Novel synthesis of thieno[2,3-c]pyridazine and pyrimido[4′,5′: 4,5]thieno[2,3-c]pyridazine derivatives

Article abstract of DOI:10.1080/104265090509216

Novel series of thieno[2,3-c]pyridazines and pyrimido[4′,5′:4, 5] thieno-[2,3-c]pyridazines have been synthesized from the readily accessible 4-cyano-5,6-dimethylpyridazin-3(2H)-thione 3b. Copyright Taylor & Francis Inc.

Full text of DOI:10.1080/104265090509216

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Phosphorus, Sulfur, and Silicon
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Novel Synthesis of
Thieno[2,3-c]Pyridazine and
Pyrimido[4',5':4,5]thieno[2,3-
c]pyridazine Derivatives
A. M. Kamal El-Dean a , M. S. A. El-Gaby b , A. M.
Gaber c , H. A. Eyada d & A. S. N. Al-Kamali
a Department of Chemistry, Faculty of Science ,
Assiut University , Assiut, Egypt
b Department of Chemistry, Faculty of Science , Al-
Azhar University at Assiut , Assiut, Egypt
c Department of Chemistry, Faculty of Science ,
Assiut University , Assiut, Egypt
d Department of Chemistry, Faculty of Science , Al-
Azhar University , Nasr City, Cairo, Egypt
Published online: 21 Dec 2010.
To cite this article: A. M. Kamal El-Dean , M. S. A. El-Gaby , A. M. Gaber , H. A.
Eyada & A. S. N. Al-Kamali (2005) Novel Synthesis of Thieno[2,3-c]Pyridazine and
Pyrimido[4',5':4,5]thieno[2,3-c]pyridazine Derivatives, Phosphorus, Sulfur, and Silicon
and the Related Elements, 180:2, 413-424, DOI: 10.1080/104265090509216
To link to this article: http://dx.doi.org/10.1080/104265090509216
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Phosphorus, Sulfur, and Silicon, 180:413–424, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090509216
Novel Synthesis of Thieno[2,3-c]Pyridazine and
Pyrimido[4’,5’:4,5]thieno[2,3-c]pyridazine Derivatives
A. M. Kamal El-Dean
Department of Chemistry, Faculty of Science, Assiut University,
Assiut, Egypt
M. S. A. El-Gaby
Department of Chemistry, Faculty of Science, Al-Azhar University at
Assiut, Assiut, Egypt
A. M. Gaber
Department of Chemistry, Faculty of Science, Assiut University,
Assiut, Egypt
H. A. Eyada
Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr
City, Cairo, Egypt
A. S. N. Al-Kamali
Novel series of thieno[2,3-c]pyridazines and pyrimido[4ꢀ,5ꢀ:4,5] thieno-[2,3-
c]pyridazines have been synthesized from the readily accessible 4-cyano-5,6-
dimethylpyridazin-3(2H)-thione 3b.
Keywords Pyridazine; pyrimidine; thieno[2,3-c]pyridazine
INTRODUCTION
The pyridazine ring is found in many pharmaceuticals, herbicides, in-
secticides and fungicides.1,2 Also, thienopyridazine derivatives are im-
portant compounds due to their broad range of biological and pharma-
cological effects.3–5 In addition, fused pyrimidines are found in a broad
variety of pharmaceuticals, agrochemicals, and veterinary products.6
In continuation of our work on pyridazine chemistry7–9, we reported
the synthesis of some novel pyridazine, thieno[2,3-c]pyridazine and
Address correspondence to Mohamed S. A. El-Gaby, Department of Chemistry, Fac-
ulty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt. E-mail: m elgaby@
hotmail.com
413

414
A. M. K. El-Dean et al.
pyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine derivatives starting from the
readily accessible 4-cyano-5,6-dimethylpyridazin-3(2H)-thione 3b.
RESULTS AND DISCUSSION
Druey and Schmidt10 reported the synthesis of 4-cyano-5,6-
dimethylpyridazin-3(2H)-one 3a by treatment of diacetyl 1 with hy-
drazine hydrate in refluxing ethanol to yield monohydrazone 2 followed
by cyclocondensation with ethyl cyanoacetate in the presence of sodium
ethoxide, Scheme 1. Our investigation describes the synthesis of pyri-
dazinone 3a via a one-pot reaction of diacetyl 1 and cyanoacetic acid
hydrazide 4 in ethanol at room temperature in quantitative yield (94%).
Thiation of compound 3a with phosphorus pentasulfide under reflux in
pyridine afforded the pyridazinethione 3b. The latter compound was
used as a key intermediate for the synthesis of thieno[2,3-c]pyridazine
and pyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine derivatives.
The cyclocondensation of compound 3b with ethyl chloroacetate was
performed in ethanol in the presence of catalytic amount of potassium
SCHEME 1

Thieno Pyridazine Derivatives
415
SCHEME 2
carbonate and yielded the novel thieno[2,3-c]pyridazine derivative 6a
in good yield (87%), Scheme 2. The structure of compound 6a was sup-
ported by its analytical and spectral data. The infrared spectrum of com-
pound 6a displayed absorption at 3440, 3330 cm−1 for NH2 stretching,
at 1665 cm−1 for C O stretching with lack of the characteristic absorp-
1
tion due to the C N stretching. In the H-NMR spectrum (CDCl3) of
compound 6a triplet at δ = 1.4 ppm, quartet at δ = 4.4 ppm assigned for
ethoxycarbonyl moiety in addition to amino and 2CH3 protons. In a sim-
ilar manner, compound 3b was cyclized with chloroacetamide and N-
substituted chloroacetamide and furnished the corresponding thienopy-
ridazines 6b and 6c,d, respectively. The mass spectrum of compound 6c
revealed a molecular ion peak at m/z = 312 (8.12%) with base peak at
m/z = 106.8. The formation of thienopyridazine 6 is assumed to proceed
through initial alkylation of compound 3b to form the intermediate 5
which readily undergo intramolecular cyclization under the reaction
condition to yield 6, Scheme 2. The intermediate compounds 5a–d were
isolated by refluxing of compound 3b with α-halocarbonyl compounds in
ethanol in the presence of fused sodium acetate. Compounds 6a–d were

416
A. M. K. El-Dean et al.
also independently synthesized via another pathway by cyclization of
compound 5 with sodium methoxide in methanol under reflux.
Cyclization of compound 6a with formamide under reflux afforded
pyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine derivative 7. The carbohy-
drazide derivative 8 was obtained by refluxing of compound 6a with
hydrazine hydrate under reflux in ethanol. The reaction of compound
6a with triethyl orthoformate in the presence of acetic anhydride pro-
vided the ethoxymethyleneamino derivative 9. Treatment of compound
9 with hydrazine hydrate in benzene at room temperature led to the
formation of amino derivative 6a and the cyclized product 11 was not
formed (mp, mmp, and TLC). The formation of compound 6a from 9 was
assumed to proceed via the addition of hydrazine at the imino function
group to form intermediate 10 followed by elimination of ethyl formate
hydrazone,11 (Scheme 3).
The carbonylazide 12 was formed by treatment of carbohydrazide
8 with sodium nitrite in glacial acetic acid at room temperature. The
infrared spectrum of compound 12 revealed the presence of absorp-
tion band characteristic for azide group at 2130 cm−1. Compound
12 underwent intramolecular cyclization in refluxing m-xylene into
imidazo[4ꢀ,5ꢀ:4,5]-thieno[2,3-c]pyridazine derivative 14. The formation
of compound 14 is assumed to proceed via Curtius rearrangement12
of compound 12 into isocyanate 13 followed by nucleophilic addition
of the NH2 function of 13 to the N C O to yield the novel condensed
imidazole 14 (Scheme 4).
Cyclocondensation of compound 8 with excess triethyl orthoformate
produced the ethoxymethylene derivative 15 (Scheme 5). In a similar
manner, compound 8 was cyclized with acetic anhydride under reflux
and furnished the diacetylamino derivative 16. Formylamino derivative
17 was achieved by refluxing of compound 8 in formic acid. Condensa-
tion of compound 8 with aromatic aldehydes in refluxing ethanol yielded
the corresponding azomethines 18a,b which on refluxing with triethyl
orthoformate gave the pyrimidothienopyridazines 19a,b. Cycloconden-
sation of carbohydrazide group in compound 8 with acetylacetone in
ethanol under reflux gave the novel pyrazole derivative 20 (Scheme 5).
EXPERIMENTAL
Melting points are 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 mea-
sured on a Varian 390-90 MHz NMR spectrometer using TMS as in-
ternal standard and mass spectra on a Jeol-JMS-600 mass spectrom-
eter. Elemental analyses were performed on a Perkin-Elmer 240 C

Thieno Pyridazine Derivatives
417
SCHEME 3
microanalyzer. The physical and spectral data are shown in Tables I
and II, respectively.
4-Cyano-5,6-dimethylpyridazin-3(2H)-one (3a)
A mixture of diacetyl 1 (0.01 mole) and cyanoacetic acid hydrazide 4
(0.01 mole) in ethanol (30 mL) was stirred at room temperature for 3 h.
The solid product was collected by filtration and recrystallized to give
3a.

418
A. M. K. El-Dean et al.
SCHEME 4
4-Cyano-5,6-dimethylpyridazin-3(2H)-thione (3b)
A mixture of compound 3a (0.01 mole) and phosphorus pentasulfide
(0.012 mole) in pyridine (15 mL) was refluxed for 2 h, then allowed
to cool and poured into cold water (100 mL). The solid product was
collected by filtration and recrystallized to give 3b.
4-Cyano-5,6-dimethyl-3-substituted Mercapto-pyridazines
(5a–d): General Procedure
A mixture of compound 3b (0.01 mole), fused sodium acetate
(0.012 mole), and α-halocarbonyl compound (0.01 mole) in ethanol
(30 mL) was heated under reflux for 2 h, allowed to cool, and poured
into water (100 mL). The solid product was collected by filtration and
recrystallized to give 5.
5-Amino-3,4-dimethyl-6-R-thieno[2,3-c]pyridazines (6a–d):
General Procedure
Method A
A mixture of compound 3b (0.01 mole), α-halocarbonyl compound
(0.01 mole) and potassium carbonate (0.012 mole) in ethanol (30 mL)

Thieno Pyridazine Derivatives
419
SCHEME 5

420
A. M. K. El-Dean et al.
TABLE I Physical Data of the Synthesized Compounds
Elemental analyses
[calcd./found]
Molecular
formula
(mol. wt.)
Compd. M.P. Yield (%) Solvent
no.
(◦C)
(color)
cryst.
C%
H% N%
S%
3a
210
94
(White)
90
(Yellow)
66
(Brown)
66
(White)
52
(White)
64
(White)
87
(Brown)
93
(Yellow)
86
(Yellow)
89
(Yellow)
66
(White)
75
(Yellow)
83
Ethanol
C7H7N3O
(149.15)
C7H7N3S
(165.21)
56.37 4.73 28.17
56.20 4.80 28.20
50.89 4.27 25.44 19.41
50.80 4.10 25.50 19.30
3b
5a
5b
5c
5d
6a
6b
6c
6d
7
213
120
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
C
11H13N3O2S 52.57 5.21 16.72 12.76
(251.31)
C9H10N4OS
(222.27)
16H16N4OS
(312.40)
16H16N4O2S 58.52 4.91 17.06
(328.40) 58.33 4.90 17.20
11H13N3O2S 52.57 5.21 16.72 12.76
(251.31)
C9H10N4OS
(222.27)
52.37 5.25 16.60 12.80
48.63 4.53 25.21 14.43
48.50 4.60 25.30 14.20
61.52 5.16 17.93 10.26
61.61 5.20 18.00 10.29
218
120
C
174
C
C
9.76
9.80
240
52.60 5.01 16.80 12.80
48.58 4.49 25.19 14.43
48.60 4.49 25.30 14.51
61.45 5.12 17.93 10.24
61.32 5.10 18.18 10.52
250
330
C
16H16N4OS
(312.40)
318
Ethanol C16H16N4O2S 58.46 4.87 17.06 9.76
(328.40)
10H8N4OS
(232.26)
58.72 4.80 16.88 10.00
51.66 3.44 24.12 13.80
51.66 3.52 24.00 14.00
45.52 4.63 29.51 13.48
45.61 4.68 29.33 13.62
>360
>300
140
Acetic
acid
Ethanol
C
8
C9H11N5OS
(237.28)
C14H17N3O3S 54.66 5.53 13.67 10.43
9
Ethanol
(White)
71
(Yellow)
90
(Yellow)
76
(White)
75
(Red)
66
(White)
80
(Yellow)
88
(Orange)
83
(307.36)
C9H8N6OS
(248.27)
C9H8N4OS
(220.25)
54.90 5.50 13.72 10.51
43.50 3.25 33.85 12.88
43.60 3.33 34.00 12.85
49.03 3.63 25.42 14.52
49.12 3.52 25.60 14.71
12
190
Chloro-
form
Ethanol
14
>300
228
15
Ethanol C13H13N5O2S 51.42 4.28 23.09 10.54
(303.34) 51.23 4.30 23.20 10.62
15H15N5O3S 52.16 4.34 20.28
16
276
Ethanol
Ethanol
C
9.28
9.15
(345.38)
11H9N5O2S
(275.29)
16H14ClN5OS 53.35 3.89 19.46
(359.84) 53.33 3.80 19.52
16H14N6O3S 51.83 3.78 22.69
(370.39) 51.77 3.90 22.62
C17H12ClN5OS 55.16 3.24 18.94
(369.83) 55.15 3.31 19.02
C17H12N6O3S 53.61 3.16 22.09
52.31 4.40 20.33
17
268
C
47.95 3.26 25.44 11.62
48.21 3.25 25.66 11.72
18a
18b
19a
19b
20
>330
>340
278
Acetic
acid
Acetic
acid
Acetic
acid
Acetic
acid
C
8.89
8.70
8.64
8.52
8.65
8.81
8.41
8.40
C
(Yellow)
90
(Brown)
65
300
(380.38)
C14H15N5OS
(301.37)
53.82 3.22 21.88
220
Ethanol
55.74 4.97 23.27 10.62
56.01 4.80 23.31 10.71
(Yellow)

Thieno Pyridazine Derivatives
421
TABLE II Spectral Data of the Synthesized Compounds
Compd
no.
IR/ν
(cm−1
)
1HNMR (δ/ppm)
max
3a
3400 (NH), 2200 (C N), 1660
(C O).
DMSO-d6; 2.3, 2.4 (2s, 6H, 2CH3), 10.8 (hump,
1H, NH).
3b
5a
3300 (NH), 2200 (C N).
2220 (C N), 1730 (C O).
CDCl3; 1.35 (t, 3H, CH3), 2.55, 2.77 (2s, 6H,
2CH3), 4.1–4.4 (m, 4H, 2CH2).
5b
5c
3380, 3280 (NH2), 2220 (C N),
1650 (C O).
3250 (NH), 2220 (C N), 1670
(C O).
DMSO-d6; 2.3, 2.5, 2.65 (3s, 9H, 3CH3), 4.38
(s, 2H, CH2), 7.2, 7.5 (2d, 4H, Ar-H), 10.7 (s,
1H, NH).
5d
3290 (NH), 2220 (C N), 1670
(C O).
CDCl3; 2.34, 2.6 (2s, 6H, 2CH3), 3.62 (s, 3H,
OCH3), 4.05 (s, 2H, CH2), 6.6, 7.3 (2d, 4H,
Ar-H), 9.2 (s, 1H, NH).
6a
6b
6c
6d
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).
3410, 3340, 3180 (NH2, NH),
1650 (C O).
DMSO-d6; 2.78, 3.4 (2s, 6H, 2CH3), 6.45 (s,
2H, NH2), 7.5 (s, 2H, NH2).
3400, 3300, 3120 (NH2, NH),
1620 (C O).
3390, 3280, 3100 (NH2, NH),
1600 (C O).
7
8
3420 (NH), 1665 (C O).
3420, 3300, 3200 (NH2, NH),
1670 (C O).
9
1680 (C O).
CF3COOD; 1.2–1.6 (m, 6H, 2CH3), 3.05, 3.1
(2s, 6H, 2CH3), 4.3–4.6 (m, 4H, 2CH2).
DMSO-d6; 2.8, 3.4 (2s, 6H, 2CH3), 5.2 (s, 2H,
NH2).
12
3420, 3320 (NH2), 2130 (N3).
14
15
3240, 3200 (NH), 1700 (C O).
1670 (C O), 1580 (C N).
CF3COOD; 1.4 (t, 3H, CH3), 3.2, 3.45 (2s, 6H,
2CH3), 4.2 (q, 2H, CH2), 8.3 (s, 1H,
CH-pyrimidine).
16
1760 (2C O), 1680 (C O).
CF3COOD; 2.35, 2.8, 2.9, 3.2, 3.5 (5s, 15H,
5CH3).
17
3280 (NH), 1690, 1670 (2C O). CF3COOD; 3.2, 3.45 (2s, 6H, 2CH3), 8.68 (s,
1H, CH-pyrimidine), 8.9 (s, 1H, CHO).
3470, 3300, 3190 (NH2, NH),
18a
18b
1620 (C O).
3480, 3290, 3185 (NH2, NH),
1670 (C O).
DMSO-d6; 2.78, 3.4 (2s, 6H, 2CH3), 6.45 (s,
2H, NH2), 7.2, 8.1 (2d, 4H, Ar-H), 8.4 (s, 1H,
CH N), 11.3 (s, 1H, NH).
19a
19b
20
1670 (C O).
1672 (C O).
CF3COOD; 3.2, 3.5 (2s, 6H, 2CH3), 7.7, 8.1
(2d, 4H, Ar-H), 8.1 (s, 1H, CH N), 9.2 (s, 1H,
CH-pyrimidine).
CF3COOD; 3.4, 3.65 (2s, 6H, 2CH3), 8.1, 8.7
(2d, 4H, Ar-H), 9.1 (s, 1H, CH N), 9.7 (s, 1H,
CH-pyrimidine).
3380, 3280 (NH2), 1660 (C O). 2.7, 3.0, 3.1, 3.4 (4s, 12H, 4CH3), 5.9 (s, 2H,
NH2), 6.2 (s, 1H, CH-pyrazole).

422
A. M. K. El-Dean et al.
was heated under reflux for 3 h, then allowed to cool. The solid product
was collected by filtration and recrystallized to give 3.
Method B
A sample of compound 5 (0.01 mole) in sodium methoxide (0.23
Na/30 mL methanol) was heated under reflux for 2 h, then allowed to
cool. The solid product was collected by filtration, washed with water,
and recrystallized to give 6.
MS (6b): 222 (M+; 13%), 221 (M − 1; 79%), 223 (M + 1; 4.8%), 205
(15%), 204 (base peak; 100%), 148 (42%), 149 (8.2%), 135 (12%), 108
(14%), 94 (4.6%), 65 (8.0%) and 43 (4%).
MS (6c): 312 (M+; 8.2%), 313 (M + 1; 2.7%), 314 (M + 2; 0.6%), 231
(0.5%), 205 (20%), 179 (0.2%), 149 (2.6%), 106 (base peak; 100%), 93
(2.4%) and 76 (0.4%).
3,4-Dimethylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazin-8(7H)-
one (7)
A sample of compound 6a (0.01 mole) in formamide (10 mL) was heated
under reflux for 2 h. The solid product which produced on heating was
collected and recrystallized to give 7.
MS (7): 232 (M+; 16%), 231 (M − 1; base peak), 204 (4.8%), 202 (74%),
174 (17%), 135 (5%), 107 (6%), 78 (0.3%) and 42 (5.3%).
5-Amino-3,4-dimethylthieno[2,3-c]pyridazine-6-
carbohydrazide (8)
A mixture of compound 6a (0.01 mole) and hydrazine hydrate (99%;
0.01 mole) in ethanol (30 mL) was heated under reflux for 5 h, then
allowed to cool. The solid product was collected by filtration and recrys-
tallized to give 8.
MS (8): 237 (M+; 13.4%), 206 (17%), 79 (base peak; 100%), 52 (72%),
50 (67%) and 40 (18%).
5-Ethoxymethyleneamino-3,4-dimethyl-thieno[2,3-
c]pyridazine-6-ethoxycarbonyl (9)
A mixture of compound 6a (0.01 mole), triethyl orthoformate (2 mL)
and acetic acid (10 mL) was heated under reflux for 4 h, then allowed to
cool. The product was collected by filtration and recrsytallized to give
9.

Thieno Pyridazine Derivatives
423
5-Amino-3,4-dimethyl-thieno[2,3-c]pyridazine-6-carboazide
(12)
To an ice-cooled solution of compound 8 (0.01 mole) in acetic acid
(10 mL), sodium ntirite solution (0.01 mole in 3 mL H2O) was added
dropwise for ten min. The stirring was continued for additional 1 h,
then allowed to stand for 2 h. The solid product was collected to give
12.
3,4-Dimethyl-5,7-dihydroimidazo[4’,5’:4,5]thieno[2,3-c]-
pyridazin-6-one (14)
A sample of carboazide derivative 12 (1 g) in dry m-xylene (20 mL) was
heated under reflux until the nitrogen gas was ceased and then allowed
to cool. The solid product was collected by filtration and recrystallized
to give 14.
7-Ethoxymethyleneamino-3,4-dimethylpyrimido[4ꢀ,5ꢀ:4,5]-
thieno-[2,3-c]pyridazin-8-one (15)
A sample of compound 8 (0.01 mole) in triethyl orthoformate (5 mL)
was heated under reflux for 5 h, then allowed to cool and poured into
cold water (100 mL). The solid product was collected by filtration and
recrystallized to give 15.
7-Diacetylamino-3,4,6-trimethylpyrimido[4ꢀ,5ꢀ:4,5]thieno-
[2,3-c]-pyridazin-8-one (16)
A sample of compound 8 (0.01 mole) in acetic anhydride (10 mL) was
heated under reflux for 3 h, then allowed to cool and poured into cold
water (100 mL). The solid product was collected by filtration and re-
crystallized to give 16.
7-Formylamino-3,4-dimethylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]-
pyridazin-8-one (17)
A sample of compound 8 (0.01 mole) in formic acid (10 mL) was heated
under reflux for 5 h, then allowed to cool and poured into cold water
(100 mL). The solid product was collected by filtration and recrystallized
to give 17.

424
A. M. K. El-Dean et al.
5-Amino-6-arylidenecarbohydrazone-3,4-dimethyl-thieno-
[2,3-c]-pyridazines (18a,b): General Procedure
A mixture of compound 8 (0.01 mole) and appropriate aldehyde
(0.01 mole) in ethanol (30 mL) was heated under reflux for 4 h, then
allowed to cool. The solid product was collected by filtration and recrys-
tallized to give 18.
7-Arylideneamino-3,4-dimethylpyrimido[4ꢀ,5ꢀ:4,5]thieno-
[2,3-c]-pyridazin-8-one (19a,b): General Procedure
Few drops of acetic acid was added to a refluxed mixture of compound
18 (0.01 mole) and triethyl orthoformate (4 mL). The reaction mixture
was heated under reflux for 2 h, then allowed to cool. The solid product
was collected by filtration and recrystallized to give 19.
(5-Amino-3,4-dimethyl-thieno[2,3-c]pyridazin-6-yl)-(3,5-
dimethyl-pyrazol-1-yl)-ketone (20)
A mixture of carbohydrazide 8 (0.01 mole) and acetylacetone (0.01 mole)
in ethanol (30 mL) was heated under reflux for 6 h, then allowed to cool.
The solid product was collected by filtration and recrystallized to give
20.
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