Selective C-H fluorination of pyridines and diazines inspired by a classic amination reaction

Science. 2013 Nov 22;342(6161):956-60. doi: 10.1126/science.1243759.

Abstract

Fluorinated heterocycles are prevalent in pharmaceuticals, agrochemicals, and materials. However, reactions that incorporate fluorine into heteroarenes are limited in scope and can be hazardous. We present a broadly applicable and safe method for the site-selective fluorination of a single carbon-hydrogen bond in pyridines and diazines using commercially available silver(II) fluoride. The reactions occur at ambient temperature within 1 hour with exclusive selectivity for fluorination adjacent to nitrogen. The mild conditions allow access to fluorinated derivatives of medicinally important compounds, as well as a range of 2-substituted pyridines prepared by subsequent nucleophilic displacement of fluoride. Mechanistic studies demonstrate that the pathway of a classic pyridine amination can be adapted for selective fluorination of a broad range of nitrogen heterocycles.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amination
  • Carbon / chemistry
  • Fluorides / chemistry
  • Fluorine / chemistry*
  • Halogenation*
  • Hydrogen / chemistry
  • Hydrogen Bonding
  • Nitrogen / chemistry
  • Pyridines / chemistry*
  • Silver Compounds / chemistry

Substances

  • Pyridines
  • Silver Compounds
  • silver fluoride
  • Fluorine
  • Carbon
  • Hydrogen
  • Nitrogen
  • Fluorides