Synthesis of Pyrazolo-[4?,3?:5,6]pyrido[2,3-d]pyrimidine-diones Catalyzed by a Nano-sized Surface-Grafted Neodymium Complex of the Tungstosilicate via Multicomponent Reaction

Article abstract of DOI:10.1002/aoc.5058

An inorganic–organic hybrid based on lanthanide clusters and Keggin type polyoxometalates (POMs) (Na[Nd (pydc-OH)(H₂O)₄]₃}[SiW₁₂O₄₀]) was used the first time as trinuclear catalyst for one pot synthesis of pyrazolo[4??,3?:5,6]pyrido[2,3-d]pyrimidine-diones, via two different four and five-component reactions involving hydrazine hydrate, ethyl acetoacetate, aryl aldehydes, and 6-amino-1,3-dimethyl uracil or barbituric acid with ammonium acetate as alternative materials in green condition. To evaluate potential application of the as-made hybrid in adsorption and separation processes, nitrogen adsorption was performed at 77?K through simulation study. The hybrid catalyst was further characterized via powder X-ray diffraction (PXRD) at room temperature which indicated the good phase purity of the catalyst. The results show that the catalytic activity of the hybrid catalyst has increased relative to each parent component due to the special interaction between Keggin anions and pydc-OH ligands.

Full text of DOI:10.1002/aoc.5058

Received: 13 April 2019
DOI: 10.1002/aoc.5058
Revised: 18 May 2019
Accepted: 22 May 2019
F U L L P A P E R
́
́
Synthesis of Pyrazolo‐[4,3:5,6]pyrido[2,3‐d]pyrimidine‐
diones Catalyzed by a Nano‐sized Surface‐Grafted
Neodymium Complex of the Tungstosilicate via
Multicomponent Reaction
Mansoureh Daraie1 | Majid M. Heravi1
| Masoud Mirzaei2
| Nahid Lotfian1
1 Department of Chemistry, School of
An inorganic–organic hybrid based on lanthanide clusters and Keggin type
Sciences, Alzahra University, Vanak,
Tehran, Iran
2 Department of Chemistry, Faculty of
Science, Ferdowsi University of Mashhad,
Mashhad, Iran
polyoxometalates (POMs) (Na[Nd (pydc‐OH)(H2O)4]3}[SiW12O40]) was used
́
́
́
the first time as trinuclear catalyst for one pot synthesis of pyrazolo[4,3:5,6]
pyrido[2,3‐d]pyrimidine‐diones, via two different four and five‐component
reactions involving hydrazine hydrate, ethyl acetoacetate, aryl aldehydes, and
6‐amino‐1,3‐dimethyl uracil or barbituric acid with ammonium acetate as
alternative materials in green condition. To evaluate potential application of
the as‐made hybrid in adsorption and separation processes, nitrogen adsorp-
tion was performed at 77 K through simulation study. The hybrid catalyst
was further characterized via powder X‐ray diffraction (PXRD) at room tem-
perature which indicated the good phase purity of the catalyst. The results
show that the catalytic activity of the hybrid catalyst has increased relative to
each parent component due to the special interaction between Keggin anions
and pydc‐OH ligands.
Correspondence
Majid M. Heravi, Department of
Chemistry, School of Sciences, Alzahra
University, Vanak, Tehran, Iran.
Email: mmheravi@alzahra.ac.ir;
mmh1331@yahoo.com
Masoud Mirzaei, Department of
Chemistry, Faculty of Science, Ferdowsi
University of Mashhad, Mashhad, Iran.
Email: mirzaeesh@um.ac.ir;
mirzaei487@yahoo.com
Funding information
Alzahra University, Tehran, Iran., Grant/
Award Number: Alzahra University, Teh-
ran, Iran.; Ferdowsi University of Mash-
had, Mashhad, Iran., Grant/Award
Number: Ferdowsi University of Mash-
had, Mashhad, Iran.
KEYWORDS
́
́
anticancer agents, Heteropoly acid, inorganic–organic hybrids, Polyoxometalates, Pyrazolo‐[4,3:5,6]
pyrido[2,3‐d]pyrimidine‐diones
1 | INTRODUCTION
efforts have been made for the discovery of new scaffolds,
especially heterocyclic systems through both industrial
The World Health Organization (WHO) has recently
reported the rate of cancer will rise globally by about
75% up to 2030. The number may be duplicated in some
of the regressive societies an developing countries.[1] Can-
cer is as a result of the uncontrolled growth of cells, tissue
damage, invasion and metastases. The advances in drug
discovery related to the cancer therapy is actually associ-
ated with the severe side effects, resistance to the conven-
tional medicines, as well as an inadequate chemical
space, leading to high demand for design and discovery
of new chemotherapeutic medicines.[2,3] So far, many
and academic projects. Among the heterocyclic com-
pounds, the fused pyrimidines have become as promising
targets due to their pharmacological significance.
In the midst of polyfunctionalized heterocycles,
pyridopyrimidines are the most favored structures for
developing drug discovery due to providing a wide
range of pharmacological activities, such as anti‐cancer,[4]
antimicrobial,[5] anti‐HIV,[6] anti‐inflammatory,[7] anti‐
malarial[8] and anti‐tubercular.[9] Moreover, such com-
pounds are valuable in chemotherapy research due to their
potential properties as inhibitors of 5‐phosphoribosyl‐1‐
Appl Organometal Chem. 2019;e5058.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
1 of 9
https://doi.org/10.1002/aoc.5058

2 of 9
DARAIE ET AL.
pyrophosphate synthetase,[10] dihydrofolate reductase,[11]
and specifically, tyrosine kinase as an important enzyme
in regulating cell division.[12] In addition, fused pyrimidine
derivatives are well‐known as anticancer agents, and
many researches describe the function of pyrimidines in
chemotherapy and treatment of cancers (Figure 1).[13]
In recent years biological activities of pyrazole, pyri-
dine and pyrimidine based organic molecules have been
approved, thus, heterocyclic systems containing the basic
aforementioned heterocycles have attracted the attention
of synthetic organic chemists.[14]
Polyoxometalates (POMs), as a unique class of anionic
metal oxide clusters, are gaining more interest due to
numerous advantageous properties and widespread appli-
cations.[15] Among the various applications of POMs,
catalysis is one of the most important area of applica-
tions.[16–19] In POM structures protons can act as
Brønsted acids, while the metal ions show Lewis acidity
originated from unoccupied orbitals as electron pair
accepters. Thus, POMs with strong Brønsted and Lewis
acidity exhibit promise as unrivaled acid catalysts for var-
ious acid‐catalyzed organic transformations.[20,21]
Although POMs are efficient homogeneous catalysts, the
accessibility to the active sites is hindered because of their
small surface area.
A promising synthetic strategy to improve POM
catalyst system is the combination of POM with metal–
organic coordination complexes to construct crystalline
inorganic–organic hybrid compounds‐based POMs with
high‐dimensional supramolecular networks.[22–24] In
comparison with the traditional POMs, inorganic–organic
hybrid of POMs can merge the merits of both components,
and the combination may lead to desirable catalytic activ-
ity.[25] Among various coordination compounds, lantha-
noid coordination complexes are particularly valuable in
this context because of their particular optical, Lewis acid
catalytic and magnetic properties.[26–29]
Given the importance of pyrazolopyridopyrimidines,
we decided to try the synthesis of heterocyclic system
based on pyridopyrimidines. In this regard we, used two
different methods, four and five component reactions,
using inexpensive and available starting materials in the
presence of a suitable catalyst under the environmentally
friendly conditions.
For this aim, we used inorganic–organic hybrid com-
pound based on neodymium cluster and Keggin type
POMs, {Na[Nd (pydc‐OH)(H2O)4]3}[SiW12O40]•15H2O
(Nd/POM hybrid) Accessibility of active sites, enhanced
the Lewis acid strength in presence of the lanthanoid ions
and insolubility of hybrid catalyst, encouraged us to
examine the catalytic activity of this hybrid in organic
transformation for the first time (Schemes 1,2).
2 | RESULTS AND DISCUSSION
2.1 | Catalyst characterization
The lower charge density on the spherical surface of HPAs
is the most main reason that they are commonly employed
as acidic catalysts. Due to the interest in POM‐based coor-
dination complexes, in the last years, our research team
introduced different lanthanoid coordination complexes
into the POMs systems and obtained a series of novel
POM‐based lanthanide clusters, which demonstrated
unusual topologies and improved properties.[41–45]
The hybrid catalyst contains a trinuclear neodymium
organic cluster that is bound to three terminal oxygen
atoms of the [SiW12O40]4− moiety to yield discrete flower-
like hybrid (Figure 2). The discrete molecules are further
packed into 3D supramolecular network by means of
hydrogen bonds and anion–π interactions. The crystalline
water molecules reside as guests in the interspaces of
the 3D supramolecular structures through extensive
hydrogen‐bonding interactions. All of these contacts play
an important role in the stabilization of the crystal struc-
ture of the hybrid catalyst.
We are interested in heteocyclic chemistry[30–33] and
their synthesis via multicomponent reaction under green
conditions.[34–36]
In two decades ago, we promoted heteropoly acids
(HPAs) and their POMs as efficient and green catalysts
in organic transformations including in the synthesis of
heterocycles.[37–40]
The morphology of catalyst was studied by SEM
analyses, Figure 3. As can be seen, the catalyst has fine
particles with a regular structure.
FIGURE 1 Pyrimidine and fused
pyrimidine marketed drugs

DARAIE ET AL.
3 of 9
To evaluate potential application of the as‐made struc-
tures in adsorption and separation processes, nitrogen
adsorption was performed at 77 K through simulation
study. Grand Canonical Monte Carlo simulation was
implemented for N2 adsorption isotherm prediction over
the hybrid and parent Keggin catalysts. The trueness of
simulated N2 isotherm in textural characterization of
porous materials has been previously reported.[46–48] As
it has been illustrated in the Figure 6, the N2 uptake
has been increased rather two times over hybrid catalyst
compared to the parent Keggin. It is worthwhile mention-
ing nitrogen adsorption uptakes over both catalysts imply
potential application of the structures in separation and
adsorption processes.
2.2 | Catalytic activity
FIGURE 2 Representation of hybrid catalyst, Red: [SiW12O40]−,
Green: lanthanoid cluster
In the sequel to our recent studies to synthesize heterocy-
clic compounds using various heterogeneous catalysts, we
are looking for a simple and sufficient protocol to synthe-
́
́
size pyrazolo‐[4,3:5,6]pyrido[2,3‐d]pyrimidine‐diones.
In this regard, firstly, the role of the catalyst on the
reaction efficiency and the time was determined. For this
aim, ethyl acetoacetate, hydrazine hydrate, 6‐amino‐1,3‐
dimethyl uracil and benzaldehyde were employed to treat
as the model reaction and water was selected as solvent.
When the catalyst was missed, the reaction progressed
slowly and only a trace amount of the desired product
was formed.
The next try was optimizing the catalyst amount. TLC
technique (7:3 n‐hexane/ethylacetate) was used for trac-
ing the reaction progress and thus, the clean and smooth
treatment of starting materials was observed along with
the production of the favored product. To reach the opti-
mized reaction conditions, the impact of temperature, sol-
vent, and the amount of catalyst were investigated in the
model reaction. By examining different polar and non‐
polar solvents in this reaction, the best one was found
and its results were compared with that of obtained under
solvent‐free system. The results concluded from solvents
such as H2O, EtOH, H2O/EtOH, CH3CN, CH2Cl2 and
DMF were summarized in Table 1. Water as the greenest
solvent gave the desired product in highest yield of 94%
which was the best one (Table 1, entry 1). So water was
chosen as the reaction solvent. To increase the efficiency,
the catalyzed model reaction was conducted under reflux
condition and the highest yield of product was obtained,
while at room temperature it gave only 60% yield. Lastly,
to find the effect of the optimal amount of catalyst, the
model reaction was catalyzed with different amounts of
catalyst. 10 mol% of the catalyst was selected as an opti-
mized amount. The increase of the product yield was
FIGURE 3 SEM analyses of Nd/POM hybrid
The FTIR spectrum of catalyst are depicted in Figure 4.
The band appears between 3300 and 3500 cm−1 are
assigned to the ‐OH vibration of coordinated molecules.
The bands at 1522 cm−1 and 1630 cm−1 are representative
of C=O asymmetric stretching. The observed band at
1459 cm−1 can be due to symmetric stretching of C=O
groups.
As shown in Figure 5 hybrid catalyst was characterized
via powder X‐ray diffraction (PXRD) at room tempera-
ture. The PXRD patterns measured for the synthesized
samples were in good agreement with the PXRD patterns
simulated from the respective single‐crystal X‐ray data
(CCDC‐995731) which indicates the good phase purity
of the catalyst.

4 of 9
DARAIE ET AL.
FIGURE 4 IR spectrum of Nd/POM hybrid
FIGURE 5 X‐ray powder diffraction patterns of catalyst: red, calculated from single‐crystal X‐ray data; green, experimental data
directly related to the increase of the Na[Nd (pydc‐OH)
(H2O)4]3}[SiW12O40] quantity that is in turn attributed to
the enhancement of the number of active sites increasing
the contact and collision opportunity among the catalyst
surface and the molecules of reagents.
In the hybrid catalyst structure, increasing the specific
surface areas and number of active sites, resulted in
better catalytic efficiency than parent compound. For
comparing the catalytic activities of the hybrid catalyst
with parent Keggin and Lanthanopolyoxotungstate
compound, the target reaction catalyzed by H4SiW12O40,
results proved that the synergistic effect of POMs and
lanthanoid complexes in the inorganic–organic hybrid
compounds leads to the enhanced catalytic properties.
Furthermore, the coordination of the SiW12O40 anion to
the neodymium ions results in a feature of the nano‐size
hybrid with the activity of the acid surface, making the
facilitation of the accessibility to active sites.
Using these results, we synthesized the target mole-
cules using a one pot four component reaction of hydra-
zine hydrate, ethyl acetoacetate, 6‐amino‐1,3‐dimethyl
uracil and benzaldehyde in the presence of catalytic
amount of Nd/POM hybrid (0.04 g) and in water as
solvent.
Na9[NdW10O36]
and
Na[Nd
(pydc‐OH)(H2O)4]3}
[SiW12O40] was performed under the optimum condi-
tions, and the results are listed in Table 1. As exhibited in
Table 1, it is found that the hybrid catalyst showed high
catalytic activity, and the yield of product is 91%. These
The extension of the present method was studied by
employing various substituted aldehydes, including either
electron withdrawing or electron donating groups.

DARAIE ET AL.
5 of 9
FIGURE 6 N2 adsorption isotherms over parent Keggin and hybrid catalysts at 77 K
TABLE 1 Optimization of the reaction conditions
Entry
Solvent
Temperature (°C)
Time (h)
Yield (%)
Catalyst amount (mol%)
1
H2O
reflux
reflux
reflux
reflux
reflux
reflux
r.t.
2
94
89
92
90
75
80
60
84
89
97
80
88
10
2
EtOH
H2O/EtOH
CH3CN
CH2Cl2
DMF
H2O
3
10
3
2.5
3.5
4
10
4
10
5
10
6
3
10
7
6
10
8
H2O
50
5
10
9
H2O
reflux
reflux
reflux
reflux
3
5
10
11
12
H2O
2
15
H2O
2.5
2.5
10 (H4SiW12O40)
10 (Na9[NdW10O36])
H2O
The corresponding pyrazolo pyrido pyrimidine‐dione
derivatives were produced with excellent yields, without
the formation of any by‐products in a relatively short time.
The results are summarized in Table 2. All compounds
were known and identified by comparison of their physical
and spectroscopic data of those authentic samples abd
were found indentical (See supporting information).[49,50]
In the next step, we decided to synthesize various
This reaction was also extended by using various
substituted aldehydes to produce the desired compounds.
The results are summarized in Table 3.
2.3 | Reaction mechanism
According to previous reports, a reliable mechanical
pathway for the four‐component reaction catalyzed by
Nd/POM hybrid has been proposed (Scheme 3). Firstly,
́
́
derivatives of pyrazolo‐[4,3:5,6]pyrido[2,3‐d]pyrimidine‐
diones via a five‐component reaction using ammonium
acetate as a source of nitrogen.
(E)‐4‐benzylidene‐3‐methyl‐1H‐pyrazol‐5(4H)‐one
was

6 of 9
DARAIE ET AL.
TABLE 2 One pot, four‐component synthesis of pyrazolo‐
[4′,3′:5,6]pyrido[2,3‐d]pyrimidinediones in refluxing water in the
presence of Nd/POM hybrid
TABLE 3 One pot, five‐component reaction in the presence of
Nd/POM hybrid
Time Yield Mp.
Mp. rep.
(°C)
Entry Ar
R
(h)
(%)
(°C)
Time Yield Mp.
Mp. rep.
(°C)[49,50]
Entry Ar
R
(h)
(%)
(°C)
1
C6H5
H
H
H
H
H
H
H
H
Ph
3
92
90
94
90
90
92
91
88
92
89
92
87
194–198 194–196
280–283 281–283
284–287 285–286
286–289 286–288
284–288 285–287
171–174 172–173
221–224 221–223
222–224 222–224
207–210 208–210
208–210 207–208
202–204 200–202
160–163 160–161
1
C6H5
H
H
H
H
H
H
H
H
Ph
2
94
91
93
90
91
94
90
90
91
90
91
89
195–198 194–196
280–284 281–283
282–285 285–286
285–288 286–288
284–286 285–287
172–174 172–173
220–224 221–223
221–225 222–224
207–210 208–210
206–207 207–208
200–203 200–202
161–163 160–161
2
4F‐C6H4
2.2
2.5
2.8
2.8
2.5
3
2
4F‐C6H4
1.5
1.8
2
3
4Cl‐C6H4
4Br‐C6H4
2,4‐Cl2‐C6H3
4NO2‐C6H4
3NO2‐C6H4
4‐N (Me)2C6H4
C6H5
3
4Cl‐C6H4
4Br‐C6H4
2,4‐Cl2‐C6H3
4NO2‐C6H4
3NO2‐C6H4
4‐N (Me)2C6H4
C6H5
4
4
5
5
1.5
1.8
2
6
6
7
7
8
3.4
4
8
2.5
3
9
9
10
11
12
4F‐C6H4
Ph 3.5
Ph
Ph 4.4
10
11
12
4F‐C6H4
Ph 2.5
Ph 2.8
Ph 3.1
4Cl‐C6H4
4Br‐C6H4
4
4Cl‐C6H4
4Br‐C6H4
used without purification. All synthesized compounds
were known and indentified by comparison of their
physical and spectroscopic data with those of authuntic
samples and were found identical[49,50]
obtained by nucleophilic substitution of benzaldehyde on
3‐methyl‐1‐pyrazolone. Simultaneously, aldehyde is
activated by the catalyst. Finally, the desired 1 pyrazole
based pyrido[2,3‐d]pyrimidine‐dione is achieved through
catalyzed cycloaddition.
3.2 | Preparation and characterization of
{Na[Nd (pydc‐OH)(H2O)4]3}[SiW12O40]
•15H2O hybrid catalyst
3 | EXPERIMENTAL
3.1 | Materials
{Na[Nd (pydc‐OH)(H2O)4]3}[SiW12O40]•15H2O hybrid
were synthesized and characterized according to the
procedure reported previously.[45] A mixture of Nd
(NO3)3•6H2O (110 mg, 0.25 mmol), H2pydcOH•H2O
(50 mg, 0.25 mmol), H4SiW12O40•nH2O (288 mg,
0.1 mmol) in 15 ml H2O was stirred for about an hour
in air and the pH value was adjusted to about 4 with
The chemicals employed for the investigating the cata-
lytic activity includes ethyl acetoacetate, hydrazine
hydrate/phenyl hydrazine, 1,3‐dimethylbarbituric acid,
ammonium acetate, 6‐amino‐1,3‐dimethyl uracil and aryl
aldehyde. All reagents were obtained from Merck and
SCHEME 1 Four component reaction
for the synthesis of pyrazole based
pyrido[2,3‐d] pyrimidine‐dione.
SCHEME 2 Model five‐component
reaction for pyrazole based pyrido[2,3‐d]
pyrimidine‐dione synthesis.

DARAIE ET AL.
7 of 9
recrystallized by dichloromethane. To recycle the catalyst,
the recovered was washed with chloroform (2 × 10 ml),
dried in an oven and used in reaction runs under the
same conditions.
3.4.1 | 3,6,8‐Trimethyl‐4‐phenyl‐8,9‐
dihydro‐1H‐pyrazolo[4′,3′:5,6]pyrido[2,3‐d]
pyrimidine‐5,7‐(4H,6H)‐dione
1H NMR (400 MHz, DMSO‐d6): δ 10.46 (brs, 2H, 2‐NH),
7.15–7.19 (t, 2H, Ar‐H), 7.00–7.08 (m, 3H, Ar‐H), 5.63
(s, 1H, CH), 3.07 (s, 3H, CH3), 2.81 (s, 3H, CH3), 2.22
(s, 3H, CH3). IR (KBr) νmax = 3332, 2971, 1654,
1248 cm−1; m. p. = 195–195 °C.
SCHEME 3 Proposed mechanism for the model reaction.
NaOH solution. Then, the mixture was transferred into a
Teflon‐lined autoclave and kept under autogenous
pressure at 120 °C for 3 days. After slow cooling to room
temperature, yellow prismatic crystals were obtained.
C21H63N3NaNd3O82SiW12 (4359.70): Calcd. C 5.79, H
1.46, N 0.96; found C 5.90, H 1.38, N 0.86, IR (KBr pellet,
cm−1) ν: 3420(br. s), 1600 (s), 1573 (s), 1492 (w), 1428 (s),
1338 (m), 1246 (m), 1123 (m), 1028 (s), 973 (s), 924 (s),
881 (m), 795 (s), 702 (w).
3.4.2 | 4‐(4‐Fluorophenyl)‐3,6,8‐trimethyl‐
8,9‐dihydro‐1H‐pyrazolo[4′,3′:5,6]pyrido[2,3‐
d]pyrimidine‐5,7(4H,6H)‐dione
1H NMR (400 MHz, DMSO‐d6): δ 11.99 (s, NH), 9.81
(s, NH), 7.36–7.38 (d, J = 7.6 Hz, 2H, Ar‐H), 7.14–7.16
(d, J = 7.6 Hz, 2H, Ar‐H), 4.99 (s, CH), 3.46 (s, 3H,
CH3), 3.06 (s, 3H, CH3), 1.96 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO‐d6) δ: 158.24, 150.19, 149.62, 142.28,
137.31, 135.63, 134.57, 130.41, 125.06, 106.23, 88.63,
33.84, 30.28, 27.15, 10.02; m. p. = 280–284 °C; IR (KBr)
́
́
3.3 | Synthesis of Pyrazolo‐[4,3:5,6]
pyrido[2,3‐d]pyrimidine‐diones: Using
4‐component reaction
Initially, 1.2 mmol of hydrazine hydrate or phenyl hydra-
zine was added drop wise to an aqueous suspension of
ethyl acetoacetate to produce 3‐methyl‐pyraxole‐1‐one as
a white precipitate, then 6‐amino‐1,3‐ dimethyl uracil
(1 mmol), an appropriate aldehyde (1 mmol) and catalytic
amount of Nd/POM hybrid (0.04 g) were added and the
resulting mixture was heated at reflux for appropriate
time. The progress was monitored by TLC. Upon comple-
tion of the reaction, the mixture was cooled and filtered
off. The resulting solid was purified by recrystallization
from CH2Cl2.
νmax = 3312, 2956, 1663, 1280 cm−1
.
3.4.3 | 3,6,8‐Trimethyl‐1,4‐diphenyl‐8,9‐
dihydro‐1H‐pyrazolo[4′,3′:5,6]pyrido[2,3‐d]
pyrimidine‐5,7(4H,6H)‐dione
1H NMR (400 MHz, DMSO‐d6): δ 11.77 (s, NH), 7.87–7.89
(d, J 8.0 Hz, 4H, Ar–H), 7.42–7.46 (t, J 8.0 Hz, 6H, Ar–H),
5.09 (s, CH), 2.82 (s, 3H,CH3), 2.70 (s, 3H, CH3), 1.55
(s, 3H, CH3), m. p. = 207–210 °C; IR (KBr) νmax = 3315,
2936, 1650, 1241.
́
́
3.4 | Synthesis of Pyrazolo‐[4,3:5,6]
pyrido[2,3‐d]pyrimidine‐diones: Using
5‐component reaction
3.4.4 | 4‐(4‐Chlorophenyl)‐3,6,8‐trimethyl‐
8,9‐dihydro‐1H‐pyrazolo[4′,3′:5,6]pyrido[2,3‐
d]pyrimidine‐5,7(4H,6H)‐dione(5 l)
Ethyl acetoacetate (1 mmol), hydrazine hydrate or phenyl
hydrazine (1.2 mmol), 1,3‐dimethylbarbituric acid
(1 mmol) and aryl aldehyde (1 mmol) were mixed in
water (10 ml). Then, Nd/POM hybrid (10 mol%) was
added and the reaction mixture was refluxed for the
appropriate time. After completion of the reaction as
indicated by TLC (n‐hexane–ethyl acetate; 7:3), the
reaction mixture was cooled to room temperature and
1HNMR (400 MHz, DMSO‐d6): δ 11.97 (s, NH), 7.96–7.98
(d, 2H, J 7.6 Hz, Ar–H), 7.54–7.56 (d, 2H, J 7.6 Hz, Ar–H),
7.14–7.19 (m, 5H, Ar –H), 4.86 (s, CH), 3.46 (s,3H, CH3),
2.88 (s, 3H,CH3), 1.96(s, 3H, CH3), m. p. = 202–204 °C; IR
(KBr) νmax = 3321, 2946, 1641, 1273.

8 of 9
DARAIE ET AL.
FIGURE 7 Recyclability of Nd/POM hybrid in four‐component reaction
MM is thankful to research council of Ferdowsi University
of Mashhad, Mashhad, Iran.
3.5 | Catalyst recycling
Recyclability is an important feature of catalysts econom-
ically. In the hybrid catalyst, highly stable crystalline 3D
supramolecular structure makes catalyst stable and
recyclable. In addition, good dispersion of POMs at the
molecular level prohibits conglomeration and high
immobilization of POMs overcomes catalyst leaching
and deactivation.
To test whether Nd/POM hybrid is recyclable, the
recycled catalyst was subjected to further reaction. The
results (Figure 7) show that catalyst recovery can be done
to five runs, and after each recycling; only a slight
decrease in catalytic activity can be seen.
ORCID
Majid M. Heravi https://orcid.org/0000-0003-2978-1157
Masoud Mirzaei https://orcid.org/0000-0002-7256-4601
REFERENCES
[1] R. K. Arafa, M. S. Nour, N. A. El‐Sayed, Eur. J. Med. Chem.
2013, 69, 498.
[2] L. Wei, S. V. Malhotra, Med. Chem. Comm. 2012, 3, 1250.
[3] M. R. Mahmoud, A. K. El‐Ziaty, M. F. Ismail, S. A. Shiba, Eur.
J. Chem. 2011, 2, 347.
[4] A. M. El‐Agrody, F. M. Ali, F. A. Eid, M. A. El‐Nassag, G. El‐
Sherbeny, A. H. Bedair, Phosphorus, Sulfur Silicon Relat. Elem.
2006, 181, 839.
4 | CONCLUSIONS
[5] N. Fujiwara, T. Nakajima, Y. Ueda, H. Fujita, H. Kawakami,
In summary, we report a green and efficient strategy for
Bioorg. Med. Chem. 2008, 16, 9804.
́
́
the synthesis of pyrazolo‐[4,3:5,6]pyrido[2,3‐d]pyrimi-
dine‐dione derivatives via a four and five component
reaction from the condensation of ethyl acetoacetate,
hydrazine hydrate or phenyl hydrazine, aryl aldehydes,
6‐amino‐1,3‐dimethyl uracil or 1,3‐dimethyl barbituric
acid and ammonium acetate in the presence of Na[Nd
(pydc‐OH)(H2O)4]3}[SiW12O40] under triply green condi-
tions. The use of the hybrid catalyst offers benefits such
as the easy operation, short reaction and excellent yields
of the products. This will not only lead to the creation
of a synthetic method, but will also enhance the
versatility of clean organic reactions in water.
[6] A. E. Amr, N. M. Sabry, M. M. Abdulla, Monatsh. Chem. 2007,
138, 699.
[7] L. K. Adsul, B. P. Bandgar, H. V. Chavan, S. S. Jalde, V. D.
Dhakane, A. L. Shirfule, J. Enzyme. Inhibit. Med. Chem. 2013,
28, 1316.
[8] L. Ballell, R. A. Field, G. A. Chung, R. J. Young, Bioorg. Med.
Chem. Lett. 2007, 17, 1736.
[9] D. W. Fry, M. A. Becker, R. L. Switzer, Mol. Pharmaceutics
1995, 47, 810.
[10] M. G. Gebauer, C. McKinlay, J. E. Gready, Eur. J. Med. Chem.
2003, 38, 719.
[11] G. W. Rewcastle, A. J. Bridges, D. W. Fry, J. R. Rubin, W. A.
Denny, J. Med. Chem. 1997, 40, 1820.
[12] M. Bakavoli, M. M. Heravi, H. Germaninajad, M. Rahimizadeh,
M. Ghassemzadeh, Phosphorus, Sulfur Silicon Relat. Elem.
2006, 181, 381.
ACKNOWLEDGMENTS
The authors appreciate partial financial supports from
Alzahra University. MMH is also thankful to Iran National
Science Foundation (INSF) for the individual given grant.
[13] A. Shaabani, M. Seyyedhamzeh, A. Maleki, M. Behnam, F.
Rezazadeh, Tetrahedron Lett. 2009, 50, 2911.

DARAIE ET AL.
9 of 9
[14] S. P. Satasia, P. N. Kalaria, D. K. Raval, Org. Biomol. Chem.
2014, 12, 1751.
[39] M. M. Heravi, S. Sadjadi, N. M. Haj, H. A. Oskooie, F. F.
Bamoharram, Catal. Commun. 2009, 10, 1643.
[15] M. T. Pope, Heteropoly and isopoly oxometalates, Springer‐
Verlag 1983.
[40] S. Sadjadi, M. M. Heravi, M. Daraie, J. Mol. Liquids. 2017,
231, 98.
[16] N. Mizuno, M. Misono, Chem. Rev. 1998, 98, 199.
[17] I. V. Kozhevnikov, Chem. Rev. 1998, 98, 171.
[41] M. Mirzaei, H. Eshtiagh‐Hosseini, N. Lotfian, A. Salimi, A.
Bauzá, R. Van Deun, R. Decadt, A. F. Barceló‐Oliver, Dalton
Trans. 2014, 43, 1906.
[18] M. M. Heravi, S. Sadjadi, J. Iran. Chem. Soc. 2009, 6, 1.
[19] S. S. Wang, G. Y. Yang, Chem. Rev. 2015, 115, 4893.
[20] I. V. Kozhevnikov, J. Mol. Catal. A: Chem. 2007, 262, 86.
[42] M. Alipour, O. Akintola, A. Buchholz, M. Mirzaei, H. Eshtiagh‐
Hosseini, H. Görls, W. Plass, Eur. J. Inorg. Chem. 2016, 2016,
5356.
[21] M. M. Heravi, M. Mirzaei, S. Y. Beheshtiha, V. Zadsirjan, F. M.
[43] A. Najafi, M. Mirzaei, J. T. Mague, CrystEngComm 2016, 18,
Ameli, M. Bazargan, App. Organometal. Chem. 2018, 32, e4479.
6724.
[22] R. Yu, X. F. Kuang, X. Y. Wu, C. Z. Lu, J. P. Donahue, Coord.
Chem. Rev. 2009, 253, 2872.
[44] M. Arab. Fashapoyeh, M. Mirzaei, H. Eshtiagh‐Hosseini, A.
Rajagopal, M. Lechner, R. Liu, C. Streb, Chem. Commun.
2018, 54, 10427.
[23] M. Mirzaei, H. Eshtiagh‐Hosseini, M. Alipour, A. Frontera,
Coord. Chem. Rev. 2014, 275, 1.
[45] N. Lotfian, M. Mirzaei, H. Eshtiagh‐Hosseini, M. Löffler, M.
Korabik, A. Salimi, Eur. J. Inorg. Chem. 2014, 2014, 5908.
[24] S. Taleghani, M. Mirzaei, H. Eshtiagh‐Hosseini, A. Frontera,
Coord. Chem. Rev. 2016, 309, 84.
[46] W. L. Xie, Z. J. C. Z. Y. Li, W. Q. Tao, Computation 2016, 4, 18.
[47] K. S. Walton, R. Q. Snurr, J. Am. Chem. Soc. 2007, 129, 8552.
[25] N. Lotfian, M. M. Heravi, M. Mirzaei, B. Heidari, Appl.
Organometal. Chem. 2019, 33, e4808.
[48] (a)A. Hassanpoor, M. Mirzaei, M. Niknam Shahrak, A. M.
Majcher, Dalton Trans. 2018, 47, 13849. (b)B. Ramezanpour,
M. Mirzaei, V. Jodaian, M. Niknam Shahrak, A. Frontera, E.
Molins, Inorg. Chim. Acta 2019, 484, 264.
[26] M. Wei, C. He, Q. Sun, Q. Meng, C. Duan, Inorg. Chem. 2007,
46, 5957.
[27] C. M. Granadeiro, R. A. Ferreira, P. C. Soares‐Santos, L. D.
Carlos, H. I. Nogueira, Eur. J. Inorg. Chem. 2009, 2009, 5088.
[49] M. Daraie, M. M. Heravi, ARKIVOC 2016, 4, 328.
[50] M. M. Heravi, M. Daraie, Molecules 2016, 21, 441.
[28] H. An, Z. Han, T. Xu, Inorg. Chem. 2010, 49, 11403.
[29] W. F. Zhao, C. Zou, L. X. Shi, J. C. Yu, G. D. Qian, C. D. Wu,
Dalton Trans. 2012, 41, 10091.
SUPPORTING INFORMATION
[30] M. M. Heravi, T. Alishiri, Adv. Heterocycl. Chem. 2014, 113, 1.
[31] M. M. Heravi, B. Talaei, Adv. Heterocycl. Chem. 2014, 113, 143.
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[32] M. M. Heravi, V. F. Vavsari, Adv. Heterocycl. Chem. 2015,
114, 77.
[33] M. M. Heravi, S. Khaghaninejad, M. Mostofi, Adv. Heterocycl.
Chem. 2014, 112, 1.
[34] M. M. Heravi, B. Baghernejad, H. A. Oskooie, R. Hekmatshoar,
Tetrahedron Lett. 2008, 49, 6101.
How to cite this article: Daraie M, Heravi MM,
Mirzaei M, Lotfian N. Synthesis of Pyrazolo‐
[4,3:5,6]pyrido[2,3‐d]pyrimidine‐diones Catalyzed
by a Nano‐sized Surface‐Grafted Neodymium
Complex of the Tungstosilicate via Multicomponent
Reaction. Appl Organometal Chem. 2019;e5058.
https://doi.org/10.1002/aoc.5058
[35] M. M. Heravi, L. Ranjbar, F. Derikvand, B. Alimadadi, H. A.
Oskooie, F. F. Bamoharram, Mol. Diversity 2008, 12, 181.
́
́
[36] M. M. Heravi, F. Derikvand, M. Haghighi, Monatsh. Chem.
2008, 139, 31.
[37] M. M. Heravi, G. Rajabzadeh, F. F. Bamoharram, N. Seifi,
J. Mol. Catal. A: Chem. 2006, 256, 238.
[38] S. Sadjadi, M. M. Heravi, M. Daraie, Res. Chem. Intermed. 2017,
43, 2201.