A facile and improved synthesis of 3-fluorothiophene

Article abstract of DOI:10.1055/s-2008-1067170

A new efficient and convenient route to 3-fluorothiophene in four steps and 49% overall yield is reported. The fluorine atom was successfully introduced into the thiophene ring in 67% yield using the Schiemann reaction on 2-methoxycarbonylthiophene-3-diazonium tetrafluoroborate. The product, methyl 3-fluorothiophene-2-carboxylate was saponified and the 3-fluorothiophene-2- carboxylic acid was decarboxylated to afford 3-fluorothiophene in 93% yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067170

PAPER
2333
A Facile and Improved Synthesis of 3-Fluorothiophene
I
mprove
d
Synthesis of
a
3-Fluoroth
riophene tin Pomerantz,* Nashaat Turkman
Department of Chemistry and Biochemistry, Box 19065, The University of Texas at Arlington, Arlington, TX 76019-0065, USA
Fax +1(817)2723808; E-mail: pomerantz@uta.edu
Received 29 January 2008; revised 23 April 2008
The fluorinated thiophene, methyl 3-fluorothiophene-2-
carboxylate (2), has been produced by the Schiemann re-
action of diazonium salt 320,22 and, additionally, the corre-
sponding 3-fluorothiophene-2-carboxylic acid (4) has
Abstract: A new efficient and convenient route to 3-fluoro-
thiophene in four steps and 49% overall yield is reported. The fluo-
rine atom was successfully introduced into the thiophene ring in
67% yield using the Schiemann reaction on 2-methoxycarbonyl-
thiophene-3-diazonium tetrafluoroborate. The product, methyl been made from thiophene-2-carboxylic acid using n-bu-
3-fluorothiophene-2-carboxylate was saponified and the 3-fluo-
rothiophene-2-carboxylic acid was decarboxylated to afford 3-fluo-
rothiophene in 93% yield.
tyllithium and the expensive and highly hygroscopic N-
fluorobenzenesulfonimide in a large excess.21,23
Finally, 3-fluorothiophene (1) has also been prepared us-
Key words: heterocycles, fluorine substitution, nucleophilic aro-
ing a lengthy procedure in low yield (8.3% overall). In one
matic substitution, 3-fluorothiophene, Schiemann reaction
step involving cesium fluoride mediated fluorination of 3-
chloro-2-cyanothiophene (5), purification was said to be
rather difficult.24 We tried this synthetic route, and at-
3-Fluorothiophene (1) is a simple compound, but reported
tempts to convert 5 to 6 (Scheme 1) provided a mixture of
rather infrequently in the literature. It has proven to be a
compounds, as shown by 1H NMR spectroscopy and TLC,
molecule whose synthesis is far from straightforward. It is
which we were unable to identify or separate. Interesting-
an important compound which, if there were a simple and
ly, 19F NMR spectroscopy of the mixture showed two
efficient synthesis, would be used to a much greater extent
doublets at –119.01 ppm and –119.03 (J = 4.6 Hz), but as-
in a number of diverse areas. For example, in conjugated
signment of these bands to a particular product is not pos-
polymers,1–3 antistatic agents,4 and various oligomers.2,5
sible at this time.
There are also numerous reported bioactive substances
which have substituted 3-fluorothiophene rings including,
F
Cl
for example, herbicides,6 xanthine oxidase inhibitors,7
and compounds for sleep modulation therapy.8 The syn-
thesis of 1 is challenging due to the higher reactivity of the
2-position of the thiophene ring relative to the 3-position
and the difficulty of introducing a fluorine substituent. Al-
though there are a number of syntheses reported for the
preparation of 3-fluorothiophene (1), most suffer from
some problems such as low yields, lengthy steps, danger-
ous or expensive reagents, or insufficient experimental
data. These include an early report on the attempted syn-
thesis of fluorothiophene using the Schiemann reaction,
which involves the thermal decomposition of an aryldiaz-
onium tetrafluoroborate to produce the corresponding flu-
oroaromatic compound,9 which was not successful10 even
though the reported Schiemann reaction was an adaption
of the synthesis of fluorobenzene taken from Organic
Syntheses.11 Other methods include a report using metal–
halogen interchange of 3-bromothiophene followed by re-
action with perchloryl fluoride,12 which is a dangerous
material,13–15 direct fluorination of thiophene to give a
mixture of 2- and 3-fluorothiophene,16–18 and reports of
the introduction of fluorine into the 3-position of the
thiophene ring using Sandmeyer and Schiemann reac-
tions.19–21
CsF
DMSO
150 °C
CO2H
CN
CN
S
S
6
S
5
1) NaOH/H2O
2) H+
1) BuLi, –78 °C
2) (PhSO2)2NF
3) HCl
F
CO2H
S
4
quinoline
Cu
∆
F
Br
F2
He
–63 °C
1) EtLi, –50 °C
2) ClO3F
S
S
S
1
Scheme 1 Reported syntheses of 3-fluorothiophene (1)
Our successful synthesis of 3-fluorothiophene (1) in-
volves the use of the special conditions for the Schiemann
reaction as reported by Kobarfard20 and Sampson22 to give
3 as shown in Scheme 2. This involves heating the diazo-
nium fluoroborate salt mixed with sand. The starting ma-
terial for the synthesis of methyl 3-fluorothiophene-2-
carboxylate (2), methyl 3-aminothiophene-2-carboxylate
(7), was diazotized using sodium nitrite and tetrafluorobo-
ric acid to give the corresponding diazonium salt, 2-meth-
oxycarbonylthiophene-3-diazonium tetrafluoroborate (3)
in 93% yield. A mixture of 3 and sand was then heated un-
SYNTHESIS 2008, No. 15, pp 2333–2336
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067170; Art ID: M00408SS
© Georg Thieme Verlag Stuttgart · New York

2334
M. Pomerantz, N. Turkman
PAPER
tion mixture. The overall yield in the four steps from 7 to
1 was 49%. It should be mentioned that metal-catalyzed
decarboxylation and decarboxylative coupling of aromat-
ic and heteroaromatic carboxylic acids is of current inter-
est and that includes not only copper-catalyzed
reactions25,26,27a but other metals as well.27b The purity of
1 was greater than approximately 97% as shown by the 1H
NMR spectrum (Figure 1).
F
NH2
N2BF4
NaNO2
160–200 °C
sand
HBF4
93%
CO2Me
F
CO2Me
CO2Me
S
S
S
67%
7
3
2
F
quinoline
NaOH
EtOH
84%
barium-promoted
copper chromite
CO2H
S
S
93%
4
1
49% overall yield
All reactions were carried out in dried glassware. All solvents were
dried over 3 Å molecular sieves. Anhyd DMSO (>99.9%) was ob-
Scheme 2 Synthesis of 3-fluorothiophene (1)
tained in Sure/Seal bottles from Aldrich Chemical Co. 1H NMR, 13
C
NMR, and 19F NMR spectra were recorded on a JEOL Eclipse 500
NMR spectrometer at 500.16 MHz, 125.76 MHz and 470.62 MHz,
respectively, using CDCl3 solvent with tetramethylsilane as an in-
der vacuum (0. 1 Torr) and when the oil-bath temperature
reached 160 °C a crystalline product started to sublime
and was trapped with a liquid nitrogen cold finger. Also,
a pale yellow liquid was further distilled and solidified in-
side the distillation apparatus. The solid and the solidified
liquid were mixed to yield methyl 3-fluorothiophene-2-
carboxylate (2) in a good yield of 67% after precipitation
1
ternal standard for H, residual CHCl3 for 13C, and CFCl3 for 19F
NMR spectra. Chemical shifts are reported in ppm (d) and coupling
constants in Hz. Flash chromatography was performed using flash
silica gel 32–63 mm, 60 Å.
3-Chloro-2-cyanothiophene (5)24 and 2-methoxycarbonylthio-
from methanol. 1H NMR, 13C NMR, and 19F NMR spec- phene-3-diazonium tetrafluoroborate (3)19 were prepared as de-
scribed in the literature.
troscopy supported the structure of the product, methyl 3-
fluorothiophene-2-carboxylate (2).
Attempted Preparation of 3-Fluoro-2-cyanothiophene (6)24
3-Chloro-2-cyanothiophene (5; 2.15 g, 0.015 mol) was dissolved in
3-Fluorothiophene-2-carboxylic acid (4) was obtained in
84% yield by the hydrolysis of 2 using sodium hydroxide. DMSO (40 mL), and CsF (4.0 g, 0.026 mol) was added to the solu-
tion. The mixture was refluxed for 24 h. After cooling, the mixture
was diluted with CH2Cl2 (100 mL). About 1 g of charcoal was add-
The decarboxylation of 4 was carried out in a fashion sim-
ilar to another reported substituted thiophenecarboxylic
ed to the mixture and then the mixture was stirred for 20 min and
acid decarboxylation25 using barium-promoted copper
filtered. The solution was washed with H2O (4 × 20 mL), and aq sat.
chromite in quinoline. Finally, 3-fluorothiophene (1) was
obtained in 93% yield by direct distillation from the reac-
NaHCO3 (2 × 20 mL), and dried (MgSO4). The solvent was re-
Figure 1 1H NMR spectrum of 1; * indicates spinning side bands
Synthesis 2008, No. 15, 2333–2336 © Thieme Stuttgart · New York

PAPER
Improved Synthesis of 3-Fluorothiophene
2335
moved with a rotary evaporator to produce white crystals (0.7 g).
TLC showed this to be a mixture of many compounds.
[Lit.24 13C NMR (CDCl3): d = 158.5 (d, J = 257.5 Hz), 124.8 (d,
J = 9.2 Hz), 117.3 (d, J = 26.9 Hz), 103.2 (d, J = 21.1 Hz)].
19F NMR (CDCl3/CFCl3): d = –119.01 (d, J = 4.6 Hz), –119.03 (d,
J = 4.6 Hz).
19F NMR (CDCl3/CFCl3): d = –131.0 (d, J = 2.3 Hz) [Lit.24 19F
NMR (CDCl3/CFCl3): d = –131.0 (d, J = 3.2 Hz)].
Methyl 3-Fluorothiophene-2-carboxylate (2)20
Acknowledgment
A mixture of 2-methoxycarbonylthiophene-3-diazonium tetrafluo-
roborate (3;19 15.4 g, 0.060 mol) and sand (80 g) in a round-bot-
tomed flask was attached to a distilling head connected to another
round-bottomed flask and a Dewar type condenser cooled with liq-
uid N2. The mixture was heated and when the temperature reached
160 °C (oil-bath temperature) under vacuum (0.1 Torr), the product
3 sublimed and was trapped on the inner surface of the condenser;
then at ca. 200 °C a pale yellow liquid distilled and solidified in the
round-bottomed flask. The products inside the condenser and the
round-bottomed flask were combined and this was washed repeat-
edly with MeOH until it all dissolved. The product 2 was collected
as a pale yellow solid upon the addition of H2O (15 mL). The prod-
uct was filtered and air dried to give 6.4 g (67%) of 2; mp 48–50 °C
(Lit.20 mp 51–53 °C).
1H NMR (CDCl3): d = 7.42 (dd, J = 5.5 Hz, JH,F = 3.8 Hz, 1 H), 6.86
(d, J = 5.5 Hz, 1 H), 3.89 (s, 3 H) [Lit.20 1H NMR (CDCl3): d = 7.42
(dd, J = 5.5, 3.8 Hz, 1 H), 6.85 (dd, J = 5.5, 0.5 Hz, 1 H), 3.89 (s, 3
H)].
13C NMR (CDCl3): d = 160.9 (d, JC,F = 3.8 Hz), 160.2 (d,
1JC,F = 276.4 Hz) 130.1 (d, JC,F = 10.5 Hz), 118.5 (d, JC,F = 24.9
Hz), 112.5 (d, JC,F = 10.1 Hz), 51.9 (s) [Lit.20 13C NMR (CDCl3):
d = 161.8 (C-3), 130.0 (C=O), 129.9 (C-5), 118.5 (C-4), 118.1 (C-
2), 51.9 (OCH3)].
The authors would like to thank Hai Minh Le and Linh M. Ly for
their valuable help and the Robert A. Welch Foundation (Grant Y-
1407) for financial support.
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1
0.80 g (93%). Based on integration of the vertically expanded H
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6.85 (ddd, J = 5.5, 2.4, 1.1 Hz, 1 H), 6.70 (ddd, J = 3.4, 2.4, 1.1 Hz,
1 H)].
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1
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Synthesis 2008, No. 15, 2333–2336 © Thieme Stuttgart · New York