1- Aryl-4-nitroimidazole

The main fragmentation pathway of I -aryl-4-nitroimidazolcs does not differ significantly from that of 1 -methyl-4-nitroimidazoles [ 1293] and 4(5)-nitroimidazoles [1298]. Nevertheless, unlike 4(5)-nitroimidazoles and l-alkyl-4-nitroimidazoles in the mass spectra of all 1 -aryl-4-nitroimidazoles and 1 -aryl-2-methyl-4-nitroimidazoles the peaks due to ArC+ ions appear [1297], In this work the El mass spectra of 2- and 5-methyl-l-aryl-4-nitroimidazoles are also analyzed in detail. 

The instability of 5-aminoimidazoles (96) has led to in situ acylation being used to obtain stable compounds and using this approach several derivatives have been prepared. For example, a solution of the appropriate 5-nitroimidazole (97) in ethyl acetate was reduced with Raney nickel, and the resulting solution of 5-aminoimidazole (96) then treated with an acid chloride to give the amides (118 R1 = Me, R2 = S02Me, COPh, R3 = alkyl, aryl, hetaryl) (25-45%) [82IJC(B)1087],... 

Whereas several l-aryl-4-nitroimidazoles are found to be good sensitizers for superoxide ion formations85 (Type I photooxidation), only l-phenyl-2-methyl-4-nitroimidazole 140 is a photosensitizer for singlet oxygen, i.e. by energy transfer of type II photooxidation (equation 70). 

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. 

The A-nitroimidazolcs are stable for a time even in the presence of water, but treatment with concentrated sulfuric acid cleaves the N-nitro group, and strong base opens the ring. Much of the interest in such compounds is related to their multistep complex substitution reactions in which sequential nucleophilic addition of arylamines, ring opening, ring closure, nitroamide elimination, and rearomatization gives l-aryl-4-nitroimidazoles, e.g., 840 839. This method can also be used to prepare isotopically labeled imidazoles when labeled amino acids are used as the amine. 

Aryl l-methyl-4-nitro-5-imidazolyl sulfones, a new class of radiosensitizing pharmaceuticals [356-359], an extensive series of nitro derivatives of methylthio-[109] and ethylsulfonylimidazoles [360, 361], 1-alkyl [362]-, 1-trialkylsilylalkyl)-2-methyl-4-nitroimidazoles [363], allylated 4-nitroimidazoles [364], 5-amino derivatives of 4-nitroimidazoles [365], 5-azido-4-nitroimidazole [366], 15N-labeled... 

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... 

In the mass spectra of l-aryl-4-nitroimidazole [N02] abstraction from the molecular ion is not observed [1297] at variance with I -rncthyl-4-nitroimidazole [1293] (Scheme 3.57). 

In the mass spectra of l-hydroxy-2-aryl-4-nitroimidazole-3-oxides the molecular ions and the fragments [M - O], [Ar-CH=NH], [Ar-CNH], [ArCN] were observed [355, 1300]. A careful mass spectrometric investigation of these oxides showed an unusual fragmentation. Along with an O-shift (with subsequent formation of 02) and the formation of the [Ar-C(0]+ the cation and other processes an unexpected release of N203 (or N20 + 02) from the molecular ion with formation of the [HC(CN(0)CHAr]+ fragment was noticed [1300],... 

The base mass spectra peaks of 5-(2-aminoethylamino)-4-nitroimidazole [365], iodo and bromo derivatives of 4-nitro-, and 5-nitro-l-methylimidazoles [461], 4(5)-nitroimidazole-5(4)-carboxaldehyde and (5(4)-nitroimidazole-4(5)-yl)methyl nitrate [462], and some l-aryl(organyl)-4-nitroimidazole [394, 400, 401, 449] have been discussed. 

High-performance liquid chromatography (HPLC) has been used to analyze metronidazole [1435-1437], misonidazole [1309,1438], and other nitroimidazoles [1435, 1439] in body fluids or pharmaceutical dosage forms. HPLC analysis of effect of hypoxic-cell radiosensitizer misonidazole on the radiation-induced reduction of DNA bases (thymine, cytosine, and adenine) has been carried out [1440, 1441], HPLC was employed to characterize different nitroimidazoles [327, 366, 388,409, 450, 1442-1444], nitropyrazoles [246, 301], nitrothiazoles [366], l-aryl(hetaryl)-4-nitro-l,2,3-triazoles [601], nitrobenzimidazoles [707], nitrobenzofurazans [774, 1445-1449], nitrobenzotriazoles [1450],... 

Both imidazole-2- and -4-carbaldehydes resist the Cannizzaro, Perkin and benzoin reactions, but the 1-substituted compounds react normally. 1-Substituted 5-nitroimidazole-2-aldehydes condense readily with alkyl aryl ketones. Examples of successful condensations... 

Earlier attempts to prepare one of the two possible isomers had employed the facile-base-catalyzed rearrangement of the readily available [l-(2-alkyl(or aryl)sulfonyl)ethyl]-2-methyl-5-nitroimidazole which is made as one isomer from 2-methyl-4-nitroimidazole and ethylvinylsulfone <89JCS(P1)1352, 90JOC3702). Such base-catalyzed migrations in tinidazole (58) and analogous compounds seem to be specific for compounds with an A(-alkyl- or A(-aryl-ethylsulfone group which is eliminated as alkyl(or aryl)vinylsulfone followed by re-alkylation of the more reactive annular nitrogen. When 2-methyl-... 

Salgado-Zamora and co-workers"" prepared a series of imidazo[5,l-h]oxazoles as potential radiosensitizers or antiprotozoal agents (Scheme 1.59). Alkylation of 4-bromo-2-methyl-5-nitroimidazole 208 with a series of phenacyl halides gave a 1 3 mixture of the regioisomeric imidazoles 209 and 210. These were separated, and 210 was cyclized to the desired 2-aryl-5-methyl-7-nitroimidazo[5,l-h]oxazoles 211. This reaction tolerates a wide variety of phenacyl halides. Selected examples are presented in Table 1.17. 

In search for new antiparasitic agents active against Trichomonas vaginalis, a number of 4-(arylsulfonylmethyl)-5-nitroimidazole derivatives have been prepared via the VNS reaction of 4-nitroimidazoles with substituted aryl chloromethyl sulfones (Scheme 32) [124]. 

Introduction of arylsulfonylmethyl substituents into nitroheteroaromatic rings is of great practical value because these sulfones are versatile intermediates in organic synthesis. Nitrobenzyl aryl sulfones and their heterocyclic analogues can easily be transformed into the corresponding ethenyl derivatives by a simple alkylation with simultaneous elimination of arylsulfinate anion [125]. Diethyl methylenemalonate substituent can be introduced in the positimi 4- of 5-nitroimidazole via the VNS reaction of 5-nitroimidazole with the carbanion of chloromethyl phenyl sulfone [112, 124], followed by condensation of the obtained 4-(phenylsulfonyl)methyl derivative with diethyl bromomalonate or diethyl ketomalonate (Scheme 33) [126]. 

Synthesis of l -Linked Oligoimidazoles and Similar Compounds. Suwinski, Jerzy Wagner, Pawel (Pol.). Zesz. Nauk. Politech. Slask., Chem. 1997, (135), 73-80 (Pol.), Wydawnictwo Politech-niki Slaskiej. Anrorc type reaction of 1,4-dinitroimidazole with 4-amino-arylimidazoles (prepd. by redn. of l-aryl-4-nitroimidazoles) afforded derivs. of 1,4 -biimidazole and triimidazole. In similar manner l,3-bis(4 -nitro-l -imidazolyl)benzenes were prepd. 

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