Pyridazine derivatives and related compounds part 19:1 The synthesis of different heterocycles from ethyl 5-amino-3,4-diphenylthieno[2,3-c] pyridazine-6-carboxylate

Article abstract of DOI:10.1080/10426500500272145

7-substituted pyrido[2′,3′:4, 5]thieno[2,3-c]pyridazines and 6-substituted pyrimido-[4′,5′:4,5]thieno[2,3-c]pyridazines were synthesized starting from ethyl 5-aminothieno[2,3-c]pyridazino-6-carboxylate 1. The reaction of amino ester 1 with benzoyl isothio

Full text of DOI:10.1080/10426500500272145

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Pyridazine Derivatives and
Related Compounds Part 19:
The Synthesis of Different
Heterocycles from Ethyl 5-
Amino-3,4-diphenylthieno[2,
3-c]pyridazine-6-carboxylate
Ali Deeb a & Mohamed El-Abbasy a
a Department of Chemistry, Zagazig University,
Zagazig, AR, Egypt
Published online: 15 Aug 2006.
To cite this article: Ali Deeb & Mohamed El-Abbasy (2006) Pyridazine Derivatives and
Related Compounds Part 19: The Synthesis of Different Heterocycles from Ethyl 5-
Amino-3,4-diphenylthieno[2, 3-c]pyridazine-6-carboxylate, Phosphorus, Sulfur, and
Silicon and the Related Elements, 181:4, 879-890, DOI: 10.1080/10426500500272145
To link to this article: http://dx.doi.org/10.1080/10426500500272145
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Phosphorus, Sulfur, and Silicon, 181:879–890, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500272145
Pyridazine Derivatives and Related Compounds Part 19:1
The Synthesis of Different Heterocycles from Ethyl 5-
Amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carboxylate
Ali Deeb
Mohamed El-Abbasy
Department of Chemistry, Zagazig University, Zagazig, AR, Egypt
7-substituted pyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-c]pyridazines and 6-substituted pyrimido-
[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazines were synthesized starting from ethyl 5-
aminothieno[2,3-c]pyridazino-6-carboxylate 1. The reaction of amino ester 1 with
benzoyl isothiocyanate affords thiourea derivative 8, which undergoes further trans-
formation to the related fused heterocyclic systems.
Keywords Pyridazinotienothiazine; pyrimdothenopyridazine; substituted pyridothi-
enopyridazine
As a part of our research program2 aimed at the preparation of
novel thiophene-fused heterocycles of therapeutical significance, we
report on the synthesis of two heteropolycyclic compounds, namely
pyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-c]pyridazine and pyrimido[4ꢀ,5ꢀ:4,5]thieno-
[2,3-c]pyridazine.
Thiophene derivatives, which are both commercially available drugs
and agents under clinical investigation, were the subject of a com-
prehensive review.3 Many compounds containing the pyridothieno
and pyridazinothieno ring systems are known to have interesting
pharma-cological properties.4,5 All these properties aroused our inter-
est in synthesing new heterocyclic compounds including the thieno[2,3-
c]pyridazine moiety.
The readily prepared ethyl 5-amino-3,4-diphenylthieno[2,3-c]pyrid-
azine-6-carboxylate 16 was used as the starting material because it has
suitable substituents for building on a third heterocyclic ring.
The base-catalyzed cyclization of amides derived from anthranilic
esters and β-keto esters or diethyl malonate is an established route
Received August 11, 2004; accepted June 10, 2005.
Address correspondence to Ali Deeb, Zagazig University, Department of Chemistry,
Faculty of Science, Zagazig, Egypt. E-mail: dralideeb@hotmail.com
879

880
A. Deeb and M. El-Abbasy
to substituted 4-hydroxy-2-quinolones.7,8 We now wish to report the
application of this approach to the synthesis of 7-substituted-8-
hydroxy-pyrido[2ꢀ,3ꢀ:4,5]-thieno[2,3-c]pyridazines 5a–e. The intermedi-
ate amides 3a–e were obtained by boiling together under reflux ethyl
5-amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carboxylate 1 and the
appropriate substituted acetic ester 2a–e (Scheme 1). In all cases, the
condensation took the indicated course, and there was no evidence for
the formation of the enamine rather than the amide in the reaction
giving 3b and 3c. In one reaction (that lead to 3e), a byproduct was
isolated and was identified as the bis-amide 4.
SCHEME 1
The chloroacetylation of the amino-ester 1 with chloroacetylchlo-
ride in dioxane afforded 3f. The assignment of structure of 3a–f was
based on analytical and spectral data. The feasibility of chlorine atom
in 5-chloroacetylamino derivative 3f to undergo nucleophilic displace-
ment was proved by the reaction with potassium cyanide, which gave
5-cyanoacetylamino derivative 3d. The structure was assigned by com-
parison with an authentic sample prepared from the reaction of com-
pound 1 and ethyl cyanoacetate.
The cyclization of the amide 3a–e to the pyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-
c]pyridazines 5a–e was affected by treatment with sodium ethoxide in
ethanol (Scheme 1).
A point of considerable interest in the study of quinolines bear-
ing oxygenated substituents in the pyridine ring concerns keto-enol

Pyridazine Derivatives and Related Compounds, Part 19
881
tautomerism. Of the various possibilities available in 2,4-dioxygenated
quinoxalines, the 4-hydroxy-2-quinolone from is preferred in the solid
9
. . .
state, with strong OH O C intermolecular hydrogen bonding. The
same is apparently true of the various 6,8-dioxygenerated pyrido-
[2ꢀ,3ꢀ:4,5]thieno[2,3-c]pyridazines prepared in the present work. The
infrared spectra of compounds 5b–e showed strong rather broad bands
in the region 1650–1660 cm−1, which is typical of the 2- rather than the
4-quinolone type. Further, in several of these structures, there is the
strong possibility that intramolecular hydrogen bonding would occur,
reinforcing the normal preference for the 2-quinolone form.
SCHEME 2
In all the 6,8-dioxypyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-c]pyridazines 5a–e,
there is a very broad band in the region 3200–3000 cm−1 and a compara-
tively weak absorption in the region 3290–3230 cm−1, which we ascribe
to H-bonded OH stretching (inter- or intramolecular, as appropriate)
and to N-H stretching, respectively. The structures of these compounds
were assigned by elemental analyses as well as IR, mass, and NMR
spectral data.
Ethyl 5-chloroacetylamino-3,4-diphenylthieno[2,3-c]pyridazine-6-
carbox-ylate 3f also proved to be a versatile synthon for the preparation
of other new thienopyridazines. Thus, on heating a suspension of 3f and
potassium thiocyanate in ethanol furnished compound 6 (Scheme 3).
The indicated intermediates cannot be isolated but can be rationalized
as follows: the 5-thiocyanoacetylamino is directly converted to the
5-(imino-4-oxothiazol-3-yl), which underwent smooth cyclization to the
corresponding fused thiazolone and finally to (8-oxo-3,4-diphenyl-7,8-
dihydropyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazin-6-ylsulfanyl)acetic
acid ethyl ester 6 (Scheme 3).
The structural elucidation of compound 6 was accomplished from
their analytical and spectral data. The mass spectra showed the ex-
pected molecular ion peak, and the IR spectra exhibited a strong
absorption band at 3448 (NH), 1731 (C O ester), and 1670 cm−1
1
(C O amide), while the H-NMR showed signals at 9.85 due to NH,

882
A. Deeb and M. El-Abbasy
SCHEME 3
7.31–6.90 due to 2Ph, 4.64 due to SCH2, 4.25 due to OCH2, and 1.31
due to CH3.
The aminolysis of compound 6 with hydrazine and with n-butylamine
gave the corresponding 6-substituted derivatives 7a,b under the elimi-
nation of the thioacetic acid moiety (Scheme 3). The data used to char-
acterize all the compounds prepared are given in the Experimental
section.
On the other hand, the reaction of benzoyl isothiocyanate with
the amino-ester 1 in boiling acetone led to the formation of the ben-
zoyl thiourea derivative 8 in a 70% yield. In an alkaline medium,
compound 8 underwent a ring closure followed by debenzoylation
to form 1,2-dihydro-8,9-diphenyl-2-thioxopyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-
c]pyridazin-4(3H)-one 9. The structure was established by microanaly-
ses and spectral data.
The cyclic amide structure of compound 9 furthermore was de-
fined using as a comparison its cyclic thioester isomer 10 obtained
by ring closure in 98% sulfuric acid at 100◦C. The two isomeric
derivatives 9 and 10 are well differentiated according to the alka-
line solubility and their infrared spectra. Compound 10 was proven to
be 2-amino-8,9-diphenylpyridazino[4ꢀ,3ꢀ:5,4]thieno[3,2-d]-1,3-thiazin-
4-one from its microanalyses and spectroscopic data. It should be noted
that no sulfonated byproducts were observed even when benzoylth-
iourea derivative 8 was heated in sulfuric acid to prepare 10.
The 2-amino derivative 10 could be converted with benzoylisothio-
cyanate to afford the corresponding heterocyclic substituted benzoyliso-
thiocyanate 11.

Pyridazine Derivatives and Related Compounds, Part 19
883
SCHEME 4
On treatment of 11 with concentrated sulfuric acid at r.t., compound
12 was obtained and established to be a derivative of the new hetero
system 1,2,4-thiadiazole condensed system 12 (Scheme 4). The struc-
tural elucidation of compounds 11 and 12 were accomplished on the
basis of microanalyses and spectral data. From the structural assign-
ment of the product, it became clear that sulfuric acid has acted as
an oxidizing agent. The yield of 12 could be improved by adding an
equimolar amount of N-bromosuccinimide10 to the reaction mixture.
The oxidative cyclization to afford fused 1,2,4-thiadiazoles from substi-
tuted thioureas (e.g. from pyridyl- or pyrimidylthioureas with bromine
or sulfuryl chloride)11 is well known.
EXPERIMENTAL
Melting points were determined on a Bu¨chi 510 apparatus and are re-
ported uncorrected. IR spectra were recorded as potassium bromide

884
A. Deeb and M. El-Abbasy
disks on a Perkin-Elmer 383 spectrophotometer. 1H-NMR spectra
were observed on a Perkin-Elmer R12 B-200 MHz, and chemical shifts
(δ) are in ppm relative to internal TMS. Mass spectra were obtained
at 70 eV by using a AE MS 30 mass spectrometer. All reactions were
monitored by thin layer chromatography and carried out on 0.2 mm
silica gel 60 F-254 (Merck) plates using U.V. light (254 and 366 nm).
Ethyl 5-Phenylacetylamino-3,4-diphenylthieno[2,3-c]-
pyridazine-6-carboxylate 3a
A mixture of compound 1 (0.5 g, 1.33 mmol) and ethyl phenylacetate
(5 mL) was boiled under an air condenser for 3 h; after cooling, the
precipitate was collected by filtration, washed with ether, dried, and
recrystallized from n-butanol, (0.43 g, 65.7%), m.p. 187–188◦C; IR: 3313
(NH), 1732 (C O ester), and 1669 (C O amide) cm−1. 1H-NMR (DMSO-
d6): 8.10 (s, 1H, NH), 7.40–7.20 (m, 15H, 3Ph), 4.20 (q, 2H, J = 7.0 Hz,
CH2), 2.60 (s, 2H, CH2) and 1.20 (t, 3H, J = 7.0 Hz CH3). Anal. calcd.
for C29H23N3O3S: C, 70.56; H, 4.69; N, 8.51. Found: C, 70.40; H, 4.50;
N, 8.40.
Ethyl 5-Benzoylacetylamino-3,4-diphenylthieno[2,3-c]-
pyridazine-6-carboxylate 3b
To a solution of compound 1 (0.5 g, 1.33 mmol) in 1,2-dichlorobenzene
(10 ml), ethyl benzoyl acetate (0.25 g, 1.33 mmol) was added. The re-
action mixture was refluxed for 6 h; the cooled reaction mixture was
poured into pet. ether 40/60◦C (50 mL). The precipitate was filtered
off, dried, and recrystallized from ethanol, (0.49 g, 71.9%), m.p. 132–
133◦C. IR: 3329 (NH), 1722 (C O, ketone), 1700 (C O, ester), 1680
1
(C O amide) cm−1. H-NMR (DMSO-d6): 10.20 (s, 1H, NH), 7.40–7.00
(m, 15H, 3Ph), 4.30 (q, 2H, J = 7.2 Hz, CH2), 2.20 (s, 2H, CH2) and 1.20
(t, 3H, J = 7.2 Hz, CH3). Anal. calcd. for C30H23N3O3S: C, 69.08; H,
4.44; N, 8.05. Found: C, 68.90; H, 4.30, N, 7.80.
Ethyl 5-Acetoacetylamino-3,4-diphenylthieno[2,3-c]-
pyridazine-6-carboxylate 3c
A mixture of compound 1 (0.5 g, 1.33 mmol) and ethyl acetoacetate
(10 mL) was boiled under an air condenser for 2 h. After cooling, the
precipitate was collected by filtration, washed with ether, and recrys-
tallized from ethanol, (0.42 g, 69.4%), m.p. 185–186◦C. IR : 3260 (NH),
1750 (C O, ketone), 1710 (C O, ester), 1680 (C O, amide) cm−1. Anal.

Pyridazine Derivatives and Related Compounds, Part 19
885
calcd. for C25H21N3O4S: C, 65.34; H, 4.60; N, 9.14. Found: C, 65.10; H,
4.50; N, 9.00.
Ethyl 5-Cyanoacetylamino-3,4-diphenylthieno[2,3-c]-
pyridazine-6-carboxylate 3d
To a solution of compound 1 (0.5 g, 1.33 mmol) in 1,2-dichlorobenzene
(10 mL), ethyl cyanoacetate (0.1 g, 1.33 mmol) was added. The reaction
mixture was refluxed for 4 h; the cooled reaction mixture was poured
into pet. ether 40/60◦C (50 mL). The precipitate was filleted off, dried,
and recrystallized from ethanol, (0.4 g, 67.8%), m.p. 100–101◦C. IR:
3448 (NH), 2100 (CN), 1731 (C O, ester), 1670 (C O, amide) cm−1
.
Anal. Calcd. for C24H18N4O3S: C, 65.14; H, 4.10; N, 12.66. Found: C,
65.00; H, 3.90; N, 12.50.
Reaction of Ethyl 5-Amino-3,4-diphenylthieno[2,3-c]-
pyridazine-6-carboxylate 1 With Diethyl Malonate
A mixture of compound 1 (1.0 g, 2.66 mmol) and diethyl malonate
(10 mL) was boiled together under an air condenser for 2 h. The excess of
the malonic ester was removed under reduced pressure to give material
(0.8 g) that was shown by thin layer chromatography to consist of two
components. The mixture was applied to a column of silica gel (40 g), and
the column was eluted with 4:1 petroleum ether/ether. The first fraction
eluted was ethyl 5-ethoxycarbonylacetylamino-3,4-diphenylthieno[2,3-
c]pyridazine-6-carboxylate 3e (0.5 g, 38%), m.p. 184–185◦C. IR: 3450
(NH), 1732 (C O, ester), 1669 (C O, amide), 1595 (C C) cm−1. Anal.
calcd. for C26H23N3O5S: C, 63.78; H, 4.73; N, 8.58. Found: C, 63.60; H,
4.60; N, 8.30.
The second fraction to be eluted from the column was N,Nꢀ-bis-(6-
ethoxycarbonyl-3,4-diphenylthieno[2,3-c]pyridazine-5-yl)propan-1,3-
diamide 4 (0.3 g, 13.8%), m.p. 109–111◦C (from light petroleum, b.p.
100–120◦C), IR: 3370 (NH), 1710 (C O, ester), 1670 (C O, amide),
1570 (C C) cm−1. Anal. calcd. for C45H34N6O6S2: C, 65.99; H, 4.18; N,
10.26. Found: C, 65.80; H, 4.00; N, 10.00.
Ethyl 5-Chloroacetylamino-3,4-diphenylthieno[2,3-c]-
pyridazine-6-carboxylate 3f
To s solution of compound 1 (0.5 g, 1.33 mmol) in dioxane (5 mL)
chloroacetylchloride (0.17 g, 1.59 mmol) was added; the reaction mix-
ture was refluxed for 8 h. The cooled reaction mixture was poured into
ice water (100 mL), and the precipitate was filtered off, dried, and
recrystallized from ethanol (0.42 g, 70.1%) of 3f, m.p. 130–131◦C. IR:

886
A. Deeb and M. El-Abbasy
3380 (NH), 1733 (C O ester), 1655 (C O amide), 1618 (C C) cm−1; 1H-
NMR (CDCl3): 7.60–7.20 (m, 10H, 2Ph), 6.10 (s, 1H, NH), 4.30 (q, 2H,
J = 7.0 Hz, CH2), 2.10 (s, 2H, CH2), 1.20 (t, 3H, J = 7.0 Hz, CH3). Anal.
calcd. for C23H18ClN3O3S: C, 61.12; H, 4.01; N, 9.29. Found: C, 60.90;
H, 3.90; N, 9.00.
The Reaction of 3f With Potassium Cyanide
To a solution of compound 3f (0.5 g, 1.1 mmol) in ethanol (10 mL) potas-
sium cyanide (0.07 g, 1.1 mmol) was added; the reaction mixture was re-
fluxed for 2 h, the solvent was then evaporated under reduced pressure,
and the residue was treated with water. The precipitate was filtered off,
dried, and recrystallized from ethanol (0.3 g, 62.5%), m.p. 100–101◦C;
it was identical with compound 3d.
7-Substituted 8-hydroxy-3,4-diphenyl[2ꢀ,3ꢀ:4,5]thieno[2,3-c]-
pyridazin-6(5H)-one 5a–e: General Procedure
Amides 3a–e (1.0 mmol) were boiled under reflux for 1–10 h (until
all starting material had disappeared as checked by tlc) with a solu-
tion of sodium ethoxide (from 0.1 g sodium) in ethanol (10 mL). The
mixture was evaporated to dryness under reduced pressure; water
(30 mL) was added to the residue, and the solution was washed with
dichloromethane (washings discarded) and then partially saturated
with salt. The solution was cooled in ice and acidified with concentrated
hydrochloric acid (2 N). The solid formed was filtered off and recystal-
lized from ethanol. The following derivatives (5a–e) were obtained.
8-Hydroxy-3,4,7-triphenylpyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-c]-
pyridazin-6(5H)-one 5a
Yield : (45.7%); m.p. 230–231◦C. IR: 3260 (NH), 3200–3100 (H-bonded
OH), 1660 (C O), 1590 (C C) cm−1 1H-NMR (DMSO-d6): 10.20 (s,
;
1H, NH), 7.40–7.00 (m, 15H, 3Ph), 2.20 (s, 1H, OH). Anal. calcd. for
C27H17N3O2S: C, 72.46; H, 3.82; N, 9.39. Found: C, 72.30; H, 3.70; N,
9.20.
7-Benzoyl-8-hydroxy-3,4-diphenylpyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-c]-
pyridazin-6(5H)-one 5b
Yield: (69.9%); m.p. 185–186◦C. IR: 3260 (NH), 3210–3000 (H-bonded
OH), 1720 (C O ketone), 1658 (C O amide) cm−1. Anal. calcd. for
C28H17N3O3S: C, 70.72; H, 3.60; N, 8.83. Found: C, 70.60; H, 3.40; N,
8.60.

Pyridazine Derivatives and Related Compounds, Part 19
887
7-Acetyl-8-hydroxy-3,4-diphenylpyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-c]-
pyridazin-6(5H)-one 5c
Yield: (54%); m.p. 198–199◦C. IR: 3260 (NH), 3200–3100 (H-bonded
OH), 1726 (C O ketone), 1640 (C O amide) cm−1; MS: m/z (%): 414
(M+ +1, 8.8), 385 (M+ −CO, 1.8, ion A), 301 (ion A OH, C C-COMe,
2.5). Anal. calcd. for C23H15N3O3S: C, 66.81; H, 3.65; N, 10.16. Found:
C, 66.70; H, 3.40; N, 9.90.
7-Cyano-8-hydroxy-3,4-diphenylpyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-c]-
pyriazin-6(5H)-one 5d
Yield: (66.9%), m.p. 199–200◦C. IR: 3260 (NH), 3200–3100 (H-bonded
OH), 2360 (CN), 1660 (C O) cm−1; MS: m/z (%): 396 (M+, 4.2), 369
(M+−CO, 9.6, ion A), 301 (ion A−NC-C C OH, 71.5). Anal. calcd. for
C22H12N4O2S: C, 66.65; H, 3.05; N, 14.13. Found: C, 66.30; H, 2.90; N,
14.00.
7-Ethoxycarbonyl-8-hydroxy-3,4-diphenylpyrido[2ꢀ,3ꢀ:4,5]-
thieno[2,3-c]pyridazin-6(5H)-one 5e
Yield: (88.3%), m.p. 148–149◦C. IR: 3260 (NH), 3200–3100 (H-bonded
OH), 1734 (C O ester), 1660 (broad C O amide) cm−1; MS: m/z (%):
443 (M+, 54), 301 (M+−NHCOC(COOEt) C OH, 100). Anal. calcd.
for C24H17N3O4S: C, 64.99; H, 3.86; N, 9.47. Found: C, 64.70; H, 3.70;
N, 9.30.
6-Carbethoxymethylmercapto-3,4-diphenylpyrimido[4ꢀ,5ꢀ:4,5]-
thieno[2,3-c]pyridazin-8(7H)-one 6
A suspension of 3f (0.5 g, 1.1 mmol) and potassium thiocyanate (0.32 g,
3.3 mmol) in abs. ethanol (20 mL) was heated to reflux for 6 h. The
reaction mixture was concentrated to its half volume; after cooling, the
precipitate was separated and washed with water several times, dried,
and recrystallized from abs. ethanol to give 6 (0.41 g, 78.4%), m.p. 160–
161◦C. IR: 3248 (NH), 1731 (C O ester) 1660 (C O amide), 1630 (C N),
1610 (C C) cm−1; 1H-NMR (DMSO-d6): 9.85 (s, 1H, NH), 7.31–6.91 (m,
10H, 2Ph), 4.64 (s, 2H, SCH2), 4.25 (q, 2H, J = 7.1 Hz, OCH2), 1.31 (t,
3H, J = 7.1 Hz, CH3). Anal. calcd. for C24H18N4O3S2: C, 60.74; H, 3.82;
N, 11.80. Found: C, 60.60; H; 3.60; N, 11.60.
6-Hydrazino-3,4-diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]-
pyridazin-8(7H)-one 7a
To a solution of compound 6 (0.5 g, 1.05 mmol) in ethanol (10 mL),
hydrazine hydrate 85% (0.1 g, 1.99 mmol) was added; the reaction

888
A. Deeb and M. El-Abbasy
mixture was refluxed for 4 h, the solvent was evaporated under reduced
pressure, and the residue was treated with water. The precipitate was
filtered off, dried, and recrystallized from ethanol to give 7a (0.3 g,
63.8%), m.p. 110–111◦C. IR: 3409, 3220 (NH, NH2), 1625 (C O), 1610
(C N), 1596 (C C) cm−1. MS: m/z (%): 386 (M+, 2.37). Anal. calcd. for
C20H14N6OS: C, 62.16; H, 3.65; N, 21.74. Found: C, 62.00; H, 3.50; N,
21.50.
6-Butylamino-3,4-diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]-
pyridazin-8(7H)-one 7b
To a solution of compound 6 (0.5 g, 1.05 mmol) in ethanol (10 mL),
n-butylamine (0.1 g, 1.38 mmol) was added; the reaction mixture was
refluxed for 6 h, the solvent was evaporated under reduced pressure,
and the residue was treated with water. The precipitate was filtered
off, dried, and recrystallized from ethanol to give 7b (0.19 g, 44.4%),
m.p. 180–181◦C. IR: 3312 (NH), 1639 (C O), 1620 (C N), 1600 (C C)
cm−1. Anal. calcd. for C24H21N5OS: C, 67.42; H, 4.95; N, 16.38. Found:
C, 67.20; H, 4.80; N, 16.10.
N-(6-Ethoxycarbonyl-3,4-diphenylthieno[2,3-c]pyridazin-5-Yl)-
N’-benzoylthiourea 8
To a stirred solution of in situ prepared benzoyl isothiocyanate (0.2 g,
1.28 mmol) in dry acetone (10 mL), a solution of compound 1 (0.5 g,
1.33 mmol) in dry acetone (10 mL) was slowly added dropwise, and the
mixture was gently refluxed for 30 min. The mixture was cooled, and
the solid was collected, dried, and recrystallized from benzene to give 8
(0.4 g, 69.7%), m.p. 120–121◦C. IR: 3449, 3310 (NH), 1731 (C O ester),
1661 (C O amide), 1162 (C S) cm−1; 1H-NMR (DMSO-d6): 8.10 (s, 1H,
NH), 7.90 (s, 1H, NH), 7.40–7.10 (m, 15H, 3Ph), 4.20 (q, 2H, J = 7.3 Hz,
CH2, 1.20 (t, 3H, J = 7.3 Hz, CH3). Anal. calcd. for C29H22N4O3S2: C,
64.66; H, 4.11; N, 10.40. Found: C, 64.40; H, 4.00; N, 10.20.
1,2-Dihydro-8,9-diphenyl-2-thioxopyrimido[4ꢀ,5ꢀ:4,5]thieno-
[2,3-c]pyridazin-4(3H)-one 9
A solution of compound 8 (0.5 g, 0.92 mmol) in 2 N methanolic sodium
hydroxide (10 mL) was refluxed for 8 h and then filtered. The clear
solution acidified (pH = 5–6) with 10% hydrochloric acid gave the com-
pound 9, recrystallized from ethanol (0.17 g, 58%), m.p. 165–166◦C. IR:
1
3176 (NH), 1676 (C O), 1194 (C S) cm−1; H-NMR (DMSO-d6): 10.24
(s, 1H, NH), 7.40–7.20 (m, 10H, 2Ph), 6.98 (s, 1H, NH). Anal. calcd. for

Pyridazine Derivatives and Related Compounds, Part 19
889
C20H12N4OS2: C, 61.83; H, 3.11; N, 14.42. Found: C, 61.70; H, 3.00; N,
14.20.
2-Amino-8,9-diphenylpyridazino[4ꢀ,3ꢀ:5,4]thieno[3,2-d]-
1,3-thiazin-4-one 10
A suspension of compound 8 (0.5 g, 0.92 mmol) in 98% sulphuric acid
(5 mL) and 3 drops of water was heated at 100◦C for 6 h; the resultant
clear solution was slowly added to ice water (30 mL), and the solid
product was collected, washed with sodium bicarbonate solution (5%)
and cold water, dried, and recrystallized from ethanol to give 10 (0.2 g,
67%), m.p. 160–161◦C. IR: 3346, 3162 (NH2), 1672 (C O), 1612 (C N)
cm−1; 1H-NMR (DMSO-d6): 7.80–7.10 (m, 10H, 2Ph), 8.06 (s, 2H, NH2).
Anal. calcd. for C20H12N4OS2: C, 61.83; H, 3.11; N, 14.42. Found: C,
61.60; H, 2.90; N, 14.10.
2-(3-Benzoylthioureido)-8,9-diphenylpyridazino[4ꢀ,3ꢀ:5,4]-
thieno[3,2-d]-1,3-thiazin-4-one 11
Compound 10 (0.5 g, 1.28 mmol) was dissolved in dry acetone (10 mL).
A solution of benzoyl isothiocyanate in acetone (1.3 mmol in 20 mL)
was added. The mixture was refluxed for 3 h and kept at r.t. over
night. The precipitate was collected by filtration, washed with n-hexane,
dried and recrystallized from ethanol (0.4 g, 57.1%) of 11, m.p. 264–
165◦C. IR: 3344, 3162 (NH), 1735 (C O, cyclic), 1666 (C O amide), 1154
1
(C S) cm−1; H-NMR (DMSO-d6): 8.05 (s, 1H, NH), 7.80 (s, 1H, NH),
7.40–7.20 (m, 15H, 3Ph). Anal. calcd. for C28H17N5O2S3: C, 90.95; H,
3.10; N, 12.69. Found: C, 90.70; H, 2.90; N, 12.50.
2-Benzoylimino-9,10-diphenyl-2H,5H-pyridazino [4ꢀꢀ,3ꢀꢀ: 4ꢀ,5ꢀ]
thieno[2ꢀ,3ꢀ:5,4]-1,2,4-thiadiazolo[3,2-b]-1,3-thiazin-5-one 12
A mixture of compound 11 (0.5 g, 0.9 mmol), N-bromosuccinimide
(0.13 g, 0.9 mmol), and concentrated sulfuric acid (5 mL) was kept at
r.t. for 7 days. The mixture was poured into ice water (50 mL). The pre-
cipitate was collected by filtration, washed with a solution of sodium
bicarbonate (5%), and dried; the crude product was recrystallized from
ethanol to give 12 (0.24 g, 50%), m.p. 220–221◦C. IR: 1722 (C O cyclic),
1
1673 (C O amide), 1631 (C N), 1610 (C C) cm−1; H-NMR (DMSO-
d6): 8.07–7.10 (m, 15H, 3Ph). Anal. calcd. for C28H15N5O2S3: C, 61.18;
H, 2.75; N, 12.74. Found: C, 61.00; H, 2.50; N, 12.60.

890
A. Deeb and M. El-Abbasy
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