Synthesis of 4- and 5-substituted 1-hydroxyimidazoles through directed lithiation and metal-halogen exchange

Electrophiles were introduced regioselectively at the 5-position of 1-(benzyloxy)imidazole by lithiation at C-5 after protection of C-2 with a chloro or a trimethylsilyl group. Subsequent treatment with an electrophile afforded 5-substituted 1-(benzyloxy)-2-chloroimidazoles 8-13 and 5-substituted 1-(benzyloxy)imidazoles 3-5, the 2-(trimethylsilyl) group being lost during workup. Electrophiles were introduced regioselectively at the 4-position of 1-(benzyloxy)imidazole by bromine-lithium exchange of 4-bromo-2-chloro-1-(benzyloxy)imidazoles, protected at C-5 with chloro or trimethylsilyl groups, followed by reaction with an electrophile. The 5-(trimethylsilyl) group was removed via base-catalyzed desilylation. Chlorine at C-2 and O-benzyl groups were removed by palladium-catalyzed hydrogenolysis.