Four‐Component Strain‐Release‐Driven Synthesis of Functionalized Azetidines

Despite the favorable properties that azetidine rings can engender on drug‐compounds, methods for the diversity‐oriented synthesis of azetidine‐based structures are significantly underdeveloped. Herein, we report the successful realization of a multicomponent [1,2]‐Brook rearrangement/strain‐release‐driven anion relay sequence and its application to the modular synthesis of substituted azetidines. The rapidity of the reaction, as confirmed by in situ infra‐red spectroscopy, leverages the strain‐release ring‐opening of azabicyclo[1.1.0]butane to drive the equilibrium of the Brook rearrangement. The three electrophilic coupling partners, added sequentially to azabicyclo[1.1.0]butyl‐lithium, could be individually varied to access a diverse compound library. The utility of this methodology was demonstrated in a 4‐step synthesis of the EP2 receptor antagonist PF‐04418948.