3- Substituted imidazole 1-oxide preparation

Substituted imidazole 1-oxides 228 can be prepared by N-oxidation of imidazoles 248, by N-alkylation of 1-hydroxyimidazoles 249, or by cycliza-tion using suitable starting materials derived from a 1,2-dicarbonyl compound, an aldehyde, an amine, and hydroxyamine. The substituents at the three first starting materials are transferred to the product and make control over the substituents in the imidazole 1-oxide 228 possible depending on the protocol used by the synthesis. The synthesis of 3-hydroxyimidazole 1-oxides is presented in Section 3.1.6. 

As the imidazole nucleus does not undergo Friedel-Crafts acylation, ketone substituents must be introduced indirectly, either before the ring is formed34,41,210,275,435 or by modification of existing substituents.210 Roe210 prepared 2-acetylimidazole (92) by oxidation of l-(imidazol-2 -yl)ethanol (91) with chromic oxide in pyridine. The acyl-substituted imidazoles have distinctive infrared and ultraviolet... 

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). 

A novel ring transformation/desulfurization of substituted 2-methyl-l,2,4-thiadiazolium salts 1481 provides a versatile entry to imidazoles 1482 with a variety of substituents. The starting 1,2,4-thiadiazolium salts 1481 can be prepared from A -(thiocarbonyl)-A -methylamidines 1480 under mild oxidative conditions. Related salts, 1,2,4-dithiazolium triiodides 1483, also react with amines to form imidazoles 1484 <1997JOC3480>. Alternatively, A -(thiocarbonyl)-A -methylamidines 1485 can be transformed into 1-substituted imidazoles 1487 via A-methylation followed by elimination of methylthiol (Scheme 383) <1997JOC3480>. 

The chemistry of azole X-oxides is relatively under developed compared, for example, with that of pyridine X-oxides, largely because of difficulty in their preparation from the azoles themselves. Some ring synthetic methods can be used, for example the reaction of 1,2-dicarbonyl mono-oximes with imines as shown. 1-Substituted imidazole 3-oxides can be converted into nitriles with loss of the oxygen using trimethylsilyl cyanide, careful choice of solvent minimising a tendency for isomeric mixtures to be formed. ... 

Substituted imidazoles 55 are prepared by dehydrogenation of 2-substituted 4,5-dihydroimidazoles 54, which are obtained (a) from nitriles and ethylenediamine in the presence of catalytic amounts of sulfur under ultrasonic irradiation [400] and (b) from aldehydes and ethylenediamine in the system I2/KI/K2CO3/H2O, which effects C-N-oxidation of the primarily formed imidazolidines 56 to the imidazolines 54 [401] ... 

Hydroxymethylation (formaldehyde) of nitro-imidazole 76 affords 77, which is oxidized to aldehyde 78. To prepare the other fragment for this convergent synthesis, reaction of epichlorohydrin with morpholine leads to the aminoepoxide 79, which is reacted with hydrazine to afford 80. Reaction of this substituted hydrazine with dimethyl carbonate affords oxazolinone 81 by sequential ester interchange reactions. Condensation of 81 with aldehyde 78 affords the antitricho-... 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

Owing to the existence of two centers for nucleophilic attack (at C2 and C5) in radical cations (220) obtained from the oxidation of 4-H -imidazole-1,3-dioxides (219), the formation of two products of methoxy group addition was observed, namely NNR (221) and NR of 3-imidazoline-3-oxide (222). The ratio of the products depends on the electronic nature of substitutes R1 and R2. Both, the donor character of R1 and acceptor character of R2 facilitate the formation of nitroxyl radicals (222) with the yield of (221) increasing with the inverted effect of the substituents. As was mentioned in Section 2.4, the results of preparative electrochemical oxidative methoxylation of 4H -imidazole-1,3-dioxides are similar to the results of chemical oxidation. 

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