Fluorinated imidazoles

Deng, W., Molinero, V. and Goddard, W. A., III. 2004. Fluorinated imidazoles as proton carriers for water-free fuel cell membranes. Journal of the American Chemical Society 126 15644-15645. 

The most important applications of the in situ photochemical fluorodediazoniation start from heterocyclic amines for which the diazonium tetrafluoroborates are impossible to isolate. In this way, fluorinated imidazoles,123-253,254-257 261 benzimidazoles,262 pyrazoles,254-256,262 indazoles,158 thiazoles,259 and triazoles259-262 have been prepared (Table 4). Some of these are the precursors of biologically active compounds such as fluoro-substituted histidines or histamines,123,253-257,258 or 5-fluoro-l/ -D-ribofuranosylimidazole-4-carboxamide.261... 

A detailed study of fluorinated imidazoles (related to relative reactivities in nucleophilic dehalogenation reactions) has shown that whereas 2-fluoroimidazole dissociates to the anion with pK = 10.45, the 4-fluoroisomer shows no sign of such dissociation up to pH 11.7 pK = 11.92). Such results parallel those for the corresponding bromo analogues the greater acidities of the 2-substituted isomers can be attributed to the symmetrical anions that they... 

Cohen, L. A., Kirk, K. L. Photochemical decomposition of diazonium fluoroborates. Application to the synthesis of ring-fluorinated imidazoles. J. Am. Chem. Soc. 1971,93, 3060-3061. 

Other routes to fluoroimidazoles have been reported, some of which are confined to specific structural motifs. For example, methyl and fluorine substituents were used in a study of the phototranspositions of the 1-methylpyrazole ring. The nitrogen walk mechanism produced ring-fluorinated imidazoles from the ring-fluorinated pyrazoles (Fig. 3.55). ° ... 

In initial attempts to prepare ring-fluorinated imidazoles, nucleophilic displacement of activated halogens with fluoride was unsuccessful. However, if sufficiently activated, hahde exchange can occur. Thus, l-methyl-2-fluoro-4,5-dicyanoimidazole was prepared from 1-methyl-2-bromo-4,5-dicyanoimidazole by reaction with spray-dried KF in the presence of 18-crown-6 ether as catalyst. ... 

FIGURE 3.56 Use of anhydrous TBAF to prepare fluorinated imidazoles. 

Fluorinated synthons have been used to access fluorinated imidazoles. Reduction of Schiff bases derived from amidines and hexafluoroacetone with SnCl2 gives rise to 5-fluoro-4-trifluoromethylimidazoles 110 (Fig. 3.57). ° ° Because the 5-fluoro substituent is readily displaced by nucleophiles such as alkoxide, cyanide, and others, this procedure provides access to a range of trifluoromefliyl-substituted imidazoles (also see below). 

There have also been reports of preparation of fluoroimidazoles by electrophilic fluorination of metalated intermediates, although results have been modest. There exists an unpublished report that a more than 50% yield of 2-fluoro-1 -methylimidazole was produced by reaction of 2-lithio-1 -methylimidazole with perchloryl fluoride. "in an another attempt to prepare fluoroimidazoles by electrophilic substitution, reaction of l-methyl-2-trimethylstannylimidazole, l-methyl-4-trimethylstannylimidazole, or l,2-dimethyl-5-trimethylstannylimidazole with dilute fluorine gas at —78°C gave crude product mixtures that contained the corresponding fluorinated imidazole as detected by NMR spectroscopy. The products were not isolated. "... 

FIGURE 3.57 A fluorinated building block approach to fluorinated imidazoles. 

Biological Properties of Fluorinated Imidazoles The importance of the imidazole ring in biological structure and function combined with the profound effects on physicochemical properties that result from fluorine substitution combine to make fluorinated imidazoles a class of compounds with a wide range of biological... 

Synthesis of Ring-Fluorinated Pyrazoles Early procedures for accessing fluoropyrazoles included the photochemical Schiemann reaction that had been developed earlier for preparation of ring-fluorinated imidazoles, as discussed above. 3-Fluoro-, 4-fluoro-, and 5-fluoro-l-methylpyrazoles were obtained in low yields (Fig. 3.65). This procedure was also used to prepare 3,4-, 4,5-, and 3,5-difluoropyrazoles. An electrochemical procedure was reported that lacked generality. ... 

Kirk, K.L. Cohen, L.A. Biochemistry and pharmacology of ring-fluorinated imidazoles. In Biochemistry of the Carbon-Fluorine Bond, ACS Symposium Series No 28 Filler, R., Ed. American Chemical Society, Washington D.C., 1976 pp. 23-36. 

Yeh, H.J.C. Kirk, K.L. Cohen, L.A. Cohen, J.S. and nuclear magnetic resonance studies of ring-fluorinated imidazoles and histidines. J. Chem. Soc., Perkin Trans. 2 1975, 928-934. 

In summary, the tactical approaches involved in the synthesis of various fluori-nated/fluoroalkylated imidazoles and benzimidazole analogs are discussed in this chapter. A deeper understanding of these synthetic protocols may provide easier access to these molecules, as well as an impetus to the discovery of new fluorinated imidazoles and benzimidazoles in the pharmaceutical and agrochemical industries. 

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