Synthesis of new derivatives of 1-(3-Aminophenyl)-4-benzoyl-5-phenyl-1H- pyrazole-3-carboxylic acid

Article abstract of DOI:10.2298/JSC101018135K

1-(3-Aminophenyl)-4-benzoyl-5-phenyl-1H-pyrazole-3-carboxylic acid (1) was synthesized according to the literature.¹ 2-(3-Aminophenyl)-2,6- dihydro-3,4-diphenyl-7H-pyrazolo[3,4-d]pyridazin-7-one (5) was obtained by the cyclocondensation reactio

Full text of DOI:10.2298/JSC101018135K

J. Serb. Chem. Soc. 75 (12) 1625–1635 (2010)
JSCS–4082
UDC 547.77+547.857.8+547.852+
547–304.4:66.095.3.095.252
Original scientific paper
Synthesis of new derivatives of 1-(3-aminophenyl)-4-benzoyl-
-5-phenyl-1H-pyrazole-3-carboxylic acid
1
1
1
*
RAHMI KASIMOGULLARI , BELMA ZENGIN , MAKBULE MADEN ,
SAMET MERT1 and CAVIT KAZAZ2
1Department of Chemistry, Art and Science Faculty, Dumlupinar University, Kutahya and
2Department of Chemistry, Science Faculty, Atatürk University, Erzurum, Turkey
(Received 18 October, revised 6 December 2010)
Abstract: 1-(3-Aminophenyl)-4-benzoyl-5-phenyl-1H-pyrazole-3-carboxylic acid
(1) was synthesized according to the literature.1 2-(3-Aminophenyl)-2,6-dihyd-
ro-3,4-diphenyl-7H-pyrazolo[3,4-d]pyridazin-7-one (5) was obtained by the
cyclocondensation reaction of 1 with hydrazine hydrate. New pyrazole deri-
vatives of compounds 1 and 5 were synthesized by their reaction with β-diketo-
nes, β-ketoesters, β-naphthol, phenol and various other reagents. The structures
1
of the synthesized compounds were characterized by H-NMR, 13C-NMR, IR
and mass spectroscopy, as well as elemental analysis.
Keywords: pyrazole-3-carboxylic acid; pyridazin; diazonium salts; cyclocon-
densation.
INTRODUCTION
It is known that pyrazole derivatives having heteroaryl groups attached as
substituents exhibit significant biological activity and that some pyrazolo-pyri-
dazine compounds containing heteroaryl groups are used to treat many disea-
2–4
ses.
On the other hand, diazonium salts have been the focus of great interest
for a long time since they play a crucial role in organic syntheses and are com-
5,6
mercially important coloring agents.
Arene diazonium groups not only couple to activated aromatic carbon atoms,
but may also undergo coupling reactions with aliphatic compounds containing
active methylene groups. The facilitated abstraction of the acidic proton in β-di-
ketones and β-ketoesters leads to the formation of a resonance stable anion,
which can, therefore, behave as a good nucleophile. Thus, the coupling of this
anion with aryl diazonium chlorides gives 2-arylazo-hydrazo derivatives, from
which azo-hydrazo substituted heterocyclic compounds can be obtained. These
*Corresponding author. E-mail: rahmikasimoglu@hotmail.com
doi: 10.2298/JSC101018135K
1625
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1626
KASIMOGULLARI et al.
compounds play a significant role in the dye industry and, in addition, enable the
synthesis of heterocyclic compounds with different biological activities. Hence,
these coupling products are among the most investigated groups of com-
2,7–9
pounds.
Commencing from these facts, an attempt was made to expand the research
on the preparation of different derivatives of pyrazole carboxylic acid com-
pounds, which are biologically very important and exhibit pharmaceutical acti-
2,5,7
vities.
RESULTS AND DISCUSSION
In this study, first the diazonium salts from compounds 1 and 5, which con-
2,5,6
tain aromatic primary amine groups, were prepared in situ (Schemes 1 and 2).
For this purpose, compounds 1 and 5 were dissolved in an ethanol–water mixture (50
%) containing sodium acetate and the temperature was kept constant (0–5 °C).
Three moles of acid were used per mole of the amine compound in the
10,11
diazotization reaction.
In the experiments, different pH ranges were tested
and the best yield was observed in the pH range 3.5−4.0.
O
O
Ph
OH
N
Ph
N
NH2
1
HCl
NaNO2
CH3COONa
C
0 o
O
O
Ar
X
R1
R2
O
O
O
O
O
O
Ph
OH
Ph
OH
OH
Ph
N
Ph
N
N
N
Ph
Ph
N
N
O
N
O
N
N
R1
N
Ar
X
H
2
3
4
R2
R1
R2
2
C6H5
a
b
c
d
e
OC2H5
CH3
OC(CH3)3
OC2H5
C6H5
4
a
b
c
d
C6H5
CH3
Ar
X
3
Br
CN
I
a
OH
OH
CH3
C6H5
OH
b
CH3
f
CH3
Scheme 1. The synthesis of compounds 2a–f, 3a–b and 4a–d.
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PYRAZOLE CARBOXYLIC ACIDS
1627
In this study, as a result of the coupling reactions of 1 with various β-dicar-
bonyl compounds that contained an active aliphatic C–H group, derivatives 2a–f
were synthesized in 42−86 % yield. In all these compounds, due to the unpaired
electron pairs on the nitrogen atoms, the proton that transferred to the base was
subject to resonance. Thus, the products formed may be in the form of azo
12–17
(–N=N–) or hydrazo (–NH–N=C) tautomeric structures.
However, in the
1
present study, an examination of the H-NMR and IR spectra clearly revealed
that the signals belonging to compounds 2a–d at δ 11.90–11.20 ppm and in the
–1
range of 3475–3414 cm stem from the hydrogen on the nitrogen in the cor-
responding hydrazo forms (–NH–N=C) (Fig. 1).
O
O
O
O
OH
Ph
OH
Ph
N
N
Ph
Ph
N
N
O
O
N
O
N
N
R1
N
R1
H
R2
O
R2
Fig. 1. Possible tautomeric structures for compounds 2a–f.
On reaction of compound 1 with phenol and β-naphthol, derivatives 3a (74 %
yield) and 3b (45% yield) were obtained, respectively. The structures of the com-
pounds were verified by their spectral data (see EXPERIMENTAL). An examina-
tion of their resonance structures revealed that although the aryl diazonium ion,
bearing partial positive charges on both nitrogen atoms, exhibits weak electro-
philic character, it normally formed azo compounds in the diazo coupling reac-
tion with the quite active aromatic compounds phenol and β–naphthol, giving the
corresponding diazo compounds 3a and 3b. The mechanism of coupling reac-
tions is the same as those of electrophilic aromatic replacement reactions. In the
first step, the electrophile binds to the carbon of the nucleophilic substrate
through a covalent bond and an intermediate product is formed. Subsequently, a
proton transfer to the base occurs. In the phenol and β-naphthol derivatives,
coupling occurs almost exclusively in the para position if the para position is
free. If the para position is occupied, then coupling occurs in the ortho posi-
18,19
tion.
20
In the syntheses, the Sandmeyer reaction was employed, in which Cu(I)
−
−
salts as catalysts together with the potassium salts of Br and CN were used to
20
obtain derivatives 4a and b in 46 and 88 % yield, respectively. For replacement
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1628
KASIMOGULLARI et al.
−
by I , having a strong nucleophilic character, the KI alone was sufficient without
any necessity for a catalyst and thus, compound 4c was obtained. On heating the
diazo compound with H O to 100 °C, derivative 4d was obtained in high yield
2
(85 %). In addition, the cyclocondensation of compound 1 with anhydrous hyd-
1,21
razine hydrate yielded a pyrazolo[3,4-d]pyridazin-7-one (5).
During the reac-
tion of intermediary 5 with different β-diketones, compounds 6a–c were ob-
tained. Derivatives 7a and 7b were synthesized by the coupling reactions of 5
with phenol and β-naphthol, respectively (Scheme 2).
N
NH
O
O
N
N
Ph
O
Ph
OH
OH
Ph
N
N
N
Ph
Ph
NH2-NH2
Ph
N
N
N
NH2
NH2
NH2
5
1
HCl
NaNO2
CH3COONa
0 oC
O
O
Ar
R1 R2
R1
R2
6
a
NH
N
N
CH3
C6H5
CH3
CH3
N
NH
N
O
Ph
b
c
C6H5
C6H5
Ph
O
Ph
N
Ph
Ar
7
a
N
O
OH
OH
N
N
R1
N
b
N
Ar
H
O
R2
6
7
Scheme 2. The synthesis of compounds 6a–c and 7a–b.
The yields, melting points, analytic data and spectral data of the prepared
compounds are given below.
4-Benzoyl-1-(3-(2-(1-benzoyl-2-ethoxy-2-oxoethylidene)hydrazinyl)phenyl)-
-5-phenyl-1H-pyrazole-3-carboxylic acid (2a). Yield: 42 %; m.p. 147–148 °C.
Anal. Calcd. for C H N O : C, 69.62; H, 4.47; N, 9.55 %. Found: C, 69.45; H,
34 26
4 6
−1
4.58; N, 9.50 %. IR (KBr, cm ): 2500−3500 (COOH), 3060 (Ar CH), 2901 and
2835 (aliphatic CH), 1724 and 1666 (C=O), 1607−1463 (Ar C=C and C=N). H-
1
-NMR (400 MHz, DMSO–d , δ / ppm): 12.70 (1H, br s, COOH), 11.90 (1H, br
6
s, NH−N=C), 7.20−7.90 (19H, m, ArH), 4.30 (2H, q, J = 7.1 Hz, OCH ), 1.30
2
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PYRAZOLE CARBOXYLIC ACIDS
1629
13
(3H, t, J = 7.0 Hz, CH ). C-NMR (100 MHz, DMSO–d , δ / ppm): 191.65 and
3
6
189.27 (benzoyl C=O), 163.46 (ester C=O), 162.75 (acid C=O), 145.60
(NH−N=C), 142.85 (pyrazole C–3), 61.79 (OCH ), 14.33 (CH ), 140.13, 138.34,
2
3
137.20, 133.67, 133.08, 130.38, 130.04, 129.83, 129.70, 129.65, 129.57, 129.53,
129.01, 128.96, 128.73, 128.61, 128.36, 128.25, 123.31, 120.35.
4-Benzoyl-1-(3-(2-(1-benzoyl-2-oxopropylidene)hydrazinyl)phenyl)-5-phe-
nyl-1H-pyrazole-3-carboxylic acid (2b). Yield: 86 %; m.p. 126–128 °C. Anal.
Calcd. for C H N O : C, 71.21; H, 4.35; N, 10.07 %. Found: C, 69.32; H,
33 24
4 5
−1
4.65; N, 9.57 %. IR (KBr, cm ): 2600−3500 (COOH), 3061 (Ar CH), 2950
(aliphatic CH), 1680 and 1665 (C=O), 1601−1461 (Ar C=C and C=N). H-NMR
1
(400 MHz, DMSO–d , δ / ppm): 13.09 (1H, br s, COOH), 11.23 (1H, br s,
6
13
NH−N=C), 6.90−7.90 (19H, m, ArH), 2.50 (3H, s, CH ). C-NMR (100 MHz,
3
DMSO–d , δ / ppm): 196.49 (acetyl C=O), 195.43 and 191.30 (benzoyl C=O),
6
162.78 (acid C=O), 144.32 (NH−N=C), 143.09 (pyrazole C–3), 25.40 (CH ),
3
140.13, 139.97, 138.09, 135.93, 133.93, 130.63, 130.02, 129.81, 129.53, 129.33,
129.21, 129.14, 129.04, 128.98, 128.91, 128.40, 128.28, 127.41, 123.50, 112.19;
MS (CI) (m/z): 557.0 (M+1).
4-Benzoyl-1-(3-(2-(1-(tert-butoxycaronyl)-2-oxopropylidene)hydrazinyl)phe-
nyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (2c). Yield: 49 %; m.p. 230–231 °C.
Anal. Calcd. for C H N O : C, 67.38; H, 5.11; N, 10.14 5. Found: C, 67.25; H,
31 28
4 6
−1
5.15; N, 10.17 %. IR (KBr, cm ): 2500−3500 (COOH), 3415 (NH), 3059 (Ar
CH), 2900 and 2835 (aliphatic CH), 1718 and 1666 (C=O), 1605−1461 (Ar C=C
1
and C=N). H-NMR (400 MHz, DMSO–d , δ / ppm): 12.70 (1H, br s, COOH),
6
11.20 (1H, br s, NH−N=C), 6.90−7.90 (14H, m, ArH), 2.60 (9H, s, OC(CH ) ),
3 3
13
1.50 (3H, s, CH ). C-NMR (100 MHz, DMSO–d , δ / ppm): 195.47 (acetyl
3
6
C=O), 191.86 (benzoyl C=O), 185.38 (acid C=O), 163.86 (ester C=O), 146.96
(NH−N=C), 145.31 (pyrazole C–3), 82.63 (OC(CH ) ), 28.39 (C(CH ) ), 21.58
3 3
3 3
(CH ), 142.54, 140.18, 138.49, 135.70, 133.52, 130.60, 130.32, 129.97, 129.48,
3
129.20, 128.95, 128.77, 127.50, 123.19, 121.95, 115.12.
4-Benzoyl-1-(3-(2-(1-(ethoxycaronyl)-2-oxopropylidene)hydrazinyl)phenyl)-
-5-phenyl-1H-pyrazole-3-carboxylic acid (2d). Yield: 47 %; m.p. 240–242 °C.
Anal. Calcd. for C H N O : C, 66.41; H, 4.61; N, 10.68 %. Found: C, 66.29;
29 24
4 6
−1
H, 4.65; N, 10.65 %. IR (KBr, cm ): 2600−3500 (COOH), 3415 (NH), 3060 (Ar
CH), 2883 (aliphatic CH), 1665 (C=O), 1609–1460 (Ar C=C and C=N). H-
1
-NMR (400 MHz, DMSO–d , δ / ppm): 12.80 (1H, br s, COOH), 11.60 (1H, br
6
s, NH−N=C), 7.80−7.10 (14H, m, ArH), 4.30 (2H, q, J = 7.1 Hz, OCH ), 2.26
2
13
(3H, s, CH ), 1.26 (3H, t, J = 7.1 Hz, OCH CH ). C-NMR (100 MHz, DMSO-d ,
3
2
3
6
δ / ppm): 195.47 (acetyl C=O), 191.86 (benzoyl C=O), 185.38 (acid C=O),
163.86 (ester C=O), 145.90 (NH−N=C), 144.21 (pyrazole C–3), 60.93 (OCH )
2 ,
24.40 (O=CCH ), 14.20 (CH CH ), 142.35, 139.15, 138.45, 135.50, 134.01,
3
2
3
130.65, 130.40, 130.12, 129.45, 129.32, 128.85, 128.53, 127.60, 123.29, 112.10.
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KASIMOGULLARI et al.
4-Benzoyl-1-(3-(2-(1-benzoyl-2-oxo-2-phenylethylidene)hydrazinyl)phenyl)-
5-phenyl-1H-pyrazole-3-carboxylic acid (2e). Yield: 55 %; m.p. 205–206 °C.
Anal. Calcd. for C H N O : C, 73.78; H, 4.24; N, 9.06 %. Found: C, 73.67; H,
38 26
4 5
−1
4.30; N, 9.11 %. IR (KBr, cm ): 2500−3500 (COOH), 3422 (NH), 3059 (Ar
CH), 1725 and 1664 (C=O), 1599–1460 (Ar C=C and C=N). H-NMR (400
1
MHz, DMSO–d , δ / ppm): 13.70 (1H, br s, COOH), 13.20 (1H, br s, NH−N=C),
6
13
7.75−7.15 (24H, m, ArH). C-NMR (100 MHz, DMSO–d , δ / ppm): 197.46,
6
196.79 and 191.28 (benzoyl C=O), 162.78 (acid C=O), 143.43 (NH–N=C),
143.21 (pyrazole C–3), 113.60 (pyrazole C–4), 143.12, 142.99, 140.13, 139.96,
138.09, 134.53, 133.94, 130.71, 130.49, 130.11, 130.04, 129.82, 129.57, 129.13,
129.03, 128.97, 128.45, 128.27, 128.18, 123.48, 122.38, 118.30, 116.96.
1-(3-(2-(1-Acetyl-2-oxo-propylidene)hydrazinyl)phenyl)-4-benzoyl-5-phenyl-
-1H-pyrazole-3-carboxylic acid (2f). Yield: 55 %; m.p. 222–224 °C. Anal. Calcd.
for C H N O : C, 68.01; H, 4.48; N, 11.33 %. Found: C, 67.89; H, 4.53; N,
28 22
4 5
−1
11.35 %. IR (KBr, cm ): 2500−3500 (COOH), 3422 (NH), 3059 (Ar CH), 1725
and 1664 (C=O), 1599−1460 (Ar C=C and C=N); H-NMR (400 MHz, DMSO–d ,
1
6
δ / ppm): 13.75 (1H, br s, COOH), 13.15 (1H, br s, NH−N=C), 7.80−7.20 (14H,
13
m, ArH), 2.45 and 2.29 (6H, s, 2CH ). C-NMR (100 MHz, DMSO–d , δ / ppm):
3
6
197.49 and 196.78 (acetyl C=O), 191.25 (benzoyl C=O), 162.70 (acid C=O),
143.43 (NH−N=C), 143.19 (pyrazole C–3), 113.57 (pyrazole C-4), 31.67 and
26.88 (CH ), 142.99, 140.11, 138.06, 134.59, 133.94, 130.72, 130.02, 129.81,
3
129.54, 129.13, 129.02, 128.16, 123.48, 122.36, 116.96. MS (CI) (m/z): 495.0
(M+1).
4-Benzoyl-1-(3-((4-hydroxyphenyl)diazenyl)phenyl)-5-phenyl-1H-pyrazole-
-3-carboxylic acid (3a). Yield: 74 %; m.p. 286–288 °C. Anal. Calcd. for
C H N O : C, 71.30; H, 4.13; N, 11.47 %. Found: C, 71.17; H, 4.18; N, 11.45 %.
29 20
4 4
−1
IR (KBr, cm ): 2700−3600 (COOH), 3416 (NH), 3060 (Ar CH), 1663 (C=O),
1607−1494 (Ar C=C and C=N), 1354 (ArOH); H-NMR (400 MHz, DMSO–d ,
1
6
δ / ppm): 12.95 (1H, br s, COOH), 7.85−7.15 (18H, m, ArH), 6.95 (1H, d, J = 8.7
13
Hz, ArOH). C-NMR (100 MHz, DMSO–d , δ / ppm): 192.38 (benzoyl C=O),
6
164.92 (acid C=O), 150.13 (C=C−OH), 149.50 (ArC−N=N), 145.15 (pyrazole
C–3), 96.37 (pyrazole C–4), 143.25, 141.87, 140.34, 138.82, 135.40, 133.24,
130.75, 130.41, 130.15, 129.86, 129.44, 129.18, 128.97, 128.82, 128.40, 122.99,
116.74.
4-Benzoyl-1-(3-((2-hydroxynaphthalen-1-yl)diazenyl)phenyl)-5-phenyl-1H-
-pyrazole-3-carboxylic acid (3b). Yield: 45 %; m.p. 261–263 °C. Anal. Calcd. for
C H N O : C, 73.60; H, 4.12; N, 10.40 %. Found: C, 73.48; H, 4.19; N, 10.47 %.
33 22
4 4
−1
IR (KBr, cm ): 2500−3600 (COOH), 3415 (NH), 3064 (Ar CH), 1665 (C=O),
1609–1493 (Ar C=C and C=N), 1354 (ArOH). H-NMR (400 MHz, DMSO–d ,
1
6
δ / ppm): 15.54 (1H, s, ArOH), 13.30 (1H, br s, COOH), 8.26−6.86 (20H, m,
13
ArH). C-NMR (100 MHz, DMSO–d , δ / ppm): 191.27 (benzoyl C=O), 171.37
6
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PYRAZOLE CARBOXYLIC ACIDS
1631
(acid C=O), 162.77 (ArC−OH), 145.47 (pyrazole C–3), 143.47, 143.37, 141.33,
140.28, 138.12, 133.96, 132.93, 130.87, 130.15, 129.92, 129.90, 129.62, 129.35,
129.33, 129.14, 129.05, 128.31, 128.29, 126.67, 124.63, 124.50, 123.64, 121.99,
119.83, 114.90. MS (CI) (m/z): 539.0 (M+1).
4-Benzoyl-1-(3-bromophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (4a).
Yield: 46 %; m.p. 273–274 °C. Anal. Calcd. for C H BrN O : C, 61.76; H,
23 15
2 3
−1
3.38; N, 6.26 %. Found: C, 61.55; H, 3.45; N, 6.22 %. IR (KBr, cm ):
2500−3500 (COOH), 3062 (Ar CH), 1666 (C=O), 1611–1448 (Ar C=C and
1
C=N). H-NMR (400 MHz, DMSO–d , δ / ppm): 13.20 (1H, br s, COOH), 7.82–
6
13
–7.21 (14H, m, ArH). C-NMR (100 MHz, DMSO–d , δ / ppm): 190.52 (ben-
6
zoyl C=O), 165.28 (acid C=O), 144.47 (pyrazole C–3), 142.55, 141.30, 139.67,
138.25, 137.64, 134.06, 130.85, 130.26, 129.60, 129.30, 129.25, 129.08, 126.27,
123.75, 123.40, 122.50.
4-Benzoyl-1-(3-cyanophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (4b).
Yield: 88 %; m.p. 255–256 °C. Anal. Calcd. for C H N O : C, 73.27; H, 3.84;
24 15
3 3
–1
N, 10.68 %. Found: C, 73.15; H, 3.87; N, 10.74 %. IR (KBr, cm ): 2800−3600
(COOH), 3061 (Ar CH), 2130 (CN), 1661 (C=O), 1601–1426 (Ar C=C and
1
C=N). H-NMR (400 MHz, DMSO–d , δ / ppm): 13.80 (1H, br s, COOH),
6
13
7.95−6.70 (14H, m, ArH). C-NMR (100 MHz, DMSO–d , δ / ppm): 190.52,
6
(benzoyl C=O), 165.35, (acid C=O), 144.48 (pyrazole C–3), 116.13 (CN),
143.25, 141.12, 139.68, 138.82, 137.63, 134.06, 130.53, 130.27, 129.62, 129.30,
129.08, 128.97, 127.88, 126.26, 123.07, 122.92.
4-Benzoyl-1-(3-iodophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (4c).
Yield: 70 %; m.p. 265–266 °C. Anal. Calcd. for C H IN O : C, 55.89; H,
23 15
2 3
−1
3.06; N, 5.67 %. Found: C, 55.78; H, 3.11; N, 5.64 %. IR (KBr, cm ):
2500−3500 (COOH), 3059 (Ar CH), 1664 (C=O), 1608−1427 (Ar C=C and
1
C=N). H-NMR (400 MHz, DMSO–d , δ / ppm): 13.10 (1H, br s, COOH),
6
13
7.80−7.17 (14H, m, ArH). C-NMR (100 MHz, DMSO–d , δ / ppm): 191.28
6
(benzoyl C=O), 162.79 (acid C=O), 143.38 (pyrazole C–3), 95.20 (ArC–I),
139.96, 138.09, 133.92, 130.49, 130.10, 129.80, 129.56, 129.12, 128.97, 128.28,
127.10, 124.95, 123.44, 118.66, 107.62. MS (CI) (m/z): 495.0 (M+1).
4-Benzoyl-1-(3-hydroxyphenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (4d).
Yield: 85 %; m.p. 235–237 °C. Anal. Calcd. for C H N O : C, 71.87; H, 4.20;
23 16
2 4
−1
N, 7.29 %. Found: C, 71.79; H, 4.26; N, 7.32 %. IR (KBr, cm ): 2700−3600
(COOH), 3059 (Ar CH), 1665 (C=O), 1607−1428 (Ar C=C and C=N). H-NMR
1
(400 MHz, DMSO–d , δ / ppm): 12.70 (1H, br s, COOH), 10.15 (1H, br s, Ar–
6
13
–OH) 7.74−7.15 (14H, m, ArH). C-NMR (100 MHz, DMSO–d , δ / ppm):
6
190.52 (benzoyl C=O), 165.30 (acid C=O), 152.13 (ArC−OH), 144.48 (pyrazole
C–3), 143.22, 139.70, 137.61, 134.07, 130.55, 130.26, 129.89, 129.77, 129.62,
129.08, 128.91, 127.89, 127.41, 123.08, 114.96.
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2-(3-(2-(1-Acetyl-2-oxopropylidene)hydrazinyl)phenyl)-2,6-dihydro-3,4-di-
phenyl-7H-pyrazolo[3,4-d]pyridayin-7-one (6a). Yield: 79 %; m.p. 214–216 °C.
Anal. Calcd. for C H N O : C, 68.56; H, 4.52; N, 17.13 %. Found: C, 68.39;
28 22
6 3
−1
H, 4.54; N, 17.13 %. IR (KBr, cm ): 3456 and 3155 (NH), 3021 (Ar–CH), 2969
(aliphatic CH), 1740 (acetyl C=O), 1663 (amide C=O), 1608−1476 (Ar C=C and
1
C=N). H-NMR (400 MHz, DMSO–d , δ / ppm): 7.31 (1H, br s, NH), 7.56−6.92
6
13
(14H, m, ArH), 2.41 and 2.26 (6H, s, 2CH ). C-NMR (100 MHz, DMSO–d , δ /
3
6
/ ppm): 197.67 and 196.95 (tautomeric acetyl C=O), 156.79 (amide C=O), 144.28
(ArC−NH−N), 143.16 (pyrazole C–3), 140.58 (pyrazole C–5), 31.82 and 27.07
(tautomeric CH ), 134.92, 131.20, 131.17, 129.66, 129.61, 128.96, 128.81,
3
128.77, 128.52, 128.47, 128.41, 128.38, 128.01, 123.17, 117.37, 117.35, 114.30.
2-(3-(2-(1-Benzoyl-2-oxo-2-phenylethylidene)hydrazinyl)phenyl)-2,6-dihyd-
ro-3,4-diphenyl-7H-pyrazolo[3,4-d]pyridayin-7-one (6b). Yield: 88 %; m.p. 234–
–236 °C. Anal. Calcd. for C H N O : C, 74.25; H, 4.26; N, 13.67 %. Found: C,
38 26
6 3
−1
74.12; H, 4.28; N, 13.65 %. IR (KBr, cm ): 3461 and 3156 (NH), 3023 (Ar
CH), 1740 (benzoyl C=O), 1670 (amide C=O), 1601−1475 (Ar C=C and C=N).
1
H-NMR (400 MHz, DMSO–d , δ / ppm): 11.60 (1H, br s, NH), 8.15−6.82
6
13
(24H, m, ArH). C-NMR (100 MHz, DMSO–d , δ / ppm): 186.02 (benzoyl
6
C=O), 156.81 (amide C=O), 144.47 (ArC−NH−N), 144.27 (NH−N=C), 142.78
(pyrazole C–3), 140.88 (pyrazole C–5), 140.32, 135.29, 134.92, 133.69, 133.15,
131.15, 130.76, 130.61, 129.73, 129.61, 129.52, 129.29, 129.17, 128.94, 128.89,
128.79, 128.47, 128.40, 128.31, 128.09, 128.01, 117.37, 93.97.
2-(3-(2-(1-Benzoyl-2-oxopropylidene)hydrazinyl)phenyl)-2,6-dihydro-3,4-di-
phenyl-7H-pyrazolo[3,4-d]pyridayin-7-one (6c). Yield: 50 %; m.p. 256–257 °C.
Anal. Calcd. for C H N O : C, 71.73; H, 4.38; N, 15.21 %. Found: C, 71.58;
33 24
6 3
−1
H, 4.41; N, 15.22 %; IR (KBr, cm ): 3393−3241 (NH), 3067 and 3028 (Ar CH),
1666 (C=O), 1608−1477 (Ar C=C and C=N). H-NMR (400 MHz, DMSO–d , δ /
/ ppm): 12.61 (1H, br s, NH), 7.45−6.92 (19H, m, ArH), 2.47 (3H, s, CH ). C-
1
6
13
3
-NMR (100 MHz, DMSO–d , δ / ppm): 199.50 (acetyl C=O), 188.25 (benzoyl
6
C=O), 156.81 (amide C=O), 144.28 (ArC−NH−N), 142.78 (pyrazole C–3),
140.89 (pyrazole C–5), 20.24 (CH ), 140.33, 134.92, 131.33, 131.17, 130.77,
3
130.61, 129.61, 129.43, 129.09, 128.94, 128.78, 128.54, 128.47, 128.41, 128.01,
127.60, 123.86, 122.57, 117.37, 95.27.
2,6-Dihydro-2-(3-((4-hydroxyphenyl)diazenyl)phenyl)-3,4-diphenyl-7H-py-
razolo[3,4-d]pyridazin-7-one (7a). Yield: 68 %; m.p. 278–279 °C. Anal. Calcd.
for C H N O : C, 71.89; H, 4.16; N, 17.35 %. Found: C, 71.78; H, 4.16; N,
29 20
6 2
−1
17.37 %. IR (KBr, cm ): 3622 (OH), 3446−3160 (NH), 3062 and 3024 (Ar CH),
1662 (amide C=O), 1608−1476 (Ar C=C and C=N). H-NMR (400 MHz,
1
DMSO–d , δ / ppm): 12.54 (1H, br s, NH), 10.31 (1H, s, OH), 7.84−6.91 (18H,
6
13
m, ArH). C-NMR (100 MHz, DMSO–d , δ / ppm): 162.28 (ArC−OH), 156.82
6
(amide C=O), 153.00 and 145.70, (ArC−N=N), 144.29, 142.90, 141.07, 140.39,
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PYRAZOLE CARBOXYLIC ACIDS
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134.91, 131.29, 130.55, 129.72, 128.98, 128.82, 128.56, 128.38, 128.18, 128.01,
125.86, 124.35, 119.31, 117.41, 116.74.
2,6-Dihydro-2-(3-((2-hydroxynaphthalen-1-yl)diazenyl)phenyl)-3,4-diphe-
nyl-7H-pyrazolo[3,4-d]pyridazin-7-one (7b). Yield: 70 %; m.p. 234–235 °C. Anal.
Calcd. for C H N O : C, 74.14; H, 4.15; N, 15.72 %. Found: C, 73.98; H,
33 22
6 2
−1
4.18; N, 15.73 %. IR (KBr, cm ): 3362 and 3170 (NH and OH), 3061 and 3027
(Ar CH), 1665 (amide C=O), 1606−1476 (Ar C=C and C=N). H-NMR (400
1
MHz, DMSO–d , δ / ppm): 8.25 (1H, br s, NH), 5.56−5.23 (1H, br s, OH),
6
13
7.31−6.90 (20H, m, ArH). C-NMR (100 MHz, DMSO–d , δ / ppm): 156.80
6
(amide C=O), 156.68 (ArC−OH), 156.59 and 144.09 (ArC−N=N), 142.54
(pyrazole C–3), 140.66 (pyrazole C–5), 140.29, 140.08, 134.80, 134.67, 131.08,
130.94, 130.87, 130.41, 130.15, 129.75, 129.49, 129.41, 129.23, 128.73, 128.58,
128.26, 128.18, 127.81, 121.95, 122.30, 117.15, 116.84, 113.80.
EXPERIMENTAL
The chemical compounds used in this research were of analytical grade purity and the
solvents were purified using appropriate purifying agents and distillation. All melting points
were measured using a Barnstead Electrothermal 9200 apparatus, and are reported uncor-
rected. The IR spectra of the compounds in KBr pellets were recorded on a Mattson 1000 FT–IR
1
spectrometer. The H-NMR and 13C-NMR spectra were recorded on Bruker DPX–400, (400
MHz), and high performance digital FT–NMR (100 MHz) spectrometers. The mass spectra
were obtained using Varian Mat III 80 eV spectrometer. At the end of the each experiment,
TLC was performed using DC Alufolien Kieselgel 60F/254 Merck and a Camag TLC device.
The elemental analyses were performed on a Leco CHNS–932 instrument.
General procedure for the syntheses of compounds 2a–f, 3a,b, 6a–c and 7a,b
To an aqueous solution of sodium acetate (3.0 g, 37 mmol) was added 2 ml HCl and then
1 mmol the required amine compound. Subsequently, ethanol was added until complete disso-
lution. The prepared solution was cooled to 0 °C on an ice bath. To this solution, a solution of
1.2 mmol NaNO2 in 2 ml water was slowly added taking care that the temperature did not ex-
ceed 5 °C. Thus, the diazonium salt solution was prepared.
An aromatic or β-dicarbonyl compound (1 mmol) was dissolved in a sufficient amount of
ethanol, then cooled and added dropwise into the prepared diazonium salt solution. The re-
sulting colored precipitate was filtered under vacuum and the crude product purified by crys-
tallization from an ethanol–water mixture.
Synthesis of 4-benzoyl-1-(3-bromophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (4a)
CuBr solution was prepared according to the procedure given in literature22 and was
slowly added by stirring continuously into the diazonium salt solution of compound 1 (pre-
pared as described in the general procedure). The resulting colored precipitate was filtered and
purified by crystallization from ethanol–water mixture (9:1).
Synthesis of 4-benzoyl-1-(3-cyanophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (4b)
A CuCN + KCN solution, which had been prepared in accordance with a procedure
given in the literature,22 was cooled to 0 °C and added dropwise under continuous stirring into
a diazonium salt solution of compound 1 (prepared as described in the general procedure).
Following the addition, the cold mixture is allowed to warm up to room temperature. When
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1634
KASIMOGULLARI et al.
the temperature reached about 15 °C, the formation of nitrogen gas began. Then the solution
was placed on a steam bath and heated at 50 °C for 15 min to complete the decomposition.
The pH was adjusted to 3–4 and left for 12 h at room temperature; the resulting precipitate
was filtered under vacuum and dried. The residue was purified by crystallization from an etha-
nol–water mixture (8:2).
Synthesis of 4-benzoyl-1-(3-iodophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (4c)
KI (0.166 g, 1 mmol) was dissolved in 10 ml water and the solution was cooled to 0 °C.
Then, it was added dropwise under continuous stirring into a diazonium salt solution of com-
pound 1, which had been prepared in accordance with the general procedure. The pH was ad-
justed to 3–4 and after standing for 12 h at room temperature, the resulting colored precipitate
was filtered under vacuum and purified by crystallization from an ethanol–water mixture
(8:2).
Synthesis of 4-benzoyl-1-(3-hydroxyphenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid (4d)
A diazonium salt solution of 1 was prepared according to the general procedure. This so-
lution was brought to room temperature and then heated in a steam bath at 100 °C to allow for
the release of nitrogen gas (approximately 15 min). Then some more water was added to the
mixture and the pH adjusted to 4. The solution was kept for about 24 h. The formed yellow-
-colored precipitate was collected by filtration and purified by crystallization from an ethanol–
–water mixture (9:1).
Acknowledgements. This study was funded by The Scientific and Research Council of
Turkey (TUBITAK) and Dumlupinar University, Scientific Research and Project Department.
In addition, the authors would like to thank the Faculty of Science of Atatürk University, Tur-
key, for spectral analysis.
И З В О Д
СИНТЕЗА НОВИХ ДЕРИВАТА 1-(3-AМИНО-ФЕНИЛ)-4-БЕНЗОИЛ-5-ФЕНИЛ-1H-
-ПИРАЗОЛ-3-КАРБОКСИЛНЕ КИСЕЛНЕ
1
1
1
1
2
RAHMI KASIMOGULLARI , BELMA ZENGIN , MAKBULE MADEN , SAMET MERT и CAVIT KAZAZ
1Department of Chemistry, Art and Science Faculty, Dumlupinar University, Kutahya и 2Department of
Chemistry, Science Faculty, Atatürk University, Erzurum, Turkey
Синтеза 4-бензоил-1-(3-аминофенил)-5-фенил-1H-пиразол-3-карбоксилне киселине (1)
извршена је према поступку описаном у литератури.1 Производ 2-(3-аминофенил)-3,4-дифе-
нил-2H-пиразол[3,4-d]пиридазин-7(6H)-oн (5) добијен је циклокондензационом реакцијом
киселине 1 и хидразин-хидрата. Нови пиразолски деривати добијени су реакцијом 1 и 5 са β-
-дикетонима, β-кетоестрима, β-нафтолом, фенолом и другим реагенсима. Добијена једињења
окарактерисана су 1H-NMR, 13C-NMR, ICи MS спектрима и микроанализом.
(Примљено 18. октобра, ревидирано 6. децембра 2010)
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