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Organocatalytic asymmetric α-C–H functionalization of alkyl amines

Abstract

Catalytic enantioselective α-C–H functionalization of widely available achiral alkyl amines could provide an ideal synthetic approach towards chiral amines. However, the inert nature of the α-C–H of alkyl amines renders their activation as carbanionic nucleophiles for catalytic asymmetric reactions an important yet unmet challenge. Here we describe how N-arylidene-protected alkyl amines could be activated as carbanions for asymmetric conjugate addition and the Mannich reaction. These results represent an intriguing and generally useful approach to the synthesis of chiral α,α-dialkyl amines. More importantly, they highlight the enormous potential of N-arylidene-protected amines as readily available and widely applicable synthons for the asymmetric synthesis of chiral amines.

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Fig. 1: Catalytic asymmetric α-C–H functionalization of simple alkyl amines.
Fig. 2: Screening studies of the N-arylidene groups.
Fig. 3: Reaction conditions and catalyst optimization.
Fig. 4: Substrate scope of amine α-C–H functionalization with enals.
Fig. 5: Catalyst optimization.
Fig. 6: Substrate scope of amine α-C–H functionalization with aldimines.
Fig. 7: Product derivatizations.
Fig. 8: Proposed catalytic cycle and pKa of amine α-C–H.

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Data availability

The data that support this study are available within this article and its Supplementary Information, or from the authors upon reasonable request. Crystallographic data for compounds 8 and 5Ca were deposited in the Cambridge Structural Database under deposition nos. 2253297 (8) and 2250265 (5Ca). Copies of the data can be obtained free of charge via the Cambridge Crystallographic Data Centre at https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank the Instrumentation and Service Center for Molecular Sciences and the Instrumentation and Service Center for Physical Sciences at Westlake University for assistance in measurement/data interpretation. We thank X. Lu and X. Shi at Westlake University for assistance in the NMR measurement, Y. Chen at Westlake University for assistance of the HRMS measurement, and X. Miao and F. Leng at Westlake University for assistance in the X-ray measurement. We thank the High-Performance Computing Center of Westlake University for providing computational resources. We thank J. Lu at Westlake University for providing amine 1m. We are grateful for financial support provided by the National Natural Science Foundation of China (U22A20389 to L.D, 22371232 to J.L.), Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang 2020R01004 and the Foundation of Westlake University.

Author information

Authors and Affiliations

Authors

Contributions

J.L. and L.D. conceived the project. J.L., T.D. and X.-L.H. designed and developed the reaction. C.C., X.L., Y.G., K.W. and Z.L. contributed to the catalysts and materials preparation. Y.Y. carried out theoretical calculation. J.L. and L.D. supervised the research. L.D. acquired funding. T.D., X.-L.H., Y.Y., J.L. and L.D. contributed to the writing and editing of the final paper.

Corresponding authors

Correspondence to Jisheng Luo or Li Deng.

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Nature Catalysis thanks Xi Lu, Gui Lui, Choon-Hong Tan and Donghui Wei for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, including materials preparation, computational methods, single X-ray crystal diffraction data, nuclear magnetic resonance spectra and SFC spectra, References, Figs. 1–332 and Tables 1–17.

Supplementary Data 1

The cif file of 5Ca.

Supplementary Data 2

The checklist of 5Ca.

Supplementary Data 3

The pdf file of structure of 5Ca.

Supplementary Data 4

The png file of structure of 5Ca.

Supplementary Data 5

The cif file of 8.

Supplementary Data 6

The checklist of 8.

Supplementary Data 7

The pdf file of structure of 8.

Supplementary Data 8

The png file of structure of 8.

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Deng, T., Han, XL., Yu, Y. et al. Organocatalytic asymmetric α-C–H functionalization of alkyl amines. Nat Catal 7, 1076–1085 (2024). https://doi.org/10.1038/s41929-024-01230-4

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