Melamine supported on hydroxyapatite-encapsulated-γ-Fe2O3: A novel superparamagnetic recyclable basic nanocatalyst for the synthesis of 1,4-dihydropyridines and polyhydroquinolines

Article abstract of DOI:10.1007/s11164-014-1808-1

In this paper, the preparation and characterization of hydroxyapatite-encapsulated γ-Fe₂O₃ nanoparticles functionalized with Melamine nanocomposite (γ-Fe₂O₃@HAp@Melamine) are presented. The resulting nanocomposite was characterized by infrared spectroscopy, scanning electron microscope, thermal gravimetric analysis, X-ray diffraction, vibrating sample magnetometer and elemental analysis. The catalytic activity of γ-Fe₂O₃@ HAp@Melamine as a magnetic powerful basic nanocatalyst was probed through one-pot synthesis of 1, 4-dihydropyridine and polyhydroquinoline derivatives through Hantzsch condensation reaction under solvent-free thermal conditions. The heterogeneous catalyst could be recovered easily by simple magnetic decantation and reused many times without significant loss of its catalytic activity.

Full text of DOI:10.1007/s11164-014-1808-1

Res Chem Intermed
DOI 10.1007/s11164-014-1808-1
Melamine supported on hydroxyapatite-encapsulated-
c-Fe2O3: a novel superparamagnetic recyclable basic
nanocatalyst for the synthesis of 1,4-dihydropyridines
and polyhydroquinolines
•
Sedighe Igder Ali Reza Kiasat
Mohamad Reza Shushizadeh
•
Received: 9 May 2014 / Accepted: 6 September 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract In this paper, the preparation and characterization of hydroxyapatite-
encapsulated c-Fe2O3 nanoparticles functionalized with Melamine nanocomposite
(c-Fe2O3@HAp@Melamine) are presented. The resulting nanocomposite was
characterized by infrared spectroscopy, scanning electron microscope, thermal
gravimetric analysis, X-ray diffraction, vibrating sample magnetometer and ele-
mental analysis. The catalytic activity of c-Fe2O3@ HAp@Melamine as a magnetic
powerful basic nanocatalyst was probed through one-pot synthesis of 1, 4-dihy-
dropyridine and polyhydroquinoline derivatives through Hantzsch condensation
reaction under solvent-free thermal conditions. The heterogeneous catalyst could be
recovered easily by simple magnetic decantation and reused many times without
significant loss of its catalytic activity.
Keywords Magnetic basic nanocatalyst Á Nano c-Fe2O3 supported Melamine Á
c-Fe2O3@HAp Á 1,4-Dihydropyridines Á Polyhydroquinolines
Introduction
A long-standing goal in catalysis has been the simple recovery and reuse of highly
active homogeneous catalysts via surface grafting to heterogeneous supports [1, 2].
Although the ability of heterogeneous catalysts has been demonstrated successfully
in many reactions, the tedious recycle of catalysts via filtration and the inevitable
loss of solid catalyst in the separation process limited their application [3–6].
S. Igder Á A. R. Kiasat (&)
Chemistry Department, College of Science, ShahidChamran University, 61357-4-3169 Ahvaz, Iran
e-mail: akiasat@scu.ac.ir
M. R. Shushizadeh
Faculty of Chemistry, Jundishapur University of Medical Sciences, Ahvaz, Iran
123

S. Igder et al.
Nowadays, to further address the issue of recyclability and reusability, magnetic
nanocarriers have been developed. The magnetic nature of these heterogeneous
nanocarriers allows for easy recovery and recycling of the catalysts by an external
magnetic field, which may optimize operational costs and enhance product purity
[7–9].
It is known that iron oxides, magnetite (Fe3O4) and maghemite (c-Fe2O3), are
inherently biocompatible and are amenable to post-synthesis surface modification,
which makes them excellent candidates for many important applications [10–14].
Although magnetic iron oxide nanoparticles are non-toxic and could be easily
synthesized by co-precipitation methods, their applications have been limited due to
low chemical and thermal stability in environmental conditions. Thus, the coating of
these nanomagnets with an oxygen-impermeable sheath is a necessary prerequisite
for their potential use in biomedical and catalyst support applications [15, 16]. Due
to good chemical stability, high surface area, and easy synthesis, hydroxyapatite-
coated magnetic nanoparticles have recently been introduced and used as a
heterogonous catalytic support [17–19].
On the other hand, heterocyclic compounds embedded with nitrogen are
prevalent in nature, and present in numerous natural products and pharmaceutical
leads. Among the nitrogen heterocycles, 1, 4-dihydropyridine (DHP) and polyhy-
droquinoline (PHQ) derivatives exhibit a wide range of notable biological properties
which expand their applications as vasodilator, antitumor, bronchodilator, antiath-
erosclerotic, geroprotective and hepatoprotective agents [20–25]. Moreover, these
compounds exhibit several medicinal applications which include neuroprotectant,
platelet anti-aggregatory activity, and chemosensitizer acting in tumor therapy [26–
31]. Thus, the development of simple synthetic routes for these nitrogen-containing
heterocyclic compounds from readily available reagents is an important task in
organic synthesis.
The straightforward procedure for this goal, first reported by Arthur Hantzsch in
1882, involves three-component, one-pot cyclocondensation of a b-ketoester with
an aldehyde and a nitrogen donor either in acetic acid or in refluxing ethanol [32].
Due to the some limitations of the Hantzsch method for the synthesis of different
substituted biologically active DHPs, recently, several methods with improved
procedures have been devoted to the preparation of DHP [33–37] and PHQ [38–40].
Although most of these processes offer distinct advantages, they have one or more
drawbacks such as unsatisfactory yields, acidic catalysts, prolonged reaction times,
tedious work-up, harsh reaction conditions, relatively expensive reagents, environ-
mentally toxic catalysts and the use of large quantities of volatile organic solvents.
Consequently, there is scope for further modification towards mild reaction
condition, increased variation of the substituents and improved yields.
By considering all the above-mentioned points and recent reports for the
application of supported Melamine on the surfaces of nanoparticles [41, 42], the aim
of this presented protocol is to highlight the synergistic effects of the combined use
of multicomponent reactions, MCRs, and reactions under solvent-free conditions
with a heterogeneous magnetic nanocatalyst for the development of new eco-
compatible strategy for heterocyclic synthesis. In that regard, we designed, for the
first time, hydroxyapatite-encapsulated c-Fe2O3 nanoparticles functionalized with
123

Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
Melamine nanocomposite (c-Fe2O3 @HAp@Melamine) and investigated its
performance as a magnetic powerful basic nanocatalyst for the synthesis of DHP
and PHQ derivatives through one-pot Hantzsch condensation reaction under
solvent-free thermal conditions.
Experimental
General remarks
Iron (II) chloride tetrahydrate (99 %), iron (III) chloride hexahydrate (98 %),
aldehydes and other chemical materials were purchased from Fluka and Merck and
used without further purification. Products were characterized by comparison of
their physical data [43–47] and IR and 1H NMR and 13C NMR spectra with known
samples. NMR spectra were recorded in CDCl3 on a Bruker Advance DPX
400 MHz instrument spectrometer using TMS as internal standard. The purity
determination of the products and reaction monitoring were accomplished by TLC
on silica gel polygram SILG/UV 254 plates. The FT-IR spectra of c-Fe2O3@ HAp
and c-Fe2O3@HAp@Melamine were measured as potassium bromide discs on a
BOMEM MB-Series 1998 FT-IR Spectrophotometer. The particle morphology was
examined by SEM. The TGA curve of the nanocomposite was recorded on a BAHR,
SPA 503 at heating rates of 10 °C min-1. The crystal structure of the
nanocomposite was examined using a PW-1840 Philips diffractometer at room
˚
temperature utilizing Cu Ka radiation wavelength of k = 1.5418A. The peak
position and intensities were obtained between 10° and 80° with a velocity of 0.02°
per second. For magnetization measurement, a vibrating sample magnetometer
(VSM) (KavirKashanMagnatics, Iran) was used at room temperature.
Synthesis of HAp-encapsulated-c-Fe2O3[Fe2O3@HAp]
Fe2O3@HAp was synthesized according to the previously reported method [41].
FeCl2.4H2O (1.85 mmol) and FeCl3.6H2O (3.7 mmol) were dissolved in deionized
water (30 mL) under Ar atmosphere at room temperature and the resulting solution
was added to a 25 wt% NH4OH solution (10 mL) with vigorous mechanical stirring.
A black precipitate of Fe3O4 was produced instantly. In order to obtain small and
uniform Fe3O4 particles, the drop rate of NH4OH was controlled precisely by a
constant dropper and the drop rate was 1 mL min-1. After 15 min, 100 mL of
Ca(NO3)2Á4H2O (33.7 mmol, 0.5 M) and (NH4)2HPO4 (20 mmol, 3.0 M) solutions
adjusted to pH 11 were added drop-wise to the obtained precipitate over 30 min
with mechanical stirring.
The resulting milky solution was heated to 90 °C. After 2 h, the mixture was
cooled to room temperature and aged overnight. The dark brown precipitate formed
was filtered, washed repeatedly with deionized water until the water was neutral,
and then air-dried under vacuum at room temperature. The synthesized sample was
calcined at 300 °C for 3 h, giving a reddish-brown powder.
123

S. Igder et al.
Synthesis of Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
[Fe2O3@HAp@Melamine]
For introducing of isocyanate groups onto the surface of the Fe2O3@HAp, the core/
shell magnetic nanostructure (0.5 g) was dispersed in dry DMF (15 mL) by
sonication and then HMDI (1.36 mL, 8.5 mmol) in dry DMF (5 mL) was added
drop-wise to the mixture. After mechanically agitation of mixture for 3 h, to graft
Melamine onto the surface, Melamine (1.5 g, 8.5 mmol) was dissolved in dry DMF
(15 mL) and added drop-wise to the reaction mixture. The mixture was stirred at
70 °C for 3 h. The precipitate was separated by magnetic decantation and washed
with CCl4 several times.
Basic capacity of c-Fe2O3@HAp@Melamine
The basic capacity of Fe2O3@HAp@Melamine was calculated based on titration of
the proton-exchanged brine solutions. To an aqueous solution of NaCl (1 M,
0.025 L) with an initial pH 5.9, the Fe2O3@HAP@Melamine (100 mg) was added
and the resulting mixture stirred for 24 h after which the pH of solution increased to
7.29. This is equal to a basic capacity of 7.01 9 10-6 mmol basic sites/g of basic
nanocatalyst. Additionally, this result confirmed by back-titration analysis of the
catalyst.
General procedure for the synthesis of 1, 4-dihydropyridine
A mixture of ethyl acetoacetate (0.26 g, 2 mmol), ammonium acetate (0.115 g,
1.5 mmol), aromatic aldehyde (1 mmol), and Fe2O3@HAP@Melamine (0.15 g)
was heated at 80 °C. After satisfactory completion of the reaction and cooling, the
reaction mixture was washed with hot ethel acetate and the catalyst was removed by
a magnetic field. The solid residue was isolated and purified by recrystallization in
hot EtOH. The formation of products was related by comparing the IR and NMR
data with authentic samples and literature data.
Selected spectral data for the synthesis of 1, 4-dihydropyridine derivatives
Diethyl
4-(4-cyanophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate:
1
(Table 2-Entry 4)Yield: 90 %; H-NMR(400 MHz, CDCl3): d = 1.2 (t, 6 H), 2.5
(s, 6 H), 4.11 (q, 4 H), 5 (s, 1 H), 5.88 (s, 1 H, NH), 7.2–8.3 (m, 4 H). 13C-NMR
(100 MHz, CDCl3): d = 13.95, 19.34, 42.12, 60.96, 100.8, 111.9, 117.4, 127.7,
131.1, 139.3, 146.5, 147.50. IR (KBr): 3,360, 2,231.89, 1,698.93, 1,681.04,
1,491.04, 1,212.61, 780 cm-1
.
Diethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate:
(Table 2-Entry 9)Yield: 93 %;. 1H-NMR(400 MHz, CDCl3): d = 1.24 (t, 6 H), 2.33
(s, 6 H), 4.11 (q, 4 H), 4.97 (s, 1 H), 5.88 (s, 1 H, NH), 7.19–7.23 (m, 4 H). 13C-
NMR (100 MHz, CDCl3): d = 14.3, 19.6, 39.2, 59.9, 103.8, 127.9, 129.4, 131.7,
144.1, 146.3, 167.5. IR (KBr): 3,360, 1,689, 1,651, 1,487, 1,212, 1,122, 789 cm-1
.
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Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
General procedure for the synthesis polyhydroquinoline
A mixture of aromatic aldehyde (1 mmol), dimedone (0.14 g, 1 mmol), ethyl
acetoacetate (0.13 g, 1 mmol), ammonium acetate (0.115 g, 1.5 mmol), and
Fe2O3@HAP@Melamine (0.15 g) was heated at for 80 °C. Completion of the
reactions was monitored by TLC (n-hexan/ethyl acetate 10:3). After satisfactory
completion of the reaction and cooling, the reaction mixture was washed with hot
ethel acetate and the catalyst was removed by a magnetic field. The solid residue
was isolated and purified by recrystallization in hot EtOH.
Spectral data for the synthesis of PHQ derivatives
Ethyl 2,7,7-trimethyl-5-oxo-4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-3-quinoline-
carboxylate (Table 3-Entry 6): Yield: 88 %; M.p 230–232 °C (Ref [42]
1
233–235 °C); H-NMR (400 MHz, CDCl3): d = 1.06 (s, 3H), 1.09 (s, 3H), 1.23
(t, 3H), 2.56 (2H), 2.62(2H), 2.80 (s, 3H), 4.50 (q, 2H), 4.74 (s, 1H), 5.2 (s, 1H),
7.15–7.27 (m, 4H); 13C-NMR(100 MHz, CDCl3): d = 13.95, 16.34, 29.81, 33.31,
38.46, 42.10, 49.81, 60.96, 100.29, 107.65, 127.31, 128.54, 141.22, 142.77, 150.42,
166.49, 196.71. IR (KBr, cm-1) 3,273, 3,209, 3,080.51, 2,945, 1,703.89, 1,649.5,
1,475, 1,367, 1,227, 1,105, 857.
Ethyl 2,7,7-trimethyl-5-oxo-4-(4-phenylphenyl)-1,4,5,6,7,8-hexahydro-3-quino-
linecarboxylate (Table 3-Entry 11): Yield: 97 %; M.p206–208 °C; 1H-NMR
(400 MHz, CDCl3): d = 1.07 (s, 3H), 1.09 (s, 3H), 1.27 (t, 3H), 2.61 (2H),
2.79(2H), 2.95 (s, 3H), 4.50 (q, 2H), 4.91 (s, 1H), 5.7 (s, 1H), 7.2–7.49 (m, 9H); 13C-
NMR(100 MHz, CDCl3): d = 13.90, 16.54, 29.88, 33.35, 38.70, 42.20, 49.81,
60.96, 124.68, 126.76, 128.19, 128.84, 139.03, 140.05, 142.77, 144.92, 150.42,
166.49, 196.71.IR (KBr, cm-1) 3,302, 3,195, 3,070, 3,218, 1,692, 1,605, 1,475,
1,360, 1,227,1,111, 870.
Results and discussion
Hydroxyapatite-encapsulated -c-Fe2O3, Fe2O3@HAp@Melamine, was synthesized
according to the procedure shown in Scheme 1. Maghemitenanocrystallities are
commonly synthesized by coprecipitation of ferrous and ferric ions in a basic
aqueous solution followed by thermal treatment. Because of the sensitivity of the c-
Fe2O3, its surface was first coated with hydroxyapatite [Ca10(PO4)6(OH)2, HAp].
Hexamethylenediisocyanate (HMDI), a widely used linker for fabrication of drug
delivery vehicles with reportedly a very low degree of toxicity, was used in the
present work for conjugating Melamine onto the surface of the c-Fe2O3@HAp. For
grafting Melamine onto the surface of the c-Fe2O3@HAp, the isocyanate groups
were preliminarily bonded onto the surface by the reaction of hydroxyl groups of c-
Fe2O3@HAp with the isocyanate group of HMDI, c-Fe2O3@HAp-NCO. After that,
the Melamine was reacted with the core/shell magnetic nanostructure.
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S. Igder et al.
FeCl2.4H2O
+
OH
NH4OH
Ca(NO3)2.4H2O
(NH4)2HPO4
Fe3O4
OH
OH
FeCl3.6H2O
3000C
p
A
O
O
H
C
N
N
C
Fe2O3
O P OH
O
O
p
A
H
NH2
N
N
H2N
N
p
A
O
O
H
N
NH2
Fe2O3
O P O
O
NH
C
O
p
A
H
NH2
p
A
O
O
N
H
H
N
N
NH
Fe2O3
O P O
O
NH
N
p
A
NH2
O
H
Scheme 1 Synthesis of c-Fe2O3@HAp@Melamine
Preparation of c-Fe2O3@HAp@Melamine was confirmed by FT-IR analysis.
Figures 1a–c shows the IR spectra of the c-Fe2O3@HAp, c-Fe2O3@HAp-NCO and
c-Fe2O3@HAp@Melamine, respectively. According to the spectra, characteristic
absorption bands due to the bending vibration mode of O–P–O surface phosphate
groups in the hydroxyapatite shell were observed at 567 and 607 cm-1 which
overlap with Fe–O stretching.
In addition,the adsorption band at 1,041 cm-1 can be attributed to the stretching
of the P–O bond. The IR spectrum of the c-Fe2O3@HAp@Melamine also showed
characteristic adsorption bands at 3,330 and 1,630 cm-1 corresponding to the NH
and C = O groups.
The NHCO stretching was also observed at 1,570 cm-1. It is worth noting that
the disappearance of the isocyanate peak (1b) in the IR spectrum of Fe2O3@-
HAP@Melamine at about 2,270 cm-1 was also observed. Thus, all the above
results indicate that Melamine has been grafted successfully onto the surface of
hydroxyapatite-encapsulated c-Fe2O3 nanoparticles.
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Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
Fig. 1 The FT-IR spectra of c-Fe2O3 @HAP (a), c-Fe2O3 @HAP-NCO (b) and
Fe2O3@HAP@Melamine (c)
Fig. 2 XRD spectrum of the c-Fe2O3@HAp (red) and c-Fe2O3@HAp@Melamine (blue), Yellow circle:
c-Fe2O3, Pink oval: HAp, Green box: Melamine. (Color figure online)
The c-Fe2O3@HAp@Melamine nanocomposite was also characterized by ion
exchange pH analysis. The ion-exchange pH analysis demonstrated a loading of
7.01 9 10-6 mmol basic sites g-1
.
c-Fe2O3@HAp@Melamine was subject to further structural characterization
with XRD (Fig. 2). The peak positions and their relative intensities were determined
from a comparison of registered standard JCPDF cards (00-047-1409: c-Fe2O3,
00-003-0747: HAp, 00-002-0164: Melamine) available in the system software with
the obtained powder diffraction files. The same peaks were observed in both of the
bare and Melamine-loaded magnetic particle.
123

S. Igder et al.
Fig. 3 The TGA analysis of c-Fe2O3@HAp@Melamine
Table 1 Elemental analysis data of c-Fe2O3@HAp@Melamine
Material
C (W %)
27.84
H (W %)
3.83
N (W %)
46.31
Fe2O3@HAp@Melamine
Figure 3 shows the TGA analysis of c-Fe2O3@HAp@Melamine one can observe
from the thermogram that the sample exhibits a three-stage degradation pattern over
the range of 30–630 °C. The first weight loss of 16.7 % below 200 °C which might
be due to the loss of the adsorbed water as well as dehydration of the surface OH
groups. The second weight loss step of about 43.6 % in the region of 310–375 °C
was due to the cleavage of the urethane linkage, which is quite high compared to
conventional urethanes which generally start to decompose around 200–220 °C.
The enhanced thermal stability of c-Fe2O3@HAp@Melamine is attributed to its
cross-linked nature. The last stage of degradation in the region of 606–637 °C,
probably, is due to thermal decomposition of Melamine. Thus, the TGA curves also
confirm the successful grafting of Melamine onto the magnetic surface of
hydroxyapatite-encapsulated -c-Fe2O3. The total weight loss over the full temper-
ature range is estimated to be 84.5 % due to the loss of the adsorbed water and
organic units. The content of the organic units was also defined by elemental
analysis data (Table 1) and is in agreement with thermogravimetric analysis data.
The amount of c -Fe2O3@HAp was evaluated by deducting the total weight loss,
whose value was obtained from the TGA curve. From these data, the amount of c-
Fe2O3@HAP is estimated to be 15.5 %.
Atomic absorption spectroscopy (AAS) was also applied to assess the Fe content
of the nanocomposite. A GBC (Avanta) Atomic Absorption spectrometer fitted with
a Fe hollow cathode lamp (Unicam, Franklin, MA, USA) was used to perform
123

Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
Fig. 4 TEM image of c-Fe2O3 @HAp@Melamine
Fig. 5 SEM images of a c-Fe2O3@HAp, and b c-Fe2O3@HAp@Melamine
123

S. Igder et al.
Fig. 6 VSM curve of a c-Fe2O3 @HAp and b c-Fe2O3 @HAp@Melamine at room temperature
Fig. 7 Magnetic recovery of the basic nanocatalyst at the end of reactions
R
R
O
O
EtO
OEt
CHO
+
O
O
O
O
Fe2 O3@HAp@Melamine (0.15g)
800C/Solvent Free
EtO
H3C
OEt
N
CH3
H
NH4OAc
Scheme 2 c-Fe2O3 @HAp@Melamine catalyzed synthesis of 1,4-dihydropyridines
atomic absorption measurements. The wavelength of 248.3 nm and spectral
bandpass of 0.50 nm were used throughout. An air–acetylene flame was used for
the determination of the Fe ions. According to the AAS, the nanocomposite contains
2.5 % Fe2O3.
123

Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
Table 2 Optimization of the
amount of catalyst
Entry
Amount
Time(min)
Yield(%)
of catalyst (mol %)
1
2
3
4
5
0
240
40
12
60
79
94
93
0.05
0.1
0.15
0.2
30
15
15
By using the thermogravimetric and AAS data, the empirical formula of the
catalyst can be calculated as c-Fe2O3(3)@HAp(1)/H2O(180)@ C11N8O2H19(44.36).
Transmission electron microscopy (TEM) revealed that the iron oxide nanopar-
ticles had been entrapped in the hydroxyapatite shell successfully, in which an
average particle size is about 45–60 nm and the diameter of the magnetic core is
about 14–29 nm, much smaller than the sizes obtained from the scanning electron
microscope (SEM) measurements (Fig. 4).
Figure 5 shows SEM photograph of the c-Fe2O3@HAp and c-Fe2O3@-
HAp@Melamine composite particles. This photograph indicates that, although c-
Fe2O3@HAp particles have a round shape, after grafting Melamine onto its surface
by HMDI, the morphology changed.
It is of great importance that the nanocomposite should possess sufficient
magnetic and super-paramagnetic properties for its practical applications. As shown
in Fig. 6, the isothermal magnetization curves of c-Fe2O3@HAp, and c-Fe2O3@-
HAp@Melamine displayed a rapid increase with nmincreasing applied magnetic
field, with a saturation magnetization (Ms) value of 4.99 and 0.96 emu/g,
respectively. Reversibility in the graphs shows that the nanocomposites did not
aggregate after the magnet device was removed. The magnetization of the c-
Fe2O3@HAp@Melamine was also revealed by the easy attraction with an external
magnet (Fig. 7).
To evaluate the catalytic activity of c-Fe2O3@HAp@Melamine as a magnetic
powerful basic nanocatalyst and with an aim to develop a simple practical method
for the synthesis of a large range of 1,4-dihydropyridines, through multicomponent
reaction, initially, three-component coupling reaction of ethyl acetoacetate and
benzaldehyde with ammonium acetate in a 2:1:1.5 ratios as a Hantzsch model
reaction (Scheme 2) was examined to determine whether the use of c-Fe2O3@-
HAp@Melamine was efficient and to investigate the optimized conditions.
After some experiments, it was found that for efficient coupling reaction presence
of 0.15 g of catalyst under solvent-free conditions at 80 °C is the best condition
(15 min, 94 %). Using lower amounts of catalyst, the corresponding DHP was
produced in lower yield, while higher amounts of catalyst have no marked effect on
the reaction time and yield (Table 2). In order to show the role of the catalyst, a
similar reaction in the absence of the catalyst was also examined. Under this
123

S. Igder et al.
Table 3 Solvent-free synthesis of 1, 4-dihydropyridine catalyzed by c-Fe2O3@HAp@Melamine
Entry
Aldehyde
Product
Time (min)
Yield(%)a
O
C
O
1
15
94
EtO
H3
OEt
CH3
CHO
NO2
N
H
NO2
O
C
O
2
3
10
40
99
83
EtO
EtO
EtO
OEt
CH3
CHO
CH3
H3
N
H
CH3
O
O
OEt
CH3
CHO
CN
H3C
N
H
CN
O
C
O
4
5
6
10
20
90
90
94
80
OEt
CHO
H3
N
H
CH3
Br
EtOOC
COOEt
Br
CHO
H3C
N
H
CH3
OCH3
OCH3
O
O
EtO
H3
OEt
CH3
CHO
OH
C
N
H
OH
O
C
O
7
30
90
83
91
EtO
H3
OEt
CH3
CHO
N
H
N(CH3
)
2
N(CH3
)
2
O
C
O
8
EtO
OEt
CH3
CHO
Cl
H3
N
H
Cl
O
O
9
15
15
93
82
EtO
H3
OEt
CHO
C
O
N
H
CH3
NO2
10
NO2
O
EtO
H3
OEt
CH3
CHO
C
N
H
a
Isolated yield
123

Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
R
R
CHO
O
OEt
O
O
Fe2O3@HAp@Melamine (0.15 g)
800C/Solvent Free
O
O
OEt
CH3
+
O
N
H
NH4OAc
Scheme 3 c-Fe2O3@HAp@Melamine catalyzed synthesis of polyhydroquinoline derivatives
condition, the reaction led to the formation of the desired product in low yield after
a long reaction time.
Subsequently, with optimal conditions in hand, 2:1:1.5 molar ratios of ethyl
acetoacetate, aldehyde and ammonium acetate and 0.15 g of Fe2O3@HAp@Mel-
amine at 80 °C under solvent-free conditions, the generality and synthetic scope of
this coupling protocol were demonstrated by synthesizing a series of DHPs having
different steric and electronic properties. As Table 3 shows, yields are good to
excellent in most cases.
With this promising result in hand, to evaluate the generality and synthetic scope
of this coupling protocol, a series of PHQ derivatives under the optimized reaction
conditions was also prepared through one-pot four-component coupling reaction of
ethyl acetoacetate, dimedone and benzaldehyde with ammonium acetate in 1:1:1:1.5
ratios (Scheme 3). The overall process involves the Knoevenagel condensation of
dimedone with aryl aldehydes, followed by in situ Michael addition of ethyl
acetoacetate in a single operation.
As shown in Table 4, in all cases, heterocyclic, conjugated and aromatic
aldehydes with substituents carrying either electron-donating or electron-withdraw-
ing groups reacted successfully and gave the expected products in good to excellent
yields and short reaction times. The kind of aldehyde has no significant effect on the
reaction. It was indicated that both electron-rich and electron-deficient aldehydes
reacted well, mostly leading to high yields of products.
The recyclability of the catalyst in the reaction of benzaldehyde, ethyl
acetoacetate, dimedone and ammonium acetate in the presence of c-Fe2O3@-
HAp@Melamine was also checked. After the completion of the reaction, the
reaction mixture was cooled to room temperature and hot ethanol was added. The
catalyst was concentrated on the sidewall of the reaction vessel using an external
magnet, the organic phases were separated by decantation, and the residual catalyst
in the reaction vessel was washed and dried and then subjected to the next run
directly. In 6 consecutive runs, the conversion stayed higher than 83 %, with no
detectable loss (Fig. 8).
123

S. Igder et al.
Table 4 Solvent-free synthesis of polyhydroquinolinecatalyzed by c-Fe2O3@HAp@Melamine
°
Entry
[Ref]
a
M.P. C
Aldehyde
Product
Time (min)
Yield(%)
Observed
202–204
Reported
O
O
1
2
5
89
91
203–20521
OEt
CH3
CHO
NO2
N
H
NO2
242–244 44
O
O
5
238–240
OEt
CH3
CHO
CH3
N
H
CH3
260–263 27
207–209 44
233–23521
O
O
3
4
5
10
10
20
89
89
95
260–262
207–209
229–231
OEt
CHO
N
H
CH3
O
Cl
Cl
COOEt
CHO
N
H
CH3
N(CH3)2
N(CH3
)
2
O
O
OEt
CH3
CHO
N
H
Cl
Cl
233–23546
O
O
6
5
88
230–232
OEt
CH3
CHO
N
H
NO2
NO2
O
O
7
10
85
178–180
172–17427
OEt
CHO
N
H
CH3
123

Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
Table 4 continued
°
Entry
[Ref]
a
M.P. C
Aldehyde
Product
Time (min)
Yield(%)
Observed
Reported
OEt
OEt
O
O
8
15
86
oil
–
OEt
CH3
CHO
N
H
O
O
9
10
10
87
95
200–202
192–194
203–20545
OEt
CHO
N
H
CH3
O
Br
NRb
Br
10
COOEt
CHO
N
H
CH3
11
10
97
206–208
NRb
O
O
OEt
CH3
CHO
N
H
O
O
O
O
CHO
12
30
79
240–242
245–24747
OEt
CH3
N
H
CN
CN
NRb
O
O
13
10
95
210–213
OEt
CH3
CHO
N
H
OH
OH
OH
OH
O
O
14
40
72
oil
–
OEt
CH3
CHO
N
H
123

S. Igder et al.
Table 4 continued
°
Entry
a
M.P. C
Aldehyde
[Ref]
Product
Time (min)
Yield(%)
Observed
252–254
Reported
Br
Br
252–25427
O
O
15
10
82
OEt
CHO
N
H
CH3
O
NO2
204–20621
NO2
16
10
10
85
81
204–206
COOEt
CHO
N
H
CH3
Br
Br
O
OH
OH
17
oil
–
COOEt
CHO
N
H
CH3
OCH3
OCH3
O
O
18
10
15
84
94
255–257
255–25727
OEt
CH3
CHO
N
H
O
OH
OH
19
oil
–
COOEt
CHO
N
H
CH3
a
Isolated yield
140
120
100
80
TOF
(min^-1)
60
40
Yield
(%)
20
0
1
2
3
4
5
6
Number of Runs
Fig. 8 Recyclability of the c-Fe2O3@HAp@Melamin
123

Melamine supported on hydroxyapatite-encapsulated-c-Fe2O3
Conclusions
In summary, a magnetically separable basic nanocatalyst was successfully prepared
through the immobilization of Melamine on hydroxyapatite-encapsulated c-Fe2O3
nanoparticles. The catalytic activity of c-Fe2O3@HAp@Melamine was probed
through one-pot synthesis of 1,4-dihydropyridines and PHQ derivatives through
Hantzsch condensation reaction under solvent-free thermal conditions. The catalyst
shows an environmental friendly character, with recyclability of the catalyst making
for the development of a greener strategy. Moreover, the procedure offers several
advantages including high yields, operational simplicity, clean reaction conditions
and minimum pollution of the environment, which makes it a useful and attractive
process for the synthesis of 1,4-dihydropyridines and PHQ derivatives.
Acknowledgment We are grateful to the Research Council of ShahidChamran University for financial
support.
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