Imidazoles acylimidazoles

Ac-Imidazole, PtCl2(C2H4), 23°, 0.5-144 h, 51-87% yield. Platinum(II) acts as a template to catalyze the acetylation of the pyridinyl alcohol, C5H4N(CH2) CH20H. Normally acylimidazoles are not very reactive acy-lating agents with alcohols. 

The reaction of iV-acylimidazole with dimethyl acetylenedicarboxylate in acetonitrile at 25 °C provided (2-imidazolyl)maleates and, as by-product, dimethyl(imidazol-l-yl)-fumarate tl57]... 

Organo copper and lithium enolates of cyclic ketones, lactones, and lactams or acyclic ketones are converted with acylimidazoles or imidazole-N-carboxylates into the corresponding / -diketones or / -ketoesters ... 

Figure 3.12 CDI reacts with carboxylate groups to form an active acylimidazole intermediate. In the presence of an amine nucleophile, amide bond formation can take place with release of imidazole.

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... 

Intramolecular general base catalysis of hycholysis (21a) was unexpected since the ester has a phenolic leaving group. Felton and Bruice (1968, 1969) reasoned that, if nucleophilic attack occurred, the leaving phenolate ion group would be properly positioned to attack the intermediate acylimidazole and thereby reverse the reaction. The normally less efficient general base reaction then becomes the favoured pathway, as in hydrolysis of acetyl salicylate (see Section 4). Likewise, Fife and McMahon (1970) explained bimolecular general base catalysis by imidazole (21b) in hydrolysis of o-(4-nitrophenylene) carbonate 3 49) by reversibility... 

The shapes of the curves in Fig. 6 are consistent with a two-step pathway, analogous to that of a hydrolytic enzyme such as a-chymotrypsin,30 in which an initial acylation burst is followed by a slow deacylation reaction. Following a fast preequilibrium binding, the first kinetic step can be attributed to acylation by substrate of the polymer imidazole residue, accompanied by simultaneous release of nit-rophenol(ate). The succeeding kinetic step would then be ascribed to hydrolysis of the acylimidazole leading to carboxylate ion and regenerated imidazole. 

In aprotic media a l-(acyloxycarbonyl)imidazole such as 16 is formed primarily which reacts to the acylimidazole and carbon dioxide. Imidazole now serves as a good leaving group and so the previously synthesized amine 6 could be added and the desired amide was formed via the usual addition elimination mechanism. One of the advantages of using this more expensive way of activation is the possibility to run the nitro reduction, acid activation and acylation in the same solvent (ethyl acetate) thus all three reactions could be telescoped into a single step during production. 

The acylimidazoles (Table 6.1, entry 10) and the A-acylpyridinium salts (entry 12) occupy additional leading positions with respect to their acylation rates. In the acylimidazoles the free electron pair of the acylated N atom is essentially unavailable for stabilization of the C=0 double bond by resonance because it is part of the 17-electron sextet, which makes the imidazole ring an aromatic compound. For a similar reason there is no resonance stabilization of the C=0 double bond in A-acylpyridinium salts in the corresponding resonance form, the aromatic sextet of the pyridine would be destroyed in exchange for a much less stable quinoid structure. 

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). 

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... 

In nucleophilic catalysis the catalytic properties are a result of the intermediate formation of a 1-acylimidazole (Scheme 27). When the ester has a good leaving group, e.g. p-nitrophenyl acetate, the effective catalyst is the imidazole neutral molecule which increases in effectiveness as the basic pKa of the heterocycle increases. Where, however, the ester has a poor leaving group, e.g. p-cresol acetate, the imidazole anion becomes involved and general base catalysis predominates. Thus, for imidazoles with pjK"a 4 catalysis by the anion is the main reaction. Imidazole is a much more effective nucleophile than other amines in this type of reaction since it is a tertiary amine with little steric hindrance, and it is able to delocalize the positive charge which results from the nucleophilic addition to... 

The mechanism of CDI-mediated acylation of amines is well understood. The first step involves a partial protonation of the basic imidazole-nitrogen, protonated A-acetylimidazole has a p a of 3.6,f l leading to an activated species which is then attacked by the carboxylate. The resulting mixed anhydride extrudes carbon dioxide giving rise to A-acylimidazole which on treatment with an amine compound leads to the desired anoide (Scheme 1). An important advantage of this method over the carbodiimide method is that the byproducts carbon dioxide and imidazole are readily and quantitatively separated from the reaction product by simple washing procedures. 

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