Synthesis of thiophene derivatives via palladium-catalyzed coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2007.12.010

Thiophene derivatives with multiple substitutions are prepared from vinylidene bromide, which is synthesized by the reaction of thiophene-2-carboxaldehyde with carbon tetrabromide in the presence of PPh₃, as a core molecule through several coup

Full text of DOI:10.1016/j.tetlet.2007.12.010

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Tetrahedron Letters 49 (2008) 1000–1003
Synthesis of thiophene derivatives via palladium-catalyzed
coupling reactions
Nobumichi Arai, Takayuki Miyaoku, Shota Teruya, Atsunori Mori *
Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
Received 1 November 2007; revised 29 November 2007; accepted 4 December 2007
Available online 21 December 2007
Abstract
Thiophene derivatives with multiple substitutions are prepared from vinylidene bromide, which is synthesized by the reaction of
thiophene-2-carboxaldehyde with carbon tetrabromide in the presence of PPh3, as a core molecule through several coupling reactions
such as Suzuki–Miyaura coupling and palladium-catalyzed CH arylation. The reactions with a wide variety of organic halides lead to
a series of substituted thiophene derivatives in moderate to good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Thiophene; Corey–Fuchs reaction; Palladium catalyst; Suzuki–Miyaura coupling; CH arylation
Thiophenes attract considerable attention in advanced
materials such as organic TFTs, light emitting devices,
Br
Br
and dye-sensitized organic solar cells. A wide variety of
thiophene derivatives have revealed to be interesting in
spectroscopic properties, electrochemical behaviors, and
liquid crystalline characteristics.1 Development of synthetic
protocols for thiophenes, which enable to afford a wide
variety of derivatives in a combinatorial manner, has there-
fore been a major concern in organic synthesis.2 We herein
describe new synthesis of substituted thiophene derivatives
with transition metal-catalyzed coupling methodologies,
which involve Suzuki–Miyaura coupling3 and palladium-
catalyzed CH arylation.4
The starting material for the thiophene derivative is
vinylidene bromide 1, which is readily synthesized from
commercially available thiophene-2-carboxaldehyde. Since
1 involves multiple reaction points as shown in Chart 1,
synthesis of a wide variety of substituted thiophenes can
be performed with transition metal-catalyzed carbon–
carbon bond-forming reactions.5
S
Chart 1.
Synthesis of 1 was carried out by Corey–Fuchs reaction,
which is the reaction of thiophene-2-carboxaldehyde with
carbon tetrabromide in the presence of PPh3.6 The reaction
proceeded smoothly to afford 1 in an excellent yield as
shown in Scheme 1.
We first envisaged the cross-coupling reaction of 1 at the
carbon–bromine bond with several organometallic reagents
in the presence of a palladium or nickel catalyst.7 The reac-
tion of arylmagnesium reagent with 1 has been attempted
using a catalytic amount of Pd(OAc)2–4PPh3 or NiCl2
(dppb) at room temperature to 50 °C to result in giving
Br
2PPh3
Br
CHO
CBr4
+
S
S
CH2Cl2
90%
1
*
Corresponding author. Tel./fax: +81 78 803 6181.
Scheme 1.
E-mail address: amori@kobe-u.ac.jp (A. Mori).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.010

N. Arai et al. / Tetrahedron Letters 49 (2008) 1000–1003
1001
Table 1
Coupling reaction of 1 with an organometallic reagenta
MeO
Br
cat.
MeO
M
Br
+
OMe
+
S
S
S
OMe
3
2
1
M
Catalyst (mol %)
Solvent
Time (°C)
Time (h)
Yield of 2
Yield of 3
MgBr
Pd(OAc)2–4PPh3 (3)
NiCl2(dppb) (1)
Pd(dba)2 (3)
THF
THF
1,4-Dioxane
50
rt
50
24
21
39
0
0
0
0
0
48
b
SnBu3
a
Unless noted, the reaction was carried out with 2–3 equiv of the organometallic reagent.
As an additive, 2.2 equiv of CsF was added.
b
Table 2
Suzuki–Miyaura coupling of 1 with boronic acid ester 4a
MeO
Pd(OAc)2-4PPh3
K2CO3
Br
O
1
MeO
B
+
+
S
THF-H2O
reflux
S
O
OMe
OMe
4a
2a
5a
Entry
Boron reagent (equiv)
K2CO3 amount (equiv)
Time (h)
Yield (%)
2a
5a
1
2
3
a
1.0
2.2
3.0
3.0
3.0
6.0
18
11
24
0
0
>99
47
80
0
The reaction was carried out with 5 mol % of the palladium catalyst in THF–H2O.
unidentified products and no desired coupling product 2 was
obtained. Migita–Kosugi–Stille coupling with arylstannane
also afforded undesired products.8 Although the reaction
proceeded under certain conditions, the major product was
found to be the disubstituted alkyne 3, which would be
obtained by the coupling reaction and following dehydro-
bromination or vice versa. The results are summarized in
Table 1.
By contrast, it was found that the Suzuki–Miyaura cou-
pling with arylboronic acid esters as an organometallic
reagent afforded the desired coupling product in a reason-
able yield.3 As summarized in Table 2, the reaction of 1
with 3 mol amounts of arylboronate 4a in the presence of
aqueous potassium carbonate under reflux conditions for
24 h afforded the desired coupling product 2a in a quanti-
tative yield. On the other hand, reducing the amount of
potassium carbonate and the boron reagent furnished the
mono-substituted product 5a. It was found that mono/
bis-substitution was controllable by the employed amount
of potassium carbonate. Even with 2.2 mol amounts of
4a, mono-substituted product 5a was obtained in 80% yield
in the presence of 3 mol amounts of potassium carbonate.
It seems to react smoothly when THF–H2O is employed as
the solvent system, which would avoid undesired elimina-
tion to alkyne in the presence of a base. Although the use
of an organic solvent such as toluene, ethanol, and DME
Br
O
O
O
MeO
B
+
B
+
5a
S
OMe
O
O
4a
5a
4b
Me
O
MeO
Pd(OAc)2 (5 mol %)
PPh3 (20 mol %)
K2CO3 (3.0 eq)
Pd(OAc)2 (5 mol %)
PPh3 (20 mol %)
K2CO3 (3.0 eq)
THF-H2O, reflux, 10 h
S
OMe
THF-H2O, reflux, 10 h
S
OMe
2a
6, 95%
, 91%
Scheme 2.
Scheme 3.

1002
N. Arai et al. / Tetrahedron Letters 49 (2008) 1000–1003
Table 3
Aryl
Coupling reaction of 1 with arylboronatesa
Aryl
Aryl'
I
+
Entry
Aryl (equiv)
Time (h)
24
Yield (%)
>99
S
2
MeO
1
Pd cat. (3-5 mol %)
AgNO3-KF
Aryl
Aryl
4a (3)
Aryl'
S
O
DMSO, 100 ºC, 24 h
2
24
>99
7
Me
4b (3)
Scheme 4.
Me
3
4
5
46
45
24
90
83
4c (2.4)
Table 4
Palladium-catalyzed CH arylation of thiophene derivative 2
Product (yield)
Product (yield)
F3C
4d (2.2)
OMe
Me
F3C
>99
O
S
4e (3)
S
F3C
EtO
Me
OMe
80%
45%
Me
N
Me
6
45
91
CF3
MeO
4f (2.4)
a
The reaction was carried out under the similar conditions to those for
the entry 3 of Table 2.
F
F
EtO
S
S
O
F
OMe
F
CF3
F
41%
78%
was preliminary examined, the reactions were found to be
unsuccessful to result in no reaction or in giving a mixture
of 2, 3, and 5.
OMe
F3C
The finding that mono-substituted product 5 has been
selectively obtained under a certain condition enables the
coupling reaction to synthesize differently-substituted thio-
phene derivatives in a facile manner. When 5a was treated
with 4a in the presence of a palladium catalyst and potas-
sium carbonate, disubstituted 2a was obtained in an excel-
lent yield (Scheme 2). However, treatment of arylstannane
instead of 4a afforded the internal alkyne 3a as a major
product, while disubstituted 2a was not obtained at all.
The reaction with the other arylboronate 4b also proceeded
smoothly to afford the differently substituted 6 in 95% yield
(Scheme 3).
The disubstituted thiophene derivatives 2 were synthe-
sized in a similar manner. As shown in Table 3, various
boron reagents 4 were employed for the reaction to obtain
thiophene derivatives bearing electron-donating or elec-
tron-withdrawing substituents in excellent yields under
similar conditions to the synthesis of 2a.
F
F
F3C
S
S
F
CF3
F
OMe
37%
F
57%
OMe
CF3
F3C
CF3
S
S
MeO
F3C
OMe
26%
50%
Me
CF3
F
CF3
F
F
O
S
S
Me
F
EtO
F
32%
86%
The thiophene derivatives 2 were then subjected to the
functionalization at the 5-position of the thiophene ring
with the palladium-catalyzed CH arylation reaction in the
presence of AgNO3/KF as an activator (Scheme 4).2b Table
4 summarizes the results. The products bearing a variety of
substituents 7 were obtained in moderate to good yields. The
reaction with an aryl halide bearing an electron-withdraw-
ing substituent proceeded in a relatively higher yield than
that bearing electron-donating group. The reaction of 6
a The reaction was carried out with 2 (0.3 mmol) and aryl iodide
(0.36 mmol) in DMSO (1.8 mL) under nitrogen atmosphere with
PdCl2(PPh3)2 (5 mol %) or PdCl2(dppb) (3 mol %).
bearing different aryl groups as substituents has also been
attempted and found that CH arylation reaction took place.
However, scrambling of the stereochemistry of the double

N. Arai et al. / Tetrahedron Letters 49 (2008) 1000–1003
1003
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bond was observed to some extent under the conditions
shown in Table 4. Further studies would be required to
undergo the reaction with retention of the stereochemistry.
In summary, we have demonstrated the preparation of
multiple substituted thiophene derivatives starting from
vinylidene bromide 1 using Suzuki–Miyaura coupling and
the palladium-catalyzed CH arylation strategies. The
method allowed to synthesize a variety of trisubstituted thio-
phene derivatives 7 in a combinatorial manner. These
molecules exhibited extended p-conjugation. Further stud-
ies on the properties of the thiophene derivative 6 leading
to find the utility of these molecules as advanced materials
are under way.
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Acknowledgments
This work was partly supported by KRI Co. Ltd and a
Grant-in-Aid for Scientific Research on Priority Areas
‘Advanced Molecular Transformation of Carbon Re-
sources’ (No. 19020043) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. The
authors thank Dr. Shigeru Yamaki and Dr. Masahiro Sato
of the KRI for a fruitful discussion.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.12.010.
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