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Site-selective amination towards tertiary aliphatic allylamines

Abstract

Aliphatic allylamines are widely used for the synthesis of diverse building blocks for agrochemicals and pharmaceuticals; there is therefore considerable interest in developing versatile and direct routes to aliphatic allylamines using common chemical feedstocks—olefins and amines. However, examples of such coupling reactions remain limited. It is even more challenging to achieve this goal with precise site control. Here we report that the combination of a photocatalyst and cobaloxime enables site-selective amination of olefins with secondary alkyl amines to afford allylic amines, eliminating the need for oxidants. This method is compatible with a broad scope of olefins and can be extended to achieve a site- and diastereoselective amination of terpenes. Mechanistic studies disclose that the reaction proceeds via a cobaloxime-promoted hydrogen atom transfer pathway to afford the product that results from cleavage of the stronger, primary allylic C–H bonds over other weaker allylic C–H bond options.

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Fig. 1: Evolution of strategies for allylic amination.
Fig. 2: Scope of olefins for site-selective allylic amination.
Fig. 3: Additional scope of di-, tri- and tetrasubstituted olefins and limitations.
Fig. 4: Scope of aliphatic amines.
Fig. 5: The influence of olefin equivalents and cobaloximes.
Fig. 6: Mechanistic studies and DFT calculations.
Fig. 7: Application and strategic expansion.

Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information, or from the authors on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China 22031008 (A.L.) and Science Foundation of Wuhan 2020010601012192 (A.L.). We thank Y. Xi (UC Santa Barbara) for helpful discussions; W.L. (WHU) for the revision of manuscript; W. Kong (WHU) and X. Dong (WHU) for assistance with chiral HPLC analysis; and C. Bao (Taiwan Photon Source, TPS-44A), J. Chen (TPS-44A) and J. Lee (TPS-44A) for XAFS testing. X.Q. acknowledges the supercomputing system in the Supercomputing Center of Wuhan University.

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A.L. and S.W. conceived the work. S.W., Y.G., L.N and R.S. designed the experiments and analysed the data. S.W., Y.G., D.R., H.S. and X.L. performed the experiments. S.W., D.Y. and D.Z. contributed to the XAFS data. S.W. contributed to the EPR data. Z.L. and X.Q. contributed to the DFT calculations.

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Correspondence to Xiaotian Qi or Aiwen Lei.

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

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Supplementary Methods, Discussion, Tables 1–7 and Figs. 1–18.

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Wang, S., Gao, Y., Liu, Z. et al. Site-selective amination towards tertiary aliphatic allylamines. Nat Catal 5, 642–651 (2022). https://doi.org/10.1038/s41929-022-00818-y

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