Synthesis of Isoquinolin-1-ones via Pd-Catalyzed Carbonylation-Heteroannulation

Significance

A palladium-catalyzed carbonylative cyclization of imines derived from diethyl (2-­iodoaryl)malonates and imidoyl chlorides provides a synthesis of substituted isoquinolin-1(2H)-ones in good yields. As shown, a mechanism involving a palladium-catalyzed carbonylation followed by decarboxylation process is proposed. The reactions depend significantly on the choice of ligand used: bidentate phosphines gave trace amounts of product, while trialkylphosphines gave complex mixtures. The optimum conditions involve use of bulky aryl phosphines with Pd(OAc)₂ and 400 psi pressure of CO at 120 ˚C in tetrahydrofuran which may therefore limit the process for large-scale synthesis.