Synthesis of 2-heterocyclic substituted pyrrolidines by copper-catalyzed domino three-component decarboxylative coupling and cyclization reactions

Accepted Manuscript Synthesis of 2-heterocyclic substituted pyrrolidines by copper-catalyzed domino three-component decarboxylative coupling and cyclization reactions Zheng-neng Jin, Hua-jiang Jiang, Jia-shou Wu, Wei-zhong Gong, Yue Cheng, Jing Xiang, Qi-Zhong Zhou PII: DOI: Reference:

S0040-4039(15)00645-0 http://dx.doi.org/10.1016/j.tetlet.2015.04.018 TETL 46157

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

26 February 2015 1 April 2015 6 April 2015

Please cite this article as: Jin, Z-n., Jiang, H-j., Wu, J-s., Gong, W-z., Cheng, Y., Xiang, J., Zhou, Q-Z., Synthesis of 2-heterocyclic substituted pyrrolidines by copper-catalyzed domino three-component decarboxylative coupling and cyclization reactions, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.018

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Synthesis of 2-heterocyclic substituted pyrrolidines by copper-catalyzed domino three-component decarboxylative coupling and cyclization reactions

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Zheng-neng Jin a, Hua-jiang Jiang a, Jia-shou Wu a, b, Wei-zhong Gong b, Yue Cheng a, Jing Xiang c and QiZhong Zhou a

1

Tetrahedron Letters journal homepage: www.elsevier.com

Synthesis of 2-heterocyclic substituted pyrrolidines by copper-catalyzed domino three-component decarboxylative coupling and cyclization reactions Zheng-neng Jin a, Hua-jiang Jiang a, Jia-shou Wu a, b, Wei-zhong Gong b, Yue Cheng a, Jing Xiang c and Qi-Zhong Zhou a a

School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, Zhejiang, P. R. of China Zhejiang Hisoar Pharmaceutical Co., LTD., Taizhou 318000, Zhejiang, P. R. of China c College of Chemistry and Environmental Engineering, Yangtze University, Jingzhou 434020, Hubei, P. R. of China b

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

A novel copper catalyzed domino three-component decarboxylative coupling and cyclization reaction using cyclic α-Amino acids has been developed. This reaction provides an efficient and atom economic approach to 2-(2-indolyl)pyrrolidine, and 2-(1,1-dioxido-2Hbenzo[e][1,2]thiazin-3-yl)pyrrolidine derivatives. 2009 Elsevier Ltd. All rights reserved.

Keywords: Domino reaction Copper-catalyzed α-Amino acid Indolyl pyrrolidines Decarboxylative coupling

Amines are widely used in pharmaceutical and agrochemical industry due to their biological activities. Among them, saturated cyclic amines especially pyrrolidine and piperidine are particular interesting building units found in numerous natural and unnatural biologically molecules.1 Thus, many synthetic approaches to substituted pyrrolidines and piperidines have been developed.1-3 α-Amino acids are readily available natural compounds. Therefore, the use of α-amino acids as the nitrogen-containing motifs in organic synthesis is very attractive. Recently, several research groups have developed useful synthetic routes to 2substituted pyrrolidine derivatives by decarboxylative coupling of proline with a variety of nucleophiles 3 such as alkynes3a-c and indoles3b-e (Scheme 1). Indolyl pyrrolines are important structural features in pharmacologically and biologically active compounds.3b The three component decarboxylative coupling reactions of proline, aldehydes and indoles provided an efficient way to 2-(3-indolyl)pyrrolidines.3c Li and co-workers developed another way to 2-(3-indolyl)pyrrolidines by the oxidative decarboxylation coupling reaction of N-benzyl-prolines with indoles.3b,e Notably, no desired 2-(2-indolyl)pyrrolidines were obtained even when 3-substitued indole was used as nucleophile.3b Although many synthetic routes to 2-(2indolyl)pyrrolidines have been developed, most of these methods suffer from drawbacks such as long synthetic routes, low atom

Scheme 1. Background of this work economy, as well as harsh reaction conditions.4 Thus, the development of new efficient synthetic methodology for 2-(2indolyl)pyrrolidines is still highly desirable.

———  Corresponding author. Tel.: +86-576-886-60177; fax: +86-576-886-60177; e-mail: [email protected]

2

Tetrahedron a

Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), 3a (0.42 mmol) and catalyst in solvent (1.5 mL) at 130 °C for 10h.

Scheme 2. Reaction design Fujji, Ohon and co-workers recently developed an efficient way to (2-aminomethyl)indoles using a Cu(I)-catalyzed domino three-component coupling and cyclization reaction of ethynylanilines, aldehydes and secondary amines (Scheme 1).5 Inspired by their work and the three component decarboxylative coupling reaction of proline, aldehydes and alkynes developed by Seidel’s and Li’s group, we envisioned

the possibility of a domino three-component decarboxylative coupling and cyclization reaction of proline, ethynylaniline derivatives and aldehydes (Scheme 2). In continuation of our ongoing research interests in the decarboxylative coupling reactions of α-amino acids,6 we’d like to describe herein a novel and atom economic approach to 2-(2-indolyl)pyrrolidine and 2(1,1-dioxido-2H-benzo[e][1,2]thiazin-3-yl)pyrrolidine derivatives. Table 1. Optimization of the reaction conditions a

Entry

Catalyst (mol%)

Solvent

Temp (°C)

Yield (%) b

1

CuI (15)

1,4-dioxane

130

65

2

CuI (15)

DMF

130

Trace

3

CuI (15)

DMSO

130

Trace

4

CuI (15)

H2O

130

-c

5

CuI (15)

Toluene

130

74

6

CuI (15)

-

130

28

7

CuI (10)

Toluene

130

70

8

CuI (30)

Toluene

130

63

9

CuI (15)

Toluene

110

70

10

CuI (15)

Toluene

100

57

11

d

CuI (15)

Toluene

130

62

12

e

CuI (15)

Toluene

130

63

13

CuBr (15)

Toluene

130

32

14

CuCl (15)

Toluene

130

35

15

CuBr2 (15)

Toluene

130

70

16

CuCl2 (15)

Toluene

130

57

17

Cu(acac)2 (15)

Toluene

130

46

18

Cu(OTf)2 (15)

Toluene

130

24

b

isolated yield based on 1a.

c

1-tosyl-1H-indole was isolated in 88% yield.

d

2a (2.0 equiv).

e

3a (1.2 equiv).

We initiated our study by examining the domino threecomponent decarboxylative coupling reaction of N-tosylated 2ethynylaniline 1a with 1.5 equiv of proline 2a and 1.4 equiv of 4nitrobenzaldehyde 3a in the presence of 15 mol % of CuI catalyst in 1,4-dioxane at 130 °C under argon (Table 1, entry 1). To our delight, the desired decarboxylative coupling and cyclization product 2-(2-indolyl)pyrrolidine 4a was isolated in 65 % yield after 10 h (entry 1). With other solvents such as DMF and DMSO, only trace amount of product 4a was obtained (entries 2 and 3). In water, 1-tosyl-1H-indole, the cyclization product of 1a, was isolated and no 4a product formed (entry 4). When Toluene was employed as the solvent, the yield increased to 74% (entry 5). Although the domino three-component reaction can be performed under solventless condition, the yield decreased to 28% (entry 6). The efforts to further improve the yield of 4a by changing catalyst loading (entries 7 and 8), reaction temperature (entries 9 and 10) or substrates ratio (entries 11 and 12) failed. Among various copper catalysts screened, CuI gave the best yield (entry 5 vs entries 13-18). With optimal reaction conditions in hand (Table 1, entry 5), the domino three-component decarboxylative coupling and cyclization reaction of N-tosylated 2-ethynylaniline 1a and proline or pipecolinic acid with various substituted benzaldehydes was examined, and the results were summarized in Table 2. A variety of benzaldehydes bearing various functional groups were employed in the reaction to give the corresponding 2-(2-indolyl)pyrrolidine products with moderate to good yields (Table 2, entries 1-15). Benzaldehyde with substituent at 4position gave better result than that at 3-position. For example, the domino decarboxylative coupling and cyclization reaction of 4-(trifluoromethyl)benzaldehyde 3c with proline 2a and Ntosylated ethynylaniline 1a afforded the indolyl pyrrolidine 4c in 60% yield (entry 3). While the yield decreased to 53% when the reaction was proceeded with 3-(trifluoromethyl)benzaldehyde 3d (entry 4). 2-Substituted benzaldehyde substrates such as 2chlorobenzaldehyde, 2,4-dichlorobenzaldehyde and 2bromobenzaldehyde also worked well, and good yields were obtained (entries 8, 9 and 12). 1-Naphthaldehyde was also good substrate, delivering 4o in 63% yield (entry 15). The reaction of pipecolinic acid with 4-nitrobenzaldehyde 3a and N-tosylated ethynylaniline 1a gave 2-(2-indolyl)piperidine 4p in 34% yield (entry 16). The scope of 2-ethynylanilines was also tested using 2a and 3a as reaction partners (Table 3). In the presence of CuI (15 mol%), ethynylaniline 1b bearing an electron-donating methyl group at 4-position reacted with 2a and 3a smoothly giving indoyl pyrrolidine 4q in 65% yield (Table 3, entry 1). While ethynylanilines with an electron-withdrawing group at 4 or 5position such as 1c, 1d and 1e were also reactive, albeit in slightly lower yields (entries 2-4). Next, the effect of nitrogenprotecting group on the domino decarboxylative coupling and cyclization reaction was evaluated. Ethynylanilines 1f and 1g having phenylsulfonyl or 4-nitrophenylsulfonyl group on nitrogen gave fairly good yields (entries 5-6). NTrifluoroacetylated 2-ethynylaniline 1h worked equally well as 1a (entry 7). In sharp contrast, when acetylated 2-ethynylaniline 1i was employed, no reaction occurred (entry 8).

3 Benzo[e][1,2]thiazine-1,1-dioxides are biologically important compounds.5a,7 The domino three-component decarboxylative coupling and cyclization reactions of 2-ethynylsulfonamides with proline and 4-nitrobenzaldehyde can also afford the desired 2(1,1-dioxido-2H-benzo[e][1,2]thiazin-3-yl)pyrrolidines in moderate yields (Scheme 3). In summary, we have developed a novel copper catalyzed domino three-component decarboxylative coupling and cyclization reaction using cyclic α-Amino acids as starting materials. This reaction provides an efficient and atom economic approach to 2-(2-indolyl)pyrrolidine, 2-(2-indolyl) piperidine and 2-(1,1-dioxido-2H-benzo[e][1,2]thiazin-3-yl)pyrrolidine derivatives.

Table 2. Domino three-component decarboxylative coupling and cyclization reaction with various substituted benzaldehydes a

Entry

2

R

1

2a

4-NO2C6H4

2

3

2a

2a

3-NO2C6H4

4-CF3C6H4

Product

Yield (%) b

9

2a

2,4-diClC6H4

60

10

2a

4-BrC6H4

67

11

2a

3-BrC6H4

54

12

2a

2-BrC6H4

60

13

2a

Ph

58

14

2a

4-CH3C6H4

49

15

2a

1-naphthyl

63

16

2b

4-NO2C6H4

34

74

41

60

a

Reaction conditions: 1a (0.3 mmol), 2 (0.45 mmol), 3 (0.42 mmol) and CuI (0.045 mmol) in toluene (1.5 mL) at 130 °C for 10h. b

4

2a

3-CF3C6H4

53

isolated yield based on 1a.

Table 3. Synthesis of 2-(2-indolyl)pyrrolidines with proline 2a and 4-nitrobenzaldehyde 3a a 5

2a

3,5-diCF3C6H4

53

6

2a

4-CNC6H4

58 Entry 1

7

2a

4-ClC6H4

71

8

2a

2-ClC6H4

70

1

Product

Yield (%) b 65

4

Tetrahedron 2

45

3

50

Scheme 3. Synthesis of 2-(1,1-dioxido-2Hbenzo[e][1,2]thiazin-3-yl)pyrrolidines 4

5

55

67

Acknowledgments We are grateful to the National Natural Science Foundation of China-China (NSFC) (No. 21402137 and No. 21172166), the Postdoctoral Research Foundation of Zhejiang Province (No. BSH1302072) and the Opening Foundation of Key Disciplines of Applied Chemistry of Zhejiang Province (Taizhou University) for financial support References and notes 1.

6

66

7

74

2.

3.

8

0

4. a

Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), 3a (0.42 mmol) and CuI (0.045 mmol) in toluene (1.5 mL) at 130 °C for 10h. b

isolated yield based on 1.

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