Organocatalytic Enantioselective [3+2] Cycloaddition of para ‐Quinamines with Cyclic N ‐Sulfonyl Ketimines: Access to Imidazolidine‐Fused Benzosultam Derivatives

Comprehensive Summary Given the well‐established pharmacological significance of both imidazolidine derivatives and benzosultam analogues, the imidazolidine‐fused benzosultam scaffold, which is accessible through molecular hybridization, represents an architecturally novel N ‐heterocyclic framework with substantial potential for medicinal chemistry research. Herein, we report an efficient protocol for the synthesis of highly substituted imidazolidine‐fused benzosultams via a mild, catalyst‐free [3+2] cycloaddition between readily available para ‐quinamines and cyclic N ‐sulfonyl ketimines. This transformation enables the convergent assembly of two privileged pharmacophoric motifs into a single polycyclic scaffold, and is characterized by high yields (up to 99%), remarkably broad substrate scope, excellent functional group tolerance, exceptionally fast reaction rates (complete within 5 min), and high diastereoselectivity. Notably, the purification can be accomplished simply by trituration, which significantly enhances both operational simplicity and environmental sustainability. Furthermore, for the first time, a bifunctional amine‐thiourea catalyst has been successfully applied to the cycloaddition of para ‐quinamines, enabling a catalytic asymmetric variant that delivers structurally unprecedented enantioenriched 6/5/6/6‐fused benzosultams in up to 90% yields with excellent diastereo‐ and enantiocontrol (up to 97.5 : 2.5 er). The practical utility of this methodology is demonstrated through scale‐up synthesis and late‐stage modification. Mechanistic investigations suggest the involvement of a single amine‐thiourea catalyst in the enantiodetermining transition state, and two plausible mechanisms, along with their corresponding asymmetric induction models, are proposed. Collectively, this methodology provides a versatile platform for the rapid construction of imidazolidine and benzosultam bioisosteres, and holds great promise for applications in medicinal chemistry.