A modular synthesis of azetidines from reactive triplet imine intermediates using an intermolecular aza Paternò–Büchi reaction

Abstract

Azetidines are four-membered saturated N-heterocycles that are of interest in discovery chemistry. However, the implementation of these structures is limited by their synthetic intractability, resulting from their inherent ring strain. An approach that circumvents this is the intermolecular [2 + 2] photocycloaddition between imines and alkenes. However, this is unworkable with simple acyclic imines and non-activated alkenes, due to the inability to generate suitably reactive imine-derived triplet intermediates. Here we show that simple acyclic imines bearing N-sulfamoyl fluoride substituents generate reactive triplet imines that react with a broad range of alkenes to produce azetidine products in high yields. Mechanistic and computational studies confirm the key role of the sulfamoyl fluoride unit in dictating the [2 + 2] pathway. In addition, the sulfamoyl fluoride substituents offer a convenient reaction site for product functionalization or for traceless removal. The advent of synthetically useful imine-derived triplets should initiate further research and applications of these elusive reactive intermediates. Azetidines are four-membered saturated N-heterocycles that are of interest in drug discovery and medicinal chemistry. Here the authors report how sulfamoyl fluoride substituents tune the reactivity of acyclic imine-derived triplet intermediates for the synthesis of azetidines via a [2 + 2] photocycloaddition reaction with alkenes.