THE INTRIGUING BENZIMIDAZOLE: A REVIEW

THE INTRIGUING BENZIMIDAZOLE: A REVIEW

Vineet Kumar Singh ^* and Amrita Parle

Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Sector-3, Pushpvihar, New Delhi - 110017, Delhi, India.

ABSTRACT: Benzimidazole is a heterocyclic aromatic organic compound containing nitrogen. This bicyclic compound is formed by the fusion of benzene with imidazole ring. It is a vital Pharmacophore and privileged structure in medicinal chemistry which exhibits various therapeutic activities like antiulcer, antihypertensive, analgesic, antiviral, antifungal, anticancer and antihistaminic. The disease conditions targeted by these activities are discussed. The present article extensively covers various procedures of synthesis of 2-substituted benzimidazole and its analogs by utilizing different catalysts, solvent conditions, reactants and microwave irradiation with the aim to obtain an inexpensive, eco-friendly, less time-consuming procedure which ensures good yield and quick isolation of the pure product. Ongoing clinical trials of different benzimidazole derivatives exploring additional pharmacological activities are also covered.

Benzimidazole, Heterocyclic, o-phenylenediamine, 2-substituted benzimidazole

INTRODUCTION: Benzimidazole is a heterocyclic aromatic organic compound which enjoys the attention as a versatile Pharmacophore in medicinal chemistry. The benzimidazole ring is one of the privileged scaffolds for the development and synthesis of novel molecules of therapeutic value ¹. This nitrogen-containing heterocyclic moiety exhibits a diverse range of biological activities like antimicrobial, anticancer, anthelmintic, anti-convulsant, antioxidant, anti-inflammatory, anti-fungal, antipsychotic, antihistaminic, antiviral ².

Chemistry: Benzimidazole is a six-membered bicyclic heteroaromatic compound in which benzene ring is fused to the 4- and 5-positions of the imidazole ring.

Benzimidazole ring contains two nitrogen atoms placed at position 1 and 3 which exhibit amphoteric nature, that is, possessing both acidic and basic characteristics ³.

BENZIMIDAZOLE

Benzimidazole ring exists in two equivalent tautomeric forms, in which the hydrogen atom can be located on either of the two nitrogen atoms ⁵.

TABLE 1: PHYSICAL CHARACTERISTICS OF BENZIMIDAZOLE ⁴

History:

TABLE 2: BIOLOGICAL HISTORY OF BENZIMIDAZOLE

Synthesis of Benzimidazole Derivative: Several synthetic methods are available for the synthesis of benzimidazole ²⁰.

Benzimidazole can be synthesized from:

1. o-phenylenediamine
2. o-Nitroarylamines and o-dinitroarenes
3. o-substituted-N-benzylidene aniline
4. Amidine
5. using of green chemistry
6. miscellaneous

1. From O-phenylenediamine: O-phenylene-diamine reacts with -

1. Carboxylic acids and their derivatives,
2. Amino-ethers
3. Substituted aldehydes
4. Ketone
5. Urea
6. lactones

Scheme 1:

Reaction with Carboxylic Acids and their Derivatives: E. Wundt et al., refluxed o-phenylenediamine (A) with formic acid (B) under the acidic conditions (4N HCl) at 120 ºC for 2 to 4 h to give 75% yield of benzimidazole (C). This is a prevalent laboratory method for synthesis of benzimidazole Scheme 1a ²¹.

SCHEME 1A

Dr. Phillips et al., refluxed o-phenylenediamine (A) with aliphatic acid in the presence of 4N-HCl at 80-120 ºC temperature for 2 to 4 h. This method yields 80 to 90% of 2-substituted benzimidazole Scheme 1b ²².

SCHEME 1B

Landenberg et al. refluxed substituted carboxylic acid with 4-methyl-1,2-diaminobenzene(F)  in the acidic medium at 180 ºC for 2 h, they found about 71%  yield  5-methyl-2-substituted benzimidazole Scheme 1c ²³.

 SCHEME 1C

Von Niemantowski et al., refluxed 4-methyl-1,2-diaminophenyl (F) with an equal amount of ethyl-carboxylic acid (G)  in the presence of 4N-HCl at 225 ºC for 3 h gives 76% yield of 2,5-dimethyl-benzimidazole(H) Scheme 1d 24.

SCHEME 1D

Maleki et al., Condensed o-phenylenediamine (A) with aromatic carboxylic acid (G) in the presence of catalyst polyphosphate ester (PPA) at 180-190ºC to get 77% yield of 2-arybenzimidazole Scheme 1e ²⁵.

SCHEME 1E

Venkateswarlu et al., Synthesised 2-substituted benzimidazole derivatives, from the reaction of o-phenylenediamine and substituted benzoic acid in the presence of lanthanum chloride in acetonitrile at room temperature, this method gives about 83% yield Scheme 1f ²⁶.

SCHEME 1F

Scheme 2:

Reaction with Acidic Anhydride: Wagner et al., condensed o-phenylenediamine with acetic anhydride at the 90 ºC temperature in the presence of dil. HCl for 2 to 3 h. They found a 68% yield of 2-methyl benzimidazole Scheme 2 ²⁷.

SCHEME 2

Scheme 3:

Reaction with Acetic Chloride: Benguer et al., condensed acetyl chloride with 5-methyl-1, 2-diaminophenyl in benzene medium at 40 to 60 ºC for 2 to 3 h it gives 71% yield of 2,6-dimethyl benzimidazole Scheme 3 ²⁸.

SCHEME 3

Scheme 4:

Reaction with Imino-Ethers Imidates: Acheson and King et al., condensed o-phenylenediamine with trichloro-acetimidate in the presence of dil. hydrochloric acid at room temperature to give about 81% yield of 2-trichloromethyl benzimidazole Scheme 4 ²⁹.

SCHEME 4

Scheme 5:

Reaction with Substituted Aldehydes: Direct condensation of o-phenylenediamine with aldehydes is not a good synthetic route for benzimidazole molecule as it yields a complex mixture of 1, 2-disubstituted benzimidazole and bisdihydrobenzimidazole as side products. But the use of metal catalysts namely copper (II) acetate and lead-tetra-acetate in these reactions gives better results. Ruthenium, palladium, and rhodium catalysts have also been used ³⁰. Smith, Rao and Ratnam et al., synthesized 2-aryl benzimidazole by the reaction between o-phenylenediamine and aryl aldehydes in the presence of the oxidising agents like- cupric acetate, mercuric oxide, chlorine, lead tetraacetate, manganese dioxide, Nickel peroxide at room temperature. This synthetic method is eco-friendly and gives good yield of about 85% Scheme 5a ³¹.

SCHEME 5A

When o-phenylenediamine is reacted with aromatic aldehydes in the presence of acidic medium at 50 ºC to 65 ºC, it yields an intermediate 2-(benzylideneamino) aniline which is converted into 2-substituted benzimidazole by treating with reducing agents which gives 78% yield Scheme 5b ³².

SCHEME 5B

Zhang et al., Developed efficient methods for the synthesis of 1, 2-disubstituted benzimidazoles under solvent-free and ultrasonic irradiation conditions, by employing rare-earth metal chlorides as catalysts to obtain 77% yield of 2-(3-methyl phenyl)-1H-benzimidazole Scheme 5c ³³.

SCHEME 5C

Veisi et al., synthesized 2-aryl -benzimidazole by reacting o-phenylenediamine and aromatic aldehyde in the presence of silica phenyl sulfonic acid as a solid, heterogeneous catalyst in water. The yield of 2-aryl –benzimidazole was 67% Scheme 5d ³⁴.

SCHEME 5D

Kokare et al., synthesized 2-aryl benzimidazoles by heating o-phenylenediamine and variously substituted aldehydes for one hour at 60 ºC, in the presence of catalyst oxalic acid, with a yield of about 76% Scheme 5e ³⁵.

SCHEME 5E

Varala et al., Synthesised 2-aryl-5-alkyl-benzimidazoles by the condensation of o-phenylenediamine with aromatic aldehydes using L-proline and chloroform as a solvent to get a yield of 72-95% at ambient temperature Scheme 5f ³⁶.

SCHEME 5F

Salehi et al., synthesized 2-aryl-5-alkyl-benzimidazoles by the reaction of 4-alkyl-o-phenylenediamines and aromatic aldehydes in the presence of silica sulphuric acid and ethanol or water with 76% yield. The catalyst can be reused Scheme 5g ³⁷.

SCHEME 5G

Yadav et al., condensed o-phenylenediamine with alkyl aldehydes at room temperature in the presence of bismuth triflate in water with stirring to get about 73% yield of 2, 5-disubstituted benzimidazole Scheme 5h ³⁸.

SCHEME 5H

Jacob et al., synthesized 2, 5-disubstituted benzimidazoles using microwave reaction between 4-substituted-o-phenylenediamine and substituted aldehydes using SiO₂/ZnCl₂. This reaction does not use any solvents. This method is economical, eco-friendly with 81% yield Scheme 5i ³⁹.

SCHEME 5I

Sharma et al., synthesized 2, 5-substituted-benzimidazoles by the reacting 4-substituted-o-phenylenediamine with the substituted aldehydes in the presence of the heterogeneous catalyst Amberlite IR-120 (strongly acidic cation exchange resin) in aqueous media, this media is ethanol and water solution (2:1). This method gives a 72% yield. The catalyst is recyclable without loss of activity Scheme 5j ⁴⁰.

SCHEME 5J

Huiqiang et al., Condensed o-phenylenediamine with aldehydes in the presence of ionic liquid (NaCl+H₂O) at 60 ºC for 1 to 2 h to obtain 2-substituted -benzimidazoles in 77% yield. This is an environmentally friendly methodology for the selective synthesis of 2-aryl-benzimidazoles Scheme 5k ⁴¹.

SCHEME 5K

Ravi et al., synthesized 1,2,4,5-tetrasubstituted benzimidazoles by reacting 4,5- substituted o-phenylenediamine with substituted aldehydes at room temperature in presence of Zn-proline, which is a water-soluble and recyclable Lewis acid catalyst for the selective synthesis of 1,2,4,5-tetrasubstituted benzimidazoles with a good yield of 81% Scheme 5l ⁴².

SCHEME 5L

Scheme 6:

Reaction with Ketones: o-phenylenediamine reacted with the substituted ketones in the presence of acidic medium at room temperature gives a 2, 2-disubstituted-benzimidazoles, which on heating 60 to 70 ºC for 1 h, breaks down into 2-substituted-benzimidazole and a hydrocarbon Scheme 6a ⁴³.

SCHEME 6

Scheme 7:

Reaction with Nitrile: Hollies and Wagner synthesized 2-substituted benzimidazole by the reaction of o-phenylenediamine with the substituted nitrile at 200 ºC for 1 to 2 h gives a 77% yield Scheme-7 ⁴⁴.

SCHEME 7

Scheme 8:

Reaction with Urea: Refluxed o-phenylene-diamine with urea in the presence of hydrochloric acid at 130 ºC for 2 h gives a 78% yield of benzimidazole Scheme 8 ⁴⁵.

SCHEME 8

Scheme 9:

Reaction with Lactones: Refluxed Valerolactone (5-methyldihydrofuran-2(3H)-one) with o-phenyl-lenediamine at 130 ºC for 1 to 2 h in the presence hydrochloric acid gives 76% yield of 1,2-(1-methyltrimethylene) benzimidazole Scheme 9 ⁴⁶.

SCHEME 9

Scheme 10:

From o-Nitroarylamines and o-dinitroarenes: Benzimidazoles are synthesized from o-Nitro-arylamines, by using of the reducing agent like-nickel. Upon reduction o-Nitroarylamines converted into the 1-alkyl-2-amino-benzimidazole, which was further heated at 60 to 80 ºC gives an excellent yield of 2-substituted benzimidazole. This procedure is used in the industries for the production of large quantity of the benzimidazole because in this method yield is so high Scheme 10a ⁴⁷.

SCHEME 10A

Benzimidazoles synthesized from the o-Nitroarylamines by using a variety of reducing agents such as Sn/AcOH, Na₂S₂O₄, H₂/PD, Ni, SnCl₂/HCl, Fe/AcOH Zn dust/AcOH. And o-aminoarylamine also gives a 1, 2-sustituted benzimidazole by heating at 80 to 120 ºC in HCl Scheme 10b ⁴⁸.

SCHEME 10B

N-substituted-o-nitro aniline gives 2-aryl-substituted benzimidazole, when heated on sand bath at 120 to 150 ºC temperature for 2 h this given 79% yield Scheme 10c ⁴⁹.

SCHEME 10C

The cyclisation of the compound under the influence of hydrochloric acid with 60 to 80 ºC temperature gives 81% yield of N-amino-benzimidazole Scheme 10d ⁵⁰.

SCHEME 10D

Scheme 11:

From o-substituted N-benzimidene-anilines: Refluxed N-benzyl-2-nitroaniline in the presence of reducing agent triethyl phosphate at 80 to 100 ºC for 2 h gives 89% yield of 2-phenyl benzimidazoles Scheme 11a ⁵¹.

SCHEME 11A

When aromatic nitro compound N-benzyl-2-nitroaniline is heated with 1, 2-dichlorobenzene in the presence of solvent dimethylformamide (DMF) at 80 to 120 ºC temperature for 2 h gives a 77% yield of 2-phenylbenzimidazole Scheme 11b ⁵².

SCHEME 11B

Scheme 12:

From Amidine: The derivative of Amidine reacts with the phenylsulfonyl-chloride in pyridine at 10 ºC for 1 to 2 h gives 81% yield of 2-substituted benzimidazole Scheme 12 ⁵³.

SCHEME 12

Scheme-13:

Green Synthesis of Benzimidazole: Davood Azarifar et al., synthesized 2-substituted-benzimidazole by the reaction of 0- phenylenediamine with a carboxylic acid by using microwaves. They find a shorter time of reaction and get a 77% yield of 2-substituted benzimidazole. This method is promoted to green chemistry and avoided using of hazardous solvents Scheme 13a ⁵⁴.

SCHEME 13A

M. Rekha et al., refluxed o-phenylenediamine with substituted aldehydes or Ketone in the presence of the green catalysts zirconium and ethanol as a solvent at 60 ºC - 80 ºC for 3 to 4 h. These procedures are very economical and eco-friendly and also give about 82% of product yield Scheme 13b ⁵⁵.

SCHEME 13B

Mita D. Khunt et al., refluxed o-phenylenediamine with substituted aldehydes in the presence of polyethyleneglycol-400 (PEG-400) at 80-85 ºC for 1.5 to 2 h gives 76% yield of 2-substituted-benzimidazole. PEG is a green and eco-friendly solvent Scheme 13c ⁵⁶.

SCHEME 13C

Scheme 14:

Miscellaneous: By the reductive cyclisation of N-[(1Z)-6-{[hydroxy(phenyl)methyl]imino}cyclohex-3-en-1-ylidene]benzamide with the triphenyl phosphate in the presence of pyridine and phenylsulfonyl-chloride at 10 ºC for 1 to 1.5 h gives a 76% yield of 1, 2-sustituted benzimidazole Scheme 14a ⁵⁷.

SCHEME 14A

Sunwoo Lee et al., condensed 4-substituted-o-phenylenediamine with substituted aldehydes in the presence of DMSO and copper as a catalyst at the 120 ºC and gives 73% yield of 5, 2-substituted benzimidazole Scheme 14b ⁵⁸.

SCHEME 14B

Dianils et al., cyclised N, N-disubstituted-phenylenediamine under the acidic condition at 50 to 60 ºC gives 69% yield of 1, 2-disubstituted benzimidazoles Scheme 14c ⁵⁹.

SCHEME 14C

Rao et al., Synthesised 2-aryl benzimidazole by the reaction of o-phenylenediamine and aryl aldehyde in the presence of acetic acid at room temperature for 2 h which gives 65% yield of 2-aryl benzimidazole Scheme 14d ⁶⁰.

SCHEME 14D

Pharmacological Activity of Benzimidazole Derivatives: ^{61, 62, 63, 64}

TABLE 3: PHARMACOLOGICAL ACTIVITY OF BENZIMIDAZOLE DERIVATIVES

S. no.

Derivative

Structure

Activity

1

1,2,5,6-substituted-benzimidazole

Anti-mycobacterium-tuberculosis, Against-methicillin-resistance- S. aureus., E. coli

R1

R2

R3

R4

Cl

Cl

C6H4F

H

Cl

Cl

C6H4Cl

H

Cl

Cl

C6H4-c-(CH3)3

H

2

2-[(E)-2-phenylethenyl]-1H- substituted benzimidazole

Potent-anti-tuberculosis, S. albus, C. abllicans.

R

R’

NO2

3,4-OCH3

NO2

4-CH3

NO2

3-OH`

3

2-substituted benzimidazole

Anthelmintic, tapeworm, hookworm.

R

CH3

C6H5

4-NH2.C6H4

4

2-(trifluoromethyl)-5,6-1H-sustituted benzimidazole

Antiprotozoal, G. intestinalis, E. histolytica, T. vaginalis

R1

R2

R3

2,3-Cl2C6H3O

H

H

2,3-Cl2C6H3O

H

CH3

Cl

C10H7O

CH3

5

2-(1-methyl-2-phenylhydrazine)-5-substituted benzimidazole

Antifungal, Aspergillus Niger, Aspergillus flavus

R

R’

H

H

H

-4-NO2

-6-NO2

-4-Cl

6

1-(3-(hydroxymethyl) tetrahydrofuran-2,4-diol)-5,6-dichloro-2-substituted benzimidazole.

Antiviral (human influenza  A3 and  respiratory syncytial virus (RSV))

R

SH

SCH3

SO2CH3

7

(E)-2-[(5,6-dichloro-2-phenyl-1H-benzimidazol-1-yl)acetyl]diazenecarbothioamide-5,6-dichloro-2-phenyl-benzimidazole

Antioxidant

R

2-chlorophenyl

4-fluorophenyl

2-bromophenyl

8

2-thio-(methyl-R)-1h-substituted benzimidazole

Anticonvulsant

R

Piperazine

Morpholine

N-phenyl benzamide

9

2,2-dimethyl-6-sustituted benzimidazole

Anti trypanosomatid

R

H

CH3

CH=NOH

10

6-alkyl-2-thio-benzoalkyl-substituted benzimidazole

Cox-2  inhibitor

R

R1

H

OCH3

CH3

H

11.

2-(dialkylamino)-6-(amino-oxo-fluorophenyl)-substituted benzimidazole

Antiasthamatic

R

R1

R2

H

pyrrolidine

Pyrrolidine

CH3

pyrrolidine

Pyrrolidine

CH3

CH3NCH2NCH2NCH3

CH3NCH2NCH2NCH3

12.

2-(trimethyl)-1-(hexo-methyl)-5-(thioalkyl)-substituted benzimidazole

Anticonvulsant

R

3-CH3-4-pyridine

3-C2H5OH-4-pyridine

3-F-4-pyridine

13.

1-(aminotrialkylpyridine)-2-oxo-3-trimethyl substituted benzimidazole

GABAA-receptor agonist

R

R1

R2

CH2

CH2

1-butoxy-4-luoro benzene

H

H

CH3

H

H

1-butoxy-4-luoro benzene

14.

2-sulfo-(1-one-2-diphenylpyrazol)-5-substituted-   benzimidazole

Hypolipidmic

R1

R2

R3

R4

H

H

H

Cl

H

CH3

CH3

Cl

OCH3

H

H

Cl

Marketed Preparation having Benzimidazole Nucleus: ^{65, 66, 67, 68}

TABLE 4: MARKETED PREPARATION OF BENZIMIDAZOLE

S. no.	Drug	Company	Structure	Use
1	Omeprazole	Dr.Reddy’s laboratories		Antiulcer agent
2	Pantoprazole	Sun Pharma		Antiulcer agent
3	Mebendazole	Cipla limited		Antiparasitic
4	Albendazole	GlaxoSmithKline		Antiparasitic
5	Astemizole	Cadila healthcare limited.		Antihistaminic
6	Telmisartan	Zydus, Intas pharma.		Antihypertensive
7	Rabeprazole	GSK-PHARMACEUTICAL,		Proton-pump-inhibitor
8	Thiabendazole	GSK-Pharmaceutical,		Antiparasitic and fungicidal
9	Oxfendazole	Boehringer Ingelheim		Anthelmintic (for cattle’s)
10	Lansoprazole	Actavis pharmaceutical		Proton-pump-inhibitor
11	Esomeprazole	Actavis pharmaceutical		Proton-pump-inhibitor
12	Candesartan	Zydus and Cadila		Antihypertensive
13	Maribavir (oral)	Viro Pharma, GSK.		Antiviral
14	Emedastine	Alcon pharmaceutical		Antihistaminic

Benzimidazole in Clinical Trials:

TABLE 5: ONGOING CLINICAL TRIALS

CONCLUSION: This review contains 39 type of reaction for synthesis of benzimidazole which covers the different kind of methods for synthesis of substituted benzimidazoles like 2-substituted, 2,5-substituted, 2,1-substituted, 2,2-disubstituted.

Benzimidazole has a wide range of pharmacological activities like- antimicrobial, antifungal, antioxidant, antiviral activity, anticancer activity, anti-inflammatory activity, etc. Thus, we can say that benzimidazole is a moiety which has exhibited versatility in pharmacological action and has further potential for exploring its unexplored pharmacological activities.

ACKNOWLEDGEMENT: The author(s) would like to acknowledge, DIPSAR College of Pharmacy, New Delhi, India for providing an institutional research platform and necessary facilities.

CONFLICT OF INTEREST: None

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    How to cite this article:

    Singh VK and Parle A: The intriguing benzimidazole: a review. Int J Pharm Sci & Res 2019; 10(4): 1540-52. doi: 10.13040/IJPSR. 0975-8232.10(4).1540-52.

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