Palladium-catalyzed direct C-H arylation of unactivated arenes with aryl Halides

Article abstract of DOI:10.1016/j.tetlet.2011.07.046

An efficient palladium-catalyzed direct C-H arylation of unactivated arenes has been discovered. This method employs aryl halides as the direct coupling partners with arenes without using any external ligands. This catalysis opens a new methodology for the preparation of symmetrical as well as unsymmetrical biaryls in a user-friendly approach.

Full text of DOI:10.1016/j.tetlet.2011.07.046

Tetrahedron Letters 52 (2011) 4916–4919
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Tetrahedron Letters
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Palladium-catalyzed direct C–H arylation ofunactivated arenes with aryl Halides
WenKun Hong a,b, Yatao Qiu a, Zhiyi Yao c, Zhaoyang Wang b, Sheng Jiang a,
⇑
a Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China
b School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China
c Shanghai Institute of Technology, Shanghai 210032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2011
Revised 7 July 2011
Accepted 12 July 2011
Available online 8 August 2011
An efficient palladium-catalyzed direct C–H arylation of unactivated arenes has been discovered. This
method employs aryl halides as the direct coupling partners with arenes without using any external
ligands. This catalysis opens a new methodology for the preparation of symmetrical as well as unsym-
metrical biaryls in a user-friendly approach.
Ó 2011 Elsevier Ltd. All rights reserved.
The biaryl motifs are widely present in pharmaceuticals, herbi-
cides, natural products, and materials.1 A lot of efficient catalytic
systems have been developed in the past few decades on the area
of aryl–aryl bond formation from aryl halides and aryl organome-
tallics.2 Despite the significant progress achieved in these estab-
lished methods, they suffer from some drawbacks, such as
handling of air and moisture sensitive Grignard type or related re-
agents, and generating stoichiometric amounts of sometimes toxic
metal salts as the reaction byproducts etc. Therefore, direct C–H
arylation of arenes with aryl halides is an attractive approach for
aryl–aryl bond formation as a environment friendly methodol-
ogy.3,4 Among these C–H bond activation reactions reported, the
most dominant class involves the use of a directing group to direct
a transition metal into a C–H bond,5 or to facilitate transition metal
oxidative addition of C–X bond.6 However, direct arylation of unac-
tivated arenes in the absence of directing groups has received little
attention. Recently, few reports on the arylation of benzene7 and
other electron-poor arenes,8 have been reported for biaryl motifs
synthesis. The synthetic scope of this reaction, however, is greatly
limited by the harsh reaction conditions such as the limited scope
of substrates, and requires several reagents. It is highly desirable
to develop a new method to further improve the efficiency and
generality of this reaction. Herein we report a facile, high-yielding,
Pd-catalyzed direct arylation reaction without any directing
groups.
and no product was obtained in such cases (Table 1, entry 7 and
8). Trace amounts of biphenyl were also detected by GC–MS. The
results of the preliminary exploratory investigations described
above showed that the optimal conditions for the cross coupling
reaction of 4-methyl iodobenzene and benzene involve the use of
10 mol % Pd(OAc)2, and 1.0 equiv AgNO3 at 110 °C.
The scope of the Pd(OAc)2/AgNO3 catalyst system was explored
under the optimum conditions. As shown in Table 2, the coupling
reactions for most of the substrates examined gave 52–89% yield
at 110 °C.9 Electron-rich aryl iodides show better reactivity than
electron-deficient ones. Initially, we extended the reaction condi-
tions to the coupling of methoxyl or CF3O substituents on the phe-
nyl ring of aryl iodides and benzene and found that, in all cases, the
reaction gave excellent yields (67–89%) (entries 1, 2, 9). And the
substitution pattern made little difference to the reaction outcome
(entries 1, 2). Even the coupling of the electron-deficient aryl io-
dides, such as nitrobenzene, ethyl benzoate, methyl benzoate,
and biaryl with benzene, good yields (52–77%) were also achieved
(entries 3–8). Noteworthy is the fact that the coupling of the steri-
cally hindered 2-nitrobenzene with benzene gave the coupling
product in 67% yield (entry 5). It is important to note that the direct
arylation of unactivated arenes, such as toluene, and 1,4-difluoro-
benzene, very challenging substrates combination, were also
accomplished in good yield by using the present catalyst system
(entries 10–12).
4-Methyl iodobenzene and benzene were selected as model
substrates to evaluate the catalytic activity of systems in this cross
coupling reaction. Using Pd(OAc)2 as the catalyst and benzene as
the solvent, reactions employing different salts, including AgOAc,
AgO2CCF3, Cu(OAc)2, and AgNO3 were explored. The results
showed that the highest yield (95%, Table 1, entry 3) was obtained
when AgNO3 was employed. Additives were much less effective,
Extension of the present catalyst system to aryl bromides is
promising and the results are shown in Table 3.10 All the examined
aryl bromides coupled with benzene with good yields at 150 °C.
High yields were obtained even for those aryl bromides with an
electron-withdrawing group (entries 1–3 and 6). Polysubstituted
aryl bromides also worked well (entries 5 and 6). Interestingly,
the catalyst system also showed high selectivity in the presence
of multiple potentially reactive groups. For example, the cross cou-
pling of 2-bromo-4-chloro-1-iodobenzene with benzene was also
tested, and the corresponding products were isolated in 50% yield,
leaving the chloride atom untouched which is highly desirable in
⇑
Corresponding author. Tel.: +86 20 32015318; fax: +86 20 32290606.
E-mail address: jiang_sheng@gibh.ac.cn (S. Jiang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.046

WenKun Hong et al. / Tetrahedron Letters 52 (2011) 4916–4919
4917
Table 1
Pd(OAc)2-catalyzed cross-coupling of p-tolyl iodide with benzenea
Pd(OAc)2, Ag salt (1.0 eq)
Additive (1.0 eq), T
H3C
+
I
H3C
3a
1a
2a
Entry
Pd source
Ag
Additive
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (0.1 equiv)
Pd(OAc)2 (0.1 equiv)
Pd(OAc)2 (0.1 equiv)
Pd(OAc)2 (0.05 equiv)
Pd(OAc)2 (0.1 equiv)
Pd(OAc)2 (0.1 equiv)
Pd(OAc)2 (0.1 equiv)
Pd(OAc)2 (0.1 equiv)
AgOAc
AgO2CCF3
AgNO3
AgNO3
AgNO3
Cu(OAc)2
AgNO3
AgNO3
None
None
None
None
None
None
HOAc
Cs2CO3
125
127
125
125
110
100
100
100
24
27
17
27
26
24
24
24
67
62
95
72
94
13
0
0
a
Compound 1a (0.5 mmol), 2a (2 mL), Pd(OAc)2 (0.05 mmol), AgNO3(85 mg, 0.5 mmol), Ar, 110 °C, 26 h.
Isolated yield.
b
Table 2
Pd(OAc)2-catalyzed direct arylation of arenes with aryl iodidesa
10 mol% Pd(OAc)2
1.0 equiv AgNO3
R2
I
+
H
R1
R1
R2
110 o
C
3
1
2
Entry
1
Product
Time (h)
16
Yieldb (%)
Entry
7
Product
Time (h)
Yieldb (%)
66
O
O
Ph
Ph
70
28
48
24
11
MeO
3b
3h
O
Ph
Ph
Ph
2
3
4
10
40
36
89
72
69
8
52
60
77
3i
3c
3d
O2N
O2N
Ph
F3CO
O
Ph
9
3j
Ph
10
3k
3e
(o/m/p =5/3/2)
NO2
O
Ph
5
6
11
48
67
77
11
12
48
48
40c
40
3f
3l
(o/m/p =7/6/2)
F
EtO2C
Ph
O
3g
F
3m
a
b
c
Compound 1 (0.5 mmol), 2 (4 mL), 10 mol % Pd(OAc)2, AgNO3 (0.5 mmol), Ar, 110 °C.
Isolated yield.
At 120 °C.
the synthesis of complex molecules through sequential orthogonal
cross-couplings (entry 8). In addition, the double coupling also
took place smoothly when 1-iodo-4-bromobenzene was used as
a substrate and the desired terphenyl was isolated in moderate
yields (45%) (entry 7).
conducted (Scheme 1). The observed high KH/KD value (5.01) re-
vealed that C–H cleavage of benzene was involved in the rate-
determining step.
Based on these results, we propose the reaction mechanism as
shown in Scheme 2. The palladium inserts into the benzene ring
to generate arylpalladium species 6. Then Ag-assisted oxidative
addition afforded the corresponding biarylpalladium species 7,
which underwent reductive elimination to generate the product
To investigate the reaction mechanism,
a
competition
experiment using an equimolar mixture of benzene (45 equiv)
and benzene-d6 (45 equiv) with 3-iodoanisole was further

4918
WenKun Hong et al. / Tetrahedron Letters 52 (2011) 4916–4919
Table 3
Pd(OAc)2-catalyzed direct arylation of arenes with aryl bromidesa
R2
10 mol% Pd(OAc)2
R2
Br +
H
R1
R1
1.0 equiv AgNO3
150 oC
5
4
2
Entry
1
Product
Time (h)
Yieldb (%)
Entry
Product
Time (h)
36
Yieldb (%)
80c
O2N
Ph
H3CO
Ph
48
80c
5
3c
5e
NO2
O2N
Ph
Ph
2
36
71
6
48
85
3e
5f
NO2
Ph
Ph
Cl
Ph
3
4
48
48
80
77
7
8
24
48
45c
50
3i
3f
F3CO
Ph
Ph
Ph
3j
5h
a
b
c
Compound 1 (0.5 mmol), 2 (4 mL), 10 mol % Pd(OAc)2, AgNO3 (0.5 mmol), Ar, 150 °C, 24 h.
Isolated yield.
At 120 °C.
prepare biaryls without any directing groups. This methodology
showed great functional group tolerance and high selectivity in
the presence of multiple potentially reactive groups at higher tem-
peratures. Further studies directed toward a detailed mechanistic
investigation are in progress.
H3CO
H3CO
2a
10 mol% Pd(OAc)2
3c
(45 equiv)
+
I
1.0 equiv AgNO3
110 oC, 10h
D
D
D
D
D
H3CO
1c
Acknowledgments
D
(1.0 equiv)
D
D
D
This research was supported by a grant from the National Nat-
ural Science Foundation (No. 20802078, 20972160, and 20772035),
973 Program (2009CB940900), the Key Project of the Knowledge
Innovation Program of the Chinese Academy of Sciences (KSCX2-
YW-R-215), Shanghai University Distinguished Professor (Eastern
scholars) Program (DF2009-02), Pujiang Talent Plan Project
(09PJ1409200) and the National Major Scientific and Technological
Program for Drug Discovery (2009ZX09103-101).
D
D
3c-d6
80% yield, KH/KD = 5.01
2a-d6
(45 equiv)
Scheme 1. Kinetic isotopic effects experiment.
2a
Supplementary data
OAc
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.046.
Pd
PdII
6
I
References and notes
-
NO3
AgI
Ph
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In summary, we have developed an unprecedented oxidative
cross-coupling between aryl halides with unactivated arenes to

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9. General procedure for cross-coupling of aryl iodides with arenes. Aryl iodides
(0.5 mmol) and AgNO3 (85 mg, 0.5 mmol) and Pd(OAc)2 (11.2 mg, 0.05 mmol)
were added to Schlenk tubes. Benzene (4 ml) was added to the tubes using a
syringe. The mixture was then stirred in a sealed tube under argon atmosphere.
Then the mixture was stirred at 110 °C until complete consumption of the
starting material was monitored by TLC. After completion of the reaction, the
mixture was diluted with ethyl acetate, passed through a fritted glass filter to
remove the inorganic salts and the solvent was removed with the aid of a
rotary evaporator. The residue was purified by column chromatography on
silica gel using petroleum ether/ethyl acetate as eluent to provide the desired
product.
10. General procedure for cross-coupling of aryl bromides with benzene. Aryl
bromides (0.5 mmol) and AgNO3 (85 mg, 0.5 mmol) and Pd(OAc)2 (11.2 mg,
0.05 mmol) were added to Schlenk tubes. Benzene (4 ml) was added to the
tubes using a syringe. The mixture was then stirred in a sealed tube under
argon atmosphere. Then the mixture was stirred at 150 °C until complete
consumption of the starting material was monitored by TLC. After completion
of the reaction, the mixture was diluted with ethyl acetate, passed through a
fritted glass filter to remove the inorganic salts and the solvent was removed
with the aid of an rotary evaporator. The residue was purified by column
chromatography on silica gel using petroleum ether/ethyl acetate as eluent to
provide the desired product.
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