Monofluoromethylation of acyl chlorides and chloroformates employing fluorobis(phenylsulfonyl)methane. Synthesis of monofluoromethyl ketones via selective zinc-mediated reductive desulfonylation

Abstract

A high yielding protocol for the synthesis of valuable monofluoromethyl ketones (MFMK) utilizing fluorobis(phenylsulfonyl)methane (FBSM) is presented. The protocol allows the incorporation of the biologically relevant monofluoromethyl group under mild reaction conditions and in short reaction times. The obtained fluorobis(phenylsulfonyl)methyl ketones can subsequently be selectively reduced to the fluoro(phenylsulfonyl)methyl- and subsequently to monofluoromethyl ketones via zinc-mediated reductive desulfonylation. Furthermore, weak intramolecular van der Waals interactions were observed in fluorobis(phenylsulfonyl)methyl ketones and they were further investigated using nuclear magnetic resonance spectroscopy and single crystal X-ray diffraction analysis. An improved method for the assessment of lipophilic properties of these fluorinated small molecules has been developed and correlated to theoretical log P values.