Preparation and reactions of 2-methyl-7-(3-methyl-5-oxo-1-phenyl-2- pyrazolin-4-yl)-5-arylthiazolo[3,2-a]-pyrimido[4,5-d]oxazin-4(5H)-one

Article abstract of DOI:10.1002/cjoc.201180268

Ethyl 7-amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-aryl-5H- thiazolo[3,2-a]pyrimidine-6-carboxylate was hydrolyzed with an ethanolic sodium hydroxide and the sodium salt thus formed underwent cyclization with acetic anhydride to afford 2-methyl-7-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5- arylthiazolo[3,2-a]pyrimido[4,5-d]oxazin-4(5H)-one. This compound was transformed to related heterocyclic systems via its reaction with various reagents. The biological activity of the prepared compounds was tested against Gram positive and Gram negative bacteria as well as yeast-like and filamentous fungi. They revealed in some cases excellent biocidal properties. Copyright

Full text of DOI:10.1002/cjoc.201180268

FULL PAPER
Preparation and Reactions of 2-Methyl-7-(3-methyl-5-oxo-1-
phenyl-2-pyrazolin-4-yl)-5-arylthiazolo[3,2-a]-
pyrimido[4,5-d]oxazin-4(5H)-one
Youssef, Mohamed Salah K.*
Ahmed, Ragaa A.
Abbady, Mohamed S.
Omar, Ahmed A.
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Ethyl 7-amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-aryl-5H-thiazolo[3,2-a]pyrimidine-6-carboxy-
late was hydrolyzed with an ethanolic sodium hydroxide and the sodium salt thus formed underwent cyclization
with acetic anhydride to afford 2-methyl-7-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-arylthiazolo[3,2-a]-
pyrimido[4,5-d]oxazin-4(5H)-one. This compound was transformed to related heterocyclic systems via its reaction
with various reagents. The biological activity of the prepared compounds was tested against Gram positive and
Gram negative bacteria as well as yeast-like and filamentous fungi. They revealed in some cases excellent biocidal
properties.
Keywords thiazolopyrimidooxazinone, thiazolopyrimidopyrimidines, antimicrobial activity
Introduction
oxo-1-phenyl-2-pyrazolin-4-yl)-6-oxo-5-aryl-7,8-
dimethyl-5H-thiazolo[3,2-a] pyrimido[4,5-d]pyrimidine
(4a, 4b) and 3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-
yl)-6-oxo-5-aryl-7-phenyl-8-methyl-5H-thiazolo[3,2-
a]pyrimido[4,5-d]pyrimidine (5a, 5b) were achieved
upon refluxing with ammonium acetate, methyl amine
and aniline respectively.
Oxazine derivatives played an important role in
synthesis of heterocyclic compounds1-12 such as pyri-
dooxazinone, pyridopyridazine, triazolopyridopyrid-
azines, pyrimidinone, thiopyrimidinone, triazinone,
oxazinoquinolinone, oxazino-, pyrano-, pyridopyr-
imidine, naphtho[2',3':4,5]thieno[2,3-d] oxazine, and
Condensation of 5a, 5b with benzaldehyde or
p-chlorobenzaldehyde in ethanol with few drops of
piperidine gave 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-oxo-5-aryl-7-phenyl-8-benzylidene
methyl-5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
(6a, 6b) or 3-(3-methyl-5-oxo-1-phenyl-2-pyrazo-lin-4-
yl)-6-oxo-5-aryl-7-phenyl-8-p-chlorobenzylidene-
methyl-5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
(7a, 7b) respectively. Refluxing of 2a, 2b with
thiosemicarbazide or ethyl glycinate hydrochloride
yielded 3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-
6-oxo-5-aryl-7-thioureido-8-methyl-5H-thiazolo[3,2-a]-
pyrimido[4,5-d]pyrimidine (8a, 8b) or 3-(3-methyl-5-
oxo-1-phenyl-2-pyrazo-lin-4-yl)-6-oxo-5-aryl-7-car-
boxymethyl-8-methyl-5H-thiazolo[3,2-a]pyrimido[4,5-
d]pyrimidine (9a, 9b) respectively. Reaction of 2a, 2b
with hydrazine hydrate afforded 3-(3-methyl-5-oxo-
1-phenyl-2-pyrazolin-4-yl)-6-oxo-5-aryl-7-amino-8-
methyl-5H-thiazolo[3,2-a]-pyrimido[4,5-d]pyrimidine
(10a, 10b).
pyrimido[5',4':4,5]pyrrolo[2,4-c]oxazine
derivatives.
They have received considrable attention of the chemists
due to their herbicidal11 and antimicrobial activity.10,12
Therefore, the aim of this study was to investigate the
synthetic utility of an oxazinone derivative to prepare
some new heterocycles and study their biological acti-
vities as antimicrobial agents.
Results and discussion
The target compounds 2a, 2b were prepared via
saponification of ethyl 7-amino-3-(3-methyl-5-oxo-1-
phenyl-2-pyrazolin-4-yl)-5-aryl-5H-thiazolo[3,2-a]pyri-
midine-6-carboxylate (1a, 1b)13,14 with an ethanolic so-
dium hydroxide solution to form sodium salt of the cor-
responding acid. This compound underwent ring closure
upon treatment with acetic anhydride to afford the
oxazinone derivative (2a, 2b). The transformation of the
latter compound into the corresponding pyrmidinone
derivative 3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-
yl)-6-oxo-5-aryl-5,7-dihydro-8-methylthiazolo[3,2-a]-
pyrimido[4,5-d]-pyrimidine (3a, 3b), 3-(3-methyl-5-
The reactivity of 3-amino group in 10a, 10b was
tested by reaction with p-nitrobenzaldehyde or
phenylisothiocyanate to give the corresponding
*
E-mail: salah_kamel2000@yahoo.com
Received October 14, 2010; revised December 6, 2010; accepted March 11, 2011.
Chin. J. Chem. 2011, 29, 1473— 1482
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Youssef et al.
FULL PAPER
derivative 3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-
yl)-6-oxo-5-aryl-7-phenylthioureado-8-methyl-5H-
thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (11a, 11b) or
3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-oxo-5-
aryl-7-p-nitrobenzylideneamino-8-dimeth-yl-5H-thiazo-
lo[3,2-a]pyrimido[4,5-d]pyrimidine (12a, 12b) (Scheme
1).
Chlorination of 2a, 2b was successfully attempted
by interaction with excess of phosphorus oxychloride to
give 6-chloro-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-aryl-8-methyl-5H-thiazolo[3,2-a]pyrimido[4,5-
d]pyrimidine (13a, 13b).
rivative can be seen from reaction with aniline, thio-
phenol, thiourea and/or methylamine giving the corre-
sponding 6-substituted thiazolo[3,2-a]-pyrimido-
[4,5-d]pyrimidine derivatives 14a, 14b, 15a, 15b, 16a,
16b and/or 18a, 18b. Methylation of compound 16a,
16b with methyl iodide in ethanol containing fused
sodium acetate afforded the corresponding methylthio
derivative, 3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-
yl)-5-aryl-6-methylmercapto-8-methyl-5H-thiazolo[3,2-
a]pyrimido[4,5-d]pyrimidine (17a, 17b) (Scheme 2).
All prepared compounds were elucidated by ele-
mental analyses, IR, 1H NMR, 13C NMR as well as mass
spectra.
The scope and synthetic utility of the 6-chloro de-
Scheme 1
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Chin. J. Chem. 2011, 29, 1473— 1482

Preparation and Reactions
Scheme 2
The biological activity of the synthesized compounds
was tested against Gram positive and Gram negative
bacteria (Table 1) as well as yeast-like and filamentous
fungi (Table 2). All microbes are potentially pathogenic
especially for debilitated, malnourished or immuno-
compromised individuals. Different compounds showed
varying antimicrobial action depending on the microor-
ganism species. Compounds 4b, 9b, 10b and 11b
proved to be excellent candidates as antibacterial agents
being able to inhibit all bacterial species tested. Other
compounds showed narrow spectrum of antibacterial
activity. Staphylococcus aureus was the most sensitive
to compounds 7a and 10a, Serratia marcescens to
compound 9b, Bacillus cereus to compounds 3a, 4b, 6b
and 10a, and Escherichia coli to compounds 3b, 8a, 9a
and 10a.
On the other hand compounds 4a, 4b, 5b, 6b, 9b,
10a, 10b, 11b, 12b and 13a were markedly inhibitory to
most or all tested fungi. Geotrichum candidum (fre-
quently reported to cause geotrichosis in humans and
animals) was the most sensitive to compounds 6b, 7a,
9b and 10a, Candida albicans (cause of candidiasis in
humans and animals) to compounds 6b, 9b, 10a and 13a,
Scopulariopsis brevicaulis (often reported as a cause of
nail infections) to compounds 6b, 9b and 10a. Tricho-
phyton rubrum (usually involved in skin and nail infec-
tions) to compounds 9b and 10a, Fusarium oxysporum
(cause of wilt diseases in many crop plants) to com-
pounds 6b and 10a and Aspergillus flavus (a famous
allergic, pathogenic and toxigenic fungus) to compound
9b (Table 2).
Experimental
All melting points were determined on APP Digital
ST 15 melting point apparatus and are uncorrected.
Elemental analyses (C, H, N, S) were conducted using a
Vario EL C, H, N, S Analyzer. The IR spectra were ob-
tained on a Pye-Unicam SP3-100 spectrophotometer
1
using the KBr disc technique. H NMR spectra were
1
recorded on EM 90 NMR and a varian H-Gemini 400
spectrometer with chemical shifts expressed in δ using
TMS as the internal reference. 13C NMR spectra were
1
obtained on a varian H-Gemini 400 spectrometer. The
mass spectra (EI＝70 eV) were run on JOEL JMS 600
spectrometer.
General procedure for preparation of 2-methyl-7-(3-
methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-arylthia-
zolo[3,2-a]pyrimido[4,5-d]oxazin-4(5H)-one (2a, 2b)
A mixture of ethyl 7-amino-3-(3-methyl-5-oxo-
1-phenyl-2-pyrazolin-4-yl)-5-aryl-5H-thiazolo[3,2-a]-
pyrimidine-6-carboxylate 1a, 1b (10 mmol) and ethano-
lic sodium hydroxide (50 mL, 4%) was refluxed for 1 h.
The precipitated sodium salt was washed with
Chin. J. Chem. 2011, 29, 1473— 1482
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Youssef et al.
FULL PAPER
Table 1 The minimum inhibitory concentrations of the com-
Table 2 The Minimum inhibitory concentrations of the com-
pounds tested against bacteria (mg/mL)
pounds tested against fungi (mg/mL)
Bacteria
Compd.
Fungi
Compd.
G.
C.
F.
A.
S.
T.
B. cereus S. aureus P. aeruginosa S. marcescens E. coli
candidum albicans oxysporum flavus brevicaulis rubrum
2a
—
5
—
—
—
—
—
2.5
—
—
—
2.5
0.6
—
5
—
—
—
—
—
5
—
—
—
—
—
1.25
—
—
—
—
—
—
—
—
—
0.6
—
2.5
—
5
—
—
2.5
0.3
—
1.25
—
—
20
20
2.5
—
0.3
—
0.6
5
—
2.5
—
—
—
—
—
—
20
20
20
20
—
—
—
—
—
—
5
—
5
2a
2b
2b
2.5
20
20
20
2.5
—
—
20
—
—
20
20
10
10
—
3a
0.3
—
5
3a
20
—
—
3b
3b
—
10
4a
4a
20
4b
0.6
10
5
4b
2.5
2.5
10
5
5a
—
—
—
—
—
—
—
—
—
5
5a
20
20
—
—
20
—
5b
5b
6a
—
0.6
1.25
10
5
6a
—
20
6b
6b
1.25
1.25
10
1.25
2.5
5
1.25
20
—
—
—
1.25
2.5
20
—
—
20
—
7a
—
—
—
—
—
—
7a
7b
7b
20
—
20
—
8a
8a
—
2.5
20
8b
2.5
—
10
0.6
5
—
—
5
8b
—
20
20
9a
—
9a
—
9b
9b
1.25
1.25
5
1.25
0.6
10
5
2.5 1.25
1.25
1.25
20
10a
10b
11a
11b
12a
12b
13a
13b
0.08
2.5
—
2.5
—
—
1.25
—
—
5
0.6
2.5
2.5
5
10a
10b
11a
11b
12a
12b
13a
13b
1.25
20
—
5
1.25
—
20
—
—
1.25
10
2.5
2.5
—
—
20
—
—
—
—
—
—
—
—
5
5
20
20
10
5
20
20
5
—
—
—
—
—
—
—
—
—
—
—
10
20
2.5
2.5
—
10
2.5
1.25
—
20
—
20
20
10
10
5
—
0.3
20
0.3
Ref.a 0.04
0.2
2.5
0.3
0.08
Ref.a 0.3
0.3
1.25 0.3
a Ref.: Reference drugs (chloramphenicol). (—): No antimicrobial
action.
a
Ref.: Reference drugs (chloramphenicol as antibacterial and
clotrimazole as antifungal). (—): No antimicrobial action.
alcohol and dried. The corresponding salts of acids (5
mmol) with acetic anhydride (20 mL) were refluxed for
3 h. On cooling, the precipitate solid product was fil-
tered off, dried and crystallized from the proper solvent.
2-Methyl-7-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-phenylthiazolo[3,2-a]pyrimido[4,5-d]oxazin-
4(5H)-one (2a) Yellow crystals (69%, EtOH); m.p.
(469.52): C 63.95, H 4.08, N 14.92, S 6.83; found C
63.78, H 3.91, N 14.76, S 6.91.
2-Methyl-7-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-p-chlorophenylthiazolo[3,2-a]pyrimido[4,5-
d]oxazin-4(5H)-one (2b) Pale yellow powder (67%,
benzene); m.p. 210—212 ℃; 1H NMR (CDCl3, 90 MHz)
δ: 2.30 (s, 3H, pyrazolone-CH3), 3.40 (s, 3H, oxazine-
CH3), 7.11 (s, 1H, pyrazolone-H), 7.20 (s, 1H,
pyrimidine-H), 7.35 (s, 1H, thiazole-H), 7.50—7.95 (m,
9H, aromatic protons); IR (KBr) ν: Disappearance of NH2
group, 2990 (CH aliphatic), 1725 (CO oxazine), 164＋0
1
200—201 ℃; H NMR (CDCl3, 400 MHz) δ: 2.20 (s,
3H, pyrazolone-CH3), 3.33 (s, 3H, oxazine-CH3), 6.71 (s,
1H, pyrazolone-H), 6.80 (s, 1H, pyrimidine-H), 7.12 (s,
1H, thiazole-H), 7.25—7.45 (m, 5CH aromatic), 7.61—
7.84 (m, 5CH aromatic); 13C NMR (CDCl3, 400 MHz) δ:
14 (CH3 pyrimidine), 18 (CH3 pyrazolone), 45 (CH
pyrimidine), 50 (CH pyrazolone), 89 (CH thiazole), 142
—124 (C and CH aromatic rings), 154 (C thiazole), 155
(C＝N pyrazolone), 159 and 103 (C＝C pyrimidine),
161 (C＝N pyrimidine), 164 (C＝N pyrimidine), 167 (C
＝O pyrimidine), 170 (CO pyrazolone); IR (KBr) ν:
Disappearance of NH2 group, 2990 (CH aliphatic), 1720
－1
(CO pyrazolone) cm ; MS (70 eV) m/z (%): 503.51 (M ,
21), 505.42 (M＋2, 9). Anal. calcd for C25H18N5O3SCl
(503.96): C 59.58, H 3.60, N 13.90, S 6.36, Cl 7.03;
found C 59.47, H 3.50, N 13.79, S 6.21, Cl 7.25.
General procedure for preparation of 3-(3-methyl-
5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-oxo-5-aryl-5,7-
dihydro-8-methylthiazolo[3,2-a]pyrimido[4,5-d]pyri-
midine (3a, 3b)
－1
(CO oxazine),1640 (CO pyrazolone) cm ; MS (70 eV)
m/z (%): 469.21 (M＋, 32). Anal. calcd for C25H19N5O3S
A mixture of 2a, 2b (10 mmol) and ammonium ace-
1476
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1473— 1482

Preparation and Reactions
tate (10 mmol) in acetic acid (50 mL) was refluxed for 2
h. On cooling, the precipitate solid product was filtered
off, dried and crystallized from the proper solvent.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-phenyl-5,7-dihydro-8-methylthiazolo-[3,2-a]-
pyrimido[4,5-d]pyrimidine (3a) White crystals (62%,
C 64.71, H 4.60, N 17.42, S 6.65; found C 64.49, H 4.72,
N 17.30, S 6.42.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7,8-dimethyl-5H-thiazolo[3,2-
a]pyrimido[4,5-d]pyrimidine (4b)
Pale yellow
1
crystals (64%, ethanol); m.p. 256—257 ℃; H NMR
(CDCl3, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3), 3.10
(s, 3H, pyrimidine-CH3), 3.30 (s, 3H, N-CH3), 7.00 (s,
1H, pyrazolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s,
1H, thiazole-H), 7.40—7.95 (m, 9H, aromatic protons);
IR (KBr) ν: 2950 (CH aliphatic), 1680 (CO pyrimidine),
1
acetic acid); m.p. 319—321 ℃; H NMR (CDCl3, 400
MHz) δ: 2.20 (s, 3H, pyrazolone-CH3), 3.10 (s, 3H,
pyrimidine-CH3), 6.71 (s, 1H, pyrazolone-H), 6.80 (s,
1H, pyrimidine-H), 6.92 (s, 1H, thiazole-H), 7.16—7.29
(m, 5CH aromatic), 7.32—7.64 (m, 5CH aromatic);
10.00 (s, 1H, NH exchangable with D2O); 13C NMR
(CDCl3, 400 MHz) δ: 14 (CH3 pyrimidine), 18 (CH3
pyrazolone), 45 (CH pyrimidine), 50 (CH pyrazolone),
89 (CH thiazole), 142—124 (C and CH aromatic rings),
154 (C thiazole), 155 (C＝N pyrazolone), 159 and 103
(C＝C pyrimidine), 161 (C＝N pyrimidine), 164 (C＝N
pyrimidine), 166 (C ＝ O pyrimidine), 170 (CO
pyrazolone); IR (KBr) ν: 3250 (NH), 2910 (CH ali-
phatic), 1680 (CO pyrimidine), 1630 (CO pyrazolone)
－1
1640 (CO＋pyrazolone) cm ; MS (70 eV) m/z (%):
516.11 (M , 27), 518.15 (M＋2, 14). Anal. calcd for
C26H21N6O2SCl (517): C 60.40, H 4.09, N 16.26, S 6.20,
Cl 6.86; found C 60.29, H 4.29, N 16.09, S 6.31, Cl
6.97.
General procedure for preparation of 3-(3-methyl-5-
oxo-1-phenyl-2-pyrazolin-4-yl)-6-oxo-5-aryl-7-phenyl-
8-methyl-5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimi-
dine (5a, 5b)
A mixture of 2a, 2b (10 mmol) and aniline (20 mmol)
in acetic acid (50 mL) was refluxed for 2 h. The reaction
mixture was poured into ice water mixture and the pre-
cipitate solid product was filtered off, dried and crystal-
lized from the proper solvent.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5,7-diphenyl-8-methyl-5H-thiazolo[3,2-a]py-
rimido[4,5-d]pyrimidine (5a) Yellow needles (60%,
ethanol); m.p. 216—218 ℃; 1H NMR (CDCl3, 90 MHz)
δ: 2.20 (s, 3H, pyrazolone-CH3), 3.10 (s, 3H,
pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-H), 7.10 (s,
1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H), 7.40—7.95
(m, 15H, aromatic protons); IR (KBr) ν: 2940 (CH ali-
phatic), 1680 (CO pyrimidine), 1640 (CO pyrazolone)
＋
－1
cm ; MS (70 eV) m/z (%): 468.11 (M , 35). Anal.
calcd for C25H20N6O2S (468.53): C 64.09, H 4.30, N
17.94, S 6.84; found C 63.89, H 4.19, N 17.75, S 6.53.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-5,7-dihydro-8-methyl-thiazolo-
[3,2-a]pyrimido[4,5-d]pyrimidine (3b) Pale yellow
crystals (69%, acetic acid); m.p. 322—323 ℃; 1H NMR
(DMSO-d6, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3),
3.10 (s, 3H, pyrimidine-CH3), 7.00 (s, 1H,
pyrazolone-H), 7.20 (s, 1H, pyrimidine-H), 7.35 (s, 1H,
thiazole-H), 7.50—7.95 (m, 9H, aromatic protons),
10.00 (s, 1H, NH exchangable with D2O); IR (KBr) ν:
3250 (NH), 2910 (CH aliphatic), 1680 (CO pyrimidine),
－1
1630 (CO＋pyrazolone) cm ; MS (70 eV) m/z (%):
＋
－1
502.21 (M , 45), 504.30 (M＋2, 14). Anal. calcd for
C25H19N6O2SCl (502.98): C 59.70, H 3.81, N 16.71, S
6.38, Cl 7.05; found C 59.58, H 3.92, N 16.58, S 6.21,
Cl 7.24.
cm ; MS (70 eV) m/z (%): 543.32 (M , 34). Anal.
calcd for C31H24N6O2S (544.63): C 68.36, H 4.44, N
15.43, S 5.89; found C 68.46, H 4.21, N 15.23, S 5.70.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7-phenyl-8-methyl-5H-thia-
zolo[3,2-a]pyrimido[4,5-d]pyrimidine (5b) Yellow
General procedure for the synthesis of 3-(3-methyl-
5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-oxo-5-aryl-7,8-
dimethyl-5H-thiazolo[3,2-a]pyrimido[4,5-]pyrimi-
dine (4a, 4b)
1
crystals (62%, ethanol); m.p. 226—227 ℃; H NMR
(CDCl3, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3), 3.10
(s, 3H, pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-H),
7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H),
7.40—7.95 (m, 14H, aromatic protons); IR (KBr) ν:
2940 (CH aliph－atic), 1680 (CO pyrimidine), 1640 (C＋O
A mixture of 2a, 2b (10 mmol) and methylamine
solution (30 mL) was refluxed for 1 h. On cooling, the
precipitate solid product was filtered off, dried and
crystallized from the proper solvent.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-phenyl-7,8-dimethyl-5H-thiazolo[3,2-a]pyrimi-
1
pyrazolone) cm ; MS (70 eV) m/z (%): 578.21 (M ,
52), 580.2 (M＋2, 28). Anal. calcd for C31H23N6O2SCl
(579.07): C 64.30, H 4.00, N 14.51, S 5.54, Cl 6.12;
found C 64.11, H 4.20, N 14.30, S 5.32, Cl 6.32.
do[4,5-d]pyrimidine (4a)
Yellow crystals (61%,
ethanol); m.p. 251—252 ℃; 1H NMR (CDCl3, 90 MHz)
δ: 2.20 (s, 3H, pyrazolone-CH3), 3.10 (s, 3H,
pyrimidine-CH3), 3.30 (s, 3H, N-CH3), 7.00 (s, 1H,
pyrazolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H,
thiazole-H), 7.40—7.95 (m, 10H, aromatic protons); IR
(KBr) ν: 2950 (CH aliphatic), 1680 (CO pyrimidine),
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-oxo-5-aryl-7-phenyl-8-benzylidene-
methyl/p-chlorobezylidenemethyl-5H-thiazolo[3,2-a]-
pyrimido[4,5-d]pyrimidines (6a, 6b) and (7a, 7b)
An equimolar mixture of 5a, 5b (5 mmol) and ben-
zaldehyde or p-chlorobenzaldehyde (5 mmol) in ethanol
－1
1640 (CO＋ pyrazolone) cm ; MS (70 eV) m/z (%):
482.03 (M , 62). Anal. calcd for C26H22N6O2S (482.56):
Chin. J. Chem. 2011, 29, 1473— 1482
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1477

Youssef et al.
FULL PAPER
(20 mL) in presence of few drops of piperidine was re-
fluxed for 3 h. The reaction mixture was cooled and the
solid precipitate was filtered off, dried and crystallized
from the proper solvent.
carbazide (10 mmol) in acetic acid (50 mL) was re-
fluxed for 2 h. The reaction mixture was poured into ice
water mixture and the solid precipitate was filtered off,
dried and crystallized from the proper solvent.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5,7-diphenyl-8-benzylidenemthyl-5H-thiazolo-
[3,2-a]pyrimido[4,5-d]pyrimidine (6a) Orange crys-
tals (61%, ethanol); m.p. 230—231 ℃; 1H NMR
(CDCl3, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3), 7.00
(s, 1H, pyrazolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20
(s, 1H, thiazole-H), 7.40—7.95 (m, 20H, aromatic pro-
tons); 8.10 (s, 2H, 2C＝H); IR (KBr) ν: 2960 (CH ali-
phatic), 1675 (CO pyrimidine), 1635 (CO pyrazolone)
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-phenyl-7-thioureido-5H-8-methylthiazolo[3,2-
a]pyrimido[4,5-d]pyrimidine (8a) Pale yellow pow-
der (59%, toluene); m.p. 239 — 240 ℃ ; 1H NMR
(DMSO-d6, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3),
3.20 (s, 3H, pyrimidine-CH3), 5.30 (s, 2H, NH2 exchan-
gable with D2O), 7.00 (s, 1H, pyrazolone-H), 7.10 (s,
1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H), 7.30—7.80
(m, 10H, aromatic protons), 9.70 (s, 1H, NH exchan-
gable with D2O); IR (KBr) ν: 3400—3250 (NH, NH2),
2950 (CH aliph－atic), 1665 (CO pyrimidine), 1635 (C＋O
36). Anal. calcd for C26H22N8O2S2 (542.64): C 57.55, H
4.09, N 20.65, S 11.82; found C 57.65, H 3.90, N 20.46,
S 11.93.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7-thioureido-8-methyl-5H-
＋
－1
cm ; MS (70 eV) m/z (%): 632.06 (M , 68). Anal.
calcd for C38H28N6O2S (632.73): C 72.13, H 4.46, N
13.28, S 5.07; found C 72.01, H 4.27, N 13.07, S 4.91.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7-phenyl-8-benzylidenemethyl-
1
pyrazolone) cm ; MS (70 eV) m/z (%): 542.30 (M ,
5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
(6b)
Pale orange powder (59%, ethanol); m.p. 233—234 ℃;
1H NMR (CDCl3, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-
CH3), 7.00 (s, 1H, pyrazolone-H), 7.10 (s, 1H,
pyrimidine-H), 7.20 (s, 1H, thiazole-H), 7.40—7.95 (m,
19H aromatic protons), 8.10 (s, 2H, 2C＝H); IR (KBr) ν:
2955 (CH aliph－atic), 1675 (CO pyrimidine), 1635 (C＋O
thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
(8b)
1
Yellow powder (60%, toluene); m.p. 242—244 ℃; H
NMR (DMSO-d6, 90 MHz) δ: 2.20 (s, 3H, pyra-
zolone-CH3), 3.20 (s, 3H, pyrimidine-CH3), 5.30 (s, 2H,
NH2 exchangable with D2O), 7.00 (s, 1H, pyrazolone-H),
7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H),
7.40—7.80 (m, 9H, aromatic protons), 9.70 (s, 1H, NH
exchangable with D2O); IR (KBr) ν: 3400—3250 (NH,
NH2), 2950 (CH aliphatic), 1665 (CO pyrimidine), 1635
1
pyrazolone) cm ; MS (70 eV) m/z (%): 666.21 (M ,
52), 668.47 (M＋2, 16). Anal. calcd for C38H27N6O2SCl
(667.18): C 68.41, H 4.08, N 12.60, S 4.81, Cl 5.31;
found C 68.21, H 4.19, N 12.41, S 4.60, Cl 5.06.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-oxo-
5,7-diphenyl-8-p-chlorobenzylidenemethyl-5H-thia-
zolo[3,2-a]pyrimido[4,5-d]pyrimidine (7a)
－1
(CO pyrazolone) cm . Anal. calcd for C26H21N8O2S2Cl
(577.08): C 54.11, H 3.67, N 19.42, S 11.11, Cl 6.14;
found C 53.90, H 3.48, N 19.20, S 11.30, Cl 5.88.
1
Red crystals (61%, ethanol); m.p. 235—236 ℃; H
NMR (CDCl3, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3),
7.00 (s, 1H, pyrazolone-H), 7.10 (s, 1H, pyrimidine-H),
7.20 (s, 1H, thiazole-H), 7.40—7.80 (m, 19H aromatic
protons), 8.10 (s, 2H, 2C＝H); IR (KBr) ν: 2940 (CH
aliphatic), 1675 (CO pyrimidine), 1635＋(CO pyrazolone)
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-oxo-5-aryl-7-carboethoxymethyl-
8-methyl-5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimi-
dine (9a, 9b)
－1
cm ; MS (70 eV) m/z (%): 666.93 (M , 42), 668.90 (M
Ethyl glycinate hydrochloride (1.50 g, 10 mmol) and
sodium acetate (1.00 g) were refluxed in acetic acid (50
mL) for 1 h and the precipitated sodium chloride was
filtered off. The oxazinone 2a or 2b (5 mmol) was
added to ethyl glycinate solution and the reaction mix-
ture was further refluxed for 3 h. The cooled reaction
mixture was poured into ice water mixture and the solid
precipitate was filtered off and crystallized from the
proper solvent.
＋2, 13). Anal. calcd for C38H27N6O2SCl (667.18): C
68.41, H 4.08, N 12.60, S 4.81, Cl 5.31; found C 68.21,
H 4.28, N 12.41, S 4.60, Cl 5.52.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7-phenyl-8-p-chlorobenzyl-
idenemethyl-5H-thiazolo[3,2-a]pyrimido[4,5-d]pyri-
midine (7b)
Crystallized brown powder (57%,
1
ethanol); m.p. 238—239 ℃; H NMR (DMSO-d6, 90
MHz) δ: 2.20 (s, 3H, pyrazolone-CH3), 7.00 (s, 1H,
pyrazolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H,
thiazole-H), 7.40—7.80 (m, 18H aromatic protons), 8.10
(s, 2H, 2C＝H); IR (KBr) ν: 2940 (CH aliphatic), 1675
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-phenyl-7-carboethoxymethyl-8-methyl-5H-
thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
(9a)
1
White crystals (58%, ethanol); m.p. 215—217 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 1.30 (t, J＝6.60 Hz, 3H,
ethyl-CH3), 2.20 (s, 3H, pyrazolone-CH3), 3.10 (s, 3H,
pyrimidine-CH3), 4.20 (q, J＝6.60 Hz, 2H, ethyl-CH2),
5.30 (s, 2H, N-CH2-CO), 6.71 (s, 1H, pyrazolone-H),
6.80 (s, 1H, pyrimidine-H), 6.92 (s, 1H, thiazole-H),
7.06—7.14 (m, 5H aromatic), 7.24 —7.64 (m, 5H
aromatic); 13C NMR (DMSO-d6, 400 MHz) δ: 10 (CH3
ethyl), 14 (CH3 pyrimidine), 18 (CH3 pyrazolone), 35
－1
(CO pyrimidine), 1635 (CO pyrazolone) cm . Anal.
calcd for C38H26N6O2SCl2 (701.62): C 65.05, H 3.74, N
11.98, S 4.57, Cl 10.11; found C 65.16, H 3.54, N 11.74,
S 4.64, Cl 10.30.
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-oxo-5-aryl-7-thiouredo-8-methyl-
5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (8a, 8b)
A mixture of 2a, 2b (10 mmol) and thiosemi-
1478
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1473— 1482

Preparation and Reactions
(CH2 aliphatic), 45 (CH pyrimidine), 50 (CH
pyrazolone), 56 (CH2 ethyl), 89 (CH thiazole), 142—
124 (C and CH aromatic rings), 154 (C thiazole), 155 (C
＝N pyrazolone), 159 and 103 (C＝C pyrimidine), 161
(C＝N pyrimidine), 164 (C＝N pyrimidine), 166 (C＝O
pyrimidine), 170 (CO pyrazolone), 173 (CO ester); IR
(KBr) ν: 2950 (CH aliphatic), 1665 (CO pyrimidine),
3.20 (s, 3H, pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-
H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H),
7.40—7.80 (m, 9H, aromatic protons), 9.70 (s, 2H, NH2
exchangable with D2O); IR (KBr) ν: 3350—3250 (NH2),
2940 (CH alipha－tic), 1660 (CO pyrimidine), 1630 (CO
pyrazolone) cm 1. Anal. calcd for C25H20N7O2SCl
(517.99): C 57.97, H 3.89, N 18.93, S 6.19, Cl 6.84;
found C 57.79, H 3.74, N 18.74, S 5.99, Cl 6.60.
－1
1635 (CO＋pyrazolone) cm ; MS (70 eV) m/z (%):
554.11 (M , 61). Anal. calcd for C29H26N6O4S (554.62):
C 62.80, H 4.73, N 15.15, S 5.78; found C 62.98, H 4.51,
N 15.00, S 5.61.
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-oxo-5-aryl-7-phenylthioureado-8-
methyl-5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
(11a, 11b)
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7-carboethoxymethyl-8-methyl-
A mixture of 10a, 10b (5 mmol) and phenylisothio-
cyanate (0.70 g, 5 mmol) in pyridine (20 mL) was re-
fluxed for 3 h. The product thus obtained was filtered
off, dried and crystallized from the proper solvent.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-phenyl-7-phenylthioureado-8-methyl-5H-
5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
(9b)
1
White crystals (59%, ethanol); m.p. 222—224 ℃; H
NMR (DMSO-d6, 90 MHz) δ: 1.25 (t, J＝6.60 Hz, 3H,
ethyl-CH3), 2.20 (s, 3H, pyrazolone-CH3), 3.20 (s, 3H,
pyrimidine-CH3), 4.20 (q, J＝6.60 Hz, 2H, ethyl-CH2),
5.30 (s, 2H, N-CH2-CO), 7.00 (s, 1H, pyrazolone-H),
7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H),
7.40—7.80 (m, 9H, aromatic protons); IR (KBr) ν: 2950
(CH aliphatic), 1665 (CO pyrimidine), 1635 (CO
thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
(11a)
1
Yellow needles (56%, toluene); m.p. 352—353 ℃; H
NMR (CDCl3, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3),
3.20 (s, 3H, pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-
H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H),
7.30—7.80 (m, 15H aromatic protons), 10.20 (s, 1H,
NH exchangable with D2O), 10.80 (s, 1H, NH
exchangable with D2O); IR (KBr) ν: 3170 (NH), 3100
(NH), 2960 (CH aliphatic), 1660 (CO pyrimidine), 1630
－ 1
pyrazolone) cm . Anal. calcd for C29H25N6O4SCl
(589.07): C 59.13, H 4.28, N 14.27, S 5.44, Cl 6.02;
found C 58.44, H 4.07, N 14.05, S 5.20, Cl 6.30.
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-oxo-5-aryl-7-amino-8-methyl-5H-
thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (10a, 10b)
A mixture of 2a, 2b (10 mmol) and hydrazine hy-
drate (1 mL, 20 mmol) in ethanol (50 mL) was refluxed
for 2 h. The product thus formed was filtered off, dried
and crystallized from the proper solvent.
－1
(CO pyrazolone) cm . Anal. calcd for C32H26N8O2S2
(618.73): C 62.12, H 4.24, N 18.11, S 10.37; found C
62.00, H 4.02, N 17.89, S 10.10.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7-phenylthioureido-8-methyl-
5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (11b)
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-phenyl-7-amino-8-methyl-5H-thiazolo[3,2-
a]pyrimido[4,5-d]pyrimidine (10a) White needles
(62%, benzene); m.p. 307 — 309 ℃ ; 1H NMR
(DMSO-d6, 400 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3),
3.10 (s, 3H, pyrimidine-CH3), 6.71 (s, 1H, pyrazolone-
H), 6.80 (s, 1H, pyrimidine-H), 6.92 (s, 1H, thiazole-H),
7.06—7.14 (m, 5CH aromatic), 7.24—7.64 (m, 5CH
aromatic); 9.80 (s, 2H, NH2 exchangable with D2O); 13C
NMR (DMSO-d6, 400 MHz) δ: 14 (CH3 pyrimidine), 18
(CH3 pyrazolone), 45 (CH pyrimidine), 50 (CH
pyrazolone), 89 (CH thiazole), 142—124 (C and CH
aromatic rings), 154 (C thiazole), 155 (C ＝ N
pyrazolone), 159 and 103 (C＝C pyrimidine), 161 (C＝
N pyrimidine), 164 (C＝N pyrimidine), 166 (C＝O
pyrimidine), 170 (CO pyrazolone); IR (KBr) ν: 3350—
3250 (NH2), 2940 (CH aliphatic), 1660 (CO pyrimidine),
1
Yellow powder (53%, toluene); m.p. 350—351 ℃; H
NMR (DMSO-d6, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-
CH3), 3.20 (s, 3H, pyrimidine-CH3), 7.00 (s, 1H,
pyrazolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H,
thiazole-H), 7.30—7.80 (m, 14H, aromatic protons),
10.20 (s, 1H, NH exchangable with D2O), 10.80 (s, 1H,
NH exchangable with D2O); IR (KBr) ν: 3170 (NH),
3100 (NH), 2960 (CH aliphatic)－, 1660 (CO pyrimidine),
1
1630 (CO pyrazolone) cm
. Anal. calcd for
C32H25N8O2S2Cl (653.18): C 58.84, H 3.86, N 17.16, S
9.82, Cl 5.43; found C 58.61, H 3.62, N 17.01, S 9.60,
Cl 5.21.
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-oxo-5-aryl-7-p-nitrobenzylidene-
amino-8-methyl-5H-thiazolo[3,2-a]pyrimido[4,5-d]-
pyrimidine (12a, 12b)
－1
1630 (CO＋pyrazolone) cm ; MS (70 eV) m/z (%):
483.12 (M , 49). Anal. calcd for C25H21N7O2S (483.55):
C 62.10, H 4.38, N 20.28, S 6.63; found C 61.40, H 4.18,
N 20.02, S 6.41.
A mixture of 10a, 10b (5 mmol) and p-nitrobenz-
aldehyde (0.75 g, 5 mmol) in pyridine (20 mL) was re-
fluxed for 3 h. The product thus obtained was filtered
off, dried and crystallized from the proper solvent.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7-amino-8-methyl-5H-thiazolo-
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-phenyl-7-p-nitrobenzylideneamino-8-methyl-
5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (12a)
Yellow powder (61%, acetic acid); m.p. 268—270 ℃;
[3,2-a]pyrimido[4,5-d]pyrimidine (10b)
Yellow
1
powder (59%, benzene); m.p. 312—313 ℃; H NMR
(DMSO-d6, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3),
Chin. J. Chem. 2011, 29, 1473— 1482
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1479

Youssef et al.
FULL PAPER
1H NMR (CDCl3, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-
CH3), 3.20 (s, 3H, pyrimidine-CH3), 7.00 (s, 1H, pyra-
zolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thi-
azole-H), 7.40—7.80 (m, 14H aromatic protons), 7.90 (s,
1H, C＝H); IR (KBr) ν: 2940 (CH aliphatic), 1660 (CO
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-phenylamino-5-aryl-8-methyl-5H-
thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (14a, 14b)
A mixture of 13a, 13b (5 mmol) and aniline (0.50
mL, 10 mmol) in ethanol (30 mL) was refluxed for 3 h.
The cooled reaction mixture was poured into ice water
mixture whereby the product separated out. The product
was filtered off, dried and crystallized from the proper
solvent.
－1
pyrimidine), 1630 (CO pyrazolone) cm . Anal. calcd
for C32H24N8O4S (616.65): C 62.33, H 3.92, N 18.17, S
5.20; found C 62.11, H 3.73, N 18.00, S 5.41.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
oxo-5-p-chlorophenyl-7-p-nitrobenzylidene amino-
8-methyl-5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimi-
dine (12b) Yellow needles (63%, acetic acid); m.p.
276—278 ℃; 1H NMR (DMSO-d6, 90 MHz) δ: 2.20 (s,
3H, pyrazolone-CH3), 3.20 (s, 3H, pyrimidine-CH3),
7.00 (s, 1H, pyrazolone-H), 7.10 (s, 1H, pyrimidine-H),
7.20 (s, 1H, thiazole-H), 7.40—7.80 (m, 13H, aromatic
protons), 7.90 (s, 1H, C＝H); IR (KBr) ν: 2940 (CH
aliphatic), 1660 (CO pyrimidine), 1630 (CO pyrazolone)
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
phenylamino-5-phenyl-8-methyl-5H-thiazolo[3,2-a]-
pyrimido[4,5-d]pyrimidine (14a)
Orange crystals
1
(65%, ethanol); m.p. 241—243 ℃; H NMR (CDCl3,
90 MHz) δ: 2.30 (s, 3H, pyrazolone-CH3
), 3.40 (s, 3H,
pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-H), 7.10 (s,
1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H), 7.40—7.95
(m, 15H, aromatic protons), 9.90 (s, 1H, NH
exchangable with D2O); IR (KBr) ν: 3310 (NH), 2940
－1
－1
cm . Anal. calcd for C32H23N8O4SCl (651.10): C 59.03,
(CH aliphatic), 1630 (CO pyrazolone) cm . Anal. calcd
H 3.56, N 17.21, S 4.92, Cl 5.45; found C 58.90, H 3.32,
N 17.00, S 4.73, Cl 5.22.
for C31H25N7OS (543.64): C 68.49, H 4.64, N 18.04, S
5.90; found C 68.24, H 4.75, N 17.92, S 5.78.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
phenylamino-5-p-chlorophenyl-8-methyl-5H-thia-
Preparation of 6-chloro-3-(3-methyl-5-oxo-1-
phenyl-2-pyrazolin-4-yl)-5-aryl-8-methyl-5H-
thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (13a, 13b)
zolo[3,2-a]pyrimido[4,5-d]pyrimidine (14b)
Red
1
powder (62%, ethanol); m.p. 249—251 ℃; H NMR
(CDCl3, 90 MHz) δ: 2.30 (s, 3H, pyrazolone-CH3), 3.40
(s, 3H, pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-H),
7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H),
7.42—7.95 (m, 14H, aromatic protons), 9.90 (s, 1H, NH
exchangable with D2O); IR (KBr) ν: 3310 (NH), 2940
A mixture of 3a, 3b (10 mmol) and excess phos-
phoryl chloride (30 mL) was refluxed for 2 h. The
cooled reaction mixture was poured into ice water mix-
ture whereby the product separated out. The product was
filtered off, dried and crystallized from the proper sol-
vent.
－1
(CH aliphatic), 1630 (CO pyrazolone) cm . Anal. calcd
6-Chloro-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-phenyl-8-methyl-5H-thiazolo[3,2-a]pyrimido-
[4,5-d]pyrimidine (13a) Yellow needles (63%, etha-
for C31H24N7OSCl (578.09): C 64.41, H 4.18, N 16.96,
S 5.55, Cl 6.13; found C 64.20, H 4.01, N 16.84, S 5.34,
Cl 5.90.
1
nol); m.p. 232—234 ℃; H NMR (CDCl3, 90 MHz) δ:
2.20 (s, 3H, pyrazolone-CH3), 3.20 (s, 3H, pyrimidine-
CH3), 7.00 (s, 1H, pyrazolone-H), 7.10 (s, 1H,
pyrimidine-H), 7.20 (s, 1H, thiazole-H), 7.40—7.80 (m,
13H, aromatic protons); MS (70 eV) m/z (%): 486.10
(M＋, 24), 488.20 (M＋2, 9); IR (KBr) ν: 2960 (CH ali-
phatic), disapper－ance of CO pyrimidine, 1630 (CO
pyrazolone) cm 1. Anal. calcd for C25H19N6OSCl
(486.98): C 61.66, H 3.93, N 17.26, S 6.58, Cl 7.28;
found C 61.41, H 3.70, N 17.04, S 6.67, Cl 7.04.
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-phenylmercapto-5-aryl-8-methyl-
5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (15a,
15b)
A mixture of 13a, 13b (5 mmol) and sodium salt of
thiophenol (0.62 g, 5 mmol) in ethanol (30 mL) was
refluxed for 3 h. The cooled reaction mixture was
poured into ice water mixture whereby the product
separated out. The product was filtered off, dried and
crystallized from the proper solvent.
6-Chloro-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-
4-yl)-5-p-chlorophenyl-8-methyl-5H-thiazolo[3,2-a]-
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
phenylmercapto-5-phenyl-8-methyl-5H-thiazolo[3,2-
a]pyrimido[4,5-d]pyrimidine (15a) Yellow crystals
(60%, ethanol); m.p. 210 — 212 ℃ ; 1H NMR
(DMSO-d6, 90 MHz) δ: 2.30 (s, 3H, pyrazolone-CH3),
3.20 (s, 3H, pyrimidine-CH3), 7.00 (s, 1H, pyra-
zolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thi-
azole-H), 7.45—7.95 (m, 15H, aromatic protons); IR
(KBr) ν: 2940 (CH aliphatic), 1630 (CO pyrazolone)
pyrimido[4,5-d]pyrimidine (13b)
Pale yellow
1
needles (61%, ethanol); m.p. 240—242 ℃; H NMR
(CDCl3, 90 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3), 3.20
(s, 3H, pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-H),
7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H),
7.40—7.80 (m, 12H aromatic protons); IR (KBr) ν:
2960 (CH aliphatic), disappera－nce of CO pyrimidine,
1
1630 (CO pyrazolone) cm
. Anal. calcd for
－1
C25H18N6OSCl2 (521.42): C 57.59, H 3.48, N 16.12, S
6.15, Cl 13.60; found C 57.36, H 3.24, N 16.01, S 6.31,
Cl 13.74.
cm . Anal. calcd for C31H24N6OS2 (560.69): C 66.41,
H 4.31, N 14.99, S 11.44; found C 66.24, H 4.22, N
14.78, S 11.56.
1480
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1473— 1482

Preparation and Reactions
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
the proper solvent.
phenylmercapto-5-p-chlorophenyl-8-methyl-5H-thia-
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-
phenyl-6-methylmercapto-8-methyl-5H-thiazolo[3,2-
a]pyrimido[4,5-d]pyrimidine (17a) White crystals
zolo[3,2-a]pyrimido[4,5-d]pyrimidine (15b)
Pale
1
yellow crystals (69%, ethanol); m.p. 219—221 ℃; H
NMR (DMSO-d6, 90 MHz) δ: 2.30 (s, 3H,
pyrazolone-CH3), 3.20 (s, 3H, pyrimidine-CH3), 7.00 (s,
1H, pyrazolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s,
1H, thiazole-H), 7.40—7.95 (m, 14H, aromatic protons);
IR －(KBr) ν: 2940 (CH aliphatic), 1630 (CO pyrazolone)
1
(66%, benzene); m.p. 322—324 ℃; H NMR (CDCl3,
90 MHz) δ: 2.30 (s, 3H, pyrazolone-CH3), 3.00 (s, 3H,
pyrimidine-CH3), 3.40 (s, 3H, S-CH3), 7.00 (s, 1H,
pyrazolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H,
thiazole-H), 7.40—7.95 (m, 10H, aromatic protons); IR
(KBr) ν: disappearance of NH group, 2952 (CH ali-
1
cm . Anal. calcd for C31H23N6OS2Cl (595.14): C 62.56,
－1
H 3.90, N 14.12, S 10.78, Cl 5.96; found C 62.47, H
3.78, N 14.02, S 10.49, Cl 5.67.
phatic), 1625 (C＋O pyrazolone) cm ; MS (70 eV) m/z
(%): 497.81 (M , 45). Anal. calcd for C26H22N6OS2
(498.62): C 62.63, H 4.45, N 16.85, S 12.86; found C
62.46, H 4.51, N 16.73, S 12.75.
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-thioxo-5-aryl-8-methyl-5,7-dihy-
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-p-
chlorophenyl-6-methylmercapto-8-methyl-5H-thia-
drothiazolo[3,2-a]pyrimido[4,5-d]pyrimidine
16b)
(16a,
zolo[3,2-a]pyrimido[4,5-d]pyrimidine (17b)
Pale
1
A mixture of 13a, 13b (5 mmol) and thiourea (0.75 g,
10 mmol) in ethanol (30 mL) was refluxed for 1 h. The
solid precipitate thus formed was filtered off and dis-
solved in boiling 10% NaOH solution followed by
acidification with acetic acid whereby the solid product
was collected, dried and crystallized from the proper
solvent.
yellow crystals (69%, benzene); m.p. 339—341 ℃; H
NMR (CDCl3, 90 MHz) δ: 2.30 (s, 3H, pyrazolone-CH3),
3.00 (s, 3H, pyrimidine-CH3), 3.40 (s, 3H, S-CH3), 7.00
(s, 1H, pyrazolone-H), 7.10 (s, 1H, pyrimidine-H), 7.20
(s, 1H, thiazole-H), 7.42—7.95 (m, 9H, aromatic pro-
tons); IR (KBr) ν: disappearance of NH group, 2952
－1
(CH aliphatic), 1625 (CO pyrazolone) cm . Anal. calcd
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
thioxo-5-phenyl-8-methyl-5,7-dihydrothiazolo[3,2-a]-
for C26H21N6OS2Cl (533.07): C 58.58, H 3.97, N 15.77,
S 12.03, Cl 6.65; found C 58.42, H 3.86, N 15.64, S
11.92, Cl 6.71.
pyrimido[4,5-d]pyrimidine (16a)
Yellow crystals
1
(69%, ethanol); m.p. 341—343 ℃; H NMR (CDCl3,
90 MHz) δ: 2.30 (s, 3H, pyrazolone-CH3), 3.20 (s, 3H,
pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-H), 7.10 (s,
1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H), 7.40—7.95
(m, 10H, aromatic protons), 9.90 (s, 1H, NH
exchangable with D2O); IR (KBr) ν: 3250 (NH), 2970
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-6-methylamino-5-aryl-8-methyl-5H-
thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (18a, 18b)
A mixture of 13a, 13b (5 mmol) and excess of me-
thylamine solution (50 mL) was refluxed for 6 h. The
reaction mixture was acidified with acetic acid whereby
a solid product was obtained. The product was filtered
off, dried and crystallized from the proper solvent.
－1
(CH aliphatic), 1625 (CO pyrazolone) cm . Anal. calcd
for C25H20N6OS2 (484.60): C 61.96, H 4.16, N 17.34, S
13.23; found C 61.87, H 4.01, N 17.11, S 13.32.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
thioxo-5-p-chlorophenyl-8-methyl-5,7-dihydrothia-
zolo[3,2-a]pyrimido[4,5-d]pyrimidine (16b) Orange
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
methylamino-5-phenyl-8-methyl-5H-thiazolo[3,2-
a]pyrimido[4,5-d]pyrimidine (18a) White crystals
1
1
crystals (67%, ethanol); m.p. 332—334 ℃; H NMR
(64%, ethanol); m.p. 252—254 ℃; H NMR (CDCl3,
(CDCl3, 90 MHz) δ: 2.30 (s, 3H, pyrazolone-CH3), 3.20
(s, 3H, pyrimidine-CH3), 7.00 (s, 1H, pyrazolone-H),
7.10 (s, 1H, pyrimidine-H), 7.20 (s, 1H, thiazole-H),
7.40—7.95 (m, 9H, aromatic protons), 9.90 (s, 1H, NH
exchangable with D2O); IR (KBr) ν: 3250 (NH), 2970
400 MHz) δ: 2.20 (s, 3H, pyrazolone-CH3), 3.10 (s, 3H,
pyrimidine-CH3), 3.8 (s, 3H, N-CH3), 6.71 (s, 1H,
pyrazolone-H), 6.80 (s, 1H, pyrimidine-H), 6.92 (s, 1H,
thiazole-H), 7.06—7.14 (m, 5CH aromatic), 7.24—7.64
(m, 5CH aromatic), 9.90 (s, 1H, NH exchangable with
D2O); 13C NMR (CDCl3, 400 MHz) δ: 14 (CH3
pyrimidine), 18 (CH3 pyrazolone), 37 (N-CH3), 45 (CH
pyrimidine), 50 (CH pyrazolone), 89 (CH thiazole), 142
—124 (C and CH aromatic rings), 154 (C thiazole), 155
(C＝N pyrazolone), 159 and 103 (C＝C pyrimidine),
161 (C＝N pyrimidine), 164 (C＝N pyrimidine), 168
(C-NH), 170 (CO pyrazolone); IR (KBr) ν: 3290 (NH),
－1
(CH aliphatic), 1625 (CO pyrazolone) cm . Anal. calcd
for C25H19N6OS2Cl (519.04): C 57.85, H 3.69, N 16.19,
S 12.36, Cl 6.83; found C 57.71, H 3.58, N 16.01, S
12.28, Cl 6.64.
Preparation of 3-(3-methyl-5-oxo-1-phenyl-2-
pyrazolin-4-yl)-5-aryl-6-methylmercapto-8-methyl-
5H-thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine (17a,
17b)
－1
2950 (CH aliphatic), 1630 (CO pyrazolone) cm . Anal.
calcd for C26H23N7OS (481.57): C 64.85, H 4.81, N
20.36, S 6.66; found C 64.71, H 4.72, N 20.19, S 6.56.
3-(3-Methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-6-
methylamino-5-p-chlorophenyl-8-methyl-5H-thia-
zolo[3,2-a]pyrimido[4,5-d]pyrimidine (18b) White
A mixture of 16a, 16b (5 mmol) and fused sodium
acetate (2 g) in ethanol (30 mL) was heated and excess
of methyl iodide (10 mmol) was added dropwise to the
cold reaction mixture with stirring for 15 min. The solid
precipitate was filtered off, dried and crystallized from
Chin. J. Chem. 2011, 29, 1473— 1482
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1481

Youssef et al.
FULL PAPER
1
powder (66%, ethanol); m.p. 272—274 ℃; H NMR
(CDCl3, 90 MHz) δ: 2.30 (s, 3H, pyrazolone-CH3), 3.40
(s, 3H, pyrimidine-CH3), 3.80 (s, 3H, N-CH3), 7.11 (s,
1H, pyrazolone-H), 7.20 (s, 1H, pyrimidine-H), 7.32 (s,
1H, thiazole-H), 7.95—7.40 (m, 9H, aromatic protons),
9.90 (s, 1H, NH exchangable with D2O); IR (KBr) ν:
3290 (NH), 2950 (CH aliphatic), 1630 (CO pyrazolone)
Acknowledgement
We are grateful to Assiut University Mycological
Center (AUMC) for biological analyses
References
1
2
3
4
Youssef, M. S. K.; Fahmy, A. F.; Abdel Halim, M. S.; Has-
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－1
cm . Anal. calcd for C26H22N7OSCl (516.02): C 60.52,
H 4.30, N 19.00, S 6.21, Cl 6.87; found C 60.38, H 4.19,
N 18.83, S 6.11, Cl 6.72.
Antimicrobial activity
Shakibaei, G. I.; Khavasi, H. R.; Mirzaei, P.; Bazgir, A. A. J.
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Chemical compounds were dissolved in DMSO to
prepare a concentration of 20 mg/mL for each com-
pound. A series of descending concentrations were also
prepared for MIC test. Microbes were grown on nutri-
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were made using a sterile cork borer. With the aid of a
micropipette, 50 µL of the tested chemical solutions
were individually pipetted in the wells. Cultures were
incubated for 24 to 48 h for bacteria or 4—7 d in case of
fungi after which inhibition zones (in mm) were meas-
ured. Chloramphenicol and Clotrimazole were used as
reference substances. The biologically active com-
pounds were diluted with DMSO to prepare a series of
concentrations in order to determine the minimum in-
hibitory concentration (MIC) of each compound. MICs
were calculated15 as mg/mL
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Conclusion
Oxazinone derivatives are obtained via saponifica-
tion of aminoester derivatives and the sodium salt thus
formed reacted with acetic anhydride. These compounds
were transformed to thiazolopyrimidopyrimidines via
reaction with various reagents. The prepared compounds
are evaluated for biological activities such as antibacte-
rial and antifungal.
15 Kwan Chung, K. J.; Bennett, J. E. Medical Mycology, Lea
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(E1010149 Cheng, F.)
1482
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1473— 1482