Microwave-Assisted Synthesis of 3-(4-Pyrazolyl)propenoic Acids

Article abstract of DOI:10.1081/SCC-120027241

Under microwave activation, pyrazole-4-carboxaldehydes react with malonic acid in the presence of a small amount of pyridine to give 3-(4-pyrazolyl)propenoic acids in high yields.

Full text of DOI:10.1081/SCC-120027241

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Microwave‐Assisted Synthesis of
3‐(4‐Pyrazolyl)propenoic Acids
Vitaliy O. Chornous a , Mykhaylo K. Bratenko a & Mykhaylo V. Vovk b
a Bukovyna State Medical Academy , Chernivtsi, 58000, Ukraine
b Institute of Organic Chemistry , National Academy of Sciences of Ukraine , Kyiv,
Ukraine
Published online: 16 Aug 2006.
To cite this article: Vitaliy O. Chornous , Mykhaylo K. Bratenko & Mykhaylo V. Vovk (2004) Microwave‐Assisted Synthesis of
3‐(4‐Pyrazolyl)propenoic Acids, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:1, 79-83, DOI: 10.1081/SCC-120027241
To link to this article: http://dx.doi.org/10.1081/SCC-120027241
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 1, pp. 79–83, 2004
Microwave-Assisted Synthesis of
3-(4-Pyrazolyl)propenoic Acids
1
Vitaliy O. Chornous,1, Mykhaylo K. Bratenko,
*
and Mykhaylo V. Vovk2
1Bukovyna State Medical Academy, Chernivtsi, Ukraine
2Institute of Organic Chemistry, National Academy of Sciences of
Ukraine, Kyiv, Ukraine
ABSTRACT
Under microwave activation, pyrazole-4-carboxaldehydes react with
malonic acid in the presence of a small amount of pyridine to give 3-(4-
pyrazolyl)propenoic acids in high yields.
Key Words: 3-(4-Pyrazolyl)propenoic acids; Microwave-assisted
synthesis; Doebner condensation.
3-(4-Pyrazolyl)propenoic acids have attracted considerable interest due
to their pronounced pharmacological activity.[1–3] In addition, they are
*
Correspondence: Vitaliy O. Chornous, Bukovyna State Medical Academy, Chernivtsi
58000, Ukraine; E-mail: chornous@chv.ukrpack.net.
79
DOI: 10.1081/SCC-120027241
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

80
Chornous, Bratenko, and Vovk
employed as starting compounds in the synthesis of 4-pyrazolylacetic acids,[4]
of which the most significant are 3-(4-chlorophenyl)-1-phenyl-4-pyrazolyl-
acetic acid, the active substance of the nonsteroid antiphlogistic drug
“Lonazolac,”[5] 1,3-diphenyl-4-pyrazolylacetamides displaying high hypogly-
cemic activity [4], and 1,5-diphenyl-3-methyl-4-pyrazolylacetonitrile applied
as a nonnucleoside reverse transcriptase inhibitor of HIV-1 replication.[6,7]
3-(1,3-Diaryl-4-pyrazolyl)propenoic acids were synthesized previously[4]
by the Doebner method[8] and used to obtain the corresponding 4-
pyrazolylacetamides. We reported[9] the condensation of 3-(het)aryl-1-
phenylpyrazole-4-carboxaldehydes 1a–i with malonic acid under the
conditions of the Doebner reaction which furnished 3-(4-pyrazolyl)propenoic
acids 2a–i in 66–80% yields. Though affording relatively high yields of the
target products, the synthesis of 3-(4-pyrazolyl)propenoic acids by the
classical procedure of the Doebner condensation has two major disadvantages:
1. pyridine is used as a solvent in large amounts (to obtain 0.01 mol of
the target acid, as much as 25 mL[4] or 15 mL[8] of pyridine is
required);
2. the reaction needs a long time for completion (18.5 h[4] or 4.5 h[9] at
100–1308C).
In the present communication, we report the results regarding the synthesis
of 3-(4-pyrazolyl)propenoic acids 2a–n under microwave activation which
enables the solvent amount and the reaction time to be reduced significantly.
It is noteworthy that the microwave method has already been applied in
the preparation of chalcones and cinnamic acids.[10]
The condensation of pyrazole-4-carboxaldehydes 1a–n with malonic
acid, if run under microwave irradiation (see Sch. 1), has been found to require
a 12 times lesser amount of pyridine and a radically cut (from 4.5 h to 5 min)
time for completion, with significant increase of the yields of acids 2a–n up to
88–98% (see Table 1). The procedure of the microwave activation proves
particularly efficient when aldehydes 1i–n sparingly soluble in pyridine are
involved. In these instances the thermal version of the Doebner condensation
allowed only 57–69% yields of the expected acids 2i–n.
Scheme 1.

3-(4-Pyrazolyl)propenoic Acids
81
Table 1. Comparison of yields of 3-(4-pyrazolyl)propenoic acids 2a–n obtained
under thermal and microwave conditions.
Compounds
Ar
Thermal conditions
Microwave conditions
2a
2b
2c
2d
2e
2f
Ph
4-FC6H4
78a
80a
83a
77a
71a
69a
67a
75a
66a
59
98
97
99
96
98
94
95
98
94
88
95
89
96
90
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-thienyl
3-pyridyl
2g
2h
2i
3-coumaryl
3-NO2C6H4
4-PhC6H4
2j
2k
2l
61
58
3-NO2-4-MeOC6H4
2-benzofuryl
6-benzodioxanyl
2m
2n
69
57
aTaken from Ref.[9]
.
The composition and the structure of the newly synthesized products have
1
been confirmed by elemental analysis (for C, H, N) as well as by IR and H
NMR spectroscopy.
In conclusion, a rapid and practical procedure for the synthesis of 3-(4-
pyrazolyl)propenoic acids from pyrazole-4-carboxaldehydes and malonic
acids under microwawe irradiation condition was developed.
EXPERIMENTAL
Melting points were determined on a Thomas Hoover apparatus and are
reported uncorrected. IR spectra were measured with a UR-20 spectrometer in
KBr tablets. 1H NMR spectra were recorded in (CD3)2SO on a Varian VXR-
300 instrument at 300 MHz with TMS as internal standard.
Synthesis of 3-(4-Pyrazolyl)propenoic Acids: General Procedure
1. Thermal Conditions
To a solution of pyrazole-4-carboxaldehyde 1 (0.04 mol) in pyridine
(60 mL), malonic acid (8.74 g, 0.084 mol) and piperidine (1 mL) were added,

82
Chornous, Bratenko, and Vovk
and the reaction mixture was heated at 1008C for 0.5 h and at 1308C for
another 4 h. On cooling, the reaction mixture was poured in the mixture of ice
(300 g) and concentrated hydrochloric acid (40 mL). The precipitate formed
was filtered off, dried, and crystallized from acetic acid.
2. Microwave Conditions
A one-neck 100-mL flask containing aldehyde 1 (0.04 mol), malonic acid
(8.74 g, 0.084 mol), and pyridine (5 mL) was placed into a microwave oven
(Lunik 600, 600 W, 2450 MHz) equipped with a reflux condenser and heated
for 5 min. On cooling, the reaction mixture was treated as in the thermal
version of the procedure. The following new compounds were obtained:
2j. m.p. 237–2398C. IR (KBr): 1645, 1720, 2580–2960. 1H
NMR[(CD3)2SO], d 6.46 (d, 1H, CH55, J ¼ 15.9 Hz), 7.37–7.85 (m, 10H,
H–Ar þ CH55), 9.22 (s, 1H, C5H pyrazole), 12.25 (bs, 1H, COOH). Found:
C, 62.28; H, 3.94; N, 12.57. C18H13N3O4. Calcd.: C, 62.48; H, 3.91; N, 12.53.
2k. m.p. 245–2478C. IR (KBr): 1650, 1715, 2600–2950. 1H NMR
[(CD3)2SO], d 6.44 (d, 1H, CH55, J ¼ 15.9 Hz), 7.34–7.98 (m, 15H, H–
Ar þ CH55), 9.18 (s, 1H, C5H pyrazole), 12.15 (bs, 1H, COOH). Found: C,
78.60; H, 4.99; N, 7.55. C24H18N2O2. Calcd.: C, 78.67; H, 4.95; N, 7.65.
2l. m.p. 235–2378C. IR (KBr): 1650, 1725, 2590–3000. 1H NMR
[(CD3)2SO], d 4.02 (s, 3H, MeO), 6.43 (d, 1H, CH55, J ¼ 15.6 Hz), 7.35–8.09
(m, 9H, H–Ar þ CH55), 9.16 (s, 1H, C5H pyrazole), 12.06 (bs, 1H, COOH).
Found: C, 62.26; H, 4.19; N, 11.57.; C19H15N3O5. Calcd.: C, 62.46; H, 4.14;
N, 11.50.
2m. m.p. 221–2228C. IR (KBr): 1640, 1715, 2560–2970. 1H NMR
[(CD3)2SO], d 6.53 (d, CH55, J ¼ 16.2 Hz), 7.28–7.95 (m, 11H, H–
Ar þ CH55), 9.25 (s, 1H, C5H pyrazole), 12.24 (bs, 1H, COOH). Found:
C, 72.80; H, 4.17; N, 8.40. C20H14N2O3. Calcd.: C, 72.72; H, 4.27; N, 8.48.
2n. m.p. 255–2578C. IR (KBr): 1645, 1720, 2590–2960. 1H NMR
[(CD3)2SO], d 4.30 [s, 2H, (CH2O)2], 6.38 (d, CH55, J ¼ 15.9), 6.97–7.91 (m,
9H, H–Ar þ CH55), 9.09 (s, 1H, C5H pyrazole), 12.06 (bs, 1H, COOH).
Found: C, 68.90; H, 4.50; N, 8.14. C20H16N2O4. Calcd.: C, 68.96; H, 4.63;
N, 8.04.
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Received in Poland July 2, 2003