Azolides imidazolides

Based on these reactivity studies on azolides, the imidazolides do not represent the most reactive members of the azolide family. In most cases, however, they are sufficiently reactive to undergo nucleophilic reactions leading to the desired products. Due to the easy and economical availability of imidazole, imidazolides are by far the most commonly used azolides for synthetic purposes. If, on the other hand, imidazolides are not sufficiently reactive in a specific case, one of the more active reagents from the arsenal of azolides might be used, as, for example, an azolide derived from a triazole or a tetrazole. 

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). 

In the preceding sections it has been shown — using the imidazolides as examples - that azolides can be prepared easily by a number of different reaction pathways. In view of the higher or lower reactivities of other members of the azolide family it becomes evident that this class of compounds contributes to a powerful arsenal in synthetic organic chemistry. The various reactions these azolides undergo are dealt with in detail in the chapters that follow. Since imidazolides are utilized for most of the azolide reactions, certain additional information is provided here for this particular group of the azolides. 

In review articles[2] published about three decades ago, data were presented for about 100 imidazolides. In the meantime azolide reactions have developed to the point of becoming standard reactions, based mainly on imidazolides, so it seemed reasonable to underscore once again the structural diversity of the group of azolides. This is done mainly in the context of the following syntheses, most of which were essentially developed within our research group. 

The reaction of a carboxylic acid with N,Af -carbonyldiimidazolellH33 (abbreviated as CDI), forming an imidazolide as the first step followed by alcoholysis or phenolysis of the imidazolide (second step), constitutes a synthesis of esters that differs from most other methods by virtue of its particularly mild reaction conditions.t41,[5] It may be conducted in two separate steps with isolation of the carboxylic acid imidazolide, but more frequently the synthesis is carried out as a one-pot reaction without isolation of the intermediate. Equimolar amounts of carboxylic acid, alcohol, and CDI are allowed to react in anhydrous tetrahydrofuran, benzene, trichloromethane, dichloromethane, dimethylformamide, or nitromethane to give the ester in high yield. The solvents should be anhydrous because of the moisture sensitivity of CDI (see Chapter 2). Even such unusual solvent as supercritical carbon dioxide at a pressure of 3000 psi and a temperature of 36-68 °C has been used for esterification with azolides.[6]... 

Preparation of Esters Using Azolides Other than Imidazolides... 

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 azolide method has also been used for the synthesis of polyamides and polyimides. These can be obtained by several routes First by condensation of two dihomofunctional components (dicarboxylic acid diimidazolides and diamines), secondly by condensation of a heterodifunctional compound (amino carboxylic acid and CDI), or through reaction on a polymer (for example, polymeric carboxylic acid imidazolides and amines). 

Polyamides can also be prepared by the reaction of polyamines with azolides, as shown by the following reaction of nucleosil—300 (7 NH2), a spherical silica derivatized with propyl amine, with lecithin imidazolide 1623... 

Besides CDI, other azolides such as A N -oxalyldiimidazole, AyST-carbonyldi-1,2,4-triazole, MN -oxalyldi-1,2,4-triazole, and phosphorous and phosphoric imidazolides have been used in the synthesis of peptide bonds, as displayed in Table 5-4. 

Using azolides, thiazolidindiones can be prepared by condensation of alkoxy-carbamoylimidazoles obtained in situ from O-alkylhydroxylamines and CDI with thio-glycolic acid methyl ester or the imidazolide of thiolactic acid obtained in situ from thiolactic acid and CDI [121]... 

Analogously to the phosphorylation of alcohols with phosphoric azolides the phos-phinylation is carried out by means of phosphinic azolides (CH2CI2/C2H5OC2H5). In the following case a I2/C2H5OC2H5) protonated diphenylphosphinic imidazolide is used to give the allylic diphenylphosphinic esters in good yields ... 

Like N-activated esters, N-activated azolides can be used in azapeptide synthesis. These include imidazolides[30 33] and 1,2,4-triazolidesJ34 These intermediates 14 can be synthesized by addition of the corresponding heterocycle 10 to a-isocyanato carboxylates Ilf30 31 or from the amino component 12 and l,T-carbonyldiimidazole (13).[32 33]... 

The rates of hydrolysis, alcoholysis, and aminolysis of imidazolides (such as 1-acetylimidazole) are readily followed spectrophotometri-cally, since the azolides normally show characteristic intense absorption bands at longer wavelengths than the products.190,191... 

UV spectroscopy has been applied to studies of 2,4,5-triarylimidazole radicals, imi-dazolones and various thioimidazoles. In addition, the rates of hydrolysis, alcoholysis and aminolysis of imidazolides such as 1-acetylimidazole can be determined readily since such azolides show characteristic intense absorptions at wavelengths longer than those of the imidazole products. In the C-acyl- and C-aroyl-imidazoles, those which have the carbonyl group attached at C-2 exhibit a bathochromic shift of about 20 nm, while in m- and p-substituted 2-aroylimidazoles intense absorptions (log,o e 3.5-4.3) appear in the 295-309 nm region, with slightly less intense peaks at about 233-266 nm (74CRV279). 

Probably the most important property of these compounds is the propensity of iV-acyl-imidazoles and -benzimidazoles (as well as other azoles) to become involved in reactions which result in acylation of an attacking nucleophile. The compounds are unlike other tertiary amides in that there is little or no contribution from resonance structures of type (251) to the hybrid (Scheme 142) hence the positive nature of the carbonyl carbon is undiminished. The electron pair on the annular nitrogen is part of the aromatic sextet. The compounds are known as azolides generally, and more specifically as imidazolides . Because the annular nitrogens are not directly adjacent imidazolides are more reactive than the corresponding pyrazolides. 

Staab introduced azolides as versatile reagents in organic synthesis. The reaction of carbonyldiimid-azolide with carboxylic acids produces imidazolides under mild conditions which can be converted by the action of hydrogen halides to acid halides in high yield (equation 20). The method does not even require the isolation of the imidazolides, but can be carried out as a one-pot synthesis. The possibility of carrying out this reaction at low temperatures allows the preparation of temperature sensitive compounds. Formyl chloride, which decomposes at -40 °C, has been prepared in this way. 

Hydrolysis rates have been measured for a number of azolides in order to compare the effects of extra annular nitrogens and benzannelation. Rate constants for A-acyl compounds are larger than for the corresponding thioacyl analogues, and benzimidazolides are less reactive than imidazolides <83BAU1525,83BAU1934). Hydroxylated surfactant micelles are powerful catalysts for the deacylation of 1-acylimidazoles under neutral conditions <89JCS(P1)1697>. 

Tetracoordinate organophosphorus compounds containing azolide ligands (17a-f) 18 and 19 react in a fully chemoselective manner with benzoyl fluoride (18). The corresponding P—F compounds 20 are formed in quantitative yield. Nucleosid-3 -yl or 5 -yl phosphorofluo-ridates 20 and difluoridates 24 and 26 are available via imidazolidates... 

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