Ru-catalyzed aerobic oxidative coupling of arylboronic acids with arenes

Article abstract of DOI:10.1039/c0cc04322b

A Ru-catalyzed oxidative coupling of arenes with boronic acids using molecular oxygen via direct C-H activation is reported. Both the scope and the mechanism of the process are discussed.

Full text of DOI:10.1039/c0cc04322b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Ru-catalyzed aerobic oxidative coupling of arylboronic acids
with arenesw
Hong Li,a Wei Wei,a Yuan Xu,a Chao Zhanga and Xiaobing Wan*ab
Received 9th October 2010, Accepted 27th October 2010
DOI: 10.1039/c0cc04322b
Table 1 Optimization of the reaction conditionsa
A Ru-catalyzed oxidative coupling of arenes with boronic acids
using molecular oxygen via direct C–H activation is reported.
Both the scope and the mechanism of the process are discussed.
The Suzuki-Miyaura reaction, cross coupling between aryl
halide and boronic acid, was among the most powerful method-
ologies available for the construction of C–C bonds and
has found widespread use in synthesis of pharmaceuticals,
materials and fine-chemicals.1 Recently, the oxidative coupling
reaction of arenes with boronic reagents via direct C–H
arylation is playing an increasingly important role in organic
synthesis since it avoids the necessary pre-halogenation to
make synthetic schemes shorter and more efficient.2 Several
transition-metal complexes based on palladium,3 iron,4
copper5 and rhodium6 have demonstrated high activity for
such catalytic reactions. Although these are elegant method-
ologies, most of them required one or more equivalents of these
often hazardous or toxic oxidizing agents. Notably, Kakiuchi
et al.7 and Sames et al.,8 in their pioneering work, disclosed an
efficient method for Ru-catalyzed C–H arylation with aryl-
boronates. In these cases, Ru(0) species participate in a C–H
bond cleavage step via oxidative addition. A shortcoming of
this methodology was that aryl boronic acids were not suitable
coupling partners. We describe here a direct arylation of arene
with aryl boronic acids which employs molecular oxygen as the
ultimate, stoichiometric oxidant.
Entry Catalyst
Additive Oxidant
Solvent Yieldb
1
2
3
RuCl3
[Ru(C6H6)Cl2]2
[Ru(PPh6)Cl2]2
BiBr3
BiBr3
BiBr3
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
Toluene 42%
Toluene 68%
Toluene 72%
Toluene 78%
Toluene 40%
Toluene N.O.
Toluene 56%
Toluene 19%
4
5
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2
—
—
BiBr3
6c
7d
8e
9
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
[Ru(cymene)Cl2]2 BiBr3
Xylene
49%
10
11
12
13
14
15
16
17
18
19
CH3NO2 8%
Dioxane 34%
DCE
71%
Trace
15%
45%
11%
DMF
PrOH
THF
MeCN
Benzoquinone Toluene Trace
Toluene Trace
Toluene Trace
H2O2
NaClO
a
All reactions were carried out in the scale of 0.2 mmol in 2.0 mL of
solvent in the presence of 3.0 equiv. KHCO3, 5 mol% Ru catalyst and
20 mol% BiBr3 under 1 atm molecular oxygen for 24 h unless noted
b
c
d
otherwise. Isolated yields. Not observed. In the absence of
e
KHCO3. Under an argon atmosphere.
Our investigation began by examining Ru-catalyzed coupling
between 2-o-tolylpyridine (1a) and phenylboronic acid (2a).9
With [Ru(cymene)Cl2]2 as a catalyst, the desired product (3a)
was achieved in moderate yield (Table 1, entry 5). Interestingly,
simple addition of BiBr3 enhanced the conversion in a
remarkable manner, resulting in the desired product in 78%
yield (Table 1, entry 4).
amount of 3a was observed when other common oxidants were
employed (Table 1, entries 17–19). The effect of the solvent was
dramatic. Among the various solvents examined, toluene was
the most suitable for the reaction under the catalytic system
(Table 1, entries 9–16). Replacement of toluene with other
solvents led to decreased yield.
Table 1 provided information on the impact of catalyst,
oxidant, solvent and additive on the efficiency of this process.
In the absence of [Ru(cymene)Cl2]2, no desired product 3a was
formed (Table 1, entry 6). When other Ru catalysts were used,
product 3a was achieved in moderate to good yield (Table 1,
entries 1–3). Another feature of the transformation was that
the use of molecular oxygen as the oxidant was essential for
efficient conversion, as demonstrated by the fact that only trace
Having established the optimized reaction conditions, we
initiated investigations into the scope of the new C–H
arylation. The transformation exhibits a broad scope and a
high tolerance for a variety of functional groups, as shown in
Table 2.
Both electron-rich and electron-poor arylboronic acids
participated in this reaction. The arylboronic acids with
electron-withdrawing substituents were somewhat more reactive
than the arylboronic acids with electron-donating substituents.
Substrates bearing halogen, F, Cl, Br, and I, were also efficiently
converted into the corresponding products in high yields,
without loss of halogen functions. Replacement of 2-o-tolyl-
pyridine (1a) with 2-(2-fluorophenyl)pyridine and 2-(biphenyl-2-yl)
pyridine also led to the desired products 3h and 3o in high
yields respectively.
a Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China.
E-mail: wanxb@suda.edu.cn; Fax: +86-0512-65880890;
Tel: +86-0512-65880334
b Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and characterization data for 3a–3o and
5a–5h. See DOI: 10.1039/c0cc04322b
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1497–1499 1497

View Article Online
Table 2 Pyridine-directed C–H arylation with aryl boronic acids
implied that C–H bond cleavage might be involved in the rate-
limiting step (eqn (1)).10
ð1Þ
On addition of D2O to the reaction system in the absence of
boronic acid, deuterium was incorporated into the starting
materials (eqn (2)). In the presence of boronic acid, both
product and D-incorporated starting material were detected
(eqn (3)). Based upon the above results, we reasoned that the
initial C–H bond cleavage and subsequent transmetalation
with boronic acid were involved in the catalytic cycle.
ð2Þ
ð3Þ
Next, further experiments were carried out to elucidate the
role of the BiBr3. Under an argon atmosphere, 19% yield was
observed in the presence of 20 mol% BiBr3. However, only
trace amount of product was generated in the absence of BiBr3
(eqn (4)).11
We envisioned expanding the scope of this reaction to
include other useful nitrogen-containing directing groups. As
shown in Table 3, 1-o-tolyl-1H-pyrazole (4a) and a variety of
aryl boronic acids were subjected to the optimized conditions,
leading to the corresponding products in moderate to good
yields.
To probe the mechanistic information, deuterated substrates
have been synthesized and subjected to the standard conditions.
A kinetic isotope effect (kH/kD = 1.5) was observed, which
ð4Þ
Table 3 Pyrazole-directed C–H arylation with aryl boronic acids
ð5Þ
Pfeffer et al. reported C–H bond electrophilic activation
between [Ru(benzene)Cl2]2 and 2-phenylpyridine.12 Recently,
several groups reported C–H activation by cooperative
action of Ru(II) catalyst and base (concerted metalation-
deprotonation pathway).13 Notably, only moderate yield was
observed in our transformation in the absence of base (Table 1,
entry 7). For a substrate bearing a strong electron-withdrawing
group, low conversion was observed (eqn (5)).
On the basis of the above results, we proposed a plausible
mechanism given in Scheme 1 for the Ru-catalyzed aerobic
arylation of arenes. Following initial C–H activation,
c
1498 Chem. Commun., 2011, 47, 1497–1499
This journal is The Royal Society of Chemistry 2011

View Article Online
M. Lautens, Chem.–Eur. J., 2009, 15, 5874; (l) C. Jia, T. Kitamura
and Y. Fujiwara, Acc. Chem. Res., 2001, 34, 633; (m) V. Ritleng,
C. Sirlin and M. Pfeffer, Chem. Rev., 2002, 102, 1731; (n) H. M.
L. Davies and J. R. Manning, Nature, 2008, 451, 417; (o) S. S. Stahl,
J. A. Labinger and J. E. Bercaw, Angew. Chem., Int. Ed., 1998, 37,
2180; (p) K. Godula and D. Sames, Science, 2006, 312, 67.
3 (a) X. Chen, C. E. Goodhue and J. Q. Yu, J. Am. Chem. Soc., 2006,
128, 12634; (b) R. Giri, N. Maugel, J. J. Li, D. H. Wang,
S. P. Breazzano, L. B. Saunders and J. Q. Yu, J. Am. Chem.
Soc., 2007, 129, 3510; (c) Z. J. Shi, B. J. Li, X. B. Wan, Z. Fang,
B. Cao, C. M. Qin and Y. Wang, Angew. Chem., Int. Ed., 2007, 46,
5554; (d) B.-F. Shi, N. Maugel, Y.-H. Zhang and J.-Q. Yu, Angew.
Chem., Int. Ed., 2008, 47, 4882; (e) D.-H. Wang, M. Wasa, R. Giri
and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 7190; (f) D.-H. Wang,
T.-S. Mei and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 17676;
(g) T. Nishikata, A. R. Abela, S. Huang and B. H. Lipshutz, J. Am.
Chem. Soc., 2010, 132, 4978; (h) H. Zhou, W.-J. Chung, Y.-H. Xu
and T.-P. Loh, Chem. Commun., 2009, 3472; (i) S.-D. Yang,
C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li and Z.-J. Shi, Angew.
Chem., Int. Ed., 2008, 47, 1473; (j) J.-H. Chu, C.-C. Chen and
M.-J. Wu, Organometallics, 2008, 27, 5173; (k) J. Zhao, Y. Zhang
and K. Cheng, J. Org. Chem., 2008, 73, 7428.
4 J. Wen, J. Zhang, S.-Y. Chen, J. Li and X.-Q. Yu, Angew. Chem.,
Int. Ed., 2008, 47, 8897.
5 O. Basle and C.-J. Li, Org. Lett., 2008, 10, 3661.
´
Scheme 1 Plausible reaction mechanism.
transmetalation with boronic acid produces the intermediate
B. This intermediate subsequently generates the desired
product and Ru(0) species via reductive elimination. Finally,
the Ru(0) species is re-oxidized to Ru(II) species by cooperative
action of molecular oxygen and BiBr3.
6 (a) K. Ueura, T. Satoh and M. Miura, Org. Lett., 2005, 7, 2229;
(b) T. Vogler and A. Studer, Org. Lett., 2008, 10, 129;
(c) S. Kirchberg, T. Vogler and A. Studer, Synlett, 2008, 2841.
7 (a) F. Kakiuchi, S. Kan, K. Igi, N. Chatani and S. Murai, J. Am.
Chem. Soc., 2003, 125, 1698; (b) F. Kakiuchi, Y. Matsuura, S. Kan
and N. Chatani, J. Am. Chem. Soc., 2005, 127, 5936; (c) S. Ueno,
T. Kochi, N. Chatani and F. Kakiuchi, Org. Lett., 2009, 11, 855;
(d) S. Ueno, N. Chatani and F. Kakiuchi, J. Org. Chem., 2007, 72,
3600; (e) K. Kitazawa, T. Kochi, M. Sato and F. Kakiuchi, Org.
Lett., 2009, 11, 1951.
In summary, we developed a novel Ru-catalyzed oxidative
coupling of arylboronic acids with arenes via direct C–H
arylation. Both pyridine and pyrazole can be used to mediate
the direct C–H activation step. Notably, O2 participates as the
ideal oxidant under mild conditions. The transformation
appeared to be highly compatible toward various functional
groups. Further studies to elucidate the detailed mechanism as
well as to expand the scope of the Ru-catalyzed C–H activation
are underway in our lab.
8 S. J. Pastine, D. V. Gribkov and D. Sames, J. Am. Chem. Soc.,
2006, 128, 14220.
9 For selected examples on pyridine-directed C–H activation, see:
(a) L. Ackermann, R. Vicente and A. Althammer, Org. Lett., 2008,
10, 2299; (b) H.-Y. Thu, W.-Y. Yu and C.-M. Che, J. Am. Chem.
Soc., 2006, 128, 9048; (c) A. R. Dick, K. L. Hull and M. S. Sanford,
J. Am. Chem. Soc., 2004, 126, 2300; (d) J. Norinder, A. Matsumoto,
N. Yoshikai and E. Nakamura, J. Am. Chem. Soc., 2008, 130, 5858;
(e) J. M. Racowski, A. R. Dick and M. S. Sanford, J. Am. Chem.
Soc., 2009, 131, 10974; (f) K. Cheng, B. Yao, J. Zhao and Y. Zhang,
Org. Lett., 2008, 10, 5309; (g) Z. Ye, W. Wang, F. Luo, S. Zhang
and J. Cheng, Org. Lett., 2009, 11, 3974; (h) P. B. Arockiam,
C. Fischmeister, C. Bruneau and P. H. Dixneuf, Angew. Chem., Int.
Ed., 2010, 49, 6629; (i) X. Zhao and Z. Yu, J. Am. Chem. Soc., 2008,
130, 8136.
Notes and references
1 For reviews on Suzuki-Miyaura reaction, see: (a) N. Miyaura and
A. Suzuki, Chem. Rev., 1995, 95, 2457; (b) S. R. Chemler,
D. Trauner and S. J. Danishefsky, Angew. Chem., Int. Ed., 2001,
40, 4544; (c) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew.
Chem., Int. Ed., 2005, 44, 4442; (d) H. Doucet, Eur. J. Org. Chem.,
2008, 2013; (e) S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron,
2002, 58, 9633.
2 For reviews on C–H activations, see: (a) D. A. Colby,
R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624;
(b) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem., Int.
Ed., 2009, 48, 9792; (c) O. Daugulis, H.-Q. Do and D. Shabashov,
Acc. Chem. Res., 2009, 42, 1074; (d) X. Chen, K. M. Engle,
D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48,
5094; (e) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (f) I. A.
I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and
J. F. Hartwig, Chem. Rev., 2010, 110, 890; (g) F. Collet,
R. H. Dodd and P. Dauban, Chem. Commun., 2009, 5061;
(h) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147;
(i) G. E. Dobereiner and R. H. Crabtree, Chem. Rev., 2010, 110,
681; (j) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer and
O. Baudoin, Chem.–Eur. J., 2010, 16, 2654; (k) P. Thansandote and
10 (a) B. Butschke, D. Schroder and H. Schwarz, Organometallics,
¨
2009, 28, 4340; (b) J. A. Mueller and M. S. Sigman, J. Am. Chem.
Soc., 2003, 125, 7005.
11 For Bi-catalyzed aerobic oxidation, see: (a) T. Shido, G. Okita,
K. Asakura and Y. Iwasawa, J. Phys. Chem. B, 2000, 104, 12263;
(b) K. Belkacemi and S. Hamoudi, Ind. Eng. Chem. Res., 2010, 49,
6878.
12 S. Fernandez, M. Pfeffer, V. Ritleng and C. Sirlin, Organometallics,
1999, 18, 2390.
13 For selected examples on this topic, see: (a) Y. Boutadla,
D. L. Davies, S. A. Macgregor and A. I. Poblador-Bahamonde,
Dalton Trans., 2009, 5820; (b) D. Balcells, E. Clot and
¨
O. Eisenstein, Chem. Rev., 2010, 110, 749; (c) I. Ozdemir,
S. Demir, B. Cetinkaya, C. Gourlaouen, F. Maseras, C. Bruneau
and P. H. Dixneuf, J. Am. Chem. Soc., 2008, 130, 1156; (d) See
¸
ref. 9a and h.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1497–1499 1499