Microwave-assisted synthesis of pyrido-dipyrimidines using magnetically CuFe2O4 nanoparticles as an efficient, reusable, and powerful catalyst in water

Article abstract of DOI:10.1007/s13738-016-0986-8

Abstract: An efficient and direct procedure for the synthesis of pyrido[2,3-d:6,5-d′]dipyrimidine derivatives has been described under microwave-assisted conditions. The reaction of 2-thiobarbituric acid with aromatic aldehydes and ammonium acetate cataly

Full text of DOI:10.1007/s13738-016-0986-8

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0986-8
ORIGINAL PAPER
Microwave‑assisted synthesis of pyrido‑dipyrimidines using
magnetically CuFe2O4 nanoparticles as an efficient, reusable,
and powerful catalyst in water
Hossein Naeimi1 · Asieh Didar1 · Zahra Rashid2
Received: 9 May 2016 / Accepted: 25 September 2016
© Iranian Chemical Society 2016
Abstract An efficient and direct procedure for the syn-
thesis of pyrido[2,3-d:6,5-d′]dipyrimidine derivatives has
been described under microwave-assisted conditions. The
reaction of 2-thiobarbituric acid with aromatic aldehydes
and ammonium acetate catalyzed by CuFe2O4 nanoparti-
cles was resulted in the formation of pyrido[2,3-d:6,5 d′]
dipyrimidine derivatives. The corresponding products have
been obtained in excellent isolated yields with high purity,
in short reaction times and easy workup.
antileishmanial [6], antibacterial [7], antifolate [8], analge-
sic [9], antimicrobial [10], anticonvulsants [11], anti-HIV
[12], tuberculostatic [13], antiallergic [14], potassium spar-
ing [15], antitumor [16], tyrosine kinase inhibitors [17],
dihydrofolate reductase (DHFR) inhibitory activity [18],
calcium channel antagonists [19], fibroblast growth factor
receptor (FGFR3) [20].
Nowadays, the employment of novel adapted tools and
techniques considering operational, economic, and environ-
mental benefits over traditional methods have been increas-
ingly recognized in organic, combinatorial, and medicinal
chemistry mainly the synthesis of complicated molecules
obtained in a very fast, efficient, and timesaving manner.
For the utility of microwave energy in these slight cases,
using microwaves as a valuable and powerful technology
has become a major motivation for both industry and aca-
demia [21–23]. Replacing the oil bath with a microwave
reactor and opening a new window in microwave-assisted
organic synthesis (MAOS) lead to perform the reactions in
dramatically shortened time as well as increasing yields in
the much cleaned simple condition reactions [24]. Moreo-
ver, this method improves the bond forming efficiency. For
these reasons, many organic reactions have been reported
under microwave activation [25–27].
Nanocatalysis is essential for chemistry, material sci-
ence, and nanoscience [1–4]. Due to extremely small size,
the large ratio of surface to volume, many noble metal
nanoparticles have been used as catalysts in various chemi-
cal reactions [28]. To allow for facile and simple recovery
and recycling of catalyst, magnetic nanoparticles are attrac-
tive catalysts since they can be separated from the reaction
medium after magnetization by an external magnet and are
cost-effective. These heterogeneous magnetic nanoparticles
catalysts can achieve many of the goals of green chemistry
[28–30].
Keywords Multicomponent reactions · Magnetic
nanoparticles · Microwave · Pyrido-dipyrimidines
Introduction
Organic compounds containing pyrido-pyrimidine scaffold
as a core unit are important targets and have received more
attention due to their wide range of biological and phar-
maceutical features as well as the presence of this frame-
work in a number of natural products [1, 2]. For example,
piromidic acid (I) as an antibacterial drug and piritrexim
isethionate (II) with antineoplastic drug are shown in Fig. 1
[3]. A great number of compounds that carry pyrido[2,3-d]
pyrimidine moieties are reported to have significant prop-
erties such as antihypertensive [4], anti-inflammatory [5],
* Hossein Naeimi
Naeimi@kashanu.ac.ir
1
Department of Organic Chemistry, Faculty of Chemistry,
University of Kashan, Kashan 87317, Islamic Republic
of Iran
2
Young Researchers and Elite Club, Central Branch, Islamic
Azad University, Tehran, Islamic Republic of Iran
1 3

J IRAN CHEM SOC
Fig. 1 Drug structures of some
known pyrido[2,3-d]pyrimi-
dines
In this research, we report greener route for one-pot,
four-component synthesis of pyrido [2,3-d]pyrimidine
derivatives via a water-mediated and CuFe2O4 nanoparti-
cles as a reusable catalyst under microwave-assisted proce-
dures. This method is simple, efficient, and fast with excel-
lent yields.
Typical experimental procedure for the preparation
of magnetic nanocatalyst
CuFe2O4 nanoparticles were prepared by coprecipitation of
Cu(NO3)2·3H2O and FeCl3·9H2O in water in the presence
of sodium hydroxide. Briefly, to a solution of FeCl3·9H2O
(0.05 mol) and Cu(NO3)2·3H2O (0.025 mol) in 100 mL of
distilled water, 75 mL of NaOH 4 M was added at room
temperature over a period of 10 min to form the reddish
black precipitate. Then the reaction mixture was warmed to
90 °C and stirred. After 2 h, it was cooled to room tempera-
ture and the formed magnetic particles were separated by a
magnetic separator. The catalyst was washed with distilled
water and kept in air oven overnight at 80 °C. Then the cat-
alyst was ground in a mortar–pestle and kept in a furnace at
800 °C at a heating rate of (2 °C/min) and cooled to 100 °C
at (5 °C/min) in the air [31].
Experimental
Chemicals and apparatus
Chemicals were purchased from the Merck and Fluka
Chemical Companies in high purity. All of the materials
were of commercial reagent grade. The aniline derivatives
and salicylaldehyde were purified by standard procedures,
and their purity determined by thin-layer chromatogra-
phy (TLC). IR spectra were obtained as KBr pellets on
a PerkinElmer 781 spectrophotometer and on an impact
General procedure for the synthesis of 2,8‑
dithioxo‑2,3,7,8,9,10‑hexahydropyrido[2,3‑d:6,5‑d′]
dipyrimidine‑4,6(1H,5H)‑dione
1
400 Nicolet FT–IR spectrophotometer. H NMR and 13C
NMR were recorded in DMSO-d6 solvents on a Bruker
DRX-400 spectrometer with tetramethylsilane as internal
reference. Melting points were obtained with a Yanagi-
moto micro melting point apparatus are uncorrected.
Mass spectra were recorded on an Agilent technology
HP 5973 Network Mass Selective Detector mass spec-
trometer operating at an ionization potential of 70 eV.
FESEM analysis was carried out using a Jeol SEM instru-
ment (model-VEGA/TESCAN). The XRD patterns were
recorded on an X-ray diffractometer (Bruker, D8 ADV
ANCE, Germany). The XRD patterns were recorded on
an X-ray diffractometer (Bruker, D8 ADV ANCE, Ger-
many). The magnetic property of the catalyst was stud-
ied by vibrating sample magnetometer (VSM, Meghnatis
Daghigh Kavir Company, Iran). The purity determination
of the substrates and reaction monitoring were accom-
plished by TLC on silica-gel polygram SILG/UV 254
plates (from Merck Company). The purity determination
of the substrates and reaction monitoring were accom-
plished by TLC on silica-gel polygram SILG/UV 254
plates (from Merck Company).
A mixture of an aldehyde (0.25 mmol), 2-thiobarbitu-
ric acid (0.5 mmol), ammonium acetate (0.3 mmol), and
CuFe2O4 (10 mol%), with distilled H2O, in an open tall
beaker was irradiated inside microwave oven at 100 W for
an appropriate time (monitored by TLC). After completion
of the reaction, for removing the catalyst, the hot solution
was filtrated with external magnetic for several times. The
solvent was evaporated, and the precipitate was washed
from ethanol and hot water to afford the pure product.
5‑Phenyl‑2,8‑dithioxo‑2,3,7,8,9,10‑hexahydropyrido
[2,3‑d:6,5‑d]dipyrimidine‑4,6(1H,5H)‑dione
Cream powder; M.P: 211 °C Lit. [32] (M.Prep: 238 °C
decompose). IR (KBr) (νmax/cm−1): 3452 (NH), 3054
(C–H, sp2 stretch), 2898 (C–H, sp3), 1637 (C=O), 1440,
1
1559 (C=C, Ar). H NMR (DMSO-d6, 400 MHz) (ppm):
5.93 (s, 1H), 6.98–6.99 (d, 2H, J = 6.0 Hz), 7.05 (s, 1H),
7.15 (s, 2H), 7.60 (s, 1H), 7.91 (s, 1H), 11.33–12 (s, 3H).
1 3

J IRAN CHEM SOC
5‑(4‑Nitrophenyl)‑2,8‑dithioxo‑2,3,7,8,9,10‑
hexahydropyrido[2,3‑d:6,5‑d]dipyrimidine‑
4,6(1H,5H)‑dione
(DMSO-d6, 400 MHz) δ (ppm): 3.63 (s, 3H), 5.91–5.97
(s, 1H), 6.49–6.52 (s, 1H), 6.56–6.57 (m, 1H), 6.62–6.64
(m, 1H), 6.93 (s, 1H),7.06 (s, 2H), 7.19–7.23 (s, 1H),
11.56–11.73 (m, 4H). 13C NMR (DMSO-d6, 100 MHz) δ
(ppm): 30.89, 55.24, 96.21, 109.8, 113.61, 119.62, 129.09,
145.24, 159.42, 173.22. Anal. Calcd for C16H15N5O3S2: C,
49.34; H, 3.88; N, 17.98 %; Found C, 49.38; H, 3.90; N,
18.02 %.
Light brown powder; M.P: 330 °C Lit. [33] (M.Prep
:
269 °C decompose). IR (KBr) (νmax/cm−1): 3447 (NH),
3175 (C–H, sp2 stretch), 1602 (C=O), 1432, 1509 (C=C,
1
Ar). H NMR (DMSO-d6, 400 MHz) δ (ppm): 6.04 (s,
1H), 6.93 (s, 1H), 7.06 (s, 1H), 7.19 (s, 1H), 7.23–7.25
(d, 2H, J = 8.4 Hz), 8.04–8.28 (d, 2H, J = 8.8 Hz), 11.62
(s, 2H), 11.75–11.97 (s, 2H), 17.1(s, 1H). 13C NMR
(DMSO-d6, 100 MHz) δ (ppm): 31.61, 95.68, 123.57,
128.26145.71, 152.56, 163.17, 164,173.5.
5‑(Pyridine‑2‑yl)‑2,8‑dithioxo‑2,3,7,8,9,10‑
hexahydropyrido[2,3‑d:6,5‑d]dipyrimidine‑
4,6(1H,5H)‑dione
Red powder; M.P: 280 °C decompose. IR (KBr) (νmax
/
5‑(2‑Nitrophenyl)‑2,8‑dithioxo‑2,3,7,8,9,10‑
hexahydropyrido[2,3‑d:6,5‑d]dipyrimidine‑
4,6(1H,5H)‑dione
cm−1): 3398 (NH), 3210 (C–H, sp2 stretch), 2881 (C–H,
sp3), 1605 (C=O), 1455, 1533 (C=C, Ar). 1H NMR
(DMSO-d6, 400 MHz) δ (ppm): 6.20 (s, 1H), 7.83 (s, 1H),
8.42 (m, 1H), 8.6 (m, 1H), 11.84 (s, 4H), 14–16 (s, 1H).
13C NMR (DMSO-d6, 100 MHz) δ (ppm): 32.03, 92.94,
124.86, 126.21, 141.98, 146.83, 158.93, 163.41, 174.28.
EI–MS (70 eV) m/z: 51 (8.31), 77 (23.27), 124 (37.53),
126 (4.96), 228 (100), 352 (3.91), 358 (0.06).
Yellow powder; M.P: 230 °C decompose. IR (KBr) (νmax
/
cm−1): 3447 (NH), 3175 (C–H, sp2 stretch), 1602 (C=O),
1
1432, 1509 (C=C, Ar). H NMR (DMSO-d6, 400 MHz)
δ (ppm): 6.09–6.21 (s, 1H), 6.93 (s, 1H), 7.06 (s, 1H),
7.19 (s, 1H), 7.30–7.32 (m, 1H), 7.45 (m, 1H), 7.49–7.51
(d, 2H), 11.57–11.99 (s, 5H). 13C NMR (DMSO-d6,
100 MHz) δ (ppm): 29.15, 95.22, 124.05, 127.11, 129.79,
131.58, 136.07, 150.17, 163.19, 173.49. Anal. Calcd for
C15H10N6O4S2: C, 44.77; H, 2.50; N, 20.88, %; Found C,
44.81; H, 2.53; N, 20.91 %.
5‑(2‑Fluorophenyl)‑2,8‑dithioxo‑2,3,7,8,9,10‑
hexahydropyrido[2,3‑d:6,5‑d]dipyrimidine‑
4,6(1H,5H)‑dione
White powder; M.P: 240 °C decompose. IR (KBr) (νmax
/
cm−1): 3432 (NH), 3108 (C–H, sp2 stretch), 1623, 1687
(C=O), 1433, 1544 (C=C, Ar). 1H NMR (DMSO-d6,
400 MHz) δ (ppm): 6.01 (s, 1H), 6.91–7 (m, 3H), 7.08–
7.12 (m, 4H), 11.49–11.75 (m, 4H), 17 (s, 1H).13C NMR
(DMSO-d6, 100 MHz) δ (ppm): 26.88, 95.44, 115.26,
123.60, 127.55, 130.05, 130.44, 159.60, 162.03, 163.32,
173.24. Anal. Calcd for C15H12FN5O2S2: C, 47.74; H, 3.20;
N, 18.56, %; Found C, 47.76; H, 3.24; N, 18.60 %.
5‑(4‑Chloro‑3‑nitrophenyl)‑2,8‑dithioxo‑
2,3,7,8,9,10‑hexahydropyrido[2,3‑d:6,5‑d]dipyrimidine‑
4,6(1H,5H)‑dione
Yellow powder; M.P: 249 °C decompose. IR (KBr) (νmax
/
cm−1): 3450 (NH), 3090 (C–H, sp2 stretch), 1615 (C=O),
1
1434, 1542 (C=C, Ar). H NMR (DMSO-d6, 400 MHz)
δ (ppm): 5.98 (s, 1H), 6.92 (s, 1H), 7.05 (s, 1H), 7.14–
7.18 (m, 1H), 7.28–7.30(m, 1H), 7.53–7.56 (m, 2H),
11.63–11.70 (m, 4H). 13C NMR (DMSO-d6, 100 MHz)
δ (ppm): 30.87, 95.31, 121.91, 123.78, 131.41, 132.75,
145.28, 147.76, 163.14, 163.94, 173.56. EI–MS (70 eV)
m/z: 43(85.88), 69 (100), 116 (42.61), 144 (96.27),
311(85.72), 431 (3.071), 436 (0.30).
5,5′‑(1,4‑Phenylene)bis(2,8‑dithioxo‑2,3,7,8,9,10‑
hexahydropyrido[2,3‑d:6,5‑d]dipyrimidine‑
4,6(1H,5H)‑dione)
Red powder; M.P: 300 °C decompose. IR (KBr) (νmax
/
cm−1): 3428 (NH), 3200 (C–H, sp2 stretch), 2923 (C–H,
sp3), 1623 (C=O), 1434, 1535 (C=C, Ar).1H NMR
(DMSO-d6, 400 MHz) δ (ppm): 5.59 (s, 2H), 7.22 (m, 2H),
7.46 (m, 1H), 7.51 (m, 2H), 7.86–7.91 (m, 4H), 7.98 (m,
2H), 11.61 (s, 1H), 12.09 (s, 1H), 12.40 (s, 2H), 13.41 (s,
2H).13C NMR(DMSO-d6, 100 MHz) δ (ppm): 30.89, 96.45,
115.36, 126.27, 163.06, 164.09, 173.46. EI–MS (70 eV)
m/z: 135 (55.28), 264 (35.19), 289 (27.58), 637 (1.06), 636
(0.55).
5‑(3‑Methoxyphenyl)‑2,8‑dithioxo‑2,3,7,8,9,10‑
hexahydropyrido[2,3‑d:6,5‑d]dipyrimidine‑
4,6(1H,5H)‑dione
Yellow powder; M.P: 242 °C decompose. IR (KBr) (νmax
/
cm−1): 3591, 3447 (NH), 3166 (C–H, sp2 stretch), 2922
(C–H, sp3), 1632 (C=O), 1437, 1536 (C=C, Ar). 1H NMR
1 3

J IRAN CHEM SOC
5‑(2‑Hydroxynaphthalen‑1‑yl)2,8‑dithioxo‑
2,3,7,8,9,10‑hexahydropyrido[2,3‑d:6,5‑d]dipyrimidine‑
4,6(1H,5H)‑dione
microwave-assisted conditions. Because of more advan-
tages of magnetic nanoparticles and our current success
for synthesis of heterocyclic compound under CuFe2O4
[34], firstly, we examined model reaction of 4-chloroben-
zaldehyde, 2-thiobarbituric acid and ammonium acetate
with 1:2:1 mol ratio (Scheme 1) in the presence of a cata-
lytic amount of CuFe2O4 in water under the lowest power
in our microwave oven (100 w). CuFe2O4 nanoparticles
with its structure are the good acidic catalyst and suit-
able for Hantzsch reaction. The excellent result (98 %)
of product and short reaction time (1 min) confirms this
suggestion.
The effect of the catalytic amount of CuFe2O4 on
the synthesis of 5-(4-chloro)-2,8-dithioxo-2,3,7,8,9,10-
hexahydropyrido[2,3-d:6,5-d′]dipyrimidine-4,6(1H,5H)-
dione (4f) is presented in Table 1. As it can be seen, the
best amount of catalyst in this reaction is 10 mol %.
Light brown powder; M.P: 308 °C decompose. IR (KBr)
(νmax/cm−1): 3530 (NH), 3069 (C–H, sp2 stretch), 2892
(C–H, sp3), 1680 (C=O), 1450, 1562 (C=C, Ar). 1H
NMR (DMSO-d6, 400 MHz) δ (ppm): 5.85 (s, 1H), 6.75
(s, 1H), 6.94 (m, 1H), 7.07 (s, 1H), 7.19 (m, 1H), 11.40
(s, 2H), 11.56 (s, 2H), 17.1 (s, 1H). 13C NMR (DMSO-d6,
100 MHz) δ (ppm): 24.82, 91.66, 97.56, 115.48, 116.86,
123.45, 125.47, 127.62, 129.25, 131.29, 147.83, 154.56,
161.67, 173.72. Anal. Calcd for C19H13FN5O3S2: C, 53.89;
H, 3.09; N, 16.54,%; Found C, 53.92; H, 3.12; N, 16.56 %.
5‑(4‑Chloro)‑2,8‑dithioxo‑2,3,7,8,9,10‑hexahydropyrido
[2,3‑d:6,5‑d]dipyrimidine‑4,6(1H,5H)‑dione
Yellow powder; M.P: 257 °C decompose. IR (KBr) (νmax
/
Table 1 Different amounts of the CuFe2O4 nanoparticles as catalyst
in model reaction
cm−1): 3433 (NH), 3130 (C–H, sp2 stretch), 1626 (C=O),
1
1434, 1534 (C=C, Ar). H NMR (DMSO-d6, 400 MHz) δ
Entry
CuFe2O4 (mol%)
Time (min)
Yielda (%)b
(ppm): 5.91 (s, 1H), 6.93–6.98 (d, 2H), 7.06 (s, 1H), 7.19
(s, 1H), 11.67 (s, 5H). 13C NMR (DMSO-d6, 100 MHz)
δ (ppm): 31.24, 93.17, 119.40, 122.08, 130.15, 133.85,
136.56, 144.09, 162.94, 165.23, 175.52. Anal. Calcd for
C15H10ClN5O2S2: C, 45.98; H, 2.57; N, 17.87, %; Found C,
46.01; H, 2.60; N, 17.92 %.
1
2
3
5
10
15
10
10
10
87
98
90
a
Reaction conditions: 4-chlorobenzaldehyde (0. 25 mmol), 2-thio-
barbituric acid (0.5 mmol), ammonium acetate (0. 3 mmol), H2O
(5 mL), catalyst (10 mol%), power (100w)
Results and discussion
Table 2 Power optimization for the synthesis of 4f
The search for new highly effective synthetic methods and
the use environmental friendly techniques in the reaction
is important strategies directed toward the development
of science and technology. Due to MAOS advantages,
this is considered as a valuable and powerful technol-
ogy. Many factors are important in the MAOS, such
as solvent composition, time, and power of microwave
oven. In the present study, in order to find the suitable
condition for synthesis of pyrido[2,3-d]pyrimidine under
Entry
Power (W)
Time (min)
Yielda (%)b
1
2
3
4
100
180
300
450
1
10
10
10
98
55
40
10
a
Reaction conditions: 4-chlorobenzaldehyde (0. 25 mmol), 2-thio-
barbituric acid (0.5 mmol), ammonium acetate (0. 3 mmol), H2O
(5 mL), catalyst (10 mol%)
Scheme 1 Reaction leading to the synthesis of novel pyrido[2,3-d]pyrimidine derivatives
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J IRAN CHEM SOC
Table 3 Comparison of the reported conditions used for the synthe-
sis of pyrido[2,3-d:6,5-d’]dipyrimidine with the present method
intermediate 3 formed by Michael-type addition of the
heterodiene 1 with intermediate 2. Then, the intermediate
3 was converted to corresponding products by cyclization
and dehydration. As shown in Scheme 3, the CuFe2O4
as Lewis acid increases the electrophilic character of the
starting materials and stabilizes the intermediates through
coordinating lone electron pairs of oxygen atom.
Entry Catalyst
Time (min) Condition Yielde (%)b/Ref.
1
2
3
CuFe2O4 NPsa
p-TSAb
1
MW
98/this work
81/[35]
4 h
6 h
Δ
Al2O3 (solid
phase)c
MW/800 w 86/[36]
4
Al2O3 (liquid
phase)c
48 h
Δ
68/[36]
Characterization of CuFe2O4 nanospheres
5
6
No catalystd
No catalystb
15 h
12 h
Δ
Δ
80/[37]
The manganese ferrite nanoparticles were prepared by
coprecipitation of Cu (NO3)2 and FeCl3 in basic solu-
tion at 95 °C using the previously reported method. The
synthesized CuFe2O4 was characterized by X-ray diffrac-
tion (XRD), field-emission scanning electron microscope
(FESEM). Figure 2 presents the XRD diffraction patterns
of the prepared CuFe2O4 nanoparticles. The position and
relative intensities of all the peaks correspond well to
the standard XRD pattern of CuFe2O4 (JCPDS card No.
34-0425) and indicating retention of the crystalline spinel
structure. Also, according to Fig. 3, the FESEM images of
fresh copper ferrite nanoparticles exhibited the morphol-
ogy with an average particle size 45-50 nm in diameter.
The magnetization curve for CuFe2O4 nanoparticles is
shown in Fig. 4. It is of great importance that a catalyst
should possess sufficient magnetic and superparamag-
netic properties for its practical application. Magnetic
hysteresis measurements on CuFe2O4 were taken in an
applied magnetic field at room temperature, with the field
sweeping from -10000 to +10,000 Oersted. As shown in
Fig. 4, the hysteresis loop for the sample was completely
reversible confirming its superparamagnetic nature. The
catalyst showed high permeability in magnetization and
high reversibility in the hysteresis loop (Fig. 4).
Due to importance of recovery and reuse of catalysts
in green chemistry, that is highly preferred for a greener
process, after having demonstrated the effectiveness of
CuFe2O4 as a catalyst, its reusability was investigated by
the reaction of 4-chlorobenzaldehyde, 2-thiobarbituric
acid, and ammonium acetate under optimized conditions.
After the completion of the reaction monitored by TLC,
the solution was filtrated and nanoparticles washed with
acetone and EtOH several times. Then washed with dis-
tilled water and dried in an oven at 70 °C overnight. The
recycled catalyst was used in subsequent reactions. The
procedure was repeated, and the results indicated that in
four consecutive runs, as shown in Fig. 5. The recovered
catalyst was added to the reaction mixture under the same
conditions for three cycles without a significant loss of
yield and catalytic activity.
<40/[35]
a
Reaction conditions: 4-chlorobenzaldehyde (0.25 mmol), 2-thiobar-
bituric acid (0.5 mmol), ammonium acetate (0.3 mmol), H2O (5 mL),
catalyst (12 mol%)
b
Reaction conditions: 4-chlorobenzaldehyde, 1,3-dimethyl-6-amin-
ouracil, barbituric acid 1:1:1, H2O (5 mL)
c
Reaction conditions: 4-chlorobenzaldehyde, 2-thiobarbituric acid,
ammonium acetate 1:2:1
d
Reaction conditions: 4-chlorobenzaldehyde, barbituric acid, ammo-
nium acetate 1:2:1, H2O:EtOH (4:1)
e
Approximate yields
Finally, to optimize the power microwave oven in
reaction, the same reaction was carried out at power
ranging from 100 to 450 W. The yield of product 4f was
decreased, and the reaction time was extended when
the power was increased from 100 to 450 W. The yield
was leveled off when the power was further increased to
450 w. Therefore, the power of 100 W was chosen for
all further microwave-assisted reactions (Table 2, entries
1–4).
To show the merit of this method, a comparison of this
condition with very few reported methods in the forma-
tion of pyrido[2,3-d] pyrimidine is presented in Table 3.
Encouraged by this success, we extended the reaction
of a 2-thiobarbituric acid with a range of other aromatic
aldehydes and ammonium acetate under similar condi-
tions. All results that are shown in Table 3 are stable sol-
ids and the structures of which were determined by IR,
Mass, 1H and 13C NMR spectroscopy. Indeed, the spec-
tral data were in good consistent with the structure of an
unprecedented product (Scheme 2).
For the investigation of the reaction mechanism,
addition of 2-thiobarbituric acid to active benzaldehyde
leads to heterodiene 1. This step was regarded as a fast
Knoevenagel condensation reaction. On the other hand,
when 2-thiobarbituric acid and ammonium acetate were
irradiated, the intermediate 2 was formed. The reaction
can mechanistically be considered to proceed through the
1 3

J IRAN CHEM SOC
Scheme 2 Structure of pyrido[2,3-d:6,5-d′]dipyrimidine derivatives under microwave irradiation
condensation reactions of benzaldehyde, 2-thiobarbi-
turic acid, and ammonium acetate by using a powerful
and green catalyst in water under microwave irradiation.
The green solvent and catalyst, mild conditions, environ-
mental acceptability and recyclability of the magnetic
Conclusions
In this paper, we have described a successful, efficient,
and convenient strategy for the synthesis of pyrido-
dipyrimidine derivatives in one-pot, four-component
1 3

J IRAN CHEM SOC
Scheme 3 Proposed mecha-
nism for the formation of 4a
Fig. 2 X-ray diffraction pat-
terns of calcinated CuFe2O4
1 3

J IRAN CHEM SOC
catalyst, convenient and simple workup, high to excellent
product yields, and short reaction times are the notable
features of this research.
Acknowledgments The authors are grateful to University of Kashan
for supporting this work by Grant No. 159148/74.
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