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Catalytic asymmetric addition of an amine N–H bond across internal alkenes

Nature volume 588, pages 254–260 (2020)Cite this article

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Abstract

Hydroamination of alkenes, the addition of the N–H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy1,2,3. The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes2,3,4; only a few examples occur by the direct addition of the N–H bond of amines across unactivated internal alkenes5,6,7, including photocatalytic hydroamination8,9, and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity10,11,12,13. Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N–H bonds of other reagents, as well as O–H and C–H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks.

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Fig. 1: Catalytic asymmetric hydroamination of unactivated internal alkenes.
Fig. 2: Development of asymmetric hydroamination of unactivated internal alkenes with 2-amino-6-methylpyridine as an ammonia surrogate.
Fig. 3: Scope of internal alkenes that undergo hydroamination.
Fig. 4: Mechanistic study of the hydroamination.

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Data availability

The data that support the findings of this study are available within the article and its Supplementary Information.

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Acknowledgements

The enantioselective aspects of the work were supported by the National Institutes of Health under grant R35GM130387 and the catalyst development was supported by the Director, Office of Science, of the US Department of Energy under contract number DE-AC02-05CH11231. Calculations were performed at the Molecular Graphics and Computation Facility at UC Berkeley funded by the NIH (S10OD023532). We gratefully acknowledge Takasago for gifts of (S)-DTBM-SEGPHOS, and H. Celik for assistance with nuclear magnetic resonance (NMR) experiments. Instruments in the College of Chemistry NMR facility are supported in part by NIH S10OD024998. We thank R. G. Bergman, B. Su and T. Butcher for discussions. Y.X. thanks Bristol-Myers Squibb for a graduate fellowship, S. Pedram for supply of NaBARF and D. Small for assistance with DFT calculations.

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Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, CA, USA

    Yumeng Xi, Senjie Ma & John F. Hartwig

  2. Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    Yumeng Xi, Senjie Ma & John F. Hartwig

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  1. Yumeng Xi
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Contributions

Y.X. and J.F.H. conceived the project. Y.X. discovered the reaction and performed experiments and DFT calculations. S.M. performed experiments for revision. Y.X. and J.F.H. wrote the manuscript.

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Correspondence to John F. Hartwig.

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Xi, Y., Ma, S. & Hartwig, J.F. Catalytic asymmetric addition of an amine N–H bond across internal alkenes. Nature 588, 254–260 (2020). https://doi.org/10.1038/s41586-020-2919-z

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