Imidazole acyl derivatives

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

In addition to acyl halides and acid anhydrides, there are a number of milder and more selective acylating agents that can be readily prepared from carboxylic acids. Imidazolides, the (V-acyl derivatives of imidazole, are examples.115 Imidazolides are isolable substances and can be prepared directly from the carboxylic acid by reaction with carbonyldiimidazole. 

The functional micellized surfactant contained both imidazole and hydroxyethyl groups and the final products of reaction with p-nitrophenyl alkanoates are acyl derivatives of the hydroxyethyl group. However, these O-acylated products were formed from an acylimidazole intermediate which... 

Heterocycles containing an NH group, such as pyrroles, indoles, imidazoles, triazoles, etc., can be linked to insoluble supports as N-alkyl, N-aryl, or N-acyl derivatives (Table 3.29). The optimal choice depends mainly on the NH acidity of the heterocycle in question. Increasing acidity will facilitate the acidolytic cleavage of N-benzyl groups and the nucleophilic cleavage of /V-acyl groups from these heterocycles. 

The hydrolysis of acetyl- (150 R = MeCO) and benzoyl-imidazoles (150 R = PhCO) involves the reversible addition of water to the imidazole to give the T=. At low acidities the decomposition of this is the slow step but, as the acidity increases and water activity decreases, its formation becomes rate determining.128 By contrast, the hydrolysis reactions of the (V-acyl derivatives of 2,4,5-triphenylimidazole proceed in a concerted maimer and do not involve tetrahedral intermediates.129... 

Only very few among the common amino acids possess a pK within the range 5.8-7.0. Therefore, the imidazole ring of histidine was suspected very early to represent the group responsible for nucleophilic attack on the substrate (38). The pK of free imidazol is 6.9 (39) that of imidazol, contained in histidine or its peptides, varies between 5.6 and 7.1 (40). Imidazol is well known to form unstable acyl derivatives, which undergo spontaneous hydrolysis because of the presence of the resonating triad unit —-N—C= N— (41). In addition, imidazol and its derivatives catalyze the hydrolysis of certain esters, especially those derived from phenols (42). Likewise, the behavior of imidazol towards thio esters reflects exactly the specificity of ChE s (see IV, 4). Thus, thiol esters are split (43), whereas thiono esters are resistant (21). 

TMS derivatives of biogenic amines are used in combination with acyl derivatives for electron-capture detection. Horning et al. [97] presented retention data of TMS-N-acetyl and TMS-N-HFB derivatives of a number of these substances on SE-30, OV-1 and OV-17. The derivatives were prepared by the following procedure. A 1-mg amount of the amine or amino hydrochloride was dissolved in 0.1 ml of acetonitrile and 0.2 ml of TMS-imida-zole was added. After heating for 3 h at 60°C, 5 mg of N-acetylimidazole (or 0.1 ml of HFB-imidazole) were added and the solution was heated at 80°C for 3 h (30 min at 60°C). The solution was used directly for the GC analysis. 

This procedure provides a method for functionalizing the pyrrole ring 1n the 3-pos1t1on, normally a difficult synthetic step when conventional electrophilic substitution is used. The technique has been extended to addition of several aldehydes and acetone and to a number of pyrroles.4 The generality Includes photoaddition to imidazoles which are substituted in the 4-posltion. Pyrrole photoadduct alcohols are readily dehydrated to 3-alkenylpyrroles or oxidized to 3-acyl derivatives. 

Ordinarily, direct Friedel-Crafts alkylation and acylation do not take place on imidazoles due to deactivation of imidazole ring after coordination to a Lewis acid catalyst (CHEC-II(1996)). Most alkylations and acylations of imidazoles have been realized via quenching of an imidazole lithium derivative with a corresponding electrophile (CHEC-II(19%)). 

V-Fluoroacyl-imidazoles react readily with hydroxyl groups and secondary or tertiary amines to form acyl derivatives. No acids are produced which could hydrolyse the products. The imidazole produced as a by-product is relatively inert. A reaction using JV-trifluoroacetylimidazole is shown below ... 

In general, acylation reactions for chromatography are carried out with three main types of acylating reagent acid anhydrides, acid halides and reactive acyl derivatives such as acylated imidazoles, acylated amides or acylated phenols, and the different types are chosen for different reasons. Acyl halides are highly reactive, which may be important with compounds that are difficult to acylate, because of steric factors for instance. A drawback to acyl halides is that a basic acceptor for the halogen acid produced in the reaction is usually required (equation (8)),... 

Although malonate derivatives were described previously, one example is included here to demonstrate their use as a carboxyl enolate. Reaction of 4.87 with carbonyl diimidazole (CDI, see chapter two, section 2.4) gave the acyl imidazole (a very highly activated acyl derivative), which reacted with the magnesium enolate of... 

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