Reduction of 5-Nitroimidazoles

In 1937 Hunter and Hlynka were able to reduce a methanolic solution of 4(5)-nitroimidazole (27 R = H) with sodium amalgam and trap the 4(5)-aminoimidazole (25 R = H) with cyanic acid giving the urea derivative (31) (37BJ488). Other reducing agents gave inferior results. Subsequently, 4(5)-aminoimidazole (25 R = H) was obtained as either its dihydrochloride (30%) or dipicrate salt but the isolation procedures were lengthy and difficult (41 Mil). 

The use of powdered zinc in hydrochloric acid has been reported to reduce 4(5)-nitroimidazole (27 R = H) to 4(5)-aminoimidazole (25 R = H), but the yield was not recorded [56JBC(223)985]. In another study, treatment of 4(5)-nitroimidazole (27 R = H) with zinc dust in tetrafluoroboric acid solution followed by in situ diazotization of the amine (25 R = H), which was presumed to be formed, gave 4-fluoroimidazole (17%) (73JA4619, 73JOC3647). 

Raney nickel reduction of 4(5)-nitroimidazole (27 R = H) in a mixture of acetic anhydride and acetic acid gave a diacetylated compound (35%) that was identified as 1- (or 3-) acetyl-4-acetamidoimidazole (57JA2188). 

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. 

The electrolytic reduction of 4(5)-nitroimidazole (27 R = H) has been shown (83MI1) to proceed readily in a six-electron process but this method has been used only to determine the electronic requirements for the reduction and not for synthetic purposes. 

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Four approaches to the synthesis of 4(5)-aminoimidazoles (25) have been described and are summarized in Scheme 1. These are (a) reduction of 4(5)-nitroimidazoles (27), (b) hydrolysis of carbamates and amides (28),... 

The HFS aN(N()2) in 2-nitroimidazole RA is much less than the one in the RA of 4(5)-nitroimidazole because the nitro group arranges between two electronegative nitrogen atoms. A similar regularity for these nitroimidazoles has been observed [852], The ESR spectra of radicals formed by electrochemical reduction of 2-nitroimidazole and 4(5)-nitroimidazole in mixed solvents have been studied [873], The behavior of HFS aN(N()2) with the solvent composition is discussed in terms of equilibrium between radicals in different solvents. 

Gamma-ray-induced reduction of both 4(5)-nitroimidazole (27 R = H) and 2-methyl-4(5)-nitroimidazole (27 R = H) in aqueous sodium formate or isopropanol solutions has been studied (83MI2) at neutral pH under inert conditions. Both compounds (27 R = H, Me) were reduced stepwise with the consumption of six electrons. 

Dumanovic with colleagues carried out polarographic investigation of various derivatives 3-, 5-nitropyrazoles and 2-, 4-, 5-nitroimidazoles in aqueous buffer solutions (pH 1.8-9.3) and 0.1 M solution NaOH [903-912], On polarograms all the investigated nitroazoles have one or two waves of reduction both in acid and neutral medium. The first four-electron wave corresponds to reduction of nitro group to hydroxylamine one. The second two-electron wave corresponds to further reduction of hydroxylamine derivative to aminoazole (Scheme 3.34). 

Polarographic reduction of pH dependence of metronidazole [931], 2-nitroimidazoles, 4(5)-nitroimidazoles, 4-nitro- and 5-nitro-l-methylimidazoles [932-936] A-nitroimidazoles [937], and l-aryl-4-nitroazoles [938] has been investigated. A smaller diffusive current for 2-nitroimidazoles in comparison with other isomers noted by the authors is thought to be possibly due to its increased acidity [932], Electrochemical reduction of the nitro group in l-aryl-4-nitroazoles occurs in... 

An unusual observation was noted when ethanolic solutions of 2-alkyl-4(5)-aminoimidazoles (25 R = alkyl) were allowed to react with diethyl ethoxymethylenemalonate (62 R = H) [92JCS(P1)2789]. In addition to anticipated products (70), which were obtained in low yield ( 10%), the diimidazole derivatives (33 R = alkyl) were formed in ca.30% yield. The mechanism of formation of the diimidazole products (33) has been interpreted in terms of a reaction between the aminoimidazole (25) and its nitroimidazole precursor (27) during the reduction process. In particular, a soft-soft interaction between the highest occupied molecular orbital (HOMO) of the aminoimidazole (25) and the lowest unoccupied molecular orbital (LUMO) of the nitroimidazole (27) is favorable and probably leads to an intermediate, which on tautomerism, elimination of water, and further reduction, gives the observed products (33). The reactions of amino-imidazoles with hard and soft electrophiles is further discussed in Section VI,C. 

The use of hydrazine hydrate in anhydrous methanol with 5% palladium on charcoal under an inert atmosphere gave excellent results for the reduction of l-benzyl-4-nitroimidazole (72 R1 = CH2Ph, R2 = H) with compound (71 R1 = CH2Ph, R2 = H) being isolated as its hydrochloride salt (96%) (74JMC1168). 

The antitrichomonal compound l-methyl-5-nitro-2-(2 -pyrimidyl)imida-zole (97 R = Me, R2 = pyrimid-2-yl) has been shown to be metabolized to the corresponding acetamide (118 R1 = Me, R2 = pyrimid-2-yl, R3 = Me) in both rats and humans (74JPS293). The acetamide (118 R1 = Me, R2 = pyrimid-2-yl, R3 = Me) was also produced synthetically by reduction of a solution of the nitroimidazole (97 R1 = Me, R2 = pyrimid-2-yl) in acetic acid with zinc powder and subsequent treatment of the aminoimidazole (96 R1 = Me, R2 = pyrimid-2-yl) in situ with acetic anhydride to give the acetamide (118 R = Me, R2 = pyrimid-2-yl, R3 = Me) (4%) (74JPS293). 

Analyses of the electrochemical data for 2-, 5-, and 4-nitroimidazoles show them to be the weakest oxidants with one-electron redox potentials (E7 ) of only -0.517 V [940], The potentials E7 for 2-nitroimidazoles and 5-nitroimidazoles vary within a range from -0.243 to 0.423 and -0.457 to -0.486 V, respectively (Table 3.47) [940, 941], A linear dependence of one-electron reduction potentials of substituted 2- and 5-nitroimidazoles on the sizes [S] is observed (Table 3.47) [940, 941],... 

This dependence may be useful in search of potential radiosensitizers. Determined with the help of pulse radiolysis, the thermodynamic potentials of one-electron reduction of 2-, 4-, and 5-nitroimidazoles (pH 7) have a higher negative values than those obtained by classical polarography (pH 7.4) [946], Probably, it is generated by the fact that the process of electrochemical reduction involves irreversible stages of the decomposition of nitroimidazole anion radicals. The correlation of E (and E1/2) of nitroimidazoles and their radiosensitizing properties is discussed. With E7 values the correlation is found to be better [946],... 

In the electrochemical reduction of 5-bromo-l-methyl-4-nitroimidazole some cleavage of the C—Br bond is evident giving rise to the debrominated product (79JGU1877). Imidazole itself is not reducible cathodically in aqueous media, but electrons have been attached to imidazole and histidine in aqueous solution the rate of oxidation depends on pH. Protonated or quaternized imidazoles form the neutral conjugate acids of the true anion radical, and a number of anion radicals have been made from nitroimidazoles under various radiolytic conditions (79AHC(25)205). The electrochemical reduction of 2-cyanobenzimidazole 3-oxide gives sequentially 2-cyanobenzimidazole and 2-aminomethylbenzimidazole (80ZC263). 

Related reactions include the formation of the 2-cyano compounds (190) when 1,2-dimethyl-5-nitroimidazole is heated with nitrosyl chloride or an AT-oxide, and when 2-methyl-l-(o-nitrophenyl)imidazoles (191) cyclize under the influence of iron(II) oxalate (Scheme 98) (74JCS(P1)1970). The last reaction product is contaminated by a large amount of amine reduction product ( 64%) but there is also some cyclization with the 4-methyl isomer of (191). In the presence of trimethylamine, 2-cyanomethylbenzimidazole condenses with acetone to give the unsaturated derivative (192 Scheme 99) (77CPB3087). Neither 2-methylimidazole nor 2-methylbenzimidazole reacts with formamide in the presence of phosphoryl chloride. 

The fully aromatic species are usually quite resistant to hydride reduction. Attempted reduction of l,2-dimethyl-5-nitroimidazole with tributyltin hydride failed to yield 1,2-dimethylimidazole <90JCS(Pl)9l9>, but the apparent reduction of 5-iodo-l-methylimidazole to l-methylimidazole by phenylsulfonylacetonitrile and sodium hydride with tetrakis(triphenylphosphine)palladium(0) as catalyst may be an example <92S552>. Lithium aluminum hydride (but not diborane) is able to convert 2-(but not 4-)fluoroimidazoles into the hydrogen species <84JOCi95i>. 

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