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Catalytic asymmetric α C(sp3)–H addition of benzylamines to aldehydes

Nature Catalysis volume 5, pages 1061–1068 (2022)Cite this article

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Abstract

Functionalization of inert C–H bonds has received tremendous attention due to the inherent atom economy and efficiency of the transformations of the starting materials. As compared to transition-metal-catalysed C–H activation, organocatalysis is much less commonly applied for direct functionalization of inert C–H bonds. The α C(sp3)–H bonds of NH2-unprotected benzylamines usually are inert in most reactions due to the extremely low Brønsted acidity. Here we utilize a chiral pyridoxal bearing a quaramide side chain as a bifunctional carbonyl catalyst to activate the α C(sp3)–H bond of NH2-unprotected benzylamines, making it acidic enough to be deprotonated under mild conditions. Based on the carbonyl catalysis strategy, we develop a direct asymmetric α C–H addition of benzylamines to aldehydes, providing one of the most straightforward methods for the synthesis of chiral β-aminoalcohols with excellent diastereo- and enantioselectivities.

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Fig. 1: α C‒H functionalization of benzylamines.
Fig. 2: Catalyst synthesis and screening.
Fig. 3: Substrate investigation.
Fig. 4: Synthetic utility and mechanistic studies.

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Data availability

The authors declare that the data supporting the findings of this study are available within the Article and its Supplementary Information file, or from the corresponding author upon reasonable request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2121718 ((R,R)-1a) and CCDC 2121753 ((R,R)-4ae). These data can be obtained free of charge from the CCDC via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We are grateful for the generous financial support from the National Natural Science Foundation of China (21871181, 22271192), the Shanghai Municipal Education Commission (2019-01-07-00-02-E00029), the Shanghai Municipal Committee of Science and Technology (20JC1416800) and Shanghai Engineering Research Center of Green Energy Chemical Engineering (18DZ2254200).

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Authors and Affiliations

  1. The Education Ministry Key Lab of Resource Chemistry, Shanghai Key Laboratory of Rare Earth Functional Materials, and Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Normal University, Shanghai, China

    Chengkang Hou, Bingfei Peng, Shen Ye, Zeyang Yin, Jing Cao, Xiao Xiao & Baoguo Zhao

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  1. Chengkang Hou
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Contributions

B.Z. conceived and directed the project and wrote the paper. C.H. conducted most of the experiments including the synthesis of the chiral pyridoxamine catalysts and the development of the reaction. B.P., S.Y. and Z.Y. performed pyridoxal catalyst development. J.C. performed MS analysis for the project. X.X. revised the manuscript.

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Correspondence to Baoguo Zhao.

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Nature Catalysis thanks Weiwei Zi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, References, Figs. 1–26, Tables 1–12 and Equations (1)–(7).

Supplementary Data 1

The .cif file of compound (R,R)-1a (CCDC 2121718).

Supplementary Data 2

The .cif file of compound (R,R)-4ae (CCDC 2121753).

Supplementary Data 3

The computational data for pKa determination.

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Hou, C., Peng, B., Ye, S. et al. Catalytic asymmetric α C(sp3)–H addition of benzylamines to aldehydes. Nat Catal 5, 1061–1068 (2022). https://doi.org/10.1038/s41929-022-00875-3

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