One-pot regioselective synthesis of 1,4,5-trisubstituted pyrazoles under solvent-free conditions without catalyst

Article abstract of DOI:10.1007/s00706-012-0721-9

A fast, one pot method with excellent yield has been developed for preparation of 1,4,5-trisubstituted pyrazoles. Treatment of β-dicarbonyl compounds with N,N-dimethylformamide dimethylacetal and hydrazine derivatives afforded immediately the desired pyrazoles under solvent-free conditions in the absence of catalyst. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-012-0721-9

Monatsh Chem (2012) 143:947–950
DOI 10.1007/s00706-012-0721-9
ORIGINAL PAPER
One-pot regioselective synthesis of 1,4,5-trisubstituted
pyrazoles under solvent-free conditions without catalyst
•
Heshmatollah Alinezhad Mahmood Tajbakhsh
•
Mahboobeh Zare
Received: 27 November 2010 / Accepted: 9 January 2012 / Published online: 2 March 2012
Ó Springer-Verlag 2012
Abstract A fast, one pot method with excellent yield has
been developed for preparation of 1,4,5-trisubstituted
pyrazoles. Treatment of b-dicarbonyl compounds with
N,N-dimethylformamide dimethylacetal and hydrazine
derivatives afforded immediately the desired pyrazoles
under solvent-free conditions in the absence of catalyst.
with N,N-dimethylformamide dimethylacetal (DMFDMA)
and derivatives [14].
1,4,5-Trisubstituted pyrazoles have usually been pre-
pared by reaction of enaminoketones with hydrazine
derivatives in solvent under acid catalysis [15–17].
Recently a microwave-assisted solution phase reaction
[18, 19] and a cellulose-based resin [14] were reported for
synthesis of these compounds. However, these syntheses
are usually carried out in organic solvents, often require
acid (AcOH) and two-step synthesis.
Keywords Cyclization Á 1,4,5-Trisubstituted pyrazoles Á
b-Dicarbonyl compounds Á N,N-Dimethylformamide
dimethylacetal Á Arylhydrazines
One-pot synthesis is a simple and efficient route to target
molecules which includes two or more transformation steps
in a single operation starting from relatively simple pre-
cursors [20]. Compared with reactions in organic solvents,
solventless reactions are often rapid, regio or chemose-
lective, occur in high yields, and have environmental and
economic advantages [21].
Introduction
Pyrazoles have been the subject of chemical and biological
studies because of their interesting pharmacology including
selective enzyme inhibitory [1], antiviral [2], estrogen
receptor agonist [3], anti-inflammatory [4], anticancer [5],
antiobesity [6], and antitumor [7] properties.
For these reasons, we decided to pursue one-pot sol-
ventless synthesis of 1,4,5-trisubstituted pyrazoles from
b-dicarbonyl compounds, DMFDMA, and arylhydrazines
without use of a catalyst. Herein we report the results.
The synthesis of these compounds has been investigated
in depth by use of so-called [2,3]-atom fragments, in which
b-difunctional electrophiles, for example enaminones are
used as three-atom building blocks and hydrazine deriva-
tives as the two-atom fragment [8]. It is well known that
enaminone moieties can be used as starting materials for
the preparation of pyrazoles [9], pyrimidines [10], pyri-
midones [11], isoxazoles [12], pyrroles [13], etc. Differently
substituted b-enaminoketones can be prepared by conden-
sation of the methylene group of b-dicarbonyl compounds
Results and discussion
In this study, we first optimized the reaction conditions
using acetonylacetone (1a), N,N-dimethylformamide
dimethylacetal (2), and phenylhydrazine (3a) as model
substrates. In our preliminary experiments 1 mmol phenyl-
hydrazine was treated with 1 mmol acetonylacetone and
1.5 mmol DMFDMA under solvent-free conditions at
70 °C. The reaction was complete in less than 1 min. After
work-up of the reaction mixture, 1-(5-methyl-1-phenyl-1H-
pyrazol-4-yl)ethan-1-one (4a) was obtained in excellent
yield (95%; Table 1).
H. Alinezhad (&) Á M. Tajbakhsh Á M. Zare
Faculty of Chemistry, University of Mazandaran, Babolsar, Iran
e-mail: heshmat@umz.ac.ir
123

948
H. Alinezhad et al.
Table 1 Preparation of pyrazole derivatives
O
O
O
MeO
MeO
Me
Me
R2
R1
Solvent free
70 °C
+
ArNHNH2
+
N
N
R1
R2
N
Ar
1a 1e
-
2
3a 3e
-
4a 4y
-
Prod.
R1
R2
Ar
Ph
Yield/%a
M.p. (lit. m.p.)/°C
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Et
95
95
96
95
90
93
92
94
96
91
92
95
94
96
90
95
94
96
96
91
97
92
95
97
91
103–107 (103 [16])
p-NO2C6H4
p-ClC6H4
o-ClC6H4
p-MeOC6H4
Ph
88–90 (174–177 [23])
110–113 (110–113 [22])
Oil
86–88 (86–88 [22])
140–142 (153 [16])
4g
4h
4i
Et
Et
p-NO2C6H4
p-ClC6H4
o-ClC6H4
p-MeOC6H4
Ph
80–85
Et
Et
55–57 (55–57 [22])
Et
Et
Oil
4j
Et
Et
84–89 (84–89 [22])
4k
4l
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OEt
OEt
OEt
OEt
OEt
49–52 (49 [14])
p-NO2C6H4
p-ClC6H4
o-ClC6H4
p-MeOC6H4
Ph
119–124 (116–120 [24])
4m
4n
4o
4p
4q
4r
4s
60–62 (60–61 [22])
Oil
62–64 (63–65 [22])
OCH2Ph
OCH2Ph
OCH2Ph
OCH2Ph
OCH2Ph
Ot-Bu
80–83
112–114
Oil
p-NO2C6H4
p-ClC6H4
o-ClC6H4
p-MeOC6H4
Ph
Oil
4t
Oil
4u
4v
4w
4x
4y
Oil [17]
Oil
Ot-Bu
p-NO2C6H4
p-ClC6H4
o-ClC6H4
p-MeOC6H4
Ot-Bu
Oil [22]
Oil
Ot-Bu
Ot-Bu
Oil [22]
Reactions were performed at 70 °C using 1 mmol b-dicarbonyl compound, 1.5 mmol DMFDMA, and 1 mmol arylhydrazine
a
Isolated yield
To demonstrate the generality of the reaction, the sub-
strate scope of the sequence was explored. As shown in
Table 1, several substituted hydrazines 3 and b-dicarbonyl
compounds 1 (b-ketoesters and b-diketones) were used
successfully in this procedure.
This reaction was also successfully performed with
b-keto esters in excellent yields. For example, when ethyl
acetoacetate (1c) and phenylhydrazine were used, the
reaction was complete\1 min at 70 °C, giving the desired
pyrazole 4k in 95% yield. Investigation of this method
indicated that reaction of ethyl acetoacetate with electron-
withdrawing or electron-donating substituted arylhydra-
zines afforded pyrazoles 4l–4o under optimum reaction
conditions. Similarly, other b-keto esters gave the expected
pyrazoles in high yield. When benzyl acetoacetate (1d) and
t-butyl acetoacetate (1e) were used, the reactions were
The reaction of acetylacetone (1a) with a variety of aryl-
hydrazines 3 in the presence of DMFDMA under optimum
reaction conditions afforded 4-acylpyrazoles 4a–4e immedi-
ately, in excellent yields. Similarly, heptane-3,5-dione (1b)
reacted with arylhydrazines and DMFDMA to give the cor-
responding 4-acylpyrazoles 4f–4j in 91–96% yields.
123

One-pot regioselective synthesis of 1,4,5-trisubstituted pyrazoles
949
1-[1-(2-Chlorophenyl)-5-ethyl-1H-pyrazol-4-yl]propan-1-
immediately complete at 70 °C, giving the desired com-
pounds 4p–4y in 91–96% yield.
one (4i, C14H15ClN2O)
Oil; 1H NMR (400 MHz, CDCl3): d = 1.06 (t, J = 7.6 Hz,
3H, Me), 1.22 (t, J = 7.6 Hz, 3H, Me), 2.86 (q,
J = 7.6 Hz, 2H, CH2), 2.67 (q, J = 7.6 Hz, 2H, CH2),
7.37–7.58 (m, 4H, Ph), 8.06 (s, 1H, CH) ppm; 13C NMR
(100 MHz, CDCl3): d = 8.08, 12.74, 18.87, 33.90, 119.14,
127.65, 129.59, 130.51, 131.15, 132.68, 136.29, 141.73,
150.19, 196.18 ppm.
Conclusion
In this study, we have developed a green, one-pot approach
for preparation of 1,4,5-trisubstituted pyrazole derivatives
starting from different b-ketoesters or b-ketones and a
variety of arylhdrazines which is completed immediately,
in excellent yields, under solvent free conditions, without
use of any catalysts. One-pot and solvent-free conditions
are additional eco-friendly attributes of this synthetic
procedure.
1-(2-Chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic
acid ethyl ester (4n, C13H13ClN2O2)
Oil; 1H NMR (400 MHz, CDCl3): d = 1.38 (t, J = 7.2 Hz,
3H, Me), 2.40 (s, 3H, Me), 4.34 (q, J = 7.2 Hz, 2H, CH2),
7.40–7.58 (m, 4H, Ph), 8.07 (s, 1H, CH) ppm; 13C NMR
(100 MHz, CDCl3): d = 11.16, 14.43, 60.01, 112.37,
127.79, 129.59, 130.41, 131.02, 132.39, 136.41, 143.30,
145.31, 163.74 ppm.
Experimental
5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid benzyl-
ester (4p, C18H16N2O2)
Materials were purchased from Fluka and Merck. Products
were characterized on the basis of their spectroscopic data
(1H NMR, 13C NMR) and elemental analysis (CHN).
M.p.: 80–83 °C; 1H NMR (400 MHz, CDCl3): d = 2.59 (s,
3H, Me), 5.35 (s, 2H, CH2), 7.34–7.54 (m, 10H, Ph), 8.09 (s,
1H, CH) ppm; 13C NMR (100 MHz, CDCl3): d = 12.04,
65.74, 112.63, 125.52, 128.11, 128.17, 128.60, 128.71,
129.29, 136.34, 142.00, 143.85, 163.59 ppm.
General procedure for preparation
of 1,4,5-trisubstituted pyrazoles
5-Methyl-1-(4-nitrophenyl)-1H-pyrazole-4-carboxylic
acid benzyl ester (4q, C18H15N3O4)
Hydrazine derivative 3 (1 mmol) was added to a mixture of
1,3-dicarbonyl compound 1 (1 mmol) and N,N-dimethyl-
formamide dimethylacetal 2 (1.5 mmol) and stirred at
70 °C. All reactions were complete in less than 1 min,
indicated by TLC. Ethyl acetate (5 cm3) was added and the
mixture was washed with 10–20 cm3 H2O. The organic
layer was separated and concentrated under vacuum to give
the pure products. If necessary the products were further
purified by column chromatography on silica gel with
suitable eluents.
M.p.: 112–114 °C; 1H NMR (400 MHz, CDCl3): d = 2.70
(s, 3H, Me), 5.35 (s, 2H, CH2), 7.37–7.47 (m, 5H, Ph), 7.70 (d,
J = 12 Hz, 2H, Ph), 8.13 (s, 1H, CH), 8.39 (d, J = 12 Hz,
2H, Ph) ppm; 13C NMR (100 MHz, CDCl3): d = 12.35,
66.03, 114.07, 124.82, 125.50, 128.18, 128.31, 128.65,
136.05, 143.08, 143.75, 144.10, 147.01, 163.12 ppm.
1-(4-Chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic
acid benzyl ester (4r, C18H15ClN2O2)
1
Oil; H NMR (400 MHz, CDCl3): d = 2.59 (s, 3H, Me),
1-[1-(2-Chlorophenyl)-5-methyl-1H-pyrazol-4-yl]-
ethan-1-one (4d, C12H11ClN2O)
5.35 (s, 2H, CH2), 7.39–7.53 (m, 9H, Ph), 8.08 (s, 1H, CH)
ppm; 13C NMR (100 MHz, CDCl3): d = 12.01, 65.8,
112.96, 126.69, 128.12, 128.20, 128.61, 129.49, 134.59,
136.25, 137.30, 142.24, 143.84, 163.41 ppm.
1
Oil; H NMR (400 MHz, CDCl3): d = 2.39 (s, 3H, Me),
2.48 (s, 3H, Me), 7.38–7.56 (m, 4H, Ph), 8.03 (s, 1H, CH)
ppm; 13C NMR (100 MHz, CDCl3): d = 11.61, 28.65,
120.44, 127.83, 129.46, 130.42, 131.13, 132.23, 136.10,
142.16, 144.77, 193.43 ppm.
1-(2-Chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic
acid benzyl ester (4s, C18H15ClN2O2)
1
Oil; H NMR (400 MHz, CDCl3): d = 2.42 (s, 3H, Me),
1-[5-Ethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl]-
5.35 (s, 2H, CH2), 7.23–7.59 (m, 9H, Ph), 8.12 (s, 1H, CH)
ppm; 13C NMR (100 MHz, CDCl3): d = 11.25, 65.79,
112.04, 127.81, 128.17, 128.19, 128.61, 129.59, 130.44,
131.08, 132.37, 136.29, 136.35, 142.30, 145.63, 163.49 ppm.
propan-1-one (4g, C14H15N3O3)
M.p.: 80–85 °C; 1H NMR (400 MHz, CDCl3): d = 1.24 (t,
J = 7.2 Hz, 3H, Me), 1.25 (t, J = 7.6 Hz, 3H, Me), 2.50
(q, J = 7.2 Hz, 2H, CH2), 3.06 (q, J = 7.6 Hz, 2H, CH2),
7.68 (d, J = 9.2 Hz, 2H, Ph), 8.09 (s, 1H, CH), 8.42 (d,
J = 9.2 Hz, 2H, Ph) ppm; 13C NMR (100 MHz, CDCl3):
d = 8.06, 13.32, 19.04, 34.19, 120.61, 124.86, 126.06,
142.46, 143.78, 149.14, 196.09 ppm.
1-(4-Methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic
acid benzyl ester (4t, C19H18N2O3)
1
Oil; H NMR (400 MHz, CDCl3): d = 2.53 (s, 3H, Me),
3.87 (s, 3H, Me), 5.30 (s, 2H, CH2), 7.01 (d, J = 12 Hz,
123

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H. Alinezhad et al.
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2H, Ph), 7.32 (d, J = 12 Hz, 2H, Ph), 7.33–7.47 (m, 5H,
Ph), 8.05 (s, 1H, CH) ppm; 13C NMR (100 MHz, CDCl3):
d = 11.91, 55.59, 65.68, 112.25, 114.38, 126.91, 128.08,
128.14, 128.59, 131.13, 136.37, 141.70, 143.94, 159.71,
163.62 ppm.
5-Methyl-1-(4-nitrophenyl)-1H-pyrazole-4-carboxylic
acid t-butyl ester (4v, C15H17N3O4)
1
Oil; H NMR (400 MHz, CDCl3): d = 1.59 (s, 9H, Me),
2.65 (s, 3H, Me), 7.67 (d, J = 9.2 Hz, 2H, Ph), 8.01 (s, 1H,
CH), 8.38 (d, J = 9.2 Hz, 2H, Ph) ppm; 13C NMR
(100 MHz, CDCl3): d = 12.28, 28.36, 80.97, 115.81,
124.77, 125.44, 143.18, 143.30, 143.94, 146.87,
163.74 ppm.
1-(2-Chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic
acid t-butyl ester (4x, C15H17ClN2O2)
1
13. Cohnen E, Dewald R (1987) Synthesis 566
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(2003) C R Chim 6:607
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16. Schenone P, Mosti L, Menozzi G (1982) J Heterocycl Chem
19:1355
Oil; H NMR (400 MHz, CDCl3): d = 1.57 (s, 9H, Me),
2.35 (s, 3H, Me), 7.35–7.54 (m, 4H, Ph), 7.99 (s, 1H, CH)
ppm; 13C NMR (100 MHz, CDCl3): d = 11.16, 28.40,
80.48, 113.73, 127.76, 129.62, 130.36, 130.94, 132.37,
136.47, 142.31, 144.79, 163.14 ppm.
17. Menozzi G, Mosti L, Schenone P (1987) J Heterocycl Chem
24:1669
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Wilson DM (2002) Synthesis 1669
Acknowledgment This work was supported by a Research Grant
from Mazandaran University, Iran.
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Org Chem 537
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