ARTICLE pubs.acs.org/IECR
Cysteine-Based Organocatalysts for the Highly Efficient Direct Stoichiometric anti- and syn-Aldol Reactions Shi Li,†,§ Chuanlong Wu,†,‡,§ Xiangkai Fu,*,† and Qiang Miao† †
College of Chemistry and Chemical Engineering and Research Institute of Applied Chemistry, Southwest University of China, and The Key Laboratory of Applied Chemistry of Chongqing Municipality, Chongqing, 400715, People’s Republic of China ‡ Chongqing Unis Chemical Co. Ltd, Chongqing, 402161, People’s Republic of China
bS Supporting Information ABSTRACT: A series of cysteine-based organocatalysts have been designed and synthesized from a simple step. The anti-aldol and syn-aldol products could be obtained with up to 98:2 anti/syn and 99% ee; the stoichiometric ratio between aldehydes and ketones is 1. This catalyst could be easily recovered and efficiently used in large-scale reactions, which demonstrates its potential application in industry.
1. INTRODUCTION Asymmetric organocatalysis has become an important area of research in organic synthesis.1,2 The advent of organocatalysis brought the prospect of a complementary mode of catalysis, with the potential for savings in cost, time, and energy, an easier Table 1. Screening of Organocatalystsa
entry catalyst
experimental procedure, and reductions in chemical waste.3,4 On the other hand, the aldol reaction is recognized as one of the most important carbon carbon bond-forming reactions in modern Table 2. Effect of the Amount of the Catalyst 1c on the Organocatalyzed anti- and syn-Aldol Reactions between Cyclohexanone and Hydroxyacetone with 4-Nitrobenzaldehydea
time (h) yieldb (%) anti:sync eec (%)
solvent
1
1a
ClCH2CH2Cl
48
3a/85
90:10
75
2
1b
ClCH2CH2Cl
48
3a/85
85:15
85
3
1c
ClCH2CH2Cl
48
3a/90
84:16
90
4
1d
ClCH2CH2Cl
48
3a/88
87:13
50
5
1e
ClCH2CH2Cl
48
3a/86
95:5
46
6 7
1f 1c
ClCH2CH2Cl ClCH2CH2Cl
48 36
3a/85 4a/82
59:41 26:74
34 83
8
1c
THF
56
3a/87
82:18
83
9
1c
THF
48
4a/79
21:79
77
10
1c
CHCl3
48
3a/92
91:9
92
11
1c
CHCl3
36
4a/86
26:74
82
12
1c
CHCl3/H2O
48
3a/93
94:6
97
13
1c
CHCl3/H2O
36
4a/91
3:97
92
14 15
1c 1c
H2O H2O
56 48
3a/83 4a/69
97:3 26:74
87 70
a The reactions were performed with p-nitrobenzaldehyde (1.0 mmol), ketone (1.0 mmol) and catalyst (0.05 mmol) in solvent (0.5 mL) at room temperature. b Isolated yield. c Determined by chiral HPLC analysis (AD-H).
r 2011 American Chemical Society
entry catalyst loading (mol %) time (h) yieldb (%) anti:sync eec (%) 1
20
36
3a/95
86:14
2
20
24
4a /89
24:76
80 80
3 4
10 10
48 36
3a/94 4a /91
91:9 12:88
86 85
5
5
48
3a/93
94:6
97
6
5
36
4a/91
3:97
92
7
2
48
3a/80
86:14
82
8
2
36
4a/83
20:80
83
a
The reactions were performed with p-nitrobenzaldehyde (1.0 mmol), ketone (1.0 mmol) and catalyst 1c (see Table) in CHCl3 (0.5 mL) and water (18 μL) at room temperature. b Isolated yield. c Determined by chiral HPLC analysis (AD-H). Received: July 10, 2011 Accepted: October 29, 2011 Revised: October 28, 2011 Published: October 29, 2011 13711
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Industrial & Engineering Chemistry Research organic synthesis.5 7 The classical aldol reaction is highly atomeconomic but suffers from problems with selectivity, notably, with respect to chemo- and regioselectivity. Barbas et al.,8 11 Hayashi et al.,12 15 Gong et al.,16 20 Xiao et al.21,22 and Teo and Lee23 reported the intermolecular aldol reactions of the ketone-aldehyde type and aldehyde-aldehyde type catalyzed by L-proline, serine, or their derivatives and analogues. Synthesis of a series of widely used industrial catalyst requires the following conditions: it should be easy Scheme 1. Synthesis of Catalysts 1a 1f
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to synthesize, and the initial material should be cheap and easy to obtain. Currently, aldol reaction catalysts sometimes are complicated, and although a relatively small amount of catalyst (1 5 mol %) is added, the cost is high. Then, in catalytic reaction, the stoichiometric ratio between aldehydes and ketones should be 1:1.24 When an expensive ketone is used in large excess, it is not reassuring for the direct aldol reaction with atom-economical “green” credentials.25 These will raise a cost concern when large amounts of chiral materials or a large excess of ketone are used for a large-scale synthesis in industrial applications. Moreover, the catalyst should be recyclable. In large-scale processes, it should maintain high enantioselectivity. However, their shortcomings have also been realized. One of the major limitations of using organocatalyst catalyzed reactions is the high catalyst loading (10 30 mol %) generally required to complete the transformations in large equivalents of ketone in reasonable time scales. This will raise a cost concern when large amounts of chiral materials are used for a large-scale synthesis in industrial applications. Our group carried out a series of reactions about threonine, serine, and cysteinebased organocatalysts for Aldol and Mannich reactions.26 30
Table 3. Organocatalyst 1c-Catalyzed Direct Stiochiometric anti-Aldol Reactionsc
a Isolated yield. b Determined by chiral HPLC analysis (AD-H and OD-H). c The reactions were performed with aldehyde (1.0 mmol), ketone (1.0 mmol) and 1c (0.05 mmol) in CHCl3 (0.5 mL) and water (18 μL) at room temperature.
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Table 4. Direct Stiochiometric syn-Aldol Reaction of Hydroxyacetone with Various Aromatic Aldehydesc
a Isolated yield. b Determined by chiral HPLC analysis (AD-H, OJ-H and OD-H). c The reactions were performed with aldehyde (1.0 mmol), hydroxyacetone (1.0 mmol) and 1c (0.05 mmol) in CHCl3 (0.5 mL) and water (18 μL) at room temperature.
These catalysts have achieved high efficiency, but the use of less volatile ketones in large excess limits their application for industry. On the basis of these points, it is valuable to synthesize an easy, cheap, and recyclable catalyst in the aldol reaction and for which the stoichiometric ratio between aldehydes and ketones is 1.
2. RESULTS AND DISCUSSION With the aim to discover simple and cheap organocatalysts for the direct asymmetric stiochiometric aldol reaction, we prepared
eight new cysteine derivatives 1a f (Scheme 1).21 32 The organocatalyzed stoichiometric aldol reaction was carried out using both cyclohexanone and hydroxyacetone with 4-nitrobenzaldehyde as a model reaction to investigate different parameters.33 As can be seen from the summarized results in Table 1, all the catalysts can catalyze the asymmetric direct intermolecular stiochiometric anti-aldol reaction of 4-nitrobenzaldehyde and cyclohexanone to give the product in good yields (85 90%) with different ee values (34 90% ee for anti) in ClCH2CH2Cl at room temperature (Table 1, entries 1 6); neither very long nor 13713
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Table 5. Recycling and Reuse of Catalyst 1cc
Table 6. Large-Scale Asymmetric Stiochiometric anti- and syn-Aldol Reactionsc
run
time(h)
yielda (%)
anti:synb
eeb (%)
1 2
24 30
91 89
96:4 95:5
94 92
3
30
89
95:5
90
4
36
86
93:7
89
5
42
84
90:10
89
6
48
80
90:10
86
a
Isolated yield. b Determined by chiral HPLC analysis (AD-H). c The reactions were performed with aldehyde (50 mmol), ketone (50 mmol) and 1c (2.5 mmol) in CHCl3 (25 mL) and water (0.9 mL) at room temperature.
very short chains were effective. Therefore, we chose 1c (Table 1, entry 3) as a catalyst for the stiochiometric aldol reaction. A solvent screening was then performed at room temperature to identify the best stiochiometric anti- and syn-aldol reaction conditions (Table 1, entries 7 15). From Table 1, CHCl3/ H2O (1 equiv) mixed solvent was selected as the solvent for the anti- and syn-aldol reactions. Then, we investigated the effects of catalyst loading on the reactions of both cyclohexanone and hydroxyacetone with 4-nitrobenzaldehyde (Table 2). Noticeably, using 5 mol % of catalyst, we obtained a good yield with excellent stereoselectivity (Table 2, entry 5 and entry 6). Thus, the optimized catalyst loading was chosen as 5 mol % of 1c. To test the substrate generality of this organocatalyzed direct stiochiometric aldol reaction, the reactions of various aromatic aldehydes with cyclic ketones were studied under the optimized conditions. The results are summarized in Table 3. It can be seen that a wide range of aromatic aldehydes can effectively participate in the stiochiometric aldol reactions. In general, the reaction between cyclohexanone and aromatic aldehydes bearing electron-withdrawing substituents furnished β-hydroxy carbonyl anti-aldol products in excellent yields (82 96%) within 48 60 h (Table 3, entries 1 9). In contrast, longer reaction time (72 h) were required for aromatic aldehydes containing an electron-donating group to give comparatively lower yields (75 76%) (Table 3, entries 10 12). This can be explained in that electron withdrawing groups enhance the electrophilicity of carbonyl carbons in aldehydes which facilitates the reaction, while electron-donating groups lessen the electrophilicity. Moreover, the direct stiochiometric aldol reaction of neutral aldehydes catalyzed by the cysteine-based organocatalyst 1c also afforded the aldol products in high enantioselectivities and diastereoselectivities (Table 3, entries 13 16). In particular, good yields of 90 92% with excellent enantioselectivities (90 94% for the anti-isomer) were obtained, however, and the diastereoselectivities (anti/syn) ranging from 55:45 to 62:38 (Table 3, entries 17 19). N-(tert-butoxycarbonyl)-4-piperidone and tetrahydrothiopyran-4-one also were effective in this transformation to provide anti-aldol adducts 3v and 3w, especially the tetrahydrothiopyran-4-one (Table 3, entry 23, 94:6 anti/syn ratio and >99% ee). Next, we focused our attention on the intermolecular syn-aldol reaction. In the presence of only 5 mol % of catalyst 1c, most
a Isolated yield. b Determined by chiral HPLC analysis (AD-H). c The reactions were performed with aldehyde (2 mol), and ketone (2 mol) and catalyst 1c (0.1 mol) in CHCl3 (1 L) and water (36 mL) at room temperature.
reactions between hydroxyacetone and various aromatic aldehydes afforded the syn-aldol products in good yield and excellent ee in CHCl3/H2O (1 equiv). The syn-aldol reactions promoted 5 mol % 1c afforded syn-aldol products in good yields (68 96%) with high diastereomeric ratios (syn/anti 80/20 97/3) and excellent enantioselectivities (87 97% for syn-isomer) at room temperature. Interestingly, the substituents of benzaldehydes, regardless of their size and electron nature, have little effect on the enantioselectivity (Table 4, entries 1 13). Meanwhile, to verify that the cysteine derivative organocatalyst 1c could be recovered and reused, we performed a recycling study of 1c using the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde (Table 5). In the first place, chloroform was evaporated out from the mixed solvents; the catalyst 1c could be easily recovered from the reaction mixture after completion of the reaction by 2.5 mmol HCl, aldol product was extracted with ethyl ether (Et2O), evaporation of the organic solution to obtain the aldol product. The catalyst 1c exists in the acidic aqueous layer; on adding an equivalent amount of triethylamine (Et3N) into the system, a white suspension could then be obtained. 13714
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Industrial & Engineering Chemistry Research The suspension was stirred at room temperature for 10 min and filtered by vacuum. The white crystals were used directly in subsequent reaction cycles without adding any new catalyst. In each reuse, the same amounts of substrates were used, and the recovered catalyst 1c retained essentially its catalytic activity without further purification. No significant decrease in the enantioselectivity was observed over six cycles (Table 5). We performed large-scale asymmetric aldol reactions with 2 mol of aromatic aldehydes and 1 equiv of ketones using a 2 L round-bottomed flask. The same catalyst loading of 5 mol % as in the experimental scale was used. The large-scale experiments can be facilely carried out using the same procedure as for the experimental scale reactions. As can be seen from the results summarized in Table 6, to our delight, the enantioselectivities were maintained at the same level for the large-scale reactions.
3. RESEARCH HIGHLIGHTS • In aldol reactions, the stoichiometric ratio between aldehydes and ketones is 1. • These cysteine-based organocatalysts were sufficient to furnish the anti- and syn-aldol products in excellent yields (up to 96%) and enantioselectivities (up to 99%). • The cysteine derivative organocatalyst 1c could be easily recycled and recovered. • This catalyst could be efficiently used in large-scale reactions. 4. CONCLUSIONS In conclusion, we have designed and synthesized a new series of combined cysteine-surfactant organocatalysts in one step, and first reported that the cysteine-based organocatalyst 1c is a robust and effective catalyst for highly enantioselective stiochiometric anti- and syn-aldol reactions in the presence of water. A wide range of aromatic aldehydes with cyclic ketones and unprotected hydroxyacetone can effectively participate in the aldol reaction. The catalyst can be readily recovered and reused without significant loss of catalytic activity and stereoselectivity. Notably, these organocatalyzed asymmetric direct stiochiometric anti- and syn-aldol reactions can be performed on a large-scale with the enantioselectivities being maintained at the same level, which demonstrates their potential application in industry. ’ ASSOCIATED CONTENT
bS
Supporting Information. Further details are given about the pexperimental procedures and results. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Phone: (+86)-23-68253704. Fax: (+86)-23-68254000. E-mail:
[email protected]. Author Contributions §
These two authors contributed equally to this work.
’ ACKNOWLEDGMENT The authors are grateful to Southwest University of China for financial support.
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