Accessing Rare α‐Heterocyclic Aziridines via Brønsted Acid‐catalyzed Michael Addition/Annulation: Scope, Limitations, and Mechanism

Abstract

We report an approach to the diastereoselective synthesis of 1,2‐disubstituted heterocyclic aziridines. A Brønsted acid‐catalyzed conjugate addition of anilines to trisubstituted heterocyclic chloroalkenes provides an intermediate 1,2‐chloroamine. Diastereocontrol was found to vary significantly with solvent selection, with computational modelling confirming selective, spontaneous fragmentation in the presence of trace acids, proceeding through a pseudo‐cyclic, protonated intermediate and transition state. These chloroamines can then be converted to the aziridine by treatment with LiHMDS with high stereochemical fidelity. This solvent‐induced stereochemical enrichment thereby enables an efficient route to rare cis‐aziridines with high dr. The scope, limitations, and mechanistic origins of selectivity are also presented.