Radical strain-release photocatalysis for the synthesis of azetidines

Abstract

The increasing popularity of four-member rings in drug discovery has prompted the synthetic chemistry community to advance and reinvent old strategies to craft these structures. Recently, the strain-release concept has been used to build complex architectures. However, although there are many strategies for accessing small carbocyclic derivatives, the synthesis of azetidines remains underdeveloped. Here we report a photocatalytic radical strategy for accessing densely functionalized azetidines from azabicyclo[1.1.0]butanes. The protocol operates with an organic photosensitizer, which finely controls the key energy-transfer process with distinct types of sulfonyl imines. The radical intermediates are intercepted by the azabicyclo[1.1.0]butanes via a radical strain-release process, providing access to difunctionalized azetidines in a single step. This radical process is revealed by a combination of spectroscopic and optical techniques and density functional theory calculations. The power and g enerality of this method is illustrated with the synthesis of various azetidine targets, including derivatives of celecoxib and naproxen. (Figure presented.)