Synthetic Communications®

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Glycine-Catalyzed Efficient Synthesis of

Pyranopyrazoles via One-Pot Multicomponent
Reaction

M. B. Madhusudana Reddy , V. P. Jayashankara & M. A. Pasha

To cite this article: M. B. Madhusudana Reddy , V. P. Jayashankara & M. A. Pasha (2010)

Glycine-Catalyzed Efficient Synthesis of Pyranopyrazoles via One-Pot Multicomponent Reaction,
Synthetic Communications®, 40:19, 2930-2934, DOI: 10.1080/00397910903340686

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Synthetic Communications1, 40: 2930–2934, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903340686

GLYCINE-CATALYZED EFFICIENT SYNTHESIS OF

PYRANOPYRAZOLES VIA ONE-POT
MULTICOMPONENT REACTION

M. B. Madhusudana Reddy, V. P. Jayashankara, and

M. A. Pasha
Department of Studies in Chemistry, Bangalore University, Central College
Campus, Bengaluru, India

A facile and convenient protocol is developed for the fast (5–20 min) and high-yielding
(85–95%) synthesis of fused pyranopyrazoles from ethyl acetoacetate, hydrazine hydrate,
an aldehyde, and malononitrile in the presence of nontoxic, simple, and readily available
organocatalyst glycine in aqueous medium at 25
C.

Keywords: Aldehydes; ethylacetoacetate; glycine; hydrazine hydrate; malononitrile; pyranopyrazoles; water

INTRODUCTION
In recent years, pyranopyrazoles have interested synthetic organic chemists and
biochemists because of their biological and pharmacological activities.[1] Pyranopyr-
azoles exhibit analgesic, anti-inflammatory activity and act as vasodilators as well as
hypotensive and hypoglycemic agents.[2] Substituted 6-aminopyrano[2,3-c]pyrazoles
were first synthesized by a reaction between 3-methyl-5-pyrazolone with tetracya-
noethylene.[3] After that, numerous methods were developed for the synthesis of
these compounds from arylidenemalononitriles and 3-methyl-5-pyrazolone,[4]
4-arylidene-3-methyl-5-pyrazolones and malononitrile, and the condensation of
aromatic aldehydes, malononitrile, and 3-methyl-5-pyrazolone.[5] Shestopalov et al.
reported a chemical[6] as well as electrochemical method[7] for their synthesis. Peng
et al. developed a two-component reaction involving pyran derivatives and hydra-
zine hydrate under combined microwave and ultrasound irradiation,[8] and recently
Vasuki and coworkers reported a four-component synthesis of pyranopyrazoles
from ethylacetoacetate, hydrazine hydrate, aldehyde, and malononitrile.[9]
Multicomponent reactions (MCRs) are processes ‘‘in which more than two
educts directly get converted into their products by one-pot reaction.’’[10] MCRs play
an important role in modern organic chemistry, because they generally exhibit higher
atom economy and selectivity as well as produce fewer by-products compared to
classical multistep synthesis.[11] Further, in many cases, MCRs are easy to perform,

Received July 22, 2009.

Address correspondence to M. A. Pasha, Department of Studies in Chemistry, Bangalore
University, Central College Campus, Bengaluru 560001, India. E-mail: [email protected]

2930
 GLYCINE-CATALYZED EFFICIENT SYNTHESIS OF PYRANOPYRAZOLES 2931

inexpensive, and quick, consume less energy, and involve simple experimental proce-
dures.[12] The first MCR was described in 1850 by Strecker,[13] and thereafter many
such reactions have been reported in the literature.[14]
Aqueous reactions have also received considerable attention in organic syn-
thesis because of environmental safety reasons. Water as a reaction medium has been
utilized for a large number of organic reactions.[15]
In addition, molecules such as cinchona alkaloids and amino acids have been
used as organocatalysts in various organic synthesis[16] and proved to be highly
efficient catalysts in MCRs.[17]
In continuation of our work on the synthesis of biologically important com-
pounds using simple, efficient, nontoxic, and readily available catalysts,[18] we have
used the organocatalyst glycine, an amino acid, for the synthesis of pyranopyrazoles
from araldehydes (1), malononitrile (2), hydrazine hydrate (3), and ethylacetoacetate
(4) at 25
C in water with good to excellent yield within 5–20 min.

EXPERIMENTAL
Araldehydes (1), malononitrile (2), ethyl acetoacetate (3), hydrazine hydrate
(4), and glycine, all commercial compounds, were used without further purification.
All reactions were performed at 25
C in water as solvent. Yields refer to isolated
yields of the products. Melting points were measured on a Büchi B-540 apparatus;
infrared (IR) and 1H NMR spectra were recorded on a Nicolet 400D Fourier trans-
form (FT)–IR and Bruker AMX (200-MHz) spectrophotometers respectively. The
IR spectra were taken as KBr pellets. Liquid chromatography–mass spectra
(LC-MS) were recorded on an Agilent Technologies 1200 series spectrometer.

RESULTS AND DISCUSSION

Initially, attempts were made to carry out the model reaction of benzaldehyde
(1, Scheme 1), malononitrile (2), ethyl acetoacetate (3), and hydrazine hydrate (4) at
room temperature without any catalyst in dicholormethane (DCM), but very little
formation of solid product (7a, 20%) was observed after 1 h. Thin-layer chromato-
graphy (TLC) of the reaction mixture indicated the presence of starting materials,
and when the reaction was performed with glycine as the catalyst, increase in the
yield was noticed. At this stage, we thought of varying the nature of solvent to
increase the product yield; and we carried out reactions in DCM, dichloroethane
(DCE), dimethylformamide (DMF), ethyl acetate, MeOH, ethanol (EtOH), and

Scheme 1. Synthesis of pyranopyrazoles from araldehydes, malononitrile, ethylacetoacetate, and

hydrazine hydrate.
2932 M. B. M. REDDY, V. P. JAYASHANKARA, AND M. A. PASHA

Table 1. Synthesis of pyranopyrazoles from various aromatic aldehydes,

malononitrile, ethyl acetoacetate, and hydrazine hydrate

Entry Aromatic aldehydes (1) Producta (7) Yield (%)b

a C6H5CHO 7a 90
b 4-NO2-C6H4CHO 7b 87
c 3-NO2-C6H4CHO 7c 95
d 4-Me-C6H4CHO 7d 91
e 4-OMe-C6H4CHO 7e 90
f 3-OMe-C6H4CHO 7f 88
g 2-OMe-C6H4CHO 7g 90
h 3,4-(OMe)2-C6H3CHO 7h 89
i 3,5-(OMe)2-C6H3CHO 7i 85
j 3,4,5-(OMe)3-C6H2CHO 7j 93
k 4-OH-C6H4CHO 7k 91
l 4-F-C6H4CHO 7l 88
m 4-Cl-C6H4CHO 7m 89
n 2,3-Cl2-C6H3CHO 7n 87
o 2,4-Cl2-C6H3CHO 7o 90
p 2-Furfural 7p 94
a
All the products were known and characterized by comparison with the
authentic samples.
b
Yield refers to isolated product.

distilled water. When the reaction mixture was stirred for 5 min at room temperature
in distilled water using a catalytic amount of glycine, the yield of 7a improved signifi-
cantly (90%). This clearly demonstrates that the solvent has an effect on the reaction:
with the increase in the polarity of the solvent, the yield of the product increased.
Thus, we optimized the reaction conditions to examine the generality of this reac-
tion. The reaction was performed using various aromatic and heterocyclic aldehydes.
It was found that the reaction proceeded smoothly with all the aldehydes at 25
C in
water to give the products in excellent yield (85–95%) within 5–20 min. To summar-
ize the effect of electron-donating or electron-withdrawing substituents on an
aromatic ring of araldehyde, the results are presented in Table 1.

General Procedure for the Synthesis of Pyranopyrazoles in Water

A mixture of ethyl acetoacetate (0.260 g, 2 mmol), hydrazine hydrate (0.107 g,
2 mmol), malononitrile (0.132 g, 2 mmol), corresponding aromatic or heterocyclic
aldehyde (2 mmol), and glycine (2 mol%) in water (5 mL) was vigorously stirred at
25
C for 5–20 min. The soild was filtered and washed with ethyl acetate=light pet-
roleum (2:8, 2  10 mL) to get nearly pure products. The product of desired purity
was obtained by silica-gel column chromatography with ethyl acetate=light pet-
roleum or by recrystallization from ethanol.

CONCLUSIONS
In conclusion, we have developed an efficient protocol for the synthesis of
pyranopyrazoles by a one-pot MCR of hydrazine hydrate, ethylacetoacetate,
 GLYCINE-CATALYZED EFFICIENT SYNTHESIS OF PYRANOPYRAZOLES 2933

araldehydes, malononitrile, and a catalytic amount of an organocatalyst, glycine, in

water at 25
C. The catalyst is simple, inexpensive, readily available, nontoxic, and
environmentally friendly, and the reaction procedure is very mild and involves
simple workup to obtain the desired products in good to excellent yields.

REFERENCES
1. Nawwar, G. A. M.; Abdelrazek, F. M.; Swellam, R. H. Cinnamoylnitrile, pyran, and
pyranopyrazole derivatives containing the salicylalinilde moiety with anticipated mollus-
cicidal activity. Arch. Pharm. 1991, 324, 875–877.
2. (a) Kuo, S. C.; Huang, L. J.; Nakamura, H. Studies on heterocyclic compounds, 6:
Synthesis and analgesic and anti-inflammatory activities of 3,4-dimethylpyrano[2,3-c]-
pyrazol-6-one derivatives. J. Med. Chem. 1984, 27(4), 539–544; (b) Huang, L. J.; Hour,
M. J.; Teng, C. M.; Kuo, S. C. Synthesis and antiplatelat activities of N-arylmethyl-
3,4-dimethylpyrano[2,3-c]pyrazole-6-one derivatives. Chem. Pharm. Bull. 1992, 40,
2547–2551.
3. Junek, H.; Aigner, H. Synthesen mit Nitrilen, XXXV: Reaktionen von Tetracyanäthylen
mit Heterocyclen. Chem. Ber. 1973, 106, 914–921.
4. Sharanin, Y. A.; Shcherbina, L. N.; Sharanina, L. G.; Puzanova, V. V. Nitrile cyclization
reactions, VI: Synthesis of 2-amino-4-(2-furyl)-4H-pyrans. Zh. Org. Khim. 1983, 19,
164–173.
5. (a) Sharanina, L. G.; Marshtupa, V. P.; Sharanin, Y. A. Synthesis of 6-amino-5-cyano-
1H, 4H-pyrazolo[3,4-b]pyrans. Khim. Geterotsikl. Soedin. 1980, 10, 1420–1424; (b)
Tacconi, G.; Gatti, G.; Desimoni, G.; Messori, V. A new route to 4H-pyrano[2,3-c]-
pyrazoles. J. Prakt. Chem. 1980, 322, 831–834.
6. Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.;
Niazimbetova, Z. I.; Evans, D. H. Cross-condensation of derivatives of cyanoacetic acid
and carbonyl compounds, part 1: Single-stage synthesis of 10 -substituted 6-amino-spiro-
4-(piperidine-40 )-2H, 4H-pyrano[2,3-c]pyrazole-5-carbonitriles. Tetrahedron 2003, 59,
7491–7496.
7. Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.;
Niazimbetova, Z. I.; Evans, D. H. One-step synthesis of substituted 6-amino-5-
cyanospiro-4-(piperidine-40 )-2H, 4H-dihydropyrazolo[3,4-b]pyrans. Org. Lett. 2002, 4,
423–425.
8. Peng, Y.; Song, G.; Dou, R. 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.
9. Vasuki, G.; Kumaravel, K. Rapid four-component reactions in water: Synthesis of
pyranopyrazoles. Tetrahedron Lett. 2008, 49, 5636–5638.
10. Armstrong, R. M.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Multiple-component condensation strategies for combinatorial library synthesis. Acc.
Chem. Res. 1996, 29, 123–131.
11. Trost, B. M. On inventing reactions for atom economy. Acc. Chem. Res. 2002, 35,
695–702.
12. Jahnisch, K.; Hessel, V.; Lowe, H.; Baerns, M. Chemistry in microstructured reactors.
Angew. Chem., Int. Ed. 2004, 43, 406–446.
13. Strecker, A. Strecker amino acid synthesis. Justus Liebigs, Ann. Chem. 1850,
75, 27–32.
14. For recent reviews on multicomponent reactions, see (a) Ugi, I. Recent progress in the
chemistry of multicomponent reactions. Pure Appl. Chem. 2001, 73, 187–191; (b) Orru,
2934 M. B. M. REDDY, V. P. JAYASHANKARA, AND M. A. PASHA

R. V. A.; de Greef, M. Recent advances in solution-phase multicomponent methodology

for the synthesis of heterocyclic compounds. Synthesis 2003, 10, 1471–1499.
15. (a) Naik, S.; Bhattacharjya, G.; Talukdar, B.; Patel, B. K. Chemoselective acylation of
amines in aqueous media. Eur. J. Org. Chem. 2004, 6, 1254–1260; (b). Yang, Y.; Chan,
T. H. Organic reactions in aqueous media: Cyclopentadienylindium(I) as the first example
of organoindium(I) reagent for carbon–carbon bond formation and the demonstration of
one-pot tandem addition=intramolecular Diels–Alder reaction in aqueous media. J. Am.
Chem. Soc. 2000, 122(2), 402–403, and references cited therein.
16. (a) Wout, A.; Wolken, M.; Have, R. T.; Mariet, J.; van der, W. Amino acid–catalyzed
conversion of citral: cis–trans isomerization and its conversion into 6-methyl-5-hepten-
2-one and acetaldehyde. J. Agric. Food Chem. 2000, 48, 5401–5405; (b) Alcaide, B.;
Almendros, P.; Luna, A.; Torres, M. S. Proline-catalyzed diastereoselective direct aldol
reaction between 4-oxoazetidine-2-carbaldehydes and ketones. J. Org. Chem. 2006, 71,
4818–4822; (c) Janey, J. M.; Hsiano, Y.; Armstrong, J. D. Proline-catalyzed, asymmetric
Mannich reactions in the synthesis of a DPP-IV inhibitor. J. Org. Chem. 2006, 71, 390–
392; (d) Chandrasekhar, S.; Reddy, N. S.; Sultana, S. S.; Narsihmulu, C.; Reddy, K. V.
L-Proline-catalysed asymmetric aldol reactions in PEG-400 as recyclable medium and
transfer aldol reactions. Tetrahedron 2006, 62, 338–345.
17. (a) Li, H.; Wang, B.; Deng, L. Enantioselective nitroaldol reation of a-ketoesters cata-
lyzed by cinchona alkaloids. J. Am. Chem. Soc. 2006, 128, 732–733; (b) Poulsen, T. B.;
Bernardi, L.; Bell, M.; Jorgensen, K. A. Organocatalytic enantioselective nucleophilic
vinylic substitution. Angew. Chem., Int. Ed. 2006, 45(39), 6551–6554; (c) Mabry, J.;
Ganem, B. Studies on the Biginelli reaction: A mild and selective route to 3,4-dihydropyr-
imidin-2(1H)-ones via enamine intermediates. Tetrahedron Lett. 2006, 47(1–2), 55–56.
18. (a) Pasha, M. A.; Jayashankara, V. P. Molecular iodine–catalyzed synthesis of aryl-14H-
dibenzo[a,j ]xanthenes under solvent-free condition. Bioorg. Med. Chem. Lett. 2006, 17,
621–623; (b) Pasha, M. A.; Jayashankara, V. P. Synthesis of a,a-bis(arylmethylidene)
cycloalkanones catalyzed by molecular iodine: An improved procedure for the Claisen–
Schmidt condensation. Indian J. Chem., 2007, 46B, 1025–1027.