A facile synthesis of 6-amino-2H, 4H-pyrano[2,3-c]pyrazole-5-carbonitriles in deep eutectic solvent

Article abstract of DOI:10.1016/j.cclet.2015.12.005

A convenient synthesis of 6-amino-2H,4H-pyrano[2,3-c]pyrazole-5-carbonitriles has been accomplished by one pot four-component cyclocondensation of aromatic aldehydes (1a-o) malanonitrile (2), ethyl acetoacetate (3), and hydrazine hydrate (4) in freshly pr

Full text of DOI:10.1016/j.cclet.2015.12.005

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CCLET 3497 1–5
Chinese Chemical Letters xxx (2015) xxx–xxx
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Chinese Chemical Letters
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Original article
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A facile synthesis of 6-amino-2H, 4H-pyrano[2,3-F]pyrazole-5-
carbonitriles in deep eutectic solvent
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Q1 Manisha R. Bhosle, Lalit D. Khillare, Sambhaji T. Dhumal, Ramrao A. Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A convenient synthesis of 6-amino-2H,4H-pyrano[2,3-F]pyrazole-5-carbonitriles has been accomplished
by one pot four-component cyclocondensation of aromatic aldehydes (1a-o) malanonitrile (2), ethyl
acetoacetate (3), and hydrazine hydrate (4) in freshly prepared deep eutectic solvent, DES (choline
chloride:urea). This protocol has afforded corresponding pyrano[2,3-F]pyrazoles in shorter reaction time
with high yields, and it avoids the use of typical toxic catalysts and solvents.
Received 7 September 2015
Received in revised form 26 October 2015
Accepted 11 November 2015
Available online xxx
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Choline chloride
Cyclocondensation
DES
One pot
Urea
Pyranopyrazoles
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1. Introduction
various catalysts viz; per-6-amino-
b-cyclodextrin [12], glycine 29
[13], -alumina [14], -proline [15], nanosized magnesium oxide 30
g
L
9
The remarkable ability of heterocyclic nuclei to serve both as
biomimetics and reactive pharmacophores has largely contributed
to their use as scaffolds in the design of therapeutically active new
compounds [1]. Polyfunctionalized pyran and their derivatives are
very important heterocyclic compounds which frequently exhibit
a variety of biological activities [2,3]. 4H-Pyran is an important and
common structural unit both in natural and synthetic heterocyclic
molecules [4,5]. The dihydropyrano[2,3-F]pyrazole represents a
fascinating template in the pharmaceutical field and is responsible
for a wide spectrum of biological activities in molecules containing
this significant unit [6]. Such compounds are exhibiting biological
activities like antimicrobial [7], anticancer [8], anti-inflammatory
[9] and inhibition of human Chk1 kinase [10] activities. Conse-
quently, there has been continuous interest in the development of
facile synthetic protocols for the construction of dihydropyr-
ano[2,3-F]pyrazoles.
[16], Mg/Al hydrotalcite [17], N-methylmorpholine [18], hetero- 31
polyacids [19], sodium benzoate [20], and amberlyst A21 [21] 32
and obtained good to moderate yields of dihydropyrano[2,3-F] 33
pyrazoles. One pot three component cyclocondensations 34
have also been reported for dihydropyrano[2,3-F]pyrazoles, in 35
which,pyrazolone derived from condensation of ethyl acetoa- 36
cetate and hydrazine hydrate is cyclocondensed with in situ 37
intermediates generated from the interaction of aldehydes and 38
malononitrile. The latter route has also been accelerated by 39
various organic and inorganic bases [22]. The reported methods 40
still have certain inadequacies, such as long reaction time, toxic 41
and expensive catalysts, excess heating, and tedious work-up 42
procedure. Therefore, an exploration of a more general, efficient, 43
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and greener approach is highly desirable.
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Green technology actively seeks new, safer, alternative solvents 45
to replace common widely used organic solvents that present 46
inherent toxicity and high volatility, leading to evaporation of 47
volatile organics to the atmosphere [23]. In performing the 48
majority of organic transformations, solvents play a critical role 49
in making the reaction homogeneous and hence facilitating 50
molecular interactions [24]. Over the last two decades more 51
attention has been directed on the use of non-volatile organic 52
media like ionic liquids, PEGs, glycerine, water etc. for carrying 53
value added transformations. Ionic liquids (ILs) are quaternary 54
A one pot four component cyclocondensations of aldehydes,
malononitrile, ethyl acetoacetate, and hydrazine hydrate was
reported for obtaining dihydropyrano[2,3-F]pyrazoles [11].
This cyclocondensation has been accelerated by incorporating
*
Corresponding author.
E-mail address: manera2011@gamil.com (R.A. Mane).
http://dx.doi.org/10.1016/j.cclet.2015.12.005
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: M.R. Bhosle, et al., A facile synthesis of 6-amino-2H, 4H-pyrano[2,3-F]pyrazole-5-carbonitriles in deep
eutectic solvent, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.12.005

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salts/PTCs/inorganic salts having melting points less than 100 8C. It
has been reported that most of the ILs less biodegradable, more
toxic, and more expensive than hoped. Because of this, ILs are now
becoming less popular as media. Recently, chemists have been
paying more attention on the use of deep eutectic solvents (DESs)
for carrying various chemical transformations safely and rapidly. A
DES is generally composed of two or three cheap and safe
components which are capable of keeping association with each
other through hydrogen bond interactions to form a eutectic
mixture. The resulting DES is characterized by its melting point,
which is lower than that of the individual components. Generally,
DESs are characterized by very large depression of freezing point,
and most are liquid at room temperature [25].
Choline chloride (ChCl), or 2-hydroxy-N,N,N-trimethyletha-
naminium chloride, has been widely used as an organic salt to
produce eutectic mixtures when blended with cheap and safe
hydrogen bond donors like urea, polyols, and carboxylic acids
[26]. Urea is cheap readily available and has better self association
with ChCl. Therefore, it is widely used in generating DES by
blending with ChCl. Novel solvent properties of ChCl:urea
mixtures have been reported by Abbott et al., who concluded
that a blend of ChCl:urea with ratio 1:2 has the best self
association through hydrogen bond interactions and forms
appropriate eutectic mixture [25c]. Such DESs are attracting
researchers as they exhibit similar physicochemical properties to
traditional ionic liquids, and are thus found to be more
advantageous in organic syntheses. DESs are lower in cost, more
biodegradable, and less toxic than the traditional ionic liquids and
therefore are replacing the traditional ionic liquids while carrying
value added organic transformations viz. Knoevenagel condensa-
tion [27], Diels–Alder reactions [28], Fischer indole annulations
[29], Perkin reaction [30], selective acylation of primary hydroxyl
groups in cellulose [31], fluorination of acetophenone [32],
bromination of substituted 1-aminoanthra-9,10-quinone, and
benzylation of phenols [33].
2.2. Synthesis of 6-amino-1,4-dihydro-4-(4-methoxyphenyl)-3-
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methyl-pyrano[2,3-F]pyrazole-5-carbonitrile (5a)
A mixture of 4-methoxy benzaldehyde (1a) (3 mmol), mal-
ononitrile (2) (3 mmol), hydrazine hydrate (3) (3 mmol), and ethyl
acetoacetate (4) (3 mmol) was added in DES (5 mL) and then the
reaction mass was stirred at 80 8C. Progress of the reaction was
monitored by TLC (ethyl acetate:n-hexane 1:9). After 20 min of
stirring, the reaction mixture was cooled to room temperature.
Then, it was extracted using ethylacetate. The ethyl acetate phase
was separated from undissolved DES and the organic layer was
separated, dried, filtered, and concentrated in vacuo. The crude
solid residue that remained was then crystallized from ethanol.
Similarly, the other compounds (5b-o) of the series were
prepared. The melting points and the yields of the derivatives are
recorded in Table 2.
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6-Amino-1,4-dihydro-4-(4-methoxyphenyl)-3-methyl-pyr-
ano[2,3-F]pyrazole-5-carbonitrile (5a): IR (KBr,
y
cmꢀ1): 3425 (N–H
stretching),3128(Ar–Hstretching), 2928(C–Hstretching), 2200(CN
stretching), 1597 (C55N stretching), 1153 and 1203 (C–O–C
stretching); 1H NMR (400 MHz, DMSO-d6):
d 1.81 (s, 3H, –CH3),
3.78 (s, 3H, –OCH3), 4.45 (s, 1H, –CH–), 6.81 (s, 2H, –NH2), 6.87 (d, 2H,
J = 8.0 Hz), 7.23 (d, 2H, J = 8.0 Hz) and 12.08 (s, 1H, –NH). 13C NMR
(75 MHz, DMSO-d6):d8.82, 34.74, 53.77, 57.75, 94.70, 96.54, 112.46,
119.71, 127.38, 134.69, 134.85, 153.85, 157.02 and 159.50; MS (ESI):
m/z: 283.2 [M+]; Elementalanalysis:Calcd. forC15H14N4O2: C, 63.82;
H, 5.00; N, 19.85; found C, 63.37; H, 5.67; and N, 19.65
6-Amino-1,4-dihydro-4-(4-phenyl)-3-methyl-pyrano[2,3-
F]pyrazole-5-carbonitrile (5b): IR (KBr,
y
cmꢀ1): 3427 (N–H
stretching), 3119 (Ar–H stretching), 2934 (C–H stretching), 2200
(CN stretching), 1595 (C55N stretching), 1149 and 1211 (C–O–C
stretching); 1H NMR (400 MHz, DMSO-d6):
d
1.76 (s, 3H, –CH3),
4.51 (s, 1H, –CH–), 6.79 (s, 2H, –NH2), 6.99–7.76 (m, 5H, Ar–H) and
12.04 (s, 1H, –NH); 13C NMR (75 MHz, DMSO-d6):
8.85, 34.69,
d
57.67, 94.69, 96.48, 112.57, 119.69, 127.35, 134.73, 134.79, 153.84,
157.23 and 159.45; MS (ESI): m/z: 253 [M+]; Elemental analysis:
Calcd. for C14H12N4O: C, 66.65; H, 4.79; N, 22.21; found C, 66.67; H,
4.75; and N, 22.21
Considering the advantages of these deep eutectic solvents and
in continuation of our efforts to develop environmentally benign
protocols for various chemical transformations [34], here an
attempt has been made to develop a modified protocol by
optimizing the reaction conditions for carrying the cycloconden-
sation of aromatic aldehydes, malanonitrile, ethyl acetoacetate,
and hydrazine hydrate in DES for obtaining polyfunctional
pyranopyrazoles in a cost effective and rapid way.
2.3. Recycling of DES, choline chloride:urea
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A mixture of 4-methoxy benzaldehyde (1a 3 mmol), malononi-
trile (2 3 mmol), hydrazine hydrate (3 3 mmol), and ethyl
acetoacetate (4 3 mmol) was added in DES (5 mL), and then the
reaction mass was stirred at 80 8C. Progress of the reaction was
monitored by TLC (ethyl acetate:n-hexane 1:9). After 20 min of
stirring, reaction mixture was cooled to room temperature. Then it
was extracted using ethylacetate. Thus obtained undissolved DES
was further extracted with ethyl acetate (10 mL), and the
undissolved viscous liquid was separated and recycled for reuse
for future cycles.
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2. Experimental
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All the chemicals used were of laboratory grade. Melting
points of all the synthesized compounds were determined in
open capillary tubes and are uncorrected. 1H NMR spectra were
recorded with a Bruker Avance 400 spectrometer operating at
400 MHz using DMSO-d6 solvent and tetramethylsilane (TMS)
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as the internal standard and chemical shift in
NMR spectra were recorded on Bruker Avance 300 MHz on
Jeol. Mass spectra were recorded on Sciex, Model; API
d
ppm. 13C
3. Results and discussion
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a
3000 LCMS/MS Instrument. The purity of each compound was
checked by TLC using silica-gel, 60F254 aluminum sheets as
adsorbent, and visualization was accomplished by iodine/
ultraviolet light.
An efficient protocol has been developed for pyranopyrazoles
(5a-o) by one pot cyclocondensation of aromatic aldehydes (1a-o),
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Table 1
Screening of reaction media for the synthesis of compound 5a.a
Yield (%)b
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2.1. Synthesis of deep eutectic solvent
Entry
Solvents
1
2
3
4
PEG-400
72
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113
114
115
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A mixture of choline chloride (70 mmol) and urea (140 mmol)
i.e. in the ratio of 1:2 was heated at 80 8C with stirring for 30 min.
The resulting eutectic solvent was then allowed to cool to room
temperature and was used for the synthesis of pyranopyrazoles
(5a-o) without further purification.
Dicationic ionic liquid
Ionic liquid (N-methylpyridinium tosylate)
DES (40, 60, 80, 100 8C)
65
62
78, 85, 91, 92
a
Reaction conditions: All the reactions were carried at 80 8C for 20 min.
Isolated yields, DES: choline chloride:urea.
b
Please cite this article in press as: M.R. Bhosle, et al., A facile synthesis of 6-amino-2H, 4H-pyrano[2,3-F]pyrazole-5-carbonitriles in deep
eutectic solvent, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.12.005

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Table 2
Physical data of 6-amino-4-(4-substituted phenyl)-3-methyl-1,4-dihydropyr-
ano[2,3-F]pyrazole-5-carbonitriles (5a-o).a
Compound
R
Yield (%)b
Mpc (8C)
5a
5b
5c
5d
5e
5f
4-OCH3-Ph
-Ph
91
92
89
91
87
81
85
90
79
87
84
82
69
72
71
209–211
243–244
230–232
174–175
171–172
223–224
254–256
221–223
244–245
190–192
189–190
235–237
240–242
224–224
214–216
4-Cl-Ph
4-CH3-Ph
4-F-Ph
Scheme 1. Schematic presentation of synthesis of DES based on choline chloride
3-Br-Ph
and urea.
5g
5h
5i
4-NO2-Ph
4-OH-Ph
2-Cl-Ph
5j
3-NO2-Ph
3,4-(OMe)2-Ph
4-OH-3-OMe-Ph
2-furyl
5k
5l
5m
5n
5o
2-thiophenyl
4-pyridyl
a
Reaction conditions: aldehydes (1a-o) (3 mmol), malononitrile (2) (3 mmol),
hydrazine hydrate (3) (3 mmol) and ethyl acetoacetate (4) (3 mmol) in DES (5 mL)
was stirred at 80 8C for 20 min.
Scheme 2. 6-Amino-4-(4-substituted phenyl)-3-methyl-1,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitriles (5a-o).
b
Isolated Yields.
c
Melting points are in good agreement with those reported in the literature [35].
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malononitrile (2), ethyl acetoacetate (3), and hydrazine hydrate (4)
in freshly prepared deep eutectic solvent choline chloride:urea
(Scheme 1) at 80 8C (Scheme 2).
PEG-400. Ionic liquids at 80 8C gave the desired pyranopyrazole 182
with moderate to better yields (Table 1, entries 1–3). Considering 183
the above results and the importance of DES, model reaction was 184
then carried out in DES, derived from a mixture with 1:2 185
composition of choline chloride:urea, and 91% yield of the 186
To examine the choice of solvents, an investigation was
initiated in to the optimization of four component one pot
condensation of 4-methoxy benzaldehyde (1a), malononitrile (2),
hydrazine hydrate (3), and ethyl acetoacetate (4) to afford
pyranopyrazole (5a) as a model reaction. Initially, the reaction
was run in the absence of a catalyst and a solvent by varying
temperature (30–100 8C). It was observed that after prolonged
heating, the cyclocondensation did not run satisfactorily. Consid-
ering the significance of green chemistry efforts were directed
towards the use of green reaction media. Hence, the above model
reaction was performed separately in various green solvents, like
pyranopyrazole (5a) was obtained.
187
In preliminary studies, the model reaction was performed by 188
condensing 2-(4-methoxybenzylidene) malononitrile (obtained by 189
Knoevenagel condensation of 4-methoxy benzaldehyde and 190
malononitrile) and pyrazolin-5-one (prepared by condensation 191
of hydrazine hydrate and ethyl acetoacetate) in DES at 80 8C and 192
the expected product 5a was obtained with 82% yield. After 193
obtaining these results, one pot four component reaction of 1a, 194
malononitrile (2), hydrazine hydrate (3), and ethyl acetoacetate (4) 195
Scheme 3. Plausible mechanism for the synthesis of pyranopyrazoles (5a-o).
Please cite this article in press as: M.R. Bhosle, et al., A facile synthesis of 6-amino-2H, 4H-pyrano[2,3-F]pyrazole-5-carbonitriles in deep
eutectic solvent, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.12.005

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was carried out at 80 8C. It successfully yielded 5a with high yields
without the need of prior isolation of the intermediates. From these
results, it was confirmed that DES promotes the formation of the
intermediates and their successive condensation to the desired
title product 5a.
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During the study, the model reaction was performed using DES
as a reaction medium at different temperatures. Model reaction in
DES at 80 8C was found to proceed with excellent yield (91%) of 5a
in 20 min (Table 1). It was also noted that under similar reaction
conditions there was no condensation at room temperature. As
temperature increased (40, 60, 80, 100 8C) the yield of the product
also increased (78%, 85%, 91%, 92%). There was no significant
change in the product yield when reaction was kept above 80 8C.
The recyclability/reuse of the DES has also been confirmed for
the model reaction and it was noticed that even after three
successive cycles, DES was found to effectively as medium and
catalyst. The details of recovery and reuse of DES is given in the
experimental section.
The generality of this protocol was tested using various
aldehydes with electron donating and withdrawing groups in
order to determine the scope of the DES as medium and catalyst. A
variety of aldehydes (1a-o) have been found to undergo
cyclocondensation smoothly to offer the respective pyranopyr-
azoles (5a-o) in good to excellent yields at 80 8C within 20 min
(Table 2).
The rate acceleration of this one pot four component
cyclocondensation leading to pyranopyrazoles is attributed to
the unique use of DES as a medium, as it has the capacity to
dissolve various organic/inorganic solutes readily. This might be
responsible for maintaining high concentrations of the reactants in
the beginning of the reaction and during its progression. High to
saturated solutions of the reactants in the reaction mass would be
responsible for rate acceleration of the cyclocondensation.
Stronger hydrogen-bonding capabilities of DES might enhance
the electrophilic character of carbonyl carbons of the reactants, viz;
aldehydes and intermediate. It might also be increasing the rate of
in situ formation of carbanion from malononitrile. A plausible
mechanism, supporting the role of the DES in rate enhancement is
presented in Scheme 3.
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(2010) 2930–2934.
235
4. Conclusion
236
237
238
239
240
241
242
243
244
245
We have been able to introduce a facile and environmentally
friendly approach for the synthesis of biologically active
substituted pyranopyrazoles via one pot cyclocondensation of
various aromatic aldehydes, ethyl acetoacetate, hydrazine hy-
drate, and malononitrile in a safe to use deep eutectic solvent,
choline chloride:urea. High yields, easy work-up, cost effective-
ness, and the reusability of the medium are the key advantages of
this approach. Therefore, DES is found to have wide scope for
rapidly making value added organics via multicomponent
cyclocondensations.
[14] H. Mecadon, M.R. Rohman, M. Rajbangshi, B. Myrboh, g-Alumina as a recyclable
catalyst for the four-component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitriles in aqueous medium, Tetrahedron
Lett. 52 (2011) 2523–2525.
[15] H. Mecadon, M.R. Rohman, I. Kharbangar, et al., L-Proline as an efficient catalyst
for the multi-component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihy-
dropyrano[2,3-F]pyrazole-5-carbonitriles in water, Tetrahedron Lett. 52 (2011)
3228–3231.
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neous basic catalyst for the synthesis of 4H-pyrano[2,3-c]pyrazoles through a
four-component reaction, Synth. Commun. 41 (2011) 1320–1325.
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novel dihydropyrano[2,3-F]pyrazoles, J. Comb. Chem. 10 (2008) 364–367.
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246
Acknowledgments
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251
252
The authors are thankful to Professor D. B. Ingle for his
invaluable discussions and guidance. One of the authors, Manisha
R. Bhosle, is thankful to Dr. Babasaheb Ambedkar Marathwada and
University authorities for awarding the Jahagirdar Research
Fellowship. The authors are also thankful to the Central Drug
Research Institute (CDRI), Lucknow for spectral analysis.
253
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Please cite this article in press as: M.R. Bhosle, et al., A facile synthesis of 6-amino-2H, 4H-pyrano[2,3-F]pyrazole-5-carbonitriles in deep
eutectic solvent, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.12.005