Palladium-catalysed direct 3- or 4-arylation of thiophene derivatives using aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2009.03.155

The palladium-catalysed direct 3- or 4-arylation of 2,5-disubstituted thiophenes using aryl bromides gives a simple access to a variety of 3- or 4-arylthiophene derivatives. Moderate to good yields of 3-arylated thiophenes were obtained using 2,5-dimethyl

Full text of DOI:10.1016/j.tetlet.2009.03.155

Tetrahedron Letters 50 (2009) 2778–2781
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalysed direct 3- or 4-arylation of thiophene derivatives
using aryl bromides
*
Jia Jia Dong, Julien Roger, Henri Doucet
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes, ‘Catalyse et Organometalliques’, Campus de Beaulieu, 35042 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium-catalysed direct 3- or 4-arylation of 2,5-disubstituted thiophenes using aryl bromides
gives a simple access to a variety of 3- or 4-arylthiophene derivatives. Moderate to good yields of 3-ary-
lated thiophenes were obtained using 2,5-dimethylthiophene. In the presence of unsymmetrically disub-
stituted, 2-acetyl-5-methylthiophene, a regioselective arylation on carbon 4 of thiophene was observed.
This reaction provides only HX associated to the base as by-product and reduces the number of steps to
prepare these compounds.
Received 12 February 2009
Revised 19 March 2009
Accepted 23 March 2009
Available online 27 March 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
C–H bond activation
Aryl halides
Palladium
Catalysis
Thiophenes
R3M
R1
X
The palladium-catalysed cross-coupling reactions of thio-
phenes with aryl halides are among the most powerful methods
for the preparation of arylthiophenes.1 The efficiency of palla-
dium-catalysed Stille,2 Negishi,3 or Suzuki,4 cross-coupling for
the reaction of aryl halides with thiophene derivatives or of halo-
thiophenes with aryl-metal derivatives has been largely de-
scribed. However, these reactions require the prior preparation
of an organometallic derivative of a heteroaromatic or an aro-
matic, and provide an organometallic salt (MX) as by-product
(Scheme 1).
Ar
R2
R2
[Pd]
[Pd]
R1
S
S
R2
R1
R3MX
+
ArX
+
S
ArMR3
R3MX
X = I, Br, Cl
M = Zn, Mg, Sn or B
Scheme 1.
Since a few years, a new palladium-catalysed procedure for
the functionalisation of heteroaromatics has emerged. It consists
in directly arylating heteroaromatics via a C–H bond activation
of the heteroarenes.5–8 This procedure proceeds nicely for the
coupling of several thiophene derivatives with aryl halides or
even triflates.9–14 For such couplings, no preparation of an orga-
nometallic derivative is required. Moreover, this reaction provides
only HX associated to a base as by-product, instead of a metallic
salt, and therefore is very interesting both in terms of atom-econ-
omy and non-toxic wastes. However, so far, most of the results
reported for this reaction were obtained with 2-substituted thio-
phenes and gave 5-arylated thiophenes (Scheme 2).10
H
R
S
[Pd], base
HX/base
+
ArX
Ar
R
S
X = I, Br, Cl
Scheme 2.
For example, Lemaire and co-workers have reported in 1998, that
the direct arylation of 3-formylthiophene or 3-cyanothiophene
gave a mixture of 2-arylthiophenes and 2,4-diarylthiophenes.12a
In most cases, the 2-arylated thiophenes were formed in high
selectivities, and the 2,4-diarylthiophenes were only obtained in
low yields. Recently, Miura and co-workers described perarylation
reactions of 3-thiophenecarboxylic acid.13 They examined the
preparation of tetraarylthiophenes having two different aryl
Some direct 3-arylations of thiophenes via intramolecular cyc-
lisations using 2-substituted thiophenes have been reported.11
Rare examples of 3- or 4-arylations of thiophenes via palla-
dium-catalysed bimolecular couplings have also been described.12
* Corresponding author. Tel.: +33 2 23 23 63 84; fax: +33 2 23 23 69 39.
E-mail address: henri.doucet@univ-rennes1.fr (H. Doucet).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.155

J. J. Dong et al. / Tetrahedron Letters 50 (2009) 2778–2781
2779
Table 1
groups at the 2,5- and 3,4-positions. 2,5-Diphenyl- and 2,5-bis(4-
methoxyphenyl)-3-thiophenecarboxylates reacted with aryl bro-
mides to give the perarylated thiophenes. To our knowledge, so
far, the selective bimolecular palladium-catalysed direct 3- or 4-
monoarylation of 2,5-disubstituted thiophenes has not been
reported.
The extension of palladium-catalysed C–H bond activation/
functionalisation procedure to a wider diversity of heteroaromatics
would be a considerable advantage for sustainable development,
because of the lower cost, lower mass and the easier access to reac-
tants, as well as for the treatment of the relatively non-toxic waste.
Therefore, the discovery of more effective and selective conditions,
for the direct 3- or 4-arylation of thiophenes with aryl halides, is
desirable. Here, we wish to report on the palladium-catalysed di-
rect 4-arylation of unsymmetrically 2,5-disubstituted thiophenes
and also on the 3-arylation of a symmetrically 2,5-disubstituted
thiophene, using aryl bromides.
Palladium-catalysed direct 3-arylation of 2,5-dimethylthiophene with 4-bromobenz-
aldehyde (Scheme 3)15,16
Entry
Catalyst
Solvent
Base
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
[PdCl(C3H5)]2
[PdCl(C3H5)]2
[PdCl(C3H5)]2
[PdCl(C3H5)]2
[PdCl(C3H5)]2
[PdCl(C3H5)]2
[PdCl(C3H5)]2
[PdCl(C3H5)]2
Pd(OAc)2
DMF
Xylene
DME
KOAc
KOAc
KOAc
KOAc
KOAc
Cs2CO3
Na2CO3
K2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
21
2
0
6
25
0
NMP
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
0
6
31
28a
27b
27b
19c
20c
48d
Pd(OAc)2
Pd(OAc)2/2 PPh3
[PdCl(C3H5)]2/4 PPh3
Pd(OAc)2/dppb
[PdCl(C3H5)]2/2 dppb
Pd(OAc)2
Conditions: catalyst [PdCl(C3H5)]2 (0.005 equiv) or Pd(OAc)2 (0.01 equiv), 4-bro-
mobenzaldehyde (1 equiv), 2,5-dimethylthiophene (3 equiv), base (2 equiv), 120 °C,
20 h, under argon, isolated yields.
In order to determine the most suitable reaction conditions for
this specific arylation, we studied the reactivity of 2,5-dimethyl-
thiophene with 4-bromobenzaldehyde in the presence of 1 mol %
[PdCl(C3H5)]2 at 120 °C using various bases and solvents (Scheme
3, Table 1). Yields of 21% and 25% in 3-arylation product 1 were ob-
tained using DMF or DMAc as solvents and KOAc as the base (Table
1, entries 1–5). Other solvents such as xylene, DME or NMP were
found to give only 0–6% yield of 1. Employing Cs2CO3 or Na2CO3
as base in the presence of DMAc, the expected product 1 was not
observed (Table 1, entries 6 and 7). Only traces of 1 were detected
when K2CO3 was used (Table 1, entry 8). Pd(OAc)2 as palladium
sources was found to give a slightly higher yield of 31% in 1 (Table
1, entry 9).
Next, we examined the influence of the presence of ligands in
the reaction mixture. However, the addition of the phosphine li-
gands, PPh3 or dppb was found to be profitless (Table 1, entries
11–14). Finally, we studied the influence of a higher reaction tem-
perature. At 150 °C instead of 120 °C, a better yield of 48% in 1 was
obtained (Table 1, entry 15). However, some side-products were
also formed.
a
5 mol % catalyst was employed.
PPh3: 0.02 equiv.
dppb: 0.01 equiv.
Reaction temperature 150 °C.
b
c
d
Table 2
Palladium-catalysed direct 3-arylations of 2,5-dimethylthiophene with aryl bromides
(Scheme 3)15,16
Entry
1
Aryl bromide
Product
Yield (%)
48
S
Br
CHO
CHO
1
S
2
61a
Br
COPh
COPh
COEt
2
Then, using the most suitable reaction conditions (DMAc, KOAc,
Pd(OAc)2 1 mol %, 120–150 °C), we examined the scope and limita-
tion of this reaction with a variety of aryl bromides (Scheme 3,
Table 2).
S
S
S
S
3
4
5
6
38a
50
Br
Br
Br
Br
COEt
CF3
CN
3
First, we examined the reactivity of electron-deficient
para-substituted aryl bromides. The 3-arylation of 2,5-dimethyl-
thiophene with 4-bromopropiophenone, 4-trifluoromethylbromo-
benzene or 4-bromobenzonitrile gave 3–5 in only 38–50% yields
(Table 2, entries 3–5). Unidentified side-products were also formed
with these reactants. In the presence of 4-bromobenzophenone or
4-bromonitrobenzene at 120 °C, compounds 2 and 6 were obtained
in 61% and 62% yields, respectively (Table 2, entries 2 and 6). With
these substrates, the reactions performed at 150 °C gave lower
yields due to the formation of side products. Electron-deficient,
ortho-substituted, 2-bromobenzonitrile reacted at 120 °C gave 7
in 64% yield (Table 2, entry 7). A low yield of 28% was obtained
with congested 1-bromonaphthalene due to partial conversion of
this aryl bromide (Table 2, entries 8 and 9).
CF3
CN
4
40
5
62a
NO2
NO2
6
NC
NC
Br
7
64a
S
S
7
8
R
8
9
27a
28
Pd(OAc)2 1 mol%
S
Br
+
DMAc, KOAc, 120-150 ºC,
20 h
S
1-8
Conditions: catalyst Pd(OAc)2 (0.01 equiv), aryl bromide (1 equiv), 2,5-dimethyl-
thiophene (3 equiv), KOAc (2 equiv), DMAc, 150 °C, 20 h, under argon, isolated
yields.
Br
R
a
Reaction temperature 120 °C.
Scheme 3.

2780
J. J. Dong et al. / Tetrahedron Letters 50 (2009) 2778–2781
can be obtained in the course of the arylation. We had previously
R
observed, using 2-acetyl-5-methylfuran or 1,5-dimethyl-2-pyr-
rolecarbonitrile as reactants, that the formation of the 4-arylation
products was favoured.14 In the presence of 2-acetyl-5-methylthi-
ophene, a good selectivity in favour of the 4-arylated compounds
was also obtained using Pd(OAc)2 as the catalyst, DMAc as the sol-
vent and KOAc as the base. The 3-arylation products were observed
in very low yields with most aryl bromides. In the presence of 4-,
3- or 2-trifluoromethylbromobenzenes, the products 9, 12 and 14
were obtained in 48–60% yields (Table 3, entries 1, 5, 6 and 8). Rel-
atively similar results were obtained using 4- or 2-bromobenzo-
nitriles. These reactants gave the 4-arylation products 10 and 13
in 63% and 54% yields, respectively (Table 3, entries 3 and 7).
Slightly activated 4- or 2-fluorobromobenzenes also led regioselec-
tively to 11 or 15, but the formation of side products was observed
(Table 3, entries 4, 9 and 10). On the other hand, a low yield in 16
was obtained when using 5-bromopyrimidine as the reactant due
to the formation of a large amount of by-products (Table 3, entries
11 and 12).
COMe
R
Pd(OAc)2 1 mol%
S
+
DMAc, KOAc, 120-150 ºC,
20 h
COMe
S
9-16
Br
Scheme 4.
Next, we examined the reactivity of 2-acetyl-5-methylthioph-
ene with various aryl bromides (Scheme 4, Table 3). With this
unsymmetrically 2,5-disubstituted thiophene, two regioisomers
Table 3
Palladium-catalysed direct 4-arylations of 2-acetyl-5-methylthiophene with aryl
bromides (Scheme 4)15,16
Entry
Aryl bromide
Product
Yield (%)
Finally, we examined the direct arylation of 2-formyl-5-methyl-
thiophene. Surprisingly, using 4-bromobenzaldehyde as reaction
partner, this heteroarene was found to give an equimolar mixture
of 3- and 4-arylated thiophenes 17 and 18 in 62% yield (Scheme 5).
The arylation of this heteroarene in the presence of other aryl
bromides such as 4-bromoacetophenone, 4-bromobenzonitrile or
4-trifluoromethylbromobenzene gave inseparable mixtures of
regioisomers. The regioselectivity of the arylations of unsymmetri-
cally 2,5-disubstituted thiophenes appears to be strongly depen-
dent on the nature of the substituents on thiophenes.
In summary, we have demonstrated that using Pd(OAc)2 as the
catalyst precursor, the direct 3- or 4-arylation via a C–H bond acti-
vation of 2,5-disubstituted thiophenes using aryl bromides pro-
ceeds in moderate to good yields. In the presence of the
unsymmetrically 2,5-disubstituted thiophene, 2-acetyl-5-methyl-
thiophene, a regioselective arylation in position 4 was observed.
This procedure is limited to activated aryl bromides. However, it
should be noted that a wide range of functions such as propionyl,
benzoyl, formyl, nitro, nitrile, fluoro or trifluoromethyl on the aryl
bromide are tolerated. The major by-product is AcOH/KBr instead
of metallic salts with classical coupling procedures. Moreover, no
preparation of an organometallic derivative is required, reducing
the number of steps to prepare these compounds. Despite their
interest, most of the products prepared by this method are new,
indicating a relatively laborious access to such compounds using
more traditional cross-coupling procedures. For these reasons,
even if the yields are moderate with some substrates, this proce-
dure should give a simple access to 3- or 4-arylthiophenes.
S
1
2
32
Br
CF3
CF3
CN
51a,b
MeOC
9
S
S
3
4
63
Br
Br
CN
F
MeOC
MeOC
10
40a,b
F
11
CF3
CF3
S
5
6
42
48a,b
Br
MeOC
12
NC
F3C
F
NC
Br
7
8
54a,b
S
S
S
MeOC
MeOC
MeOC
13
14
15
F3C
Br
60a,b
OHC
F
9
10
50
56a,b
Br
31% 17
CHO
S
CHO
Pd(OAc)2 1 mol%
S
N
N
N
+
+
CHO
S
DMAc, KOAc,
120 ºC, 20 h
11
12
15
Br
15a,b
N
Br
CHO
MeOC
16
Conditions: catalyst Pd(OAc)2 (0.01 equiv), aryl bromide (1 equiv), 2-acetyl-5-
methylthiophene (3 equiv), KOAc (2 equiv), DMAc, 120 °C, 20 h, under argon, iso-
lated yields.
31% 18
CHO
S
a
2-Acetyl-5-methylthiophene: 2 equiv.
b
Reaction temperature 150 °C.
Scheme 5.

J. J. Dong et al. / Tetrahedron Letters 50 (2009) 2778–2781
2781
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Acknowledgements
J.R. is grateful to MEN for a grant. We thank the Centre National
de la Recherche Scientifique and ‘Rennes Metropole’ for providing
financial support.
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15. As
a typical experiment (Table 3, entry 3), the reaction of 2-acetyl-5-
methylthiophene (0.420 g, 3 mmol), 4-bromobenzonitrile (0.182 g, 1 mmol)
and KOAc (0.196 g, 2 mmol) at 120 °C over 20 h in dry DMAc (5 mL) in the
presence of Pd(OAc)2 (0.01 mmol) under argon affords the corresponding
product 10 after evaporation and filtration on silica gel in 63% (0.152 g)
isolated yield.
16. All compounds gave satisfactory 1H, 13C and elementary analysis. 1H NMR
(200 MHz, CDCl3) of new compounds: 1: d 10.0 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H),
7.55 (d, J = 8.5 Hz, 2H), 6.77 (s, 1H), 2.48 (s, 6H); 2: d 7.95–7.80 (m, 4H), 7.70–
7.40 (m, 5H), 6.78 (s, 1H), 2.51 (s, 3H), 2.49 (s, 3H); 3: d 8.02 (d, J = 8.5 Hz, 2H),
7.47 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 3.05 (q, J = 7.5 Hz, 2H), 2.48 (s, 6H), 1.27 (t,
J = 7.5 Hz, 3H); 4: d 7.67 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 6.73 (s, 1H),
2.47 (s, 6H); 5: d 7.69 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 6.72 (s, 1H),
2.47 (s, 6H); 6: d 8.27 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 6.76 (s, 1H),
2.49 (s, 6H); 7: d 7.77 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50–7.30 (m,
2H), 6.69 (s, 1H), 2.50 (s, 3H), 2.43 (s, 3H); 8: d 8.00–7.65 (m, 3H), 7.58–7.27 (m,
4H), 6.69 (s, 1H), 2.52 (s, 3H), 2.22 (s, 3H); 9: d 7.72 (d, J = 8.1 Hz, 2H), 7.71 (s,
1H), 7.52 (d, J = 8.1 Hz, 2H), 2.57 (s, 6H); 10: d 7.78 (d, J = 8.3 Hz, 2H), 7.61 (s,
1H), 7.50 (d, J = 8.3 Hz, 2H), 2.52 (s, 6H); 11: d 7.61 (s, 1H), 7.30 (dd, J = 8.0 and
4.5 Hz, 2H), 7.12 (t, J = 8.0 Hz, 2H), 2.52 (s, 3H), 2.50 (s, 3H); 12: d 7.69–7.60 (m,
5H), 2.57 (s, 3H), 2.56 (s, 3H); 13: d 7.77 (d, J = 8.3 Hz, 1H), 7.72 (m, 1H), 7.68 (s,
1H), 7.55–7.25 (m, 2H), 2.53 (s, 3H), 2.46 (s, 3H); 14: d 7.80 (d, J = 8.1 Hz, 1H),
7.70–7.45 (m, 3H), 7.25 (d, J = 8.1 Hz, 1H), 2.54 (s, 3H), 2.30 (s, 3H); 15: d 7.61
(s, 1H), 7.45–7.05 (m, 4H), 2.54 (s, 3H), 2.45 (s, 3H); 16: d 9.21 (s, 1H), 8.80 (s,
2H), 7.63 (s, 1H), 2.52 (s, 6H); 17: d 10.10 (s, 1H), 9.89 (s, 1H), 7.99 (d, J = 8.5 Hz,
2H), 7.76 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 2.63 (s, 3H); 18: d 10.10 (s, 1H), 9.79 (s,
1H), 7.99 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 6.98 (s, 1H), 2.62 (s, 3H).
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