One-pot synthesis of pyrido[2,3-d]pyrimidine-2-thiones and a study of their reactivity towards some reagents

Article abstract of DOI:10.1002/jccs.200700184

A series of pyrido[2,3-d]pyrimidine-2-thione derivatives (5a-c) were synthesized by the one-pot reaction of the appropriate aldehyde, malononitrile and 6-aminothiouracil (1) in dimethyl-formamide. The same compounds were also synthesized by the reaction o

Full text of DOI:10.1002/jccs.200700184

Journal of the Chinese Chemical Society, 2007, 54, 1303-1312
1303
One-Pot Synthesis of Pyrido[2,3-d]pyrimidine-2-thiones and a Study of
their Reactivity Towards Some Reagents
A. B. A. El-Gazzar,a H. N. Hafeza and E. M. A. Yakoutb*
aPhotochemistry Department, National Research Centre, Dokki, Giza, Egypt
bPesticide Chemistry Department, National Research Centre, Dokki, Giza, Egypt
A series of pyrido[2,3-d]pyrimidine-2-thione derivatives (5a-c) were synthesized by the one-pot reac-
tion of the appropriate aldehyde, malononitrile and 6-aminothiouracil (1) in dimethyl-formamide. The
same compounds were also synthesized by the reaction of arylidine malononitrile (4) with 6-amino-
thiouracil (1). Moreover, the chemical behaviour of the produced pyrimidines towards different reagents
was studied.
Keywords: 6-Aminothiouracil; Arylidene-malononitriles; One-pot synthesis; Pyrido[2,3-d]pyrim-
idine; Triazolopyridopyrimidine.
1
INTRODUCTION
Pyrido[2,3-d]pyrimidines possess diverse biological
serve formation of this product. The H- and 13C-NMR
spectra of the resulting products are in agreement with the
proposed structures. The 1H-NMR spectrum (DMSO-d6) of
5a, for example, showed signals at d 7.30-7.33 (d, 2H,
phenyl), 7.34-7.51 (d, 2H, phenyl), 7.73-7.79 (brs, 2H, NH2,
D2O exchangeable), 12.16 (brs, NH, D2O exchangeable)
and 12.80 (brs, NH, D2O exchangeable). Also, the mass
spectrum showed the molecular ion peak [M+] at m/z 329
(100%).
activities.1 This structural motif is present in pirenperone
(tranquilizer),2 and ramastine (anti-allergic),3 as well as in
some anti-ulcerative,4 and anti-asthmatic agents.5 Our
group has been actively working on the development of
synthetic strategies for the preparation of 2-thioxopyrido-
[2,3-d]pyrimidin-4(1H)-ones.6-8 The present work describes
our approach for the synthesis of polyfunctional hetero-
cyclic compounds and convenient methods for the synthe-
sis of triazolopyridopyrimidines 8, 12. Thus, heating 6-
aminothiouracil 1 with aromatic aldehydes and malono-
nitrile in boiling dimethylformamide for a long time af-
forded a mixture of 6-(7-amino-5-aryl-2,3-dihydro-2-thi-
oxopyrido[2,3-d]pyrimidin-4(1H)-one) carbonitriles (5a-
c) (80-75%) and 6-(7-amino-5-aryl-2,3,5,8-tetrahydro-
2-thioxopyrido[2,3-d]pyrimidin-4(1H)-one) carbonitriles
(3a-c) (25-20%). On the other hand, the same reaction prod-
ucts were obtained from the reacting of arylidine malono-
nitrile 4 with 6-aminothiouracile (1) in refluxing dimethyl-
formamide, but short times are required to complete the re-
actions.
Reacting compound 5a with 1-arylazo-1-chloro-
acetone (6a-c) in dry chloroform TLC control afforded 2-
[S-(acetonyl-1-p-arylazo)]-7-amino-5-aryl-6-cyano-
pyrido[2,3-d]pyrimidin-4(4H)-4-ones (7a-c). The 1H-NMR
(DMSO-d6) spectrum of compound 7a, for example, showed
signals at d 2.64 (s, 3H, COCH3), 7.39-7.44 (2d, 4H, phen-
yl), 7.56-7.61 (d, 2H, phenyl), 7.73-7.76 (d, 2H, phenyl)
and 11.20 (brs, NH, D2O exchangeable).
Meanwhile, refluxing compound 5a with 6 in dry
chloroform in the presence of a few drops of triethylamine
for a long time (20-30 hours) under TLC control afforded
1-aryl-3-(aryl or acetyl)-8-amino-6-(4-chlorophenyl)-7-
cyano-5H-pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyrimidin-5-
ones (8a-d), respectively. Structures 8a-d was assigned on
the basis of 1H- and 13C-NMR spectral data. Thus, 1H-NMR
(DMSO-d6) spectrum for compound 8a, for example, showed
signals at d 7.25-7.29 (d, 2H, phenyl), 7.37-7.45 (m, 5H,
phenyl), 7.53-7.62 (m, 5H, phenyl), 7.89 (d, 2H, phenyl)
9.80 (brs, NH, D2O exchangeable). 13C-NMR (DMSO-d6)
Compound 5 is assumed to be formed via initial Mi-
chael adduct 2 (not 2¢) followed by intramolecular cyclo-
dehydration and spontaneous autoxidation under the reac-
tion conditions. Although cyclization of 2¢ to pyrido[2,3-
d]pyrimidine 5¢ derivative is also possible, we did not ob-
* Corresponding author. E-mail: sm_yakout@yahoo.com

1304 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
El-Gazzar et al.
Scheme I
a, Ar = 4-Chlorophenyl
b, Ar = 4-Tolyl
c, Ar = 4-N,N-dimethylaminophenyl
Scheme II
a, R = COCH3, Ar¢ = C6H4-Cl-p
b, R = COCH3, Ar¢ = C6H4-OCH3-p
c, R = COCH3, Ar¢ = C6H4-NO2-p
spectrum showed signals at 118.17 (CN) ppm, 121.11,
126.97, 127.59, 127.70, 127.81, 128.33, 128.86, 129.27,
129.56 129.61, 130.14, 130.42, 135.69, 136.88, 137.25,
137.27, 143.15, 155.02, 156.10 ppm (19C, sp2 carbon at-
oms with six symmetric carbons) and 164.12 ppm (CO).
Also the mass spectrum for compound 8c showed the mo-

The Chemistry of 6-Amino Uracil
J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1305
Scheme III
a, R = Ar¢ = C6H5
b, R = COCH3, Ar¢ = C6H4-Cl-p
c, R = COCH3, Ar¢ = C6H4-OCH3-p
d, R = COCH3, Ar¢ = C6H4-NO2-p
lecular ion peak [M+] at m/z 485 (100%).
which gave 9b on further heating with acetic acid for a long
time (Scheme IV).
Heating compound 5a with aliphatic carboxylic ac-
ids, namely formic or acetic acid for a long time, resulted in
the formation of 9-(4-chlorophenyl)-2-thioxo-4H,8H-pyri-
mido[4¢,5¢:4,5]pyrido[2,3-d]pyrimidine-4,8-diones (9a,b).
On the other hand, heating compound 5a with acetic acid
for 3 hours only yielded the 5-acetylamino derivative 10,
Beside correct elementary analyses, the IR, and 1H-
NMR spectra of 9a,b are in agreement with the assigned
structures. The IR spectra of 9a,b revealed the absence of
the cyanide group. The 1H-NMR (DMSO-d6) spectrum of
9a, showed signals at 7.29-7.33 (d, 2H, phenyl), 7.65-7.68
Scheme IV

1306 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
El-Gazzar et al.
(d, 2H, phenyl), 8.72 (s, 1H, triazole ring-proton), 12.16
(brs, NH, D2O exchangeable), 12.80 (brs, NH, D2O ex-
changeable). Also, the mass spectrum for the same com-
pound showed the molecular ion peak [M+] at m/z 357
(100%).
C6H5], m/z 448 (12%). The reaction mechanism may be as
follows, Scheme V.
Moreover, the same reaction products 12a-d were
isolated from the reaction of 2-methylthio-pyrido[2,3-d]-
pyrimidines (13) with the same hydrozonyl chlorides (6).
Also, we believe that the reaction mechanism proceeds
through the removel of methyl mercapten as shown in
Scheme VI.
Finally, as mentioned before, pyrido[2,3-d]pyrimi-
dines derivatives 11 react with hydrazonoyl chlorides to
form pyridotriazolo-pyrimidines after removel of hydro-
gen sulphide. Thus, compound 11a reacted with hydrazo-
noyl chloride 6 in dry chloroform in the presence of a few
drops of triethylamine under reflux for a long time (20-30
hours) (under TLC control) to afford 8-(4-chlorophenyl)-6-
phenyl-5H-pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyrimidin-
5-ones (12a-d), respectively.
The structure of compounds 12a-d was established
on the following facts: (a) The IR-spectrum of the com-
pound revealed the absence of (NH) and only the keto-goup
around cm-1: 1689 (CO), 1645 (C=N), 1561 (C=C). (b)
Compatible elemental analyses. (c) It was reported in the
literature10,11 that azoniaallene (1-aza-2-azoniaalene) salts
react as four-electron-three-center components in 1,3-cy-
cloadditions with many types of multiple bonds as shown
in Scheme VII.
EXPERIMENTAL
All melting points are uncorrected. The 1H-NMR and
13C-NMR spectra were recorded on a JEOL JNM-LA-400
FT-NMR Spectrometer (Germany) and chemical shifts
were expressed as d values against SiMe4 as an internal
standard. IR spectra were recorded as potassium bromide
pellets on a Perkin-Elmer 1430 spectrometer. Mass spectra
were recorded at 70 eV on a GCMS-Q P1000 EX Shimadzu
(Japan). Micro-analytical data were performed by the Mi-
croanalytical Center at Cairo University. The starting mate-
rials are prepared according to El-Gazzar6-8 and Quiroga.9
12a-d
a, R = Ar¢ = C6H5
b, R = COCH3, Ar¢ = C6H4-Cl-p
c, R = COCH3, Ar¢ = C6H4-OCH3-p
d, R = COCH3, Ar¢ = C6H4-NO2-p
Structures 12a-d were evidenced on the basis of 1H-
NMR and 13C-NMR spectral data. The 1H-NMR (DMSO-
d6) spectrum of 12a showed signals at 7.37-7.45 (m, 5H,
phenyl), 7.53-7.62 (m, 5H, phenyl), 7.75-7.77 (d, 2H,
p-substituted phenyl), 7.89 (s, 1H, pyridine ring-proton),
8.25-8.27 (d, 2H, phenyl), 8.29-8.31 (m, 5H, phenyl). More-
over, the 13C-NMR spectrum showed signals at 118.17,
121.11, 126.97, 127.59, 127.70, 127.81, 128.33, 128.86,
129.27, 129.56 129.61, 130.14, 130.42, 135.69, 136.88,
137.25, 137.27, 155.02, 156.10 ppm (31C, sp2 carbon at-
oms) and a signal at 160.11 ppm (CO). Also, the 1H-NMR
(DMSO-d6) spectrum for compound 12b showed signals at
d 2.65 (s, 3H, COCH3), 7.40-7.45 (m, 5H, phenyl), 7.54-
7.60 (d, 2H, p-substituted phenyl), 7.70-7.75 (2d, 4H, p-
substituted phenyl), 8.30-8.35 [m, 3H (2H for p-substituted
phenyl and 1H for CH pyridine ring)]. The mass spectrum
of compound 12a showed the molecular ion peak [M+] at
m/z 525 (100%) and peak at [M++1] m/z 526 (36%), [M+-
6-(7-Amino-5-aryl-2,3-dihydro-2-thioxopyrido[2,3-d]-
pyrimidin-4(1H)-one)carbonitriles (5a-c)
Method A
A mixture of compound 1 (10 mmol), malononitrile
(10 mmol), and aromatic aldehyde (10 mmol) was refluxed
in 50 mL dimethylformamide for 20-30 hours (under TLC
control). The reaction mixture was left overnight. The de-
posited precipitate was filtered off, washed with ethanol,
dried, and crystallized from the appropriate solvent to pro-
duce 5a-c in a good yield. The filtrate was concentrated and
left overnight at 0 °C. The precipitate formed was filtered
off and crystallized from the appropriate solvent to afford
3a-c in a low yield.
Method B
A mixture of compound 4 (10 mmol) and 6-amino-

The Chemistry of 6-Amino Uracil
J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1307
Scheme V
thiouracil (1) (10 mmol) was refluxed in 50 mL dimethyl-
formamide for 15 hours (under TLC control). The reaction
mixture was cooled. The deposited precipitate was filtered
off, washed with ethanol, dried, and crystallized from the
appropriate solvent to produce 5a-c in a good yield. The fil-
trate was concentrated and left overnight at 0 °C. The pre-
cipitate formed was filtered off and crystallized from the
appropriate solvent to afford 3a-c in a low yield.
able), 12.80 (brs, NH, D2O exchangeable). MS: m/z 329
(M+, 100%). Analysis: C14H8ClN5OS (329.7) Requires: C,
50.98; H, 2.44; N, 21.24; Found: C, 51.03; H, 2.48; N,
21.19.
6-(7-Amino-5-(4-tolyl)-2,3-dihydro-2-thioxopyrido[2,3-d]-
pyrimidin-4(1H)-one)carbonitrile (5b)
This compound was obtained from 4b (10 mmol), as a
yellow powder, crystallized from dimethylformamide
(82%), m.p. > 390 °C; IR (cm-1): 3454 (brs, NH), 3083 (CH
aryl), 2913 (CH, alkyl), 2211 (CN), 1694 (CO), 1623 (C=N),
6-(7-Amino-2,3-dihydro-5-(4-chlorophenyl)-2-thioxo-
pyrido[2,3-d]pyrimidin-4(1H)-one)carbonitrile (5a)
This compound was obtained from 4a (10 mmol), as
a yellow powder, crystallized from dimethylformamide
(85%), m.p. > 390 °C; IR (cm-1): 3458 (brs, NH), 3107 (CH
aryl), 2925 (CH, alkyl), 2216 (CN), 1695 (CO), 1626
(C=N), 1542 (C=C). 1H-NMR (DMSO-d6): d 7.30-7.33 (d,
2H, phenyl), 7.34-7.51 (d, 2H, phenyl), 7.73-7.79 (brs, 2H,
NH2, D2O exchangeable), 12.16 (brs, NH, D2O exchange-
1
1526 (C=C). H-NMR (DMSO-d6): 2.98 (s, 3H, CH3),
6.70-6.74 (d, 2H, phenyl), 7.13-7.18 (d, 2H, phenyl), 7.63-
7.64 (brs, 2H, NH2, D2O exchangeable), 12.05 (brs, NH,
D2O exchangeable), 12.80 (brs, NH, D2O exchangeable).
MS: m/z 309 (M+, 100%). Analysis: C15H11N5OS (309.3);
Requires: C, 58.23; H, 3.58; N, 22.64; Found: C, 58.30; H,
3.61; N, 22.70.

1308 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
El-Gazzar et al.
Scheme VI
Scheme VII
6-(7-Amino-5-(4-N,N-dimethylamino-phenyl)-2,3-di-
hydro-2-thioxopyrido[2,3-d]pyrimidin-4(1H)-one)
carbonitrile (5c)
12.00 (brs, NH, D2O exchangeable), 12.90 (brs, NH, D2O
exchangeable). MS: m/z 338 (M+, 100%). Analysis:
C16H14N6OS (338.3); Requires: C, 56.78; H, 4.16; N,
24.83; Found: C, 56.81; H, 4.09; N, 25.02.
This compound was obtained from 4c (10 mmol), as a
yellow powder, crystallized from dimethylformamide (89%),
m.p. > 390 °C; IR (cm-1): 3452 (brs, NH), 3077 (CH aryl),
2907 (CH, alkyl), 2209 (CN), 1693 (CO), 1628 (C=N),
2-[S-(Acetonyl)]-1-(4-arylazo)-7-amino-5-(4-aryl)-6-
cyano-pyrido[2,3-d]pyrimidin-4(4H)ones (7a-c)
(General Procedure)
1
1540 (C=C). H-NMR (DMSO-d6): d 2.98-2.99 (s, 6H,
N(CH3)2), 6.70-6.74 (d, 2H, phenyl), 7.12-7.17 (d, 2H,
phenyl), 7.61-7.62 (brs, 2H, NH2, D2O exchangeable),
A suspension of compound 5a (10 mmol) and hydra-
zonoyl chloride (6a-d) (10 m mol) in 30 mL dry chloroform

The Chemistry of 6-Amino Uracil
J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1309
was stirred under reflux for 5 hours. The deposited precipi-
tate was filtered off, washed with 30 mL chloroform, dried
and crystallized from the appropriate solvent to produce
(7a-d), in high yields.
C, 51.64; H, 2.83; N, 20.95; Found: C, 51.65; H, 2.84; N,
20.93.
1-Aryl-3-acetyl-8-amino-6-(4-chlorophenyl)-7-cyano-
5H-pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyrimidin-5-ones
(8a-d)
2-[S-(Acetonyl-1-p-chlorophenylazo)]-7-amino-5-(4-chlo-
rophenyl)-6-cyano-pyrido[2,3-d]pyrimidin-4(4H)-one
(7a)
(General procedure)
A mixture of compound 5a (10 mmol) and the appro-
priate hydrazonoyl chloride 6a-d (10 mmol) was stirred un-
der reflux in dry chloroform (30 mL) and 4 drops of trieth-
ylamine for 5 hours. The solvent was evaporated under re-
duced pressure. The solid produced was washed three times
with 30 mL methanol and recrystallized from the appropri-
ate solvent to produce (8a-d) in a high yield.
This compound was obtained from 5a (10 mmol) and
hydrazonoyl chloride 6a (10 mmol), as yellow crystals,
crystallized from dioxane (76%), m.p. 311-313 °C; IR
(cm-1): 3370 (brs NH), 3047 (CH aryl), 2964 (CH alkyl),
1
1712 (CO), 1685 (CO), 1630 (C=N), 1543 (C=C); H-
NMR (DMSO-d6): d 2.64 (s, 3H, COCH3), 7.39-7.44 (2d,
4H, phenyl), 7.56-7.61 (d, 2H, phenyl), 7.73-7.76 (d, 2H,
phenyl), 11.20 (brs, NH, D2O exchangeable). MS: m/z 524
(M+, 100%) and m/z 525 (M+H, 33%). Analysis:
C23H15Cl2N7O2S (524.4). Requires: C, 52.68; H, 2.88; N,
18.70; Found: C, 52.65; H, 2.90; N, 18.67.
8-Amino-6-(4-chlorophenyl)-7-cyano-1,3-diphenyl-5H-
pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyrimidin-5-one (8a)
This compound was obtained from 5a (10 mmol) and
N-phenyl-benzene-carbo-hydrazonoyl chloride 6a (10
mmol), as white powder, crystallized from dimethylform-
amide (78%); m.p. 379-380 °C; IR (cm-1): 3420 (brs, NH),
3039 (CH aryl), 2926 (CH alkyl), 2217 (CN) 1686 (CO),
1629 (C=N), 1567 (C=C). 1H-NMR (DMSO-d6): d 7.25-
7.29 (d, 2H, phenyl), 7.37-7.45 (m, 5H, phenyl), 7.53-7.62
(m, 5H, phenyl), 7.89 (d, 2H, phenyl), 9.80 (brs, NH, D2O
exchangeable). 13C-NMR (DMSO-d6): d 118.17 (CN) ppm,
121.11, 126.97, 127.59, 127.70, 127.81, 128.33, 128.86,
129.27, 129.56 129.61, 130.14, 130.42, 135.69, 136.88,
137.25, 137.27,143.15, 155.02, 156.10 ppm (19C, sp2 car-
bon atoms with six symmetric carbons) and 164.12 ppm
(CO). MS: m/z 489 (M+, 100%). Analysis: C27H16ClN7O
(489.9). Requires: C, 66.19; H, 3.29; N, 20.01; Found: C,
66.17; H, 3.27; N, 19.98.
2-[S-(Acetonyl-1-p-methoxyphenylazo)]-7-amino-5-(4-
chlorophenyl)-6-cyano-pyrido-[2,3-d]pyrimidin-4(4H)-
one (7b)
This compound was obtained from 5a (10 mmol) and
hydrazonoyl chloride 6b (10 mmol), as yellow powder,
crystallized from ethanol (82%), m.p. 324-327 °C; IR
(cm-1): 3390 (brs NH), 3096 (CH aryl), 2956 (CH alkyl),
2213 (CN), 1725 (CO), 1697 (CO), 1670 (C=N), 1586
(C=C); 1H-NMR (DMSO-d6): d 2.69 (s, 3H, COCH3), 3.87
(s, 3H, OCH3), 7.40-7.42 (d, 2H, phenyl), 7.48-7.54 (two
doublets, 4H, phenyl), 7.83-7.85 (d, 2H, phenyl), 10.80
(brs, NH, D2O exchangeable). MS: m/z 519 (M+, 100%).
Analysis: C24H18ClN7O3S (519.9). Requires: C, 55.44; H,
3.49; N, 18.86; Found: C, 55.41; H, 3.51; N, 18.82.
8-Amino-3-acetyl-1,6-di(4-chlorophenyl)-7-cyano-5H-
pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyrimidin-5-one (8b)
This compound was obtained from 5a (10 mmol) and
2-oxo-N-(4-chlorophenyl)-propane hydrazonoyl chloride
6b (10 mmol), as a yellow powder, crystallized from etha-
nol (72%), m.p. 341-343 °C; IR (cm-1): 3067 (CH aryl),
2919 (CH alkyl), 2215 (CN), 1721, 1687 (2CO), 1630 (C=N),
1541 (C=C). 1H-NMR (DMSO-d6): d 2.67 (s, 3H, COCH3),
7.40-7.45 (2d, 4H, phenyl), 7.54-7.60 (d, 2H, phenyl),
7.70-7.75 (d, 2H, phenyl), 10.50 (brs, NH, D2O exchange-
able). MS: m/z 490 (M+, 100%). Analysis: C23H13Cl2N7O2
(490.3). Requires: C, 56.34; H, 2.67; N, 19.99; Found: C,
56.33; H, 2.64; N, 19.96.
2-[S-(Acetonyl-1-p-nitrophenyllazo)]-7-amino-5-(4-chlo-
rophenyl)-6-cyano-pyrido[2,3-d]pyrimidin-4(4H)-4-ons
(7c)
This compound was obtained from 5a (10 mmol) and
hydrazonoyl chloride 6c (10 mmol), as white powder, crys-
tallized from dioxane (78%), m.p. 278-281 °C; IR (cm-1):
3420 (brs NH), 3073 (CH aryl), 2941 (CH alkyl), 2218
(CN), 1708 (CO), 1689 (CO), 1635 (C=N), 15538 (C=C);
1H-NMR (DMSO-d6): d 2.60 (s, 3H, COCH3), 7.33-7.37 (d,
2H, phenyl), 7.54-7.62 (2d, 4H, phenyl), 7.81-7.83 (d, 2H,
phenyl), 11.50 (brs, NH, D2O exchangeable). MS: m/z 534
(M+, 100%). Analysis: C23H15ClN8O4S (534.9). Requires:

1310 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
El-Gazzar et al.
8-Amino-3-acetyl-6-(4-chlorophenyl)-7-cyano-1-(4-meth-
oxyphenyl)-5H-pyrido[2,3-d]-[1,2,4]triazolo[4,5-a]pyrimi-
din-5-one (8c)
D2O exchangeable). MS: m/z 357 (M+, 100%). Analysis:
C15H8ClN5O2S (357.7). Requires: C, 50.35; H, 2.25; N,
19.58; Found: C, 50.29; H, 2.23; N, 19.49.
This compound was obtained from compound 5a (10
mmol) and 2-oxo-N-(4-methoxyphenyl)-propane hydrazo-
noyl chloride 6c (10 mmol), as white powder, crystallized
from dimethylformamide (69%), m.p. 309-311 °C; IR
(cm-1): 3400 (brs, NH), 3039 (CH aryl), 2927 (CH alkyl),
2217 (CN), 1720, 1689 (2CO), 1656 (C=N), 1539 (C=C).
1H-NMR (DMSO-d6): d 2.63 (s, 3H, COCH3), 3.97 (s, 3H,
OCH3), 7.36-7.41 (d, 2H, phenyl), 7.57-7.65 (2d, 4H,
phenyl), 7.78-7.80 (d, 2H, phenyl), 10.30 (brs, NH, D2O
exchangeable). MS: m/z 485 (M+, 100%). Analysis:
C24H16ClN7O3 (485.8). Requires: C, 59.32; H, 3.32; N,
20.18; Found: C, 59.29; H, 3.31; N, 20.15.
9-(4-Chlorophenyl)-6-methyl-2-thioxo-4H,8H-pyrimido-
[4¢,5¢:4,5]pyrido[2,3-d]pyrimidine-4,8-dione (9b)
A mixture of 5 (10 mmol) and glacial acetic acid (30
mL) was stirred under reflux for 6 hours (under TLC analy-
sis). The reaction mixture was allowed to cool to room tem-
perature, then poured onto water (100 mL). The solid so-
formed was collected by filtration, washed with ethanol (20
mL), dried, and crystallized from dimethylformamide (65%),
m.p. 362-365 °C (dec.); IR (cm-1): 3380 (brs, NH), 3089
(CH aryl), 2928 (CH, alkyl), 1687 (CO), 1643 (C=N), 1527
1
(C=C). H-NMR (DMSO-d6): d 2.14 (s, 3H, CH3), 7.26-
7.30 (d, 2H, phenyl), 7.63-7.66 (d, 2H, phenyl), 10.50 (brs,
NH, D2O exchangeable), 11.20 (brs, NH, D2O exchange-
able). MS: m/z 371 (M+, 100%). Analysis: C16H10ClN5O2S
(371.8). Requires: C, 51.68; H, 2.71; N, 9.53; Found: C,
51.65; H, 2.69; N, 9.47.
8-Amino-3-acetyl-6-(4-chlorophenyl)-7-cyano-1-(4-nitro-
phenyl)-5H-pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyrimidin-
5-one (8d)
This compound was obtained from compound 5a (10
mmol) and 2-oxo-N-(4-nitrophenyl)-propane hydrazonoyl
chloride 6d (10 mmol). The compound was obtained as
pale yellow crystals, crystallized from dimethylformamide
(65%), m.p. 334-336 °C; IR (cm-1): 3380 (brs, NH), 3086
(CH aryl), 2930 (CH alkyl), 2221 (CN), 1725, 1698 (2CO),
1634 (C=N), 1559 (C=C). 1H-NMR (DMSO-d6): d 2.59 (s,
3H, COCH3), 7.34-7.39 (d, 2H, phenyl), 7.52-7.60 (2d, 4H,
phenyl), 7.82-7.84 (d, 2H, phenyl), 11.10 (brs, NH, D2O
exchangeable). MS: m/z 500 (M+, 100%). Analysis:
C23H13ClN8O4 (500.8). Requires: C, 55.15; H, 2.61; N,
22.38; Found: C, 55.13; H, 2.58; N, 22.29.
5-Acetylamino-7-(4-chlorophenyl)-2,3-dihydro-2-thioxo-
pyrido[2,3-d]pyrimidin-4(1H)-one)-6-carbonitrile (10)
A solution of compound 5 (10 mmol) in glacial acetic
acid was refluxed for 3 h. The reaction mixture was then al-
lowed to cool to room temperature, then poured onto cold
water (100 mL). The solid so-formed was collected by fil-
tration, dried and crystallized from dimethylformamide
(73%), m.p. 348-351 °C (dec.); IR (cm-1): 3406 (brs, NH),
3098 (CH aryl), 2935 (CH alkyl), 2213 (CN), 1700, 1678
1
(2CO), 1675 (C=N), 1538 (C=C). H-NMR (DMSO-d6)
ppm: d 2.24 (s, 3H, CH3), 7.32-7.35 (d, 2H, phenyl), 7.68-
7.72 (d, 2H, phenyl), 11.50 (brs, NH, D2O exchangeable),
12.30 (brs, NH, D2O exchangeable). MS: m/z 371 (M+,
28%). Analysis: C16H10ClN5O2S (371.8). Requires: C,
51.68; H, 2.71; N, 9.53; Found: C, 51.69; H, 2.70; N, 9.45.
9-(4-Chlorophenyl)-2-thioxo-4H,8H-pyrimido[4¢,5¢:4,5]-
pyrido[2,3-d]pyrimidine-4,8-dione (9a)
A mixture of compound 5 (10 mmol), formic acid (10
mL) and catalytic amount of concentrated hydrochloric
acid was heated under reflux for 6 hours. The reaction
mixture was allowed to cool to room temperature and
poured onto water (100 mL). The formed solid was col-
lected by filtration, washed with ethanol (20 mL), dried
and crystallized from dimethylformamide (75%), m.p.
386-388 °C (dec.); IR (cm-1): 3410 (brs, NH), 3100 (CH
aryl), 2922 (CH, alkyl), 1688 (CO), 1639 (C=N), 1540
(C=C). 1H-NMR (DMSO-d6): d 7.29-7.33 (d, 2H, phenyl),
7.65-7.68 (d, 2H, phenyl), 8.72 (s, 1H, triazole ring-pro-
ton), 12.16 (brs, NH, D2O exchangeable), 12.80 (brs, NH,
8-(4-Chlorophenyl)-6-phenyl-5H-pyrido[2,3-d][1,2,4]-
triazolo[4,5-a]pyrimidin-5-ones (12a-d)
(General procedure)
A mixture of compound 11a (or 13) (10 mmol) and
the appropriate hydrazonoyl chlorides (6a-d) (10 mmol)
was stirred under reflux in dry chloroform (30 mL) and 4
drops of triethylamine for 5 hours. The solvent was evapo-
rated under reduced pressure. The solid produced was
washed three times with 30 mL methanol and crystallized

The Chemistry of 6-Amino Uracil
J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1311
form appropriate solvent to produce (12a-d) in high yields.
1H, pyridine), 8.02-8.05 (d, 2H, phenyl), 8.35 (d, 2H, phen-
yl). MS: m/z 521 (M+, 100%), m/z 522 (M+H, 33%) and m/z
478 (M-COCH3, 16%). Analysis: C29H20N5ClO3 (521.9).
Requires: C, 66.72; H, 3.86; N, 13.41. Found: C, 66.69; H,
3.84; N, 13.43.
8-(4-Chlorophenyl)-1,3,6-triphenyl-5H-pyrido[2,3-d]-
[1,2,4]triazolo[4,5-a]pyrimidin-5-one (12a)
This compound was obtained from 11a (10 mmol)
and N-phenyl-benzene-carbo-hydrazonoyl chloride 6a (10
mmol), as white powder, crystallized from dimethylform-
amide (78%); m.p. 379-380 °C; IR (cm-1): 3054 (CH aryl),
2926 (CH alkyl), 1689 (CO), 1640 (C=N), 1554 (C=C).
1H-NMR (DMSO-d6): d 7.37-7.45 (m, 5H, phenyl), 7.53-
7.62 (m, 5H, phenyl), 7.75-7.77 (d, 2H, phenyl), 7.89 (s,
1H, pyridine proton), 8.25-8.27 (d, 2H, phenyl), 8.29-8.31
(m, 5H, phenyl). 13C-NMR (DMSO-d6): d 118.17, 121.11,
126.97, 127.59, 127.70, 127.81, 128.33, 128.86, 129.27,
129.56 129.61, 130.14, 130.42, 135.69, 136.88, 137.25,
137.27, 155.02, 156.10 ppm (31C, sp2 carbon atoms) and
160.11 ppm (CO). MS: m/z 525 (M+, 100%), m/z 526
(M+H, 36%) and m/z 448 (M+-C6H5, 12%). Analysis:
C32H20ClN5O (525.9). Requires: C, 73.06; H, 3.83; N,
13.31; Found: C, 73.04; H, 3.79; N, 13.26.
3-Acetyl-8-(4-chlorophenyl)-1-(4-nitrophenyl)-6-phenyl-
5H-pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyrimidin-5-one
(12d)
This compound was obtained from 11a (10 mmol)
and 2-oxo-N-(4-nitrophenyl)-propane hydrazonoyl chlo-
ride 6d (10 mmol). The compound was obtained as pale
yellow crystals, crystallized from dimethylformamide (65%),
m.p. 334-336 °C; IR (cm-1): 3097 (CH aryl), 2923 (CH
alkyl), 1717, 1685 (2CO), 1628 (C=N), 1515 (C=C). 1H-
NMR (DMSO-d6): d 2.68 (s, 3H, CH3), 7.45-7.51 (m, 5H,
phenyl), 7.54-7.63 (d, 2H, phenyl), 7.80 (s, 1H, pyridine),
8.43-8.45 (d, 2H, phenyl), 8.57-8.60 (2d, 4H, phenyl). MS:
m/z 536 (M+, 100%), m/z 537 (M+H, 36%) and m/z 493
(M-COCH3, 19%). Analysis: C28H17N6O4Cl (536.9). Re-
quires: C, 62.63; H, 3.19; N, 15.65; Found: C, 62.58; H,
3.21; N, 15.70.
3-Acetyl-1,8-di(4-chlorophenyl)-6-phenyl-5H-pyrido[2,3-
d][1,2,4]triazolo[4,5-a]pyrimidin-5-one (12b)
This compound was obtained from 11a (10 mmol)
and 2-oxo-N-(4-chlorophenyl)-propane hydrazonoyl chlo-
ride 6b (10 mmol), as a yellow powder, crystallized from
ethanol (76%), m.p. 304-306 °C; IR (cm-1): 3060 (CH aryl),
2934 (CH alkyl), 1725, 1705 (2CO), 1634 (C=N), 1546
(C=C). 1H-NMR (DMSO-d6): d 2.65 (s, 3H, COCH3), 7.40-
7.45 (m, 5H, phenyl), 7.54-7.60 (d, 2H, phenyl), 7.70-7.75
(2d, 4H, phenyl), 8.30-8.35 [m, 3H, (2H, phenyl + H, pyri-
dine)]. MS: m/z 525 (M+, 100%), m/z 526 (M+H, 39%), m/z
482 (M-COCH3, 15%) and m/z 455 (M-2Cl, 18%). Analy-
sis: C28H17Cl2N5O2 (526.3). Requires: C, 63.88; H, 3.25; N,
13.30; Found: C, 63.85; H, 3.27; N, 13.32.
Received December 20, 2006.
REFERENCES
1. Boschelli, D. H.; Wu, Z.; Klutchko, S. R.; Showalter, H. D.
H.; Hamby, J. M.; Lu, G. H.; Major, T. C.; Dahring, T. K.;
Batley, B.; Panek, R. L.; Keiser, J.; Hartl, B. G.; Kraker, A.
J.; Klohs, W. D.; Roberts, B. J.; Patmore, S.; Elliott, W. L.;
Steinkampf, R.; Bradford, L. A.; Hallak, H.; Doherty, A. M.
J. Med. Chem. 1988, 41, 4365.
2. Smith, R. L.; Barette, R. J.; Sanders-Bush, E. J. Pharmacol.
Exp. Ther. 1995, 275, 1050.
3-Acetyl-8-(4-chlorophenyl)-1-(4-methoxyphenyl)-6-
phenyl-5H-pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyrimidin-
5-one (12c)
3. Awoutters, F.; Vermeire, J.; Smeyers, F.; Vermote, P.; Van
Beek, R.; Niemegeers, C. J. E. Drug Dev. Res. 1986, 8, 95.
4. Matsutani, S.; Mizushima, Y. Chem. Abstr. 1990, 112,
98557.
This compound was obtained from 11a (10 mmol)
and 2-oxo-N-(4-methoxyphenyl)-propane hydrazonoyl chlo-
ride 6c (10 mmol), as white powder, crystallized from di-
methylformamide (69%), m.p. 309-311°C; IR (cm-1): 3066
(CH aryl), 2928 (CH alkyl), 1736, 1679 (2CO), 1656
(C=N), 1543 (C=C). 1H-NMR (DMSO-d6): d 2.65 (s, 3H,
CH3), 3.80 (s, 3H, OCH3), 7.32-7.35 (d, 2H, phenyl), 7.43-
7.50 (m, 5H, phenyl), 7.56-7.60 (d, 2H, phenyl), 7.75 (s,
5. Yanagihara, Y.; Kasai, H.; Kawashima, T.; Shida, T. Jpn. J.
Pharmacol. 1988, 48, 91.
6. El-Gazzar, A. B. A.; Gaafar, A. E. M.; Hafez, H. N.; Aly, A.
S. Phousphours. Sulphur Silicon and Related Elements
2006, 181, 1859.
7. El-Gazzar, A. B. A.; Abu-Zied, Kh. M.; Khir El-Din, N.
Heteroat. Chem. 2007, 18, 34.

1312 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
El-Gazzar et al.
8. El-Gazzar, A. B. A.; Gaafar, A. E. M.; Aly, A. S. Phous-
phours, Sulphur Silicon Relat. Elem. 2002, 177, 45.
9. Quiroga, J.; Insuasty, B.; Sanchez, A.; Nogueras, M.; Meier,
H. J. Heterocycl. Chem. 1992, 29, 1045. And references
sited therein.
10. El-Gazzar, A. B. A.; Scholten, K.; Guo, Y.; Weissenbach, K.;
Hitzler, M. J.; Roth, G.; Fischer, H.; Jochims, J. C. J. Chem.
Soc. Perkin Trans. 1 1999, 1999.
11. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley:
New York, 1984; Vols. 1.2.