4-trifluoromethyl substituted imidazole

Disubstituted 1/f-imidazoles are classic examples of prototropic annular tautomerism. Depending on the nature of substituents, one tautomer may predominate over the other, as in the case of trifluoromethyl-substituted imidazole 50, where form 50A is the major component in solution in DMSO or CH3CN. In an unusual case, the two tautomers, 4-nitro-5-methoxyimidazole 136A and 5-nitro-4-methoxyimidazole 136B, were found as a 50 50 mixture in the crystal structure (Scheme 30) <2004AXB191>. 

Cohen and co-workers have reported a facile synthesis of 2-(trifluoro-methyl)histamine and 2-(trifluoromethyl)-L-histidine using histamine and L-histidine as starting materials, repectively. The desire to use histamine and histidine was mainly due to ready availability, which would lead to rapid synthetic sequences and a direct entry into the fluorinated L-amino acid series. cw-l,2-Dibenzamido-l-alkenes (34) prepared by the Bamberger imidazole cleavage of corresponding imidazoles (33) were condensed with trifluoroacetic anhydride at reflux (40 °C) to yield 2-trifluoromethyl substituted imidazoles (35) in about 70% yield. 

Ethyl substitution at the imidazole 5-position (469) was found to increase potency over the unsubstituted analogue (468), while methyl substitution (470) had a slightly deleterious effect on binding (Table 6.41). Chloro (491), bromo (492), cyano (493) and fluoromethyl (494) substitution at this position were all well tolerated (Table 6.43). Introduction of a chloro-substituted pyridine (475) in place of the more usual / -chlorophenyl group (470) resulted in a slight loss of affinity for the CBi receptor, as did replacement of the p-chloro group of (470) with bromo (471), fluoro (472) and in particular, met-hoxy (473). Trifluoromethyl substitution (474) however, was well tolerated. 

Although a number of such radical reactions are known, few promise much synthetic potential, Examples include the 2-phenylation of imidazole and benzimidazole by benzoyl peroxide, but both products are more readily obtained by other routes. Homolytic alkylations of imidazole and benzimidazole also occur at C-2, but usually give indifferent yields [10]. A potentially useful reaction is the synthesis of 2- and 4-trifluoromethylimidazoles from imidazoles and photochemically generated trifluoromethyl radicals. 1-Substituted imidazoles are largely substituted at C-5 in these reactions benzimidazole reacts initially at the 4-position [11-14]. 

Direct introduction of the trifluoromethyl group provides another general route. Irradiation of a methanolic solution of trifluoromethyl iodide and imidazole produces a mixture of 2- and 4-trifluoromethylimidazoles and 2,4-bistrifluoromethylimidazole. This can be applied to simple imidazoles and substituted imidazoles. The photochemical procedure provides a convenient synthesis of trifluoromethyl derivatives of histidine and histamine. ... 

Base-induced cycloaddition of TosMlC 37 to N-sulfonylaldimines 36 affords 4(5)-monosubstituted imidazoles 38 from which the parent imidazoles 39 can be prepared <97T11355>. This type of chemistry has been extended to reaction with arylazosulfones <97T2125>. N-Sulfonyl-2-imidazolines are derived from the ruthenium complex catalyzed reaction between isocyanoacetate and analogs of 36 <97JOC1799>. Cycloaddition of ylide 40 with trifluoroacetonitrile gives trifluoromethyl substituted imidazolines <97TL4359>. 

A (1/7-imidazol-l-yl) silver species (55) has been postulated as the key intermediate in the 3-l-2-cycloaddition reaction of diazoalkanes (54) with benzynes yielding 2-aryl-2H-indazoles (56) (Scheme 18). The 3-I-2-cycloaddition reaction of 3-trifluoromethyl-4-diazopyrazolinones with dialkyl acetylene dicarboxylates, in refluxing toluene, produced spiro 3/f-pyrazole adducts that rearranged to the trifluoromethyl-substituted pyrazolo[l,5-fi(][l,2,4]triazin-7-ones. ° The 1,3-dipolar cycloaddition reaction of aromatic thioketones (58) with 2-aza-1,3-dicarbonyl compounds (57), at 20-50 C, yielded thiadiazoline adducts (59) that readily eliminate nitrogen to produce oxathioles (60) in moderate yields (up to 70%) (Scheme 19). ... 

Evidence for the tetrahedral intermediate includes a Hammett p constant of+2.1 for the deacylation reaction of substituted benzoyl-chymotrypsins and the formation of tetrahedral complexes with many inhibitors, such as boronates, sulfonyl fluorides, peptide aldehydes, and peptidyl trifluoromethyl ketones. In these last the chemical shift of the imidazole proton is 18.9 ppm, indicating a good low-barrier H-bond, and the pJQ of the imidazolium is 12.1, indicating that it is stabilized by 7.3 kcal mol 1 compared to substrate-free chymotrypsin. The imidazole in effect is a much stronger base, facilitating proton removal from the serine. 

Imidazole (basic pK 7, i.e. N NH ) is much more basic a molecule than pyrimidine (basic pK 1.31) and the combination of the rings in purine results in a basic pK of 2.39. Since the basicity of purine is depressed by electron-withdrawing groups such as trifluoromethyl and since the decrease in basicity is greatest with the 6-substituted purine. 

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