Graphene oxide: A carbocatalyst for the one-pot multicomponent synthesis of 5-aryl-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione

Article abstract of DOI:10.3184/174751918X15161933697835

A simple, straightforward and efficient method is described for the synthesis of 5-aryl-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine- 2,4,6(3H)-trione via one-pot multicomponent reaction of indane-1,3-dione, arylaldehydes and 6-aminopyrimidin-2,4(1H,3H)-dione in presence of catalytic amount of graphene oxide in water. Graphene oxide is a versatile carbocatalyst and this is the first report on its application in a pyrido[2,3-d]pyrimidine synthesis. Good yield, use of readily available starting materials, operational simplicity, easy work-up and eco-friendly re-usable catalyst are the key features of this protocol.

Full text of DOI:10.3184/174751918X15161933697835

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 JANUARY, 35–39
RESEARCH PAPER 35
Graphene oxide: a carbocatalyst for the one-pot multicomponent synthesis of
5-aryl-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione
Hamid Reza Dehghanpour, Mohammad H. Mosslemin* and Razieh Mohebat
Department of Chemistry, Yazd Branch, Islamic Azad University, Yazd, Iran
A simple, straightforward and efficient method is described for the synthesis of 5-aryl-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H)-trione via one-pot multicomponent reaction of indane-1,3-dione, arylaldehydes and 6-aminopyrimidin-2,4(1H,3H)-dione in
presence of catalytic amount of graphene oxide in water. Graphene oxide is a versatile carbocatalyst and this is the first report on its
application in a pyrido[2,3-d]pyrimidine synthesis. Good yield, use of readily available starting materials, operational simplicity, easy
work-up and eco-friendly re-usable catalyst are the key features of this protocol.
Keywords: pyrido[2,3-d]pyrimidines, carbocatalyst, multicomponent reaction, heterogeneous catalysis, graphene oxide
The pyrimidine core has been widely studied because of its
presence in numerous natural products and structurally diverse
synthetic derivatives.1 In particular, pyridopyrimidines have
received considerable attention over recent years because of
their wide-ranging biological activities, mainly as antifolates,2
showing related antiproliferative properties, such as anticancer,3
anti-inflammatory,4 antimicrobial5 or antihistaminic6 activity.
Scheme 1 shows two examples of bioactive compounds with this
core structure. 5-(3-Bromophenyl)-5,11-dihydro-1,3-dimethyl-
1H-indeno[2,1:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione)
(BPIPP) (A) has been identified as a novel potent inhibitor of
cyclic nucleotide biosynthesis and a promising lead compound for
treatment of diarrhoea and other diseases.7 The second compound
contains a pyrimido[4,5-b]quinolones structure (B)8 and exhibits
significant anticancer activity (Scheme 1).
a considerable variety of organic reactions have been reported to
be catalysed efficiently by graphene oxide. Single or few layers of
graphene oxide with large surface area and oxygenated functional
groups, such as carboxyl groups, on the edges, and hydroxyl or
epoxy on the basal plane have shown acidic and oxidative properties
in catalytic processes (Scheme 2).
Considering the great potential of pyrido[2,3-d]pyrimidine
derivatives as a source of valuable drug candidates and with our
continued interest in MCRs and our ongoing programme for
the synthesis of heterocyclic systems based on green chemistry
protocols,11–14 here we report a green and efficient method for
the synthesis of indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H,5H,11H)-triones 4 through a one-pot, three-component
condensation reaction between 6-aminopyrimidin-2,4(1H,3H)-
dione 1, arylaldehydes 2 and indane-1,3-dione 3 catalysed by
graphene oxide as an eco-friendly, efficient, non-toxic and reusable
solid catalyst in water (Scheme 3).
Multicomponent reactions (MCRs) have become a powerful
tool for accessing a vast number of synthetic and pharmaceutically
relevant compounds. The main advantages of the MCRs are high
reaction rates, selectivity and efficiency, as well as, low costs,
high variability, high bond-forming efficiency, simplicity and
environmentally friendly properties.9
COOH
OH
COOH
COOH
Carbonaceous nanomaterials are important in various fields, such
as nanotechnology, tailoring new composites, electrochemistry,
sensors, catalysis, etc. A structural model for graphene oxide was
published by Klinowski and co-workers in 1998.10 Since then,
HOOC
HO
OH
O
OH
HOOC
HO
OH
COOH
OH
OH
O
Br
O
O
N
Ar
O
N
O
HN
N
HOOC
S
N
H
O
N
COOH
H
HO
B
Ar
HOOC
A
OH
Scheme 1
Scheme 2 Structural model for graphene oxide.
O
O
O
Ar
O
3
Graphene oxide
HN
HN
O
+
o C 4 h
H O ,
60
,
2
O
O
N
H
NH2
O
N
H
N
4
Ar
H
1
2
Scheme 3
* Correspondent. E-mail: mhmosslemin@iauyazd.ac.ir

36 JOURNAL OF CHEMICAL RESEARCH 2018
Results and discussion
found that H2O in combination with 50 mg of catalyst gave the
best results. With these optimised conditions, the scope and
generality of this three-component reaction was investigated.
The reaction was successful with various substituted
arylaldehydes to provide the corresponding pyrido[2,3-d]
pyrimidines 4a–p in good to excellent yields. As can be seen,
very good yields of products were obtained for arylaldehydes
bearing either electron-withdrawing or electron-donating
groups (Scheme 4). Compounds 4a–p were new and their
structures were deduced from their elemental analyses and their
IR, 1H NMR and 13C NMR spectra.
The vast biological and pharmacological importance of
pyrido[2,3-d]pyrimidine derivatives inspired us to develop a
novel protocol for their efficient synthesis. We aimed to find a
practical and general method for their synthesis in high yields and
purities and, as the development of efficient and environmentally
friendly synthetic procedures is always desirable, we decided to
determine whether pyrido[2,3-d]pyrimidine derivatives could
be prepared by condensation of 6-aminopyrimidin-2,4(1H,3H)-
dione, indane-1,3-dione and arylaldehydes in the presence of
graphene oxide as carbocatalyst in water.
We chose indane-1,3-dione (1 mmol), 4-fluoro benzaldehyde
(1 mmol) and 6-aminopyrimidin-2,4(1H,3H)-dione (1 mmol) as
model substrates for the optimisation study. Indane-1,3-dione,
4-fluorobenzaldehyde and 6-aminopyrimidin-2,4(1H,3H)-
dione were heated at 60 °C in the presence of 50 mg of graphene
oxide for 4 h in water. To improve the yield of the reaction,
various solvents and catalyst loadings were screened and the
results are shown in Table 1.
The mass spectra of compounds 4a–p are fairly similar and
display molecular ion peaks. For example, the IR spectrum of 4a
showed two absorptions at 3221 and 3438 cm−1 for NH groups
and one at 1698–1660 cm−1 for carbonyl groups, indicating the
presence of these functional groups in the proposed structure.
1
The H NMR spectrum of 4a exhibited two triplet signals at
δ 7.08 and 7.38 ppm (J = 8.4 Hz) and three doublet signals at
7.24–7.63 ppm (J = 8.8, 8.0, 7.2 Hz) for the aromatic hydrogens,
and two singlet signals at δ 10.23 and 10.37 ppm for the NH
hydrogen atoms. The 13C NMR spectrum of 4a showed 18
resonances.
Among the various tested mediums (H2O, CH3CN, EtOAc,
THF) and scanned catalyst loadings (10, 20, 30, 40 mg), it was
Table 1
A proposed mechanism for this reaction is shown in Scheme 5.
Graphene oxide acts as an acid catalyst. Therefore, we propose
that the arylaldehyde is activated by graphene oxide and the
activated carbonyl 2 reacts with activated indane-1,3-dione 3
to afford intermediate 5. Then, 6-aminopyrimidin-2,4(1H,3H)-
dione 1 attacks the intermediate 5 and affords intermediate 6 via
Michael addition. The intermediate 6 undergoes intramolecular
cyclisation with participation of the amino function and one
of the indane-1,3-dione carbonyl groups to form 7. Then the
removal of water from 7 forms 8 and finally derivatives 4a–p
as the target molecules formed from oxidation of 8 by graphene
oxide.
Entry
Solvent
CH3CN
EtOH
H2O
EtOAc
THF
H2O
H2O
H2O
H2O
Amount of catalyst (mg)
Yield (%)a
64
76
95
38
45
60
65
89
1
2
3
4
5
6
7
8
9
50
50
50
50
50
10
20
30
40
92
aIsolated yield.
O
O
O
Ar
O
3
Graphene oxide
HN
HN
O
+
60 oC 4 h
,
H2O ,
O
O
N
H
NH2
O
N
H
N
4
Ar
H
1
2
4
a
4
i
ꢌr
ꢅꢆieꢇda
ꢈꢉ
ꢑꢒpꢒꢓꢔꢀꢕ
ꢄꢋꢋꢍꢄꢋꢄ
ꢌr
ꢁ ꢃ
ꢃꢍꢎꢂ ꢀ ꢂ
ꢅꢆieꢇda
ꢗꢁ
ꢑꢒpꢒꢓꢔꢀꢕ
ꢊꢈꢊꢍꢊꢈꢃ
ꢃꢍꢝꢀꢁꢂꢃ
ꢃꢍꢎ ꢏ ꢀꢁꢂꢃ
ꢁ
ꢃ
b
c
j
ꢊ
ꢈꢉ
ꢈꢊ
ꢄꢐꢉꢍꢄꢐꢖ
ꢄꢋꢗꢍꢄꢊꢐ
ꢊꢍꢏꢀ ꢀ ꢂ
ꢈꢋ
ꢈꢐ
ꢄꢐꢉꢍꢄꢐꢖ
ꢄꢐꢗꢍꢄꢋꢐ
k
l
ꢁ
ꢂ
ꢃ
ꢃꢍꢏꢀ ꢀꢁꢂꢃ
ꢊꢞꢃꢍꢟrꢊ ꢀꢁꢂꢄ
ꢄꢍꢎꢊꢏ ꢀꢁꢂꢃ
ꢃꢍꢟr ꢀ
ꢊ
d
ꢈꢋ
ꢈꢄ
ꢄꢐꢃꢍꢄꢐꢁ
ꢃꢍꢀꢇꢍꢄꢍꢎ ꢏ ꢀꢁꢂꢄ
ꢗꢈ
ꢗꢉ
ꢄꢊꢋꢍꢄꢊꢄ
e
f
m
n
ꢊꢈꢈꢍꢄꢐꢋ
ꢊꢈꢉꢍꢊꢈꢖ
ꢊꢍꢎꢂꢍꢉꢍꢟrꢀꢁꢂꢄ
ꢊꢖꢉꢍꢊꢖꢖ
ꢊꢗꢐꢍꢊꢗꢊ
ꢊꢍꢎꢂꢍꢉꢍꢎꢊꢏ ꢀꢁꢂꢄ ꢈꢐ
ꢊꢍꢎꢂꢍꢄꢍꢎꢀꢂꢄ ꢀꢁꢂꢄ ꢗꢖ
g
o
ꢀ ꢂꢄ ꢗꢈ
ꢄꢐꢐꢍꢄꢐꢊ
ꢊꢗꢗꢍꢊꢈꢐ
ꢃꢍꢎꢀꢂꢄ ꢀꢁꢂꢃ
ꢊꢍꢟrꢍꢉꢍꢀꢇꢀꢁꢂꢄ
ꢗꢉ
ꢈꢐ
ꢄꢋꢄꢍꢄꢋꢉ
ꢊꢗꢈꢍꢊꢈꢋ
ꢊꢍꢎꢂꢍꢉꢍꢀꢂꢄ
ꢁ
h
p
ꢊꢍꢎꢂꢍꢉꢍꢎꢀꢂꢄ ꢀꢁꢂꢄ ꢗꢉ
aꢆieꢇdꢘ reꢙer ꢚo ꢚhe pꢛre iꢘoꢇaꢚed prodoꢛꢜꢚꢘ
Scheme 4

JOURNAL OF CHEMICAL RESEARCH 2018 37
O
O
OH
GO
_
H2O
O
2
+
Ar
H
O
Ar
5
3
O
GO
O
O
Ar
O
NH
+
H2N
N
H
O
Ar
_
O
5
1
NH
O
+
2HN
N
H
O
O
Ar
O
Ar
O
O
O
Ar
H
O
_
NH
H2O
NH
NH
O
O
N
H
N
H
O
N
H
N
H
O
2HN
HO
N
8
H
6
7
Oxidation
4
Scheme 5
Conclusion
and reused for a consecutive run under the same reaction conditions.
Then, the reaction mixture was cooled to room temperature and the
solid residue was collected by filtration and recrystallised from ethanol
to afford the pure product.
We report a simple and efficient one-pot condensation of
6-aminopyrimidin-2,4(1H,3H)-dione with indane-1,3-dione
and an arylaldehyde in the presence of catalytic amounts of
graphene oxide as a good carbocatalyst in water at 60 °C to give
indeno-fused pyrido[2,3-d]pyrimidines. The advantages of this
method are simple available starting materials, short reaction
times, easy and clean work-up, and excellent yields. Also
the catalyst is recyclable; after five runs the yields were very
good. For example, for the model reaction when 50 mg of fresh
graphene oxide was used, the yield was 95% and after using the
recovered catalyst the yield was about 91%. Towards the effort
to harness the catalytic activity of sustainable carbon materials,
such as graphene oxide, in diverse organic reactions, the present
protocol is another example of the catalytic application of
carbon materials in the synthesis of heterocyclic molecules of
biological importance, the exploration of which has been very
limited until now.
5-(4-Fluorophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H)-trione (4a): Red powder; m.p. 311–313 °C; IR (KBr) (νmax
1
cm−1): 3225, 3153 (NH), 1697, 1671, 1661 (C=O); H NMR (400 Hz,
DMSO-d6): δ 7.08 (2H, t, J = 8.5 Hz, aromatic), 7.24 (1H, d, J = 8.7 Hz,
aromatic), 7.38 (1H, t, J = 8.5 Hz, aromatic), 7.44 (2H, d, J = 8.1 Hz,
aromatic), 7.63 (1H, d, J = 7.1 Hz, aromatic), 10.23 and 10.37 (2H,
s, 2NH); 13C NMR (100 Hz, DMSO-d6): δ 109.6, 115.2 (JCF = 21 Hz,
Cortho), 119.5, 129.7, 129.6, 130.4 (JCF = 9 Hz, Cmeta), 130.8, 132.6, 133.4,
136.2, 140.6 (JCF = 2 Hz, Cortho), 150.2, 154.3, 157.9 (JCF = 246 Hz, Cipso),
158.9 (aromatic and olefinic carbons), 153.9, 163.3, 191.3 (3C=O); MS
m/z (%): 359 (38). Anal. calcd for C20H10FN3O3: C, 66.86; H, 2.81; N,
11.69; found: C, 66.69; H, 2.91; N, 11.61%.
5-(4-Nitrorophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H)-trione (4b); Red powder; m.p. 305–307 °C; IR (KBr) (νmax
cm−1): 3221, 3131 (NH), 1701, 1673, 1664 (C=O), 1538, 1335 (NO2);
1H NMR (400 Hz, DMSO-d6): δ 7.32–7.50 (4H, m, aromatic) 7.57, 8.10
(4H, 2d, J = 12 Hz, aromatic), 10.42, 11.01 (2H, 2s, 2NH); 13C NMR
(100 Hz, DMSO-d6): δ 108.6, 119.9, 122.7, 123.5, 129.7, 129.4, 130.5,
131.1, 132.8, 132.6, 136.2, 146.2, 150.3, 152.9, 158.7 (aromatic and
olefinic carbons), 154.6, 163.1, 191.2 (3C=O); MS m/z (%): 386 (31).
Anal. calcd for C20H10N4O5: C, 62.18; H, 2.61; N, 14.50; found: C,
61.99; H, 2.77; N, 14.43%.
5-(4-Cyanophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H)-trione (4c): Red powder; m.p. 318–320 °C; IR (KBr) (νmax
cm−1): 3231, 3152 (NH), 2221 (CN), 1702, 1678, 1651 (C=O); 1H NMR
(400 Hz, DMSO-d6): δ 7.24–7.72 (4H, m, aromatic), 7.71, 7.86 (4H, 2d,
J = 12 Hz, aromatic), 10.37–10.44 (2H, 2s, 2NH); 13C NMR (100 Hz,
DMSO-d6): δ 106.9, 109.3, 119.6, 119.8 (CN), 129.2, 130.5, 131.2,
131.3, 132.7, 132.7, 133.1, 133.4, 136.3, 149.6, 153.4, 159.1 (aromatic
and olefinic carbons), 154.5, 163.4, 191.2 (3C=O); MS m/z (%): 366
(39). Anal. calcd for C21H10N4O3: C, 68.85; H, 2.75; N, 15.29; found: C,
68.91; H, 2.66; N, 15.34%.
5- (2,4-Dibromophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4d): Red powder; m.p. 304–306 °C; IR
(KBr) (νmax cm−1): 3166, 3149 (NH), 1701, 1686, 1655 (C=O); 1H NMR
(400 Hz, DMSO-d6): δ 7.33 (1H, s, aromatic), 7.49 (1H, dd, JHH = 8.3,
2.1 Hz, aromatic), 7.65 (1H, s, aromatic), 7.67 (1H, s, aromatic), 7.71
(1H, d, J = 2.1 Hz, 1H), 7.78 (1H, dt, J = 8.3, 2.1 Hz, aromatic), 7.86
(1H, s, aromatic), 7.97 (1H, s, aromatic), 10.38–10.39 (2H, 2s, 2NH);
Experimental
Melting points were determined with an Electrothermal 9100
apparatus. Elemental analyses were performed using a Heraeus CHN-
O-Rapid analyser. Mass spectra were recorded on a FINNIGAN-
MAT 8430 mass spectrometer operating at an ionisation potential of
70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer.
NMR spectra were obtained on a Bruker DRX 400 MHz spectrometer
(1H NMR at 400 Hz, 13C NMR at 100 Hz) in DMSO-d6 using TMS as
an internal standard. Chemical shifts (δ) are given in ppm and coupling
constants (J) are given in Hz. All chemicals used in this work were
purchased from Fluka (Buchs, Switzerland) and were used without
further purification.
Synthesis of pyrido[2,3-d]pyrimidines (4a–p); general procedure
Equimolar amounts of the indane-1,3-dione, (1 mmol), an arylaldehyde
(1 mmol) and 6-aminopyrimidin-2,4(1H,3H)-dione (1 mmol) in
the presence of catalytic amounts of graphene oxide and water (5
mL) was placed in a 50 mL round-bottomed flask mounted over a
magnetic stirrer. The contents were stirred magnetically in an oil bath
maintained at 60 °C for 4 h. On reaction completion, monitored by
TLC, the reaction mixture was filtered and the resulting precipitate
diluted with hot ethanol. The catalyst was easily separated from the
reaction mixture by filtration, washing with hot ethanol and drying,

38 JOURNAL OF CHEMICAL RESEARCH 2018
13C NMR (100 Hz, DMSO-d6): δ 107.1, 119.5, 124.2, 128.7, 128.9,
130.7, 131.1, 132.2, 132.5, 132.8, 133.3, 136.6, 141.8, 142.2, 150.1,
153.4, 158.7 (aromatic and olefinic carbons), 154.5, 163.1, 190.7
(3C=O); MS m/z (%): 499 (28). Anal. calcd for C20H9Br2N3O3: C,
48.13; H, 1.82; N, 8.42; found: C, 48.03; H, 1.86; N, 8.51%.
5-(3-Nitrophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H)-trione (4e): Red powder; m.p. 299–301 °C; IR (KBr) (νmax
cm−1): 3332, 3181 (NH), 1712, 1656, 1643 (C=O), 1520, 1337 (NO2);
1H NMR (400 Hz, DMSO-d6): δ 7.28 (1H, d, J = 7.1 Hz, aromatic),
7.39 (1H, dt, J = 7.1, 1.5 Hz, aromatic), 7.50 (1H, s, aromatic), 7.57
(1H, t, J = 7.9 Hz, aromatic), 7.77 (1H, t, J = 7.9 Hz, aromatic), 8.05
(1H, dd, J = 7.9, 1.5 Hz, aromatic), 8.11 (1H, s, aromatic), 10.34, 10.48
(2H, 2s, 2NH); 13C NMR (100 Hz, DMSO-d6): δ 108.6, 119.9, 121.2,
121.7, 122.5, 130.1, 131.3, 132.8, 132.7, 133.4, 135.3, 136.3, 145.7, 147.5,
150.4, 152.6, 158.2 (aromatic and olefinic carbons), 154.5, 163.4, 191.1
(3C=O); MS m/z (%): 386 (36). Anal. calcd for C20H10N4O5: C, 62.18;
H, 2.61; N, 14.50; found: C, 62.25; H, 2.57; N, 14.46%.
cm−1): 3218, 3180 (NH), 2219 (CN) 1706, 1682, 1657 (C=O); 1H NMR
(400 Hz, DMSO-d6): δ 7.09–7.57 (8H, m, aromatic), 10.25, 10.36 (2H,
2s, 2NH); 13C NMR (100 Hz, DMSO-d6): δ 107.1, 119.4, 120.1 (CN),
124.4, 127.2, 127.9, 129.5, 131.1, 131.7, 132.4, 132.9, 133.4, 136.6, 140.6,
145.4, 150.1, 153.7, 159.2 (aromatic and olefinic carbons), 161.3, 163.1,
190.7 (3C=O); MS m/z (%): 366 (34). Anal. calcd for C21H10N4O3: C,
68.85; H, 2.75; N, 15.29; found: C, 68.79; H, 2.69; N, 15.23%.
5-(4-Bromophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H)-trione (4k): Red powder; m.p. 308–310 °C; IR (KBr) (νmax
1
cm−1): 3214, 3133 (NH), 1699, 1667, 1654 (C=O); H NMR (400 Hz,
3
DMSO-d6): δ 7.23, 7.46 (2H, 2d, JHH = 12 Hz, aromatic), 7.26–7.68
(4H, m, aromatic), 10.28, 10.41 (2H, 2s, 2NH); 13C NMR (100 Hz,
DMSO-d6): δ 109.3, 119.7, 121.1, 130.6, 130.5, 131.1, 131.4, 132.7,
132.6, 133.6, 136.1, 136.5, 145.2, 145.5, 150.1, 154.7, 160.1 (aromatic
and olefinic carbons), 154.6, 163.5, 191.0 (3C=O); MS m/z (%): 320
(37). Anal. calcd for C20H10BrN3O3: C, 57.17; H, 2.40; N, 10.00; found
C, 57.07; H, 2.41; N, 9.93%.
5-(2-Hydroxy-5-nitrophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4f): Red powder; m.p. 295–297 °C;
IR (KBr) (νmax cm−1): 3272, 3111 (NH), 3215 (OH), 1707, 1660, 1647
(C=O), 1541, 1339 (NO2); 1H NMR (400 Hz, DMSO-d6): δ 7.64–8.35
(7H, m, aromatic), 10.91 (1H, s, OH), 11.44, 11.98 (2H, 2s, 2NH);
13C NMR (100 Hz, DMSO-d6): δ 107.5, 120.9, 122.2, 123.4, 123.8,
124.1, 129.5, 129.4, 130.8, 133.2, 136.7, 140.1, 147.4, 150.1, 153.7, 159.6,
161.4 (aromatic and olefinic carbons), 157.4, 168.6, 188.9 (C=O); MS
m/z (%): 402 (31). Anal. calcd for C20H10N4O6: C, 59.71; H, 2.51; N,
13.93; found: C, 59.64; H, 2.46; N, 13.86%.
5-(4-Chloro-3-nitrophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4l): Red powder; m.p. 321–323 °C; IR
(KBr) (νmax cm−1): 3216, 3162 (NH), 1710, 1682, 1661 (C=O), 1523,
1335 (NO2); 1H NMR (400 Hz, DMSO-d6): δ 7.32–7.99 (7H, aromatic),
10.43 (2H, b, 2NH); 13C NMR (100 Hz, DMSO-d6): δ 108.1, 120.1,
124.7, 127.3, 131.2, 131.5, 132.6, 132.8, 133.4, 136.1, 136.3, 142.4,
146.6, 148.1, 150.1, 154.1, 158.6 (aromatic and olefinic carbons),
154.7, 163.1, 191.3 (3C=O); MS m/z (%): 420 (28). Anal. calcd for
C20H9ClN4O5: C, 57.09; H, 2.16; N, 13.32; found: C, 57.16; H, 2.24; N,
13.42%.
5-(2-Hydroxy-5-methylphenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4g): Red powder; m.p. 300–302 °C;
IR (KBr) (νmax cm−1): 3271, 3109 (NH), 3216 (OH), 1707, 1663, 1645
5-(5-Bromo-2-hydroxyphenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4m): Red powder; m.p. 275–277 °C;
IR (KBr) (νmax cm−1): 3291, 3115 (NH), 3210 (OH), 1699, 1672, 1643
1
1
(C=O); H NMR (400 Hz, DMSO-d6): δ 2.32 (3H, s, 3CH3), 6.84
(C=O); H NMR (400 Hz, DMSO-d6): δ 6.70 (1H, d, J = 8.4 Hz,
(1H, d, J = 8.4 Hz, aromatic), 7.03 (1H, m, aromatic), 7.12 (1H, dd,
J = 8.4, 2.8 Hz, aromatic), 7.25 (1H, d, J = 6.9 Hz, aromatic), 7.37 (1H,
dt, J = 8.8, 0.9 Hz, aromatic), 7.46 (1H, dt, J = 8.8, 0.9 Hz, aromatic),
7.68 (1H, m, aromatic), 9.31 (1H, s, OH), 10.59, 10.63 (2H, 2s, 2NH);
13C NMR (100 Hz, DMSO-d6): δ 23.1 (CH3), 108.9, 116.8, 119.5, 121.1,
124.9, 129.8, 131.0, 131.9, 133.7, 134.6, 136.9, 140.1, 149.7, 151.6,
154.4, 157.1, 160.3 (aromatic and olefinic carbons), 155.2, 161.4, 189.3
(3C=O); MS m/z (%): 371 (34). Anal. calcd for C21H13N3O4: C, 67.92;
H, 3.53; N, 11.32; found: C, 68.02; H, 3.61; N, 11.27%.
aromatic), 7.05 (1H, m, aromatic), 7.10 (1H, dd, J = 8.4, 2.8 Hz,
aromatic), 7.22 (1H, d, J = 6.9 Hz, aromatic), 7.36 (1H, dt, J = 8.8,
0.9 Hz, aromatic), 7.44 (1H, dt, J = 8.8, 0.9 Hz, aromatic), 7.65 (1H,
m, aromatic), 9.27 (1H, s, OH), 10.62–10.80 (2H, 2s, 2NH); 13C NMR
(100 Hz, DMSO-d6): δ 107.6, 111.5, 117.1, 119.4, 121.8, 124.5, 130.2,
130.6, 131.7, 133.3, 135.7, 136.6, 140.5, 150.0, 153.9, 157.8, 160.1
(aromatic and olefinic carbons), 154.8, 161.1, 188.8 (3C=O); MS m/z
(%): 436 (36). Anal. calcd for C20H10BrN3O4: C, 55.07; H, 2.31; N, 9.63;
found: C, 54.89; H, 2.36; N, 9.55%.
5- (2-Hydrox y-5-methox yphenyl) -1H-indeno [2 ′,1′:5,6]
pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (4h): Red powder; m.p.
284–286 °C; IR (KBr) (νmax cm−1): 3266, 3106 (NH), 3211 (OH),
1708, 1659, 1644 (C=O); 1H NMR (400 Hz, DMSO-d6): δ 3.43 (3H, s,
OCH3), 6.53 (1H, d, J = 8.3 Hz, aromatic), 6.98 (1H, m, aromatic), 7.03
(1H, dd, J = 8.3, 2.8 Hz, aromatic), 7.19 (1H, d, J = 6.9 Hz, aromatic),
7.34 (1H, dt, J = 8.8, 0.9 Hz, aromatic), 7.45 (1H, dt, J = 8.8, 0.9 Hz,
aromatic), 7.62 (1H, m, aromatic), 9.47 (1H, s, OH), 10.59, 10.78 (2H,
2s, 2NH); 13C NMR (100 Hz, DMSO-d6): δ 51.7 (OCH3), 109.4, 112.1,
117.3, 119.8, 122.3, 125.7, 129.8, 130.6, 131.5, 132.7, 136.4, 137.9,
141.3, 146., 151.3, 154.1, 158.1, 162.7 (aromatic and olefinic carbons),
155.3, 164.1, 191.8 (3C=O); MS m/z (%): 387 (30). Anal. calcd for
C21H13N3O5: C, 65.12; H, 3.38; N, 10.85; found: C, 65.18; H, 3.29; N,
10.76%.
5-(4-Hydroxyphenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H)-trione (4i): Red powder; m.p. 292–294 °C; IR (KBr) (νmax
cm−1): 3280, 3153 (NH), 3209 (OH), 1705, 1680, 1646(C=O); 1H NMR
(400 Hz, DMSO-d6): δ 6.60 (2H, d, J = 12 Hz, aromatic), 7.13 (2H, d,
J = 12 Hz, aromatic), 7.27 (2H, d, J = 6.7 Hz, aromatic), 7.36 (1H, dt,
J = 8.9, 0.9 Hz, aromatic), 7.39 (1H, d, J = 6.7 Hz, aromatic), 7.45 (1H, dt,
J = 8.9, 0.9 Hz, aromatic), 9.21 (1H, s, OH), 10.13, 10.30 (2H, 2s, 2NH);
13C NMR (100 Hz, DMSO-d6): δ 110.7, 114.9, 115.3, 121.4, 128.9, 129.7,
130.4, 132.8, 133.2, 133.0, 136.7, 136.9, 144.5, 150.4, 152.9, 153.3, 159.3
(aromatic and olefinic carbons), 156.1, 163.4, 191.1 (C=O); MS m/z (%):
357 (41). Anal. calcd for C20H11N3O4: C, 67.23; H, 3.10; N, 11.76; found:
C, 67.32; H, 3.15; N, 11.81%.
5- (2-Hydrox y-3-methox yphenyl) -1H-indeno [2 ′,1′:5,6]
pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (4n): Red powder; m.p.
280–282 °C; IR (KBr) (νmax cm−1): 3273, 3181 (NH), 3211 (OH),
1
1705, 1677, 1656 (C=O); H NMR (400 Hz, DMSO-d6): δ 3.35 (3H,
s, OCH3), 6.66 (2H, d, J = 7.7 Hz, aromatic), 6.72 (1H, t, J = 8.9 Hz,
aromatic), 7.26 (1H, d, J = 8.9 Hz, aromatic), 7.38 (1H, dt, J = 7.1, 1.2
Hz, aromatic), 7.50 (3H, m, aromatic), 8.77 (1H, br, OH), 10.24, 10.42
(2H, 2s, 2NH); 13C NMR (100 Hz, DMSO-d6): δ 56.1 (CH3), 109.5,
110.3, 119.1, 119.5, 121.2, 121.9, 130.5, 132.9, 132.1, 133.3, 136.6, 144.5,
145.3, 148.9, 150.1, 152.9, 159.7 (aromatic and olefinic carbons), 154.3,
164.5, 191.4 (C=O); MS m/z (%): 387 (47). Anal. calcd for C21H13N3O5:
C, 65.12; H, 3.38; N, 10.85; found: C, 65.25; H, 3.30; N, 10.79%.
5- (4-Methoxyphenyl) -1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4o): Red powder; m.p. 313–315 °C;
IR (KBr) (νmax cm−1): 3369, 3170 (NH), 1706, 1679, 1658 (3C=O);
1H NMR (400 Hz, DMSO-d6): δ 3.83 (3H, s, OCH3), 6.93, 6.96 (4H, 2d,
3JHH = 12 Hz, aromatic), 7.62–7.87 (4H, m, aromatic), 11.30, 12.21 (2H,
2s, 2NH); 13C NMR (100 Hz, DMSO-d6): δ 55.4 (OCH3), 110.7, 115.2,
115.8, 121.1, 128.8, 129.7, 130.9, 132.3, 133.5, 136.2, 144.8, 150.1,
153.2, 154.1, 158.8 (aromatic and olefinic carbons), 156.1, 163.3, 191.4
(3C=O); MS m/z (%): 371 (37). Anal. calcd for C21H13N3O4: C, 67.92;
H, 3.53; N, 11.32; found: C, 67.83; H, 3.44; N, 11.41%.
5-(2-Bromo-5-chloropheyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4p): Red powder; m.p. 289–291 °C; IR
(KBr) (νmax cm−1): 3268, 3111 (NH), 1705, 1659, 1642 (C=O); 1H NMR
(400 Hz, DMSO-d6): δ 7.35–8.41 (7H, m, aromatic), 11.39, 11.74 (2H,
2s, 2NH); 13C NMR (100 Hz, DMSO-d6): 107.3, 119.6, 121.1, 122.3,
123.5, 124.7, 124.9, 128.6, 130.0, 130.9, 133.9, 135.8, 141.1, 146.8,
5-(2-Cyanophenyl)-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-
2,4,6(3H)-trione (4j): Red powder; m.p. 305–307 °C; IR (KBr) (νmax

JOURNAL OF CHEMICAL RESEARCH 2018 39
5
6
O. El-Sayed and H. Aboul-Enein, Arch. Pharm., 2001, 334, 117.
J. Quintela, C. Peinador, L. Botana, M. Estevez and R. Riguera, Bioorg.
Med. Chem., 1997, 5, 1543.
A. Kots, B.-k. Choi, M. Estrella-Jimenez, C. Warren, S. Gilbertson, R.
Guerrant and F. Murad, Proc. Natl Acad. Sci. USA, 2008, 105, 8440.
B. Insuasty, D. Becerra, J. Quiroga, R. Abonia, M. Nogueras and J. Cobo,
Eur. J. Med. Chem., 2013, 60, 1.
152.1, 153.9, 161.8 (aromatic and olefinic carbons), 156.3, 169.1, 189.6
(C=O); MS m/z (%): 454 (33). Anal. calcd for C20H9BrClN3O3: C,
52.83; H, 2.00; N, 9.24; found: C, 52.91; H, 1.85; N, 9.31%.
7
8
9
Received 24 November 2017; accepted 2 January 2018
Paper 1705122
https://doi.org/10.3184/174751918X15161933697835
Published online: 26 January 2018
A. Dömling, Chem. Rev., 2006, 106, 17.
10 H. He, J. Klinowski, M. Forster and A. Lerf, Chem. Phys. Lett., 1998, 287,
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11 M. Anary-Abbasinejad, H.D. Farashah, A. Hassanabadi, H. Anaraki-
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13 A. Havasian, M.H. Mosslemin, M.R. Nateghi and F. Kalantari-Fotooh, J.
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