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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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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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.
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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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DOI: https://doi.org/10.1038/nchem.2871
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