A Simple and Environmentally Benign Synthetic Protocol of Indeno-Fused Pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1002/jhet.2959

An efficient and environmentally benign protocol for the synthesis of indeno [2ˊ,1ˊ:5,6] pyrido[2,3-d] pyrimidines has been developed. The synthesis of these pharmacologically important compounds can be achieved by the one-pot three-component condensation of 6-amino-1,3-dimethyluracil, aromatic aldehydes, and 1,3-indandione in ethanol without using catalyst and oxidizing agent. This protocol has the advantages of easier work-up, milder reaction conditions, and an environmentally benign procedure compared with other methods.

Full text of DOI:10.1002/jhet.2959

Month 2017 A Simple and Environmentally Benign Synthetic Protocol of Indeno-Fused
Pyrido[2,3-d]pyrimidines
*
Mohammad Bayat
and Shima Nasri
Department of Chemistry, Imam Khomeini International University, Qazvin, Iran
*
E-mail: bayat_mo@yahoo.com, m.bayat@sci.ikiu.ac.ir
Received March 14, 2017
DOI 10.1002/jhet.2959
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and environmentally benign protocol for the synthesis of indeno [2 ,1 :5,6] pyrido[2,3-d] py-
rimidines has been developed. The synthesis of these pharmacologically important compounds can be
achieved by the one-pot three-component condensation of 6-amino-1,3-dimethyluracil, aromatic aldehydes,
and 1,3-indandione in ethanol without using catalyst and oxidizing agent. This protocol has the advantages
of easier work-up, milder reaction conditions, and an environmentally benign procedure compared with
other methods.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
its dihydropyrido[2,3-d]pyrimidines form, as a starting
point for the discovery of anti-cancer drugs [23].
One aspect of multicomponent reactions that has
received relatively little attention is their development in
green environments [1]. Ethanol is an inexpensive
solvent, miscible with water, and environmentally
friendly and shows good reactivity and selectivity in
comparison with conventional organic solvents [2,3]. For
these reasons, the development of synthetically useful
multicomponent reactions using ethanol as the green
medium has earned considerable interest.
Organic compounds containing pyrido pyrimidine
skeleton are some of the most important type of
chemical compounds for their diverse range of
extraordinary biological and pharmaceutical activities
[4] such as anti-folate [5], anti-bacterial [6], tyrosine
kinase inhibitors [7], antimicrobial [8], calcium channel
antagonist [9], anti-inflammatory [10], analgesic [10],
anti-leishmania [11], tuberculostatic [12], anti-convulsant
[13], diuretic and potassium-sparing [14], anti-
aggressive activities [15], and its dihydro form exhibit
central nervous system (CNS) depressant activities [16].
For example, Palbociclib has been reported as a drug for
the treatment of estrogen receptor-positive and HER2-
negative breast cancer. This drug is a selective inhibitor
of the kinase [17,18]. Pemirolast (INN) used as an anti-
Previous synthetic methods for producing these
compounds are reported as follows: in 2005, Agarwal et al.
have reported solid supported synthesis of dihydropyrido
[2,3-d]pyrimidines using microwave irradiation [16]. In
2008, Shi et al. reported synthesis of pyrimidine derivatives
in ionic liquid [bmim]Br with 75–93% yields [24]. In 2011,
these products were synthesized in two stages; in the first
stage, three components refluxed in a mixture of acetic acid
and ethylene glycol, leading to dihydropyridine form; then,
dihydropyridines was oxidized to the corresponding
indenopyridine by chloranil as an excellent oxidizing agent
in dimethylformamide at reflux [23]. In 2012, this reaction
also reported in water promoted by p-toluenesulfonic acid
(20 mol%) with an efficiency of 60–90% [25]. In 2012,
Khurana et al. described a method for the synthesis of these
systems using 20 mol% InCl3 (20 mol%) as catalyst in
water, and the products were obtained with 87–90% yields
[26]. In 2013, these products were synthesized in the
presence of 10 mol% of Zr(HSO4)4 as a catalyst in solvent-
free condition [27]. Gilbertson et al. evaluated some of
these pyridopyrimidine derivatives for their ability to inhibit
cyclic nucleotide synthesis in the presence of stable toxin
[28]. Almost all of these procedures suffer from certain
drawbacks such as expensive catalysts, harsh reaction
conditions, or toxic solvents.
allergy drug treatment [19]. Pipemidic acid is
a
component of antibacterial drugs [20]. Tasosartan is an
angiotensin II receptor antagonist (Fig. 1) [21,22].
In 2011, Evdokimov and coworkers reported that flat
pyridines [23] inhibit topoisomerase enzyme activity and
lead to growth inhibition and cell death. They have been
studied pyrido pyrimidine with the desired structure and
RESULTS AND DISCUSSION
Owing to the importance of this pharmacophore, we
became interested in the synthesis of indeno[2 ,1 :5,6]
© 2017 Wiley Periodicals, Inc.

M. Bayat and S. Nasri
Vol 000
pyrido[2,3-d]pyrimidine derivatives 4 by one-pot three-
component condensation of 1,3-indandione (1), aromatic
aldehydes (2), and 6-amino-1,3-dimethyl uracil (3)
without any catalyst and oxidizing agent in EtOH at
reflux (Scheme 1).
The reaction was completed after 3–8 h to afford
corresponding heterocyclic systems 4a–4h, in moderate
1
to good yields (54–96%). H and 13C NMR spectra of
crude product clearly indicated the formation of pyrido
[2,3-d]pyrimidine 4. The structures of the products 4a–4l
1
were deduced from their IR, H, and 13C NMR spectra.
The IR spectrum of 4a displayed characteristic carbonyl
1
bands (1717 and 1668 cmꢀ1). The H NMR spectrum of
4a consisted of two single sharp lines for methyl groups
(δ = 3.36 and 3.91 ppm). The AB system is observed for
aromatic protons (δ = 7.13 and 7.23 ppm), along with
multiplets for the indenone aromatic protons. The 1H
decoupled 13C NMR spectrum of 4a showed 23 sharp
signals in agreement with proposed structure. The key
signals are the two methyl carbons (δ = 28.4 and
30.6 ppm) and three signals (δ = 155.4, 159.8, and
Figure 1. Selected chemical compounds containing pyrido pyrimidine
skeleton.
pyrido[2,3-d]pyrimidine derivatives from readily available
electron-rich amino heterocycles like 6-amino-1,3-
dimethyl uracil in new and efficient routes. We now
report a method for the synthesis of indeno[2 ,1 :5,6]
Scheme 1. Synthesis of pyrido pyrimidines.
Figure 2. The structure of novel pyrimidine annulated heterocyclic compounds.
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Synthesis of Indeno-Fused Pyrido[2,3-d]pyrimidines
Scheme 2. Proposed mechanism for the formation of compound 4.
188.3 ppm) for three carbon atoms of carbonyl groups.
Partial assignments of these resonances are given in the
Experimental section (See supporting information). The
1H and 13C NMR spectra of 4b–4l were similar to those
of 4a except for the aryl moieties, which exhibited
characteristic resonances in appropriate regions of the
spectrum. The product 4a–4f are novel compounds that
have not been reported in the literatures (Fig. 2).
such as halogen, hydroxyl, and nitro group, which were
tolerated. The aromatic aldehydes substituted by electron-
affinity groups in ortho or para position did work well.
But the aromatic aldehydes with electron withdrawing
groups such as 2,6-dichlorobenzaldehyde was examined,
but it did not give the corresponding product 4 (entry 4l).
The results on the synthesis of pyrido[2,3-d]pyrimidines
4 are given in Table 1.
A plausible mechanism for the reaction is shown in
Scheme 2. The formation of these heterocycles can be
rationalized by initial formation of a conjugated electron-
deficient heterodiene by Knoevenagel condensation of
1,3-indandione 1 and aldehyde 2 to generate adduct 5,
followed by a Michael-type addition reaction with 6-
CONCLUSION
In summary, we have developed an easy, green, and
efficient one-pot method for the synthesis of pyrimidine
annulated heterocyclic systems without using any catalyst
in ethanol. The advantages of this method include
operational simplicity, mild reaction conditions, high
yield, easy isolation of products, and does not involve
any purification techniques like column chromatography.
amino-1,3-dimethyl uracil
3
to afford 6. Then,
nucleophilic addition of the amino group to the carbonyl
group leads to the formation of dihydropyridine, which is
then oxidized to product 4 (Scheme 2) [26].
The product 4 is insoluble in ethanol, so easily be
purified by filtration and washing with ethanol, and
column chromatography is unnecessary. As shown in
Table 1, several functionalities present in the aryl moiety
EXPERIMENTAL
General.
The 6-amino-1,3-dimethyl uracil, 1,3-
Table 1
indandione, aromatic aldehydes, and other reagents and
solvents used in this work were obtained from Aldrich
(St. Louis, MO) and Merck Chemical Co. (Germany) and
used without further purification. IR spectra were
recorded on Bruker Tensor 27 Fourier transform infrared
instrument (Germany). NMR spectra were recorded with
Synthesis of pyrido[2,3-d]pyrimidines 4a–4k.
Time
(h)
Entry
Ar
Yield (%)
Mp (°C)
326–328
294–296
329–330
277–279
327–329
368–369
309–311 [25]
299–301 [25]
261–263 [25]
286–288 [25]
266–268 [25]
4a
4b
4c
4d
4e
4f
4g
4h
4i
3-ClC6H4
4-CF3C6H4
2-NO2C6H4
3,4-F2C6H3
3-FC6H4
4-OHC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-FC6H4
4-
5
8
4
6
7
8
4
5
3
6
8
75
54
82
60
65
58
82
84
96
69
75
1
a Bruker DRX-300 Avance instrument (300 MHz for H
and 75.4 MHz for 13C) with CDCl3 and DMSO as
solvents. Chemical shifts are given in ppm (δ) relative to
internal tetramethylsilane, and coupling constants (J) are
reported in hertz (Hz). Mass spectra were recorded with
an Agilent 5975C VL MSD (USA) with Triple-Axis
Detector (Santa Clara, CA) operating at an ionization
potential of 70 eV. Melting points were measured with an
electrothermal 9100 apparatus (England).
4j
4k
OMeC6H4
2,6-
Cl2C6H3
4l
–
No
reaction
–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Bayat and S. Nasri
Vol 000
General procedure for the synthesis of indeno-fused pyrido
C24H15F3N2O3: C, 66.06; H, 3.46; N, 6.42. Found C,
pyrimidine compound 4a. A mixture of 1,3-indandione
66.3; H, 3.6; N, 6.5.
5-(2-Nitro-phenyl)-1,3-dimethyl-1H-indeno[20,10:5,6]pyrido
(1 mmol, 0.146 g) and 3-chlorobenzaldehyde (1 mmol,
0.150 g) in ethanol (6 mL) in a 25 mL round-bottomed
flask fitted with a reflux condenser was heated with
stirring in an oil-bath maintained at 80°C for the
appropriate time as mentioned in Table 1. After complete
appearance of the yellow solid, the 6-amino-1,3-
dimethyluracil (1 mmol, 0.155 g) in 4 mL ethanol was
added. The initial deposit disappeared, and product
reprecipitated. The reaction mixture was cooled to room
temperature, and resulting solid product was filtered,
washed with ethanol, and dried to obtain the pure product
[2,3-d]pyrimidine-2,4,6-trione (4c).
Yellow powder: mp
329–330°C, 0.329 g, yield 82%; IR (KBr): (ῡmax
/cmꢀ1): 3392, 3067, 2948, 1716, 1666, 1573, 1513,
1
1355, 1286, 1166, 788. H NMR (300 MHz, CDCl3): δ
3.32 (3H, s, CH3), 3.92 (3H, s, CH3), 7.23 (1H, d,
3JHH = 7.5 Hz, ArH), 7.56 (1H, d, JHH = 7.2 Hz,
3
CHind.), 7.60–7.77 (4H, m, ArH and CHind), 7.99 (1H,
3
3
d, JHH = 7.5 Hz, CHind), 8.42 (1H, d, JHH = 8.4 Hz,
ArH). 13C NMR (75 MHz, CDCl3): δ 28.5 (CH3), 30.7
(CH3), 106.5 (C─C═N), 120.3 (Cind), 122.2 (Ar), 124.0
(CHind), 124.8 (CHind), 129.0 (Cind), 129.1, 129.3 (Ar),
131.8 (CHind), 132.9 (Cind), 133.7 (CHind), 135.2 (Cipso
Ar), 136.48 (Ar), 141.0 (Cind), 146.5 (Ar), 149.6 (C-Ar),
150.9 (C3ind), 155.6, 160.4 (2C═O), 168.9 (N═C─N),
188.8 (C═O). MS (EI, 70 eV): m/z (%) = 414 (5) [M]+,
368 (100), 324 (21), 312 (10), 227 (9), 169 (12). Anal.
Calcd (%) for C23H15N3O5: C, 66.83; H, 3.66; N, 10.16.
1
4a in good yield (75%) and analyzed by H NMR and
13C NMR.
5-(3-Chloro-phenyl)-1,3-dimethyl-1H-indeno[20,10:5,6]pyrido
[2,3-d]pyrimidine-2,4,6-trione (4a).
Yellow powder: mp
326–328°C, 0.290 g, yield 75%; IR (KBr) (ῡmax /cmꢀ1):
3066, 2946, 1716, 1668, 1567, 1492, 1367, 1286, 1166,
1
1088,786, 738. H NMR (300 MHz, CDCl3): δ 3.36 (3H,
3
s, CH3), 3.91 (3H, s, CH3), 7.13 (1H, d, JHH = 8.5 Hz,
Found C, 66.7; H, 3.5; N, 10.1.
5-(3,4-Difluoro-phenyl)-1,3-dimethyl-1H-indeno[20,10:5,6]
ArH), 7.22–7.26 (1H, m, ArH), 7.40–7.47 (2H, m, ArH
3
pyrido[2,3-d]pyrimidine-2,4,6-trione (4d).
Yellow powder:
and CHind.), 7.57 (1H, d, JHH = 6.8 Hz, ArH), 7.65–7.70
3
mp 277–279°C, 0.235 g, yield 60%; IR (KBr): (ῡmax
(2H, m, ArH and CHind.), 7.96 (1H, d, JHH = 8.8 Hz,
/cmꢀ1): 3390, 3071, 2962, 1718, 1671, 1572, 1508, 1278,
CHind.). 13C NMR (75 MHz, CDCl3): δ 28.4 (CH3), 30.6
(CH3), 106.8 (C─C═N), 120.9 (Cind.), 122.0 (CHind.),
123.7 (CHind.), 125.2, 126.9, 128.0, 128.9, 132.8 (Ar),
132.9 (Cind.), 133.3 (CHind.), 135.1 (Cind.), 136.2 (CHind.),
136.3 (Cipso Ar), 140.5 (Cind.), 150.4 (C-Ar), 150.7
(C3ind.), 155.4, 159.8 (2C═O) 168.4 (N═C─N), 188.2
(C═O). MS (EI, 70 eV): m/z (%) = 403 (63) [M + 1]+,
402 (80) [M]+, 289 (51), 256 (33), 227 (81), 214 (72),
200 (77), 187 (40), 138 (43), 114 (55), 100 (100), 74
(77), 56 (67), 50 (44). Anal. Calcd (%) for
C23H15ClN2O3: C, 68.58; H, 3.75; N, 6.95. Found C,
1
1170, 760. H NMR (300 MHz, CDCl3): δ 3.36 (3H, s,
CH3), 3.91 (3H, s, CH3), 6.93–6.98 (1H, m, ArH),
7.03–7.10 (1H, m, ArH), 7.23–7.32 (1H, m, CHind), 7.54–
7.59 (1H, m, CHind), 7.69 (2H, d, JHH = 7.5 Hz, CHind
3
,
ArH), 7.99 (1H, d, JHH = 8.2 Hz, CHind). 13C NMR
(75 MHz, CDCl3): δ 28.6 (CH3), 30.8 (CH3), 107.0
(C─C═N), 116.9 (Ar), 121.2 (Ar), 122.1 (Cind), 123.4
(CHind), 124.0 (CHind), 130.9 (Cind), 131.0 (Ar), 131.1
(CHind), 133.1 (Cind), 135.2 (CHind), 136.5 (Cipso Ar),
148.5 (Ar), 140.6 (Cind), 150.2 (C-Ar), 150.9 (C3ind),
151.7 (Ar), 155.7, 160.0 (2C═O), 169.0 (N═C─N), 188.7
(C═O). MS (EI, 70 eV): m/z (%) = 405 (62) [M + 1]+,
404 (93) [M]+, 291 (46), 287 (100), 263 (31), 250 (31),
235 (27), 202 (33), 140 (29), 118 (30), 102 (42), 77 (27),
58 (44). Anal. Calcd (%) for C23H14F2N2O3: C, 68.32; H,
3
68.7; H, 3.9; N, 6.8.
5-(4-Trifluoromethyl-phenyl)-1,3-dimethyl-1H-indeno[20,10:5,6]
pyrido[2,3-d]pyrimidine-2,4,6-trione (4b). Yellow powder:
mp 294–296°C, 0.229 g, yield 54%; IR (KBr): (ῡmax
/cmꢀ1): 3391, 3058, 2956, 1719, 1667, 1571, 1499,
1322, 1245, 1162, 1114, 1066, 834, 786. 1H NMR
(300 MHz, CDCl3): δ 3.36 (3H, s, CH3), 3.92 (3H, s,
3.49; N, 6.93. Found C, 68.5; H, 3.3; N, 6.7.
5-(3-Fluoro-phenyl)-1,3-dimethyl-1H-indeno[20,10:5,6]pyrido
[2,3-d]pyrimidine-2,4,6-trione (4e). Light orange powder:
3
CH3), 7.34 (2H, d, JHH = 9 Hz, ArH), 7.56 (1H, d,
3JHH = 8.4 Hz, CHind.), 7.65–7.69 (2H, m, CHind.), 7.73
mp 327–329°C, 0.243 g, yield 65%. IR (KBr): (ῡmax
3
(2H, d, JHH
=
9
Hz, ArH), 7.99 (1H, d,
/cmꢀ1): 3392, 3075, 2954, 1717, 1669, 1570, 1497,
3JHH = 7.5 Hz, CHind). 13C NMR (75 MHz, CDCl3): δ
28.6 (CH3), 30.8 (CH3), 106.9 (C─C═N), 121.8 (CF3),
122.4 (Cind), 124.0 (CHind), 124.9 (CHind), 125.9, 130.1
(Cind), 127.35, 130.54 (Ar), 133.1 (CHind), 135.2 (Cind),
136.5 (CHind), 138.4 (Cipso Ar), 140.7 (Cind), 150.9 (C-
Ar), 151.1 (C3ind), 155.7, 160.2 (2C═O), 168.8
(N═C─N), 188.5 (C═O). MS (EI, 70 eV): m/z
(%) = 437 (67) [M + 1]+, 436 (68) [M]+, 323 (56),
256 (24), 227 (40), 214 (44), 200 (38), 130 (31), 102
(62), 76 (77), 69 (100), 56 (88). Anal. Calcd (%) for
1292, 1169, 786. H NMR (300 MHz, CDCl3): δ 3.36
1
(3H, s, CH3), 3.91 (3H, s, CH3), 6.96–7.02 (2H, m,
ArH), 7.17–7.26 (1H, m, CHind), 7.43–7.50 (1H, m,
3
CHind), 7.54 (1H, d, JHH = 6.9 Hz, CHind), 7.69 (2H, d,
3JHH = 7.5 Hz, ArH), 7.98 (1H, d, JHH = 7.5 Hz, CHind).
3
13C NMR (75 MHz, CDCl3): δ 28.5 (CH3), 30.7 (CH3),
106.9 (C─C═N), 114.4 (Ar), 119.7 (Ar), 121.1 (Cind),
121.4 (Ar), 122.6 (CHind), 123.8 (CHind), 131.0 (CHind),
131.54 (Ar), 132.9 (Cind), 135.1 (CHind), 136.4 (Cipso
Ar), 140.6 (Cind), 150.87 (C-Ar), 151.0 (C3ind), 155.7,
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Synthesis of Indeno-Fused Pyrido[2,3-d]pyrimidines
3
160.0 (2C═O), 162.1 (Ar), 168.9 (N═C─N), 188.6 (C═O).
MS (EI, 70 eV): m/z (%) = 387 (61) [M + 1]+, 386 (75)
[M]+, 268 (37), 302 (30), 294 (52), 273 (78), 246 (64),
232 (65), 218 (57), 193 (100), 137 (45), 130 (47), 109
(54), 102 (63), 75 (48), 44 (30). Anal. Calcd (%) for
C23H15FN2O3: C, 71.50; H, 3.91; N, 7.25. Found C,
71.8; H, 4.1; N, 7.1.
3JHH = 6.6 Hz, CHind), 7.67 (2H, d, JHH = 7.2 Hz, ArH),
7.98 (1H, d, JHH = 7.2 Hz, CHind).
3
5-(4-Methoxy-phenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno
[20,10:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (4k). Yellow
1
powder: mp 266–268°C, 0.290 g, yield 75%. H NMR
(300 MHz, CDCl3): δ 3.36 (3H, s, CH3), 3.89 (3H, s,
OMe), 3.90 (3H, s, CH3), 7.04 (2H, d, JHH = 8.5 Hz,
3
3
ArH), 7.20 (2H, d, JHH = 8.5 Hz, ArH), 7.54 (1H, d,
5-(4-Hydroxy-phenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno
3JHH = 7.2 Hz, CHind), 7.64–7.68 (2H,m, CHind), 7.95
[20,10:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (4f).
Yellow
3
(1H, d, JHH = 7.5 Hz, CHind).
powder: mp 368–369°C, 0.228 g, yield 58%. IR (KBr):
(ῡmax /cmꢀ1): 3379, 3048, 2956, 1710, 1660, 1571,
1506, 1367, 1277, 1207 749. 1H NMR (300 MHz,
REFERENCES AND NOTES
CDCl3): δ 3.37 (3H, s, CH3), 3.90 (3H, s, CH3), 6.95
3
(2H, d, JHH
=
8.4 Hz, ArH), 7.15 (2H, d,
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3
(1H, d, JHH
= 7.9 Hz, CHind), 7.98 (1H, d,
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N, 7.1.
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J.; Desai, A. J.; Ginther, C.; Atefi, M. Breast Cancer Res 2009, 11,
77.
[18] Rocca, A.; Farolfi, A.; Bravaccini, S.; Schirone, A.; Amadori,
D. Expert Opin Pharmacother 2014, 15, 407.
5-(4-Chloro-phenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno
[20,10:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (4g).
powder: mp 309–311°C, 0.320 g, yield 82%. H NMR
Yellow
1
(300 MHz, CDCl3): δ 3.36 (3H, s, CH3), 3.91 (3H, s,
3
CH3), 7.18 (2H, d, JHH = 8.1 Hz, ArH), 7.47 (2H, d,
3
3JHH = 8.1 Hz, ArH), 7.55 (1H, d, JHH = 6.9 Hz, CHind),
3
7.65–7.70 (2H, m, CHind), 7.98 (1H, d, JHH = 7.2 Hz,
CHind).
5-(4-Bromo-phenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno
[20,10:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (4h).
Yellow
1
powder: mp 299–301°C, 0.366 g, yield 84%. H NMR
(300 MHz, CDCl3): δ 3.36 (3H, s, CH3), 3.90 (3H, s,
3
CH3), 7.11 (2H, d, JHH = 8.4 Hz, ArH), 7.57 (1H, d,
3
3JHH = 7.5 Hz, CHind), 7.62 (2H, d, JHH = 8.4 Hz, ArH),
3
7.63–7.70 (2H, m, CHind), 7.98 (1H, d, JHH = 7.5 Hz,
CHind).
5-(4-Nitro-phenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno
[20,10:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione
(4i).
[19] Tinkelman, D. G.; Berkowitz, R. B. Ann Allergy 1991, 66,
162.
Orange powder: mp 261–263°C, 0.386 g, yield 96%.
[20] Iacovino, R.; Rapuano, F.; Caso, J. V.; Russo, A.; Lavorgna,
M.; Russo, C.; Isernia, C. Int J Mol Sci 2013, 14, 13022.
[21] Atkinson, A. J. Jr.; Huang, S. M.; Lertora, J. J.; Markey, S. P.
Principles of Clinical Pharmacology; Academic Press, 2012.
[22] Dina, R.; Jafari, M. Am J Health Syst Pharm 2000, 57,
1231.
[23] Evdokimov, N. M.; Van Slambrouck, S.; Heffeter, P.; Tu, L.;
Le Calve, B.; Lamoral-Theys, D.; Steelant, W. F. J Med Chem 2011, 54,
2012.
[24] Ji, S. J.; Ni, S. N.; Yang, F.; Shi, J. W.; Dou, G. L.; Li, X. Y.;
Shi, D. Q. J Heterocycl Chem 2008, 45, 693.
[25] Verma, G. K.; Raghuvanshi, K.; Kumar, R.; Singh, M. S. Tet-
rahedron Lett 2012, 53, 399.
1H NMR (300 MHz, CDCl3): δ 3.35 (3H, s, CH3),
3
3.92 (3H, s, CH3), 7.42 (2H, d, JHH = 8.7 Hz, ArH),
3
7.57 (1H, d, JHH = 7.2 Hz, CHind), 7.66–7.70 (2H, m,
3
CHind), 7.99(1H, d, JHH = 7.5 Hz, CHind), 8.37 (2H,
3
d, JHH = 8.7 Hz, ArH).
5-(4-Fluoro-phenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno
[20,10:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (4j).
Yellow
1
powder: mp 286–288°C, 0.258 g, yield 69%. H NMR
(300 MHz, CDCl3): δ 3.36 (3H, s, CH3), 3.91 (3H, s,
CH3), 7.15–7.26 (4H, m, ArH, CHind), 7.55 (1H, d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Bayat and S. Nasri
Vol 000
[26] Khurana, J. M.; Chaudhary, A.; Nand, B.; Lumb, A. Tetrahe-
dron Lett 2012, 53, 3018.
SUPPORTING INFORMATION
[27] Abdolmohammadi, S.; Balalaie, S.; Barari, M.; Rominger, F.
Comb Chem High Throughput Screen 2013, 16, 150.
[28] Tanifum, E. A.; Kots, A. Y.; Choi, B. K.; Murad, F.;
Gilbertson, S. R. Bioorg Med Chem Lett 2009, 19, 3067.
Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet