Nitro-imidazole derivatives

By way of illustration, nitration of 2-isopropyl-imidazole (55) affords the 4- or 5-nitro derivative (56, 57). Alkylation with methyl iodide affords isomer 58. The same reaction carried out with dimethyl sulfate under neutral or acidic conditions provides the isomer methylated at the alternate... 

The MS of some nitro derivatives of imidazole-4(5)-carboxaldehyde have been studied100. Based on the compounds 15-17, several new features caused by the interaction between the nitro group and adjacent substitutents were disclosed. It should be noted that for the compounds 16 and 17, there is a rapid equilibrium between the two possible tautomers resulting in equivalence of the 4 and 5 positions. 

Dioxo-4.5-dime thy l-bexahydro-[imidazolo-4,.5 4 5-imidazol, f. y and 3.y-Diureylen-butan This compound can be nitrated to a di-nitro deriv. See /9,y-Diurelylen-butan and Derivatives... 

Analogous high-yield cyclizations were reported with l-amino-2-nitro-derivatives of pyridines and isoquinolines, which gave the corresponding furoxans [53,54], Anilines oxidized in the presence of indoles afforded Schiff s bases from 2- and/or 3-position in low yield [55], An unexpected rearrangement occurred on treatment of l-phenyl-4-methyl-5-aminopyrimidinone with DIB and catalytic amounts of nickel dichloride, resulting in the formation of an imidazole derivative [56] ... 

Very little has been reported on the theoretical aspects of most (5,5)-fused heterocycles, especially classical systems. Hiickel molecular orbital (HMO) calculations for 1,6-dimethyl-and l,6-dimethyl-5-nitroimidazo[l,2-a]imidazole have been used to assign the site (R) of nitration of the l,6-dimethyl-5-nitro derivative (35) (73JOC1955). 

In spite of extensive investigations into the electrophilic substitution of imidazoles, no rational explanation has yet been found for certain features of the reaction [78], The nitration of imidazoles takes place exclusively at position 4 or 5. In reaction with the sulfuric-nitric acid mixture imidazole itself forms the 4(5)-nitro derivative [79-85], A large number of papers have been devoted to the production of 2-methyl-4(5)-nitroimidazole by the nitration of 2-methylimidazole [79, 82, 86-94], This is due to the fact that 2-methyl-4(5)-nitroimidazole is an important intermediate product in the synthesis of highly effective medical products (metronidazole, tinidazole, dimetridazole, etc.). 

The oxidation of the hydroxymethyl group probably takes place more readily than nitration of the ring [124-127], However, the entry of a nitro group into the imidazole ring without oxidation of the hydroxymethyl group has been reported [107, 110]. Imidazolecarboxylic acids are not nitrated, and their nitro derivatives are therefore obtained by different methods. Nevertheless, the 4- and 5-mononitro-substituted compounds were isolated with the 4,5-dinitro derivative as impurity during the nitration of ethyl l-methylimidazole-2-carboxylate with a mixture of 100% nitric and sulfuric acids at 95°C [128],... 

The nitration of 1,2-disubstituted imidazoles also leads to a mixture of 4-nitro and 5-nitro derivatives [128,134-139], The nature of the substituents in the imidazole ring has an effect on the ratio of the isomers. However, specific investigations in this direction have not yet been undertaken. During the nitration of 1,2-disubstituted imidazoles only the 4-nitro [140-143] or the 5-nitro [144-148] derivatives were isolated. It is not impossible that a mixture of isomers was obtained here. 

The nitration of 1,4,5-trimethylimidazole 3-oxide with the sulfuric-nitric acid mixture leads to the 2-nitro derivative [76, 162], Both this compound and 1-meth-ylpyrazole 2-oxide enter into reaction in the form of the free base [76], The nitration of 2-aryl-1-hydroxyimidazole 3-oxides leads either to cleavage of the imidazole ring or to the formation of the 4-nitro or 4,5-dinitro derivatives, depending on the reaction conditions [162] (Scheme 15). 

The A-nitro derivatives of imidazole can only be isolated in the case where the imidazole ring contains strong electron-withdrawing substituents (e.g., N02) [79, 322-329], In other cases the C-nitro derivatives are formed directly [101,133, 330-335], It was suggested that the A-nitro derivative is formed during the nitration of the intermediate 1,2,3-triazole [336], However, no evidence was presented for this mechanism. 

Although imidazole is too basic to form the 1-nitro derivative when treated with nitric acid-acetic anhydride (indeed, the nitrate salt forms in preference), less basic imidazoles can be Af-nitrated under these conditions. Thus, 4-nitroimidazole gives 1,4-dinitroimidazole (81UP40700, 80AHC(27)24l), and the corresponding 2- and 5-methyl-4-nitroimidazoles react in the same way. Of interest is the orientation of Af-nitration which parallels that of methylation of the anion. Whether the anion reacts in the nitronium acetate medium or whether steric factors control the site of attack is not known. 

Both 1-methyl-4- and l-methyl-5-chloroimidazoles can be nitrated in sulfuric acid. Exhaustive nitration of imidazole in mixed acids yields in succession 4-mono-, 4,5-di-, and 2,4,5-trinitroimidazole. With dinitrogen tetroxide in acetonitrile 4-substituted imidazoles with electron-withdrawing substituents yield a mixture of 5- and 2-nitro derivatives." Nitrations at C-2 are most unexpected. The nitration of 4-(4 -alkoxyphe-nyl)imidazoles with 3-4 M nitric acid occurs ortho to the alkoxy group and in the imidazole 5-position. With concentrated nitric acid di- and trinitro compounds are formed." ... 

Klotzer and co-workers reported in 1982 a successful amination of an imidazole and its 2-nitro and 2-methyl-4(5)-nitro derivatives with the use of 0-diphenylphosphynyl hydroxylamine [Eq. (10)] (82S592). The reaction was carried out by the action of DPPH on a sodium or lithium salt of the corresponding imidazole in N-methylpyrrolidone media. The product was isolated as an N-benzylideneamino derivative, then hydrolyzed to the unsubstituted N-amine. Since the parent of the series, 1-aminoimidazole, is unstable, this compound was isolated only as its hydrochloride. Ali attempts made by the authors of this review to synthesize 1-aminoimidazole by amination of imidazole with HOSA in alkaline media led to resinification and regeneration of the initial compound. 

Although there have been very few references to imidazole nitrations via the anion the approach would seem to hold promise. Conversion of 1-methylimidazole into its 2-nitro derivative by successive lithiation and reaction with N2O4 <74URP437763> has led to further successful 2-nitrations of... 

Imidazole is much more reactive towards nitration than thiazole, snbstitution taking place via the salt, as does nitration of alkyl-thiazoles. Thiazole itself is nntonched by nitric acid/oleum at 160 °C, but methyl-thiazoles are sufficiently activated to undergo substitntion, the typical regioselectivity being for formation of more 5-nitro than 4-nitro derivatives the 2-position is not attacked 4,5-dimethylimidazole is resistant to nitration. The much less reactive oxazoles do not nndergo nitration. 

This reasoning is supported by the observation that the reaction of 2-nitrofuran with trichloromethyl carbanion proceeds in both 3- and 5-positions, because in this case the base-induced p-elimination of HCl from the intermediate o adducts is a fast process [54]. Also the VNS reactions of nitro derivatives of other 5-membered heterocycles, imidazoles [20, 56] and thiazoles [34], with a variety of a-halogeno carbanions have been shown to proceed efficiently. 

The VNS is the reaction of choice for incorporation of a-sulfonylalkyl substituents into nitroarenes and their heteroanalogues. Particularly accessible and useful are nitroarylmethyl phenyl sulfones and their heteroanalogues that are efficiently produced in the VNS reactions of carbanions of chloromethyl aryl sulfones with a great variety of nitroarenes and nitroheteroarenes. Nitro derivatives of heterocycles, such as pyrrole [54,55], furan [54], thiophene [54], imidazole [106, 112, 113], pyrazole [114], pyridine [57], indole [115], indazole [116, 117], benzimidazole [118], benzotriazole [119], benzofuroxan [120], quinoline [121], and porphyrins [122, 123], have been shown to enter this reaction. 

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