Engaging vinylene carbonate in ruthenium-catalyzed regioselective C-4 methylenation and C-8 formylmethylation of isoquinolinones

Abstract

Herein, we disclose the first reports on the utilization of vinylene carbonate as a C1 methylene source in ruthenium-catalyzed additive controlled regioselective C4-methylenation and weak chelation-assisted C8-formylmethylation of isoquinolinones. Adopting vinylene carbonate as both a C2 and C1 synthon is an important highlight of this work. Amide carbonyl acts as the traceless directing group in C8-formylmethylation. Remarkably, in this reaction, two C–C bonds form in one-pot producing dimeric isoquinolinones by employing vinylene carbonate as a methylene surrogate in the presence of copper acetate as an additive. Importantly, unsymmetrical dimers were achievable, albeit in low yield. Extensive control experiments are conducted to decipher the reaction mechanism. It is evident from the mechanistic studies, that the formation of a formylmethyl group in situ at the C4-carbon undergoes dimerization, oxidation and subsequent decarboxylation to produce methylene-bridged isoquinolinone dimers. This protocol is scalable and compatible with a repertoire of substrates and shows high functional group tolerance. Harnessing vinylene carbonate as both a C2 and C1 synthon is an important highlight of this work.