Facile one-pot four component synthesis of pyrido[2,3-d:6,5-d′]dipyrimidines catalyzed by CuFe2O4 magnetic nanoparticles in water

Article abstract of DOI:10.1016/j.molstruc.2017.02.044

A simple, efficient and green method for the synthesis of pyrido[2,3-d:6,5-d′]dipyrimidine derivatives via one-pot four-component reaction of aromatic aldehyde, 2-thiobarbituric acid, ammonium acetate in the presence of catalytic amount of a magnetically

Full text of DOI:10.1016/j.molstruc.2017.02.044

Accepted Manuscript
Facile one-pot four component synthesis of pyrido[2,3-d:6,5-d′]dipyrimidines
catalyzed by CuFe O magnetic nanoparticles in water
2
4
Hossein Naeimi, Asieh Didar
PII:
S0022-2860(17)30190-4
DOI:
10.1016/j.molstruc.2017.02.044
MOLSTR 23438
Reference:
To appear in: Journal of Molecular Structure
Received Date: 7 September 2016
Revised Date: 16 January 2017
Accepted Date: 10 February 2017
Please cite this article as: H. Naeimi, A. Didar, Facile one-pot four component synthesis of pyrido[2,3-
d:6,5-d′]dipyrimidines catalyzed by CuFe O magnetic nanoparticles in water, Journal of Molecular
2
4
Structure (2017), doi: 10.1016/j.molstruc.2017.02.044.
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ACCEPTED MANUSCRIPT
Graphical Abstract
A simple, efficient and green m
e
thod for the synthesis of pyrido dipyrimidine derivatives via
a one-pot four component reac
developed.
tt
ion catalyzed by CuFe magnetic nanoparti cc les has been
2 4
O

ACCEPTED MANUSCRIPT
Facile one-pot four component synthesis of pyrido[2,3-d:6,5-d']dipyrimidines catalyzed
by CuFe O magnetic nanoparticles in water
2
4
Hossein Naeimi*, Asieh Didar
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan,
8
7317, I.R. Iran; Tel: 983615912388; Fax; 983615912397; Email: naeimi@kashanu.ac.ir.
Abstract: A simple, efficient and green method for the synthesis of pyrido[2,3-d:6,5-
d']dipyrimidine derivatives via one-pot four-component reaction of aromatic
aldehyde, 2-thiobarbituric acid, ammonium acetate in the presence of catalytic
amount of a magnetically heterogeneous catalyst has been developed. This protocol
includes some important advantages such as; high to excellent product yields, high
atom economy, usage of water as a green reaction medium, reusability of catalyst,
and simple work-up procedure.
Keywords: Pyrido[2,3-d:6,5-d']dipyrimidine, CuFe O , Nanoparticles, Green media,
2
4
Catalyst
1
. Introduction
The green chemistry has been created the great development in the chemical reaction and
would like to change in the conventional ways in synthesis by draw new efficiency of
synthetic approach. These targets are to reduce the synthetic stages to; use less toxic and
cheap solvents, lower the energy use, increase efficiency with higher yields and to minimize
waste. By changing the methodologies of synthesis, health, safety, environmental credentials
by reducing toxicity and increase recyclability will be advanced [1]. To achieve these goals
chemists have adopted water as the chosen solvent in organic synthesis. Water offers many
practical advantages over conventional organic solvents [2] such as easy availability, cheap,
non-corrosive, non-toxic, non-flammable, easy work up and environmentally acceptable [2-
5
].
Multicomponent reactions (MCRs) provide an opportunity for the coupling of three or more
different starting materials in one pot operation, to produce a final product containing diverse
substituents from all of the reactants [6-7]. That is important from the atom economic

ACCEPTED MANUSCRIPT
standpoint. Environmentally friendly operation via reducing the number of synthetic steps
and work up, the energy consumption, reaction time, waste production, eliminating the
isolation of unstable intermediates are among the advantages of MCRs [7-12]. Over the last
few decades, with increasing environmental concerns, the design of new MCRs with eco-
friendly, green procedures have become increasingly useful tools, especially in the fields of
drug discovery, organic synthesis, and material science [13,14].
Pyridopyrimidines and their derivatives are a privileged heterocyclic motif that form the core
of a large family of natural products and drug molecules with interesting structural features
and a wide range of useful pharmacological and biological properties [15,16]. For instance,
some representative pyrido[2,3-d]pyrimidine derivatives are shown in Fig 1. The pyrido[2,3-
d]pyrimidine carboxylate (Ι) a significant anti-cancer or cancer-causing agents properties [17]
and pyrido[2,3-d:6,5-d']dipyrimidine (ΙΙ) were reported to show antibacterial activity [18] and
in 2,4-dioxo pyrido[2,3-d]pyrimidine (ΙΙΙ) has been found antitumor activity [19].
Fig. 1 Some representative compounds containing pyrido[2,3-d]pyrimidine
Moreover, some of pyrido[2,3-d]pyrimidines have been shown to possess another important
biological activities such as; antiallergic [20], antitumor [21,22] antifolate [23], fibroblast
growth factor receptor 3 (FGFR3) [24,25], tyrosine kinase inhibitors [26,27], antimicroibial
[
[
28], dihydrofolate reductase (DHFR) inhibitory activity [29,30], calcium channel antagonists
31], antibacterial [32], anti-inflammatory [33], analgesic [33], antihypertensive [34],
antileishmanial [35], tuber-culostatic [29], potassium sparing [36], anti-HIV [37]. Due to the
such activities of pyrido[2,3-d]pyrimidine, several methods for synthesis of these compounds
have been reported [18,38-40].
2

ACCEPTED MANUSCRIPT
In recent years, the synthesis of magnetic nanoparticles (MNPs) and their use in organic
synthesis are among the most active research areas in chemistry. The suitable features in
magnetic nanoparticles such as extremely small size, large surface to volume ratio, simple
recovery and recycling the catalysts by an external magnet and cost-effective encouraged us
to utilize magnetic nanoparticles as efficient and reusable catalyst for the organic
transformations. For this purpose, iron-based materials benefiting from their terrestrial
abundance and low toxicity have been more extensively used [41-49].
Moreover, considering the unique structural array and extremely prominent pharmacological
activities of pyrido[2,3-d]pyrimidine and with the aim to develop efficient synthetic processes
for the preparation of heterocyclic compounds, we report, a facile, efficient, eco-friendly, and
one pot protocol for the synthesis of novel pyrido[2,3-d:6,5-d']dipyrimidine derivatives
through a four-component condensation reaction of aldehyde, 2-thiobarbituric acid,
ammonium acetate in the presence of copper ferrite nanoparticles as an efficient and reusable
catalyst in water.
2
2
. Materials and Methods
.1. General information
All commercially available reagents were used without further purification and purchased
from the Merck Chemical Company in high purity. The used solvents were purified by
standard procedure.
FT-IR spectra were obtained as KBr pellets on a Perkin–Elmer 781 spectrophotometer and on
1
13
an impact 400 Nicolet FT–IR spectrophotometer. H NMR and C NMR were recorded in
DMSO-d solvents on a Bruker DRX-400 spectrometer with tetramethylsilane as internal
6
reference. Uv–vis spectra were obtained with a Perkin–Elmer 550 was recorded in EtOH
solvent. Melting points were obtained with a Yanagimoto micro melting point apparatus are
uncorrected. Mass spectra were recorded on an Agilent technology HP 5973 Network Mass
Selective Detector mass spectrometer operating at an ionization potential of 70 eV. FE-SEM
analysis was carried out using a Jeol SEM instrument (model- VEGA/TESCAN). The XRD
patterns were recorded on X-ray diffractometer (Bruker, D8 ADV ANCE, Germany). The
purity determination of the substrates and reaction monitoring were accomplished by TLC on
silica-gel polygram SILG/UV 254 plates (from Merck Company).
3

ACCEPTED MANUSCRIPT
2
.2. Typical experimental procedure for the preparation of magnetic nanocatalyst
CuFe O nanoparticles were prepared by co-precipitation of Cu(NO ) ·3H O and
2
4
3 2
2
FeCl ·9H O in water in the presence of sodium hydroxide. Briefly, to a solution of
3
2
FeCl ·9H O (0.05 mol) and Cu(NO ) ·3H O (0.025 mol) in 100 mL of distilled water, 75 mL
3
2
3 2
2
of NaOH 4 M was added at room temperature over a period of 10 min to form reddish-black
o
precipitate. Then the reaction mixture was warmed to 90 C and stirred. After 2 h, it was
cooled to room temperature and the formed magnetic particles were separated by a magnetic
separator. The catalyst was washed with distilled water and kept in air oven over night at 80
o
o
C. Then the catalyst was ground in a mortar–pestle and kept in a furnace at 800 C at a
o
o
o
heating rate of (2 C /min) and cooled to 100 C at (5 C /min) in air [50].
2
.3. A typical 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
A mixture of aldehyde (0.25 mmol), 2-thiobarbituric acid (0.5 mmol), ammonium acetate
0.3 mmol) and CuFe O (10 mol%) in distilled H O was stirred for an appropriate time.
[
(
2
4
2
After completion of the reaction (monitored by TLC), the resulted precipitate was filtered and
dissolved in hot methanol and the catalyst was separated and collected by an external
magnetic and washed with acetone and EtOH several times and dried in an oven at 70 °C to
reuse in next reactions. The pure solid product was obtained via evaporation the 2/3 of
methanol and filtration. The solid product was recrystallized from water/ethanol as solvent to
afford the pure products. All of the products were identified by physical and spectroscopic
data.
5
4
-Phenyl-2,8-dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-
,6(1H,5H)-dione (4a);
o
-1
Cream powder; M.P: 211 C Lit. [51] (M.P : 238˚C, decompose). IR (KBr) ν (cm ): 3452
rep
2
3
1
(
(
(
NH), 3054 (C-H, sp stretch), 2898 (C-H, sp ), 1637 (C=O), 1440, 1559 (C=C, Ar). H NMR
DMSO-d , 400 MHz) δ (ppm): 5.93 (s, 1H), 6.95-6.99 (d, 2H, J = 6.0 Hz), 7.05 (s, 1H), 7.15
6
s, 2H), 7.60 (s, 1H), 7.91 (s, 1H), 11.33-12.00 (s, 3H).
5
4
-(4-Nitrophenyl)-2,8-dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-
,6(1H,5H)-dione (4c);
4

ACCEPTED MANUSCRIPT
-1
Light brown powder; M.P: 330˚C Lit. [52] (M.P : 269˚C, decompose). IR (KBr) ν (cm ):
rep
2
1
3
447 (NH), 3175 (C-H, sp stretch), 1602 (C=O), 1432, 1509 (C=C, 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,
1
3
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). C
NMR (DMSO-d , 100 MHz) δ (ppm): 31.61, 95.68, 123.57, 128.26, 145.71, 152.56, 163.17,
6
1
5
4
64.00, 173.50.
-(2-Nitrophenyl)-2,8-dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-
,6(1H,5H)-dione (4d);
-1
2
Yellow powder; M.P: 230˚C, decompose. IR (KBr) ν (cm ): 3447 (NH), 3175 (C-H, sp
1
stretch), 1602 (C=O), 1432, 1509 (C=C, Ar). H NMR (DMSO-d , 400 MHz) δ (ppm): 6.09-
6
6
7
1
.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-
1
3
.51 (d, 2H), 11.57-11.99 (s, 5H). C NMR (DMSO-d , 100 MHz) δ (ppm): 29.15, 95.22,
6
24.05, 127.11, 129.79, 131.58, 136.07, 150.17, 163.19, 173.49. Anal. Calcd for
C H N O S : C, 44.77; H, 2.50; N, 20.88, %; Found C, 77.81; H, 2.53; N, 20.91%.
15
10
6
4 2
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 (4e);
Yellow powder; M.P: 242˚C decompose. IR (KBr) ν (cm ): 3591, 3447 (NH), 3166 (C-H,
-1
2
3
1
sp stretch), 2922 (C-H, sp ), 1632 (C=O), 1437, 1536 (C=C, Ar). H NMR (DMSO-d , 400
6
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-
1
3
6
.64 (m, 1H), 6.93 (s, 1H),7.06 (s, 2H), 7.19-7.23 (s, 1H), 11.56-11.73 (m, 4H). C NMR
(
DMSO-d , 100MHz) δ (ppm): 30.89, 55.24, 96.21, 109.8, 113.61, 119.62, 129.09, 145.24,
6
1
4
5
4
59.42, 173.22. Anal. Calcd for C H N O S : C, 49.34; H, 3.88; N, 17.98, %; Found C,
16 15 5 3 2
9.38; H, 3.90; N, 18.02%.
-(4-Chloro)-2,8-dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-
,6(1H,5H)-dione (4f);
-1
2
Yellow powder; M.P: 257˚C decompose. IR (KBr) ν (cm ): 3433 (NH), 3130 (C-H, sp
1
stretch), 1626 (C=O), 1434, 1534 (C=C, Ar). H NMR (DMSO-d , 400 MHz) δ (ppm): 5.91
6
1
3
(
s, 1H), 6.93-6.98 (d, 2H), 7.06 (s, 1H), 7.19 (s, 1H), 11.67 (s, 5H). C NMR (DMSO-d , 100
6
MHz) δ (ppm): 31.24, 93.17, 119.40, 122.08, 130.15, 133.85, 136.56, 144.09, 162.94, 165.23,
5

ACCEPTED MANUSCRIPT
1
2
5
75.52. Anal. Calcd for C H ClN O S : C, 45.98; H, 2.57; N, 17.87, %; Found C, 46.01; H,
15
10
5
2 2
.60; N, 17.92%.
-(2-Fluorophenyl)-2,8-dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']
dipyrimidine-4,6(1H,5H)-dione (4g);
-1
2
White powder; M.P: 240˚C decompose. IR (KBr) ν (cm ): 3432 (NH), 3108 (C-H, sp
1
stretch), 1623, 1687 (C=O), 1433, 1544 (C=C, Ar). H NMR (DMSO-d , 400 MHz) δ (ppm):
6
1
3
6
.01 (s, 1H), 6.91-7 (m, 3H), 7.08-7.12 (m, 4H), 11.49-11.75 (m, 4H), 17 (s, 1H). C NMR
(
DMSO-d , 100 MHz) δ (ppm): 26.88, 95.44, 115.26, 123.60, 127.61, 130.05, 130.48,
6
1
59.60, 162.03, 163.32, 173.24. Anal. Calcd for C H FN O S : C, 47.74; H, 3.20; N, 18.56,
15 12 5 2 2
%; Found C, 47.76; H, 3.24; N, 18.60%.
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 (4h);
Light brown powder; M.P: 308˚C decompose. IR (KBr) ν (cm ): 3530 (NH), 3069 (C-H, sp
-1
2
3
1
stretch), 2892 (C-H, sp ), 1680 (C=O), 1450, 1562 (C=C, Ar). H NMR (DMSO-d , 400
6
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,
1
3
2
9
1
3
5
4
H), 11.56 (s, 2H), 17.1 (s, 1H). C NMR (DMSO-d , 100MHz) δ (ppm): 24.82, 91.66,
6
7.56, 115.48, 116.86, 123.45, 125.47, 127.62, 129.25, 131.29, 147.83, 154.56, 161.67,
73.72. Anal. Calcd for C H FN O S : C, 53.89; H, 3.09; N, 16.54, %; Found C, 53.92; H,
19
13
5
3 2
.12; N, 16.56%.
-(Pyridine-2-yl)-2,8-dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-
,6(1H,5H)-dione (4l);
-1
2
Red powder; M.P: 280˚C decompose. IR (KBr) ν (cm ): 3398 (NH), 3210 (C-H, sp stretch),
3
1
2
881 (C-H, sp ), 1605 (C=O), 1455, 1533 (C=C, Ar). H NMR (DMSO-d , 400 MHz) δ
6
(ppm): 6.20 (s, 1H), 7.83 (s, 1H), 8.42 (m, 1H), 8.60 (m, 1H), 11.84 (s, 4H), 14.00-16.00 (s,
1
3
1
1
2
5
H). C NMR (DMSO-d , 100 MHz) δ (ppm): 32.03, 92.94, 124.86, 126.21, 141.98, 146.83,
6
58.93, 163.41, 174.28. EI-MS (70 eV) m/z: 51 (8.31), 77 (23.27), 124 (37.53), 126 (4.96),
28 (100), 352 (3.91), 358 (0.06).
,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) (4k);
Red powder; M.P: 300˚C decompose. IR (KBr) ν (cm ): 3428 (NH), 3200 (C-H, sp stretch),
-1
2
3
1
2
923 (C-H, sp ), 1623 (C=O), 1434, 1535 (C=C, Ar). H NMR (DMSO-d , 400 MHz) δ
6
6

ACCEPTED MANUSCRIPT
(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,
1
3
2
1
H), 11.61 (s, 1H), 12.09 (s, 1H), 12.40 (s, 2H), 13.41 (s, 2H). C NMR (DMSO-d ,
6
00MHz) 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).
-(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 (4l);
5
-1
2
Yellow powder; M.P: 249˚C decompose. IR (KBr) ν (cm ): 3450 (NH), 3090 (C-H, sp
1
stretch), 1615 (C=O), 1434, 1542 (C=C, Ar). H NMR (DMSO-d , 400 MHz) δ (ppm): 5.98
6
(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),
1
3
1
1
1.63-11.70 (m, 4H). C NMR (DMSO-d , 100 MHz) δ (ppm): 30.87, 95.31, 121.91, 123.78,
6
31.41, 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).
3
. Results and discussion
During the past few years, significant interest has been focused on the development of
environmental friendly technique and new highly effective synthetic methods and procedures
for organic reactions.
Water as a unique solvent, in contrast to many organic solvents with disadvantages such as
volatility and toxicity, is the most environmentally accepted, safest, and most abundant
solvent. According to this and due to the significant properties of pyrido pyrimidine
compounds, we draw a simple and environmentally synthetic method for the impressive
preparation of pyrido pyrimidine heterocycle, a four component synthesis was planned based
on forecasting one pot reaction by magnetic nano catalyst in water. In the beginning stage of
research, the model reaction of 4-chloro benzaldehyde, 2-thiobarbituric acid, and ammonium
acetate with 1:2:1 mole ratio using copper ferrite nanoparticles in water was conducted to
screen the optimal reaction conditions (Scheme 1).
7

ACCEPTED MANUSCRIPT
Scheme 1 The reaction leading to the synthesis of pyrido[2,3-d]pyrimidine derivatives.
A catalyst plays a central role in the success of a reaction in terms of the reaction rate and
yield. On the basis of the Hantzsch reaction mechanism, this reaction was accelerated with
acidic catalysts. We focused on finding a suitable catalyst to improve the products yields and
reaction times (Table 1). In the first time, the reaction was carried out without catalyst for 4 h
at room temperature in water as a solvent; the obtained product yield was only 15% (Table 1,
entry 2). Furthermore, in the presence of methane sulfonic acid as a catalyst, the model
reaction was carried out but as determined by TLC analysis, the obtained product yield was
only 40% after 4 h under reflux condition (Table 1, entry 3).
Due to magnetically separable, air-stable, inexpensive and economical of nano CuFe O and
2
4
based on our past success in the use of copper ferrite nanoparticles as catalyst [53], the model
reaction was performed in the presence of nano CuFe O catalyst; the excellent results have
2
4
been achieved.
To show the merit of this method, a brief comparison of the present method and those
previously reported works in literature in terms of reaction times and yields is shown in Table
1
, entries 4,5. Also, we have recently synthesized the pyrimidines using the mesoporous silica
nanoparticles as a catalyst in water [54] that as can be seen in Table 1, the products were
obtained in lower yields and longer times than the resulted product by the present work
(Table 1, entries 6, 7 compared to entry 1). These few methods suffer from one or more
disadvantages such as; low product yields, long reaction time and harsh and unclean reaction
conditions.
Table 1 Comparison of the present method with the previous reported works for synthesis of
8

ACCEPTED MANUSCRIPT
pyrido[2,3-d]pyrimidines.
Entry
Yield
%)
Catalyst
Time (min)
Condition
(
a
1
2
3
4
5
6
7
Nano CuFe O4
20
4h
R.T.
R.T.
98
15
40
86
68
89
84
2
None
MeSO H
4h
reflux
MW/800 w
ꢀ
3
b
Al O (solid phase)
6h
2
3
b
Al O (liquid phase)
48h
40
2
3
c
Fe-MCM-41-IL
R.T.
d
Fe-MCM-41-IL
57
RT
a
Starting materials: benzaldehyde (0.25 mmol), 2-thiobarbituricacid (0.5 mmol), ammonium
acetate (0.3 mmol), H O:EtOH (4:1, 5 mL), catalyst (12 mol%).
2
b
Starting materials: benzaldehyde, 2-thiobarbituric acid, ammonium acetate 1:2:1, Lit. [51].
c
Starting materials: benzaldehyde (0.25 mmol), 2-thiobarbituricacid (0.5 mmol), ammonium
acetate (0.3 mmol), H O (5 mL), catalyst (20 mg Fe-MCM-41-IL), Lit. [54]
.
2
d
Starting materials: 4-OMe-benzaldehyde, 2-thiobarbituric acid, ammonium acetate 1:2:1,
H O (5 mL), catalyst (20 mg Fe-MCM-41-IL), Lit. [54].
2
To achieve suitable conditions, a model reaction performed in various solvents in the
presence of a catalytic amount of copper ferrite nanoparticles at room temperature. Because
dissolving the ammonium acetate salt, the nonpolar solvents are unsuitable for this reaction.
Among the screened different solvents, using water gave the products in high to excellent
yields in a shorter reaction times, and the mixture of EtOH and water also was equally
effective but in longer time. The reaction in the other solvents was produced the desired
products in lower yields (Table 2, entries 1–3).
9

ACCEPTED MANUSCRIPT
a
Table 2 Screening of solvents for the synthesis of pyrido[2,3-d]pyrimidine
b
Entry
1
Solvent
EtOH
Time (min)
25
Yield (%)
70
2
3
4
5
acetone
25
30
30
25
40
40
99
99
acetonitrile
H O/EtOH (4:1)
2
H O
2
a
Reaction conditions: 4-chlorobenzaldehyde (0.25 mmol), 2-thiobarbituric acid (0.5 mmol),
ammonium acetate (0.3 mmol), H O (5 mL), catalyst (10 mol%).
2
b
Isolated yields
In the next step, to optimize the more suitable reaction conditions, we evaluated the amount
of catalyst required. Our optimization studies revealed that when the model reaction was
carried out in the presence of 5 mol% of catalyst, 85% yield is obtained. It was found that
catalyst loadings above 10 mol% decrease the reaction yield. Thus 10 mol% of catalyst was
chosen as the maximum quantity of the catalyst for the reaction (Table 3, entry 2).
a
Table 3 Different amounts of the CuFe O nanoparticles as catalyst in model reaction
2
4
b
Entry
Catalyst (mol%)
Time (min)
Yield (%)
1
2
5
30
25
30
85
99
97
10
15
3
a
Reaction conditions: 4-chlorobenzaldehyde (0.25 mmol), 2-thiobarbituric acid (0.5 mmol),
ammonium acetate (0.3 mmol), H O (5 mL).
2
b
Isolated Yields
In order to generalize the optimum conditions and check the feasibility of this protocol,
different derivatives of 2,8-dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-
4
,6(1H,5H)-dione were prepared from the one-pot reaction mixture of aldehyde, 2-
1
0

ACCEPTED MANUSCRIPT
thiobarbituric acid and ammonium acetate in the presence of a catalytic amount of CuFe O4
2
(10 mol%) in water at room temperature. The results are summarized in Table 4. It is notable
that the reaction with 2-hydroxybenzaldehyde and 4-(N,N-dimethylamino)benzaldehyde as
substrate obtained any product yields in long times due to the highly electron donating of the
-
OH and -NMe substituents to deactivated carbonyl groups through resonance (Table 4,
2
entries 2, 10). These resulted compounds are stable solids and their structures were
1
13
determined by IR, Mass, H and C NMR spectroscopy. Indeed, the data were in good
agreement with the structure of an unprecedented product, and showed the structure of the
unexpected product. Moreover, to study leaching the catalyst, it was separated from the
reaction mixture by external magnetic several times and analyzed by flame atomic absorption
spectrophotometry. The results were indicated that no Cu and Fe elements were observed in
the reaction mixture.
Table 4 Three component synthesis of pyrido[2,3-d]pyrimidine derivatives using
a
CuFe O NPs
2
4
Time
min)
b
Entry
Aldehyde (1)
Product
Yield (%)
(
O
O
2
0
98
HN
NH
1
C H CHO
6
5-
S
N
N
N
S
H
H
H
(4a)
1
1

ACCEPTED MANUSCRIPT
2
3
2-HO-C H CHO
100
25
-
6
4-
(4b)
4-NO -C H CHO
98
2
6
4-
(4c)
4
5
2-NO -C H CHO
38
30
98
98
2
6
4-
(4d)
3-MeO-C H CHO
6
4-
(4e)
6
4-Cl-C H CHO
25
99
6
4-
(4f)
7
8
2-F-C H CHO
35
25
85
90
6
4-
(4g)
2-OH-Naphthaldehyde
(4h)
1
2

ACCEPTED MANUSCRIPT
9
Pyridine-2-carbaldehyde
25
95
(4i)
1
0
1
2
4-Me N-C H CHO
120
-
2
6
4-
(
4j)
1
4-OHC-C H CHO
20
95
6
4-
(4k)
1
4-Cl-3-NO -C H CHO
25
98
2
6
3-
(4l)
a
Reaction conditions: aldehyde (0.25 mmol), 2-thiobarbituric acid (0.5 mmol), ammonium
acetate (0.3 mmol), H O (5 mL), catalyst (10 mol%).
2
b
Isolated yields
A proposed mechanism for this reaction is postulated in Scheme 2. The reaction may proceed
in a stepwise manner, in which the activated aldehyde 1 can be firstly condensed with 2-
1
3

ACCEPTED MANUSCRIPT
thiobarbituric acid 2 to afford heterodiene 3 in the presence of CuFe O in water. This step
2
4
was regarded as a fast Knoevenagel condensation reaction. Then, compound 3 is attacked by
a Michael type addition with another 2-thiobarbituric acid that reacts with ammonium acetate
4
and tautomerization to produce the intermediate 5. We suspect in the presence of CuFe O4
2
as a Lewis acid and water, the carbonyl group in the intermediate 5, was activated for attack
amine group. Subsequently, by cyclization and dehydration affords the corresponding
products. The catalyst as Lewis acid plays an important role in increasing the electrophilic
character of the starting materials and stabilizing the intermediates by the coordination of
oxygen lone electron pairs with the catalyst [18].
Scheme 2. Proposed mechanism for the formation of hexahydropyrido[2,3-d:6,5-
d']dipyrimidine.
1
4

ACCEPTED MANUSCRIPT
3
.1. Characterization of CuFe O nanospheres
2 4
The copper ferrite nanoparticles were prepared by coprecipitation of Cu(NO ) and FeCl in
3
2
3
basic solution at 95°C using the previous reported method [50]. The prepared CuFe O was
2
4
characterized by flame atomic absorption spectrophotometry (AAS), X-ray diffraction
XRD), Field-emission Scanning Electron Microscope (FESEM).
(
In order to analyze the nanoparticles, it was studied by flame atomic absorption
spectrophotometry. The obtained results with this method were found as; Fe: 48.06 g %, Cu:
2
7.92 g %. It is notable that the calculated amounts of these elements in CuFe O NPs were:
2 4
Fe: 46.68 g %, Cu: 26.56 g %.
The crystal structure of the product was examined using X-ray diffraction pattern (XRD).
Thus, the X-ray diffraction patterns of calcinated CuFe O before (A) and after (B) the
2
4
reaction were reported in Fig. 2. As can be seen from this Figure, the position and relative
intensities of all peaks were confirmed as well as with standard XRD pattern of CuFe O4
2
(
tetragonal, JCPDS card N 34-0425) and show peaks characteristic of the tetragonal CuFe O ,
2 4
with a good crystallinity in CuFe O both before and after the reaction.
2
4
Fig. 2. The X-ray diffraction patterns of calcinated CuFe O before (A) and after (B) the
2
4
reaction
1
5

ACCEPTED MANUSCRIPT
Furthermore, the FESEM image of catalyst was provided and shown that the morphology and
nanoparticles size of the catalyst. The average particle size of calcinated copper ferrite is
determined about 45-50 nm (Fig. 3).
Fig. 3 The FESEM image of nano CuFe O
2
4
The magnetization curve for CuFe O nanoparticles is shown in Fig. 4. It is of great
2
4
importance that a catalyst should possess sufficient magnetic and super paramagnetic
properties for its practical application. Magnetic hysteresis measurements on CuFe O were
2
4
conducted in an applied magnetic field at room temperature, with the field sweeping from -
0,000 to +10,000 Oersted. As shown in Fig. 4, the hysteresis loop for the sample was
1
completely reversible confirming its super paramagnetic nature. The catalyst showed high
permeability in magnetization and high reversibility in the hysteresis loop. Also, the image of
transmission electron microscope (TEM) analysis of the nano CuFe O confirmed the
2
4
morphology and the size of nanoparticles (Fig. 5).
1
6

ACCEPTED MANUSCRIPT
Fig. 4. The vibrating sample magnetometer curve of prepared CuFe O nanoparticles
2
4
at room temperature
Fig. 5. The TEM image of CuFe O nanoparticles
2
4
The recovery and reuse of catalysts is highly preferable for a greener process. Finally, as
shown in Fig. 6, the reusability of the catalyst examined by using 4-chlorobenzaldehyde, 2-
thiobarbituric acid and ammonium acetate as model substrates. In the end of reaction, the
1
7

ACCEPTED MANUSCRIPT
resulted precipitate was filtered and dissolved in hot methanol and the catalyst was
magnetically recovered by an external magnetic field and washed with acetone and EtOH
several times, followed by distilled water and drying in an oven at 70 °C before being reused
for other reaction runs. The procedure was repeated, and the results indicated that in four
consecutive runs, as can be seen in Fig.6, the isolated yields remained similar without any
significant loss of yield and catalytic activity. After being dried, it was subjected to another
reaction.
Fig. 5 Catalyst recyclability study 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.
4
. Conclusions
In this study, the application of heterogeneous nano copper ferrite nanoparticles has been
demonstrated for the synthesis of pyridopyrimidine derivatives through the one pot reaction
of benzaldehyde, 2-thiobarbituric acid and ammonium acetate in water as a facile, highly
efficient, green procedure. The notable features of this procedure are green solvent and
catalyst, mild conditions, convenient and simple workup and high to excellent product yields.
Easy magnetic separation of the catalyst eliminates the requirement of catalyst filtration after
1
8

ACCEPTED MANUSCRIPT
completion of the reaction. Furthermore, the catalyst remained highly active even after
several repeated uses.
Acknowledgement
The authors are grateful to University of Kashan for supporting this work by Grant No.
1
59148/57.
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Highlight Research




The CuFe O NPs was prepared via simple chemical process.
2 4
The catalyst was characterized by XRD, FE-SEM and VSM, techniques.
The catalyst can be recovered several cycles without any loss of catalytic activity.
The CuFe O NPs was employed in synthesis of pyrimidines in water.
2
4