Computational and Experimental Studies on the α-Functionalization of Ketones Using Domino Reactions: A Strategy to Increase Chemoselectivity at the α-Carbon of Ketones

A facile strategy to increase the chemoselectivity of domino reactions was proposed and successfully applied in the α-functionalization of ketones. The strategy involved widening the activation energy of the main reaction and side reaction through intermolecular interactions, thereby increasing the chemoselectivity of the domino reaction. In the proposed α-functionalization reaction, TMSCF₃ acted as an excellent reagent which increased the nucleophilicity of DMF through the Van der Waals force and reduced the nucleophilicity of H₂O through a hydrogen bond. We found that TMSCF₃ can increase the activation energy difference between the main reaction and side reaction using DFT calculations, which greatly increased chemoselectivity and avoided the formation of by-products. TMSCF₃ was recycled by rectification, and the average recovery rate was 87.2%. DFT calculations, XRD experiments, and control experiments were performed to support this mechanism. We are confident that this strategy has the potential to deliver significant practical advancements while simultaneously fostering broader innovation in the field of domino synthesis.