An efficient synthesis of 1-cyanoacetyl-5-halomethyl-4,5-dihydro-1H- pyrazoles in ionic liquid

Article abstract of DOI:10.1007/s00706-008-0874-8

The synthesis of eleven 1-cyanoacetyl-5-hydroxy-5-halomethyl-4,5-dihydro- 1H-pyrazoles from the reaction of 4-alkoxy-3-alken-2-ones f(R ³C(O)C(R²) = C(R¹)OR, where R ³ = CF₃, CCl₃, CHCl

Full text of DOI:10.1007/s00706-008-0874-8

Monatsh Chem 139, 1049–1054 (2008)
DOI 10.1007/s00706-008-0874-8
Printed in The Netherlands
An efficient synthesis of 1-cyanoacetyl-5-halomethyl-4,5-dihydro-
1H-pyrazoles in ionic liquid
Dayse N. Moreira, Clarissa P. Frizzo, Kelvis Longhi, Nilo Zanatta, Helio G. Bonacorso,
Marcos A. P. Martins
´
´
Nucleo de Quımica de Heterociclos – NUQUIMHE, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
Received 5 December 2007; Accepted 17 December 2007; Published online 24 July 2008
# Springer-Verlag 2008
Abstract The synthesis of eleven 1-cyanoacetyl-
5-hydroxy-5-halomethyl-4,5-dihydro-1H-pyrazoles
from the reaction of 4-alkoxy-3-alken-2-ones
(R3C(O)C(R2) ¼ C(R1)OR, where R3 ¼ CF3, CCl3,
CHCl2, CO2Et; R2=R1 ¼ H=H, H=Me, H=Et, -(CH2)4-,
Me=H, H=Pr, and R ¼ Me, Et) with cyanoacetohy-
drazide is reported. The reaction was carried out in
the ionic liquid ([bmim][BF4]) and molecular sol-
vents. The results showed that when the ionic liquid
was used as reaction medium, the reaction time was
drastically decreased and the yield was improved.
istry [1]. Pyrazolines are used as antitumour [2], im-
munosuppressive [3], and antibacterial agents [4],
and some pyrazoline derivatives have been reported
to possess antiinflammatory [5], anticancer [6], anti-
diabetic [7], and antidepressant properties [8]. In
recent years, it has been reported that the incorpo-
ration of a fluorine atom could alter the course of the
reaction as well as the biological properties of the
product [9]. Fluorinated pyrazolines and pyrazoles
have found applications as antifertility, antibacterial,
and antifungal agents [10]. Numerous chlorinated
heterocycles have various bioactivities which render
them as valuable active ingredients of medicines or
plant protecting agents [11]. Several methods for the
synthesis of non-halogenated pyrazoles have been
well documented in previous studies [12, 13], and
some include methodologies for the preparation
of trifluoro[chloro]methylated pyrazoles [14–26].
General methods for the preparation of these com-
pounds involve reactions of hydrazine derivatives
with trifluoromethylated precursors such as 1-trifluo-
romethylated 1,3-diketones [14–16], trifluoromethyl-
acetylenic esters [17], pentafluoroethylacetylenes
[18], trifluoroacetylacetylenes [19], ꢀ-alkoxyvinyl
trifluoromethyl ketones [20, 21], ꢀ-trifluoromethyl
enaminones [22, 23], N-aryl-1-trifluoromethylacet-
ylenic imines [24], and 1-pentafluoroethyl-2-iodo-
alkenes [25]. 1,3-Dipolar cycloaddition reactions of
diazoalkanes or nitrilimines with olefins or alkynes
have also been carried out, but this procedure has
Keywords Pyrazoles; Cyanoacetohydrazide; Enones; Halo-
methyl compounds.
Introduction
Pyrazolines are important nitrogen-containing five-
membered heterocyclic compounds, with applications
as dyestuffs, analytical reagents, and agrochemicals
[1]. In addition, pyrazolines possess important phar-
macological activities and, therefore, they are useful
materials in drug research. Several pyrazolines have
played a crucial role in the development of theoreti-
cal studies in heterocyclic chemistry and are also
extensively useful building blocks in organic chem-
´
´
Correspondence: Marcos A. P. Martins, Nucleo de Quımica
de Heterociclos – NUQUIMHE, Universidade Federal de
Santa Maria, Santa Maria, RS, Brazil. E-mail: mmartins@
base.ufsm.br

1050
D. N. Moreira et al.
been little used in pyrazole synthesis because 1,3-
dipoles are often difficult to prepare and are poten-
tially explosive [26]. Over the last few years, our
research group has reported the synthesis and im-
portance of ꢀ-alkoxyvinyl trifluoro[chloro]methyl
ketones as versatile building blocks to be used in
the construction of halomethyl-heterocyclic rings.
[27–30]. We have developed a general procedure
for preparing ꢀ-alkoxyvinyl halomethyl ketones
from the ꢀ-haloacetylation of enol ethers using func-
tionalized acyl groups CX3CO (with X ¼ F and Cl)
[27, 28]. Over time, we have demonstrated that
these compounds are of general interest as building
blocks for a variety of trihalomethylated hetero-
cycles, e.g., isoxazoles, pyrazoles, pyrazolium chlor-
ides, pyrrolidinones, pyrimidines, pyrimidinones,
pyridines, thiazolopyrimidinones, selenazoles, qui-
nolines, and diazepines [28]. In spite of the impor-
tance of trifluoro[chloro]methylpyrazoles in recent
years, methods for their preparation have been quite
limited in previous references [31–33]. It remains an
important challenge to develop concise and effective
methodologies for preparing combinatorial assem-
blies of small molecules for drug discovery research.
Recently, ionic liquids have attracted much attention
in the synthesis of heterocycles [34]. Although ionic
liquids were initially introduced as alternative green
reaction media because of their unique chemical and
physical properties of nonvolatility, nonflammability,
thermal stability, and controlled miscibility, today
they have marched far beyond this boundary, show-
ing their significant role in controlling reactions as
solvent=catalysts. Prompted by the above-mentioned
biological properties of pyrazolines and chlorine and
fluorine incorporated heterocycles and considering
our recent interest in ionic liquids [35], we con-
templated the synthesis of a novel series of fluorine-
[chloro] containing pyrazolines.
Results and discussion
The enones 1–4 (Scheme 1) were synthesized from
the reaction of the respective acyl chloride or an-
hydride with enol ether or acetal, in accordance
with the methodology developed in our laboratory
[27a, 28]. Cyanoacetic acid hydrazide was obtained
commercially. We started our study with the evalua-
tion of reaction conditions for use with ionic liquids
Table 1 Reaction conditions of enone 1b with cyanoacetic
acid hydrazide
Entry Time= Solvent
h
T=ꢀC Acid Product Yield=
molar
ratio
%
5b:9ba
1
2
3
4
0.4
3
2
16
[bmim][BF4] 50
HCl 1:0
HCl 1:0
reflux HCl 0:1
rt 1:0
89
80
75
80
H2O
H2O
EtOH
rt
–
a
9b 5-Trifluoromethyl-3-methyl-1H-pyrazole
Scheme 1

1-Cyanoacetyl-5-halomethyl-4,5-dihydro-1H-pyrazoles
1051
in the reaction of enone 1b with cyanoacetic acid
hydrazide. After establishing the best conditions, we
compared our results with conventional methodolo-
gies described in literature and reproduced in our
laboratories (Table 1).
isomer pair (3R3aS)=(3S3aR) of compound 5d was
4.69 kJ ꢁ molꢂ1 more stable than its diastereoisomer
pair (3S,3aS)=(3R,3aR) and the diastereoisomer pair
(4S,5R)=(4R,5S) of compound 5e was 6.19 kJ ꢁ molꢂ1
more stable than its diastereoisomer pair (4R,5R)=
(4S,5S). These data are supported by previously
reported crystallographic studies for analogous com-
pounds [38]. The difference in energy between the
two pairs of diastereoisomers for compounds 5d
and 5e indicates that the preferable formation of
the diastereoisomer pair (>90%) of compounds is
that where the hydroxyl group and methylene (5d)
and=or methyl group (5e) are situated cis to each
other. The structure of compound 5d was also con-
firmed by crystal X-ray diffraction (Fig. 1).
The mechanism of formation of 4,5-dihydropyra-
zoles involves a cyclocondensation reaction, which
is depicted in Scheme 2. The reaction proceeds by a
Michael addition=elimination on the ꢀ-carbon atom
of the enone [39] by the more nucleophilic function
of the cyanoacetic acid hydrazide. The enamino ke-
tone intermediate formed undergoes cyclization by
the addition of a second NH2 function at the carbon-
yl group to provide 4,5-dihydropyrazoles 5–8.
From Table 1, it is possible to affirm that the ionic
liquid [bmim][BF4] allowed the reaction to proceed
in a shorter time than in molecular solvents, even
when a Brønsted catalyst (HCl) was present. We be-
lieve that this enhancement of the reaction rate is a
result of the decrease of activation energy in the slow
reaction step caused by the general ionic liquid ef-
fect. This would be expected for reactions such as
condensations, which involve activated complexes
(highly polar or charge concentrated) and could be-
come more stable and long-lived in these media [36].
Based on the results shown in Table 1, we devel-
oped a fast and efficient general method to produce
pyrazoles 5–8 (Scheme 1). Thus, the cyclocondensa-
tion reactions were performed in [bmim][BF4] as
reaction medium with catalytic amounts of concen-
trated HCl, with a reaction time of 25 min (to obtain
products 5) or 3 h (to obtain products 6–8) at 50ꢀC,
and a series of 1-cyanoacetyl-5-hydroxy-5-halo-
methyl-4,5-dihydro-1H-pyrazoles 5–8 was obtained
in reasonable to good yields (Scheme 1).
In conclusion, we demonstrated that obtainment
of the reaction products of cyanoacetic acid hydra-
zide with trihalomethylated ꢂ,ꢀ-unsaturated ketones
was more efficient in ionic liquid than it was in
molecular solvents. In addition, we developed an ef-
ficient and regiospecific method for preparing 1-
cyanoacetyl-5-halomethyl(carboxyethyl)-4,5-dihydro
pyrazoles in good yields and under mild conditions.
All the isolated products were well characterized
1
by their melting points, H and 13C NMR, and
mass spectral data. Although the 4,5-dihydropyrazoles
5a–c and 6e are commercially available, their syn-
thesis and spectral characterization are not reported
in literature. 4,5-Dihydropyrazoles 5–8 showed
1
sets of H and 13C NMR data that corresponded to
the proposed structures. Compounds 5a–5e, 6a–6c,
1
6f, 7b, and 8b showed H NMR chemical shifts for
diastereotopic methylene protons (H-4a and H-4b)
as a characteristic AB system and as a doublet at
the range of ꢁ ¼ 3.26–3.70 ppm, with a geminal
2
coupling constant at the range of J ¼ 18–20 Hz.
The same compounds showed typical 13C NMR
chemical shifts for 4,5-dihydro-1H-pyrazole rings
in the ranges of ꢁ ¼ 146.8–163.6 (C-3), 42.7–53.4
(C-4), 90.1–92.5 (C-5, 5), 100.0–101.7 (C-5, 6),
72.3 (C-5, 7), 87.8 (C-5, 8), 122.1–123.6 (CF3),
101.2–106.9 (CCl3), 96.0 (CHCl2), 159.8 (CO2Et)
ppm. Although the attainment of two pairs of dia-
stereoisomers for compounds 5d and 5e was ex-
1
pected from the synthesis, the H and 13C NMR
data for these compounds showed that only one pair
of diastereoisomers was obtained. Semi-empirical
AM1 calculations [37] showed that the diastereo-
Fig. 1 ORTEP obtained from crystal structure of 3,3a,4,5,6,7-
hexahydro-3 trifluoromethyl-3-hydroxy-[2,1]-benzocyano-
acetylpyrazole (5d)

1052
D. N. Moreira et al.
Scheme 2
product (5–8) was extracted with CH2Cl2 (3ꢄ5 cm3) and then
the organic phases were dried (Na2SO4) and the solvent was
evaporated under reduced pressure. The 4,5-dihydropyrazoles
were obtained in a pure form, without further purification.
When necessary, products were recrystallized from n-hexane=
dichloromethane.
Experimental
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial supplies without
further purifications. H and 13C NMR spectra were recorded
1
on a Bruker DPX 400 (1H NMR at 400.13MHz and 13C NMR
at 100.62 MHz) in 5 mm sample tubes at 298 K (digital resolu-
tion ꢃ0.01 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 injector, autosampler, cross-linked to a HP-5
capillary column (30 m length 0.32 internal diameter), and
He was used as the carrier gas. All melting points were deter-
mined on a Reichert Thermovar apparatus. Elemental analyses
were performed on a Perkin Elmer CHN elemental analyser,
their results agreed favourably with the calculated values. The
refraction index was obtained from a refractometer, using wa-
ter as reference at 20ꢀC. X-Ray data were collected on a Bruker
SMART CCD diffractometer. The wavelength of diffracto-
rac-1-Cyanoacetyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-
1H-pyrazole (5a, C7H6F3N3O2)
1
Mp 110–115ꢀC; H NMR (400MHz, CDCl3): ꢁ ¼ 3.24 (d,
1H, J ¼ 19.8Hz, H4a), 3.42 (d, 1H, J ¼ 19.8Hz, H4b), 3.85
(d, 1H, J ¼ 18.8Hz, H7a), 3.88 (d, 1H, J ¼ 18.8Hz, H7b), 7.06
(s, 1H, H3) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 26.3 (C7),
2
44.9 (C4), 91.3 (q, J ¼ 35Hz, C5), 112.9 (CN), 122.6 (q,
1J ¼ 287 Hz, CF3), 146.8 (C3), 163.3 (C¼O) ppm; MS (EI,
70ev): m=z (%) ¼ 221 (Mþ, 5), 152 (25), 85 (100), 69 (25).
rac-1-Cyanoacetyl-5-hydroxy-3-methyl-5-trifluoromethyl-
4,5-dihydro-1H-pyrazole (5b, C8H8F3N3O2)
˚
meter is 0.71073 A and the crystal size was 0.777ꢄ0.26ꢄ
1
20
nD ¼ 1.4615; H NMR (400 MHz, CDCl3): ꢁ ¼ 2.08 (s, 3H,
Me), 3.18 (d, 1H, 2J ¼ 19.1Hz, H4a), 3.30 (d, 1H, 2J ¼
19.1Hz, H4b), 3.81 (d, 1H, J ¼ 18.8Hz, H7a), 3.87 (d, 1H,
J ¼ 18.8Hz, H7b), 5.72 (s, 1H, OH) ppm; 13C NMR (100 MHz,
CDCl3): ꢁ ¼ 14.8 (CH3), 25.4 (C7), 46.4 (C4), 90.6 (q,
2J ¼ 35Hz, C5), 112.6 (CN), 122.1 (q, 1J ¼ 287 Hz, CF3),
156.3 (C3), 162.1 (C¼O) ppm; MS (EI, 70 ev): m=z
(%) ¼ 235 (Mþ, 10), 166 (25), 99 (100), 69 (15).
0.16 mm. The crystallographic structure was solved by direct
methods (SHELXS-97) [40]. Refinements were carried out
with the SHELXL-97 [41] package. The ORTEP [42] diagram
of the molecule indicating atom numbering scheme with ther-
mal ellipsoids at 50% probability is illustrated in Fig. 1. Ionic
liquid was synthesized in accordance to Ref. [43].
Typical procedure for the synthesis of 4,5-dihydropyrazoles 5–8
To a stirred solution of 0.1188 g cyanoacetic acid hydrazide
(1.2mmol) in 0.225 g [bmim][BF4] (1mmol) containing
0.1 cm3 conc. HCl at room temperature, 1 mmol 1–4 was
added. The mixture was stirred at 50ꢀC for 30–180 min. The
rac-1-Cyanoacetyl-5-hydroxy-3-ethyl-5-trifluoromethyl-4,5-
dihydro-1H-pyrazole (5c, C9H10F3N3O2)
1
20
nD ¼ 1.4585; H NMR (400MHz, CDCl3): ꢁ ¼ 1.19 (t, 3H,
Me), 2.41 (q, 2H, CH2), 3.16 (d, 1H, 2J ¼ 19.3Hz, H4a), 3.31

1-Cyanoacetyl-5-halomethyl-4,5-dihydro-1H-pyrazoles
1053
2
2
2
(d, 1H, J ¼ 19.3Hz, H4b), 3.80 (d, 1H, J ¼ 19.3Hz, H7a),
(d, 1H, J ¼ 19.3Hz, H4b), 3.79 (d, 1H, J ¼ 19.0Hz, H7a),
3.90 (d, 1H, J ¼ 18.8 Hz, H7b) ppm; 13C NMR (100MHz,
CDCl3): ꢁ ¼ 10.0 (CH3), 23.3 (C9), 26.1 (C7), 45.6 (C4),
3.90 (d, 1H, J ¼ 19.0Hz, H7b) ppm; 13C NMR (100 MHz,
2
CDCl3): ꢁ ¼ 10.2 (C10), 23.7 (C9), 27.1 (C7), 48.9 (C4),
101.7 (C5), 103.0 (CCl3), 113.6 (CN), 163.6 (C3), 164.6
(C¼O) ppm; MS (EI, 70ev): m=z (%) ¼ 181 (MHþ – CCl3,
17), 125 (60), 113 (100), 97 (76), 63 (71).
2
1
91.2 (q, J ¼ 35 Hz, C5), 113.2 (CN), 122.7 (q, J ¼ 287 Hz,
CF3), 161.4 (C3), 162.9 (C¼O) ppm; MS (EI, 70ev): m=z
(%) ¼ 249 (Mþ, 10), 180 (20), 113 (100), 85 (15).
rac-1-Cyanoacetyl-3,3a,4,5,6,7-hexahydro-3-trifluoro-
rac-1-Cyanoacetyl-5-hydroxy-3-propyl-5-trichloromethyl-
methyl-3-hydroxy-[2,1]-benzopyrazole (5d, C11H12F3N3O2)
Crystallographic data for structure 5d, reported in this paper,
have been deposited with the Cambridge Crystallographic
Data Center (CCDC 660730). Copies of the data can be ob-
tained, free of charge, on application to CCDC 12 Union Road,
Cambridge CB2 1EZ, UK (Fax: þ44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk). Mp 95–100ꢀC; 1H NMR (400MHz,
CDCl3): ꢁ ¼ 1.38–1.53 (m, 2H, CH2), 1.53–1.77 (m, 2H, CH2),
1.97–2.13 (m, 2H, CH2), 2.24–2.34 (m, 2H, CH2), 2.63–2.72
4,5-dihydro-1H-pyrazole (6f, C10H12Cl3N3O2)
1
20
nD ¼ 1.3890; H NMR (400MHz, CDCl3): ꢁ ¼ 1.00 (t, 3H,
Me), 1.56–1.77 (m, 2H, H10), 2.37 (t, 2H, H9), 3.29 (d, 1H,
2
2J ¼ 19.1Hz, H4a), 3.56 (d, 1H, J ¼ 19.1Hz, H4b), 3.87 (s,
2H, H7), 6.65 (s, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-
d6): ꢁ ¼ 15.5 (C11), 19.2 (C10), 26.7 (C7), 31.8 (C9), 48.8
(C4), 100.0 (C5), 101.2 (CCl3), 113.2 (CN), 162.2 (C3), 164.2
(C¼O) ppm; MS (EI, 70ev): m=z (%) ¼ 194 (Mþ – CCl3, 37),
167 (5), 113 (100), 71 (30).
2
(m, 2H, CH2), 3.092 (d, 1H, J ¼ 6 Hz, H3a) ppm; 13C NMR
(100 MHz, CDCl3): ꢁ ¼ 21.2 (C4), 26.3 (C9), 26.8 (C5,6), 28.3
(C7), 53.4 (C3a), 92.5 (q, 2J ¼ 34 Hz, C3), 113.9 (CN), 123.6
(q, 1J ¼ 287 Hz, CF3), 163.6 (C7a), 163.9 (C¼O) ppm; MS (EI,
70ev): m=z (%) ¼ 275 (Mþ, 10), 206 (80), 139 (100), 81 (5), 68
(45).
rac-1-Cyanoacetyl-5-hydroxy-3-methyl-5-dichloromethyl-
4,5-dihydro-1H-pyrazole (7b, C8H9Cl2N3O2)
1
20
nD ¼ 1.5250; H NMR (400 MHz, CDCl3): ꢁ ¼ 2.10 (s, 3H,
Me), 3.04 (d, 1H, 2J ¼ 19.1Hz, H4a), 3.53 (d, 1H, 2J ¼
19.1Hz, H4b), 3.81 (s, 2H, H7), 4.75 (s, 1H, OH), 6.51 (s,
1H, CHCl2) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 15.8
(Me), 25.7 (C7), 46.6 (C4), 72.3 (C5), 96.0 (CHCl2), 113.4
(CN), 157.7 (C3) 161.6 (C¼O) ppm; MS (EI, 70ev): m=z
(%) ¼ 250 (MHþ, 1), 166 (68), 99 (100), 68 (18).
rac-1-Cyanoacetyl-5-hydroxy-4-methyl-5-trifluoromethyl-
4,5-dihydro-1H-pyrazole (5e, C8H8F3N3O2)
1
20
nD ¼ 1.4499; H NMR (400MHz, CDCl3): ꢁ ¼ 1.28 (d, 3H,
J ¼ 7.8 Hz, Me), 3.49 (d, 1H, J ¼ 2 Hz, H4), 3.82 (d, 1H, 2J ¼
2
19.4Hz, H7a), 3.91 (d, 1H, J ¼ 19.4Hz, H7b), 5.60 (s, 1H,
rac-1-Cyanoacetyl-5-hydroxy-3-methyl-5-ethoxycarbonyl-
OH), 6.96 (d, 1H, J ¼ 2 Hz, H3) ppm; 13C NMR (100MHz,
4,5-dihydro-1H-pyrazole (8b, C10H13N3O4)
1
CDCl3): ꢁ ¼ 9.8 (Me), 26.2 (C7), 48.4 (C4), 90.1 (q, 2J ¼
nD ¼ 1.4169; H NMR (400 MHz, CDCl3, 25ꢀC): ꢁ ¼ 1.31
20
1
(t, 3H, Me), 2.10 (s, 3H, Me), 3.00 (d, 1H, 2J ¼ 18.8Hz, H4a),
35Hz, C5), 113.0 (CN), 122.9 (q, J ¼ 287 Hz, CF3), 152.1
(C3), 163.7 (C¼O) ppm; MS (EI, 70 ev): m=z (%) ¼ 235 (Mþ,
2
2
3.26 (d, 1H, J ¼ 18.8Hz, H4b), 3.75 (d, 1H, J ¼ 18.8Hz,
H7a), 3.82 (d, 1H, 2J ¼ 18.6Hz, H7b), 4.32 (q, 2H, CH2)
ppm; 13C NMR (100MHz, CDCl3): ꢁ ¼ 13.9 (C12), 15.6
(C9), 25.1 (C7), 49.7 (C4), 63.4 (CH2), 87.8 (C5), 113.7
(CN), 156.1 (C3), 159.8 (C¼O), 169.1 (C6) ppm; MS (EI,
70ev): m=z (%) ¼ 166 (Mþ – CO2Et, 30), 99 (100).
5), 166 (20), 99 (100), 69 (15).
rac-1-Cyanoacetyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-
1H-pyrazole (6a, C7H6Cl3N3O2)
1
Mp 109–112ꢀC; H NMR (400MHz, CDCl3): ꢁ ¼ 3.38 (d,
1H, 2J ¼ 19.8 Hz, H4a), 3.70 (d, 1H, 2J ¼ 19.8 Hz, H4b),
3.90 (s, 2H, H7), 6.50 (s, 1H, OH), 7.16 (s, 1H, H3) ppm;
13C NMR (100 MHz, DMSO-d6): ꢁ ¼ 23.9 (C7), 48.9 (C4),
97.6 (C5), 102.9 (CCl3), 115.3 (CN), 152.1 (C3), 160.8 (C¼O)
ppm; MS (EI, 70 ev): m=z (%) ¼ 152 (Mþ – CCl3, 5), 117 (4),
99 (69), 71 (100).
Acknowledgements
The authors thank the Conselho Nacional de Desenvolvimento
´
´
Cientıfico e Tecnologico (CNPq), Coordenac°
a˜o de Aper-
´
feic
°oamento de Pessoal de Nıvel Superior (CAPES) and Fun-
`
daca˜o de Apoio a Pesquisa do Estado do Rio Grande do Sul
(FAPERGS) for financial support. The fellowships from
CNPq, CAPES, and FAPERGS are also acknowledged.
°
rac-1-Cyanoacetyl-5-hydroxy-3-methyl-5-trichloromethyl-
4,5-dihydro-1H-pyrazole (6b, C8H8Cl3N3O2)
Mp 132–137ꢀC; 1H NMR (400 MHz, CDCl3): ꢁ ¼ 2.10 (s, 3H,
2
2
Me), 3.32 (d, 1H, J ¼ 19 Hz, H4a), 3.54 (d, 1H, J ¼ 19Hz,
H4b), 3.83 (d, 1H, 2J ¼ 19Hz, H7a), 3.88 (d, 1H, J ¼ 19Hz,
2
References
H7b), 6.64 (s, 1H, OH) ppm; 13C NMR (100MHz, CDCl3):
ꢁ ¼ 15.7 (Me), 26.8 (C7), 50.1 (C4), 101.5 (C5), 106.9 (CCl3),
113.3 (CN), 159.0 (C3), 164.2 (C¼O) ppm; MS (EI, 70 ev): m=z
(%) ¼ 166 (Mþ – CCl3, 25), 99 (100), 83 (12), 68 (25).
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1054
D. N. Moreira et al.
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