2-Substituted-benzimidazoles synthesis

K. Bahrami, M.M. Khodaei, 1. Kavianinia, A simple and efficient one-pot synthesis of 2-substituted benzimidazoles. Synthesis 4 (2007) 0547-0550. 

The finding that the anthelmintic thiazoloimidazole levamisole showed immunoregulatory activity spurred further investigation of this heterocyclic system. Synthesis of a highly modified analogue starts by displacement of bromine in keto ester 149 by sulfur in substituted benzimidazole 148. Cyclization of the product (150), leads initially to the carbinol 151. Removal of the ester group by saponification in base followed by acid-catalyzed dehydration of the carbinol affords the immune regulator tilomisole (152) [28]. 

Stump, G.L., Lynch, J.J., Macaulay, A., Wafford, K.A., Koblan, K.S. and Liverton, N.J. (2004) NR2B-selective N-methyl-D-aspartate antagonists synthesis and evaluation of 5-substituted benzimidazoles. Journal of Medicinal Chemistry, 47, 2089-2096. 

A facile method for the synthesis of N-substituted 2-benzimidazolinones 142 has been developed by Romero et al. (96TL2361) using A-substituted ureas 139, which are cyclized to 142 with IBTA as an oxidant. The reaction probably proceeds via intermediates 140 and 141. Besides the iV-alkyl or aryl substituent, presence of the 1-methoxy group is necessary for the success of this cyclization. Another benzimidazoles synthesis involves cycli-zation of N-phenyl-C-alkyl formimidamides with IBD [95JCS(P1)615]... 

Synthesis of 2-Substituted Benzimidazoles via o-Lithiation of N-Protected Derivatives... 

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. 

Lu, J., Yang, B. and Bai, Y., Microwave irradiation synthesis of 2-substituted benzimidazoles using PPA as a catalyst under solvent-free conditions, Synth. Commun., 2002, 32, 3703-3709. 

Historically, the first example of such a cyclization was the high-yield synthesis of 2-substituted benzimidazoles 104, on treatment of A -aryl-A -hydroxyamidines 101 with benzenesulfonyl chloride in the presence of a base (usually Et3N or pyridine) under anhydrous conditions (58JCS2086). The reaction most likely proceeds through... 

Fig. 2.4 Substituted benzimidazoles tested in the search for the optimal inhibition of gastric acid secretion. Substituents added to the pyridine ring resulted in the synthesis of H 168/88 (omeprazole).

Tandon, V.K. and Kumar, M., 2004. BFjEtjO promoted one-pot expeditious and convenient synthesis of 2-substituted benzimidazoles and 3,1,5-benzoxadiazepines. Tetrahedron Letters, 45 4185-87. 

Probably the best method for synthesizing 2-substituted benzimidazoles makes use of the cyclodehydration reaction between a carboxylic acid or derivative and 1,2-arylenediamines under acidic conditions (81HC6). Both 2-(pyridyl)-l//-benzimidazoles 72, 73 and l-alkyl-(l//-benzimidazol-2-yOpyridinium salts 74 shown in Eq.(l 1) have been efficiently synthesized by Hein s benzimidazole synthesis (92S395, 92UP1 93CPB614) [Eq.(16) and (17)]. 

A one-pot microwave-assisted relay reaction for the synthesis of 2-substituted benzimidazoles (xi) have been reported by Pattabiraman et al. [20]. The products were obtained in good yields and the reaction times were significantly reduced. 

Vaidyanathan and Surber [33] gave the synthesis of H-substituted benzimidazoles (xxvi) by a hydrogen deuterium exchange reaction, mediated by micro-waves. 

Bayatah et al. [36] efficiently synthesized the 2-substituted benzimidazole-4, 7-diones (xxx). The intermediate 2-chloromethyl-l,5,6-trimethylbenzimidazole-4,7-dione (xxix) served as a point of departure for the synthesis of desired products. 

Zhang and Tempest [37] showed that the incorporation of microwave technology of an Ugi/de-BOC/cyclization strategy for the synthesis of substituted benzimidazoles (xxxi). 

Rao A, Chimirri A, De Clercq E et al (2002) Synthesis and anti-HIV activity of l-(2, 6-difluorophenyl)-lH, 3H-thiazolo[3, 4-a]benzimidazole structurally-related 1, 2-substituted benzimidazoles. II Earmaco 57 819-823... 

Vaidyanathan S, Surber BW (2005) Microwave mediated hydrogen deuterium exchange a rapid synthesis of 2H-substituted benzimidazole. Tetrahedron Lett 46 5195-5197... 

Chen C, Chen YJ (2004) Liquid-phase synthesis of 2-substituted benzimidazoles, benzoxazoles and benzothiazoles. Tetrahedron Lett 45 113-115... 

The reaction between o-phenylenediamine and an equimolar amount of an aromatic or heterocyclic aldehyde has been shown to proceed by initial formation of a monoanil (74). In the presence of oxidizing agents (e.g. nitrobenzene, which also acts as the solvent) this can form the 2-substituted benzimidazole. With two moles of aldehyde the bis-anil (75) forms, giving rise to a 1,2-disubstituted benzimidazole (Scheme 42). This aldehyde route to benzimidazoles is particularly suited to the synthesis of compounds with a heterocyclic group (e.g. 2-thienyl-, 2-pyridyl-) at C-2. Reaction of 2,2,4,4-tetrakis(trifluoromethyl)-l,3-dithietane with o-phenylenediamine gives 2,2-bis(trifluoromethyl)benzimidazoline (7430785). 

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... 

Benzimidazole synthesis. Nair and Adams" found that the reagent oxidizes 2-substituted aniline derivatives of type (I) to benzimidazoles (2) under very mild conditions in yields of 60-90%, depending upon the substituents in the aromatic... 

PPE is superior to PPA for the synthesis of 2-substituted benzimidazoles by the condensation of o-phenylenediamine with carboxylic acids. An aliphatic acid is heated with the amine and excess PPE at 100° for 10 min. (yields about 70%). Aromatic acids require a temperature of 120° and a reaction period of 20-40 min. (yields 50-60%). PPE has been used successfully in the Fischer synthesis of indoles from phenylhydrazones. ... 

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