Difluoromethoxide Is a Strong Leaving Group in the Photoredox Deoxyradiofluorination of 2-Phenylpyridines

J Org Chem. 2024 Sep 20;89(18):13768-13773. doi: 10.1021/acs.joc.4c01505. Epub 2024 Sep 11.

Abstract

A 2-phenyl-3-difluoromethoxy-pyridinyl moiety features in potent phosphodiesterase 4D inhibitors that are considered to be candidate radiotracers for positron emission tomography if they are labeled with fluorine-18. Fluorine-18 could be installed as desired at the 3'-phenyl position with acridinium-mediated photoredox radiodeoxyfluorination in homologues bearing variously substituted 3'-aryloxy groups. However, a distal 3-difluoromethoxide (-OCHF2) group strongly competes as a leaving group, especially when an electron-deficient aryloxy group is present at position 3'. A yield of up to 50% may occur without observable 19F for 18F exchange.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Fluorine Radioisotopes* / chemistry
  • Halogenation
  • Hydrocarbons, Fluorinated / chemical synthesis
  • Hydrocarbons, Fluorinated / chemistry
  • Molecular Structure
  • Oxidation-Reduction*
  • Photochemical Processes
  • Pyridines* / chemical synthesis
  • Pyridines* / chemistry

Substances

  • Pyridines
  • Fluorine Radioisotopes
  • Hydrocarbons, Fluorinated
  • Fluorine-18