An E-factor minimized solvent-free protocol for the preparation of 4,5-dihydro-5-(trifluoromethyl)-1H-pyrazoles

Article abstract of DOI:10.1007/s00706-011-0464-z

The efficient synthesis of 4,5-dihydro-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF₃C(O)CH=C(R ¹)(OR), where R = Me, Et and R¹ = H, Me, Et, Pr, i-Bu, Ph, 4-Me-C₆H₄, 4-F-C₆H₄, 4-Cl-C ₆H₄, fur-2-yl, Naphth-2-yl, biphenyl-4-yl] and ethyl 3-hydrazino-3-oxopropionate [NH₂NHC(O)CH₂C(O)OEt] is reported. The products were obtained in good yields (72-87%). Two protocols were developed: (1) conventional thermal heating using EtOH as solvent and under solvent-free conditions, and (2) a microwave-assisted method using EtOH as solvent and under solvent-free conditions. The E-factor was determined for all protocols, and the results showed that the microwave-assisted method under solvent-free conditions results in a greener process.

Full text of DOI:10.1007/s00706-011-0464-z

Monatsh Chem (2011) 142:515–520
DOI 10.1007/s00706-011-0464-z
ORIGINAL PAPER
An E-factor minimized solvent-free protocol for the preparation
of 4,5-dihydro-5-(trifluoromethyl)-1H-pyrazoles
•
Lilian Buriol Clarissa P. Frizzo Dayse N. Moreira Lizie D. T. Prola Mara R. B. Marzari
•
•
•
•
ˆ
•
•
•
Taiana S. Mu¨nchen Nilo Zantta Helio G. Bonacorso Marcos A. P. Martins
Received: 5 December 2010 / Accepted: 21 February 2011 / Published online: 22 March 2011
Ó Springer-Verlag 2011
Abstract The efficient synthesis of 4,5-dihydro-1H-pyr-
azoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3-
alken-2-ones [CF3C(O)CH=C(R1)(OR), where R = Me, Et
and R1 = H, Me, Et, Pr, i-Bu, Ph, 4-Me-C6H4, 4-F-C6H4,
4-Cl-C6H4, fur-2-yl, Naphth-2-yl, biphenyl-4-yl] and ethyl
3-hydrazino-3-oxopropionate [NH2NHC(O)CH2C(O)OEt]
is reported. The products were obtained in good yields
(72–87%). Two protocols were developed: (1) conven-
tional thermal heating using EtOH as solvent and under
solvent-free conditions, and (2) a microwave-assisted
method using EtOH as solvent and under solvent-free
conditions. The E-factor was determined for all protocols,
and the results showed that the microwave-assisted method
under solvent-free conditions results in a greener process.
have appointed global green chemistry managers. In this
context, in the late 1980s Sheldon [1] introduced the con-
cept of the E- (environmental) factor for assessing the
environmental impact of manufacturing processes. The
E-factor is designated as the weight of waste generated per
weight of product. Waste is defined as everything produced
in the process except the desired product. To calculate the
E-factor, the product yield, reagents, solvent losses, all
process aids, and even energy consumption (though this
is frequently difficult to estimate) are taken into account
[2–4].
The combination of the use of microwave irradiation
and solvent-free conditions may have an important role in
reducing or eliminating waste in chemical processes. The
main impact of microwave irradiation in the calculation of
the E-factor is due to the increases in the product yield,
purity of products, and sometimes different product dis-
tribution as compared with the conventional methods
[5, 6].
Keywords Microwave irradiation Á Solvent-free Á
E-factor Á Pyrazoles Á Cyclocondensation reactions
Introduction
In the last 20 years, we have developed a general syn-
thesis of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [7–10],
important halogen-containing building blocks, and shown
their usefulness in heterocyclic preparations [7–10]. In
particular, 4,5-dihydro-1H-pyrazoles are important five-
membered heterocyclic compounds with significant agro-
chemical [11] and pharmacological activities [12–16]. Our
research program is committed to the optimization of
synthetic procedures by employing eco-friendly reaction
protocols, including the use of solvent-free conditions
[17, 18], and substitute classic organic solvents in organic
reactions [19–23]. So, as part of our research program in this
work we present the synthesis of 4,5-dihydro-1H-pyrazoles
from the reaction between 4-alkoxy-1,1,1-trifluoro-3-alken-
2-ones and ethyl 3-hydrazino-3-oxopropionate for which we
(1) developed different protocols: a microwave-assisted
In the last 30 years, the amount of attention devoted
worldwide to the concept of chemistry sustainability, both
in industry and academia, has undergone an explosive
growth. The design of greener, more sustainable products
and processes has become a top priority item in annual
reports, and many chemical and pharmaceutical companies
L. Buriol Á C. P. Frizzo Á D. N. Moreira Á L. D. T. Prola Á
M. R. B. Marzari Á T. S. Mu
¨nchen Á N. Zantta Á
H. G. Bonacorso Á M. A. P. Martins (&)
´
Departamento de Quımica, Universidade Federal de Santa
Maria, Santa Maria, RS 97105-900, Brazil
e-mail: mmartins@base.ufsm.br
URL: http://www.ufsm.br/nuquimhe
123

516
L. Buriol et al.
method (MM) in the presence of EtOH as solvent and under
solvent-free (SF) conditions and a conventional thermal
heating method (CM) using EtOH as solvent and under
solvent-free conditions; (2) determined the E-factor for each
process to determine which is greener; and (3) applied the
greener process to the synthesis of a novel series of fluorine-
containing 4,5-dihydro-1H-pyrazoles.
all process are depicted in Table 1. From the results we
concluded that, in general, yields of products were very
similar in both methods and solvents, or slightly higher
with the MM method.
In sequence, we determined the E-factor of all processes
to accurately evaluate which method minimizes environ-
mental impacts. The E-factor may be obtained (1) only for
the synthesis step (SYS), (2) for the synthesis and product
isolation steps (SYS ? PIS), (3) for the synthesis and
product purification steps (SYS ? PPS), or (4) for the
synthesis and workup steps (SYS ? PIS ? PPS) (Fig. 1).
For the case studied, data involved in each synthetic
procedure were recorded for the E-factor calculation, such
as the amount of reactants and the volume of solvents used
in the synthesis step, and in the workup, (SYS ? PIS) at
one purification step are not necessary. The E-factor was
calculated from the equation described in Fig. 2. E-factor
values found for all processes are described in Table 2.
As expected, better E-factor values were found for
products 3a and 3b using solvent-free conditions for both
methods, MM and CM. However, the E-factor for forma-
tion of 3b was more favorable than for the formation of 3a.
Although the yield of 3b was slightly superior to 3a, it was
probably caused by differences in E-factor values.
Results and discussion
Enones 1a–1l were obtained from the acylation reaction of
enol ether or acetal with trifluoroacetic anhydride in
accordance with the methodology developed in our labo-
ratory [7–10]. Ethyl 3-hydrazino-3-oxopropionate (2) was
obtained commercially.
In order to determine the E-factor of the synthesis pro-
cess of 4,5-dihydro-1H-pyrazoles we started with the
reaction of enones 1a, 1b with hydrazine 2 at a molar ratio
of 1:1.2. The reactions were performed using the micro-
wave-assisted method (MM) and the conventional method
(CM) to obtain the products 3a, 3b. Both methods were
performed in the presence of EtOH (5 cm3) and under
solvent-free conditions. Reaction conditions and yields of
Recently, we published a review about solvent-free
heterocyclic synthesis in which we used the E-factor to
evaluate the magnitude of waste generated by a wide range
of cyclocondensation reactions carried out under solvent-
free conditions on a laboratorial scale [23]. The E-factor
was determined for each individual compound, and the
E-factor was obtained as an average value for a series of
individual E-factors. We found that reactions involving
both synthesis (SYS) and isolation steps (PIS) of com-
pounds showed E-factors in a range of 24.2–388.9. In this
review, we also evaluate the impact of excluding the mass
of water formed in solvent-free cyclocondensation reac-
tions on the E-factor. The data obtained showed that the
exclusion of the mass of water from E-factors for cyclo-
condensation reactions that led to the formation of water in
the reaction medium brought about a reduction in the range
of 0.01–1 units in E-factor values; therefore, we do not
consider it relevant to present this calculation in this paper.
In this work, we found that the E-factor values for all
protocols are in the range of 59.3–91.3, which falls within
the range found in the review for the SYS ? PIS E-factor
Table 1 Reactions of enones 1a, 1b with hydrazine 2 using different
conditions
R1
H2N
F3C
HO
NH
N
O
R1
N
O
+
O
F3C
OR
O
O
OEt
OEt
1a 1b
,
3a 3b
,
2
R
R1 Prod. MM methoda
CM methodb
Solvent Yield (%) Solvent Yield (%)
1a Et
1a Et
H
H
3a
3a
EtOH
SF
73
78
76
80
EtOH
SF
71
63
77
61
1b Me Me 3b
EtOH
SF
EtOH
SF
1b Me Me 3b
a
Reaction time 6 min, reaction temperature 50 °C
Reaction time 1 h, reaction temperature 78 °C
b
Fig. 1 Synthetic procedure steps to obtain products
123

An E-factor minimized solvent-free protocol
517
temperatures, whereas 4-aryl substituents required higher
reaction temperatures. These results are presented in
Table 3.
mreactants mproducts
mproducts
E factor
1
4,5-Dihydro-1H-pyrazoles 3 showed sets of H and 13C
Fig. 2 Equation used for the E-factor calculation
NMR data that correspond to the proposed structures.
1
Compound 3 showed H NMR chemical shifts of the dia-
Table 2 E-Factors for the synthesis of compounds 3a and 3b
stereotopic methylene protons (H-4a and H-4b) as a
characteristic AB system and as a doublet at the range of
3.09–3.86 ppm, respectively, with a geminal coupling
constant at the range of 2J = 18.6–19.7 Hz. Previous
studies have demonstrated that the doublet in the low field
corresponds to the hydrogen cis in relation to the hydroxyl
group [24]. Interestingly, the protons present between the
carbonyl groups at position 1 of the pyrazole ring also
showed different chemical shifts as a doublet at the range
of 3.65–3.91 ppm, with a geminal coupling constant in the
range of 2J = 16–17 Hz. The same compounds showed
13C NMR spectra with typical chemical shifts at the ranges
of 145.2–159.6 (C-3), 42.3–42.8 (C-4), 89.9–91.8 (C-5),
and 122.9–123.0 (CF3).
Method
E-factor
3a
3b
CM/EtOH
CM/SF
91.3
76.9
88.7
64.1
79.9
78.1
80.9
59.3
MW/EtOH
MW/SF
and falls within the range of fine chemical and pharma-
ceuticals industry segments (\25–100) [23].
After checking the best reaction conditions to obtain the
4,5-dihydro-1H-pyrazoles 3a, 3b, new compounds with
different substituents were synthesized. The scope of this
solvent-free microwave irradiation method for the synthe-
sis of 4,5-dihydro-1H-pyrazoles 3a–3l was demonstrated
by the use of enones with various substituents (R1) as
shown in Table 3. The results obtained show that the
presence of a substituent R1 at the 4-position of the enone
was sensitive to the reaction conditions. Enones containing
4-alkyl were more reactive and presented lower reaction
The mechanism of formation of 4,5-dihydro-1H-pyra-
zoles involves a cyclocondensation reaction. The reaction
proceeds by a Michael addition/elimination on the b-car-
bon atom of the enone [25] by the more nucleophilic
function of hydrazide. The enamino ketone intermediate
formed undergoes cyclization by the addition of the second
NH function at the carbonyl group to provide 4,5-dihydro-
1H-pyrazoles 3a–3l.
In conclusion, we developed an efficient method for
obtaining a new series of fluorine-containing 4,5-dihydro-1H-
pyrazoles using microwave irradiation and solvent-free con-
ditions. The efficiency of this methodology was also verified
by the lower E-factor values found herein. The products were
obtained in good yields and under mild conditions.
Table 3 Reaction conditions for the synthesis of 4,5-dihydro-1H-
pyrazoles 3a–3l
R1
H2N
F3C
NH
N
O
R1
MW
HO
N
O
+
O
Solvent-free
F3C
OR
O
O
OEt
OEt
Experimental
1a-1l
2
3a-3l
Microwave experiments were performed in a CEM Dis-
cover using the simultaneous cooling mode of operation.
1H and 13C NMR spectra were recorded on a Bruker DPX
400 (1H at 400.13 MHz and 13C at 100.62 MHz) and
Bruker DPX-200 (1H at 200.13 MHz and 13C at
50.32 MHz) in CDCl3/TMS solutions at 298 K. 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
Product
R
R1
H
T (8C) Time (min) Yield (%)
3a
3b
3c
3d
3e
3f
Et
50
6
6
6
6
6
6
6
6
6
6
6
6
78
80
85
87
83
80
79
83
77
72
87
78
Me Me
Me Et
Me Pr
Me i-Bu
Me Ph
50
50
50
50
100
100
100
100
100
100
3g
3h
3i
Me 4-Me-C6H4
Me 4-F-C6H4
Me 4-Cl-C6H4
Me fur-2-yl
´
measured using a Microquımica MQAPF 301. Elemental
3j
analyses were performed on a Perkin Elmer CHN ele-
mental analyzer and results agreed favorably with
calculated values.
3k
3l
Me Naphth-2-yl
Me Biphenyl-4-yl 100
123

518
L. Buriol et al.
General procedure for the preparation of compounds
3a, 3b by conventional methods
166.6 (C6, C=O), 167.3 (C8, C=O) ppm; MS (EI, 70 eV):
m/z (%) = 282 (M?, 3), 237 (9), 168 (39), 99 (100).
Ethyl 3-ethyl-4,5-dihydro-5-hydroxy-b-oxo-5-
(trifluoromethyl)-1H-pyrazole-1-propanoate
(3c, C11H15F3N2O4)
Enone 1a, 1b (1 mmol), hydrazine 2 (1.2 mmol), and when
required 5 cm3 of EtOH were placed in a round-bottomed
flask. The mixture was kept under magnetic stirring at the
time and temperature indicated in Table 1. Then 10 cm3
dichloromethane was added, and the reaction mixture was
washed with water (3 9 15 cm3). The organic phases were
dried over anhydrous Na2SO4, and the solvent was evap-
orated under reduced pressure.
1
Yield 85%; oil; H NMR (200 MHz, CDCl3): d = 1.16 (t,
3H, H12), 1.26 (t, 3H, H10), 2.37 (q, 2H, H11), 3.12 (d,1H,
2J = 18.6 Hz, H4a), 3.27 (d, 1H, 2J = 18.6 Hz, H4b), 3.66
2
2
(d, 1H, J = 16.1 Hz, H7a), 3.75 (d, 1H, J = 16.1 Hz,
H7b), 4.20 (q, 2H, H9), 6.01 (br s, 1H, OH) ppm; 13C NMR
(100 MHz, CDCl3): d = 10.0 (C12), 13.9 (C10), 23.2
(C11), 42.5 (C4), 45.5 (C7), 61.3 (C9), 91.1 (q,
2J = 34 Hz, C5), 123.0 (q, 1J = 287 Hz, CF3), 159.6
(C3), 166.6 (C6, C=O), 167.6 (C8, C=O) ppm; MS (EI,
70 eV): m/z (%) = 296 (M?, 5), 251 (17), 182 (49), 113
(100).
General procedure for the preparation of compounds
3a–3l under microwave irradiation
A 10 cm3 microwave vessel equipped with a standard cap
(commercially furnished with a vessel by CEM Discover)
was filled with enone 1a–1l (1 mmol), hydrazine 2
(1.2 mmol), and when necessary 5 cm3 of EtOH. After the
vessel was sealed, the sample was irradiated for the time
and temperature indicated in Table 3. The data were then
plotted in Synergies Version 3.5.9 software applying a
maximum irradiation level of 200 W and a maximum level
of internal vessel pressure of 250 psi. The reactions were
carried out at 50–100 °C with simultaneous cooling. The
reaction mixture was subsequently cooled to 50 °C by
compressed air. Then, 10 cm3 dichloromethane was added,
and the reaction mixture was washed with water
(3 9 15 cm3). The organic phases were dried over anhy-
drous Na2SO4, and the solvent was evaporated under
reduced pressure to furnish the products 3a–3l.
Ethyl 4,5-dihydro-5-hydroxy-b-oxo-3-propyl-5-(trifluoro-
methyl)-1H-pyrazole-1-propanoate (3d, C12H17F3N2O4)
1
Yield 87%; oil; H NMR (200 MHz, CDCl3): d = 1.00 (t,
3H, H13), 1.26 (t, 3H, H10), 1.61 (st, 2H, H12), 2.32 (t, 2H,
H11), 3.08 (d, 1H, 2J = 19.1 Hz, H4a), 3.26 (d, 1H,
2J = 18.9 Hz, H4b), 3.65 (d, 1H, 2J = 16.1 Hz, H7a), 3.75
2
(d, 1H, J = 16.1 Hz, H7b), 4.19 (q, 2H, H9), 6.03 (br s,
1H, OH) ppm; 13C NMR (100 MHz, CDCl3): d = 13.4
(C13), 13.9 (C10), 19.2 (C12), 31.6 (C11), 42.5 (C4), 45.6
(C7), 61.3 (C9), 91.0 (q, 2J = 34 Hz, C5), 123.0 (q,
1J = 284 Hz, CF3), 158.7 (C3), 166.7 (C6, C=O), 167.6
(C8, C=O) ppm; MS (EI, 70 eV): m/z (%) = 310 (M?, 18),
265 (35), 196 (89), 127 (100).
Ethyl 4,5-dihydro-5-hydroxy-3-(2-methylpropyl)-
b-oxo-5-(trifluoromethyl)-1H-pyrazole-1-propanoate
(3e, C13H19F3N2O4)
Ethyl 4,5-dihydro-5-hydroxy-b-oxo-5-(trifluoromethyl)-1H-
pyrazole-1-propanoate (3a, C9H11F3N2O4)
1
Yield 78%; oil; H NMR (200 MHz, CDCl3): d = 1.27 (t,
Yield 83%; oil; 1H NMR (200 MHz, CDCl3): d =
0.95–0.98 (m, 6H, H13, H13’), 1.26 (t, 3H, H10), 1.93
(sp, 1H, H12), 2.21 (d, 2H, H11), 3.14 (d, 1H, 2J = 18 Hz,
H4a), 3.26 (d, 1H, 2J = 18 Hz, H4b), 3.65 (d, 1H,
2J = 16.1 Hz, H7a), 3.76 (d, 1H, 2J = 16.1 Hz, H7b),
4.21 (q, 2H, H9), 6.00 (br s, 1H, OH) ppm; 13C NMR
(100 MHz, CDCl3): d = 13.7 (C10), 21.9 (C13), 22.1
(C13’), 26.0 (C12), 38.4 (C11), 42.4 (C4), 45.9 (C7), 61.1
2
3H, H10), 3.20 (d,1H, J = 19.7 Hz, H4a), 3.39 (d, 1H,
2J = 19.7 Hz, H4b), 3.69 (d, 1H, 2J = 16.1 Hz, H7a), 3.78
(d, 1H, 2J = 16.1 Hz, H7b), 4.20 (q, 2H, H9), 6.98 (s, 1H,
H3) ppm; 13C NMR (100 MHz, CDCl3): d = 13.9 (C10),
2
42.6 (C4), 44.9 (C7), 61.6 (C9), 89.9 (q, J = 35 Hz, C5),
122.9 (q, 1J = 287 Hz, CF3), 145.3 (C3), 166.5 (C6, C=O),
168.0 (C8, C=O) ppm; MS (EI, 70 eV): m/z (%) = 268
(M?, 10), 223 (41), 181 (4), 115 (66), 85 (100).
2
1
(C9), 90.8 (q, J = 34 Hz, C5), 123.0 (q, J = 287 Hz,
CF3), 158.0 (C3), 166.5 (C6, C=O), 167.2 (C8, C=O) ppm;
MS (EI, 70 eV): m/z (%) = 324 (M?, 3), 279 (9), 210 (38),
141 (100).
Ethyl 4,5-dihydro-5-hydroxy-3-methyl-b-oxo-5-
(trifluoromethyl)-1H-pyrazole-1-propanoate
(3b, C10H13F3N2O4)
1
Yield 80%; oil; H NMR (200 MHz, CDCl3): d = 1.27 (t,
Ethyl 4,5-dihydro-5-hydroxy-b-oxo-3-phenyl-5-
(trifluoromethyl)-1H-pyrazole-1-propanoate
(3f, C15H15F3N2O4)
2
3H, H10), 2.05 (s, 3H, CH3), 3.13 (d, 1H, J = 19.6 Hz,
H4a), 3.27 (d, 1H, 2J = 19.1 Hz, H4b), 3.69 (d, 1H,
2J = 16.1 Hz, H7a), 3.74 (d, 1H, 2J = 16.1 Hz, H7b), 4.20
(q, 2H, H9) ppm; 13C NMR (100 MHz, CDCl3): d = 13.8
(C10), 15.4 (C11), 42.3 (C4), 46.9 (C7), 61.3 (C9), 91.1 (q,
2J = 34 Hz, C5), 122.9 (q, 1J = 287 Hz, CF3), 155.2 (C3),
1
Yield 80%; m.p.: 60–63 °C; H NMR (200 MHz, CDCl3):
2
d = 1.24 (t, 3H, H10), 3.55 (d, 1H, J = 18.7 Hz, H4a),
3.72 (d, 1H, 2J = 18.7 Hz, H4b), 3.77 (d, 1H,
2J = 16.0 Hz, H7a), 3.86 (d, 1H, 2J = 16.0 Hz, H7b),
123

An E-factor minimized solvent-free protocol
519
4.20 (q, 2H, H9), 7.44–7.70 (m, 5H, Ph) ppm; 13C NMR
(100 MHz, CDCl3): d = 13.9 (C10), 42.8 (C4), 43.5 (C7),
61.5 (C9), 91.7 (q, 2J = 34 Hz, C5), 123.0 (q,
1J = 287 Hz, CF3), 126.6, 128.9, 129.5, 131.3 (C–Ar),
153.6 (C3), 166.6 (C6, C=O), 167.7 (C8, C=O) ppm; MS
(EI, 70 eV): m/z (%) = 344 (M?, 19), 299 (12), 230 (84),
161 (100), 103 (13).
Ethyl 3-(2-furanyl)-4,5-dihydro-5-hydroxy-b-oxo-5-
(trifluoromethyl)-1H-pyrazole-1-propanoate
(3j, C13H13F3N2O5)
1
Yield 72%; m.p.: 91–93 °C; H NMR (200 MHz, CDCl3):
2
d = 1.26 (t, 3H, H10), 3.51 (d, 1H, J = 18.6 Hz, H4a),
3.68 (d, 1H, 2J = 18.6 Hz, H4b), 3.76 (d, 1H,
2J = 17.1 Hz, H7a), 3.85 (d, 1H, 2J = 16.1 Hz, H7b),
4.21 (q, 2H, H9), 6.04 (br s, 1H, OH), 6.55 (q, 1H, H13),
6.86 (d, 1H, H12), 7.58 (d, 1H, H14) ppm; 13C NMR
(100 MHz, CDCl3): d = 13.9 (C10), 42.4 (C4), 43.2 (C7),
61.4 (C9), 91.2 (q, 2J = 35 Hz, C5), 123.0 (q,
1J = 288 Hz, CF3), 112.2, 113.6, 145.1, 145.4 (2-furanyl),
145.2 (C3), 166.5 (C6, C=O), 167.8 (C8, C=O) ppm; MS
(EI, 70 eV): m/z (%) = 334 (M?, 25), 289 (11), 220 (100),
151 (79).
Ethyl 4,5-dihydro-5-hydroxy-3-(4-methylphenyl)-b-oxo-5-
(trifluoromethyl)-1H-pyrazole-1-propanoate
(3g, C16H17F3N2O4)
1
Yield 79%; m.p.: 58–60 °C; H NMR (200 MHz, CDCl3):
d = 1.23 (t, 3H, H10), 2.40 (s, 3H, CH3), 3.53 (d, 1H,
2J = 18.5 Hz, H4a), 3.70 (d, 1H, 2J = 18.7 Hz, H4b), 3.76
2
2
(d, 1H, J = 16.1 Hz, H7a), 3.85 (d, 1H, J = 16.1 Hz,
H7b), 4.20 (q, 2H, H9), 6.00 (br s, 1H, OH), 7.24 (d,
3J = 8 Hz, 2H, H–Ar), 7.56 (d, 3J = 8 Hz, 2H, H–
Ar) ppm; 13C NMR (100 MHz, CDCl3): d = 13.9 (C10),
21.4 (C15), 42.8 (C4), 43.5 (C7), 61.4 (C9), 91.6 (q,
2J = 34 Hz, C5), 123.0 (q, 1J = 287 Hz, CF3), 126.6,
126.8, 129.5, 141.8 (C–Ar), 153.6 (C3), 166.6 (C6, C=O),
167.6 (C8, C=O) ppm; MS (EI, 70 eV): m/z (%) = 358
(M?, 23), 313 (12), 244 (97), 175 (100).
Ethyl 4,5-dihydro-5-hydroxy-3-(naphthalen-2-yl)-
b-oxo-5-(trifluoromethyl)-1H-pyrazole-1-propanoate
(3k, C19H17F3N2O4)
Yield 87%; m.p.: 110–113 °C; 1H NMR (200 MHz,
CDCl3): d = 1.25 (t, 3H, H10), 3.68 (d,1H, 2J =
2
18.9 Hz, H4a), 3.86 (d, 1H, J = 18.7 Hz, H4b), 3.81 (d,
1H, 2J = 16.1 Hz, H7a), 3.91 (d, 1H, 2J = 16.1 Hz, H7b),
4.22 (q, 2H, H9), 6.01 (br s, 1H, OH), 7.51-7.93 (m, 7H, H–
Ar) ppm; 13C NMR (100 MHz, CDCl3): d = 13.9 (C10),
Ethyl 3-(4-fluorophenyl)-4,5-dihydro-5-hydroxy-
b-oxo-5-(trifluoromethyl)-1H-pyrazole-1-propanoate
(3h, C15H14F4N2O4)
2
42.8 (C4), 43.4 (C7), 61.5 (C9), 91.8 (q, J = 34 Hz, C5),
1
123.0 (q, J = 287 Hz, CF3),122.6, 127.0, 127.1, 127.7,
1
Yield 83%; m.p.: 82–84 °C; H NMR (200 MHz, CDCl3):
127.8, 127.9, 128.5, 128.8, 132.7, 134.4 (C–Ar), 153.6
(C3), 166.6 (C6, C=O), 167.7 (C8, C=O) ppm; MS (EI,
70 eV): m/z (%) = 394 (M?, 35), 349 (10), 280 (100), 211
(79), 153 (18).
d = 1.24 (t, 3H, H10), 3.54 (d, 1H, 2J = 19 Hz, H4a), 3.70
(d, 1H, 2J = 19 Hz, H4b), 3.76 (d, 1H, 2J = 16.1 Hz,
2
H7a), 3.85 (d, 1H, J = 16.1 Hz, H7b), 4.20 (q, 2H, H9),
5.98 (br s, 1H, OH), 7.09–7.64 (m, 4H, H–Ar) ppm; 13C
NMR (100 MHz, CDCl3): d = 13.9 (C10), 42.8 (C4), 43.5
(C7), 61.5 (C9), 91.8 (q, 2J = 34 Hz, C5), 116.2 (d,
Ethyl 3-(biphenyl-4-yl)-4,5-dihydro-5-hydroxy-
b-oxo-5-(trifluoromethyl)-1H-pyrazole-1-propanoate
(3l, C21H19F3N2O4)
1
2J = 22.7 Hz, C–Ar), 123.0 (q, J = 287 Hz, CF3), 125.9
(d, 4J = 2.9 Hz, C–Ar), 128.8 (d, 3J = 8.8 Hz, C–Ar),
152.6 (C3), 164.5 (d, 1J = 253.2 Hz, C14), 165.8 (C6,
C=O), 167.7 (C8, C=O) ppm; MS (EI, 70 eV): m/z
(%) = 362 (M?, 5), 317 (5), 248 (63), 179 (100), 121 (15).
Yield 78%; m.p.: 101–104 °C; 1H NMR (200 MHz,
CDCl3): d = 1.26 (t, 3H, H10), 3.58 (d, 1H,
2J = 18.8 Hz, H4a), 3.75 (d, 1H, 2J = 18.6 Hz, H4b),
3.79 (d, 1H, 2J = 16.1 Hz, H7a), 3.88 (d, 1H,
2J = 16.0 Hz, H7b), 4.22 (q, 2H, H9), 6.00 (br s, 1H,
OH), 7.40–7.77 (m, 9H, H–Ar) ppm; 13C NMR (100 MHz,
CDCl3): d = 14.0 (C10), 42.8 (C4), 43.5 (C7), 61.5 (C9),
91.4 (q, J = 34 Hz, C5), 123.0 (q, J = 287 Hz, CF3),
127.0, 127.1, 127.5, 128.2, 128.4, 128.5, 128.9, 139.7,
144.1 (C–Ar), 153.4 (C3), 166.6 (C6, C=O), 167.8 (C8,
C=O) ppm; MS (EI,70 eV): m/z (%) = 420 (M?, 39), 375
(14), 306 (100), 237 (91), 178 (26).
Ethyl 3-(4-chlorophenyl)-4,5-dihydro-5-hydroxy-
b-oxo-5-(trifluoromethyl)-1H-pyrazole-1-propanoate
(3i, C15H14ClF3N2O4)
2
1
1
Yield 77%; m.p.: 79–82 °C; H NMR (200 MHz, CDCl3):
d = 1.24 (t, 3H, H10), 3.53 (d, 1H, 2J = 19 Hz, H4a), 3.70
2
2
(d, 1H, J = 19 Hz, H4b), 3.76 (d, 1H, J = 16 Hz, H7a),
3.85 (d, 1H, 2J = 16 Hz, H7b), 4.20 (q, 2H, H9), 5.97 (br s,
1H, OH), 7.42 (d, 3J = 9 Hz, 2H, H–Ar), 7.61 (d,
3J = 9 Hz, 2H, H–Ar) ppm; 13C NMR (100 MHz, CDCl3):
d = 13.9 (C10), 42.7 (C4), 43.4 (C7), 61.5 (C9), 91.8 (q,
2J = 34 Hz, C5), 123.0 (q, 1J = 287 Hz, CF3), 127.8,
128.0, 129.2, 137.4 (C–Ar), 152.5 (C3), 166.5 (C6, C=O),
167.6 (C8, C=O) ppm; MS (EI, 70 eV): m/z (%) = 378
(M?, 19), 333 (13), 264 (100), 195 (83).
Acknowledgments The authors are grateful to Conselho Nacional
´
de Desenvolvimento Cientıfico e Tecnologico (CNPq procs. nos.
578426/2008-0; 471519/2009-0), Fundac¸a˜o de Amparo a Pesquisa do
´
`
Estado do Rio Grande do Sul (FAPERGS/CNPq-PRONEX Edital No.
008/2009, Proc. No. 10/0037-8), and Coordenac¸a˜o de Aperfeic¸oa-
´
mento de Pessoal de Nıvel Superior (CAPES/PROEX) for financial
support. The fellowships from CNPq (M.A.P.M., L.B., M.R.B.M.,
123

520
L. Buriol et al.
L.D.T.P., T.S.M., N.Z., H.G.B.) and CAPES (D.N.M., C.P.F.) are also
acknowledged.
14. Tabarelli Z, Rubin MA, Berlese DB, Sauzem PD, Missio TP,
Teixeira MV, Sinhorin AP, Martins MAP, Zanatta N, Bonacorso
HG, Mello CF (2004) Braz J Med Biol Res 37:1531
15. Ahn JH, Kim HM, Jung SH, Kang SK, Kim KR, Rhee SD, Yang
SD, Cheon HG, Kim SS (2004) Bioorg Med Chem Lett 14:4461
16. Rajendera PY, Lakshmana RA, Prasoona L, Murali K, Ravi KP
(2005) Bioorg Med Chem Lett 15:5030
17. Buriol L, Frizzo CP, Marzari MRB, Moreira DN, Prola LDT,
Zanatta N, Bonacorso HG, Martins MAP (2010) J Braz Chem
Soc 21:1037
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