C3-H Methylenephosphonylation of Azaarenes Enabled by Catalyst-controlled Regioselective Cyclizative Rearrangement

Abstract

The incorporation of phosphonate moieties into azaarenes via C-H functionalization is of paramount importance in pharmaceutical research, yet it remains a formidable synthetic challenge. Herein, we report an intermolecular cyclizative rearrangement approach for the efficient site-selective methylenephosphonylation of diverse azaarenes. This reaction proceeds via an orchestrated cascade sequence comprising regioselective 1,3-dipolar cycloaddition, [3,5]-sigmatropic rearrangement, and selective C-C bond cleavages. As a Lewis acid catalyst, ZnBr2 is crucial to this transformation: it not only delivers high conversion but also controls the regioselectivity of the initial cyclization, which in turn dictates the chemoselectivity of the entire process. This protocol is applicable to late-stage functionalization of various pharmaceuticals and ligands, and facilitates further product diversification for advanced uses. This reaction represents the first example of the C-H methylenephosphonylation of arenes.