Nickel-catalyzed trifluoromethylthiolation of Csp2–O bonds

Abstract

While nickel catalysts have previously been shown to activate even the least reactive Csp²–O bonds, i.e. aryl ethers, in the context of C–C bond formation, little is known about the reactivity limits and molecular requirements for the introduction of valuable functional groups under homogeneous nickel catalysis. We identified that due to the high reactivity of Ni-catalysts, they are also prone to react with existing or installed functional groups, which ultimately causes catalyst deactivation. The scope of the Ni-catalyzed coupling protocol will therefore be dictated by the reactivity of the functional groups towards the catalyst. Herein, we showed that the application of computational tools allowed the identification of matching functional groups in terms of suitable leaving groups and tolerated functional groups. This allowed for the development of the first efficient protocol to trifluoromethylthiolate Csp²–O bonds, giving the mild and operationally simple C–SCF₃ coupling of a range of aryl, vinyl triflates and nonaflates. The novel methodology was also applied to biologically active and pharmaceutical relevant targets, showcasing its robustness and wide applicability.