Mg-al hydrotalcite as a first heterogeneous basic catalyst for the synthesis of 4H-pyrano[2,3-c]pyrazoles through a four-component reaction

Article abstract of DOI:10.1080/00397911.2010.481753

Mg/Al hydrotalcite acts as an efficient heterogeneous basic catalyst for the synthesis of 4H-pyrano[2,3-c]pyrazoles via a multicomponent reaction of aromatic hydrazine hydrate, ethyl acetoacetate, aldehydes, and malononitrile in ethanol at ambient tempera

Full text of DOI:10.1080/00397911.2010.481753

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Mg-Al Hydrotalcite as a First
Heterogeneous Basic Catalyst for the
Synthesis of 4H-Pyrano[2,3-c]pyrazoles
Through a Four-Component Reaction
a
a
a
Siddheshwar W. Kshirsagar , Nitin R. Patil & Shriniwas D. Samant
a
Organic Chemistry Research Laboratory, Institute of Chemical
Technology, Matunga, Mumbai, India
Published online: 30 Mar 2011.
To cite this article: Siddheshwar W. Kshirsagar , Nitin R. Patil & Shriniwas D. Samant (2011) Mg-Al
Hydrotalcite as a First Heterogeneous Basic Catalyst for the Synthesis of 4H-Pyrano[2,3-c]pyrazoles
Through a Four-Component Reaction, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:9, 1320-1325, DOI: 10.1080/00397911.2010.481753
To link to this article: http://dx.doi.org/10.1080/00397911.2010.481753
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1
Synthetic Communications , 41: 1320–1325, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.481753
Mg-Al HYDROTALCITE AS A FIRST HETEROGENEOUS
BASIC CATALYST FOR THE SYNTHESIS OF
H-PYRANO[2,3-c]PYRAZOLES THROUGH A
4
FOUR-COMPONENT REACTION
Siddheshwar W. Kshirsagar, Nitin R. Patil, and
Shriniwas D. Samant
Organic Chemistry Research Laboratory, Institute of Chemical Technology,
Matunga, Mumbai, India
GRAPHICAL ABSTRACT
Abstract Mg/Al hydrotalcite acts as an efficient heterogeneous basic catalyst for the
synthesis of 4H-pyrano[2,3-c]pyrazoles via a multicomponent reaction of aromatic hydra-
zine hydrate, ethyl acetoacetate, aldehydes, and malononitrile in ethanol at ambient tem-
perature. The hydrotalcite catalyst was easily separated from the reaction mixture and
can be reused.
Keywords Heterogeneous catalyst; hydrotalcite; multicomponent reactions
INTRODUCTION
Multicomponent reactions (MCRs) have emerged as a means to achieve atom
economy and benign synthesis by virtue of their convergence, productivity, easy
execution, and generation of highly diverse and complex products from easily avail-
[
1]
able starting materials in a single operation. One-pot MCRs that involve economi-
cally and environmental friendly chemical processes have received attention as a
strategy for ‘‘green’’ organic syntheses. The importance of MCRs in organic syn-
thesis has been recognized, and considerable efforts from both academic
and industrial researchers have been focused on the design and development of
Received December 9, 2009.
Address correspondence to Shriniwas D. Samant, Organic Chemistry Research Laboratory,
Institute of Chemical Technology, N. M. Parekh Marg, Matunga, Mumbai 400 019, India. E-mail:
samantsd@yahoo.com
1
320

Mg-Al HYDROTALCITE AS BASIC CATALYST
1321
Figure 1.
multicomponent procedures for the generation of libraries of heterocyclic
[
compounds. 4H-Pyrano[2,3-c]pyrazoles (1) are important because of their pharma-
2]
[3]
[4]
cological properties such as antimicrobial and anti-inflammatory activities. Fur-
[5]
thermore, they show molluscicidal activity and have been identified as a screening
[6]
hit for Chk1 kinase inhibitor. Otto first attempted synthesis of 4H-pyrano[2,3-c]
pyrazole from 3-methyl-3-pyrazolin-5-one and arylidenemalononitrile using base
[
catalyst. From the literature, we observed that very few catalysts have been used
7]
[
for the synthesis of 4H-pyrano[2,3-c]pyrazoles (e.g., triethylamine, piperidine,
8]
[9]
[
10]
[11]
morpholine,
[
bromide,
p-dodecylbenzenesulfonic acid,
[13]
potassium fluoride dehydrate,
hexadecyltrimethylammonium
[14]
and electrogenerated bases ). In
12]
these methodologies, two- or three-component strategies have been employed
for the preparation of 4H-pyrano[2,3-c]pyrazoles. Michael addition of ethyl aceto-
acetate to the Knoevenagel product of malononitrile and benzaldehyde leads to
[
15]
the formation of 2-amino-3-cyano-4H-pyran (Fig. 1). 4H-pyrano[2, 3-c]pyrazoles
Fig. 2) are obtained when a mixture of 2, hydrazine hydrate, and a catalytic amount
of piperazine is heated in water under combined microwave and ultrasound
(
[
16]
irradiation.
Looking at these reactions, we thought it worthwhile to attempt a four-
component, one-pot reaction, combining the essence of these reactions of 3, 4, 5,
and 6 to obtain 1.
Heterogeneous catalysts are vital in green synthesis because of their easy recov-
ery and subsequent reuse. Our research group has been developing efficient and
[
17]
environmentally benign protocols using hydrotalcites as heterogeneous catalysts.
In continuation of our efforts to develop efficient and environmentally benign pro-
tocols for the synthesis of heterocycles, we report herein for the first time the use of a
solid base, Mg=Al hydrotalcites, for the catalysis of an MCR of hydrazine hydrate
Figure 2.

1322
S. W. KSHIRSAGAR, N. R. PATIL, AND S. D. SAMANT
Scheme 1.
(
(
3), ethyl acetoacetate (4), aldehydes (5), and malononitrile (6) at room temperature
Scheme 1), making the synthesis highly effective and green.
RESULTS AND DISCUSSION
In the present paper, we describe the use of calcined (Mg=Al ¼ 3) hydrotalcite
(
(
HT) as a first heterogeneous catalyst for the synthesis of 4H-pyrano[2,3-c]pyrazoles
Scheme 1). Mg–Al HT with Mg=Al molar ratio of 2, 3, and 5 were prepared by the
[18]
reported procedures and were characterized by x-ray diffraction (XRD), Fourier
transform infrared (FT-IR), and differential scanning calorimetry (DSC).
The reaction of hydrazine hydrate, ethyl acetoacetate (EAA), 4-methoxyben-
zaldehyde, and malononitrile was selected as the model reaction for optimization
of various parameters. The reaction was carried out using different HTs (Mg=
Al ¼ 2, 3, 5), calcined HTs (Mg=Al ¼ 2, 3, 5), and classical bases at room temperature
ꢀ
(
Table 1). The HTs (Mg=Al ¼ 2, 3, 5) were calcined at 500 C to tune the basicity.
The basicity of HT is sensitive to the Mg=Al ratio. The total amount of basic sites
of HT increases gradually with the Mg=Al molar ratio but the proportion of basic
sites (i.e., those catalyzing the reaction) decreases. The catalytic activity of the cal-
cined HTs was more than that of the corresponding uncalcined HT. It is known that
the calcined HT contains basic sites of pKa values up to 16.5. However, most of its
basic sites have 10.7 ꢁ pKa ꢁ 13.3, and only a few of them show strengths
[19]
1
3.3 ꢁ pKa ꢁ 16.5. Thus, the total basicity of calcined HT is more than that of the
corresponding uncalcined form. In the absence of the catalyst, very little product was
Table 1. Reaction of hydrazine hydrate, EAA, 4-methoxybenzaldehyde, and
malononitrile in the presence of Mg=Al HT with different Mg=Al ratios and
classical bases in EtOH at room temperature
Entry
Catalyst
Yield (%)
1
2
3
4
6
7
8
9
Mg=Al: 2
Mg=Al: 3
Mg=Al: 5
41
57
50
80
17
55
35
64
a
Mg=Al: 3
Na CO
MgO
Basic Al
Piperidine
2
3
2
O
3
Notes. Reaction conditions: hydrazine hydrate (2 mmol), ethyl acetoacetate
2 mmol), benzaldehdye (2 mmol), malononitrile (2 mmol), EtOH (10 ml); cat-
(
alyst ¼ 0.1 g; time 1.5 h; room temperature.
a
ꢀ
Hydrotalcite calcined at 500 C.

Mg-Al HYDROTALCITE AS BASIC CATALYST
1323
ꢀ
Table 2. Reusability of Mg=Al HT (calcined at 500 C)
Run
Yield (%)
1
2
3
80
77
77
Notes. Reaction conditions: hydrazine hydrate
2 mmol), ethyl acetoacetate (2 mmol), benzaldehdye
2 mmol), malononitrile (2 mmol), EtOH (10 ml); cal-
(
(
cined HT ¼ 0.1 g; time 1.5 h; room temperature.
Table 3. Synthesis of pyranopyarazole derivatives via a multicomponent condensation of hydrazine
hydrate, ethyl acetoacetate, aromatic aldehydes, and malononitrile in the presence of Mg=Al HT at room
temperature
Entry
Aldehyde
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
Benzaldehyde
1
87
71
64
81
75
86
80
70
62
79
2-Nitrobenzaldehyde
3-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Bromobenzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
3,4,5-Trimethoxybenzaldehyde
2-Methylbenzaldehyde
Thiophenyl
3
3
3
4
4
1.5
3.5
5
1
0
2
Notes. Reaction conditions: hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol), aldehdye
2 mmol), malononitrile (2 mmol), EtOH (10 ml); calcined HT ¼ 0.1 g.
(
formed. For further reaction, the calcined HT (Mg=Al ¼ 3) was used. The hydrotalcite is
a heterogeneous catalyst and could easily be separated from the reaction mixture by fil-
tration. The recovered catalyst was used for successive runs to test its reusability
(Table 2). It was observed that there was a decrease in the yield of the product.
Under the optimized conditions, various substituted aromatic aldehydes were
reacted to obtain the corresponding 4H-pyrano[2,3-c]pyrazoles in good yield
Table 3). It was observed that the aldehydes containing electron-withdrawing sub-
(
stituents reacted faster and gave a better yield of the product as compared to those
containing electron-donating substituents.
In conclusion, Mg=Al (Mg=Al ¼ 3) was found to be a simple and efficient solid
base catalyst for the synthesis of 4H-pyrano[2,3-c]pyrazoles through an MCR of
hydrazine hydrate, ethyl acetoacetate, aldehyde, and malononitrile. This is the first
report of the synthesis of 4H-pyrano[2,3-c]pyrazoles through a four-component reac-
tion in the presence of a solid catalyst.
EXPERIMENTAL
The Mg=Al HTs were prepared following the literature procedure. All pro-
ducts have been described previously and were fully characterized by FT-IR and
1
H NMR.

1324
S. W. KSHIRSAGAR, N. R. PATIL, AND S. D. SAMANT
Typical Reaction Procedure
Ethanol (10 ml) and Mg=Al HT (0.1 g) were added to a mixture of hydrazine
hydrate 1 (0.107 g, 2 mmol) and ethyl acetoacetate 2 (0.260 g, 2 mmol), aldehyde 3
2 mmol), malononitrile 4 (0.132 g, 2 mmol). The reaction mixture was stirred at
(
room temperature under an open atmosphere. After completion of the reaction,
the reaction mixture was heated to dissolve the product in ethanol and filtered
hot. The filtrate was allowed to stand at room temperature when the product sepa-
rated. It was filtered and washed with water, followed by a mixture of ethyl acetate=
hexane (20:80 v=v). The products were characterized by NMR and FT-IR.
Selected Data
6
-Amino-3-methyl-4-phenyl-1,4-dihyropyrano[2,3-c]pyrazole-5-carboni-
ꢂ1
1
trile (Entry 1). IR (KBr) n: 3368, 3307, 3170, 2197, 1648, 1610 cm . H NMR
DMSO, 300 MHz) d : 1.76 (s, 3H), 4.58 (s, 1H), 6.87 (s, 2H), 7.16–7.30 (m, 5H),
(
H
1
2.09 (s, 1H) ppm.
6
-Amino-3-methyl-4-(4-nitrophenyl)-1,4-dihyropyrano[2,3-c]pyrazole-5-
ꢂ1
1
carbonitrile (Entry 4). IR (KBr) n: 3472, 3230, 3120, 2192, 1648, 1621 cm . H
NMR (DMSO, 300 MHz) d : 1.78 (s, 3H), 4.61 (s, 1H), 7.05 (s, 2H), 7.44 (d, 2H),
H
8
.19 (d, 2H), 12.20 (s, 1H) ppm.
6
-Amino-4-(4-methoxyphenyl)-3-methyl-1,4-dihyropyrano[2,3-c]pyrazole-
ꢂ1
1
5
-carbonitrile (Entry 7). IR (KBr) n: 3483, 3258, 3115, 2192, 1640, 1600 cm . H
NMR (DMSO, 300 MHz) d : 1.77 (s, 3H), 3.72 (s, 3H), 4.52 (s, 1H), 6.84 (m, 4H),
H
7
.06 (s, 2H), 12.07 (s, 1H) ppm.
6-Amino-3-methyl-4-(3,4,5-trimethoxyphenyl)-1,4-dihyropyrano[2,3-c]-
pyrazole-5-carbonitrile (Entry 8). IR (KBr) n: 3379, 3285, 3142, 2186, 1643,
ꢂ1
1
1
6
599 cm . H NMR (DMSO, 300 MHz) d : 1.85 (s, 3H), 3.62 (s, 3H), 3.70 (s,
H
H), 4.57 (s, 1H), 6.45 (s, 2H), 6.87 (s, 2H), 12.09 (s, 1H) ppm.
ACKNOWLEDGMENTS
The authors thank the Council of Scientific and Industrial Research (CSIR),
New Delhi, for a research grant (No. 01 (2056)=06=EMR-II). S. W. K. thanks the
CSIR for providing a senior research fellowship.
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