Mechanochemical and Piezo-Accelerated Stereoselective Synthesis of Isoindolinones

In this study, we report on the use of mechanochemistry for the synthesis of trifluoromethylated isoindolinones via a cascade radical sequence involving intermolecular addition/cyclization reactions of ynamides. This minimum solvent approach, involving liquid-assisted grinding, provides the products in good yields with complete E stereoselectivity, contrasting with the E/Z mixtures obtained under previously reported photoredox conditions. Mechanistic investigations revealed two complementary activation pathways: mechanical activation alone can trigger the radical cascade, while the presence of piezoelectric materials (BaTiO₃) significantly accelerates product formation. Furthermore, we identified an unexpected role of Celite® as an abrasive agent that promotes metal leaching and enables alternative activation pathways. This methodology showcases mechanochemistry as a valuable alternative to photoredox catalysis for stereoselective radical transformations, with distinct mechanistic advantages that can be strategically exploited.