Catalyst-free domino reaction in water/ethanol: An efficient, regio- and chemoselective one-pot multi-component synthesis of pyranopyrazole derivatives

Article abstract of DOI:10.1039/c3ra47639a

The synthesis of pyrano[2,3-c]pyrazole derivatives has been described by regio- and chemoselective four-component reaction of a dialkyl 3-oxopentanedioate, an active carbonyl compound, hydrazine and malononitrile in water/ethanol as a green medium under catalyst-free condition.

Full text of DOI:10.1039/c3ra47639a

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Catalyst-free domino reaction in water/ethanol: an
efficient, regio- and chemoselective one-pot multi-
component synthesis of pyranopyrazole
derivatives†
Cite this: RSC Adv., 2014, 4, 10669
Received 14th December 2013
Accepted 31st January 2014
a
a
b
*
*
Majid Koohshari, Minoo Dabiri and Peyman Salehi
DOI: 10.1039/c3ra47639a
www.rsc.org/advances
The synthesis of pyrano[2,3-c]pyrazole derivatives has been described several of pharmacological properties including anti-inam-
by regio- and chemoselective four-component reaction of a dialkyl 3- matory,7 anticancer,8 insecticidal,9 antimicrobial, and inhibi-
oxopentanedioate, an active carbonyl compound, hydrazine and tors of human Chk1 kinase.10
malononitrile in water/ethanol as a green medium under catalyst-free
Some novel multi-component reactions have been intro-
duced by employing in situ preparation of pyrazolone ring
through the reaction between hydrazine and a b-dicarbonyl
compound.4,11
condition.
The pollution of nature is a major problem in the design of
chemical reactions. “Green chemistry” encourages chemists to
alter the chemical procedures so production and consumption
Herein we report a one-pot synthesis of pyranopyrazole
derivatives by in situ preparation of alkyl 2-(5-oxo-4,5-dihydro-
1H-pyrazol-3-yl)acetate (7) through the reaction between
hydrazine and dialkyl 3-oxopentanedioate (1) and subsequent
reaction to synthesize the target pyranopyrazole derivatives
(Scheme 1).
Two products is possible for this reaction that it is note-
worthy proceeded in highly regio- and chemoselective
manner and it only produced compound 5 as shown in
Scheme 1.
Encouraged by gaining acceptable results in our rst
attempts, the synthesis of 5a was selected for optimization of
the reaction conditions. As shown in Table 1, the optimal
conditions for the reaction of 4-chlorobenzaldehyde, hydrazine
hydrate, diethyl 3-oxopentanedioate and malononitrile were
screened and H2O/ethanol (80 : 20) was found to be the best
solvent for this reaction. The uses of combination of EtOH/H2O
of hazardous substances in chemical reactions reach
minimum value.1
a
Designing simple and environmentally benign reactions for
the synthesis of medicinal structures is an attractive aspect of
chemical researchs. Multi-component reaction (MCR) especially
in water and ethanol, eco-friendly solvents, is one of the most
suitable routs which can helps chemists to conform their
reaction procedures to the requirements of “green chemistry” as
well as to extend libraries of medicinal scaffolds.2
Designing organic reactions in aqueous media as an abun-
dant and environmentally secure solvent has several advantages
including simple work up and purication, exhibit high reac-
tivity and selectivity, control over exothermic reactions, salting
in and salting out, increasing in rate of reactions and variation
of pH.3
Pyrazoles are important constituents in many pharmaceu-
tical scaffolds.4 Also pyrazoles connected to other heterocyclic
rings are very attractive targets in both combinatorial chemistry
and emersion biological activities.5,6
Pyranopyrazoles are an important class of biological and
pharmaceutical active compounds. They are reported to possess
aDepartment of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716,
Tehran, Iran. E-mail: m-dabiri@sbu.ac.ir
bDepartment of Phytochemistry, Medicinal Plants and Drugs Research Institute,
Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran. E-mail:
p-salehi@sbu.ac.ir
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra47639a
Scheme 1 Synthesis of pyranopyrazole.
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Table 1 Optimization of reaction conditions (5a)
As shown in Table 2, this protocol can be applied for
aromatic aldehydes with electron-withdrawing groups.
Then, we examined the possibility of the synthesis of the
spiro products from isatin derivatives and acenaph-
thenquinone instead of aldehyde. As shown in Table 3,
the spiro-products showed partly better yields than the
others.
Finally, the structure of the compound 5f was conrmed
precisely by single-crystal X-ray analysis (Fig. 1).
Entry
Solvent
Catalyst
Temp. (ꢀC)
Yielda (%)
A plausible mechanism according to the same reaction13
is presented in Scheme 2. The mechanism involves initial
condensation of b-ketoester (1) and hydrazine (2) to
form pyrazolone ring (7) and subsequent attack on Knoeve-
nagel condensation product (8) that is formed from alde-
hyde (3) (or 1,2-dicarbonyle compound) and malononitrile
(4). In the next step, cyclization occurs to yield the nal
product (5).
1
2
3
4
5
6
7
8
9
H2O/MeOH 50/50
CH3CN
Etyl acetate
H2O/MeOH 50/50
H2O/MeOH 50/50
MeOH
H2O/EtOH 80/20
H2O/EtOH 80/50
H2O
—
—
—
Et3N
PTSA
—
—
—
65
82
77
60
60
65
80
25
60
65
50
20
60
20
—
75
65
40
—
a
Reaction conditions: hydrazine (1.0 mmol), diethyl-3-oxopentanedioate
(1.0 mmol), malononitrile (1 mmol), 4-chlorobenzaldehyde (1 mmol),
solvent (10 mL), 12 h.
Table 3 The synthesized of spiro products
Table 2 Pyranopyrazoles synthesized from aldehydes
Product
R1
R2
X
Yielda (%)
5f
5g
5h
5i
5j
5k
5l
Et
Et
Et
Me
Et
5-Br
5-F
H
H
—
CN
CN
CN
CN
CN
CN
CO2Et
85
82
85
85
87
76
68
Product
R1
Yielda (%)
5a
5b
5c
5d
5e
4-Cl
3-Br
2-NO2
3-NO2
4-NO2
75
78
60
65
68
Me
Me
—
—
a
Reaction
conditions:
hydrazine
(1.0
mmol),
dialkyl-3-
oxopentanedioate (1.0 mmol) in water/ethanol (10 mL/8 : 2), isatin or
acenaphthenquinone (1 mmol) and malononitrile (1 mmol) or etyl
cyanoacetate, 12 h, 60 ꢀC.
a
Reaction conditions: hydrazine (1.0 mmol), dialkyl-3-oxopentanedioate
(1.0 mmol) in water/ethanol (10 mL/8 : 2), aldehyde (1 mmol) and
malononitrile (4, 1 mmol), 12 h, 60 ꢀC.
as solvent in multi-component reaction have already been
reported.12 We also used an acid (p-toluenesulfonic acid, Table
1, entry 5) and a base (triethylamine, Table 1, entry 4) asꢀcata-
lysts in this reaction, but the catalyst-free approach at 60 C in
H2O/EtOH (80 : 20) (entry 7) gave the best result.
With the optimized reaction conditions in hand, we then
probed the generality and scope of the present multi-compo-
nent reaction. We were pleased to nd that the reaction pro-
ceeded well with a series of different aldehydes, some isatin
derivatives and acenaphthenquinone as active carbonyl
compounds, malononitrile or ethyl cyanoacetate, hydrazine and
dimethyl 3-oxopentanedioate or diethyl 3-oxopentanedioate to
give a library of ethyl 2-(6-amino) (2,4-dihydropyrano[2,3-c]pyr-
azol-3-yl)acetate derivatives of type 5.
Fig. 1 X-ray crystal structure of 5f.
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precipitated product was ltered and washed with water. The
products were further puried by recrystallization in ethanol.
Acknowledgements
We gratefully acknowledge nancial support from the Research
Council of Shahid Beheshti University. The authors are grateful
to Dr Hamid Reza Khavasi and SBU X-Ray Crystallography
Centre for their helpful analysis X-Ray data that helped the
authors to improve the quality of this paper.
Notes and references
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Scheme 2 Mechanism of the reaction.
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S. Narayan, M. G. Fokin, H. C. Kolb and K. B. Sharpless,
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´
¨¨
¨
¨
S. Gyonfalvi, Z. Szadonyi, R. Sillanpaa and F. Fulop, Green
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In summary, a facile regio- and chemoselective one-pot
procedure for the synthesis of ethyl 2-(6-amino) (2,4-dihy-
dropyrano[2,3-c]pyrazol-3-yl)acetate derivatives has been
reported via a condensation reaction of a dialkyl 3-oxo-
pentanedioate, an aldehyde (isatin derivatives or acenaph-
thenquinone), hydrazine and malononitrile (or ethyl
cyanoacetate) in water/ethanol under catalyst-free condi-
tions. The versatility of the functionality such as amino, ester
and cyano groups makes these compounds proper candi-
dates as precursors for further synthetic transformations in
drug discovery, combinatorial chemistry and chemical
biology. The simple performance, green media, good yields
and easy purication are some of the advantages of this
protocol.
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Experimental
General procedure
A mixture of the dialkyl-3-oxopentanedioate (1, 1 mmol) and
hydrazine hydrate (2, 1 mmol, 0.05 mL) in water/ethanol
(10 mL/8 : 2) was magnetically stirred for 30 min at 60 C fol-
ꢀ
lowed by the addition of aldehyde (3, 1 mmol) and malononi- 12 M. M. Heravi, M. Vazin Fard and Z. Faghihi, Green Chem.
trile (4, 1 mmol). The reaction mixture was stirred for 12 h at
60 C. Then, the mixture was cooled to r.t. and 10 mL of water 13 S. Pal, M. N. Khan, S. Karamthulla, S. J. Abbas and
Lett. Rev., 2009, 2, 12.
ꢀ
was added and the resulting mixture was stirred for 30 min. The
L. H. Choudhury, Tetrahedron Lett., 2013, 54, 5434.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 10669–10671 | 10671