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

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.