Synthesis and preliminary antimicrobial activity of new pyrimido[4,5-b]-quinoline and pyrido[2,3-d]pyrimidine

Article abstract of DOI:10.1080/10426500701851283

4-Chloro-2-methylthio-benzo[h]pyrimido[4,5-b]quinoline (5) and pyrido[2,3-d]-pyrimidine (12), were easily prepared from the cyclo-condensation of α,β -unsaturated ketones and 6-aminothiouracil. Compound 5 reacted with different amines to give 8-aryl-amino- (6,7), 2,4-dihydrazino-pyrimido[4, 5-b]quinoline (9). Compound 7 was converted into benzo[h]-12,13-dihydrobenzo[a]- pyrimido[3',2':1,6]pyrimido[4,5-b]-quinoline (8) with a new ring system. The 2,4-dihydrazino-reacted with formic acid to afford benzo[h]-s-triazolo[4',3':1, 6]-s-triazolo[3'',4'':2,3]pyrimido[4,5-b]quinoline (10) with a new ring system. Also, reaction of (12) with bromomalononitrile gave 3-amino-thiazolo[4,5-a] pyrido[2,3-d]pyrimidine-2-carbonitrile (13). Compound 13 reacted with formic acid, urea, thiourea, formamide to affording the pyrimido[4',5':-4,5]thiazolo[3, 2-a]pyrido[2,3-d]pyrimidin-12-one (14, 15, 16a,b, 21) and reacted with carbon disulfide to give pyrido[2'',3'':4',5']pyrimido[2',1':2,3]thiazolo[4,5-d][1,3]- thiazine (17). Some of the synthesized derivatives exhibited, upon screening, antibacterial and antifungal activities. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500701851283

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Synthesis and Preliminary
Antimicrobial Activity of New
Pyrimido[4,5-b]-quinoline and
Pyrido[2,3-d]pyrimidine
A. B. A. El-Gazzar a , A. S. Aly a , M. E. A. Zaki a & H.
N. Hafez a
a Photochemistry Department (Heterocyclic Unit) ,
National Research Center , Dokki, Giza, Egypt
Published online: 12 Aug 2008.
To cite this article: A. B. A. El-Gazzar , A. S. Aly , M. E. A. Zaki & H. N. Hafez (2008)
Synthesis and Preliminary Antimicrobial Activity of New Pyrimido[4,5-b]-quinoline and
Pyrido[2,3-d]pyrimidine, Phosphorus, Sulfur, and Silicon and the Related Elements,
183:9, 2119-2138, DOI: 10.1080/10426500701851283
To link to this article: http://dx.doi.org/10.1080/10426500701851283
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Phosphorus, Sulfur, and Silicon, 183:2119–2138, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701851283
Synthesis and Preliminary Antimicrobial Activity of New
Pyrimido[4,5-b]-quinoline and Pyrido[2,3-d]pyrimidine
A. B. A. El-Gazzar, A. S. Aly, M. E. A. Zaki, and H. N. Hafez
Photochemistry Department (Heterocyclic Unit), National Research
Center, Dokki, Giza, Egypt
4-Chloro-2-methylthio-benzo[h]pyrimido[4,5-b]quinoline (5) and pyrido[2,3-
d]-pyrimidine (12), were easily prepared from the cyclo-condensation of
α,β-unsaturated ketones and 6-aminothiouracil. Compound
5 reacted with
different amines to give 8-aryl-amino- (6,7), 2,4-dihydrazino-pyrimido[4,5-
b]quinoline (9). Compound 7 was converted into benzo[h]-12,13-dihydrobenzo[a]-
pyrimido[3ꢀ,2ꢀ:1,6]pyrimido[4,5-b]-quinoline (8) with a new ring system. The
2,4-dihydrazino- reacted with formic acid to afford benzo[h]-s-triazolo[4ꢀ,3ꢀ:1,6]-
s-triazolo[3ꢀꢀ,4ꢀꢀ:2,3]pyrimido[4,5-b]quinoline (10) with a new ring system. Also,
reaction of (12) with bromomalononitrile gave 3-amino-thiazolo[4,5-a]pyrido[2,3-
d]pyrimidine-2-carbonitrile (13). Compound 13 reacted with formic acid, urea,
thiourea, formamide to affording the pyrimido[4ꢀ,5ꢀ:-4,5]thiazolo[3,2-a]pyrido[2,3-
d]pyrimidin-12-one (14, 15, 16a,b, 21) and reacted with carbon disulfide to give
pyrido[2ꢀꢀ,3ꢀꢀ:4ꢀ,5ꢀ]pyrimido[2ꢀ,1ꢀ:2,3]thiazolo[4,5-d][1,3]-thiazine (17). Some of the
synthesized derivatives exhibited, upon screening, antibacterial and antifungal
activities.
Keywords 4-Chlorobenzo[h]pyrimido[4,5-b]quinoline; benzo[h]-12,13-dihydro-benzo
[a]pyrimido[3ꢀ,2ꢀ:1,6]pyrimido[4,5-b]quinoline;
[3ꢀꢀ,4ꢀꢀ:2,3]pyrimido[4,5-b]quinoline
benzo[h]-s-triazolo-[4ꢀ,3ꢀ:1,6]-s-triazolo
INTRODUCTION
Pyrimidine-containing molecules are of paramount importance in nu-
cleic acid chemistry. Their derivatives, including uracil, cytosine, ade-
nine, and guanine, are fundamental building blocks for deoxyribonu-
cleic acid (DNA) and ribonucleic acid (RNA). Pyrimidine derivatives
exist extensively in nature. They have biological and pharmaceutical
activities. N-3-substituted pyrimidinones are potent AT1 selective an-
giotensin II receptor antagonists.1
Received 21 October 2007; accepted 11 November 2007.
Address correspondence to A. B. A. El-Gazzar, Photochemistry Department (Het-
erocyclic Unit), National Research Center, Dokki, Giza, Egypt. E-mail: profelgazzar@
yahoo.com
2119

2120
A. B. A. El-Gazzar et al.
SCHEME 1
Pyrimidine amide derivatives are novel antiallergic agents.2
S-alkylated derivatives are potent antiviral agents.3 6-Alkylamino-
derivatives are inhibitors of bacillus subtilis DNA polymerase III.4
Aziridino derivatives are new cytotoxic agents with tumor-inhibitory
activity.5 Arylamino derivatives of pyrimidines are potential anti-
cytomegalovirus agents,6 2- or 4-(4-methylpiperazino)-pyrimidines
are 5-HT2A receptor antagonists.7 Due to the electronegativity of
the two nitrogen atoms, pyrimidine is a 2-electron-deficient hete-
rocycle. Therefore, nucleophilic displacements of nucleofugal leav-
ing groups take place readily. This trend also translated to the
4-chloropyrimidoquinoline chemistry.
RESULTS AND DISCUSSION
In this work, the synthesis of some poly-condensed heterocyclic
based on pyrimido-quinoline and pyridopyrimidine are described.
6-Aminothiouracil 1 was reacted with α,β-unsaturated ketones 2
in dimethylformamide solution with stirring for a long time under
thin layer chromatography control afforded 5-(4-aryl)-2-thioxo-1,3,6,7-
tetrahydro-4H-benzo[h]pyrmido[4,5-b]quinolin-4-one derivatives (3) in
good yield, Scheme 1.
It is well known in pyrimidines chemistry that position 4 in
pyrimidines and fused pyrimidines shows distinct activities towards
nucleophiles. Therefore, 4-chloro-2-methylthio-5-(4-chlorophenyl)-6,

Pyrimidoquinolines and Pyridopyrimidines
2121
7-dihydrobenzo[h]pyrimido[4,5-b]quinoline (5) was prepared by the
method of Shishoo,8 and its activity towards nucleophiles such as
primary aromatic amines and hydrazine hydrates were investigated.
Thus, heating under reflux compound 5 with arylamine, namely
aniline, 4-chloroaniline and p-anisidine in acetic acid, produced
the
4-arylamino-2-methylthio-5-(4-chlorophenyl)-6,7-dihydrobenzo
[h]pyrimido[4,5-b]quinoline derivatives (6a-c). The IR and 1H NMR
(CDCl3) spectrum of compound 5 revealed the absence of any absorp-
tion bands in the NH region. While the 1H NMR (DMSO-d6) spectrum
of 6a showed broad signal at 11.50 ppm corresponding the NH group,
in addition to the sp3 and sp2 hydrogen atoms in the compound. Also
1
the H NMR (DMSO-d6) spectrum of 6c revealed the signal for OCH3
at 3.87 ppm and the broad signal NH at 11.43 which exchangeable by
D2O in addition to the two duplet signals for the p-substituted phenyl
at 7.00–7.08 and 7.63–7.75 ppm as AAꢀBBꢀ system with coupling
constant J = 13.2 Hz.
Moreover, the reaction of 4-chloropyrimidoquinoline (5) with an-
thranilic acid in glacial acetic acid afforded 4-(o-carboxyphenyl)-amino-
pyrimidoqinoline derivative 7. The IR spectra of 7 displayed an ab-
sorption band at 3520 cm−1 (OH), 3365 cm−1 (NH) and 1713 cm−1
for carbonyl group. Its 1H NMR (DMSO-d6) spectrum showed sig-
nals at δ 2.47–2.49 (t, 2H, CH2), 2.73–2.78 (t, 2H, CH2), 2.99 (s,
3H, SCH3), 6.85–6.87 (d, 2H, phenyl), 7.07–7.10 (d, 2H, phenyl),
7.28–7.32 (m, 2H, phenyl), 7.37–7.41 (t, 2H, phenyl), 7.44–7.62 (m,
2H, phenyl), 7.64–7.99 (m, 2H, phenyl), 11.48 (brs, NH), and 12.13
(brs, OH). The latter compound 7 underwent cyclization when boiled
with glacial acetic acid in presence of catalytic amount of sulfuric
acid (1 ml) to give 7-(4-chlorophenyl)-benzo[h]-5,6-dihydrobenzo[a]pyri-
mido[3ꢀ,2ꢀ:1,6]pyrimido[4,-5-b]quinolin-13-one (8) with a new ring sys-
1
tem, (Scheme 2). Structure 8 was preferred on the basis of H NMR
spectral data. Thus, 1H NMR (DMSO-d6) spectrum for the compound 8
showed signals at δ 2.45–2.48 (t, 2H, CH2), 2.71 (s, 3H, SCH3), 2.81–
2.88 (t, 2H, CH2), 7.21–7.22 (d, 2H, phenyl), 7.23–7.25 (m, 2H, phenyl),
7.27–7.29 (m, 2H, phenyl), 7.38–7.40 (t, 2H, phenyl), 7.44–7.69 (m, 2H,
phenyl), and 8.30–8.31(d, 2H, phenyl).
Similarly, the 2,4-dihydrazinopyrimidoquinoline derivative 9 was
synthesized from 5 and hydrazine hydrate by heating in dry dioxane.
The reactivity of 9 towards the aliphatic acids was studied. Where stir-
ring it under reflux in formic acid afforded the 7-(4-chlorophenyl)-5,6-
dihydrobenzo[h]-s-triazolo[4ꢀ,3ꢀ:1,6]-s-triazolo[3ꢀꢀ,4ꢀꢀ:2,3]-pyrimido[4,5-
b]quinoline (10), with a new ring system. Beside the correct values of
elemental analysis and spectral data of 9 are in agreement with the
assigned structure. The IR spectrum of 9 displayed absorption bands

2122
A. B. A. El-Gazzar et al.
SCHEME 2
around 3438 cm−1 for NH’s. While the IR spectrum of 10 revealed the
1
absence of NH’s groups. Also, the H NMR (DMSO-d6) spectrum of 9
showed the signals corresponding to NH2’s and NH’s at δ 2.00, 10.70,
and 11.60 ppm, which disappeared in compound 10, in addition to the
presence of two absorption bands at 9.23, 9.39 in compound 10 corre-
sponding to the triazole proton was observed. Moreover, its 13C NMR
(DMSO-d6) spectrum of 10 showed signals at δ 24.09, 26.98 two sp3 car-
bon atoms and 19 sp2 carbon atoms around 105.71–153.27 ppm, and its
mass spectrum showed the molecular ion peak [M+] at m/z 423 (100%).
Also, the pyridopyrimidine9 as a part of our study designed to
synthesize polyheterocyclic compounds possessing thiazolopyridopy-
rimidine derivatives containing enaminonitrile nucleus, which could
be used as a precursor for the synthesis of a series of new compounds
having new ring systems such as pyrimidothiazolopyridopyrimidine

Pyrimidoquinolines and Pyridopyrimidines
2123
SCHEME 3
and pyridopyrimidothiazolothiazine. Thus, reaction of 12 with bro-
momalononitrile in aqueous alcoholic potassium carbonate solution,
gave 3-amino-9-(4-arylmethylene)-6-(4-aryl)-1,2,10,11-tetrahydro-5H-
thiazolo[4,5-a]cyclo-pentenopyrido[2,3-d]pyrimidine-2-carbonitrile-5-
one (13) (Scheme 3).
Thiazolo[4,5-a]cyclopentenopyrido[2,3-d]pyrimidine-2-carbonitrile
(13) was established on the following facts:
a) IR spectrum displayed absorption bands correspond to amino, cyano
and carbonyl groups;
b) Compatible data in elemental analysis;
c) Compound 13 underwent characteristic reactions of β-
enaminonitriles;
d) it was reported in the literature that N-3 and not N-1 nitrogen atom
participates in cyclization of 2-substituted thiopyrimidine deriva-
tives; 10
1
e) the H NMR (DMSO-d6) spectrum of 13 showed signals at δ 2.63–
2.74 (m, 2H, CH2), 2.75–2.88 (m, 2H, CH2), 7.16 (brs, NH2), 7.46–7.48
(d, 2H, phenyl), 7.60–7.63 (d, 2H, phenyl), 7.63–7.65 (d, 2H, phenyl),
7.95–7.99 (d, 2H, phenyl), and 8.01 (s, 1H, methylenic proton);
f) its 13C NMR (DMSO-d6) spectrum showed signals δ 26.97, 28.06 for
two sp3 carbon atoms, one signals at 116.46 support to CN group, 18
signals corresponding to sp2 carbon atoms around 108.48–158.68,
and the signal of (C O) at 163.88; and

2124
A. B. A. El-Gazzar et al.
g) its mass spectrum showed the absorption molecular ion peak [M+],
m/z 516, (100%), [M+2 H2N C C CN], m/z 450 (17%).
Compound 13 as a typical β-enaminonitrile derivative, reacted
with aliphatic acids namely, formic and acetic acids, afforded 8-
(4-chlorophenylmethylene)-11-(chlorophenyl)-4-hydroxypyrimido[4ꢀ,5ꢀ:
4,5]thiazolo[3,2-a]cyclopentenopyrido[2,3-d]pyrimidin-12-one deriva-
tives (14a,b), with a new ring system.
The IR spectrum of 14 displayed absorption bands around 3420 cm−1
(NH) and around 1696, 1689 for two carbonyl. Also, the 1H NMR
(DMSO-d6) spectrum of compound 14b as an example showed signals
at δ 2.32 (s, 3H, CH3), 2.75–2.78 (t, 2H, CH2), 2.85–2.97 (t, 2H, CH2),
7.10–7.12 (d, 2H, phenyl), 7.39–7.41 (d, 2H, phenyl), 7.42–7.44 (d, 2H,),
7.45–7.47 (d, 2H, phenyl), 8.02 (s, 1H, methylenic proton), 10.00 (brs,
NH, D2O exchangeable). Formation of 14 from 13 and formic acid may
proceed as shown in Scheme 4.
Similarly, compound 13 reacted with formamide, in the pres-
ence of formic acid and dimethylformamide, to yield 4-amino-
9,10-dihydropyrimido[4ꢀ,5ꢀ:4,5]-thiazolo[3,2-a]cyclopentenopyrido[2,3-
d]pyrimidin-12-one derivative (15).
The 1H NMR (DMSO-d6) spectrum of 15 showed the signals at
δ 2.68–2.73 (t, 2H, CH2), 2.88–3.00 (t, 2H, CH2), 7.21–7.26 (d, 2H,
phenyl), 7.28–7.39 (d, 2H, phenyl), 7.41–7.44 (d, 2H, phenyl), 7.51–7.57
(d, 2H, phenyl), 7.95 (s, 1H, methylenic proton), 8.15 (s, 1H, pyrimi-
dine), and 8.35 (brs, NH2). Also, when heated compound 13 with urea
or thiourea at 180◦C, it gave 4-amino-pyrimido[4ꢀ,5ꢀ:4,5]thiazolo[3,2-
a]-cyclopentenopyrido[2,3-d]pyrimidine-2,12-dione (16a), and the 4-
amino-pyrimido-[4ꢀ,5ꢀ:4,5]thiazolo[3,2-a]cyclopentenopyrido[2,3-d]
pyrimidine-2-thioxo-12-one 16b, respectively (Scheme 5). The 1H NMR
(DMSO-d6) spectrum of 16b showed signals at δ 2.71–2.73 (t, 2H,
CH2), 3.02–3.05 (t, 2H, CH2), 7.26–7.28 (d, 2H, phenyl), 7.30–7.39 (d,
2H, phenyl), 7.43–7.45 (d, 2H, phenyl), 7.50–7.53 (d, 2H, phenyl), 7.56
(s, 1H, methylenic), 11.87 (brs, NH), and 12.55 (brs, NH). Also, its IR

Pyrimidoquinolines and Pyridopyrimidines
2125
SCHEME 4
SCHEME 5

2126
A. B. A. El-Gazzar et al.
SCHEME 6
spectrum for the compounds 16a,b displayed absorption bands around
3395 (NH) and 1686 cm−1 (CO).
On the other hand, when compound 13 was heated with
carbon
disulphide
in
pyridine,
1,2,9,10-tetrahydro-4H-10H-
cyclopentenopyrido[2ꢀꢀ,3ꢀꢀ:4ꢀ,5ꢀ]pyrimido[2ꢀ,1ꢀ-:2,3]thiazolo[4,5-d][1,3]
thiazine-12-one (17),11 with a new ring system, was obtained. The H
NMR (DMSO-d6) spectrum of 17 showed signals at δ 2.73–2.78 (t, 2H,
CH2), 3.20–3.32 (t, 2H, CH2), 6.97–6.99 (d, 2H, phenyl), 7.09–7.12 (d,
2H, phenyl), 7.29–7.41 (d, 2H, phenyl), 7.42–7.44 (d, 2H, phenyl), 8.26
(s, 1H, methylenic), and 12.10, 12.95 (two broads band, 2NH, D2O
exchangeable). Moreover, its IR spectrum displayed absorption bands
at 3400 cm−1 (NH), 1685 cm−1 (CO).
1
Condensation of 13 with triethyl orthoformate, yielded the corres-
ponding 3-ethoxymethyleneamino-1,2,10,11-tetrahydro-5H-thiazolo
[4,5-a]cyclopentenopyrido-[2,3-d]pyrimidine-2-carbonitrile-5-one deri-
vative 18, with compatible IR and 1H NMR data. The latter com-
pound reacted with hydrazine hydrate in boiling dioxane, to give
3-hydrazinomethyleneamino-1,2,10,11-tetrahydro-5H-thiazolo[4,5-a]
cyclopent-enopyrido[2,3-d]pyrimidine-2-carbonitrile-5-one19, which on
boiling in ethanolic sodium ethoxide solution, underwent cyclization
to give 3-amino-4-imino-3,4,9,10-tetrahydropyrimido[4ꢀ,5ꢀ:4,5]thiazolo
[3,2-a]cyclopentenopyrido[2,3-d]pyrimidin-12-one (20), (Scheme 6).
The IR spectrum of 18 displayed absorption bands at 2213 cm−1(CN),
while that of 20 revealed the absence of CN group. The 1H NMR
(DMSO-d6) spectrum of 20, showed signals at δ 2.68–2.73 (t, 2H, CH2),
2.88–3.00 (t, 2H, CH2), 7.19–7.27 (d, 2H, phenyl), 7.36–7.39 (d, 2H,
phenyl) 7.40–7.43 (d, 2H, phenyl), 7.44–7.46 (d, 2H, phenyl), 8.26

Pyrimidoquinolines and Pyridopyrimidines
2127
(s, 1H, methylenic), 8.29 (s, 1H, pyrimidine proton), 10.82 (brs, NH2,
D2O exchangeable), and 11.30 (brs, NH, D2O exchangeable).
Finally, compound 18 was heated with ammonium hydroxide
solution, in boiling ethanol, it gave 3-aminomethyleneamino-1,2,10,11-
tetrahydro-5H-thiazolo-[4,5-a]cyclopentenopyrido[2,3-d]pyrimidine-2-
carbonitrile-5-one (21). The IR spectrum of 21 displayed absorption
bands at 3395, 3310 cm−1 (NH2), 2216 cm−1 (CN) and 1694 cm−1(CO),
and that 1H NMR (DMSO-d6) spectrum of 21 showed signals at
δ 2.66–2.70 (t, 2H, CH2), 2.80–3.00 (t, 2H, CH2), 6.97–7.00 (d, 2H,
phenyl), 7.11–7.16 [m, 3H,(d, 2H, phenyl + 1H, methylenic)], 7.23–7.31
(d, 2H, phenyl), 7.45–7.50 (d, 2H, phenyl), 8.43 (s, 1H, methylenic
proton), and 12.55 (brs, NH, D2O exchangeable). Moreover, the latter
compound 21 could be converted into 15 upon heating in ethanolic
sodium ethoxide solution.
Antimicrobial Activity
Twenty compounds were screened in vitro for their antimicrobial ac-
tivities against four strains of bacteria species namely Staphylococ-
cus aureus (ATCC 29737),Bacillus subtilis (NCIMB8054), Escherichia
coli (NCTC10418), and Salmonella typhi and two strains of fungi
Aspergillus terrus and Aspergillus Flavus by the agar diffusion
technique.12 A 1mg/mL solution in dimethylformamide was used. The
bacteria and fungi were maintained on nutrient agar and Czapek,s-Dox
agar media, respectively. DMF showed no inhibition zones. The agar
media were inoculated with different microorganisms culture tested.
After 24 h incubation at 30◦C for bacteria and 48 h of incubation at
28◦C for fungi, the diameter of inhibition zone (mm) was measured
(Table I). Chloramphenicol in a concentration (25 µgm−1, and Grisoflu-
vine (30 µgm−1); used as a references for antibacterial and antifungal
activities respectively. The minimal inhibitory concentration (MIC) of
some of the tested compounds was measured by a two fold serial dilution
method.13 The most of the synthesized compounds exhibited various
antimicrobial activity towards all the micro-organisms used.
CONCLUSIONS
The prepared new ring systems seem to be interesting for biological
activity studies. Furthermore, the present investigation offers rapid
and effective new routes for the synthesis of poly-condensed heterocyclic
based on pyrimidoquinolines and pyridopyrimidine derivatives.

2128
A. B. A. El-Gazzar et al.
TABLE I Antimicrobial Activity of Some Synthesized Compounds
and Inhibition Zones
Gram (−) bacteria
Gram (+) bacteria
Fungi
Compd.
no
Salmonella Staphylococcus Bacillus Aspergillus Aspergillus
C.* E.Coli
typhi
aureus
subtillus
terrus
flavus
6a
1
2.5
5
+
+
+
+
++
+
+
+
++
+
++
+
+
+
+
+
+
+
8
1
++
+
+
+
++
+
++
++
+
2.5 ++
+
+
+
5
1
+
+
+
+
+
+
10
13
14b
15
16a
17
20
St.
+
+
+
+
+
2.5 ++
+
+
+
+
+
5
1
++
+
+
+
++
+
+
+
+
+
+
+
2.5
5
1
2.5
5
1
2.5
5
1
2.5
5
1
+
+
+
+
+
+
++
++
+
+
+
+
+
+
+
++
+
++
++
+
++
+
++
++
+
+
+
+
+
+
+
+
+
+
++
++
++
++
+
++
++
++
++
++
+
+
+
+
+
+
+
+
+
++
+
+
++
++
+
+
+
+
+
+
+
+
+
++
++
+
+
+
+
+
2.5
5
1
+
+
+
+
+
+
+
+
+
+
++
++
++
++
+ + +
+ + +
+ + +
++
++
++
+ + +
+ + +
+ + +
++
++
++
++
+ + +
+ + +
++
++
++
++
+ + +
+ + +
++
++
++
+ + +
+ + +
+ + +
2.5 ++
5
1
++
++
2.5 + + +
5
+ + +
*C = Concentration of the sample in mg/ml; + = Inhibition values = 0.1–0.5 cm
beyond control; ++ = Inhibition values = 0.6–1.0 cm beyond control; and + + + =
Inhibition values = 1.1–1.5 cm beyond control.
EXPERIMENTAL
All melting points are uncorrected and measured using an Electro-
1
thermal IA 9100 apparatus (Shimadzu, Japan). The H NMR and 13C
NMR spectra were recorded on JEOL JNM-LA-400 FT NMR Spec-
trometer (Universitat Konstanz, Germany) and chemical shifts were
expressed as δ values against SiMe4 as internal standards. IR spectra

Pyrimidoquinolines and Pyridopyrimidines
2129
were recorded as KBr pellets on a Perkin-Elmer 1430 spectrometer,
(National Research Center and Department of Chemistry Cairo Uni-
versity). Mass spectra were recorded on GCMS-Q P1000 EX Shimadzu
Japan (Gas Chromatography-Mass spectrometer). Microanalytical data
were performed by the Microanalytical Center at Cairo University
(Egypt). The starting materials are prepared according to Quiroga14
and El-Gazzar.15,16 The biological evaluation of the products was car-
ried out at the Fermentation Biotechnology & Applied Microbiology
(Ferm- BAM) Center at Al-Azhar University, Cairo, Egypt.
4-Chloro-2-methylthio-5-(4-chlorophenyl)-6,7-
dihydrobenzo[h]pyrimido[4,5-b]-quinoline (5)
A solution of compound 4 (4.05 g, 10 mmol) in dry dioxane (30 mL)
was treated with 7 ml of phosphorus-oxychloride and the mixture was
stirred under reflux for 3 h, the reaction mixture was allowed to cool to
room temperature. It was poured into cold water (100 mL), whereby a
solid was separated, filtered off, and crystallized from dioxane (yellow
powder), in 56% yield, m.p. 313+ + −315◦C (melted); IR, cm−1: 3029
1
(CH aryl), 2919 (CH alkyl), 1601 (C N), 1520 (C C), 1160 (C-Cl); H
NMR (CDCl3) ppm: δ 2.29 (s,3H, S-CH3) 2.46–2.50 (m, 2H, CH2), 2.74–
2.78 (m, 2H, CH2), 7.06–7.09 (d, 2H, phenyl), 7.13–7.17 (d, 2H, phenyl),
7.29–7.35 (m, 1H, phenyl), 7.41–7.46 (m, 2H, phenyl), 8.30–8.33 (m, 1H,
phenyl); Analysis: C22H15Cl2N3S (424.3); Requires: C, 62.26;H, 3.56;
N, 9.90. Found: C, 62.19; H, 3.61; N, 9.84.
4-Arylamino-2-methylthio-5-(4-chlorophenyl)-6,7-
dihydrobenzo[h]pyrimido[4,5-b]-quinoline
(6a-c)—General Procedure
In a warm solution of compound 5 (4.24 g, 10 mmol) in glacial acetic
acid (40 ml), the freshly distilled arylamine (10 mmol) was added. The
reaction mixture was stirred under reflux for 3 h, allowed to cool to
0◦C for 4 h, and the solid obtained was filtered, washed with water
(100 mL) dried, and crystallized from appropriate solvent to produce
(6a,b) in high yields.
5-(4-Chlorophenyl)-4-phenylamino-2-methylthio-6,7-
dihydrobenzo[h]pyrimido-[4,5-b]quinoline (6a)
The compound was obtained from 5 (4.24 g, 10 mmol) and aniline
(0.93 g, 10 mmol), as pale yellow crystals, crystallized from dixane/
dimethylformamide (1:1) in 67% yield, m.p. 385–389◦C (melted); IR,

2130
A. B. A. El-Gazzar et al.
cm−1: 3400 (brs NH), 3042 (CH aryl), 2931 (CH alkyl), 1601 (C N), 1520
(C C).1H NMR (DMSO-d6) ppm: δ δ 2.31 (s,3H, S-CH3) 2.47–2.51(m,
2H, CH2), 2.75–2.78 (m, 2H, CH2), 7.05–7.08 (d, 2H, phenyl), 7.11–7.15
(d, 2H, phenyl), 7.20–7.39 [m, 6H, (1H, phenyl + 5H, phenyl)], 7.40–
7.46 (m, 2H, phenyl), 8.30–8.33 (m, 1H, phenyl), 11.50 (brs, NH, D2O
exchangeable). Analysis: C28H21ClN4S (480.9); Requires: C, 69.91; H,
4.40; N, 11.65. Found: C, 69.79; H, 4.33; N, 11.56.
4-(Chlorophenylamino)-5-(4-chlorophenyl)-2-methylthio-6,7-
dihydrobenzo[h]-pyrimido[4,5-b]quinoline (6b)
The compound was obtained from 5 (4.24 g, 10 mmol) and 4-
chloroaniline (1.27 g, 10 mmol), as yellow crystals, crystallized from
dimethylformamide in 71% yield, m.p. 292–294◦C (melted); IR, cm−1
:
3395 (brs, NH), 3039 (CH aryl), 2926 (CH alkyl), 1617 (C N), 1532
(C C).1H NMR (DMSO-d6) ppm: δ 2.28 (s,3H, S-CH3) 2.45–2.51 (m, 2H,
CH2), 2.75–2.79 (m, 2H, CH2), 7.08–7.10 (d, 2H, phenyl), 7.16–7.23 (2d,
4H, phenyl), 7.30–7.34 (m, 1H, phenyl), 7.42–7.46 (m, 2H, phenyl), 7.65–
7.78 (d, 2H, phenyl), 8.29–8.32 (m, 1H, phenyl), 11.43 (brs, NH, D2O
exchangeable). Analysis: C28H20Cl2N4S (515.4); Requires: C, 65.24;
H, 3.91; N, 10.87. Found: C, 65.19; H, 3.90; N, 10.76.
5-(4-Chlorophenyl)-4-(4-methoxyphenylamino)-2-methylthio-
6,7-dihydrobenzo[h]-pyrimido[4,5-b]quinoline (6c)
The compound was obtained from 5 (4.24 g, 10 mmol) and 4-anisidine
(1.23 g,10 m mol), as yellow crystals, crystallized from dimethylfor-
mamide in 76% yield, m.p. 270–272◦C (melted); IR, cm−1: 3390 (brs,
1
NH), 3021 (CH aryl), 2916 (CH alkyl), 1614 (C N), 1523 (C C). H
NMR (DMSO-d6) ppm: δ 2.29 (s,3H, S-CH3) 2.46–2.52 (m, 2H, CH2),
2.74–2.78 (m, 2H, CH2), 3.87 (s, 3H, OCH3) 7.00–7.08 (d, 2H, pheny, J =
13.0 Hz), 7.12–7.18 (two duplet, 4H, phenyl), 7.23–7.29 (m, 1H, phenyl),
7.42–7.47 (m, 2H, phenyl), 7.63–7.75 (d, 2H, phenyl, J = 13.2 Hz), 8.26–
8.29 (m, 1H, phenyl), 11.43 (brs, NH, D2O exchangeable). Analysis:
C29H23ClN4OS (511.0); Requires: C, 68.15; H, 4.53; N, 10.96. Found:
C, 68.09; H, 4.51; N, 10.87.
4-(o-Carboxyphenyl)amino-5-(4-chlorophenyl)-2-methylthio-
6,7-dihydrobenzo[h]-pyrimido[4,5-b]quinoline (7)
In a warm solution of compound 5 (4.24 g, 10 mmol) in glacial acetic
acid (30 ml) was added (1.37 g, 10 mmol) of anthranilic acid. The reac-
tion mixture was stirred under reflux for 5 h, then allowed to cool to

Pyrimidoquinolines and Pyridopyrimidines
2131
0◦C for 5 h, and the solid obtained was filtered off, washed with water
(100 ml) dried, and crystallized from dioxane in 74% yield, m.p. 311–
313◦C (melted); IR, cm−1: 3520 (brs, OH), 3365 (NH), 3051 (CH aryl),
1
2917 (CH alkyl), 1713 (CO), 1604 (C N); H NMR (DMSO-d6) ppm:
δ 2.47–2.49 (t, 2H, CH2), 2.73–2.78 (t, 2H, CH2), 2.99 (s, 3H, SCH3),
6.85–6.87 (d, 2H, phenyl), 7.07–7.10 (d, 2H, phenyl), 7.28–7.32 (m, 2H,
phenyl), 7.37–7.41 (t, 2H, phenyl), 7.44–7.62 (m, 2H, phenyl), 7.64–
7.99 (m, 2H, phenyl), 11.48 (brs, NH), and 12.13 (brs, OH). Analysis:
C29H21ClN4O2S (525.0); Requires: C, 66.34; H, 4.03; N, 10.67. Found:
C, 66.23; H, 4.00; N, 10.54.
7-(4-Chlorophenyl)-benzo[h]-5,6-dihydrobenzo
[a]pyrimido[3’,2’:1,6]pyrimido[4,5-b]quinolin-13-one (8)
A solution of compound 7 (5.26 g, 10 mmol) in glacial acetic acid (40 mL)
and catalytic amount of sulfuric acid (1 mL) was stirred under reflux for
8 h. The reaction mixture was allowed to cool, poured into cold water
(100 mL), neutralized by ammonia solution, the precipitate was filtered
off washed with water, dried and crystallized from dimethylformamide
(yellow crystals) in 65% yield, m.p. 356–358◦C (dec.); IR, cm−1: 3039
(CH aryl), 2908 (CH alkyl), 1701 (CO), 1631 (C N); 1H NMR (DMSO-d6)
ppm: δ 2.45–2.48 (t, 2H, CH2), 2.71 (s, 3H, SCH3), 2.81–2.88 (t, 2H, CH2),
7.21–7.22 (d, 2H, phenyl), 7.23–7.25 (m, 2H, phenyl), 7.27–7.29 (m, 2H,
phenyl), 7.38–7.40 (t, 2H, phenyl), 7.44–7.69 (m, 2H, phenyl), and 8.30–
8.31(d, 2H, phenyl). Analysis: C29H19ClN4OS (506.9); Requires: C,
68.70; H, 3.78; N, 11.05. Found: C, 68.67; H, 3.75; N, 10.96.
5-(4-Chlorophenyl)-2,4-dihydrazino-6,7-
dihydrobenzo[h]pyrimido[4,5-b]quinoline (9)
A mixture of compound 5 (4.24 g, 10 mmol) and hydrazine hydrate
(99–100%) (10 ml) was stirred under reflux in dioxane (30 mL) and
ethanol (5 ml) for 5 h. The reaction mixture was allowed to cool to
0◦C for 5 h, the solid was collected by filtration and crystallized from
dioxane (pale yellow powder) in 79% yield, m.p. 207–210◦C (melted); IR,
cm−1: 3438 (brs, NH), 3039 (CH aryl), 2928 (CH alkyl), 1624 (C N); 1H
NMR (DMSO-d6) ppm: δ 2.00 (brs, 2H, NH2, D2O exchangeable), 2.45–
2.50 (m, 2H, CH2), 2.75–2.78 (m, 2H, CH2), 7.05–7.09 (d, 2H, phenyl),
7.14–7.18 (d, 2H, phenyl), 7.27–7.34 (m, 1H, phenyl), 7.40–7.45 (m, 2H,
phenyl), 8.32–8.35 (m, 1H, phenyl), 10.70, 11.60 (two, brs, 2NH, D2O
exchangeable). Analysis: C21H18ClN7 (403.8); Requires: C, 62.45;H,
4.49; N, 24.28. Found: C, 62.38; H, 4.51; N, 24.19.

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A. B. A. El-Gazzar et al.
7-(4-Chlorophenyl)-5,6-dihydrobezo[h]-s-triazolo[4’,3’:1,6]-s-
triazolo[3”,4”:2,3]-pyrimido[4,5-b]quinoline (10)
A mixture of compound 9 (4.03 g, 10 mmol), formic acid (20 ml) and cat-
alytic amount of concentrated hydrochloric acid was heated under reflux
for 20 h. The reaction mixture was allowed to cool to room temperature
and poured into cold water (100 ml). The solid formed was collected
by filtration, washed with water, ethanol, dried, and crystallized from
dimethylformamide (white powder) in 68% yield, m.p. 340–342◦C (dec.);
IR, cm−1: 3026 (CH aryl), 2935 (CH alkyl), 1631 (C N), 1560 (C C);
1H NMR (DMSO-d6) ppm: δ 2.46–2.50 (m, 2H, CH2), 2.74–2.78 (m, 2H,
CH2), 7.02–7.08 (d, 2H, phenyl), 7.13–7.17 (d, 2H, phenyl), 7.28–7.34 (m,
1H, phenyl), 7.40–7.45 (m, 2H, phenyl), 8.31–8.34 (m, 1H, phenyl), 9.23
(s, 1H, triazole proton), 9.39 (s, 1H, triazole proton).13C NMR (DMSO-
d6) ppm: δ 24.09, 26.98 (2C, 2CH2) 105.71, 125.76, 126.00, 126.34,
127.36, 127.80, 128.21, 128.42, 129.53, 130.67, 130.78, 132.96, 136.55,
139.18, 148.23, 148.56, 149.78, 150.09, 153.27 (19C, sp2 carbon atoms).
Its MS, [M+] m/z 423 (100%). Analysis: C23H14ClN7 (423.8); Requires:
C, 65.17; H, 3.33; N, 23.13. Found: C, 65.13; H, 3.26; N, 23.08.
3-Amino-9-(4-chlorophenylmethylene)-6-(4-chlorophenyl)-1,
2,10,11-tetrahydro-5H-thiazolo[4,5-a]cyclopentenopyrido[2,3-
d]pyrimidine-2-carbonitrile-5-one (13)
A mixture of compound 12 (4.52 g, 10 mmol), bromomalononitrile
(1.45 g, 10 mmol) and potassium carbonate anhydrous (2.76 g, 20 mmol)
was stirred under reflux in 30 mL ethanol for 12 h (under TLC con-
trol). The reaction mixture was allowed to cool to room temperature
and then poured into cold water (100 mL). The precipitate was filtered
off, dried, and crystallized from benzene, brown crystals, in 56% yield,
m.p. 330–332◦C (dec.); IR, cm−1: 3451 (brs, NH2), 3091 (CH aryl), 2921
(CH, alkyl), 2214 (CN), 1690 (CO), 1643 (C N), 1521 (C C); 1H NMR
(DMSO-d6) ppm: δ 2.63–2,74 (m, 2H, CH2), 2.75–2.88 (m, 2H, CH2),
7.16 (brs, NH2),7.46–7.48 (d, 2H, phenyl), 7.60–7.63 (d, 2H, phenyl),
7.63–7.65 (d, 2H, phenyl), 7.95–7.99 (d, 2H, phenyl), and 8.01 (s, 1H,
methylenic proton). 13C NMR (DMSO-d6) ppm: δ. 26.97, 28.06 (2C,
2CH2), 66.46 (1C, CN), 108.48, 125.04, 127.79, 128.07, 128.71, 128.77,
129.27, 129.51, 130.79, 131.00, 132.60, 135.25, 135.64, 135.89, 141.58,
147.92, 152.77, 158.68 (19C, sp2 carbon atoms) and 163.88 (CO); Its MS,
[M+], m/z 516, (100%), [M+2-H2N-C C-CN], m/z 450 (17%); Analysis:
C26H15Cl2N5OS (516.4); Requires: C, 60.47; H, 2.92; N, 13.56. Found:
C, 60.43; H, 2.90; N, 13.60.

Pyrimidoquinolines and Pyridopyrimidines
2133
8-(4-Chlorophenylmethylene)-11-(chlorophenyl)-4H-9,10-
dihydropyrimido[4’,5’:-4,5]thiazolo[3,2-a]
cyclopentenopyrido[2,3-d]pyrimidine-4,12-dione (14a)
A mixture of compound 13 (5.16 g, 10 mmol), formic acid (10 mL) and
catalytic amount of concentrated hydrochloric acid was heated under
reflux for 16 h. The reaction mixture was allowed to cool to room temper-
ature, poured into cold water (100 mL). The formed solid was collected
by filtration, washed by ethanol (20 mL), dried, and crystallized from
ethanol (pale brown) in 66% yield, m.p. 359–362◦C (melted); IR, cm−1
:
3406 (brs, NH), 3096 (CH aryl), 2941 (CH alkyl), 1693, 1687 (2CO),
1643 (C N), 1529 (C C); 1H NMR (DMSO-d6) ppm: δ 2.68–2.86 (m, 2H,
CH2), 3.02–3.14 (m, 2H, CH2), 7.25–7.31 (d, 2H, phenyl), 7.42–7.45 (2d,
4H, phenyl), 7.51–7.55 (d, 2H, phenyl), 7.62 (s, 1H, methylenic proton),
and 13.20 (brs, NH, D2O exchangeable); Analysis: C27H15Cl2N5O2S
(544.4); Requires: C, 59.56; H, 2.77; N, 12.86. Found: C, 59.60; H,
2.68; N, 12.90.
8-(4-Chlorophenylmethylene)-11-(chlorophenyl)-4H-2-methyl-
9,10-dihydropyri-mido[4’,5’:4,5]thiazolo[3,2-
a]cyclopentenopyrido[2,3-d]pyrimidine-4,12-dione (14b)
A mixture of compound 13 (5.16 g, 10 mmol), acetic acid (30 mL) was
heated under reflux for 20 h. The reaction mixture was allowed to cool
to room temperature, poured into cold water (100 mL). The formed
solid was collected by filtration, washed by ethanol (20 mL), dried, and
crystallized from ethanol (brown powder) in 67% yield, m.p. 275–277◦C
(melted); IR, cm−1: 3420 (brs, NH), 3084 (CH aryl), 2939 (CH alkyl),
1696, 1689 (2CO), 1639 (C N), 1521 (C C); 1H NMR (DMSO-d6) ppm:
δ 2.32 (s, 3H, CH3), 2.75–2.78 (t, 2H, CH2), 2.85–2.97 (t, 2H, CH2),
7.10–7.12 (d, 2H, phenyl), 7.39–7.41 (d, 2H, phenyl), 7.42–7.44 (d, 2H,
phenyl), 7.45–7.47 (d, 2H, phenyl), 8.02 (s, 1H, methylenic proton), 10.00
(brs, NH). Analysis: C28H17Cl2N5O2S (558.4); Requires: C, 60.21; H,
3.07; N, 12.54. Found: C, 62.39; H, 2.99; N, 12.60.
4-Amino-8-(4-chlorophenylmethylene)-12-(chlorophenyl)-9,10-
dihydropyrimido-[4’,5’:4,5]thiazolo[3,2-
a]cyclopentenopyrido[2,3-d]pyrimidin-12-one (15)
Method (A)
A mixture of compound (13) (5.16 g, 10 mmol), formamide (0.45 g,
10 mmol) and formic acid (2 mL) was stirred under reflux in dimethyl-
formamide (20 mL) for 6 h. The reaction mixture was allowed to cool

2134
A. B. A. El-Gazzar et al.
to room temperature, poured into water (100 mL) neutralized by am-
monia solution. The precipitate was collected by filtration washed by
water, ethanol, dried, and crystallized from dioxane in 64% yield, m.p.
295◦C (dec.); IR, cm−1: 3390 (brs, NH), 3076 (CH aryl), 2952 (CH alkyl),
1693 (CO), 1663 (NH2), 1656 (C N), 1545 (C C); 1H NMR (DMSO-d6)
ppm: δ 2.68–2.73 (t, 2H, CH2), 2.88–3.00 (t, 2H, CH2), 7.21–7.26 (d, 2H,
phenyl), 7.28–7.39 (d, 2H, phenyl), 7.41–7.44 (d, 2H, phenyl), 7.51–7.57
(d, 2H, phenyl), 7.95 (s, 1H, methylenic proton), 8.15 (s, 1H, pyrimi-
dine proton), and 11.30 (brs, NH). Analysis: C27H16Cl2N6OS (543.4);
Requires: C, 59.67; H, 2.96; N, 15.46. Found: C, 59.70; H, 2.89; N,
15.38.
Method (B)
To a warmed ethanolic sodium ethoxide solution (prepared by dis-
solving (0.23 g, 10 mmol) sodium metal in 50 mL absolute ethanol) was
added (5.43, 10 mmol) of compound (21). The mixture was stirred under
reflux for 5 h. The reaction mixture was allowed to cool to room tem-
perature, poured into cold water (100 mL), neutralized by acetic acid.
The precipitate was filtered off, dried and crystallized from dioxane in
45% yield, m.p. 293–296◦C (dec.), with the same identical data.
4-Amino-8-(4-chlorophenylmethylene)-12-(chlorophenyl)-9,10-
dihydropyrimido-[4’,5’:4,5]thiazolo[3,2-a]pyrido[2,3-d]
pyrimidine-2-(oxo/or thioxo)-12-ones (16a,b)— General
Procedure
A mixture of compound 13 (5.16 g, 10 mmol) and urea or thiourea
(10 mmol) was heated at 180◦C in test tube on sand-bath for 4 hours.
The mixture was allowed to cool to room temperature; the product was
solidified by cooling and addition of methanol (50 mL). The precipitate
formed was collected by filtration and crystallized from the proper sol-
vent to produce (16a,b).
4-Amino-8-(4-chlorophenylmethylene)-12-(chlorophenyl)-9,10-
dihydropyrimido-[4’,5’:4,5]thiazolo[3,2-a]cyclopentenopyrido
[2,3-d]pyrimidine-2,12-dione (16a)
The compound was obtained from 13 and urea (0.61g, 10 mmol),
as a dark brown, crystallized from dimethylformamide in 71% yield,
m.p. 345–346◦C (melted.); IR, cm−1: 3410 (brs, NH), 3079 (CH aryl),
2938 (CH alkyl), 1694, 1686 (2CO), 1654 (C N), 1530 (C C); 1H
NMR (DMSO-d6) ppm: δ 2.72–2.88 (m, 2H, CH2), 3.04–3.15 (m,
2H, CH2), 7.29–7.32 (d, 2H, phenyl), 7.45–7.48 (2d, 4H, phenyl),

Pyrimidoquinolines and Pyridopyrimidines
2135
7.54–7.57 (d, 2H, phenyl), 7.82 (s, 1H, methylenic proton) 12.30 (brs,
NH, D2O exchangeable), and 13.01 (brs, NH, D2O exchangeable). Anal-
ysis: C27H16Cl2N6O2S (559.42); Requires: C, 57.96; H, 2.88; N, 15.02.
Found: C, 58.01; H, 2.89; N, 15.11.
4-Amino-8-(4-chlorophenylmethylene)-12-(chlorophenyl)-9,10-
dihydropyrimido-[4’,5’:4,5]thiazolo[3,2-a]cyclopentenopyrido
[2,3-d]pyrimidine-2-thioxo-12-one (16b)
The compound was obtained from 13 and thiourea (0.77 g, 10 mmol),
as a brown crystals, crystallized from dioxane in 62% yield, m.p. 330◦C
(dec.); IR, cm−1: 3397 (brs, NH), 3084 (CH aryl), 2929 (CH alkyl), 1683
(CO), 1658 (C N), 1526 (C C); 1H NMR (DMSO-d6) ppm: δ 2.71–2.73 (t,
2H, CH2), 3.02–3.05 (t, 2H, CH2), 7.26–7.28 (d, 2H, phenyl), 7.30–7.39
(d, 2H, phenyl), 7.43–7.45 (d, 2H, phenyl), 7.50–7.53 (d, 2H, phenyl),
7.56 (s, 1H, methylenic proton), 11.87 (brs, NH), and 12.55 (brs, NH).
Analysis: C27H16Cl2N6OS2 (575.5); Requires: C, 56.34; H, 2.80; N,
14.60. Found: C, 56.36; H, 2.78; N, 14.39.
8-(4-Chlorophenylmethylene)-11-(4-chlorophenyl)-1,2,9,10-
tetrahydro-4H-10H-cyclopentenopyrido[2”,3”:4’,5’] pyrimido
[2’,1’:2,3]thiazolo[4,5-d][1,3]thiazine-12-one (17)
A mixture of compound 13 (5.16 g,10 mmol) and carbon disulphide (ex-
cess 10 mL) was heated under reflux on a water-bath (80◦C) in 20 mL
pyridine for 8 h (under TLC control). The reaction mixture was allowed
to cool to 0◦C for 3 h, the precipitate was filtered off, washed by ethanol
(20 mL), dried, and crystallized from dioxane in 59% yield, m.p. 283◦C
(dec.); IR, cm−1: 3400 (brs, NH), 3096 (CH aryl), 2947 (CH alkyl), 1685
(CO), 1661 (C N), 1535 (C C); 1H NMR (DMSO-d6) ppm: δ 2.73–2.78 (t,
2H, CH2), 3.20–3.32 (t, 2H, CH2), 6.97–6.99 (d, 2H, phenyl), 7.09–7.12
(d, 2H, phenyl), 7.29–7.41 (d, 2H, phenyl), 7.42–7.44 (d, 2H, phenyl),
8.26 (s, 1H, methylenic proton), and 12.10, 12.95 (2brs, 2NH, D2O ex-
changeable). Analysis: C27H15Cl2N5OS3 (592.5); Requires: C, 54.72; H,
2.55; N, 11.82. Found: C, 54.80; H, 2.57; N, 11.79.
3-Ethoxymethyleneamino-9-(4-chlorophenylmethylene)-6-(4-
chlorophenyl)-1,2,10,-11-tetrahydro-5H-thiazolo[4,5-a]
cyclopentenopyrido[2,3-d]pyrimidine-2-carbo-nitrile-5-
one (18)
A mixture of compound 13 (5.16 g, 10 mmol) and triethylorthoformate
(2.96 g, 20 mmol) was stirred under reflux in acetic anhydride (30 mL)

2136
A. B. A. El-Gazzar et al.
for 6 h. The reaction mixture was allowed to cool to room tempera-
ture, poured into cold water (100 mL) and neutralized by ammonia
solution. The precipitate was collected by filtration, washed by water,
dried and crystallized from methanol in 70% yield, m.p. 236–238◦C
(melted); IR, cm−1: 3390 (brs, NH), 3086 (CH aryl), 2924 (CH alkyl),
2213 (CN), 1690 (CO), 1650 (C N), 1523 (C C).1H NMR (DMSO-d6)
ppm: δ 1.24–1.28 (t, 3H, CH3), 2.56–2.58 (t, 2H, CH2) 2.81–2.84 (t, 2H,
CH2), 4.38–4.43 (q, 2H, CH2), 7.24–7.28 (d, 2H, phenyl), 7.38–7.40 (d,
2H, phenyl), 7.44–7.48 (d, 2H, phenyl), 7.5–7.63 (d, 2H, phenyl), 8.20 (s,
1H, methylenic proton), 8.44 (s, 1H, CH). Analysis: C29H19Cl2N5O2S
(572.4); Requires: C, 60.84; H, 3.34; N, 12.23. Found: C, 60.91; H,
3.38; N, 12.18.
3-Hydrazinomethyleneamino-9-(4-chlorophenylmethylene)-6-
(4-chlorophenyl)-1,2,-10,11-tetrahydro-5H-thiazolo[4,5-a]
cyclopentenopyrido[2,3-d]pyrimidine-2-carbo-nitrile-5-one
(19)
A mixture of compound 18 (5.72 g, 10 mmol), hydrazine hydrate (99–
100%) (10 mL) was stirred under reflux in a mixture of dioxane/ethanol
(20 mL/5 mL) for 8 h. The reaction mixture was allowed to cool to
room temperature, poured into cold water (100 mL), neutralized by
acetic acid. The precipitate was collected by filtration, washed by wa-
ter, dried and crystallized from dioxane in 68% yield, m.p. 289–291◦C
(melted); IR, cm−1: 3420 (brs, NH), 3069 (CH aryl), 2934 (CH alkyl),
2218 (CN), 1683 (CO), 1640 (C N), 1553 (C C).1H NMR (DMSO-d6)
ppm: δ 2.72–2.87 (m, 2H, CH2), 3.03–3.16 (m, 2H, CH2), 7.28–7.31 (d,
2H, phenyl), 7.38–7.45 (2d, 4H, phenyl), 7.48–7.53 [t, 3H, (d, 2H, phenyl
+ s, 1H, methylenic)], 7.56 (s, 1H, methylenic proton) 12.30 (brs, NH,
D2O exchangeable), and 13.00 (brs, NH, D2O exchangeable). Analysis:
C27H17Cl2N7OS (558.4); Requires: C, 58.06; H, 3.07; N, 17.55. Found:
C, 58.03; H, 3.11; N, 17.48.
3-Amino-8-(4-chlorophenylmethylene)-12-(chlorophenyl)-4-
imino-3,4,9,10-tetra-hydropyrimido[4’,5’:4,5]thiazolo[3,2-
a]cyclopentenopyrido[2,3-d]pyrimidin-12-one (20)
To a warmed ethanolic sodium ethoxide solution (prepared by dissolv-
ing (0.23 g, 10 mmol) sodium metal in 50 mL absolute ethanol) was
added (5.58 g, 10 mmol) of compound 19. The mixture was stirred under
reflux for 8 h. The reaction mixture was allowed to cool to room temper-
ature, poured into cold water (100 mL), neutralized by acetic acid. The
deposited so-precipitate was filtered off, dried, and crystallized from

Pyrimidoquinolines and Pyridopyrimidines
2137
benzene in 67% yield, m.p. 316–318◦C (melted); IR, cm−1: 3400 (brs,
NH), 3091 (CH, aryl), 2937 (CH, alkyl), 1692 (CO), 1635 (C N), 1546
1
(C C); H NMR (DMSO-d6) ppm: δ 2.68–2.73 (t, 2H, CH2), 2.88–3.00
(t, 2H, CH2), 7.19–7.27 (d, 2H, phenyl), 7.36–7.39 (d, 2H, phenyl), 7.40–
7.43 (d, 2H, phenyl), 7.44–7.46 (d, 2H, phenyl), 8.26 (s, 1H, methylenic
proton), 8.29 (s, 1H, pyrimidine proton), 10.82 (brs, 2H, NH2) and 11.30
(brs, NH). Analysis: C27H17Cl2N7OS (558.4); Requires: C, 58.07; H,
3.06; N, 17.55. Found: C, 58.10; H, 3.09; N, 17.63.
3-Aminomethyleneamino-9-(4-chlorophenylmethylene)-6-(4-
chlorophenyl)-1,2,10,-11-tetrahydro-5H-thiazolo[4,5-a]
cyclopentenopyrido[2,3-d]pyrimidine-2-carbo-nitrile-5-
one (21)
A mixture of compound 18 (5.72 g, 10 mmol) and ammonia solution
(40–50%) (10 mL) was stirred under reflux in 50 mL ethanol for 12 h.
The reaction mixture was allowed to cool to room temperature, poured
into cold water (100 mL), and neutralized by acetic acid. The deposited
so-precipitate was filtered off, washed with water, dried and crystallized
from dimethylformamide in 52% yield, m.p. 337–339◦C (dec.); IR, cm−1
:
3395, 3310 (brs, NH2), 3091 (CH aryl), 2932 (CH alkyl), 2216 (CN), 1694
(CO), 1647 (C N), 1550 (C C).1H NMR (DMSO-d6) ppm: δ 2.66–2.70 (t,
2H, CH2), 2.80–3.00 (t, 2H, CH2), 6.97–7.00 (d, 2H, phenyl), 7.11–7.16
[m, 3H, (2H, phenyl + 1H, methylenic)], 7.23–7.31 (d, 2H, phenyl), 7.45–
7.50 (d, 2H, phenyl), 8.43 (s, 1H, methylenic proton) and 12.55 (brs, NH,
D2O exchangeable). Analysis: C27H16Cl2N6OS (543.4); Requires: C,
59.67; H, 2.96; N, 15.46. Found: C, 59.71; H, 3.00; N, 15.50.
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