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Direct α-C–H bond functionalization of unprotected cyclic amines

Nature Chemistry volume 10, pages 165–169 (2018)Cite this article

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Abstract

Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C–H bonds is an attractive strategy for preparing valuable functionalized amines from their readily available parent heterocycles, this approach has largely been limited to substrates that require protection of the amine nitrogen atom. In addition, most methods rely on transition metals and are incompatible with the presence of amine N–H bonds. Here we introduce a protecting-group-free approach for the α-functionalization of cyclic secondary amines. An operationally simple one-pot procedure generates products via a process that involves intermolecular hydride transfer to generate an imine intermediate that is subsequently captured by a nucleophile, such as an alkyl or aryl lithium compound. Reactions are regioselective and stereospecific and enable the rapid preparation of bioactive amines, as exemplified by the facile synthesis of anabasine and (–)-solenopsin A.

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Figure 1: Methods for amine α-C–H bond functionalization and the new concept for secondary amines.
Figure 2: Control studies and simplification of the set-up conditions.

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Acknowledgements

Financial support from the NIH–NIGMS (R01GM101389) is gratefully acknowledged. We thank T. Emge (Rutgers University) for the crystallographic analysis.

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Author notes

  1. Anirudra Paul & Daniel Seidel

    Present address: Department of Chemistry, University of Florida, Gainesville, Florida, 32611, USA

  2. Weijie Chen and Longle Ma: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA

    Weijie Chen, Longle Ma, Anirudra Paul & Daniel Seidel

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  1. Weijie Chen
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Contributions

W.C. and L.M. developed the amine α-functionalization and contributed equally to this work. A.P. further developed the reaction and expanded the scope. D.S. conceived and supervised the project and wrote the manuscript. All the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Daniel Seidel.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 7926 kb)

Supplementary information

Crystallographic data for compound ±45. (CIF 148 kb)

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Chen, W., Ma, L., Paul, A. et al. Direct α-C–H bond functionalization of unprotected cyclic amines. Nature Chem 10, 165–169 (2018). https://doi.org/10.1038/nchem.2871

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