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. 2021 Jan 27;12(1):638.
doi: 10.1038/s41467-020-20888-5.

NiH-catalyzed asymmetric hydroarylation of N-acyl enamines to chiral benzylamines

Yuli He  1 , Huayue Song  1 , Jian Chen  1 , Shaolin Zhu  2
Affiliations

NiH-catalyzed asymmetric hydroarylation of N-acyl enamines to chiral benzylamines

Yuli He et al. Nat Commun. .

Abstract

Enantiomerically pure chiral amines and related amide derivatives are privilege motifs in many pharmacologically active molecules. In comparison to the well-established hydroamination, the transition metal-catalysed asymmetric hydrofunctionalization of enamines provides a complementary approach for their construction. Here we report a NiH-catalysed enantio- and regioselective reductive hydroarylation of N-acyl enamines, allowing for the practical access to a broad range of structurally diverse, enantioenriched benzylamines under mild, operationally simple reaction conditions.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Asymmetric hydroarylation of N-acyl enamines to access chiral benzylamines.
a Representative natural products & drugs with a chiral benzylamine motif. b Two reductive hydrofunctionalization strategies for their synthesis. c NiH-catalyzed enantioselective reductive hydrofunctionalization of alkenes.
Fig. 2
Fig. 2. Variation of reaction parameters.
*Yields determined by crude 1H NMR using 1,1,2,2-tetrachloroethane as the internal standard, the yield in parentheses is the isolated yield. †Enantioselectivity was determined by chiral HPLC analysis. Bz benzoyl, PMP p-methoxyphenyl, DMA N,N-dimethylacetamide, DMF N,N-dimethylformamide.
Fig. 3
Fig. 3. Substrate scope of aryl iodide component.
Yield under each product refers to the isolated yield of purified product (0.20 mmol scale, average of two runs), >95:5 regioisomeric ratio (rr) unless otherwise noted. Enantioselectivities were determined by chiral HPLC analysis. *5 mol% Ni(ClO4)2∙6H2O, DMA (0.10 M), 1.5 equiv ArI. †Diastereoisomeric ratio (dr) was determined by crude 1H NMR analysis. TBS, tert-butyldimethylsilyl.
Fig. 4
Fig. 4. Substrate scope of the N-acyl enamine component.
Yield and ee are as defined in Fig. 3 legend. Ac acetyl.
Fig. 5
Fig. 5. Gram-scale, derivatization, and deuterium-labeling experiments.
a Gram-scale experiment and reduction of the amide. b NiD experiment: NiD syn-hydrometallation is not the enantio-determining step.
See this image and copyright information in PMC

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