Green and rapid synthesis of dihydropyrimido [4,5-b]quinolinetrione derivatives using CoFe2O4@PPA as high efficient solid acidic catalyst under ultrasonic irradiation

Article abstract of DOI:10.1002/aoc.4996

A new high efficient and green protocol for the preparation of dihydropyrimido[4,5-b]quinolinetrione derivatives using magnetically solid acid catalyst was presented. High performance solid acid catalyst was prepared through a three-step reaction. Firstly

Full text of DOI:10.1002/aoc.4996

Received: 30 January 2019
DOI: 10.1002/aoc.4996
Revised: 21 April 2019
Accepted: 23 April 2019
F U L L P A P E R
Green and rapid synthesis of dihydropyrimido [4,5‐b]
quinolinetrione derivatives using CoFe2O4@PPA as high
efficient solid acidic catalyst under ultrasonic irradiation
Leila Moradi
| Pegah Mahdipour
Department of Organic Chemistry,
Faculty of Chemistry, University of
Kashan, Kashan, I. R. Iran
A new high efficient and green protocol for the preparation of dihydropyrimido
[4,5‐b]quinolinetrione derivatives using magnetically solid acid catalyst was
presented. High performance solid acid catalyst was prepared through a
three‐step reaction. Firstly, CoFe2O4 nano particles were synthesized using
co‐precipitation method. In second step, CoFe2O4 nano particles were coated
with SiO2 shell through treatment with tetraethyl orthosilicate (CoFe2O4
@SiO2). Finaly, CoFe2O4@SiO2 was modified with polyphosphoric acid
(CoFe2O4@SiO2/PPA) in a simple manner. Green reusable catalyst was char-
acterized in details using FTIR, VSM, TEM, FESEM, EDX and used as cata-
lyst for the synthesis of dihydropyrimido[4,5‐b]quinolinetrione derivatives.
Reaction was performed under ultrasonic irradiation as green, effective and
mild conditions and products were achieved in high to excellent yields.
Green and eco‐friendly conditions, short reaction times with high yield of
products in addition to easy workup are some merits of presented method.
Correspondence
Leila Moradi, Department of Organic
Chemistry. Faculty of Chemistry,
University of Kashan, P.O. Box
8731753153, Kashan, I.R. Iran.
Email: l_moradi@kashanu.ac.ir
Funding information
Chemistry Department of University of
Kashan, Grant/Award Number: 784946
KEYWORDS
CoFe2O4@SiO2/PPA, dihydropyrimido[4,5‐b]quinolinetrione, green chemistry, solid acidic catalyst,
ultrasonic irradiation
1 | INTRODUCTION
rapid, safe, clean and efficient condition for synthetic
chemistry.[15–20]
Now a day, sonochemistry as a new approach in organic
synthesis has attracted much attention. Ultrasonic irra-
diation as an energy source, offers a versatile and effec-
tive route for the synthesis of a wide variety of organic
compounds.[1–10] Ultrasonic effect on molecules doesn't
come from direct interaction of ultrasonic irradiation
in solution.[11,12] Instead, sonochemistry created from
acoustic cavitations (the formation, growth, and implo-
sive collapse of bubbles in a liquid). Bubble collapse
made enormous amounts of energy from the conversion
of the kinetic energy of the liquid motion into heating.
The temperature of these bubbles is around 5000 K,
with pressures of roughly 1000 atm.[13,14] Thus, the
Multi component reactions (MCRs) as an effective syn-
thetic method have been used to the formation of carbon–
carbon or carbon‐heteroatom bonds through combined
multiple reactions. This type of reactions offers a wide
range of complex molecules in a single step. Environmen-
tally benign, time and reagent saving, atom economy in
addition to operational simplicity and reduced steps of
work ups are some of the advantages of MCRs.[21–28] In
recent years, MCRs were used for the synthesis of het-
erocyclic compounds. Heterocycles containing pyrimi-
dine scaffold (as a core unit) and their analogues have
received considerable attentions due to their biological
and pharmaceutical activities[29–33] such as antibacte-
rial,[34] antileishmaniasis,[35] antitumor[36] and anti‐
ultrasonic irradiation provided
a green, powerful,
Appl Organometal Chem. 2019;e4996.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4996

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MORADI AND MAHDIPOUR
inflammatory.[37] Furthermore, due to unique biological
and pharmacological properties of pyrimido [4, 5‐b] quin-
oline derivatives such as antioxidant,[38] antitumore[39]
and antiviral[40] activities, synthesis of this class of com-
pounds have gained great interest in synthetic organic
chemistry. Recently, various methods were published
for the synthesis of pyrimido [4, 5‐b] quinolintriones
through multicomponent condensation reaction in the
presence of different catalyst such as RuCl3, xH2O,[41]
tungstoposphoric acid (H3PW12O40) under ultrasonic
irradiation,[42] TEBAC[43] and [MSim]Cl ionic liquid.[44]
In spite of potential benefits of these methods, some of
them suffer from disadvantages such as long reaction
times, low yields, high temperature and the use of toxic
solvents in addition to the formation of side products.
In this paper, we developed a green and efficient pro-
tocol for the synthesis of dihydropyrimido[4,5‐b]
quinolinetrione derivatives through one‐pot condensa-
tion of benzaldehyde derivatives, dimedone, barbituric
acid and amines in the presence of polyphosphoric acid
supported on CoFe2O4 nanoparticles (CoFe2O4@SiO2/
PPA) as a magnetically recoverable solid acid catalyst.
The reaction was performed under ultrasonic irradiation
as a powerful and green rout in ambient conditions.
High yield of products and short reaction times are the
considerable merits of presented protocol (Scheme 1).
FIGURE 1 FTIR of a) CoFe2O4 nanoparticles, b) CoFe2O4@SiO2
c) PPA and d) CoFe2O4@SiO2/PPA
CoFe2O4@SiO2 exhibits strong band in 586 cm−1 due
to metal oxide skeleton. The characteristic band of Si‐O
is observed at 1164 cm−1 and also the peak at
1628 cm−1 shows the existence of Fe‐O vibrations. Also,
the broad band at 3415 cm−1 is from stretching vibration
of –OH groups (Figure 1b). In FTIR spectra of PPA
(Figure 1c), a broad peak at about 2400 to 3400 cm−1
can be assigned to P‐OH stretching vibrations. Peaks at
1005 and 1065 cm−1 regions are from stretching vibration
of P‐O bands; also the sign at 1638 cm−1 come from O
groups. In FTIR spectra of CoFe2O4@SiO2/PPA
(Figure 1d), the main peaks of Si‐O and PPA are existed
and confirmed the chemically attachment of PPA
(through TEOS as linker) to nanoparticle surfaces.
2 | RESULTS AND DISCUSSION
Study on the formation of CoFe2O4 nanoparticles was
supported by FTIR spectroscopy. As can be seen in
Figure 1a, the broad absorption peak in the FTIR spectra
of CoFe2O4 nanoparticles around 3414 cm−1 is attributed
to the normal stretching vibration of ‐OH groups on
nanoparticle surfaces and H2O molecules, which come
from moisture in the nanocrystalline sample and
adsorbed water with KBr. The weak doublet band at
2850 and 2921 cm−1 regions is from symmetric and anti-
symmetric stretching modes of ‐CH group of methylene
(–CH2–) from remained solvents between nanoparticles.
The band in 587 cm−1 and 1624 cm−1 regions are from
metal–oxygen stretching vibration bonds.[45]
XRD pattern of as prepared and modified CoFe2O4 are
presented in Figure 2. As can be seen, the XRD patterns
show the reflections namely (220), (311), (222), (400),
(422), (511) and (440) that are indexed based on the
JCPDS standard. All peaks are in agreement with the
SCHEME 1 Synthesis of dihydropyrimido[4,5‐b]quinolinetriones using CoFe2O4@SiO2/PPA under ultrasonic irradiation

MORADI AND MAHDIPOUR
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pattern of modified nanoparticles is as the same of pris-
tine nanoparticles and demonstrates that modification
process had no damaging effect on crystality of CoFe2O4
structure.
Further characterization of raw and modified nanopar-
ticles was done using FESM technique (Figure 3). It is
clear that the dually metal oxide nanoparticles were pre-
pared in nanoscale with size of about 22 to 27 nm and
good distribution. Also, FESEM image of treated nano-
particles (CoFe2O4@SiO2/PPA) show that the size of
nanoparticles becomes larger than raw material due to
surface modification and also no changes and damaging
occurred on nanoparticles structure. TEM images of cata-
lyst (Figure 3c, 3d), demonstrated the nanometric size
and good dispersion of nano catalyst particles. Obtain
results from FESEM and TEM techniques are in good
agreement with those concluded from the XRD analysis
(Figure 2).
The EDX spectra display the composition of as pre-
pared and modified CoFe2O4 nanoparticles. As can be
seen in Figure 4a, pristine CoFe2O4 nanoparticles are
contained to Fe, O and Co elements. In the EDX spec-
trum of CoFe2O4@SiO2/PPA (Figure 4b), Si and P were
observed in addition to Fe, Co and O elements. The pres-
ence of Si and P in composition of prepared catalyst (13
and 10% respectively), demonstrated the attachment of
SiO2/PPA on nanoparticle surfaces.
FIGURE 2 XRD pattern of: CoFe2O4 nanoparticles (a) and
CoFe2O4@SiO2/PPA (b)
single‐phase spinel structure. The average crystal size of
CoFe2O4 nanoparticles was about 28 nm (calculated by
Scherrer equation).[46] On the other hand, the XRD
Thermogravimetric analysis was used to confirm the
attachment of SiO2/PPA groups on CoFe2O4 nanoparti-
cles surfaces (Figure 5). Figure 5a shows that there is no
FIGURE 3 FESEM images of: a) CoFe2O4 and b) CoFe2O4@SiO2/PPA and TEM images of CoFe2O4@SiO2/PPA (C,d)

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MORADI AND MAHDIPOUR
Magnetic characterization of CoFe2O4 nanoparticles
and CoFe2O4@SiO2/PPA was done using vibrating sam-
ple magnetometer (VSM) at room temperature with
maximum applied field of 15 kOe (Figure 6). For
CoFe2O4@SiO2/PPA, the saturation magnetization (MS)
was 20 emu/g, while in case of CoFe2O4 nanoparticles
the value for the same parameter was 68 emu/g. This
result is attributed to the effect of modification which
subsequently decreases the saturation magnetization
FIGURE 4 EDX spectra of a: CoFe2O4 and b: CoFe2O4@SiO2/
PPA
weight loss in TGA curve of CoFe2O4 nanoparticles.
Instead, TGA analysis of catalyst shows a weight loss of
3% at the range of 50 to 150 °C which is related to the
removal of water that physically adsorbed on nanoparti-
cle surfaces. The weight loss of about 19% between 150
to 600 °C is attributed to the thermal decomposition of
PPA and linker (TEOS) that were chemically attached
on nanoparticle surfaces (Figure 5b). Results from TGA
curves confirmed the immobilization of SiO2/PPA groups
to the CoFe2O4 nanoparticle surfaces.
FIGURE 6 VSM analysis of: a) CoFe2O4 nanoparticles and b)
CoFe2O4@SiO2/PPA
FIGURE 5 TGA curves of a: CoFe2O4
and b: CoFe2O4@SiO2/PPA

MORADI AND MAHDIPOUR
5 of 14
TABLE 2 Optimization of solvent for preparation of compound
4a
value. Consequently, synthesis of catalyst has been
occurred successfully.
In continue of our research, the prepared and charac-
terized catalyst was applied for multicomponent prepara-
tion of dihydropyrimido[4,5‐b]quinolinetrione derivatives
under ultrasonic irradiation. Firstly, the best amount of
catalyst was estimated using the four component reaction
of aniline, barbituric acid, dimedone and benzaldehyde
(as model reaction) in EtOH. Several tests were done in
the presence of various amounts of catalyst under ultra-
sonic irradiation with the power of 50 w. As can be seen
in Table 1, 0.01 g of catalyst was the best quantity to
achieve the product in the highest yield (95% entry 4).
Also, the further amount of catalyst has any effect on
the yield of product.
Entry
Solvent
Time (min)
Yield (%)a
1
2
3
4
5
CHCl3
10
8
27
35
46
95
88
CH3CN
H2O
9
C2H5OH
C2H5OH/H2O
4
5
aIsolated yield.
TABLE 3 Optimization of the power of ultrasonic irradiation for
synthesis of 4a
Entry
Power (w)
Time (min.)
Yield (%)a
After determining the best amount of catalyst, solvent
effect on the time and yield of reaction was studied.
Model reaction was done in the presence of 0.01 g of cat-
alyst under ultrasonic irradiation (with power of 50 w) in
different solvent media. Results depicted in Table 2 shows
that EtOH can be considered as suited solvent (entry 4).
The influence of various power of ultrasonic irradia-
tion on reaction has been investigated using the perfor-
mance of model reaction under ultrasonic irradiation
with different powers (Table 3). It was observed that the
power of 50 w was afforded the best result (entry 3). Also
In order to determine the ultrasound irradiation effect on
the performance of model reaction, one test was done
under silent condition with magnetic stirring at room
temperature (entry 5). Result shows the low yield of the
desired product (after 30 min) and consequently proved
the strong effect of ultrasonic waves on time, yield and
performance of reaction.
1
2
3
4
5
30
40
50
60
‐
6
5
83
85
4
95
4
92
30
21b
aIsolated yield
bIsolated yield under silent conditions
through the preparation of dihydropyrimido[4,5‐b]
quinolinetriones using various aniline and aldehyde
derivatives. Results were collected in Table 4. As can
be seen, in all cases, products were obtained in excellent
yields and short reaction times. Also when
terephthaldehyde was used, the reaction time was
increased to 10 min due to two aldehyde sites (4e). On
the other hand, in the case of aliphatic amines and
ammonium acetate (as NH3 source), no enhancement
of reaction times was observed (4i‐4 l).
The efficiency of catalyst in the presence of opti-
mized solvent and ultrasonic power was investigated
TABLE 1 Optimization of the catalyst amounta
Entry
Catalyst (g)
Time (min.)
Yield (%)b
1
2
3
4
5
‐
10
8
12
48
65
95
95
0.001
0.005
0.01
0.015
6
4
4
aaniline (1 mmol), barbituric acid (1 mmol), dimedone (1 mmol) and benzaldehyde (1 mmol), EtOH (5 ml) under ultrasonic irradiation with power of 50 w.
bIsolated yield.

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MORADI AND MAHDIPOUR
TABLE 4 Synthesis of dihydropyrimido[4,5‐b]quinolinetriones using CoFe2O4@SiO2/PPA
product
Aldehyde
Amine
Product
Time (min)
Yield (%)
m.p (°C)
Ref.
[42]
4a
4
95
230–232
[42]
4b
4
96
257–259
4c
3
95
253–255
‐
4d
3
92
250–252
‐
[42]
4e
10
92
>300
(Continues)
The efficiency of catalyst was studied through the com-
parison of the time and yield of reaction in the presence of
other catalysts (under thermal and ultrasonic conditions).
Results in Table 5 show that CoFe2O4@SiO2/PPA had the
highest efficiency both in thermal and ultrasonic condi-
tions (entry 11, 12).
The role of catalyst during the reaction process dis-
plays in scheme 3. According to the Khalafi‐Nejhad et al.
proposed reaction mechanism,[42] initially, barbituric acid
reacted with activated aldehyde through a Knovenagel
condensation to generate of intermediate A. then,
dimedone (in the enol form) added to A in a conjugate

MORADI AND MAHDIPOUR
7 of 14
TABLE 4 (Continued)
product
Aldehyde
Amine
Product
Time (min)
Yield (%)
m.p (°C)
Ref.
[42]
4f
3
95
218–220
[42]
4 g
3
93
281–283
[42]
4 h
5
91
225–227
[42]
4i
4j
4
5
90
94
210–212
[43]
>300
[47]
4 k
4
3
88
92
>300
>300
[43]
4la
a1,3‐cyclohexadione was used instead of dimedone

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MORADI AND MAHDIPOUR
TABLE 5 Comparison the efficiency of catalysts for the synthesis
of 4a
water elimination, lead to the desired product
(Scheme 2).
Further evidence for demonstrating the proposed
mechanism was the separation and characterization of
intermediate C (8,8‐Dimethyl‐5‐phenyl‐8,9‐dihydro‐1H‐
chromeno[2,3‐d]pyrimidine‐2,4,6(3H,5H,7H)‐trione) that
generates from the reaction of barbituric acid,
arylaldehyde and dimedone in the presence of catalyst.
Entry Catalyst/condition
Time Yield (%)a
1
s‐NFCb/Ethanol, reflux
s‐BCc/Ethanol, reflux
none/EtOH, US
45 min 92
40 min 94
10 min 16
2
3
4
none/EtOH, 80 °C
AlCl3/EtOH, 80 °C
CoFe2O4 NPs/EtOH,80 °C
CoFe2O4 NPs/EtOH, US
PPA/EtOH, 80 °C
24 h
12 h
3 h
12
35
47
1
Spectral data from FTIR and HNMR analysis of C was
5d
shown that mentioned intermediate was made through
the reaction process and the reaction was proceeded
according to mechanism which presented in Scheme 2.
Reusability of catalyst was examined using model
reaction under optimized conditions. As shown in
Figure 7a, the catalyst can be easily separated from the
reaction mixture by an external magnet. After comple-
tion of the reaction, catalyst was separated and washed
with ethanol (twice) and dried at 80 °C for 4 h. The
dried catalyst was reused six times for the same reac-
tion. As can be seen in Figure 7b, the catalyst has good
efficiency after six times recycling with low decreasing
in yield of product. Figure 8 shows the SEM photograph
of reused catalyst. As can be seen, there are no changes
in morphology of nanocatalyst after recycling and this
result is consistent with FTIR and XRD pattern of
recycled sample (Figure 9).
6
7
9 min 65
7 h 70
6 min 80
8
9
PPA/EtOH, US
10d
11
12
13
14
15b
PTSA/EtOH, 80 °C
5 h
81
90
CoFe2O4@SiO2/PPA/EtOH, 80 °C 4 h
CoFe2O4@SiO2/PPA/EtOH, US
CoFe2O4@SiO2/SO3H/EtOH, 80 °C 5 h
4 min 95
88
7 min 72
5 h 91
CoFe2O4@SiO2/SO3H/EtOH, US
H3PW12O40/EtOH, 80 °C
aIsolated yield
bNanofibrillated cellulose sulfuric acid[48]
cNanobacterial cellulose sulfuric acid[48]
Reference 39
In order to verify the stability of catalyst during the
reaction process, hot filtration method was carried out.
In this way, the catalytic synthesis of compound 4a was
carried out under ultrasonic irradiation. The reaction
was performed for 2.5 min and then the catalyst was
route to produced intermediate B. after the intramolecu-
lar condensation of B, and then water removal, C is
formed. In continue, the reaction of amine with C and
SCHEME 2 Reaction mechanism for
the preparation of dihydropyrimido[4,5‐b]
quinolinetriones using CoFe2O4@SiO2/
PPA

MORADI AND MAHDIPOUR
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FIGURE 9 XRD pattern (a) and FTIR (b) of recycled catalyst
FIGURE 7 Separeation of magnetically catalyst by external
magnet (a), reusability of CoFe2O4@SiO2/PPA (b)
FIGURE 10 Hot filtration result for the synthesis of
dihydropyrimido [4,5‐b]quinolinetrione derivatives without
catalyst filtration (blue diagram) and catalyst filtration after 2 min
(red diagram)
yield of product was stable after removal of catalyst and
obtained result proved that CoFe2O4@SiO2/PPA is stable
during the reaction and no catalyst leaching was observed.
To continue, ICP‐AES analysis was carried out for
CoFe2O4, CoFe2O4@SiO2/PPA and recycled catalyst.
According to results depicted in Table 6, the content of
Co and Fe was 19.8 and 46.4% in CoFe2O4 nanoparticles
that was in agreement with EDX result. The weight
percentage of Co and Fe in the fresh catalyst
FIGURE 8 SEM image of recycled catalyst
separated using external magnetic field. After that, reac-
tion mixture (without CoFe2O4@SiO2/PPA) was contin-
ued for other 1.5 min. as can be seen in Figure 10, the

10 of 14
MORADI AND MAHDIPOUR
TABLE 6 BET and ICP analysis of CoFe2O4, CoFe2O4@SiO2/
PPA and recovered catalyst
catalyst with inductively coupled plasma optical emission
spectroscopy (ICP‐AES) were obtained from an ICP‐AES
simultaneous instrument (VISTA‐PRO). Brunauer
Emmett Teller (BET) analysis was used to determine
the surface area of catalyst by Microtrac BEL Corp
instrument. All of characterisation data for prepared cat-
alyst were cited in results and discussion section and also
the analysis data of synthesized products will cited in
experimental section (Supporting Information).
ICP
Sample
BET (m2/g) %Co %Fe
CoFe2O4
110.2
82.1
79.6
19.8
16.5
16.2
46.4
23.6
23.1
CoFe2O4@SiO2/PPA
CoFe2O4@SiO2/PPA after 1st use
(CoFe2O4@SiO2/PPA) was 16.5 and 23.6% respectively
also the content of Co and Fe in the recovered catalyst
was 16.2 and 23.1 wt%. Based on these results, it can
be concluded that there is no substantial difference in
weight percentage of Co and Fe in fresh and recovered
catalyst and subsequently, no leaching occurred.
The surface area of CoFe2O4 nanoparticles, fresh and
recycled catalyst was determined by the nitrogen physical
adsorption and was carried out at liquid nitrogen boiling
point. The surface area of CoFe2O4 nanoparticles and
CoFe2O4@SiO2/PPA was 110.5 and 82.1 m2 g−1, respec-
tively (Table 6). The lower surface area of catalyst is a con-
sequence of successful immobilizing the polyphosphoric
acid onto the surfaces of silica coated CoFe2O4 nanoparti-
cles. Also the surface area of the first recycled catalyst was
79.6 m2 g−1 that shows the surface area of recycled catalyst
was close to the fresh sample and no considerable
poisoning happened on the catalyst surfaces.
3.2 | Preparation of CoFe2O4 nanoparticles
A mixture of FeCl3·6H2O (0.54 g, 2 mmol) and
CoCl2·6H2O (0.13 g, 1 mmol) dissolved in distilled water
((100 ml) was poured to a three‐necked flask equipped
with a mechanical stirrer. Then, a solution of NaOH
(3 mol/L, 50 ml) was added and stirred vigorously for
20 min. After that, the mixture was heated to reflux for
2 hr to yield a black dispersed mixture. Then, nanoparti-
cles were separated with an external magnet and washed
with distilled water and ethanol for three times to reach
the neutral PH and finally dried at 100 °C for 24 hr.
3.3 | Preparation of CoFe2O4@SiO2/PPA
In order to prepare of the catalyst, firstly, CoFe2O4 nanopar-
ticles were coated with silica layer. A dispersed solution of
CoFe2O4 nanoparticles (1 g in 50 ml EtOH) was prepared
using sonication in a bath sonicator for 30 min. Then, a con-
centrated ammonia solution (2 ml) was added and stirred
for 30 min at 60 °C. After that, tetraethylorthosilicate
(TEOS) (1.0 ml dissolved in 10 ml EtOH) was added drop
wise to the reaction mixture and continuously stirred at
60 °C for 24 hr. After the time, the silica coated nanoparti-
cles (CoFe2O4@SiO2) were separated using an external
magnetic field and washed with methanol (three times)
and dried. For preparing the CoFe2O4@SiO2/PPA,
polyphosphoric acid (0.5 g) dissolved in CHCl3 (50 ml)
was poured in a round‐bottom flask and stirred at 50 °C
for 2 hr; then, CoFe2O4@SiO2 (1 g) was added and stirred
for 4 hr. After that, resulted solid was separated and washed
with cold absolute EtOH and dried in vacuo at 80 °C
(Scheme 3). The amount of H+ determined by acid–base
titration was about 0.7 mmol/g.
3 | EXPERIMENTAL
3.1 | Materials and methods
Chemical reagents were purchased from the Merck and
Aldrich Company. Melting points were determined in
open capillaries using an Electro thermal MK3 apparatus.
FTIR spectra were recorded using a Perkin‐Elmer FT‐IR
1
550 Spectrometer. H NMR and 13CNMR spectra were
recorded with a Bruker Avance DPX‐400 spectrometer
at 400 and 100 MHz, respectively. Magnetic properties
were characterized by a vibrating sample magnetometer
(VSM, MDKFD) at room temperature. FE‐SEM images
and EDX analysis were used by a Sigma ZEISS, Oxford
Instruments Field Emission Scanning Electron Microscope.
Ultrasonication was performed in a BANDELIN ultrasonic
HD 3200 instrument with probe model US 70/T with diam-
eter of 6 mm that was immersed directly into the reaction
mixture. The operating frequency was 20 KHz and the out-
put power was 30–60 W through manual adjustment.
Mass spectroscopic analysis was recorded on a Finnigan
MAT 44S by Electron Ionization (EI) mode with an ion-
ization voltage of 70 eV. Elemental analyses of the
3.4 | General procedure for preparation of
dihydropyrimido[4,5‐b]quinolinetrione
derivatives
A mixture of barbituric acid (1 mmol), dimedone (1 mmol),
aromatic aldehyde (1 mmol), and CoFe2O4@SiO2/PPA

MORADI AND MAHDIPOUR
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SCHEME 3 Preparation process of CoFe2O4@SiO2/PPA
(0.01 g) in EtOH (5 ml) was sonicated (by probic
sonicator) for 1 min with power of 50 w; after that,
amine (1 mmol) was added and sonicated under the
same power. The progress of the reaction was monitored
by TLC. After the completion of the reaction, the mix-
ture was cooled to room temperature and 5 ml EtOH
was added and the catalyst was separated using an
external magnet. Obtained product was separated using
simple filtration and washed with EtOH and n‐hexane
to afford the pure products.
(ppm): 1.02 (s, 6H, 2CH3), 2.18–2.39 (m, 4H, 2CH2), 3.37
(s, 3H, CH3), 6.15 (s,1H, CH), 6.95 (d, 2H, J = 8 Hz,
H‐Ar), 7.14 (d, 2H, J = 8 Hz, H‐Ar), 7.46 (d, J = 8 Hz,
2H, H‐Ar), 7.80 (s, 1H, H‐Ar), 7.88–7.92 (m, 1H, H‐Ar),
9.71 (s, 1H, NH), 10.22 (s, 1H, NH); Anal. Calcd for
C26H24N4O6 (488.49): C, 63.93; H, 4.95; N, 11.47; O,
19.65; Found: C, 63.90; H, 4.91; N, 11.43; O, 19.59.
10‐(4‐methoxyphenyl)‐8,8‐dimethyl‐5‐(4‐nitrophenyl)‐
5,8,9,10‐tetrahydropyrimido[4,5‐b]quinoline‐
2,4,6(1H,3H,7H)‐trione (4c)
Yield: 95%; white solid; mp 253–252 °C; FTIR (KBr) υ (cm
3.4.1 | Spectral data
−1): 3100 (NH), 3031 (C=C‐H), 2984 (C‐H), 1688 (C=O),
1
8,8‐Dimethyl‐5,10‐diphenyl‐8,9‐dihydropyrimido[4,5‐b]
quinoline‐2,4,6(1H,3H,5H,7H,10H)‐trione (4a)
1601 (C=C aromatic), 1154 (C‐O); H NMR (DMSO‐d6,
400 MHz): δ (ppm) 0.91 (s, 6H, 2CH3), 2.00–2.31 (m,
4H, 2CH2), 3.72 (s, 3H, CH3), 6.12 (s, 1H, CH), 6.93 (d,
2H, J = 8 Hz, H‐Ar), 7.12 (d, 2H, J = 8 Hz, H‐Ar), 7.65
(d, 2H, J = 8 Hz, H‐Ar), 7.79–7.97 (m, 4H, Ar‐H), 9.81 (s,
1H, NH), 10.22 (s, 1H, NH); 13C NMR (DMSO‐d6,
75 MHz): δ (ppm) 27.30, 30.20, 31.40, 56.20, 88.35, 90.50,
119.15, 120.25, 122.50, 124.40, 127.35, 128.20, 130.10,
148.60, 149.30, 152.30, 153.40, 155.50, 164.10; Anal. Calcd
for C26H24N4O6 (488.49): C, 63.93; H, 4.95; N, 11.47; O,
19.65, Found: C, 63.90; H, 4.91; N, 11.43, O, 19.59.
Yield: 95%; pale yellow solid; mp 230–232 °C; FTIR (KBr)υ
(cm−1): 3200 (NH), 3000 (C=C‐H), 2923 (C‐H), 1692
(C=O), 1493 (C=C aromatic); 1H NMR (DMSO‐d6,
400 MHz): δ (ppm) 0.93 (s, 3H, CH3), 1.30 (s, 3H, CH3),
2.29–2.49 (m, 4H, 2CH2), 5.98 (s,1H, CH), 6.73 (d, 2H,
J = 8 H, H‐Ar), 6.98–7.16 (m, 6H, H‐Ar), 10.30 (s, 1H,
NH), 10.90 (s, 1H, NH); Anal. Calcd for C25H23N3O3
(413.47): C, 72.62; H, 5.61; N, 10.16; O, 11.61; Found: C,
72.58; H, 5.59; N, 10.13; O, 11.58.
10‐(4‐Methoxyphenyl)‐8,8‐dimethyl‐5‐(3‐nitrophenyl)‐
8,9‐di‐hydropyrimido[4,5‐b]quinoline‐
2,4,6(1H,3H,5H,7H,10H)‐tri‐ one (4b)
8,8‐dimethyl‐5‐(4‐nitrophenyl)‐10‐phenyl‐5,8,9,10‐
tetrahydropyrimido[4,5‐b]quinoline‐2,4,6(1H,3H,7H)‐
trione (4d)
Yield: 96%; yellow color; mp 257–259 °C, FTIR (KBr) υ
Yield: 92%; white solid; mp 250–252 °C; FTIR (KBr) υ
(cm−1): 3336 (NH), 3023 (C=C‐H), 1692 (C=O), 1616
(C=C aromatic), 1406 (NO2); 1H NMR (DMSO‐d6,
(cm−1): 3200 (NH), 2956 (C‐H), 1692 (C=O), 1596 (C=C
1
aromatic), 1344 (NO2); H NMR (DMSO‐d6, 400 MHz) δ

12 of 14
MORADI AND MAHDIPOUR
400 MHz): δ (ppm) 1.01(s, 6H, 2CH3), 2.06 (s, 4H, 2CH2),
6.11 (s, 1H), 6.91–7.95 (m, 3H, H‐Ar), 7.25 (d, 4H,
J = 8 Hz, H‐Ar), 8.04–8.21 (m, 2H, H‐Ar), 10.12 (s, 1H,
NH), 10.91 (s, 1H, NH); Anal. Calcd for C25H22N4O5
(458): C, 65.50; H, 4.80; N, 17.46; O, 12.24, Found: C,
65.51; H, 4.78; N, 17.42; O, 12.29; MS (ESI) m/z: 458
(M+), 256 (55), 226 (100), 128 (30), 93 (90), 55 (17).
(C=O), 1630 (C=C aromatic); 1H NMR (DMSO‐d6,
400 MHz) δ (ppm): 0.92 (s, 3H, CH3), 1.00 (s, 3H,
CH3), 2.00–2.40‐ (m, 4H, 2CH2), 2.52 (m, 4H, 2CH2),
2.64 (s, 3H, NMe2), 2.81 (s, 3H, NMe2) 5.90 (s, 1H,
CH), 6.21 (s, 1H, CH), 6.45 (d, 1H, J = 8 Hz, Ar‐H),
6.63 (d, 1H, J = 8 Hz, Ar‐H), 6.90–7.40 (m, 4H, Ar‐H),
10.01(s, 1H, NH), 10.90 (s, 1H, NH); Anal. Calcd for
C22H27N5O2S (425.55): C, 62.09; H, 6.40; N, 16.46; O,
7.52 Found: C, 62.06; H, 6.38; N, 16.45; O, 7.49.
1,4‐Bis[10‐(4‐methoxyphenyl)‐8,8‐dimethyl‐8,9‐
dihydropyrim‐ido[4,5‐b]quinoline‐2,4,6
(1H,3H,5H,7H,10H)‐trione]benzene (4e)
8,8‐Dimethyl‐5‐phenyl‐8,9‐dihydropyrimido[4,5‐b]quin-
oline‐2,4,6(1H,3H,5H,7H,10H)‐trione (4i)
Yield: 92%; yellow solid; >300 °C; FTIR (KBr) υ (cm−1):
3078 (NH), 2959 (C=C‐H), 1703 (C=O), 1568 (C=C aro-
Yield: 90%; white solid; mp 210–212 °C; FTIR (KBr) υ
(cm−1): 3200 (NH), 2954 (C=C‐H), 1701 (C=O), 1584
(C=C aromatic); 1H NMR (DMSO‐d6, 400 MHz) δ (ppm):
0.91 (s, 6H, 2CH3), 2.00–2.31 (m, 4H, 2CH2), 6.01 (s, 1H),
6.91–7.32 (m, 5H, H‐Ar), 9.51 (s, 1H, NH), 1.00 (s, 1H,
NH); Anal. Calcd for C19H19N3O3 (337.37): C, 67.64; H,
5.68; N, 12.46; O, 14.22, Found: C, 67.61; H, 5.65; N,
12.42; O, 14.25.
1
matic); H NMR (DMSO‐d6, 400 MHz): δ (ppm) 1.00 (s,
6H, CH3), 2.06–2.25 (m, 4H, CH2), 3.33 (s, 3H, OCH3),
5.91 (s, 1H, CH), 6.90–7.12 (m, 6H, H‐Ar), 9.48(s, 1H,
NH), 10.06 (s, 1H, NH); Anal. Calcd for C46H44N6O8
(808.88): C, 68.30; H, 5.48; N, 10.39; O, 15.83, Found: C,
68.25; H, 5.44; N, 10.36; O, 15.95.
8,8‐Dimethyl‐10‐[2‐(piperazin‐1‐yl)ethyl]‐5‐(thiophen‐
2‐yl)‐8,9‐dihydropyrimido[4,5‐b]quinoline‐2,4,6
(1H,3H,5H,7H,10H)‐trione (4f)
5‐(4‐Hydroxyphenyl)‐8,9‐dihydropyrimido[4,5‐b]quino-
line‐2,4,6(1H,3H,5H,7H,10H)‐trione (4j)
Yield: 95%; yellow color; mp 218–220 °C; FTIR (KBr) υ
(cm−1): 3200 (NH), 2963 (C=C‐H), 1688 (C=O), 1596
(C=C aromatic); 1H NMR (DMSO‐d6, 400 MHz) δ
(ppm): 0.93 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.91 (s,
1H, NH), 2.23 (m, 4H, 2CH2), 2.48 (m, 8H, 4CH2), 2.81
(s, 2H, CH2), 2.95 (s, 2H, CH2), 6.12 (s, 1H, CH), 6.31–
6.54 (m, 1H, Ar‐H), 6.62–6.81 (m,1H, Ar‐H), 6.92–7.12
(m, 1H, Ar‐H), 9.52 (s, 1H, NH), 10.00(s, 1H, NH); Anal.
Calcd for C23H29N5O3S (455.57): C, 60.64; H, 6.42; N,
15.37; O, 10.54, Found: C, 60.61; H, 6.38; N, 15.32, 10.51.
Yield: 94%; white solid; mp >300 °C; FTIR (KBr) υ (cm−1):
3200 (NH), 2955 (C=C‐H), 1691 (C=O), 1596 (C=C aro-
1
matic); H NMR (DMSO‐d6, 400 MHz) δ (ppm): 1.01 (s,
6H, 2CH3), 2.21 (s, 2H, CH2), 2.49 (m, 2H, CH2), 6.05 (s,
1H, CH), 6.95 (d, 2H, J = 8 Hz, H‐Ar), 7.16 (d, 2H,
J = 8 Hz, H‐Ar), 7.43 (q, 2H, J = 8 Hz, H‐Ar), 7.80 (s, 1H,
OH), 7.94 (s, 1H, NH), 9.81 (s, 1H, NH), 10.32 (s, 1H,
NH); Anal. Calcd. For C19H19N3O4: C, 64.58; H, 5.42; N,
11.89; O, 18.11, Found: C, 64.63; H, 5.36; N, 11.97; O, 18.04.
5‐(4‐Chlorophenyl)‐8,8‐dimethyl‐7,8,9,10‐tetrahydro‐
pyrimido[4,5‐b]quinoline‐2,4,6(1H,3H,5H)‐trione (4 k)
Yield: 88%; white solid; mp > 300 °C; FTIR (KBr) υ (cm−1):
3142 (NH), 3055 (C=C‐H), 1690 (C=O), 1595 (C=C aro-
10‐(4‐Iodophenyl)‐8,8‐dimethyl‐5‐(4‐nitrophenyl)‐8,9‐
dihydro‐ pyrimido[4,5‐b]quinoline‐2,4,6(1H,3H,5H,7H,
10H)‐trione (4 g)
1
Yield: 93%; yellow solid; mp 281–283 °C; FTIR (KBr) υ
(cm−1): 3336 (NH), 3100 (C=C‐H), 1691 (C=O), 1599
(C=C aromatic); 1H NMR (DMSO‐d6, 400 MHz): δ
(ppm) 0.93 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.16–2.31
(m, 4H, 2CH2), 5.92 (s, 1H, CH), 6.85–6.87 (d, 2H,
J = 8 Hz, H‐Ar), 7.00–7.02 (d, 2H, J = 8 Hz, H‐Ar),
7.20–7.28 (m, 4H, Ar‐H), 10.06 (s, 1H, NH), 10.85 (s, 1H,
NH); Anal. Calcd for C25H21IN4O5 (584.36): C, 51.38; H,
3.62; N, 9.59; O, 13.69, Found: C, 51.35; H, 3.59; N, 9.57;
O, 13.72.
matic); H NMR (DMSO‐d6, 400 MHz) δ (ppm): 1.00 (s,
6H, 2CH3), 2.06–2.21 (m, 4H, 2CH2), 5.82 (s, 1H, NH),
6.95 (d, 2H, J = 8 Hz, H‐Ar), 7.05–7.28 (m, 2H, H‐Ar),
9.35 (s, 1H, NH), 9.81 (s, 1H, NH), 1.032 (s, 1H, NH); Anal.
Calcd. For C19H18ClN3O3: C, 61.38; H, 4.88; N, 11.30, O,
12.92, Found: C, 61.42; H, 4.92; N, 11.25; O, 12.89.
5‐(4‐Nitrophenyl)‐8,9‐dihydropyrimido[4,5‐b]quino-
line‐2,4,6(1H,3H,5H,7H,10H)‐trione (4 l)
Yield: 92%; yellow solid; >300 °C; FTIR (KBr) υ (cm−1):
3370 (NH), 3135 (C=C‐H), 1711 (C=O), 1652 (C=C aro-
1
10‐[2‐(Dimethylamino)ethyl]‐8,8‐dimethyl‐5‐(pyridin‐4‐
yl)‐2‐thioxo‐2,3,8,9 tetrahydropyrimido[4,5‐b]quinoline‐
4,6(1H,5H,7H,10H)‐dione (4 h)
matic), 1518, 1350)NO2); H NMR (DMSO‐d6, 400 MHz)
δ (ppm): 1.80 (d, 2H, J = 4 Hz, CH2), 2.21 (m, 2H,
CH2), 2.58 (d, 2H, J = 4 Hz, CH2), 4.87 (s, 1H, CH), 7.34
(d, 2H, J = 8 Hz, Ar‐H), 7.45)d, 2H, J = 8.8 Hz, Ar‐H),
8.06 (d, 1H, J = 8 Hz, Ar‐H), 9.03 (s, 1H, NH), 10.20 (s,
Yield: 91%; pale yellow solid; mp 225–227 °C; FTIR
(KBr) υ (cm−1): 3355 (NH), 3159 (C=C‐H), 1716

MORADI AND MAHDIPOUR
13 of 14
[7] M. Atobe, Y. Kado, R. Asami, T. Fuchigami, T. Nonaka,
1H, NH), 10.60 (s, 1H, NH); Anal. Calcd. For
C17H14N4O5: C, 57.63; H, 3.98; N, 15.81; O, 22.58, Found:
C, 57.68; H, 4.09; N, 15.74; O, 22.49.
Ultrason. Sonochem. 2005, 12, 1.
[8] A. M. A. Al‐Kadasi, G. M. Nazeruddin, J. Chem. Pharm. Res.
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[9] G. V. Ambulgekar, B. M. Bhanage, S. D. Samant, Tetrahedron
Lett. 2005, 46, 2483.
8,8‐Dimethyl‐5‐phenyl‐8,9‐dihydro‐1H‐chromeno[2,3‐d]
pyrimidine‐2,4,6(3H,5H,7H)‐trione (C)
Yield: 95%; white solid; 161 °C[49]; FTIR (KBr) υ (cm−1):
[10] A. M. A. Al‐Kadasi, G. M. Nazeruddin, J. Chem. Pharm. Res.
2010, 2, 536.
1
3478, 2936, 2864, 1683; H NMR (DMSO‐d6, 400 MHz)
[11] K. S. Suslick, Science 1990, 247, 1439.
δ (ppm): 0.96 (3H, s, CH3), 1.13 (3H, s, CH3), 2.11–2.57
(4H, m, 2CH2), 4.56 (1H, s, CH), 7.16–7.23 (5H, m, H‐
Ar), 11.03 (1H, s, NH), 12.12 (1H, brs, NH).
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59, 659.
[13] T. G. Leighton, The Acoustic Bubble, Academic Press, London
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4 | CONCLUSIONS
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Soc. 1986, 108, 5641.
A green, facile, safe and eco‐friendly protocol for the syn-
thesis of dihydropyrimido[4,5‐b]quinolinetriones in the
presence of CoFe2O4@SiO2/PPA under ultrasonic irradia-
tion was presented. High efficient solid acid nanocatalyst,
exhibited strong activity for the synthesis of mentioned
products in excellent yields and short reaction times.
The reaction conditions provided a green and facile
pathway for the preparation of dihydropyrimido[4,5‐b]
quinolinetrione derivatives. Also, prepared solid acid
catalyst can be considered as an excellent catalyst for
use in other organic synthesis.
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S. Hu, Ultrason. Sonochem. 2015, 22, 144.
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[17] K. Rabiei, H. Naeimi, Ultrason. Sonochem. 2015, 24, 150.
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2018.08.001
[20] B. Banerjee, Ultrason. Sonochem. 2017, 35, 1.
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[23] S. Heck, A. Domling, Synlett 2000, 424.
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[26] D. Gandhi, S. Agarwal, J. Heterocycl. Chem. 2018, 55, 2977.
ACKNOWLEDGMENTS
Authors gratefully acknowledge the Chemistry Depart-
ment of University of Kashan for supporting this work
by grant number of 784946.
[27] D. Gandhi, P. Kalal, P. Prajapat, D. K. Agarwal, S. Agarwal,
Comb. Chem. High Throughput Screening 2018, 21, 236.
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CONFLICT OF INTEREST
[29] E. Lunt, in Comprehensive Organic Chemistry, (Eds: D. Barton,
W. D. Ollis), Pergamon, Oxford 1974.
There are no conflicts to declare.
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Chemistry, C. W. Rees), Pergamon, Oxford 1984.
ORCID
[31] T. K. Bradshow, D. W. Hutchinson, Chem. Soc. Rev. 1977, 6, 43.
Leila Moradi https://orcid.org/0000-0001-6830-907X
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How to cite this article: Moradi L, Mahdipour P.
Green and rapid synthesis of dihydropyrimido [4,5‐
b]quinolinetrione derivatives using CoFe2O4@PPA
as high efficient solid acidic catalyst under
ultrasonic irradiation. Appl Organometal Chem.
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