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.
Eriksen
B L
BL
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Vedsø
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Begtrup
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D002384:Catalysis; D006219:Halogens / Q000737:chemistry*; D007093:Imidazoles / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D008094:Lithium / Q000737:chemistry*; D010165:Palladium
D006219:Halogens; D007093:Imidazoles; D007202:Indicators and Reagents; D010165:Palladium; D008094:Lithium