Synthesis of novel polyfunctionally substituted thieno[2,3-c]pyridazines

Article abstract of DOI:10.1002/jccs.200400192

4-Cyano-5,6-dimethylpyridazin-3-(2H)-thione 3b was used as a key intermediate for the synthesis of novel polysubstituted thieno[2,3-c] pyridazines.

Full text of DOI:10.1002/jccs.200400192

Journal of the Chinese Chemical Society, 2004, 51, 1325-1331
1325
Synthesis of Novel Polyfunctionally Substituted Thieno[2,3-c]pyridazines
Abd El-Aal M. Gaber,a Mohamed S. A. El-Gaby,b* Adel M. Kamal El-Dean,a
Hassan A. Eyadac and Ahmed S. N. Al-Kamalia
aDepartment of Chemistry, Faculty of Science, Assiut University, Assiut 71516, Egypt
bDepartment of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt
cDepartment of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
4-Cyano-5,6-dimethylpyridazin-3-(2H)-thione 3b was used as a key intermediate for the synthesis of
novel polysubstituted thieno[2,3-c]pyridazines.
Keywords: Pyridazine; Thieno[2,3-c]pyridazine and pyrrole derivatives.
INTRODUCTION
Scheme I
H3C
H3C
C
C
O
O
Derivatives of thienopyridazines are important com-
pounds due to their broad range of biological and pharmaco-
logical effects.1-3 Also, it is observed from the literature that
the pyrrole nucleus plays a vital role in many biological activ-
ities.4-8 On the basis of these reports and in continuation of
our work on pyridazine chemistry,9-11 we report in this contri-
bution a novel synthesis of functionalized thieno[2,3-c]pyri-
dazines starting from the readily accessible 4-cyano-5,6-di-
methylpyridazin-3(2H)-thione 3b.
H3C
H3C
C
C
N
O
NH2
NH2NH2 / EtOH
reflux
1
2
CN
CH2COOC2H5
NaOC2H5, reflux
CH3
H3C
N
H3C
CN
X
NH
-H2O
N
O
H3C
O
N
H
CN
3a; X= O
3b; X= S
1 / EtOH
-H2O
RESULTS AND DISCUSSION
CH2CONHNH2
Druey et al.12 reported the synthesis of 4-cyano-5,6-
dimethylpyridazin-3(2H)-one 3a by treatment of diacetyl 1
with hydrazine hydrate in refluxing ethanol to yield mono-
hydrazone 2 followed by cyclocondensation with ethyl cya-
noacetate in the presence of sodium ethoxide, Scheme (I).
Our investigation describes the synthesis of pyridazinone 3a
through a one-pot reaction of diacetyl 1 and cyanoacetic acid
hydrazide 4 in ethanol at room temperature in good yield
(94%). Thiation of compound 3a with phosphorus penta-
sulfide under reflux in pyridine afforded the pyridazinethione
3b. The latter compound was used as a key intermediate for
the synthesis of polysubstituted thieno[2,3-c]pyridazine.
Cyclocondensation of compound 3b with ethyl chloro-
acetate was performed in ethanol in the presence of a cata-
lytic amount of potassium carbonate under reflux and yielded
the novel thieno[2,3-c]pyridazine derivative 6 in quantitative
CN
4
yield (87%), Scheme (II). The structure of compound 6 was
supported by its analytical and spectral data. The infrared
spectrum of compound 6 displayed absorption at 3440, 3330
cm-1 for NH2 stretching at 1665 cm-1 for C=O stretching with
lack of the characteristic absorption due to the CºN stretch-
ing. In the 1H-NMR spectrum (CDCl3) of compound 6 triplet
at d = 1.4 ppm, quartet at d = 4.4 ppm assigned for ethoxycar-
bonyl moiety in addition to amino and 2CH3 protons. The for-
mation of thienopyridazine 6 is assumed to proceed through
initial alkylation of compound 3b to form the intermediate 5
which readily undergoes intramolecular cyclization under
the reaction condition to yield 6. The intermediate compound
5 was isolated by refluxing of compound 3b with ethyl chlo-
* Corresponding author. E-mail: m_elgaby@hotmail.com

1326 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Gaber et al.
nol yielded the mercapto derivative 11. The 1,2,4-triazole de-
rivative 13 was obtained by reaction of compound 9 with
phenyl isothiocyanate in refluxing pyridine, via the forma-
tion of thiourea intermediate 12 followed by elimination of
the water molecule, Scheme (IV). Cyclocondensation of
compound 9 with acetylacetone in ethanol under reflux fur-
nished the novel pyrazole derivative 14. Treatment of com-
pound 9 with sodium nitrite in glacial acetic acid at room tem-
perature yielded the carbonylazide derivative 15.
Scheme II
CH3
Cl
H3C
CN
S
CH2COOC2H5
3b
EtOH / AcONa
reflux
N
CH2
N
COOC2H5
5
CH3ONa
CH3OH
reflux
CH3
Our investigation was extended to study the reactivity
of carbonylazide 15 towards some nucleophilic reagents.
Thus, the carbamate derivatives 17a,b were obtained by in-
teraction of compound 15 with alcohols in benzene under re-
flux, via the formation of isocyanate 16 by Curtius rearrange-
ment reaction.13 Also, treatment of compound 15 with cyclic
secondary amine in refluxing benzene led to the formation of
the urea derivatives 18a,b. Compound 15 was converted into
pyrrolo[1²,2²:1¢,6¢]-pyrazino[2¢,3¢:4,5]thieno[2,3-c]pyrida-
zine derivative 19 by refluxing in m-xylene. The formation of
19 is assumed to proceed through Curtius rearrangement of
compound 15 into isocyanate 16 followed by intramolecular
ring closure13 to form 19, Scheme (V).
Cl
H3C
NH2
CH2COOC2H5
EtOH / K2CO3
3b
N
COOC2H5
N
S
6
roacetate in refluxing ethanol in the presence of sodium ace-
tate. Also, compound 6 was independently synthesized via
another pathway by the refluxing of compound 5 with sodium
methoxide in methanol.
The amino group in compound 6 readily reacted with
2,5-dimethoxytetrahydrofuran in acetic acid13 to give the
pyrrolyl derivative 7. Its infrared spectrum showed the pres-
ence of an absorption band at 1720 cm-1 (C=O) with absence
of NH2 absorption. The acid hydrazide 8 was prepared by the
refluxing of the corresponding ester 6 with hydrazine hydrate
in ethanol, Scheme (III).
The reaction of compound 8 with carbon disulfide in
pyridine furnished the 1,3,4-oxadiazole derivative 20 which
was reacted with phenacyl bromide to give compound 21.
Finally, the pyrrolyl derivative 10 was obtained by treatment
of compound 20 with 2,5-dimethoxytetrahydrofuran in boil-
ing acetic acid, Scheme (VI).
Scheme III
CH3
H3C
N
OCH3
H3CO
O
EXPERIMENTAL
N
N
S
COOC2H5
AcOH
reflux
7
Melting points are recorded on a Fisher-John melting
points apparatus and are uncorrected. IR spectra were re-
corded on a Shimadzu 470 spectrophotometer using KBr pel-
6
CH3
N
H3C
NH2
1
lets. H-NMR spectra were measured on a Varian 390-90
NH2NH2
N
EtOH
reflux
CONHNH2
MHz NMR spectrometer using TMS as internal standard and
mass spectra on a Jeol-JMS-600 mass spectrometer. Elemen-
tal analyses were performed on a Perkin-Elmer 240 C mi-
cro-analyzer. The physical and spectral data are collected in
Tables 1 and 2, respectively.
S
8
The ester 7 was reacted with hydrazine hydrate under
reflux in ethanol to yield the carbohydrazide 9. The latter
compound was used as a precursor for the synthesis of 1,3,4-
oxadiazole, 1,2,4-triazole, pyrazole and carbonylazide deriv-
atives. Thus, treatment of compound 9 with carbon disul-
fide11 in refluxing pyridine gave 1,3,4-oxadiazole derivative
10. Reaction of compound 10 with p-bromophenacyl bro-
mide in the presence of sodium acetate under reflux in etha-
4-Cyano-5,6-dimethylpyridazin-3(2H)-one (3a)
A mixture of diacetyl 1 (86 mg) and cyanoacetic acid
hydrazide 4 (99 mg) in ethanol (20 mL) was stirred at room
temperature for 3 h. The solid separated was filtered off and
recrystallized to give 3a (Lit.12 m.p 211-2).

Substituted Thieno[2,3-c]pyridazines
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1327
Scheme IV
CH3
H3C
N
N
CS2
N
O
SH
pyridine
reflux
N
S
7
10
N
NH2NH2
p-BrC6H4COCH2Br
EtOH / reflux
EtOH / AcONa
reflux
CH3
N
CH3
H3C
N
H3C
N
N
N
O
S
S
CONHNH2
N
S
CH2COC6H4Br-p
9
N
N
11
NaNO2 / HCl
AcOH
CH3
H3C
N
PhNCS
pyridine
reflux
CH3
N
N
S
CONHNHCSNHPh
H3C
N
12
N
N
S
CON3
-H2O
15
CH3
H3C
N
N
N
S
N
NH
13
N
Ph
S
CH3
N
H3C
N
CH2(COCH3)2
EtOH / reflux
N
S
C
N
N
O
H3C
14
CH3
4-Cyano-5,6-dimethylpyridazin-3(2H)-thione (3b)
lected and recrystallized to give 5.
A mixture of compound 3a (149 mg) and phosphorus
pentasulfide (266 mg) in pyridine (10 mL) was refluxed for 2
h, then allowed to cool and poured into cold water (10 mL)
and neutralized with HCl. The solid product was collected
and recrystallized to give 3b.
5-Amino-3,4-dimethyl-6-ethoxycarbonylthieno[2,3-c]pyri-
dazine (6)
Method A: A mixture of compound 3b (165 mg), ethyl
chloroacetate (122 mg) and anhydrous potassium carbonate
(166 mg) in ethanol (30 mL) was heated under reflux for 3 h,
then allowed to cool and acidified with HCl. The solid prod-
uct was collected and recrystallized to give 6.
4-Cyano-3-ethoxycarbonylmethylthio-5,6-dimethyl
pyridazine (5)
A mixture of compound 3b (165 mg), fused sodium ac-
etate (98 mg) and ethyl chloroacetate (122 mg) in ethanol (30
mL) was heated under reflux for 2 h, then allowed to cool,
then poured into water (10 mL). The solid product was col-
Method B: A sample of compound 5 (351 mg) in so-
dium methoxide (23 mg Na/30 mL methanol) was heated un-
der reflux for 2 h, then allowed to cool and poured into cold
water (20 mL) and acidified with HCl. The solid product was

1328 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Gaber et al.
Scheme V
CH3
N
H3C
N
ROH
benzene
reflux
N
S
NHCOOR
17a,b
X
CH3
CH3
H3C
N
H3C
N
N
H
N
N
benzene
reflux
N
S
N=C=O
N
S
NHCON
X
16
18a,b
6
7
Curtius
rearrangement
CH3
4
8
H3C
N
3
5
xylene
reflux
15
9
10
N
H
N
2
N
1
S
O
11
17a; R= CH3
18a; X= CH2
18b; X= O
19
17b; R= CH2CH3
Scheme VI
CH3
N
H3C
NH2
CH3
PhCOCH2Br
H3C
NH2
O
O
SCH2COPh
N
EtOH / AcONa
reflux
S
SH
N
N
N
N
S
21
N
N
20
H3CO
O
OCH3
CS2 / pyridine
reflux
10
AcOH
reflux
8
drazine hydrate (99%; 51 mg) in ethanol (30 mL) was heated
under reflux for 5 h, then allowed to cool. The solid product
was collected and recrystallized to give 8 or 9.
The mass spectrum of compound 8 exhibited a molecu-
lar ion peak at m/z = 237.17 (13.4%) with base peak at m/z =
79.05.
collected by filtration, washed with water and recrystallized
to give 6.
3,4-Dimethyl-6-ethoxycarbonyl-5-(pyrrol-1-yl)thieno[2,3-
c]pyridazine (7)
A solution of compound 6 (251 mg) and 2,3-dimeth-
oxytetrahydrofuran (132 mg) in acetic acid (1 mL) was
heated under reflux for one h, then allowed to cool and
poured into cold water (20 mL). The solid product was col-
lected and recrystallized to give 7.
3,4-Dimethyl-6-(2-mercapto-1,3,4-oxadiazol-5-yl)-5-(pyr-
rol-1-yl)-thieno[2,3-c]pyridazine (10) and 5-amino-3,4-di-
methyl-6-(2-mercapto-1,3,4-oxadiazol-5-yl)-thieno[2,3-c]-
pyridazine (20): General procedure
A mixture of carbohydrazide 9 or 8 (287 mg or 237 mg)
and carbon disulfide (2 mL) in pyridine (5 mL) was heated
under reflux for 12 h, then allowed to cool and poured into
cold water (30 mL) and acidified with HCl. The solid product
5-Amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carbohy-
drazide (8) and 3,4-dimethyl-5-(pyrrol-1-yl)-thieno[2,3-
c]pyridazine-6-carbohydrazide (9): General procedure
A mixture of ester 6 or 7 (251 mg or 301 mg) and hy-

Substituted Thieno[2,3-c]pyridazines
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1329
Table 1. Physical data of the synthesized compounds
Elemental analyses
Solvent Cryst
Compd. No. M.p. (°C) Yield (%)
(Color)
Molecular formula
(Mol. Wt.)
C%
H%
N%
S%
3a
3b
5
210-2
213-5
120-1
240-2
170-1
> 300
286-7
> 340
280-2
240-1
194-5
140-1
232-3
280-1
170-3
180-1
> 300
> 300
220-2
94
90
66
87
82
75
94
81
83
80
90
90
92
85
81
71
95
68
82
Ethanol
(White)
Ethanol
(Yellow)
Ethanol
(Brown)
Ethanol
(Yellow)
Ethanol
(Brown)
Ethanol
(Yellow)
Ethanol
(Yellow)
Ethanol
(Yellow)
Ethanol
(White)
DMF
C7H7N3O
(149.15)
C7H7N3S
(165.21)
C11H13N3O2S
(251.31)
C11H13N3O2S
(251.31)
C15H15N3O2S
(301.37)
C9H11N5OS
(237.28)
C13H13N5OS
(287.35)
C14H11N5OS2
(329.40)
C22H16BrN5O2S2
(526.44)
C20H16N6S2
(404.52)
C18H17N5OS
(351.43)
C13H10N6OS
(298.33)
C14H14N4O2S
(302.36)
C15H16N4O2S
(316.38)
C18H21N5OS
(355.46)
56.37
56.20
50.89
50.80
52.57
52.37
52.57
52.60
59.78
59.70
45.55
45.60
54.34
54.20
51.05
51.10
50.19
50.20
59.38
59.30
61.52
61.50
52.34
52.30
55.62
55.70
56.94
56.80
60.82
60.80
57.13
57.20
57.77
57.80
43.00
43.00
54.39
54.39
4.73
4.80
4.27
4.10
5.21
5.25
5.21
5.01
5.02
5.10
4.67
4.68
4.56
4.50
3.37
3.30
3.06
3.00
3.99
3.80
4.88
4.90
3.38
3.40
4.67
4.50
5.10
5.00
5.95
5.80
5.36
5.30
3.73
3.70
3.25
3.50
3.80
3.80
28.17
28.20
25.44
25.50
16.72
16.60
16.72
16.80
13.94
13.80
29.51
29.33
24.37
24.40
21.26
21.30
13.30
13.40
20.78
20.80
19.93
19.80
28.17
28.20
18.53
18.50
17.71
17.70
19.70
19.80
19.59
19.50
20.73
20.80
25.07
25.10
17.62
17.60
19.41
19.30
12.76
12.80
12.76
12.80
10.64
10.70
13.51
13.62
11.16
11.70
19.47
19.50
12.18
12.20
15.85
15.80
9.12
6
7
8
9
10
11
13
14
15
17a
17b
18a
18b
19
20
21
(Yellow)
Ethanol
(White)
CHCl3
9.13
10.75
10.40
10.60
10.60
10.13
10.10
9.02
9.10
8.97
8.90
11.86
11.80
22.96
22.90
16.13
16.20
(Yellow)
Ethanol
(White)
Ethanol
(White)
Ethanol
(White)
Ethanol
(White)
DMF
(Yellow)
Ethanol
(Yellow)
Ethanol
(Yellow)
C17H19N5O2S
(357.44)
C13H10N4OS
(270.31)
C10H9N5OS2
(279.34)
C18H15N5O2S2
(397.48)
was collected and recrystallized to give 10 or 20, respec-
was heated under reflux for 3 h. On cooling, the precipitated
solid was collected and recrystallized to give 11 or 21, re-
spectively.
tively.
3,4-Dimethyl-5-(pyrrol-1-yl)-6-[5-(4-bromobenzoylmethyl-
thio)-1,3,4-oxadiazol-2-yl]-thieno[2,3-c]pyridazine (11)
and 5-amino-3,4-dimethyl-6-(5-benzoylmethylthio-1,3,4-
oxadiazol-2-yl)-thieno[2,3-c]pyridazine (21): General pro-
cedure
3,4-Dimethyl-5-(pyrrol-1-yl)-6-(4-phenyl-3-thioxo-1,2,4-
triazolin-3-yl)-thieno[2,3-c]pyridazine (13)
A mixture of compound 9 (287 mg) and phenyl isothio-
cyanate (135 mg) in dry pyridine (10 mL) was heated under
reflux for 24 h, then allowed to cool and poured into cold wa-
ter (10 mL) and acidified with HCl. The solid product was
collected and recrystallized to give 13.
A mixture of compound 10 or 20 (329 mg or 279 mg),
p-bromophenacyl bromide or phenacyl bromide (278 mg or
199 mg) and fused sodium acetate (98 mg) in ethanol (30 mL)

1330 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Gaber et al.
Table 2. Spectral data of the synthesized compounds
Compd No.
IR/nmax (cm-1)
3a 3400 (NH), 2200 (CºN), 1660
1H NMR (d/ppm)
DMSO-d6: 2.3, 2.4 (2s, 6H, 2CH3), 10.8 (hump, 1H, NH).
(C=O).
3b
5
3300 (NH), 2200 (CºN).
2220 (CºN), 1730 (C=O).
CDCl3: 1.35 (t, 3H, CH3), 2.55, 2.77 (2s, 6H, 2CH3), 4.1-4.4
(m, 4H, 2CH2).
6
3440, 3330 (NH2), 1665 (C=O). CDCl3: 1.4 (t, 3H, CH3), 2.7, 3.3 (2s, 6H, 2CH3), 4.4 (q, 2H,
CH2), 6.8 (s, 2H, NH2).
7
1720 (C=O)
CDCl3: 1.1 (t, 3H, CH3), 1.73, 2.65 (2s, 6H, 2CH3), 4.2 (q,
2H, CH2), 6.3, 6.7 (2m, 4H, pyrrole ring).
8
3420, 3300, 3200 (NH2, NH),
1670 (C=O).
9
3300, 3210, 3100 (NH, NH2),
1640 (C=O).
DMSO-d6: 1.9, 2.7 (2s, 6H, 2CH3), 4.7 (hump, 3H, NH +
NH2), 6.4, 7.1 (2m, 4H, pyrrole ring).
10
11
13
14
15
17a
2930-2730 (SH).
CF3COOD: 2.3, 3.15 (2s, 6H, 2CH3), 6.7, 7.05 (m, 4H,
pyrrole ring).
1670 (C=O).
CF3COOD: 2.2, 3.1 (2s, 6H, 2CH3), 4.8 (s, 2H, SCH2), 6.5,
6.9 (2m, 4H, pyrrole ring), 7.8-8.2 (m, 4H, Ar-H).
DMSO-d6: 1.7, 2.7 (2s, 6H, 2CH3), 6.4, 7.2 (2s, 4H, pyrrole
ring), 7.3-7.5 (m, 5H, Ar-H), 10.30 (s, 1H, NH).
CDCl3: 1.8, 1.95, 2.08, 2.7 (4s, 12H, 4CH3), 6.3, 6.8 (2s, 4H,
pyrrole ring), 7.3 (s, 1H, pyrazole-H).
CDCl3: 1.85, 2.88 (2s, 6H, 2CH3), 6.5, 6.8 (2s, 4H, pyrrole
ring).
CDCl3: 1.7, 2.72 (2s, 6H, 2CH3), 3.8 (s, 3H, OCH3), 6.6, 6.8
(2s, 4H, pyrrole ring), 7.2 (hump, 1H, NH).
3140 (NH).
1690 (C=O).
2180 (N3), 1650 (C=O).
3240 (NH), 1685 (C=O).
17b
18a
18b
3250 (NH), 1685 (C=O).
3390 (NH), 1660 (C=O).
3400 (NH), 1680 (C=O).
CDCl3: 1.9, 2.8 (2s, 6H, 2CH3), 3.2-3.6 (m, 8H, morpholine
ring), 6.5, 6.8 (2s, 4H, pyrrole ring), 7.4 (s, 1H, NH).
CF3COOD: 1.9, 2.8 (2s, 6H, 2CH3), 6.6, 6.8 (2s, 3H, pyrrole
ring).
19
20
21
3100 (NH), 1670 (C=O).
3450, 3320 (NH2), 2920-2800
(SH).
3340, 3240 (NH2), 1690 (C=O). CF3COOD: 3.3, 3.6 (2s, 6H, 2CH3), 5.3 (s, 2H, SCH2), 7.8-
8.2 (m, 5H, Ar-H).
(3,4-Dimethyl-5-(pyrrol-1-yl)-thieno[2,3-c]pyridazin-6-yl)-
(3,5-dimethylpyrazol-1-yl)-ketone (14)
3,4-Dimethyl-5-(pyrrol-1-yl)-6-(alkyloxycarbonylamino)-
thieno-[2,3-c]pyridazines (17a,b) and 3,4-dimethyl-5-
(pyrrol-1-yl)-6-(1-piperidino or 4-morpholino carbonyl-
amino)-thieno[2,3-c]pyridazines (18a,b): General proce-
dure
A mixture of carbohydrazide 9 (287 mg) and acetyl-
acetone (100 mg) in ethanol (30 mL) was heated under reflux
for 6 h, then allowed to cool. The solid product was collected
and recrystallized to give 14.
A mixture of compound 15 (298 mg) and alcohol or cy-
clic secondary amine (33 mg, 47 mg or 85 mg, 87 mg) in dry
benzene (10 mL) was refluxed for 1 h, then allowed to cool.
The solid product was collected and recrystallized to give
17a,b or 18a,b, respectively.
3,4-Dimethyl-5-(pyrrol-1-yl)-thieno[2,3-c]pyridazine-6-
carbonylazide (15)
To an ice cooled solution of compound 9 (287 mg) in
acetic acid (5 mL), sodium nitrite solution (69 mg in 3 mL
H2O) was added dropwise during ten minutes. The stirring
was continued after that addition 1 h, then allowed to stand
for 2 h. The solid product was collected to give 15.
3,4-Dimethylpyrrolo[1²,2²:1¢,6¢]pyrazino[2¢,3¢:4,5]thieno-
[2,3-c]pyridazin-9(10H)-one (19)
A sample of compound 15 (298 mg) in dry m-xylene (5

Substituted Thieno[2,3-c]pyridazines
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1331
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223.
mL) was heated under reflux for 1 h, then allowed to cool.
The solid product was collected and recrystallized to give 19.
7. Baucke, D.; Lange, U.; Mack, H.; Seitz, W.; Zierke, T.;
Hoffken, H. W.; Hornberger, N. PTC International Applica-
tion Feb. 1998, WO 9806, 741 (Cl. Co 7K5106) 19, DE Ap-
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