Unveiling the mechanisms of gold/copper bimetallic catalysis in the synthesis of complex heterocyclic compounds

Abstract

Bimetallic catalysis offers enhanced reactivity, selectivity, and cooperative effects compared to traditional monometallic catalysis. However, the detailed understanding of coordination and metal interactions in such bimetallic systems is still elusive. Herein, we employ density functional theory (DFT) calculations to systematically investigate the reaction mechanism and selectivity of a gold/copper bimetallic system in the tandem cyclization reaction of pyridylhomopropargylic alcohol and propargyl alcohol. Our findings unveil a distinct "handshake relay" mechanism: In the initial cycle, gold activates the substrate pyridylhomopropargylic alcohol via π-acid activation, facilitating a 5-endo-dig cyclization to generate a pivotal 2,3-dihydrofuran intermediate. In the subsequent cycle, gold activates propargyl alcohol to enable intermolecular carbon-carbon coupling, dehydration and cyclization. Copper then takes over through coordination, dramatically lowering the energy barrier for the Friedel-Crafts cyclization and promoting H2 elimination to ultimately yield the polycyclic dihydrobenzofuran product. This study not only clarifies the dynamic transition of active metal centers during bimetallic relay catalysis but also elucidates the distinct roles of gold and copper at different stages of the reaction. Our findings significantly advance the understanding of synergistic catalysis in gold/copper systems, providing valuable insights into the efficient synthesis of complex heterocycles and overcoming the limitations of traditional monometallic catalysis.