Superparamagnetic core-shell metal–organic framework Fe3O4@Ni-MOF as efficient catalyst for oxidation of 1,4-dihydropyridines using hydrogen peroxide

Article abstract of DOI:10.1002/aoc.6350

A facile and efficient method was described for oxidation of some 3,5-diacyl or 3,5-diester 1,4-dihydropyridines using H₂O₂ in the presence of superparamagnetic core-shell metal–organic framework Fe₃O₄@Ni-MOF. The Fe₃O₄@Ni-MOF has been obtained by Step-by-Step method in which magnetic Fe₃O₄ magnetic nanoparticles were coated with Ni-MOF using a mercaptoacetic acid linker. The synthesized catalyst was characterized using thermogravimetric analysis, FT-IR spectroscopy, powder X-ray diffraction, field emission scanning electron microscopy and energy-dispersive X-ray analysis. The novel superparamagnetic core-shell metal–organic framework Fe₃O₄@Ni-MOF revealed high efficiency for oxidation of various 1,4-dihydropyridines using hydrogen peroxide. The Box–Behnken design matrix and the response surface method were applied to investigate the optimization of the reaction conditions. The conditions for optimal reaction yield and time were: amount of catalyst ≈17 mmol, temperature ≈78°C and amount of hydrogen peroxide ≈ 1 ml. A variety of 3,5-diacyl or 3,5-diester 1,4-dihydropyridines with different substituted functional groups have been converted to corresponding pyridines with good to excellent isolated yields using H₂O₂ and Fe₃O₄@Ni-MOF. The catalyst was reused up to five times for the oxidation of 1,4-dihydropyridines without a significant loss in catalytic activity. The short reaction times, simplicity of method, good to excellent yields and reusability of catalyst were some advantages of the proposed procedure.

Full text of DOI:10.1002/aoc.6350

Received: 17 March 2021
DOI: 10.1002/aoc.6350
Revised: 12 June 2021
Accepted: 17 June 2021
F U L L P A P E R
Superparamagnetic core-shell metal–organic framework
Fe3O4@Ni-MOF as efficient catalyst for oxidation of
1,4-dihydropyridines using hydrogen peroxide
Marzieh Janani
| Masumeh Abdoli Senejani
| Tahereh Momeni Isfahani
Department of Chemistry, Arak Branch,
Islamic Azad University, Arak, Iran
Abstract
A facile and efficient method was described for oxidation of some
3,5-diacyl or 3,5-diester 1,4-dihydropyridines using H2O2 in the presence of
superparamagnetic core-shell metal–organic framework Fe3O4@Ni-MOF.
The Fe3O4@Ni-MOF has been obtained by Step-by-Step method in which
magnetic Fe3O4 magnetic nanoparticles were coated with Ni-MOF using a
mercaptoacetic acid linker. The synthesized catalyst was characterized using
thermogravimetric analysis, FT-IR spectroscopy, powder X-ray diffraction,
field emission scanning electron microscopy and energy-dispersive X-ray
analysis. The novel superparamagnetic core-shell metal–organic framework
Fe3O4@Ni-MOF revealed high efficiency for oxidation of various
1,4-dihydropyridines using hydrogen peroxide. The Box–Behnken design
matrix and the response surface method were applied to investigate the
optimization of the reaction conditions. The conditions for optimal reaction
yield and time were: amount of catalyst ≈17 mmol, temperature ≈78ꢀC and
amount of hydrogen peroxide ≈ 1 ml. A variety of 3,5-diacyl or 3,5-diester
1,4-dihydropyridines with different substituted functional groups have been
converted to corresponding pyridines with good to excellent isolated yields
using H2O2 and Fe3O4@Ni-MOF. The catalyst was reused up to five times
for the oxidation of 1,4-dihydropyridines without a significant loss in
catalytic activity. The short reaction times, simplicity of method, good to
excellent yields and reusability of catalyst were some advantages of the
proposed procedure.
Correspondence
Masumeh Abdoli-Senejani, Department of
Chemistry, Arak Branch, Islamic Azad
University, Arak, Iran.
Email: mabdoli@iau-arak.ac.ir
Funding information
Islamic Azad University
K E Y W O R D S
1–4-dihydropyridine, hydrogen peroxide, magnetic nanoparticles, metal organic
framework, oxidation
1 | INTRODUCTION
analgesic, and antithrombotic effects.[1,2] It was found
that 1,4-dihydropyridines are analogues of nicotinamide
1,4-Dihydropyridines (DHPs) have played a dominant
role in biological activities and have been employed as
potential drugs due to their calcium antagonistic, anti-
anginal, antitumor, anti-inflammatory, antitubercular,
adenosine dinucleotide hydride (NADH) coenzyme that
undergo oxidative aromatization to the corresponding
pyridine due to the catalysis of cytochrome P-450 in
biological systems.[3] Recently, the synthesis of
Appl Organomet Chem. 2021;e6350.
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© 2021 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.6350

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JANANI ET AL.
pyridines has attracted considerable attention due to
their use as natural products, pharmaceuticals, building
blocks, dyes, reagents, and ligands in organic chemis-
try.[4] Oxidation of 1,4 dihydropyridines is one of the
main methods for the preparation of 4-substuted pyri-
dine derivatives which are hard to access via the
friedel crafts alkylation. Several reagents and chemicals
have been used for the oxidation of DHPs such as
2 | RESULTS AND DISCUSSION
Recently, we have been using Nickel (II) MOF (Ni-MOF)
as a new and effective catalyst for the preparation of
2-aryl benzimidazole and benzothiazole derivatives.[39] In
continuation of our research to develop efficient and
green methods for the synthesis of heterocyclic
compounds,[40–42] here, we describe a facile and conve-
nient procedure for the oxidation of 3,5-diacyl or
3,5-diester 1,4-dihydropyridines using H2O2 in the pres-
ence of Fe3O4@Ni-MOF as a catalyst (Scheme 1).
The superparamagnetic core-shell MOF Fe3O4@Ni-
MOF was prepared by Step-by-Step method.[43] At first,
Fe3O4 magnetic nanoparticles were functionalized by
mercaptoacetic acid (MAA). Next, functional MNPs were
covered with MOF (Ni-MOF) after repeated cycles
(Scheme 2). The growth of Ni-MOF shell on the MAA-
functionalized Fe3O4 core can be started by the metal
ions binding to the MAA on the Fe3O4 surface and then
attaching the ligands from the solution.[43] The structural
properties of synthesized Fe3O4@Ni-MOF were identified
by FT-IR, thermogravimetric analysis (TGA), X-ray dif-
fraction, TEM, and FESEM spectroscopy.
The powder XRD patterns of Fe3O4, Ni-MOF and
Fe3O4@Ni-MOF in the range 10–80ꢀare shown in
Figure 1. The diffraction peaks for the samples confirm
the crystal structures of them. The XRD pattern of
Fe3O4@Ni-MOF indicate that peaks observed at 30.1,
35.5ꢀ, 43.1ꢀ, 53.4ꢀ, 57.0ꢀ, and 62.6ꢀ corresponded to the
crystalline state of cubic Fe3O4 magnetic nanoparticles
and their crystal structure is well retained. Furthermore,
additional peaks agree with the XRD pattern of Ni-
MOF.[39]
NaBrO3, NaClO2, V2O5/SiO2 nanoparticles,[7] Bi2O3
nanorods,[8] Na2S2O4/TBHP (tert-butylhydroperoxide),[9]
and SiO2-CAN (ceric ammonium nitrate).[10] In this
study, H2O2 and Fe3O4@Ni-MOF were selected as the
oxidant and catalyst, respectively, for oxidation of
1,4-dihydropyridines. Hydrogen peroxide is a cheap
and green oxidant for oxidation of a large number of
substrates.[11] Literature survey shows that oxidation of
[5]
[6]
1,4-dihydropyridine derivatives using H2O2 in the pres-
ence of urea,[12,13] acetic acid,[14] AlCl3,
NaI,[16]
[15]
[17]
[18]
SiO2-VO (OH)2,
MoO3,
KBr/HOAc[19] as a cata-
lyst, has been reported. In addition, metal–organic
frameworks (MOFs) as heterogeneous catalysts have
been successfully applied as catalysts in oxidation and
hydrogenation reactions.[20] MOFs, also called Porous
Coordination Polymers, (PCPs) are novel three dimen-
sional organic–inorganic hybrids self-assembled by
metal ions and organic ligands. The large density of
active sites in MOFs, with respect to other porous
materials, enhances their catalytic application effi-
ciency.[21] A Ni-MOF nanosheet with catalytic activities
was used as a peroxidase mimetic and could catalyze
the oxidation of 3,3,5,5-tetramethylbenzidine (TMB)
using hydrogen peroxide (H2O2).[22]
It has been found that the magnetic MOFs have obvi-
ous advantages in catalytic activity, stability, biological
activity, convenient separation and recovery.[23–27]
Recently, nanomaterials have been used as catalyst or
very effective supports for immobilization of many cata-
lysts due to their very large surface areas and ease of
functionalization.[28–33] Among a variety of promising
supports, magnetic iron (III) oxide nanoparticles (Fe3O4
MNPs) has attracted great attention due to its preparation
simplicity, biological compatibility and recyclability with
an external magnetic field.[34,35] Herein, we hope to
report a facile and impressive approach to prepare the
new magnetic MOF composite (Fe3O4@Ni-MOF) and
study its catalytic activity for oxidation of
1,4-dihydropyrines using hydrogen peroxide. A three-
level Box–Behnken design (BBD) was applied in this
research to identify optimal conditions and estimate the
effects of temperature, the amounts of catalyst and hydro-
gen peroxide on yield and reaction time. The design of
experiments (DOE) using the Box–Behnken design has
recently received significant attention.[36–38]
Figure 2 shows the FT-IR spectra of Fe3O4, Ni-MOF
and Fe3O4@Ni-MOF. The relatively strong adsorption
peak at 560 cmꢁ1 could be attributed to the Fe-O
stretching vibration of Fe3O4, indicating the existence of
Fe3O4 in the catalyst.[44] The other bands, 1142 and 1298
(stretching vibration of SO2), 1498 and 1623 (aromatic
C=C), 1594 (bending vibration of N-H) confirmed the
presence Ni-MOF.[39]
In order to study thermal stability of the synthesized
Fe3O4@Ni-MOF, TGA of Fe3O4@Ni-MOF under a nitro-
gen atmosphere from room temperature to 800ꢀC is given
SCHEME 1 Oxidation of 1,4-dihydropyridine derivatives using
H2O2 in the presence of Fe3O4@Ni-MOF

JANANI ET AL.
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SCHEME 2 Preparation of Fe3O4@Ni-MOF
FIGURE 1 XRD patterns of Fe3O4, Ni-MOF
and Fe3O4@Ni-MOF
in Figure 3. The initial weight loss of 2.71% from 30.66ꢀC
to 108.16ꢀC was observed resulting from the loss of
adsorbed water. The second step shows a weight loss
of 10.19% from 108.16 to 797.88ꢀC which can be attrib-
uted to the decomposition of organic moiety and the
breakdown of the MOF. However, the results of TGA
showed that the catalyst is stable below 300ꢀC.
N، S، Ni, Fe, and O atoms was demonstrated using EDX
analysis confirming that Fe3O4 was coated with Ni-MOF
(Figure 5).
The TEM image of Fe3O4@Ni-MOF was showed in
Figure 6. TEM image demonstrated that synthesized
Fe3O4@Ni-MOF were composed of a Fe3O4 core and a
Ni-MOF shell.
The surface morphology of synthesized Fe3O4@Ni-
MOF was characterized by FESEM. As shown in
Figure 4, the FESEM image exhibited a uniform mor-
phology for the catalyst. In addition, the presence of C،
In the next step, catalytic activity of synthesized
Fe3O4@Ni-MOF was investigated for the oxidation of
1,4-dihydropyridin derivatives. For the optimization of the
reaction conditions, oxidation of diethyl 2,6-dimethyl-

4 of 13
JANANI ET AL.
FIGURE 2 FT-IR spectra of Fe3O4
(a), Ni-MOF (b), and Fe3O4@Ni-MOF (c)
FIGURE 3 Thermogravimetric analysis (TGA) plot for the synthesized Fe3O4@Ni-MOF
4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (0.5 mmol)
using hydrogen peroxide (30%, 1 ml) in the presence of
15 mg of catalyst in 3 ml of a different solvent was selected
as a model reaction (Table 1).
The results in Table 1 indicate that the presence of
catalyst and solvent was necessary for the reaction
(entries 1 and 2). In addition, it was found that
Fe3O4@Ni-MOF is more appropriate than the others. In
this work, Ni-MOF acted the key role as a catalyst
in Fe3O4@Ni-MOF and was supported on Fe3O4 MNPs,
which can easily be recovered by applying an external
magnetic field.
The results in Table 1 led us to investigate the effect
of various reaction parameters such as temperature, the
amounts of catalyst and hydrogen peroxide on the oxida-
tion of 1,4-dihydropyridines with a three-level 15-run
Box–Behnken design (BBD) method which was used by
utilizing Design-Expert 7.0.0 Trial software (Stat-Ease
Inc., Minneapolis). Table 2 shows the level of parameters,
experimental design matrix and results. The input

JANANI ET AL.
5 of 13
parameters in the reaction process optimization include
(A) temperature (i.e., 30ꢀC, 55ꢀC, and 80ꢀC), (B) the
amount of catalyst (i.e., 10, 15, and 20 mg), and (C) the
amount of hydrogen peroxide (i.e., 0.2, 0.6, and 1 ml).
The response function (Y) had a shorter reaction time
and a greater yield for oxidation of diethyl 2,6-dimethyl-
4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1b).
Response surface methodology and the BBD were
used to study the interaction of three factors on the yield
and reaction times, and to determine optimal conditions
for the reaction (Tables 3 and 4). The analysis of variance
(ANOVA) test at 95% confidence level was used and the
smaller p values (p value < 0.05) indicate a greater signif-
icance. The results revealed that A, B, C, AB, A2, B2, and
C2 were statistically significant.
The Equations 1 and 2 show second-order polynomial
models for time and yield based on significant levels and
actual values.
FIGURE 6 Thermogravimetric analysis (TEM) image of
FIGURE 4 FESEM image of Fe3O4@Ni-MOF
Fe3O4@Ni-MOF
FIGURE 5 EDX analysis of
Fe3O4@Ni-MOF

6 of 13
JANANI ET AL.
TABLE 1 Optimization of reaction
Entry
Catalyst
condition
Time (h)
Yield (%)
conditions
1
2
3
4
5
6
7
8
9
—
EtOH/reflux
Solvent free/80ꢀC
EtOAc/reflux
CH3CN/reflux
H2O/reflux
5
4
5
6
5
4
8
6
5
—
30
63
70
—
97
25
93
92
Fe3O4@Ni-MOF
Fe3O4@Ni-MOF
Fe3O4@Ni-MOF
Fe3O4@Ni-MOF
Fe3O4@Ni-MOF
Fe3O4@Ni-MOF
Ni-MOF
EtOH/reflux
EtOH/r.t.
EtOH/reflux
EtOH/reflux
Fe3O4
TABLE 2 The experimental factors, levels and results for the BBD
Levels
Factors
Unit
ꢀC
Symbol
High (+1)
Central (0)
Low (ꢁ1)
Temperature
Catalyst amount
H2O2
A
B
C
30
10
0.2
55
15
0.6
80
20
1
mg
ml
Independent variables
Dependent variable (Time/min)
Dependent variable (Yield/%)
Run
1
A
B
C
Experimental
Predicted
228.00
360.25
418.75
299.00
301.25
321.75
299.00
299.00
419.25
299.00
398.25
220.75
440.50
299.00
422.00
355.75
Experimental
Predicted
99.25
55.38
34.13
66.00
67.88
84.38
66.00
66.00
10.13
66.00
19.00
85.00
28.50
66.00
4.00
80.00
55.00
55.00
55.00
55.00
80.00
55.00
55.00
30.00
55.00
30.00
80.00
30.00
55.00
30.00
55.00
15.00
10.00
10.00
15.00
20.00
10.00
15.00
15.00
10.00
15.00
20.00
20.00
15.00
15.00
15.00
20.00
1.00
1.00
0.20
0.60
1.00
0.60
0.60
0.60
0.60
0.60
0.60
0.60
1.00
0.60
0.20
0.20
230
360
420
297
300
320
298
300
420
300
400
220
440
300
420
356
97
56
34
65
68
86
65
65
8
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
67
19
85
30
68
5
30
30.63
Y ðTimeÞ ¼ þ299 – 68:75Aꢁ30:5Bꢁ28:25Cꢁ20AB
ꢁ37:5 ACþBCþ22:25A2 þ18:75B2
þ41:25 R2
Y ðYied%Þ ¼ þ66þ34:13Aþ2:25Bþ14:63Cꢁ3AB
þ1:25 ACþ4 BCꢁ7:13A2 – 9:37B2
ꢁ9:63C2 R2
¼ 0:9959 Adjusted R2 ¼ 0:9930
ð1Þ
¼ 0:9968 Adjusted R2 ¼ 0:9991
ð2Þ

JANANI ET AL.
7 of 13
TABLE 3 ANOVA for Box–Behnken quadratic model for reaction time of oxidation of 1b
Source
Sum of squares
70652.53
37812.5
7442
Df
9
Mean square
7850.28
37812.5
7,442
F value
2035.26
9803.24
1929.41
1655.24
414.81
1458.33
1.04
p value
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.3424
Remark
Model
significant
A—Temperature
1
B—Catalyst amount
1
C—H2O2
AB
6384.5
1600
1
6384.5
1,600
1
AC
5625
1
5,625
BC
4
1
4
A2
B2
C2
2084.47
1480.26
7164.47
27
1
2084.47
1480.26
7164.47
3.86
540.42
383.77
1857.46
<0.0001
<0.0001
<0.0001
1
1
Residual
Lack of Fit
Pure Error
Cor Total
7
19
3
6.33
3.17
0.1473
not significant
8
4
2
70679.53
16
TABLE 4 ANOVA for Box–Behnken quadratic model for yield of oxidation of 1b
Source
Sum of squares
12259.78
9316.13
40.5
Df
9
Mean square
1362.2
9316.13
40.5
F value
252.59
1727.49
7.51
p Value
<0.0001
<0.0001
0.0289
Remark
Model
significant
A—Temperature
1
B—Catalyst amount
1
C—H2O2
AB
1711.13
36
1
1711.13
36
317.29
6.68
<0.0001
0.0363
1
AC
6.25
1
6.25
1.16
0.3174
BC
A2
B2
C2
64
1
64
11.87
39.64
68.62
72.33
0.0108
213.75
370.07
390.07
37.75
1
213.75
370.07
390.07
5.39
0.0004
1
<0.0001
<0.0001
1
Residual
Lack of Fit
Pure Error
Cor Total
7
29.75
3
9.92
4.96
0.078
not significant
8
4
2
12297.53
16
where Y is the predicted response as yield and reac-
tion time; A, B, and C are temperature, amount of cata-
lyst, and the amount of hydrogen peroxide, respectively;
and AB, AC, and BC are the interaction coefficients of
these factors.
The determination coefficients of the two equations
(R2 = 0.9959 and 0.9968 for time and yield respectively)
indicate a good correlation between the observed and
predicted results. The contour plots and 3D response sur-
faces can be applied for investigation of the interaction
between the reaction parameters on the response reac-
tion yield and time. The optimal experimental conditions
for obtaining the minimum time and maximum yield are
presented in Figures S1 and S2 represented by dark blue
and dark red areas respectively. The results of DOE indi-
cated that the optimal conditions for oxidation of diethyl
2,6-dimethyl-4-phenyl-1,4-dihydropyridine-
3,5-dicarboxylate (1b) for the minimum reaction time
of 214 min (3.57 h) and maximum yield of 97% are
temperature = 77.97ꢀC (reflux condition), amount

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JANANI ET AL.
TABLE 5 Oxidation of 1b under optimized conditions
Dependent variable (Time/
min)
Factors
Dependent variable (Yield/%)
Experimental
Temperature
Approach (ꢀC)
Amount of
catalyst (mg)
H2O2
(ml)
Experimental
(Mean SD)
Predicted (Mean SD)
Predicted
BBD 77.97
17.07
0.93
215 2.49
214.357 96.66 1.24
97.370
TABLE 6 Oxidation of some 1,4-dihydropyridines using hydrogen peroxide in the presence of Fe3O4@Ni-MOF
Entry
R1
R2
Product
2a
Time (h)
Yield (%)
Melting pointd OC [Found.]
Melting pointd OC [Ref.]
69–71[46]
63–65[47]
Oil[47]
62–64[41]
64–65[48]
113–114[48]
Oil[48]
49–52[49]
58–60[49]
1
H
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
CH3
0.5
3.5
6.5
7
90
97
86
88
98
83
92
92
84
85
95
84
88
93
90
68–69
64–66
oil
2
C6H5
2b
3
4-BrC6H4
3-NO2C6H4
4-ClC6H4
4-NO2C6H4
2-furyl
2c
4
2d
61–63
64–65
112–114
oil
5
2e
4
6
2f
7
7
2 g
2 h
2i
2.5
3.5
3
8
4-CH3OC6H4
2-CH3OC6H4
H
48–50
57–60
64–65
184–186
123–125
174–176
165–167
140–142
9
10
11
12
13
14
15
2j
2
65–67[46]
C6H5
CH3
2 k
2 L
2 m
2n
5.5
7.5
5.5
4
186–188[41]
124–126[41]
172–174[41]
165–166[41]
142–143[50]
3-NO2C6H4
4-ClC6H4
4-CH3OC6H4
2-CH3OC6H4
CH3
CH3
CH3
CH3
2o
5
of catalyst = 17.07 mg and amount of hydrogen
peroxide = 0.93 ml (Figure S3).
In order to investigate the validity of the model, four-
time reactions were done using these optimal experimen-
tal conditions, so that predicted values were in a good
agreement with experimental values (Table 5).
Following the optimization of the reaction conditions,
a variety of 1,4-dihydropyridine derivatives were oxidized
using H2O2 in the presence of Fe3O4@Ni-MOF to study
the generality of this method (Table 6).
1,4-dihydropyridines. We do not find a clear correlation
between substituent in position 4 of dihydropyridine
ring and reaction times. Nevertheless some electron
releasing groups, such as methoxy, facilitate the reaction,
and some electron withdrawing groups, such as
nitro, increase the reaction times. When synthesized
Fe3O4@Ni-MOF was used for oxidation of some
1,4-dihydropyridines under identical conditions after
several months, the reaction was performed without
reducing initial catalyst activity.
As shown in Table 6, this procedure is effective for
oxidation of 3,5-diacetyl and 3,5-diester 1,4-dihydro
pyridine derivatives to afford corresponding pyridines
with retention of the substituent in position 4 in good to
excellent yields. Furthermore, 3,5-diester 1,4-dihydro
pyridines converted to the corresponding pyridine more
readily than 3,5-diacetyl 1,4-dihydropyridines under
identical conditions. However, compounds 1a and 1j,
with no substituent in position 4 of the dihydropyridine
ring, were oxidized in a shorter time than other
It has been found that some MOFs were applied as
peroxidase mimetic with catalytic activities and non-
enzymatic electrochemical hydrogen peroxide sen-
sors.[22,45] Thus, in this work, it is proposed that H2O2
was adsorbed in the pores of Ni-MOF and absorbed
hydrogen peroxide was reduced into H2O along with the
oxidation of 1,4-dihydropyrines to corresponding pyri-
dines (Scheme 3).
The reaction mechanism probably consists of two
steps. First, hydrogen peroxide was adsorbed in the pores

JANANI ET AL.
9 of 13
of Ni-MOF onto the surface of Fe3O4@Ni-MOF, and the
OꢁO bond was broken into hydroxyl radical.[22] Then,
abstraction of a hydrogen of dihydropyridine ring by
hydroxyl radical yielding.monohydropyridyl radical
which reduces the hydroxyl radical to produce
corresponding pyridine (Scheme 4).[51]
Moreover, reusability of Fe3O4@Ni-MOF was stud-
ied in the oxidation of diethyl 2,6-dimethyl-4-phenyl-
1,4-dihydropyridine-3,5-dicarboxylate (1b) under opti-
mized conditions. After completion of the reaction, the
mixture was cooled to room temperature and the
catalyst was easily separated using a strong external
permanent magnet. The separated Fe3O4@Ni-MOF was
washed four times with methanol (5 ml) and then
dried. The recovered catalyst was reused five times for
the oxidation of 1a without a significant loss in cata-
lytic activity (Figure 7). The stability of the recovered
Fe3O4@Ni-MOF was investigated using EDX analysis
(Figure 8). The comparison of the results showed that
the main composition of the fresh catalyst and the
recycled catalyst were the same.
Finally, the performance of this procedure was com-
pared with various procedures for the oxidation of
1,4-dihydropyridines (Table 7). Most of these methods
are applied only for oxidation of 3,5-diester
1,4-dihydropyridines. The results indicate that core-shell
MOF Fe3O4@Ni-MOF is an efficient catalyst for oxida-
tion of 3,5-diacyl or 3,5-diester 1,4-dihydropyridines using
hydrogen peroxide and this procedure is comparable with
some other reported methods in terms of reaction times
and yield.
3 | EXPERIMENTAL
3.1 | General
All chemicals and reagents were purchased from
Sigma-Aldrich and were used without further purifica-
tion. All Hantzsch 1,4-dihydropyridines were prepared
similar to the reported methods,[49,52] Their physical
and spectroscopic data were in agreement with those
of authentic samples. All yields are from the isolated
products after purification. Melting points were
SCHEME 3 Schematic illustration of the reduction of H2O2
and oxidation of DHPs by Fe3O4@Ni-MOF
SCHEME 4 A plausible mechanism for
oxidation of DHPs by Fe3O4@Ni-MOF
FIGURE 7 Recyclability of Fe3O4@Ni-MOF
as a catalyst for the oxidation of 1b as a model
reaction

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JANANI ET AL.
FIGURE 8 EDX analysis of
recycled Fe3O4@Ni-MOF
TABLE 7 Comparison of the efficiency of some method used in the oxidation of 1,4-dihydropyridines
Entry
Reagent
Condition
Yield (%)
83–98
94–100
70–95
90–96
92–99
90–98
74–95
88–100
73–96
72–100
50–98
92–99
89–99
time [Ref.]
0.5–7.5 h[This work]
3–8 min[15]
25–240 min[49]
3 h[53]
15–560 min[54]
30–60 min[48]
10–45 min[55]
6 h[18]
2–6 h[9]
4–24 h[8]
9–90 min[56]
12–35 min[57]
20 min[6]
1
H2O2/Fe3O4@Ni-MOF
H2O2/AlCl3 6H2O
EtOH/Reflux
H2O/EtOH/Microwave
MeOH/r.t.
2
3
NaIO4/Mn (III)-BSMP
Graphite Oxide
4
Toluene/100ꢀC
5
Guanidinium nitrate/Silica sulfuric acid
O2/Transition metal chloride/Sodium nitrite/TEMPO
silica-supported/metal (Ni,Co,Fe,Cu)nitrates/
H2O2/MoO3
CH2Cl2/r.t.
6
MeCN/AcOH/r.t.
infra-red radiations
EtOH/Reflux
EtOAc/r.t.
7
8
9
Air/Na2S2O4/TBHP
10
11
12
13
Bi2O3
EtOH/Reflux
CH3CN/r.t.
H2O2/SiO2-VO (OH)2
DHPDMDO/NH4Br/HOAc
NaClO2/HCl
H2O/MeCN/r.t.
EtOH/H2O/50ꢀC
measured using a Barnstead Electrothermal apparatus.
1H NMR spectra were recorded on a Brüker 300-MHz
spectrometer in CDCl3. elemental analysis was
obtained using a Perkin–Elmer 2400 Series II CHNS/O
analyzer. Surface morphology and elemental composi-
tion were obtained using a field emission SEM instru-
ment (Tescan Mira III). TGA and DTA curves were
measured using a TGA/DSC 1 (Mettler Toledo) at a
heating rate of 10ꢀC minꢁ1 from 25ꢀC to 800ꢀC under
nitrogen atmosphere. The morphology of the catalyst
was characterized by transmission electron microscopy
(TEM, Zeiss—EM10C—100 KV). X-ray diffraction anal-
ysis was carried out using X'Pert Pro X-ray
diffractometer using a Cu tube over the 2θ range from
10ꢀ to 80ꢀ.
3.2 | General procedure for the
preparation of Fe3O4 nanoparticles
Magnetic nanoparticles were synthesized by a modified
chemical precipitation method.[58] FeCl2.4H2O (2.0 g)
and FeCl3.6H2O (5.4 g) were dispersed to double-
distilled water (20 ml) and concentrated hydrochloric
acid (2 ml). The solution was stirred vigorously
under N2 gas at 80ꢀC. Ammonium hydroxide (2 M)

JANANI ET AL.
11 of 13
solution was added dropwise in to the solution under
mechanical stirring to adjust the pH to 10 and
cause precipitation. The precipitated particles were
separated using a strong permanent magnet and were
washed three times using double distilled water. After
that the powder was dried to obtain nanomagnetic
Fe3O4.
3.5 | Selected spectroscopic data
Diethyl-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (2b)
1
IR (KBr): ν˜ = 1720 cmꢁ1 (C=O); HNMR (300 MHz,
CDCl3, 25ꢀC, TMS): δ = 0.86 (t, J = 6.8 Hz, 6H, CO2C-
H2CH3), 2.58 (s, 6H, 2 and 6-CH3), 3.97 (q, J = 6.8 Hz,
4H, CO2CH2CH3), 7.28 ppm (m, 5H, C6H5); Anal. Calcd
for C19H21NO4: C 69.71; H 6.47; N, 4.28. Found: C,
69.60; H, 6.48; N, 4.32.
3.3 | General procedure for the
preparation of Fe3O4@Ni-MOF
Diethyl-4-(4-methoxyphenyl)-2,6-dimethylpyridine-
3,5-dicarboxylate (2 h)
IR (KBr): ν˜ = 1,697 cmꢁ1 (C=O); 1HNMR (300 MHz,
CDCl3, 25ꢀC, TMS): δ = 0.97 (t, J = 7.0 Hz, 6H, CO2C-
H2CH3), 2.60 (s, 6H, 2 and 6-CH3), 3.90 (s, 3H,
40-OCH3),4.00 (q, J = 7.0 Hz, 4H, CO2CH2CH3),
7.28 ppm (m, 4H, C6H4OCH3); Anal. Calcd for
C20H23NO5: C 67.21, H 6.49; N 3.92, Found: C 67.28; H
6.40; N 3.95.
Superparamagnetic core-shell MOF Fe3O4@Ni-MOF
was synthesized according to a previous procedure of
Qiu with minor modifications.[59] In a typical proce-
dure, 20 ml of ethanol solution of Fe3O4 MNPs (0.1 g)
was added to 20 ml of ethanol solution of mer-
captoacetic acid (0.58 mM) with shaking for 24 h.
Mercaptoacetic acid (MAA)-functionalized Fe3O4
nanoparticles were collected by a strong magnet and
washed two times with distilled ethanol and water.
Subsequently, 0.1 g of modified Fe3O4 was dispersed in
2.5 ml of methanol solution of Nickel (II) nitrate
hexahydrate (1 mmol) and shaken for 15 min at room
temperature. Then 5 ml of methanol solution of 4,40-
diaminodiphenyl sulfone (DDS) (1 mmol) was added to
the mixture and stirred at room temperature for
30 min and again at 50ꢀC for 30 min. After each step,
the obtained powder was separated with a strong
magnet and rinsed with ethanol. Finally, the magnetic
core-shell MOF Fe3O4@Ni-MOF was obtained after
40 cycles. The synthesized catalyst was washed with
ethanol, dried and identified by FT-IR, TGA, FE-SEM,
TEM and XRD techniques.
3,5-Diacetyl-4-(4-chlorophenyl)-2,6-dimethylpyridine
(2 m)
1
IR (KBr): ν˜ = 1710 cmꢁ1 (C=O); HNMR (300 MHz,
CDCl3, 25ꢀC, TMS): δ = 1.80 (s, 6H, 2-and 6-CH3), 2.40
(s, 6H, 3-and 5-COCH3), 7.20 ppm (m, 4H, C6H4Cl);
Anal. Calcd for C17H16ClNO2: C 67.66, H 5.34, N 4.64,
Found: C 66.98, H 5.37, N 4.70.
4 | CONCLUSIONS
We described a facile and environmentally friendly
method for oxidation of 1,4-dihydropyridines using
H2O2 in the presence of Fe3O4@Ni-MOF. The core-shell
MOF Fe3O4@Ni-MOF was successfully prepared using
coating Ni-MOF on Fe3O4 magnetic nanoparticles with
a mercaptoacetic acid linker utilizing the Step-by-Step
method. The Fe3O4@Ni-MOF was applied as catalyst
for oxidation of some 3,5-diacyl or 3,5-diester
1,4-dihydropyridines using H2O2. Following optimiza-
tion of the reaction conditions with a three-level 15-run
Box–Behnken design (BBD) method, several 3,5-diacyl
or 3,5-diester 1,4-dihydropyridines were oxidized using
H2O2 in the presence of Fe3O4@Ni-MOF with good to
excellent isolated yields. The catalyst could be easily
recovered with an external magnet and recycled with
high activity. The simplicity of method, high yields of
products, short reaction times, stability, reusability, and
easy separation of the catalyst are the advantages of this
methodology.
3.4 | General procedure for oxidation of
1,4-dyhdropyridine derivatives
A
suspension of Hantzsch 1,4-dihydropyridines
(0.5 mmol), Fe3O4@Ni-MOF (17 mg), and H2O2 (30%,
1 ml) in ethanol (3 ml) were stirred under reflux for
a specific time. The reaction progress was followed
by thin layer chromatography (ethyl acetate: petroleum
ether 1:3). After completion of the reaction, the
catalyst was easily separated using a strong external
permanent magnet. The solvent was removed, and
the crude product was purified by recrystallization
from petroleum ether/ethyl acetate (4:1) to obtain
a pure product. The structures of the products were
characterized using IR and 1H NMR spectroscopy
which were in correlation with those reported before.
ACKNOWLEDGEMENT
We are grateful to the Islamic Azad University–Arak
Branch for its lab supplies.

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Marzieh Janani https://orcid.org/0000-0003-3117-759X
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