A Multicomponent Reaction to Access Functionalized Azetidine Derivatives

Significance

Owing to the propensity to both enhance bioavailability and metabolic stability, azetidine moieties have been incorporated into a wide variety of biologically active entities. Furthermore, the introduction of a quaternary carbon center into the 3-position of the structurally rigid ring presents an additional advantage in avoiding chirality. While numerous approaches have been reported for the synthesis of azetidines, these are often not applicable for the preparation of derivatives featuring a C₃ all-carbon quaternary center. The current report describes a multicomponent reaction for the synthesis of azetidines exploiting the strain-release functionalization of azabicyclobutanes (ABBs).

Comment

Model studies on the reaction between benzoyl-ABB, 1,3-butadiene (0.2 M solution in THF) and TMS-CN showed that a variety of photocatalysts could be used, while the choice of the copper salt did not impact the reaction outcome with product even observed in the absence of copper. However, selection of the halide anion was a critical consideration, while solvent selection was also important for optimum yields to be obtained. A broad reaction scope was demonstrated with both (hetero)aryl- and alkyl-substituted ABBs performing well, with the protocol also applied for the derivatization of complex drug-like substrates. Mechanistic studies suggest that the reaction proceeds through a radical mechanism via the intermediacy of a 3-brominated azetidine derivative.

Publication History

Article published online:
23 June 2025

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