Construction of C–X (X = S, O, Se) Bonds via Lewis Acid-Promoted Functionalization of Trifluoromethylarenes

Abstract

The conversion of easily available trifluoromethylarenes through C–F bond activation provides an attractive pathway for rapid access to difluorobenzylic substructures in producing pharmaceuticals and agrochemicals. However, recent advances in this area have been confined to C–C(H) bond construction, thus limiting the diversity of the accessible motifs. In contrast, the selective formation of a carbon–heteroatom bond via C–F bond functionalization, which enable fast and convenient access to diverse fluorine-containing motifs with high chemical diversity, remains a formidable synthetic challenge. Herein, we disclosed a Lewis acid promoted photoredox-catalyzed strategy for the construction of C–X (X = S, O or Se) bonds by single C(sp3)–F bond activation of trifluoromethylarenes, which enable the direct synthesis of medicinally interesting aryldifluoromethyl ether [ArCF2X– (X = S, O, or Se)] scaffolds. This method relies on readily available reagents and can tolerate a range of thiol, phenol, and selenol nucleophiles. Its utility was exemplified in the late-stage modifications of several pharmaceutical ingredients. Preliminary studies suggest two parallel pathways: a photocatalytic single electron-transfer (SET), and an electron donor–acceptor (EDA) process.