Synergistic Cu/Ag Dual Regioselective Cyclization Catalysis to Access Functionalized 3-Amido and 3-Indolyl Phthalides

To address the increasing demands for selectivity and sustainability in modern synthesis, integrated multicatalytic strategies such as synergistic dual catalysis, regioselective cyclization, and combo catalysis have emerged as powerful tools for accessing complex, highly functionalized, and valuable molecules. In this study, we first report a unique, straightforward, and practicable domino Cu/Ag synergistic-cooperative cyclization catalysis for the efficient derivatization of variably functionalized 3-amido phthalides and 3-indolyl phthalides in good to excellent yields through regioselective C-C/C-N/C-O bond formation. These pharmaceutically relevant and important scaffolds are widely recognized for their diverse therapeutic potential, ranging from cardiovascular to Alzheimer's disease applications. The developed protocol utilizes readily producible, inexpensive precursors and proceeds under robust, moisture-insensitive, and step-economic conditions, avoiding expensive catalytic systems, harsh reaction conditions, or hazardous chemicals. Plausible mechanistic insights are proposed and supported by literature surveys, control experiments, and DFT computations for this easily practicable protocol. Furthermore, the scale-up to gram-scale production with good yields and postmodifications of the core 3-substituted phthalide products demonstrates the practical potency and versatility of this synergistic multicatalytic strategy.