One-pot synthesis of 1,4-dihydropyridine derivatives using the Fe2ZnAl2O7 catalyzed Hantzsch three-component reaction

Article abstract of DOI:10.1002/jccs.202000322

A facile, low-cost, and effective one-pot method was developed for the synthesis of 1,4-dihydropyridine derivatives with high yields through the three-component reaction of ammonium acetate, ethyl acetoacetate, and aromatic aldehydes using Fe₂ZnAl₂O₇ as catalyst. The reaction was conducted at 70–80°C temperature under solvent free conditions. The developed method had some great advantages, including safe and clean reaction conditions, high to excellent product yields, short reaction time, and a novel and powerful heterogeneous catalyst. The developed heterogeneous solid catalyst had high efficiency and reusability in one-pot multi-component syntheses such that it was easily reused four to five times without significant loss in efficiency and product yield. The catalyst was characterized by scanning Electron Microscopy (SEM)/energy-dispersive X-ray spectroscopy (EDS) and X-ray diffraction techniques. N2 sorption isotherms of the prepared nanocomposite exhibited surface area 2.1313E+01 m²/g and total pore volume of 3.0957E-02 cm³/g. Substituted dihydropyridine derivatives were characterized and confirmed using ¹H NMR and ¹³C NMR, and elemental spectral data.

Full text of DOI:10.1002/jccs.202000322

Received: 26 September 2020
DOI: 10.1002/jccs.202000322
Revised: 10 December 2020
Accepted: 24 January 2021
A R T I C L E
One-pot synthesis of 1,4-dihydropyridine derivatives using
the Fe2ZnAl2O7 catalyzed Hantzsch three-component
reaction
Reza Zargarzadeh1
| Karim Akbari Dilmaghani1
| Abbas Nikoo2
1Department of Organic Chemistry,
Faculty of chemistry, Urmia University,
Urmia, Iran
2Shahid Bakeri High Education Center,
Urmia University, Urmia, Iran
Abstract
A facile, low-cost, and effective one-pot method was developed for the synthesis
of 1,4-dihydropyridine derivatives with high yields through the three-component
reaction of ammonium acetate, ethyl acetoacetate, and aromatic aldehydes using
Fe2ZnAl2O7 as catalyst. The reaction was conducted at 70–80ꢀC temperature
under solvent free conditions. The developed method had some great advantages,
including safe and clean reaction conditions, high to excellent product yields,
short reaction time, and a novel and powerful heterogeneous catalyst. The devel-
oped heterogeneous solid catalyst had high efficiency and reusability in one-pot
multi-component syntheses such that it was easily reused four to five times with-
out significant loss in efficiency and product yield. The catalyst was characterized
by scanning Electron Microscopy (SEM)/energy-dispersive X-ray spectroscopy
(EDS) and X-ray diffraction techniques. N2 sorption isotherms of the prepared
nanocomposite exhibited surface area 2.1313E+01 m2/g and total pore volume of
3.0957E-02 cm3/g. Substituted dihydropyridine derivatives were characterized
and confirmed using 1H NMR and 13C NMR, and elemental spectral data.
Correspondence
Karim Akbari Dilmaghani, Department of
Organic Chemistry, Faculty of chemistry,
Urmia University, Urmia, Iran.
Email: k.adilmaghani@urmia.ac.ir
K E Y W O R D S
1,4-dihydropyridine, Hantzsch reaction, heterogeneous solid catalyst, one-pot synthesis,
recyclable, solvent free
1 | INTRODUCTION
in terms of green chemistry. In addition, since solid-
phase catalysts are reusable, they have high economic
Developing novel catalysts with higher selectivity, activ-
ity, and reusability, especially solid phase catalysts as
replacements for homogenous ones, has attracted many
researchers.[1–6]
Heterogeneous basic catalysts have become very popu-
lar since they offer great advantages and minor disadvan-
tages compared to their homogenous counterparts.[7–10]
Application of solid bases makes it possible to carry out
reactions at high temperatures, even in vapor phase.[7–11]
In addition, solid-phase catalysts are less corrosive
and can be easily separated from reaction media highly
decreasing waste problems, which is an important issue
efficiency.[12–13]
The catalytic activity of solid-phase catalysts depends
on the number of available basic sites on their surface
and their strength; therefore, the fabrication of a basic
catalysts with high surface areas is of particular impor-
tance. 1,4-dihydropyridine (1,4-DHP) derivatives present
a wide range of biological activities and have been used
as antianxiety, antidepressive, vasodilator, anticonvul-
sant, bronchodilator, hypnotic, antitumor, analgesic, and
anti-inflammatory agents. Some derivatives, such as
isradipine, felodipine, nifedipine, amlodipine, and
lacidipine are applied as calcium-channel blocker drugs
J Chin Chem Soc. 2021;1–7.
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1

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ZARGARZADEH ET AL.
SCHEME 1 Synthesis of 1,4-DHP Derivatives
TABLE 1 Optimization of Fe2ZnAl2O7-catalyzed model
reaction
Entry
Catalyst (mol%)
Time (min)
Yields (%)
1
2
3
4
5
6
—
5
60
60
40
40
40
40
Trace
68
10
15
20
25
90
89
91
90
Note: 1 mmol benzaldehyde, 2 mmol ethyl acetoacetate, 1 mmol ammonium
acetate, and 0.01 g of catalyst in various solvents at 70–80ꢀC.
TABLE 2 Fe2ZnAl2O7-catalyzed synthesis of 1,4-DHP
derivatives
Entry
R
R/
Time (min)
Yield (%)
1
2-HO-Ph
3-HO-Ph
4-HO-Ph
2-O2N-Ph
3-O2N-Ph
4-O2N-Ph
2-Cl-Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
120
100
80
80
84
83
82
91
95
81
85
79
92
78
75
2
3
SCHEME 2 Proposed mechanism for one-pot synthesis of
4
90
1,4-DHP derivatives
5
50
6
40
7
100
90
8
4-Cl-Ph
9
2,4-diCl-Ph
Furyl
110
40
10
11
12
3-HO-4-MeO-Ph
4-HO-3-MeO-Ph
120
120
FIGURE 1 XRD pattern of Fe2ZnAl2O7 nanoparticles
TABLE 3 Reusability of Fe2ZnAl2O7 nanoparticles
Note: 1 mmol benzaldehyde, 2 mmol ethyl acetoacetate, 1 mmol ammonium
acetate, and 0.01 g of catalyst in solvent free conditions at 70–80ꢀC.
Entry
Yield (%)
Time (min)
in the treatment of hypertension and cardiovascular
diseases.[14]
1
2
3
4
5
90
88
85
84
84
40
40
40
40
40
Some of these derivatives are efficient in the preparation
of the reduced forms of nicotinamine adenine dinucleotide,
which is a key compound for living organisms.[15]
Hantzsch discovered the structure of DHP in 1882.[16]
Since these compounds play important biological
roles, several methods have been developed to improve
the synthesis of DHP. One-pot multi-component reac-
tions for the synthesis of organic chemicals have attracted
many organic chemists because they involve rapid into
products. This method has even more important
Note: 1 mmol benzaldehyde, 2 mmol ethyl acetoacetate, 1 mmol ammonium
acetate, and 0.01 g of catalyst in solvent free conditions at 70–80ꢀC.
advantages of easy handling and environmentally friend-
liness because it decreases the number of steps and
improves atom economy.[17]

ZARGARZADEH ET AL.
3
FIGURE 2 SEM images of Fe2ZnAl2O7 nanoparticles
FIGURE 3 The EDX spectrum of Fe2ZnAl2O7 nanoparticles
Different catalysts have been proposed for the synthesis
of DHP derivatives such as Preyssler heteropolyacids,[15]
zinc oxide,[18] NiO/ZrO2,[19] Fe-TUD-1,[20] glycine-HCl,[21]
iron(III) phosphate,[22] V2O5/SiO2,[23] MgCl2,[24] and Fe[(L)
However, some of these methods have green chemis-
try disadvantages, including low yields, prolonged reac-
tion times, toxicity and low reusability, and recovery of
catalyst. Iron is among the most commonly found ele-
ments in the earth's crust composing 5% of its
composition.[27]
Recently, metal oxides have become the largest het-
erogeneous catalyst family due to their redox properties
and acidic base. In addition, bulk zinc oxide has been
[25]
proline]2.
Nano catalysts present higher catalytic activities than
their counterparts with greater sizes. Highly active het-
erogeneous Nano catalysts have attracted great attention
because of their high specific surface area.[26]

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ZARGARZADEH ET AL.
FIGURE 4 N2 adsorption–desorption isotherms of Fe2ZnAl2O7 nanoparticle
applied as a heterogeneous catalyst in a variety of organic
transformations.[28]
characteristics closely rely on the preparation method
of support.[29]
Support is an important component of supported
metallic catalysts Alumina is widely applied as a cata-
lytic support in different chemical reactions. The tex-
tural and structural properties of these compounds
depend on their preparation steps and their catalytic
Therefore, developing clean synthesis procedures
and application of environmentally friendly and
green catalysts with simple recyclability at the end of
reactions is a great challenge in scientific communi-
ties. The most commonly used preparation procedure

ZARGARZADEH ET AL.
5
2.3 | Preparation of fused
1,4-dihydropyridines
A mixture of ethyl acetoacetate (2 mmol), aryl aldehyde
(1 mmol), NH4OAc (1 mmol), and Fe2ZnAl2O7 catalyst
(0.01 g) was heated at 70–80ꢀC under solvent free condi-
tions for the required reaction time. Reaction progress
was monitored by thin-layer chromatography (EtOAc/
petroleum ether 1:3). Once the reaction was completed,
the mixture was cooled to room temperature, extracted
with CH2Cl2, and the residue was recrystallized from eth-
anol to give fused 1,4-DHP derivatives as a pure crystal-
line product with 80–94% yields (Scheme 1).
FIGURE 5 Reusability of Fe2ZnAl2O7 nanoparticles
for the preparation of symmetric 1,4-DHPs is the
classical Hantzch synthesis. This reaction is a mul-
ticomponent condensation reaction of an aldehyde
with two equivalent of a β-ketoester in the presence
of ammonia. Demand for environmentally friendly
procedures with heterogeneous and reusable catalysts
encouraged us to develop a safe alternative procedure
for the synthesis of 1,4-DHPs using Fe2ZnAl2O7 as
catalyst.[30]
3 | RESULTS AND DISCUSSION
Then, we investigated other amounts of Fe2ZnAl2O7
nanocrystalline powder (5–25 mol%) in the same reac-
tion. The optimum yield of 1,4-DHPs was obtained when
10 mol% Fe2ZnAl2O7 nanocrystalline powder was used
(Table 1).
Therefore, under optimized reaction condition, benz-
aldehydes (1 mmol), ethyl acetoacetate (2 mmol), and
ammonium acetate (1 mmol) were mixed with
Fe2ZnAl2O7 nanocrystalline powder (10 mol%) under sol-
vent free condition. The obtained results are summarized
in Table 2. As shown in the table, when benzaldehyde
substituted with electron-withdrawing groups the electro-
philicity of the Carbonyl Carbon and reaction rate was
increased but when benzalehyde substituted with
electron-donating groups the reaction rate and the yield
of reaction were reduced.
A tentative mechanism of Fe2ZnAl2O7-catalyzed
synthesis of 1,4-DHPs has been proposed. Fe2ZnAl2O7
Nanoparticles could act as Lewis acid and would play a
substantial role in increasing the electrophilic charac-
ter of the electrophiles in the reaction. According to
this mechanism, catalyst would assist the formation of
key intermediates, I, II, and III. In terms of mecha-
nism, the first step of the reaction could be considered
the nano doped-catalyzed formation of Knoevenagel
product I. Knovenagel reaction involves coupling of
aldehyde with active methylene compound such as
β-ketoester. A second key intermediate might be ester
enamine II, fabricated by the condensation of the sec-
ond equivalent of β-ketoester with ammonia. The
Michael addition of these two intermediates gave inter-
mediate III, which subsequently cyclized to 1,4-DHP
(Scheme 2).
2 | EXPERIMENTAL
2.1 | Apparatus
The obtained products were separated and character-
ized by spectral and physical techniques. H and 13C
1
NMR spectra were obtained on a Bruker Avance-
300 MHz spectrometer with tetramethylsilane as inter-
nal standard. Melting points were recorded on Electro
thermal 9200 and were not corrected. The microscopic
morphologies of the products were observed by SEM
(LEO 1455VP). X-ray diffraction (XRD) technique gave
valuable information on the structural properties of the
catalyst. Specific Brunauer–Emmett–Teller (BET) sur-
face area (SBET) values were calculated with 0.05 < P/
P0 < 0.30. The total pore volume (Vt) was estimated
from the adsorption data at a P/P0 value of 0.99.
2.2 | Synthesis of Fe2ZnAl2O7 catalyst
A total of 8.08 g Fe(NO3)3Á9H2O, 2.88 g ZnSO4Á7H2O,
and 7.50 g Al(NO3)3Á9H2O were dissolved in 400 ml
distilled water. Then, KOH solution (7.86 g KOH in
100 ml distilled water) was added and the mixture was
stirred for 3 hr. Then, the reaction mixture was filtered
and washed with distilled water. Finally, the filtered
solid was dried at room temperature and calcined at
750ꢀC for 4 hr.
The prepared catalyst was characterized by XRD tech-
nique (Figure 1). The XRD pattern of Fe2ZnAl2O7
nanoparticles showed peaks, which corresponded to

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ZARGARZADEH ET AL.
hexagonal quartzite structure. Particle sizes were calcu-
lated from the width of first peak using Debye Scherer
equation D = K λ/β COS θ, where K is a constant value, λ
is the wavelength of employed X-ray radiation
(1.54056 Å), β is corrected full width at half maximum,
and θ is Bragg angle. The 2θ value was 19.0104 (Table 3).
The crystalline size of Fe2ZnAl2O7 nanoparticles was
calculated to be about 30 nm. The morphology of the sam-
ple was observed with SEM (Figure 3), which showed the
nanostructure of Fe2ZnAl2O7. The SEM images shown in
Figure 2 revealed that Fe2ZnAl2O7 nanoparticles had a
mean diameter of about 11–40 nm with nearly spherical
shape.
ORCID
Reza Zargarzadeh https://orcid.org/0000-0002-4700-
512X
Karim Akbari Dilmaghani https://orcid.org/0000-0002-
0084-3580
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ACKNOWLEDGMENTS
The authors are grateful to Urmia University for provid-
ing a fellowship for the present work.

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How to cite this article: Zargarzadeh R, Akbari
Dilmaghani K, Nikoo A. One-pot synthesis of 1,4-
dihydropyridine derivatives using the Fe2ZnAl2O7
catalyzed Hantzsch three-component reaction.
J Chin Chem Soc. 2021;1–7. https://doi.org/10.
1002/jccs.202000322