Conformational rigidity controlled copper catalyzed chemodivergent annulation

Abstract

The conformational rigidity of substrates is critical in determining reaction outcomes, impacting both reactivity and product selectivity. The impact of conformational rigidity on mechanistic divergence is an area that remains underexplored. In this study, we present a straightforward Cu/PhPyBox-catalyzed chemodivergent annulation reaction, wherein the rigidity of α-aminoketones dictates a switch in mechanism under identical reaction conditions. Mechanistically, hydrogen bonding interactions are critical to suppress the nucleophilicity of the amine, facilitating the formation of a common enaminal intermediate from cyclic ethynylethylene carbonate (EEC) derived allenals, instead of propargylic substitution. This unified strategy offers access to three distinct classes of valuable nitrogenous heterocycles that are prevalent in bioactive molecules. Among these heterocycles, indolone derivatives exhibit significant antibacterial activity compared to the marketed drug ampicillin against multi-drug-resistant Gram-negative Pseudomonas aeruginosa bacteria, highlighting their potential as a source of new therapeutic agents.