Rapid synthesis of polyfunctionalized pyrano[2,3-c]pyrazoles via multicomponent condensation in room-temperature ionic liquids

Article abstract of DOI:10.1080/00397910903576669

A highly efficient synthesis of 4H-pyrano[2,3-c]pyrazoles has been completed using four-component cyclocondensation of hydrazine monohydrate/phenyl hydrazine, ethyl acetoacetate, aldehydes, and malononitrile in the presence of L-proline and room-temperatu

Full text of DOI:10.1080/00397910903576669

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Rapid Synthesis of Polyfunctionalized
Pyrano[2,3-c]pyrazoles via
Multicomponent Condensation in Room-
Temperature Ionic Liquids
Jitender M. Khurana a , Bhaskara Nand a & Sanjay Kumar a
a Department of Chemistry, University of Delhi, Delhi, India
Version of record first published: 13 Jan 2011
To cite this article: Jitender M. Khurana, Bhaskara Nand & Sanjay Kumar (2011): Rapid Synthesis of
Polyfunctionalized Pyrano[2,3-c]pyrazoles via Multicomponent Condensation in Room-Temperature
Ionic Liquids, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:3, 405-410
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Synthetic Communications1, 41: 405–410, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903576669
RAPID SYNTHESIS OF POLYFUNCTIONALIZED
PYRANO[2,3-c]PYRAZOLES VIA MULTICOMPONENT
CONDENSATION IN ROOM-TEMPERATURE IONIC
LIQUIDS
Jitender M. Khurana, Bhaskara Nand, and Sanjay Kumar
Department of Chemistry, University of Delhi, Delhi, India
A highly efficient synthesis of 4H-pyrano[2,3-c]pyrazoles has been completed using four-
component cyclocondensation of hydrazine monohydrate/phenyl hydrazine, ethyl aceto-
acetate, aldehydes, and malononitrile in the presence of L-proline and room-temperature
ionic liquids.
Keywords: 1-Butyl-3-methylimidazolium tetrafloroborate; clean synthesis; combinatorial chemistry;
heterocycles; pyrano[2,3-c]pyrazoles
INTRODUCTION
In recent years, the ‘‘greening’’ of chemical processes to attain environmental
friendliness[1] and sustainability has become a major issue in academia and industry.
The search for alternative reaction media to replace volatile, flammable, and often
toxic solvents commonly used in organic synthesis is an important objective in the
development of green chemical processes.[2] Room-temperature ionic liquids have
emerged as efficient alternatives to conventional solvents and are known to promote
several organic reactions[3] along with added advantages such as chemoselectivity[4]
and rate enhancement of some condensation reactions.[5] Multicomponent reactions
(MCRs) enjoy outstanding status in organic and medicinal chemistry because these
comply with the principles of green chemistry in terms of economy of steps and
applications in the diversity-oriented convergent synthesis of complex organic
molecules.[6]
Pyranopyrazoles, the structural units of a series of natural products,[7] are
known for their insecticidal[8] and anti-inflammatory activity,[9] molluscicidal
activity,[10] and use in screening for chk 1 kinase inhibitor.[11] Pyrano[2,3-c]pyrazoles
provide an interesting template for medicinal chemistry; some of the recent methods
include synthesis in aqueous media,[13] in ethanol under reflux,[14] under microwave
irradiation,[15] and under solvent-free conditions.[16] The reported methods offer
some advantages and also suffer from disadvantages such as the requirement for
Received October 3, 2009.
Address correspondence to Jitender M. Khurana, Department of Chemistry, University of Delhi,
Delhi 110007, India. E-mail: jmkhurana1@yahoo.co.in
405

406
J. M. KHURANA, B. NAND, AND S. KUMAR
excess solvent, longer reaction times, and poor yields. Therefore, development of a
facile and efficient methodology for the synthesis of pyranopyrazoles is desired. In
continuation of our endeavor to develop methodologies aimed at synthesis of poly-
functionalized heterocyclic moieties,[17] we present an ionic-liquid-mediated synthesis
of pyranopyrazole derivatives.
RESULTS AND DISCUSSION
We report herein an efficient synthesis of 4H-pyrano[2,3-c]pyrazoles (5) by
multicomponent cyclocondensation of hydrazine monohydrate (1a) or phenyl hydra-
zine (1b), ethyl acetoacetate (2), aldehydes (3), and malononitrile (4) in the presence
of L-proline in room-temperature ionic liquids. This method provides an ecofriendly
protocol for the synthesis of 5a–u. The reaction of hydrazine monohydrate (1a),
ethyl acetoacetate (2), 4-chlorobenzaldehyde (3b), and malononitrile (4) was carried
out using equimolar ratios in [Bmim]BF4 in the presence of different bases at 50ꢀC to
optimize the conditions for rapid reactions and good yields. L-Proline was found to
be the base of choice, affording the maximum yield (94%) of 5b in 5 min. Reactions
in other ionic liquids, such as [Bmim]Br and [Bmim]PF6, also worked well, but the
yield of 5b was slightly inferior than that of [Bmim]BF4 (Table 1).
The catalyst plays a crucial role in the success of the reaction in terms of the
rate and yields as 3b reacted with 1a, 2, and 4 in the presence of 1 mol%, 5 mol%,
10 mol%, and 15 mol% of L-proline to yield 65%, 87%, 94%, and 94%, of the product
(5b). Lesser amounts of catalyst also required longer reaction times. Thus, heating all
the components in the presence of 10 mol% of L-proline at 50ꢀC in [Bmim]BF4
Table 1. Effect of catalyst and ionic liquids in reaction of hydrazine hydrate, ethylacetoacetate,
4-chlorobenzaldehyde, and malononitrile
Entry
Base
Ionic liquids
Time (min)
Yield (%)
1
2
3
4
5
6
7
Et3N
Et2NH
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]Br
40
40
20
5
41
52
66
94
53
71
84
Piperidine
L-Proline
K2CO3
30
15
10
L-Proline
L-Proline
[Bmim]PF6
Scheme 1. Ionic liquid–mediated four-component synthesis of pyrano[2,3-c]pyrazoles.

PYRANO[2,3-c]PYRAZOLES IN MCRs
407
Table 2. [Bmim]BF4-mediated synthesis of pyranopyrazoles 5(a–u) via four-component cyclocondensa-
tion reaction
Product
R
R1
Yield (%)
Obs. mp (ꢀC)
Lit. mp (ꢀC)
5a
5b
5c
5d
5e
5f
C6H5
4-ClC6H4
H
H
90
94
96
94
94
90
84
86
87
85
95
92
91
89
87
93
86
84
83
83
86
244
233
196
211
251
222
226
245
224
232
218
251
248
246
241
232
226–228
174
190
171
182
245–246[13c]
234–235[13c]
197–198[18]
212–213[13c]
251–252[13c]
223–224[13c]
228[18]
247–248[18]
223–224[13c]
232–233[18]
219–220[18]
252–253[18]
249–250[18]
245–246[13c]
242–243[18]
233–234[18]
—
4-CH3C6H4
4-CH3OC6H4
4-O2NC6H4
3-BrC6H4
H
H
H
H
5g
5h
5i
3,4,5-(CH3O)3C6H2
4-FC6H4
H
H
4-HOC6H4
3-O2NC6H4
4-(CH3)2NC6H4
2-CH3OC6H4
4-BrC6H4
H
5j
H
5k
5l
H
H
5m
5n
5o
5p
5q
5r
5s
5t
H
2-ClC6H4
2-O2NC6H4
2-Furanyl
H
H
H
1-Naphthyl
4-ClC6H4
H
C6H5
C6H5
C6H5
C6H5
174–175[15]
188–190[15]
170–172[15]
183–184[15]
3-O2NC6H4
4-CH3OC6H4
4-BrC6H4
5u
proved to be optimum for this reaction. These optimized reaction conditions were
applied to a variety of aromatic aldehydes bearing both electron-donating and
electron-withdrawing substituents as well as heterocyclic carbaldehydes to achieve
Scheme 2. Proposed pathway for the four-component synthesis of pyrano[2,3-c]pyrazoles.

408
J. M. KHURANA, B. NAND, AND S. KUMAR
the synthesis of 4H-pyrano[2,3-c]pyrazoles. The reactions proceeded to completion
almost instantaneously (5–10 min), and pure products were obtained simply by
recrystallization from hot ethanol, thereby eliminating the need for any chromato-
graphic techniques (Scheme 1, Table 2). The ionic liquid could be recycled without
significant loss in the yields of products.
A plausible reaction pathway is given in Scheme 2. The proposed mechanism
was confirmed by an independent reaction between 4-chlorobenzylidinemalononi-
trile (prepared from Knoevenagal condensation of 3b and 4) and 3-methyl-5-pyrazo-
lone (prepared from condensation of 1a and 2) in an equimolar ratio to give 5b after
tautomerization.
In conclusion, a rapid, ecofriendly, and efficient method for the synthesis of
4H-pyrano[2,3-c]pyrazoles by four-component cyclocondensation reaction in the
presence of L-proline in room-temperature ionic liquids has been reported. More-
over, recyclability of the ionic liquid without significant loss of activity was an added
advantage.
EXPERIMENTAL
All the melting points were recorded on a Tropical Labequip apparatus.
Elemental analysis (C, H, N, S) was done using the Elementar Vario EL III analyzer,
and their results agreed favorably with calculated values. Infrared (IR) spectra were
recorded on a Perkin-Elmer Fourier transform (FT)–IR Spectrum-2000. NMR spec-
tra were recorded on a Brucker Avance Spectrospin (300 MHz) with tetramethylsi-
lane (TMS) as the internal standard. Mass spectra were recorded on a Quattro II
(Micromass).
General Procedure
A mixture of hydrazine hydrate (96%) or phenyl hydrazine (2 mmol), ethyl
acetoacetate (2 mmol), aldehyde (2 mmol), malononitrile (2 mmol), and L-proline
(10 mol%) in 1.5 g of [Bmim]BF4 was stirred at 50 ꢀC for 5–10 min. Progress of the
reaction was monitored by thin-layer chromatography (TLC) (eluent ethyl acetate–
petroleum ether 60:30, v=v). Upon completion of the reaction, water (10 mL) was
added and the contents were stirred. The mixture was filtered at pump, washed with
water followed by washing with a mixture of ethylacetate=hexane (20:80), and then
dried under vacuum. The product obtained was further purified by recrystallization
from hot ethanol. The products were identified by melting point, 1H NMR, IR, and
MS data. Compound 5q is not reported in the literature. [Bmim]BF4 was recovered
from the resulting aqueous solution and reused for the condensation reaction several
times in consecutive runs; no significant loss in the yield of the products was
observed even after four cycles as 3b was yielded in 94%, 92%, 91%, and 92% after
one, two, three, and four cycles.
Selected Spectral Data
Amino-3-methyl-5-cyano-4-(2-furanyl)-1,4-dihydropyrano[2,3-c]pyrazo-
1
le(5p). White solid; mp 232ꢀC; H NMR (300 MHz, DMSO-d6) d ¼ 12.11 (s, 1H),

PYRANO[2,3-c]PYRAZOLES IN MCRs
409
7.5 (s, 1H), 6.89 (s, 2H), 6.34 (s 1H), 6.16 (d, J ¼ 3 Hz, 1H), 4.75 (s, 1H), 1.96 (s, 3H)
ppm; IR (KBr): cmꢁ1 ¼ 3355, 3310, 3172, 2187, 1649, 1601, 1493, 1405, 1165, 1147,
1070, 1043, 774, 751, 659, 562; MS (ESI): m=z 242.7 (Mþ); CHNS analysis calculated
for C12H10N4O2: C, 59.50; H, 4.16; N, 23.13%. Found: C, 59.37; H, 4.27; N, 22.94%.
6-Amino-3-methyl-5-cyano-4-(1-naphthayl)-1,4-dihydropyrano[2,3-c]-
pyrazole (5q). White solid, mp 226–228ꢀC; 1H NMR (300 MHz, DMSO-d6):
d ¼ 12.08 (s, 1H), 8.2 (brs, 1H), 7.96 (d, J ¼ 8.1 Hz, 1H), 7.85 (d, J ¼ 8.1 Hz, 1H),
7.38–7.50 (m, 4H), 6.91 (s, 2H), 5.43 (s, 1H), 1.54 (s, 3H) ppm; IR (KBr):
cmꢁ1 ¼ 3402, 3344, 3160, 2192, 1655, 1610, 1512, 1486, 1407, 1161, 1050, 791, 774;
MS (ESI) m=z 303.2 (M þ 1); CHNS analysis calculated for C18H14N4O: C, 71.71;
H, 4.67; N, 18.53. Found: C, 71.42; H, 4.77; N, 18.33.
ACKNOWLEDGMENTS
Financial assistance by the Council of Scientific and Industrial Research, New
Delhi, India, as a junior research fellowship to Bhaskara Nand and junior and senior
research fellowships to Sanjay Kumar is gratefully acknowledged.
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