Imidazoles 1-hydroxyimidazole 3-oxides

Oximes can be also used for the imidazole ring synthesis. Thus, reaction of a-amino-oximes 122 and orthoesters leads to imidazole Af-oxides 123 (equation 53) . Interaction of a-ketooxime 124 with triazinanes also afforded imidazole Af-oxides 125 in good yields (equation 54) . Similarly, a-ketooximes in the system NH3/H20/aromatic aldehyde afforded trisubstituted 1-hydroxyimidazoles . ... 

The aromatic imidazole N-oxides have structure 245. The parent compound 246 displays tautomerism between the N-oxide tautomer 246 and the 1-hydroximidazole tautomer 247 (Scheme 68). 1-Hydroxyimidazole 247 and substituted 1 -hyd roxyimidazoIes 249 belong to a separate group of compounds, which is not discussed in the present review. 

The 3-hydroxyimidazole 1-oxides 267 should be handled with care because they undergo violent decomposition upon heating (1971RZC1747, 1998HCA1585). At room temperature imidazole 1-oxides 228 are usually stable, crystalline, polar, and hygroscopic compounds. An exception is imidazole 1-oxides devoid of substituents at the 2-position, which may rearrange to... 

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. 

At-Alkylation of 1-hydroxyimidazoles 249 produces 3-substituted imidazole 1-oxides 228 (R=Aik) in low yields due to competing O-alkylation and dialkylation leading to 1-alkoxyimidazoles 250 and l-alkyl-3-alkyloxy-imidazolium salts 251, respectively (1970ZC211,1990S795) (Scheme 70). 

Several of the methods used for synthesis of 3-alkyl or aryl-imidazole 1-oxides 228 can be modified to produce 3-hydroxyimidazole 1-oxides 267 by replacing an amine or imine functionality in the starting materials with an oxime group. 

When an isonitrosoketone reacts with an aldoxime, the product is an imidazole W-oxide.122 In a similar reaction Allan and Allan123 prepared 1-hydroxyimidazoles by the reaction of 2,3-butanedione-monoxime with aldehydes in aqueous ammonia. The overall reaction is undoubtedly the reaction of the isonitrosoketone with an aldimine by a mechanism similar to the following ... 

One of the common properties of imidazole N-oxides is their strong association even in dilute solution, and in the solid state such association can mask distinction in the IR between NH and OH bands. Thus IR studies of such compounds in the solid state may give rise to confusing results. Careful UV studies of 1-hydroxybenzimidazoles show that with a variety of substituents (e.g. 6-nitro, 2-alkyl or 2-aryl) the hydroxy form (73) is favoured in organic solvents, and the more polar oxide form (74) in water (there is a mixture of both in aqueous ethanol). With 1-hydroxybenzimidazole the N-methyl model (75) is not sterically hindered, and the value of Kt (74173) = 12 deduced from the pK values of the models (75/76) in water should be much more reliable than that for the hydroxyimidazoles (Scheme 24). In other solvents (benzene, chloroform, acetonitrile, dioxane), UV results show that the OH form (73) predominates in 75% aqueous ethanol Kt=1. 

Cyclization of a-oximinoketones with an aldehyde in the presence of ammonia or an amine is a common way of making 1-hydroxyimidazoles or imidazole A -oxides (5) (Scheme 5.1.4) [58-63]. Yields are often very high... 

Many workers in recent years have been interested in the tautomeric equilibria pertaining to oxygenated imidazoles such as imidazolones, " " N-hydroxyimidazoles, and imidazole iV-oxides. The earlier results have been critically summarized. In the solid state l,2-dimethyl-5-phenylimidazol-4-one exists in the OH form, but insolubility prevented studies in solution. Theoretically l-methylimidazol-5-ones can exist in the forms 93-96 shown in Eq. (22). French workers ... 

The formation of 1-hydroxyimidazole 3-oxides had been reported in the mid 1940s in a closely related reaction involving the condensation of dimethylglyoxime with benzaldehyde <45G216). In contrast, the products formed from the condensation of phenanthraquinone dioxime (68) with benzaldehyde have been shown to be temperature dependent <69CB4177>. At low temperature (5°C) the phenanthro[9,10-d]imidazole A-oxide is obtained as the hydrochloride (69) in 85% yield. 

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 N-hydroxy structure (26) was preferred123 to an iV-oxide representation on account of the amphoteric nature of the product and because the derived acetate formed a well-defined hydrochloride salt. Hydrogenation of these N-hydroxyimidazoles over Raney nickel gives imidazoles in 60-94% yields.122 The reaction has been adapted for the preparation of 4-mercaptoimidazoles, using an a-ketothionamide (27) with an aldimine.124... 

Such hydroxyimidazoles or oxides are capable of complete reduction to the unoxygenated imidazoles, while the 1-hydroxyimidazole 3-oxides can also be partically reduced with, for example, NaBUi [53], or completely deoxygenated with Raney nickel [52, 54], Although most cyclizations of a-ketooximes lead to A -oxygenated imidazoles, there are exceptions. When an o(-oximino-)6-dicarbonyl compound is refluxed with benzylamine in a suitable solvent (c.g. DMSO, acetonitrile, toluene), 4-acylimidazoles (11) are formed in moderate to good yields. The reaction is readily adapted to the synthesis of imidazole-4-carboxylates and -amides (Scheme 4.1.7)... 

Much of the synthetic activity involving formation of the 1,5- and 2,3-bonds has centered on the preparation of hydroxyimidazoles and their Af-oxides. Since direct A -oxidation of the imidazole ring has not been accomplished, ring-synthetic methods provide the only means of access to compounds of this type. While not all of the reactions described below conform strictly to the classification of this section, the methods are sufficiently similar to permit... 

Dihydropyrazine derivatives, on irradiation, give good yields of imidazoles.The thermolysis of 2-azidopyrazine 1-oxide gives 2-cyano-1 -hydroxyimidazole. ... 

Preparation of A-hydroxyimidazoles or their A-oxides by direct reaction with peracids is not a viable route <93CHE127>. Direct A-silylation of imidazoles and benzimidazoles is common <83CPB1213>. Although A-halogenated imidazoles are rather unstable, charge transfer complexes of... 

Hydroxyimidazole iV-oxide can be transformed into 1-benzyloxyimidazole and this undergoes useful 2-lithiations hydrogenolysis produces 2-substituted 1-hydro-xyimidazoles and these, in turn, can be converted into the 2-substituted imidazole by reduction with titanium(III) chloride. 

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