Pyridazine derivatives and related compounds, part 20: 1 synthesis of different heterocycles from 5-aminothieno[2,3-c]pyridazine-6- carbohydrazide

Article abstract of DOI:10.1080/104265091000912

7-substituted 3,4-diphenylpyrimido[4′,5′:4,5]thieno[2,3-c] pyridazines were synthesized starting from 5-amino-3,4-diphenylthieno[2,3-c] pyridazine-6-carbohydrazide (1). Reaction of carbohydrazide 1 with phthalic anhydride afforded 12,13-diphenyl-6H-pyrida

Full text of DOI:10.1080/104265091000912

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Phosphorus, Sulfur, and Silicon
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Pyridazine Derivatives
and Related Compounds,
Part 20:1 Synthesis of
Different Heterocycles
from 5-Aminothieno[2,3-
c]pyridazine-6-carbohydrazide
Ali Deeb a & Mohamed El-Abbasy a
a Department of Chemistry, Zagazig University,
Zagazig, Egypt
Published online: 16 Aug 2006.
To cite this article: Ali Deeb & Mohamed El-Abbasy (2006) Pyridazine Derivatives
and Related Compounds, Part 20:1 Synthesis of Different Heterocycles from 5-
Aminothieno[2,3-c]pyridazine-6-carbohydrazide, Phosphorus, Sulfur, and Silicon and
the Related Elements, 181:2, 397-404, DOI: 10.1080/104265091000912
To link to this article: http://dx.doi.org/10.1080/104265091000912
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Phosphorus, Sulfur, and Silicon, 181:397–404, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265091000912
Pyridazine Derivatives and Related Compounds, Part 20:1
Synthesis of Different Heterocycles from
5-Aminothieno[2,3-c]pyridazine-6-carbohydrazide
Ali Deeb
Mohamed El-Abbasy
Department of Chemistry, Zagazig University, Zagazig, Egypt
7-substituted 3,4-diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazines were synthe-
sized starting from 5-amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carbohydrazide
(1). Reaction of carbohydrazide 1 with phthalic anhydride afforded 12,13-diphenyl-
6H-pyridazino-[3ꢀꢀ,4ꢀꢀ: 5ꢀ,4ꢀ]thieno[3ꢀ,2ꢀ:4,5]pyrimido-[2,1-a]phthalazine-5,6-dione,
(6) which underwent further transformation to the related compounds.
Derivatives of the thienopyridazine ring systems are known to pos-
sess potent biological and pharmacological properties.2 As a part of
our continuing study on the synthesis of fused pyridazine,3 we became
interested in the synthesis of new heterocyclic systems derived from
thienopyridazine. In this context, we now wish to report the conver-
sion of 5-amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carbohydrazide
(1) into derivatives of the new heterocyclic system in corporating the
thieno-pyridazine moiety.
Compound 1 was used as the starting material because it has
suitable substituents for building on other heterocyclic rings and could
be obtained from refluxing a solution of ethyl 5-amino-3,4-diphenyl-
thieno[2,3-c]pyridazine-6-carboxylate and hydrazine hydrate in
ethanol.4 The pyrimidine rings were attached to the thiophene ring with
different cyclization conditions. When carbohydrazide 1 was cyclized
via refluxing with formaldehyde in presence of methanol, 7-amino-3,4-
diphenyl-5,6-dihydropyrimido [4ꢀ,5ꢀ:4,5] thieno[2,3-c]pyridazin-8(7H)-
one (2) was obtained in good yield (Scheme 1). Compound 2 was charac-
terized by microanalyses and spectroscopic data. The mass spectra of 2
showed the expected molecular ion peak, and the IR spectra exhibited
the characteristic bands of the amide group. Moreover, compound 2
Received December 10, 2004; accepted February 24, 2005.
Address correspondence to Ali Deeb, Zagazig University, Department of Science, Fac-
ulty of Chemistry, Zagazig, Egypt. E-mail: dralideeb@hotmail.com
397

398
A. Deeb and M. El-Abbasy
showed a characteristic peak between δ 5.73 and δ 6.55 for the 2 H-6
protons in the 1H-NMR spectra and two signals δ 4.08–5.16 and δ 6.03
exchangeable with deuterium, which can be attributed to the N-bound
proton at position 5 and the NH2 at position 7, respectively.
SCHEME 1
Mechanistically, the formation of the tricyclic compound 2 from 1
and formaldehyde involves the initial condensation with two hydro-
gen atoms of the amino and hydrazido primary groups, forming 1,2,4-
triazepine derivative I. The latter involves transfer of the hydrogen
atom from an NH group to the oxygen atom to form a hybrid II
(Scheme 2). The hybrid, following a translocation of the hydrogen atom
from the nitrogen atom at position 7, changes into a transient structure
III. The strongly electronegative nitrogen atom, in an internuclear nu-
cleophilic rearrangement, forms a link with the carbonyl carbon atom
and displaces the C N bond. Structure IV, formed as a result of that
rearrangement, is not stable and, after transolcation of the hydrogen
atom from the carbonyl oxygen atom, is transformed into compound 2.
Similarly, the expected formylamino derivative 3 (Scheme 1) was
obtained in high yield by refluxing 5-amino-6-carbohydrazide 1 with
formic acid. Structural elucidation of compound 3 was accomplished
from its analytical and spectral data. The mass spectrum showed the
expected molecular ion peak and the IR spectra of compound 3 exhibited
strong absorption bands at 3310–3360 cm−1 due to an NH group at 1670
and 1690 cm−1 due to the carbonyl groups. The 1H-NMR spectrum ex-
hibited two singlet signals at δ 8.70 and δ 11.30 due to the NH and CHO
groups, respectively; in addition, the 2Ph and H-6 protons resonated as
a multiplet at δ 7.20–7.60, confirming the proposed structure.

Pyridazine Derivatives and Related Compounds, Part 20
399
SCHEME 2
The cyclocondensation of 5-amino-6-carbohydrazide 1 in pres-
ence of dimethylformamide at refluxing temperature afforded a
single product in a 60% yield. The isolated product was proven
to be 7-amino-3,4-diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazin-
8(7H)-one (4) (Scheme 1).
Alternatively, compound 4 was obtained upon heating with
dimethyl-formamide and benzlidenecarbohydrazone 5,4 which under-
went formylation and cyclization, followed by hydrolysis, to furnish 4.
The molecular structure of 4 was supported by spectral data and ele-
mental analysis.
On the other hand the condensation of phthalic anhydride with the
carbohydrazide 1 in dimethylformamide gave the 12,13-diphenyl-6H-
pyridazino [3ꢀꢀ,4ꢀꢀ:5ꢀ,4ꢀ]thieno[3ꢀ,2ꢀ:4,5]pyrimido[2,1-a] phthalazine-5,8-
dione (6) (Scheme 3). Structural elucidation of compound 6 was ac-
complished from its analytical and spectral data. The mass spectrum
showed the expected molecular ion peak, and the IR spectrum exhibited
strong absorption bands at 3310–3350 cm−1 due to an NH group and at
1690 cm−1and 1665 cm−1 due to the carbonyl groups. Mechanistically,
the formation of the pentacyclic 6 involved the initial formation of a
cyclic isoindole derivative, which underwent immediate intramolecu-
lar nucleophilic attack by the thiophene amino group on the isoindole
carbonyl group with the elimination of a water molecule.
The reaction of compound 6 with phosphoryl chloride gave the cor-
responding 5-chloro derivative 7, which has served as a facile point
of departure into the desired molecules. The chloride atom of 7 showed
the expected reactivity towards nucleophilic reagents such as azide and

400
A. Deeb and M. El-Abbasy
SCHEME 3
ethyl thioglycolate anions, giving the phthalazines 8 and 9, respectively,
while with hydrazine hydrate, hydrazinophthalazine 10 formed. Alter-
natively, the thionation of 7 with thiourea, followed by basic hydrolysis,
resulted in the 5-mercaptophthalazine derivative 11 (Scheme 3). On
the other hand, reacting 11 with ethyl chloroacetate in boiling ace-
tone in presence of potassium carbonate afforded a single product.
The isolated product proved to be identical in every respect with 5-
carbethoxymercapto 9. The structure of these compounds was assigned
by elemental analyses as well as IR, mass, and NMR spectral data and
are summarized under the Experimental section.
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 pel-
1
lets, and frequencies are reported in cm−1. The H-NMR spectra were
observed on a Perkin-Elmer R12B spectrometer, and chemical shifts
(δ) are in δ (ppm) relative to internal TMS. Mass spectra were ob-
tained at 70 eV by using a AEI MS 30 mass spectrometer. All reac-
tions were monitored by thin layer chromatography and carried out on
0.2 mm silica gel 60F-254 (Merck) plates using UV light (254 nm and
366 nm).

Pyridazine Derivatives and Related Compounds, Part 20
401
7-Amino-3,4-Diphenyl-5,6-Dihydropyrimido[4ꢀ,5ꢀ:4,5]thieno-
[2,3-c]-Pyridazin-8(7H)-One (2)
To a solution of compound 1 (0.5 g, 1.38 mmol) in methanol (20 mL),
was added formaldehyde (5 mL), and the reaction mixture was refluxed
for 2 h. The solvent was evaporated under reduced pressure, and the
residue was treated with water. The precipitate was filtered off, dried,
and recrystallized from ethanol to give2 (0.46 g, 90%), m.p. 195–196◦C.
IR: 3302, 3180 (NH, NH2), 1671 (C O), 1613 (C C) cm−1; MS m/z (%):
371 (M+, 3.9), 343 (M+-CO, 10.3, ion A) 299 (ion A-CH2 = N-NH2, 4.3);
1H-NMR (DMSO-d6): δ 6.8–7.1 (m, 10H, 2Ph), 6.55 (s, 2H, 2H-6), 6.03
(s, 2H, NH2 exchangeable with deuterium), 5.16–4.98 (brs, 1H, NH,
exchangeable with deuterium). Anal. Calcd. for C20H15N5OS: C, 64.32;
H, 4.04; N, 18.75. Found: C, 64.10; H, 3.90; N, 18.50.
7-Formylamino-3,4-Diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]-
pyridazin-8(7H)-One (3)
A mixture of compound 1 (0.5 g, 1.38 mmol) and formic acid (10 mL) was
refluxed for 2 h. The reaction mixture was poured into water (50 mL),
and the precipitate was filtered off, dried, and recrystallized from n-
butanol to give 3 (0.3 g, 76.7%), m.p. 260–261◦C. IR: 3360–310 (NH),
1690 (C O formyl), 1670 (C O cyclic) cm−1; MS, m/z (%): 400 (M+ + 1,
1
2.1); H-NMR (DMSO-d6): δ 1.3 (s, 1H, CHO), 8.7 (s, 1H, NH), 7.6–7.2
(m, 11H, 2Ph + H-6). Anal. Calcd. for C21H13N5O2S: C, 63.14; H, 3.28;
N, 17.53. Found: C, 63.00; H, 3.10; N, 17.40.
7-Amino-3,4-Diphenylpyrimido[4ꢀ,5ꢀ:4,5]thieno[2,3-c]-
pyridazin-8(7H)-One (4)
Method A
A mixture of compound 1 (0.5 g, 1.38 mmol) and dimethylformamide
(5 mL) was refluxed for 12 h; the cooled reaction mixture was poured into
water (50 mL), and the precipitate was filtered off, dried, and recrys-
tallized (ethanol) to give 4 (0.3 g, 60%), m.p. 177–178◦C. IR: 3388, 3177
1
(NH2), 1735 (C O), 1692 (C N), 1610 (C C) cm−1; H-NMR (DMSO-
d6): δ8.2 (s, 1H, H-6), 7.4–7.1 (m, 10H, 2Ph), 3.4 (s, 2H, NH2). Anal.
Calcd for C20H13N5OS: C, 64.67; H, 3.52; N, 18.85. Found: C, 64.50; H,
3.40; N, 18.70.
Method B
A mixture of compound 54 (0.5 g, 1.11 mmol) and dimethyl-
formamide (10 mL) was refluxed for 16 h. The cooled reaction mixture

402
A. Deeb and M. El-Abbasy
was poured into water (50 mL), and the precipitate was filtered off,
dried, and recrystallized (ethanol) to give 4 (0.29 g, 72.6%). It was iden-
tical with that prepared by Method A.
12,13-Diphenyl-6H-Pyridazino[3ꢀꢀ,4ꢀꢀ:5ꢀ,4ꢀ]thieno[3ꢀ,2ꢀ:4,5]-
pyrido-[2,1-a]phthalazine-5,8-Dione (6)
To a solution of compound 1 (0.5 g, 1.38 mmol) in dimethyl-formamide
(5 mL), was added phthalic anhydride (0.2 g, 1.38 mmol). The reac-
tion mixture was refluxed for 4 h, was cooled, and poured into water
(50 mL). The precipitate was filtered off, washed with ethanol, dried,
and recrystallized from n-butanol to give 6 (0.4 g, 58.8%), m.p. 182–
183◦C. IR: 3350, 3310 (NH), 1690 and 1665 for carbonyl groups, 1651
(C N), 1610 (C C) cm−1; 1H-NMR (CDCl3) : δ 9.8 (s, 1H, NH), 7.9–7.7
(m, 4H, aromatic), 7.4–7.1 (m, 10H, 2Ph). Anal. Calcd. for C27H15N5O2S:
C, 68.48; H, 3.19; N, 14.79. Found: C, 68.30; H, 3.00; N, 14.60.
5-Chloro-12,13-Diphenylpyridazino[3ꢀꢀ,4ꢀꢀ:5,4]thieno-[3ꢀ,2ꢀ:4,5]-
pyrido-[2,1-a]phthalazin-8-One (7)
A mixture of compound 6 (0.5 g, 1.05 mmol) and phosphoryl chloride
(5 mL) was refluxed for 4 h. The reaction mixture was poured into water
(30 mL), and the precipitate was filtered off, dried, and recrystallized
(ethanol) to give 7 (0.46 g, 89.2%), m.p. 280–281◦C. IR: 3100 (CH aro-
1
matic), 1740 (C O), 1623 (C N), 1599 (C C) cm−1; H NMR (CDCl3):
δ7.8–7.2 (m, 14H, aromatic protons). Anal. Calcd for C27H14ClN5OS: C,
65.91; H, 2.86; N, 14.23. Found: C, 65.80; H, 2.80; N, 14.10.
5-Azido-12,13-Diphenylpyridazino[3ꢀꢀ,4ꢀꢀ:5ꢀ,4ꢀ]thieno-[3ꢀ,2ꢀ:4,5]
pyrido-[2,1-a]phthalazin-8-One (8)
To a solution of compound 7 (0.5 g, 1.01 mmol) in ethanol (10 mL),
was added sodium azide (0.19 g, 3.03 mmol). The reaction mixture was
refluxed for 6 h. The solvent was evaporated under reduced pressure
and the residue was treated with water. The precipitate was filtered off,
dried, and recrystallized from ethanol to give 8 (0.4 g, 80%), m.p. 220–
221◦C. IR: 2200 (N3), 1716 (C O), 1640 (C N), 1603 (C C) cm−1. Anal.
Calcd. for C27H14N8OS: C, 65.04; H, 2.83; N, 22.47. Found: C, 64.90; H,
2.70; N, 22.20.
5-Carbethoxymethylmercapto-12,13-Diphenylpyridazino-
[3ꢀꢀ,4ꢀꢀ:5ꢀ,4ꢀ]-Thieno[3ꢀ,2ꢀ:4,5] pyrido[2,1-a]phthalazin-8-One (9)
To a solution of compound 7 (0.5 g, 1.01 mmol) in dry acetone (20 mL),
were added ethyl 2-mercaptoacetate (0.12 g, 1.01 mmol) and unhydrous

Pyridazine Derivatives and Related Compounds, Part 20
403
potassium carbonate (0.11 g, 1.01 mmol). The reaction mixture was
refluxed for 10 h. The insoluble solid was removed by filtration and
washed with acetone. The combined filtrate was evaporated under re-
duced pressure, and the residue was washed with water, filtered off,
dried, and recrystallized (ethanol) to give 9 (0.3 g, 51.7%), m.p. 190–
191◦C. IR: 1738 (C O ester), 1659 (C O cyclic), 1625 (C N) cm−1; MS,
m/z (%): 575 (M+, 1.4), 502 (M+- CO2Et 3.8), 456 (M+-SCH2CO2Et, 2.2).
Anal. Calcd. for C31H21N5O3S2: C, 64.67; H, 3.67; N, 12.16. Found: C,
64.40; H, 3.50; N, 12.00.
5-Hydrazino-12,13-Diphenylpyridazino[3ꢀꢀ,4ꢀꢀ:5ꢀ,4ꢀ]thieno-
[3ꢀ,2ꢀ:4,5]-Pyrido[2,1-a]Phthalazin-8-One (10)
To a solution of compound 7 (0.5 g, 1.01 mmol) in ethanol (10 mL) was
added hydrazine hydrate 85% (0.5 g, 1.01 mmol). The reaction mix-
ture was refluxed for 3 h. The solvent was evaporated under reduced
pressure, and the residue was treated with water. The precipitate was
filtered off, dried and recrystallized (ethanol) to give 10 (0.3 g, 61.2%),
m.p. 180–181◦C. IR: 3173, 3075 (NH, NH2), 1655 (C O), 1600 (C N),
1595 (C C) cm−1. Anal. Calcd for C27H17N7OS: C, 66.51; H, 3.51; N,
20.11. Found: C, 66.30; H, 3.20; N, 19.90.
5-Mercapto-12,13-Diphenylpyridazino[3ꢀꢀ,4ꢀꢀ:5ꢀ,4ꢀ]thieno-
[3ꢀ,2ꢀ:4,5]-Pyrido[2,1-a]phthalazin-8-One (11)
To a solution of compound 7 (0.5 g, 1.01 mmol) in ethanol (10 mL) was
added thiourea (0.07 g, 1.01 mmol). The mixture was refluxed for 4 h.
The solvent was evaporated under reduced pressure, and the residue
treated with 2.5 N sodium hydroxide (15 mL). The mixture was refluxed
for 2 h. The reaction mixture was filtered hot, and the cooled filtrate
was neutralized with 3 N hydrochloric acid (pH = 6). The precipitate
was filtered off, washed with water, dried, and recrystallized (ethanol)
to give 11 (0.3 g, 61.2%), m.p. 250–251◦ C. IR: 2400 (SH), 1640 (C O),
1620 (C N) cm−1. Anal. Calcd. for C27H15N5OS2: C, 66.23; H, 3.08; N,
14.30. Found: C, 66.00; H, 2.90; N, 14.10.
Reaction of Compound 11 With Ethyl Chloroacetate
To a solution of compound 11 (0.5 g, 1.02 mmol) in dry acetone (10 mL),
were added ethyl chloroacetate (0.12 g, 1.02 mmol) and anhydrous
potassium carbonate (0.14 g, 1.02 mmol). The reaction mixture was
refluxed for 4 h and filtered hot. The filtrate was evaporated under re-
duced pressure. The solid residue was washed with water, dried, and

404
A. Deeb and M. El-Abbasy
recrystallized (ethanol) to give 9 (0.35 g, 60.3%). It was identical with
that prepared by previous method.
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[1] Part 19 was Submitted for publication.
[2] (a) M. Yamaguchi, T. Marvyama, K. Kamei, M. Akima, T. Kuroki, M. Hamana, and
N. Ohi, Chem. Pharm. Bull., 43, 236 (1995); (b) R. S. Vartanyan, Zh. V. Kazavyan,
M. A. Sheiranyan, A. S. Agaronyan, and N. O. Stepanyan, Khim, Farm Zh., 30, 29
(1996).
[3] A. Deeb, M. Kotb, and M. El-Abbasy, Pyridazine Derivatives and Related Compounds.
Part II: Synthesis of some pyrimido[14ꢀ,5ꢀ:4,5]thieno[2,3-c]pyridazines, Phosphorus,
Sulfur, and Silicon, 179, 2245 (2004).
[4] A. Deeb, M. Kotb, and M. El-Abbasy, Phosphorus, Sulfur, and Silicon (in press),
(2006).