Fluoro-l -methylimidazole

JOC3570). Diazotization of l-methylimidazole-5-carbohydrazide (103) followed by treatment with r-butanol gave the carbamate (104), which was dissolved in cold tetrafluoroboric acid when evolution of gas had ceased, the solution was treated with sodium nitrite and irradiated. However, unlike the 4-aminoimidazoles (Section III,A,2), this reaction produced none of the desired 5-fluoro-l-methylimidazole (105) (Scheme 10). Although 5-amino-1-methylimidazole (96 R = Me, R2 = H) was almost certainly formed, ultraviolet spectral analysis showed only traces of a diazo-nium chromophore after addition of nitrite, indicating compound (96 R1 = Me, R2 = H) to be extremely unstable under the acidic reaction conditions (78JOC3570). 

There are some examples of nucleophilic displacement of a suitably activated bromine by fluoride, but there have been instances where such reactions are unsuccessful <93AHC(57)291>. Electrophilic methods do not include direct fluorination, but metallic derivatives provide carbanions which react with fluorine sources. Thus, 2- and 4-fluoroimidazoles have been made from the lithioimidazoles, for example, perchloryl fluoride converts 2-lithio-l-methylimidazole into the 2-fluoro derivative in more than 50% yield. Access to 4- and 5-fluoroimidazoles is even more convenient from the trimethylstannyl derivatives using fluorine or caesium fluoroxysulfate as the electrophile . Mercury groups react in much the same way, but they are more difficult to prepare and purify <86BSF930>. 

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 There exists an unpublished report that a more than 50% yield of 2-fluoro-1 -methylimidazole was produced by reaction of 2-lithio-1 -methylimidazole with perchloryl fluoride.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. "... 

A) l-(2-Amino-5-chlorophenyl)-l-(2-fluorophenyl)-2-aza-butyl-en-4-ol A mixture of 40 g of 2-methylimidazole hydrochloride and of 90 g of 2-amino-5-chloro-2 -fluoro-benzophenone in 240 ml of ethanolamine is heated at 135°C for 2 hours. After cooling, the reaction mixture is poured into an aqueous sodium bicarbonate solution. The mixture is extracted with ether, the organic phase is washed repeatedly with water and is dried over sodium sulfate, and the solvent is evaporated to dryness. The residual oil is chromatographed on a silica column, elution being carried out with a 50/50 mixture of cyclohexane and ethyl acetate. 

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