Ligand-accelerated non-directed C-H functionalization of arenes

Nature. 2017 Nov 22;551(7681):489-493. doi: 10.1038/nature24632.

Abstract

The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.

Publication types

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

MeSH terms

  • Alkenes / chemistry
  • Biological Products / chemistry
  • Carbon / chemistry*
  • Catalysis
  • Hydrocarbons, Aromatic / chemistry*
  • Hydrogen / chemistry*
  • Ligands
  • Palladium / chemistry
  • Pharmaceutical Preparations / chemistry
  • Pyridones / chemistry*

Substances

  • Alkenes
  • Biological Products
  • Hydrocarbons, Aromatic
  • Ligands
  • Pharmaceutical Preparations
  • Pyridones
  • Palladium
  • 2-hydroxypyridine
  • Carbon
  • Hydrogen