Synthesis of some quinazoline-2(1H),4(3H)-dione derivatives

Article abstract of DOI:10.1002/jccs.200500022

Several quinazoline-2(1H),4(3H)-dione derivatives were synthesized from pyrimidine-2(1H),4(3H)-dione derivative.

Full text of DOI:10.1002/jccs.200500022

Journal of the Chinese Chemical Society, 2005, 52, 141-148
141
Synthesis of Some Quinazoline-2(1H),4(3H)-dione Derivatives
H. H. Abdel-Razik
Chemistry Department, Faculty of Science, Mansoura University, New Damietta 34517, Egypt
Several quinazoline-2(1H),4(3H)-dione derivatives were synthesized from pyrimidine-2(1H),4(3H)-
dione derivative.
Keywords: Quinazoline-2(1H),4(3H)-dione derivatives.
INTRODUCTION
droxide solution to afford 6-[1-(cyano)-2-(hydroxyl)ethenyl
acetic acid]pyrimidine-2(1H),4(3H)-dione-5-carboxylate 2
1
Synthesis of quinazoline-2,4-diones with various sub-
stituents has been reported.1 The characterization and cyclo-
addition reaction of 5,6-dihydro-1,3-dimethyl-6-methylene-
5-(substituted amino) methylenopyrimidine-2(1H),4(3H)-
diones with olefinic dienophiles was carried out in highly
regio- and stereoselective ways to give quinazoline deriva-
tives.2 Novel 4-substituted 2-piperazinylquinazolines as po-
tent anticonvulsive and antihypoxic agents have been re-
ported.3 Novel quinazoline derivatives based on cycloaddi-
tion between 2,4-disubstituted pyrimidine ortho-quinodi-
methanes and suitable dienophiles have been reported.4
Quinazoline derivatives often lead to very interesting biolog-
ical and pharmaceutical activities.5-10 In continuation of pre-
vious work, the pyrimidine derivative11 1 was used as precur-
sor for the synthesis of some quinazoline-2(1H),4(3H)-dione
derivatives which are expected to have biological activity.
whose H NMR spectra revealed an enol hydrogen at 13.4
ppm, two carboxylic hydrogens at 10.2, 10.7 ppm, methylene
hydrogen at 2.65 ppm and the absence of the characteristic
signals for ethyl moity.
On the treatment of 2 with sodium ethoxide it yielded
compound 3 whose 1H and 13C NMR spectra showed the ab-
sence of a characteristic signal for methylene group, and its
mass spectra revealed a parent peak at 263 for M+. Since only
one set of signals is observed in the 1H NMR spectra, it is as-
sumed that if tautomerism exists, it is fast on the NMR time-
scale.12 The structures of the prepared compounds are in
agreement with their spectral data (cf experimental, Scheme
I).
Several 6-substituted-5,7-dihydroxy-8-cyanoquinazo-
line-2(1H),4(3H)-dione derivatives were synthesized through
the reaction of 3 with appropriate reagents. Thus, compound
3 reacted with hydrazine hydrate afforded 4 which on the re-
action with triethylorthoformate yielded 5. Also, the reaction
of 3 with phenylenediamine or ethylenediamine afforded 6,
7, respectively. Decarboxylation of 3 was maintained by
treatment with orthophosphoric acid at room temperature to
RESULTS AND DISCUSSION
Pyrimidine derivative 1 was refluxed in 4% sodium hy-
Scheme I
* Corresponding author. E-mail: Hamada600@yahoo.co.uk

142 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Abdel-Razik
afford 8 (cf experimental, Scheme II).
16. Pyrano[2,3-a]benzo[3,4-d]pyrimidine derivatives 17, 18
were synthesized by the treatment of 8 with diethylmalonate
and ethylcyanoacetate, respectively.
Compound 8 was subjected to further reactions af-
fording 6-substituted-5,7-dihydroxy-8-cyanoquinazoline-
2(1H),4(3H)-dione derivatives. Thus, compound 8 reacted
with formaldehyde and piperazine to yield 9. The reaction of
8 with formaldehyde in the presence of dimethylamine yielded
10. Nitration of 8 with 20% HNO3 afforded 11. Compound 8
reacted with diazonium salt of p-chloroaniline to yield the
dye 12 which on treatment with zinc in acetic acid afforded
13.
The treatment of 8 with phosphorousoxychloride af-
forded 19. By applying the Reiman-Tiemann reaction using
an alkaline solution of 8, compound 20 was obtained which,
when treated with hydrazine hydrate, afforded 21. The struc-
tures of the prepared compounds are in agreement with their
spectral data (cf experimental, Scheme III).
Quinazoline-2(1H),4(3H)-dithione derivative 14 was
synthesized by the reaction of 8 with phosphorouspenta-
sulphide. Compound 14 was methylated by the reaction with
methyl iodide and sodium hydroxide affording 15 which was
oxidized using concentrated nitric and sulfuric acids to yield
EXPERIMENTAL
Melting points were determined on a Gallenkamp elec-
trothermal apparatus and are uncorrected. The IR spectra
Scheme II

Synthesis of Some Quinazoline-2(1H),4(3H)-dione Derivatives
J. Chin. Chem. Soc., Vol. 52, No. 1, 2005 143
Scheme III

144 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Abdel-Razik
were recorded on a Pye-Unicam SP 110 spectrophotometer as
KBr disks. The 1H and 13C NMR spectra were recorded on a
Preparation of 8-cyano-6-carboxylic acid hydrazide-5,7-
dihydroxyquinazoline-2(1H),4(3H)-dione 4
1
Varian Gemini NMR spectrometer 300 (300 MHz for H,
A solution of compound 3 (2.63 g, 0.01 mol) in H2O (50
mL) and hydrazine hydrate (5 mL) were heated under reflux
for 2 h. After cooling, the precipitate formed is collected and
crystallized from ethanol. 2.52 g (91%); m.p. 286 °C; IR
(KBr) nmax/cm-1: 1720 (CO), 2222 (CN), 3362 (NH), 3244
(NH2), 1608 (C=C ring stretch); 1H NMR (CDCl3) d/ppm: 8.4
(br, s, 1H, NH) D2O exchangeable, 10.4, 10.5 (s, 1H, OH),
8.4, 9.2, 9.8 (s, 1H, NH), 6.5 (s, 2H, NH2); 13C NMR (CDCl3)
d: 117.5 (CN), 130.2 (C), 132.3 (C), 132.8 (C), 134.4 (C),
138.5 (C), 139.3 (C), 162.2, 162.5, 163.0 (CO); MS m/z: 277
(M+, 27%).
75.5 MHz for 13C) using Me4Si as an internal reference. Mass
spectra were measured on a Hitachi 80-B spectrometer at 70
eV. The progress of the reaction was monitored by TLC using
precoated silica gel plates (F254, Merck, Darmstadt).
Preparation of 6-[1-(cyano)-2-(hydroxyl)ethenyl acetic
acid]pyrimidine-2(1H),4(3H)-dione-5-carboxylate 2
Compound 1 (4.08 g, 0.01 mole) was refluxed with 1 N
NaOH13 (50 mL) for 4 h. Monitor the reaction by tlc (1 drop
of the reaction mixture was added to two drops of 5 N HCl;
this aqueous sample was extracted with ten drops of ethyl ac-
etate, and the ethyl acetate extracted was spotted on the tlc
plate, which was eluted with hexane:ethyl acetate 1:1) for the
disappearance of the starting material. The reaction mixture
was cooled, triturated with water, acidified to pH 2 with conc.
HCl, then extracted with ethyl acetate to remove the organic
impurities. The resulting aqueous mixture was concentrated.
This concentrate was stored in a freezer for about 24 h, and
the resulting crystals were collected by filtration and then
dried. 2.33 g (83%); m.p. > 300 °C; IR (KBr) nmax/cm-1: 1730
(CO), 2224 (CN), 3355 (NH), 1605 (C=C); 1H NMR (CDCl3)
d/ppm: 8.2, 9.5 (br, s, H, NH) D2O exchangeable, 10.2, 10.7,
13.4 (br, 1H, OH), 2.65 (s, 2H, CH2); 13C NMR (CDCl3) d:
28.7 (CH2), 117.8 (CN), 132.3 (C), 134.9 (C), 138.2 (C),
139.6 (C), 162.7, 163.5, 169.3, 170.4 (CO); MS m/z: 281 (M+,
16%).
Anal. Calc. For C10H7N5O5 (Mr = 277.20): C, 43.33; H,
2.55; N, 25.26%, found C, 43.24; H, 2.44; N, 25.19%.
Preparation of 8-cyano-5,7-dihydroxy-6-(1,3,4-oxadiazol-
2-yl)quinazoline-2(1H),4(3H)-dione 5
A mixture of 4 (2.77 g, 0.01 mol), an equimolar amount
of triethylorthoformate14 (1.48 g, 0.01 mole) and acetic anhy-
dride (15 mL) was refluxed for 5 h. The solvent was removed
under reduced pressure. Water was added to the resulting
solid product followed by filtration. Further purification was
accomplished by recrystallization from chloroform. 2.38 g
(83%); m.p. 267 °C; IR (KBr) nmax/cm-1: 1695 (CO), 2225
(CN), 3346 (NH), 1610 (C=C ring stretch); 1H NMR (CDCl3)
d/ppm: 8.7, 9.4 (br, s, 1H, NH) D2O exchangeable, 10.5, 10.8
(s, 1H, OH), 7.31 (s, 1H, oxadiazole-H); 13C NMR (CDCl3) d:
118.7 (CN), 128.6 (CH), 129.0 (C), 130.5 (C), 131.8 (C), 132.6
(C), 134.3 (C), 138.6 (C), 139.9 (C), 162.2, 162.8 (CO); MS
m/z: 287 (M+, 19%).
Anal. Calc. For C10H7N3O7 (Mr = 281.18): C, 42.72; H,
2.51; N, 14.94%, found C, 42.66; H, 2.45; N, 14.83%.
Anal. Calc. For C11H5N5O5 (Mr = 287.19): C, 46.00; H,
1.75; N, 24.39%, found C, 45.92; H, 1.68; N, 24.30%.
Preparation of 8-cyano-5,7-dihydroxyquinazoline-
2(1H),4(3H)-dione-6-carboxylate 3
A solution of 2 (2.81 g, 0.01 mol) in ethanolic sodium
ethoxide [prepared from sodium (0.04 g) in dry ethanol (20
mL)] was refluxed for 6 h. To the reaction mixture was added
water (30 mL) and the product was collected by filtration.
Further purification was accomplished by recrystallization
from chloroform. 1.959 g (83%); m.p. > 300 °C; IR (KBr)
Preparation of 8-cyano-5,7-dihydroxy-6-(benzoimidazol-
2-yl)quinazoline-2(1H),4(3H)-dione 6
A mixture of 3 (2.63 g, 0.01 mol), phenylene diamine
(1.08 g, 0.01 mol) and freshly fused sodium acetate (0.3 g) in
glacial acetic acid (40 mL) was refluxed for 3 h. The reaction
mixture was cooled and the precipitate solid was filtered,
dried and crystallized from dilute acetic acid. 2.64 g (79%);
m.p. 251 °C; IR (KBr) nmax/cm-1: 1715 (CO), 2222 (CN),
n
max/cm-1: 1726 (CO), 2225 (CN), 3353 (NH), 1610 (C=C
1
ring stretch); H NMR (CDCl3) d/ppm: 8.3, 9.5 (br, s, 1H,
NH) D2O exchangeable, 10.4, 10.6, 12.7 (s, 1H, OH); 13C
NMR (CDCl3) d: 117.2 (CN), 130.6 (C), 131.7 (C), 132.5 (C),
134.4 (C), 138.0 (C), 140.3 (C), 162.4, 162.7, 169.5 (CO);
MS m/z: 263 (M+, 45%).
1
3358 (NH), 1612 (C=C ring stretch); H NMR (CDCl3)
d/ppm: 8.4, 8.8, 9.8 (br, s, 1H, NH) D2O exchangeable, 10.4,
10.6 (s, 1H, OH), 7.10 (dd, J = 8, Ar-H), 7.65 (dd, J = 8, 1H,
Ar-H), 8.20 (d, J = 8, Ar-H), 8.75 (d, J = 8, Ar-H); 13C NMR
(CDCl3) d: 117.8 (CN), 128.4 (C), 129.3 (C), 129.7 (C), 130.5
(C), 130.9 (2C), 131.8 (C), 132.5 (2C), 133.6 (C), 135.9 (C),
Anal. Calc. For C10H5N3O6 (Mr = 263.17): C, 45.64; H,
1.92; N, 15.97%, found C, 45.58; H, 1.88; N, 15.89%.

Synthesis of Some Quinazoline-2(1H),4(3H)-dione Derivatives
J. Chin. Chem. Soc., Vol. 52, No. 1, 2005 145
138.0 (C), 138.8 (C), 162.7, 163.2 (CO); MS m/z: 335 (M+,
44%).
NMR (CDCl3) d: 20.8 (2CH2), 22.5 (4CH2), 119.7 (2CN),
130.6 (2C), 131.8 (2C), 132.3 (2C), 134.9 (2C), 138.2 (2C),
139.6 (2C), 162.6, 163.7 (4CO); MS m/z: 548 (M+, 36%).
Anal. Calc. For C24H20N8O8 (Mr = 548.48): C, 52.56; H,
3.68; N, 20.43%, found C, 52.49; H, 3.59; N, 20.33%.
Anal. Calc. For C16H9N5O4 (Mr = 335.28): C, 57.32; H,
2.71; N, 20.89%, found C, 57.24; H, 2.66; N, 20.83%.
Preparation of 8-cyano-5,7-dihydroxy-6-(4,5H-imidazol-
2-yl)quinazoline-2(1H),4(3H)-dione 7
Preparation of 8-cyano-5,7-dihydroxy-6-dimethylamino-
methylquinazoline-2(1H),4(3H)-dione 10
A mixture of 1 (0.01 mol), ethylene diamine (0.66 mL,
0.01 mol) and freshly fused sodium acetate (0.3 g) in glacial
acetic acid (30 mL) was refluxed for 3 h. The reaction mix-
ture was cooled and the precipitate solid was filtered, dried
and crystallized from dilute acetic acid. 2.35 g (82%); m.p.
277 °C; IR (KBr) nmax/cm-1: 1708 (CO), 2224 (CN), 3360
(NH), 1606 (C=C ring stretch); 1H NMR (CDCl3) d/ppm: 8.3,
9.3 (br, s, 1H, NH), 11.6 (t, J = 4.6, 1H, NH) D2O exchange-
able, 10.3, 10.7 (s, 1H, OH), 4.4 (t, J = 10, 2H, CH2), 1.7 (m,
2H, CH2); 13C NMR (CDCl3) d: 19.6, 19.8 (2CH2), 116.8
(CN), 126.4 (C), 130.8 (C), 131.7 (C), 132.3 (C), 134.4 (C),
138.7 (C), 139.5 (C), 162.8, 163.4 (CO); MS m/z: 287 (M+,
58%).
A mixture of 8 (2.19 g, 0.01 mol) formaline (37%, 1
mL) and dimethylamine hydrochloride (0.41 g) in ethanol
(20 mL) was stirred at room temperature for 6 h. The product
was cooled, filtered, washed with water and recrystallized
from ethanol. 2.23 g (81%); m.p. 196 °C; IR (KBr) nmax/cm-1:
1718 (CO), 2220 (CN), 3348 (NH), 1610 (C=C ring stretch);
1H NMR (CDCl3) d/ppm: 8.0, 9.3 (br, s, H, NH) D2O ex-
changeable, 10.8, 11.5 (s, 1H, OH), 5.46 (s, 2H, CH2), 3.34 (s,
3H, NMe2); 13C NMR (CDCl3) d: 22.5 (CH2), 34.4 (2CH3),
116.7 (CN), 130.4 (C), 131.7 (C), 132.7 (C), 134.9 (C), 138.2
(C), 139.8 (C), 162.2, 162.8 (2CO); MS m/z: 276 (M+, 48%).
Anal. Calc. For C12H12N4O4 (Mr = 276.25): C, 52.17; H,
4.38; N, 20.28%, found C, 52.09; H, 4.32; N, 20.23%.
Anal. Calc. For C12H9N5O4 (Mr = 287.24): C, 50.18; H,
3.16; N, 24.38%, found C, 50.09; H, 3.05; N, 24.29%.
Preparation of 8-cyano-5,7-dihydroxy-6-nitroquinazo-
line-2(1H),4(3H)-dione 11
Preparation of 8-cyano-5,7-dihydroxyquinazoline-
2(1H),4(3H)-dione 8
Compound 8 (2.19 g, 0.01 mol) and HNO3 (20%, 2 mL)
were refluxed for 2 hours. After cooling, the product was fil-
tered, washed with water and recrystallized from chloroform.
2.29 g (87%); m.p. 291 °C; IR (KBr) nmax/cm-1: 1726 (CO),
2223 (CN), 3352 (NH), 1560, 1378 (N=O), 1605 (C=C ring
stretch); 1H NMR (CDCl3) d/ppm: 8.3, 9.6 (br, s, H, NH) D2O
exchangeable, 11.3, 11.7 (s, 1H, OH); 13C NMR (CDCl3) d:
118.5 (CN), 130.8 (C), 131.7 (C), 132.4 (C), 134.7 (C), 138.5
(C), 139.4 (C), 162.3, 162.8 (CO); MS m/z: 264 (M+, 33%).
Anal. Calc. For C9H4N4O6 (Mr = 264.16): C, 40.92; H,
1.53; N, 21.21%, found C, 40.83; H, 1.46; N, 21.14%.
A mixture of 3 (2.63 g, 0.01 mol) and orthophosphoric
acid (2 mL) was stirred at room temperature for 10 h. The re-
action mixture was cooled, filtered, washed with water and
recrystalized from ethanol. 1.7 g (78%); m.p. > 300 °C; IR
(KBr) nmax/cm-1: 1716 (CO), 2226 (CN), 3345 (NH), 1608
(C=C ring stretch); 1H NMR (CDCl3) d/ppm: 8.6, 9.5 (br, s,
1H, NH) D2O exchangeable, 9.8, 10.2 (s, 1H, OH), 7.25 (s,
1H, H-6); 13C NMR (CDCl3) d: 116.7 (CN), 130.6 (CH),
131.7 (C), 132.3 (C), 134.5 (C), 138.5 (C), 139.7 (C), 162.9,
163.2 (CO); MS m/z: 219 (M+, 21%).
Anal. Calc. For C9H5N3O4 (Mr = 219.16): C, 49.33; H,
2.30; N, 19.17%, found C, 49.26; H, 2.22; N, 19.06%.
Preparation of 8-cyano-6-(p-chlorophenylazo)-5,7-
dihydroxy-quinazoline-2(1H),4(3H)-dione 12
Preparation of 1N,4N-bis(8-cyano-5,7-dihydroxyquinazo-
line-2(1H),4(3H)-dione-6-methyleno)piperazine 9
To a well stirred solution of p-chloroaniline (1.27 g,
0.01 mol) in concentrated hydrochloric acid (10 mL) and wa-
ter (20 mL) cooled in an ice bath slowly was added a solution
of sodium nitrite (0.92 g, 0.013 mol) in water (20 mL). A light
yellow solution resulted. After stirring at 0 °C for 10 minutes,
this cooled solution of p. chlorobenzenediazonium chloride15
was added dropwise to a mixture containing 8 (2.19 g, 0.01
mol) buffered with sodium acetate (14 g) and acetic acid (50
mL) in water (100 mL). A yellow precipitate appeared. The
mixture was allowed to stir at room temperature for 24 h. The
A mixture of 8 (2.19 g, 0.01 mol), formaline (37%, 1
mL) and piperazine (0.8 g) in ethanol (20 mL) was stirred at
room temperature for 6 h. The product was cooled, filtered,
washed with water and recrystallized from ethanol. 4.0 g
(73%); m.p. 226 °C; IR (KBr) nmax/cm-1: 1734 (CO), 2228
(CN), 3367 (NH), 1630 (C=C ring stretch); 1H NMR (CDCl3)
d/ppm: 8.8, 9.7 (br, s, H, NH) D2O exchangeable, 11.4, 11.9
(s, 1H, OH), 3.36-3.60 (m, 2H, CH2), 3.11 (s, 2H, CH2); 13
C

146 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Abdel-Razik
precipitate brown solid was filtered, washed with water and
dried. This material was used in the next step without any fur-
ther purification. An analytical sample was prepared by flash
column chromatography (2:1 hexane-acetone) followed by
recrystallization from hexane/acetone. 3.219 g (90%); m.p.
184 °C; IR (KBr) nmax/cm-1: 704 (C-Cl), 1722 (CO), 2224
(CN), 1815 (N=N), 3352 (NH), 1650 (C=C ring stretch); 1H
NMR (CDCl3) d/ppm: 8.6, 9.6 (br, s, H, NH) D2O exchange-
able, 10.4, 10.6 (s, 1H, OH), 7.58 (d, J = 8, 2H, Ar-H), 7.72
(d, J = 8, 2H, Ar-H); 13C NMR (CDCl3) d: 117.4 (CN), 128.6
(CH), 128.9 (CH), 129.4 (CH), 129.8 (CH), 130.7 (C), 131.7
(C), 132.3 (C), 134.8 (C), 135.7 (C), 136.4 (C), 138.3 (C),
139.5 (C), 162.4, 162.8, (2CO); MS m/z: 359 (M+, 42%).
Anal. Calc. For C15H8N5O4Cl (Mr = 357.71): C, 50.36;
H, 2.25; N, 19.57%, found C, 50.29; H, 2.18; N, 19.48%.
132.5 (C), 134.9 (C), 138.0 (C), 139.7 (C), 180.4, 180.7
(2CS); MS m/z: 251 (M+, 17%).
Anal. Calc. For C9H5N3O2S2 (Mr = 251.29): C, 43.02;
H, 2.01; N, 16.72%, found C, 42.95.24; H, 1.91; N, 16.66%.
Preparation of 8-cyano-5,7-dihydroxy-2,4-methylthio-
quinazoline 15
A stirred solution of compound 14 (2.51 g, 0.01 mol) in
NaOH solution (1 N, 10 mL) and methyl iodide17 (3.2 g, 1.4
mL, 0.022 mol) was heated at 40 °C for 1 h. After cooling, the
product was purified by filtration, washed with water and
recrystallized from ethanol. 2.15 g (77%); m.p. 193 °C; IR
1
(KBr) nmax/cm-1: 1612 (C=N), 2224 (CN), 1634 (C=C); H
NMR (CDCl3) d/ppm: 2.67 (s, 3H, Me), 9.7, 10.0 (s, 1H, OH),
7.22 (s, 1H, H-6); 13C NMR (CDCl3) d: 14.8 (2CH3), 118.5
(CN), 130.8 (C), 131.9 (C), 132.5 (C), 135.7 (C), 138.0 (C),
140.2 (C); MS m/z: 279 (M+, 35%).
Preparation of 6-amino-8-cyano-5,7-dihydroxy-quinazo-
line-2(1H),4(3H)-dione 13
Anal. Calc. For C11H9N3O2S2 (Mr = 279.34): C, 47.30;
H, 3.25; N, 15.04%, found C, 47.23; H, 3.21; N, 14.93%.
A suspension of 12 (3.57 g, 0.01 mol), zinc dust (4.00 g,
75 mg-atoms) in acetic acid (3 mL) and water was refluxed
under nitrogen for 4 h. The excess zinc was filtered from the
still-warm solution and washed with ethanol. The dark fil-
trate and washings were evaporated in vacuo. Traces of water
were azeotropically removed with benzene. The brown resi-
due was purified by flash column chromatography (2:1 hex-
Preparation of 8-cyano-5,7-dihydroxy-2,4-methylsulfinyl-
quinazoline 16
Compound 15 (2.79 g, 0.01 mol) was dissolved in 96%
sulphuric acid (3 mL) at 0 °C. The nitrating mixture18 (fum-
ing nitric acid, d = 1.5 g/mL, 0.16 mL, 3.6 mmole of nitric
acid and 0.16 mL of conc. sulphuric acid) was then added
dropwise at 0-5 °C within ten minutes and then the reaction
mixture was poured onto ice water and neutralized at 0 °C
with 25% aqueous ammonia. The solid was filtered off,
washed with cooled water and air dried. The product was
recrystallized from methanol. 2.148 g (69%); m.p. 210 °C; IR
(KBr) nmax/cm-1: 1630 (C=C ring stretch), 2220 (CN), 1025
(S=O); 1H NMR (CDCl3) d/ppm: 2.85 (s, 3H, Me), 9.8, 10.5
(s, 1H, OH), 7.24 (s, 1H, H-6); 13C NMR (CDCl3) d: 14.5
(2CH3), 116.7 (CN), 125.7 (C), 126.4 (C), 130.8 (C), 131.7
(C), 132.3 (C), 134.9 (C), 138.2 (C), 140.5 (C); MS m/z: 311
(M+, 22%).
ane/acetone). 2.01 g (86%); m.p. > 300 °C; IR (KBr) n
/
max
cm-1: 1725 (CO), 2224 (CN), 3347 (NH), 2353 (NH2), 1610
(C=C ring stretch); 1H NMR (CDCl3) d/ppm: 8.5, 9.4 (br, s,
H, NH) D2O exchangeable, 10.2, 10.4 (s, 1H, OH), 6.3 (br, s,
2H, NH2); 13C NMR (CDCl3) d: 118.4 (CN), 130.8 (C), 131.7
(C), 132.3 (C), 135.3 (C), 138.2 (C), 139.5 (C), 162.7, 163.3
(2CO); MS m/z: 234 (M+, 18%).
Anal. Calc. For C9H6N4O4 (Mr = 234.17): C, 46.16; H,
2.58; N, 23.93%, found C, 46.07; H, 2.51; N, 23.86%.
Preparation of 8-cyano-5,7-dihydroxyquinazoline-
2(1H),4(3H)-thione 14
To a solution of 8 (2.19 g, 0.01 mol) in xylene (30 mL),
phosphorouspentasulphide16 (4.44 g, 0.02 mole) was added
and the reaction mixture was refluxed for 2 h. After cooling,
the reaction was shaken vigorously with aqueous sodium hy-
droxide solution (10%, 10 mL). The alkaline extract was
cooled and acidified with conc. HCl. The product was filtered
and crystallized from ethanol. 1.96 g (78%); m.p. 276 °C; IR
(KBr) nmax/cm-1: 1175 (CS), 2222 (CN), 3353 (NH), 1605
(C=C ring stretch); 1H NMR (CDCl3) d/ppm: 7.8, 8.7 (br, s,
H, NH) D2O exchangeable, 9.8, 10.3 (s, 1H, OH), 7.22 (s, 1H,
H-6); 13C NMR (CDCl3) d: 117.8 (CN), 130.8 (C), 131.8 (C),
Anal. Calc. For C16H9N3O4S2 (Mr = 311.34): C, 42.44;
H, 2.91; N, 13.50%, found C, 42.37; H, 2.85; N, 13.42%.
Preparation of 10-amino-9-carboxyethyl-5-hydroxy-8-
oxo-4,5H-pyrano[2,3-h]quinazoline-2(1H),4(3H)-dione 17
A mixture of 8 (2.19 g, 0.01 mol) and diethylmalonate
(1.5 mL, 0.01 mol) was refluxed in ethanol (50 mL) for 3 h.
The reaction mixture was cooled, triturated with H2O, fil-
tered and recrystallized from ethanol. 2.78 g (83%); m.p. 216
°C; IR (KBr) nmax/cm-1: 1735 (CO), 2345 (NH2), 3348 (NH),
1
1606 (C=C ring stretch); H NMR (CDCl3) d/ppm: 8.5, 9.4

Synthesis of Some Quinazoline-2(1H),4(3H)-dione Derivatives
J. Chin. Chem. Soc., Vol. 52, No. 1, 2005 147
(br, s, H, NH) D2O exchangeable, 11.2 (s, 1H, OH), 7.30 (s,
2H, NH2), 8.4 (1H, d, J = 4.8 CHNH2), 9.8 (d, J = 7, 1H,
CHCOOC2H5), 7.15 (s, 1H, H-6), 4.48 (q, 2H, J = 8,
COOCH2CH3), 1.24 (t, 3H, J = 6, COOCH2CH3); 13C NMR
(CDCl3) d: 124.6 (CH), 126.8 (CH), 130.6 (C), 131.7 (C),
132.5 (C), 134.7 (C), 138.6 (C), 139.6 (C), 163.4, 164.7,
164.8, 165.3 (4CO); MS m/z: 335 (M+, 14%).
acid, and then steam-distilling it leaves behind compound 20.
2.0 g (81%); m.p. 278 (chloroform); IR (KBr) nmax/cm-1: 1735
1
(CO), 2220 (CN), 3350 (NH), 1607 (C=C ring stretch); H
NMR (CDCl3) d/ppm: 8.7, 9.6 (br, s, H, NH) D2O exchange-
able, 10.7, 11.3 (s, 1H, OH), 9.8 (s, 1H, CHO); 13C NMR
(CDCl3) d: 118.7 (CN), 130.4 (C), 131.9 (C), 132.7 (C), 135.9
(C), 138.7 (C), 139.8 (C), 162.7, 163.5, 182.5 (3CO); MS
m/z: 247 (M+, 28%).
Anal. Calc. For C14H13N3O7 (Mr = 335.28): C, 50.15; H,
3.91; N, 12.53%, found C, 50.07; H, 3.84; N, 12.44%.
Anal. Calc. For C10H5N3O5 (Mr = 247.17): C, 48.59; H,
2.04; N, 17.00%, found C, 48.51; H, 2.00; N, 16.89%.
Preparation of 10-amino-9-cyano-5-hydroxy-8-oxo-4,5H-
pyrano[2,3-h]quinazoline-2(1H),4(3H)-dione 18
Preparation of N,N¢-(bis-5,7-dihydroxy-8-cyanoquinazo-
line-2(1H),4(3H)-dione-6-methylidine)hydrazine 21
A mixture of 8 (2.19 g, 0.01 mol), ethylcyanoacetate
(1.06 mL, 0.01 mol) was refluxed in ethanol (50 mL) for 3 h.
The reaction mixture was cooled, triturated with H2O, fil-
tered and recrystallized from ethanol. 2.50 g (87%); m.p. 224
°C; IR (KBr) nmax/cm-1: 1727 (CO), 2226 (CN), 3350 (NH),
A solution of compound 20 (2.47 g, 0.01 mol) in H2O
(50 mL) and hydrazine hydrate (5 mL) were heated under re-
flux for 2 h. After cooling, the precipitate formed is collected
and crystallized from ethanol. 4.216 g (86%); m.p. 242; IR
(KBr) nmax/cm-1: 1738 (CO), 2230 (CN), 3366 (NH), 1640
(C=C ring stretch); 1H NMR (CDCl3) d/ppm: 8.8, 9.5 (br, s,
H, NH) D2O exchangeable, 10.0, 10.6 (s, 1H, OH), 8.6 (s, 1H,
CH=N); 13C NMR (CDCl3) d: 119.6 (2CN), 126.8 (2CH),
130.4 (2C), 131.9 (2C), 132.9 (2C), 136.1 (2C), 138.4 (2C),
141.3 (2C), 162.8, 163.7 (4CO); MS m/z: 490 (M+, 21%).
Anal. Calc. For C20H10N8O8 (Mr = 490.34): C, 48.99; H,
2.05; N, 26.10%, found C, 48.88; H, 2.00; N, 26.02%.
1
2345 (NH2), 1610 (C=C ring stretch); H NMR (CDCl3)
d/ppm: 8.6, 9.5 (br, s, H, NH) D2O exchangeable, 11.3 (s, 1H,
OH), 7.44 (s, 2H, NH2), (d, J = 4.8, 1H, CHNH2), 10.3 (d, J =
7 CHCN), 7.18 (s, 1H, H-6); 13C NMR (CDCl3) d: 119.7
(CN), 124.6 (CH), 125.8 (CH), 130.8 (C), 131.8 (C), 132.6
(C), 134.5 (C), 138.7 (C), 139.8 (C), 162.7, 163.8, 164.9
(3CO); MS m/z: 288 (M+, 26%).
Anal. Calc. For C12H8N4O5 (Mr = 288.22): C, 50.01; H,
2.80; N, 19.44%, found C, 57.24; H, 2.66; N, 20.83%.
Preparation of 8-cyano-2,4,5,7-tetrachloroquinazoline 19
A mixture of 8 (2.19 g, 0.01 mol), 20 mL of phospho-
rousoxychloride and 2 mL of N,N-dimethylaniline19 was
refluxed for 3 h. After removal of the excess of phosphorous-
oxychloride, to the residue was added 200 mL of ice water.
The precipitate was collected by filtration and recrystallized
CONCLUSION
Quinazoline-2,4-diones with various substituents on
aromatic rings were obtained from pyrimidine-2(1H),4(3H)-
dione derivative. Decarboxylation of compound 3 makes it
easier to prepare several 6-substituted quinazoline-2(1H),
4(3H)-dione derivatives in high yields. These derivatives
would facilitate researchers’ studies to target them for cancer
therapy and inhibition of tumor activity.
from ethanol. 2.577 g (88%); m.p. 116 °C; IR (KBr) n
/
max
1
cm-1: 725 (C-Cl), 2228 (CN), 1628 (C=C ring stretch); H
NMR (CDCl3) d/ppm: 6.92 (s, 1H, H-6), 13C NMR (CDCl3) d:
116.6 (CN), 125.6 (C), 126.5 (C), 130.6 (C), 131.6 (C), 132.3
(C), 135.7 (C), 138.2 (C), 140.4 (C); MS m/z: 292 (M+, 52%).
Anal. Calc. For C9HN3Cl4 (Mr = 292.94): C, 36.90; H,
0.34; N, 14.34%, found C, 36.80; H, 0.29; N, 14.26%.
Received April 5, 2004.
Preparation of 8-cyano-5,7-dihydroxy-6-formylquinazo-
line-2(1H),4(3H)-dione 20
REFERENCES
1. Okuzumi, T.; Nakanishi, E.; Tsuji, T.; Makino, S. Tetrahe-
dron 2003, 59, 5603.
2. Michihiko, N.; Yasutoshi, K.; Takashi, U.; Shoji, K. Bull.
Chem. Soc. Jpn. 1990, 63, 2938.
Riemer-Tiemann reaction was carried out using an al-
kaline solution of 8. Thus, a mixture of 8 (2.19 g, 0.01 mol),
NaOH (10%, 20 mL), and chloroform (50 mL) was refluxed
at 60 °C for 4 h. After cooling, the excess of chloroform was
distilled off. Acidifying the residual liquid with sulphuric
3. Manabu, H.; Ryuichi, I.; Hideaki, H.; Akio, O.; Takayuki, S.;

148 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Abdel-Razik
Hiroshi, O. Chem. Pharm. Bull. 1990, 38, 1286.
4. Chioua, R.; Benabdelouahab, F.; Chioua, M.; Martínez-
Alvarez, R.; Herrera-Fernández, A. Molecules 2002, 7, 507.
5. Szarics, E.; Nyikos, L.; Barabas, P.; Kovacs, I.; Skuban, N.;
Temesvarine-Major, E.; Egyed, O.; Nagy, P. I.; Kokosi, J.;
Takacs-Novak, K.; Kardos, J. Mol. Pharmacol. 2001, 59,
920.
2004, 31, 469.
11. Abdel-Razik, H. H. J. Chin. Chem. Soc. 2003, 50, 887.
12. Detsi, A.; Markopoulos, J.; Igglessi-Markopoulou, O. J.
Chem. Soc. Chem. Commun. 1996, 1323.
13. Danthi, S. N.; Hill, R. A. J. Heterocyclic Chem. 1997, 34,
835.
14. Shafiee, A.; Naimi, E.; Mansobi, P.; Foroumadi, A.; Shekari,
M. J. Heterocyclic Chem. 1995, 32, 1235.
6. Sosunov, E. A.; Gainullin, R. Z.; Danilo, P. Jr.;
Anyukhovsky, E. P.; Kirchengast, M.; Rosen, M. R.
Pharmacol. Exp. Ther. 1999, 290, 146.
J
15. Sznaidman, M. L.; Beauchamp, L. M. J. Heterocyclic Chem.
1996, 33, 1905.
7. Godde, F.; Toulmé, J.; Moreau, S. Nucleic Acids Res. 2000,
28, 2977.
8. Sedlak, M.; Hanusek, J.; Hejtmankova, L.; Kasparova, P.
Org. Biomol. Chem. 2003, 1, 1204.
16. Ismail, M. F.; Kaddah, A. M.; Elkafrawy, A. F.; Sayed, F. S.;
El-Sawy, O. M. J. Prakt. Chem. 1988, 330, 415.
17. Erb, B.; Akue, R.; Rigo, B.; Pirotte, B.; Couturier, D. J.
Heterocyclic Chem. 2000, 37, 523.
9. Beier, P.; Mindl, J.; Sterba, V.; Hanusek, J. Org. Biomol.
Chem. 2004, 2, 562.
10. Mishani, E.; Abourbeh, G.; Rozen, Y.; Jacobson, O.; Laky,
D.; Ben David, I.; Levitzki, A.; Shaul, M. Nucl Med Biology
18. Maslankiewicz, M. J. J. Heterocyclic Chem. 2000, 37, 697.
19. Kohra, S.; Tominaga, Y.; Hosomi, A. J. Heterocyclic Chem.
1988, 25, 959.