Imidazolides of Carboxylic Acids

The reaction of imidazolides of carboxylic acids with sulfamoyl compounds affords the corresponding acylsulfamoyl derivatives. 

Alkylidenetriphenylphosphoranes can be C-acylated in good yield by reacting them with imidazolides of carboxylic acids in a molar ratio of 2 1 at room temperature in benzene, benzene/ether, or benzene/THF. The second mole of alkylidenetriphenylphosphorane acts as a proton acceptor in the subsequent transylidation .[11... 

A mild and convenient method has been attained by using the imidazolide (8 equation 6) or triazolide (9 equation 7) of carboxylic acids as a key intermediate. Treatment of an imidazolide of carboxylic acid with 1.2 equiv. of benzeneselenol and 0.02 equiv. of sodium phenoxide provided the selenol ester in a quantitative yield. In the case of the triazolide of carboxylic acids, the reaction proceeded in the absence of base.2 ... 

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). 

Preparation of Imidazolides from Carboxylic Acids Using AyV -Carbonyldiimidazole (CDI)... 

The transformation of carboxylic acids with CDI into imidazolides has a wide range of applicability. CDI reacts with aliphatic, aromatic, and heterocyclic carboxylic acids under very mild conditions, and these reactions are not affected by the presence of functional groups unless the latter are strongly nucleophilic and themselves react with CDI in such cases a reversible protection of the functional groups is necessary. The reaction of CDI also works in such specific cases as trifluoro- and trichloroacetic acids, leading to the very reactive Af-trifluoro- and N-trichloroacetylimidazoles. 1 111... 

Of great preparative potential with respect to the activation of carboxylic acids to imidazolides is A -oxalyldiimidazole, which reacts with carboxylic acids or their sodium or lithium salts under release of CO and CO2 to give imidazolides in excellent yield.[23]... 

Table 2-1 lists some examples of carboxylic acid imidazolides of various structures prepared by the use of A -carbonyldiimidazole (CDI), A -thiocarbonyldiimidazole (Im-CS-Im), and A -sulfinyldiimidazole (Im-SO-Im). Independent of the specific method applied, the data in Table 2-1 show that reasonable yields of imidazolides and diimidazolides are quite general, irrespective of various substituents and of steric factors. The rather mild reaction conditions also permit the formation of imidazolides of highly unsaturated systems. As a further advantage, it should be mentioned that almost all imidazolides are crystalline compounds, which can be conveniently handled. Melting points are therefore included for the imidazolides listed in Table 2—1. 

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]... 

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) ... 

Imidazolides of aromatic sulfonic acids react much more slowly in alcoholysis reactions than the carboxylic acid imidazolides. Although the reaction with phenols is quantitative when a melt is heated to 100 °C for several hours, with alcohols under these conditions only very slight alcoholysis is observed. In the presence of 0.05 equivalents (catalytic amount) of sodium ethoxide, imidazole sodium, of NaNH2, however, imidazolides of sulfonic acids react with alcohols almost quantitatively and exothermically at room temperature in a very short time to form sulfonic acid esters (sulfonates). (If the ratio of sulfonic acid imidazolide to alcoholate is 1 2, ethers are formed see Chapter 17). The mechanism of catalysis by base corresponds to that operative in the synthesis of carboxylic esters by the imidazolide method. Because of the more pronounced nucleophilic character of alkoxide ions, sulfonates can also be prepared in good yield by alcoholysis of their imidazolides in the presence of hydroxide ions i.e., with alcoholic sodium hydroxide. 45 Examples of syntheses of sulfonates are presented below. 

Reaction of imidazolide with carboxylic acid in a 1 2 ratio at room temperature leads to carboxylic acid antydride and imidazolium carboxylate. 

Reactions of imidazolides with the magnesium enolates of malonates (Mg2+/malo-nate, ratio 1 1) are used for the elongation of carboxylic acids by two carbon atoms to give jS-ketoesters (Tables 14—3 and 14-4). 

The presence of water is essential for the success of these reductions. In anhydrous THF, for example, treatment of iV-benzoylimidazole with NaBH4 leads to benzyl benzoate as the main product (73%), along with 19% benzyl alcohol.[33] Other reports, however, describe the conversion of carboxylic acid imidazolides to the corresponding alcohols by complex hydrides in organic solvents. Further alcohols have been synthesized via imidazolides ... 

A method with an enormous potential for dextran modification is the homogeneous one-pot synthesis after in situ activation of the carboxylic acids with CDI, which is a rather well known technique in general organic chemistry and was published in 1962 [ 197]. It is especially suitable for the functionalisation of the biopolymers, because during conversion the reactive imidazolide of the acid is generated and only CO2 and imidazole are formed as by-products (Fig. 29). 

Fig. 6.13. Acid-free activation of carboxylic acids as carboxylic acid imidazolides.

Instead of alkylating reagents, the use of acyl or aroyl halides in fhis reaction conveniently leads to the synthesis of selenoesters as useful acylating reagents in organic synthesis. A mild and convenient method is reaction of trimethylsilyl selenides with acyl halides [27] or reaction of selenols with imidazolide (or triazolide) of carboxylic acids (Scheme 15.8) [28]. 

Peroxycarboxylic acid esters are utilized as initiators for radical polymerization and are interesting intermediates for the decarboxylation of carboxylic acids. They are generally prepared by the acylation of hydro peroxides with acid chlorides, acid anhydrides, or imidazolides in the presence of a base. Condensation of carboxylic acids (20) with /-butyl-hydroperoxide (21) has been smoothly achieved by the use of diethyl phophorocyanidate and NEt3 under mild conditions giving f-butyl peroxycarboxylates (22) in good yield.9... 

In addition to acyl halides and acid anhydrides, there are a number of milder and more selective acylating agents that can be readily prepared from carboxylic acids. Imidazolides, the (V-acyl derivatives of imidazole, are examples.115 Imidazolides are isolable substances and can be prepared directly from the carboxylic acid by reaction with carbonyldiimidazole. 

To complete the synthesis of finasteride, carboxylic acid 17 in lOml(gTHF)"1 was activated with CDI (1.02equiv) to form the acyl imidazolide 18 (Scheme 3.11). Without isolation, the acyl imidazolide was reacted with 4.6equiv of t-BuNHMgBr heating to reflux in THF for 18h to give finasteride in 98% yield [9]. 

Scheme 3.11 Preparation of finasteride from carboxylic acid 16 via the acyl imidazolide.

Fig. 1—2. Hammett diagram for the hydrolysis of imidazolides of aromatic carboxylic acids in water/ tetrahydrofuran (3 1) at 21 °C.[91...

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. 

With carboxylic acids there was no activation to carboxylic acid imidazolides observed. Reaction with p-toluenesulfonic acid in boiling tetrahydrofuran did not yield the />-toluenesulfonic acid imidazolide, but rather the double p-toluene sulfonate, from which A -sulfonyldiimidazole can be released again quantitatively with imidazole or aniline. Only from the melt of water-free p-toluenesulfonic acid and AyV -sulfonyldiimidazole at 90 °C p-toluenesulfonic imidazolide (m.p. 75.5-77 °C 87% yield) could be obtained1201 (see also Section 10.1.1). 

Table 2-1. Various carboxylic acid imidazolides prepared by the use of AyV -carbonyldiimid-azole (CDI), V /V -thiocarbonyldiimidazole (Im-CS-Im) and A -sulfinyldiimidazole (Im-SO-Im).

The second step, nucleophilic attack of an alcohol or phenol on the activated carboxylic acid RCOIm (carboxylic acid imidazolide), is usually slow (several hours), but it can be accelerated by heating[7] or by adding a base[8] [9] such as NaH, NaNH2, imidazole sodium (ImNa), NaOR, triethylamine, diazabicyclononene (DBN), diazabicycloimdecene (DBU), or /7-dimethylaminopyridine to the reaction mixture (see Tables 3—1 and 3—2). This causes the alcohol to become more nucleophilic. Sodium alcoholate applied in catalytic amounts accelerates the ester synthesis to such an extent that even at room temperature esterification is complete after a short time, usually within a few minutes.[7H9] This catalysis is a result of the fact that alcoholate reacts with the imidazolide very rapidly, forming the ester and imidazole sodium. 

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