Organocatalysis in Enantioselective α-Functionalization of 2-Cyanoacetates

DOI: 10.1002/adsc.201400404

Organocatalysis in Enantioselective a-Functionalization of2-Cyanoacetates

Mar�a D. D�az-de-Villegas,a,* Jos� A. G�lvez,a Ram�n Badorrey,a

and Pilar L�pez-Ram-de-V�ua

a Departamento de Cat�lisis y Procesos Catal�ticos, Instituto de S�ntesis Qu�mica y Cat�lisis Homog�nea (ISQCH), CSIC –Universidad de Zaragoza, c/Pedro Cerbuna 12, 50009 Zaragoza, SpainFax: + (34)-97-676-1202; phone: (+ 34)-97-676-2274; e-mail: [email protected]

Received: April 24, 2014; Revised: July 29, 2014; Published online: October 21, 2014

Abstract: Recent progress in asymmetric organoca-talysis has led to the development of several asym-metric transformations that employ various sub-strates. Among these, cyanoacetates have emergedas excellent nucleophiles in conjugate addition, alky-lation, Mannich and a-heterofunctionalization reac-tions. In this review we discuss the enantioselectivefunctionalization of 2-cyanoacetates through organo-catalytic reactions.

1 Introduction2 Conjugate Addition Reactions2.1 Conjugate Addition of 2-Cyanoacetates to Nitro-

olefins2.2 Conjugate Addition of 2-Cyanoacetates to Vinyl

Sulfones and Vinyl Selenones2.3 Conjugate Addition of 2-Cyanoacetates to Acryl-

onitriles2.4 Conjugate Addition of 2-Cyanoacetates to a,b-

Unsaturated Imides

2.5 Conjugate Addition of 2-Cyanoacetates to a,b-Unsaturated Aldehydes

2.6 Conjugate Addition of 2-Cyanoacetates to a,b-Unsaturated Ketones

2.7 Conjugate Addition of 2-Cyanoacetates to Al-kynyl Ketones

2.8 Conjugate Addition of 2-Cyanoacetates to Al-kynyl Esters

3 Alkylation Reactions4 Allylic Substitution Reactions5 Mannich Reactions6 Reaction with Imidoyl Chlorides7 Amination Reactions8 Nitroso-aldol Reactions9 Phosphination Reactions10 Fluorination Reactions11 Multicomponent Reactions12 Conclusions and Outlook

Keywords: cyanides; cyano esters; enantioselectivity;organic catalysis; synthetic methods

1 Introduction

After more than a decade of continuous progress inthe field, asymmetric organocatalysis is nowadaysconsidered without doubt the third pillar in the �trioof asymmetric catalysis�.[1] Organic catalysts can suc-cessfully replace metal complexes in key steps in theasymmetric synthesis of chiral compounds[2] and, withrecent progress in the design and development of lowloading chiral organocatalysts,[3] their implementationin one-pot multistep processes[4] and the developmentof more sustainable asymmetric organocatalyzed syn-thetic protocols[5] will lead to more and more exam-ples of their use in the asymmetric synthesis of natu-ral products and pharmaceutically relevant mole-cules.[6]

Chiral 2-cyanoacetates (1) are an important class ofsubstrates that serve as precursors for the synthesishighly functionalized chiral compounds with differentstructural features. The versatility of both the carboxyand the cyano group as precursors of different func-tional groups even makes possible the enantiodiver-gent synthesis of a,a-dialkylamino acids froma common substrate,[7] their easy transformation intob-amino acids and b-lactams,[8] or the synthesis of g-amino acids[9] among others.[10]

This review provides an overview on the use ofasymmetric organocatalysis in the a-functionalizationof 2-cyanoacetates and, for convenience in terms ofpresentation and ease of understanding, it is organ-ized according to the type of organocatalytic reaction.The structures of the different organocatalysts testedto promote the enantioselective reaction are given in

Adv. Synth. Catal. 2014, 356, 3261 – 3288 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3261

REVIEW

Figure 1, Figure 2, Figure 3, Figure 4, Figure 5 andFigure 6.

2 Conjugate Addition Reactions

Conjugate addition of nucleophiles to activated ole-fins is one of the most widely used methodologies forthe creation of carbon-carbon bonds and excellent re-sults have already been reported for the enantioselec-tive conjugate addition of various nucleophiles to un-saturated acceptors using chiral organocatalysts.[11]

The use of 2-cyano esters as nucleophiles in this re-action provides direct access to highly functionalizedchiral building blocks and, as a result, the develop-ment of efficient methodologies to perform the enan-tioselective addition of 2-cyano esters to Michael ac-ceptors is a subject of continued interest.

Apart from an isolated study by Wynberg andHelder in 1975[12] concerning the use of quinine in theMichael addition of ethyl 2-phenyl-2-cyanoacetate tomethyl vinyl ketone, metal complexes were the onlycatalysts used to promote conjugate addition of 2-cyano esters to activated olefins until 2005. Since then

Mar�a Dolores D�az de Ville-gas graduated in chemistryfrom the University of Zara-goza in 1981. In 1985 she re-ceived her Ph.D. (Ph.D.Thesis Award) from the Uni-versity of Zaragoza, Spain.After a period (1986–1988) asAssistant Professor at theUniversity of Zaragoza, in1989 she joined the SpanishCouncil for Scientific Re-search (CSIC) as Tenured Scientist. In 2001, she waspromoted to a position of CSIC Research Scientist.Her research interests focus on the development ofnew methodologies in stereoselective synthesis andenantioselective organocatalysis.

Jos� Antonio G�lvez was bornin La Paul (Huesca), Spain in1963. He studied chemistry atthe University of Zaragozawhere he obtained his Ph.D.degree in 1990. After a two-year period at the Universityof La Rioja as Assistant Pro-fessor, he returned to the Uni-versity of Zaragoza in 1993where he was appointedSenior Lecturer in 1997. Hiscurrent research interestsfocus on the asymmetric syn-thesis of biologically active compounds (alkaloidswith a piperidine or pyrrolidine skeleton, azasugars,amino alcohols and amino acids) and the design ofnew organocatalysts and axially chiral ligands andtheir applications in asymmetric catalysis.

Ram�n Badorrey receivedhis Ph.D. in 2000 from theUniversity of Zaragoza. In1998 he took a predoctoralposition at the Centro deInvestigaci�n y Desarrollode Barcelona under the su-pervision of Prof. G. Valen-cia. In 2003 he undertooka postdoctoral stay in theStratingh Institute at the

University of Groningen under the supervision ofProf. B. L. Feringa and in 2004 he joined the Dipar-timento di Chimica G. Ciamician at the BolognaUniversity under the supervision of Prof. A. Umani-Ronchi. He is a Senior Lecturer at the University ofZaragoza and investigates the development of enan-tiopure nitrogen compounds that are easily tuneablefor their evaluation as chiral organocatalysts in dif-ferent enantioselective processes.

Pilar L�pez-Ram-de-Viu,BS in chemistry at the Uni-versity of Zaragoza (1987),received her Ph.D. (Ph.D.Thesis Award) from thesame University in 1991.Between 1992 and 1993 shetook a postdoctoral positionat the Conservatoire Na-tional des Arts et M�tiers(CNAM) of Paris under thesupervision of Dr. L. Oli-veros. After this period she joined the Departmentof Organic Chemistry at the University of Zaragoza,where she carried out teaching and research activi-ties, first as Assistant Professor and later as SeniorLecturer. Her research interests focus on the synthe-sis of optically active compounds with potential bio-logical activity in enantiomerically pure form, com-bining the use of different stereoselective syntheticstrategies and resolution techniques.

3262 asc.wiley-vch.de � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2014, 356, 3261 – 3288

REVIEWMar�a D. D�az-de-Villegas et al.

http://asc.wiley-vch.de

organocatalysts have taken the place of metal com-plexes as catalysts in this reaction. The literature onorganocatalyzed and metal-promoted enantioselective

addition of 2-cyano esters to Michael acceptors up tothe middle of 2009 has been reviewed by Jautze andPeters.[13]

Figure 1. Cinchona alkaloids tested as organocatalysts in the enantioselective a-functionalization of 2-cyanoacetates.

Figure 2. Ureas and thioureas derived from Cinchona alkaloids tested as organocatalysts in the enantioselective a-functional-ization of 2-cyanoacetates.

Adv. Synth. Catal. 2014, 356, 3261 – 3288 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3263

REVIEW Organocatalysis in Enantioselective a-Functionalization of 2-Cyanoacetates


Figure 3. Ureas and thioureas tested as organocatalysts in the enantioselective a-functionalization of 2-cyanoacetates.

Figure 4. Cinchona alkaloid-derived quaternary ammonium salts tested as organocatalysts in the enantioselective a-function-alization of 2-cyanoacetates.




Figure 5. Quaternary ammonium salts tested as organocatalysts in the enantioselective a-functionalization of 2-cyanoace-tates.

Figure 6. Amines and other nitrogen derivatives tested as organocatalysts in the enantioselective a-functionalization of 2-cy-anoacetates.




2.1 Conjugate Addition of 2-Cyanoacetates toNitroolefins

Deng and co-workers[14] described the first efficientorganocatalyzed Michael addition of a 2-alkyl-2-cya-noacetate to a Michael acceptor. Nitroalkenes wereused as activated olefins and two contiguous stereo-genic centers were created. Excellent levels of enan-tio- and diastereoselectivity were obtained in the con-jugate addition of ethyl 2-cyanopropanoate to b-nitro-styrene catalyzed by 10–20 mol% of Cinchona alka-loid-derived organocatalysts OC-6, OC-11 or OC-18(Table 1). In order to achieve good yields the reactionwas carried out in THF at low temperature for severaldays.

Organocatalyst OC-5 efficiently promoted conju-gate addition of ethyl 2-cyanopropanoate to 1-nitro-hept-1-ene under similar reaction conditions. It isworth mentioning that the use of metal-based cata-lysts in this conjugate addition has not been reportedto date.

2.2 Conjugate Addition of 2-Cyanoacetates to VinylSulfones and Vinyl Selenones

Deng and co-workers studied the efficiency of severalCinchona alkaloid derivatives – OC-1, OC-6, OC-7,OC-9, OC-11, OC-12, OC-13, OC-18, OC-20, OC-21,OC-23 and OC-24 – to promote conjugate additionsof 2-substituted-2-cyanoacetates to vinyl sulfones.[7b,15]

The addition of ethyl 2-phenyl-2-cyanoacetate tophenyl vinyl sulfone in toluene at room temperatureand in the presence of 20 mol% of the Cinchona alka-loid derivative was used as the model reaction to de-termine which structural features in the organocata-lysts led to the best results. Cinchona alkaloids bear-ing a C-9 substituent and a C-6’ hydroxy (Table 2)gave better results than those bearing a C-6’ methoxy,and among them pseudo-enantiomeric organocata-lysts OC-7 and OC-13 bearing a phenanthren-9-yloxysubstituent at C-9 were found to be the most effec-tive. These catalysts gave rise to opposite enantiomers

with moderate enantioselectivity levels, which weresignificantly improved on working at �25 8C.

Under these conditions phenyl vinyl sulfone was re-acted with several 2-substituted-2-cyanoacetates. 2-Aryl- and 2-hetaryl-2-cyanoacetates worked well inthe reaction to give the corresponding Michael ad-ducts with excellent yields and enantioselectivities(Table 3).

Table 1. Cinchona alkaloid-organocatalyzed conjugate addi-tion of ethyl 2-cyanopropanoate to nitroolefins.

R OC (mol%) Temp. [8C] Yield [%] dr ee [%]

Ph OC-6 (20) �50 77 >98/2 >99Ph OC-11 (10) �20 76 86/14 �95Ph OC-18 (10) �20 74 86/14 �88n-Pent OC-5 (10) �20 75 93/7 98

Table 2. Cinchona alkaloid-organocatalyzed conjugate addi-tion of ethyl 2-phenyl-2-cyanoacetate to phenyl vinyl sul-fone.

OC Conversion [%] ee [%]

OC-6 65 74OC-7 >98 84OC-11 90 45OC-12 >98 63OC-13 91 74OC-18 >98 42OC-7[a] 95 95OC-13[a] 85 91

[a] The reaction was carried out at �25 8C.

Table 3. Cinchona alkaloid-organocatalyzed conjugate addi-tion of ethyl 2-substituted-2-cyanoacetates to phenyl vinylsulfone.

R OC Yield [%] ee [%]

Ph OC-7 89 95Ph OC-13 80 �914-MeC6H4

[a] OC-7 96 934-MeOC6H4

[a] OC-7 92 934-FC6H4 OC-7 90 944-ClC6H4 OC-7 95 944-ClC6H4 OC-13 94 �894-BrC6H4 OC-7 95 944-BrC6H4 OC-13 95 �883-ClC6H4 OC-7 96 932-naphthyl OC-7 96 972-naphthyl OC-13 95 �902-thienyl OC-7 95 932-thienyl OC-13 91 �88allyl[b] OC-7 17[c] 87

[a] The reaction was carried out at 0 8C.[b] The reaction was carried out at 23 8C.[c] Conversion.




Nevertheless, 2-alkyl-2-cyanoacetates were signifi-cantly less active and, to overcome this lack of reac-tivity, the more electrophilic 3,5-bis-(trifluoromethyl)-phenyl vinyl sulfone was used as the Michael acceptor(Table 4). With this vinyl sulfone the reaction withethyl 2-allyl-2-cyanoacetate at room temperature pro-ceeded to a greater extent under the same reactionconditions. On working at 0 8C for extended reactiontimes, the Michael adduct was obtained with goodyield and excellent enantioselectivity and the reactioncould be extended to ethyl 2-cyanopropanoate.

The use of b-substituted a,b-unsaturated sulfonesas Michael acceptors gave rise to compounds with ad-jacent stereogenic atoms. Good yields and good to ex-cellent levels of enantio- and diastereoselectivity wereobtained when (E)-1-(trifluoromethylsulfonyl)hept-1-ene was used as a Michael acceptor in the conjugateaddition of 2-aryl-2-cyanoacetates catalyzed by10 mol% of pseudo-enantiomeric Cinchona alkaloid-derived organocatalysts OC-7 or OC-13 in dichloro-methane at �50 8C (Table 5).

Soon after, Chen and co-workers described similarresults in the conjugate addition of 2-substituted-2-cy-anoacetates to vinyl sulfones catalyzed by chiral bi-functional thioureas OC-27, OC-31, OC-35, OC-38,OC-44, OC-45 and OC-49 (Table 6).[8f] Good yieldsand moderate enantioselectivities were observed inthe addition of ethyl 2-phenyl-2-cyanoacetate tophenyl vinyl sulfone in the presence of 20 mol% oforganocatalyst on working in toluene at room temper-ature. The enantioselectivity of the reaction improvedon working at �40 8C with all tested organocatalysts.The best enantioselectivities were obtained on usingthiourea OC-44 as the organocatalyst at both roomand low temperatures. The corresponding Michaeladduct was obtained in 94% ee and 83% isolated

yield after 96 h in toluene at �40 8C in the presenceof 20 mol% of organocatalyst OC-44. The enantiose-lectivity of the reaction was not sensitive to the estergroup and was worse in non-arene solvents.

Under the optimized reaction conditions 2-aryl-2-cyanoacetates worked well and the corresponding Mi-chael adducts were obtained with excellent yields andenantioselectivities (Table 7).

With 2-alkyl-2-cyanoacetates the use of a moreelectrophilic sulfone – 1,1-bis(phenylsulfonyl)ethene –was required to observe good reactivity. On using 2-alkyl-2-cyanoacetates as Michael donors the best re-sults were obtained with the more rigid thiourea OC-38 as the organocatalyst (Table 8).

Table 4. Cinchona alkaloid-organocatalyzed conjugate addi-tion of ethyl 2-alkyl-2-cyanoacetates to 5-bis(trifluorome-thyl)phenyl vinyl sulfone.

R OC Temp.[8C]

Conversion[%]

Yield[%]

ee[%]

allyl OC-7 23 88 – 86[a]

allyl OC-7 0 100 76 94[a]

Me OC-7 0 100 85 92Me OC-13 0 100 83 �88

[a] The absolute configuration was determined to be S by X-ray diffraction analysis.

Table 5. Cinchona alkaloid-organocatalyzed conjugate addi-tion of ethyl 2-aryl-2-cyanoacetates to (E)-1-(trifluorome-thylsulfonyl)hept-1-ene.

Ar OC Yield [%][a] dr ee [%]

Ph OC-7 87 85/15 93Ph OC-13 76 82/18 �874-FC6H4 OC-7 94 96/4 924-FC6H4 OC-13 91 92/8 �844-BrC6H4 OC-7 92 98/2 814-BrC6H4 OC-13 92 96/4 �86

[a] Yield of major diastereoisomer.

Table 6. Bifunctional thiourea-organocatalyzed conjugateaddition of ethyl 2-phenyl-2-cyanoacetate to phenyl vinylsulfone.

OC Temp. [8C] Yield [%] ee [%]

OC-27 20 96 43OC-31 20 95 54OC-35 20 95 53OC-38 20 94 52OC-44 20 75 68OC-45 20 75 66OC-49 20 81 62OC-31 �40 90 72OC-38 �40 89 81OC-44 �40 83 94OC-45 �40 75 81




High pressure hydrogenation catalyzed by Raney-Ni allowed the conversion of Michael adducts intob2,2-amino acids (Scheme 1).[8f]

More recently, Marini and co-workers[16] studiedthe behavior of vinyl selenones as Michael acceptorsin this reaction. Cinchona alkaloids – OC-1, OC-5,OC-10, OC-22 and OC-25 –, urea – OC-34, OC-43and OC-48 – and thiourea – OC-33 and OC-44 – de-rivatives were screened as organocatalysts in the addi-

tion of ethyl 2-phenyl-2-cyanoacetate to phenyl vinylselenone. Urea and thiourea derivatives (Table 9)gave better results than Cinchona alkaloids and theresults obtained on working in toluene at room tem-perature highlighted thiourea OC-44 as the best orga-nocatalyst for this reaction. The enantioselectivity wasimproved on working at �70 8C. The use of benzyl orisopropyl esters as Michael donors led to a decreasein the enantioselectivity to some extent.

For vinyl sulfones, the reaction can be efficientlyextended to other 2-aryl-2-cyanoacetates but not to 2-alkyl-2-cyanoacetates, which proved to be significantlyless reactive (Table 10).

The synthetic versatility of the selenone moiety al-lowed conversion of the Michael adduct obtained inthe addition of ethyl 2-phenyl-2-cyanoacetate to

Table 7. Bifunctional thiourea-organocatalyzed conjugateaddition of ethyl 2-aryl-2-cyanoacetates to phenyl vinyl sul-fone.

R Yield [%] ee [%]

Ph 83 944-ClC6H4 90 954-BrC6H4 93 964-FC6H4 92 933-CF3C6H4

[a] 92 913-MeOC6H4 73 942-thienyl 96 95

[a] The reaction was carried out at �50 8C

Table 8. Bifunctional thiourea-organocatalyzed conjugateaddition of ethyl 2-alkyl-2-cyanoacetates to 1,1-bis(phenyl-sulfonyl)ethene.

R Yield [%] ee [%]

Me 96 73n-Bu 98 82Bn 98 72ACHTUNGTRENNUNG(EtO)2CH2 52 96

Scheme 1. Enantioselective synthesis of b2,2-amino acids.

Table 9. Organocatalyzed conjugate addition of ethyl 2-phenyl-2-cyanoacetate to phenyl vinyl selenone.

OC Yield [%] ee [%]

OC-33 80 �32OC-34 88 �44OC-43 74 40OC-44 96 52OC-48 91 44OC-34[a] 97 �70OC-44[a] 90 80OC-48[a] 87 74


Table 10. Organocatalyzed conjugate addition of ethyl 2-sub-stituted-2-cyanoacetates to phenyl vinyl selenone.

R Yield [%] ee [%]

Ph 90 804-MeOC6H4 88 904-MeC6H4 80 904-FC6H4 97 824-ClC6H4 93 804-BrC6H4 90 803-MeC6H4 75 762-naphthyl 93 82allyl[a] 53 70





phenyl vinyl selenone into synthetically valuablechiral intermediates (Scheme 2).

The reaction has also been performed using b-sub-stituted a,b-unsaturated selenones as Michael accept-ors.[17] Among the different organocatalysts tested –OC-33, OC-34, OC-42, OC-43, OC-44 and OC-48 –ureas (Table 11) showed better performance thanthio ACHTUNGTRENNUNGureas and OC-34 was the most effective organoca-talyst in the addition of ethyl 2-phenyl-2-cyanoacetateto (E)-[2-(phenylselenonyl)vinyl]benzene.

Diastereo- and enantioselectivity decreased whenthe reaction was conducted in solvents other than tol-uene and also on increasing the size of the ester.

Treatment of the diastereomeric mixture with LiClin HMPA or NaOEt led to the formation of 1-cyano-1,2-diphenylcyclopropane of cis configuration derivedfrom the exclusive conversion of the major Michaeladduct into the cyclic compound (Scheme 3). Thevery different reactivities of the two diastereoisomerswas confirmed by cyclization of chromatographicallyseparated adducts promoted by NaOEt in EtOH. Theprocess has been rationalized as Krapcho-type de-ACHTUNGTRENNUNGethoxycarbonylation followed by an intramolecular

nucleophilic substitution of the selenonyl moiety bythe enolate intermediate. The 3S absolute configura-tion at the tertiary stereocenter was assigned to themajor enantiomer.

The procedure has been extended to the one-potsynthesis of several highly substituted cyclopropanes.(Table 12).

To date the conjugate addition of 2-cyanoacetatesto vinyl sulfones and vinyl selenones catalyzed bymetal-based systems has not been reported.

2.3 Conjugate Addition of 2-Cyanoacetates toAcrylonitriles

In 2007 Deng and co-workers[18] reported the firsthighly enantioselective addition of 2-substituted-2-cy-anoacetates to acrylonitrile using pseudo-enantiomer-ic thioureas OC-32 and OC-37 as organocatalysts. Ex-cellent yields and enantioselectivities were observedin the presence of 20 mol% of the organocatalyst onworking in toluene at room temperature. Quinine-and quinidine-derived thioureas led to the formation

Scheme 2. Conversion of Michael adducts into syntheticallyvaluable intermediates.

Table 11. Organocatalyzed conjugate addition of ethyl 2-phenyl-2-cyanoacetate to (E)-[2-(phenylselenonyl)vinyl]ben-zene.

OC Yield [%] dr ee [%]

OC-34 94 85/15 80OC-43 81 78/22 68OC-48 21 68/32 58

Scheme 3. Conversion of Michael adduct into 1-cyano-1,2-diphenylcyclopropane.

Table 12. One-pot synthesis of 1,2-disubstituted 1-cyanocy-clopropanes.

Ar R Yield [%][as] ee [%][a]

Ph Ph 65 (54) 66 (76)Ph 4-MeOC6H4 64 (40) 66 (74)Ph 4-MeC6H4 51 (58) 68 (76)Ph 4-ClC6H4 40 (40) 72 (72)Ph 4-FC6H4 55 (65) 74 (74)Ph 2-MeC6H4 56 (45) 48 (68)4-BrC6H4 Ph 52 (50) 61 (70)4-FC6H4 4-ClC6H4 42 (66) 74 (66)Ph n-Hex 81 (18) 48 (54)Ph[b] n-Hex 90 524-MeOC6H4 n-Hex 91 52

[a] Results obtained in LiCl-promoted cyclization and, in pa-rentheses, results obtained in EtONa-promoted cycliza-tion.

[b] The reaction was carried out at �20 8C.




of Michael adducts with the opposite configurationbut with similar enantioselectivity levels (Table 13).

In the only precedent for the metal-promoted enan-tioselective reaction, a chiral cationic [2,6-bis(2’-oxa-zolinyl)phenyl]palladium(II) complex promoted theMichael addition of ethyl 2-cyanopropanoate to acryl-onitrile to give the product in good yield but witha very low enantioselectivity.[19]

When 2-chloroacrylonitrile was used as the Michaelacceptor two stereogenic centers were created. Modi-fied Cinchona alkaloids and thioureas derived fromalkaloids have been used to promote this reac-tion.[10d,18]

Initial studies performed with related 2-cyano ke-tones led to the identification of organocatalyst OC-14, bearing an acetoxy substituent at C-9, as a moreappropriate organocatalyst for this reaction.[10d] Theuse of this catalyst improved both the diastereo- andenantioselectivity in the addition of ethyl 2-phenyl-2-cyanoacetate to 2-chloroacrylonitrile in the presenceof organocatalyst OC-13 which has a phenanthren-9-yloxy substituent at C-9. On the other hand, thioureaOC-32 proved to have complementary diastereoselec-tivity to alkaloid derivative OC-8 and led to Michaeladducts with the same configuration at the tertiarystereocenter but opposite configuration at the quater-nary stereocenter. As quinine and quinidine deriva-tives afforded enantiomeric Michael adducts with sim-ilarly high yields and diastereo- and enantioselectivi-ties, an appropriate design of the catalyst allowedcontrol of the stereochemical course of the Michaeladdition and subsequent protonation reaction and itwas possible to obtain all of the stereoisomers(Table 14).

The same organocatalysts also promoted diastereo-and enantioselective addition of 2-alkyl-2-cyanothio-ACHTUNGTRENNUNGacetates to acrylonitrile and 2-chloroacrylonitrile.[10d,18]

As before, the appropriate design of the catalyst al-lowed control of the stereochemical course of the Mi-chael addition and subsequent protonation reactionand this made it possible to obtain all stereoisomers(Table 15).

The Michael adduct was obtained in the OC-14-promoted reaction in 71% yield, a diastereomericratio of 10:1 and a 93% enantiomeric excess. Thisadduct has served as a chiral precursor in the synthe-sis of a direct precursor of (�)-Manzacidin A(Scheme 4). This synthetic transformation allowed theabsolute configuration of the Michael adduct to be as-signed.

2.4 Conjugate Addition of 2-Cyanoacetates to a,b-Unsaturated Imides

Bifunctional thiourea OC-38 has served as an efficientorganocatalyst in the enantioselective Michael addi-

Table 13. Organocatalyzed conjugate addition of ethyl 2-aryl-2-cyanoacetates to acrylonitrile.

Ar OC Yield [%] ee [%]

Ph OC-32 95 89Ph OC-37 93 �904-FC6H4 OC-32 84 884-FC6H4 OC-37 87 �904-ClC6H4 OC-32 96 884-ClC6H4 OC-37 96 �894-BrC6H4 OC-32 89 894-BrC6H4 OC-37 82 �894-MeC6H4 OC-32 92 904-MeOC6H4 OC-32 85 904-MeOC6H4

[a] OC-32 97 872-naphthyl OC-32 89 89

[a] The reaction was carried out at 50 8C.

Table 14. Organocatalyzed conjugate addition of ethyl 2-aryl-2-cyanoacetates to 2-chloroacrylonitrile.

Ar OC Yield [%] dr ee [%]

Ph OC-8 45 5/1 86Ph OC-14 85 4/1 88Ph OC-32 98 15/1 95Ph OC-37 99 16/1 95Ph[a] OC-37 98 25/1 974-BrC6H4 OC-8 75 3/1 804-BrC6H4 OC-14 98 4/1 864-BrC6H4 OC-32 98 12/1 954-BrC6H4 OC-37 98 12/1 944-FC6H4 OC-32 98 13/1 954-FC6H4 OC-37 98 12/1 954-MeOC6H4 OC-32 99 13/1 954-MeOC6H4 OC-37 99 15/1 954-ClC6H4 OC-32 98 13/1 944-MeC6H4 OC-32 100 14/1 952-naphthyl OC-32 100 14/1 95





tion of methyl 2-cyanoacetate to 2-methoxybenz-ACHTUNGTRENNUNGimides (Table 16).[20]

Michael addition of methyl 2-cyanoacetate to ali-phatic imides in toluene at room temperature and inthe presence of 10 mol% of the organocatalyst led tothe corresponding Michael adducts as a 60/40 mixtureof diastereoisomers with high yield and high enantio-selectivity. With aromatic imides the reaction at roomtemperature was very slow and it was necessary to in-crease the temperature up to 80 8C. Under these con-ditions the Michael adducts were obtained with highyield and also with high enantioselectivity, which wasdetermined after methanolysis and decarboxylationaccording to Scheme 5. These results compare wellwith those reported by Jacobsen on using chiral salen-aluminum complexes to promote conjugate additionof 2-cyano esters to a,b-unsaturated imides.[10a,b,e]

The asymmetric organocatalytic addition of nucleo-philes to maleimides has proven to be a useful toolfor the asymmetric synthesis of chiral succinimide de-rivatives.[21] In this context, organocatalytic asymmet-ric conjugate addition of 2-substituted 2-cyanoacetatesto maleimides has recently been reported at almostthe same time by Yan and co-workers[10h] and byYuan and co-workers.[22]

Among the Cinchona alkaloids and modified Cin-chona alkaloids – OC-1, OC-5, OC-6 and OC-10 –and bifunctional thioureas – OC-31, OC-32, OC-37,OC-44, OC-47, OC-49, OC-50 and OC-51 – evaluatedas catalysts by both groups, bifunctional thiourea-ter-tiary amine OC-49 was the most efficient organocata-lyst for the reaction of ethyl 2-phenyl-2-cyanoacetateand N-phenylmaleimide. The best results achieved bythe Yan group were obtained on working in xylene atroom temperature and in the presence of only1 mol% of organocatalyst OC-49.[10h] Under theseconditions the corresponding Michael adduct couldbe isolated in 99% yield, with excellent diastereose-lectivity (dr=93/7) and very good enantioselectivity(87% ee).

The study of other 2-substituted-2-cyanoacetates asnucleophiles and other N-substituted maleimides asMichael acceptors revealed that under optimal reac-tion conditions the reaction of ethyl 2-aryl-2-cyano-

Table 15. Organocatalyzed conjugate addition of methyl 2-alkyl-2-cyanothioacetates to acrylonitrile and 2-chloroacryl-ACHTUNGTRENNUNGonitrile.

R X OC Yield [%] dr ee [%]

Me H OC-37 80 – 93allyl H OC-37 82 – 91Me Cl OC-8 44 7/1 88Me Cl OC-14 71 10/1 93Me Cl OC-32 98 9/1 96Me Cl OC-37 98 9/1 96allyl Cl OC-14 60 7/1 89allyl Cl OC-32 99 9/1 95allyl Cl OC-37 98 10/1 95

Scheme 4. Conversion of Michael adduct into a direct pre-cursor of (�)-Manzacidin A.

Table 16. Organocatalyzed conjugate addition of methyl 2-cyanoacetate to a,b-unsaturated imides.

R Temp. [8C] Yield [%] dr ee [%][a]

Me r.t. 90 60/40 92TBSO ACHTUNGTRENNUNG(CH2)5 r.t. 96 60/40 92Ph 80 94 60/40 824-FC6H4 80 91 60/40 85[b]

[a] Determined after methanolysis and decarboxylation.[b] The absolute configuration was determined to be 3S by

transformation to known compound. Other absolute con-figurations were presumed on the basis of this asignment.

Scheme 5. Conversion of Michael adducts into decarboxylat-ed methyl esters.




ACHTUNGTRENNUNGacetates with different N-arylmaleimides worked verywell (Table 17). Reactivity, diastereoselectivity andenantioselectivity were worse with maleimide or N-alk ACHTUNGTRENNUNGylmaleimides or when ethyl 2-cyanobutanoate wasused as the nucleophile, for which higher catalystloadings and longer reaction times were required.

Reduction of the cyano group followed by in situlactamization led to g-lactams without loss of theenantiomeric purity (Scheme 6).

After optimization of the reaction conditions theYuan group reported[22] that, on working in mesity-lene at 0 8C in the presence of 5 mol% organocatalystOC-49 and 4 molecular sieves, the Michael adductfrom the reaction of ethyl 2-phenyl-2-cyanoacetateand N-phenylmaleimide could be isolated in 96%yield, with excellent diastereoselectivity (dr=93/7)

and excellent enantioselectivity (97% ee). When thecatalyst loading was reduced to 2 mol% the corre-sponding Michael adduct was obtained in 95% yieldwith a 93/7 diastereomeric ratio and 93% enantiomer-ic excess. The reaction of ethyl 2-phenyl-2-cyanoace-tate has been extended to other maleimides(Table 18). As in previous cases, reactivity, diastereo-selectivity and enantioselectivity were worse with N-alkylmaleimides.

Other ethyl 2-substituted 2-cyanoacetates have alsobeen used as nucleophiles in the reaction with N-phe-nylmaleimide (Table 19).

Methyl or tert-butyl 2-phenyl-2-cyanoacetate canalso be used as nucleophile in the reaction with N-phenylmaleimide without a marked detrimental effecton the results. It is worth mentioning that the reactionof ethyl 2-phenyl-2-cyanoacetate and N-phenylmale-ACHTUNGTRENNUNGimide under Yuan�s optimal reaction conditions hasbeen scaled up with similar results.

Very recently, Tao and co-workers[23] reported theasymmetric conjugate addition of 2-substituted 2-cya-noacetates to maleimides organocatalyzed by bifunc-tional thioureas OC-54, OC-55, OC-56 and OC-57 de-rived from isosteviol. High yields and diastereoselec-tivities were observed in the reaction of ethyl 2-phenyl-2-cyanoacetate and N-phenylmaleimide in di-chloromethane at room temperature in the presence

Table 17. Organocatalyzed conjugate addition of ethyl 2-sub-stituted-2-cyanoacetates to maleimides.

R1 R2 Yield [%] dr ee [%]

Ph Ph 99 93/7 87Ph 4-MeOC6H4 93 90/10 84Ph 4-MeC6H4 97 93/7 89Ph 4-ClC6H4 97 92/8 91Ph 4-BrC6H4 99 91/9 94[b]

Ph 4-FC6H4 96 90/10 84Ph 4-NO2C6H4 96 84/16 81Ph 3-MeC6H4 86 91/9 87Ph 3-ClC6H4 95 96/4 91Ph 3-BrC6H4 97 93/7 90Ph[a] H 95 75/25 41Ph[a] Et 87 80/20 33Ph[a] Bn 98 79/21 634-MeC6H4 Ph 93 93/7 914-MeOC6H4 Ph 94 88/12 884-BrC6H4 Ph 99 87/13 85Et[a] Ph 80 56/44 71

[a] 10 mol% of catalyst.[b] The absolute configuration was determined to be 2R,3S

by X-ray diffraction analysis. Other absolute configura-tions were assigned by analogy.

Scheme 6. Conversion of Michael adducts into g-lactams.

Table 18. Organocatalyzed conjugate addition of ethyl 2-phenyl-2-cyanoacetate to maleimides.

R Yield [%] dr ee [%]

Ph 96 97/3 974-ClC6H4 94 96/4 98[b]

4-BrC6H4 92 97/3 983-ClC6H4 95 98/2 963-BrC6H4 93 98/2 964-MeC6H4 93 98/2 973-MeOC6H4 96 97/3 963,4-Cl2C6H3 93 96/4 963-NO2C6H4 97 93/7 88Bn[a] 84 83/17 82allyl[a] 65 90/10 81t-Bu[a] trace – –Me[a] trace – –

[a] The reaction was carried out at 25 8C with 20 mol % ofcatalyst.

[b] The absolute configuration was determined to be 2R,3Sby X-ray diffraction analysis. Other absolute configura-tions were assigned by mechanistic considerations.




of 10 mol% of any of the organocatalysts mentioned.Nevertheless, enantioselectivities were only moderateand, of the different thioureas tested as organocata-lysts, OC-54 provided the corresponding Michaeladduct with the best enantioselectivity. This resultwas substantially improved on working in toluene at�30 8C, even with half the catalyst loading (Table 20).The presence of 4 molecular sieves did not improvethe results.

Under the optimal conditions the reaction of ethyl2-phenyl-2-cyanoacetate with N-arylmaleimides(Table 21) or other ethyl 2-aryl-2-cyanoacetates with

N-phenylmaleimide (Table 22) also worked well. Theuse of N-alkylmaleimides as Michael acceptors led tomarkedly worse results. On the other hand, the use ofmethyl 2-phenyl-2-cyanoacetate as the nucleophileled to a slight decrease in the yield and the diastereo-and enantioselectivity.

It is worth mentioning that the yield and the dia-stereo- and enantioselectivity in the reaction of ethyl2-phenyl-2-cyanoacetate to N-phenylmaleimide weremaintained on working on a gram-scale.

Table 19. Organocatalyzed conjugate addition of ethyl 2-sub-stituted-2-cyanoacetates to N-phenylmaleimide.


4-ClC6H4 96 98/2 963-ClC6H4 94 95/5 944-MeOC6H4 96 95/5 964-BrC6H4 95 94/6 962-thienyl 95 93/7 94Bn[a] 92 52/48 68/3[b]

allyl[a] 90 69/41 11/76[b]

[a] The reaction was carried out at 25 8C with 20 mol % ofcatalyst.

[b] Enantiomeric excess for major and minor diastereoiso-mers.

Table 20. Organocatalyzed conjugate addition of ethyl 2-phenyl-2-cyanoacetate to N-phenylmaleimide.

OC Solvent Temp. [8C] Yield [%] dr ee [%]

OC-54 CH2Cl2 r.t. 95 82/18 42OC-55 CH2Cl2 r.t. 92 80/20 �20OC-56 CH2Cl2 r.t. 90 81/19 35OC-57 CH2Cl2 r.t. 93 81/19 39OC-54 toluene r.t. 94 92/8 79OC-54 toluene �30 97 97/3 93OC-54[a] toluene �30 90 96/4 87

[a] 5 mol% of catalyst.

Table 21. Organocatalyzed conjugate addition of ethyl 2-phenyl-2-cyanoacetates to maleimides.


Ph 97 97/3 93Ph[a] 94 91/9 843-BrC6H4 94 96/4 934-BrC6H4 93 98/2 903-ClC6H4 96 98/2 924-ClC6H4 96 97/3 904-FC6H4 92 97/3 753-NO2C6H4 95 96/4 734-MeC6H4 96 93/7 914-MeOC6H4 89 96/4 871-naphthyl 90 95/5 86Bn 71 81/19 20t-Bu trace – –

[a] Methyl 2-phenyl-2-cyanoacetate was used as the nucleo-phile.

Table 22. Organocatalyzed conjugate addition of ethyl 2-aryl-2-cyanoacetates to N-phenylmaleimide.

Ar Yield [%] dr ee [%]

4-MeC6H4 96 95/5 854-MeOC6H4 95 92/8 844-ClC6H4 96 97/3 774-BrC6H4 93 93/7 80




2.5 Conjugate Addition of 2-Cyanoacetates to a,b-Unsaturated Aldehydes

Deng and co-workers also described the first organo-catalytic asymmetric conjugate addition of 2-substitut-ed 2-cyanoacetates to acrolein.[24]

As far as the metal-catalyzed reactions are con-cerned, the use of chiral organometallic complexesderived from rhodium and chiral phenylbisoxazo-lines,[25] rhodium and chiral phosphoramidites,[26] andiridium and chiral phosphanyloxazolines[27] in asym-metric conjugate addition of 2-cyanopropanoates toacrolein has been described. In this context, rhodiumcomplexes proved to be more efficient catalysts thanthe iridium complexes.

Initial attempts to use Cinchona alkaloids OC-11,OC-12, OC-13, OC-14 and OC-15 led to the forma-tion of the corresponding Michael adduct with almostinstantaneous total conversion but low enantioselec-tivity. As a result, a new organocatalyst structurallymodified at 6’-OH was designed to attain good enan-tioselectivity levels. Slow addition of acrolein to ethyl2-phenyl-2-cyanoacetate in dichloromethane at�50 8C and using OC-19 (10 mol%) as the organoca-talyst led to the corresponding Michael adduct witha 91% ee. Under these conditions the reaction alsoworked with other 2-aryl- and 2-heteroaryl-2-cyano-ACHTUNGTRENNUNGacetates and the corresponding Michael adducts wereobtained with excellent yields and enantioselectivities(Table 23).

It is worth mentioning that this organocatalyst canbe prepared on a multigram scale from dihydroquini-dine.

2.6 Conjugate Addition of 2-Cyanoacetates to a,b-Unsaturated Ketones

As mentioned previously, the use of metal complexesdominated the field of enantioselective conjugate ad-

dition of 2-cyano esters to activated olefins in general,and a,b-unsaturated ketones in particular, until 2005.Complexes derived from rhodium and chiral diphos-phines,[28] palladium and chiral ligands with trans-che-lating donor sites,[19,29] iridium[27] and platinum com-plexes[30] with chiral phosphanyloxazolines, chiralsalen-aluminum complexes[10e] and, more recently,a ferrocenyl-1,1’-diyl bis-imidazoline bis-palladacyclecomplex[31] have been used to promote this reaction.The first efficient organocatalyzed conjugate additionsusing a,b-unsaturated ketones as Michael acceptorswere not described until 2007.

Different bifunctional thiourea/tertiary amine de-rivatives – OC-27, OC-32, OC-38, OC-39 and OC-44– were screened by Chen[8g] as organocatalysts in theconjugate addition of ethyl 2-phenyl-2-cyanoacetateto methyl vinyl ketone (Table 24). Among them OC-38 provided the best enantioselectivity on working intoluene at room temperature and in the presence of4 molecular sieves. On working with 10 mol% ofOC-38 the corresponding Michael adduct was ob-tained in excellent yield and with a 73% enantiomericexcess. When working at �60 8C the enantioselectivitywas improved up to 91% ee without a loss in yield.

Thiourea OC-38 shows a broad substrate scope andalso induces a high enantioselectivity on using otherethyl 2-aryl-2-cyanoacetates as nucleophiles and othervinyl ketones as Michael acceptors (Table 25).

The addition of 2-alkyl-2-cyanoacetates to methylvinyl ketone showed very poor reactivity but providedgood results when aryl vinyl ketones were used as Mi-chael acceptors (Table 26).

The resulting Michael adducts have proven to beuseful precursors in the synthesis of b2,2-amino acidesters (Scheme 7).[8g]

Numerous different types of organocatalyst havebeen tested in the conjugate addition of ethyl 2-cya-noacetate to chalcone; natural Cinchona alkaloidsOC-1, OC-4, OC-9 and OC-10, modified Cinchona al-

Table 23. Organocatalyzed conjugate addition of ethyl 2-aryl-2-cyanoacetates to acrolein.

Ar Yield [%] ee [%]

Ph 100 914-ClC6H4 98 883-ClC6H4 100 804-MeOC6H4 99 952-thienyl[a] 90 87


Table 24. Organocatalyzed conjugate addition of ethyl 2-phenyl-2-cyanoacetate to methyl vinyl ketone.


OC-27 20 95 60OC-32 20 97 62OC-38 20 96 73OC-39 20 80 60OC-44 20 54 56OC-38 �60 95 91




kaloids based on quinine OC-2, OC-5, OC-6 and OC-17 and bifunctional thioureas OC-33, OC-52 and OC-53. Of these, bifunctional thiourea OC-33 proved tobe the best organocatalyst.[32]

Although the syn/anti diastereoselectivity was onlymoderate (63/37), both Michael adducts were ob-tained with acceptable enantioselectivity levels (ca.88% ee) when the reaction was performed in tolueneat room temperature and in the presence of 10 mol%of the organocatalyst. Variations in the reaction tem-perature mainly affected the reaction rate. ThioureaOC-33 also promoted the addition of ethyl 2-cyano-ACHTUNGTRENNUNGacetate to a wide range of chalcones with moderatesyn/anti diastereoselectivities and high yields andenantioselectivities (Table 27).

Jørgensen and co-workers described the use of b-chloroalkenones as Michael acceptors in the enantio-selective conjugate addition of tert-butyl 2-substitut-ed-2-cyanoacetates promoted by phase-transfer cata-lysts OC-58, OC-59, OC-75 and OC-76.[33] The result-ing b-halo-substituted enolate underwent rapid elimi-nation of the halide and this resulted in the substitu-tion of the vinylic halide by the 2-substituted 2-cyanoacetate with good control of the double bondgeometry. Dimeric Cinchona alkaloid OC-76 possesesthe optimal structure to achieve the best asymmetricinduction in the reaction of tert-butyl 2-phenyl-2-cya-noacetate with (Z)-3-chloro-1-phenylprop-2-en-1-one.Under optimal reaction conditions, which consisted ofthe use of chloroform as solvent and aqueous cesiumcarbonate as base at �35 8C, the correspondingadduct was obtained with almost total conversion anda 93% enantiomeric excess with a catalyst loading ofonly 3 mol%. It is worth mentioning that it is essentialto use tert-butyl esters to obtain good enantioselectivi-ty levels.

When this methodology was extended to the use ofother b-haloalkenones as Michael acceptors(Table 28), it was observed that an increase in thesteric bulk of the electrophile or the use of (Z)-4-bro-

Table 25. Organocatalyzed conjugate addition of ethyl 2-aryl-2-cyanoacetates to vinyl ketones.

Ar R Yield [%] ee [%]

Ph Me 95 914-ClC6H4 Me 87 874-BrC6H4 Me 86 864-FC6H4 Me 94 922-FC6H4 Me 95 953-CF3OC6H4 Me 95 854-MeOC6H4 Me 95 903,4-(MeO)2C6H3 Me 88 952-thienyl Me 93 82Ph Ph 94 864-BrC6H4 Ph 93 852-FC6H4 Ph 90 97[a]

4-MeOC6H4 Ph 95 891-naphthyl Ph 97 912-FC6H4 4-BrC6H4 99 922-FC6H4 4-MeOC6H4 97 912-FC6H4 2-thienyl 97 97Ph 2-thienyl 99 93

[a] The absolute configuration was determined to be S bytransformation to a b2,2-amino acid derivative and X-raydiffraction analysis. Other absolute configurations wereassigned by analogy.

Table 26. Organocatalyzed conjugate addition of ethyl 2-alkyl-2-cyanoacetates to aryl vinyl ketones.

R Ar Temp. [8C] Yield [%] ee [%]

Me Ph 20 81 73Me Ph �60 76 91[a]

n-Bu Ph �60 72 92Bn Ph �60 90 92i-Pr Ph �20 66 93Me 4-BrC6H4 �60 67 85Me 4-MeOC6H4 �60 61 85Me 2-thienyl �60 91 96Bn 2-thienyl �60 98 97

[a] The absolute configuration was determined to be S bycomparison with the reported optical rotation value.Other absolute configurations were assigned by analogy.

Scheme 7. Enantioselective synthesis of b2,2-amino acids.




mobut-3-en-2-one was detrimental for the enantiocon-trol.

On using other tert-butyl 2-substituted 2-cyanoace-tates as nucleophiles (Table 29) comparable results

were obtained in most cases. The reactivity of 2-alkyl-substituted 2-cyanoacetates was lower and theamount of catalyst had to be doubled and the excessof Michael acceptor increased.

The vinylic substitution using (E)-3-chloro-1-phe-nylprop-2-en-1-one as the substrate occurred with netretention of the double bond configuration butshowed very low enantiocontrol.

The (Z)-alkene obtained by reaction of tert-butyl 2-phenyl-2-cyanoacetate with (Z)-3-chloro-1-phenyl-prop-2-en-1-one can be converted into the corre-sponding (E)-alkene without racemization by treat-ment with catalytic iodine (Scheme 8).

2.7 Conjugate Addition of 2-Cyanoacetates toAlkynyl Ketones

Maruoka and co-workers described the enantioselec-tive conjugate addition of 2-alkyl-2-cyanoacetates toalkynyl ketones under phase-transfer conditions usingOC-77, OC-80 or OC-83 as the organocatalyst.[34] Theuse of other catalytic systems to perform this reactionhas not been reported to date.

The reaction of tert-butyl 3-phenyl-2-cyanopropan-ACHTUNGTRENNUNGoate and 3-butyn-2-one in toluene at 0 8C usingK2CO3 as the base proceeded to give high yield, mod-erate E/Z selectivity and high enantioselectivity forboth (E)- and (Z)-adducts in the presence of 1 mol%of OC-80 as the phase-transfer catalyst. The amount

Table 27. Organocatalyzed conjugate addition of ethyl 2-cya-noacetate to chalcones.

Ar1 Ar2 Yield [%] syn/anti ee [%][a]

Ph Ph 84 63/37 88/894-BrC6H4 Ph 88 64/36 88/884-MeC6H4 Ph 82 60/40 88/894-MeOC6H4 Ph 82 59/41 83/83Ph 4-ClC6H4 88 62/38 92/944-NO2C6H4 4-ClC6H4 92 60/40 89/864-ClC6H4 4-ClC6H4 89 63/87 88/884-MeC6H4 4-ClC6H4 93 60/40 91/914-MeOC6H4 4-ClC6H4 84 59/41 88/88Ph 2-furyl 95 67/33 93/924-ClC6H4 2-furyl 91 62/38 93[b]/93[c]

4-BrC6H4 2-furyl 90 63/37 94/934-MeC6H4 2-furyl 89 60/40 93/934-MeOC6H4 2-furyl 94 61/39 93/93Ph 2-thienyl 92 61/39 87/874-ClC6H4 2-pyridyl 80 60/40 94/95

[a] Values for ee syn/ee anti.[b] The absolute configuration of major syn adduct was de-

termined to be 2S,3S by X-ray diffraction analysis.[c] The absolute configuration of major syn adduct was de-

termined to be 2R,3S by chemical correlation.

Table 28. Organocatalyzed conjugate addition of tert-butyl 2-phenyl-2-cyanoacetate to b-haloalkenones.

R X Yield [%] Z/E ee [%]

Ph[a] Cl 95 99/1 934-CF3C6H4 Cl 99 97/3 754-MeOC6H4 Cl 92 97/3 952-thienyl Cl 95 97/3 97[c]

1-naphthyl[b] Cl 93 88/12 43Me[b] Br 99 95/5 38

[a] The reaction was carried out at �35 8C.[b] 6 mol% of catalyst.[c] The absolute configuration was determined to be R by

X-ray diffraction analysis. Other absolute configurationswere assigned by analogy.

Table 29. Organocatalyzed conjugate addition of tert-butyl 2-substituted-2-cyanoacetates to (Z)-3-chloro-1-phenylprop-2-en-1-one.

R Yield [%] Z/E ee [%]

2-FC6H4 80 >95/5 843-MeC6H4 97 99/1 924-ClC6H4 92 99/1 902-naphthyl 93 98/2 941-methyl-3-indolyl 86 >95/5 98Me[a] 95 99/1 92n-Bu[a] 75 >95/5 76

[a] 6 mol% of catalyst.

Scheme 8. Iodine-promoted isomerization.




of base could be reduced without a detrimental effecton the results, which were not improved witha change in the solvent or the base. On the otherhand, a decrease in temperature led to an increase inenantioselectivity for both (E)- and (Z)-adducts. Thereaction was extended to other tert-butyl 2-alkyl-2-cy-anoacetates and other acetylenic ketones and in mostcases the E/Z selectivity and the enantioselectivitylevel were maintained (Table 30).

2.8 Conjugate Addition of 2-Cyanoacetates toAlkynyl Esters

Maruoka and co-workers also described the firstenantioselective conjugate addition of 2-alkyl-2-cya-noacetates to alkynyl esters under phase-transfer con-ditions.[35] Only very recently has the use of chiralruthenium or iridium complexes in this reaction beenreported.[36]

Asymmetric conjugate addition of 2-alkyl-2-cyano-ACHTUNGTRENNUNGacetates to acetylenic esters was tested using the addi-tion of tert-butyl 2-(2-phenylethyl)-2-cyanoacetate toethyl propiolate as a model reaction. Among the dif-ferent chiral ammonium salts tested as phase-transfercatalysts – OC-77, OC-78, OC-79, OC-80, OC-81,OC-82, OC-83, OC-84 and OC-85 – spiro compoundOC-80 showed the best enantioselectivity for both(E)- and (Z)-adducts on using Cs2CO3 as the base intoluene at 0 8C (Table 31).

On using tert-butyl propiolate as the Michael ac-ceptor and working at low temperature, E/Z selectivi-ty and enantioselectivity were improved even with

Table 30. Organocatalyzed conjugate addition of tert-butyl 2-alkyl-2-cyanoacetates to acetylenic ketones.

R1 R2 Yield [%] Z/E ee[a] [%]

Bn Me 99 2.7/1 88/86Bn Ph 98 2.1/1 69/71Bn i-Bu 95 4.4/1 83/89Bn ACHTUNGTRENNUNG(CH3)3CCH2 99 5.0/1 85/80Bn cyclohexyl 94 4.3/1 82/64Bn t-Bu 98 4.3/1 86/83i-Pr Me 70 1.6/1 86/89o-Me-benzyl Me 97 2.2/1 90/85ACHTUNGTRENNUNG(CH3)3CCH2 Me 96 2.9/1 85/86Et Me 80 3.6/1 72/75Ph ACHTUNGTRENNUNG(CH2)2 Me 99 2.3/1 85/69Ph ACHTUNGTRENNUNG(CH2)2 cyclohexyl 99 3.0/1 78/81Ph ACHTUNGTRENNUNG(CH2)2 t-Bu 99 3.3/1 93/87Me Me 99 2.2/1 71[b]/64[b]

[a] Enantiomeric excess for E and Z diastereoisomers.[b] The absolute configuration was determined to be S by

transformation to known compound.

Table 31. Organocatalyzed conjugate addition of tert-butyl 2-(2-phenylethyl)-2-cyanoacetate to ethyl propiolate.

OC Yield [%] E/Z ee[a] [%]

OC-77 99 3.7/1 10/11OC-78 99 1.7/1 55/72OC-79 99 3.2/1 48/45OC-80 99 2.8/1 77/71OC-81 99 2.2/1 53/39OC-82 99 2.7/1 41/47OC-83 95 2.7/1 58/54OC-84 99 4.4/1 31/35OC-85 99 2.8/1 47/65

[a] Enantiomeric excesses for E and Z diastereoisomers.

Table 32. Organocatalyzed conjugate addition of tert-butyl 2-substituted-2-cyanoacetates to tert-butyl propiolate.

R Yield [%] E/Z ee[a] [%]

Ph ACHTUNGTRENNUNG(CH2)2 99 3.6/1 94/84Ph ACHTUNGTRENNUNG(CH2)2

[b] 97 4.0/1 94/80Ph ACHTUNGTRENNUNG(CH2)2

[c] 99 4.1/1 93/87n-Bu 90 3.8/1 95/95Pr 99 4.6/1 94/93Et 99 4.6/1 95/–Me 99 6.7/1 93[d]/–Me[b] 99 6.5/1 93[d]/–i-Pr 99 5.4/1 96/–i-Pr[b] 80 7.5/1 96/–CH2=CH ACHTUNGTRENNUNG(CH2)2 99 3.3/1 92/89allyl 99 6.2/1 92/81ACHTUNGTRENNUNG(CH3)2CH ACHTUNGTRENNUNG(CH2)2 99 3.8/1 95/93ACHTUNGTRENNUNG(CH3)3Si ACHTUNGTRENNUNG(CH2)2 96 5.1/1 95[e]/93ACHTUNGTRENNUNG(CH3)3Si ACHTUNGTRENNUNG(CH2)2

[b] 72 5.8/1 97[e]/904-BrC6H4ACHTUNGTRENNUNG(CH2)2 99 3.7/1 95[e]/91[e]

Ph 89 2.2/1 18/–

[a] Enantiomeric excess for E and Z diastereoisomers.[b] The reaction was performed with 0.5 equiv. of base.[c] The reaction was performed with 0.2 equiv of base.[d] The absolute configuration was determined to be S by

transformation to known compound.[e] The absolute configuration was determined to be S by X-

ray diffraction analysis.




a reduced amount of base. The 2-substituent on thetert-butyl 2-cyanoacetate was varied and the yield andenantioselectivity obtained were similar, except fortert-butyl 2-phenyl-2-cyanoacetate (Table 32).

3 Alkylation Reactions

Enantioselective alkylation of active methylene com-pounds is a fundamental reaction in the creation ofC�C bonds in chiral molecules and, as far as organo-catalyzed reactions are concerned, phase-transfer or-ganocatalysis has dominated this field.[37]

Whereas there are no reports on metal-catalyzedenantioselective alkylation of 2-cyano esters, highlyefficient enantioselective alkylation and allylation of2-cyano esters under phase-transfer catalysis has beenreported by Itoh and co-workers.[10f,g]

Among the different phase-transfer catalysts initial-ly tested, namely OC-69, OC-70, OC-71, OC-86, OC-87 and OC-88, binaphthyl derivative OC-86 showedthe best performance in the alkylation of ethyl 2-cya-nopropanoate with benzyl bromide.

A study into the effect of the ester group on theenantioselectivity showed that the best results wereobtained on using the tert-butyl ester in the nucleo-phile and optimization of the reaction conditions ledto the use of ether as the solvent, cesium hydroxide asthe base and �60 8C as the reaction temperature.Under these conditions only 1 mol% of phase-transfercatalyst OC-86 was required to obtain the correspond-ing tert-butyl 2-benzyl-2-cyanopropanoate in 96%yield and with a 93% enantiomeric excess.

Alkylation of tert-butyl 2-cyanopropanoate withother alkyl halides under optimal reaction conditionsled to the corresponding 2,2-dialkyl-2-cyanoacetatewith excellent yield and quite good enantioselectivity.Comparing OC-86 and OC-87 better results were ob-tained on using OC-87 as the phase-transfer catalyst(Table 33).

This reaction has been used as the key step in theasymmetric synthesis of 3,3-disubstituted 2-oxindolesusing tert-butyl 2-bromophenyl-2-cyanoacetate as thesubstrate, allyl iodide as the alkylating reagent and5 mol% of OC-87 as the organocatalyst (Scheme 9)The reaction temperature had to be raised to �10 8Cand toluene had to be used as solvent to reach totalconversion at an acceptable reaction rate and highenantioselectivity (93% enantiomeric excess).

The allylation product was transformed intoa known b-lactam in order to determine its absoluteconfiguration unambiguously (Scheme 10).

4 Allylic Substitution Reactions

Metal-catalyzed asymmetric allylic substitution ofallyl carbonates by 2-cyano esters using chiral organo-metallic complexes is a known procedure for the

Table 33. Organocatalyzed alkylation of tert-butyl 2-alkyl-2-cyanoacetates.

OC R1 R2X Yield [%] ee [%]

OC-86 Me BnBr 98 93[a]

OC-87 Me BnBr 96 97[a]

OC-86 Me allylI �100 89[a]

OC-87 Me allylI 90 92[a]

OC-86 Me 2-BrCH2Pyr �100 70OC-86 Me ICH2CO2Et �100 76OC-87 Me ICH2CO2Et 97 85OC-86 Me BrCH2CO2-t-Bu �100 92OC-86 allyl MeI 81 67[b]

OC-86 allyl BnBr �100 91OC-87 allyl BnBr �100 >99OC-86 allyl ICH2CO2Et �100 80OC-87 allyl ICH2CO2Et �100 90

[a] The absolute configuration was determined to be R bytransformation to known compound.

[b] The absolute configuration was determined to be S bytransformation to known compound.

Scheme 9. Conversion into key intermediate in the synthesisof 3,3-disubstituted 2-oxindoles.

Scheme 10. Determination of the absolute configuration ofthe allylation compound.




enantioselective construction of quaternary carbonstereocenters. To this end, bimetallic Rh-Pd catalyticsystems,[38] palladium complexes[39] and molybdenumcomplexes[40] with chiral ligands have been used. Themolybdenum-catalyzed asymmetric procedure recent-ly developed by Trost and co-workers proceeds withexcellent regio-, diastereo-, and enantioselectivity fora wide range of substrates.

In 2007 Hiemstra and co-workers described the or-ganocatalyzed asymmetric allylic substitution ofMorita–Baylis–Hillman carbonates using ethyl 2-phenyl-2-cyanoacetate as the nucleophile.[41] The reac-tion in toluene in the presence of 20 mol% of OC-18,a strained derivative, as organocatalyst led to denselyfunctionalized compounds with moderate diastereo-and enantioselectivity in most cases (Table 34). Thereaction was performed with an excess of the allyl car-bonate and under these conditions kinetic resolutionin the first step of the reaction was observed.

5 Mannich Reactions

The Mannich reaction is one of the most potent C�Cbond-forming reactions and it has wide applicationsin synthetic organic chemistry. In recent years organo-catalysis has emerged as a valuable tool to efficientlyperform asymmetric Mannich reactions.[42]

In this context, Jørgensen described the first enan-tioselective Mannich reaction of 2-aryl-2-cyanoace-tates and N-Boc-protected iminoglyoxylates.[43] An in-itial screening of Cinchona alkaloid-derived organoca-talysts – OC-1, OC-20, OC-21, OC-23, OC-24 andOC-26 – showed that OC-24 was the most effectiveorganocatalyst in the reaction of propyl 2-phenyl-2-cyanoacetate with ethyl N-Boc iminoglyoxylate in di-chloromethane at �78 8C. The nature of the estergroup had a noticeable influence on the results, withthe best results obtained with the benzyl ester

(Table 35). An increase in the reaction temperatureor a change in the reaction solvent led to a decreasein the diastereo- and enantioselectivity. On the otherhand slow addition of the imine improved both dia-stereo- and enantioselectivity.

It is worth mentioning that the catalyst loading canbe reduced to 1 mol% without a notable loss of dia-stereo- or enantioselectivity.

The reaction can be extended to other benzyl 2-aryl-2-cyanoacetates with similar results, except forthe benzyl 2-cyano ester with a 2-bromo-substitutedaryl moiety (Table 36). In this case, the structure ofthe a-imino ester had a significant influence on thediastereoselectivity of the reaction. On using tert-butyl N-Boc iminoglyoxylate as the electrophile, theMannich reaction provided the major diastereoisomerwith almost total diastereo- and enantioselectivity.Using pseudoenantiomeric OC-25 the opposite enan-tiomer of the Mannich products can also be obtained.

6 Reaction with Imidoyl Chlorides

The only example of the reaction of trifluoroacetim-ACHTUNGTRENNUNGidoyl chlorides with 2-substituted-2-cyanoacetates wasdescribed by Jørgensen and co-workers,[44] who usedCinchona alkaloid-derived phase-transfer catalysts. Toattain good enantioselectivity levels the substituent atthe nitrogen atom of the imidoyl chloride has to bean electron-deficient aryl substituent and the estergroup in the 2-substituted-2-cyanoacetate has to bea bulky one. Thus, 2,2,2-trifluoro-N-(2-nitrophenyl)-ACHTUNGTRENNUNGacetimidoyl chloride was reacted with tert-butyl 2-cya-

Table 34. Organocatalyzed allylic substitution reaction byethyl 2-phenyl-2-cyanoacetate.

R Temp. [8C] dr Yield [%] ee [%]

Ph �20 80/20 94 832-MeC6H4 0 80/20 95 794-NO2C6H4 �20 52/48 95 161-naphthyl 20 80/20 66 853-BrC6H4 �20 75/25 95 80

Table 35. Organocatalyzed Mannich reaction of 2-phenyl-2-cyanoacetates with ethyl N-Boc-iminoglyoxylate.

OC R dr ee [%][a]

OC-1 Pr 55/45 29/46OC-20 Pr 58/42 68/58OC-21 Pr 57/43 42/13OC-23 Pr 58/42 40/18OC-24 Pr 72/28 85/41OC-26 Pr 58/42 41/41OC-24 Bn 87/13 96/38OC-24[b] Bn 84/16 94/39

[a] Enantiomeric excess for major and minor diastereoiso-mers.

[b] 1 mol% catalyst.




nopentanoate under phase-transfer catalytic condi-tions using Cinchona alkaloid-derived ammoniumsalts OC-58, OC-59, OC-60, OC-61, OC-62, OC-63,OC-64, OC-65, OC-72 and OC-74 as organocatalysts.Organocatalysts bearing an unprotected C-9 hydroxygroup and, a bulky substituent or a substituent withtwo or three methoxy gropus on the N-benzyl sub-stituent (Table 37) showed better performance. Onusing organocatalyst OC-65 the reaction in o-xylene/CHCl3 7:1 at �20 8C led to the substitution compoundin 89% yield and with 86% enantiomeric excess.

On using other 2-alkyl-2-cyanoacetates as nucleo-philes the high enantioselectivity level was maintainedbut the presence of an aryl group near to the a-carbon atom proved detrimental and the enantiose-lectivity was markedly lower (Table 38).

7 Amination Reactions

Direct a-amination of active methines using azodicar-boxylate derivatives as the electrophilic nitrogensource has been extensively used for the constructionof important molecules bearing a carbon-nitrogen

bond. Organocatalysis has played an important role inthe enantioselective version of the reaction and al-lowed the efficient synthesis of the correspondingchiral compounds.[45]

As far as amination of 2-cyanoacetates is con-cerned, apart from the work of Ikariya and co-work-ers[46] on the enantioselective amination of 2-substitut-ed-2-cyanoacetates catalyzed by bifunctional chiralruthenium and iridium amido complexes, there are no

Table 36. Organocatalyzed Mannich reaction of benzyl 2-aryl-2-cyanoacetates with ethyl N-Boc-iminoglyoxylate.

Ar Yield [%] dr ee [%]

Ph 98 89/11 97Ph[a] 96 79/11 �894-ClC6H4 99 80/20 91[d]

3-MeC6H4 97 86/14 974-MeOC6H4 97 85/15 962-naphthyl 99 88/12 962-thienyl 89 82/18 923,4-(MeO)2C6H3 97 85/15 972-BrC6H4 95 18/82 112-BrC6H4

[b] 98 85/15 982-BrC6H4

[c] 99 98/2 982-BrC6H4

[a,c] 99 95/5 �92

[a] Reaction catalyzed by OC-25.[b] Reaction in toluene using isopropyl N-Boc-iminoglyoxy-

late as the Mannich base.[c] Reaction in toluene using tert-butyl N-Boc-iminoglyoxy-

late as the Mannich base and 10 mol% of catalyst.[d] The absolute configuration was determined to be 2S,3R

by X-ray diffraction analysis. Other absolute configura-tions were inferred on the basis HPLC traces and NMRspectra.

Table 37. Organocatalyzed reaction of tert-butyl 2-cyanopen-tanoate with (E)-2,2,2-trifluoro-N-(2-nitrophenyl)acetimido-yl chloride.

OC Conversion [%] ee [%]

OC-59 96 72OC-62 84 76OC-63 92 81OC-64 95 71OC-65 89 86OC-74 nd �79

Table 38. Organocatalyzed reaction of tert-butyl 2-substitut-ed-2-cyanoacetates with (E)-2,2,2-trifluoro-N-(2-nitrophen-ACHTUNGTRENNUNGyl)acetimidoyl chloride.

R Yield [%] ee [%]

Pr 76 86Bn 99 622-furanylCH2 70 65[a]

cyclohexyl 30 86i-Pr 27 90Me 90 84TBSO ACHTUNGTRENNUNG(CH2)5 95 88Ph ACHTUNGTRENNUNG(CH2)3 98 90Ph 78 34

[a] The absolute configuration was determined to be S by X-ray diffraction analysis. Other absolute configurationswere assigned by analogy.




examples in the literature on the use of metal cataly-sis to promote this reaction.

In this context, in 2004 Jørgensen and co-workersdescribed the organocatalytic amination of 2-substi-tuted-2-cyanoacetates with azodicarboxylates cata-lyzed by chiral amines derived from alkaloids.[47]

In a model reaction OC-18 proved to be superior toother tested organocatalysts in terms of enantioselec-tivity. In the presence 5 mol% of the organocatalystamination of ethyl 2-phenyl-2-cyanoacetate with di-ethyl azodicarboxylate in toluene at �78 8C led to theformation of the amination compound in nearly quan-titative yield and with 84% enantiomeric excess. Theenantioselectivity was improved on using di-tert-butylazodicarboxylate as the reagent and tert-butyl 2-phenyl-2-cyanaocetate as the substrate. The tempera-ture can be increased and the catalyst loading de-creased with the high enantioselectivity level main-tained. Other 2-aryl-2-cyanoacetates can be used assubstrates under the same reaction conditions toafford the corresponding hydrazine compounds withexcellent yields and enantioselectivities (Table 39).

Among the different Cinchona alkaloid-derived or-ganocatalysts (OC-5, OC-6, OC-11, OC-12, OC-13)tested by Deng in the reaction of ethyl 2-phenyl-2-cy-anoacetate with dialkyl azodicarboxylates, 6’-hydroxy-substituted Cinchona alkaloids bearing a benzyl ethergroup at C-9 showed the best performance.[48]

On using 5 mol% of OC-6 or OC-12 the enantiose-lectivity, which depended on temperature, concentra-tion, solvent and structure of the electrophile, reachedmore than 95% enantiomeric excess on working intoluene at �78 8C at a 0.08M concentration and with

di-tert-butyl azodicarboxylate as the electrophile. Inthis case it was also possible to decrease the catalystloading while maintaining a high enantioselectivity.On using pseudo-enantiomeric modified alkaloidsOC-6 or OC-12 it was possible to access nitrogen-sub-stituted compounds with the opposite configuration.Amination of other 2-substituted 2-cyanoacetates alsooccurred in excellent yield and enantioselectivity for2-aryl-substituted substrates but not for 2-methyl-sub-stituted substrates (Table 40).

The low enantioselectivity achieved in the amina-tion of ethyl 2-cyanopropanoate could be overcomeby using 2,2,2-trifluoroethyl 2-cyanopropanoate as thesubstrate.[7c] Amination of this compound with di-tert-butyl azodicarboxylate in toluene at �60 8C and using10 mol% pseudo-enantiomeric organocatalysts OC-6or OC-12 led to the corresponding amination prod-ucts of opposite configuration in nearly quantitativeyield and with 91% and 81% ee, respectively.

The compound obtained in the OC-6-promotedamination of 2,2,2-trifluoroethyl 2-cyanopropanoatewas converted into (S)-methyl a-methylserinate,

Table 39. Organocatalyzed amination of tert-butyl 2-aryl-2-cyanoacetates.

Ar Temp. [8C] Yield [%] ee [%]

Ph �78 99 >982-FC6H4 �50 99 983-MeC6H4 �78 99 974-ClC6H4 �78 99 98[b]

4-NO2C6H4 �50 99 914-MeOC6H4 r.t. 95 892-naphthyl �20 99 982-thienyl �78 99 972-thienyl[a] �50 84 93

[a] 0.1 mol% of catalyst.[b] The absolute configuration was determined to be S by X-


Table 40. Organocatalyzed amination of ethyl 2-substituted-2-cyanoacetates.

OC R1 R2 Yield [%] ee [%]

OC-6 Ph t-Bu 92 97OC-12 Ph t-Bu 92 �95OC-6 4-FC6H4 t-Bu 95 96OC-12 4-FC6H4 t-Bu 97 �94OC-6 4-ClC6H4 t-Bu 94 97OC-12 4-ClC6H4 t-Bu 96 �93[c]

OC-6 4-BrC6H4 t-Bu 97 96OC-12 4-BrC6H4 t-Bu 99 �93OC-6[a] 1-naphthyl t-Bu 98 99OC-12[a] 1-naphthyl t-Bu 99 �93OC-6 4-MeC6H4 t-Bu 96 94OC-12 4-MeC6H4 t-Bu 96 �94OC-6[a] 4-MeOC6H4 t-Bu 96 97OC-12[a] 4-MeOC6H4 t-Bu 96 �94OC-6 4-BrC6H4 Bn 83 92OC-12 4-BrC6H4 Bn 86 �91OC-6 2-MeC6H4 Bn 72 87OC-12 2-MeC6H4 Bn 71 �82OC-6[a,b] Me Bn 74 23OC-12[a,b] Me Bn 75 �35

[a] 10 mol% of catalyst.[b] The reaction was carried out at room temperature.[c] The absolute configuration was determined to be S by X-





which has been used as a key intermediate in a totalsynthesis of conagenin (Scheme 11).

A plethora of chiral amines (OC-91 to OC-105)[49]

and 2,5-diazabicycloACHTUNGTRENNUNG[2.21]heptane derivatives (OC-106 to OC-122)[50] have been examined as potentialorganocatalysts in the enantioselective amination ofethyl 2-phenyl-2-cyanoacetate with di-tert-butyl azodi-carboxylate by Juaristi and co-workers.

An initial screening using 50 mol% of the corre-sponding chiral amine in toluene at low temperatureshowed that OC-93, OC-96, OC-100, and OC-101were the most effective organocatalysts in terms ofenantioselectivity. Further optimization of the reac-tion conditions for this selected organocatalyst led tosatisfactory results. When the amination reaction wasperformed in toluene/hexane 1:1 at low temperatureenantioselectivities in the range 74–84% ee were ob-tained for OC-93, OC-96 and OC-100 (Table 41).

With OC-93 a decrease in catalyst loading led toa slight decrease in the enantioselectivity of the ami-nation reaction, which was maintained at 64% enan-tiomeric excess even with catalyst loadings as low as1 mol%.

Although 2,5-diazabicyclo ACHTUNGTRENNUNG[2.2.1]heptanes catalyzedthe amination reaction, they were not very effectivein terms of enantioselectivity. The best results, 40%enantiomeric excess, were obtained on working in tol-uene at �78 8C and in the presence of 25 mol% ofOC-107.

Terada and co-workers described the enantioselec-tive amination of related 2-cyanothioacetates usingaxially chiral guanidine OC-89 or OC-90 as organoca-talyst.[7d]

Excellent yields and high enantioselectivity levelswere obtained in the amination of O-ethyl 2-cyano-3-phenylpropanethioate with di-tert-butyl azodicarboxy-late in ethereal solvents at low temperature in thepresence of 1 mol% of the corresponding organocata-lyst. 1,2-Dimethoxyethane was particularly effectiveand, to avoid freezing at �80 8C, the reaction was con-ducted in mixed solvent systems with diethyl ether oracetone. The reaction has been extended to other sub-strates with different substituents and works quitewell with primary 2-alkyl substituents (Table 42).

Scheme 11. Conversion into (S)-methyl a-methylserinate,a key intermediate in the synthesis of conagenin.

Table 41. Organocatalyzed amination of ethyl 2-phenyl-2-cy-anoacetates.


OC-93 �78 95 74[b]

OC-96 �78 96 �76OC-100 �78 91 �84OC-93 �100 95 80OC-96 �100 93 �74OC-100 �100 94 �76OC-93[a] �100 90 64

[a] 1 mol% of catalyst.[b] Absolute configuration S was presumed on the basis of

the sign of optical rotation.

Table 42. Organocatalyzed amination of 2-substituted-2-cya-nothioacetates.

OC R Yield [%] ee [%]

OC-89 Bn >98 98OC-89[a] Bn 97 98OC-90[a] Bn >98 87OC-89 Me 98 85OC-89[a] Me 98 89[c]

OC-90[a] Me >98 91OC-89 Et 96 97OC-89 allyl 91 97OC-89 i-Bu >98 94OC-89[b] i-Pr >98 54OC-89 Ph 65 41OC-89 NCCH2 92 96OC-89 2-furylCH2 99 96OC-89 N-Boc-2-indolylCH2 >99 99OC-89 4-MeOC6H4CH2 97 96

[a] The reaction was performed in DME/acetone 3:1.[b] The reaction was performed in DME at �50 8C.[c] The absolute configuration was determined to be R by

transformation to known compound.




It is worth mentioning that amination of O-ethyl 2-cyano-3-phenylpropanethioate with di-tert-butyl azo-dicarboxylate can be performed on a gram scale witha reduced catalyst loading as low as 0.1 mol% withvery high yield and excellent enantioselectivity, i.e. ,92% yield and 98% enantiomeric excess.

The compound obtained in the amination of O-ethyl 2-cyanopropanethioate using OC-89 as organo-catalyst can be conveniently elaborated to afford the(S)-a-methylserinate derivative shown in Scheme 12which has allowed the unambiguous assignment ofthe R configuration to the major product obtained inthe amination reaction.

8 Nitroso-aldol Reactions

The enantioselective reaction of nitroso compoundswith enolizable carbonyl compounds is a useful syn-thetic methodology for the synthesis of chiral carbon-yl compounds with a heteroatom at the a-posi-tion.[45b,51] Nucleophilic attack may occur at either theoxygen or the nitrogen atom of the nitroso com-pound, leading to the formation of carbon-oxygenbonds (a-aminoxylation) or carbon-nitrogen bonds(a-hydroxyamination). The regioselectivity of the re-action depends on the nature of the enolate and thecatalyst and the O-nitroso aldol reaction is more com-monly observed than the N-nitroso aldol reaction.

Jørgensen and co-workers described[52] for the firsttime the N-nitroso-aldol reaction of nitrosobenzenewith 2-aryl-2-cyanoacetates. On using Cinchona alka-loids OC-1, OC-3, OC-4, OC-9, OC-16, OC-17, OC-18 and OC-25 as organocatalysts the hydroxyamina-tion reaction proceeds with total regioselectivity andthe enantioselectivity depended on the catalyst, sol-vent, nature of the ester moiety and concentration.Moreover, the amount of catalyst had a noticeable in-fluence on enantioselectivity, which decreased whenthe catalyst loading was increased. When more than1 equivalent of catalyst was used the stereochemicalcourse of the reaction was inverted. This effect hasbeen attributed to differences in the aggregation stateof the catalyst.

Optimal results in the nitroso-aldol reaction ofesters of 2-phenyl-2-cyanoacetate were observedwhen the reaction of the tert-butyl ester was conduct-ed in dichloromethane at �78 8C and in the presenceof 10 mol% of organocatalyst. The highest enantiose-lectivity was observed on using organocatalyst OC-

1 (Table 43). The resulting hydroxylamine derivativeswere immediately reduced to the correspondingamines as they were chemically and configurationallyunstable. This procedure has been extended to othertert-butyl 2-aryl-2-cyanoacetates with modest results

The compound obtained in the nitroso-aldol reac-tion of tert-butyl 2-phenyl-2-cyanoacetate was trans-formed into the corresponding 1,2-diamine derivativewithout loss of the enantiomeric purity (Scheme 13).

9 Phosphination Reactions

Phosphorus-containing compounds have found wideapplication in many areas of modern organic chemis-try and in recent years catalytic asymmetric construc-tion of P�C bonds has attracted considerable atten-tion. In this context, metal-catalyzed[53] as well as or-ganocatalyzed[54] strategies to perform the asymmetricsynthesis of organophosphorus compounds have beendeveloped.

Scheme 12. Conversion into methyl a-methylserinate.

Table 43. Organocatalyzed reaction of 2-aryl-2-cyanoace-tates with nitrosobenzene.

OC Ar Yield [%] ee [%]

OC-1 Ph 80 59[a]

OC-3 Ph 20 8OC-4 Ph 84 �15OC-9 Ph 85 �42OC-16 Ph 33 8OC-17 Ph 82 50OC-18 Ph 78 0OC-25 Ph 46 �30OC-1 4-ClC6H4 85 59OC-1 3-MeC6H4 71 52OC-1 4-MeOC6H4 80 22OC-1 4-CNC6H4 78 49OC-1 2-naphthyl 73 52


Scheme 13. Conversion into 1,2-diamines.




Jørgensen and co-workers recently described[55] thefirst electrophilic phosphination of 2-alkyl-2-cyano-ACHTUNGTRENNUNGacetates using diarylphosphine chlorides as the elec-trophiles.

Cinchona alkaloids OC-9, OC-10, OC-21, OC-23,OC-24 and OC-25 have been tested as organocata-lysts to obtain optically active 2-phosphinated-2-cya-noacetates, which were transformed into a-phosphi-no-b-amino acids. Reaction of ethyl 2-cyanooctanoatewith chlorodiphenylphosphine in chloroform at roomtemperature and in the presence of a sub-stoichiomet-ric amount of OC-24 as the organocatalyst gave onlytraces of product. However, on using 5 equivalents of1,8-bis(dimethylamino)naphthalene (proton sponge)as an acid scavenger, 10 mol% of the organocatalystproved sufficient to achieve 90% conversion of thesubstrate.

Screening for the most appropriate organocatalyst,substrate and reaction conditions revealed that the re-action worked better when performed with the butylester in chloroform at �40 8C with a large excess ofelectrophile and using 10 mol% of OC-24 as the orga-nocatalyst in conjunction with 5 equivalents of protonsponge. Under these conditions a-phosphino-b-aminoacids with different side chains and arylphosphinogroups were obtained in satisfactory yield and goodenantioselectivity levels from the initially obtained a-phosphinated cyanoesters (Table 44). The use of

pseudo-enantiomeric OC-25 as organocatalyst result-ed in the formation of the enantiomeric product witha similar enantioselectivity level.

The a-phosphino-b-amino acid obtained from thereaction of butyl 2-cyanopentanoate with chlorobis(4-methoxy-3,5-dimethylphenyl)phosphine has been re-duced as shown in Scheme 14. X-Ray diffraction anal-ysis of the obtained alcohol derivative has allowedthe unambiguous assignment of the R configurationto the major product obtained in the phosphinationreaction.

10 Fluorination Reactions

Owing to their unique properties, the development ofenantioselective synthetic routes to fluorinated com-pounds is highly valuable. Among the different ap-proaches to chiral fluoro-organic molecules with a flu-orine atom on the stereogenic center, enantioselectiveelectrophilic fluorinations catalyzed by chiral metalcomplexes and organocatalysts are especiallyuseful.[56]

In 2000 Shibata and co-workers[57] reported thatchiral fluorinated reagents derived from Cinchona al-kaloids and Selectfluor can be used for the enantiose-lective fluorination of 2-cyano esters. In this case anexcess of the alkaloid is used to perform the fluorina-tion reaction. Purely organocatalytic fluorination of 2-cyano esters was published some years later by Kimand Park,[58] who performed the fluorination of estersof 2-phenyl-2-cyanoacetic acid with NFSI in the pres-ence of 10 mol% of phase-transfer catalysts derivedfrom Cinchona alkaloids OC-66, OC-67 and OC-68and an inorganic base in toluene at room tempera-ture.

An initial screening showed that the best resultswere obtained using Cs2CO3 as the base and the Cin-chona alkaloid-derived quaternary ammonium saltOC-67 as the phase-transfer catalyst. The ester groupalso had an effect on the enantioselectivity, which wasbetter with the para-nitrobenzyl ester. Fluorination ofother para-nitrobenzyl 2-aryl-2-cyanoacetates provid-ed the corresponding 2-fluoro-2-cyano esters withgood yields and moderate enantioselectivities(Table 45). These results are not as good as those ob-tained on using chiral palladium complexes.[59]

Table 44. Organocatalyzed reaction of butyl 2-substituted-2-cyanoacetates with chlorodiarylphosphines.

R Ar Yield [%] ee [%]

Pr Ph 55 92[b]

Pr[a] Ph 52 �93Pr 4-MeC6H4 52 92Pr 3,5-Me2-4-MeOC2H2 54 88Me Ph 56 87Et Ph 60 93n-Hex Ph 53 92n-Hex 4-MeC6H4 54 92MeO ACHTUNGTRENNUNG(CH2)2 Ph 46 85Bn Ph 36 92

[a] Reaction catalyzed by OC-25.[b] The absolute configuration was determined to be R by

transformation to an a-phosphino-b-amino alcohol deriv-ative and X-ray diffraction analysis. Other absolute con-figurations were assigned by analogy.

Scheme 14. Conversion of phosphination adduct into anamino alcohol derivative.




11 Multicomponent Reactions

Asymmetric multicomponent reactions, in whichthree or more reagents form a new chiral compoundderived from all the reagents, are powerful tools forthe simple and efficient synthesis of chiral compoundsfrom simple starting materials.[60]

In this context, Yang et al. recently reported[61] thethree-component reaction of salicylaldehydes, ethyl 2-cyanoacetate and nitromethane catalyzed by chiralamino-thioureas OC-32, OC-38, OC-40 and OC-41.

The reaction carried out in dichloromethane atroom temperature and in the presence 10 mol% of or-ganocatalyst OC-38 and 4 molecular sieves led tothe synthesis of highly functionalized 2-amino-4H-chromenes in good yields and enantioselectivities(Table 46).

12 Conclusions and Outlook

Asymmetric organocatalysis has proven to be extraor-dinarily useful for the enantioselective a-functionali-zation of 2-cyano esters. In the presence of the appro-priate organocatalyst it is possible to obtain denselyfunctionalized chiral compounds with remarkablelevels of enantioselectivity under simple experimentalconditions. In many of the reported reactions organo-catalysis is the only synthetic approach described todate for the enantioselective a-functionalization ofthe 2-cyano ester and, in cases where there are litera-ture precedents for metal-based catalysis, in mostcases organocatalysis is a valuable alternative.

Organocatalysts used in the a-functionalization of2-cyano esters include Cinchona alkaloids and modi-fied Cinchona alkaloids, bifunctional ureas and thiour-eas, quaternary ammonium salts, amines and guani-dines. Whereas for Cinchona alkaloids and modified

Cinchona alkaloids the catalyst loading is usually 10–20 mol%, for other organocatalysts the loading can beconsiderably reduced; 5–10 mol% for some bifunc-tional thioureas, 1–10 mol% for phase-transfer orga-nocatalysts and only 1% for chiral guanidines.

Cinchona alkaloid-derived organocatalysts havebeen used in the conjugate addition of 2-cyano estersto different activated olefins, including nitroolefins,vinyl sulfones, vinyl selenones, acrylonitriles, a,b-un-satutared imides, a,b-unsatutared aldehydes and a,b-unsatutared ketones. Cinchona alkaloid-derived orga-nocatalysts have also been used to promote enantiose-lective allylic substitution reactions of carbonates by2-cyano esters, Mannich reactions of 2-cyano esterswith iminoglyoxylates, N-nitroso-aldol reactions of ni-trosobenzene with 2-cyano esters and a-aminationand a-phosphination of 2-cyano esters.

Bifunctional thioureas have been used in the conju-gate addition of 2-cyano esters to vinyl sulfones, vinylselenones, acrylonitriles, maleimides and a,b-unsatu-tared ketones.

Phase-transfer catalysts have been used in the con-jugate addition of 2-cyano esters to alkynyl ketonesand alkynyl esters and the reaction of 2-cyano esterswith imidoyl chlorides as well as in the a-alkylationand a-fluorination of 2-cyano esters.

Finally, chiral guanidines have been used in the al-kylation and a-amination of 2-cyano esters.

As a general trend, remarkable results have beenachieved in enantioselective organocatalytic a-func-

Table 45. Organocatalyzed fluorination of 2-aryl-2-cyanoace-tates.

R Ar Yield [%] ee [%]

Me Ph 76 50Et Ph 65 42Bn Ph 77 614-NO2C6H4CH2 Ph 76 734-NO2C6H4CH2 4-ClC6H4 72 764-NO2C6H4CH2 4-naphthyl 71 764-NO2C6H4CH2 4-MeC6H4 64 724-NO2C6H4CH2 4-FC6H4 76 73

Table 46. Organocatalyzed multicomponent reaction of ethyl2-cyanoacetate with salicylaldehydes and nitromethane.

R1 R2 R3 R4 Yield [%] ee [%]

H H H H 76 87H H Br H 83 91[a]

H H Cl H 76 84Br H Br H 78 89Cl H Cl H 81 77H H MeO H 86 77H Cl H Cl 76 87H H H MeO 41 61





tionalization of 2-arylcyanoacetates. Nevertheless, theefficient a-functionalization of 2-alkylcyanoacetatesremains to be achieved.

Conjugate addition reactions with diverse activatedolefins have been studied and the extension to morecomplex activated substrates would provide denselyfunctionalized chiral building blocks with several ste-reogenic centres and a higher complexity.

As far as a-heterofunctionalization is concerned,significant progress has been made in organocatalytica-amination, a-phosphination and a-fluorination of 2-cyano esters. However, the development of other val-uable a-heterofunctionalization reactions such as oxi-dation, chlorination, bromination or sulfenylation stillremains unexplored.

Future developments in this field should focus onbroadening the scope of known a-functionalizationreactions; exploring new processes, exploiting otherpowerful bifunctional organocatalysts, such as chiralphosphoric acid, phosphoramides, chiral squaramides,etc., and understanding the mechanism and the fac-tors that govern enantioselective organocatalytic a-functionalization of 2-cyano esters.

Acknowledgements

The financial support of the Government of Arag�n (GA E-102) is acknowledged.

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Organocatalysis in Enantioselective α-Functionalization of 2-Cyanoacetates

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