Efficient access to 2-aryl-3-substituted benzo[b]thiophenes

Article abstract of DOI:10.1021/jo0500378

(Chemical Equation Presented) Benzo[b]thiophene derivatives are important in part because of their use as selective estrogen receptor modulators. They are usually synthesized by intramolecular cyclization. Here, we propose a method for the synthesis of 2-

Full text of DOI:10.1021/jo0500378

Efficient Access to 2-Aryl-3-Substituted Benzo[b]thiophenes
Emilie David, Julie Perrin, Ste´phane Pellet-Rostaing, Je´re´mie Fournier dit Chabert, and
Marc Lemaire*
Universite´ Claude Bernard Lyon 1, Laboratoire de Catalyse et Synthe`se Organique, CPE baˆt 308,
UMR 5181, 43 Bd du 11 novembre 1918, 69622 Villeurbanne Cedex, France
marc.lemaire@univ-lyon1.fr
Received January 7, 2005
Benzo[b]thiophene derivatives are important in part because of their use as selective estrogen
receptor modulators. They are usually synthesized by intramolecular cyclization. Here, we propose
a method for the synthesis of 2-arylbenzo[b]thiophenes with heteroatoms at the 3-positions directly
from the benzo[b]thiophene core by using an aromatic nucleophilic substitution reaction and Heck-
type coupling. This methodology provides 2-aryl-3-amino or phenoxybenzo[b]thiophenes in about
35% overall yield in 5 steps.
Introduction
The effect of naturally occurring estrogens, such as
17â-estradiol, on numerous tissues has been recognized
for a long time. The declining levels of estrogens during
and after menopause have been connected to a large
number of post-menopausal pathologies, not only os-
teoporosis1 but also cardiovascular diseases, depression
and schizophrenia, and Alzheimer’s disease.2 Hormone
replacement therapy can restore estrogen levels; there-
fore, it reduces the risks associated with these patholo-
gies, but it has also been linked to an increased risk of
hormone dependent cancers along with numerous side
effects. Therefore, researchers have focused on the de-
velopment of treatment alternatives to better satisfy this
medical need.3 Several synthetic molecules have been
described as selective estrogen receptor modulators
(SERMs).4 These molecules antagonize the effects of
FIGURE 1. Structures of Raloxifene and Arzoxifene.
estrogen on reproductive tissues while mimicking the
effects of estrogen on bone and the cardiovascular
system.5 The combination of these effects is thought to
provide a uniquely advantageous therapeutic profile for
the post-menopausal female population.
A few years ago, particular interest was given to the
synthesis of SERM analogues, such as Raloxifene and
Arzoxifene (Figure 1).
In fact, Raloxifene, a 2-arylbenzo[b]thiophene, is al-
ready commercially available for the prevention of os-
(1) Lindsay, R. Lancet 1993, 341, 801.
(2) (a) Pennisi, E. Science 1996, 273, 1171. (b) Fink, G.; Sumner, B.
E. Nature 1996, 383, 306. (c) Dempster, D. W.; Lindsay, R. Lancet 1993,
341, 797.
(3) Sato, M.; Grese, T. A.; Dodge, J. A.; Bryant, H. U.; Turner, C.
H. J. Med. Chem. 1999, 42, 1.
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(5) Evans, G. L.; Turner, R. T. Bone 1995, 17, 181S.
10.1021/jo0500378 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/26/2005
J. Org. Chem. 2005, 70, 3569-3573
3569

David et al.
SCHEME 1. Synthesis of
3-Phenoxybenzo[b]thiophene 1-Oxides
teoporosis. A structure-activity relationship study showed
that the replacement of the carbonyl group with an
oxygen resulted in a 10-fold increase in antiestrogen
potency both in vivo and in vitro.6 In addition, the
methoxy analogue, Arzoxifene, has improved bioavail-
ability compared with that of Raloxifene.7 Arzoxifene is
currently under investigation as a breast cancer therapy
in advanced disease.8
Substituted 2-arylbenzo[b]thiophenes are usually syn-
thesized by multistep intramolecular cyclization of thio-
phenol derivatives, according to the procedures of Kost,9
De,10 and Flynn.11 Nevertheless, these methods often
require many steps as well as acidic and/or basic condi-
tions which are not compatible with sensitive functional
groups. Surprisingly, little interest has been given to
direct access to substituted 2-arylbenzo[b]thiophenes
from benzo[b]thiophene. This paper describes a new and
rapid route to Arzoxifene analogues with heteroatoms at
the 3-positions. This synthetic approach is based on the
nucleophilic aromatic substitution (SNAr) of 3-bromo-
benzo[b]thiophene followed by a one-step Heck-type
coupling of the corresponding 3-substituted benzo[b]-
thiophenes with aryl halides.12,13
method described by our laboratory,19 we used a copper-
catalyzed aromatic nucleophilic substitution of 3-bromo-
benzo[b]thiophene by 2,2,2-trifluoroethanol to produce
3-(2,2,2-trifluoroethoxy)benzo[b]thiophene 1 in a 54%
yield. Nevertheless, assays with other nonfluorinated
alcohols, such as methanol, n-butanol, phenol, and benzyl
alcohol, failed.
As 3-bromo-2-nitrobenzo[b]thiophene reacted, probably
by an SNAr mechanism,20 with neutral and anionic
nucleophiles to give the expected 3-amino-2-nitrobenzo-
[b]thiophene, the activation of 3-bromobenzo[b]thiophene
seemed to be necessary. For the synthesis of Arzoxifene
and its derivatives, 2-aryl-3-bromobenzo[b]thiophene 1-ox-
ides underwent an SNAr reaction with both phenol and
thiophenol derivatives.6 Recently, De Nanteuil et al.21
performed the substitution of 2-carboxaldehyde-3-chloro-
5,6-disubstituted benzo[b]thiophenes with various phe-
nols. Therefore, we assumed that an electron-withdraw-
ing group at the 2-position of 3-bromobenzo[b]thiophene
as well as its oxidation into the corresponding sulfoxide
favors the nucleophilic displacement of bromide by
decreasing the charge density at the 3-position and
increasing the stabilization of the intermediate (probably
a Meisenheimer-like intermediate).
The use of 3-bromobenzo[b]thiophene 1-oxide 2 as the
starting material for the SNAr reaction allowed the direct
introduction of various phenols and secondary amines.
Commercially available 3-bromobenzo[b]thiophene12 was
oxidized at room temperature with hydrogen peroxide in
a trifluoroacetic acid and dichloromethane mixture to
produce 3-bromobenzo[b]thiophene 1-oxide 2 in a yield
of 85%.6
The SNAr reaction of compound 2 was then completed
with various phenolate salts formed in situ with K2CO3
as a base (Scheme 1). Reactions were carried out with 2
equiv of both alcohol and K2CO3 in DMF to favor
nucleophilic attack (Table 1).
Results and Discussion
SNAr. Few methods are described for the introduction
of an heteroatom at the 3-position of the benzo[b]-
thiophene core. Although Netchitailo14 synthesized 3-meth-
oxybenzo[b]thiophene by reaction of sodium methoxide
with 3-bromobenzo[b]thiophene, the reaction failed with
other substrates, such as phenol derivatives. The syn-
thesis of 3-(p-methoxyphenoxy)benzo[b]thiophene by the
copper iodide-catalyzed reaction of 3-bromobenzo[b]-
thiophene was reported with a very low yield.15
The Buchwald copper iodide-catalyzed amination16 and
etherification17 of aryl iodides and the Nolan18 amination
reaction of aryl halides were tested on 3-bromobenzo[b]-
thiophene. Unfortunately, they both failed. Following a
(6) Palkowitz, A. D.; Glasebrook, A. L.; Thrasher, K. 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.
(7) Sato, M.; Turner, C. H.; Wang, T.; Adrian, M. D.; Rowley, E.;
Bryant, H. U. J. Pharmacol. Exp. 1998, 287, 1.
(8) Munster, P. N.; Buzdar, A.; Dhingra, K.; Enas, N.; Ni, L.; Major,
M.; Melemed, A.; Seidman, A.; Booser, D.; Theriault, R.; Norton, L.;
Hudis, C. J. Clin. Oncol. 2001, 19, 2002.
(9) Kost, A. N.; Budylin, V. A.; Matveeva, E. D.; Sterligov, D. O.
Zh. Org. Khim. 1970, 6, 1503.
(10) Mukherjee, C.; Kamila, S.; De, A. Tetrahedron 2003, 59, 4767.
(11) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3,
651.
Although total conversions were observed, partial
degradation of 3-bromobenzo[b]thiophene 1-oxide 2 oc-
curred at high temperature (during the reaction) produc-
ing only 60-80% isolated yields. As shown in Table 1,
the effectiveness of the SNAr reaction is influenced by
the electronic effects of the phenol substituents. Electron-
donating groups worked better than electron-withdraw-
ing groups in terms of the reaction temperatures and
(12) Fournier Dit Chabert, J.; Gozzi, C.; Lemaire, M. Tetrahedron
Lett. 2002, 43, 1829.
(13) Fournier Dit Chabert, J.; Joucla, L.; David, E.; Lemaire, M.
Tetrahedron 2004, 60, 3221.
(14) Netchitailo, P.; Decroix, B.; Morel, J.; Pastour, P. J. Heterocycl.
Chem. 1978, 15, 337.
(15) Sall, D. J.; Bailey, D. L.; Bastian, J. A.; Buben, J. A.; Chirgadze,
N. Y.; Clemens-Smith, A. C.; Denney, M. L.; Fisher, M. J.; Giera, D.
D.; Gifford-Moore, D. S.; Harper, R. W.; Johnson, L. M.; Klimkowski,
V. J.; Kohn, T. J.; Lin, H. S.; McCowan, J. R.; Palkowitz, A. D.; Richett,
M. E.; Smith, G. F.; Snyder, D. W.; Takeuchi, K.; Toth, J. E.; Zhang,
M. J. Med. Chem. 2000, 43, 649.
(16) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581.
(19) El Kassmi, A.; Heraud, G.; Buchner, W.; Fache, F.; Lemaire,
M. J. Mol. Catal. 1992, 72, 299.
(17) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973.
(20) Van Zyl, G.; Bredeweg, C. J.; Rynbrandt, R. H.; Neckers, D. C.
Can. J. Chem. 1966, 44, 2283.
(18) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem.
2001, 66, 7729.
(21) De Nanteuil, G.; Lila-Ambroise, C.; Rupin, A.; Vallez, M.-O.;
Verbeuren, T. J. Bioorg. Med. Chem. Lett. 2003, 13, 1705-1708.
3570 J. Org. Chem., Vol. 70, No. 9, 2005

2-Aryl-3-Substituted Benzo[b]thiophenes
TABLE 1. Results for the Synthesis of
SCHEME 3. Reduction of Sulfoxide Derivatives
3-Phenoxybenzo[b]thiophene 1-Oxides
entry
product
R1
R2
T (°C)
isolated yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3d
3e
3f
OMe
OMe
H
H
70
90
80
68
70
63
72
73
68
0
OMe
H
70
F
H
70
F
Cl
CN
NO2
H
110
110
110
120
H
H
3g
H
SCHEME 2. Synthesis of
3-Aminobenzo[b]thiophene 1-Oxides
3-aminobenzo[b]thiophene 1-oxides 4a-c were obtained
in better yields (85-95%).
TABLE 2. Results for the Synthesis of
3-Aminobenzo[b]thiophene 1-Oxides
After total conversion, 4a was easily isolated with a
94% yield after extraction and aqueous washing. When
flash chromatographies were required (4b,c), the use of
a neutral silica gel gave the desired products, whereas
partial hydrolysis of 3-aminobenzo[b]thiophene 1-oxide
into benzo[b]thiophen-3-one 1-oxide occurred with acidic
silica gel. Indeed, it is known that tertiary enamines can
be hydrolyzed in acidic medium to give the corresponding
ketones.23 For instance, the acidic hydrolysis of 2-(dim-
ethylamino)-6-methoxybenzo[b]thiophene into 6-meth-
oxybenzo[b]thiophen-2-one has been reported by Grese
et al.24
Reduction. When tested with sulfoxide derivatives,
no reaction was observed for the catalytic Heck-type
coupling. The reduction of sulfoxides using different
reducing agents, such as LiAlH46 or Dibal-H,25 has been
described. Benzo[b]thiophene 1-oxide derivatives 3a-e
and 4a-c were generally reduced with total conversion
when a slight excess of Dibal-H (1.3 equiv) in anhydrous
toluene was added (Scheme 3). Reduced products were
obtained in a 60-80% yield (Table 3). 3-Amino deriva-
tives 4a-c were reduced in short times at room temper-
ature (Table 3, entries 9-11), whereas heating at 65 °C
for about 5 h was necessary for the reduction of 3-phe-
noxy derivatives 3a-e (Table 3, entries 1-6). At room
temperature, the reduction time of the 3-phenoxy deriva-
tives was greatly increased and conversion was not
complete (Table 3, entries 3 and 4).
entry product
X
reaction time (h) isolated yield (%)a
1
2
3
4
5
4a
4b
4b
4b
4c
CH2
O
2
3
3
3
3
94b
85
O
34c
82d
86
O
NCH3
a At 80 °C in toluene. b Obtained after simple extraction. c At
100 °C in DMF. d At 80 °C in DMF.
yields in accordance with Hammett constants.22 At an
identical temperature (70 °C), the best result was ob-
tained with p-methoxyphenol (Table 1, entry 1). Never-
theless, similar yields were obtained with electron defi-
cient phenols in the same reaction time by increasing the
temperature (Table 1, entries 5-7). With p-nitrophenol
(Table 1, entry 8), no conversion was observed at 70 °C
in accordance with the strong electron-withdrawing effect
of the nitro group (higher Hammett constant, σp+ ) 0.78).
At 120 °C, the consumption of 3-bromobenzo[b]thiophene
1-oxide 2 was complete, but no expected product was
detected. We assumed that a degradation of the sulfoxide
2 occurred at this temperature.
The SNAr reaction of compound 2 was also carried out
with secondary amines and no other base (Scheme 2).
With 2 equiv of amine, yields are significantly improved
by decreasing the reaction temperature to 80 °C. Indeed,
a yield of only 34% was obtained with morpholine at 100
°C in DMF (Table 2, entry 2) versus a yield of about 85%
at 80 °C in DMF or toluene (Table 2, entries 3 and 4). At
temperatures higher than 80 °C, degradation of 3-ami-
nobenzo[b]thiophene 1-oxides 4a-c was observed. Tolu-
ene was preferred over DMF because it is easier to
remove. In conclusion, lower reaction temperatures as-
sociated with shorter reaction times (2-3 h) minimized
degradation of 3-bromobenzo[b]thiophene 1-oxide 2. Hence,
The reduction of 3-(p-cyanophenoxy)benzo[b]thiophene
1-oxide 3f with Dibal-H produced an imine derivative
characterized by 1H and 13C NMR analyses. Purification
of this crude product by flash chromatography produced
aldehyde 6 and amine 7 in 39% and 33% yields, respec-
(23) (a) Johnson, F.; Duquette, L. G.; Whitehead, A.; Dorman, L. C.
Tetrahedron 1974, 30, 3241-3251. (b) Maas, W.; Janssen, M. J.;
Stamhuis, E. J.; Wynberg, H. J. Org. Chem. 1967, 32, 1111.
(24) Grese, T. A.; Pennington, L. D.; Sluka, J. P.; Adrian, M. D.;
Cole, H. W.; Fuson, T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.;
Shetler, P. K.; Short, L. L.; Venugopalan, M.; Yang, N. N.; Sato, M.;
Glasebrook, A. L.; Bryant, H. U. J. Med. Chem. 1998, 41, 1272.
(25) Yoon, N. M.; Gyoung, Y. S. J. Org. Chem. 1985, 50, 2443.
(22) Smith, M. B.; March, J. Advanced Organic Chemistry: Reac-
tions, Mechanisms, and Structure, 5th ed.; Wiley-Interscience: New
York, 2001.
J. Org. Chem, Vol. 70, No. 9, 2005 3571

David et al.
TABLE 3. Reduction of Sulfoxide Derivatives
TABLE 4. Arylation of Benzo[b]thiophene Derivatives
entry substrate product reaction time (h) isolated yield (%)a
reaction
time (h)
conversiona
entry
substrate
product
(isolated yield)b (%)
1
2
3a
3b
3c
3c
3d
3e
3f
5a
5b
5c
5c
5d
5e
6
5
5
81
63
85
-
72
80
39c
33c
72
75
68
1
2
5a
5b
5c
5c
5c
5d
5e
5f
5g
5g
5g
5h
5i
8a
8b
8c
9c
10c
8d
8e
8f
8g
9g
10g
8h
8i
7
7
6
8
9
8
9
5
3
7
4
9
9
94 (67)
92 (61)
91 (69)
97 (73)
91 (70)
96 (60)
95 (60)
90 (73)
95 (80)
91 (63)
98 (75)
100 (65)
94 (52)
3
5
4
24b
5
3
5
4
6
5
5
7
5
6
8
3f
7
5
7
9
4a
4b
4c
5g
5h
5i
2b
8
10
11
0.5b
9
3b
10
11
12
13
a At 65 °C with 1.3 equiv of Dibal-H. b At room temperature with
1.3 equiv of Dibal-H, no total conversion. c With 4 equivs of Dibal-
H.
a Determined by GC. b Performed with 5% Pd(OAc)2, 3 equiv of
K2CO3, 1.1 equiv of aryl bromide, and 1 equiv of DCH-18-C-6 in
DMF at 110 °C.
SCHEME 4. Reduction of
3-(p-Cyanophenoxy)benzo[b]thiophene 1-Oxide
step, whereas usual arylation reactions,32 such as
Stille-,33 Kumada-,34 or Suzuki-type35 coupling, require
a prior regioselective halogenation of the substrate and
the use of organometallic reagents. On the basis of this
efficient one-step catalytic benzo[b]thiophene arylation
(Scheme 5), 3-substituted benzo[b]thiophenes 5a-i were
arylated at the 2-position.
The activation of the 2,3-double bond by a functional
group at the 3-position is necessary to obtain acceptable
yields without any phosphine. This reaction was per-
formed with electron-donating and electron-withdrawing
substituents at the 3-position. To avoid the symmetrical
Ullmann-type coupling side reaction of the aryl halide,
aryl bromides were preferred to their iodide analogues.36
Heck-type couplings were carried out using a slight
excess of aryl bromide, an excess of potassium carbonate
as a base, and a crown ether, DCH-18-C-6, in DMF at
110 °C (Table 4).
Moderate to good yields (60-80%) were obtained with
3-phenoxybenzo[b]thiophenes (Table 4, entries 1-8) as
well as with 3-aminobenzo[b]thiophenes (Table 4, entries
9-13). No influence from the electron-rich or electron-
poor nature of the aryl bromide was noticed (Table 4,
entries 3-5 and 9-11). Generally, conversions are above
90% with short to moderate reaction times. However,
isolated yields rarely exceeded 70%. In fact, without an
external reducing agent, such as phosphine, small quan-
tities of benzo[b]thiophene dimer were formed during the
Heck-like coupling along with the reduction of Pd(II) into
Pd(0), hence the gap between the conversion and the
isolated yield. Moreover, this dimerization and the
byproduct resulting from the symmetrical Ullmann-type
coupling of the aryl halide complicated further purifica-
tions leading to moderate isolated yields of the pure
desired product.
tively (Scheme 4) (Table 3, entries 7 and 8). According
to a recent procedure described by Carretero et al.26 for
the reduction of a tert-butylsulfoxide group into a tert-
butylsulfinyl group, a chemoselective sulfoxide reduction
of the cyano derivative 3f was undertaken with a mixture
of HSiCl3 and N,N-dimethylaniline in xylene27 to produce
3-(p-cyanophenoxy)benzo[b]thiophene 5f in a yield of 75%
(Scheme 4).
Coupling. Miura28 and Ohta29 were the first to report
the synthesis of 2-arylbenzo[b]thiophenes in moderate
yields using palladium salts and triphenylphosphine.
Recently, Sall15 and Samat30 described the synthesis of
2-arylbenzo[b]thiophene derivatives by Suzuki coupling
in better yields. On the basis of the improvements of a
catalytic Heck-type reaction previously developed on
thiophene derivatives,31 we succeeded in the direct ary-
lation of 3-substituted benzo[b]thiophenes.12,13 This method
allowed us to synthesize 2-arylbenzo[b]thiophenes in one
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Patent 771812, 1997.
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Chem. Rev. 2002, 102, 1359.
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3572 J. Org. Chem., Vol. 70, No. 9, 2005

2-Aryl-3-Substituted Benzo[b]thiophenes
SCHEME 5. Heck-Type Coupling of Benzo[b]thiophene Derivatives
Conclusion
Acknowledgment. The authors thank the MRT for
E.D.’s grant.
The use of the sulfoxide form of 3-bromobenzo[b]-
thiophene allowed its nucleophilic substitution with
various phenolates and secondary amines in good yields.
3-Phenoxy and 3-aminobenzo[b]thiophene 1-oxide deriva-
tives were reduced and then coupled with various aryl
halides according to a Heck-type reaction to produce a
series of 3-phenoxy and 3-amino-2-arylbenzo[b]thiophenes.
This new methodology allows direct access to a large
number of 2,3-disubstituted benzo[b]thiophenes of great
potential biological properties.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds, 1H NMR
and 13C NMR spectra of compounds 2, 3c, 4a, 5c, 5g, 6, 7, 8c,
9c, 10c, 8g, 9g, and 10g. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0500378
J. Org. Chem, Vol. 70, No. 9, 2005 3573