1- Substituted-2-nitroimidazoles

The reaction of the corresponding 2-lithioimidazoles with nitrogen tetroxide has been used for the production of 1-substituted 2-nitroimidazoles [354, 355] (Scheme 41). 

Nitro-l-imidazolyl)-l,2-propandiol), Ro-5-9963 AA2-Hydroxyethyl)-2-nitro-1-imidazoleacetamide - etanidazol Other 1-substituted 2-nitroimidazoles... 

Stillman MJ, Shaw CF III, Suzuki KT (1992) Metallothioneins. Synthesis, structure, and properties of metallothioneins, phytochelatins and metal-thiolate complexes. VCH Publishers, New York Stratford IJ, Hoe S, Adams GE, Hardy C, Williamson C (1983) Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles. Int J Radiat Biol 43 31-43 Stubbe J, Kozarich JW (1987) Mechanisms of bleomycin-induced DNA degradation. Chem Rev 87 1107-1136... 

The comparison of nitro group nitrogen constants in 1-methyl-substituted nitroimidazole RAs shows that the spin density transmission degree to the heterocycle is decreased in the following order of the nitro group position in the imidazole ring (Table 3.36) ... 

The mechanism of nitroimidazole EC reduction has been fairly well considered in the literature [921-926], The way of iV-substituted nitroimidazoles EC reduction at the first half-wave potentials is presented in Scheme 3.37 ... 

Thus, /V-substituted nitroimidazoles are reduced to form radical anions [852, 921, 924], the ESR signals of which are fixed [852],... 

During the catalytic reduction of nitroimidazoles, diimidazole products are observed, presumably as a consequence of nucleophilic substitution. Nitroimidazoles have low energy LUMOs (they are... 

Intramolecular cyclizations of suitably substituted nitroimidazoles can give bicyclic 7V-oxides (Equation (53)) <85CHE1303>. 

P. Wardman and E.D. Clarke, One-electron reduction potentials of substituted nitroimidazoles measured by pulse radiolysis, J. Chem. Soc., Faraday Trans. 1, 72 (1976) 1377. 

Absorptiometric, Polarographic, and Gas Chromatographic Assays for the Determination of N-1-Substituted Nitroimidazoles in Blood and Urine J. Pharm. Sci. 59(2) 201-210 (1970) ... 

Theoretical studies of the relative stabilities of tautomers 14a and 14b were carried out mostly at the semiempirical level. AMI and PM3 calculations [98JST(T)249] of the relative stabilities carried out for a series of 4(5)-substituted imidazoles 14 (R = H, R = H, CH3, OH, F, NO2, Ph) are mostly in accord with the conclusion based on the Charton s equation. From the comparison of the electronic spectra of 4(5)-phenylimidazole 14 (R2 = Ph, R = R3 = H) and 2,4(5)-diphenylimidazole 14 (R = R = Ph, R = H) in ethanol with those calculated by using ir-electron PPP method for each of the tautomeric forms, it follows that calculations for type 14a tautomers match the experimentally observed spectra better (86ZC378). The AMI calculations [92JCS(P1)2779] of enthalpies of formation of 4(5)-aminoimidazole 14 (R = NH2, R = R = H) and 4(5)-nitroimidazole 14 (R = NO2, R = R = H) point to tautomers 14a and 14b respectively as being energetically preferred in the gas phase. Both predictions are in disagreement with expectations based on Charton s equation and the data related to basicity measurements (Table III). These inconsistencies may be... 

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-... 

The reaction of l,2-dimethyl-5-nitroimidazole with 2-nitropropane anion gives the new highly branched imidazole derivative, which is formed via cine-substitution and SRN I substitution (Eq. 5.67).slb... 

Two tautomeric equilibria have been considered for substituted imidazoles, that between 2-imidazolone 3 and its 2-hydroxyimidazole tautomer 4 [268] and also that between the 1H and 3H tautomers of 4-nitroimidazole, 6 and 5, respectively [269, 270], Karelson et al. used the D02 model with a spherical cavity of 2.5 A radius and found 2-imidazolone to be better solvated than its tautomer by 7.7 kcal/mol at the AMI level. [The asterisk in D02 indicates that the reaction field... 

The TV-protected nitrosoimidazole carbonitrile 42 - which can easily be obtained from the commercially available 4-nitroimidazole in 4 reaction steps - was treated with phenyl methylcarbazate 43 to give a substituted triazenyli-midazole 44. The cyano group of this compound was first hydrolyzed to an amide function to produce 45, and then irradiation yielded the end product 9a in high yield (79%). 

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. 

Aminotriazole can transfer the amino group to substituted 4-nitroimidazoles in the presence of sodium methoxide in DMSO <93T5339>. 

Metronidazole, a nitroimidazole (Figure 52-3), is the drug of choice in the treatment of extraluminal amebiasis. It kills trophozoites but not cysts of E histolytica and effectively eradicates intestinal and extraintestinal tissue infections. Tinidazole, a related nitroimidazole available in the USA since 2004, appears to have similar activity and a better toxicity profile than metronidazole. It offers simpler dosing regimens and can be substituted for the indications listed below. 

Some Michael additions of unsaturated reagents to imidazoles involve the neutral species of the heterocycles, but others may be reactions of the anion. Fluoride ion catalyzed addition of 2-methyl-4-nitroimidazole (113) to a suitable Michael acceptor gives almost quantitative yields of the 1-substituted 4-nitroisomers (114) (90JOC3702,91JCR(S)35o). 

Adams GE, Fielden EM, Hardy C, Millar BC, Stratford IJ, Williamson C (1981) Radiosensitization of hypoxic mammalian cells in vitro by some 5-substituted-4-nitroimidazoles. Int J Radiat Biol 40 153-162... 

The regioselectivity in the methoxydefluorination reactions of difluoroquinolines has been examined.48 Studies of the substitution patterns in 2-cyano-3-nitroimidazole[l,2-a lpyridine have shown that nitrogen and oxygen nucleophiles substitute the 2-cyano group whereas sulfur nucleophiles replace the 3-nitro group.49... 

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. 

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