Amidation, imidazolide

Imidazolides can also be activated by N-alkylation with methyl triflate.116 Imidazolides react with alcohols on heating to give esters and react at room temperature with amines to give amides. Imidazolides are particularly appropriate for acylation of acid-sensitive materials. 

Since formamide is a weak nucleophile, the use of imidazole or 4-dimethylaminopyridine (DMAP) is necessary for acyl transfer to formamide via an activated amide (imidazolide) or acylpyridinium ion. As Scheme 22 illustrates, the reaction starts with the oxidative addition of aryl bromide 152 to Pd(0) species, followed by CO insertion to form acyl-Pd complex 154. Imidazole receives the aroyl group to form imidazolide 155 and liberates HPdBr species. Then, imidazolide 155 reacts with formamide to form imide 156. Finally, decarbonylation of imide 156 gives amide 157. In fact, the formations of imidazolide intermediate 155 and imide 156 as well as the subsequent slow transformation of imide 156 to amide 157 by releasing CO were observed. This mechanism can accommodate the CO pressure variations observed during the first few hours of aminocarbonylation. When the reaction temperature (120 °C) was reached, a fast drop of pressure occurred. This corresponds to the formation of the intermediary imide 156. Then, the increase of pressure after 3 h of reaction was observed. This phenomenon corresponds to the release of CO from imide 156 to form amide 157. ... 

An amide anion will prefer substitution if its basicity is sufficiently lowered by resonance, and can be useful where the neutral nitrogen is unreactive or otherwise unsuitable. Quaterniza-tion cannot be prevented in the alkylation of even free neutral imidazole, but an imidazolide anion will match with only one of the electrophilic sites terminating dimethylene spacer on polystyrene. 

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. 

A mixed anhydride probably is formed as an intermediate which is cleaved inter-molecularily by the imidazole set free in the first step. For example, reaction with the compound in which R1 =thymyl and R2 = C6H5 yielded quantitatively O-thymylphos-phoric imidazolide and benzoylimidazole.[25 Phosphoryldiimidazoles are also used as condensing agents for the synthesis of amides and peptides, as well as for phosphorylations (see Chapters 4, 5 and 12). 

Amides are conveniently prepared by the azolide method, usually in two steps first by reaction of the free carboxylic acid at room temperature with CDI in a 1 1 molar ratio under elimination of C02 the carboxylic acid imidazolide is formed after C02 evolution has ceased an equimolar amount of amine is then added.[1]... 

The reaction is complete after one to two hours at room temperature. Amides are usually obtained in very good yields. A wide range of solvents can be used, including tetrahydrofuran, chloroform, acetonitrile, dimethylformamide, and benzene. 21 The reaction can also be carried out in the melt. Examples have been collected in the following pages. In some cases the intermediate imidazolides were isolated, but the reactions are preferably carried out as one-pot reactions . 

For the preparation of sterically crowded amides amino magnesium salts have been recommended for the reaction with imidazolides in order to increase the nucleophilicity of the amine moiety. Amino magnesium salts are prepared from the appropriate amines and ethyl magnesium bromide in tetrahydrofuran [90]... 

Examples are given in Table 4—1 for the synthesis of amides of AT-protected amino acids by means of imidazolides and triazolides (where Z and Boc represent the protecting groups benzyloxycarbonyl and terf-butoxycarbonyl) ... 

The reaction of an amino acid imidazolide with a diamino compound could be directed so that a mono amide was obtained in good yield,[1091 as shown by the following example ... 

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... 

In the context of synthesis and exchange reactions of biodegradable drug-binding matrices, starch trisuccinic acid was loaded via imidazolides with amines such as n-butylamine, morpholine, 4-aminobenzoic acid, or 3,4-dihydroxyphenylalanine to prepare the respective amides in high yields [160] an example is presented below. 

Hydrazides of carboxylic acids can be prepared by the imidazolide method in a similar manner as amides. 2 These syntheses are also conveniently carried out as one-pot reactions (room temperature, 12 h) ... 

The broad use of A -carbonyldiimidazole (CDI) for the synthesis of amide and peptide linkages became a routine method only in the early sixties. JV-Protected amino acids were treated at room temperature with an equimolar amount of CDI to give imidazolides. Anhydrous tetrahydrofuran, dimethoxyethane, dichloromethane, pyridine, dimethylfor-mamide, and diethyl phosphite were utilized as solvents. In the second step the esters of amino acids, their hydrochlorides, or sodium salts were added to yield the peptide after several minutes or hours of reaction time. 

Nucleotide imidazolides react with amino components to produce the corresponding nucleotide amides ... 

Phenols can be converted with trifluoromethylsulfonic imidazolide in the presence of sodium hydride into the corresponding trifluoromethylsulfonates, which react with potassium amide/ammonia to give aromatic amines. 15]... 

Having obtained stable rotamers of compound 6, Staab and Lauer (45) extended the work to see whether rotamers of amides that normally have lower barriers as a result of a disfavored canonical structure 2 due to electronic effects are also isolable. They found that the rotamers of 2,4,6-trwm-butylbenzoben-zimidazolide (7) were isolable, but those of the corresponding imidazolide (8) were not. The barrier to rotation of the former in hexachlorobutadiene solution was 28.7 kcal/mol for the E Z process at 80°C. The barrier to rotation of the latter was estimated at less than 23 kcal/mol. It is possible to attribute this result to electronic effects that raise the ground state energy, because the aromatic... 

Two factors are responsible for the high reactivity of the imidazolides as acylating reagents. One is the relative weakness of the amide bond. Because of the aromatic character of imidazole, there is little of the N —> C=0 delocalization that stabilizes normal amides. The reactivity of the imidazolides is also enhanced by protonation of the other imidazole nitrogen, which makes the imidazole ring a better leaving group. 

Alcoholysis of amides is possible but is seldom performed,678 except for the imidazolide type of amide (101). 

This synthesis also gives a small glimpse at the chemistry of heterocyclic compounds. Most active compounds in today s pharmaceuticals or agrochemicals include heterocycles, as well as most vitamins and natural products. The chemistry of heterocycles is thus very important and lectures or textbooks should be consulted.6 Formation of amide bonds also plays a large role in this problem. It was demonstrated that the strong amide bond can be formed from an amine and a carboxylic acid only after the acid has been activated. This can be done by transformation into the carboxylic halide or imidazolide or by application of an activating agent developed for peptide synthesis. 

The 6th rank in terms of acylation reactivity that is attributed to the acyl imidazolides in Table 6.1 (entry 10) is also plausible. In the acyl imidazolides, 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 -electron sextet, which makes the imidazole ring an aromatic compound. This is why acyl imidazolides, in contrast to normal amides (entry 2 in Table 6.1) can act as acylating agents. Nevertheless, acyl imidazolides do not have the same acylation capacity as acylpyridinium salts because the aromatic stabilization of five-mem-bered aromatic compounds—and thus of imidazole—is considerably smaller than that of six-membered aromatic systems (e. g., pyridine). This means that the resonance form of the acyl imidazolides printed red in Table 6.1 contributes to the stabilization of the C=0 double bond. For a similar reason, there is no resonance stabilization of the C=0 double bond in N-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. 

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