CTACl AS catalyst for four-component, one-pot synthesis of pyranopyrazole derivatives in aqueous medium

Article abstract of DOI:10.1080/00397911.2012.666315

An environmentally benign four-component reaction in aqueous medium in the presence of cetyltrimethylammonium chloride (CTACl) has been developed for the synthesis of 6-amino-3-methyl-4-aryl-/1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole- 5-carbonitrile. The

Full text of DOI:10.1080/00397911.2012.666315

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CTACl as Catalyst for Four-Component,
One-Pot Synthesis of Pyranopyrazole
Derivatives in Aqueous Medium
a
b
a
a
Mingshu Wu , Qinqin Feng , Dehui Wan & Jinya Ma
a
College of Chemistry and Chemical Engineering, Hainan Normal
University, Haikou, China
b
College of Chemistry and Chemical Engineering, Anyang Normal
University, Anyang, Henan, China
Accepted author version posted online: 10 Aug 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Mingshu Wu , Qinqin Feng , Dehui Wan & Jinya Ma (2013): CTACl as Catalyst for
Four-Component, One-Pot Synthesis of Pyranopyrazole Derivatives in Aqueous Medium, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:12, 1721-1726
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1
Synthetic Communications , 43: 1721–1726, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.666315
CTACl AS CATALYST FOR FOUR-COMPONENT,
ONE-POT SYNTHESIS OF PYRANOPYRAZOLE
DERIVATIVES IN AQUEOUS MEDIUM
1
2
1
Mingshu Wu, Qinqin Feng, Dehui Wan, and Jinya Ma
1
1
College of Chemistry and Chemical Engineering, Hainan Normal University,
Haikou, China
2
College of Chemistry and Chemical Engineering, Anyang Normal
University, Anyang, Henan, China
GRAPHICAL ABSTRACT
Abstract An environmentally benign four-component reaction in aqueous medium in the
presence of cetyltrimethylammonium chloride (CTACl) has been developed for the synthesis
of
6-amino-3-methyl-4-aryl-/1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile.
The method presented is mild, environmentally friendly, inexpensive, and functionality
tolerant and gives the products in good to excellent yields.
Keywords CTACl catalysis; four-component reaction; pyrano[2,3-c]pyrazole derivatives;
water medium
INTRODUCTION
Multicomponent reactions (MCRs) are of increasing importance in organic and
medicinal chemistry because the strategies of MCR offer significant advantages over
conventional linear syntheses. MCRs leading to interesting heterocyclic scaffolds are
particularly useful for the creation of diverse chemical libraries of ‘‘drug-like’’ mole-
cules for biological screening, as the combination of three or more low-molecular-
[
1,2]
weight building blocks in a single operation leads to high combinatorial efficacy.
[
3]
Designing MCRs in water is another attractive area in chemistry because water is a
cheap, safe, and environmentally benign solvent. There is need for MCRs in water
with suitable catalysts and without any harmful organic solvents. As a reaction
Received November 11, 2011.
Address correspondence to Mingshu Wu, College of Chemistry and Chemical Engineering, Hainan
Normal University, Haikou 571158, China. E-mail: wumingshu@126.com
1
721

1722
M. WU ET AL.
medium, water offers several benefits including control over exothermic reactions,
salting in and salting out, and variation of pH. Workup 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
[
4]
occur faster in water than in organic solvents. Multicomponent reactions are
5]
[
suggested to have a negative activation volume.
Pyranopyrazoles are an important class of heterocyclic compounds. They consti-
tute one of the privileged heterocyclic scaffolds known to exhibit important biological
[
6]
[7]
activities, such as analgesic, antitumor, anticancer, and anti-inflammatory proper-
[8]
[9]
ties and also serve as potential inhibitors of human Chk1 kinase. Furthermore, the het-
erocyclic compounds bearing pyrano and pyrazol units have played increasing roles in
[10]
[11]
synthetic strategies to promising compounds. Junek and Aigner first established
the synthesis of pyrano[2,3-c]pyrazole derivatives from 3-methyl-1- phenylpyrazolin-5-
one and tetracyanoethylene in the presence of triethylamine. A number of synthetic
approaches have also been made for the synthesis of 6-amino-4-aryl-3-methyl-2,4-
[
12a,12b]
[12c]
[12d]
dihydropyrano[2,3-c]pyrazoles using triethylamine,
piperazine,
piperidine,
as prominent catalysts with
However, most of these syntheses have been achieved through
a two-component or three-component reaction except for the works reported recently by
[12e]
[12f]
[12g]
heteropolyacid,
microvave irradiation.
alumina,
and cinchona alkaloid,
[
12h]
[12d]
Vasuki et al.,
[12f]
[12g]
Mecadon et al.,
and Gogoi and Zhao,
where four-component
syntheses have been accomplished. Although each of the reported methods for the syn-
thesis of corresponding pyranopyrazoles system has its merits, further studies are still
necessary for the essence of facile, environmental, and economical multicomponent
methodology.
RESULTS AND DISCUSSION
In water, organic reactions arising from hydrophobic effect will have reduced
activation energies and faster reactions.
[13]
Mechanisms of reactions in water can
be explored by addition of antihydrophobic agents, which reduce the hydrophobic
rate acceleration. Reaction rates will be slowed or sped up depending on the extent
to which the hydrophobic surfaces and substituents of the reactants are exposed to
[
14]
or shielded from water in the transition state relative to the initial state.
This
inspired us to seek an additive agent in water to increase the hydrophobic surfaces.
We therefore tried to use cetyltrimethylammonium chloride (CTACl) as phase-
transfer catalyst, improve further hydrophobic surfaces, and accelerate the hetero-
geneous multicomponent reaction rates.
Thus, in conjunction with our continued research aimed at the development of
[
15]
environmentally benign synthetic methodologies,
component reaction of ethyl acetoacetate (1), hydrazine hydrate=phenylhydrazine
we report herein the four-
(
2), aromatic aldehydes (3), and malononitrile (4), using water as a solvent at
ꢀ
90 C in the presence of a catalytic amount of cetyltrimethylammonium chloride
CTACl) for the synthesis of pyrano[2,3-c]pyrazoles (Scheme 1).
(
To optimize the reaction conditions, we studied the reaction of ethyl acetoacetate
1), phenylhydrazine (2a), m-nitrobenzaldehyde (3a), and malononitrile (4) to give the
corresponding 6-amino-3-methyl-4-(3-nitrophenyl)-1-phenyl-1,4-dihydro pyrano[2,3-c]
(

PYRANOPYRAZOLE DERIVATIVES
1723
Scheme 1. Synthetic approach to compounds 5.
pyrazole-5-carbonitrile (5a), as depicted in Table 1. The structure of 5a was also
[16]
established by x-ray crystallography.
As shown in Table 1 the rate of the reaction is markedly affected by the catalyst.
The uncatalyzed reaction cannot afford the corresponding compound (5a) after 4 h,
whereas the presence of the CTACl strongly increases the rate of the process. The
activation of reactants is most likely due to the increase of their concentration into
the hydrophobic field, and lower yields of products (5a) were observed by carrying
out the same reactions in ethanol, where all the compounds are soluble.
Formation of the product is suggested to involve the tandem reactions. Thus
the benzylidenemalononitrile (7) containing the electron-poor C=C double bond
is quantitatively produced by fast Knoevenagel reaction of malononitrile to the
aromatic aldehyde. This reaction easily occurs in protic solvents including water
[
17]
without adding any catalyst, although it results in a net dehydration. A similar
rapid reaction between ethyl acetoacetate and hydrazine was instantaneously carried
a
Table 1. Optimization of the reaction conditions
ꢀ
b
Yield 5a (%)
Entry
Catalyst (mol%)
Temp. ( C)
Time (h)
1
2
3
4
5
6
7
8
9
—
—
25
60
4
4
4
4
4
4
4
4
4
4
4
4
0
30
50
30
65
76
76
80
50
88
80
89
—
—
90
Reflux
90
60
CTACl (5)
CTACl (10)
CTACl (10)
CTACl (10)
CTACl (20)
CTACl (20)
CTACl (20)
CTACl (30)
90
Reflux
25
90
1
1
1
0
1
2
Reflux
90
a
Reaction carried out using compounds 1 (2.5 mmol), 2a (2.5 mmol), 3a
2.5 mmol), and 4 (2.5 mmol) in 10 ml water.
(
b
Isolated yield.

1724
M. WU ET AL.
Scheme 2. Reaction mechanism of compounds 5.
[18]
out in water to produce pyrazoles (6). The second step that requires the presence of
[
19]
CTACl presumably involves, as also previously reported,
Michael addition of 6
to 7, and the hydroxyl tautomer group in pyrazolone undergoes fast nucleophilic
addition to the CN moiety, producing the corresponding intermediate (9) subse-
quently rearranging in formation of the final 6-amino-3-methyl-4-aryl-(1-phenyl)-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5) (Scheme 2).
Table 2. Synthesis
pyrano[2,3-c]pyrazole-5-carbonitrile (5)
of
6-amino-3-methyl-4-aryl-(1-phenyl)-1,4-dihydro
1
R
2
R
a
Yield (%)
ꢀ
Entry
Product
Mp ( C)
[
12h]
12e]
12h]
12e]
1
2
3
4
5
6
7
8
9
C
C
C
C
C
C
C
C
C
6
6
6
6
6
6
6
6
6
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
m-NO
p-CH
2
5a
5b
5c
5d
5e
5f
88
87
81
88
80
86
89
85
80
90
78
82
78
81
82
86
72
186–188 (188–190)
[
3
180–182 (177–179)
[
p-OCH
p-OH
3
178–180 (170–172)
[
208–210 (210–213)
198–200
3,4-(Cl)
p-Br
2
[12h]
187–189 (183–185)
[
12h]
H
p-F
5g
5h
5i
170–172 (168–170)
183–185
192–194
2,4-(Cl)
2
[12f]
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
H
H
H
H
H
H
H
H
m-NO
p-CF
p-CH
2
5j
196–198 (193–195)
232–233
3
5k
5l
[
12f]
12f]
12f]
3
210–212 (206–208)
[
p-OH
H
p-F
5m
5n
5o
5p
5q
226–228 (224–226)
[
250–252 (244–246)
233–235
[12f]
p-OCH
3
210–212 (210–212)
220–222
3 2
P-N(CH )
a
Isolated yields.

PYRANOPYRAZOLE DERIVATIVES
1725
Once we realized that cetyltrimethylammonium chloride (CTACl) was an
excellent catalyst for this transformation, we studied the scope of the reaction. The
results presented in Table 2 indicate the scope and generality of the method, which
is efficient not only for hydrazine hydrate but also for phenylhydrazine, against the
[
12]
limited hydrazine hydrate reported previously.
An important feature of this
method is that both electron-releasing and withdrawing groups give excellent yields.
When this reaction was carried out with an aliphatic aldehyde such as butanal or
1
pentanal, the thin-layer chromatography (TLC) and H NMR spectra of the crude
reaction mixture showed the presence of a combination of starting materials and
numerous by-products. The yield of the expected product was very poor, probably
because of the aldol condensation side reaction.
CONCLUSIONS
In conclusion we have demonstrated a green and facile method for the synthesis
of 6-amino-3-methyl-4-aryl-(1-phenyl)-1,4-dihydropyrano [2,3-c]pyrazole-5-carboni-
trile in the presence of cetyltrimethylammonium chloride (CTACl) using water as the
solvent. Prominent among the advantages of this new method are novelty, good
yields, ecofriendliness, and easy workup.
EXPERIMENTAL
All reagents and solvents were obtained from commercial sources and used
without purification, unless indicated otherwise. Melting points were determined
on a WRS-1 digital melting-point apparatus and are uncorrected. Infrared (IR) spec-
À1
tra were determined on a Bruker spectrometer and are expressed in cm (KBr disc).
NMR spectra were recorded on a Bruker DRX-400 NMR spectrometer (400 MHz
1
3
for 1H and 100 MHz for C) with dimethylsulfoxide (DMSO) as the solvent and tet-
ramethylsilane (TMS) as internal reference. Elemental analysis was carried out with
a Yanaco Chncorder MT-3 Analyzer.
Aldhyde 3 (2 mmol), malononitrile 4 (2 mmol), and cetyltrimethylamm onium
chloride (CTACl) (20 mol%) were added successively to a stirred aqueous mixture
of phenylhydrazine=hydrazine hydrate 2 (2 mmol) and ethyl acetoacetate 1 (2 mmol),
at room temperature under an open atmosphere with vigorous stirring for 10 min.
ꢀ
The mixture was allowed to heat to 90 C with vigorous stirring for 4 h, and the pre-
cipitated solid was filtered off and washed with water to afford the crude product,
which was recrystallized from ethanol=water (9.5:0.5) or purified by column chroma-
tography over silica gel (100–200 mesh) using methanol=dichloromethane (2:8) as the
eluent to afford pure compound 5.
ACKNOWLEDGMENT
The work was supported by the National Natural Science Foundation of
China (No. 21162008).

1726
M. WU ET AL.
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