Imidazole 3-oxides

Imidazole 1-oxide, l-methoxy-2,4,5-triphenyl-pK, 5, 384 B-76MI40701, 70AHC(12)103, 80AHC(27)241)... 

H-Imidazole 1-oxide, 2,4,4,5-tetramethyl- H NMR, 5, 16 <83UP40100> 4H-Imidazole-2,4,5-triamine, hexaethyl-... 

Condensation of hydroxyamino-ketones (166) with ketones and ammonium acetate leads to the formation of 2H -imidazole-1 -oxides (167) (Scheme 2.59) (324). 

The AH-i midazole-3-ox ides (223) have electrochemical potentials similar to 4H-imidazole-l,3-dioxides (219) AH -imidazole-1-oxides (224) are more difficult to oxidize (Fig. 2.17) (Table 2.6) (425). 

In contrast, the reaction of acid-catalyzed nucleophilic addition of alcohols to derivatives of AH -imidazol-1 -oxide (219) and (224) leads only to nitronyl nitroxyl (221) and imino nitroxyl (274) radicals (518). 

Diphenyl-2//-imidazole-1 -oxide (180) cycloadds DMAD in cold chloroform, the imidazoisoxazole 182 was obtained, whereas in hot benzene the oxalacetate 181 was secured. The type of product is also dependent on the nature of the substituent at the 5-position.149... 

The aromatic imidazole 1-oxides 228 discussed in Section 3.1 are derived from imidazoles 248 by appending an oxygen atom to the pyridine type ring nitrogen atom of the imidazole nucleus. The second nitrogen atom of the imidazole ring can be attached to an alkyl or aryl group or to a... 

The formula for the parent 3-substituted imidazole 1-oxide 245 is shown in Scheme 67... 

The resonance structures of the 3-substituted imidazole 1-oxides 245 are discussed in Section 1.1.1. According to IUPAC nomenclature, structure 245 is a 1-substituted lH-imidazole 3-oxide since the rules dictate that when R=H the indicated hydrogen position takes numbering precedence. Other names found in the literature are 1-substituted imidazole 3-oxides or 1-substituted 3-oxo-lH-imidazoles. Frequently the numbering is switched to give the names 3-substituted 2H-imidazole 1-oxide, 3-substituted imidazole 1-oxides, or 3-substituted 1 -oxo-3H-imidazoles. In the present review the most commonly used naming, which is accepted by IUPAC, Chem. Abstr. Autonom., is used calling structure 245 a 3-substituted imidazole 1-oxide. Consistently, structure 245 (R=OH, OAlk, or NH2) is named 3-hydroxy, 3-alkoxy, or 3-aminoimidazole 1-oxide, respectively. 

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... 

X-ray spectra of a number of imidazole 1-oxides 228 have been published (1999JCS(P1)615, 1974JHC615, 2006HCA1304, 2007ZN(A)295, 2008TA1600, 2008ZN447). 

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). 

This issue was addressed taking into advance that butyloxycarbonyl (Boc)protection of 249 takes place regioselectively at the oxygen atom to give 252. Subsequent alkylation finds only N-3 accessible for attack (1990S795). Subsequent methanolysis and neutralization afforded the 3-substituted imidazole 1-oxide 228 (Scheme 71). 

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. 

Substituted imidazole 1-oxides 228 are predicted to be activated toward electrophilic aromatic substitution, nucleophilic aromatic substitution, and metallation as described in Section 1. Nevertheless little information about the reactivity of imidazole 1-oxides in these processes exists. The reason for this lack may be the high polarity of the imidazole 1-oxides, which makes it difficult to find suitable reaction solvents. Another obstacle is that no method for complete drying of imidazole 1-oxides exists and dry starting material is instrumental for successful metallation. Well documented and useful is the reaction of imidazole 1-oxide 228 with alkylation and acylation reagents, their function as 1,3-dipoles in cycloadditions, and their palladium-catalyzed direct arylation. 

Trimethyl-imidazole 1-oxide 263 could be nitrated at the 2-position. According to reaction kinetics it is the neutral imidazole species which undergoes nitration (1977JCS(P1)672) (Scheme 82). 

Protons at C2 of imidazole 1-oxides 228 are acidic and are exchanged with deuterium even in weakly acidic solution. The exchange rate increases with increasing pH (2004S2678). Although the mechanism is not fully understood, the palladium-catalyzed direct arylation of imidazole 1-oxides most likely involves deprotonation so that the observed regi-oselective arylation reflects the propensity to proton abstraction found to decrease in the order C2 > C5 > C4 (2009JA3291). 

Although protons at C2 of imidazole 1-oxides 228 are fairly acidic as shown by their facile exchange with deuterium in deuterium oxide solution (2004S2678), subsequent trapping of the anion with electrophiles has not been exploited. 

The palladium-catalyzed and the copper-cocatalyzed direct arylation of imidazole 1-oxides 280 shown in Scheme 83 may involve transmetallation (2008JA3276, 2009JA3291). However, classical transmetallation like conversion of imidazolyllithium compounds to imidazolylzinc compounds has not been reported. 

Only few imidazole 1-oxides possessing leaving groups like compound 278 are known. Although predicted to be apt to undergo nucleophilic aromatic substitution (see Section 1.4.2) such reactions have not been reported. 

Substituted imidazole 1-oxides 263 upon treatment with dimethyl or diethyl sulfate furnish l-alkoxy-3-subtituted imidazolium salts 283 that were converted to the tetrafluoroborate 283 (A- = BF4 ) or hexafluorophos-phates 283 (A = PF6-) by treatment with sodium tetrafluoroborate or hexa-fluorophosphate (2007ZN(A)295). The tetrafluoroborates 283 (A = BF4 ) reacted with cyanide ion to give 2-cyanoimidazoles 285 (1975JCS(P1)275). The reaction probably follows a mechanism similar to that suggested to be operative in the pyrazole series encompassing O-alkylation succeeded by nucleophilic addition and elimination of methanol (Scheme 85). 

If the 2-position possesses a substituent, hydrogen atoms situated at lateral positions at C3 and C4 can be replaced with an acyl group. Thus 2,4,5-trimethyl-imidazole 1-oxide 291 reacted with acetic anhydride to give a 4.3 1 mixture of the 3-acetoxymethyl 292 and 5-acetoxymethyl-imidazoles 293 (2010UP1) (Scheme 87). 

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