Palladium-catalysed C2 or C5 direct arylation of 3-substituted thiophenes with aryl bromides

Article abstract of DOI:10.1055/s-0030-1260213

The Pd(OAc)₂/dppb system was found to be an efficient catalyst for the direct arylation of 3-substituted thiophene derivatives. The regioselectivity of the arylation strongly depends on the thiophene substituent and also on the nature of the aryl bromide. When using 3-formyl, 3-cyano, 3-methyl, 3-hydroxymethyl or 3-bromothiophene, the 2-arylated thiophenes were obtained with 76-95% regioselectivity; whereas, the arylation of 3-formylthiophene diethylacetal or 3-acetylthiophene gave the 5-arylated thiophenes with 52-90% regioselectivity. The use of congested aryl bromides favours the arylation at C5. These reactions were performed using only 0.1 mol% of catalyst. Moreover, this procedure has been found to be tolerant to a variety of functional groups on the aryl bromide such as formyl, propionyl, benzoyl, nitrile, and nitro. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1260213

3530
PAPER
Palladium-Catalysed C2 or C5 Direct Arylation of 3-Substituted Thiophenes
with Aryl Bromides
P
d-Cataly
i
sed Ary
a
lation of 3-Subst
J
ituted Thio
i
phene
s
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes ‘Catalyse et Organometalliques’, Campus de Beaulieu,
35042 Rennes, France
Fax +33(2)23236939; E-mail: henri.doucet@univ-rennes1.fr
Received 1 July 2011; revised 29 July 2011
carboxylate.8 The use of Pd(PPh3)4 in toluene gave selec-
Abstract: The Pd(OAc)2/dppb system was found to be an efficient
tively the 2-arylated thiophene; whereas Pd2(dba)3 in
NMP gave a mixture of 2- and 5-arylated thiophenes in a
15:51 ratio. In 1998, Lemaire and co-workers reported the
catalyst for the direct arylation of 3-substituted thiophene deriva-
tives. The regioselectivity of the arylation strongly depends on the
thiophene substituent and also on the nature of the aryl bromide.
When using 3-formyl, 3-cyano, 3-methyl, 3-hydroxymethyl or 3- direct arylation of 3-formyl, 3-cyano, and 3-ni-
trothiophene with aryl iodides.9 In most cases, they ob-
bromothiophene, the 2-arylated thiophenes were obtained with 76–
95% regioselectivity; whereas, the arylation of 3-formylthiophene
tained mixtures of 2-arylated and 2,4-diarylated
diethylacetal or 3-acetylthiophene gave the 5-arylated thiophenes
thiophenes together with a good amount of homocoupled
with 52–90% regioselectivity. The use of congested aryl bromides
product of the aryl iodide. For example, 3-formyl-
favours the arylation at C5. These reactions were performed using
thiophene reacted with iodobenzene using Pd(OAc)2 (8
mol%), PPh3 (16 mol%), and K2CO3 in DMF at 140 °C to
give 2-phenyl-3-formylthiophene in 35% yield.10 Bilo-
deau and co-workers have examined the regioselectivity
of the arylation of 3-methylthiophene with bromobenzene
using Pd[(P(t-Bu)3]2 as the catalyst. They obtained a mix-
ture of the 2- and 5-phenylated thiophenes in a 3.3:1 ratio
(30% yield of 2-phenylation and 9% yield of the 5-phenyl-
ated thiophene).11 Recently, Fagnou and co-workers have
reported the direct arylation of 3-n-hexylthiophene with
4-bromonitrobenzene.12 A mixture of C2 and C5 arylation
products was obtained in a 1.3:1 ratio. Therefore, in order
to obtain selectively the arylation at C2 or at C5, they
blocked one position (C2 or C5) using a chloro substitu-
ent. The direct arylation of 3-methoxythiophene has been
explored by Borghese and co-workers.13 With this reac-
tant, the 2-arylated thiophenes were obtained regioselec-
tively in 28–60% yields. Rhodium catalysts have also
been found to promote the direct arylation at C2 of 2-
methoxythiophene.15,16
only 0.1 mol% of catalyst. Moreover, this procedure has been found
to be tolerant to a variety of functional groups on the aryl bromide
such as formyl, propionyl, benzoyl, nitrile, and nitro.
Key words: catalysis, palladium, thiophenes, arylation, C–H bond
activation
Substituted thiophenes continue to attract the attention of
synthetic organic chemists, due to their inherent biologi-
cal activity and physical properties. Conventional meth-
ods for the synthesis of aryl thiophenes include metal
catalysed cross-coupling reactions such as Suzuki, Stille,
and Negishi type reactions,1 which permit the coupling of
aryl halides with organometallic derivatives of
thiophenes. Nevertheless, these procedures require the ap-
propriate functionalisation of one or both of the coupling
partners, and they produce stoichiometric amounts of me-
tallic salts as by-products. Moreover, when functionalised
thiophene derivatives are employed, the access to the cor-
responding organometallic derivatives might be tricky.
In summary, if some different catalysts and reaction con-
ditions have been employed for such couplings, the influ-
ence of the nature of the substituent at C3 of thiophenes
on the regioselectivity of the arylation remains unclear.
Moreover, only a few examples of direct arylation of 3-
formylthiophene, 3-methylthiophene, 3-bromothiophene,
and 3-cyanothiophene have been described; and to our
knowledge, 3-thiophenemethanol, ethyl thiophen-3-yl-
acetate, and 3-formylthiophene diethylacetal have never
been employed. Thus, it would be useful to develop a sim-
ple procedure, employing low catalyst loadings and a va-
riety of functionalised aryl bromides, allowing the direct
arylation of 3-substituted thiophenes to obtain either ary-
lation at C2 or at C5 in a regioselective manner. More-
over, a better understanding of the influence of electronic
and steric parameters on the regioselectivity of the aryla-
tion is also highly desirable. We have already reported
preliminary results for such couplings using 3-formyl-
The direct coupling of functionalised thiophenes with aryl
halides via a C–H bond activation/functionalisation
should provide a cost-effective and environmentally at-
tractive procedure for the preparation of functionalised
aryl thiophenes. The selective C5 arylation of 2-substitut-
ed thiophenes via a palladium-catalysed C–H bond
activation2–4 has been largely described in recent years.5,6
The polyarylation of 3-thiophenecarboxylic acid has been
reported by Miura and co-workers.7 On the other hand, the
palladium-catalysed regiocontrolled direct arylation of 3-
substituted thiophenes has attracted less attention.8–14 In
2003 Sharp and co-workers have reported conditions that
allow the regioselective arylation of methyl 3-thiophene-
SYNTHESIS 2011, No. 21, pp 3530–3546
x
x.
x
x
.
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0
1
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Advanced online publication: 07.09.2011
DOI: 10.1055/s-0030-1260213; Art ID: Z66011SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pd-Catalysed Arylation of 3-Substituted Thiophenes
3531
thiophenes.17 Here we report on the regioselectivity of the sulted in low to moderate conversions of 4-bromoben-
palladium-catalysed direct arylation of a wide variety of zonitrile, and the regioselectivity of the arylation was not
3-substituted thiophenes with a set of aryl bromides.
improved (Table 1, entries 10 and 11). In the presence of
xylene, the coupling products 1a or 1b were not detected
(Table 1, entry 14). The selectivity of the reaction was
also slightly dependent on the catalyst. We observed that
[Pd(C3H5)Cl]2, in the absence of phosphine, exhibits a
high regioselectivity (80%) towards the product 1a
(Table 1, entry 19). Similar regioselectivities (80–81% of
1a) were obtained in the presence of Pd(OAc)2 associated
to the phosphine ligands dppb, dppe, dppf, PPh3, and PCy3
(Table 1, entries 12, 13, 15–18). The GC and NMR anal-
ysis of the crude mixtures revealed that the reaction per-
formed with Pd(OAc)2 associated to dppb was very clean.
With this catalyst 1a was isolated in 57% yield (Table 1,
entry 13). Therefore, this catalyst precursor was selected
to explore the scope and limitations of this reaction using
various aryl bromides.
Initially our efforts were directed towards palladium-
catalysed direct arylation of 3-formylthiophene with 4-
bromobenzonitrile (Scheme 1, Table 1). The reaction was
found to produce a mixture of 1a and 1b in a 79:21 ratio,
using only 0.1 mol% of Pd(OAc)2 as the catalyst, in the
presence of KOAc as the base and DMA (dimethylacet-
amide) as the solvent at 150 °C. In order to improve the
regiocontrol of the arylation, we performed a series of ex-
periments using various solvents, bases, and catalysts.
Bases exhibit a considerable difference of efficiency and
regioselectivity for this reaction (Table 1, entries 1–9).
Carbonates or KF led to the formation of the C2 arylated
thiophene 1a in lower regioselectivities than KOAc or
NaOAc. The NMR of the crude mixtures using KOAc was
found to be cleaner than with NaOAc. Next, we examined
the influence of the solvent. The use of DMF or NMP re-
Table 1 Influence of the Reaction Conditions on the Arylation of 3-Formylthiophene with 4-Bromobenzonitrile (Scheme 1)a
Entry
1
Solvent
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
NMP
DMA
DMA
xylene
DMA
DMA
DMA
DMA
DMA
Base
Catalyst
Temp (°C)
150
130
130
130
130
130
130
130
130
130
130
130
150
130
130
150
130
150
130
Conv. (%)
100
70
Ratio (%) 1a/1b
79:21
KOAc
KF
Pd(OAc)2
2
Pd(OAc)2
69:31
3
Cs2CO3
Na2CO3
K2CO3
K3PO4
NaOAc
KOAc
CsOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
Pd(OAc)2
50
mixtureb
72:28
4
Pd(OAc)2
52
5
Pd(OAc)2
82
62:38
6
Pd(OAc)2
2
traces
7
Pd(OAc)2
100
76
79:21
8
Pd(OAc)2
78:22
9
Pd(OAc)2
100
55
71:29
10
11
12
13
14
15
16
17
18
19
Pd(OAc)2
75:25
Pd(OAc)2
20
mixture
81:19
Pd(OAc)2/dppbc
Pd(OAc)2/dppbc
Pd(OAc)2/dppbc
Pd(OAc)2/dppec
Pd(OAc)2/dppfc
Pd(OAc)2/2 PPh3
100
100
0
81:19d,e
–
100
100
100
100
100
80:20
80:20d
81:19
f
80:20d
80:20
f
Pd(OAc)2/2 PCy3
[Pd(C3H5)Cl]2
a Conditions: [Pd] (0.1 mol%), 4-bromobenzonitrile (1 mmol), 3-formylthiophene (2 mmol), base (2 mmol), solvent (3 mL), 16 h; conversions
and ratios of 1a/1b were determined by GC and NMR.
b The formation of an important amount of biphenyl-4,4¢-dicarbonitrile was observed.
c Diphosphine ligand used: 0.1 mol%.
d 3-Formylthiophene used: 1.5 mmol.
e Isolated yield of 1a: 57%.
f PPh3 or PCy3 used: 0.2 mol%.
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

3532
J. J. Dong et al.
PAPER
O
none, 4-bromobenzophenone, and 4-bromonitrobenzene,
resulting in 55–61% yields of the products 2a–5a
(Table 2, entries 3 and 5–7). meta-Substituted aryl bro-
mide, 3-bromobenzonitrile, gave 6a in 58% yield
(Table 2, entry 9). A slightly lower regioselectivity in
favour of C2 arylation was observed when ortho-substi-
tuted aryl bromides were employed. 2-Bromobenzalde-
hyde and 2-bromobenzonitrile gave mixtures of
regioisomers a/b in 76:24 and 77:23 ratios, respectively
(Table 2, entries 10 and 11). This is certainly due to the
steric hindrance of these aryl bromides. Pyridines or quin-
olines are p-electron deficient heterocycles and therefore,
their oxidative addition to palladium is, in general, rela-
tively easy. 3-Bromopyridine and 3-bromoquinolines
gave the regioisomers 10a and 11a with 83 and 82%
regioselectivity, respectively (Table 2, entries 14 and 15).
O
H
O
H
H
+
[Pd], base
S
+
Ar
Ar
1a–11a
S
S
ArBr
1b–11b
Scheme 1
3-Formylthiophene was coupled to a set of aryl bromides
using 0.1 mol% Pd(OAc)2 associated to 0.1 mol% dppb as
the catalytic system and KOAc as the base (Table 2). The
reactions performed with para-substituted electron-defi-
cient aryl bromides proceed conveniently in most cases.
High regioselectivities in favour of C2 arylation were ob-
served using 4-bromobenzaldehyde, 4-bromopropiophe-
Table 2 2-Arylation of 3-Formylthiophene (Scheme 1)a
Entry
Aryl halide
Major product
Ratio a/b
Yield of regioisomer a (%)b
O
H
1
81:19
57
Br
CN
CN
S
CN
1a
2
3
–
0c
Cl
Br
O
H
O
H
85:15
55
O
S
H
2a
O
H
4
5
–
0c
Cl
Br
O
H
O
84:16
56
O
S
Ph
Ph
3a
O
H
O
6
86:14
58
Br
S
O
4a
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

PAPER
Pd-Catalysed Arylation of 3-Substituted Thiophenes
3533
Table 2 2-Arylation of 3-Formylthiophene (Scheme 1)a (continued)
Entry
7
Aryl halide
Major product
Ratio a/b
Yield of regioisomer a (%)b
O
H
85:15
61
Br
NO2
NO2
S
NO2
5a
8
9
–
0c
Cl
Br
O
H
CN
CN
80:20
58
S
6a
O
H
O
H
10
11
76:24
77:23
44
48
S
H
Br
O
7a
O
H
NC
Br
S
NC
8a
NC
Cl
c
12
13
–
0
O
H
Br
80:20
52
54
S
9a
O
H
14
15
83:17
82:18
Br
S
N
N
10a
O
H
50
Br
S
N
N
11a
a Conditions: Pd(OAc)2 (0.1 mol%), dppb (0.1 mol%), aryl halide (1 mmol), 3-formylthiophene (1.5 mmol), KOAc (2 mmol), DMA (3 mL),
150 °C, 16 h.
b Isolated yields of regioisomers a.
c Pd(OAc)2: 1 mol%; dppb: 1 mol%.
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

3534
J. J. Dong et al.
PAPER
The coupling of 2- or 4-chlorobenzonitriles, 4-chloroace-
tophenone, and 4-chloronitrobenzene with 3-formylthio-
phene using 1 mol% Pd(OAc)2 associated to 1 mol% dppb
at 150 °C was also studied. However, using these reaction
conditions, no formation of desired coupling products was
detected, and the aryl chlorides were recovered unreacted
(Table 2, entries 2, 4, 8, and 12). For such challenging
substrates more efficient catalysts should be employed.5u
Table 3 Influence of the Reaction Conditions on the Arylation of
3-Formylthiophene Diethylacetal with 4-Bromobenzonitrile
(Scheme 2)a
Entry Solvent Base
Catalyst
Temp Conv.Ratio
(°C)
(%) (%)
1a/1b
1
2
DMA KOAc
DMA KF
Pd(OAc)2
Pd(OAc)2
150
130
130
130
130
130
130
130
130
130
130
130
150
130
90 25:75
30 28:72
Next, the reactivity of 3-formylthiophene diethylacetal
with 4-bromobenzonitrile was examined (Scheme 2,
Table 3). A similar set of reaction conditions were em-
ployed, identical with those used for 3-formylthiophene,
and again, KOAc as the base was found to give a good
conversion of the aryl bromide and also a quite regioselec-
tive arylation (Table 3, entries 1–9). However, with this
substrate, the C5 arylation was predominant. This might
be due to steric factors, as carbon C2 of 3-formyl-
thiophene diethylacetal is more hindered than carbon C2
of 3-formylthiophene. The use of other solvents such as
NMP or DMF did not allow to improve the regioselectiv-
ity of the arylation (Table 3, entries 10 and 11). Again, the
cleanest NMR of the crude mixtures was obtained using
Pd(OAc)2/dppb as the catalyst precursor, KOAc as the
base, and DMA as the solvent at 150 °C (Table 3, entry
13). Using these reaction conditions, the ratio of product
1a/1b was 24:76 and the yield in 1b was 53%.
3
DMA Cs2CO3 Pd(OAc)2
DMA Na2CO3 Pd(OAc)2
DMA K2CO3 Pd(OAc)2
8
24:76
4
22 28:72
11 32:68
5
6
DMA K3PO4
DMA NaOAc Pd(OAc)2
DMA KOAc Pd(OAc)2
DMA CsOAc Pd(OAc)2
Pd(OAc)2
0
–
7
70 26:74
77 23:77
80 29:71
80 24:76
82 25:75
100 27:73
100 24:76c
90 25:75
90 24:76
92 25:75
8
9
10
11
12
13
14
15
16
DMF
NMP
KOAc
KOAc
Pd(OAc)2
Pd(OAc)2
DMA KOAc
DMA KOAc
DMA KOAc
DMA KOAc
DMA KOAc
Pd(OAc)2/dppbb
Pd(OAc)2/dppbb
Pd(OAc)2/dppeb
EtO
d
Pd(OAc)2/2 PPh3 130
[Pd(C3H5)Cl]2 130
O
O
OEt
H
H
1) [Pd], base
S
a Conditions: [Pd] (0.1 mol%), 4-bromobenzonitrile (1 mmol), 3-
formylthiophene diethylacetal (2 mmol), base (2 mmol), solvent (3
mL), 16 h, conversions and ratios of 1a/1b determined by GC and
NMR.
+
Ar
Ar
1a–11a
2) HCl–THF
25 °C, 3 h
S
S
+
1b–11b
ArBr
b Diphosphine ligand: 0.1 mol%.
Scheme 2
c 3-Formylthiophene diethylacetal (1.5 mmol); isolated yield of 1b:
53%.
Then, the arylation of 3-formylthiophene diethylacetal
with several aryl bromides was explored (Table 4). In the
presence of aryl bromides electronically and sterically
similar to 4-bromobenzonitrile, such as 4-bromobenzal-
dehyde, 4-bromobenzophenone, and 4-bromopropiophe-
none, similar regioselectivities (76–78% of 5-arylation)
and yields were obtained (Table 4, entries 2–4). On the
other hand, when the sterically congested aryl bromides,
2-bromobenzonitrile, 2-bromobenzaldehyde, and 1-bro-
monaphthalene were employed, the regioselectivities of
the arylation in favour of regioisomers 7b–9b were in-
creased to 83–88% (Table 4, entries 7–9). In the presence
of 3-bromopyridine or 3-bromoquinoline, the compounds
10b and 11b were obtained with 64% and 70% regioselec-
tivity, respectively (Table 4, entries 10 and 11).
d PPh3: 0.2 mol%.
zonitrile, 4-bromobenzaldehyde, 4-bromonitrobenzene,
and 3-bromopyridine (Table 5). We observed that the for-
mation of the 2-arylated products 12a–15a was predomi-
nant in all cases (79–83%). This regioselectivity was
expected, as the hindrance and electronic properties of cy-
ano and formyl as substituents are quite similar.
R
R
R
Pd(OAc)2 (0.1 mol%)
dppb (0.1 mol%)
S
+
+
Ar
Ar
12a–33a
KOAc, DMA, 130 °C
S
S
ArBr
Next, the influence of other substituents at the 3-position
of thiophene on the regioselectivity of the arylation was
studied using similar reaction conditions (Scheme 3).
First, 3-cyanothiophene was coupled with 4-bromoben-
12b–33b
R = CN, Me, COMe, CH2OH, CH2CO2Et, Br
Scheme 3
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

PAPER
Pd-Catalysed Arylation of 3-Substituted Thiophenes
3535
Table 4 5-Arylation of 3-Formylthiophene Diethyl Acetal (Scheme 2)a
Entry
1
Aryl bromide
Major product
Ratio a/b
Yield of regioisomer b (%)b
O
H
24:76
53
48
Br
CN
S
NC
1b
O
H
O
H
2
3
4
24:76
22:78
24:76
Br
O
S
H
2b
O
H
O
50
48
Br
O
S
Ph
Ph
3b
O
H
O
Br
S
O
4b
O
H
5
6
7
8
28:72
28:72
12:88
17:83
53
55
40
62
Br
NO2
S
O2N
5b
O
H
CN
NC
Br
S
6b
O
O
H
O
H
H
S
Br
7b
O
H
NC
CN
Br
S
8b
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

3536
J. J. Dong et al.
PAPER
Yield of regioisomer b (%)b
51
Table 4 5-Arylation of 3-Formylthiophene Diethyl Acetal (Scheme 2)a (continued)
Entry
9
Aryl bromide
Major product
Ratio a/b
O
H
Br
13:87
S
9b
O
H
10
11
36:64
30:70
42
40
Br
N
N
S
10b
O
H
Br
S
N
N
11b
a Conditions: 1. Pd(OAc)2 (0.1 mol%), dppb (0.1 mol%), aryl bromide (1 mmol), 3-formylthiophene diethyl acetal (1.5 mmol), KOAc (2 mmol),
DMA (3 mL), 150 °C, 16 h; 2. HCl, THF, 25 °C, 3 h.
b Isolated yields of regioisomers b.
Table 5 Direct Arylation of 3-Cyanothiophene with Aryl Bromides (Scheme 3)a
Entry
Aryl bromide
Major product
Ratio a/b
Yield of regioisomer a (%)b
N
1
80:20
60
Br
CN
S
CN
12a
N
O
H
2
78:22
58
Br
O
S
H
13a
N
3
4
83:17
79:21
64
40
Br
NO2
S
NO2
14a
N
Br
S
N
N
15a
a Conditions: Pd(OAc)2 (0.1 mol%), dppb (0.1 mol%), aryl bromide (1 mmol), 3-cyanothiophene (2 mmol), KOAc (2 mmol), DMA (3 mL),
130 °C, 20 h.
b Isolated yields of regioisomers a.
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

PAPER
Pd-Catalysed Arylation of 3-Substituted Thiophenes
3537
Then, the reactivity of a thiophene bearing an electron- with 82–87% regioselectivities (Table 6). These results
donating group at C3 was examined using the same reac- reveal that with our reaction conditions, the regioselectiv-
tion conditions (Table 6). For 3-methylthiophene, a regio- ity of the arylation of thiophenes mainly depends on the
selectivity similar to that obtained for 3-formylthiophene steric properties of the substituents at C3 rather than on
or 3-cyanothiophene was observed. The 2-aryl-3-methyl- their electronic properties.
thiophenes 16a–20a were obtained in 45%–69% yields
Table 6 Direct Arylation of 3-Methylthiophene or 3-Acetylthiophene with Aryl Bromides (Scheme 3)a
Entry
1
Aryl bromide
Major product
Ratio a/b
Yield of regioisomer a (%)b
87:13
65
Br
CN
S
CN
16a
2
86:14
64
S
Br
Br
O
O
17a
3
4
5
84:16
82:18
87:13
62
45
69
NO2
S
NO2
18a
Br
S
N
N
19a
S
Br
N
N
20a
O
6
7
48:52
25:75
38c
Br
CN
S
NC
21b
O
CN
NC
Br
57a
S
22b
O
Br
8
10:90
73a
S
23b
a Conditions: Pd(OAc)2 (0.1 mol%), dppb (0.1 mol%), aryl bromide (1 mmol), 3-methylthiophene or 3-acetylthiophene (2 mmol), KOAc (2
mmol), DMA (3 mL), 130 °C, 20 h.
b Isolated yields of regioisomers a.
c Isolated yields of regioisomers b.
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In order to confirm these observations, the slightly more To our knowledge, the direct arylation of 3-thiophene-
congested thiophene, 3-acetylthiophene (Table 6, entries methanol has also not been reported.18 The use of such
6–8) was used. To our knowledge, so far this reactant has substrate bearing an unprotected functions would be very
not been employed for palladium-catalysed direct aryla- useful in organic synthesis since it would allow to avoid
tions. In the presence of 4-bromobenzonitrile, and 0.1 the protection/deprotection sequence, and therefore
mol% Pd(OAc)2 associated to 0.1 mol% dppb as the cata- should provide a more environmentally and economically
lytic system, an almost equimolar amount of regioisomers attractive access to such arylated heteroaromatics. More-
a and b was formed, and the 5-arylated product 21b was over, the presence of such functional group on thiophene
isolated in 38% yield (Table 6, entry 6). It was also ob- might have an influence on the regioselectivity of the ary-
served that the regioselectivity shifts to the predominant lation due to a possible coordination of the hydroxy group
formation of 4-acetyl-2-arylthiophenes 22b or 23b in the to palladium. It was observed that when the reaction is
presence of sterically more hindered aryl bromides. For performed in DMA with Pd(OAc)2 (0.1 mol%) associated
example, with 2-bromobenzonitrile, the product 22b was to dppb (0.1 mol%) using KOAc as the base, the reaction
obtained in 57% yield with 75% regioselectivity. The very of 4-bromobenzonitrile with 3-thiophenemethanol gives
bulky aryl bromide, 9-bromoanthracene led to a highly re- predominantly the arylation at C2 (ratio C2/C5 = 79:21)
gioselective arylation at C5, forming 23b in 73% yield (Table 7, entry 1). This result indicates that with these re-
with 90% regioselectivity (Table 6, entry 8). Under these action conditions, the presence of such hydroxymethyl
reaction conditions, the regioselectivity of the arylation function at C3 has almost no influence on the regioselec-
mostly depends on the steric influence of both coupling tivity. This is consistent with the previously reported re-
partners.
sults using 2-thiophenemethanol.18 It should be noted that
the use of n-Bu3N as the base gave no coupling product
Table 7 Direct Arylation of 3-Thiophenemethanol with Aryl Bromides (Scheme 3)a
Entry
Aryl bromide
Major product
Conversion (%) Ratio a/b
Yield of regioisomer a (%)b
OH
1
100
79:21
66
Br
CN
S
CN
24a
2
3
4
5
0
–
0c
35d
0e
68
95:5
mixture
mixture
–
–
0f
OH
6
100
81:19
65
Br
Br
S
O
O
25a
OH
7
8
100
100
82:18
82:18
55
69
NO2
S
NO2
26a
OH
Br
S
N
N
27a
a Conditions: Pd(OAc)2 (0.1 mol%), dppb (0.1 mol%), aryl bromide (1 mmol), 3-thiophenemethanol (2 mmol), KOAc (2 mmol), DMA (3 mL),
130 °C, 20 h.
b Isolated yields of regioisomers a.
c n-Bu3N as the base.
d Xylene as the solvent.
e Cs2CO3 as the base.
f CsOAc as the base.
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Pd-Catalysed Arylation of 3-Substituted Thiophenes
3539
24a (Table 7, entry 2). On the other hand, a better regio- 51–63% yields with 69–76% regioselectivities. It should
selectivity in favour of the arylation at C2 was observed in be noted that the use of xylene as the solvent instead of
xylene, but only a partial conversion of 4-bromobenzoni- DMA gave only a slightly more regioselective reaction,
trile was obtained (Table 7, entry 3). Sharp and co-work- and a poor conversion of 4-bromobenzonitrile of only
ers have already reported that the use of toluene as the 27% was obtained (Table 8, entry 3). n-Bu3N was found
solvent favours the arylation at C2.8 Then, the reactivity to be an ineffective base for this reaction (Table 8, entry
of three other aryl bromides with thiophene-3-methanol 2).
was examined. 4-Bromoacetophenone, 4-bromonitroben-
zene, and 3-bromopyridine gave the products 25a–27a in
55–69% yields with 81–82% regioselectivities (Table 7,
entries 6–8).
Then, the direct arylation of 3-bromothiophene using our
reaction conditions was studied (Table 8, entries 7 and 8).
Fagnou and co-workers have reported the direct arylation
of this thiophene derivative with 4-iodoanisole using 5
A few reactions using ethyl 3-thiophenylacetate as the re- mol% Pd(OAc)2 associated to 10 mol% of an electron-
actant was also performed (Table 8). In DMA using 0.1 rich phosphine ligand at 60 °C. They obtained the aryla-
mol% Pd(OAc)2 and 0.1 mol% dppb as the catalytic sys- tion at C2 in 72% yield.14 Using 0.1 mol% Pd(OAc)2 as-
tem, the C2 arylated thiophenes 28a–31a were obtained in sociated to 0.1 mol% of dppb at 130 °C and 4-bromo-
Table 8 Direct Arylation of Ethyl 3-thiopheneacetate or 3-Bromothiophene with Aryl Bromides (Scheme 3)a
Entry
Aryl bromide
Major product
Ratio a/b
Yield of regioisomer a (%)b
CO2Et
1
69:31
61
Br
CN
S
CN
28a
c
2
3
–
0
–
76:24d
CO2Et
4
5
73:27
63
53
Br
Br
NO2
S
NO2
29a
CO2Et
76:24
O
S
O
30a
CO2Et
6
7
8
76:24
89:11
93:7
51
58
46
Br
Br
Br
CO2Me
S
CO2Me
31a
Br
NO2
S
NO2
32a
Br
CO2Me
S
CO2Me
33a
a Conditions: Pd(OAc)2 (0.1 mol%), dppb (0.1 mol%), aryl bromide (1 mmol), ethyl 3-thiopheneacetate or 3-bromothiophene (2 mmol), KOAc
(2 mmol), DMA (3 mL), 130 °C, 20 h.
b Isolated yields of regioisomers a.
c n-Bu3N as the base.
d Xylene as the solvent, conversion of 4-bromobenzonitrile 27%.
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Table 9 Direct Arylation of Ethyl 3-Furoate with Aryl Bromides (Scheme 4)a
Entry
1
Aryl bromide
Major product
Ratio a/b
Yield of regioisomer b (%)b
CO2Et
NO2
O2N
28:72
45
O
Br
Br
34b
CO2Et
2
26:74
43
O
O
O
35b
a Conditions: Pd(OAc)2 (0.2 mol%), dppb (0.2 mol%), aryl bromide (1 mmol), ethyl 3-furoate (2 mmol), KOAc (2 mmol), DMA (3 mL),
130 °C, 20 h.
b Isolated yields of regioisomers b.
nitrobenzene or methyl 4-bromobenzoate, the products Larger amounts of C5 arylated thiophenes were generally
32a and 33a were obtained with high regioselectivities of obtained in the presence of ortho-substituted aryl bro-
89% and 93%, but in moderate yields of 58% and 46% mides. This procedure should be industrially and environ-
due to the formation of some unidentified side-products.
mentally attractive as it employ only 0.1 mol% palladium
catalyst, has proved to be tolerant to a variety of function-
al groups on the aryl bromide such as formyl, propionyl,
benzoyl, nitrile, and nitro and as the major by-products are
AcOH/KBr instead of metallic salts using more classical
coupling procedures. Moreover, no prior preparation of an
organometallic derivative is required for these couplings,
reducing the number of required steps to obtain these ary-
lated thiophenes.
Finally, the regioselectivity of the arylation of the 3-sub-
stituted furan, ethyl 3-furoate, was studied (Scheme 4).
Sharp and co-workers had observed that the use of Pd/C
as the catalyst in NMP led to the formation of 5-arylated
ethyl 3-furoate 34b in 42% yield, whereas, the use of 5
mol% Pd(PPh3)4 in toluene led to 34a in 73% yield.8 We
observed that using our reaction conditions, 0.2 mol%
Pd(OAc)2 associated to 0.2 mol% dppb in DMA, the ma-
jor product was 34b (Table 9, entry 1). A similar regiose-
lectivity was observed for the coupling with 4-
bromoacetophenone to give 35b in 43% yield with 74%
regioselectivity (Table 9, entry 2).
All chemical reactants and metal complexes were obtained from
commerical sources and used without further purification. DMA
analytical grade (99%) was not distilled before use. KOAc (99+%)
was employed. All reactions were run under argon using vacuum
lines in Schlenk tubes in oven-dried glassware. Flash chromatogra-
phies were performed on silica gel (230–400 mesh).
CO2Et
CO2Et
CO2Et
Pd(OAc)2 (0.2 mol%)
dppb (0.2 mol%)
+
Ar
Ar
Reaction of 3-Formylthiophene with Aryl Bromides (Products
1a–11a); General Procedure
KOAc, DMA, 130°C
O
O
O
+
34a, 35a
34b, 35b
In a typical experiment, the aryl bromide (1 mmol), 3-formylthio-
phene (0.168 g, 1.5 mmol), and KOAc (0.196 g, 2 mmol) were in-
troduced in an oven-dried Schlenk tube, equipped with a magnetic
stirring bar. Then, Pd(OAc)2 (0.22 mg, 0.001 mmol), dppb (0.42
mg, 0.001 mmol), and DMA (3 mL) were added, and the Schlenk
tube purged several times with argon. The Schlenk tube was placed
in a preheated oil bath at 150 °C and the reactants were allowed to
stir for 16 h. Then, the reaction mixture was analysed by GC and
NMR to determine the ratio of regioisomers a/b and the conversion
of the aryl bromide. The solvent was removed by heating of the re-
action vessel under vacuum and the residue was charged directly
onto a silica gel column. The products were eluted, using an appro-
priate ratio of Et2O and pentane (Table 2).
ArBr
Scheme 4
In summary, we have described here on the influence of
several substituents at C3 of thiophene derivatives on the
regioselectivity of palladium-catalysed direct arylations.
Although the electronic properties of such substituents on
thiophene seem relatively limited, their steric properties
are important. Thiophenes substituted at C3 by a methyl,
a cyano, a formyl, a hydroxymethyl, and a bromo gave the
2-arylated thiophenes in quite high regioselectivities. On
the other hand, the presence of an acetyl or a formyl pro-
tected as an acetal at C3 led to a predominant formation of
5-arylated thiophenes. Therefore, this reaction gives a
simple access to either 2-aryl-3-formylthiophenes or 2-
aryl-4-formylthiophenes. The steric hindrance of the aryl
bromides has also an influence on the regioselectivity.
4-(3-Formylthiophen-2-yl)benzonitrile (1a)
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 1a in
57% (0.122 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.41 (d, J = 5.3 Hz, 1 H), 7.62 (d,
J = 5.3 Hz, 1 H), 7.65 (d, J = 8.3 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H),
9.89 (s, 1 H).
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Pd-Catalysed Arylation of 3-Substituted Thiophenes
3541
13C NMR (125 MHz, CDCl3): d = 113.6, 118.5, 127.0, 127.9, 131.1,
133.0, 136.5, 138.3, 154.4, 185.2.
Anal. Calcd for C12H7NOS: C, 67.58; H, 3.31. Found: C, 67.62; H,
3.28.
Anal. Calcd for C12H7NOS: C, 67.58; H, 3.31. Found: C, 67.67; H,
3.22.
2-(3-Formylthiophen-2-yl)benzaldehyde (7a)
The reaction of 2-bromobenzaldehyde (0.186 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 7a in
44% (0.095 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.44–7.72 (m, 5 H), 8.10 (d,
J = 5.3 Hz, 1 H), 9.65 (s, 1 H), 10.01 (s, 1 H).
4-(3-Formylthiophen-2-yl)benzaldehyde (2a)
The reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 2a in
55% (0.118 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.40 (d, J = 5.3 Hz, 1 H), 7.62 (d,
J = 5.3 Hz, 1 H), 7.70 (d, J = 8.3 Hz, 2 H), 8.02 (d, J = 8.3 Hz, 2 H),
9.89 (s, 1 H), 10.11 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 126.8, 127.7, 130.5, 131.1, 136.9,
137.7, 138.2, 153.8, 185.5, 191.8.
13C NMR (50 MHz, CDCl3): d = 126.9, 127.2, 128.9, 130.5, 133.0,
134.0, 134.2, 135.8, 140.2, 150.1, 185.0, 190.7.
Anal. Calcd for C12H8O2S: C, 66.65; H, 3.73. Found: C, 66.58; H,
3.81.
2-(3-Formylthiophen-2-yl)benzonitrile (8a)
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 8a in
48% (0.102 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.46 (d, J = 5.3 Hz, 1 H), 7.56–
7.94 (m, 5 H), 9.75 (s, 1 H).
Anal. Calcd for C12H8O2S: C, 66.65; H, 3.73. Found: C, 66.69; H,
3.69.
4-(3-Formylthiophen-2-yl)benzophenone (3a)
The reaction of 4-bromobenzophenone (0.260 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 3a in
56% (0.163 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.34 (d, J = 5.3 Hz, 1 H), 7.46–
7.63 (m, 6 H), 7.81–7.92 (m, 4 H), 9.90 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 114.2, 117.7, 127.3, 127.6, 130.2,
132.5, 133.2, 134.0, 137.6, 139.3, 149.2, 184.7.
Anal. Calcd for C12H7NOS: C, 67.58; H, 3.31. Found: C, 67.41; H,
3.40.
13C NMR (50 MHz, CDCl3): d = 126.5, 127.5, 128.8, 130.4, 130.5,
130.9, 133.2, 135.7, 137.5, 138.1, 138.5, 154.4, 185.6, 196.1.
1-(3-Formylthiophen-2-yl)naphthalene (9a)19
The reaction of 1-bromonaphthalene (0.206 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 9a in
52% (0.123 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.45 (d, J = 5.3 Hz, 1 H), 7.50–
7.65 (m, 4 H), 7.67 (d, J = 5.3 Hz, 1 H), 7.80–8.03 (m, 3 H), 9.52 (s,
1 H).
Anal. Calcd for C18H12O2S: C, 73.95; H, 4.14. Found: C, 73.82; H,
4.29.
4-(3-Formylthiophen-2-yl)propiophenone (4a)
The reaction of 4-bromopropiophenone (0.212 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 4a in
58% (0.141 g) yield.
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.5 Hz, 3 H), 3.01–3.12
(m, 2 H), 7.36 (d, J = 5.3 Hz, 1 H), 7.60–7.64 (m, 3 H), 8.08 (d,
J = 8.3 Hz, 2 H), 9.90 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 8.5, 32.4, 126.4, 127.5, 128.9,
130.7, 136.1, 137.6, 138.0, 154.4, 185.6, 200.3.
3-(3-Formylthiophen-2-yl)pyridine (10a)
The reaction of 3-bromopyridine (0.157 g, 1 mmol) and 3-formyl-
thiophene (0.168 g, 1.5 mmol) afforded the product 10a in 54%
(0.102 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.36–7.46 (m, 2 H), 7.61 (d,
J = 5.3 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 8.71 (m, 2 H), 9.85 (s, 1
Anal. Calcd for C14H12O2S: C, 68.83; H, 4.95. Found: C, 68.91; H,
4.92.
H).
13C NMR (50 MHz, CDCl3): d = 124.0, 126.7, 127.6, 128.2, 137.6,
4-(3-Formylthiophen-2-yl)nitrobenzene (5a)
The reaction of 4-bromonitrobenzene (0.199 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 5a in
61% (0.142 g) yield.
138.3, 150.4, 150.8, 151.4, 185.4.
Anal. Calcd for C10H7NOS: C, 63.47; H, 3.73. Found: C, 63.52; H,
3.63.
1H NMR (200 MHz, CDCl3): d = 7.44 (d, J = 5.3 Hz, 1 H), 7.64 (d,
J = 5.3 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 2 H), 8.37 (d, J = 8.3 Hz, 2 H),
9.92 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 124.5, 127.3, 128.1, 131.3, 138.3,
138.5, 148.6, 152.1, 185.1.
3-(3-Formylthiophen-2-yl)quinoline (11a)
The reaction of 3-bromoquinoline (0.208 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 11a in
50% (0.119 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.42 (d, J = 5.3 Hz, 1 H), 7.61–
7.93 (m, 4 H), 8.20 (d, J = 8.4 Hz, 1 H), 8.30 (s, 1 H), 9.05 (s, 1 H),
9.94 (s, 1 H).
Anal. Calcd for C11H7NO3S: C, 56.64; H, 3.02. Found: C, 56.72; H,
3.05.
13C NMR (50 MHz, CDCl3): d = 123.8, 125.4, 126.2, 126.3, 126.8,
3-(3-Formylthiophen-2-yl)benzonitrile (6a)
The reaction of 3-bromobenzonitrile (0.182 g, 1 mmol) and 3-
formylthiophene (0.168 g, 1.5 mmol) afforded the product 6a in
58% (0.123 g) yield.
127.1, 128.4, 129.7, 135.9, 137.0, 146.9, 149.2, 150.3, 183.8.
Anal. Calcd for C14H9NOS: C, 70.27; H, 3.79. Found: C, 70.33; H,
3.66.
1H NMR (200 MHz, CDCl3): d = 7.39 (d, J = 5.3 Hz, 1 H), 7.59–
Reaction of 3-Formylthiophene Diethyl Acetal with Aryl Bro-
mides (Products 1b–11b); General Procedure
In a typical experiment, the aryl bromide (1 mmol), 3-formylthio-
phene diethyl acetal (0.279 g, 1.5 mmol), and KOAc (0.196 g, 2
mmol) were introduced in an oven-dried Schlenk tube, equipped
7.82 (m, 5 H), 9.86 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 113.8, 118.3, 126.7, 127.7, 130.2,
133.1, 133.3, 133.6, 134.7, 138.1, 152.4, 185.1.
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3542
J. J. Dong et al.
PAPER
with a magnetic stirring bar. Then, Pd(OAc)2 (0.22 mg, 0.001
mmol), dppb (0.42 mg, 0.001 mmol), and DMA (3 mL) were added,
and the Schlenk tube purged several times with argon. The Schlenk
tube was placed in a preheated oil bath at 150 °C and the reactants
were allowed to stir for 16 h. After cooling to r.t., THF (5 mL) and
aq HCl (pH 2, 5 mL) were added, and the mixture allowed to stir for
3 h. The reaction mixture was analysed by GC and NMR to deter-
mine the ratio of regioisomers a/b and the conversion of the aryl
bromide. After separation and drying (MgSO4), the solvent was re-
moved under vacuum, and the residue was charged onto a silica gel
column. The products were eluted, using an appropriate ratio of
Et2O and pentane (Table 4).
1H NMR (200 MHz, CDCl3): d = 7.75 (d, J = 8.3 Hz, 2 H), 7.88 (s,
1 H), 8.21 (s, 1 H), 8.30 (d, J = 8.3 Hz, 2 H), 9.94 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 123.5, 124.9, 126.9, 138.0, 139.6,
143.9, 144.3, 147.8, 185.1.
Anal. Calcd for C11H7NO3S: C, 56.64; H, 3.02. Found: C, 56.51; H,
3.09.
3-(4-Formylthiophen-2-yl)benzonitrile (6b)
The reaction of 3-bromobenzonitrile (0.182 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 6b in 55% (0.117 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.51–7.66 (m, 2 H), 7.78–7.89 (m,
3 H), 8.15 (s, 1 H), 9.92 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 113.8, 118.6, 122.4, 129.8, 130.4,
130.5, 132.1, 134.8, 137.2, 144.0, 144.2, 185.2.
4-(4-Formylthiophen-2-yl)benzonitrile (1b)
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 1b in 53% (0.113 g) yield.
Anal. Calcd for C12H7NOS: C, 67.58; H, 3.31. Found: C, 67.53; H,
3.42.
1H NMR (200 MHz, CDCl3): d = 7.70–7.80 (m, 4 H), 7.85 (d,
J = 1.2 Hz, 1 H), 8.18 (d, J = 1.2 Hz, 1 H), 9.94 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 112.2, 118.9, 122.9, 126.8, 133.3,
2-(4-Formylthiophen-2-yl)benzaldehyde (7b)
137.6, 137.7, 144.3, 144.4, 185.2.
The reaction of 2-bromobenzaldehyde (0.186 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 7b in 40% (0.086 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.52–7.72 (m, 4 H), 8.05 (s, 1 H),
8.25 (s, 1 H), 9.95 (s, 1 H), 10.20 (s, 1 H).
Anal. Calcd for C12H7NOS: C, 67.58; H, 3.31. Found: C, 67.41; H,
3.47.
4-(4-Formylthiophen-2-yl)benzaldehyde (2b)
The reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 2b in 48% (0.103 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.81(d, J = 8.3 Hz, 2 H), 7.96 (d,
J = 8.3 Hz, 2 H), 7.88 (s, 1 H), 8.17 (s, 1 H), 9.94 (s, 1 H), 10.05 (s,
1 H).
13C NMR (50 MHz, CDCl3): d = 127.1, 128.8, 129.6, 131.8, 134.2,
134.6, 136.7, 138.1, 141.4, 143.6, 185.2, 191.5.
Anal. Calcd for C12H8O2S: C, 66.65; H, 3.73. Found: C, 66.74; H,
3.62.
2-(3-Formylthiophen-2-yl)benzonitrile (8b)
13C NMR (50 MHz, CDCl3): d = 122.8, 126.8, 131.0, 136.3, 137.5,
139.1, 144.3, 145.1, 185.3, 191.7.
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 8b in 62% (0.132 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.44–7.81 (m, 4 H), 7.94 (s, 1 H),
8.22 (s, 1 H), 9.94 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 111.0, 118.6, 125.9, 129.1, 130.2,
133.6, 134.7, 136.7, 137.5, 141.7, 143.8, 185.1.
Anal. Calcd for C12H8O2S: C, 66.65; H, 3.73. Found: C, 66.53; H,
3.81.
4-(4-Formylthiophen-2-yl)benzophenone (3b)
The reaction of 4-bromobenzophenone (0.260 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 3b in 50% (0.146 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.48–7.63 (m, 3 H), 7.72–7.91 (m,
7 H), 8.15 (s, 1 H), 9.93 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 122.3, 126.1, 128.8, 130.4, 131.4,
133.0, 137.2, 137.3, 137.5, 137.8, 144.2, 145.5, 185.3, 196.2.
Anal. Calcd for C12H7NOS: C, 67.58; H, 3.31. Found: C, 67.69; H,
3.42.
1-(4-Formylthiophen-2-yl)naphthalene (9b)
The reaction of 1-bromonaphthalene (0.206 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 9b in 51% (0.121 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.53–7.58 (m, 4 H), 7.70 (s, 1 H),
7.92–8.23 (m, 3 H), 8.23 (s, 1 H), 9.99 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 125.3, 125.6, 125.7, 126.7, 127.3,
128.8, 128.9, 129.7, 131.3, 131.9, 134.2, 137.4, 143.6, 144.5, 185.6.
Anal. Calcd for C18H12O2S: C, 73.95; H, 4.14. Found: C, 74.02; H,
4.38.
4-(4-Formylthiophen-2-yl)propiophenone (4b)
The reaction of 4-bromopropiophenone (0.212 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 4b in 48% (0.117 g) yield.
1H NMR (200 MHz, CDCl3): d = 1.24 (t, J = 7.5 Hz, 3 H), 2.96–3.07
(m, 2 H), 7.79 (d, J = 8.3 Hz, 2 H), 7.81 (s, 1 H), 8.01 (d, J = 8.3 Hz,
2 H), 8.13 (s, 1 H), 9.90 (s, 1 H).
Anal. Calcd for C15H10OS: C, 75.60; H, 4.23. Found: C, 75.62; H,
4.33.
3-(4-Formylthiophen-2-yl)pyridine (10b)
The reaction of 3-bromopyridine (0.157 g, 1 mmol) and 3-formyl-
thiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the product
10b in 42% (0.079 g) yield.
13C NMR (50 MHz, CDCl3): d = 8.6, 32.2, 122.2, 126.3, 129.3,
136.8, 137.3, 137.5, 144.2, 145.4, 185.3, 200.3.
1H NMR (200 MHz, CDCl3): d = 7.37 (m, 1 H), 7.78 (s, 1 H), 7.92
(m, 1 H), 8.14 (s, 1 H), 8.60 (d, J = 4.2 Hz, 1 H), 8.91 (s, 1 H), 9.92
(s, 1 H).
13C NMR (50 MHz, CDCl3): d = 122.1, 124.3, 129.6, 134.0, 137.1,
142.9, 144.2, 147.5, 149.9, 185.2.
Anal. Calcd for C14H12O2S: C, 68.83; H, 4.95. Found: C, 68.79; H,
4.97.
4-(4-Formylthiophen-2-yl)nitrobenzene (5b)
The reaction of 4-bromonitrobenzene (0.199 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 5b in 53% (0.123 g) yield.
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

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Pd-Catalysed Arylation of 3-Substituted Thiophenes
3543
Anal. Calcd for C10H7NOS: C, 63.47; H, 3.73. Found: C, 63.39; H,
3.45.
Anal. Calcd for C11H6N2O2S: C, 57.38; H, 2.63. Found: C, 57.43; H,
2.59
3-(4-Formylthiophen-2-yl)quinoline (11b)
3-(3-Cyanothiophen-2-yl)pyridine (15a)10
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and 3-cyano-
thiophene (0.218 g, 2 mmol), KOAc (0.196 g, 2 mmol) afforded the
product 15a in 40% (0.074 g) yield.
The reaction of 3-bromoquinoline (0.208 g, 1 mmol) and 3-
formylthiophene diethyl acetal (0.279 g, 1.5 mmol) afforded the
product 11b in 40% (0.075 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.50–7.91 (m, 4 H), 8.11–8.17 (m,
1H NMR (200 MHz, CDCl3): d = 7.34 (d, J = 5.3 Hz, 1 H), 7.40–
7.46 (m, 2 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.68 (d, J = 4.4 Hz, 1 H),
8.90 (s, 1 H).
2 H), 8.33 (s, 1 H), 9.20 (s, 1 H), 9.94 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 122.3, 123.1, 126.7, 128.0, 128.3,
129.7, 130.4, 132.6, 137.1, 143.2, 144.3, 148.0, 148.5, 185.2.
4-(3-Methylthiophen-2-yl)benzonitrile (16a)
Anal. Calcd for C14H9NOS: C, 70.27; H, 3.79. Found: C, 70.24; H,
3.81.
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 3-meth-
ylthiophene (0.196 g, 2 mmol), KOAc (0.196 g, 2 mmol) afforded
the product 16a in 65% (0.129 g) yield.
1H NMR (200 MHz, CDCl3): d = 2.38 (s, 3 H), 6.98 (d, J = 5.3 Hz,
1 H), 7.32 (d, J = 5.3 Hz, 1 H), 7.59 (d, J = 8.3 Hz, 2 H), 7.71 (d,
J = 8.3 Hz, 2 H).
Reactions of Other 3-Substituted Thiophenes with Aryl Bro-
mides (Products 12a–20a, 21b–23b, and 24a–33a); General Pro-
cedure
In a typical experiment, the aryl bromide (1 mmol), thiophene (1.5
mmol), and KOAc (0.196 g, 2 mmol) were introduced in an oven-
dried Schlenk tube, equipped with a magnetic stirring bar. Then,
Pd(OAc)2 (0.22 mg, 0.001 mmol), dppb (0.42 mg, 0.001 mmol),
and DMA (3 mL) were added, and the Schlenk tube purged several
times with argon. The Schlenk tube was placed in a preheated oil
bath at 130 °C and the reactants were allowed to stir for 16 h. Then,
the reaction mixture was analysed by GC and NMR to determine the
ratio of regioisomers a/b and the conversion of the aryl bromide.
The solvent was removed by heating of the reaction vessel under
vacuum and the residue was charged directly onto a silica gel col-
umn. The products were eluted, using an appropriate ratio of Et2O
and pentane (Tables 5– 8).
13C NMR (50 MHz, CDCl3): d = 15.6, 110.8, 119.3, 125.6, 129.6,
132.1, 132.7, 135.4, 136.1, 139.9.
Anal. Calcd for C12H9NS: C, 72.33; H, 4.55. Found: C, 72.40; H,
4.52
4-(3-Methylthiophen-2-yl)acetophenone (17a)
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol) and 3-
methylthiophene (0.196 g, 2 mmol), KOAc (0.196 g, 2 mmol)
afforded the product 17a in 64% (0.138 g) yield.
1H NMR (200 MHz, CDCl3): d = 2.39 (s, 3 H), 2.65 (s, 3 H), 6.98
(d, J = 5.3 Hz, 1 H), 7.30 (d, J = 5.3 Hz, 1 H), 7.59 (d, J = 8.3 Hz, 2
H), 8.02 (d, J = 8.3 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 15.6, 27.0, 125.0, 129.0, 129.2,
4-(3-Cyanothiophen-2-yl)benzonitrile (12a)
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 3-cy-
anothiophene (0.218 g, 2 mmol) afforded the product 12a in 60%
(0.126 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.37 (d, J = 5.3 Hz, 1 H), 7.49 (d,
J = 5.3 Hz, 1 H), 7.78 (d, J = 8.3 Hz, 2 H), 7.90 (d, J = 8.3 Hz, 2 H).
132.0, 134.9, 135.8, 136.9, 140.0.
Anal. Calcd for C13H12OS: C, 72.19; H, 5.59. Found: C, 72.24; H,
5.62
4-(3-Methylthiophen-2-yl)nitrobenzene (18a)20
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 3-
methylthiophene (0.196 g, 2 mmol), KOAc (0.196 g, 2 mmol)
afforded the product 18a in 62% (0.135 g) yield.
1H NMR (200 MHz, CDCl3): d = 2.41 (s, 3 H), 7.00 (d, J = 5.3 Hz,
1 H), 7.35 (d, J = 5.3 Hz, 1 H), 7.65 (d, J = 8.3 Hz, 2 H), 8.29 (d,
J = 8.3 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 108.1, 113.5, 115.6, 118.5, 127.7,
128.6, 131.4, 133.4, 135.9, 151.2.
Anal. Calcd for C12H6N2S: C, 68.55; H, 2.88. Found: C, 68.57; H,
2.83.
4-(3-Cyanothiophen-2-yl)benzaldehyde (13a)
The reaction of 4-bromobenzaldehyde (0.186 g, 1 mmol) and 3-cy-
anothiophene (0.218 g, 2 mmol) afforded the product 13a in 58%
(0.123 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.38 (d, J = 5.3 Hz, 1 H), 7.47 (d,
J = 5.3 Hz, 1 H), 7.96 (d, J = 8.3 Hz, 2 H), 8.02 (d, J = 8.3 Hz, 2 H),
10.09 (s, 1 H).
3-(3-Methylthiophen-2-yl)pyridine (19a)21
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and 3-methyl-
thiophene (0.196 g, 2 mmol), KOAc (0.196 g, 2 mmol) afforded the
product 19a in 45% (0.078 g) yield.
1H NMR (200 MHz, CDCl3): d = 2.35 (s, 3 H), 6.98 (d, J = 5.3 Hz,
1 H), 7.28–7.37 (m, 2 H), 7.79 (d, J = 5.3 Hz, 1 H), 8.60–8.78 (m, 2
13C NMR (50 MHz, CDCl3): d = 107.9, 115.8, 127.4, 128.7, 130.9,
131.3, 137.0, 137.1, 152.0, 191.7.
H).
Anal. Calcd for C12H7NOS: C, 67.58; H, 3.31. Found: C, 67.61; H,
3.34.
3-(3-Methylthiophen-2-yl)quinoline (20a)
The reaction of 3-bromoquinoline (0.207 g, 1 mmol) and 3-meth-
ylthiophene (0.196 g, 2 mmol), KOAc (0.196 g, 2 mmol) afforded
the product 20a in 69% (0.155 g) yield.
4-(3-Cyanothiophen-2-yl)nitrobenzene (14a)
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 3-cy-
anothiophene (0.218 g, 2 mmol), KOAc (0.196 g, 2 mmol) afforded
the product 14a in 64% (0.147 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.40 (d, J = 5.3 Hz, 1 H), 7.53 (d,
J = 5.3 Hz, 1 H), 7.96 (d, J = 8.3 Hz, 2 H), 8.35 (d, J = 8.3 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 108.4, 115.5, 124.9, 128.1, 129.0,
131.5, 137.7, 148.4, 150.6.
1H NMR (200 MHz, CDCl3): d = 2.42 (s, 3 H), 7.03 (d, J = 5.3 Hz,
1 H), 7.34 (d, J = 5.3 Hz, 1 H), 7.55–7.88 (m, 3 H), 8.13–8.21 (m, 2
H), 9.08 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 15.4, 125.2, 127.5, 128.1, 128.3,
128.5, 129.7, 129.9, 131.8, 134.4, 135.2, 135.3, 147.3, 151.3.
Anal. Calcd for C14H11NS: C, 74.63; H, 4.92. Found: C, 74.59; H,
4.94
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

3544
J. J. Dong et al.
PAPER
4-(4-Acetylthiophen-2-yl)benzonitrile (21b)
1H NMR (200 MHz, CDCl3): d = 4.68 (s, 2 H), 7.21 (d, J = 4.7 Hz,
1 H), 7.39 (d, J = 4.7 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 2 H), 8.21 (d,
J = 8.1 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 58.5, 123.9, 126.4, 129.5, 130.2,
138.6, 138.7, 140.3, 146.8.
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 3-
acetylthiophene (0.252 g, 2 mmol), KOAc(0.196 g, 2 mmol) afford-
ed the product 21b in 38% (0.086 g) yield.
1H NMR (200 MHz, CDCl3): d = 2.58 (s, 3 H), 7.72 (s, 4 H), 7.85
(s, 1 H), 8.08 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 27.1, 111.4, 118.4, 124.2, 126.1,
132.7, 132.9, 137.5, 142.8, 143.5, 191.9.
Anal. Calcd for C11H9NO3S: C, 56.16; H, 3.86. Found: C, 56.04; H,
3.98.
(2-Pyridin-3-ylthiophen-3-yl)methanol (27a)
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and 3-thio-
phenemethanol (0.228 g, 2 mmol) afforded the product 27a in 69%
(0.132 g) yield.
1H NMR (200 MHz, CDCl3): d = 4.62 (s, 2 H), 7.21 (d, J = 4.7 Hz,
1 H), 7.25–7.40 (m, 2 H), 7.82 (d, J = 7.2 Hz, 1 H), 8.44 (d, J = 4.5
Hz, 1 H), 8.63 (s, 1 H).
Anal. Calcd for C13H9NOS: C, 68.70; H, 3.99. Found: C, 68.66; H,
3.95
2-(4-Acetylthiophen-2-yl)benzonitrile (22b)
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and 3-
acetylthiophene (0.252 g, 2 mmol) afforded the product 22b in 57%
(0.129 g) yield.
1H NMR (200 MHz, CDCl3): d = 2.58 (s, 3 H), 7.47–7.80 (m, 4 H),
7.95 (s, 1 H), 8.15 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 57.9, 123.4, 125.2, 129.8, 130.1,
136.2, 136.4, 138.7, 148.1, 149.1.
13C NMR (50 MHz, CDCl3): d = 27.9, 110.8, 118.7, 127.4, 128.8,
130.2, 133.6, 133.8, 134.7, 137.0, 140.8, 143.5, 192.4.
Anal. Calcd for C10H9NOS: C, 62.80; H, 4.74. Found: C, 62.87; H,
4.61.
Anal. Calcd for C13H9NOS: C, 68.70; H, 3.99. Found: C, 68.75; H,
3.94
Ethyl [2-(4-Cyanophenyl)thiophen-3-yl]acetate (28a)
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and ethyl 3-
thiophenylacetate (0.340 g, 2 mmol) afforded the product 28a in
61% (0.165 g) yield.
1H NMR (200 MHz, CDCl3): d = 1.25 (t, J = 7.5 Hz, 3 H), 3.72 (s,
2 H), 4.21 (q, J = 7.5 Hz, 2 H), 7.11 (d, J = 5.1 Hz, 1 H), 7.37 (d,
J = 5.1 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 2 H), 7.70 (d, J = 8.1 Hz, 2 H).
9-(4-Acetylthiophen-2-yl)anthracene (23b)
The reaction of 9-bromoanthracene (0.255 g, 1 mmol) and 3-
acetylthiophene (0.252 g, 2 mmol) afforded the product 23b in 73%
(0.220 g) yield.
1H NMR (200 MHz, CDCl3): d = 2.66 (s, 3 H), 7.43–7.55 (m, 4 H),
7.66 (s, 1 H), 7.84–8.08 (m, 4 H), 8.33 (s, 1 H), 8.57 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.1, 34.6, 61.1, 111.3, 118.6,
125.7, 129.8, 130.4, 130.9, 132.4, 138.4, 138.6, 170.8.
13C NMR (50 MHz, CDCl3): d = 28.0, 125.8, 126.5, 126.7, 128.9,
129.0, 129.3, 131.5, 132.0, 134.2, 140.8, 143.2, 192.9.
Anal. Calcd for C15H13NO2S: C, 66.40; H, 4.83; Found: C, 66.51;
H, 4.78.
Anal. Calcd for C20H14OS: C, 79.44; H, 4.67. Found: C, 79.48; H,
4.63.
Traces of 28b were also isolated.
1H NMR (200 MHz, CDCl3): d = 1.25 (t, J = 7.5 Hz, 3 H), 3.70 (s,
2 H), 4.21 (q, J = 7.5 Hz, 2 H), 7.21 (s, 1 H), 7.41 (s, 1 H), 7.68–7.72
(m, 4 H).
4-(3-Hydroxymethylthiophen-2-yl) benzonitrile (24a)
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 3-
thiophenemethanol (0.228 g, 2 mmol) afforded the product 24a in
66% (0.142 g) yield.
1H NMR (200 MHz, CDCl3): d = 4.67 (s, 2 H), 7.17 (d, J = 4.7 Hz,
1 H), 7.38 (d, J = 4.7 Hz, 1 H), 7.50–7.80 (m, 4 H).
Ethyl [2-(4-Nitrophenyl)thiophen-3-yl]acetate (29a)
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and ethyl
3-thiophenylacetate (0.340 g, 2 mmol) afforded the product 29a in
63% (0.183 g) yield.
1H NMR (200 MHz, CDCl3): d = 1.25 (t, J = 7.5 Hz, 3 H), 3.72 (s,
2 H), 4.21 (q, J = 7.5 Hz, 2 H), 7.12 (d, J = 5.1 Hz, 1 H), 7.40 (d,
J = 5.1 Hz, 1 H), 7.69 (d, J = 8.1 Hz, 2 H), 8.28 (d, J = 8.1 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 58.5, 111.1, 118.6, 126.0, 129.5,
130.0, 132.4, 138.3, 138.4, 139.1.
Anal. Calcd for C12H9NOS: C, 66.95; H, 4.21. Found: C, 66.87; H,
4.30.
13C NMR (50 MHz, CDCl3): d = 14.4, 34.8, 61.5, 124.2, 126.3,
130.1, 130.7, 131.5, 138.3, 140.8, 147.0, 171.0.
1-[4-(3-Hydroxymethylthiophen-2-yl)phenyl]ethanone (25a)
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol) and 3-
thiophenemethanol (0.228 g, 2 mmol) afforded the product 25a in
65% (0.151 g) yield.
1H NMR (200 MHz, CDCl3): d = 2.60 (s, 3 H), 4.68 (s, 2 H), 7.20
(d, J = 4.7 Hz, 1 H), 7.32 (d, J = 4.7 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 2
H), 7.97 (d, J = 8.1 Hz, 2 H).
Anal. Calcd for C14H13NO4S: C, 57.72; H, 4.50. Found: C, 57.64; H,
4.65.
Traces of 29b were also isolated.
1H NMR (200 MHz, CDCl3): d = 1.25 (t, J = 7.5 Hz, 3 H), 3.70 (s,
2 H), 4.21 (q, J = 7.5 Hz, 2 H), 7.28 (s, 1 H), 7.45 (s, 1 H), 7.71 (d,
J = 8.1 Hz, 2 ), 8.26 (d, J = 8.1 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 26.5, 58.7, 125.5, 128.7, 129.0,
129.8, 135.9, 138.0, 138.5, 139.7, 197.6.
Ethyl [2-(4-Acetylphenyl)thiophen-3-yl]acetate (30a)
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol) and ethyl
3-thiophenylacetate (0.340 g, 2 mmol) afforded the product 30a in
53% (0.153 g) yield.
Anal. Calcd for C13H12O2S: C, 67.21; H, 5.21. Found: C, 67.10; H,
5.32.
[2-(4-Nitrophenyl)thiophen-3-yl]methanol (26a)
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 3-
thiophenemethanol (0.228 g, 2 mmol) afforded the product 26a in
55% (0.129 g) yield.
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.5 Hz, 3 H), 2.62 (s,
3 H), 3.65 (s, 2 H), 4.19 (q, J = 7.5 Hz, 2 H), 7.10 (d, J = 5.1 Hz, 1
H), 7.32 (d, J = 5.1 Hz, 1 H), 7.58 (d, J = 8.1 Hz, 2 H), 8.00 (d,
J = 8.1 Hz, 2 H).
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

PAPER
Pd-Catalysed Arylation of 3-Substituted Thiophenes
3545
13C NMR (50 MHz, CDCl3): d = 14.1, 26.6, 34.6, 61.0, 125.2, 128.6,
129.4, 130.2, 130.4, 136.0, 138.6, 139.3, 171.0, 197.5.
umn. The product was eluted, using an appropriate ratio of Et2O and
pentane to afford the product 34b in 45% (0.117 g) yield (Table 9).
Anal. Calcd for C16H16O3S: C, 66.64; H, 5.59. Found: C, 66.48; H,
5.75.
Ethyl 5-(4-Acetylphenyl)furan-3-carboxylate (35b)
Similar procedure as for 34b using 4-bromoacetophenone (0.199 g,
1 mmol). Product 35b was isolated in 43% (0.111 g) yield.
Traces of 30b were also isolated.
1H NMR (200 MHz, CDCl3): d = 1.28 (t, J = 7.5 Hz, 3 H), 2.63 (s,
3 H), 3.65 (s, 2 H), 4.19 (q, J = 7.5 Hz, 2 H), 7.18 (s, 1 H), 7.38 (s,
1 H), 7.66 (d, J = 8.1 Hz, 2 H), 7.95 (d, J = 8.1 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 1.36 (t, J = 7.5 Hz, 3 H), 2.60 (s,
3 H), (q, J = 7.5 Hz, 2 H), 7.09 (s, 1H), 7.73 (d, J = 8.4 Hz, 2 H),
7.98 (d, J = 8.4 Hz, 2 H), 8.05 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 26.2, 60.4, 106.5, 121.3,
123.5, 128.6, 133.5, 135.9, 147.3, 153.6, 162.4, 196.9.
Methyl 4-(3-Ethoxycarbonylmethylthiophen-2-yl)benzoate
(31a)
The reaction of methyl 4-bromobenzoate (0.215 g, 1 mmol) and eth-
yl 3-thiophenylacetate (0.340 g, 2 mmol) afforded the product 31a
in 51% (0.155 g) yield.
Anal. Calcd for C15H14O4: C, 69.76; H, 5.46. Found: C, 69.70; H,
5.54.
1H NMR (200 MHz, CDCl3): d = 1.25 (t, J = 7.5 Hz, 3 H), 3.65 (s,
2 H), 3.93 (s, 3 H), 4.19 (q, J = 7.5 Hz, 2 H), 7.10 (d, J = 5.1 Hz, 1
H), 7.32 (d, J = 5.1 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 2 H), 8.08 (d,
J = 8.1 Hz, 2 H).
Acknowledgment
We thank the Centre National de la Recherche Scientifique and
‘Rennes Metropole’ for providing financial support.
13C NMR (50 MHz, CDCl3): d = 14.1, 34.6, 52.2, 61.0, 125.1, 129.2,
129.9, 130.2, 130.3, 138.4, 139.4, 166.7, 171.0.
References
Anal. Calcd for C16H16O4S: C, 63.14; H, 5.30. Found: C, 63.20; H,
5.41.
(1) (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon: Amsterdam, 2000. (b) Handbook of
Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002, Part
III, 213.
(2) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.;
Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles
1990, 31, 1951.
(3) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200. (c) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrichimica Acta 2007, 40, 35. (d) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (e) Li, B.-
J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (f) Mori, A.;
Sugie, A. Bull. Chem. Soc. Jpn. 2008, 81, 548.
Traces of 31b were also isolated.
1H NMR (200 MHz, CDCl3): d = 1.28 (t, J = 7.5 Hz, 3 H), 3.64 (s,
2 H), 3.92 (s, 3 H), 4.19 (q, J = 7.5 Hz, 2 H), 7.17 (s, 1 H), 7.37 (s,
1 H), 7.64 (d, J = 8.1 Hz, 2 H), 8.02 (d, J = 8.1 Hz, 2 H).
3-Bromo-2-(4-nitrophenyl)thiophene (32a)
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 3-bro-
mothiophene (0.326 g, 2 mmol) afforded the product 32a in 58%
(0.165 g) yield.
1H NMR (200 MHz, CDCl3): d = 7.09 (d, J = 5.3 Hz, 1 H), 7.39 (d,
J = 5.3 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 2 H), 8.23 (d, J = 8.1 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 109.5, 123.8, 126.9, 129.6, 132.4,
135.5, 139.3, 147.2.
(g) McGlacken, G. P.; Batman, L. M. Chem. Soc. Rev. 2009,
38, 2447. (h) Ackermann, L.; Vincente, R.; Kapdi, A. R.
Angew. Chem. Int. Ed. 2009, 48, 9792. (i) Roger, J.;
Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2,
20. (j) Fischmeister, C.; Doucet, H. Green Chem. 2011, 13,
741.
Anal. Calcd for C10H6BrNO2S: C, 42.27; H, 2.13. Found: C, 42.34;
H, 2.21.
Methyl 4-(3-Bromothiophen-2-yl)benzoate (33a)
The reaction of methyl 4-bromobenzoate (0.215 g, 1 mmol) and 3-
bromothiophene (0.326 g, 2 mmol) afforded the product 33a in 46%
(0.137 g) yield.
1H NMR (200 MHz, CDCl3): d = 3.94 (s, 3 H), 7.07 (d, J = 5.1 Hz,
1 H), 7.33 (d, J = 5.1 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 2 H), 8.08 (d,
J = 8.1 Hz, 2 H).
(4) For recent examples of palladium-catalysed direct arylation
or vinylation of heteroaromatics with aryl halides from our
laboratory, see: (a) Gottumukkala, A. L.; Doucet, H. Adv.
Synth. Catal. 2008, 350, 2183. (b) Gottumukkala, A. L.;
Derridj, F.; Djebbar, S.; Doucet, H. Tetrahedron Lett. 2008,
49, 2926. (c) Fall, Y.; Doucet, H.; Santelli, M.
13C NMR (50 MHz, CDCl3): d = 52.2, 108.5, 125.9, 128.7, 129.7,
129.4, 132.0, 136.9, 137.2, 166.6.
ChemSusChem 2009, 2, 153. (d) Roger, J.; Doucet, H. Adv.
Synth. Catal. 2009, 351, 1977. (e) Fall, Y.; Reynaud, C.;
Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2009, 4041.
(f) Dong, J. J.; Roger, J.; Pozgan, F.; Doucet, H. Green
Chem. 2009, 11, 1832. (g) Derridj, F.; Gottumukkala, A. L.;
Djebbar, S.; Doucet, H. Eur. J. Inorg. Chem. 2008, 2550.
(h) Roger, J.; Doucet, H. Tetrahedron 2009, 65, 9772.
(i) Roger, J.; Verrier, C.; Le Goff, R.; Hoarau, C.; Doucet, H.
ChemSusChem 2009, 2, 951. (j) Ionita, M.; Roger, J.;
Doucet, H. ChemSusChem 2010, 3, 367. (k) Fall, Y.;
Doucet, H.; Santelli, M. Synthesis 2010, 127.
Anal. Calcd for C12H9BrO2S: C, 48.50; H, 3.05. Found: C, 48.41; H,
3.24.
Ethyl 5-(3-Nitrophenyl)furan-3-carboxylate (34b)8
3-Bromonitrobenzene (0.202 g, 1 mmol), ethyl 3-furoate (0.280 g,
2 mmol), and KOAc (0.196 g, 2 mmol) were introduced in an oven-
dried Schlenk tube, equipped with a magnetic stirring bar. Then,
Pd(OAc)2 (0.44 mg, 0.002 mmol), dppb (0.84 mg, 0.002 mmol),
and DMA (3 mL) were added, and the Schlenk tube purged several
times with argon. The Schlenk tube was placed in a preheated oil
bath at 130 °C and the reactants were allowed to stir for 20 h. Then,
the reaction mixture was analysed by GC and NMR to determine the
ratio of regioisomers a/b and the conversion of the aryl bromide.
The solvent was removed by heating of the reaction vessel under
vacuum and the residue was charged directly onto a silica gel col-
(5) For selected examples of palladium-catalysed direct
arylations of thiophenes, see: (a) Penalva, V.; Lavenot, L.;
Gozzi, C.; Lemaire, M. Appl. Catal., A 1999, 182, 399.
(b) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am.
Chem. Soc. 2002, 124, 5286. (c) Masui, K.; Ikegami, H.;
Mori, A. J. Am. Chem. Soc. 2004, 126, 5074. (d) Masui, K.;
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York

3546
J. J. Dong et al.
PAPER
Mori, A.; Okano, K.; Takamura, K.; Kinoshita, M.; Ikeda, T.
Org. Lett. 2004, 6, 2011. (e) Yokooji, A.; Satoh, T.; Miura,
M.; Nomura, M. Tetrahedron 2004, 60, 6757. (f) Mitsudo,
K.; Thansandote, P.; Wilhelm, T.; Mariampillai, B.;
Lautens, M. Org. Lett. 2006, 8, 3939. (g) Mashraqui, S. H.;
Ashraf, M.; Ghadigaonkar, S. G. Synlett 2006, 2423.
(h) Amaladass, P.; Clement, J. A.; Mohanakrishnan, A. K.
Tetrahedron 2007, 63, 10363. (i) Turner, G. L.; Morris, J.
A.; Greaney, M. F. Angew. Chem. Int. Ed. 2007, 46, 7996.
(j) David, E.; Pellet-Rostaing, S.; Lemaire, M. Tetrahedron
2007, 63, 8999. (k) Arai, N.; Miyaoku, T.; Teruya, S.; Mori,
A. Tetrahedron Lett. 2008, 49, 1000. (l) Derridj, F.; Roger,
J.; Geneste, F.; Djebbar, S.; Doucet, H. J. Organomet. Chem.
2009, 694, 455. (m) Smaliy, R. V.; Beauperin, M.; Cattey,
H.; Meunier, P.; Hierso, J.-C.; Roger, J.; Doucet, H.; Coppel,
Y. Organometallics 2009, 28, 3152. (n) Liégault, B.;
Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org.
Chem. 2009, 74, 1826. (o) Roger, J.; Pozgan, F.; Doucet, H.
Green Chem. 2009, 11, 425. (p) Dong, J. J.; Roger, J.;
Doucet, H. Tetrahedron Lett. 2009, 50, 2778. (q) Dong, J.
J.; Roger, J.; Verrier, C.; Martin, T.; Le Goff, R.; Hoarau, C.;
Doucet, H. Green Chem. 2010, 12, 2053. (r) Derridj, F.;
Roger, J.; Djebbar, S.; Doucet, H. Org. Lett. 2010, 12, 4320.
(s) Laidaoui, N.; Miloudi, A.; El Abed, D.; Doucet, H.
Synthesis 2010, 2553. (t) Beydoun, K.; Doucet, H.
(7) For examples of palladium-catalysed direct polyarylations
of 3-substituted thiophenes, see: (a) Nakano, M.; Tsurugi,
H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1851.
(b) Shibahara, F.; Yamaguchi, E.; Murai, T. Chem.
Commun. 2010, 2471.
(8) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. F. Org. Lett. 2003, 5, 301.
(9) Lavenot, L.; Gozzi, C.; Ilg, K.; Orlova, I.; Penalva, V.;
Lemaire, M. J. Organomet. Chem. 1998, 567, 49.
(10) Fournier dit Chabert, J.; Marquez, B.; Neville, L.; Joucla, L.;
Broussous, S.; Bouhours, P.; David, E.; Pellet-Rostaing, S.;
Marquet, B.; Moreau, N.; Lemaire, M. Bioorg. Med. Chem.
2007, 15, 4482.
(11) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.;
Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128,
11350.
(12) Liégault, B.; Petrov, I.; Gorlesky, S. I.; Fagnou, K. J. Org.
Chem. 2010, 75, 1047.
(13) Borghese, A.; Geldhof, G.; Antoine, L. Tetrahedron Lett.
2006, 47, 9249.
(14) Rene, O.; Fagnou, K. Org. Lett. 2010, 9, 2116.
(15) Yanagisawa, S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am.
Chem. Soc. 2009, 131, 14622.
(16) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. Tetrahedron
2008, 64, 6073.
(17) Dong, J. J.; Doucet, H. Eur. J. Org. Chem. 2010, 611.
(18) Roger, J.; Pozgan, F.; Doucet, H. Adv. Synth. Catal. 2010,
352, 696.
J. Organomet. Chem. 2011, 696, 1749. (u) Roy, D.; Mom,
S.; Beaupérin, M.; Doucet, H.; Hierso, J.-C. Angew. Chem.
Int. Ed. 2010, 49, 6650.
(6) For examples of palladium-catalysed intramolecular direct
2-arylations of 3-substituted thiophenes, see: Mori, A.; Arai,
N.; Hatta, T.; Monguchi, D. Heterocycles 2010, 80, 103.
(19) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M.
Angew. Chem. Int. Ed. 2006, 45, 3140.
(20) Roth, G. P.; Farina, V. Tetrahedron Lett. 1995, 36, 2191.
(21) Denton, T. T.; Zhang, X.; Cashman, J. R. J. Med. Chem.
2005, 48, 224.
Synthesis 2011, No. 21, 3530–3546 © Thieme Stuttgart · New York