Pyrrolidine–diaminomethylenemalononitrile organocatalyst for solvent-free asymmetric direct aldol reactions

Pyrrolidine–diaminomethylenemalononitrile organocatalyst for solvent-free asymmetric direct aldol reactions

Tetrahedron Letters 56 (2015) 558–561 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet...

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Tetrahedron Letters 56 (2015) 558–561

Contents lists available at ScienceDirect

Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Pyrrolidine–diaminomethylenemalononitrile organocatalyst for solvent-free asymmetric direct aldol reactions Kosuke Nakashima a, Shin-ichi Hirashima a, Hiroshi Akutsu a, Yuji Koseki a, Norihiro Tada b, Akichika Itoh b, Tsuyoshi Miura a,⇑ a b

Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan

a r t i c l e

i n f o

Article history: Received 8 September 2014 Revised 13 November 2014 Accepted 25 November 2014 Available online 9 December 2014

a b s t r a c t Pyrrolidine–diaminomethylenemalononitrile (pyrrolidine–DMM) organocatalyst has been an efficient reaction medium to promote asymmetric direct aldol reactions to afford the corresponding addition products in high yields with up to 99% ee under solvent-free conditions. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Organocatalyst Diaminomethylenemalononitrile Aldol Ketone Solvent-free

Development of solvent-free reactions is one of the most significant research themes in the field of green chemistry because solvent-free conditions afford many valuable benefits involving short reaction times, easy work-up procedures, simple reactors, and environmentally benignancy.1 Organocatalysts are often used for reactions under solvent-free conditions due to their mild reactivity. Since catalytic activity of L-proline for direct aldol reactions was reported,2 various types of aldol reactions using organocatalysts accomplished remarkable developments over the past decade.3 Several research groups have reported direct aldol reactions using organocatalysts under solvent-free conditions.4 Organocatalysts with double hydrogen donating functional groups, such as thiourea 1 and squaramide 2, show highly efficient catalytic activity for various asymmetric reactions and make it possible to readily produce enantiomerically enriched molecules (Fig. 1).5 The double hydrogen donating functional groups play an important role in the appearance of catalytic activity. Recently, we revealed that the diaminomethylenemalononitrile (DMM) motif is an efficient double hydrogen donating functional group; DMM organocatalysts 3–5 promote the conjugate additions of aldehydes to vinyl sulfone6 and Michael addition of malonates to enones under solvent-free conditions,7 conjugate addition of 1,3-dikentone to nitroalkenes,8 and Michael additions of ketones to ⇑ Corresponding author. Tel./fax: +81 42 676 4479. E-mail address: [email protected] (T. Miura). http://dx.doi.org/10.1016/j.tetlet.2014.11.117 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

nitroalkenes,9 respectively. To demonstrate further effectiveness of the DMM motif for organocatalysis, we considered the application of 5 to direct aldol reactions. Herein, we report efficient direct aldol reactions of ketones to aldehydes using organocatalyst 5 under solvent-free conditions. To optimize the reaction conditions for the direct aldol reactions, we evaluated a representative solvent and additive, as shown in Table 1. The direct aldol reactions were performed with p-nitrobenzaldehyde (6a) and cyclohexanone as test reactants in the presence of a catalytic amount of 5 and a protic acid at room temperature. As a result of screening solvents, solvent-free conditions were the most suitable by considering yield, stereoselectivity, and toxicity of organic solvents (entries 1–9). Next, we investigated the effects associated with the presence of other protic acids. 2,4Dinitrobenzoic acid was found to be the most suitable additive (entries 9–14). Although the effectiveness of a protic acid for enantioselectivities is not clear, an extreme reduction of enantioselectivity was observed when no protic acid was added (entry 15). The reaction at 0 °C provided the highest stereoselectivity, up to 92% ee (entry 17). Additions of 5 or 20 mol % 2,4-dinitrobenzoic acid resulted in a significant reduction in yield or stereoselectivity (entries 18 and 19). When the level of cyclohexanone was reduced to 5 equiv, a slight lowering of stereoselectivity was observed (entry 20). Therefore, the optimal conditions were determined to be 10 mol % of 5 and 2,4-dinitrobenzoic acid under solvent-free conditions at 0 °C (entry 17).

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CF3 F3 C

S F3 C

N H

N H

NMe2

O

O

N H

N H

CF3

N H

NC NH2

H N

2

NC CN N H

N

CF3

1

F 3C

the corresponding products 7d–f in good to high yields with high enantioselectivities (entries 3–5). The reactions of benzaldehydes 6g–i with bromo, cyano, and trifluoromethyl groups at the p-position provided the corresponding products 7g–i, respectively, in high yields with high to excellent enantioselectivities (entries 6–8). Multi-substituted aromatic aldehydes 6j–k smoothly reacted with cyclohexanone, affording the corresponding adducts 7j–k, respectively, in high yields with 99% ee (entries 9 and 10). Benzaldehyde (6l) as an unreactive reactant is a poor substrate and returned low yields; however, high enantioselectivity was obtained (entry 11). Organocatalyst 5 promoted the reaction of cyclohexanone with an aldehyde 6m bearing the methoxy group as an electron donating group to provide the corresponding adduct 7m in good yields with high stereoselectivity (entry 12). Cyclopentanone and acetone as other types of ketones reacted with p-nitrobenzaldehyde (6a) to give the corresponding products 7n–o in 78% and 40% yields with lower stereoselectivities, respectively (entries 13 and 14). Although the reaction mechanism is not clear, we presume that the direct aldol reactions of ketones to aldehydes might progresses via a transition state that a 1:1 complex of DMM-organocatalyst 5 and 2,4-dinitrobenzoic acid participates. The pyrrolidine unit of 5 condenses with ketone to form the enamine intermediates. Then, the two amine protons of the DMM function as a hydrogen bonding donor to interact rigidly with the oxygen of aldehydes. These interactions can control the approach direction (Re face attack) of the enamine intermediates to aldehydes 6. This ultimately affords the corresponding addition products with high stereoselectivity. In conclusion, the DMM-organocatalyst 5 is an excellent catalyst for direct aldol reactions of ketones to aldehydes under solvent-free conditions to afford the corresponding addition products 7 in high yields with high enantioselectivities. We believe that

H

F3 C

N H

3

CF3

CN N N H

N

MeO 4

NC CN F 3C

N H CF3

N H HN 5

Figure 1. Structure of organocatalysts.

Having determined optimal conditions, the scope and limitations of the direct aldol reactions of ketones to various aldehydes were examined (Table 2).10 We investigated substrates with various electron-withdrawing groups such as nitro, halogen, cyano, and trifluoromethyl groups on the aromatic aldehydes. Reactions of nitrobenzaldehydes 6b–c with cyclohexanone proceeded smoothly, giving the corresponding adducts 7b–c, respectively, in high yields with excellent stereoselectivities (entries 1 and 2). Chlorobenzaldehydes 6d–f reacted with cyclohexanone to afford

Table 1 Optimization of reaction conditions

NC F3 C O

O H

O 2N

a b c d e

6a

+ (10 equiv)

CN

N H

N H HN 5 CF3 (10 mol%)

O

OH

Additive

Solvent, rt

7a

NO2

Entry

Solvent

Additive (mol %)

Time (h)

Yielda (%)

anti/synb

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16d 17d 18d 19d 20d,e

Toluene Hexane CH2Cl2 THF MeCN DMF H2O Brine Neat Neat Neat Neat Neat Neat Neat Neat Neat Neat Neat Neat

Trifluoroacetic acid (10) Trifluoroacetic acid (10) Trifluoroacetic acid (10) Trifluoroacetic acid (10) Trifluoroacetic acid (10) Trifluoroacetic acid (10) Trifluoroacetic acid (10) Trifluoroacetic acid (10) Trifluoroacetic acid (10) Acetic acid (10) Chloroacetic acid (10) Benzoic acid (10) 4-Nitrobenzoic acid (10) 2,4-Dinitrobenzoic acid (10) None 2,4-Dinitrobenzoic acid (10) 2,4-Dinitrobenzoic acid (10) 2,4-Dinitrobenzoic acid (5) 2,4-Dinitrobenzoic acid (20) 2,4-Dinitrobenzoic acid (10)

72 76 72 72 72 72 76 72 72 72 72 72 72 72 72 72 48 48 48 48

65 89 32 78 29 88 91 89 94 89 95 89 98 98 98 93 90 92 42 94

84:16 79:21 88:12 81:19 85:15 85:15 74:26 76:24 81:19 63:37 60:40 53:47 55:45 81:19 77:23 92:8 92:8 71:29 88:12 89:11

Isolated yield. Determined by 1H NMR spectroscopic analysis. Determined by HPLC analysis. The reaction was carried out at 0 °C. Cyclohexanone (5 equiv) was used.

% eec 67 59 80 70 49 68 52 66 64 4 47 14 28 69 11 91 92 37 86 81

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Table 2 Direct aldol reactions using organocatalyst 5

O Ar

Entry

Aldehyde

1

H

6

H + (10 equiv)

O

O

O

O

6d

4

Cl

Cl

H

d

O

Cl

O

Br

CN

O CF3

6j

O

F

H 10

F

F

O

O

O

OMe

O

F

F

93:7

94

96

83

95:5

93

48

91

95:5

93

48

89

94:6

96

48

100

>99:1

99

48

87

>99:1

99

120

43

94:6

92

120

68

93:7

92

120

78

24:76f

79

48

40



75

OH

7m OH

H 6a

85

OH

OMe

O

O

14g

120

7l

6m

d,e

89

OH F F 7k

6l

12d

96:4

OH Cl

H

H

94

F

F

O

120

Cl 7j

F 6k

d

98

CF3

7i O

Cl

Cl

94:6

OH

H

9

75

CN

7h

O

6i

120

OH

H

O

96

Br

H

8

87:13

OH

7g O

O

6h

71

OH Cl

H

7

48

7f O

6g

95

OH Cl

6f

6

93:7

7e

O d

95

Cl

H

5d

48

OH

7d

6e O

% eec

OH NO2

H

O

anti/synb

7c

6c

3d

Yielda (%)

7b

NO2

H

2

Product 7

OH NO2

6b

13

Time (h)

NO2

O

2,4-dinitrobenzoic acid (10 mol%)

solvent-free, 0 °C

Product

O

11

5 (10 mol%)

Ketone

NO2

7n

NO2

561

K. Nakashima et al. / Tetrahedron Letters 56 (2015) 558–561 Table 2 (continued) Entry

Aldehyde

Product

O

O

Time (h)

Yielda (%)

anti/synb

% eec

OH

H 6a a b c d e f g

NO2

7o

NO2

Isolated yield. Determined by 1H NMR spectroscopic analysis. Determined by HPLC analysis. The reaction was carried out using catalyst 5 (20 mol %) and 2,4-dinitrobenzoic acid (20 mol %). The reaction was conducted with cyclopentanone (10 equiv) instead of cyclohexanone. The enantioselectivity of syn-isomer is 62% ee. The reaction was conducted with acetone (10 equiv) instead of cyclohexanone.

the DMM motif functions as an efficient double hydrogen bond donor for direct aldol reactions. Studies of remarkable effect using 2,4-dinitorobenzoic acid, further application of organocatalysts with the DMM motif to other types of stereoselective reactions, and the development of additional novel DMM-organocatalysts are currently underway in our laboratory. Acknowledgments The authors would like to thank Enago (www.enago.jp) for the English language review. References and notes 5. 1. For reviews, see: (a) Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH: Weinheim, 2003; (b) Walsh, P. J.; Li, C.; de Parrodi, C. A. Chem. Rev. 2007, 107, 2503; (c) Hernández, J. G.; Juaristi, E. Chem. Commun. 2012, 5396. 2. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395. 3. For selected reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (b)Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vols. 1, 2, (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (d) Pellisier, H. Tetrahedron 2007, 63, 9267; (e) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (f) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33; (g) Lattanzi, A. Chem. Commun. 2009, 1452; (h) Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2009, 6145; (i) Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687; (j) Bhowmick, S.; Bhowmick, K. C. Tetrahedron: Asymmetry 2011, 22, 1945; (k) Bhanushali, M.; Zhao, C.-G. Synthesis 2011, 1815; (l) Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23, 1431; (m) Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541; (n) Scheffler, U.; Mahrwald, R. Chem. Eur. J. 2013, 19, 14346; (o) Mlynarski, J.; Bas´, S. Chem. Soc. Rev. 2014, 43, 577. 4. For examples of direct aldol reactions using organocatalysts under solvent-free conditions, see: (a) Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji, M. Chem. Commun. 2007, 957; (b) Guillena, G.; Hita, M. C.; Nájera, C.; Viózquez, S. F Tetrahedron: Asymmetry 2007, 18, 2300; (c) Rodríguez, B.; Bruckmann, A.; Bolm, C. Chem. Eur. J. 2007, 13, 4710; (d) Yan, J.; Wang, L. Synthesis 2008, 2065;

6. 7. 8. 9. 10.

(e) Almasßi, D.; Alonso, D. A.; Nájera, C. Adv. Synth. Catal. 2008, 350, 2467; (f) Guillena, G.; Nájera, C.; Viózquez, S. F. Synlett 2008, 3031; (g) Guillena, G.; Hita, M. C.; Nájera, C.; Viózquez, S. F. J. Org. Chem. 2008, 73, 5933; (h) Almasßi, D.; Alonso, D. A.; Nájera, C. Adv. Synth. Catal. 2009, 351, 1123; (i) Worch, C.; Bolm, C. Synlett 2009, 2425; (j) Bradshaw, B.; Etxebarría-Jardi, G.; Bonjoch, J.; Viózquez, S. F.; Guillena, G.; Nájera, C. Adv. Synth. Catal. 2009, 351, 2482; (k) Agarwal, J.; Peddinti, R. K Tetrahedron: Asymmetry 2010, 21, 1906; (l) Hernández, J. G.; Juaristi, E. J. Org. Chem. 2011, 76, 1464; (m) MartínezCastañeda, Á.; Poladura, B.; Rodríguez-Solla, H.; Concellón, C.; Amo, V. Org. Lett. 2011, 13, 3032; (n) Hernández, J. G.; Juaristi, E. Tetrahedron 2011, 68, 6953; (o) Hernández, J. G.; García-López, V.; Juaristi, E. Tetrahedron 2012, 68, 92; (p) Martínez-Castañeda, A.; Poladura, B.; Rodríguez-Solla, H.; Concellón, C.; del Amo, V. Chem. Eur. J. 2012, 18, 5188; (q) Zhang, F.; Li, C.; Qi, C. Tetrahedron: Asymmetry 2013, 24, 380; (r) Bañón-Caballero, A.; Guillena, G.; Nájera, C.; Faggi, E.; Sebastián, R. M.; Vallribera, A. Tetrahedron 2013, 69, 1307; (s) Wan, W.; Gao, W.; Ma, G.; Ma, L.; Wang, F.; Wang, J.; Jiang, H.; Zhu, S.; Hao, J. RSC Adv. 2014, 4, 26563. For reviews, see: (a) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81, 785; (b) Connon, S. J. Chem. Commun. 2008, 2499; (c) Connon, S. J. Synlett 2009, 354; (d) Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593; (e) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890; (f) Bhadury, P. S.; Li, H. Synlett 2012, 23, 1108; (g) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051; (h) Tsakos, M.; Kokotos, C. G. Tetrahedron 2013, 69, 10199. Kanada, Y.; Yuasa, H.; Nakashima, K.; Murahashi, M.; Tada, N.; Itoh, A.; Koseki, Y.; Miura, T. Tetrahedron Lett. 2013, 54, 4896. Hirashima, S.; Sakai, T.; Nakashima, K.; Watanabe, N.; Koseki, Y.; Mukai, K.; Kanada, Y.; Tada, N.; Itoh, A.; Miura, T. Tetrahedron Lett. 2014, 55, 4334. Hirashima, S.; Nakashima, K.; Fujino, Y.; Arai, R.; Sakai, T.; Kawada, M.; Koseki, Y.; Murahashi, M.; Tada, N.; Itoh, A.; Miura, T. Tetrahedron Lett. 2014, 55, 4619. Nakashima, K.; Hirashima, S.; Kawada, M.; Koseki, Y.; Tada, N.; Itoh, A.; Miura, T. Tetrahedron Lett. 2014, 55, 2703. A typical procedure of the aldol reactions using 5 is as follows: To a mixture of p-nitrobenzaldehyde (6a, 30.2 mg, 0.200 mmol) and cyclohexanone (209 lL, 2.00 mmol) was added organocatalyst 5 (8.3 mg, 0.020 mmol) and 2,4dinitrobenzoic acid (4.2 mg, 0.020 mmol) at 0 °C. After stirring at 0 °C for 48 h, the reaction mixture was directly purified by flash column chromatography on silica gel with a 2:1 mixture of hexane and AcOEt to afford 7a (44.9 mg, 90%) as a white powder.