New heterocycles from thienopyridocinnolines

Article abstract of DOI:10.1139/v98-048

3-Cyano-4-(p-tolyl)pyrido[3,2-c]cinnolin-2(1H) thione 3 was reacted with α-halo ketones, esters, or amides to give the intermediates, S-alkylated products 5b-h, respectively, which underwent intramolecular ring closure reactions with ethanolic sodium ethoxide to give thienopyridocinnolines 6a- h. Pyrimidothienopyridocinnolines 9 and 11 were obtained by treatment of oxazino compound 8 with hydrazine hydrate and ammonium acetate. Treatment of hydrazino derivative 13 with acetylacetone, triethylorthoformate, carbon disulphide, ethyl chloroformate, and acetic anhydride afforded triazolopyrimidothienopyridocinnolines 14-16, 18, and 21, while with nitrous acid the corresponding tetrazolo compound 19 was produced. 3-Cyano-4-(p-tolyl)pyrido[3,2-c]cinnolin-2(1H) thione 3 was reacted with α-halo ketones, esters, or amides to give the intermediates, S-alkylated products 5b-h, respectively, which underwent intramolecular ring closure reactions with ethanolic sodium ethoxide to give thienopyridocinnolines 6a-h. Pyrimidothienopyridocinnolines 9 and 11 were obtained by treatment of oxazino compound 8 with hydrazine hydrate and ammonium acetate. Treatment of hydrazino derivative 13 with acetylacetone, triethylorthoformate, carbon disulphide, ethyl chloroformate, and acetic anhydride afforded triazolopyrimidothienopyridocinnolines 14-16,18, and 21, while with nitrous acid the corresponding tetrazolo compound 19 was produced.

Full text of DOI:10.1139/v98-048

469
New heterocycles from thienopyridocinnolines
M.Z.A. Badr, A.A. Geies, M.S. Abbady, and A.A. Dahy
Abstract: 3-Cyano-4-(p-tolyl)pyrido[3,2-c]cinnolin-2(1H) thione 3 was reacted with α-halo ketones, esters, or amides to give
the intermediates, S-alkylated products 5b–h, respectively, which underwent intramolecular ring closure reactions with
ethanolic sodium ethoxide to give thienopyridocinnolines 6a–h. Pyrimidothienopyridocinnolines 9 and 11 were obtained by
treatment of oxazino compound 8 with hydrazine hydrate and ammonium acetate. Treatment of hydrazino derivative 13 with
acetylacetone, triethylorthoformate, carbon disulphide, ethyl chloroformate, and acetic anhydride afforded
triazolopyrimidothienopyridocinnolines 14–16, 18, and 21, while with nitrous acid the corresponding tetrazolo compound 19
was produced.
Key words: thienopyridocinnolines; their pyrimido, triazolopyrimido, and heteroannelated systems.
Résumé : La 3-cyano-4-(p-tolyl)pyrido[3,2-c]cinnolin-2(1H) thione (3) réagit avec les α-halogéno cétones, esters ou amides
pour conduire respectivement aux produits S-alkylés intermédiaires 5b–h qui, sous l’influence de l’éthylate de sodium en
solution dans l’éthanol, subissent des réactions de fermetures de cycle intramoléculaires fournissant les thiénopyridocinnolines
6a–h. On a obtenu les pyrimidothiénopyridocinnolines 9 et 11 par traitement du composé oxazine 8 avec de l’hydrate
d’hydrazine et de l’acétate d’ammonium. Le traitement du dérivé hydrazino 13 par de l’acétylacétone, de l’orthoformate
d’éthyle, du disulfure de carbone, du chloroformate d’éthyle et de l’anhydride acétique conduit aux
triazolopyrimidothiénopyridocinnolines 14–16, 18 et 21 alors que sa réaction avec l’acide nitreux conduit à la formation du
composé tétrazolo correspondant 19.
Mots clés : thiénopyridocinnolines; systèmes pyrimido, triazolopyrimido et hétérocycliques correspondants.
[Traduit par la rédaction]
Introduction
in dry pyridine, gave the corresponding-2(1H)thione deriva-
tive 3. Alkylation of 3 with alkyl (benzyl)halides or ethyl chlo-
roformate in the presence of anhydrous sodium acetate gave
the corresponding 2-alkylthio compounds 4a–d (Scheme 1).
Similarly, treatment of 3 with α-halo ketones, esters, and
(or) acylamides or acetanilides in basic medium gave the cor-
responding 2-substituted thio compounds 5b–h, which in turn,
as active starting materials, underwent nucleophilic ring clo-
sure reactions when treated with ethanolic sodium ethoxide
solution to produce a new series of tetracyclic substituted
thieno[3′,2′:5,6]pyrido[3,2-c]cinnolines 6b–h. The corre-
sponding 6a isomer was produced directly from treatment of
3 with α-chloroacetone without separation of the acyclic al-
kylthio intermediate 5a. 3-Amino-2-ethoxycarbonyl-4-(p-
tolyl)thieno[3′,2′:5,6]pyrido[3,2-c]cinnoline 6c was success-
fully used as a strategic starting material to synthesize the
novel pentaheterocyclic target compound 11 together with
other analogs 9 and 10 through the intermediate oxazine com-
pound 8.
Cinnoline derivatives have been reported to constitute an im-
portant class of biologically active reagents (1). They have
shown antibacterial (2), antifungal (3), and other microbicide
(4) activities. Similarly, thienocinnolines and other derivatives
have shown various pharmacological activities, such as acting as
antihypertensive agents (5), bronchodilators (6), antioxylate
drugs to improve brain functions (7), and immunostimulants (8),
together with many other activities reported in the literature (9).
Results and discussion
As a continuation of our studies on the synthesis and chemistry
of different new heteroannelated ring systems related to
phthalazines, quinoxalines, pyrimidines, and other systems
(10), we report in the present paper the synthesis and chemistry
of a novel series of linear and angular tetra-, penta-, and hexa-
heterocyclic ring systems based on the cinnoline moiety. An
approach to ring closure reactions leading to target compounds
started from 4-amino-3-(p-methylbenzoylcinnoline 1 (11),
which reacted with ethyl cyanoacetate and ammonium acetate
to produce 3-cyano-4-(p-tolyl)pyrido[3,2-c]cinnolin-2(1H)-one
2, which in turn, on refluxing with phosphorus pentasulphide
Alkaline hydrolysis of 2-ethoxycarbonyl derivative 6c gave
the corresponding 2-carboxylic acid derivative 7.
Ring closure reactions of the 3-amino-2-carboxylic acid
compound 7 by heating with acetic anhydride gave the pen-
tacyclic intermediate oxazino [4′′,5′′:4′,5′]thieno[3′,2′:5,6]-
pyrido[3,2-c]cinnolin-11-one 8. Refluxing of oxazino
compound 8 with ammonium acetate in acetic acid produced
pyrimido thienopyridocinnolin-11(10H)one 11. Refluxing 8
with hydrazine hydrate in dry pyridine produced the corre-
sponding 10-amino-11(10H)pyrimidone 9, which condensed
with aromatic aldehydes to give the corresponding arylidene-
amine derivatives 10a and 10b. Treatment of the 11-pyrimidone
Received April 18, 1997.1
M.Z.A. Badr,2 A.A. Geies, M.S. Abbady, and A.A. Dahy.
Chemistry Department, Faculty of Science, Assiut University,
Assiut, Egypt.
1
Revision received October 10, 1997.
Author to whom correspondence may be addressed.
2
Can. J. Chem. 76: 469–476 (1998)
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Can. J. Chem. Vol. 76, 1998
Scheme 1.
11 with phosphorus oxychloride gave the corresponding 11-
chloropyrimidine derivative 12 (Scheme 2). The chlorine
group of 12 underwent nucleophilic displacement by reflux
with hydrazine hydrate in dioxane to produce 11-hydrazi-
nopyrimidothienopyridocinnoline 13, which condensed with
aromatic aldehydes to give the corresponding 11-arylidinehy-
drazono derivatives 18a and 18b. Similarly, heating 13 with
acetylacetone produced the corresponding 11-(3,5-di-
methylpyrazolyl) derivative 14.
The hydrazino compound 13 containing an active nitrogen
nucleophile was used as strategy material and on treatment
with carbonyl, thionyl, or other electrophilic reagents under-
went ring closure reactions into a novel series of hexahetero-
cyclic target compounds. Such reactions favor the existence of
the hydrazone tautomer 13 (12).
pyrimido[4′′,5′′:4′5′]thieno[3′,2′:5,6]pyrido[3,2-c]-cinnoline
15. The reaction between 13 and acetic anhydride produced
the corresponding 3-methyltriazolo derivative 21.
The interaction of 13 with carbon disulphide in pyridine
produced the triazolopyrimidothienopyridocinnolin-3-thione
16. The latter interacted with ethyl chloroacetate to give the
3-ethoxycarbonylmethylthio derivative 17. On the other hand,
condensation of 13 with ethyl chloroformate led to the forma-
tion of the correspondingtriazolo-3-one compound 20. The in-
teraction of 13 with sodium nitrite in dilute hydrochloric acid,
while cooling, afforded the corresponding tetrazolopyrimi-
dothieno-pyridocinnoline 19.
Experimental
Treatment of 13 U 13′ with triethylorthoformate in acetic
acid afforded 5-methyl-7-(p-tolyl)triazolo[3′′′,4′′′:1′′,6′′]-
All melting points are uncorrected and were determined on an
electric melting point (Gallenkamp) apparatus. IR spectra were
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Badr et al.
Scheme 2.
3-Cyano-4-(p-tolyl)pyrido[3,2-c]cinnolin-2(1H)-one (2)
determined with a Shimadzu 470 IR spectrophotometer using
1
KBr wafer technique. H NMR spectra were recorded on a
90 MHz Varian EM-390 spectrometer in an appropriate sol-
A mixture of 1 (0.1 mol), ethyl cyanoacetate (0.03 mol), and
ammonium acetate (0.05 mol) was heated under reflux for 3 h.
After cooling, the precipitate was filtered off, washed with
boiling ethanol, and recrystallized from dioxane as yellow
crystals, mp >360°C, yield 56%. IR: 3100 (NH); 2200 (CN),
1650 (CO) cm–1; 1H NMR (DMSO) δ: 3.50 (s, 3H, CH3) and
7.2–9.1 (m, 8H, ArH). Anal. calcd. for C19H12N4O: C 73.07, H
3.87, N 17.94; found: C 72.92, H 3.76, N 17.62%.
vent (CDCl3, DMSO-d6, or deuterated trifluoroacetic acid
1
(TFA)) using TMS as internal standard. H 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
GC–MS QP 1000 EX spectrometer at an ionizing potential of
70 eV. Elemental analyses were carried out using a 240C Per-
kin Elmer analyser.
3-Cyano-4-(p-tolyl)pyrido[3,2-c]cinnolin-2(1H)-thione (3)
A mixture of 2 (0.01 mol) and phosphorus pentasulphide (0.01
mol) in dry pyridine (20 mL) was refluxed for 4 h, then poured
into ice-water. The precipitated solid was filtered, washed with
water, and recrystallized from dioxane as orange crystals, mp
315–317°C, yield 86%. IR: 3280 (NH), 2200 (CN), 1250
4-Amino-3-(p-methyl benzoyl)cinnoline (1)
A mixture of phenylhydrazonomalononitrile (0.1 mol), tolu-
ene (150 mL), and aluminium chloride (0.4 mol) was refluxed
for 3 h. The separated product was crystallized from ethanol,
mp 210°C (lit. (11) mp 210–212°C).
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Table 1. Analytical, spectral, and physical data of compounds, 4a–4d.
Analysis calcd./found (%)
Spectral data
Comp.
no.
Mol.
mp,°C Color Yield%
formula
C
H
N
S
IR (KBr) cm–1
(CN) 2200
1H NMR δ (ppm)
1H NMR (TFA-d) δ: 2.50 (s, 3H,
p-CH3), 3.20 (s, 3H, SCH3), 7.5–9.5
(m, 8H, ArH)
70.15 4.12 16.36 9.36
69.89 4.07 16.08 9.18
4aa
4b
4c
306°C Yellow
285°C Yellow
265°C Yellow
87
80
83
C22H14N4S
C21H16N4S
C26H18N4S
1H NMR (CDCl3) δ: 1.60 (t, 3H, CH3
ester), 2.50 (s, 3H, p-CH3), 3.60 (q,
2H, CH2), 7.4–9.2 (m, 8H, ArH)
70.76 4.52 15.72 8.99
70.55 4.72 15.54 8.67
(CN) 2200
(CN) 2200
1H NMR (CDCl3) δ: 2.50 (s, 3H,
p-CH3), 4.80 (s, 2H, CH2), 7.2–9.2
(m, 13H, ArH)
74.60 4.30 13.39 7.66
74.50 4.18 13.56 7.38
1H NMR (CDCl3) δ: 1.45 (t, 3H,
CH2CH3), 2.55 (s, 3H, p-CH3), 4.50
(q, 2H, CH2), 7.25–9.3 (m, 8H, ArH)
Yellow-
65.98 4.30 13.99 8.01
(CN) 2200,
(CO) 1720
4d
154°C orange
70
C22H16N4O2S 65.86 3.90 13.77 7.65
a All products were recrystallized from ethanol except 4a from acetic acid.
(CTS) cm–1.1H NMR (TFA-d) δ: 2.42 (s, 3H, p-CH3) and
7.2–9.4 (m, 8H, ArH). Anal. calcd. for C19H12N4S: C 69.5, H
3.68, N 17.06, S 8.76; found: C 69.65, H 3.80, N 17.12, S
8.68%.
2-(3-Amino-4-(p-tolyl)thieno[3′,2′:5,6]pyrido[3,2-c]-
cinnolinyl)carboxylic acid (7)
A mixture of 6c (0.01 mol) and alcoholic sodium ethoxide
(30 mL, 25%) was refluxed for 3 h. Sodium salt precipitated
and was filtered and acidified in water (200 mL) with dilute
HCl. The solid free acid was filtered and recrystallized from
acetic acid as yellow crystals, mp 330°C, yield 70%. IR: 3400,
3300 (NH2) cm–1. 1H NMR (DMSO) δ: 2.48 (s, 3H, CH3), 6.55
(s, 2H, NH2), 10.20 (s, 1H, OH), both of them exchangeable
with D2O, and 7.1–9.2 (m, 8H, ArH). Anal. calcd. for
C21H14N4O2S: C 65.27, H 3.65, N 14.50, S 8.30; found: C
65.31, H 3.87, N 14.06, S 7.97%.
2-Alkyl (aralkyl)thio-3-cyano-4-(p-tolyl)pyrido[3,2-c]-
cinnoline (4a–d)
General procedure
A mixture of 3 (0.01 mol) and alkyl (or benzyl) halide or ethyl
chloroformate (0.01mol) was refluxed in ethanol (30 mL) and
anhydrous sodium acetate (2 g) for 1 h. The reaction mixture
was concentrated to half volume and cooled. The precipitated
solid was filtered and recrystallized from an appropriate sol-
vent. The analytical, spectral, and physical data are summa-
rized in Table 1.
9-Methyl-7-(p-tolyl)oxazino[4′′,5′′:4′,5′]thieno[3′,2′:5,6]-
pyrido[3,2-c]cinnolin-11-one (8)
A mixture of 7 (0.01 mol) and acetic anhydride (20 mL) was
refluxed for 2 h. The solid separated on cooling was filtered
and recrystallized from dioxane as yellow crystals, mp 320°C,
yield 74%. IR: 1750 (CO) cm–1. 1H NMR (TFA-d) δ: 2.58 (s,
3H, p-CH3), 2.70 (s, 3H, CH3), 7.4–9.85 (m, 8H, ArH). MS,
m/z (%): 411 (M + 1, 29), 410 (M+, 100). Anal. calcd. for
C23H14N4O2S: C 67.3, H 3.44, N 13.65, S 7.81; found: C 66.96,
H 3.89, N 13.60, S 8.00%.
3-Cyano-4-(p-tolyl)-2-substituted
thiopyrido[3,2-c]cinnoline (5b–h)
The corresponding α-halo compound was treated with 3
following the same procedure as above. The separated solid
was filtered, washed with water, and recrystallized from an
appropriate solvent. The analytical, spectral, and physical data
are summarized in Table 2.
10-Amino-9-methyl-7-(p-tolyl)pyrimido[4′′,5′′:4′,5′]thieno-
[3′,2′:5,6]pyrido[3,2-c]-cinnolin-11(10H)-one (9)
A mixture of the oxazino compound 8 (0.01 mol) and hydra-
zine hydrate (0.01 mol) in dry pyridine (30 mL) was refluxed
for 1 h. The solid separated on cooling was filtered and recrys-
tallized from dioxane into yellow crystals, mp >360°C, yield
82%. IR: 3402, 3300 (NH2), 1660 (CO) cm–1. 1H NMR (TFA-
d) δ: 2.90 (s, 3H, p-CH3), 3.18 (s, 3H, CH3), 7.65–9.95 (m, 8H,
ArH). Anal. calcd. for C23H16N6OS: C 65.08, H 3.80, N 19.80,
S 7.55; found: C 64.90, H 4.00, N 19.32, S 7.23%.
3-Amino-2-substituted-4-(p-tolyl)thieno[3′,2′:5,6]pyrido-
[3,2-c]cinnoline (6a–h)
General procedure
A mixture of each of the mercapto derivatives (5b–h) (0.01
mol) in ethanol (50 mL) and five drops of ethanolic sodium
ethoxide was refluxed for 30 min. The solid product was fil-
tered and recrystallized from a suitable solvent. 6a was sepa-
rated directly on treating α-chloracetone and 3 with anhydrous
sodium acetate as above. The analytical, spectral, and physical
data are summarized in Table 3.
10-Arylidene amine derivatives of 9 (10a and 10b)
These were prepared by refluxing 9 (0.01 mol) with each of
(a) benzaldehyde and (b) p-anisaldehyde (0.01 mol) in glacial
acetic acid (20 mL) for 30 min. The solid product in each case
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Badr et al.
Table 2. Analytical, spectral, and physical data of compounds, 5b–5h.
Analysis calcd./found (%)
Spectral data
Comp.
no.
Mol.
mp, °C
Color Yield%
formula
C
H
N
S
IR (KBr) cm–1
1H NMR δ (ppm), and MS, m/z (%)
72.63 4.03 12.55 7.18
(CN) 2200,
(CO) 1670
1H NMR (DMSO) δ: 2.85 (s, 3H, p-CH3),
5.00 (s, 2H, SCH2), 7.3–8.9 (m, 13H,ArH)
5b
5c
5d
5e
5f
230°C Yellow 75
C27H18N4OS 72.78 3.89 12.32 7.32
1H NMR (CDCl3) δ: 1.20 (t, 3H, CH2
CH3), 2.40 (s, 3H, p-CH3), 4.20 (q, 2H,
CH2), 7.2–9.2 (m, 8H, ArH)
66.65 4.38 13.52 7.74
(CN) 2200,
(CO) 1720
221°C Yellow 79
C23H18N4O2S 66.85 4.36 13.29 7.48
(NH2) 3800, 3600, 1H NMR (TFA-d) δ: 2.50 (s, 3H, p-CH3),
65.43 3.90 18.17 8.37
(CN) 2200,
4.55 (s, 2H, CH2), 7.2–9.5 (m, 8H, ArH)
286–287°C Yellow 76
Green-
C21H15N5OS 65.21 3.88 18.34 8.16
(CO) 1670
(NH) 3300,
(CN) 2200,
(CO) 1660
1H NMR (CDCl3 + drop TFA-d) δ: 2.50 (s,
3H, CH3), 4.35 (s, 2H, CH2), 6.9–9.4 (m,
13H, ArH) MS, m/z (%): 461 (M+, 51%)
70.26 4.15 15.17 6.95
289–290°C yellow
76
70
81
C27H19N5OS 70.06 4.10 14.98 6.82
1H NMR (DMSO) δ: 2.20 (s, 3H, p-CH3),
2.50 (s, 3H, p-CH3), 4.40 (s, 2H, CH2),
6.95–9.2 (m, 12H, ArH), 10.55 (s, 1H, NH)
Green-
70.72 4.45 14.73 6.74 (NH) 3300, (CN)
300°C
yellow
Green-
C28H21N5OS 70.53 4.28 14.64 6.48 2200, (CO) 1655
(NH) 3300,
1H NMR (DMSO) δ: 2.20 (s, 3H, p-CH3),
3.20 (s, 3H, OCH3), 4.20 (s, 2H, CH2),
6.5–8.95 (m, 12H, ArH), 10.30 (1H, NH)
68.42 4.31 14.25 6.52
(CN) 2200,
(CO) 1650
5g
300–302°C yellow
C28H21N5OS 68.66 4.45 14.14 6.51
(NH) 3300,
(CN) 2200,
(CO) 1660
1H NMR (DMSO) δ: 2.50 (s, 3H, p-CH3),
4.50 (s, 2H, CH2), 7.2–9.2 (m, 12H,
ArH), 7.85 (s, 1H, NH)
Green-
65.38 3.66 14.12 6.47
5ha
325°C
yellow
84 C27H18 CIN4OS 65.28 3.76 14.00 6.35
a Chlorine analysis for 5h, calcd.: 7.15; found: 7.34%.
was filtered and recrystallized from ethanol. The analytical,
spectral, and physical data are summarized in Table 4.
11-Hydrazino-9-methyl-7-(p-tolyl)pyrimido[4′′,5′′:4′,5′]-
thieno[3′,2′:5.6]pyrido[3.2-c]-cinnoline (13)
The chloro compound 12 (0.01 mol) and hydrazine hydrate
(0.01 mol) in dioxane (30 mL) were refluxed for 30 min. The
separated solid was filtered and recrystallized from dioxane as
yellow crystals, mp 300°C, yield 85%. IR: 3350 (NH2), 3200
(NH) cm–1; 1H NMR (TFA-d) δ: 2.69 (s, 3H, p-CH3), 2.73 (s,
3H, CH3), 7.6–9.9 (m, 8H, ArH). Anal. calcd. for C23 H17N7S:
C 65.23, H 4.05, N 23.15, S 7.57; found: C 64.92, H 4.25, N
23.25, S 7.87%.
9-Methyl-7-(p-tolyl)pyrimido[4′′,5′′:4′,5′]thieno[3′,2′:5,6]-
pyrido[3,2-c]cinnolin-11(10H)-one (11)
Refluxing the oxazino compound 8 (0.01 mol) and ammonium
acetate in acetic acid (30 mL) for 30 min precipitated a solid
that was filtered and recrystallized from acetic acid as yellow
crystals, mp 320°C, yield 80%. IR: 3600 br (NH), 1650
(CO) cm–1; 1H NMR (TFA-d) δ: 2.70 (s, 3H, p-CH3), 2.92 (s,
3H, CH3), 7.7–9.9 (m, 8H, ArH). Anal. calcd. for C23H15N5OS:
C 67.47, H 3.69, N 17.10, S 7.83; found: C 65.7, H 4.00, N
16.95, S 7.69%.
9-Methyl-11-(3,5-dimethylpyrazolyl)-7-(p-tolyl)pyrimido-
[4′′,5′′:4′,5′]thieno[3′,2′:5,6]pyrido[3,2-c]cinnoline (14)
The hydrazino compound 13 (0.001 mol) and acetylacetone
(0.005 mol) in ethanol (40 mL) were refluxed for 6 h. The
separated solid was filtered and recrystallized from ethanol as
pale brown crystals, mp 320°C, yield 77%. IR: NH and NH2
11-Chloro-9-methyl-7-(p-tolyl)pyrimido[4′′,5′′:4′,5′]thieno-
[3′,2′:5,6] pyrido[3,2-c]-cinnoline (12)
1
absorptions disappeared. H NMR (TFA-d) δ: 2.45 (s, 3H,
The pyrimidinone 11 (0.01 mol) in phosphorus oxychloide
(40 mL) was refluxed for 4 h. The cooled mixture was stirred
in ice-water for 30 min. The solid product was filtered, washed
with water, and recrystallized from dioxane as yellow crystals,
mp 283°C, yield 68%. IR: both NH and CO absorptions disap-
peared. 1H NMR (TFA-d) δ: 2.60 (s, 3H, p-CH3), 2.85 (s, 3H,
CH3), 7.55–9.8 (m, 8H, ArH). Anal. calcd. for C23H14N5SCl:
C 64.56, H 3.30, N 16.37, S 7.49, Cl 8.29; found: C 64.50, H
3.60, N 16.02, S 7.60, Cl 8.58%.
p-CH3), 2.60 (s, 3H, CH3), 2.80 (s, 3H, CH3), 6.40 (s,,1H,
TCH), 7.6–9.8 (m, 8H, ArH). MS, m/z (%): 488 (M + 1, 35),
487(M+, 100), 486(M – 1, 16). Anal. calcd. for C28H21N7S: C
68.97, H 4.34, N 20.11, S 6.58; found: C 64.10, H 4.62, N
19.90, S 6.82%.
5-Methyl-7-(p-tolyl)-1,2,4-triazolo[4′′′,3′′′:1′′,6′′]pyrimido-
[4′′,5′′:4′,5′]thieno-[3′,2′:5,6]pyrido[3,2-c]cinnoline(15).
The hydrazino compound 13 (0.001 mol), triethylorthoformate
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Can. J. Chem. Vol. 76, 1998
Table 3. Analytical, spectral, and physical data of compounds, 6a–6h.
Analysis calcd./found (%)
Spectral data
Comp.
no. a mp, °C Color Yield %
Mol.
formula
C
H
N
S
IR (KBr) cm–1
(NH2) 3500,
1H NMR δ (ppm), and MS, m/z (%)
1H NMR (CDCl3) δ: 2.55 (s, 3H,
p-CH3), 2.90 (s, 3H, COCH3), 6.20
(s, 2H, NH2), 7.2–9.1 (m, 8H, ArH)
68.73 4.19 14.57 8.34
6a
6b
310°C Orange
69
78
C22H16N4OS 68.46 4.35 14.55 8.11 3300(CO), 1610
1H NMR (CDCl3)δ: 2.60 (s, 3H, p-CH3),
7.12 (s, 2H, NH2), 7.2–9.3 (m, 13H,
ArH); MS, m/z (%): 446 (M+, 100%)
72.63 4.06 12.55 7.18 (NH2) 3400, 3300,
265°C
Red
C27H18N4OS 72.70 4.12 12.36 7.31
(CO) 1560
1H NMR (CDCl3) δ: 1.50 (t, 3H, CH3
ester), 2.60 (s, 3H, p-CH3), 4.10 (q, 2H,
CH2), 5.90 (s, 2H, NH2), 7.2–9.3 (m,
8H, ArH); MS, m/z (%): 414(M+, 100%)
66.65 4.38 13.52 7.74 (NH2) 3470, 3350,
6c
290°C Orange
82
C23H18N4O2C 66.82 4.31 13.30 7.52
(CO) 1670
1H NMR (DMSO) δ: 3.30 (s, 3H,
p-CH3), 6.00 (s, 2H, NH2), 7.35
(s, 2H, CONH2), 7.35–9.1 (m, 8H,
ArH); MS, m/z (%); 385 (M+, 69%)
65.43 3.90 18.17 8.32 (NH2) 3450, 3300,
6d
6e
270°C
Red
75
69
C21H15N5OS 65.60 3.98 17.94 8.16
(CO) 1630
(NH2) 3450,
1H NMR (CDCl3) δ: 3.00 (s, 3H,
p-CH3),6.05 (s, 2H, NH2), 7.73
(s, 1H, NH), 7–9.2 (m, 13H, ArH)
70.26 4.15 15.17 6.95 3400, (NH) 3300,
297°C Orange
C28H19N5OS 70.36 4.28 15.32 6.80
(CO) 1640
(NH2) 3460–3400, 1H NMR (DMSO) δ: 2.25 (s, 3H,
(NH) 3300,
(CN) 2200,
(CO) 1622
p-CH3), 2.52 (s, 3H, p-CH3), 6.03
(s, 2H, NH2), 7.52 (s, 1H, NH),
7–9.1 (m, 12H, ArH)
70.72 4.45 14.73 6.74
6f
194°C
Red
70
C28H21N5OS 70.53 4.25 14.50 6.81
1H NMR (CDCl3) δ: 2.60 (s, 3H,
p-CH3), 2.80 (s, 3H, p-OCH3), 6.15
(s, 2H, NH2), 7.80 (s, 1H, NH),
6.8–9 (m, 12H, ArH)
(NH2) 3500, 3450,
(NH) 3300,
69.17 4.20 13.91 6.37
6g
257°C
285°C
Red
Red
72
74
C28H21N5O2S 68.94 4.06 13.72 6.57
(CO) 1630
(NH2) 3450,
(NH) 3300,
(CO) 1620
1H NMR (CDCl3) δ: 2.60 (s, 3H, CH3),
6.20 (s, 2H, NH2), 8.90 (s, 1H, NH),
7.15–9.3 (m, 12H, ArH)
65.38 3.66 14.12 6.47
6hb
C27H18 CIN5OS 65.20 3.71 13.92 6.32
a All products were recrystallized from ethanol except 6a from acetic acid.
b Chlorine analysis for 6h, calcd.: 7.15; found: 7.23%.
3H, CH3), 7.5–9.82 (m, 8H, ArH). Anal. calcd. for
C24H15N7S2: C 61.92, H 3.25, N 21.06, S 13.78; found: C
62.06, H 3.57, N 20.89, S 13.56%.
(5 mL) and five drops of acetic acid were refluxed for 6 h. The
separated product was filtered and recrystallized from acetic
acid as yellow crystals, mp >360 °C, yield 75%. IR: NH and
NH2 absorptions disappeared. 1H NMR (TFA-d) δ: 2.40 (s, 3H,
p-CH3), 2.96 (s, 3H, CH3), 7.35–9.9 (m, 8H, ArH), 9.65 (s, 1H,
TCH). MS, m/z (%); 434 (M + 1, 48), 433 (M+, 60), 432 (M –
1, 32). Anal. calcd. for C24H15N7S: C 66.50, H 3.49, N 22.62,
S 7.40; found: C 66.26, H 3.86, N 22.81, S 7.73%.
5-Methyl-7-(p-tolyl)-3-(ethoxycarbonylmethylthio)1,2,4-
triazolo-[4′′′,3′′′:1′′,6′′]pyrimido[4′′,5′′:4′,5′]thieno-
[3′,2′:5,6]pyrido[3,2-c]cinnoline (17)
The triazolo compound 16 (0.001 mol) and ethyl chloroacetate
(0.5 mL) in ethanol (30 mL) were refluxed for 30 min. The
separated solid was filtered and recrystallized from ethanol as
greenish yellow crystals, mp 275°C, yield 77%. IR: 1720
(CO) cm–1. 1H NMR (CDCl3) δ: 1.17 (t, 3H, CH3 ester), 2.50
(s, 3H, p-CH3), 2.77 (s, 3H, CH3), 4.08 (s, 2H, SCH2), 4.17 (q,
2H, CH2 ester), 7.2–9 (m, 8H, ArH). Anal. calcd. for
C28H21N7O2S2: C 60.96, H 3.84, N 17.77, S 11.63; found: C
59.51, H 3.89, N 17.56, S 11.80%.
5-Methyl-7-(p-tolyl)1,2,4-triazolo[4′′′,3′′′:1′′,6′′]pyrimido-
[4′′,5′′:4′,5′]thieno-[3′,2′:5,6]pyrido[3,2-c]cinnolin-
3(2H)-thione (16)
The hydrazino compound 13 (0.001 mol) and carbon disul-
phide (2 mL) in dry pyridine (20 mL) were refluxed for 8 h.
The separated solid was filtered and recrystallized from etha-
nol as brown crystals, mp >360°C. IR: 3450 (NH), 1280
(CTS) cm–1. 1H NMR (TFA-d) δ: 2.70 (s, 3H, p-CH3), 3.30 (s,
© 1998 NRC Canada

475
Badr et al.
Table 4. Analytical, spectral, and physical data of compounds 10a, 10b and 18a, 18b.
Analysis calcd./found (%)
Spectral data
Comp.
no.
Yield
%
Mol.
mp, °Ca Color
formula
C
H
N
S
IR (K Br) cm–1
(CO) 1650
1H NMR δ (ppm) and MS, m/z (%)
1H NMR (TFA-d) δ: 2.70 (s, 3H, p-CH3),
2.90 (s, 3H, CH3), 8.98 (s, 1H, =CH),
7.4–9.9 (m, 14H, ArH)
Pale
70.30 3.93 16.40 6.26
10a
10b
18a
325°C yellow
74
78
81
C30H20N6OS 70.04 4.20 13.21 6.40
1H NMR (TFA-d) δ: 2.70 (s, 3H, p-CH3),
2.93 (s, 3H, CH3), 4.20 (s, 3H, p-OCH3),
7.1–9.8(m, 13H, ArH+ 1H, =CH)
68.62 4.09 15.49 5.91
315°C Yellow
320°C Yellow
C31H22N6O2S 68.39 4.10 15.67 6.08
(CO) 1660
(NH) 3250
1H NMR (TFA-d) δ: 2.30 (s, 3H, p-CH3),
2.63 (s, 3H,CH3), 4.15 (s, 3H, p-OCH3),
8.50 (s, 1H, =CH), 7.1–9.9 (m, 12H, ArH)
68.74 4.28 18.10 5.92
C31H23N7OC 68.48 4.40 17.89 5.78
1H NMR (TFA-d) δ: 2.20 (s, 3H, p-CH3),
2.64 (s, 3H, CH3), 7.7–9.8 (m, 13H,
ArH + H, = CH)
Pale
64.50 3.61 20.06 5.74
18b
330°C yellow
74
C30H20N8O2S 64.69 3.81 19.91 5.48
(NH) 3210
a All products were recrystallized from ethanol.
1H NMR (TFA-d) δ: 2.50 (s, 3H, p-CH3), 2.95 (s, 3H, CH3),
3.20 (s, 3H, CH3 triazol), 7.2–9.7 (m, 8H, ArH). Anal. calcd.
for C25H17N7S: C 67.10, H 3.83, N 21.91, S 7.17; found: C
63.70, H 4.05, N 22.10, S 6.98%.
11-(Arylidenehydrazono)-9-methyl-7-(p-tolyl)pyrimido-
[4′′,5′′:4′,5′]thieno-[3′,2′:5,6]pyrido[3,2-c]cinnoline
(18a and 18b)
The hydrazino compound 13 and each of (a) p-anisaldehyde
and (b) p-nitrobenzalehyde (0.001 mol) in acetic acid (20 mL)
were refluxed for 30 min. The solid product was filtered and
recrystallized from ethanol. The analytical, spectral, and
physical data are reported in Table 4.
References
1. S. Kneubuehler, V. Carta, A. Vincengo, C. Altomare,
A. Carotti, and B. Testa. Helv. Chim. Acta, 76, 1956(1993);
T. Nakao, M. Kawakami, M. Hisadome, and T. Tahara. PCT Int.
Appl. WO 89 04,306, 18 May, 1989; JP Appl. 87/278,009, 2
Nov. 1987; Chem. Abstr. 111, 214498 (1989).
2. S. Inoue, A. Yazaki, H. Mochizuki, H. Tsutsumi, M. Murata,
and K. Sakane. Jpn. Kokai Tokkyo Koho, JP 06 228, 138[94,
228, 138]; Chem. Abstr. 123, 9452 (1995); S. Inoe, J. Yoshida,
M. Yokomoto, A. Yazaki, N. Hayashi, and H. Amano. Jpn.
Kokai Tokkyo Koho, JP 06, 228, 138 [94, 228, 138], JP Appl.
92/22, 407; Chem. Abstr. 121, 179602 (1994); M. Yokomoto,
A. Yazaki, N. Hayashi, S. Hatono, S. Inoue, and Y. Kuramato.
Eur. Pat. Appl. Ep 470, 578; JP Appl 90/211, 190; Chem. Abstr.
117, 7943(1992); R. Fusco, L.F. Piselli, and P.M. Boschi. Eur.
Pat. Appl. Ep 287, 853 IT Appl. 87/20,230; Chem. Abstr. 110,
75540 (1989); T. Miyamoto and J. Matsumoto. Chem. Pharm.
Bull. 37, 93 (1989); 36, 1321 (1988).
5-Methyl-7-(p-tolyl)tetrazolo[4′′′,3′′′:1′′,6′′]pyrimido-
[4′′,5′′:4′,5′]thieno- [3′,2′:5,6]pyrido[3,2-c]cinnoline (19)
Sodium nitrite (7 mL, 10%, 0.01 mol) was added dropwise to
a solution of the hydrazino derivative 13 (0.002 mol) in dilute
hydrochloric acid (10 mL, 50%) at 0°C and stirred for 10 min.
The solid product separated and recrystallized from ethanol as
pale yellow crystals, mp >360°C, yield 70%. IR: NH and NH2
1
absorptions disappeared. H NMR (TFA-d) δ: 2.65 (s, 3H,
p-CH3), 3.30 (s, 3H, CH3), 7.4–9.95 (m, 8H, ArH). Anal. calcd.
for C23H14N8S: C 63.58, H 3,25, N 25.79, S 7.38; found: C
63.30, H 3.40, N 25.37, S 7.19%.
5-Methyl-7-(p-tolyl)-1,2,4-triazolo[4′′′,3′′′:1′′,6′′]pyrimido-
[4′′,5′′:4′,5′]thieno-[3′,2′:5,6]pyrido[3,2-c]cinnolin-
3(2H)-one (20)
3. M. Mizutani, M. Shiroshita, M. Sasaki, H. Okuda, and N. Mito.
Eur. Pat. Appl. EP 273, 325; JP Appl. 86/309, 981; Chem. Abstr.
110, 75532 (1989).
The hydrazino compound 13 (0.001 mol) and ethyl chlorofor-
mate (0.002 mol) in acetic acid (20 mL) were refluxed for
30 min. The solid product was recrystallized from acetic acid
as yellow crystals, mp 300°C, yield 66%. IR: 1725 (CO), 3400
(NH) cm–1. 1H NMR (TFA-d) δ: 2.60 (s, 3H, p-CH3), 2.95 (s,
3H, CH3), 7.45–9.8 (m, 8H, ArH). MS, m/z (%): 449 (M+, 4).
Anal. calcd. for C24H16N7OS: C 24.0, H 3.28, N 21.76, S 7.12;
found: C 64.20, H 3.76, N 21.58, S 6.96%.
4. G.A. Pinna, M.M. Curzu, G. Cignarella, D. Barlocco,
M. D’Amico, A. Filippelli, V. DeNovellis, and F. Rossi. Eur. J.
Med. Chem. 29, 447 (1994); G. Cignarella, D. Barrlocco,
S. Villa, M.M. Curzu, G.A. Pinna, A. Lavezzo, and A. Bestetti.
27, 819 (1992); G. Cignarella, D. Barlocco, M.M. Curzu,
G.A. Pinna, P. Cazzulani, M. Cassin, and B. Lumachi. Eur. J.
Med. Chem. 25, 749,(1990); G. Cignarella, D. Barlocco,
G.A. Pinna, M. Loriga, M.M. Curzu, O. Toffametti, M. Ger-
mini, P. Cazzulani, and E. Cavelletti. J. Med. Chem. 32, 2277
(1989).
3,5-Dimethyl-7-(p-tolyl)-1,2,4-triazolo[4′′′,3′′′:1′′,6′′]pyrimido-
[4′′,5′′:4′,5′]- thieno[3′,2′:5,6]pyrido[3,2-c]cinnoline (21)
The hydrazino compound 13 (0.001 mol) and acetic anhydride
(20 mL) were refluxed for 6 h. The solid product was recrys-
tallized from acetic acid as greenish yellow crystals, mp
>360°C, yield 71%. IR: NH and NH2 absorptions disappeared.
5. N. Garcia-Dominguez, E. Ravina, L. Santana, C. Teran, G. Gar-
cia-Mera, F. Orallo, M. Crespo, and J.A. Fontenla. Arch. Pharm.
321, 735 (1988).
6. J.F. Patoiseau, J.M. Autin, J.L. Maurel, and D. Bigg. PCT Int.
Appl. Wo 93/09, 098, FR Appl. 91/13,571; Chem. Abstr. 119,
© 1998 NRC Canada

476
Can. J. Chem. Vol. 76, 1998
225963 (1993); E. Ravina, J. Fueyo, C. Teran, J. Cid, G. Garcia-
Mera, F. Orallo, and B. Bardan. Pharmazie, 47, 574(1992).
7. J.F. Resch. Ger. (East) DD 249, 011, Appl. 291, 515, 86; Chem.
S.A. Mahgoub. Bull. Chem. Soc. Jpn. 57, 1653 (1984);
M.Z.A. Badr, S.A. Mahgoub, O.S. Moustafa, and F.F.A. Latif. J.
Indian Chem. Soc. 67, 216 (1990); M.Z.A.Badr, S.A. Mahgoub,
F.M. Atta, and O.S. Moustafa. J. Indian Chem. Soc. 74, 30
(1997); M.Z.A. Badr, S.A. Mahgoub, O.S. Moustafa, and
A.A. Geies. Phosphorus, Sulfur Silicon Relat. Elem. 73, 27,
(1992); M.Z.A..Badr, S.A. Mahgoub, O.S. Moustafa, and
A.A. Geies. Phosphorus, Sulfur Silicon Relat. Elem. 79, 77
(1993); M.Z.A. Badr and O.S. Moustafa. Phosphorus, Sulfur
Silicon Relat. Elem. 1,127(1996).
Abstr. 108, 186758 (1988).
8. G. Doria, A.M. Isetta, M. Ferrari, and D. Trizio. Eur. Pat. Appl.
Ep 277, 791, IB Appl. 87/2,288; Chem. Abstr. 109, 231043
(1988); L.V.G. Nargund, V.V. Badiger, and S.M. Yarnal. J.
Pharm. Sci. 81, 365 (1992).
9. G. Dattolo, G. Cirrincione, A.M. Almerico, E. Aiello, and
I. D’Asdia. J. Heterocycl. Chem. 23, 1371 (1986); S. Radl,
J. Moural, and R. Bendova. Collect. Czech. Chem. Commun. 55,
1311 (1989); S.J. Bakewell, W.J. Coates, M.B. Comer,
M.L. Reeves, and B.H. Warrington. Eur. J. Med. Chem. 25, 765
(1990); G.A. Pinna, M.M. Curzu, G. Cignarella, D. Barlocco,
M. Cassin, and B. Lumachi. Eur. J. Med. Chem. 25,249 (1990);
H. Sasaki, H. Tsutsumi, M. Murata, T. Terasawa, and
K. Sakane. J. Org. Chem. 60, 3928 (1995).
11. K. Gewald, O. Calderon, H. Schafer, and U Hain. Liebigs Ann.
Chem. 1390 (1983), and ref. 5 cited therein.
12. M.Z.A. Badr, H.A. El-Sherief, G.M. El-Naggar, and
S.A. Mahgoub. J. Heterocycl. Chem. 21, 471 (1984); K.T. Potts
and C. Lovelette. J. Org. Chem. 34, 3221 (1969); A. Amer,
K. Weisz, and H. Zimmer. Heterocycles, 26, 1853 (1987);
H.Zimmer, J. McManus, T. Novinson, E.V. Hess, and A. Litwin.
Arzneim.-Forsch. 20, 1586 (1970).
10. M.Z.A. Badr, G.M. El-Naggar, H.A. El-Sherief, and
© 1998 NRC Canada