Journal of Saudi Chemical Society (2017) 21, 229–237

King Saud University

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ORIGINAL ARTICLE

Synthetic approaches to benzimidazoles from

o-phenylenediamine: A literature review
Shatha Ibrahim Alaqeel

Department of Chemistry, College of Science, King Saud University (034), Riyadh 11495, Saudi Arabia

Received 17 December 2015; revised 2 February 2016; accepted 5 August 2016

Available online 13 August 2016

KEYWORDS
Benzimidazole nucleus;
o-Phenylenediamine;
Pharmacological activity;
Therapeutic compound
Abstract The methods for the synthesis of benzimidazoles have become a focus of synthetic
organic chemists, as they are useful building blocks for the development of important therapeutic
compounds in medicine. Benzimidazole nucleus plays a very important role as a therapeutic agent
e.g. antiulcer and anthelmintic drugs. Other benzimidazole derivatives exhibit pharmacological
activities such as antimicrobial, antiviral, anticancer, anti-inflammatory and analgesic.
Ó 2016 King Saud University. Production and hosting by Elsevier B.V. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction azomycin, metronidazole, misonidazole, and chlotrimazole,

Among heterocyclic pharmacophores, the benzimidazole ring
system is quite common. These substructures are often called
‘privileged’ due to their wide recurrence in bioactive com-
pounds. Although there is great interest in benzimidazole
ligands and structural chemistry, the main interest is in their
biological activities.
The early 1950s was an important period regarding discov-
ery of the biological significance of benzimidazole-containing
structures and the closely-related purines (Fig. 1). The 5,6-di
methyl-1-(a-D-ribofuranosyl)benzimidazole ring system was
discovered in 1948 as an integral part of the structure of vita-
min B12 [1] (Fig. 1).
Subsequently pharmaceutical, veterinary and agrochemical
products were discovered including thiabendazole, cimetidine,
E-mail address: shalaqeel@ksu.edu.sa
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1319-6103 Ó 2016 King Saud University. Production and hosting by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
antihistamines, astemizole and the anti-ulcerative omeprazole)
[2].
Benzimidazole-based drugs exhibit a wide range of different
biological activities as a result of changing the groups on the
core structure, as shown in Fig. 2. These biological activities
include anti-cancer (1) [3], bactericidal (2), [4], fungicidal (3)
[5] and [6], analgesic (4) [7] and anti-viral properties (5) [8].
Some have cardiovascular applications (6) [9] while some
derivatives have been synthesized and evaluated for inhibition
of HIV-1 infectivity [10].
2. Synthesis of benzimidazoles
The first benzimidazole was prepared by Hoebrecker [11], who
obtained 2,5-dimethylbenzimidazole by the reduction and
dehydration of 2-nitro-4-methylacetanilide (Scheme 1).
Almost all syntheses of benzimidazoles start with benzene
derivatives possessing nitrogen-containing functions ortho to
each other (Fig. 3) that is, the starting material possesses the
function designated by formula many methods have been
reported for the synthesis of benzimidazols. Most of these
methods involve the condensation of ortho-
230 S.I. Alaqeel

N
N 2.1. By reaction with carboxylic acids

N N
H Literature survey has revealed that o-phenylenediamines react
Purine readily with most carboxylic acids to give 2-substituted benz-
imidazoles, usually in very good yields. The reaction is carried
O out usually by heating the reactants together on a steam bath,
NC
NH2
NH2 by heating together under reflux or at an elevated temperature,
O H3C
or by heating in a sealed tube [13] (Scheme 2).
NH2
The most commonly used (Phillip’s method [14], involves
H3 C
N
the condensation of o-diaminobenzenes with carboxylic acids
O
H2N N or its derivatives, including heating the reagents together in
Co
O H3C
H CH3
the presence of concentrated hydrochloric acid (Scheme 3), this
N N
H2N is the most common synthetic method for preparation of a
CH3 wide range of benzimidazoles.
O
CH3 CH3 CH3 Hollan et al. who have reported the reaction of the
O
N CH3 appropriate imidate ester (trichloroacetimidate) with o-
NH phenylenediamine or its salt gives the 2-trichloromethyl
- N CH3 benzimidazole (Scheme 4) only at room temperature, and this
O HO
H3C C C is an important precursor for 2-carboxylic benzimidazoles [15].
O P
H O
H O Rithe et al. have reported various of 2-substituted benzim-
O
H idazole derivatives in moderate to good yield have been
CH2 OH prepared in one-spot reaction by condensation of
vitamin B 12 o-phenylenediamine (0.01 mol) and different aromatic acid
(0.01 mol) in the presence of ammonium chloride as catalyst
Figure 1 Some imidazole containing bioactive compounds. at 80–90 °C (Scheme 5). The reaction is green and economi-
cally viable [16].
phenylenediamine, and its derivatives with carboxylic acids, or Recently Saberi has reported synthesis of 2-benzimidazoles
aldehydes. under microwave irradiation and solvent-free conditions which
Various catalyzed synthesis of benzimidazole derivatives is catalyzed by alumina, silica gel and zeolite HY As shown in
are known condensation of o-phenylenediamine with ortho Scheme 6, o-phenylenediamine (2 mmol) with aromatic, ali-
esters in the presence of various lewis acid catalyst is also phatic and heterocyclic carboxylic (2 mmol) and 50 mg of Alu-
known such as ZrCl4, SnCl4, TiCl4, ZrOCl2
9H2O and HFCl4. mina or Silica gel or Zeolite were mixed thoroughly in a
Here a number of different synthetic methods for benzimi- mortar. The reaction mixture was then irradiated in a domestic
dazoles have been grouped according to the starting material microwave oven for 5–9 min at 160–560 W [17].
of o-phenylene diamines [12].

ClH2CH2C O
N N N OCH3
ClH2CH2C
CH2CH2CH2CO2H NH
N N
H H
Imet 3393 (Anticancer)
S
1
N OCH3 Carbendazim (Fungicide)
O
3
N S
H
(Bactericide)
COOEt
O 2 H
N N
N
CH2PhCl
S N N
N
H CH2CH2CO2H H
N
Diabazole (Vasodilator spasmlytic
Bezitramide (Analgesic) hypotensive)
4 6

Cl
(Anti-viral)

Figure 2 Some benzimidazole containing drugs.

Synthetic approaches to benzimidazoles from o-phenylenediamine 231

H 3C NH2 H 3C N
H3C NO2
Sn -H2O CH3
HCl N
NHCOCH3 NHCOCH3
H

Scheme 1

H 2.2. By reaction with aldehydes

N
H
R
H Under the correct conditions aldehydes may react with o-
N
H phenylenediamines to yield 2-substituted benzimidazoles
(Scheme 7).
Figure 3 Ortho di nitrogen compounds. Since an oxidation is involved, the reaction is best carried
out under oxidative conditions. This oxidation may be brought
about by the air or, more conveniently, by the use of other oxi-
NH2 O N dizing agents such as cupric acetate. This latter reagent was
R R + 2H2O first introduced by Weidenhagen [13]. Weidenhagen’s method
NH2 OH N consists in reacting the diamine and aldehyde in water or alco-
H holic solution in the presence of cupric acetate or a similar cup-
ric salt. The cuprous salt of the benzimidazole separates, and
Scheme 2 by means of hydrogen sulfide it may be readily decomposed
to the free benzimidazole and cuprous sulfide. The sulfide
may be removed readily by filtration (Scheme 8). By means
NH2 O H of Weidenhagen’s method excellent yields of 2-substituted ben-
N
HCl (4N) zimidazoles may be obtained.
R
R OH The condensation of phenylenediamines with aldehydes is
NH2 N
achieved by various reported conditions. As shown in
Scheme 3 Scheme 9, this can be achieved in the presence of sodium
metabisulphite [18].
Suheyla et al. who have reported this reaction rely on pre-
forming the bisulfite adduct of the aryl aldehyde to prepare
CCl3 H
NH2
AcOH
N benzimidazole, in which an ethanolic solution of aryl aldehyde
CCl3 was added separately to an aqueous solution of sodium
+ O
NH RT N metabisulphite; the adduct formed precipitated from the reac-
NH2
tion was filtered and dried. The o-phenylenediamine in DMF
Scheme 4 was then added to the adduct and the mixture was heated at
130 °C for several hours affording benzimidazole (Scheme 10).
Or heating in the presence of nitro benzene [19]. Mann et al.
used a mixture of unsubstituted or substituted phenylenedi-
NH2 O H
EtOH.NH4Cl
N amine and appropriate aldehyde in nitrobenzene heated at
R OH
R 140 °C., the mixture was cooled and filtered after adding water
80-90 oC N
NH2 which gives benzamidazole (Scheme 11).
Venkateswarlu et al. have reported the synthesis of benzim-
Scheme 5 idazole derivatives, with the use of lanthanum chloride as an
efficient catalyst One-pot synthesis of 2-substituted benzimida-
zole derivatives from o-phenylenediamine and a variety of
MW aldehyde were carried out in the presence of lanthanum chlo-
Zeolite HY ride (10 mol%) in acetonitrile at room temperature [20]
(Scheme 12).
NH2 O H The other way was synthesized by Lin et al. involving a
N
R direct one step synthesis of various benzimidazoles from
R OH
NH2 MW N phenylenediamines and aldehydes that includes air as oxidant
Silica gel [21] (Scheme 13).
Rushi et al. have reported 2-substituted benzimidazoles
have been synthesized in excellent yields in a single pot under
solvent-free conditions from o-phenylenediamine and aldehy-
MW des in the presence of a catalytic amount of indium triflate
[In(OTf)3] at room temperature [22] (Scheme 14).
Alumina
(acidic) A series of benzimidazole derivatives were synthesized in
good to high yields by reaction of o-phenylenediamine and dif-
Scheme 6 ferent aromatic aldehydes in the presence of sodium hex-
232 S.I. Alaqeel

NH2 N N
-H2
RCHO CHR R
+
NH2 N
NH2 H

Scheme 7

NH2
N
.2HCl +R1CHO + 2(CH3COO)2Cu R1 . Cu2Cl2 + 4 CH3COOH + H2O
NH2 N
H

Scheme 8

Cl O Cl
F NH2 H
F N
+ H Cl
Na2S2O5
N NH2 N
Cl DMF N
O
O

Scheme 9

NH2
H
H
NH2 N
Ar-CHO Ar OH
Ar
N
SO3Na

Scheme 10

O
NH2 H
PhNO2 N
H
+ NO2
heat N
NH2 O 2N

Scheme 11

NH2 CHO LaCl3 N R

+ R
NH2 N
CH3CN R.T
H

R= H,Alkyl, Aryl

Scheme 12

O
NH2 N
air solvent
H
+
N
NH2 reflux or 100 oC
H

Scheme 13

afluroaluminate, Na3AlF6, as an efficient catalyst at 50 °C [23] oxidative cyclization of o-phenylenediamine and different alde-
(Scheme 15). hydes using dioxane dibromide, as a user-friendly reagent. This
Birajdar et al. have synthesized a mild and efficient is a new, convenient and facile methodology for the synthesis
approach for the synthesis of benzimidazole ring [24] through of 2-substituted-1H-benzo[d]imidazoles (Scheme 16).
Synthetic approaches to benzimidazoles from o-phenylenediamine 233

O O
NH2 N NH2 N
In(OTf)3
Iodine / Water
+ R H R + 2 R H R
NH2 N NH2 80-90 oC / 1.2-1.5 h N
H
R
Scheme 14
Scheme 20

O
(0.1 mmol) that was stirred magnetically with CHCl3 at room
NH2 N temperature as shown in Scheme 19.
EtOH
+ Ar H Ar Iodine catalyzed synthesis of 2-Aryl-1-arylmethyl-1H-
NH2 Na3AlF6 N benzimidazoles is demonstrated by Aniket et al. using
H phenylenediamine and aldehydes which are carried out at
80–90 °C. New approach is promising and giving moderate
Scheme 15 yields with high purity and selectively single product in aque-
ous media [28] (Scheme 20).
Pardeshi et al. have synthesized a simple, efficient and selec-
O
NH2 N tive method [29] for the synthesis of 2-aryl benzimidazole
Dioxane dibromide through the reaction of ophenylenediamine with aryl aldehydes
+ R H R
NH2 Acetonitrile 30-60 min. ,rt. N in aqueous media in the presence of sodium dodecyl sulfate as
H shown in Scheme 21.

Scheme 16 2.3. By reaction with acid anhydrides

Srinivasulu1 et al. one-pot synthesis of 2-substituted benz-
imidazole derivatives from o-phynelyenediamine and substi-
tuted aldehydes were developed under zinc triflate in ethanol
solvent at reflux temperature [25] as shown in Scheme 17.
Sehyun et al. have reported the reaction of o-
phenylenediamine and a variety of aliphatic/aromatic aldehy-
des [26] in methanol proceeds at room temperature with only
natural sources, molecular oxygen and visible light irradiation
with blue LEDs (Scheme 18).
Vishvanath et al. have used nickel acetate efficiently cat-
alyzed the synthesis of benzimidazole derivatives [27] and in
this method is involved a mixture of benzaldehyde (1 mmol)
and o-phenylene diamine (1 mmol) with Nickel Acetate
Literature survey has revealed that the reaction of acid anhy-
drides and o-phenylenediamines will lead to benzimidazoles
or to N,N0 -diacylphenylenediamines depending on the condi-
tions employed. It was formerly thought that o-
phenylenediamine yields benzimidazoles with acids and diacyl
derivatives with acid anhydrides; however, this was shown to
be incorrect. Time appears to be a decisive factor and if the
refluxing is continued long enough benzimidazoles may be
obtained, usually in good yields. o-Phenylenediamines when
heated under reflux for several hours with acetic anhydride is
completely converted to 2-methylbenzimidazole [13]
(Scheme 22).

NH2 O
N
Zn (OTf)2 R
+ H
NH2 Ethanol N
reflux, 8h
R H

Scheme 17

O
NH2 N
O2 (from air)
+ R H R
NH2 MeOH (0.1M) ,r.t N
blue LEDs (7W) H

R= aliphatic, aromatic

Scheme 18

O
NH2 N
Ni (OAc)2
+ R' H R'
NH2 CHCl3 ,RT N
R R
H

Scheme 19
234
O
NH2
sodium dodecyl sulfate (10 mol
+ Ar H Ar
R NH2
Scheme 21
NH2
+ 2 ( CH3CO)2O
NH2
Scheme 22
The reaction of o-phenylenediamines with acetic anhydride
has been carried out with acetic anhydride alone or with acetic
anhydride to which has been added sodium acetate, mineral
acids, or acetic acid.
Excellent results have been obtained by employing the
modification of Phillips involving the addition of dilute min-
eral acids (usually about 4 N hydrochloric acid) to the reaction
mixture. Thus, 2-methylbenzimidazole may be obtained in
93.3% yield from o-phenylenediamine and acetic anhydride
on heating with 15% hydrochloric acid.
2.4. By reaction with esters
Reaction of o-phenylenediamines with esters also yields benz-
imidazoles. Von Niementowski first investigated the reaction
of esters and o-phenylenediamines to give benzimidazoles.
Equimolecular amounts of 3,4-diaminotoluene dihydrochlo-
ride and ethyl formate when heated in a sealed tube for 3 h
at 225 °C give 84% of 5(or 6)-methylbenzimidazole hydrochlo-
ride [13] (Scheme 23).
The product is not further alkylated by the ethyl chloride
formed. Ethyl acetate under the same conditions gives only a
poor yield of 2,5(or 2,6)-dimethylbenzimidazole, and poor
yields of benzimidazoles would probably be obtained from
esters of acids of higher molecular weight. A good yield of 2-
methylbenzimidazole may be obtained by allowing a mixture
of o-phenylenediamine and ethyl acetate to stand.
2.5. By reaction with amides
Relatively few amides have been used for the synthesis of ben-
zimidazoles. However, good yields have been obtained in most
cases. The amides that have been used are listed in Table 1.
Equimolecular amounts of o-phenylenediamine dihy-
drochloride and benzamide when heated to 240–250 °C give
an almost quantitative yield of 2-phenylbenzimidazole.
2.6. by reaction with urea
Rathod et al. have used o-phenylenediamine dihydrochloride
and when it was heated with urea at 130 °C. gives 2(3H)-
benzimidazolone (Scheme 24).
This general method has been used also for the preparation
of substituted benzimidazolones [13]. By heating o-
phenylenediamine and urea under reflux in amyl alcohol solu-
S.I. Alaqeel
N
Water N
R
H
N
CH3 + 3 CH3COOH
N
H
tion until the evolution of ammonia ceased, Mistry and Guha
have obtained a 95% yield of 2(3H)-benzimidazolone.
2.7. By reaction with acid chlorides
The action of acid chlorides on o-phenylenediamines leads to
benzimidazoles or monoacylated or diacylated o-
phenylenediamines, depending upon experimental conditions.
Acetyl chloride with 3,4-diaminotoluene in benzene solution
yields 2,5 (or 2, 6)-dimethylbenzimidazole if the reaction is car-
ried out without cooling and diacetyl-o-phenylenediamine
when the reaction is cooled (Scheme 25).
Most reactions between o-phenylenediamines and acid
chlorides to give benzimidazoles have been carried out with
aroyl chlorides. The reactions are carried out usually by heat-
ing the components together at about 200–220 °C., by heating
under reflux, or by heating on a steam bath in the presence of
pyridine or a similar basic substance. Since benzimidazoles
which possess no grouping in the l-position may undergo acy-
lation with acid chlorides, most reactions have been carried out
with N-substituted o-phenylenediamines. Table 2 lists the com-
pounds that have been prepared by the reaction of acid chlo-
rides and N-substituted o-phenylenediamines.
2.8. By reaction with nitriles
Cyanogen bromide will react with o-phenylenediamines to
yield 2-aminobenzimidazoles in good yields; for example, 2-
aminobenzimidazole may be prepared from cyanogen bromide
and o-phenylenediamine (Scheme 26).
The reaction is carried out by mixing equimolecular
amounts of the reactants in aqueous suspension.
Pellizzari has obtained benzimidazole derivatives by treat-
ment of o-aminophenylurea with cyanogen bromide
(Scheme 27).
O-phenylene-a-guanylurea is unstable and tends to hydro-
lyze to 2-aminobenzimidazole.
Heating the monohydrochloride of o-phenylenediamine
with an aliphatic or an aromatic nitrile at 200 °C results in
the formation of a 2-substituted benzimidazoles. o-
Phenylenediamine, itself, fails to react with benzonitrile at
200 °C, indicating that benzimidazole formation depends upon
the presence of acid. Formation of a mixture of an imino chlo-
ride and o-phenylenediamine may be the rate-determining step
of the reaction. The combination of these two substances could
Synthetic approaches to benzimidazoles from o-phenylenediamine 235

H 3C NH2 H 3C N
.2HCl + HCOOC2H5 HCl + 2H2O + C2H5Cl
NH2 N
H

Scheme 23

Table 1 Benzamidazoles from amides.

Diamine Amide Product
H 3C NH2 H 3C N
.2HCl
HCONH2 N
NH2
H
H 3C NH2 H3C N
.2HCl CH3
CH3 CONH2 N
NH2
H
H 3C NH2 H 3C N
.2HCl C 6H 5
C6 H5 CONH2 N
NH2
H

NH2 H
N
.2HCl + NH2CONH2 CO + 2NH4HCl
NH2 N
H

Scheme 24

NH2 O H 3C N
C 6H 6
Cl CH3
NH2 N
H

Scheme 25

NH2
N
Table 2 Benzamidazoles from acid chlorides and N-substi- + BrCN NH2 .HBr
tuted-o-phenylenedimines. NH2 N
H
Diamine Acid chloride Product
NH2 N Scheme 26
CH3
CH3 COCl N
NHC2H5 Nitriles that have been used in the synthesis of benzimida-
C 2H 5 zoles are listed in Table 3.
NH2 N
C6H5 2.9. By reaction with ketones
C6 H5 COCl N
NHC6H5
C 6H 5 The reaction of o-phenylenediamines with a number of ketones
has been investigated by Elderfield and Kreysa. The reaction
occurs as indicated in Scheme 29.
lead to formation of hydrochloride of an o-aminophenyl sub- In several cases the product represented by R00 H was iso-
stituted amidine, which could lose the elements of ammonium lated and identified.
chloride to give the 2-substituted benzimidazole (Scheme 28). Ladenburg and Rugheimer have obtained 2-phenyl-5 (or
This scheme is supported by the observation that N- 6)-methylbenzimidazole by heating 3,4-diaminotoluene with
phenylbenzimino chloride react with o-phenylenediamine to acetophenone at 180 °C for some time. Here again the methyl
give 2-phenylbenzimidazole. group is the one that is eliminated preferentially (Scheme 30).
236 S.I. Alaqeel

NHCONH2
NHCONH2 N
BrCN moist air
+ NH2
NH2 NHCN or water N
CONH2
o-Phenylene-a-guanylurea

Hydrolysis

N
NH2
N
H

Scheme 27

NH2 NH2 Cl
D
.HCl + RCN + HN C R
NH2 NH2

H H
N N
NH4Cl + C R
R
N NH2Cl
NH2

Scheme 28

o-Phenylenediamine reacts with ketones to form 2-

disubstituted benzimidazolines, these decompose under the
Table 3 Benzimidazoles from nitriles.
influence of heat with the formation of a 2-substituted benzim-
Diamine Nitrile Product idazole and a hydrocarbon. The decomposition of unsymmet-
o-Phenylenediamine HCN Benzimidazole rically substituted benzimidazoline may lead to formation of
o-Phenylenediamine CH3CN 2-Methylbenzimidazole two different benzimidazoles depending upon whether the sub-
o-Phenylenediamine C2H5CN 2-Ethylbenzimidazole stituent R or the substituent R0 is eliminated preferentially
o-Phenylenediamine C6H5CN 2-phenylbenzimidazole (Scheme 31).

NH2 H
N N
+ R1COR11 CR1R11 -R11H R1
NHR N N
R R

R = H or alkyl

Scheme 29

H3C NH2 H3C N

+ CH3COC6H5 C 6H 5 + CH4 + H2O
NH2 N
H

Scheme 30
H
N
R R1 H
NH2 H
R N R N
heat
+ O C C
NH2 R1 N R1
H
H N
R1 + R H
N

Scheme 31
Synthetic approaches to benzimidazoles from o-phenylenediamine
O2N NH2
HC(OC2H5)3
NHC6H5
Scheme 32
2.10. By reaction with potassium hydroxide and chloroform
Grassi-Cristaldi and Lambarbi have reported the synthesis of
benzimidazole by heating o-phenylenediamine with chloro-
form and potassium hydroxide (dissolved in ethanol). This
convenient method for the preparation of benzimidazole is
related to the method involving the use of ethyl orthoformate.
Ethyl orthoformate was first used for the preparation of
benzimidazoles by von Walther and Kessler who have synthe-
sized 1-phenyl-5-nitrobenzimidazole by the reaction between
ethyl orthoformate and 4-nitro-2-aminodiphenylamine
(Scheme 32).
Very recently, the use of ethyl orthoformate has been inves-
tigated more fully by Mamalis, Petrow, and Sturgeon who
have reported o-phenylenediamines or N-alkylated o-
phenylenediamines which may be converted to the correspond-
ing benzimidazoles in almost quantitative yields by the use of
an excess of ethyl orthoformate at an elevated temperature or
in a solvent such as ethanol or ethyl acetate.
3. Conclusion
Benzimidazoles possess one of the most useful biological activ-
ities. Benzimidazoles are utilized in many therapeutic applica-
tions such as anti-inflammatory, anti anxiety and antimicrobial
compounds.
The efficient and economical methods of synthesizing ben-
zimidazole by condensation reaction between ortho phenylene
diamine and various compounds in the presence of various
conditions presented in this review helps chemists to get the
first hand information for the synthesis of benzimidazole and
become very useful for chemists and workers in this field, to
develop protocols for the large production of benzimidazoles
and this can be developed from year to year to produce new
economical and environmental clean protocols for the large
scale production of important pharmacophores based on syn-
thesized benzimidazoles in the future.
Acknowledgement
This research project was supported by a Grant from the
‘‘Research Center of the Female Scientific and Medical Col-
leges”, Deanship of Scientific Research, King Saud University.
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