Catalytic Asymmetric Dearomative [3+2] Cycloaddition of Electron

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Catalytic Asymmetric Dearomative [3+2] Cycloaddition of Electron-Deficient Indoles with All-Carbon 1,3-Dipoles Meng Sun, Zi-Qi Zhu, Ling Gu, Xiao Wan, Guang-Jian Mei, and Feng Shi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03259 • Publication Date (Web): 24 Jan 2018 Downloaded from http://pubs.acs.org on January 24, 2018

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The Journal of Organic Chemistry

Catalytic Asymmetric Dearomative [3+2] Cycloaddition of Electron-Deficient Indoles with All-Carbon 1,3-Dipoles Meng Sun‡, Zi-Qi Zhu‡, Ling Gu, Xiao Wan, Guang-Jian Mei and Feng Shi* School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, China E-mail: [email protected] ‡

These authors contributed equally to the work.

NO2 R

N R1 +

Ph 5 mol% L* 2.5 mol% Pd(dba)2 MeCN, -15 oC

NC NC

O2N R

CN N H CN R1 19 examples up to 80%, 88:12 dr, 97% ee

O P N O

Me Me

Ph L*

Abstract: The first catalytic asymmetric dearomative [3+2] cycloaddition of 3-nitroindoles with vinylcyclopropanes has been established, which constructed chiral cyclopenta[b]indoline scaffolds in generally high enantioselectivities (up to 97% ee). This reaction also represents the first application of all-carbon 1,3-dipoles in catalytic asymmetric dearomative [3+2] cycloadditions of 3-nitroindoles. This approach will not only advance the catalytic asymmetric dearomatization reactions of electron-deficient indoles, but also provide an efficient method for constructing chiral cyclopenta[b]indoline scaffolds.

Introduction Catalytic asymmetric dearomatization (CADA) reactions have proven to be robust methods for converting planar aromatic compounds into stereoselective chiral molecules.1 As a result, the CADA reactions of indoles have developed rapidly in recent years2 due to the importance of chiral indole derivatives.3 Especially, the CADA via cycloaddition reactions of indoles has emerged as a powerful tool for constructing indole-fused chiral cyclic frameworks (Scheme 1).4 However, most

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of the transformations employed electron-rich indoles as reaction partners to perform catalytic asymmetric dearomative cycloadditions (eq. 1).2,4 In sharp contrast, electron-deficient indoles have seldom been utilized as reaction partners in catalytic asymmetric dearomative cycloadditions (eq. 2).4 Therefore, it is highly desirable to develop CADA reactions of electron-deficient indoles.

Scheme 1. Profile of CADAs via cycloaddition reactions of indoles In this context, 3-nitroindoles as a class of electron-deficient indoles have showed their potential in performing catalytic asymmetric dearomative cycloadditions.5-6 However, until recently, only limited examples of catalytic asymmetric dearomative [3+2] cycloadditions of 3-nitroindoles have been reported (Scheme 2a).5 For example, the Arai group5a and the Stanley group5b established chiral copper (II)-catalyzed asymmetric [3+2] cycloadditions of 3-nitroindoles with azomethine ylide (eq. 3). The Yuan group realized asymmetric [3+2] cycloadditions of 3-nitroindoles with 3-isothiocyanato oxindoles in the presence of a chiral organocatalyst or a chiral zinc (II)/ligand (eq. 4).5c-5d In spite of these elegant work, the catalytic asymmetric dearomative [3+2] cycloadditions of 3-nitroindoles are still rather limited and are confined to heteroatom-based 1,3-dipoles. On the other hand, it is still an unknown chemistry to use all-carbon 1,3-dipoles in catalytic asymmetric dearomative [3+2] cycloadditions of 3-nitroindoles (eq. 5) in spite of the fact that this transformation will construct chiral cyclopenta[b]indoline scaffolds, which constitute the core structures of many natural products and biologically important


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compounds.7 The challenges imbedded in this transformation mainly include: 1) to discover all-carbon 1,3-dipoles or surrogates which are compatible with 3-nitroindoles; 2) to control the diastereo- and enantioselectivity of the reactions.

Scheme 2. Limited examples and challenges of CADAs via [3+2] cycloadditions of 3-nitroindoles In order to confront these challenges, and as our continuous efforts in constructing chiral indole frameworks,8 we decided to use vinylcyclopropanes (VCPs)9 as surrogates of all-carbon 1,3-dipoles10 because this class of substrates can form zwitterionic π-allyl palladium intermediates to perform catalytic asymmetric [3+2] cycloadditions with electron-deficient alkenes under the catalysis of chiral palladium (0) complexes.11-12 So, based on the properties of VCPs, we designed a chiral palladium-catalyzed asymmetric [3+2] cycloaddition of 3-nitroindoles with VCPs (Scheme 3), which would construct chiral cyclopenta[b]indoline scaffolds in an enantioselective manner. It should be mentioned that during our investigation, the Vitale group13 and the Hyland group14 reported a racemic [3+2] cycloaddition of 3-nitroindoles with VCPs. Nevertheless, the catalytic asymmetric version of this reaction has not been realized, and the challenge in controlling the enantioselectivity of the reaction has not been tackled yet.



Scheme 3. Design of catalytic asymmetric dearomative [3+2] cycloadditions of electron-deficient indoles with all-carbon 1,3-dipoles Herein, we report the first catalytic asymmetric dearomative [3+2] cycloaddition of 3-nitroindoles with VCPs, which constructed chiral cyclopenta[b]indoline scaffolds in generally high enantioselectivities (up to 97% ee). This reaction also represents the first application of all-carbon 1,3-dipoles in catalytic asymmetric dearomative [3+2] cycloadditions of 3-nitroindoles. This approach will not only advance the CADA reactions of electron-deficient indoles, but also provide an efficient method for constructing chiral cyclopenta[b]indoline scaffolds.

Results and Discussion

Based on our design, the [3+2] cycloaddition of 3-nitroindole 1a with VCP 2a was employed as a model reaction to optimize the reaction conditions (Table 1). In previously reported catalytic asymmetric transformations of VCPs, chiral P, N-ligands or chiral bisphosphines often exhibited high catalytic activity in controlling the enantioselectivity.11a,11b-d,12a-c,12g So, initially, a series of chiral P, N-ligands or chiral bisphosphines L1-L9 were screened (entries 1-9), which found ligand L9 could deliver the desired product 3aa in the highest enantioselectivity of 80% ee (entry 9) although the yield and the diastereoselectivity were not satisfying. Then, in the presence of L9, the palladium catalyst was altered (entries 10-11). However, none of them was better than the original


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catalyst Pd(dba)2 in terms of controlling the enantioselectivity (entries 10-11 vs 9). So, under the optimal catalytic system of Pd(dba)2/L9, several representative solvents were evaluated (entries 9 and 12-16), which found that the reaction could only proceed in acetonitrile, dichloromethane and ethyl acetate (entries 9 and 14-15). Among them, acetonitrile still proved to be the best solvent with regard to controlling the reactivity and the stereoselectivity (entry 9 vs entries 14-15). Subsequently, the reaction temperature was carefully modulated (entries 17-20), which revealed that the enantioselectivity could be improved to 86% ee and the yield could be elevated to 73% when the reaction temperature was lowered to -15 oC (entry 18). Finally, suitably increasing the stoichiometry of VCP 2a could further enhance the enantioselectivity to an excellent level of 92% ee although the diastereoselectivity could hardly be improved (entry 21). Thus, this condition was set as the optimal one for catalytic asymmetric dearomative [3+2] cycloadditions of 3-nitroindoles with VCPs. Table 1. Screening of chiral ligands and condition optimizationa

O

O P N O

O

O

O O

P N

P N

O

O

L2

L1 Ph

O

PPh2 O

O

Ph

PPh2 P

P N O

L3

NH HN P

Ph

Ph Ph Ph

L4

L6

L5 O

Ph

N PPh2

O P N O

Bn

O P N O

Me Me

Ph L7

NO2 N Bz 1a

L9

L8

+ NC NC

5 mol% Ligand 2.5 mol% Pd(dba)2 o

solvent, T C

2a


O2N * * * CN N CN Bz 3aa


a

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entry

Ligand

solvent

T (oC)

yield (%)b

drc

ee (%)d

1 2 3 4 5 6 7 8 9 10e 11f

L1 L2 L3 L4 L5 L6 L7 L8 L9 L9 L9

MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN

25 25 25 25 25 25 25 25 25 25 25

61 78 87 89 85 99 75 68 60 65 90

90:10 84:16 82:18 74:26 65:35 84:16 84:16 78:22 71:29 71:29 73:27

Catalytic Asymmetric Dearomative [3+2] Cycloaddition of Electron

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