Direct C-H-sulfonylation of pyridine and related 6-membered N-heteroaromatics

Heteroaromatic sulfones and sulfonamides constitute important scaffolds in medicinal chemistry and the development of new drugs. Herein we describe a straightforward approach for the direct installation of sulfonyl functionalities onto 6-ring N-heteroaromatics via the direct functionalization of C-H-bonds. This novel method is based on preactivation of the N-heterocycle with trifle anhydride, followed by a base-mediated addition of sulfinate nucleophile and a subsequent elimination-rearomatization. Using this straightforward process, various N-heteroaromatics could be converted directly into the desired sulfonylated products in moderate to high yields. By exploiting either sulfur dioxide or the sulfur dioxide surrogates DABSO and rongacyl, this methodology could be extended to a modular construction of the key sulfonyl functionality. Furthermore, application of this protocol to the late-stage diversification of drug-like scaffolds and natural products is demonstrated. Further studies towards a base-mediated regioselective C4-sulfonylation of pyridines are described as well. In summary, our methods enable a a straightforward synthesis of biologically relevant sulfonylated N-heterocycles, an important motif in drug development.