Bromination of 3-substituted benzo[b]thiophenes: Access to Raloxifen intermediate

Article abstract of DOI:10.1016/j.tetlet.2011.05.043

A practical route to prepare halogeno-derivatives is described, starting from easily available 3-cyano-benzo[b]thiophene. Main efforts have been devoted to the optimization of the experimental procedures (solvent, bromination) to promote selectivity. Synt

Full text of DOI:10.1016/j.tetlet.2011.05.043

Tetrahedron Letters 52 (2011) 3736–3739
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bromination of 3-substituted benzo[b]thiophenes: access
to Raloxifen intermediate
⇑
⇑
François Liger, Stéphane Pellet-Rostaing , Florence Popowycz, Marc Lemaire
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR-CNRS 5246, Equipe Catalyse Synthèse Environnement, Université de Lyon,
Université Claude Bernard–Lyon 1, Bâtiment Curien, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical route to prepare halogeno-derivatives is described, starting from easily available 3-cyano-
benzo[b]thiophene. Main efforts have been devoted to the optimization of the experimental procedures
(solvent, bromination) to promote selectivity. Synthetic studies investigate the potential access to an
advanced intermediate of Raloxifen.
Received 11 April 2011
Revised 6 May 2011
Accepted 10 May 2011
Available online 18 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzo[b]thiophene
Bromination
Electrophilic aromatic substitution
Raloxifen
Raloxifen, a 2-arylbenzo[b]thiophene marketed by Eli Lilly on
the trademark EvistaÒ, displayed excellent properties as a selective
estrogen receptor modulator. Its therapeutic benefit is devoted to
reduce the risk of invasive breast cancer in postmenopausal wo-
men with osteoporosis or presenting a high class of risk for inva-
sive breast cancer.1 During the last five years, the laboratory has
been interested in the reactivity of benzo[b]thiophenes especially
developing new pallado-catalyzed direct arylation on C-2 posi-
tion.2 In this Letter, we wish to report the optimization and studies
related to the access of 6-bromo-3-cyanobenzo[b]thiophene, envi-
sioned as a synthetic intermediate of Raloxifen (Scheme 1).
O
O
CN
N
OMe
OH
S
MeO
S
HO
Raloxifen
direct arylation
CN
S
Br
Scheme 1. Retrosynthetic access to Raloxifen.
The electrophilic aromatic substitution (EAS) is a classical func-
tionalization method of aromatic compounds based on the relative
high electronic density of aromatic systems. EAS requires activa-
tion of the electrophile (strongly dependent of the reagents) and
occurs in a two-step mechanism: after addition of the in situ gen-
erated electrophilic species on the aromatic ring, a cyclohexadienyl
substitution have been already described in literature. Activation
by electro-donating group promoted regioselective substitution
on electronically enriched benzene.3 Other cases reported the
mono-functionalization of benzene requiring substituents in C-2
and/or C-3 positions.4,5 The most representative work was devel-
oped by Dickinson with an electrophilic bromination of 2-bromo-
3-methyl-benzo[b]thiophene allowing a mixture of regioisomers
(C-4 and C-6 positions) followed by a debromination of the C-2
position by a halogen-lithium exchange/hydrolysis sequence. An
inseparable mixture of 6-bromo-3-methylbenzo[b]thiophene and
4-bromo-3-methylbenzo[b]thiophene in a ratio 4:1 was obtained
within 62% global yield.6
carbocation ring is formed (named as
r complex). The arenium ion
(Wheland complex), evolves rapidly to regenerate the aromaticity
of the system. The benzo[b]thiophene nucleus is composed of two
fused aromatic rings with the thiophene scaffold which is electron-
ically enriched by the presence of the sulphur atom, reacting thus
quickly in comparison with the benzene ring. Some strategies to
functionalize the benzene moiety through electrophilic aromatic
In this Letter, the laboratory describes some strategies to
functionalize the benzenic part through electrophilic aromatic
substitution remaining free the C-2 position and to promote the
methodology to target intermediates that could be involved in
⇑
Corresponding authors. Tel.: +3 346 633 9308; fax: +3 346 679 7611 (S.P-R.);
tel.: +33 47 243 1409; fax: +33 47 243 1408 (M.L.).
E-mail addresses: stephane.pellet-rostaing@cea.fr (S. Pellet-Rostaing), marc.le-
maire@univ-lyon1.fr (M. Lemaire).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.043

F. Liger et al. / Tetrahedron Letters 52 (2011) 3736–3739
3737
a. NBS (2 equiv), CHCl3
TFA (10%), r.t., 24 h
b. MeOH, H2SO4
reflux, 18 h
Br
4
CN
CN
COOMe
COOH
COOMe
Br
S
Br
major
S
6
S
S
S
90%
Br
CN
1
2a
2b
4
6
Br2 (3 equiv), solvent
r.t., 18 h
ratio 1.5 : 1 no separation
CN
S
Scheme 2. Bromination on 3-benzo[b]thiophene carboxylic acid.
CN
3
5
Br
S
7
S
the synthesis of therapeutic drug Raloxifen. Thus, the preliminary
researches investigated the bromination of the benzo[b]thio-
phene-3-carboxylic acid 1. Treatment with N-bromosuccinimide
(2 equiv) led to the formation of two regioisomers functionalized
at the C-6 and C-5 positions respectively in a 1.5:1 ratio (Scheme
2). The reaction was conducted in chloroform associated with
10% of trifluoroacetic acid, enhancing the solubility of the starting
material and favoring the activation of the electrophilic bromine.
The acidic conditions promoted the reactivity of NBS as 2 equiv
were required to fulfill complete disappearance of 3-benzo[b]
thiophene carboxylic acid. The presence of a carboxylic acid group
provided attractive mesomeric effect (-M) to decrease the density
of thiophene ring and to avoid the C-2 halogenation. No trace
of 2-bromo-3-benzo[b]thiophene carboxylic acid was detected.
Unfortunately, both regioisomers were impossible to separate by
flash column chromatography even after derivatization into their
corresponding esters 2a and 2b.
The reactivity of the benzo[b]thiophene to EAS and the func-
tionalization of the positions were predicted by the work of Tay-
lor.7 Concerning the benzenic ring, the established order of
preferred position is the following: C-6 > C-5 > C-4 > C-7. The re-
sults obtained are in accordance with this order as the C-6 and
C-5 brominated derivatives were only obtained with a rather
favorable proportion in C-6 position.
Br
minor
5
7
Scheme 4. Regioselectivity studies on bromination.
carried out on 3-cyano-benzo[b]thiophene 3 with 3 equiv of Br2
in CHCl3 provided a global conversion of 75% in mono-bromi-
nated compounds 4, 5, 6, 7 (isolated yield: 60%). More interest-
ing was the presence of compounds 4 and 6 in major quantity
(in comparison with compounds 5 and 7 isolated in minor
quantity).
The influence of the solvent was mainly investigated screening
a wide variety of polar, apolar, protic, aprotic characteristics. Start-
ing material 3 was dissolved in the appropriate solvent (0.5 M), in
the presence of 3 equiv of bromine at room temperature during
24 h.9 The 1H NMR analysis assigned the relative ratio of all the
regioisomers 4, 5, 6, 7 (Table 1).
In view of the results obtained by analysis of the crude reac-
tion mixture by NMR, the solvent seems to influence moderately
the impact of the bromination on the different C-4, C-5, C-6 and
C-7 positions. Only DMF increases significantly the general selec-
tivity of the reaction to 15.7/1 (major vs minor) in comparison
with other solvents (average selectivity 6/1). But DMF was not
the most efficient for the selectivity 6-Br/4-Br. Valuable informa-
tion was also obtained with acetonitrile providing the best ratio
6-Br/4-Br of 2.6 and to a certain extent, nitromethane also sug-
gested interesting selectivity. Considering the donating capacity
of both solvents in the classification of Gutmann (DNMeCN
14.1; DNDMF: 26.6), the solvatation of the bromine species, the
stabilization of complexes could be some factors explaining
the difference of regioselectivity. Table 2 summarized the influ-
ence of the Br2 concentration using 3-cyano-benzo[b]thiophene
3 dissolved at 0.5 M in the appropriate solvent. As already
described above, DMF and MeCN were the most efficient and
selective solvents for the bromination reaction. Best yields were
finally obtained with 5 equiv of Br2 in DMF or acetonitrile
(Table 2).10
Classical aromatic electrophilic brominations by bromine are
under kinetic control: the presence of the C-4 brominated deriva-
tive 4 as secondary major product (instead of the C-5 brominated
derivative 5, in accordance to Taylor’s7 prediction) may come from
an enhanced stability of the Wheland complex intermediate. The
arenium intermediates associated to the four brominated regioi-
somers were studied (Table 3). We evaluated their global energies
after geometrical optimization with HyperchemÒ (ab-initio meth-
od, 3-21G algorithm, RMS gradient = 0.001).
Increase of the number of equivalents of NBS (5.5 equiv) on
compound 1 provided, after esterification the 5,6-dibrominated
compound with a modest yield of 23% (two steps). The carboxylic
acid group allowed the access to new halogenated derivative of
benzo[b]thiophene pattern with a control of the bromination in
favor of the benzenic ring. Some major drawbacks were faced:
separation problems and low yield which encouraged us to focus
on 3-cyano-benzo[b]thiophene derivative 3.
:
r
In a presence of a slight excess of NBS (1.2 equiv), the formation
of four mono-brominated regioisomers was observed with 45% of
recovery of starting material (Scheme 3).
The 1H NMR analysis allowed us to assign the proportion of all
the regioisomers, respectively, 37% (Br in C-4), 9% (in C-5), 48% (in
C-6) and 6% (in C-7). Nevertheless, the conversion remained low
and the introduction of additional quantity of NBS (until 2 equiv)
ran to failure (several di-brominated derivatives, partial conver-
sion). The dibromination, on a kinetically aspect, appears to be
faster than the first bromination step.
The brominating agent was thus replaced by molecular bro-
mine, supposed to be less electrophilic in comparison with NBS
(Scheme 4).8 The purpose of using Br2 is to find a balance
between efficient conversion and selectivity. First experiment
The difference of energy (compared to
and 7 (>3 kcal/mol) while that of 4 is relatively low (>1 kcal/
mol). The theoretical stability order is: r6-Br 4-Br > > r5-Br
r7-Br and this is in appropriateness with experimental results
pointing out the compounds 4 and 6 as major products of the reac-
tion. The carboxylic acid, an electro-withdrawing group as nitrile
function, should also orientate the substitution in favor of C-6
and C-4 positions. The bulky influence of CO2H probably led to
r6) is higher with r5
CN
CN
NBS (1.2 equiv), CHCl3, TFA
1% H2SO4, r.t., 24 h
r
r
>
r
>
Br
S
(conversion: 55%)
S
3
Regioisomers ratio
4
5
6
7
4-Br : 37%
5-Br : 9%
6-Br : 48%
7-Br : 6%
destabilized
r
complex in C-4 position. This un-stabilization may
complexes
Scheme 3. Bromination on 3-cyanobenzo[b]thiophene.
induce a modification of the stability order of the
r

3738
F. Liger et al. / Tetrahedron Letters 52 (2011) 3736–3739
Table 1
Solvent optimization conditions
Solvent
% 4-Br 4
% 5-Br 5
% 6-Br 6
% 7-Br 7
Ratio major/minor
Ratio 6-Br/4-Br
CHCl3
Et2O
34
7
51
8
5.7
—
1.5
—
No conversion
Cl(CH2)2Cl
MeNO2
AcOH
MeCN
DMF
31
28
33
24
39
38
7
8
7
8
4
6
53
58
52
63
55
49
9
6
8
5
2
7
5.3
6.1
5.7
6.7
15.7
6.7
1.7
2.1
1.6
2.6
1.4
1.3
HmimPF6
In summary, we have developed expertize on the synthesis of
new halogenated benzo[b]thiophenes by electrophilic aromatic
substitution. The presence of an electro-withdrawing group on
the nucleus promoted the mono-bromination as well as the orien-
tation of the substitution on the benzenic part. The proportion of
isomers is strongly dependent on the experimental conditions
(nature of the substituent in C-3 position, strong effect solvent)
but in adequation with the theoretical predictions. The major com-
pound 6 was obtained with a good isolated yield of 60% and should
be an excellent building block for more complex molecules of ther-
apeutic interest such as Raloxifen.
Table 2
Overview of optimized isolated yields
Solvent
Br2 (equiv)
Yield 6-Br (%)
Yield 4-Br (%)
Yield (%)
CHCl3
Cl(CH2)2Cl
DMF
3.5
4.0
5.0
5.0
32
41
54
60
22
20
30
22
54
61
87
82
MeCN
as following: r6-Br > r5-Br > > r4-Br > r7-Br and should be an expla-
nation of the major formation of 6-bromo- and 5-bromo-
benzo[b]thiophene carboxylic acids.
References and notes
In the aim of promoting the bromination methodology, devel-
oped in our laboratory, the 6-bromo-3-cyanobenzo[b]thiophene 6
was converted into derivative 8 in the Miyaura conditions in the
presence of bis(pinacolato)diboron (1.2 equiv). Boronic ester 8 was
directly oxidized by hydroxylamine11 in basic medium providing
phenol 9 in 74% within two steps.12 Subsequent alkylation with
iodomethane provided in excellent yield methyl ether 10.13 Direct
arylation of benzo[b]thiophene in C-2 position was performed in
the presence of 4-bromoanisole (2 equiv), Pd(OAc)2 (5 mol %)/PPh3
(10 mol %) as a catalytic system and potassium carbonate as a base
affording synthetic intermediate 11 of Raloxifen (Scheme 5).14
1. (a) Delmas, P. D.; Ensrud, K. E.; Adachi, J. D.; Harper, K. D.; Sarkar, S.; Gennari,
C.; Reginster, J.-Y.; Pols, H. A. P.; Recker, R. R.; Harris, S. R.; Wu, W.; Genant, H.
K.; Black, D. M.; Eastell, R. J. Clin. Endocrinol. Metab. 2002, 87, 3609–3617; (b)
Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, 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.; Philipps, D. L.; Rowley, E. R.; Short, L. L.; Glasebrook,
A. L.; Bryant, H. U. J. Med. Chem. 1997, 40, 146–167; (c) Jones, C. D.; Jevnikar, M.
G.; Pike, A. J.; Peters, M. K.; Black, L. J.; Thompson, A. R.; Falcone, J. F.; Clemens, J.
A. J. Med. Chem. 1984, 27, 1057–1066.
2. (a) Popowycz, F.; Métay, E.; Lemaire, M. C. R. Chimie 2011. doi:10.1016/
j.crci.2010.06.006; (b) Li, L.; Chang, L.; Pellet-Rostaing, S.; Liger, F.; Lemaire, M.;
Buchet, R.; Wu, Y. Bioorg. Med. Chem. 2009, 17, 7290–7300; (c) David, E.;
Table 3
Molecular modeling tool for the four arenium intermediates with Hyperchem
CN
Br
H
CN
CN
CN
H
Br
+
+
+
+
r
Intermediate
H
Br
S
S
S
S
σ7
σ5
H
σ4
Br
σ6
E (kcal/mol)
With
À2102952.289
À2102951.676
À2102949.215
À2102947.734
r
6
—
613 cal/mol
3074 cal/mol
4555 cal/mol
O
O
O
O
B
B
1.2 eq.
CN
NH2OH.HCl (2 equiv)
CN
CN
PdCl2(dppf).CH2Cl2 (3 mol%)
AcOK (5 equiv)
NaOH 3 M, EtOH
r.t., 24 h
O
B
DMSO, 80°C, 20 h
S
S
S
Br
HO
74%, 2 steps
O
6
8
9
MeO
2 eq.
Br
Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
K2CO3 (3 eq), DMF, 120°C, 40 h
CN
CN
CH3I (2 equiv), K2CO3 (4 equiv)
acetone, r.t., 18 h
OMe
S
S
MeO
66%
MeO
85%
11
10
Scheme 5. Access to the synthetic intermediate 12 of Raloxifen.

F. Liger et al. / Tetrahedron Letters 52 (2011) 3736–3739
3739
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Tetrahedron Lett. 2008, 49, 1860–1864; (d) David, E.; Pellet-Rostaing, S.;
Lemaire, M. Tetrahedron 2007, 63, 8999–9006; (e) Fournier Dit Chabert, J.;
Chatelain, G.; Pellet-Rostaing, S.; Bouchu, D.; Lemaire, M. Tetrahedron Lett.
2006, 47, 1015–1018; (f) David, E.; Rangheard, C.; Pellet-Rostaing, S.; Lemaire,
M. Synlett 2006, 2016–2020; (g) David, E.; Perrin, J.; Pellet-Rostaing, S.;
Fournier Dit Chabert, J.; Lemaire, M. J. Org. Chem. 2005, 70, 3569–3573; (h)
Fournier Dit Chabert, J.; Joucla, L.; David, E.; Lemaire, M. Tetrahedron 2004, 60,
3221–3230; (i) Hassan, J.; Gozzi, C.; Schulz, E.; Lemaire, M. J. Organomet. Chem.
2003, 687, 280–283; (j) Fournier Dit Chabert, J.; Gozzi, C.; Lemaire, M.
Tetrahedron Lett. 2002, 43, 1829–1833.
after cooling, partitioned between Et2O (50 mL), H2O (40 mL) and saturated
aqueous NaHCO3 solution (10 mL). The organic layer was separated, and
aqueous layer was extracted twice (2 Â 50 mL) with Et2O. The combined
organic extracts were dried (MgSO4), filtered, concentrated in vacuum and
afforded 8 as a pale brown solid: mp 121–123 °C (Et2O). 1H NMR (300 MHz,
DMSO-d6) d = 1.31 (s, 12 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.96 (d, J = 7.5 Hz, 1 H),
8.48 (s, 1 H), 8.97 (s, 1 H) ppm. 13C NMR (75 MHz, DMSO-d6) d = 24.6 (4 CH3),
84.0 (2 C), 105.2 (C), 114.2 (C), 121.1 (CH), 126.0 (C), 130.1 (CH), 131.2 (CH),
138.0 (C), 139.0 (C), 142.8 (CH) ppm.
The corresponding residue 8 was dissolved in EtOH (10 mL). Then NH2OH.HCl
(140 mg, 2 mmol) followed by 3 M aqueous NaOH solution (1 mL) was added.
After stirring for 24 h at room temperature, the mixture was dissolved in H2O
(30 mL), neutralized to pH 7 with CH3COOH and extracted with CH2Cl2. The
organic layer was dried with Na2SO4, filtered and evaporated in vacuum.
Purification by flash chromatography (SiO2, cyclohexane/EtOAc 80:20) gave 9
(130 mg, 74% yield in two steps) as a white solid: mp 178–180 °C (CH2Cl2/
pentane). 1H NMR (300 MHz, acetone-d6) d = 7.17 (dd, J = 8.6, 2.3 Hz, 1 H), 7.50
(d, J = 2.3 Hz, 1 H), 7.78 (d, J = 8.6 Hz, 1 H), 8.34 (s, 1 H), 8.96 (s, 1 H) ppm. 13C
NMR (75 MHz, acetone-d6) d = 107.0 (C), 108.8 (CH), 115.0 (C), 117.2 (CH),
123.5 (CH), 131.2 (C), 136.5 (CH), 141.3 (C), 157.4 (C) ppm.
3. Rahman, L. K. A.; Scrowston, R. M. J. Chem. Soc., Perkin Trans. 1 1983, 2973–
2977.
4. Cagniant, P.; Faller, P.; Cagniant, D. Bull. Soc. Chim. Fr. 1966, 3055–3065.
5. Kim, E.; Kim, M.; Kim, K. Tetrahedron 2006, 62, 6814–6821.
6. Cross, P. E.; Dickinson, R. P. Heterocycles 1989, 23, 2391–2399.
7. Amin, H. B.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1978, 1053–1058.
8. Djerassi, C. Chem. Rev. 1948, 43, 271–317.
9. General procedure for the synthesis of bromo-benzo[b]thiophene-3-carbonitriles
derivatives:
To a stirred solution of benzo[b]thiophene-3-carbonitrile (1.23 g, 7.7 mmol) in
appropriate anhydrous solvent (15 mL) were slowly added 3 equiv of bromine
(1.2 mL, 23.1 mmol). The resulting mixture was stirred at room temperature
overnight. If the reaction was not complete (as observed by TLC or 1H NMR),
additional bromine was added (0.5 equiv per 0.5 equiv) until total
consumption of the starting material. Then the mixture was partitioned
between CH2Cl2 (120 mL) and 10% aqueous NaHCO3 solution (120 mL). To this
biphasic solution was added dropwise, under vigorous stirring, saturated
aqueous Na2S2O3 solution until discoloration of the organic medium. The
organic layer was separated, and the aqueous layer was extracted twice with
CH2Cl2 (2 Â 50 mL). The combined extract was dried (MgSO4), filtered and
concentrated under vacuum. The resulting residue was purified by flash
chromatography (SiO2, cyclohexane/EtOAc 93:7) to afford the pure desired
product.
13. Experimental procedure and physical data for compound 10:
To
(110 mg, 0.63 mmol) in anhydrous acetone (6.3 mL) were added, under
argon atmosphere, K2CO3 (348 mg, 2.52 mmol) and iodomethane (78 L,
a stirred solution of 6-hydroxy-benzo[b]thiophene-3-carbonitrile 9
l
1.26 mmol). The mixture was stirred for 24 h at room temperature and
partitioned between H2O and CH2Cl2. The organic layer was separated, and
aqueous layer was extracted twice with CH2Cl2. The combined extracts were
dried (MgSO4), filtered and concentrated in vacuum. The resulting residue was
purified by flash chromatography (SiO2, cyclohexane/EtOAc 70:30) to give 10
(101 mg, 85% yield) as a white solid: mp 88–90 °C (CH2Cl2/pentane). 1H NMR
(300 MHz, CDCl3) d = 3.90 (s, 3 H, OMe), 7.16 (dd, J = 8.9, 2.3 Hz, 1 H), 7.34 (d,
J = 2.3 Hz, 1 H), 7.87 (d, J = 8.9 Hz, 1H), 7.94 (s, 1H) ppm. 13C NMR (75 MHz,
CDCl3) d = 55.8 (CH3), 105.1 (CH), 106.8 (C), 114.6 (C), 116.3 (CH), 123.2 (CH),
131.3 (C), 135.0 (CH), 140.3 (C), 158.8 (C) ppm.
10. Physical data for major compounds 4 and 6:
14. Experimental procedure and physical data for compound 11:
4-Bromo-benzo[b]thiophene-3-carbonitrile (4). Solvent: anhydrous N,N-
dimethyformamide; isolated yield: 30%; white solid; mp: 159–161 °C
(MeOH). 1H NMR (300 MHz, CDCl3): d = 7.32 (t, J = 7.9 Hz, 1 H), 7.69 (dd,
J = 7.9, 1.0 Hz, 1H), 7.86 (dd, J = 7.9, 1.0 Hz, 1 H), 8.26 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): d = 108.0 (C), 115.2 (C), 117.2 (C), 122.4 (CH), 127.1 (CH),
130.9 (CH), 134.7 (C), 140.2 (C), 140.9 (CH) ppm.
A Schlenk tube was charged with benzo[b]thiophene 10 (1 mmol), Pd(OAc)2
(11 mg, 0.05 mmol), PPh3 (26 mg, 0.10 mmol), K2CO3 (415 mg, 3 mmol) under
argon atmosphere and sealed with a rubber septum. Then anhydrous N,N-
dimethylformamide (1 mL) and 4-bromoanisole (2 mmol) were added and the
mixture was heated at 120 °C for 40 h. After cooling, the mixture was
partitioned between H2O and CH2Cl2. The organic layer was separated, and
aqueous layer was extracted twice with CH2Cl2. The combined organic extracts
were dried (MgSO4), filtered and concentrated in vacuum. The resulting residue
was purified by flash chromatography (SiO2, cyclohexane/EtOAc 80:20) to
afford 6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene-3-carbonitrile 11
(195 mg, 66%); white solid; mp 129–131 °C (CH2Cl2/pentane). 1H NMR
(300 MHz, CDCl3) d = 3.88 (s, 3 H), 3.90 (s, 3 H), 7.02 (d, J = 9.0 Hz, 2 H), 7.12
(dd, J = 8.9, 2.3 Hz, 1 H), 7.28 (d, J = 2.3 Hz, 1 H), 7.80 (d, J = 8.9 Hz, 1 H), 7.82 (d,
J = 9.0 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3) d = 55.6 (CH3), 55.8 (CH3), 100.3
(C), 105.0 (CH), 114.8 (2 CH), 115.7 (C), 115.9 (CH), 123.1 (CH), 124.3 (C), 129.5
(2 CH), 133.2 (C), 138.5 (C), 152.6 (C), 158.5 (C), 161.2 (C) ppm.
6-Bromo-benzo[b]thiophene-3-carbonitrile (6). Solvent: acetonitrile; isolated
yield: 60%; white solid; mp: 148–150 °C (MeOH). 1H NMR (300 MHz, CDCl3):
d = 7.66 (dd, J = 8.5, 1.0 Hz, 1 H), 7.87 (d, J = 8.5 Hz, 1 H), 8.07 (d, J = 1.0 Hz, 1 H),
8.10 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): d = 107.2 (C), 113.9 (C), 120.5 (C),
123.7 (CH), 125.5 (CH), 129.7 (CH), 136.1 (C), 138.0 (CH), 140.0 (C) ppm.
11. Kianmehr, E.; Yahyaee, M.; Tabatai, K. Tetrahedron Lett. 2007, 48, 2713–2715.
12. Experimental procedure and physical data for compound 9:
A Schlenk tube was charged with 6-bromo-benzo[b]thiophene-3-carbonitrile 6
(238 mg, 1 mmol), PdCl2(dppf).CH2Cl2 (24 mg, 0.03 mmol), bis(pinacolato)
diboron (305 mg, 1.2 mmol), AcOK (491 mg, 5 mmol) and anhydrous DMSO
(3 mL) under argon atmosphere. The mixture was heated at 80 °C for 20 h and,