SHORT PAPER
Preparation of 4-Hydroxy-2-trifluoromethylthiophene
1079
1H NMR (300 MHz, CDCl3): d = 5.75 (s, 1H), 4.19 (q, 2H, J = 7.1
Hz), 4.01 (s, 3H), 1.28 (t, 3H, J = 7.1 Hz).
within the limits of detection. The chemical reactivity of
1 in many cases is similar to that of a,a,a-trifluoro-m-
cresol.10,11
2
13C NMR (75 MHz, CDCl3): d = 163.7, 154.0 (q, JCF = 33 Hz),
119.8 (q, 1JCF = 277 Hz), 101.9 (q, 3JCF = 3.7 Hz), 62.6, 61.1, 14.2.
O
O
OCH3 O
Methyl 3-Hydroxy-5-trifluoromethyl-2-thiophenecarboxylate
(6)
a
F3C
OEt
F3C
OEt
A magnetically stirred solution of 5 (525 g, 2.65 mol) and methyl
thioglycolate (281 g, 2.65 mol) in absolute MeOH (4 L) was cooled
to 5 °C. A solution of methanolic KOH (1 M, 3.2 L) was then added
over 1 h. After a small exotherm (< 30 °C), the reaction mixture was
stirred overnight at ambient temperature. The reaction mixture was
then poured over a stirred mixture of ice (5 kg), H2O (5.2 L) and
concd H2SO4 (250 mL). After stirring for 15 min, the mixture was
extracted with EtOAc (3 ¥ 2.5 L) and the combined extracts were
washed with sat. NaHCO3 (2 ¥ 2 L). The NaHCO3 washings were
back-extracted with EtOAc (2 L). The combined organic layers
were washed with sat. brine (2 ¥ 2 L), dried and then concentrated
to afford an oil containing a small amount of insolubles. The mate-
rial was stirred in hexanes, filtered to remove the insolubles, and
then concentrated to an oil. Fractional distillation (60-62 °C,
2.5 mm) through a Vigreux column (30 cm) afforded 378 g (63%)
of 6.20
5
OH
c
b
CO2Me
F3C
S
6
O
OH
d
1
CO2H
F3C
F3C
S
S
8
7
Reagents and conditions: a, Cs2CO3/DMF/MeOTs, r.t.-70 °C, 60%;
b, methyl thioglycolate, MeOH/KOH, 63%; c, NaOH/MeOH-H2O,
reflux, 65%; d, 100 °C (neat), 82%.
1H NMR (300 MHz, CDCl3): d = 9.48 (br s, 1H), 7.06 (s, 1H), 3.92
(s, 3H).
2
Scheme
13C NMR (75 MHz, CDCl3): d = 166.2, 162.7, 135.5 (q, JCF = 40
Hz), 121.8 (q, 1JCF = 270 Hz), 120.5 (q, 3JCF = 3.5 Hz), 106.7, 52.5.
3-Hydroxy-5-trifluoromethyl-2-thiophenecarboxylic Acid (7)
To a stirred solution of NaOH (168 g, 4.21 mol) in H2O (2.1 L) was
added a solution of 6 (238 g, 1.05 mol) in MeOH (2.1 L). After the
initial exotherm, the reaction mixture was heated at reflux until hy-
drolysis was complete (approx. 3 h) and then cooled to r.t. The re-
action mixture was concentrated to about half volume and cooled to
about 5 °C. Acidification to pH 1 with concd HCl (350 mL) resulted
in a suspension. After stirring the suspension for 30 min at 5 °C, the
solid was collected by filtration, washed with H2O (3 ¥ 1 L) and
dried to afford 145 g (65%) of free acid 7 as a white solid, mp >
100 °C (dec.).
In summary, we report the first synthesis of 1, a thiophene
bioisostere of a,a,a-trifluoro-m-cresol, in four steps from
readily available ethyl 4,4,4-trifluoroacetoacetate and me-
thyl thioglycolate. The above sequence is amenable to
large-scale synthesis. Over one kg of 1 has been obtained
without purification of the intermediates in 35-40% over-
all yield. Compound 1 should offer the potential for fur-
ther utility in both medicinal and agrochemical pursuits.
All reactions were carried out under an atmosphere of N2 or Ar. Un-
less otherwise noted, all materials were obtained from commercial
suppliers and were used without further purification. DMF was
stored over 4 Å sieves. Organic layers from aqueous extractions
1H NMR (400 MHz, DMSO-d6): d = 11.7 (br s, 2 H), 7.30 (s, 1H).
13C NMR (100.6 MHz, DMSO-d6): d = 164.3, 159.9, 132.7 (q,
2JCF = 38.4 Hz), 122.4 (q, 1JCF = 269.6 Hz), 123.4 (q, 3JCF = 3.5 Hz),
110.4.
1
were dried over MgSO4 or Na2SO4 and concentrated in vacuo. H
and 13C NMR spectra were recorded on a Varian Inova 400 or Vari-
an Unity 300 spectrometers in CDCl3 or DMSO-d6. Coupling con-
stants J are given in Hz and unless otherwise indicated represent
proton-proton coupling. IR spectra were recorded on a Perkin-Elm-
er 1600 FTIR. Mass spectra were obtained on a Finnegan MAT
TSQ 700 or MAT 9005 mass spectrometer using chemical ioniza-
tion techniques.
MS: m/z (%) = 211 (M-H-) (100).
Anal. Calcd for C6H3F3O3S: C, 33.97; H, 1.42; S, 15.12. Found: C,
33.91; H, 1.46, S, 15.09.
4-Hydroxy-2-trifluoromethylthiophene (1)
Compound 7 (180 g, 849 mmol) was slowly heated under Ar. Rapid
evolution of gas was observed at 90 °C. Heating was continued for
an additional 3.5 h to complete the decarboxylation. The resulting
oil was vacuum distilled (70-74 °C, 4 mm) through a Vigreux col-
umn (6 in.) to obtain 118 g (82%) of a pale yellow liquid.
IR (neat): n = 3700-2900, 1696, 1570, 1465, 1415, 1297 cm-1.
1H NMR (400 MHz, CDCl3), enol (major): d = 7.06 (m, 1H), 6.52
(d, J = 1.7 Hz), 6.01 (br s, 1H).
1H NMR (400 MHz, CDCl3), keto (minor): d = 6.60 (br s, 1H), 3.90
(br s, 2H).
13C NMR (75.6 MHz, CDCl3), enol (major): d = 152.1, 130.3 (q,
2JCF = 26.2 Hz), 122.3 (q, 1JCF = 268.7 Hz), 121.0 (q, 3JCF = 3.8 Hz),
104.9.
Ethyl 4,4,4-Trifluoro-3-methoxycrotonate (5)
To a mechanically stirred solution of ethyl 4,4,4-trifluoroacetoace-
tate (444 g, 2.41 mol) in DMF (2.40 L) was added Cs2CO3 (785 g,
2.41 mol). The reaction mixture was heated to 70 °C. A solution of
methyl-p-toluenesulfonate (494 g, 2.65 mol) in DMF (890 mL) was
then added dropwise during 1.5 h and the reaction mixture was
stirred for an additional hour. After cooling to r.t., the reaction mix-
ture was diluted with H2O (4.5 L) and extracted with Et2O (4 ¥ 1 L).
The Et2O extracts were combined, washed successively with H2O
(3 ¥ 1 L), and saturated brine (1 L) and then dried and concentrated
to an oil. Fractional distillation through a Vigreux column [40-
48 °C, 9 mm (Lit.19 bp 90-100 °C, 120 mm)] afforded 285 g (60%)
of pure product.
Synthesis 2000, No. 8, 1078–1080 ISSN 0039-7881 © Thieme Stuttgart · New York