4-trifluoromethyl substituted imidazole synthesis

Cohen and co-workers have reported a facile synthesis of 2-(trifluoro-methyl)histamine and 2-(trifluoromethyl)-L-histidine using histamine and L-histidine as starting materials, repectively. The desire to use histamine and histidine was mainly due to ready availability, which would lead to rapid synthetic sequences and a direct entry into the fluorinated L-amino acid series. cw-l,2-Dibenzamido-l-alkenes (34) prepared by the Bamberger imidazole cleavage of corresponding imidazoles (33) were condensed with trifluoroacetic anhydride at reflux (40 °C) to yield 2-trifluoromethyl substituted imidazoles (35) in about 70% yield. 

Although a number of such radical reactions are known, few promise much synthetic potential, Examples include the 2-phenylation of imidazole and benzimidazole by benzoyl peroxide, but both products are more readily obtained by other routes. Homolytic alkylations of imidazole and benzimidazole also occur at C-2, but usually give indifferent yields [10]. A potentially useful reaction is the synthesis of 2- and 4-trifluoromethylimidazoles from imidazoles and photochemically generated trifluoromethyl radicals. 1-Substituted imidazoles are largely substituted at C-5 in these reactions benzimidazole reacts initially at the 4-position [11-14]. 

Direct introduction of the trifluoromethyl group provides another general route. Irradiation of a methanolic solution of trifluoromethyl iodide and imidazole produces a mixture of 2- and 4-trifluoromethylimidazoles and 2,4-bistrifluoromethylimidazole. This can be applied to simple imidazoles and substituted imidazoles. The photochemical procedure provides a convenient synthesis of trifluoromethyl derivatives of histidine and histamine. ... 

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