C-H Alkylation of Heterocycles via Light-Mediated Palladium Catalysis

Abstract

Methods enabling direct C-H alkylation of heterocycles are of fundamental importance in the late-stage modification of natural products, bioactive molecules, and medicinally relevant compounds. However, there is a scarcity of a general strategy for the direct C-H alkylation of a variety of heterocycles using commercially available alkyl surrogates. We report an operationally simple palladium-catalyzed direct C-H alkylation of heterocycles using alkyl halides under the visible light irradiation with good scalability and functional group tolerance. Our studies suggest that the photoinduced alkylation proceeds through a cascade of events comprising, site-selective alkyl radical addition, base-assisted deprotonation, and oxidation. A combination of experiments and computations was employed for the generalization of this strategy, which was successfully translated towards the modification of natural products and pharmaceuticals.

Keywords: Computational Studies; C−H functionalization; Heterocycles; Palladium; Photochemistry.