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

Nat Chem. 2018 Feb;10(2):165-169. doi: 10.1038/nchem.2871. Epub 2017 Nov 6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry
  • Amines / chemical synthesis*
  • Amines / chemistry*
  • Anabasine / chemical synthesis*
  • Anabasine / chemistry
  • Chemistry Techniques, Synthetic
  • Molecular Structure
  • Stereoisomerism

Substances

  • Alkaloids
  • Amines
  • Solenopsin A
  • Anabasine

Associated data

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