Rapid four-component reactions in water: synthesis of pyranopyrazoles

Article abstract of DOI:10.1016/j.tetlet.2008.07.055

An environmentally benign four-component reaction in aqueous medium at room temperature has been developed for the synthesis of 6-amino-5-cyano-3-methyl-4-aryl/heteroaryl-2H,4H-dihydropyrano[2,3-c]pyrazoles.

Full text of DOI:10.1016/j.tetlet.2008.07.055

Tetrahedron Letters 49 (2008) 5636–5638
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Rapid four-component reactions in water: synthesis of pyranopyrazoles
*
Gnanasambandam Vasuki , Kandhasamy Kumaravel
Department of Chemistry, Pondicherry University, Puducherry 605 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An environmentally benign four-component reaction in aqueous medium at room temperature has
been developed for the synthesis of 6-amino-5-cyano-3-methyl-4-aryl/heteroaryl-2H,4H-dihydro-
pyrano[2,3-c]pyrazoles.
Received 6 June 2008
Revised 4 July 2008
Accepted 9 July 2008
Available online 12 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Green chemistry
MCR
Water medium
Heterocycles
Green chemistry emphasizes the development of environmen-
tally benign chemical processes and technologies.1 Multi-compo-
nent reactions (MCR) are processes in which three or more
reactants are combined in a single chemical step to produce prod-
ucts that incorporate substantial portions of all the reactants. MCRs
comply with the principles of green chemistry in terms of economy
of steps as well as many of the stringent criteria of an ideal organic
synthesis. These reactions are effective in building highly function-
alized small organic molecules from readily available starting
materials in a single step with inherent flexibility for creating
molecular complexity and diversity coupled with minimization
of time, labour, cost and waste production.2 Hence, the develop-
ment of multi-component reaction protocols for the synthesis of
heterocyclic compounds has attracted significant interest from
pharmaceutical groups.
Designing organic reactions in aqueous media is another attrac-
tive area in green chemistry.3 Water is an abundant and environ-
mentally benign solvent. As a reaction medium, it offers several
benefits including control over exothermic reactions, salting in
and salting out and variation of pH. Work up and purification can
be carried out by simple phase separation techniques. Also, organic
reactions in water exhibit unique reactivity and selectivity that are
different from reactions in organic solvents. In particular, reactions
with negative activation volume are reported to occur faster in
water than in organic solvents.4 Multi-component reactions are
suggested to have a negative activation volume.5
biodegradable agrochemicals.6–8 The first reported pyranopyrazole
was synthesized from the reaction between 3-methyl-1-phenyl-
pyrazolin-5-one and tetracyanoethylene.6 Various 6-amino-5-cyano-
4-aryl-4H-pyrazolo[3,4-b]pyrans were synthesized by the reaction
of arylidienemalononitrile with 3-methylpyrazoline-5-ones or by
the condensation of 4-arylidienepyrazoline-5-one with malononit-
rile.7 Sharanin et al.8 have developed a three-component reaction
between pyrazolone, an aldehyde and malononitrile in ethanol
using triethylamine as the catalyst. Shestopalov and co-workers9
reported the synthesis of pyrazolopyran via a three-component
condensation between N-methylpiperidone, pyrazoline-5-one and
malononitrile in absolute ethanol. However, this reaction occurred
only on heating or when induced by electrochemical methods un-
der an inert atmosphere. Peng and co-workers have developed a
two-component reaction involving pyran derivatives and hydra-
zine hydrate to obtain pyranopyrazoles in water.10 The reaction
was promoted by a combination of microwave and ultrasonic
irradiation In the present work, we report an efficient and eco-
friendly four-component reaction protocol in aqueous medium at
room temperature for the synthesis of pyranopyrazole derivatives
(Scheme 1).
This protocol offers flexibility in tuning the molecular complex-
ity and diversity. The reactions proceeded to completion almost
instantaneously, and pure product was obtained, without using
any chromatographic techniques, simply by recrystallization from
ethanol. The reaction between hydrazine hydrate 1, ethyl aceto-
acetate 2, benzaldehyde 3 and malononitrile 4 resulted in pyrano-
pyrazole 5a without need of a base. However, reactions with other
aldehydes proceeded only in the presence of a catalytic amount
(5–10 mol %) of a base. The reaction between 1, 2, 4-methylbenzal-
dehyde 3b and 4 was carried out with different bases to optimize
Pyranopyrazoles are an important class of heterocyclic com-
pounds. They find applications as pharmaceutical ingredients and
* Corresponding author. Tel.: +91 413 2654498; fax: +91 413 2655211.
E-mail address: vasukig@gmail.com (G. Vasuki).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.055

G. Vasuki, K. Kumaravel / Tetrahedron Letters 49 (2008) 5636–5638
5637
R
R
H
O
O
O
O
water, base
rt, 5-10 min
3
CN
NH
CN
HN
NH2
H2N
N
O
2
CN
5
1
2
4
Scheme 1.
Table 2
Four-component synthesis of pyranopyrazoles 5
the procedure (Table 1). Reaction in the presence of piperidine pro-
duced the maximum yield (94%) of 5b (Table 1). The above reaction
was also carried out in conventional organic solvents, to investi-
gate the effect of solvent. Water as the solvent provided the best
yields compared to common organic solvents (Table 1). The use
of ultra pure (milli-Q) water was better than using double distilled
(DD) water. However, all the reactions were carried out in DD
water only. The process was compatible with aliphatic aldehydes,
substituted benzaldehydes and heterocyclic carbaldehydes as
component 3 in the reaction (Table 2).11
All the synthesized compounds were characterized by IR, NMR,
elemental analysis and LCMS. The structure of 5q12 was estab-
lished by X-ray crystallography and was found to be the 2H isomer
which is consistent with an earlier report13 (Fig. 1). The formation
of the product is proposed to involve the following tandem reac-
tions: pyrazolone 6 formation by reaction between 1 and 2, Knoe-
venagal condensation between 3 and 4 (7), Michael addition of 6 to
7, followed by cyclization and tautomerization, (Scheme 2). To
investigate the role of water in the reaction, a two-component
reaction between ethyl acetoacetate and hydrazine hydrate was
carried out in water and organic solvents. It was observed that pyr-
azolone 6 formation was instantaneous in water, whilst the same
reaction occurred slowly in organic solvents. A similar rapid reac-
tion between a 1,3-diketone and hydrazine in water in the pres-
ence of polystyrenesulfonic acid (PSSA) catalyst to yield
pyrazoles was reported by Polshettiwar and Varma.14 The lower
yield of pyranopyrazole 5 and slow reaction rate in organic sol-
vents may be ascribed to the slower rate of the formation of pyraz-
olone 6 with concomitant competitive reactions.
Entry
Aldehyde
Yield
5a
5b
5c
5d
5e
5f
5g
5h
5i
C6H5
83, 80a
94
85
79
89
86
76
80
87
66
74
76
81
78
74
76
83
67
89
74
40-Me–C6H4
40-MeO–C6H4
40-O2N–C6H4
40-Cl–C6H4
40-HO–C6H4
40-F–C6H4
20-MeO–C6H4
30-MeO–C6H4
30-O2N–C6H4
30-MeO,40–MeO–C6H3
30-MeO,50–MeO–C6H3
20-Cl,30–Cl–C6H3
20-Cl,40–Cl–C6H3
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
30-MeO,40-MeO, 50-MeO–C6H2
30-Pyridinyl
40-Pyridinyl
20-Furanyl
20-Thiophenyl
Isopropyl
a
Without catalyst.
The aqueous medium, four-component reaction protocol
developed in the present study offers a fast and eco-friendly
Table 1
Effect of base and solvent
Entry
Base
Solvent
Time (min)
Yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Et3N
Et2NH
Water
Water
Water
Water
Water
Water
Water
Brine
30
30
30
5
30
30
60
60
5
38
58
53
94
62
63
71
22
91
96
66
—
Pyrrolidine
Piperidine
Morpholine
Piperazine
K2CO3
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
DD Watera
Milli-Q Water
EtOH
DMSO
DMF
MeCN
THF
5
90
120
120
60
120
120
60
90
15
—
35
Trace
43
31
37
71
Figure 1. ORTEP diagram of the single-crystal X-ray structure of pyranopyrazole
5q.
CHCl3
CH2Cl2
ClCH2CH2Cl2
Toluene
method for the synthesis of pyranopyrazoles. The protocol also
offers flexibility in tuning the molecular complexity and diversity
in a single step.
a
Double distilled water.

5638
G. Vasuki, K. Kumaravel / Tetrahedron Letters 49 (2008) 5636–5638
cited therein; (b) Tejedor, D.; Garcia-Tellado, F. Chem. Soc. Rev. 2007, 36, 484;
O
(c) Ugi, I. Pure Appl. Chem. 2001, 73, 187; For MCR based heterocyclic libraries
see: (d) Lie’by-Muller, F.; Simon, C.; Constantieux, T.; Rodriguez, J. QSAR Comb.
Sci. 2006, 25, 432; (e) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem.
2004, 4957; (f) Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Y.;
Magedov, I. V.; Kornienko, A. J. Org. Chem. 2007, 72, 3443; For drug discovery
see: (g) Weber, L. Drug Discovery Today 2002, 7, 143; (h) Hulme, C.; Gore, V.
Curr. Med. Chem. 2001, 10, 51.
R
CN
NH2
H2N
H
O
CN
EtO
O
1
2
3
4
3. (a) Herrerias, C. I.; Yao, X.; Li, Z.; Li, C. Chem. Rev. 2007, 107, 2546; (b)
Comprehensive Organic Reactions in Aqueous Media; Li, C. J., Chan, T. H., Eds.;
John Wiley & Sons, 2007; (c) Grieco, P. A. Organic Reactions in Water; Thomson
Science: Glasgow, Scotland, 1998; (d) For recent examples, see: Varma, R. S.
Org. Chem. High. 2007, February 1, Clean Chemical Synthesis in Water. http://
www.organic-chemistry.org/highlights/2007/01February.shtm.; (e) Bonifacio,
V. D. B. Org. Chem. High. 2005, July 25, Organic Reactions in Water. http://
www.organic-chemistry.org/highlights/2005/25July.shtm.
R
CN
N
N
H
CN
O
4. (a) Kljin, J. E.; Engberts, J. B. N. Nature 2005, 435, 746; (b) Narayan, S.; Fokin, M.
G.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275; (c)
Kanizsai, I.; Gyónfalvi, S.; Szadonyi, Z.; Sillanpää, R.; Fülöp, F. Green Chem. 2007,
9, 357.
5. (a) Pirrung, M. C.; Das Sarma, K. Tetrahedron 2005, 61, 11456; (b) Pirrung, M. C.;
Das Sarma, K. J. Am. Chem. Soc. 2004, 126, 444; (c) Hailes, H. C. Org. Process Res.
Dev. 2007, 11, 114.
7
6
R
R
O
H
CN
CN
NH
N
HN
N
C
N
6. Junek, H.; Aigner, H. Chem. Ber. 1973, 106, 914.
N
7. (a) Wamhoff, H.; Kroth, E.; Strauch, K. Synthesis 1993, 11, 1129; (b) Tacconi, G.;
Gatti, G.; Desimoni, G. J. Prakt. Chem. 1980, 322, 831; (c) Sharanina, L. G.;
Marshtupa, V. P.; Sharanin Yu, A. Khim. Geterosikl. Soedin. 1980, 10, 1420.
8. Sharanin Yu, A.; Sharanina, L. G.; Puzanova, V. V. Zh. Org. Khim. 1983, 19, 2609.
9. (a) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya, L.
A.; Niazimbetova, Z. I.; Evans, D. H. Tetrahedron 2003, 59, 7491; (b) Shestopalov,
A. M.; Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.;
Niazimbetova, Z. I.; Evans, D. H. Org. Lett. 2002, 4, 423.
O
9
8
R
O
CN
10. Peng, Y.; Song, G.; Ruiling Dou, R. Green Chem. 2006, 8, 573.
HN
11. General procedure for Pyranopyrazoles: To
hydrazine hydrate 96% 1 (0.107 g, 2 mmol) and ethyl acetoacetate 2 (0.260 g,
2 mmol), aldehyde (2 mmol), malononitrile (0.132 g, 2 mmol) and
a stirred aqueous mixture of
N
NH2
3
4
5a-t
piperidine (5 mol %) were added successively at room temperature under an
open atmosphere with vigorous stirring for 5–10 min. The precipitated solid
was filtered, washed with water and then with a mixture of ethyl acetate/
hexane (20:80). The product obtained was pure by TLC and 1H NMR
spectroscopy. However, the products were further purified by
recrystallization from ethanol.
Scheme 2.
Compound 5q: White solid, mp 218–221 °C (EtOH); 1H NMR (400 MHz, DMSO-
d6): 12.16 (s, 1H), 8.45 (s, 2H), 7.14 (s, 2H), 6.99 (s, 2H), 4.60 (s, 1H), 1.75 (s,
3H); 13C NMR (100 MHz, DMSO-d6) 161.7, 155.2, 153.3, 150.4, 136.3, 123.2,
121.0, 96.7, 56.1, 36.0, 10.2. IR (KBr): 3414, 3325, 3057, 2172, 1662, 1612,
1581, 1493, 1429, 1146, 1086, 1045, 796, 683, 617 cmꢀ1. LC–MS m/z (ESI)
found: 254.0; calcd for C13H12N5O: (M+1)+: 254.1. Anal. Calcd for C13H11N5O: C,
61.65; H, 4.38; N, 27.655. Found: C, 61.89; H, 4.52; N, 27.99.
Acknowledgement
G.V. thanks the Department of Science and Technology (DST),
Government of India, for financial support (Ref. No. SR/S5/GC-22/
2007) under the green chemistry open ended project scheme.
12. Crystallographic data for 5q has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
664522. Copy of the data may be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44 (0) 1223 33603 or
e-mail: deposit@ccdc.cam.ac.uk).
13. Shestopalov, A. M.; Yakubov, A. P.; Tsyganov, D. V.; Emel’yanova, Yu M.;
Nesterov, V. N. Khimiya Geterotsiklicheskikh Soedinenii [Chem. Heterocycl.
Compd.] 2002, 38, 1180 [CAN 139:36480].
References and notes
1. (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford
University Press: Oxford, UK, 1998; (b) Anastas, P. T.; Williamson, T. Green
Chemistry, Frontiers in Benign Chemical Synthesis and Process; Oxford University
Press: Oxford, UK, 1998.
2. (a) Zhu, J.; Bienayme, H. In Multicomponent Reactions; Zhu, J., Bienayme, H.,
Eds.; WILEY-VCH Verlag GmbH & Co: KGaA, Weinheim, 2005. and references
14. Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 397.