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

Year: 2026

Type: article

Abstract: 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.

Source: Chinese Journal of Chemistry

DOI: 10.1002/cjoc.70762