Pyrazole synthesis under microwave irradiation and solvent-free condition

Article abstract of DOI:10.1590/S0103-50532010000600012

This paper presents a study of solvent-free reaction conditions using microwave irradiation (MW) to obtain 4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles by the cyclocondensation reaction of 4-alkoxy-1,1,1-trifuoro-3-alken- 2-ones [CF₃C(O)CH=C(R¹)OR, where R/R1 = Et/H, Me/Me and Me/Ph] with hydrazines [NH₂NH-R², where R² = CO₂Me, Ph, CH₂CH₂OH]. Some reactions were performed under the same reaction conditions using methanol as solvent. The results obtained using MW equipment for synthesis under solvent-free conditions were also compared with those described in literature for conventional thermal heating and heating with a domestic MW oven. In general, the products furnished by reaction in MW equipment for synthesis presented better yields and shorter reaction times. In addition, it was demonstrated that the reaction temperature altered the formation of products for each hydrazine showing that MW equipment for synthesis is effcient for reacting hydrazines and 4-alkoxy-1,1,1-trifuoro-3- alken-2-ones to procedure the products 4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles.

Full text of DOI:10.1590/S0103-50532010000600012

J. Braz. Chem. Soc., Vol. 21, No. 6, 1037-1044, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Pyrazole Synthesis under Microwave Irradiation and Solvent-free Conditions
Lilian Buriol, Clarissa P. Frizzo, Mara R. B. Marzari, Dayse N. Moreira,
Liziê D. T. Prola, Nilo Zanatta, Helio G. Bonacorso and Marcos A. P. Martins*
Núcleo de Química de Heterociclos, Departamento de Química,
Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil
Este trabalho descreve a síntese de 4,5-diidro-1H-pirazóis pela reação de ciclocondensação de
hidrazinas [NH2NH-R2, onde R2 = CO2Me, Ph, CH2CH2OH] com 4-alcóxi-1,1,1-trifluor-3-alquen-
2-onas [CF3C(O)CH=C(R1)OR, onde R/R1 = Et/H, Me/Me and Me/Ph] sob irradiação de micro-
ondas utilizando um equipamento de micro-ondas para síntese e em condição livre de solvente.
Algumas reações foram realizadas na presença de metanol. Os resultados obtidos utilizando
micro-ondas para síntese foram comparados com aqueles obtidos quando a reação foi feita pelo
método convencional e no forno de micro-ondas doméstico. Os produtos foram obtidos com bons
rendimentos em um intervalo de tempo pequeno. Além disso, foi demonstrado que a temperatura
da reação alterou a formação dos produtos para cada hidrazina mostrando que o equipamento de
micro-ondas para síntese é eficiente para as reações de hidrazinas com 4-alcóxi-1,1,1-trifluor-3-
alquen-2-onas levando à formação dos produtos 4,5-diidro-1H-pirazóis e pirazóis.
This paper presents a study of solvent-free reaction conditions using microwave irradiation
(MW) to obtain 4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles by the cyclocondensation
reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH=C(R1)OR, where R/R1 = Et/H,
Me/Me and Me/Ph] with hydrazines [NH2NH-R2, where R2 = CO2Me, Ph, CH2CH2OH]. Some
reactions were performed under the same reaction conditions using methanol as solvent. The results
obtained using MW equipment for synthesis under solvent-free conditions were also compared with
those described in literature for conventional thermal heating and heating with a domestic MW
oven. In general, the products furnished by reaction in MW equipment for synthesis presented better
yields and shorter reaction times. In addition, it was demonstrated that the reaction temperature
altered the formation of products for each hydrazine showing that MW equipment for synthesis
is efficient for reacting hydrazines and 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones to procedure the
products 4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles.
Keywords: microwave irradiation, solvent-free, pyrazoles, cyclocondensation reactions
Introduction
detail the utility of MAOS, however the exact reasons why
microwave (MW) heating enhances chemical processes are
still unknown.5-10
Sustainability is an increasingly important issue in
the wider context of population, health, the environment,
energy, technology, renewable resources, and, in the
sciences, as an integral part of the rapidly emerging field
called Green Chemistry.1-3 Removing organic solvents
in chemical synthesis is important in the drive towards
benign chemical technologies. In this context, the use of
microwave-assisted organic synthesis (MAOS) has emerged
as an alternative and efficient tool, especially in heterocyclic
synthesis.4 Many reviews have been published recently that
Although reports of procedures that use domestic MW
ovens can be found in the literature, their lack of control
systems presents a serious drawback. In general, it is
not possible to determine the reaction temperature in an
accurate way.Additionally, performing chemical synthesis
in domestic MW ovens can be troublesome because of
the lack of a pressure control and of a means of stirring
the reaction mixture. Furthermore, the pulsed irradiation
resulting from having no homogeneous microwave field
may lead to problems of reproducibility. Another concern
is safety. Heating organic solvents in open vessels in a
microwave oven can lead to violent explosions induced by
*e-mail: mmartins@base.ufsm.br

1038
Pyrazole Synthesis under Microwave Irradiation and Solvent-free Conditions
J. Braz. Chem. Soc.
electric arcs inside the cavity or sparking resulting from
the switching of magnetrons.10
conditions with the results obtained under conventional
thermal heating and domestic MW oven in order to evaluate
the effect of the MW equipment for synthesis in these
reactions (Scheme 1).
Recent improvements in controlling reactions have
been made possible by MW equipment for synthesis. These
equipments have new tools, such as simultaneous external
cooling of the reaction mixture (maintaining below room
temperature), in this case, the reaction vessel is cooled from
the outside by compressed air or with the aid of a cooling
fluid while being irradiated by microwaves.11,12This allows a
higher level of microwave power to be directly administered
to the reaction mixture but will prevent overheating by
continuously removing heat.11,12 According to some studies,
transformations of this type involving polar intermediates or
transition states are likely to be accelerated by microwave
irradiation due to a specific interaction of the electric field
with the polar reaction species, which is not connected to
the reaction temperature.9
O
R1
F3C
OR
H2N NHR2
R1
R1
N
R1
CF3
HO
F3C
N
R1
N
N
F3C
F3C
N
R2
N
N
R2
N
R2
H
1,5-isomers
1,3-isomers
R/R1 = Et/H, Me/Me, Me/Ph
R2 = CO2Me, Ph, CH2CH2OH
Scheme 1.
Reactions performed in microwave ovens must be
considered in relation to the reaction medium. Solvent
effects are of especially great importance. If polar
solvents are involved, either aprotic (e.g. DMF) or protic
(e.g. alcohols), the main absorption occurs between the
microwaves and the polar molecules of the solvent. In this
case, energy transfer is from the solvent to the reaction
mixtures and reactants. Consequently, the results should
be nearly the same as under classic heating. The absence
of MW effects was demonstrated by several experiments
carefully carried out in DMF.13 More interesting may
be the use of nonpolar solvents (e.g. xylene, toluene,
hydrocarbons) as there is only a very weak solvent-MW
interaction (they can be considered transparent solvents).
By far, the best situation is that of solvent-free reactions,
where the absorption of microwave irradiation should be
limited only to the reacting species.14
Several methods for the pyrazole scaffold have been
described in literature, including MW assisted methods.15-17
4,5-Dihydro-1H-pyrazolesareimportantnitrogen-containing
five-memberedheterocycliccompounds, withapplicationsas
analytical reactants and agrochemicals,18 besides possessing
important pharmacological activities such as antitumor19 and
anti-inflammatory.20 Our research group has worked with
cyclocondensation reactions to obtain pyrazoles in both
domestic MW ovens and MW equipment for synthesis.21
Thus, the aims of this work are: (i) to investigate the use
of microwave irradiation to promote and accelerate the
cyclocondensation reaction between enones (4-alkoxy-
1,1,1-trifluoro-3-alken-2-one) and three hydrazines in
MW equipment for synthesis; (ii) to determinate the
reaction conditions to obtain 4,5-dihydro-1H-pyrazoles and
dehydrated pyrazoles in MW for synthesis under solvent-
free conditions and in MeOH; (iii) to compare the reaction
Results and Discussion
In order to evaluate the cyclocondensation reaction
conditions to obtain 4,5-dihydro-1H-pyrazoles or pyrazoles
from the reaction of enones and hydrazines using MW
equipment for synthesis, a series of experiments was
performed. These experiments were organized into three
groups and in each group, three enones 1a-c were reacted
with hydrazines 2, 5 and 9 under solvent-free conditions
(Schemes 2, 3 and 4).
The first experiment evaluated the reaction of enones
1a-c with methyl hydrazinocarboxylate 2, which furnished
the 4,5-dihydro-1H-pyrazoles 3a-c or the dehydrated
products 4a-c. In accordance with Scheme 2, it is possible to
assert that product 3b was the least stable 4,5-dihydro-1H-
pyrazole, undergoing partial loss of the methyl carboxylate
group at 150 °C and total loss at 200 °C. 4,5-Dihydro-1H-
pyrazole 3a was slightly more stable than 3b, undergoing
total loss of the methyl carboxylate group at 200 °C,
followed by 4,5-dihydro-1H-pyrazole 3c, the most stable,
undergoing partial loss of the methyl carboxylate group
at 200 °C for 6 min and total loss at 200 °C for 12 min.
From the results, it was possible to presume that for methyl
hydrazinocarboxylate, 4,5-dihydro-1H-pyrazole was
obtained in mild temperatures and the NH-pyrazole was
formed at more drastic temperature conditions.
Many studies have shown that the presence of the
trifluoromethyl group is one of the most important factors
in the stability of 4,5-dihydro-1H-pyrazoles.22 Thus, we
found it extremely important to investigate the possibility
of dehydrating 4,5-dihydro-1H-pyrazoles to obtain the
aromatic 1-carboxymethyl-5-trifluoromethylpyrazole-1H-
pyrazoles. However, in this case, the expected aromatic

Vol. 21, No. 6, 2010
Buriol et al.
1039
R1
R1
temperatures and shorter reaction times were required to
obtain the products and an isomeric mixture (1,5-isomer
and 1,3-isomer) was formed in the case of enones 1a
and 1b. In addition, the NH-pyrazole was not isolated in
any of the experiments when enones 1a-c reacted with
phenylhydrazine 5.
O
HO
F3C
O
R1
i
N
N
or
+
H2N
Me
F3C
N
N
N
O
F3C
OR
H
H
1a-c
O
OMe
3a-c
2
4a-c
i: Solvent-free, MW
T
time
Molar
ratio 3:4
Yielda
(%)
R1
Product(s)
R1
R1
Enone
R
(ºC) (min)
HO
N
N
F3C
F3C
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1c
Et
Et
H
H
50
100
150
200
50
8
8
3a
3a
-
70
73
78
74
62
90
81
80
80
82
71
80
94
N
N
Ph
Ph
H2N
-
NH
7a-c
6a-c
O
R1
i
+
Et
H
8
3a
-
F3C
OR
CF3
1a-c
Et
H
8
4a
-
5
N
R1
N
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
6
3b
-
Ph
8a-b
Me 100
Me 150
Me 200
6
3b
-
3:1
-
6
3b:4b
4b
i: Solvent-free, MW
Molar Yieldb
ratio
6
T
(°C)
time
(min)
Enone
R
R1
Product(s)a
(%)
74
84
75
88
95
93
92
82
93
70
90
82
Ph
Ph
Ph
Ph
Ph
50
6
3c
-
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
Et
Et
H
H
50
6
6
6
6
1
6
6
6
6
6
6
6
6a
6a
-
-
100
150
200
200
6
3c
-
100
150
200
50
6
3c
-
Et
H
7a:8a
7a:8a
6b
1:5
1:2.5
-
6
3c:4c
4c
1:1
-
Et
H
12
aYield of isolated products.
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
100
150
200
50
6b:7b:8b 5:10:3
Scheme 2.
7b:8b
7b:8b
6c
3:1
3:1
-
product was not formed, but rather the NH-pyrazole due to
loss of the carboxylate group. Product 4c was obtained only
after 12 min of irradiation at 200 °C, which demonstrates
that the dehydratation reaction under MW conditions was
susceptible to the substituent effect, showing that the phenyl
substituent stabilized the 1-carboxymethyl-4,5-dihydro-
5-trifluoromethyl-1H-pyrazoles. This failure to obtain
dehydrated pyrazoles was a surprise, because in previous
studies23 we obtained similar trihalomethylated 4,5-dihydro-
1H-pyrazoles containing a strong electron-withdrawing
group attached to the N1-atom, where it was possible
to eliminate a water molecule and obtain the aromatic
pyrazole without the loss of the N1-group, by stirring
the reaction mixture in sulfuric acid, for 8 h, at 25 °C.
However, we have also observed that some 4,5-dihydro-
1H-pyrazoles with an electron-withdrawing group attached
to the N1-atom undergo dehydration when heated with a
simultaneous loss of the carboxylate group, leading to the
formation of 5-trifluoromethyl-1H-pyrazole.24
100
150
200
6c:7c
7c
1:5
-
7c
-
1
a Isomer ratio was determined by H NMR. The formation of 1,3- and
1,5-isomers was determined by comparison with literature date.26,27 bYield
of isolated products.
Scheme 3.
In previous works, our research group demonstrated
that the reaction of phenylhydrazine 5 with enone 1b,
under conventional thermal heating (ethanol reflux, during
4 h) resulted in product 6b and the attempt to obtain
5-trifluoromethyl-1-phenyl-1H-pyrazoles by dehydration
of compound 6a with sulfuric acid was unsuccessful.25 Our
research group has also demonstrated that these reactions,
when performed in a domestic MW oven, led to formation
of 4,5-dihydro-1H-pyrazoles from which it was possible
to obtain a dehydrated product.26 Therefore, although
the formation of 6a-c was probably due to the electronic
conjugation between the p-system of the phenyl group
and the lone pair of electrons of the nitrogen atom (N1)
of the pyrazoline-ring, which makes the aromatization of
the pyrazole-ring more difficult, in the domestic MW oven
the reaction of phenylhydrazine with enones resulted in
The second experiment evaluated the reaction of enones
1a-c with phenylhydrazine 5, which furnished the 1-phenyl-
4,5-dihydro-1H-pyrazoles 6a-c or dehydrated products
7a-c and 8a-b in mild temperature conditions. The results
are summarized in Scheme 3. The results demonstrate
that due to the higher reactivity of phenylhydrazine 5 in
comparison with methyl hydrazinocarboxylate 2, lower

1040
Pyrazole Synthesis under Microwave Irradiation and Solvent-free Conditions
J. Braz. Chem. Soc.
R1
dehydrated products.26 The reaction of phenylhydrazine 5
with enone 1a resulted in a mixture of products 6a and 7a;
and with enone 1b it resulted in a mixture of products 7b
and 8b; while the reaction of phenylhydrazine with enone
1c did not produce 7c.26 These results showed the efficiency
of MW equipment for synthesis when compared with
domestic MW oven. With MW equipment for synthesis,
the products 4,5-dihydro-1H-pyrazole 6a and pyrazoles 7a
and 8a, were obtained separated from enone 1a. In addition,
the 1,5-diphenyl-pyrazole 7c from enone 1c was isolated
for the first time.
CF3
i
+
O
R1
N
R1
N
+
H2N
OH
F3C
N
N
N
F3C
OR
H
9
1a-c
HO
10a-c
HO
11a-c
i: Solvent-free, MW
T
time
(°C) (min)
Molar Yieldb
Enone
R
R1
Product(s)a
ratio
(%)
75
74
83
67
79
74
78
72
76
70
73
75
80
64
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
Et
Et
H
H
50
50
2
6
6
6
6
1
6
6
6
6
6
6
6
6
11a
-
10a:11a
10a:11a
10a:11a
10a:11a
10b:11b
10b:11b
10b:11b
10b:11b
10b:11b
10c:11c
10c:11c
10c:11c
10c:11c
1:10
1:10
1:1.3
1.5:1
1:5
Et
H
100
150
200
50
The cyclocondensation reaction of enones 1a-c with
2-hydroxyethylhydrazine 9 demonstrated once again the
difference in the reactivity of hydrazines 2, 5 and 9. The
results are summarized in Scheme 4. As was expected,
1-alkyl-4,5-dihydro-1H-pyrazoles were not isolated due
to the reactivity of hydrazine and the lower stability of
this compound. All enones, under all microwave reaction
conditions evaluated, resulted in pyrazoles 10a-c and 11a-c.
Enone 1a was reacted with 2-hydroxyethylhydrazine 9,
under microwave irradiation, at 50 °C for 2 min furnishing
only product 11a. The presence and the ratio of isomers
10 (1,5-isomer) and 11 (1,3-isomer) were verified using
Et
H
Et
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
50
1:10
1:5
100
150
200
50
1:1.4
1:1.4
1:1
100
150
200
1:1
3:1
3:1
1
the H and 13C NMR spectra and mass spectrometric
a Isomer ratio was determined by H NMR. The formation of 1,3- and
1,5-isomers was determined by GC-MS, H, and 13C NMR.26,27 bYields
1
fragmentation.
1
The initial results also showed a difference in reactivity
among the hydrazines, which increased in the order:
methyl hydrazinocarboxylate 2, phenylhydrazine 5, and
2-hydroxylethylhydrazine 9. This difference in reactivity
was also evidenced by the fact that the substituent attached
at the N-atom was required in order to obtain the products.
When the substituent was an electron-withdrawing group,
such as methyl carboxylate, the nucleophilicity of the
N-atom decreased, while with an electron-donating
group, such as hydroxyethyl, the nucleophilicity of the
N-atom increased. In addition, it was possible to observe
the important influence of the reaction temperature in the
obtainment of the 4,5-dihydro-1H-pyrazoles or pyrazoles,
with 100 °C of variation in the reaction temperature.
Reactions performed using hydrazine 2 showed that the
4,5-dihydro-1H-pyrazoles were the most stable products
and the dehydrated pyrazole was not obtained, while the
NH-pyrazole was obtained from the loss of the carboxylate
group. When 5 was reacted with 1a-c, the intermediate
1-phenyl-4,5-dihydro-1H-pyrazole was formed at a lower
temperature in comparison with the reaction of 1a-c with 2.
In this context, the hydrazine 9, which is the most reactive
hydrazine, reacted with enones 1a-c resulting in pyrazoles
at very low temperatures and short reaction times. The data
from the reactions between enones 1a-c and hydrazines 2,
5 and 9 are shown in Table 1.
of isolated products.
Scheme 4.
Table 1. Comparison of the reaction conditions between hydrazines 2, 5,
9 and enones 1a-c under microwave irradiation
T
(°C)
time
(min)
Yieldsa
(%)
Hydrazine
Products
H2NNHCO2Me 2
H2NNHCO2Me 2
H2NNHPh 5
3a-c
4a-c
6a-c
50
200
6 -8
6 -12
1-6
6
73-98
74-94
84-94
88-93
66-74
50-100
H2NNHPh 5
7a-c and 8a-b 150-200
H2NNHCH2CH2OH 9 10a-c and 11b-c
50
1-6
a Yields of isolated products.
There is an intense discussion in the literature about
solvent effects in reactions performed with MW,5 and it
has been established that some solvents are more efficient
than others in transferring the MW energy absorbed in heat.
This information is furnished by a mathematical coefficient
called the loss tangent (tan d) and the higher this coefficient
is, the faster the temperature increases.5 On the other
hand, it has been demonstrated that for some microwave
reactions, the solvent-free condition is the best condition,
resulting in better yields and higher regioselectivity when

Vol. 21, No. 6, 2010
Buriol et al.
1041
compared with the reaction using solvents.6 In this case,
the MW absorption irradiation should be limited only
to reactive species. In this context, the performance of
cyclocondensation reactions presented in this study using
MW in the presence of a solvent is very important.
1a-c with methyl hydrazinocarboxylate 2, though the
reaction times and yields were similar, in the domestic
MW oven, the reproducibility of these reactions was lower.
When comparing the efficiency in obtaining product 3b
in the conventional method and using MW equipment for
synthesis, it was observed that the microwave for synthesis
furnished the product in better yield, shorter time and with
a ‘greener’ method, due to the absence of solvent.
For reactions of enones 1a-c with phenylhydrazine 5,
the reactions in a domestic MW oven were faster (3 min),
however the products were formed in the presence of
toluene, a toxic and dangerous solvent. In addition,
the reaction of enone 1a with 5 furnished a mixture of
4,5-dihydro-1H-pyrazole and pyrazole in a molar ratio
of 2:1, respectively. Product 6c was obtained only after
15 min of irradiation, while product 7c was not observed.
Therefore, the reaction of enones 1a-c with 5 in MW
equipment for synthesis furnished better results in terms of
yields, absence of solvent and reaction time (6 min for all
compounds) when compared with the reaction performed
in a domestic MW oven. Comparing the results obtained
by the reactions performed in MW equipment for synthesis
and those carried out in conventional methods for products
6a-c, we observed greater efficiency in MW equipment
for synthesis, demonstrated by the better yields, shorter
reaction time and absence of solvent.
The compounds formed from the reaction of enones
1a-c and 2-hydroxyethylhydrazine 9 described in this paper
are novel and their synthesis in domestic MW oven has not
yet been reported. In conventional conditions, the reaction
of 4,4,4-trifluoro-1-pyridin-2-yl-butane-1,3-dione with
2-hydroxyethylhydrazine at 0 °C for 7 h gave 4,5-dihydro-
1H-pyrazole and at 25 °C for 15 h furnished a mixture of
4,5-dihydro-1H-pyrazoles and pyrazoles.29
It is worthy to note that in many cyclocondensation
reactions performed in MW or using a conventional
method,26 it was necessary to use pyridine and/or toxic
solvents such as toluene and the regioselectivity of the
reaction was unsatisfactory. In this context, the novel
method developed by our research group is very satisfactory
in terms of both chemical and environmental aspects.
The reaction of enone 1b was performed with each
hydrazine (2, 5 or 9) in the presence of methanol. Hydrazine
5 was also reacted with enone 1c. The choice of methanol as
solvent was based on two experimental factors: (i) methanol
is the solvent generally employed in cyclocondensation
reactions;28 (ii) methanol possesses one of the greatest
values for tan d (0.941) among the organic solvents, thus
the transfer of MW energy in heat is considered more
efficient. The reactions between enones (1b and 1c) and
hydrazines (2, 5 and 9) were performed in MeOH (1 mL) at
the same molar ratio (1 mmol enone:1.2 mmol hydrazine),
temperatures and reaction times as the reaction performed
under solvent-free conditions. In all cases, the presence of
MeOH as solvent resulted in decreased yields. These results
are depicted in Table 2. Products of all reactions were
obtained in better yields under solvent-free conditions than
in the presence of MeOH. In the last case, for products 10a
and 11a, the reduction in yields in the presence of MeOH
was smaller than that for other products, however the
regioselectivety was unaltered. These results demonstrate
the importance of the high efficiency and environmentally
benign conditions of solvent-free reactions.
Table 2. Synthesis of 4,5-dihydro-1H-pyrazoles using MeOH as solvent
under microwave irradiation
Product(s)a
T (°C)
100
50
time (min) Molar ratio Yieldb (%)
3b
6
1
6
1
-
-
60
82
78
57
6b
6c
50
-
10b : 11b
50
1:5
aAll reactions were performed with 1 mmol enone:1.2 mmol hydrazine
in 1 mL MeOH. bYields of isolated products.
The results of the cyclocondensation reactions to
obtain 4,5-dihydro-1H-pyrazoles using MW equipment for
synthesis were compared with those obtained by domestic
MW oven and with the conventional method (reflux in
molecular solvent), as shown in Table 3. The comparison of
the reactions performed in MW equipment for synthesis and
the reactions performed in domestic MW oven was difficult
because of the inaccurate evaluation of reaction conditions
such as the presence or the absence of solvent and MW
criteria such as temperature and power measurements in
domestic MW ovens. However, the comparison established
in Table 3 demonstrates that, for the reaction of enones
Conclusion
In conclusion, in the present study, we presented a
new, simple and ‘greener’ method for the formation of
4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles, using
microwave irradiation under solvent-free conditions.
In the reaction of 1a-c with 2 and 5, the 4,5-diidro-1H-
pirazóis was obtained in mild conditions and the pyrazole
was formed at more drastic temperature conditions. In

1042
Pyrazole Synthesis under Microwave Irradiation and Solvent-free Conditions
J. Braz. Chem. Soc.
Table 3. 4,5-Dihydro-1H-pyrazoles obtained using both MW equipment for synthesis, domestic MW oven and conventional method
MW for synthesis under
solvent-free conditions
Domestic MW ovena
Conventional methodb
Prod.
time
(min)
T
(°C)
Yieldc
(%)
Solv.
time
(min)
T
(°C)
Yieldc (%)
Solv.
time
(h)
T
(°C)
Yieldc (%)
e
3a
3b
3c
6a
6b
6c
8
6
6
6
1
6
100
100
50
73
90
82
84
95
94
-
6
6
80
80
82
85
93
77d
91
80
-
-
5
-
-
78
-
-
62
-
-
EtOH
e
-
6
80
-
100
50
Toluene
Toluene
Toluene
3
86
EtOH
EtOH
4
4
-
78
78
-
73
70
-
3
86
e
50
15
104
-
aReferences used for domestic MW oven data: Compounds 3a-b,30 compounds 6a-c.26 bReferences used for conventional method: Compounds 6a-b.25
cYields of isolated products. dMixture of 4,5-dihydro-1H-pyrazole and pyrazole in a molar ratio of 2:1, respectively. eThis reaction has not yet been reported
in the literature.
the reaction of 1a-c with 9, the 4,5-dihydro-1H-pyrazole
was not isolated, and in all reaction conditions evaluated,
the dehydrated pyrazoles were obtained. In addition,
we verified that while the conventional thermal heating
method gives only moderate yields of the expected
cyclocondensation reaction products, microwave irradiation
under solvent-free conditions leads to the same products
with a drastic reduction of reaction time and improved
yields. The use of MW equipment for synthesis allowed
for safe and reproducible reaction conditions.
3.5.9 software applying the power of 200 W as the
maximum level of irradiation and a maximum level of
internal vessel pressure of 250 psi. The irradiation power
was in the range of 1-95 W for reactions at 50-100 °C,
with simultaneous cooling and 30-190 W for reaction at
150-200 °C, without simultaneous cooling. The reaction
mixture was subsequently cooled to 50 °C by compressed
air. The reaction mixture was isolated with chloroform
(5 mL) and washed with water (3 × 5 mL). The chloroform
was evaporated under vacuum (reduced pressure) and
the products were obtained in a pure form without
further purification. The data report of some reactions
furnished by the software are depicted in Supplementary
Information.
Experimental
General
The experiments were performed in MW Discover
CEM using both modes of operation (with and without
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-
dihydro-1H-pyrazole (3a): mp 78-81 °C; 1H NMR (CDCl3)
d 3.17 ( d, 1H, 2J 19 Hz, H4b), 3.36 (d, 1H, 2J 19 Hz, H4a),
3.89 (s, 3H, OCH3), 6.95 (s, H, H3); 13C NMR (CDCl3) d 44.8
(C4), 53.5(OCH3), 89.3(q, 2J33Hz, C5), 122.8(q, 1J268Hz,
CF3), 144.3 (C3), 153.5 (C=O); GC/MS (EI, 70 eV) m/z 212
(M+, 8%), 181 (5), 143 (100), 69 (25).
1
simultaneous cooling). H and 13C NMR spectra were
recorded on a Bruker DPX 400 (1H at 400.13 MHz and
13C at 100.62 MHz) in CDCl3/TMS solutions at 298 K and
chemical shifts (d) are givem in ppm. Mass spectra were
registered in a HP 5973 MSD connected to a HP 6890 GC
and interfaced by a Pentium PC. The GC was equipped
with a split-splitless injector, cross-linked to a HP-5
capillary column (30 m, 0.32 mm i.d.), and helium was
used as the carrier gas. The melting points were measured
using a Microquímica MQAPF 301. The melting points
were not corrected.
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-3-methyl-
4,5-dihydro-1H-pyrazole(3b):mp55-56ºC;1HNMR(CDCl3)
d 2.07 (t, 3H, CH3), 3.13 (d, 1H, 2J 19 Hz, H4a), 3.38 (d, 1H,
13
2J 19 Hz, H4b), 3.88 (s, 3H, OCH3); C NMR (CDCl3) d
15.1 (CH3), 44.8 (C4), 53.3 (OCH3), 90.6 (q, 2J 34 Hz, C5),
122.9 (q, 1J 286 Hz, CF3), 153.4 (C3), 153.9 (C =O); GC/MS
(EI, 70 eV) m/z 226 (M+, 23%), 195 (5), 157 (100), 126 (5),
98 (10), 81 (18).
General procedure for the cyclocondensation reaction of
enones with hydrazines (Schemes 1-3)
A 10 mL microwave vessel equipped with a standard
cap (vessel commercially furnished by CEM Discover)
was filled with 1 mmol of enone 1a-c and 1.2 mmol of
hydrazines 2, 5, 9. After the vessel was sealed, the sample
was irradiated for the times and temperatures indicated
in Schemes 1-3, which was plotted in Synergies Version
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-3-phenyl-
1
4,5-dihydro-1H-pyrazole (3c): mp 153-155 °C; H NMR
(CDCl3) d 3.55 (d, 1H, 2J 18 Hz, H4a), 3,69 (d, 1H, 2J 18 Hz,
H4b), 3.94 (s, 3H, OCH3), 7.43-7.45 (m, 3H, Ph), 7.69-7.73

Vol. 21, No. 6, 2010
Buriol et al.
1043
(m, 2H, Ph); 13C NMR (CDCl3) d 43.3 (C4), 53.8 (OCH3),
5-Trifluoromethyl-1-(2-hydroxyethyl)-3-methyl-1H-
pyrazole (10b): Oil; 1H NMR (CDCl3) d 2.27 (s, 3H, CH3),
4.03 (t, 2H, CH2), 4.24 (t, 2H, CH2), 6.42 (s, 1H, H4);
13C NMR (CDCl3) d 141.0 (C3), a(q, C5) and a(CF3), 106.0
(C4), 61.3 (CH2-OH), 52 (CH2-N), 13.2 (CH3); GC/MS (EI,
70 eV) m/z 195 (M+, 33%), 177 (6),163 (100), 151 (32);
Calc. for C7H9N2F3O: C, 43.30; H, 4.67; N, 14.43. Found:
C, 43.51; H, 4.49; N, 14.13%. a Due the low concentration
of 1,5-isomer, the signals of C5 and CF3 were not observed.
2
1
91.6 (q, J 34 Hz, C5), 123.5 (q, J 286 Hz, CF3), 130.9,
129.7, 128.7, 126.6 (Ph), 152.9 (C3), 158.2 (C=O); GC/MS
(EI, 70 eV) m/z 288 (M+, 85%), 257 (2), 229 (2), 219 (100).
1
5-Trifluoromethyl-1H-pyrazole (4a): Oil; H NMR
(CDCl3)d6.60(d, 1H, 3J2Hz, H4), 7.86(d, 1H, 3J2Hz, H3),
13.57 (s, 1H, NH); 13C NMR (CDCl3) d 103.2 (C4), 122.1 (q,
1J 267 Hz, CF3), 130.5 (C3), 141.3 (q, 2J 36 Hz, C5); GC/MS
(EI, 70 eV) m/z 136 (M+, 100%), 117 (49), 69 (65).
5-Trifluoromethyl-1-(2-hydroxyethyl)-3-phenyl-1H-
pyrazole(10c):Oil;1HNMR(CDCl3)d4.11(t,2H,CH2),4.38
(t,2H,CH2),6.93(s,1H,H4),7,35-7.41(m,5H,Ph);13CNMR
(CDCl3) d 52.5 (CH2-N), 61.1 (CH2-OH), 104.3 (C4), 119.8
(q, 1J 268 Hz, CF3), 125.6, 128.7, 128.8, 128.5 (Ph), 133.4 (q,
2J38Hz,C5),150.9(C3);GC/MS(EI,70eV)m/z256(M+,8%),
212 (100), 143 (8), 77 (64); Calc. for C16H11N2F3O: C, 52.25;
H, 4.33; N, 10.93. Found: C, 52.59; H, 4.32; N, 10.87%.
5-Trifluoromethyl-3-methyl-1H-pyrazole (4b): mp
84-85 °C; 1H NMR (CDCl3) d 2.30 (s, 3H, CH3), 6.40 (s,
1H, H4), 13.29 (s, 1H, NH); 13C NMR (CDCl3) d 10.1 (CH3),
102.1 (C4), 122.0 (q, J 267 Hz, CF3), 140.6 (C3), 141.2
(q, 2J 36 Hz, C5); GC/MS (EI, 70 eV) m/z 150 (M+,100%),
1
131(17), 81 (18).
5-Trifluoromethyl-3-phenyl-1H-pyrazole (4c): Oil;
1H NMR (CDCl3) d 6.80 (s, 1H, H4), 7.26-7.59 (m, 5H,
Ph); C NMR (CDCl3) d 100.9 (C4), 125.6, 127.9, 129.1,
129.3 (Ph), 121.1 (q, 1J 268 Hz, CF3), 143.5 (q, 2J 38 Hz, C5),
145.1 (C3); GC/MS (EI, 70 eV) m/z 212 (M+,100%), 193 (9),
143 (25), 77 (27).
3-Trifluoromethyl-1-(2-hydroxyethyl)-1H-pyrazole
13
(11a): Oil; 1H NMR (CDCl3) d 4.01 (t, 2H, CH2), 4.29 (t,
13
2H, CH2), 6.53 (s, 1H, H4), 7.53 (s, 1H, H5); C NMR
(CDCl3) d 54.6 (CH2-N), 60.9 (CH2-OH), 104.2 (C4),
121.1 (q, 1J 268 Hz, CF3), 131.7 (C5), 142.5 (q, 2J 38 Hz,
C3); GC/MS (EI, 70 eV) m/z 181 (M+, 29%), 149 (100),
137 (45), 69 (31); Calc. for C6H7N2F3O: C, 40.01; H, 3.92;
N, 15.55. Found: C, 40.39; H, 4.09; N, 15.83%.
5-Trifluoromethyl-1,3-diphenyl-1H-pyrazole (7c): mp
53,7-55,8 ºC; 1H NMR (CDCl3) d 7.11 (s, 1H, H4), 7.3-7.88
13
(m, 10H, 2Ph); C NMR (CDCl3) d 106.0 (C4), 121.1 (q,
1J 269 Hz CF3), 125.6, 125.8, 128.6, 128.7, 129.0, 129.2,
3-Trifluoromethyl-1-(2-hydroxyethyl)-5-methyl-1H-
pyrazole (11b): Oil; 1H NMR (CDCl3) d 2.33 (s, 3H, CH3),
4.04 (t, 2H, CH2), 4.15 (t, 2H, CH2), 6.30 (s, 1H, H4);
13C NMR (CDCl3) d 11.0 (CH3), 51.2 (C-N), 61.2 (C-OH),
103.7 (C4), 121.3 (q, 1J 268 Hz, CF3),141.5 (C5), 142.0 (q,
2J 38 Hz, C3); GC/MS (EI, 70 eV) m/z 195 (M+, 100%),
177 (16),163 (79), 151 (62); Calc. for C7H9N2F3O: C, 43.30;
H, 4.67; N, 14.43. Found: C, 43.51; H, 4.49; N, 14.13%.
2
131.7, 139.1 (Ph), 133.8 (q, J 38 Hz, C5), 151.6 (C3);
GC/MS (EI, 70 eV) m/z 288 (M+, 100%), 219 (13), 77 (88);
Calc. for C16H11N2F3: C, 67.00%; H, 4.26; N, 9.47. Found:
C, 67.01; H, 4.03; N, 9.41.
3-Trifluoromethyl-1-phenyl-1H-pyrazole (8a): Oil;
1HNMR(CDCl3)d6.70(d, 3J2Hz, 1H, H4), 7.32(d, 3J2Hz,
1H, H3), 7.41-7.67 (m, 5H, Ph); 13C NMR (CDCl3) d 105.9
(C4), 121.2 (q, 1J 269 Hz, CF3), 125.6, 129.0, 129.2, 138.0
(Ph), 139.4 (C5), 143.9 (q, 2J 39 Hz, C3); GC/MS (EI, 70 eV)
m/z 212 (M+, 100%), 193 (15), 143 (17), 77 (72); Calc. for
C10H7N2F3: C, 56.61; H, 3.33; N, 13.20. Found: C, 56.43;
H, 3.58; N, 13.53%.
3-Trifluoromethyl-1-(2-hydroxyethyl)-5-phenyl-1H-
pyrazole (11c): Oil; 1H NMR (CDCl3) d 4.03 (t, 2H, CH2),
4.25 (t, 2H, CH2), 6.57 (s, 1H, H4), 7,41-7.80 (m, 5H, Ph);
13C NMR (CDCl3) d 51.6 (CH2-N), 61.2 (CH2-OH), 104.3
(C4), 120.5 (q, 1J 268 Hz, CF3), 128.9, 129.2, 129.3, 131.6
(Ph), 142.0 (q, 2J 38 Hz, C3), 145.9 (C5); GC/MS (EI, 70 eV)
m/z 256 (M+, 49%), 225 (100), 103 (10), 77 (98); Calc. for
C16H11N2F3O: C, 52.25; H, 4.33; N, 10.93. Found: C, 52.59;
H, 4.32; N, 10.87%.
The spectroscopy data for compounds 6a-c, 7a-b and 8b
are present in the references 26 and 27.
5-Trifluoromethyl-1-(2-hydroxyethyl)-1H-pyrazole (10a):
Oil; 1H NMR (CDCl3) d 4.08 (t, 2H, CH2), 4.34 (t, 2H, CH2),
6.64 (s, 1H, H4), 7.53 (s, 1H, H3); 13C NMR (CDCl3) d
52.3(CH2-N),60.9(CH2-OH),107.5(C4),120.0(q,1J268Hz,
CF3), 132.3 (q, 2J 39 Hz, C5), 138.7 (C3); GC/MS (EI, 70 eV)
m/z 181 (M+, 29%), 149 (100), 137 (60), 69 (14).
Supplementary Information
Supplementary Information is available free of charge
at http://jbcs.org.br, as PDF file.

1044
Pyrazole Synthesis under Microwave Irradiation and Solvent-free Conditions
J. Braz. Chem. Soc.
Acknowledgements
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Fundação de Amparo à Pesquisa do Estado do Rio Grande
do Sul (FAPERGS) and CAPES for financial support and
fellowships.
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Received: October 7, 2009
Web Release Date: March 4, 2010

J. Braz. Chem. Soc., Vol. 21, No. 6, S1-S5, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Pyrazole Synthesis under Microwave Irradiation and Solvent-free Conditions
Lilian Buriol, Clarissa P. Frizzo, Mara R. B. Marzari, Dayse N. Moreira,
Liziê D. T. Prola, Nilo Zanatta, Helio G. Bonacorso and Marcos A. P. Martins*
Núcleo de Química de Heterociclos, Departamento de Química,
Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil
Data obtained microwave (MW) equipment
Figure S1. Reaction condition (MW parameters to obtainment of product 6a).
*e-mail: mmartins@base.ufsm.br

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Pyrazole Synthesis under Microwave Irradiation and Solvent-free Conditions
J. Braz. Chem. Soc.
Figure S2. Reaction condition (MW parameters to obtainment of product 7a and 8a).
Figure S3. Reaction condition (MW parameters to obtainment of product 6b).

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Buriol et al.
S3
Figure S4. Reaction condition (MW parameters for obtainment of product 7b and 8b).
Figure S5. Reaction condition (MW parameters for obtainment of product 6c).

S4
Pyrazole Synthesis under Microwave Irradiation and Solvent-free Conditions
J. Braz. Chem. Soc.
Figure S6. Reaction condition (MW parameters for obtainment of product 7c).
Figure S7. Reaction condition (MW parameters for obtainment of product 6b in the presence of MeOH).

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Buriol et al.
S5
Figure S8. Reaction condition (MW parameters for obtainment of product 6c in the presence of MeOH).