IV-Acylimidazole

Chemical modifications of proteins (enzymes) by reacting them with iV-acylimidazoles are a way of studying active sites. By this means the amino acid residues (e.g., tyrosine, lysine, histidine) essential for catalytic activity are established on the basis of acylation with the azolides and deacylation with other appropriate reagents (e.g., hydroxylamine). 

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]... 

In the reaction of 1,3-dithiane oxide anions with iV-acylimidazoles the optimum procedure involved a sodium hexamethyldisilazide/butyllithium mixture as base [101]... 

Acyl halides, activated esters, carboxylic anhydrides and iV-acylimidazoles react with alkylidenephos-phoranes to yield acylated ylides. " - " ... 

As mentioned earlier (Section IV,B,l,a) iV-acylimidazoles, although resistant to quatemization by virtue of the electron-withdrawing nature of the acyl group, can be methylated by reagents such as methyl fluorosulfo-nate and trimethyloxonium fluoroborate. ° ° ... 

Acylation reactions which lead ultimately to 2-acylimidazoles will be discussed as electrophilic substitutions at ring carbon atoms (Section 4.07.1.4.6) in spite of the almost certain intermediacy of the iV-acyl compounds. 

Such synthetic approaches can only be valid if the other heterocycles are readily available, or if their transformations lead to imidazoles difficult to make by other means. It is certainly important to be able to aromatize imidazolines since a number of ring-synthetic procedures lead to reduced imidazoles. 4-Aminoisoxazoles are sources of a-acylaminoenaminones which cyciize with bases to give 4-acylimidazoles. Oxazole-imidazole conversion has largely historical importance, but it is also implicated in some ring-synthetic procedures (e.g. the Bredereck method, see Chapter 5). Transformations of benzofuroxans into 2-substituted benzimidazole iV-oxides have some synthetic importance. Few, if any, ring contractions appear to have major application. 

Acylainino-4-acylimidazoles have been made from 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl reagents (see Section 2.2.1 and Scheme 2.2.5). 4(5)-Acylimidazoles can be derived from 4-acylaininoisoxazoles (see Section 6.1.2 and Scheme 6.1.3). (See also the discussion in Section 2.2.1 on 4-acylimidazole synthesis.) 5-Acyl-l-arylimidazoles can be made from or-oxoketene-SJV-acetals and nitrosoaromatics (see Section 3.2 and Scheme 3.2.5), and 4-acyl-imidazoles by nitration of 1,3-dicarbonyl compounds in their enolic forms, reduction to iV-alkenylformamides and subsequent cyclization (see Section 3.2 and Scheme 3.2.4). Examples have also been isolated from reactions of 2-oximino-l,2,3-tricarbonyls and amines (see Section 4.1 and Scheme 4.1.7), from compounds such as 3-chloro-4,4-dimethoxy-2-butanone and 3,4-disubstituted 3-buten-2-ones (see Section 4.3 and Scheme 4.3.5), and by ultraviolet irradiation of 1-alkenyltetrazoles which bear an acyl group conjugated with the exocyclic double bond (see Section 6.1.2.3). 

Acylation reactions leading ultimately to 2-acylimidazoles will be discussed in Section IV,B,2,a. 

Hoskins and Crout have synthesized C-9 monoesters of retronecine (127) in reasonable yields by using iV,N -dicyclohexylcarbodiimide as the coupling reagent.The use of AT,JV -carbonyldiimidazole, with prior formation of the acylimidazole, was necessary with aj8-unsaturated acids and bulky a-trisubstituted acids. Subsequent esterification at C-7 of the retronecine ester with a suitable acid chloride produced unsymmetrical diesters of retronecine. 

N-Acylimidazoles (azolides) have continued to provide a synthetic source of acid derivatives,and the various olysis reactions of these compounds have been studied. - The reactions of acetyl-imidazolium ions with amines have been found to depend largely on amine basicity. The thermal decarboxylation of Af-alkoxycarbonylimid-azoles provides a convenient synthetic route to iV-alkylimidazoles. At low temperatures the -isomer of 1-acetylimidazole predominates. ... 

For this reason, acylimidazoles are much more reactive than Af,iV-dialkylamides and, like acid anhydrides or acid chlorides, are able to transfer the acyl group to water, alcohols, phenols and amines ... 

Activation of Carboxylic Acids Synthesis of Acyl Imidazoles. iV,AA-Carbonyldiimidazole (1) converts carboxylic acids into the corresponding acylimidazoles (2) (eq 1). The method can be applied to a wide range of aliphatic, aromatic, and heterocyclic carboxylic acids, including some examples (such as formic acid and vitamin A acid) where acid chloride formation is difficult. The reactivity of (2) is similar to that of acid chlorides, but the former have the advantage that they are generally crystalline and easily handled. Isolation of (2) is sirr5>le, but often unnecessary further reaction with nucleophiles is usually performed in the same reaction vessel. Conversion of (2) into acid chlorides (via reaction with HCl), hydrazides, hydroxamic acids, and peroxy esters have all been described. Preparation of the more irr5)ortant carboxylic acid derivatives is described below. 

While Friedel-Crafts acylations do not occur readily with imidazoles, quatemization can lead to 2-acylimidazoles. The reaction of iV-phenyl imidazole with benzoyl chloride and EtsN in MeCN provides first the N-... 

Reagents i, Oj ii, AcaO-NaOAc iii, HO(CH2)aOH-H+ iv, NaOH v, LKOBuOsAlH on acylimidazole vi, RuOa-NaI04 vii, NaOMe viii, CF3CO3H, Na,HP04 ix, C5HiiCOCH2PO(OMe)a-NaH... 

Acyl Imidazole Formation. iV-(Trimethylsilyl)imidazole has proven to be a useful reagent in the synthesis of 1-acylimidazoles and amides under mild conditions. Aroyl chlorides react rapidly to form 1-aroylimidazoles which, after removal of the generated chlorotrimethylsilane, were used without further purification... 

Aldehydes and Ketones from Carboxylic Acids. Reduction of the derived acylimidazole (2) with Lithium Aluminum Hydride achieves conversion of an aliphatic or aromatic carboxylic acid to an aldehyde (eq 6). Diisobutylaluminum Hydride has also been used, allowing preparation of a-acylamino aldehydes from iV-protected amino acids. Similarly, reaction of (2) with Grig-nard reagents affords ketones, with little evidence for formation of tertiary alcohol. 

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