Synthesis of pyrazoleacrylic acids and their derivatives

Article abstract of DOI:10.14233/ajchem.2013.14670

Various pyrazole acrylic acid derivatives were obtained by the Knoevenagel condensation of pyrazole-4-carbaldehydes with 'active methylene' compounds. In the condensation reaction with malonic acid and cyanoacetic acid, decarboxylation of the resulting ac

Full text of DOI:10.14233/ajchem.2013.14670

Asian Journal of Chemistry; Vol. 25, No. 14 (2013), 7879-7882
http://dx.doi.org/10.14233/ajchem.2013.14670
Synthesis of Pyrazoleacrylic Acids and Their Derivatives
1
1
3,*
2,†
3
4
FARYAL CHAUDHRY , NADIA ASIF , MUHAMMAD NAEEM KHAN , JORGE RIBEIRO , ABDUL QAYYUM ATHER , SAJILA HINA ,
1
5
1
1
1,2,5
MUNAWAR ALI MUNAWAR , MUHAMMAD NASRULLAH , QURA TUL AIN , FARAH SUHAIL and MISBAHUL AIN KHAN
1Institute of Chemistry, University of the Punjab, Quaid-e-Azam Campus, Lahore, Pakistan
2Secao de Quimica, Instituto Militar de Engenharia, Praia Vermelha, Rio de Janeiro, Brasil
3Applied Chemistry Research Centre, PCSIR Laboratories Complex, Lahore, Pakistan
4Food and Biotechnology Research Centre, PCSIR Laboratories Complex, Lahore, Pakistan
5Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
*Corresponding author: E-mail: changwani_1@yahoo.com
†Deceased
(Received: 11 October 2012;
Accepted: 22 July 2013)
AJC-13832
Various pyrazole acrylic acid derivatives were obtained by the Knoevenagel condensation of pyrazole-4-carbaldehydes with ‘active
methylene’ compounds. In the condensation reaction with malonic acid and cyanoacetic acid, decarboxylation of the resulting acids was
not observed. The products were characterized through spectroscopic techniques and elemental analysis.
Key Words: Pyrazoles, Knoevenagel condensation, Pyrazole-4-carbaldehydes.
An appropriate pyrazolecarbaldehyde through Knoevenagel
condensation could provide such a scaffold for posterior
manipulation. Pyrazole-4-carbaldehydes are readily obtainable
from various reactions such as: by the Rosenmund reduction
of pyrazole-4-carbonyl chloride5a,b, by the Sommelet reaction
of the corresponding 4-chloromethylpyrazole5c, by the
Vilsmeier-Haack reaction of pyrazoles6-9 or by the reaction of
appropriate semicarbazones or hydrazones with Vilsmeier
reagent10,11. Recently, a review on 1,3-diarylpyrazol-4-carbalde-
hyde has appeared in literature12. Some of these aldehydes
have previously been condensed with various substrates such
as acetophenones7,13, 4-acetylpyrazole14, pyruvic acid15, hippuric
acid16, malonic acid7,17, indole-3-acetonitrile18 and benzopy-
rillium salts19.
INTRODUCTION
Knoevenagel condensation1 is a very effective way of
extending carbon chains and often exploited for the purpose.
Pyrazole chemistry has afforded some interesting biological
materials; one of these is COX-2 inhibitor i.e., celecoxib2 (a),
already in clinical use, other is a well known agrochemical
i.e., furamtpyr3 (b), used as a fungicide. In another azole
researches such as with pyrrole some interesting pyrrole-3-
acetic acid derivatives are being explored as NSAIDs4. Similar
acid derivatives could easily be obtained from pyrazole-4-
carbaldehydes.
F3C
These considerations prompt us to continue our work on
pyrazole chemistry and we have already reported some of our
work on pyrazole derivatives20. Now we would like to present
our results of Knoevenagel condensations of some pyrazole-
4-carbaldehydes.
O
H
N
N
O
N
H
EXPERIMENTAL
N
All the chemicals were purchased from Aldrich and used
without further purification. The 1H NMR spectra were taken on
a Hitachi Perkin-Elmer spectrometer model R-20B operating
at 60MHz (tetramethylsilane as internal reference). The IR
absorption spectra were recorded as potassium bromide discs
on a Perkin-Elmer model 180 spectrophotometer. Elemental
Cl
S
N
O
O
NH2
(b) Furamptyr
Fig. 1. Important pyrazole containing biological compounds
(a) Celecoxib

7880 Chaudhry et al.
Asian J. Chem.
O
R2
analysis was carried out on a Perkin-Elmer model 240. Melting
points were obtained on a Fisher-Johns apparatus and are
uncorrected.
R1
H
R1
R2
R3
pyridine / piperidine
EtOH,
Pyrazole-4-carbaldehydes: The following starting
materials were prepared according to the literature methods:
1-Phenylpyrazole-4-carbaldehyde21 (1): m.p. 76-78 ºC, yield
85 %. 1-p-Methoxyphenylpyrazole-4-carbaldehyde22 (2): m.p.
83-84 ºC, yield 89 %. 3-Phenylpyrazole-4-carbaldehyde11 (3):
m.p. 128-129 ºC, yield 87 %. 1-p-Nitrophenylpyrazole-4-
carbaldehyde23 (4): m.p. 167-168 ºC, yield 78 %.
N
N
N
N
R3
R
R
(1 - 4)
(5 - 9)
(10 - 27)
R = H, Ph, p-MeOC6H4, p-NO2C6H4 ; R1 = H, Ph; R2 = Ph, COOH, COOEt, CN;
R3 = COOH, COOEt, CN,
Scheme-I
Knoevenagal condensations
2-phenylacrylonitrile (19): m.p. 276-278 ºC, yield 2.81 g;
85 %. (E)-Ethyl 2-cyano-3-(1-phenyl-1H-pyrazol-4-
yl)acrylate (20): m.p. 132-133 ºC, yield; 2.20 g; 83 %. (E)-
Ethyl 2-cyano-3-(1-(4-methoxyphenyl)-1H-pyrazol-4-
yl)acrylate (21): m.p. 151-152 ºC, yield 0.88 g; 30 %. (E)-
Ethyl 2-cyano-3-(3-phenyl-1H-pyrazol-4-yl)acrylate (22):
m.p. 167-168 ºC, yield 0.72 g; 27 %. (E)-Ethyl 2-cyano-3-(1-
(4-nitrophenyl)-1H-pyrazol-4-yl)acrylate (23): m.p. 187-189
ºC, yield 0.87 g; 28 %. (E)-2-Cyano-3-(1-phenyl-1H-pyrazol-
4-yl)acrylic acid (24): m.p. 212-214 ºC, yield 1.76 g; 74 %.
(E)-2-Cyano-3-(1-(4-methoxyphenyl)-1H-pyrazol-4-
yl)acrylic acid (25): m.p. 236-238 ºC, yield 2.19 g; 82 %. (E)-
2-Cyano-3-(3-phenyl-1H-pyrazol-4-yl)acrylic acid (26): m.p.
249 ºC, yield; 1.99 g; 84 %. (E)-2-Cyano-3-(1-(4-nitrophenyl)-
1H-pyrazol-4-yl)acrylic acid (27): m.p. 320-322 ºC, yield; 2.26
g; 80 %. The results are presented in Tables 1 and 2.
General procedure:A mixture of 0.01 mol of the aldehyde,
0.01 mol of the "active methylene" compound, three drops of
piperidine and five drops of pyridine in 10 mL of ethanol was
heated under reflux for the required time as monitored by TLC.
The reaction mixture was cooled and inverted over crushed
ice, acidified with hydrochloric acid (pH 6), filtered, washed
with cold water and dried. The dried precipitates were crysta-
llized from an appropriate solvent. The following products
(Scheme-I). were synthesized: 2-((1-Phenyl-1H-pyrazol-4-
yl)methylene)malonic acid (10): m.p. 206-207 ºC, yield 1.93
g; 75 %. 2-((1-(4-Methoxyphenyl)-1H-pyrazol-4-yl)-
methylene)malonic acid (11): m.p. 165-166 ºC, yield 2.12 g;
74 %. 2-((3-Phenyl-1H-pyrazol-4-yl)methylene)malonic acid
(12): m.p. 169 ºC, yield 1.93 g; 75 %. 2-((1-(4-Nitrophenyl)-
1H-pyrazol-4-yl)methylene)malonic acid (13): m.p. 204-
206 ºC, yield 2.02 g; 67 %. Diethyl 2-((1-phenyl-1H-pyrazol-
4-yl)methylene)malonate (14)24: m.p. 57-58 ºC, yield 2.34 g;
75 %. Diethyl 2-((1-(4-methoxyphenyl)-1H-pyrazol-4-
yl)methylene)malonate (15): m.p. 74-75 ºC, yield 2.43 g; 71 %.
Diethyl 2-((1-(4-nitrophenyl)-1H-pyrazol-4-yl)methylene)-
malonate (16): m.p. 128-129 ºC, yield; 2.47 g; 69 %. (Z)-2-
Phenyl-3-(1-phenyl-1H-pyrazol-4-yl)acrylonitrile (17): m.p.
121-122 ºC, yield 1.63 g; 57 %. (Z)-3-(1-(4-Methoxyphenyl)-
1H-pyrazol-4-yl)-2-phenylacrylonitrile (18): m.p. 169 ºC, yield
2.14 g; 68 %. (Z)-3-(1-(4-Nitrophenyl)-1H-pyrazol-4-yl)-
RESULTS AND DISCUSSION
We had already reported the synthesis of various pyrazole-
4-carbaldehydes and their derivatives25. The results of the
present Knoevenagel condensations between the pyrazole-4-
carboxaldehydes and the "active methylene" compounds are
presented in Scheme-I. A mixture of pyridine and piperidine
was used in these condensations1. The reactions were carried
out in refluxing ethanol. The results are collected in Table-1.
Table-2 contains the spectral data for the compounds obtained
TABLE-1
PHYSICAL DATA OF PRODUCTSa
Elemental analysis (%): calcd. (found)
Solvents for
crystallization
Compd. No.
m.p. (ºC)
Yield (%)
m.f.
C
H
N
206-7
165-6
169
Chloroform
Chloroform
Acetic acid
DMFb
75
74
75
67
75
71
69
57
68
85
83
30
27
28
74
82
84
80
C13H10N2O4
C14H12N2O5
C13H10N2O4
C13H9N3O6
C17H18N2O4
C18H20N2O5
C17H17N3O6
C18H13N3
60.46 (60.68)
58.33 (57.97)
60.46 (60.11)
51.49 (51.56)
64.96 (65.05)
62.73 (62.68)
56.82 (56.54)
79.68 (79.44)
75.73 (75.58)
68.35 (68.80)
67.40 (67.18)
64.64 (64.45)
67.40 (67.52)
57.69 (57.53)
65.26 (65.50)
62.45 (62.30)
65.27 (65.27)
54.93 (54.76)
3.90 (4.06)
4.20 (4.36)
3.90 (3.73)
2.99 (2.94)
5.77 (5.81)
5.85 (5.68)
4.77 (4.59)
4.83 (4.73)
5.02 (5.07)
3.82 (3.84)
4.90 (4.80)
5.08 (5.03)
4.90 (4.84)
3.87 (3.69)
3.79 (3.86)
4.12 (4.15)
3.79 (3.96)
2.84 (2.93)
10.85 (11.05)
9.72 (9.34)
10
11
10.85 (10.47)
13.86 (14.22)
8.91 (8.72)
12
204-6
(57)24
74-75
128-9
121-2
169
13
Ethanol
14
Ethanol
8.14 (7.98)
15
Acetic acid
Ethanol
11.69 (11.62)
15.49 (15.23)
13.94 (13.88)
17.71 (17.92)
15.72 (15.87)
14.13 (14.03)
15.72 (16.00)
17.94 (17.83)
17.56 (17.54)
15.61 (15.43)
17.57 (17.34)
19.71 (19.73)
16
17c
18c
19c
20
Chloroform
Acetic acid
Aq. Ethanol
Ethanol
C19H15N3O
C18H12N4O2
C15H13N3O2
C16H15N3O3
C15H13N3O2
C15H12N4O4
C13H9N3O2
C14H11N3O3
C13H9N3O2
C13H8N4O4
276-8
132-3
151-2
167-8
187-9
212-4
236-8
249
21
Ethanol
22
Ethanol
23
24d
25d
26d
27d
Chloroform
Acetic acid
Ethanol
320-2
DMFb
asee Scheme-I; bdimethyl formamide; creaction time 6 h; dreaction time 10 h.

Vol. 25, No. 14 (2013)
Compd. No.
Synthesis of Pyrazoleacrylic Acids and Their Derivatives 7881
TABLE-2
SPECTROSCOPIC DATA OF PRODUCTSa
IR (νmax, cm-1)b 1H NMR δ in ppm (J in Hz) (solvent)
3000-2500 (br., OH), 1700 and 1675 (C=O), 1645, 1580, 7.60 (m, 5H, Ar), 8.50 (s, 1H, CH=C), 8.92 (s, 1H, H-3), 9.07 (s, 1H,
10
1520, 1490, 1480, 1450, 1265, 1200, 1180, 755, 730.
H-5), (CF3COOH)
3200-2500 (br., OH), 1710 and 1675 (C=O), 1640, 1580, 4.00 (t, 3H, OCH3), 7.20 (d, 2H, J = 9.00, H-3’ and H-5’), 7.60 (d 2H,
11
J-9.00, H-2’ and H-6’ ), 8.59 (s, 1H, CH=C), 9.00 (s, 1H, H-3), 9.03
(s, 1H, H-5), (CF3COOH)
1520, 1380, 1260, 1180, 1015, 825, 725.
3400-2500 (br., NH and OH), 1725 and 1670 (C=O), 7.50 (m, 6H, NH and Ar), 7.95 (s, 1H, H-5), 8.22 (s, 1H, CH=C),
12
1585, 1470, 1445, 1270, 1200, 810, 765, 740, 695.
3200-2500 (br., OH), 1730 (C=O), 1595, 1530 (NO2),
1500, 1400, 1340 (NO2), 1250, 1225, 1110, 950, 855,
815, 765, 750, 680, 670, 655.
(DMSO-d6)
–
13c
1725 and 1710 (C=O), 1630, 1600, 1545, 1500, 1425, 1.30 (t, 3H, J = 7.00, -OCH2CH3), 1.35 (t, 3H, J = 7.00, -OCH2CH3),
1400, 1385, 1345, 1285, 1230, 1200, 1070, 1040, 1030, 4.28 (q, 2H, J = 7.00, -OCH2CH3), 4.38 (q, 2H, J = 7.00, -
14
15
1010, 955, 940, 870, 840, 760, 710, 690, 670.
OCH2CH3), 7.55 (m, 6H, Ar and H-3), 7.86 (s, 1H, H-5), 8.23 (s, 1H,
CH=C), (CDCl3)
1710 (C=O), 1630, 1540, 1510, 1450, 1380, 1340, 1300, 1.30 (t, 3H, J = 7.00, -OCH2CH3), 1.35 (t, 3H, J = 7.00, -OCH2CH3),
1255, 1215, 1200, 1060, 1035, 1020, 1005, 955, 860, 3.83 (s, 3H, OCH3), 4.28 (q, 2H, J = 7.00, -OCH2CH3), 4.38 (q, 2H,
840, 795, 750, 695, 655.
J = 7.00, -OCH2CH3), 6.95 (d, 2H, J = 9.00, H-3’ and H-5’), 7.58 (d,
2H, J = 9.00, H-2’ and H-6’), 7.65 (s, 1H, H-3), 7.83 (s, 1H, H-5),
8.13 (s, 1H, CH=C), (CDCl3)
1730 and 1700 (C=O), 1630, 1590, 1545, 1515 (NO2), 1.32 (t, 3H, J = 7.00, -OCH2CH3), 1.35 (t, 3H, J = 7.00, -OCH2CH3),
1500, 1435, 1365, 1335 (NO2), 1270, 1230, 1205, 1010, 4.30 (q, 2H, J = 7.00, -OCH2CH3), 4.40 (q, 2H, J = 7.00, -
16
950, 855, 750, 685, 660.
OCH2CH3), 7.55-8.10 (m, 3H, H-2’, H-6’ and H-3), 8.15-8.55 (m,
3H, H-3’, H-5’ and H-5), 8.65 (s, 1H, CH=C), (CF3COOH)
7.15-7.75 (m, 11H, arom. and H-3), 8.05 (s, 1H, H-5), 8.58 (s, 1H,
CH=C), (CDCl3)
17
18
2210 (C≡N), 1610, 1600, 1535, 1500, 1450, 1420, 1255,
1245, 1190, 1025, 955, 905, 860, 750, 685, 660.
3.84 (s, 3H, OCH3), 7.00 (d, 2H, J = 9.00, H-3’ and H-5’), 7.20-7.80
(m, 8H, Ar and H-2’ and H-6’ and H-3), 8.28 (s, 1H, H-5), 8.56 (s,
1H, CH=C), (CDCl3-CF3COOH)
2210 (C≡N), 1610, 1545, 1510, 1300, 1245, 1165, 1020,
960, 825, 755, 685, 655.
7.20-7.80 (m, 9H, arom.), 8.38 (s, 1H, H-3), 8.45 (s, 1H, H-5), 8.85
(s, 1H, CH=C), (CF3COOH)
19
20
21
2210 (C≡N), 1610, 1595, 1520, 1500 (NO2), 1440, 1405,
1385, 1335 (NO2), 1255, 1190, 1110, 1020, 950, 860,
770, 750, 690.
1.40 (t, 3H, J = 7.00, -OCH2CH3), 4.35 (q, 2H, J = 7.00, -
OCH2CH3), 7.20-7.80 (m, 6H, Ar and H-3), 8.23 (s, 1H, H-5), 8.75
(s, 1H, CH=C), (CDCl3)
2220 (C≡N), 1710 (C=O), 1610, 1590, 1535, 1505,
1430, 1400, 1385, 1275, 1205, 1010, 950, 870, 760, 725,
665.
1.40 (t, 3H, J = 7.00, -OCH2CH3), 3.88 (s, 3H, OCH3), 4.35 (q, 2H, J
= 7.00, -OCH2CH3), 6.98 (d, 2H, J = 9.00, H-3’ and H-5’), 7.63 (d,
2H, J = 9.00, H-2’ and H-6’), 8.20 (s, 2H, H-3 and H-5), 8.65 (s, 1H,
CH=C), (CDCl3)
2220 (C≡N), 1710 (C=O), 1610, 1520, 1380, 1255,
1205, 1180, 1040, 1010, 870, 830.
1.35 (t, 3H, J = 7.00, -OCH2CH3), 4.30 (q, 2H, J = 7.00, -
OCH2CH3), 7.50 (s, 5H, Ar), 8.17 (s, 1H, H-5), 8.65 (s, 1H, CH=C)
(CDCl3)
22
23
3250 (NH), 2220 (C≡N), 1710 (C=O), 1600, 1530, 1480,
1430, 1260, 1010, 890, 770, 760, 730, 700, 670.
1.30 (t, 3H, J = 7.00, -OCH2CH3), 4.15 (q, 2H, J = 7.00, -
OCH2CH3), 7.75 (s, 1H, H-3), 7.80 (d, 2H, J = 9.00, H-2’ and H-6’),
7.95 (s, 1H, H-5), 8.25 (s, 1H, CH=C), 8.35 (d, 2H, J = 9.00, H-3’
and H-5’) (CDCl3)
2210 (C≡N), 1725 (C=O), 1590, 1510 (NO2), 1395,
1370, 1335 (NO2), 1305, 1240, 1175, 1105, 1025, 950,
855, 750.
7.58 (m, 5H, Ar), 8.35 (s, 1H, H-3), 8.43 (s, 1H, H-5), 8.78 (s, 1H,
CH=C), (CDCl3-CF3COOH)
24
25
26
27c
3300-2500 (br., OH), 2220 (C≡N), 1710 (C=O), 1605,
1590, 1540, 1495, 1375, 1325, 1270, 1220, 1180, 1020,
755, 705.
3.95 (s, 3H, OCH3), 7.12 (d, 2H, J = 9.00, H-2 and H-6), 7.60 (d, 2H,
J = 9.00, H-3 and H-5), 8.48 (s, 1H, H-3), 8.56 (s, 1H, H-5), 8.75 (s,
1H, CH=C), (CF3COOH)
3200-2800 (br., OH), 2220 (C≡N), 1685 (C=O), 1600,
1535, 1510, 1380, 1290, 1220, 1175, 755, 715.
7.71 (m, 6H, Ar and NH), 8.49 (s, 1H, H-5), 9.25 (s, 1H, CH=C),
(CF3COOH)
3290 (br., NH), 3000-2400 (br., OH), 2220 (C≡N), 1695
(C=O), 1600, 1480, 1280, 1265, 1235, 1010, 950, 880,
775, 710, 695, 970.
–
3200 (br., OH), 2230 (C≡N), 1710 (C=O), 1610, 1590,
1550, 1520 (NO2), 1495, 1335 (NO2), 1235, 1080, 850,
750, 695.
aSee Scheme-1; ball strong bands;cnot very soluble in common NMR solvents.
during the reactions. As can be seen from the yields of the
products (Table-1), the condensations worked well with the
carbaldehydes studied. The following "active methylene"
compounds were used: malonic acid, diethyl malonate,
phenylacetonitrile, ethyl cyanoacetate and cyanoacetic acid.
For the compounds (21-23) obtained during these reactions
the yields were low but can be improved by increasing the
reaction time as was the case with compounds (17-19 and 24-27).
The Knoevenagel reaction when carried out between an
aldehyde and malonic acid or cyanoacetic acid in the presence
of pyridine-piperidine catalyst at water bath temperature usu-
ally leads to the corresponding acrylic acid or acrylonitrile,

7882 Chaudhry et al.
Asian J. Chem.
respectively by undergoing decarboxylation during the reaction.
The non-decarboxylated products in the earlier reported reactions
have been isolated by conducting the reactions at room temperature
and with ammonia as catalyst1. However, in our present work,
we found that the reactions carried out with these pyrazole-4-
carbaldehydes with pyridine-piperidine catalyst in refluxing
ethanol also gave the non-decarboxylated products (10-13 and
24-27) in good yields. No decarboxylated products were
isolated from these reactions. All isolated products were well
characterized through their Infrared absorption (IR) and proton
magnetic resonance spectra (NMR) were consistent with the
structures (Table-2).
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It may be noted that some recent publications deal with
the Knoevenagal reaction of pyrazole-4-carbaldehydes with
malonic acid under microwave irradiation giving the corres-
ponding acrylic acids26.
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IR spectra: With the help of IR spectra (Table-2) it was
easy to confirm the presence of carboxylic group in products.
There were two carbonyl peaks appearing in between 1730-
1675 cm-1 in case of dicarboxylated compounds and a broad
peak at 3000-2500 cm-1 for -OH group. This points out that no
decarboxylation has taken place during the condensation and
pointing to the structures as (10-13 and 24-27). For -NO2 group
containing compounds two bands appeared in the region of
1545-1495 cm-1 (asymmetric stretching) and 1350-1310 cm-1
(symmetric stretching).
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1H NMR spectra: The PMR spectra were very helpful in
elucidating structures of the products of condensation and
readily confirmed the absence of decarboxylation during the
reaction. The PMR spectra showed a singlet between 8.10 and
9.25 due to a single vinyl proton instead of two doublets
expected for the two vinyl protons in case a decarboxylation
would have occurred. All the products (10-13 and 24-27)
displayed this feature. Other signals due to the remaining
groups, aryl and pyrazole protons were also easily identified27
(Table-2).
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Conclusion
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(1977); Chem. Abstr., 87, 135320 (1977).
Knoevenagel condensation of pyrazole-4-carbaldehydes
and various "active methylene" compounds using pyridine and
piperidine as base in refluxing ethanol were studied during
this research work (Scheme-I). In the present study condensa-
tions with malonic acid or cyanoacetic acid did not accompany
decarboxylations and the expected products retaining the
carboxylic groups were isolated. IR, 1H NMR and elemental
analysis helped in characterizing these products. In some cases
yields are improved by increasing reaction times.
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Abstr., 53, 4983 (1959).
ACKNOWLEDGEMENTS
The authors thank HEC for indigenous scholarships to
Faryal Chaudhry, NadiaAsif, Muhammad Nasrullah and Qura
Tul Ain. Cel. Jorge Ribeiro indebted to the Ministerio de
Exercito, Brazil for study leave.
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