A facile and highly chemoselective synthesis of 1,2-disubstituted benzimidazoles using hierarchical nanoporous material

Article abstract of DOI:10.1016/j.tetlet.2014.01.140

A highly ordered nanoporous aluminosilicate (MMZ_Y) is prepared and employed as a catalyst for the synthesis of benzimidazoles from 1,2-diaminobenzene and aromatic aldehydes. In all the cases, the reactions are highly chemoselective and afford 1,2-disubstituted benzimidazoles in excellent yield. The catalyst was characterized by electron microscopy and X-ray methods and its other advantages like functional tolerance, mildness of the reaction conditions, easy separation, and reusability are also highlighted.

Full text of DOI:10.1016/j.tetlet.2014.01.140

Accepted Manuscript
A facile and highly chemoselective synthesis of 1,2-disubstituted benzimida-
zoles using hierarchical nanoporous material
Samuthirarajan Senthilkumar, Mayilvasagam Kumarraja
PII:
S0040-4039(14)00196-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.140
TETL 44173
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 December 2013
26 January 2014
28 January 2014
Please cite this article as: Senthilkumar, S., Kumarraja, M., A facile and highly chemoselective synthesis of 1,2-
disubstituted benzimidazoles using hierarchical nanoporous material, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.01.140
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A facile and highly chemoselective synthesis of 1,2-disubstituted benzimidazoles using
hierarchical nanoporous material
Samuthirarajan Senthilkumar & Mayilvasagam Kumarraja*
Centre for Research and Post-graduate Studies in Chemistry,
Ayya Nadar Janaki Ammal College (Autonomous), Sivakasi – 626 124, Tamilnadu, India.
GRAPHICAL ABSTRACT
N
N
NH2
NH2
MMZY
rt, 10h
OHC
+
2
X
X
X
Where, X= H, o-OH, p-Cl, p-F, p-NO2, p-CH3, p-OCH3, p-iPr and furyl.
Abstract - A highly ordered nanoporous aluminosilicate (MMZY) is prepared and employed as a
catalyst for the synthesis of benzimidazoles from 1,2-diaminobenzene and aromatic aldehydes.
In all the cases, the reactions are highly chemoselective and afford 1,2-disubstituted
benzimidazoles in excellent yield. The catalyst was characterized by electron microscopy and X-
ray methods and its other advantages like functional tolerance, mildness of the reaction
conditions, easy separation and reusability are also highlighted.
Keywords: Nanoporous zeolite; chemoselectivity; 1,2-disubstituted benzimidazole; solid acid;
bisimine; o-phenylenediamine; aromatic aldehyde.
1

A facile and highly chemoselective synthesis of 1,2-disubstituted benzimidazoles using
hierarchical nanoporous material
Samuthirarajan Senthilkumar & Mayilvasagam Kumarraja*
Centre for Research and Post-graduate Studies in Chemistry,
Ayya Nadar Janaki Ammal College (Autonomous), Sivakasi – 626 124, Tamilnadu, India.
In medicinal chemistry, the benzimidazole scaffold acts as an important class of
heterocyclic compounds that shows a wide range of biological properties1 such as anesthetic,
antipyretic, antiulcer, antihypertensive, anticancer and antiviral activities,2 including non-
nucleoside inhibitors of HIV-1 reverse transcriptase and NS5B polymerase of the hepatitis C
virus(HCV).3 Recently it is reported that benzimidazole derivatives are also used for the
treatment of diseases like hypertension and obesity.4 Though many reports are available for the
syntheses of 2-substituted benzimidazoles,5 only very few reports are available for the selective
synthesis of 1,2-disubstituted benzimidazoles. The classical methods for the synthesis of 1,2-
disubstituted benzimidazoles normally involve (i) N-alkylation/arylation of benzimidazole in the
presence of a strong base/transition metal ions6 (ii) cyclocondensation of N- substituted o-
aminoanilides7 (iii) Suzuki coupling of 2-halo-1-arylbenzimidazole with arylboronic acids.8
However, the straightforward synthesis of 1,2-disubstituted benzimidazole from o-
phenylenediamine with an aldehyde is still in demand due to its easy approach and can be
applied to a variety of substituents in the benzimidazole scaffold. Synthesis of disubstituted
benzimidazole include the use of catalysts such as TFE/ HFIP,6 montmorillonite K-10,9 CuI/L-
proline,10 TMSCl,11 amberlite IR–120,12 SiO2/ZnCl2,13 Dowex- 50W,14 SDS micelles,15
*Corresponding author: Phone: +91-9443570835; Fax: +91-4562 254970
E-mail address: dr.kumarraja@gmail.com
2

AcOH/O2,16 SbCl3/Al2O3,17 silica sulfuric acid,18 FePO4,19 CAN,20 Cu(NO3)2.3H2O21 and
22
FeCl3/Al2O3. But in many cases, the reaction shows poor selectivity in terms of N-1
substitution, which results in the formation of a mixture of 1,2-disubstituted and 2-substituted
benzimidazoles. In addition, most of the described procedures suffer from the disadvantages such
as use of expensive catalysts, hazardous solvents, tedious work-up, longer reaction time and
functional intolerance. As a consequence, search for new methods or catalysts to overcome these
limitations are still an important experimental challenge to synthetic organic chemists.
In recent years, hierarchical nanoporous materials23 have been receiving a great
attention due to its multidisciplinary field of study,24 drug delivery,25 gas separation and
hydrocarbon cracking,26 etc.; However, the catalytic applications of nanoporous materials in fine
chemical synthesis are very few in number. We have already successfully explored the catalytic
efficiency of zeolite as a mesoporous material,27 microporous material for shape selectivity,28
solid acid catalyst29 and source of metal ions30 for various organic transformations. In
continuation of our interest in studying the catalytic applications of zeolites, herein we
investigate the use of zeolite as a hierarchical nanoporous material for the synthesis of
benzimidazoles by the condensation of 1,2-phenylenediamine with aromatic aldehydes in a
simple experimental procedure and the results are discussed below.
In order to study the feasibility of cyclocondensation reaction in zeolite framework, o-
phenylenediamine(1) and benzaldehyde(2) were added to three different kinds of Y-type
faujasite zeolites namely NaY, HY and MMZY for the synthesis of 1,2-disubstituted
benzimidazoles. These three zeolites differ mainly in their acidity and pore size. Generally NaY
of high purity contains no detectable acidity. Upon removal of ammonia by calcination of
ammonium ion-exchanged Y-zeolite, HY is obtained generating Bronsted acidic sites.31 In the
3

preparation of MMZY from HY under basic conditions, the initially formed nanounits are
assembled into highly ordered hierarchically nanoporous architecture. It is noteworthy that the
preparation of nanoporous zeolite and its characterization have been well demonstrated in
previous reports.32, 33
The catalytic activities of these three different zeolites are studied and the observed
results are presented in Table 1. In the absence of zeolite, the reaction afforded only 1-H-2-
substituted benzimidazole(4) in less than 5% yield, even after a very long time of stirring the
solution. However in presence of NaY, the reaction between 1,2-phenylenediamine and
benzaldehyde yielded a mixture of (3) and (4) benzimidazoles (entry 2).
In contrast to NaY, the reaction is sensitive to Bronsted acidity as evident from that HY
catalyzed reaction produces the 1,2-disubstituted benzimidazole (3) but also with the significant
amount of 1-H-2-arylbenzimidazole(4) (entry 3). When the same reaction is carried out in
presence of MMZY zeolite, we have obtained chemoselectively, an excellent amount of 1,2-
disubstituted benzimidazole at the expense of 4. We have also examined the recycling of the
catalyst to see its efficiency which afforded the same yield even after two times usage.
To check the functional tolerance of MMZY zeolite, we have employed substituted
benzaldehydes to synthesize 1,2-disubstituted benzimidazole derivatives 3a- i (Table 2). The
reaction proceeds faster and also there is not much difference in yield with substituted
benzaldehydes containing electron releasing as well as electron withdrawing groups as evident
from the entries 1-8, Table 2. However, the reaction involving salicylaldehyde (entry 9) led to
the unexpected formation of Schiff base product (bisimine) under the present experimental
conditions. Bisimine was isolated and confirmed by NMR. The unexpected formation of
4

bisimine may be due to the presence of intramolecular hydrogen bonding which prevents the
further cyclization of bisimine intermediate to yield the final product.11 However, when heating
the same reaction at 80 ⁰C, it produced the expected product by breaking the energy barrier. This
reaction also supports the proposed mechanistic pathway6,11 which involves the presence of
acidic sites in MMZY facilitating (i) the formation of bisimine followed by cyclization and (ii)
1,3-hydride shift followed by deprotonation leading to the selective formation of the 1,2-
disubstituted benzimidazole. The chemoselectivity of MMZY may be attributed to its
nanomorphic structure within zeolite pore walls which facilitate the improved diffusion of more
number of reactant molecules, leading to significant enhancement in catalytic activity. Moreover
the presence of increased surface area and acidic sites33 promotes the catalytic conversion of
o-phenylenediamine and aldehydes selectively into 1,2-disubstituted benzimidazoles in excellent
yield. The morphology of the as prepared hierarchical MMZY zeolite was characterized by
Powder XRD, SEM and TEM methods, which clearly demonstrate the uniform formation of pore
structure and particles about 1µm (See Fig. 1 & 2 in supporting data).
Thus the present study offers a simple procedure for the selective synthesis of 1,2-
disubstituted benzimidazoles promoted by an inexpensive, reusable, non-toxic and
environmentally benign solid acid MMZY zeolite. The other advantages of this procedure are
high chemoselectivity, shorter reaction time and functional groups tolerance. Further works are
now in progress to explore the scope of the catalyst for other organic synthesis.
Acknowledgement
The authors thank the Principal and the Management of ANJA College as well as the
University Grants Commission, New Delhi, for financial support.
5

Supporting Data
Supplementary data associated with this article can be found in the online version.
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34. General procedure for the synthesis of 1,2-disubstituted benzimidazole derivatives
using Nanoporous zeolite:100mg of nanoporous material from zeolite HY (designated
as MMZY) was taken in a silica crucible and activated in a muffle furnace at 450 oC for
6 hours. A mixture of o-phenylenediamine(1mmol) and aldehyde(2mmol) were added to
the reaction tube which contains acetonitrile (3ml) and 100mg of freshly activated
MMZY. The reaction mixture was stirred for 10h at room temperature. The proceeding
8

of the reactions was constantly monitored by TLC carried out on silica plates with iodine
and UV light for visualization. Column chromatography was performed on silica gel 60-
120 mesh with a mixture of petether and ethylacetate (80:20) solvent as eluent.
The products were isolated and characterized by the IR Spectra recorded on a
1
13
Shimadzu 8004S model FT-IR using KBr pellets and the H NMR and C NMR, were
obtained on Bruker NMR(300MHz) instrument in CDCl3 and DMSO. The melting point
of solid products were determined and also compared with the literature report.
1-Benzyl-2-phenyl-1H-1,3-benzimidazole (3a): mp = 130 ⁰C (lit.[6] 130 – 132 ⁰C ); IR
1
(KBr) γmax = 3031, 2923, 1602, 1581, 1490, 1278, 1155, 1114, 1027cm-1; H NMR (300
MHz, CDCl3): δ 7.74 (d, 1H) ; 7.53 – 7.49 (m, 2H) ; 7.47 – 7.42(m, 3H); 7.29 – 7.21 (m,
13
6H); 7.0 (dd, 2H); 5.58 (s, 2H). C NMR (CDCl3): δ 155.01, 142.9, 136.25, 135.9,
129.91, 129.81, 129.15, 128.93, 128.63, 127.98, 127.65, 125.84, 122.94, 122.59, 119.85,
110.43, 48.23.
Bisimine from salicylaldehyde:
2,2’-(1,2-phenylenebis(azan-1-yl-1-ylidene))bis(methan-1-yl-1-ylidene)diphenol:
mp:161 °C (lit.[11] mp 160 – 162 ⁰C); IR (KBr) γmax = 3317, 2923, 1614, 1479, 1336,
1
1276, 1191; H NMR (300 MHz, CDCl3 ): δ 13.15 (s, OH); 8.63 (s, NH); 7.38 (s, 2H);
7.35 (s,2H); 7.33-7.31 (m, 2H); 7.25-7.20 (m, 2H); 7.05 (s, 1H); 7.03 (s, 1H); 6.94-6.88
13
(m, 2H); C NMR (CDCl3) 163.74, 161.35, 142.55, 133.30, 132.26, 127.57, 119.76,
119.21, 118.88, 117.50.
9

A facile and highly chemoselective synthesis of 1,2-disubstituted benzimidazoles using
hierarchical nanoporous material
Samuthirarajan Senthilkumar & Mayilvasagam Kumarraja*
Centre for Research and Post-graduate Studies in Chemistry,
Ayya Nadar Janaki Ammal College (Autonomous), Sivakasi – 626 124, Tamilnadu, India.
GRAPHICAL ABSTRACT
N
N
NH2
NH2
MMZY
rt, 10h
OHC
+
2
X
X
X
Where, X= H, o-OH, p-Cl, p-F, p-NO2, p-CH3, p-OCH3, p-iPr and furyl.
Abstract - A highly ordered nanoporous aluminosilicate (MMZY) is prepared and employed as a
catalyst for the synthesis of benzimidazoles from 1,2-diaminobenzene and aromatic aldehydes.
In all the cases, the reactions are highly chemoselective and afford 1,2-disubstituted
benzimidazoles in excellent yield. The catalyst was characterized by electron microscopy and X-
ray methods and its other advantages like functional tolerance, mildness of the reaction
conditions, easy separation and reusability are also highlighted.
10