Modular synthesis of conjugated enamidines and cascade annulation toward benzofuran-3-oxoacetate

Abstract

A three-component reaction of aryne, DMF and isonitrile for the synthesis of the otherwise inaccessible chemotype, conjugated enamidinesis reported. The linear conjugated functionality is unambiguously evidenced by X-ray crystallography. Incubation with a Brønsted acid causes a cascade skeleton rearrangement of the enamidines to benzofuran-3-oxoacetates. A wide range of enamidines and downstream benzofuran-3-oxoacetates have been synthesized in moderate to good yields. We propose a multistep rearrangement involving a 1,3-benzoxazepine intermediate and conduct control experiments to support this mechanistic proposal. We also showcase the application of this method in the synthesis of two highly potent and selective glycogen synthase kinase-3β (GSK-3β) inhibitors.