Synthesis of new 2-arylbenzo[b]thiophenes using 'Heck-type' technology

Article abstract of DOI:10.1016/S0040-4039(02)00128-4

Direct 3-substituted benzothiophene arylation using a Heck-type reaction with Pd(OAc)₂/n-Bu₄NBr as a catalytic system is reported. This reaction was found to perform relatively fast whatever the electron-donating or the electron-withdrawing group at position 3. We also extended this reaction to several aromatic halides, such as benzene, naphthalene and pyridine derivatives, synthesising new 2-arylbenzo[b]thiophenes in moderate to good yields.

Full text of DOI:10.1016/S0040-4039(02)00128-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1829–1833
Synthesis of new 2-arylbenzo[b]thiophenes using ‘Heck-type’
technology
Je´re´mie Fournier Dit Chabert, Christel Gozzi and Marc Lemaire*
Laboratoire de Catalyse et Synthe`se Organique, Universite´ Claude Bernard Lyon 1, UMR 5622, Baˆt 308 CPE,
43 Bd. Du 11 Novembre 1918, 69616 Villeurbanne Cedex, France
Received 6 December 2001; accepted 17 January 2002
Abstract—Direct 3-substituted benzothiophene arylation using a Heck-type reaction with Pd(OAc)2/n-Bu4NBr as a catalytic
system is reported. This reaction was found to perform relatively fast whatever the electron-donating or the electron-withdrawing
group at position 3. We also extended this reaction to several aromatic halides, such as benzene, naphthalene and pyridine
derivatives, synthesising new 2-arylbenzo[b]thiophenes in moderate to good yields. © 2002 Published by Elsevier Science Ltd.
1. Introduction
We used a catalytic arylation reaction developed in our
laboratory on thiophenes,10 which involved the use of a
catalytic amount of palladium diacetate, in the presence
of tetra-n-butylammonium bromide and an excess of
potassium carbonate as an inorganic base. By analogy
with the Heck reaction,11 we assumed that if we could
conveniently activate the benzothiophene 2,3-double
bond at the 3-position by an electron-withdrawing
group, the coupling would thus be facilitated. Hence we
first performed the reaction on benzo[b]thiophene-3-
carbonitrile 1.12
Over the past few years, 2-arylbenzo[b]thiophenes
derivatives were found to be promising agents for the
treatment of various diseases such as hypolipemia1 and
estrogen dependant diseases.2 2-Arylbenzo[b]thiophenes
are usually synthesised via an intramolecular cyclisation
from thiobenzyls.3 However, most of these methods are
not compatible with fragile groups and the cyclisations
are often carried out in moderate overall yields after
several steps. In this paper, we focussed on a method
allowing the direct arylation of benzo[b]thiophenes.
Contrary to the usual arylation methods,4 of the Stille,5
Kumada6 and Suzuki-type,7 which all involve a regiose-
lective halogenation of the substrate and the use of an
organometallic reagent prior to the coupling, we suc-
ceeded in synthesising several 2-arylbenzo[b]thiophenes
in a one-step reaction. Indeed, Miura8 and Otha9 previ-
ously managed to arylate benzo[b]thiophene selectively
in moderate yields by utilising palladium salts,
triphenylphosphine and, for the first one, an over stoi-
chiometric amount of copper salt.
2. Results and discussion
Firstly, we achieved the arylation of the compound 1 at
relatively low temperature (90°C, Fig. 1) with aryl
iodides such as iodobenzene, 4-iodoanisole, 4-iodoben-
zotrifluoride and 1-iodonaphthyl (Table 1, entries 1–4).
Even if we observed a low reaction rate, we obtained a
good chemical yield but also a moderate selectivity of
CN
CN
Pd(OAc)2 5%, K2CO3, DMF
n-Bu4NBr 1 eq., 90 °C
Ar
Ar-X
Ar-Ar
+
+
S
S
1
2a-f
Figure 1. Arylation of benzo[b]thiophene-3-carbonitrile.
Keywords: benzo[b]thiophene; Heck-type aryl coupling; palladium catalysis.
* Corresponding author. Tel.: +33-4-72-44-82-09; fax: +33-4-72-43-14-08; e-mail: marc.lemaire@univ-lyon1.fr
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00128-4

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J. Fournier Dit Chabert et al. / Tetrahedron Letters 43 (2002) 1829–1833
Table 1. Arylation of 1 with aryl iodides
For typical procedure, see Ref. 15. (a) Values in parentheses are isolated yields. (b) Determined by GC analysis. (c) Temperature=140°C.
the arylation relative to the major side-reaction: a sym-
metrical Ullmann-type coupling of the aryl halide.13
Subsequent purification was complicated by the pres-
ence of these by-products, leading to moderate isolated
yields of the pure desired compound. Indeed, it is
noteworthy to outline that the most selective coupling
(entry 4) gave one of the best isolated yields (60%). At
higher temperature (140°C), we only noticed a decrease
of the selectivity and no better chemical yield. We also
performed the arylation on aryl bromides (entries 5 and
6), which are cheaper and more available than their
iodide homologues. It appeared that, at a higher tem-
perature (140°C), the reaction was still very selective
and did not involve any degradation of the ben-
zo[b]thiophene-3-carbonitrile due to lower reaction
times. We also observed a good selectivity of the cou-
pling toward the halogen type, as no reaction occurred
on the carbonꢀchlorine bond (entry 6). As these prod-
ucts were prepared in order to evaluate their biological
activity towards the diseases mentioned at the begin-
ning of this article, the resulting purification of these
compounds was performed very carefully (until +98%
1
purity, determined by microanalysis and H NMR) and
therefore several flash chromatographs and/or recrys-
tallisations were required.
With an electron-rich benzo[b]thiophene, such as 3-
methoxybenzo[b]thiophene14 3 (Fig. 2), isolated yields
were slightly higher (Table 2). Within shorter reaction
times
and
at
100°C,
2-aryl-3-methoxyben-
zo[b]thiophenes 4a–d were obtained in quite good iso-
lated yields (from 50 to 77%). This benzothiophene
even underwent coupling with 3-bromopyridine in an
acceptable reaction time and in a good yield (95% in 25
OMe
OMe
Pd(OAc)2 5%, K2CO3, DMF
n-Bu4NBr 1 eq., 100 °C
Ar
Ar-Ar
Ar-X
+
+
S
S
3
4a-e
Figure 2. Arylation of 3-methoxybenzo[b]thiophene.

J. Fournier Dit Chabert et al. / Tetrahedron Letters 43 (2002) 1829–1833
Table 2. Arylation of 3 with aryl halides
1831
(a) Values in parentheses are isolated yields. (b) Determined by GC analysis.
h, entry 4). Unfortunately, several attempts at higher
temperature (140°C) did not give better results. We
therefore assumed that the catalytic cycle was different
depending on the activating group on position 3.
Indeed, only very low conversion was observed by
coupling non-substituted benzo[b]thiophene with iodo-
benzene (12% conv. in 2 days) whatever the tempera-
ture (100°C or 140°C). In addition, it appeared that
2-substituted benzo[b]thiophenes, such as benzo[b]-
thiophene-2-carbonitrile, did not undergo any efficient
conversion with aryl halides (less than the amount of
catalyst, i.e. 5%). Thus, it is reasonable to suppose that
the transition state involves a stabilisation by the sul-
phur atom.
References
1. Sauter, F. FR 79-2897, 1979.
2. 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, 2002–2009.
3. (a) 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; (b)
Arnoldi, A.; Carughi, M. Synthesis 1988, 155–157; (c)
Watanabe, M.; Date, M.; Kawanishi, K.; Akiyoshi, R.;
Furukawa, S. J. Heterocyclic Chem. 1991, 28, 173–176;
(d) Capozzi, G.; De Sio, F.; Menichetti, S.; Nativi, C.;
Pacini, P. L. Synthesis 1994, 521–525.
4. For a review, see: Hassan, J.; Se´vignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, in press.
5. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508–524.
6. Kumada, M. Pure Appl. Chem. 1980, 52, 669–679.
7. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
8. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467–473.
9. Ohta, A.; Akita, Y.; Ohkuwa, T.; Fukunaga, M. C. R.;
Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocy-
cles 1990, 11, 1951–1958.
10. Lavenot, L.; Gozzi, C.; Ilg, K.; Orlova, I.; Penalva, V.;
Lemaire, M. J. Organomet. Chem. 1998, 567, 49–55.
11. Heck, R. F. Org. React. 1982, 27, 345–390.
12. For the synthesis of this molecule, see: Martynoff, M.
C.R. Hebd. Seances Acad. Sci. 1953, 236, 385–387.
3. Conclusions
We have developed an efficient one step benzo[b]thio-
phene arylation on the 2-position by utilising
Pd(OAc)2/n-Bu4NBr as a catalytic system. This reaction
proceeds with moderate to good yields with ben-
zo[b]thiophenes activated at the 3-position. This
method is compatible both with electron-rich and elec-
tron-poor aryl halides and may therefore be a good
alternative to the synthesis of raloxifene analogues.2
Additional experiments are now under investigation in
order to determine the catalytic mechanism as well as
to improve the efficiency of the reaction. Biological
studies of the synthesised molecules are currently
running.

1832
J. Fournier Dit Chabert et al. / Tetrahedron Letters 43 (2002) 1829–1833
N, 4.82; S, 11.00%, calcd for C19H11NS C, 79.96; H, 3.89;
N, 4.91; S, 11.24%; lH (300 MHz, CDCl3) 7.38–7.42 (m,
5H), 7.58 (dd, 1H, Haryl, J 1.3 and 7.2 Hz), 7.80 (ddd, 1H,
Hbenzo, J 0.8, 1.2 and 7.9 Hz), 7.84–7.92 (m, 3H), 7.96
(ddd, 1H, Hbenzo, J 0.8, 1.3 and 7.9 Hz); lC (75 MHz,
CDCl3) 107.4 (C), 115.0 (CN), 123.1 (CH), 123.4 (CH),
125.8 (CH), 125.9 (CH), 126.9 (CH), 127.0 (CH), 127.4
(CH), 128.0 (CH), 129.3 (CH), 129.4 (CH), 129.9 (CH),
131.6 (C), 132.1 (C), 134.5 (C), 138.9 (C), 139.4 (C), 154.6
(C) ppm; m/z 286 (55), 285 (100), 258 (60), 129 (55).
2e isolated yield: 66%, beige solid; mp 113–114°C; Rf 0.25
(silica, cyclohexane/AcOEt 95:5); found C, 76.87; H, 4.40;
N, 5.53; S, 13.23%, calcd for C16H11NS C, 77.07; H, 4.45;
N, 5.62; S, 12.86%; lH (300 MHz, CDCl3) 2.46 (s, 3H,
CH3), 7.32–7.48 (m, 4H), 7.50 (ddd, 1H, Hbenzo, J 1.3, 7.4
and 7.7 Hz), 7.58 (ddd, 1H, Hbenzo, J 1.3, 7.4 and 7.9 Hz),
7.90 (ddd, 1H, Hbenzo, J 0.8, 1.3 and 7.8 Hz), 8.03 (ddd,
1H, Hbenzo, J 0.8, 1.3 and 7.7 Hz); lC (75 MHz, CDCl3)
20.7 (CH3), 106.4 (C), 114.8 (CN), 122.8 (CH), 122.9
(CH), 126.5 (2 CH), 126.6 (CH), 130.7 (CH), 131.0 (CH),
131.4 (CH), 137.5 (2 C), 138.5 (C), 138.8 (C), 155.8 (C)
ppm; m/z 249 (100), 222 (30), 221 (50), 110 (40).
13. Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174–2184.
14. For the synthesis of this molecule, see: Acheson, M. R.;
Cooper, M. W. J. Chem. Soc., Perkin Trans. 1 1980,
1185–1193.
15. Typical procedure: A suspension of potassium carbonate
(3.75 mmol), tetra-n-butylammonium bromide (1.25
mmol), substituted benzothiophene (1.25 mmol) and aryl
halide (0.75 mmol) in N,N-dimethylformamide (1 mL)
was stirred under argon at the indicated temperature for
5 min. Palladium diacetate (0.0625 mmol) was then added
and the resulting mixture was allowed to stir for the time
indicated, adding stepwise aryl halide (0.375 by 0.375
mmol) until no change of the chemical yield (determined
by GC). After cooling to room temperature, the mixture
was filtered over Celite®, rinsed with dichloromethane (10
mL) and then successively washed with brine (10 mL), a
saturated sodium thiosulfate solution (10 mL) and water
(10 mL). The organic phase was dried over MgSO4,
filtered and concentrated to give a brown residue. The
latter was then purified by flash column chromatography
(silica, cyclohexane/ethyl acetate) and, if necessary, by
recrystallisation in pentane, to afford the pure desired
compound.
2f isolated yield: 72%; pale yellow solid; mp 145–146°C;
Rf 0.20 (silica, cyclohexane/AcOEt 95:5); found C, 66.90;
H, 3.02; N, 5.10; S, 12.08%, calcd for C15H8ClNS C,
66.79; H, 2.99; N, 5.19; S, 11.89%; lH (500 MHz, CDCl3)
7.45–7.47 (m, 2Haryl), 7.48 (ddd, 1H, Hbenzo, J 1.3, 7.3
and 8.2 Hz), 7.54 (ddd, 1H, Hbenzo, J 1.0, 7.3 and 8.2 Hz),
7.78–7.82 (m, 2Haryl), 7.85 (ddd, 1H, Hbenzo, J 0.6, 1.0
and 8.2 Hz), 7.97 (ddd, 1H, Hbenzo, J 0.6, 1.3 and 8.2 Hz);
lC (75 MHz, CDCl3) 103.3 (C), 115.1 (CN), 122.8 (CH),
123.2 (CH), 126.7 (2 CH), 126.9 (CH), 128.6 (CH), 131.8
(CH), 131.0 (CH), 133.5 (C), 135.7 (C), 137.8 (C), 139.4
(C), 153.3 (C) ppm; m/z 271 (30), 269 (100), 233 (30), 190
(30), 117 (20).
2a isolated yield: 46%, white solid; mp 97–98°C; Rf 0.4
(silica, cyclohexane/AcOEt 95:5); found C, 76.31; H, 3.82;
N, 5.99; S, 13.85%, calcd for C15H9NS C, 76.50; H, 3.82;
N, 5.94; S, 13.60%; lH (500 MHz, CDCl3) 7.47 (ddd, 1H,
H
benzo, J 1.0, 8.2 and 8.2 Hz), 7.54 (m, 1H, Hbenzo%),
7.56–7.60 (m, 3H, 2 Haryl and Hbenzo), 7.87 (ddd, 1H,
benzo, J 0.8, 1.6 and 8.0 Hz), 7.92 (ddd, 2H, 2 Haryl, J
H
0.9, 1.6 and 7.4 Hz), 8.01 (ddd, 1H, Hbenzo, J 0.8, 1.0 and
8.2 Hz); lC (50 MHz, CDCl3) 102.1 (C), 115.2 (CN),
122.4 (CH), 122.6 (CH), 126.2 (2 CH), 128.3 (2 CH),
129.4 (2 CH), 130.5 (CH), 131.5 (C), 137.4 (C), 139.3 (C),
155.1 (C) ppm; m/z 235 (100).
2b isolated yield: 66%, white solid; mp 118–120°C; Rf 0.4
(silica, cyclohexane/AcOEt 95:5); found C, 72.60; H, 4.24;
N, 5.33; O, 6.28; S, 12.03; calcd for C16H11NOS C, 72.38;
H, 4.15; N, 5.27; O, 6.03; S, 12.06%; lH (300 MHz,
CDCl3) 3.80 (s, 3H, OCH3), 6.94 (d, 2H, 2 Haryl, J 8.9
Hz), 7.34 (ddd, 1H, Hbenzo, J 1.3, 7.8 and 7.8 Hz), 7.43
(ddd, 1H, Hbenzo, J 1.3, 7.8 and 7.8 Hz), 7.75 (dd, 1H,
4a isolated yield: 51%; colourless oil; Rf 0.45 (silica,
cyclohexane/AcOEt 95:5); found C, 74.77; H, 5.27; O,
6.35; S, 13.61%, calcd for C15H12OS C, 74.97; H, 5.03; O,
6.66; S, 13.34%; lH (300 MHz, CDCl3) 3.91 (s, 3H, CH3),
7.34–7.44 (m, 3H), 7.44–7.52 (m, 2H), 7.81 (dd, 2H, Haryl
,
J 1.3 and 7.4 Hz), 7.88–7.94 (m, 2H); lC (75 MHz,
CDCl3) 61.3 (CH3), 121.4 (CH), 123.2 (CH), 124.7 (CH),
125.4 (CH), 127.2 (C), 128.2 (CH), 128.3 (2 CH), 129.2 (2
CH), 133.4 (C), 135.2 (C), 136.2 (C), 147.8 (C) ppm; m/z
240 (90), 225 (100), 197 (90), 77 (30).
H
benzo, J 1.3 and 7.8 Hz), 7.77 (d, 2H, 2 Haryl, J 8.9 Hz),
7.85 (dd, 1H, Hbenzo, J 1.3 and 7.8 Hz); lC (75 MHz,
CDCl3) 55.9 (OCH3), 101.0 (C), 115.1 (2 CH), 115.9
(CN), 122.6 (CH), 122.7 (CH), 124.4 (C), 126.2 (CH),
126.4 (CH), 130.0 (2 CH), 137.3 (C), 139.7 (C), 155.5 (C),
161.8 (C) ppm; m/z 265 (100), 250 (80), 222 (80).
4b isolated yield: 69%; pink crystals; mp 120–121°C; Rf
0.3 (silica, cyclohexane/AcOEt 95:5); found C, 72.32; H,
4.15; N, 5.28; O, 6.06; S, 12.19%, calcd for C16H11NOS
C, 72.43; H, 4.18; N, 5.28; O, 6.03; S, 12.09%; lH (500
MHz, CDCl3) 3.82 (s, 3H, CH3), 7.40 (ddd, 1H, Hbenzo, J
1.7; 7.1 and 7.1 Hz), 7.43 (ddd, 1H, Hbenzo, J 1.7, 7.1 and
7.2 Hz), 7.49 (ddd, 1H, Haryl, J 1.4, 7.3 and 7.8 Hz), 7.66
(ddd, 1H, Haryl, J 1.5, 7.3 and 7.9 Hz), 7.69 (ddd, 1H,
Haryl, J 0.7, 1.5 and 7.8 Hz), 7.78 (ddd, 1H, Hbenzo, J 0.8,
1.7 and 7.2 Hz), 7.80 (ddd, 1H, Haryl, J 0.7, 1.4 and 7.9
Hz), 7.86 (ddd, 1H, Hbenzo, J 0.8, 1.7 and 7.1 Hz); lC (125
MHz, CDCl3) 61.6 (CH3), 113.8 (C), 118.4 (C), 120.1
(CN), 122.1 (CH), 123.0 (CH), 124.8 (CH), 126.0 (CH),
128.8 (CH), 132.1 (CH), 132.8 (CH), 133.6 (C), 133.8 (C),
136.7 (C), 137.3 (C), 149.3 (C) ppm; m/z 265 (90), 250
(100), 222 (60), 146 (40).
2c isolated yield: 58%; white solid; mp 74–76°C; Rf 0.45
(silica, cyclohexane/AcOEt 95:5); found C, 63.30; H, 2.80;
N, 4.65; F, 18.48; S, 10.85%, calcd for C16H8NF3S C
63.32; H, 2.61; N, 4.61; F, 18.80; S, 10.55%; lH (300
MHz, CDCl3) 7.49 (ddd, 1H, Hbenzo, J 1.3, 7.5 and 7.9
Hz), 7.58 (ddd, 1H, Hbenzo, J 1.3, 7.5 and 7.9 Hz), 7.80
(bd, 2H, 2 Haryl, J 8.3 Hz), 7.92 (ddd, 1H, Hbenzo, J 0.6,
1.5 and 7.5 Hz), 8.01 (m, 3H, 1 Hbenzo and 2 Haryl); lC (75
MHz, CDCl3) 101.3 (C), 112.6 (CN), 120.4 (CH), 120.8
(CH), 124.3 (2 CH), 124.4 (CH), 124.7 (CH), 126.5 (2
CH), 129.8 (q, CF3), 132.7 (C), 132.8 (C), 135.6 (C), 136.9
(C), 159.5 (C) ppm; m/z 303 (100), 284 (20), 233 (25).
2d isolated yield: 60%; white solid, mp 125–131°C; Rf 0.4
(silica, cyclohexane/AcOEt 95:5); found C, 79.61; H, 3.98;

J. Fournier Dit Chabert et al. / Tetrahedron Letters 43 (2002) 1829–1833
1833
4c isolated yield: 77%; pink crystals; mp 130–132°C; Rf
0.3 (silica, cyclohexane/AcOEt 95:5); found C, 78.25; H,
4.89; O, 5.75; S, 11.46%, calcd for C19H14OS C, 78.59; H,
4.86; O, 5.51; S, 11.04%; lH (500 MHz, CDCl3) 3.56 (s,
3H, CH3), 7.41 (ddd, 1H, Hbenzo, J 1.3, 7.3 and 7.9 Hz),
7.46 (ddd, 1H, Hbenzo, J 1.1, 7.3 and 7.9 Hz), 7.50–7.55
(m, 2H), 7.55 (dd, 1H, Haryl, J 7.0 and 8.2 Hz), 7.70 (dd,
1H, Haryl, J 1.1 and 7.0 Hz), 7.80 (ddd, 1H, Hbenzo, J 0.8,
1.3 and 7.9 Hz), 7.88 (ddd, 1H, Hbenzo, J 0.8, 1.1 and 7.9
Hz), 7.91–7.96 (m, 2H), 8.02 (dd, 1H, Haryl, J 1.8 and 7.1
Hz); lC (75 MHz, CDCl3) 60.9 (CH3), 120.7 (C), 121.7
(CH), 122.8 (CH), 124.7 (CH), 125.5 (CH), 125.6 (CH),
126.7 (CH), 126.8 (CH), 127.1 (CH), 128.7 (CH), 129.5
(CH), 129.9 (CH), 131.0 (C), 133.2 (C), 134.0 (C), 134.5
(C), 137.4 (C), 148.2 (C) ppm; m/z 290 (90), 275 (100),
247 (90), 127 (40).
4b isolated yield: 66%; orange-red oil; Rf 0.15 (silica,
cyclohexane/AcOEt 95:5); found C, 69.85; H, 4.69; N,
5.74; O, 6.51; S, 13.21%, calcd for C14H11NOS C, 69.68;
H, 4.59; N, 5.80; O, 6.63; S, 13.29%; lH (300 MHz,
CDCl3) 3.88 (s, 3H, CH3), 7.33 (ddd, 1H, Haryl, J 0.7, 4.9
and 8.0 Hz), 7.34–7.41 (m, 2H), 7.73–7.80 (m, 2H), 8.10
(ddd, 1H, Haryl, J 1.7, 2.3 and 8.0 Hz), 8.54 (dd, 1H,
Haryl, J 1.7 and 4.9 Hz), 9.10 (bd, 1H, Haryl, J 2.3 Hz); lC
(75 MHz, CDCl3) 61.5 (CH3), 121.6 (CH), 123.3 (CH),
123.4 (C), 124.0 (CH), 125.0 (CH), 125.9 (CH), 129.6 (C),
134.6 (C), 135.1 (CH), 136.5 (C), 149.0 (CH), 149.1 (C),
149.4 (CH) ppm; m/z 241 (70), 226 (100), 198 (40).