Fangting Huang, Jie Liu, Zhongyi Zeng, Zhi Zhou, Wei Yi, Shengdong Wang
Isoindolinones are valuable nitrogen-containing heterocycles, yet efficient access to highly functionalized derivatives remains challenging. Herein, we report a bioinspired carbonyl alkylative amination enabled by Ca(II)/HFIP cooperative catalysis for the modular synthesis of 3-alkyl- N -substituted isoindolinones. This three-component cascade combines amines, ketoesters, and alkyl-1,4-dihydropyridines via sequential imine formation, alkyl transfer, and intramolecular cyclization. The protocol proceeds under mild conditions with a broad substrate scope and excellent functional-group tolerance, affording diverse isoindolinones in good to excellent yields. Its synthetic utility is demonstrated in the late-stage functionalization of pharmaceuticals, natural products, and AIEgen labeling. This work extends Ca(II)/HFIP catalysis from hydride to alkyl transfer, providing a practical platform for sustainable C–C and C–N bond formation.