Chemo selective C-H alkylation of isoquinolones with maleimides: A combined experimental and computational case study

Abstract

• A case study of transition metal catalysis for chemoselectivity . • Theoretical and experimental case study. • Detail mechanistic analysis i.e., KIE, Hammett study, NCI plot, etc., with three metal catalysis. • The developed catalytic method applied for gram-scale synthesis and late-stage modification. A comparative study of C8-alkylation of isoquinolone with maleimides is reported under different catalytical systems. Among different catalytical systems, Ru and Rh catalysts were found to be excellent in providing C8-alkylated products in good yields, and complete selectivity was achieved using Ru-catalyst. Density functional theory (DFT) investigations suggest a reaction mechanism involving three major steps: C-H activation at C8 position of the isoquinolone, maleimide migratory insertion into the metal-aryl bond, and protonation by the acetic acid. Non-covalent interaction (NCI) analysis was also executed to understand the reaction feasibility and selectivity pattern. Experimental mechanistic studies combined with DFT calculations and NCI analysis provide in-depth information to unravel the mystery behind the selective formation of alkylated products. The current catalytic methodology is further elaborated with a broad substrate scope and late-stage modification.