Since the classical studies of Balaban and Pyman in the 1920's, very few novel synthetic methods have been introduced into imidazole chemistry. Such limitations have restricted the development and testing of many analogues of histidine and histamine. Our program in imidazole chemistry has had both theoretical and practical goals: (1) to explain, in electronic terms, a multitude of puzzling reactions and nonreactions in the chemistry of imidazoles (and of nitrogen heterocycles in general); (2) to provide practical synthetic routes for previously inaccessible derivatives. Although we have developed routes for certain new derivatives of simple imidazoles, extension of these routes to polyfunctional bioimidazoles often introduces severe obstacles which require the creation of a totally different approach. For example, the 2-haloimidazoles are accessible by halogenation of the metallo-organic product of an N-protected imidazole and butyllithium. Butyllithium cannot be used for polyfunctional imidazoles; thus, it became necessary to develop alternative procedures including (1) the copper-catalyzed decomposition of 2-diazonium imidazoles in the presence of halide ion and (2) the one-electron reduction of 2,4-dihaloimidazoles by chemical or physico-chemical means. We have now discovered a host of new reactions for the introduction of carbon functionality, not only into complex bioimidazoles but even directly into histidine-containing peptide hormones: (1) Photochemical trifluoromethylation, under very mild conditions, provides mixtures of 2- and 4-trifluoromethyl derivatives; these derivatives, in turn, can be converted into cyano, carboxyl, amide, ester and orthoester functions - even into carbon analogues of dihydropurines. (2) Trifluoroacetaldehyde condenses, under neutral aldol conditions, to give trifluoromethyl carbinols which are oxidized to trifluoromethyl ketones. (3) Chloroform gives the classical Reimer-Tiemann reaction in alkaline methanol, to produce carboxaldehydes as their dialkylacetals.
