Constructing four-membered heterocycles by cycloisomerization

12 December 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Four-membered heterocycles are highly sought after in modern drug discovery as they provide beneficial properties to the target molecules. Despite tremendous efforts by the synthetic research community, there is a need for a simple and new method to incorporate these motifs into the design molecules. Herein, we reveal a cycloisomerization strategy for the construction of oxetane and azetidine rings via metal hydride hydrogen atom transfer/radical polar crossover, which is challenging both enthalpically and entropically. This method is suitable for synthesizing polysubstituted four-membered heterocycles. This mild and functional-group tolerant reaction has a broad substrate scope, including the spiro structure, which is an important motif in drug discovery research. Various four-membered heterocyclic building blocks can be synthesized by product derivatization. We also discuss the reaction mechanism, focusing on the four membered ring formation, by deuterium experiment and DFT studies.


hydrogen atom transfer
radical polar crossover

Supplementary materials

supporting information
experimental procedure compound data additional data DFT study X-ray analysis Charts


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