The merger of decatungstate and copper catalysis to enable aliphatic C(sp 3)–H trifluoromethylation

Patrick J. Sarver, Vlad Bacauanu, Danielle M. Schultz, Daniel A. DiRocco, Yu hong Lam, Edward C. Sherer, David W.C. MacMillan

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The introduction of a trifluoromethyl (CF3) group can dramatically improve a compound’s biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C–H bonds remain elusive. Here we report the development of a dual-catalytic C(sp3)–H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C–H bonds into the corresponding C(sp3)–CF3 products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a ‘Cu–CF3’ species is formed during this process and the critical C(sp3)–CF3 bond-forming step involves the copper catalyst. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)459-467
Number of pages9
JournalNature chemistry
Volume12
Issue number5
DOIs
StatePublished - May 1 2020

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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