The mechanism investigation in substitution of 21-bromo-3alpha-hydroxyl-3beta-methoxymethyl-5alpha-pregnan-20-one with nucleophiles

A mechanistic study on the nucleophilic substitution of a strictly geometric 21-bromo-3alpha-hydroxyl-3beta-methoxymethyl-5alpha-pregnan-20-one was described. Reaction of the alpha-bromoketone with excess lithium imidazole followed by the addition of extra bases including n-butyllithium, methyllithium, lithium piperidine, and lithium pyrrolidine provided unexpected alpha-nucleophilic carbonyl adducts that derived from strong base. Data from HPLC and proton NMR suggested an epoxide as the intermediate. Two possible reaction pathways were proposed for the nucleophilic substitution reaction. One pathway is the normal SN2 substitution reaction, directly provided the imidazoly product without the formation of the unexpected alpha-substituted products. The other pathway went through an epoxide intermediate, in which imidazole anion or the strong bases added would attack from the less hindered site of the epoxide to give the substitution product.