ALLENES AND IONIC L IQUIDS IN ASYMMETRIC SYNTHES IS

VOL. 40 , NO. 4 • 2007

Recent Advances in the Chemistry of Allenes

Chiral Imidazolium Ionic Liquids: Their Synthesis and Influence on the Outcome of Organic Reactions

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New Products from Aldrich R&DAldrich Is Pleased to Offer Cutting-Edge Reagents for Organic SynthesisDeoxygenation ReagentDeveloped by the Movassaghi group at MIT, N-isopropylidene-N’-2-nitrobenzenesulfonyl hydrazine (IPNBSH) is a useful reagent for the mild deoxygenation of allylic and propargylic alcohols to give allylically transposed alkenes and allenes, respectively.1 This reagent exhibits excellent reactivity in difficult reductive fragmentations, as demonstrated in the total syntheses of (–)-acylfulvene and (–)-irofulven.2

1) IPNBSH, DEAD, PPh3

2) TFE–H2O

OH

R2

R3

R2

R3

R1 R1

OH

R1

R2

R1 R2

or or

(1) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838. (2) Movassaghi, M. et al. Angew. Chem., Int. Ed. 2006, 45, 5859.

N-Isopropylidene-N’-2-nitrobenzenesulfonyl hydrazine, 97% IPNBSH687855

NO2

SNH

N CH3

CH3

OO1 g $52.50

[6655-27-2]C9H11N3O4S

5 g 175.00

FW: 257.27

Bromination ReagentBromodimethylsulfonium bromide (BDMS) is an easy-to-handle and highly effective bromination reagent as well as a catalyst for various organic transformations.1 BDMS has been employed in numerous reactions including the preparation of α-bromo-β-keto esters and α-bromo enones, from their corresponding keto esters and enones, respectively;2 the conversion of epoxides and enamines to α-bromoketones;3 and electrophilic aromatic bromination.4 BDMS has also been employed in the synthesis of α-aminonitriles and homoallylic amines, and in Michael additions of amines to electron-deficient olefins.5

R1 OR3

O O

R2 Br

R1

O

R2

BrY

Br

R1

OR2

Br

(1) Choudhury, L. H. Synlett 2006, 1619. (2) (a) Khan, A. T. et al. J. Org. Chem. 2006, 71, 8961. (b) Chow, Y. L.; Bakker, B. H. Can. J. Chem. 1982, 60, 2268. (3) Olah, G. A. et al. Tetrahedron Lett. 1979, 20, 3653. (4) (a) Majetich, G. et al. J. Org. Chem. 1997, 62, 4321. (b) Megyeri, G.; Keve. T. Synth. Commun. 1989, 19, 3415. (5) (a) Das, B. et al. Synthesis 2006, 1419. (b) Das, B. et al. Tetrahedron Lett. 2006, 47, 5041. (c) Khan, A. T. Tetrahedron Lett. 2007, 48, 3805.

Bromodimethylsulfonium bromide, 95% BDMS694142

H3CS

CH3

BrBr

5 g $60.00[50450-21-0] C2H6Br2S

25 g 217.50

Cumulated YlideThe cumulated ylide (triphenylphosphoranylidene)ketene is a versatile two-carbon building block useful in preparing numerous classes of oxygen- and nitrogen-containing heterocycles. While typically not Wittig-active itself, this reagent reacts with a host of electrophiles to yield Wittig-active products that can participate in subsequent intra- or intermolecular olefination reactions.

Ph3P C C OTMSEO2C

CO2Bn

OH

C6H6, reflux

O

O

OBnTMSEO2C

85%

(1) Schobert, R.; Jagusch, C. Synthesis 2005, 2421. (2) Schobert, R. et al. Synthesis 2006, 3902. (3) Boeckman, R. K., Jr. et al. J. Am. Chem. Soc. 2006, 128, 11032.

(Triphenylphosphoranylidene)ketene Bestmann ylide688185

Ph3P C C O

1 g $55.00[15596-07-3] C20H15OPFW: 302.31

Mg(HMDS)2

While lithium amides, such as LDA and LiHMDS, are the predominant bases of choice for the selective generation of enolates, magnesium amide bases have garnered recent attention due to their enhanced thermal stabilities and selectivity characteristics.1 Magnesium bis(hexamethyldisilazide), Mg(HMDS)2, has demonstrated efficacy in ketone–aldehyde aldol addition reactions2 and in the regio- and stereoselective synthesis of silyl enol ethers.3

1) Mg(HMDS)2, –78 ºC

2) PhCHO, –78 ºC, then 1M HCl

O O

Ph

OH

90%

(1) He, X. et al. J. Am. Chem. Soc. 2006, 128, 13599. (2) Allan, J. F. et al. Chem. Commun. 1999, 1325. (3) Bonafoux, D. et al. J. Org. Chem. 1996, 61, 5532.

Magnesium bis(hexamethyldisilazide) Mg(HMDS)2

692352

N Mg NSi(CH3)3

Si(CH3)3(H3C)3Si

(H3C)3Si

5 g $36.00[857367-60-3] C12H36MgN2Si4

25 g 120.00

FW: 345.07

Reagent for Disulfide SynthesisThe reaction of alkyl halides or pseudohalides with the sulfur-based nucleophile sodium methanethiosulfonate (NaMTS) yields organic methanethiosulfonates, intermediates that are highly reactive towards sulfhydryl groups, yielding unsymmetrical disulfides. NaMTS has been extensively used in glycosylations, spin-labeling, and photoprobe chemistry.1–3

R1 X

H3C SO

OSNa

R1 S S CH3

O

OR1 S S R2

SHR2

(1) Grayson, E. J. et al. J. Org. Chem. 2005, 70, 9740. (2) Kálai, T. et al. Synthesis 2006, 439. (3) Guo, L.-W. et al. Bioconjugate Chem. 2005, 16, 685.

Sodium methanethiosulfonate, 95% NaMTS684538

H3C SO

OSNa

1 g $39.50[1950-85-2] CH3O2NaS2

FW: 134.15

89

VO

L. 4

0, N

O. 4

• 2

007

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VOL. 40, NO. 4 • 2007

“PLEASE BOTHER US.”

Professor Keith Fagnou of the University of Ottawa (Canada) kindly suggested that we make cesium pivalate. This versatile base has been used by several research groups in transition-metal-catalyzed direct arylations of indoles.1 Cesium pivalate has also been employed as a base in the study of aryl-to-aryl palladium migration in Heck and Suzuki couplings of o-halobiaryls.2

(1) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Campeau, L.-C. et al. Aldrichimica Acta 2007, 40, 35. (c) Wang, X. et al. J. Am. Chem. Soc. 2005, 127, 4996. (2) Campo, M. A. et al. J. Am. Chem. Soc. 2007, 129, 6298.

O

O

Cs

694037 Cesium pivalate, 98% 5 g $40.00 25 g 134.00

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

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TABLE OF CONTENTSRecent Advances in the Chemistry of Allenes .........................................................................................................................91Shengming Ma, Shanghai Institute of Organic Chemistry

Chiral Imidazolium Ionic Liquids: Their Synthesis and Influence on the Outcome of Organic Reactions ..........................................................................................................................................................................................................107Allan D. Headley* and Bukuo Ni, Texas A&M University-Commerce

ABOUT OUR COVERIn the last decades of Monet’s life, his prized water garden became his most important—and eventually his only—subject. Monet began to paint his lily pond and our cover, The Japanese Footbridge (oil on canvas, 81.3 3 101.6 cm), in his garden at Giverny in 1899. He constructed the water garden soon after he moved to Giverny with his family in 1893, petitioning local authorities to divert water from the nearby river. Monet remade the landscape with the same artifice he applied to his paintings—and then he used it, in turn, as his creative focus. When Monet exhibited his lily ponds, a number of critics mentioned his debt to Japanese art and the idea of the hortus conclusus (closed garden) of medieval images.

Monet painted his garden from the same vantage point as our cover twelve times, focusing on the arching blue-green bridge and a microcosm of the water. He gave equal emphasis to the physical qualities of his painting materials and to the landscape motif he depicted. In this painting, the sky has already disappeared; the lush foliage rises all the way to the horizon; and the decorative arch of the bridge flattens the space. Floating lily pads and mirrored reflections assume equal stature, blurring distinctions between solid objects and transitory effects of light. Monet had always been interested in reflections, seeing their fragmented forms as the natural equivalence for his own broken brushwork. The artist—who, as a leader of the impressionists, had espoused the spontaneity of directly observed works that capture the fleeting effects of light and color—had in these later paintings subjected a nature he re-created to sustained, meditated scrutiny.

This painting is a gift to the National Gallery of Art from Victoria Nebeker Coberly, in memory of her son, John W. Mudd, and Walter H. and Leonore Annenberg.

Joe Porwoll, President Aldrich Chemical Co., Inc.

Photograph © Board of Trustees, National Gallery of Art, Washington.

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Allenes are becoming highly sought building blocks for their ability to react with many different classes of substrates. In addition, the allene moiety itself is present in many bioactive natural products and pharmaceutical agents. Recent work by Reissig1 and Zhang2 demonstrates the utility of lithiated allenyl ethers in the synthesis of various carbocycles and heterocycles. Other work by Suginome and co-workers reports the use of cyclohexylallene in a palladium-catalyzed asymmetric silaboration.3 Sigma-Aldrich is pleased to add these and other allenes to our expanding portfolio of reactive building blocks.

New Reactive Allenes

• OR1

Li

O

OR1

R2

R3

N

NR3

R4R2

I

H

OOR1

H

• OR1n-BuLi

many steps

many steps

many steps

References: (1) (a) Brasholz, M.; Reissig, H.-U. Synlett 2007, 1294. (b) Brasholz, M.; Reissig, H.-U. Angew. Chem., Int. Ed. 2007, 46, 1634. (c) Gwiazda, M.; Reissig, H.-U. Synlett 2006, 1683. (2) Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398. (3) Ohmura, T. et al. J. Am. Chem. Soc. 2006, 128, 13682.

New Allenes

Other Allenes

• OCH3

•

694126 694118

• BO

O

CH3CH3

CH3

H3C

•

CH3

678554 694894

• H

H

H

H

• SnBu3

•O

O

294985 499854 494992

•

CH3

H3C

•

CH3

TMS

• CH3

CH3

CH3

H3C

110930 409596 272965

91

VO

L. 4

0, N

O. 4

• 2

007

Outline1. Introduction2. IonicAdditionReactions 2.1. NucleophilicAdditions 2.2.ElectrophilicAdditions3. ReactionsInitiatedbyMetallation 3.1. ReactionsInitiatedbyHydrometallation 3.2. ReactionsInitiatedbyCarbometallation 3.3. ReactionsInitiatedbyNucleometallation4. Cycloisomerization and Eliminative Cyclization of

FunctionalizedAllenes 4.1. Cycloisomerization 4.2. EliminativeCyclization5. CycloadditionReactions6. CyclometallationReactions7. Conclusions8. Acknowledgments9. References

1. IntroductionThehistoryofallenesdatesbackto1874.Atthattime,Jacobus H.van’tHoff,thefirstNobellaureateinchemistry,predictedthecorrectcorestructureofallenes.1It isquite interestingtonotethatthefirstsynthesisofanallene(pentadienoicacid)2,3was used to prove the nonexistence of this class of “highlyunstable”organiccompounds.During thepast10–15years,chemistshavewitnessedarapiddevelopmentofthechemistryof allenes, which have proven very powerful in modernsyntheticorganic chemistry.4–6Someof thesedevelopmentshave been summarized in a monograph5 and a review.6Followingpublicationof thesetwosurveys,furtheradvancesin allene chemistry have been reported in the followingareas: the Myers–Saito reaction,7 the radical chemistry ofallenes,4m,8 the reaction of allenes with metallocarbenes,6,9silicometallation leading to optically active allylsilanes10 orvinylsilanes,11andtheRCMreactionofallenesgivingrise tonewallenederivatives.12Inthisbriefreview,recentadvancesinthechemistryofallenes—mostlycoveringtheperiod2005toMarchof2007—specifically,ionicaddition;hydro-,carbo-,ornucleometallation-initiatedreactions;cycloisomerizationandeliminative cyclization; cycloaddition; and cyclometallationwillbedescribedinaselectivemanner.

2. Ionic Addition Reactions13

2.1. Nucleophilic AdditionsMukaiandco-workersobservedthattheintramolecularamination–acetate elimination reaction of 2-(2’-aminophenyl)-2,3-allenylacetatesandthesubsequentDiels–Alderreactionaffordtetrahydro-ordihydrocarbazolederivativesin54–93%yields.14However,theyieldsofthecorrespondingreactionwithalkynesarelow.Alcaideetal. reportedthattheintramolecularnucleophilicadditionof2-phenyl-substitutedbuta-2,3-dienylmethyletherwithanamine,followedbyeliminationofthemethoxygroup,affordpyrroles.15

Startingin1998,wehavedemonstratedthatelectron-deficientallenes,suchas1,2-allenyliccarboxylates,carboxylicacids,ketones,sulfoxides, sulfones, nitriles, phosphine oxides, phosphonates,andotherssmoothlyundergoconjugateadditionwith inorganichalides to afford β-halo-β,γ-unsaturated olefins.16 In 2002, wealsoreportedthatstabilizedcarbonnucleophilesundergotandemMichaeladditionandlactonizationwith1,2-allenylketones.Thereactioncanbecontrolledtoyieldtheconjugateadditionproductswith anE/Z ratioof96:4 to99:1.17Chelatedenolatesof aminoacid esters react similarly.18Huang andShen reported in2006that, in addition to ketones, 2,3-allenoates react with α-cyanoketones,β-ketoesters,and1,3-diketones toaffordα-pyrones.19Evensodiumazides,thiolates,selenolates,andtellurrolatesreactasnucleophileswith2,3-allenoatesor1,2-phosphineoxidestogiveriseto3-alkenoatesorallylphosphineoxides.13,20IndolesundergoSc(OTf)3-catalyzedreactionwith1,2-allenylketonestoformEβ-indolyl-α,β-unsaturatedenonesandβ,β-bis(1H-indolyl)ketones.21Theintramolecularconjugateadditionofacarbonnucleophileorahydroxylgroupwith1,2-allenylsulfonesinthepresenceoft-BuOKgenerates5–8-membered-ringproductsin41–72%yields.22

2,3-Allenoatesareknowntoreactwithelectron-deficientolefinsundercatalysisbyorganophosphinestoform[3+2]cycloadditionproducts.4k,23 In2006,Luetal. furtherobserved thatethyl2,3-butadienoateunderwentPh3P-catalyzedreactionwith2-substituted1,1-dicyanoalkanestoform4,4-dicyano-2-(ethoxycarbonyl)cyclo-pentenesastheonlyproducts.24Therequisite1,1-dicyanoalkaneswereeasilypreparedinsitubycondensationofaromaticaldehydeswithmalononitrile.Veryrecently,Wallaceetal.reportedthatthePh3P-orDIOP-catalyzedreactionof1,2-propadienylmethylketonewithα,β-unsaturatedenones1affordedcyclopentenyldiketones2 asthemajorproducts.25Intheabsenceofα,β-unsaturatedenones,1,2-allenylmethylketoneactsasaMichaelacceptorbyundergoing

Recent Advances in the Chemistry of Allenes

Shengming MaState Key Laboratory of Organometallic ChemistryShanghai Institute of Organic ChemistryChinese Academy of Sciences354 Feng Lin LuShanghai 200032, P. R. of ChinaEmail: masm@mail.sioc.ac.cn

92

Rece

nt A

dvan

ces

in t

he C

hem

istr

y of

Alle

nes

VO

L. 4

0, N

O. 4

• 2

007

Scheme 1. Reaction of Allenyl Ketones with α,β-Unsaturated Enones.

O

+R1

O

n n

O

+n

O O

2:3 = 80:20 to 95:5

O

R2

O RR

O

R1

1n = 1, 2, 3R1 = H, Ph

246–84%

46–77% ee

3

426–54%

O

R1

R = Me, Ar

Ph3P(20 mol %)

PhMert, 20 h

DIOP(20 mol %)

PhMert, 12 h

a[3+2]cyclizationtoform6-acylmethylene-6H-pyrandimers,4 (Scheme 1).25

Theenantioselectiveversionofthis[3+2]cycloadditionwasfirst investigatedbyZhangandco-workers in1997.26 In2006,WilsonandFudisclosedthatbinaphthyl-basedchiralphosphine(R)-5efficientlycatalyzestheenantioselective[3+2]cycloadditionofethyl2,3-butadienoatewithα,β-unsaturatedarylenones,providing3-acyl-2-(ethoxycarbonyl)cyclopentenes,6,asthemajorproductsin75–90%ee’s(eq 1).27

Aldehydes can also be used instead of the electron-deficientolefins.Kwonandco-workersreportedthatthePMe3-catalyzed reaction of 2,3-butadienoate with two molecules ofan aromatic aldehyde affordedcis-(E)-2,6-diaryl-1,3-dioxan-4-ylidenecarboxylate8 (Scheme 2).Thisoverallprocessisbelievedtoproceed througha sequential conjugate additionofPMe3 tobutadienoate,double1,2additionofthealdehyde,cyclicconjugateaddition, and elimination of PMe3.28 However, when stericallydemandingtrialkylphosphineswereutilized,ethyl2,3-butadienoatereacted with just one molecule of aldehyde to form α-pyronederivatives9.Whenaliphaticaldehydeswereusedinthereaction,theyieldsofthecorrespondingα-pyroneswerelow.29

Furthermore, substituted 2,3-allenoates also react witharomaticN-sulfonyliminesunderP(n-Bu)3catalysistoafford2,5-disubstituted-3-pyrrolinecarboxylates10highlystereoselectively(Scheme 3).4kThediastereoselectivity for thecis isomer,10, isdependentonthestericbulkoftheRgroup.30Anenantioselectiveversion of this reaction has recently been demonstrated byMarinetti’s and Gladysz’s groups with enantioselectivities of37–60%beingreported.31However,theterminalcarbon–carbondoublebondof1,2-allenylmethylketonesorof2,3-butadienoatesundergoesaDABCO®-catalyzed,highlyregioselectiveformal[2+2]cycloadditionwithiminestoaffordtheunsaturatedazetidines11.Incontrast,whenDMAPwasemployedinsteadofDABCO®,thesamereactantsafforded1,2-dihydropyridine-3-carboxylates12inloweryields.Theauthorsproposedamechanisminvolvinga nucleophilic addition of the amine instead of PR3 and, forcomparison, the authors reported that the PhMe2P-catalyzedreactionof2,3-pentadienoatewithN-tosylaldiminesafforded3-pyrrolines.32

Whentheαpositionof1,2-allenylmethylketonesisblockedwithanalkylgroup,anaza-Baylis–Hillman-typeγ-additionproduct,13,isformedinthepresenceofDMAPascatalyst;whereasamixtureoftwotetrahydropyridines,14and15,isformedinthepresenceofP(n-Bu)3.33TheDMAP-catalyzedreactionof1-alkyl-substituted1,2-allenylmethylketoneswith aldehydes alsoprovided theγ-additionproducts,16,in45–75%yields(Scheme 4).

WurzandFuusedchiralphosphine(R)-5tocatalyzethereactionofN-tosylaldimineswith2-substituted-2,3-butadienoatesor1,2-propadienylphenylketone toafford14-type tatrahydropyridinederivativeswithhighdiastereo-andenantioselectivity. Inmostcases,theenantioselectivityreachedthe96–99%level.34However,inthepresenceofquinuclidine,ethyl2,3-butadienoatereactedwithα,β-unsaturatedenonestoaffordBaylis–Hillman-typeconjugateaddition products, i.e., 2-(3-oxoalkyl)-2,3-allenoates.6,35 In thepresenceof10mol%DBUorDABCO®,salicylicaldehydesorN-tosyliminesreactwith1,2-allenylketones,2,3-butadienoates,or 2-methyl-2,3-butadienoates to afford2H-1-benzopyrans36 orchromenes,37respectively.

Nair et al. reported that, in the reaction of 2,3-allenoates,PPh3,anddialkylazodicarboxylates,PPh3attackedthenitrogen–nitrogendoublebondfirsttogenerateanewtypeofzwitterionicintermediate, 17.Conjugate additionof17 onto2,3-allenoates,followedbyintramolecular1,2additionandeliminationofPh3PO

Ref. 25

eq 1

CO2Et

+R Ar

O

P t-Bu

(R)-5 (10 mol %)PhMe, rt

CO2Et

R

Ar

O CO2Et

R

OAr

39–76%6:7 = 3:1 to >20:1

+

675–90% ee

7R = alkyl, alkynyl, aryl, furan-2-yl, quinolin-2-ylAr = Ph, thien-2-yl, 5-methylfuran-2-yl, substituted phenyl

Ref. 27

Scheme 2. Reaction of 2,3-Butadienoate Esters with Aldehydes.

CO2i-Pr PMe3(20 mol %)

CHCl3, rt24 h

O O

Ar

ArCO2i-Pr

847–99%

E:Z = 4:1 to >20:1

+ 2 ArCHO

OR O

R = aryl, alkylR' = i-Pr, Cyp, Cy

924–91%

Ar = Ph, Pyr, substituted phenyl

CO2Et PR'3(10 mol %)

CHCl3, 60 oC14–96 h

+ RCHO

Ref. 28,29

Scheme 3. The Reaction of 2,3-Allenoates with N-Sulfonylimines.

CO2Et PBu3(20 mol % )

PhH, rt

R

+ NPh

Ts

NTs

CO2Et

PhR

1089–99%

cis:trans = 91:9 to 100:0

DMAP, CH2Cl2

rt, 10 minEWG = CO2Et

DABCO®

MS (4 Å)

PhH, rt, 1 hor DCM, rt, 3 h

EWG = CO2Et, Ac

NAr

TsH

EWG

N

CO2Et

ArTs

Ar

1131–99%

1231– 60%

R = H, Me

EWG

+ NAr

Ts

Ar = Ph, 1-Np, pyridin-3-yl, substituted phenyl

Ref. 4k,31,32

93

Shen

gmin

g M

aV

OL.

40,

NO

. 4 •

200

7

formedpyrazolines18orpyrazoles19,dependingonthepositionofthesubstituentonthe2,3-allenoatestartingmaterial(Scheme 5).38

Nucleophilic attack of hydrazine on allenes initiates acyclizationreactionthatleadstofusedtetracyclicheterocyclesor4H-pyrazolo[1,2-b]pyrazoles,respectively.39,401,2-Allenylbromidesundergo1,3-anti-substitutionwith(RCuBr)MgBr•LiBrtoaffordterminalalkynes.41Cu(I)catalyzesthefacilecouplingof1,2-allenyliodideswithamides,carbamates,andureastogiveallenylamines.421,2-Allenyl bromides 20 and 22 undergo intramolecularsubstitutiontoformbicyclicsulfonamides21 and23,respectively(Scheme 6).43 Recently, an intermolecular tandem addition–cyclizationofbromoalleneswithmalonatesor1,3-diketonesledtoalkylidenecyclopropanesorfurans24,respectively.44Inthesetworeactions,thenucleophileregioselectivelyattacksthecentralcarbonatomoftheallenylbromide;thisisfollowedbyhydrogentransferandintramolecularnucleophilicsubstitutiontoaffordthecyclicproducts.

Allenylsilylethers,easilypreparedfrompropargylicsilylethersandKOt-Bu, reacted readilywitharomaticaldehydes toaffordβ-branched Baylis–Hillman-type adducts.45 In 26, the lithiumallenolatemoietyreactedintramolecularlywiththealkenemoietyto formthe5-tert-butylidene-2-cyclopentenonederivative27 in70%yield (eq 2).46

2.2. Electrophilic AdditionsOnthebasisofpriorreports,13wehaveshownthattheelectrophiliccyclizationoffunctionalizedallenesaffordsheterocyclessuchasbutenolides, furans, lactams, iminolactones,andothers.47Morerecently,thiscyclizationhasproventobeaverypowerfultoolforthesynthesisofvariousheterocyclicproducts.48Inaddition,wehaveobservedthatthehalohydroxylationreactionof1,2-allenylsulfoxides,sulfones,sulfides,orselenidesresultsintheelectrophilichalogenattackingthecentralcarbonatomoftheallenemoiety.13Thestereoselectivityisdeterminedbythenatureofthesubstituents:withsulfoxidesandsulfones,Eisomersareformed;whileZisomersareproducedfromsulfidesandselenides.49,50A5-membered-ringintermediatehasrecentlybeenisolatedandcharacterizedbyX-raydiffraction,whichcorroboratesthestereochemicalcourseofthehalohydroxylationofsulfoxidesandsulfones.51

3. Reactions Initiated by Metallation3.1. Reactions Initiated by HydrometallationBäck va l l a nd co -worke r s repor t ed t ha t 3 - (2 ,3 -alkadienyl)cyclohexenes undergo cycloisomerization in thepresenceofHOAcandPd(dba)2 toaffordamixtureof isomericbicyclicproducts.Thecycloisomerizationtakesplacethroughahydropalladation, cycliccarbopalladation, andβ-Heliminationunder microwave irradiation.52 Hydrometallation of (1-alkoxy-propadienyl)cyclobutanols, 28, leads to chiral 2-alkoxy-2-vinylcyclopentanones 30 in 84–95% ee’s by an efficient andenantioselectiveringexpansion(eq 3).53

Thehydrozirconationofallenesandsubsequenttransmetallationwithdialkylzincformallylzincreagents,whichreactreadilywithiminestoaffordhomoallylicamines.Theregioselectivitydependsonthenatureofthesubstituentsontheallenes.54TheintermolecularhydroaminationofopticallyactivealleneswithanilineefficientlyformsopticallyactiveallylaminesunderAuBr3catalysis.55

Kanai,Shibasaki,andco-workersdevelopedtheenantioselectiveCu(OAc)2–(R)-DTBM–SEGPHOS®-catalyzedhydrometallationof2,3-butadienoatesandthesubsequent1,2-additionreactionwithmethylketonestoaffordopticallyactive(Z)-5-(ethoxycarbonyl)-4-alken-2-ols, 31, in 84–99% ee’s. The corresponding CuF•3PPh3•2 EtOH–TANIAPHOS®-catalyzed reaction produced 3-

Scheme 4. Reactions of 1-Alkyl-Substituted 1,2-Allenyl Methyl

Ketones with N-Sulfonylimines and Aldehydes.

Ac

(n-Bu)3P (10 mol %)

DCE, 80 oC, 0.5 h

DMAP (10 mol %)

DMSO, rt, 10 min

N

Ac

1340–81%

1414–29%

R1 = Me, BnR2 = Ph, substituted phenyl

Ac

+ NAr

Ts

Ar = Ph, 1-Np substituted phenyl

AcAr

NHTs

TsAr

1549–67%

NTs

Ar+

O

Ar

R1

+ R2CHODMAP (20 mol %)

DMSO, 80 oC0.2–12 h 16

45–75%

Ac

R1

R2

OH

Ref. 33

Scheme 5. Reaction of 2,3-Allenoates with Azodicarboxylates.

CO2Et

R1

NN

CO2R

RO2C

NN

OR

CO2R

EtO2CR1

CO2Et

R3

DME, rt, 3 h

NN

RO2COEt

CO2R

1833–74%

1935–72%

17

NN

CO2R

Ph3P CO2R

R2

R2

R3

THF, reflux5 h

R = Me, Et, i-Pr; R1 = ArR2 = Me, Ar; R3 = H, Ph

PPh3

argon

Ref. 38

Scheme 6. The Reactions of 1,2-Allenyl Bromides.

Br

NHSO2NHR

R1

R2

NaH, MeOH60 oC, 2–24 h

or TBAF, THF60 oC, 0.25–1 h

N SO2

NRR1

R2

2117–95%

20

+HN

SO2

NR

R1 R2

10–98%

O R3

Ar

OR3

Ar = Ph, substituted phenylR3 = Me, or R3, R3 = –CH2C(Me2)CH2–

R3R3

OO

2465–84%

R = Me, Bn, PhR1, R2 = H, H; H, Me; Me, Me; 1,2-C6H4; C(CH2OTBS)2; C[(CH2O)2CMe2]

Br

NHSO2NHPh

TBAF, THF

N

2396%

22

reflux, 30 hSO2

NPh

Br

Ar K2CO3, acetone(n-Bu)4NBr

55 oC, 26–56 h

alkylidene-cyclopropanesor

Ref. 43,44

eq 2

O

H t-Bu

Br

Ph

O

Ni-Pr

i-Pr

HOOLi

H t-Bu

Br

Ph

O(i-Pr)2N

O

Br O

t-BuPh

2770%

25 26

12

3 s(a) (b)

(a) (i) n-BuLi, TMEDA, PhMe, –78 oC, 1 h. (ii) rt, 1 h(b) 2 N HCl

Ref. 46

94

Rece

nt A

dvan

ces

in t

he C

hem

istr

y of

Alle

nes

VO

L. 4

0, N

O. 4

• 2

007

(ethoxycarbonyl)-4-alken-2-ols,32,in66–84%ee’s(Scheme 7).56Byutilizingdialkylzincinsteadofpinacolborane,thealkylativealdol reaction with methyl ketones formed α,β-unsaturated δ-lactones.56

The Ni(cod)2-catalyzed addition of organoboronates to 1,2-allenesaffordedhydroarylationorhydroalkenylationproductswithgoodE/Zselectivitybutpoorregioselectivity.However, thePd-catalyzedreactionofalleneswithorganoboronicacidsintroducedthesubstituentfromtheorganoboronicacidstranstothesubstituentinthestartingallenestogivestereodefinedfunctionalizedalkenesasthemajorproducts.57AmechanisminvolvinghydropalladationoftheallenesandsubsequentSuzukicouplinghasbeenproposedbased on ESI-MS studies.58 In addition, the three-componentreactionof symmetrical allenes, organoboronates, andalkynesafforded1,3-dienederivativesstereoselectively.59

Scheme 7. The Hydrometallation of 2,3-Butadienoates Followed

by 1,2 Addition to Methyl Ketones.

CO2Et

OH

MeR'

3180–97%

84–99% ee

CO2R

OH

MeR'

86–91%32:33 = 6:1 to 11:1

66–84% ee

32

+ CO2R

OH

MeR'

CO2R

(a) R' = alkyl, Ph, substituted phenyl, cinnamyl(b) R' = Ph, substituted phenyl, cinnamyl

+ R'

O

(a) (i) CuOAc (2.5 mol %), (R)-DTBM-SEGPHOS® (5 mol %), PCy3 (5 mol %), pinacolborane, THF, 0 oC, 16 h. (ii) H2O. (b) (i) CuF•3 PPh3•2 EtOH (2.5 mol %), TANIAPHOS® (5 mol %) pinacolborane, THF, –20 oC, 16 h. (ii) H2O.

33

R = Et

R = Me Et

5

43

(a)

(b)

Ref. 56

Scheme 8. Multicomponent Reactions Involving Carbopallada-

tion, Intramolecular Trapping, and [3 + 2]-Dipolar Cycloaddition.

Y

H

X

O

+H2N CO2Me

R

NMe

O

O

Pd2(dba)3(2.5 mol %)

TFP (10 mol %)Cs2CO3, PhMe

100 oC, 48 hX = Br, IY = CH, N

N

N

MeN

HH H

RCO2Me

OO

3453–69%

I

N

OR1

R1 R2

R2

+ +

Pd2(dba)3(2.5 mol %)

TFP (10 mol %)

KOAc, DMF70 oC, 24 h

NN

N

R2

R2

O

NR1

R1

H

H

3662–84%

35

TMSN3

R = H, Me, Bn, Ph, CH2CO2Me, (CH2)2SMe

+

+

= secondary amineR2 = H, MeNR2

1

Ref. 68,69

3.2. Reactions Initiated by CarbometallationThe Pd-catalyzed reaction of organic halides with allenesusually affords conjugated dienes via β-H elimination fromthe π-allylPd intermediate initially formed by regioselectivecarbopalladation.4a,4e,6,60 Even 1,2-allenylboronates undergo thecarbopalladation forming π-allylPd intermediates, which aretrappedwithaminesorcarbonnucleophilesundercatalysisbyPd2(dba)3 and TFP to yield stereodefined 3-substituted 2-aryl-1-alkenylboronateshighlystereoselectively.61However, thefirstHeck-typecouplingofalleneswitharylhalideswasobservedbyourgroupinthecaseof1,2-allenylsulfonesbyusing5mol%Ag2CO3and 4 equivalents of K2CO3 as the base.62 The following year,ChakravartyandSwamyreportedasimilarreactionwith3-methyl-2,3-butadienylphosphonateusingAg2CO3asthebase.63However,byswitchingtoK2CO3asthebase,thereactionproceededmorereadilythroughaπ-allylPdintermediatetogive1,3-dienylphosphonates.63TheLarock-typecyclizationreaction64ofo-hydroxyiodobenzeneorbenzoicacidwith1,2-allenylphosphonateswasalsoreportedtogivebenzocyclicproducts.63

Grigg’sgrouphasusedaminestotrapinsituformedπ-allylPdintermediates to afford allylamines.65 By utilizing allylic orhomoallylictosylamides,bisallylictosylamidesormixedallylichomoallylictosylamideswereproduced,whichcyclizedviaRCMto3-pyrrolinesor3-piperidines.65Benzoxapineswerealsopreparedbyusing2-allylphenol.66InthepresenceofCO,therelatedfour-component reaction afforded 3-acylpyrrolidines.67 Recently,Grigg’sgroupalsodeveloped thePd-catalyzed four-componentreactionof a2-haloaromatic aldehyde, propadiene, aminoacidester,andN-methylmaleimide,providingaverypowerfulentryintotetracyclicproducts34viacarbopalladation,intramoleculartrapping,and[3+2]-dipolarcycloaddition(Scheme 8).682-Haloarylhydrazines and oximes have also been employed.68 The sametypeofπ-allylPd intermediatewas formed in thePd-catalyzedreaction of 2-(2-iodophenyl)propenamides 35 with allenes andwasefficientlytrappedbyTMSN3.Subsequentintramolecular1,3-dipolarcycloadditionproducedtriazolotetraisoquinolines36highlyefficiently.69With5-bromo-2-iodobenzonitrile,tetrazolederivativeswere formed.Inaddition, theseallylicpalladium intermediatesunderwentumploungwithindiumtoformπ-allylInintermediates,whichreactedreadilywithN-sulfinylα-iminoesterstogiverisetoα-(2-arylallyl)α-aminoacidesters.70

ThePd(PPh3)4-catalyzedreactionofN-(o-bromobenzyl)-4,5-hexadienamide (37)with2-thienyl iodideandPhB(OH)2 formstricyclicamide38viaanintermolecularallenecarbopalladation,aminetrapping,cycliccarbopalladation,andintermolecularSuzukicoupling.71 Cyclic carbopalladation of the aryl iodide moietywith the allene moiety in39 has been applied to the insertionandringopeningofoxabenzonorbornadieneforthesynthesisofmethanederivatives40,possessingtwobenzocyclicsubstitutents (Scheme 9).72

Intermolecular carbopalladation of functionalized alleneshasbeenfurtherdemonstrated toaffordcyclicproductsvia theintroduction of a third component containing a C=C or N=Nbond.4g,73Thenitrogen-centerednucleophilethattrapstheinsituformedπ-allylPdintermediateisgeneratedbythe1,2additionoftheoriginalcarbonnucleophileinthestartingallenestotheC=NorN=Nbond.Thistypeofπ-allylPdintermediatealsoundergoesacycliccarbopalladationwithanintramolecularcarbon–carbondouble bond to produce a species containing an sp3-carbon–palladiumbond.Subsequentcarbopalladationwiththearomaticringintroducedbythefirstintermolecularcarbopalladationefficientlyaffords tricyclic compound 42 with high diastereoselectivity(eq 4).74

eq 3

R1R1 R1

R1

O

OR2

3078–100%

84–95% ee

28

Pd2(dba)3•CHCl3 (2.5 mol %)PhCO2H (10 mol %)

(R,R)-29 (7.5 mol %)Et3N (10 mol %)

DCE, 23–60 oC, 12 h

NH HN

Ph PhO O

PPh2 Ph2P

(R,R)-29Trost's (R,R)-LST DPPBA ligand

R1 = H, Et, Ph, (CH2)2CO2Et; R1, R1 = –(CH2)4– R2 = Bn, PMB, alkyl, alkenyl, alkynyl

OH

OR2

Ref. 53

95

Shen

gmin

g M

aV

OL.

40,

NO

. 4 •

200

7

Alkoxycarbonylnickel cyanide formed from the oxidativeadditionofα-cyanocarboxylatewithNi(0)undergoessequentialcarbonickellationofallenesandreductiveeliminationtoafford2-(1-cyanoalkyl)-2-alkenoates asthemajorproducts.75

TransmetallationoforganoboronicacidswithaPd(II)complexformsaryl-,alkenyl-,orevenalkylpalladiumspecies.Thesespeciesreadilyundergocarbopalladationwith2,3-allenoatestoformπ-allylPdintermediates.Subsequent1,2additionwithaldehydesandlactonizationprovideα,β-unsaturatedδ-lactones.76Recently,ourgroupachievedasimilarreactionbyemployingRhCl(PPh3)3asthecatalyst.77Intramolecularconjugateadditionofsuchaπ-allylPdspecieswith2-alkynoatesaffords7-or8-memberedcyclicalkenes.78Byutilizing[Rh(OH)((R)-BINAP)]2asthecatalyst,Hayashiandco-workershavedemonstratedthatthereactionof1-alkyl-substituted1,2-allenylphosphineoxideswitharylboronicacidsleadsto(S)-2-aryl-3-diphenylphosphinylalkenesin96–98%ee’s.Incontrast,theenantioselectivitywiththe1-phenyl-substitutedsubstrate is low(69%ee).79

3.3. Reactions Initiated by NucleometallationThe intramolecular oxypalladation of 2,3-allenoic acids formsdifferentlyβ-substitutedbutenolidesinthepresenceofω-alkenylbromides, 1,2-allenyl ketones, 2,3-allenoic acids, 2,3-allenols,propargyliccarbonates,andpropargylicpropiolates.4g,80Asimilarreactionofallenylamineswithorganichalidesaffordsazacyclicproducts.21

4. Cycloisomerization and Eliminative Cyclization of Functionalized Allenes4.1. CycloisomerizationThe Au(I) -catalyzed, regioselect ive, int ramolecularhydroaminationof4,5-or5,6-allenylaminesisanefficientstepinthehighlyregioselectivesynthesisofpyrrolidines,pyrrolines,andpiperidines.81,82Tosteandco-workershavereportedagold-catalyzed,enantioselectiveversionofthisreactionthatefficientlyformstheopticallyactive,5-or6-membered-ringazacycliccompounds44(eq 5).83 2,3-Allenylamines undergo hydroamination to affordpyrrolinesbyemployinginorganicAgorAusaltsorK2CO3.84

Likewise,thecycloisomerizationof2,3-or3,4-allenolsinthepresenceofAu(I)orAu(III)catalystaffords2,5-dihydrofuransordihydropyrans.85MoritaandKrauserecentlyreportedthatunderAuClcatalysis,even2,3-allenylthiolssimilarlycycloisomerizetoyield2,5-dihydrothiophenes.86Anenantioselective,Au-catalyzedcyclativehydroalkoxylationof4,5-or5,6-allenols45affords2-vinyltetrahydrofuransor tetrahydropyrans,46, ingood-to-highyieldsandenantioselectivities(eq 6).87

Thecycloisomerizationof1,2-allenylketonesinthepresenceofaAu(III)-porphyrincomplexproduces2,3,5-trisubstitutedfurans.88aMoreover,3-halo-1,2-allenylketonesundergoAuCl3-catalyzed,1,2-halogenmigrativecyclizationtogeneratethenot-readily-available3-halofurans.88Thethioethergroupin2-phenylthio-3,4-allenoatesor ketones nucleophilically initiates a cyclization that leads to2-phenylthiomethylfuran derivatives.89 CuCl has been used tocatalyzethecycloisomerizationof2,3-allenoicacidsaccompaniedbyahighlyefficientchiralitytransfer.90

(3’-Acetoxy-1’,2’-allenyl)benzenes 48 cyclize to indenederivatives49and50withtheassistanceof[i-PrAuCl]–AgBF4inCH2Cl2 (Scheme 10).91PtCl2

92orPh3PAuCl–AgSbF693 catalyzes

thecyclizationofsimplevinylicallenes51intocyclopentadienederivatives52.

Ph3P•AuOTf catalyzes the hydropyrrolation of allenes,leadingtosix-memberedringsandhighefficiencyofchiralitytransfer.Thisreactionhasbeensuccessfullyappliedtothetotal

Scheme 9. Further Examples of Allene Carbopalladation.

BrHN

O

+

37

S I

1. Pd(PPh3)4 (10 mol %) Cs2CO3 (3 equiv) MeCN, 70 oC, 16 h

2. PhB(OH)2

PPh3 (10 mol %) 100 oC, 22 h

N

PhH

O

S

3864%

I

Xn

R

+

O

39n = 0, 1; X = O, NTs

XOHn

(PPh3)2PdCl2, Zn

THF, 80 oC, 16 h

4045–86%

R

R = H, Me, MeO, (MeO)2, OCH2O, HC=CHCH=CH

Ref. 71,72

eq 4

N

R

MtsPh

+

Pd(PPh3)4(10 mol %)

K2CO3, dioxane100 oC, 6–29 h

N

R

Mts

H

PhH

41R = i-Pr, i-Bu, t-Bu, Bn

Mts = 2,4,6-Me3C6H2SO2

4235–54%

trans:cis = 1.3:1 to 4.9:1

I

Ref. 74

eq 5

R2

R2

(R)-xylyl-BINAP(AuOPNB)2or

(R)-Cl(MeO)BIPHEP(AuOPNB)2

(CH2Cl)2, 23 oC, 15–25 hor

MeNO2, 50 oC, 15–24 h

NR1

R1 R2

R2

Ts

n

4441–98%

70–99% ee

43n = 1, 2

NHTsR1

R1 n

R1 = H, Me, Ph; R1, R1 = –(CH2)n– (n = 5, 6)R2 = Me, Et; R2, R2 = –(CH2)n– (n = 4, 5, 6)

Ref. 83

eq 6

Au2Cl2•(S)-47

R2

OHR1

R1 n AgOTs, PhMe–20 oC, 12–24 h

O

R1R1

R2

n

4667–99%

E:Z = 1:1 to > 20:167–99% ee

45n = 1, 2

PAr2

PAr2MeOMeO

(S)-47

Ar = OMe

t-Bu

t-Bu

R1 = H, Me, PhR2 = H, Me, n-Pr, n-Pent

Ref. 87

Scheme 10. Cycloisomerization of Functionalized Allenes.

OAc

R

[i-PrAuCl]/AgBF4(2 mol %)

CH2Cl2rt, 0.25 h R

n-BuOAc

+

R

OAc

n-Bu

48R = H, Me, OMe

49 50

R

R

5238–98%

51R = Ph, Ph(CH2)2, i-Pr

n-Bu

Catalyst = PtCl2 (5 mol %) or Ph3PAuCl (1–2 mol %)–AgSbF6 (1–2 mol %)

catalyst

solventrt, 19–64 h

76–94%49:50 = 3:1 to 5:1

Ref. 91,92,93

96

Rece

nt A

dvan

ces

in t

he C

hem

istr

y of

Alle

nes

VO

L. 4

0, N

O. 4

• 2

007

eq 7

t-BuO2C

MeO2C CO2Me

120 oC, 24 h

MeO2C CO2Me MeO2C CO2Me

+

82%54:55 = 9:1

t-BuO2C

H H

t-BuO2C

H

53 54 55

DMF

Ref. 95

synthesis of (–)-rhazinilam,94 and its intramolecular variant,involvingindoles,hasbeenobservedbyWidenhoeferandco-workers.821,4-Allene–enes53undergoathermal,Alder-ene-typecycloisomerizationtoformthecyclopenteneunitin54(eq 7).95The[2+2]-cycloadditionproduct,55, isformedas theminorproduct.Sucha reactionalso takesplacewith1-(4-pentenyl)-1,2-allenylsulfonesinthepresenceofGrubbssecond-generationcatalyst.96

Inpropargyl2,3-allenylethersortosylamides, 56,theallenefunctionalgroupattacksthealkynecoordinatedwithPttoformvinylcyclobutenes,57.97Similarly,thetreatmentofallene–ynes 58withacatalyticamountofAuCl3orAu(PPh3)NTf2inCH2Cl2affords 6-membered-ring products 60–62 via the commonintermediate59(Scheme 11).98

4.2. Eliminative CyclizationAuCl3 catalyzes the dealkylative cyclization of tert-butyl2,3-allenoates to butenolides.99 Wan and Tius have appliedthe Nazarov reaction of allenyl methoxymethyl ether 63 tothe total synthesis of (+)-madindoline A (65a) and B (65b)(Scheme 12).100

The intramolecularattackof thesilylenoletheronto thetungsten-coordinatedallenederivedfrom66leadstothecyclicalkenyltungstenintermediate67,whichaffords2,2-dimethyl-3-phenyl-3-cyclohexenone(68)uponprotonolysis (Scheme 13).101Toste and co-workers observed that Ph3PAuCl–AgBF4 alsocatalyzes this typeof transformation,converting69 into thebicyclicproduct70.102

Huang and Zhang reported that, under catalysis by thegoldcomplex72,vinylic1-OMOM-1,2-propadienylcarbinoltrimethylsilyl ethers, 71, cyclize via 73, 74, and 75 tocyclopentenederivatives76in44–99%yields(Scheme 14).103

5. Cycloaddition Reactions1,2-Bis(1-phosphinyl-1,2-allenyl)benzenes undergo [2 + 2]cycloaddition, affording naphtha[h]cyclobutenes in 81–99%yields.104Bravermanandco-workersreportedthatconjugatedbisallenes bearing two electron-withdrawing sulfoxide orsulfonefunctionalitiescyclizeto3,4-bis(methylene)cyclobuten-es.105Irradiationof3-(N-2,3-butadienyl)aminocyclopentenonesorcyclohexenones,77,provides[2+2]-cycloadditionproducts78,whichundergoanα-carbon–carbonsingle-bondcleavagetoformpyrroles80via79 (Scheme 15).106

Asimilar intramolecular[2+2]cycloadditionbetweenanalleneandacarbon–carbondoubleortriplebondwasreportedby thegroupofOhnoandTanakaand thatofBrummond.107

Theintermolecular[2+2]cycloadditionofthemoreelectron-richC=Cbondsin2-silyloxy-1,3-dieneswithethyl2-methyl-2,3-butadienoateleadstovinyl3-(ethoxycarbonylpropylidene)-cyclobutanols in35–80%yields.1081,1-Bis(ethoxy)ethenealsoreactswithethyl2-methyl-2,3-butadienoatetogive3-(ethoxy-carbonylpropylidene)cyclobutanone diethyl ketal in 28%yield.108bAnaza-Diels–Alderreactionwasobservedbetweenthe2,4-dieneunit inallenyltrimethylsilylthioketenes81 andimines,affordingδ-thiolactams82 (Scheme 16).109

TheDiels–Alderreactionof1,1,3-trioxygenated-1,3-dieneswithallenesbearingtwononequivalentelectron-withdrawinggroups at the 1 and 3 positions gives rise to a mixture ofpolysubstitutedaromaticproducts.1103-(Ethoxycarbonyl)-3,4-pentadienoate isomerizes to form 3-(ethoxycarbonyl)-2,4-pentadienoate,whichundergoesa(n-Bu)3P-catalyzedaza-[4+2]cycloadditionwith2-imino-N-methylindole.Thisreactionhasbeen applied to the formal synthesis of (±)-alstonerine and

Scheme 11. Cycloisomerization of Allene–Ynes.

R1 = Me, R2 = HAuCl3 (1 mol %)

CD3ODrt, 10 min

R1 = Ph, R2 = HAuCl3 (1 mol %), 98%

or Au(PPh3)SbF6

(1 mol %), 87%CH2Cl2, 0 oC, 0.25 h

MeO

H

D

OCD3

MeO

MeO

MeO

MeO

MeO

R1

MeO

MeO

Au–

XR1

R2 R3

R3

PtCl2 (10 mol %)

PhMe80 oC, 12 h

X

R1

R2 R3

R3

56X = O, TsN

5735–85%

58

62616079–92%

59

R1

MeO

MeO

R1 = R2 = MePtCl2 (5 mol %),AuCl3 (1 mol %),

AuCl (1 mol %), or [Au(PPh3)SbF6] (1

mol %)DCM or PhMert, 5 min–48 h

R1 = Me, 3- & 4-MeOC6H4, Ph, 2-Np, MeSR2 = Me, i-Pr; R3 = H, Me

R2

R2

Ref. 97,98

O OMe

HO

Me

OSi(i-Pr)3n-Bu

TFA, lutidine

CH2Cl2, –20 oC1.25 h

Me

n-Bu

O

OSi(i-Pr)3

Me

n-Bu

O

O

Me

N

O

OH

63 6488%

Me

n-Bu

O

O

Me

N

O

OH

65b(+)-madindoline B

65a(+)-madindoline A

Ref. 100

Scheme 12. The Eliminative Cyclization of Allenyl Ethers in the

Total Synthesis of (+)-Madindoline A and B.

Ph

OTES W(CO)6 (20 mol %)H2O (300 mol %)

O

Ph

OTES

(CO)6W–

Phhν, THF

40 oC, 24 h

66 6868%

67

OTBSR1

R2H

n

[AuClPPh3], AgSbF6, or AgBF4

(10 mol %)

CH2Cl2 / H2O (or MeOH)or CHCl3

40 oC, 0.5 h69

n = 0 or 1R1 = R2 = Me

O

H

n

7059–97%

R1

R2

Ref. 101,102

Scheme 13. Intramolecular Eliminative Cyclization between

Allenes and Silyl Enol Ethers.

97

Shen

gmin

g M

aV

OL.

40,

NO

. 4 •

200

7

(±)-macroline.111TheDiels–Alderreactionalsooccursbetweentherelativelyelectron-deficientcarbon–carbondoublebondofopticallyactiveallenicketonesandthe1,3-dieneunitinfuran.112Vinylallenesactas1,3-dienesintheircycloadditionreactionswithDEAD,aldehydes,orSO2 toafford5-or6-membered-ringproducts.113,114(Z)-Bis(allenyl)ethene84readilyundergoesa 6π electrocyclization to afford 3,4-bis(alkylidene)-1,5-cyclohexadiene,85.InthepresenceoftheintramolecularC=Cbond,a [4+2]cycloadditionfollows, leading tosteroid-liketetracyclicproduct87 afterreductionof 86(Scheme 17).115

The diazo moiety in allenyl 1,4-dicarbonyl compoundsreacts intramolecularly, under Rh2(OAc)4 catalysis, withthe carbonyl group closer to the allene moiety to form acarbonyl–ylideintermediate,whichundergoesintramolecularcycloaddition with the proximal C=C bond of the allene toconstruct tricyclic bridged products (eq 8).9a,b In addition,the intramolecular[3+2]cycloadditionof3,4-allenylazidesaffordspyrrolidine-containingbi-or tricyclicproducts in thepresenceofTMSCN.116

6. Cyclometallation ReactionsTheintermolecular, three-componentreactionofanaldehyde,allene,anddialkylzincgiveshomoallylicalcohols.6,117NgandJamisonhavereportedthattheNi(cod)2-catalyzedintermolecularreaction of allenes and aldehydes in the presence of R3SiHaffordsallylsilylethersinhighyieldsandstereoselectivities.Starting with optically active allene 88 (95% ee), opticallyactiveallylsilylether89isformedin95%ee(eq 9).118

EvenCO2undergoesNi(cod)2-catalyzed cyclometallationwith3-substituted1,2-allenylsilanes, leadingtostereodefinedsyn-anti-π-allylnickelintermediates.TheseintermediatesreactwithanotherequivalentofCO2toform(E)-3-(methoxycarbonyl)-4-silyl-3-alkenylcarboxylatesafterhydrolysiswithHClandesterificationwithCH2N2.119Pd(O2CCF3)2catalyzestheefficientcyclometallationanddoubledehydropalladationofallene–ene90 toproduce thecis-fusedbicyclicproduct91 (eq 10).120 Inthis reaction, O2, p-benzoquinone (4 mol %), and iron(II)phthalocyanine (FePc) were used to complete the catalyticcycle.

Wegneretal.reportedthat thecyclometallationofallenes93withvinylcyclopropanes92formsintermediates94,which,uponβ-decarbometallationtoopenthethree-memberedring,produce intermediates95.Subsequent reductive eliminationandhydrolysisafford4-(1-alkynylalkylidene)cycloheptanones96 (Scheme 18).121

Furthermore,Pd2(dba)3catalyzestheintramolecular,overall[3+2]cycloadditionofthealkylidenecyclopropaneandallenemoietiesin97.Theoveralltransformationisaccomplishedviacyclometallationof97,decarbopalladationof98,andreductiveeliminationof99,givingriseto thefusedbicyclicproducts100and101in68–90%yields(Scheme 19).122

The cyclic Pauson–Khand reaction of an allene witha 1,3-diene affords bicyclic ketones .123 Similarly, theMo(CO)3(MeCN)3-catalyzed, intramolecular Pauson–Khandreaction of an allene and an alkyne that are tethered by abenzene ring,as in102, forms tricyclicketones103 inhighyields(eq 11).124

[RhCl(CO)(dppp)]2 or [RhCl(CO)2]2 catalyzes theintramolecular Pauson–Khand reaction of the 1,2-allenylsulfone and the alkyneunits in 104, affording the expectedbicyclic ketones106 in an atmosphereofCO.However, thecorrespondingβ-hydrideandreductiveeliminationproducts,107,arealsoformed.125Withanoxygenornitrogentether,the

OMOMTMSO R

NAu OClCl

O

71

72

OMOMHO R

73

Au–

OMOMHO R

74

Au

75

Au

OMOMROH

OMOM

H

R O

7644–99%

72

R = H, Me, Ph, –(CH2)n– (n = 4, 5)

CH2Cl20–25 oC0.2–0.5 h

Ref. 103

Scheme 14. Gold-Catalyzed, Intramolecular, Eliminative

Cyclization.

O

Xn

X

O

O

X

O–

X

77n = 1, 2

X = NH or O

78

798031–87%

n

nn

hv

anhyd. MeCN11 °C, 2.25–25 h

Ref. 106

Scheme 15. Intramolecular [2 + 2] Cycloaddition of Allenic

Cyclic Enones.

solvent0 oC to rt or reflux

12–14 h

STMSR

S

TMS

R

N

R1 R2

R3

NTMS

R

S

R3

R1R2

R = H, Me, Ph; R1 = alkyl, Ph; R2 = H, alkyl; R3 = Bn, alkylSolvent = THF, THF–Et2O, or PhH

81 8235–82%

2

34

Ref. 109

Scheme 16. Aza-Diels–Alder Reaction of Imines with Allenyl-

trimethylsilylthioketenes.

PhOS

PhOSOH

HO

O

PhSCl, Et3N

THFrt to reflux, 17 h

O

SOPh

SOPh

O

HSOPh

SOPh

O

H HRaney®-Ni

THF, reflux1 d

H

O

H H

84

8587, 32%(overall)

83

86

12

3

Ref. 115

Scheme 17. 6π Electrocyclization of (Z)-Bis(allenyl)ethene.

98

Rece

nt A

dvan

ces

in t

he C

hem

istr

y of

Alle

nes

VO

L. 4

0, N

O. 4

• 2

007

eq 8

O

ON2

R

n

R = H, CO2Etn = 2, 3

Rh2(OAc)4 (3 mol %)

CH2Cl2, 0 oC, 0.8 h

R

O

50–79%

n-1

O

H

Ref. 9b

eq 9

H

n-Pr n-Pr

H+ ArCHO + HSiEt3

Ni(cod)2 (20 mol %)

i-Pr-NHC (40 mol %)THF

–78 oC to rt, 18 hn-Pr

Arn-Pr

OSiEt3

8895% ee

8940–80%

Z:E > 95:595% ee

Ar = Ph, substituted phenyl

Ref. 118a

selectivityfortheformationofketonesbecomesveryhigh.Ofcourse,underaN2atmosphere, theβ-Helimination–reductiveeliminationproductsaretheonlyonesformed.Byemployinga benzene tether to connect the alkyne and the 1,2-allenylsulfoneunits,tricyclicketones,withaneight-memberedringinthemiddle,areproducedinhighyields.126Similarlystructuredallene–ene108 leads tobicyclicα,β-unsaturatedketones109efficiently(Scheme 20).127

TheanalogousMo(CO)6-catalyzedreactionof2,3-allenyl1-alkynylcarbinolsortheirTBSethers,110,producesthebicyclicketones111ingood-to-highyields.128Themetallacyclopenteneintermediate formed by such a cyclometallation of allenewithalkynein112 in thepresenceofPdCl2(PPh3)2undergoesreductiveeliminationtoformthefusedbicycliccyclobutene113 (Scheme 21).129

The cyclometallation, β-H elimination, and reductiveeliminationsequenceofallenediyne114 leadstointermediate115 (Scheme 22).6,130,131 The conjugated diene unit in 115 easily undergoes an intramolecular Diels–Alder reactiontoafford tricyclicproducts116 in77%yields.Thisprotocolhasrecentlybeenapplied to thesynthesisofα-alkylidene-β-vinyl-β,γ-unsaturatedlactams.132Similarly,Co(I)mediatestheintramolecular[2+2+2]cyclizationofallenediyne117,leadingtothesteroid-liketetracyclicketone118.133

Dixneuf and co-workers observed a Cp*RuCl(cod)-catalyzed intermolecular [2 + 2] cycloaddition of the twoterminalcarbon–carbondoublebondsofthetwomoleculesofpropadienylboronate.Incontrast,theanalogousreactionofphen-ylpropadienylboronatewithCp*Ru(MeCN)2(PPh3)PF6affordedthe[2+2]cycloadditionproductoftheinternalC=Cbonds.134WehaverecentlydemonstratedaPd-catalyzedintramolecular

eq 10

MeO2C CO2Me Pd(O2CCF3)2 (1 mol %)p-benzoquinone (4 mol %)FePc (1 mol %), O2 (1 atm)

PhMe, 95 oC, 8 h

H

H

MeO2CCO2Me

90 9196%

Pc = phthalocyanine

Ref. 120

R3 Me

R2

O+

R1

1. [Rh(CO)2Cl]2 DCE, 80 oC, 1–5 h

OR3

MeR2

92 93

9622–95%

R2

R1

O

R1

R2

R1

Rh

R3

Me

Rh

R3 Me

94

95

R1 = Ph, CH2OMe, CH2NBn2, CH2CH2OH, TMSR2 = H, n-Bu, CH2CO2Et; R3 = H, Me

2. HCl/EtOH (1%)

O

MeO

OMe

OMe

Ref. 121

Scheme 19. The Overall, Intramolecular Allene–Alkene [3 + 2] Cycloaddition Achieved via Cyclometallation, Decarbopallada-tion, and Reductive Elimination.

X

R2R1

Pd2(dba)3(2 mol %)

X

R2 R1

H

H

X

R1

R2

+(ArO)3P (5.2 mol %)

dioxane90–100 oC, 0.25–1.5 h

100 101

X Pd

R2

R1

XPd

R2 R1

97 98 99

H

H

Ar =

t-Bu

R1 = H, Me; R2 = H, MeX = O, Ph2CHN, C(CO2Et)2

carbopalladationdecarbo-

palladation

reductiveelimination

68–90%100:101 = 6:1 to 20:1t-Bu

Ref. 122

Scheme 18. Cyclometallation of Allenes with Vinylcyclo-propanes.

eq 11

R2

R1R1

R2

O

10387–93%

102

Mo(CO)3(MeCN)3

CH2Cl2, 25 oC, 4 h

R1 = H, alkyl, Ph, TMSR2 = H, n-Pent

Ref. 124

Scheme 20. Intramolecular Pauson–Khand Reaction of an Allenyl Sulfone with an Alkene or Alkyne.

PhO2S

R1R2

n

[Rh] (2.5 mol %)CO (1 atm)

PhMe, reflux0.2–12 h

n = 2

Rh

SO2Ph

R2

R1R2

R1

O

β-Helimination

reductiveelimination

R1

H

R2

104 105

106, 4–59%

107, 21–95%

XY

SO2Ph

R

n

X, Y = C, N, O; R = H, Me

PhMe, COn = 0, 1

XY

n-1

SO2PhR

O

108 10930–89%

SO2Ph

CO

[RhCl(CO)2]2

R1 = H, Me; R2 = H, Ph, TMS

PhO2S

Ref. 125,127

99

Shen

gmin

g M

aV

OL.

40,

NO

. 4 •

200

7

[2+2] cycloadditionof the two internalC=Cbonds in1,5-bisallenes 119, affordingbicyclicproductswithtwoexoC=Cbonds.Uponheatinginxylene,thetwoterminalC=Cbondsin119undergo[2+2]cycloaddition.135Wehavealsoshownthatthebimolecularcyclizationof119formssteroid-liketetracyclicproducts 120 in the presence of trans-[RhCl(CO)(PPh3)2] ascatalyst(eq 12).136

Pd(0) undergoes cyclometallation with the 1,3-diene unitintheinsituformed2-aryl-1,3,4-pentatrienes121 togenerateα-methylenepalladacyclopentenes122.Palladacycles122reactwithanothermoleculeof121 formingpalladacyclononadieneintermediates 123. Reductive elimination affords 3,4-dimethylene-1,5-octadienes 124, which readily undergo anintermolecularDiels–Alderreactionwithadienophiletobuildthefused6-memberedringin125 (Scheme 23).137

7. ConclusionsThrough the systematic study of the chemistry of allenes,intrinsicchemicalpropertiesofalleneshavebeendemonstratedshowingtheirpotentialinmodernsyntheticorganicchemistry.Insomecases,chemistshavesuccessfullyappliedthedevelopedreactions to the efficient synthesis of natural products. It isrelativelysafetopredictthatmanyexcitingreactionsofalleneswillbeunveiledbychemistsinthenot-so-distantfuture.Duetotheirsubstituent-loadingcapability,thereactionsofallenesmaynicelyshowdiversityinorganicsynthesis;theaxialchiralityinallenesmayopennewdoorsonasymmetricsynthesis.

8. AcknowledgmentsWe thank the Ministry of Science and Technology of China(G2006CB806105), the National Natural Science FoundationofChina (GrantNo.20332060,20121202,and20423001), theChineseAcademyofSciences,andtheMinistryofEducationforfinancialsupportofourresearchinthisarea.IwouldliketothankMr.XuefengJiangandMs.HuaGongfortheirhelpinpreparingthismanuscript.

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Scheme 21. The Intramolecular Cyclometallation of 2,3-Allenyl 1-Alkynyl Carbinols.

R2R1O Mo(CO)6

(10 mol %)

CO (1 atm)PhMe, DMSO60 oC, 4–7 h

O

R2R1O

11179–91%

110

CO2EtHO PdCl2(PPh3)2

(5 mol %)

110 oC, 12 h

OHCO2Et

112 11387%

R1 = H, TBSR2 = H, Ph, CO2Et

Ref. 128,129a

Scheme 22. The Intramolecular Cyclometallation of Allenediynes.

Ph OCpCo(CO)2 (1 equiv)

xylenes, hν, ∆

OPh

CoCp118, 60%>95% ee

117>95% ee

H

O Me

[Rh(CO2)Cl]2(5 mol %)

DCE, rt, 1 hO

114 115

[Rh(dppe)Cl]2(5 mol %)

AgSbF6(10 mol %)

DCE, rt, 0.5 h

O

11677%

H

H

Ref. 131,133

Scheme 23. Cyclopalladation–Reductive Elimination Sequence in 1,3,4-Pentatrienes.

Ref. 137

eq 12

XX

Xtrans-[RhCl(CO)(PPh3)2]

(5 mol %)

PhMe, 90 oC, 2–3 h

H

H

H

119 12057–74%

X = C(CO2Me)2, C(CN)2, NTs, C(PhSO2)2

Ref. 136

ArAr Br X+

Pd(PPh3)4 (4 mol %)In (1 equiv)

Ar

Ar

Pd

Ar

Ar

Ar

Ar

X'

Pd

Ar

121

123

124 12564–84% (overall)

122

Ar = Ph, substituted phenyl; X = Br, Cl

1 23

4

LiCl (3 equiv), N2

50 oC, 2 h

Ar

PhH70 oC, 18 h

X'

X' =

CN

CNNC

NC

CO2MeMeO2C

O

O

O

OEt

O

NH

O

CO2Me

MeO2C

H CO2Et

O

O

100

Rece

nt A

dvan

ces

in t

he C

hem

istr

y of

Alle

nes

VO

L. 4

0, N

O. 4

• 2

007

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101

Shen

gmin

g M

aV

OL.

40,

NO

. 4 •

200

7

(59) Takahashi,G.;Shirakawa,E.;Tsuchimoto,T.;Kawakami,Y.Adv. Synth. Catal.2006,348,837.

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2006,575.(98) (a)Lemière,G.;Gandon,V.;Agenet,N.;Goddard,J.-P.;deKozak,

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R.Org. Lett. 2005,7,1565.

102

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ces

in t

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hem

istr

y of

Alle

nes

VO

L. 4

0, N

O. 4

• 2

007

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2019.(120)Pìera,J.;Närhi,K.;Bäckvall,J.-E.Angew. Chem., Int. Ed.2006,

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4171.(129)(a)Oh,C.H.;Park,D.I.;Jung,S.H.;Reddy,V.R.;Gupta,A.K.;

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Lee,P.H.;Lee,K.;Kang,Y.J. Am. Chem. Soc. 2006,128,1139.

The following are registered t rademarks: DABCO(Air Products and Chemicals, Inc.), SEGPHOS (TakasagoInternationalCorporation),TANIAPHOS(OMGAG&Co.KG,L.P.),andRaney(W.R.GraceandCo.).

About the AuthorShengmingMaisoriginallyfromZhejiangProvince,China.HereceivedaB.S.degreeinchemistryfromHangzhouUniversity(1986),anM.S.degree(1988)andaPh.D.degree(1990)fromtheShanghaiInstituteofOrganicChemistry(SIOC),ChineseAcademy of Sciences. After postdoctoral research at ETH,Switzerland,andPurdueUniversity,U.S.A.,hejoined,in1997,thefacultyofSIOC,whereheisnowtheDirectoroftheStateKeyLaboratoryofOrganometallicChemistry.SinceFebruary2003,hehashelddualappointments:ResearchProfessorofChemistryat SIOC and Cheung Kong Scholars Program Professor atZhejiangUniversity.

Cyclopentyl Methyl Ether Cat. No.

Anhydrous, ;99.9% 675970

ReagentPlus®, ;99.9% 675989

Green TidbitCyclopentyl Methyl Ether (CPME)Safe, Environmentally Friendly Alternative to Tetrahydrofuran, tert-Butyl Methyl Ether (MTBE), 1,4-Dioxane, and Other Ether Solvents.

CPME provides a green alternative for those looking to improve their chemical process. CPME not only reduces energy waste, but its low water solubility limits it as a potential environmental contaminant.

Features and Benefits• More stable than THF when it comes to forming peroxides

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For more information on Green Solvent Alternatives, visit us at sigma-aldrich.com/solvents.

ReagentPlus is a registered trademark of Sigma-Aldrich Biotechnology, L.P.

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UMICORE Precatalysts for Asymmetric ReactionsSigma-Aldrich and Umicore have partnered to offer a portfolio of metal precatalysts for rapid screening of asymmetric and cross-coupling reactions. This partnership ensures the reproducibility of milligram-to-ton-scale reactions.

RhCl

Cl

ClRh

Cl

RuCl Cl

ClRu

Cl

Pd2dba3

683094 683108

683140

683183 686891

683213 683221 683191

683124 683345

693774 683086

683116 683132 683175

683167

683205

683353

683388 683396

IrBARF Ir

OH3C

OH3C

IrCl

ClIr

RhO

H3C

OH3C

RhO

H3C

OH3C

RhCl

ClRh Rh

BF4 • x H2O RhBF4

Rh

Cl

ClRh

RhO

H3C

OH3C

CO

CO Ru

H3C

H3C

RuCl

Cl

n

PdO

H3C

OH3C

OCH3

OCH3

IRu

I

IRu

I

PdCl

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ClRu

Cl

ClRu

Cl

Pd(OAc)2

For more information, visit sigma-aldrich.com/umicore.

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8 Privileged Ligands for Asymmetric CatalysisTakasago PortfolioThe quest to find chiral catalysts capable of achieving high enantiomeric excess for a variety of asymmetric transformations has been an ongoing endeavor for the past 30 years. Takasago’s research team has developed a portfolio of such chiral ligands and catalysts. Based on a biphenyl architecture, several phosphine-based ligands have been synthesized. Two large families of ligands can be distinguished, BINAP and SEGPHOS®. BINAP is based on a bisnaphthalene backbone with different phosphine derivatives. SEGPHOS is based on a bis(1,3-benzodioxole) with different phosphine substituents. BINAP and SEGPHOS are highly reactive and selective in the asymmetric hydrogenation of α-, β-, and γ-functionalized ketones. In conjunction with Ru complexes, these ligands allow for enantioselectivities >99% in the asymmetric hydrogenation of ketones.

Sigma-Aldrich and Takasago International Corporation are pleased to announce their collaboration to offer a portfolio of ligands and complexes for asymmetric catalysis.

References: Saito, T. et al. Adv. Synth. Catal. 2001, 343, 264. Sumi, K.; Kumobayashi, H. Top. Organomet. Chem. 2004, 6, 63. Noyori, R. et al. J. Am. Chem. Soc. 1987, 109, 5856.

R OR'

O O

nOCH3

OH O (R)-SEGPHOS 97.6% ee

(R)-BINAP 87% ee

OCH3

OH O

(R)-SEGPHOS(R)-BINAP >99% ee

ClOCH2CH3

OH O

OCH2CH3

OH

O

OOCH2CH3

OOH(R)-SEGPHOS 99.4% ee

(R)-TolBINAP 97.4% ee

(R)-SEGPHOS 98.5% ee (R)-BINAP 95.9% ee

(S)-SEGPHOS 99% ee (S)-TolBINAP 97.2% ee

PP

2

2

(R) -H8-BINAP692387

(S) -H8-BINAP693014

PP

2

2

(R) -BINAP693065

(S) -BINAP693057

PP

2

2

CH3

CH3

(R) -TolBINAP693049

(S) -TolBINAP693030

PP

2

2

CH3

CH3

CH3

CH3

(R) -XylBINAP692379

(S) -XylBINAP693022

PPO

O

O

O 2

2

(R) -SEGPHOS692395

(S) -SEGPHOS693006

PPO

O

O

O 2

2

CH3

CH3

CH3

CH3

(R) -DM-SEGPHOS692476

(S) -DM-SEGPHOS692999

PPO

O

O

O 2

2

C(CH3)3

C(CH3)3

C(CH3)3

C(CH3)3

OCH3

OCH3

(R) -DTBM-SEGPHOS692484

(S) -DTBM-SEGPHOS692980

Takasago (R)-Ligand Kit IThis kit includes 50 mg of all of the Takasago (R)-ligands for rapid screening of chiral catalysts.

695270

Sold in collaboration with Takasago International Corp.

U.S. Patent No. 2041996

U.S. Patent No. 2681057 U.S. Patent No. 3148136 U.S. Patent No. 3148136

U.S. Patent No. 3148136

SEGPHOS is a registered trademark of Takasago International Corp.

Evonik PortfolioEvonik developed a new family of highly tunable chiral ligands for a variety of rhodium-catalyzed asymmetric transformations. Based on phospholane ligands, catASium® M(R)Rh showed high enantioselectivity for the hydrogenation of E or Z β-acylamido acrylates under mild conditions and low pressure. Several derivatives of this ligand have been synthesized with a different range of reactivities. Even with very low loadings, high enantioselectivities are obtained in the hydrogenation of terminal alkenes.

Evonik’s catASium products are available as free ligands or in the form of their Rh complexes.Reference: Holz J. et al. J. Org. Chem. 2003, 68, 1701.

P

O

O

O

P

Rh

+

-BF4

O

R1OO

OR2 (0.02 mol %)

H2 (4 bar), 3 h, 25 °CO

R1OO

OR2

O

H3COO

OCH3

99% ee

O

HOO

OH

97% ee

O

HOO

OCH3

99% ee

670804

P

N

O

O

P

CF3

CF3

catASium MNXylF(R)670030

N

PPh2Ph2P

Ph

catASium D(R)672653

N

Ph2P

PPh2

Bn

+BF

-

Rh

4

catASium D(R)Rh672777

P

N

O

O

P

catASium MNXyl(R)669814

P

N

O

O

P

Rh

+-

BF4

OCH3

catASium MNAn(R)Rh670251

P

N

O

O

P

CH3Rh

+-

BF4

catASium MN(R)Rh669598

P

N

O

O

P

BnRh

+-

BF4

catASium MNBn(R)Rh669709

catASium® Ligand Toolbox (Product No. 672556)

This new kit for the rapid screening of chiral catalysts includes 100 mg of each of the catASium ligands and complexes.

Sold in collaboration with Evonik for research purposes.

P

N

O

O

P

Rh

+

-BF4

CF3

CF3

catASium MNXylF(R)Rh670154

P

N

O

O

P

Rh

+-

BF4

F

F

F

F

F

catASium MNF(R)Rh670367

P

O

O

O

P

catASium M(R)670693

P

O

O

O

P

Rh

+

BF4

catASium M(R)Rh670804

Rh

P

NN

O

OP

+

BF4

catASium MNN(R)Rh670588

P

O

O

O

P

Rh

+

BF4

catASium M(R)RhNor670928

P

P

CF2

CF2Rh

+

BF4

catASium MQF(R)Rh670472

PPh2

S

Ph2P

catASium T1(R)671029

PPh2

S

Xyl2P

catASium T2(R)671142

PXyl2

S

Ph2P

catASium T3(R)671258

P

N

O

O

P

Rh

+

BF4

catASium MNXyl(R)Rh669938

catASium is a registered trademark of Evonik Industries AG.

To view our extensive portfolio of privileged ligands, please visit sigma-aldrich.com/privileged.

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AccelerateIonic Liquid Synthesis with CBILS® Reagents

The use of CBILS (Carbonate Based Ionic Liquid Synthesis) reagents, developed by the Austrian company proionic, offers one of the simplest and most elegant synthetic methods for the production of ionic liquids. With CBILS reagents, it is possible to synthesize 20 or more new ionic liquids per day in a modular and systematic way!

N

N

H3C

CH3

+

CBILSEMIM HCO3 Brønsted acid

O

OH3C

Ionic liquidEMIM acetate

N

N

H3C

CH3

O

O CH3+ CO2 + H2O

HO OH

O

Key Features • Choose the CBILS precursor containing the cation of interest.

• Select the anion of choice in the form of the corresponding Brønsted acid.

• Calculate the necessary stoichiometry to form the new ionic liquid.

• Mix the components and stir until CO2 generation subsides.

• Remove the solvent and reaction byproduct (water or methanol).

For more information, please visit sigma-aldrich.com/cbils.

How Does the CBILS Technique Work?CBILS reagents are composed typically of a nitrogen or phosphorus ionic liquid cation and a hydrogencarbonate or

methylcarbonate anion. When CBILS reagents are treated with virtually any Brønsted acid, the anion moiety is decomposed to one equivalent of water or methanol and one equivalent of CO2.

CBILS is a registered trademark of proionic Production of Ionic Substances GmbH.

107

VO

L. 4

0, N

O. 4

• 2

007

Outline1.Introduction2.DesignandSynthesisofChiral ImidazoliumIonicLiquids

(CIILs) 2.1. CIILsofChiralAnions 2.2.CIILsofChiralCations 2.2.1. CIILs from Chiral Chlorides, Amines, and

Alcohols 2.2.2.CIILs from Amino Acids and Amino Acid

Derivatives 2.2.3.CIILsfromProlineandHistidine 2.2.4.CIILsfromLactateandTartrate 2.2.5.CIILswithFusedandSpiroRings 2.2.6.CIILswithaUreaUnit 2.2.7.OtherTypesofCIIL3.ApplicationsofCIILsinAsymmetricReactions 3.1. AsSolvents 3.2.AsOrganocatalysts 3.3. AsOrganometallicCatalysts4.ConclusionsandOutlook5.Acknowledgements6.References

1. IntroductionResearchinthefieldofionicliquids(ILs)hasgrownexponentiallyinrecentyears.Theneed tohavealternativesolvents thatareenvironmentallyfriendly,andcanserveaseffectivesubstitutesforconventionalorganicsolvents,hasdriventhisrapidgrowth.Thefirstreportofaroom-temperatureionicliquidappearedin1914;1sincethen,ionicliquidshavebeenutilizedinnumerousapplications, including as electrolytes for batteries.2 Ionicliquids seem tobe ideal replacement solvents, since they aretypicallyliquidsbelow100oCandare thermallystableoveraverywidetemperaturerange;somemaintaintheirliquidstateattemperaturesashighas200oC.3Ionicliquidsconsistofcationsandanionsand,owing totheverystrongion–ioninteractions,theyexhibit lowvaporpressuresandhighboilingpoints.The

factorsthatdictatetheirphysicalpropertiesdependonthenatureofboththecationandanion.Ionicliquidsthatcontainaromaticheterocycliccationstendtohavelowermeltingpointsthanthosecontainingaliphaticammoniumions.Ionicliquidsthatcontainhighlyelectronegativeanions,suchasorganicamides,typicallyhavelowermeltingpointsthanthosecontaininghalideanions.Asaresult,mostionicliquidsthatcanserveaseffectiveorganicsolventsconsistofimidazoliumorpyridiniumcationsandanionssuchasAlX4

–,BF4–,PF6

–,CF3SO3–,(CF3SO3)2N–,orhalides.

Themodificationofthestructuresofthecationsoranionsof ionic liquids can result in unique solvent properties thatdramatically inf luence the outcome of various reactions,including asymmetric reactions. Recently, there has been adramaticincreaseintheuseofroom-temperatureionicliquids(RTILs)assolventsfororganicsynthesis.4RTILshavebecomethesolventsofchoicefor‘greenchemistry’andareemployedinawidevarietyofreactions.5OneofthemainadvantagesofionicliquidsassolventsoverconventionalonesisthatRTILsaretypicallyrecyclable.

Ionic liquids that have gained widespread use as solventsfororganicreactionscanbedividedintotwocategories:chiralandachiralRTILs.Owing to thevastnumberof structurallydifferentRTILsthathavebeensynthesized,thisreviewfocusesonimidazoliumionicliquidsthatpossesschiralityeitherintheimidazoliummoietyorintheanionmoiety.Itdiscussesfirstthedesignandsynthesisofchiral imidazolium ionic liquids, andthenhighlights their influenceon theoutcomeofasymmetricreactions.

2. Design and Synthesis of Chiral Imidazolium Ionic Liquids (CIILs)2.1. CIILs of Chiral AnionsIn1999,Seddonandco-workersreportedthefirstexampleofachiral ionic liquid,1-n-butyl-3-methylimidazoliuml-lactate([BMIM][lactate], 1), prepared simply by reacting sodium(S)-2-hydroxypropionateand [BMIM]Cl inacetone, followedbyastraightforwardworkup(eq 1).6

Chiral Imidazolium Ionic Liquids: Their Synthesis and Influence on the Outcome of Organic Reactions

Allan D. Headley* and Bukuo NiDepartment of ChemistryTexas A&M University-CommerceCommerce, TX 75429-3011, USAEmail: allan_headley@tamu-commerce.edu

ProfessorAllanD.Headley Dr.BukuoNi

108

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Chi

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eq 1

N N+n-Bu

Cl–

+CO2Na

OH acetoneN N+

n-Bu CO2–

OH

1

Thesynthesisofotherionicliquidsthatcontainchiralanionsrelies on anion-exchange techniques. For example, Ohno’sresearchgroup synthesized20 room-temperature chiral ionicliquids(RTCILs)inwhichthechiralanionswerederivedfromnaturallyoccurring amino acids.The synthesis involved twosteps: theconversionof1-ethyl-3-methylimidazoliumbromide([EMIM][Br]) into 1-ethyl-3-methylimidazolium hydroxide([EMIM][OH]) using an anion-exchange resin, followed byneutralizationwithaseriesofnaturalaminoacidstogiveaminoacidionicliquids2 (Scheme 1).7

These ionic liquids are transparent and nearly colorlessliquids at room temperature; they are miscible with variousorganicsolventssuchasmethanol,acetonitrile,andchloroform.However,chiral ionicliquidsthataresimilar to2andcontaintwo carboxyl groups—[EMIM][Glu] and [EMIM][Asp]—areinsoluble in chloroform. Nineteen of the 20 ionic liquids arethermallystableattemperaturesabove200oC;only[EMIM][Cys]

Ref. 6

MeN NEt

Br–

anionexchange

HO–

NH2

CO2HR NH2

CO2–R

2

AA Moietyin 2

GlyAlaMetValIle

LeuSerProLysThr

Tg(oC)

–65–57–57–52–52–51–49–48–47–40

Yieldof 2

82%86%78%79%82%80%79%83%78%84%

AA Moietyin 2

PheTrpHisTyrCysArgAsnGlnAspGlu

Tg(oC)

–36–31–24–23–19–18–16–1256

Yieldof 2

83%82%78%70%77%74%83%66%89%80%

+ MeN NEt+ MeN NEt+H2O, 12 h

Scheme 1. Synthesis of Ionic Liquids of Chiral Anions from Amino Acids.

Ref. 7

MeN N-n-Bu

HO–

NH2

CO2HR

NH2

CO2MeR

Tf2O

Et3NCH2Cl2rt, 12 h

TfNH

CO2MeRneutralization

TfN–

CO2MeR

R = Me, i-Pr, i-Bu

+

MeN N-n-Bu+

53–66%

SOCl2, MeOH

0 oC, 12 h

Scheme 2. Preparation of CIILs from Amino Acid Derivatives.Ref. 8

MeN N-n-Bu

SO3–

O

O

OP

O

O–

3 4

+MeN N-n-Bu

+

Figure 1. Chiral Imidazolium Ionic Liquids of Chiral Anions.

Ref. 9

eq 2

OCH2Cl

1. MeIm, CH3CCl3 rt, 1 h

2. LiNTf2, H2O, rt

5, 90%(2 steps)

Tf2N–O

N

NMe

+

Ref. 10

exhibitsthermalstabilityupto173oC.Theauthorsalsoexploredthe effects different side chains haveon theglass transition-temperature(Tg)ofionicliquidsinthetemperaturerange–65oCto6 oC. Itwasobserved that an increase in the lengthof thealkylsidechainresultsinagradualincreaseinTg,whichwasattributedtoanincreaseinthevanderWaalsattractionbetweenthealkylgroups.

Morerecently,FukumotoandOhnoreportedthesynthesisofanewcategoryofCIILs,whichcontainchiralanionsderivedfromaminoacidderivatives(Scheme 2).8Conversionofaminoacidsintotheirmethylesterswiththionylchlorideinmethanol,followedbytreatmentwithtrifluoromethanesufonicanhydrideandtriethylamineindichloromethane,gavethecorrespondingmethyl esters of N-trif luoromethanesulfonylamino acids. Anexchange reaction of the ester with an aqueous solution of[BMIM][OH] afforded the desired CIILs as liquids at roomtemperature.Itwasobservedthatthemeltingpointsandglass-transitiontemperaturesfortheseCILsarehigherthanthoseofthetypicalhydrophobicCILsshowninScheme1.

Other naturally occurring molecules have also served asstartingmaterials for thesynthesisofchiral ionic liquids thatcontain chirality in the anionic moiety. Machado and Dortadescribed thesynthesisofCILs3and4onamultigramscalebyasimpleexchangeofcommerciallyavailable[BMIM]Clwiththe potassium salts of (S)-10-camphorsulfonate and (R)-1,1’-binaphthyl-2,2’-diylphosphateinCH2Cl2–H2O(Figure 1).9Bothsaltsarehygroscopic;3isaveryviscousgoldenoil,while4isawhitesolidwithameltingpointof78–80oC.Astheprecedingexamplesdemonstrate,anionexchangeusingchiralanionsisaproventechniqueforsynthesizingCILsthatcontainthechiralityintheanionicmoiety.

2.2. CIILs of Chiral CationsA greater number of known chiral ionic liquids derive theirchiralityfromthecationicmoiety.Owingtothereadyavailabilityofnaturallyoccurringchiralamines,alcohols,andaminoacids,theyaretypicallythemostprevalentinCIILsofchiralcations.

2.2.1. CIILs from Chiral Chlorides, Amines, and AlcoholsCommerciallyavailable(+)-and(–)-chloromethylmenthylethershavebeenusedforthepreparationofbothenantiomersofCIIL5intwosteps:alkylationfollowedbyanionexchange(eq 2).10In2003,Baoetal.reportedthesynthesisofachiralimidazoliumionic liquid with cationic chirality obtained from the chiralamine(R)-(+)-α-methylbenzylamine.11Imidazoliumsalt7wasobtained in three steps involving condensation of the chiralamine with ammonia, glyoxal, and formaldehyde; alkylationwithbromoethaneinCH3CCl3;andanionexchangewithNaBF4inacetone(Scheme 3).Unfortunately,duetothehighmeltingpointofthisionicliquid(90oC),itcouldnotserveasaneffectivesolventforasymmetricreactions.

Asimilarstrategywasutilizedfor thepreparationof ionicliquid 8, which contains two chiral centers, each bonded toanitrogenatomof theimidazoliumcation.For thissynthesis,twoequivalentsofα-methylbenzylaminewereconsumedandanoverallyieldof30%wasobtained(eq 3).10

Recently, Génisson et a l . a lso used (R) - (+) -α -methylbenzylamine as the starting material for a series ofnovelchiral imidazoliumderivatives(Scheme 4).12Alkylationof (R)-(+)-α-methylbenzylamine with chloroethylamine gavechiral 1,2-diamines, which were subjected to a ring-closingreactionwithanappropriateorthoesterelectrophile toobtain

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4,5-dihydroimidazoles.Dehydrogenationofthedihydroimida-zoleswithmanganese-basedoxidantsgavevariousC-2substitutedandunsubstitutedimidazolerings.ThetargetCIILs,9,wereobtainedbyN-alkylationwithn-pentylbromideandanionexchangewithNaBF4orLiNTf2.TheresultingBF4

–andTf2N–saltsarewater-immiscibleliquidsatroomtemperature,andtheirglass-transitiontemperaturesareaslowas–39oCand–48oC,respectively.

The chiral alcohols (S)-2-hexanol and (R)-α-methylbenzylalcoholwereutilized for thepreparationof a similar typeofchiralimidazoliumionicliquid.13TheMitsunobualkylationofimidazolewasthekeystepleadingtochiralN-alkyl-substitutedimidazoles. The configuration of the stereogenic carbinolcarbonwasconfirmedbycomparisonwithauthenticsamples.Theinversionofconfigurationwasvirtuallycomplete(>99%)in thecaseof (S)-2-hexanol,butonlyan86%selectivitywasobservedinthecaseof(R)-α-methylbenzylalcohol.TwoofthechiralN-alkyl-substitutedimidazoleswereusedasprecursorsinthesynthesisofthecorrespondingCIILsbyN-alkylationwithiodomethane(Scheme 5).

Commercially available (1S,2S,5S)-(–)-myrtanol has alsobeenused as a precursor in the synthesis of another class ofCIILs. Imidazoliumtosylatesalt11 wasformed in63%yieldfromthereactionoftosylate10andneatmethylimidazoleat100oCfor24h(Scheme 6).9

Novel, (3R)-citronellol-basedCIILshavebeensynthesizedstartingwith thebrominationof (3R)-citronellolwithBr2andPPh3inCH2Cl2atroomtemperaturetogivethecorrespondingcitronellylbromide(Scheme 7).14Heatingofthisbromidewith1-alkyl-1H-imidazolesforseveraldaysprovidedtheimidazoliumbromidesaltswhich,afteranionexchangewithNaBF4inacetone,led to the corresponding imidazolium tetraf luoroborates in46–94%yields. Inaddition,1,3-dicitronellyl-1H-imidazoliumbromidewasobtainedbydeprotonationof1H-imidazolewith(n-Bu)4NOH and subsequent treatment with 2 equivalents ofthe chiral bromide. All the (3R)-citronellol-based CIILs thuspreparedareliquidsatroomtemperature.

2.2.2. CIILs from Amino Acids and Amino Acid DerivativesAminoacidsformoneofthemostprominentpoolsofnaturalproducts thatcanserveasprecursors forchiral ionic liquids.In2003,Baoandco-workers reported, for the first time, thesynthesisofCIILsfromnaturalaminoacids.Usingl-alanine,l-leucine, or l-valine as the chiral starting material, theypreparedchiralionicliquidswithonechiralcarboninfourstepsandin30–33%overallyields(Scheme 8).11Theimidazoleringwasformedbycondensationoftheaminofunctionalityoftheaminoacidwithformaldehyde,glyoxal,andaqueousammoniaunderbasicconditions.Theinitiallyformedsodiumsaltswereesterifiedwithanhydrousethanolsaturatedwithdryhydrogenchloride.ReductionoftheresultingethylestersusingLiAlH4inanhydrousEt2Oledtothecorrespondingalcohols,whichweresubjectedtoalkylationwithbromoethanetoaffordthedesiredCIILspossessingmeltingpoints in the5–16 oC range.TheseCIILsaremisciblewithwater,methanol,acetone,andotherverypolarorganicsolvents; theyareimmisciblewithweaklypolarorganicsolvents,suchasetherand1,1,1-trichloroethane.

More recently,Xuandco-workersdescribed the synthesisand properties of novel chiral amine-functionalized ionicliquids, which were derived from the natural amino acidsl-alanine, l-valine, l-leucine, l-isoleucine, and l-proline infoursteps(Scheme 9).15Thekeyprecursors,12,wereobtainedbyreductionof theaminoacidswithNaBH4/I2,followedbya

Ph

NH2 NH3, CH2ON N

Ph

N NEt

Ph Br–

NaBF4

acetone

6

+

EtBrCH3CCl3

N NEt

Ph BF4–

7

+

OHCCHO∆

Ref. 11

Scheme 3. Bao’s Synthesis of CIILs from (R)-(+)-α-Methylbenzyl-amine.

Ph

NH21. OHCCHO CH2O, HCl

2. LiNTf2N N

Ph

8, 30%

PhTf2N–

+

Ref. 10 eq 3

Ref. 12

Scheme 4. Génisson’s Synthesis of CIILs from (R)-(+)-α-Methyl-benzylamine.

Ph

NH2 ClCH2CH2NH2NH NH2

Ph RC(OEt)3

9X = BF4, Tf2N

76–93% (R = Et)

N NPh

R

N NPh

R

n-C5H11BrN NPh

R

n-C5H11

+

Br–

N NPh

R

n-C5H11

+

X–

100 oC, 6 h

45%

AcOHMeCN

reflux, 1 h80–93%

BaMnO4, DCM4 Å MS

reflux, 20 h

R = H, Me, Et58–59%

CH3CCl3reflux, 5 d

R = Et91%

or LiNTf2H2O, 70 oC

0.5 h

NaBF4acetonert, 4 d

Ref. 13

Scheme 5. Synthesis of CIILs by a Mitsunobu Alkylation.

HN N N NR*MeI

N NMeR*I–

R*OH = OH andPh

OH

75–88% 100%

R*OH

+(n-Bu)3P–TMAD60 oC, 12 h

Ref. 9

Scheme 6. Synthesis of (–)-Myrtanol-Based, Chiral Imidazolium Tosylate Salt.

TsOHO tosylation MeN N

neat, 100 oC

MeN N

TsO–

1110

+

63%

24 h

Ref. 14

Scheme 7. Synthesis of CIILs from (3R)-Citronellol.

Br2, PPh3

CH2Cl2

R'N N

40 oC, 5 d

N NR' R

Br–

N NR' R

BF4–

NaBF4

acetone

R' = Me, n-Bu, n-C6H13 n-C12H25, n-C14H29 n-C18H37

R' = Me, n-C12H2546–94%

HN N1. (n-Bu)4NOH

N N RR

++

+

R =

ROH RBr

2. RBr (2 equiv) rt, 3 d

58%Br–

rt

110

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ions neutralization step and bromination with PBr3. N-alkylation

of12withmethylimidazoleinrefluxingacetonitrilefollowedby neutralization with NaOH gave bromides 13a–e. Anionexchange with AgBF4 or KPF6 in MeCN–H2O at roomtemperatureafforded14a–eor15a–ein66–71%overallyields.Ionicliquidbromides13a–ehavehighermeltingpoints(Tm’s)orglass-transitiontemperatures(Tg’s) thanthecorrespondingtetraf luoroborates,14a–e.Allexhibit thermalstabilityup to210°C(Table 1)andaremoremiscibleinpolarsolventsandlessmiscibleinnonpolarsolventsthantherelatedunfunctionalizedimidazolium-typeionicliquids.

Aminoacidderivatives in theformofaminoalcoholsarealsogoodstartingmaterialsforthesynthesisofCIILs.Recently,ourgroupdesignedandsynthesizedanewfamilyofCIILsfromchiralaminoalcohols(Scheme 10).16ThiswasthefirsttimethatCIILshavebeensynthesizedbyintroducingchiralscaffoldsattheC-2positionof the imidazoliumcationof ILs.Owing tothe relativeacidityof thehydrogen in theC-2position,17 theintroductionofsubstituentsat thispositionshouldresult inamoreinertcategoryofchiralionicliquidsforreactionscarriedoutunderbasicconditions.

The synthesis involved the condensation of 1-methyl-2-imidazolecarboxaldehydeandchiralaminoalcohols[(S)-(+)-2-amino-3-methyl-1-butanol,(S)-leucinol,(R)-leucinol,(S)-tert-leucinol,or(S)-3-phenyl-2-aminopropanol]inMeOHtogivethecorrespondingSchiffbaseprecursors,whichwerereducedinsituwithNaBH4togivethedesiredchiralimidazolederivatives16a–e in 72–92% yields. N-Alkylation was carried out byheatingimidazoles16a–ewithoneequivalentofbromobutaneintolueneat85–90oCfor24htoformimidazoliumbromides17a–e.Anionexchangeofthesesaltswithvariousanions[BF4

–,PF6

–,(CF3SO2)2N–]affordedaseriesofCIILs,18,ingoodyieldsascolorlessoilsatroomtemperature.Thesenewionicliquidsavoid theshortcomingsof their traditionalC-2-unsubstitutedcounterparts, which can participate in deprotonation sidereactionsattheirC-2position.18

More recently,OuandHuang19developedapracticalandefficient method for synthesizing CIILs from chiral aminoalcoholsintwoorthreesteps.Chiralimidazoliumchlorides,19,wereobtainedingoodyieldsbyreacting1-(2,4-dinitrophenyl)-3-methylimidazolium chloride with chiral primary aminoalcohols in n-butanol under ref lux for 18–22 h. Anionexchangeofchlorides19with f luoroboricacidorpotassiumhexafluorophosphateaffordedanewcategoryofCIILs,20and21,in67–81%overallyields(Scheme 11).

2.2.3. CIILs from Proline and HistidineThe amino acid proline is a very versatile starting materialforthesynthesisofchiral ionicliquids; it isreadilyavailable,inexpensive, and chiral. Recently, Luo et al. designed andsynthesized a series of pyrrolidine-containing CIILs froml-proline (Scheme 12).20Reductionof l-prolinewithLiAlH4followedbyreactionwithBoc2OgeneratedthecorrespondingN-Boc-protected (S )-prolinol. Tosylat ion followed bynucleophilic substitution with imidazolate anion gave thedesiredchiral imidazolederivative,22.Butylationof22 andremoval of Boc gave the pyrrolidine-based imidazoliumbromidesalt24a in45%overallyield froml-proline.Anionexchange of 24a with NaBF4 or KPF6 afforded CIILs 24band24c, respectively.Usingasimilarprocedure, theauthorssynthesizedvariousotherCIILs,25a–c, thatcontainamethylgroupatC-2oftheimidazoliummoiety,and26a,b,thatvaryinthetypeofsubstitutionatpositions1and2oftheimidazolium

HO2C

R NH2NH3, (CHO)2 N NR

NaO2C

N NR

EtO2C

LiAlH4Et2Ort, 4 h

N NRN N+R

HOHO Br–

R = Me, i-Pr, i-Bu80–82%

EtBr

EtOH

HCl, refluxH2CO, NaOHH2O, 50 oC

4.5 h65–70%(2 steps)

57–60%

CH3CCl3reflux, 5 h

Ref. 11

Scheme 8. CIILs from Naturally Occurring Amino Acids.

CO2HR1

NHR2

N NMe

NaBH4, I2R1

NHR2

OHR1

NHR2

Br1. HBr, H2O

2. PBr3 reflux 10 min

•HBr

1. CH3CN, 80 oC, 8 h2. NaOH

N+ NMeR1

NHR2

Br–

AgBF4 orKPF6

N+ NMeR1

NHR2

X–

R1 = Me, i-Pr, i-Bu, 2-Bu; R2 = HR1,R2 = (CH2)3

14a–e, X = BF4 15a–e, X = PF6

12a–e≥86%

13a–e≥92%

THFreflux20 h ≥88%

MeCN–H2Ort, 2–20 h

≥95%

Ref. 15

Scheme 9. Chiral-Amine-Functionalized CIILs from Natural Amino Acids.

Table 1. Properties of CIILs 13a–e, 14a–e, and 15a–e.

No. R1 R2 X Tm, °C Tg, °C Tdec, °C

13a Me H Br 131 --- 226

13b i-Pr H Br 145 --- 270

13c i-Bu H Br 134 --- 267

13d 2-Bu H Br 135 --- 268

13e –(CH2)3– Br 141 --- 257

14a Me H BF4 --- –46 261

14b i-Pr H BF4 --- –49 281

14c i-Bu H BF4 --- –47 291

14d 2-Bu H BF4 --- –35 285

14e –(CH2)3– BF4 --- –45 291

15a Me H PF6 6 --- 218

15b i-Pr H PF6 --- 38 287

15c i-Bu H PF6 69 --- 287

15d 2-Bu H PF6 73 --- 281

15e –(CH2)3– PF6 --- 67 274

MeN N+

HN

ROH

n-Bu

X–

*

2. KPF6 or (CF3SO2)2NLi H2O, rt, 1 h

MeN N

H O

+ ROH

NH2MeN N

HN

ROH

MeN N+

HN

ROH

n-Bu

Br–

*

*

*

70 oC, 24 h2. NaBH4

rt

16a–e72–92%

17a–e75–90%

18, 86–100%R = i-Pr, i-Bu, t-Bu, BnX = BF4, PF6, NTf2

n-BuBr, PhMe85–90 oC, 24 h

1. KBF4, MeOH–H2O, rt, 3 d

1. MeOH 4 Å MS

Ref. 16

Scheme 10. Synthesis of CIILs Lacking an Acidic Hydrogen at C-2 of the Imidazolium Ring.

a The melting point (Tm) and glass-transition temperature (Tg) were determined by DSC. b Tdec

was determined by TG.

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MeN N+

O2N

NO2Cl–R

OHNH2

MeN N+

RCl–OH+

HBF4, H2O, rt, 48 hor KPF6, Me2CO, rt, 48 h

MeN N+

RBF4–

OHMeN N+

RPF6–

OH or

19a–c

20a–c21a–c

a, R = Me; b, R = i-Pr; c, R = i-Pent

n-BuOH

reflux18–22 h

67–81%(overall)

Ref. 19

fragment.CIILs24–26areviscousliquidsatroomtemperatureandsoluble inmoderatelypolarsolventssuchaschloroform,dichloromethane, and methanol; but insoluble in less polarsolventssuchasdiethylether,ethylacetate,andhexane.

MiaoandChandescribed thesynthesisofother typesofCIILfromproline(Scheme 13).21Couplingof ionic liquid27withcommerciallyavailableBoc-Pro-OHin thepresenceofDCC–DMAPaffordedtheionic-liquid-supportedBoc-proline28which,upondeprotectionwithtrif luoroacetaticacid,gaveTFAsalt29.ThesynthesisofCIIL32,whichretainsthefreecarboxylic acid group, utilized a variation of this method.After coupling the ionic liquid carboxylic acid 30 with thereadily available N-Cbz-(2S,4R)-4-hydroxyproline benzylester, the resultingsupportedproline31wasdeprotectedbyhydrogenationtoaffordthe ionic-liquid-supportedproline32inverygoodyieldandhighpurity.

More recently, our group designed and synthesized anew pyrrolidine-based CIIL, 35, from l-proline (Scheme 14).22Thereactionof3-chloropropanesulfonylchloridewith(S)-2-aminomethyl-1-Boc-pyrrolidine, readilyobtainedfroml-proline, provided sulfonamide 33. Conversion of 33 intoimidazoliumiodide34wasaccomplishedin86%yield(2steps)firstbyiodinationwithNaIandthenalkylationoftheresulting3-iodopropanesulfonamidewith1-methylimidazoleinCH3CN.CIIL35wasobtainedin88%yield(2steps)bycleavageoftheBocgroup,followedbyanionexchangewithTf2N–.

Histidine is a unique amino acid for the synthesis ofimidazolium-containing ionic liquids since it is chiral andincorporates an imidazole fragment in its structure. Erkerand co-workers were first to exploit histidine as a startingmaterialforCIILs(Scheme 15).23l-HistidinewasO-protectedbymethylesterformationandthenN-protectedwithbenzoylorBoc togive theCIILprecursors36a and36b.Treatmentof36awithn-propylbromideor isopropyl iodideunderbasicconditionsinCH3CNatrefluxforseveraldaysgaveCIILs37aand 37b, respectively. CIILs 37c,d were obtained similarlyfrom histidine derivative 36b. CIILs 37 exhibit high watersolubilityandhavemeltingpointsintherange39–55oC.

Ayearlater,Guillenetal.employedhistidineasthestartingmaterial in the synthesis of a new series of imidazolium-containingchiral ionicliquids, inwhichthebifunctionalunitofhistidineremainedunchanged(Scheme 16).24Protectionofhistidinemethylesterviaacyclicureastructure,followedbyalkylationwithiodomethaneandopeningofthecyclicureabyt-BuOHinthepresenceof(i-Pr)2NEt,gavehistidinederivative38. Alkylation of 38 with bromobutane followed by anionexchangeaffordedCIILs39a–cin65–90%yields.CIILs39a–c,possessinganesterandaprotectedaminefunctionalgroups,wereconvenientlytransformedintovariousotherchiral ionicliquidsbyknownreactions(Scheme 17).24

2.2.4. CIILs from Lactate and TartrateIn2004, JodryandMikami reported the synthesisofanewcategoryofhydrophobicCIILs fromcommerciallyavailableand inexpensive (S)-ethyl lactate (Scheme 18).25 (S)-Ethyllactatewasconverted into the trif latederivative,whichwasN-alkylated to give the corresponding imidazolium trif latesalt.Exchangeof the trif lateanionwith theanionsofHPF6,LiNTf2,LiN(SO2C2F5)5,andLiN(SO2C4F9)TfprovidedaseriesofhydrophobicCIILsthatareliquidatroomtemperature.

TheresearchgroupsofBao26andKubisa27havealsoutilizedlactateasastartingmaterialforthepreparationofCIILs40a–cin5–6stepsand54–60%overallyields(Figure 2).Ethyltartrate

Scheme 11. Synthesis of CIILs from Chiral Amino Alcohols.

N N

NH

CO2H NOH

Boc

1. LiAlH4, THF, 75%

2. Boc2O, NaOH NOTs

Boc

NBoc

n-BuBrN N+

NBoc

n-BuBr–

1. HCl, EtOH2. NaHCO3 NaBF4

or KPF6rt

25a, X = Br25b, X = BF425c, X = PF6

26a, R = H26b, R = Me

22, 83%23, 93%

L-proline

s TsCl

Pyr

Na+Im–

MeCN

N N+

NH

n-BuBr–

24a, 90%(47% overall from L-proline)

N N+

NH

n-BuX–

24b, X = BF424c, X = PF6

N N+

NH

n-BuX–

Me

N N+

NH

(CH2)2OHBr–

R

PhMe70 oC

90%(2 steps)

Ref. 20

Scheme 12. Synthesis of Functionalized CIILs from l-Proline.

BF4–

BF4–

N CO2HMeN N+

BF4–

OH

Boc

+ MeN N+O

O

NBoc

TFA, DCMMeN N+

O

O

H2N+

TFA–

28, 89%

29, 98%

MeN N+O

O

N CO2Bn

CbzMeN N+

O

O

NH

CO2H

H2, Pd/C

31, 80%

32, 99%

27

BF4–

BF4–

DCC, DMAP

N CO2BnMeN N+

BF4–

OH

Cbz

+

30

OHO

MeCN–DCMrt, 18 h

rt, 0.5 h

DCC, DMAP

MeCN–DCMrt, 18 h

MeOHrt, 5 h

Ref. 21

Scheme 13. Preparation of Ionic-Liquid-Supported l-Proline.

NBoc

NH2

I–Tf2N–

Et3N, CH2Cl2

33, 72%

34, 86%(2 steps)

35, 88%(2 steps)

1. NaI, acetone2. ImMe, MeCN

1. CF3CO2H CH2Cl2

NBoc

CO2H NBoc

HN S

O

OCl

NBoc

HN S

O

ON

NMe

+

ClS ClO

O

2. LiNTf2, H2ONH

HN S

O

ON

NMe

+

Ref. 22

Scheme 14. Synthesis of Pyrrolidine-Based CIILs from l-Proline.

112

VO

L. 4

0, N

O. 4

• 2

007

Chi

ral I

mid

azol

ium

Ioni

c Li

quid

s: T

heir

Synt

hesi

s an

d In

fluen

ce o

n th

e O

utco

me

of O

rgan

ic R

eact

ions

NH

NHO

O

NH2 NH

NMeO

O

RNH

36a, R = Bz36b, R = Boc

N

N+MeO

O

RNH

R'

R'

X–

L-histidine

s

R'X, NaHCO3

MeCN, reflux65 oC, 2.5–8 d

37

abcd

R

BzBzBocBoc

R'

n-Pri-Prn-Pri-Pr

X

BrI

BrI

Yield

72%95%92%69%

Scheme 15. Erker’s Synthesis of CIILs from Histidine.

Ref. 23

hasbeenemployedasachiralstartingmaterialfordicationicCIILs (Scheme 19).25Thebis(imidazoliumbromide)saltwaspreparedinfivestepsfromchiraltartratein51%overallyield.AnionexchangewithNaBF4andNH4PF6gavethecorrespondingbis(imidazolium tetraf luoroborate) and hexaf luorophosphateionicliquidsassolidsatroomtemperaturewithmeltingpointsinthe41–90oCrange.Tosyltartratehasalsoservedasastartingmaterialforthesynthesisofadicationicimidazoliumtosylatesalt(eq 4).9

2.2.5. CIILs with Fused and Spiro RingsThe introduction of a rigid skeleton into ionic liquids wasenvisaged as a method of creating a class of efficient, task-specificsolventscapableofinducingasymmetry.Veryrecently,ourgroupdescribedthesynthesisofanovelsetofchiral,fused-ring RTILs, in which the chiral moiety is bonded to one oftheimidazolenitrogensand,mostimportantly, inwhichthe2positionissubstituted.28Treatmentofimidazolederivatives1616with p-toluenesulfonylchloridegavethecorrespondingdoubletosylates,43,whichunderwentringclosureat90oCintoluenetoformfused-ring,chiraltosylatesalts44(Scheme 20).Anionexchangeof44 led to thecorrespondingPF6andNTf2CIILs45–47 in63–68%overallyields.Atroomtemperature,CIILs45a, 46a,and47a(containingthePF6anion)aresolids,whereastheNTf2anion-containingones(45b,46b,and47b)areviscousliquids.

Sasai and co-workers synthesized another type of novel,chiralionicliquidthatcontainsaspiroskeleton(Scheme 21).29The alkylation of diethyl malonate with 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride or 2-(chloromethyl)-1-isopropyl-1H-imidazolehydrochloride, followedby reductionwithLiAlH4, produceddiols48 in highyields.Treatmentofdiols48withPBr3produceddibromides49,whichunderwentintramolecular N-alkylation smoothly in ref luxing tolueneto yield spiro imidazolium salts 50. Anion exchange of thebromidecounterionswithAgBF4,AgOTf,LiNTf2,orbis(hept-afluoropropanesulfonyl)imidegaveaseriesofspiroCIILs,51.Unfortunately,themeltingpointsofCIILs50a,band51a,bareintheneighborhoodof166oC,whilethosewiththeNTf2anion(51c,d)exhibitlowermeltingpoints(68–112oC).Byincreasingthe lengthof the f luoroalkylchainof thecounteranion,as in51e,CIILs thatare liquidsat roomtemperature(Tg=–10oC)wereobtained.ToobtainCIILswithevenlowermeltingpoints,Sasai’sgrouppreparedunsymmetricalspiroCIILs52a–dusinga similar synthetic protocol (Figure 3). CIIL 52d, with anN-propyl-N’-isopropylsubstituentandTf2N–,isaliquidatroomtemperaturewithaTgof–20oC.

2.2.6. CIILs with a Urea UnitUrea derivatives serve as efficient Lewis acid catalysts inorganic reactions due to the effective hydrogen bonds thatare formed by their amide hydrogens. Urea compounds thatcontainelectron-withdrawingsubstituentsreadilyformstableco-crystals with a variety of proton acceptors, includingcarbonylcompounds.30Recently,ourgroupsynthesizedCIILsinwhichtheureafunctionalgroupispartofthechiralmoietythatisbondedtotheimidazoliumring(Scheme 22).31Reactionof 1-(3-aminopropyl)imidazole with commercially availableisocyanate-substitutedaminoacidestersinCH2Cl2,followedbyalkylationwithoneequivalentofneatiodomethaneat40oCfor24h,gaveimidazoliumiodides53a–cinexcellentyields.AnionexchangewithBF4

–,PF6–,and(CF3SO2)2N–producedCIILs54–

56,allofwhichareviscousliquidsatroomtemperature.

NNH

CO2Me

NH22. MeI, 40 oC, 16 h

CO2Me

NHNMeN

O

I–

DIEA, t-BuOH80 oC, 3 h

CO2Me

NMeN

1. n-BuBr, neat

2. LiNTf2, KPF6 or NaBF4

CO2Me

NHBocN+MeN

n-Bu

38, 69%39a, X = Tf2N; 90%39b, X = PF6; 83%39c, X = BF4; 65%

X–

1. Im2CO, 80 oC, 0.5 h

80% (2 steps)

+

NHBoc

Scheme 16. Synthesis of O- and N-Protected Histidinium Salts.

Ref. 24

Tf2N–

CO2Me

HNN+MeN

n-BuO

NHBoc

CO2H

NH2•HClN+MeN

n-Bu

NHBocN+MeN

n-Bu

NH

O

CO2t-Bu

HCl, H2O

Tf2N–

Tf2N–

39a

1. LiOH, H2O

2. H-Ala-Ot-Bu HATU, DIEA THF

1. MeOH, HCl

2. Boc-Ala-OH HATU, DIEA THF

83% (2 steps)

60% (2 steps)

>99%

Scheme 17. Transformation of O- and N-Protected Histidinium Salts into Other CHILs.

Ref. 24

MeN N+

OH

O

OEt

1. Tf2O, 2,6-lutidine CH2Cl2, 0 oC

2. ImMe, Et2O –78 oC, 0.5 h

O

OEt

anionexchange

X = PF6, NTf2, N(SO2C2F5)2 N(SO2C4F9)Tf

TfO–

92% (2 steps)

MeN N+

O

OEt

X–

Scheme 18. Preparation of Hydrophobic CIILs from (S)-Lactate.

Ref. 25

X–

40a, X = Br40b, X = BF440c, X = PF6

N+MeNOBz

Figure 2. CIILs from Lactate.

Ref. 26

113

Alla

n D

. Hea

dley

* an

d Bu

kuo

Ni

VO

L. 4

0, N

O. 4

• 2

007

NN

NMe

MeN

CO2EtEtO2C

OH

OH

or NaBF4Me2CO

90%

41, 51%(5 steps)

2 Br–

++

BzO

OBz

5 steps

NN

NMe

MeN

42a, X = BF442b, X = PF6

2 X–

++

BzO

OBz

NH4PF6H2O92%

Scheme 19. Synthesis of Bis(CIILs) from Tartrate.

Ref. 26

2.2.7. Other Types of CIILIn 2002, Saigo’s group described the f irst example of aplanar-chiral ionic liquid (Scheme 23).32 The cyclophane-type imidazolium saltswereobtained in about 40%overallyieldsbymonoalkylationofsubstitutedimidazoleswith1,10-dibromodecaneunderbasicconditions,followedbycyclizationof the resulting 1-(10-bromodecyl)imidazoles in ref luxingacetonitrile for8–10days.The introductionofa substituentat C-4 of the imidazolium ring not only induced planarchirality,butalsodramaticallyloweredthemeltingpoint.ThesubstituentatC-2suppressedtheracemizationoftheseplanar-chiralcyclophanes.

Using a similar synthetic methodology, planar-chiralimidazolium chlorides with a tris(oxoethylene) bridge wereobtained ingoodyields(81–82%)withoutanysidereactions(Figure 4).33 The high selectivity for the formation of the“crowned” imidazolium salts is most likely due to theconformationalpreferenceof the tri(oxoethylene)chain.Thevicinal oxygens have a strong tendency to adopt a gaucheconformation and, as a result, the tri(oxoethylene) chain isexpected to form a curved structure that is suitable for theintramolecularcyclization.

In 2004, Geldbach and Dyson introduced a class ofhighly active ruthenium catalysts, in which chiral 1,2-diamine or 1,2-amino alcohol ligands are coordinated toruthenium (Scheme 24).34 These new ruthenium complexesalsocontainedη6-arenessubstitutedwith2-(imidazolyl)ethylgroups.Quaternizationof1,2-dimethylimidazolewithchloro-ethylcyclohexadiene and subsequent anion exchange withNaBF4yieldthefunctionalizedimidazoliumionicliquid57asasolidwithameltingpointof85oC.ReductionofRuCl3withthreeequivalentsof57 inmethanolunder ref luxconditionsleadstothedinuclearcomplex58,whichis insolubleinmostcommonorganicsolvents,but ishighlysoluble inwaterandionic liquids. Addition of (1R,2R)-N-tosyl-1,2-diphenyl-1,2-ethylenediamine or (1S,2R)-2-amino-1,2-diphenylethanol to58inDMFaffordscationiccomplexes59and60,respectively,inexcellentyields.

3. Applications of CIILs in Asymmetric Reactions3.1. As SolventsSeebach and Oei first introduced the idea of using chiralsolvents to inf luence the outcome of asymmetric reactionsbackin1975.35Sincethattime,therehavebeenmanyattemptsto use chiral solvents to affect the outcome of asymmetricreactions,buttheobservedenantioselectivitieshavebeenfairlylow.Thishasledtotheconclusionthatasymmetricinductioneffectedbychiralsolvents is typically low.Even though theenantioselectivityobservedfor theelectrochemicalreductionofketones inchiral aminoetherswas low, itopenedup thefield todevelopchiral solvents to inf luence theoutcomeofasymmetricreactions.Althoughalargenumberofchiralionicliquidshavebeensynthesized,onlyalimitednumberhavebeensuccessfulinaffectingtheoutcomeofasymmetricreactions.

In 2005, Armstrong and co-workers reported the use ofCIILsaschiralsolventsforthephotorearrangementofdiben-zobicyclo[2.2.2]octatrienes.10 This was the first report onchiral induction by CIILs for an irreversible, unimolecularphotochemicalisomerization,withenantioselectivitiesrangingfrom3.3%to6.8%ee(eq 5).Theenantioselectivityincreasedto11.6%eewhenchiralammoniumionicliquidswereusedassolvents.Theauthorsdidnotobserveanyenantioselectivitywhen the corresponding methyl or isopropyl diesters were

O O 70 oC, 20 h O O

TsO OTs N NMeN NMe

2 TsO–ImMe, neat

+ +

61%

Ref. 9 eq 4

NMeN

HN

ROH

NMeN

TsN

ROTs

NMeN

NTs

R

TsO–

TsCl, Pyridine

CH2Cl2, rt

90 oC

43* *

*

NMeN

NTs

R

X–

KPF6 or LiNTf2

MeOH–H2Oor H2O, rt

16 44

PhMe

R

MeMei-Bui-BuBnBn

X

PF6Tf2NPF6Tf2NPF6Tf2N

No.

45a45b46a46b47a47b

Config.

RRRRSS

Yielda

68%67%66%63%67%65%

a Overall yield from 16.

Scheme 20. Synthesis of Fused-Ring CIILs.

Ref. 28

N

N

Cl

R = Me, i-Pr

THF, NaH, NaI rt, 36 h

N

N

N

N

EtO2C CO2Et

LiAlH4, THF

0 oC–rt, 1.5 h N

N

N

N

HO OH

1. PBr3, PhMe reflux, 48 h

2. NaHCO3(aq)N

N

N

N

Br Brreflux, 36 hN

N

N

N

50a, R = Me; 50b, R = i-Pr 54–62% (2 steps)

48, 90–92%

49

80–89%

or LiN[CF3(CF2)nSO2]2H2O, rt, 16 h

N

N

N

N

2 Br–

2 X–

H2C(CO2Et)2•HCl

R

PhMe

++

++

R R R R

R RR R

R RAgX, MeOH

rt, 16 h51

abcde

R

MeMeMei-Pri-Pr

X

BF4TfOTf2NTf2N

(n-C3F7SO2)2N

Yield

90%95%95%95%85%

Ref. 29

Scheme 21. Synthesis of Symmetric, Spiro Bis(imidazolium) Salts.

N

N

NN N

N

2 X2 X–++

R1 R2

No.

52a52b52c52d

R1

Men-PrMen-Pr

R2

Eti-PrEt

i-Pr

X

BrBr

Tf2NTf2N

Tm

>300 oC 119 oC 116 oC

–20 oCa

a Value for Tg.

Figure 3. Physical Properties of Unsymmetrical Spiro Bis(imidazolium) Salts.

Ref. 29

114

VO

L. 4

0, N

O. 4

• 2

007

Chi

ral I

mid

azol

ium

Ioni

c Li

quid

s: T

heir

Synt

hesi

s an

d In

fluen

ce o

n th

e O

utco

me

of O

rgan

ic R

eact

ions employed, but noted increased enantioselectivities when the

diacidwasutilizedinthepresenceofNaOH.ItisbelievedthatNaOHallowsion-pairformationbydeprotonatingthediacid;however,morecomplexinteractionswiththechiraldiscriminatormaybeatplay.

Baoandco-workershaveutilizedCIILs40a–cand42baschiralco-solventsintheasymmetricMichaeladditionofdiethylmalonateto1,3-diphenyl-2-propenone(eq 6).26Exceptinthecaseof42b,betterresultswereobtainedintoluenethaninDMSOorDMF.Comparablechemicalyieldsandenantioselectivitieswereobtainedwith40a–c,whichdifferonly in their anions,withCIILbromide40agivingthebestyieldandeeofthethree.

More recently, Ou and Huang also reported on the sameasymmetricMichaeladditionusingCIILs19–21andacetonitrileas co-solvent (eq 7).19 They found that most of these CIILsexhibitedsomechiraldiscrimination,withCIIL20cgivingrisetothebestee(15%).

In 2003, Kiss et al. reported the palladium-catalyzedHeck oxyarylation of 7-benzyloxy-2H-chromene with2-iodophenol usingCIILboth as a chiral solvent and ligand(eq 8).36 The transformation gave low yields (13–28%) andpoorenantioselectivities(4–5%)withPd(OAc)2andPdCl2.Noasymmetric inductionwasobservedwhenPh3Pwasaddedasauxiliaryligand.

3.2. As OrganocatalystsMetal-free catalysis of asymmetric reactions by simpleorganocatalystshasbecomean importantareaof research inrecentyears.37Amongtoday’sorganocatalysts,prolineanditsderivatives are particularly interesting.Pyrrolidine catalystshavebeenused successfully for thedirect asymmetric aldolandMichaeladditionreactions,37whichareregardedastwoofthemostpowerful carbon–carbon-bond-forming reactions inorganicsynthesis.37For these reactions, theorganocatalyst isusuallyusedinsubstantialquantity,andtheefficientrecoveryandreuseoftheorganocatalystareamajorconcern.Therefore,thereisaneedtodevelopneworganocatalysts,whichareeasilyrecyclable and possess enhanced catalytic abilities. In thisregard, ionic liquids thatcontain specific functionalitiesandare capableof actingasorganocatalystshave receivedmuchattentionrecently.Oneadvantageof ionic-liquid-basedchiralorganocatalysts is that theycanbe recoveredeasily fromthereaction mixtures simply by capitalizing on their solubilitycharacteristics.

Recently, Miao and Chan reported proline-based chiralimidazolium ionic liquid 29 as organocatalyst for the directasymmetricaldolreactionof4-cyanobenzaldehydewithacetone,butobtainedthealdolproduct,61a,inonly10%yieldand11%ee. CIIL 32 fared better as organocatalyst under the sameconditions,leadingto 61ain59%yieldand72%ee(eq 9).21Theresultsindicatethattheacidicprotonofprolineisessentialforefficientcatalysistooccur.Thus,thealdolreactionofabroadrangeofaldehydeacceptors, includingaromaticandaliphaticaldehydes,andtwoketonedonors,acetoneand2-butanone,wascarriedoutingoodyieldsandenantioselectivitiesinthepresenceoforganocatalyst32underthesameconditions.Furthermore,the authors carried out the reactions of 4-nitrobenzaldehydein deuterated acetone with CIIL 32 or proline as catalyst,respectively, and proved that CIIL 32 is a more efficientorganocatalyst than proline itself. The recyclability of CIIL32asorganocatalystwasalsoexamined(eq 10).CIIL32wasrecycled and reused at least four times in the same reactionwithoutsignificantlossinyieldandenantioselectivity.

+CO2MeR

N C OH

HN

CO2Me

O

R

53a–c95–99%

NN NH2

3NN

HN

3

HN

CO2Me

O

R

NMeN+HN

3I–

CH2Cl2

KPF6or LiNTf2

H2O, rt, 1 hHN

CO2Me

O

R

NMeN+HN

3X–

MeI, 40 oC24 h

No.

R

X

54a

i-Pr

BF4

54b

i-Pr

PF6

54c

i-Pr

Tf2N

55a

i-Bu

BF4

55b

i-Bu

PF6

55c

i-Bu

Tf2N

56a

Bn

BF4

56b

Bn

PF6

56c

Bn

Tf2N

54a–c, 55a–c, and 56a–c all have the S configuration.

54–5688–97%

rt, 24 h

95–98%

KBF4MeOH–H2O

rt, 2 d

Ref. 31

Scheme 22. Chiral, Ionic Liquids Containing a Urea Functionality.

N NH

R1

R2

1. NaHN N(CH2)10Br

R1

R2

N+N

R1

R2

X–

R1 = H, Me; R2 = H, MeX = Br, Tf2N, (C2F5SO2)2N, (1S)-(+)-10-camphorsulfonate

2. Br(CH2)10Br THF

MeCN

reflux, 8–10 d

~40%(overall yields)

Ref. 32

Scheme 23. Cyclophane-Type Chiral Imidazolium Salts.

N+NO

OO

R1

R2

Cl–R1 = R2 = HR1 = Me, R2 = HR1 = R2 = Me

Figure 4. Planar-Chiral Imidazolium Salts with a Tris(oxo-ethylene) Bridge.

Ref. 33

BF4–

+

Cl +N NMe

MeBF4–

57, 86%(2 steps)

+N NMe

Me

58, 95%

RuCl

ClRu

ClN

MeNMe

+N NMe

Me

RuClH2N

NHTs

PhPh

+N NMe

Me

RuClCl

NH2

Ph

PhHO

59, 94% 60, 97%

(1S,2R)-2-amino-1,2-diphenylethanolDMF, rt, 0.33 h

BF4–

BF4–

BF4–

80 oC, 10 h

(1R,2R)-N-tosyl-1,2-diphenyl-1,2-ethylenediamine DMF, rt, 0.5 h

RuCl3, MeOH(a), (b)

(a) 1,2-Me2Im, PhMe, 110 oC, 24 h(b) NaBF4, CH2Cl2, rt, 24 h

Cl

Ref. 34

Scheme 24. Synthesis of Ruthenium-Based CIIL Catalysts.

115

Alla

n D

. Hea

dley

* an

d Bu

kuo

Ni

VO

L. 4

0, N

O. 4

• 2

007

FunctionalizedCIILs24a–26bhavebeenemployedashighlyefficientasymmetricorganocatalystsfortheMichaeladditionofcyclohexanonetonitroalkenes(eq 11).20CIILs24a–cand26a,lackingasubstituentatC-2oftheimidazolering,weresuperiorto their 2’-methyl counterparts (25a–c and 26b) in terms ofyieldsandselectivities.Introductionofaproticgroup(OH)inthesidechain(see26a,b)didnotimprovethecatalyticactivityandselectivity,andCIILswithBr–andBF4

–weremuchmoreactiveandselectivethanthosewithPF6

–.Overall,catalysts24a–bperformedbest, leading tonear-quantitativeyields,excellentdiastereoselectivities(syn/anti=99:1),andenantioselectivities(97–99%ee’s).TheseCIILswereeasilyrecycledbyprecipitationwithdiethylether,andtheymaintainedtheirhighactivityalbeitwithaslightlydecreasedselectivity,asdemonstratedfor24boverfourreactioncycles.

Thescopeof theprecedingreactionwasinvestigatedwithrespecttotheketoneandthenitroalkene.Cyclohexanonereactedwithavarietyofnitroalkenes togenerateMichaeladducts innear-quantitativeyields(94–100%),highdiastereoselectivities(dr ≥ 97:3), and excellent enantioselectivities (95–99% ee).Substituting cyclopentanone or acetone for cyclohexanoneshowed only moderate selectivities, whereas the use of analdehyde instead of cyclohexanone led to good selectivities(eq 12).

Ourgroupalsohasdevelopedanew typeofpyrrolidine-basedCIIL,35,whichcatalyzestheMichaeladditionofvariousaldehydes to nitrostryenes in Et2O at 4 oC with moderateyields (≤64%),goodenantioselectivities (≤82%ee), andhighdiastereoselectivities (syn:anti ≤ 97:3) (eq 13).22 Moreover,catalyst35alsocatalyzestheMichaeladditionofcyclohexanoneto trans-β-nitrostyreneinacetonitrileatroomtemperature togivetheadduct inmoderateyieldandhighstereoselectivities(syn:anti=95:5,88%ee).Ourresultsalsodemonstratethatthepresenceofanacidichydrogenisnecessaryfortheselectivity;theacidicN–Hadjacent to theelectron-withdrawingsulfonylgroupplaysanimportantroleintheselectivityofthereaction.The newly designed ionic-liquid-tethered chiral pyrrolidinecatalyst,35,iseasilyrecycledwithoutlossofactivity.

3.3. As Organometallic CatalystsThetransfer-hydrogenationreaction,inwhicharutheniumcomplexisemployedascatalyst,hasattractedconsiderableinterest.38Dyson’sgrouphasattachedarutheniumcomplexwithchiralligandsontoanionicliquid,andexaminedtheresultingrutheniumionicliquids,59and60,ascatalystsfortheasymmetrictransferhydrogenationof acetophenone (eq 14).34 The reaction was carried out in2-propanolwith2equivalentsofKOHand60asorganometalliccatalystin1-butyl-2,3-dimethylimidazoliumhexafluorophosphate,[BDMIM][PF6],assolventtogivetheadductwith95%conversionand27%ee for the first run.Evenunder lessbasicconditions,catalyst60wasdeactivatedquickly,andreuseoftheionicliquidphasewasnotviable.However,catalyst59wasstableunderthereactionconditionsforatleast72h,andrecyclingoftheionic-liquidphasewasfeasible,butconversiondroppedfrom80%inthefirstcycleto21%inthefourthcycle.Whenaformicacid–triethylamineazeotrope was substituted for 2-propanol–KOH as the protonsource,catalyst59providedessentiallyquantitativeconversionandexcellentenantioselectivity(>99%).Theproductwasextractedfromthehomogeneousphasetogetherwith[BDMIM][PF6]usinghexaneandEt2O,andtheremainingsolutionwasrechargedwithketoneandformicacidandreused(eq 15).Furthermore,arangeofdifferentsubstratesincludingcyclicketonesandaldehydeshavebeenreducedusingthesame59–[BDMIM][PF6]combination.

Enantiomeric excess was determined from the optical rotation.

Ph Ph

O

+CO2Et

CO2Et

CIIL, co-solvent

K2CO3, rtPh Ph

OEtO2C CO2Et

*

CIIL

40a40b40b40b40c42b

Co-Solvent

PhMePhMeDMSODMFPhMePhMe

Time

10 h10 h 6 h 7 h10 h12 h

Yield

96%95%90%91%93%95%

ee

25%24%17%16%23%10%

Ref. 26 eq 6

Enantiomeric excess was determined from the optical rotation.

Ph Ph

O

+CO2Et

CO2Et

CIIL, MeCN

K2CO3, rtPh Ph

OEtO2C CO2Et

*

CIIL

19a19b19c20a20b20c21a21b21c

Time

5 d5 d5 d5 d4 d4 d3 d3 d5 d

Yield

63%76%81%66%80%86%52%78%76%

ee

5% 8%11%10% 7%15% 3% 0% 5%

Ref. 19 eq 7

OBnO I

HO

+[Pd], Ag2CO3

CIIL, 100 oC4–18 h

OBnO

O

MeN N+

PF6–

CIIL = Pd(OAc)2: 13%, 5% eePdCl2: 28%, 4% ee

Ref. 36eq 8

R1CHO +

O

MeR2 29 or 32

acetonert, 25 h

O

R2

R1

OH

R1

4-NCC6H4

4-NCC6H4

2-NpPh

4-AcNHC6H4

4-BrC6H4

2-ClC6H4

Cy4-O2NC6H4

4-O2NC6H4

a CIIL 32 was used in all cases, except table entry 1. b In all cases, R2 = H, except for 61h, in which R2 = Me.

61

aabcdefghi

Yield

10%59%50%50%40%58%92%43%51%64%

ee

11%72%80%76%64%73%71%85%71%85%

61

Ref. 21eq 9

60–95%3.3–6.8% ee

HO2C

CO2HHO2C CO2H

hν

5 or 8BnNMe2

Ref. 10 eq 5

116

VO

L. 4

0, N

O. 4

• 2

007

Chi

ral I

mid

azol

ium

Ioni

c Li

quid

s: T

heir

Synt

hesi

s an

d In

fluen

ce o

n th

e O

utco

me

of O

rgan

ic R

eact

ions

4. Conclusions and OutlookThefieldoftask-specificionicliquidsisonlyinitsinfancy,buthasaverypromisingfuture.Themainadvantageofthesetypesofionicliquidsisthattheyareeasilyrecoveredandrecycledwithoutlossofactivitywhenusedforasymmetricreactions.Owingtoareadilyavailablesourceofchiralcompounds—suchasnaturallyoccurringaminoacidsandothercompounds,whichcanserveasprecursorsinthesynthesisofchiralionicliquids—anewopportunitynowexistsforthesynthesisofaveryimportantclassoforganiccompounds.Thepastfewyearshaveseenatremendousgrowthinthenumberofchiralionicliquidssynthesized,buttheireffectontheoutcomeofasymmetricreactionshasbeenlimited,withmoststillgivinglowenantioselectivities.Therefore,aneedexistsforthedevelopmentofadditional,improved,andtask-specificchiralionicliquidsthatarebetterabletoinfluencetheoutcomeofasymmetricreactions.

5. AcknowledgmentsWegratefullyacknowledgefinancialsupportofthisresearchbytheRobertA.WelchFoundation(T-1460)andTexasA&MUniversity-Commerce.Weexpressourdeepgratitudetoourco-workerswhosenamesappearinthecitedreferences,andtoDr.GuigenLiforhisvaluablediscussions.

6. References(1) Walden,P.Bull. Acad. Imper. Sci.(St.Petersburg)1914,405.(2) (a)Wilkes,J.S.;Levisky,J.A.;Wilson,R.A.;Hussey,C.L.Inorg.

Chem.1982, 21,1263.(b)Diaw,M.;Chagnes,A.;Carre,B.;Willmann,P.;Lemordant,D.J. Power Sources2005,146,682.

(3) (a)Park,S.;Kazlauskas,R. J.J. Org. Chem.2001,66, 8395. (b)Chiappe,C.;Pieraccini,D.J. Phys. Org. Chem.2005,18,275.(c)Wilkes,J.S.Green Chem.2002,4,73.

R1CHO +

O

MeMe

32

rt, 25 h

O

MeR1

OH

61aR1 = 4-O2NC6H4

Cycle

1234

Yield

68%68%66%64%

ee

85%85%83%82%

Ref. 21

eq 10

O

+ PhNO2

cat. (15 mol %)

TFA (5 mol %)rt

ONO2

Ph

Cycle

111234111111

Cat.

24a24a24b24b24b24b24c25a25b25c26a26b

Time

10 h20 h 8 h 8 h24 h48 h12 h20 h16 h12 h18 h18 h

Yield

99% 99%100% 97% 99% 96% 86% 97%100% 40% 86% 25%

Syn/Anti

99:199:199:197:396:497:398:297:396:496:497:394:6

ee

98%97%99%94%91%93%87%97%94%82%89%70%

Ref. 20

eq 11

R

O

+ R3 NO224b (15 mol %)

TFA (5 mol %)rt

R

R1

ONO2

R3

R1

H

R2 R2

R

aaaaab

MeMeHH

R1

aaaaabHH

Mei-Pr

R2

HHHHHHHH

MeH

R3

4-ClC6H4

3-O2NC6H4

4-MeC6H4

4-MeOC6H4

2-NpPhPhd

PhPh

Time

10 h10 h12 h12 h10 h60 h12 h24 h96 h60 h

Yield

100% 94% 99% 99% 99% 87% 83% 92% 70%100%

Syn/Anti

99:0198:0299:0199:0199:0163:37

----85:15

----90:10

ee

99%96%95%95%97%79%c

43%76%e

86%72%

a R,R1 = (CH2)4. b R,R1 = (CH2)3. c 82% ee for the anti isomer. d 1-nitrocyclohexene used. e 80% ee for the anti isomer. f The yield is that of the isolated product; the syn/anti ratio was determined by 1H NMR, while ee was determined by HPLC.

Ref. 20

eq 12

H

O

+ ArNO2

35 (20 mol %)

Et2O, 4 oC, 6 d H

R1

ONO2

Ar

R1

H

R2 R2

R1

Men-Bun-Bun-Pri-Pri-Prn-Prn-Pra,b

R2

MeHHHHHHH

a,b

Ar

PhPh

p-Tolp-AnPh

p-TolPh

p-TolPh

Yield

58%64%60%29%53%64%49%38%38%

Syn/Anti

----97:0396:0492:0896:0497:0389:1196:0495:05

ee

82%68%67%67%66%73%64%68%88%

a R,R1 = (CH2)4. b In MeCN. The syn/anti and ee ratios are for the stereoisomer with opposite configurations at the two chiral centers.

Ref. 22

eq 13

Run

121234

Cat.

606059595959

Conv.a

95%15%80%66%57%21%

eeb

27

98

Leachingc

5% Ru

8% Ru

a Determined by GC. b Determined by GC using a Chromapack CP-Cyclodex B column. c Determined by ICP-OES.

Ph Me

Ocat., KOH (2 equiv)

i-PrOH, [BDMIM][PF6]35 oC, 24 h

Ph Me

OH

*

Ref. 34

eq 14

Run

1234

Meth. Aa

>99%68%19%01%

Meth. Bb

>99%>99%80%52%

a Product extracted with hexane, ionic liquid washed with H2O and dried in vacuo. b Product extracted with hexane and ionic liquid dried in vacuo.

Ph Me

O59, HCO2H

Et3N, [BDMIM][PF6]40 oC, 24 h

Ph Me

OH

*

Recovered 59

Ref. 34

eq 15

117

Alla

n D

. Hea

dley

* an

d Bu

kuo

Ni

VO

L. 4

0, N

O. 4

• 2

007

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(5) (a)Wasserscheid,P.;Keim,W.Angew. Chem., Int. Ed.2000,39,3772.(b)Handy,S.T.Chem.—Eur. J.2003,9,2938.(c)Sheldon,R.Chem. Commun.2001,2399.(d)Meracz,I.;Oh,T.Tetrahedron Lett.2003,44,6465.(e)Handy,S.T.;Okello,M.Tetrahedron Lett.2003,44,8399.(f)Dzyuba,S.V.;Bartsch,R.A.Tetrahedron Lett.2002,43,4657.(g)Xiao,J.-C.;Shreeve,J.M.J. Org. Chem.2005,70,3072.(h)Xu,X.;SaibabuKotti,S.R.S.;Liu,J.;Cannon,J.F.;Headley,A.D.;Li,G.Org. Lett.2004,6,4881.(i)SaibabuKotti,S.R.S.;Xu,X.;Wang,Y.;Headley,A.D.;Li,G.Tetrahedron Lett.2004,45,7209.(j)Kabalka,G.W.;Venkataiah,B.;Dong,G.Tetrahedron Lett.2003,44,4673.(k)Laali,K.K.;Gettwert,V.J.J. Org. Chem.2001,66,35.(l)Davis,J.H.,Jr.;Forrester,K.J.;Merrigan,T.Tetrahedron Lett.1998,39,8955.

(6) Earle,M.J.;McCormac,P.B.;Seddon,K.R.Green Chem.1999,1,23.

(7) Fukumoto,K.;Yoshizawa,M.;Ohno,H.J. Am. Chem. Soc.2005,127,2398.

(8) Fukumoto,K.;Ohno,H.Chem. Commun.2006,3081.(9) Machado,M.Y.;Dorta,R.Synthesis2005,2473.(10) Ding,J.;Desikan,V.;Han,X.;Xiao,T.L.;Ding,R.;Jenks,W.S.;

Armstrong,D.W.Org. Lett.2005,7,335.(11) Bao,W.;Wang,Z.;Li,Y.J. Org. Chem.2003,68,591.(12) Génisson, Y.; Lauth-de Viguerie, N.; André, C.; Baltas, M.;

Gorrichon,L.Tetrahedron: Asymmetry2005, 16,1017.(13) Kim,E.J.;Ko,S.Y.;Dziadulewicz,E.K.Tetrahedron Lett.2005,

46,631.(14) Tosoni, M.; Laschat, S.; Baro, A. Helv. Chim. Acta. 2004, 87,

2742.(15) Luo,S.-P.;Xu,D.-Q.;Yue,H.-D.;Wang,L.-P.;Yang,W.-L.;Xu,

Z.-Y.Tetrahedron: Asymmetry2006, 17,2028.(16) Ni,B.;Headley,A.D.;Li,G.J. Org. Chem.2005,70,10600.(17) (a)Headley,A.D.;SaibabuKotti,S.R.S.;Ni,B.Heterocycles

2007,71,589.(b)Headley,A.D.;SaibabuKotti,S.R.S.;Nam,J.;Li,K.J. Phys. Org. Chem.2005,18,1018.(c)Headley,A.D.;Jackson,N.M.J. Phys. Org. Chem.2002,15,52.

(18) (a)Handy,S.T.;Okello,M.J. Org. Chem. 2005,70, 1915. (b)Aggarwal,V.K.;Emme, I.;Mereu,A.Chem. Commun.2002,1612.

(19) Ou,W.-H.;Huang,Z.-Z.Green Chem.2006,8,731.(20) Luo,S.;Mi,X.;Zhang,L.;Liu,S.;Xu,H.;Cheng,J.-P.Angew.

Chem., Int. Ed.2006,45,3093.(21) Miao,W.;Chan,T.H.Adv. Synth. Catal.2006,348,1711.(22) Ni,B.;Zhang,Q.;Headley,A.D.Green Chem. 2007, 9, 737.(23) Hannig,F.;Kehr,G.;Fröhlich,R.;Erker,G.J. Organomet. Chem.

2005,690,5959.(24) Guillen, F.; Brégeon, D.; Plaquevent, J.-C. Tetrahedron Lett.

2006,47,1245.(25) Jodry,J.J.;Mikami,K.Tetrahedron Lett.2004,45,4429.(26) Wang,Z.;Wang,Q.;Zhang,Y.;Bao,W.Tetrahedron Lett.2005,

46,4657.(27) Biedron,T.;Kubisa,P.J. Polym. Sci., Part A: Polym. Chem.2005,

43,3454.(28) Ni, B.; Garre, S.; Headley, A. D. Tetrahedron Lett. 2007, 48,

1999.

(29) Patil,M.L.;Rao,C.V.L.;Yonezawa,K.;Takizawa,S.;Onitsuka,K.;Sasai,H.Org. Lett.2006,8,227.

(30) (a)Maher,D.J.;Connon,S.J.Tetrahedron Lett.2004,45,1301.(b)Berkessel,A.;Cleemann,F.;Mukherjee,S.;Müller,T.H.;Lex,J.Angew. Chem., Int. Ed.2005,44,807.(c)Sigman,M.S.;Jacobsen,E.N.J. Am. Chem. Soc.1998,120,4901.(d)Sigman,M.S.;Vachal,P.;Jacobsen,E.N.Angew. Chem., Int. Ed.2000,39,1279.(e)Yoon,T.P.;Jacobsen,E.N.Angew. Chem., Int. Ed.2005,44,466.

(31) Ni,B.;Headley,A.D.Tetrahedron Lett.2006,47,7331.(32) Ishida, Y.; Miyauchi, H.; Saigo, K. Chem. Commun. 2002,

2240.(33) Ishida,Y.;Sasaki,D.;Miyauchi,H.;Saigo,K.Tetrahedron Lett.

2004,45,9455.(34) Geldbach,T.J.;Dyson,P.J.J. Am. Chem. Soc.2004,126,8114.(35) Seebach,D.;Oei,H.A.Angew. Chem., Int. Ed. Engl.1975,14,

634.(36) Kiss,L.;Kurtán,T.;Antus,S.;Brunner,H.Arkivoc2003,5,69.(37) For reviews, see: (a) Jarvo, E. R.; Miller, S. J. Tetrahedron

2002,58,2481.(b)List,B.Tetrahedron2002,58,5573.(c)List,B.Acc. Chem. Res.2004,37,548. (d)Dalko,P. I.;Moisan,L.Angew. Chem., Int. Ed.2004,43,5138.(e)Notz,W.;Tanaka,F.;Barbas,C.F., IIIAcc. Chem. Res.2004,37,580.(f)Lelais,G.;MacMillan,D.W.C.Aldrichimica Acta2006,39,79.

(38) (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (b)Rautenstrauch,V.;Hoang-Cong,X.;Churlaud,R.;Abdur-Rashid,K.;Morris,R.H.Chem.—Eur. J. 2003,9,4954. (c)Éll,A.H.;Johnson,J.B.;Bäckvall,J.-E.Chem. Commun.2003,1652.(d)Yi,C.S.;He,Z.;Guzei,I.A.Organometallics 2001,20,3641.(e)Hennig,M.;Püntener,K.;Scalone,M.Tetrahedron: Asymmetry 2000,11,1849.(f)Haack,K.-J.;Hashiguchi,S.;Fujii,A.;Ikariya,T.;Noyori,R.Angew. Chem., Int. Ed. Engl.1997,36,285.

About the AuthorsAllan D. Headley was born in Jamaica. He received hisBachelor’sdegreeinchemistryin1976fromColumbiaUnionCollege,Maryland,andhisPh.D.degreeinchemistryin1982fromHowardUniversity,Washington,DC,whereheworkedunderthesupervisionofProfessorMartinR.Feldman.HethenmovedtotheUniversityofCalifornia,Irvine,whereheworkedwithProfessorRobertW.Taftasapostdoctoralassociate. In1983,hejoinedthefacultyattheUniversityoftheWestIndies,Mona, Jamaica, as a lecturer. He then worked as a lecturerin chemistry at the University of California, Irvine, beforebecoming assistant professor of chemistry at Texas TechUniversity in 1989. In 1995, he was promoted to associateprofessor and, in 2002, to the rank of professor. Headley’sresearchfocuseson thedesignandsynthesisof ionic liquidsandtheirapplicationstoasymmetricreactions.HeispresentlyaprofessorofchemistryatTexasA&MUniversity-Commerce,whereheisalsotheDeanofGraduateStudiesandResearch.

Bukuo NiwasborninZhejiangProvince,People’sRepublicofChina.HeobtainedhisB.S.degreeinchemistryin1999fromZhejiangUniversity.HereceivedhisPh.D.degree inorganicchemistryin2004underthedirectionofProfessorShengmingMa at the Shanghai Institute of Organic Chemistry of theChineseAcademyofSciences.Hedevelopedmethodologiesforpalladium-andruthenium-catalyzedmulticenterreactions,andappliedthemtothesynthesisofnaturalproducts.In2005,hejoinedProfessorHeadley’sgroupatTexasA&MUniversity-Commerce,whereheiscurrentlycarryingoutresearchonthedesign, synthesis, and application of chiral ionic liquids assolventsandcatalystsforasymmetricorganicreactions.

sigma-aldrich.com

Sigma-Aldrich CongratulatesProfessor Dieter Seebach on His 70th Birthday

Prof. Dr. Dieter Seebach was born on October 31,1937 in Karlsruhe, Germany, and studied chemistry under Prof. Rudolf Criegee at the University of Karlsruhe, where he completed his Ph.D. thesis in 1964. He went on to Harvard University to spend two years under the supervision of Prof. E. J. Corey as a postdoctoral fellow and lecturer before returning to Karlsruhe to work on his “Habilitation” in 1969. Just two years later—and at

the young age of 33—he served as Chair of Organic Chemistry at the Justus Liebig University of Giessen, Germany. In 1977, the faculty of the Swiss Federal Institute of Technology (ETH) in Zürich appointed him Professor of Chemistry to succeed the retiring Nobel laureate Vladimir Prelog as the Chair of Stereochemistry, from which he retired in 2003. Presently, Prof. Seebach is Akademischer Gast at ETH as well as a guest professor at Harvard University throughout the 2007 fall term.

Prof. Seebach’s numerous honors, awards, and prizes include the very first Fluka prize for “Reagent of the Year” (1987), the ACS Award for Creative Work in Synthetic Organic Chemistry (1995), an honorary Ph.D. degree from the University of Montpellier, France (1989), membership in the Deutsche Akademie der Naturforscher, Leopoldina (1984), FRSC fellow of the Royal Society of Chemistry (1984), corresponding member of the Akademie der Wissenschaften und Literatur in Mainz (1990), the Schweizerischen Akademie der Technischen Wissenschaften (1998), Academia

Mexicana de Ciencias (2001), and Foreign Associate of the National Academy of Sciences, U.S.A. (2007).

The extraordinarily broad scope of research activities and the exceptional creativity of Professor Seebach’s work have been dedicated to the development of new synthetic methods (umpolung of reactivity; use of organometallic derivatives of aliphatic nitro-compounds, of small rings, and of tartaric acid; enantioselective synthesis and catalysis (TADDOLs); self-regeneration of stereogenic centers (SRS); use of microorganisms and enzymes; backbone modifications of peptides), natural product synthesis (macrodiolides; alkaloids, unnatural amino acids), mechanistic studies (dissociation of C–C bonds; stability of carbenoids; aggregation of Li compounds; pyramidalization of trigonal centers; TiX4 catalysis), and structure determination (Li enolates and Li dithianes; chemical and biochemical aspects of oligo- and poly(hydroxyalkanoates); β-peptides). This last area is the focus of his present research efforts.

You can read more about Professor Seebach’s life and professional career in the following accounts:

(1) Seebach, D. How We Stumbled into Peptide Chemistry. Aldrichimica Acta 1992, 25, 59–66.

(2) Beck, A. K.; Matthews, J. L. Full of Enthusiasm for Chemistry—Dieter Seebach Reaches 60. Chimia 1997, 51, 810–814.

(3) Marcel Benoist-Preis 2000 an Prof. Dr. Dieter Seebach. Chimia 2000, 54, 745–759.

(4) Seebach, D.; Beck, A. K.; Rueping, M.; Schreiber, J. V.; Sellner, H. Excursions of Synthetic Organic Chemists to the World of Oligomers and Polymers. Chimia 2001, 55, 98–103.

(5) Seebach, D.; Beck, A. K.; Brenner, M.; Gaul, C.; Heckel, A. From Synthetic Methods to γ-Peptides—from Chemistry to Biology. Chimia 2001, 55, 831–838.

(6) Enders, D. Laudatio for Prof. Dr. Dieter Seebach. Synthesis 2002, No. 14 (October 2002; Special Issue Dedicated to Prof. Dieter Seebach).

(7) Beck, A. K.; Plattner, D. A. A Life for Organic Synthesis—Dieter Seebach at 65. Chimia 2002, 56, 576–583.

Professor Seebach

X

O

Nu

O

R E

O

LiSS

δ+ δ−

X

O Nu

ER-Li

"Natural" reactivity

Umpolung of reactivity

Umpolung of Reactivity

TADDOL

β-Peptide

Professor Seebach’s remarkable creativeness in chemical synthesis has led to innovative products that have found their way into Sigma-Aldrich’s catalogs.

Below is a selection of products that are strongly associated with his outstanding contributions to organic chemistry.

UmpolungBrand Prod. No. NameAldrich 157872 1,3-DithianeAldrich 359130 2-Methyl-1,3-dithianeAldrich 220817 2-(Trimethylsilyl)-1,3-dithianeAldrich 282138 Bis(trimethylsilyl)methaneAldrich 226335 Bis(methylthio)methaneAldrich 278076 Tris(phenylthio)methane

Chiral Building BlocksBrand Prod. No. NameFluka 20264 (R)-2-tert-Butyl-6-methyl-1,3-dioxin-4-

oneFluka 15372 (R)-(+)-1-Boc-2-tert-butyl-3-methyl-4-

imidazolidinoneFluka 96022 (R)-1-Z-2-tert-butyl-3-methyl-4-

imidazolidinoneAldrich 337579 (S)-1-Z-2-tert-butyl-3-methyl-4-

imidazolidinoneAldrich 156841 (+)-Diethyl l-tartrateAldrich 163457 (+)-Dimethyl l-tartrateAldrich 294055 (+)-2,3-O-Benzylidene-d-threitolAldrich 248223 1,4-Di-O-tosyl-2,3-O-isopropylidene-

d-threitolAldrich 384313 (+)-Dimethyl 2,3-O-isopropylidene-

d-tartrate

TADDOLsBrand Prod. No. NameAldrich 265004 (4R,5R)-2,2-Dimethyl-α,α,α’,α’-

tetraphenyldioxolane-4,5-dimethanolAldrich 264997 (4S,5S)-2,2-Dimethyl-α,α,α’,α’-

tetraphenyldioxolane-4,5-dimethanolAldrich 395242 (4S-trans)-2,2-Dimethyl-α,α,α’,α’-

tetra(1-naphthyl)-1,3-dioxolane-4,5-dimethanol

Aldrich 393754 (4R,5R)-2,2-Dimethyl-α,α,α’,α’-tetra- (2-naphthyl)dioxolane-4,5-dimethanol

Aldrich 393762 (4S-trans)-2,2-Dimethyl-α,α,α’,α’-tetra(2-naphthyl)-1,3-dioxolane-4,5-dimethanol

Fluka 40875 (–)-2,3-O-Benzylidene-1,1,4,4-tetraphenyl-l-threitol, polymer-bound

Fluka 40876 (+)-2,3-O-Benzylidene-1,1,4,4-tetraphenyl-d-threitol, polymer-bound

PHBBrand Prod. No. NameAldrich 298360 (R)-(–)-3-Hydroxybutyric acid sodium

saltAldrich 363502 Poly[(R)-3-hydroxybutyric acid]

Peptide SynthesisBrand Prod. No. NameAldrich 193453 1,3-Dimethyl-2-imidazolidinoneAldrich 251569 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-

pyrimidinoneFluka 47587 Fmoc-β-Ala-OHFluka 47935 Fmoc-β-Homoala-OHFluka 03676 Fmoc-β-Leu-OHFluka 47946 Fmoc-β-Homoleu-OHFluka 03671 Fmoc-β-Homoile-OHFluka 47878 Fmoc-β-Homophe-OHFluka 03692 Fmoc-β-Homotyr(tBu)-OHFluka 47901 Fmoc-β-Homotrp-OHFluka 03696 Fmoc-β-Homoser(tBu)-OHFluka 47911 Fmoc-β-Homothr(tBu)-OHFluka 03658 Fmoc-β-Homomet-OHFluka 03689 Fmoc-β-Glu(OtBu)-OHFluka 03652 Fmoc-β-Gln-OHFluka 47837 Fmoc-β-Homoglu(OtBu)-OHFluka 03666 Fmoc-β-Homogln-OHFluka 47874 Fmoc-β-Homolys(Boc)-OHFluka 03673 Fmoc-β-Homoarg(Pmc)-OHFluka 47912 Fmoc-l-β3-Homoproline

Chiral AuxiliariesBrand Prod. No. NameAldrich 551104 (S)-(–)-4-Isopropyl-5,5-diphenyl-2-

oxazolidinoneAldrich 551120 (R)-(+)-4-Isopropyl-5,5-diphenyl-2-

oxazolidinone

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Ace Pressure Filter ReactorsThese complete bench-top systems include all components required for operation.* The design allows for complete capture or containment and recovery of the products of the reaction—whether liquids, solids, or both.

These systems complement bench-scale ones with product volumes between 0.6–2 L, and are rated up to 35 psig at 100 °C.

Applications• Oxidation/reduction reactions, where the particulate

can be drawn down to a filter cake

• Nanotechnology, where the material must be contained and the filtrate is the actual product or nanoparticle needed

• Simple bioreactor, where gases are introduced through pressure head via a pressure or NPT fittings and tubing

• Paints/pigments and other viscous solutions

Components/Construction• Heavy-wall borosilicate glass vessel with flanged top,

internally threaded bottom with PTFE fitting and integral filter assembly

• Interchangeable glass filter frits allow for various particulate sizes

• Bottom outlet valve with tube fitting permits easy draining and piping away of filtered solvents

• Jacketed reactor body available for cooling/heating

• Removable head simplifies product loading, removal and cleaning

Reactor Assemblies Include• Glass reactor body and head, CAPFE O-ring and stainless

steel quick-release clamp

• PTFE stirrer bearing, glass shaft with PTFE agitator

• Addition funnel, West condenser, PTFE stoppers, stirrer motor chuck adapter

• Support package (holed plate, stand, chain clamp, and holder)

Visit our Web site sigma-aldrich.com for standard filter reactor systems, IKA® stirrer motors, and additional product information.

Capacity Body ID x Depth (mm) Description Cat. No.

600 mL 83 x 185 unjacketed Z564079-1EA1 L 100 x 180 unjacketed Z564109-1EA2 L 130 x 180 unjacketed Z564133-1EA

600 mL 83 x 185 jacketed Z564087-1EA

1 L 100 x 180 jacketed Z564117-1EA

2 L 130 x 180 jacketed Z564141-1EA

*IKA® stirrer motor (model RW 20) recommended for all reactor sizes (not included).

Filter Reactor Assembly with Standard Taper Joints –

Exploded View

Pressure Filter Reactor Assembly with Threaded Joints

Please see the

Pressure Reactors section of the

Labware Catalogfor additional filter

reactor listings.

IKA is a registered trademark of IKA Works, Inc.

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As a leading Life Science and High Technology company, we are always looking for talented individuals to join our team. At Sigma-Aldrich we value the contributions of our employees, and recognize

the impact they have on our success. We strive to foster creativity and innovation, and encourage professional development.

Our biochemical and organic chemical products and kits are used in scientific and genomic research, biotechnology, pharmaceutical development, the diagnosis of disease, and as key components in pharmaceutical and other high technology manufacturing. We have customers in life science companies, university and government institutions, hospitals, and in industry.

Learn more about our career opportunities by visiting our award-winning Web site at sigma-aldrich.com/careers.

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ChemDose® is a novel High-Throughput Screening (HTS) technology allowing for the use of chemical

reagents and catalysts in the form of tablets. Co-developed with Reaxa Ltd., the ~5 millimeter tablets

are composed of a chemically inert magnesium aluminosilicate matrix, together with an absorbed reagent

or catalyst. Upon exposure to solvents, the reagent or catalyst readily dissolves out, leaving behind an easily

removed insoluble tablet.1

Fast, Accurate, and Convenient Dosing of Catalysts and Reagents

Convenient handling and dispensing of reagents and catalysts.

Eliminates the tedious weighing process for milli- and micromolar chemical quantities.

Simple reaction workup: inert tablet easily removed upon completion of reaction.

Consistent chemical loadings of tablets, controlled release rates, microwave compatible.

Virtually no “learning curve” when using ChemDose®.

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X-Phos Pd(OAc)2 Pd(dppf)Cl2•CH2Cl2 PEPPSI™-IPr PdCl2(PPh3)2 Pd2(dba)3 HATU

Discovery Chemistry with ChemDose®Simplify

For more information, visit sigma-aldrich.com/chemdose.

Reference: (1) Ruhland, T. et al. J. Comb. Chem. 2007, 9, 301.

PEPPSI is a trademark of Total Synthesis Ltd. (Toronto, Canada). ChemDose is a registered trademark of Reaxa Ltd.

(Sampling of available tablets)