Deoxyfluorination of Ketones with Sulfur Tetrafluoride (SF4) and Dialkylamines in Continuous Flow Mode

Abstract

Fluorinated molecules are prevalent in biologically active substances, in particular, the gem-difluoro motif. However, the selective incorporation of a gem-difluoro motif into organic molecules is a laborious task. Deoxyfluorination is a promising and widely used methodology to achieve this transformation, which is usually costly or highly hazardous. Herein, we report a deoxyfluorination protocol using sulfur tetrafluoride (SF₄) and diethylamine (Et₂NH) to prepare gem-difluorides in continuous flow mode. The process does not require the addition of exogenous HF, and in situ generated reagents were quenched in-line, which improved safety. The methodology was successfully applied to convert a broad range of 4-, 5-, and 6-membered ketone derivatives to their corresponding difluorinated compounds while minimizing the undesired vinyl fluoride formation. In summary, these findings improve safety and selectivity toward the synthesis of gem-difluoro compounds drastically, enabling a more efficient production of fluorinated active pharmaceutical ingredients.