3- Substituted imidazole-1-oxides

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. 

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). 

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. 

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). 

Cycloaddition with thioketones 3-Substituted imidazole 1-oxides 228 react with 2,2,4,4-tetramethylcylobutane-l,3-dithione with formation of l,3-dihydro-2H-imidazol-2-thiones 305 (1998HCA1585, 2011H765). 

N-Dealkylation of 3-substituted imidazole 1-oxides 228 has not been reported. 

The rearrangements taking place when 3-substituted imidazole 1-oxides 228 are treated with acetic anhydride are discussed in Section 3.1.8.8. 

Acylation, O-silylation, or O-phosphorylation, expected to follow the trends observed for 3-substituted imidazole 1-oxides, have not been reported. 

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