Mechanism of the TiIII-Catalyzed Acyloin-Type Umpolung: A Catalyst-Controlled Radical Reaction

The titanium­(III)-catalyzed cross-coupling between ketones and nitriles provides an efficient stereoselective synthesis of α-hydroxyketones. A detailed mechanistic investigation of this reaction is presented, which involves a combination of several methods such as EPR, ESI-MS, X-ray, in situ IR kinetics, and DFT calculations. Our findings reveal that C–C bond formation is turnover-limiting and occurs by a catalyst-controlled radical combination involving two titanium­(III) species. The resting state is identified as a cationic titanocene-nitrile complex and the beneficial effect of added Et3N·HCl on yield and enantioselectivity is elucidated: chloride coordination initiates the radical coupling. The results are fundamental for the understanding of titanium­(III)-catalysis and of relevance for other metal-catalyzed radical reactions. Our conclusions might apply to a number of reductive coupling reactions for which conventional mechanisms were proposed before.