Bentonite clay: An efficient catalyst for the synthesis of 2-substituted benzimidazoles

Article abstract of DOI:10.1007/s00706-015-1423-x

Benzimidazoles have been reported to have a wide range of biological and therapeutic properties. For this reason a variety of methods for their synthesis has been described, following one of the two general routes: the coupling of o-phenylenediamine and c

Full text of DOI:10.1007/s00706-015-1423-x

Monatsh Chem
DOI 10.1007/s00706-015-1423-x
ORIGINAL PAPER
Bentonite clay: an efficient catalyst for the synthesis
of 2-substituted benzimidazoles
•
Victor A. Cardozo Ruben Sanchez-Obregon
•
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Hector Salgado-Zamora Rogelio Jimenez-Juarez
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•
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Received: 23 December 2014 / Accepted: 12 January 2015
Ó Springer-Verlag Wien 2015
Abstract Benzimidazoles have been reported to have a
wide range of biological and therapeutic properties. For
this reason a variety of methods for their synthesis has been
described, following one of the two general routes: the
coupling of o-phenylenediamine and carboxylic acids or
their derivatives using a strong acid and high temperature,
or a two-step sequence that involves oxidative cyclodehy-
drogenation of Schiff’s bases, obtained by the reaction of
o-phenylenediamines and aromatic aldehydes. A simple,
efficient, and environmentally friendly procedure for the
synthesis of substituted 2- and 2,5(6)-substituted benzimi-
dazoles is herein described. The procedure is carried out by
treatment of o-phenylenediamine or 4-chloro-o-phenyl-
enediamine with aryl or heteroaryl aldehydes. Bentonite
clay is used as catalyst in dry acetonitrile at room tem-
perature. This procedure has several important advantages,
including short reaction times, large-scale preparations,
easy isolation of the products, and good to excellent yields.
Graphical abstract
R
NH2
R
H
R1
NH2
N
N
O
R1
Bentonite clay
Acetonitrile, r.t., 1 h
H
Keywords Bentonite clay ꢀ Benzimidazoles ꢀ
Aryl aldehyde ꢀ Heteroaryl aldehyde ꢀ
4-Chloro-o-phenylenediamine ꢀ o-Phenylenediamine
Introduction
Benzimidazoles have received considerable attention due
to their wide range of biological and therapeutic properties.
For example, they have been investigated as anti-helmin-
thic [1, 2], anti-parasitic [3, 4], anti-thrombosis, anti-
inflammatory, anti-bronchoconstrictive, anti-neoplastic [5–
8], neuroprotective [9], antifungal [10], and antiviral agents
[11]. Therefore, it is not surprising that a wide variety of
methods for synthesizing the benzimidazole nucleus have
been developed and described in the literature.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1423-x) contains supplementary
material, which is available to authorized users.
Within the abundance of methods, there are two general
routes for the synthesis of benzimidazoles. One is the cou-
pling of o-phenylenediamine and carboxylic acids [12, 13] or
their derivatives [10, 14–16] using a strong acid and high
temperature (i.e., harsh experimental conditions). The other
is a two-step sequence that involves oxidative cyclodehy-
drogenation of Schiff’s bases, obtained by the reaction of
o-phenylenediamines and aromatic aldehydes [17–19].
´
´
V. A. Cardozo ꢀ H. Salgado-Zamora ꢀ R. Jimenez-Juarez (&)
´
Departamento de Quımica Organica, Escuela Nacional de
Ciencias Biologicas, Instituto Politecnico Nacional,
Prolongacion de Carpio y Plan de Ayala S/N,
´
´
´
´
11340 Mexico D.F., Mexico
e-mail: rogeliojj@gmail.com
´
R. Sanchez-Obregon
Instituto de Quımica, UNAM, Coyoacan, 04510 Mexico D.F.,
´
´
´
Mexico
123

V. A. Cardozo et al.
A variety of catalysts, including In(OTf)3 [20], functional-
ized silica gel with sulfonic acid [21], and SiO2/ZnCl2 [22],
have recently been used for the synthesis of these compounds
under strictly anhydrous reaction conditions.
aldehydes 1 in a 1:1.1 molar ratio, with bentonite clay (one
part by weight relative to aldehyde) in dry acetonitrile. The
reaction mixture was stirred at room temperature for 1 h.
Compounds 3a–3h were obtained as beige amorphous
solids in excellent yields, with melting points similar to
those described in the literature. The products were char-
acterized by analysis of their spectroscopic data. Their
infrared spectra showed an intense absorption band near
3,300 cm-1, which was assigned to the stretching fre-
quency of the amino group of the imidazole ring.
Additionally, compounds 3c, 3d, 3f, 3g, and 3h showed an
intense absorption band close to 1,500 cm-1, which was
assigned to the stretching frequency of the nitro group.
The proton nuclear magnetic resonance (1H NMR)
showed two kinds of signals for the substituted benzimi-
dazoles. One is due to the benzimidazole nucleus and the
other corresponds to the substituents. For such compounds
substituted with a 2-thienyl or 2-furyl, the 1H NMR spectra
showed signals below 8 ppm with overlapping, thus mak-
ing structural assignments for these benzimidazoles
difficult. Nevertheless, the 2-nitrophenylbenzimidazole
showed more separate signals, with some protons for the
core observed below 8 ppm and other protons found above
8 ppm.
In the search for more efficient and environmentally
friendly methods, bentonite clay is herein considered as a
catalyst. Given that bentonite clays work as both Lewis and
¨
Bronsted [23] acids, their acidic properties are well known.
They are able to interact with carbon–oxygen double bonds to
promote the addition of a nucleophile to the electrophilic
carbon. Therefore, they are widely employed as heteroge-
neous catalysts in several interesting organic transformations,
such as condensation reactions between carbonyl compounds
and amines.
Thus, Eynde described the N–C bond formation catalyzed
by bentonite clay in imidazolidine synthesis [24]. Likewise,
Penieres reported the synthesis of benzimidazoles assisted
by bentonite clay under IR irradiation [25]. Recently, Pitc-
humani reported the synthesis of 2-phenylbenzimidazole by
two procedures. In one of them he used K10-clay as a het-
erogeneous catalyst, with water/methanol as solvent, and
stirred the mixture for 24 h at room temperature. In the other
he used Zn2?-K10-clay under the same conditions. Yields
were 26 and 98 % of the benzimidazoles [26].
An important focus of our group is the synthesis of mol-
ecules to be used as potential antimicrobial agents. Since we
require an efficient and inexpensive method for benzimid-
azole synthesis, we decided to investigate bentonite clay as a
possible catalyst in the absence of other Lewis acids
(Table 1). We herein report a simple and straightforward
procedure to obtain 2- and 2,5(6)-substituted benzimidaz-
oles, starting with commercially available compounds and
employing bentonite clay as a heterogeneous catalyst.
On the other hand, the carbon nuclear magnetic reso-
nance (13C NMR) for the synthesized compounds showed a
different number of signals. Some of them were observed
at around 129 ppm, which was assigned to the imine car-
bon (N=C–N) and ipso carbon (C–NO2). In the case of the
2-furanyl substituent, there were signals at 144.5, 145.0,
and 144.0 ppm, corresponding to the imine carbon (N=C–
N), and the C-20 and C-50 furan system (C2–O–C5),
respectively. The clorobenzimidazoles 3e–3h showed a
signal near 133 ppm, which was assigned to the ipso car-
bon (C–Cl).
Results and discussion
The benzimidazoles 3a–3h (Scheme 1) were prepared
using o-phenylenediamine
Conclusion
2
and aryl (heteroaryl)
A new and a convenient one-pot synthesis of 2- and 2,5(6)-
substituted benzimidazoles is reported, using bentonite clay
as a heterogeneous catalyst. The synthetic strategy led to
the formation of a benzimidazole pharmacophore that is
well recognized for its diverse biological activity.
Table 1 Benzimidazoles 3a–3h prepared from o-phenylenediamines
and (hetero)aryl aldehydes using bentonite clay (Scheme 1)
Prod.
R
R1
Yield/% M.p./°C Lit. m.p./°C
3a
3b
3c
3d
3e
3f
H
H
H
H
2-Thienyl
2-Furanyl
90
75
333–334 330–332 [19]
289–290 284–286 [27]
328–329 308 [27]
Experimental
4-Nitrophenyl 89
3-Nitrophenyl 94
213–215 204–206 [28, 29]
228–229 226.5–227.5 [30]
224–226 257 [31]
Bentonite clay was donated by Dr. Delgado and was heated
at 200 °C for 2 h. As bentonite clay swells when it absorbs
water, it must be activated previous to use at 100 °C.
Acetonitrile was dried with phosphoric pentoxide at room
temperature. Melting points were determined on an
Cl 2-Thienyl
64
Cl 4-Nitrophenyl 64
Cl 3-Nitrophenyl 64
Cl 2-Nitrophenyl 64
3g
3h
245–246 243 [14]
110–111 108–109 [32]
123

Bentonite clay as an efficient catalyst
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R
NH2
NH2
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Acknowledgments Financial support from IPN Mexico through
Grants SIP 20120756, SIP 20130724 is gratefully acknowledged. We
´
thank Javier Peralta Cruz, Ma. de los Angeles Pen˜a, Beatriz Quiroz,
´
Elizabeth Huerta, Hector Rıos (NMR), Daniel Arrieta Baes, Luis
Velasco (MS), and Marisela Gutierrez Franco (IR) for analytical
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support. Hector Salgado Zamora and Rogelio Jimenez Juarez are
fellows of the COFAA and EDI fellowship programs of the IPN.
Victor A. Cardozo thanks IPN for a PIFI scholarship. We thank Bruce
Allan Larsen for reviewing the use of English in the manuscript.
123