Nickel-Catalyzed Cross Coupling of N-Alkenyl Heterocycles and Aryl Sulfonium Salts: Expedient Access to N-Benzyl Heterocycles

Abstract

A nickel-catalyzed system is developed that enables the coupling between aryldibenzothiophenium salts and N-alkenyl heterocycles. Traditionally, medicinally relevant N-benzylic heterocycles are constructed via harsh substitution conditions between the N-H heterocycle and a benzyl electrophile in the presence of strong bases. The CC cross coupling strategy presents attractive potential for the synthesis of these important scaffolds, e.g., carboetomidate. Herein, it is documented that the combination of a site-selective CH dibenzothiophenation with a nickel-catalyzed C(sp³)–C(sp²) cross coupling grants access to a diverse range of synthetically useful N-benzylic heterocycles, i.e., alkylated arenes. In particular, the mild conditions and good functional group compatibility permit the rapid assembly of molecular complexity and late-stage functionalization of bioactive compounds, such as clofibrate, fenofibrate, and fenbufen, thus providing an orthogonal protocol to existing S_N2 and CN coupling approaches.