Studies on the reactions of cyclic oxalyl compounds with hydrazines or hydrazones: Synthesis and reactions of 4-benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid

Article abstract of DOI:10.1002/jhet.5570390503

The 1H-pyrazole-3-carboxylic acid 2, obtained from the furan-2,3-dione 1 and N-Benzylidene-N′-(3-nitrophenyl) hydrazine, was converted via reactions of its acid chloride 3 with various alcohols or N-nucleophiles into the corresponding ester or amide derivatives 4 or 5, respectively. Nitrile 6 and anilino-pyrazole acid 7 derivatives of 2 were also obtained by dehydration of 5a in a mixture of SOCl₂ with DMF and reduction of 2 with sodium polysulphide, respectively. While cyclocondensation reactions of 2 or 7 with phenyl hydrazine or hydrazine hydrate and 6 with only anhydrous hydrazine lead to derivatives of pyrazolo[3,4-d]-pyridazinone 8 and pyrazolo[3,4-d]pyridazine amine 9, respectivel. The reaction of 2 with 2-hydrazinopyridine provided hydrazono-pyrazole acid derivative 10, which was decarboxylated to give hydrazono-pyrazole derivative 11. Pyrazolo[4,3-d]oxazinone 12 and 2-quinolyl pyrazolo[3,4-d]pyridazine 13 derivatives were also prepared by cyclocondensation reactions of 2 with hydroxylamine hydrochloride and 7 with acetaldehyde, respectively.

Full text of DOI:10.1002/jhet.5570390503

Sep-Oct 2002
Studies on the Reactions of Cyclic Oxalyl Compounds With
Hydrazines or Hydrazones : Synthesis and Reactions of 4-Benzoyl-1-
(3-Nitrophenyl)-5-Phenyl-1H-Pyrazole-3-Carboxylic Acid
Ahmet S¸ener [a], Rahmi Kasimogullari [b], M. Kasım S¸ener [a],
869
·
Ishak Bıldırıcı [a] and Yunus Akçamur [c]
[a]100. Yıl University, Art and Science Faculty, Chemistry Department, 65080-Van-Turkey
[b] Atatürk University, Art and Science Faculty, Chemistry Department, Erzurum-Turkey
[c] Erciyes University, Art and Science Faculty, Chemistry Department, Kayserı-Turkey
Received October 15, 2001
The 1H-pyrazole-3-carboxylic acid 2, obtained from the furan-2,3-dione 1 and N-Benzylidene-N'-(3-
nitrophenyl) hydrazine, was converted via reactions of its acid chloride 3 with various alcohols or N-nucleo-
philes into the corresponding ester or amide derivatives 4 or 5, respectively. Nitrile 6 and anilino-pyrazole
acid 7 derivatives of 2 were also obtained by dehydration of 5a in a mixture of SOCl2 with DMF and reduc-
tion of 2 with sodium polysulphide, respectively. While cyclocondensation reactions of 2 or 7 with phenyl
hydrazine or hydrazine hydrate and 6 with only anhydrous hydrazine lead to derivatives of pyrazolo[3,4-d]-
pyridazinone 8 and pyrazolo[3,4-d]pyridazine amine 9, respectivel. The reaction of 2 with 2-hydrazinopyri-
dine provided hydrazono-pyrazole acid derivative 10, which was decarboxylated to give hydrazono-pyra-
zole derivative 11. Pyrazolo[4,3-d]oxazinone 12 and 2-quinolyl pyrazolo[3,4-d]pyridazine 13 derivatives
were also prepared by cyclocondensation reactions of 2 with hydroxylamine hydrochloride and 7 with
acetaldehyde, respectively.
J. Heterocyclic Chem., 39, 869(2002).
Pyrazole chemistry has been the focus of high attention
mole) neat about 1 hour, the time during which benzalde-
hyde odor is detected, led to the formation of the titled
compound 2 in approximately 55% yield. The moderate
yield of the reaction can be explained by the chemical
behavior of furandione 1 towards H-active nucleophiles.
Addition of nucleophiles to furandione 1 usually starts
with nucleophilic attack at one of the C-2, C-3 and C-5
positions of the furan ring system. Simultaneous attack of
H-active nucleophiles to both C-2 and C-3 positions of
furan ring could convert furandione 1 into starting materi-
als; these materials are dibenzoylmethane and oxalic acid
derivatives [14]. The by-products formed this way, are
removed when the raw product is treated with ether or
toluene.
for more than three decades due to versatile biological
activities of pyrazole derivatives appearing as anti-micro-
bial [1], anti-viral [2], anti-tumor [3], anti-inflammatory
[4], anti-histaminic [5] pesticidal [6], anti-fungal [7],
against rheumatoid arthritis [8], anti-convulsant [9], anti-
depressant [10] and anti-pyretic [11] agents. Our studies
related to preparing pyrazole and fused pyrazole deriva-
tives by the functionalization and cyclization reactions of
4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid
with various nucleophiles was previously reported [12,13].
In this last study, we attempted both to prove reproducibil-
ity of the reaction of furandione 1 with another hydrazone
and to extend our investigations related to preparing new
pyrazole derivatives.
A reasonable proposal different from that discussed with
phenyl hydrazone [13] for reaction pathway from furan-
dione 1 to pyrazole carboxylic acid 2 is outlined briefly in
Scheme 1.
In this work, we studied the reaction of furandione 1
with N-benzylidene-N'-(3-nitrophenyl) hydrazine. Without
any solvent, heating of furandione 1 and hydrazone (1/1

·
870
A. S¸ener, R. Kasimogullari, M. K. S¸ener, I. Bıldırıcı and Y. Akçamur
Vol. 39
Ring opening for the formation of first intermediate may
Reactions of pyrazole derivative having the dicarbonyl
groups in the suitable position with hydrazines are conve-
nient methods to build the pyrazolo[3,4-d]pyridazine sys-
tems [12,17]. Thus, the pyrazole acids 2,7 were cyclized
with hydrazines to the pyrazolo[3,4-d]pyridazinones 8a-d,
in approximately 45-66 % yields. Additionally, 8c was
also obtained by the second method which is reduction of
8a with sodium polysulphide (Scheme 3).
be initiated by nucleophilic attack of the NH group adja-
cent to the phenyl ring of hydrazone at the C-5 position of
the furandione ring similar to the reactions of furandione 1
with various H-active nucleophiles [15]. Ring closure of
the first intermediate to the oxadiazepine intermediate via
addition of N=CHPh group to the C=O moiety takes place
by the catalytic effect of carboxylic acid proton similar to
the addition of azines to furandiones [16]. Rearrangement
of the second intermediate generates the pyrazole carboxy-
late intermediate, and finally loss of benzaldehyde gives
compound 2.
Structure of compound 2 was confirmed by analytical
and spectral data. In addition, the acid 2 could be easily
converted into the corresponding acid chloride 3, ester 4,
amide 5 and nitrile 6 derivatives by conventional chemical
procedures (Scheme 2). The pyrazole-3-carboxylic acid
chloride 3, obtained in approximately 65% yield, is
remarkably stable.
In a similar way, pyrazole-3-carbonitrile 6 with anhy-
drous hydrazine in boiling 1-butanol containing a catalytic
amount metallic sodium was also cyclized to the
7-aminopyrazolo[3,4-d]pyridazine derivative 9 in approxi-
mately 35% yield (Scheme 4). Structure elucidation of 8a-
13
d and 9 is mainly based on C-nmr spectroscopy (See
experimental for details).
On the other hand, the reaction of 2 with 2-hydrazinopy-
ridine instead of phenylhydrazine or hydrazine hydrate did
not lead to form the corresponding pyrazolo-pyridazine
derivative. Surprisingly, however, 2-hydrazinopyridine
was added to 2 to yield a new pyrazole acid 10 containing
a hydrazone group; hydrazono-pyrazole acid of this type
from analogous pyrazole acids have not been described
previously [12,13]. The failure or the difficulty in forming
the pyridazine nucleus from 10 can be explained by low
nucleophilicity of the nitrogen atom adjacent to the pyri-
dine ring. Additionally, decarboxylation of 10 on an oil-
bath at elevated temperature led to cleavage of C-C bond
The correct structures of the unsymmetrically substi-
tuted urea derivatives 5d-f were established by another
chemical procedure consisting of the reaction of the pri-
mary amide 5a with phenylisocyanate which resulted in
formation of phenylurea derivative 5d, originally prepared
from the acid chloride 3 in the usual way.
Reduction of 2 with sodium polysulphide led to form the
derivative of anilino-pyrazole acid 7 (Scheme 1). Structure
of the anilino acid 7 was proved by analytical and spectral
data (See experimental). In addition, cyclization deriva-
tives of the anilino-pyrazole acid with hydrazines 8c,d and
acetaldehyde cyclize to give quinoline derivatives, struc-
tures of which were also elucidated by elemental analysis
and spectroscopic data (Scheme 7).
with loss of CO finally yielding the corresponding hydra-
2
zono-pyrazole derivative 11 (Scheme 5).

Sep-Oct 2002
Studies on the Reactions of Cyclic Oxalyl Compounds With Hydrazines or Hydrazones
871
lin-7-yl)-pyrazolo[3,4-d]pyridazin-7-one derivatives 13a or
13b. The choice of one of the two alternative structures is
1
based on the H-nmr spectra of 13a and 13b, where a few
signals are observed down-field in the aromatic region
1
compared to the H-nmr signals of 8 c and 8 d.
Compound 10 and 11 show characteristic ir absorption
-1
-1
-1
bands at 3437 cm (NH), 1651 cm (C=N), 3361 cm
-1
(NH ) and 1676 cm (C=N). Ir spectra of compound 10
showed no absorption bands corresponding to the COOH
-1
group such as 3300-2500 cm (b, OH, COOH) and 1700-
-1
1750 cm (C=O, COOH) like that of 4-benzoyl-1,5-
diphenyl pyrazole-3-carboxylic acid [13]. However,
-1
absorbtion bands at approximately both 1610 cm and
-1
1577 cm corresponding to ionized carboxylate group
[18] were observed. From its ir spectrum, it may be
deduced that the compound 10 is found as the betaine form
1
in the solid state. Their characteristic H- nmr signals at d
=10.2 (b, 1H, acidic proton), 8.92 (b, 1H,NH), 8.25-6.57
ppm (m, 18H, ArH) and 8.70 (b, 1H, NH), 8.48-6.84 ppm
13
(m, 19H, ArH ) and C-nmr signals at d =167.06 (COO),
157.9 (C-2', Pyr), 146.13 ppm (C=N ) and 156.83 (C-2',
Pyr), 154.73 ppm (C=N), respectively, are in full agree-
ment with their proposed structures.
Additionaly, direct reaction of 2 with hydroxylamine
hydrochloride, on an oil-bath at approximately 150-155
°C led to the formation of the pyrazolo[4,3-d]oxazinone
12 in about 65% yield (Scheme 6). The structural proof of
12 is based on elemental analysis and spectral data (See
experimental).
The probable structures of compounds 13 a,b are sup-
ported by elemental analysis and spectroscopic data. In the
ir spectra of 13a and 13b, characteristic absorption bands
-1
-1
at about 3455 cm (NHDOH), 1673 cm (C=O) and 1676
-1
1
cm (C=O) were observed, respectively. In the H-nmr
spectra of compounds 13 the signals corresponding to NH
2
groups observed in compounds 8c,d are not present, and
with the exception of singlet signal for methyl groups at d
=2.64-2.69, all signals appeared in the aromatic region.
1
Also, the H-nmr spectra of 13a and 13b show that H-4'
and H-6' appear as a doublet at d =8.30 (J=8.4 Hz)-8.05
(J=8.4 Hz) and d =8.00 (J=8.8 Hz)-7.98 (J=9.2 Hz),
respectively. Also, signals corresponding to H-8' at
d =7.91(J < 2 Hz)-7.88 (J < 2 Hz) were observed as a mul-
tiplet; the very slight splitting indicates the absence of a
vicinal proton next to H-8'. This evidence establishes the
Finally, cyclization reactions of compounds 8c-d with
acetaldehyde in strong acidic medium lead to form quino-
line derivatives13a-b. Thus, the stability of the compounds
of type 8 in strong acidic medium was also confirmed by
these reactions, outlined briefly in Scheme 7. Due to lack of
substituents at the ortho- positions relative to the amino
group, the Skraup reaction of anilino-pyrazolo-pyridazi-
nones 8c-d may produce two isomeric quinoline deriva-
tives [19]. However, the results of tlc studies for each reac-
tion illustrate the presence of only one product, the proba-
ble structure of which was identified as 2-(2-methylquino-
reaction route 8 c,d
13 a,b, and rules out the formation
of compounds 13 a',b'. Other spectral and analytical data
of 13 a and 13 b are in full agreement with their proposed
structures as well(see experimental).
EXPERIMENTAL
Solvents were dried by refluxing with the appropriate drying
agents and distilled before use. Melting points were determined

·
872
A. S¸ener, R. Kasimogullari, M. K. S¸ener, I. Bıldırıcı and Y. Akçamur
Vol. 39
on an Electrothermal Gallenkamp apparatus and are uncorrected.
Microanalyses were performed on a Carlo Erba Elemental
Analyser Model 1108. The ir spectra were obtained as potassium
bromide pellets using a Mattson 1000 FTIR spectrometer. The 1H
and 13C-nmr spectra were recorded on ASR 18 YUICH (200
MHz) and ASR 18 YUICH (50 MHz) spectrometers, respec-
tively, using TMS as an internal standard. The mass spectrum of
2 was measured on a Varian mat III at 80 eV. All experiments
were followed by tlc using DC Alufolien Kieselgel 60 F 254
Merck and Camag TLC lamp (254/366 nm).
(C-4), 125.06, 122.46, 66.28 (O-CH2), 38.80 (CH), 26.66 (CH2),
24.27 ppm (CH3).
Anal. Calcd. for C28H25N3O5 : C, 69.55; H, 5.21; N, 8.69.
Found : C, 69.61; H, 5.24; N, 8.66.
Butyl 4-Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-car-
boxylate (4b).
Compound 4b was obtained in 82% yield (0.385 g); mp 175oC
(n. butanol); ir: 1753 cm-1 (C=O, ester), 1676 cm-1 (C=O, ben-
zoyl).
Anal. Calcd. for C27H23N3O5: C, 69.07; H, 4.94; N, 8.95.
Found : C, 68.87; H, 4.95; N, 8.93.
4-Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-car-
boxylic Acid (2).
4–Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H–pyrazole-3-carbox-
amide (5a).
An equimolar mixture of furandione 1 (0.278 g, 1 mmole) and
(3-nitrophenyl hydrazono) (phenyl) methane (0.241 g, 1 mmole)
was heated to 85-90 °C for approximately 60 minutes, at which
time the odor of the benzaldehyde was no longer detectable,
without any solvent. After cooling to room temperature, the
residue was treated with dry toluene and the formed crude prod-
uct was recrystallized from ethanol to give 0.227 g (55%) of a
colorless solid, mp 210 °C (decomp.); ir: 3400-2500 cm-1 (b, OH,
COOH), 1716 cm-1 (C=O, COOH), 1670 cm-1 (C=O, benzoyl);
1H-nmr (deuteriochloroform): d 8.28 (s, H-2'), 7.82-7.21 ppm (m,
ArH); 13C-nmr (deuteriochloroform): d 193.53 (C=O, benzoyl),
165.41 (C=O, COOH), 150.35 (C-NO2), 147.10 (C-3), 144.43
(C-5), 141.47 (N-PhNO2), 139.25 (C-Ph), 135.53, 132.91,
132.07, 132.02, 131.88, 131.45, 130.98, 130.37, 128.91 (C-Ph),
125.53 (C-4), 125.33, 122.51 ppm. Mass (80 eV): m/e= 414.1;
385.3; 369.3; 352.8.
A moderate stream of gaseous ammonia was allowed to bubble
through a solution of pyrazole-3-carboxylic acid chloride 3
(0.432 g, 1 mmole) in 20 ml of carbon tetrachloride during 30
minutes with ice-cooling. Then the crude precipitate was isolated
by filtration and recrystallized from methanol to give 0.268 g
(65%) of 5a, mp 210 °C, ir: 3489 cm-1 (NH2), 1676 cm-1 (C=O,
1
benzoyl), 1638 cm-1 (C=O, amide). H-nmr (DMSO-d6): d 5.74
and 7.0 (b, NH2), 7.15-8.33 ppm (m, 14H, ArH).
Anal. Calcd. for C23H16N4O4: C, 66.99; H, 3.91; N, 13.59.
Found: C, 67.23; H, 3.90, N, 13.65.
4-Benzoyl-1-(3-nitrophenyl)-N-pentyl-5-phenyl-1H-pyrazole-3-
carboxamide (5b).
General Procedure.
Anal. Calcd. for C23H15N3O5: C, 66.83; H, 3.66; N, 10.16.
Found: C, 66.69; H, 3.67, N, 10.18.
An equimolar mixture of the acid chloride 3 (0.431 g, 1 mmole)
and n-pentyl amine (1 mmole) was refluxed in xylene for 3 hours.
After evaporation, the oily residue was treated with dry ether and
the formed crude product was recrystallized from isopropanol. The
yield 0.29 g (60%), mp 179 °C; ir : 3361 cm-1 (NH), 1676 cm-1
4-Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl
Chloride (3).
Compound 2 (0.413 g, 1 mmole) and thionylchloride (1 ml.,
13.8 mmoles) were refluxed on a steam bath for 5 hours. After
cooling, the crude precipitate was isolated by filtration and
recrystallized from a mixture of toluene and n-hexane, yield
0.281 g (65%), mp 166 °C; ir: 1758 cm-1 (C=O, acyl), 1676 cm-1
(C=O, benzoyl); 13C-nmr (deuteriochloroform): d 191.55 (C=O,
benzoyl), 163.61 (C=O, acyl), 150.48 (C-NO2), 147.09 (C-3),
146.93 (C-5), 141.34 (N-PhNO2), 138.96 (C-Ph), 135.99, 132.81,
132.40, 132.28, 131.69, 131.39, 131.17, 130.72, 128.40 (C-Ph),
126.14 (C-4), 125.68, 122.48 ppm.
-1
(C=O), 1642 cm (C=O, amide); 1H-nmr (deuteriochloroform): d
7.11-8.31 (m, 14H, ArH), 3.34 (t, 2H, N-CH2), 1.54 (m, 2H, CH2),
1.28 (m, 2H, CH2), 1.15 (m, 2H, CH2), 0.85 ppm (t, 3H, CH3); 13C-
nmr (deuteriochloroform): d 193.37 (C=O), 162.09 (C=O), 150.43
(C-NO2), 148.57 (C-3), 145.80 (C-5), 141.84 (N-PhNO2), 139.90
(C-Ph), 135.20, 132.50, 131.97, 131.82, 131.71, 131.37, 130.94,
130.33, 129.43 (C-Ph), 127.77, 122.10 (C-4), 41.33 (N-CH2),
31.28 (CH ), 31.04 (CH2), 24.32 (CH2), 15.96 ppm (CH3).
2
Anal. Calcd. for C28H26N4O4: C, 69.70; H, 5.43; N, 11.61;
found : C, 69.82; H, 5.39, N, 11.58.
Anal. Calcd. for C23H14N3O4Cl: C, 63.97; H, 3.27; N, 9.73;
Cl, 8.21. Found: C, 63.92; H, 3.26, N, 9.71; Cl, 8.19.
4-Benzoyl-1-(3-nitrophenyl)-N-phenyl-5-phenyl-1H-pyrazole-3-
carboxamide (5c).
Isopentyl 4-Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-
carboxylate (4a).
Compound 5c was prepared by the general procedure above
with a reflux time of 1 hour (aniline) resulting in a yield of 55%
(0.269 g); mp 203 °C (1-propanol); ir: 3387,3336 cm-1 (NH),
1676 cm-1 (C=O), 1625 cm-1 (C=O).
Anal. Calcd. for C29H20N4O4: C, 71.30; H, 4.13; N, 11.47.
Found: C, 71.42; H, 4.14, N, 11.45.
General Procedure.
The acid chloride 3 (0.431 g, 1 mmole) and a moderate excess
of the isopentyl alcohol were refluxed together with a catalytic
amount of pyridine for 3 hours. After cooling, the solution was
acidified by adding diluted hydrochloric acid (12%) to give a
crude solid that was recrystallized from the same alcohol. The
yield 0.387 g (80%), mp 160 °C (isopentyl alcohol); ir: 1753
cm-1 (C=O, ester), 1676 cm-1 (C=O, benzoyl); 13C-nmr
(deuteriochloroform): d 192.47 (C=O, benzoyl), 162.98
(C=O,ester), 150.38 (C-NO2), 145.84 (C-3), 145.36 (C-5),
141.74 (N-PhNO2), 139.83 (C-Ph), 135.48, 132.81, 131.97,
131.91, 131.77, 131.40, 130.99, 130.67, 129.13 (C-Ph), 125.73
N-[4-Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-car-
bonyl]-N'-phenylurea (5d).
a) Compound 5d was prepared by the general procedure above
with a reflux time of 4 hours (phenylurea) resulting in a yield of
45% (0.239 g); mp 214 °C (1-propanol); ir : 3397, 3250 cm-1
(NH), 1753 cm-1 (C=O, urea), 1676 cm-1 (C=O) 1625 cm-1
(C=O); 13C-nmr (deuteriochloroform): d 192.42 (C=O), 162.75

Sep-Oct 2002
Studies on the Reactions of Cyclic Oxalyl Compounds With Hydrazines or Hydrazones
873
(C=O), 151.92 (C=O, urea), 150.42 (C-NO2), 146.64 (C-3),
145.49 (C-5), 141.33 (N-PhNO2), 139.19 (N-Ph), 139.03 (C-Ph),
135.87, 132.40, 132.22, 131.61, 131.52, 131.17, 130.94, 130.65,
128.74 (C-Ph), 126.37, 125.37, 122.36, 122.05 ppm (C-4).
Anal. Calcd. for C30H21N5O5: C, 67.79; H, 3.98; N, 13.18.
Found: C, 68.02; H, 3.97, N, 13.21.
tered off. Then, the filtrate was made alkaline by adding concen-
trated aqueous ammonia (slight excess) and kept in refrigerator
over-night. The crude precipitate was washed with water and
recrystallized from ethanol to give 2.49 g (65%) of 7 mp 181 °C;
-1
ir: 3384 cm-1 (NH2), 3258-2700 cm (b, OH, COOH), 1709 cm-1
1
(C=O, COOH), 1667 cm-1 (C=O, benzoyl). H-nmr (deuterio-
b) The acid amide 5a (0.412 g, 1 mmole) and phenylisocyanate
(0.2 ml, 1,8 mmoles) were refluxed in xylene for 5 hours. Then
the solvent was evaporated and the residue was recrystallized
from 1-butanol to give 0.4 g (75%) of 5d, identical in mp and ir
spectrum with that product obtained as described above.
chloroform): d 7.69-6.39 ppm (m, 14H, ArH), 5.76 ppm (b,
NH2). 13C-nmr (deuteriochloroform): d 194.85 (C=O), 164.61
(COOH), 147.26 (H2N-Ph), 144.67 (C-3), 141.37 (C-5), 139.41
(N-PhNH2), 135.19, 131.97, 131.64 (C-Ph), 131.50, 131.33,
130.39, 130.17, 129.77 (C-Ph), 124.00, 117.91, 117.74, 114.63
(C-4), 114.47 ppm.
N-[4-Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-car-
bonyl]-N'-ethylurea (5e).
Anal. Calcd. for C23H17N3O3: C, 72.05; H, 4.47; N, 10.96.
Found: C, 72.23; H, 4.48, N, 10.93.
Compound 5e was prepared by the general procedure above
with a reflux time of 4 hours (ethyl urea) resulting in a yield of
48% (0.232 g); mp 195 °C (1-propanol); ir: 3362 cm-1 (NH),
1702 cm-1 (C=O, urea), 1676 cm-1 (C=O), 1625 cm-1 (C=O); 1H-
nmr (deuteriochloroform): d 8.87 (s, 1H, NH), 8.28-7.15 (m,
14H, ArH), 3.32 (m, 2H, N-CH2), 1.63 (b, C-NH), 1.15 ppm (t,
3H, CH3).
2-(3-Nitrophenyl)-3,4,6-triphenyl-2,6-dihydropyrazolo-[3,4-d]-
pyridazin-7-one (8a).
General Procedure.
A milliequimolar mixture of 2 and phenylhydrazine was
refluxed in xylene for 3 hours. After the solvent was removed by
evaporation, the oily residue was treated with ether and the
formed crude product was recrystallized from methanol.
Anal. Calcd. for C26H21N5O5: C, 64.59; H, 4.38; N, 14.49.
Found: C, 64.66; H, 4.39, N, 14.47.
Compound 8a was obtained in 58% yield (0.28 g); mp 186 °C;
1
ir: 1687 cm-1 (C=O); H-nmr (DMSO-d6): d 8.24-6.87 ppm (m,
N-[4-Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-car-
bonyl]-N'-benzylurea (5f).
19H, ArH); 13C-nmr (DMSO-d6): d 157.32 (C=O), 150.18
(C-NO2), 145.95 (C-7a), 143.66 (C-4), 142.59 (C-3), 141.82
(N-PhNO2), 135.79 (N-Ph), 133.50, 132.37, 132.23 (C-Ph),
132.15 (C-Ph), 132.00, 131.77, 130.73, 130.66, 130.59, 129.72,
129.61, 129.23, 127.99, 125.56, 123.09, 119.09 ppm (C-3a).
Anal. Calcd. for C29H19N5O3: C, 71.74; H, 3.94; N, 14.42.
Found: C, 72.01; H, 3.93, N, 14.40.
Compound 5f was prepared by the general procedure above
with a reflux time of 4 hours (benzyl urea) resulting in yield 0.3 g
(55%), mp 212 °C (1-butanol); ir: 3361-3336 cm-1 (NH), 1727
cm-1 (C=O, urea), 1676 cm-1 (C=O), 1625 cm-1 (C=O); 1H-nmr
(DMSO-d6): d 8.96 (s, 1H, NH), 8.43 (t, 1H, NH), 8.28-7.15 (m,
19H, ArH), 4.48 ppm (d, 2H, CH2).
Anal. Calcd. for C31H23N5O5: C, 68.25; H, 4.25; N, 12.84.
Found: C, 68.37; H, 4.24, N, 12.80.
2-(3-Nitrophenyl)-3,4-diphenyl-2,6-dihydropyrazolo-[3,4-d]-
pyridazin-7-one (8b).
4-Benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbo-
nitrile (6).
Compound 8b was prepared according to the general proce-
dure above with a reflux time of 1 hour (hydrazinehydrate)
resulting in 55% yield (0.225 g); mp 302 °C (isopentyl alcohol);
A cold solution of the acid amide 5a (0.412 g, 1 mmole) in a
mixture of DMF (0.7 ml) and SOCl2 (0.15 ml) was stirred at 0-5
°C for 2 hours. After heating to room temperature, stirring was
continued overnight, then the reaction mixture was poured over
crushed ice and the separated solid isolated by filtration, washed
with water and crystallized from 1-propanol to give 0.229 g
(58%) of 6 mp 190 °C; ir: 2263 cm-1 (CN), 1676 cm-1 (C=O);
13C-nmr (deuteriochloroform): d 189.81 (C=O), 150.37
(C-NO2), 147.56 (C-3), 141.05 (C-5), 138.43 (N-PhNO2),
135.62, 132.81, 132.45, 132.26, 132.14, 131.59, 131.02, 130.39,
129.63 (C-Ph), 128.28 (C-Ph), 127.32 (C-4), 125.72, 122.47,
113.99 ppm (CN).
1
ir :3300-2750 cm-1 (b, NHDOH), 1679.3 cm-1 (C=O); H-nmr
(DMSO-d6): d 12.64 (b, 1H, OH), 8.29-6.99 ppm (m, 14H, ArH);
13C-nmr (DMSO-d6): d 157.75 (C=O), 149.41 (C-NO2), 145.31
(C-7a), 144.29 (C-4), 142.53 (C-3), 141.29 (N-PhNO2), 135.92,
134.21, 132.45, 132.35, 131.04 (C-Ph), 130.08, 129.98 (C-Ph),
129.98, 129.13, 125.60, 123.00, 118.63 ppm (C-3a).
Anal. Calcd. for C23H15N5O3: C, 67.48; H, 3.69; N, 17.11.
Found: C, 67.54; H, 3.68, N, 17.15.
2-(3-Aminophenyl)-3,4,6-triphenyl-2,6-dihydropyrazolo-
[3,4-d]pyridazin-7-one (8c).
a) Compound 8c was prepared according to the general proce-
dure above with a reflux time of 4 hours (phenylhydrazine)
resulting in 45% yield (0.205 g); mp 253 °C (1-butanol); ir: 3453-
3358 cm-1 (NH2), 1685.43 cm-1 (C=O); 1H-nmr (deuteriochloro-
form): d 7.77-6.42 (m, 19H, ArH), 3.79 ppm (b, 2H, NH2);
13C-nmr (deuteriochloroform): d 157.72 (C=O), 149.47 (C-
NH2), 146.23 (C-7a), 145.08 (C-4), 143.91 (C-3), 141.97 (N-Ph),
141.78 (N-PhNH2), 136.23, 132.42, 131.51 (C-Ph), 131.31,
131.13 (C-Ph), 130.96, 130.63, 130.49, 130.04, 129.62, 129.43,
128.28, 118.51 (C-3a), 117.60, 117.49, 114.59 ppm.
Anal. Calcd. for C23H14N4O3: C, 70.05; H, 3.58; N, 14.21.
Found: C, 70.25; H, 3.57, N, 14.18.
1-(3-Aminophenyl)-4-benzoyl-5-phenyl-1H-pyrazole-3-car-
boxylic Acid (7).
A cold solution of sodium polysulphide (10 mmoles), prepared
from Na2S•9H2O (2.5 g, 10 mmoles) with powdered sulphur (0.7
g) in boiling water, was added into the solution of 2 (4.13 g, 10
mmoles) in methanol with stirring. The reaction mixture was
refluxed on a steam-bath for 60 minutes. After cooling and acidi-
fication with concentrated HCl, it was refluxed again for 30 min-
utes to precipitate sulphur, cooled and the seperated solid was fil-
Anal. Calcd. for C29H21N5O: C, 76.47; H, 4.65; N, 15.37.
Found: C, 76.40; H, 4.66, N, 15.34.

·
874
A. S¸ener, R. Kasimogullari, M. K. S¸ener, I. Bıldırıcı and Y. Akçamur
Vol. 39
0.23 g (50%), mp 239 °C; ir: 3361 cm-1 (NH), 1676 cm-1 (C=N);
13C-nmr (deuteriochloroform): d 156.83 (C-2', pyr.), 154.73
(C=N-), 150.69 (C-6', pyr.), 149.52 (C-NO2), 145.74 (C-3),
145.08 (C-5), 142.15, 141.09 (C-PhNO2), 139.33, 134.93 (C-Ph),
132.79, 131.65, 131.30, 131.05, 130.00, 129.93, 129.00, 128.43
(C-Ph), 124.89, 124.69, 123.28, 122.38, 118.67 ppm (C-4).
Anal. Calcd. for C27H20N6O2: C, 70.42; H, 4.38; N, 18.25.
Found: C, 70.53; H, 4.39; N, 18.20.
b) Compound 8a (0.485 g, 1 mmole) and Na2SX (1 mmole)
were refluxed in a mixture of ethanol and water on a steam-bath
for about 60 minutes. The crude product which precipitated in
boiling solvents was isolated by filtration and recrystallized from
a mixture of methanol and water to give 0.25 g (55%) of 8c, iden-
tical in mp and ir spectrum with that product obtained as
described above.
2-(3-Aminophenyl)-3,4-diphenyl-2,6-dihydropyrazolo-[3,4-d]-
pyridazin-7-one (8d).
2-(3-Nitrophenyl)-3,4-diphenylpyrazolo[4,3-d][1,2]oxazin-
7(2H)-one (12).
Compound 8d was prepared according to the general proce-
dure above with a reflux time of 4 hours (hydrazinehydrate)
resulting in a 40% yield (0.152 g); mp 301 °C (ethanol); ir:
3437.5-3344.2 cm-1 (NH2) 3300-2750 cm-1 (b, NHDOH),
1668.43 cm-1 (C=O); 13C-nmr (DMSO-d6): d 157.99 (C=O),
151.19 (C-NH2), 145.44 (C-7a), 143.49 (C-4), 141.61 (C-3),
141.38 (N-PhNH2), 136.16, 132.19, 130.78 (C-Ph), 130.53
(C-Ph), 130.06, 129.83, 129.75, 129.45, 129.08, 118.19 (C-3a),
116.17, 115.07, 113.14 ppm.
Pyrazole acid 2 (0.413 g, 1 mmole) and a large excess of
hydroxylamine hydrochloride were heated to about 150-155 °C
on an oil-bath for approximately 30 minutes, until of sublimation
of excess hydroxylamine hydrochloride ceased, with stirring.
After cooling to room temperature, the resulting mixture was first
washed with water then treated with ether, the crude product
which was formed in this way was recrystallized from a mixture
of ethanol and water to give 0.267 g (65%) of pure 12, mp 149
°C; ir: 1696 cm-1 (C=O); 13C-nmr (deuteriochloroform): d
161.33 (C=O), 149.65 (C-NO2), 143.90 (C-7a), 143.09 (C-4),
141.33 (C-3), 138.93 (N-PhNO2), 133.32 (C-Ph), 132.20, 131.99,
131.75, 131.45, 131.18, 130.25, 129.44 (C-Ph), 125.59, 123.67,
121.00, 120.90, 120.52 (C-3a).
Anal. Calcd. for C23H17N5O: C, 72.81; H, 4.52; N, 18.46.
Found: C, 72.68; H, 4.51, N, 18.51.
2-(3-Nitrophenyl)-3,4-diphenyl-2H-pyrazolo[3,4-d]pyridazin-7-
yl-amine (9).
Compound 6 (0.394 g, 1 mmole) and anhydrous hydrazine
(0.032 g, 1 mmole) were refluxed in 1-butanol containing a cat-
alytic amount of metallic sodium on an oil-bath for 8 hours. The
precipitate formed in boiling 1-butanol was isolated by filtration
and recrystallized from methanol to give 0.143 g (35%) of 9, mp
281 °C; ir: 3483-3182 cm-1 (NH), 1683 cm-1 (C=NH); 13C-nmr
(DMSO-d6): d 157.84 (C=NH), 145.41 (C-NO2), 145.08 (C-7a),
142.25 (C-3), 140.88 (N-PhNO2), 135.93 (C-4), 132.41, 131.70
(C-Ph), 131.34, 131.04, 130.90 (C-Ph), 130.08, 129.69, 129.68,
129.14, 129.00, 128.95, 127.98, 122.00 ppm (C-3a).
Anal. Calcd. for C23H14N4O4: C, 67.31; H, 3.44; N, 13.65.
Found: C, 67.11; H, 3.44, N, 13.64.
2-(2-Methylquinolin-7-yl)-3,4-diphenyl-2,6-dihydropyrazolo-
[3,4-d]-pyridazin-7-one (13a).
General Procedure.
To the cold solution of compound 8d (1 mmole) in concen-
trated HCl (15-20 ml) was added acetaldehyde (0.1 ml, 2
mmoles) and nitrobenzene (0.123 g, 1 mmole), with stirring and
the stirring continued at room temperature for 60 minutes. Then,
the reaction mixture was refluxed on a steam-bath for 12 hours
with stirring and filtered. The filtrate was made alkaline by
adding concentrated aqueous ammonia and kept in a refrigerator
overnight. The separated solid was isolated by filtration, washed
with water and recrystallized from acetone. The yield 0.193 g
(45%), mp 287 °C; ir: 3435.52 cm-1 (NHDOH), 1673.48 cm-1
(C=O); 1H-nmr (DMSO-d6): d 12.68 (b, NHDOH), 8.30 (d,
J=8.4 Hz, 1H, H-4'), 8.00 (d, J=8.8 Hz, 1H, H-6'), 7.91 (m, 1H,
J<2, H-8'), 7.73-6.80 (m, 12H, ArH), 2.64 ppm (s, 3H, CH3);
13C-nmr (DMSO-d6): d 162.30 (C=O), 157.94 (C-2'), 148.23 (C-
8'a), 145.43 (C-7a), 144.00 (C-4), 142.39 (C-3), 140.99 (N-
Quin), 137.82, 136.03, 132.39 (C-Ph), 131.99 (C-Ph), 130.79,
130.62, 130.07, 129.65, 129.51, 129.14, 127.71, 127.29, 125.44,
25.22, 118.54 (C-3a), 26.52 ppm (CH3).
Anal. Calcd. for C23H16N6O2 : C, 67.64; H, 3.95; N, 20.58.
Found: C, 67.55; H, 3.95, N, 20.53.
1-(3-Nitrophenyl)-5-phenyl-4-[phenyl-(pyridin-2-yl-hydrazono)-
methyl]-1H-pyrazole-3-carboxylic Acid (10).
Compound 2 (0.413 g, 1 mmole) and 0.109 g (1 mmole) of
2-hydrazinopyridine were refluxed in xylene on an oil-bath for 4
hours. The solvent was evaporated and the remaining oily residue
was treated with ether to give a crude product which was recrystal-
lized from ethanol, yield 0.479 g (95%), mp 231 °C (decomp.); ir:
3437.53 cm-1 (NH), 1651.25 cm-1 (C=N-), 1609.1, 1576.33
(COO); 1H-nmr (deuteriochloroform): d 10.20 (b, acidic proton),
8.92 (b, 1H, NH), 8.18-6.57 ppm (m, 18H, ArH); 13C-nmr (deu-
teriochloroform): d 167.06 (COO), 157.90 (C-2', pyr.), 149.64
(C-NO2), 146.13 (C=N-), 145.56 (C-3), 145.10 (C-6', pyr.), 143.34
(C-5), 142.86, 141.49 (N-PhNO2), 141.12, 136.08, 136.01, 131.37,
131.28 (C-Ph), 131.21, 130.65, 130.24, 130.11 (C-Ph), 128.57,
124.42, 122.74, 116.94, 116.60, 111.44 ppm (C-4).
Anal. Calcd. for C27H19N5O: C, 75.51; H, 4.46; N, 16.31.
Found: C, 75.78; H, 4.44, N, 16.28.
2-(2-Methylquinolin-7-yl)-3,4,6-triphenyl-2,6-dihydropyra-
zolo[3,4-d]pyridazin-7-one (13b).
Anal. Calcd. for C28H20N6O4: C, 66.66; H, 4.00; N, 16.66.
Found: C, 66.47; H, 4.01, N, 16.69.
Compound 13b was prepared according to the general proce-
[1-(3-Nitrophenyl)-5-phenyl-1H-pyrazol-4-yl](phenyl)-
methanone-N-pyridin-2-yl Hydrazone (11).
dure above with a reflux time of 8 hours resulting in 40% yield
1
(0.2 g); mp 265 °C (methanol); ir: 1676 cm-1 (C=O); H-nmr
Compound 10 (0.46 g, 1 mmole) was heated to 235-240 °C on
an oil-bath for about 30 minutes without any solvent. After cool-
ing to room temperature, the residue was treated with ether to
give crude product which was recrystallized from ethanol, yield
(deuteriochloroform): d 8.05 (d, J=8.4 Hz, 1H, H-4'), 7.98 (d,
J=9.2 Hz, 1H, H-8'), 7.88 (m, J<2 Hz, 1H, H-6'), 7.74-6.90 ppm
(m, 17H, ArH), 2.69 ppm (s, 3H, CH3); 13C-nmr (deuteriochloro-
form): d 162.50 (C=O), 157.70 (C-2'), 149.44 (C-8'a), 146.24

Sep-Oct 2002
Studies on the Reactions of Cyclic Oxalyl Compounds With Hydrazines or Hydrazones
875
Herbicides, 13th. Ed., Thomson Publications, California-USA, 1997,
pp 268-269-278; [b] M. Londershausen, Pestic. Sci., 48, 269, (1996).
[7a] V. V. Badiger and S. C. Bennur, Indian J. Heterocyclic.
Chem., 6, 63, (1996); [b] H. S. Chen and Z. M. Li, Chem. J. Chinese
Univ., 19, 572, (1998).
[8] M. Kurowaski, A. Dunky and M. Geddawi, Eur. J. Clin.
Pharmacol., 307, 31, (1987).
[9] F. Lepage, B. Hublot, Eur. Pat. Appl. EP, 459, 887; Chem.
Abstr., 116, 128917, (1992).
(C-7a), 145.06 (C-4), 143.87 (C-3), 141.96 (N-Quin), 141.78 (N-
Ph), 136.18, 135.73, 132.51 (C-Ph), 132.41, 131.33, 131.18,
130.96, 130.62, 130.50, 130.29, 130.04 (C-Ph), 129.87, 129.62,
129.44, 128.08, 125.28, 117.61, 114.55 ppm (C-3a), 27.32 ppm
(CH3).
Anal. Calcd. for C33H23N5O: C, 78.40; H, 4.59; N, 13.85.
Found: C, 78.61; H, 4.58, N, 13.88.
Acknowledgment.
[10] D. M. Bailey, P. E. Hansen, A. G. Hlavac, E. R. Baizman,
J. Pearl, A. F. Defelice and M. E. Feigenson, J. Med. Chem., 28, 256,
(1985).
The authors thank the research fund of Y.Yıl University for finan-
cial support.
[11] R. H. Wiley, P. Wiley, Pyrazolones, Pyrazolidones and
Derivatives, John Wiley and sons, New York, 1964, pp. 102.
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