Aluminum Cation-Catalyzed C2–H Activation and Enantioselective Michael Addition of Indoles

Abstract

While C–H functionalization reactions are widely achieved using precious metal-based catalysts, such transformations are far less common for earth-abundant main-group metals. In this work, we demonstrate that prolinol-supported tetracoordinate aluminum cations can activate the C2–H bond of 3-substituted indoles and facilitate an enantioselective Michael addition to enones, furnishing alkylated indoles with good to excellent enantioselectivity. In contrast to transition-metal-catalyzed systems, the use of specially designed chelating enone substrates is no longer essential for the aluminum cation catalyst to induce stereoselectivity. Mechanistic studies suggest that the ligand-assisted concerted metalation-deprotonation of the C2–H bond is the rate-determining step (RDS). Stoichiometric NMR experiments provide direct evidence for an on-cycle aluminum complex, further supporting the proposed C2–H activation pathway. These findings are also consistent with the observed complete suppression of the C2–H activation when the amine basic site of the ligand was blocked or other Lewis acid catalysts were used. Our findings highlight the unique catalytic reactivity of prolinol-supported aluminum cations and provide a foundation for the future development of main-group catalysts for enantioselective C–H functionalization of heterocycles.