Facile one-pot clean synthesis of benzimidazole motifs: Exploration on bismuth nitrate accelerated subtle catalysis

Article abstract of DOI:10.1016/j.cclet.2015.04.012

Abstract In the present letter, an efficient, clean and one-pot synthesis of 2-substituted benzimidazole and 1,2-disubstituted benzimidazole derivatives has been explored by reacting o-phenylenediamine with aromatic aldehydes using bismuth nitrate as a ca

Full text of DOI:10.1016/j.cclet.2015.04.012

Accepted Manuscript
Title: Facile one-pot clean synthesis of benzimidazole motifs:
Exploration on bismuth nitrate accelerated subtle catalysis
Author: Vilas N. Mahire Pramod P. Mahulikar
PII:
S1001-8417(15)00145-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2015.04.012
CCLET 3279
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
8-2-2015
9-3-2015
19-3-2015
Please cite this article as: V.N. Mahire, P.P. Mahulikar, Facile one-pot clean synthesis
of benzimidazole motifs: Exploration on bismuth nitrate accelerated subtle catalysis,
Chinese Chemical Letters (2015), http://dx.doi.org/10.1016/j.cclet.2015.04.012
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Graphical Abstract
Facile one-pot clean synthesis of benzimidazole motifs: Exploration on bismuth nitrate accelerated subtle catalysis
Vilas N. Mahire, Pramod P. Mahulikar*
School of Chemical Sciences, North Maharashtra University, P.B. No.80, Jalgaon - 425 001, (M.S.) India
The present letter, one pot clean synthesis of 2-substituted benzimidazole and 1,2-disubstituted benzimidazole derivatives have been explored
using bismuth nitrate as an efficient catalyst.
Page 1 of 9

Original article
Facile one-pot clean synthesis of benzimidazole motifs: Exploration on bismuth nitrate
accelerated subtle catalysis
Vilas N Mahire, Pramod P Mahulikar
School of Chemical Sciences, North Maharashtra University, Jalgaon - 425 001, (M.S.) India
ARTICLE INFO
ABSTRACT
Article history:
In the present letter, an efficient, clean and one pot synthesis of 2-substituted benzimidazole
and 1,2-disubstituted benzimidazole derivatives have been explored by reacting
o-phenylenediamine with aromatic aldehydes using bismuth nitrate as a catalyst in ethanol at
ambient temperature. This methodology avails with faster reactions, excellent yield, mild
reaction conditions, use of inexpensive and non-toxic catalyst compared to literature reported
hitherto.
Received 8 February 2015
Received in revised form 9 March 2015
Accepted 19 March 2015
Available online
Keywords:
Benzimidazole
o-Phenylenediamine
Aldehydes
Bismuth nitrate
Green chemistry.
1. Introduction
At the beginning of this century, green chemistry has attracted a considerable importance in the development of environmentally
benign routes to numerous materials. Green chemistry mainly emphasizes towards the pollution prevention through eco-friendly design
of chemical products and processes [1]. The development of greener methodologies for syntheses of heterocyclic compounds is still a
stimulating task in the field of organic synthesis. Among the heterocycles, benzimidazole derivatives are the important class of nitrogen
containing heterocycles with a wide range of medicinal properties such as serotoninergic 5-HT3 and 5-HT4 receptors in the CNS [2],
antihistamine [3], anticancer [4, 5], antibacterial [6], antifungal [7], anti-inflammatory, antianalgesic [8], antioxidant [9], antidiabetic
[10], selective neuropeptide YY1 receptor antagonists [11], antimalerial, antitubercular [12], antiulcer [13], etc. where moiety plays the
role of ‘Master Key’ [14]. Therefore, it is an imperative anchor for development of new therapeutic drugs, as illustrated and supported
by some commercial benzimidazole products in Fig. 1.
H3C
OCH3
CH3
O
H
N
S
H
N
O
H3CO
NH
S
N
N
N
O
Albendazole - Antimicrobial drug
Omeprazole - Antiulcer drug
N
N
N
CH3
COOH
HN
N
COOH
Cl
N
N
OC2H5
N
Cl
Bendamustine - Antitumor drug
Candesartan - Antihypertensive drug
Fig. 1. Benzimidazole containing important commercial drugs.
Generally, the synthesis of benzimidazole involves the reaction of o-phenylenediamine either with carboxylic acids,
carboxaldehydes or their derivatives (chlorides, nitriles, and orthoesters) under strongly acidic conditions with high temperature [15],
Furthermore, Cascade reactions of o-haloaniline with amidine hydrochlorides [16] and intramolecular palladium-catalyzed aryl
amination are alternative ways for synthesis of benzimidazole [17, 18]. A variety of catalysts are reported in the benzimidazole
———
Corresponding author.
E-mail address: mahulikarpp@rediffmail.com
Page 2 of 9

synthesis, such as FeCl3-doped polyaniline nanoparticles [19], solvent free SiO2/ZnCl2 [20], cobalt (II) chloride hexahydrate [21],
[Sm(OTf)3] [22], [In(OTf)3] [23], sodium metabisulfite [24], silphox[POCl3-n (SiO2)n] [25], potassium persulfate-CuSO4 [26], indion
190 resin [27], ammonium acetate [28], thiamine hydrochloride [29], SDS micelles, DBSA, Fe3O4@SiO2@(NH4)6-Mo7O24 magnetic
core-shell nanocomposite, boron trifluoride etherate (BF3.OEt2), Cu-nanoparticles/SiO2, LiBr [30] etc.
At present, bismuth (III) compounds have recently attracted much attention in organic transformations due to their high acidity,
thermal stability, low toxicity, low cost, and good stability [31], Furthermore, bismuth nitrate is reported as an eco-friendly nitrating
agent for selective nitration of organic compounds [32, 33]. Current literature reveals that bismuth nitrate has been utilized as an
effective catalyst in the synthesis of 3,4-dihydropyrimidin-2(1H)-ones [34], guanidylation of N-benzoylthioureas [35], synthesis of
coumarins [36], Paal–Knorr synthesis of pyrroles [37], chemoselective synthesis of acylals [38] etc.
Nevertheless, most of the aforesaid methods of benzimidazole synthesis have disadvantages like, use of expensive reagents and
catalysts, harsh reaction conditions and long reaction time etc. Moreover, several of these reactions have been reported at higher
temperatures which are not accepted as environmentally friendly. Therefore, the search continues for a better catalyst to synthesize
benzimidazoles in term of operational simplicity. To address this problem, in our present research investigation, we wish to report
bismuth nitrate as an efficient catalyst for synthesis of 2-substituted benzimidazoles and 1,2-disubstituted benzimidazoles. Very
interestingly, herein, we revealed that a change of substituent, specifically a replacement of C3 or C4 hydrogen by either hydroxyl or
methoxy group on the aldehyde unit, dramatically influences the course of the reaction.
2. Experimental
2.1. Chemicals and instruments
All chemicals and materials are procured from S. D. Fine Chemicals Ltd. and Spectrochem Chemicals Pvt. Ltd. and used without
further purification. Melting points were determined with open capillary method and are uncorrected. IR spectra were recorded in KBr
1
on Shimadzu IR Affinity-1 FT-IR spectrophotometer and H NMR spectra were recorded on a Bruker Avance II 300 and 400 MHz
NMR spectrophotometer in CDCl3/DMSO using TMS as internal standard. Mass spectra were recorded on Waters, Q-Tof Micromass
(LCMS) spectrometer and Varian Inc. 410 Prostar Binary LC with 500 Mass Spectrophotometer.
2.2. General procedure for the synthesis of 2-substituted benzimidazoles and 1, 2- disubstituted benzimidazoles
A mixture of o-phenylenediamine (1 mmol), ethanol (5 mL), and bismuth nitrate (10 mol %) was taken in a round-bottom flask. To
this mixture, a solution of aldehyde 1.1 mmol for the synthesis of 2-substituted benzimidazoles and 2.1 mmol for the synthesis of 1,2
disubstituted benzimidazole in ethanol (5 mL) was added dropwise with stirring and stirring was continued until the completion of
reaction at room temperature. After completion of the reaction (monitored by TLC, hexane: ethyl acetate), the reaction mixture was
poured into crushed ice to give solid product, which was filtered, washed with water and dried. The crude product was recrystallized
from ethanol to afford pure 2-substituted benzimidazoles or 1,2-disubstituted benzimidazoles in good to better yields. Spectroscopic
data for all the synthesized compounds are depicted in supplementary data, which is in harmony with the structures.
3. Results and discussion
In this study, we examined the synthesis of 2-substituted benzimidazoles by the reaction of o-phenylenediamine with 4-
nitrobenzaldehyde using bismuth nitrate as catalyst in ethanol at room temperature. The reaction was completed within 60 min to give
the 2-(4-nitrophenyl)-1H-benzimidazole as a product with quantitative yield (Scheme 1). Encouraged by this result, we studied different
parameters of reaction and the obtained results are summarized in Tables 1-3. In order to find out optimum reaction condition for the
synthesis of 2-substituted benzimidazole, a separate study with different catalysts and solvents was performed. Bismuth nitrate was
found to be an efficient catalyst for synthesis of 2-substituted benzimidazoles over the other catalyst studied.
N
CHO
NH2
NH2
N
Bi(NO3)3.5H2O (10 mol %)
Ethanol, r.t.
R
N
R
N
H
R
R = NO2, Cl, OH,
OCH3, NN(CH3)2
1a-1i
2j-2n
R
Scheme 1. Bismuth nitrate mediated synthesis of 2-substituted benzimidazole derivatives.
3.1. Effect of catalyst and solvent
In order to study the performance of catalyst, a controlled reaction was performed using o-phenylenediamine with 4-
nitrobenzaldehyde in ethanol without catalyst. The percentages of products formed under controlled condition and with the different
catalysts are summarized in Table 1. The results revealed that, under the controlled condition the percentage of products were less even
after 8 h in most of the cases, whereas in the presence of bismuth nitrate the obtained yield was highest within a short reaction period of
1 h only. Amidst, in order to get more insides about the amount of catalyst required for the efficient conversion, we performed the
experiments by using different percentage loading of catalyst in ethanol at room temperature (Table 1, entries 4-7). The
experimentation revealed that 10 mol % loading of catalyst afforded the desired products with highest yield just within 1 h. Thus, it was
Page 3 of 9

found that bismuth nitrate plays a benign role of accelerator promoting the time and cost effective formation of product. In order to
study the effect of solvents over the oxidative coupling of 4-nitrobenzaldehyde with o-phenylenediamine, we carried out the reaction in
different solvents. Less polar and aprotic solvents like dichloromethane, toluene and tetrahydrofuran were found to be unsuitable for the
reactions, whereas, more polar and protic solvents like ethanol, glycerol, polyethylene glycol (PEG), etc., were appropriate solvents to
afford the higher yields (Table 2).
Table 1
Effect of catalyst on synthesis of 2-(4-nitrophenyl) benzimidazole.a
CHO
NH2
N
Bi(NO3)3.5H2O) 10 mol %
Ethanol, RT
NO2
N
H
NH2
NO2
Entry Catalyst
Temp (oC)
r.t.
78-80
r.t.
r.t.
r.t.
r.t.
r.t.
78-80
Time (h)
Yield (%)b
1
2
None
None
8
7
8
1
1
1
1
4
4
5
4
4
5
8
8
8
45
60
52
96
84
91
94
61
56
70
67
74
65
58
71
58
3
L-Proline
4
5
6
7
Bi(NO3)3·5H2O
Bi(NO3)3·5H2Oc
Bi(NO3)3·5H2Od
Bi(NO3)3·5H2Oe
ZrO(NO3)·H2O
8
9
1,10-Phenanthroline r.t.
10
11
12
13
14
15
16
1,10-Phenanthroline 78-80
Cd(NO3)·5H2O
Cd(NO3)·5H2O
Ba(NO3)2
CsNO3
Pb(NO3)2
r.t.
78-80
r.t.
r.t.
r.t.
Ca(NO3)2.4H2O
r.t.
a Reaction condition: o-Phenylenediamine (1 mmol), 4-nitrobenzaldehyde (1.1 mmol), catalyst (10 mol%) and ethanol 10 mL.
b Isolated yield.
c Catalyst loading: 5 mol%.
d Catalyst loading: 15 mol%.
e Catalyst loading: 20 mol%.
Table 2
Effect of solvent on synthesis of 2-(4-nitrophenyl)benzimidazole.a
CHO
NH2
NH2
N
Bi(NO3)3.5H2O) 10 mol %
NO2
N
H
Ethanol (10 mL)
RT
NO2
Entry
1
2
3
4
5
6
7
8
Solvent
Solvent free
THF
Acetonitrile
DMF
Ethanol
Temp
r.t.
r.t.
r.t.
r.t.
Time (h)
Yield (%)b
1
4
2
2
1
1
5
3
4
6
7
3
49
21
63
65
96
76
58
76
78
40
81
82
r.t.
r.t.
Methanol
Dichloromethane r.t.
Glycerol
Glycerol
Toluene
PEG – 400
PEG – 400
r.t.
9
90 oC
r.t.
10
11
12
r.t.
90 oC
a Reaction condition: o-Phenylenediamine (1 mmol), 4-nitrobenzaldehyde (1.1 mmol), and bismuth nitrate (10 mol %) as catalyst.
b Isolated yield.
Under the optimized reaction conditions, we performed the reactions of aromatic and heteroaromatic aldehydes with o-
phenylenediamine to give quantitative yields of products (Table 3). In some reactions, dialdimines were formed as byproducts (1%-5%)
which were separated during recrystallization. Several functional groups such as Cl, Br, NO2, OCH3 and sensitive heterocyclic
molecules like indole-3-carboxaldehyde and pyridyl-3-carboxaldehyde were compatible with the reaction conditions. All the
1
1
synthesized compounds were isolated, purified and characterized by FT-IR, H NMR, and LC-MS spectroscopic techniques. In H
NMR analysis (Supporting information), the compound (2n) shows the two sharp singlets for -NCH3. This is due to conjugation of
unpaired electrons on the nitrogen atom with aromatic π electrons and this conjugation makes a partial double bond between ipso
carbon and nitrogen atom.
Page 4 of 9

Table 3
Synthesis of benzimidazole derivatives from o-phenylenediamine and aldehydes.
M.P. (oC)
Found
314-316
144-146
264
234
290
246
222-224
218-220
242
250-252
210-212
214-216
168-170
172-174
Entry
R
Product
Time (min)
Yield (%)b
Ref
Reported
317
144
260-263
234
292
241-243
225
--
242
255-257
222
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4-NO2-C6H4
3-NO2-C6H4
2-NO2-C6H4
2-Cl-C6H4
4-Cl-C6H4
3-Pyridinyl
3-Indolyl
2, 5-(OCH3)2-C6H3
2-OH-C6H4
3-OH-C6H4
4-OH-C6H4
1a
1b
1c
1d
1e
1f
1g
1h
1i
2j
2k
2l
2m
2n
60
90
60
55
60
90
60
60
90
300
300
300
300
300
96
97
95
76
84
73
85
86
85
49
50
48
48
42
[21]
[21]
[25]
[25]
[29]
[26]
[26]
--
[24]
[39]
[39]
[39]
[39]
[40]
4-OH,3-OCH3-C6H3
3,4 (OCH3)2-C6H3
4-(CH3)2N-C6H4
190-192
170-172
165-167
a Reaction condition: o-Phenylenediamine (1 mmol), 4-nitrobenzaldehyde (1.1 mmol), bismuth nitrate (10 mol%) as catalyst.
b Isolated yield
From the above data, it was observed that all the reactions would have offered the expected corresponding 2-substituted
benzimidazoles, but surprisingly the reactions with aromatic aldehydes carrying either hydroxyl or methoxy groups at meta or para
positions, resulted in the formation of 1,2-disubstituted benzimidazoles. As per the optimized conditions, we have used o-
phenylenediamine: aldehydes (1:1.1 mmol), and found that, still after 5 h o-phenylenediamine was unreacted whereas other precursor
i.e. aldehyde gets completely consumed. After isolation and purification of product it was observed that the obtained products was 1,2-
disubstituted benzimidazoles and not expected 2-substituted benzimidazole. With this observation, we planned to set the reactions with
two equivalents of aldehydes and one equivalent of o-phenylenediamine under the optimized conditions, where, 1,2-disubstituted
benzimidazoles was obtained as major product with excellent yields (Table 4, Scheme 2).
N
CHO
NH2
NH2
R
N
.
Bi(NO3)3 5H2O (10 mol %)
2
Ethanol, r.t.
R
R
R = OH, OCH3, NN(CH3)2
2j-2n
Scheme 2. Bismuth nitrate mediated synthesis of 1, 2-disubstituted benzimidazole derivatives
Table 4
Synthesis of 1, 2-disubstituted benzimidazole derivatives from o-phenylenediamine and aldehydes
Entry
Product
Time (min)
Yield (%)b
1
2j
2k
2l
2m
2n
60
65
75
60
60
90
81
91
84
85
2
3
4
5
a Reaction condition: o-Phenylenediamine (1 mmol), 4-nitrobenzaldehyde (2.1 mmol), and bismuth nitrate (10 mol%) as catalyst.
b Isolated yield.
3.2. Plausible mechanism
At the initial stage of synthesis of 2-substituted benzimidazoles, bismuth nitrate forms hydrogen bonding with aldehyde which
leads to the activation of carbonyl carbon and subsequently facile attack of diamine over aldehyde forms 2-substituted benzimidazoles.
Furthermore, In the synthesis of 1,2-disubstituted benzimidazoles, aldehyde initially reacted with diamine to form Schiff base as an
intermediate in the presence of electrophilic catalyst, followed by intramolecular 1,3-hydride migration led to the formation of 1,2-
disubstituted benzimidazoles (Scheme 3).
Page 5 of 9

Bi(NO3)3
Bi(NO3)3
H
N
O
O
H
N
Ph
NH2
NH2
H
Ph
Ph
NH2
NH2
Bi(NO3)3
Bi(NO3)3
(i)
H
N
N
Ph
N
Air Oxidation
Ph
Ph
N
H
N
H
NH2
O
(a)
(ii)
H
Ph
Ph
Ph
Ph
N
N
Ph
Ph
[1, 3] H-migration
N
N
H
Ph
N
(b)
Bi(NO3)3
Bi(NO3)3
Bi(NO3)3
Scheme 3. Plausible mechanism for synthesis of (i) 2-substituted benzimidazoles (a) and (ii) 1,2-disubstituted benzimidazoles (b).
4. Conclusion
In summary, bismuth nitrate played a crucial role of mild and efficient green catalyst for the syntheses of 2-substituted and 1,2-
disubstituted benzimidazoles in quantitative yields from o-phenylenediamine and a wide variety of aldehydes. This methodology
followed column chromatography-free protocol availing the abolishment of large amount of organic solvents. A one pot synthesis with
short reaction time; use of inexpensive, non-toxic, and easily available catalyst; easy isolation of products with higher yields are the key
leads of the methodology executed herein. Thus, this work furthered a green, time as well as cost effective route to researcher’s further
dealing with these scaffolds in future.
Acknowledgments
Authors are thankful to UGC, New Delhi for financial assistance under UGC-Major Research Project [No. 41-302/2012 (SR)] and
SAIF, Panjab University, Chandigarh for NMR analysis.
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