Nitration of imidazoles

The direct nitration of imidazole with acidic reagents is difficult due to facile nitrogen protonation (pA aH 7). Nitration of imidazoles proceeds in the 4- and 5-positions with the amidine 2-position being quite inert. Imidazole can be directly nitrated to 4,5-dinitroimidazole but no further. 2,4,5-Trinitroimidazole (TNI) can be prepared from the successive nitration of 2-nitroimidazole the latter synthesized from the diazotization of 2-aminoimidazole in the presence of excess sodium nitrite and a copper salt. The nitrative cleavage of polyiodoimidazoles also provides a route to polynitroimidazoles. " ... 

A quantitative study has been carried out by Ridd and co-workers126 on the nitration of imidazole and pyrazole in 98% sulfuric acid the partial rate factors for the 4-positions of imidazolium and pyrazolium cations are 3.0 xlO-9 and 2.1 x 10-10, respectively. Thiazole and isoxazole cations are also far less reactive than benzene. As a consequence, phenyl derivatives give products substituted in the benzene ring, on sulfonation or nitration.208-210... 

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.). 

At low temperature pyrazole is easily A-nitrated giving 1-nitropyrazole in contrast to classical nitration based on the use of mixed acid 4-nitropyrazole is not formed. On prolonged reaction, a mixture of 4(5)-nitro- and 1,4-dinitropyrazole is obtained, whereas the last is prepared in the kyodai nitration of 4-nitropyrazole [363], The kyodai nitration of imidazoles gave a mixture of 4-nitro- and 1,4-dini-troimidazoles and 1,2,4-triazole - only a few percent of mononitro derivatives even after prolonged reaction [363],... 

The kinetics of nitration of imidazole have been studied in sulfuric acid medium. The yields of 4-nitroimidazoIe are dependent on the acidity, e.g. %H2S04, yield (%) 83.7, 46 89.6, 26 93.8, 19 98.8, 19 1% SO3, 90. Ring opening accompanies the process giving rise to ammonia and, presumably, oxidation products. The kinetic results which could be separated indicate that the species being nitrated is the imidazole cation, but side reactions complicate matters. The suggested mechanism is outlined in Scheme 30 (B-76MI40701). 

Nitroimidazoles are readily made by nitration of imidazole or 1-substituted imidazoles in concentrated sulfuric acid (see Section 7.2.1). It is much more difficult to make 2-nitroimidazoles since direct nitration is seldom observed in the 2-position. Although electrophilic nitrodehalogenation reactions, too, occur mainly at C-4(5) [1], Katritzky has recently selectively nitrodeiodinated 2,4,5-triiodoimidazole to prepare 2,4(5)-dinitro-5(4)-iodo-and 2,4,5-triiiitroimidazoles, albeit in poor yield [2], Other routes to 2-nitroimidazoles include those which react a diazonium fluoroborate with the nitrite ion, and methods which oxidize 2-amino derivatives, themselves often only available by laborious sequences. The most appealing routes to 2-nitroimidazoles are the methods which make the 2-lithio derivative and treat it with a source of nitronium ion (e.g. n-propyl nitrate or N2O4) [3-5] (see Section 7.2.2). 

Ozone-mediated nitration (Kyodai nitration) of imidazole under neutral condition gave poor yields of 4-nitroimi-dazole. However, the yield improved dramatically with the addition of methanesulfonic acid. The combination NO2-O3 is a much more reactive electrophilic reagent since a reaction temperature of 0°C was sufficient (Scheme 56), <1996JCM244>. The 4-nitro product 238 could also be converted into 1,4-dinitroimidazole 239 over a long period. 

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." ... 

The first reaction is the nitration of imidazole in one of only two free positions. The position nex .. only one nitrogen is more reactive than the one between the two nitrogens. This shows t --imidazole, with one pyrrole-like and one pyridine-like nitrogen, is more reactive than pyridine i-ic more controlled than pyrrole. 

Reagents and reaction conditions play important roles in determining the facility of reactions with imidazoles and benzimidazoles. Electrophilic substitution may occur with considerable ease if the neutral molecule or anion are involved (e.g., halogenation), but protonation or complexing with Lewis acids, can greatly reduce reactivity. Nitration of imidazole with mixed acids has = 10 compared with benzene. 

SnAr reactions like nitration (with HNO3/H2SO4) or sulfonation (with H2SO4 or oleum) proceed very slowly, since in strongly acidic medium imidazolium ions are the participants in the SnAr processes. Thus, nitration of imidazole leads to 4-nitroimidazole (11), and under more drastic conditions to 4,5-dinitroimidazole (12). Sulfonation of imidazole in oleum at 160 °C yields imidazole-4-sulfonic acid ... 

Thekinetics of nitration in sulphuric acid of both pyrazole and imidazole have been studied. Data have already been quoted (tables 8.1, 8.3) to support the view that the nitration of both of these compounds at C(4)... 

Electrophilic bromination (and nitration) of pyrido[l, 2-a]benzimidazole (analogous to 132) cannot take place in the imidazole moiety. Initial substitution, using NBS as reagent, was shown to occur at the 8-position, and subsequently at C-4 and C-6 (90JOU1166). 

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... 

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 studies by Gilman et al. and Sawicki on the nitration of derivatives of 2- and 3-aminodibenzothiophene have made available for the first time diaminodibenzothiophenes in which both amine functions are present in the same ring. Eeduction of 2-amino-1-nitrodibenzothiophene with stannous chloride yields 1,2-diaminodibenzothiophene (80%). As expected this compound reacts readily with acetic acid to give the imidazole (104) and with selenium dioxide to give the selenadiazole... 

A large number of imidazole (4) and benzimidazole (5) silver(I) complexes have been prepared.64 Early reports predicted that the site of complex formation of the imidazole molecule would be the pyridine nitrogen rather than the pyrrole nitrogen. However, the crystal structure of bis(imidazole)silver nitrate showed that the two pyrrole nitrogens were bound in almost linear arrangement (Ag—N 212.0, 213.2 pm, N—Ag—N, 1720).65... 

Further nitration of 4-methyl-2-(4-nitrophenyl) imidazole using mixed acid gives the 5-nitro product (21JCSI893), and dinitration of 4-methyl-2-phenylimidazole using fuming nitric acid, produces 5-nitro-2-(4-nitro-phenyl)-imidazole (40JPJ312). 

Figure 8-11. The nitration of an imidazole ligand co-ordinated to a kinetically inert cobalt(iu) centre.

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