Palladium/2,2′-bipyridyl/Ag2CO3 catalyst for C-H bond arylation of heteroarenes with haloarenes

Article abstract of DOI:10.1016/j.tet.2011.03.093

A Pd/bipy-based catalytic system for the C-H bond arylation of heteroarenes with haloarenes is described. The complex PdBr₂(bipy)·DMSO, whose structure was unambiguously determined by X-ray crystallography, turned out to be a general catalyst precursor for the process. The reaction is applicable to a range of electron-rich five-membered heteroarenes, such as thiophenes, thiazoles, benzofurans, and indoles.

Full text of DOI:10.1016/j.tet.2011.03.093

Tetrahedron 67 (2011) 4425e4430
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Tetrahedron
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Palladium/2,20-bipyridyl/Ag2CO3 catalyst for CeH bond arylation of heteroarenes
with haloarenes
*
Shuichi Yanagisawa, Kenichiro Itami
Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A Pd/bipy-based catalytic system for the CeH bond arylation of heteroarenes with haloarenes is de-
scribed. The complex PdBr2(bipy)$DMSO, whose structure was unambiguously determined by X-ray
crystallography, turned out to be a general catalyst precursor for the process. The reaction is applicable to
a range of electron-rich five-membered heteroarenes, such as thiophenes, thiazoles, benzofurans, and
indoles.
Received 13 January 2011
Received in revised form 26 March 2011
Accepted 28 March 2011
Available online 3 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Catalysis
CeH arylation
Heterobiaryl
1. Introduction
was obtained in 88% yield with 99% regioselectivity (Scheme 1). We
further found that the unique C4-selective CeH arylation exerted by
Heterobiaryls are one of the most important molecules that are
frequently found in functional materials, pharmaceuticals, and
natural products.1 Consequently, the development of efficient
methods to connect heteroarene and arene has been a topic of
immense importance in chemical synthesis.2 Although transition
metal-catalyzed cross-coupling reactions have been a reliable and
excellent method for constructing the biaryl structures,3 there are
common drawbacks, such as inevitable production of stoichio-
metric amount of metallic waste and necessity for preparing or-
ganometallic reagents from arenes prior to cross-coupling.
Recently, transition metal-catalyzed direct CeH bond arylation of
heteroarenes has received much attention as an alternative method
for heterobiaryl synthesis by a number of research groups including
our own (Pd, Rh, Cu, Ni, Ir, Ru, and Fe).4e6
During the study of programmed synthesis of tetraarylth-
iophenes, we discovered ligand-controlled regiodivergent CeH bond
arylations of 3-methoxy-2-phenylthiophene with iodoarenes
(Scheme 1).6i For example, the reaction of 3-methoxy-2-phenyl-
thiophene and iodobenzene in the presence of PdCl2, P[OCH(CF3)2]3,
and Ag2CO3 in m-xylene at 120 ꢀC furnished C4-phenylated product
in 80% yield with 97% regioselectivity. Interestingly, the C4 regiose-
lectivity could be switched to C5 regioselectivity by simply changing
the neutral ligand from P[OCH(CF3)2]3 to 2,20-bipyridyl (bipy), with
which 3-methoxy-2,5-diphenylthiophene (C5-phenylated product)
PdCl2/P[OCH(CF3)2]3 catalyst is applicable not only to 3-methoxy-2-
phenylthiophene but also to a wide range of thiophene derivatives in
general.6j We envisaged that the Pd/bipy/Ag2CO3 catalyst system
might also have excellent potential for the CeH bond arylation of
other heteroarenes.
PdCl2 (5 mol%)
P[OCH(CF3)2]3 (10 mol%)
MeO
Ph
Ph
Ag2CO3 (1.0 equiv)
H
m-xylene, 120 °C
S
80% yield
MeO
Ph
H
97% regioselectivity
I
+
H
S
PdCl2 (5 mol%)
2,2'-bipyridyl (10 mol%)
Ag2CO3 (1.0 equiv)
MeO
Ph
H
Ph
m-xylene, 120 °C
S
88% yield
99% regioselectivity
Scheme 1. Discovery of ligand-controlled regiodivergent CeH bond arylation.
To date, a number of Pd-catalyzed direct CeH arylation reactions
have been developed. However, most of the reported systems uti-
lize phosphine-based supporting ligands and the example using
nitrogen-based bidentate ligands, such as bipy is very rare.4 Other
* Corresponding author. Tel./fax: þ8152 788 6098; e-mail address: itami.kenichiro@
a.mbox.nagoya-u.ac.jp (K. Itami).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.093

4426
S. Yanagisawa, K. Itami / Tetrahedron 67 (2011) 4425e4430
than our catalytic system (Pd/bipy/Ag2CO3),6i there is only a few
examples for the direct CeH bond arylation of heteroarenes cata-
lyzed by a Pd complex having nitrogen-based bidentate ligand.7,8
Very recently, Shibahara and Murai demonstrated that the cat-
ionic palladium complex bearing 1,10-phenanthroline (phen) li-
gand, [Pd(phen)2](PF6)2, promotes the direct CeH bond arylation of
various five-membered heteroarenes with haloarenes.7 Cesium
carbonate was used as a basic additive for the coupling.
Considering these backgrounds, we decided to investigate our
Pd/bipy catalyst system in detail. The focal points of this study has
been (i) to identify catalyst components necessary for the coupling,
(ii) to develop user-friendly and air-stable pre-catalyst, and (iii) to
identify the scope of heteroarene/haloarene coupling partners.
4), ligands bearing substituents at C4 or C6 position (L2eL5) were
ineffective (entries 5e8). Moreover, the use of 1,10-phenanthroline
was found to be ineffective (entry 9). Monodentate pyridine-based
ligands (pyridine and L6eL8) did not promote the reaction effi-
ciently (entries 10e13).
Table 2
Effect of liganda
PdCl2
ligand
Ag2CO3
Br
+
Et
S
Et
H
1,4-dioxane
120 °C,13 h
S
1a
3aa
ligands:
Me
R
R
2. Results and discussion
Me
N
N
N
N
N
R
N
R
2.1. Effect of catalyst components
L1
R = OMe (L3)
R = Me (L6)
R = Bu (L7)
R = F (L8)
Following the finding of Pd/bipy/Ag2CO3 catalysis, the effect of
catalyst components was investigated in detail.
t
t
R = Bu (L4)
R = CF3 (L5)
N
Me
Me
L2
2.1.1. Effect of solvent. We began by examining the solvent effect in
the coupling reaction between 2-ethylthiophene (1a) and bromo-
benzene. When bromobenzene was used as a substrate instead of
iodobenzene (suitable phenylating agent established previously6i)
in the presence of PdCl2 (5 mol %), bipy (5 mol %), and Ag2CO3
(1.0 equiv) in m-xylene at 120 ꢀC, 2-ethyl-5-phenylthiophene (3aa)
was obtained only in 2% yield (Table 1, entry 1). To our surprise,
DMAc and DMF, which are usually used in CeH bond arylation of
(hetero)arenes, showed poor results (entries 2 and 3). As a result, it
was found that 1,4-dioxane is the best solvent for the present
system, which afforded the desired coupling product 3aa in 32%
yield (entry 4). On the other hand, DMSO, cyclopentyl methyl ether
(CPME), ethanol, 1,2-dichloroethane, and n-octane were ineffective
solvents (entries 5e9).
Entry
Ligand
Yield (%)b
1
2
3
None
TMEDA
Bipy
L1
L2
L3
<2
5
32
21
2
3
6
8
12
8
4
5c
6
7
L4
L5
8c
9
1,10-Phenanthroline
Pyridine
L6
L7
L8
10d
11d
12d
13d
<2
<2
<2
a
Conditions: 1a (1.0 equiv), bromobenzene (1.0 equiv), PdCl2 (5 mol %), ligand
(5 mol %), Ag2CO3 (1.0 equiv), 1,4-dioxane, 120 ꢀC, 13 h.
b
GC yield.
PdBr2 was used instead of PdCl2.
Ligand (10 mol %) was employed.
Table 1
c
Effect of solventa
d
PdCl2
2,2'-bipyridyl
Ag2CO3
Br
2.1.3. Effect of Pd precursor. The effect of Pd precursor was also
investigated and the results are summarized in Table 3. Pd(II) salts
with two halogen ligands, such as PdCl2, PdBr2, and PdI2, worked
well (entries 1e3). On the other hand, Pd(OAc)2 and Pd(OCOCF3)2
were not effective for this transformation (entries 4 and 5). The
cationic palladium complex, [Pd(CH3CN)4](BF4)2, displayed almost
no catalytic activity with bipy ligand (entry 6). Based on the in-
efficiency with 1,10-phenanthroline ligand and the fact that
+
Et
S
Et
H
solvent
S
1a
120 °C,13 h
3aa
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
m-Xylene
DMAc
DMF
1,4-Dioxane
DMSO
CPME
Ethanol
1,2-Dichloroethane
n-Octane
2
14
7
32
3
Table 3
Effect of Pd precursora
3
<2
<2
<2
Pd precursor
bipy
Ag2CO3
Br
a
+
Conditions: 1a (1.0 equiv), bromobenzene (1.0 equiv), PdCl2 (5 mol %), 2,20-
Et
S
Et
H
1,4-dioxane
120 °C,13 h
S
1a
bipyridyl (5 mol %), Ag2CO3 (1.0 equiv), solvent, 120 ꢀC, 13 h.
b
3aa
GC yield.
Entry
Pd precursor
Yield (%)b
2.1.2. Effect of ligand. Subsequently, the ligand effect was examined
focusing on nitrogen-based ligands (Table 2). First of all, the cou-
pling reaction conducted without any ligand gave only trace
amount of product (Table 2, entry 1). The sp3 nitrogen ligand, such
as TMEDA was ineffective for this reaction (entry 2). Since bipy gave
relatively good result (entry 3), a variety of bipy-based ligands were
investigated (entries 4e8). It was found that the reactivity is
influenced by the steric environment around bipy core. While C5-
substituted bipy ligand L1 brought relatively good result (entry
1
2
3
4
5
6
7
PdCl2
PdBr2
PdI2
Pd(OAc)2
Pd(OCOCF3)2
[Pd(CH3CN)4](BF4)2
Pd2(dba)3$CHCl3
32
59
39
12
3
<2
3
a
Conditions: 1a (1.0 equiv), bromobenzene (1.0 equiv), Pd precursor (5 mol %),
bipy (5 mol %), Ag2CO3 (1.0 equiv), 1,4-dioxane, 120 ꢀC, 13 h.
b
GC yield.

S. Yanagisawa, K. Itami / Tetrahedron 67 (2011) 4425e4430
4427
cationic palladium complex possesses poor reactivity, the present
Pd system is likely to be different from the Pd catalysis developed
by Shibahara and Murai.7 When Pd2(dba)3$CHCl3 was used as
a precursor, the desired biaryl 3aa was obtained only in 3% yield
(entry 7). This result implies that Pd(0) species might not be in-
cluded in the catalytic cycle under the present conditions.
2.1.4. Effect of silver salt. The investigation of silver salt was also
conducted with PdBr2/bipy system in 1,4-dioxane. The results are
shown in Table 4. The reaction in the absence of silver salt under the
standard catalytic conditions did not give the arylated product 3aa
(entry 1). Silver salts that are generally used for the generation of
cationic transition metal species, such as AgBF4, AgPF6, AgSbF6, and
AgOTf, did not work well (entries 2e5). Silver acetate and silver
fluoride also did not promote the reaction (entries 6 and 7). Though
AgO promoted the reaction, the efficiency was low (21% yield, entry
8). Finally, Ag2CO3 was found to be the best silver-based additive
giving rise to 3aa in 59% yield (entry 9). It is clear from these results
that the counter anion of silver salts play key role in catalysis.
Fig. 1. X-ray crystal structure of 4 (50% thermal ellipsoids). All hydrogen atoms are
omitted for clarity.
Subsequently, the reaction of 2-ethylthiophene (1a: 1.0 equiv)
and bromobenzene (1.0 equiv) was carried out in the presence of
5 mol % of PdBr2(bipy)$DMSO (4) and Ag2CO3 (1.0 equiv) in 1,4-
dioxane at 120 ꢀC for 13 h, and the CeH arylation product 3aa was
obtained in 52% isolated yield. Based on these results, we decided to
use the complex PdBr2(bipy)$DMSO (4) as a catalyst precursor for
further investigation.
Table 4
Effect of silver salta
PdBr2
bipy
2.3. Substrate scope in CeH bond arylation of heteroarenes
with haloarenes catalyzed by PdBr2(bipy)$DMSO (4)
Ag salt
Br
+
Et
S
Et
H
1,4-dioxane
120 °C,13 h
S
1a
Withthe optimized conditions and the air-stablepre-catalyst 4 in
hand, we investigated the substrate scope with respect to haloar-
enes 2 (Table 5). Although the present system was not applicable to
chlorobenzene and phenyl triflate, the coupling reactions using
3aa
Entry
Silver salt
Yield (%)b
1
2
3
4
5
6
7
8
9
None
AgBF4
AgPF6
AgSbF6
AgOTf
AgOAc
AgF
<2
<2
<2
<2
<2
2
<2
21
59
Table 5
Scope of haloarenesa
4 (5 mol%)
Ag2CO3 (1.0 equiv)
X
+
Et
R
R
S
Et
H
1,4-dioxane
120 °C,13 h
S
AgO
Ag2CO3
1a
2
3
(1.0 equiv)
(1.0 equiv)
a
Conditions: 1a (1.0 equiv), bromobenzene (1.0 equiv), PdBr2 (5 mol %), bipy
(5 mol %), silver salt (1.0 equiv), 1,4-dioxane, 120 ꢀC, 13 h.
Entry
1
2
3 (Yield, %)b
3aa (70)
b
GC yield.
X¼I (2a)
2.2. Synthesis, structure, and catalytic activity of PdBr2(bipy)
complex
X
2
3
4
X¼Br
X¼OTf
X¼Cl
3aa (52)
3aa (2)
3aa (<2)
Considering the results obtained during the optimization of
catalyst components, PdBr2/bipy seems to be the best combination
for the coupling. To simplify the reaction system, we prepared
PdBr2(bipy) complex. Although the preparation and crystal struc-
ture of PdBr2(bipy) complex was already reported,10 we developed
a new simple synthetic route to PdBr2(bipy). Treatment of PdBr2
(1.0 equiv) with bipy (1.5 equiv) in refluxing MeCN, followed by
recrystallization from DMSO/n-hexane gave PdBr2(bipy)$DMSO (4)
in 68% yield as orange crystal (Scheme 2). The molecular structure
of 4 was confirmed by X-ray crystal structure analysis (Fig. 1).9 The
crystal packing of 4 was found to be different from that of the
previously reported PdBr2(bipy) complex.10
5
R¼2-Me (2b)
3 ab (80)
I
R
6
7
R¼3-Me (2c)
R¼4-Me (2d)
3ac (82)
3ad (78)
I
8
9
2e
3ae (77)
3af (52)
OMe
I
2f
PdBr2
CO2Et
(1.0 equiv)
MeCN
reflux
recrystallization
N
N
I
+
Pd ·DMSO
Br
10
2g
3ag (43)
DMSO/n-hexane
Br
NO2
N
N
4 (68%)
a
(1.5 equiv)
Conditions: 1a (1.0 equiv), 2 (1.0 equiv), 4 (5 mol %), Ag2CO3 (1.0 equiv), 1,4-
dioxane, 120 ꢀC, 13 h.
b
Scheme 2. Synthesis of PdBr2(bipy)$DMSO (4).
Isolated yield.

4428
S. Yanagisawa, K. Itami / Tetrahedron 67 (2011) 4425e4430
bromo- and iodobenzene (2a) took place efficiently (entries 1e4). To
our delight, various electronically and structurally diverse iodoar-
enes were applicable to this coupling (entries 5e10). Noteworthy,
the utilization of sterically hindered 2-iodotoluene (2b) also affor-
ded the desired coupling product 3ab in excellent yield (entry 5).
Moreover, a range of functional groups, such as methoxy, ester, and
nitro groups were tolerated in this coupling (entries 8e10). Hal-
oarenes possessing electron-donating groups tend to show higher
reactivity compared with those with electron-withdrawing groups.
By using the optimized conditions, we also surveyed hetero-
arenes that could be applied to this system. It was found that
a variety of electron-rich five-membered heteroarenes, such as
thiophenes, thiazoles, benzofurans, and indoles, were arylated
with iodoarenes (Table 6). For example, 2-methylthiophene (1b),
2-phenylthiophene (1c), and 2-chlorothiophene (1d) were arylated
in good to high yields (entries 2e4). 2-Phenylthiazole (1e), which
could potentially be arylated at the phenyl ring through thiazole-
directed arylation, was selectively arylated at the C5 position on
thiazole ring with iodobenzene (2a) in 63% yield (entry 5). The
arylation of benzofuran (1f) and N-methylindole (1g) took place,
albeit as a mixture of regioisomers (entries 6 and 7). Unfortunately
the electron-deficient aromatics, such as pyridine and pyrazine
could not be arylated with haloarenes under the present system.
3. Conclusion
In summary, we describe the effect of catalyst components and
the scope of Pd/bipy/Ag2CO3 catalyzed CeH bond arylation of
heteroarenes with haloarenes. The complex PdBr2(bipy)$DMSO,
whose structure was unambiguously determined by X-ray crys-
tallography, turned out to be a general catalyst precursor for the
process. The reaction is applicable to a range of electron-rich five-
membered heteroarenes, such as thiophenes, thiazoles, benzofu-
rans, and indoles.
4. Experimental section
4.1. General
Unless otherwise noted, all materials including dry solvents
were obtained from commercial suppliers and used without further
purification. Unless otherwise noted, all reactions were performed
with dry solvents under an atmosphere of argon in flame-dried
glassware, using standard vacuum-line techniques. All arylation
reactions were carried out in glass vessels equipped with J. YoungÒ
O-ring tap, heated in oil bath (heaterþmagnetic stirrer). All work-
up and purification procedures were carried out with reagent-
grade solvents in air. Analytical thin-layer chromatography (TLC)
was performed using E. Merck silica gel 60 F254 precoated plates
(0.25 mm). The developed chromatogram was analyzed by UV lamp
(254 nm) and ethanolic phosphomolybdic acid/sulfuric acid. Flash
column chromatography was performed with E. Merck silica gel 60
(230e400 mesh). Preparative recycling gel permeation chroma-
tography (GPC) was performed with a JAI LC-9204 instrument
equipped with JAIGEL-1H/JAIGEL-2H columns using chloroform as
an eluent. Preparative thin-layer chromatography (PTLC) was per-
formed using Wako-gelÒ B5-F silica coated plates (0.75 mm) pre-
pared in our laboratory. Gas chromatography (GC) analysis was
conducted on a Shimadzu GC-2010 instrument equipped with an
HP-5 column (30 mꢁ0.25 mm, HewlettePackard). GC/MS analysis
was conducted on a Shimadzu GCMS-QP2010 instrument equipped
with an HP-5 column (30 mꢁ0.25 mm, HewlettePackard). High-
resolution mass spectra (HRMS) were obtained from a JMS-
T100TD (direct analysis in real time mass spectrometry, DARTMS)
or a JEOL JMS-700 (fast atom bombardment mass spectrometry,
FABMS) instrument. Nuclear magnetic resonance (NMR) spectra
were recorded on a JEOL JNM-ECA-600 (1H 600 MHz, 13C 150 MHz)
spectrometer. Chemical shifts for 1H NMR are expressed in parts per
Table 6
Scope of heteroarenesa
4 (5 mol%)
Ag2CO3 (1.0 equiv)
R
R
+
Het
Het
H
I
1,4-dioxane
120 °C,13 h
1
2
3
(1.0 equiv)
(1.0 equiv)
Entry
1
1
2
3 (Yield, %)b
Et
S
2-Ethylthiophene (1a)
2-Methylthiophene (1b)
2-Phenylthiophene (1c)
2-Chlorothiophene (1d)
2-Phenylthiazole (1e)
2a
3aa (70)
Me
S
2
2d
2a
2d
2a
Me
3bd (80)
Ph
S
3
3ca (59)
Cl
S
4
Me
3dd (41)
N
S
Ph
5c
million (ppm) relative to tetramethylsilane (
d 0.0 ppm). Chemical
shifts for 13C NMR are expressed in ppm relative to CDCl3
(d
3ea (63)
77.0 ppm). Data are reported as follows: chemical shift, multiplicity
(s¼singlet, d¼doublet, dd¼doublet of doublets, t¼triplet,
q¼quartet, m¼multiplet, br s¼broad signal), coupling constant
(Hz), and integration.
e
6d
Benzofuran (1f)
2a
2a
O
3fa (48)e
4.2. Synthesis and X-ray crystal structure analysis of Pd
complex 4
f
7d
N-Methylindole (1g)
N
Me
3ga (60)f
a
A solution of PdBr2 (79.9 mg, 0.3 mmol) in dry acetonitrile
(1.5 mL) was refluxed for 0.5 h under argon. After cooling the re-
action mixture to room temperature, bipy (70.3 mg, 0.45 mmol)
was added, and the resultant mixture was stirred at room tem-
perature for 1 h. Recrystallization from DMSO/n-hexane followed
by filtration and washing with MeOH and ether afforded
PdBr2(bipy)$DMSO (4: 102 mg, 68%) as orange crystal. 1H NMR
Conditions: 1 (1.0 equiv), 2 (1.0 equiv), 4 (5 mol %), Ag2CO3 (1.0 equiv), 1,4-di-
oxane, 120 ꢀC, 13 h.
b
Isolated yield.
Compound 1e (1.5 equiv) was employed.
c
d
Conditions: 1 (1.5 equiv), 2 (1.0 equiv), 4 (10 mol %), Ag2CO3 (1.0 equiv), 1,4-
dioxane, 150 ꢀC, 13 h.
e
C3-isomer was also obtained. Isomer ratio: C2/C3¼90:10.
f
C3-isomer was also obtained. Isomer ratio: C2/C3¼93:7.

S. Yanagisawa, K. Itami / Tetrahedron 67 (2011) 4425e4430
4429
(600 MHz, DMSO-d6)
d
7.79e7.81 (m, 2H), 8.36 (dd, J¼7.9, 7.6 Hz,
4.4.4. Ethyl 4-(5-ethylthiophen-2-yl)benzoate (3af). Yield (52%)
from 2-ethylthiophene (1a) and ethyl 4-iodobenzoate (2f). 1H NMR
2H), 8.59 (d, J¼7.6 Hz, 2H), 9.39 (d, J¼5.5 Hz, 2H).
Intensity data were collected at 123 K on a Rigaku Single Crystal
(600 MHz, CDCl3)
d
1.34 (t, J¼7.6 Hz, 3H), 1.40 (t, J¼7.6 Hz, 3H), 2.87
CCD X-ray Diffractometer (Saturn 70 with MicroMax-007) with
graphite-monochromated Mo K
(q, J¼7.6 Hz, 2H), 4.38 (q, J¼7.6 Hz, 2H), 6.78 (d, J¼3.5 Hz, 1H), 7.23
a
radiation (
l
¼0.7107 A). A total
(d, J¼3.5 Hz, 1H), 7.60 (d, J¼8.9 Hz, 2H), 8.01 (d, J¼8.9 Hz, 2H). 13C
ꢀ
9953 reflections were corrected, of which 2704 were independent
reflections (Rint¼0.0290). The structure was solved by direct
methods (SIR-97) and refined by the full-matrix least-squares
techniques against F2 (SHELXL-97). All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were placed using AFIX
instructions. The crystal data are as follows: C12H14Br2N2OPdS,
FW¼500.53, crystal size 0.10ꢁ0.10ꢁ0.05 mm3, monoclinic, space
NMR (150 MHz, CDCl3) d 14.3, 15.8, 23.6, 60.9, 124.2, 124.7, 124.9,
128.5, 130.1, 138.9, 140.2, 148.9, 166.3. HRMS (DART) m/z calcd for
C15H16O2S [MH]þ: 261.0949, found 261.0957.
4.4.5. 2-Ethyl-5-(4-nitrophenyl)thiophene (3ag). Yield (43%) from
2-ethylthiophene (1a) and 4-iodonitrobenzene (2g). 1H NMR
(600 MHz, CDCl3)
d
1.35 (t, J¼7.6 Hz, 3H), 2.89 (q, J¼7.6 Hz, 2H), 6.83
ꢀ
ꢀ
ꢀ
group C2/c (No.15). a¼29.710(8) A, b¼7.9377(14) A, c¼22.102(6) A,
(d, J¼3.5 Hz, 1H), 7.30 (d, J¼3.5 Hz, 1H), 7.66 (d, J¼8.9 Hz, 2H), 8.20
b
¼143.908(7) , V¼3070.4(12) A , Z¼8, Dcalcd¼2.166 g/cm3. The re-
(d, J¼8.9 Hz, 2H). 13C NMR (150 MHz, CDCl3)
d 15.8, 23.7, 124.3,
3
ꢀ
ꢀ
finement converged to R1¼0.0232, wR2¼0.0469 (I>2
s
(I)),
125.2, 125.3, 125.6, 138.7, 140.9, 146.1, 150.7. HRMS (DART) m/z calcd
R1¼0.0270, wR2¼0.0484 (for all data), GOF¼1.047. Selected bond
for C12H12NO2S [MH]þ: 234.0589, found 234.0587.
ꢀ
lengths (A): Pd(1)eN(1)¼2.035(2), Pd(1)eN(2)¼2.040(2), Pd(1)e
Br(1)¼2.4118(6), Pd(1)eBr(2)¼2.4179(7). Selected angles (deg):
N(1)ePd(1)eN(2)¼80.66(10), N(2)ePd(1)eBr(2)¼95.49(7), Br(2)e
Pd(1)eBr(1)¼88.96(3), Br(1)ePd(1)eN(1)¼94.93(7), N(1)ePd(1)e
Br(2)¼175.15(6), N(2)ePd(1)eBr(1)¼175.48(7).
Acknowledgements
We thank Dr. Yasutomo Segawa for assistance in X-ray crystal
structure analysis and valuable discussions. This work was sup-
ported in part by Grants-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), Japan, the Kurata Memorial Hitachi Science and Technol-
ogy Foundation, and the Asahi Glass Foundation. S.Y. is a recipient
of JSPS Predoctoral Fellowship.
4.3. Typical procedure for CeH bond arylation of
heteroarenes 1 with haloarenes 2 catalyzed by 4
A 20-mL glass vessel equipped with J. YoungÒ O-ring tap, con-
taining a magnetic stirring bar, was flame-dried under vacuum and
filled with argon after cooling to room temperature. To this vessel
References and notes
were added Pd complex 4 (8.1 mg, 16 mmol), Ag2CO3 (82.4 mg,
0.3 mmol), and dry 1,4-dioxane (0.75 mL) under a stream of argon.
The vessel was heated at 60 ꢀC for 0.5 h. To this vessel were added
2-ethylthiophene (1a: 33.7 mg, 0.30 mmol), iodobenzene (57 mg,
0.28 mmol), and dry 1,4-dioxane (0.75 mL) under a stream of argon.
The vessel was sealed with O-ring tap, and then heated at 120 ꢀC for
13 h in oil bath with stirring. After cooling the reaction mixture to
room temperature, the mixture was passed through a short silica
gel pad (EtOAc). The filtrate was evaporated and the residue was
subjected to gel permeation chromatography (CHCl3) to afford
2-ethyl-5-phenylthiophene (3aa: 36.9 mg, 70%) as colorless oil.
€
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2-ethylthiophene (1a) and 2-iodotoluene (2b). 1H NMR (600 MHz,
CDCl3)
d
1.34 (t, J¼7.6 Hz, 3H), 2.43 (s, 3H), 2.87 (q, J¼7.6 Hz, 2H),
6.75 (d, J¼3.4 Hz, 1H), 6.86 (d, J¼3.4 Hz, 1H), 7.18e7.24 (m, 3H), 7.38
(d, J¼7.6 Hz, 1H). 13C NMR (150 MHz, CDCl3)
d 15.8, 21.2, 23.4, 123.3,
125.8, 126.0, 127.4, 130.2, 130.7, 134.6, 135.9, 140.4, 147.3. HRMS
(DART) m/z calcd for C13H15S [MH]þ: 203.0895, found 203.0892.
4.4.2. 2-Ethyl-5-(3-methylphenyl)thiophene (3ac). Yield (82%) from
2-ethylthiophene (1a) and 3-iodotoluene (2c). 1H NMR (600 MHz,
CDCl3)
d
1.32 (t, J¼7.6 Hz, 3H), 2.36 (s, 3H), 2.84 (q, J¼7.6 Hz, 2H),
6.73 (d, J¼3.4 Hz, 1H), 7.04 (d, J¼7.6 Hz, 1H), 7.09 (d, J¼3.4 Hz, 1H),
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15.9, 21.4, 23.6, 122.5, 122.6, 124.2, 126.2, 127.8, 128.6, 134.6, 138.3,
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from 2-ethylthiophene (1a) and 4-iodoanisole (2e). 1H NMR
(600 MHz, CDCl3)
d
1.32 (t, J¼7.6 Hz, 3H), 2.84 (q, J¼7.6 Hz, 2H), 3.80
(s, 3H), 6.71 (d, J¼3.4 Hz,1H), 6.88 (d, J¼8.9 Hz, 2H), 6.99 (d, J¼3.4 Hz,
1H), 7.47 (d, J¼8.9 Hz, 2H). 13C NMR (150 MHz, CDCl3)
d 15.9, 23.5,
55.3,114.2,121.6,124.1,126.7,127.7,141.5,146.2,158.8. HRMS (DART)
m/z calcd for C13H15OS [MH]þ: 219.0844, found 219.0847.

4430
S. Yanagisawa, K. Itami / Tetrahedron 67 (2011) 4425e4430
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