NOVEL NEW RESEARCH STRATEGIES OF BENZIMIDAZOLE DERIVATIVES: A REVIEW

INTRODUCTION

Benzimidazole is an example of aromatic heterocyclic organic compound. The new method of benzimidazole based on poly heterocycles draw the attention of pharmacists from last few decades^[1]. It has important pharmocophore in medicinal chemistry and pharmacology. Benzimidazole and its derivatives are an example of bicyclic compound consisting of the fusion of benzene with imidazole^[2]. The structure of benzimidazole and its derivatives are given below; The worsening of asthma at night, is commonly referred to as nocturnal asthma (NA).

It has magical properties with many pharmacological properties. Benzimidazole possess many biological activities such as anti- microbial, anti-fungal, anti-histaminic, anti-inflammatory, anti- viral, anti-oxidant, anti-cancer, anti-ulcerative^[4-6] etc so that it having important moiety for the development of molecules of pharmaceutical interest. Many benzimidazole derivatives having heterocyclic building blocks is due to the structural similarity to purine nucleobase. It selectively inhibits the endothelial cell growth and then suppresses the process of angiogenesis in vitro as well as in vivo biological activity ^[7]. Benzimidazole is also known as 1H-benzimidazole or 1,3-benzodiazole. Five-membered nitrogen-containing heterocyclic ring was present in the structures of various biologically active synthetic compounds. The magical properties of the benzimidazole related drugs have encouraged the medicinal chemists to synthesize a large number of novel derivatives with chemotherapeutic agents. Benzimidazole and its derivatives are commonly used for the prevention and treatment of parasitic infections ^[8]. Some examples of benzimidazole containing drug are given below;

• Omeprazole
• Rabeprazole
• Lansoprazole
• Pantoprazole
• Esomeprazole

They are well known discovered benzimidazole drugs. There are some other drugs with different hetero atoms like Thiabendazole (TBZ); Parbendazole (PAR) Cambendazole (CAM) Mebendazole (MBZ) Oxibendazole.  Thiabendazole (TBZ)was the first benzimidazole to be marked over 40 years ago^[9].

 

 

 

 

 

 

Benzimidazoles having the well known heterocyclic compounds which have common and characteristic features of a variety of medicinal agents. Benzimidazole is soluble in water and other polar solvents. Benzimidazoles exist in two equivalent tautomeric forms because the hydrogen atom can be located on either of the two nitrogen atoms. It having calculated dipole of 3.61D, and it was soluble in water [10]. Benzimidazole and its derivatives are classified as aromatic due to the presence of a sextet of π-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring. When it having acidic pka is 14.5, then it gives less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. When it having basic pka is approximately 7 then it gives benzimidazole approximately sixty times more basic than pyridine [11].

SYNTHETIC APPROACHES FOR BENZIMIDAZOLE DERIVATIVES:

Synthesis of benzimidazole and its derivatives through the direct condensation reaction by OPD i.e. o-Phenylene diamine and formic acid was reported but sometimes in many synthetic reaction; a few shortcomings like less yield, extreme reaction conditions, longer reaction time and difficult workup process were noticed. Some synthetic reaction of benzimidazole and its derivatives are given below;

Scheme 1:

Synthesizing Benzimidazoles through the coupling of benzne-1,2-diamine or OPD with different Aldehydes in ethanol at room temperature. These chemical easily available cheap catalysts are more efficient than various reported expensive heterogeneous catalysts. Yields of Pt, TiO2 catalyst are higher (72-88%) in shorter reaction time (3-7h) (Scheme 1).

 

 

 

Scheme 2:

Literature survey has revealed that o-phenylenediamine or benzne-1,2-diamine react readily with most carboxylic acids to give 2-substituted benzimidazole, usually in very good yields. (Scheme 2).

 

 

 

Scheme 3:

The most commonly used (Phillip’s method[12], involves the condensation of o-diaminobenzenes or Benzne-1,2-diamine with carboxylic acids or its derivatives, including heating the reagents together in the presence of concentrated hydrochloric acid (Scheme 3),

 

 

 

Scheme 4:

In the same context, Ghosh[13] and coworkers employed a new, potent, less toxic catalyst: CH3CN for the synthesis of substituted benzimidazole from 1, 2-phenylenediamine with aryl, heteroaryl aldehydes (Scheme 4). High yield, clean reaction profile, cheaper and green in nature are the significant features of this methodology.

 

 

Scheme 5:

In the same context, phylum[14] and coworkers employed a new, potent, less toxic catalyst such as DBSA; for the synthesis of substituted benzimidazole from 4 methylbenzne-1,2-diamine and aliphatic aldehyde; it gives different benzimidazole derivatives (Scheme 5).

 

 

 

 

Scheme 6:

Hollan[15] et al. who have reported the reaction of the appropriate Trichloro acetimidate with o- phenylenediamine or benzene-1,2-diamine; it gives the 2-trichloromethyl benzimidazole (Scheme 6) only at room temperature.

 

 

 

 

Scheme 7:

o-phenylenediamine (0.01 mol) and different aromatic acid (0.01 mol) in the presence of ammonium chloride as catalyst at 80–90 °C (Scheme 7). The reaction is green and economic.

 

 

 

Scheme 8:

Recently Saberi[16] has reported synthesis of 2-benzimidazoles under microwave irradiation and solvent-free conditions which is catalyzed by zeolite HY. As shown in scheme 8, o-phenylenediamine (2 mmol) with aromatic, aliphatic and heterocyclic carboxylic (2 mmol) and 50 mg of Zeolite was mixed thoroughly in a mortar. The reaction mixture was then irradiated in a domestic microwave oven for 5–9 min at 160–560 W (Scheme 8).

 

 

Scheme 9:

Recently Saberi has reported synthesis of 2-benzimidazoles under microwave irradiation and solvent-free conditions which is catalyzed by Silica Gel. As shown in scheme 9, o-phenylenediamine (2 mmol) with aromatic, aliphatic and heterocyclic carboxylic (2 mmol) and 50 mg of Silica gel was mixed thoroughly in a mortar. The reaction mixture was then irradiated in a domestic microwave oven for 5–9 min at 160–560 W(Scheme 9).

 

 

Scheme 10:

Recently Saberi has reported synthesis of 2-benzimidazoles under microwave irradiation and solvent-free conditions which is catalyzed by Alumina. As shown in scheme 10, o-phenylenediamine (2 mmol) with aromatic, aliphatic and heterocyclic carboxylic (2 mmol) and 50 mg of Alumina was mixed thoroughly in a mortar. The reaction mixture was then irradiated in a domestic microwave oven for 5–9 min at 160–560 W. (Scheme 10).

 

 

Scheme 11:

Under  the  correct  conditions  aldehydes  may  react  with  o- phenylenediamines   to   yield   2-substituted   benzimidazoles(Scheme 11).

 

 

 

 

 

 

Scheme 12:

Heating in the presence of nitro benzene Mann[17] et al used a mixture of unsubstituted or substituted phenylenediamine  and  appropriate  aldehyde  in  nitrobenzene  heated  at 140 °C., the mixture was cooled and filtered after adding water which gives benzimidazole (Scheme 12).

 

 

 

 

Scheme 13:

The other way was synthesized by Lin[17] et al. involving a direct  one  step  synthesis  of  various  benzimidazoles  from phenylenediamines and aldehydes that includes air as oxidant(Scheme 13).

 

 

 

 

Conclusion

The review has concluded with the key synthetic approaches and pharmacological activities of the Benzimidazole. It gives one of the most useful biological activities. Benzimidazoles and its derivatives are utilized in much therapeutic or biological activity such as anti-inflammatory, anti anxiety and antimicrobial activity. The efficient and economical methods of synthesizing benzimidazole and its derivatives by condensation reaction between OPD i.e. orthophenylenediamine and various compounds in the presence of various conditions presented in this review. This review helps to other chemist chemists to get the first hand information for the synthesis of benzimidazole and become very useful for chemists and workers in this field. This can be developed from year to year to produce new economical and environmental clean protocols for the large scale production of important heterocyclic compounds.

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