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Copper-catalysed selective hydroamination reactions of alkynes

Nature Chemistry volume 7, pages 38–44 (2015)Cite this article

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An Erratum to this article was published on 23 January 2014

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Abstract

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine.

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Figure 1: Bioactive amines, the synthesis of amines from alkynes, and the reductive hydroamination cascade strategy.
Figure 2: Concise routes to drugs through cascade reductive hydroamination of alkynes.
Figure 3: Proposed catalytic cycles and mechanistic experiments.

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Change history

  • 18 December 2014

    In the version of this Article originally published, the red arrow at the top right of Fig. 1c should have been solid not dashed. This has now been corrected in the online versions of the Article.

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Acknowledgements

The authors acknowledge the National Institutes of Health for financial support (GM58160). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank S. Zhu (MIT), P.J. Milner (MIT) and M. Pirnot (MIT) for discussions. The authors thank Y. Wang (MIT) and N.T. Jui (Emory University) for help with the preparation of this manuscript.

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  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Shi-Liang Shi & Stephen L. Buchwald

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  1. Shi-Liang Shi
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S-L.S. and S.L.B. designed the project, analysed the data and wrote the manuscript. S-L.S. performed the experiments.

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Correspondence to Stephen L. Buchwald.

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Shi, SL., Buchwald, S. Copper-catalysed selective hydroamination reactions of alkynes. Nature Chem 7, 38–44 (2015). https://doi.org/10.1038/nchem.2131

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