Mild, four-component synthesis of 6-amino-4-aryl-3-methyl-1,4- dihydropyrano[2,3-c]pyrazole-5-carbonitriles catalyzed by titanium dioxide nano-sized particles

Article abstract of DOI:10.1007/s11164-012-0991-1

A convenient and efficient solvent-free procedure is described for preparation of 6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5- carbonitriles by four-component reaction of hydrazine hydrate, ethyl acetoacetate, aryl aldehyde, and malononitri

Full text of DOI:10.1007/s11164-012-0991-1

Res Chem Intermed
DOI 10.1007/s11164-012-0991-1
Mild, four-component synthesis of 6-amino-4-aryl-3-
methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitriles catalyzed by titanium dioxide
nano-sized particles
•
Hamid Reza Shaterian Kobra Azizi
Received: 17 December 2012 / Accepted: 20 December 2012
Ó Springer Science+Business Media Dordrecht 2013
Abstract A convenient and efficient solvent-free procedure is described for
preparation of 6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-car-
bonitriles by four-component reaction of hydrazine hydrate, ethyl acetoacetate, aryl
aldehyde, and malononitrile in the presence of a catalytic amount of titanium
dioxide nano-sized particles. Short reaction times, high yields under ambient con-
ditions, simple reaction, clean work-up, and reusability of the nano heterogeneous
catalyst are the advantages of this method.
Keywords Nano TiO2 Á Four-component reaction Á Solvent-free conditions Á
6-Amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles Á
Hydrazine hydrate
Introduction
1,4-Dihydropyrano[2,3-c]pyrazole-5-carbonitriles are important compounds with
biological [1], anticancer [1], antimicrobial [2], anti-inflammatory [3], insecticidal
[4], and molluscicidal [5] activity. Pyranopyrazole was first synthesized by two-
component reaction of 3-methyl-1-phenylpyrazolin-5-one and tetracyanoethylene in
the presence of triethylamine [6]. Later, several two-component reactions involving
pyran derivatives and hydrazine hydrate [7] or the reaction between 3-methyl-2-
pyrazolin-5-one and benzylidenemalononitrile [8] to obtain pyranopyrazoles were
used to prepare this class of medicinal compounds.
Several three-component syntheses of 6-amino-4-aryl-3-methyl-1,4-dihydropyr-
ano[2,3-c]pyrazole-5-carbonitriles from pyrazolin-5-one, malononitrile, and aryl
H. R. Shaterian (&) Á K. Azizi
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan,
PO Box 98135-674, Zahedan, Iran
e-mail: hrshaterian@chem.usb.ac.ir
123

H. R. Shaterian, K. Azizi
aldehydes, catalyzed by cinchona alkaloid organocatalysts [8] or triethylammonium
acetate [9], have been reported in the literature. Recently, per-6-amino-b-cyclodextrin
[10], c-alumina [11], and L-proline [12] have been studied for synthesis of 6-amino-4-
aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles via four-component
reactions from hydrazine hydrate, ethyl acetoacetate, aldehydes, and malononitrile.
Despite many reported methods, development of new synthetic strategies using
readily accessible heterogeneous catalysts still attracts much attention because of the
importance of these molecules, especially if the new methods can overcome the
disadvantages of reported procedures.
Efficient and environmentally benign chemical processes and methods in the
presence of heterogeneous recyclable catalysts under mild and solvent-free
conditions are a major challenge for chemists in organic synthesis [13]. In
continuation of our research on solid heterogeneous catalysts [14–18], herein we
report a facile, general, and efficient method for preparation of 6-amino-4-aryl-3-
methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles by four-component reac-
tion of hydrazine hydrate, ethyl acetoacetate, aryl aldehydes, and malononitrile,
using titanium dioxide nano-sized particles as an expedient and recyclable catalyst
under mild, solvent-free conditions (Scheme 1). The reaction has several advan-
tages over other reported methods.
Nanocatalysts have attracted the attention of researchers working on catalysis and
nanoparticles, because their high surface-to-volume ratio results in high efficiency
and selectivity [19, 20]. Titanium dioxide nano-sized particles have been proved to
be a good catalyst because of their high activity, non-toxicity, ready availability,
reusability, strong oxidizing power, and long-term stability [21, 22].
Experimental
All reagents were purchased from Merck and Sigma-Aldrich and used without
further purification. Nano-TiO2 ellipsoids of size \3 nm (95 % anatase, 5 %
brokite; CAS no. 1317-70-0) were purchased from Merck. All yields refer to
isolated products after purification. Products were characterized by comparison of
physical data with those of authentic samples and by use of spectroscopic data (IR
and NMR). NMR spectra were recorded on a Bruker Avance DPX 400-MHz
instrument. The spectra were measured in DMSO-d6 relative to TMS (0.00 ppm).
IR spectra were recorded on a Jasco FT-IR 460 Plus spectrophotometer. Melting
R
H
O
O
NC
Nano TiO2
O
NC
CN
H2O.NH2NH2
N
OEt
RT, Solvent free
N
H2N
O
R
H
R= H,Cl,NO2,CH3,OCH3,N(Me)2,Br,F,OH
Scheme 1 Preparation of 6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles by
a four-component reaction using titanium dioxide nano-sized particles as recyclable catalyst under
solvent-free conditions
123

Titanium dioxide nano-sized particles-catalyzed synthesis
points were determined in open capillaries with a Buchi 510 melting point
apparatus. TLC was performed on Polygram silica–gel SILG/UV 254 plates.
General procedure for synthesis of 6-amino-4-aryl-3-methyl-1,
4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile derivatives
A mixture of hydrazine hydrate (1 mmol) and ethyl acetoacetate (1 mmol) was
stirred at room temperature until 3-methyl-2-pyrazolin-5-one was precipitated and
its formation was complete (5 min). The mixture was cooled to 0 °C then aryl
aldehyde (1 mmol), malononitrile (1 mmol), and titanium dioxide nano-sized
particles (0.25 mmol) were added at room temperature. The progress of the reaction
was monitored by TLC. After completion of the reaction, the mixture was washed
with ethyl acetate and filtered to recover the catalyst. The filtrate solution was
evaporated and the crude product was recrystallized from ethanol to afford the pure
pyranopyrazole derivatives in 81–96 % yields.
The desired pure products were characterized by comparison of their physical
data with those of known compounds [11, 23].
6-Amino-1,4-dihydro-3-methyl-4-(2-nitrophenyl)pyrano[2,3-c]pyrazole-
5-carbonitrile (Table 2, entry 10)
(KBr, cm-1): 1076, 1169, 1348, 1407, 1527, 1600, 1653, 2196, 2932, 3118, 3217,
1
3469; H NMR (400 MHz, (DMSO-d6): d (ppm) = 1.92 (s, 3H, CH3), 4.79 (s, 1H,
4H), 6.20 (s, 2H, NH2), 7.55 (t, 1H, J = 8.0 Hz, Ar–H), 7.62 (d, 1H, J = 7.6 Hz,
Ar–H), 8.00–8.03 (m, 2H, Ar–H), 11.34 (s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6): d (ppm) = 9.70, 29.0, 56.5, 112.6, 120.2, 123.2, 128.4, 128.6, 135.7, 141.3,
146.3, 151.3, 154.6, 160.9.
Results and discussion
In our initial experiments, condensation of hydrazine hydrate, ethyl acetoacetate,
benzaldehyde, and malononitrile (molar ratio 1:1:1:1) was performed in the
presence of different amounts of the catalyst at room temperature under solvent-free
conditions. The results (Table 1) clearly indicate that 0.25 mmol (0.02 g) nano-
TiO2 is an effective amount of catalyst for this transformation.
We also used bulk TiO2 for synthesis of 6-amino-4-aryl-3-methyl-1,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitriles (Table 1, entry 6). The reaction was not
complete after 3 h; almost 50 % of the starting materials were intact and the desired
product was obtained in low yield. Thus, it is necessary to use titanium dioxide
nano-sized particles.
Under these optimized reaction conditions, the scope and efficiency of the
reaction were investigated for synthesis of a wide variety of substituted 6-amino-4-
aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles. The results are
summarized in Table 2.
123

H. R. Shaterian, K. Azizi
Table 1 Optimization of the amount of titanium dioxide nano-sized particles used as catalyst in the
reaction of hydrazine hydrate, ethyl acetoacetate, benzaldehyde, and malononitrile under solvent-free
conditions at room temperature
Entry
Catalyst (mmol)
Time (min)
Yield (%)a
1
2
3
4
5
6
a
0.1
25
12
7
75
78
87
96
95
50b
0.15
0.2
0.25
0.3
3
3
0.25
3 h
Yields refer to isolated pure product
b
The reaction was performed in the presence of bulk TiO2 for synthesis
Table 2 Four-component synthesis of 6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitriles
Entry
R
Time (min)
Yield (%)a
Found M.P. (°C)/[Lit. M.P (°C)] [Ref.]
1
H
3
6
4
5
4
4
5
3
5
2
4
5
4
5
5
6
6
6
4
96
81
93
89
87
85
86
86
85
82
87
87
85
85
82
84
81
81
92
245–247 [245–247] [11, 23]
235–237 [235–237] [11, 23]
234–235 [234–235] [11, 23]
159–160 [157–159] [11, 23]
244–245 [245–247] [11, 23]
235–237 [235–237] [11, 23]
178–180 [178–180] [11, 23]
223–225 [222–224] [11, 23]
146–148 [146–148] [11, 23]
221–223 [221–223] [11, 23]
183–185 [183–185] [11, 23]
173–175 [173–175] [11, 23]
207–209 [206–208] [11, 23]
212–213 [210–212] [11, 23]
192–194 [193–195] [11, 23]
209–211 [209–211] [11, 23]
225–227 [224–226] [11, 23]
167–169 [167–169] [11, 23]
194–196 [193–195] [11, 23]
2
3-CH3O-4-HO
4-Cl
3
4
4-CH3O
4-NO2
5
6
2,4-Cl2
4-Br
7
8
3-Br
9
2-Cl
10
11
12
13
14
15
16
17
18
19
a
2-NO2
2,4-Cl2
4-F
4-CH3
2,5-(CH3O)2
3,4(CH3O)2
3,4,5-(CH3O)3
4-HO
4-N(CH3)2
3-NO2
Yields refer to the isolated pure products. The products were characterized by comparison of their
physical data (melting points, and IR and 1H and 13C NMR spectra) with those of known compounds
[11, 23]
Interestingly, a variety of aryl aldehydes with electron-withdrawing or releasing
substituents (ortho, meta, and para-substituted) participated well in this reaction and
gave the 6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles
in good to excellent yield.
123

Titanium dioxide nano-sized particles-catalyzed synthesis
On the basis of the literature [23], we propose following mechanism for synthesis
of 6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles in the
presence of titanium dioxide nano-sized particles as catalyst. First, pyrazolone 3 is
formed by reaction of 1 and 2. Knoevenagel condensation of 4 and 5 produced
2-benzylidenemalononitrile (6), Michael addition of 3 and 6, and subsequent
cyclization and tautomerization afforded the corresponding product (Scheme 2).
In Table 3 the results obtained in this work are compared with those recently
reported in the literature for use of such catalysts as L-proline [12], c-alumina [11],
cinchona alkaloids [8], and nano-sized magnesium oxide MgO [23] to prepare
6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles. The table
O
O
H2O.NH2NH2
1
OEt
2
NC
4
CN
+
H
CN
CN
O
Titanium dioxide
nano-sized particles
R
R
6
5
O
R
N
N
R
3
R
CN
NC
C
N
N
7
R
O
N
H2N
O
N
H
N
9(Product)
H
CN
H
NH
O
N
N
8
Scheme 2 Proposed mechanism for synthesis of 6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]-
pyrazole-5-carbonitriles in the presence of titanium dioxide nano-sized particles as catalyst
Table 3 Comparison of results obtained by use of titanium dioxide nano-sized particles as catalyst for
synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles with those obtained by use of L-proline, c-alumina,
cinchona alkaloids, and nano-sized magnesium oxide MgO
Entry
Catalyst
Time
Yield (%)a
1
2
3
4
5
a
L-Proline
10 min
50 min
12 h
90
c-Alumina
80
Cinchona alkaloids
84
Nano-sized magnesium oxide MgO
Nano-sized titanium dioxide TiO2
10 min
3 min
97
96 (Present work)
Based on reaction of hydrazine hydrate, ethyl acetoacetate, benzaldehyde, and malononitrile
123

H. R. Shaterian, K. Azizi
100
98
97
96
96
100
90
80
70
60
50
40
30
20
10
94
93
88
93
90
Product yield(%)
Catalyst yield(%)
0
1
2
3
4
5
Number of runs
Fig. 1 Reusability of titanium dioxide nano-sized particles as catalyst
shows that titanium dioxide nano-sized particles are the most efficient catalyst with
regard to reaction time. Yield is equivalent to that reported for the other catalysts.
We also investigated recycling of the catalyst under solvent-free conditions
using, as model reactants, hydrazine hydrate, ethyl acetoacetate, benzaldehyde, and
malononitrile. After completion of the reaction, the crude solid product was
dissolved in ethyl acetate. The mixture was filtered for separation of the catalyst.
The catalyst was washed twice with ethyl acetate (2 9 5 mL). The recovered
catalyst was dried under vacuum and was used for subsequent catalytic runs
(Table 2, entry 1). The recovered catalyst was reused five times without any loss of
activity (Fig. 1).
Conclusion
We have developed an environmentally benign and straightforward procedure for
synthesis of 6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbo-
nitriles using titanium dioxide nano-sized particles as catalyst under solvent-free
and ambient conditions. This procedure has several advantages over previously
reported catalysts, for example milder and cleaner reactions, easier workup, reduced
reaction times, reusable catalyst, and eco-friendly promising strategy.
Acknowledgments We are thankful to Sistan and Baluchestan University Research Council for partial
support of this research.
References
1. E.S. El-Tamany, F.A. El-Shahed, B.H. Mohamed, J. Serb. Chem. Soc. 64, 9 (1999)
2. M.E.A. Zaki, H.A. Soliman, O.A. Hiekal, A.E.Z. Rashad, Naturforsch. C. 61, 1 (2006)
3. Z.H. Ismail, G.M. Aly, M.S. El-Degwi, H.I. Heiba, M.M. Ghorab, Egypt. J. Biot. 13, 73 (2003)
4. F.M. Abdelrazek, P. Metz, N.H. Metwally, S.F. El- Mahrouky, Arch. Pharm. 339, 456 (2006)
5. N. Oloppe, L.M. Fisher, R. Howes, A. Potter, G.S. Robertson Alan, A.E. Surgenor, Bioorg. Med.
Chem. 14, 4792 (2006)
6. H. Junek, H. Aigner, Chem. Ber. 106, 914 (1973)
123

Titanium dioxide nano-sized particles-catalyzed synthesis
7. Y. Peng, G. Song, R. Dou, Green Chem. 8, 573 (2006)
8. S. Gogoi, C.G. Zhao, Tetrahedron Lett. 50, 2250 (2009)
9. R.S Balaskar, S.N. Gavade, M.S. Mane, B.B. Shingate, M.S. Shingare, D.V. Mane, Chin. Chem. Lett.
21, 1175 (2010)
10. K. Kanagaraj, K. Pitchumani, Tetrahedron Lett. 51, 3312 (2010)
11. H. Mecadon, M.R. Rohman, M. Rajbangshi, B. Myrboh, Tetrahedron Lett. 52, 2523 (2011)
12. H. Mecadon, M.R. Rohman, I. Kharbangar, B.M. Laloo, I. Kharkongor, M. Rajbangshi, B. Myrboh,
Tetrahedron Lett. 52, 3228 (2011)
13. M.M. Heravi, F. Derikvand, L. Ranjbar, F.F. Bamoharram, J. Mol. Catal. Chem. A. 261, 156 (2007)
14. H.R. Shaterian, H. Yarahmadi, Tetrahedron Lett. 49, 1297 (2008)
15. H. R Shaterian, H. Yarahmadi, Arkivoc 2, 105 (2008)
16. H.R. Shaterian, M. Ghashang, A. Hassankhani, Dyes Pigments. 76, 564 (2008)
17. H.R. Shaterian, A. Hosseinian, M. Ghashang, Synth. Commun. 38, 4097 (2008)
18. H.R Shaterian, A. Hosseinian, M. Ghashang, Synth. Commun. 19, 3375 (2008)
19. S. Yamazaki, Bull. Chem. Soc. Jpn. 69, 2955 (1996)
20. H.J. Reich, F. Chow, S.L. Peake, Synthesis 2, 299 (1978)
21. I. Mohammadpoor-Baltork, M. Moghadama, S. Tangestaninejada, V. Mirkhani, Z. Eskandari,
H. Salavati, J. Iran. Chem. Soc. 8, 17 (2011)
22. S. Tangestaninejada, M. Moghadama, V. Mirkhani, I. Mohammadpoor-Baltork, H. Salavati, J. Iran.
Chem. Soc. 7, 161 (2010)
23. M. Babaie, H. Sheibani, Arab. J. Chem. 4, 159 (2010)
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