Double-Activation Catalysis Enables Highly Diastereoselective Cascade Mannich/5-endo-dig Cyclization of 2-(2-Oxoindolin-3-yl)malononitriles with Alkynyl Ketimines

Double-activation catalytic systems are potent for making complex molecules in natural products and pharmaceutical fields, yet regulating the synergistic effect between the two catalysts is extremely challenging. Herein, a Cu/Ag double-activation catalysis that enabled the cascade Mannich/5-endo-dig cyclization was developed for the synthesis of a variety of spiro-cyclopentene-oxindole derivatives with three adjacent quaternary centers (up to 88% yield, >19:1 dr). Mechanistic investigations showed that it was not base-catalyzed, a single-metal catalyst showed poor performance, and the bimetallic catalyst was vital for highly efficient conversion.