CHAPTER-1

INTRODUCTION TO THE CHEMISTRY OF

BENZIMIDAZOLES
1.1 INTRODUCTION:
In organic chemistry the heterocycles form is most varied and largest classical family. The
heterocyclic compounds are the most important in industry, biology and indeed to use of
developed human society. The Carbocyclic compound was converted to Hetero cyclic
compound replacing by one or more carbon atom of ring by different element like oxygen ,
nitrogen, sulfur etc., example furan, Pyrrol, thiophene, pyridine, etc. (Fig -1:- Structure of furan,
Pyrrol, thiophene, pyridine )

S N
NH O

furan Pyrrol thiophene Pyridine

Fig -1

These compounds play an important role in pharmaceutically synthetic product and significant
natural products. 85% pharmaceutically active compounds are heterocycles.
Number of heterocyclic compounds naturally found and are participated in biological processes,
like nucleic acid bases, which are derivatives of the pyrimidine and purine rings systems, as
being crucial to the mechanism of replication. Carbohydrates are heterocyclic, and these are the
chlorophyll and heme, which makes leaves green and blood red, as well as fetch life to plants
and animals. Heterocycles become the primary site of reaction for many enzymes and
coenzymes. It too takes on a major function in heredity as DNA is also composed of many
heterocyclic rings. Vitamins, penicillin and some amino acids like histidine, tryptophan, and
proline are also having heterocyclic compounds.
The earlier concepts of structure activity relationship, chemical and biological forms of active
molecules and other consideration such as the lead from the natural products were strengthening
the guidelines of medicinal chemistry in development of new molecules.
For over century, search objectives are study of various heterocyclic compounds. The chemistry of
heterocyclic compounds and their synthetic routes form the platform of medicinal, chemical and
pharmaceutical research. The amazing potency of heterocyclic nuclei to help both as biomimetic &
reactive pharmacophores made them key elements of numerous drugs.
During last two decades, much emphasis on the biological feedback particularly in mechanism
and mode of action of the drugs, bioavailability and pharmacokinetic studies such as ADME
(where A- absorption, D-distribution, M-metabolism E-excretion) have taken a great importance
in development of new molecules. The nitrogen containing heterocycles has been an attractive
target for synthesis over many years. They are found in various natural products and have been
identified as products of chemical and biological importance. The maximum of agro chemical
product, biological active molecules, synthesized drugs and naturally founded drugs are made of
heterocyclic compounds & most of these having nitrogen heterocyclic molecules. Hence, need to
development better process for preparation of heterocycles. Each group of heterocycles such as
benzimidazoles, indoles, coumarins, quinolines, benzofurans etc., has become an independent
field of chemistry over the last few decades. The striking structural features of heterocycles
include their capacity to show substituents around a center framework in characterized three
dimensional portrayals.
Medicinal or Pharmaceutical chemistry is a leadership at the joining of chemistry &
pharmacology, which involved scheme drawing, preparation, identification & improvement of
new appropriate moiety for remedial use. Additionally it incorporates the investigation of present
drugs, their medicinal characteristics & QSAR (where Q-quantitative, S- structure A-activity R-
relationships). Drug science is concentrate around quality of medications & expects to guarantee
qualification for use of drug product.
During the beginning phases of therapeutic science development, Researcher was basically
worried about the isolation of active drugs having in plants. Today, researchers in this field are
additionally concerned with the production of new designed molecule as drugs.
The practice & approach of medicinal chemistry is synthesis & development of new molecule, this
approach based on known activity of structures. Presently Computers are useful for medicinal researcher
for gathering, manipulating, storing, analyzing & reviewing the information. Further, it gives a link to
hypothetical science & realistic displaying, giving estimates of properties of molecule, biological location
& drug activity.
In current study, the investigator has concentrated on the derivatives of benzimidazole
heterocycles because of their synthetic utility, a wide spectrum of biological activities and key
structures in various therapeutic agents.

Benzimidazole
(benz·im·id·a·zole)
Benzimidazole is an organic heterocyclic aromatic compound is a benzene ring is joint to 4 & 5
location of an imidazole ring with bicyclic nature. Due to benzimidazole nucleus compound shows no.
of pharmacological properties these moieties having no. of applications in pharmaceutical chemistry i.e.
Benzimidazole nucleus is an important part of several bioactive compounds.
The synonyms of benzimidazoles are benziminazoles, benzoglyoxalines and 1,3-benzodiazoles.
having amphoteric properties i.e. acidic & basic. The - NH functional gr. in benzimidazoles is
showing weak basic nature & strong acidic nature. It has the capacity to form salts.
In vitamin B12 [1] structure having a naturally occurring benzimidazole compounds of N-
nitrosyl- dimethyl benzimidazole with an axial cobalt ligand.
N –alkylation & N-acylation reaction of benzimidazole are same as imidazole, but reactivity
reduced due to attached benzene ring.
In list of oldest heterocyclic compound benzimidazole is well known nitrogen heterocycles. The
scientist Hoebrecker was first synthesized benzimidazole then later by Wundt and Ladenberg
during 1872-1878 [2]. But after 80 years therapeutic potential in parasite chemotherapy was
known when formulation of phenothiazine with 2-phenylbenzimidazole was introduced by ICI ,
which was used as anthelmintic for sheep, After that In 1961, Dohme and Merck Sharp
Laboratories discovered [3], thiabendazole 2-(thiazol-4-yl)benzimidazole) as a wide range
vermifuge [4]. Which is used Therapy for helminth contaminations of homegrown animal &
peoples.
Today, most important class of anthelmintic is a benzimidazoles. It also provided to numerous
viable medications for tissue-dwelling & intestinal helminths. The benzimidazoles are reactive
to nucleophilic, cyclocondensation & electrophilic reactions. and gives stable derivative product,
therefore it conceivable to synthesize an enormous varieties of subbed benzimidazoheterocycles
& benzimidazoles, a large number of drugs are used for treatment of tapeworm, round worm and
fluke infections homegrown animals such as horses, sheep, goats, steers, dogs, felines, pigs,
poultry & humans. Also some benzimidazoles used to control of various pests [5–7].
5-subbed thiabendazoles, like 4 ( i.e. 5-aminothiabendazole) & 5 (i.e. Cambendazole) were
synthesized by Merck scientists, which have an indicated good activity. These have strong
activity of anthelmintic compared to thiabendazole [8,9].
S. Kline & laboratories of French was synthesized compound 6 by replacing the thiazole ring of
thiabendazole with thiocarbamate which is high anthelmintic activity [10].
Benzimidazole N- substituted derivatives were synthesized at 1991 by nucleophilic substitution
reaction with acetomido,propyl, thio, tetramethyl piperadine, thiazole-amino to give good
resulting compound which having activity of antiulcer. The benzimidazole derivatives having
wide biological role. It is utilized as clinical medication agents like anti-(ulcer, tumer and
viral). These days, diseases like microbial infection increases continuously in worldwide due to
resistance of antimicrobial agents like macrolides, Beta - lactam, vancomycin & quinolones and
so on. An assortment of clinically remarkable types of microbes has developed a major health
difficulty around the world. One approach for battling against this challenge is the proper use of
the accessible marketed anti-microbial & improvement of new anti- microbial drugs.
Consequently there will always be need requirement to find modern chemotherapeutic drugs to
defeat resistance & reduce time of treatment. Benzimidazoles and purine are structurally similar,
therefore antibacterial ability of benzimidazoles compared with purines.
Different therapeutic activities found in derivatives of Benzimidazole therefore it is usable in
different therapeutic categories as antithrombotic, [11] anthelmintic[12-16], anti-psychotics,
[17] anti hypertensives, [18-20] analgesics,(21-24), anti-fungal, [25] fungicides, [26] anti
hyperthyroidals, [27] anti histamines, [28-30] anti ulcerative, [31] anti emetics, [32] anti-
cancer agents, [33] antibiotics, [34] MCP-I antagonists, [35] adrenergic agonists, [36]
hypoglycemic agents, [37] anti-inflammatory agents, [38] anti-viral, [39] anti-tumor
compounds, [40] anti-microbial, [41] anti-allergic,[42] anti HIV agents, [43] and anti
phytovirucides [44,45].
During few last decades Benzimidazol-2-thiols have received considerable attention as they are
enriched with diversity of biological activities of which the most profound are anti-microbial,
[46] anti-ulcer, [47] anti-cancer activity, [48] anti-hypertensive activity, [49] anti-inflammatory,
[50] anti-hyperlipidemic activities. [51].
Recently various 2-mercapto BZD deriv. were synthesized & screened its activity of anti-
(bacterial/Fungal) . [52.53]. Benzimidazole is important in the list of chemotherapeutic agents
due to their pharmacological activities. Using benzimidazole nucleus many successive drugs like
Azomycin, metronidazole etc.( antibacterial agent ), thiabendazole (anthelmintic agents ) and
benomyl (fungicides) were synthesized. Also benzimidazole nucleus used in different
therapeutic categories drugs like; Domperidone as antiemetic, Albendazole (as anthelmintic,
Bendazol as coronary vasodilator, Prazole family i.e. Ome, Rabe, Lanso, panto are PPI’s (proton
pump inhibitors), Pimobendan as cardiotonic. Other than that many examples of benzimidazole
derivatives, which are commercially important, some example listed as follows.

Table-1: Some Commercially Important Benzimidazole derivatives

Therapeutic
Name Structure
category
O CH3
H
S N O
Anthelmintic Albendazole H3C
NH
N

Cl
H
Cl O N CH3
Thiabendazole S
Cl N

O
O CH3
H
N O
Mebendazole NH
N

O
O CH3
H
N O
Flubendazole NH
F N

O CH3
H
S N O
Fenbendazole NH
N

NH N
CH3 O
Cambendazole S
H3C O NH N
 O
O CH3
H
N O
Ciclobendazole
NH
N

O
O CH3
H
S N O
Oxfendazole NH
N

O CH3
H
O N O
Oxibendazole H3C
NH
N

F O CH3
N O
O
Luxabendazole NH
S
O NH
O

Cl

O NH
Triclabendazole
Cl N S
CH3
Cl
-
O
O CH3
+ H
S N O
Ricobendazole H3C
NH
N

O CH3
NH O
Lobendazole
NH
N
F

O
NH
Anti-Psychotics Pimozide N

S
NH
O
Timiperone N
N
F

O
NH O
Droperidol N
N
F
 –
O N
+
N
O N

Analgesics Etonitazene O

N
CH3 CH3
H3C

Cl

CH3

N N N
Clonitazene CH3

+
O N
–
O

N
N
Benzitramide N
O
O

CH3

H3C
CH3

OH F
H
Mavatrep N F
F
N

O
NH N
OH N
N

N
Hypertensives Candesartan
N O

CH3

H3C
O

Mibefradil NH O
N
N
H3C F
H3C

CH3

O CH3
N O
NH
Fungicides Benomyl N CH3

NH
O

H
N O
Fuberidazole
N
 Cl

Anti-fungal Chlorimidazole N
CH3
N

Antihistamine Astemizole N NH

N N

CH3
O

Cl

N
Clemizole
N N

H
N O
S N
H3C
Anti-Ulcerative Omeprazole O N CH3

H3C O CH3

O
N
NH
S
Lansoprazole N F
O
H3C
F F

H
N O
F
S N
Pantoprazole F O N

H3C O O CH3

O
N
NH S
Rabeprazole
N O CH3
H3C O

Cl O
N

OH
Anti-cancer agent Imet3393 N N
H

Cl

Cl CH3 O
N
N
Bendamustine OH
N
Cl
 N
H3C
H
H3C
N OH
Galeterone
H H

H3C
CH3
OH
N O
S
O
Anti-viral Enviroxime N
NH2
N

H3C CH3

H
N NH

Maribavir Cl N
O

Cl HO OH
OH
F

Antiallergics Astemizole
N
N O
NH N CH3

NH CH3
O N
Cardiotonics and NH O
Pimobendan
Iododilator CH3
N

O
H
N
Immunopotentiator Procodazole OH
N

Cl

N
Antileukemia Bendamustine OH
Cl N N
O
Cl

O
NH N
S
Gastric acid N
Pantoprazole O CH3
O
inhibitor H3C O

F
F

O
NH
S N
CH3
Tenatoprazole N
O
O CH3
CH3 H3C
 H
N CH3

Excretion of uric
N
Irtemazole
acid N

O
NH
Antinematodal NH
Nocodazole O
agents N CH3
S O

F F

F N
O N
Acaricide Fenzaflor
O Cl

Cl

Cl

NH O
Anti-dopaminergic Domperidone
N N NH
N
O

O
O CH3
H
Antineoplastic N O
Nocodazole
NH
agent S
N

Vasodilator
N.HCl
Millot spasmolytic Dia bazole
N
hypotensive
O CH3
H
Antinematodal N O
Parbendazole H3C
NH
Agents N

1.2 CHEMISTRY
1.2.1. Structure
Benzimidazole is a heterocycle molecule having two nitrogen atoms. BZD is a fused heterocycle
of benzene and imidazole nucleus (Fig-2) (ring of benzene is combined with ring of imidazole at
the position of 4 & 5). It has an extraordinary synthetic design which can form hydrogen bonds
with enzymes & receptors in living beings arrange with ions of metal & have hydrophobic π-π
interactions.
 N

NH

Fig -2 : Structure of benzimidazole

Numbering system in the benzimidazole ring given in Fig-3

4 3
5 N
2
6 NH
7 1

Fig - 3: Numbering of Benzimidazole

The literature data the substitutions at 1, 2 & 5 location in benzimiazole moiety is deciding for
the molecule to display wide scope of medicinal activities.
The benzimidazole is formed by joining of an imidazole ring with benzene ring for its 4 - 5
bonds. Imidazole ring having two nitrogen which are different from each other belonging to
nature characteristic of the ring. The nitrogen having hydrogen atom is sp3 hybridization and
nitrogen which not having hydrogen is sp2 hybridization & mention as pyridine nitrogen.
The joint of hydrogen & nitrogen in benzimidazole which shows tautomerism as demonstrated
below (Fig-4).

4 3 7 1
N N
Basic 6 N Acidic
5 Tautomerization
+ 2 2
NH 6 NH 5 NH3
1 4 Basic
7
Benzene Imidazole Acidic

Fig.4 : Fusion of benzene and imidazole ring and tautomerism in benzimidazole

The principal compound containing benzimidazole nucleus, found naturally is N-ribosyl-
dimethylbenzimidazole, is an imperative building block of cyanocobalamine (vitamin B12)
(Barker et al., 1960).
A set of resonance structures drawn for BZD display as amphoteric nature & infers that
electrophilic reaction will be on N-1 or benzene ring; for nucleophilic reaction C-2 position is
anticipated 5, An evidence of tautomerism in the benzimidazole ring has been reported (Fig. 5),
2- BZD unsubstituted on nitrogen display quick phototrophic tatuomerism, which prompts
balance combinations of unsymmetrical subbed compounds. Tautomerism happens through with
an inter molecular or intra molecules process of benzimidazole or interactions of protic solvent
like water. It delivers the 5 & 6-locations & any gr. in the ring framework at that location is
chemically same.
–
N N N –
N
– +
CH CH
+ +
NH NH NH NH

–
N CH N
– N N
HC
– + +
NH NH + –
CH HC +
NH NH

Fig.5 : Tautomerism in the benzimidazole ring

This tautomerism is practically equivalent to that show in amidines & imidazoles. The certain
benzimidazole subsidiaries that look from the outset as isomers but it actuality the tautomers.
Due to tautomerism the position 4 &5 are same to positions 6 & 7. i.e., 5-methylbenzimidazole
and 6-methyl benzimidazole are tautomers of each other’s. (Fig-6) - 6). However two non-
identical structures can be composed, these are tautomers & are address the same molecules.
4 3 7
H3C H3C
N NH1
5 6
2 2
6 NH 5 N
1
7 4 3
Fig - 6: 5-methylbenzimidazole and 6-methyl benzimidazole are tautomers of each others
For preventing any confusion tautomers, these are composed by the second one in parenthesis,
e.g., 5(6)- methylbenzimidazole. If larger gr. joint to nitrogen in 1-location then such
tautomerism not occurred just isomeric structures shown. Hence, 1, 5-dimethyl & 1, 6-
dimethylbenzimidazole are exist as well defined isomeric molecules (Fig - 7).

In N-subbed benzimidazoles, tautomerisrn is not conceivable & two distant non-identical

molecules or isomers might be prepared & characterized. e.g. the two dimethylated BZD’s are
shown an isomeric set of nonequivalent molecules, the mono-methylated BZD’s are tautomers &
equivalent.
CH3
4 3 7
H3C H3C
N N1
5 6
2 2
6 N1 5 N
7 4 3
CH3

Fig - 7: Isomeric compounds

1.3 SYNTHESIS
For synthesis of benzimidazole there are no of synthetic methodogies. Generally for synthesis of
benzimidazole, widely used method is the reaction of OPDA with carbonic acids & their imidates
nitrile & o-ester subsidiaries.
1.2.2.1 Methods for the synthesis of benzimidazole
There is no. of method for synthesis of benzimidazole. The synthesis methods and chemistry
were given detailed in review [54].Generally, for synthesis of benzimidazoles variety of starting
materials can be used, out of these, some are listed in detail as follows,
1. Benzene- 1,2 diamine (ortho- phenylene diamine)
2. Ortho - (N-acyl & -aryolamino)arylamines & nitrobenzenes
3. Ortho –Dinitroarenes/-Nitroarylamines
4. Ortho - substituted benzalaniline
5. Amidines & their derivatives
6. Other heterocyclic compounds.

1) From Benzene- 1,2 diamine (ortho- phenylene diamine)

Benzene- 1,2 diamine (Ortho-Phenylenediamine) react with different reagent like a) carboxylic
acid & derivatives of their, b) Imidates(imino-ethers and imino-thioethers), c) carbonyl
products d) Cyano compound e) Preparation of 2(3H)-benzimidazolethiones to form
respective substituted benzimidazoles with different yield.

A) By reaction 1,2 benzene diamine with carboxylic acids

a) Mono basic acids

The preparation of 2- substituted BZD’s by using OPDA & carboxylic acids gives good yield
using variety of reaction condition. Ladienburg18synthsized 2, 5 (or 2, 6)-dimethylbenzimidazole
by using 4-methyl- Benzene- 1,2 diamine in glacial acetic acid.at reflux temperature or elevated
temperature in a sealed tube. The benzimidazole (parent) was synthesized in 1878 by using
formic acid (scheme-1). If 90% formic acid is used then obtained 83 to 85% yield [55]. By using
low concentration of formic acid i.e. 25% also reaction has been given good performance.

NH2 heat
+ HCOOH N
+ 2H 2O

NH2
NH
benzene-1,2-diamine

Scheme - 1

The 2-substituted benzimidazoles were synthesized by Phillips[56,57] by using aliphatic acid.

For this reaction aliphatic carboxylic acid and diamine were used as equal moles proportional in
presence of 4NHCl at reflux temperature conditions as per scheme-2. If Acetic acid used for
reaction then obtained 2-methylbenzimidazole [55]with 68% yield.

NH2
4N HCl, heat
+ RCOOH N
+ 2H 2O

NH2
(R = Alkyl) NH R
benzene-1,2-diamine

Scheme - 2

The Phillips procedure is not suitable for synthesis of 2- aryl benzimidazoles [57]. 2- Aryl
benzimidazoles were synthesized by using polyphosphoric acid [58,59] (PPA) or poly
phosphate ester [60] (PPE) as dehydrating Reagent to obtain better yields (Scheme – 3). Also
phosphorus pentoxide also used as dehydrating agent for synthesis of 2- aryl benzimidazoles [61]
.
NH2
PPA or PPE NH2 -H 2O NH
+ RCOOH R
R
NH2 P 2O 5 NH
N
O
Scheme - 3

b) Dibasic acids – Benzene- 1,2 diamine was reacted with dibasic acids formed are bis
benzimidazoles [62] (Shriner et al., 1941), if two moles Benzene- 1,2 diamine and one mole
dibasic acid are used (scheme – 4) .

H2N CH3 CH3

HN
N
H3C NH2 -H 2O
(CH 2)n(COOH) 2 -H 2O NH
+ O

NH2 O
NH
NH N

H3C NH2 H3C

Scheme - 4

B] Reaction of 1,2 benzene diamine & acid anhydrides

a) Anhydrides of monobasic acids –- OPDA & acid anhydrides were reacts to obtain two
product i.e. benzimidazole or N, N‟ diacyl phenylenediamine [63]. The formation of products
depends on reaction conditions. If OPDA reacts with acetic anhydride to get 2- methyl BZD [64]
by several hours heated at reflux temperature.
If Benzene- 1,2 diamine react with only acetic anhydride/acetic anhydride & sodium acetate
[65-68], acetic acid [69] or mineral acids to give excellent result by applying modified process of
phillips [70,71,72,73]. In reaction added Diluted HCl (about 4 N) to give 2-methylbenzimidazole
with 93.3 % yield from Benzene- 1,2 diamine and acetic anhydride were heated with 15 % HCl
[74]. (Scheme- 5).
 NH2
-H 2O NH
CH 3COOH
+ (CH 3CO) 2O NH2 CH3
NH2 CH3 N
NH
benzene-1,2-diamine O
N-(2-aminophenyl)acetamide 2-methyl-1H-benzimidazole

Scheme - 5

b) Dibasic acid anhydrides – The reaction of anhydride of monobasic acid and dibasic acid are
similar. e.g. Benzene- 1,2 diamine react with dihydrofuran-2,5-dione (Succinic anhydride) to
gives 3-(1H-benzimidazol-2-yl)propanoic acid [75-78] (Scheme – 6). and Benzene- 1,2 diamine
react with 2-benzofuran-1,3-dione (phthalic anhydride) to gives 2-(1H-benzimidazol-2-
yl)benzoic acid [79,80,81] (Scheme – 7).
NH2 O O
-H 2O NH
O
+ O
NH2 N
OH
benzene-1,2-diamine dihydrofuran-
2,5-dione 3-(1H-benzimidazol-2-yl)propanoic acid

Scheme - 6

OH
O O
NH2
-H 2O NH
+ O

NH2 N
O
2-(1H-benzimidazol-2-yl)benzoic acid
benzene-1,2-diamine 2-benzofuran-1,3-dione

Scheme - 7

If the reaction of o-phenylenediamine & 2-benzofuran - 1,3-dione (phthalic anhydride) were

carry out at higher temperature using same mole equivalent gives cyclized product ortho-
benzoylene-2, l-benzimidazole [82] (Scheme – 8).

OH O
O O
NH2 - H 2O
NH N
+ O

NH2 N N
O
benzene-1,2-diamine 2-benzofuran-1,3-dione 2-(1H-benzimidazol-2-yl)benzoic acid Ortho-benzoylene-2, l-benzimidazole

Scheme - 8

C) By reaction Benzene- 1,2 diamine with Imidates (imino-ethers):

Benzene- 1,2 diamine (ortho-Phenylenediamine ) react with Imidates(Imino ether) in presence
of acidic medium to form benzimidazoles with good yields (Scheme-9).
NH2 NH
Heat
+ H O
CH3
Acid
N
NH2
NH R
benzene-1,2-diamine

Scheme - 9

This imidates method is more superior than conventional Phillips procedure because in Phillips
procedure, the diamine frequently contends effectively for the H +of the acid catalyst, therefore
nucleophilic reaction is inhibiting, that problem was solved by changing the carbonyl gr. by the
imino gr., which is more basic. For example, The treatment of benzene-1, 2 diamine & 2,4-
dinitrophenylacetic acid were done just under extreme conditions & also occurs significant
resinification[83] under Phillips conditions, conversely, reaction of the OPDA with ethyl 2, 4-
dinitrophenyl acetimidate hydrochloride (11) under reflux temperature to obtain wanted 2-(2,4-
dinitrobenzyl) benzimidazole (12) 84% [83] (Scheme-10).
NH
N
NH2 Heat

+ O
N
O
CH3
NH

NH2 solvent
O

benzene-1,2-diamine O N O
O N

Scheme - 10 N O
O O

Similarly Benzene- 1,2 diamine hydrochloride react with ethyl 2, 2, 2-trichloroethanimidoate at

room temperature [84,85] to form 2-(trichloromethyl)-1H-benzimidazole(14) in 95% yield
(Scheme-11).

NH2 NH
Cl Heat
CH3
O
+ Cl Cl Acid
NH
Cl
NH 2.2HCl
ethyl N C
benzene-1,2-diamine hydrochloride 2,2,2-trichloroethani Cl
Cl
midoate
2-(trichloromethyl)-1H-benzimidazole
Scheme - 11

Other benzimidazoles like 2-aminoethyl [86], 2-Nitroalkyl [87], 2-aryl aminoethyl [88], and 2-
bromoalkyl [89]. 2-alkylesters of earbamic acids [90,91] and 2-hetaryl benzimidazoles [92] were
prepared from OPDA & the corresponding imino-ethers.
King and Acheson [93] were investigated the preparation of benzimidazoles using imino-
thioethers/ imino-ethers & OPDA. This reaction used for synthesis of 2-phenyl-1H-BZD from
OPDA & benzimino methyl ether (equation 7) [94] (Scheme-12).
NH2 N
+ NH2CNHC6H5 C6H5
NH2 NH

benzene-1,2-diamine 2-phenyl-1H-benzimidazole
Scheme - 12

D) By reaction Benzene- 1, 2 diamine with carbonyl compounds:

(i) Aldehydes
Rao and Ratnam [95], and Smith and Ho [96] were reviewed independently the synthesis method
of benzmidazole, where Reaction of o-phenylenediamine & aldehydes. Different 2-subbed
benzimidazoles (3, R = alkyl) & (4, R = aryl) were prepared by reacting aldehydes & Benzene-
1,2 diamine with in the sight of oxidizing agents like Cu(OAc)2 [97], chloranil (for 2-furyl) [98],
mercuric oxide (for 2-NHCOOMe) [99], lead Tetraacetate [100], manganese dioxide [101],
nitrobenzene [102] and nickel peroxide [103]. sodium bisulfite is used in conventional method
[104] for an improvement (Scheme-13).
O
NH2
H Oxiding agent
+ R N
NH2
NH R
benzene-1,2-diamine
Scheme - 13

1-methyl Benzimidazoles [105,106] synthesized By o-phenylenediamine reacted with

formaldehyde and these types of reactions were studied in detail [107]. If Benzene- 1,2 diamine
react with aldehydes( aromatic) & using methanol to give Schiff bases like monoanils & dianils
[108] ( di-Schiff bases) .The monoanils and dianils dependes on molar ratio aldehyde
utilized.The monoanils & CH3COOH treated at room temp. to obtained 2-arylbenzimidazoles
and the dianils gives l -aryhnethyl -2- arylbenzimidazoles The equi molar quantity of substituted
aromatic aldehyde, sodium bisulfite adduct of substituted aromatic aldehyde & OPDA were
heated to 140ºC about four hour in presence of N,N-dimethyl formamide as solvent to obtained
was 2-substituted benzimidazole (Scheme-14)with substituted aromatic moieties [109]
(Devmurari et al., 2010). In the majority of cases excellent yields have been obtained.
 NH2
Reflux
+ ArCHO
NaHSO 3 N
NH2
–
NH Ar
benzene-1,2-diamine Scheme - 14

1-arylmethyl 2-aryl-1H-1, 3-BZD was prepared by Khodabakhsh Niknam et al [110] by reaction

of Benzene- 1, 2 diamine and Ar. aldehydes with [M(HSO4)n] in H2O as catalyst & reaction
did without solvent to get better yields (Scheme-15).
NH2
M(HSO4)n N
+ ArCHO –
Ar
RT, under O2
NH2 NH

Scheme - 15

(ii) By reaction Benzene- 1, 2 diamine with ketones:

2, 2 – disubstituted benzimidazolines was preapared by reaction of OPDA with ketones. This
has been reported [111-113]. Which decomposes by warmth to give 2-subbed benzimidazole (3
or 4, R = R'=differently subbed) & a hydrocarbon. In a few cases, the hydro carbon was isolated
and distinguished. In the deterioration of an asymmetrically subbed benzimidazoline, it has been
seen that the C-C bond, which has more degree level of replacement, is normally broken
(Scheme-16).
O
NH2
R Heat
NH NH
+ R' + R' -H

NH2 R
NH NH R
R'
benzene-1,2-diamine
Scheme - 16

(iii)Reaction Benzene- 1, 2 diamine with esters

The method for synthesis of Benzimidazole by o-phenylenediamine reacted with ester is not
convient. The Niementowski Von [114] was worked on that reaction and first investigate the
reaction of 1, 2 Benzene diamine with esters to form benzimidazole. The equal mole ratio of 4-
methylbenzene-1,2-diamine .2HCl & ethyl formate were take in a sealed tube & heated to 225
°C about 3 hour to 5 or 6 methyl benzimidazole hydrochloride [115] (yield 84%)(Scheme-17).
H3C NH2
Heat - 225°C H3C NH
.2HCl HCOOC 2H 5
+ .HCl + C 2H 5Cl
-2H 2O
NH2
N
4-methylbenzene-1,2-diamine 6-methyl-1H-benzimidazole
hydrochloride
hydrochloride
Scheme - 17

1,2 Benzene-diamine was reacted with ethyl acetoacetate to obtain several products, depending
upon which condition is used i.e.acidic, basic, neutral, etc. If Reaction carried out in acid
condition and equimolecular quantity is taken of both reactant to formed ethyl (2Z)-3-[(2-
aminophenyl) amino] but-2-enoate [116]. Which on heated to obtained 2-methyl benzimidazole
[117] (Scheme-18).
NH2 CH3
Heat N
Acidic condition
+ CH3COCH 2COOC 2H5 NH
CH3 + CH 3COOC 2H 5
NH2 NH
NH2
benzene-1,2-diamine O O

H3C
2 - methyl benzimidazole
Scheme - 18 ethyl
(2Z)-3-[(2-aminophenyl)
amino]but-2-enoate

iv) Reaction of Benzene- 1,2 diamine with Amides

Benzimidazoles synthesized by reaction of amides and Benzene- 1, 2 diamine . For example, 4-
methylbnzne -1,2 diamine dihydrochloride react with benzamide at 240-250ºC temperature to 6-
methyl-2- phenyl-1H-benzimidazole [118] with quantitative yield (Scheme-19).
O
H3C NH2 H3C N
NH2
.2HCl
+ NH
NH2

4-methylbenzene-1,2-d benzamide 6-methyl-2-phenyl-1H-benzimidazole

iamine

Scheme - 19

v) By reaction of acylating agent

Acid chlorides & Benzene- 1,2 diamine when reacted to formation of benzimidazoles or
monoacylated or diacylated Benzene- 1,2 diamine, The product formation depends on
experimental conditions of reactions (Scheme-20). Diacylated Benzene- 1, 2 diamine product
formed by procedure of Schotten-Baumann. 2-tolyl benzimidazole [119,120] was synthesized by
reaction of p-Toluoyl chloride with Benzene- 1,2 diamine in benzene solution, but obtained
yield was less.
Phthaloyl chloride and OPDA were heated to forms 2-BZD benzoic acid & other byproducts
[121].
Reaction of Benzene- 1,2 diamine and acid chlorides to get benzimidazoles, the reaction
was done using aroyl chlorides, reaction temperature require 200-220°C., base like pyridine ( or
similar) is required.
3 ,4-diaminotoluene and Acetyl chloride reacted in presence of benzene solution at heating to
get 2, ,5(or 2 , 6)- dimethylbenzimidazole if at cooling condition to get diacetyl-o-
phenylenediamine[122].Also Benzoyl chloride, benzene sulfonyl chloride and phenyl acetyl
chloride gives only acylated OPDA [122].
only acylated OPDA [122]. Acetyl chloride & l- tert -Butyl 3,4 di-NH2-5-NO2benzene were
treated to got 2-methyl 5(or 6)- tert - butyl-7(or 4)- nitrobenzimidazole[123].
NH2 O

N
+ Cl

NH2 R
NH R
benzene-1,2-diamine Scheme - 20

vi) Reaction of Lactones

Reaction of OPDA & lactones was first investigated by Bistrzycki and Schmutz [124]. They
Investigated different phenol acid and γ- lactones of alcohol acids. The reaction of 5-
methyloxolan-2-one with OPDA at reflux temp. to gives 1-CH3-2,3-dihydro-1H-pyrrolo[1,2-a]
BZD [125] (Scheme-21) with less yield.
NH2 O O N
CH3 Reflux
+ N
NH2

benzene-1,2-diamine 5-methyloxolan-2-one H3C

1-methyl-2,3-dihydro-1H-pyrrolo[1,
Scheme - 21 2-a]benzimidazole

(D) Reaction with Nitriles:

a) Cyno bromide
Benzene- 1, 2 diamine was reacting with cyanogens bromide to form 2-aminobenzimidazoles
(Scheme-22) with better yield;

NH2 N
+ CNBr NH2. HBr
NH2 NH

Scheme - 22
For this reaction both reactant used equimolar quantities and used water is reaction media
[126,127]. Pellizzari [128] investigated that Ortho - aminophenylurea was treated with cyanogen
bromide to obtained derivative of benzimidazoles (Scheme-23).

O
O
NH NH2
NH NH2 N
CNBr NH2
NH2 H N
H O
NH O
N
NH2
Scheme - 23

b) Reaction with other nitriles

When Benzene- 1, 2 diamine was heated with Nitriles at 200°C to form
2-substituted benzimidazoles (Scheme-24), Holljes and Wagner [129] were studied this
reactions. Nitriles reactions goes in acidic media & most likely includes H+catalysis
NH2 N
.2HCl + RCN R + NH 4Cl
NH
NH2
Scheme - 24

this reaction carried out higher temperature i.e 200°C, at this temp. NH4Cl will undergo break
down & to give extra HCl, which is to continue more reaction. By utilizing this synthesis method
2-alkyl [129], 2-aryl[129], 2-guanidino benzimidazoles [130], 2-heteroarylbenzimidazoles [131]
& 2-alkyl esters of carbamic acids [132] were prepared.
E) By reaction of Benzene- 1,2 diamine with amidines and guanidines
Benzene- 1,2 diamine was reacted with amidines to form benzimidazoles (Scheme-25). The
mechanism suggested [133] as follows,

NH2 NH NH2 NH2 NH

NH
NH2 - NH 3
HN H2N NH2
NH2 - NH 3 NH NH N
N

Scheme - 25

Diphenylformamidinea and Benzene- 1,2 diamine were heated 125°C to obtained

benzimidzazole in 85.3% yield [134] (Scheme-26).
 NH2 N
C6H5N=CHNHC6H5
+ + 2C6H5NH2
NH2 NH

Scheme - 26

F) Synthesis of 2(3H) -benzimidazolones by OPDA with phosgene & urea

2-hydroxybenzimidazole (or 2-be~aimidazolol) and 2(3H) - Benzimidazolone are tautomeric of
each other. If 2- position has oxygenated function then it behaves in the –C=O structure, while in
different reactions it acts as a C-OH gr. The 2(3H) -benzimidazolones synthesized by different
following methods
a. 1,2 -Benzene diamine & phosgene
Hartmann [135] synthesized 2(3H) -benzimidazones by reaction of phosgene & 1,2 -
Benzenediamine in existence of solvent like toluene , benzene, chloroform and aqueous solution
of diamine hydrochloride salt (Scheme-27). For this reaction excess quantity of Phosgene is
required.

NH2 O
- HCl NH
.2HCl + Cl Cl O
NH2
NH
Scheme - 27

b. 1,2 -Benzene diamine & urea

Urea was treated with 1,2 -Benzene diamine dihydrochloride at 130ºC temp. to obtains 2-(3H) -
benzimidazolone [136] (Scheme-28) .

NH2
NH
.2HCl + NH2CONH2 O
NH2 NH
+ 2NH4Cl

Scheme - 28

The substituted benzimidazolones were synthesized by using general methods (444, 649).
Mistry
and Guha [139] were synthesized 2(3H) -benzimidazolone by heating of OPDA & urea at
reflux temp. in presence of amyl alcohol (up to ammonia gas evolution stopped) to obtain with
95% yield, it also synthesized by using ortho –aminophenyl urea. The ortho – aminophenyl urea
is also intermediate of in the synthesis of 2( 3H)- beneimidazolones from OPDA & urea. Ortho-
aminophenyl urea was cyclized by heated above melting point or 150°C temperature or heated in
presence of mineral acids. [140,141].
for example, 2 (3H) -benzimidaeolone was prepared by o-aminophenyl urea heated at 150°C. for
few min. Pelliaaari, [142] (Scheme-29).

NH2
150°C NH

NH
O + NH3 + 2NH 4Cl
NH
O
H2N Scheme - 29

c. By reaction of phenylurethans
Rudolph [143] was synthesized 2(3H)-Benzimidazolone from ortho-aminophenylurethan
For reaction temperature required above its melting point (Scheme-30).
O NH
O + H3C OH
NH O CH3 NH
NH2
Scheme - 30

d. “pseudo bases” Oxidation

The quaternary salts or “pseudo bases” were oxidized by using potassium permanganate to
obtained 1,3-Disubstituted 2(3H)-benzimidazolones. 1,3-di-CH3-2 (3H)-benzimidazolone [144]
was prepared oxidation of 1,2,3-Trimethylbenzimidazolium hydroxide, in presence of
potassium permanganate and cold water (Scheme-31).
CH3 CH3
N

CH3
O + CO 2 + 2H 2O
N
N
OH
CH3
CH3
Scheme - 31

e. By reaction o-nitro-N, N-dimethylanilines

Huyser and van Romburgh [145,146] was investigated synthesis of l-methyl-3-acetyl-2 (3H)-
benzimidazolone. In their work Ortho-Nitro-N , N-dimethylaniline treated with
zinc chloride and acetic anhydride (1:4 ratio) at reflux temperature up to reaction conversion
(Scheme-32).
 O
+ – O
N O
ZnCl 2 CH3
CH3 N

N O
CH3 Acetic anhydride NH

Scheme - 32

f. Miscellaneous methods
Recchi and Manuelli [147] was synthesized 2(3H)-benzimidazolone by reaction Benzene- 1,2
diamine dihydrochloride, urethan and molten sodium acetate to obtain. Monoacetylacetanilide
as intermediate , which was converted to 2(3H)-benzimidazolone in presence of strong acid
[148] (Scheme-33) .
NH2
O
H 2SO 4 NH

NH
O + H3C CH3
NH
O

O
Scheme - 33
CH3

g) Preparation of 2(3H)-benzimidazolethiones from Benzene

1,2 diamine-mercaptobenzimidazole and 2(3H)-Benzimidazolethione are tautomers,
like keto enol of 2(3H)-benzimidazolone and 2-hydroxybenzimidazole.
a. Synthesis from Benzene- 1,2 diamine & carbon disulfide
2(3H)-Benzimidazolethione [149-151] were synthesized by reaction of 1,2 Benzene diamine &
carbon disulfide in existence of alcohol & base or without base (Scheme-34).
NH2 N
KOH SH
+ CS 2
NH
NH2

Scheme - 34

b. From Benzene- 1,2 diamine & thiourea

2(3H)-Benzimidazolethione was synthesized by reaction of 1,2 Benzene diamine
dihydrochloride, thiourea & amyl alcohol at 170-180 °C temp. [152] until the evolution of
ammonia becomes negligible [153] (Scheme-35).
 NH2 O N
SH
+ H2N
S
NH2
+ NH3
NH
NH2

Scheme - 35

c. From Benzene- 1,2 diamine & thiophosgene

Steiner and Billeter [154] were prepared 2(3H)-benzimidazolethione by the treatment of
thiophosgene & OPDA & 2( 3H )- 5-methyl benzimidazolethione synthesized by the reaction of
thiophosgene on 3,4-diaminotoluene. The reaction of thiophosgene & 3 4-Diaminobenzene
arsonic acid obtained 2(3H)-benzimidazolethioned-arsonic acid with 78% yield [155] (Scheme-
36).

NH2 O N
+ S SH
+ 2HCl
NH2 Cl Cl
NH

Scheme - 36

2) From o-(N-acyl\aroylamino) arylamines & nitrobenzenes:

The benzimidazoles were synthesized by treatment of OPDA & carboxylic acids or its deriv.
[156].
The 1,2 sustituted benzimidazole compounds were preapared by cyclisation of N- monoacyl-
OPDA under uncatalysed thermal conditions or acid catalysed conditions [157-164]. Also
Compound 1,2 sustituted benzimidazole can synthesized from corresponding ortho -
nitroarylamine by using reducing agents such as sodium dithionite [165], Tin/acetic acid [166],
palladium/carbon and H2/C [167], Tin(II) chloride/HCl [168] 103, Raney-Nickel [169],
ferries/acetic acid[170] etc. Thus 1,2 substituted benzimidazoles [171-172] were synthesized by
cyclisation of N-monoacyl- Benzene- 1,2 diamine (Scheme-37).
O R2
R1

N O N N
Aq. HCl Reductant
R1
R2
R2 Heat O
NH2 NH
N

O
Scheme - 37

3) From o-Nitroarylamines & o-dinitroarenes:

The preparation of benzimidazoles from o-nitroarylamine/ o- dinitroarenes in single step by
utilizing reagents like Barium sulfate/palladium/ H2 [173], sodium bisulfate [174], Zinc [175],
sodium sulfite [176], aluminium oxide [177], Tin/ HCl [178], etc.
Ortho-nitroanilines are on thermolysis, forms 2-alkylbenzimidazoles into 1, 2-
Dialkylbenzimidazoles[179]. Also, ortho - Dinitroarenes performed in same way to obtained 2-
alkylbenzimidazoles.
The carbanilic acid derivatives on reduction with Raney Nickel inprsence of hydrogen gas to
form alkyl esters of 2-NH2-1-BZD carboxylic acids, Which was converted by thermic into alkyl
esters of BZD-2-carbamic acids [180](Scheme--38).

NH(CN)COOR

H 2 Raney Nikel NH Heat NH

N
O + RCOOH
NH2 NHCOOR
N N
O
COOR
Scheme - 38

4) From o-substituted N-benzyllideneanilines:

The 2-phenylbenzimidazoles [181] were synthesized Weidenhagen aldehyde method [182]. In
this reaction N-benzylidene-2-nitroaniline was first reduced by triethylphosphite [183] and
related reagents and then cyclised at reflux temperature to obtained substituted 2-
phenylbenzimidazoles (Scheme-39).

NHCHPh
(EtO) 3P/t-BuC 6H 5 N
O Ph
N Reflux
NH
O
Scheme - 39

2- Substituted benzimidazoles were prepared by heating N-benzylidene-2-

azidoanilines in dimethylformide [184] or 1, 2-dichlorobenzene [185] (Scheme-40).

NHCHPh
Heat N
Ph
N3 NH

Scheme - 40
Donglai Yang et al [186] were synthesized BZD’s in single step by using the Na2S2O4 for
reduction of ortho –NO2 anilines. Then treated with aldehyde to form product (Scheme-41).
2-arylbenzothiazoles and imidazoles were synthesized using Takashi Itoh et al [187] by using
Sc(OTf)3 used as a catalyst for oxidation & a ring closing steps (Scheme-42).

NH2 Sc(OTf)3 (cat.)

N
+ ArCHO
Ar
– 5) From Amidines:
RT, under O2
NO 2 NH Partridge and Turner
Scheme - 42 [188] was first
synthesized benzimidazoles by using N-arylamidine. In their synthesis the hydroxy derivatives
(1) treated with benzenesulfonyl chloride in presence of triethylamine or pyridine under dried
condition to gives benzimidazoles.
By using this method the method variety of derivatives with substituents in the aryl
ring can be synthesis.
R1
NH R2 1 , R 1 = Cl, alkoxy, alkyl; R 2 = Ph; R 3 = OH
2 , R 1= H; R 2 = 4 - thiazolyl, Ph, Et; R 3=H

3 , R 1= H; R 2 = 4 - thiazolyl, Ph, Et; R 3=Cl

N R3

Grenda, et al[189] prepared derivatives of benzimidazole using compound (2)

by oxidation in presence of sodium hypochlorite under alkaline conditions.
Also from N-Chloro derivatives (3) synthesized 2- substituted benzimidazole.
A variety of heterocycles synthesized by amidine cyclization [189-192] method using
hetarylamidines containing one or more heteroatoms.
6) From heterocyclic compounds:
Derivatives of Benzimidazole have been synthesized [193] from o-benzoquinonedibenzimide
by using reductive cyclisation in presence of triphenylphosphine (Scheme-43).

NCOPh N
Ph 3P
Ph
N
NCOPh
COPh
benzene-1,2-diamine Scheme - 43
Benzimidazoles are synthesized from indazoles by the photolysis method, but reaction depends
on substituent position in heterocyclic ring [194] (Scheme-44).
hv
N
N
NH
NH

hv
N R N
N
N
Scheme - 44 R

7. Preparation of 2-aminobenzimidazoles
Cyanogen bromide & o-phenylenediamines were treated together to got 2-aminobenzimidazoles
[126-127]
a). 2-Aminobenzimidazoles also synthesized from CNBr/ Cl & phenylhydrazines [128]
(Scheme-45) .

CNBr N
CNBr
NHCN
NH2 NH2
NH N N

CN CN
Scheme - 45

In synthesis of benzimidazole using direct condensation method gives side product that effect
on yield and quality , if used transition metal catalyst for reaction avoids by products and
improved yield.
Chan B.K., Hanan E.J., Estrada A. A., Lyssikatos J.P. and Shore D.G. (2010) [195].
Synthesized bicyclic 2H-benzimidazoles by treated aromatic 2-nitroamine or hetero aromatic 2-
nitroamine with formic acid in presence of iron powder and ammonium chloride. as per
following (Scheme -46)
R
NO 2 Fe, NH 4Cl N

R
IPA, formic acid, 80°C N
NH
R1
R1
R 1 = H, Ph, Et
Scheme - 46
Bhanage B.M., Nale D. B., (2015) [196],
N-substituted benzimidazole were synthesized by treatment of different OPDA with N-
substituted formamides in presence of a Zn-catalyst and poly(methylhydrosiloxane). This
presences gives better yield. By this process benzothiazole and Benzoxazole derivates also be
synthesized (Scheme-47) .
R
NH2 Zn(OAC) 2 .2H 2O N

R PHMS N
NH DMF, 120°C R1
R1
R 1 = H, Ph, Me
Scheme - 47

Punniyamurthy T., Mahesh D, Sadhu P (2015) [197].

2- substituted derivatives of benzimidazole were synthesis by multicomponent reaction of aryl
amine, aldehyde and azides in presence of copper iodide as catalyst. In this reaction amination
of N-aryl imines, & imine reacts as a directing gr. by chelating for the metal center (Scheme-48).
CuI
R
O PHMS
NH2 DMSO, 60°C N
–
Ar
R + H Ar
– TMSN 3
NH
TBHP

Scheme - 48

Sadhu P., Mahesh D., Punniyamurthy T. (2016) [198].

Oxidative cross-coupling of aniline, sodium azide and primary alkyl amine with a copper (II) as
catalyst and TBHP to form benzimidazoles at moderate temperature(Scheme-49)
Cu(OAc) 2 R
NaN 3
NH2 N
HOAc –
Ar
R + H2N Ar
– DMSO
NH
TBHP
Yang Y., Song T. and

Scheme - 49 Wang Z.( 2019) [199].

phenylenediamines and aldehydes were coupling by using nonnoble cobalt nanocomposite as
catalyst to obtained benzimidazoles the obtained high yield with good oxidant-free conditions.
In this process used catalyst easily recycled for successive uses (Scheme-50) .
 R
O
NH2 CoOx/NC -800 N
R'
R + H R' THF NH
NH2
100°C -
NC - nitrogen doped carbon
R' - Ar, 1° alkyl
Scheme - 50

Mondal A., Das K., Srimani D., (2018) [200] The 2-substituted and N-substituted
benzimidazoles were synthesized by dehydrogenative coupling of primary alcohols with
aromatic diamine in presence of tridentate NNS ligand-derived complex of manganese (I)
(Scheme-51).
Catalyst
NH2 Catalyst N
–
Ar
+ HO Ar
–
KOH
N N
N.
4–
HBr
NH 140°C Mn
OC S
R R
R - H, Bn OC CH3
CO

Scheme - 51

Fazaeli R., Mssah Ahmad R., Fazaeli N., Aiyan H., Naghash H.J., Emami G and Alizadeh
N.M.(2009) [201] Synthesized of 2-Arylbenzimidazoles and 2-Arylbenzothiazoles using
catalyst CU3/2PMO12O40/SIO2 without solvent. Phenylenediamines and aldehyde were treated
with 40% HTP/ZrP in a mortar with a pestle to formed benzimidazoles at room temperature for
15 min(Scheme-52).
O
NH2 N
HTP/ZrP
+ H R
R

NH2 NH

Scheme - 52

Wu J., Hu Z., Chang J., Zhao T., Yu W., Wang M, (2017) [202] N-protected 2-substituted
benzimidazoles were synthesized by condensation of a broad range of aldehydes with simple o-
phenylenediamine derivatives in presence of molecular iodine at basic conditions (Scheme-53).
 O Ethanol
NH2 N
MDC
R
+ H R K2CO3
N
NH Ts
Ts
Scheme - 53 R - Ar, 1° alkyl,CO2Et

Fukutake T., a Quifeng, aKyosuke I., a Shinobu U. A Kenji W.b, Han Yu, aTomomo H., C
Shinji I.(2020) [203]
Synthesized of 2-phenylbenzimidazole by treating 2-nitroaniline with benzyl alcohol in presence
of mesitylene as solvent and Ir/TiO2 as catalyst (Scheme-54) .
O
+
N – Ir/P - TiO 2 N
O
H3C OH
+ H 2O
+ NH CH3
NH2
Scheme - 54

1.4 PROPERTIES OF BENZIMIDAZOLE

1.4.1 Physical properties of benzimidazoles:
a) Melting Point:- If insertion of substituents in a 1-position of benzimidazole the melting
point of benzimidazole decreases, it is indication of 1-substituted benzimidazole.
b) Solubility
Benzimidazole which having hydrogen at 1-position are generously slightly dissolvable in non -
polar & dissolvable in polar solvents. Benzimidazole is dissolve in warm water, insoluble in
benzol & only slightly soluble in ether. By introducing non polar substituents in benzimidazole’s
different position the the dissolvation in nonpolar solvents is enhanced of benzimidazole. e.g. 2-
methylbenzimidazole is highly soluble in ether(non polar) due to methyl moiety at 2 position. On
the other side, introducing of polar functional groups in molecule raise dissolvability in polar
solvents; example, 1H-benzimidazole-2-amine is freely dissolve in water. Benzimidazoles are
slightly basic, so that they are soluble in dilute acids. Benzimidazoles are moreover satisfactorily
acidic and dissolve in aq. solution of base & formed N - metallic products [204]. The strong
acidic benzimidazoles are dissolvable in weak basic solution, i.e. solution of K2CO3.
c) Stability
The benzimidazole ring is extremely stable in conc. H2SO4 at 270°C under press. [205] (Wright,
1951) and hot concentrated HCl. It does not influenced by the reaction strong bases.
benzimidazole cleavage only takes place by oxidation under strong drastic conditions. But
reduction is takes place somewhat defiant, the tetrahydro and hexahydro benzimidazoles are
synthesized by reduction of benzene ring using appropriate catalyst.
d) Spectral Properties
1) IR spectroscopy:
The absorption spectra near 3107 A° indicates N-H stretching of benzimidazole), 2850A° specifies C-H
aromatic stretching (presence of aryl ring ), 1690A° indicates C-N stretching.
2) Mass spectroscopy:
Benzimidazole and imidazole are shows same pathway of fragmentation. By applying deuterium
naming systems it demonstrates that two atoms loss of hydrogen cyanide from the molecular
ion. A trademark include in the discontinuity of 2-n- propyl BZD is the get rid of CH2=CH2 from
the molecular ion, 2- acylthiophenes, 2-acyl & 2-benzoyl BZD’s are portrayed by loss of CO
from the MI i.e molecular ion.
3) NMR spectroscopy:
The chemical shift value for benzimidazole aryl ring shows up between δ 7-9 ppm when
contrasted and TMS as standard norm.
A significant component of this work is that the protonation boundaries got from basic 5 & 6
membered heterocycles can be utilized to anticipate chemical shift changes coming about because
of nitrogen protonation & de-protonation in higher perplexing molecules.  value7 -9 display
multiplet demonstrates the existence of BZD aryl ring when it compared and TMS as internal norm.
4) 13C NMR:
The spectra display distinctive carbon tops at scope of  0 -200 compared with TMS. For
benzimidazoles the range begins from  115-144. Overlapping is effectively affirmed by doublet,
triplet peaks obtained. Small intensity peaks indicates the existance of proton free carbons. So
the position of carbonyl gr. is identified.
1.4.2. Chemical Reactions of benzimidazole
1.4.2.1 Reactions of benzimidazole ring:
1) Reactions of 1 and 3 positions: Benzimidazole easily reacts with acid to form into salts for
example it reacts with hydrochloric acid , picric acid, acetic acid , niric acid to forms its salt like
monohydrochloride, monopicrate monoacetate and mononitrate. They react with alkyl halide to
form 1 –substituted alkylated product and substituted 1, 3-dialkylbenzimidazolium halides under
more harsh conditions. Benzimidazoles are reacts with acylating agents. and Grignard reagents.
They react with formaldehyde and primary amine or secondary amine to form its mannish base
[206] (Selvam et al., 2010). (Scheme-55).
R
N +
RX N N -
RX
.X
NH
N N
R R

Scheme - 55

1) Hydrogenation and dehydrogenation reactions of benzimidazole: Reduction of

Benzimidazole ring does not happed easily, it is very stable for reduction. Benzimidazole does
not reduced even if treated with nickel in presence of high hydrogen pressure and high
temperature. 2-phenyl benzimidazole on reduction with catalytic hydrogenation it is converted
into 2-cyclohexylbenzimdazole, Phenyl ring reduced but benzimidazole remains intact. also
olefinic linkage at 2-position of benzimidazole was reduced to form only saturated in 2(4-
dimethylaminostyryl)-benzimidazole by hydrogenation with nickel at atmospheric pressure
(Scheme-56).

N N
Ni,H 2
CH3 CH3
NH NH
N N

CH3 CH3
Scheme - 56

2) Halogenation: the benzimidazole on halogenations to 1-halogen substituted product.

When 2,5 (or 2,6)-dimethylbenzimidazole reacted with CaOCl2 in presence of acidic media at 0-
5ºC temperature to obtained 1-chloro-2,5 -dimethylbenzimidazole (15) (Scheme-57).
H3C N H3C
CaOCl 2 N
CH3 CH3
NH N

Scheme - 57 Cl

3) Nitration reaction: benzimidazole on nitration reaction gives 5, 6 substituted nitro

product. if 5,6 substituted benzimidazole takes for nitration reaction then nitration would take
place at 4 or 7 position (Scheme-58).

N O 2N N
Nitration

NH NH
O 2N

NO 2
H3C N Nitration H3C N

NH NH
H3C H3C
NO 2
Scheme - 58

1.4.2.2 Reactions involving substituent groups:

1) 2-benzimidazole carboxylic acids: Decarboxylation product was formed by heating 2-
benzimidazole carboxylic acid to gives benzimidazole (Scheme-59).

N N
COOH
NH
+ CO 2
NH

Scheme - 59

2-(α-haloalkyl) BZD: 2-(α-chloroisopropyl)-BZD was treated with moisture free ethyl alcohol &
pyridine at boiling temp. to obtained 2-(α-ethoxyisopropyl) benzimidazoles with good yield
(Scheme-60).
 N N
Ethanol
C(CH 2)Cl C(CH 2)OC 2H 5
NH NH

Scheme - 60

2-(3H) – Benzimi dazolones : 2-(3H) – Benzimi dazolones was treated with POCl3 or PCl5 to
gives 2- substituted Cl-derivatives of benzimidazole (Scheme-61).

N POCl 3
NH N
OH
O Cl
NH PCl 3
NH NH

Scheme - 61

2-(3H)-Benzimidazolethiones: The reaction of 2-(3H)-Benzimidazolethiones & 2-

ClCH2COOH & sodium hydroxide to form S-alkylated benzimidazole . Generally 2-mercapto
benzimidazoles are stable and alkylation of the SH to give S-alkylated analogues (Scheme-62),
by this process several S-alkylated product was synthesized .
O
N N
ClCH 2COOH
SH S OH
NH Sodium hydroxide NH

Scheme - 62

2-Aminobenzimidazoles: The reaction of 2-NH2-BZD & (CH3CO)O to obtained 2-

acetylaminoBZD (Scheme-63).
O
N
N CH3
NH2 (CH 3CO) 2O
NH
NH
NH
Scheme - 63

2) Oxidation: Benzimidazoles does not oxidized easily. Even if strong oxidizing agent like
KMNO4 does not oxidized in drastic condition, thus the benzimidazole ring is very stable for
oxidation, therefore it easy to prepare carboxylic acid derivatives of benzimidazole by
decarboxylation of substituted group of benzimidazoles.
1.5 Need of the research in Benzimidazole derivatives:
The enormous difficulties have been created in the innovation and creation of restorative, drug
and agricultural items. Numerous snags are made for preparation of organo chemical products to
the bio - assay examination. The excursion of substance items experiencing synthesis to the
production as medicine or drugs or some other farming items turns out to be exceptionally more.
It need considerably longer time to go nearer being used in market. A portion of the substance
responses can't be effectively finished by simple design. for upgrading these frameworks, we
need to create and receive new techniques for arrangement just as utilize some responsive
synthetics. Heterocyclic compounds like benzimidazole shows the several biological,
pharmaceutical, therapeutic activities. Practically all the benzimidazole derivatives have been
demonstrated their advantageous activities regarding disease relieving & satisfaction of in
sufficiencies in plants, human & animals. the intense & inhibitory roll observed in heterocyclic
benzimidazole compound ,that shows anti-viral, anti-inflammatory, anti-cancer, ant
mycobacterial, anti-feedant, anti-malarial, methodologies. Their derivatives may give the proof
of their potencies. In such manner, dynamic examination ought to be done in the preparation of
heterocyclic science. Henceforth specialist were presented the synthesis of new benzimidazole
and its derivatives. These derivatives were synthesized by various different techniques.
1.6 Scope of the research work:
For synthesis benzimidazole derivatives have significant scope because its utilized for the
formulation of a many therapeutic medications & vaccines, practiced for precautionary control
of different life scary sicknesses. Many benzimidazole derivatives may be used for the
development of agrochemical items, fungicides and acaricides because of their intense activities.
According to the multi-functional activities of benzimidazole compound, the investigater is
picked the subject of the synthesis of benzimidazole compounds from various starting raw
materials.
Rationale – The main point of the current examination is to exhibit the significance of organic
synthesis & its opportunity in the various criteria against therapeutic, pharmacological,
biological fields. By interpreting the perseverance of ebb and flow circumstance; here the analyst
will set up a prepare of the significant compounds, for example, benzimidazole derivatives from
various substituted benzimidazole and anticipate look at their physical properties, spectral
investigation & biological activities.
1.7 Research Outline & problem statement:
Benzimidazole derivatives showed their incredible moiety towards the pathogens, bacteria,
fungi & viruses. The benzimidazole derivatives having wide biological purpose, consequently
they utilized as clinical medication of anti-tumer, antiulcer &anti- viral agents. These days,
microbial infection diseases increases continuously in worldwide due to obstruction to no. of
antimicrobial agents for example Beta - lactam, quinolones, vancomycin, macrolides & so forth
they may be delivered by chemical synthesis & furthermore found naturally in other common
origins & plants.
Research Scheme:
Methodology: A short plan of the work to be completed:
The absolute work will be separated into following sections;
Section No.1: A survey of BZD Deriv. and its synthetic benefit with up-to- date references will
be portrayed.
Section No.2: In this section strategy for the preparation of compounds n-alkylated 2-(4-
bromophenyl)-1H-benzimidazole derivatives as pictured in (Scheme-I) will be talked about.
Reactions: A total composing study reveals that the chemistry of N-subbed benzimidazole but
there is scope to synthesis new benzimidazole derivative i.e. 2-(4-bromophenyl)-
1Hbenzimidazole.
To accomplish our point we have created economical & proficient synthesis followed by 2-(4-
bromophenyl)-1Hbenzimidazole by using acyl and alkyl halide as a beginning material for the
development of n-alkylated or acylated 2-(4-bromophenyl)-1H-benzimidazole derivatives. In
this method 2-(4-bromophenyl)-1hbenzimidazole was treated with different acyl and alkyl
halide in presence of K2CO3,KI and DMF which gives n-alkylated or acylated 2-(4-
bromophenyl)-1H-benzimidazole derivatives as visualized in (Scheme-I).
Potasium carbonate
N N
Potassium iodide
Br + R-X Br
NH DMF/ 80 -90°C N
R

Scheme - I

Section No.3:
The Compounds n-alkylated/n-acylated 2-[(4-bromobenzyl) sulfanyl]-1H-benzimidazole
derivatives were synthesized by condensation of 2-[(4-bromobenzyl) sulfanyl]-1H-
benzimidazole with acylated or alkylated agent (Scheme-II). These compounds will be
synthesized and characterized in this section.
Reactions:
Sulfanyl benzimidazole subsidiaries have bothered a lot of thought by virtue of their wide scope
of use in biological, drug & medicinal areas. To achieve the target we have planned eco-friendly,
proficient & financially synthesis.
An extensive literature review unveils that the chemistry of N-subbed benzimidazole but there is
scope to synthesis new benzimidazole derivative i.e. 2-[(4-bromobenzyl) sulfanyl]-1H-
benzimidazole . To achieve our point we have made beneficial and prudent synthesis succeeded
by 2-[(4-bromobenzyl) sulfanyl]-1H-benzimidazole by using acyl and alkyl halide as a beginning
material for the preparation of n-alkylated/n-acylated 2-[(4-bromobenzyl) sulfanyl]-1H-
benzimidazole derivatives.
In this method 2-[(4-bromobenzyl) sulfanyl]-1H-benzimidazole was treated with different acyl
and alkyl halide in presence of K2CO3,KI and DMF which gives n-alkylated/n-acylated 2-[(4-
bromobenzyl) sulfanyl]-1H-benzimidazole derivatives as visualized in (Scheme-II).

N Potasium carbonate
S N
Potassium iodide
NH Br + R-X S
DMF/ 80 -90°C N Br
R

Scheme -II

Section No.4:
The Compounds N-substituted 2-(4-( DMETC)phenyl)-1H-benzo[d]imidazole derivatives were
synthesized by reaction of 2-(4-( DMETC)phenyl)-1H-BZD with acylated or alkylated agent
(Scheme-III).. These compounds will be synthesized and characterized in this section.
Reactions: By considering the versatile application of N-substituted derivative of in medicinal &
biological fields, it was course of action to synthesize the new substituted
2-(4-(DMETC) phenyl)-1H-BZD subordinates with expect to obtain significant antimicrobial
agents. For attaining the objective work subbed 2-(4-( DMETC) phenyl)-1H-BZD derivatives
were prepared from 2-(4-( DMETC) phenyl)-1H-BZD with treatment of different acyl and
alkyl halide in presence of tert-BuOK and DMSO as shown in the Scheme -III.
 CH3 CH3
H3C H3C
Alkylation/Acylation

N N
S S
NH N

R
Scheme - III

1.8 Aim of the study:

The major interest is to grow new benzimidazole derivatives using simple benzimidazole
compound.
Chapter 3rd depicts the examinations on synthesis of N-alkylated 2-(4-bromophenyl)-1H-
benzimidazole using different acyl and alkyl halides.
Chapter 4th describes the investigation of synthesis of N-alkylated/n-acylated 2-[(4-
bromobenzyl) sulfanyl]-1H-benzimidazole derivatives, in the continuity of this chapter subbed
benzimidazole were synthesized from different acyl and alkyl halides.
5th chapter depicts the investigation of synthesis of N- 2-(4-( DMETC)phenyl)-1H-BZD
derivatives using different acyl and alkyl halids.
1.9 Objectives of the proposed work:
1) Synthesis N-alkylated 2-(4-bromophenyl)-1h-benzimidazole derivatives using 2-(4-
bromophenyl)-1Hbenzimidazole & their characterization.
2) To synthesize N-alkylated/N-acylated 2-[(4-bromobenzyl) sulfanyl]-1H-benzimidazole
derivatives & scrutinize their characterization.
3) To synthesize of N- 2-(4-(DMETC) phenyl)-1H-BZD derivatives & examine their
identification..
4) The whole synthesized series of compound will be checked for their biological potencies