Acylation of imidazoles

Direct acylation of imidazole can also be achieved with carboxylic acid anhydrides. For example, if imidazole is dissolved at room temperature in acetic anhydride, crystals of iV-acetylimidazole begin to separate out after removal of excess anhydride and the resulting acetic acid under vacuum at 60 °C, nearly pure iV-acetylimidazole (m.p. 100-102 °C) is obtained in almost quantitative yield.[4]... 

The preparation of imidazolides by acylation of imidazole with acid chlorides is sometimes limited by the inaccessibility or instability of the required acid chlorides (e.g., formyl chloride, highly unsaturated acid chlorides, etc.) or by side-reactions in the case of multifunctional systems. For these reasons and due to the availability of an easy and convenient procedure involving very mild conditions, imidazolides today are usually prepared directly from the corresponding carboxylic acids with jV -carbonyldiimida-zole (CDI) or one of its analoga (see page 16). Use of these reagents has become more and more the preferred method for activation of carboxylic acids to azolides and their further transacylation to esters, amides, peptides, etc. (see subsequent Chapters). 

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%)). 

Direct acylation of AT-protected imidazole involves formation of an AT-acyl azolium salt, which is then deprotonated at C-2 followed by rearrangement of the acylazolium ylide to the 2-acylated imidazole (for mechanism and a number of applications, see CHEC-II(1996)). An example is shown in Scheme 82 N-acylation of imidazole 350 followed by 2-deprotonation of the azolium cation, then migration of the acyl group to C-2 gives product 351 <2005JME2154>. 

Kinetic studies of the acylation of imidazoles with benzoyl halides and sulfonyl halides have been carried out. In acetonitrile, benzoyl fluoride reacts with imidazole in a mixed third- and fourth-order reaction i.e., the rate-determining transition state contains the acid fluoride and two or three molecules of imidazole. With benzoyl chloride in benzene a second-order equation is followed similar to the aroylation of anilines ... 

The acylation of imidazoles under Schotten-Baumann conditions has been studied. ... 

Kinetic studies of the acylation of imidazoles with benzoyl halides and sulfonyl halides have been carried out. In acetonitrile, benzoyl fluoride reacts with imidazole in a mixed third- and fourth-order reaction ... 

Acylation of imidazole produces A-acylimidazoles via loss of proton from the initially-formed A-3-acyl-imidazolium salt. A-Acyl-imidazoles are even more easily hydrolysed than A-acyl-pyrroles moist air is sufficient. The ready susceptibility to nucleophilic attack at carbonyl carbon has been capitalised upon commercially available l,l -carbonyldiimidazole (CDI), prepared from imidazole and phosgene, can be used as a safe, phosgene synthon, and also in the activation of acids for formation of amides and esters via the A-acyl-imidazole. ... 

Direct C-acylation of imidazole and pyrazoles in Friedel-Crafts reactions were previously unknown and it was predicted that this is not possible at all. It was previously necessary to rely on other more expensive methods of preparation. This direct acylation in the gas phase has been made possible by zeolite catalysts [15]. For example, if a mixture of 2-methylimidazole and acetic acid or acetic anhydride is reacted at 400 °C over a pentasil zeolite, the result is a conversion of 63 % and a selectivity of 85 % for 2-methyl-4-acetylimidazole. 

By the same token, acylation of imidazole produces A>acylimidazoles via loss of proton from the initially formed A -3-acylimidazolium salt. A device which has been employed frequently for the synthesis of 1-acylimidazoles is to use two mol equivalents of the heterocycle for one of the acylating agent, the second mole of imidazole serving to deprotonate the first-formed A-acylimidazolium salt. 

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. 

Cefpimizole (51) appears to be less active in vitro than cefotaxime and cefoperazone and to have a somewhat narrower activity spectrum although some strains of Pseudomonas are susceptible. It is not orally active, but its performance in vivo appears superior to what would be expected from its in vitro data. Its synthesis begins by acylation of cephaloglycin (48) with the bis acid chloride of imidazole-4,5-dicarboxylic acid (49) to give amide 50. The acetyl moiety at C-3 of this intermediate is displaced with 4-pyridineethanesulfonic acid and sodium iodide to give cef-pimazole (51) [16]. 

Acylation of the common starting 3,4-diaminonitrobenzene with furoyl chloride proceeds on the more basic amino group meta to the nitro group to give 140. This is then cyclized to imidazole 141 by means of acetic anhydride. Reduction of the nitro group (142), followed by condensation with ethyl acetoacetate affords furodazole (143) [26]. 

Acylation of 2-aroylimidazoles 492 gave 1-acyl-4,5-disubstituted imidazoles 493, whose cyclocondensation with hydrazine hydrate gave (88JIC784) imidazotriazines 494. 

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 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 ... 

Table 3-4. Acylation of 4-methyl-2-pentanol with acetic anhydride to produce the acetate, with the indicated N-substituted imidazoles as catalysts. 1451...

Table 3-5. Imidazole catalyzed acylation of 3-phenyl-2-propanol with acid chloride RC0C1.[145]...

Improved selective acylation of 4,6 4, 6 -di-0-benzylidene-a,a-trehalose was achieved in acetone by the following method, in which a gentle liberation of -acyl-imidazole occurs on the conversion of benzotriazolyl-iV-oxytris(dimethylamino)phos-phonium hexafluorophosphate with the carboxylic acid in the presence of triethylamine and addition of imidazole 1199 ... 

Ester formation from polysaccharides can be achieved in several ways First by acylation of the OH groups with carboxylic or sulfonic acid azolides, second by converting the OH groups with imidazole carboxylates into carbonates, and third by reaction of an acid leash on the polysaccharide with an alcohol by means of CDI or analogous azolides. The acid leash might, for example, be a succinate attached to the polysaccharide. 

In the reaction of an aminoalcohol with a methyl imidazole-AT-carboxylate or tert-butyl imidazole-AT-peroxycarboxylate, selective acylation of the amino function can be achieved11903 to give the carbamate and peroxycarbamate, respectively, the hydroxy groups of which can be further acylated ... 

The acylation of the carbanions derived from nitroalkanes with acyl imidazoles or alkoxy-carbonylimidazoles takes place at the carbon atom to yield a-nitro ketones or a-nitro esters, respectively (Eq. 5.10).21 The lithium salts of nitroalkanes were isolated and used in THF or DMSO in the original procedure. Later, potassium salts generated in situ on treatment with r-BuOK in DMSO are reactive enough to give a-nitro ketones in good yield (Eq. 5.11).22... 

Although acyl imidazoles can be replaced by phenyl esters in some cases,23 acyl imidazoles are more effective for the acylation of nitroalkanes. A combination of diethyl phosphorcyani-dates and triethylamime allows the direct C-acylation of nitromethane by aromatic carboxylic... 

---