Green approach to the design of functionalized medicinally privileged 4-aryl-1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile scaffold

Article abstract of DOI:10.1002/jhet.1737

"On water" multicomponent condensation of aromatic aldehydes, malononitrile, and 3-methyl-2-pyrazoline-5-one in the presence of sodium hydroxide as catalyst leads to 6-amino-3-methyl-4-aryl-1,4-dihydropyrano[2,3-c] pyrazole-5-carbonitriles in 85-98% yield

Full text of DOI:10.1002/jhet.1737

March 2014
Green Approach to the Design of Functionalized Medicinally Privileged
523
4-Aryl-1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile Scaffold
*
Alexey I. Ilovaisky, Michael G. Medvedev, Valentina M. Merkulova, Michail N. Elinson, and Gennady I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991 Moscow, Russia
*
E-mail: elinson@ioc.ac.ru
Received April 4, 2012
DOI 10.1002/jhet.1737
Published online 18 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
“On water” multicomponent condensation of aromatic aldehydes, malononitrile, and 3-methyl-2-pyrazoline-
5-one in the presence of sodium hydroxide as catalyst leads to 6-amino-3-methyl-4-aryl-1,4-dihydropyrano
[2,3-c]pyrazole-5-carbonitriles in 85–98% yields.
J. Heterocyclic Chem., 51, 523 (2014).
INTRODUCTION
[2,3-c]pyrazoles 2a–g under solvent-free conditions or in
the presence of small amounts of such ecologically pure
solvent as water, according with the requirements of “green
chemistry” (Scheme 1).
First, to evaluate the synthetic potential of the solvent-
free procedure and to optimize the general conditions, the
multicomponent condensation of benzaldehyde 1a, malono-
nitrile, and 3-methyl-2-pyrazolin-5-one under solvent-free
conditions was studied (Table 1, Scheme 2).
It was found that under solvent-free conditions, formation
of both open 3a and cyclic 2a forms was observed (Table 1).
Moreover, some other by-products [benzalmalononitrile and
4,40-(phenylmethanediyl)bis(3-methyl-1H-pyrazol-5-ol)]
were found in the reaction mixture in 5–12% yields.
Then, the water, as the most ecologically pure solvent,
was chosen as a solvent for the carrying out of the multi-
component reaction of benzaldehyde, malononitrile, and
3-methyl-2-pyrazoline-5-one. Sodium hydroxide was chosen
as a base catalyst because it is not toxic, cheap and is the
strongest base in water conditions.
Functionalized pyrano[2,3-c]pyrazoles have a broad
spectrum of biological activities [1–5]. These compounds
are known as different pharmacologically active substances,
including antibiotics [1,2], enzyme inhibitors [3–5], and
anticancer drugs [2]. The methods of pyrano[2,3-c]pyrazoles
synthesis have long been documented and consist of
two main groups: (1) two-step synthesis and (2) “one-pot”
multicomponent condensation. The reaction of aromatic
aldehydes, malononitrile, and 3-methyl-2-pyrazoline-5-one
is well known and most efficient way to pyrano[2,3-c]
pyrazoles [6–12]. This multicomponent process includes
Knoevenagel condensation of aromatic aldehyde and
malononitrile, Michael reaction of formed Knoevenagel
adduct with 3-methyl-2-pyrazolin-5-one, and final cycli-
zation step to appropriate pyrano[2,3-c]pyrazole. The
main disadvantages of the known processes are large
volumes of toxic solvents [6–8,11,12], 10–20 mol% of
expensive or complex catalysts (indium(III) chloride
[9], H14[NaP5W30O110] [10]), and specific reaction condi-
tions: sonication [11] and microwave irradiation [9,12]).
Also, the most part of known methods are characterized by
long and complex isolation stage. Thus, we were prompted
to design ecologically convenient simple and efficient
method for synthesis of substituted pyrano[2,3-c]pyrazoles
in connection with demands of “green chemistry”.
The process was carried out as “one-pot” reaction by
stirring of suspension of benzaldehyde 1a, malononitrile,
and 3-methyl-2-pyrazolin-5-one in water, in the presence
of sodium hydroxide. When stirring of the reaction mixture
for 15 min at 60ꢀC without base (Table 2, entry 1), the
open form 3a was obtained in 100% yield. Addition of
NaOH (Table 2, entries 2–4) resulted in partial cyclization
of 3a into 2a, but the yield of 2a was still low.
RESULTS AND DISCUSSION
Increasing the temperature of the reaction to 100ꢀC
(Table 2, entry 5) provides full cyclization of 3a to
pyrano[2,3-c]pyrazole 2a, but 4,40-(phenylmethanediyl)bis
(3-methyl-1H-pyrazol-5-ol) was also found in the reaction
In the present study, we report our results on the
direct “one-pot” transformation of aromatic aldehydes 1a–g,
malononitrile, and 3-methyl-2-pyrazolin-5-one to pyrano
© 2013 HeteroCorporation

524
A. I. Ilovaisky, M. G. Medvedev, V. M. Merkulova, M. N. Elinson, and G. I. Nikishin
Vol 51
Scheme 1
mixture in small amount (5%) because of partial polymeriza-
tion of malononitrile in alkaline medium [13]. To compensate
the loss of malononitrile, 10% excess of malononitrile was
used in further experiments (Table 2, entries 6 and 7). Thus,
under optimal conditions (10% excess of malononitrile,
100ꢀС, 5 mol% NaOH, 1 h), pyrano[2,3-c]pyrazole 2a was
isolated in 98% yield.
Under these optimal conditions thus found, that is, 10%
excess of malononitrile, 100ꢀС, 1 h, 5 mol% NaOH in water,
the benzaldehydes 1a–g, malononitrile, and 3-methyl-2-
pyrazolin-5-one were transformed into corresponding sub-
stituted pyrano[2,3-c]pyrazoles 2a–g in 85–98% yields
(Scheme 1, Table 3).
Table 1
Multicomponent condensation of benzaldehyde 1a, malononitrile, and
3-methyl-2-pyrazoline-5-one under solvent-free conditions.a
Time
(min)
Temperature
(ꢀC)
Yield
Yield
Entry Catalyst
3a (%)b 2a (%)b
1
2
3
4
5
—
KF
KF
NaOAc
NaOAc
15
15
60
15
60
60
60
60
60
60
74
61
46
78
72
17
22
38
14
23
aBenzaldehyde 1a (5 mmol), malononitrile (5 mmol), 3-methyl-2-pyrazo-
lin-5-one (5 mmol), catalyst (0.5 mmol).
b1H NMR data.
Scheme 2
Table 2
Multicomponent condensation of benzaldehyde 1a, malononitrile, and 3-methyl-2-pyrazoline-5-one in the presence of water and sodium hydroxide.a
Entry
Excess of CH2(CN)2
Catalyst
Amount of base (%mol)
Time (min)
Temperature (ꢀC)
Yield 3a (%)b
Yield 2a (%)b
1
2
3
4
5
6
7
—
—
—
—
—
—
—
2
5
5
5
15
15
15
60
60
30
60
60
60
60
100
88
81
65
0
0
7
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
15
33
95
93
100
60
100
100
100
10%
10%
5
5
5
0
aBenzaldehyde 1a (5 mmol), malononitrile (5–5.5 mmol), 3-methyl-2-pyrazolin-5-one (5 mmol), 5 mL of H2O.
b1H NMR data.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

525
March 2014
Green Approach to the Design of Functionalized Medicinally Privileged
4-Aryl-1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile Scaffold
Table 3
5-one in a small amount of water (“on water reaction”
[15]) in the presence of 5 mol% of sodium hydroxide leads
to pyrano[2,3-c]pyrazoles selectively in excellent yields.
This novel multicomponent process offers an efficient
and convenient way to create pyrano[2,3-c]pyrazoles, the
prominent compounds with approved different biomedical
applications [1–5]. The procedure utilizes inexpensive
reagents, it is easily carried out, and the work up is not
complicated. Pyrano[2,3-c]pyrazoles are crystallized directly
from the reaction mixture; consequently, the isolation
includes only filtration and washing with cold water. Thus,
the proposed process is more efficient and environmentally
friendly compared with those known today.
Multicomponent condensation of aromatic aldehydes 1a–g, malononitrile,
and 3-methyl-2-pyrazoline-5-one into pyrano[2,3-c]pyrazoles 3a–g.a
Pyrano[2,3-c]
pyrazoles
Aldehyde
R1
R2
Yield (%)b
1a
1b
1c
1d
1e
1f
H
4-Me
4-F
H
H
H
H
H
3a
3b
3c
3d
3e
3f
98
93
90
85
89
94
86
4-Cl
4-OMe
3-OMe
4-NO2
4-OMe
H
1g
3g
aAromatic aldehyde (5 mmol), malononitrile (5.5 mmol, 0.36 g), 3-methyl-
2-pyrazolin-5-one (5 mmol, 0.49 g), sodium hydroxide (0.25 mmol,
0.01 g), water (5 mL), 100ꢀC, 60 min.
bIsolated yields.
EXPERIMENTAL
All melting points were measured with a Gallenkamp melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded with a Bruker Avance II 300 (300 MHz) spectrometer in
DMSO-d6 solutions at ambient temperature. Chemical shifts are
given in d scale relative to Me4Si. IR spectra were registered with a
SPECORD M82 spectrometer in KBr pellets. Mass spectra (EI,
70 eV) were obtained directly with a Finningan MAT INCOS 50
spectrometer. All materials were purchased from Aldrich (Sigma-
Aldrich Company Ltd., The Old Brickyard, New Road, Gillingham,
Dorset, SP8 4XT, UK) and Acros (ACRUS, Leninsky Prospekt 47,
Taking into consideration our and literature [6,7] data,
the following reaction scheme was proposed for the direct
multicomponent transformation of aromatic aldehydes,
malononitrile, and 3-methyl-2-pyrazolin-5-one into substi-
tuted pyrano[2,3-c]pyrazoles.
First, by the action of base, the anions of malononitrile
arise in the solution, and then, by the usual way, Knoevenagel
condensation of carbonyl compound with anion of malononi-
trile takes place with the formation of arylidenemalononitrile.
Addition of 3-methyl-2-pyrazolyn-5-one to arylidenemalono-
nitrile leads to anion A, which cyclized into anion B. Subse-
quent protonation of anion B leads to the corresponding
pyrano[2,3-c]pyrazoles 3a–g (Scheme 3).
117913 Moscow, Russian Federation).
General solvent-free procedure. A mixture of benzaldehyde
(5mmol, 0.53 g), malononitrile (5mmol, 0.33 g), 3-methyl-2-
pyrazolin-5-one (5mmol, 0.49g), and base (0.5mmol if used) was
stirred at 60ꢀC. Then, the reaction mixture was cooled and
suspended in cold water (5 mL). The suspension was filtered,
washed with cold water (2ꢁ 10 mL), and dried at 20mmHg.
General “on water” procedure. A suspension of benzaldehyde
CONCLUSION
(5 mmol, 0.53 g), malononitrile (5 or 5.5 mmol, 0.33 or 0.36 g), 3-
methyl-2-pyrazolin-5-one (5 mmol, 0.49 g), and sodium hydroxide
(up to 0.25 mmol) was stirred in 5 mL of water. Then, the reaction
In conclusion, “one-pot” multicomponent reaction of
aromatic aldehydes, malononitrile, and 3-methyl-2-pyrazoline-
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

526
A. I. Ilovaisky, M. G. Medvedev, V. M. Merkulova, M. N. Elinson, and G. I. Nikishin
Vol 51
mixture was cooled and diluted with 5 mL of water. The precipitate was
(5), 246 (5), 175 (100), 138 (8), 79 (10), 42 (12). Anal. Calcd
filtered, washed with cold water (2 ꢁ 10 mL), and dried at 20 mmHg.
for C16H16N4O3: C, 61.53; H, 5.16; N, 17.94. Found: C, 61.59; H,
Synthesis of pyrano[2,3-c]pyrazoles 2a–g. General procedure.
A
5.14; N, 17.90.
suspension of arylaldehyde (5 mmol), malononitrile (5.5 mmol),
3-methyl-2-pyrazolin-5-one (5 mmol), and sodium hydroxide
(0.25 mmol) in 5 mL of water was stirred at 100ꢀC for 60min.
Then, the reaction mixture was cooled and diluted with 5 mL of
water. The precipitate was filtered, washed with cold water
6-Amino-3-methyl-4-(4-nitrophenyl)-1,4-dihydropyrano[2,3-c]
pyrazole-5-carbonitrile (2g).
Pale yellow solid. Yield
1.28 g (86%); mp 257–259ꢀC (lit. mp [6] 251–252ꢀC). 1Н
NMR: 1.79 (s, 3Н, СН3), 4.81 (s, 1Н, СН), 7.01 (s, 2Н,
NН2), 7.46 (d, J= 8.8 Hz, 2H, Ar), 8.20 (d, J=8.8Hz, 2Н, Ar),
12.18 (s, 1Н, NH).
(2ꢁ 10mL), and dried at 20mmHg.
6-Amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile (2a). Pale yellow solid. Yield 1.24g (98%); mp
256–258ꢀC (lit. mp [6] 244–245ꢀC). 1Н NMR: 1.77 (s, 3Н, СН3),
4.59 (s, 1Н, СН), 6.83 (s, 2Н, NН2), 7.10–7.35 (m, 5Н, Ph), 12.08
Acknowledgments. The authors gratefully acknowledge the financial
support of Russian Foundation for Basic Research (Project No.
09-03-00003a).
(s, 1Н, NH).
6-Amino-3-methyl-4-(4-methylphenyl)-1,4-dihydropyrano
[2,3-c]pyrazole-5-carbonitrile (2b). Pale yellow solid. Yield 1.23 g
1
(93%); mp 213–215ꢀC (lit. mp [6] 197–198ꢀC). Н NMR: 1.77
(s, 3Н, СН3), 2.23 (s, 3Н, СН3), 4.52 (s, 1Н, СН), 6.81 (s, 2Н,
NН2), 7.04 (d, J= 7.3 Hz, 2H, Ar), 7.11 (d, J=7.3Hz, 2Н, Ar),
REFERENCES AND NOTES
12.08 (s, 1Н, NH).
[1] Mishriky, N.; Girgis, A. S.; Asaad, F. M.; Ibrahim, Y. A.;
Sobieh, U. I.; Fawzy, N. G. Boll Chim Farm 2001, 140, 129.
[2] Coen, D. M.; Loregian, A. Int Pat Appl WO 2006019955, CA
147:398624 (2007).
[3] Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.; Robertson,
A. G. S.; Surgenor, A. E. Bioorg Med Chem 2006, 14, 4792.
[4] Kaiser, D.; Terfloth, L.; Kopp, S.; Schulz, J.; de Laet, R.;
Chiba, P.; Ecker, G. F.; Gasteiger, J. J Med Chem 2007, 50, 1698.
[5] La Motta, C.; Sartini, S.; Tuccinardi, T.; Nerini, E.; Da
Settimo, F.; Martinelli, A. J Med Chem 2009, 52, 964.
[6] Sharanin, Y. A.; Sharanina, L. G.; Puzanova, V. V. J Org
Chem USSR 1983, 2291.
[7] Abdel-Latif, F. F. Z.; Naturforsch, B. Chem Sci 1990, 45,
1675.
[8] Sheibani, H.; Babaie, M. Synth Commun 2010, 40, 257.
[9] Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetrahedron
2007, 63, 2057.
6-Amino-4-(4-fluorophenyl)-3-methyl-1,4-dihydropyrano
[2,3-c]pyrazole-5-carbonitrile (2c). Pale yellow solid. Yield 1.20 g
(90%); mp 244–245ꢀC (lit. mp [14] 245ꢀC). 1Н NMR: 1.77 (s, 3Н,
СН3), 4.62 (s, 1Н, СН), 6.87 (s, 2Н, NН2), 7.08–7.25 (m, 4Н, Ar),
12.11 (s, 1Н, NH).
6-Amino-(4-chlorophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]
pyrazole-5-carbonitrile (2d). Pale yellow solid. Yield 1.22 g (85%);
1
mp 233–234ꢀC (lit. mp [14] 233ꢀC). Н NMR: 1.78 (s, 3Н, СН3),
4.63 (s, 1Н, СН), 6.90 (s, 2Н, NН2), 7.19 (d, J= 8.4 Hz, 2H, Ar),
7.37 (d, J=8.4Hz, 2Н, Ar), 12.12 (s, 1Н, NH).
6-Amino-4-(4-methoxyphenyl)-3-methyl-1,4-dihydropyrano
[2,3-c]pyrazole-5-carbonitrile (2e). Pale yellow solid. Yield 1.25 g
1
(89%); mp 224–225ꢀC (lit. mp [6] 225–226ꢀC). Н NMR: 1.78
(s, 3Н, СН3), 3.72 (s, 3Н, OСН3), 4.52 (s, 1Н, СН), 6.82 (s, 2Н,
NН2), 6.87 (d, J= 8.4 Hz, 2H, Ar), 7.08 (d, J =8.4Hz, 2Н, Ar),
[10] Heravi, M. M.; Ghods, A.; Derikvand, F.; Bakhtiari, K.;
Bamoharram, F. F. J Iran Chem Soc 2010, 7, 615.
[11] Dandia, A.; Jain, A. K.; Bhati, D. S. Synth Commun 2011, 41,
2905.
[12] Zhou, J. F.; Tu, S. J.; Zhu, H. Q.; Zhi, S. J. Synth Commun
2002, 32, 3363.
[13] Fatiadi, A. F. Synthesis 1978, 165.
[14] Khurana, J. M.; Nand, B.; Kumar, S. Synth Commun 2011,
41, 405.
12.08 (s, 1Н, NH).
6-Amino-4-(3,4-dimethoxyphenyl)-3-methyl-1,4-dihydropyrano
[2,3-c]pyrazole-5-carbonitrile (2f). White solid. Yield 1.46g
1
(94%); mp 201–203ꢀC. Н NMR: 1.81 (s, 3Н, СН3), 3.70 (s, 6Н,
2OСН3), 4.64 (s, 1Н, СН), 6.83 (s, 2Н, NН2), 6.6–6.9 (m, 3Н,
Ar), 12.08 (s, 1Н, NH). 13C NMR: 9.8, 35.9, 55.4, 55.5, 57.5,
97.7, 111.3, 111.8, 119.5, 120.8, 133.6, 136.9, 147.6, 148.6,
154.7, 160.8 ppm. IR (KBr): nmax 3458, 3254, 3123, 2191, 1638,
1599, 1515, 1491, 1398 cmꢂ1. MS, m/z (%) = 312 (M+, 33), 281
[15] Chanda, A.; Fokin, V. V. Chem Rev 2009, 109, 725.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet