Azolides reactivity

The compounds referred to as azolides are heterocyclic amides in which the amide nitrogen is part of an azole ring, such as imidazole, pyrazole, triazole, tetrazole, benzimidazole, benzotriazole, and their substituted derivatives. In contrast to normal amides, most of which show particularly low reactivities in such nucleophilic reactions as hydrolysis, alcoholysis, aminolysis, etc., the azolides are characterized by high reactivities in reactions with nucleophiles within the carbonyl group placing these compounds at about the same reactivity level as the corresponding acid chlorides or anhydrides. 11... 

The reactivity of the various azolides as well as the order of reactivities within this group can be explained on the basis of the quasi-aromatic character of the azole rc-system the lone electron pairs on the acyl-substituted nitrogens N(l) are part of the cyclic tc-system of the azole units, leading to a partial positive charge on N(l) that interferes with the normal carboxamide resonance and exerts an electron-withdrawing effect on the... 

Thus, the family of azolides represents a versatile system of reagents with graduated reactivity, as will be shown in the following section by a comparison of kinetic data. Subsequent chapters will then demonstrate that this reactivity gradation is found as well for alcoholysis to esters, aminolysis to amides and peptides, hydrazinolysis, and a great variety of other azolide reactions. The preparative value of azolides is not limited to these acyl-transfer reactions, however. For example, azolides offer new synthetic routes to aldehydes and ketones via carboxylic acid azolides. In all these reactions it is of special value that the transformation of carboxylic acids to their azolides is achieved very easily in most cases the azolides need not even be isolated (Chapter 2). 

The azolide concept can be extended further to other TV-substituted azoles, such as N-sulfonyl- or TV-phosphorylazoles, for which an analogous gradation of reactivity is observed depending on the choice of the specific azole system. The reactions of these compounds are dealt with in Chapters 10 and 12, respectively. 

Not only this manifold and graduated reactivity of azolides, but also the facile preparation and generally very mild conditions for their reactions make this group of compounds a useful addition to the repertory of synthetic organic chemistry. Starting from the first synthetic applications described by our group in the late 50s and early 60s, azolides attracted increasing attention, and continues still to do so. 

Substitution on the carbon atoms of the azole rings has the expected effect electron-withdrawing substituents such as nitro or halogen increase the reactivity of the azolides, whereas alkyl substituents lead to a decrease in transacylation rates. 101... 

The same order of reactivity observed for the hydrolysis of A-acetylazoles (Table 1-1) is also found for azolides with other N-acyl groups. Exceptional, however, are the Af-formylazoles A-formylimidazole in neutral water is hydrolyzed immeasurably rapidly even in a 1 1 mixture of water/tetrahydrofuran at 20.6 °C the half-life is in the order of only 3.7 min, approximately a factor of 100 faster than that for A-acetylimidazole under the same conditions. 131... 

Following the adoption of azolides as valuable and versatile reagents in synthetic organic chemistry,[1] and also in the context of their potential role in biochemistry, a great many kinetic, mechanistic, and theoretical papers appeared concerning this group of compounds and their properties. Some of these papers[18],[20] are very useful for a better understanding of the reactivity of azolides. 

For the mechanism of azolide hydrolysis under specific conditions like, for example, in micelles,[24] in the presence of cycloamyloses,[25] or transition metals,[26] see the references noted and the literature cited therein. Thorough investigation of the hydrolysis of azolides is certainly important for studying the reactivity of those compounds in chemical and biochemical systems.[27] On the other hand, from the point of view of synthetic chemistry, interest is centred instead on die potential for chemical transformations e.g., alcoholysis to esters, aminolysis to amides or peptides, acylation of carboxylic acids to anhydrides and of peroxides to peroxycarboxylic acids, as well as certain C-acylations and a variety of other preparative applications. 

In addition to CDI, just as in the family of the carboxylic acid azolides (see the preceding Section), changes in the azole units have permitted preparation of a whole series of CDI analogues with graduated reactivities A V7 -carbony ldipyrazole,[311 NJVf-carbonyldi-1,2,4-triazole,[32] as well as Af,Af -carbonyldibenzimidazole and A /V -car-bonyldibenzotriazole.t33]... 

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. 

In analogy to the reaction of CDI with carboxylic acids, the even more reactive NJf -carbonyldi-1,2,4-triazole 5bl has been used instead of CDI in cases where specific structural effects require a higher reactivity of the azolide. On the other hand, the example of the last paragraph of the preceding section showed that A -carbonyldi-benzimidazole 151 141 and AyV -carbonyldibenzotriazole 151 have been useful for the syntheses of azolides with reduced reactivities when these are essential and sufficient for the specific reaction in question. 

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. 

The UV-spectra of azolides have already been discussed in the context of hydrolysis kinetics in Chapter 1. Specific infrared absorptions of azolides were mentioned there as well increased reactivity of azolides in nucleophilic reactions involving the carbonyl group is paralleled by a marked shift in the infrared absorption of the corresponding carbonyl bond toward shorter wavelength. For example, for the highly reactive N-acetyl-tetrazole this absorption is found in a frequency range (1780 cm-1) that is very unusual for amides obviously the effect is due to electron attraction by the heterocyclic sys-tem.[40] As mentioned previously in the context of hydrolysis kinetics of both imidazo-... 

Even tetrazolides, which are among the most reactive azolides, have been applied in esterifications. 

A modification of this method, related to the Beckmann rearrangement, entails treatment of a ketoxime with one equivalent of CDI, then four to five equivalents of a reactive halide such as allyl bromide or methyl iodide (R3X) under reflux in acetonitrile for 0.5-1.5 h. Quatemization of the imidazole ring effectively promotes the reaction by increasing the electron-withdrawing effect. The target amides then are obtained by hydrolysis. High yields, neutral conditions, and a very simple procedure make this modification of the synthesis of amides by azolides a very useful alternative. 1243... 

The mesoionic azolides are reported to be relatively stable toward hydrolytic decomposition, but more reactive against amines than the corresponding imidazo-lides.[194] -Protection of the amino compounds (for example by the Boc group) takes place smoothly at room temperature in about one to five hours and with high yield. The amino acids are introduced as sodium salts in aqueous acetone. 

The condensation reactions are preferentially carried out in pyridine. As reactive species for phosphorylation of the nucleoside R OH (synthesis of a phosphortriester), the phosphoric acid azolide has been assumed. The mixed phosphoric sulfonic anhydride and a pyrophosphate tetraester have been suggested as intermediates leading to the phosphoric acid azolide. 

Ref. [152] discusses the transformation of a dinucleoside pyrophosphate into a reactive azolide with an azole (e.g., 3-nitro-1,2,4-triazole or tetrazole). With quinoline-8-sulfonyl chloride the concomitantly formed phosphordiester can be converted back to the dinucleoside pyrophosphate (see scheme on the next page). 

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. 

Among the most useful of these azolides is l,l -carbonyldiimidazole (253). This compound is extremely reactive towards nucleophilic reagents because the carbonyl group is subject to electron withdrawal from both sides. Also, although it is very rapidly hydrolyzed by water at room temperature with vigorous carbon dioxide evolution, tihe compound is crystalline, and much more easily handled than phosgene which has similar reactivity. In the formation of 1-acylimidazoles compound (253) reacts in equimolar proportions with a carboxylic acid in an inert solvent to give practically quantitative yields. This reaction comprises a two-step mechanism (Scheme 145) in which the carboxylic acid reacts initially... 

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