Enantioselective Aldol Reactions and Michael Additions Using Proline Derivatives as Organocatalysts

Mathieu Wagner, Yohan Contie, Clotilde Ferroud, Gilbert Revial

Conservatoire National des Arts et Métiers, Laboratoire de Transformations Chimiques et Pharmaceutiques, Paris, France.

DOI: 10.4236/ijoc.2014.41008                

Abstract

Six compounds including five proline derivatives have been prepared and tested as chiral organocatalysts for enantioselective aldol reactions and Michael additions. The enantiomeric excesses, which are highly dependent on the molecular structure of catalysts as well as experimental conditions, have reached over 98%.

Keywords

Aldol Reactions; Michael Additions; Enantioselective; Organocatalysts; Proline Derivatives

1. Introduction

The aldol reaction and the Michael addition are very precious tools of the synthetic organic chemist. Indeed, these reactions are widely applied to generate carbon-carbon bonds allowing to link building blocks to generate large and complex molecules. The steric control of chiral centers created during these reactions was initially attained using chiral auxiliaries as is the case, for instance, of chiral imines in Michael additions [1] [2] . For over a decade, many studies have been undertaken worldwide to extend the enantioselectivity in catalytic manner using small organic chiral molecules. These metal-free catalysts, highly efficient, more environmentally friendly, and often stable under both aerobic and aqueous reaction conditions, are always extensively investigated [3] -[8] .

 

The synthesis of azapyridinomacrocycles N-oxides and their use as organocatalysts for enantioselective allylations of 4-nitrobenzaldehyde with allyltrichlorosilane were reported from our laboratory [9] . The described asymmetric inductions were interesting and promising but too low to afford synthetic applications. Therefore we thought to experiment some of these chiral intermediates themselves as organocatalysts in aldol reactions and Michael additions. This kind of reactions has been extensively described as model to establish the efficiency of small molecules regarding the enantioselectivity. Herein we wish to report the results using some new derivatives 1 - 6 (figure 1) as chiral catalysts in both enantioselective aldol and Michael reactions [10] -[17] .

2. Results and Discussion

The preparation of new proline derivatives 2, 3, 5 and 6 is displayed in Scheme 1. Compound 2 was synthesized starting from amine 1 [9] with N-Boc-(S)-proline to give 7 followed by elimination of the Boc protecting group. In the case of 3, the amidation was carried out through the same pathway starting with the corresponding epimer of 1 derived from (1S,2S)-1,2-diaminocyclohexane. The proline derivative 9 was produced by condensation of commercially available 2-nitrobenzenesulfonamide with N-Boc-(S)-proline while 10 and 11 [18] resulted from the reaction of N-Boc-prolinamine [19] with respectively 2- and 4-nitrobenzenesulfonyl chloride. After acid deprotection, catalysts 4, 5 and 6 were obtained in very good yields. It should be noted that the 4-nitrophenyl regioisomer of 4 was already described [20] .

2.1. Aldol Reaction

With the new derivatives 1 - 6 in hand, we began to evaluate their catalytic behavior in the classical aldol reaction between acetone and 4-nitrobenzaldehyde [21] , and the results are displayed in Table 1. As can be seen, the reaction proceeded smoothly at room temperature under solvent free conditions and was almost total only beyond several dozen hours, except for catalyst 2 (entry 2). If the chemical yields were acceptable (catalysts 2 and 3), the enantiomeric excesses were very low except for catalyst 2. Indeed in that case, a very interesting enantioselectivity of the aldol product was obtained. Regarding the results, we observed the following facts: firstly, the catalyst 2 having proline moieties exhibited higher catalytic efficiencies compared to 1 (entries 1, 2); then, we could notice a strong mismatch effect related to the absolute stereochemistry of the cyclohexane moiety (entries 2, 3). After these initial investigations, catalyst 2, giving the best result, was selected to carry out the optimization of the reaction conditions. We first investigated the solvent effect with or without some additives and the results are displayed in Table 1. While no reaction occurred in aprotic polar solvents (entries 4, 5), apolar solvents (entries 6, 7) induced a significant decrease in catalytic efficiency. Moreover, a catalytic amount of TfOH (entry 9) induced a decrease both rate and yield without significantly affecting the enantiomeric excess. On the other hand, catalytic quantities of AcOH (entry 8) induced an increase of the yield, but involved a slightly decreasing of the enantiomeric excess. With water as additive (entries 10, 11) no significant variations were observed in the reaction rate and enantioselectivity. The reactions, carried out at lower temperatures, have shown as expected a positive effect on the catalytic efficiency and thus the best results were obtained at −20˚C but requiring prolonged reaction time (entries 12, 15). Regarding the loading of the catalyst, the reactions carried out with only 10 mol% of 2 (entries 13 - 15) provided the aldol product with almost the same enantioselectivity but with an expected decreasing of the reaction rate. In order to exclude a quite possible retro-aldol process that could lead to partial racemization, the enantiomeric excess of the reaction was measured several times throughout the reaction, showing no significant variation in value.

To explain the experimental results and especially the different behavior between catalysts 2 and 3, we proposed transition states displayed in Figure 2 for the aldol reaction. Thus, the enamine resulting from the condensation of the catalyst (S,R,R)-2 with acetone adding to the aromatic aldehyde forms a pseudo-cycle stabilized by strong binding interactions between the carbonyl oxygen and two acidic hydrogen atoms. In this cycle, the largest substituent “Ar” is located at the equatorial position. This compact and rigid transition state can explain the relative high enantiomeric excess (78%) promoting the R-isomer of the aldol product. With the isomer (S,S,S)-3 this binding interaction can arise with only one hydrogen, the second one being pushed to the rear of the figure induced by the reverse stereochemistry of the cyclohexane moiety. These very different behaviors between 2 and 3 allowed us to highlight one main characteristic required for catalysts, namely the ability to form a compact cyclic transition state induced by the presence of acidic hydrogen atoms [22] . Following these observations, we thought design proline derivatives 4, 5 and 6 having acidic hydrogen of a sulfonamide function. In addition, one could be expected a significant difference between the catalysts, given the presence in the catalyst 4 of an additional carbonyl group increasing the hydrogen acidity [23] . The experimental results of aldol reactions are displayed in Table 1. The low solubility of catalyst 4 in apolar solvents has limited the range of sol-

Figure 1. Organocatalysts derived from (R,R)- or (S,S)-1, 2-diaminocyclohexane and/or (S)-proline.

Scheme 1. Reaction conditions: (a) CF₃CO₂H, CH₂Cl₂, rt, 2 h; (b) ₂Nos-NH₂, DMAP, EDC.HCl, THF, rt, 8 h; (c) HCl/ MeOH, Et₂O; (d) Reference [18]; (e) ₂NosCl, NEt₃, CH₂Cl₂, rt, 4 h; (f) ₄NosCl, NEt₃, CH₂Cl₂, rt, 3 h.

Figure 2. Proposed transition state for the aldol reaction.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Pfau, M., Revial, G., Guingant, A. and d’Angelo, J. (1985) Enantioselective Synthesis of Quaternary Carbon Centers through Michael-Type Alkylation of Chiral Imines. Journal of the American Chemical Society, 107, 273-274. http://dx.doi.org/10.1021/ja00287a061
[2]	Pfau, M., Tomas, A., Lim, S. and Revial, G. (1995) Diastereo Selectivity in the Michael-Type Addition of Imines Reacting as their Secondary Enamine Tautomers. Journal of Organic Chemistry, 60, 1143-1147. http://dx.doi.org/10.1021/jo00110a015
[3]	List, B. (2006) The Ying and Yang of Asymmetric Amino-Catalysis. Chemical Communications, 2006, 819-824. http://dx.doi.org/10.1039/b514296m
[4]	Taylor, M.S. and Jacobsen, E.N. (2006) Asymmetric Catalysis by Chiral Hydrogen-Bond Donors. Angewandte Chemie International Edition, 45, 1520-1543. http://dx.doi.org/10.1002/anie.200503132
[5]	Pellissier, H. (2007) Asymmetric Organocatalysis. Tetrahedron, 63, 9267-9331. http://dx.doi.org/10.1016/j.tet.2007.06.024
[6]	Enders, D., Grondal, C. and Hüttl, M.R.M. (2007) Asymmetric Organocatalytic Domino Reactions. Angewandte Chemie International Edition, 46, 1570-1581. http://dx.doi.org/10.1002/anie.200603129
[7]	Chai, Z. and Zhao, G. (2012) Efficient Organocatalysts Derived from Simple Chiral Acyclic Amino Acids in Asymmetric Catalysis. Catalysis Science & Technology, 2, 29-41. http://dx.doi.org/10.1039/c1cy00347j
[8]	Pellissier, H. (2012) Asymmetric Organocatalytic Cycloadditions. Tetrahedron, 68, 2197-2232. http://dx.doi.org/10.1016/j.tet.2011.10.103
[9]	Sylla-Iyarreta Veitia, M., Joudat, M., Wagner, M., Falguière, A., Guy, A. and Ferroud, C. (2011) Ready Available Chiral Azapyridinomacrocycles n-Oxides; First Results as Lewis Base Catalysts in Asymmetric Allylation of 4-Nitro-benzaldehyde. Heterocycles, 83, 2011-2030.
[10]	Geary, L.M. and Hultin, P.G. (2009) The State of the Art in Asymmetric Induction: The Aldol Reaction as a Case Study. Tetrahedron: Asymmetry, 20, 131-173. http://dx.doi.org/10.1016/j.tetasy.2008.12.030
[11]	Trost, B.M. and Brindle, C.S. (2010) The Direct Catalytic Asymmetric Aldol Reaction. Chemical Society Reviews, 39, 1600-1632. http://dx.doi.org/10.1039/b923537j
[12]	Liu, Y.X., Yang, L., Ma, Z.W., Wang, C.C. and Tao, J.C. (2011) Research Progress in Supported Proline and Proline Derivatives as Recyclable Organocatalysts for Asymmetric C-C Bond Formation Reactions. Chinese Journal of Catalysis, 32, 1295-1311.
[13]	Roca-Lopez, D., Sadaba, D., Delso, I., Herrera, R.P., Tejero, T. and Merino, P. (2010) Asymmetric Organocatalytic Synthesis of γ-Nitrocarbonyl Compounds through Michael and Domino Reactions. Tetrahedron: Asymmetry, 21, 2561-2601.
[14]	Quintard, A., Belot, S., Marchal, E. and Alexakis, A. (2010) Aminal-Pyrrolidine Organocatalysts—Highly Efficient and Modular Catalysts for α-Functionalization of Carbonyl Compounds. European Journal of Organic Chemistry, 2010, 927-936. http://dx.doi.org/10.1002/ejoc.200901283
[15]	Tsakos, M. and Kokotos, C.G. (2012) Organocatalytic “Difficult” Michael Reaction of Ketones with Nitrodienes Utilizing a Primary Amine-Thiourea Based on Ditert-Butyl Aspartate. European Journal of Organic Chemistry, 2012, 576-580. http://dx.doi.org/10.1002/ejoc.201101402
[16]	Sun, Z.W., Peng, F.Z., Li, Z.Q., Zou, L.W., Zhang, S.X., Li, X. and Shao, Z.H. (2012) Enantioselective Conjugate Ad- dition of both Aromatic Ketones and Acetone to Nitroolefins Catalyzed by Chiral Primary Amines Bearing Multiple Hydrogen-Bonding Donors. Journal of Organic Chemistry, 77, 4103-4110. http://dx.doi.org/10.1021/jo300011x
[17]	Wang, L., Zang, X. and Ma, D. (2012) Organocatalytic Michael Addition of Aldehydes to Trisubstituted Nitroolefins. Tetrahedron, 68, 7675-7679.
[18]	Dahlin, N., Bøgevig, A. and Adolfsson, H. (2004) N-Arene-Sulfonyl-2-Aminomethylpyrrolidines. Novel Modular Ligands and Organocatalysts for Asymmetric Catalysis. Advanced Synthesis & Catalysis, 346, 1101-1105. http://dx.doi.org/10.1002/adsc.200404098
[19]	Veverková, E., Štrasserová, J., Šebesta, R. and Toma, Š. (2010) Asymmetric Mannich Reaction Catalyzed by N-Arylsulfonyl-L-proline Amides. Tetrahedron: Asymmetry, 21, 58-61. http://dx.doi.org/10.1016/j.tetasy.2009.12.013
[20]	List, B., Lerner, R.A. and Barbas III, C.F. (2000) Proline-Catalyzed Direct Asymmetric Aldol Reactions. Journal of the American Chemical Society, 122, 2395-2396. http://dx.doi.org/10.1021/ja994280y
[21]	Bisai, V., Bisai, A. and Singh, V.K. (2012) Enantioselective Organo-catalytic Aldol Reaction Using Small Organic Molecules. Tetrahedron, 68, 4541-4580. http://dx.doi.org/10.1016/j.tet.2012.03.099
[22]	Huang, X.-Y., Wang, H.-J. and Shi, J. (2010) Theoretical Study on Acidities of (S)-Proline Amide Derivatives in DMSO and Its Implications for Organocatalysis. The Journal of Physical Chemistry A, 114, 1068-1081. http://dx.doi.org/10.1021/jp909043a
[23]	Lao, J.-H., Zhang, X.-J., Wang, J.-J., Li, X.-M., Yan, M. and Luo, H.-B. (2009) The Effect of Hydrogen Bond Donors in Asymmetric Organocatalytic Conjugate Additions. Tetrahedron: Asymmetry, 20, 2818-2822. http://dx.doi.org/10.1016/j.tetasy.2009.11.029
[24]	List, B., Pojarliev, P. and Martin, H.J. (2001) Efficient Proline-Catalyzed Michael Additions of Unmodified Ketones to Nitro-Olefins. Organic Letters, 3, 2423-2425. http://dx.doi.org/10.1021/ol015799d
[25]	Betancort, J.M. and Barbas III, C.F. (2001) Catalytic Direct Asymmetric Michael Reactions: Taming Naked Aldehyde Donors. Organic Letters, 3, 3737-3740. http://dx.doi.org/10.1021/ol0167006
[26]	Lu, A., Liu, T., Wu, R., Wang, Y., Wu, G., Zhou, Z., Fang, J. and Tang, C.A. (2011) Recyclable Organocatalyst for Asymmetric Michael Addition of Acetone to Nitroolefins. Journal of Organic Chemistry, 76, 3872-3879.
[27]	Singh, K.N., Singh, P., Singh, P., Lal, N. and Sharma, S.K. (2012) Pyrrolidine Based Chiral Organocatalyst for Efficient Asymmetric Michael Addition of Cyclic ketones to β-Nitrostyrenes. Bioorganic & Medicinal Chemistry Letters, 22, 4225-4228.
[28]	Sevin, A., Tortajada, J. and Pfau, M. (1986) Toward a Transition-State Model in the Asymmetric Alkylation of Chiral Ketone Secondary Enamines by Electron-Deficient Alkenes. A Theoretical MO Study. Journal of Organic Chemistry, 51, 2671-2675. http://dx.doi.org/10.1021/jo00364a011
[29]	Sevin, A., Masure, D., Giessnerprettre, C. and Pfau, M. (1990) A Theoretical Investigation of Enantioselectivity— Michael Reaction of Secondary Enamines with Enones. Helvetica Chimica Acta, 73, 552-573. http://dx.doi.org/10.1002/hlca.19900730303
[30]	Lattanzi, A. (2009) α,α-Diarylprolinols: Bifunctional Organocatalysts for Asymmetric Synthesis. Chemical Communications, 2009, 1452-6352. http://dx.doi.org/10.1039/b900098d