Elucidating the mechanism of the FeCl3-Catalyzed quinoline synthesis by A3 multicomponent reaction

Abstract

Access to the quinoline scaffold through a multicomponent A3 (Aldehyde-Amine-Alkyne) protocol has emerged as a successful synthetic route owing to their experimental simplicity and relevant sustainable potential. Since the original report for A3 synthesis of quinolines based on Cu(I) catalyst, a substantial part of scientific literature has considered propargylamine formation via acetylide metal coupling as the key reaction intermediate for many Lewis acid catalysts, despite the obvious competition with a Povarov-like [4 + 2] cycloaddition mechanism. Considering the positive economic and environmental impacts of using non-precious metal catalysts, and the lack of solid evidence to support the preferential pathway in Fe(III)-catalyzed quinoline synthesis, we employed isotopic labeling and kinetic experiments associated with DFT calculations to support the formal [4 + 2] cycloaddition as the most favorable mechanism in A3-Fe catalyzed MCR protocol under aerobic conditions.