Green synthesis of new pyrimido[4,5-d]pyrimidine derivatives using 7-aminonaphthalene-1,3-disulfonic acid-functionalized magnetic Fe3O4@SiO2 nanoparticles as catalyst

Article abstract of DOI:10.1002/aoc.4003

We, herein, describe a novel, simple, efficient and one-pot multi-component procedure for the synthesis of substituted pyrimido[4,5-d]pyrimidines via reaction of N,N-dimethyl-6-amino uracil, isothiocyanate and aromatic aldehydes promoted by 7-aminonaphthalene-1,3-disulfonic acid (ANDSA)-functionalized magnetic Fe₃O₄@SiO₂ in water as solvent and without using any other harmful organic reagents. Compared with other reactions, using these organic–inorganic hybrid heterogeneous catalysts can help us to achieve a green procedure, high catalytic activity, easy recovery with an external magnetic field, and short reaction times.

Full text of DOI:10.1002/aoc.4003

Received: 3 April 2017
DOI: 10.1002/aoc.4003
Revised: 9 June 2017
Accepted: 29 June 2017
F U L L P A P E R
Green synthesis of new pyrimido[4,5‐d]pyrimidine
derivatives using 7‐aminonaphthalene‐1,3‐disulfonic acid‐
functionalized magnetic Fe3O4@SiO2 nanoparticles as
catalyst
Ramin Ghorbani‐Vaghei
| Narges Sarmast
Department of Chemistry, Bu‐Ali Sina
University, PO Box 65174, Hamedan, Iran
Abstract
We, herein, describe a novel, simple, efficient and one‐pot multi‐component
procedure for the synthesis of substituted pyrimido[4,5‐d]pyrimidines via
reaction of N,N‐dimethyl‐6‐amino uracil, isothiocyanate and aromatic
aldehydes promoted by 7‐aminonaphthalene‐1,3‐disulfonic acid (ANDSA)‐
functionalized magnetic Fe3O4@SiO2 in water as solvent and without using
any other harmful organic reagents. Compared with other reactions, using
these organic–inorganic hybrid heterogeneous catalysts can help us to achieve
a green procedure, high catalytic activity, easy recovery with an external mag-
netic field, and short reaction times.
Correspondence
Ramin Ghorbani‐Vaghei, Department of
Chemistry, Bu‐Ali Sina University, PO Box
65174, Hamedan, Iran.
Email: rgvaghei@yahoo.com
KEYWORDS
green chemistry, magnetic nanoparticles, N,N‐dimethyl 6‐amino uracil, phenylisothiocyanate,
pyrimido[4,5‐d]pyrimidine
1 | INTRODUCTION
reaction solvents like heterogeneous catalysts that cause
their ease of separation from the reaction mixture
In recent years, the use of hazardous solvents, expensive
and toxic reagents, and formation of undesirable
byproducts are some constraints for synthetic
chemists.[1,2] Chemists use selective and environmentally
friendly catalysts, such as porous solids, heterogeneous
catalysts and nano‐catalysts,[3,4] as well as non‐toxic
solvents that are directly related to the principles of green
chemistry.
makes the product isolation stage effortless. However,
nano‐sized particles like homogeneous catalysts enhance
the contact between reactants and catalyst dramatically,
and increase the exposed surface area of the active
component of the catalyst. Also, chemical and physical
properties of nano‐catalysts like size, shape, composition
and morphology can impress their activity and
selectivity.[8]
Nanoparticles due to their high surface area, high
activity and selectivity, easy separation and isolation of
products from the reaction mixture have been developed
as suitable replacements for conventional heterogeneous
catalysts.[5–8] The nano‐sized particles increase the
exposed surface area of the active component of the
catalyst, so appending the contact between reactants
and catalyst dramatically, and mimicking the homoge-
neous catalysts. Insolubility of nano‐sized particles in
Recently, supported magnetic metal nanoparticles
have been introduced as a new class of nano‐catalysts.
Because of their high surface area, they generally display
higher catalytic activity than traditional heterogeneous
acid catalysts.[9,10]
One class of heterocyclic compounds known to display
various pharmaceutical and biological activities is pyrim-
idines. Among them, the pyrido[2,3‐d]pyrimidines and
pyrimido[4,5‐d]pyrimidines are an important class of
Appl Organometal Chem. 2017;e4003.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4003

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GHORBANI‐VAGHEI AND SARMAST
annulated uracil with biological significance, such as
antiallergic, anticancer, antihypertensive, vasodilators
and bronchodilators agents.[11] Moreover, various
attempts that have been made towards the synthetic
manipulation of uracil for the preparation of
pyrimido[4,5‐d]pyrimidine derivatives include three‐
component reactions,[12–15] as well as cycloaddition
reactions.[16–19] Some of them use p‐toluenesulfonic
acid,[14] AcOH[13,16] and iodine[19] as catalysts. Few
reported procedures[12,17,18] are solvent‐free, while
one of them[14] uses water as solvent. However, these
methods require forcing conditions, long reaction
times, high energy and complex synthetic path-
ways.[20] To overcome these difficulties, there is a
need to develop more effective and sustainable chem-
ical procedures for the synthesis of pyrimido[4,5‐d]
pyrimidines.
network mass‐selective detector (70 eV). Fourier trans-
form infrared (FT‐IR) spectra were recorded on a
PerkinElmer 10.02.00 FT spectrophotometer from KBr
pellets. Melting points were measured on a BUCHI 510
apparatus in open capillary tubes.
2.2 | Preparation of ANDSA‐
functionalized magnetic Fe3O4
nanoparticles (Fe3O4@SiO2@Propyl‐
ANDSA)
The magnetic nanoparticles (Fe3O4) were synthesized
according to Massart's method using FeCl3·6H2O and
FeCl2·4H2O. As illustrated in Scheme 2, preparation of
catalyst followed with coating a layer of silica on the sur-
face of the Fe3O4 nanoparticles and then functionalization
of the iron oxide with two sulfonic acid groups was
achieved by treatment with tetraethyl orthosilicate
[(EtO)4Si] and then with 3‐chloropropyltriethoxysilane,
followed by ANDSA (Scheme 2). Fe3O4@SiO2@Propyl‐
ANDSA nanoparticles were characterized by FT‐IR, scan-
ning electron microscopy, transmission electron micros-
copy (TEM), thermo‐gravimetric analysis (TGA), X‐ray
powder diffraction, X‐ray photoelectron spectroscopy,
energy‐dispersive X‐ray spectroscopy (EDX), vibrating
sample magnetometer (VSM) and ion exchange pH‐anal-
ysis.[21] In order to determine the amount of ANDSA
loaded on the surface of fe3o4@sio2@Propyl, we mea-
sured the percentage of sulfur in Fe3O4@SiO2@Propyl‐
ANDSA and Fe3O4@SiO2@Propyl, with elemental analy-
sis. Using the obtained data (Tables S1 and S2), the
amount of ANDSA loaded on the Fe3O4@SiO2@Propyl
was calculated as 6.48%.
It is on this basis that we have recently introduced 7‐
aminonaphthalene‐1,3‐disulfonic
acid‐functionalized
magnetic Fe3O4@SiO2 nanoparticles (Fe3O4@SiO2@Pro-
pyl‐ANDSA) as an easily prepared and effective
heterogeneous
catalyst
for
the
synthesis
of
polysubstituted pyrrolidinones.[21] Now, in this article,
we have presented another important application of
Fe3O4@SiO2@Propyl‐ANDSA as an efficient, mild, safe,
non‐toxic and magnetic powerful solid acid catalyst in
three‐component condensation of aldehydes, isothiocya-
nate and N,N‐dimethyl 6‐amino uracil in water leading
to the formation of pyrimido[4,5‐d]pyrimidine deriva-
tives without requiring any hazardous solvent
(Scheme 1).
2 | EXPERIMENTAL
2.1 | Chemicals and instruments
2.3 | General procedure for the synthesis
of pyrimido[4,5‐d]pyrimidine
All commercial materials were purchased from Merck. 1H
NMR and 13C NMR spectra were measured at Bruker
BioSpin GmbH 400 MHz FT NMR spectrometers. Ele-
mental analyses (C, H, N, S) were performed with Leco‐
932, and mass analysis was also performed on 5973
In a 10‐ml flask, a mixture of phenylisothiocyanate (1
mmol, 0.120 ml), aldehyde (1 mmol) and N,N‐dimethyl‐
6‐amino uracil (1 mmol, 0.155 g) in water (5 ml) was
refluxed for an appropriate time in the presence of
0.05 g of Fe3O4@SiO2@Propyl‐ANDSA as catalyst. After
completion of the reaction, the catalyst was separated
by an external magnet, and the resulting precipitates
were collected and washed with hot water (5 ml) and
cold ethanol (10 ml). The crude product was purified
by recrystallization from EtOH. The structures of all
the products were established on the basis of their
1
physical and spectral [FT‐IR, H NMR, 13C NMR, CHNS
and mass spectroscopy (MS)] data, and compared with
those reported for known C4, C6, C8, C13 and C15
products.
SCHEME 1 Fe3O4@SiO2@Propyl‐ANDSA catalyzed synthesis of
pyrimido[4,5‐d]pyrimidine

GHORBANI‐VAGHEI AND SARMAST
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SCHEME 2 Stepwise synthesis pathway of Fe3O4@SiO2@Propyl‐ANDSA as a nano‐magnetic core–shell supported solid acid catalyst
114.2, 122.9, 128.2, 128.3, 135.4, 150.4, 153.9, 154.1,
2.4 | 5‐(2‐Fluorophenyl)‐1,3‐dimethyl‐6‐
158.9, 161.3, 162.7; MS: m/z = 396 (M+).
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 1)
2.6 | 5‐(2‐Chlorophenyl)‐1,3‐dimethyl‐6‐
Cream powder (80%); m.p.: 244–245 °C; [found: C, 59.73;
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
H, 4.64; N, 14.47; S, 7.28. C20H17FN4O2S requires: C,
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
60.59; H, 4.32; N, 14.13; S, 8.09%]; IR (KBr) (vmax, cm−1
)
Entry 3)
3207, 1698, 1591; δH (400 MHz, DMSO‐d6); 3.12 (s, 6H,
2CH3), 5.61 (s, 1H, CH), 6.96–7.44 (m, 10H, ArH, NH);
δC (400 MHz, DMSO‐d6); 27.9, 29.9, 31.2, 114.6, 114.8,
123.5, 127.1, 127.2, 127.3, 128.7, 129.8, 150.3, 153.5, 153.6,
159.4, 161.9. MS: m/z = 396 (M+).
White powder (83%); m.p.: 273–276 °C; IR (KBr) (vmax, cm−1)
3447, 1693, 1655; [found: C, 57.54; H, 4.59; N, 13.18; S,
7.61. C20H17ClN4O2S requires: C, 52.52; H, 3.75; N, 12.25; S,
7.01%; C, 58.15; H, 4.15; N, 13.57; S, 7.76%]; δH (400 MHz,
DMSO‐d6); 3.15 (s, 6H, 2CH3), 5.53 (s, 1H, CH), 6.95–7.49
(m, 10H, ArH, NH); δC (400 MHz, DMSO‐d6); 30.0, 34.6,
85.1, 86.4, 126.4, 127.1, 129.1, 129.3, 132.3, 138.3, 150.3,
154.0, 161.8, 162.9, 176.6; MS: m/z = 412 (M+).
2.5 | 5‐(4‐Fluorophenyl)‐1,3‐dimethyl‐6‐
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 2)
2.7 | 5‐(2‐Bromophenyl)‐1,3‐dimethyl‐6‐
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 4)
White solid (90%); m.p.: 259–261 °C; IR (KBr) (vmax, cm−1
)
3369, 1697, 1679; [found: C, 52.22; H, 4.16; N, 12.54; S,
Cream powder (90%); m.p.: 264–266 °C; [found: C, 60.73;
H, 3.94; N, 14.89; S, 7.00. C20H17FN4O2S requires: C,
60.59; H, 4.32; N, 14.13; S, 8.09%]; IR (KBr) (vmax, cm−1
)
3363, 1702, 1680; δH (400 MHz, DMSO‐d6); 3.22 (s, 6H,
2CH3), 5.63 (s, 1H, CH), 7.07–7.51 (m, 10H, ArH, NH);
δC (400 MHz, DMSO‐d6); δ 27.9, 29.9, 34.7, 85.7, 114.0,
6.85. C20H17BrN4O2S requires: C, 52.52; H, 3.75; N,

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GHORBANI‐VAGHEI AND SARMAST
12.25; S, 7.01%]; δH (400 MHz, DMSO‐d6); 3.04 (s, 3H,
CH3), 3.19 (s, 3H, CH3), 5.47 (s, 1H, CH), 7.08–7.48 (m,
10H, ArH, NH); δC (400 MHz, DMSO‐d6); 28.1, 29.9,
36.7, 85.2, 86.4, 122.8, 126.9, 127.3, 129.2, 132.8, 139.9,
150.3, 154.0, 161.8, 162.9; MS: m/z = 457 (M+).
(400 MHz, DMSO‐d6); 3.15 (s, 6H, 2CH3), 5.66 (s, 1H,
CH), 7.40 (s, 7H, ArH), 8.06 (s, 3H, ArH, NH); δC
(400 MHz, DMSO‐d6); 28.0, 30.0, 35.8, 122.8, 127.9,
145.2, 148.8, 150.3. MS: m/z = 423 (M+).
2.8 | 5‐(3‐Bromophenyl)‐1,3‐dimethyl‐6‐
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 5)
2.12 | 5‐(2,3‐Dichlorophenyl)‐1,3‐dimethyl‐
6‐phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 9)
White powder (87%); m.p.: 226–229 °C; IR (KBr) (vmax, cm−1)
3415, 1702, 1675; [found: C, 47.13; H, 4.46; N, 11.61; S,
6.43. C20H17BrN4O2S requires: C, 52.52; H, 3.75; N, 12.25; S,
7.01%]; δH (400 MHz, DMSO‐d6); 3.23 (s, 6H, 2CH3), 5.67
(s, 1H, CH), 7.21–7.50 (m, 10H, ArH, NH); δC (400 MHz,
DMSO‐d6); 27.9, 29.9, 35.1, 55.9, 121.3, 125.7, 127.8, 129.1,
129.7, 142.8, 150.4. MS: m/z = 457 (M+).
White powder (96%); m.p.: 275–278 °C; IR (KBr) (vmax
,
cm−1) 3373, 1697, 1662; [found: C, 52.98; H, 4.55; N,
12.83; S, 7.61. C20H16Cl2N4O2S requires: C, 53.70; H,
3.61; N, 12.52; S, 7.17%]; δH (400 MHz, DMSO‐d6); 3.03
(s, 3H, CH3), 3.18 (s, 3H, CH3), 5.55 (s, 1H, CH), 6.95
(m, 2H, ArH), 7.23 (m, 2H, ArH), 7.33 (m, 2H, ArH),
7.44 (m, 4H, ArH, NH); δC (400 MHz, DMSO‐d6); 28.3,
30.1, 64.8, 85.1, 86.0, 127.1, 127.7, 127.8, 130.0, 131.5,
141.3, 150.2, 153.7, 154.1, 158.2, 161.8, 161.9, 162.9,
163.5; MS: m/z = 447 (M+).
2.9 | 5‐(4‐Bromophenyl)‐1,3‐dimethyl‐6‐
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 6)
Light yellow powder (98%); m.p.: 283–284 °C (278–279
°C)24d; IR (KBr) (vmax, cm−1) 3368, 1699, 1691; δH
(400 MHz, DMSO‐d6); 3.13 (s, 6H, 2CH3), 5.53 (s, 1H,
CH), 7.04–7.35 (m, 10H, ArH, NH); δC (400 MHz,
DMSO‐d6); 27.9, 29.9, 34.9, 85.4, 117.8, 128.9, 129.0,
130.3, 139.2, 150.3, 154.3, 163.0; MS: m/z = 457 (M+).
2.13 | 5‐(2,4‐Dichlorophenyl)‐1,3‐dimethyl‐
6‐phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 10)
White powder (90%); m.p.: 265–268 °C; IR (KBr) (vmax
,
cm−1) 3352, 1702, 1680; [found: C, 53.34; H, 4.44; N,
11.89; S, 6.86. C20H16Cl2N4O2S requires: C, 53.70; H,
3.61; N, 12.52; S, 7.17%]; δH (400 MHz, DMSO‐d6); 3.03
(s, 3H, CH3), 3.18 (s, 3H, CH3), 5.49 (s, 1H, CH), 6.96
(m, 2H, ArH), 7.42 (m, 7H, ArH, NH); δC (400 MHz,
DMSO‐d6); 30.1, 34.3, 55.9, 104.1, 123.6, 126.4, 128.7,
130.4, 130.6, 131.0, 133.2, 137.6, 150.2, 153.6, 154.1,
188.8; MS: m/z = 447 (M+).
2.10 | 1,3‐Dimethyl‐5‐(2‐nitrophenyl)‐6‐
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 7)
Light yellow powder (95%); m.p.: 282–283 °C; IR (KBr)
(vmax, cm−1) 3436, 1693, 1655; [found: C, 55.88; H, 4.88;
N, 16.47; S, 7.01. C20H17N5O4S requires: C, 56.73; H,
4.05; N, 16.54; S, 7.57%]; δH (400 MHz, DMSO‐d6); 3.01
(s, 3H, CH3), 3.23 (s, 3H, CH3), 6.10 (s, 1H, CH), 7.20–
7.58 (m, 10H, ArH, NH); δC (400 MHz, DMSO‐d6); 28.2,
29.8, 32.1, 80.3, 83.6, 85.6, 123.4, 126.6, 128.6, 131.3,
133.3, 149.6, 150.2, 154.4, 158.3, 161.8, 163.3, 163.5. MS:
m/z = 423 (M+).
2.14 | 5‐(4‐Chloro‐3‐nitrophenyl)‐1,3‐
dimethyl‐6‐phenyl‐7‐thioxo‐5,6,7,8‐
tetrahydropyrimido[4,5‐d]pyrimidine‐2,4
(1H,3H)‐dione (Table 2, Entry 11)
White powder (95%); m.p.: 275–277 °C; IR (KBr) (vmax, cm−1)
3473, 1693, 1662; [found: C, 51.80; H, 4.07; N, 14.92;
S, 6.65. C20H16ClN5O4S requires: C, 52.46; H, 3.49;
N, 15.30; S, 6.99%]; δH (400 MHz, DMSO‐d6); 3.15 (s,
6H, 2CH3), 5.62 (s, 1H, CH), 7.44–8.30 (m, 9H, ArH,
NH); δC (400 MHz, DMSO‐d6); 27.9, 29.9, 35.0, 79.1,
120.8, 123.4, 128.1, 130.3, 132.2, 136.6, 141.7, 147.7,
150.4; MS: m/z = 457 (M+).
2.11 | 1,3‐Dimethyl‐5‐(4‐nitrophenyl)‐6‐
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 8)
Light yellow powder (98%); m.p.: 283–284 °C (272–273
°C)24d; IR (KBr) (vmax, cm−1) 3339, 1695, 1668; δH

GHORBANI‐VAGHEI AND SARMAST
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2.15 | 1,3‐Dimethyl‐6‐phenyl‐7‐thioxo‐5‐(o‐
tolyl)‐5,6,7,8‐tetrahydropyrimido[4,5‐d]
pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 12)
2.19 | 1,3‐Dimethyl‐6‐phenyl‐7‐thioxo‐5‐
(3,4,5‐trimethoxyphenyl)‐5,6,7,8‐
tetrahydropyrimido[4,5‐d]pyrimidine‐
2,4(1H,3H)‐dione (Table 2, Entry 16)
White powder (86%); m.p.: 270–272 °C.; IR (KBr) (vmax
cm−1) 3454, 1693, 1654; [found: C, 64.54; H, 5.59; N,
14.80; S, 8.07. C21H20N4O2S requires: C, 64.27; H, 5.14;
N, 14.28; S, 8.17%]; δH (400 MHz, DMSO‐d6); 2.00 (s, 3H,
CH3), 3.12 (s, 6H, 2CH3), 5.47 (s, 1H, CH), 7.03–7.45 (m,
10H, ArH, NH); δC (400 MHz, DMSO‐d6); 19.6, 29.9,
34.3, 79.1, 86.3, 125.1, 125.2, 126.7, 130.2, 135.3, 138.8,
150.3, 153.7; MS: m/z = 392 (M+).
,
White powder (80%); m.p.: 291–292 °C; IR (KBr) (vmax, cm−1)
3367, 1686, 1667; [found: C, 60.04; H, 5.63; N, 11.55; S, 6.32.
C23H24N4O5S requires: C, 58.96; H, 5.16; N, 11.96; S, 6.84%];
δH (400 MHz, DMSO‐d6); 3.15 (s, 6H, CH3), 3.63 (s, 9H,
3OCH3), 5.54 (s, 1H, CH), 6.36 (s, 2H, ArH), 7.39 (s, 5H,
ArH, NH); δC (400 MHz, DMSO‐d6); 28.0, 29.9, 35.3, 55.8,
59.9, 104.2, 135.2, 148.0, 150.4, 152.2, 154.0, 154.1, 154.2,
156.7, 161.3, 180.8; MS: m/z = 468 (M+).
2.16 | 1,3‐Dimethyl‐6‐phenyl‐7‐thioxo‐5‐(p‐
tolyl)‐5,6,7,8‐tetrahydropyrimido[4,5‐d]
pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 13)
White powder (80%); m.p.: 268–271 °C (271–272 °C)24d; IR
(KBr) (vmax, cm−1) 3364, 1697, 1674; δH (400 MHz, DMSO‐
d6); 2.25 (s, 3H, CH3), 3.15 (s, 6H, 2CH3), 5.55 (s, 1H, CH),
6.99 (s, 6H, ArH), 7.44 (s, 4H, ArH, NH); δC (400 MHz,
DMSO‐d6); 20.4, 27.9, 29.9, 34.9, 86.1, 103.0, 126.4, 128.2,
133.5, 136.3, 150.4, 154.2, 162.5; MS: m/z = 392 (M+).
3 | RESULTS AND DISCUSSION
Sulfuric acid is a basic and efficacious catalyst for practical
chemical processes, and is widely used in the generation
of industrially important chemicals.[22] Sulfuric acid that
functionalized silica‐coated magnetite nanoparticles as
recyclable strong solid acid catalysts opened up a new
path to show an amazing and efficient system to simplify
catalyst recovery in different organic reactions. This
catalyst allows the mixture of well‐known methods for
catalyst heterogenization with techniques for magnetic
separation.[10,23]
In order to evaluate the catalytic capability of the syn-
thesized heterogeneous catalyst (Fe3O4@SiO2@Propyl‐
ANDSA) in organic reactions, we chose to examine its
activity in a one‐pot reaction for the synthesis of
pyrimido[4,5‐d]pyrimidine. In order to establish the con-
ditions of the involved reactions, we initially investigated
the reaction between isothiocyanate, 4‐nitrobenzaldehyde
and N,N‐dimethyl 6‐amino uracil as the model reaction.
The effects of different reaction parameters such as the
catalyst loading, temperature and solvent were screened
on the rates and yields of this model reaction. As summa-
rized in Table 1, the best results were obtained for the
model synthesis of 1,3‐dimethyl‐5‐(4‐nitrophenyl)‐6‐phe-
nyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido[4,5‐d]pyrimi-
dine‐2,4(1H,3H)‐dione in terms of the reaction rate and
yield when the reaction was carried out in reflux condi-
tions in water using 0.05 g of the catalyst (Entry 14). A fur-
ther decrease or increase in the amount of catalyst
(Table 1, Entries 9–13 and 15, 16) did not improve the
yield of the product.
2.17 | 4‐(2‐Methoxyphenyl)‐6,8‐dimethyl‐
3‐phenyl‐2‐thioxo‐2,3,4,8‐tetrahydropyrido
[2,3‐d]pyrimidine‐5,7(1H,6H)‐dione (Table 2,
Entry 14)
White powder (89%); m.p.: 239–241 °C; IR (KBr) (vmax, cm−1)
3405, 1689, 1672; [found: C, 59.73; H, 5.64; N, 13.47; S, 7.01.
C21H20N4O3S requires: C, 61.75; H, 4.94; N, 13.72; S, 7.85%];
δH (400 MHz, DMSO‐d6); 3.12 (s, 6H, 2CH3), 3.58 (s, 3H,
OCH3), 5.50 (s, 1H, CH), 6.85 (m, 3H, ArH), 7.09 (m, 7H,
ArH, NH); δC (400 MHz, DMSO‐d6); 29.8, 31.9, 55.5, 86.2,
110.7, 119.6, 126.5, 127.4, 128.4, 150.4, 153.3, 157.4, 162.4;
MS: m/z = 408 (M+).
2.18 | 5‐(4‐Methoxyphenyl)‐1,3‐dimethyl‐6‐
phenyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido
[4,5‐d]pyrimidine‐2,4(1H,3H)‐dione (Table 2,
Entry 15)
White powder (90%); m.p.: 272–274 °C (271–272 °C)24d; IR
(KBr) (vmax, cm−1) 3353, 1694, 1680; δH (400 MHz, DMSO‐
d6); 3.12 (s, 6H, 2CH3), 3.68 (s, 3H, OCH3), 5.51 (s, 1H,
CH), 6.73 (m, 2H, ArH), 6.96 (m, 3H, ArH), 7.40 (m, 5H,
ArH, NH); δC (400 MHz, DMSO‐d6); 27.9, 29.9, 34.5,
54.8, 85.9, 113.0, 127.4, 127.5, 131.1, 150.4, 154.0, 156.8,
162.6; MS: m/z = 408 (M+).
In order to establish the important role of this catalyst,
the reaction was repeated using 0.05 g of each one of
Fe3O4 magnetic nanoparticles (MNPs) and ANDSA. It was
suggested that the catalytically active site of Fe3O4 NPs is
Fe3+ (as a Lewis acid) and of ANDSA is two ‐SO3H groups
(as acidic sites) that coordinate to the nitrogen group of

6 of 9
GHORBANI‐VAGHEI AND SARMAST
TABLE 1 Screening the reaction parameters for the synthesis of 1,3‐dimethyl‐5‐(4‐nitrophenyl)‐6‐phenyl‐7‐thioxo‐5,6,7,8‐
tetrahydropyrimido[4,5‐d]pyrimidine‐2,4(1H,3H)‐dionea
Entry
Catalyst (g)
Solvent
Temperature (°C)
Time (min)
Yield (%)b
1
0.02
–
25
120
20
2
0.02
H2O
25
120
90
38
20
25
43
55
30
42
70
52
50
60
85
98
98
98
30
27
–
3
0.02
EtOH
CH3CN
–
25
4
0.02
25
90
5
0.02
50
100
120
90
6
0.02
H2O
50
7
0.02
EtOH
CH3CN
H2O
50
8
0.02
50
90
9
0.02
reflux
reflux
100
120
120
100
100
100
60
10
11
12
13
14
15
16
17
18
19
0.02
EtOH
–
0.02
0.02
H2O/EtOH
H2O
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
0.04
0.05
H2O
0.06
H2O
60
0.07
H2O
60
Fe3O4 (MNPs)
ANDSA
–
H2O
300
300
300
H2O
H2O
aConditions: phenylisothiocyanate (1 mmol), 4‐nitrobenzaldehyde (1 mmol), N,N‐dimethyl‐6‐amino uracil (1 mmol), solvent (5 ml).
bIsolated pure yield.
phenylisothiocyanate and carbonyl group of the aldehyde.
This interaction accelerates the conjugation and directs
the additions of the nucleophiles to the corresponding sub-
strates. When these catalysts were applied, the reaction
yields obtained were only about 30% and 27%, respectively.
In the absence of the catalyst under optimized conditions,
a very low yield of the expected product was obtained after
a long reaction time (Table 1, Entries 17–19). To evaluate
the effects of temperature, we performed this reaction at
various temperatures using Fe3O4@SiO2@Propyl‐ANDSA
as the catalyst (Table 1, Entries 2, 6, 9). The results ascertain
that reflux conditions (100 °C) appeared to be optimum.
The effect of the solvent on this reaction is another
factor that was also investigated. As seen in Table 1, the
best conditions along with higher yield were prepared by
H2O among different solvents (EtOH, CH3CN, EtOH/
H2O and solvent‐free conditions). In this reaction, the
organic product, aldehyde and phenylisothiocyanate are
hardly water soluble, whereas N,N‐dimethyl 6‐amino ura-
cil is slightly soluble in hot water. This repulsive interac-
tion between hydrophobic molecules and water leads to
the formation of hydrophobic aggregates that allow reduc-
ing the contact surface between water and organic mole-
cules. To maintain the network of hydrogen bonds
(related to its high cohesive energy density), water swabs
itself around these aggregates, thus acting as an internal
pressure that speeded up reactions with negative activa-
tion volume.
Having optimized the conditions, we next examined
the generality of these conditions to other substrates using
varying electron‐withdrawing and electron‐donating aro-
matic aldehydes (Scheme 1). As shown in Table 2, gener-
ally, the aldehydes containing electron‐withdrawing
groups display higher reactivity in comparison to the

GHORBANI‐VAGHEI AND SARMAST
7 of 9
TABLE 2 Synthesis of pyrimido[4,5‐d]pyrimidine using Fe3O4@SiO2@Propyl‐ANDSA as a heterogeneous catalysta
m.p. (°C)
Time
(min)
Yield
(%)b
Entry
r
Product
Found
Reported
1
2‐FC6H4
C1
120
150
180
90
80
90
83
90
87
98
95
98
96
90
95
86
80
89
90
80
244–245
–
2
4‐FC6H4
C2
264–266
273–276
259–261
226–229
283–284
282–283
283–284
275–278
265–268
275–277
270–272
268–271
239–241
272–274
291–292
–
3
2‐ClC6H4
C3
–
4
2‐BrC6H4
C4
–
5
3‐BrC6H4
C5
180
75
–
6
4‐BrC6H4
C6
278–279[15]
7
2‐O2NC6H4
4‐O2NC6H4
2,3‐Cl2C6H3
2,4‐Cl2C6H3
3‐Cl,4‐O2NC6H3
2‐MeC6H4
C7
45
–
8
C8
60
272–273[15]
9
C9
210
180
90
–
10
11
12
13
14
15
16
C10
C11
C12
C13
C14
C15
C16
–
–
45
–
4‐MeC6H4
20
271–272[15]
2‐OMeC6H4
4‐OMeC6H4
3,4,5‐(OMe)3C6H2
25
30
271–272[15]
20
–
aReaction conditions: phenylisothiocyanate (1 mmol), aldehyde (1 mmol), N,N‐dimethyl‐6‐amino uracil (1 mmol) and Fe3O4@SiO2@Propyl‐ANDSA in water (5
ml) at reflux condition.
bYield refer to the isolated pure products.
aldehydes carrying electron‐releasing groups. As shown
in Scheme 3, in the present of catalyst that activated the
carbonyl group, nucleophilic attack of intermediate A to
aldehyde occurred. The electron‐withdrawing groups
intensified the positive charge on carbon in carbonyl
groups and caused higher reactivity of aldehydes contain-
ing electron‐withdrawing groups in comparison with the
aldehydes carrying electron‐releasing groups. Moreover,
in previous reports, only para‐ and ortho‐substituted
aldehydes undergo this reaction, but in this method we
could react meta‐substituted aldehydes and aldehydes
with two substitutes. The results are summarized in
Table 2. As indicated above, in all cases the reaction pro-
duces the products in good yields, and with the use of
water as solvent it eliminates problems associated with
solvent use, such as cost, safety and pollution. All prod-
ucts were characterized on the basis of their spectroscopic
A
plausible mechanism to explain the three‐
component condensation reactions between
phenylisothiocyanate, aldehyde and N,N‐dimethyl‐6‐
amino uracil based on previously reported reactions[14]
is depicted in Scheme 3. Initially, the catalyst‐accelerated
condensation of N,N‐dimethyl 6‐amino uracil with
phenylisothiocyanate was applied to produce the interme-
diate (A). Subsequently, in the presence of the catalyst,
nucleophilic attack of intermediate A to aldehyde acti-
vated with MNPs produced intermediate B, which is
followed by cyclization and loss of one molecular water
to give intermediate C. Finally, the intermediate C is
tautomerized using the MNP catalyst to produce the fully
aromatized pyrimido[4,5‐d]pyrimidine.
The ability to recycle, catalytic activity and reuse it
was studied in the model one‐pot three‐component reac-
tion between 4‐nitrobenzaldehyde, phenylisothiocyanate
and N,N‐dimethyl‐6‐amino uracil in water and reflux
condition using 0.05 g of the catalyst. At the end of the
1
data, such as FT‐IR, H and 13C NMR spectra, mass and
CHNS.

8 of 9
GHORBANI‐VAGHEI AND SARMAST
SCHEME 3 Suggested mechanism for
the synthesis of pyrimido[4,5‐d]
pyrimidines catalyzed by
Fe3O4@SiO2@Propyl‐ANDSA MNPs
4 | CONCLUSION
In this paper, we have developed a green method for the
synthesis of pyrimido[4,5‐d]pyrimidine derivates via one‐
pot three‐components reaction under reflux conditions
in water and using Fe3O4@SiO2@Propyl‐ANDSA as an
excellent heterogeneous nano‐catalyst. High yield, a sim-
ple work‐up procedure, ease of separation and recyclabil-
ity of the magnetic catalyst, waste reduction, and
generated products with meta as well as with two substi-
tute aldehydes that have not yet been reported are some
advantages of this method.
FIGURE 1 Recyclability test of Fe3O4@SiO2@Propyl‐ANDSA
reaction, the separated catalyst can be reused after being
washed with warm EtOH and drying at 80 °C.
Fe3O4@SiO2@Propyl‐ANDSA was used again for subse-
quent experiments under similar reaction conditions.
Figure 1 illustrates that the catalyst could be reused for
the next cycle without any notable loss of its activity.
Yields of the product decreased only slightly after reusing
the catalyst five times. Therefore, one possible reason for
the decrease in the yield could be due to weight loss of
the catalyst after each stage of retrieval. Another reason
is infected and non‐activated catalyst surface. The FT‐IR
analysis of Fe3O4@SiO2@Propyl‐ANDSA after the sixth
run confirms the stability of the nano‐catalyst during the
recycling procedure (Figure S61). In addition, the TEM
image of the catalyst after recycling did not show a consid-
erable change in the morphology, which clearly indicated
that Fe3O4@SiO2@Propyl‐ANDSA is recyclable and
stable under the reaction conditions (Figure S62).
ACKNOWLEDGEMENT
The authors wish to thank the Research Council of Bu‐Ali
Sina University for financial support to carry out this
research.
ORCID
Ramin Ghorbani‐Vaghei http://orcid.org/0000-0001-8322-
6299
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How to cite this article: Ghorbani‐Vaghei R,
Sarmast N. Green synthesis of new pyrimido[4,5‐d]
pyrimidine derivatives using 7‐aminonaphthalene‐
1,3‐disulfonic acid‐functionalized magnetic
Fe3O4@SiO2 nanoparticles as catalyst. Appl
Organometal Chem. 2017;e4003. https://doi.org/
10.1002/aoc.4003
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