A convenient synthesis of novel functionalized pyrimido[5′,4′: 4,5]thieno[3,2-c]pyridazines and related fused systems

Article abstract of DOI:10.1080/10426500802060040

Possible approaches to the synthesis of functionalized, pyrimido[5′,4′:4,5]thieno [3,2-c]pyridazines 2-18, pyridazino[3′,4′:4,5]thieno[2,3-d]triazines 19, 20a,b and pyrido[3′,2′:4,5]thieno[3,2-c]pyridazines 22a,b are described. The sequence involves the heterocyclization of 6-amino-1,3-diphenyl-1,4- dihydrothieno[3,2-c]pyridazine-7-carboxamide (1) with appropriate reagents. The antimicrobial activity of some the newly synthesized compounds was examined. All tested compounds proved to be active as antibacterial and antifungal agents. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500802060040

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A Convenient Synthesis
of Novel Functionalized
Pyrimido[5′,4′:4,5]thieno[3,2-
c]pyridazines and Related
Fused Systems
A. A. Aly a
a Chemistry Department, Faculty of Science , Benha
University , Benha, Egypt
Published online: 03 Nov 2008.
To cite this article: A. A. Aly (2008) A Convenient Synthesis of Novel Functionalized
Pyrimido[5′,4′:4,5]thieno[3,2-c]pyridazines and Related Fused Systems,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:12, 3079-3096, DOI:
10.1080/10426500802060040
To link to this article: http://dx.doi.org/10.1080/10426500802060040
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Phosphorus, Sulfur, and Silicon, 183:3079–3096, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802060040
A Convenient Synthesis of Novel Functionalized
Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines and Related
Fused Systems
A. A. Aly
Chemistry Department, Faculty of Science, Benha University,
Benha, Egypt
Possible approaches to the synthesis of functionalized, pyrimido[5ꢀ,4ꢀ:4,5]thieno
[3,2-c]pyridazines 2-18, pyridazino[3ꢀ,4ꢀ:4,5]thieno[2,3-d]triazines 19, 20a,b and
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-c]pyridazines 22a,b are described. The sequence involves
the heterocyclization of 6-amino-1,3-diphenyl-1,4-dihydrothieno[3,2-c]pyridazine-
7-carboxamide (1) with appropriate reagents. The antimicrobial activity of some
the newly synthesized compounds was examined. All tested compounds proved to
be active as antibacterial and antifungal agents.
Keywords Antimicrobial activities; pyrimidothienopyridazines; pyridazinothienotri-
azines; pyridothienopyridazines; thieno[3,2-c]pyridazine
INTRODUCTION
Pyridazines and their annelated derivatives occupy a pivotal position
in modern medicinal chemistry because the pyridazine ring is a promi-
nent structural motif found in numerous natural and synthetic bio-
logically active compounds. In addition to their powerful antioxidant
and free radical scavenging properties.1−6 The pyrimidine moiety is
a frequent partner in many heterocyclic systems. It displays a wide
range of pharmacological activities as fungicide, viricide, leishmani-
cide, phosphodiesterase inhibitor, besides the use as a component in
photographic materials and agrochemical industries.7−11 Encouraged
by these assessment and continuing our interest in the chemistry and
pharmacology of heterocyclic systems,12,13 we report herein on efficient
incorporation the latter heterocyclic moiety into pyridazine condensed
Received 19 October 2007; accepted 20 February 2008.
The author is grateful to the Botany Department, Faculty of Science, Benha Univer-
sity for biological screening.
Address correspondence to A. A. Aly, Chemistry Department, Faculty of Science,
Benha University, Benha, Egypt. E-mail: alymaboud@yahoo.com
3079

3080
A. A. Aly
systems to develop a new synthetic strategy of functionalized bio-
logically active derivatives, utilizing the readily available, 6-amino-
1,3-diphenyl-1,4-dihydrothieno[3,2-c]pyridazine-7-carboxamide (1) as
a key starting material.
RESULTS AND DISCUSSION
The required 6-amino-1,3-diphenyl-1,4-dihydrothieno[3,2-c]pyridazine
-7-carboxamide (1) was prepared in a facile one-pot reaction via
a
three-component cyclocondensation of 2,6-diphenyl-2H-4,5-
dihydropyridazin-3-one, cyanoacetamide and elemental sulfur in
ethanolic triethylamine solution.14 The structure of compound 1 was
assigned by elemental analysis and spectroscopic data (IR, 1H and
13C NMR spectra) which agree with the assigned structure. The H
1
NMR (CDCl3) of 1 showed signals at δ 3.99 as singlet for methylene
protons, (5.95 and 6.30) two singlets for two amino groups and mul-
tiplet signals at 7.12−7.85 for aromatic protons. The reactivity of the
conveniently accessible o-amino amide derivative 1 toward a variety
of chemical reagents was investigated. It was found that the reaction
of compound 1 with aromatic aldehyde viz benzaldehyde and 4-
chlorobenzaldehyde in glacial acetic acid afforded 2-aryl-5,7-diphenyl-
1H-2,3,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-4-ones
(2a,b) (Scheme 1).
The treatment of compound 1 with cyclopentanone and/or cy-
clohexanone in glacial acetic acid, yielded the tricyclic compounds
3a,b. The reaction of compound 1 with triethyl orthoformate in
the presence of acetic anhydride afforded pyrimidothienopyridazine
derivative 4. Moreover, the treatment of compound 1 with acetyl chlo-
ride and/or benzoyl chloride afforded the acyl derivatives 5a,b. Com-
pounds 5a,b underwent cyclization upon refluxing in concentrated
sulfuric acid at 160◦C, to give 1,3-diphenyl-7-methyl/phenyl-8H-1,4-
dihydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-9-ones (6a,b). A con-
clusive evidence for the structure of 6a was achieved by independent
synthesis via an alternative route through the reaction of compound 1
with excess of acetic anhydride, which gave a single product that was
found to be identical in all respects (m.p., m.m.p., and spectroscopic
data) with 6a.
The work was further extended to shed more light on the reactiv-
ity of compound 1 as bifunctional reagent toward other electrophilic
reagents. Thus, the reaction of 1 with carbon disulfide in boiling
1,4-dioxane solution gave the corresponding pyrimidothienopyridazine
derivative 7. The IR spectrum of 7 displayed absorption bands at

Novel Functionalized Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines
3081
SCHEME 1 (i) ArCHO, AcOH; (ii) cyclopentanone or cyclohexanone, AcOH;
(iii) CH(OEt)3, Ac2O; (iv) RCOCl; (v) H2SO4, 160◦C; (vi) Ac2O; (vii) CS2, dioxane;
(viii) PhNCS, EtOH, Et3N.
1
3250−3200 cm−1 (NH), 1670 cm−1 (CO) and 1280 cm−1 (CS). Its H
NMR spectrum (CDCl3) showed singlet at δ 4.10 (CH2), multiplet at
(7.30–8.20) (ArH) and two singlets at 9.21, 9.32 for 2 NH which disap-
pear on addition of D2O to the NMR sample. The reaction of compound
1 with phenyl isothiocyanate in refluxing absolute ethanol containing
a catalytic amount of triethylamine afforded 3,5,7-triphenyl-2-thioxo-
1,3,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-4- one (8)
(Scheme 1).
The acetylation of 1 with chloroacetyl chloride resulted in the
formation of thienopyridazine 9, which in turn underwent cycliza-
tion to give 7-chloromethyl-1,3-diphenyl-8H-1,4-dihydropyrimido
[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-9-one (10) (Scheme 2).
The assignment of structure 10 was based on analytical and spec-
troscopic data. The feasibility of the chlorine atom in compound 10 to
undergo nucleophilic displacement was proved by reaction with sodium
ethoxide, piperidine and/or morpholine which gave the pyridazine

3082
A. A. Aly
SCHEME 2 (i) ClCH2COCl; (ii) Ac2O, AcOH; (iii) EtONa, EtOH; (iv) piperidine
or morpholine; (v) thiourea, NaOH, AcOH.
derivatives 11 and 12a,b respectively. The reaction of compound 10
with thiourea gave adduct which upon treatment with sodium hydrox-
ide followed by acidification furnished the mercaptomethylpyridazine
derivative 13.
As an extension of this synthetic route, the behavior of compound
1 toward some cyanomethylene reagents was investigated. Thus, the
reaction of equimolar amounts of compound 1 and malononitrile or
ethyl cyanoacetate in refluxing absolute ethanol containing a catalytic
amount of triethylamine yielded the corresponding pyrimidothienopy-
ridazines 15a,b respectively (Scheme 3).
The formation of compounds 15a,b was assumed to proceed via the
intermediacy of 14a,b, which underwent cyclization via the elimina-
tion of ammonia yielding the final isolable products 15a,b. The ace-
tonitrile 15a seemed to be suitable for the synthesis of interesting
related systems as well as thiophene derivatives. Thus, the condensa-
tion of 1 with aromatic aldehyde in boiling absolute ethanol containing

Novel Functionalized Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines
3083
SCHEME 3 (i) NCCH2CN or NCCH2COOEt, EtOH, piperidine; (ii) ArCHO,
EtOH, piperidine; (iii) ArN2Cl, AcONa; (iv) NCCH2CN or NCCH2COOEt, S,
EtOH.
a catalytic amount of piperidine, afforded the corresponding arylidene
derivatives 16a,b. The coupling of 1 with aryl diazonium chlorides at
0−5◦C in ethanolic sodium acetate solution gave the hydrazono deriva-
tives 17a,b. The reaction of equimolar amounts of 15a with elemental
sulfur and active methylene compounds in refluxing ethanol containing
triethylamine afforded the thiophene derivatives 18a,b, (Scheme 3).
Recently, there is a widespread interest in the design and syn-
thesis of triazine derivatives as well as pyridine derivatives be-
cause of their potential biological activities associated with their

3084
A. A. Aly
skeletons.15−17 Thus, the diazotization and self-coupling reaction18 of
amino amide derivative 1 with sodium nitrite and acetic acid af-
forded 5,7-diphenyl-5,8-dihydropyridazino[3ꢀ,4ꢀ:4,5]thieno[2,3-d]-1,2,3-
triazin-4(3H)-one (19). The treatment of 19 with electrophilic reagents
viz methyl iodide and 2-bromoacetophenone furnished 3-substituted
triazine derivatives 20a,b (Scheme 4).
Finally, the behavior of 1 toward β-addition was also investigated.
It was treated with equimolar amounts of α-substituted cinnamoni-
trile derivatives in absolute ethanol containing a catalytic amount
of piperidine, to afford the corresponding pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-
c]pyridazine derivatives 22a,b (Scheme 4). The reaction took place via
the intermediacy of 21a,b through a Michael-type addition, subsequent
intramolecular cyclization via loss of ammonia, followed by elimination
of hydrogen cyanide.19 The structures of the synthesized derivatives
were assigned on the basis of elemental analysis and spectroscopic
data (cf. experimental).
ANTIMICROBIAL ACTIVITY
The antimicrobial activity of some synthesized compounds against
some pathogenic bacteria and fungi was tested in vitro using the
hole plate and filter paper disc methods.20 Chloramophenicol as an
SCHEME 4 (i) NaNO2, AcOH; (ii) CH3I, PhCOCH2Br, acetone, KOH; (iii)
PhCH CXCN, EtOH, piperidine.

Novel Functionalized Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines
3085
antibacterial agent and Terbinafin as an antifungal agent were used
as references to evaluate the potency of the tested compounds un-
der the same conditions. The results in Table I reveal that the tested
compounds exhibited the highest or similar degree of inhibition area
against the organisms relative to the standard antibacterial and anti-
fungal agents.
EXPERIMENTAL
Melting points are uncorrected. IR spectra in KBr were recorded on a
1
Perkin-Elmer 298 spectrophotometer. H and 13C NMR spectra were
obtained on Varian Gemini 200 MHz instrument using TMS as internal
reference with chemical shifts expressed as δ ppm. Mass spectra were
recorded on a Shimadzu GCMS-QP 1000 instrument (70 eV El mode).
13C NMR values of two phenyl groups attached to pyridazine moi-
ety for compounds 2−22 are the same as in compound 1 with δ
0.1−0.4 ppm.
TABLE I The Antimicrobial Activity of the Tested Compounds
Staphylococcus Pseudomon Bacillus Escherichia Aspergillus Penicillium Penicillium
aureus
aeruginosa subtilis
coli
fumigatus
italicum
notatum
Compd
no.
A
MIC
A
MIC
A
MIC
A
MIC
A
MIC
A
MIC
A
MIC
1
2a
3b
4
6a
8
12a
13
15a
16b
17b
18a
19
22a
CH
TE
+
++
++
+
250
500
250
125
250
125
250
125
500
125
250
125
125
250
250
−
++ 500
+
250
+
125
250
125
250
125
250
125
125
250
125
250
125
250
125
250
−
−
+
+
+
−
−
−
−
+
+
−
−
125
125
−
+
250 ++ 250 ++
125 ++ 125
++ 125
250
+
+
125 ++
250
250
125
+
+
+
+
+
+
+
+
−
125
250
+
+
++
+
++ 125 ++ 125 ++
++ 125
250 ++ 250
++ 250 ++ 250
+
+
+
250
125
250 ++ 250
+ + +
+
++ 125 + + + 125 ++
125
250
+
+
250
125
+
+
+
+
+
+
+
250 ++ 250 ++
125 ++ 125 ++
++ 500
++
+
+
125
++ 250
125
125 ++ 250
250 + + + 250
+
125 ++ 125
++
++
+
125 ++ 125 ++
250 ++ 250 ++
125 + + + 125 ++
+
−
−
+
−
−
125
−
++ 250 ++ 500
+
+
−
125
125
−
−
+
−
−
+
250 ++ 500
+
250 ++ 500
++
−
+ + + 250 + + + 250 ++
−
−
−
−
−
−
−
−
++ 250 ++ 250 ++ 125
A = Antimicrobial activity of tested compounds; MIC = Minimum inhibitory
concentration; −, inactive; + > 5mm, slightly active; ++ > 7 mm, moderately active;
+ + + > 9 mm, highly active; CH = chloramophenicol; TE = Terbinafin.

3086
A. A. Aly
6-Amino-1,3-diphenyl-1,4-dihydrothieno[3,2-c]pyridazine-7-
carboxamide (1)
A mixture of 2,6-diphenyl-2H-4,5-dihydropyridazin-3-one (5.00 g, 20
mmol), cyanoacetamide (1.68 g, 20 mmol) and elemental sulfur (0.64 g,
20 mmol) in absolute ethanol (30 mol) containing a catalytic amount of
triethylamine (1 ml) was heated at reflux for 8h. The solvent was re-
moved under reduced pressure and the residue was triturated with ice-
cold water and neutralized with concentrated hydrochloric acid (3 ml).
The solid product, so formed, was collected by filtration and recyrstal-
lized from n-butanol to give 1. Yield, 5.22 g (75%); m.p. 216−218◦C; IR:
1
ν = 3460−3325 (NH2), 1670 cm−1 (CO); H NMR (CDCl3): δ = 3.99 (s,
2H, CH2), 5.95 (s, 2H, NH2), 6.30 (s, 2H, CONH2), 7.12−7.85 (m, 10H,
ArH); 13C NMR: δ = 31.3 (CH2), 130.2 (C-7a), 140.2 (C-8), 145.3 (C-4a),
147.2 (C-7), 158.4 (C-3), 173.3 (CO), 112.1, 112.9, 119.2, 124.2, 124.8,
136.5 (C-phenyl attached to nitrogen atom), 125.2, 125.9, 131.2, 133.1,
133.9, 135.2 (C-phenyl at C-3); Anal. calcd. for C19H16N4OS (348.42):
C, 65.50; H, 4.63; N, 16.08%. Found: C, 65.71; H, 4.85; N, 16.31%.
2,5,7-Triphenyl-1H-2,3,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]thieno-
[3,2-c]pyridazin-4-one (2a) and 2-(4-chlorophenyl)- 5,7-
diphenyl-1H-2,3,5,8-tetrahydropyrimido-[5ꢀ,4ꢀ:4,5]thieno[3,2-
c]pyridazin-4-one (2b)
A mixture of compound 1 (1.04 g, 3 mmol) and benzaldehyde or 4-
chlorobenzaldehyde (3 mmol) in glacial acetic acid (20 ml) was heated
at reflux for 5 h. The reaction mixture was cooled, poured onto ice (20 g).
The solid formed was collected by filtration and recrystallized to give
2a,b.
2a; Yield, 0.92 g (71%) (1,4-dioxane); m.p. 231−233◦C; IR:ν =
1
3320−3300 (NH), 1675 cm−1 (CO); H NMR (DMSO): δ = 3.97 (s, 2H,
CH2), 5.31 (s, 1H, CH), 7.21−7.81 (m, 15H, ArH), 9.35, 9.61 (2s, 2H,
2NH, exchangeable); 13C NMR: δ = 30.2 (CH2), 76.2 (C-2), 130.1 (C-4b),
139.2 (C-9a), 143.2 (C-8a), 146.1 (C-4a), 160.3 (C-7), 176.3 (CO), 126.7,
127.2, 129.3, 130.1, 132.3, 140.1 (C6H5); Anal. calcd. for C26H20N4OS
(436.53): C, 71.54; H, 4.62; N, 12.83%. Found: C, 71.31; H, 4.29; N,
12.98%.
2b; Yield, 1.06 g (76%) (n-butanol); m.p. 243−245◦C; IR:ν =
3340−3310 (NH), 1670 cm−1 (CO); MS: m/z: 470 (M+); Anal. calcd.
for C26H19ClN4OS (470.97): C, 66.30; H, 4.07; N, 11.90%. Found: C,
66.65; H, 4.34; N, 11.70%.

Novel Functionalized Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines
3087
General Procedure for the Preparation of Compounds 3a,b
A mixture of compound 1 (1.04 g, 3 mmol) and cyclopentanone or cyclo-
hexanone (3 mmol) in glacial acetic acid (20 ml) was heated at reflux
for 5h. The reaction mixture was cooled and poured onto ice (20 g). The
resulting solid product was collected by filtration and recrystallized to
give 3a,b.
5,7-Diphenyl-2,2-tetramethylene-1H-2,3,5,8-
tetrahydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-4-one
(3a)
Yield, 0.86 g (69%) (DMF); m.p. 207–9◦C; IR:ν = 3320-3290 (NH),
1673 cm−1 (CO); 1H NMR (DMSO): δ = 1.53 (br s, 2H, CH2 of cy-
clopentylidene ring), 1.85–2.30 (br s, 6H, (CH2)3 of cyclopentylidene
ring), 4.11 (s, 2H, CH2), 7.13-7.95 (m, 10H, ArH), 9.12, 9.21 (2s, 2H,
2NH, exchangeable); Anal. calcd. for C24H22N4OS (414.52): C, 69.54;
H, 5.35; N, 13.52%. Found: C, 69.85; H, 5.61; N, 13.25%.
5,7-Diphenyl-2,2-pentamethylene-1H-2,3,5,8-
tetrahydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-4-one
(3b)
Yield, 0.81 g (63%) (1,4-dioxane); m.p. 236−238◦C; IR:ν = 3340−3300
(NH), 1675 cm−1 (CO); 1H NMR (CDCl3): δ = 0.90−1.10 (m, 2H, CH2 of
cyclohexylidene ring), 1.50−2.0 (m, 4H, (CH2)2 of cyclohexylidene ring),
2.30−2.60 (m, 4H, (CH2)2 of cyclohexylidene), 3.95−4.11 (m, 4H, (CH2)2
of cyclohexylidene ring), 4.25 (s, 2H, CH2), 7.51−8.21 (m, 10H, ArH),
9.41, 9.52 (2s, 2H, 2NH, exchangeable); Anal. calcd. for C25H24N4OS
(428.55): C, 70.07; H, 5.64; N, 13.07%. Found: C, 70.40; H, 5.85; N,
13.42%.
1,3-Diphenyl-8H-1,4-dihydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-
c]pyridazin-4-one (4)
A mixture of compound 1 (1.04 g, 3 mmol) in acetic acid (20 ml) con-
taining acetic anhydride (5 ml) and triethyl orthoformate (3 mmol)
was heated at reflux for 4 h. The reaction mixture was cooled, poured
onto ice-cold water and the solid product formed was collected by fil-
tration and recrystallized from 1,4-dioxane to give 4. Yield, 0.65 g
1
(61%); m.p. 286−288◦C; IR:ν = 3300 (NH), 1665 cm−1 (CO); H NMR
(CDCl3): δ = 4.30 (s, 2H, CH2), 7.31−8.10 (m, 11H, ArH), 9.20 (s, 1H,

3088
A. A. Aly
NH, exchangeable); Anal. calcd. for C20H14N4OS (358.42): C, 67.02; H,
3.94; N, 15.63%. Found: C, 67.40; H, 4.20; N, 15.36%.
6-Acetylamino-1,3-diphenyl-1,4-dihydrothieno[3,2-
c]pyridazine-7-carboxamide (5a)
A mixture of compound 1 (1.04 g, 3 mmol) and acetyl chloride (3 mmol)
in glacial acetic acid (10 ml) was heated at reflux for 4 h. The reaction
mixture was cooled to room temperature and poured onto ice-cold water.
The resulting solid product was collected by filtration and recrystallized
from ethanol to give 5a. Yield, 0.75 g (64%); m.p. 205−207◦C; IR:ν =
3400−3210 (NH2, NH), 1670−1665 cm−1 (CO); MS: m/z: 390 (M+); Anal.
calcd. for C21H18N4O2S (390.46): C, 64.60; H, 4.65; N, 14.35%. Found:
C, 64.30; H, 4.11; N, 14.55%.
6-Benzoylamino-1,3-diphenyl-1,4-dihydrothieno[3,2-
c]pyridazine-7-carboxamide (5b)
To a cold solution (0−5◦C) of compound 1 (1.04 g, 3 mmol) in pyri-
dine (15 ml), benzoyl chloride (3 mmol) was added dropwise with stir-
ring for 1 h. The reaction mixture was heated, at reflux for 4 h and
then evaporated in vacuo, the remaining product was triturated with
ethanol and the formed solid product was filtered off and recrystallized
from ethanol to give 5b. Yield, 0.85 g (63%); m.p. 225−227◦C; IR:ν =
1
3410−3300 (NH2, NH), 1675−1670 cm−1 (CO); H NMR (CDCl3): δ =
4.10 (s, 2H, CH2), 5.60 (br s, 2H, NH2), 7.20−8.15 (m, 15H, ArH), 8.95
(s, 1H, NH, exchangeable); Anal. calcd. for C26H20N4O2S (452.53): C,
69.01; H, 4.45; N, 12.38%. Found: C, 69.39; H, 4.73; N, 12.02%.
1,3-Diphenyl-7-(methyl/phenyl)-8H-1,4-dihydropyrimido[5ꢀ,4ꢀ:
4,5]thieno[3,2-c]pyridazin-9-ones (6a,b)
Method A
A suspension of compound 5a or 5b (3 mmol) in concentrated sulfuric
acid (10 ml) was heated in an oil bath (160◦C) for 5 h, then left to
cool. The reaction mixture was poured onto cold water (30 ml) and
neutralized with sodium hydroxide (25%, 64 ml) and left overnight at
room temperature. The formed solid product was collected by filtration
and recrystallized from ethanol to give 6a,b.

Novel Functionalized Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines
3089
Method B
A solution of compound 1 (1.04 g, 3 mmol) in acetic anhydride (15 ml)
was heated at reflux for 1 h. The reaction mixture was cooled, poured
onto ice (30 g) and the separated solid was filtered off and recrystallized
from ethanol to give 6a. Yield, 0.84 g (76%).
6a; Yield, 0.81 g (72%); m.p. 193−195◦C; IR:ν = 3260 (NH),
1
1670 cm−1 (CO); H NMR (CDCl3): δ = 1.95 (s, 3H, CH3), 4.15 (s, 2H,
CH2), 7.40−8.10 (m, 10H, ArH), 9.21 (s, 1H, NH, exchangeable); Anal.
calcd. for C21H16N4OS (372.44): C, 67.72; H, 4.33; N, 15.04%. Found: C,
67.30; H, 4.10; N, 15.39%.
6b; Yield, 0.69 g (53%); m.p. 185−187◦C; IR:ν = 3290 (NH),
1665 cm−1 (CO); MS: m/z: 434 (M+); Anal. calcd. for C26H18N4OS
(434.51): C, 71.87; H, 4.18; N, 12.89%. Found: C, 71.99; H, 4.46; N,
12.60%.
5,7-Diphenyl-2-thioxo-1H-2,3,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]
thieno[3,2-c]pyridazin-4-one (7)
A suspension of compound 1 (1.04 g, 3 mmol) and carbon disulfide
(3 ml) in 1,4-dioxane (20 ml) was heated at reflux for 10 h. The solid
product which formed after cooling was filtered off and recrystallized
from ethanol to give 7. Yield, 0.60 g (61%); m.p. 251−253◦C; IR:ν =
1
3250−3200 (NH), 1670 (CO), 1280 cm−1 (CS); H NMR (CDCl3): δ =
4.10 (s, 2H, CH2), 7.30−8.20 (m, 10H, ArH), 9.21, 9.32 (2s, 2H, 2NH,
exchangeable); 13C NMR: δ = 30.5 (CH2), 130.1 (C-4b), 140.3 (C-9a),
145.2 (C-4a), 147.3 (C-8a), 159.1 (C-7), 176.3 (CO), 184.3 (CS); Anal.
calcd. for C20H14N4OS2(390.48): C, 61.52; H, 3.61; N, 14.35%. Found:
C, 61.23; H, 3.25; N, 14.62%.
3,5,7-Triphenyl-2-thioxo-1,3,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]
thieno[3,2-c]pyridazin-4-one (8)
A mixture of compound 1 (1.04 g, 3 mmol) and phenyl isothiocyanate
(3 mmol) in absolute ethanol (25 ml) containing a catalytic amount of
triethylamine (0.5 ml) was heated at reflux for 7 h. The reaction mixture
was poured onto ice-cold water and neutralized with dilute hydrochloric
acid (5 ml). The solid product which formed was recrystallized from
1,4-dioxane to give 8. Yield, 1.01 g (73%); m.p. 243−245◦C; IR:ν = 3310
1
(NH), 1670 (CO), 1275 cm−1 (CS); H NMR (CDCl3): δ = 3.99 (s, 2H,
CH2), 7.50−8.41 (m, 15H, ArH), 9.13 (s, 1H, NH, exchangeable); Anal.
calcd. for C26H18N4OS2(466.58): C, 66.93; H, 3.89; N, 12.01%. Found:
C, 66.60; H, 3.51; N, 12.36%.

3090
A. A. Aly
6-(2-Chloroacetylamino)-1,3-diphenyl-1,4-dihydrothieno[3,2-
c]pyridazine-7-carboxamide (9)
A mixture of compound 1 (2.78 g, 8 mmol) and chloroacetyl chloride (10
mmol) in dimethylformamide (25 ml) was stirred at room temperature
for 2 h. The reaction mixture was poured onto ice-cold water. The formed
solid product was filtered off and recrystallized from n-butanol to give
9. Yield, 2.24 g (66%); m.p. 237−239◦C; IR:ν = 3410−3340 (NH2, NH),
1675−1670 cm−1 (CO); 1H NMR (CDCl3): δ = 3.65 (s, 2H, CH2Cl), 4.12
(s, 2H, CH2), 5.85 (br s, 2H, NH2), 7.25−8.15 (m, 10H, ArH), 9.35 (s, 1H,
NH, exchangeable); Anal. calcd. for C21H17ClN4O2S (424.90): C, 59.36;
H, 4.03; N, 13.19%. Found: C, 59.67; H, 4.39; N, 13.41%.
7-Chloromethyl-1,3-diphenyl-8H-1,4-
dihydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-9-one
(10)
A solution of compound 9 (1.27 g, 3 mmol) in glacial acetic acid (20 ml)
containing acetic anhydride (5 ml) was heated at reflux for 5h. The
reaction mixture was cooled, poured onto crushed ice (30 g), and the
formed solid product was collected by filtration and recrystallized from
benzene to give 10. Yield, 0.66 g (54%); m.p. 177−179◦C; IR:ν = 3290
(NH), 1675 cm−1 (CO); 1H NMR (CDCl3): δ = 3.85 (s, 2H, CH2Cl), 4.23
(s, 2H, CH2), 7.15−8.20 (m, 10H, ArH), 9.20 (s, 1H, NH, exchangeable);
13C NMR: δ = 30.2 (CH2), 52.1 (CH2Cl), 129.2 (C-9b), 141.1 (C-5a),
146.2 (C-9a), 147.3 (C-4a), 160.5 (C-3), 168.4 (C-7), 177.2 (CO); Anal.
calcd. for C21H15ClN4OS (406.89): C, 61.99; H, 3.72; N, 13.77%. Found:
C, 61.60; H, 3.32; N, 13.98%.
7-Ethoxymethyl-1,3-diphenyl-8H-1,4-dihydropyrimido[5ꢀ,4ꢀ:
4,5]thieno[3,2-c]pyridazin-9-one (11)
A solution of compound 10 (1.22 g, 3 mmol) in sodium ethoxide solution
(0.46 g of sodium in 30 ml of absolute ethanol) was heated at reflux for
1 h. The precipitate that formed on cooling was collected and recrys-
tallized from toluene to give 11. Yield, 0.91 g (73%); m.p. 202−204◦C;
1
IR:ν = 3260 (NH), 1670 cm−1 (CO); H NMR (CDCl3): δ = 1.40 (t, 3H,
CH3), 3.75 (q, 2H, CH2CH3), 3.95 (s, 2H, CH2O), 4.10 (s, 2H, CH2),
7.13−8.15 (m, 10H, ArH), 9.31 (s, 1H, NH, exchangeable); Anal. calcd.
for C23H20N4O2S (416.50): C, 66.33; H, 4.84; N, 13.45%. Found: C, 66.70;
H,4.98; N, 13.10%.

Novel Functionalized Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines
3091
1,3-Diphenyl-7-(piperidin-1-ylmethyl/morpholin-4-ylmethyl)-
8H-1,4-dihydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-9-ones
(12a,b)
Compound 10 (1.22 g, 3 mmol) in piperidine or morpholine (10 ml)
was heated on a water bath for 4 h. The reaction mixture was then
triturated with ethanol (20 ml) and left to cool. The precipitate was
collected and recrystallized from ethanol to give 12a,b.
12a; Yield, 1.04 g (76%); m.p. 183−185◦C; IR:ν = 3260 (NH), 1672
cm−1 (CO); MS: m/z: 455 (M+); Anal. calcd. for C26H25N5OS (455.58):C,
68.55; H, 5.53; N, 15.37%. Found: C, 68.81; H, 5.84; N, 15.10%.
12b; Yield, 0.99 g (72%); m.p. 196−198◦C; IR:ν = 3290 (NH), 1670
cm−1 (CO); 1H NMR (DMSO): δ = 2.40−2.60 (m, 4H, CH2NCH2),
3.20−3.50 (m, 4H, CH2OCH2), 3.77 (s, 2H, CH2N), 4.10 (s, 2H, CH2),
7.30−8.21 (m, 10H, ArH); 9.11 (s, 1H, NH, exchangeable); Anal. calcd.
for C25H23N5O2S (457.55): C, 65.63; H, 5.07; N, 15.31%. Found: C, 65.95;
H, 5.30; N, 15.05%.
1,3-Diphenyl-7-mercaptomethyl-8H-1,4-dihydropyrimido-
[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-9-one (13)
A mixture of compound 10 (1.22 g, 3 mmol) and thiourea (0.23 g, 3 mmol)
in absolute ethanol (25 ml) was refluxed for 4 h. The product that formed
while hot was collected and dissolved in aqueous sodium hydroxide
(10%, 10 ml), then heated on a water bath for 1 h. The reaction mixture
was filtered off and the clear filtrate was acidified with acetic acid.
The formed yellow precipitate was collected and recrystallized from
ethanol to give 13. Yield, 1.00 g (83%); m.p. 281−283◦C; IR:ν = 3290
1
(NH), 2585 (SH), 1670 cm−1 (CO); H NMR (CDCl3): δ = 2.40 (s, 1H,
SH), 3.75 (s, 2H, CH2S), 4.20 (s, 2H, CH2), 7.13−8.12 (m, 10H, ArH);
13C NMR: δ = 30.1 (CH2), 33.5 (CH2SH), 128.3 (C-9b), 130.3 (C-5a),
136.8 (C-9a), 143.4 (C-4a), 152.3 (C-3), 156.7 (C-7), 176.5 (CO); Anal.
calcd. for C21H16N4OS2 (404.51): C, 62.35; H, 3.99; N, 13.85%. Found:
C, 62.10; H, 3.65; N, 13.51%.
General Procedure for the Preparation of Compounds 15a,b
A mixture of compound 1 (1.04 g, 3 mmol) and malononitrile or ethyl
cyanoacetate (3 mmol) in ethanol (30 ml) containing a catalytic amount
of triethylamine (0.6 ml), was heated at reflux for 8 h. The reaction
mixture was cooled, poured onto cold water (25 ml), neutralized with

3092
A. A. Aly
dilute HCl. The formed solid product was collected by filtration and
recrystallized to give 15a,b.
(5,7-Diphenyl-4-oxo-3,4,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]-
thieno[3,2-c]pyridazin-2-yl)acetonitrile (15a)
Yield, 0.61 g (51%) (ethanol); m.p. 192−194◦C; IR:ν = 3260 (NH),
2225 (C N), 1670 cm−1 (CO); 1H NMR (CDCl3): δ = 4.12 (s, 2H, CH2),
4.50 (s, 2H, CH2CN), 7.15−8.10 (m, 10H, ArH), 9.15 (s, 1H, NH, ex-
changeable); 13C NMR: δ = 29.3, 30.2 (2CH2), 120.1 (CN), 127.3 (C-4b),
130.2 (C-9a), 136.4 (C-4a), 145.2 (C-8a), 153.4 (C-2), 156.3 (C-7), 176.5
(CO); Anal. calcd. for C22H15N5OS (397.45): C, 66.48; H, 3.80; N, 17.62%.
Found: C, 66.75; H, 3.98; N, 17.30%.
2-(5,7-Diphenyl-4-oxo-3,4,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]-
thieno[3,2-c]pyridazin-2-yl)acetamide (15b)
Yield, 0.66 g (53%) (ethanol); m.p. 205−207◦C; IR:ν = 3410−3240
1
(NH2, NH), 1670−1665 cm−1 (CO); H NMR (DMSO): δ = 3.50 (s, 2H,
CH2CO), 4.20 (s, 2H, CH2), 5.95 (br s, 2H, NH2), 7.30−8.20 (m, 10H,
ArH), 9.20 (s, 1H, NH, exchangeable); Anal. calcd. for C22H17N5O2S
(415.47): C, 63.60; H, 4.12; N, 16.86%. Found: C, 63.95; H, 4.41; N,
16.52%.
2-(5,7-Diphenyl-4-oxo-3,4,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]-
thieno[3,2-c]pyridazin-2-yl)-3-[phenyl/(4-methoxyphenyl)]
acrylonitriles (16a,b)
A mixture of compound 15a (1.19 g, 3 mmol) and the aromatic aldehyde
(3 mmol) in absolute ethanol (40 ml) containing a catalytic amount of
piperidine (0.4 ml), was heated at reflux for 6 h. The reaction mix-
ture was poured onto ice (30 g) and neutralized with dilute HCl.
The formed solid product was filtered off and recrystallized to give
16a,b.
16a; Yield, 1.02 g (70%) (DMF-H2O); m.p. 212−214◦C; IR:ν = 3290
(NH), 2215 (C N), 1665 cm−1 (CO); MS: m/z: 485 (M+); Anal. calcd. for
C29H19N5OS (485.56): C, 71.73; H, 3.94; N, 14.42%. Found: C, 71.40; H,
3.61; N, 14.75%.
16b; Yield, 0.97 g (63%) (1,4-dioxane); m.p. 202−204◦C; IR:ν = 3280
(NH), 2224 (C N), 1675 cm−1 (CO); 1H NMR (CDCl3): δ = 3.95 (s, 3H,
OCH3), 4.20 (s, 2H, CH2), 7.30−8.25 (m, 15H, ArH and benzylic proton);
9.20 (s, 1H, NH, exchangeable); Anal. calcd. for C30H21N5O2S (515.59):
C, 69.89; H, 4.11; N, 13.58%. Found: C, 69.95; H, 4.31; N, 13.22%.

Novel Functionalized Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines
3093
(5,7-Diphenyl-4-oxo-3,4,5,8-tetrahydropyrimido[5ꢀ,4ꢀ:4,5]
thieno[3,2-c]pyridazin-2-yl)phenylhydrazono/(4-
methoxyphenylhydrazono)acetonitriles (17a,b)
To a cold solution (0−5◦C) of compound 15a (1.19 g, 3 mmol) in absolute
ethanol (40 ml) containing sodium acetate (1.80 g), a cold solution of
aryl diazonium chlorides [prepared from the corresponding aryl amine
(3 mmol) and appropriate quantities of concentrated HCl (10 ml) and
NaNO2 (2.00 g)] were added dropwise with stirring for 30 min. After
the complete addition, the reaction mixture was stirred at room tem-
perature for additional 1 h. The precipitated product was filtered off,
washed with water (3 × 40 ml) and recrystallized to give 17a,b.
17a; Yield, 1.01 g (67%) (1,4-dioxane); m.p. 190−192◦C; IR:ν =
3290−3200 (NH), 2215 (C≡N), 1673 cm−1 (CO); 1H NMR (CDCl3): δ =
4.11 (s, 2H, CH2), 7.40−8.13 (m, 15H, ArH), 9.10, 9.23 (2s, 2H, 2NH,
exchangeable); Anal. calcd. for C28H19N7OS (501.56): C, 67.05; H, 3.82;
N, 19.55%. Found: C, 67.38; H, 3.99; N, 19.21%.
17b; Yield, 0.95 g (60%) (n-butanol); m.p. 201−203◦C; IR:ν =
3310−3250 (NH), 2220 (C N), 1670 cm−1 (CO); Anal. calcd. for
C29H21N7O2S (531.59): C, 65.52; H, 3.98; N, 18.44%. Found: C, 65.21;
H, 3.59; N, 18.77%.
2,4-Diamino-5-(5,7-diphenyl-4-oxo-3,4,5,8-tetrahydropyrimido-
[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-2-yl)thiophene-3-carbonitrile
(18a) and 4-amino-2-hydroxy-5-(5,7-diphenyl-4-oxo-3,4,5,8-
tetrahydropyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazin-2-yl)-
thiophene-3-carbonitrile (18b)
A mixture of compound 15a (1.19 g, 3 mmol), elemental sulfur (0.096 g,
3 mmol) and malononitrile or ethyl cyanoacetate (3 mmol) in absolute
ethanol (25 ml) containing a catalytic amount of triethylamine (0.5 ml)
was heated at reflux for 6 h. The reaction mixture was cooled, poured
onto ice (20 g) and neutralized with dilute hydrochloric acid. The formed
solid product was collected by filtration and recrystallized to give 18a,b.
18a; Yield, 0.87 g (59%) (1,4-dioxane); m.p. 230−232◦C; IR:ν =
3480−3310 (NH2, NH), 2215 (C N), 1675 cm−1 (CO); 1H NMR (CDCl3):
δ = 4.10 (s, 2H, CH2), 5.85, 5.95 (2br s, 4H, 2NH2), 7.20−8.12 (m, 10H,
ArH); 9.21 (s, 1H, NH, exchangeable); 13C NMR: δ = 30.3 (CH2), 108.2
(C-3 of thiophene), 110.2 (CN), 120.1 (C-4 of thiophene), 123.3 (C-5 of
thiophene), 128.3 (C-2 of thiophene), 119.3 (C-4b), 132.1 (C-9a), 135.2
(C-8a), 136.3 (C-4a), 150.2 (C-2), 151.3 (C-7), 176.4 (CO); Anal. calcd. for
C25H17N7OS2 (495.58): C, 60.59; H, 3.46; N, 19.78%. Found: C, 60.21;
H, 3.12; N, 19.96%.

3094
A. A. Aly
18b; Yield, 0.86 g (58%) (DMF-H2O); m.p. 260−262◦C; IR:ν =
1
3495−3300 (OH, NH2, NH), 2217 (C N), 1670 cm−1 (CO); H NMR
(CDCl3): δ = 4.11 (s, 2H, CH2), 5.85 (br s, 2H, NH2), 7.30−8.20 (m, 10H,
ArH), 9.12 (s, 1H, NH, exchangeable); Anal. calcd. for C25H16N6O2S2
(496.57): C, 60.47; H, 3.25; N, 16.92%. Found: C, 60.81; H, 3.57; N,
16.61%.
5,7-Diphenyl-5,8-dihydropyridazino[3ꢀ,4ꢀ:4,5]thieno[2,3-d]-
1,2,3-triazin-4(3H)-one (19)
To a cold solution of compound 1 (1.04 g, 3 mmol) in acetic acid (25
ml), a cold solution of sodium nitrite (1.20 g in 3 ml H2O) was added
dropwise with stirring. The stirring was continued for 1 h and left to
stand at room temperature for 2 h. The solid product formed was col-
lected by filtration and recrystallized from n-butanol to give 19. Yield,
1
0.57 g (53%); m.p. 221−223◦C; IR:ν = 3325 (NH), 1675 cm−1 (CO); H
NMR (CDCl3): δ = 4.13 (s, 2H, CH2), 7.12−8.20 (m, 10H, ArH), 9.10 (s,
1H, NH, exchangeable); 13C NMR: δ = 30.9 (CH2), 118.3 (C-4b), 138.3
(C-9a), 144.3 (C-8a), 148.3 (C-4a), 157.4 (C-7), 177.3 (CO); Anal. calcd.
for C19H13N5OS (359.41): C, 63.49; H, 3.65; N, 19.49%. Found: C, 63.20;
H, 3.25; N, 19.76%.
5,7-Diphenyl-3-(methyl/phenacyl)-5,8-dihydropyridazino-
[3ꢀ,4ꢀ:4,5]thieno[2,3-d]-1,2,3-triazin-4(3H)-ones (20a,b)
A solution of compound 19 (0.72 g, 2 mmol), potassium hydroxide (15%,
2 ml) and methyl iodide or phenacyl bromide (4 mmol) in acetone (20 ml)
was refluxed for 5 h. The solvent was removed under reduced pressure,
cold water (25 ml) was added. The mixture was neutralized with 2N HCl
(18 ml). The solid formed was collected by filtration and recrystallized
to give 20a,b.
20a; Yield, 0.44 g (59%) (DMF); m.p. 231−233◦C; IR:ν = 1670 cm−1
(CO); MS: m/z: 373 (M+); Anal. calcd. for C20H15N5OS (373.43): C, 64.33;
H, 4.05; N, 18.75%. Found: C, 64.67; H, 4.38; N, 18.40%.
20b; Yield, 0.48 g (50%) (1,4-dioxane); m.p. 217−219◦C; IR:ν =
1680−1675 cm−1 (CO); 1H NMR (CDCl3): δ = 4.13 (s, 2H, CH2), 4.85 (s,
2H, CH2CO), 7.13−8.15 (m, 15H, ArH); Anal. calcd. for C27H19N5O2S
(477.54): C, 67.91; H, 4.01; N, 14.67%. Found: C, 67.55; H, 3.84; N,
14.92%.

Novel Functionalized Pyrimido[5ꢀ,4ꢀ:4,5]thieno[3,2-c]pyridazines
3095
General Procedure for the Preparation of Compounds 22a,b
To a suspension of 1 (1.04 g, 3 mmol) in absolute ethanol (25 ml) con-
taining a catalytic amount of piperidine (0.4 ml), the appropriate α-
substituted cinnamonitrile derivatives (3 mmol) were added. The re-
action mixture was refluxed for 8 h. The reaction mixture was cooled
and triturated with cold water (20 ml), then neutralized with HCl. The
resulting solid product was collected by filtration and recrystallized to
give 22a,b.
9-Hydroxy-1,3,7-triphenyl-1,4-dihydropyrido[3ꢀ,2ꢀ:4,5]-
thieno[3,2-c]pyridazine-8-carbonitrile (22a)
Yield, 0.86 g (63%) (ethanol); m.p. 251−253◦C; IR:ν = 3495−3200 (OH),
2215 cm−1 (C N); MS: m/z: 458 (M+); Anal. calcd. for C28H18N4OS
(458.53): C, 73.34; H, 3.96; N, 12.22%. Found: C, 73.10; H, 3.79; N,
12.01%.
Ethyl 9-Hydroxy-1,3,7-triphenyl-1,4-dihydropyrido[3ꢀ,2ꢀ:4,5]-
thieno[3,2-c]pyridazine-8-carboxylate (22b)
Yield, 1.07 g (71%) (n-butanol); m.p. 273−275◦C; IR:ν = 3490−3210
(OH), 1725 cm−1 (CO); 1H NMR (CDCl3): δ = 1.75 (t, 3H, CH3), 4.10 (s,
2H, CH2), 4.50 (q, 2H, CH2), 7.15−8.20 (m, 15H, ArH), 10.50 (br s, 1H,
OH, exchangeable); Anal. calcd. for C30H23N3O3S (505.59): C, 71.27; H,
4.59; N, 8.31%. Found: C, 71.53; H, 4.85; N, 8.67%.
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