Conjugate Addition of Grignard Reagents to Enones and Dienones

Sandeep P. Modi, John O. Gardner, Arnold Milowsky, Mark Wierzba, Lisa Forgione, Paul Mazur, Alan J. Solo*, William L. Duax, Z. Galdecki, P. Grochulski, Z. Wawrzak

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    24 Scopus citations

    Abstract

    Grignard reaction with 16-dehydropregnenolone acetate, 1, results in 1,4-addition to the enone system. Introduction of even trace amounts of oxygen before the reaction has been fully quenched results in formation of 17a-hydroperoxides as well as the expected products. During saponification and Oppenauer oxidation, the intermediate hydroperoxide can decompose to form 160-alkyl-17-keto steroids. The structure of one such byproduct, 160-(4'-phenoxybutyl)-4-androstene-3,17-dione, 3, was established by X-ray crystallography. Rigorous exclusion of air, even during quenching, permitted (4-phenoxybutyl)magnesium bromide and phenylmagnesium bromide to be added to 1 to form 3β-hydroxy-16α-(4'-phenoxybutyl)-5-pregnen-20-one, 7β, and 30-hydroxy-16a-phenyl-5-pregnen-20-one, 7c, in good yields. Similarly, rigorous exclusion of air until quenching was complete caused copper-catalyzed Grignard addition to 170-hydroxyandrosta-4,6-dien-3-one propionate, 9, to become reproducible and to give greatly increased yields of 1,6-addition products. These reactions seem to reflect a tendency for enolates formed on conjugate Grignard additions to enones or to dienones to react with oxygen faster than they protonate under commonly employed reaction conditions.

    Original languageEnglish (US)
    Pages (from-to)2317-2321
    Number of pages5
    JournalJournal of Organic Chemistry
    Volume54
    Issue number10
    DOIs
    StatePublished - May 1 1989

    ASJC Scopus subject areas

    • Organic Chemistry

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