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.
ASJC Scopus subject areas
- Organic Chemistry