Green synthesis of benzimidazoloquinazolines and 1,4-dihydropyridines using magnetic cyanoguanidine-modified chitosan as an efficient heterogeneous nanocatalyst under various conditions

Article abstract of DOI:10.1007/s00706-019-02542-z

Abstract: In the present study, we demonstrated the synthesis of magnetic cyanoguanidine-modified chitosan (MCGC) as an efficient and green retrievable heterogeneous nanocatalyst for one-pot three-component synthesis of benzimidazoloquinazolines (from 2-aminobenzimidazole, aromatic aldehydes, and dimedone) and 1,4-dihydropyridines (via Hantzsch-type condensation of ethyl acetoacetate, aromatic aldehydes, and ammonium acetate) under the ultrasonic irradiation and reflux conditions. The structure of the catalyst was fully confirmed using Fourier transform infrared spectroscopy, vibrating sample magnetometer, field emission scanning electron microscopy, energy dispersive spectroscopy, and thermogravimetric analysis. Increased amount of amino groups that are generated by modifying the surface of chitosan with cyanoguanidine as well as presence of hydroxyl groups determined the catalytic activity of MCGC. Furthermore, as experimental results confirmed, the ultrasonic-promoted reactions gave the better results in terms of reaction time, yield, and purity of isolated products. Cost effectiveness, mild conditions, low catalyst loading, convenient work-up, and ecofriendly solvent are some of the remarkable advantages of this protocol.

Full text of DOI:10.1007/s00706-019-02542-z

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-019-02542-z
ORIGINAL PAPER
Green synthesis of benzimidazoloquinazolines
and 1,4‑dihydropyridines using magnetic cyanoguanidine‑modifed
chitosan as an efcient heterogeneous nanocatalyst under various
conditions
Kaveh Javanmiri1 · Ramin Karimian1
Received: 11 July 2019 / Accepted: 27 December 2019
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
In the present study, we demonstrated the synthesis of magnetic cyanoguanidine-modifed chitosan (MCGC) as an efcient
and green retrievable heterogeneous nanocatalyst for one-pot three-component synthesis of benzimidazoloquinazolines (from
2-aminobenzimidazole, aromatic aldehydes, and dimedone) and 1,4-dihydropyridines (via Hantzsch-type condensation of
ethyl acetoacetate, aromatic aldehydes, and ammonium acetate) under the ultrasonic irradiation and refux conditions. The
structure of the catalyst was fully confrmed using Fourier transform infrared spectroscopy, vibrating sample magnetometer,
feld emission scanning electron microscopy, energy dispersive spectroscopy, and thermogravimetric analysis. Increased
amount of amino groups that are generated by modifying the surface of chitosan with cyanoguanidine as well as presence of
hydroxyl groups determined the catalytic activity of MCGC. Furthermore, as experimental results confrmed, the ultrasonic-
promoted reactions gave the better results in terms of reaction time, yield, and purity of isolated products. Cost efectiveness,
mild conditions, low catalyst loading, convenient work-up, and ecofriendly solvent are some of the remarkable advantages
of this protocol.
Graphic abstract
H
N
NH2
O
N
Ar
MCGC
O
Ar CHO
N
Reflux or Ultrasonic
NH
N
O
H2
N
H2N
NH
HN
OH
NH
OH
NH
NH
HN
OH
OH
NH
NH
O
O
O
O
O
HO
O
HO
O
HO
O
NH
HO
O
O
O
HO
NH
NH
n
OH
HN
HN
HN
NH
NH
NH
HN
HN
HN
NH2
NH2
NH2
MCGC Catalyst
Ar CHO
O
Ar
O
O
O
Et
Et
O
O
Et
O
MCGC
Reflux or Ultrasonic
Et
O
N
H
O
O
NH4OAc
Keywords Chitosan · Ultrasonic irradiation · Benzimidazoloquinazolines · 1,4-Dihydropyridines · Magnetic nanocatalyst ·
Cyanoguanidine
Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-019-02542-z) contains
The use of homogeneous catalysts is restricted by two
supplementary material, which is available to authorized users.
important factors, high cost of materials and tedious sepa-
ration procedures. In this respect, the recovery of homogene-
* Ramin Karimian
ous catalysts by fltration or centrifugation involves tedious
work-up as well as these procedures result in the remark-
able loss amount of nanocatalyst. As an ideal choice, the
development of magnetically separable nanocatalysts has
Karimian.r@gmail.com
1
Chemical Injuries Research Center, Systems Biology
and Poisonings Institute, Baqiyatallah University of Medical
Sciences, Tehran, Iran
Vol.:(0123456789)
1 3

K. Javanmiri, R. Karimian
been emerged as an efective technique [1]. Recently, the
magnetic catalysts have been utilized in various organic
transformations [2–4]. “Green Chemistry” rules, monitor
the design of chemicals and processes to decrease or elimi-
nate the use and production of hazardous substances [5].
The application of biopolymers such as starch [6], cellulose
[7], chitosan [8], and wool [9] as a support in heterogeneous
catalysis is an emerging feld. Of these, chitosan is especially
demanding because it is a non-toxic, hydrophilic, biocom-
patible, biodegradable, and antibacterial bifunctional bio-
polymer. Chitosan directly promotes several organic reac-
tions such as transamidation [10], Strecker reaction [11],
Biginelli reaction [12], Ullmann reaction [13], aldol and
Knoevenagel reactions [14, 15], and pyridazine synthesis
[16] owing to the existence of –NH2 and –OH groups on
its surface. In fact, chitosan serves as an organocatalyst and
promotes the green and metal-free processes. In addition,
chitosan plays an important role as a support for metals
to catalyze several reactions such as Suzuki-Miyaura and
Heck cross-coupling reactions [17, 18], oxidation [19, 20],
and [3+2] Huisgen cycloaddition [21]. Besides, chitosan is
used in food packing, adhesives, medicine, drug delivery,
agriculture, membrane, treatment, and fuel cells [22]. By
modifying the surface of chitosan with organic molecules,
new properties appear in the modifed chitosan. Various
techniques for modifcation of chitosan have been reported
[23]. For example, Kumar and co-workers described a diiso-
cyanate-modifed chitosan with antibacterial activity against
E. coli [24]. In the feld of catalyst, Dekamin et al. reported
a melamine-modifed chitosan materials as an organocata-
lyst for the synthesis of dihydropyrano[2,3-c]pyrazole and
benzylpyrazolyl coumarin derivatives. Guanidinylation of
chitosan increases the amount of the amino groups on the
chitosan as reported by independent groups [25, 26]. Mul-
ticomponent reactions (MCRs) demonstrate superior atom
economy and efciency as compared to the classical meth-
ods for the synthesis of complex molecules. Therefore, the
improvement of new multicomponent reactions (MCRs)
and the progression of known MCRs are utmost important
in medicinal and organic chemistry [27–29]. MCRs pave
the synthesis of desired structures from three or more than
three starting materials [30, 31]. The reactions under the
ultrasonic irradiation beneft from various advantages in
the terms of reaction rates, yields, purity of the products,
selectivity, short reaction times, and milder conditions, and
etc. [32–34]. In the ultrasound-assisted reactions a huge
number of cavitation bubbles are generated and their col-
lapsing forms micro-jets that provide fne emulsion between
substrates [35]. Due to their potent physiological proper-
ties, nitrogen-containing heterocycles play a vital role in
the pharmaceutical and agrochemical industries [36]. Of
these, quinazolinone derivatives display a wide range of
pharmacological and biological activities such as antihy-
pertensive [37], antihistaminic [38], analgesic and anti-
infammatory [39], anticancer [40], and anti-HIV [41], etc.
In addition, quinazolines exist in the structure of many natu-
ral products, ligands, and C−H bond activation partners [42,
43]. Benzimidazoles are common pharmacophores in the
modern drug design due to their presence in natural prod-
ucts and biologically active molecules [44]. Benzimidazoles
are reported as bactericides and anti-carcinogens [45–47].
Benzimidazoloquinazolines incorporate both benzimidazole
and quinazole moieties. Intrigued by their importance, many
methods have been reported by independent groups [48–50].
Recently, Singh et al. developed a method for the synthesis
of benzimidazolo/benzothiazolo quinazolinone derivatives
using Sc(OTf)3 under the microwave irradiation [51]. As
one of the most frequented MCRs, Hantzsch reaction has
attracted much attention in the synthesis of 1,4 dihydropyri-
dines (1,4-DHPs) due to their remarkable biological activi-
ties and pharmacological properties [52, 53]. 1,4-DHPs are
used as anticonvulsant, antidiabetic, antianxiety, antidepres-
sive, antitumor, radio- and neuroprotectant platelet anti-
aggregratory [54–57]. Besides, 1,4-DHPs are also useful
as reducing agents for imines in the presence of a catalytic
amount of Lewis acid [58]. 1,4-DHPs are generally prepared
by the classical Hantzsch method, which is a cyclocondensa-
tion reaction of aldehyde, β-ketoesters, and ammonia either
in acetic acid or in refuxing ethanol that sufers from long
reaction times and low yields [59]. Several methods have
been reported to modify this reaction by various catalyst
such as p-TSA [60], cellulose sulfuric acid [61], L-proline
[62], chitosan-supported copper(II) sulfate (CSCS) [63],
aminated multi-walled carbon nanotubes [64], silica-sup-
ported ceric ammonium nitrate (CAN) [65], nicotinic acid
[66], sulfated polyborate [67], benzyltrimethylammonium
fuoride hydrate, and supported chitosan [68]. Although the
described methods are efective, however, these protocols are
associated with remarkable disadvantages such as hazardous
solvents, toxic reagents, prolonged reaction time, high tem-
perature, use of toxic metals, strongly acidic condition, and
sometimes loss of recyclability of the catalyst. To pave these
disadvantages, in this paper, we would like to demonstrate
a magnetic cyanoguanidine-modifed chitosan (MCGC) as
an efcient heterogeneous magnetic organocatalyst for the
synthesis of benzimidazoloquinazoline and 1,4-DHPs under
refux and ultrasonic-assisted conditions (Scheme 1). Benzi-
midazoloquinazoline derivatives 5 were prepared via a one-
pot three-component condensation reaction starting from
2-aminobenzimidazole (2), aromatic aldehydes 3a–3h, and
dimedone (4) under ultrasonic-assisted conditions. Addition-
ally, 1,4-DHPs were produced through a multicomponent
reaction using 2 eq. ethyl acetoacetate (6), 1 eq. of aromatic
aldehydes 3a-3h’, and 1 eq. ammonium acetate (7).
1 3

Green synthesis of benzimidazoloquinazolines and 1,4-dihydropyridines using magnetic…
Scheme 1
O
Ar
O
H
N
N
1
MCGC ( )
NH
+
+
NH2
Ar CHO
Reflux or Ultrasonic
N
N
O
2
3a-3h
4
5
H2N
H2N
NH
OH
NH
OH
NH
NH
HN
OH
HN
OH
OH
O
NH
NH
O
O
O
O
HO
HO
O
O
HO
O
HO
O
O
O
HO
NH
NH
NH
HN
n
HN
HN
NH
NH
NH
HN
HN
HN
NH2
NH2
NH2
1
MCGC Catalyst ( )
Ar
3a-3h'
CHO
Ar
O
O
O
O
Et
Et
O
O
Et
Et
1
MCGC ( )
O
O
Reflux or Ultrasonic
N
H
O
O
6
6
8
NH
4OAc
7
thermogravimetric analysis (TGA). The FT-IR spectroscopy
analysis was performed to confrm the structure of chitosan
(a), CGC (b), MCGC (c), and recycled MCGC (d) by identi-
fying the desired functional groups as shown in Fig. 1. In the
FT-IR spectrum of chitosan (a), the absorption band at 3442
cm−1 is ascribed to the vibrational stretching of the N–H and
O–H groups with an overlapping. The stretching vibration of
aliphatic C–H groups appeared at 2910 cm−1. Furthermore,
the stretching vibrations of C–O–C bond is located at 1100
cm−1. After modifcation of chitosan with cyanoguanidine
a new band appeared at 1645 cm−1 which is assigned to
functional groups of CGC [69]. In the FT-IR spectrum of
MCGC a new adsorption peak appeared at 592 cm−1 which
corresponds to the Fe–O that indicates the presence of FeO
linkages in ferric oxide.
Results and discussion
Catalyst preparation
General description for the preparation of MCGC catalyst
(1) from commercial chitosan is shown in the Scheme 2.
Firstly, chitosan was modifed by cyanoguanidine in the
37% HCl solution to produce CGC. Next, stirring the CGC
with a mixture of FeCl3·6H2O and FeCl2·4H2O dissolved in
deionized water and then addition of aqueous 25% aqueous
ammonia followed by washing and drying aforded magnetic
cyanoguanidine-modifed chitosan (MCGC, 1).
Catalyst characterization
To understand the composition and distribution of indi-
vidual components in the chitosan and MCGC (1) nanocom-
posites, we performed energy-dispersive X-ray spectroscopy
(EDX) and elemental mapping at diferent parts of the speci-
mens. The results are depicted in Fig. 2a, b and c.
The synthesized nanocatalyst 1 was characterized using dif-
ferent physicochemical techniques such as Fourier transform
infrared spectroscopy (FT-IR), vibrating sample magnetom-
eter (VSM), feld emission scanning electron microscopy
(FESEM), energy dispersive spectroscopy (EDX), and
1 3

K. Javanmiri, R. Karimian
Scheme 2
CH3
CH3
O
O
OH
OH
OH
NH
NH
O
O
O
O
O
HO
HO
Chitin
O
HO
O
HO
O
O
O
O
HO
NH
NH
NH
OH
n
OH
H
H
H
3C
3C
3C
O
O
O
Deacetylation
OH
OH
OH
NH2
NH2
O
O
O
O
O
O
HO
O
HO
O
Chitosan
HO
O
HO
O
O
HO
NH2
NH2
NH2
OH
n
OH
NH
C N
(Cyanoguanidine)
solution
H2N
N
H
37% HCl
H2N
H2N
NH
OH
NH
OH
NH
NH
HN
HN
OH
NH
NH
O
O
O
O
O
O
HO
O
HO
O
O
HO
O
CGC
HO
O
HO
NH
NH
NH
OH
n
OH
HN
HN
HN
NH
NH
NH
HN
HN
HN
NH2
NH2
NH2
FeCl3.6H2O, FeCl2.5H2O, 25% aqueous ammonia, 2.5 h, 50 ºC
H2N
NH
H2N
NH
OH
NH
OH
NH
HN
OH
HN
OH
OH
HN
NH
NH
O
O
O
O
O
HO
HO
O
1
MCGC Catalyst ( )
O
HO
O
HO
O
O
O
HO
NH
NH
NH
n
HN
HN
NH
NH
NH
HN
HN
HN
NH2
NH2
NH2
=
Fe3O4
To investigate the particle size, surface shape and the
morphology of MCGC (1), we performed the FESEM
analysis. As it can be seen from the FESEM micrograph
of MCGC (1), the nanocomposite was made up of almost
spheroidal nanoparticles. The majority of the nanoparticles
were in the range of 28-33 nm particle size (Fig. 3). Addi-
tionally, the Fe3O4 nanoparticles are properly loaded on the
surface of CGC. Magnetization behavior of the Fe3O4 and
MCGC (1) nanoparticles under the applied magnetic feld at
room temperature has been depicted in Fig. 4. The values of
the magnetization saturation (Ms) for Fe3O4 and MCGC (1)
were 80.08 and 47.85 emu/g, respectively. The lower Ms for
MCGC (1) compared with Fe3O4 may be due to the larger
size of particles in MCGC (1).
1 3

Green synthesis of benzimidazoloquinazolines and 1,4-dihydropyridines using magnetic…
results are summarized in Table 1. First, a reaction was car-
ried out in the absence of catalyst and solvent (Table 1, entry
1) that only a trace amount of desired product (5g and 8g)
was resulted. Besides, an improvement in the yield of reac-
tion was observed by using 5 mg of MCGC (1) in CH3CN
as solvent (Table 1, entry 2). In the next step, to evaluate
the efect of ultrasonic irradiation equivalent reactions were
carried out with 5 mg of MCGC (1) in the various sol-
vents such as CH3CN, H2O, MeOH, EtOH:H2O, and EtOH
under the ultrasonic irritation (25 kHz frequency) at 20–22
°C for 30 min (Table 1, entries 3–7). As shown (Table 1,
entry 7), the best result was obtained in EtOH as the sol-
vent for benzimidazoloquinazolines and 1,4-DHPs because
of its benign nature, better homogenity of substrates, low
cost and wide availability as compared with other organic
solvents, although the reaction could even be successfully
accomplished in the protic solvents like MeOH and H2O or
EtOH:H2O.
With 15 mg of catalyst loading, the yield of the prod-
ucts 5g and 8g were increased to 89% and 85% respectively
(Table 1, entry 9). The reaction temperature also has an
appreciable infuence on the reaction yield under the ultra-
sound irradiation. Therefore, we increased the temprerature
to 30–32 °C and surprisingly the reaction yield improved
(Table 1, entry 10).
Unlike to 1,4-DHPs, in the case of benzimidazoloquina-
zolines no signifcant improvement in the reaction yield
was observed by increasing the temperature to 40–42 °C
(Table 1, entry 12). In addition, the reaction with 40 kHz
ultrasound irradiation also aforded the same reaction yield
that showed the frequency of irradiation had not remarkable
infuence on the yield of both reactions.
Fig. 1 FT-IR spectra of chitosan (a), cyanoguanidine-modifed chi-
tosan (CGC) (b), and magnetic cyanoguanidine-modifed chitosan
(MCGC) (c)
The thermal stability of MCGC (1) was analyzed by
thermogravimetric analysis (TGA). The initial weight loss
before 100 °C is related to the removal of the adsorbed water
and surface hydroxyl groups of the Fe3O4 nanoparticles. Fig-
ure 5 represents the TG curve of MCGC (1) catalyst under
the nitrogen atmosphere over 20–800 °C. The weight loss in
the range of 220–750 °C was ascribed to the decomposition
of organic moieties (chitosan and cyanoguanidine). Total
weight loss of the MCGC (1) was around 40% until 800 °C.
According to the above results, the optimized reaction
conditions for the synthesis of benzimidazoloquinazolines
was determined as: 2-aminobenzimidazole (2, 1 mmol),
aromatic aldehyde (3f, 1 mmol), dimedone (4, 1 mmol),
EtOH as solvent (5 cm3), MCGC (1, 15 mg), bath tempera-
ture 40–42 °C, and irradiation frequency 25 kHz (Table 1,
entry 10). The optimized reaction condition for the synthesis
of 1,4-DHPs was determined as: aromatic aldehyde (3, 1
mmol), ethyl acetoacetate (6, 2 mmol) ammonium acetate (7,
1 mmol) aromatic aldehydes (1 mmol), MCGC (1, 15 mg),
ethanol (5 cm3) bath temperature 30–32 °C, and irradiation
frequency 25 kHz (Table 1, entry 11).
Application of MCGC as an efcient nanocatalyst
for the synthesis of benzimidazoloquinazolines
and 1,4‑DHPs
The catalytic activity of MCGC (1) was initially investi-
gated in a standard reaction using 2-aminobenzimidazole
(2, 1 mmol), benzaldehyde (3g, 1 mmol) and dimedone (4,
1 mmol) for the synthesis of benzimidazoloquinazoline
derivatives and benzaldehyde (3g, 1 mmol), ethyl acetoac-
etate (6, 2 mmol) and ammonium acetate (7, 1 mmol) for the
synthesis of 1,4-DHPs. The efect of the solvent, tempera-
ture, amount of the catalyst, and irradiation frequency was
explored to establish the general reaction conditions. The
With the optimal reaction conditions in hand, we inves-
tigated the scope and generality of this protocol for the
preparation of benzimidazoloquinazolines and 1,4-DHPs.
The results shown in Table 2 confrmed the compatibility of
this methodology with a broad range of aromatic aldehydes
(3a–3h) bearing electron donating and electron withdrawing
groups on the benzene ring.
All experiments reported in Table 2 were carried out
under the ultrasonic irradiation and in the refux conditions.
1 3

K. Javanmiri, R. Karimian
Fig. 2 EDX spectra and elemental mapping of chitosan (a), CGC (b), and MCGC (c) nanoparticle
The advantages of ultrasonic irradiation were the shorter
reaction times, high yield and remarkable purity of products
comparing with condensation in the refuxing ethanol. For
example, the synthesis of 5a and 5b in the refuxing ethanol
needed 80 min and 90 min to obtain 87% and 85% yield,
respectively. Whereas, the same experiment by applying
ultrasonic irradiation at 30–32 °C resulted 5a and 5b within
35 min and 40 min with 95% and 92% yield respectively.
These results indicated that, to prepare the benzimi-
dazoloquinazoline derivatives (Table 2, entries 1–8) and
1 3

Green synthesis of benzimidazoloquinazolines and 1,4-dihydropyridines using magnetic…
Fig. 3 FESEM micrograph of
MCGC (1)
Presence of hydroxyl and amino groups appears bifunc-
tional characteristics in the MCGC (1) catalyst. Initially,
a Knoevenagel condensation between activated aldehyde
3a-3h and dimedone (4) produces the intermediate A. In
the next step, activation of carbonyl group on the interme-
diate (A) facilitates the attack of 2-aminobenzimidazole
(2) to intermediate A that results in intermediate B. Next,
intermediate B converts to intermediate C upon releasing
the water molecule. Finally, cyclization of intermediate
C leads to the corresponding benzimidazoloquinazoline
5a–5h. A plausible reaction mechanism for the prepara-
tion of 1,4-DHPs using MCGC (1) catalyst is presented in
Scheme 4. In the frst step, 1 equiv. of ethyl acetoacetate
(6) is converted into its enol form by MCGC (1), which
afords nucleophilic addition to the activated carbonyl
groups 3a–3h’ to form Knoevenagel product A’. Next step
involves the formation of β-enaminoester B’ from the sec-
ond equiv. of ethyl acetoacetate (6) and in-situ produced
ammonia from ammonium acetate (7). After that, Michael
addition between B’ and A’ generates C’ which is con-
verted to the corresponding 1,4-DHP 8a–8h’ through a
cyclization and elimination of H2O.
Fig. 4 Magnetization curves of Fe3O4, fresh MCGC and recovered
MCGC after run 8 at room temperature
The efciency of present protocol was compared with
some of recently reported methods for the synthesis of benz-
imidazoloquinazolines 5a–5h and 1,4-DHPs 8a–8h’. The
results are collected in Table 3 for 5g and 8g as model sub-
strates. As it can be seen, this method is superior to some
of these methods in terms of catalyst loading, solvent, tem-
perature, reaction time, and yield.
Fig. 5 The TGA curve of MCGC (1) nanoparticles
For a heterogeneous catalyst ease of separation and reus-
ability are two important factors. The reusability of MCGC
(1) was evaluated for 5g and 8g as model substrates. After
the completion of each reaction an external magnet was
used to separate the MCGC (1). Then, the catalyst was
washed with water (3 × 10 cm3) and ethanol (1 × 10 cm3)
and fnally, dried in an oven at 50 °C for 1 h. The efciency
1,4-DHPs using MCGC (1) nanocatalyst, the ultrasonic
irradiation is a superior method as compared to the refux
conditions [75].
Proposed reaction mechanism for the synthesis of benz-
imidazoloquinazoline derivatives 5a–5h based on the
available literature [48–50, 76] is depicted in Scheme 3.
1 3

K. Javanmiri, R. Karimian
Table 1 Optimization of reaction conditions for the preparation of benzimidazoloquinazolinesa and 1,4-DHPb derivatives in a model reaction
O
O
Ph
H
N
+
NH2 + Ph CHO
N
N
O
NH
2
4
N
3g
5f
1
MCGC ( )
Ultrasonic
Ph
O
CHO
3g
O
O
Ph
O
O
Et
Et
Et
Et
O
O
O
O
O
N
H
6
6
NH
4OAc
8f
7
Conditions
Entry
Benzimidazoloquinazolines
1,4-DHPs
Time/in
Catalyst/mg
Solvent
Temp./°C
Time/min
Yieldc/%
Yieldc/%
1
2
3
4
5
6
7
8
–
5
5
5
5
5
5
10
15
15
15
20
–
–
r.t.
30
30
30
30
30
30
30
30
30
30
30
30
Trace
30
40
35
55
45
65
77
89
15
15
15
15
15
15
15
15
15
15
15
15
Trace
20
25
30
55
50
60
76
85
CH3CN
CH3CN
H2O
MeOH
EtOH-H2O
EtOH
EtOH
EtOH
EtOH
EtOH
20–22
20–22
20–22
20–22
20–22
20–22
20–22
30–32
40–42
40–42
9
10
11
12d
93
93
93
92
95
95
EtOH
aReaction conditions: 2-aminobenzoimidazole (2, 1 mmol), benzaldehyde (3g, 1 mmol), dimedone (4, 1 mmol) in the presence of MCGC (1), 5
cm3 of each solvent, and irradiation frequency of 25 kHz
bReaction conditions: benzaldehyde (3g, 1 mmol), ethyl acetoacetate (6, 2 mmol), ammonium acetate (7, 1 mmol) in the presence of MCGC (1),
5 cm3 of each solvent, and irradiation frequency of 25 kHz
cIsolated yields
dIrradiation frequency of 40 kHz
of the recycled catalyst was examined up to eight consecu-
tive runs and its catalytic efciency remained almost the
same (Fig. 6).
attributed to leaching of Fe3O4 nanoparticles from surface of
CGC. This fact also was confrmed by ICP-OES analysis in
which the results showed a decrement in the concentration
of Fe from 42.885 wt% for fresh MCGC to 41.335 wt% for
recovered MCGC after 8th run.
Figure 7 depicts the FT-IR spectrum of fresh MCGC (a)
and recycled MCGC (b) after run 8th. As it can be seen, the
FT-IR of recycled MCGC (b) is similar to the fresh MCGC
(a) with a decrement in the intensity of some peaks that con-
frms the stability of MCGC. In addition, magnetic proper-
ties of the recycled MCGC after the 8th run (Fig. 4) showed
a very slight decrease in the Ms value (Fig. 4) that could be
1 3

Green synthesis of benzimidazoloquinazolines and 1,4-dihydropyridines using magnetic…
Table 2 One-pot synthesis of benzimidazoloquinazolinone derivativesa and 1,4-DHPsb using MCGC (1) nanocatalyst
O
O
Ar
H
N
+
NH2
+
Ar CHO
N
N
O
NH
2
3a-3h
4
N
5a-5h
1
MCGC ( )
Ultrasonic
Ar
CHO
3g-3h'
O
O
Ar
O
O
Et
Et
Et
Et
O
O
O
O
O
O
N
H
6
6
NH
4OAc
8f-8h'
7
Ultrasonic irradiation
Refux
Entry
Ar
Product
Time/min
Yield/%c
Time/min
Yield/%c
M.p. /°C
Obs. (Lit.)
1
2
3
4
5
6
7
8
4-Cl-C6H4 (3a)
2-Cl-C6H4 (3b)
4-NO2-C6H4 (3c)
3-NO2-C6H4 (3d)
4-CH3-C6H4 (3e)
4-OH-C6H4 (3f)
C6H5 (3g)
5a
5b
5c
5d
5e
5f
5g
5h
8a
8b
8c
8d
8e
8f
35
40
37
33
55
66
30
14
12
15
10
12
16
18
15
12
95
92
96
91
90
91
93
89
96
92
94
93
90
92
95
94
80
90
83
77
95
85
75
48
15
17
15
16
24
27
17
17
87
85
91
87
86
88
90
84
89
87
89
86
85
86
92
89
330–333 (336–339 [70])
352–354 (352–355 [70])
> 360 (374–378 [71])
340–342 (338–340 [51])
325–327 (325–328 [72])
331–333 (> 300 [70])
307–309 (308–310 [73])
297 (298–300 [74])
142–144 (144–146 [26])
126–128 (127–128 [26])
130–132 (127–129 [67])
163–165 (163–164 [67])
133–135 (134–135 [67])
229–231 (230–231 [67])
156–158 (157–158 [67])
165–166 (164–167 [69])
4-Pyridinyl (3h)
4-Cl-C6H4 (3a)
2-Cl-C6H4 (3b)
4-NO2-C6H4 (3c)
3-NO2-C6H4 (3d)
4-CH3-C6H4 (3e)
4-OH-C6H4 (3f)
C6H5 (3g)
9
10
11
12
13
14
15
16
8g
8h’
2-Furyl (3h’)
aUltrasonic irradiation: 2-aminobenzoimidazole (2, 1 mmol), aldehyde 3a–3h (1 mmol), dimedone (4, 1 mmol), MCGC (1, 15 mg), 5 cm3
EtOH, irradiation frequency of 25 kHz and 30–32 °C temperature. Refux conditions: 2-aminobenzoimidazole (2, 1 mmol), aldehyde 3a–3h (1
mmol), dimedone (4, 1 mmol) and MCGC (1, 15 mg) in 5 cm3 refuxing EtOH
bUltrasonic irradiation: aldehyde 3a-3h’ (1 mmol), ethyl acetoacetate (6, 2 mmol), ammonium acetate (7, 1 mmol), MCGC (1, 15 mg), 5 cm3
EtOH, irradiation frequency of 25 kHz and 40–42 °C temperature. Refux conditions: aldehyde 3a–3h’ (1 mmol), ethyl acetoacetate (6, 2 mmol),
ammonium acetate (7, 1 mmol) and MCGC (1, 15 mg) in 5 cm3 refuxing EtOH
cIsolated yields
magnetic nanocatalyst for one-pot three-component syn-
thesis of benzimidazoloqunazolines (from 2-aminobenz-
imidazole, aromatic aldehydes, and dimedone) and
1,4-DHPs (via Hantzsch-type condensation of ethyl ace-
toacetate, aromatic aldehydes, and ammonium acetate)
Conclusion
In conclusion, we have found magnetic cyanoguanidine-
modifed chitosan (MCGC) as an efcient and reusable
1 3

K. Javanmiri, R. Karimian
Scheme 3
H
H
NH2
NH
Ar
O
O
O
N
H
Ar
HO
N
O
+
H
2O
N
H
N
H
5a-5h
O
4
O
NH
3a-3h
H2N
NH
OH
H
Ar
O
δ
O
O
NH2
NH
1
HN
H
N
N
N
H
C
O
O
H
H
H
NH2
O
N
NH
H2N
H2N
OH
=
HN
HN
Ar
H
NH
2O
O
NH
1
MCGC ( )
OH
HO
Ar
H
OH
N
NH
N
H
H2N
N
H
HO
NH
A
O
OH
B
OH
Ar
H
N
O
δ
H
H2N
O
N
HN
2
HN
NH2
under the ultrasonic irradiation and refux conditions. The
results confrmed that the ultrasonic irradiation is a supe-
rior method as compared to the refux conditions. Ease of
work-up procedures, mild conditions, short reaction times,
high yields, reusable catalyst, low catalyst loading, and
compatibility with a broad range of aromatic aldehydes
are some of precious advantages of the described method.
apparatus. The surface morphology, size, and shape of the
catalyst was evaluated by feld emission scanning electron
microscopy (FESEM, MIRA3, TESCAN, Czech Repub-
lic). Energy dispersive spectroscopy (EDX) patterns were
obtained using MIRA III instrument of TESCAN Com-
pany, Czech Republic to identify the chemical elements.
The concentration of Fe was assessed using Shimadzu
AA-680 fame atomic absorption spectrophotometer and
inductively coupled plasma optical emission spectrometer
(ICP-OES) Varian Vista PRO Radial. The crystal structure
of MCGC (1) was analysed on an X’Pert MPD Philips
difractometer with Cu radiation source (λ = 1.54050 Å)
at 40 kV voltage and 40 mA current. The magnetic prop-
erties of MCGC (1) were analysed using vibrating sam-
ple magnetometer (VSM, BHV-55, Riken, Japan) at room
temperature. Thermal stability of desired MCGC (1) was
determined by thermogravimetric analysis (TGA) using
Bahr company STA 504 instrument. Ultrasonic irradiation
was performed by using a Shanghai Branson-BUG25-06
ultrasonic cleaner with a frequency of 25 or 40 kHz.
Experimental
All chemicals were procured from Merck or Aldrich com-
panies and used without further purifcations. Commercial
chitosan (MW = 6,00,000–8,00,000 Dalton) was procured
from Acros Organics. Moreover, the products were charac-
terized by comparison of their spectral data and physical
properties with those reported in the literature. The reac-
tion progress was monitored by TLC using Merck 0.2 mm
silica gel 60F-254 Al-plates. FT-IR spectra were obtained
as KBr pellets on a Shimadzu FTIR-8400S spectrometer
1
in the range of 4000-400 cm−1. H NMR spectra were
recorded on a Bruker DRX 300 MHz Avance spectrom-
eter in CDCl3 or DMSO-d6 as solvent at ambient tempera-
ture. Melting point of products were determined in open
capillaries with a Electrothermal IA9100 melting point
1 3

Green synthesis of benzimidazoloquinazolines and 1,4-dihydropyridines using magnetic…
Scheme 4
OH
δ
NH2
O
Ar
1
HN
HN
H 3a-3h'
Ar
O
H
H
Me
-H
2O
OEt
-H
2O
EtO
Me
EtO
Me
OH
O
O
O
O
6
A'
B'
HOAc
NH
4OAc
NH3
-H
2O
EtO
EtO
Me
NH
Me
EtO
7
Me
O
O
NH2
O
O
HO
NH
NH2
H2N
HN
OH
HN
H
HN
OEt
Ar
O
Ar
O
O
O
Michael addition
O
EtO
Me
EtO
OEt
H2N
Me
O
H2N
NH2
HN
C'
OH
HN
NH2
OH
HN
HN
Ar
O
O
Ar
O
O
O
H
Cyclization
EtO
OEt
EtO
OEt
-H
2O
N
H
NH2
OH
2O
H
Ar
O
O
EtO
OEt
N
H
8a-8h'
NH2
OH
HN
HN
1
= MCGC ( )
Preparation of cyanoguanidine‑modifed chitosan
(CGC)
Preparation of magnetic cyanoguanidine‑modifed
chitosan (MCGC)
First, 0.5 g chitosan was dissolved in 30 cm3 of 37% HCl
solution and stirred for 30 min at room temperature. Then,
2.0 g cyanoguanidine was added to the premixed solution
and the obtained mixture was stirred at 60 °C for 24 h.
After that, a solution of NaOH in distilled water (0.5 M)
was slowly added to the mixture to obtain a clear precipitate.
The obtained precipitate was thoroughly washed with dis-
tilled water and ethanol to remove unreacted materials and
then dried in an oven at 80 °C for 12 h.
Briefly, 1.56 g FeCl3·6H2O (0.0057 mol) and 0.76 g
FeCl2·4H2O (0.0038 mol) were dissolved in 40 cm3 water
and stirred for 10 min. Then, 0.5 g CGC was added to the
premixed solution and after addition of 10 cm3 of 25% aque-
ous ammonia during 30 min the mixture was stirred for 2.5
h at 50 °C. Finally, the obtained MCGC (1) was separated
from the solution using an external magnet, thoroughly
washed with distilled water and ethanol and dried in an oven
at 60 °C for 24 h.
1 3

K. Javanmiri, R. Karimian
Table 3 Comparative synthesis of compounds 5g and 8g with reported methods compared with the present method
Entry
Catalyst
Catalyst loading
Solvent
Temp/°C
Time/min
Yield/%
Product
References
1
2
3
4
5
6
7
8
9
NH2SO3H
Fe3O4@IM
Fe3O4@GO
Nano-WO3-SO3H
MCGC (1)/Ultrasonic
MGCS
Aminated MWCNTs
Nicotinic acid
ChVO
5 mg
30 mg
65 mg
19 mg
15 mg
30 mg
1 mg
0.1 g
5 mg
15
CH3CN
EtOH
EtOH
Solvent-free
EtOH
EtOH
Refux
78
Refux
100
30–32
Refux
Refux
80
15
40
35
15
30
15
240
5
94
87
91
94
93
89
85
95
89
95
5g
5g
5g
5g
5g
8g
8g
8g
8g
8g
[50]
[70]
[77]
[78]
–
[26]
[64]
[66]
[69]
–
EtOH
Solvent-free
Solvent-free
EtOH
85
40–42
55
15
10
MCGC (1)/Ultrasonic
Fig. 6 Recycling of MCGC (1) in the synthesis of 5g and 8g as model
substrates
General procedure for the synthesis
of benzimidazoloquinazoline derivatives 5a–5h
A 10 cm3 round-bottomed fask was charged with 2-amin-
obenzimidazole (2, 1 mmol), aromatic aldehyde (3, 2 mmol),
dimedone (4, 1 mmol), MCGC (1, 15 mg), and 5 cm3 etha-
nol and placed in an ultrasonic cleaner. The surface of water
in the water bath of ultrasonic cleaner was slightly upper
than the surface of reactants. After that, the reaction mixture
was irradiated under the irradiation frequency of 25 kHz
at 30–32 °C for the time mentioned in the Table 2. After
completion of the reaction, as monitored by TLC (eluent
n-hexane:ethyl acetate 1:3) the reaction was cooled down
to room temperature, the catalyst 1 was separated using an
external magnet and the residue was dried at room tempera-
ture to aford the crude product. Finally, the crude product
was recrystallized from ethanol and water to obtain the pure
product.
Fig. 7 FT-IR of fresh MCGC (a) and recycled MCGC (b) after run
8th
ammonium acetate (7, 1 mmol), MCGC (1, 15 mg), and
5cm3 ethanol and placed in an ultrasonic cleaner. The level
of water in the water bath of ultrasonic cleaner was slightly
upper than the surface of reactants in the round-bottomed
fask. The irradiation of reaction mixture was carried out
under the irradiation frequency of 25 kHz at 40–42 °C for
the appropriate time as indicated in the Table 2. The progress
General procedure for the synthesis
of 1,4‑dihydropyridines derivatives 8a–8h’
A 10 cm3 round-bottomed fask was flled with aromatic
aldehyde (3, 1 mmol), ethyl acetoacetate (6, 2 mmol),
1 3

Green synthesis of benzimidazoloquinazolines and 1,4-dihydropyridines using magnetic…
32. Mamaghani M, Tabatabaeian K, Shirini F, Rassa M (2012) Bioorg
of the reaction was monitored by TLC (eluent n-hexane:ethyl
acetate 3:1). After completion of the reaction, the catalyst
1 was separated using an external magnet. Then, the cata-
lyst 1 was collected by an external magnet and the residue
was dried at room temperature to aford the crude product.
Finally, after addition of 10 cm3 ethanol to the reaction mix-
ture, the desired product obtained by cooling in an ice-bath
with high purity.
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Acknowledgements We are thankful for the fnancial support from
Chemical Injuries Research Center, Systems Biology and Poisonings
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1 3