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

Authors
  • Wang, Peng1
  • Verma, Pritha1
  • Xia, Guoqin1
  • Shi, Jun2
  • Qiao, Jennifer X3
  • Tao, Shiwei2
  • Cheng, Peter T W2
  • Poss, Michael A3
  • Farmer, Marcus E1
  • Yeung, Kap-Sun4
  • Yu, Jin-Quan1
  • 1 Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
  • 2 Discovery Chemistry, Bristol-Myers Squibb Company, 350 Carter Road, Princeton, New Jersey 08540, USA. , (Jersey)
  • 3 Discovery Chemistry, Bristol-Myers Squibb Company, PO Box 4000, Princeton, New Jersey 08543, USA. , (Jersey)
  • 4 Discovery Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
Type
Published Article
Journal
Nature
Publisher
Springer Nature
Publication Date
Nov 22, 2017
Volume
551
Issue
7681
Pages
489–493
Identifiers
DOI: 10.1038/nature24632
PMID: 29168802
Source
Medline
License
Unknown

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.

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