Direct coupling of arenes and iodoarenes catalyzed by a rhodium complex with a strongly π-accepting phosphite ligand

Article abstract of DOI:10.1016/j.tet.2008.01.053

A new rhodium-based catalytic system for the direct C-H coupling of arenes and iodoarenes that shows high activity with reasonably broad scope was developed. Under the catalytic influence of RhCl(CO){P[OCH(CF₃)₂]₃}₂ and Ag₂CO₃, the direct C-H arylation of heteroarenes and arenes took place with iodoarenes to afford a range of biaryls in good to excellent yields with high regioselectivity. Thiophenes, furans, pyrroles, indoles, and alkoxybenzenes are applicable to this arylation protocol.

Full text of DOI:10.1016/j.tet.2008.01.053

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6073e6081
www.elsevier.com/locate/tet
Direct coupling of arenes and iodoarenes catalyzed by a rhodium
complex with a strongly p-accepting phosphite ligand
Shuichi Yanagisawa a, Tomoko Sudo a, Ryoji Noyori a, Kenichiro Itami a,b,
*
a Department of Chemistry and Research Center for Materials Science, Nagoya University, Nagoya 464-8602, Japan
b PRESTO, Japan Science and Technology Agency (JST) Kawaguchi, Saitama 332-0012, Japan
Received 1 September 2007; accepted 17 October 2007
Available online 16 January 2008
Abstract
A new rhodium-based catalytic system for the direct CeH coupling of arenes and iodoarenes that shows high activity with reasonably broad
scope was developed. Under the catalytic influence of RhCl(CO){P[OCH(CF3)2]3}2 and Ag2CO3, the direct CeH arylation of heteroarenes and
arenes took place with iodoarenes to afford a range of biaryls in good to excellent yields with high regioselectivity. Thiophenes, furans, pyrroles,
indoles, and alkoxybenzenes are applicable to this arylation protocol.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
and halogenated arenes (AreMþAreX/AreArþMeX) are
undoubtedly among the most important and reliable methodol-
ogies for making biaryls (Scheme 1).1,2 The development of
improved catalysts and reagents continues to evolve at a rapid
pace, and many important organic substances (pharmaceuti-
cals as well as advanced electronic and photonic materials)
are now made using this technology.2 However, there is a com-
mon limitation and inefficiency in this cross-coupling technol-
ogy: it requires extra steps to install the metallic fragments on
arenes.
Organic molecules having (hetero)aryle(hetero)aryl bonds
represent privileged structural motifs frequently found in natu-
ral products or used in pharmaceuticals and functional organic
materials. Therefore, the development of efficient methods
for biaryl formation has been a topic of great importance in
all aspects of pure and applied chemistry.1 Currently, the palla-
dium-catalyzed cross-coupling reactions of metalated arenes
By contrast, the direct CeH coupling of arenes and halo-
arenes (AreHþAreX/AreArþHeX) offers the promise of
a solution to many of these drawbacks and therefore holds sig-
nificant synthetic potential (Scheme 1).3,4 Indeed, recent world-
wide research has resulted in impressive progress for the direct
CeH coupling methodology in making biaryls (mainly palla-
dium-based systems).3e11 However, there still exists consider-
able room for further development. For example, a universal
catalyst that can directly arylate all heteroarenes as well as
simple arenes has not been forthcoming (Scheme 1).
Typical cross-coupling
catalyst
+
Ar
Ar
C M
X C
Ar = aryl, heteroaryl
M = Mg, B, Sn, Si, etc
X = halogen
Ar
Ar
C
C
Direct C–H coupling
catalyst
+
Ar
Ar
C
H
X C
Scheme 1. Synthesis of biaryls through typical cross-coupling and direct CeH
coupling catalyzed by transition metal complexes.
As a part of our program aimed at establishing programmed
synthesis of (hetero)arene-core functional molecules,12 we re-
cently reported that a direct coupling of arenes and iodoarenes
proceeds with the agency of a catalytic amount of RhCl(CO)-
{P[OCH(CF3)2]3}2 (1) and silver carbonate, furnishing
* Corresponding author. Tel./fax: þ81 52 788 6098.
E-mail address: itami@chem.nagoya-u.ac.jp (K. Itami).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.053

6074
S. Yanagisawa et al. / Tetrahedron 64 (2008) 6073e6081
privileged biaryls in good to excellent yields (Scheme 2).13
Herein we report the details of this study in full.
+
Ar
Ar
C
H
I C
CF3
F3C
F3C
O
P
CF3
CF3
cat. RhCl(CO)L2 (1)
L =
O
Ag2CO3
O
CF3
Ar
Ar
C
C
Scheme 2. Direct coupling of arenes and iodoarenes catalyzed by Rh/
P[OCH(CF3)2]3/Ag2CO3 system.
2. Results and discussion
2.1. Synthesis and structure of rhodium complex 1
The synthesis of RhCl(CO){P[OCH(CF3)2]3}2 (1) is
straightforward and easy to conduct (Scheme 3). Thus, a solu-
tion of [RhCl(CO)2]2 and P[OCH(CF3)2]3 in dry toluene was
stirred at 50 ꢀC for 2 h under argon. After cooling the reaction
mixture to room temperature, solvent was removed under re-
duced pressure. Reprecipitation from THF/toluene followed by
filtration and vacuum drying afforded 1 as yellow solid (>99%
yield). This complex is very stable in air and moisture in the
solid state. Virtually no decomposition of 1 has been detected
after extended (>10 months) exposure to air.
Figure 1. The X-ray structure of 1 (upper: ORTEP drawing, bottom: space-
filling model). Thermal ellipsoids are drawn at the 50% probability level.
CF3
F3C
(DME) (1/2a/3a/Ag2CO3/DME¼0.03:1.5:1.0:1.0:1.0 molar ra-
tio), a direct CeH coupling took place at the 2-position of 2a to
afford 4aa in 75% yield with virtually complete regioselectivity
(Scheme 4).16 When the reaction was conducted at 200 ꢀC
under microwave irradiation, the reaction was complete within
0.5 h to furnish 4aa in 73% yield.
O
CF3
CF3
+
1/2 [RhCl(CO)2]2
2
P
O
O
F3C
CF3
Cl
toluene
50 °C, 2 h
(– CO)
[(CF3)2CHO]3P Rh P[OCH(CF3)2]3
CO
OMe
OMe
H
I
Rh complex 1
Ag2CO3, DME
m-xylene
+
1 (>99% yield)
S
S
Scheme 3. Synthesis of rhodium complex 1.
2a
3a
4aa
1/2a/3a/Ag2CO3/DME =
75% (150 °C, 12 h)
73% (200 °C, 0.5 h, W)
0.03:1.5:1.0:1.0:1.0 mol ratio
The X-ray crystal structure of 1 indicates that the high sta-
bility of 1 may be due to the effective shielding of the rhodium
atom by two bulky phosphite ligands (Fig. 1). In addition,
a ‘push’ electronic effect of Cl, rendering the rhodium center
less unsaturated than a formal 16-electron species through a
p-donation from Cl to Rh, might also contribute to its high
stability.14,15
Scheme 4. Direct coupling of 3-methoxythiophene and iodobenzene catalyzed
by Rh/P[OCH(CF3)2]3/Ag2CO3 system.
2.3. Direct coupling of heteroarenes and iodoarenes
With a new rhodium-based system catalyzing the direct CeH
coupling in hand, we surveyed heteroarenes and haloarenes
that could be applied to our system (Table 1). We first identi-
fied that the direct coupling proceeded efficiently with elec-
tron-neutral and electron-deficient iodoarenes by using 2a as
a model substrate. Electron-rich iodoarenes and iodoheteroar-
enes were also found to be applicable, but they tend to possess
somewhat lower reactivity. Unfortunately, the corresponding
bromides, chlorides, and triflates were found to be poor sub-
strates with this first-generation catalytic system.
2.2. Discovery of rhodium catalysis
We discovered that the rhodium complex 1 functions as an
efficient catalyst precursor, with the assistance of silver carbon-
ate, for the direct coupling of electron-rich heteroarenes and io-
doarenes. For example, when a mixture of 3-methoxythiophene
(2a) and iodobenzene (3a) in m-xylene was stirred at 150 ꢀC for
12 h in the presence of 1, Ag2CO3, and 1,2-dimethoxyethane

S. Yanagisawa et al. / Tetrahedron 64 (2008) 6073e6081
6075
Table 1
Direct coupling of heteroarenes and iodoarenes catalyzed by 1a
Rh complex 1
Ag2CO3, DME
+
Ar
Ar
Ar
Ar
C
H
I
C
C C
m-xylene
150~200 °C, 0.5 h
(microwave)
2
3
4
Entry
1
2
3
Product 4
Yieldb (%)
73 (80)
OMe
OMe
I
I
I
3a
2a
4aa
S
S
OMe
O
O
2
3
2a
94 (99)
52 (58)
3b
4ab
S
OMe
2a
3c
S
4ac
4ba
S
S
53 (80)c
2b
4
5
6
3a
3b
3a
S
S
S
O
2b
83c
4bb
4ca
4cb
2c
76 (99)
S
S
O
7
8
2c
2c
3b
79 (87)
50 (64)
S
S
4cd
I
3d
O
S
9
3b
3b
64
64
2d
S
S
4db
S
O
10
2e
4eb
O
O
O
CN
4ee
11
12
2e
66
I
CN
3e
O
O
3b
3b
58 (86)
2f
N
N
4fb
Ph
Ph
4gb (C-3)
57
23
N
Me
2g
13
O
N
Me
4gb' (C-2)
N
Me
a
Molar ratio: 1/2/3/Ag2CO3/DME¼0.03:1.5:1.0:1.0:1.0.
b
c
Isolated yield. The yield in parentheses is determined by NMR.
Molar ratio: 1/2/3/Ag2CO3/DME¼0.1:15:1.0:1.0:0. Reactions were conducted under conventional heating (150 ꢀC, 14e15 h).

6076
S. Yanagisawa et al. / Tetrahedron 64 (2008) 6073e6081
As for heteroarenes, we found that a range of electron-rich
such an assumption. For example, when deuterium-labeled
thiophene was subjected to the coupling with iodobenzene un-
der the influence of 1 and Ag2CO3, both CeH and CeD bonds
adjacent to sulfur were phenylated to a degree virtually equal,
indicating a negligible kinetic isotope effect (Scheme 5). This
result indicates that the CeH bond-cleaving step (possibly
electrophilic rhodation; B/C in Fig. 2) is not a turnover-
limiting step in our catalysis.
five-membered heteroarenes, such as thiophenes, furans, pyr-
roles, and indoles, were applicable to the present catalysis (Ta-
ble 1). Not only 3-methoxythiophene (2a), but also thiophene
(2b), 2-ethylthiophene (2c), and bithiophene (2d) were
found to cross-couple with iodoarenes, affording the corre-
sponding biaryls in good yields (entries 1e9). Furans such
as 2,3-dimethylfuran (2e) were also arylated well (entries 10
and 11). For all thiophenes and furans examined, the direct
coupling proceeded selectively at carbons adjacent to sulfurs
or oxygens. When 1-phenylpyrrole (2f) was used as a substrate,
the direct coupling with 3b took place selectively at the 3-po-
sition of the pyrrole ring (entry 12). The direct coupling of
1-methylindole (2g) and 3b also took place efficiently, but
resulted in a 71:29 mixture of regioisomers favoring the
C3-arylation product (entry 13). Unfortunately, the CeH coupling
did not proceed with electron-deficient six-membered hetero-
arenes such as pyridine using our first-generation catalyst.
Rh complex 1
Ag2CO3
I
1
:
+
H
D
S
S
H
D
m-xylene
200 °C, 0.5 h
(microwave)
S
large excess
1
Scheme 5. Intramolecular competitive reaction using deuterium-labeled
thiophene.
In line with our mechanistic assumption that the use of
strongly p-accepting P[OCH(CF3)2]3 as a ligand has a strong
impact on the energetic profile in the catalytic cycle, we ob-
served a strong ligand effect in the present catalysis (Table
2). For example, when a less p-accepting ligand such as
P(C6H5)[OCH(CF3)2]2, P(OC6H5)3, P[OCH(CH3)2]3, and
P(C6H5)3 was used in place of P[OCH(CF3)2]3 for the reaction
of 2a and 3b, the yield of the arylation product 4ab decreased
from 94% to 31%, 6%, 9%, and 0%, respectively (Table 2).
There is a clear correlation between the arylation efficiency
and the p-accepting ability of the ligand, as judged by elec-
tronic parameters19 based on the carbonyl stretching frequency
(nCO) in trans-RhCl(CO)L2 complexes. In particular, the dra-
matic difference between P[OCH(CF3)2]3 and P[OCH(CH3)2]3,
which are almost identical in size, is a clear indication that the
p-accepting nature of the ancillary ligand has the greatest
benefit in our catalysis.
2.4. Mechanistic considerations
Although the precise mechanism remains unknown, our
current approximation is shown in Figure 2. We surmise that
ligand dissociation (most likely the phosphite) from 1 is an ini-
tial step generating a coordinatively unsaturated rhodium(I)
species A, which thereafter initiates a RhI/RhIII redox cycle.13
This includes (i) oxidative addition of iodoarene 3 (AreI) to
A, (ii) generation of cationic arylrhodium(III) species B with
the assistance of silver carbonate, (iii) electrophilic metalation
(rhodation) of arene 2 (AreH) with B giving diarylrho-
dium(III) species C, and (iv) reductive elimination of biaryl
product (4) with the regeneration of A.17,18
The beneficial effect of strongly p-accepting
P[OCH(CF3)2]3 might be to render the rhodium center elec-
tron-deficient, thereby facilitating electrophilic metalation as
well as a reductive elimination step. A preliminary experimen-
tal study using deuterium-labeled substrates is in line with
Table 2
Effect of ligand in Rh-catalyzed direct coupling
OMe
RhCl(CO)L
2
I
OMe
P(OR)3
Ag2CO3
CO
m-xylene
200 °C, 0.5 h
(microwave)
Rh
Cl
S
S
R = CH(CF3)2
P(OR)3
1
O
O
2a
3b
4ab
Ligand (L)
Yield of 4ab (%)
nCO in RhCl(CO)L2 (cmꢁ1
)
P(OR)3
P[OCH(CF3)2]3
P(C6H5)[OCH(CF3)2]2
P(OC6H5)3
94
31
6
2070
2038
2018
2002
1983
CO
Rh
Ar1–I (3), Ag+
AgI
Cl
P(OR)3
A
Ar1–Ar2 (4)
P[OCH(CH3)2]3
P(C6H5)3
9
0
I
III
Rh /Rh
redox cycle
Ar2
Rh
+
Ar1
Cl
Ar1
Cl
CO
CO
Rh
2.5. Direct coupling of benzene derivatives and iodoarenes
P(OR)3
C
P(OR)3
B
The aforementioned substrate survey (Table 1) revealed that
our first-generation catalyst has a reasonably broad scope of
substrates but is not yet truly universal, which encourages us
to develop it further. However, we found that our catalyst can
H+
Ar2–H (2)
Figure 2. A possible mechanism of our rhodium catalysis.

S. Yanagisawa et al. / Tetrahedron 64 (2008) 6073e6081
6077
H
NO2
NO2
NO2
Rh complex 1
10
Ag2CO3
I
I
200 °C, 0.5 h
(microwave)
H
S
S
OMe
I
OMe
Rh complex 1
Ag2CO3
51% yield
(6:7 = 71:29)
11 (62%)
5
3f
m-xylene
H
S
2c
6
7
OMe
NO2
150 °C, 0.5 h
(microwave)
H
NO2
Rh complex 1
Ag2CO3
S
S
OMe
I
I
12
13 (46%)
200 °C, 0.5 h
(microwave)
Scheme 7. Synthesis of benzene-core p-systems (11 and 13) through multiple
CeH coupling.
OMe
I
OMe
8
3f
9 (76%)
3. Conclusion
OMe
Scheme 6. Arylation of benzene derivatives.
In summary, a new rhodium-based catalytic system for the
direct CeH coupling of electron-rich arenes and iodoarenes
that shows high activity with reasonably broad scope was de-
veloped. In many aspects, the present reaction can be best
described as a FriedeleCrafts-type arylation of arenes. Eluci-
dation of the reaction mechanism, development of second-
generation catalysts, and applications of the direct arylation
technology to materials science and pharmaceutical chemistry
are currently underway.
effect the direct CeH coupling of benzene derivatives, which
have proven to be the most challenging substrate class in this
field (Scheme 6).3,4 For example, when anisole (5) was treated
with p-nitrophenyl iodide (3f) under the influence of 1 and
Ag2CO3 (1/3f/5/Ag2CO3¼0.05:1.0:27:1.0 molar ratio), ary-
lated anisoles (6 and 7) were obtained as a mixture of
regioisomers (51% yield; o/m/p¼29:0:71).20 When 1,3-dime-
thoxybenzene (8) was used as a substrate, arylation occurred
exclusively at the 4-position giving the corresponding biaryl
9 in 76% yield. These reactions not only serve as successful
examples of the functionalization of relatively simple benzene
derivatives, but also shed some light on the mechanism. The
manifestation of clear orthoepara selectivity in the arylation
of alkoxybenzenes is consistent with the CeH bond cleavage
based on electrophilic metalation (Fig. 2) but not with those
through directed ortho-metalation and/or CeH oxidative addi-
tion as have been proposed in some other CeH bond function-
alization reactions.4 A preliminary examination revealed that
CeH arylation of alkylbenzenes also took place, albeit with
low efficiency. Nevertheless, the successful arylation of
benzene derivatives without catalyst-directing groups is
noteworthy.4
4. Experimental
4.1. General
Unless otherwise noted, all materials including dry solvents
(toluene and m-xylene) were obtained from commercial sup-
pliers and used without further purification. The ligand
P[OCH(CF3)2]3 was prepared according to procedures reported
in the literature.21 Unless otherwise noted, all reactions were
performed with dry solvents under an atmosphere of argon in
flame-dried glassware with standard vacuum-line techniques.
All coupling reactions using conventional heating were carried
out in glass vessels equipped with J. YoungÒ O-ring tap, heated
in a 8-well reaction block (heaterþmagnetic stirrer). All micro-
wave reactions were performed in a regularly calibrated CEM
Focused MicrowaveÔ Synthesis System (Discover) with IR
temperature monitor and non-invasive pressure transducer
using 10 mL vials with septa. All work-up and purification pro-
cedures were carried out with reagent-grade solvents in air.
Preparative recycling gel permeation chromatography (GPC)
was performed with a JAI LC-9204 instrument equipped with
JAIGEL-1H/JAIGEL-2H columns using chloroform as an
eluent. High-resolution mass spectra (HRMS) were obtained
from a Waters Micromass LCT Premier (electrospray ionization
time-of-flight massspectrometry, ESI-TOFMS) or a JEOL JMS-
700 (fast atom bombardment mass spectrometry, FABMS).
Infrared spectra were recorded on a JASCO FTIR-6100 spec-
trometer. Nuclear magnetic resonance (NMR) spectra were
recorded on a JEOL JNM-ECA-600 (1H 600 MHz, 13C
150 MHz, 31P 243 MHz) spectrometer. Chemical shifts for 1H
NMR are expressed in parts per million (ppm) relative to
2.6. Synthesis of extended p-systems through multiple CeH
coupling
We envisage that the current direct CeH coupling tech-
nology has broad potential for further applications. For exam-
ple, a range of extended p-electron systems can be easily
constructed through multiple CeH coupling. When 1,3-diio-
dobenzene (10) was treated with an excess amount of 2-ethyl-
thiophene (2c, 5.0 equiv to 10), a double CeH arylation took
place giving an interesting benzene-core p-system 11 in 62%
yield (Scheme 7). When 1,4-diiodobenzene (12) was used as
a core substrate, fully conjugated p-system 13 was obtained
in 46% yield (Scheme 7). On the basis of these preliminary
but promising results, we are currently working on the gener-
ation of novel functional oligoarenes using our direct CeH
coupling technology.

6078
S. Yanagisawa et al. / Tetrahedron 64 (2008) 6073e6081
tetramethylsilane (d 0.0 ppm). Chemical shifts for 13C NMR are
expressed in parts parts per million relative to CDCl3 (d
77.0 ppm). Chemical shifts for 31P{1H} NMR are reported
downfield in parts per million relative to external 85% H3PO4
(d 0.0 ppm). Data are reported as follows: chemical shift, multi-
plicity (s¼singlet, d¼doublet, dd¼doublet of doublets,
t¼triplet, q¼quartet, m¼multiplet, br¼broad signal), coupling
constant (Hz), and integration. The structures of arylation prod-
ucts were determined based on 2D NMR experiments.
0.60 mmol), iodobenzene (3a: 81.6 mg, 0.40 mmol), and dry
m-xylene (2.0 mL) under a stream of argon. The vessel was
sealed with O-ring tap, and then heated at 150 ꢀC for 12 h in
a 8-well reaction block with stirring. After cooling the reaction
mixture to room temperature, the mixture was passed through
a short silica gel pad (EtOAc/CHCl3). The filtrate was evapo-
rated and the residue was subjected to gel permeation chroma-
tography (CHCl3) to afford 3-methoxy-2-phenylthiophene
1
(4aa: 57.1 mg, 75%) as pale yellow oil. H NMR (600 MHz,
CDCl3) d 3.91 (s, 3H), 6.92 (d, J¼5.5 Hz, 1H), 7.14 (d,
J¼5.5 Hz, 1H), 7.21 (t, J¼7.6 Hz, 1H), 7.35 (t, J¼7.6 Hz,
2H), 7.73 (d, J¼7.6 Hz, 2H). 13C NMR (150 MHz, CDCl3)
d 58.7, 117.5, 120.2, 122.1, 126.4, 126.9, 128.5, 133.4, 153.7.
HRMS (ESI-TOF) m/z calcd for C11H11OS [MH]þ: 191.0531,
found: 191.0540.
4.2. Synthesis and crystal structure analysis of rhodium
complex 1
A solution of [RhCl(CO)2]2 (200.4 mg, 0.51 mmol) and
P[OCH(CF3)2]3 (1.09 g, 2.06 mmol) in dry toluene (2.0 mL)
was stirred at 50 ꢀC for 2 h under argon. After cooling the reac-
tion mixture to room temperature, solvent was removed under
reduced pressure. Reprecipitation from THF/toluene followed
by filtration and vacuum drying afforded trans-RhCl(CO)-
{P[OCH(CF3)2]3}2 (1: 1.25 g, quant) as yellow solid. 1H
NMR (600 MHz, CDCl3) d 5.64 (br, 6H). 31P{1H} NMR
(243 MHz, THF-d8) d 123.3 (d, JRheP¼224 Hz). IR (KBr)
2070, 1371, 1302, 1250, 1207, 1113, 1088 cmꢁ1. Single crys-
tals suitable for X-ray analysis were obtained by slow diffusion
of toluene into an acetonitrile solution of 1. Intensity data were
collected at 173 K on a Rigaku Single Crystal CCD X-ray
Diffractometer (Saturn 70 with MicroMax-007) with graph-
ite-monochromated Mo Ka radiation. A total of 30,758 reflec-
tions were corrected, of which 8832 were independent
reflections (Rint¼0.0312). The structure was solved by direct
methods (SHELXS-9722) and refined by the full-matrix least-
squares on F2 (SHELEXL-9722). All non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were refined iso-
tropically. The crystal data are as follows: C19H6ClF36O7P2Rh,
FW¼1230.54, crystal size 0.20ꢂ0.20ꢂ0.20 mm3, monoclinic,
4.4. Typical procedure for coupling of heteroarenes and
iodoarenes (microwave heating protocol)
A 10-mL flame-dried microwave vial containing a magnetic
stirring bar was fitted with a septum and cooled under a stream of
argon. To this vial were added Rh complex 1 (18.8 mg,
15 mmol), Ag2CO3 (138.7 mg, 0.50 mmol), 1,2-dimethoxyethane
(45.1 mg, 0.50 mmol), 3-methoxythiophene (2a: 86.6 mg,
0.75 mmol), iodobenzene (3a: 102.0 mg, 0.50 mmol), and dry
m-xylene (2.5 mL). The vial was sealed and heated with stirr-
ing at 200 ꢀC for 30 min in a CEM Discover microwave
apparatus. After the reaction vial was cooled down to room
temperature, the mixture was passed through a short silica
gel pad (EtOAc/CHCl3). The filtrate was evaporated and the
residue was subjected to gel permeation chromatography
(CHCl3) to afford 4aa (69.7 mg, 73%) as pale yellow oil.
4.4.1. 2-(p-Acetylphenyl)-3-methoxythiophene (4ab)
Isolated yield, 94% (99% NMR yield) from 3-methoxythio-
phene (2a) and 4-iodoacetophenone (3b) (microwave heating,
˚
˚
space group C2/c (No. 15). a¼33.050(5) A, b¼17.903(2) A, c¼
1
ꢀ
ꢀ
ꢀ
˚
13.525(2) A, a¼90.0000(5) , b¼105.3324(7) , g¼90.0000(5) ,
200 ꢀC, 30 min). H NMR (600 MHz, CDCl3) d 2.59 (s, 3H),
3
3
˚
V¼7717.8(19) A , Z¼4, Dc¼1.059 g/cm . The refinement con-
verged to R1¼0.0419, wR2¼0.1010 (I>2s(I)), GOF¼1.105. Se-
3.95 (s, 3H), 6.94 (d, J¼5.5 Hz, 1H), 7.24 (d, J¼5.5 Hz, 1H),
7.83 (d, J¼8.9 Hz, 2H), 7.94 (d, J¼8.9 Hz, 2H). 13C NMR
(150 MHz, CDCl3) d 26.5, 58.7, 117.3, 118.7, 124.0, 126.2,
128.7, 134.4, 138.3, 155.3, 197.4. HRMS (ESI-TOF) m/z calcd
for C13H13O2S [MH]þ: 233.0636, found: 233.0635.
˚
lective bond length (A): Rh(1)eCl(1)¼2.3561(8), Rh(1)eP(1)¼
2.2597(8), Rh(1)eP(2)¼2.2550(7), Rh(1)eC(19)¼1.853(3),
C(19)eO(7)¼1.127(4). Selected angles (ꢀ): P(1)eRh(1)eCl(1)¼
90.90(3), Cl(1)eRh(1)eP(2)¼89.87(3), P(2)eRh(1)eC(19)¼
89.74(9), C(19)eRh(1)eP(1)¼89.50(9), P(1)eRh(1)eP(2)¼
177.93(3), Cl(1)eRh(1)eC(19)¼179.58(10), Rh(1)eC(19)e
O(7)¼179.5(3).
4.4.2. 3-Methoxy-2,30-bithiophene (4ac)
Isolated yield, 52% (58% NMR yield) from 3-methoxythio-
phene (2a) and 3-iodothiophene (3c) (microwave heating,
200 ꢀC, 30 min). 1H NMR (600 MHz, CDCl3) d 3.92 (s,
3H), 6.88 (d, J¼5.5 Hz, 1H), 7.06 (d, J¼5.5 Hz, 1H), 7.29
(dd, J¼4.8, 2.8 Hz, 1H), 7.38 (dd, J¼4.8, 1.4 Hz, 1H), 7.57
(dd, J¼2.8, 1.4 Hz, 1H). 13C NMR (150 MHz, CDCl3)
d 58.6, 116.0, 116.9, 119.5, 121.1, 125.2, 126.5, 133.3,
153.4. HRMS (ESI-TOF) m/z calcd for C9H9OS2 [MH]þ:
197.0095, found: 197.0094.
4.3. Typical procedure for coupling of heteroarenes and
iodoarenes (conventional heating protocol)
4.3.1. 3-Methoxy-2-phenylthiophene (4aa)
A 20-mL glass vessel equipped with J. YoungÒ O-ring tap,
containing a magnetic stirring bar, was flame-dried under vac-
uum and filled with argon after cooling to room temperature.
To this vessel were added Rh complex 1 (14.9 mg, 12 mmol),
Ag2CO3 (111.9 mg, 0.41 mmol), 1,2-dimethoxyethane
(36.0 mg, 0.40 mmol), 3-methoxythiophene (2a: 68.5 mg,
4.4.3. 2-Phenylthiophene (4ba)23
Isolated yield, 53% (80% NMR yield) from thiophene (2b)
and iodobenzene (3a) (conventional heating, 150 ꢀC, 15 h).

S. Yanagisawa et al. / Tetrahedron 64 (2008) 6073e6081
6079
Molar ratio: 1/2b/3a/Ag2CO3/DME¼0.1:15:1.0:1.0:0. 1H
NMR (600 MHz, CDCl3) d 7.08 (dd, J¼5.5, 3.4 Hz, 1H),
7.26e7.29 (m, 2H), 7.31 (d, J¼3.4 Hz, 1H), 7.38 (t,
J¼8.2 Hz, 2H), 7.62 (d, J¼8.2 Hz, 2H). 13C NMR (150 MHz,
CDCl3) d 123.1, 124.8, 126.0, 127.4, 128.0, 128.9, 134.4, 144.4.
125.33, 128.0, 129.1, 135.7, 137.0, 138.4, 138.5, 141.4,
197.2. HRMS (ESI-TOF) m/z calcd for C16H13OS2 [MH]þ:
285.0408, found: 285.0416.
4.4.9. 2-(p-Acetylphenyl)-4,5-dimethylfuran (4eb)
4.4.4. 2-(p-Acetylphenyl)thiophene (4bb)24
Isolated yield, 64% from 2,3-dimethylfuran (2e) and 4-
iodoacetophenone (3b) (microwave heating, 200 ꢀC, 30 min).
1H NMR (600 MHz, CDCl3) d 1.99 (s, 3H), 2.29 (s, 3H),
2.58 (s, 3H), 6.59 (s, 1H), 7.64 (d, J¼8.2 Hz, 2H), 7.93 (d,
J¼8.2 Hz, 2H). 13C NMR (150 MHz, CDCl3) d 9.9, 11.6,
26.4, 111.1, 116.8, 122.7, 128.9, 134.8, 135.2, 149.1, 149.7,
197.3. HRMS (ESI-TOF) m/z calcd for C14H15O2 [MH]þ:
215.1072, found: 215.1073.
Isolated yield, 83% from thiophene (2b) and 4-iodoaceto-
phenone (3b) (conventional heating, 150 ꢀC, 14 h). Molar
ratio: 1/2b/3b/Ag2CO3/DME¼0.1:15:1.0:1.0:0. 1H NMR
(600 MHz, CDCl3) d 2.61 (s, 3H), 7.12 (dd, J¼4.8, 3.4 Hz,
1H), 7.37 (dm, J¼4.8 Hz, 1H), 7.43 (d, J¼3.4 Hz, 1H), 7.69
(d, J¼7.6 Hz, 2H), 7.96 (d, J¼7.6 Hz, 2H). 13C NMR
(150 MHz, CDCl3) d 26.5, 124.6, 125.6, 126.4, 128.3, 129.1,
135.8, 138.8, 142.9, 197.2.
4.4.10. 2-(p-Cyanophenyl)-4,5-dimethylfuran (4ee)
Isolated yield, 66% from 2,3-dimethylfuran (2e) and
4-iodobenzonitrile (3e) (microwave heating, 150 ꢀC, 30 min).
1H NMR (600 MHz, CDCl3) d 1.99 (s, 3H), 2.29 (s, 3H),
6.59 (s, 1H), 7.59 (d, J¼8.3 Hz, 2H), 7.63 (d, J¼8.3 Hz,
2H). 13C NMR (150 MHz, CDCl3) d 9.8, 11.6, 109.1, 111.7,
117.0, 119.2, 123.1, 132.4, 134.9, 148.9, 149.5. HRMS (ESI-
TOF) m/z calcd for C13H12NO [MH]þ: 198.0919, found:
198.0918.
4.4.5. 2-Ethyl-5-phenylthiophene (4ca)
Isolated yield, 76% (99% NMR yield) from 2-ethylthio-
phene (2c) and iodobenzene (3a) (microwave heating,
200 ꢀC, 30 min). 1H NMR (600 MHz, CDCl3) d 1.34 (t,
J¼7.6 Hz, 3H), 2.86 (q, J¼7.6 Hz, 2H), 6.75 (d, J¼3.4 Hz,
1H), 7.12 (d, J¼3.4 Hz, 1H), 7.23 (t, J¼7.6 Hz, 1H), 7.34 (t,
J¼7.6 Hz, 2H), 7.56 (d, J¼7.6 Hz, 2H). 13C NMR
(150 MHz, CDCl3) d 15.9, 23.6, 122.7, 124.3, 125.5, 127.0,
128.8, 134.8, 141.6, 147.2. HRMS (FAB) m/z calcd for
C12H12S [M]þ: 188.0660, found: 188.0661.
4.4.11. 3-(p-Acetylphenyl)-1-phenylpyrrole (4fb)
4.4.6. 2-(p-Acetylphenyl)-5-ethylthiophene (4cb)
Isolated yield, 58% (86% NMR yield) from 1-phenylpyr-
role (2f) and 4-iodoacetophenone (3b) (microwave heating,
200 ꢀC, 30 min). 1H NMR (600 MHz, CDCl3) d 2.56 (s,
3H), 6.66e6.67 (m, 1H), 7.09e7.11 (m, 1H), 7.24e7.27 (m,
1H), 7.40e7.44 (m, 5H), 7.60 (d, J¼8.3 Hz, 2H), 7.92 (d,
J¼8.3 Hz, 2H). 13C NMR (150 MHz, CDCl3) d 26.4, 108.8,
117.0, 120.5, 120.9, 124.7, 125.6, 126.1, 129.0, 129.7,
134.4, 140.19, 140.22, 197.5. HRMS (FAB) m/z calcd for
C18H15NO [M]þ: 261.1154, found: 261.1153.
Isolated yield, 79% (87% NMR yield) from 2-ethylthio-
phene (2c) and 4-iodoacetophenone (3b) (microwave heating,
200 ꢀC, 30 min). 1H NMR (600 MHz, CDCl3) d 1.34 (t,
J¼7.6 Hz, 3H), 2.58 (s, 3H), 2.87 (q, J¼7.6 Hz, 2H), 6.78
(d, J¼3.4 Hz, 1H), 7.23 (d, J¼3.4 Hz, 1H), 7.61 (d, J¼
8.3 Hz, 2H), 7.92 (d, J¼8.3 Hz, 2H). 13C NMR (150 MHz,
CDCl3) d 15.7, 23.6, 26.5, 124.4, 124.8, 125.0, 129.0, 135.2,
139.1, 140.0, 149.2, 197.2. HRMS (ESI-TOF) m/z calcd for
C14H15OS [MH]þ: 231.0844, found: 231.0843.
4.4.7. 2-Ethyl-5-p-tolylthiophene (4cd)
4.4.12. (p-Acetylphenyl)-1-methylindole (4gb, C-3 arylation
product)
Isolated yield, 50% (64% NMR yield) from 2-ethylthio-
phene (2c) and 4-iodotoluene (3d) (microwave heating,
180 ꢀC, 30 min). 1H NMR (600 MHz, CDCl3) d 1.33 (t,
J¼7.6 Hz, 3H), 2.34 (s, 3H), 2.85 (q, J¼7.6 Hz, 2H), 6.73
(d, J¼3.4 Hz, 1H), 7.07 (d, J¼3.4 Hz, 1H), 7.15 (d, J¼
7.6 Hz, 2H), 7.44 (d, J¼7.6 Hz, 2H). 13C NMR (150 MHz,
CDCl3) d 15.9, 21.1, 23.6, 122.1, 124.2, 125.4, 129.4, 132.0,
136.8, 141.7, 146.6. HRMS (FAB) m/z calcd for C13H14S
[M]þ: 202.0816, found: 202.0819.
Isolated yield, 57%. 1H NMR (600 MHz, CDCl3) d 2.62 (s,
3H), 3.84 (s, 3H), 7.23 (dd, J¼8.3, 6.8 Hz, 1H), 7.31 (dd,
J¼8.3, 6.8 Hz, 1H), 7.34 (s, 1H), 7.38 (d, J¼8.3 Hz, 1H),
7.74 (d, J¼8.3 Hz, 2H), 7.97 (d, J¼8.3 Hz, 1H), 8.02 (d,
J¼8.3 Hz, 2H). 13C NMR (150 MHz, CDCl3) d 26.5, 33.0,
109.8, 115.5, 119.8, 120.5, 122.3, 125.8, 126.6, 127.6,
129.0, 134.2, 137.7, 140.8, 197.6. HRMS (ESI-TOF) m/z calcd
for C17H16NO [MH]þ: 250.1232, found: 250.1234. 4gb0 (C-2
1
arylation product): 23% isolated yield. H NMR (600 MHz,
4.4.8. 5-(p-Acetylphenyl)-2,20-bithiophene (4db)
CDCl3) d 2.66 (s, 3H), 3.79 (s, 3H), 6.66 (s, 1H), 7.16 (dd,
J¼8.2, 6.8 Hz, 1H), 7.29 (dd, J¼8.2, 6.8 Hz, 1H), 7.38 (d,
J¼8.2 Hz, 1H), 7.63 (d, J¼8.3 Hz, 2H), 7.65 (d, J¼8.2 Hz,
1H), 8.06 (d, J¼8.3 Hz, 2H). 13C NMR (150 MHz, CDCl3)
d 26.7, 31.4, 103.0, 109.8, 120.2, 120.8, 122.4, 127.9, 128.6,
129.2, 136.1, 137.4, 138.9, 140.2, 197.6. HRMS (ESI-
TOF) m/z calcd for C17H16NO [MH]þ: 250.1232, found:
250.1224.
Isolated yield, 64% from 2,20-bithiophene (2d) and 4-
iodoacetophenone (3b) (microwave heating, 200 ꢀC, 30 min).
1H NMR (600 MHz, CDCl3) d 2.61 (s, 3H), 7.04 (dd, J¼5.5,
4.1 Hz, 1H), 7.17 (d, J¼3.4 Hz, 1H), 7.23 (d, J¼3.4 Hz,
1H), 7.25 (d, J¼5.5 Hz, 1H), 7.34 (d, J¼4.1 Hz, 1H), 7.67
(d, J¼8.3 Hz, 2H), 7.96 (d, J¼8.3 Hz, 2H). 13C NMR
(150 MHz, CDCl3) d 26.5, 124.1, 124.8, 124.9, 125.27,

6080
S. Yanagisawa et al. / Tetrahedron 64 (2008) 6073e6081
4.5. Coupling of benzene derivatives and iodoarenes
of argon. To this vial were added Rh complex 1 (30.3 mg,
25 mmol), Ag2CO3 (220.1 mg, 0.80 mmol), 2-ethylthiophene
(2c: 224.7 mg, 2.0 mmol), 1,3-diiodobenzene (10: 133.3 mg,
0.40 mmol), and dry m-xylene (2.5 mL). The vial was sealed
and heated with stirring at 150 ꢀC for 30 min in a CEM Dis-
cover microwave apparatus. After the reaction vial was cooled
down to room temperature, the mixture was passed through
a pad of CeliteÒ with copious washing with CHCl3. The fil-
trate was evaporated and the residue was subjected to gel per-
meation chromatography (CHCl3) to afford 11 (74.5 mg, 62%)
4.5.1. Arylation of anisole
A 10-mL flame-dried microwave vial containing a magnetic
stirring bar was fitted with a septum and cooled under a stream
of argon. To this vial were added Rh complex 1 (32.3 mg,
26 mmol), Ag2CO3 (139.9 mg, 0.51 mmol), anisole (5: 1.49 g,
13.8 mmol), and 1-iodo-4-nitrobenzene (3f: 128.5 mg,
0.52 mmol). The vial was sealed and heated with stirring at
200 ꢀC for 30 min in a CEM Discover microwave apparatus.
After the reaction vial was cooled down 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 biaryls
(58.1 mg, 51%) as a mixture of para-isomer (6) and ortho-iso-
1
as pale yellow oil. H NMR (600 MHz, CDCl3) d 1.33 (t,
J¼7.6 Hz, 6H), 2.85 (q, J¼7.6 Hz, 4H), 6.75 (d, J¼3.8 Hz,
2H), 7.15 (d, J¼3.8 Hz, 2H), 7.31 (t, J¼7.6 Hz, 1H), 7.42
(dd, J¼7.6, 2.0 Hz, 2H), 7.73 (t, J¼2.0 Hz, 1H). 13C NMR
(150 MHz, CDCl3) d 15.9, 23.6, 122.6, 123.0, 124.2, 124.3,
129.2, 135.3, 141.2, 147.4. HRMS (ESI-TOF) m/z calcd for
C18H19S2 [MH]þ: 299.0928, found: 299.0927.
1
mer (7). The ratio of 6/7 was determined to be 71:29 by H
NMR analysis. These isomers could be separated by HPLC
(silica gel). 4-Methoxy-40-nitrobiphenyl (6): 1H NMR
(600 MHz, CDCl3) d 3.87 (s, 3H), 7.01 (d, J¼8.9 Hz, 2H),
7.57 (d, J¼8.9 Hz, 2H), 7.67 (d, J¼8.9 Hz, 2H), 8.25 (d,
J¼8.9 Hz, 2H). 13C NMR (150 MHz, CDCl3) d 55.4, 114.6,
124.1, 127.0, 128.5, 131.0, 146.5, 147.1, 160.4. HRMS (FAB)
m/z calcd for C13H11NO3 [M]þ: 229.0739, found: 229.0739.
4.6.2. 5,50-(1,4-Phenylene)bis(2-ethylthiophene) (13)
A 10-mL flame-dried microwave vial containing a magnetic
stirring bar was fitted with a septum and cooled under a stream
of argon. To this vial were added Rh complex 1 (30.4 mg,
25 mmol), Ag2CO3 (225.7 mg, 0.82 mmol), 2-ethylthiophene
(2c: 224.7 mg, 2.0 mmol), 1,4-diiodobenzene (12: 132.8 mg,
0.40 mmol), and dry m-xylene (2.5 mL). The vial was sealed
and heated with stirring at 150 ꢀC for 30 min in a CEM Dis-
cover microwave apparatus. After the reaction vial was cooled
down to room temperature, the mixture was passed through
a pad of CeliteÒ with copious washing with CHCl3. The fil-
trate was evaporated and the residue was subjected to gel per-
meation chromatography (CHCl3) to afford 13 (56.0 mg, 46%)
1
40-Methoxy-2-nitrobiphenyl (7): H NMR (600 MHz, CDCl3)
d 3.80 (s, 3H), 6.98 (d, J¼8.3 Hz, 1H), 7.03 (t, J¼7.6 Hz,
1H), 7.29 (d, J¼7.6 Hz, 1H), 7.36 (dd, J¼8.3, 7.6 Hz, 1H),
7.65 (d, J¼8.9 Hz, 2H), 8.21 (d, J¼8.9 Hz, 2H). 13C NMR
(150 MHz, CDCl3) d 55.6, 111.4, 121.1, 123.2, 128.2, 130.1,
130.3, 130.6, 145.4, 146.6, 156.4. HRMS (FAB) m/z calcd
for C13H11NO3 [M]þ: 229.0739, found: 229.0739.
1
4.5.2. Arylation of 1,3-dimethoxybenzene
as pale yellow solid. H NMR (600 MHz, CDCl3) d 1.34 (t,
A 10-mL flame-dried microwave vial containing a magnetic
stirring bar was fitted with a septum and cooled under a stream
of argon. To this vial were added Rh complex 1 (31.5 mg,
26 mmol), Ag2CO3 (139.7 mg, 0.51 mmol), 1,3-dimethoxyben-
zene (8: 1.90 g, 13.7 mmol), and 1-iodo-4-nitrobenzene (3f:
127.5 mg, 0.50 mmol). The vial was sealed and heated with stir-
ring at 200 ꢀC for 30 min in a CEM Discover microwave appara-
tus. After the reactionvial was cooled down to room temperature,
themixturewaspassedthroughashortsilicagelpad(EtOAc).The
filtratewasevaporatedandtheresiduewassubjectedtogelperme-
ation chromatography (CHCl3) to afford 9 (98.5 mg, 76%) as
pale yellow solid. 2,4-Dimethoxy-40-nitrobiphenyl (9): 1H NMR
(600 MHz, CDCl3) d 3.82 (s, 3H), 3.86 (s, 3H), 6.58 (d,
J¼2.1 Hz, 1H), 6.59 (dd, J¼8.4, 2.1 Hz, 1H), 7.26 (d,
J¼8.4 Hz, 1H), 7.65 (d, J¼8.9 Hz, 2H), 8.21 (d, J¼8.9 Hz, 2H).
13C NMR (150 MHz, CDCl3) d 55.4, 55.5, 99.0, 105.1, 121.0,
123.2, 129.9, 131.3, 145.3, 146.1, 157.5, 161.5. HRMS (FAB)
m/z calcd for C14H13NO4 [M]þ: 259.0845, found: 259.0847.
J¼7.6 Hz, 6H), 2.87 (q, J¼7.6 Hz, 4H), 6.76 (d, J¼3.4 Hz,
2H), 7.13 (d, J¼3.4 Hz, 2H), 7.53 (s, 4H). 13C NMR
(150 MHz, CDCl3) d 15.9, 23.6, 122.6, 124.4, 125.7, 133.4,
141.2, 147.2. HRMS (ESI-TOF) m/z calcd for C18H19S2
[MH]þ: 299.0928, found: 299.0927.
Acknowledgements
The authors are grateful for financial support from Japan
Science and Technology Agency (PRESTO), The Ministry
of Education, Culture, Sports, Science, and Technology
(Grant-in-Aid for Scientific Research), and The Kurata Memo-
rial Hitachi Science and Technology Foundation. We thank
Dr. Atsushi Wakamiya for assistance in X-ray analysis, and
Dr. Olivier Coutelier for valuable discussions.
References and notes
´
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˚
˚
˚
´
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