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Synlett 2013; 24(7): 839-842
DOI: 10.1055/s-0032-1318491
letter
© Georg Thieme Verlag Stuttgart · New York

Highly Enantioselective Organocatalytic Michael Addition of Ketones to Nitroolefins in the Presence of Water

Qiankun Chen
Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA   Fax: +1(903)4686020   Email: bukuo.ni@tamuc.edu
,
Yupu Qiao
Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA   Fax: +1(903)4686020   Email: bukuo.ni@tamuc.edu
,
Bukuo Ni*
Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA   Fax: +1(903)4686020   Email: bukuo.ni@tamuc.edu
› Author Affiliations
Further Information

Publication History

Received: 04 February 2013

Accepted after revision: 01 March 2013

Publication Date:
11 March 2013 (online)

 
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Abstract

Chiral pyrrolidine-based organocatalysts, in combination with ionic-liquid-supported Brønsted acids, catalyze the enantioselective Michael addition of ketones and aldehyde to nitroolefins in high yields with high enantioselectivities (ee ≤ 96%) and diastereoselectivities (syn/anti ratio ≤ 98:2). This novel process provides synthetically useful γ-nitrocarbonyl compounds, which can be easily transformed into other invaluable precursors of biologically active compounds. In addition, the synthetic procedure presented is simple and practical.


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Key words

organocatalysts - asymmetric synthesis - Michael addition - ketones - nitroolefins

The organocatalytic enantioselective Michael addition of ketones or aldehydes to electron-deficient nitroolefins is one of the most powerful tools for the stereocontrolled formation of carbon–carbon bonds in organic synthesis.[ 1 ] The resulting optically active Michael adducts, γ-nitrocarbonyl compounds, are versatile building blocks since the nitro and carbonyl groups can be further transformed into other invaluable precursors of biologically active compounds.[ 2 ] As a consequence, a great deal of effort has been devoted toward the development of more active and stereoselective organocatalysts for this cornerstone reaction, and significant progress has been achieved in recent years.[ 3 ] Especially, the pyrrolidine-based secondary amines, which stand out as one of the most efficient and enantioselective catalysts with broad substrate generality, have expanded the scope of organocatalysis.[ 4 ] However, most of organocatalytic reactions are performed in organic solvents, and only limited reactions have been reported which effectively proceed in water with high enantioselectivities.[ 5 ] From a green chemistry perspective, the use of water instead of organic solvent has many advantages in terms of economic, environmental, and processing benefits. Therefore, it would be highly desirable to develop a water-compatible organocatalyst that effectively catalyzes asymmetric Michael addition in water with high selectivity.

Recently, chiral pyrrolidine derivative organocatalysts, bearing long alkyl side chains,[ 6 ] naphthyl,[ 7 ] and bulky[ 8 ] groups, have been developed for asymmetric Michael addition of ketones or aldehydes to nitroolefins in aqueous media with high stereoselectivity (Figure [1]).[ 9 ] However, all these organocatalysts developed for asymmetric Michael addition in aqueous media have a common feature that the catalysts were specifically designed to contain large hydrophobic groups (long alkyl side chains, naphthyl, and bulky groups), which accurately serve as a ‘concentrated organic phase’.[ 10 ] The hydrophobicity of these catalysts forces them into close contact with hydrophobic reactants in water and excludes the reaction transition state from water. Interestingly, to the best of our knowledge, there is no report in the literature using such pyrrolidine derivative bearing hydrophilic or less hydrophobic groups (short alkyl side chain) as an efficient organocatalyst for the asymmetric Michael addition in aqueous media.[ 11 ]

Zoom Image
Figure 1 Examples of organocatalysts for the asymmetric Michael addition in water

To this end, our group has recently developed such organocatalysts, which possess hydrophilic groups and promote highly asymmetric transformations in aqueous media.[ 12 ] With our continuing goal of developing water-compatible catalysts that display high activity and enantioselectivity in aqueous media, we wish to report the chiral pyrrolidine–ionic-liquid-supported (ILS) Brønsted acid conjugates as effective catalysts for the asymmetric direct Michael addition of ketones to nitroolefins in high yields (≤ 99%) and stereoselectivities (ee ≤ 96%, syn/anti ≤ 98:2).

Zoom Image
Figure 2 Pyrrolidine-based organocatalysts 1a–e and ionic liquid supported Brønsted acid 2–4

To examine the performance of catalysts 1a–e,[ 4g ] , [13] [14] [15] the Michael addition of cyclohexanone with nitrostyrene was selected as a model reaction for screening the catalysts and Brønsted acids as additives (Figure [2]). The results are listed in Table [1]. Initially, the reaction was performed in water with 20 mol% of catalyst 1a in the presence of ILS benzoic acid 2a as additive. The reaction proceeded smoothly to afford the Michael adduct 5a in good yield (79%) and diastereoselectivity (syn/anti = 89:11), but in low enantioselectivity (ee: 17%, Table [1], entry 1). Among this series of catalysts examined, diamine catalyst 1e in combination with 2a gave the best yield (91%) as well as enantio- and diastereoselectivity (ee: 88%, syn/anti = 95:5, Table [1], entries 2–5).[ 16 ] However, when general Brønsted acids (TsOH and TFA) were used as additives, only powdery and insoluble solid side products were formed (Table [1], entries 7 and 8). The same phenomenon of polymerization of nitrostyrene was observed by Barbas’ research group using A (Figure [1]) as catalyst and TFA as additive in water.[ 17 ] Interestingly, when catalyst 1e in combination with benzoic acid was used as catalytic system, Michael adduct 5a was obtained in moderate yield (78%) with high stereoselectivity (ee = 88%, syn/anti = 95:5, Table [1], entry 9). In light of the above results, we further optimized the reaction conditions using catalyst 1e by screening acid additives. The influence of catalyst loading was also investigated (Table [1], entries 6 and 10–14). When the amount of catalyst 1e and ILS acidic additive 2a were decreased to 10 mol%, the reaction time was increased to 12 hours with comparable yield and stereoselectivity (Table [1], entry 5 vs. entry 10). Other ILS acidic additives 2b, 3a,b, and 4 were also examined (Table [1], entries 6 and 11–13), and the use of acid 3a provided the best results in terms of both the yield (99%) and selectivity (ee = 92%, syn/anti = 97:3, Table [1], entry 12). Further decrease in both the catalyst 1e and acid 3a loading to 5 mol%, the reaction time was increased to 36 hours with slightly dropped selectivity (Table [1], entry 14). The absolute stereochemical outcome of product 5a can be explained by a model based on the literature.[ 6a ]

Table 1 Optimization of the Reaction Conditions of Cyclohexanone to Nitrostyrenea

Entry

Catalyst (mol%)b

Time (h)

Yield (%)c

ee (%)d

syn/anti e

 1

1a/2a (20)

 2

79

17

89:11

 2

1b/2a (20)

 2

91

66

93:7

 3

1c/2a (20)

 2

85

68

94:6

 4

1d/2a (20)

 2

75

69

92:8

 5

1e/2a (20)

 2

91

88

95:5

 6

1e/4 (20)

 2

71

88

85:15

 7

1e/TFA (20)

 2

f

–

–

 8

1e/TsOH (20)

 2

f

–

–

 9

1e/PhCO2H (20)

 2

78

88

95:5

10

1e/2a (10)

12

92

89

95:5

11

1e/2b(10)

12

85

90

95:5

12

1e/3a (10)

10

99

92

97:3

13

1e/3b (10)

10

97

87

94:6

14

1e/3a (5)

36

90

91

93:7

a Reactions performed on 0.4 mmol scale using catalyst 1a–e, additives, cyclohexanone (5 equiv), and H2O (0.8 mL).

b Equivalent amount of catalyst and additive were used.

c Isolated yield.

d Determined by chiral HPLC of the product.

e Determined by 1H NMR spectroscopy.

f Polymerization.

On the basis of the results summarized in Table [1], the reaction conditions of entry 12 (Table [1]) were chosen to study the scope of the asymmetric Michael addition of a few cyclic ketones to a variety of nitroolefins with catalyst 1e in combination with acid additive 3a, and the results are summarized in Table [2].[ 18 ] The results showed that the reactions proceeded efficiently with cyclohexanone and nitroolefins bearing both electron-deficient and electron-rich substituents on the phenyl ring affording the corresponding products 5b–i in high yields (84–99%) with high selectivities (ee ≤ 92%, syn/anti ≤ 98:2, Table [2], entries 1–8). Tetrahydrothiopyran-4-one was also a suitable Michael donor and afforded the corresponding Michael adduct 5j in 98% yield with 96% ee and a syn/anti ratio of 95:5 (Table [2], entry 9). 2-(2-Nitrovinyl)furan was also a suitable Michael acceptor (Table [2], entry 10). However, when cyclopentanone was used as a substrate, only moderate yield and enantioselectivity were obtained despite of high diastereoselectivity (Table [2], entry 11). Acetone was also examined as a Michael donor; however, only a powdery and insoluble solid side product was formed. Furthermore, catalyst 1e is also effective for the Michael addition of the aldehyde pentanal to nitrostyrene providing the desired product 5m in good yield (80%) and enantioselectivity (75% ee, Table [2], entry 12).

Table 2 Michael Addition of Ketones to Nitroolefinsa

Entry

R1, R2

Ar

Time (h)

Yield (%)b

ee (%)c

syn/anti d

 1

(CH2)4

4-MeC6H4

10

5b 98

90

94:6

 2

(CH2)4

4-MeOC6H4

12

5c 97

92

93:7

 3

(CH2)4

3-MeOC6H4

12

5d 98

90

98:2

 4

(CH2)4

2-FC6H4

12

5e 98

92

97:3

 5

(CH2)4

4-ClC6H4

16

5f 84

89

94:6

 6

(CH2)4

4-BrC6H4

10

5g 98

91

94:6

 7

(CH2)4

2-BrC6H4

14

5h 86

91

97:3

 8

(CH2)4

4-O2NC6H4

 8

5i 99

90

95:5

 9e

C2H4SCH2

Ph

 9

5j 98

96

95:5

10

(CH2)4

2-furyl

10

5k 99

92

94:6

11

(CH2)3

Ph

24

5l 60

57

94:6

12

H, n-Pr

Ph

36

5m 80

75

71:29

a Reactions performed on 0.4 mmol scale using ketones (5 equiv) in H2O (0.8 mL).

b Isolated yield.

c Determined by chiral HPLC of the product.

d Determined by 1H NMR spectroscopy.

e Ketone (3 equiv) was used.

In conclusion, a highly efficient asymmetric Michael addition of ketones and aldehyde to nitroolefins catalyzed by a water-compatible organocatalyst, diamine 1e in combination with ILS sulfonic acid 3a, in water has been developed. The present reactions accommodated a range of Michael acceptors providing products in high yields, high enantio- and diastereoselectivities under rather mild reaction conditions. In addition, the synthetic procedure presented is simple. These remarkable advantages make this approach very suitable for practical use.


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Acknowledgment

This research was supported by start-up funds from the College of Science, Engineering & Agriculture, Texas A&M University-Commerce and National Science Foundation (CHE-1213287). We also gratefully acknowledge Prof. Allan D. Headley for his fruitful discussion for this research work.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
  • Supporting Information


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Zoom Image
Figure 1 Examples of organocatalysts for the asymmetric Michael addition in water
Zoom Image
Figure 2 Pyrrolidine-based organocatalysts 1a–e and ionic liquid supported Brønsted acid 2–4