alberico,D.;Scott,M.E.;Lautens,M.Chem. Rev.2007,107,174.

(4) Akita,Y.;Itagaki,Y.;Takizawa,S.;Ohta,A.Chem. Pharm. Bull.1989,37,1477.

(5) For a recent reportonbenzothiazoles andbenzoxazoles, see (a)Alagille,D.;Baldwin,R.M.;Tamagnan,G.D.Tetrahedron Lett.2005,46,1349.Forrecentreportsonazoles,see:(b)Bellina,F.;Cauteruccio,S.;Mannina,L.;Rossi,R.;Viel,S.Eur. J. Org. Chem.2006,693.(c)Bellina,F.;Cauteruccio,S.;Rossi,R. Eur. J. Org. Chem.2006,1379.Forarecentreportonanoxazole,see(d)Hoarau,C.;DuFoudeKerdaniel,A.;Bracq,N.;Grandclaudon,P.;Couture,A.;Marsais,F.Tetrahedron Lett.2005,46,8573.Forrecentreportsonthiopheneandbenzothiophene,see:(e)Kobayashi,K.;Sugie,A.;Takahashi,M.;Masui,K.;Mori,A.;Org. Lett.2005,7,5083.(f)David,E.;Perrin,J.;Pellet-Rostaing,S.;FournierditChabert,J.;Lemaire,M.J. Org. Chem.2005,70,3569.

(6) Lane,B.S.;Brown,M.A.;Sames,D.J. Am. Chem. Soc.2005,127,8050andreferencestherein.

(7) Wang,X.;Lane,B.S.;Sames,D.J. Am. Chem. Soc.2005,127,4996.

(8) Touré,B.B.;Lane,B.S.;Sames,D.Org. Lett.2006,8,1979.(9) Deprez,N.R.;Kalyani,D.;Krause,A.;Sanford,M.S.J. Am. Chem.

Soc. 2006,128,4972.(10) Lewis,J.C.;Wiedemann,S.H.;Bergman,R.G.;Ellman,J.A.Org.

Lett. 2004,6,35.(11) Lewis,J.C.;Wu,J.Y.;Bergman,R.G.;Ellman,J.A.Angew. Chem.,

Int. Ed. 2006,45,1589.(12) Yanagisawa,S.;Sudo,T.;Noyori,R.;Itami,K.J. Am. Chem. Soc.

2006,128,11748.(13) Campeau,L.-C.;Rousseaux,S.;Fagnou,K.J. Am. Chem. Soc. 2005,

127,18020.(14) (a) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45,

7781. (b) Campeau, L.-C.; Stuart, D. R.; Lecavalier, M.; Sun,H.-Y.;Fagnou,K.UniversityofOttawa,Ottawa,ON,Canada.Unpublishedresults,2006.

41

Loui

s-C

harle

s C

ampe

au, D

avid

R. S

tuar

t, a

nd K

eith

Fag

nou*

VO

L. 4

0, N

O. 2

• 2

007

(15) Campeau,L.-C.;Zahariev,F.;Woo,T.K.;Fagnou,K.UniversityofOttawa,Ottawa,ON,Canada.Unpublishedresults,2006.

(16) Zhuravlev,F.A.Tetrahedron Lett.2006,47,2929.(17) (a)Jensen,M.S.;Hoerrner,R.S.;Li,W.;Nelson,D.P.;Javadi,

G.J.;Dormer,P.G.;Cai,D.;Larsen,R.D.J. Org. Chem.2005,70, 6034. (b) Gauthier, D. R., Jr.; Limanto, J.; Devine, P. N.;Desmond,R.A.;Szumigala,R.H.,Jr.;Foster,B.S.;Volante,R.P.J. Org. Chem.2005,70,5938. (c)Cameron,M.;Foster,B.S.;Lynch,J.E.;Shi,Y.-J.;Dolling,U.-H.Org. Process Res. Dev.2006,10,398.

(18) Kalyani,D.;Deprez,N.R.;Desai,L.V.;Sanford,M.S.J. Am. Chem. Soc.2005,127,7330.

(19) Daugulis,O.;Zaitsev,V.G.Angew. Chem., Int. Ed.2005,44,4046.

(20) Shabashov,D.;Daugulis,O.Org. Lett. 2005,7,3657.(21) Shabashov,D.;Daugulis,O.Org. Lett. 2006,8,4947.(22) Lazareva,A.;Daugulis,O.Org. Lett. 2006,8,5211.(23) (a) Ackermann, L. Org. Lett. 2005, 7, 3123. (b) Ackermann,

L.;Althammer,A.;Born,R.Angew. Chem., Int. Ed.2006,45,2619.

(24) Ueura,K.;Satoh,T.;Miura,M.Org. Lett.2005,7,2229.(25) Gürbüz,N.;Özdemir,I.;Çetinkaya,B.Tetrahedron Lett. 2005,

46,2273.(26) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.

Chem. Soc.2006,128,8754.(27) (a)Garcia-Cuadrado,D.;Braga,A.A.C.;Maseras,F.;Echavarren,

A.M.J. Am. Chem. Soc.2006,128,1066.(b)Campeau,L.-C.;Parisien,M.;Jean,A.;Fagnou,K.J. Am. Chem. Soc.2006,128,581.

(28) Lafrance,M.;Fagnou,K.J. Am. Chem. Soc. 2006,128,16496.

About the AuthorsLouis-Charles Campeauwasbornin1980inCornwall,Ontario,Canada.In2003,hereceivedhisbachelor’sdegreewithdistinctioninbiopharmaceuticalsciences(medicinalchemistryoption)fromtheUniversityofOttawa.He then joined theresearchgroupofProfessorKeithFagnou,whereheiscurrentlyworkingtowardshisPh.D.degreebyconductingstudiesonthedevelopmentofnewtransition-metal-catalyzedprocesses.HehasbeenarecipientofanOntarioGraduateScholarshipinScienceandTechnology(M.Sc.),andiscurrentlyholdinganNSERCPGS-Ddoctoralscholarship.This summer,hewillbe joining theprocess researchgroupatMerckFrosst.

David R. Stuartwasbornin1981inVictoria,BritishColumbia,Canada.In2005,hereceivedhisB.Sc.degreeinchemistry,withdistinction, fromtheUniversityofVictoria.He then joined theresearch group of Professor Keith Fagnou at the University ofOttawa,whereheiscurrentlyconductingPh.D.levelstudiesonthedevelopmentofnewtransition-metal-catalyzedprocesses.HehasbeenarecipientofanNSERCCGS-M(M.Sc.levelscholarship),andiscurrentlyholdinganNSERCPGS-Ddoctoralscholarship.

Keith Fagnouwasbornin1971inSaskatoon,Saskatchewan,Canada.HereceivedaBachelorofEducation(B.Ed.)degreewithdistinction from the University of Saskatchewan in 1995 and,afterteachingatthehighschoollevelforashortperiodoftime,hecontinuedhisstudiesinchemistryattheUniversityofToronto.In2000,hereceivedanM.Sc.degreeand,in2002,completedhisPh.D.requirementsunderthesupervisionofMarkLautens.HehassincebeenonthechemistryfacultyattheUniversityofOttawa,andhasinitiatedresearchprogramsfocusingonthedevelopmentofnewcatalyticreactionsforuseinorganicsynthesis.̂

2007 ACS Award RecipientsAldrich, a proud sponsor of three ACS awards, congratulates the following recipients

for their outstanding contributions to chemistry.

Congratulations to each and all!

ACS Award for Creative Work in

Synthetic Organic Chemistry

Professor Steven V. Ley University of Cambridge

ACS Award in Inorganic Chemistry

Professor Sheldon G. Shore The Ohio State University

Herbert C. Brown Award for Creative

Research in Synthetic Methods

Professor David A. Evans Harvard University

Nobel Prize Winning Metathesis Catalyst TechnologyOlefin metathesis has led scientists to discover new disconnections in organic synthesis, paving the way for new advances in polymer chemistry, drug discovery, and natural product synthesis. Sigma-Aldrich is proud to be the exclusive provider of Materia’s ruthenium-based metathesis catalysts for research scale.

RuCl

Cl

PCy3

PCy3

Ph

Grubbs 1st generation catalyst

579726

Useful in ROMP of strained cyclic olefins, ethenolysis of internal olefins, and in ADMET, CM, and RCM of terminal olefins.

RuCl

Cl

PCy3

PCy3

CH3

CH3

578681

Kinetic and application profile similar to that of Grubbs 1st generation catalyst.

RuCl

Cl

PCy3

NNMes Mes

Ph

Grubbs 2nd generation catalyst

569747

More active than 1st generation catalysts. Increased activity in RCM and has been employed in challenging CM of sterically demanding or deactivated olefins.

RuCl

Cl

PCy3

NNMes Mes

CH3

CH3

682365 8

Slower to initiate than Grubbs 2nd generation catalyst, thus potentially useful in exothermic ROMP applications. Typically, reaction temperatures of 50 to 60 °C are employed.

PhRu

Cl

Cl

PCy3

NNH3C

CH3

682284 8

Highly efficient catalyst for the preparation of tetrasubstituted olefins by RCM or CM of sterically hindered olefins.

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RuCl

O

PCy3Cl

i-Pr

Hoveyda–Grubbs 1st generation catalyst

577944

Similar reactivity as Grubbs 1st generation catalyst. Proved to be particularly useful in the industrial production of macrocycles via RCM.

RuCl

O

NNH3C

CH3 Cl

i-Pr

682373 8

Hoveyda–Grubbs analog of 682284 with similar reactivity profile. Depending on substrate and reaction conditions, may prove more efficient than 682284.

RuCl

O

NNMes Mes

Cl

i-Pr

Hoveyda–Grubbs 2nd generation catalyst

569755

Comparable reactivity to Grubbs 2nd generation catalyst, but initiates more readily at lower temperatures. Efficient for the metathesis of electron-deficient substrates.

RuCl

Cl

N

NNMes Mes

682381 8

Latent initiator that possesses the high activity of 2nd generation catalysts once initiated. Useful in ROMP applications where longer monomer/catalyst resin handling times are desired.

PhRu

Cl

Cl

NNMes Mes

N

N

Br

Br682330 8

Faster initiator than Grubbs 2nd generation catalyst; can be used at low temperatures (~0 °C, depending on reaction conditions). Less soluble than Grubbs 2nd generation catalyst in nonpolar solvents. Has been employed in polymer synthesis.

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VITON is a registered trademark of E. I. du Pont de Nemours and Co., Inc.

45

VO

L. 4

0, N

O. 2

• 2

007

Outline1. Introduction2. Second-Generation Grubbs and Other Early NHC-Based

Catalysts 2.1. DiscoveryofNHC-BasedOlefinMetathesisCatalysts 2.2. MechanisticConsiderationsandDevelopmentofSecond-

GenerationDerivatives 2.3. ApplicationsofSecond-GenerationGrubbsCatalysts3. Phosphine-Free,SIMes-BasedSecond-GenerationCatalysts4. Slow-andFast-InitiatingNHC-BasedCatalysts5. Other Recent Developments in the Design of Second-

GenerationCatalysts 5.1. Second-GenerationCatalystsBasedonUnsymmetrical

Alkyl,Aryl-NHCLigands 5.2. Chiral, Second-Generation Ruthenium Metathesis

Catalysts 5.3. Immobilized,Second-GenerationCatalystsandRelated

Developments 5.4. Second-Generation Catalysts for the Metathesis of

HinderedOlefins6. Practical Considerations for Using Olefin Metathesis

Catalysts7. Conclusions8. ReferencesandNotes

1. IntroductionOlefinmetathesisisafundamentalchemicalreactioninvolvingtherearrangementofcarbon–carbondoublebonds,andcanbeusedtocouple,cleave,ring-close,ring-open,orpolymerizeolefinicmolecules. The widely accepted view that olefin metathesisrevolutionizedthedifferentfieldsofsyntheticchemistryledtotheawardingofthe2005NobelPrizeinChemistrytoYvesChauvin,RobertH.Grubbs,andRichardR.Schrock“forthedevelopmentofthemetathesismethodinorganicsynthesis”.1WhileChauvinhad proposed the “carbene” mechanism to explain how themetathesisprocessfunctions1a,2andSchrockhadprepared thefirstwell-definedhighlyactivemetathesiscatalysts,1b,3Grubbs

providedsyntheticchemistswithactivecatalyststhatcouldbehandledinairandwere tolerantofvariousfunctionalgroups,such as esters, amides, ketones, aldehydes, and even proticfunctionalitieslikealcohols,water,andacids.1c,4

The Grubbs catalysts are based on a ruthenium atomsurroundedbyfiveligands:twoneutralelectron-donatingentities(e.g., trialkylphosphines,N-heterocycliccarbenes), twomono-anionicgroups(e.g.,halides),andonealkylidenemoiety(e.g.,unsubstitutedandsubstitutedmethylidenes).Thesecatalystsaredividedinto twocategoriesbasedonthenatureof theneutralligands:L2X2Ru=CHRcomplexes(whereLisaphosphineligand)werediscoveredfirstandarereferredtoasthefirst-generationGrubbscatalysts,and(L)(L’)X2Ru=CHRcomplexes(whereLisaphosphineligandandL’asaturatedN-heterocycliccarbeneorNHCligand)weresubsequentlydevelopedandarereferredtoasthesecond-generationGrubbscatalysts(Figure 1).

The first-generation Grubbs catalysts have demonstratedattractivefunctional-group toleranceandhandlingproperties,andhavebeenwidelyusedashighlyefficientpromotersforring-openingmetathesispolymerizations,5 ring-closingmetathesisreactionstomakedisubstitutedolefins,6ethenolysis(i.e.,cleavageofthecarbon–carbondoublebond),7cross-metathesisofterminalolefins,8andthepreparationof1,3-dienesviaenynemetathesis.9As such, these catalysts and analogues10 remain very usefuland are still employed in important processes, including theethenolysisoffeedstocksderivedfrombio-renewableseedoils7b,candthemanufactureofmacrocyclichepatitisCtherapeutics.11Nonetheless,theutilityoffirst-generationcatalystsissomewhatlimited,becausetheysufferfromreducedactivityascomparedtothemoresensitivebuthighlyactiveSchrockcatalysts.Examplesoftransformationsthatarepoorlyorsimplynotenabledbyfirst-generationGrubbscatalystsincludethering-closingmetathesisto form tri- and tetrasubstituted cycloalkenes and the cross-metathesisofstericallyhinderedorelectronicallydeactivatedolefins.Manyoftheselimitationshavebeenaddressedthroughthe development of the second-generation Grubbs catalysts,whichpossessexcellentmetathesisactivitywhileretainingthe

Evolution and Applications of Second-Generation Ruthenium Olefin Metathesis Catalysts

Yann Schrodi*,† and Richard L. Pederson‡

Materia, Inc.12 N. Altadena DrivePasadena, CA 91107, USAEmail: yschrodi@materia-inc.com

† Catalyst R&D Department‡ Fine Chemicals R&D Department

Dr.YannSchrodi Dr.RichardL.Pederson

46

VO

L. 4

0, N

O. 2

• 2

007

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utio

n an

d A

pplic

atio

ns o

f Se

cond

-Gen

erat

ion

Ruth

eniu

m O

lefin

Met

athe

sis

Cat

alys

ts handlingcharacteristicsandbroadfunctional-grouptoleranceoftheearlierGrubbscatalysts.

Since their discovery in 1999, second-generation Grubbssystemshave rapidly evolved into a large familyof catalystswith varying properties. These catalysts have been widelyutilizedtofacilitatenewtransformationsandtoallowimportantapplications that extend to a broad range of areas includingfinechemicals,pharmaceuticals,andmaterials.As it isoftenthecaseinhomogeneouscatalysis,theredoesnotexistasinglesecond-generationcatalystthatisbestforalltransformationsandapplications.Infact,manyofthesecond-generationcatalystshavebeendevelopedtoprovidesystemswithoptimalcharacteristicsfor specific purposes. Therefore, the aim of this article is toreview the evolution of this group of catalysts, point out thepropertiesandspecificityofitsmembers,andpresentsomeoftheveryinterestingapplicationsenabledbythem.

2. Second-Generation Grubbs and Other Early NHC-Based Catalysts2.1. Discovery of NHC-Based Olefin Metathesis CatalystsThe first examples of NHC-containing, olefin metathesiscatalystsweredisclosedbyHerrmannandco-workersin1998.12Thesecomplexeswerebis-NHCrutheniumbenzylidenespecies,1, where the NHC ligands were unsaturated and containedidenticalordifferent,chiralorachiralalkylsubstituentsonthe

PhRu

Cl

Cl

PCy3

first-generationGrubbs catalyst

PCy3

PhRu

Cl

Cl

PCy3

NN

second-generationGrubbs catalyst

nitrogenatoms(Figure 2).Thesesystemswereoriginallyaimedattuningthepropertiesofthecatalystsbychangingthenatureofthealkylsubstituentsonthenitrogenatomsandatproducingchiralcomplexes.13Althoughtheywerefirstthoughttobemoreactivethanthefirst-generationcatalysts,12thisnotionturnedoutnottobegenerallytrue.14Ayearlater,mixedNHC–phosphinerutheniummetathesis catalystswere reported:Herrmannandco-workershadfocusedonspeciescontainingalkyl-substitutedunsaturatedNHCs,2,15whiletheGrubbs16andNolan17groupsindependentlydevelopedcatalystsderivedfromaryl-substitutedunsaturated NHCs, in particular 1,3-dimesitylimidazolin-2-ylidene or IMes, 3. The mixed NHC–phosphine complexes2and3werefoundtopossessgreatermetathesisactivityandenhanced thermal stability than the first-generation Grubbscatalysts.15a,c,16,17Inparticular,compound3,developedbyGrubbsandNolan,provedtobeanespeciallyefficientcatalyst.18OtherIMes-basedsystemscontainingmoietiessuchasvinylidene,19allenylidene,20orindenylidene21werepreparedbytheGrubbs,Fürstner,andNolangroups.Theallenylidenesystemsturnedouttobeinactiveinmetathesis,whilethevinylidenecomplexeswereactivebutslowerthantheirrutheniumbenzylideneanalogues,andtheindenylidenecomplexesprovedtobe“equipotent”tothebenzylidenederivatives.SoonafterdevelopingtheIMescatalyst,theGrubbsgroupdiscoveredthatreplacingonephosphineofthefirst-generation systems with a saturated mesityl-substitutedNHC (orSIMes) ligandafforded a catalystwith evengreateractivitythantheIMes-basedcompounds.22TheSIMescatalyst,4,commonlyreferredtoasthesecond-generationGrubbscatalyst,quicklysuperseded the IMesspeciesbecause itdemonstratedsuperiorefficiencyinpracticallyallmetathesisreactions.23,24

2.2. Mechanistic Considerations and Development of Second-Generation Derivatives Mechanisticstudiesof4indicatedthatthecatalyticstepsinvolvean initiation event where a 16-electron species, 5, undergoesreversiblephosphinedissociationtofurnisha14-electron,activecatalyticcomplex,6.Complex6caneitherrebindadissociatedphosphine or proceed to reversibly coordinate an olefinicsubstrate toformaruthenacyclobutane,7.Thebreakingapartof the ruthenacyclobutane follows to expel the new olefinicproducts(Scheme 1).25Inaddition,thesestudiesshowedthatthesecond-generationcatalystsinitiatemuchmoreslowlythanthefirst-generationones,andthattheirenhancedactivityisduetothefactthattheiraffinitytocoordinateanolefinicsubstrateinthepresenceoffreephosphineismuchgreaterthanthatofthefirst-generationsystems.

Thesemechanistic insightsguidedGrubbsandco-workerstoprepareafamilyofsecond-generationcatalystswithdifferentinitiation rates by varying the detachable phosphine ligands.Depending on the application, it is advantageous to employcatalysts that initiatemoreor less rapidly.Forexample,whenperforming ring-opening olefin metathesis polymerizations(ROMP)ofstrainedcyclicolefinicmonomers,slower-initiatingcatalysts are often desirable because they allow for longerhandlingofthemonomer/catalystresinbeforethepolymerizationstarts.26 Conversely, fast-initiating catalysts, able to promotemetathesisat reducedtemperatures,areuseful inapplicationswherelowreactiontemperaturesarerequiredtopreventcatalystdecompositionandformationofundesiredbyproducts.27

Thus,analoguesof4,suchascomplexes8–10containingtri(n-butyl)phosphine,tri(p-tolyl)phosphine,andtriphenylphosphine,havebeen synthesized and their phosphinedissociation ratesfound to vary dramatically with the nature of the phosphine

Figure 1. Most Commonly Used First- and Second-Generation Grubbs Catalysts.

PhRu

Cl

Cl

PCy3

NNMes Mes

PhRu

Cl

Cl

PCy3

NNAr Ar

PhRu

Cl

Cl

PCy3

NNR R'

PhRu

Cl

Cl

NNR R'

NNR R'

1Herrmann

bis-NHC catalyst

2Herrmann NHC-

phosphine catalyst

3Grubbs, Nolan

catalyst

4second-generation

Grubbs catalyst

R and R' are achiral or chiral alkyl groups such as i-Pr, Cy, or CHMePhAr = aryl; Mes = mesityl

increasing metathesis activity

Figure 2. Evolution and Relative Activity of Early NHC-Based Metathesis Catalysts.

RuCl

ClR – PCy3

+ PCy3[Ru]

R

R R

[Ru]

R R

R

5

7

SIMes

PCy3

RuCl

ClR

6

SIMesRR

R

R

R

R

[Ru]

R

Scheme 1. Mechanism of the Metathesis of a Symmetrical Cis Olefin to Its Trans Isomer.

Ref. 25

47

Yann

Sch

rodi

* an

d Ri

char

d L.

Ped

erso

nV

OL.

40,

NO

. 2 •

200

7

ligand(Figure 3).28,29 Indeed, thephosphinedissociationrateof10wasabout60 times greater,andthatof8about170 times smaller,thanthatof4(measuredat80°Cintoluene).29,30

Thenatureofthehalideandalkylideneligandsalsohasanimpacton thecatalyst initiationrate. Inparticular,catalystscontaining largerhalide ligands initiatemore rapidly,whilesystemswithsmalleralkylidenemoieties (e.g.,methylidene)initiate more slowly.25b Similarly, complex 13, containing alargeNHCligand(i.e.,1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylorSIDIPP)andfirstsynthesizedbyFürstnerandco-workers,31hasprovedtobeafastinitiatorandahighlyactivecatalyst(Figure 4).23,25b,32

2.3. Applications of Second-Generation Grubbs Catalysts By virtue of their greatly enhanced activity vis-à-vis theirfirst-generationcounterparts, thesecond-generationcatalystspromotethemetathesisofstericallydemandingordeactivatedolefins. In particular, second-generation Grubbs complexeshave shown increased activity in ring-closing metatheses(eq 1–3),22,33,34andinmacrocyclizations.35Theyalsocatalyzechallenging cross-metatheses1h,36 including the coupling ofolefinswithα,β-unsaturatedcarbonyls,37vinylphosphonates,38and1,1-disubstitutedalkenes(Scheme 2).39

A model for the prediction of the outcome of cross-metathesis reactions has been developed based on thecategorizationofolefinsaccordingtotheirrelativepropensitytohomodimerizeviacross-metathesisandtheabilityof theirhomodimers to undergo secondary metathesis.40 Based onthismodel,olefinicsubstratesaredividedintofourdifferenttypes.Whetheracertainolefinbelongstoonetypeoranotherdependsonthenatureof themetathesiscatalystused(Table 1). Cross-metatheses between two olefins of Type I yieldproductmixtures thatcorrespond tostatisticaldistributions.Additionally,reactionsbetweentwoolefinsof thesametype(butnotofTypeI)givenonselectiveproductmixtures,whilereactionsbetweenolefinsof twodifferent typesareselectiveprocesses.

The ability of the second-generation catalysts to coupleolefins with α,β-unsaturated carbonyls has been utilizedto prepare A,B-alternating copolymers by ring-openinginsertionmetathesispolymerization(ROIMP).41Additionally,these catalysts promote the enyne metathesis of alkynes tomake interesting1,3-dienes (eq 4,5).9,34,42,43Finally, second-generation systems are often the catalysts of choice for thepreparationofnovelROMPpolymers,includingROMP-basedimmobilizedreagentsandscavengers.44

3. Phosphine-Free, SIMes-Based Second-Generation CatalystsA phosphine-free catalyst, 14, containing an SIMes and achelating benzylidene ether ligand has been introduced byHoveydaandco-workers(Figure 5).45,46Thiscomplexshowsefficiencies similar to the Grubbs systems, but has slightlydifferent substrate specificities. It is aparticularlyefficientcatalyst for metatheses involving highly electron-deficientsubstratessuchasacrylonitrileandfluorinatedalkenes.47

Otherphosphine-freecatalystsof theHoveyda typehavebeenpreparedby introducingdifferentsubstitutionpatternsonthechelatingbenzylideneetherligand.Thus,Blechertandco-workershavereportedcomplexesbearingmorestericallyhindered chelating ligands (15 and 16),48 while Grela andco-workers have disclosed benzylidene ether moieties with

Figure 3. Effect of the Nature of the Phosphine Ligand on the Initiation Rate of the Second-Generation Catalyst.

PhRu

Cl

Cl

PPh3

NNMes Mes

PhRu

Cl

Cl

P(p-Tol)3

NNMes Mes

PhRu

Cl

Cl

PCy3

NNMes Mes

4 9 10

PhRu

Cl

Cl

P(n-Bu)3

NNMes Mes

8

increasing catalyst initiation rate

Ref. 28,29

Figure 4. Influence of the Nature of the Alkylidene and NHC Ligands on the Initiation Rate of the Second-Generation Catalyst.

PhRu

Cl

Cl

PCy3

NN

PhRu

Cl

Cl

PCy3

NNMes Mes

RuCl

Cl

PCy3

NNMes Mes

12 4 13

increasing catalyst initiation rate

CH2RuCl

Cl

PCy3

NNMes Mes

11

i-Pr

i-Pri-Pr

i-Pr

Ref. 23,25b,32

eq 1

CO2EtEtO2C CO2EtEtO2C4 (5 mol %)

t-Bu t-Bu

99%

45 °C, 1 h

Ref. 22

eq 2

99%

4 (5 mol %)O OPO

OPhOPh O O

PO

OPhOPh

CH2Cl240 °C

Ref. 34b

eq 3

Cl

RCO2EtEtO2C CO2EtEtO2C

Cl

4 (10 mol %)

n nC6H665 °C, 4–10 h

n

11223

R

HMeH

MeH

Yield

85%96%99%98%92%

Ref. 34c

Scheme 2. Cross-Metatheses Catalyzed by Second-Generation Grubbs Catalysts.

R3

R1

R2

R1R2

R3

CHO

R1

CHO

R1

O

CO2Me

CO2MeR1

CO2Me

R1

CO2Me

BO

OBO

OR1

O

OO

OR1

O

PR1

O

OR4OR4

PO

OR4OR4

Ref. 37–39

48

VO

L. 4

0, N

O. 2

• 2

007

Evol

utio

n an

d A

pplic

atio

ns o

f Se

cond

-Gen

erat

ion

Ruth

eniu

m O

lefin

Met

athe

sis

Cat

alys

ts electron-withdrawingsubstituents in thepositionpara to thealkoxygrouptomakecatalystssuchascompounds17and18.49Bothof thesestericandelectronicalterationsof theoriginalligandhaveresultedinfaster-initiatingcatalyststhantheparentHoveydacomplex14,presumablybecausetheetherligandsinspecies15–18dissociate faster fromthe rutheniumthan theetherligandincatalyst14.

4. Slow- and Fast-Initiating NHC-Based CatalystsAdditionaltuningoftheinitiationratesledtothedevelopmentof exceptionally slow- and exceptionally fast-initiatingmetathesiscatalysts.Thus,complex19 (Figure 6) isa latentphosphine-free initiator, but ahighly active catalystonce ithas initiated.50,51 As such, complex 19 is a useful promoterfor theROMPof strainedcyclicolefinicmonomers suchasdicyclopentadiene.26Ontheotherhand,catalyst20 isaveryfastphosphine-freeinitiator,52whichhasprovedusefulfortheproductionofpolymerswithnarrowpolydispersitiesandforthesynthesisofblockcopolymers.53,54

Catalysts such as compound 21, developed by Piers andco-workers, are extremely fast initiators and are capable ofcatalyzing the ring-closingmetathesisof terminaldienes at0°C.55TheabilityofPiers’ssystemstoturnoveratverylowtemperatureshasproveduseful inveryelegantmechanisticstudiesresultinginthedirectobservationofolefinmetathesismetallacyclobutaneintermediates,56andhasmadethemidealcandidatesforlow-temperatureapplications.

5. Other Recent Developments in the Design of Second-Generation Catalysts5.1. Second-Generation Catalysts Based on Unsymmetrical Alkyl,Aryl-NHC LigandsSecond-Generation-type systems bearing unsymmetricalsaturatedNHCligands,substitutedwithanalkylgroupononenitrogenatomandanarylgroupon theother,were initiallyinvestigatedbyMolandco-workers,whopreparedthemixed1-adamantyl,mesitylcomplex22(Figure 7).57Thiscompoundturned out to be an extremely poor metathesis catalyst,presumably because of the large steric hindrance resultingfromtheadamantylsubstituent.57

More recently, Blechert’s research group reported thepreparationofmixedmethyl,mesitylandethyl,mesitylsystemsoftheGrubbsandHoveyda–Grubbstypes(23and24).58Thesecomplexesdemonstratedactivitiescomparable to theGrubbsandHoveyda–Grubbsanalogues4and14inthemetathesisofseveralcommonsubstrates.However,catalyst24performedmuchmorepoorly than14 inachallengingcross-metathesiswithacrylonitrile.58Additionally,complex23 gavelowerE/Zratios than4and14 invariouscross-metatheses.While thisspecificitymayproveuseful incertainapplications, it isalsoanadditionalhintthatmixedalkyl,arylsystemstendtobelessactivethanbisarylones.59

5.2. Chiral, Second-Generation Ruthenium Metathesis Catalysts60

Although the syntheses of the first ruthenium metathesiscatalystswithchiral,saturatedNHCligands(e.g.,complex25)gobacktothetimeofthediscoveryofthesecond-generationcatalysts,22 asymmetric metatheses affording appreciableenantiomericexcesseswerenotachieveduntilchiralcomplexessuchas26and27weredevelopedbytheGrubbsandHoveydagroups, respectively (Figure  8).61,62 Complex 26 effectivelycatalyzed the desymmetrizing RCM of prochiral trienes to

Olefin TypeFirst-Generation Grubbs Catalysts

Second-Generation Grubbs Catalysts

Type I(facile homodimerization; homo­dimers are readily consumable)

terminal olefins; allyl silanes; 1° allylic alcohols, ethers, and esters; allyl boronate esters; allyl halides

terminal olefins, 1° allylic alcohols and esters; allyl boronate esters; allyl halides; styrenes (without large ortho substituents); allyl phosphonates; allyl silanes; allyl phosphine oxides; allyl sulfides; protected allylic amines

Type II(more difficult homodimeri­zation; homodimers sparingly consumable)

styrenes; 2° allylic alcohols; vinyl dioxolanes; vinyl boronates

styrenes (with large ortho sub­stituents); acrylates; acrylamides; acrylic acid; acrolein; vinyl ketones; unprotected 3° allylic alcohols; vinyl epoxides; 2° allylic alcohols; perfluorinated alkane olefins

Type III(no homodimerization)

vinyl siloxanes

1,1­disubstituted olefins; non­bulky trisubstituted olefins; vinyl phosphonates; phenyl vinyl sulfone; 4° allylic hydrocarbons; protected 3° allylic alcohols

Type IV(spectator substrates: do not undergo cross­metathesis)

1,1­disubstituted olefins; di­substituted α,β­unsaturated carbonyls; 4° allylic carbon­containing olefins; perfluo­rinated alkane olefins; protected 3° allylic amines

olefins with vinylic nitro group; protected trisubstituted allylic alcohols

Table 1. Olefin Categories Based on Their Metathesis Reactivity

eq 4

4 (5 mol %)H2C=CH2 (60 psi)

99%

OH

Ph

OH

PhCH2Cl2rt, 2 h

Ref. 42

eq 5

>99%

4 (10 mol %)

NH

O

O

AcO

Cl–NH

O

OCl–

AcO++

CH2Cl2rt, 18 hh

Ref. 43

Figure 5. Phosphine-Free, SIMes-Based Second-Generation Catalysts.

RuCl

i-PrO

NNMes Mes

Cl

14

RuCl

i-PrO

NNMes Mes

Cl

15

i-PrO

RuCl

i-PrO

NNMes Mes

Cl

16

RuCl

i-PrO

NNMes Mes

Cl

17

NO2

Ru

O

NNMes MesCl

18

NO2

O

MeO

Cl

Ref. 45,48,49

Figure 6. Very Slow and Very Fast Initiating, Second-Generation Catalysts.

PhRu

Cl

Cl

NNMes Mes

20

N

NRuCl

Cl

N

NNMes Mes

19

Br

Br

PCy3

RuCl

Cl

NNMes Mes

BF4–

21

+

Ref. 50,52,55

49

Yann

Sch

rodi

* an

d Ri

char

d L.

Ped

erso

nV

OL.

40,

NO

. 2 •

200

7

afford enantiomeric excesses ranging from 13% to 90%.61Catalyst27ledtohighenantioselectivitiesintheasymmetric,tandem,ring-openingmetatheses–cross-metathesesoftricyclicnorbornenederivatives.62However,complex27 isaltogetheralessactivecatalystandrequireselevatedreactiontemperaturesandprolongedreaction times.Hoveydaandco-workershavesubsequentlyreportedanalogsof27withenhancedcatalyticactivityusinglowercatalystloadings.63Morerecently,Grubbsandcollaboratorsdevelopedhighlyactiveanaloguesofcatalyst25 (e.g.,28) thatcan inducechiralitywithgreaterefficiencythan25.64

5.3. Immobilized, Second-Generation Catalysts and Related DevelopmentsConsiderableresearcheffortshavebeenappliedtoimmobilizingsecond-generation catalysts on various supports.65 Many ofthesystemspreparedinvolvetheattachmentoftherutheniumcomplexvia its alkylidenemoiety.45,66This approach,by itsnature,doesnot leadtoapermanentanchoringof thesystemon the support, but rather to a controlled release of thecatalyticspecies intothereactionsolution.Dependingonthespecific systems employed, the releasedmetal species havebeen observed to partially return and reattach themselvesto the support.45 Other approaches consist of attaching therutheniumcatalystsvia theNHCor theanionic ligands.66c,67The most noteworthy examples of this approach are thecatalysts immobilized on silica, polymers, or monolithicsupports developedbyBuchmeiser and co-workers.68Usingsimilar strategies,Grubbsandco-workershavepreparedanactive,water-solublecatalystbyconnecting theNHCligandtoapoly(ethyleneglycol)chain.69ArelateddevelopmentwasrecentlyreportedbytheGladyszgroup,whopreparedasecond-generationGrubbscatalystbearinga f luorinatedphosphineligandanduseditinbiphasicreactions.70

5.4. Second-Generation Catalysts for the Metathesis of Hindered OlefinsThemost exciting recent additions to the familyof second-generationcatalystsconcernthemetathesisofhinderedolefinsand,inparticular,RCMtoformtetrasubstitutedcycloalkenes.While catalysts 2, 3, 4, and 14 have enabled several suchtransformations,15c,16,23,24RCMtomaketetrasubstituted, five-membered-ringolefins (e.g.,RCMofdimethallylmalonates)had remained especially challenging until very recently.Indeed,catalysts4and14gavea6%anda17%conversion,respectively, in the RCM of diethyl dimethallylmalonateafter 4 days at30°C.23Thebestcatalystsystemsformakingtetrasubstituted,five-memberedcycloalkenes,theunsaturatedNHC-basedcatalysts(e.g.,complexes2and3),gave a modest 31% conversion after 4 days at30°C.23Asaresult,anextensivesearch for improvedcatalysts for themetathesisofhinderedolefinswasundertaken.Complexes29–31,preparedbyGrubbsandco-workers(Figure 9),71–73aremoreefficientcatalystsforsuch transformations than 2–4 and 14. For example, 29–31all afford high conversions (~ 90%) in the RCM of diethyldimethallylmalonate after 24 hours at 60 °C.72,73 However,attempts to optimize and scale up the preparation of thesecatalysts revealed that theywouldberelativelydifficultandexpensivetoproduceatscale.74Mostrecently,catalysts32and33 weredevelopedandthescopeof theirutility investigated.ThesecomplexesprovedtobethemostefficientcatalystsinthebenchmarkRCMofdimethallylmalonates,affordinggreater than 95% conversion in less than 1 hour (eq 6).75

Figure 7. Second-Generation Catalysts Based on Unsymmetrical Alkyl,Aryl-Substituted NHCs.

PhRu

Cl

Cl

PCy3

NNAd Mes

22

PhRu

Cl

Cl

PCy3

NNR Mes

23

RuCl

i-PrO

NNR Mes

Cl

24

Ad = 1-adamantyl; R = Me, Et; and Mes = mesityl

Ref. 57,58

Figure 8. Examples of Chiral Ruthenium Olefin Metathesis Catalysts.

PhRu

Cl

Cl

PCy3

NN

26

RuCl

i-PrO

NN Mes

O

27

PhPhi-Pr

i-Pr

PhRu

Cl

Cl

PCy3

NN

28

PhPhi-Pr

i-Pri-Pr

i-Pr

PhRu

Cl

Cl

PCy3

NNMes Mes

25

PhPh

Ref. 22,61,62,64

Figure 9. Highly Efficient Catalysts for the Metathesis of Hin-dered Olefins.

PhRu

Cl

Cl

PCy3

NN

32

Ru

i-PrO

33

R

R Cl

NNR

R

Cl

Ru

i-PrO

29

Cl

NNF

Cl

F

F

FRu

i-PrO

31

Cl

NN

Cl

t-Bu

t-But-Bu

t-Bu

Ru

i-PrO

30

Cl

NN

Cl

R = Me, Et, i-Pr

Ref. 71,72,73,75

eq 6

CO2EtEtO2C CO2EtEtO2C33 (R = Me)(5 mol %)

>95%conversion

PhMe60 °C, 0.5 h

Ref. 75

6. Practical Considerations for Using Olefin Metathesis CatalystsManyofthefirst-andsecond-generationGrubbsandHoveyda–Grubbscatalystsdiscussedsofararecommerciallyavailable.Olefin metathesis reactions catalyzed by these ruthenium-basedcatalystscanbeconductedinneatolefinicsubstratesorinsolventsofvariedpolarities.Tolueneanddichloromethanearemostcommonlyused,but1,2-dichloroethane,chlorinatedbenzenes,diethylether,tetrahydrofuran,ethylacetate,acetone,and methanol may also be employed. Of further utility,

50

VO

L. 4

0, N

O. 2

• 2

007

Evol

utio

n an

d A

pplic

atio

ns o

f Se

cond

-Gen

erat

ion

Ruth

eniu

m O

lefin

Met

athe

sis

Cat

alys

ts solventsandsubstratesdonotneedtobeanhydrous.Althoughruthenium-based catalysts are relatively robust to oxygen,degassingthereactionsolventsandolefinicsubstratesbeforeaddingthecatalysts isrecommended.Additionally, improvedefficienciesmaybeobtaineduponfurtherpurificationof theolefinicsubstratesbyfiltrationthroughsilicageloractivatedalumina.

Reaction temperaturesof about30 to50°Care typical forsecond-generationGrubbsandHoveyda–Grubbscatalysts (i.e.,complexes4and14, respectively).Catalysts8,12,and 19willusuallyrequirehighertemperatures(e.g.,about50to60°Cfor12,andabout60to80°Cfor8and19)toperformadequately,whilecatalysts10and20maybeusedatlowertemperatures(e.g.,about10°Cfor10,andabout0°Cfor20).Table 2summarizesthespecificitiesofdifferentcatalysts.Optimalcatalystandsubstrateloadings may vary depending on the metathesis reaction, thecatalyst,andthereactionconditions,buttypicalloadingsareintherangeof0.1–5mol%.Finally,uponcompletionofthemetathesisreaction,thecatalystcanberemovedfromtheproductsorfromtheorganicphasebyemployingpublishedmethods.76

7. ConclusionsAlthoughfirst-generationolefinmetathesiscatalystssuchasthefirst-generationGrubbs andHoveyda–Grubbs systems remainextremelyusefultoolsinsyntheticchemistry,theintroductionandevolutionofthesecond-generationcatalystshavegreatlywidenedthe scope of chemical transformations enabled by metathesisreactions. The second-generation Grubbs (e.g., 4  and  12) and

Catalyst Comments

First­generation GrubbsUseful in the ROMP of strained cyclic olefins, in the ethenolysis of internal olefins, as well as in the ADMET, CM, and RCM of terminal olefins.

First­generation Hoveyda–Grubbs

Possesses reactivity similar to that of first­generation Grubbs. Especially useful in the industrial production of macrocycles via RCM.

4

Known as the second­generation Grubbs catalyst and is considerably more active than the first­generation catalysts. Has shown increased activity in RCM and has been employed in challenging CMs of sterically demanding or deactivated olefins, including 1,1­disubstituted olefins and α,β­unsaturated carbonyls. Typically used at 30–50 °C.

8A much slower initiator than 4 and requires higher reaction temperatures (e.g., 60–80 °C).

10A faster initiator than 4 and can therefore be used at lower temperatures than 4 (e.g., 10–30 °C).

12Slower to initiate than 4, but faster than 8. Requires reaction temperatures of typically 50 to 60 °C.

14

Known as the second­generation Hoveyda–Grubbs catalyst and possesses reactivity comparable to that of 4. However, it initiates more readily at lower temperatures (e.g., 5–30 °C), depending on the other reaction conditions such as catalyst loading and substrate concentration. Is also an efficient catalyst for the metathesis of highly electron­deficient substrates such as acrylonitrile.

19

A latent initiator that possesses the high activity of second­generation catalysts once it has initiated. Was developed mainly for industrial ROMP applications, in which longer monomer or catalyst resin handling times are desired. Its latency could also prove useful in other applications.

20

A much faster initiator than 4 and can therefore be used at lower temperatures (e.g., ~0 °C), depending on the other reaction conditions. It tends to be less soluble than 4 in nonpolar solvents, and is generally less stable than 4 in solution. Has been employed in the production of block copolymers and polymers with narrow polydispersities.

32 (R = Me)A highly efficient catalyst for the metathesis of hindered olefins. Is particularly useful in the preparation of tetrasubstituted olefins via RCM and in CM involving sterically highly demanding olefins.

33 (R = Me)

This is the Hoveyda–Grubbs analogue of 32 (R = Me). Is also useful in the synthesis of tetrasubstituted olefins via RCM and in CM involving sterically highly demanding olefins. Depending on the substrate and reaction conditions, it may prove more efficient than 32 (R = Me).

Table 2. Specificities of Olefin Metathesis Catalysts

Hoveyda–Grubbs(e.g.,14)catalystshaveopenedthewaytonewmetathesisapplicationsincludingtheformationoftrisubstitutedcycloalkenesviaRCMandthepolymerizationandcross-metathesisof sterically hindered or electronically deactivated olefins.Moreover,manysecond-generationcatalystshavebeendevelopedtoaddressadditionalneedsofsyntheticchemists.Slow-initiating,phosphine-containing (e.g., 8) and phosphine-free (e.g., 19)catalystsweredesignedforthecontrolledROMPofstrainedcyclicolefins,whilefast-initiatingphosphine-containing(e.g.,10)andextremelyfast-initiatingphosphine-free(e.g.,20)systemsmaybeusedinlow-temperaturemetathesisprocessesorintheproductionofpolymerswithnarrowpolydispersities.Additionally,recentlydevelopedsystemsthatcontainsmall,saturatedNHCligands(e.g.,32and33)areveryefficientatpromotingthemetathesisofhinderedalkenes,evenRCMtoformtetrasubstituted,five-membered-ringcyclicolefins.Byopeningthesenewavenues,catalysts32and33promisetoleadtonewexcitingapplications.

Together,compounds4,8,10,12,14,19,20,32,and33,alongwiththefirst-generationGrubbsandHoveyda–Grubbscomplexes,constituteapowerful toolkit thatallowssyntheticchemists toperformmostmetathesistransformationscurrentlyfacilitatedbytheclassofruthenium-basedolefinmetathesiscatalysts.Thesecatalystshaveenabledandwillcontinuetoenablethepreparationofpreviouslyunattainablemoleculesandmaterialsinallfieldsofchemistryandmaterialsscience.

8. References and Notes(1) (a)Chauvin,Y.Angew. Chem., Int. Ed.2006,45,3740.(b)Schrock,

R. R. Angew. Chem., Int. Ed. 2006, 45, 3748. (c) Grubbs, R. H.Angew. Chem., Int. Ed.2006,45,3760.(d)Despagnet-Ayoub,E.;Ritter,T.Top. Organomet. Chem.2007,21,193.(e)Grubbs,R.H.Tetrahedron2004,60,7117.(f)Handbook of Metathesis;Grubbs,R.H.,Ed.;Wiley-VCH:Weinheim,2003;Vols.1–3.(g)Schrock,R.R.;Hoveyda,A.H.Angew. Chem., Int. Ed.2003,42,4592.(h)Connon,S.J.;Blechert,S.Angew. Chem., Int. Ed.2003,42,1900.(i)Frenzel,U.;Nuyken,O.J. Polym. Sci., Part A: Polym. Chem.2002,40,2895.(j)Trnka,T.M.;Grubbs,R.H.Acc. Chem. Res.2001,34,18.(k)Fürstner,A.Angew. Chem., Int. Ed.2000,39,3012.(l)Buchmeiser,M.R.Chem. Rev.2000,100,1565.(m)Nicolaou,K.C.;Bulger,P.G.;Sarlah,D.Angew. Chem., Int. Ed. 2005,44,4490.

(2) Hérisson,J.-L.;Chauvin,Y.Makromol. Chem.1971,141,161.(3) (a)Schrock,R.R.;DePue,R.T.;Feldman, J.;Schaverien,C. J.;

Dewan, J.C.;Liu,A.H.J. Am. Chem. Soc.1988,110,1423. (b)Schrock,R.R.;Murdzek,J.S.;Bazan,G.C.;Robbins,J.;DiMare,M.;O’Regan,M.J. Am. Chem. Soc.1990,112,3875.

(4) (a)Nguyen,S.T.;Grubbs,R.H.;Ziller,J.W.J. Am. Chem. Soc.1993,115,9858.(b)Schwab,P.;Grubbs,R.H.;Ziller,J.W.J. Am. Chem. Soc.1996,118,100.

(5) Nguyen,S.T.;Johnson,L.K.;Grubbs,R.H.;Ziller,J.W.J. Am. Chem. Soc.1992,114,3974.

(6) (a)Fu,G.C.;Nguyen,S.T.;Grubbs,R.H.J. Am. Chem. Soc.1993,115,9856.(b)Ferguson,M.L.;O’Leary,D.J.;Grubbs,R.H.Org. Synth.2003,80,85.

(7) (a)Andrade,R.B.;Plante,O.J.;Melean,L.G.;Seeberger,P.H.Org. Lett.1999,1,1811.(b)Burdett,K.A.;Harris,L.D.;Margl,P.;Maughon,B.R.;Mokhtar-Zadeh,T.;Saucier,P.C.;Wasserman,E.P.Organometallics2004,23,2027.(c)Schrodi,Y.MetathesisofBio-RenewableSeedOilsCatalyzedbyGrubbsCatalysts.Presentedatthe232ndNationalMeetingoftheAmericanChemicalSociety,SanFrancisco,CA, September10–14,2006;PaperINOR551.

(8) Blackwell,H.E.;O’Leary,D.J.;Chatterjee,A.K.;Washenfelder,R.A.;Bussmann,D.A.;Grubbs,R.H.J. Am. Chem. Soc.2000,122,58.

51

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(9) Diver,S.T.;Giessert,A.J.Chem. Rev.2004,104,1317.(10) Hoveydaandco-workersdiscoveredacatalystbasedonamotif

similartothatofGrubbs,whereoneoftheneutralligandswasatrialkylphosphineandtheotheranethermoietyattachedto thealkylidenefragmentviaaphenylenebridge.Theactivespeciesinvolved incatalyticcyclesusing thiscatalystarepresumablythesameasthosepresentinreactionscatalyzedbyGrubbsfirst-generationcatalyst,i.e.,14-electronbis(trialkylphosphine)dichloro-rutheniumalkylideneandthecorrespondingruthenacyclobutanespecies.For a lead reference, seeKingsbury, J.S.;Harrity, J.P.A.;Bonitatebus,P.J.,Jr.;Hoveyda,A.H.J. Am. Chem. Soc.1999,121,791.

(11) Nicola,T.;Brenner,M.;Donsbach,K.;Kreye,P.Org. Process Res. Dev.2005,9,513.

(12) Weskamp,T.;Schattenmann,W.C.;Spiegler,M.;Herrmann,W.A.Angew. Chem., Int. Ed.1998,37,2490.

(13) Herrmann,W.A.;Schattenmann,W.C.;Weskamp,T.U.S.Patent6,635,768,October10,2003.

(14) Seethecorrectiontoreference12in theCorrigendasectiononpage262ofAngew. Chem., Int. Ed.,Vol.38,No.3(1999).

(15) (a)Weskamp,T.;Kohl,F.J.;Hieringer,W.;Gleich,D.;Herrmann,W.A.Angew. Chem., Int. Ed.1999,38,2416.(b)Weskamp,T.;Kohl,F.J.;Herrmann,W.A.J. Organomet. Chem.1999,582,362.(c)Ackermann,L.;Fürstner,A.;Weskamp,T.;Kohl,F.J.;Herrmann,W.A.Tetrahedron Lett.1999,40,4787.(d)Frenzel,U.;Weskamp,T.;Kohl,F.J.;Schattenmann,W.C.;Nuyken,O.;Herrmann,W.A.J. Organomet. Chem.1999,586,263.

(16) Scholl,M.;Trnka,T.M.;Morgan,J.P.;Grubbs,R.H.Tetrahedron Lett.1999,40,2247.

(17) (a)Huang,J.;Stevens,E.D.;Nolan,S.P.;Petersen,J.L.J. Am. Chem. Soc.1999,121,2674.(b)Huang,J.;Schanz,H.-J.;Stevens,E.D.;Nolan,S.P.Organometallics1999,18,5375.

(18) CompareTable1ofreference16toTable2ofreference15c.(19) Louie,J.;Grubbs,R.H.Angew. Chem., Int. Ed.2001,40,247.(20) Schanz, H.-J.; Jafarpour, L.; Stevens, E. D.; Nolan, S. P.

Organometallics1999,18,5187.(21) (a) Jafarpour, L.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P.

Organometallics1999,18,5416. (b)Fürstner,A.;Thiel,O.R.;Ackermann,L.;Schanz,H.-J.;Nolan,S.P.J. Org. Chem.2000,65,2204.(c)Fürstner,A.;Guth,O.;Düffels,A.;Seidel,G.;Liebl,M.;Gabor,B.;Mynott,R. Chem.—Eur. J.2001,7,4811.

(22) Scholl,M.;Ding,S.;Lee,C.W.;Grubbs,R.H.Org. Lett.1999,1,953.

(23) For a systematic comparison of catalyst activity in variousmetathesis reactions, see Ritter, T.; Hejl, A.; Wenzel, A. G.;Funk,T.W.;Grubbs,R.H.Organometallics2006,25,5740.

(24) The only transformations where IMes catalysts outperformSIMescatalystsseemtobering-closingmetathesestoformfive-membered–ring,tetrasubstitutedolefins.Seereferences16, 17b, 21a, 21b, 23, and 31.SeealsoSection5.4.

(25) (a)Sanford,M.S.;Ulman,M.;Grubbs,R.H.J. Am. Chem. Soc.2001,123,749.(b)Sanford,M.S.;Love,J.A.;Grubbs,R.H.J. Am. Chem. Soc.2001,123,6543.

(26) CertainROMPsofstrainedcyclicolefinicmonomersarehighlyexothermic.Dependingon themonomer, thecatalyst, and theconditions,someROMPscanstartandreacha200°Cexothermwithinseconds.

(27) Pederson,R.L.;Fellows,I.M.;Ung,T.A.;Ishihara,H.;Hajela,S.P.Adv. Synth. Catal.2002,344,728.

(28) Sanford,M.S.;Love,J.A.;Grubbs,R.H.Organometallics2001,20,5314.

(29) Love,J.A.;Sanford,M.S.;Day,M.W.;Grubbs,R.H.J. Am. Chem. Soc.2003,125,10103.

(30) SeeSection6 formoredetailsonreaction temperature rangeswhenusingtheseolefinmetathesiscatalysts.

(31) Fürstner,A.;Ackermann,L.;Gabor,B.;Goddard,R.;Lehmann,C.W.;Mynott,R.;Stelzer,F.;Thiel,O.R. Chem.—Eur. J. 2001,7,3236.

(32) Dinger,M.B.;Mol,J.C.Adv. Synth. Catal.2002,344,671.(33) Lee,C.W.;Grubbs,R.H.J. Org. Chem.2001,66,7155.(34) (a)VandeWeghe,P.;Bisseret,P.;Blanchard,N.;Eustache,J.J.

Organomet. Chem.2006,691,5078.(b)Whitehead,A.;Moore,J.D.;Hanson,P.R.Tetrahedron Lett.2003,44,4275.(c)Chao,W.;Weinreb,S.M.Org. Lett.2003,5,2505.

(35) (a)Garbaccio,R.M.;Danishefsky,S.J.Org. Lett.2000,2,3127.(b)Garbaccio,R.M.;Stachel,S.J.;Baeschlin,D.K.;Danishefsky,S.J.J. Am. Chem. Soc.2001,123,10903.(c)Fürstner,A.;Müller,C.Chem. Commun.2005,5583.

(36) Vernall,A.J.;Abell,A.D.Aldrichimica Acta2003,36,93.(37) (a)Chatterjee,A.K.;Morgan,J.P.;Scholl,M.;Grubbs,R.H.

J. Am. Chem. Soc.2000,122,3783.(b)Choi,T.-L.;Chatterjee,A.K.;Grubbs,R.H.Angew. Chem., Int. Ed.2001,40,1277.(c)Choi,T.-L.;Lee,C.W.;Chatterjee,A.K.;Grubbs,R.H.J. Am. Chem. Soc.2001,123,10417.

(38) Chatterjee, A. K.; Choi, T.-L.; Grubbs, R. H. Synlett 2001,1034.

(39) (a)Chatterjee,A.K.;Grubbs,R.H. Org. Lett.1999,1,1751.(b)Chatterjee,A.K.;Sanders,D.P.;Grubbs,R.H. Org. Lett.2002,4,1939.

(40) Chatterjee,A.K.;Choi,T.-L.;Sanders,D.P.;Grubbs,R.H. J. Am. Chem. Soc. 2003,125,11360.

(41) Choi,T.-L.;Rutenberg,I.M.;Grubbs,R.H.Angew. Chem., Int. Ed.2002,41,3839.

(42) Fora lead reference, seeSmulik, J.A.;Diver,S.T.Org. Lett.2000,2,2271.

(43) Shimizu,K.;Takimoto,M.;Sato,Y.;Mori,M.J. Organomet. Chem.2006,691,5466.

(44) Harned,A.M.;Zhang,M.;Vedantham,P.;Mukherjee,S.;Herpel,R.H.;Flynn,D.L.;Hanson,P.R.Aldrichimica Acta2005,38,3.

(45) Garber,S.B.;Kingsbury,J.S.;Gray,B.L.;Hoveyda,A.H.J. Am. Chem. Soc.2000,122,8168.

(46) These types of compound are often referred to as second-generationHoveyda–Grubbscatalysts.

(47) (a)Randl,S.;Gessler,S.;Wakamatsu,H.;Blechert,S.Synlett2001,430.(b)Imhof,S.;Randl,S.;Blechert,S.Chem. Commun.2001, 1692. (c) Hoveyda, A. H.; Gillingham, D. G.; vanVeldhuizen,J.J.;Kataoka,O.;Garber,S.B.;Kingsbury,J.S.;Harrity,J.P.A.Org. Biomol. Chem.2004,2,8.

(48) (a)Wakamatsu,H.;Blechert,S.Angew. Chem., Int. Ed.2002,41,794.(b)Wakamatsu,H.;Blechert,S.Angew. Chem., Int. Ed.2002,41,2403.

(49) (a)Grela,K.;Harutyunyan,S.;Michrowska,A.Angew. Chem., Int. Ed.2002,41,4038.(b)Michrowska,A.;Bujok,R.;Harutyunyan,S.;Sashuk,V.;Dolgonos,G.;Grela,K.J. Am. Chem. Soc. 2004,126,9318.(c)Bieniek,M.;Bujok,R.;Cabaj,M.;Lugan,N.;Lavigne,G.;Arlt,D.;Grela,K.J. Am. Chem. Soc. 2006,128,13652.

(50) Ung,T.;Hejl,A.;Grubbs,R.H.;Schrodi,Y.Organometallics2004,23,5399.

(51) Foradditionalexamplesoflatentcatalystdesign,see:(a)Gulajski,L.;Michrowska,A.;Bujok,R.;Grela,K.J. Mol. Catal. A: Chem.2006, 254, 118. (b) Fürstner, A.; Thiel, O. R.; Lehmann, C. W.Organometallics2002,21,331.(c)Slugovc,C.;Perner,B.;Stelzer,F.;Mereiter,K.Organometallics2004,23,3622. (d)Slugovc,C.;Burtscher,D.;Stelzer,F.;Mereiter,K.Organometallics2005,24,2255.(e)Barbasiewicz,M.;Szadkowska,A.;Bujok,R.;Grela,K.

52

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ts Organometallics 2006, 25, 3599.(f)Hejl,A.;Day,M.W.;Grubbs,R.H.Organometallics 2006,25,6149.

(52) Love,J.A.;Morgan,J.P.;Trnka,T.M.;Grubbs,R.H.Angew. Chem., Int. Ed.2002,41,4035.

(53) Choi, T.-L.; Grubbs, R. H. Angew. Chem., Int. Ed. 2003, 42,1743.

(54) Foranotherexampleofanactiverutheniumcatalystbearingapyridine ligand,seeConrad,J.C.;Amoroso,D.;Czechura,P.;Yap,G.P.A.;Fogg,D.E.Organometallics2003,22,3634.

(55) Romero,P.E.;Piers,W.E.;McDonald,R.Angew. Chem., Int. Ed.2004,43,6161.

(56) Romero,P.E.;Piers,W.E.J. Am. Chem. Soc.2005,127,5032.(57) Dinger,M.B.;Nieczypor,P.;Mol,J.C.Organometallics2003,

22,5291.(58) Vehlow,K.;Maechling,S.;Blechert,S.Organometallics2006,

25,25.(59) Themoreactivemetathesiscatalystsgiveolefinicmixtureswith

higherpercentagesofthethermodynamicEalkenes(i.e.,higherE/Zratios).ForadiscussionontheE/Zselectivityofmetathesiscatalysts,seereferences1dand23.

(60) Highly active andhighly enantioselective chiralmolybdenumcatalysts have been developed by Schrock and Hoveyda. Forlead referencesand reviews, see: (a)Totland,K.M.;Boyd,T.J.;Lavoie,G.G.;Davis,W.M.;Schrock,R.R.Macromolecules1996, 29, 6114. (b) Alexander, J. B.; La, D. S.; Cefalo, D. R.;Hoveyda,A.H.;Schrock,R.R.J. Am. Chem. Soc. 1998,120,4041. (c)Zhu,S.S.;Cefalo,D.R.;La,D.S.; Jamieson, J.Y.;Davis,W.M.;Hoveyda,A.H.;Schrock,R.R.J. Am. Chem. Soc. 1999,121,8251.(d)Hoveyda,A.H.;Schrock,R.R.Chem.—Eur. J.2001,7,945.Seealsoreference1g.

(61) Seiders,T. J.;Ward,D.W.;Grubbs,R.H.Org. Lett.2001,3,3225.

(62) VanVeldhuizen,J.J.;Garber,S.B.;Kingsbury,J.S.;Hoveyda,A.H.J. Am. Chem. Soc. 2002,124,4954.

(63) (a) Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.;Kataoka,O.;Hoveyda,A.H.J. Am. Chem. Soc. 2003,125,12502.(b)Gillingham,D.G.;Kataoka,O.;Garber,S.B.;Hoveyda,A.H.J. Am. Chem. Soc. 2004,126,12288.

(64) Funk,T.W.;Berlin,J.M.;Grubbs,R.H.J. Am. Chem. Soc. 2006,128,1840.

(65) Kingsbury, J. S.; Hoveyda, A. H. In Polymeric Materials in Organic Synthesis and Catalysis;Buchmeiser,M.R.,Ed.;Wiley-VCH:Weinheim,2003;Chapter11.

(66) (a)Yao,Q.Angew. Chem., Int. Ed.2000,39,3896.(b)Dowden,J.;Savović, J. Chem. Commun.2001,37.(c)Randl,S.;Buschmann,N.;Connon,S.J.;Blechert,S.Synlett2001,1547.(d)Kingsbury,J.S.;Garber,S.B.;Giftos,J.M.;Gray,B.L.;Okamoto,M.M.;Farrer,R.A.;Fourkas,J.T.;Hoveyda,A.H.Angew. Chem., Int. Ed.2001,40,4251. (e) Jafarpour,L.;Heck,M.-P.;Baylon,C.;Lee,H.M.;Mioskowski,C.;Nolan,S.P.Organometallics2002,21, 671. (f )Connon,S. J.;Dunne,A.M.;Blechert,S.Angew. Chem., Int. Ed.2002,41,3835. (g)Connon,S. J.;Blechert,S.Bioorg. Med. Chem. Lett.2002,12, 1873. (h)Yao,Q.;Zhang,Y.J. Am. Chem. Soc. 2004,126, 74. (i)Yao,Q.;Motta,A.R.Tetrahedron Lett.2004,45,2447.

(67) (a) Schürer, S. C.; Gessler, S.; Buschmann, N.; Blechert, S.Angew. Chem., Int. Ed.2000,39,3898.(b)Prühs,S.;Lehmann,C.W.;Fürstner,A.Organometallics2004,23,280.

(68) (a)Mayr,M.;Buchmeiser,M.R.; Wurst,K.Adv. Synth. Catal. 2002, 344, 712. (b) Krause, J. O.; Lubbad, S.; Nuyken, O.;Buchmeiser,M.R.Adv. Synth. Catal.2003,345,996.(c)Yang,L.;Mayr,M.;Wurst,K.;Buchmeiser,M.R.Chem.—Eur. J. 2004, 10,5761.(d)Halbach,T.S.;Mix,S.;Fischer,D.;Maechling,S.;

Krause,J.O.;Sievers,C.;Blechert,S.;Nuyken,O.;Buchmeiser,M.R.J. Org. Chem.2005,70,4687.

(69) (a)Gallivan,J.P.;Jordan,J.P.;Grubbs,R.H.Tetrahedron Lett.2005,46,2577.(b)Hong,S.H.;Grubbs,R.H.J. Am. Chem. Soc. 2006,128,3508.

(70) Corrêa da Costa, R.; Gladysz, J. A. Chem. Commun. 2006,2619.

(71) Ritter,T.;Day,M.W.;Grubbs,R.H.J. Am. Chem. Soc. 2006,128,11768.

(72) Grubbs,R.H.OrganicSynthesisUsingTheOlefinMetathesisReactions. Presented at the 231st National Meeting of theAmericanChemicalSociety,Atlanta,GA,March26–30,2006;PaperORGN179.

(73) Berlin,J.M.;Campbell,K.;Ritter,T.;Funk,T.W.;Chlenov,A.;Grubbs,R.H.Org. Lett.2007,9,ASAP.

(74) Pletnev,A.A.;Ung,T.;Schrodi,Y.Materia,Inc.,Pasadena,CA.Unpublishedresults,2006.

(75) Stewart,I.C.;Ung,T.;Pletnev,A.A.;Berlin,J.M.;Grubbs,R.H.;Schrodi,Y.Org. Lett.2007,9,inpress.(Patentpending.)

(76) (a)Maynard,H.D.;Grubbs,R.H.Tetrahedron Lett.1999,40,4137. (b)Ferguson,M.L.;O’Leary,D. J.;Grubbs,R.H.Org. Synth.2003,80,85.(c)U.S.Patent6,376,690,April23,2002.(d)U.S.Patent6,215,019,April19,2001.

About the AuthorsYann  Schrodi was born in 1972 in Strasbourg, Alsace,France.HeobtainedaB.S.degree inchemistry in1994andan M.S. degree in transition-metal chemistry in 1995 fromL’UniversitéLouisPasteurStrasbourg,whereheworkedunderthesupervisionofProfessorJohnA.Osborn.AfterservingintheFrenchmilitaryfor tenmonths,hespentfiveyears inthelaboratoryofProfessorRichardR.SchrockatMIT,whereheearnedhisPh.D.degree in inorganicchemistry in2001.Dr.Schrodi joinedMateria, Inc., in2001,wherehe is currentlyleading the Catalyst Research and Development Group.Notableachievementsof thisgroupunderhis leadershipandincollaborationwithProfessorRobertH.Grubbsincludethedevelopmentofseveralnewolefinmetathesiscatalysts,suchashighlyactivebut latentcatalystsforring-openingmetathesispolymerizations, highly efficient and selective ethenolysiscatalysts,andhighlyefficientcatalysts for theproductionoftetrasubstitutedolefins.Dr.Schrodi isacoauthoronseveralpublicationsandpatents in theareaofhomogeneouscatalystdevelopmentandcatalyticprocessdevelopment.

Richard  L.  Pederson was born in 1962 in Albert Lea,Minnesota.HeearnedhisB.S.degreeinchemistryin1985fromtheUniversityofWisconsin-RiverFalls,wherehedidresearchunderProfessorJohnHill.Heworkedunder thesupervisionof Professor Chi-Huey Wong at Texas A&M University,earning his Ph.D. degree in organic chemistry in 1990. HejoinedBendResearch,Inc. inBend,Oregon,where, in1997,heandProfessorRobertH.Grubbspatented theproductionof insect pheromonesusing rutheniummetathesis catalysts.Dr.Pedersonhasspentthelasttwelveyearsinentrepreneurialstart-ups using olefin metathesis to develop new routes toinsectpheromonesandpharmaceutical intermediates,whilealsomanagingnumerousprojectsandtechnicalpersonnel.In2000,he joinedMateria, Inc., tostartup theFineChemicalsGroup,whereheis theDirectorofFineChemicalsR&D.Dr.Pedersonis theauthorofnumerouspatentsandpublications,includingkeypatents related to theproductionof chelatingmetathesisligandsandtheuseofmetathesisintheproductionofinsectpheromones.̂

Coates Carbonylation CatalystsThese complexes are efficient and versatile carbonylative ring-expansion catalysts that have been applied in the synthesis of various lactones and cyclic anhydrides.1–3

O

N

O

NM+

[Co(CO)4]-

O

O

674699 M = Al

674680 M = Cr

N

N

N

N

[Co(CO)4]-

O

O

Ar

Ar Ar

Ar

Al+

Ar = 4-Cl-C6H4

681474

NN

NN

P

TrippyPhos676632

A-taPhos677264

NH3C

CH3

P

Me2N P NMe2PPdCl

Cl

(A-taPhos)2PdCl2

678740

New Efficient Systems for Cross-CouplingDeveloped at pharmaceutical companies, these non-proprietary ligands and catalyst are efficient in mediating Pd-catalyzed aminations5 or Suzuki–Miyaura cross-coupling reactions.6

NN

P

BippyPhos681555

References(1) (a) Church, T. L. et al. J. Am. Chem. Soc. 2006, 128, 10125. (b) Getzler, Y. D. Y. L. et al. J. Am. Chem. Soc. 2004, 126, 6842. (c) Getzler, Y. D. Y. L. et al. J. Am. Chem. Soc. 2002, 124, 1174. (2) Kramer, J. W. et al. Org. Lett. 2006, 8, 3709. (3) Rowley, J. M. et al. J. Am. Chem. Soc. 2007, 129, in press. (4) Fuerstner, A.; Seidel, G. J. Organomet. Chem. 2000, 606, 75. (5) (a) Singer, R. A. et al. Tetrahedron Lett. 2006, 47, 3727. (b) Singer, R. A. et al. Synthesis 2003, 1727. (6) Guram, A. S. et al. Org. Lett. 2006, 8, 1787. (7) (a) Kwon, M. S. et al. Angew. Chem., Int. Ed. 2005, 44, 6913. (b) Kwon, M. S. et al. Org. Lett. 2005, 7, 1077. (8) Park, I. S. et al. Chem. Commun. 2005, 5667. (9) Kim, M.-J. et al. Org. Lett. 2007, 9, ASAP.

L E A D E R S H I P I N L I F E S C I E N C E , H I G H T E C H N O L O G Y A N D S E R V I C EALDRICH • BOX 355 • MILWAUKEE • WISCONSIN • USA

sigma-aldrich.com

C WO

OO

666440

New Schrock Alkyne Metathesis CatalystTris(tert-butoxy)(2,2-dimethylpropylidyne)tungsten(VI) has emerged as an effective alkyne metathesis catalyst under fairly mild conditions. The usefulness of this catalyst is illustrated by the concise and stereoselective synthesis of cis-civetone—a valuable, macrocyclic, olfactory compound.4

Nanoparticulate Pd and RhNanoparticulate palladium in an aluminum hydroxide matrix (674133) is a versatile, recyclable, and amphiphilic heterogeneous catalyst that can be applied to a variety of reactions with low catalyst loadings.7 Nanoparticulate rhodium entrapped in a highly porous and fibrous boehmite matrix (679488) has been used in the facile and mild hydrogenation of a variety of arenes, can be recovered effortlessly by simple filtration, and reused several times without a noticeable loss of activity.8–9

Other Metal Catalysts679771 (2-Biphenyl)di-tert-butylphosphinegold(I) chloride, 98%

677876 Trichloro(pyridine)gold(III), 97%

677892 Tetrakis(acetonitrile)copper(I) tetrafluoroborate, 97%

679763 Bis(dibenzylideneacetone)platinum(0)

New Chiral Technologies from Sigma-Aldrich

Chiral phospholane ligands are sold in collaboration with Kanata Chemical Technologies Inc. for research purposes only. These compounds were made and sold under license from E. I. du Pont de Nemours and Company; license does not include the right to use the compounds in producing products for sale in the pharmaceutical field.

Chiral phospholane ligands have been used extensively in transition metal catalyzed asymmetric hydrogenations and other novel asymmetric reactions including [4+1] cycloadditions, imine alkylations, and allylborations. Available in either enantiomeric form with Me, Et, and i-Pr substituents. For a detailed product listing, visit sigma-aldrich.com/phospholane.

Chiral Phospholane Ligands

ChiroSolvTM kits are 96-well format kits that enable rapid screening of resolving agents and solvents for chiral separation. Each of these ready-to-use disposable kits contains a combination of eight resolving agents and twelve solvents. Racemates that can be separated include: acids, bases, alcohols, amino acids, aldehydes, and ketones. Optimum resolution that typically requires over two months can be achieved within one day.

ChiroSolvTM Kits

Available in three Acid Series kits (681431, 681423, 681415) and three Base Series kits (681407, 681393, 681377). For more information visit sigma-aldrich.com/chirosolv.

Mac-H is a convenient formulation of the MacMillan Imidazolidinone OrganoCatalystTM and Hantzsch ester for asymmetric reductions, effectively serving as “asymmetric hydrogenation in a bottle.”

MacMillan OrganoCatalystsTM

NH

CH3H3C

OEt

O

EtO

O

· CF3CO2H

N

NH

O

CH3

CH3

CH3

CH3OO

PO

OH

SiPh3

SiPh3

OO

PO

OH

SiPh3

SiPh3

683558

674745 680184

MacMillan TiPSY Catalysts have been used in the first direct enantioselective organocatalytic reductive amination reaction.

P P

R

R

R

R

BPE

P P

R

R

R

R

DuPhosFe

P

P

R

R

R

R

Ferrocenyl Phospholanes

Mac-H MacMillan TiPSY Catalysts

To see our comprehensive solutions for chiral chemistry, visit sigma-aldrich.com/gochiral.

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Visit sigma-aldrich.com for full details.

Aldrich AtmosBag™

NEW Micro, Mini, and Small Sizes with Front, Side, and Dual-Side Entry

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If a glove box is not a suitable option for you then the Aldrich AtmosBag could be the solution. The AtmosBag provides an economical, reliable, isolated, and controlled environment.

• Constructed of sturdy polyethylene • Seams heat-sealed for strength• Inflation tested to ensure they are leak-free • Two-hand configuration• Built-in gas ports • Convenient clip closure

Cat. No. Size Opening (in.) W X L (in.) Gas Ports

Front Entry

Z564397 Micro 11½ 17 x 17 2

Z564400 Mini 22 27 x 17 2

Z564419 Small 22½ 27 x 27 2

Side Entry

Z564427 Mini 12 20 x 20 4

Z564435 Small 12 30 x 20 2

Dual-Side Entry

Z564443 Mini 12 20 x 20 2

Z564451 Small 12 30 x 20 2

View table of contents, search, browse, or order from our entire library at sigma-aldrich.com/books.

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CHeMICAL SyNtHeSISHandbook of Metathesis, 3-Volume Set

R. H. Grubbs, Ed., Wiley­VCH, 2003, 1234 pp. Hardcover. There is probably no name more closely linked to metathesis than that of Robert H. Grubbs of the California Institute of Technology. His pioneering work has led to the success of this important and fascinating reaction, and, in this comprehensive three­volume set, he presents all of its important aspects. The team of contributing authors reads like a “Who’s Who” of metathesis. The handbook is clearly divided into three major topics: catalyst developments, organic synthesis applications, and polymer synthesis. Z551570-1EA

Modern Organonickel Chemistry

Y. Tamaru, Ed., Wiley­VCH, 2005, 346 pp. Hardcover. Nickel catalyzes many unique reactions and thus enormously widens the scope of feasible transformations in organic chemistry. Over the past few years, interest in organonickel chemistry has grown such that it is now just as keen as that in organopalladium chemistry. Yet, while there are numerous books on the latter topic, a book specializing in organonickel chemistry is long overdue. This volume covers the many discoveries made over the past 30 years. Active researchers working at the forefront of organonickel chemistry provide a comprehensive review of the topic, including Nickel­Catalyzed Cross­Coupling Reactions, Reactions of Alkenes Including Allylnickel Complexes, Reactions of Alkynes, Reactions of Dienes and Allenes, Cycloisomerization; Carbonylation and Carboxylation, Asymmetric Synthesis, and Heterogeneous Catalysis. Z705802-1EA

Handbook of Heterocyclic Chemistry, 2nd Edition

A. R. Katritzky and A. F. Pozharskii, Pergamon Press, 2000, 758 pp. Hardcover. Heterocyclic chemistry is the largest of the classical divisions of organic chemistry. Heterocyclic compounds are widely distributed in nature, playing a vital role in the me­tabolism of living cells. Their practical applications range from extensive clinical use to fields as diverse as agriculture, photog­raphy, biocide formulation, and polymer science. The range of known heterocyclic compounds is enormous, encompassing the whole spectrum of physical, chemical, and biological proper­ties. This handbook is illustrated throughout with thousands of clearly drawn chemical structures and contains over 1500 chemical figures and reactions. The highly systematic coverage given to the subject makes this handbook one of the most authoritative single­volume accounts of modern heterocyclic chemistry available. Z515213-1EA

Hydrocarbon Chemistry, 2nd Edition

G. A. Olah and Á. Molnár, Wiley, 2003, 871 pp. Hardcover. Hydrocarbon Chemistry begins by discussing the general aspects of hydrocarbons, the separation of hydrocarbons from natural sources, and the synthesis from C1 precursors with recent developments for possible future applications. Each successive chapter deals with a specific type of hydrocarbon transforma­tion. The second edition includes a new section on the chemi­cal reduction of carbon dioxide—focusing on catalytic, ionic, electrocatalytic, photocatalytic, and enzymatic reductions—as well as a new chapter on new catalysts and activation methods, combinatorial chemistry, and environmental chemistry.

Z550949-1EA

Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals, 2nd Revised and Enlarged Edition, 2-Volume Set

M. Beller and C. Bolm, Eds., Wiley­VCH, 2004, 1344 pp. Hard­cover. Already in its second edition, over 70 internationally renowned authors cover the vast range of possible applications for transition metals in industry as well as academia. This two­volume work presents the current state of research and ap­plications in this economically and scientifically important area of organic synthesis. Over 1,000 illustrations and a balanced presentation allow readers fast access to a thorough compila­tion of applications, making this an indispensable reference for everyone working with such metals.

Z703451-1EA

Supported Catalysts and Their Applications

D. C. Sherrington and A. P. Kybett, Eds., Royal Society of Chemistry, 2001, 278 pp. Hardcover. The need to improve both the efficiency and environmental acceptability of indus­trial processes is driving the development of heterogeneous catalysts in commodity, specialty and fine chemicals, as well as in pharmaceuticals and agrochemicals. This book discusses aspects of the design, synthesis, and application of solid­sup­ported reagents and catalysts, including supported reagents for multistep organic synthesis, selectivity in oxidation catalysis, mesoporous molecular sieve catalysts, and the use of Zeolite Beta in organic reactions. In addition, the two discrete areas of heterogeneous catalysis (inorganic oxide materials and polymer­based catalysts) that were developing in parallel are now shown to be converging.

Z555517-1EA

Handbook of Organopalladium Chemistry for Organic Synthesis, 2-Volume Set

E. Negishi, Ed., Wiley, 2002, 3424 pp. Hardcover. This is the au­thoritative reference on organopalladium compounds, designed for synthetic chemists. Transition metals and their complexes represent one of the most important groups of catalysts for organic reactions. Among these, palladium has emerged as one of the most versatile catalysts in modern organic synthesis. Negishi assembles contributions from several dozen interna­tional authorities on the use of palladium reagents and catalysts. The handbook’s contents are organized by reaction type, which provides maximum utility to the synthetic chemist.

Z513865-1EA

Microwaves in Organic and Medicinal Chemistry (Methods and Principles in Medicinal Chemistry Series, Volume 25)

C. O. Kappe and A. Stadler, Eds., Wiley­VCH, 2005, 422 pp. Hardcover. The authors of this guide are experts on the use of microwaves for drug synthesis, as well as having extensive experience in teaching courses held under the auspices of ACS and IUPAC. In this handy source of information for any practicing synthetic chemist, they focus on common reaction types in medicinal chemistry, including solid­phase and combi­natorial methods. They consider the underlying theory and the latest developments in microwave applications, and include a variety of examples from the recent literature, as well as less common applications that are equally relevant for organic and medicinal chemists.

Z704679-1EA

Modern Rhodium-Catalyzed Organic Reactions

P. A. Evans, Ed., Wiley­VCH, 2005, 496 pp. Hardcover. Rhodium is an extremely useful metal due to its ability to catalyze an array of synthetic transformations. Hydrogenation, C–H activation, al­lylic substitution, and numerous other reactions are catalyzed by this metal, which presumably accounts for the dramatic increase in the number of articles that have recently emerged on the topic. P. Andrew Evans has assembled an internationally renowned team to present the first comprehensive coverage of this im­portant area. The book features contributions from leaders in the field of rhodium­catalyzed reactions, and thereby provides a detailed account of the most current developments.

Z705810-1EA

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