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Updated: Jan 10, 2026

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
A Unified Synthetic Approach to 2-Alkyl Azetidines, Oxetanes, Thietanes and Cyclobutanes from Unactivated Alkenes
Louis Buck1,2, Maria Pelosi1,2, Subhasis Paul1,2
1The GSK Carbon Neutral Laboratories for Sustainable Chemistry, University of Nottingham, Jubilee Campus, Nottingham NG7 2TU, United Kingdom.
Abstract:
2-Alkyl substituted four-membered carbocycles and heterocycles are relevant motifs in pharmaceuticals and agrochemicals. However, synthetic methods to access these scaffolds mostly rely on functional group interconversion of a narrow subset of preformed cyclic building blocks, impeding access to a broad chemical space. In this report, we introduce a general method to transform readily available unactivated alkenes into 2-alkyl four-membered rings. In contrast to classic [2 + 2] cycloaddition chemistry─which is not viable for this class of products─our strategy leverages a homologative alkene dielectrophilic activation, converting the starting alkene into a transient 1,3-iodo-sulfonium intermediate, which undergoes sequential nucleophilic substitutions to promote ring formation. The chemical versatility of the intermediate enables modulation of the order of substitutions, crucial to targeting the full matrix of four-membered rings─i.e., azetidines, oxetanes, thietanes, and cyclobutanes. This functional group tolerant process is applicable to a wide range of alkenes─including complex structures─opening new avenues for applications in pharmaceutical and agrochemical synthesis.
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