Rign-trifluoromethylated imidazoles show the unique property of losing hydrogen fluoride above pH 8 to form metastable difluorodiazafulvenes, whch then react with any available nucleophile to form new covalent bonds. Such intermediates, derived from trifluormethylhistamine 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 reativities, and to be able to correlate reactivity with some substituent parameter. Our discovery of a simple photochemical mehtod for the trifluormethylation of imidazoles has made available a large series of analogs for study. We have now developed procedures for the conversion of aminohistidines into azido and nitrohistidine, of amino to chloro, bormo and iodo, of trifluoromethyl into methyl, cyano, carboxy, carbomethoxy, etc. Recently, we synthesized 2- and 4-(pentafluoroehtyl)-histidines by photochemical radical substitution. These compounds are converted by base into the corresponding (trifluoroacetyl)histidines, which have such reactive coarbonyl 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 trifluroacetaldehyde. In turn, the secondary alcohols can be oxidized to the trifluoroacetyl ketones. Upon treatment with methanolic base, (trifluoromethyl)histidine can be coverted into (trimethoxymethyl)histidine and pentafluoroethyl into the corresponding ketal. There ortho functionalities are also of interest as potential covalent affinity labels.
