Synthesis of some new hetarylpyranopyridazines, cinnolines, and hetarylpyridazine derivatives

Article abstract of DOI:10.1007/s10593-010-0433-1

4-Acetyl-5,6-diphenylpyridazin-3(2H)-one was condensed with 6-chloro-3-formylchromone under different reaction conditions to yield the enone or pyranopyridazine. Both compounds were used in the synthesis of some new hetarylpyranopyridazines. Pyranodipyrid

Full text of DOI:10.1007/s10593-010-0433-1

Chemistry of Heterocyclic Compounds, Vol. 45, No. 11, 2009
SYNTHESIS OF SOME NEW HETARYL-
PYRANOPYRIDAZINES, CINNOLINES,
AND HETARYLPYRIDAZINE DERIVATIVES
M. Abdel-Megid1, Y. Gabr1*, M. A. A. Awas1, and N. M. Abdel-Fatah1
4-Acetyl-5,6-diphenylpyridazin-3(2H)-one was condensed with 6-chloro-3-formylchromone under
different reaction conditions to yield the enone or pyranopyridazine. Both compounds were used in the
synthesis of some new hetarylpyranopyridazines. Pyranodipyridazine was obtained via a sequence of
reactions of 4-acetyl-5,6-diphenylpyridazin-3(2H)-one with diethyl carbonate, acetic anhydride, and
4-bromobenzenediazonium chloride. The reactions of pyridazinylbutane-1,3-dione with conc. H2SO4,
POCl3, hydrazines, hydroxylamine hydrochloride, cyanoacetamide, thiourea, and thiosemicarbazone
were also studied.
Keywords: cinnolines, pyranopyridazines, ring−chain tautomerism.
N-Containing heterocycles are of biological importance. The design of newer strategies for their synthesis is
an important area of research in organic chemistry [1]. Pyridazines are an important class of nitrogen heterocycles,
which are known for a wide range of biological activities [2]. It has been reported that pyridazinones displayed
antinociceptive activity such as reduction of blood pressure [3], anti-inflammatory activity [4], inhibition of platelet
aggregation [5], and positive inotropic effects [6].
Motivated by these facts and as a part of our program directed to the synthesis of some new pyridazine
derivatives [7, 8] the present investigation deals with the combination of pyridazine with γ-pyrone in a
molecular frame-work via different methods starting from 4-acetyl-5,6-diphenylpyridazin-3(2H)-one (1) [9].
Condensation of 4-acetyl-5,6-diphenylpyridazin-3(2H)-one (1) with 6-chloro- 3-formylchromone [10] (2)
in sodium ethoxide solution afforded 4-[3-(6-chlorochromen-3-yl)prop-2-enoyl]-5,6-diphenylpyridazin-3(2H)-
one (3) in good yield. Heating of compound 3 in boiling ethanol containing a catalytic amount of piperidine and
intramolecular Michael addition of the lactam OH group to the olefinic CH=CH bond [11] yielded the ring–
chain tautomer of compound 3 7-(6-chloro-4-oxochromen-3-yl)-3,4-diphenyl-6,7-dihydropyrano[2,3-c]-
pyridazin-5-one (4). Compound 4 was also obtained directly on heating compound 1 with compound 2 in
ethanol-containing piperidine as a catalyst (Scheme 1).
_______
* To whom correspondence should be addressed, e-mail: yasingabr@yhaoo.com.
1Department of Chemistry, Faculty of Education of the Ain Shams University, Roxy, Cairo 11711, Egypt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1684-1696, November, 2009.
Original article received August 11, 2009.
1354
0009-3122/09/4511-1354©2009 Springer Science+Business Media, Inc.

Scheme 1
O
C
O
C
O
O
Ph
Cl
Ph
Me
H
+
N
N
H
O
2
1
EtOH/C5H10NH
NaOEt
Cl
O
O
Ph
O
Ph
O
O
Ph
Ph
O
O
EtOH
N
N
Cl
N
C5H10NH
O
N
H
4
3
Scheme 2
Cl
Ph
N
O
O
Ph
OH
N
N
N
NHX
10, 11
H
NH
N
O
N
N
H2NCNHX
Chr
Py
Chr
Py
6
5
NH2OH
N2H4·H2O
3
Cl
Cl
H2NNHCONH2
Ph
O
Ph
N
O
OH
Ph
OH
Ph
Cl
N
N
O
N
N
N
O
Ph
O
O
NH
8
7
OH
Ph
N
N2H4·H2O
N
N
NH2OH
N
O
4
4
CONH2
9
Ph
O
Ph
Py =
Chr =
N
N
H
O
O
10 X = H, 11 X = CN
1355

1
The structure of compound 4 was deduced from its H NMR spectrum (DMSO-d6), which revealed the
presence of a triplet at δ 4.81-5.10 and a doublet at 3.15-3.40 ppm, which indicated the presence of CHCH2
moiety formed as a result of addition of lactam OH to the β-position of the CH=CH bond. In continuation of our
work on biheterocyclic enones [12, 13], azoles [14], and pyrimidines [15, 16], we observed that the pyridazinyl-
chromenylenone 3 exhibited an interesting reaction with nitrogen bifunctional reagents different from the
normal characteristic reactions of α,β-unsaturated ketonic moiety. Thus, when compound 3 was subjected to
react with hydrazine hydrate and hydroxylamine in boiling ethanol containing triethylamine, the expected
pyrazoline 5 or isoxazoline 6 were not formed but instead of them pyrazolylpyranopyridazine 7 and
isoxazolpyranopyridazine 8 derivatives were produced. Formation of compounds 7 and 8 involves nucleophilic
attack by the amino group to position 2 of the chromone ring to form the pyrazole and isoxazole ring and
addition of the lactam OH to the β-position of the CH=CH bond to form the pyranopyridazine moiety under the
same reaction conditions. The structure of compounds 7 and 8 was confirmed by their identity with an authentic
sample prepared by the reaction of compound 4 with hydrazine hydrate or hydroxylamine, respectively. Similarly,
the pyrazolylpyranopyridazine derivative 9 was obtained on treatment of either compound 3 or compound 4 with
semicarbazide hydrochloride in boiling ethanol. Moreover, interaction of compound 3 or compound 4 with
guanidine hydrochloride and/or cyanoguanidine afforded the respective pyrimidinylpyranopyridazines 10 and
11. The IR spectrum of compound 11 showed a band at 2218 cm–1 attributed to the CN function in addition to
those reported for the pyranopyridazines. All of the compounds 7-11 gave a violet coloration with neutral FeCl3
solution, which proved the presence of the phenolic OH group arising from the broken γ-pyrone ring in
chromone (Scheme 2).
Scheme 3
Ph
O
O
O
C
Ph
Na
OEt
1
EtO
OEt
+
N
+
N
O Na
12
Ac2O
Ph
O
O
Ph
O
O
COOEt
Me
Ph
Ph
OEt
O
N
N
N
N
–
Me
O
14
13
+
N
N Cl
Br
Ph
N
O
COOEt
Ph
Ph
O
O
Ph
N
H
N
N
N
Br
O
C
N
H
N
15
N
O
16
Br
1356

In searching for another route for the synthesis of the target compounds, it has been found that the
acetylpyridazine 1 reacted with diethyl carbonate in the presence of finely divided sodium to yield ethyl 3-oxo-
3-(3-hydroxy-5,6-diphenyl-2H-pyridazin-4-yl)propanoate (12) in the form of the sodium salt. Its mass spectrum
showed the highest m/z value at 384 attributed to M+ + 23. Acetylation of compound 12 with acetic anhydride–
sodium acetate mixture afforded the intermediate 13, which underwent a ring closure to give 6-ethoxycarbonyl-
7-methyl-5-oxo-3,4-diphenylpyrano[2,3-c]pyridazine (14). Also, the reaction of compound 14 with p-bromo-
benzenediazonium chloride gave the hydrazone intermediate 15, which on cyclocondensation yielded the
pyranodipyridazine derivative 16 (Scheme 3).
Moreover, 1-(3-oxo-5,6-diphenyl-2H-pyridazin-4-yl)butane-1,3-dione (17), which was obtained from
the reaction of 4-acetyl-5,6-diphenylpyridazin-3(2H)-one (1) with ethyl acetate under Claisen condensation, was
used to synthesize some new pyranopyridazines and cinnolines. The structure of compound 17 was established
on the basis of its correct elemental analysis and spectroscopic data. Its 1H NMR spectrum (DMSO-d6) displayed
signals at δ 3.36 and 1.92 ppm attributed to CH2 and CH3, respectively. The mass spectrum of compound 17
showed a molecular ion peak at m/z 332 and base peak at 289 (100%), which was formed as a result of loss of
the acetyl radical (CH3CO•) from the molecular ion (cf. fragmentation pattern). When compound 17 was treated
with concentrated sulfuric acid, ring closure of the pyrano[2,3-c]pyridazine-5-one derivative 18 took place. The
mass spectrum of compound 18 exhibited a peak at m/z 314 (100%) corresponding to both molecular ion and
base peak, which showed the higher stability of the mentioned compound. The presence of a methyl group at
position 7 was deduced from its ability to condense with both benzaldehyde and 3-formyl-6-methylchromone
[10] to afford 7-styrylpyrano[2,3-c]pyridazin-5-one 19 and 1-(chromon-3-yl)-2-(pyranopyridazin-7-yl)ethene 20
derivatives, respectively.
Ph
O
O
Ph
+
Me
Ph 77 (2.53%)
N
289 (100%)
M COMe
N
H
O
247 (5.18%)
COCH2COMe
M
M –
(1.03%)
M CO
178 (5.15%)
+
M 332 (4.28%)
Ph
N
O
17
Ph
N
O
O
R
CH=CH
Me
18 – 20
20 R =
18 R = Me, 19 R = CH=CH–Ph,
Treatment of compound 17 with phosphorous oxychloride in a water bath furnished a compound
showing a peak at m/z 314 (100%) in its mass spectrum corresponding to both molecular ion and base peak,
indicating its higher stability under electron impact spectroscopy and represented by the structure of compound
22. The formation of compound 22 was explained via the formation of 3-chloropyridazine derivative 21 as an
intermediate, which underwent cyclocondensation with the removal of hydrogen chloride molecule to yield the
tetrahydrocinnolinedione derivative 22. The presence of two active methylene groups in compound 22 was
1
proved by its H NMR spectrum, which exhibited a broad singlet at 5.02−5.43 ppm attributed to four protons.
Compound 22 was coupled with 4-bromobenzenediazonium chloride to afford 6,8-bis[(4-bromophenyl)-
hydrazono]-3,4-diphenylcinnoline-5,7-dione 23, which showed a higher stability due to the intramolecular
hydrogen bonding. 5,7-Dichloro-3,4-diphenylcinnoline 24 was obtained on treatment of compound 22 with a
POCl3–PCl5 mixture (Scheme 4).
1357

Scheme 4
O
Ph
Ph
+
N
–
Cl
N
Br
N
Ph
N
O
N
O
Br
–HCl
Ph
22
H
N
POCl3
Ph
N
N
17
O
N
N
Cl
O
Ph
CH2
POCl3–PCl5
Cl
H
N
Ph
N
O
H
21
Ph
N
N
Cl
24
23
Br
N
Scheme 5
X
N
O
R
Ph
Ph
N
O
NH
Me
Ph
Me
Ph
N
N
N
H
X
C
N
H
RNHNH2
NH2
25, 26
H2N
28, 29
N
O
O
O
S
Ph
NH2OH
Ph
C
H2N
NH
N
Me
C
17
N
Me
NO2
30
N
H
27
S
CN
CH2CONH2
C
Ph
N
O
N
N
NC
Ph
NH
Me
Me
Me
Ph
NO2
Ph
N
31
N
H
HSCH2COOH
N
N
H
O
S
O
N
S
33
Ph
N
O
N
Ph
Me
Me
NO2
N
N
H
32
25 R = H, 26 R = Ph; 28 X = S, 29 X = NH
1358

In view of the wide biological activities of pyrazoles and pyrimidines, it was of interest to combine
pyrazole and pyrimidine moieties with pyridazine in a molecular frame which this may enhance their biological
applications. Therefore, when compound 17 was subjected to reaction with hydrazine hydrate and
phenylhydrazine, pyrazolylpyridazinones 25 and 26 were obtained, respectively, while interaction of compound
17 with hydroxylamine hydrochloride gave isoxazolylpyridazinone 27.
On the other hand, treatment of compound 17 with thiourea and guanidine hydrochloride in boiling
ethanol containing catalytic amount of triethylamine afforded the pyrimidinylpyridazinones 28 and 29,
respectively.
Moreover, when compound 17 was allowed to react with N-1-(3-nitrophenyl)ethylidenethiosemi-carbazone
30, the thioxopyrimidinylpyridazinone derivative 31 was obtained. When it reacted with thioglycolic acid in dry
benzene, cyclocondensation took place to yield oxothiazolidinyl pyrimidinylpyridazinone derivative 32.
Furthermore, 4-[3-cyano-6-methyl-2-oxo-1H-pyridin-4-yl]-5,6-diphenyl-2H-pyridazinone 33 was synthe-
sized by the reaction of compound 17 with cyanoacetamide in boiling ethanol containing a catalytic amount of
triethylamine (Scheme 5). The IR spectrum of compound 33 showed absorption bands at 2220 cm–1 corresponding to
the C≡N group.
EXPERIMENTAL
Melting points were determined on a Stuart SMP10 apparatus. The IR spectra were recorded on FTIR
1
Brücher Vector 22 spectrophotometer using the KBr wafer technique. H NMR spectra were measured on a
Varian Gemini spectrophotometer (200 MHz) in DMSO-d6 using TMS as internal standard. Mass spectra were
obtained using a gas chromatography/mass spectrometry GCMS Hewlett Packard 5988 Shimadzu instrument at
70 eV. Elemental analyses were done at the Microanalytical Center, Cairo University.
4-Acetyl-5,6-diphenylpyridazin-3(2H)-one (1) was prepared according to the reported method [9].
6-Chloro-3-formylchromone (2) was prepared according to the reported method [10].
4-[3-(6-Chloro-4-oxochromen-3-yl)prop-2-enoyl]-5,6-diphenylpyridazin-3(2H)-one (3). To
a
solution of sodium ethoxide prepared from sodium (0.23 g, 10 mmol) in absolute ethanol (20 ml), equimolar
amounts of compounds 1 and 2 (2.9 and 2.08 g, 10 mmol) were added. The reaction mixture was refluxed for 6
h, then cooled and neutralized with dil. HCl. The solid obtained was filtered off and dried to give compound 3
(4.2 g, 87%) as yellow crystals; mp 97oC (ethanol). IR spectrum, ν, cm–1: 3186 (NH); 3056 (CH olefinic), 1713,
1
1640 (2C=O), 1604 (C=N). H NMR spectrum, δ, ppm: 7.11–7.88 (13H, m, H Ar); 8.02 (1H, s, H-2 pyrone);
8.26, 8.69 (2H, 2s, CH=CH); 13.60 (1H, s, enolic OH pyridazine). Mass spectrum, m/z (I, %): 480.5 [M+] (0.91),
290 (100), 391 (4.08), 383 (3.42), 191(60.80), 105 (16.69), 77 (33.50). Found, %: C 70.05; H 3.66; Cl 7.39; N 5.88.
C28H17ClN2O4. Calculated, %: C 69.93; H 3.54; Cl 7.39; N 5.83.
7-(6-Chloro-4-oxochromen-3-yl)-3,4-diphenyl-6,7-dihydropyrano[2,3-c]pyridazin-5-one
(4).
Method A. A mixture of compound 1 (2.9 g, 10 mmol) and compound 2 (2.08 g, 10 mmol) in ethanol (20 ml) and
a few drops of piperidine were refluxed for 8 h. The reaction mixture was cooled and then poured into crushed
ice, and the solid obtained was filtered off to give compound 4 (2.64 g, 55%) as yellow crystals; mp 226oC
1
(ethanol–water). IR spectrum, ν, cm–1: 3470 (OH), 3031 (CH olefinic), 1703, 1688 (2C=O), 1616 (C=N). H
NMR spectrum, δ, ppm (J, Hz): 3.15-3.40 (2H, d, J = 6, H-6); 4.81–5.10 (1H, t, J = 6, H-7); 7.01–7.71 (13H, m,
H Ar); 8.02 (1H, s, H-2 chromone). Mass spectrum, m/z (I, %): 480.5 [M+] (6.00), 289 (100), 385 (42.09), 317
(17.5), 282 (50.19), 182 (54.26), 77 (59.9). Found, %: C 70.15; H 3.65; Cl 7.59; N 5.88. C28H17ClN2O4.
Calculated, %: C 69.93; H 3.54; Cl 7.39; N 5.83.
Method B. Compound 3 (2.4 g, 10 mmol) in absolute ethanol (20 ml) containing a few drops of
piperidine was heated under reflux for 3 h. The solid obtained was collected and crystallized from ethanol–water
to give compound 4; mp 266-267oC and mixed mp 265oC.
1359

7-[3-(5-Chloro-2-hydroxyphenyl)pyrazol-4-yl]-3,4-diphenyl-6,7-dihydropyrano-[2,3-c]pyridazin-5-one
(7). Method A. A mixture of compound 3 (4.8 g, 10 mmol) and hydrazine hydrate (0.5 g, 10 mmol) in absolute
ethanol (20 ml) was refluxed for 6 h. The solid obtained was filtered to give compound 7 (4.1 g, 83%) as
yellowish-white crystals; mp 295–296oC (ethanol). IR spectrum, ν, cm–1: 3652 (OH, phenolic), 3190 (NH), 1703
(C=O pyrone), 1614 (C=N). 1H NMR, δ, ppm (J, Hz): 3.13–3.38 (2H, d, J = 6, H-6); 4.79–5.07 (1H, t, J = 6, H-
7); 7.00–7.53 (14H, m, H Ar and H-3 pyrazole); 9.68 (1H, s, OH); 9.91 (1H, s, NH). Mass spectrum, m/z (I, %):
494.5 [M+] (2.09), 288 (100), 396 (6.00), 317 (17.5), 382 (1.71), 245 (4.10), 77 (6.74). Found, %: C 68.10; H 4.35;
Cl 7.35; N 11.45. C28H19ClN4O3. Calculated, %: C 67.95; H 3.84; Cl 7.18; N 11.32.
Method B. A mixture of compound 4 (4.8 g, 10 mmol) and hydrazine hydrate (0.5 g, 10 mmol) in
absolute ethanol (20 ml) was refluxed for 6 h. The solid obtained was filtered off and recrystallized from ethanol
to give compound 7 (4.1 g, 83%) as yellowish-white crystals; mp 295oC and mixed mp 295oC.
7-[3-(5-Chloro-2-hydroxyphenyl)isoxazol-4-yl]-3,4-diphenyl-6,7-dihydropyrano[2,3-c]pyridazin-5-one
(8). Method A. A mixture of compound 3 (4.8 g, 10 mmol) and hydroxylamine hydrochloride (0.7 g, 10 mmol)
in ethanol (20 ml) containing a few drops of DMF was heated under reflux for 5 h. The solid obtained was
filtered off to give compound 8 (4.2 g, 84%) as pale yellow crystals; mp above 300oC (ethanol). IR spectrum, ν,
1
cm–1: 3447 (OH), 3002 (CH olefinic), 1656 (C=O), 1626 (C=N). H NMR spectrum, δ, ppm (J, Hz):
3.13-3.35 (2H, d, J = 6, H-6); 4.80–5.15 (1H, t, J = 6, H-7); 7.38–7.95 (13H, m, H Ar); 8.34 (1H, s, H-5
isoxazole); 10.95 (1H, s, OH). Mass spectrum, m/z (I, %): 495.5 [M+] (1.7), 55 (100), 391 (1.62), 333 (12.26),
288 (13.36), 264 (9.19), 77 (17.90). Found, %: C 67.55; H 3.65; Cl 7.46; N 8.55. C28H18ClN3O4. Calculated, %:
C 67.81; H 3.636; Cl 7.16; N 8.47.
Method B. A mixture of compound 4 (4.8 g, 10 mmol) and hydroxylamine hydrochloride (0.7 g,
10 mmol) in ethanol (20 ml) containing a few drops of DMF was heated under reflux for 5 h. The solid obtained
was filtered off and recrystallized from ethanol to give compound 8 (84%) as pale-yellow crystals; mp and
mixed mp above 300°C.
7-[1-Carboxamido-3-(5-chloro-2-hydroxyphenyl)pyrazol-4-yl]-3,4-diphenyl-6,7-dihydropyrano-
[2,3-c]pyridazin-5-one (9). A mixture of compound 3 (4.8 g, 10 mmol) and semicarbazide hydrochloride (1.11 g,
10 mmol) in ethanol (20 ml) containing a few drops of triethylamine was heated under reflux for 4 h. The solid
obtained was filtered off to give compound 9 (3.6 g, 67%) as yellow crystals; mp 211°C (ethanol–water).
IR spectrum, ν, cm–1: 3408 (OH), 3295–3207 (NH2), 1702, 1659 (2C=O), 1624 (C=N). Mass spectrum,
m/z (I, %): 537.5 [M+] (6.39), 289 (100), 523 (6.60), 477 (7.42), 368 (34.14), 188 (53.25), 77 (33.20). Found, %:
C 64.62; H 3.35; Cl 6.50; N 13.25. C29H20ClN5O4. Calculated, %: C 64.74; H 3.72; Cl 6.60; N 13.02.
7-[2-Amino-4-(5-chloro-2-hydroxyphenyl)pyrimidin-5-yl]-3,4-diphenyl-6,7-dihydropyrano-
[2,3-c]pyridazin-5-one (10). A mixture of compound 3 (4.8 g, 10 mmol), guanidine hydrochloride (1.0 g,
10 mmol), and a few drops of piperidine in DMF (30 ml) was heated under reflux for 3 h. The mixture was left to
cool at room temperature, and the solid product so formed was collected to give compound 10 (2.7 g, 51%) as
pale-brown crystals; mp 209°C (ethanol–water). IR spectrum, ν, cm–1: 3484 (OH,), 3281–3186 (NH2), 1713
(C=O), 1614 (C=N). Mass spectrum, m/z (I, %): 521.5 [M+] (2.39), 288 (100), 477 (29.88), 465 (7.71),
391(57.54), 286 (32.89), 133 (13.48), 97 (26.51). Found, %: C 67.05; H 3.35; Cl 6.80; N 13.88. C29H20ClN5O3.
Calculated, %: C 66.73; H 3.83; Cl 6.81; N 13.42.
7-[4-(5-Chloro-2-hydroxyphenyl)-2-cyanoaminopyrimidin-5-yl]-3,4-diphenyl-6,7-dihydropyrano-
[2,3-c]pyridazin-5-one (11). A mixture of compound 3 (4.8 g, 10 mmol) and cyanoguanidine (0.84 g, 10 mmol)
in absolute ethanol (20 ml) containing a few drops of piperidine was heated under reflux for 4 h. The solid
obtained was filtered off to give compound 11 (3.9 g, 71%) as brown crystals; mp 227°C (ethanol). IR spectrum,
ν, cm–1: 3486 (OH), 3231 (NH), 2204 (CN), 1713 (C=O). Mass spectrum, m/z (I, %): 546.5 [M+] (13.48), 479
(16), 384 (31.56), 300 (18.85), 288 (57.54), 134 (44.87), 58 (48.19). Found, %: C 65.98; H 3.35; Cl 6.60;
N 15.55. C30H19ClN6O3. Calculated, %: C 65.87; H 3.48; Cl 6.50; N 15.37.
1360

Sodium salt of ethyl 3-(3-hydroxy-5,6-diphenyl-2H-pyridazin-4-yl)-3-oxo-propanoate (12). A
mixture of compound 1 (2.9 g, 10 mmol), finely divided sodium (0.46 g, 20 mmol), and diethyl carbonate (20
ml) was refluxed for 4 h. The reaction mixture on neutralization with diluted AcOH was filtered off to give
compound 12 (2.2 g, 56%) as pale yellow crystals; mp > 300°C (water). IR spectrum, ν, cm–1: 3470 (OH, H–
1
bonded), 2931 (CH aliphatic), 1703 (C=O ester), 1614 (C=N). H NMR spectrum, δ, ppm (J, Hz): 1.05 (3H, t,
J = 7.5, CH3); 1.71 (2H, s, COCH2CO); 3.41–3.61 (2H, q, J = 7.5, OCH2); 7.01-7.71 (10H, m, H Ar). Mass
spectrum, m/z (I, %): 384 [M+] (56.00), 385 [M+1] (16.58), 177 (100), 383 (92.09), 317 (17.5), 282 (52.79), 152
(24.26), 77 (39.91). Found, %: C 65.98; H 4.35; N 7.38. C21H17N2O4Na. Calculated, %: C 65.63; H 4.43; N 7.29.
6-Ethoxycarbonyl-7-methyl-5-oxo-3,4-diphenylpyrano[2,3-c]pyridazine
(14).
A mixture
of
compound 12 (3.84 g, 10 mmol), acetic anhydride (10 ml), and sodium acetate (0.82 g, 10 mmol) was refluxed
for 6 h. The reaction mixture was poured gradually into crushed ice. The solid obtained was filtered off to give
compound 14 (3.1 g, 81%) as yellow crystals; mp 81–82°C (ethanol). IR spectrum, ν, cm–1: 3085 (CH aromatic),
2980 (CH aliphatic), 1705 (C=O ester), 1643 (C=O pyrone), 1411 (C–O–C). Mass spectrum, m/z (I, %): 386
[M+] (2.47), 57 (100), 368 (1.92), 279 (2.90), 149 (37.78), 97 (51.45), 77 (2.30). Found, %: C 71.68; H 4.55;
N 7.58. C23H18N2O4. Calculated, %: C 71.50; H 4.66; N 7.25.
1-(4-Bromophenyl)-7,8-diphenylpyridazino[4,5-b]pyrano[2,3-c]pyridazine-9,10-dione (16) . An ice
cold solution of 4-bromobenzenediazonium chloride (3.3 g, 15 mmol) (prepared from the reaction of sodium
nitrite, hydrochloric acid, and p-bromoaniline) was added dropwise to an ice cold solution of compound 14
(3.86 g, 10 mmol) in ethanol (20 ml) containing sodium acetate (0.82 g, 10 mmol). The solid obtained was
filtered off to give compound 16 (2.9 g, 55%) as dark brown crystals; mp 255-256°C (ethanol). IR spectrum, ν,
cm–1: 3088 (CH, aromatic), 1652 (C=O pyridazinone), 1400 (C–O–C). Mass spectrum, m/z (I, %): 523 [M+]
(3.90), 55 (100), 417 (19.86), 388 (13.92), 289 (14.43), 149 (84.00), 77 (56.20). Found, %: C 61.55; H 3.01;
Br 15.50; N 10.44. C27H15BrN4O3. Calculated, %: C 61.95; H 2.87; Br 15.30; N 10.71.
1-(3-Oxo-5,6-diphenyl-2H-pyridazin-4-yl)butane-1,3-dione (17). A mixture of compound 1 (2.9 g,
10 mmol), finely divided sodium metal (0.28 g, 12 mmol), and dry sodium acetate (1.64 g, 20 mmol) was
refluxed for 6 h. The reaction mixture was kept at room temperature overnight then poured into dilute acetic
acid. The solid obtained was washed with water and dried to give compound 17 (2.8 g, 83%) as pale yellow
crystals; mp 281=282°C (ethanol). IR spectrum, ν, cm–1: 3191 (NH), 2994 (CH aliphatic), 1646 (C=O), 1580
(C=N). 1H NMR spectrum, δ, ppm (J, Hz): 1.92 (3H, s, CH3); 3.36 (2H, s, CH2); 7.1−7.5 (10H, m, H Ar); 13.01
(1H, s, enolic OH, pyridazine). Mass spectrum, m/z (I, %): 332 [M+] (4.28), 289 (100), 304 (1.03), 247 (5.18),
196 (1.82), 189 (6.68), 129 (2.77), 89 (2.15), 77 (2.53). Found, %: C 72.55; H 4.89; N 8.66. C20H16N2O3.
Calculated, %: C 72.29; H 4.82; N 8.43.
7-Methyl-3,4-diphenylpyrano[2,3-c]pyridazin-5-one (18). A mixture of compound 17 (3.32 g,
10 mmol) and concentrated sulfuric acid (10 ml) was stirred for 5 min at room temperature. The reaction mixture
was poured into crushed ice. The solid obtained was filtered off to give compound 18 (2.8 g, 89%) as
dark-brown crystals; mp 190-192°C (ethanol–water). IR spectrum, ν, cm–1: 2996 (CH aliphatic), 1648 (C=O),
1580 (C=N) 1294 (C–O pyran). Mass spectrum, m/z (I, %): 314 [M+] (100), 285 (8.78), 229 (8.20), 189 (34.66),
97 (12.287), 77 (12.24), 57 (21.6). Found, %: C 76.65; H 4.89; N 8.66. C20H14N2O2. Calculated, %: C 76.43;
H 4.46; N 8.92.
3,4-Diphenyl-7-styrylpyrano[2,3-c]pyridazin-5-one (19). A mixture of compound 18 (3.14 g,
10 mmol) and benzaldehyde (1.6 g, 12 mmol) in ethanol (20 ml) containing a few drops of concentrated
hydrochloric acid was heated under reflux for 6 h. The solid obtained upon cooling was collected to give
compound 19 (2.3 g, 57%) as brown crystals; mp 116-118oC (ethanol). IR spectrum, ν, cm–1: 3059 (CH
olefinic), 1699 (C=O), 1648, 1580 (C=N and C=C), 1277 (C–O pyran). Mass spectrum, m/z (I, %): 402 [M+]
(4.30), 377 (100), 256 (12.24), 188 (32.19), 157 (14.04), 129 (38.30), 77 (19.38). Found, %: C 80.99; H 4.56;
N 6.66. C27H18N2O2. Calculated, %: C 80.60; H 4.48; N 6.97.
1361

1-(6-Methyl-4-oxo-chromen-3-yl)-2-(4-oxo-3,4-diphenylpyrano[2,3-c]pyridazin-7-yl)ethene (20). The
titled compound was obtained by the same method applied for compound 19 using 6-chloro-3-formylchromone
instead of benzaldehyde. Compound 20 (4.2 g, 86%) was recrystallized from ethanol as brown crystals; mp
105−106oC. IR spectrum, ν, cm–1: 3059 (CH olefinic), 2927 (CH aliphatic), 1697, 1654 (2C=O), 1610 (C=N),
1281 (C–O pyran). Mass spectrum, m/z (I, %): 484 [M+] (1.34 %), 185 (100), 460 (3.13), 431 (2.3), 330 (8.15),
314 (22.07) 227 (13.30), 160 (29.26), 77 (22.87). Found, %: C 76.67; H 4.25; N 5.82. C31H20N2O4. Calculated, %:
C 76.86; H 4.13; N 5.79.
3,4-Diphenyl-6,8-dihydrocinnoline-5,7-dione (22). A mixture of compound 17 (3.32 g, 10 mmol) and
phosphorus oxychloride (5 ml) was refluxed in a water bath for 2 h. The reaction mixture was cooled and poured
gradually onto crushed ice. The solid obtained was filtered off and dried to give compound 22 (2.85 g, 91%) as
dark-brown crystals; mp 242oC (DMF–water). IR spectrum, ν, cm–1: 3424 (OH enolic), 3057 (CH olefinic),
1
1700-1648 (C=O), 1585 (C=N). H NMR spectrum, δ, ppm: 5.02–5.43 (4H, br. s, H-6, H-8); 7.28 (10H, m, H
Ar). Mass spectrum, m/z (I, %): 314 [M+] (100), 287 (54.41), 265 (15.25), 227 (11.93), 129 (32.62), 77 (18.37).
Found, %: C 76.98; H 4.35; N 8.88. C20H14N2O2. Calculated, %: C 76.43; H 4.46; N 8.92.
6,8-Bis[(4-bromophenyl)hydrazono]-3,4-diphenylcinnoline-5,7-dione (23). 4-Bromobenzene-
diazonium chloride (5.25 g, 25 mmol) (prepared from the reaction of hydrochloric acid, sodium nitrite, and
4-bromoaniline) was added to an ice cold solution of compound 22 (3.14 g, 10 mmol) in ethanol (20 ml)
containing sodium chloride (1.16 g, 20 mmol). The solid obtained was filtered off to give compound 23 (4.3 g,
63%) as brown crystals; mp > 300oC (DMF). IR spectrum, ν, cm–1: 3650-3150 (NH, OH hydrogen bonded),
3058 (CH aromatic), 1652 (C=O). Mass spectrum, m/z (I, %): 680 [M+] (1.20), 313 (13.10), 577 (36.65), 551
(30.61), 466 (10.58), 499 (11.00). Found, %: C 56.55; H 3.01; Br 23.24; N 12.44. C32H20Br2N6O2. Calculated,
%: C 56.47; H 2.94; Br 23.53; N 12.35.
5,7-Dichloro-3,4-diphenylcinnoline (24). A mixture of compound 22 (3.14 g, 10 mmol), phosphorous
oxychloride (10 ml), and phosphorus pentachloride (2 g) was refluxed in water bath for 6 h. The reaction
mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off to give compound
24 (2.35 g, 67%) as yellow crystals; mp 288-289oC (1-propanol). IR spectrum, ν, cm–1: 3055 (CH aromatic), 1617
(C=N). Mass spectrum, m/z (I, %): 351 [M+] (12.60), 313 (100), 262 (17.25), 236 (27.14), 211 (10.65), 129
(42.12), 77 (16.55). Found, %: C 58.55; H 4.31; Cl 20.19; N 7.44. C20H12Cl2N2. Calculated, %: C 68.38; H 3.42;
Cl 20.23; N 7.98.
4-(5-Methyl-1H-pyrazol-3-yl)-5,6-diphenylpyridazin-3(2H)-one (25). A mixture of compound 17
(3.32 g, 10 mmol) and hydrazine hydrate (0.6 g, 12 mmol) in absolute ethanol (20 ml) was refluxed for 4 h. The
reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained after cooling was filtered
off to give compound 25 (2.9 g, 88%) as colorless crystals; mp 250-252oC (ethanol). IR spectrum, ν, cm–1: 3279,
3159 (NH), 2926 (CH aliphatic), 1641 (C=O), 1587 (C=N). 1H NMR spectrum, δ, ppm: 2.03 (3H, s, CH3); 6.09
(1H, s, H-4 pyrazole); 7.13-7.20 (10H, m, H Ar); 12.94 (1H, s, NH pyrazole); 13.58 (1H, s, enolic OH
pyridazine). Mass spectrum, m/z (I, %): 328 [M+] (100), 286 (8.34), 266 (5.29), 202 (7.59), 77 (12.17) 57 (5.92).
Found, %: C 73.31; H 4.86; N 16.88. C20H16N4O. Calculated, %: C 73.17; H 4.88; N 17.07.
4-(5-Methyl-1-phenylpyrazol-3-yl)-5,6-diphenylpyridazin-3(2H)-one (26). This compound was
prepared by the same manner used for compound 25 using phenylhydrazine instead of hydrazine hydrate.
Compound 26 (2.8 g, 72%) was recrystallized from ethanol; mp above 300oC. IR spectrum, ν, cm–1: 3291 (NH),
2911 (CH aliphatic), 1647 (C=O), 1597 (C=N). 1H NMR spectrum, δ, ppm: 2.22 (3H, s, CH3); 6.15 (1H, s, H-4
pyrazole); 6.96-7.40 (15H, m, H Ar); 13.54 (1H, s, enolic OH pyridazine). Mass spectrum, m/z (I, %): 404 [M+]
(100), 327 (29.37), 300 (41.63) 258 (13.70), 169 (24.78), 77 (45.8). Found, %: C 77.27; H 4.73; N 13.66.
C26H20N4O. Calculated, %: C 77.23; H 4.95; N 13.86.
4-(5-Methylisoxazol-3-yl)-5,6-diphenylpyridazin-3(2H)-one (27). A mixture of compound 17 (3.32 g,
10 mmol) and hydroxylamine hydrochloride (0.7 g, 10 mmol) in ethanol (20 ml) containing a few drops of
triethylamine was refluxed for 5 h. The solid obtained upon cooling was filtered off and dried to give compound
1362

27 (2.85 g, 87%) as colorless crystals; mp 255-256oC (ethanol). IR spectrum, ν, cm–1: 3292 (NH), 3003 (CH
aromatic), 2924 (CH aliphatic), 1646 (C=O pyridazinone). Mass spectrum, m/z (I, %): 329 [M+] (14.44), 330
[M+1] (3.44), 287 (100), 227 (11.93), 289 (10.96), 176 (20.75) 149 (19.64), 77 (0.36). Found, %: C 72.98;
H 4.35; N 12.85. C20H15N3O2. Calculated, %: C 72.95; H 4.56; N 12.77.
4-(6-Methyl-1H-2-thioxopyrimidin-4-yl)-5,6-diphenylpyridazin-3(2H)-one (28). This compound was
prepared by the same method used in preparing compound 25 using thiourea instead of hydrazine hydrate. It was
crystallized from absolute ethanol (2.57 g, 69%) as yellowish crystals; mp 203-205oC. IR spectrum, ν, cm–1:
1
3191 (NH), 2994 (CH aliphatic), 1646 (C=O), 1580 (C=N), 1193 (C=S). H NMR spectrum, δ, ppm (J, Hz):
1.97 (3H, s, CH3); 5.66 (1H, s, H-5 pyrimidine); 7.12-7.30 (10H, m, H Ar); 13.64, 13.77 (2H, 2s, 2NH). Mass
spectrum, m/z (I, %): 372 [M+] (0.23), 369 [M–3] (1.82), 289 (100), 77 (7.92), 57 (15.29). Found, %: C 67.56; H
4.45; N 15.22; S 8.55. C21H16N4OS. Calculated, %: C 67.74; H 4.30; N 15.05; S 8.60.
4-(2-Imino-6-methyl-1H-pyrimidin-4-yl)-5,6-diphenylpyridazin-3(2H)-one (29). This compound
was prepared by the same method used for compound 25 using guanidine hydrochloride instead of hydrazine
hydrate. Compound 29 (2.4 g, 67%) was recrystallized from ethanol as brownish-red crystals; mp 215–216oC.
1
IR spectrum, ν, cm–1: 3422, 3298 and 3190 (NH and NH2), 2993 (CH aliphatic), 1647 (C=O), 1580 (C=N). H
NMR spectrum, δ, ppm: 1.97 (3H, s, CH3); 5.67 (1H, s, H-5 pyrimidine); 7.12–7.23 (10H, m, H Ar); 13.60,
13.77 (2H, s, 2NH pyrimidine); 13.78 (1H, s, enolic OH pyridazine). Mass spectrum, m/z (I, %): 355 [M+]
(8.45), 289 (100), 129 (13.15), 89 (22.07), 77 (24.41). Found, %: C 70.70; H 4.69; N 19.66. C21H17N5O.
Calculated, %: C 70.99; H 4.79; N 19.72.
4-[α-(3-Nitrophenylethylideneamino)-6-methyl-2-thioxopyrimidin-4-yl]-5,6-diphenylpyridazin-3(2H)-
one (31). This compound was prepared by the same method applied for compound 25 using N-1-(m-
nitrophenylethylidene)thiosemicarbazide 30 (obtained from condensation of acetophenone with thiosemi-
carbazide). Compound 31 (3.3 g, 62%) was crystallized from ethanol as colorless crystals; mp 212-213oC.
1
IR spectrum, ν, cm–1: 3370, 3219 (NH), 2996 (CH aliphatic), 1646 (C=O), 1603 (C=N), 1180 (C=S). H NMR
spectrum, δ, ppm: 1.97 (3H, s, 6-CH3 pyrimidine); 2.39 (s, 3H, CH3); 5.65 (s, 1H, H-5 pyrimidine); 7.11-7.61
(14H, m, H Ar); 10.41 (1H, s, NH). Mass spectrum, m/z (I, %): 534 [M+] (30), 310 (100), 521 (17.86), 500
(33.33), 295 (55.95), 334 (52.76), 56 (19.05). Found, %: C 65.37; H 4.32; N 15.80; S 6.00. C29H22N6O3S.
Calculated, %: C 65.17; H 4.12; N 15.73; S 5.99.
4-{6-Methyl-1-[(2-methyl-2-(3-nitrophenyl)-4-oxothiazolidin-3-yl]-2-thioxo-1,2-dihydropyrimidin-
4-yl}-5,6-diphenylpyridazin-3(2H)-one (32). A mixture of compound 31 (5.35 g, 10 mmol) and thioglycolic
acid (1.1 g, 12 mmol) in dry benzene was refluxed in water bath for 4 h. The solid obtained was collected to give
compound 32 (3.84 g, 63%) as colorless crystals; mp 218-220oC (ethanol). IR spectrum, ν, cm–1: 3369 (OH
1
enolic thiazolidinone), 3214 (NH), 2975 (CH aliphatic), 1637 (C=O), 1602 (C=N). H NMR spectrum, δ, ppm:
2.02 (3H, s, 6-CH3 pyrimidine); 2.38 (3H, s, 2-CH3, thiazolidinone); 7.06–8.62 (15H, m, H Ar and H-5
pyrimidine); 10.42 (1H, s, enolic OH thiazolidinone); 13.58 (1H, s, enolic OH pyridazine). Mass spectrum, m/z
(I, %): 608 [M+] (22.3), 388 (20.27), 333 (14.70), 238 (22.05). Found, %: C 60.90; H 4.01; N 13.67; S 10.36.
C31H24N6O4S2. Calculated, %: C 61.18; H 3.95; N 13.82; S 10.53.
4-(3-Cyano-6-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5,6-diphenylpyridazin-3(2H)-one (33).
A
mixture of compound 17 (3.32 g, 10 mmol) and cyanoacetamide (1 g, 12 mmol) in absolute ethanol (20 ml)
containing a catalytic amount of triethylamine was heated under reflux for 4 h. The solid obtained upon cooling
was collected to give compound 33 (3.26 g, 83%) as yellow crystals; mp 201–203oC (ethanol). IR spectrum, ν,
cm–1: 3407 (OH enolic pyridine), 3192 (NH), 2967 (CH aliphatic), 2270 (C≡N), 1646 (C=O), 1580 (C=N) cm–1.
1H NMR spectrum, δ, ppm: 2.05 (3H, s, CH3); 5.64 (1H, s, H-3 pyridine); 7.11–7.26 (10H, m, H Ar); 7.66 (1H, s,
NH pyridine); 13.63 (1H, s, enolic OH pyridazine). Mass spectrum, m/z (I, %): 380 [M+] (0.22), 289 (100), 332
(8.08), 304 (8.51), 290 (24.71), 77 (20.01). Found, %: C 72.50; H 4.15; N 14.55. C23H16N4O2. Calculated, %:
C 72.63; H 4.21; N 14.74.
1363

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