A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides

Nathan W. Dow, Albert Cabré, David W.C. MacMillan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The catalytic union of amides, sulfonamides, anilines, imines, or N-heterocycles with a broad spectrum of electronically and sterically diverse alkyl bromides has been achieved via a visible-light-induced metallaphotoredox platform. The use of a halogen abstraction-radical capture (HARC) mechanism allows for room temperature coupling of C(sp3)-bromides using simple Cu(II) salts, effectively bypassing the prohibitively high barriers typically associated with thermally induced SN2 or SN1 N-alkylation. This regio- and chemoselective protocol is compatible with >10 classes of medicinally relevant N-nucleophiles, including established pharmaceutical agents, in addition to structurally diverse primary, secondary, and tertiary alkyl bromides. Furthermore, the capacity of HARC methodologies to engage conventionally inert coupling partners is highlighted via the union of N-nucleophiles with cyclopropyl bromides and unactivated alkyl chlorides, substrates that are incompatible with nucleophilic substitution pathways. Preliminary mechanistic experiments validate the dual catalytic, open-shell nature of this platform, which enables reactivity previously unattainable in traditional halide-based N-alkylation systems.

Original languageEnglish (US)
Pages (from-to)1827-1842
Number of pages16
JournalChem
Volume7
Issue number7
DOIs
StatePublished - Jul 8 2021

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry
  • Environmental Chemistry
  • Chemical Engineering(all)
  • Biochemistry, medical
  • Materials Chemistry

Keywords

  • copper catalysis
  • cyclopropylation
  • halogen abstraction
  • N-alkylation
  • organochloride activation
  • photoredox
  • SDG12: Responsible consumption and production
  • SDG9: Industry innovation and infrastructure

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