Straightforward microwave-assisted synthesis of 1-carboxymethyl-5- trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazoles under solvent-free conditions

Article abstract of DOI:10.1002/jhet.309

(Chemical Equation Presented) An efficient microwave-assisted synthesis of 1-carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazoles from the cyclocondensation reaction between enones [CF₃C(O)C(R²) = C(R¹)(OR), where R² = H, Me; R¹ = H, Me, Et, Pr, i-Pr, t-Bu, i-Bu, Ph, 4-NO₂-Ph, 4-Cl-Ph, 4-Br-Ph, 4-F-Ph and R = Me, Et] and methyl hydrazinocarboxylate under solvent-free conditions is reported. This process is an efficient alternative to the traditional thermal heating and furnishes the heterocyclic compounds in good to excellent yields in a short reaction time. To show the versatility of 1-carboxymethyl-5- trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazoles, dehydration reactions of these compounds are also demonstrated.

Full text of DOI:10.1002/jhet.309

March 2010
Straightforward Microwave-Assisted Synthesis of 1-
Carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-
1H-pyrazoles under Solvent-Free Conditions
301
Marcos A. P. Martins,* Paulo H. Beck, Dayse N. Moreira, Lilian Buriol,
Clarissa P. Frizzo, Nilo Zanatta, and Helio G. Bonacorso
´
´
´
ˆ
Nucleo de Quımica de Heterociclos (NUQUIMHE), Departamento de Quımica, Centro de Ciencias
Naturais e Exatas, Universidade Federal de Santa Maria, 97.105-900, Santa Maria, RS, Brazil
*E-mail: mmartins@base.ufsm.br
Received June 10, 2009
DOI 10.1002/jhet.309
Published online 23 February 2010 in Wiley InterScience (www.interscience.wiley.com).
An efficient microwave-assisted synthesis of 1-carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-dihy-
dro-1H-pyrazoles from the cyclocondensation reaction between enones [CF3C(O)C(R2) ¼ C(R1)(OR),
where R2 ¼ H, Me; R1 ¼ H, Me, Et, Pr, i-Pr, t-Bu, i-Bu, Ph, 4-NO2-Ph, 4-Cl-Ph, 4-Br-Ph, 4-F-Ph and
R ¼ Me, Et] and methyl hydrazinocarboxylate under solvent-free conditions is reported. This process is
an efficient alternative to the traditional thermal heating and furnishes the heterocyclic compounds in
good to excellent yields in a short reaction time. To show the versatility of 1-carboxymethyl-5-trifluoro-
methyl-5-hydroxy-4,5-dihydro-1H-pyrazoles, dehydration reactions of these compounds are also
demonstrated.
J. Heterocyclic Chem., 47, 301 (2010).
INTRODUCTION
chemical reactions on a laboratory scale [9]. In this con-
text, the use of microwave-assisted organic synthesis
(MAOS) has emerged as an alternative and efficient
tool, especially in heterocyclic synthesis [10]. 4,5-Dihy-
dropyrazoles are important nitrogen-containing five-
membered heterocyclic compounds, with an extensive
application in the agrochemical [11] and pharmaceutical
fields [12–15]. 4,5-Dihydropyrazoles are quite stable,
and have inspired chemists to utilize this fragment in
bioactive moieties to synthesize new compounds pos-
sessing biological activities. In addition, the presence of
fluorine at strategic positions in the molecules can alter
the course of the reaction as well as the biological prop-
erties of the product [16]. Several 4,5-dihydropyrazoles
have played a crucial role in the development of theoret-
ical studies in heterocyclic chemistry and are also exten-
sively used building blocks in organic chemistry [11].
The introduction of halogens and halogenated groups
into organic molecules often confers significant and use-
ful changes in their chemical and physical properties.
In recent years, the progress in the field of solvent-
free reactions has gained significance because of the
high efficiency, operational simplicity and environmen-
tally benign processes. The use of microwave energy to
heat chemical reactions on a laboratory scale is growing
at a rapid rate. In many instances, controlled microwave
heating under sealed vessel conditions has been shown
to dramatically reduce reaction times, increase product
yields, and enhance product purities by reducing
unwanted side reactions when compared to conventional
synthetic methods [1,2]. The advantages of this useful
technology have more recently also been exploited in
the context of multistep total synthesis [3] and medicinal
chemistry/drug discovery [4] and have additionally
penetrated other important fields [5–8]. The use of
microwave irradiation in chemistry has thus become
such a popular technique in the scientific community
that it might be assumed that, in a few years, most
chemists will probably use microwave energy to heat
C
V
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302
M. A. P. Martins, P. H. Beck, D. N. Moreira, L. Buriol, C. P. Frizzo,
N. Zanatta, and H. G. Bonacorso
Vol 47
Therefore, methods for the synthesis of halogenated
compounds have received considerable interest in recent
years, in particular, fluorinated compounds [17a,b]. The
presence of a trifluoromethyl group into cyclic com-
pounds especially at a strategic position of drug mole-
cules has become an important aspect of pharmaceutical
research owing to the unique physical and biological
properties of fluorine [17c]. The steric requirement of
the fluorine atom resembles that of hydrogen (Van der
RESULTS AND DISCUSSION
The enones 1a–m were obtained from the acylation
reaction of enol ether or acetal with trifluoroacetic anhy-
dride in accordance with the methodology developed in
our laboratory [27]. Methyl hydrazinocarboxylate 2 was
obtained commercially.
The synthesis of 1-carboxymethyl-5-trifluoromethyl-5-
hydroxy-4,5-dihydro-1H-pyrazoles 3a–m was performed
in a microwave equipment specially designed for organic
synthesis. The reaction was carried out under solvent-free
conditions by the mixture of enones 1a–m with methyl
hydrazinocarboxylate 2, in a molar ratio of 1:1.25, respec-
tively, under solvent-free conditions in a range of time
between 6 and 8 min and at temperatures indicated in
Scheme 1. Under these reaction conditions, the products
4,5-dihydro-1H-pyrazoles 3a–m were obtained in good to
high yields and in short reaction times (Scheme 1).
The scope of this microwave-assisted method devel-
oped for 4,5-dihydropyrazoles was demonstrated by using
enones with various substituents (R1). The results obtained
show that the presence of a substituent R1 in the 4-position
of the enone 1 influenced the reaction conditions. Enones
containing 4-alkyl and 4-aryl substituents were more reac-
tive and presented shorter reaction times, while the non-
substituted enone 1a (R1 ¼ H) required a longer reaction
time. This behavior can be explained by the inductive and
hyperconjugative/mesomeric effects of the alkyl and aryl
substituents, which make the C-b of the enone more
˚
˚
Waals radii: CF3 ¼ 1.35 A versus CH3 ¼ 1.29 A). Thus
substitution of a methyl by a trifluoromethyl group in a
drug candidate usually allows the trifluoromethylated
analog to be comparable in size and follow similar
drug-protein interactions of parent methyl compound.
However, the strong covalent bonding of CAF bond
(116 kcal molꢀ1) versus that of the CAH bond (100
kcal molꢀ1) [17d] can often avoid unwanted metabolic
transformations. The high electronegativity of fluorine
enables a trifluoromethyl group to decrease the electron
density and the basicity or enhance the electrophilicity
of the neighboring functional groups within a molecule.
In many systems, the substitution of the methyl group
by a trifluoromethyl group results in added lipophilicity
(pCF3 ¼ 1.07 versus pCH3 ¼ 0.50) [17e], which may
lead to easier absorption and transportation of the mole-
cules within biological systems and thereby improve the
overall pharmacokinetic properties of drug candidates.
General methods for the preparation of these com-
pounds involve reactions of hydrazine derivatives with tri-
fluoromethylated precursors such as 1-trifluoromethylated
1,3-diketones [18], b-alkoxyvinyl trifluoromethyl ketones
[19], b-trifluoromethyl enaminones [20], and others [21–
25]. 1,3-Dipolar cycloaddition reactions of diazoalkanes
or nitrilimines with olefins or alkynes have also been car-
ried out, but this procedure has been little used in pyrazole
synthesis because 1,3-dipoles are often difficult to prepare
and are potentially explosive [26]. In recent years, we
have developed a general synthesis of 1,1,1-trihalo-4-
methoxy-3-alken-2-ones [27], important halogen-contain-
ing building blocks, and shown their usefulness in hetero-
cyclic preparations, such as isoxazoles, pyrazoles, pyrroli-
dinones, pyrimidines, pyridines, thiazines, and diazepines
[27]. Our research group is continuously interested in a
more environmentally benign synthesis, which can be
demonstrated by our recent articles that focus on solvent-
free synthesis [28] and the use of ionic liquids as reaction
media [29], associated to efficient techniques such as
microwave [30] and ultrasound irradiation [31]. In our
sustained interest on the study of heterocyclic synthesis,
herein, we wish to report a mild and efficient microwave-
assisted method for the preparation of 1-carboxymethyl-5-
trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazoles and
their derivatives, 5-trifluoromethylpyrazoles, under sol-
vent-free conditions.
Scheme 1
T
Time Yield
Reactanta
R
R2
R1
Product (ꢁC) (min) (%)b
1a
1b
1c
1d
1e
1f
1g
1h
1i
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
100
100
100
100
100
100
100
50
8
6
6
6
6
6
6
6
6
6
6
6
6
78
90
92
89
90
80
87
82
73
90
85
80
50
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Pr
i-Pr
t-Bu
i-Bu
Ph
4-NO2-Ph
4-Cl-Ph
4-Br-Ph
4-F-Ph
H
50
50
1j
1k
1l
3j
3k
3l
50
50
1m
Et Me
3m
100
a Molar ratio of reactants 1:2 was of 1:1.25.
b Yields of isolated products.
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DOI 10.1002/jhet

March 2010 Straightforward Microwave-Assisted Synthesis of 1-Carboxymethyl-5-trifluoromethyl-5-
hydroxy-4,5-dihydro-1H-pyrazoles under Solvent-Free Conditions
303
reactive. It is also possible to note that aryl substituted
enones (1h–l) furnished the products at lower
temperatures.
carboxy-5-trifluoromethylpyrazole was not obtained, and
the formation of 5-dehydropyrazoles 4a,b,h was
observed, as a result of dehydration with simultaneous
loss of the carboxylate group (Scheme 2). Product 4h
was obtained after only 12 min of irradiation at 200ꢁC,
demonstrating that the dehydration reaction under MW
conditions was sensitive to the substituent effect, and
that the phenyl substituent stabilized the products 1-car-
boxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazoles.
This failure to obtain dehydrated 5-trifluoromethyl-
1H-pyrazole was a surprise, considering that in previous
studies [33], we obtained similar trihalomethylated 4,5-
dihydropyrazoles containing a strong electron-withdraw-
ing group attached to the N1-atom, where it was possi-
ble to eliminate a water molecule and to obtain the aro-
matic pyrazole without the loss of the N1-group, by stir-
ring the reaction mixture in ethanol, for 24 hours, at
45ꢁC, followed by reflux in the presence of sulfuric acid
for 4 hours. However, we also observed that some 4,5-
dihydropyrazoles with an electron-withdrawing group
attached to the N1-atom underwent dehydration when
heated, with the simultaneous loss of the methyl carbox-
ylate group leading to the formation of 5-trifluorome-
thylpyrazole [34]. Scheme 3 shows the mechanistic
pathway for the formation of products 4a,b,h [35].
Firstly, the base removes the acid hydrogen leading to
water elimination. Then, ester hydrolysis occurs by
nucleophilic attack of water on the carboxyl carbon of
the ester and subsequent decarboxylation, leading to
NH-pyrazole formation.
Although the 4,5-dihydropyrazoles 3b,m have been
reported in the literature, their synthesis and spectral charac-
terization have not yet been reported. 4,5-Dihydropyrazoles
3 showed sets of 1H and 13C NMR data that correspond to
1
the proposed structures. Compounds 3 showed H NMR
chemical shifts of the diastereotopic methylene protons (H-
4a and H-4b) as a characteristic AB-system and as a doublet
at the range of 3.10–3.74 ppm, respectively, with a geminal
2
coupling constant at the range of J 18–20 Hz. Previous
studies have demonstrated that the doublet in the low field
is correspondent to the hydrogen ‘‘cis’’ in relation to the
hydroxyl group [32]. The same compounds showed 13C
NMR spectra with typical chemical shifts of 4,5-dihydro-
pyrazole rings at the ranges of 144.3–153.9 (C-3), 38.5–
45.6 (C-4), 89.3–92.0 (C-5), 122.5–124.3 (CF3).
The efficiency of this synthetic route was more apparent
when the same reaction was performed using conventional
thermal heating. Under these conditions of heating, the
addition of a solvent was necessary. Ethanol was the sol-
vent chosen due to its polarity and environmental proper-
ties that make it a good solvent for cyclocondensation
reactions. The reaction of enone 1m with methyl hydrazi-
nocarboxylate 2 was performed in a molar ratio of 1:1.25,
respectively. After 20 h, at room temperature the product
3m was isolated in moderate yield (70%).
Many studies have shown that the presence of the tri-
fluoromethyl group in 4,5-dihydro-1H-pyrazoles is one
of the important factors involved in their stability [27].
Thus, it is extremely important to investigate the possi-
bility of dehydrating 4,5-dihydropyrazoles to obtain the
aromatic 1-carboxymethyl-pyrazoles. In a strategy to
obtain the dehydrated products using microwave irradia-
tion, the reaction of enones 1 with methyl hydrazinocar-
boxylate 2 was carried out in a molar ratio of 1:1.2
under solvent-free conditions at 200ꢁC. However, the 1-
In summary, we have developed a simple and fast
microwave-assisted and solvent-free method to obtain
both 1-carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-
dihydro-1H-pyrazoles and their 5-dehydropyrazoles
derivatives. This method furnished the products in high
to excellent yields through the employment of an envi-
ronmentally benign approach.
EXPERIMENTAL
Scheme 2
Unless otherwise indicated, all common reactants and sol-
vents were used as obtained from commercial suppliers with-
out further purifications. Reactions were performed using a
CEM Discover (300 W) microwave mono Mode for Synthesis
controlled by Synergis Version 3.5.9 software. The irradiation
power was established at a maximum level of 200 W, the in-
ternal vessel pressure at a maximum level of 250 psi. The
exact power and pressure was different for each reaction and
depended on the reaction temperature, as shown in Figures 1
and 2. The reaction temperatures were constant and recorded
by an infrared probe provided by the instrument manufacturer
for direct monitoring of the internal temperature, as shown in
Figures 1 and 2. Reactions to obtain 3a–m were performed in
simultaneous cooling mode (Power On) and with maximum
stirring, while the reactions to obtain 4a,b,h were performed in
Power Off mode.
Enone
R
R1 T (ꢁC) Time (min) Producta Yieldb (%)
1a
1b
1h
Et
H
200
200
200
8
6
4a
4b
4h
74
94
80
Me Me
Me Ph
12
a Molar ratio of reactants 1:2 was 1:1.2.
b Yield of isolated products.
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M. A. P. Martins, P. H. Beck, D. N. Moreira, L. Buriol, C. P. Frizzo,
N. Zanatta, and H. G. Bonacorso
Vol 47
Scheme 3
1H and 13C NMR spectra were recorded on a Bruker DPX
diated at 200ꢁC, the power irradiated during the reaction was
in the range of 25–200 W, where the internal pressure was of
54–86 psi. The reaction was performed without simultaneous
cooling (Power Off) at high magnetic stirring, during the times
and temperatures described in Scheme 2. After the completion
of the reaction, dichloromethane (10 mL) was added and the
solution was washed with water (3 ꢂ 10 mL). The organic
layer was dried with Na2SO4 and the solvent was removed
under reduced pressure. The products 4a,b,h were obtained in
their pure form without further purification.
400 (1H at 400.13 MHz and 13C at 100.62 MHz) in 5 ppm
sample tubes at 298 K (digital resolution 6 0.01 ppm) in
CDCl3/TMS solutions. 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 injec-
tor, autosampler, cross-linked to a HP-5 capillary column (30
m 0.32 mm of internal diameter), and helium was used as the
carrier gas. All melting points were determined on a Reichert
Thermovar apparatus.
Conventional method typical procedure for the synthesis
of 1-carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-
1H-pyrazoles (3m). Enones 1m (1 mmol), methyl hydrazino-
carboxylate 2 (1.2 mmol) and ethanol (3 mL) were placed into
a round-bottom flask equipped with a stir bar. The mixture
was stirred at room temperature during 20 h. After the comple-
tion of the reaction, ethanol was removed, dichloromethane
(10 mL) was added and the solution was washed with water (3
ꢂ 10 mL). The organic layer was dried with Na2SO4 and the
solvent was removed under reduced pressure. The product 3m
was obtained in their pure form without further purification.
Microwave irradiation typical procedure for the synthe-
sis of 1-carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-
dihydro-1H-pyrazoles (3a–m). Enones 1a–m (1 mmol) and
methyl hydrazinocarboxylate 2 (1.25 mmol) were placed into a
10 mL reaction vessel equipped with a stir bar. The mixture
was irradiated at 50 or 100ꢁC (Scheme 1), the power irradiated
during the reaction was in the range of 45–80 W, where the
internal pressure was of 31–34 psi. The reaction was per-
formed in simultaneous cooling mode (Power On) with high
magnetic stirring, during the times and temperatures described
in Scheme 1. After completion of the reaction, dichlorome-
thane (10 mL) was added and the solution was washed with
water (3 ꢂ 10 mL). The organic layer was dried with Na2SO4
and the solvent was removed under reduced pressure. The
products 3a-m were obtained in their pure form without fur-
ther purification.
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-
1H-pyrazole (3a). Oil; 1H NMR (400 MHz, CDCl3) d (ppm)
3.17 (d, 1H, 2J ¼ 19 Hz, H4b), 3.36 (d, 1H, 2J ¼ 19 Hz,
H4a), 3.89 (s, 3H, OMe), 6.95 (s, 1H, H3). 13C NMR (100
MHz, CDCl3) d (ppm) 44.8 (C4), 53.5 (OMe), 89.3 (q, 2J ¼
1
33 Hz, C5), 122.85 (q, J ¼ 286 Hz, CF3), 144.3 (C3), 153.5
(C¼¼O). GC/MS (m/z, %) 212 (Mþ, 8), 181 (5), 143 (100), 69
(25).
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-3-methyl-4,5-
1
dihydro-1H-pyrazole (3b). M.p. 54-56ꢁC; H NMR (400 MHz,
2
CDCl3) d (ppm) 2.07 (t, 3H, CH3, H9), 3.13 (d, 1H, J ¼ 19
2
Hz, H4b), 3.38 (d, 1H, J ¼ 19 Hz, H4a), 3.88 (s, 3H, OMe).
13C NMR (100 MHz, CDCl3) d (ppm) 15.1 (CH3), 44.8 (C4),
2
1
53.3 (OMe), 90.6 (q, J ¼ 34 Hz, C5), 122.9 (q, J ¼ 286 Hz,
CF3), 153.4 (C3), 153.9 (C¼¼O). GC/MS (m/z, %) 226 (Mþ,
23), 195 (5), 157 (100), 126 (5) 98 (10), 81 (18).
1-Carboxymethyl-3-ethyl-5-trifluoromethyl-5-hydroxy-4,5-
dihydro-1H-pyrazole (3c). M.p. 82–84ꢁC; 1H NMR (400
MHz, CDCl3) d (ppm) 1.17 (t, 3H, CH3, H10), 2.43 (q, 2H,
2
2
CH2, H9), 3.07 (d, 1H, J ¼ 19 Hz, H4b), 3.23 (d, 1H, J ¼
19, H4a), 3.85 (s, 3H, OMe). 13C NMR (100 MHz, CDCl3) d
(ppm) 10.3 (CH3), 22.9 (CH2), 44.7 (C4), 53.4 (OMe), 90.4 (q,
2J ¼ 34 Hz, C5), 122.9 (q, 1J ¼ 286 Hz, CF3), 153.7 (C3),
158.5 (C¼¼O). GC/MS (m/z, %) 240 (Mþ, 15), 209 (5), 171
(100), 112 (10), 95 (18).
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-3-propyl-4,5-
dihydro-1H-pyrazole (3d). M.p. 49–53ꢁC; 1H NMR (400
MHz, CDCl3) d (ppm) 0.94 (t, 3H, CH3, H11), 1.60 (q, 2H,
CH2, H10), 2.35 (t, 2H, CH2, H9), 3.08 (d, 1H, 2J ¼ 19 Hz,
Typical procedure for the synthesis of 5-trifluoromethyl-
1H-pyrazoles (4a,b,h). Enones 1a,b,h (1 mmol) and methyl
hydrazinocarboxylate 2 (1.2 mmol) were placed into a 10 mL
reaction vessel equipped with a stir bar. The mixture was irra-
2
H4b), 3.24 (d, 1H, J ¼ 19 Hz, H4a), 3.87 (s, 3H, OMe). 13C
NMR (100 MHz, CDCl3) d (ppm) 13.2 (CH3), 19.5 (CH2),
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March 2010 Straightforward Microwave-Assisted Synthesis of 1-Carboxymethyl-5-trifluoromethyl-5-
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305
Figure 1. Range of temperature (1) and power (2) furnished by MW for obtaining compound 3a. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
2
31.4 (CH2), 44.9 (C4), 53.4 (OMe), 90.4 (q, J ¼ 34 Hz, C5),
122.9 (q,1J ¼ 286 Hz, CF3), 153.8 (C3), 157.5 (C¼¼O). GC/
MS (m/z, %) 254 (Mþ, 19), 185 (100), 153 (38), 142 (10),
125 (10).
157.0 (C¼¼O), 123.2 (q,1J ¼ 286 Hz, CF3); GC/MS (m/z, %)
254 (Mþ, 30), 211 (5), 185 (100), 153 (38), 126 (8.5).
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-3-(1,1-dime-
thylethyl)-4,5-dihydro-1H-pyrazole (3f). M.p. 97–99ꢁC; 1H
NMR (400 MHz, CDCl3) d (ppm) 1.21 (s, 9H, 3CH3, H10),
3.13 (d, 1H, 2J ¼ 18 Hz, H4b), 3.29 (d, 1H, 2J ¼ 18 Hz,
H4a), 3.88 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) d
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-3-(1-meth-
ylethyl)-4,5-dihydro-1H-pyrazole (3e). M.p. 69–71ꢁC; 1H
NMR (400 MHz, CDCl3) d (ppm) 1.18 (s, 6H, 2CH3, H10),
2
2
2.76 (d, 1H, CH, H9), 3.10 (d, 1H, J ¼ 18 Hz, H4b), 3.27 (d,
(ppm) 27.6 (3 CH3), 42.5 (C4), 58.0 (OMe), 90.9 (q, J ¼ 34
1H, 2J ¼ 18 Hz, H4a), 3.88 (s, 3H, OMe); 13C NMR (100
MHz, CDCl3) d (ppm) 26.4 (CH3), 21.9 (CH3), 22.3 (CH),
Hz, C5), 123.1 (q, 1J ¼ 286 Hz, CF3), 153.9 (C3), 164.2
(C¼¼O); GC/MS (m/z, %) 268 (Mþ, 19), 199 (100), 167 (19),
140 (10).
2
38.5 (C4), 53.5 (OMe), 90.4 (q, J ¼ 34 Hz, C5), 153.6 (C3),
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M. A. P. Martins, P. H. Beck, D. N. Moreira, L. Buriol, C. P. Frizzo,
N. Zanatta, and H. G. Bonacorso
Vol 47
Figure 2. Range of temperature (1) and power (2) furnished by MW for obtaining compound 4a. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
2
1H, J ¼ 18 Hz, H4b), 3.94 (s, 3H, OCH3), 7.43–7.45 (m, 3H,
1-Carboxymethyl-5-trifluoromethyl-5-hydroxy-3-(2-meth-
ylpropyl)-4,5-dihydro-1H-pyrazole (3g). M.p. 41–43ꢁC; 1H
NMR (400 MHz, CDCl3) d (ppm) 0.99 (2s, 6H, 2CH3, H11),
H-Ar), 7.69–7.73 (m, 2H, H-Ar); 13C NMR (100 MHz,
2
CDCl3) d (ppm) 43.3 (C4), 53.8 (OMe), 91.6 (q, J ¼ 34 Hz,
C5), 123.5 (q, 1J ¼ 286 Hz, CF3), 130.9, 129.7, 128.7, 126.6
(C-Ar), 152.9 (C3), 158.2 (C¼¼O); GC/MS (m/z, %) 288 (Mþ,
85), 257 (2), 229 (2), 219 (100).
2
1.94 (q, 1H, CH, H10), 2.30 (t, 2H, CH2, H9), 3.12 (d, 1H, J
¼ 19 Hz, H4b), 3.28 (d, 1H, 2J ¼ 19 Hz, H4a), 3.91 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3) d (ppm) 13.1 (CH3),
29.0 (CH2), 28.0 (CH2), 21.8 (CH2), 45.06 (C4), 57.38 (OMe),
1-Carboxymethyl-3-(4-nitrophenyl)-5-trifluoromethyl-5-
hydroxy-4,5-dihydro-1H-pyrazole (3i). M.p. 180–182ꢁC;
1H NMR (400 MHz, CDCl3) d (ppm) 3.59 (d, 1H, 2J ¼ 18
2
90.8 (q, J ¼ 34 Hz, C5), 122.7 (q,1J ¼ 286 Hz, CF3), 153.17
(C3), 157.35 (C¼¼O); GC/MS (m/z, %) 268 (Mþ, 33), 251
(4.5), 199 (100), 167 (40).
2
Hz, H4b), 3.74 (d, 1H, J ¼ 18 Hz, H4a), 3.97 (s, 3H, OCH3),
8.20–8.31 (m, 4H, H-Ar); 13C NMR (100 MHz, CDCl3) d
1-Carboxymethyl-3-phenyl-5-trifluoromethyl-5-hydroxy-4,5-
dihydro-1H-pyrazole (3h). M.p. 153–155ꢁC; 1H NMR (400
(ppm) 43.1 (C4), 54.1 (OMe), 92.0 (q, 2J ¼ 34 Hz, C5),
1
2
122.85 (q, J ¼ 286 Hz, CF3), 150.5, 135.7, 127.5, 124.0 (C-
MHz, CDCl3) d (ppm) 3.55 (d, 1H, J ¼ 18 Hz, H4a), 3.69 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010 Straightforward Microwave-Assisted Synthesis of 1-Carboxymethyl-5-trifluoromethyl-5-
hydroxy-4,5-dihydro-1H-pyrazoles under Solvent-Free Conditions
307
Ar), 148.9 (C3), 153.7 (C¼¼O); GC/MS (m/z, %) 333 (Mþ,
REFERENCES AND NOTES
28), 316 (1), 274 (1), 264 (100).
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7.40 (d, 2H, H-Ar), 7.69 (d, 2H, H-Ar); 13C NMR (100 MHz,
2
CDCl3) d (ppm) 43.2 (C4), 55.9 (OMe), 91.4 (q, J ¼ 34 Hz,
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1
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2
1
43.1 (C4), 53.8 (OMe), 90.4 (q, J ¼ 32 Hz, C5), 122.9 (q, J
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¨
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2
CDCl3) d (ppm) 43.3 (C4), 53.8 (OCH3), 91.3 (q, J ¼ 34 Hz,
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2
1
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1
90ꢁC; H NMR (400 MHz, CDCl3) d (ppm) 2.33 (s, 3H, Me),
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2
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´
´
Desenvolvimento Cientıfico e Tecnologico (CNPq/PADCT), for
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