Photocatalytic Defluoroalkylation of Trifluoromethylaromatics with arylethylenes

Abstract

We present a novel fluorine atom transfer technique for the selective functionalization of robust C-F bonds in trifluoromethylated aromatic compounds. This approach employs neutral boron radicals to generate aryl difluoromethyl radicals through a C-F cleavage process. These radicals engage in highly effective intermolecular coupling with aryl alkenes throughout the defluoroalkylation process. This mild, catalytic reaction system accommodates a diverse array of substrates, producing difluoroalkyl structures of medicinal importance with total regioselectivity. Organofluorine compounds are pivotal in medicines, agrochemicals, and functional materials. 1 The fluorine atom's elevated electronegativity, diminutive atomic radius, and distinctive chemical, physical, and biological characteristics might augment a compound's hydrophobicity, lipophilicity, and solubility, while concurrently enhancing its metabolic or oxidative stability and bioavailability. 2 Difluoroalkyl groups are garnering heightened interest owing to their distinctive electrical properties and capacity to augment the biological efficacy of organic compounds. 3 At now, difluoroalkyl modification techniques have been effectively utilized in various commercial pharmaceuticals. 4 For instance, RWJ-671818 is an orally bioavailable α-thrombin inhibitor, 5 while BMS serves as a frequently utilized agonist (Scheme 1A). Moreover, trifluoromethyl compounds possess a diverse array of readily accessible sources. 6 Consequently, the selective cleavage of the C(sp 3 )-F link from accessible trifluoromethyl compounds to directly produce useful difluoromethyl compounds constitutes a technique that is both atom-and step-efficient. The primary problems of this approach stem from the elevated dissociation energy of the C-F bonds in polyfluorinated compounds (PhCF3, which has a C-F bond dissociation energy of roughly 115 kcal/mol) and the regulation of selective defluorination. 7 In trifluoromethyl groups, the bond energy of the residual C-F bond diminishes with the removal of each C-F link.In certain instances, all three equivalent C-F bonds may cleave concurrently, and C-F bonds in monofluorinated and Scheme 1. A) Difluoroalkyl drug molecules. B) The reported defluorination methods. C) Boron radical activation of C-F bond.