English

• Optically active 3,3-disubstituted oxindoles are identified as privileged structures in natural products and pharmaceuticals [1]. Among those structures, spiro N-heterocyclic oxindoles fused with a five- or six-membered ring system at the C3-position have drawn considerable attention from both synthetic and medicinal chemists because it contains two pharmaceutical and biological characteristics of both heterocycle and oxindole motifs [2].

  Given the significance of such skeleton, several elegant and efficient approaches have been developed for constructing 3-spiro N-heterocyclic oxindoles in the last ten years [3-5]. Among the reported methods, the asymmetric 1,3-dipolar cycloaddition of N,N'-cyclic azomethine imines are one of the most effective and direct approaches for the construction of chiral 3-spiro heterocyclic oxindoles [6]. In this context, Wang and Feng group independently identified the azomethine imines as a versatile and robust building block in the asymmetric 1,3-dipolar cycloaddition for the construction of 3-spiroheterocyclicoxindoles. Despite the elegant work, the substrates are still limited: 1) azomethine imines are prepared by the condensation of pyrazolidin-3-one with aldehydes; 2) the dipolarophiles are limited to 2-oxoindolin-3-ylidene (Scheme 1) [7, 8].

  Scheme 1

  

  Scheme 1.  Asymmetric construction of spiro N-heterocyclic oxindole derivatives by N,N'-cyclic azomethine imines.

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  Recently, Wang and co-workers designed a new isatin N,N'-cyclic azomethine imine synthon, which performed unexpected reactivity in the [3 + 2] annulation and Michael addition with electron-deficient alkenes (Scheme 2) [9, 10]. However, the asymmetric version of the above protocol was not achieved, or only poor enantioselectivity was obtained. In view of the limitations of current methods and the importance of 3-spiro heterocyclic oxindoles, we envisaged that chiral 3-spiro heterocyclic oxindoles could be obtained via the asymmetric annulation of isatin N,N'-cyclic azomethine imines with enals in the presence of chiral secondary amine catalysts (Scheme 2) [11].

  Figure 2

  

  Figure 2.  Synthetic applications of isatin N,N'-cyclic azomethine imine.

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  In order to verify our assumption, we investigated the asymmetric annulation between model substrates isatin N,N'-cyclic azomethine imine 1a and cinnamaldehyde 2a in the presence of TMS-protected secondary amine catalyst C1 (Fig. 1). Surprisingly, an unexpected C-N-N [3 + 3] annulation process was observed, which was different from previously reported reaction mode, and corresponding product 3aa was obtained in good yield (72%), modest diastereoselectivity (1.2:1) and high enantioselectivity (87%/80% ee) (Table 1, entry 1). Encouraged by this promising result, various chiral amine catalysts (C2-C5, Fig. 1) were screened (entries 2-5). Gratifyingly, bulkier amine catalyst C2 exhibited the optimal reaction outcome, both yield (81%) and stereoselectivity (1.7:1 dr, 91%/90% ee) were improved (entry 2).

  Figure 1

  

  Figure 1.  Chiral secondary-amine catalysts investigated in this reaction.

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  Table 1

  

  Table 1.  Screenings of catalysts.^a

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  Subsequently, by varying the base for this reaction, no better results could be obtained compared with Et₃N (Table 2, entries 1-6). Then, the effect of solvents was tested. When using CH₂Cl₂ as solvent, the yield was slightly reduced (80%), but the stereoselectivity was significantly improved (1.9:1 dr, 96%/95% ee) (entry 7). DMF reduced the reaction time greatly (12 h), but the yield (52%) and stereoselectivity (1:1.5 dr, 66%/76% ee) were not ideal (entry 13). Other solvents, such as CH₃CN, CH₃OH, THF, Et₂O and toluene led to a significant decrease in reactivity due to the reduced solubility of isatin N,N'-cyclic azomethine imine 1a (entries 8-12). In addition, investigation of the reaction temperature showed that CH₂Cl₂ at 0 ℃ gave better result (82% yield, 2.1:1 dr, 98%/96% ee) in comparison with CHCl₃ (entries 14 and 15).

  Table 2

  

  Table 2.  Optimization of reaction conditions.^a

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  With the optimal conditions in hand, the substrate scope of isatin N,N'-cyclic azomethine imines and α,β-unsaturated aldehydes was subsequently investigated. Firstly, various protecting groups on substituted isatin N,N'-cyclic azomethine imines were explored with cinnamaldehyde 2a (Scheme 3). N-Allyl protected substrate 1b afforded the [3 + 3] cycloadduct in good yield with excellent enantioselectivity (85%, 1.3:1 dr, 97%/95% ee). Due to the influence of high steric hindrance and poor solubility, N-C(Ph)₃ protected 1c only afforded the trace amount of product. On the other hand, the electron-withdrawing group Boc-protected 1d showed no reactivity. Then various electron-donating or electron-withdrawing groups at 5-, 6-, 7-positions on the indole ring were also tolerated, the corresponding products could be obtained in good yields, while electron-withdrawing substitutions on the indole ring gave lower yield and decreased enantioselectivity compared with electron-donating substitutions (3ea-3ka).

  Scheme 3

  

  Scheme 3.  Scope of isatin N,N'-cyclic azomethine imines 1. General reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), C2 (0.04 mmol), Et₃N (0.04 mmol), CH₂Cl₂ (2.0 mL), 0 ℃. Isolated yields for two diastereomers; dr values were determined by ¹H NMR spectroscopy; ee values were determined by chiral HPLC analysis.

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  Subsequently, the potential of this [3 + 3] annulation with a variety of α,β-unsaturated aldehydes was further explored (Scheme 4). The reaction all proceeded smoothly, good yields and moderate to excellent enantioselectivities were obtained with the aryl rings bearing electron-withdrawing Cl, Br, NO₂ or -donating Me, OMe substitutions (3ab-3ag, 3ai-3ak). Furthermore, heteroaromatic aldehydes such as pyridyl and furyl were also tolerated under optimal conditions (3ah, 3al). In addition, the absolute configuration of 3ab (major diastereoisomer) was determined as (3R, 6'S, 8'R) by X-ray crystallographic analysis, and the absolute configuration of minor diastereoisomer was determined as (3S, 6'S, 8'R) by X-ray crystallographic analysis (for details see the Supporting information). Notably, aromatic aldehyde 2g bearing para-nitryl substituent and heteroaromatic aldehyde 2h bearing 3-pyridyl substituent merely delivered moderate enantioselectivities (68%/50% ee, 85%/80% ee), presumably because the strong electron-withdrawing group obviously enhanced the reaction activities. It should be mentioned that in all cases except 3ah and 3ai, the corresponding diastereoisomers can be easily separated by flash column chromatography.

  Scheme 4

  

  Scheme 4.  Scope of α,β-unsaturated aldehydes 2. General reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), C2 (0.04 mmol), Et₃N (0.04 mmol), CH₂Cl₂ (2.0 mL), 0 ℃. Isolated yields for two diastereomers; dr values were determined by ¹H NMR spectroscopy; ee values were determined by chiral HPLC analysis.

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  To further demonstrate the synthetic utility of this process, the [3 + 3] annulation between 1a and 2a was carried out on a gram scale, and compound 3aa was obtained in 80% yield, 2:1 dr and 98%/96% ee (Scheme 5).

  Scheme 5

  

  Scheme 5.  Gram-scale experiments.

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  A plausible reaction pathway was proposed to rationalize the formation of product 3aa (Scheme 6). According to Wang's previous report [9] key intermediate III is formed through the resonance of 1a in the presence of Et₃N, and imine IV is formed through the condensation reaction between enal 2a and catalyst C2 at the same time. Then enantioselective Michael addition of intermediate III to chiral imine IV occurs, and generates the intermediate VI with a double bond shift. Finally, the target product 3aa is afforded via the hydrolysis/intramolecular cyclization.

  Scheme 6

  

  Scheme 6.  Proposed reaction pathway.

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  In summary, we have presented the first example of enantioselective C-N-N [3 + 3] annulation of isatin N,N'-cyclic azomethine imines with α,β-unsaturated aldehydes by employing the chiral secondary amine as catalyst. A wide range of highly substituted spiro N-heterocyclic oxindole derivatives were synthesized in good yields (up to 91%) and good to excellent enantioselectivities (up to > 99% ee). The present approach is a supplement to the previous methods for the diversity-oriented synthesis of biologically crucial enantioenriched spiro N-heterocyclic oxindole derivatives in high efficiency.

  Declaration of competing interest

  The authors declare no competing financial interest.

  Acknowledgments

  This work is supported by the National Natural Science Foundation of China (No. 21572053) and Opening Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University (Traditional Chinese Pharmacology), Zhejiang Chinese Medical University (No. ZYAOX2018029).

  Appendix A. Supplementary data

  Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.cclet.2020.06.010.

  
  ^* Corresponding authors at: College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  E-mail addresses: zhixiangliu88@163.com (Z. Liu), weiping_deng@ecust.edu.cn (W. Deng).
  
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• 

  Scheme 1  Asymmetric construction of spiro N-heterocyclic oxindole derivatives by N,N'-cyclic azomethine imines.

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  Figure 2  Synthetic applications of isatin N,N'-cyclic azomethine imine.

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  Figure 1  Chiral secondary-amine catalysts investigated in this reaction.

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  Scheme 3  Scope of isatin N,N'-cyclic azomethine imines 1. General reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), C2 (0.04 mmol), Et₃N (0.04 mmol), CH₂Cl₂ (2.0 mL), 0 ℃. Isolated yields for two diastereomers; dr values were determined by ¹H NMR spectroscopy; ee values were determined by chiral HPLC analysis.

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  Scheme 4  Scope of α,β-unsaturated aldehydes 2. General reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), C2 (0.04 mmol), Et₃N (0.04 mmol), CH₂Cl₂ (2.0 mL), 0 ℃. Isolated yields for two diastereomers; dr values were determined by ¹H NMR spectroscopy; ee values were determined by chiral HPLC analysis.

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  Scheme 5  Gram-scale experiments.

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  Scheme 6  Proposed reaction pathway.

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  Table 1.  Screenings of catalysts.^a

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  Table 2.  Optimization of reaction conditions.^a

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•