Conformation-induced remote meta-C-H activation of amines

Nature. 2014 Mar 13;507(7491):215-20. doi: 10.1038/nature12963.

Abstract

Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C-H bonds in any given organic molecule can lead to the activation of undesired C-H bonds by a non-selective catalyst. One solution to this problem is to distinguish C-H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C-H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied. However, the directed activation of C-H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C-H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C-H bonds--as far as 11 bonds away--of anilines and benzylic amines. This template is able to direct the meta-selective C-H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemistry
  • Amines / chemistry*
  • Aniline Compounds / chemistry
  • Benzylamines / chemistry
  • Carbon / chemistry*
  • Drug Design
  • Hydrogen / chemistry*
  • Quinolines / chemistry

Substances

  • Alkenes
  • Amines
  • Aniline Compounds
  • Benzylamines
  • Quinolines
  • Carbon
  • Hydrogen
  • benzylamine
  • 1,2,3,4-tetrahydroquinoline
  • methylaniline