Synthesis and reactions of some new thieno[2,3-c]pyridazine derivatives

Article abstract of DOI:10.1080/10426500802353213

The alkylation of 4-cyano-5,6-dimethylpyridazin-3(2H)-thione 3 with some halo compounds gave the S-alkylated products 4a-c, which upon treatment with ethanolic sodium ethoxide afforded the cyclized thienopyridazines 5a-c as products. Pyridazothienotriazin

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Phosphorus, Sulfur, and Silicon
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Synthesis and Reactions
of Some New Thieno[2,3-
C]pyridazine Derivatives
Ahmed S. N. Al-Kamali a
a Chemistry Department, Faculty of Science, Taiz
University, Republic of Yemen
Published online: 22 Jun 2009.
To cite this article: Ahmed S. N. Al-Kamali (2009) Synthesis and Reactions of Some
New Thieno[2,3-C]pyridazine Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 184:7, 1812-1824, DOI: 10.1080/10426500802353213
To link to this article: http://dx.doi.org/10.1080/10426500802353213
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Phosphorus, Sulfur, and Silicon, 184:1812–1824, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802353213
Synthesis and Reactions of Some New
Thieno[2,3-C]pyridazine Derivatives
Ahmed S. N. Al-Kamali
Chemistry Department, Faculty of Science, Taiz University,
Republic of Yemen
The alkylation of 4-cyano-5,6-dimethylpyridazin-3(2H)-thione 3 with some halo
compounds gave the S-alkylated products 4a–c, which upon treatment with ethano-
lic sodium ethoxide afforded the cyclized thienopyridazines 5a–c as products. Pyri-
dazothienotriazines 6a–c were prepared by the treatment of compounds 5a–c with
nitrous acid, while their reaction with triethyl orthoformate and with carbon disul-
fide gave the corresponding pyrimidothienopyridazines 7a–c, and 8a–c, respec-
tively. S-alkylated products 9a–o were obtained by the reaction of 8a–c with some
halo compounds.
Keywords Pyridazine; pyridazothienotriazine; pyrimidothienopyridazine; thieno[2,3-
c]pyridazine
INTRODUCTION
The pyridazine moiety is found in many pharmaceuticals, herbicides,
insecticides, and fungicides.1,2 In addition, a considerable number of
pyridazine derivatives were found to have antibacterial,3 analgesic,4
anti-inflammatory,5 and acetyl-cholinesterase inhibitor properties,6
and act as aldose reductase inhibitors and antioxidants.7 Moreover,
thienopyridazine derivatives are also important compounds because of
their broad range of biological and pharmacological effects.8–13
In view of the above and in continuation of the work on pyri-
dazine chemistry,14–16 we report here the synthesis of some new pyri-
dazine, thieno[2,3-c]pyridazine, pyridazothienotriazine, and pyrimi-
dothienopyridazine derivatives starting from the readily accessible 4-
cyano-5,6-dimetheylpyridazin-3(2H)-thione 3.
Received 7 January 2008; accepted 15 July 2008.
Address correspondence to Ahmed S. N. Al-Kamali, Chemistry Department, Faculty
of Science, Taiz University, Republic of Yemen. E-mail: ah-s-alkamali@hotmail.com.
1812

New Thieno[2,3-C]pyridazine Derivatives
1813
RESULTS AND DISCUSSION
The starting compound 4-cyano-5,6-dimethylpyridazin-3(2H)-one 1
was prepared by the reaction of diacetyl and cyanoacetic acid hy-
drazide in ethanol at room temperature in a good yield (94%). When
compound 1 was refluxed with phosphorus oxychloride, it gave the 3-
chloropyridazine derivative 2 in 90% yield. Compound 2 was subjected
to an addition–elimination reaction with thiourea in ethanol under re-
flux to afford 4-cyano-5,6-dimethylpyridazin-3(2H)-thione 3.
Also, the structure of compound 3 was established by another syn-
thetic route, via thionation of compound 1 with phosphorus pentasul-
fide under reflux in pyridine as shown in Scheme 1.
CH3
CH3
H3C
CN
O
H3C
POCl3
CN
Cl
N
N
N
H
N
2
1
(NH2)2CS
CH3
H3C
P2S5
Pyridine
CN
S
1
N
N
H
3
SCHEME 1
The thione derivative 3 was used as a versatile compound for build-
ing fused heterocyclic systems condensed with the pyridazine moiety.
Thus, reaction with N-substituted chloroacetamide in refluxing ethanol
in the presence of fused sodium acetate furnished the s-alkylated
products 4a–c, which underwent a Thorpe–Ziegler type of cyclization
in the presence of sodium ethoxide to produce the novel thieno[2,3-
c]pyridazines 5a–c. An alternative one-step synthesis of 5a–c was
achieved by the reaction of 3 with the alkylating agents in the presence
of potassium carbonate in boiling ethanol (Scheme 2).
The chemical structures of 4a–c and 5a–c were determined by their
1
IR and H-NMR spectra. The IR spectra of 4a–c showed the charac-
teristic bands at 1670–1680 cm−1 due to a carbonyl group and the

1814
A. S. N. Al-Kamali
CH3
N
H3C
RCH2Cl
EtOH/AcONa
CN
3
N
SCH2R
4a-c
EtONa
reflux
EtOH
CH3
H3C
NH2
R
RCH2Cl
3
EtOH/K2CO3
N
N
S
4,5 a R = CONHC6H5
5a-c
-p
b R =
c R =
CONHC6H4Cl
-p
CONHC6H4OCH3
SCHEME 2
disappearance of the band at about 3300 cm−1 due to the -NH group of
compound 3.
The 1H-NMR spectrum (DMSO-d6) of 4a showed two singlets at δ =
2.35 ppm and δ =2.6 ppm due to methyl groups, and a singlet at δ =
4.2 ppm due to the methylene protons. The IR spectra of compounds
5a–c showed the absence of bands for the carbonitrile group and the
appearance of bands at 3440–3280 cm−1 for (NH2) 3300–3280 cm−1 and
at 1600–1585 cm−1 for carbonyl groups; the lowering of the frequency
is due to intermolecular hydrogen bonding. The 1H-NMR spectra of
compounds 5a–c exhibited the absence of the signal for the methylene
protons and the appearance of a new signal at δ = 7.2–7.05 ppm due to
the amino groups.
Pyridazo[ꢀ4,ꢀ3:4,5] thieno[3,2-d][1,2,3]triazine derivatives 6a–c were
obtained by diazotization of 5a–c with sodium nitrite in glacial acetic
acid at 0◦C. The structures of 6a–c were confirmed by elemental anal-
ysis and spectral data. The IR spectra of 6a–c showed the absence of
any absorption bands attributed to NH2 and NH functional groups.
Moreover, the 1H-NMR spectra of compounds 6a–c revealed the disap-
pearance of the signals due to -NH2 and -NH protons. Cyclization of
compounds 5a–c with triethyl orthoformate in the presence of catalytic
amounts of glacial acetic acid produced the pyrimidothienopyridazine
derivatives7a–c. Refluxing of compounds 5a–c with carbon disulfide in

New Thieno[2,3-C]pyridazine Derivatives
1815
pyridine afforded the corresponding pyrimidothienopyridazinethione
derivatives 8a–c.
S-substituted pyrimidothienopyridazines 9a–o were achieved by the
reaction of compounds 8a–c with some halo compounds in ethanol con-
taining sodium acetate (Scheme 3).
CH3
H3C
N
O
NaNO2
AcOH
N
N
N
R
N
S
6a-c
CH3
N
H3C
N
CH(OC2H5)3
AcOH/reflux
5a-c
N
N
R
S
O
7a-c
CH3
H
H3C
N
S
CS2
N
N
R
Pyridine/reflux
N
S
8a-c
O
RX
AcONa
CH3
C6H5
6,7,and 8a,R =
-p
C6H4Cl
6,7, and 8b,R =
6,7, and 8c,R =
-p
C6H4OCH3
H3C
N
O
SR
N
N
R
N
S
9a-o
9
R
Rꢀ
9
R
Rꢀ
a
b
c
d
e
f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C6H4Cl-p
CH2COCH3
CH2COPh
i
j
C6H4Cl-p
C6H4Cl-p
C6H4Cl-p
C6H4OMe-p
C6H4OMe-p
C6H4OMe-p
C6H4OMe-p
CH (Me)CO2Me
CH2COPh
CH2COC6H4Cl-p
CH2COPh
CH2CONHC6H4OMe-p
CH2CO2Et
CH2CONHC6H4Cl-p
CH2COC6H4Cl-p
CH2COC6H4Br-p
CH2COOEt
CH (Me)CO2Me
CH2CN
k
l
m
n
o
g
h
CH2CO2Et
SCHEME 3

1816
A. S. N. Al-Kamali
EXPERIMENTAL
Melting points were determined on a Fisher John melting points appa-
ratus and are uncorrected. IR spectra were recorded on a Shimadzu 470
spectrophotometer using KBr pellets. 1H-NMR spectra were measured
on a Varian 390–90 MHz NMR spectrometer using TMS as internal
standard. Elemental analyses were performed on a Perkin Elmer 240
C microanalyzer. The mass spectra were recorded on a Jeol JMS 600
apparatus. Physical and spectral data are shown in Table I, together
with suitable solvents for recrystallization.
4-Cyano-5,6-dimethylpyridazin-3(2H)-one (1)
This compound was prepared according to the reported method.14
3-Chloro-5,6-dimethylpyidazin-4-carbonitrile (2)
Compound 1 (10 mmol) was refluxed with phosphorus oxychloride
(15 mL) for 3 h. The cooled reaction mixture was slowly added into
crushed ice water (100 mL). The resulting solid was collected by filtra-
tion and recrystallized from the proper solvent to give 2.
4-Cyano-5,6-dimethylpyridazin-3(2H)-thione(3)
Method A
A mixture of compound 2 (10 mmol) and thiourea (13 mmol) in dry
ethanol (50 mL) was heated under reflux for 4 h. The obtained solid
product was collected by filtration and recrystallized from the proper
solvent to give 3.
Method B
A mixture of compound 1 (10 mmol) and phosphorus pentasulfide
(13 mmol) in dry pyridine (20 mL) was refluxed for 4 h, then allowed to
cool, and was poured into cold water (100 mL). The solid product was
collected by filtration and recrystallized from the proper solvent to give
3.
Alkylation of 4-Cyano-5,6-dimethylpyridazin-3(2H)-thione:
Formation of (4a–c)
A mixture of compound 3 (10 mmol), α-halo carbonyl compound
(10 mmol), and fused sodium acetate (14 mmol) in ethanol (30 mL) was
heated under reflux for 2 h, then allowed to cool. The solid product was
collected by filtration and recrystallized from the proper solvent to give
4a–c.

1817

1818

1819

1820

1821

1822

New Thieno[2,3-C]pyridazine Derivatives
1823
3-Amino-4,5-dimethyl-2-substitutedthieno[2,3-c]pyridazines
(5a–c): General Procedure
Method A
A sample of compound 4a–c (10 mmol) in sodium ethoxide (10 mmol
Na/30 mL ethanol) was heated under reflux for 3 h, then allowed to
cool. The solid product was collected by filtration, washed with water,
and recrystallized from the proper solvent to give 5a–c.
Method B
A mixture of compound 3 (10 mmol), α-halocarbonyl compound (10
mmol), and potassium carbonate (12 mmol) in ethanol (40 mL) was
heated under reflux for 3 h. The separated product was collected when
cooled, washed with water, and recrystallized from the proper solvent
to give 5a–c.
3,4-Dimethyl-7-substitutedpyridazo[ꢀ4,ꢀ3:4,5]thieno[3,2-d]
[1,2,3]triazine-8-ones (6a–c): General Procedure
To an ice cold solution of compound 5a–c (10 mmol) in acetic acid (20
mL), sodium nitrite solution (0.5 g/2 mL H2O) was added dropwise
with stirring during 30 min. After the addition was finished, stirring
was continued for additional 1 h. The solid product was collected by
filtration and recrystallized from the proper solvent to give 6a–c.
3,4-Dimethyl-7-substitutedpyrimido[ꢀ4,ꢀ5:4,5]thieno[2,3-c]
pyridazine-8-ones (7a–c)
To mixture of 5a–c (10 mmol) and triethyl orthoformate (5 mL), drops
of acetic acid were added. The reaction mixture was heated for 2 h. The
solid product 7a–c was collected by filtration and recrystallized from
the proper solvent.
3,4-Dimethyl-7-substituted -8-oxo–5,6,7,8–tetrahydropyrimido-
[ꢀ4,ꢀ5:4,5]thieno[2,3-c]pyridazine-6-thiones (8a–c): General
Procedure
A mixture of 5a–c (10 mmol) and carbon disulfide (10 mL ) in dry
pyridine (30 mL) was heated on a water bath for 15 h. The solid product
was collected by filtration and recrystallized from the proper solvent to
give 8a–c.

1824
A. S. N. Al-Kamali
Reaction of Pyrimidothienopyridazinethiones (8a–c) with Halo
Compounds: Formation of Compounds (9a–o)
A mixture of 8a–c (10 mmol) and sodium acetate (12 mmol) in ethanol
(30 mL) was refluxed for 2 h, then the respective halo compound (10
mmol) was added and refluxed for an additional 1 h. The solid product
that separated upon cooling was collected by filtration, washed with
water, and recrystallized from the proper solvent to give 9a–o.
MS (9h) 460 (M+; 42.70%) 462 (M+2, 0.02%), 415 (0.2%), 387 (11.7%),
341 (19.6%), 313 (0.9%), 249 (5.1%), 197 (9.3%), 149 (6.2%),125 (14.6%),
and 92 (9.1%).
MS (9n) 517 (M+; 62.7%), 483 (7.5%), 460 (15.9%), 443 (base peak;
100%), 411 (48.6%), 337 (52%), 254 (47.8%), and 121 (66.3%).
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