A convenient method for the synthesis 1-substituted imidazoles was developed by the reaction of α-bromoketone with lithium imidazole. The reaction gave the desired products in improved yields without the formation of 1,3-disubstituted imidazolium salts. A mechanistic study on the newly developed nucleophilic substitution was elucidated by use of a strictly geometric 21-bromo-3α-hydroxyl-3β-methoxymethyl-5α-pregnan-20-one. Data from HPLC and proton NMR suggested an epoxide as the intermediate. Lithium imidazole was thus applied for the synthesis of biologically active 3α-hydroxyl-21-(1’-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one. The key steps were the improvement of stereoselectivity for acetyl isomers in C-17 and the introduction of imidazole into the core structure by use of lithium imidazole. This latter key step provided the desired product in 82% yield without the formation of 1,3-disubstituted imidazolium salt as impurity, which is generally observed in traditional method.
