Aromatic ring-opening of 2-fluorobenzothiophenes by alkyllithiums

Article abstract of DOI:10.1055/s-2004-837230

Diphenylacetylenes are obtained when alkyllithium reagents are added to 3-aryl-2-fluorobenzothiophenes at low temperature. The aromatic ring-opening mechanism involves a nucleophilic addition of the alkyllithium to the sulfur atom of the thiophene. The re

Full text of DOI:10.1055/s-2004-837230

LETTER
247
Aromatic Ring-Opening of 2-Fluorobenzothiophenes by Alkyllithiums
A
romatic Ring-Openin
i
g
of 2-
c
Fluorobenz
h
othiophenes
e
by Alkyllit
l
hiums Belley,* Zohra Douida, John Mancuso, Marc De Vleeschauwer
Merck Frosst Center for Therapeutic Research, P. O. Box 1005, Pointe Claire-Dorval, Québec, H9R 4P8, Canada
Fax +1(514)4284900; E-mail: belley@merck.com
Received 1 October 2004
Abstract: Diphenylacetylenes are obtained when alkyllithium
reagents are added to 3-aryl-2-fluorobenzothiophenes at low tem-
perature. The aromatic ring-opening mechanism involves a nucleo-
philic addition of the alkyllithium to the sulfur atom of the
thiophene. The resulting 2,2-diaryl-1-fluorovinyl anion subsequent-
ly undergoes a Fritsch–Buttenburg–Wiechell rearrangement to
afford the diphenylacetylene.
Equation 2
Key words: ring-opening, Fritsch–Buttenberg–Wiechell rear-
rangements, benzothiophenes, alkyllithium reagents, addition to
sulfur
Thiophenes usually react with organolithium reagents to
yield 2-lithiothiophenes, which are quite stable and can
react with various electrophiles. However, 3-lithio-
thiophenes are obtained from deprotonation of a 2,5-di-
substituted thiophene (with BuLi or LDA) or by halogen-
metal exchange between 3-bromothiophenes and BuLi.
3-Lithiothiophenes are generally stable at –78 °C, where
they can react with electrophiles, but they rearrange to
acetylenic thiolates 1 at 0 °C (Equation 1).1
Equation 3
We initially prepared 2-(trifluoromethyl)-3-phenylben-
zothiophene (6, Figure 1),4 but this substrate was inert to-
ward butyllithium. We then discovered that the fluoro
analog 2-fluoro-3-phenylbenzothiophene (7a) reacted
with butyllithium to yield 1-(butylthio)-2-(phenylethy-
nyl)benzene 5a5 (Table 1).
Diphenylacetylene 5a has been synthesized previously
from two closely related reactions. It was obtained first
from the reaction of BuLi with 3-bromo-2-phenyl-
benzothiophene, via the rearrangement of a 3-lithio-
benzothiophene intermediate to an acetylenic
thiophenolate (as in Equation 1), and its subsequent reac-
tion with the butyl bromide generated in situ.1a The acetyl-
ene 5a was also obtained via a nucleophilic attack with
BuLi onto the sulfur atom of 3-chloro-2-phenyl-
benzothiophene 4 at –78 °C (Equation 3).2 However, the
formation of 5a from 2-fluorobenzothiophene 7a cannot
be explained using the mechanisms operating in these two
processes.
Equation 1
We have recently discovered that organolithium reagents
can also undergo nucleophilic addition onto the sulfur
atom of some thiophenes, which lead to their cleavage at
low temperature.2 Two examples of this unexpected reac-
tion are given in Equation 2 and Equation 3. In general,
these nucleophilic additions are only observed with chlo-
rothiophenes fused to another aromatic ring, with only
one known exception: addition of butyl- or phenyllithium
to 3,4-dichloro-2,5-dimethoxythiophene affords dibutyl
or diphenyl sulfide at room temperature.3 Herein, we de-
scribe the effect of replacing the chlorine with other elec-
tron withdrawing substituents on the aromatic ring-
opening of thiophenes.
SYNLETT 2005, No. 2, pp 0247–0250
0
1.
0
2.
2
0
0
5
Advanced online publication: 22.12.2004
DOI: 10.1055/s-2004-837230; Art ID: S09404ST
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

248
M. Belley et al.
LETTER
Table 1 Reactions of Organolithium Reagents with 2-Fluoro-3-phenylbenzothiophenes15
SM
No
X
Ar
RLi
Temp (°C)
Product 5
Recovered SM
Yield (%)
Yield (%)
38
7a
7a
7a
7a
7b
7b
7b
7c
H
Ph
BuLia
–78, 4 h
–40, 1 h
–72, 1 h
–78 to r.t.
–78 to 0
–78 to 0
–78 to 0
–78 to 0
–78 to 0
–78 to 0
–78 to 0
–78 to 0
5a
5a
5b
49
66
68
0
H
Ph
BuLib
Trace
H
Ph
t-BuLia
s-BuLib
BuLi
H
Ph
100
Trace
18
H
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
Ph
5c
5d
5e
5f
48c
43
51
17
25
44
0–5d
0
H
t-BuLi
H
s-BuLi
32
Cl
Cl
Cl
H or Cl
H
BuLi
7c
Ph
t-BuLi
5g
5h
Trace
7c
Ph
s-BuLi
26
7a–c
7d
Ph or 4-(MeO)C6H4
2,4-Cl2C6H3
MeLi or PhLi
All RLi above
20–80
Major product (HPLC)
a 2 Equiv.
b 5 Equiv.
c 24% Yield of 2-butyl-3-(4-methoxyphenyl)benzothiophene (10a).
d 0–29% Yields of 2-methyl- or 2-phenyl-3-arylbenzothiophenes 10.
Our proposed mechanism for this new reaction6 is sum- halogen,9 either through a carbene or a carbenoid-like
marized in Scheme 1. The first and rate-limiting step7 in- mechanism, to yield the diphenylacetylene 5.
volves a nucleophilic addition of the organometallic
reagent onto the sulfur atom of benzothiophene 7 to gen-
In order to study the scope and limitations of this novel
diphenylacetylene synthesis, the four fluorinated benzo-
erate the intermediate 2,2-diaryl-1-fluorovinyllithium 8.
thiophenes 7a–d, bearing electron-withdrawing or donat-
As the second step, intermediate 8 undergoes a Fritsch–
ing substituents, were prepared as summarized in
Buttenberg–Wiechell (FBW) rearrangement,8 during
Scheme 2. The key steps were a Suzuki–Miyaura cou-
which the migration of the aryl group occurs trans to the
pling reaction between triflate 8a or 3-bromo-
benzothiophene 8b10 and a phenylboronic acid in the
Scheme 2
Synlett 2005, No. 2, 247–250 © Thieme Stuttgart · New York

LETTER
Aromatic Ring-Opening of 2-Fluorobenzothiophenes by Alkyllithiums
249
presence of tetrakis(triphenylphosphine) palladium(0)11 5a was obtained only as a minor product (max. 10%
to prepare the intermediates 9a–d, which were then depro- yield). The major product, 3-phenylbenzothiophene (13,
tonated in position 2 with butyllithium and fluorinated 84% yield by 1H NMR of the crude reaction mixture), was
with N-fluorobenzenesulfonimide12 to give the 2-fluoro- formed via a chlorine–metal exchange, showing that 2-
benzothiophenes 7a–d in fair to excellent yields. The tri- chlorobenzothiophenes are not good substrates for the
flate 8a was obtained from an intramolecular Friedel– thiophene ring-opening reaction. The low yield of diphe-
Craft acylation of [(4-chlorophenyl)thio]acetyl chloride, nylacetylene 5a isolated in this example was strikingly
prepared in situ from the acid and PCl3,13 followed by its different from what was observed in Equation 2, where
reaction with trifluoromethanesulfonic anhydride.14
the 2-chlorothieno[3,2-d]thiazole (2) was found to yield
exclusively the ring-opened product 3, and where the
chlorine–metal exchange was absent.2 Thienothiazoles
are evidently more susceptible to nucleophilic organo-
lithium addition than their benzothiophene analogs.
As can be seen from Table 1, the formation of diphenyl-
acetylenes from 2-fluoro-3-phenylbenzothiophene is not
general and the yields vary with the substitution pattern of
the benzothiophene and the nature of the organolithium
reagent. With the exception of methyllithium, alkyllithi- In conclusion, we have reported here new examples of a
um reagents usually gave diphenylacetylenes in moderate surprising ring-opening of thiophenes in which alkyllithi-
to good yield. With methyllithium and phenyllithium, the um reagents add to the sulfur atom of the thiophene and in
major products observed, other than the unreacted starting which diphenylacetylenes are produced after a FBW rear-
material (SM), are products 10, arising from nucleophilic rangement of the intermediate carbenoids.
aromatic substitution (SNAr) of the fluoride by the orga-
General Experimental Procedure15
nometallic reagent. Addition of a co-solvent such as
DMPU, or a complexing agent such as TMEDA, had no
effect on the reactivity of methyllithium. Finally, with 2-
fluoro-(2,4-dichlorophenyl)benzothiophene 7d, the start-
ing material was mostly recovered unchanged in many
reactions, along with small amounts of unidentified com-
pounds, which did not contain any alkyl group coming
from the organometallic reagent. It seems that the pres-
ence of EWG on the 3-aryl substituent greatly decreases
the speed of the alkyllithium addition onto the sulfur atom
of the thiophene.
Reaction of 2-Fluoro-3-arylbenzothiophenes 7 with Organo-
lithium Reagents:
Compound 7 (100 mg) was dissolved in 5 mL of dry THF and
cooled to –78 °C under a nitrogen atmosphere. Then, 1.2 equiv of
organolithium reagent was added and the reaction mixture was
slowly warmed up to 0 °C over 40 min. A sat. solution of NH4Cl
was added and the products of the reaction were extracted into
EtOAc and dried over Na2SO4. The mixture was analyzed by HPLC
(NovaPak column, gradient 20–95% MeCN–NH4OAc buffer (2 g/
L containing 10% MeOH). Purification of the products was per-
formed either by flash chromatography on silica or normal phase
HPLC (Luna 10 mm silica column, 250 × 10 mm).
This diphenylacetylene formation proceeds when THF is
used as solvent. No ring-opening of benzothiophenes is
observed in diethyl ether, even in the presence of TMEDA
or with a large excess of BuLi at room temperature. The
temperature of the reaction and quantity of alkyllithium
reagent are also important. For example, when 7a was
reacted with an excess of alkyllithium at –20 °C, the side
product 11, arising from addition of a second molecule
of butyllithium across the triple bond of the diphenyl-
acetylene 5a,16 was also isolated (12% yield).
Acknowledgment
The authors would like to thank Dr Laird Trimble for the structure
elucidation of compound 11 and Julie Farand for proofreading this
manuscript.
References
(1) (a) Dickinson, R. P.; Iddon, B. J. Chem. Soc. C 1970, 2592.
(b) Karlsson, J. O.; Svensson, A.; Gronowitz, S. J. Org.
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(3) Hallberg, A.; Frejd, T.; Gronowitz, S. Chem. Scr. 1979, 13,
186.
(4) Lithiation of 9a with BuLi in THF at –78 °C, in the presence
of TMEDA, followed by reaction with iodine,19 yielded
quantitatively 2-iodo-3-phenylbenzothiophene.
Trifluoromethylation of this iodide (2.0 g) was then
performed in 59% yield with CF3I (2.3 mL) and copper (5.0
g) in pyridine (13 ml) at 130 °C for 24 h. See: Kobayashi, Y.;
Yamamoto, K.; Kumadaki, I. Tetrahedron Lett. 1979, 42,
4071; for a related procedure.
(5) The structure of the diphenylacetylene 5a was confirmed by
its preparation via an alternative synthetic route. o-Bromo-
thiophenol was butylated with butyl iodide in the presence of
NaH in DMF. Phenylacetylene was converted to its lithium
salt and treated with B-MeO-9-BBN in situ to form a
Figure 1
In order to compare the behavior of 2-fluorobenzo-
thiophenes with their 2-chloro analogs toward such orga-
nolithium addition, 2-chloro-3-phenylbenzothiophene
(12)17 was treated with butyllithium under similar condi-
tions. In this particular reaction,18 the diphenylacetylene
Synlett 2005, No. 2, 247–250 © Thieme Stuttgart · New York

250
M. Belley et al.
LETTER
1-(tert-Butylthio)-4-chloro-2-(phenylethynyl)benzene
tetrahedral borate complex, which was reacted with 1-
bromo-2-(butylthio)benzene in the presence of Pd(0)20 to
yield 5a.
(5g): 1H NMR (500 MHz, acetone): d = 7.68 (m, 2 H), 7.63–
7.61 (m, 2 H), 7.48–7.44 (m, 4 H), 1.38 (s, 9 H). 13C NMR
(126 MHz, acetone): d = 140.44, 134.93, 134.19, 132.65,
132.55, 131.90, 129.36, 129.09, 128.83, 123.31, 94.60,
88.54, 48.24, 30.97. IR (neat): 2220 cm–1. HRMS (FAB,
glycerol): m/z calcd for C18H17ClS [M+]: 300.0740; found:
300.0738. Anal. Calcd for C18H17ClS: C, 71.86; H, 5.70; S,
10.66. Found: C, 71.93; H, 5.90; S, 10.27.
(6) The reverse of this reaction, the synthesis of benzothio-
phenes from phenylacetylenes, has been reported by:
(a) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett.
2001, 3, 651. (b) Yue, D.; Larock, R. C. J. Org. Chem. 2002,
67, 1905. (c) Aitken, R. A.; Burns, G. Tetrahedron Lett.
1987, 28, 3717.
(7) The first step was found to be rate limiting based on the
following observations. 1) The FBW rearrangement was
reported repeatedly to occur rapidly and at temperature
below –20 °C.8 2) We haven’t been able to isolate any of the
non-rearranged products from the intermediate 2,2-diaryl-1-
fluorovinyllithium 8, even when the reaction was quenched
at –78 °C (first entry in Table 1). 3) In most reactions where
there is no diphenylacetylene produced, the major product
isolated is the starting benzothiophene 7.
(8) For recent articles describing FBW rearrangements, see:
(a) Creton, E.; Rezaeï, H.; Marek, I.; Normant, J. F.
Tetrahedron Lett. 1999, 40, 1899. (b) Mouriès, V.;
Waschbüsch, R.; Carran, J.; Savignac, P. Synthesis 1998,
271. (c) Shi Shun, A. L. K.; Chernick, E. T.; Eisler, S.;
Tykwinski, R. R. J. Org. Chem. 2003, 68, 1339.
(9) Köbrich, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 41.
(10) Smuszkovicz, J.; Modest, E. J. J. Am. Chem. Soc. 1950, 72,
571.
2-Fluoro-3-(4-methoxyphenyl)benzothiophene (7b): 1H
NMR (500 MHz, acetone): d = 7.91–7.87 (m, 1 H), 7.72–
7.68 (m, 1 H), 7.52 (d, 2 H, J = 8.1 Hz), 7.46–7.40 (m, 2 H),
7.14–7.12 (m, 2 H), 3.89 (s, 3 H). 13C NMR (126 MHz,
acetone): d = 160.00, 159.31 (d, J = 289 Hz), 136.49 (d,
J = 3.9 Hz), 131.02 (d, J = 2.6 Hz), 130.89, 125.80, 125.30
(d, J = 4.6 Hz), 123.35, 123.28, 122.87 (d, J = 6.0 Hz),
117.13 (d, J = 7.3 Hz), 114.74, 55.18. MS (+APCI): m/e
258.0 [M+]. Anal. Calcd for C15H11FOS: C, 69.75; H, 4.29;
S, 12.41. Found: C, 69.84; H, 4.34; S, 12.28.
5-Chloro-2-fluoro-3-phenylbenzothiophene (7c): 1H
NMR (500 MHz, acetone): d = 7.99 (d, 1 H, J = 8.6 Hz), 7.67
(d, 1 H, J = 2.0 Hz), 7.61 (m, 4 H), 7.52 (m, 1 H), 7.46 (dd,
1 H, J = 2.0, 8.6 Hz). 13C NMR (126 MHz, acetone): d =
161.58 (d, J = 291 Hz), 138.02 (d, J = 4.3 Hz), 132.28,
131.06, 130.11, 129.92, 129.82 (d, J = 2.9 Hz), 129.24,
126.08 (d, J = 4.1 Hz), 125.56, 122.71 (d, J = 6.2 Hz),
117.71 (d, J = 8.0 Hz). MS (+APCI): m/e 262.0 [M+], 264.0.
Anal. Calcd for C14H8ClFS: C, 64.00; H, 3.07. Found: C,
64.45; H, 3.00.
(11) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
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(12) Differding, E.; Ofner, H. Synlett 1991, 187.
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5478.
(16) The structure of 11 was confirmed by 2D-NOE studies. This
reaction was also described by: Mulvaney, J. E.; Gardlund,
Z. G.; Gardlund, S. L. J. Am. Chem. Soc. 1963, 85, 3897.
(17) 2-Chloro-3-phenylbenzothiophene was prepared in 64%
yield from 9a by lithiation with BuLi at –78 °C followed by
reaction with N-chlorosuccinimide.
(18) The same reaction with s-BuLi yielded only 3-phenyl-
benzothiophene 13.
(19) Yoshida, S.; Fujii, M.; Aso, Y.; Otsubo, T.; Ogura, F. J. Org.
Chem. 1994, 59, 3077.
(15) All new compounds gave satisfactory analytical and
spectroscopic data. Selected data:
1-(tert-Butylthio)-2-[(4-methoxyphenyl)ethynyl]benzene
(5d): 1H NMR (500 MHz, acetone): d = 7.67 (d, 1 H, J = 7.7
Hz), 7.64 (dd, 1 H, J = 1.0, 7.6 Hz), 7.54 (d, 2 H, J = 8.8 Hz),
7.46–7.44 (m, 1 H), 7.41–7.37 (m, 1 H), 7.01 (d, 2 H, J = 8.8
Hz), 3.86 (s, 3 H), 1.37 (s, 9 H). 13C NMR (126 MHz,
acetone): d = 160.49, 139.14, 135.01, 133.26, 133.00,
131.43, 129.35, 128.33, 115.83, 114.65, 93.56, 88.61, 55.25,
47.74, 31.04. IR (neat): 2216 cm–1. HRMS (FAB, glycerol):
m/z calcd for C19H20OS [M+]: 296.1234; found: 296.1236.
Anal. Calcd for C19H20OS: C, 76.98; H, 6.80; S, 10.82.
Found: C, 76.98; H, 7.04; S, 9.97.
(20) Soderquist, J. A.; Matos, K.; Rane, A.; Ramos, J.
Tetrahedron Lett. 1995, 36, 2401.
Synlett 2005, No. 2, 247–250 © Thieme Stuttgart · New York