Substituted imidazoles

SH 1-Substituted imidazole Liquid film, MeOH, EtOH NH, C=S... 

Imidazoles are hydroxymethylated by CH2O at the 4-position 1-substituted imidazoles react at the 2-position. Isoxazoles can be chloromethylated in the 4-position (63AHC(2)365). 

Uncharged azoles not containing oxygen or sulfur are often resistant to attack by hydroxide ions at temperatures up to 100 °C and above. However, neutral azoles react with hydroxide ions under extreme conditions, e.g. 1-substituted imidazoles such as (153) at 300°C give the corresponding imidazolinone (154) 80AHC(27)24l). 

Substituted imidazoles can be acylated at the 2-position by acid chlorides in the presence of triethylamine. This reaction proceeds by proton loss on the (V-acylated intermediate (241). An analogous reaction with phenyl isocyanate gives (242), probably via a similar mechanism. Benzimidazoles react similarly, but pyrazoles do not (80AHC(27)24l) cf. Section 4.02.1.4.6). 

The formation of quaternary salts by the action of the common quatemizing reagents on 1-substituted imidazoles and benzimidazoles (29) to give salts of type 30 is well known. Only N-3 possesses a free... 

The reactive 1-acyl-3-alkylimidazolium species also plays a role in acylation of alcohols with carboxylic anhydrides or carboxylic acid chlorides using 1-substituted imidazoles as catalysts.[145] In this case the reactive species is formed in situ ... 

Oxazoles resemble 1-substituted imidazoles in their positional reactivity order for electrophilic substitution, 5 > 4 > 2 [59LA(626)83, 59LA(626)92 74AHC(17)99 84MI29]. The compounds can be regarded as hybrids of... 

In 1-substituted imidazoles C-5 is slightly more reactive than C-4. Partial rate factors are discussed in (90AHC(47)165). 

Similar imidazolium ylides are implicated in the aroylation of TV-phenyl benzimidoyl chlorides (92CPB2627), and in reactions of 1-substituted imidazoles with cyanogen bromide to form 2-cyano- or 2-bromo-imidazoles (88S470). 

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-4,5-dicarbohydroxamic acids on Lossen rearrangement form 1-hydroxyxanthines. Thiazole-4,5-dicarbohydroxamic acids in their partial Lossen degradation, however, show little differentiation between the 4- and 5-position and hence mixtures of the [4,5-d] and the [5,4-d] structures (447) and (448) are formed. The isomer distribution appears to be affected by the solvent as well as by the sulfonyl chloride utilized in the reaction (68JHC331). 

The reaction of 5-bromo-3-nitro-l,2,4-triazole and 3,5-dinitro-l,2,4-triazole with a variety of oxiranes yielded the expected 1-substituted imidazoles, and also resulted in the formation of 5,6-dihydrooxazolo[3,2-6]-s-triazoles upon treatment with base (75CHE612). The proposed pathway involves proton abstraction from the imidazole and subsequent attack of the oxirane on the N-anion followed by cyclization in a concerted fashion (equation 56). 2,4(5)-Dinitroimidazole reacts analogously with oxiranes to give isomeric nitro-imidazo[2,1 -f>]oxazoles in good overall yield (8UMC601). 

The quaternization of 1-substituted imidazoles is usually easy unless steric factors intervene, or strongly electron-attracting groups are present, for example, 1-acylimidazoles can only be alkylated at N(3) with powerful alkylating agents such as methyl fluorosulfonate or trialkyloxonium fluoroborates. Trimethyloxonium fluoroborate does not methylate 1-dimethylaminosulfonylimidazole. Regiospecific synthesis of 3-substituted L-histidines can be achieved by alkylation of Ar-/-butoxycarbonyl-l-phenacyl-L-histidinc methyl ester at N(3), followed by reductive removal of the phenacyl group (Scheme 15). 

Substitution generally occurs first at the 4-position, but further reaction at other available nuclear positions takes place readily, especially in the imidazole series. In 1-substituted imidazoles, C(5) is slightly more reactive than C(4). When halogenation of the nucleus involves electrophilic attack on anions of type 155, the 4-position of imidazole is... 

The Wallach synthesis79 involves ring closure of an iV,jV -disubsti-tuted oxamide with PC15 to give a chlorine-containing compound, which, on reduction with hydriodic acid, yields a 1-substituted imidazole. The method has been adapted for the formation of halogen-substituted imidazoles.8 ° 8 2... 

Most of the reactions and properties of 1-substituted imidazoles have been discussed earlier in this review. Apart from the utilization of the readily removable benzyl substituent in synthetic procedures leading to 2-substituted imidazoles, perhaps the mostexciting advances have stemmed from the reactions of the 1 -acylimidazoles (imidazolides) which are extremely reactive in such nucleophilic reactions as hydrolysis and alcoholysis.12 The use of such compounds as N,N -carbonyl-diimidazole in peptide synthesis is now commonplace. The silicon-nitrogen bond in N-trimethylsilylimidazoles is also extremely reactive, so reactive that it is attacked by a-halogenocarboxylic esters.361... 

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