Synthesis of new ring systems: Isomeric 1,2,4-triazolopyrimido [4″,5″:4′,5′]thieno[3′,2′:5,6]pyrido[3,2-c] cinnolines and other related systems

Article abstract of DOI:10.1080/10426500490494642

3-Amino-2-Cyano-4-(p-tolyl)thieno[3′,2′:5,6]pyrido[3,2-c] cinnoline 1 underwent ring closures with formamide and carbon disulphide to afford pyrimidothienopyridocinnaline 2 and its pyrimido-9,11-thione derivative 3, respectively. Treatment of 1 with triethylorthoformate followed by hydrazine hydrate produced 10-amino-11-imino-pyrimido system 5, which in turn reacted with triethylorthoformate, acetic acid, carbon disulphide, and acetylacetone to cyclize into the systems, 1,2,4-triazolo, 2-methyltriazolo, triazolo-2-thione, and 1,2,4-triazepinopyrimido thienopyridocinnolines 6-8, 11, respectively. Similarly, 3-amino-2-carboxamido-thienopyridocinnoline 12 was reacted with triethylorthoformate to give pyrimidothienopyridocinnoline-11-one 13, which was treated with phosphorous oxychloride and then hydrazine hydrate to produce 11-hydrazinopyrimido system 16. Treatment of 16 with triethylorthoformate, acetic anhydride, carbon disulphide, and ethyl chloroformate afforded the systems, 1,2,4-triazolopyrimidothienopyrido-cinnoline derivatives 16-18, 20, respectively.

Full text of DOI:10.1080/10426500490494642

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SYNTHESIS OF NEW RING
SYSTEMS: ISOMERIC 1,2,4-
TRIAZOLOPYRIMIDO
[4″,5″:4′,5′]THIENO[3′,2′:5,6]PYR
AND OTHER RELATED SYSTEMS
M.Z. A. Badr , A. A. Geies , M. S. Abbady & A. A.
Dahy
a Chemistry Department, Faculty of Science, Assiut
University , Assiut, Egypt
Published online: 16 Aug 2010.
To cite this article: M.Z. A. Badr , A. A. Geies , M. S. Abbady & A. A. Dahy
(2004) SYNTHESIS OF NEW RING SYSTEMS: ISOMERIC 1,2,4-TRIAZOLOPYRIMIDO
[4″,5″:4′,5′]THIENO[3′,2′:5,6]PYRIDO[3,2C]CINNOLINES AND OTHER RELATED
SYSTEMS, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:12,
2581-2593, DOI: 10.1080/10426500490494642
To link to this article: http://dx.doi.org/10.1080/10426500490494642
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Phosphorus, Sulfur, and Silicon, 179:2581–2593, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490494642
SYNTHESIS OF NEW RING SYSTEMS:
ISOMERIC 1,2,4-TRIAZOLOPYRIMIDO
[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]THIENO[3ꢀ,2ꢀ:5,6]PYRIDO[3,2-
C]CINNOLINES AND OTHER RELATED
SYSTEMS
M. Z. A. Badr, A. A. Geies, M. S. Abbady, and A. A. Dahy
Chemistry Department, Faculty of Science, Assiut University,
Assiut, Egypt
(Received October 29, 2002; accepted May 21, 2004)
3-Amino-2-Cyano-4-( p-tolyl )thieno[ 3ꢁ,2ꢁ:5,6 ]pyrido[ 3,2-c ]cinnoline 1
underwent ring closures with formamide and carbon disulphide to
afford pyrimidothienopyridocinnaline 2 and its pyrimido-9,11-thione
derivative 3, respectively. Treatment of 1 with triethylorthoformate
followed by hydrazine hydrate produced 10-amino-11-imino-pyrimido
system 5, which in turn reacted with triethylorthoformate, acetic
acid, carbon disulphide, and acetylacetone to cyclize into the sys-
tems, 1,2,4-triazolo, 2-methyltriazolo, triazolo-2-thione, and 1,2,4-
triazepinopyrimido thienopyridocinnolines 6–8, 11, respectively. Sim-
ilarly, 3-amino-2-carboxamido-thienopyridocinnoline 12 was reacted
with triethylorthoformate to give pyrimidothienopyridocinnoline-11-
one 13, which was treated with phosphorous oxychloride and
then hydrazine hydrate to produce 11-hydrazinopyrimido system
16. Treatment of 16 with triethylorthoformate, acetic anhydride,
carbon disulphide, and ethyl chloroformate afforded the systems,
1,2,4-triazolopyrimidothienopyrido-cinnoline derivatives 16–18, 20,
respectively.
INTRODUCTION
During last few years many cinnoline derivatives have attracted con-
siderable attention because of their various pharmacological activities
such as antihypertensive,1 antithrombotic,2 anti-inflammatory,3
bronchodilators,4
immunostimulants,5
cardiovascular agents,6
Address correspondence to M. Z. A. Badr, Chemistry Department, Faculty of Science,
Assiut University, Assiut, Egypt. E-mail: m.z.badr@acc.aun.eg
2581

2582
M. Z. A. Badr et al.
anxiolytics to activate brain functions,7 and antileukemic activity.8
Similarly, they showed antibacterial, antifungal, and microbicidal
activities,9 as well as some other activities. We have reported sev-
eral research programs concerning the synthesis of novel fused S,
N-heterocycles.10 The present article deals with methods leading to a
new series of linear and angular tetra-, penta-, and hexaheterocyclic
systems of promising biological properties derived from the parent
system thienopyridocinnolines.
RESULTS AND DISCUSSION
An approach to ring closure reactions leading to target compounds
started from treatment of 3-cyano-4-(p-tolyl) pyrido [3,2-c] cinnolin-
2(1H) thione11 with chloroacetonitrile in ethanolic sodium ethox-
ide solution to produce 3-amino-2-cyano-4-(p-tolyl) thieno [3ꢁ,2ꢁ:5,6]
pyrido[3,2-c] cinnoline 1. The latter was successfully used as a strategic
starting material for synthesis of novel target polyheterocyclic systems.
Ring closure reactions of 1 by heating with formamide gave the pen-
tacyclic product 11-amino-7-(p-tolyl) pyrimido [4ꢁꢁ,5ꢁꢁ,:4ꢁ,5ꢁ] thieno [3ꢁ,2ꢁ,
-5,6] pyrido [3,2-c] cinnoline 2. Refluxing 1 with carbon disulphide in dry
pyridine produced the corresponding pyrimidothienopyridocinnoline-
9(8H), 11(10H)-dithione 3. Treatment of 1 with triethylorthoformate
in acetic acid produced the corresponding 3-ethoxymethyleneamino
derivative 4, which underwent ring closure on refluxing with hydrazine
hydrate to produce 10-amino-7-(p-tolyl) pyrimido[4ꢁꢁ,5ꢁꢁ:4ꢁ,5]thieno
[3ꢁ,2ꢁ:5,6]pyrido[3,2-c]cinnoline-11-imine 5. Treatment of 5 with tri-
ethylorthoformate in acetic acid produced 7-(p-tolyl)-1,2,4-triazolo
[4ꢁꢁꢁ,3ꢁꢁꢁ:1ꢁꢁ,6ꢁꢁ]pyrimido[4ꢁꢁ,5ꢁꢁ:4ꢁ,5ꢁ] thieno[3ꢁ,2ꢁ:5,6]pyrido[3,2-c]cinnoline
6, while refluxing 5 with acetic acid produced the corresponding 2-
methyl-1,2,4-triazolo derivative 7. Interaction of 5 with carbon disul-
phide in pyridine produced 1,2,4-triazolopyrimidothienopyridocinnolin-
2(3H)-thione 8. The latter compound was interacted separately with
ethyl chloroacetate and chloroacetaniside with anhydrous sodium ac-
etate in ethanol to give 2-ethoxycarbonylmethylthio derivative 9 and
2-p-anisilidomethylthio derivative 10, respectively. Condensation of 5
with acetylacetone in ethanol produced 12,14-dimethyl-7(p-tolyl)-1,2,4-
triazepino[6ꢁꢁꢁ,7ꢁꢁꢁ:1ꢁꢁ,6ꢁꢁ]pyrimido[4ꢁꢁ,5ꢁꢁ:4ꢁ,5ꢁ]thieno [3ꢁ,2ꢁ:5,6] pyrido[3,2-
c]cinnoline 11 (Scheme 1).
On the other hand, treatment of 3-cyano-4-(p-tolyl) pyrido [3,2-c]
cinnolin-2(1H)-thione11 with chloroacetamide in ethanolic sodium
ethoxide solution produced 3-amino-4-(p-tolyl) thieno[3ꢁ,2ꢁ:5,6]pyrido
[3,2-c] cinnolin-2-carboxamide 12, which was successfully used as

Isomeric Triazolopyrimido Cinnolines
2583
SCHEME 1
starting material for synthesis of other new heterocyclic ring sys-
tems. Ring closure reaction of 12 by heating with triethylortho-
formate in glacial acetic acid gave 7-(p-tolyl) pyrimido [4ꢁꢁ,5ꢁꢁ:4ꢁ,5ꢁ]
thieno[3ꢁ,2ꢁ:5,6]pyrido[3,2-c] cinnolin-11(10H)-one 13, which on treat-
ment with phosphorus oxychloride gave the corresponding 11-
chloropyrimidine derivative 14. The chlorine group of 14 un-
derwent nucleophilic displacement by refluxing with hydrazine
hydrate in dioxane to produce the corresponding product 11-
hydrazinopyrimidothienopyridocinnoline 15.
The hydrazino compound 15, containing an active nitrogen nucle-
ophile, was used as a strategic starting material that on treatment
with carbonyl, thionyl, and other electrophilic reagents resulted in ring
closure reactions to form the target novel series of hexaheterocyclic
systems. Annelation of 15 into an s-triazolo moiety points to high nu-
cleophilicity of the N-3 atom of the hydrazone tautomer 15ꢀ as observed
with other comparable systems.12
Thus, treatment of 15 with triethylorthoformate in acetic
acid afforded 7-(p-tolyl)-1,2,4-triazolo[4ꢁꢁꢁ,3ꢁꢁꢁ:1ꢁꢁ,6ꢁꢁ]pyrimido[4ꢁꢁ,5ꢁꢁ:4ꢁ,5ꢁ]
thieno[3ꢁ,2ꢁ:5,6] pyrido [3,2-c]cinnoline 16. The reaction of 15 with acetic
anhydride produced the corresponding 3-methyltriazolo derivative 17.
Interaction of 15 with carbon disulphide in dry pyridine produced

2584
M. Z. A. Badr et al.
triazolopyrimidothieno-pyridocinnolin-3(2H)-thione 18, which in turn
interacted with ethyl chloroacetate to give the corresponding 3-
ethoxycarbonylmethylthio derivative 19. Condensation of 15 with ethyl
chloroformate led to the formation of the corresponding triazolo-3(2H)-
one 20. On the other hand, heating 15 with acetylacetone produced 11-
(3,5-dimethylpyrazolyl) pyrimido derivative 21, while treatment of 15
with nitrous acid produced only the 11-azidopyrimido derivative 22. On
the other hand, thionation of 13 on treatment with phosphorus penta-
sulphide produced pyrimidothienopyridocinnolin-11(10H)-thioine 23,
which in turn was alkylated with ethyl iodide and ethyl chloroacetate
to produce 11-ethylthio derivative 24 and 11-ethoxycarbonylmethylthio
derivative 25, respectively (Scheme 2).
SCHEME 2
BIOLOGICAL ACTIVITY
Twelve compounds were selected and screened in vitro for their antimi-
crobial activity against three strains of bacteria (Serratia marcescens,
Staphyococcus aureus, Bacillus cereus) using filter paper disc method.13
The biological activity, as expressed by the growth of the inhibition
zones of the tested microorganism, are summarized in Table I.

Isomeric Triazolopyrimido Cinnolines
2585
TABLE I The Antimicrobial Activity of
Selected Compounds
Compd. no S. marcescens
S. aureus
B. cereus
2
3
6
8
9
10
11
14
18
19
24
25
—
12
9
—
13
—
—
—
9
11
—
—
15
13
—
—
—
15
13
9
10
12
11
—
—
12
14
12
15
9
12
—
—
—
—
14
EXPERIMENTAL
All melting points are uncorrected and were determined on an electric
melting point (GallenKamp) apparatus. IR spectra were determined
with a Shimadzu 470 IR spectrophotometer using KBr wafer technique.
1H NMR spectra were recorded on a 90 MHz Varian EM-390 spectrome-
ter in an appropiate solvent [CDCl3, dimethylsulfoxide (DMSO)-d6 and
deuterated trifluoroacetic acid (TFA-d) using tetramethylsilane (TMS)
as internal standard. 1H NMR signals for NH or NH2 in (TFA-d) solvent
were downfield. Chemical shifts are expressed in δ (ppm). Mass spectra
were measured on a GCMS-QP 1000 EX spectrometer at an ionizing
potential of 70 ev. Elemental analyses were carried out using a 240 C
Perkin Elmer analyzer.
3-Amino-2-cyano-4-( p-tolyl)thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]-
cinnoline (1)
A mixture of 3-cyano-4(p-tolyl)pyrido[3,2-c]cinnolin-2(1H)-thione11
(0.01 mol) and α-chloroacetonitrile (0.01 mol) in ethanol (50 ml) and
anhydrous sodium acetate (2 g) was refluxed for 1 h. The solid prod-
uct was separated while hot and was filtered, washed with water, and
recrystallized from acetic acid as red crystals, m.p. 250◦C, yield (80%).
IR, 3450,3300 (NH2), 2200 (CN) cm−1. 1H NMR (DMSO-d6) δ = 2.50 (s,
3H, p-CH3), 5.80 (s, 2H, NH2), 7.5–9.1 (m, 8H, ArH). Anal. Calcd for
C21C13N5S: C, 68.65; H, 3.57, N, 19.06; S, 8.73. Found: C, 68.46; H, 3.78;
N, 18.94; S, 8.85.

2586
M. Z. A. Badr et al.
11-Amino-7-( p-tolyl)pyrido[4ꢀꢀ,5ꢀꢀ,4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]-
pyrido[3,2-c]cinnoline (2)
A mixture of 1 (0.001 mol) and formamide (10 ml) was refluxed for 2 h.
The solid, which separated on cooling, was filtered and recrystallized
from ethanol as green crystals, m.p. > 360◦C, yield (75%). IR, 3450, 3350
(NH2) cm−1. 1H NMR (TFA-d) δ = 2.70 (s, 3H, p-CH3), 7.6–9.9 (m, 9H,
ArH). Anal. Calcd. for C22H14N6S: C, 66.99; H, 3.58; N, 21,31; S,8.13.
Found: C, 67.12; H, 3.70; N, 21.26; S, 8.32.
7-(p-Tolyl)pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-
c]cinnolin-9(8H), 11(10H)-dithione (3)
A mixture of 1 (0.001 mol) and carbon disulphide (4 ml) in dry pyri-
dine (20 ml) was refluxed on a water bath for 10 h. The solid product
was filtered and recrystallized from dioxane as orange crystals, m.p. >
360◦C, yield (90%). IR, 3350 (NH), 1260 (CS), 1210 (CS) cm−1. 1H NMR
(TFA-d) δ = 2.70 (s, 3H, p-CH3), 7.5–9.85 (m, 8H, ArH). MS; m/z (%),
445 (28.3), 444 (100), 443 (M+, 92.2), 442 (22.9), 429 (39.4), 428 (43.4),
376 (15.3), 213 (18.6). Anal. Calcd. for C22H13N5S3: C, 59.57; H, 2.95;
N, 15.79; S, 21.69. Found: C, 59.71; H, 3.08; N, 15.64; S, 21.86.
2-Cyano-3-(ethoxymethyleneamino)thieno[3ꢀ,2ꢀ:5,6]-
pyrido[3,2,-c]cinnoline (4)
A mixture of 1 (0.001 mol) and triethylorthoformate (10 ml) in acetic
acid (2 ml) was refluxed for 2 h. The solid product was filtered and
recrystallized from ethanol as brown crystals, m.p. 205◦C, yield (90%).
1
IR, 2200 (CN), 1623 (C N) cm−1. H NMR (DMSO-d6) δ = 1.20 (t, 3H,
CH3), 2.60 (s, 3H, p-CH3), 3.65 (q, 2H, CH2), 7.4–9.2 (m, 8H, ArH), 8.05
(s, 1H, CH O). Anal. Calcd. for C24H17N5OS; C, 68.06; H, 4.05; N,
16.54; S, 7.57. Found: C, 68.20; H, 4.22; N, 16.39; S, 7.66.
10-Amino-7-(p-tolyl)pyrimido[4ꢀ,5ꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]-
pyrido[3,2-c]cinnoline-11-imine (5)
Hydrazine hydrate (0.5 ml, 0.01 mol) was added dropwise to a solution of
4 (0.001 mol) in dioxane (40 ml) and stirred for 1 h. The precipitate was
filtered and recrystallized from dioxane as yellow crystals, m.p. 340◦C,
1
yield (80%). IR, 3300 (NH2), 3190 (NH), 1630 (C N) cm−1. H NMR
(TFA-d) δ = 2.50 (s, 3H, p-CH3), 8.70 (s, 1H, CH, pyrimido), 7.3–9.8 (m,
8H, ArH). Anal. Calcd. for C22H15N7S; C, 64.53; H, 3.69; N, 23.95; S,
7.83. Found: C, 64.62; H, 3.76; 23.86; S, 7.90.

Isomeric Triazolopyrimido Cinnolines
2587
7-(p-Tolyl)-1,2,4-triazolo[2ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]-
thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnoline (6)
A mixture of 5 (0.001 mol) and triethylorthoformate (10 ml) in acetic
acid (20 ml) was refluxed for 5 h. The precipitate was filtered and recrys-
tallized from acetic acid as yellow crystals, m.p. > 360◦C, yield (70%).
IR, 1605 (C N) cm−1. 1H NMR (TFA-d) δ = 2.65 (s, 3H, p-CH3), 7.0–9.9
(m, 8H, ArH), 9.25 (s, 1H, CH, triazolo), 9.70 (s, 1H, CH, pyrimido).
Anal. Calcd. for C23H13N7S: C, 65.86; H, 3.12; N 23.38; S, 7.64. Found:
C, 65, 78; H, 3.25; N, 23.30; S, 7.72.
2-Methyl-7-(p-tolyl)-1,2,4-triazolo[2ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido-
[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno [3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnoline (7)
A mixture of 5 (0.001 mol) and acetic acid (20 ml) was refluxed for
5 h. The precipitate was filtered and recrystallized from acetic acid as
green crystals, m.p. > 360◦C, yield (76%), IR, 1610 (C N) cm−1. 1H NMR
(TFA-d) δ = 2.65 (s, 3H, p-CH3), 3.00 (s, 3H, CH3, triazolo), 7.5–9.9 (m,
8H, ArH), 9.60 (s, 1H, CH, pyrimido). Anal. Calcd. for C24H15N7S: C,
66.50; H, 3.49; N, 22.62; S, 7.40. Found: C, 66.58; H, 3.59; N, 22.68;
S, 7.49.
7-(p-Tolyl)-1,2,4-triazolo[2ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]-
thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnolin-2(3H)-thione (8)
A mixture of 5 (0.001 mol), carbon disulphide (3 ml) and dry pyridine
(20 ml) was refluxed for 8 h. The precipitate was filtered and recrys-
tallized from pyridine as yellow crystals, m.p. > 360◦C, yield (65%).
IR, 3250 (NH), 1250 (CS), 1635 (C N) cm−1. 1H NMR (TFA-d) δ = 2.68
(s, 3H, p-CH3), 7.5–9.85 (m, 9H, 8H, ArH + 1H, CH, pyrimido). Anal.
Calcd. for C23H13N7S2: C, 61.18; H, 2.90; N, 21.72; S, 14.20. Found: C,
61.26; H, 3.03; N, 21.66; S, 14.32.
7-(p-Tolyl)-2-(ethoxycarbonylmethylthio)-1,2,4-triazolo-
[2ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrido-
[3,2-c]cinnoline (9)
A mixture of 8 (0.001 mol) and ethyl chloroformate (0.5 ml) in ethanol
(40 ml) and anhydrous sodium acetate (2 g) was refluxed for 1 h and con-
centrated. The precipitate was filtered and recrystallized from ethanol
as yellow crystals, m.p. 255◦C, yield (67%). IR, 1720 (CO), 1605 (C N)
cm−1. 1H NMR (CDCl3) δ = 1.25 (t, 3H, CH3), 2.35 (s, 3H, p-CH3), 4.10
(s, 2H, SCH2), 4.20 (q, 2H, CH2), 7.1–9.2 (m, 8H, ArH), 7.70 (s, 1H, CH,

2588
M. Z. A. Badr et al.
pyrimido). Anal. Calcd. for C27H19N7O2S2: C, 60.32; H, 3.56; N, 18.24;
S, 11.93. Found; C, 60.39; H, 3.68; N, 18.38; S, 12.04.
7-(p-Tolyl)-1,2,4-triazolo[2ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]-
thieno[3ꢀ,2ꢀ:5,6]pyrido 3,2-c]cinnolin-2-N-
( p-methoxyphenyl)thioacetamide (10)
A mixture of 8 (0.001 mol) and p-methoxychloroacetanilide (0.002 mol)
in ethanol (40 ml) and anhydrous sodium acetate (2 g) was refluxed
for 1 h. The precipitate was filtered and recrystallized from ethanol as
yellow crystals, m.p. 340◦C, yield (70%). IR, 3200 (NH), 1685 (CO), 1618
1
(C N), 1030 ( OCH3) cm−1. H NMR (TFA-d) δ = 2.52 (s, 3H, p-CH3),
2.82 (s, 3H, p-OCH3), 4.38 (s, 2H, SCH2), 7.3–9.7 (m, 13H, 12H, ArH +
1H, CH, pyrimido). Anal. Calcd. for C32H22N8O2S2: C, 62.52; H, 3.61;
N, 18.23; S, 10.43. Found: C, 62.63; H, 3.73; N, 18.30; S, 10.36.
12,14-Dimethyl-7-(p-tolyl)-1,2,4-triazepino[3ꢀꢀꢀ,2ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]-
pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]-
cinnoline (11)
A mixture of 5 (0.001 mol) and acetylacetone (0.5 ml) in ethanol (30 ml)
was refluxed for 8 h. The precipitate was filtered and recrystallized from
ethanol as brown crystals, m.p. 350◦C, yield (65%). IR, 1605 (C N), 1540
1
(C N) cm−1. H NMR (TFA-d) δ = 2.55 and 2.90 (2d, 6H, 2CH3), 2.60
(s, 3H, p-CH3), 6.50 (s, 1H, CH, triazepino), 7.5–9.9 (m, 8H, ArH), 9.55
(s, 1H, CH, pyrimido). MS; m/z (%), 475 (32.3), 474 (100), 473 (M+,
90.4), 472 (19.4), 460 (20), 459 (50.7), 458 (47.8), 434 (44.6), 433 (46.8),
432 (24.7), 420 (27.2), 419 (82.4), 418 (82.5), 213 (18.6). Anal. Calcd. for
C27H19H7S: C, 68.48; H, 4.04; N, 20.71; S, 6.77. Found: C, 68.56; H, 4.18;
N, 20.66; S, 6.82.
3-Amino-4-(p-tolyl)thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnolin-
2-carboxamide (12)
Compound 12 was prepared by heating 3-cyano-4-(p-tolyl) pyrido[3,2-
c] cinnolin-2-thioacetamide (0.01 mol) in ethanol (50 ml) and sodium
ethoxide (2 ml) at reflux for 1 h. The solid product was filtered and
recrystallized from ethanol as red crystals, m.p. 270◦C, yield (75%). IR,
3450, 3300 (NH2),1650 (CO) cm−1. 1H NMR (DMSO-d6) δ = 3.30 (s, 3H,
p-CH3), 6.10 (s, 2H, NH2), 7.40 (s, 2H, NH2), 7.4–9.1 (m, 8H, ArH). MS;
m/z(%), 386 (58.4), 385 (M+, 69.7), 384 (11.2), 369 (19.7), 368 (29.7), 367
(27.9), 353 (35.8), 352 (17.5), 342 (24.3), 341 (70.2), 340 (100), 339 (34.1),
328 (21.5), 327 (23), 326 (35.3), 325 (45), 296 (16.1), 295 (21.5). Anal.

Isomeric Triazolopyrimido Cinnolines
2589
Calcd. for C21H15N5OS: C, 65.42; H, 3.95; N, 18.17; S, 8.32. Found: C,
65.50; H, 4.03; N, 18.23; S, 8.26.
7-(p-Tolyl)pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-
c]cinnolin-11(10H)-one (13)
A mixture of 12 (0.01 mol), triethylorthoformate (20 ml) and glacial
acetic acid (2 ml) was refluxed for 2 h. The precipitate was filtered
and recrystallized from dioxane as green crystals, m.p. > 360◦C, yield
(75%). IR, 3300 (NH), 1680 (CO) cm−1. 1H NMR (TFA-d) δ = 2.60 (s, 3H,
p-CH3), 7.6–9.85 (m, 8H, ArH), 9.30 (s, 1H, CH, pyrimido). MS; m/z(%),
397(32.2), 396 (82.3), 395 (M+, 72.3), 394(39), 382(27), 381(62.3), 380
(100). Anal. Calcd. for C22H13N5OS: C, 66.82; H, 3.31; N, 17.71; S, 8.11.
Found: C, 66.90; H, 3.45; N, 17.66; S, 8.20.
11-Chloro-7-(p-tolyl)pyrimido[4ꢀꢀ,5ꢀꢀ,4ꢀ,5ꢀ]thieno-
[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnoline (14)
A mixture of 13 (0.001 mol) and phosphorous oxychloride (40 ml) was
refluxed for 4 h. The precipitate from ice/water was filtered, washed
with water, and recrystallized from dioxane as brown crystals, m.p.
295◦C, yield (83%). IR, 1580 (C N) cm−1. 1H NMR (TFA-d) δ = 2.80 (s,
3H, p-CH3), 7.6–9.80 (m, 8H, ArH), 9.32 (s, 1H, CH, pyrimido). Anal.
Calcd. for C22H12N5SCl: C, 63.84; H, 2.92; N 16.92; S, 7.75; Cl, 8.57.
Found: C, 63.95; H, 3.03; N, 16.85; S, 7.81; Cl, 8.65.
11-Hydrazino-7-(p-tolyl)pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno-
[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnoline (15)
A mixture of 14 (0.01 mol) and hydrazine hydrate (0.01 mol) in diox-
ane (30 ml) was refluxed for 30 min. The precipitate was filtered and
recrystallized from dioxane as greenish-yellow crystals, m.p. 328◦C,
1
yield (87%). IR, 3350, 3220 (NH2), 3200 (NH) cm−1. H NMR (TFA-d)
δ = 2.65 (s, 3H, p-CH3), 7.6–9.9 (m, 9H, 8H, ArH+1H,CH, pyrimido).
Anal. Calcd. for C23H13N7S: C, 65.86; H, 3.12; N, 23.83; S, 7.64. Found:
C, 65.92; H, 3,25; N, 23.76; S, 7.72.
7-(p-Tolyl)-1,2,4-triazolo[4ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]-
thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnoline (16)
A mixture of hydrazino compound 15 (0.001 mol), triethylorthoformate
(5 ml) and acetic acid (0.01 mol) was refluxed for 6 h. The precipitate was
filtered and recrystallized from acetic acid as greenish-yellow-crystals,

2590
M. Z. A. Badr et al.
1
m.p. > 360◦C, yield (80%). IR, 1595 (C N) cm−1. H NMR (TFA-d) δ =
2.50 (s, 3H, p-CH3), 8.70 (s, 1H, CH, triazolo), 7.5–9.95 (m, 8H, ArH),
9.66 (s, 1H, CH, pyrimido). MS; m/z(%), 421 (27.5), 420 (75.2), 419 (M+,
45.6), 418 (47.7), 406 (45.6), 405 (100), 404 (81.2), 183 (20.1), 182 (16.1),
67 (20.8). Anal. Calcd. for C23H13N7S: C, 65.86; H, 3.12; N, 23.38; S,
7.64. Found: C, 65.94; H, 3.25; N, 23.29; S, 7.71.
3-Methyl-7-(p-tolyl)-1,2,4-triazolo[4ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido-
[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ] thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c] cinnoline (17)
A mixture of 15 (0.001 mol) and acetic anhydride (20 ml) was re-
fluxed for 6 h. The solid product was filtered and recrystallized from
acetic acid as greenish-yellow crystals, m.p. > 360◦C, yield (78%). IR,
1600(C N) cm−1. 1H NMR (TFA-d) δ = 2.65 (s, 3H, p-CH3), 3.22 (s, 3H,
CH3), 9.35 (s, 1H, CH, pyrimido), 7.47–9.9 (m, 8H, ArH). Anal. Calcd.
for C24H15N7S: C, 66.50; H, 3.49; N, 22.62; S, 7.40. Found: C, 66.57; H,
3.56; N, 22.54; S, 7.46.
7-(p-Tolyl)-1,2,4-triazolo[4ꢀꢀꢀ,3ꢀꢀꢀ: 1ꢀꢀ,6ꢀꢀ]pyrimido-
[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ] thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnolin-3(2H)-
thione (18)
A mixture of 15 (0.001 mol), carbon disulphide (2 ml) and dry pyridine
(20 ml) was refluxed on water bath for 8 h. The precipitate was filtered
and recrystallized from pyridine as golden crystals, m.p. > 360◦C, yield
(80%). IR, 3500 (NH), 2700(SH), 1280 (CS) cm−1. 1H NMR (TFA-d) δ =
2.70 (s, 3H, p-CH3), 7.5–9.85 (m, 9H, 8H, ArH + 1H, CH, pyrimido).
Anal. Calcd. for C23H13N7S2: C, 61.18; H, 2.90; N, 21.72; S, 14.20. Found:
C, 61.23; H, 2.98; N, 21.66; S, 14.28.
7-( p-Tolyl)-3-(ethoxycarbonylmethylthio)-1,2,4-triazolo-
[4ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrido-
[3,2-c]cinnoline (19)
A mixture of 18 (0.001 mol), ethyl chloroacetate (0.5 ml) in ethanol
(30 ml) and anhydrous sodium acetate (2 g) was refluxed for 30 min.
The solid product was filtered and recrystallized from ethanol as yellow
crystals, m.p. 300◦C, yield (85%). IR, 1720 (CO) cm−1. 1H NMR (CDCl3)
δ = 1.25 (t, 3H, CH3), 2.35 (s, 3H, p-CH3), 4.28 (s, 2H, SCH2), 4.42 (q, 2H,
CH2), 7.2–9.3 (m, 8H, ArH), 7.60 (s, 1H, CH, pyrimido). MS; m/z(%), 538
(18); 537 (M+, 45.8), 522(29.5), 420 (35.2), 419 (100), 418(87), 405(19.7),
404(23.1), 403 (20.3) 365 (19.1). Anal. Calcd. for C27H19N7O2S2: C,

Isomeric Triazolopyrimido Cinnolines
2591
60.32; H, 3.56; N, 18.24; S, 11.93. Found: C, 60.39; H, 3.64; N, 18.19;
S, 11.98.
7-(p-Tolyl)-1,2,4-triazolo[4ꢀꢀꢀ,3ꢀꢀꢀ:1ꢀꢀ,6ꢀꢀ]pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]-
thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnolin-3(2H)-one (20)
A mixture of 15 (0.001 mol), ethyl chloroformate (0.002 mol) and dry
pyridine (20 ml) was refluxed for 30 min. The precipitate was filtered
and recrystallized from acetic acid as yellow crystals, m.p. > 360◦C,
yield (70%). IR, 3200 (NH), 1700 (CO) cm−1. 1H NMR (TFA-d) δ = 2.50
(s, 3H, p-CH3), 7.5–9.9 (m, 8H, ArH), 8.90 (s, 1H, CH, pyrimido). Anal.
Calcd. for C23H13N7OS: C, 63.44; H, 3.01; N, 22.52; S, 7.36. Found: C,
63.50; H, 3.10; N, 22.46; S, 7.41.
7-(p-Tolyl)-11-(3,5-dimethylpyrazolyl)pyrimido-
[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrido [3,2-c]cinnoline (21)
A mixture of 15 (0.001 mol) and acetylacetone (0.005 mol) in ethanol
(40 ml) was refluxed for 6 h. The precipitate was filtered while hot and
recrystallized from ethanol as orange crystals, m.p. 327◦C, yield (82%).
1
IR, 1590 (C N) cm−1. H NMR (TFA-d) δ = 2.40 (s, 3H, CH3), 2.70 (s,
3H, CH3) 2.89 (s, 3H, p-CH3), 6.50 (s, 1H, CH, pyrazolo), 7.7–9.9 (m, 8H,
ArH), 9.20 (s, 1H, CH, pyrimido). MS; m/z (%), 475 (20.6), 474 (47.5),
473 (M+, 100), 472 (46), 459 (33.8), 458 (54.4), 437 (22.4), 436 (17.5), 77
(14.1). Anal. Calcd. for C27H19N7S: C, 68.48; H, 4.04; N, 20.71; S, 6.77.
Found: C, 68.54; H, 4.11; N, 20.66; S, 6.85.
11-Azido-7-(p-tolyl)pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]-
pyrido[3,2-c]cinnoline (22)
Sodium nitrite solution (7 ml, 10%, 0.01 mol) was added dropwize to
a solution of hydrazino compound 15 (0.002 mol) in dilute HCl (10 ml,
50%) at 0◦C during 10 min with stirring. The precipitate was filtered
and recrystallized from ethanol as green crystals, m.p. 280◦C (dec),
yield (70%). IR, 2130(N3)cm−1. 1H NMR (TFA-d) δ = 2.67 (s, 3H, p-CH3),
7.55–9.0 (m, 8H, ArH), 9.20 (s, 1H, CH, pyrimido). Anal. Calcd. for
C22H12N8S: C, 62.84; H, 2.88; N, 26.65; S, 7.63. Found: C, 62.79; H,
2.97; N, 26.59; S, 7.69.
7-(p-Tolyl)pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-
c]cinnolin-11(10H)-thione (23)
A mixture of pyrimidone 13 (0.001 mol) and phosphorous pentasulphide
(0.0012 mol) in dry pyridine (15 ml) was refluxed for 4 h and poured on

2592
M. Z. A. Badr et al.
ice/water. The precipitate was filtered, washed with water, and recrys-
tallized from acetic acid as brown crystals, m.p. > 360◦C, yield (80%).
IR, 3200 (NH), 1280 (CS), 1630 (C N) cm−1. 1H NMR (TFA-d) δ = 2.61
(s, 3H, p-CH3), 9.40 (s, 1H, CH, pyrimido), 7.68–9.86 (m, 8H, ArH). Anal.
Calcd for, C22H13N5S2: C, 64.21; H, 3.18; N, 17.02; S, 15.58. Found: C,
64.27; H, 3.26; N, 17.08; S, 15.63.
7-(p-Tolyl)-11-(ethylthio)pyrimido[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno-
[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnoline (24)
A mixture of 23 (0.001 mol), iodoethane (0.05 ml) in ethanol (20 ml) and
anhydrous sodium acetate (1.5 g) was refluxed for 1 h. The precipitate
was filtered and recrystallized from ethanol as yellow crystals, m.p.
280◦C, yield (70%). IR, 1520 (C N) cm−1. 1H NMR (TFA-d) δ = 1.65 (t,
3H, CH3), 2.50 (s, 3H, p-CH3), 3.80 (q, 2H, CH2), 7.7–9.8 (m, 8H, ArH),
9.10 (s, 1H, CH, pyrimido). Anal. Calcd. for C24H17N5S2: 65.58, H, 3.90;
N, 15.93; S, 14.59. Found: C, 65.63; H, 3.98; N, 15.88; S, 14.66.
7-(p-Tolyl)-11-(ethoxycarbonylmethylthio)pyrimido-
[4ꢀꢀ,5ꢀꢀ:4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrido[3,2-c]cinnoline (25)
A mixture of 23 (0.001 mol), ethyl chloroacetate (0.25 ml) in ethanol
(20 ml), and anhydrous sodium acetate (2 g) was refluxed for 1 h. The
precipitate was filtered and recrystallized from ethanol as yellow crys-
1
tals, m.p. 185◦C, yield (85%). IR, 1720 (CO) cm−1. H NMR (CDCl3)
δ = 1.35 (t, 3H, CH3), 2.50 (s, 3H, p-CH3), 4.19 (q, 2H, CH2), 4.20 (s, 2H,
SCH2), 7.2–9.25 (m, 9H, 8H, ArH + 1H, CH, pyrimido). Anal. Calcd. for,
C26H19N5O2S2: C, 62.76; H, 3.85; N, 14.08; S, 12.89. Found: C, 62.82; H,
3.92; N, 14.13; S, 12.83.
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