An efficient and regiospecific preparation of trifluoromethyl substituted 4-(1H-pyrazol-1-yl)-7-chloroquinolines

Article abstract of DOI:10.1002/jhet.5570420604

A new series of 4-[3-alkyl(aryl)(heteroaryl)-5-hydroxy-5-trifluoromethyl-4, 5-dihydro-1H-pyrazol-1-yl]-7-chloroquinolines, where [alkyl = CH₃; aryl = C₆H₅, 4-CH₃C₆H₄, 4-FC₆H

Full text of DOI:10.1002/jhet.5570420604

Sep-Oct 2005
1055
An Efficient and Regiospecific Preparation of Trifluoromethyl
Substituted 4-(1H-Pyrazol-1-yl)-7-chloroquinolines
Helio G. Bonacorso,* Cleber A. Cechinel, Marli R. Oliveira, Michelle B. Costa,
Marcos A. P. Martins, Nilo Zanatta and Alex F. C. Flores
Núcleo de Química de Heterociclos, NUQUIMHE, Departamento de Química,
Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
Fax: +55-55-3220-8031 heliogb@base.ufsm.br (H.G. Bonacorso)
Received February 2, 2005
A new series of 4-[3-alkyl(aryl)(heteroaryl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazol-1-yl]-
7-chloroquinolines, where [alkyl = CH ; aryl = C H , 4-CH C H , 4-FC H , 4-ClC H , 4-BrC H , 4-
3
6
5
3
6
4
6
4
6
4
6 4
CH OC H , 4-NO C H , 4-biphenyl, 1-naphthyl; heteroaryl = 2-furyl and 2-thienyl] has been regiospecifi-
3
6
4
2 6 4
caly obtained from the reaction of 7-chloro-4-hydrazinoquinoline with 4-substituted-1,1,1-trifluoro-4-
methoxybut-3-en-2-ones in 61 – 96 % yield. Subsequently, dehydration reaction of 4,5-dihydropyra-
zolylquinolines under acid conditions furnished a new series of 4-(3-substituted-5-trifluoromethyl-1H-pyra-
zol-1-yl)-7-chloroquinolines in 73 – 96 % yield.
J. Heterocyclic Chem., 42, 1055 (2005).
Fluorine-containing quinolines are of significant interest
conditions (refluxing ethanol for 3 hours), the aryl trifluo-
due to biological properties of fluorine that play a pivotal
role in bioactive compounds [1,2] The routes to aromatic
heterocycles are of ongoing interest, especially methods of
placing fluorine selectively on heterocycle moieties since
these derivates often exhibit bioactivity [3]. Many substi-
tuted pyrazolines and pyrazoles are important biological
agents and a significant amount of research has been
directed to this class [4]. These compounds are used as
antibacterial, antifungal, anti-inflammatory, antitumor,
antiviral, antiparasitic, anti-tubercular, anti-diabetic, agro-
chemicals and insecticidal agents, anesthetic, and anal-
gesic properties [3-7]. Specifically, trichloromethyl substi-
tuted pyrazoles obtained recently have demonstrated
hypothermic, antipyretic, and antinociception activity,
according to biological tests in mice [8,9].
romethyl-β-diketones (aryl = C H , thien-2-yl) gave not
6
5
only a mixture of aromatic and non-aromatic products, but
also the corresponding isomers such as 5-hydroxy-5-triflu-
oromethyl-4,5-dihydropyrazolylquinolines and 3-trifluo-
romethyl-pyrazolylquinolines. In accordance with biologi-
cal screening was demonstrated that β-diketones, trifluo-
romethylated or not, were less interesting to obtain new
compounds with pharmaceutical application, due to the
possibility of loosing the regiochemistry during the cyclo-
condensation reaction, when these 1,3-dicarbonyl com-
pounds are non-symmetrical.
The aim of our research is to report a facile, efficient and
regiospecific synthesis of 4-(3-substituted-5-hydroxy-5-
trifluoromethyl-4,5-dihydro-1H-pyrazol-1-yl)-7-chloro-
quinolines (2) from the reaction of 7-chloro-4-hydrazino-
quinoline with 1,1,1-trifluoro-4-methoxybut-3-en-2-ones
(1) to generate new compounds for further antimalarial
screening. Subsequently, the quinolines 2 were submitted
to dehydration reaction to obtain a new series of 4-(3-sub-
stituted-5-trifluoromethyl-1H-pyrazol-1-yl)-7-chloro-
quinolines (3).
Recently, Singh et al. [6,7,10] reported structural and
mechanistic studies about the synthesis of pyrazolylquino-
lines. Specifically, when 4-hydrazino-2-methyl- and 4-
hydrazino-7-chloroquinoline, in a synthetic method with
limited scope, were allowed to react with 1,1,1-trifluo-
ropentane-2,4-dione in boiling ethanol for 6 hours [7],
only stable crystalline trifluoroacetyl hydrazone deriva-
tives were obtained in good yields (70 – 72 %). The elimi-
nation of the second molecule of water from the respective
hydrazones to obtain the aromatic pyrazole was effected
only by treatment with hot acetic acid for 4 hours in 72 –
75 % yields. This procedure allowed to synthesize and iso-
late the corresponding mixtures of 5(3)-trifluoromethyl-
5(3)-hydroxy-4,5-dihydropyrazolylquinolines. On the
other hand, the reactions of 2-hydrazino-4-methylquino-
line with aliphatic and aromatic trifluoromethyl-β-dike-
tones have been reported [7]. It was determined that
aliphatic trifluoromethyl-β-diketones (alkyl = CH , CF )
3
3
gave only 2-(3-alkyl-5-trifluoromethyl-5-hydroxy-4,5-
dihydropyrazolyl)quinolines. However, by similar reaction

1056
H. G. Bonacorso, C. A. Cechinel, M. R. Oliveira, M. B. Costa,
M. A. P. Martins, N. Zanatta and A. F. C. Flores
Vol. 42
pure 5-hydroxy-dihydropyrazolylquinolines (2) in 61 –
96 % yield (Scheme II). Using this method we were
unable to isolate the corresponding pyrazoline 2a and 2j-
l. When these reactions were carried out in refluxing
methanol only aromatic heterocycles 3a and 3j-l could be
isolated and no traces of 2a, 2j-l (2-pyrazolines) are
detected. Compounds 2b-i were converted in the respec-
tive aromatic system 3 by an easy treatment of 2 with
acetic acid at reflux for 4 hours (73 – 96 % yields). As
expected, the dehydration reaction of p-nitrophenyl sub-
stituted pyrazoline derivative 2h was very difficult
(reflux for 10 hours) but resulted in 82 % yield. It is well-
known that, in most cases, 5-hydroxy-4,5-dihydro-1H-
pyrazoles have been obtained, as stable compounds,
when some pyrazoline atoms are substituted with a strong
electron-withdrawing group. This electronic effect hin-
ders the elimination of water and makes the subsequent
aromatization of the pyrazoline ring difficult [15].
Complementary, to confirm that the pyrazoles 3 could be
obtained regiospecificaly and directly from the reaction of
1 with 7-chloro-4-hydrazinoquinoline, the synthesis of 3b
was also performed in a single step reaction without the
isolation of the quinoline 2b (Scheme III). This was possi-
ble when the respective reaction was carried out in
methanol under reflux for 15 min. After this time, the
methanol was evaporated and the reaction treated with
acetic acid at reflux for 4 hours to give 3b in 84% yield.
β-Alkoxyvinyl trifluoromethyl ketones (1a-l) were
prepared as previously reported [11-14], with the excep-
tion of 1i and 1j, which were prepared as described in
this paper (Scheme I). In order to obtain compounds,
bearing a new aromatic substituent at the 3-position of
pyrazole rings (2, 3), new 4-aryl-4-methoxy-1,1,1-triflu-
oro-3-buten-2-ones (1) were prepared from the reaction
of 4-acetylbiphenyl and 1-acetylnaphthalene, respec-
tively, with trimethyl orthoformate in the presence of p-
toluenesulfonic acid. The acylation reaction of acetals
with trifluoroacetic anhydride in pyridine and chloro-
form as solvent was carried out in a molar ratio of 1:2:2,
respectively. An exception using this methodology 9-
acetylanthracene did not furnish the acetal, as well the
respective vinyl ketone (Scheme I). We suggest that the
steric effect is the main factor to explain the results of
the reaction from acetophenone, 4-acetylbiphenyl, 1-
acetylnaphthalene and 9-acetylanthracene with trimethyl
orthoformate. As an exception, only 9-acetylanthracene
presents H-1 and H-8 hindering a nucleophilic attack to
the carbonyl carbon of the acetyl group. The other three
above mentioned ketones have the carbonyl carbon with
at least one free face for the reaction with trimethyl
orthoformate to take place.
The reactions of 1 with 4-hydrazino-7-chloroquinoline,
in a molar ratio of 1:1, were carried out in methanol for
15 to 30 minutes under reflux to give a novel series of

Sep-Oct 2005
An Efficient and Regiospecific Preparation of Trifluoromethyl
1057
1
13
reaction step, in a shorter time, and in high yields. In addi-
tion, it was possible to introduce regiospecificaly alkyl,
aryl or heteroaryl substituents in the 3-position of the pyra-
zole ring of compounds 2 and 3. We hope that the new tri-
fluoromethylated compounds describe here contribute to a
combinatorial library of 7-chloro-4-pyrazolylquinolines
aiming to determine the most potent drug and its action
pathway as an antimalarial agent.
The unambiguous H- and C-NMR chemical shift
assignments of compounds 1-3 were obtained with the
help of homo- and heteronuclear COSY, HMQC and
HMBC 2D-NMR experiments and by comparison with
NMR data of other 2-pyrazolines formerly synthesized in
our laboratory.
The structures of 4-(5-hydroxy-5-trifluoromethyl-4,5-
dihydro-1H-pyrazol-1-yl)quinolines (2) were deduced from
their NMR spectra. Compounds 2 show the H chemical
1
shifts of the methylene protons (H4a and H4b) as a charac-
teristic AB system with a doublet in average at δ 3.70 and
the other doublet at δ 4.07, respectively, with a geminal
EXPERIMENTAL
Unless otherwise indicated all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. All melting points were determined using open cap-
illaries on a Reichert Thermovar apparatus and are uncorrected.
2
coupling constant J 18.7 Hz. Compounds 2 present the
13
typical C chemical shifts of the pyrazoline ring at δ ca.
113.8 (C3) and 43.7 (C4). The C5 presents a characteristic
1
13
H and C NMR spectra were acquired on a Bruker DPX 200
2
quartet at δ ca. 93.90 with J
31.78 Hz, due to the OH
C-F
1
13
spectrometer ( H at 200.13 MHz and C at 50.32 MHz), 5 mm
sample tubes, 298 K, digital resolution 0.01 ppm, in chloro-
and the CF group that are attached. The CF group shows
a typical quartet at δ ca. 123.7 with J 285.4 Hz.
3
3
1
C-F
form-d for compounds 1 and methyl sulfoxide-d for 2 and 3
3
6
The structures of the 4-(5-trifluoromethyl-1H-pyrazol-
1-yl)-7-chloroquinolines (3) were also deduced from their
using TMS as internal reference. Mass spectra were registered in
a HP 6890 GC connected to a HP 5973 MSD and interfaced by a
Pentium PC. The GC was equipped with a split-splitless injector,
auto sampler, cross-linked HP-5 capillary column (30 m, 0.32
mm of internal diameter), and helium was used as the carrier gas.
The CHN elemental analyses were performed on a Perkin–Elmer
2400 CHN elemental analyzer (São Paulo University,
USP/Brazil).
13
NMR spectra. Compounds 3 present the typical C chem-
ical shifts of the pyrazole ring in average at δ 151.3 (C3)
and 107.0 (C4). The C5 presents a characteristic quartet in
2
average at δ 134.5 with J
38.8 Hz, due to the attached
C-F
CF group. The CF group shows a typical quartet in aver-
3
3
1
age at δ 119.3 with J
269.5 Hz. Thus, the trifluo-
C-F
General Procedure for the Preparation of 4-Aryl-1,1,1-trifluoro-
4-methoxybut-3-en-2-ones (1i-j).
romethyl group for compounds 2 and 3 must be attached to
the carbon at position 5 of the ring and the regioisomer
must be as shown.
To a stirred solution of dimethoxy acetals derived from 4-
acetylbiphenyl or 1-acetylnaphthalene (30 mmol) and pyridine
(60 mmol, 4.8 g) in chloroform (30 ml) kept at 0 ºC (ice bath), tri-
fluoroacetic anhydride (60 mmol) was added drop wise. The mix-
ture was stirred for 16 h at 45 ºC. The mixture was quenched and
extracted with 0.1 M hydrochloric acid solution (3 x 15 ml) and
after with water (1 x 15 ml). The organic layer was dried with
magnesium sulfate and filtered. The solvent was evaporated and
the products were obtained in high purity by recrystallization
from methanol. Yield: 80 – 81%.
Compounds 2 and 3 were also characterized by mass
spectroscopic studies in which, significantly, molecular
ions were observed corresponding to the 4-(1H-pyrazol-1-
yl)-7-chloroquinolines. As an exception in the series 2b-i,
compounds 2e-i underwent thermal dehydration during
acquisition of the mass spectrum and mass ions values cor-
responding to the aromatic pyrazolylquinolines 3e-i were
obtained.
In conclusion, the present methodology allowed to
obtain a new series of 4-(5-hydroxy-5-trifluoromethyl-4,5-
dihydro-1H-pyrazol-1-yl)-7-chloroquinolines (2) and the
bis-heterocyclic and tris-heterocyclic aromatic systems (3)
from β-alkoxyvinyl trifluoromethyl ketones 1, in a single
4-(4-Biphenyl)-1,1,1-trifluoro-4-methoxybut-3-en-2-one (1i).
This compound was obtained as a white solid, yield 80 %, Mp.
1
68 - 70 ºC. H NMR (CDCl ) (Biphenyl) δ = 7.62-7.56 (m, 6H,
3
Ph); 7.44-7.37 (m, 2H, Ph); 7.36-7.33 (m, 1H, Ph); 5.83 (s, H3);
3.93 (s, OMe). C NMR (CDCl ) (Biphenyl) δ = 140.1; 132.2;
13
3

1058
H. G. Bonacorso, C. A. Cechinel, M. R. Oliveira, M. B. Costa,
M. A. P. Martins, N. Zanatta and A. F. C. Flores
Vol. 42
129.4; 128.8; 127.8; 127.1; 126.6 (12C); 177.7 (C=O); 144.1
This compound was obtained as a yellow solid, yield 96 %,
1
(C4); 118.2 (q, J = 292.4, CF ); 91.8 (C3); 57.2 (OMe).
Mp. 169 - 171 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 8.76 (s,
CF
3
6
Anal. Calcd. for C
H
F O (306.28): C, 66.67; H, 4.28 %.
OH); 4.07 (d, J=18.7, Ha); 3.74 (d, J= 18.7, Hb); (Quinolyl) δ =
17 13
3 2
Found: C, 66.55; H, 4.56 %.
8.87 (d, H2); 8.42 (d, H8); 8.08 (s, H6); 7.85 (s, H5); 7.62 (d,
13
H3); (Phenyl) δ = 7.32-7.30 (m, 4H). C NMR (DMSO-d )
6
4-(1-Naphthyl)-1,1,1-trifluoro-4-methoxybut-3-en-2-one (1j).
(Pyrazol) δ = 148.3 (C3); 123.4 (q, J = 285.9, CF ); 93.9 (q,
CF
3
2
This compound was obtained as a yellow solid, yield 81 %,
J
= 31.7, C5); 43.8 (C4); (Quinolyl) δ =151.3 (C2); 149.7
CF
1
Mp. 75 - 77 ºC. H NMR (CDCl ) (Naphthyl) δ = 7.93-7.84 (m,
(C8a); 146.4 (C4); 133.8 (C7); 129.5 (C8); 128.2 (C6); 126.1
3
2H, Ar); 7.70-7.65 (m, 1H, Ar); 7.54-7.36 (m, 4H, Ar); 6.13 (s,
H3); 3.91 (s, OMe). C NMR (CDCl ) (Naphthyl) δ = 132.1;
131.1; 130.3; 130.0; 128.5; 127.9; 126.9; 126.1; 124.9; 123.8
(C5); 122.6 (C4a); 113.8 (C3); (Phenyl) δ = 129.0; 128.1; 127.8;
13
+
127.5 (6C). MS (EI, 70 eV): m/z (%) = 409 (M , 72), 340 (100),
3
121 (62), 95 (23), 176 (20).
(10C, Ar); 177.3 (C=O); 133.3 (C4); 116.4 (q, J = 292.4, CF );
Anal. Calcd. for C
H ClF N O (409.77): C, 55.69; H, 2.95;
CF
3
19 12 4 3
94.6 (C3); 57.2 (OMe).
N, 10.25 %. Found: C, 55.40; H, 2.58; N, 9.90 %.
Anal. Calcd. for C H F O (280.24): C, 64.29; H, 3.96 %.
15 11
3 2
4-[3-(4-Chlorophenyl)-5-hydroxy-5-trifluoromethyl-4,5-dihy-
dro-1H-pyrazol-1-yl]-7-chloroquinoline (2e).
Found: C, 64.55; H, 4.00 %.
General Procedure for the Preparation of 4-(3-Substituted-5-tri-
fluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-7-chloro-
quinolines (2b-i).
This compound was obtained as a yellow solid, yield 95 %,
1
Mp. 206 - 208 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 8.79 (s,
6
OH); 4.06 (d, J=18.7, Ha); 3.68 (d, J= 18.7, Hb); (Quinolyl) δ =
8.85 (d, H2); 8.35 (d, H8); 8.06 (d, H6); 7.83-7.76 (m, H5); 7.64-
To a magnetically stirred solution of 1b-i (1 mmol) in MeOH
(10 ml), 7-chloro-4-hydrazinoquinoline (1 mmol) was added at
room temperature. The mixture was stirred under reflux (64 ºC)
for 15 to 30 minutes. The solvent was evaporated under reduced
pressure and the solid products 2b-i recrystallized from a mixture
of acetone and water 5:1. Yield: 61 – 96 %.
13
7.61 (m, H3); (Phenyl) δ = 7.83-7.76; 7.55-7.53 (m, 4H).
C
=
NMR (DMSO-d ) (Pyrazol) δ = 148.0 (C3); 124.9 (q, J
6
CF
2
284.6, CF ); 94.0 (q, J = 31.7, C5); 43.6 (C4); (Quinolyl) δ =
3
CF
151.3 (C2); 149.7 (C8a); 146.2 (C4); 133.8 (C7); 129.7 (C8);
128.7 (C6); 126.1 (C5); 122.1 (C4a); 113.8 (C3); (Phenyl) δ =
134.2; 129.0; 127.5; 127.3 (6C). MS (EI, 70 eV): m/z (%) = 407
4-(5-Hydroxy-3-phenyl-5-trifluoromethyl-4,5-dihydro-1H-pyra-
zol-1-yl)-7-chloroquinoline (2b).
(M – H O, 100), 338 (78), 135 (20), 75 (18), 162 (16).
2
Anal. Calcd. for C
H Cl F N O (426.22): C, 53.54; H, 2.84;
19 12 2 3 3
This compound was obtained as a yellow solid, yield 92%,
N, 9.86 %. Found: C, 53.83; H, 2.67; N, 10.12 %.
1
Mp. 195-198 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 8.59 (s,
6
4-[3-(4-Bromophenyl)-5-hydroxy-5-trifluoromethyl-4,5-dihy-
dro-1H-pyrazol-1-yl]-7-chloroquinoline (2f).
OH); 3.92 (d, J=18.7, Ha); 3.56 (d, J= 18.7, Hb); (Quinolyl) δ
= 8.70 (d, H2); 8.26 (d, H8); 7.92 (d, H6); 7.68 (d, H5); 7.45
13
(d, H3); (Phenyl) δ = 7.63-7.61; 7.33-7.31 (m, 5H).
C
=
This compound was obtained as a yellow solid, yield 87 %,
NMR (DMSO-d ) (Pyrazol) δ = 149.0 (C3); 122.2 (q, J
1
6
CF
Mp. 220 - 222 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 8.75 (s,
6
2
285.3, CF ); 93.8 (q, J = 31.7, C5); 43.7 (C4); (Quinolyl)
3
CF
OH); 4.05 (d, J=18.5, Ha); 3.68 (d, J= 18.5, Hb); (Quinolyl) δ =
8.85 (d, H2); 8.34 (d, H8); 8.06 (d, H6); 7.79 (d, H5); 7.60 (d,
δ = 151.3 (C2); 149.7 (C8a); 146.4 (C4); 133.8 (C7); 129.6
(C8); 128.7 (C6); 125.0 (C5); 122.6 (C4a); 113.7 (C3);
(Phenyl) δ = 130.8; 127.5; 126.0; 125.8 (6C). MS (EI, 70
13
H3); (Phenyl) δ = 7.63-7.62 (m, 4H). C NMR (DMSO-d )
6
(Pyrazol) δ = 148.1 (C3); 124.9 (q, J = 285.3, CF ); 94.1 (q,
CF
3
+
eV): m/z (%) = 391 (M , 73), 322 (100), 176 (27), 77 (26),
2
J
= 31.7, C5); 43.5 (C4); (Quinolyl) δ = 151.8 (C2); 149.7
CF
373 (6).
(C8a); 146.2 (C4); 133.8 (C7); 130.0 (C8); 127.7 (C6); 126.1
Anal. Calcd. for C
H ClF N O (391.77): C, 58.25; H, 3.34;
19 13 3 3
(C5); 122.1 (C4a); 113.9 (C3); (Phenyl) δ = 131.7; 127.6; 127.3;
N, 10.73 %. Found: C, 57.98; H, 3.36; N, 10.53 %.
122.9 (6C). MS (EI, 70 eV): m/z (%) = 453 (M – H O, 100), 384
2
(45), 135 (25), 75 (20), 162 (17).
4-[5-Hydroxy-3-(4-methylphenyl)-5-trifluoromethyl-4,5-dihy-
dro-1H-pyrazol-1-yl]-7-chloroquinoline (2c).
Anal. Calcd. for C
H BrClF N O (470.67): C, 48.49; H,
19 12 3 3
2.57; N, 8.93 %. Found: C, 48.78; H, 2.79; N, 8.71 %.
This compound was obtained as a yellow solid, yield 83 %,
1
Mp. 191 - 193 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 8.73 (s,
4-[5-Hydroxy-3-(4-Methoxyphenyl)-5-trifluoromethyl-4,5-dihy-
dro-1H-pyrazol-1-yl]-7-chloroquinoline (2g).
6
OH); 4.02 (d, J=18.7, Ha); 3.67 (d, J= 18.7, Hb); (Quinolyl) δ
= 8.83 (d, H2); 8.40 (d, H8); 8.05 (d, H6); 7.80 (d, H5); 7.62
(d, H3); (Phenyl) δ = 7.66-7.63; 7.29-7.27 (m, 4H); 2.35 (s,
This compound was obtained as a yellow solid, yield 94 %, Mp.
1
221 - 223 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 8.67 (s, OH);
6
13
Me). C NMR (DMSO-d ) (Pyrazol) δ = 149.1 (C3); 122.7
6
4.01 (d, J=18.7, Ha); 3.66 (d, J= 18.7, Hb); (Quinolyl) δ = 8.82 (d,
2
(q, J = 284.6, CF ); 93.7 (q, J = 31.7, C5); 43.8 (C4);
CF
3
CF
H2); 8.43 (d, H8); 8.05 (d, H6); 7.80 (d, H5); 7.62-7.59 (m, H3);
(Quinolyl) δ = 151.3 (C2); 149.8 (C8a); 146.2 (C4); 133.8
(C7); 129.3 (C8); 128.0 (C6); 125.8 (C5); 122.6 (C4a); 113.5
(C3); (Phenyl) δ = 139.5; 127.6; 127.5; 125.9 (6C); 20.8
13
(Phenyl) δ = 7.72-7.70; 7.05-7.02 (m, 4H); 3.82 (s, OMe).
C
NMR (DMSO-d ) (Pyrazol) δ = 148.9 (C3); 123.7 (q, J = 285.0,
6
CF
2
CF ); 93.6 (q, J = 31.7, C5); 43.9 (C4); (Quinolyl) δ = 151.2
3
CF
+
(Me). MS (EI, 70 eV): m/z (%) = 405 (M , 67), 336 (100), 115
(C2); 149.7 (C8a); 146.5 (C4); 133.6 (C7); 130.3 (C8); 128.4 (C6);
125.0 (C5); 123.3 (C4a); 113.3 (C3); (Phenyl) δ = 127.6; 127.5;
127.3; 125.8 (6C); 55.1 (OMe). MS (EI, 70 eV): m/z (%) = 403 (M
(41), 176 (15), 91 (13).
Anal. Calcd. for C
H ClF N O (405.80): C, 59.20; H, 3.73;
20 15 3 3
N, 10.35 %. Found: C, 59.53; H, 3.91; N, 10.18 %.
– H O, 100), 334 (21), 69 (18), 162 (17), 135 (16).
2
4-[3-(4-Fluorophenyl)-5-hydroxy-5-trifluoromethyl-4,5-dihy-
Anal. Calcd. for C H ClF N O (421.80): C, 56.95; H, 3.58;
20 15 3 3 2
dro-1H-pyrazol-1-yl]-7-chloroquinoline (2d).
N, 9.96 %. Found: C, 57.13; H, 3.29; N, 9.75 %.

Sep-Oct 2005
An Efficient and Regiospecific Preparation of Trifluoromethyl
1059
4-[5-Hydroxy-3-(4-Nitrophenyl)-5-trifluoromethyl-4,5-dihydro-
1H-pyrazol-1-yl]-7-chloroquinoline (2h).
8.25 (d, H6); 7.74-7.68 (m, H5); (Naphthyl) δ = 8.00-7.78 (m,
13
4H); 7.74-7.68 (m, 2H). C NMR (DMSO-d ) (Pyrazol) δ =
6
2
149.1 (C3); 133.7 (q, J = 38.8, C5); 119.6 (q, J = 269.1,
CF
CF
This compound was obtained as a yellow solid, yield 61 %,
CF ); 110.2 (C4); (Quinolyl) δ = 152.3 (C2); 142.2 (C8a); 135.4
1
3
Mp. 217 - 219 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 8.98 (s,
6
(C7); 133.4 (C4); 129.8 (C8); 128.4 (C6); 124.5 (C5); 123.0
(C4a); 120.1 (C3); (Naphthyl) δ = 133.6; 129.4; 129.3; 128.1;
128.0; 127.8; 126.9; 125.3; 123.7; 123.3 (10C). MS (EI, 70 eV):
OH); 4.17 (d, J=18.8, Ha); 3.80 (d, J= 18.8, Hb); (Quinolyl) δ =
8.91 (d, H2); 8.35 (d, H8); 8.10 (d, H6);7.69-7.63 (m, H5); 7.86
(d, H3); (Phenyl) δ = 8.34-8.30; 8.04-7.99; 7.69-7.63 (m, 4H).
+
m/z (%) = 423 (M , 100), 354 (25), 127 (35), 166 (12), 192 (9).
13
C NMR (DMSO-d ) (Pyrazol) δ = 147.4 (C3); 124.8 (q, J
=
6
CF
Anal. Calcd. for C
H ClF N (423.82): C, 65.18; H, 3.09; N,
2
23 13 3 3
283.9, CF ); 94.4 (q, J = 31.7, C5); 43.2 (C4); (Quinolyl) δ =
3
CF
9.91 %. Found: C, 65.03; H, 3.47; N, 9.94 %.
151.4 (C2); 149.7 (C8a); 147.2 (C4); 133.9 (C7); 128.4 (C8);
127.6 (C6); 123.9 (C5); 122.6 (C4a); 114.0 (C3); (Phenyl) δ =
136.9; 127.0; 126.8; 126.4 (6C). MS (EI, 70 eV): m/z (%) = 418
4-[3-(2-Thienyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-chloro-
quinoline (3k).
(M – H O, 100), 349 (70), 135 (21), 162 (13), 75 (10).
2
This compound was obtained as a yellow solid, yield 82 %,
Anal. Calcd. for C
H ClF N O (436.77): C, 52.25; H, 2.77;
19 12 3 4 3
1
Mp. 183 - 185 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 7.63 (s,
6
N, 12.83 %. Found: C, 52.32; H, 2.51; N, 12.55 %.
H4); (Quinolyl) δ = 9.20 (d, H2); 8.32 (d, H8); 7.93-7.86 (m, H5
and H6); 7.48 (d, H3); (Thienyl) δ = 7.75 (d, 2H); 7.18-7.29 (m,
4-[3-(4-Biphenyl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-
pyrazol-1-yl]-7-chloroquinoline (2i).
13
1H). C NMR (DMSO-d ) (Pyrazol) δ = 149.0 (C3); 134.0 (q,
6
2
J
= 38.8, C5); 118.5 (q, J = 269.1, CF ); 106.7 (C4);
CF
CF 3
This compound was obtained as a yellow solid, yield 80 %,
(Quinolyl) δ = 152.2 (C2); 147.9 (C8a); 141.8 (C4); 135.4 (C7);
129.2 (C8); 128.5 (C6); 124.4 (C5); 122.9 (C4a); 120.1 (C3);
(Thienyl) δ = 133.1; 127.9; 126.9; 126.7 (4C). MS (EI, 70 eV):
1
Mp. 219 - 221 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 8.88 (s,
6
OH); 4.14 (d, J=18.6, Ha); 3.80 (d, J= 18.6, Hb); (Quinolyl) δ =
8.92 (d, H2); 8.50 (d, H8); 8.13 (s, H6); 7.92 (s, H5); 7.70 (d,
+
m/z (%) = 379 (M , 100), 310 (47), 135 (21), 162 (9), 75 (6).
13
H3); (Biphenyl) δ = 7.89-7.78; 7.54-7.37; (m, 9H). C NMR
Anal. Calcd. for C H ClF N S (379.79): C, 53.76; H, 2.39;
17
9
3 3
(DMSO-d ) (Pyrazol) δ = 148.6 (C3); 123.6 (q, J = 285.4,
6
CF
N, 11.06%. Found: C, 53.54; H, 2.56; N, 10.86%.
2
CF ); 93.9 (q, J = 31.7, C5); 43.7 (C4); (Quinolyl) δ = 151.3
3
CF
(C2); 149.8 (C8a); 146.4 (C4); 133.8 (C7); 129.8 (C8); 128.8
(C6); 126.0 (C5); 122.6 (C4a); 114.0 (C3); (Biphenyl) δ = 139.1;
129.8; 127.9; 127.7; 127.6; 127.5; 126.8; 126.4 (12C). MS (EI,
4-[3-(2-Furyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-chloro-
quinoline (3l).
This compound was obtained as a yellow solid, yield 73%,
70 eV): m/z (%) = 449 (M – H O, 100), 207 (26), 152 (25), 380
2
1
Mp. 166-168 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 7.75-7.68
6
(22), 135 (19).
(m, H4 + H5
); (Quinolyl) δ = 9.20 (d, H2); 8.30 (d, H8);
Quinl
Anal. Calcd. for C
H ClF N O (467.87): C, 64.18; H, 3.66;
25 17 3 3
7.84-7.83 (m, H6); 7.73 (d, H3); (Furyl) δ = 7.90 (d, 1H); 7.05
N, 8.98 %. Found: C, 64.48; H, 3.75; N, 8.53 %.
13
(d, 1H); 6.67-6.66 (m, 1H). C NMR (DMSO-d ) (Pyrazol) δ =
6
2
149.0 (C3); 134.2 (q, J = 39.5, C5); 118.8 (q, J = 269.8,
General Procedure for the Preparation of 4-(3-Substituted-5-tri-
CF
CF
CF ); 106.5 (C4); (Quinolyl) δ = 152.2 (C2); 145.7 (C8a); 144.6
fluoromethyl-1H-pyrazol-1-yl)-7-chloroquinolines (3a, 3j-l).
3
(C4); 135.4 (C7); 129.2 (C8); 127.9 (C6); 124.5 (C5); 122.8
To a magnetically stirred solution of 1a, 1j-l (1 mmol) in
MeOH (10 ml), 7-chloro-4-hydrazinoquinoline (1 mmol) was
added at room temperature. The mixture was stirred under reflux
(64 ºC) for 15 to 30 minutes (3a, 3j-l). The solvent was evapo-
rated under reduced pressure and the solid products 3 recrystal-
lized from a mixture of ethanol and water 5:1. Yield: 73 – 89 %.
(C4a); 120.0 (C3); (Furyl) δ = 143.7; 141.1; 111.7; 108.7 (4C).
+
MS (EI, 70 eV): m/z (%) = 363 (M , 100), 294 (27), 135 (14), 75
(9), 162 (8).
Anal. Calcd. for C H ClF N O (363.72): C, 56.14; H, 2.49;
17
9
3 3
N, 11.55%. Found: C, 55.97; H, 2.79; N, 11.50%.
General Procedure for the Preparation 4-(3-Substituted-5-trifluo-
romethyl-1H-pyrazol-1-yl)-7-chloroquinolines (3b-i).
4-(3-Methyl-5-trifluoromethyl-1H-pyrazol-1-yl)-7-chloroquino-
line (3a).
To a magnetically stirred pure acetic acid (10 ml), dihydropy-
razole 2b-i (1 mmol) was added at room temperature. The mix-
ture was stirred under reflux (116 ºC) for 4 hours (3b-g, 3i) or for
10 hours (3h). The solvent was evaporated under reduced pres-
sure and solid products 3 were recrystallized from a mixture of
ethanol and water 5:1. Yield: 73 - 96 %.
This compound was obtained as a yellow solid, yield 80 %,
1
Mp. 58 - 60 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 7.10 (s, H4);
6
(Quinolyl) δ = 9.17 (d, H2); 8.29 (d, H8); 7.80-7.72 (m, H6 and
13
H3); 7.41 (d, H5); 2.38 (s, Me). C NMR (DMSO-d ) (Pyrazol)
6
2
δ = 150.8 (C3); 133.3 (q, J = 38.5, C5); 118.7 (q, J = 269.1,
CF
CF
CF ); 105.7 (C4); (Quinolyl) δ = 152.1 (C2); 148.2 (C8a); 143.4
3
(C4); 136.7 (C7); 129.9 (C8); 128.4 (C6); 125.7 (C5); 120.2
4-(3-Phenyl-5-trifluoromethyl-1H-pyrazol-1-yl)-7-chloroquino-
line (3b).
(C4a); 110.0 (C3); 13.2 (Me). MS (EI, 70 eV): m/z (%) = 312
+
(M , 7), 260 (100), 176 (30), 242 (10), 75 (9).
This compound was obtained as a yellow solid, yield 96 %,
Anal. Calcd. for C H ClF N (311.69): C, 53.95; H, 2.91; N,
14
9
3 3
1
Mp. 143 - 145 ºC. H NMR (DMSO-d ) (Phenylpyrazol) δ =
13.48 %. Found: C, 53.64; H, 3.25; N, 13.30 %.
6
8.00-7.92; 7.55-7.49 (m, 6H, H4 + 5H ); (Quinolyl) δ = 9.24 (d,
H2); 8.34 (d, H8); 8.04 (s, H6); 8.00-7.92; (m, H3); 7.78-7.74 (m,
Ar
4-[3-(2-Naphthyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-chloro-
quinoline (3j).
13
H5). C NMR (DMSO-d ) (Pyrazol) δ = 151.1 (C3); 134.5 (q,
6
This compound was obtained as a yellow solid, yield 76%,
J
= 39.5, C5); 118.8 (q, J = 269.1, CF ); 106.9 (C4);
CF CF 3
1
Mp. 102-104 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 7.61-7.48
(Quinolyl) δ = 152.1 (C2); 149.0 (C8a); 142.0 (C4); 135.3 (C7);
129.0 (C8); 127.9 (C6); 124.4 (C5); 122.8 (C4a); 120.4 (C3);
6
(m, H4 + H3
); (Quinolyl) δ = 9.16 (d, H2); 8.54 (d, H8);
Quinl

1060
H. G. Bonacorso, C. A. Cechinel, M. R. Oliveira, M. B. Costa,
M. A. P. Martins, N. Zanatta and A. F. C. Flores
Vol. 42
(Phenyl) δ = 127.8; 127.7; 127.2; 126.0 (6C). MS (EI, 70 eV):
131.8; 129.3; 127.7; 124.9 (6C). MS (EI, 70 eV): m/z (%) = 453
(M , 100), 384 (45), 135 (25), 75 (20), 162 (17).
+
+
m/z (%) = 373 (M , 99), 304 (100), 77 (22), 186 (17), 135 (16).
Anal. Calcd. for C H ClF N (373.76): C, 61.06; H, 2.97; N,
Anal. Calcd. for C H BrClF N (452.66): C, 50.42; H, 2.23;
19 11
3
3
19 10 3 3
11.24 %. Found: C, 60.81; H, 3.07; N, 10.99 %.
N, 9.28 %. Found: C, 50.58; H, 2.44; N, 9.31 %.
4-[3-(4-Methylphenyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-
chloroquinoline (3c).
4-[3-(4-Methoxyphenyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-
chloroquinoline (3g).
This compound was obtained as a yellow solid, yield 79 %,
This compound was obtained as a yellow solid, yield 79%,
1
1
Mp. 144 - 146 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 7.07 (s,
Mp. 133-135 ºC. H NMR (DMSO-d ) (pyrazol) δ = 7.39-7.31
6
6
H4); (Quinolyl) δ = 9.25 (d, H2); 8.35 (d, H8); 7.96-7.89 (m, H6)
(m, H4 + H3
); (Quinolyl) δ = 9.23 (d, H2); 8.36 (d, H8);
Quinl
7.80-7.74 (m, H5); 7.07 (d, H3); (Phenyl) δ = 7.96-7.89; 7.58-
7.95 (d, H6); 7.53 (d, H5); (Phenyl) δ = 7.91-7.77 (m, 4H); 2.38
13
13
7.53 (m, 4H); 3.84 (s, OMe). C NMR (DMSO-d ) (Pyrazol) δ =
(s, Me). C NMR (DMSO-d ) (Pyrazol) δ = 152.1 (C3); 134.6
6
6
2
2
151.8 (C3); 134.4 (q, J = 38.8, C5); 119,5 (q, J = 269.8,
(q, J = 38.8, C5); 120.5 (q, J = 269.1, CF ); 106.8 (C4);
CF
CF
CF
CF
3
CF ); 106.4 (C4); (Quinolyl) δ = 152.0 (C2); 148.6 (C8a); 142.3
(Quinolyl) δ = 152.2 (C2); 149.0 (C8a); 142.1 (C4); 135.8 (C7);
129.8 (C8); 127.9 (C6); 124.5 (C5); 122.9 (C4a); 119.9 (C3);
(Phenyl) δ = 129.7; 129.3; 129.1; 125.5 (6C); 39.4 (Me). MS (EI,
3
(C4); 135.3 (C7); 129.0 (C8); 126.9 (C6); 124.5 (C5); 122.8
(C4a); 114.0 (C3); (Phenyl) δ = 127.5; 126.4; 124.6; 123.0 (6C);
+
+
54.9 (OMe). MS (EI, 70 eV): m/z (%) = 403 (M , 100), 334 (21),
70 eV): m/z (%) = 387 (M , 100), 318 (71), 192 (12), 135 (12),
69 (18), 162 (17), 135 (16).
65 (11).
Anal. Calcd. for C
H ClF N O (403.79): C, 59.49; H, 3.25;
Anal. Calcd. for C
H ClF N (387.79): C, 61.95; H, 3.38; N,
20 13 3 3
20 13 3 3
N, 10.41 %. Found: C, 59.76; H, 3.40; N, 10.52 %.
10.84%. Found: C, 61.82; H, 3.54; N, 10.64%.
4-[3-(4-Nitrophenyl)-trifluoromethyl-1H-pyrazol-1-yl]-7-
chloroquinoline (3h).
4-[3-(4-Fluorophenyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-
chloroquinoline (3d).
This compound was obtained as a yellow solid, yield 82 %,
This compound was obtained as a yellow solid, yield 77%,
1
1
Mp. 199 - 200 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 7.95 (s,
Mp. 117-119 ºC. H NMR (DMSO-d ) (Phenylpyrazol) δ =
6
6
H4); (Quinolyl) δ = 9.22 (d, H2); 8.35 (s, H8); 8.29-8.26 (m,
8.08-8.06; 8.04-7.93; 7.37-7.32 (m, 5H, H4 + 4H ); (Quinolyl) δ
Ar
H6); 8.24 (d, H5); 7.51 (d, H3); (Phenyl) δ = 8.33-8.29; 8.29-
= 9.24 (d, H2); 8.33 (d, H8); 8.08-8.06 (m, H6); 7.78-7.74 (m,
13
13
8.26; 7.76-7.73 (m, 4H). C NMR (DMSO-d ) (Pyrazol) δ =
H5); 7.54 (d, H3). C NMR (DMSO-d ) (Pyrazol) δ =151.3
6
6
2
2
151.3 (C3); 134.4 (q, J = 38.8, C5); 118.3 (q, J = 269.8,
(C3); 134.5 (q, J = 38.8, C5); 119.6 (q, J = 269.1, CF );
CF
CF
CF
CF
3
CF ); 106.9 (C4); (Quinolyl) δ = 152.1 (C2); 149.0 (C8a); 142.1
106.9 (C4); (Quinolyl) δ = 152.1 (C2); 149.0 (C8a); 142.0 (C4);
135.3 (C7); 129.0 (C8), 127.9 (C6); 124.5 (C5); 122.8 (C4a);
115.8 (C3); (Phenyl) δ = 127.8; 127.7; 125.2; 124.4 (6C). MS
3
(C4); 135.4 (C7); 129.1 (C8); 128.0 (C6); 124.5 (C5); 122.9
(C4a); 115.8 (C3); (Phenyl) δ = 127.9; 127.8; 127.2; 126.4 (6C).
+
+
MS (EI, 70 eV): m/z (%) = 418 (M , 100), 349 (70), 135 (21),
(EI, 70 eV): m/z (%) = 391 (M , 100), 322 (88), 135 (19), 195
162 (13), 75 (10).
(15), 75 (14).
Anal. Calcd. for C
H ClF N O (418.76): C, 54.50; H, 2.41;
Anal. Calcd. for C
H ClF N (391.75): C, 58.25; H, 2.57; N,
19 10 3 4 2
19 10 4 3
N, 13.38 %. Found: C, 54.08; H, 2.38; N, 13.11 %.
10.73 %. Found: C, 58.19; H, 2.60; N, 11.05 %.
4-[3-(4-Biphenyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-chloro-
quinoline (3i).
4-[3-(4-Chlorophenyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-
chloroquinoline (3e).
This compound was obtained as a yellow solid, yield 83%,
This compound was obtained as a yellow solid, yield 92 %,
1
1
Mp. 127-129 ºC. H NMR (DMSO-d ) (Pyrazol) δ = 7.57-7.41
Mp. 154 - 156 ºC. H NMR (DMSO-d ) (Phenylpyrazol) δ =
6
6
(m, H4 + H3
); (Quinolyl) δ = 9.25 (d, H2); 8.35 (d, H8);
8.04-7.95; 7.59-7.53 (m, 5H, H4 + 4H ); (Quinolyl) δ =9.24 (s,
Quinl
Ar
13
8.13-7.97 (m, H5 and H6); (Biphenyl) δ = 8.13-7.97 (m, 2H);
7.95-7.75 (m, 5H); 7.57-7.41 (m, 2H). C NMR (DMSO-d )
H2); 8.34 (s, H8); 8.04 (s, H6); 7.76 (d, H5); 7.50 (s, H3).
NMR (DMSO-d ) (Pyrazol) δ = 151.1 (C3); 134.5 (q, J
38.8, C5); 121.9 (q, J = 269.1, CF ); 107.2 (C4); (Quinolyl) δ =
C
=
13
2
6
6
CF
2
(Pyrazol) δ = 151.8 (C3); 134.4 (q, J = 38.8, C5); 119.8 (q,
CF
CF
3
J
= 269.8, CF ); 107.0 (C4); (Quinolyl) δ = 152.1 (C2); 149.0
152.2 (C2); 149.0 (C8a); 142.0 (C4); 135.4 (C7); 129.2 (C8);
127.9 (C6); 124.5 (C5); 122.8 (C4a); 119.9 (C3); (Phenyl) δ =
129.5; 128.9; 127.4; 127.6 (6C). MS (EI, 70 eV): m/z (%) = 407
CF
3
(C8a); 142.1 (C4); 135.4 (C7); 129.7 (C8); 127.9 (C6); 124.5
(C5); 122.9 (C4a); 117.8 (C3); (Biphenyl) δ = 140.5; 139.2;
129.0; 128.9; 127.5; 126.9; 126.4; 126.2; (12C). MS (EI, 70 eV):
+
(M , 100), 338 (78), 135 (20), 75 (18), 162 (16).
+
m/z (%) = 449 (M , 100), 207 (26), 152 (25), 380 (22), 135 (19).
Anal. Calcd. for C
H Cl F N (408.20): C, 55.90; H, 2.47;
19 10 2 3 3
Anal. Calcd. for C
H ClF N (449.86): C, 66.75; H, 3.36; N,
N, 10.29 %. Found: C, 55.47; H, 2.38; N, 9.89 %.
25 15 3 3
9.34 %. Found: C, 66.35; H, 3.38; N, 9.26 %.
4-[3-(4-Bromophenyl)-5-trifluoromethyl-1H-pyrazol-1-yl]-7-
chloroquinoline (3f).
Acknowledgments.
This compound was obtained as a yellow solid, yield 87 %,
The authors are thankful to Conselho Nacional de
Desenvolvimento Científico e Tecnológico – CNPq (Process. No.
303636/2002-5) for financial support. Fellowships from
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -
CAPES (to M. R. Oliveira and M. B. Costa and L. B. Silva ) and
Fundação de Apoio à Tecnologia e Ciência da Universidade
Federal de Santa Maria (FATEC / UFSM) (to C. A. Cechinel) are
also acknowledged.
1
Mp. 162 - 164 ºC. H NMR (DMSO-d ) (Phenylpyrazol) δ =
6
7.96-7.91; 7.72-7.68 (m, 5H, H4 + 4H ); (Quinolyl) δ = 9.24 (d,
Ar
13
H2); 8.33 (d, H8); 7.99 (s, H6); 7.77 (d, H5); 7.50 (d, H3).
C
=
2
NMR (DMSO-d ) (Pyrazol) δ = 151.2 (C3); 134.5 (q, J
6
CF
39.5, C5); 121.7 (q, J = 269.1, CF ); 107.2 (C4); (Quinolyl) δ =
CF
3
152.3 (C2); 149.0 (C8a); 142.1 (C4); 135.4 (C7); 129.9 (C8);
128.0 (C6); 124.5 (C5); 122.3 (C4a); 120.0 (C3); (Phenyl) δ =

Sep-Oct 2005
An Efficient and Regiospecific Preparation of Trifluoromethyl
1061
REFERENCES AND NOTES
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