Synthesis of 2-Isoxazolines: Enantioselective and Racemic Methods Based on Conjugate Additions of Oximes

Research output: Contribution to journalArticleScientificpeer-review

Researchers

  • Antti Pohjakallio
  • Petri M. Pihko
  • Ulla M. Laitinen

Research units

  • University of Jyväskylä

Abstract

The formation of 3-unsubstituted 2-isoxazolines by means of condensation reactions between alpha,beta-unsaturated aldehydes and oximes proceeds readily in the presence of catalytic amounts of anilinium salts. Mechanistically, the process involves a fast conjugate addition of the oxime and a slower intramolecular oxime-transfer reaction. The rate of oxime transfer was found to correlate with the acidity of the catalyst. This finding enabled us to discover an enantioselective process in which the fragile conjugate-addition product generated in the first stage is rapidly cyclized into the stable isoxazoline under acidic conditions, with conservation of enantiomeric excess. In summary, herein we describe synthetically useful protocols for accessing 3-unsubstituted 2-isoxazolines in both the enantioselective and racemic manner. The mechanism of the condensation reaction catalyzed by the anilinium salt was also investigated by NMR spectroscopy experiments in which the effect of differently substituted aldehydes and oximes as well as water on the reaction rate was studied. The results point to the rate-limiting elimination of water from the 3-hydroxy-2-isoxazolidine intermediate.

Details

Original languageEnglish
Pages (from-to)11325-11339
Number of pages15
JournalCHEMISTRY: A EUROPEAN JOURNAL
Volume16
Issue number37
Publication statusPublished - 2010
MoE publication typeA1 Journal article-refereed

    Research areas

  • acidity, amines, cyclization, enantioselectivity, isoxazolines, ASYMMETRIC 1,3-DIPOLAR CYCLOADDITION, NITRILE OXIDE CYCLOADDITIONS, PROTON-TRANSFER PROCESS, ACHIRAL ALLYL ALCOHOL, OXY-MICHAEL ADDITION, ALPHA,BETA-UNSATURATED ALDEHYDES, ORGANOCATALYTIC SYNTHESIS, BETA-HYDROXYLATION, ORGANIC CATALYSIS, ALDOL REACTION

ID: 14102243