Synthesis of benzimidazoles by two methods (C–H functionalization and condensation reaction) catalyzed by α-zirconium hydrogen phosphate-based nanocatalyst

Article abstract of DOI:10.1007/s13738-020-01884-4

In this report, two heterogeneous nanocatalysts based on α-zirconium hydrogen phosphate were applied. These heterogeneous catalysts have demonstrated the promising catalytic activity for the synthesis of 2-substituted benzimidazoles in two different methods. One of these reactions is the functionalization of the C–H bond and the formation of C–N bond, and the other reaction involves the condensation reaction between aldehydes and 1,2-phenylenediamine. The activity of both catalysts was compared in two methods, and the superior catalyst was introduced. The prepared catalysts are easily separated from the reaction mixture by centrifugation and reused several times without significant loss of activity.

Full text of DOI:10.1007/s13738-020-01884-4

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-01884-4
ORIGINAL PAPER
Synthesis of benzimidazoles by two methods (C–H functionalization
and condensation reaction) catalyzed by α‑zirconium hydrogen
phosphate‑based nanocatalyst
Abdol R. Hajipour1 · Saedeh Zakery1 · Zahra Khorsandi1
Received: 11 June 2019 / Accepted: 17 February 2020
© Iranian Chemical Society 2020
Abstract
In this report, two heterogeneous nanocatalysts based on α-zirconium hydrogen phosphate were applied. These heterogene-
ous catalysts have demonstrated the promising catalytic activity for the synthesis of 2-substituted benzimidazoles in two
diferent methods. One of these reactions is the functionalization of the C–H bond and the formation of C–N bond, and the
other reaction involves the condensation reaction between aldehydes and 1,2-phenylenediamine. The activity of both catalysts
was compared in two methods, and the superior catalyst was introduced. The prepared catalysts are easily separated from
the reaction mixture by centrifugation and reused several times without signifcant loss of activity.
Keywords C–H functionalization · Condensation reaction · Heterocycles · Nanocatalyst · α-Zirconium hydrogen phosphate
Introduction
low-cost catalytic system with negligible toxicity and easy
preparation manner. The preparation and characterization of
this catalyst (α-ZrP/Uracil/Cu2+) are thoroughly explained
in the mentioned paper [26]. We were eager to outstretch
the profciency of this catalyst in other chemical reactions
such as benzimidazoles synthesis by the C–H bond func-
tionalization procedure and employing the amidines as the
starting material and O2 as an oxidative agent [27–29]. Fur-
thermore, the utilization of α-ZrP/Uracil/Cu2+ could over-
come the disadvantages of the previous research, including
the stoichiometric amounts of transition metals [30], low
products output and the production of side products [29]. To
extend the results, another prevalent pathway for benzimi-
dazoles synthesis, containing the condensation of aromatic
aldehydes and 1,2-phenylenediamine, was surveyed. In this
way, some major bugs and limitations [31, 32] such as high
temperature, long reaction time, low efciency and rough
reaction conditions attracted the attention of chemists to a
solution to these problems. These studies in modern organic
synthesis showed that catalysts play a key role in improv-
ing these conditions. Some of these catalysts include Co/
Ce–ZrO2 [33], WOx/ZrO2 [34], Er(OTf)3 [35], Ir/TiO2 [36],
PVP/TfOH [37] and Lewis acids such as ZrCl4, SnCl4·5H2O,
TiCl4, BF3·Et2O, ZrOCl2·8H2O and HfCl4 [38].
Since benzimidazoles are a specifc category of heterocyclic
compounds, both in terms of chemical [1–7] and pharma-
ceutical [8–12], over the past decades, chemists were always
trying to provide numerous methodologies for the synthesis
of these compounds with remarkable interests. By review-
ing a variety of researches in this feld, it became clear that
one of the most reputable approaches is C–H functionali-
zation and C–N formation, in which, of course, transition
metals have a catalytic role in [13–16]. Among these metals
are palladium [17], ruthenium [18, 19] and rhodium [20,
21]. Due to environmental and economic aspects, quantita-
tive research has been accomplished in which cheaper and
less toxic metals, such as copper, have been used [22–25].
Recently, this research group has reported a novel nanocat-
alyst based on α-zirconium hydrogen phosphate/copper, a
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-020-01884-4) contains
supplementary material, which is available to authorized users.
* Abdol R. Hajipour
haji@cc.iut.ac.ir
This reaction is one of the multicomponent reactions.
Many supported metal complexes have been used in these
reactions, including:
1
Pharmaceutical Research Laboratory, Department
of Chemistry, Isfahan University of Technology,
Isfahan 84156-83111, Iran
Vol.:(0123456789)
1 3

Journal of the Iranian Chemical Society
Synthesis of water-dispersed magnetic nanoparticles
(H2O-DMNPs) of β-cyclodextrin-modifed Fe3O4 and its
catalytic application in Kabachnik–Fields multicomponent
reaction [39], synthesis of 1-(α-aminoalkyl)-2-naphthol
and α-aminonitrile derivatives with molybdenum Schif
base complex covalently bonded on silica-coated magnetic
nanoparticles [40], superparamagnetic polymer composite
microspheres-supported Schif base palladium complex as
a catalyst for the Suzuki coupling reactions [41], Schif base
complex-coated Fe3O4 nanoparticles as a nanocatalyst for
the selective oxidation of sulfdes and oxidative coupling of
thiols [42], catalytic application of new manganese Schif
base complex immobilized on chitosan-coated magnetic nan-
oparticles for one-pot synthesis of 3-iminoaryl-imidazo[1,2-
a]pyridines [43] and dithiocarbamate to modify magnetic
graphene oxide nanocomposite (Fe3O4–GO), a new strategy
for covalent enzyme (lipase) immobilization to fabricate a
new nanobiocatalyst for enzymatic hydrolysis of PNPD [44].
This team attempted to design two potent heterogeneous
catalysts for the synthesis of these heterocyclic compounds.
In both catalysts, α-zirconium hydrogen phosphate (α-ZrP)
was employed as a support, for the stabilization and distribu-
tion of copper particles in α-ZrP/Uracil/Cu2+ and the acidic
portions in butane-sulfonic acid@α-ZrP.
coupled plasma PerkinElmer Optima 7300 DV was used.
1H NMR spectra were recorded with a Bruker (300 MHz)
Avance DRX in the pure DMSO-d6 solvent with tetramethyl-
silane as an internal standard. TGA of the α-ZrP/Uracil/
Cu2+ catalyst was conducted using a laboratory made TGA
instrument.
Preparation of α‑ZrP and BSA@α‑ZrP nanoparticles
By dissolving the polyvinylpyrrolidone (PVP;
M.W=40,000) in hot deionized water, the 30 wt% aqueous
solution was prepared. Then, 20 mL of 1 M aqueous solution
of zirconium(IV) chloride (ZrCl4) was added dropwise to
the 20 mL of the prepared solution of the polymer at 90 °C
for 1 h. Then, the solution has been sonicated for 15 min.
Ten milliliters of 12 M H3PO4 was slowly added to the soni-
cated solution for 1/2 h. The solution was stirred for 12 h at
90° C. The white solid, α-ZrP, was isolated by fltering of
the solution and washed wholly with deionized water. By
calcination and removing the polymer chains from the α-ZrP
particles at 300 °C for 4 h, α-ZrP nanoparticles are obtained.
For the preparation of butane-sulfonic acid@α-ZrP, 1 g
of α-ZrP was added in 50 mL dry toluene. Then, APTS
(1 mmol) was added and refuxed under N2 atmosphere for
24 h at 100 °C. The resulting coated α-ZrP (α-ZrP/APTS)
was washed with dry toluene and dried in the vacuum oven
at 110 °C. In the next step, to 5 mmol of 1,4-butane sultone
in 50 mL of dry THF, 1 g of α-ZrP/APTS was added under
the refux condition and stirred under N2 atmosphere for
20 h. Without separation, 5 mmol of concentrated H2SO4
was added to the previous mixture and stirred at 100 °C for
6 h. The resulting catalyst (butane-sulfonic acid@α-ZrP)
was collected, washed with methanol and acetone several
times and dried in the oven overnight at 100 °C.
α-Zirconium hydrogen phosphate (α-ZrP),
Zr(HPO4)2·H2O, is one of the precious phosphate minerals
with a layered crystalline structure [45, 46]. The presence
of pronged hydroxyl groups on its surface, in addition to
generating the acidic attributes [47], has made this com-
pound the suitable support for a variety of homogeneous
catalysts [26, 48, 49]. α-ZrP is prepared from Zr(IV) ion
salts, and its particles can also be converted into nanoscale
by a polymeric network during a simple process [50, 51]. In
the following, butane-sulfonic acid@α-ZrP is prepared and
identifed and the efciency of both catalysts is investigated
in two benzimidazoles synthetic methods.
General procedure for the preparation
of benzimidazoles catalyzed by α‑ZrP/Uracil/Cu2+
Experimental
A mixture of benzamidine (1 mmol), HOAc (3 eq.) and α-
ZrP/Uracil/Cu2+ (20 mg: 1.3 mol%) in CH3CN (3 mL) was
refuxed at 80 °C under the direct fow of O2 (followed up by
TLC). After consumption of benzamidine, the catalyst was
separated by centrifugation and the reaction mixture was
cooled to room temperature. The catalyst was thoroughly
washed with ethyl acetate, and then, the extraction with ethyl
acetate (3×10 ml) was performed on the reaction mixture.
The organic extract was dried over anhydrous CaCl2, and the
solvent was vaporized under reduced pressure. The remain-
ing solid was purifed by recrystallization from ethanol.
Product specifcations are provided in the supplementary
information.
All chemical reagents were procurement from Aldrich and
Merck Chemical Company and were used without further
purifcation. X-ray difraction (XRD) powder patterns were
obtained using a Philips X’pert X-ray difractometer, with Cu
Kα radiation (40 kV, 30 mA). The Brunauer–Emmett–Teller
(BET) method on a Quantachrome ChemBET 3000 instru-
ment was used for N2 adsorption–desorption isotherm. TEM
(Philips CM10 microscope) and SEM (MIRA3 TESCAN)
were used to characterize the catalyst. TPD-NH3 with a
Quantachrome ChemBET 3000 was used for measuring the
total acidity of α-ZrP. FT-IR spectroscopy (JASCO FT-IR
680-Plus spectrophotometer) was employed for characteri-
zation of the α-ZrP/Uracil/Cu2+ catalyst. Also inductive
1 3

Journal of the Iranian Chemical Society
TON for α-ZrP/Uracil/Cu2+ (for 90% yield of desired
product) = 4.66 × 102.
General procedure for the preparation
of benzimidazoles catalyzed by BSA@α‑ZrP
TOF for α-ZrP/Uracil/Cu2+ =4.66×102/7=0.67×102.
At frst, 1,2-phenylenediamine (1 mmol) was dissolved in
3 ml of ethanol. Then, aromatic aldehyde (1.1 mmol) and
catalyst (15 mg: 0.10 mol%) were added to the previous
solution. The mixture was constantly stirred under refux
conditions at 60 °C. The reaction progress was moni-
tored by TLC. After the completion of the reaction, 5 mL
of ethyl acetate was added to the reaction mixture. The
catalyst was easily fltered and washed with ethyl acetate
several times. The solvent was evaporated, and impure
products were recrystallized from ethanol or ethanol/H2O
(70:30). The spectral data of some compounds are listed
in the supporting information.
Results and discussion
Synthesis and characterization of α‑ZrP
and butane‑sulfonic acid@α‑ZrP (BSA@α‑ZrP)
For the synthesis of α-ZrP in nanoscale, ZrCl4 material was
broadcasted between PVP polymer chains in aqueous solu-
tion. Appending PO43− ions to this solution resulted in the
formation of α-ZrP distributed particles between the chains.
One of the reasons for this distribution can be the forma-
tion of the hydrogen bonds between the hydroxyl groups in
the α-ZrP structure and the polar regions of PVP. In fact,
polymer chains, like coverage, surround the α-ZrP particles
and prevent them from sticking and accumulation together.
Ultimately, the removal of PVP chains through calcination
produced pure α-ZrP nanoparticles.
The calculations for TON and TOF of BSA@α‑ZrP
and α‑ZrP/Uracil/Cu2+
In the following, a sample of calculations was performed
for each and more complete results are listed in Tables 2
and 4.
To prepare the APTS@α-ZrP, the α-ZrP surface rectifca-
tion was accomplished with 3-aminopropyltrimethoxysilane
(APTS) according to the reference [52–54]. Preparation of
the fnal catalyst (BSA@α-ZrP) was performed with the
reaction of 1,4-butane sultone, APTS@α-ZrP and then the
addition of H2SO4 (Scheme 1). The presence of the linker
and acidic section functional groups on the α-ZrP surface
was confrmed by FT-IR spectroscopy (Fig. 1). The absorp-
tion bands at 3360 (O–H: stretching) and 1632 (O–H: bend-
ing), 1055 (P–O: stretching) and 590 cm−1 (Zr–O: stretch-
ing) are related to the α-ZrP structure (Fig. 1a).
Turnover number (TON) = mole of reactant/mole of
catalyst.
Turnover frequency (TOF) = TON/time of reaction
(hour).
Desired product: 2-phenyl-1H-benzo[d]imidazole.
In the FT-IR spectra of BSA@α-ZrP (Fig. 1b), in the
addition to observation of the α-ZrP absorption bands in
3409 (O–H), 1050 (P–O) and 588 cm−1 (Zr–O), the char-
acteristic bands of linker at 2927 (sp3 C–Haliph stretch),
3074 (N–H stretch), 1587 (N–H bend) and also the absorp-
tion bands of butane-sulfonic acid at 1249 (S–O–H) and
1137 cm−1 (S=O) [55, 56] demonstrated the correct struc-
ture of catalyst.
TON for BSA@α-ZrP (for 100% yield of desired
product) = 91 × 10−2/22 × 10−4 = 4.11 × 102.
TON for BSA@α-ZrP (for 90% yield of desired
product) = 3.70 × 102.
TOF for BSA@α-ZrP = 3.70 × 102/2 = 1.85 × 102.
TON for α-ZrP/Uracil/Cu2+ (for 100% yield of desired
product) = mole of reactant/mole of Cu2+
According to the X-ray pattern, analogous refections
were observed for α-ZrP and BSA@α-ZrP in the 2θ range
of 10°–55°. The interlayer spacing of the layers, deduced
from (002) layer in 2θ = 13.3° for α-ZrP and 2θ = 13° for
the catalyst, is equal to 7.5 Å (Fig. 2) [57, 58]. The absence
of change in the spacing of the layers in the fnal catalyst
shows that the linker and the acid section were located on the
BSA@α-ZrP surface, not between its layers [49].
Desired product: 2-phenyl-1H-benzo[d]imidazole.
The SEM–EDX analysis and the elemental analysis
(Fig. 3) confrmed the presence of the organic phase in the
structure of the catalyst. Based on the CHNS analysis, the
contents of the elements were C, 10.85; H, 1.96; N, 0.45; S,
5.13 wt%. The contents of other elements were determined
TON for α-ZrP/Uracil/Cu2+ (for 100% yield of desired
product) = 83 × 10−2/18 × 10−4 = 4.66 × 102.
1 3

Journal of the Iranian Chemical Society
Scheme 1 BSA@α-ZrP prepa-
OH
HO
ration
OH
OMe
Si
OH
OH
OH
OMe
Si
O
O
H2N
NH2
ZrP
HO
(OMe)3Si(CH2)3NH2
Dry toluene
ZrP
O
O
HO
OH
HO
OH
OH
SO3H
SO3H
HO3S
O
O
O
S
OH
OMe
Si
OMe
Si
and dry THF
Concentrated H2SO4
O
HO3S
O
SO3H
N
N
ZrP
O
O
HSO4
HSO4
HO
OH
HO3S
OH
Fig. 3 SEM–EDX spectrum of BSA@α-ZrP
by ICP-OES analysis: Zr (10.35), Si (0.98), P (15.02) and
O (55.26) wt%. The Zr, P, O, N, S, Si and C elements were
clearly visible from the EDS spectrum. The EDS data for the
unfunctionalized α-ZrP are as follows: Zr (14.65), P (20.23)
and O (65.12) wt% [57].
Fig. 1 FT-IR spectra of α‐ZrP (a) and BSA@α-ZrP (b)
The SEM–EDX mapping of catalyst is shown in Fig. S1
in the supporting information. The monotone dispersion of
the elements in this image is obvious.
The BSA@α-ZrP surface morphology was shown in
the SEM image (Fig. 4a). The agglomeration at this image
can be due to the condensation of non-interacting hydroxyl
groups with the linker. The catalyst particles in the nanoscale
are clearly identifed in the TEM image (Fig. 4b). It can be
seen from this image that BSA segments did not agglomer-
ate upon immobilization on α-ZrP/APTS, and the α-ZrP is a
worthy host for BSA. The average particle size of 12.61 nm
was achieved by the catalyst particles size distribution chart
(Fig. 5).
Thermal gravimetric analysis (TGA) result for BSA@α-
ZrP is presented in Fig. 6. The frst weight change of cata-
lyst (4.05%) is started at 98.00–110.37 °C that shows the
loss of water molecules. The major weight variation of
Fig. 2 XRD pattern of α‐ZrP (a) and BSA@α-ZrP (b)
1 3

Journal of the Iranian Chemical Society
Fig. 4 SEM (a) and TEM
images (b) of BSA@α-ZrP
Fig. 7 NH3-TPD profle of BSA@α-ZrP
decomposition reactions occurs at a temperature range of
340.00–470.25 °C (40.13% weight loss). After this reduc-
tion step, no change in weight was observed at 750° C that
indicates a high thermal stability of the catalyst.
Fig. 5 The catalyst particles size distribution
The quantitative estimation of surface acidity of the
BSA@α-ZrP was given by temperature-programmed
desorption (NH3-TPD) method. The NH3-TPD curve of
BSA@α-ZrP is presented in Fig. 7. The absorption of NH3
by the catalyst is carried out at the temperature ranging from
50 to 900 °C. The acid strength of the catalyst is determined
by the position of the NH3 desorption peaks and desorption
temperature. The desorption peak at 480 °C and a peak at
350 °C are consistent with the sites with high acidity, respec-
tively. Despite these numbers of strong acid sites, the cata-
lyst has become an acidic signifcant catalyst. The NH3-TPD
at 195 °C is related to the medium acidic sites [59].
Catalytic activity
Initially, using the previously reported procedures, the
types of benzamidines were synthesized and the physical
and spectral properties of some of them are presented in
Fig. 6 TGA analysis of BSA@α-ZrP
1 3

Journal of the Iranian Chemical Society
The obtained results from Table 1 show that the use of
1.3 mol% catalyst and 3 equivalents of HOAc in CH3CN at
80 °C, under the direct fow of oxygen, leads to the high-
est conversion of the 4-chloro-N-phenylbenzamidine to
2-(4-chlorophenyl)-1H-benzimidazole (Table 1, entry 8).
Using the optimum conditions, we next followed the
extent and popularity of the process and synthesized vari-
ous benzimidazoles derivatives using substituted benza-
midines (Table 2). We noticed that the presence of ortho
substituents in the benzamidine structure attenuated the
conversion to benzimidazole. In addition, according to
Table 2, high yields were acquired when the benzamidine
contains the electron-withdrawing substitutions.
Cl
H
N
H
N
Catalyst
Solvent, Heat
Cl
N
NH
Scheme 2 Optimization of the reaction conditions for the synthesis
of benzimidazoles
Table 1 Efect of diferent parameters for the synthesis of benzimida-
zoles in C–H functionalization process
Entry Solvent
Additive
T (°C) Catalyst
amount
Yielda (%)
(mol%)
An explanation of the reaction mechanism is difcult.
Scheme 3 illustrates our suggested mechanism with the
succor of the background from the previous literature
[62–64]. Based on this mechanism, the reaction of benza-
midine with Cu(II) in α-ZrP/Uracil/Cu2+ presumably leads
to the formation of (A). HOAc helps in the coordination of
copper and nitrogen. The transfer of the ring bond creates
a positive charge on the aromatic ring, which is quickly
compensated by the bond shift, and a metal cycle with the
copper center is created (B). The aromatization and reduc-
tive elimination processes give the benzimidazole product
(C). The catalyst and HOAc were recovered at the end.
In the further studies, the efciency of two catalysts in
another method of benzimidazoles synthesis, i.e., conden-
sation reaction of aldehydes and 1,2-phenylenediamine,
was investigated. The reaction of benzaldehyde with
1,2-phenylenediamine was selected as a model reaction
(Scheme 4). Initially, to demonstrate the benefcial role
of catalyst, the reaction was carried out without the cata-
lyst that no product was formed. In addition, in order to
verify and prove the duty of grafted butane-sulfonic acid
and copper on the performance of the catalysts, the model
reaction was followed out in the presence of α-ZrP as a
catalyst. The low conversion percentage refects the efec-
tive role of mentioned portions (35% conversion).
1
2
3
4
5
6
7
8
H2O
EtOH
THF
HOAc
HOAc
HOAc
80
80
80
80
80
80
80
80
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.1
1.5
1.3
1.3
35
50
68
53
62
86
81
90
78
80
90
82
73
88
70
32
EtOH/H2O HOAc
EtOAc
DMSO
DMF
HOAc
HOAc
HOAc
HOAc
Formic acid 80
Lactic acid 80
HOAc
HOAc
HOAc
HOAc
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
15
16
85
75
80
80
80
80
NEt3
Reaction conditions: benzamidine (1 mmol), time (7 h), direct fow of
O2, additive (3 eq.)
aIsolated yield
supplementary information [60, 61]. Then, we started our
study by checking the activity of two catalysts in C–H func-
tionalization process and the conversion of 4-chloro-N-phe-
nylbenzamidine to 2-(4-chlorophenyl)-1H-benzimidazole as
the pattern reaction (Scheme 2). To demonstrate the efective
role of catalyst, the reaction was carried out without a cata-
lyst that no product was formed. Under the similar condi-
tions, it was found that the use of α-ZrP/Uracil/Cu2+ led to
the product with 70% efciency, while using BSA@α-ZrP,
efciency dropped by 25%. It is noteworthy that the addition
of acetic acid to the reaction enhanced the output by 70% to
90%, while the efciency of 25% did not change with using
BSA@α-ZrP. Pursuant to the results, α-ZrP/Uracil/Cu2+ was
chosen as the selected catalyst for the synthesis of benzimi-
dazole during the C–H functionalization and the reaction
conditions (such as solvents, temperatures, acidic additive
and catalyst quantities) were ameliorated in the presence of
this catalyst (Table 1).
Subsequently, the reaction was performed in a com-
pletely identical manner with both catalysts individually,
and it was observed that the yield of benzimidazole when
using BSA@α-ZrP and α-ZrP/Uracil/Cu2+ was 90% and
73%, respectively. According to the result, BSA@α-ZrP
was considered to be the preferred catalytic option in this
method, although α-ZrP/Uracil/Cu2+ also provided an
acceptable result.
To achieve the best conditions for this reaction, the
model’s reaction was examined in diferent conditions,
such as the types of solvents, reaction temperatures and
catalyst amounts (Table 3). According to Table 3: entry
2, using 1.0 mol% of catalyst, ethanol solvent and tem-
peratures of 60 °C were introduced as optimal reaction
1 3

Journal of the Iranian Chemical Society
Table 2 The synthesis of 2-aryl (1H) benzimidazoles with copper in C–H functionalization
Entry
1
R
H
Product
Time (h)
7
Yield (%)a
90
TON
TOF (h−1
)
4.66×102
0.67×102
0.69×102
0.57×102
2
3
4-Cl
7
7
92
94
4.81×102
4.01×102
3-NO2
4
4-NO2
6
97
4.23×102
0.70×102
5
6
4-OMe
2-NO2
7
7
80
90
3.24×102
3.98×102
0.46×102
0.57×102
7
8
4-Me
2-OH
7.5
7.5
80
87
3.24×102
3.90×102
0.43×102
0.52×102
9
3-Me
7
85
4.66×102
0.67×102
Reaction conditions: benzamidine (1 mmol), CH3CN (3 mL), α-ZrP/Uracil/Cu2+ catalyst (1.3 mol%), 80 °C, HOAc (3 eq.), O2
aIsolated yield
conditions. The total consumption of benzaldehyde, which
was the reason for the completion of the reaction, was 2 h.
The optimized conditions were used in the synthesis
of the types of 2-aryl (1H) benzimidazoles. As shown in
Table 4, aromatic aldehydes containing the electron-with-
drawing substituents condense efectively with 1,2-phe-
nylenediamine. The position of the substituents in the alde-
hyde structure also has no signifcant efect on the yield
of the products. Aliphatic aldehydes did not exhibit any
reaction. Interestingly, this reaction, as opposed to the C–H
functionalization, is easily accomplished in the peripheral
atmosphere.
A feasible mechanism for the synthesis of benzimida-
zoles is described in Scheme 5. Initially, BSA@α-ZrP acti-
vates the aromatic aldehyde. The condensation of an alde-
hyde with the amino group of 1,2-phenylenediamine leads
to the formation of imine (A). The nucleophilic attack of
the remaining NH2 in the presence of catalyst causes the
1 3

Journal of the Iranian Chemical Society
Scheme 3 Proposed mechanism
for the conversion of benzami-
dine into benzimidazole
A
R
R
H
H
H
N
N
Catalyst
HOAc and O2
N
NH
Cu
AcO
H2O
H2O
ZrP
R
Catalyst
HOAc
H
R
N
H
N
N
Aromatization
Reductive elimination
Cu
H2O
ZrP
N
H
OAc
B
C
formation of intermediate (B). Finally, the oxidative aroma-
tization of intermediate (B) was performed at room tempera-
ture, and the benzimidazole product was synthesized (C).
To ensure the important role of air/O2 in the fnal step, the
reaction was performed under argon atmosphere; no product
was synthesized. These observations confrm the validity of
the suggested mechanism.
O
NH2
H
N
Catalyst
N
H
NH2
Scheme 4 Optimization of the reaction conditions for the synthesis
of 2-aryl benzimidazoles
Consequently, in all conditions, the second reaction is
milder than the frst, such as solvent type (EtOH instead of
CH3CN), reaction temperature (60 °C instead of 80 °C), use
of air instead of oxygen, lower catalyst content (1.0 mol%
instead of 1.3 mol%) and insensitivity of this method to the
position of the substitutes in the structure of the starting
materials.
Table 3 Efect of diferent parameters for the condensation reaction
of benzaldehyde with 1,2-phenylenediamine
Entry
Solvent
T (°C)
Catalyst amount Yielda (%)
(mol%)
1
2
3
4
5
6
7
8
H2O
EtOH
THF
EtOH/H2O
DMSO
CH3CN
EtOAc
EtOH
EtOH
EtOH
60
60
60
60
60
60
60
55
65
60
60
1
1
1
1
1
1
1
1
65
90
40
76
54
65
60
77
90
67
85
Comparison of catalytic activity between α-ZrP/Uracil/
Cu2+, BSA@α-ZrP and other reported catalysts for the syn-
thesis of benzimidazoles was performed in two synthetic
mentioned methods, the results of which are presented in
Tables 5 and 6.
According to the results of Tables 5 and 6, the efective
efcacy of the two catalysts prepared for the easy synthesis
of diferent benzimidazoles is revealed in this study.
8
10
11
1
0.8
2
The recyclability and reusability of α‑ZrP/Uracil/Cu2+
and BSA@α‑ZrP
EtOH
Reaction conditions: benzaldehyde (1 mmol), 1,2-phenylenediamine
(1 mmol), time (2 h)
The sustainability of the catalytic system is associated
with its potency to recover. This is a valuable issue both
aIsolated yield
1 3

Journal of the Iranian Chemical Society
Table 4 The synthesis of 2-aryl (1H) benzimidazoles with aromatic aldehydes and 1,2-phenylenediamine
Entry
1
R or aldehyde
H
Product
Time (min)
120
Yield (%)a
90
TON
TOF (h−1
)
3.70×102
1.85×102
1.65×102
5.01×102
2
3
4-Cl
130
40
88
96
3.56×102
4.01×102
3-NO2
4
4-NO2
40
98
4.23×102
5.28×102
5
6
4-OMe
2-NO2
55
45
80
95
3.24×102
3.98×102
3.53×102
5.30×102
7
8
4-Me
2-OH
55
50
80
93
3.24×102
3.90×102
3.53×102
4.68×102
9
2-Me
50
50
86
90
3.46×102
3.70×102
4.15×102
4.44×102
10
Reaction conditions: aromatic aldehydes (1.1 mmol), 1,2-phenylenediamine (1 mmol), EtOH, air, BSA@α-ZrP (1.0 mol%), reaction tempera-
ture: 60 °C
aIsolated yield
economically and environmentally. In order to assay this
subject, after performing the model reaction in C–H func-
tionalization in optimal conditions, α-ZrP/Uracil/Cu2+ was
separated by centrifugation (or nanofltration) and washed
with ethyl acetate several times, dried at 60 °C and used for
the next run. Recovery and reuse of the catalyst were at least
1 3

Journal of the Iranian Chemical Society
Scheme 5 Proposed mechanism
for the synthesis of benzimida-
zoles via BSA@α-ZrP catalyst
:
ZrP
H O3S
Ar O H
Ar
Ar
H
:
ZrP
O :
O
H O3S
H
N
H
H2N
H
H
:
H
NH
-
SO3
ZrP
NH2
Ar
H
SO3
ZrP
H
A
Ar
NH2
H
N
:
Ar
H
H
H
N
H
HN
NH2
N
:
-
SO3
ZrP
ZrP
Air
O3S
H
N
H
N
Ar
H
Ar
N
N
H
C
B
Table 5 Comparison of
Entry
Catalyst ref
Reaction conditions
2 mol% catalyst in NMP at 130 °C
0.2 mol% catalyst in perfuorodecalin at 90 °C
10 mol% catalyst in NMP at r.t
10 mol% catalyst in CH3CN at r.t
10 mol% catalyst in NMP at r.t
1.3 mol% catalyst in EtOH at 80 °C
1.0 mol% catalyst in EtOH at 60 °C
Time (h)
Yield (%)
the catalytic activity of two
prepared catalysts with those
of the reported catalysts for the
synthesis of benzimidazoles
between benzaldehyde and
1,2-phenylenediamine
1
2
3
4
5
6
7
WOx/ZrO2 [34]
Yb(OPf)3 [65]
Co3O4(II,III) [66]
LaCl 3 [67]
Co(OH)2 [66]
α-ZrP/Uracil/Cu2+
BSA@α-ZrP
2
6
6
3
4
2
2
90
98
79
88
96
73
90
Table 6 Comparison of the
catalytic activity of α-ZrP/
Uracil/Cu2+ catalyst with those
of the reported catalysts for the
synthesis of benzimidazoles
from benzamidine
Entry
Catalyst ref
Reaction conditions
Time (h)
Yield (%)
1
2
3
4
5
6
I2 [14]
10 mol% catalyst in CH3CN at r.t
10 mol% catalyst in DMF at 135 °C
10 mol% catalyst in DMSO at 120 °C
5 mol% catalyst in H2O at 100 °C
10 mol% catalyst in DMF at 120 °C
1.3 mol% catalyst in CH3CN at 80 °C
2
92
90
77
99
90
90
Pd(OAc)2[16]
CuBr [68]
Cu2O [69]
Cu(OAc)2 [70]
35/60
8
30
4
7
α-ZrP/Uracil/Cu2+
4 times with no signifcant decadence in its activity (Fig. 8).
From run 4, the reaction efciency started to decrease.
To check the character of the active catalytic kind,
leached Cu or Cu on the α-ZrP surface, a hot-fltration
experiment was performed on the model’s reaction. After
30 min of reaction time (conversion: 67%), the catalyst
was removed from the hot reaction and the reaction was
continued without the α-ZrP/ Uracil/Cu2+. After 30 min,
the reaction did not continue. Simultaneously, the ICP
analysis was performed on a solution without a catalyst;
only 0.1 ppm of copper was found in this solution. Based
1 3

Journal of the Iranian Chemical Society
Fig. 8 Reusability of α-ZrP/Uracil/Cu2+ catalyst in the synthesis of
Fig. 10 Reusability of BSA@α-ZrP catalyst in the synthesis of ben-
benzimidazoles
zimidazoles
Fig. 9 TEM images of the recovered α-ZrP/ Uracil/Cu2+ after sixth
run
Fig. 11 TEM images of the recovered BSA@α-ZrP after ffth run
on this result, it is determined that the active copper spe-
cies is the same copper on the α-ZrP surface.
and from the seventh run, the catalyst was abandoned
(Fig. 10).
By comparing the TEM images of the fresh catalyst and
recovered catalyst (Fig. 9), it is obvious that the distribu-
tion and size of catalyst particles are maintained even after
several uses.
The comparison of the TEM image of recovered
BSA@α-ZrP catalyst with fresh catalyst showed that the
morphology and size of the catalyst do not change consid-
erably after the ffth run of recycling (Fig. 11).
A comparison was also performed between the fresh
catalyst FT-IR spectra and the recycled catalyst after the
ffth run. The retention of the major absorption bands
related to α-ZrP at 3434 (O–H), 1048 (P–O), 601 cm−1
(Zr–O) and 2970–2900 (sp3 C–Haliph stretch), 1595 (N–H
bend) and also the observation of absorption bands
of (S–O–H) at 1250 cm−1 indicate that the structure of
the recycled catalyst has not changed after the ffth run
(Fig. 12).
Furthermore, the amount of Cu metal of the catalyst
was checked using ICP after sixth run of reuse, and the
observation revealed that only 0.050 ppm of Cu was
removed from the catalyst, giving further explanation for
its stable catalytic activity.
The same approach for reusability was conducted for
the second reaction and the BSA@α-ZrP catalyst. Up to 5
times the reuse of the catalyst, the efciency was impres-
sive, but after this cycle, the efciency slowly decreased,
1 3

Journal of the Iranian Chemical Society
11. V.G. Atyam, C.S. Raidu, J. Young Pharm. 2, 273 (2010)
12. I. Mohammadpoor-Baltork, M. Moghadam, S. Tangestaninejad,
V. Mirkhani, M.A. Zolfgol, S.F. Hojati, J. Iran. Chem. Soc. 5, S65
(2008)
13. L.H. Chen, T.Y. Wu, V. Paike, C.M. Sun, Mol. Divers. 17, 641
(2013)
14. S.V. Patil, S.S. Patil, V.D. Bobade, Arab. J. Chem. 9, S515 (2016)
15. J. Li, H. Gu, C. Wu, L. Du, Dalton Trans. 43, 16769 (2014)
16. D. Ma, X. Ji, Z. Wu, C. Cheng, B. Zhou, Y. Zhang, Adv. Synth.
Catal. 361, 739 (2019)
17. J.E. Sadig, R. Foster, F. Wakenhut, M.C. Willis, J. Org. Chem. 77,
9473 (2012)
18. Y. Matsuura, M. Tamura, T. Kochi, M. Sato, N. Chatani, F. Kaki-
uchi, J. Am. Chem. Soc. 129, 9858 (2007)
19. Y. Kobayashi, M. Kashiwa, M. Sonoda, M. Kirihata, S. Tanimori,
Synthesis 46, 3185 (2014)
20. R.P. Reddy, H.M. Davies, Org. Lett. 8, 5013 (2006)
21. B.J. Stokes, H. Dong, B.E. Leslie, A.L. Pumphrey, T.G. Driver, J.
Am. Chem. Soc. 129, 7500 (2007)
Fig. 12 FT-IR spectra of the recovered BSA@α-ZrP after ffth run
22. T. Uemura, S. Imoto, N. Chatani, Chem. Lett. 35, 842 (2006)
23. X. Chen, X.S. Hao, C.E. Goodhue, J.Q. Yu, J. Am. Chem. Soc.
128, 6790 (2006)
Conclusions
24. P. Feng, G. Ma, T. Zhang, C. Wang, Asian. J. Org. Chem. 7, 788
(2018)
In summary, this study highlights the multifaceted benefts
of α-ZrP as a stable support for green organic compounds
and homogeneous catalysts such as uracil and butane sul-
fonic acid as well as the tuning of the metal–support inter-
action. This research is summarized in the synthesis of
benzimidazoles with two catalysts in two methods, C–H
functionalization in benzamidines and condensation reaction
between aldehydes and 1,2-phenylenediamine. Mild reac-
tions conditions (palladium-free, ethanol as the solvent, 60
and 80 °C) enables the synthesis of benzimidazoles to be
performed in good yields with low metal contamination, and
easy and good recyclability of catalyst.
25. X. Wang, Y. Jin, Y. Zhao, L. Zhu, H. Fu, Org. lett. 14, 452 (2011)
26. A.R. Hajipour, S. Zakery, Appl. Organomet. Chem. 32, e4487
(2018)
27. D. Yang, H. Fu, L. Hu, Y. Jiang, Y. Zhao, J. Org. Chem. 73, 7841
(2008)
28. K. Liubchak, K. Nazarenko, A. Tolmachev, Tetrahedron 68, 2993
(2012)
29. V.J. Grenda, R.E. Jones, G. Gal, M. Sletzinger, J. Org. Chem. 30,
259 (1965)
30. S. Chaudhury, A. Debroy, M. Mahajan, Can. J. Chem. 60, 1122
(1982)
31. J. Lu, B. Yang, Y. Bai, Synth. Commun. 32, 3703 (2002)
32. L.M. Dudd, E. Venardou, E. Garcia-Verdugo, P. Licence, A.J.
Blake, C. Wilson, M. Poliakof, Green Chem. 5, 187 (2003)
33. F.K. Behbahani, E. Rezaee, Z. Fakhroueian, Catal. Lett. 144, 2184
(2014)
Acknowledgements The authors are grateful to the Research Council
34. R.V. Shingalapur, K.M. Hosamani, Catal. Lett. 137, 63 (2010)
35. N.C. Herrera, J.G. Uranga, M. Nardi, A. Procopio, D.A. Wunder-
lin, A.N. Santiago, Beilstein J. Org. Chem. 12, 2410 (2016)
36. K. Tateyama, K. Wada, H. Miura, S. Hosokawa, R. Abe, M. Inoue,
Catal Sci. Technol. 6, 1677 (2016)
of Isfahan University of Technology (IUT).
37. C. Karami, K. Ghodrati, M. Izadi, A. Farrokh, S. Jafari, M.
Mahmoudiyani, N. Haghnazari, J. Chil. Chem. Soc. 58, 1914
(2013)
References
38. Z.H. Zhang, L. Yin, Y.M. Wang, Catal. Commun. 8, 1126 (2007)
39. S. Rostamnia, E. Doustkhah, J. Magn. Magn. Mater. 386, 111
(2015)
1. V.O. Rodionov, S.I. Presolski, S. Gardinier, Y.H. Lim, M.G. Finn,
J. Am. Chem. Soc. 129, 12696 (2008)
2. P. Dubey, P. Prasada Reddy, K. Srinivas, Arkivoc 15, 192 (2007)
3. H. Wu, F. Kou, F. Jia, B. Liu, J. Yuan, Y. Bai, Bioinorg. Chem.
Appl. 2011, 2011 (2011)
40. J. Rakhtshah, B. Shaabani, S. Salehzadeh, N.H. Moghadam,
Bioorg. Chem. 85, 420 (2019)
41. D. Yuan, L. Chen, L. Yuan, S. Liao, M. Yang, Q. Zhang, Chem.
Eng. J. 287, 241 (2016)
4. R. Sharma, M. Abdullaha, S.B. Bharate, Asian J. Org. Chem. 6,
1370 (2017)
42. A. Ghorbani-Choghamarani, B. Ghasemi, Z. Safari, G. Azadi.
Catal. Commun. 60, 70 (2015)
5. J. Lu, H. Fu, J. Org. Chem. 76, 4600 (2011)
6. R.T. Stibrany, M.V. Lobanov, H.J. Schugar, J.A. Potenza, Inorg.
Chem. 43, 1472 (2004)
43. J. Rakhtshah, F. Yaghoobi, Int. J. Biol. Macromol. 139, 904 (2019)
44. M. Heidarizadeh, E. Doustkhah, S. Rostamnia, P.F. Rezaei, F.D.
Harzevili, B. Zeynizadeh, Int. J. Biol. Macromol. 101, 696 (2017)
45. A.R. Hajipour, H. Karimi, Appl. Catal. A. Gen. 482, 99 (2014)
46. C. Trobajo, S.A. Khainakov, A. Espina, J.R. Garcia, Chem. Mater.
12, 1787 (2000)
7. K. Niknam, A. Fatehi-Raviz, J. Iran. Chem. Soc. 4, 438 (2007)
8. H. Zarrinmayeh, A.M. Nunes, P.L. Ornstein, D.M. Zimmerman,
M.B. Arnold, D.A. Schober, B.E. Cantrell, J. Med. Chem. 41,
2709 (1998)
9. P. Martins, J. Jesus, S. Santos, L.R. Raposo, C. Roma-Rodrigues,
P.V. Baptista, A.R. Fernandes, Molecules 20, 16852 (2015)
10. E.I. Elnima, M.U. Zubair, A.A. Al-Badr, Antimicrob. Agents
Chemother. 19, 29 (1981)
47. D. Lanari, F. Montanari, F. Marmottini, O. Piermatti, M. Orru, J.
Catal. 277, 80 (2011)
48. M. Pica, Catalysts 7, 190 (2017)
1 3

Journal of the Iranian Chemical Society
49. R. Silbernagel, A. Diaz, E. Stefensmeier, A. Clearfeld, J. Blumel,
J. Mol. Catal A Chem. 394, 217 (2014)
61. X. Liu, H. Yue, J. Jia, L. Guo, M. Rueping, Chem. Eur. J. 23,
11771 (2017)
50. V.K. Gupta, D. Pathania, P. Singh, B.S.P. RathoreChauhan, Car-
bohydr. Polym. 95, 434 (2013)
62. K. Yamada, T. Kubo, H. Tokuyama, T. Fukuyama, Synlett 2002,
0231 (2002)
51. Y. Yang, C. Liu, P.R. Chang, Y. Chen, D.P. Anderson, M. Stum-
borg, J. Appl. Polym. Sci. 115, 1089 (2010)
63. H. Wang, Y. Wang, C. Peng, J. Zhang, Q. Zhu, J. Am. Chem. Soc.
132, 13217 (2010)
52. A.R. Hajipour, G. Azizi, Chin. J. Catal. 35, 1547 (2014)
53. A.R. Hajipour, F. Mohammadsaleh, Catal. Lett. 148, 1035 (2018)
54. A.R. Hajipour, P. Abolfathi, Catal. Lett. 147, 188 (2017)
55. A. Periasamy, S. Muruganand, M. Palaniswamy, Rasayan J. Chem.
2, 981 (2009)
64. K. Kamanna, Intech. Open 15, 3657 (2019)
65. M.-G. Shen, C. Cai, J. Fluor. Chem. 128, 232 (2007)
66. M.A. Chari, D. Shobha, T. Sasaki, Tetrahedron Lett. 52, 5575
(2011)
67. Y. Venkateswarlu, S.R. Kumar, P. Leelavathi, Org. Med. Chem.
Lett. 3, 7 (2013)
56. J. Jaganathan, M. Sivapragasam, C. Wilfred, J. Chem. Eng. Pro-
cess Technol. 7, 309 (2016)
68. M.H. Sayahi, M. Khoshneviszadeh, M. Soheilizad, S.J. Saghan-
ezhad, M. Mahdavi, Chem. Heterocycl. Compd. 54, 351 (2018)
69. J. Peng, M. Ye, C. Zong, F. Hu, L. Feng, X. Wang, Y. Wang, C.
Chen, J. Org. Chem. 76, 716 (2010)
57. A.R. Hajipour, H. Karimi, Mater. Lett. 116, 356 (2014)
58. L. Sun, W.J. Boo, H.J. Sue, A. Clearfeld, New J. Chem. 31, 39
(2007)
59. A.R. Hajipour, H. Karimi, Chin. J. Catal. 35, 1136 (2014)
60. S.D. Veer, K.V. Katkar, K.G. Akamanchi, Tetrahedron Lett. 57,
4039 (2016)
70. J. Li, S. Bénard, L. Neuville, J. Zhu, Org. lett. 14, 5980 (2012)
1 3