A green and convenient 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

Article abstract of DOI:10.1016/j.tetlet.2012.08.010

A green and efficient one-pot, four-component synthesis of methyl 6-amino-5-cyano-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates in water is described. The method is catalyst-free, atom-economical, and does not involve tedious work-up or purification affording the target compounds in good yields. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.010

Tetrahedron Letters 53 (2012) 5519–5522
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A green and convenient 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
Adeleh Moshtaghi Zonouz a, , Issa Eskandari a, Hamid Reza Khavasi b
⇑
a Chemistry Department, Faculty of Science, Azarbaijan Shahid Madani University, Tabriz, Iran
b Shahid Beheshti University, G.C., Evin, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A green and efficient one-pot, four-component synthesis of methyl 6-amino-5-cyano-4-aryl-2,4-dihydro-
pyrano[2,3-c]pyrazole-3-carboxylates in water is described. The method is catalyst-free, atom-economi-
cal, and does not involve tedious work-up or purification affording the target compounds in good yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 16 May 2012
Revised 23 July 2012
Accepted 2 August 2012
Available online 10 August 2012
Keywords:
Pyrano[2,3-c]pyrazole
Multi-component reaction
Tandem reaction
Green synthesis
Green chemistry techniques continue to grow in importance.
Alternative processes help to conserve resources and can reduce
costs. The replacement of conventional solvents with water, which
is harmless to health and is available in large quantities, is an inter-
esting basic approach along these lines.1–3
Multi-component reactions (MCRs) have emerged as a powerful
tool for the construction of novel and complex molecular struc-
tures due to their advantages over conventional multi-step synthe-
sis. The major advantages of MCRs include lower costs, shorter
reaction times, high atom-economy, energy saving, and the avoid-
ance of time consuming and expensive purification processes. It is
established that MCRs are generally much more environmentally
friendly, and offer rapid access to large compound libraries with di-
verse functionalities.4–7
Pyranopyrazoles are fused heterocyclic compounds that exhibit
bactericidal,8 fungicidal,9 insecticidal,10 molluscicidal,11,12 analges-
tic,13 and anti-inflammatory activities,14 and act as vasodilators
and hypotensive,15 hypoglycemic, and anticancer agents.16,17 They
are also potential inhibitors of human Chk1 kinase.18 Due to their
biological significance, there has been considerable interest in
developing synthetic methods for the preparation of pyranopyraz-
ole derivatives.19–26 Four-component syntheses of pyranopyraz-
oles using hydrazine hydrate, ethyl acetoacetate, malononitrile,
and aromatic aldehydes have been reported in the presence of
catalysts such as b-cyclodextrin,27 triethylamine,28 cinchona alka-
loid derivatives,29 and imidazole.30
As part of our efforts to develop new synthetic methods in
heterocyclic chemistry,31–34 herein we report for the first time, a
catalyst-free, four-component reaction of dimethyl acetylenedicar-
boxylate, hydrazine hydrate, malononitrile, and aromatic aldehydes
for the synthesis of novel 3-methoxycarbonyl substituted
pyrano[2,3-c]pyrazoles in water.
Initially, we carried out the MCR between dimethyl acetylenedi-
carboxylate, hydrazine hydrate, malononitrile, and aromatic alde-
hydes in water at 55–60 °C. After completion of the reaction (TLC
monitoring), TLC indicated the mixture of products, so the reaction
was conducted in two stages, first of all treatment of arylaldehyde
and malononitrile in water at 55–60 °C gave the benzylidene mal-
ononitrile which, without isolation, was directly treated with di-
methyl acetylenedicarboxylate and hydrazine hydrate. Stirring
was maintained for an additional 0.5 h. The precipitated solid
was filtered and purified by recrystallization from EtOH to give
the pyrano[2,3-c]pyrazole derivatives 5a–j in good yields (Ta-
ble 1).35 As indicated in Table 1, both electron-poor and electron-
rich aldehydes were well tolerated.
The structures of the products were deduced from their elemen-
tal analysis and spectral data. In addition, the structure of 5i was
determined by an X-ray crystallographic study.36,37
Figure 1 shows the structure and the atomic numbering scheme
used for compound 5i.
The formation of pyranopyrazole derivatives 5a–j can be
rationalized by the following tandem reactions: (1) formation of
⇑
Corresponding author.
E-mail address: adelehmz@yahoo.com (A. Moshtaghi Zonouz).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.010

5520
A. Moshtaghi Zonouz et al. / Tetrahedron Letters 53 (2012) 5519–5522
Table 1
Synthesis of 3-methyl carboxylate substituted pyrano[2,3-c]pyrazoles via a four-component reaction
Ar
CO2Me
CO2Me
NH
O
CN
H2O, 1.5-2.5 h
NC
H2N NH2
H2O
Ar
H
55-60 o
C
CN
N
H2N
O
CO2Me
5a-j
1
2
3
4
Entry
ArCHO
Product
Time (h)
Mp (°C)
Yielda (%)
CHO
CO2Me
NH
NC
1
1.5
231–232
78
N
H2N
O
5a
CHO
Me
Me
NC
CO2Me
NH
2
3
4
2.5
239–240
220–222
242–244
75
70
73
N
H2N
Me
O
5b
CHO
CO2Me
NH
Me
NC
2.5
N
H2N
O
5c
CHO
Br
Br
CO2Me
NH
NC
2.5
N
H2N
O
5d
Br
CHO
Br
CO2Me
NH
5
2.5
247–248
75
NC
N
H2N
O
5e
CHO
NO2
O2N
NC
CO2Me
NH
6
2.5
230–232
64
N
H2N
O
5f

A. Moshtaghi Zonouz et al. / Tetrahedron Letters 53 (2012) 5519–5522
5521
Table 1 (continued)
Entry
ArCHO
Product
Time (h)
Mp (°C)
Yielda (%)
CHO
O2N
CO2Me
NH
7
8
9
NO2
NC
2.5
236–237
66
N
H2N
O
5g
NO2
CHO
O2N
CO2Me
NH
1.5
244–245
76
NC
H2N
HO
N
O
5h
CHO
CO2Me
NH
OH
NC
H2N
MeO
1.5
219–220
84
N
O
5i
CHO
CO2Me
NH
OMe
NC
10
2.5
208–210
75
N
H2N
O
5j
a
Yield of isolated pure product after recrystallization.
CO2Me
O
CN
H2O, 1.5-2.5 h
H2N NH2
H2O
Ar
H
55-60o
C
CN
CO2Me
1
2
3
4
Ar
CO2Me
CO2Me
NH
CN
CN
NC
H2N
HN
HN
N
Ar
O
5a-j
O
6
7
Scheme 1. Proposed reaction pathway.
In summary, a simple, efficient, eco-friendly, and catalyst-free
process has been developed for the synthesis of novel pyranopy-
razole derivatives in water. This green, four-component reaction,
reported for the first time with dimethyl acetylenedicarboxylate,
does not involve tedious work-up or purification operations, and
gives rise to the target compounds in good yields.
Figure 1. ORTEP structure of 5i.
benzylidine malononitrile 7 via Knoevenagal condensation be-
tween aldehyde 1 and malononitrile 2; (2) formation of pyrazolone
6 by reaction of hydrazine hydrate 3 and dimethyl acetylenedicar-
boxylate 4; and (3) Michael addition of 6,7, followed by cyclization
and tautomerization (Scheme 1).
Acknowledgements
The authors sincerely acknowledge the Research Office of
Azarbaijan Shahid Madani University for financial support.

5522
A. Moshtaghi Zonouz et al. / Tetrahedron Letters 53 (2012) 5519–5522
23. Mecadon, H.; Rohman, M. D. R.; Kharbangar, I.; Laloo, B. M.; Kharkongor, I.;
Supplementary data
Rajbangshi, M.; Myrboh, B. Tetrahedron Lett. 2011, 52, 3228.
24. Dyachenko, V. D.; Rusanov, E. B. Chem. Heterocycl. Compd. 2004, 40, 231.
25. Al-Matar, H. M.; Khalil, K. D.; Adam, A. Y.; Elnagdi, M. H. Molecules 2010, 15,
6619.
26. Litvinov, Y. M.; Rodinovskaya, L. A.; Shestopalov, A. M. Russ. Chem. Bull., Int. Ed.
2009, 58, 2362.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.010.
27. Vasuki, G.; Kumaravel, K. Tetrahedron Lett. 2008, 49, 5636.
28. Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.;
Niazimbetova, Z. I.; Evans, D. H. Tetrahedron 2003, 59, 7491.
29. Gogoi, S.; Zhao, C. G. Tetrahedron Lett. 2009, 50, 2252.
30. Siddekha, A.; Nizam, A.; Pasha, M. A. Spectrochem. Acta A 2011, 81, 431.
31. Moshtaghi, Z. A.; Baradaran, H. S. Synth. Commun. 2008, 38, 290.
32. Moshtaghi, Z. A.; Raisossadati, O. M.; Sadeghi, Sh. Q. Arkivoc. 2006, xiv, 15.
33. Moshtaghi, Z. A.; Sahranavard, N. EJOC 2010, 7(S1), S372.
34. Moshtaghi, Z. A.; Eskandari, I.; Moghani, D. Chem. Sci. Trans. 2012, 1, 91.
References and notes
1. Li, C. J.; Chan, T. H. Comprehensive Organic Reactions in Aqueous Media, Eds.
John Wiley & Sons, 2007.
2. Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725.
3. Breslow, R. Acc. Chem. Res. 1991, 24, 159.
4. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
5. Wender, P. A.; Hanhdy, S. T.; Wright, D. L. Chem. Ind. 1997, 765.
6. Weber, L. Curr. Opin. Chem. Biol. 2000, 4, 295.
35. Typical procedure for the synthesis of pyranopyrazoles 5a–j:
A mixture of
malononitrile (2) (0.066 g, 1 mmol) and benzaldehyde (0.1 ml, 1 mmol) in H2O
(3 ml) was stirred at 55–60 °C under an open atmosphere for 1 h. Next,
7. Dömling, A. Curr. Opin. Chem. Biol. 2002, 6, 306.
8. Nasr, M. N.; Gineinah, M. M. Arch. Pharm. Med. Chem. 2002, 335, 289.
9. Feurer, A.; Luithle, J.; Wirtz, S.; Koenig, G.; Stasch, J.; Stahl. E.; Schreiber, R.;
Wunder, F.; Lang, D. Bayer Healthcare AG, Germany, PCT Int. Appl., WO
2004009589; Chem. Abstr. 2004, 140, 146157.
10. Ismail, Z. H.; Aly, G. M.; El-Degwi, M. S.; Heiba, H. I.; Ghorab, M. M. Egypt. J.
Biotech. 2003, 13, 73.
11. Abdelrazek, F. M.; Metz, P.; Metwally, N. H.; El-Mahrouky, S. F. Arch. Pharm.
Med. Chem. 2006, 339, 456.
12. Abdelrazek, F. M.; Metz, P.; Kataeva, O.; Jaeger, A.; El-Mahrouky, S. F. Arch.
Pharm. Med. Chem. 2007, 340, 543.
13. Kuo, S. C.; Huang, L. J.; Nakamura, H. J. Med. Chem. 1984, 27, 539.
14. Zaki, M. E. A.; Soliman, H. A.; Hiekal, O. A.; Rashad, A. E. Z. Naturforsch. C 2006,
61, 1.
15. Ahluwalia, V. K.; Dahiya, A.; Indian, V. Indian J. Chem. 1997, 36B, 88.
16. Nadia, M. R.; Nahed, Y. K.; Fahmyb, A.; El-Sayeda, A. A. F. Pharma Chem. 2010, 2,
400.
17. Wang, J. L.; Liu, D.; Zheng, Z. J.; Shan, S.; Han, X.; Srinivasula, S. M.; Croce, C. M.;
Alnemri, E. S.; Huang, Z. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7124.
18. Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.; Robertson, A. G. S.; Surgenor, A.
E. Bioorg. Med. Chem. 2006, 14, 4792.
19. Mecadon, H.; Rohman, M. D. R.; Rajbangshi, M.; Myrboh, B. Tetrahedron Lett.
2011, 52, 2523.
hydrazine
hydrate
(3)
96%
(0.05 ml,
1 mmol)
and
dimethyl
acetylenedicarboxylate (4) (0.14 ml, 1.2 mmol) were added. The mixture was
stirred until completion of the reaction as indicated by TLC (30 min). After
cooling, the precipitated solid was filtered, washed with H2O, and
recrystallized from EtOH. Compound 5a was obtained as white crystals.
Methyl
6-amino-5-cyano-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-3-
carboxylate (5a). White crystals; mp 231–232 °C; yield: 0.232 g (78%). IR
(KBr) (
m
max; cmÀ1): 3386, 3325, 3266, 2953, 2202, 1723, 1654, 1613, 1469,
1396, 1077. 1H NMR (250 MHz, DMSO-d6): d = 3.59 (3H, s, OMe), 4.70 (1H, s,
CH), 7.04–7.27 (5H, m, CH), 7.24 (2H, NH2), 13.73 (1H, s, NH) ppm. 13C NMR
(62.5 MHz, DMSO-d6): d = 37.45 (CH), 52.15 (CH3 ester), 58.16 (C), 104.65 (C),
120.74 (CN), 127.10 (CH), 127.79 (CH), 128.67 (CH), 129.17 (C), 145.36 (C),
155.86 (C), 158.83 (C), 160.61 (C@O) ppm. Anal. Calcd. for C15H12N4O3: C,
60.81; H, 4.08; N, 18.91. Found: C, 60.64; H, 3.95; N, 18.84.
36. X-ray data for 5i: CCDC 875556; C15H12N4O4, Mw = 312.29 g/mol, monoclinic
system, space group P21/c, a = 8.7489(12), b = 20.648(3), c = 8.3466(11) Å,
b = 103.748(10) °, V = 1464.6(3) Å3, Z = 4, Dcalc = 1.416 g cmÀ3
,
l(Mo–
K
a
) = 0.103 mmÀ1, crystal dimensions = 0.33 Â 0.30 Â 0.25 mm. The structure
was solved using SHELXS. The structure refinement and data reduction were
carried out with SHELXL from the X-Step32 suite of programs. The non-
hydrogen atoms were refined anisotropically by full matrix least-squares on F2
values to final R1 = 0.0610, wR2 = 0.1401 and S = 1.115 with 16504 parameters
using 3964 independent reflections (h range = 2.40–29.16 °). Hydrogen atoms
were located from expected geometries and were not refined.
20. Kanagaraj, K.; Pitchumani, K. Tetrahedron Lett. 2010, 51, 3312.
21. (a) Shaabani, A.; Sarvary, A.; Rezayan, A. H.; Keshipour, S. Tetrahedron 2009, 65,
3492; (b) Shaabani, A.; Soleimani, E.; Sarvary, A.; Rezayan, A. H. Bioorg. Med.
Chem. Lett. 2008, 18, 3968.
22. Litvinov, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.; Shestopalov, A. M. J.
Comb. Chem. 2009, 11, 914.
37. X-STEP32 Version 1.07b, X-ray structure evaluation package, 2000, Stoe&Cie,
Darmstadt, Germany.