Radical cascade cyclization of chalcone skeleton enynes with sulfonylhydrazides: access to meta-sulfonyl-functionalized pyridines

Abstract

Pyridine and its derivatives are commonly present in natural products and drug molecules. However, the synthesis of meta-functionalized pyridines has always been a challenge in the field of organic synthesis due to the regioselectivity of C–H bond activation. Here, we developed an efficient strategy for synthesizing meta-sulfonyl functionalized poly-substituted pyridine compounds via a cascade cyclization process involving 1,5-enynes bearing a chalcone skeleton and a sulfonyl radical generated by tert-butyl hydroperoxide (TBHP). This strategy can avoid the extremely difficult and challenging regioselective meta-CH bond activation of pyridines. Meanwhile, this method facilitates the one-step synthesis of various 3-sulfonyl-functionalized pyridines under metal-free and mild reaction conditions. Furthermore, the representative product 3i could be transformed into a new type of bidentate sulfur ligand, which has enormous potential for application in transition metal-catalyzed reactions. Mechanistic investigations suggest that the reaction proceeds via a free-radical pathway.