Benzimidazole-2-carboxylic acid, preparation

Benzimidazoles are generally synthesized from ortho-diamino-benzenes and carboxylic acid derivatives. The antihistaminic agent, clemizole (60), for example, can be prepared by first reacting ortho-diaminobenzene (57) with chloroacetic acid to form 2-chloro-methylbenzimidazole (58). Displacement of the halogen with pyro-... 

A variety of methods have been developed for the preparation of substituted benzimidazoles. Of these, one of the most traditional methods involves the condensation of an o-phenylenediamine with carboxylic acid or its derivatives. Subsequently, several improved protocols have been developed for the synthesis of benzimidazoles via the condensation of o-phenylenediamines with aldehydes in the presence of acid catalysts under various reaction conditions. However, many of these methods suffer from certain drawbacks, including longer reaction times, unsatisfactory yields, harsh reaction conditions, expensive reagents, tedious work-up procedures, co-occurrence of several side reactions, and poor selectivity. Bismuth triflate provides a handy alternative to the conventional methods. It catalyzes the reaction of mono- and disubstituted aryl 1,2-diamines with aromatic aldehydes bearing either electron-rich or electron-deficient substituents on the aromatic ring in the presence of Bi(OTf)3 (10 mol%) in water, resulting in the formation of benzimidazole [119] (Fig. 29). Furthermore, the reaction also works well with heteroaromatic aldehydes. 

Several quaternary salts of type 39, 43-46 have been prepared either by Hein s benzimidazole synthesis [see Eqs.(17) and (18)] or using an acylchloride, instead of the carboxylic acid or derivative, as shown in Eq.(19) (Table IV). 

The most important synthetic methods for preparation of a wide range of benzimidazoles condense o-diaminobenzenes with carboxylic acids or derivatives. Benzimidazole itself can be made in greater than 80% yield merely by standing a mixture of o-phenylenediamine and formic acid at room temperature for 5 days. At around 100°C the process takes only 2 h, and it is applicable to a wide range of 2-substituted benzimidazoles. Careful choice of reaction conditions is, however, essential if good yields are to be obtained in all instances [53, 54]. 

Usually decarboxylation is accomplished by heating the acids above their melting points, often in the presence of a copper-chromium catalyst. Imidazole-4,5-dicarboxylic acid can be monodecarboxylated by heating its monoanilide imidazole- and benzimidazole-2-carboxylic acids decarboxylate very readily indeed, so readily that the carboxyl function makes a useful blocking group in metallation procedures (see Scheme 7.2.1) [3-5]. A potentially useful method of preparation of imidazole-4-carboxylic acid derivatives heats the 4,5-dicarboxylic acid (2) with acetic anhydride to form (1), which is essentially an azolide and very prone to nucleophilic attack which cleaves the nitrogen-carbonyl bond (Scheme 8.3.1). With methanol the methyl ester (3) is formed with hydrazines the 4-hydrazides (4) result [6]. 

Several reports of the synthesis and chemistry of benzimidazoles have been published. The most common methods involved the condensation of 1,2-phenylenediamine with a carbonyl group. 2-Substituted benzimidazoles were prepared from 1,2-phenylenediamine and esters under microwave conditions <06SC2597>. A highly selective synthesis of 2-aryl-l-arylmethyl-l/7-1,3-benzimidazoles from the reaction of 1,2-phenylenediamines and aromatic aldehydes in the presence of silica sulfuric acid in ethanol or water has been reported <06TL2557>. Microwave-assisted one-step high-throughput synthesis of benzimidazoles from phenylenediamine and carboxylic acids in the presence of triphenyl phosphite has been disclosed <06TL2883>. A... 

Thiabendazole has been prepared utilizing two major approaches. The first approach consists of building up a 2-benzimidazolyl group at 4-position of thiazole. Accordingly, thiazole-4-carboxylic acid (67a), thiazole-4-carbonyl chloride (67b) or 4-cyanothiazole (69) are allowed to react with aniline, o-nitroaniline or o-phenyle-nediamine to get thiabendazole (2) through the reaction sequence shown in scheme 1 [114-122]. The second approach involves the preparation of 2-(2-hy-droxyethyl)benzimidazole (79) by condensation of o-phenylenediamine with 78 and lactic acid. The 2-substituted benzimidazoles (79), thus obtained, may be converted into thiabendazole (2) as described in scheme 2 [123-128]. 

Benzimidazole has been prepared from o-phenylenediamine by the action of chloroform and alcoholic potassium hydroxide and of formic acid, and by the reduction of o-nitroformanilide. Less serviceable methods include the interaction of o-phenylene-diamine and dichloromethylformamidine or formoacetic anhydride, and the thermal decarboxylation of benzimidazole-2-carboxylic add. The procedure described was developed from that of Wundt. ... 

The classical synthesis of IPs consisted in cyclization of o-DAP with carboxylic acids, their derivatives and precursors. This method was used to prepare the majority of IP derivatives with various substituents in the imidazole and pyridine rings. However, it should be mentioned that cyclization of o-diaminopyridines with carboxylic acids and their derivatives occurs less readily than that of o-phenylenedia-mines. Whereas the latter are cyclized into benzimidazoles when heated with carboxylic acid for a short time (51CRV397), boiling a 2,3-DAP and an acetic anhydride mixture for 2h affords only 2,3-diacetylaminopyridine, and fusion of this diamine with benzoic anhydride resulted only in the formation of 2,3-dibenzoyl-aminopyridine (64JOC3403). 

Dieckmann-type cyclizations have been used in the preparation of 5//-pyrrolo[l,2-a]azepine and 7//-pyrrolo[l,2-a]azepine <82JCS(P1)1123>, 5,6,7,8-tetrahydro-9if-pyrrolo[l,2-a]azepine-9-carboxylic acid <82CJC2295>, and 5-methyl-7,8,9,10-tetrahydro-5if-azepino[l,2-a]benzimidazol-7-one and... 

Although the first benzimidazole was prepared by Hobrecker in 1872, it was Ladenburg who extensively explored the preparation of benzimidazole derivatives by the condensation between ort/to-amino aniline and carbonyl compounds (aldehydes and ketones) in 1875. Subsequently, Phillips further extended Ladenburg s preparation to the condensation between ort/io-amino aniline and acetic acid to produce different kinds of carboxylic acids in the presence of dilute mineral acid. Therefore, the preparation of benzimidazole from ort/io-amino aniline is referred to as the Ladenburg method," Phillips method, Phillips modification, or the Phillips-Ladenburg reaction. It has been proposed that the condensation between ortho-dxaim aniline and carbonyl compounds involves the formation of a Schiff base intermediate," whereas the condensation between ort/io-amino aniline and acid proceeds via the A,lV -diacyl and monoacyl intermediated This condensation generally works for aliphatic acids and is feasible for aromatic acids if the condensations are carried out above 180°C in sealed reaction vessels. ... 

This experiment illustrates the classic method of forming the benzimidazole ring system. This heterocycle is generally prepared from 1,2-diaminobenzene (o-phenylenediamine) derivatives by reaction with carboxylic acids, or their derivatives, under acidic conditions. The ring system is aromatic thus it is difficult to oxidize or reduce, and it is stable to both acids and bases. It is an important heterocyclic ring system that occurs in vitamin B12 and in many other biologically important compounds. Benzimidazole itself inhibits the growth of certain yeasts and bacteria. 

For preparation of acid-base membranes of this type, the used polyacids include polycar-boxylic acids, polyphosphonic acid, polysulfonic acid, as well as perfluorinated sulfonic acid membranes. Carboxylic acids and phosphoric acid are weak acids with pK ranging from 2 to 5 (see Fig. 3.1), showing a low proton conductivity of 10 S cm level in its crystalline state. When blended with a stronger base than water, e.g., benzimidazole, a high conductivity of 4 X 10 S cm was reported at 130 °C [78]. Bozkurt et al. [79] prepared polyacrylic... 

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