Synthesis of novel 1-H-pyrazole-4-carboxylic acid esters by conventional and microwave assisted Vilsmeier cyclization of hydrazones

Article abstract of DOI:10.1081/SCC-120018766

A convenient method for the synthesis of 1H-pyrazole-4-carboxylic acid esters is described. A comparison between the conventional and microwave assisted Vilsmeier reaction is carried out.

Full text of DOI:10.1081/SCC-120018766

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Synthesis of Novel 1-H-Pyrazole-4-carboxylic Acid
Esters by Conventional and Microwave Assisted
Vilsmeier Cyclization of Hydrazones
Radhakrishnan Sridhar a & Paramasivan T. Perumal a
a Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai, India
Version of record first published: 16 Aug 2006.
To cite this article: Radhakrishnan Sridhar & Paramasivan T. Perumal (2003): Synthesis of Novel 1-H-Pyrazole-4-carboxylic
Acid Esters by Conventional and Microwave Assisted Vilsmeier Cyclization of Hydrazones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:9, 1483-1488
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 9, pp. 1483–1488, 2003
Synthesis of Novel 1-H-Pyrazole-4-carboxylic
Acid Esters by Conventional and Microwave
Assisted Vilsmeier Cyclization of Hydrazones
*
Radhakrishnan Sridhar and Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research
Institute, Adyar, Chennai, India
ABSTRACT
A convenient method for the synthesis of 1H-pyrazole-4-carboxylic
acid esters is described. A comparison between the conventional and
microwave assisted Vilsmeier reaction is carried out.
Key Words: Hydrazones; Vilsmeier cyclization; Microwave assis-
tance; Pyrazole.
*Correspondence: Paramasivan T. Perumal, Organic Chemistry Division,
Central Leather Research Institute, Adyar, Chennai-600 020, India; Fax:
91-044-491 1589; E-mail: ptperumal@hotmail.com.
1483
DOI: 10.1081/SCC-120018766
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1484
Sridhar and Perumal
Pyrazoles find a wide range of applications in medicine. Steroids
containing pyrazole moiety are of interest as psychopharmacological
agents.[1] Pyrimidinopyrazoles are being studied in the fight against
cancer.[2] Pyrazole derivatives have been found to have antimalarial activ-
ity[3] and antihyperglycemic activity.[4] Some alkyl and aryl substituted
pyrazoles have a sharply pronounced sedative action on the central ner-
vous system.[5] Certain alkyl pyrazoles show significant bacteriostatic,
bacteriocidal and fungicidal, analgesic and antipyretic activities.[6] The
versatile pollen formation inhibitor activity,[7] herbicidal and insecticidal
activity[8] of 1H-pyrazole-4-carboxylic acid esters prompted us to
synthesize these compounds in high yields through Vilsmeier reaction.
Hydrazones of aliphatic and aromatic methyl ketones yield pyra-
zole-4-carboxaldehyde upon diformylation on treatment with Vilsmeier
reagent.[9] Hydrazones of aromatic ethyl and propyl ketones yield methyl
and ethyl pyrazoles respectively without undergoing diformylation.[10]
Our interest was to study the reactivity hydrazones of b-keto esters
towards the Vilsmeier reagent, to target the title compound, both in
conventional and microwave methods, and to compare their yields.
Hydrazones of b-keto esters when treated with Vilsmeier reagent
yield upon neutralization with aqueous NaOH a pale yellow solid pyr-
azoles (Sch. 1). The NMR spectrum of the recrystallized sample showed
the disappearance of the methylene proton signal and N–N–H signal.
The proton signal for the newly formed pyrazole appears at ꢀ 8.2 ppm,
leaving the other proton signals almost unchanged. This confirmed the
formation of the target molecule, which was also characterized by mass
spectral and elemental analysis. Similar results were obtained when the
reaction mixture was subjected to microwave irradiation, however, the
yield was increased considerably, with the reaction completed after a
short duration of time. Even better yields were noticed upon microwave
irradiation of the reaction mixture on SiO2 support.
Scheme 1. Synthesis of 1H-pyrazole-4-carboxylic acid esters.

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Novel 1-H-Pyrazole-4-carboxylic Acid Esters
1485
The chloromethyleniminium ion attacks selectively the active
methylene carbon and no side products were obtained. No further
addition of the Vilsmeier complex occurs even when excess of reagent
is employed (8 equiv. of POCl3 and 12 equiv. of DMF).
We have provided an efficient methodology for the preparation of
1H-pyrazole-4-carboxylic acid esters in high yield, both by conventional
and by microwave irradiation methods. Results obtained are tabulated in
the Table 1. The uniqueness of the application of microwave irradiation
lies not only in the reduction of reaction time but also in the increase of
product yield.
EXPERIMENTAL
All the reagents were distilled prior to use from an appropriate
drying agent. Infrared spectra were recorded as KBr pellets on a
Perkin Elmer FT-IR instrument. Nuclear Magnetic Resonance spectra
recorded on a Brucker Spectrometer, at 300 MHz (PMR) and at 75 MHz
(13C NMR). Mass spectra were obtained on a Perkin Elmer Mass
Spectrometer.
General Procedure for the Preparation of
1H-Pyrazole-4-carboxylic Acid Esters
Method I
Four point six zero grams of POCl3 (0.003 mol) was added dropwise
to an ice-cold stirred solution of hydrazone (0.001 mol) in 4 mL dry
DMF. The reaction mixture was allowed to attain room temperature
and then refluxed at 70–80ꢀC for about 4 h. The resulting mixture was
poured onto crushed ice, neutralized with dilute sodium hydroxide and
left standing overnight. The pale yellow precipitate obtained was purified
by Silica gel (60–120 mesh) column chromatography with ethyl acetate–
petroleum ether mixture (15:85) to yield the product.
Method II
Four point six zero grams of POCl3 (0.003 mol) was added dropwise
to a stirred, ice-cold solution of hydrazone (0.001 mol) in 4 mL dry DMF.

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1486
Sridhar and Perumal

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Novel 1-H-Pyrazole-4-carboxylic Acid Esters
1487
The reaction mixture was then allowed to attain room temperature and
subjected to microwave irradiation in a domestic microwave oven
(BPL microwave cooking system model BMO-7007) for about 3 min
with a pulse of 20 s each at 70% power corresponding to 210 Watts.
Then, the reaction mixture was poured onto crushed ice, neutralized,
filtered and column chromatographed to afford pure product as described
above.
Method III
After dropwise addition of POCl3 (0.003 mol) to an ice-cold solution
of 0.001 mol of hydrazone in 4 mL of dry DMF, the reaction mixture was
slurried with SiO2 (60–120 mesh). The slurry was subjected to microwave
irradiation as described above. Finally, the slurry was washed with ice-
cold water, allowed to settle and the supernatent washings are collected.
The process is repeated 3 to 4 times and the combined water washings is
filtered to get the crude pyrazole which was filtered and recrystallized
with chloroform to yield the pure product.
Methyl 1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazole-4-carboxylate 2:
1H NMR (300 MHz, CDCl3) ꢀ: 8.73 (d, J ¼ 2.4 Hz, 1H), 8.55 (dd,
J ¼ 2.4 Hz, J ¼ 8.7 Hz, 1H), 8.21 (s, 1H), 7.85 (d, J ¼ 8.7 Hz, 1H), 3.87
(s, 3H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) ꢀ: 162, 154, 146, 143,
137, 134, 128, 126, 121, 115, 52, 13; IR (KBr) cmÀ1: 3090, 1725, 1690,
1546, 1353, 1267; MS (m/z): 306 (Mþ); Anal. calcd. for C12H10N4O6:
C, 47.06; H, 3.27; N, 18.30; Found: C, 47.45; H, 3.36; N, 18.51.
Ethyl 1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazole-4-carboxylate 4:
1H NMR (300 MHz, CDCl3) ꢀ: 8.70 (d, J ¼ 2.4 Hz, 1H), 8.50 (dd,
J ¼ 2.4 Hz, J ¼ 8.7 Hz, 1H), 8.20 (s, 1H), 7.83 (d, J ¼ 8.7 Hz, 1H), 4.35
(q, J ¼ 7.1 Hz, 2H), 2.49 (s, 3H), 1.37 (t, J ¼ 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) ꢀ: 163, 155, 147, 144, 137, 135, 128, 126, 122, 117,
61, 15, 14; IR (KBr) cmÀ1: 3074, 1722, 1693, 1550, 1349, 1276; MS
(m/z): 320 (Mþ); Anal. calcd. for C13H12N4O6: C, 48.75; H, 3.75; N,
17.50; Found: C, 48.82; H, 3.81; N, 17.46.
ACKNOWLEDGMENT
One of the authors (R.S.) is grateful to Council of Scientific and
Industrial Research, New Delhi, India for financial support.

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1488
Sridhar and Perumal
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Received in the USA June 15, 2002