Pyridazine derivatives and related compounds. Part 11: 1Synthesis of some pyrimido[4′,5′:4,5]thieno[2,3-c] pyridazines

Article abstract of DOI:10.1080/10426500490475175

3-Substituted pyrimido[4′,5′:4,5]thieno[2,3-c/pyridazine-2,4- di-ones and 3-amino-2-methylpyrimido[4′,5′:4,5]thieno[2,3-c] pyridazine-4-ones were synthesized starting from ethyl 5-aminothieno[2,3-c] pyridazine-6-carboxylate 1. Reaction of amino ester 1 with phenyl isothiocyanate affords thiourea derivative 10 which undergo further transformation to the related fused heterocyclic systems.

Full text of DOI:10.1080/10426500490475175

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Phosphorus, Sulfur, and Silicon
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Pyridazine Derivatives and
Related Compounds. Part
11: 1Synthesis of Some
Pyrimido[4′,5′:4,5]thieno[2,3-
c]pyridazines
Ali Deeb a , Mahmoud Kotb & Mohamed El-Abbasy
a Department of Chemistry, Faculty of Science,
Zagazig University, Egypt
Published online: 16 Aug 2010.
To cite this article: Ali Deeb , Mahmoud Kotb & Mohamed El-Abbasy (2004):
Pyridazine Derivatives and Related Compounds. Part 11: 1Synthesis of Some
Pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazines, Phosphorus, Sulfur, and Silicon and the
Related Elements, 179:11, 2245-2252
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Phosphorus, Sulfur, and Silicon, 179:2245–2252, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490475175
PYRIDAZINE DERIVATIVES AND RELATED
COMPOUNDS. PART 11: 1SYNTHESIS OF SOME
PYRIMIDO[4ꢀ,5ꢀ:4,5]THIENO[2,3-c]PYRIDAZINES
Ali Deeb, Mahmoud Kotb, and Mohamed El-Abbasy
Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt
(Received November 26, 2003; accepted April 7, 2004)
3-Substituted pyrimido[4ꢁ,5ꢁ :4,5]thieno[2,3-c]pyridazine-2,4-di-ones
and 3-amino-2-methylpyrimido[4ꢁ,5ꢁ :4,5]thieno[2,3-c]pyridazine-4-
ones were synthesized starting from ethyl 5-aminothieno[2,3-c]
pyridazine-6-carboxylate 1. Reaction of amino ester 1 with phenyl isoth-
iocyanate affords thiourea derivative 10 which undergo further trans-
formation to the related fused heterocyclic systems.
Pyridazine derivatives and heterocyclic-annelated pyridazines con-
tinue to attract interest due to a wide spectrum of biological activities.2,3
In particular, some thienopyridazines have been reported to possess
considerable antiasthmatic4 and fibrinolytic activities.5 As a continua-
tion of our previous work on the synthesis and biological properties of
fused systems of pyridazine and different heterocycles, we have been
interested in the synthesis and biological properties of thieno[2,3-c]-
pyridazine derivatives. In this article we report our results on the an-
nulation of the pyrimidine ring to a preformed thieno[2,3-c]pyridazine
system employing an amino ester as a conveniently accessible precursor
and evaluate their antimicrobial activities.
Our synthesis began with the preparation of ethyl 5-amino-3,4-
diphenyl-thieno[2,3-c]pyridazine-6-carboxylate 1, which was obtained
from the reaction of 3-chloro-4-cyanopyridazine or 4-cyanopyridazine-
3-thione with ethyl mercapto-acetate or ethyl chloro(bromo)acetate,
respectively.6
Boiling a solution of 1 and ethoxycarbonyl chloride in acetone, 2 (95%)
was obtained. This last compound was cyclized to 3 with hydrazine
Address correspondence to Ali Deeb, Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt.
2245

2246
A. Deeb et al.
hydrate. From the elemental analysis and IR spectra, the com-
pound 3 would be 3-amino-8,9-diphenylpyrimido[4ꢁ,5ꢁ:4,5]thieno[2,3-
c]pyridazine-2,4-dione or the isomeric triazepinedione 3a resulting
from the ring expansion (Scheme 1). The 1H NMR spectra showed that
the correct structure is the aminopyrimidinedione. According to the
literature,7 3-aminopyrimidine-4-ones show a signal at about δ 6.0–
5.0 ppm (s or bs, 2H, 3-NH2), in the 1H NMR spectra, which disappears
with the addition of deuterium oxide. In the isomeric triazepinones, the
signals for the protons of the system CONHNHCO appear at values
of >8.0 ppm8 as two different signals (s or bs). The 1H NMR spectra of 3
shows a signal at about 5.56 (bs, 2H), which was assigned to the 3-amino
SCHEME 1

Pyridazine Derivatives
2247
group. However, compound 3 does not show any expected signal for the
proton of the group N(1)H CO . This proton seems to interchange
very easily with the protons of water in the solvent dimethylsulfoxide-
d6 (DMSO-d6). The structure 3 for this compound was confirmed by the
preparation of the p-nitrobenzylidene derivative 4 (60%). The struc-
ture of compound 3 was also confirmed by the fact that 3, on treatment
with sodium nitrite in 50% acetic acid, undergoes smooth by deamina-
tion to give 8,9-diphenylpyrimido[4ꢁ,5ꢁ:4,5]thieno[2,3-c]pyridazine-2,4-
dione 5, which is identical to the product obtained by treatment of the
aminoester 1 with urea at 180◦C.
The reaction of 1 with either with acetyl chloride or acetic anhy-
dride at reflux temperature led to the formation of the monoacetyl
derivative 6. Compound 6 on heating with hydrazine hydrate
in ethanol produced 3-amino-2-methyl-3,4-dihydro-4-oxo-8,9-diphenyl-
pyrimido[4ꢁ,5ꢁ:4,5]thieno[2,3-c]pyridazine 7, along with amino carbo-
hydrazide 8. The formation of 8 is probably due to the simultaneous
partial deacetylation of 6 with hydrazine hydrate while it is being con-
verted into the corresponding carboxyhydrazide, and subsequent ring
closure is effected. Compound 7, on treatment with sodium nitrite in
50% acetic acid, underwent deamination to give 2-methyl-3,4-dihydro-
4-oxo-8,9-diphenylpyrimido-[4ꢁ,5ꢁ:4,5]-thieno[2,3-c]pyridazine 9. It was
found to be identical (m.p., mixed m.p., and super imposable IR) with
an authentic sample synthesized unambiguously.9
On the other hand, we employed compound 1 as a starting material
to synthesize other heterocyclic systems. Reaction with phenylisothio-
cyanate in toluene resulted in thiourea derivative 10. Upon treatment
with hydrazine hydrate (98%), 10 undergoes cyclization to 3-amino-
2-anilino-4-oxo-8,9-diphenylpyrimido[4ꢁ,5ꢁ:4,5]thieno[2,3-c]pyridazine
11. Compound 11 in turn could be transformed to other fused hete-
rocyclic systems. Reaction with triethylorthoformate in the presence
of catalytic amounts of p-toluenesulfonic acid affords the tetracyclic
compound 12 (Scheme 2). The most salient features of IR and 1H NMR
spectra are given in the Experimental section below.
ANTIMICROBIAL SCREENING
The synthesized compounds were evaluated for their antimicrobial ac-
tivity by the agar diffusion techniques.11 A 0.1% solution in dimethyl-
formamide (DMF) was used. The test organisms were Staphylococcus
aureus NCTS 4163, Escherichia coli NCTC 5933, and Candida albi-
cans 3501. Inhibition zones against E. coli for 3, 18 mm; 4, 21 mm; 5,
16 mm; 7, 9, 10, 14 mm; and 11 and 12, 17 mm. The other compounds

2248
A. Deeb et al.
SCHEME 2
showed no inhibition zones against E. coli. The reference compound
was Streptomycin (inhibition zone: 34 mm). DMF showed no inhibition
zones. The minmum inhibitory concentrations (MICs) for compounds 3,
4, 7, 9, and 10 were 0.05, 0.0125, 0.025, 0.1, and 0.023 mg/ml, respec-
tively. The MIC for Streptomycin was 0.006 mg/ml. None of the tested
compounds was superior to Streptomycin in the test against E. coli. The
compounds showed no inhibition against S. aureus and C. albicans.
EXPERIMENTAL
All the melting points are uncorrected. The IR spectra of the compounds
were recorded on a Perkin-Elmer spectrophotometer model 1310 as
potassium bromide pellets, and frequencies are reported in cm−1. The
1H NMR spectra were observed on a Perkin-Elmer R 12 B spectrometer
and chemical shifts (δ) are in ppm relative to internal TMS. Reactions
were routinely followed by thin layer chromatography (TLC) on silica
gel F254 aluminium sheets (Merck). The spots were detected by UV ir-
radiation at 254–365 nm.
Ethyl 5-Amino-3,4-diphenylthieno[2,3-c]pyridazine-6-
carboxylate 1
Na2CO3 (3.99 g, 37.64 mmol) was added to a solution of 3-chloro-
4-cyano-5,6-diphenylpyridazine6 (9.14 g, 31.36 mmol) and ethyl 2-
mercaptoacetate (4.11 g, 37.64 mmol) in EtOH/THF (5:1) (600 ml).
The reaction mixture was refluxed for 2.5 h. The reaction mixture was

Pyridazine Derivatives
2249
collected by filtration while hot, concentrated and left to cool. The solid
product formed was filtered off and recrystallized from ethanol to give
1 (10.82 g, 92%); m.p. 182–184◦C (lit10 m.p. 180–182◦C).
Ethyl 5-Ethoxycarbonylamino-3,4-diphenylthieno[2,3-
c]pyridazine-6-carboxylate 2
To a solution of 1 (0.38 g, 1 mmol) in dry acetone (50 ml), anhydrous
potassium carbonate (0.5 g) and ethoxycarbonyl chloride (0.11 g, 1
mmol) were added. The reaction mixture was refluxed for 5 h. After
filtration, the solvent was removed in vacuo and the solid residue was
recrystallized to give 2, m.p. 117–118◦C (ethanol), yield 0.27 g (60%) as
yellow crystals. IR: 3330 and 3260 (NH), 1690 (multiple, C O), 1630
1
(C N), 1550 (C C). H NMR (DMSO-d6)δ: 8.75 (s, 1H, CO NH), 7.4
(s, 10H, 2Ph), 4.4–4.0 (m, 2H, CH2), 3.8–2.45 (m, 2H, CH2), 1.3 (t, 3H,
CH3), 1.2 (t, 3H, CH3). Anal. Calcd for C24H21N3O4S: C, 64.41; H, 4.73;
N, 9.39. Found: C, 64.30; H, 4.60; N, 9.20.
3-Amino-8,9-diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-
c]pyridazine-2,4-dione 3
A mixture of 2 (0.45 g, 1 mmol) and hydrazine hydrate (98%; 5 ml) was
boiled for 4 h. Excess hydrazine was removed in vacuo and the solid
residue recrystallized to give 3, m.p. 206–207◦C (ethanol), yield 0.22 g
(56%) as pale brown crystals. IR: 3340 (w, NH), 3190 (s, NH), 1680 (m,
1
C O), 1640 (s, C O), 1630 (C N), 1520 (C C). H NMR (DMSO-d6)
δ: 7.4–7.0 (m, 10H, 2Ph), 5.56 (s, 2H, NH2). No any signal was observed
for N(1)H ; this proton seems to interchange with the protons of the
trace of water in the solvent. The signal at 5.56 (s) disappeared following
the addition of deuterium oxide. Anal. Calcd for C20H13N5O2S: C, 62.00;
H, 3.38; N, 18.08. Found: C, 61.80; H, 3.10; N, 17.90.
3-(4-Nitrobenzilideneamino)-8,9-diphenylpyrimido-
[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine-2,4-dione 4
A mixture of 3 (1.00 g, 2.58 mmol), p-nitrobenzaldehyde (0.54 g, 3 mmol)
and ethanol (20 ml) was boiled for 6 h. Solvent was removed in vacuo
and the residual material was recrystallized to give 4 as brown crystals,
m.p. 235–236◦C (ethanol), yield 0.8 g (60%). IR: 3170 (bs, NH), 1685 (s,
C O), 1630 (w, C O, C N), 1540 (C C). Anal. Calcd for C27H16N6O4S:
C, 62.29; H, 3.09; N, 16.14. Found: C, 62.00; H, 2.90; N, 15.80.

2250
A. Deeb et al.
8,9-Diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine-
2,4-dione 5
Method A
To a suspension of 3 (0.4 g, 1.03 mmol) in 50% acetic acid (30 ml)
warmed to 45–50◦C, sodium nitrite (0.4 g, 5.8 mmol) was added in por-
tions. The reaction mixture was maintained at this temperature till
the evolution of brown fumes ceased. The product that separated as a
colorless solid on dilution with water was collected and further puri-
fied by dissolving in alkali and reprecipitating with acid. It was finally
recrystallized from DMF as colorless granules, yield 0.3 g, (80%), m.p.
335–336◦C. IR: 3160 (bs NH), 1680 (s, CO), 1635 (w, CO, C N), 1550
(C C). Anal. Calcd for C20H12N4O2S: C, 64.50; H, 3.24; N, 15.04. Found:
C, 64.30; H, 3.00; N, 14.80.
Method B
Compound 1 (1 g, 2.6 mmol) and urea (1.5 g, 25 mmol) were heated to-
gether at 180◦C for 30 min. The reaction mixture became almost liquid.
The temperature was then raised to 190◦C, and it was further heated
for 20 min at this temperature. The reaction product was cooled, dis-
solved in hot aqueous NaOH (2N), and filtered. The filtrate was acidified
with acetic acid in hot condition, and the product was filtered and re-
crystallized from DMF to give 5 as colorless plates (0.4 g, 41%), m.p.
335–336◦C. The compound is identical to that obtained according to
Method A.
Ethyl 5-Acetylamino-3,4-diphenylthieno[2,3-c]-
pyridazine-6-carboxylate 6
Acetyl chloride (0.08 g, 1 mmol) was added to a solution of 1 (0.38 g,
1 mmol) in dry pyridine (10 ml). The reaction mixture was heated on
water bath for 3 h, the cooled reaction mixture was poured into water
(100 ml). The precipitated product was filtered, dried, and recrystal-
lized, m.p. 147–148◦C (ethanol), yield 0.38 g, (90%). IR: 3230 (NH),
1
1700, 1690 (C O groups), 1640 (C N), 1565 (C C). H NMR (DMSO-
d6) δ: 7.5–7.0 (s, 10H, 2Ph), 4.2–4.0 (m, 2H, CH2), 1.8 (s, 3H, CH3), 1.2
(t, 3H, CH3). Anal. Calcd for C23H19N3O3S: C, 66.17; H, 4.59; N, 10.06.
Found: C, 66.00; H, 4.40; N, 9.90.
3-Amino-2-methyl-3,4-dihydro-4-oxo-8,9-diphenylpyrimido-
[4ꢀ,5ꢀ:4,5]thieno[2,3-c]-pyridazine 7 and 3-amino-4,5-
diphenylthieno[2,3-c]pyridazine-2-carbohydrazide 8
A mixture of 6 (3 g, 7.18 mmol) and hydrazine hydrate 80% (6 ml)
was heated under reflux in ethanol (60 ml). Within 1 h, a crystalline

Pyridazine Derivatives
2251
product started to separate. After refluxing for a further period of 1 h,
the reaction mixture was cooled and 7, which separated as a crystalline
solid (0.5 g, 40%), was collected, m.p. 205–206◦C (DMF). IR: 3500, 3310,
3180 (NH groups), 1660, 1640 (C O), 1620 (C N), 1530 (C C). 1H NMR
(DMSO-d6)δ: 9.89 (s, 2H, NH2), 7.4–7.0 (m, 10H, 2Ph), 3.3 (s, 3H, CH3).
Anal. Calcd for C21H15N5OS: C, 65.43; H, 3.92; N, 18.17. Found: C, 65.20;
H, 3.80; N, 18.00.
The filtrate after dilution with water was cooled thoroughly to get
8 as a colorless solid. It was collected and crystallized from ethanol
as needles (0.25 g, 40%), m.p. 245–246◦C. IR: 3450, 3320, 3260 (NH
1
groups), 1640 (C O), 1600 (C N), 1530 (C C). H NMR (DMSO-d6) δ:
9.4 (s, 1H, NH), 8.0–7.6 (d, 2H, NH2), 7.4–7.0 (s, 10H, 2Ph), 4.2 (s, 2H,
5-NH2). Anal. Calcd for C19H15N5OS: C, 63.14; H, 4.18; N, 19.38. Found:
C, 63.00; H, 4.10; N, 19.20.
3.4-Dihydro-2-methyl-4-oxo-8,9-diphenylpyrimido-
[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine 9
A suspension of 7 (0.2 g) in 50% acetic acid (15 ml) was treated with
sodium nitrite (0.2 g) at 45–50◦C. Subsequent work up as described
above gave 9 as colorless long needles (0.18 g, 94.7%), m.p. > 300◦C
(DMF). TLC chromatography in three solvent systems and IR spectra
showed the compound to be same as that previously reported.9
N-(6-Ethoxycarbonyl-3,4-diphenylthieno[2,3-c]pyridazin-
5-yl)-Nꢀ-phenylthiourea 10
A solution of amino ester 1 (0.38 g, 1 mmol) and phenyl isothiocyanate
(0.14 g, 1 mmol) in benzene (10 ml) was heated at reflux. After 2 h the
mixture was cooled, and the solid was collected and dried, m.p. 130–
131◦C (benzene), yield 0.28 g (54%). IR: 3443, 3309 (NH), 1723 (C O),
1
1665 (C N), 1620, 1155 (C S). H NMR (DMSO-d6) δ: 8.05, (s, 1H,
NH), 7.84 (s, 1H, NH), 7.4–7.1 (m, 15H, 3Ph), 4.2 (q, 2H, CH2), 1.2 (t,
3H, CH3). Anal. Calcd for C28H22N4O2S2: C, 65.86; H, 4.34; N, 10.97.
Found: C, 65.70; H, 4.20; N, 10.80.
3-Amino-2-anilino-3,4-dihydro-4-oxo-8,9-
diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine 11
Hydrazine hydrate 98% (3 ml) was slowly added to a stirred solution
of thiourea derivative 10 (1 g, 1.95 mmol) in 15 ml of ethanol. The
mixture was refluxed for 8 h and the solid crystallized on cooling was
collected, repeatedly washed with water, and dried, m.p. 239–240◦C
(ethanol), yield 0.63 g, (70%). IR: 3501, 3319, 3176 (NH), 1655 (C O),
1
1618 (C N), 1491 (C C). H NMR (DMSO-d6) δ: 9.3 (br s, 1H, NH),

2252
A. Deeb et al.
7.4–7.0 (m, 15H, 3Ph), 4.1 (s, 2H, NH2). Anal. Calcd for C26H18N6OS:
C, 67.51; H, 3.92; N, 18.17. Found: C, 67.30; H, 3.70; N, 18.00.
1,9,10-Triphenyl-5-oxo-[1,2,4]triazolo[2ꢀꢀ,3ꢀꢀ:1ꢀ,2ꢀ]pyrimido-
[4ꢀ,5ꢀ:4,5]thieno-[2,3-c]pyridazine 12
A suspension of 11 (2.7 g, 5.85 mmol) and p-toluenesulfonic acid
(1.5 g, 8.72 mmol) in triethylorthoformate (45 ml) was refluxed under
stirring for 18 h. The solid material was collected by filtration, washed
with water, dried and recrystallized from DMF, the yield of 12 was
1
50%, m.p. > 300◦C. IR: 3057 (NH), 1686 (C O), 1545 (C C). H NMR
(CDCl3)δ: 7.66 (s, 1H, triazole), 7.35–7.05 (m, 15 H, 3Ph). Anal. Calcd
for C27H16N6OS: C, 68.62; H, 3.41; N, 17.78. Found: C, 68.30; H, 3.20;
N, 17.60.
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