The smallest organocatalyst in highly enantioselective direct aldol reaction in wet solvent-free conditions

Abstract

The catalytic efficacy of the smallest organocatalyst, L-proline hydrazide, prepared from a cheaply available natural amino acid, such as L-proline, was studied for the direct asymmetric aldol reaction of various ketones with aromatic aldehydes at room temperature in the presence of several acid additives. A loading of 10 mol% of catalyst 1 and p-toluenesulphonic acid as an additive was employed in this reaction, and good yields (up to 99%) with high anti/syn diastereoselectivities (up to 95 : 5) and enantioselectivities (up to >99.9%) were achieved in aqueous media.

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Asymmetric organocatalysis, a metal-free catalysis, is currently a widely used environmentally benign catalytic methodology in asymmetric organic synthesis.¹ The past two decades have witnessed an explosive growth in the field of asymmetric organocatalysis, in which water has been used as a solvent or co-solvent.^2,3 The pioneering observations reported by Breslow et al. and Grieco et al. on the Diels–Alder reaction in the early 1980s revealed the new concept regarding the improved effect of water on reaction rates and regioselectivities compared with organic solvents.⁴ The use of water as a reaction media in organocatalyzed asymmetric organic transformations has many advantages because it is abundant, safe, and environmentally benign.^3b,5 Moreover, it can significantly influence the course of a reaction via increased hydrophobic–hydrophobic interaction and hydrogen-bond formation between the reactants and water molecules, resulting in high reactivity and stereoselectivity.^2c,6 Since Breslow's observation, existence of such interactions and their effects are now a well-documented fact in aqueous-phase reactions irrespective of “in water” or “on water” concept in the background.^2c,7 In this direction, massive efforts have been concentrated on the development of L-proline- and 4-hydroxy-L-proline-based organocatalysts by primarily modifying their basic skeletons in three ways.^8–10 One modification was aimed at the carboxylic-acid functionality,^3c,8 another was performed on the hydroxyl group of 4-hydroxy-L-proline,^6a,9 whereas the third was performed on both groups simultaneously.¹⁰ Suitably substituted molecules from L-proline and 4-hydroxy-L-proline have been found to act as efficient chiral catalysts for different asymmetric carbon–carbon bond-forming reactions in aqueous media.^2b The modified catalysts were mostly bulky molecules, which were conjugates of two or more molecular units such as 4-hydroxy-L-proline or L-proline or its derivatives.^2b,8–10 It is well known that in organic solvents, the smallest organocatalyst, L-proline, requires high loadings (∼30 mol%) and does not catalyze the aldol reaction in water.^11a Some of the examples are present in the literature where aldol reactions were performed under wet solvent-free or solvent-free conditions with moderate to high asymmetric induction.^8w,9f,11b,c In addition, there are few examples where small modifications on the L-proline structure generated organocatalysts, which showed poor to moderate catalytic activity in aqueous media.^8b,u,v Simple amino acids could also provide abysmally low yields of aldol product in water, unless derivatized with a suitable hydrophobic group.^3f In fact, some efficient organocatalysts derived from L-proline have been reported with double hydrogen-bonding ability in aqueous media but these catalysts were structurally not very small.^{3e,6b,8q,s,12} Now, the question is why would L-proline itself or a very negligibly modified L-proline-based organocatalyst not be able to impart good stereoselectivity in aqueous media? Is it because of any lack of suitable placement of more than one hydrogen-bonding unit in the catalyst structure? Therefore, we are interested in identifying an organocatalyst that is structurally very small and the missing link between the L-proline and its longer derivatives in an aqueous environment. Herein, we present the smallest chiral organocatalyst, L-proline hydrazide 1, for direct aldol reactions in aqueous environment. Such a small molecule containing a simple hydrazide unit has never been reported as an asymmetric organocatalyst for any carbon–carbon bond-forming reaction in wet solvent-free conditions. The idea of selecting such a system is to achieve a small but strong hydrogen-bond-forming pocket in the catalyst structure. Our presumption has been proven to be true; catalyst 1 provided aldol products during the reaction between aromatic aldehydes and ketones with good yields (up to 99%), high anti/syn diastereoselectivities (up to 95 : 5) and enantioselectivities (up to >99.9%) in wet solvent-free conditions.

The L-proline hydrazide 1 was synthesized from readily available L-proline using an inexpensive reagent such as hydrazine in two simple steps after slight modification of the reported method (Scheme 1).¹³ For the esterification step, acetyl chloride was used instead of thionyl chloride and a better overall yield (77%) was obtained using our modified method.

Scheme 1

Aldol reactions were systematically carried out using 4-nitrobenzaldehyde and cyclohexanone as substrates to optimize different parameters such as the volume of water, catalyst loading, and the effect of acid additives for this small organocatalyst 1. It is reported that for aldol reactions performed under wet solvent-free conditions, the reactivity and stereoselectivities are significantly influenced because of such factors as increased hydrophobic interactions between the substrate molecules as well as hydrogen-bond formation between the reactants and water molecules in the transition state.^2c In our experiments, it has been observed that there was gradual deterioration in the enantioselectivities in the aldol products from 93% to 38%, with an increase in the amount of water from 0.01 ml to 1 ml in the presence of 4-nitrobenzoic acid as an acid additive (Table 1, entry 2–5). The same reaction, even in the absence of water, did not improve enantiomeric excess (Table 1, entry 1). This indicates that an appropriate amount of water is necessary for the formation of suitable micelles, in which stereo-controlled hydrophobic interactions and hydrogen bonding between the organic reactants can occur to obtain enhanced stereoselectivity. We also observed that when the reaction was carried out with 10 mol% of catalyst 1 in 0.01 ml of water in the absence of 4-nitrobenzoic acid, the enantioselectivity dropped from 93% to 77% (Table 1, entries 2 and 6). Thus, it is clear from the aforementioned experiments that an appropriate volume of water and the presence of a suitable acid additive are essential for obtaining optimum results for a particular organocatalyst. Previously reported studies also support the fact that water volume and acid additives can significantly influence the yield as well as the stereoselectivity in organocatalyzed synthesis in aqueous media.^2c,8l,w,x In this case, the optimum volume of water was determined to be 0.01 ml with catalyst 1 for the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde at room temperature in the presence of 4-nitrobenzoic acid as an acid additive (Table 1, entry 2).

Table 1 Effect of water volume and catalyst loading in aldol reaction between cyclohexanone and 4-nitrobenzaldehyde catalyzed by 1

Entry	Catalyst 1 (mol%)	H2O (ml)	Time (h)	Yield^a (%)	anti/syn^b	ee^c
a Isolated yield after purification by column chromatography.b Diastereomer ratios (anti/syn) were determined by ^1H NMR spectrum of the crude product mixture.c Determined by chiral HPLC analysis.d In the absence of 4-nitrobenzoic acid additive.
1	10	—	22	95	78/22	50
2	10	0.01	24	95	86/14	93
3	10	0.1	48	90	87/13	86
4	10	0.5	72	96	72/28	70
5	10	1	96	90	65/35	38
6^d	10	0.01	20	96	81/19	77
7	1	0.01	96	81	72/28	48
8	5	0.01	72	86	69/31	54
9	20	0.01	20	98	83/17	86
10	—	0.01	—	—	—	—

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After optimizing the volume of water, we investigated the amount of catalyst loading. With an increase or decrease in the catalyst loading from 10 mol%, enantioselectivity dropped from 93% to 86% and 48%, respectively, at room temperature for the same aldol reaction (Table 1, entries 7–9). It is notable that with a gradual increase in catalyst loading from 1 mol% to 20 mol%, the yield of aldol product jumped from 81% to 98%, whereas the reaction time was reduced from 96 h to only 20 h (Table 1). A blank experiment was carried out in the absence of the catalyst 1 and we observed that there was no product formation even after 5 days (Table 1, entry 10).

Once the volume of water (0.01 ml) and catalyst loading (10 mol%) was optimized, we began screening various acid additives to determine the most appropriate additive for our catalyst 1 in the same aldol reaction between p-nitrobenzaldehyde and cyclohexanone. A broad spectrum of acid additives with a long range of pK_a, starting from simple aromatic acids such as benzoic acid, 4-nitrobenzoic acid, picric acid to p-toluenesulphonic acid, were chosen for the optimization study (see ESI, Table 2†). The effect of long-chain fatty acids such as stearic and oleic were also tested in this reaction. Although the reactions were comparatively faster in the presence of these fatty acids, the enantioselectivities were not very impressive. At the outset, PTSA has been determined to be the best acid additive for the hydrazide 1-catalyzed aldol reaction in water at room temperature with 99% yield and 97% enantiomeric excess (see ESI, entry 1, Table 2†). In the aforementioned experiments, although a non-linear relationship (specifically a non-monotonic relationship) between the pK_a and the obtained ees have been observed, we were observed that the strongest acid additive, such as PTSA, among the screened acids provided the best results in terms of yield (99%), anti : syn ratio (93 : 7) and enantioselectivity (97%). This result indicates the requirement of a strong acid additive for achieving the best results for the present catalyst 1. Nevertheless, presently, we are unsure of the existence of any additional fundamental effects of acid additives exist in the solution in addition to the established facts such as reactivity enhancement through hydrogen bonding and maintaining the pH of the reaction media.

Finally, we have screened many substituted aromatic aldehydes for aldol reactions between various cyclic aliphatic ketones, such as cyclopentanone, cyclohexanone, and open-chain ketones, such as acetone, to investigate the general efficacy of this small hydrazide catalyst 1 in water under optimized conditions (Table 2). For substrates containing an electron-withdrawing group, such as p/m-nitrobenzaldehydes, and an electron-donating group, such as p-chlorobenzaldehyde and o-methoxybenzaldehyde, responded well in the presence of catalyst 1 as far as the enantioselectivity of the aldol product is concerned. Perhaps some of the substrates provided very poor enantioselectivity but the entire results are extremely significant since catalyst 1 is very small and does not possess significant bulk around the catalytic site. This preliminary observation has been recorded in Table 2. We have also observed an extremely fast reaction when acetone and cyclopentanone were the aldol donors in the presence of catalyst 1. The reactions were completed within 6–8 h with impressive enantioselectivity (Table 2, entries 14 and 15). These results are highly encouraging as far as such a small-sized organocatalyst is concerned in aqueous media.

Table 2 Substrate scope was investigated under optimal conditions and organocatalyst 1 catalyzed direct aldol reactions in the presence of water

Entry (product no.)	R3CHO	Time (h)	Yield^a (%)	anti/syn^b	ee^c (%) (anti)
a Isolated yield after purification by column chromatography.b Diastereomer ratios (anti/syn) were determined by ^1H NMR spectrum of the crude product mixture.c Determined by chiral HPLC analysis.
1 (2a)	p-NO2-C6H4-CHO	72	99	93/7	97
2 (2b)	m-NO2-C6H4-CHO	36	87	91/9	98
3 (2c)	o-NO2-C6H4-CHO	36	85	89/11	88
4 (2d)	o-F-C6H4-CHO	48	86	88/12	68
5 (2e)	m-F-C6H4-CHO	36	87	73/27	32
6 (2f)	o-MeO-C6H4-CHO	72	86	92/8	89
7 (2g)	o-Cl-C6H4-CHO	48	83	95/5	64
8 (2h)	m-Cl-C6H4-CHO	36	85	85/15	46
9 (2i)	p-Cl-C6H4-CHO	48	87	89/11	91
10 (2j)	p-Me-C6H4-CHO	48	87	84/16	49
11 (2k)	1-Naphthaldehyde	60	84	82/18	44
12 (2l)	2-Naphthaldehyde	72	85	86/14	61
13 (2m)	p-CF3-C6H4-CHO	36	96	93/7	80
14 (3a)	p-NO2-C6H4-CHO	8	91	—	98
15 (3b)	p-NO2-C6H4-CHO	6	96	94/6	>99.9

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The most probable transition state for the hydrazide 1-catalyzed aldol reaction has been depicted in Fig. 1 similar to the one in the previously reported.^8l,w,14,15 In the T.S. 1, we have considered the anti-enamine at the below and the aldehyde acceptor in the upper face where the –CO–NH–NH₂ moiety of the catalyst 1 is present, and a strong hydrogen bonding effectively results in a stable and favorable transition state, leading to the formation of the corresponding anti-enantiomer as a major enantiomer. Whereas in the case of another T.S. 2 for the formation of minor anti-enantiomer described by Noto et al., considering the syn-enamine at the below and aldehyde at the above with an aromatic group toward the hydrophilic region, is unfavorable due to the hydrophobic–hydrophilic interaction.¹⁴ The aromatic moiety will always remain toward the hydrophobic region for a better hydrophobic–hydrophobic interaction in an aqueous environment. The syn-enantiomers are also unfavourable for the similar reason reported in the literature.¹⁴

Fig. 1 Proposed transition state model for major and minor anti-enantiomers.

In summary, we have found a catalyst 1, which is the smallest organocatalytic system reported thus far in the literature for an aqueous-phase asymmetric aldol reaction. The attachment of a hydrazide unit in the L-proline structure has been proven to be very effective for the reactivity and enantioselectivity in the aldol reaction. The existence of a suitable hydrogen-bonding pocket (two hydrogen bonds within a short space) in the catalyst structure is considered to be the probable reason for this impressive result. It should be noted that the L-proline hydrazide 1 is the smallest and, most importantly, the best among the small organocatalysts in an aqueous environment reported thus far in the literature.^3f,8b,u,v Some substrates screened in the presence of this small catalyst 1 provided enantioselectivity higher than 90%, which is an undoubtedly impressive result so far as the least bulk around the active site of the catalyst is concerned in aqueous media. Additional structural modification on catalyst 1 considering the steric and electronic effect is under way in our laboratory to thoroughly understand the detailed catalytic activity in an aqueous-phase aldol reaction. The present work will guide us in the future to identify the minimum bulk (steric environment) as well as the hydrogen-bonding unit (electronic environment) required in the organocatalyst structure in an aqueous environment.

Acknowledgements

This work has been funded by Department of Science and Technology, Government of India [Grant no. SR/FT/CS-013/2009]. S.B. acknowledges support from the University Grants Commission, Government of India, through a research fellowship.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, NMR, spectra, and HPLC traces. See DOI: 10.1039/c4ra02690j

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