Organocatalytic Aza-Michael/Retro-Aza-Michael Reaction:Pronounced Chirality Amplification in Aza-Michael Reaction and

Racemization via Retro-Aza-Michael ReactionYONG-FENG CAI,1 LI LI,1,2 MENG-XIAN LUO,1 KE-FANG YANG,1 GUO-QIAO LAI,1 JIAN-XIONG JIANG,1 AND LI-WEN XU1*

1Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University,Hangzhou, People’s Republic of China

2College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou, People’s Republic of China

ABSTRACT A detailed experimental investigation of an aza-Michael reaction of aniline andchalcone is presented. A series of Cinchona alkaloid-derived organocatalysts with different func-tional groups were prepared and used in the aza-Michael and retro-aza-Michael reaction. Therewas an interesting finding that a complete reversal of stereoselectivity when a benzoyl groupwas introduced to the cinchonine and cinchonidine. The chirality amplification vs. time pro-ceeds in the quinine-derived organocatalyst containing silicon-based bulky group, QN-TBS, -cat-alyzed aza-Michael reaction under solvent-free conditions. In addition, we have demonstratedfor the first time that racemization was occurred in suitable solvents under mild conditionsdue to retro-aza-Michael reaction of the Michael adduct of aniline with chalcone. These indicatethe equilibrium of retro-aza-Michael reaction and aza-Michael reaction produce the happeningof chirality amplification in aza-Michael reaction and racemization via retro-aza-Michael reactionunder different conditions, which would be beneficial to the development of novel chiral cata-lysts for the aza-Michael reactions. Chirality 23:397–403, 2011. VVC 2011 Wiley-Liss, Inc.

KEY WORDS: chirality amplification; racemization; aza-Michael reaction; retro-aza-Michaelreaction; organocatalysis

INTRODUCTION

Aza-Michael reaction is a convenient way to introduce anamine-based functionality to a b-carbon attached to an elec-tro-withdrawing group and generate b-amino carbonylcompounds, such as b-amino acids.1,2 The first report on aza-Michael reaction was published early in 1874,3,4 surprisingly,catalytic aza-Michael reaction was attracted much attentiononly in the past 20 years, and various nitrogen-centered sour-ces, such as hydroxylamine derivatives,5–7 aliphatic and aro-matic amines,8–11 azides,12–14 carbamates,15–19 aldoximes,20

N-heterocycles,21,22 has been used widely in aza-Michaelreaction.23–26 However, while the catalytic asymmetric ver-sion of the classic Michael addition with carbon nucleophilesis well established, the highly enantioselective catalyticaza-Michael reaction is still presents a significant challengein organic synthesis.27–29

Since the first example of asymmetric aza-Michael reactionof aromatic amines was published by Jørgensen in 2001,30

considerable effort has been directed towards the develop-ment of chiral catalyst systems especially with palladiumcomplexes for the aza-Michael reaction of aromaticamines.31–38 It is worthy to note that Scettri et al. employedcommercial available Cinchona alkaloids as the organocata-lysts for the aza-Michael addition of aniline to chalconesunder solvent-free conditions.39 The catalytic performance ofsix Cinchona alkaloids was tested under the same solvent-free conditions, and the use of cinchonine was found to begave the best results with moderate level of enantioselectiv-ities (up to 58%ee). As a common theme, these Cinchonaalkaloids with similar bifunctional chiral alcohol and tertiaryamine, however, the enantioinduction is different dramati-cally from 0 to 58%ee. It is also interesting that the substi-tuted MeO-group in 6-position and olefin group in Cinchona

alkaloid gave strong impact on enantioselectivity. Despitesome impressive demonstrations of the enantioselectiveaza-Michael reactions, this reaction still has a number ofunaccountable features and unverified mechanistic details. Inthe present article, a series of protected Cinchona alkaloid-derived organocatalysts were prepared and used in theaza-Michael and retro-aza-Michael reaction. Furthermore, weprovided the direct findings and mechanistic discussion forthe Cinchona alkaloids-derived organocatalysts-promotedaza-Michael reaction because there are no detailed mecha-nistic information on the organocatalytic aza-Michael reac-tion and factors responsible for chiral-control in the Cinchonaalkaloid-catalyzed aza-Michael reaction. In addition, we firstdemonstrated that the chirality amplification happened inthis aza-Micheal reaction and related racemization due to theretro-aza-Michael reaction.

EXPERIMENTALGeneral Procedures

All reagents and solvents were used directly without purification.Flash column chromatography was performed over silica (200–300

Contract grant sponsor: Natural Science Foundation of China; Contract grantnumber: 20973051Contract grant sponsor: Zhejiang Provincial Natural Science Foundation ofChina; Contract grant number: Y409013Contract grant sponsor: Hangzhou Science and Technology Program;Contract grant number: 20090231T03*Correspondence to: Li-Wen Xu, Key Laboratory of Organosilicon Chemistryand Material Technology, Ministry of Education, Hangzhou Normal Univer-sity, Hangzhou. E-mail: licpxulw@yahoo.com, liwenxu@hznu.edu.cnReceived for publication 21 March 2010; Accepted 9 December 2010DOI: 10.1002/chir.20940Published online 4 April 2011 in Wiley Online Library(wileyonlinelibrary.com).

CHIRALITY 23:397–403 (2011)

VVC 2011 Wiley-Liss, Inc.

mesh). 1H NMR and 13C NMR spectra were recorded at Bruker Avance400 and 100 MHz, respectively, and were referenced to the internal sol-vent signals. IR spectra were recorded using a FTIR apparatus (Nicolot5700). Thin layer chromatography was performed using silica gel; F254

TLC plates and visualized with ultraviolet light. HPLC was carried outwith a Waters 2695 Millennium with photodiode array detector. All theMichael adducts and organocatalysts were known compounds and con-firmed by GC-MS (Thermo Finnigan Trace DSQ) or ESI-MS, and usualspectral methods (NMR and IR).

Preparation of Cinchona Alkaloid-DerivedOrganocatalysts 4-8

The corresponding Cinchona alkaloid-derived compounds, catalysts 4-8 containing silicon-based bulky group (TBS, TMS),40,41 Bz,42 Ms,43 orprimary amine,44 were synthesized from the corresponding Cinchonaalkaloids via silylation, acylation or amination, respectively. All the orga-nocatalysts 4-8 were known and confirmed by GC-MS, and usual spec-tral methods (NMR and IR).

General Method for Organocatalyzed Aza-Michaeland Retro-Aza-Michael Reaction

General procedure of Cinchona alkaloid-catalyzed aza-Michaelreaction. A mixture of chalcone (0.25 mmol), aniline (0.5 mmol),and catalysts (20 mol%) was stirred for 12 to 72 hours (Table 1)under solvent-free conditions at room temperature. The resultingreaction mixture was monitored by TLC and HPLC. The ees of theaza-Michael products were determined by chiral-phase HPLC analy-sis [Chiralcel AD-H, hexane/2-propanol 5 95/5, 0.7 mL/min, k 5

254 nm, retention times: 28.2 min (major), 31.7 min (minor)]. Theknown compound was identified by comparison of spectral data withthat of reported.45,46

General procedure of Cinchona alkaloid-catalyzed aza-Mi-chael/retro-aza-Michael reaction of 3. A mixture of chalcone (0.25mmol), aniline (0.5 mmol), and catalysts (20 mol%) was stirred for 24to 96 hours (if appropriate) under solvent-free conditions at room tem-perature. Upon the completion, the different solvent was introduced

in one portion to the residue. The ees of the aza-Michael productswere determined by chiral-phase HPLC analysis every 12 or 24 hoursafter general work-up.

RESULTS AND DISCUSSION

In a first set of experiments, we prepared several Cinchonaalkaloids derived organocatalysts according to reportedmethods40–44 and examined the aza-Michael reaction ofScheme 1 using aniline and chalcone as model reaction. Asshown in Scheme 1, Cinchona alkaloid-derived catalysts 4-8,containing silicon-based bulky group (TBS, TMS),40,41 Bz,42

Ms,43 or primary amine,44 gave different enantioselectivitiesin the aza-Michael reaction of aniline to chalcone. In compari-son to corresponding parent Cinchona alkaloids, the intro-duction of TMS, Ms, Bz (catalysts 4b-d) resulted in lowerenantioselectivities (Table 1, entries 1-4), which showed thealcohol group in cinchonine (4a) with hydrogen bondingplay crucial to the obtaining promising enantioselectivity.However, catalysts 5b and 6b, that derived from the protec-tion of alcohol of quinine (5a) and quinidine (5b) withbulkyl TBS group, the enantioselectivity was increased dra-matically (Table 1, entries 5 and 6, 44%ee versus 9%ee, andentries 10 and 11, 219%ee versus 3%ee) in comparison to thatof corresponding parent quinine or quinidine, in which thedifference including the inversion of the enantioselectivitycould be obviously due to the contribution of silicon-basedbulky group. It should be noted that a complete reversal ofstereoselectivity was observed in the presence of catalytic4c, 6b, 7b, and 7c (Table 1, entries 3, 11, 13, 14). For exam-ple, benzoyl-substituted cinchonine derivative 4c and ben-zoyl-substituted cinchonidine 7c derivative gave 27%ee and18% ee along with a changeover of enantioselectivity. This re-markable result obtained with benzoyl-modified organocata-lysts maybe due to weak interaction, such as p-p stacking,between phenyl ring of catalyst 4c or 7c and chalcone. Simi-larly, the TMS-protected cinchonidine derivative 7b gave18%ee of aza-Michael adduct in (R)-form with a complete re-versal of stereoselectivity in comparison to that of parent cin-chonidine (216% ee). These results showed the reasonableutilization of steric function is very important in the design ofchiral catalyst, which could fine-tune the catalytic efficiencyand enantioselectivity of functional molecules dramatically.47

During the screening studies of Cinchona alkaloid-derivedcatalysts and inspired by the iminium catalysis with primaryamine organocatalysts,48 we prepared the privileged primaryamine catalyst 8 for the aza-Michael reaction, however, theenantio-induction of 8 is not good, although the enhance-ment in enantioselectivity was obviously in comparison tothat of 5a or 6a.

In an earlier study, we found that the catalyst 5b or 6bwas not perfect in terms of efficiency after 48 h and thereforewe performed the aza-Michael reaction by increasing thetime to 72 hours (Table 1, entry 9). As expected, the yield isexcellent (>99% yield). Interestingly, the enantioselectivitywas increased from 44 to 55%ee. It is an exciting finding thatthe amplification of enantioselectivity is observed clearly inthis QN-TBS (5b) catalyzed aza-Michael reaction aniline tochalcone under solvent-free conditions. As shown in Table 1(Entries 6-9), when the resulting reaction mixture was moni-tored for certain time, the enantioselectivity is found to beincreased corresponding to time, as it were, chirality amplifi-cation is occurred in this case. This showed that the competi-

TABLE 1. The enantioselectivities in Cinchona alkaloidsderivatives (4-8) catalyzed aza-Michael reaction of chalcone

and aniline

Entrya Cat. Time (h) Yield (%)b ee (%)c Noted

1 4a 20 75 49e –2 4b 48 90 23 D 5 2263 4c 48 93 227 Inversion4 4d 48 68 24 D 5 2255 5a 20 88 9e –6 5b 12 24 35 D 5 1267 5b 24 46 41 D 5 1328 5b 48 92 44 D 5 1359 5b 72 >99 55 D 5 14610 6a 20 >99 3e –11 6b 48 62 219 Inversion12 7a 20 >99 216e –13 7b 48 98 19 Inversion14 7c 48 94 18 Inversion15 8 48 99 13 D 5 110

aReaction conditions: chalcone (0.25 mmol), aniline (0.5 mmol), and catalysts(20 mol%)., solvent-free, at room temperature.bNMR yield.cReported data in ref. 38.dEnantiomeric excess of the aza-Michael adduct determined by HPLC analy-sis using a chiral phase column.

398 CAI ET AL.

Chirality DOI 10.1002/chir

tion of retro-aza-Michael and aza-Michael addition might leadto higher level of enantioselectivity (55%ee).

Encouraged by these results, we then conducted experi-ments to access the influence of additives with differentstructure in the aza-Michael reaction or the retro-aza-Michaelreaction. Lewis base (DBU, Et3N) and Brønsted acids withhydrogen bonding (Boc- phenylalanine, S- or R-BINOL) wasadded to the mixture of aniline, chalcone, and catalyticQN-TBS (2) under solvent-free conditions, however, thereare no any enantioselectivity after 24 hours despite the con-version is excellent to >99%. These results further confirmthat Cinchona alkaoids-catalyzed aza-Michael reaction is notthrough iminium catalysis or hydrogen bonding activation ofchalcone but with tertiary amine of Lewis base activation ofaniline.

To search the direct evidence for the equilibrium in aza-Michael reaction and retro-aza-Michael reaction, we addedthe benzaldehyde 9 in the aza-Michael adduct obtained fromthe product of chalcone/aniline (1:1) under solvent-free con-ditions, as expected, the aldimine 10 was obtained in highyield after 2 days (Scheme 2). The control experimentshowed the aza-Michael reaction is reversible and retro-aza-Michael released chalcone and aniline slowly. Therefore inasymmetric aza-Micahel reaction, the major problem is thepossible reversibility for the chiral aza-Michael adducts,which usually resulted in the loss or enhancement of enantio-selectivity. The example of chirality amplification in QN-TBS(5b)-catalyzed aza-Michael reaction aniline to chalconeunder solvent-free conditions is a good case in this context.Our results support the supposition that the stereochemicaloutcome of the aza-Michael addition of aniline and chalcone

depends on the equilibrium in aza-Michael reaction andretro-aza-Michael reaction.

Based on our experimental results, a suggested mecha-nism of organocatalyst catalyzed aza-Michael reaction is pro-posed in Scheme 3. As illustrated in Scheme 3, the catalyticcycle consists of an important initiation phase that generationof the active complex i-1 through hydrogen bonding betweencatalyst 5 and aniline. And then it interacts with chalcone viap-p stacking of aromatic rings and hydrogen bonding to fin-ish the Michael addition.

To gain support for the hypothesis of the interaction ofcatalyst and aniline, we made use of 29Si-NMR analysis. Inthe NMR investigation, we simply compared the 29Si NMRof the pure TMS-substituted catalyst 4b and the mixture of4b and aniline (1:2). As shown in Figure 1, the pure catalyst4b showed two signals at 19.651 and 19.407 ppm due to thepossible weak Si-N coordination at silicon atom.49 By com-parison with the starting catalyst 4b, there is slightly differ-ence after the addition of excess aniline. This assignment is

Scheme 1. Cinchona alkaloid derivatives catalyzed aza-Michael reaction of aniline to chalcone.

Scheme 2. Catalytic retro-aza-Michael reaction in the presence of benzal-dehyde.

399ORGANOCATALYTIC AZA-MICHAEL/RETRO-AZA-MICHAEL REACTION

Chirality DOI 10.1002/chir

Scheme 3. Proposed Mechanism of Catalytic aza-Michael and retro-aza-Michael reaction.

Fig. 1. 29Si-NMR spectrum for CN-TMS (4b) and the mixture of 4b and aniline (1:2).

supported by the fact that the hydrogen bonding interactionof catalyst 4b and aniline. The complex i-1 gives rise to thesignals at around 19.767 and 19.528 ppm, respectively.

To obtained more information in support of the proposedtentative mechanism of Scheme 3, the retro-aza-Michaelreaction was carried out. Foremost among the factors thatcan produce the possible chirality amplification and racemi-zation in organocatalytic retro-aza-Michael reaction are thesolvents and catalysts, therefore we decide to carry outthe reaction in the presence of different solvent. In general,different enantioselectivities were obtained due to the lowenantioselectivity of the catalysts. Initially, we have foundcatalytic amount of Cinchona alkaloids and its derivatives(4-8) showed poor catalytic activity in organic media, whichmaybe due to the fast retro-aza-Michael reaction. For exam-ple, the aza-Michael reaction was not complete (70–80%yields) in MeOH or toluene even with 100 mol% of base cata-lyst for 24h, and unfortunately, the enantioselectivityobtained was low (22%ee in MeOH, 31%ee in toluene). Asdescribed above, the equilibrium in aza-Michael reaction andretro-aza-Michael reaction is unavoidable, and the role ofcatalyst is important in this equilibrium, which would beresulted in the chirality racemization and amplification.Therefore, the retro-aza-Michael raection of 3 is designed tostudy the equilibrium of aza-Michael reaction and retro-aza-Michael reaction: the aza-Michael reaction was carried outfirstly at room temperature for 72 or 24 hours under solvent-

free conditions, and then different solvents was added to thereaction mixtures of 3 with catalyst, the enantiomerexcesses of resulting solution was monitored directly byHPLC after suitable time. As shown in Table 2, the resultedenantioselectivities of various Cinchona alkaloid-derivedorganocatalysts are different according to solvent effect50

and the concentration of the chiral organocatalysts. The lossin enantiomeric excess for the aza-Michael reaction shownin Table 2 occurred under very specific conditions that theconcentration of organocatalyst was low (Entries 3-9). Underthe same conditions (Entries 10-12), toluene and i-propanolresulted in the obvious loss in enantiomeric excess. Unfortu-nately, no clear trend emerges from these data, as the rela-tive racemization or amplification does not correlate withthe concentration of the catalyst. When the concentration ofcatalyst or aza-Michael adduct is enough high, there are noracemization but with maintenance of enantioselectivity evenwith longer time (Entries 13-19). Similarly, the loss of enan-tioselectivity of 3 was slightly in the presence of catalyst 4a.As shown in Table 3, the solvent effect in cinchonine(4a)-catalyzed retro-aza-Michael reaction is pronounced thatthe enantioselectivity is decreasing in MeOH when the reac-tion time is longer.

CONCLUSIONS

In summary, we prepared a series of Cinchona alkaloid-derived organocatalysts with different functional groups forthe aza-Michael of aniline and chalcone and demonstratedthe mechanism of this reaction based on a detailed experi-mental investigation and 29Si NMR analysis. In addition, therewas an interesting finding that a complete reversal of stereo-selectivity when a benzoyl group was introduced to the cin-chonine and cinchonidine. It was found that the chiralityamplification vs. time proceeds in the quinine-derived organo-catalyst containing silicon-based bulky group, QN-TBS, -cata-lyzed aza-Michael reaction under solvent-free conditions. Allthese results suggested that the enantioselectivity could befine-tuned by the introduction of different group due to thechanging of different populations of transition states. To thisend, we have demonstrated for the first time that racemiza-tion was occurred in suitable solvents under mild conditionsdue to retro-aza-Michael reaction of the Michael adduct of ani-line with chalcone. These indicate the equilibrium of retro-aza-Michael reaction and aza-Michael reaction produce the

TABLE 3. The pronounced solvent effects in catalyst4a-catalyzed retro-aza-Michael reaction of 3

Entrya Cat. Time (h)

Solvent-free MeOH

Yield (%)b Ee (%)c Yield (%)b Ee (%)c

1 4a 0 >99 49 90 492 4a 12 >99 49 77 463 4a 24 >99 47 86 444 4a 48 >99 50 90 405 4a 72 >99 48 91 396 4a 96 >99 43 89 36

aThe reaction condition as Table 1 described. The reaction was carried out inMeOH (0.25 M) and under solvent-free conditions, respectively.bNMR yields.cThe enantiomeric excess was determined by HPLC using chiral AD-Hcolumn.

TABLE 2. Chirality amplification and racemization inorganocatalytic aza-Michael/retro-aza-Michael adduct of

aniline to chalconea

Entry Catalyst SolventMcat.

(1022 mol/L)Time(h)

Ee(%)b

Yield(%)c

1 4a MeOH 1.2 24 19 –d

2 5b MeOH 1.2 24 76 –3 8 MeOH 1.2 24 5 –4 4d MeOH 1.2 24 4 –5 4c MeOH 1.2 24 28 –6 7c MeOH 1.2 24 6 –7 4b MeOH 1.2 24 7 –8 7b MeOH 1.2 24 2 –9 6b MeOH 1.2 24 25 –10 5b Toluene 3.4 24 7 –11 5b i-PrOH 3.4 24 29 1412 5b MeOH 3.4 24 36 3113 5b MeOH 5.0 17 39 4714 5b MeOH 5.0 39 43 3215 5b MeOH 5.0 62 44 –16 5b THF 5.0 39 44 3317 5b Toluene 5.0 39 42 3418 5b i-PrOH 5.0 39 43 3519 5b EA 5.0 39 42 4220 4a MeOH 5.0 24 44 86

aReaction conditions44,45: The mixture of 0.25 mmol of chalcone, 0.5 mmol ofaniline, and catalysts (20 mol%) was stirred for 72 h (entries 1–9) or 24 h(entries 10–20) under solvent-free conditions, and then the different solventswas added to the reaction mixture, the reaction was stirred at room tempera-ture.bThe enantiomeric excess was determined by HPLC using chiral AD-H col-umn.cNMR yields.dThe yield is not determined because the enantioselectivity of aza-Michaeladduct 3 was determined directly with solution by HPLC without purificationor separation by flash column chromatography.

401ORGANOCATALYTIC AZA-MICHAEL/RETRO-AZA-MICHAEL REACTION

Chirality DOI 10.1002/chir

happening of chirality amplification in aza-Michael reactionand racemization via retro-aza-Michael reaction under differ-ent conditions, which would be beneficial to the developmentof novel chiral catalysts for the aza-Michael reactions.

LITERATURE CITED

1. Perlmutter P. Conjugate addition reactions in organic synthesis. In: Bald-win JE, Magnus PD, editors. Oxford: Pergamon Press; 1992.

2. Juaristi E, Soloshonok VA. Enantioselective synthesis of b-amino acids.Weiheim: Wiley-VCH; 1997.

3. Sokoloff N, Latschinoff P. Ueber die Einwirkung des Ammoniaks aufAceton. Ber Desch Chem Ges 1874;7:1384–1387.

4. Heintz W, Sokoloff N, Latschinoff P. Bemerkungen zu der Mittheilung.Uber die Einwirkung des Ammoniaks auf Aceton. Ber Dtsch Chem Ges1874;7:1518–1520.

5. Ibrahem I, Rios R, Vesely J, Zhao GL, Cordova A. Catalytic enantioselec-tive 5-hydroxyisoxazolidine synthesis: an asymmetric entry to b-aminoacids. Synthesis 2008;7:1153–1157.

6. Ibrahem I, Rios R, Vesely J, Zhao GL, Cordova A. Organocatalytic asym-metric 5-hydroxyisoxazolidine synthesis: a highly enantioselective routeto -amino acids. Chem Commun 2007;8:849–851.

7. Pettersen D, Plana F, Bernardi L, Fini F, Fochi M, Sgarzani V, Ricci A.Organocatalytic asymmetric aza-Michael reaction: enantioselective addi-tion of O-benzylhydroxylamine to chalcones. Tetrahedron Lett 2007;48:7805–7808.

8. Vicario J, Aparicio D, Palacios F. Conjugate addition of amines to ana,b-unsaturated imine derived from a-aminophosphonate. Synthesis ofg-amino-a-dehydroaminophosphonates. J Org Chem 2009;74:452–455.

9. Xu LW, Li JW, Xia CG, Zhou SL, Hu XX. Efficient copper-catalyzedchemo selective conjugate addition of aliphatic amines to a,b-unsaturatedcompounds in water. Synlett 2003:2425–2427.

10. Hamashima Y, Tamura T, Suzuki S, Sodeoka M. Enantioselective proto-nation in the aza-Michael reaction using a combination of chiralPd-l-hydroxo complex with an amine salt. Synlett 2009;10:1631–1634.

11. Reboule I, Gil R, Collin J. Enantioselective conjugate addition of aromaticamines to N-alkenoyloxazolidinones catalyzed by iodido(binaphtholato)-samarium. 2009;3:532–539.

12. Horstmann TE, Guerin DJ, Miller SJ. Asymmetric conjugate additionof azide to a,b-unsaturated carbonyl compounds catalyzed by simple pep-tides. Angew Chem Int Ed 2000;39:3635–3638.

13. Guerin DJ, Miller SJ. Asymmetric azidation-cycloaddition with open-chainpeptide-based catalysts. A sequential enantioselective route to triazoles.J Am Chem Soc 2002;124:2134–2136.

14. Xu LW, Xia CG, Li JW, Zhou SL. Efficient Lewis base-catalyzed conjugateaddition of azide ion to cyclic enones in water. Synlett 2003;14:2246–2248.

15. Wabnitz TC, Spencer JB. A general, Brønsted acid-catalyzed hetero-michael addition of nitrogen, oxygen, and sulfur nucleophiles. Org Lett2003;5:2141–2144.

16. Xu LW, Li L, Xia CG. Highly efficient aza-Michael reactions of enoneswith carbamates using a combination of quaternary ammonium salts andBF3�OEt2 as a catalyst. Synlett 2003;15:2337–2340.

17. Xu LW, Xia CG, Hu XX. An efficient and inexpensive catalyst system forthe aza-Michael reactions of enones with carbamates. Chem Commun2003;20:2570–2571.

18. Palomo C, Oiarbide M, Halder R, Kelso M, Gomez-Bengon E, Garcıa JM.Catalytic enantioselective conjugate addition of carbamates. J Am ChemSoc 2004;126:9188–9189.

19. Lee J, Kim MH, Jew SS, Park HG, Jeong BS. Phase-transfer catalytic aza-Michael addition of tert-butyl benzyloxycarbamate to electron-deficientolefins Chem Commun 2008;16:1932–1934.

20. Nakama K, Seki S, Kanemasa S. Enantioselective conjugate additions ofaldoximes to 3-crotonoyl-2-oxazolidinone and 1-crotonoyl-3-phenyl-2-imi-dazolidinone catalyzed by the aqua complex between R,R-DBFOX/Phand zinc(II) perchlorate. Tetrahedron Lett 2002;43: 829–832.

21. Yang L, Xu LW, Zhou W, Li L, Xia CG. Highly efficient aza-Michaelreactions of aromatic amines and N-heterocycles catalyzed by a basicionic liquid under solvent-free conditions. Tetrahedron Lett 2006;47:7723–7726.

22. Luo GS, Zhang SL, Duan WH, Wang W. Enantioselective conjugate addi-tion of N-heterocycles to a,b-unsaturated ketones catalyzed by chiral pri-mary amines. Synthesis 2009;9:1564–1572.

23. Azad S, Kobayashi T, Nakano K, Ichikawa Y, Kotsuki H. EfficientBrønsted acid-catalyzed aza-Michael reaction of amides and ureas witha,b-unsaturated enones under high-pressure conditions. TetrahedronLett 2009;50:48–50.

24. Hill R, Yudin AK. Amphoteric amino aldehydes reroute the aza-Michaelreaction. J Am Chem Soc 2009;131:16404–16405.

25. Xu LW, Xia CG, Wu H, Yang L, Zhou W, Zhang Y. Progress in Aza-Michael reaction. Chin J Org Chem 2005;25:167–175.

26. Sibi MP, Soeta T. Enantioselective conjugate addition of hydrazines toa,b-unsaturated imides. Synthesis of chiral pyrazolidinones. J Am ChemSoc 2007;128:4522–4523.

27. Xu LW, Xia CG. A catalytic enantioselective aza-Michael reaction: Novelprotocols for asymmetric synthesis of b-amino carbonyl compounds. EurJ Org Chem 2005;4:633–639.

28. Krishna PR, Sreeshailam A, Srinivas R. Recent advances and applicationsin asymmetric aza-Michael addition chemistry. Tetrahedron 2009;65:9657–9672.

29. Enders D, Wang C, Liebich JX. Organocatalytic asymmetric aza-Michaeladditions. Chem Eur J 2009;15:11058–11076.

30. Zhuang W, Hazell RG, Jørgensen KA. Catalytic enantioselective additionof aromatic amines to enones: synthesis of optically active -amino acidderivatives. Chem Commun 2001;14:1240–1241.

31. Kang SH, Kang YK, Kim DY. Catalytic enantioselective conjugate addi-tion of aromatic amines to fumarate derivatives: asymmetric synthesis ofaspartic acid derivatives. Tetrahedron 2009;65:5676–5679.

32. Uraguchi D, Nakashima D, Ooi T. Chiral arylaminophosphonium bar-fates as a new class of charged Brønsted acid for the enantioselectiveactivation of nonionic lewis bases. J Am Chem Soc 2009;131:7242–7243.

33. Phua PH, White AJP, de Vries JG, Hii KK. Enabling ligand screening forpalladium-catalysed enantioselective aza-Michael addition reactions. AdvSynth Catal 2006;348:587–592.

34. Li K, Hii KK. Dicationic [(BINAP)Pd(solvent)2]21[TfO–]2: enantioselec-

tive hydroamination catalyst for alkenoyl-N-oxazolidinones. Chem Com-mun 2003;10:1132–1133.

35. Li K, Cheng X, Hii KK. Asymmetric synthesis of b-amino acid and amidederivatives by catalytic conjugate addition of aromatic amines to N-alke-noylcarbamates. Eur J Org Chem 2004;5:959–964.

36. Hamashima Y, Somei H, Shimura Y, Tamura T, Sodeoka M. Amine-salt-controlled, catalytic asymmetric conjugate addition of various amines andasymmetric protonation. Org Lett 2004;6:1861–1864.

37. Fadini L, Togni A. Ni(II) Complexes containing chiral tridentate phos-phines as new catalysts for the hydroamination of activated olefins.Chem Commun 2003;1:30–31.

38. Yang L, Xu LW, Xia CG. Efficient catalytic aza-Michael additions of carba-mates to enones: revisited dual activation of hard nucleophiles and softelectrophiles by InCl3/TMSCl cartalyst system. Tetrahedron Lett2007;48:1599–1603.

39. Scettri A, Massa A, Palombi L, Villano R, Acocella MR. Organocatalyticasymmetric aza-Michael addition of aniline to chalcones under solvent-free conditions. Tetrahedron Asymmetry 2008;19:2149–2152.

40. Xu X, Wang K, Nelson SG. Catalytic asymmetric [4 1 2] cycloadditionsof ketenes and N-thioacyl imines: alternatives for direct Mannich reac-tions of enolizable imines. J Am Chem Soc 2007;129:11690–11691.

41. Busygin I, Nieminen V, Taskinen A, Sinkkonen J, Toukoniitty E, SillanpaaR, Yu D, Murzin , Leino R. A combined NMR, DFT, and X-ray investiga-tion of some Cinchona alkaloid O-ethers. J Org Chem 2008;73:6559–6569.

42. Dogo-Isonagie C, Bekele T, France S, Wolfer J, Weatherwax A, TaggiAE, Lectka T. Scalable methodology for the catalytic, asymmetric a-bro-mination of acid chlorides. J Org Chem 2006;71:8946–8949.

43. Roper S, Franz MH, Wartchow RW, Hoffmann HMR. Preparation ofenantioselective 1-azabicyclo[3.2.2]nonanes functionalized at carbon C3,from cinchonine and cinchonidine. Stereoselective solvolysis and an eas-ily enolizable ketone. J Org Chem 2003;68:4944–4946.

44. Brunner H, Bugler J, Nuber B. Enantioselective catalysis 98. Preparationof 9-amino(9-deoxy)Cinchona alkaloids. Tetrahedron Asymmetry 1995;6:1699–1702.

402 CAI ET AL.

Chirality DOI 10.1002/chir

45. Akiyama T, Takaya J, Kagoshima H. Brønsted acid-catalyzed man-nich-type reactions in aqueous media. Adv Synth Catal 2002;344:338–347.

46. Ranu BC, Samamta S, Guchhait SK. Zinc tetrafluoroborate catalyzedMannich-type reaction of aldimines and silyl enol ethers in aqueous me-dium. Tetrahedron 2002;58:983–988.

47. Xu LW, Li L, Shi ZL. Asymmetric synthesis with silicon-based bulkyamino organocatalysts. Adv Synth Catal 2010;352:243–279.

48. Xu LW, Luo J, Lu Y. Asymmetric catalysis with chiral primary amine-based organocatalysts. Chem Commun 2009;14:1807–1821.

49. Chult C, Corriu, RJP, Reye C, Young JC. Reactivity of penta- and hexa-coordinate silicon compounds and their role as reaction intermediates.Chem Rev 1993;93:1371–1448.

50. Cainelli G, Galletti P, Giacomini D. Solvent effects on stereo-selectivity: more than just an environment. Chem Soc Rev 2009;38:990–1001.

403ORGANOCATALYTIC AZA-MICHAEL/RETRO-AZA-MICHAEL REACTION

Chirality DOI 10.1002/chir