Nitroimidazoles, hydrogenation

Nitroimidazoles substituted by an aromatic ring at the 2-position are also active as antitrichomonal agents. Reaction of p-fluorobenzonitrile (83) with saturated ethanolic hydrogen chloride affords imino-ether 84. Condensation of that intermediate with the dimethyl acetal from 2-aminoacetaldehyde gives the imidazole 85. Nitration of that heterocycle with nitric acid in acetic anhydride gives 86. Alkylation with ethylene chlorohydrin, presumably under neutral conditions, completes the synthesis of the anti-... 

An unexpected reaction occurs when 2-alkyl-4(5)-nitroimidazoles (27 R = alkyl) are reduced in protic solvents [92JCS(P1)2779]. Catalytic hydrogenation of 2-methyl-4(5)-nitroimidazole (27 R = Me) in a solution of acetic anhydride and acetic acid gave 4,4 -diacetamido-2,2 -dimethyl-5,5 -diimidazole (32 yield 10%) in addition to the expected 4-acetamido-l-acetyl-2-methylimidazole (28%). Similarly, reduction of the 2-alkyl-4(5)-nitroimidazoles (27 R = Me, Et, iPr) in ethanol solution in the presence of diethyl ethoxymethylenemalonate [EMME (135)] gives predominantly the 5,5 -diimidazole adducts (33). The formation of these products (33) is believed to involve an electrophilic addition of the starting material (27) to the electron-rich aminoimidazoles (25) [92JCS(P1)2779]. Interestingly, replacement of ethanol by dioxane suppressed diimidazole formation. 

Catalytic hydrogenation of methanolic solutions of the 4-nitroimidazoles (72 R1 = D-glucopyranosyl, D-arabinopyranosyl, D-xylopyranosyl R2 = H) using platinum oxide as catalyst gave the corresponding 4-aminoimidazole nucleosides (71 R1 = D-glucopyranosyl, D-arabinopyra-nosyl, D-xylopyranosyl R2 = H) (yields 16, 33, and 25%, respectively), which were apparently isolated as the free bases but no mention of the stability of these compounds was made (72LA67). 

Various nitropyrazoles and nitroimidazoles have been studied96-99 see Table 1. The loss of OH from methyl-substituted nitropyrazoles and nitroimidazoles appears as a useful probe in determining the actual location of the substituents. Thus, it could be established that in the case of adjacent methyl and nitro groups, the loss of OH originates exclusively from these substituents96-98. In addition to the loss of OH the presence of a mobile N-bonded hydrogen atom leads to the elimination of H2O, as is visualized by the mechanisms for loss of OH and H2O from 3(5)-methyl-4-nitropyrazole and 4-methyl-3(5)-nitropyrazole, respectively98 see Scheme 28. 

Apart from hydrogen-bonding forces, a number of other interactions of varying importance may also occur between the analyte and matrix components. Including in this category are covalent, ionic, dipole-dipole, induced dipole-dipole, and dispersion interactions that have a force of 100-300 kcal/mol, 50-200 kcal/mol, 3-10 kcal/mol, 2-6 kcal/mol, and 1-5 kcal/mol, respectively (5). Covalent binding, for example, of nitroimidazole, nitrofuran, and benzimidazole residues to macromolecular matrix components is the cause of the more or less persistent nonextractable residues appearing in foods (11, 21, 22). 

Despite many attempts it has not been possible to oxidize 2-substituted 1,2,3-triazoles 382 to the corresponding 1-oxides 326. Peracetic acid, 3-chloroperbenzoic acid, dichloropermaleic acid, trifluoroperacetic acid, peroxydisulfuric acid, and f-pentyl hydrogen peroxide in the presence of molybdenum pentachloride all failed to oxidize 382 (1981JCS(P1)503). Alkylation of 1-hydroxytriazoles 443 invariantly produced the isomeric 3-substituted 1,2,3-triazole 1-oxides 448 (see Scheme 132). However, the 2-substituted 1,2,3-triazole 1-oxides 326 can be prepared by oxidative cyclization of 2-hydroxyiminohydrazones (1,2-hydrazonooximes, a-hydrazonooximes) 345 or by cyclization of azoxyoximes 169. Additional methods of more limited scope are reaction of nitroisoxazoles 353 with aryl-diazonium ion and base, and reaction of nitroimidazoles 355 with hydroxy-amine- or amine-induced rearrangement of nitro-substituted furoxanes 357. 

Nitroimidazole in solution (amphiprotic medium) is stabilized as the 5-nitro isomer due to formation of hydrogen bond with an aprotic protophilic solvent [1124], The medium favors displacement of the tautomeric equilibrium toward the 4-nitro isomer via formation of a solvate complex at the same time 4-nitroimi-dazole acts as hydrogen-bond acceptor. The specific solvatochromic effect in the UV spectrum of 4-nitroimidazole is caused by the electronic configuration of the excited jr,ji -state [1124],... 

The iV-methyl group is the source of one of the eliminated hydrogen. The subsequent loss of water by 1,2-elimination gives rise to the formation of the nitrile structure. Mass spectra of mono-, di-, and trideuterated nitroimidazoles were investigated in order to prove the fragmentation mechanism [1307],... 

Limited solubility of nitroimidazole in water and other polar solvents can be explained not only by hydrophobic properties of nitroimidazole, but also with decreased basicity of the N-3 nitrogen atom. Hydrophobic properties of nitroimidazole are conditioned by the presence of the nitro group unsubstituted imidazole is, as known, highly hydrophilic [1478], Solubility of azaheterocycles in protic solvents is determined much by the azagroup (=N-) and less by the - NH-group, since the lone electron pair increases the strength of the hydrogen bond and hence the N-3 atom solvation. 

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