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Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
C3-H methylenephosphonylation of azaarenes enabled by catalyst-controlled regioselective cyclizative rearrangement
Dan Liu1, Fang-Zhou Li1, Yu-Ping He2
1Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University Shanghai 200240 China hua.wu@sjtu.edu.cn.
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.
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