1-Hydroxyimidazole 3-oxides

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). 

Hydroxyimidazole 3-oxide, which does not have substituents at position 2, is unstable under the conditions of nitration. Uncommon nitration of l-hydroxy-2-cy-anoimidazole 3-oxide and l-hydroxy-2-carbamoylimidazole 3-oxide was observed in [162] (Scheme 16). 

In the 1-hydroxyimidazole 3-oxides a single signal is observed in the NMR spectrum for the 4- and 5-methyl groups of (77). This requires an autotropic form of rearrangement (Scheme 25). 

Dehydrogenation of 1-hydroxyimidazoles and their 3-oxides with lead dioxide gives A/ -oxides and A(,Ar -dioxides of imidazolyls. These short-lived radicals are also formed when alkali salts of 1-hydroxyimidazole 3-oxides react with halogen in polar organic solvents. Hydroquinone converts the AT,AT -dioxides back into 1-hydroxy 3-oxides. 

Examples of reactions which have used 1,2-diketones and ammonia with or without added aldehyde include the isolation of good yields of lophine (2,4,5-triphenylimidazole) from benzil and ammonia, a rather elegant synthesis of 4,5-di-t-butylimidazole (135), and the preparation of a series of 2-aryl-5-trifluoromethyl-4-phenylimidazoles (136) from 3,3,3-trifluoro-l-phenylpropane-l,2-dione monohydrate (Scheme 74). Additionally, the formation of 1-hydroxyimidazole 3-oxides (137) from a-diketones, hydroxylamine and aldehydes (74CI(L)38), and the preparations of 2,2 -bis- (138) and 2,2, 2"-tris-imidazolyls (139) from benzil, ammonia and polyformyl aromatics provide further examples of this versatile reaction (Scheme 74). There is yet some doubt about the pathway or pathways involved in these... 

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)... 

In the above reaction sequences, when the ammonia or amine is replaced by hydroxylamine, one can prepare I-hydroxyimidazole 3-oxides, e.g. 1-hydroxyimidazole 3-oxide (68%) and its 2-methyl (74%) and 2-ethyl derivatives (70%). Subsequent hydrogenation with palladium on carbon in aqueous hydrochloric acid gives the 1 -hydroxyimidazoles. It should be noted that the oxides decompose violently when heated [24], Titanium(III) chloride in aqueous solution at room temperature is a suitable reducing agent [25]. 

Attempts to distil 1-methoxyimidazole 3-oxide in vacuo caused a violent explosion at 180°C. Subsequent thermal analysis of the compound revealed a large exothermic decomposition in the range 140-180 °C. The analogous 1-hydroxyimidazole 3-oxide exhibited a similar exotherm at 200-250°C <84CBR30>. 

Direct IV-oxidation of these heterocycles invariably fails (see Section 3.02.7.2.8), making ring synthetic methods the only viable alternative <93CHE127>. Although there has been considerable interest in the chemistry of compounds of this type, there are no new synthetic approaches of a general nature. The most common approach is to react a-oximinoketones with aldehydes and primary amines. With formaldehyde, however, the 2-unsubstituted 1-oxides rearrange to 2-imi-dazolones. Variations on this theme allow synthesis of 1-hydroxyimidazole 3-oxides. Thus, treatment of an a-dicarbonyl compound with an aldehyde and hydroxylamine, or reaction of the aldehyde oxime or aldehyde with a 1,2-dioxime are common approaches <898773 >. Similarly, a-hydroxyamino-... 

The reactivity of A -sub tituted pyridinium salts is shown in the cyclization of the salt (53.2). A -Phenylhydroxylamine reacts with benzonitrile oxide (review [B-43]) at ambient temperature to form a fused 1-hydroxyimidazole 3-oxide. 

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. 

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