Perfluoroalkylimidazoles have attracted considerable interest because of their utility in providing lipophilic sites in medicinal agents and because of their potential use as """"""""receptor-activated affinity labels"""""""" (RAAL's) for irreversible blocking of receptors in chemotherapy. The simplest and most general methods for perfluoroalkylation of all heterocyclic rings have been developed in this laboratory and are based on the photochemical generation of perfluoroalkyl radicals. Photochemical perfluoroalkylation of imidazoles leads to mixtures of 2- and 4-isomers while the reaction with pyrroles occurs only at C-2. The practicality of the method for complex substrates has been demonstrated by the facile trifluoromethylation of histidine in peptides (e.g., TRH), followed by HPLC separation of the isomers. Exposure of the trifluoromethyl derivatives of TRH to aqueous ammonia leads to their conversion to the corresponding cyano derivatives. All of these derivatives show very selective binding to low affinity TRH receptor sites in the brain. We have now developed a procedure for regiospecific substitution removed with Raney nickel. Thus, 3- perfluoroalkylpyrroles have been made for the first time. Perfluoroalkylimidazoles have been found to undergo facile nitration and halogenation without destruction; therefore, methods are now available to prepare photosensitive ligands (azido, diazo) and ligands labeled with radioiodine. We have also synthesized pentafluoroethylhistidine and histamine isomers by photochemical radical substitution. These compounds are converted by base into the corresponding trifluoroacetyl derivatives, which have such reactive carbonyl groups that they may serve as affinity labels for bioimidazole-binding sites. Upon treatment with methanolic base, the trifluoromethyl analogs can be converted into trimethoxymethyl and the pentafluoroethyl derivatives into ketals. These ortho functionalities are also of interest as potential covalent affinity labels.
