Bioinspired Alkyl Transfer Enabled by Ca(II)/HFIP Cooperative Catalysis: Modular Synthesis of Functionalized Isoindolinones

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.