Copper-Catalyzed Three-Component Aminofluorination of Alkenes and 1,3-Dienes: Direct Entry to Diverse β-Fluoroalkylamines.

Journal Article (Journal Article)

Rapid and efficient access to structurally diverse β-fluoroalkylamines is in high demand, with their wide presence and great importance in medicinal chemistry and drug development. Direct 1,2-aminofluorination of alkenes offers an ideal strategy for one-step entry to β-fluorinated amines from readily available starting materials. Yet the synthesis of valuable β-fluorinated alkylamines remains an unsolved challenge, due to the inherent incompatibility between electrophilic fluoride sources and the electron-rich alkylamines. We report an unprecedented, catalytic, three-component aminofluorination of diverse alkenes and 1,3-dienes, which has been achieved by an innovative copper-catalyzed electrophilic amination strategy using O -benzoylhydroxylamines as alkylamine precursors. The use of Et3 N·3HF is also critical, not only as a commercially available and inexpensive fluoride source to enable effective fluorination but also as an acid source for the formation of aminyl radical cations for electrophilic amination. Mechanistic experiments suggest the involvement of aminyl radical species and carbon-radical intermediates under reaction conditions. This method features high regioselectivity and good tolerance of diverse functional groups and provides a practical and direct entry to a broad range of β-fluorinated electron-rich alkylamines. Synthetic applications of this method have also been highlighted by its use for the rapid entry to β-fluoridated amine-containing pharmaceuticals, natural products, and bioactive compounds.

Full Text

Duke Authors

Cited Authors

  • Feng, G; Ku, CK; Zhao, J; Wang, Q

Published Date

  • November 2022

Published In

Volume / Issue

  • 144 / 44

Start / End Page

  • 20463 - 20471

PubMed ID

  • 36278925

Pubmed Central ID

  • PMC9650613

Electronic International Standard Serial Number (EISSN)

  • 1520-5126

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/jacs.2c09118

Language

  • eng