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

Antti Pohjakallio, Petri M. Pihko*, Ulla M. Laitinen

*Corresponding author for this work

    Research output: Contribution to journalArticleScientificpeer-review

    22 Citations (Scopus)

    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.

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

    Keywords

    • 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

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