Synthesis of novel 2-aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione derivatives

Article abstract of DOI:10.1002/jhet.2183

Twenty-one novel 2-aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-diones 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m, 5n, 5o, 5p, 5q, 5r, 5s, 5t, 5u were designed and easily synthesized via a tan

Full text of DOI:10.1002/jhet.2183

Month 2014
Synthesis of Novel 2-Aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-
dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione Derivatives
*
Zhong-Xia Wang, Li-Zhuang Chen, Fang-Ming Wang, Bei Li, and Guang-Fan Han
Department of Applied Chemistry, School of Biological and Chemical Engineering, Jiangsu University of Science and
Technology, Zhenjiang, Jiangsu, China
*
E-mail: gf552002@163.com
Received July 16, 2013
DOI 10.1002/jhet.2183
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Twenty-one novel 2-aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-3H-chromeno[2,3-d]
pyrimidine-4,6(5H,7H)-diones 5a–5u were designed and easily synthesized via a tandem aza-Wittig reac-
tion. Treatment of iminophosphorane 3 with 4-chlorophenyl iso-cyanate gave carbodiimide 4, which reacted
with phenols to provide the title compounds in 50–73% isolated yields. All compounds 3 and 5 were con-
firmed by infrared, 1H-NMR, mass spectra, and elemental analysis, and compound 5a was further analyzed
by single-crystal X-ray diffraction, and the title compounds were synthesized with the purpose of bringing in
some new chemical and biological interests.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
used to synthesize quinolinone [10], thienopyrimidinone
[11], triazolopyrimidinone [12], which have good biologi-
cal activities. However, the attempt to obtain a series of
chromenopyrimidione by this mean has not been reported.
According to the previous information, the present study
carried out the research program concerned with structural
modification of certain biological active heterocyclic nuclei
through studying the synthesis of several novel analogs of
chromeno[2,3-d]pyrimidinone derivatives with the purpose
of enhancing their biological activity and bringing in some
chemical and biological interests (Scheme 1).
The development of efficient and mild methods of the
synthesis of heterocyclic compound represents a broad area
of organic chemistry [1]. Because of their biological activity,
compounds containing such units often play an essential role
in medical science, particularly in anticancer and antivirus
researches [2]. Among these heterocycles, chromeno-
pyrimidione derivatives are one important class of nitrogen-
containing heterocyclic compounds with good biological
and pharmacological activities, such as antivirus [3],
antischistosomals [4], antibacterial activity [5], antiplatelet
activity [6], anticancer [7], antitubercular [8], and so on.
Aza-Wittig reaction has gained a rapid development in
recent years and it has become an excellent approach to
synthesize nitrogen heterocyclic and thick heterocyclic ow-
ing to its simple reaction process, available raw materials,
mild reaction conditions, and high yield [9]. It has been
reported that a three-component aza-Wittig reaction was
RESULTS AND DISCUSSION
The synthetic pathway of the title compounds are
shown in Scheme 1. 2-Amino-7-substituted-5-oxo-4-
aryl-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate deriva-
tives 2 were synthesized by reaction of 5-substituted-1,
© 2014 HeteroCorporation

Z.-X. Wang, L.-Z. Chen, F.-M. Wang, B. Li, and G.-F. Han
Vol 000
Scheme 1. The synthetic route of synthesis of novel 2-aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6
(5H,7H)-dione derivatives.
3-cyclohexanedione with 2-cyano-3-arylacrylate derivatives
1, which were prepared by the reaction of aromatic alde-
hydes and ethyl cyanoacetate with KF · 2H2O as catalyst
in ethanol [13]. Iminophosphorane 3 were subsequently
obtained in a satisfactory yield when compounds 2 reacted
with triphenylphosphine, hexachloroethane and
triethylamine, and then, compounds 3 reacted with 4-
chlorophenyl iso-cyanate to receive carbodiimides 4. The
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel 2-Aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione Derivatives
direct reaction of carbodiimide 4 with phenols produced the
final product 2-aryloxy-3-(4-chlorophenyl)-8-substituted-5-
aryl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6
(5H,7H)-dione derivatives 5 in good yields with anhydrous
K2CO3 as catalyst [14]. The melting points and yields of
compounds 3 and 5 are shown in Tables 1 and 2,
respectively.
several typical absorption bands of 1700 cmÀ1 for (C═O),
2920 cmÀ1 for (ÀCH2), 2980 cmÀ1 for (ÀCH3).
1
In the H-NMR spectrum of compound 5a, a sharp sin-
gle proton peak at δ 4.96 was the characteristic absorption
proton peak of 5-H. The structures of these compounds
were further testified by their IR spectra. Several typical
absorption bands of 1680 cmÀ1 for (C═O) and
2950 cmÀ1 for (ÀCH3) were observed, respectively. The
monocrystal structure of 5a was also unequivocally
established by single-crystal X-ray diffraction analysis
(Figs 1 and 2), and a summary of the crystal data and struc-
ture refinement are presented in Table 3.
In the synthesis process of compounds 2, a series of ar-
omatic aldehydes and 5-substituted-1,3-cyclohexanedione
were involved in the reaction. Aromatic aldehydes
containing electron-withdrawing group (such as halide)
ran well to obtain the corresponding products 2. However,
it was found that aromatic aldehydes containing electron-
donating group (such as methoxy) played a negative role
in receiving target compounds. It was for in the presence
of the electron-donating group, the activity of aromatic
aldehydes was increased as well as the side reactions. So,
aromatic aldehydes containing electron-donating group
were not allowed to bring into the experiment.
1
The data of H-NMR, mass spectra (MS), and infrared
(IR) shown in the experimental section are in accordance
with the chemical structures of the target compounds.
In the 1H-NMR spectrum of compound 3a, a sharp
single proton peak at δ 4.88 was the characteristic absorp-
tion proton peak of 4-H. The structures of these
compounds were further proved by their IR spectra through
Table 1
Synthesis of ethyl 2-(triphenylphosphoranylidene)amino-4-aryl-5,6,7,8-
tetrahydro-7-substituted-5-oxo-4H-chromene-3-carboxylate derivatives 3a–3i.
Entry
R1
R2
R
mp(°C)
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH3
CH3
CH3
H
H
H
H
H
H
CH3
CH3
CH3
H
H
H
C6H5
C6H5
C6H5
H
174–176
168–170
176–178
162–164
196–198
222–224
208–210
196–198
148–150
80
82
80
75
78
76
73
76
75
4-Cl
3-NO2
H
4-Cl
3-NO2
H
The reaction temperature controlled at 0–5°C was the
key to synthesize compounds 3. If the temperature of the
reaction was higher, the reaction was too intense to
receive product.
From the yield data of compounds 5, it was seen that the
yield of aryloxy containing electron-withdrawing group
4-Cl
3-NO2
Table 2
Synthesis of 2-aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione derivatives 5a–5u.
Entry
R1
R2
R
Ar
mp(°C)
Yield (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
C6H5
4-ClC6H4
C6H5
4-ClC6H4
C6H5
4-ClC6H4
C6H5
3-NEt2C6H4
C6H5
C6H5
3-NEt2C6H4
4-ClC6H4
C6H5
4-ClC6H4
C6H5
244–246
>300
65
58
60
50
72
65
66
70
61
61
70
53
65
57
59
65
51
68
73
59
54
4-Cl
4-Cl
3-NO2
3-NO2
H
152–154
252–254
246–248
264–266
234–236
186–188
252–254
252–254
192–194
292–194
214–216
258–260
248–250
146–148
>300
H
4-Cl
4-Cl
4-Cl
4-Cl
3-NO2
3-NO2
H
H
H
4-Cl
4-Cl
4-Cl
H
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
3-NEt2C6H4
4-ClC6H4
C6H5
3-NEt2C6H4
4-ClC6H4
4-ClC6H4
266–268
148–150
270–272
264–266
H
H
5u
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z.-X. Wang, L.-Z. Chen, F.-M. Wang, B. Li, and G.-F. Han
Vol 000
Table 3
Crystallographic data for compound 5a.
Empirical formula
C31H25Cl N2O4
Formula weight
Wavelength / nm
Crystal system
Space group
524.98
0.71073
Triclinic
P-1
a/nm
b/nm
10.609(4)
11.434(5)
11.685(5)
78.742(5)
74.180(5)
77.002(5)
1315.2(9)
2
c/nm
α/(o)
β/(o)
γ/(o)
Volume/nm3
Z
Calculated density/g · cmÀ3
Absorption coefficient/mmÀ1
F (000)
1.326
0.185
548
Figure 1. Molecular structure of compound 5a.
Final R indices [I > 2sigma(I)]
R indices (all data)
R1 = 0.0398, wR2 = 0.1358
R1 = 0.0564, wR2 = 0.1597
was lower than that containing electron-donating group in
the same reaction time. This phenomenon can be explained
by the reduction of the activity of reaction in the existence
of the phenol containing electron-withdrawing group. In
addition, there was no need for purification when synthe-
sizing carbodiimides 4, which parallel reacted with phenol
directly. The method not only made the reaction steps
simplified, but also improved the yield of products. More-
over, all reagents used in reaction must be dried.
CONCLUSION
In summary, the present study synthesized a series of
novel 2-aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-
8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-
dione derivatives via tandem aza-Wittig and cyclization
reaction smoothly in good yields, which also provides a
useful route for drug research. Moreover, the new path-
way offers several advantages including simple operation,
available raw materials, mild reaction conditions, and
high yields, which makes it an attractive process for the
synthesis of these compounds.
EXPERIMENTAL
Melting points were determined by an electrothermal appara-
tus, and the temperature was not calibrated. Microanalysis was
performed by the Perkin-Elmer 2400 (Waltham, Massachusetts)
microanalytical service. Infrared spectra were taken on a Perkin-Elmer
1700 spectrophotometer (Waltham, Massachusetts) of which
potassium bromide were used as pellets unless otherwise stated.
The 1H-NMR spectra were recorded by a Bruker DRX-500
spectrometer (Switzerland). The solvent for 1H-NMR spectra
was CDCl3 unless otherwise stated. Mass spectra was recorded
by JMS-DX300 mass spectrometer with an ionization potential
of 70 eV. The X-ray single-crystal diffraction was performed
by SMART APEX II instrument. All reactions were monitored
Figure 2. Packing diagram of compound 5a in unit-cell.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel 2-Aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione Derivatives
by thin layer chromatography, which carried out on 0.2 mm
silica gel 60 F254 (Merck) plates using UV light (254 and
365 nm) for detection.
7.06–7.90 (m, 20H, Ph–H); IR (KBr) υ: 2980, 2920,
1700 cmÀ1 MS m/z: 602.3 (M++1); Anal. Calcd for
C38H36NO4P: C, 75.86; H, 6.03; N, 2.33. Found: C, 75.82; H,
;
6.07; N, 2.37.
All chemical reagents were commercially available and puri-
fied with standard methods before use. Solvents were dried in
routine ways and redistilled. 5-substituted-1,3-cyclohexanedione
were obtained from the reaction of aromatic aldehyde, acetone,
and dimethyl calonate according to the literature [15] with slight
Ethyl 4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-2-((triphenylphos-
phoranylidene)amino)-5,6,7,8-tetrahydro-4H-chromene-3-carbo-
xylate (3b). Yield: 82%, mp 168–170°C; 1H-NMR(CDCl3,
500 MHz) δ: 0.99(s, 3H, –CH3), 1.12 (s, 3H, –CH3), 1.18 (t,
J= 7.1 Hz, 3H, –OCH2CH3), 2.16–2.27 (m, 2H, C8–H), 2.44 (s, 2H,
C6–H), 4.06 (q, J=7.2Hz, 2H, –OCH2CH3), 4.69 (s, 1H, C4–H),
7.20–7.72 (m, 19H, Ph–H); IR (KBr) υ: 2957, 2921, 1654 cmÀ1; MS
m/z: 636.3 (M++1); Anal. Calcd for C38H35ClNO4P: C, 71.75; H,
modifications.
General method for the synthesis of 2-cyano-3-arylacrylate
derivatives (1). A mixture of aromatic aldehydes (10 mmol) and
ethyl cyanoacetate (10 mmol) with KF · 2H2O (0.3 g) as catalyst in
ethanol (15 mL) was stirred at 60°C for 2 h. And then, the mixture
was cooled to room temperature, 200 mL ice water was added, the
precipitated solid was isolated by filtration, washed with water, and
recrystallized from ethanol.
5.55; N, 2.20; Found: C, 75.78; H, 6.11; N, 2.33.
Ethyl 7,7-dimethyl-4-(3-nitrophenyl)-5-oxo-2-((triphenylphos-
phoranylidene)amino)-5,6,7,8-tetrahydro-4H-chromene-3-carbo-
xylate (3c).
Yield: 80%, mp 162–164°C; 1H-NMR(CDCl3,
General method for the synthesis of ethyl 2-amino-7,7-
dimethyl-5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate
derivatives (2). To a solution of the corresponding 2-cyano-3-
phenylacrylate (10 mmol) in ethylene glycol (15 mL), 5-substituted-
1,3-cyclohexanedione (10 mmol) were added. The mixture was
stirred at 80°C for 4 h, the reaction progress was monitored by
TLC. Then, the resultant mixture was cooled to room temperature.
100 mL water was added, and the precipitated solid was isolated by
filtration, washed with water, and recrystallized from ethanol.
General method for the synthesis of ethyl 2-(triphenyl-
phosphoranylidene)amino-4-aryl-5,6,7,8-tetrahydro-7-substituted-
5-oxo-4H-chromene-3-carboxylate derivatives (3a–3i). To a mixture
of ethyl 2-amino-4-aryl-5,6,7,8-tetrahydro-7-substituted-5-oxo-4H-
chromene-3-carboxylate (10 mmol), PPh3 (5.26g, 20mmol) and
C2Cl6 (4.80 g, 20 mmol) in dry CH3CN (100 mL), NEt3 (20 mL) was
added dropwise to the solution, which previously prepared at
0–5°C, and then stirred for 6 h at 5–10°C. The mixture was poured
into ice water, and the resultant precipitate was dissolved in absolute
ethanol to get pure crystalline ethyl 2-(triphenylphosphoranylidene)
500 MHz) δ: 0.82 (s, 3H, CH3), 0.90 (s, 3H, CH3), 1.25(t,
J = 7.1Hz, 3H, –OCH2CH3), 1.53–1.90 (m, 2H, C8–H), 2.01–2.15
(m, 2H, C6–H), 4.13 (q, J = 7.2 Hz, 2H, –OCH2CH3), 4.96 (s, 1H,
C4–H ), 7.28–8.10 (m, 19H, Ph–H); IR (KBr) υ: 2990, 2920,
1700 cmÀ1
.
MS m/z: 647.3 (M++1); Anal. Calcd for
C38H35N2O6P: C, 70.58; H, 5.46; N, 4.33; Found: C, 70.55; H,
5.49; N, 4.33.
Ethyl 5-oxo-4-phenyl-2-((triphenylphosphoranylidene)amino)-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (3d). Yield: 75%,
1
mp 176–178°C; H-NMR(CDCl3, 500 MHz) δ: 1.15 (t, J=7.1Hz,
3H, –OCH2CH3), 1.94–2.08 (m, 2H, C7–H), 2.33–2.35 (m, 2H,
C8–H), 2.55–2.57 (m, 2H, C6–H), 4.04 (q, J = 7.1 Hz, 2H,
–OCH2CH3), 4.88 (s, 1H, C4–H ), 7.11–7.89 (m, 20H, Ph–H);
IR (KBr) υ: 2980, 2930, 1710 cmÀ1; MS m/z: 574.2 (M++1);
Anal. Calcd for C36H32NO4P: C, 75.38; H, 5.62; N, 2.44;
Found: C, 75.40; H, 5.60; N, 2.48.
Ethyl 4-(4-chlorophenyl)-5-oxo-2-((triphenylphos-phoranylidene)
amino)-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (3e).Yield: 78%,
mp 196–198°C; 1H-NMR(CDCl3, 500 MHz) δ: 1.16
(t, J = 7.1 Hz, 3H, –OCH2CH3), 1.94–2.07 (m, 2H, C7–H),
2.34–2.37 (m, 2H, C8–H), 2.56–2.59 (m, 2H, C6–H), 4.05
(q, J = 7.1 Hz, 2H, –OCH2CH3), 4.72 (s, 1H, C4–H), 7.20–7.72
(m, 19H, Ph–H); IR (KBr) υ: 2983, 2935, 1657 cmÀ1; MS m/z:
608.3 (M++1); Anal. Calcd for C36H31ClNO4P: C, 71.11; H,
amino-4-aryl-5,6,7,8-tetrahydro-7-substituted-5-oxo-4H-chromeno-
3-carboxylate derivatives 3.
General method for the synthesis of 2-aryloxy-3-(4-
chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-3H-chromeno
[2,3-d]pyrimidine-4,6(5H,7H)-dione derivatives (5a–5u).
Iminophosphorane 3 (2 mmol) was dissolved in dry methylene
dichloride (5 mL) , and 4-chlorophenyl iso-cyanate (0.30 g, 2 mmol)
was added to the solution, which previously prepared at room
temperature, then the mixture was stood for 8–12 h at 0–5°C. After
the reaction, the solvent was removed under reduced pressure to
give carbodiimide 4, which was generally used directly without
further purification. 20 mL anhydrous acetonitrile (20 mL), phenols
(2 mmol), and anhydrous potassium carbonate (0.14 g) were added
to the mixture, and stirred for 30 min at room temperature. Then,
the mixture was stirred for another 4 h under reflux. After that, the
mixture was filtered while hot. The filtration was condensed under
reduced pressure, and the residue was recrystallized with
dichloromethane/ethanol to give pure 2-aryloxy-3-(4-chlorophenyl)-
8-substituted-5-aryl-8,9-dihydro-3H-chromeno[2,3-d] pyrimidine-
4,6(5H,7H)-dione derivatives 5.
5.14; N, 2.30; Found: C, 71.14; H, 5.19; N, 2.28.
Ethyl 4-(3-nitrophenyl)-5-oxo-2-((triphenylphos-phoranylidene)
amino)-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (3f).
1
Yield: 76%, mp 222–224°C; H-NMR(CDCl3, 500 MHz) δ: 1.20
(t, J= 7.1 Hz, 3H, –OCH2CH3), 1.75–1.82 (m, 2H, C7–H), 1.97–
2.10 (m, 2H, C8–H), 2.18–2.40 (m, 2H, C6–H), 4.10 (q, J=7.1Hz,
2H, –OCH2CH3), 4.99 (s, 1H, C4–H), 7.40–8.12 (m, 19H, Ph–H);
IR (KBr) υ: 2989, 2949, 1655 cmÀ1; MS m/z: 619.2 (M++1); Anal.
Calcd for C36H31N2O6P: C, 69.90; H, 5.05; N, 4.53. Found: C,
69.95; H, 5.08; N, 4.49.
Ethyl 5-oxo-4,7-diphenyl-2-((triphenylphosphoranylidene)amino)-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (3g). Yield: 73%, mp
1
208–210°C; H-NMR(CDCl3, 500 MHz) δ: 1.17 (t, J=7.1Hz, 3H,
–OCH2CH3), 2.56–2.68 (m, 2H, C8–H), 2.80–2.82 (t, 2H, C6–H),
3.28–3.35 (m, 1H, C7–H), 4.06 (dd, J1 =4.0Hz, J2 =7.0Hz, 2H,
–OCH2CH3), 4.80 (s, 1H, C4–H), 7.17–7.72 (m, 25H, Ph–H); IR
(KBr) υ: 2975, 2944, 1662 cmÀ1; MS m/z: 650.3 (M++1); Anal.
Calcd for C42H36NO4P: C, 77.64; H, 5.58; N, 2.16. Found: C,
77.68; H, 5.55; N, 2.19.
Data of compounds.
Ethyl 7,7-dimethyl-5-oxo-4-phenyl-2-((triphenylphosphoranylidene)
amino)-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (3a).
Yield: 80%, mp 174–176°C; 1H-NMR(CDCl3, 500 MHz) δ:
0.83(s, 3H, –CH3), 0.89 (s, 3H, –CH3), 1.24 (t, J = 7.1 Hz, 3H,
–OCH2CH3), 1.50–1.89 (m, 2H, C8–H), 2.02–2.14 (m, 2H, C6–
H), 4.12(q, J = 7.2 Hz, 2H, –OCH2CH3), 4.89 (s, 1H, C4–H),
Ethyl
4-(4-chlorophenyl)-5-oxo-7-phenyl-2-((triphenylphos-
phoranylidene)amino)-5,6,7,8-tetrahydro-4H-chromene-3-carbo-
xylate (3h). Yield: 76%, mp 196–198°C; 1H-NMR(CDCl3,
500 MHz) δ: 1.17 (t, J = 7.1 Hz, 3H, –OCH2CH3), 2.51–2.74 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z.-X. Wang, L.-Z. Chen, F.-M. Wang, B. Li, and G.-F. Han
Vol 000
2H, C8–H), 2.80–2.88 (m, 2H, C6–H), 3.27-3.34 (m, 1H, C7–H),
4.06 (dd, J1 = 4.2 Hz, J2 = 6.9 Hz, 2H, –OCH2CH3), 4.77 (s, 1H,
C4–H), 7.08–7.72 (m, 24H, Ph–H); IR (KBr) υ: 2976, 2948,
CH3), 2.25 (dd, J1 = 16.3 Hz, J2 = 31.4 Hz, 2H, C9–H), 2.60
(dd, J1 = 17.9 Hz, J2 = 37.8 Hz, 2H, C7–H), 5.03 (s, 1H, C5–
H), 7.08–7.49 (m, 9H, Ph–H), 7.89 (d, J = 7.4 Hz, 1H, 5-6′-
H), 8.04–8.06 (m, 2H, 5-(2′ + 4′)-H); IR (KBr) υ: 2961,
1704cmÀ1
;
MS m/z: 684.3 (M++1); Anal. Calcd for
C42H35ClNO4P: C, 73.73; H, 5.16; N, 2.05. Found: C, 73.77; H,
1686 cmÀ1 MS m/z: 604.2 (M++1); Anal. Calcd for
;
5.14; N, 2.08.
C31H23Cl2N3O6: C, 61.60; H, 3.84; N, 6.95. Found: C,
Ethyl 4-(3-nitrophenyl)-5-oxo-7-phenyl-2-((triphenylphos-
61.62; H, 3.88; N, 6.93.
3-(4-Chlorophenyl)-2-phenoxy-5-phenyl-8,9-dihydro-3H-chromeno
phoranylidene)amino)-5,6,7,8-tetrahydro-4H-chromene-3-carbo-
xylate (3i). Yield: 75%, mp 148–150°C; 1H-NMR(CDCl3, 500 MHz)
δ: 1.16 (t, J=7.0Hz, 3H, –OCH2CH3), 2.58–2.76 (m, 2H, C8–H),
2.80–2.99 (m, 2H, C6–H), 3.31–3.35 (m, 1H, C7–H), 4.06 (dd,
J1 =4.0Hz, J2 =7.0Hz, 2H, –OCH2CH3), 4.89 (s, 1H, C4–H), 7.16-
8.16 (m, 24H, Ph–H); IR (KBr) υ: 2989, 2926, 1661 cmÀ1; MS
m/z: 695.3 (M++1); Anal. Calcd for C42H35N2O6P: C, 72.61;
H, 5.08; N, 4.03. Found: C, 72.65; H, 5.06; N, 4.04.
[2,3-d]pyrimidine-4,6(5H,7H)-dione (5g). Yield: 66%, mp 234–236°
C; 1H-NMR(CDCl3, 500 MHz) δ: 2.02–2.11 (m, 2H, C8–H), 2.33–2.45
(m, 2H, C9–H), 2.61–2.77 (m, 2H, C7–H), 4.99 (s, 1H, C5–H), 7.11–7.47
(m, 14H, Ph–H); IR (KBr) υ: 2946, 1687 cmÀ1; MS m/z: 497.1 (M++1);
Anal. Calcd for C29H21ClN2O4: C, 70.09; H, 4.26; N, 5.64. Found: C,
70.11; H, 4.28; N, 5.61.
3-(4-Chlorophenyl)-2-(3-(diethylamino)phenoxy)-5-phenyl-
8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione
(5h). Yield: 70%, mp 186–188°C; 1H-NMR(CDCl3, 500 MHz) δ:
1.06–1.21 (m, 6H, 2 × CH3), 2.07–2.09 (m, 2H, C8–H), 2.37–2.41 (m,
2H, C9–H), 2.65–2.75 (m, 2H, C7–H), 3.34–3.38 (m, 4H, 2 × CH2),
5.01 (s, 1H, C5–H), 6.29–6.36 (m, 2H, 2-(2′+6′)-H), 6.55–6.58 (m,
1H, 2-4′-H), 7.18–7.46 (m, 10H, Ph–H); IR (KBr) υ: 2971,
1697 cmÀ1; MS m/z: 568.1 (M++1); Anal. Calcd for C33H30ClN3O4:
3-(4-Chlorophenyl)-8,8-dimethyl-2-phenoxy-5-phenyl-8,9-
dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5a). Yield:
65%, mp 244–246°C; 1H-NMR(CDCl3, 500 MHz) δ: 1.06
(s, 3H, –CH3), 1.12 (s, 3H, –CH3), 2.26 (dd, J1 = 16.3 Hz,
J2 = 26.8 Hz, 2H, C9–H), 2.55 (dd, J1 = 17.7 Hz, J2 = 25.9 Hz,
2H, C7–H), 4.96 (s, 1H, C5–H), 7.11–7.72 (m, 14H, Ph–H); IR
(KBr) υ: 2950, 1680 cmÀ1; MS m/z: 525.2 (M++1); Anal. Calcd
for C31H25ClN2O4: C, 70.92; H, 4.80; N, 5.34. Found: C,
C, 69.77; H, 5.32; N, 7.40. Found: C, 69.79; H, 5.33; N, 7.38.
3-(4-Chlorophenyl)-2-(3-methoxyphenoxy)-5-phenyl-8,9-dihydro-
70.95; H, 4.83; N, 5.32.
2-(4-Chlorophenoxy)-3-(4-chlorophenyl)-8,8-dimethyl-5-phenyl-
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5i).
Yield:
72%, mp 212–214°C; 1H-NMR(CDCl3, 500MHz) δ: 2.04–2.11 (m,
2H, C8–H), 2.32–2.47 (m, 2H, C9–H), 2.64–2.77 (m, 2H, C7–H),
3.83 (s, 3H, –OCH3), 4.99 (s, 1H, C5–H), 6.64–6.72 (m, 2H, 2-
(2′+6′)–H), 6.84 (d, J= 8.4 Hz, 1H, 2-4′–H), 7.17–7.46 (m, 10H,
Ph–H); IR (KBr) υ: 2955, 1698 cmÀ1; MS m/z: 527.2 (M++1);
Anal. Calcd for C30H23ClN2O5: C, 68.38; H, 4.40; N, 5.32. Found:
8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione
(5b). Yield: 58%, mp >300°C; 1H-NMR(CDCl3, 500 MHz) δ:
1.07 (s, 3H, –CH3), 1.13 (s, 3H, –CH3), 2.25 (dd, J1 = 16.5 Hz,
J2 = 26.1 Hz, 2H, C9–H), 2.58 (dd, J1 = 17.6 Hz, J2 = 28.5 Hz,
2H, C7–H), 4.96 (s, 1H, C5–H), 7.06–7.47 (m, 13H, Ph–H); IR
(KBr) υ: 2957, 1692 cmÀ1; MS m/z: 559.1 (M++1); Anal. Calcd
for C31H24Cl2N2O4: C, 66.55; H, 4.32; N, 5.01. Found: C,
66.58; H, 4.35; N, 4.98.
C, 68.41; H, 4.39; N, 5.30.
3,5-Bis(4-chlorophenyl)-2-phenoxy-8,9-dihydro-3H-chromeno
[2,3-d]pyrimidine-4,6(5H,7H)-dione (5j). Yield: 61%, mp 252–
3,5-Bis(4-chlorophenyl)-8,8-dimethyl-2-phenoxy-8,9-dihydro-
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5c). Yield:
60%, mp 152–154°C; 1H-NMR(CDCl3, 500MHz) δ: 1.06 (s, 3H,
–CH3), 1.12 (s, 3H, –CH3), 2.25 (dd, J1 = 16.3 Hz, J2 = 29.0 Hz, 2H,
C9–H), 2.54 (dd, J1 = 18.0 Hz, J2 = 21.6 Hz, 2H, C7–H), 4.92 (s, 1H,
1
254°C; H-NMR(CDCl3, 500 MHz) δ: 2.03–2.08 (m, 2H, C8–H),
2.37–2.40 (m, 2H, C9–H), 2.65–2.75 (m, 2H, C7–H), 4.95 (s, 1H,
C5–H), 7.11–7.48 (m, 13H, Ph–H); IR (KBr) υ: 2950,
1698 cmÀ1
;
MS m/z: 531.2 (M++1); Anal. Calcd for
C5–H), 7.11–7.48 (m, 13H, Ph–H); IR (KBr) υ: 2960, 1675 cmÀ1
;
C29H20Cl2N2O4: C, 65.55; H, 3.79; N, 5.27. Found: C, 65.57; H,
MS m/z: 559.2 (M++1); Anal. Calcd for C31H24Cl2N2O4: C, 66.55;
3.77; N, 5.28.
3,5-Bis(4-chlorophenyl)-2-(3-(diethylamino)phenoxy)-8,9-dihydro-
H, 4.32; N, 5.01. Found: C, 66.53; H, 4.34; N, 4.99.
2-(4-Chlorophenoxy)-3,5-bis(4-chlorophenyl)-8,8-dimethyl-
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5k). Yield: 70%,
1
mp 192–194°C; H-NMR(CDCl3, 500MHz) δ: 1.16–1.19 (m, 6H,
8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione
(5d). Yield: 50%, mp 252–254°C; 1H-NMR(CDCl3, 500 MHz)
δ: 1.06 (s, 3H, –CH3), 1.13 (s, 3H, –CH3), 2.25 (dd, J1 = 16.5 Hz,
J2 = 28.3 Hz, 2H, C9–H), 2.55 (dd, J1 = 18.0 Hz, J2 = 23.9 Hz,
2H, C7–H), 4.92 (s, 1H, C5–H), 7.07–7.49 (m, 12H, Ph–H); IR
(KBr) υ: 2953, 1689 cmÀ1; MS m/z: 593.2 (M++1); Anal.
Calcd for C31H23Cl3N2O4: C, 62.69; H, 3.90; N, 4.72. Found:
2×CH3), 2.04–2.09 (m, 2H, C8–H), 2.38–2.44 (m, 2H, C9–H), 2.62–
2.76 (m, 2H, C7–H), 3.34–3.37 (m, 4H, 2 × CH2), 4.95 (s, 1H, C5–H),
6.29–6.35 (m, 2H, 2-(2′+6′)-H), 6.57 (d, J= 8.2 Hz, 1H, 2-4′-H),
7.19–7.47 (m, 9H, Ph–H); IR (KBr) υ: 2967, 1698 cmÀ1; MS m/z:
602.3 (M++1); Anal. Calcd for C33H29Cl2N3O4: C, 65.78; H, 4.85; N,
6.97. Found: C, 65.76; H, 4.88; N, 6.95.
2-(4-chlorophenoxy)-3,5-bis(4-chlorophenyl)-8,9-dihydro-3H-
C, 62.71; H, 3.88; N, 4.73.
3-(4-Chlorophenyl)-8,8-dimethyl-5-(3-nitrophenyl)-2-phenoxy-
chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5l). Yield: 53%,
mp 292–294°C; 1H-NMR(CDCl3, 500MHz) δ: 2.03–2.09 (m, 2H,
C8–H), 2.35–2.45 (m, 2H, C9–H), 2.63–2.77 (m, 2H, C7–H), 4.95
(s, 1H, C5–H), 7.07–7.48 (m, 12H, Ph–H); IR (KBr) υ: 2952,
8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-
dione (5e). Yield: 72%, mp 246–248°C; 1H-NMR(CDCl3, 500 MHz)
δ: 1.07 (s, 3H, –CH3), 1.14 (s, 3H, –CH3), 2.26 (q, J = 16.3 Hz,
2H, C9–H), 2.61 (q, J = 17.8 Hz, 2H, C7–H), 5.04 (s, 1H, C5–
H), 7.13–8.07 (m, 10H, Ph–H), 7.89 (d, J = 7.6 Hz, 1H, 5-6′-H),
1692 cmÀ1
;
MS m/z: 565.2 (M++1); Anal. Calcd for
C29H19Cl3N2O4: C, 61.56; H, 3.38; N, 4.95. Found: C, 61.58; H,
8.04–8.12 (m, 2H, 5-(2′ + 4′)–H); IR (KBr) υ: 2960, 1673 cmÀ1
;
3.35; N, 4.98.
MS m/z: 570.2 (M++1); Anal. Calcd for C31H24ClN3O6: C,
3-(4-Chlorophenyl)-5-(3-nitrophenyl)-2-phenoxy-8,9-dihydro-
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5m). Yield:
65.32; H, 4.24; N, 7.37. Found: C, 65.35; H, 4.23; N, 7.39.
2-(4-Chlorophenoxy)-3-(4-chlorophenyl)-8,8-dimethyl-5-(3-
1
65%, mp 214–216°C; H-NMR(CDCl3, 500 MHz) δ: 2.04–2.12
(m, 2H, C8–H), 2.38–2.43 (m, 2H, C9–H), 2.64–2.82 (m, 2H, C7–
H), 5.06 (s, 1H, C5–H), 7.13–7.47 (m, 10H, Ph–H), 7.90 (d,
J = 7.6Hz, 1H, 5-6′-H), 8.04–8.06 (m, 2H, 5-(2′ + 4′)-H); IR
nitrophenyl)-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6
1
(5H,7H)-dione (5f). Yield: 65%, mp 264–266°C; H-NMR
(CDCl3, 500 MHz) δ: 1.08 (s, 3H, –CH3), 1.14 (s, 3H, –
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel 2-Aryloxy-3-(4-chlorophenyl)-8-substituted-5-aryl-8,9-dihydro-
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione Derivatives
(KBr) υ: 2926, 1697cmÀ1; MS m/z: 542.1 (M++1); Anal. Calcd for
C29H20ClN3O6: C, 64.27; H, 3.72; N, 7.75. Found: C, 64.25; H,
2-(4-Chlorophenoxy)-3,5-bis(4-chlorophenyl)-8-phenyl-8,9-
dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5t).
Yield: 59%, mp 270–272°C; 1H-NMR(CDCl3, 500 MHz) δ:
2.58–2.76 (m, 2H, C9–H), 2.86–3.04 (m, 2H, C7–H), 3.37–
3.53 (m, 1H, C8–H), 4.98 (s, 1H, C5–H), 7.05–7.49 (m, 17H,
Ph–H); IR (KBr) υ: 2961, 1683 cmÀ1; MS m/z: 641.2 (M++1);
Anal. Calcd for C35H23Cl3N2O4: C, 65.49; H, 3.61; N, 4.36.
3.73; N, 7.77.
2-(4-Chlorophenoxy)-3-(4-chlorophenyl)-5-(3-nitrophenyl)-
8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione
(5n). Yield: 57%, mp 258–260°C; 1H-NMR(CDCl3, 500MHz)
δ: 2.04–2.09 (m, 2H, C8–H), 2.35–2.44 (m, 2H, C9–H), 2.66–2.82
(m, 2H, C7–H), 5.05 (s, 1H, C5–H), 7.09–7.49 (m, 9H, Ph–H),
7.90 (d, J = 7.4Hz, 1H, 5-6′-H), 8.05 (s, 2H, 5-(2′ + 4′)-H); IR
(KBr) υ: 2944, 1691cmÀ1; MS m/z: 576.2 (M++1); Anal. Calcd
for C29H19Cl2N3O6: C, 60.43; H, 3.32; N, 7.29. Found: C, 60.45;
Found: C, 65.47; H, 3.63; N, 4.37.
2-(4-Chlorophenoxy)-3-(4-chlorophenyl)-5-phenyl-8,9-dihydro-
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5u). Yield:
1
54%, mp 264–266°C; H-NMR(CDCl3, 500 MHz) δ: 2.05–2.08
H, 3.36; N, 7.25.
3-(4-Chlorophenyl)-2-phenoxy-5,8-diphenyl-8,9-dihydro-3H-
(m, 2H, C8–H), 2.35–2.46 (m, 2H, C9–H), 2.66–2.79 (m, 2H,
C7–H), 4.99 (s, 1H, C5–H), 7.06–7.48 (m, 13H, Ph–H); IR
(KBr) υ: 2950, 1691 cmÀ1; MS m/z: 531.1 (M++1); Anal.
Calcd for C29H20Cl2N2O4: C, 65.55; H, 3.79; N, 5.27. Found:
C, 65.57; H, 3.76; N, 4.29.
chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5o).
Yield:
1
59%, mp 248–250°C; H-NMR(CDCl3, 500 MHz) δ: 2.57–2.73
(m, 2H, C9–H), 2.87–2.99 (m, 2H, C7–H), 3.38–3.43 (m, 1H,
C8–H), 5.04 (s, 1H, C5–H), 7.11–7.47 (m, 19H, Ph–H); IR
(KBr) υ: 2939, 1700 cmÀ1; MS m/z: 573.2 (M++1); Anal. Calcd
for C35H25ClN2O4: C, 73.36; H, 4.40; N, 4.89. Found: C,
Acknowledgment. This work was funded by the National Natural
Science Foundation of China (Grant no. 21201087) and sponsored
by Qing Lan Project of Jiangsu province.
73.38; H, 4.42; N, 4.86.
3-(4-Chlorophenyl)-2-(3-(diethylamino)phenoxy)-5,8-diphenyl-
8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione
(5p). Yield: 65%, mp 146–148°C; 1H-NMR(CDCl3, 500 MHz)
δ: 1.16–1.18 (m, 6H, 2 × CH3), 2.57–2.72 (m, 2H, C9–H), 2.85–2.99
(m, 2H, C7–H), 3.34–3.44 (m, 5H, C8 +2×CH2), 5.04 (s, 1H, C5–H),
6.30–6.35 (m, 2H, 2-(2′+6′)-H), 6.55 (d, J= 8.3 Hz, 1H, 2-4′-H),
7.18–7.45 (m, 15H, Ph–H); IR (KBr) υ: 2972, 1698 cmÀ1; MS m/z:
644.3 (M++1); Anal. Calcd for C39H34ClN3O4: C, 72.72; H, 5.32;
REFERENCES AND NOTES
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Kem, E. R.; Torrence, P. F. J Med Chem 2006, 14, 4052.
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(Weinheim). 2004, 9, 482.
[5] Agrody, A. M.; Hakim, M. H.; Latif, M. S.; Fakery, A. H.;
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[6] Li, Y. L.; Du, B. X.; Wang, X. S.; Shi, D. Q.; Tu, S. J. J Chem
Res 2006, 3, 157–159.
N, 6.52. Found: C, 72.76; H, 5.34; N, 6.48.
2-(4-Chlorophenoxy)-3-(4-chlorophenyl)-5,8-diphenyl-8,9-
dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione
1
(5q). Yield: 51%, mp >300°C; H-NMR(CDCl3, 500 MHz) δ:
2.58–2.73 (m, 2H, C9–H), 2.86–3.01 (m, 2H, C7–H), 3.39–3.44
(m, 1H, C8–H), 5.03 (s, 1H, C5–H), 7.07–7.48 (m, 18H, Ph–H);
IR (KBr) υ: 2887, 1683cmÀ1; MS m/z: 607.2 (M++1); Anal.
Calcd for C35H24Cl2N2O4: C, 69.20; H, 3.98; N, 4.61. Found: C,
69.25; H, 3.96; N, 4.63.
3,5-Bis(4-chlorophenyl)-2-phenoxy-8-phenyl-8,9-dihydro-
[7] Shestopalov, A. A.; Rodinovskaya, L. A.; Shestopalov, A. M.;
Litvinov, V. P. Russ Chem Bull 2004, 53, 2342.
[8] Nimesh, R.; Kamdar, D. D.; Haveliwala, P. T.; Mistry, S. K. P.
Eur J Med Chem 2010, 45, 5056.
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Yang, G. Z.; Fu, L. W. Eur J Med Chem 2012, 47, 206.
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9052.
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Biomol Chem 2006, 4, 130.
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23, 1004.
3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (5r). Yield:
68%, mp 266–268°C; 1H-NMR(CDCl3, 500 MHz) δ: 2.57–2.73
(m, 2H, C9–H), 2.85–2.99 (m, 2H, C7–H), 3.37–3.39 (m, 1H,
C8–H), 4.99 (s, 1H, C5–H), 7.12–7.49 (m, 18H, Ph–H); IR (KBr)
υ: 2961, 1684 cmÀ1; MS m/z: 607.2 (M++1); Anal. Calcd for
C35H24Cl2N2O4: C, 69.20; H, 3.98; N, 4.61. Found: C, 69.23; H,
3.95; N, 4.65.
3,5-Bis(4-chlorophenyl)-2-(3-(diethylamino)phenoxy)-8-phenyl-
8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione
1
(5s). Yield: 73%, mp 148–150°C; H-NMR(CDCl3, 500 MHz) δ:
1.17–1.19 (m, 6H, 2 × CH3), 2.61–2.72 (m, 2H, C9–H), 2.88–2.99
(m, 2H, C7–H), 3.33–3.40 (m, 5H, C8 + 2 × CH2), 4.99 (s, 1H,
C5–H), 6.30–6.35 (m, 2H, 2-(2′ + 6′)-H), 6.56 (d, J = 7.8 Hz,
1H, 2-4′-H), 7.18–7.47 (m, 14H, Ph–H); IR (KBr) υ: 2971,
1696 cmÀ1; MS m/z: 678.2 (M++1); Anal. Calcd for C39H33Cl2N3O4:
C, 69.03; H, 4.90; N, 6.19. Found: C, 69.05; H, 4.96; N, 6.15.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet