Efficient synthesis of 3-oxygenated benzothiophene derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.01.141

An efficient synthesis of 2-bromo-3-aryloxybenzothiophene derivatives by a conjugate addition-elimination sequence of 2,3-dibromo benzothiophene dioxides with phenolic nucleophiles has been developed. These benzothiophene derivatives serve as important in

Full text of DOI:10.1016/j.tetlet.2007.01.141

Tetrahedron Letters 48 (2007) 2349–2352
Efficient synthesis of 3-oxygenated benzothiophene derivatives
Fuyao Zhang,* David Mitchell, Patrick Pollock and Tony Y. Zhang
Chemical Product R&D, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 20 November 2006; revised 23 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—An efficient synthesis of 2-bromo-3-aryloxybenzothiophene derivatives by a conjugate addition–elimination sequence of
2,3-dibromo benzothiophene dioxides with phenolic nucleophiles has been developed. These benzothiophene derivatives serve as
important intermediates for the synthesis of SERM analogues.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Benzothiophenes are emerging as an important class of
pharmacophores for medicinal chemistry, as exemplified
by the successful launch of raloxifene (Evistaꢁ, 1), a rep-
resentative of a class of compounds known as selective
estrogen receptor modulators (SERMs) that exhibit
estrogen agonist-like actions on bone tissues and serum
lipids while displaying potent estrogen antagonist prop-
erties in the breast and uterus. Recently, 3-oxygenated
benzothiophene (2) has been reported to display a sub-
stantial (10-fold) increase in estrogen antagonist potency
relative to raloxifene.1–5 To further expand the structure
activity relationship (SAR) studies for this class of mol-
ecules, compound 3 was identified as a pivotal interme-
diate to explore the chemical space around the 2-
position of this particular platform (Fig. 1). However,
there is paucity for the existence, let alone method of
preparation for this type of compound in the chemical
literature. Herein we wish to report our efforts on the
preparation of 2-bromo-3-aryloxybenzothiophenes as
versatile intermediates for SAR.
reported.2–5 We envisioned applying the same synthesis
strategy of activation to prepare compound 3 and
analogues via sulfoxide 4. However, bromination of
6-methoxybenzothiophene (5) gave 2,3-dibromo-6-
methoxybenzothiophene (6) in only 5% yield (Scheme
1). Furthermore, sulfoxide 4 (prepared from 6 by selec-
tive oxidation) proved to be an unstable intermediate for
the nucleophilic displacement.
We then investigated the use of a 2,3-dibromo benzothio-
phene dioxide (sulfone) for the nucleophilic displace-
ment. It has long been known that the halide atom in
the 3-position of benzothiophene dioxide could be dis-
placed by amines, alcohols, and phenols in the presence
of a base; however, this transformation has attained al-
most no practical synthesis utility.6–8 Toward this end,
compound 9, 2,3-dibromo-6-methoxybenzothiophene
dioxide, was prepared from 6-methoxybenzothiophene
(5) by oxidation with m-CPBA, followed by bromina-
tion in 72% overall yield (Scheme 2). Attempts to selec-
tively brominate at the 3-position proved to be futile due
to superior activity at the 2-position and complications
from other sites.
The nucleophilic displacement of a bromide in the
3-position of a benzothiophene sulfoxide has been
O
N
O
O
N
N
O
C
O
O
OH
OH
Br
S
HO
S
S
HO
MeO
3
1, Raloxifene
2
Figure 1.
*
Corresponding author. Tel.: +1 317 651 1264; fax: +1 317 276 4507; e-mail: zhang_fuyao@lilly.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.141

2350
F. Zhang et al. / Tetrahedron Letters 48 (2007) 2349–2352
Br2, KOAc
CHCl3, 23 oC, 0.5 h
Br
Br
Br
+
Br
Br
Br
S
MeO
S
S
O
MeO
MeO
S
MeO
Br
6
5
7
4
5%
63%
Scheme 1.
Br
m-CPBA, CH2Cl2
Br2, CH2Cl2
Et3N
40 oC, 3 h
Br
S
S
O
S
MeO
MeO
MeO
84%
O
O
85%
O
5
8
9
Scheme 2.
Table 1. Conjugate addition–elimination reaction of benzothiophene
dioxides and phenols
To our delight, reaction of benzothiophene dioxide 9
with 4-(2-piperidin-1-yl-ethoxy)-phenol (10) in the
presence of cesium carbonate at ambient temperature
provided the desired 2-bromo-3-aryloxy-6-methoxy-
benzothiophene dioxide 11 in 86% yield. Excellent regio-
selectivity was achieved as manifested by the single
mono-addition product 11 being the only product iso-
lated (Scheme 3). As in the case of the sulfoxide adduct,
the sulfone adduct may proceed via a conjugate addi-
tion–elimination pathway. Since the C2–C3 bond in
benzothiophene dioxide is likely olefinic and has limited
aromatic character,6 2,3-dibromo-6-methoxybenzothio-
phene dioxide (9) can be considered as an unsaturated
sulfone, which serves as a conjugate acceptor.9,10
R
R
O
Br
HO
Br
Br
R1
R1
S
S
Cs2CO3, THF, RT
O
O
O
O
Entry
R1
R
Time (h)
Yield (%)
1
2
H
H
H
F
2
2
95
95
O
N
3
4
5
H
3
3
5
86
85
86
OMe
OMe
H
In order to investigate the scope of conjugate addition–
elimination reaction, several 2,3-dibromo-6-substitued
benzothiophene dioxides were prepared to serve as con-
jugate acceptors. The results of conjugate addition–elim-
ination reaction between benzothiophene dioxides and
phenols are summarized in Table 1.
O
N
N
O
6
CH3CO
24
52
reagents. Unfortunately, none of these methods proved
satisfactory for the reduction of sulfone 11 to benzo-
thiophene 3, providing a complicated mixture from
reduction, debromination, and decomposition. We
found that reaction of 11 with sodium borohydride gave
only debromination product 12, with the sulfone moiety
intact. Eventually sulfone 12 was successfully reduced to
3-aryloxy-6-methoxybenzothiophene 13 with DIBAL in
94% yield. Bromination of 13 with N-bromo succinimide
provided 3 in 82% yield (Scheme 4). The net outcome is
a six-step process for the synthesis of benzothiophene 3
in 43% overall yield starting from 6-methoxybenzothio-
phene (5).15
As indicated in Table 1, a series of phenols were found
to add to 2,3-dibromo-benzothiophene dioxides with
or without an electron-donating group in good to excel-
lent yield. However, the yield was low when an electron-
withdrawing group was present on the phenyl ring of the
benzothiophene (entry 6) as a result of attenuated
nucleophilicity.
With benzothiophene dioxide 11 on hand, we investi-
gated the reduction of benzothiophene dioxide 11 to
benzothiophene 3. A number of methods have been
reported for the reduction of sulfones to sulfides using
14
LAH,11 DIBAL,12 Zn13, and SmI2
as reducing
O
Cs2CO3, THF, 23 oC, 5 h
86%
O
O
HO
9
N
N
Br
S
MeO
O
O
10
11
Scheme 3.

F. Zhang et al. / Tetrahedron Letters 48 (2007) 2349–2352
2351
Ar
Ar
DIBAL, THF
50 oC, 24 h
NaBH4, MeOH
23 oC, 2 h
NBS, HOAc
55 oC, 2 h
82%
O
O
11
3
91%
94%
S
O
S
MeO
MeO
O
12
13
O
Ar =
N
Scheme 4.
W.; Krushiski, J. H.; Beedle, E. E.; Pollock, G. D.; Wyss,
V. Eur. J. Med. Chem. Chim. Ther. 1986, 21, 223; (c)
Block, E.; Wall, A. J. Org. Chem. 1987, 52, 809; (d) Eisch,
J. J.; Hallenbeck, L. E.; Han, K. I. J. Am. Chem. Soc.
1986, 108, 7763.
In conclusion, the conjugate addition–elimination reac-
tion of benzothiophene dioxides and phenols has been
investigated and has been applied to a six-step process
for the synthesis of the target compound 3. This key
intermediate was used for the preparation of hundreds
of 2-substituted 3-oxygenated benzothiophene deriva-
tives for drug discovery. The developed process for pre-
paring 3 is also amenable to multi-kilogram preparative
scale.
12. (a) Pettett, M. G.; Holmes, A. B.; Andrew, B. J. Chem.
Soc., Perkin Trans. 1 1985, 1161; (b) Williams, T. M.;
Hudcosky, R. J.; Hunt, C. A.; Shepard, K. L. J.
Heterocycl. Chem. 1991, 28, 13; (c) Daly, C. M.; Iddon,
B.; Suschitzky, H.; Jordis, U.; Sauter, F. J. Chem. Soc.,
Perkin Trans. 1 1988, 1933; (d) Daly, C. M.; Iddon, . B.;
Suschitzky, H. Tetrahedron Lett. 1983, 24, 5147.
13. Bordwell, F. G.; McKellin, W. H. J. Am. Chem. Soc. 1951,
73, 2251.
Acknowledgments
14. Handa, Y.; Inanaga, J.; Yamaguchi, M. J. Chem. Soc.,
Chem. Commun. 1989, 5, 298.
15. Typical procedures are as follows:
We gratefully acknowledge the LRL Physical Chemistry
Group analytical data and Dr. Marvin Miller, Dr. Wil-
liam Roush, Dr. Paul Wender, and Dr. Peter Wipf for
helpful discussion during this work.
Preparation of 8: To a solution of 6-methoxythianaphth-
ene 5 (30.0 g, 183 mmol) in 300 mL of methylene chloride
was added slowly m-CPBA (99.0 g, 70%, 400 mmol) over a
60-minute period. The mixture was heated at 40 ꢂC for 3 h,
and then cooled to room temperature. Ethyl acetate
(600 mL) was added to dissolve the white precipitates.
Saturated sodium thiosulfate solution (200 mL) was added
and stirred at ambient temperature for 1 h to quench the
excess of m-CPBA. The organic layer was separated and
the aqueous layer was extracted with ethyl acetate
(2 · 50 mL). The combined organic solutions was washed
with saturated sodium bicarbonate and brine. After
concentrated and recrystallized from ethanol and MTBE
(1:20), 30.1 g of the desired product 8 was obtained as
References and notes
1. (a) McDonnell, D. P.; Clemm, D. L.; Hermann, T.;
Goldman, M. E.; Pike, J. W. Mol. Endocrinol. 1995, 9,
659; (b) Kauffman, R. F.; Bryant, H. U. Drug News
Perspect. 1995, 8, 531; (c) Sato, M.; Rippy, M. K.; Bryant,
H. U. FASEB J. 1996, 10, 905.
2. Palkowitz, A. D.; Glasebrook, A. L.; Thrasher, T. J.;
Hauser, K. L.; Short, L. L.; Phillips, D. L.; Muehl, B. S.;
Sato, M.; Shetler, P. K.; Cullinan, G. J.; Pell, T. R.;
Bryant, H. U. J. Med. Chem. 1997, 40, 1407.
3. Grese, T. A.; Cho, S.; Finley, D. R.; Dogfrey, A. G.;
Jones, C. D.; Lugar, c. W., III; Martin, M. J.; Matsumoto,
K.; Pennington, L. D.; Winter, M. A.; Adrian, M. D.;
Cole, H. W.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.;
Short, L. L.; Glasebrook, A. L.; Bryant, H. U. J. Med.
Chem. 1997, 40, 146.
4. Jones, C. D.; Jevnikar, M. G.; Pike, A. L.; Peters, M. K.;
Black, L. J.; Thompson, A. R.; Falcone, J. F.; Clemms,
J. A. J. Med. Chem. 1984, 27, 1057.
5. Grese, T. A.; Cho, S.; Bryant, H. U.; Cole, H. W.;
Glasebrook, A. L.; Magee, D. E.; Phillips, D. L.; Rowley,
E. R.; Short, L. L. Bioorg. Med. Chem. Lett. 1996, 6, 201.
6. Bordwell, F. G.; Albisetti, C. J., Jr. J. Am. Chem. Soc.
1948, 70, 1558.
1
white crystals. Yield 84%. H NMR (300 MHz, CDCl3) d
7.25 (d, 2H, J = 8.1 Hz), 7.16 (d, 1H, J = 6.9 Hz), 7.10
(dd, 1H, J = 8.1 and 2.4 Hz), 6.59 (d, 1H, J = 7.2 Hz),
3.87 (s, 3H). 13C NMR (100 MHz, CDCl3) d 162.3, 138.7,
132.7, 129.1, 126.6, 123.5, 118.9, 107.8, 56.3.
Preparation of 9: To a mixture of sulfone 8 (19.6 g,
100 mmol) in 200 mL of methylene chloride was added
dropwise a solution of bromine (6.1 mL, 120 mmol) in
50 mL of methylene chloride at ambient temperature. The
resulting solution was stirred at ambient temperature for
15 min and then 10 mL of triethylamine was added. After
stirring at ambient temperature for 20 min, the reaction
was quenched by the addition of water. The organic layer
was separated and dried over sodium sulfate. After
filtration, a pale yellow solution was obtained. To this
pale yellow solution was added a solution of bromine
(6.1 mL, 120 mmol) in 50 mL of methylene chloride. The
resulting red solution was stirred at ambient temperature
for 4 h. Triethylamine (10 mL) was added and stirred at
ambient temperature for 30 min. The reaction was
quenched by the addition of 200 mL of water and extracted
with methylene chloride (2 · 100 mL). The combined
organic solutions were dried over sodium sulfate. After
filtering and concentrating, 30.0 g of desired product 9 was
obtained without further purification. Yield 85%. 1H
NMR (500 MHz, CDCl3) d 7.47 (d, 1H, J = 8.0 Hz), 7.30
(d, 1H, J = 2.5 Hz), 7.10 (dd, 1H, J = 8.0 and 2.5 Hz), 3.91
7. Bordwell, F. G.; Lampert, B. B.; McKellin, W. H. J. Am.
Chem. Soc. 1949, 71, 1702.
8. Schlesinger, A. H.; Momry, A. T. J. Am. Chem. Soc. 1951,
73, 2614.
9. Sedergran, T. C.; Yokoyama, M.; Dittmer, D. C. J. Org.
Chem. 1984, 49, 2408.
10. Padwa, A.; Austin, D. J.; Ishida, M.; Muller, C. L.;
Murphree, S. S.; Yeske, P. E. J. Org. Chem. 1992, 57,
1161.
11. (a) Klaerner, F. G.; Kleine, A. E.; Oebels, D.; Scheidt, F.
Tetrahedron: Asymmetry 1993, 4, 479; (b) Robertson, D.

2352
F. Zhang et al. / Tetrahedron Letters 48 (2007) 2349–2352
(s, 3H). 13C NMR (125 MHz, CDCl3) d 162.3, 137.1, 128.8,
Preparation of 13: To a solution of sulfone 12 (10.5 g,
25.3 mmol) in 100 mL of THF was added a solution of
DIBAL (100 mL, 1.0 M, 100 mmol) in methylene chloride
at ambient temperature. The resulting solution was heated
at 50 ꢂC for 18 h. Additional 50 mL of DIBAL was added
and continued to stir at 50 ꢂC for additional 6 h. The
reaction was quenched by the addition of saturated sodium
sulfate. White solids were removed by filtration. The
filtrate was washed with water and brine, and dried over
sodium sulfate. After concentrating, 9.1 g of the desired
product 13 was obtained as a pale yellow solid without
further purification. Yield 94%. 1H NMR (500 MHz,
125.6, 123.6, 120.2, 119.0, 108.0, 56.2.
Preparation of 11: To a solution of 2, 3-dibromo-6-
methoxybenzothiophene dioxide 9 (27.0 g, 76.5 mmol)
and
4-(2-piperidin-1-yl-ethoxy)-phenol
10
(18.9 g,
85.4 mmol) in 300 mL of THF was added cesium carbon-
ate (74.7 g,229.0 mmol) to form a green mixture. After
stirring at ambient temperature for 5 h, the reaction was
quenched by the addition of water and extracted with ethyl
acetate (2 · 200 mL), and dried over sodium sulfate. After
purification by recrystallization from ethanol, 32.4 g of the
desired product 11 was obtained as a white solid. Yield
86%. 1H NMR (300 MHz, CDCl3) d 7.37 (d, 1H,
J = 8.7 Hz), 7.30 (d, 1H, J = 2.1 Hz), 7.03 (m, 2H), 6.99
(d, 1H, J = 2.4 Hz), 6.86 (m, 2H), 4.08 (m, 2H), 3.86 (s,
3H), 2.75 (t, 2H, J = 6.0 Hz), 2.75 (t, 4H, J = 4.8 Hz), 1.59
(m, 4H), 1.43 (m, 2H). 13C NMR (100 MHz, CDCl3) d
162.0, 156.9, 152.8, 147.1, 138.9, 122.9, 122.2, 120.9, 118.8,
115.5, 107.8, 95.5, 66.8, 58.2, 56.4, 55.4, 26.3, 24.5.
CDCl3)
d 7.66 (d, 1H, J = 8.7 Hz), 7.23 (d, 1H,
J = 2.5 Hz), 7.07 (m, 2H), 6.99 (dd, 1H, J = 8.7 and
2.5 Hz). 6.88 (m, 3H), 4.08 (t, 2H, J = 6.0 Hz), 3.87 (s, 3H),
2.77 (t, 2H, J = 6.0 Hz), 2.51 (m, 4H), 1.61 (m,4H), 1.46
(m, 2H). 13C NMR (125 MHz, CDCl3) d 158.3, 155.5,
151.1, 149.5, 139.7, 126.4, 122.0, 120.2, 115.8, 114.5, 105.6,
101.8, 66.7, 58.2, 55.8, 55.3, 26.2, 24.4.
Preparation of 12: A solution of sulfone 11 (15.0 g,
30.4 mmol) in 150 mL of methanol was treated with
sodium borohydride (2.3 g, 60.0 mmol) at ambient tem-
perature for 2 h. Acetone (5 mL) was added to quench the
reaction. Solvents were evaporated. The residue was
dissolved in 200 mL of ethyl acetate and 100 mL of water.
The organic layer was separated and dried over sodium
sulfate. After evaporating and recrystallizing from meth-
ylene chloride and pentane (1:9), 11.5 g of the desired
Preparation of 3: A solution of benzothiophene 13 (7.6 g,
19.8 mmol) in 80 mL of acetic acid was treated with NBS
(3.9 g, 21.8 mmol) at ambient temperature for 10 min. The
resulting solution was heated at 55 ꢂC for 2 h. The reaction
was quenched by the addition of 200 mL of water and
200 mL of ethyl acetate. The organic layer was separated.
The aqueous layer was extracted with ethyl acetate. The
combined organic solutions were washed with saturated
sodium bicarbonate, water and brine, dried over sodium
sulfate. After concentrating and recrystallizing from eth-
anol, 7.5 g of the desired product 3 was obtained as a white
solid. Yield 82%. 1H NMR (500 MHz, CDCl3) d 7.33–6.79
(m, 7H), 4.05 (t, 2H, J = 6.0 Hz), 3.84 (s, 3H), 2.75 (t, 2H,
1
product 12 was obtained as white crystals. Yield 91%. H
NMR (500 MHz, CDCl3) d 7.37 (d, 1H, J = 8.0 Hz), 7.27
(d, 1H, J = 2.5 Hz), 7.10 (m, 3H), 6.95 (m, 2H), 4.11 (t, 2H,
J = 6.0 Hz), 3.90 (s, 3H), 2.79 (t, 2H, J = 6.0 Hz), 2.52 (m,
4H), 1.62 (m, 4H), 1.46 (m, 2H). 13C NMR (125 MHz,
CDCl3) d 162.9, 161.9, 157.5, 147.5, 141.8, 122.8, 121.7,
121.3, 118.7, 115.9, 106.7, 101.4, 66.7, 58.1, 56.3, 55.3, 26.1,
24.4.
J = 6.0 Hz), 2.50 (m, 4H), 1.60 (m, 4H), 1.42 (m, 2H). 13
C
NMR (125 MHz, CDCl3) d 158.1, 154.0, 151.8, 144.1,
138.7, 125.8, 121.6, 116.7, 115.5, 114.6, 105.3, 99.8, 64.5,
56.9, 55.6, 54.3, 23.8, 22.7.