Chiral Phosphoric Acid-Catalyzed Enantioselective Synthesis of 2,2-Disubstituted 2,3-Dihydro-4-quinolones from Isatins and 2'-Aminoacetophenones

Org Lett. 2025 Jan 10;27(1):258-263. doi: 10.1021/acs.orglett.4c04249. Epub 2024 Dec 24.

Abstract

Herein, we present the enantioselective synthesis of 2,3-dihydro-4-quinolones bearing chiral tetrasubstituted carbons from isatins and 2'-aminoacetophenones. The transformation is mediated by a chiral phosphoric acid catalyst and proceeds via an in situ generated ketimine and subsequent enantioselective intramolecular cyclization. The methodology features a broad scope and functional group tolerance with yields and enantioselectivities of up to 99% and 98% ee. Detailed density functional theory (DFT) calculations support the proposed reaction mechanism and the origin of asymmetric induction.