Palladium-Catalyzed Direct C2-Arylation of Benzo[ b ]thiophenes with Electron-Rich Aryl Halides: Facile Access to Thienoacene Derivatives

Article abstract of DOI:10.1055/s-0036-1588994

Direct coupling reaction of benzo[ b ]thiophene and electron-rich aryl bromides was achieved under Pd ₂ (dba) ₃ /SPhos catalysis in the presence of NaO t -Bu. The reaction system was applied for the installation of 2-(methylthio)phenyl group onto thiophene-fused polyaromatic molecules, demonstrating facile synthesis of precursors for thienoacene derivatives.

Full text of DOI:10.1055/s-0036-1588994

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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A
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F. Ichioka et al.
Letter
Synlett
Palladium-Catalyzed Direct C2-Arylation of Benzo[b]thiophenes
with Electron-Rich Aryl Halides: Facile Access to Thienoacene
Derivatives
Fumiki Ichiokaa
Yuhei Itaia
Yuji Nishiib
Masahiro Miura*a
cat. Pd/SPhos
NaOtBu
Br
S
S
H
R2
Ar
Ar
+
R2
R1
0
0
0
0
0-
0
0
1
8-
2
8
8
6-
4
3
9
R1
16 examples, 15–81% yield
R1 or R2 = alkyl, OMe, SMe, NMe2
(R1 = SMe: precursors for thienoacenes)
a Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
miura@chem.eng.osaka-u.ac.jp
b Frontier Research Base for Global Young Researchers, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-0871,
Japan
Dedicated to Professor Victor Snieckus on the occasion of his 80th
birthday
Received: 22.02.2017
Accepted after revision: 16.03.2017
Published online: 11.04.2017
for the synthesis of thienoacenes, the Suzuki–Miyaura
coupling reaction of thiophene fragments with 2-(meth-
ylthio)phenyl counterparts has been frequently adopted.4
Consecutive oxidation to the corresponding sulfoxides fol-
lowed by acid-mediated annulation furnishes an extra thio-
phene ring (Scheme 1, A). Alternatively, treatment of 2-
aryl-3-bromothiophenes with NaSMe gives the corre-
sponding thienoacene precursors which cyclize in the op-
posite direction (Scheme 1, B).5 These methods, however,
require prefunctionalization steps of the thiophenes, so
that the direct transformation of readily available unfunc-
tionalized thiophenes is highly attractive for quick access to
the thiophene-based polyaromatic molecules.
DOI: 10.1055/s-0036-1588994; Art ID: st-2017-r0128-l
Abstract Direct coupling reaction of benzo[b]thiophene and electron-
rich aryl bromides was achieved under Pd2(dba)3/SPhos catalysis in the
presence of NaOt-Bu. The reaction system was applied for the installa-
tion of 2-(methylthio)phenyl group onto thiophene-fused polyaromatic
molecules, demonstrating facile synthesis of precursors for thienoacene
derivatives.
Key words palladium catalyst, C–H functionalization, thiophene,
polyaromatic hydrocarbons, heteroacenes
Fused polyaromatic molecules have been of significant
interest due to their potential use for organic electronic de-
vices,1 and, particularly, thiophene-based π-conjugated
compounds have been attractive candidates for semicon-
ductor materials in organic field-effect transistors (OFETs).2
Thienoacene derivatives exhibit high environmental stabili-
ty as compared to analogous hydrocarbons (acenes)3 and
elaborate packing structures which are beneficial for better
performance of organic devices. As a conventional approach
Transition-metal-catalyzed direct arylation of thio-
phene C–H bonds have been extensively studied since a pi-
oneering research by Ohta and co-workers.6 A number of
catalytic conditions have been developed mainly with pal-
ladium complexes to date,7 but limitations have frequently
been encountered with electron-rich aryl halides. Especial-
ly, only limited examples were proved to be effective for
aryl halides with electron-donating substituents at the or-
tho position.8,9 As mentioned above, 2-(methylthio)phenyl
A: Suzuki–Miyaura coupling reaction of 2-(methylthio)aryl fragments
S
Br
ArB(OR)2
or ArBr
1. oxidant
S
S
2. acid
or
S
S
MeS
B(OR)2
B: Bromination and thiomethylation of 2-arylthiophenes
1. oxidant
2. acid
S
S
S
NaSMe
S
Br
SMe
Scheme 1 Conventional synthetic methods for thienoacene derivatives
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
F. Ichioka et al.
Letter
Synlett
halides are attractive coupling partners for thienoacene
synthesis; however, there is no successful report for such
sulfur-containing substrates probably due to its steric hin-
drance and potential coordination to palladium species
which might encumber the catalytic turnover. To address
these issues, we herein develop a Pd/SPhos catalyst system
which effectively triggers the direct coupling of ben-
zo[b]thiophenes and various electron-rich aryl bromides.
This catalytic system is applicable to multiarylation of thio-
phene-based polycyclic molecules, demonstrating facile
synthesis of a novel benzo-fused thienoacene molecule.
We first examined a reaction of benzo[b]thiophene (1)10
with (2-bromophenyl)(methyl)sulfane (2a) in the presence
of LiOt-Bu10d and Pd2(dba)3/SPhos catalyst, and the corre-
sponding coupling product 3a was obtained in 32% yield
(Table 1, entry 1). The reaction proceeded predominantly at
the C2 position. Further optimization revealed that use of
NaOt-Bu in dioxane solvent gave higher yield (entries 2–6).
A comparable result was obtained when the reaction was
conducted in o-xylene (entry 7), and higher reaction tem-
perature resulted in significant increase of the yield (entries
8 and 9). Ligand screening was then carried out under the
reaction conditions. RuPhos, JohnPhos, and MePhos were
less effective (entries 10–12). It was notable that simple tri-
aryl- and trialkylphosphines were also compatible albeit
the yields were moderate (entries 13–15). Catalyst loading
and amount of the aryl bromide 2a could be decreased
without drop of the yield, and the product was isolated in
81% yield (entry 16).
Table 1 Optimization Studya
Pd2(dba)3 (2.0 mol%)
ligand (4.0 mol%)
base (3.0 equiv)
MeS
SMe
S
S
+
solvent, conditions
Br
1
2a
3a
Entry Ligandb
Base
Solvent
Conditions
Yield (%)c
1
2
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
RuPhos
JohnPhos
MePhos
PPh3
LiOt-Bu
DMF
100 °C, 15 h
100 °C, 15 h
100 °C, 15 h
100 °C, 15 h
100 °C, 20 h
100 °C, 20 h
100 °C, 20 h
120 °C, 15 h
140 °C, 15 h
140 °C, 15 h
140 °C, 20 h
140 °C, 20 h
140 °C, 15 h
140 °C, 15 h
140 °C, 15 h
140 °C, 15 h
32
7
NaOt-Bu
LiOt-Bu
DMF
3
dioxane
dioxane
DMF
5
4
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
48
23
53
54
62
81
74
45
56
56
66
56
(81)
5d
6d
dioxane
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
7d
8d
9d
10d
11d
12d
13d
14d
15d
16e
PCy3
PtBu3
SPhos
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Pd2(dba)3 (2.0 mol%),
ligand (4.0 mol%), and base (1.5 mmol) in solvent (2.0 mL).
b SPhos = 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; RuPhos = 2-
dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl; Johnphos = 2-(di-tert-
butylphosphino)biphenyl; Mephos = 2-(dicyclohexylphosphino)-2′-methyl-
biphenyl.
Next, we evaluated the substrate generality with re-
spect to electron-rich aryl bromides (Scheme 2).11 Aryl bro-
mides which have an electron-donating substituent at the
para position, such as methyl (2b), methoxy (2c), meth-
ylthio (2d), and dimethylamino group (2e) underwent the
reaction to furnish 3b–e in moderate to good yields. The or-
tho-substituted aryl bromides 2f and 2g were also applica-
ble to the present reaction. Polyalkoxyphenyl groups could
be installed to afford the 2-arylbenzo[b]thiophenes 3h–j.
c Determined by GC analysis. Isolated yield in parentheses.
d 1.0 mmol (2.0 equiv) of 2a was used.
e 1a (1.0 mmol), 2a (1.5 mmol), NaOt-Bu (3.0 mmol), Pd2(dba)3 (0.5
mol%), and SPhos (1.0 mol%) were used.
Pd2(dba)3 (0.5 mol%)
SPhos (1.0 mol%)
NaOtBu (3.0 equiv)
S
S
R
+
R
Br
o-xylene, 140 °C
1
2b–j
3b–j
Me
S
S
S
S
S
Me
OMe
SMe
NMe2
3b: 57% yield (15 h)
3c: 73% yield (20 h)
3d: 72% yield (15 h)
3e: 66% yield (24 h)
3f: 54% yield (15 h)
MeO
OMe
OMe
OMe
OMe
OMe
OMe
S
S
S
S
OMe
3j: 54% yield (15 h)
3g: 58% yield (40 h)
3h: 71% yield (15 h)
3i: 66% yield (15 h)
Scheme 2 Substrate scope for aryl bromides 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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F. Ichioka et al.
Letter
Synlett
The developed coupling reaction was applied to polyar-
omatic substrates (Table 2).12 Thieno[3,2-b]thiophene (4)
was successfully transformed into diarylated products 5
and 6, which are precursors of linear ladder-type tetrathie-
noacene derivatives (entries 1 and 2).5c,e This result clearly
underlines that the catalytic system is of utility for synthe-
sizing a series of thiophene-based polyaromatic molecules
in short steps.
were, respectively, converted into the corresponding prod-
ucts in moderate yields (entries 4 and 5). A trithiophene 13
underwent threefold coupling reaction to give a two-
dimensional thienoacene precursor 14 (entry 6). 4c
We finally synthesized a novel naphtho-fused thieno-
acene 16 according to a conventional method from the cou-
pling product 12 (Equation 1). Oxidation of thiomethyl
groups of 12 into sulfoxides was first attempted by treating
with H2O2 in acetic acid; however, the reaction was sluggish
and not completed. Subsequently, mCPBA was used as an
additional oxidant, and the corresponding sulfoxide 15 was
Dithieno[3,2-b:2′,3′-d]thiophene (7) was also applica-
ble, and the compound 8 was obtained in 58% yield (entry
3). Benzo- and naphtho-fused dithiophenes (9 and 11)
Table 2 Direct Arylation of Polyaromatic Compoundsa
Pd2(dba)3 (2.0 mol%)
SPhos (4.0 mol%)
NaOtBu (3.0 equiv)
S
S
R
Ar
Ar
+
o-xylene
140 °C, 24 h
R
Br
2
Entry
1
Substrate
Product
Yield (%)
69
SMe
MeS
S
S
S
S
S
4
5
S
n
nC8H17
H17C8
2
3
47
58
S
S
4
6
S
SMe
MeS
MeS
S
S
S
S
S
7
9
8
SMe
S
S
4
5
65
54
S
S
10
S
S
MeS
SMe
S
S
11
12
MeS
S
S
MeS
6 b
15
S
S
S
S
13
SMe
14
a Reaction conditions: substrate (0.5 mmol), 2 (1.5 mmol), Pd2(dba)3 (1.0 mol%), SPhos (2.0 mol%), and NaOt-Bu (1.5 mmol) in o-xylene (2.0 mL).
b 2a (4.5 equiv) was used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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furnished in 84% yield. Acid treatment of the sulfoxide
prompted cyclization to afford the desired thienoacene 16
in 82% yield. Further purification was performed by subli-
mation to obtain an analytically pure material.
N. E.; Lou, S. J.; Chen, L. X.; Yu, L. Macromolecules 2014, 47, 6252.
(f) Li, J.; Qiao, X.; Xiong, Y.; Li, H.; Zhu, D. Chem. Mater. 2014, 26,
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Carsten, B.; Strzalka, J.; Darling, S. B.; Chen, L. X.; Yu, L. Adv.
Mater. 2013, 25, 838. (e) Huang, J.; Luo, H.; Wang, L.; Guo, Y.;
Zhang, W.; Chen, H.; Zhu, M.; Liu, Y.; Yu, G. Org. Lett. 2012, 14,
3300.
O
S
1. H2O2 (3 equiv)
AcOH, r.t., 17 h
S
12
2. mCPBA (1 equiv)
CH2Cl2, r.t., 40 h
S
S
O
15: 84% yield
S
S
1. TfOH, r.t., 24 h
2. H2O/pyridine
reflux, 10 min
S
S
(6) Ohta, A.; Akita, Y.; Ohkuna, T.; Chiba, M.; Fukunaga, R.; Miyafuji,
A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951.
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174. (d) Miura, M.; Satoh, T.; Hirano, K. Bull. Chem. Soc. Jpn.
2014, 87, 751; and references cited therein.
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Zhang, M.; Jie, X.; Su, W. Angew. Chem. Int. Ed. 2012, 51, 227.
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1290.
16: 82% yield (crude)
Equation 1 Synthesis of a naphtho-fused thienoacene molecule 16
In conclusion, we developed a palladium-catalyzed di-
rect arylation of benzo[b]thiophene derivatives with elec-
tron-rich aryl bromides involving ortho-substituted sub-
strates. The catalytic system could be applied to di- and tri-
arylation of thiophene-based condensed molecules. Further
studies on the synthesis of a series of thienoacenes and an
investigation of their optoelectronic properties are ongoing.
(10) Selected examples for the arylation of benzo[b]thiophene:
(a) Chabert, J. F. D.; Joucla, L.; David, E.; Lemaire, M. Tetrahedron
2004, 60, 3221. (b) David, E.; Perrin, J.; Pellet-Rostaing, S.;
Chabert, J. F. D.; Lemaire, M. J. Org. Chem. 2005, 70, 3569.
(c) Liégault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826. (d) Tamba, S.; Okubo, Y.; Tanaka, S.;
Monguchi, D.; Mori, A. J. Org. Chem. 2010, 75, 6998. (e) Zhao, L.;
Bruneau, C.; Doucet, H. Tetrahedron 2013, 69, 7082.
Funding Information
This work was partly supported by a grant to M.M. from the JSPS KA-
KENHI (Grant-in Aid for Scientific Research (S)) (JP 24225002)
Supporting Information
(11) General Procedure for Scheme 2
In a Schlenk tube, a mixture of benzo[b]thiophene (1, 1.0
mmol), aryl bromide 2 (1.5 mmol), NaOt-Bu (3.0 mmol),
Pd2(dba)3 (0.005 mmol), and SPhos (0.01 mmol) in o-xylene (2.0
mL) was heated at 140 °C for specified reaction time under N2.
The resulting mixture was poured into H2O and extracted with
EtOAc three times. Combined organic layers were dried over
Na2SO4 and concentrated in vacuo. The residue was subjected to
silica gel chromatography and/or preparative gel permeation
chromatography (GPC).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588994.
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References and Notes
(1) For selected reviews, see: (a) Sun, Z.; Ye, Q.; Chi, C.; Wu, J. Chem.
Soc. Rev. 2012, 41, 7857. (b) Wang, C.; Dong, H.; Hu, W.; Liu, Y.;
Zhu, D. Chem. Rev. 2012, 112, 2208. (c) Figueira-Duarte, T. M.;
Müllen, K. Chem. Rev. 2011, 111, 7260. (d) Pron, A.; Gawrys, P.;
Zagorska, M.; Djuradoa, D.; Demadrillea, R. Chem. Soc. Rev.
2010, 39, 2577. (e) Anthony, J. E. Angew. Chem. Int. Ed. 2008, 47,
452.
2-(4-Methylphenyl)benzo[b]thiophene (3b)
Purified by column chromatography (eluent: hexane–EtOAc,
40:1) followed by GPC, 57% yield, orange solid, mp 56–57 °C. 1H
NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 7.20 (dd, J = 1.5, 7.0 Hz,
1 H), 7.32–7.37 (m, 4 H), 7.46 (dd, J = 1.5, 5.5 Hz, 1 H), 7.46 (s, 1
(2) For a review, see: Takimiya, K.; Shinamura, S.; Osaka, I.;
Miyazaki, E. Adv. Mater. 2011, 23, 4347.
H), 7.80 (dd, J = 1.5, 7.0 Hz, 1 H), 7.84 (dd, J = 1.5, 7.0 Hz, 1 H). 13
C
(3) Clar, E. Polycyclic Hydrocarbons;
1
V
o.
l
Academic Press: New York,
NMR (100 MHz, CDCl3): δ = 16.29, 122.23, 123.88, 124.38,
124.46, 124.47, 124.91, 125.86, 128.96, 131.23, 133.32, 138.39,
140.09, 140.38, 141.67. HRMS (APCI): m/z [M + H]+ calcd for
1964.
(4) (a) Abe, M.; Mori, T.; Osaka, I.; Sugimoto, K.; Takimiya, K. Chem.
Mater. 2015, 27, 5049. (b) Zou, S.; Wang, Y.; Gao, J.; Liu, X.; Hao,
W.; Zhang, H.; Zhang, H.; Xie, H.; Yang, C.; Li, H.; Hu, W. J. Mater.
Chem. C 2014, 2, 10011. (c) Chen, L.; Baumgarten, M.; Guo, X.;
Li, M.; Marszalek, T.; Alsewailem, F. D.; Pisula, W.; Muellen, K.
J. Mater. Chem. C 2014, 2, 3625. (d) Guo, X.; Tsao, H. N.; Gao, P.;
Xia, D.; An, C.; Nazeeruddin, M. K.; Baumgarten, M.; Grätzel, M.;
Müllen, K. RSC Adv. 2014, 4, 54130. (e) Zheng, T.; Lu, L.; Jackson,
C
15H13S2: 257.0487; found: 257.0481. For other compounds, see
the Supporting Information.
(12) General Procedure for Table 2
In a Schlenk tube, a mixture of thiophene-based fused com-
pound (0.5 mmol), aryl bromide 2 (1.5 mmol), NaOt-Bu (1.5
mmol), Pd2(dba)3 (0.005 mmol), and SPhos (0.01 mmol) in o-
xylene (2.0 mL) was heated at 140 °C for 24 h. The resulting
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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F. Ichioka et al.
Letter
Synlett
mixture was poured into H2O and extracted with EtOAc three
times. Combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was subjected to silica gel
chromatography and/or GPC.
(400 MHz, CDCl3): δ = 2.45 (s, 6 H), 7.20 (dt, J = 1.6, 7.3 Hz, 2 H),
7.32–7.35 (m, 4 H), 7.44 (s, 2 H), 7.44 (dd, J = 1.4, 7.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):δ = 16.20, 119.93, 124.80, 125.70,
128.65, 131.01, 133.36, 138.21, 139.37, 142.62. HRMS (APCI):
m/z [M + H]+ calcd for C20H17S4: 385.0208; found: 385.0201. For
other compounds, see the Supporting Information.
2,5-Bis(2-methylthiophenyl)thieno[3,2-b]thiophene (5)
Purified by GPC, 69% yield, white solid, mp 198–199 °C. 1H NMR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E