A Scalable Synthesis of 4-Functionalized Isoxazolidines and Pyrazolidines

Authors

  • Oleksandr V. Kaliberda Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd., Ukraine
  • Evgenij V. Zarudnitskii Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, Ukraine https://orcid.org/0000-0003-2038-4243

DOI:

https://doi.org/10.24959/ophcj.25.353295

Keywords:

synthesis, isoxazolidine, pyrazolidine, scale-up, functionalization

Abstract

A practical and scalable cyclization method for the preparation of C4-functionalized isoxazolidine and pyrazolidine building blocks is described. The methodology is based on the use of commercially available 1,3-dihalide and protected hydroxylamine or hydrazine derivatives under unified NaH/DMF conditions, enabling direct assembly of both N,O- and N,N-heterocycles. The process is operationally robust and successfully implemented on an over 100 g scale. The oxidative conversion of exocyclic alkene intermediates made it possible to obtain isoxazolidin-4-one and pyrazolidin-4-one scaffolds. The resulting pyrazolidine derivatives demonstrate a broad tolerance to reductive and oxidative conditions, whereas isoxazolidines exhibit certain stability limitations. The combination of the modular C4 diversification, orthogonal nitrogen protection, and preparative scalability transforms these saturated heterocycles into practically accessible building blocks for medicinal chemistry applications.

Supporting Agency

  • The authors received no specific funding for this work.

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Published

2026-04-07

How to Cite

(1)
Kaliberda, O. V.; Zarudnitskii, E. V. A Scalable Synthesis of 4-Functionalized Isoxazolidines and Pyrazolidines. J. Org. Pharm. Chem. 2026, 23, 33-43.

Issue

Vol. 23 No. 4 (2025)

Section

Original Researches

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