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Chinese Chemical Letters 21 (2010) 1175–1179

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Greener approach towards the facile synthesis of

1,4-dihydropyrano[2,3-c]pyrazol-5-yl cyanide derivatives
at room temperature
Ravi S. Balaskar a, Sandip N. Gavade a, Madhav S. Mane a, Bapurao B. Shingate b,
Murlidhar S. Shingare b, Dhananjay V. Mane a,*
a
Organic Research Laboratory, S.C.S. College, Omerga 413 606, (MS), India
b
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, (MS), India
Received 24 February 2010

Abstract
This report describes triethylammonium acetate (TEAA) ionic liquid catalyzed one pot synthesis of 6-amino-4-aryl-5-cyano-3-
methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles by the reaction of aromatic aldehyde, malononitrile and 3-methyl-1-phenyl-2-
pyrazolin-5-one at room temperature. TEAA plays dual role as reaction media and catalyst. It can also be easily recovered and
reused in several runs. TEAA provides greener reaction protocol to present methodology which obviates the need of organic
solvents, expensive and toxic catalyst.
# 2010 Dhananjay V. Mane. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: Triethylammonium acetate (TEAA); 1,4-Dihydropyrano[2,3-c]pyrazol-5-yl cyanides; Room temperature

Multicomponent reactions (MCRs) have attracted considerable interest because of their exceptional synthetic and
practical efficiency [1,2]. One of the important example of MCR is three component synthesis of dihydropyrano[2,3-
c]pyrazoles which are potential inhibitors of human Chk1 kinase [3]. Dihydropyrano[2,3-c]pyrazoles have been
described in literature as biologically important compounds which possess anticancer [4], antimicrobial [5], anti-
inflammatory [6], insecticidal [7] and molluscicidal activities [8,9]. Recently, some new catalyst have been reported to
facilitate synthesis of dihydropyrano[2,3-c]pyrazole derivatives such as cupreine [10], N-methylmorpholine [11],
MgO [12], D,L-proline [13], DBSA [14]. However, industrial application of some of the above mentioned catalytic
systems suffers from some limitations such as non-recoverability, stringent conditions, high catalyst loading and also
high cost of some of these reported catalyst encouraged us to develop alternative clean and cheap methodology.
In past several years great deal of attention has been given towards imidazolium based ionic liquids [15]. Although as
the unique advantages of ionic liquid as reaction media and catalyst [16], they were not been applied in industry, the
reason for this is probably related to high cost of ionic liquids, difficulty in separation or recycling, the paucity of data with
regard to their toxicity and biodegradability. Therefore, low-cost and environmentally practicable ionic liquids have
drawn more attention for their use in synthetic methodology. Wang et al. studied ammonium based ionic liquids in the

* Corresponding author.
E-mail address: dr_dvmane@rediffmail.com (D.V. Mane).

1001-8417/$ – see front matter # 2010 Dhananjay V. Mane. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.06.013
1176 R.S. Balaskar et al. / Chinese Chemical Letters 21 (2010) 1175–1179

cracking reaction of dialkoxypropanes to alkoxypropenes without the use of traditional volatile organic compounds and
additional catalyst [17]. Ganeshpure et al. [18] recently reported simple ammonium ionic liquid for the Fischer
esterification. Verma et al. had also reported chemoselective aza- and thia-Michael reactions using (TEAA)
triethylammonium acetate [19].
As part of ongoing research [20–24] work to reduce toxic waste and by-products arising from chemical processes
using less toxic and environmentally compatible materials in the design of new synthetic methods, we have implemented
triethylammonium acetate (TEAA) as catalyst and greener reaction media for the one pot three component synthesis of 6-
amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles. The reason behind choosing TEAA
ionic liquid for this reaction is due to its high air and moisture stability, reusable, relatively cheaper compared with
imidazolium ionic liquid [17]. It also obviates the need of toxic, volatile organic solvents and additional catalyst.

1. Experimental

Liquid aldehydes were distilled before use. Melting points were determined in open capillaries and are uncorrected.
IR spectra were recorded on JASCO FT-IR 4100 spectrometer in KBr with absorption in cm 1. 1H NMR was measured
on Bruker DPX 400-MHz spectrometer in CDCl3 with TMS as internal standard. Mass spectra were obtained using a
Water-Micro Mass Quattro-II.
When mixture of benzaldehyde (0.10 g, 1 mmol), malononitrile (0.06 g, 1 mmol) and 3-methyl-1-phenyl-2-
pyrazolin-5-one (0.17 g, 1 mmol) in the presence of triethylammonium acetate (40 mol%) was stirred at room
temperature for appropriate time period. Course of the reaction was monitored by TLC. After completion of reaction,
mixture was poured on ice-cold water and obtained solid product was collected by filtration. Further purification was
accomplished by recrystallization from ethanol to afford final product which was in full agreement with the spectral data.
4a: IR (KBr) nmax: 3451, 3322, 2223, 1661, 1587 cm 1. 1H NMR (CDCl3): d 1.92 (s, 3H, CH3), 4.67 (s, 1H, 4-H),
4.71 (br, s, 2H, NH2), 7.75–7.31 (m, 10H, ArH). EI-MS m/z: 328 [M+]. 4d: IR (KBr) nmax: 3420, 3330, 2200, 1680,
1600 cm 1. 1H NMR (CDCl3): d 1.87 (s, 3H, CH3), 4.73 (s, 1H, 4-H), 4.81 (br, s, 2H, NH2), 8.22–7.31 (m, 9H, ArH). EI-
MS m/z: 406 [M+]. 4e: IR (KBr) nmax: 3455, 3326, 2193, 1663, 1590, 1391, 1267, 1122, 1048 cm 1; 1H NMR (CDCl3):
d 1.78 (s, 3H, CH3), 5.12(s, 1H, 4-H), 6.73(s, 2H, NH2), 7.31–7.78(m, 8H, ArH). EI-MS m/z: 396 [M+]. 4j: IR (KBr)
nmax: 3411, 3321, 3202, 2199, 1660, 1588 cm 1. 1H NMR (CDCl3): d 1.97 (s, 3H, CH3); 3.72 (s, 3H, CH3O); 3.76 (s,
3H, CH3O); 4.92 (s, 1H, 4-H) 7.06 (s, 2H, NH2); 7.27–7.79 (m, 8H, ArH). EI-MS m/z: 342 [M+]. 4l: IR (KBr) nmax:
3445, 2227, 1611, 1576; 1H NMR (CDCl3): d 2.01 (s, 3H, CH3); 4.89 (s, 1H, 4-H); 5.98 (s, 2H, OCH2O); 6.94 (m, 2H,
NH2); 7.07–7.26 (m, 8H, ArH). EI-MS m/z: 372 [M+].

2. Results and discussion

Initially, choosing an appropriate solvent is of crucial importance for the successful organic synthesis. For
optimization, the reaction of 4-Cl-benzaldehyde (1 mmol), malononitrile (1 mmol), 3-methyl-1-phenyl-2-pyrazolin-
5-one (1 mmol) was examined in various solvents using TEAA as catalyst (Table 1) at room temperature. The reaction
does not proceed when it was carried out without solvent and catalyst (Table 1. entry 1). The use of solvents retards the

Table 1
Optimization of solvent effecta.
Entry Solvent:Catalyst Time Yield (%) b
1 – 6h –
2 Water:TEAA 6h 28
3 DCM:TEAA 6h 37
4 THF:TEAA 6h 64
5 EtOH:TEAA 6h 77
6 CH3CN:TEAA 6h 83
7 TEAA 25 min 96
a
Reaction condition: 4-Cl-benzaldehyde (1 mmol), malononitrile (1 mmol), 3-methyl-1-phenyl-2-pyrazolin-5-one (1 mmol) and triethylammo-
nium acetate (40 mol%) stirred at RT.
b
Yields were isolated.
[(Fig._1)TD$IG] R.S. Balaskar et al. / Chinese Chemical Letters 21 (2010) 1175–1179 1177

Fig. 1. Optimization of quantity of catalyst.

rate of reaction which ultimately resulted into decrease in the product yield with prolonged reaction time (Table 1,
entries 2–6). After complete optimization TEAA was found to be appropriate reaction media and catalyst for this
reaction (Table 1, entry 7). From the results it is noticeable that triethylammonium acetate (TEAA) plays a crucial role
in the success of reaction and proved to be most effective.
The catalyst plays, a crucial role in the success of the reaction in terms of rate of the reaction and yield. We have also
optimized the quantity of catalyst for the reaction of 4-Cl-benzaldehyde, malononitrile and 3-methyl-1-phenyl-2-
pyrazolin-5-one stirring at room temperature (Fig. 1.) When the reaction was carried out in the presence of 10 mol% of
catalyst (TEAA) gives 52% of the yield. As we increase the percentage of the catalyst as 20 mol%, 30 mol%, 40 mol% the
yields were also found to be increased upto 68%, 82%, 96% respectively. Higher amount of the catalyst did not improve
the result to greater extent. Thus, 40 mol% of catalyst was chosen as maximum quantity of the catalyst for the reaction.
In order to explore the scope of the methodology wide range of structurally diverse and functionalized aromatic
aldehydes were examined, which underwent cyclocondensation with excellent yields (Table 2). When the mixture of
benzaldehyde (0.10 g, 1 mmol), malononitrile (0.06 g, 1 mmol) and 3-methyl-1-phenyl-2-pyrazolin-5-one (0.17 g,
1 mmol) in the presence of triethylammonium acetate (40 mol%) was stirred at room temperature (Scheme 1), the
reaction proceeds smoothly to afford corresponding products (Table 2, entries 4a–l). When aromatic aldehydes
containing electron-withdrawing groups (such as –Cl, –Br, –NO2) and electron-donating groups (such as –OCH3, –CH3,
–OH) were employed the reaction proceeds smoothly with improved reaction time and excellent yields were observed.
There is no any obvious effect observed due to electronic effect and nature of the substituents during the reaction.
The recovery and reuse of solvent and catalyst are highly preferable in terms of green synthetic process. Therefore,
with the success of these above reactions, we continued our research by studying reusability and recycling of TEAA.
After completion of reaction, the reaction mixture was poured on ice-cold water and filtered off. The filtrate was

Table 2
Synthesis of pyrano[2,3-c]pyrazoles by stirring at room temperature.
Compd. R Time (min) Yield (%) a M.P. (8C)
Found b Reported
4a H 20 97 167–169 168–170 [13]
4b 2-Cl 25 98 145–147 144–146 [13]
4c 4-Cl 25 96 175–177 174–175 [13]
4d 4-Br 30 97 180–182 183–184 [13]
4e 2,4-Cl2 30 96 183–185 182–184 [13]
4f 4-NO2 35 94 191–193 192–194 [13]
4g 3-NO2 35 95 189–191 190–191 [13]
4h 4-OH 45 90 209–210 211–212 [13]
4I 4-CH3O 45 92 172–174 170–172 [13]
4j 4-CH3 50 91 175–177 176–178 [13]
4k 2,4-(CH3O)2 55 89 176–178 178–179 [25]
4l 3,4-OCH2O 55 87 173–175 174–175 [25]
a
Isolated yields. Reaction condition: benzaldehyde (0.10 g, 1 mmol), malononitrile (0.06 g, 1 mmol) and 3-methyl-1-phenyl-2-pyrazolin-5-one
(0.17 g, 1 mmol) in the presence of triethylammonium acetate (40 mol%) [TEAA] stirred at room temperature.
b
Melting points were matched with authentic samples and literature data.
[(Schem_1)TD$FIG]
1178 R.S. Balaskar et al. / Chinese Chemical Letters 21 (2010) 1175–1179

Scheme 1.

Table 3
Reusability of TEAA considering (Table 2 compound 4c) as reaction model.
Runs Time (min) Yieldb
Fresh 25 97
1 25 97
2 27 95
3 30 94
b
Yields were isolated.

distilled under reduced pressure and obtained IL was reused for the same reaction. From results catalytic activity of
catalyst did not show any significant decrease even after four runs (Table 3).

3. Conclusion

It can be concluded that, introduction of triethylammonium acetate (TEAA) can be considered as an interesting new
alternate route for synthesis of 1,4-dihydropyrano[2,3-c]pyrazol-5-yl cyanides derivatives and the merit of this method
includes solvent-free, highly inexpensive, ease of handling, easily recycling and reuse of the catalyst. Therefore with
increasing ‘‘green’’ concern, the solvent-free conditions employed in the present method will make it environment
friendly and useful for industrial applications. Further application of triethylammonium acetate (TEAA) for other
reaction systems is under investigation.

Acknowledgment

The authors are thankful to The Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, for providing laboratory facilities.

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