1
CHAPTER - I
INTRODUCTION TO THE
CHEMISTRY OF BENZIMIDAZOLES
2
GENERAL
Heterocyclic compounds posses a cyclic structure with two or more different kinds of
atoms in the ring. These type of compounds are very widely distributed in nature and
are essential to life, playing a vital role in the metabolism of all living cells e.g. the
pyrimidine and purine bases of the genetic material DNA, the essential amino acids,
proline, hisitidine, the vitamins and coenzymes etc. There are a vast number of
pharmacologically active heterocyclic compounds, many of which are in regular
clinical use. A wide range of synthetic and naturally occurring heterocyclic compounds
find their use in medicines and also in pesticides, agrochemicals, polymers etc. This
attracts the attention of scientists for carrying out more and more research leading to
novel heterocyclic molecules having useful biological activities.
Of the wide variety of heterocyclic systems known till date, the nitrogen heterocycles
are of great importance and benzimidazole is one amongst such important nitrogen
heterocyclic species because of its synthetic utility and broad spectrum of
pharmacological activity1-10. The benzimidazole nucleus is an important heterocyclic
ring since several of its derivatives have pharmacological properties and have been
marketed as commercial products. Most significantly, the benzimidazole ring system
has been found to be an integral part of Vitamin-B12 (Figure-1) and (Figure-2) in the
form of 5,6-dimethyl-1-(-D-ribofuranosyl) benzimidazole.
Many benzimidazole derivatives with different pharmacological properties such as
anthelmentic11, antiulcer12-14, cardiotonic15, antihypertensive16, etc., have already been
reported. The literature precedence revealed that the substitutions at 1, 2 and 5
positions of the benzimidazole moiety is crucial for the compounds to exhibit wide
range of pharmacological activities.
3
Figure-1: Chemical structure of Vitamin B12
Figure-2: Vitamin B12- 3D structure [C63H90CoN14O14P]
4
The benzimidazole ring system can be theoretically derived by fusion of an imidazole
ring through its 4 -5 bond to a benzene ring (Figure-3).
NH
N
NH
N
1
2
34
5
1
2
34
5
Figure-3
The numbering in the benzimidazole ring system is done as shown below (Figure-4).
NH
N
1
2
34
6
7
5
Figure-4
The two nitrogens present in the imidazole ring are different from one another in their
nature and this makes the properties of the ring system diverse in character. The
nitrogen bearing hydrogen atom is sp3 in character and is often referred as pyrrole
nitrogen and the other is sp2 in character and is often referred as pyridine nitrogen. The
hydrogen atom attached to the nitrogen in benzimidazole exhibits tautomerism as
shown below (Figure-5).
N
NH
NH
N
Figure-5
This tautomerism is analogous to that found in imidazoles and amidines. Due to this
tautomerism, certain benzimidazole derivatives that appear at first as isomers are in
reality the tautomers. The 4 and 5 positions are equivalent to 6 and 7 positions because
of this tautomerism. For example, 5-methylbenzimidazole is a tautomer of 6-methyl
benzimidazole (Figure-6). Although two non-equivalent structures can be written, the
two structures are tautomers and both structures represent the same compound.
CH3
N
NHCH3
NH
N 1
34
5
674
5
6
71
3
2 2
Figure-6
To prevent any confusion between the two tautomers, both the designating structures
are written with the second one in parenthesis, e.g., 5(6)-methylbenzimidazole. When
5
the group attached to the nitrogen in the 1-position is other than hydrogen, such
tautomerism is prevented and only isomeric forms exist. Thus, 1,5-
dimethylbenzimidazole and 1,6-dimethylbenzimidazole exist as distinct, isomeric
compounds (Figure-7).
N
NCH3
CH3CH3
N
N
CH3
1
2
345
6
7
1
2
345
67
Figure-7
IMPORTANCE OF BENZIMIDAZOLE RING SYSTEM
A wide range of benzimidazoles and their derivatives find use in pharmaceuticals and
veterinary drugs showing varied therapeutic activities. Some of the commercially
important benzimidazole derivatives are presented in Table-1.
Table-1: Some of the benzimidazole derivatives of commercial importance
Generic
Name
Brand
Name
Innovator
Company
Therapeutic
category Structure
Fuberidazole Voronit Bayer Fungicide N
N
O
H
Lansoprazole Agopton Takeda Anti
secretary
agent N
NS
N
O
OF
F
F
H
Astemizole
Hismanal Janssen Anti allergic
& anti
histaminic N
N
N
N
F
O
H
Tenatoprazole Protop Mitsubishi
pharma
Gastric Anti
secretory
drug NN
N O
SN
O
O
H
6
Rabeprazole
Sodium
Aciphex Janssen Antiulcer
agent
N
N
SN
O
OO
Na+
Pantoprazole
Sodium
Protonix
or
Apton
Altana
pharma
Antiulcer
drugs N
NN
S
O
O
O
O F
F
Na+-
Enviroxime --- --- Antiviral
OH
N
NNH2
SO2iPr
Thiabenda-
zole
Mintezol Merck,
Sharpe &
Dohme
Human anti
helmintic&
fungicide
N
N
N
S
H
Oxibenda-
zole
Anthel
cide EQ
Or
Filaribits
plus
Glaxo
Smith-
kline
Treatment of
helmintic
diseases N
NN
O
OO
H
7
METHODS FOR SYNTHESIS OF BENZIMIDAZOLES
Detailed reviews17 covering the synthesis and chemistry of both imidazoles and
benzimidazoles have been published. Generally, benzimidazoles can be synthesized
from a variety of starting materials and a few of them are listed below in detail.
1. o-Phenylenediamines
2. o-(N-acylamino and N–aryolamino)arylamines and nitroarenes
3. o-Nitroarylamines and o-dinitroarenes
4. o-substituted-N-benzylideneanilines
5. Amidines
6. Other heterocyclic compounds
1. From o-Phenylenediamine
o-Phenylenediamine (1) reacts with (a) carboxylic acids and their derivatives, (b)
imino-ethers, (c) carbonyl compounds and (d) nitriles to yield differently substituted
benzimidazoles.
a) By reaction with carboxylic acids and their derivatives
2-Substituted benzimidazoles may be synthesized in good yields by condensing o-
phenylenediamine (1) with carboxylic acids under a wide variety of conditions.
Ladenburg18 first prepared 2, 5 (or 2, 6)-dimethylbenzimidazole by refluxing 4-methyl-
o-phenylenediamine in glacial acetic acid. The parent benzimidazole (2) was prepared
in 1878 by heating (1) with formic acid19 (Scheme-1).
NH2
NH2
N
N
H
H-COOH
(1) (2)
+
Scheme-1
Since then, a large number of benzimidazoles have been synthesized from 1 and
aliphatic acids20-23. The most satisfactory method for the synthesis of 2-
alkylbenzimidazoles (3, R = alkyl) was developed by Phillips24-25, which involves
refluxing equimolar quantities of the diamine and the aliphatic carboxylic acid in 4N
hydrochloric acid for 3 to 4 hr (Scheme-2).
8
NH2
NH2
N
N
R
H
R-COOH
(1) (3)
+
(R = Alkyl)
4N HCl
Reflux, 3-4hr
(R = Alkyl)
Scheme-2
The mechanistic pathway for the formation of benzimidazoles by the reaction of 1 with
organic acids has already been studied26-29. Further, the role of hydrochloric acid in the
reaction has also been investigated30. The catalytic action of hydrochloric acid is
explained on the basis of activation of the carboxyl group by the protonation of oxygen.
The intermediate in the reaction is the addition product formed by the attack of the
unshared electron pair of one nitrogen onto the carbonyl group of the protonated acid.
However, Phillips25 concluded that the monoacyl derivative was the necessary key
intermediate for formation of benzimidazole ring.
For aromatic carboxylic acids, however, Phillips procedure fails to give any respectable
yields of 2-arylbenzimidazoles25. Aromatic carboxylic acids were reported31 to give
good yields of 2-arylbenzimidazoles (4, R = Ar) when heated with 1 in a sealed tube at
180-190 oC. A better procedure for the preparation of 2-arylbenzimidazoles (4), from 1
and aromatic carboxylic acid involves the use of polyphosphoric acid32,33 (PPA) or
polyphosphate ester34 (PPE) as dehydrating agent. Alternatively, phosphorus pentoxide
has also been reported as a dehydrating agent for the preparation of 2-
arylbenzimidazole derivatives35 (Scheme-3).
NH2
NH2
N
N
R
H
R-COOH
(1) (4)
+
(R = Aryl)
PPA or PPE
or P2O5
(R = Aryl)
Scheme-3
The methods described above have been utilized in recent years for the synthesis of a
variety of benzimidazoles carrying thiazolyl, thiadiazolyl and isothiazolyl substiutuents
at 2-position36-37. Similarly, the other benzimidazoles synthesized include 1-aryl-5-
amino38; 2-trifluoromethyl39; 2, 6-bis (trifluromethyl)-4-nitro40; 2--mercaptoethyl41; 2-
(1-amino-alkyl)42 and 2-(p-iodostyryl)43 benzimidazole etc.
The reaction between 4-methyl-o-phenylenediamine dihydrochloride (5) and esters was
first investigated by Niementowski44, who prepared 5(6)-methylbenzimidazole (6, X =
9
5(6)-methyl) by condensation of equimolar amounts of (5) and ethyl formate at 225oC
in a sealed tube for 3 hr (Scheme-4).
NH2
NH2CH3 N
N
H
H O
O
C2H5
X+
(5)
225°C
Sealed tube, 3 hrs
(6)
.2HCl
Scheme-4
2-Methylbenzimidazole (3, R = CH3) was obtained by prolonged treatment of 1 with
acetic anhydride, whereas treatment for a shorter period yielded only N, N’-diacetyl o-
phenylenediamine (7)45 (Scheme-5). Wagner46
reported improved yields of 2-
methylbenzimidazole from 1 and acetic anhydride by using dilute hydrochloric acid.
Similarly, it was also observed that treatment of the free base of 5 i.e., 4-methyl-o-
phenylenediamine with acetyl chloride in refluxing benzene yielded 2,5 (2,6)-
dimethylbenzimidazole whereas the corresponding 4-methyl-N,N’-diacetyl-o-
phenylenediamine was the sole product when the reaction was carried out at room
temperature47.
NH2
NH2
N
N
R
H
NHCOCH3
NHCOCH3
(1)
(3)Acetic anhydride
Prolongedheating
Shortheating
(R = Methyl)
(7)
Scheme-5
Niementowski obtained 2-substiuted 5(6)-methylbenzimidazoles (8, X=5(6)-methyl, R
= H, CH3 or Ph) by heating free base (5) with the corresponding amides48 (Scheme-6).
NH2
NH2CH3 N
N
R
H
R
O
NH2
X+
(5)(8)
(R = H, CH3, Ph)(R = H, CH3, Ph)
Scheme-6
10
Bisbenzimidazoles (10) were synthesized by heating OPDA (1) or its dihydrochloride
salt with aliphatic dicarboxylic acid amides in high boiling solvents like ethylene glycol
or glycerol49 (Scheme-7).
N
N(CH2)n
N
N
H H
NH2
NH2
(CH2)n(CONH2)2+
(1) (10)
Ethylene Glycol
OR Glycerol
Scheme-7
b) By reaction with imino-ethers (Imidates)
o-Phenylenediamine (1) on treating with imino-ethers in dilute acidic medium led to the
formation of benzimidazoles in high yields (Scheme-8).
NH
N
R
NH2
NH2
R
NH
OMe
+
(1) (3)
( R = Alkyl)( R = Alkyl)
H+
Scheme-8
The main problem concerned with the Phillips procedure is that the diamine often
competes successfully for the proton of the acid catalyst, hence inhibiting nucleophilic
addition to the carbonyl group, this difficulty has been overcome by replacing the
carbonyl group by the more basic imino group, and very often the imidate method is
superior to the conventional Phillips procedure. For example, under Phillips conditions
the reaction of compound 1 with 2,4–dinitrophenylacetic acid takes place only under
drastic conditions and considerable resinification also occurs50, conversely, reaction of
the diamine with the hydrochloride of ethyl 2,4–dinitrophenylacetimidate (11) under
reflux gives the desired 2-(2,4-dinitrobenzyl)benzimidazole (12) in 84% yield50
(Scheme-9).
N
N
NO2
NO2
HNH2
NH2OC2H5
N
O2N
O2N H
+
(1) (12)
Solvent reflux
(11)
Scheme-9
11
Similarly 2-trichloromethylbenzimidazole (14) was synthesized in 95% yield by
reacting o-phenylenediamine hydrochloride (9) with ethyl trichloacetimidate (13) at
room temperture51, 52 (Scheme-10).
N
N
CCl3
HNH2
NH2 NH
CCl3O
RT
(9) (13) (14)
+.2HCl
Scheme-10
Other benzimidazoles like 2-nitroalkyl53, 2-aminoethyl54, 2-arylaminoethyl55, 2-
alkylesters of carbamic acids56, 57, 2-bromoalkyl58 and 2-heteroaryl benzimidazoles59
were also synthesized from 1 and the corresponding imino-ethers. In addition to this the
scope of imidates procedure for benzimidaoles synthesis has been assessed by King and
Acheson60.
c) By reaction with carbonyl compounds
(i) By reaction with aldehydes
The reaction between 1 and aldehydes as a method to synthesize benzimidazoles has
been reviewed independently by Rao and Ratnam61 and Smith and Ho62. Various 2-
substituted benzimidazoles (3, R = alkyl), (4, R = aryl) were synthesized by condensing
1 with aldehydes in the presence of oxidizing agents such as cupric acetate
(Weidenhagen procedure63), mercuric oxide (for 2-NHCOOMe)64, chloranil (for 2-
furyl)65, lead tetraacetate66, manganese dioxide67, nickel peroxide68 and nitrobenzene69.
An improvement in the conventional method is the use of the sodium bisulfite addition
product of the aldehyde70, which in boiling ethanol often results in good yields
(Scheme-11).
N
N
R
HNH2
NH2
R H
O
(1) (15)
+
Oxidising agent
(R = Alkyl, Aryl)(3, R = Alkyl)(4, R = Aryl) .
Scheme-11
The reaction of o-arylenediamines with formaldehyde gives rise to 1-methyl
benzimidazoles71,72 and these types of processes have been studied in detail73. Its
noteworthy to mention here that the reaction of 1 with aromatic aldehydes in methanol
12
medium gave monoanils (16) (Schiff bases, commonly known as monoanils in
benzimidazole chemistry) and in some cases the di-Schiff bases i.e., dianils61 (17)
depending on molar proportions of the aldehyde used in the reaction. The monoanils
when treated with acetic acid at room temperature resulted in the dehydrogenatively
cyclized products 2-arylbenzimidazoles (4, 1:1 products) and the dianils resulted in the
formation of 1-arylmethyl-2-arylbenzimidazoles (18, 1:2 product) in varying
proportions (Scheme-12).
NH2
NH2
N
NH
Ar
NH2
N=CH-Ar
N=CH-Ar
N=CH-Ar
N
N
Ar
CH2-Ar
(1)
(4)(16)
(17) (18)
Scheme-12
The monoanils (16) prepared separately could be converted to 2-substiuted
benzimidazoles (4) with the help of dehydrogenating agents68, 69, 74-76 (Scheme-13).
N
N
R
H
NH2
N CHAr
(16) (4)
DehydrogenatingAgent
Scheme-13
Similarly, the dianils (17) obtained from 1 with two moles of aldehyde were cyclised to
1,2-diarylsubstitutedbenzimidazoles (18) both under acidic as well as thermal
conditions73, 75, 77-79 (Scheme-14).
N=CH-Ar
N=CH-Ar
N
N
Ar
CH2
Ar(17) (18)
Acidic conditions/Thermal conditions
Scheme-14
Rao and co-workers80, reported the isolation, although in poor yields of other products,
1,3-diarylmethyl-2-arylbenzimidazolines (19, 1:3 product) in the condensation of 1
13
with o-chloro and m-nitrobenzaldehyde in acetic acid at room temperature (Scheme-
15).
N
N
Ar
CH2-Ar
N
NH
Ar
NH2
NH2 N
N
CH2-Ar
H
Ar
CH2-Ar
R H
O+ + +
(1)(R = Aryl)
(4) (18) (19)
Scheme-15
Obviously, the above reaction proceeds through the disproportionation of the initially
formed monoanils. The monoanils have been shown81 to exist in tautomeric equilibrium
with the corresponding dihydrobenzimidazoles (20) by NMR (Scheme-16).
NH
NH
H
Ar
N=CH-Ar
NH2
(16) (20)
Scheme-16
These dihydroderivatives could not be isolated in free state in the reaction of 1 with
aromatic aldehydes. However, the intermediate dihydroderivative 22 was isolated in
pure form, during the preparation of imidazo[4,5-b]pyridine 23 obtained from the
reaction of 2,3-pyridinediamine (21) with aromatic aldehydes82 (Scheme-17).
N
NH2
NH2 N
N
NH
ArAr H
O
N
NH
NH
OH
Ar
(21) (23)
+ Acetic acid
RT
(22)
Acetic acid
100°C
Scheme-17
(ii) By reaction with ketones
o-Phenylenediamine (1) has been reported83-85 to condense with ketones to form 2,2-
disubstitutedbenzimidazolines (24) which decomposes under the influence of heat to
give 2-substituted benzimidazole (3 or 4, R = R’=Variously substituted) and a
hydrocarbon. In several cases, the hydrocarbon was isolated and identified. In the
decomposition of an asymmetrically substituted benzimidazoline (24), it has been
14
observed84 that the C-C bond, which has greater degree of substitution, is generally
broken (Scheme-18).
NH
NH
R
R'
NH2
NH2
N
NH
R
R R'
O
R' > R R'-H+ +
(1) (R, R' = Variously substituted)
(24) (3, R = Alkyl)(4, R = Aryl)
Scheme-18
(d) By reaction with Nitriles
Nitriles when heated with o-phenylenediamine dihydrochloride (9) at 200°C gave 2-
substituted benzimidazoles (3). This reaction has been studied by Holljes and Wagner86
who have proposed the following mechanism for the reaction according to which the
reaction proceeds under acidic conditions and probably involves hydrogen–ion
catalysis (Scheme-19).
NH2
NH2
NH2
NH2
N
NH
R
NH2
H
N
N
R
NH3Cl
H
H
N
N
R
H
. .
.2HCl
RCN R-C=NH.Cl+
.HCl
+
NH4Cl+ -
+ +
+
(9)
(3, R = Alkyl)(4, R = Aryl)
Scheme-19
At this reaction temperature ammonium chloride will undergo decomposition to
generate additional hydrogen chloride and cause the reaction to proceed further. Using
this procedure 2-alkyl86, 2-aryl86, 2-heteroarylbenzimidazoles87, 2-guanidino
benzimidazoles88 and 2-alkylesters of carbamic acids89 have been synthesized.
2) From o-(N-acylamino and N-aroylamino) arylamines and nitroarenes
The formation of benzimidazoles by the reaction of 1 with carboxylic acids and related
compounds90 is presumed to involve the formation of (monoaroylamino) arylamines. A
number of benzimidazole compounds (27) have been synthesized by cyclisation of N-
15
monoacyl-o-phenylenediamines (25), under acid catalysed conditions or in uncatalysed
thermal conditions91-98. Compound 27 can also be generated in situ from the appropriate
o-nitroarylamine (26) by using a variety of reducing agents such as Sn/AcOH99,
Na2S2O4100, H2/Pd/C101, Raney-Ni102, SnCl2/HCl103, Fe/AcOH104, sodium sulfide105 etc.
(Scheme-20).
NCOR2
NH2
R1
N
R2
N
R1
NCOR2
R1
NO2
Reductantaq. HCl
or heat
(25) (26)(27)
Scheme-20
Thus, differently substituted benzimidazoles (27) and related compounds106,107 have
been synthesized by the cyclisation of N-monoacyl-o-phenylenediamines (25).
3) From o-Nitroarylamines and o-dinitroarenes
Benzimidazoles have been synthesized in a single step from o-nitroarylamine or
o-dinitroarenes by using reductants such as NaHSO3108, BaSO4/Pd/H2
109, Zn110,
Na2S2O5111 and Na2SO3
112. Benzimidazoles are also obtained by the thermolysis of
nitroarenes and alcohol mixtures in the gas phase. Since reasonable yields are obtained,
these processes have got commercial importance. When o-nitroanilines are used in
thermolysis, a secondary reaction occurs which converts the 2-alkylbenzimidazoles into
1,2-dialkylbenzimidazoles113. o-Dinitroarenes behave in a similar fashion with alcohols
over alumino–copper or vanadium, but in this case the products are exclusively 2-
alkylbenzimidazoles (3).
The direct reductive method from the carbanilic acid derivatives (28) leading to alkyl
esters of 2-amino-1-benzimidazolecarboxylic acids (29) is of commercial value, since
products of the latter type are transformed thermally into alkyl esters of benzimidazole-
2-carbamic acids (30)114 (Scheme-21).
16
NO2
N
N
O
O
R
N
N
NH2
OO
R
N
N
N
H
O
O R
HH2/Raney Ni
(28) (29) (30)
Scheme-21
4) From o-substituted-N-benzylideneanilines
The reduction of aromatic nitro compounds by triethylphosphite and related reagents
has been widely used as a simple and effective route to a variety of nitrogen containing
heterocycles115. Derivatives of N-benzylidene-2-nitroaniline (31) were converted into
substituted 2-phenylbenzimidazoles116 (4) in this manner and the yields were slightly
higher than those obtained by the use of classical Weidenhagen aldehyde method63
(Scheme-22).
N=CH-Ph
NO2
N
N
Ph
H
(EtO)3P/t-BuC6H5
reflux
(31) (4)
Scheme-22
Good yields of benzimidazoles can be obtained by heating N-benzylidene-2-
azidoanilines (32) in 1,2–dichlorobenzene117 or dimethylformamide118 and the method
can be used to prepare 2-substituted benzimidazoles (Scheme-23).
N=CH-Ph
N3
N
N
Ph
H(32) (4)
Scheme-23
5) From Amidines
Generally benzimidazoles are synthesized from 1 and its derivatives. Their
preparation119 from N’-aryl-N-hydroxylamidines (33) is unusual in the sense that both
nitrogen atoms of the imidazole ring arise from one side chain (Scheme-24).
17
N R
N
H
OH
N
N
R
H
(33) (4)
PhSO2Cl / Et3N
or Pyridine
(R = Aryl)
Scheme-24
The reactions are carried out under mild conditions using benzene sulfonyl chloride in
pyridine or triethylamine giving good yields .This method has been used to prepare a
variety of compounds with substiutuents in the aryl ring119.
6) From other heterocyclic compounds
Benzimidazole derivatives can be prepared by reductive cyclisation of o-
benzoquinonedibenzimide by using triphenylphosphine120. Benzimidazoles are also
formed during the photolysis of indazoles121.
18
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