Electrosynthesis of fluorinated benzo[ b ]thiophene derivatives

Article abstract of DOI:10.1055/s-0030-1260549

Anodic fluorination of benzo[b]thiophene derivatives provided a complex mixture of di- and trifluorinated products. On the other hand, anodic fluorination of 3-oxo-2,3-dihydrobenzo[b]thiophene and methyl 3-oxo-2,3-dihydrobenzo[b]thiophene-2-carboxylate gave the corresponding monofluorinated products selectively in moderate yields. Anodic fluorination of methyl α-(2-cyanophenylthio)acetate followed by intramolecular cyclization provided 3-amino-2-fluorobenzo[b]thiophene in excellent yield. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260549

LETTER
1313
Electrosynthesis of Fluorinated Benzo[b]thiophene Derivatives
Electrosynthesis
of
Fluo
n
rinated Benzo[
b
]th
Y
iophenes in, Shinsuke Inagi, Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
Fax +81(45)9245406; E-mail: fuchi@echem.titech.ac.jp
Received 25 February 2011
electrochemical fluorination of benzo[b]thiophenes has
not been reported so far.
Abstract: Anodic fluorination of benzo[b]thiophene derivatives
provided a complex mixture of di- and trifluorinated products. On
the other hand, anodic fluorination of 3-oxo-2,3-dihydroben-
zo[b]thiophene and methyl 3-oxo-2,3-dihydrobenzo[b]thiophene-
2-carboxylate gave the corresponding monofluorinated products
selectively in moderate yields. Anodic fluorination of methyl a-(2-
cyanophenylthio)acetate followed by intramolecular cyclization
provided 3-amino-2-fluorobenzo[b]thiophene in excellent yield.
With these facts in mind, we studied anodic fluorination
of 2-, or 3-substituted benzo[b]thiophene derivatives 1
and benzo[b]thiophene-3(2H)-one derivatives. In addi-
tion, we also investigated an efficient synthesis of fluori-
nated benzo[b]thiophene through anodic fluorination of
open-chain sulfide as a key step followed by base-cata-
lyzed cyclization.
Key words: fluorine, heterocycles, cyclization, sulfur, electron
transfer
Anodic fluorination of 1 was carried out under various
electrolysis conditions. The reaction became very compli-
cated although several fluorinated products were detected
by 19F NMR and GC–MS as shown in Scheme 1. Since
the products are cis and trans mixtures, their separation
was attempted. Unfortunately, the separation of these
compounds failed. Therefore, their exact structures could
not be determined. This result suggested that the product
selectivity of anodic fluorination of benzo[b]thiophene
derivatives was much lower compared to that of the ben-
zofuran and indole derivatives.
Sulfur-containing heterocyclic compounds have been
used for intensive research in pharmaceutical chemistry.
Nowadays, the benzo[b]thiophene moiety has been found
to be an important core structure in biologically active sul-
fur-containing heterocycles. Its derivatives in combina-
tion with other ring systems have been extensively applied
to pharmaceuticals due to their wide spectrum of pharma-
cological properties such as serotonin N-acetyltransferase
inhibitor,1a antiallergic,1b and ocular hypotensive activi-
ties.1c
In the previous work, we had successfully carried out the
regioselective monofluorination of various sulfides bear-
ing electron-withdrawing substituents at the a-position of
sulfur atom by the anodic oxidation in Et3N-3HF–MeCN
using an undivided cell.5 Therefore, we prepared ben-
zo[b]thiophene-3(2H)-one (5)6 and carried out its anodic
fluorination as shown in Scheme 2.
Fluorinated heterocyclic compounds are one of current
topics in organofluorine chemistry since introduction of
fluorine(s) into a heterocyclic ring greatly enhances and/
or dramatically changes biological activities.2 We have
developed electrochemical partial fluorination of organic
compounds as a straightforward method. For example, we
found that 3-substituted benzofuran derivatives were an-
odically fluorinated to give cis-2,3-difluoro adducts main-
ly in good yield.3 However, in the case of anodic
fluorination of N-acetyl 3-subsitituted indole derivatives
under the same electrolysis conditions, the corresponding
trans-2,3-difluoro-2,3-dihydroindoles were obtained ex-
clusively or selectively.4 To our knowledge, selective
O
O
– 2 e, – H+
F
constant current
Et3N-5HF, DME
2 F/mol
S
S
5
6 (30%)
Scheme 2
X
F
F
O
X
X
– n e
Y
+
F
Y
F
Y
F
Y
+
Et4NF-nHF
S
S
S
S
MeCN or DME
F
(n = 4, 5)
1a–d
2a–d
3a–d
4b,d
a: X = Ac, Y = H
b: X = H, Y = Ac
c: X = COOMe, Y = H
d: X = H, Y = COOMe
Scheme 1
SYNLETT 2011, No. 9, pp 1313–1317
x
x.
x
x.
2
0
1
1
Advanced online publication: 05.05.2011
DOI: 10.1055/s-0030-1260549; Art ID: U02011ST
© Georg Thieme Verlag Stuttgart · New York

1314
B. Yin et al.
LETTER
responding a-fluorinated product devoid of the acetyl
group as shown in Scheme 4. However, in the anodic
fluorination of 7, C–CO bond cleavage did not take place
at all.
F
S
COOEt
32%
COMe
COOEt
– 2 e
F–
+
F
S
COMe
S
COOEt
16%
Figure 1 Keto-enol tautomerization of 7 and graphical diagrams of
HOMO of 7 and 7¢
Scheme 4
It was found that the corresponding monofluorinated
product 6 was obtained selectively in 30% yield using
Et3N-5HF–dimethoxyethane (DME) as an electrolytic
solution. The starting material was mostly consumed at
theoretical amount of electricity (2F/mol). The instability
of product 6 through purification process resulted in low
yield. Moreover, rather high oxidation potentials of 5
(Epox = 2.31 V vs. SCE) and 6 prevented the formation of
the difluorinated product.
Since anodic fluorination of benzo[b]thiophenes 1 result-
ed in low yields and low selectivity of fluorinated prod-
ucts,
we
attempted
to
prepare
fluorinated
benzo[b]thiophenes through intramolecular cyclization of
anodically fluorinated sulfides.9 Previously, we demon-
strated the synthetic utility of anodically fluorinated het-
erocyclic sulfides to obtain the corresponding cyclized
products in good to moderate yields.10 Taking these re-
sults into consideration, we prepared various substituted
phenyl sulfides.7b,11
Next, we investigated the anodic fluorination of methyl 3-
oxo-2,3-dihydrobenzo[b]thiophene-2-carboxylate (7),7 in
which an ester group was introduced at the a-position of
sulfur atom. The oxidation potential of 7 was measured by
cyclic voltammetry in 0.1 M n-BuN4BF4–MeCN. It was
found that the oxidation potential of 7 (Epox = 1.46 V vs.
SCE) was significantly lower than that of compound 5
that was devoid of the ester group. This may suggest that
the acidity of the a-proton is increased by the introduction
of the electron-withdrawing ester group, which leads to
the formation of the corresponding enol form 7¢ as a major
tautomer and showing much lower oxidation potential. In
order to confirm this assumption, calculation of HOMO
energies of 7 and 7¢ were carried out by DFT B3LYP 6-
311G+(2d, p)//B3LYP 6-31G (d) using a Gaussian 03
program (Figure 1).8 The HOMO energy of enol form 7¢
was significantly higher than that of keto form 7, which is
in good agreement with the CV result.
Anodic fluorination of sulfides 8 was investigated at a
constant current in DME containing various fluoride salts
as a supporting electrolyte and fluorine source using an
undivided cell, and the results are summarized in Table 1.
Initially, anodic fluorination of sulfide 8a was performed
using various fluoride salts. When Et3N-3HF was used,
the corresponding monofluorinated sulfide 9a was formed
in 52% yield after passing 4 F/mol of electricity (entry 1).
However, when Et3N-4HF was used, starting material 8a
was completely consumed at 2 F/mol of electricity and the
desired monofluorinated 9a was obtained in 67% yield
(entry 2). On the other hand, Et3N-5HF, Et4NF-4HF, and
Et4NF-5HF were less effective compared to Et3N-4HF.
According to the results, the anodic fluorination of 8b was
similarly carried out using Et3N-3HF and Et3N-4HF as
fluorine source (entries 3 and 4). However, fluorination
did not take place under these conditions although starting
material 8b was consumed. In these cases, bis(2-methoxy-
carbonylphenyl) disulfide12 was detected as a by-product
which was determined by 1H NMR and GC–MS.
Then, anodic fluorination of 7 was carried out using Et3N-
5HF as a supporting electrolyte and fluorine source in
DME (Scheme 3). The corresponding fluorinated product
4d was obtained in 61% yield.
In our previous work, anodic fluorination of 2-(3-cyan-
opyridyl)sulfides having electron-withdrawing groups at
the a-position of the sulfur atom was achieved at a con-
stant potential using Et3N-3HF to give the corresponding
monofluorinated products in moderate yields.10 There-
fore, anodic fluorination of methyl a-(2-cyanophenyl-
thio)acetate (8c) was carried out in the presence of Et3N-
3HF. The corresponding fluorinated product 9c was ob-
tained in 61% yield by a passage of a large excess amount
of electricity (10 F/mol; entry 5). The anodic oxidation of
8c, having relatively high oxidation potential (Epox = 2.03
O
O
– 2 e, – H+
COOMe
F
COOMe
Et3N-5HF, DME
2 F/mol
S
S
4d
61%
7
Scheme 3
Previously, we carried out anodic fluorination of ethyl a-
(phenylthio)acetoacetate.5 In this case, elimination of an
acetyl group was accompanied mainly to provide the cor-
Synlett 2011, No. 9, 1313–1317 © Thieme Stuttgart · New York

LETTER
Electrosynthesis of Fluorinated Benzo[b]thiophenes
1315
Table 1 Anodic Fluorination of Sulfide 9 in DME
X
X
– 2 e, – H+
F
F–, DME
S
Y
S
Y
8
9
ox
Entry
Substrate
X
Y
Ep
Supporting
electrolyte
Charge passed Product
(F/mol)
Yield (%)b
(V vs. SCE)a
1
2
3
4
5
6
7
8
8a
8a
8b
8b
8c
8c
8c
8d
COOMe
COOMe
COOMe
COOMe
CN
COOMe
COOMe
Ph
1.78
Et3N-3HF
Et3N-4HF
Et3N-3HF
Et3N-4HF
Et3N-3HF
Et3N-4HF
Et3N-5HF
Et3N-3HF
4
9a
9a
9b
9b
9c
9c
9c
9d
52
1.78
2
67 (55)
0c
1.71
4
Ph
1.71
2
0c
COOMe
COOMe
COOMe
Ph
2.03
10
2
61
CN
2.03
68 (60)
67
CN
2.03
2
CN
1.91
4
75
a Measured in 0.1 M Bu4NBF4–MeCN using Pt disk electrode at a scan rate of 100 mV/s.
b Determined by 19F NMR. Isolated yields are shown in parentheses.
c Bis(2-methoxycarbonylphenyl) disulfide was detected by 1H NMR and GC–MS.
V vs. SCE), involved the simultaneous oxidation of free
Et3N included in Et3N-3HF.
X
X
– e
•
Next, anodic fluorination of 8c was carried out using other
S
Ph
S
H
Ph
fluoride salts like Et3N-4HF and Et3N-5HF. The electrol-
ysis with Et3N-4HF and Et3N-5HF at theoretical amount
of electricity (2 F/mol) gave the corresponding monoflu-
orinated product 9c in ca. 70% yields (entries 6 and 7).
These fluoride salts having higher HF content are much
more anodically stable compared to Et3N-3HF because
they do not contain free Et3N. Therefore, starting substrate
8c was readily oxidized prior to fluoride salts and com-
pletely consumed when theoretical amount of electricity
(2 F/mol) was passed.
A
8b: X = COOMe
8d: X = CN
+
– PhCH2
– H+, – e
COOMe
CN
S
CN
S
S
F–
F
MeOOC
Ph
S
Ph
9d
Scheme 5
Anodic fluorination of 2-(benzylthio)benzonitrile (8d)
was also performed similarly in Et3N-3HF/DME (entry
8). Due to the lower oxidation potential of 8d (Epox = 1.91
V vs. SCE) than that of 8c, the highest yield (75%) of flu-
orinated product 9d was obtained at 4 F/mol of electricity
even when anodically unstable Et3N-3HF was used. This
result is in sharp contrast to the case of 8b, which provided
no a-fluorinated product. This can be explained in terms
of the difference of acidities13 of a-proton of anodically
formed radical cation of 8b and 8d as shown in Scheme 5.
Namely, stronger electron-withdrawing cyano group
greatly promotes the deprotonation of radical cation inter-
mediate A while less strong electron-withdrawing ester
group does not. The generation of stable benzyl cation
also seems to promote C–S bond cleavage. Consequently,
in the case of 8b, C–S bond cleavage takes place prior to
the deprotonation.
substrate 9a with potassium carbonate in MeCN or MeOH
at ambient temperature; however, the expected cyclized
product 4d was not formed. In this case, unreacted 9a was
mostly recovered. On the other hand, cyclization of 9c in
acetonitrile under the similar reaction conditions provided
the corresponding fluorinated imino product 10c in low
yield (6%), and 77% of starting substrate 9c was recov-
ered. However, cyclization of fluorinated 9c was success-
fully carried out in methanol to give the fused 3-amino-2-
fluoro-benzo[b]thiophene (11c) in excellent yield.
A plausible cyclization mechanism is shown in Scheme 7.
The elimination of a proton at the a-position of the ester
group takes place in the presence of a base, and the result-
ing anion attacks the carbon atom of the cyano group to
form intermediate 10c having an imino group. Immediate
addition of methanol to the imino group forms another in-
termediate 10c¢ followed by elimination of dimethyl car-
bonate to provide the corresponding fluorinated
benzo[b]thiophene product 11c.
In order to obtain fluorinated benzo[b]thiophenes, in-
tramolecular cyclization of fluorinated products 9a and 9c
was attempted as shown in Scheme 6. First, we treated the
Synlett 2011, No. 9, 1313–1317 © Thieme Stuttgart · New York

1316
B. Yin et al.
LETTER
O
COOMe
F
K2CO3
COOMe
F
MeCN or MeOH
S
S
COOMe
9a
4d
NH
NH2
CN
K2CO3, MeCN
r.t., 5 h
K2CO3, MeOH
r.t., 3 h
COOMe
F
F
F
S
S
S
COOMe
10c
6%
9c
11c
93%
Scheme 6
(6) Oh, K.; Kim, H.; Cardelli, F.; Bwititi, T.; Martynow, A. M.
J. Org. Chem. 2008, 73, 2432.
NH
CN
(7) (a) Nobumasa, K.; Chie, K.; Michio, K. Sulfur Lett. 1986, 4,
101. (b) Cabiddu, M. G.; Cabiddu, S.; Cadoni, E.; Demontis,
S.; Fattuoni, C.; Melis, S. Tetrahedron 2002, 58, 4529.
(8) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Version C.01; Gaussian Inc.: Wallingford (CT), 2004.
(9) (a) Xie, H.; Ng, D.; Savinov, S. N.; Dey, B.; Kwong, P. D.;
Wyatt, R.; Smith, A. B.; Hendrickson, W. A. J. Med. Chem.
2007, 50, 4898. (b) Zlotin, S. G.; Kislitsin, P. G.; Kucherov,
F. A.; Gakh, A. A. Heterocycles 2006, 68, 1109.
base
COOMe
F
MeOH
F
S
S
COOMe
9c
10c
NH2
MeO
NH2
– MeOCO2Me
COOMe
F
F
S
S
10c'
11c
Scheme 7
In conclusion, anodic fluorination of benzo[b]thiophene-
3(2H)-one was achieved in Et3N-5HF–DME while direct
anodic fluorination of substituted benzo[b]thiophene de-
rivatives provided a mixture of di- and trifluorinated prod-
ucts.14 On the other hand, fluorinated benzo[b]thiophene
derivative was successfully prepared by the intramolecu-
lar cyclization of anodically fluorinated open-chain sul-
fide having a 2-cyanophenyl group as a key step.
References and Notes
(1) (a) Mesangeau, C.; Yous, S.; Chavatte, P.; Ferry, G.;
Audinot, V.; Boutin, J. A.; Delagrange, P.; Bennejean, C.;
Renard, P.; Lesieur, D. J. Enz. Inhib. Med. Chem. 2003, 18,
119. (b) Connor, D. T.; Cetenko, W. A.; Mullican, M. D.;
Sorenson, R. J.; Unangst, P. C.; Weikert, R. J.; Adolphson,
R. L.; Kennedy, J. A.; Thueson, D. O.; Wright, C. D.;
Conroy, M. C. J. Med. Chem. 1992, 35, 958. (c) Graham,
S. L.; Shepard, K. L.; Anderson, P. S.; Baldwin, J. J.; Best,
D. B.; Christy, M. E.; Freedman, M. B.; Gautheron, P.;
Habecker, C. N. J. Med. Chem. 1989, 32, 2548.
(2) (a) Fluorinated Heterocyclic Compounds: Synthesis,
Chemistry and Applications; Petrov, V. A., Ed.; Wiley:
Hoboken, 2009. (b) Buscemi, S.; Pace, A.; Piccionello,
A. P.; Pibiri, I.; Vivona, N. Heterocycles 2005, 65, 387.
(c) Buscemi, S.; Pace, A.; Piccionello, A. P.; Macaluso, G.;
Vivona, N. J. Org. Chem. 2005, 70, 3288. (d) Pace, A.;
Pibiri, I.; Buscemi, S.; Vivona, N. Heterocycles 2004, 63,
2627.
(10) Erian, A. W.; Konno, A.; Fuchigami, T. J. Org. Chem. 1995,
60, 7654.
(11) (a) Cabiddu, M.; Cabiddu, S.; Cadoni, E.; Demontis, S.;
Fattuoni, C.; Melis, S. Tetrahedron 2002, 58, 4529.
(b) Naso, F.; Capozzi, M. A. M.; Bottoni, A.; Calvaresi, M.;
Bertolasi, V.; Capitelli, F.; Cardellicchio, C. Chem. Eur. J.
2009, 15, 13417. (c) Zarghi, A.; Faizi, M.; Shafaghi, B.;
Ahadian, A.; Khojastehpoor, H. R.; Zanganeh, V.;
Tabatabai, S. A.; Shafiee, A. Bioorg. Med. Chem. Lett. 2005,
15, 3126. (d) Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.;
Cara, C. L.; Preti, D.; Fruttarolo, F.; Pavani, M. G.; Tabrizi,
M. A.; Tolomeo, M.; Grimaudo, S.; Cristina, A. D.;
Balzarina, J.; Hadfield, J. A.; Brancale, A.; Hamel, E.
J. Med. Chem. 2007, 50, 2273.
(12) Shimizu, M.; Kikumoto, H.; Konakahara, T.; Gama, Y.;
Shibuya, I. Heterocycles 1999, 51, 300.
(13) (a) Yoon, V. C.; Mariano, P. S. Acc. Chem. Rec. 1992, 25,
233. (b) Fuchigami, T.; Ichikawa, S. J. Org. Chem. 1994, 59,
607.
(14) In the following spectral data of novel compounds, the
chemical shifts for 19F NMR spectra are given in d (ppm)
with monofluorobenzene (C6H5F, d = –36.5 ppm) as an
internal standard.
(3) Dawood, K. M.; Fuchigami, T. J. Org. Chem. 2004, 69,
5302.
(4) Yin, B.; Inagi, S.; Fuchigami, T. Tetrahedron 2010, 66,
6820.
(5) Fuchigami, T.; Shimojo, M.; Konno, A. J. Org. Chem. 1995,
60, 3459.
Synlett 2011, No. 9, 1313–1317 © Thieme Stuttgart · New York

LETTER
General Procedure for Anodic Fluorination of
Electrosynthesis of Fluorinated Benzo[b]thiophenes
1317
Methyl a-Fluoro-a-(2-cyanophenylthio)acetate (9c):
colorless oil. 1H NMR (270 MHz, CDCl3): d = 3.78 (s, 3 H),
6.13 (d, 1 H, J = 50.5 Hz), 7.53 (td, 1 H, J = 7.6, 1.4 Hz), 7.62
(td, 1 H, J = 7.8, 1.6 Hz), 7.76 (t, 1 H, J = 8.1 Hz), 7.76 (td,
1 H, J = 7.8, 0.3 Hz). 19F NMR (254 MHz, CDCl3): d =
–83.84 (d, 1 F, J = 50.5 Hz). 13C NMR (68 MHz, CDCl3): d
= 53.24, 92.37 (d, J = 233.7 Hz), 116.55, 118.16 (d, J = 2.2
Hz), 130.06, 132.39 (d, J = 1.7 Hz), 133.12, 133.89, 136.23
(d, J = 1.2 Hz), 164.90 (d, J = 30.1 Hz). MS: m/z = 225 [M+],
207, 193, 166, 146, 134, 117, 102, 90, 75. HRMS (ESI):
m/z [M + Na+] calcd for C10H8FNO2SNa: 248.0157; found:
248.0157.
Substrates 1, 5, 7, and 8: Electrolysis was conducted with
platinum anode and cathode (1 × 1 cm2) in 0.3 M HF salt/
solvent (2 mL) containing 0.1 mmol substrate using an
undivided cell at ambient temperature.15 After the substrate
was completely consumed (monitored by TLC), the
electrolytic solution was passed through a short column
filled with silica gel using EtOAc as an eluent. After removal
of the solvent, the residue was purified via column
chromatography on silica gel using hexane–EtOAc as an
eluent.
2-Acetyl-2-fluorobenzo[b]thiophen-3(2H)-one (4b):
19F NMR (254 MHz, CDCl3) d = –72.60 (s, 1 F). MS: m/z =
210 [M+], 191 [M+ – F], 167 [M+ – Ac].
a-Fluoro-a-(benzylthio)benzonitrile (9d): Due to its
instability, this compound could not be purified by column
chromatography on silica gel. Only characteristic methyne
proton signal on 1H NMR is shown as follows.
Methyl 2-Fluoro-3-oxo-2,3-dihydrobenzo[b]thiophene-
2-carboxylate (4d): pale yellow solid; mp 85–86 °C. 1H
NMR (270 MHz, CDCl3): d = 3.86 (s, 3 H), 7.33 (td, 1 H,
J = 7.4, 0.8 Hz), 7.39 (d, 1 H, J = 8.1 Hz), 7.66 (td, 1 H, J =
7.7, 1.4 Hz), 7.84 (ddd, 1 H, J = 8.1, 1.1, 0.5 Hz). 19F NMR
(254 MHz, CDCl3): d = –72.10 (s, 1 F). 13C NMR (68 MHz,
CDCl3): d = 53.83 (d, J = 1.1 Hz), 98.19 (d, J = 239.7 Hz),
124.36 (d, J = 2.2 Hz), 126.29, 126.57, 128.41, 137.59,
148.81, 165.37 (d, J = 32.9 Hz), 191.55 (d, J = 16.1 Hz). MS:
m/z = 226 [M+], 167 [M+ – COOMe], 139 [M+ – COOMe –
CO], 76, 59. HRMS (ESI): m/z [M + Na+] calcd for
C10H7FO3SNa: 248.9998; found: 248.9999.
1H NMR (270 MHz, CDCl3): d = 6.89 (d, 1 H, J = 54.8 Hz).
19F NMR (254 MHz, CDCl3) d = –70.18 (d, 1 F, J = 54.8 Hz).
MS: m/z = 243 [M+], 223, 134, 109. HRMS (ESI): m/z [M +
Na+] calcd for C14H10FNSNa: 266.0416; found: 266.0409.
General Procedure for Intramolecular Cyclization of
Anodically Fluorinated Product 9: A solution of 9 (0.1
mmol) in MeCN or MeOH (5 mL) containing potassium
carbonate (0.15 mmol, 1.5 equiv) was stirred at r.t. for 5 h or
3 h. After filtration of insoluble material, the filtrate was
concentrated under reduced pressure to give the imino
product 10 or the amino product 11.
2-Fluorobenzo[b]thiophen-3(2H)-one (6): Due to its
instability, this compound could not be purified by column
chromatography on silica gel. Only characteristic methyne
proton signal on 1H NMR is shown as follows.
Methyl 2-Fluoro-3-imino-2,3-dihydrobenzo[b]-
thiophene-2-carboxylate (10c): 19F NMR (254 MHz,
CDCl3): d = –72.08 (s, 1 F). MS: m/z = 225 [M+], 206 [M+ –
F], 166 [M+ – COOMe], 147.
1H NMR (270 MHz, CDCl3): d = 6.79 (d, 1 H, J = 49.9 Hz).
19F NMR (254 MHz, CDCl3): d = –91.47 (d, 1 F, J = 49.9
Hz). MS: m/z = 168 [M+].
3-Amino-2-fluorobenzo[b]thiophene (11c): dark green
solid; mp 141–142 °C. IR (KBr): 3384, 3303 cm–1. 1H NMR
(270 MHz, CDCl3): d = 3.52 (br s, 2 H), 7.30 (td, 1 H, J =
7.8, 1.6 Hz), 7.37 (td, 1 H, J = 7.6, 1.4 Hz), 7.50 (ddd, 1 H,
J = 7.8, 1.4, 0.8 Hz), 7.61 (dd, 1 H, J = 7.3, 1.1 Hz). 19F NMR
(254 MHz, CDCl3): d = –75.55 (s, 1 F). 13C NMR (68 MHz,
CDCl3): d = 118.55 (d, J = 7.8 Hz), 119.54 (d, J = 6.7 Hz),
122.74 (d, J = 1.2 Hz), 124.34 (d, J = 4.5 Hz), 124.42, 128.85
(d, J = 2.8 Hz), 131.63 (d, J = 3.9 Hz), 144.33 (d, J = 278.3
Hz). MS: m/z = 168 [M + H]+, 167 [M+]. HRMS (ESI): m/z
[M + H+] calcd for C8H7FNS: 168.0283; found: 168.0274.
(15) Scale-up of the electrochemical reaction step may be
possible by using a larger setup or a flow cell.
Methyl 2-[(a-Fluoro)-a-(methoxycarbonyl)methylthio]-
benzoate (9a): colorless oil. 1H NMR (270 MHz, CDCl3):
d = 3.80 (s, 3 H), 3.93 (s, 3 H), 6.27 (d, 1 H, J = 53.5 Hz),
7.36 (td, 1 H, J = 7.6, 1.1 Hz), 7.52 (td, 1 H, J = 7.8, 1.6 Hz),
7.68 (dd, 1 H, J = 8.1, 1.1 Hz), 7.93 (dd, 1 H, J = 7.8, 1.4 Hz).
19F NMR (254 MHz, CDCl3): d = –82.82 (d, 1 F, J = 53.5
Hz). 13C NMR (68 MHz, CDCl3): d = 30.91, 52.44, 93.53 (d,
J = 230.3 Hz), 127.32, 130.23 (d, J = 2.2 Hz), 130.78 (d, J =
2.2 Hz), 130.91, 132.69, 134.76 (d, J = 3.4 Hz), 165.81 (d, J
= 28.4 Hz), 166.75. MS: m/z = 258 [M+], 238, 226, 199, 179,
167, 152, 137, 121, 108, 76, 63. HRMS (ESI): m/z [M + Na+]
calcd for C11H11FO4SNa: 281.0260; found: 281.0262.
Synlett 2011, No. 9, 1313–1317 © Thieme Stuttgart · New York