A unified flow strategy for the preparation and use of trifluoromethyl-heteroatom anions

Abstract

The trifluoromethyl group (CF 3 ) is a key functionality in pharmaceutical and agrochemical development, greatly enhancing the efficacy and properties of resulting compounds. However, attaching the CF 3 group to heteroatoms such as sulfur, oxygen, and nitrogen poses challenges because of the lack of general synthetic methods and reliance on bespoke reagents. Here, we present a modular flow platform that streamlines the synthesis of heteroatom-CF 3 motifs. Our method uses readily available organic precursors in combination with cesium fluoride as the primary fluorine source, facilitating the rapid generation of N -trifluoromethyl(R) [NCF 3 (R)], SCF 3 (trifluoromethylthio), and OCF 3 (trifluoromethoxy) anions on demand without reliance on perfluoroalkyl precursor reagents. This strategy offers a more environmentally friendly synthesis of trifluoromethyl(heteroatom)–containing molecules, with the potential for scalability in manufacturing processes facilitated by flow technology.