Decoration of β-CD on Fe3O4@Ag core–shell nanoparticles as a new magnetically recoverable and reusable catalyst for the synthesis of 3,4-dihydropyrimidinones and 2,4-dihydropyrano[2,3-c]pyrazoles in H2O

Article abstract of DOI:10.1016/j.ica.2018.11.009

This report provides a description of the preparation and characterization of a Fe₃O₄@Ag-β-CD composite as a new magnetically recoverable catalyst for the synthesis of a number of biologically and pharmaceutically significant organic

Full text of DOI:10.1016/j.ica.2018.11.009

Accepted Manuscript
Research paper
Decoration of β-CD on Fe O @Ag core-shell nanoparticles as a new magneti-
3
4
cally recoverable and reusable catalyst for the synthesis of 3,4-dihydropyrimi-
dinones and 2,4-dihydropyrano[2,3-c]pyrazoles in H O
2
Fatemeh Mirhashemi, Mohammad Ali Amrollahi
PII:
S0020-1693(18)31530-5
https://doi.org/10.1016/j.ica.2018.11.009
ICA 18624
DOI:
Reference:
To appear in:
Inorganica Chimica Acta
Received Date:
Revised Date:
Accepted Date:
17 September 2018
23 October 2018
6 November 2018
Please cite this article as: F. Mirhashemi, M. Ali Amrollahi, Decoration of β-CD on Fe O @Ag core-shell
3
4
nanoparticles as a new magnetically recoverable and reusable catalyst for the synthesis of 3,4-dihydropyrimidinones
and 2,4-dihydropyrano[2,3-c]pyrazoles in H O, Inorganica Chimica Acta (2018), doi: https://doi.org/10.1016/j.ica.
2
2
018.11.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Decoration of β-CD on Fe O @Ag core-shell nanoparticles as a new magnetically
3
4
recoverable and reusable catalyst for the synthesis of 3,4-dihydropyrimidinones and
,4-dihydropyrano[2,3-c]pyrazoles in H O
2
2
Fatemeh Mirhashemi, Mohammad Ali Amrollahi*
Department of Chemistry, Yazd University, P. O. Box: 89195-741, Yazd, Iran. Fax: 98-35-38210644; E-mail:
mamrollahi@yazd.ac.ir
Abstract. This report provides a description of the preparation and characterization of a Fe O @Ag-
3
4
β-CD composite as a new magnetically recoverable catalyst for the synthesis of a number of
biologically and pharmaceutically significant organic compounds in aqueous medium. The magnetic
composite was characterized by TEM, EDS, XRD, VSM and FT-IR techniques. The result of the
TEM analysis shows that the average size of Fe O @Ag-β-CD is less than 30 nm. Application of this
3
4
hybrid material, as a catalyst, was studied efficiently in the one-pot multicomponent synthesis of 3,4-
dihydropyrimidinone and 2,4-dihydropyrano[2,3-c]pyrazole derivatives. The main advantages of our
method are simple isolation of products, easy recovery of the magnetic catalyst by an external magnet,
reusability of the catalyst, and use of water as a green solvent.
Keywords: β-CD; heterogeneous magnetic catalyst; 3,4-dihydropyrimidinones; 2,4-
dihydropyrano[2,3-c]pyrazoles; inclusion complex; Fe O @Ag-β-CD nanocomposite
3
4
Introduction
The interest in nanoparticles, owing to their high surface area, excellent accessibility, low toxicity
and high biocompatibility, has grown substantially [1-5]. Magnetite (Fe O ) nanoparticles exhibit
3
4
many interesting properties that can be exploited in a variety of applications such as catalysis and in
biomedicine [6-8]. Pure Fe O nanoparticles are likely to form large aggregates with fewer activating
3
4
groups and are easily oxidized or dissolved in acidic medium [9]. In order to overcome these
problems, Fe O nanoparticles are coated with various organic and inorganic materials [10-16]. β-
3
4
Cyclodextrin (β-CD), a naturally occurring cyclic oligosaccharide, was used to prevent magnetite
nanocomposites from aggregating and represents an attractive choice for the preparation of novel
composites. Low cost, solubility in water [0.0163 mol L-1 (25 C)], low toxicity, recyclability,
reusability, and also the formation of inclusion complexes with a range of molecules are other
advantages of this cyclic oligosaccharide [17-22].
o
The use of water as a solvent for organic synthesis has attracted considerable attention due to
advantages such as low cost, wide availability, non-toxicity and non-flammability, thus providing
more economic and sustainable synthetic routes [23]. However, one of the major disadvantages of
using water as a solvent is the low solubility of most organic substrates. This problem can be
overcome by the use of a decorated β-CD composite which consists of a hydrophobic cavity that can
form an inclusion complex and solubilize the organic substances in water. It is accepted that the
binding forces involved in the inclusion complex formation are Van der Waals interactions,
hydrophobic interactions, hydrogen bonding and electrostatic interactions between guest molecules
1

and β-CDs [24, 25]. Due to their hydrophobic cavity, β -CDs provide a microenvironment for organic
reactions [26], where they catalyze reactions through non-covalent interactions. Decorated β-CD
materials such as Fe O @β-CD [27], β-CD-Pd [28], Fe O -β-CD-Pd [29], Cu(II)-β-CD [30], and
3
4
3
4
Fe O @Cu(II)-β-CD [31] as organic-inorganic hybrid catalysts have been used to synthesize
3
4
organic compounds in aqueous solution.
,4-Dihydropyrimidinone and 2,4-dihydropyrano[2,3‐c]pyrazole derivatives, as important class of
3
heterocycles, have been synthesized under various methods [32-44]. However, these methods have
some limitations such as long reaction times, use of organic solvents, relatively low yield and non-
recoverable catalyst. In continuation of our previous study on the catalytic activity of nanocomposite
[
45], in this work, we wish to report the preparation and characterization of Fe O @Ag decorated β-
3 4
CD as a novel magnetic catalyst. The catalytic activity of the Fe O @Ag-β-CD nanocomposite was
3
4
also studied for the synthesis of 3,4-dihydropyrimidinone and 2,4-dihydropyrano[2,3‐c]pyrazole
derivatives by four-component reactions in aqueous medium.
Experimental
Materials and instrument
All commercial reagents were purchased from Aldrich, Fluka and Merck chemical companies and
used without any purification. The melting points were measured by a Büchi melting point B-540 B.
V.CHI apparatus and are uncorrected. Thin layer chromatography (TLC) was carried out by using
Merck 0.2 mm silica gel 60 F-254 Al plates. The FT-IR spectra were recorded as KBr pills on a
-1
Bruker Equinox spectrometer in the 400-4000 cm region. The NMR spectra were obtained on a
Bruker AC 500 Avance DPX spectrometer at 500 MHz for H and at 125 MHz for 13C NMR in
DMSO in the presence of tetramethylsilane as internal standard. Transmission electron microscopy
1
(TEM) was performed using a Zeiss EM10C with an accelerating voltage of 100 kV. EDS analysis
was carried out using Zeiss SIGMA VP-500. The X-ray diffraction (XRD) data were collected with a
Philips X-pert diffractometer equipped with a Cu-Ka radiation (( = 1.54 Å) in the 2θ range from 5 to
8
0°. The magnetic measurements were performed using vibrating sample magnetometer
Model VSM-4 inh.
Synthesis of β-CD containing Fe O @Ag core–shell nanoparticles
3
4
Synthesis of the Fe O nanoparticles
3
4
The magnetite Fe O nanoparticles were synthesized by the simple co-precipitation method as
3
4
reported in the literature [46]. Briefly, a mixture of FeCl ·6H O (5.4 g, 20 mmol) and FeCl ·4H O
3
2
2
2
(
1.99 g, 10 mmol) was dissolved in deionized water (20 mL) under the protection of N atmosphere
2
and underwent an ultrasound treatment for 15 min. Afterward, NH OH (25%, 15 mL) was added
4
drop-wise into this solution within 30 min with vigorous stirring. The result black precipitate was
2

isolated with the aid of a magnet and then washed with distilled water. The wet Fe O was dried at 70
3
4
°
C in an oven.
Synthesis of the Fe O @Ag nanocomposite coated with β-CD
3
4
The prepared Fe O nanoparticles (0.5 g) were dispersed in deionized water (10 mL) and then AgNO
3
3
4
solution (47 mM in EtOH/ 80 mL) was added. Thereafter, excess hydrazine (0.9 M) and NaOH
solution (1 M, 0.1 mL) were added sequentially under ultrasound treatment for 20 min. The
synthesized product was separated with an external magnet and then washed with distilled water and
finally dried at 90 °C. The prepared Fe O @Ag core-shell particles were dispersed in deionized water
3
4
(10 mL) and then β-CD (0.5 g) was added. The dispersion was stirred overnight. The suspension was
separated by with the aid of a magnet and dried at 90 °C in an oven.
General procedure for the synthesis of 3,4-dihydropyrimidinone derivatives
Aldehyde (1 mmol), ethyl acetoacetate (1 mmol, 0.13 g), urea (3 mmol, 0.18 g) and Fe O @Ag-β-CD
3
4
(
0.02 g) in H O (5 mL) were stirred for 2 h at 60 °C. After completion of the reaction, Fe O @Ag-β-
2
3
4
CD was separated from the mixture by using an external magnet and the precipitated product was
filtered. Thereafter for further purification the white product was recrystallized in EtOH and 3,4-
dihydropyrimidinone derivatives in good to high yields (85-97 %) were obtained.
General procedure for the synthesis of 2,4-dihydropyrano[2,3-c]pyrazole derivatives
A mixture of aldehyde (1 mmol), malononitrile (1 mmol, 0.06 g), ethylacetoacetate (1 mmol, 0.13 g),
hydrazine hydrate (2 mmol, 0.06 g) and Fe O @Ag-β-CD (0.02 g) was stirred in H O (5 mL) at 60
3
4
2
°
C. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst
was separated using an external magnet. Then, the obtained precipitate was recrystallized from
ethanol. The pure 2,4-dihydropyrano[2,3-c]pyrazole derivatives were obtained in good to excellent
yields (89-94%).
Results and discussion
Fe O @Ag-β-CD was synthesized via the following steps. Initially, magnetite nanoparticles
3
4
2
+
3+
(
Fe O ) were easily prepared via the chemical co-precipitation of Fe and Fe ions in basic solution.
3 4
Then, the prepared magnetite was coated with silver to obtain Fe O @Ag core-shell nanoparticles.
3
4
The silver-coated magnetic nanoparticles were used as precursor materials for the surface
modification by conversion to Fe O @Ag-β-CD through the treatment with β-CD. The newly
3
4
synthesized magnetic composite (Fe O @Ag-β-CD) showed high stability and great catalytic
3
4
performance in the synthesis of 3,4-dihydropyrimidinone and 2,4-dihydroprano[2,3-c]pyrazole
derivatives. Fe O nanoparticles were chosen as heterogeneous support because of their high surface
3
4
area, easy preparation and functionalization and also easy separation from the reaction mixture [16].
As previously mentioned, Fe O nanoparticles have a tendency to aggregate. In order to establish the
3
4
hydrophobic cavity on the surface of the Fe O @Ag core–shell nanoparticles, the synthesized
3
4
3

magnetic composite was coated with β-CD. The synthesized catalyst was highly active and stable,
possibly due to incorporating β-CD and Ag into Fe O nanoparticles.
3
4
Characterization of the novel catalyst (Fe O @Ag-β-CD)
3
4
The structure of Fe O @Ag-β-CD was characterized by FT-IR, SEM, TEM, elements mapping
3
4
analysis, XRD, and VSM techniques.
Figure 1 depicts the FT-IR spectra of Fe O (Fig. 1a), β-CD (Fig. 1b), Fe O @Ag (Fig. 1c), and
3
4
3
4
Fe O @Ag-β-CD (Fig. 1d). For Fe O , Fe O @Ag and Fe O @Ag-β-CD, the peaks of Fe–O bands
3
4
3
4
3
4
3
4
−
1
(
from magnetic nanoparticle cores) was observed at about 578 cm , proving the presence of Fe O in
3 4
the structure of these composites. The broad band around 3000–3500 cm−1 is assigned to the
−
1
-1
stretching vibrations of surface hydroxyl groups. For β-CD, the peaks at 1028 cm and 2926 cm are
attributed to the asymmetric C–O–C stretching and the C-H stretching, respectively. The peaks at
−
1
-1
1
020 cm and 2919 cm are attributed to the asymmetric C–O–C stretching and the stretching of the
C-H bonds indicating that the magnetic Fe O @Ag nanoparticles is coated by β-CD. No specific
3
4
IR signal was observed to indicate the presence of silver in the Fe O @Ag-β-CD composite.
3
4
3 4 3 4 3 4
Figure 1. FT-IR spectrum of (a) Fe O , (b) β-CD, (c) Fe O @Ag core-shell, and (d) Fe O @Ag-β-CD
Fig. 2 shows SEM and TEM images of Fe O @Ag-β-CD. These images were applied to investigate
3
4
the morphology and particle size of the composite. The TEM image of the Fe O @Ag-β-CD
3
4
composite shows nanoparticles with nearly spherical shape. The diameter of these nanoparticles was
found to be between 20 and 30 nm.
The energy-dispersive X-ray chemical maps acquired for the C, O, Fe and Ag elements are also
shown in Fig. 2. The X-ray maps of each constituent element present in the Fe O @Ag-β-CD
3
4
composite visualizes their distributions throughout the network.
4

Figure 2. SEM image of Fe
3
O
4
@Ag-β-CD (a), TEM image of Fe
3
O
4
@Ag-β-CD (b), EDX- Map image of
distribution of C (c), O (d), Fe (e) and Ag (f) in Fe
3
4
O @Ag-β-CD composite
Fig. 3 shows the magnetic characterization of Fe O (a) and Fe O @Ag-β-CD (b). The saturation
3
4
3
4
-1
magnetization values for Fe O and Fe O @Ag-β-CD are 60 and 12 emu g respectively. These
3
4
3
4
results indicate that the magnetization of Fe O decreased considerably by coating it with Ag and β-
3
4
CD. Even with this reduction in the saturation magnetization, the catalyst can still be efficiently
separated from solution with a permanent magnet.
5

3 4 3 4
Figure 3. VSM curves for (a) Fe O and (b) Fe O @Ag-β-CD
The EDS spectrum of the Fe O @Ag-β-CD confirms the presence of Fe, Ag, C and O species in the
3
4
composite (Fig 4). As it is clear, the intensity of the Ag peak is higher than that of the Fe peak, which
indicates that Ag is located outside the Fe particles.
3 4
Figure 4. EDS analysis of Fe O @Ag-β-CD nanoparticles
The structure of the Fe O @Ag-β-CD nanoparticles was also studied by XRD analysis (Fig. 5). All
3
4
positions and diffraction peaks for Fe O @Ag-β-CD match well with those of the standard XRD
3
4
patterns of Fe O (JCPDS card No. 00-001-1111) and Ag (JCPDS card No. 00-001-1167). This shows
3
4
that the structure of the Fe O in the Fe O @Ag-β-CD catalyst is that of a cubic spinel and that the
3
4
3
4
coating of the surface of the Fe O with Ag and then β-CD does not change the phase of the magnetic
3
4
nanoparticles. There were seven characteristic peaks in the XRD pattern of Fe O @Ag-β-CD. The
3
4
6

signals at 2θ = 30.34, 38.17 and 57.19 represent the nano-Fe O structure and the other peaks at 2θ =
3
4
3
8.17, 44.34, 64.50 and 77.44 prove the presence of Ag.
3 4 3 4
Figure 5. XRD patterns of (a) Fe O nanoparticles, (b) Ag nanoparticles and (c) Fe O @Ag-β-CD nanoparticles
Catalytic activity of Fe O @Ag-β-CD nanocomposite for the synthesis of 3,4-
3
4
dihydropyrimidinones
After preparation and characterization of Fe O @Ag-β-CD, it was applied for the synthesis of ethyl 6-
3
4
methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate. Reaction of benzaldehyde,
ethylacetoacetate and urea in the presence of the Fe O @Ag-β-CD nanocomposite was selected as a
3
4
model reaction. The model reaction behaviour was studied by adjusting various parameters such as
type of catalyst, amount of the catalyst and temperature. The results are summarized in Table 1. We
explored the catalytic efficiency of β-CD and the other composites such as Fe O @Ag and
3
4
Fe O @Ag-β-CD (Table 1, entries 1-3). These results showed that the Fe O @Ag-β-CD as a
3
4
3
4
magnetic catalyst is the most effective catalyst for the synthesis of 3,4-dihydropyrimidinones. To
optimize the required catalyst amount, the model reaction was carried out in the presence of various
amount of Fe O @Ag-β-CD (Table 1, entries 3-6). Based on the results, the use of 0.02 g of catalyst
3
4
results in the best activity. The effect of temperature on the model reaction was also studied in the
presence of 0.02 g of the Fe O @Ag-β-CD nanocomposite in H O (Table 1, entries 5 and 7-11). We
3
4
2
found that the best results were obtained at 60°C.
7

Table 1. Synthesis of ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine- 5-carboxylate under
s
different conditions
CHO
O
O
O
O
+
+
O
NH
O
H2N
NH2
N
O
H
Entry
1
Catalyst (g)
Temperature (°C)
60
Time (h)
3
Yield (%)
58
β-CD (0.04)
Fe O @Ag (0.04)
2
3
60
60
3
2
87
97
3
4
Fe O @Ag-β-CD (0.04)
3
4
4
5
6
Fe O @Ag-β-CD (0.03)
60
60
60
2
2
2
97
97
92
3
4
Fe
3 4
O @Ag-β-CD (0.02)
Fe O @Ag-β-CD (0.01)
3
4
7
8
9
Fe O @Ag-β-CD (0.02)
70
80
2
2
2
2
97
97
90
90
3
4
Fe O @Ag-β-CD (0.02)
3
4
Fe O @Ag-β-CD (0.02)
100
120
3
4
1
0
Fe O @Ag-β-CD (0.02)
3 4
1
1
1
2
Fe O @Ag-β-CD (0.02)
r.t.
60
24
4
60
30
3
4
-
a)
Reaction conditions: benzaldehyde (1 mmol), urea (3 mmol), ethyl acetoacetate (1 mmol), water (5 mL)
The reusability of the catalysts was investigated in this reaction (Fig 6). The catalyst can be recovered
from the model reaction by an external magnet. The recovered catalysts were washed with EtOH,
dried at 90 °C for 4 h, weighed and used for 4 times under the same reaction conditions without
noticeable loss of catalytic activity.
Fig. 6 Reusability of the Fe
3
O
4
@Ag-β-CD for the synthesis of ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine- 5-carboxylate
After optimization of the reaction conditions, 3,4-dihydropyrimidinone derivatives were synthesized
by the reaction of aldehydes (1 mmol), ethylacetoacetate (1 mmol) and urea (3 mmol) in the presence
of Fe O @Ag-β-CD (0.02 g) at 60 °C in H O (Table 2).
3
4
2
8

Table 2. Fe
3
O
4
@Ag-β-CD-catalyzed synthesis of 3,4-dihydropyrimidinones
R1
CHO
+
O
O
O
O
Fe O @Ag--CD
3
4
+
O
H2N
NH2
H O
O
NH
2
R1
2
N
H
O
3
1
4
a-f
o
Entry
R
Product
Time (h)
Yield (%)
Mp ( C)
Ref.
1
1
2
H
4-F
4a
4b
2
1.5
97
94
203-204
181-182
[32]
[19]
3
4-Br
4c
1.5
94
215
[35]
4
5
4-OH
4d
4e
1
2
90
87
227-228
220-221
[19]
[36]
3-OCH
3
6
4-NO
4f
3
97
210-211
[35]
2
A comparison of the catalytic role of the Fe O @Ag-β-CD nanocomposite for the synthesis of 3,4-
3
4
dihydropyrimidinones with previously reported methods is summarized in Table 3. As it is clear from
Table 3, in the present method the reaction time is shorter than in some formerly reported methods.
Moreover, Fe O @Ag-β-CD given an improved yield in the synthesis of 3,4-dihydropyrimidinones.
3
4
The concurrent operation of β-CD as an organic compound collector and silver as a Lewis acid are
responsible for this superiority.
3 4
Table 3. Comparison of the efficiency of Fe O @Ag-β-CD as a catalyst with those of reported syntheses of 3,4-
dihydropyrimidinones
CHO
O
O
O
O
+
+
O
NH
O
H2N
NH2
N
O
H
conditions
Yield
Ref.
Entry
Catalyst/Temp/Time/Solvent
(%)
20
92
90
95
97
1
2
3
4
5
[19]
[14]
[34]
[37]
β-CD/ref/8 h/H O
2
Fe O -bpy-Ni(II) /MW, 130
3
4
̊
a
3
4
3
2
3
Cu(OTf) /25 ̊C /6 h/CH CN
Fe O @Ag- β-CD/60
3
4
̊
2
this work
a)
3 4
Sulfonated-phenylacetic acid coated Fe O nanoparticles
A reasonable mechanism for the model reaction is outlined in Scheme 1. It is proposed that β-CD
behaves as an efficient host molecule deposited on the Fe O @Ag nanocomposite. All starting
3
4
material is trapped in the hydrophobic cavity of β-CD, then Fe O @Ag nanoparticles catalyze the
3
4
formation of activated acylimine, the addition of the enolate, the cyclization and dehydration
reactions, respectively.
9

H2N
2
O
CHO
H N
H
O
O
N
NH2
+
H2N
NH2
H
O
EtO2C
NH
N
O
H
H
O
N
NH2
OEt
O
O
H
H
EtO2C
EtO2C
NH
NH
O
N
O
O
H2N
HO
H
Scheme 1. Proposed mechanism for preparation of ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate
Ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a). White solid; mp
-1 1
2
03-204
̊C . FT-IR (KBr): 3244, 3116, 2979, 1727, 1701, 1649, 1465, 1313, 1090, 758 cm . H NMR
(
500 MHz, DMSO-d ): δ = 9.18 (s, 1H, NH), 7.73 (br s, 1H, NH), 7.32-7.21 (m, 5H, ArH), 5.12 (d,
6
1
H, J = 3.5 Hz, CH), 3.94 (q, 2H, J = 7.0 Hz, OCH CH ), 2.23 (s, 3H, CH ), 1.06 (t, 3H, J = 7.0 Hz,
2 3 3
1
3
OCH CH ). C NMR (125 MHz, DMSO-d ): δ = 165.7, 152.5, 148.7, 145.3, 128.8, 127.6, 126.6,
2
3
6
9
9.7, 59.6, 54.4, 18.2, 14.5.
Ethyl
4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(4b).
Yellow solid; mp 181-182
̊
-
1 1
7
4
64 cm . H NMR (500 MHz, DMSO-d ): δ = 9.22 (s, 1H, NH), 7.74 (br s, 1H, NH), 7.26-7.12 (m,
6
H, ArH), 5.13 (d, 1H, J = 3.0 Hz, CH), 3.95 (q, 2H, J = 7.0 Hz, OCH CH ), 2.24 (s, 3H, CH ), 1.06
2
3
3
1
3
(
t, 3H, J = 7.0 Hz, OCH CH ). C NMR (125 MHz, DMSO-d ): δ = 165.6, 162.7, 152.7 (d, J = 241.2
2
3
6
Hz), 148.9, 141.56, 128.7, 115.4, 99.5, 59.6, 53.8, 18.2, 14.5.
Ethyl
White solid; mp 215
1. 1
ArH), 7.17 (d, 2H, J = 8.5 Hz, ArH), 5.11 (d, 1H, J = 3.5 Hz, CH), 3.94 (q, 2H, J = 7.0 Hz,
4-(4-bromophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(4c).
-
̊C . FT-IR (KBr): 3238, 3109, 2979, 1735, 1695, 1643, 1475, 1220, 1089, 777 cm
H NMR (500 MHz, DMSO-d ): δ = 9.24 (s, 1H, NH), 7.76 (br s, 1H, NH), 7.51 (d, 2H, J = 8.5 Hz,
6
1
3
OCH CH ), 2.23 (s, 3H, CH ), 1.06 (t, 3H, J = 7.0 Hz, OCH CH ). C NMR (125 MHz, DMSO-d ):
2
3
3
2
3
6
δ = 165.6, 152.3, 149.1, 144.6, 131.7, 128.9, 120.7, 99.2, 59.7, 53.9, 18.2, 14.5.
1
0

Ethyl 4-(4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4d).
Yellow solid; mp 227-228 C. FT-IR (KBr): 3280, 3097, 1732, 1698, 1651, 1511, 1446, 1172, 1093,
82 cm . H NMR (500 MHz, DMSO-d ): δ = 9.26 (s, 1H, OH), 9.05 (s, 1H, NH), 7.55 (br s, 1H,
̊
-1 1
7
6
NH), 7.70 (d, 2H, J = 8.5 Hz, ArH), 6.66 (d, 2H, J = 8.5 Hz, ArH), 5.03 (d, 1H, J = 3.5 Hz, CH), 3.95
1
3
(
q, 2H, J = 7.0 Hz, OCH CH ), 2.22 (s, 3H, CH ), 1.07 (t, 3H, J = 7.0 Hz, OCH CH ). C NMR (125
2 3 3 2 3
MHz, DMSO-d ): δ = 165.8, 156.9, 152.6, 148.1, 135.8, 127.8, 115.4, 100.2, 59.5, 53.9, 18.1, 14.5.
6
Ethyl 4-(3-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4e).
Yellow solid; mp 220-221 ̊C . FT-IR (KBr): 3223, 3116, 2988, 1729, 1698, 1644, 1518, , 1212, 1086,
-
1 1
7
8
77 cm . H NMR (500 MHz, DMSO-d ): δ = 9.16 (s,1H, NH), 7.70 (br s,1H, NH), 7.21 (t, 2H, J =
6
.0 Hz, ArH), 6.82-6.76 (m, 2H, ArH), 5.10 (d, 1H, J = 3.5 Hz, CH), 3.96 (q, 2H, J = 7.0 Hz,
1
3
OCH CH ), 3.71 (s, 3H, OCH ), 2.23 (s,3H, CH ), 1.08 (t, 3H, J = 7.0 Hz, OCH CH ). C NMR
2
3
3
3
2
3
(
125 MHz, DMSO-d ): δ = 165.7, 159.6, 152.6, 148.8, 129.9, 118.6, 112.8, 99.6, 59.6, 55.4, 54.2,
6
1
8.2, 14.5.
Ethyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4f). Yellow
-1
solid; mp 210-211 ̊C . FT-IR (KBr): 3244, 3121, 2979, 1725, 1698, 1643, 1600, 1480, 1153, 777 cm .
1
H NMR (500 MHz, DMSO-d ): δ = 9.34 (s,1H, NH), 7.88 (br s,1H, NH), 8.20 (d, 2H, J = 9.0 Hz,
6
ArH), 7.48 (d, 2H, J = 9.0 Hz, ArH), 5.26 (d, 1H, J = 3.5 Hz, CH), 3.95 (q, 2H, J = 7 Hz, OCH CH ),
2
3
1
3
2
1
.25 (s,3H, CH ), 1.07 (t, 3H, J = 7.0 Hz, OCH CH ). C NMR (125 MHz, DMSO-d ): δ = 165.4,
3 2 3 6
52.4, 152.1, 149.8, 147.1, 128.1, 124.2, 98.6, 59.8, 54.1, 18.3, 14.5.
Catalytic activity of the Fe O @Ag-β-CD nanocomposite for the synthesis of 1,4
3
4
dihydropyrano[2,3-c]pyrazole derivatives
The catalytic activity of the Fe O @Ag-β-CD nanocomposite was also studied in the synthesis of 6-
3
4
amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
via
reaction
of
benzaldehyde, malononitrile, ethylacetoacetate and hydrazine hydrate as a model reaction. The model
reaction behavior was investigated by adjusting various parameters such as type of catalyst, amount of
the catalyst, and temperature. We found that using a 0.02 g of Fe O @Ag-β-CD nanocomposite at 60
3
4
°
C in H O gave optimum results (Table 4).
2
1
1

Table 4. Synthesis of 6-amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile under
a)
different conditions
CHO
Me
N
O
O
CN
CN
CN
+
H NNH .H O
2 2 2
+
+
O
N
O
NH2
H
Entry
1
Catalyst (gr)
Temperature (°C)
80
Time (min)
Yield (%)
60
β-CD (0.04)
60
30
2
3
4
5
6
7
8
9
Fe O @Ag (0.04)
60
60
60
60
60
r.t
75
98
98
98
90
40
87
98
3
4
Fe O @Ag-β-CD (0.04)
5
5
3
4
Fe O @Ag-β-CD (0.03)
3
4
Fe O @Ag-β-CD (0.02)
5
3
4
Fe O @Ag-β-CD (0.01)
15
60
40
5
3
4
Fe O @Ag-β-CD (0.02)
3
4
Fe O @Ag-β-CD (0.02)
40
80
3
4
Fe O @Ag-β-CD (0.02)
3
4
1
1
1
0
1
2
-
-
-
r.t
90
100
60
60
60
8
12
27
a)
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), ethyl acetoacetate (1 mmol), hydrazine hydrate
1mmol), water (5 mL).
(
The recyclability of the catalyst was studied for the reaction of benzaldehyde, malononitrile, ethyl
acetoacetate and hydrazine hydrate at 60°C in H O. Towards this end, the Fe O @Ag-β-CD
2
3
4
nanocomposite was retrieved using an external magnet, washed with EtOH, dried at 90 °C for 4 h,
weighed and reused 4 times under the same reaction conditions without relevant loss of activity (Fig
7
).
Figure 7. Reusability of the Fe
3
O
4
@Ag-β-CD nanocomposite for the synthesis of 6-amino-3-methyl-4-phenyl-
1
,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
Under optimized conditions, 1,4-dihydropyrano[2,3-c]pyrazoles were synthesized (Table 5). In all
cases, the reactions proceeded efficiently to afford the corresponding products. All products were
1
13
characterized by m.p., IR, H- and C-NMR spectra.
1
2

Table 5. Synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives
R1
CHO
Me
O
O
Fe3O4@Ag-b-CD
CN
CN
+
H2NNH2.H2O
6
N
+
+
O
CN
H2O
N
O
NH2
R1
H
1
2
5
7
a-f
o
Entry
R
Product
7a
Time (min)
Yield (%)
Mp ( C)
244-245
241-243
179-180
224-226
210-211
Ref.
[41]
[41]
[40]
[43]
[40]
1
1
2
3
4
5
H
4-F
5
98
90
89
92
89
7b
5
4-Br
7c
10
20
20
4-OH
4-OCH
7d
7e
3
6
4-NO
7f
15
94
220-222
[43]
2
Finally, in order to assess the efficiency and generality of this methodology, we compared this
method with some reported methods from the literature. By comparing our results with those depicted
in Table 6, it was found that Fe O @Ag-β-CD is the most efficient magnetic catalyst with respect to
3
4
reaction time, reaction temperature and yield of the product. Reusability of the catalyst is another
advantage of this method.
Table 6. Comparison of the efficiency of Fe
3 4
O @Ag-β-CD with those of reported catalysts for the synthesis of 1,4-
dihydropyrano[2,3-c]pyrazoles
CHO
Me
N
O
O
CN
CN
+
H2NNH2.H2O
+
+
O
CN
N
O
NH2
H
conditions
Catalyst/Temp./Time/Solvent
Entry
Yield (%)
Ref.
1
2
3
4
β-CD/80
̊
90
90
88
92
[41]
[42]
[43]
[38]
2
Ag NPs/r.t./15 min/H O
Ag/TiO /70 ̊C /30 min/H O:EtOH (1:2)
2
2
Fe
3
O
4
@SiO
*BSA/45
Fe O @Ag-β-CD/60
5
6
95
98
[40]
this work
3
4
*bovine serum albumin
A schematic representation of the catalytic role of Fe O @Ag-β-CD nanoparticles for the tandem
3
4
synthesis of 1,4-dihydropyrano[2,3-c]pyrazole is proposed in Scheme 2. In the first step, Fe O @Ag-
3
4
β-CD promotes both the Knoevenagel condensation of the benzaldehyde with malononitrile and the
condensation of ethyl acetoacetate with hydrazine hydrate to produce the intermediate olefin and the
1
3

pyrazolone. Then, the Michael addition reaction of the olefin and the pyrazolone is catalyzed by the
Fe O @Ag-β-CD nanocomposite. Finally, the resulting intermediate undergoes an intramolecular
3
4
cyclization followed by tautomerization to give the 6-amino-3-methyl-4-phenyl-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile.
CN
CHO
NC
CN
CN
CN
CN
+
H
O
O
O
NH2NH2.H2O
HO
O
OEt
EtO
+
N
N
NH NH .H O
O
O
H
N
2
2
2
N
H
H
H
N
N
O
H
H
CN
C
CN
NH
CN
N
N
N
NC
C
N
N
O
O
NH2
N
N
N
H
H
H
OH
Scheme 2. Plausible mechanism for the synthesis of 6-amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile
1
4

6
-Amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (7a): gray solid;
mp 244-245 C. FT-IR (KBr): 3374, 3311, 3173, 2876, 2193, 1650, 1612, 1597, 1490, 1161, 1045, 746
cm . H NMR (500 MHz, DMSO-d ): δ = 12.00 (s, 1H, NH), 7.27-7.13 (m, 5H, ArH), 6.85 (s, 2H,
̊
-1 1
6
1
3
NH ), 4.53 (s, 1H, CH), 1.76 (s, 3H, CH ). C NMR (125 MHz, DMSO-d ): δ = 161.2, 155.2, 144.8,
2
3
6
1
35.9, 128.7, 127.8, 127.0, 121.1, 109.4, 87.7, 36.8, 10.1.
6
-Amino-4-(4-fluorophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
C. FT-IR (KBr): 3468, 3233, 3120, 2971, 2195, 1648, 1587, 1491, 1070,
010, 825 cm . H NMR (500 MHz, DMSO-d ): δ = 12.11 (s, 1H, NH), 7.11-7.19 (m, 4H, ArH), 6.89
(7b):
yellow solid; mp 241-243
̊
-1 1
1
6
1
3
(
s, 2H, NH ), 4.62 (s, 1H, CH), 1.77 (s, 3H, CH ). C NMR (125 MHz, DMSO-d ): δ = 162.3, 160.4
2 3 6
(d, J = 241.2 Hz), 161.2, 155.1, 141.12, 141.1, 136.0, 129.8, 129.7, 121.1, 105.2, 77.6, 35.9, 10.1.
6
-Amino-4-(4-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
white solid; mp 179-180 C. FT-IR (KBr): 3478, 3235, 3119, 2971, 2193, 1648, 1597, 1492, 1396,
069, 1010, 825 cm . H NMR (500 MHz, DMSO-d ): δ = 12.12 (s, 1H, NH), 7.49 (d, 2H, J = 8.5
(7c):
̊
-1 1
1
6
1
3
Hz), 7.11 (d, 2H, J = 8.5 Hz), 6.92 (s, 2H, NH ), 4.61 (s, 1H, CH), 1.78 (s, 3H, CH ). C NMR (125
2
3
MHz, DMSO-d ): δ = 161.3, 155.1, 144.3, 136.1, 132.4, 131.8, 130.6, 130.1, 101.1, 84.1, 36.1, 10.2.
6
6
-Amino-4-(4-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (7d):
yellow solid; mp 224-226 C. FT-IR (KBr): 3390, 3307, 3140, 2876, 2176, 1648, 1611, 1599, 1513,
̊
-
1 1
1
1
492, 1408, 1195, 1048, 812 cm . H NMR (500 MHz, DMSO-d ): δ = 12.03 (s, 1H, NH), 9.27 (s,
6
H, OH), 6.92 (d, 2H, J = 7.0 Hz), 6.78 (s, 2H, NH ), 6.66 (d, 2H, J = 7.0 Hz), 4.45 (s, 1H, CH), 1.76
2
1
3
(
s, 3H, CH ), C NMR (125 MHz, DMSO-d ): δ = 161.0, 156.4, 155.2, 139.4, 135.9, 135.2, 128.8,
3
6
1
15.5, 98.5, 88.2, 35.9, 10.2.
6
-Amino-4-(4-methoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (7e):
yellow solid; mp 210-211
̊
-
1
1
1
8
3
1
392, 1172, 1031, 804 cm . H NMR (500 MHz, DMSO-d ): δ = 12.05 (s, 1H, NH), 7.06 (d, 2H, J =
6
.5 Hz), 6.85 (d, 2H, J = 8.5 Hz), 6.79 (s, 2H, NH ), 4.52 (s, 1H, CH), 3.71 (s, 3H, OCH ), 1.77 (s,
2
3
H, CH3). 13C NMR (125 MHz, DMSO-d ): δ = 161.1, 158.4, 155.2, 136.9, 135.9, 128.9, 121.2,
6
14.2, 98.1, 79.8, 59.5, 35.9, 10.2.
6
-Amino-3-methyl-4-(4-nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(7f):
brown solid; mp 220-222
̊
-
1 1
1
6
347, 1107, 1051, 852 cm . H NMR (500 MHz, DMSO-d ): δ = 12.17 (s, 1H, NH), 8.19 (d, 2H, J =
6
1
3
.0 Hz), 7.45 (d, 2H, J = 6.0 Hz), 7.01 (s, 2H, NH ), 4.82 (s, 1H, CH), 1.79 (s, 3H, CH ). C NMR
2
3
(
125 MHz, DMSO-d ): δ = 161.5, 152.2, 146.8, 136.3, 132.0, 129.2, 124.3, 120.8, 97.0, 78.4, 36.3,
6
1
0.1.
In conclusion, we report the synthesis and characterization of a Fe O @Ag-β-CD composite as an
3
4
effective, reusable and environmentally friendly catalyst for the one-pot synthesis of 3,4-
dihydropyrimidinone and 1,4-dihydroprano[2,3-c]pyrazole derivatives in aqueous medium with good
1
5

to excellent yields. We suggest that organic compounds accumulate in the hydrophobic cavity of the
cyclodextrin molecules, and the Fe O @Ag composite, as a Lewis acid, catalyzes the reactions. Short
3
4
reaction times, an easy recovery of the catalyst, mild reaction conditions, a clean reaction, an easy of
workup and high yields are other advantages of this method.
Acknowledgements
The authors thank the Research Council of Yazd University for the financial support.
[1] R. Dey, N. Mukherjee, S. Ahammed, B.C. Ranu, Chem. Commun. 48 (2012) 7982-
7
984.
[2] A.L. Gajengi, C.S. Fernandes, B.M. Bhanage, Molecular Catalysis (2017) in press.
[3] S.S.A. Darbandizadeh Mohammad Abadi, M.A. Karimi Zarchi, New J. Chem, 41 (2017)
1
0397-10406
4] A. Mobinikhaledi, H. Moghanian, F. Sasani, Int. J. Green Nanotechnol. Phys. Chem. 2
2010) 47-52.
5] J. Gao, Z. Guo, F. Su, L. Gao, X. Pang, W. Cao, B. Du, Q. Wei, Biosens. Bioelectron.
3 (2015) 465-471.
[
[
(
6
[6] A.S. Teja, P.Y. Koh, Prog. Cryst. Growth Charact. Mater. 55 (2009) 22-45.
[7] M. Godoi, D.G. Liz, E.W. Ricardo, M.S.T. Rocha, M.B. Azeredo, A.L. Braga, 70 (2014)
3
349-3354.
8] J. Kudr, Y. Haddad, L. Richtera, Z. Heger, M. Cernak, V. Adam, O. Zitka, Nanomaterials
(2017) 243-272.
9] H. Deng, X. L. Li, Q. Peng, X. Wang, J. P. Chen, Y. D. Li, Angew. Chem. 117 (2005)
842-2845.
[
[
7
2
[
[
10] M.B. Gawande, P.S. Branco, R.S. Varma, Chem. Soc. Rev. 42 (2013) 3371-3393.
11] V.C. dos Santos-Durndell, T.M. Peruzzolo, G.M. Ucoski, L.P. Ramos, S. Nakagaki,
Biofuel Research Journal 18 (2018) 806-812.
[
[
[
12] L. Lin, C. Zou, J. Chem. Eng. Data, 62 (2017) 762-772.
13] S. Mahpishanian, H. Sereshti, J. Chromatogr. A 1485 (2017) 32-43.
14] D. Girija, H.S.B. Naik, B.V. Kumar, C.N. Sudhamani, K.N. Harish, Arab. J. Chem.
(2014) in press.
[15] H. Woo, K. Lee, S. Park, K.H. Park, Molecules 19 (2014) 699-712.
[16] Q. An, M. Yu, Y. Zhang, W. Ma, J. Guo, C. Wang, J. Phys. Chem. C. 116 (2012)
2
2432-22440.
[
[
[
17] A. Harada, Acc. Chem. Res. 34 (2001) 456-464.
18] G. Chen, M. Jiang, Chem. Soc. Rev. 40 (2011) 2254-2266.
19] N. Aparecida Liberto, S. Paiva Silva, A. Fatima, S. Antonio Fernandes, Tetrahedron 69
(
2013) 8245-8249.
20] Y. Ren, Y. Liu, R. Niu, X. Liao, J. Zhang , B. Yang, Journal of Molecular Structure
117 (2016) 1-7.
[
1
[
[
21] S.V. Bhosale1, S.V. Bhosale, Mini-Reviews in Organic Chemistry 4 (2007) 231-242.
22] P. Tang, H. Yang, B. Tang, D. Wu, Q. Du, K. Xu, H. Li Carbohydr. Polym. 156 (2017)
2
15-222.
[
[
[
[
23] M.O. Simon, C.J. Li, Chem. Soc. Rev. 41 (2012) 1415-1427.
24] S. Li, W.C. Purdy, Chem. Rev. 92, (1992) 1457-1470.
25] J. Szeitli, Chem. Rev. 98 (1998) 1743.
26] M. Komiyama, M.L. Bender, "The Chemistry of Enzyme Action" Elsevier (1984) 505-
5
27.
[27] X. Chen, J. Rao, J. Wang, J.J. Gooding, G. Zou, Q. Zhang, Chem. Commun. 47
1
6

(2011) 10317-10319.
[28] B. Kaboudin, H. Salemi, R. Mostafalu, F. Kazemi, T. Yokomatsu, J. Organomet.
Chem. 818 (2016) 195-199.
[29] H. Salemi, B. Kaboudin, F. Kazemi, T. Yokomatsu, RSC Adv. 6 (2016) 52656-
5
2664.
[
[
[
[
[
[
[
[
[
30] B. Kaboudin, Y. Abedi, T. Yokomatsu, Eur. J. Org. Chem. 33 (2011) 6656-6662.
31] B. Kaboudin, R. Mostafalua, T. Yokomatsu, Green Chem. 15 (2013) 2266-2274.
32] M. Nasresfahani, S.J. Hoseini, F. Mohammadi, Chin. J. Catal. 32 (2011) 1484-1489.
33] D. Elhamifar, P. Mofatehnia, M. Faal, J. Colloid Interface Sci. 504 (2017) 268-275.
34] F. Zamani, E. Izadi, Catal. Commun. 42 (2013) 104-108.
35] M.M. Heravi, K. Bakhtiari, F.F. Bamoharram, Catal. Commun. 7 (2006) 373-376.
36] B.F. Mirjalili, A. Bamoniri, A. Akbari, J. Iran. Chem. Soc. 8 (2011) 135-140.
37] A.S. Paraskar, G.K. Dewkar, A. Sudalai, Tetrahedron Lett. 44 (2003) 3305-3308.
38] R. Ghorbani Vaghei, J. Mahmoodi, A. Shahriari, Y. Maghbooli, Appl Organometal
Chem. (2017) 3816-3824.
[39] H. Mecadon, R. Rohman, I. Kharbangar, B.M. Laloo, I. Kharkongor, M. Rajbangshi,
B. Myrboh, Tetrahedron Lett. 52 (2011) 3228-3231.
[
[
40] X. Huang, Z. Li, D. Wang, Y. Li, J. Chin, Catal. 37 (2016) 1461-1467.
41] Y.A. Tayade, S.A. Padvi, Y.B. Wagh, D.S. Dalal, Tetrahedron Lett. 56 (2015) 2141-
2
147.
[
[
42] S.Yadav, J.M. Khurana, Chinese. J. Catal. 36 (2015) 1042-1046.
43] M. Fatahpour, F. Noori Sadeh, N. Hazeri, M.T. Maghsoodlou, M.S. Hadavi, S.
Mahnaei, J. Saudi. Chem. Soc. 21 (2017) 998-1006.
[
[
44] W. Li, R. Ruzi, K. Ablajan, Z. Ghalipt, Tetrahedron 73 (2016) 164-171.
45] M. A. Amrollahi, F. Vahidnia, Research on Chemical Intermediates, 2018,
doi.org/10.1007/s11164-018-3574-y, in press.
[46] K. Can, M. Ozmen, M. Ersoz, Colloids Surf. B 71 (2009) 154-159.
Graphical Abstract
OH
O
HO
O
O
OH
HO
OH
O
OH
HO
HO
O
OH
O
O
OH
O
OH
HO
Raw materials
OH
O
OH
OH
OH
OH O
O
OH
O
O
OH
HO
O
R1
OH
O
O
CHO
H N
2
NH2
O
NH
Reaction 1
Reaction 2
O
O
N
O
R1
H
O
Products
Raw materials
1
7
R1
CN
CHO
CN
Me
N
CN
H NNH .H O
2
2
2
Fe O @Ag--CD
3
4
R1
O
O
N
O
NH2
H
O

In this work, we wish to report the preparation and characterization of Fe O @Ag decorated β-CD as
3
4
a novel magnetic catalyst. The catalytic activity of Fe O @Ag-β-CD nanocomposite was also studied
3
4
for the synthesis of 3,4-dihydropyrimidinone and 2,4-dihydropyrano[2,3‐c]pyrazole derivatives.
Highlights


Preparation of novel hydrophobicity-enhanced magnetic catalyst.
The catalytic behavior of the Fe O @Ag-β-CD composite in synthesis of 3,4-
3
4
dihydropyrimidinone and 2,4-dihydroprano[2,3-c]pyrazole derivatives in aqueous
medium.

Study of reusability of Fe O @Ag-β-CD heterogeneous catalyst in organic reactions.
3
4
1
8