A general route to 4-substituted imidazoles

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Abstract
Literature routes to di(imidazol-4-yl)methanol (1a) dinitrate and tri(imidazol-4-yl)methanol (2a) trihydrochloride were improved to give 32 and 16% overall yields, respectively; but we failed to synthesize bis-(1b) and tris-(1-methylimidazol-4-yl)methanol (2b) by the methylation of the corresponding N-methoxymethyl compounds (3; X= 2 and X= 3). Attempted 4-lithiation of the 1,2,5-protected imidazole (4a) with BuLi–TMEDA failed, giving after hydrolysis 1-methyl-5-trimethylsilylimidazole (4b); similar failures were observed for 2,5-dicarboxy-1-methylimidazole, which after metallation with BuLi–TMEDA and hydrolysis afforded 1-methylimidazole-5-carboxylic acid (5). Our attempts to obtain 4-bromo-1-methylimidazole (10a) and 4-bromo-1-ethylimidazole suitable for a halogen–lithium exchange or for Grignard reaction also failed. Attempted selective lithiation of 2-phenylthio-1-tritylimidazole (16) at the 4-position, then treatment with ethyl formate, led only to a mixture of 4- and 5-substituted products in very low yield, and 1-diethoxymethyl-2-phenylthioimidazole (18) was unstable and difficult to purify. 4-Bromoimidazole with two mol equiv. of t-butyl-lithium gives 1,4-dilithioimidazole, which is now shown to provide a general route to 4-substituted imidazoles.