Haloacetylated enol ethers, 19: Synthesis of 3-(2-thienyl)- and 3-(2-furyl)-5-trihalomethyl substituted azoles

Article abstract of DOI:10.1055/s-2005-872140

Heterocyclization of 1,1,1-trifluoro[chloro]-4-methoxy-4-[2-tienyl]-3- buten-2-one and 1,1,1-trifluoro[chloro]-4-methoxy-4-[2-furyl]-3-buten-2-ones into isoxazoles and pyrazoles derivatives as a new type of trihalomethylated bicyclic heterocycles is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872140

2744
PAPER
Haloacetylated Enol Ethers, 19:1 Synthesis of 3-(2-Thienyl)- and 3-(2-Furyl)-5-
trihalomethyl Substituted Azoles
S
ynthesis of 3-(2-T
l
hienyl
e
)- and 3-(2
x
F
thyl Substitute
.
d Azoles C. Flores,* Sergio Brondani, Lucas Pizzuti, Marcos A. P. Martins, Nilo Zanatta, Helio G. Bonacorso,
Darlene C. Flores
NUQUIMHE, Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brasil
Fax +55(55)32208031; E-mail: alexflores@smail.ufsm.br
Received 22 April 2005
dimethoxy-1-(2-heteroaryl)ethanes with trichloroacetyl
Abstract: Heterocyclization of 1,1,1-trifluoro[chloro]-4-methoxy-
4-[2-tienyl]-3-buten-2-one and 1,1,1-trifluoro[chloro]-4-methoxy-
4-[2-furyl]-3-buten-2-ones into isoxazoles and pyrazoles deriva-
tives as a new type of trihalomethylated bicyclic heterocycles is re-
ported.
chloride or trifluoroacetic anhydride in CHCl3–pyridine is
a very convenient approach to trichloro- and trifluoro-
methyl 1,3-dielectrophiles.9
In order to prepare isoxazole derivatives, compounds 1a,b
and 2a,b were reacted with NH2OH·HCl in MeOH under
reflux for four hours. The crystalline products were ob-
tained in 90–95% yields (Scheme 1). These compounds
were characterized as 5-trihalomethyl-3-(2-heteroaryl)-5-
hydroxy-4,5-dihydroisoxazole derivatives 3a,b and 4a,b
based on the analysis and spectral data. The presence of
the strong electron-withdrawing substituent at the 5-posi-
tion guarantees the high stability of the 5-hydroxy-4,5-di-
hydroisoxazole structures. The dehydration of 3 and 4
with 98% H2SO4 at 50 °C for 2–6 hours afforded aromatic
isoxazole derivatives 5b and 6a, b. The dehydration of 3a
did not occur in this medium; the high reflux temperature
leads to complex mixtures probably from furyl ring open-
ing. In an attempt to prepare the 3-thienyl-5-isoxazole car-
boxylic acid the 4,5-dihydroisoxazole 4b was refluxed in
95% H2SO4; however after 12 hours only the reactant
isoxazoline was isolated without any changes. The struc-
ture of 5, 6 was supported by elemental analysis, mass
Keywords: [3+2] cyclocondensation, furyl isoxazoles, thienyl
isoxazoles, furyl pyrazoles, thienyl pyrazoles
The wide range of biological activities of pyrazoles, isox-
azoles has made them popular synthetic targets.2 Numer-
ous methods for the synthesis of these heterocycles
involve approaches based on either intermolecular [2+3]
cycloadditions of 1,3-dipoles to alkenes and alkynes, or
cyclocondensations of hydroxylamine and hydrazines
with 1,3-dielectrophiles.3 Moreover the thiophenes and
furans in oligosystems have attracted considerable atten-
tion as the active component of organic electronic devic-
es.4
In recent years we have focused our interest on b-dike-
tones and a,b-unsaturated ketones with trifluoromethyl or
trichloromethyl substituent.5 These represent interesting
building blocks for the synthesis of heterocyclic systems,
which often show high biological activities.6 The re-
giospecific synthesis of fluorinated N-heterocyclic com-
pounds have drawn much more attention, the literature
has reported series of CF3-substituted pyrazoles and isox-
azoles obtained from the reactions of trifluoromethyl-b-
diketones and a,b-unsaturated trifluoromethyl ketones (b-
alkoxyvinyl trifluoromethyl ketones or diethylamino-
methylene hexafluoromethylacetone) with the corre-
sponding nitrogen nucleophiles.7
1
spectrometry and H, 13C NMR spectral data (Table 1)
and 19F NMR.10
In connection with our studies on the synthesis of isox-
azole and pyrazole derivatives,8 we were interested in de-
veloping general and convenient methods for the
synthesis of biheterocyclic systems from acetyl heterocy-
cles. Here we report the syntheses of 2-thienyl- and 2-fu-
rylazoles with trihalomethyl and carboxyl substituents.
The trihaloacetylated precursors were obtained by acetal
acylation method, from which 1,1,1-trihalo-4-heteroaryl-
4-methoxybut-3-en-2-ones 1a,b and 2a,b were isolated as
pure mixtures of E/Z isomers. The reaction of 1,1-
Scheme 1
Next we examined the synthesis of pyrazole derivatives
by cyclocondensations of 1 and 2 with hydrazine as sum-
marized in Scheme 2. The reaction of 1a and 2a with hy-
drazine hydrochloride in MeOH or EtOH at 50–60 °C
SYNTHESIS 2005, No. 16, pp 2744–2750
Advanced online publication: 04.08.2005
DOI: 10.1055/s-2005-872140; Art ID: M02405SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

PAPER
Synthesis of 3-(2-Thienyl)- and 3-(2-Furyl)-5-trihalomethyl Substituted Azoles
2745
gave pyrazoles 7a and 8a as crystals, quantitatively. The The cyclocondensations of 1 and 2 with phenylhydrazine
same substrates reacting with hydrazine monohydrate are summarized in Scheme 3. The reaction of 1a with phe-
gave the same pyrazoles in somewhat lower yields (70– nylhydrazine hydrochloride in refluxing MeOH for four
75%). The 13C NMR spectra of these tautomeric 3(5)-tri- hours gave a mixture of 3- and 5-trifluoromethyl substitut-
fluoromethyl-5(3)-(2-heteroaryl)-1H-pyrazoles 7a, 8a in ed pyrazole isomers (15a and 15a¢) in 82% yield
CDCl3 revealed only one quartet signal assignable to CF3 (Scheme 3, Table 1). However, when 2a was allowed to
at d = 121.6 (JC,F = 268.7) for 7a and d = 120.8 (JC,F = 269) react with phenylhydrazine hydrochloride under the same
for 8a. The 19F NMR spectra showed only one signal for conditions only one isomer was obtained in 75% yield. It
5-trifluoromethyl group at –64.10 for 7a and at –64.30 for was attributed as 5-trifluoromethyl-1-phenyl-3-thienyl-
8a.11
1H-pyrazole (16a). The regiochemical assignment of 15a,
15a¢ and 16a was made on the basis of the 13C (Table 1)
and 19F NMR spectra.3b,11
The reactions of 1b and 2b with hydrazine hydrochloride
in MeOH or EtOH at 50–60 °C afforded the respective
3(5)-ester pyrazoles 9–12 as crystals in good yields of 81– The reaction of 1a or 2a with free phenylhydrazine fur-
89% (Table 1). The same reaction with hydrazine mono- nished different results on changing the reaction time and
hydrate at 25 °C gave the same 3(5)-esters pyrazoles 9–12 solvent of the reaction. A short reaction period (30 min) in
quantitatively. The structural assignments were based on CHCl3 at 5–10 °C afforded the 4,5-dihydropyrazoles 13a
the signals due to the pyrazole ring carbons at ca d = and 14a in good yields. The 1H NMR signals from diaste-
140.1, 104.3 and 138.8 for 9, and d = 146.2, 105.9 and reotopic hydrogens at 4 position of the pyrazole ring con-
138.4 for 11. The signals from ester carboxyl groups were firmed the assignment. Nevertheless, a longer period of
observed at d = 160.2–160.9 (Table 1). The reaction of 1b four hours in the same solvent led to the aromatic products
with hydrazine monohydrate in a concentrated solution of 15a and 16a. On using EtOH as solvent, a complex mix-
EtOH afforded a 40:60 mixture of 9 and 10 in 95% yield. ture of 4,5-dihydropyrazole, aromatic pyrazole isomers
The medium with hydrazine monohydrate was preferred and tar material was obtained.
to that with hydrazine hydrochloride when the targets
were ester pyrazoles 9–12 (Table 1).
Scheme 3
In reactions of 1b and 2b with phenylhydrazine hydro-
chloride in MeOH or EtOH at 25–50 °C the respective 5-
ester pyrazoles 17–20 were furnished as crystals in good
yields 76–89% (Table 1 and Scheme 4). Moreover when
1b or 2b were allowed to react with free phenylhydrazine
in MeOH or EtOH at 25–35 °C the same 5-ester pyrazoles
were obtained with equivalent yields. In order to preserve
the trichloromethyl group at pyrazole ring the cyclocon-
densation reaction was carried out in CHCl3 at 5–25 °C for
one hour. It was then possible to isolate the 5-trichloro-
methyl-3-(2-heteroaryl)-1-phenyl-1H-pyrazoles 15b and
Scheme 2
However, intending to preserve the trichloromethyl group
on pyrazole products the reaction of 1b or 2b with hydra-
zine monohydrate was carried out in a polar aprotic sol-
vent (CHCl3) at 25–30 °C for 30 minutes, which gave the
5-trichloromethyl-1H-pyrazoles 7b and 8b in quantitative
yields (Table 1). The presence of the signals at d = 101
from CCl3, as well as the chemical shifts of the pyrazole
carbons supported the assignment (Table 1).
Synthesis 2005, No. 16, 2744–2750 © Thieme Stuttgart · New York

2746
A. F. C. Flores et al.
PAPER
1
16b. The H and 13C NMR spectra of these pyrazoles in mation of trichloromethyl group attached to 3-heteroaryl-
CDCl3 revealed only one set of signals assigned to the 3- 1H-pyrazoles into alkoxycarbonyl groups have permitted
heteroaryl substituted isomers.
us to conclude the azole effect over the trichloromethyl
hydrolysis. The higher resonance energies13 of 3-(2-het-
eroaryl)-1H-pyrazoles (7b, 8b, 15b and 16b) have fa-
vored the trichloromethyl hydrolysis whereas the 3-(2-
heteroaryl)isoxazoles 5b and 6b have blocked that trans-
formation under mild cyclocondensation conditions.
EtOH, MeOH and CHCl3 were purchased from Merck. Hydroxyl-
amine, hydrazine and phenylhydrazine hydrochloride were pur-
chased from Aldrich. All chemicals were used as obtained from
suppliers. The 1,1,1-trihalo-4-(2-heteroaryl)-4-methoxy-3-buten-2-
ones 1 and 2 were prepared according to ref.9 All melting points
were determined on a Reichert Thermovar apparatus and are uncor-
1
rected. H and 13C NMR spectra were acquired on a Bruker DPX
400 spectrometer (1H at 400.13 MHz and 13C at 100.62 MHz) in 5
mm sample tubes at 298 K and digital resolution of 0.01 ppm, in
CDCl3 and using TMS as the internal reference. Mass spectra were
registered on a HP 6890 GC equipment connected to a HP 5973
MSD and interfaced by a Pentium PC. The GC was equipped with
a split-splitless injector, autosampler, cross-linked HP-5 capillary
column (30 m, 0.32 mm of internal diameter), and He was used as
the carrier gas. The elemental analyses were performed on a Perkin-
Elmer 2400 CHN elemental analyzer (São Paulo University-USP/
Brazil).
Scheme 4
The presented regiospecific reactions have been being
useful and convenient alternative to obtain important bi-
heterocyclic systems containing thiophene or furan ring.
That one-pot cyclocondensation and conversion of
trichloromethyl group into carboxyl groups allowed the
production of a new series of pyrazole-5-carboxylic esters
in good yields. Moreover, it was possible to verify that the
effect of the 3-(2-heteroaryl) substituent on the isoxazole
ring does not permit the conversion of the trichloromethyl
group to carboxyl groups; the same trend observed with 3-
aryl substituents.12 On the other hand, the facile transfor-
Synthesis of 5-Trihalomethyl-5-hydroxy-3-(2-heteroaryl)-4,5-
dihydroisoxazoles (3a,b, 4a,b)
A solution of 1,1,1-trihalo-4-(2-heteroaryl)-4-methoxy-3-buten-2-
ones 1 or 2 (5 mmol) and hydroxylamine hydrochloride (5.5 mmol)
in MeOH (7 mL) was stirred for 2–4 h at reflux. The solvent was re-
moved and the residue was dissolved in CHCl3 (20 mL) and washed
with water (2 × 10 mL). The solution was dried with Na2SO4 and the
solvent was evaporated, which gave the pure isoxazoles 3a,b and
4a,b. Yields, melting points, and 1H, 13C NMR data are presented in
Table 1 and elemental analysis in Table 2.
Table 1 Yields, Melting Points and 1H and 13C NMR Data of Heteroarylazoles 3–20
Product X/R
W
O
Yield (%)a Mp (°C)
NMR datac
3ad
4ad
3bd
4bd
F
90
90
95
93
117–119
123–125
155–157
168–171
1H NMR: d = 3.52 (d, J = 18.0 Hz, 1 H), 3.83 (d, J = 18.0 Hz, 1 H), 6.62 (dd, J = 3.4,
1.8 Hz, 1 H), 6.95 (d, J = 3.4 Hz, 1 H), 7.74 (d, J = 1.8 Hz, 1 H)
13C NMR: d = 148.7 (C-3), 42.5 (C-4), 103.6 (JCF = 33.5 Hz, C-5), 122.6 (JCF = 283.6
Hz, CF3), 143.6 (C-2¢), 113.8 (C-3¢), 111.9 (C-4¢), 145.5 (C-5¢)
F
S
O
S
1H NMR: d = 3.56 (d, J = 18.5 Hz, 1 H), 3.93 (d, J = 18.5 Hz, 1 H), 7.18 (dd, J = 5.6,
3.7 Hz, 1 H), 7.50 (dd, J = 3.7, 1.0 Hz, 1 H), 7.73 (dd, J = 5.6, 1.0 Hz, 1 H)
13C NMR: d = 153.0 (C-3), 42.8 (C-4), 103.8 (JCF = 33.1 Hz, C-5), 122.4 (JCF = 284.2
Hz, CF3), 129.7 (C-2¢), 130.0 (C-3¢), 127.9 (C-4¢), 131.3 (C-5¢)
Cl
Cl
1H NMR: d = 3.66 (d, J = 18.5 Hz, 1 H), 4.02 (d, J = 18.5 Hz, 1 H), 6.61 (dd, J = 3.5,
1.8 Hz, 1 H), 6.96 (d, J = 3.5 Hz, 1 H), 7.74 (d, J = 1.8 Hz, 1 H)
13C NMR: d = 149.0 (C-3), 44.0 (C-4), 111.4 (C-5), 101.2 (CCl3), 143.5 (C-2¢), 113.5
(C-3¢), 111.8 (C-4¢), 145.2 (C-5¢)
1H NMR: d = 3.73 (d, J = 18.5 Hz, 1 H), 4.16 (d, J = 18.5 Hz, 1 H), 7.15 (dd, J = 5.0,
3.7 Hz, 1 H), 7.50 (dd, J = 3.7, 1.0 Hz, 1 H), 7.65 (dd, J = 5.0, 1.0 Hz, 1 H )
13C NMR: d = 154.1 (C-3), 45.9 (C-4), 112.8 (C-5), 102.2 (CCl3), 131.5 (C-2¢), 130.1
(C-3¢), 128.6 (C-4¢), 131.3 (C-5¢)
Synthesis 2005, No. 16, 2744–2750 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-(2-Thienyl)- and 3-(2-Furyl)-5-trihalomethyl Substituted Azoles
2747
Table 1 Yields, Melting Points and 1H and 13C NMR Data of Heteroarylazoles 3–20 (continued)
Product X/R
W
S
Yield (%)a Mp (°C)
NMR datac
6a
F
89
112–115
1H NMR: d = 6.56–6.59 (dd, J = 3.5, 1.8 Hz, 1 H), 6.97 (s, 1 H), 7.02 (d, J = 3.5 Hz, 1
H), 7.60 (d, J = 1.8 Hz, 1 H)
13C NMR: d = 157.7 (C-3), 103.4 (C-4), 159.0 (JCF = 34.0 Hz, C-5), 117.7 (JCF = 280.2
Hz, CF3), 128.5 (C-2¢), 128.6 (C-3¢), 127.9 (C-4¢), 128.8 (C-5¢).
5b
Cl
O
76
55–57
1H NMR: d = 6.47–6.49 (dd, J = 3.5, 1.8 Hz, 1 H), 6.81 (s, 1 H), 6.92 (d, J = 3.5 Hz, 1
H), 7.51 (d, J = 1.8 Hz, 1 H)
13C NMR: d = 168.7 (C-3), 101.3 (C-4), 154.7 (C-5), 84.2 (CCl3), 142.7 (C-2¢), 111.9
(C-3¢), 111.3 (C-4¢), 144.5 (C-5¢)
6b
7a
Cl
F
S
82
80
101–103
48–50
1H NMR: d = 6.85 (s, 1 H), 7.14 (dd, J = 5.0, 3.6 Hz, 1 H), 7.45–7.52 (m, 2 H)
13C NMR: d = 169.0 (C-3), 101.7 (C-4), 157.7 (C-5), 84.3 (CCl3), 129.1 (C-2¢), 128.6
(C-3¢), 128.3 (C-4¢), 128.6 (C-5¢)
O
1H NMR: d = 6.67 (s, 1 H, H-4), 6.46 (dd, J = 1.8, 3.4 Hz, 1 H, H-4¢), 6.65 (d, J = 3.4
Hz, 1 H, H-3¢), 7.43(d, J = 1.8 Hz, 1 H, H-5¢)
13C NMR: d = 143.3 (C-3), 99.9 (JCF = 1.8 Hz, C-4), 143.2 (JCF = 26.0 Hz, C-5), 121.6
(JCF = 268.7 Hz, CF3), 136.4 (C-2¢), 108.0 (C-3¢), 111.6 (C-4¢), 143.0 (C-5¢).
8a
7b
8b
9
F
S
84
82
87
85
81
103–105
53–54
115–117
Oil
1H NMR: d = 6.66 (s, 1 H, H-4), 7.07 (dd, J = 3.7, 4.9 Hz, 1 H, H-4¢), 7.30 (d, J = 3.7
Hz, 1 H, H-3¢), 7.35(d, J = 4.9 Hz, 1 H, H-5¢)
13C NMR: d = 139.9 (C-3), 101.5 (JCF = 1.6 Hz, C-4), 143.0 (JCF = 31.2 Hz, C-5), 120.8
(JCF = 269.0 Hz, CF3), 129.8 (C-2¢), 128.0 (C-3¢), 125.5 (C-4¢), 126.5 (C-5¢)
Cl
Cl
Me
Et
O
S
1H NMR: d = 6.47 (dd, J = 1.7, 3.2 Hz, 1 H, H-4¢), 6.77 (d, J = 3.2 Hz, 1 H, H-3¢), 6.81
(s, 1 H, H-4), 7.45 (d, J = 1.7 Hz, 1 H, H-5¢)
13C NMR: d = 154.8 (C-3), 100.3 (C-4), 143.3 (C-5), 89.52 (CCl3), 136.9 (C-2¢), 108.6
(C-3¢), 111.77 (C-4¢), 143.16 (C-5¢)
1H NMR: d = 6.80 (s, 1 H, H-4), 7.09 (dd, J = 3.4, 4.4 Hz, 1 H, H-4¢), 7.36 (d, J = 3.9
Hz, 1 H, H-3¢), 7.37 (d, J = 4.4 Hz, 1 H, H-5¢)
13C NMR: d = 154.8 (C-3), 101.8 (C-4), 140.3 (C-5), 89.6 (CCl3), 130.3 (C-2¢), 125.6
(C-3¢), 126.5 (C-4¢), 128.0 (C-5¢)
O
O
3.90 (s, 3 H, Me), 6.46 (dd, J = 1.8, 3.4 Hz, 1 H, H-4¢), 6.73 (d, J = 3.4 Hz, 1 H, H-3¢),
6.99 (s, 1 H, H4), 7.44 (d, J = 1.8 Hz, 1 H, H-5¢)
13C NMR: d = 140.9 (C-3), 104.8 (C-4), 139.0 (C-5), 160.9 (CO2R), 145.8 (C-2¢), 107.2
(C-3¢), 111.5 (C-4¢), 142.5 (C-5¢)
10
Oil
1.32 (t, J = 7.0 Hz, 3 H, Me), 4.34 (q, J = 7.0 Hz, 2 H, CH2), 6.56 (dd, J = 1.8, 3.4 Hz,
1 H, H-4¢), 6.96 (d, J = 3.4 Hz, 1 H, H-3¢), 7.05 (s, 1 H, H-4), 7.65 (d, J = 1.8 Hz, 1 H,
H-5¢)
13C NMR: d = 140.1 (C-3), 104.3 (C-4), 138.8 (C-5), 160.7 (CO2R), 145.6 (C-2¢), 107.5
(C-3¢), 111.9 (C-4¢), 143.3 (C-5¢)
11
12
Me
Et
S
S
87
89
Oil
1H NMR: d = 3.89 (s, 3 H, Me), 6.96 (s, 1 H, H-4), 7.03 (dd, J = 3.6, 5.1 Hz, 1 H, H-
4¢), 7.26 (d, J = 5.1 Hz, 1 H, H3¢), 7.37 (d, J = 3.6 Hz, 1 H, H-5¢)
13C NMR: d = 144.8 (C-3), 105.5 (C-4), 137.9 (C-5), 160.5 (CO2R), 133.4 (C-2¢), 127.6
(C-3¢), 124.8 (C-4¢), 125.5 (C-5¢)
132–134
1H NMR: d = 1.34 (t, J = 7.1 Hz, 3 H, Me), 4.35 (q, J = 7.1 Hz, 2 H, CH2), 7.11 (dd, J
= 3.6, 5.1 Hz, 1 H, H-4¢), 7.27 (s, 1 H, H-4), 7.47 (dd, J = 1.06, 5.1 Hz, 1 H, H-3¢), 7.58
(dd, J = 1.06, 3.6 Hz, 1 H, H-5¢).
13C NMR: d = 146.2 (C-3), 105.9 (C-4), 138.4 (C-5), 160.2 (CO2R), 135.2 (C-2¢), 128.6
(C-3¢), 125.8 (C-4¢), 126.5 (C-5¢)
13a
14a
F
F
O
S
81
78
Oil
Oil
1H NMR: d = 3.59 (dd, J = 18.6, 1.6 Hz, 1 H, H-4a), 3.83(d, J = 18.6 Hz, 1 H, H-4b),
6.57 (dd, J = 3.5, 1.84 Hz, 1 H, H-4¢), 6.79 (d, J = 3.5 Hz, 1 H, H-3¢), 7.27 (m, 3 H, Ph),
7.51 (m, 2 H, Ph), 7.66 (d, J = 1.84 Hz, 1 H, H-5¢)
13C NMR: d = 139.7 (C-3), 45.0 (C-4), 94.1 (JCF = 31.7 Hz, C-5), 120.3 (JCF = 284.0
Hz, CF3), 143.5 (C-2¢), 111.0 (C-3¢), 113.3 (C-4¢), 144.7 (C-5¢)
1H NMR: d = 3.42 (d, J = 18.15 Hz, 1 H, H-4a), 3.71 (d, J = 18.15 Hz, 1 H, H-4b), 7.05
(d, 1 H, H-3¢), 7.31 (dd, 1 H, H-4¢), 7.30–7.60 (m, 6 H, H-5¢, Ph)
13C NMR: d = 140.9 (C-3), 44.8 (C-4), 93.5 (JCF = 31.8 Hz, C-5), 121.0 (JCF = 284.8
Hz, CF3), 144.3 (C-2¢), 129.1 (C-3¢), 128.7 (C-4¢), 140.9 (C-5¢)
Synthesis 2005, No. 16, 2744–2750 © Thieme Stuttgart · New York

2748
A. F. C. Flores et al.
PAPER
Table 1 Yields, Melting Points and 1H and 13C NMR Data of Heteroarylazoles 3–20 (continued)
Product X/R
W
O
Yield (%)a Mp (°C)
80 Oil
NMR datac
15a
F
1H NMR: d = 5.96 (d, J = 3.3 Hz, 1 H, H-3¢), 6.32 (dd, J = 1.8, 3.3 Hz, 1 H, H-4¢), 6.89
(s, 1 H, H-4), 7.42 (d, J = 1.8 Hz, 1 H, H-5¢), 7.43 (m, 2 H, Ph), 7.47–7.51 (m, 3 H,Ph)
13C NMR: d = 136.1 (C-3), 103.7 (JCF = 1.8 Hz, C-4), 143.1 (JCF = 38.5 Hz, C-5), 121.0
(JCF = 269.0 Hz, CF3), 143.1 (C-2¢), 109.8 (C-3¢), 111.3 (C-4¢), 143.1 (C-5¢)
15a1,3
16a
1H NMR: d = 6.47 (dd, J = 1.8, 3.3 Hz, 1 H, H-4¢), 6.79 (d, J = 3.3 Hz, 1 H, H-4¢), 7.03
(s, 1 H, H-4), 7.39 (d, J = 1.8 Hz, 1 H, H-5¢), 7.47–7.51 (m, 5 H, Ph)
13C NMR: d = 133.6 (JCF = 39.5 Hz, C-3), 105.7 (JCF = 2.4 Hz, C-4), 147.0 (C-5), 119.5
(JCF = 269.3 Hz, CF3), 144.1 (C-2¢), 107.1 (C-3¢), 111.4 (C-4¢), 142.5 (C-5¢)
F
S
81
53–55
1H NMR: d = 6.98(s, 1 H, H-4), 7.06 (dd, J = 5.06, 3.6 Hz, 1 H, H-4¢), 7.28 (dd, J =
5.05, 1.1 Hz, 1 H, H-3¢), 7.39 (dd, J = 3.6, 1.1 Hz, 1 H, H-5¢), 7.46 (m, 3 H, Ph), 7.51
(m, 2 H, Ph)
13C NMR: d = 147.1 (C-3), 105.7 (JCF = 1.8 Hz, C-4), 133.8 (JCF = 39.6 Hz, C-5), 121.4
(JCF = 269.0 Hz, CF3), 144.1 (C-2¢), 129.8 (C-3¢), 127.3 (C-4¢), 141.4 (C-5¢)
15b
16b
Cl
Cl
O
S
79
82
119–121
134–136
1H NMR: d = 5.97 (d, J = 3.5 Hz, 1 H, H-3¢), 6.32 (dd, J = 3.5, 1.9 Hz, 1 H, H-4¢), 6.99
(s, 1 H, H-4), 7.40 (d, J = 1.9 Hz, 1 H, H-5¢), 7.43–7.49 (m, 5 H, Ph).
13C NMR: d = 136.2 (C-3), 103.8 (C-4), 143.09 (C-5), 90.5 (CCl3), 143.2 (C-2¢), 109.8
(C-3¢), 111.3 (C-4¢), 139.4 (C-5¢)
1H NMR: d = 7.07 (dd, J = 5.6, 1.2 Hz, 1 H, H-3¢), 7.08 (s, 1 H, H-4), 7.28 (dd, J = 5.6,
3.6 Hz, 1 H, H-4¢), 7.41 (dd, J = 3.6, 1.2 Hz, 1 H, H-5¢), 7.44–7.49 (m, 3 H, Ph), 7.58
(m, 2 H, Ph)
13C NMR: d = 145.6 (C-3), 105.9 (C-4), 139.6 (C-5), 86.5 (CCl3), 134.7 (C-2¢), 129.6
(C-3¢), 125.4 (C-4¢), 127.5 (C-5¢)
17
18
19
20
Me
Et
O
O
S
80
89
76
83
65–67
1H NMR: d = 3.94 (s, 3 H, Me), 5.94 (d, J = 3.34 Hz, 1 H, H-3¢), 6.32 (dd, J = 3.34, 1.7
Hz, 1 H, H-4¢), 7.17 (s, 1 H, H-4), 7.39 (d, J = 1.7 Hz, 1 H, H-5¢), 7.40–7.48 (m, 5 H,
Ph)
13C NMR: d = 139.5 (C-3), 107.9 (C-4), 136.1 (C-5), 162.4 (CO2Me), 143.2 (C-2¢),
109.4 (C-3¢), 111.2 (C-4¢), 142.9 (C-5¢)
Oil
1H NMR: d = 1.40 (t, J = 7.1 Hz, 3 H, Me), 4.43 (q, J = 7.1 Hz, 2 H, CH2), 5.94 (d, J
= 3.4 Hz, 1 H, H-3¢), 6.31 (dd, J = 3.4, 1.76 Hz, 1 H, H-4¢), 7.17 (s, 1 H, H-4), 7.39 (d,
J = 1.76 Hz, 1 H, H-5¢), 7.40–7.48 (m, 5 H, Ph)
13C NMR: d = 139.4 (C-3), 107.9 (C-4), 136.0 (C-5), 161.9 (CO2Et), 143.2 (C-2¢),
109.4 (C-3¢), 111.1 (C-4¢), 142.9 (C-5¢)
Me
Et
68–70
Oil
1H NMR: d = 3.94 (s, 3 H, Me), 6.82(d, J = 3.74 Hz, 1 H, H-3¢), 6.92 (dd, J = 5.0, 3.34
Hz, 1 H, H-4¢), 7.08 (s, 1 H, H-4), 7.26 (d, J = 5.0 Hz, 1 H, H-5¢), 7.38–7.43 (m, 5 H,
Ph)
13C NMR: d = 138.9 (C-3), 109.3 (C-4), 138.6 (C-5), 162.4 (CO2Me), 143.7 (C-2¢),
129.1 (C-3¢), 127.0 (C-4¢), 127.6 (C-5¢)
S
1H NMR: d = 1.41 (t, J = 7.2 Hz, 3 H, Me), 4.44(q, J = 7.2 Hz, 2 H, CH2), 6.82 (d, J =
2.8 Hz, 1 H, H-3¢), 6.93 (dd, J = 4.8, 2.8 Hz, 1 H, H-4¢), 7.08 (s, 1 H, H-4), 7.28 (d, J
= 4.8 Hz, 1 H, H-5¢), 7.40–7.45 (m, 5 H, Ph)
13C NMR: d = 139.0 (C-3), 109.4 (C-4), 138.7 (C-5), 162.1 (CO2Et), 144.1 (C-2¢),
129.1 (C-3¢), 127.1 (C-4¢), 127.7 (C-5¢)
a Yield refers of the pure products.
b Melting points were determined with a Reichert Thermovar apparatus and are uncorrected.
c NMR spectra were recorded on a Bruker DPX400 spectrometer in CDCl3–TMS.
d In DMSO-d6/TMS. See ref.9
Synthesis of 5-Trihalomethyl-3-(2-heteroaryl)isoxazoles (5b,
6a,b)
Synthesis of 3(5)-Trihalomethyl-5(3)-(2-heteroaryl)-1H-pyra-
zoles (7a,b, 8a,b)
To the respective 4,5-dihydroisoxazole 3b or 4a,b (1 mmol) was
added at room temperature 98% H2SO4. The black mixture was
stirred for 2 h (3b and 4b) or 6 h for 4a. After that the acidic solution
was diluted with cooled water and precipitated solid was filtered
and dried over CaCl2 under vacuum. Yields, melting points and 1H,
13C NMR data for the obtained pure isoxazoles 5b and 6a,b are pre-
sented in Table 1 and elemental analysis in Table 2.
To a stirred solution of 1,1,1-trihalo-4-(2-heteroaryl)-4-methoxy-3-
buten-2-ones 1 or 2 (5 mmol) in CHCl3 (20 mL) was added hydra-
zine monohydrate (5.2 mmol). The mixture was stirred for 2 h at r.t.
After that the solution was dried with Na2SO4, filtered and the sol-
vent was removed. Then pure 1H-pyrazoles 7a,b, 8a,b were ob-
tained. Yields, melting points and 1H, 13C NMR data are presented
in Table 1 and elemental analysis in Table 2. The synthesis of 5-tri-
fluoromethyl-3-(2-thienyl)-1H-pyrazole (8a) has been previously
Synthesis 2005, No. 16, 2744–2750 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-(2-Thienyl)- and 3-(2-Furyl)-5-trihalomethyl Substituted Azoles
2749
Table 2 Elemental Analyses of Isolated Compoundsa
Product
3a
Molecular Formula
C8H6F3NO3
C8H6F3NO2S
C8H6Cl3NO3
C8H6Cl3NO2S
C8H5F3NOS
C8H5Cl3NO2
C8H5Cl3NOS
C8H5F3N2O
C8H5F3N2S
C (%) Calcd.
43.45
40.51
35.52
33.53
43.84
38.06
35.78
47.54
44.04
38.21
35.91
56.25
51.91
58.25
54.04
60.44
57.14
51.33
48.93
67.16
68.08
63.36
64.41
C (%) Found
43.40
40.50
35.70
33.40
43.80
38.00
35.75
47.40
44.00
38.20
36.10
56.30
51.95
58.25
54.10
60.50
57.20
51.50
48.90
67.10
68.10
63.35
64.30
H (%) Calcd.
2.73
2.55
2.24
2.11
1.84
1.60
1.50
2.49
2.31
2.00
1.88
4.20
3.87
4.89
4.53
3.26
3.08
2.77
2.64
4.51
5.00
4.25
4.73
H (%) Found
2.75
2.50
2.35
2.13
2.00
1.65
1.50
2.45
2.30
2.00
1.90
4.35
4.00
4.90
4.55
3.35
3.15
2.90
2.65
4.50
4.90
4.30
4.65
4a
3b
4b
6a
5b
6b
7a
8a
7b
C8H5Cl3N2O
C8H5Cl3N2S
C9H8N2O3
8b
9
10
C10H10N2O3
C9H8N2O2S
C10H10N2O2S
C14H9F3N2O
C14H9F3N2S
C14H9Cl3N2O
C14H9Cl3N2S
C15H12N2O3
C15H12N2O2S
C16H14N2O3
C16H14N2O2S
11
12
15a
16a
15b
16b
17
18
19
20
a Perkin-Elmer 2400 CHN elemental analyzer (São Paulo University-USP/Brazil)
reported and the analytical and spectral data are reported in refer-
ence 11a.
Acknowledgment
Financial support from Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) and Coordenação de Aperfeiço-
mento de Pessoal de Nível Superior (CAPES) is acknowledged.
Two of us (SB and LP) thank the CNPq for doctoral and master fel-
lowships.
Synthesis of 3(5)-(2-Heteroaryl)-1H-pyrazole-5(3)-carboxylic
Acids (9–12)
A solution of 1,1,1-trihalo-4-(2-heteroaryl)-4-methoxy-3-buten-2-
ones 1 or 2 (5 mmol) and hydrazine hydrochloride (5.2 mmol) in
MeOH or EtOH (7 mL) was stirred for 2 h at reflux. The solvent was
removed and the residue was dissolved in CHCl3 (20 mL) and
washed with water (2 × 10 mL). The solution was dried with
Na2SO4 and the solvent was evaporated. Then pure 1H-pyrazole-5-
carboxylic acids 9–12 were obtained. Yields, melting points, mass
and 1H, 13C NMR data are presented in Table 1 and elemental anal-
ysis in Table 2.
References
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Synthesis 2005, No. 16, 2744–2750 © Thieme Stuttgart · New York

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A. F. C. Flores et al.
PAPER
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Synthesis 2005, No. 16, 2744–2750 © Thieme Stuttgart · New York