Synthesis of substituted 3-trifluoromethylbenzo[b]thiophenes

Article abstract of DOI:10.1016/S0040-4039(03)01811-2

A straightforward method for the synthesis of 5/6-substituted 3-trifluoromethylbenzo[b]thiophenes and their precursor o-fluorinated trifluoro acetophenones is reported.

Full text of DOI:10.1016/S0040-4039(03)01811-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7147–7149
Synthesis of substituted 3-trifluoromethylbenzo[b]thiophenes
W. M. Owton*
Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK
Received 5 June 2003; revised 11 July 2003; accepted 25 July 2003
Abstract—A straightforward method for the synthesis of 5/6-substituted 3-trifluoromethylbenzo[b]thiophenes and their precursor
o-fluorinated trifluoro acetophenones is reported.
© 2003 Elsevier Ltd. All rights reserved.
The trifluoromethyl group is a very valuable substituent
to include in any organic series owing to the unique
physical and biological properties it confers.1 Access
was recently required to 5- and 6-substituted-3-tri-
fluoromethyl benzo[b]thiophenes. A review of the litera-
lene with ethyl thioglycolate in acetonitrile (Scheme
1).
Ethyl thioglycolate has also been reported5 to displace
fluoride from 2-fluorobenzonitriles and the products
spontaneously cyclise to give high yields of ethyl 3-
aminobenzothiophene-2-carboxylates in triethylamine/
DMSO at 100°C.
ture
revealed
a
paucity
of
references
to
3-trifluoromethylbenzothiophenes. 3-Trifluoromethyl-
benzo[b]thiophene itself has been noted2 as a con-
stituent of the product mixture arising from the
reaction of benzothiophene with bis(trifluoroacetylper-
oxide) at 70°C in Freon 113. 7-Methyl-3-tri-
fluoromethylbenzo[b]thiophene has been prepared3 in
54% yield from 7-methyl-3-bromobenzo[b]thiophene by
reaction with sodium trifluoroacetate and copper(I)
iodide in N-methylpyrrolidine at 180°C. Neither of
these methods were thought appropriate to the project
needs. It was felt necessary therefore to devise a new,
scaleable route to 3-trifluoromethylbenzo[b]thiophenes
that could provide substituents in the 5 or 6 position
capable of further elaboration.
These references prompted the consideration of the
possibility of displacing fluorine from 2-fluoro-tri-
fluoroacetophenones with thioglycolate, and subsequent
ring closure and decarboxylation, as a route to the
desired 3-trifluoromethyl benzo[b]thiophene-2-carboxyl-
ates (Scheme 2). As benzo[b]thiophene-2-carboxylic
acids are known6 to undergo decarboxylation to ben-
zothiophenes, this four step sequence was considered a
viable possibility for the synthesis of 3-trifluoromethyl
benzo[b]thiophenes.
Thus 2-fluoro-2%,2%,2%-trifluoroacetophenone was reacted
with methylthio- glycolate in the presence of triethyl-
amine.7 Work-up and chromatography gave the
required methyl-3-trifluoromethylbenzo[b]thiophene-2-
carboxylate in 66% yield.
There is one example in the literature4 of the formation
of a 2-carboxyethyl-3-trifluoromethyl-naphtho[1,2-b]t-
hiophene by the displacement of dimethylamine from
1-N,N-dimethylamino-2,4-bis(trifluoroacetyl)naphtha-
Scheme 1.
Keywords: lithiation; trifluoromethylbenzothiophenes.
* Tel.: 44-1276-478-3521; fax: 44-1276-478-3525; e-mail: owton w m@lilly.com
–
–
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01811-2

7148
W. M. Owton / Tetrahedron Letters 44 (2003) 7147–7149
Scheme 2.
Table 1.
ones; this proved to be the case10 (Table 1). In the case
of 3-bromofluorobenzene, a survey of the literature8
shows that the first lithiation occurs in the 2-position;
to access the required 4-bromo-2-fluorotrifluoroaceto-
phenone it was necessary to block the 2 position with a
trimethylsilyl group and lithiate again using lithium
2,2,6,6-tetramethylpiperidide, before quenching with
ethyl trifluoroacetate and desilylating with Bu4NF (1N
in THF, rt for 12 h).
Starting material
Product
Yielda
R=4-Br
4-Cl
4-CN
3-Br
R=5-Br
5-Cl
5-CN
4-Br
65
40
63
With these materials in hand we proceeded with the
reaction with methyl thioglycolate. In the case of 5-
cyano-2-fluoro-2%,2%,2%-trifluoroacetophenone it was
found that reaction with methyl thioglycolate and tri-
ethylamine at room temperature in acetonitrile was
sufficient to produce the methyl 3-trifluoromethyl-5-
cyano benzo[b]thiophene-2-carboxylate (Table 2).
Hydrolysis of the methyl esters was accomplished in
near quantitative yield with lithium hydroxide in THF/
water (19:1) at room temperature. Decarboxylation was
accomplished in good yield with DBU in dimethyl-
acetamide at 200°C for one hour in a CEM MARS
microwave reactor.11,12 All new materials were charac-
41 (via trimethylsilyl)
a Reported yields (%) are for pure isolated products after chromato-
graphy.
With the demonstration of the utility of this route, we
set out to prepare a series of substituted 3-tri-
fluoromethylbenzo[b]thiophenes. However, the required
4- or 5-substituted-2-fluoro-2%,2%,2%-trifluoroacetophen-
ones are not commercially available or even reported;
we therefore had to consider their synthesis.
1
terised by H NMR and accurate mass measurement.13
Fluorine has been reported8 to be an effective ortho-
directing group in aromatic metalation in the presence
of a number of other aromatic substituents. Quenching
of a lithio species generated by such o-directed metala-
tion with ethyl trifluoroacetate9 should give entry to the
required 4- or 5-substituted 2-fluoro trifluoroacetophen-
In conclusion the chemistry described provides a
straightforward route via o-fluorinated trifluoroaceto-
phenones to previously inaccessible 3-trifluoromethyl
benz[b]thiophenes ring substituted with substituents
capable of further synthetic elaboration.
Table 2.
Starting material
Benzo[b]thiophene estera
Benzo[b]thiophenea
R=H
5-Br
5-Cl
5-CN
4-Br
66
70
54
49
76
75
65
62
78
78
a Reported yields (%) are for pure isolated products after chromatography.

W. M. Owton / Tetrahedron Letters 44 (2003) 7147–7149
7149
Acknowledgements
Schwartz, C. E. Tetrahedron Lett. 1992, 33, 7495 and 7499.
9. Morita, C.; Hashimoto, K.; Okuno, T.; Shirahama, H.
Heterocycles 2000, 52, 1163.
The assistance of Mr. F. Cordier with the microwave
decarboxylation is gratefully acknowledged.
10. Experimental conditions (as Ref. 5): lithium diisopropyl-
amide (1.1 equiv.) in dry THF was stirred under nitrogen
and cooled to −75°C. 4-Bromofluorobenzene (1 equiv.) in
dry THF was added slowly, keeping the temperature below
−70°C. The reaction mixture was stirred for 1 h and ethyl
trifluoroacetate (1.1 equiv.) was added over 5 min keeping
the temperature below −70°C. The reaction was allowed to
warm to room temperature overnight and was quenched
by addition of saturated aqueous NH4Cl soln. Ethyl
acetate was added and the organic phase was collected,
dried (MgSO4), filtered and concentrated under reduced
pressure. The crude product was passed through a pad of
silica (eluent: hexane/ethyl acetate, 4:1) to give 2-fluoro-5-
chloro-2%2%2%-trifluoroacetophenone in 40% yield.
References
1. Filler, R.; Kobayashi, Y.; Yagupoyashi, L. M.
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Application; Elsevier Science: Amsterdam,
1993.
2. Sawada, H.; Nakayama, M.; Yoshida, M.; Yoshida, T.;
Kamigata, N. J. Fluorine Chem. 1990, 46, 423.
3. Nussbaumer, P.; Petranyi, G.; Stutz, A. J. Med. Chem.
1991, 34, 65.
4. Okada, E.; Masuda, R.; Hojo, M.; Imazaki, N.; Miya, H.
Heterocycles 1992, 43, 103.
11. A mixture of 3-trifluoromethylbenzothiophene-2-car-
boxylic acid (3.12 g, 12.7 mmol) and diazobicycloundecane
(8 g, 52.5 mmol) in dimethylacetamide (20 ml) was heated
in a sealed vessel in a microwave reactor (300 W, 100%)
for 1 h. After cooling to room temperature the mixture was
poured into 1N HCl(aq) and extracted into ethyl acetate.
The organic phase was collected, dried (MgSO4), filtered
and concentrated under reduced pressure. The crude
product was passed through a pad of silica (eluent:
hexane/ethyl acetate, 19:1) to give 3-trifluoromethylbenzo-
thiophene (1.92 g, 9.5 mmol) in 75% yield.
5. Bridges, A. J.; Zhou, H. J. Heterocycl. Chem. 1997, 34,
1163.
6. Zambias, R. A.; Hammond, M. L. Synth. Commun. 1991,
21, 959.
7. Methylthioglycolate (1.1 equiv.) and triethylamine (1.3
equiv.) were dissolved in acetonitrile and stirred under
nitrogen at room temperature. 2-Fluoro-2%,2%,2%-trifluoro
acetophenone (Rieke chemicals) (1 equiv.) was added and
the reaction mixture was heated under reflux for 18 h. The
solvent was removed under reduced pressure and the
residue was partitioned between ethyl acetate and dilute
aqueous NaOH. The organic phase was dried (MgSO4),
filtered and concentrated under reduced pressure. The oily
residue was passed through a pad of silica (eluent: hexane/
ethyl acetate 5:1) to give methyl-3-trifl-uoromethylbenzo-
thiophene-2-carboxylate as a yellow oil (66% yield).
8. Bridges, A. J.; Hammond, A. L.; Maduakor, E. C.;
12. CEM (Microwave Technology) Ltd, website: http://
www.cemsynthesis.com
13. e.g. 3-Trifluoromethyl-6-bromobenzo[b]thiophene. 1H
NMR (CDCl3, 300 MHz) l: 8.0 (1H, d, J=1.5 Hz), 7.88
(1H, s), 7.79 (1H, d, J=8.3 Hz), 7.58 (1H, dd, J=8.7, 1.9
Hz). MS: C9H4F3BrS requires 279.9169, found 279.9160.