Pyridazine derivatives and related compounds, part 21: Synthesis of different heterocycles from 2-methyl-4H-pyridazino[4′,3′:4,5] thieno[3,2-d]-1,3-oxazin-4-one

Article abstract of DOI:10.1080/104265090968451

Starting with ethyl 5-amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carboxyl- ate, the syntheses of 2-methyl-8,9-diphenyl-4H-pyridazino[4′,3′:4,5] thieno[3,2-d]-1,3-oxazin-4-one (1), 7-amino-6-methyl-8-oxo-3,4-diphenyl-7,8- dihydropyrimido-[4′,5′:4,5]thieno

Full text of DOI:10.1080/104265090968451

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Phosphorus, Sulfur, and Silicon
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Pyridazine Derivatives
and Related Compounds,
Part 21:1 Synthesis of
Different Heterocycles
from 2-Methyl-4H-
pyridazino[4′,3′:4,5]thieno[3,2-
d]-1,3-oxazin-4-one
Ali Deeb a & Mohamed El-Abbasy a
a Department of Chemistry, Zagazig University,
Zagazig, AR, Egypt
Published online: 01 Feb 2007.
To cite this article: Ali Deeb & Mohamed El-Abbasy (2006) Pyridazine Derivatives and
Related Compounds, Part 21:1 Synthesis of Different Heterocycles from 2-Methyl-4H-
pyridazino[4′,3′:4,5]thieno[3,2-d]-1,3-oxazin-4-one, Phosphorus, Sulfur, and Silicon
and the Related Elements, 181:1, 15-23, DOI: 10.1080/104265090968451
To link to this article: http://dx.doi.org/10.1080/104265090968451
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Phosphorus, Sulfur, and Silicon, 181:15–23, 2006
Copyright © Taylor & Francis LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090968451
Pyridazine Derivatives and Related Compounds, Part 21:1
Synthesis of Different Heterocycles from 2-Methyl-4H-
pyridazino[4ꢀ,3ꢀ:4,5]thieno[3,2-d]-1,3-oxazin-4-one
Ali Deeb
Mohamed El-Abbasy
Department of Chemistry, Zagazig University, Zagazig, AR Egypt
Starting with ethyl 5-amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carboxyl-ate,
the syntheses of 2-methyl-8,9-diphenyl-4H-pyridazino[4ꢀ,3ꢀ:4,5]thieno[3,2-d]-
1,3-oxazin-4-one (1), 7-amino-6-methyl-8-oxo-3,4-diphenyl-7,8-dihydropyrimido-
[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine (3), and some related compounds are described.
INTRODUCTION
The pyrimidine ring is a frequent partner in polycyclic heterocyclic sys-
tems of biological significance.2 Compounds containing a fused pyrimi-
dine ring make up a broad class that has attracted attention in the past
few years owing to its wide range of biological activity. Many potential
drugs have been modeled on these compounds, particularly in cancer
and virus research.3 On the other hand, thienopyridazines have also at-
tracted attention because of their promising biological activities.4 This
prompted us to consider new synthetic routes leading to substituted
pyrimidothieno-pyridazine. Amino esters serve as good synthons for
the formation of a pyrimidine ring.5
RESULTS AND DISCUSSION
Ethyl 5-amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carboxylate was
used as the starting material because it has suitable substituents for
building other heterocyclic rings. The initial synthesis of a pyrimidine
ring could be achieved via the preparation of 2-methyl-8,9-diphenyl-4H-
Received January 4, 2004; in final form March 16, 2005.
Address correspondence to Ali Deeb, Zagazig University, Department of Chemistry,
Faculty of Science, Zagazig, AR Egypt. E-mail: dralideeb@hotmail.com
15

16
A. Deeb and M. El-Abbasy
pyridazino-[4ꢀ,3ꢀ:4,5]thieno-[3,2-d]-1,3-oxazin-4-one6 (1) as a key start-
ing material (Scheme 1).2
SCHEME 1
Treatment of 1 with ethanolamine, hydrazine hydrate, or thiosemi-
carbazide, or all of these, gave the corresponding tricyclic 7-substituted
6-methyl-8-oxo-3,4-diphenyl-7,8-dihydropyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]
pyridazine derivatives 2–4 as illustrated (Scheme 2):
SCHEME 2
The structures of compounds 2–4 were established on the basis of
elemental analyses as well as spectroscopic data. Compound 3 also was
obtained by condensing ethyl 5-acetylamino-3,4-diphenylthieno[2,3-
c]pyrid-azine-6-carboxylate with hydrazine hydrate, as previously
described.6

Pyridazine Derivatives and Related Compounds, Part 21
17
Mechanistically, the formation of 7-amino derivative 3 probably in-
volves a nucleophilic ring opening of an oxazinone ring with a hydrazine
hydrate to form a carbohydrazide intermediate. Then follows an in-
tramolecular nucleo-philic cyclization of the hydrazido primary amino
group to give the acetamido carbonyl group. The latter forms a triazepin
intermediate, which rearranges to the product 3 (Scheme 3).1
SCHEME 3
The reactivity of the 7-amino group in compound 3 was tested
through its ease of reactions with aromatic aldehydes p-nitrobenzal-
dehyde, p-methoxy-benzaldehyde, and p-N,N-dimethylaminobenzal-
dehyde, which gave the corresponding arylideneamino derivatives 5a–
c. Acetylation of 7-amino derivative 3 using acetyl chloride in pyridine
yielded N-acetylamino derivative 6. The structure of 6 was elucidated
from elemental analysis and spectral data. The IR spectrum showed
peaks at 3200, 1690, and 1660 cm−1 due to NH and two C O groups,
respectively. The mass spectra recorded a molecular ion peak at m/z
427.
On the other hand, compound 3, when refluxed with ammonium
thiocyanate in acetone, gave a product identified as an N-substituted
thiourea 4 in the basis of m.p., mixed m.p., and super-imposable IR
spectra. Upon fusion of compound 3 and thiourea at 150–160◦C, cy-
clization occurred with a loss of ammonia to form the triazolopyrimi-
dothienopyridazine 7. An alternative route to 7 was found in heating 4
in glacial-acetic-acid-fused sodium acetate.
It was of interest to react 7-amino derivative 3 with nitrous
acid, which yields 6-methyl-8-oxo-3,4-diphenyl-7,8-dihydropyrimido
[4ꢀ,5ꢀ:4,5]thieno-[2,3-c]pyridazine (8). Since the N-diazonium ion was
generated as an intermediate, it decomposes with the ultimate

18
A. Deeb and M. El-Abbasy
SCHEME 4
deamination and formation of dinitrogen monoxide.7 Compound 8
was identical (m.p., mixed m.p., and super impossible IR) with
an authentic sample synthesized unambiguously from 5-acetamido-
3,4-diphenylthieno[2,3-c]pyridazine-6-carboxamide, which under-went
smooth cyclization to 8.8 A single example of a new hetero-
cyclic system was made by treating the 7-amino derivative 3 with
chloroacetamide at a refluxed temperature in dimethylformamide
to produce the 6-methyl-8,9-diphenyl-3,4-dihydropyridazino[3ꢀꢀ,4ꢀꢀ:5ꢀ,4ꢀ]
thieno[2ꢀ,3ꢀ:5,6]pyrimido[3,4-b]-1,2,4-triazin-2-one (9). Its mass spec-
trum showed an intense peak at m/z = 424 corresponding to the molecu-
lar ion. The most salient features of the IR, 1 H-NMR, and mass spectra
are given in the Experimental section (Scheme 4).
EXPERIMENTAL
Melting points were determined on a Bu¨chi 510 apparatus and were
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 R12B spectrometer and chemical
shifts (δ) are in ppm relative to internal TMS. Mass spectra were

Pyridazine Derivatives and Related Compounds, Part 21
19
obtained at 70 eV by using a AEI MS 30 mass spectrometer. All re-
actions were monitored by thin layer chromatography and carried out
on 0.2 mm silica gel 60 F-254 (Merck) plates using UV light (254 and
366 nm).
2-Methyl-8,9-diphenyl-4H-pyridazino[4ꢀ,3ꢀ:4,5]thieno[3,2-
d]1,3-oxazin-4-one (1)
A sample of ethyl 5-amino-3,4-diphenylthieno[2,3-c]pyridazine-6-
carboxylate6 (1.0 g, 2.66 mmol) was refluxed in ethanolic sodium
hydroxide (30 mL, 4%) for 2 h. The solvent then was evaporated un-
der reduced pressure and the residue was used without purification
in the following reaction: The sodium salt was heated in acetic anhy-
dride (10 mL) at reflux temperature for 2 h; the cooled mixture was
poured into water (30 mL); and the solid product formed was filtered
off, dried, and recrystallized (ethanol) to give 1 (0.7 g, 60.6%), m.p.
1
160–161◦C. IR: 1762 (C O), 1660 (C N), 1555 (C C) cm−1; H-NMR
(DMSO-d6): δ 7.45–7.10 (m, 10H, 2 Ph), 1.45 (s, 3H, CH3). Anal. calcd
for C21H13N3O2S: C, 67.90; H, 3.52; N, 11.31. Found: C, 67.80; H, 3.40;
N, 11.10.
7-β-Hydroxyethyl-6-methyl-8-oxo-3,4-diphenyl-7,8-
dihydropyrimido-[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine (2)
To a solution of compound 1 (0.5 g, 1.34 mmol) in n-butanol (15 mL)
ethanolamine (0.1 g, 1.34 mmol) and sodium acetate (0.1 g) were
added. The reaction mixture was refluxed for 8 h. Upon cooling, a
precipitate formed and was filtered off, washed several times with
water, dried, and recrystallized (ethanol) to give 2 (0.4 g, 71.8%),
m.p. 260–261◦C. IR: 3449 (OH), 1655 (C O), 1631 (C N) cm−1; MS
m/z (%): 414 (M+, 9.5), 355 (M+-N(CH2) OH, 11.3, ion A), 327 (M+-
2
CONCH2CH2OH, 32.3), 286 (ion A-N = C CH3, 18.4). Anal. calcd for
C23 H18N4O2 S: C, 66.64; H, 4.37; N, 13.51. Found: C, 66.50; H, 4.10; N,
13.30.
7-Amino-6-methyl-8-oxo-3,4-diphenyl-7,8-dihydropyrimido
[4ꢀ,5ꢀ:4,5]-thieno[2,3-c]pyridazine (3)
To a solution of compound 1 (0.5 g, 1.34 mmol) in ethanol (10 mL) was
added hydrazine hydrate 85% (0.1 g, 1.99 mmol). The reaction mixture
was refluxed for 30 min, and the solvent was evaporated under reduced
pressure. The residue was treated with water (50 mL). A precipitate
formed and was filtered off, dried, and recrystallized (ethanol) to give 3
(0.4 g, 7.71%), m.p. 190–191◦C. IR: 3350, 3190 (NH2), 1672 (C O), 1620

20
A. Deeb and M. El-Abbasy
(C N)cm−1; 1H-NMR (DMSO-d6): δ 10.2 (s, 2H, NH2), 7.4–7.0 (m, 10H,
2 Ph), 6.8 (s, 3H, CH3). Anal. calcd for C21H15N5OS: C, 65.43; H, 3.92;
N, 18.17. Found: C, 65.30; H, 3.70; N, 17.90.
N-(6-Methyl-8-oxo-3,4-diphenyl-7,8-dihydropyrimido
[4ꢀ,5ꢀ:4,5]thieno-[2,3-c]pyridazin-7-yl)thiourea (4)
Method A
To a solution of compound 1 (0.5 g, 1.34 mmol) in n-butanol (10 mL)
was added to thiosemicarbazide (0.1 g, 1.34 mmol). The reaction mix-
ture was refluxed for 6 h, and, upon cooling, a precipitate was filtered off,
dried, and recrystallized (ethanol) to give 4 (0.4 g, 67.02%), m.p. 105–
106◦C. IR: 3421, 3058 (NH2), 1681 (C O), 1620 (C N), 1550 (C C),
1154 (C S) cm−1; MS m/z (%): 444 (M+, 1.1), 372 (M+-NHCSNH2, 21),
428 (M+-NH2, 12.8), 384 (M+-CSNH2, 3.9), 327 (M+-CONNHCSNH2,
19.3). Anal. calcd for C22H16N6OS2: C, 59.43; H, 3.62; N, 18.90. Found:
C, 59.20; H, 3.50; N, 18.70.
Method B
To a solution of compound 3 (0.5 g, 1.29 mmol) in dry acetone (10 mL)
ammonium thiocyanate (0.1 g, 1.29 mmol) was added. The reaction mix-
ture was refluxed for 4 h; the solvent was evaporated under reduced
pressure and the residue was treated with water (50 mL). The precipi-
tate was filtered off, dried, and recrystallized (ethanol) to give 4 (0.3 g,
56%). It was identical with that prepared by Method A.
7-Arylideneamino-6-methyl-8-oxo-3,4-diphenyl-7,8-
dihydropyrimido-[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine 5a–c:
General procedure
A mixture of compound 3 (0.5 g, 1.29 mmol) and the appropriate aro-
matic aldehyde (1.29 mmol) was refluxed in glacial acetic acid (10 mL)
for 6 h, cooled, and poured into water (50 mL). The separated solid was
filtered off, washed with water, dried, and recrystallized (ethanol) to
give 5a–c.
7-(p-Nitrobenzylideneamino)-6-methyl-8-oxo-3,4-diphenyl-
7,8-dihydro-pyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine (5a)
Yield (0.4 g, 80%), m.p. 282–283◦C. IR: 1699 (C O), 1521, 1345 (NO2)
cm−1. Anal. calcd for C28H18N6O3S: C, 64.85; H, 3.49; N, 16.20. Found:
C, 64.60; H, 3.20; N, 16.00.

Pyridazine Derivatives and Related Compounds, Part 21
21
7-(p-Methoxybenzylideneamino)-6-methyl-8-oxo-3,4-
diphenyl-7,8-di-hydropyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-
c]pyridazine (5b)
Yield (0.4 g, 61.5%), m.p. >300◦C. IR: 1681 (C O), 1610 (C N), 1550
(C C) cm−1. Anal. calcd for C29H21N5O2S: C, 69.16; H, 4.20; N, 13.90.
Found: C, 68.90; H, 4.00; N, 13.70.
7-(p-N,N-Dimethylaminobenzylideneamino)-6-methyl-8-oxo-
3, 4-di-phenyl-7,8-dihydropyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-
c]pyridazine (5c)
Yield (0.5 g, 75.7%), m.p. > 300◦C. IR: 1664 (C O), 1610 (C N), 1550
(C C) cm−1. Anal. calcd for C30H24N6OS: C, 69.74; H, 4.68; N, 16.26.
Found: C, 69.50; H, 4.40; N, 16.00.
7-Acetylamino-6-methyl-8-oxo-3,4-diphenyl-7,8-
dihydropyrimido-[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazine (6)
A mixture of compound 3 (0.5 g, 1.29 mmol) and acetyl chloride (10 mL)
was refluxed for 2 h. The cooled reaction mixture was poured into wa-
ter (30 mL), and the precipitate formed was filtered off, dried, and
recrystallized (ethanol) to give 6 (0.2 g, 36%), m.p. 146–147◦C. IR:
3396 (NH), 1768 (C O), 1730 (C O), 1621 (C N) cm−1; MS m/z(%):
427 (M+, 30), 384 (M+-Ac, 12.8, ion A), 355 (ion A-N NH, 6.3 ion B),
327 (ion B-CO, 8.9, ion C), 286 (ion C CH3 CN, 13). Anal. calcd for
C23H17N5O2S: C, 64.62; H, 4.01; N, 16.38. Found: C, 64.40; H, 3.90; N,
16.10.
2-Mercapto-5-methyl-7,8-diphenyl-1,2,4-triazolo[2ꢀꢀ,3ꢀꢀ:3ꢀ,4ꢀ]-
pyrimido-[5ꢀ,6ꢀ:4,5]thieno[2,3-c]pyridazine (7)
Method A
A mixture of compound 3 (0.5 g, 1.29 mmol) and thiourea (0.1 g,
1.29 mmol) was heated at 150–160◦C for 1 h. Methanol (30 mL) was
added to the cooled reaction mixture, and the precipitate was filtered
off, dried, and recrystallized (ethanol) to give 7 (0.4 g, 72.7%), m.p.
>300◦C. IR: 2400 (SH), 1620 (C N), 1560 (C C) cm−1; MS m/z (%): 426
(M+, 33), 385 (M+ -CH3CN, 12.3 ion A), 186 (ion A-substituted triazole,
6.9). Anal. calcd for C22H14N6S2: C, 61.95; H, 3.30; N, 19.70. Found: C,
61.70; H, 3.10; N, 19.60.

22
A. Deeb and M. El-Abbasy
Method B
To a solution of 4 (0.5 g, 1.12 mmol) in acetic acid (10 mL) sodium
acetate (0.1 g) was added. The reaction mixture was refluxed for 8 h, and
the cooled solution was poured into water (100 mL). The precipitate was
filtered off, dried, and recrystallized (ethanol) to give 7 (0.3 g, 58.02%).
It was identical with that prepared by Method A.
6-Methyl-8-oxo-3,4-diphenyl-7,8-dihydropyrimido[4ꢀ,5ꢀ:4,5]-
thieno[2,3-c]pyridazine (8)
A solution of sodium nitrite (0.38 g, 5.3 mmol) in water (10 mL) was
added dropwise to a stirred solution of compound 3 (0.5 g, 1.29 mmol)
in acetic acid (10 mL) at room temperature. The reaction mixture was
stirred for 2 h, and the precipitate was filtered off, washed with wa-
ter, dried, and recrystallized (acetic acid) to give 8 (0.4 g, 83.2%), m.p.
>300◦C. IR: 3400 (NH), 1690 (C O), 1620 (C N) cm−1; MS m/z (%):
370 (M+, 6.8), 342 (M+-CO, 5.2, ion A), 286 (ion A-N C-NHCH3, 22.3);
1H-NMR (DMSO-d6 ): δ 8.3 (s, 1H, NH), 7.8–7.6 (m, 10H, 2 Ph), 1.8
(s, 3H, CH3). Anal. calcd for C21H14N4OS: C, 68.07; H, 3.81; N, 15.12.
Found: C, 68.10; H, 3.60; N, 15.50.
6-Methyl-8,9-diphenyl-3,4-dihydropyridazino[3ꢀꢀ,4ꢀꢀ:5ꢀ,4ꢀ]-
thieno-[2ꢀ,3ꢀ:5,6]pyrimido[3,4-b]-1,2,4-triazin-7-one (9)
A solution of compound 3 (0.5 g, 1.29 mmol) in dimethylformamide
(10 mL) and 2-chloroacetamide (0.1 g, 1.29 mmol) was refluxed for 12 h.
The cooled reaction mixture was poured into water (50 mL). The pre-
cipitate was filtered off, washed with water, dried, and recrystallized
(ethanol) to give 9 (0.3 g, 54.4%), m.p. 196–197◦C. IR: 3427 (NH), 1658
(C O), 1610 (C N), 1550 (C C) cm−1; MS m/z (%): 424 (M+, 16.3), 395
(M+-NH CH2), 35.6 ion A), 353 (ion A - NCO, 17.6). Anal. calcd for
C23H16 N6OS: C, 65.07; H, 3.79; N, 19.79. Found: C, 64.80; H, 3.60; N,
19.70.
REFERENCES
[1] A. Deeb and M. El-Abbasy, Pyridazin Derivatives and Related Compounds Part
20: Synthesis of Different Heterocycles from 5-Aminothieno[2,3-c] pyridazine-6-
carbohydrazide, Phosphorus, Sulfur, and Silicon, 181(2), (2004, in press).
[2] D. J. Brown, in Comprehensive Heterocyclic Chemistry, Vol. 3, A. R. Katritzky, C. W.
Rees, A. J. Boulton, and A. Mckillop, Eds. (Pergamon Press, Oxford, 1983) p. 57.
[3] J. L. Kelley, J. A. Linn, and J. W. T. Selway, J. Med. Chem., 32, 218 (1989).
[4] R. S. Vartanyan, Zh. V. Kazaryan, M. A. Sheriranyan, A. S. Agaronyan, and N. O.
Stepanyan, Khim, Farm. Zh., 30, 29 (1996).

Pyridazine Derivatives and Related Compounds, Part 21
23
[5] H. Wamhoff, Lectures in Heterocyclic Chemistry, Vol. V, 1980, p. 61 and the references
cited therein.
[6] A. Deeb, M. Kotb, and M. El-Abbasy, Pyridazine Derivatives and Related Compounds.
Part II: Synthesis of Some Pyrimido[4ꢀ,5ꢀ:4,5] thieno[2,3-c] pyridazines, Phosphorus,
Sulphur, and Silicon, 179, 2245–2252 (2004).
[7] M. P. Doyle, J. G. Kalmbacher, W. Wierenha, and J. E. DeBoer, Tetrahedron Lett.,
1455 (1974).
[8] A. Deeb, A. Essawy, F. Yasine, and R. Fikry, Z. Naturforsch., 466, 835 (1990).