Imidazole-4-carboxylic acid amides

Five approaches to the synthesis of 5-amino-4-unsubstituted imidazoles (96) have been described and are summarized in Scheme 9. These are (a) reduction of 5-nitroimidazoles (97), (b) hydrolysis of carbamates and amides (98), (c) decarboxylation of imidazole carboxylic acids (99), (,d) ring transformations of 5-aminothiazoles (100), and (e) cyclisation of nitrile derivatives (101). 

Imidazole carboxylic acids are readily converted into hydrazides,436 acid halides,437 amides,437-439 and esters,439-440 and they may be reduced to alcohols with lithium aluminum hydride,441 and to aldehydes by controlled potential reduction.442 Anodic oxidation of l-methylimidazole-5-acetic acid (94) using cooled platinum electrodes yields l,2-bis(l-methylimidazol-5-yl)ethane (95).443... 

An example of a more standard, carboxyhc acid amide functionalised imidazolium salt and its apphcations come from the Ghosh group [120]. They reacted chloroacetic acid anilide with A-mesityl imidazole and obtained the respective carboxylic acid amide functionalised imidazolium salt which was reacted with sUver(I) oxide to form the corresponding silver(l) carbene complex featuring two trans-coordinated carbene ligands on the silver(I) ion (see Figure 4.39). 

The mass spectrum of I-methyl-4-nitroimidazole-5-carboxylic acid amide shows the elimination of water by an electron impact as distinct from the usual thermal process. In l,4,5-trimethylimidazole-2-carboxylic acid the principal loss is that of CO2. Subsequent loss of O, OH, and HCN was also observed (Schofield et al., p. 173). Ferguson and Schofield (pp. 172,173) have reported considerable data for imidazole JV-oxides. Thus 1-methoxy-4,5-dimethyl-2-phenylimidazole (which loses OCH3 and CH3CN from the fragment m/e 171) is readily distinguished from l,4,5-trimethyl-2-phenyl-imidazole 3-oxide (loss of O and OH). The spectra of 1-benzylimidazoles are dominated by the tropylium ion. ... 

Imidazoles from purines o-Aminocarboxylic acid amides from pyrimidine ring Carboxylic acid amides from hydroxamic acid benzyl esters... 

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). 

A V -Carbonyldiimidazole (CDI) is prepared in a convenient and safe procedure from phosgene and imidazole as a non-toxic crystalline compound (m.p. 116-118 °C).[5],[6] It reacts almost quantitatively at room temperature or by short and moderate heating with an equimolar quantity of a carboxylic acid in tetrahydrofuran, chloroform, or similar inert solvents within a few minutes to give the corresponding carboxylic acid imidazolide, which is formed under release of carbon dioxide, together with one equivalent of readily separable and recyclable imidazole.Thus, this reaction leads under very mild conditions to the activation of a carboxylic acid appropriate for transacylation onto a nucleophile with an alcohol to an ester, with an amino compound to an amide or peptide, etc. 

Amides prepared from carboxylic acids and primary amines using azolides obtained from acid chloride/imidazolea) or ketene/imidazole systems.b)... 

Amides prepared from secondary amines and acylchloride/imidazole,[391 carboxylic acid/oxalyldiimidazole,[41 ] carboxylic acid/sulfinyldiimidazole[61 ] or isolated imidazo-... 

A special case of amide formation was observed in the reaction of a furan-2-carboxylic acid with two moles of CDI and subsequent conversion with amines, hi this reaction, besides formation of the imidazolide, addition of imidazole also takes places.1-1411... 

Reactions of Phosphonic and Phosphinic Acid Derivatives.—The reactions of phos-phonic and thiophosphonic amides and chlorides with carboxylic acid chlorides and amides have been discussed.101 Dialkyl alkylphosphonates and alkyl dialkylphos-phinates may be used for the iV-alkylation of imidazoles, triazoles, and pyrroles.105... 

Irradiation of matrix-isolated imidazole-2-carboxylic acid gave the 2,3-dihydro-imidazol-2-ylidene-C02 complex (31) characterized by IR spectroscopy and calculated to lie 15.9 kcal mol above the starting material. A series of non-aromatic nucleophilic carbenes (32) were prepared by desulfurization of the corresponding thiones by molten potassium in boiling THF. The most hindered of the series (32 R = Bu) is stable indefinitely under exclusion of air and water and can be distilled without decomposition. The less hindered carbenes slowly dimerize to the corresponding alkenes. Stable aminoxy- and aminothiocarbenes (33 X = O, S) were prepared by deprotonation of iminium salts with lithium amide bases. The carbene carbon resonance appears at 260-297 ppm in the NMR spectrum and an X-ray structure determination of an aminooxycarbene indicated that electron donation from the nitrogen is more important than that from oxygen. These carbenes do not dimerize. 

Alcohol, thiol, amine, amide, carboxylic acid, guanidine, and imidazole side chains are polar ... 

Enantioselective additions of a,f)-unsaturated 2-acyl imidazoles, catalyzed by bis(oxazolinyl)pyridine-scandium(III)triflate complex, were used for the asymmetric synthesis of 3-substituted indoles. The complex 114 was one of the most promising catalysts. The choice of acetonitrile as the solvent and the use of 4 A molecular sieves were also found to be advantageous. The 2-acyl imidazole residue in the alkylation products of u,(i-unsaturated 2-acyl imidazoles could be transformed into synthetically useful amides, esters, carboxylic acid, ketones, and aldehydes (Scheme 32) [105]. Moreover, the catalyst 114 produced both the intramolecular indole alkylation and the 2-substituted indoles in good yield and enantioselectivity (Scheme 33) [106]. The complex... 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

The synthetic utility of azolides is exemplified by many examples of their use in the synthesis of carboxylic acids, esters, and thioesters, amides and thioamides, aldehydes and ketones, and phosphorylated imidazoles and benzimidazoles. 

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