[InCl4]-catalyzed addition of hydrazones to β-diketones: An efficient regioselective synthesis of pyrazoles and pyrazole-fused cyclohexanones

Article abstract of DOI:10.1055/s-0032-1316900

The Lewis acidic room-temperature ionic liquid, [bmim][InCl₄], was found to be an efficient catalyst for the regio-selective synthesis of fully substituted pyrazoles and pyrazole-fused cyclohexanones through condensation of hydrazones with symm

Full text of DOI:10.1055/s-0032-1316900

1086▌
LETTER
letter
[Bmim][InCl4]-Catalyzed Addition of Hydrazones to β-Diketones: An Efficient
Regioselective Synthesis of Pyrazoles and Pyrazole-Fused Cyclohexanones
Pyrazoles and Pyrazole-Fused Cyclohexanones
Shirin Safaei,a Iraj Mohammadpoor-Baltork,*a Ahmad Reza Khosropour,*a Majid Moghadam,a
Shahram Tangestaninejad,a Valiollah Mirkhani,a Hamid Reza Khavasib
a
Catalysis Division, Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran
Fax +98(311)6689732; E-mail: imbaltork@sci.ui.ac.ir; E-mail: khosropour@chem.ui.ac.ir
b
Department of Chemistry, Shahid Beheshti University, Tehran 19839-63113, Iran
Received: 21.02.2013; Accepted after revision: 17.03.2013
ponent reactions catalyzed by Zn(OTf)2.19 In continuation
Abstract: The Lewis acidic room-temperature ionic liquid,
of our interest in developing new and efficient protocols
[bmim][InCl4], was found to be an efficient catalyst for the regio-
for the preparation of heterocyclic compounds,20 herein
we report a novel one-pot and regioselective synthesis of
selective synthesis of fully substituted pyrazoles and pyrazole-fused
cyclohexanones through condensation of hydrazones with symmet-
rical and unsymmetrical 1,3-diketones. This procedure is simple, fully substituted pyrazoles and pyrazole-fused cyclohexa-
affording the corresponding products in good to high yields.
nones from aldehydes, arylhydrazines, and acyclic or cy-
clic 1,3-diketones catalyzed by [bmim][InCl4] (Scheme
Key words: pyrazoles, arylhydrazones, Lewis acid room-tempera-
ture ionic liquid, regioselective
1).21
O
R1
O
O
O
Substituted pyrazoles have received considerable atten-
tion in the field of synthetic organic chemistry due to their
numerous applications in the pharmaceutical industry.
Functionalized pyrazoles have shown antimicrobial,1 an-
titumor,2 hypoglycemic,3and hypolipidemic4 activities,
and act as HIV-1 reverse transcriptase inhibitors.5 Two
commercially known drugs, Celebrex6 and Viagra,7 have
pyrazole scaffolds.
[bmim][InCl4] (1equiv)
Y
+ R2NHNH2
+
N
R1
H
Y
140 °C
N
R2
1
2
3
4
R1 = Ar, heteroaryl, alkyl
R2 = Ph, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4
Y = Me, Ph, c-Hex
Scheme 1 Regioselective synthesis of fully substituted pyrazoles
Different methods such as condensation of hydrazonoyl
chlorides with acetylenic esters8 or 1,3-diketones,9 1,3-di-
polar cycloaddition of active dipoles to the triple bonds10
and cyclization of 1,3-diketones with hydrazines11 have
been reported for the synthesis of these heterocyclic com-
pounds. Low regioselectivity and consequent difficult iso-
lation of the two regioisomers resulting from
unsymmetrical diketones are the most important limita-
tions of some of these methods.
and pyrazole-fused cyclohexanones catalyzed by [bmim][InCl4]
In order to investigate the effect of the catalyst on the re-
gioselectivity, the reaction of benzaldehyde (1 mmol) and
phenylhydrazine (1 mmol) with 1-phenylbutane-1,3-di-
one (1.2 mmol) was examined in the presence of different
catalysts at 140 °C under solvent-free conditions (Table 1,
entries 1–9). As shown, in the presence of Lewis acid cat-
alysts (10 mol%), two regioisomeric products were pro-
duced with poor selectivity (Table 1, entries 1–4);
whereas, the regioselectivity was improved using Lewis
acidic ionic liquids (Table 1, entries 5–9). Among differ-
ent Lewis acidic ionic liquids, the best selectivity was
achieved with [bmim][InCl4], which afforded only one re-
gioisomer (Table 1, entry 5). It should be noted that, in the
absence of the catalyst, the reaction failed to give the de-
sired product, even after extended reaction time (10 h, Ta-
ble 1, entry 1). Subsequently, the effects on the yield of
the product like temperature, the amount of the catalyst,
and the reaction time were examined. Increasing either the
temperature or the amount of the catalyst did not improve
the yield (Table 1, entries 11 and 13), while decreasing ei-
ther led to reduction in yield (Table 1, entries 12 and 14).
Therefore, 1 mmol of [bmim][InCl4] at 140 °C under sol-
vent-free conditions was found to be optimal.
Although much research effort has been directed towards
the development of versatile protocols for the synthesis of
pyrazole derivatives, there are only few reports on the re-
gioselective formation of pyrazoles from unsymmetrical
diketones.12 Consequently, there continues to be a need to
develop efficient methods for the regioselective synthesis
of pyrazole derivatives.
Over the years, ionic liquids have received a great interest
as reaction media and/or catalysts, as they allow more en-
vironmentally friendly processes and display unique reac-
tivity and selectivity.13 Numerous organic reactions
promoted by ionic liquids have been reported with high
selectivity.14–18 Recently, we reported the synthesis of ful-
ly substituted pyrazoles and bispyrazoles via three-com-
SYNLETT 2013, 24, 1086–1090
Advanced online publication: 18.04.2013
In order ascertain the effect of [bmim] on the rgioselectiv-
ity, the model reaction was also performed with Na[InCl4]
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316900; Art ID: ST-2013-D0165-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pyrazoles and Pyrazole-Fused Cyclohexanones
1087
Table 1 The Effect of Reaction Parameters on the Regioselective Synthesis of 4aa
O
O
Ph
Ph
O
O
O
catalyst
PhNHNH2
+
+
+
Ph
Ph
H
N
N
Ph
Ph
Ph
Ph
N
N
1
2
3
4
5
Entry
Catalyst (mmol)
Time (min)
Yield (%)b
4a/5a
1
2
no catalyst
10
60
60
60
60
60
60
60
60
60
60
60
60
60
–
–
Zn(OTf)2 (0.1)
90
82
86
85
78
60
15
80
86
75
85
70
85
80:20
55:45
80:20
100:0
90:10
100:0
100:0
65:35
100:0
100:0
100:0
100:0
80:20
3
Bi(OTf)3(0.1)
4
InCl3·4H2O (0.1)
[bmim][InCl4] (1)
[bmim][CuCl3] (1)
[bmim][FeCl4] (1)
[bmim][PF6] (1)
[bpy][InCl4] (1)
[bmim][InCl4] (1.2)
[bmim][InCl4] (0.85)
[bmim][InCl4] (1)
[bmim][InCl4] (1)
Na[InCl4] (1)
5
6
7
8
9
11
12
13c
14d
15
a Reaction conditions: aldehyde (1 mmol), phenylhydrazine (1 mmol), benzoylacetone (1.2 mmol), solvent-free conditions, 140 °C.
b Isolated yield.
c Reaction was performed at 150 °C.
d Reaction was performed at 130 °C.
under the same reaction conditions. As can be seen, the in Table 1, it seems that the synergistic effect of anion and
yield is comparable to [bmim][InCl4] but the regioselec- cation in [bmim][InCl4] enhances the regioselctivity.
tivity is lower (Table 1, entry 15). According to the data
IL
O
O
H
IL
H
O
O
O
O
Ph
[bmim][InCl4]
Ph
R
+
Ph
3
O
NHNH2
••
X
N
R
H
N
X
H
1
2
IL
A
cyclization
X
X
X
N
N
air
N
N
dehydration
HN
HN
oxidation
OH
Ph
R
R
R
Ph
Ph
B
4
C
Scheme 2 Proposed mechanism for the regioselective synthesis of fully substituted pyrazoles catalyzed by [bmim][InCl4]
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1086–1090

1088
S. Safaei et al.
LETTER
Under the optimized conditions, aldehydes or hydrazines fully substituted pyrazoles in high yields and total regiose-
containing electron-withdrawing and electron-donating lectivity (Table 2, entries 1–7). The symmetrical 1,3-di-
groups in the aromatic ring reacted smoothly with unsym- ketone, acetylacetone, also reacted efficiently to give the
metrical 1,3-diketones such 1-phenylbutane-1,3-dione in desired products in high yields (Table 2, entries 8 and 9).
the presence of [bmim][InCl4] to afford the corresponding
Table 2 Synthesis of Fully Substituted Pyrazoles and Pyrazole-Fused Cyclohexanones Catalyzed by [bmim][InCl4]a
Entryb R1
R2
1,3-Diketone
Product 4
Time (min)
Yield (%)
85
O
O
O
1
2
Ph
Ph
4a
4b
60
Ph
N
N
O
O
O
O
O
4-CNC6H4
4-MeC6H4
70
60
80
83
Ph
Ph
N
N
CN
O
N
3
3-MeOC6H4
Ph
4c
N
OMe
O
O
O
O
O
4
5
4-MeC6H4
Ph
4d
4e
60
60
90
78
Ph
Ph
N
N
O
2,4-Cl2C6H3
4-ClC6H4
N
N
Cl
Cl
Cl
O
O
O
Ph
Ph
6
2,4-Cl2C6H3
4-MeOC6H4
4f
60
82
N
N
Cl
MeO
Cl
O
O
O
O
O
7
8
2-thiophene
4-CNC6H4
Ph
Ph
4g
4h
60
72
68
N
N
N
N
S
O
120
CN
Synlett 2013, 24, 1086–1090
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pyrazoles and Pyrazole-Fused Cyclohexanones
1089
Table 2 Synthesis of Fully Substituted Pyrazoles and Pyrazole-Fused Cyclohexanones Catalyzed by [bmim][InCl4]a (continued)
Entryb R1
R2
1,3-Diketone
Product 4
Time (min)
90
Yield (%)
O
O
O
9
4-BrC6H4
4-MeOC6H4
4i
4j
71
70
N
N
O
MeO
Br
O
O
O
10
Ph
Ph
60
N
O
O
O
N
O
11
12
4-MeOC6H4
4-MeC6H4
4k
41
60
60
80
61
N
N
Me
OMe
O
n-Bu
Ph
N
N
a Reaction conditions: aldehyde (1 mmol), arylhydrazine(1 mmol), 1,3-diketone (1.2 mmol), catalyst (1 mmol), solvent-free conditions,
140 °C.
b Isolated yield.
To expand the scope of this new multicomponent reaction X-ray crystallographic analysis (Figure 1; CCDC
further and cognizant of the applications of heterocycle- 905447).
fused cyclohexanone in medicinal chemistry,22 the syn-
thesis of pyrazole-fused cyclohexanones was also exam-
ined. The reaction of several hydrazones with dimedone
in the presence of [bmim][InCl4] proceeded efficiently to
provide the corresponding pyrazole-fused cyclohexa-
nones in high yields (Table 2, entries 10–12). To the best
of our knowledge, there are only a few reports on the syn-
thesis of pyrazole-fused cyclohexanones,23 but there is no
report on the regioselective synthesis of fully substituted
pyrazoles and pyrazole-fused cyclohexanones through the
one-pot multicomponent reaction of aldehydes and aryl-
hydrazines with unsymmetrical diketones or dimedone.
Consequently, this strategy can be considered as a useful
advance in the preparation of such heterocycle libraries.
A plausible mechanism for the regioselective formation of
pyrazoles is proposed in Scheme 2. The hydrazone A is
first produced by the reaction of aldehyde with arylhydra-
zine, which upon reaction with the enol form of 1,3-dicar-
bonyl compound gives intermediate B. Dehydration of the
intermediate B affords pyrazoline C, which upon aroma-
tization gives the corresponding pyrazole 4.
Figure 1 X-ray crystal structure of 4g
The recyclability of the catalyst was investigated in the
model reaction. After completion of the reaction, the mix-
ture was cooled to room temperature and water was add-
ed. The crude product was filtered, and the aqueous layer
was evaporated under reduced pressure. The recovered
The structures of the products were confirmed by their IR,
mass, 1H NMR, and 13C NMR spectra and elemental anal-
ysis. Furthermore, the structure of 4g was confirmed by
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1086–1090

1090
S. Safaei et al.
LETTER
50, 2505. (f) Polshettiwar, V.; Varma, R. S. Tetrahedron
catalyst was dried and reused at least three times without
showing obvious loss of activity.
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In summary, we have demonstrated a regioselective, effi-
cient, and novel three-component synthesis of fully sub-
stituted pyrazoles and pyrazole-fused cyclohexanones in
the presence of the Lewis acidic room-temperature ionic
liquid, [bmim][InCl4], as a reusable and green catalyst.
Short reaction times, high yields of products, and opera-
tional simplicity make this method a practical and attrac-
tive process for the synthesis of pyrazole derivatives.
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Acknowledgment
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The authors are grateful to the Centre of Excellence of Chemistry
and the Research Council of the University of Isfahan for financial
support of this work.
(19) Safaei, S.; Mohammadpoor-Baltork, I.; Khosropour, A. R.;
Moghadam, M.; Tangestaninejad, S.; Mirkhani, V. Synlett
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(20) (a) Safaei, S.; Mohammadpoor-Baltork, I.; Khosropour, A.
R.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V. Adv.
Synth. Catal. 2012, 354, 3095. (b) Safaei, S.;
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(21) General Procedure for the Synthesis of Fully Substituted
Pyrazoles and Pyrazole-Fused Cyclohexanones
A mixture of aldehyde 1 (1 mmol) and arylhydrazine 2 (1
mmol) was stirred for 20 min, then 1,3-diketone 3 (1.2
mmol) and [bmim][InCl4] (1 mmol) were added, and the
mixture was stirred at 140 °C for the appropriate time
according to Table 2. The progress of the reaction was
monitored by TLC (eluent: n-hexane–EtOAc, 10:1). After
completion of reaction, the mixture was cooled to r.t. and
H2O was added (30 mL). The mixture was filtered, and the
crude residue was purified by recrystallization from EtOH to
afford the pure product. If necessary, the product was
purified by silica gel column chromatography (eluent:
n-hexane–EtOAc, 12:1).
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Synlett 2013, 24, 1086–1090
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