An efficient and recyclable nanocatalyst for the green and rapid synthesis of biologically active polysubstituted pyrroles and 1,2,4,5-tetrasubstituted imidazole derivatives

Article abstract of DOI:10.1039/c9ra02325a

An effective process for the green and rapid synthesis of biologically active polysubstituted pyrroles and 1,2,4,5-tetrasubstituted imidazoles derivatives using Cu@imine/Fe₃O₄ MNPs catalyst under solvent-free conditions is explained. This catalyst showed high reactivity for the synthesis of a set of different derivatives of polysubstituted pyrroles and 1,2,4,5-tetrasubstituted imidazole derivatives under appropriate reaction conditions and short times. Moreover, the catalyst was also recycled and reused for six runs with no considerable reduction in reactivity and yields. Compared to the reported procedures, this method consistently demonstrates the advantages of low catalyst loading, short reaction times, easy separation and purification of the products, high yields, and high recoverability and recoverability of the catalyst.

Full text of DOI:10.1039/c9ra02325a

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PAPER
An efficient and recyclable nanocatalyst for the
green and rapid synthesis of biologically active
polysubstituted pyrroles and 1,2,4,5-
Cite this: RSC Adv., 2019, 9, 15966
tetrasubstituted imidazole derivatives†
a
b
c
d
*
Boshra Mahmoudi, Olga A. Ivaschuk and Qahtan A. Yousif
Myo Thwin,
An effective process for the green and rapid synthesis of biologically active polysubstituted pyrroles and
1,2,4,5-tetrasubstituted imidazoles derivatives using Cu@imine/Fe3O4 MNPs catalyst under solvent-free
conditions is explained. This catalyst showed high reactivity for the synthesis of a set of different
derivatives of polysubstituted pyrroles and 1,2,4,5-tetrasubstituted imidazole derivatives under
appropriate reaction conditions and short times. Moreover, the catalyst was also recycled and reused for
six runs with no considerable reduction in reactivity and yields. Compared to the reported procedures,
this method consistently demonstrates the advantages of low catalyst loading, short reaction times, easy
separation and purification of the products, high yields, and high recoverability and recoverability of the
catalyst.
Received 27th March 2019
Accepted 9th May 2019
DOI: 10.1039/c9ra02325a
rsc.li/rsc-advances
insensitivity, and low toxicity are the other factors that have
attracted more attention of scientists to these nanoscale
materials.5–9
Introduction
Recently, studies for nding separable and reusable nano-
catalysts are seeing rapid progress in chemistry, especially in
modern catalysis research. The immobilization of organic and
inorganic functional groups on heterogeneous supports is in
fact an effective process to achieve this goal.1 Nowadays,
compared to the typical separation, magnetic separation is
receiving more attention due to activity as a highly efficient and
rapid separation procedure for products and catalysts.2
Magnetic nanoparticles (MNPs) have unique physical and
chemical features such as large surface area per weight that
causes these materials to act as supports of homogeneous
catalysts or heterogeneous promoters for catalytic reactions.
The functionalized magnetic nanoparticles can be simply iso-
lated from the reaction solution by an appropriate external
magnetic eld, without any tedious workup procedures, which
reduces the catalyst loss during separation.3,4 In addition,
magnetic-supported catalysts can be recovered several times
with no considerable reduction in their initial activity. High
coercivity, greater selectivity, environmental friendliness,
noncorrosive nature, operational simplicity, moisture
Poly substituted imidazoles are one of the core structural
skeleton in many key molecules that have attracted consider-
able interest because of their biological activities such as
histidine, histamine, and biotin.10–12 These were rstly prepared
by via cyclocondensation reaction between 1,2-dicarbonyl
compounds, different aldehydes, and a nitrogen resource.13,14
A
variety of catalysts in the papers following this method have
been reported.15–22 Although most of these synthetic approaches
provide an improvement in the production of the above
mentioned heterocyclic compounds, many of these procedures
suffer from one or more drawbacks like applying dangerous
organic solvents and costly reagents, harsh reaction conditions,
difficult and complex work-up and purication, considerable
values of waste ingredients, use of toxic reagents and non-
recoverability of the catalyst as well as long reaction time and
low efficiencies.23,24 Consequently, the improvement of easy,
effective, and mild procedures with easily separable and reus-
able novel catalysts to overcome these shortcomings.
Pyrroles, as an important class of N-heterocyclic derivatives
and signicant building blocks, are one of the most important
groups of heterocyclic compounds that have attracted consid-
erable interest in organic production as well as in the drug
exploration. They have been extensively utilized due to their
promising pharmacological and therapeutic activities such as
antianginal, antitumor antifungal, anti-oxidant, antibacterial,
and anti-inammatory.25 Moreover, polysubstituted pyrroles
owing to their enormous importance exhibited other medicinal
aYangon Technological University, Myanmar
bResearch Center, Sulaimani Polytechnic University, Sulaimani 46001, Kurdistan
Region, Iraq
cBelgorod National Research University, Belgorod, Russia
dUniversity of Al-Qadisiyah, College of Science, Department of Chemistry, Republic of
Iraq. E-mail: Qahtan.Adnan@qu.edu.iq; Tel: +9647813112362
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra02325a
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applications. Because of the aforementioned merits of the pol- vibration; then, 2 mL of aminopropyltriethoxysilane (APTES)
ysubstituted pyrroles, to date various approaches have been was added, and the obtained solution was mechanically
improved to synthesize these kinds of heterocyclic compounds. agitated for 24 h under reux conditions. At the end of the
These were synthesized through Paal–Knorr condensation reaction, the Fe3O4@APTES nanoparticles were recovered from
reaction, Knorr reaction and Hantzsch reaction.26 Herein we the solution using an external magnet, washed with deionized
decided to study the preparation of polysubstituted pyrrole water and anhydrous ethanol to eliminate any unreacted
derivatives with various substituents from the reaction of chemicals, and dried under vacuum oven.
aromatic aldehydes, ethyl acetoacetate, nitromethane and
Preparation of the Fe3O4@APTES/AMTBA. To connect of 4-
aniline under solvent-free conditions using Cu@imine/Fe3O4 (4-amino-5-mercapto-4H-[1,2,4]H-1,2,4 triazol-3-yl)-benzoic acid
MNPs as a new, eco-friendly, reusable and promising hetero- (AMTBA) to the NH2 functional group on the surface Fe3O4@-
geneous nanocatalyst. Although numerous methods have been APTES nanoparticles, dried Fe3O4@APTES (2 g) was poured in
utilized for the preparation of polysubstituted pyrrole deriva- ethanol (100 mL) in a 250 mL round-bottom ask and then
tives, some of these strategies suffer from disadvantages such as AMTBA (4 mmol) was poured in to this solution under dry
use of high temperature, the need for excess amounts of the nitrogen atmosphere. The reaction mixture was reuxed for
catalyst, long reaction times, and need for microwave or ultra- 24 h and aer that Fe3O4@APTES/AMTBA was separated by
sound irradiation. Therefore, it is necessary to develop an using an external magnet, washed thoroughly several times with
improved strategy for the preparation of polysubstituted pyrrole ethanol and deionized ꢀwater to remove the unreacted reagents,
derivatives under mild reaction conditions.
and nally dried at 80 C in a vacuum oven.
Preparation of the imine@Fe3O4 MNPs. To prepare
imine@Fe3O4 MNPs, 2 g of Fe3O4@APTES/AMTBA was poured
in 20 mL of dry CH2Cl2 for 30 min using ultrasonication. Aer
that, 4 mmol of 2-formylpyridine was added to the reaction
solution and the obtained mixture was reuxed for 8 h. Finally,
these precipitates were isolated using an external magnetic
eld, washed with 20 mL of water to eliminate the unreacted
residue of the 2-formylpyridine, and next dried in a vacuum
oven.
Preparation of Cu@imine/Fe3O4 MNPs. 2 g of imine@Fe3O4
MNPs was suspended in 50 mL of CH2Cl2 under a nitrogen
atmosphere. Thereaer, CuCl2 (0.5 mmol) was added to the
reaction solution, and agitated for 24 h. Aer 24 h, the sediment
formed was isolated by a strong magnet, rinsed twice with
ethanol (15 mL) to remove unreacted metal precursors and
dried under the reduced pressure to obtain a pure product. All
stages of the Cu@imine/Fe3O4 MNPs synthesis are demon-
strated in Scheme 1.
Experimental
General
All the pure chemical substances were prepared from Fluka,
Aldrich, and Merck chemical companies and applied with no
further purication. Melting points of the substrate were
measured with Electrothermal-9100 apparatus and uncor-
rected. Fourier transform infrared (FT-IR) spectra were recorded
with a PerkinElmer PXI spectrometer in KBr wafers. X-ray
diffraction (XRD) patterns of samples were taken on
a Siemens D-5000 Xray diffractometer (Germany) with Cu Ka
radiation. Magnetic susceptibility measurements were
measured by a vibrating sample magnetometry (VSM; Lake
Shore 7200 at 300 kVsm). Thermogravimetric analysis was
examined by a PerkinElmer instrument under nitrogen atmo-
sphere at a heating rate of 10 ꢀC minÀ1. Scanning electron
microscope (SEM) images were recorded with a SEM-LEO
1430VP instrument. The chemical composition of synthesized
nanoparticles was obtained with an energy dispersive X-ray
spectroscopy (EDX) (ESEM, Philips, and XL30).
Results and discussion
Catalyst characterization
FTIR analysis of Cu@imine/Fe3O4 MNPs. The infrared
spectra corresponding to the Fe3O4 and Cu@imine/Fe3O4 MNPs
Catalyst synthesis
Preparation of Fe3O4. The magnetite nanoparticles were samples in the area of 400–4000 cmÀ1 are demonstrated in
synthesized based on the reported chemical co-precipitation Fig. 1. The bands at 586 cmÀ1 in the Fe3O4 are associated to the
method, and the detailed process has been described herein- stretching vibration for the Fe–O bond while the absorption
aer. Briey, 5.4 g of FeCl3$6H2O and 2 g of FeCl2$4H2O were peak at the 3405 cmÀ1 region can be dedicated to the water
dissolved in 40 mL of distilled water followed by adding 0.9 mL molecule OH stretching modes. Also, the absorption peaks at
of concentrated HCl in a three-necked bottom (250 mL) under 1617 cmÀ1 is related to the bending vibrations of the water
vigorous agitating and nitrogen protection. Next, 250 mL of molecule HO–H bonds. In the FTIR spectrum of Cu@imine/
1.5 M NaOH solution was dropped into the resultant mixture in Fe3O4 MNPs catalyst, the bands between 1400–1600 cmÀ1 and
the absence of temperature under intense mechanical stirring. the absorption peaks at 1045 cmÀ1 region can be respectively
In the last step, the attained magnetic nanoparticles were iso- attributed to the C]C and Si–O groups. The bands at 1635,
lated using a powerful magnet and rinsed several times with 2584 and 2987 cmÀ1 have been attributed to C]N, S–H and
200 mL deionized water. Eventually, the Fe3O4 nanoparticles C–H stretching vibrations, respectively.
ꢀ
dried under vacuum at 40 C for 24 h.
Thermal analysis of Cu@imine/Fe3O4 MNPs. TGA curves of
Preparation of the Fe3O4@APTES. 1 g of Fe3O4 nanoparticles Fe3O4, Fe3O4@APTES, Cu@imine/Fe3O4 MNPs was also inves-
was dispersed poured in 50 mL dry toluene by ultrasonic tigated by thermogravimetric analyzer (Fig. 2). The weight loss
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Scheme 1 All steps of the Cu@imine/Fe3O4 MNPs synthesis.
Fe3O4@APTES, one below 200 ꢀC which can be related to
evaporating water from the MNPs surface; however the other
ꢀ
one up to 430 C was ascribed to the decomposition of APTES.
Cu@imine/Fe3O4 MNPs have three weight loss stages; the rst
weight loss up to 180 ꢀC, which is related to evaporation of H2O
molecules connected to the MNPs surface. The second and
third weight loss up to 370 and 520 ꢀC, respectively, associated
to the decomposition of functionalized groups on MNPs
surface. These weight losses exhibits the existence of functional
groups graed to the MNPs surface.
VSM analysis of Cu@imine/Fe3O4 MNPs. Fig. 3 shows the
magnetization measurements of Fe3O4 MNPs and Cu@imine/
Fe3O4 MNPs, determined by VSM technique. The saturation
magnetization (Ms) is observed to be 35.94 emu gÀ1 for Cu@i-
mine/Fe3O4 MNPs, less than the Fe3O4 MNPs (62.59 emu gÀ1).
This difference suggests that functional groups are attached on
the surface of Fe3O4 nanoparticles.
Fig. 1 FT-IR spectra of Fe3O4 and Cu@imine/Fe3O4 MNPs.
XRD analysis of Cu@imine/Fe3O4 MNPs. The XRD patterns
corresponding to the synthesized Fe3O4, imine@Fe3O4 MNPs,
Cu@imine/Fe3O4 MNPs are shown in Fig. 4. The characteristic
broad diffraction peaks shown in high-angle XRD pattern can
be corresponded to cubic spinel magnetite Fe3O4 structure,
which shows diffraction peaks, corresponding to (220), (311),
(400), (422), (511) and (440). The relative intensities and posi-
tion of imine@Fe3O4 MNPs and Cu@imine/Fe3O4 MNPs peaks
agree well with the Fe3O4 MNPs, representing retention of the
crystalline cubic spinel structure over immobilization of Fe3O4
MNPs.
due to evaporation of physically adsorbed H2O molecules in the
temperature range below 220 C was observed for all samples.
Two weight loss stages were observed in thermogram for
ꢀ
EDX analysis of Cu@imine/Fe3O4 MNPs. Based on the EDX
spectrum (Fig. 5), the existence of copper in the Cu@imine/
Fe3O4 MNPs catalyst structure represents that copper was
coordinates to the functional groups of imine@Fe3O4 MNPs.
The EDX spectrum also illustrates other elements including Fe,
S, Si, C and N which are existent in the catalyst substrate.
This survey is aimed to report the efficient and rapid
production of polysubstituted pyrrole and 1,2,4,5-tetrasub-
stituted imidazoles derivatives using lower loading of the very
recently introduced nanocatalyst, i.e., Cu@imine/Fe3O4 MNPs,
under solvent-free conditions. The catalytic activity of Cu@i-
mine/Fe3O4 MNPs was investigating to report the efficient and
rapid production of polysubstituted pyrrole derivatives under
solvent-free conditions. To achieve the optimum conditions
Fig. 2 TGA thermogram of Fe3O4, Fe3O4@APTES, Cu@imine/Fe3O4
MNPs.
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Fig. 3 Magnetization curves of Fe3O4 and Cu@imine/Fe3O4 MNPs.
reactions for synthesizing polysubstituted pyrrole to examine
the impacts of the amount of used catalyst, solvent, and
temperature. The results of the optimization reactions were
presented in Table 1. The outcomes were evaluated qualitatively
using thin layer chromatography (TLC). As observed, in polar
organic solvents such as ethanol and acetonitrile, under reux
conditions, the reaction yield was good in long reaction times
(Table 1, Entries 1–2). In order to improve the eco-friendly of the
reaction conditions, the reaction was occurred in water, but this
solvent wasn't observed to be effective and only 37% of product
was achieved aer 70 min (Table 1, Entry 3). Finally, the reac-
tion was performed in non-polar organic solvents such as
dichloromethane, chloroform and tetrahydrofuran under reux
conditions, but none of these solvents were observed to be
impressive (Table 1, Entries 4–6). The outcomes presented that
when the reaction was performed under solvent-free conditions
at 100 ꢀC, the target product afforded in best optimal conditions
in terms of rate and yield (Table 1, Entry 7). Due to the key role
of the catalyst amount as a signicant factor for a reaction, we
studied the catalytic performance of the Cu@imine/Fe3O4
Fig. 4 The XRD patterns of Fe3O4, imine@Fe3O4 MNPs, Cu@imine/
Fe3O4 MNPs.
especially in agreement with green chemistry, the reaction
between ethyl acetoacetate, nitromethane, benzaldehyde, and
aniline with 1 : 1 : 1 : 1 molar ratios were selected as the model
Fig. 5 EDX spectra of Cu@imine/Fe3O4 MNPs.
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Table 1 Optimization corresponding to the four-component reaction for ethyl acetoacetate, nitromethane, benzaldehyde, and aniline under
various conditionsa
Entry
Solvent
Catalyst (mol%)
Temp.
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
Ethanol
Acetonitrile
Water
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.24
0.48
—
0.36
0.36
0.36
0.36
0.36
0.36
Reux
Reux
Reux
Reux
Reux
Reux
50
50
70
70
70
70
25
45
30
70
70
40
35
35
30
25
25
120
90
100
79
71
37
52
56
49
95
76
94
Trace
31
82
85
88
92
93
91
71
59
62
Dichloromethane
Chloroform
Tetrahydrofuran
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
C
C
C
C
C
C
9
10
11
12
13
14
15
16
17
18
19
20
25 ꢀ
60 ꢀ
70 ꢀ
C
80 ꢀC
90 ꢀ
C
110 ꢀ
120 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
C
C
C
C
C
0.36
BF3–SiO2/0.36
MgCl2/0.36
SbCl5–SiO2/0.36
a
Reaction conditions: ethyl acetoacetate (1 mmol), nitromethane (1 mmol), benzaldehyde (1 mmol), aniline (1 mmol), and the required amount of
catalyst. b The yields represent the separated product.
MNPs using 0.24–0.48 mol% of the catalyst under solvent-free halides (Table 3, Entries 18–20), low to moderate yields of the
conditions (Table 2, Entries 7–9), and the yield has increased desired product was obtained.
remarkably in the existence of 0.36 mol% of catalyst, whereas
Aer optimization of the reaction conditions and to estab-
the reaction time has decreased (Table 2, Entry 7). By reducing lish the effectiveness and the acceptability of the technique, we
the value of catalyst to 0.24 mol%, the performance of the explored the scope and generalization of the reaction with
product was dropped (Table 1, Entry 8). It was observed that the a wide range of aldehydes and amines including benzylamine,
reaction yield was remained unchanged even in quantities more aniline and substituted anilines under the optimal conditions.
than the optimum catalyst amount, and 0.48 mol% of the The outcomes were listed in Table 2. It was observed that under
catalyst could not cause the obvious increase in yield of the similar conditions, a variety of benzaldehydes containing
product (Table 1, Entry 9). When the reaction was surveyed electron-withdrawing and electron-donating groups, such as H,
without using the catalyst, no formation of product was found CH3, CH3O, NO2 and Cl in the para positions of the benzene
in this case (Table 1, Entry 10). To complete the reaction, effect ring as well as heteroaromatic aldehydes in the existence of
of temperature on the rate of model reaction was investigated by methyl acetoacetate, nitromethane, benzylamine, and the
ꢀ
diverse temperatures from room temperature to 120 C under required amount of the Cu@imine/Fe3O4 MNPs, simply con-
solvent-free conditions (Table 1, Entries 11–17). It was observed verted to the resulted products in short reaction times with
that the yield of the product increases signicantly by good to excellent isolated yields (Table 2, Entries 1–7). Also,
ꢀ
increasing the temperature from room temperature to 100 C using above aromatic aldehydes, ethyl acetoacetate, nitro-
(Table 1, Entries 7 and 11–15), but a further enhance in methane and aniline the target products were achieved in good
temperature did not demonstrate any signicant impact on the to high separated yields (Table 2, Entries 8–11). Various
product yield (Table 1, Entries 16–17). It should be noted that aromatic aldehydes containing electron-withdrawing and
when the reaction was carried out in the presence of metal electron-donating groups (H, CH3, CH3O, and Cl) and anilines
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Table 2 Preparation of polysubstituted pyrrole derivatives using Cu@imine/Fe3O4 MNPs as a catalysta
Entry R2CHO (3)
R1
R3
Product Time (min) Yield (%) TONb TOFc (hÀ1
)
Mp (obsd) (ꢀC) Mp (lit) (ꢀC)
1
2
3
4
5
6
7
8
C6H5–
OMe Ph–CH2–
OMe Ph–CH2–
OMe Ph–CH2–
OMe Ph–CH2–
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
20
15
15
20
15
20
15
15
20
20
20
25
20
20
20
20
93
95
97
91
92
94
96
93
95
91
89
95
90
91
93
91
258
264
269
253
256
261
266
258
264
253
247
264
250
253
258
253
774
Oil
Oil
Oil
Oil
Oil27
4-Cl–C6H4–
4-NO2–C6H4–
4-CH3–C6H4–
4-OCH3–C6H4– OMe Ph–CH2–
2-Furyl–
2-Thienyl–
4-Cl–C6H4–
4-NO2–C6H4–
4-CH3–C6H4–
4-OCH3–C6H4– OEt
C6H5–
1056
1076
759
1024
783
1064
1032
792
759
741
634
750
Oil28
Oil28
Oil28
Oil
Oil27
OMe Ph–CH2–
OMe Ph–CH2–
128–131
120–123
Oil
Oil
Oil
Oil
Oil
126–128
119–122
128–131
106–109
130–132 (ref. 30)
122–124 (ref. 30)
Oil28
OEt
OEt
OEt
Ph–CH2–
Ph–CH2–
Ph–CH2–
Ph–CH2–
C6H5–
C6H5–
4-Cl–C6H4–
4-OCH3–C6H4– 5o
C6H5– 5p
9
Oil29
10
11
12
13
14
15
16
Oil27
Oil29
OEt
OEt
OEt
OEt
Oil31
4-Cl–C6H4–
4-CH3–C6H4–
4-Cl–C6H4–
127–129 (ref. 32)
120–122 (ref. 32)
130–132 (ref. 28)
108–110 (ref. 32)
759
774
759
4-OCH3–C6H4– OEt
a
Reaction conditions: ethyl acetoacetate (1 mmol), nitromethane (1 mmol), benzaldehyde (1 mmol), and aniline (1 mmol)) and Cu@imine/Fe3O4
MNPs (0.36 mol%) at 100 ꢀC. b Number of moles of product produced from 1 mole of catalyst. TON per unit of time.
c
Table 3 Optimization of the four-component reaction of benzil, benzaldehyde, benzylamine and ammonium acetate under various conditionsa
Entry
Solvent
Catalyst (mol%)
Temp.
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
Ethanol
Acetonitrile
Water
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.24
0.48
0.36
0.36
0.36
0.36
0.36
BF3–SiO2/0.36
MgCl2/0.36
SbCl5–SiO2/0.36
Reux
Reux
Reux
Reux
Reux
Reux
55
55
80
70
70
70
35
55
35
120
65
45
35
35
150
80
150
69
61
78
45
49
43
95
79
92
35
69
75
93
91
68
56
65
Dichloromethane
Chloroform
Tetrahydrofuran
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
80 ꢀ
80 ꢀ
80 ꢀ
25 ꢀ
60 ꢀ
70 ꢀ
90 ꢀ
C
C
C
C
C
C
C
9
10
11
12
13
14
15w
16
17
100 ꢀ
C
80 ꢀ
80 ꢀ
80 ꢀ
C
C
C
a
Reaction conditions: benzil (1 mmol), benzaldehyde (1 mmol), benzylamine (1 mmol), ammonium acetate (4 mmol), and the required amount of
catalyst. b The yields refer to the separated product.
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ꢀ
with the above-mentioned substituted electron-withdrawing from room temperature to 100 C in the existence of required
and electron-donating groups in the para positions of the amount of catalysts under solvent-free conditions (Table 3,
benzene ring were efficiently reacted with ethyl acetoacetate and Entries 7 and 10–14). It was found that by raising the reaction
nitromethane in excellent yields and times (Table 2, Entries 12– temperature, yield of the product increases. Maximum yield
16).
(95%) was obtained when the temperature of 80 ꢀC was applied
To obtain the optimize reaction conditions of the production to the reaction system (Table 3, Entry 7). Further rise in the
of 1,2,4,5-tetrasubstituted imidazoles derivatives, the reaction temperature had no considerable impact on the product yield
between benzil, benzylamine, benzaldehyde and ammonium (Table 3, Entries 13–14). It should be mentioned that the
acetate with 1 : 1 : 1 : 4 molar ratios using 0.36 mol% of catalyst product yield has decreased remarkably at temperatures below
was examined in the existence of diverse solvents, the concen- 80 ꢀC, whereas the reaction time has increased (Table 3, Entries
tration of used catalyst, and temperatures. To nd the solvent 10–12). Therefore, as shown in Table 3, using 0.36 mol% of
ꢀ
effect, the reaction was carried out in the existence of various Cu@imine/Fe3O4 MNPs under solvent-free and 80 C gave the
polar and non-polar solvents such as ethanol, acetonitrile, maximum yield of the target product in the shortest time. It is
water, dichloromethane, chloroform and tetrahydrofuran. noteworthy that when the reaction was carried out in the pres-
When water was applied as a solvent, the reaction proceeded ence of metal halides (Table 3, Entries 15–17), low to moderate
smoothly for producing the desired product (5a) in good yield yields of the desired product was obtained.
(Table 3, Entry 3). The model reaction in the rest of the solvents
With the optimized condition in hand, we explored the scope
mentioned above demanded long reaction times, and provided and generalization of the catalyst over a variety of aldehydes and
the product 5a in poor to moderate yields (Table 1, Entries 1–2 amines as substrates for synthesizing 1,2,4,5-tetrasubstituted
and 4–6). Interestingly, none of these solvents were impressive imidazoles. The outcomes were presented in Table 4. These
and the model reaction proceeded rapidly to obtain the desired results illustrates that the reactions are similarly facile with
product in excellent yield 95% under solvent-free conditions both electron-withdrawing and electron-donating groups, such
(Table 3, Entry 7). Over optimizing the reaction conditions, the as H, CH3, CH3O, NO2 and Cl in the meta and para positions of
impact of catalytic activity of the Cu@imine/Fe3O4 MNPs on the the benzene ring and amines, causing good to high yields of the
model reaction was also studied at 0.24, 0.36, and 0.48 mol% to relating imidazoles.
test their efficiency under solvent-free conditions (Table 3,
A proposed mechanism of the synthesis of replaced imid-
Entries 7–9). It was observed that the product yield has azoles catalyzed by Cu@imine/Fe3O4 MNPs is depicted in
increased in the existence of 0.36 mol% of catalyst (Table 3, Scheme 2. In the beginning, carbonyl oxygen of aldehyde is
Entry 7). Hence, 0.36 mol% was chosen as optimum catalyst coordinated to copper center on the nanocomposites surface to
amount for the reaction. Following choice of the optimal generate a better electrophilic species which more readily reacts
concentration of catalyst, the effect of the temperature on yield with amine to give diamine intermediate 6. The next step
of the model reaction was evaluated by diverse temperatures involves formation of imino intermediate 7 by condensing
Table 4 Preparation of 1,2,4,5-tetrasubstituted imidazoles derivatives using Cu@imine/Fe3O4 MNPs as a catalysta
Entry
RCHO (2)
R1
Product
Time (min)
Yield (%)
TONb
TOFc (hÀ1
)
Mp (obsd) (ꢀC)
Mp (lit) (ꢀC)
1
2
3
4
5
6
7
8
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
n-Pr–NH2
n-Pr–NH2
n-Pr–NH2
n-Pr–NH2
n-Pr–NH2
4-EtC6H4
4-EtC6H4
4-EtC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
35
30
30
35
35
35
30
20
20
20
25
35
25
35
95
95
97
93
92
94
96
97
98
98
93
96
98
94
264
264
269
258
256
261
266
269
272
272
258
266
272
261
453
528
538
442
439
447
532
807
816
816
619
456
653
447
215–217
150–152
254–257
186–188
170–172
173–176
88–91
216–218 (ref. 33)
149–151 (ref. 33)
255 (ref. 34)
185–188 (ref. 33)
171–173 (ref. 35)
175–178 (ref. 35)
87–89 (ref. 36)
4-Cl–C6H4–
3-NO2–C6H4–
4-CH3–C6H4–
4-OCH3–C6H4–
3,4-(OCH3)2–C6H4–
C6H5–
4-Cl–C6H4–
4-NO2-C6H4-
3-NO2–C6H4–
4-CH3–C6H4–
C6H5–
84–86
87–85 (ref. 36)
9
159–162
139–141
80–83
141–143
130–133
157–160
161–163 (ref. 37)
141–142 (ref. 37)
78–83 (ref. 36)
142–144 (ref. 37)
131–132 (ref. 37)
159–161 (ref. 37)
10
11
12
13
14
3-NO2–C6H4–
4-CH3–C6H4–
a
Reaction conditions: benzil (1 mmol), benzaldehyde (1 mmol), benzylamine (1 mmol), ammonium acetate (4 mmol) and Cu@imine/Fe3O4 MNPs
b
c
(0.36 mol%) at 80 ꢀC. Number of moles of product produced from 1 mole of catalyst. TON per unit of time.
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Fig. 6 The recycling of Cu@imine/Fe3O4 MNPs in the preparation of
polysubstituted pyrrole derivatives.
Scheme 2 A plausible mechanism of the creation of 1,2,4,5-tetra-
substituted imidazoles derivatives in the existence of Cu@imine/Fe3O4
MNPs under solvent-free conditions.
solution by a permanent magnet, washed with chloroform,
dried and recovered for a minimum of six runs (Fig. 6).
To evaluate recycling and recoverability of the Cu@imine/
Fe3O4 MNPs, aer six periods of recycling, this catalyst was
reused in the reaction of benzil, benzaldehyde, benzylamine
and ammonium acetate under the optimal reaction conditions
(Fig. 7). To achieve this purpose, at the end of the reaction, a hot
mixture of ethyl acetate and ethanol (4 : 10 ratio) was added to
the reaction solution and then the catalyst was removed simply
by means of a permanent external magnet. The recovered
Cu@imine/Fe3O4 MNPs was rinsed with chloroform, dried, and
recovered for alternative reaction.
Table 5 shows the efficiency of Cu@imine/Fe3O4 MNPs as the
novel heterogeneous magnetic nanocatalyst in preparing 1-
benzyl-4-(4-chloro-phenyl)-2-methyl-1H-pyrrole-3-carboxylic
acid methyl ester and 1,2,4,5-tetraphenyl-1H-imidazole
compared with those obtained by some of the other reported
homogeneous and heterogeneous catalysts. As clearly shown in
Table 5, although all the reported catalysts can catalyze the
reactions, most of them suffer from one or more disadvantages,
such as long reaction times, low yields of the products, use of
toxic catalyst, tedious work-up procedures, and high catalyst
diamine with 1,2-diketone, followed by dehydrating the relating
products 5.
The mechanism corresponding to production of greatly
substituted pyrrole mediated with the Cu@imine/Fe3O4 MNPs
catalyst was presented in Scheme 3. The reaction occurs via
initial production of the enamine 6 by nucleophilic addition of
amine to b-ketoester followed by dehydration. Then, nitro-
methane reacts with aldehyde to generate intermediate 7.
Subsequently, the enamine 6 reacts with intermediate 7 to
afford Michael adduct 8. Following intramolecular nucleophilic
cyclization by dehydration delivers the desired pyrrole.
Recycling and recoverability of the Cu@imine/Fe3O4 MNPs
were evaluated in the reaction between ethylacetoacetate,
nitromethane, benzaldehyde, and aniline. At the end of the
reaction, 10 mL hot mixture of ethyl acetate and ethanol (4 : 10
ratio) was poured in to the reaction solution to dissolve the raw
product. Then, the catalyst was isolated from the reaction
Scheme 3 A plausible mechanisms for the creation of polysubstituted
pyrrole derivatives in the existence of Cu@imine/Fe3O4 MNPs under Fig. 7 The recycling of Cu@imine/Fe3O4 MNPs in the synthesis of
solvent-free conditions.
1,2,4,5-tetrasubstituted imidazoles derivatives.
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Table 5 Comparison of the current methods with other reported strategies for synthesizing 1-benzyl-4-(4-chloro-phenyl)-2-methyl-1H-
pyrrole-3-carboxylic acid methyl ester and 1,2,4,5-tetraphenyl-1H-imidazole derivatives
Entry
Catalyst
Temp (ꢀC)
Time (min)
Yield (%)
Ref.
1
2
3
4
5
6
7
Nickel(II) chloride hexahydrate/solvent-free
Nickel ferrite nanoparticles/solvent-free
Nano copper oxide/solvent-free
Heterogenized tungsten complex/solvent-free
Amberlyst-15/solvent-free
rt
480
240
720
270
30
78
96
78
85
91
88
95
30
28
29
27
25
32
100
100
100
110
rt
SbCu@silica-Fe3O4/solvent-free
Cu@imine/Fe3O4 MNPs/solvent-free
25
25
100
This work
1
2
3
4
5
6
7
8
BF3/SiO2/solvent-free
TiCl4/SiO2/solvent-free
Glycerol as solvent
PEG-400 as a solvent
140
110
90
110
120
110
100
80
120
190
180
360
35
55
20
35
92
75
96
86
90
96
98
95
39
40
41
38
42
43
44
NaH2PO4/solvent-free
Fe3O4–PEG–Cu/solvent-free
g-Fe2O3@TiO2–EG–Cu(II)/solvent-free
Cu@imine/Fe3O4 MNPs/solvent-free
This work
loading. For these reasons, the catalytic behaviour of our cata-
lytic system is signicant in terms of easy work-up procedures,
low catalyst loading, low reaction times, and simple recovery of
the catalyst.
Acknowledgements
The results were obtained in the framework of the imple-
mentation of the initiative scientic project No. 40.5084.2017/
BCH “Study of methods and modeling processes in biotech-
nology and plant systematics”.
Conclusion
We have described a simple, facile, and effective process for the
eco-friendly and fast production of biologically active poly-
substituted pyrroles and 1,2,4,5-tetrasubstituted imidazoles
derivatives. The reaction system was signicantly affected by
catalyst loading and reaction temperature. The catalyst could be
recovered and reused at least six times without any signicant
decrease in its activity. The attractive properties of this proce-
dure are short reaction times, simple workup, high yields,
reusability and re-activity of the catalyst as well as simple
purication of the products.
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