Green and highly efficient synthesis of pyranopyrazoles in choline chloride/urea deep eutectic solvent

Article abstract of DOI:10.1080/00397911.2015.1129668

A simple and efficient multicomponent protocol, using ammonium deep eutectic solvent as a dual catalyst and environmentally benign reaction medium, is developed for the synthesis of dihydropyrano[2,3-c]pyrazole derivatives. This operationally simple proto

Full text of DOI:10.1080/00397911.2015.1129668

Synthetic Communications
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Green and Highly Efficient Synthesis of
Pyranopyrazoles in Choline Chloride/Urea Deep
Eutectic Solvent
Adeleh Moshtaghi Zonouz & Davood Moghani
To cite this article: Adeleh Moshtaghi Zonouz & Davood Moghani (2015): Green and Highly
Efficient Synthesis of Pyranopyrazoles in Choline Chloride/Urea Deep Eutectic Solvent,
Synthetic Communications, DOI: 10.1080/00397911.2015.1129668
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Date: 27 December 2015, At: 21:08

Green and Highly Efficient Synthesis of Pyranopyrazoles in Choline Chloride/Urea
Deep Eutectic Solvent
Adeleh Moshtaghi Zonouz1, Davood Moghani1
1Chemistry Department, Faculty of Science, Azarbaijan Shahid Madani University,
Tabriz, Iran
Corresponding author Adeleh Moshtaghi Zonouz, Email: adelehmz@yahoo.com
Supplemental data for this article can be accessed on the publisher‟s website
Abstract
A simple and efficient multi-component protocol, using ammonium deep eutectic solvent
as a dual catalyst and environmentally benign reaction medium, is developed for the
synthesis of dihydropyrano[2,3-c]pyrazole derivatives. This operationally simple protocol
does not involve tedious work-up or purification affording the target compounds in short
reaction times and excellent yields, and avoiding the use of environmentally hazardous
solvents and catalysts.
Graphical Abstract:
KEYWORDS: deep eutectic solvent; pyranopyrazole; multi-component reaction; green
chemistry
1

INTRODUCTION
One of the main challenges in medicinal chemistry is the design and synthesis of
biologically active molecules.[1] Dihydropyrano[2,3-c]pyrazoles play an essential role as
biologically active compounds and represent an interesting template for medicinal
chemistry. Many of these compounds are known for their antimicrobial,[2] insecticidal[3]
and anti-inflammatory activities.[4] Furthermore dihydropyrano[2,3-c]pyrazoles show
molluscicidal activity[5,6] and are identified as a screening kit for Chk1 kinase inhibitor.[7]
They also find applications as pharmaceutical ingredients and biodegradable
agrochemicals.[8-10] Several modifications have been developed over the past decade for
the synthesis of these biologically important scaffolds. These include using CTACl,[11a]
piperazine,[11b] piperidine, [11c] N-methylmorpholine,[11d] L-proline,[11e]
heteropolyacids,[11f] alumina,[11g] sodium benzoate, [11h] amberlyst A21, [11i] per-6-amino-
cyclodextrin,[11j] imidazole,[11k] I2, [11l] and glycine[11m] as catalysts. Dihydropyrano [2,3-c]
pyrazole molecules are also synthesized under ultrasound irradiation using piperidine as
catalyst in EtOH.[12] Although, the reported methods are effective, they are confronted
with certain drawbacks of environment compatibility by using of toxic or hazardous
catalysts and/or solvents.
Within the framework of green chemistry, solvents occupy a strategic place. Green
Chemistry aims to replace the hazardous and/or harmful solvents with more
environmentally friendly alternatives. One group of solvents that have been investigated
for this purpose over recent years is ionic liquids. However, it is now felt that not all ionic
liquids can be classified as „green‟ and that their environmental impact is strongly
2

dependent on the cation and anion used to make them. A new family of ionic fluids, so-
called Deep Eutectic Solvents (DES), exhibit similar physico-chemical properties to the
traditionally used ionic liquids, while being much cheaper and environmentally friendlier.
Owing to these remarkable advantages, DESs are now of growing interest in many fields
of research.[13] A DES is a fluid generally composed of two or three cheap and safe
components that are capable of self-association, often through hydrogen bond
interactions, to form a eutectic mixture with a melting point lower than that of each
individual component. DESs are generally liquid at temperatures lower than 100 °C. The
most commonly employed example of DESs is the combination of choline chloride
(ChCl) and urea in a 1:2 molar ratio. The combination of these two inexpensive, non-
toxic solids results in a mixture that is a viscous liquid at room temperature (mp 12 ºC).
The basic nature of ChCl–urea DES and/or hydrogen-bond donor ability of urea are the
reasons for the high catalytic activity of this system.[14-16]
As part of our efforts to develop new synthetic methods in heterocyclic chemistry,[17]
herein we report a facile, green and efficient four-component synthesis of
dihydropyrano[2,3-c] pyrazole derivatives from aromatic aldehydes, malononitrile,
hydrazine hydrate and ethyl acetoacetate in ChCl–urea DES medium.
RESULTS AND DISCUSSION
The four-component reaction of benzaldehyde (1 mmol), malononitrile (1 mmol),
hydrazine hydrate (1 mmol) and ethyl acetoacetate(1mmol) in ChCl–urea DES was
selected for initial optimization studies, and we were pleased to isolate 96% of
3

pyranopyrazole 5a by performing the reaction at 80 °C in 10 min. The optimized
conditions were then applied to a range of aldehyde substrates. Both electron-poor and
electron-rich aldehydes were well tolerated (Table 1).
The formation of pyranopyrazole derivatives 5a-j can be rationalized by the following
tandem reactions: 1) formation of arylidene malononitrile via Knoevenagel condensation
between aldehyde 1 and malononitrile 2; 2) formation of pyrazolone by reaction of
hydrazine hydrate 3 and ethyl acetoacetate 4; and 3) Michael addition of arylidene
malononitrile to pyrazolone, followed by cyclization and tautomerization. It was
anticipated that ChCl–Urea DES could serve as a organocatalyst in this reaction.
In summary, we have developed a simple and efficient multi-component protocol for the
synthesis of dihydropyrano[2,3-c]pyrazole derivatives using ChCl–Urea deep eutectic
solvent as a dual catalyst and environmentally benign reaction medium. The significant
advantages offered by this green protocol are short reaction times, operational simplicity,
high yields and avoiding the use of environmentally hazardous solvents and catalysts.
EXPERIMENTAL
General: The 1H- and 13C-NMR spectra were taken on Bruker SP-400 AVANCE
spectrometers. The IR spectra were recorded on a Bruker PS-15 spectrometer. The
melting points were measured on an Electrothermal 9100 apparatus in open capillaries
without correction. All the commercial reagents were used without prior purification.
4

Typical procedure for the preparation of dihydropyrano[2,3-c]pyrazoles 5a-j:
Benzaldehyde (0.5 mmol), malononitrile (0.5 mmol), ethyl acetoacate (0.5 mmol),
hydrazine hydrate (0.5 mmol) and choline chloride-urea based DES[14] (1mL) were taken
in a test tube. The reaction mixture was stirred at 80 °C till the completion of the reaction
as indicated by TLC(10 min). Then water (5 mL) was added and the precipitated solid
was filtered, washed with water and recrystallized from ethanol. Compound 5a (6-
Amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile) was
obtained as white powder in 95% yield.
m.p. 245-246 °C [Lit[18] 244-245]; IR (KBr): 3373, 3310, 3169, 2192, 1649, 1611, 1518,
1401 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 1.77 (s, 3H, CH3), 4.59(s, 1H, C(4)-H),
6.88 (s, 2H, NH2), 7.15–7.33 (m, 5H, Ar-H), 12.11 (s, 1H, NH) ppm; 13C NMR(100
MHz, DMSO-d6): δ 9.77 (CH3), 36.28 (CH), 57.20 (C), 97.96 (C), 120.84 (CN), 126.80
(CH), 127.51 (2CH), 128.49 (2CH), 135.67 (C), 144.47 (C), 154.81 (C), 160.91 (C) ppm.
SUPPLEMENTARY DATA
Supporting information associated with this article can be found via the “Supplementary
Content” section of this article‟s webpage.
ACKNOWLEDGEMENTS
The authors acknowledge the Research Office of Azarbaijan Shahid Madani University
for financial support.
5

REFERENCES
1.
Hailes, H. C. Reaction solvent selection: The potential of water as a solvent for
organic transformations. Org. Process Res. Dev. 2007, 11, 114-120.
2. El-Tamany, E. S.; El-Shahed, F. A.; Mohamed, B. H. Synthesis and biological
activity of some pyrazole derivatives. J. Serb. Chem. Soc.1999, 64, 9-18.
3. Ismail, Z. H.; Aly, G. M.; El-Degwi, M. S.; Heiba, H. I.; Ghorab, M. M. Synthesis
and insecticidal activity of some new pyranopyrazoles, pyrazolopyranopyrimidines, and
pyrazolopyranopyridines. Egypt J. Biotech. 2003, 13, 73-82.
4.
Zaki, M. E. A.; Soliman, H. A.; Hiekal, O. A.; Rashad, A. E.
Pyrazolopyranopyrimidines as a class of anti-inflammatory agents. Z. Naturforsch. 2006,
C 61, 1-5.
5.
Abdelrazek, F. M.; Metz, P.; Metwally, N. H.; El-Mahrouky, S. F. Synthesis and
molluscicidal Aativity of new cinnoline and pyrano[2,3-c]pyrazole derivatives. Arch.
Pharm. 2006, 339, 456-460.
6.
Abdelrazek, F. M.; Metz, P.; Kataeva, O.; Jaeger, A.; El-Mahrouky, S. F.
Synthesis and molluscicidal activity of new chromene and pyrano[2,3-c]pyrazole
derivatives. Arch. Pharm. 2007, 340, 543-548.
7.
(a) Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.; Robertson, A. G. S.;
Surgenor, A. E. Identification of chemically diverse Chk1 inhibitors by receptor-based
virtual screening. Bioorg. Med. Chem. 2006, 14, 4792-4802; (b) Kimata, A.; Nakagawa,
H.; Ohyama, R.; Fukuuchi, T.; Ohta, S.; Suzuki, T.; Miyata, N. New series of antiprion
compounds: Pyrazolone derivatives have the potent activity of inhibiting protease-
resistant prion protein accumulation. J. Med. Chem. 2007, 50, 5053-5056.
6

8.
Sosnovskikh, V. Y.; Barabanov, M. A.; Usachev, B. I.; Irgashev, R. A.; Moshkin,
V. S. Synthesis and some properties of 6-di(tri)fluoromethyl- and 5-di(tri)fluoroacetyl-3-
methyl-1-phenylpyrano[2,3-c]pyrazol-4(1H)-ones. Russ. Chem. Bull., Int. Ed. 2005, 54,
2846-2850.
9.
El-Assiery, S. A.; Sayed, G. H.; Fouda, A. Synthesis of some new annulated
pyrazolo-pyrido (or pyrano) pyrimidine, pyrazolopyridine and pyranopyrazole
derivatives. Acta Pharm. 2004, 54, 143-150.
10.
Rodinovskaya, L. A.; Gromova, A. V.; Shestopalov, A. M.; Nesterov, V. N.
Synthesis of 6-amino-4-aryl-5-cyano-3-(3-cyanopyridin-2-ylthiomethyl)-2,4-
dihydropyrano[2,3-c]pyrazoles and their hydrogenated analogs. Molecular structure of 6-
amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-
dihydropyrano[2,3-c]pyrazole. Russ. Chem. Bull., Int. Ed. 2003, 52, 2207-2213.
11.
(a) Wu, M.; Feng, Q.; Wan, D.; Ma, J. CTACl as catalyst for four-component
one-pot synthesis of pyranopyrazole derivatives in aqueous medium. Synth. Commun.
2013, 43, 1721-1726; (b) Peng, Y.; Song, G.; Dou, R. Surface cleaning under combined
microwave and ultrasound irradiation: Flash synthesis of 4H-pyrano[2,3-c]pyrazoles in
aqueous media. Green Chem. 2006, 8, 573-575; (c) Vasuki, G.; Kumaravel, K. Rapid
four-component reactions in water: synthesis of pyranopyrazoles.Tetrahedron Lett. 2008,
49, 5636-5638; (d) Lehmann, F.; Holm Mand Laufer , S. Three-component
combinatorial synthesis of novel dihydropyrano[2,3-c]pyrazoles. J. Comb. Chem. 2008,
10, 364-367; (e) Mecadon, H.; Rohman, Md. R.; Kharbangar, I.; Laloo, B. M.;
Kharkongor, I.; Rajbangshi, M.; Myrboh, B. L-Proline as an efficicent catalyst for the
multi-component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-
7

c]pyrazole-5-carbonitriles in water. Tetrahedron Lett. 2011, 52, 3228-3231; (f) Heravi,
M. M.; Ghods, A.; Derikvand, F.; Bakhtiari, K.; Bammoharram, F.F. J. Iran. Chem.
Soc. 2010, 7, 615-620; (g) Mecadon, H.; Rohman, M. R.; Rajbangshi, M.; Myrboh, B.
γ-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. 2011, 52, 2523-2525; (h) Kiyania, H.; Samimib, H. A.;
Ghorbania, F.; Esmaielia, S. Curr. Chem. Lett. 2013, 2, 197-206; (i) Bihani, M.; Bora,
P. P.; Bez, G.; Askari, H. ACS Sustainable Chem. Eng. 2013, 1, 440-447; (j) Kanagaraj,
K.; Pitchumani, K. Solvent-free multicomponent synthesis of pyranopyrazoles: per-6-
amino-β-cyclodextrin as a remarkable catalyst and host. Tetrahedron Lett. 2010, 51,
3312-3316; (k) Siddekha, A.; Nizam, A.; Pasha, M. A. An efficient and simple approach
for the Ssnthesis of pyranopyrazoles using imidazole (catalytic) in aqueous medium, and
the vibrational spectroscopic studies on 6-amino-4-(4‟methoxyphenyl)-5-cyano-3-
methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole using density functional theory.
Spectrochim. Acta A. 2011, 81, 431-440; (l) Madhusudana Reddy, M. B.; Pasha, M. A.
One-pot, multicomponent synthesis of 4H-pyrano[2,3-c]pyrazoles in water at 25°C.
Indian J. Chem.(Sec-B), 2012, 51, 537-541; (m) Madhusudana Reddy, M. B.; Jayashan
Kara, V. P.; Pasha, M. A. Glycine-catalyzed efficient synthesis of Pyranopyrazoles via
one-pot multicomponent reaction. Synth. Commun. 2010, 40, 2930-2934.
12.
Zou , Y.; Hu, Y.; Liu, H.;. Shi, D. Rapid and efficient ultrasound-assisted method
for the combinatorial synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] derivatives.
ACS Comb. Sci. 2012, 14, 38-43.
8

13.
(a) Zhang, Q.; Vigier, K. D. O.; Royer, S.; Jérôme, F. Deep eutectic solvents:
syntheses, properties and applications. Chem. Soc. Rev. 2012, 41, 7108–7146; (b)
Carriazo, D.; Serrano, M. C.; Gutiérrez, M. C.; Luisa Ferrer, M.; Del Monte, F. Deep
eutectic solvents playing multiple roles in the synthesis of polymers and related materials.
Chem. Soc. Rev. 2012, 41, 4996–5014; (c) Abbott, A. P.; Cullis, P. M.; Gibson, M. J.;
Harris, R. C.; Raven, E. Novel choline-chloride-based deep-eutectic-solvents with
renewable hydrogen bond donors: levulinic acid and sugar based polyols. Green Chem.
2007, 9, 868–872; (d) Maugeri, Z.; Leitner, W.; Domínguez de María, P. Practical
separation of alcohol–ester mixtures using deep eutectic solvents. Tetrahedron Lett.
2012, 53, 6968–6971; (e) Handy, S.; Lavender, K. Organic synthesis in deep eutectic
solvents: Paal–Knorr reactions. Tetrahedron Lett. 2013, 54, 4377–4379.
14.
solvent properties of choline chloride/urea mixtures. Chem. Commun. 2003, 70-71.
15. Sonawane, Y. A.; Phadtare, S. B.; Borse, B. N.; Jagtap A. R.; Shankarling, G. S.
Abbott, A. P.; Capper, G.; Davies, D.L.; Rasheed, R.K.; Tambyrajah, V. Novel
Synthesis of diphenylamine-based novel fluorescent styryl colorants by Knoevenagel
condensation using a conventional method, biocatalyst, and deep eutectic solvent. Org.
Lett. 2010, 12, 1456–1459.
16.
eutectic solvent. J. Mol. Liq. 2014, 62-67.
17. (a) Moshtaghi Z., A.; Eskandari, I.; Khavasi, H.R. A green and convenient
Azizi, N.; Dezfooli, S.; Hashemi, M. Greener synthesis of spirooxindole in deep
approach for the synthesis of methyl 6-amino-5-cyano-4-aryl-2,4-dihydropyrano[2,3-
c]pyrazole-3-carboxylates via a one-pot, multi-component reaction in water. Tetrahedron
Lett. 2012, 53, 5519-5522; (b) Moshtaghi Z., A.; Baradaran H., S. Montmorillonite K10
9

Clay: An efficient catalyst for Hantzsch synthesis of 1,4‐ dihydropyridine derivatives.
Synth. Commun. 2008, 38, 290-296; (c) Moshtaghi Z., A.; Eskandari, I.; Notash, B. An
efficient and green procedure for the synthesis of highly substituted
polyhydronaphthalene derivatives via a one-pot, multi-component reaction in aqueous
media. Curr. Chem. Lett. 2015, 4, 85-92.
18.
c]pyrazoles catalyzed by lipase from Aspergillus niger. J. Mol. Cata. B. 2013, 92, 24.
19. El Aleem, M. A.; El-Remaily, A. A. Synthesis of pyranopyrazoles using
Bez, Gh.; Bora, p.; Bihani, M. Multicomponent synthesis of dihydropyrano[2,3-
magnetic Fe3O4 nanoparticles as efficient and reusable catalyst. Tetrahedron 2014, 70,
2971-2975.
20.
Guo, R-Y.; An, Z-M.; Mo, L-P.; Yang, Sh-T.; Liu, H-X.; Wang, Sh-X.; Zhang,
Zh-H. Meglumine promoted one-pot, four-component synthesis of pyranopyrazole
derivatives. Tetrahedron 2013, 69, 9931-9938.
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Table 1. Synthesis of dihydropyrano[2,3-c]pyrazoles via a four-component reaction in
ChCl–Urea DES medium
Entry
1
ArCHO
Producta
Time (min)
10
Yield (%)b
95
NC
NH
N
H2N
O
5a
2
3
10
10
97
97
O2N
NC
NH
N
H2N
O
5b
O2N
NC
NH
N
H2N
O
5c
NO2
4
5
15
15
90
87
NC
NH
N
H2N
O
5d
CHO
Cl
Cl
NC
NH
N
H2N
O
5e
11

CHO
Cl
6
15
86
Cl
NC
NH
N
H2N
O
5f
CHO
OMe
7
8
10
15
90
88
MeO
NC
NH
N
H2N
O
5g
CHO
OMe
OMe
NC
NH
N
H2N
O
5h
CHO
OMe
9
15
15
89
89
MeO
NC
NH
N
H2N
O
5i
CHO
10
O
O
NC
NH
N
H2N
O
5j
a All the products are known and were identified by their comparison of their IR and
NMR spectra, or by melting points. [18-20] b isolated Yields.
12