1- Substituted imidazoles acylation

Advantage can be taken of the enhanced polarity of a carbon-silicon bond over that of a carbon-hydrogen bond in the displacement of 2-tri-methylsilyl groups by reaction with a number of carbonyl reagents to give imidazoles substituted at C-2 by secondary alcohol, acyl, aroyl, ester, and amide functions. ... 

Amino acid residues, except hydrocarbon chains, may provide nucleophilic sites (electron-rich centers) or electrophilic sites (electron-deficient centers) for chemical modifications. Electron-rich centers include sulfur nucleophiles (thiol of Cys and thioether of Thr), nitrogen nucleophiles (e-amino of Lys, imidazole of His and Guanidyl of Arg), oxygen nucleophiles (phenolic of Tyr, carboxyl of Asp and Glu and hydroxyl of Ser and Thr), and carbon nucleophile (a-position of indole ring of Trp), with an increasing nucleophilicity in that order. They provide nucleophilic sites for alkylation (nncleophilic substitution), acylation, addition and oxidation at pH near or above their pK values. Electron-deficient centers include ammonium cation of Lys, guanidiiun cation of Arg and imidazolium cation of His. They provide electrophilic sites for metalation and reduction at pH near or below their pK values. 

One main issue for Moore s procedure is that the reaction needs a substrate as solvent. In 1996, Murai and his researchers solved this challenge [53, 54] by carrying out the coupling reaction with imidazoles in toluene, under 20 bar of CO, at 160 °C. After 20 h, various substituted imidazoles were acylated under the assistant of 4 mol% of Ru3(CO)i2- The reaction proceeded with excellent linear selectivity. Besides imidazoles, 1-methylpyrazoles were also acylated in good... 

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). 

These Br nsted-type plots often seem to be scatter diagrams until the points are collated into groups related by specific structural features. Thus, p-nitrophenyl acetate gives four separate, but parallel, lines for reactions with pyridines, anilines, imidazoles, and oxygen nucleophiles.Figure 7-4 shows such a plot for the reaction of trans-cmmm c anhydride with primary and secondary aliphatic amines to give substituted cinnamamides.All of the primary amines without substituents on the a carbon (R-CHi-NHi) fall on a line of slope 0.62 cyclopentylamine also lies on this line. If this line is characteristic of normal behavior, most of the deviations become qualitatively explicable. The line drawn through the secondary amines (slope 1.98) connects amines with the structure R-CHi-NH-CHi-R. The different steric requirements in the acylation reaction and in the model process... 

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 ... 

Illustrative yields for the two acylation methods catalyzed by -substituted imidazoles are given in the following tables. 

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...

Hubbard and Kirsch (1972) have recently proposed that histidine may act as a nucleophile in a-chymotrypsin acylation reactions of esters having a good leaving group (jO-nitrophenol). This suggestion was based on a similarity in p-value for acylation by p-substituted nitrophenyl and dinitrophenyl benzoates and nucleophilic attack on these compounds by imidazole, in contrast with less positive p-values for hydroxide ion catalysis. Hammett p-values for hydrolysis of substituted phenyl esters are given in Table 6 and show little apparent trend. The values for hydroxide ion and alcoholate ions are... 

Starting from acylated 2-azidomethylbenzimidazoles (145), an additional imidazole ring can be condensed by transformation of the azido group with tri-n-butylphosphane into the appropriate iminophosphorane intermediate 146. After extrusion of phosphane oxide, cyclization occurs to the 1-substituted 4//-imidazo[l,5-a]benzimidazole 147 (Scheme 58) (89T1823 94S1197). 

This method accommodates aryl aldehydes with both electron-deficient and electron-rich aryl substitutents. Acetaldehyde is also a competent couphng partner, providing the corresponding amido ketone in 62% yield. Acyl substitution of the tosyl amide varies to include hydrogen, methyl, tert-butoxy, and phenyl producing the desired a-amido ketones in moderate to high yields. Expansion of this methodology to synthesize di- and tri-substituted imidazoles was reported by Murry and co-workers (Scheme 7) [54]. 

Treatment of 2-mercaptoimidazoles 33 with a-halo ketones gives 2-(acyl-alkylthio)-imidazoles 34, which can be cyclized to substituted imidazo[2,l-fejthiazoles 35 [86HC(46)77]. A one-step synthesis from 33 with a-halo ketones is also successful. 

Reaction of methyl 3-(dimethylamino)-2-isocyanoacrylate (Ri = Me) with acyl chlorides gave 2-acyl-4-(dimethylaminomethylene)-5(477)-oxazolones 375. ° The same reaction with arenesulfenyl chlorides gave either 2-arylthio-4-(dimethylami-nomethylene)-5(477)-oxazolones 376 or an unsaturated 5(477)-oxazolone 377 containing an imidazole at C-2 depending on the substitution present in the arenesulfenyl chloride. Nitroarenesulfenyl chlorides favored 376. ° ° Selected examples of 372, 375, and 376 are shown in Table 7.33 (Fig. 7.44 Scheme 7.121). 

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