Silver-Catalyzed Dearomative Skeletal Editing of Indazoles by Donor Carbene Insertion.

Abstract

Given the prevalence of heterocyclic scaffolds in drug-related molecules, converting these highly modular heterocyclic scaffolds into structural diversified and dearomatized analogs is an ideal strategy for improving their physicochemical and pharmacokinetic properties. Here, we described an efficient method for silver carbene-mediated dearomative N-N bond cleavage leading to skeletal hopping between indazole and 1,2-dihydroquinazoline via a highly selective single-carbon insertion procedure. Using this methodology, a series of dihydroquinazoline analogues with diarylmethylene-substituted quaternary carbon centers were constructed with excellent yields and good functional group compatibility, which was further illustrated by the late-stage diversification of important pharmaceutically active ingredients. DFT calculations indicated that the silver catalyst not only induces the formation of the silver carbene, but also activates the diazahexatriene intermediate, which plays a crucial role in the formation of the C-N bond.