Benzimidazole is heterocyclic aromatic organic compound formed by the fusion of benzene and imidazole ring. Benzimidazoles and its derivatives represent one of the most biologically active classes of compounds, possessing a wide scale of activities such as antioxidant,1,2 antimicrobial,3-8 antihelmintic,9-11 anticancer,12 antihypertensive,13 antineoplastic,14 anti-inflammatory,15,16 analgesic,17 antiprotozoal18,19 and anti-hepatitis B virus activity;20 and therefore, a number of reviews are available for biochemical and pharmacological studies which confirmed that these molecules are valuable against a wide variety of microorganisms.
Benzimidazole core is found in a variety of naturally occurring compounds such as vitamin B12 and its derivatives; it is structurally similar to purine bases, the building block of nucleic acids. The benzimidazole having hydroxyl and/ or free N1-H moiety which would have hydrogen bond donor and/or acceptor properties; and therefore, N-heterocyclic carbenes (NHCs) are usually used as ligands for transition metal complexes21 and are used as important intermediates in many organic reactions.22
Introduction of a small substitution on 2nd and 5th position of benzimidazole shows anti-helmintics activity whereas bulky substitution on 2nd position shows proton pump inhibitory and antihistaminic activity. Thus benzimidazole framework is therapeutically important moiety.24 Pantoptazole, Omeprazole, Lansoprazole, Rabeprazole etc. are some commercially available benzimidazole-based drugs. These drugs are used in combination with antibiotics to treat the gastric infection.25
The Electronic structure and Basic Strength:
Benzimidazole is a benz-annulated ring system wherein benzene ring is fused with a five member ring system having hetero atom at 1 and 3 positions (Figure 184.108.40.206). It is also known as 1, 3- benzodiazole.
They possess both acidic and basic characteristics. The NH group of benzimidazole is relatively strongly acidic and weakly basic. Benzimidazole (pKa 5.5) is basic, noticeably weaker than the imidazole (pKa 7.0); this difference in the basic strength is a reflection of the conjugation between the imidazole and benzene rings. Conjugation increases the number of contributing states in the resonance structures. Another characteristic of benzimidazole is that they have the ability to form salts. Benzimidazole with un-substituted NH group, exhibit fast prototropic tautomerism which leads to equilibrium mixtures of asymmetrically substituted compounds. Like imidazole, benzimidazole exhibit annular tautomerism in solution (Figure 220.127.116.11).
This important group of substances has found practical applications in a number of fields. Historically, the first benzimidazole was prepared in 1872, by Hoebrecker who obtained 2, 5 (or 2, 6)-dimethylbenzimidazole (Figure 18.104.22.168) by the reduction of 2-nitro-4-methylacetanilide.26
Figure 22.214.171.124: Synthesis of 2, 5 (or 2, 6)-dimethylbenzimidazole
3.2.2 Synthesis of substituted benzimidazoles: A literature review:
Synthesis of substituted benzimidazole is commonly achieved by heating o-phenylenediamine (OPD) and carboxylic acid in refluxing aqueous hydrochloric acid or in a slurry of the dehydrating agent polyphosphoric acid (PPA) at very high temperature (~150 – 200oC). As for example, Verdugo et al. has synthesized 2-substituted benzimidazole under refluxing condition using 1,2-aromatic diamines and carboxylic acid in aqueous hydrochloric acid or polyphosphoric acid at 200oC (Scheme 126.96.36.199).27
Solid phase synthesis28 and microwave irradiation using silica gel as a solid acid are also developed for synthesis of 2-substituted benzimidazole.29
Garcia-Verdugo and co-worker have shown that supercritical water can be utilized as an alternative environmentally benign solvent to synthesize the framework.30
Another method introduced by Roy et. al. the reaction between ??- bromoalkanonitriles and 1, 2- phenylenediamine under strong acidic conditions (Scheme 188.8.131.52).31
Whiting and co-worker have reported the synthesis of N-alkylbenzimidazole involving condensation of N-methyl-1, 2-phenylenediamine and 2-bromobenzoic acid in polyphosphoric acid (Scheme 184.108.40.206).32
Mukhopadhyay et al. has repored33 PEG-mediated synthesis of 2- substituted benzimidazoles under solvent-free condition. The reaction of aryl aldehyde and 1, 2-phenylenediamine occurred under heating at 110oC (Scheme 220.127.116.11).
An enzymatic synthesis of 2-alkyl-benzimidazoles has been illustrated by G. Renard and D. Lerner; an one step condensation of free acids with 1, 2-phenylenediamine under mild conditions involving a supported enzyme Lipozymes to afford 2-alkylbenzimidazoles (Scheme 18.104.22.168).34
B. Das et al. has synthesized benzimidazole by the treatment of 1, 2-aromaticdiamine with aryl aldehydes using (bromodimethyl)sulfonium bromide at room temperature (Scheme 22.214.171.124).35
Gogoi and Konwar have reported a green protocol using combination of reagents (I2/ KI/K2CO3 /H2O) which can oxidize carbon-nitrogen bonds toward synthesis of benzimidazoles under anaerobic conditions at 90oC (Scheme 126.96.36.199).36
S. Lin et al. have synthesized simple benzimidazoles from 1, 2-phenylenediamines and aldehydes at high temperature by aerial oxidation (Scheme 188.8.131.52)37.
Ramachary and co-worker have reported a chemoselective metal-free catalytic transfer of benzimidazoles as a side product using benzaldehyde and 1, 2-aromatic diamine and ethyl cyanoacetate (Scheme 184.108.40.206).38
K. Bahrami and co-worker have reported one pot synthesis of 2- substituted benzimidazoles through condensation of o-phenylenediamines with aryl aldehydes in presence of H2O2/HCl system in acetonitrile at room temperature (Scheme 220.127.116.11).39
Ranu et al. has developed an efficient procedure for synthesis of 2-substituted benzimidazoles by a one-pot condensation of o-phenylenediamines with aromatic aldehydes in presence of ionic liquid, 1-methyl-3-pentylimidazolium tetrafluoroborate, [PMIm]BF4 at