Carboxylic acid imidazolides

C iH FjNO, J254S3-3I-0) see Dolasetron mesilate indole-3-carboxylic acid imidazolide (CiiHoNjO 99445-26-S) see Tropisetron (S)-indoline-2-carboxylic acid (QjH.jNOj 79815-20-6) see Perindopril ( )-2-(lH-indol-5-yl)-A -methylethenesulfonamide (CiiHijNjOjS 98623-49-5) see Naratriptan 5-(3-indolylmcthyl)hydantoin (Ci2H N,02 21753-16-2) see L-Tryptophan... 

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. 

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).

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]... 

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. 

Preparation of Esters by Use of a Polymer-Supported Carboxylic Acid Imidazolide... 

Further acylations/selective acylations of carbohydrates are compiled in Table 3—11. The acylations are carried out either by using imidazolides prepared in situ from the carboxylic acid and CDI (method A), or by using the isolated carboxylic acid imidazolides (method B). 

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). 

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. 

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 ... 

The photolysis of cis- and tai/is-decalin-9-carboxylic acid imidazolide has also been investigated. ... 

Shibasaki et al. have reported a new approach to a,/3-epoxy esters the epoxidation of cv. j-unsaturated carboxylic acid imidazolides with a La(OPr )3, BINOL, Ph3As=0, and TBHP system provides epoxy-peroxy-esters (41), which are generated in situ from the intermediary epoxy acid imidazolide and converted to the corresponding methyl ester (42) upon treatment with methanol (Scheme 27).134... 

Another carboxylic acid activation in a neutral environment together with all mechanistic details is shown in Figure 6.13 carboxylic acids and carbonyldiimidazole (A) react to form the reactive carboxylic acid imidazolide B. 

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

Also under the rubric of reaction acceleration, the carboxylic acid imidazolides 34 were found to undergo epoxidation 12 times faster than the corresponding esters, using lanthanoid catalysts of type 32. The resultant epoxy peroxyesters (35) could be converted to alkyl esters 36 under mild conditions <01JA9474>. 

Carboxylic acid derivatives are resistant to reduction with NaBH4 and various catalysts have been used to facilitate the reaction [69]. A variety of aromatic and aliphatic carboxylic acid imidazolides are readily reduced in H2O, H20-dioxan and H2O-THF solution to primary alcohols by NaBH4 [69] ... 

Nemoto T, Ohshima T, Shibasaki M. Catalytic asymmetric synthesis of a,p-epoxy esters, aldehydes, amides, and -y,8-epoxy p-keto esters unique reactivity of a,p-unsaturated carboxylic acid imidazolides. J. Am. Chem. Soc. 2001 123 (38) 9474-9475. 

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