Synthesis of some new thiazolo[3,2-a]pyrido[2,3-d]pyrimidinones and isoxazolo[5′,4′:4,5]thiazolo[3,2-a]pyrido[2,3-d]pyrimidinone

Article abstract of DOI:10.1080/10426500210230

6-Amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone 1 reacts in boiling DMF with a cyclic α,β-unsaturated ketones 2 affording the pyrido [2,3-d]pyrimidinone 6a,b, the latter compound condensed with aldehyde in presence of chloroacetic acid to yield thiazolo[3,2-a] pyrido [2,3-d]-pyrimidinones (7, 8) respectively. The alkylation of pyridopyrimidinone it gave the 2-alkylthio derivatives 10a-e, compound 10b cyclized to thiazolopyridopyrimidinone derivative 13. Also, the condensation of compounds 7a,b with hydoxylamine gave the corresponding isoxazolo[5′,4′:4,5]thiazolo[3,2-a]pyrido[2,3-d]pyrimidinone.

Full text of DOI:10.1080/10426500210230

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Some New Thiazolo[3,2- a ]pyrido[2,3-
d ]pyrimidinones and Isoxazolo[5′,4′:4,5]thiazolo [3,2-
a ]pyrido[2,3- d ]pyrimidinone
A. B. A. El-Gazzar a , A. M. Gaafar a & A. S. Aly a
a National Research Centre, Cairo, Egypt
Version of record first published: 27 Oct 2010.
To cite this article: A. B. A. El-Gazzar , A. M. Gaafar & A. S. Aly (2002): Synthesis of Some New Thiazolo[3,2- a ]pyrido[2,3-
d ]pyrimidinones and Isoxazolo[5′,4′:4,5]thiazolo [3,2- a ]pyrido[2,3- d ]pyrimidinone, Phosphorus, Sulfur, and Silicon and the
Related Elements, 177:1, 45-58
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SYNTHESIS OF SOME NEW
THIAZOLO[3,2-a]PYRIDO[2,3-d]PYRIMIDINONES
AND ISOXAZOLO[50,40:4,5]THIAZOLO
[3,2-a]PYRIDO[2,3-d]PYRIMIDINONE
A. B. A. El-Gazzar, A. M. Gaafar, and A. S. Aly
National Research Centre, Cairo, Egypt
(Received April 24 2001.)
6-Amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone 1 reacts in boiling
DMF with a cyclic , -unsaturated ketones 2 affording the pyrido
[2,3-d]pyrimidinone 6a,b, the latter compound condensed with alde-
hyde in presence of chloroacetic acid to yield thiazolo[3,2-a] pyrido
[2,3-d]-pyrimidinones (7, 8) respectively. The alkylation of pyrido-
pyrimidinone it gave the 2-alkylthio derivatives 10a–e, compound 10b
cyclized to thiazolopyridopyrimidinone derivative 13. Also, the conden-
sation of compounds 7a,b with hydoxylamine gave the corresponding
isoxazolo[50,40:4,5]thiazolo[3,2-a]pyrido[2,3-d]pyrimidinone.
Keywords: 6-Aminothiouracil; , -unsaturated ketones; spectroscopic
analysis (NMR, mass)
It is well known that among pyrimidinone (6-amino uracil) derivatives
and their nucleosides, there are many compounds containing a fused
pyrimidine ring. These make up a broad class owing to the wide range
of biological activity. Many potential drugs have been modelled on these
compounds, particularly in cancer and virus research.1
On the other hand, pyrido[2,3-d]pyrimidines and their oxo and
thioxo derivatives deserve great interest by virtue of their biolog-
16
ical and physiological properties.2
Thus, in connection with our
19
recent work,17
we report a new approach to some novel thiazolo
[3,2-a]pyrido[2,3-d]pyrimidinone and isoxazolo[50,40:4,5]thiazolo[3,2-a]
pyrido[2,3-d]pyrimidinone derivatives utilizing readily available start-
ing materials.
According to Skrap and Doebner-v. Miller20,21 synthesis of pyridines,
the reaction of 6-amino-2-thiouracil and , -unsaturated ketones is
Address correspondence to A. B. A. El-Gazzar, National Research Center, Cairo, Egypt.
45

46
A. B. A. El-Gazzar et al.
a very convenient and versatile method for the fusion of a pyridine
25
ring to the pyrimidinone as a heterocycle ring.22
Where, the neucle-
ophilic amine 1 can attack on the carbonyl carbon C-1 or on C-3 of the
ketones 2,26 the formation of 3 or 30 not only depends on the educts
but also on the reaction condition.27 Thus, 6-amino thiouracil 1,28 con-
densed with , -unsaturated ketones 2 forming the 5,7-diaryl-2,3,5,8-
tetrahydro-2-thioxopyrido[2,3-d]pyrimidin-4(1H)-ones 4 or 40. Actually,
only one reaction route is realized. Depending on the reaction condi-
tions, the compounds 5 or 6 were isolated. Boiling of 3 in DMF in an
argon atmosphere leads to 5, an energetically favorable tautomer of 4,26
(Scheme 1).
However, we reported here, that the prolonged reaction for com-
pounds 5 are smoothly oxidized to 6 in boiling DMF in presence of air,
with yield 85%, respectively. Also, the structure form of the oxidized
product 6 was investigated by NMR spectrum and elemental analysis,
where the low field shift for the protons of the aryl group linked to C-5
is due to the anisotropy effect of the pyrido[2,3-d]pyrimidine skeleton,
particularly of its carbonyl group.
Also, we can investigated the reaction of 1 and 3-(4-chlorophenyl)-1-
(2-theinyl)-2-propen-1-one (2b) as , -unsaturated ketone containing a
heterocycle ring, yielding 5-(2-theinyl)pyrido[2,3-d]pyrimidinone (6b),
respectively. Its NMR showed signals at 7.23 (t, 1H, thienyl proton),
7.40 (d, 1H, thienyl proton), 7.45–7.60 (d, 2H), 7.73 (d, 1H, thienyl pro-
ton), 7.97 (s, 1H, pyridine proton), 8.28 (d, 2H), 12.15, 13.00 (two, br, s,
2NH, D2O exchangable), which were identical with the structure form.
Also, MS showed the molecular ion peak (M+) 371, 100%. (See Experi-
mental Section and Scheme 1).
As mentioned before, the development of the syntheses of var-
ious derivatives of pyrido[2,3-d]pyrimidines and fused pyrim-
idines was promoted to us. Thus, when a ternary mixture of
compound 6a,b, chloroacetic acid, and a proper aldehyde was
heated under reflux in a mixture of acetic acid, acetic anhydride,
in the presence of anhydrous sodium acetate, 8-(4-chlorophenyl)-
6-phenyl (or 2-theinyl)-2-arylmethylene-2,3,4,5-tetrahydrothiazolo
[3,2-a]pyrido[2,3-d]pyrimidine-3,5-dione (7a–e). Assignment of struc-
ture 7 to the reaction products is based on correct values of elemental
analysis and compatible spectral data. Mass spectrum showed [M+],
m/z 507 (100%) as a molecular ion peak for compound 7e as an
example. Also, the condensation of 2,3-dihydro-5H-thiazolo[3,2-
a]pyrido[2,3-d]pyrimidine-3,5-dione (8a) with benzaldehyde in acetic
acid and anhydrous sodium acetate under reflux afforded a similar
reaction to product 7a, with identical data (see Experimental Section;
Scheme 2).

Thiazolo Pyrimidinones
47
SCHEME 1
Compounds 7a,b underwent cycloaddition with hydroxyl amine
hydrochloride, by refluxing in acetic acid in the presence of anhydrous
sodium acetate to give 3-aryl-7-(4-chlorophenyl)-9-phenyl-2,3-dihydro
isoxazolo[50,40:4,5]thiazolo[3,2-a]pyrimido[2,3-d]pyrimidin-10 (10H )-
1
ones (9a,b). The H NMR spectrum (DMSO-d6 ) of 9a as an example,
showed signals at 6.45 (s, 1H, isoxazole proton), 7.03–7.50 (m, 10H,

48
A. B. A. El-Gazzar et al.
SCHEME 2

Thiazolo Pyrimidinones
49
two phenyl proton), 7.55 (d, 2H), 7.95 (s, 1H, pyridine proton), 8.25 (d,
2H), 11.25 (br, s, NH, D2O exchangeable). The IR spectra of 9a displayed
absorption bands around 3290 cm 1 (NH) and 1688 cm 1 for the amidic
carbonyl group (see Experimental Section; Scheme 2).
Alkylation of 6a in an ethanolic potassium hydroxide solution with
a proper halogeno compounds, mainly, methyl iodide, chloroacetyl ace-
tone, 2-chloro aceto(4-chlorophenyl)anilide, chloroacetone and phenacyl
bromide, yielded the 2-alkylthio derivatives 10a–e, respectively. As-
signment of structure 10 to the reaction products is based on the fact
that each of 10a,b gave the same 2-hydrazino derivatives 11 when re-
fluxed with hydrazine hydrate in dioxane. Also, 1H NMR and mass spec-
tronomy showed reasonable data, (Scheme 3). Also, when compound
10a was fused with anilines derivatives mainly, 4-chloroaniline and
4-nitroaniline at 140 C, it gave 2-aryl amino derivatives 12a,b, respec-
tively. The structure was confirmed by elemental analysis, and spectral
data (Scheme 3).
Furthermore, heating under reflux compound 10b, in a mix-
ture of acetic anhydride/pyridine (1:1), led to cyclization and forma-
tion of 2-acetyl-8-(4-chlorophenyl)-3-methyl-6-phenyl-5H-thiazolo[3,2-
a]pyrido[2,3-d]pyrimidin-5-one (13), (Scheme 3). Structural elucidation
of compound 13 was accomplished from analytical and spectral data.
The mass spectra showed the expected molecular ion peak (m/z 445,
100%) and the IR spectra displayed two carbonyl absorption bands at
1729 and 1689 cm 1 and no signals for NH. Also, the 1H NMR spectrum
(DMSO-d6 ) showed signals at 2.60 (s, 3H), 2.85 (s, 3H), 7.35–7.50 (m,
5H, phenyl), 7.60, 8.30 two doublet signals for 4-chlorophenyl, and 7.80
ppm (s, CH, pyridine proton attached to C-7).
In conclusion, pyrido[2,3-d]pyrimidinones, which are easily pre-
pared by the cycloaddition of , -unsaturated ketones to 6-amino
thiouracil, were found to be useful starting materials for the synthesis of
thiazolo[3,2-a]pyridino[2,3-d]pyrimidinone derivatives. The advantage
of this method over the other existing methods is that pyrido[2,3-d]
pyrimidinones are obtained in the oxidized form in quantitative yields,
and further reaction with hydroxyl amine, aromatic amines, and halo-
compounds produce excellent yields of 2-alkylthio, thiazolo, isoxazolo
thiazolo pyridopyrimidinones. No other side products are obtained.
EXPERIMENTAL
All melting points are uncorrected, the NMR spectra were recorded on
a Varian 1H Gemini 200 spectrometer (NRC) and chemical shifts were
expressed as values against SiMe4 as internal standards. IR spectra

50
A. B. A. El-Gazzar et al.
SCHEME 3

Thiazolo Pyrimidinones
51
were recorded as KBr pellets on a Perkin-Elmer 1430 spectrometer,
(National Research Centre and Department of Chemistry, Cairo Uni-
versity). Mass spectra were recorded on GCMS-QP 1000Ex Shimadzu
Japan (Gas Chromatography-Mass Spectrometer). Microanalyses data
were performed by the Microanalytical Centre at Cairo University and
National Research Centre.
7-(4-Chlorophenyl)-2,3-dihydro-5-Phenyl or (2-theinyl)-2-
thioxopyrido[2,3-d]pyrimidin-4(1H)-one (6a,b)
General Procedure
A mixture from compound 1 (10 mmol) and , -unsaturated ketones
2 (10 mmol) was refluxed in DMF (50 ml) for 30 h (under TLC con-
trol). The mixture was cooled, and the percipitate was filtered off and
crystallized from appropriate solvent to produce (6a,b), respectively.
7-(4-Chlorophenyl)-2,3-dihydro-5-phenyl-2-thioxopyrido[2,3-d]pyri-
midin-4(1H)-one (6a). From compound 1 (1.43 g, 10 mmol) and 2a
(2.43 g, 10 mmol). The compound was obtained as a yellow crys-
tals, crystallized from DMF, m.p. 344–346 C (dec.) in 88% yield;
(C19H12ClN3OS) (365.8). IR (KBr) cm 1: 3219 (NH), 1678 (C O), 1663
1
(C N); H NMR (DMSO-d6 ) ppm: 7.45–7.60 (m, 5H, phenyl), 7.65
(d, 2H), 7.95 (s, 1H, pyridine proton), 8.25 (d, 2H), 12.40, 13.10 (two br,
s, NH, D2O exchangeable). Mass: (70 ev) m/z (%) 365 (M+, Cl35, 100),
367 (M+, Cl37, 30).
7-(4-Chlorophenyl)-2,3-dihydro-5-(2-theinyl)-2-thioxopyrido[2,3-d]-
pyrimidin-4(1H)-one (6b). From compound 1 (1.43 g, 10 mmol) and
2b (2.49 g, 10 mmol). The compound was obtained as a yellow
crystals, crystallized from DMF, m.p. 328–330 C (dec.) in 78% yield;
(C17H10ClN3OS2) (371.8). IR (KBr) cm 1: 3306 (NH), 1683 (C O), 1661
1
(C N); H NMR (DMSO-d6 ) ppm: 7.23 (t, 1H, thienyl proton), 7.40
(d, 1H, thienyl proton), 7.45–7.60, 8.28 (two, d, 4H, 4-chlorophenyl),
7.73 (d, 1H, thienyl proton), 7.97 (s, 1H, pyridine proton), 12.15, 13.00
(two br, s, NH, D2O exchangeable).
8-(4-Chlorophenyl)-6-Aryl-2-arylmethylene-2,3,4,5-
tetrahydrothiazolo[3,2-a]pyrido[2,3-d]pyrimidine-3,5-
Dione (7a--e)
General Procedure
Method A: A mixture of compound 6 (10 mmol), the appropriate aro-
matic aldehyde (10 mmol), and (1.64 g, 20 mmol) of anhydrous sodium
acetate was stirred under reflux in glacial acetic acid (30 ml) and acetic
anhydride (15 ml) for 2 h. The reaction mixture was allowed to cool to

52
A. B. A. El-Gazzar et al.
room temperature and poured into cold water (100 ml). The deposited
precipitate was filtered off, and crystallized from appropriate solvent to
produce 7a–e.
Method B: A mixture of compound 8a (4.06 g, 10 mmol), benzalde-
hyde (1.06 g, 10 mmol), and (1.64 g, 20 mmol) of anhydrous sodium
acetate was stirred under reflux in glacial acetic acid (30 ml) and acetic
anhydride (15 ml) for 3 h. The reaction mixture was allowed to cool to
room temperature and poured into cold water (100 ml). The deposited
precipitate was filtered off and crystallized from DMF to produced 7a.
8-(4-Chlorophenyl)-6-phenyl-2-phenylmethylene-2,3,4,5-tetrahydro-
thiazolo[3,2-a]pyrido[2,3-d]pyrimidine-3,5-dione (7a). From compound
6a (3.66 g, 10 mmol) and benzaldehyde (1.06 g, 10 mmol). The com-
pound was obtained as a yellow powder, crystallized from dioxane/DMF
(1:1); m.p. 273–275 C (dec.) in 68% yield; (C28H16ClN3O2S) (493.9). IR
(KBr) cm 1: 1681, 1678 (2 C O), 1662 (C N); 1H NMR (DMSO-d6 )
ppm: 7.38–7.65 (m, 10H, two phenyl protons), 7.71 (d, 2H), 7.80 (s,
1H, methylenic proton), 7.98 (s, 1H, pyridine proton), 8.31 (d, 2H).
8-(4-Chlorophenyl)-2-(4-chlorophenyl methylene)-6-phenyl-2, 3, 4, 5-
tetrahydrothiazolo[3,2-a]pyrido[2,3-d]pyrimidine-3,5-dione (7b). From
compound 6a (3.66 g, 10 mmol) and 4-chlorobenzaldehyde (1.41 g,
10 mmol). The compound was obtained as a yellow powder, crystallized
from DMF; m.p. 332–335 C (dec.) in 71% yield; (C28H15Cl2N3O2S)
(528.4). IR (KBr) cm 1: 1693, 1684 (2 C O), 1661 (C N); 1H NMR
(DMSO-d6 ) ppm: 7.40–7.55 (m, 5H, phenyl proton), 7.65–7.70 (two,
d, 4H), 7.78 (s, 1H, methylenic proton), 7.97 (s, 1H, pyridine proton),
8.25–8.35 (two, d, 4H).
8-(4-Chlorophenyl)-2-phenylmethylene-6-(2-thienyl)-2,3,4,5-tetrahy-
drothiazolo[3,2-a]pyrido[2,3-d]pyrimidine-3,5-dione (7c). From com-
pound 6b (3.72 g, 10 mmol) and benzaldehyde (1.06 g, 10 mmol). The
compound was obtained as a pale yellow crystals, crystallized from diox-
ane/DMF (1:1); m.p. 293–295 C (dec.) in 56% yield; (C26H14ClN3O2S2)
(499.9). IR (KBr) cm 1: 1691, 1685 (2 C O), 1659 (C N); 1H NMR
(DMSO-d6) ppm: 7.21 (t, 1H, thienyl proton), 7.40–7.56 (m, 6H, 5H
phenyl + 1H thienyl), 7.63 (d, 2H), 7.71 (d, 1H, thienyl proton), 7.73 (s,
1H, methylenic proton), 7.96 (s, 1H, pyridine proton), 8.26 (d, 2H).
8-(4-Chlorophenyl)-2-(4-chlorophenylmethylene)-6-(2-thienyl)-2,3,4,
5-tetrahydrothiazolo[3,2-a]pyrido[2,3-d]pyrimidine-3,5-dione (7d).
From compound 6b (3.72 g, 10 mmol) and 4-chlorobenzaldehyde
(1.41 g, 10 mmol). The compound was obtained as a yellow powder,
crystallized from DMF; m.p. 318–321 C (dec.) in 63% yield;

Thiazolo Pyrimidinones
53
(C26H13Cl2N3O2S2) (534.4). IR (KBr) cm 1: 1689, 1681 (2 C O),
1
1654 (C N); H NMR (DMSO-d6 ) ppm: 7.22 (t, 1H, thienyl proton),
7.42 (d, 1H, thienyl proton), 7.58–7.63 (two, d, 4H), 7.72, (d, 1H, thienyl
proton), 7.79 (s, 1H, methylenic proton), 7.95 (s, 1H, pyridine proton),
8.21 (d, 2H), 8.28 (d, 2H).
8-(4-Chlorophenyl)-2-(4-tolyl)-6-phenyl-2,3,4,5-tetrahydrothiazolo[3,
2-a]pyrido[2,3-d]pyrimidine-3,5-dione (7e). From compound 6a (3.66 g,
10 mmol) and 4-methylbenzaldehyde (1.20 g, 10 mmol). The compound
was obtained as a yellow crystals, crystallized from DMF; m.p. 328–
1
330 C (dec.) in 81% yield; (C29H18ClN3O2S) (507.9). IR (KBr) cm
:
1
1695, 1688 (2 C O), 1667 (C N); H NMR (DMSO-d6) ppm: 2.65 (s,
3H, CH3), 7.38–7.52 (m, 7H, 5 phenyl proton + 2H(4-sub)), 7.62 (d,
2H), 7.69 (s, 1H, methylenic proton), 7.93 (s, 1H, pyridine proton), 8.09
(d, 2H), 8.28 (d, 2H); Mass (70 ev) m/z (%): 507.2 (M+, Cl35, 100), 509.2
(M+, Cl37, 29.8), 478 (7), 365 (10), 332 (46).
8-(4-Chlorophenyl)-2,3-dihydro-6-phenyl or (2-thienyl)-
5H-thiazolo[3,2-a]pyrido[2,3-d]pyrimidine-3,5-dione
(8a,b)
General Procedure
A mixture of compound 6a,b (10 mmol), chloroacetic acid (0.95 g,
10 mmol), and (1.64 g, 20 mmol) anhydrous acetate was gently heated
with stirring on a waterbath (60 C) for 2 h. The reaction mixture was
allowed to cool to room temperature and poured into water (100 ml).
The deposited precipitate was filtered off and crystallized from dioxane
to produce 8a,b respectively.
8-(4-Chlorophenyl)-2,3-dihydro-6-phenyl-5H-thiazolo[3,2-a]pyrido-
[2,3-d] pyrimidine-3,5-dione (8a). From compound 6a (3.66 g,
10 mmol). The compound was produced as a white powder, crys-
tallized from dioxane in 49%; m.p. 214–216 C (dec.); (C21H12ClN3O2S)
(405.8). IR (KBr) cm 1: 1703, 1689 (2 C O), 1668 (C N); 1H NMR
(DMSO-d6 ) ppm: 3.62 (s, 2H, CH2), 7.40–7.50 (m, 5H, phenyl proton),
7.60 (d, 2H), 7.95 (s, 1H, pyridine proton), 8.30 (d, 2H).
8-(4-Chlorophenyl)-2,3-dihydro-6-(2-thienyl)-5H-thiazolo[3,2-a]pyr-
ido[2,3-d]pyrimidine-3,5-dione (8b). From compound 6b (3.72 g,
10 mmol). The compound was produced as a yellow crystals, crystal-
lized from dioxane in 47%; m.p. 239–241 C (dec.); (C19H10ClN3O2S2)
(411.8). IR (KBr) cm 1: 1708, 1689 (2 C O), 1658 (C N); 1H NMR
(DMSO-d6 ) ppm: 3.63 (s, 2H, CH2), 7.21 (t, 1H, thienyl proton), 7.41

54
A. B. A. El-Gazzar et al.
(d, 1H, thienyl proton), 7.65 (d, 2H), 7.72 (d, 1H, thienyl proton), 7.98
(s, 1H, pyridine proton), 8.27 (d, 2H).
7-(4-Chlorophenyl)-3-phenyl or (4-chlorophenyl)-
9-phenyl-2,3-dihy-dro-isoxazolo[50 ,40 : 4,5]thiazolo-
[3,2-a]pyrido[2,3-d]pyrimidin-10(10H)-one (9a,b)
General Procedure
A mixture of compound 7a,b (10 mmol), hydroxylamine hydrochlo-
ride (0.70 g, 10 mmol) and (1.64 g, 20 mmol) anhydrous acetate was
stirred under reflux in glacial acetic acid (30 ml) for 5 h. The reaction
mixture was allowed to cool to room temperature and poured into cold
water (100 ml). The deposited precipitate was filtered off, dried, and
crystallized from appropriate solvent to produce 9a,b.
7-(4-Chlorophenyl)-3,9-diphenyl-2,3-dihydroisoxazolo[50,40: 4,5]-thi-
azolo[3,2-a]pyrido[2,3-d]pyrimidin-10(10H)-one (9a). From compound
7a (4.94 g, 10 mmol). The compound was produced as a colorless
crystals, crystallized from benzene in 61% yield; m.p. 317–319 C (dec.);
(C28H17ClN4O2S) (508.9). IR (KBr) cm 1: 3219 (NH), 1689 (C O),
1659 (C N); 1H NMR (DMSO-d6 ) ppm: 6.45 (s, 1H, isoxazoloproton),
7.30–7.50 (m, 10H, two phenyl proton), 7.58 (d, 2H), 7.94 (s, 1H,
pyridine proton), 8.25 (d, 2H), 11.25 (br, s, NH).
3,7-Di(4-chlorophenyl)-9-phenyl-2,3-dihydroisoxazolo[50,40:4,5]-thia-
zolo [3, 2-a]pyrido[2, 3-d] pyrimidin-10 (10H)-one (9b). From compound
7b (5.28 g, 10 mmol). The compound was produced as a colorless
crystals, crystallized from cyclohexane in 58% yield; m.p. 307–309 C
(dec.); (C28H16Cl2N4O2S) (543.4). IR (KBr) cm 1: 3228 (NH), 1686
(C O), 1653 (C N); 1H NMR (DMSO-d6 ) ppm: 6.42 (s, 1H, isoxazole
proton), 7.32–7.50 (m, 5H, phenyl), 7.61 (two, d, 4H), 7.97 (s, 1H,
pyridine proton), 8.11 (d, 2H), 8.27 (d, 2H), 10.58 (br, s, NH).
2-(S-Alkyl)-5-Phenyl-7-(4-Chlorophenyl)-3H,4H-pyrido[2,
3-d]-pyrimidin-4-one (10a--e)
General Procedure
To a warmed ethanolic potassium hydroxide solution (prepared by
dissolving 0.56 g, 10 mmol of potassium hydroxide in 50 ml ethanol)
was added each of compound 6a (3.66 g, 10 mmol), the heating was con-
tinued for 30 min, then the mixture was allowed to cool to room tem-
perature and the proper halo-compound (10–12 mmol) was added. The
mixture was stirred under reflux for 5 h, then cool to room temperature
and poured into cold water (100 ml). The solid produced so-precipitated
was filtered off and washed with (100 ml) water; the product was

Thiazolo Pyrimidinones
55
dried and crystallized from appropriate solvent to produce (10a–e)
respectively.
7-(4-Chlorophenyl)-2-methylthio-5-phenyl-3H,4H-pyrido[2,3-d]pyri-
midin-4-one (10a). From compound 6a (3.66 g, 10 mmol) and methyl
iodide (1.72 g, 12 mmol). The compound was obtained as a white
crystals, crystallized from dioxane in 87%; m.p. 273–275 C (dec.);
(C20H14ClN3OS) (379.8). IR (KBr) cm 1: 3220 (NH), 1689 (C O), 1657
1
(C N); H NMR (DMSO-d6 ) ppm: 3.45 (s, 3H, SCH3), 7.30–7.50 (m,
5H, phenyl proton), 7.65 (d, 2H), 7.75 (s, 1H, pyridine proton), 8.30 (d,
2H), 12.60 (br, s, NH, D2O exchangeable). Mass; (70 ev) m/z (%): 379.1
(M+, Cl35, 100), 381.1 (M+, Cl37, 48.7), 332 (M+ SMe, 9), 304 (M+
2 C6H5, 65).
+
2-(Acetylacetonethio)-7-(4-chlorophenyl)-5-phenyl-3H,4H-pyrido[2,3-
d]pyrimidin-4-one (10b). From compound 6a (3.66 g, 10 mmol) and
chloroacetylacetone (1.61 g, 12 mmol). The compound was obtained
as a white powder, crystallized from dioxane in 81%; m.p. 206–208 C
(melted); (C24H18ClN3O3S) (463.9). IR (KBr) cm 1: 3301 (br, NH),
1743 (br, 2 C O), 1682 (C O), 1654 (C N); Mass; (70 ev) m/z (%):
463 (M+, 7), 421 (M+ + 1-CH3CO, 100), 378 (M+-2 COCH3, 78%), 332
(M+-SCH(COCH3)2, 15%).
2-[S-(N-4-Chlorophenylacetamido)]-7-(4-chlorophenyl)-5-phenyl-3H,
4H-pyrido[2,3-d]pyrimidin-4-one (10c). From compound 6a (3.66 g,
10 mmol) and 4-chloroacetanilide-2-chloride (2.04 g, 10 mmol). The
compound was obtained as a white powder, crystallized from dioxane in
1
68%; m.p. 267–269 C (dec.); (C27H18Cl2N4O2S) (497.8). IR (KBr) cm
:
1693, 1689 (2 C O), 1658 (C N); 1H NMR (DMSO-d6 ) ppm: 3.32 (br,
s, NH, D2O exchangeable), 3.65 (s, 2H, CH2), 7.35–7.50 (m, 5H, phenyl
proton), 7.65 (two mixed doublet, 4H), 7.82 (s, 1H, pyridine proton),
8.25 (two mixed doublet, 4H), 10.46 (br, s, NH, D2O exchangeable).
2-Acetylthio-7-(4-chlorophenyl)-3H,4H-pyrido[2,3-d]pyrimidin-4-one
(10d). From compound 6a (3.66 g, 10 mmol) and chloroacetone (0.93 g,
10 mmol). The compound was obtained as a colorless crystals, crystal-
lized from dioxane in 54%; m.p. 214–216 C (melted.); (C22H16ClN3O2S)
1
(421.9). IR (KBr) cm 1: 1720,, 1687 (2 C O), 1659 (C N); H NMR
(DMSO-d6 ) ppm: 2.32, (s, 3H, CH3), 3.61 (s, 2H, CH2), 7.33–7.52 (m,
5H, phenyl proton), 7.67 (d, 2H), 7.78 (s, 1H, pyridine proton), 12.70
(br, s, NH, D2O exchangeable).
7-(4-Chlorophenyl)-2-phenacylthio-5-phenyl-3H,4H-pyrido[2,3-d]py-
rimidin-4-one (10e). From compound 6a (3.66 g, 10 mmol) and
phenacylbromide (1.99 g, 10 mmol). The compound was obtained as a
white powder, crystallized from dioxane in 46% yield; m.p. 116–118 C

56
A. B. A. El-Gazzar et al.
(melted.); (C27H18ClN3O2S) (483.9). IR (KBr) cm 1: 1719, 1688 (2
C O), 1657 (C N); 1H NMR (DMSO-d6 ) ppm: 3.65 (s, 2H, CH2),
7.40–7.55 (m, 10H, two phenyl proton), 7.63 (d, 2H), 7.72 (s, 1H,
pyridine proton), 7.80 (s, NH, D2O exchangeable), 8.28 (d, 2H).
7-(4-Chlorophenyl)-2-hydrazino-3H,4H-pyrido[2,3-d]pyrimidin-4-
one (11). A suspension of compound 10a (3.80 g, 10 mmol) in hydrazine
hydrate (99%; 10 ml) was stirred under gentle reflux. The insoluble
solid went into solution within 10 min with copious evolution of
methylmercaptan to form a clear solution. After 30 min, when the
solid product started separating out, heating continued for 4 h and
the reaction mixture was allowed to cool to room temperature. The
solid that separated was filtered, washed with ethanol, dried, and
crystallized from dioxane/DMF (1:1) to produce a white powder in
83% yield; m.p. 313–315 C (melted.); (C19H14ClN5O) (363.8). IR (KBr)
1
cm 1: 3290 (br, NH), 1689 (C O), 1658 (C N); H NMR (DMSO-d6 )
ppm: 3.31 (br, NH, D2O exchangeable), 7.36–7.54 (m, 5H, phenyl
proton), 7.61 (d, 2H), 7.89 (s, 1H, pyridine proton), 8.28 (d, 2H), 10.28
(br, s, NH, D2O exchangeable).
7-(4-Chlorophenyl)-2-(4-substituted phenylamino)-3H,4H-pyrido[2,
3-d]pyrimidin-4-one (12a,b).
General Procedure
A mixture of compound 10a (3.80 g, 10 mmol) and substituted aniline
(10 mmol) was heated at 140 C in a test tube on sand bath for 6 h. The
mixture was allowed to cool to room temperature. The product was
solidified by cooling and addition methanol (50 ml). The precipitate
was collected by filtration and crystallized from the proper solvent to
produce 12a,b.
7-(4-Chlorophenyl)-2-(4-chlorophenylamino)-3H,4H-pyrido[2,3-d]
pyrimidin-4-one (12a). From 10a (3.80 g, 10 mmol) and 4-chloroaniline
(1.28 g, 10 mmol). The compound was obtained as a white pow-
der, crystallized from dioxane in 63% yield, m.p. 352–354 C (dec.);
(C25H16Cl2N4O) (459.3). IR (KBr) cm 1: 3235 (NH), 1679 (C O), 1659
1
(C N); H NMR (DMSO-d6 ) ppm: 7.38–7.56 (m, 5H, phenyl proton),
7.63 (d, 2H), 7.69 (d, 2H), 7.96 (s, 1H, pyridine proton), 8.18 (d, 2H),
8.26 (d, 2H), 9.58, 10.63 (two, br, s, NH, D2O exchangeable). Mass;
(70 ev) m/z (%): 458 (M+ H, 7), 379.1 [(M+-2)-C6H5, Cl35, 100], 381
[(M+-2)-C6H, Cl,37, 40], 350 [(M+-2)-(C6H5 + CO), 21].
7-(4-Chlorophenyl)-2-(4-nitrophenylamino)-3H,4H-pyrido[2,3-d]pyr-
imidin-4-one (12b). From 10a (3.80 g, 10 mmol) and 4-nitroaniline
(1.38 g, 10 mmol). The compound was obtained as a white powder,

Thiazolo Pyrimidinones
57
crystallized from dioxane in 67% yield, m.p. 325–327 C (dec.);
(C25H16ClN5O3) (469.8). IR (KBr) cm 1: 3243 (NH), 1683 (C O), 1657
1
(C N); H NMR (DMSO-d6 ) ppm: 7.43–7.58 (m, 5H, phenyl proton),
7.62 (d, 2H), 7.68 (d, 2H), 7.98 (s, 1H, pyridine proton), 8.21 (d, 2H),
8.29 (d, 2H), 9.36, 10.89 (two, br, s, NH, D2O exchangeable). Mass;
(70 ev) m/z (%): 469 (M+, 35), 393 (M+-C6H5, 42), 359 (M+-C6H5Cl,
100).
2-Acetyl-8-(4-chlorophenyl)-3-methyl-6-phenyl-5H-
thiazolo[3,2-a]pyrido[2,3-d]pyrimidin-5-one (13)
A solution of compound 10b (4.64, 10 mmol) in a mixture of
acetic anhydride-pyridine (20:10) ml was stirred under reflux for
3 h. The reaction mixture was allowed to cool to room temper-
ature, then poured into cold water (100 ml). The deposited pre-
cipitate was filtered off, dried, and crystallized from dioxane. The
compound was obtained as a light pale green crystals in 69%
yield; m.p. 173–175 C (melted); (C24H16ClN5O2S) (445.9). IR (KBr)
cm 1: 1729, 1689 (2 C O), 1663 (C N); 1H NMR (DMSO-d6 ) ppm:
2.60 (s, 3H), 2.85 (s, 3H), 7.35–7.50 (m, 5H, phenyl proton), 7.60
(d, 2H), 7.80 (s, 1H, pyridine proton), 8.30 (d, 2H). Mass; (70 ev) m/z
(%): 445.1 (M+, Cl35, 100), 447.1 (M+, Cl37, 37.6), 402 (M+ COCH3, 14),
363 (M+-C5H6O, 40).
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