We have now developed procedures for the conversion of aminohistidines into azido and nitrohistidine, of amino to chloro, bromo and iodo, of trifluoromethyl into methyl, cyano, carboxy, carbomethoxy, etc. Recently, we synthesized 2- and 4- (pentafluoroethyl)-histidines by photochemical radical substitution. The compounds are converted by base into the corresponding (trifluoroacetyl)histidines, which have such reactive carbonyl groups that they may serve as affinity labels for histidine-binding sites. The trifluoroacetylimidazoles can be reduced to the secondary alcohols, also obtainable by direct condensation of imidazoles with trifluoroacetaldehyde. In turn, the secondary alcohols can be oxidized to the trifluoroacetyl ketones. Upon treatment with methanolic base, (trifluoromethyl) histidine can be converted into (trimethoxymethyl)histidine and pentafluoroethyl into the corresponding ketal. These ortho functionalities are also of interest as potential covalent affinity labels. Ring-trifluoromethylated imidazoles show the unique property of losing hydrogen fluoride above pH 8 to form metastable difluorodiazafulvenes, which then react with any available nucleophile to form new covalent bonds. Such intermediates, derived from trifluoromethylhistamine or histidine, may be able to serve as covalent affinity labels for specific binding sites, both in vitro and in vivo. It would be desirable, therefore, to have available a series of trifluoromethyl analogs with a range of reactivities, and to be able to correlate reactivity with some substituent parameter. Our discovery of a simple photochemical method for the trifluoromethylation of imidazoles has made available a large series of analogs for study. The long-sought 2-bromo and 2-iodoimidazoles can now be obtained by simple reduction of the 2,4-dihalo compounds with hot hydrochloric acid. In the case of the dihalohistamine or histidine, hot water is sufficient to achieve selective reduction.
