Copper-catalyzed, chloroamide-directed benzylic C-H difluoromethylation

Xiaojun Zeng, Wenhao Yan, Matthew Paeth, Samson B. Zacate, Pei Hsun Hong, Yufei Wang, Dongqi Yang, Kundi Yang, Tao Yan, Chang Song, Zhi Cao, Mu Jeng Cheng, Wei Liu

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5 Citations (Scopus)

Abstract

We report herein the first catalytic strategy to harness amidyl radicals derived from N-chloroamides for C-C bond formation, allowing for the discovery of the first catalytic benzylic C-H difluoromethylation. Under copper-catalyzed conditions, a wide variety of N-chlorocarboxamides and N-chlorocarbamates direct selective benzylic C-H difluorome-thylation with a nucleophilic difluoromethyl source at room temperature. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage difluoromethylation of bioactive molecules. This copper-catalyzed, chloroamide-directed strategy has also been extended to benzylic C-H pentafluoroethylation and trifluor-omethylation. Mechanistic studies on the difluoromethylation reactions support that the reactions involve the formation of benzylic radicals via intramolecular C-H activation, followed by the copper-mediated transfer of difluoromethyl groups to the benzylic radicals.

Original languageEnglish
Pages (from-to)19941-19949
Number of pages9
JournalJournal of the American Chemical Society
Volume141
Issue number50
DOIs
Publication statusPublished - 2020 Jan 1

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Zeng, X., Yan, W., Paeth, M., Zacate, S. B., Hong, P. H., Wang, Y., Yang, D., Yang, K., Yan, T., Song, C., Cao, Z., Cheng, M. J., & Liu, W. (2020). Copper-catalyzed, chloroamide-directed benzylic C-H difluoromethylation. Journal of the American Chemical Society, 141(50), 19941-19949. https://doi.org/10.1021/jacs.9b11549