Highly efficient Suzuki-Miyaura coupling reactions catalyzed by bis(oxazolinyl)phenyl-Pd(II) complex

Article abstract of DOI:10.1016/j.tetlet.2007.03.063

Bis(oxazolinyl)phenyl-palladium(II)(Phebox-Pd) complexes were found to be efficient catalysts for Suzuki-Miyaura coupling reactions of aryl boronic acids and their derivatives with aryl halides to give the corresponding biaryl products in high yield along with moderate enantioslectivities in the case of axially chiral induction. The catalytic activity was attained more than 900,000 of TON and 45,000 of TOF. The catalyst can be recovered quantitatively and could be reused for Suzuki-Miyaura reactions.

Full text of DOI:10.1016/j.tetlet.2007.03.063

Tetrahedron Letters 48 (2007) 3397–3401
Highly efficient Suzuki–Miyaura coupling reactions catalyzed
by bis(oxazolinyl)phenyl–Pd(II) complex
a
a,
a
a
*
Toshihide Takemoto, Seiji Iwasa, Hiroshi Hamada, Kazutaka Shibatomi,
b
c
d
Masayuki Kameyama, Yukihiro Motoyama and Hisao Nishiyama
a
Department of Materials Science, Toyohashi University of Technology, Tempaku-cho, Toyohashi 441-8580, Japan
Department of Materials Chemistry and Bioengineering, Oyama National College of Technology, Nakakuki, Oyama,
Tochigi 323-0806, Japan
b
c
Institute of Materials Chemistry and Engineering, Division of Applied Chemistry Research Section of Cluster Chemistry,
Kyushu University, Kasuga, Fukuoka 816-8580, Japan
Graduate School of Engineering, Department of Applied Chemistry, Nagoya University, Chikusa, Nagoya 464-860, Japan
d
Received 2 February 2007; revised 6 March 2007; accepted 9 March 2007
Available online 13 March 2007
Abstract—Bis(oxazolinyl)phenyl–palladium(II)(Phebox–Pd) complexes were found to be efficient catalysts for Suzuki–Miyaura cou-
pling reactions of aryl boronic acids and their derivatives with aryl halides to give the corresponding biaryl products in high yield
along with moderate enantioslectivities in the case of axially chiral induction. The catalytic activity was attained more than 900,000
of TON and 45,000 of TOF. The catalyst can be recovered quantitatively and could be reused for Suzuki–Miyaura reactions.
Ó 2007 Elsevier Ltd. All rights reserved.
We recently reported enantioselective carbon–carbon
bond forming reactions such as allylation, alkylations,
aldol type reactions, hetero Diels–Alder reactions, and
Michael reactions using tridentate chiral Lewis acid
catalysts, which were a series of 2,6-bis(oxazolinyl)-
phenyl(phebox)/transition metal complexes (1) involv-
view, since pincer type ligands and their transition metal
complexes have been proven to be highly active catalysts
in organic synthesis. Our initial research in this area is
described herein. A series of phebox ligands were syn-
thesized from 2-chloro-xylene in five steps in 50–60%
isolated yields. Previous studies have shown that phe-
box–transition metal complexes can be prepared by
3
ing a carbon–transition metal bond in C -symmetry
2
1
chiral environment as shown below (Fig. 1).
transmetalation of the low valent transition metals to
2
2
-stannyl-1,3-bis(oxazolinyl)benzene derivatives. We
During the course of our continuous studies on the
development of phebox ligands, we became interested
in phebox–Pd complexes for the carbon–carbon bond
forming reaction including oxidative addition and
reductive elimination process in mechanistic point of
elected to pursue a different approach to the synthesis
of phebox–Pd complexes that did not depend on the
use of organo tin compound 2a (Scheme 1).
2
Denmark et al. had previously shown that oxidative
addition of palladium(0) could be used for the conver-
sion of 1-bromo-2,6-bis(oxazolinyl)benzene derivatives
4
to phebox–Pd(II). The desire phebox–Pd complexes
O
O
were obtained in high yields by using slightly modified
method of Denmark, Richards, and van Kotene’s
research group. 1-Chloro-2,6-bis(oxazolinyl)benzene
was treated with Pd(0) in toluene at 80 °C for 5 h under
N
N
M
Ln
R
R
1
: phebox-MLn
N atmosphere to give the corresponding phebox–Pd
2
Figure 1.
complex via oxidative addition in high yield. Specifi-
cally, we investigated the reaction of a phenylboronic
acid with an aryl halide, namely Suzuki–Miyaura cou-
*
Corresponding author. Tel.: +81 532 44 6817; fax: +81 532 48
833; e-mail: iwasa@tutms.tut.ac.jp
5
5
pling reaction, using catalysis by a chiral phebox–Pd(II)
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.063

3398
T. Takemoto et al. / Tetrahedron Letters 48 (2007) 3397–3401
PdCl (PhCN)2
2
O
O
O
O
or [Pd (dba) ]CHCl
2
3
3
toluene
N
N
N
X
N
Pd
Cl
2
2
a: X=SnMe3
b: X=Cl
3: i-Pr-phebox-PdCl
Scheme 1.
cat.,3
(
S/C = 20)
K CO (5 equiv.)
2
3
I
(HO) B
2
DMF, 90 °C, 14 h
4
5
6: 95%yield
O
O
N
N
Pd
I
i
-Pr
i-Pr
7: i-Pr-phebox-PdI
Scheme 2.
complex since palladium catalyst has been proven to be
a wide variety for catalytic chemical process. The reac-
tion of phenyl boronic acid and iodobenzene proceeded
smoothly in the presence of 5 mol % of phebox–Pd(II)
without any palladium black or metal aggregations to
give the corresponding biphenyl in quantitative yield
to room temperature followed by removal of the solvent
and the residue was purified by flash column chromato-
graphy on silica gel to give the corresponding biaryl cou-
pling product in high yield along with recovery of the
catalyst in quantitative yield.
(
Scheme 2). Surprisingly, the catalyst was completely
Various aryl boronic acids were screened using phebox–
Pd(II) catalyst (Scheme 3). Phebox–Pd(II) catalyst
worked well in the various substrates for Suzuki–Miya-
ura coupling reactions. Boronic acids involving both
electron withdrawing groups and electron donating
groups such as nitro, carbonyl and methoxy functional
groups also gave high yields (10a–i) and high recovery
of the catalyst. In the case of chloro- and bromo-aryl
compounds, the catalytic activity was decreased and
further high temperature and long reaction time seem
to be necessary (10d–f and 10i). Boronic esters also
screened and found to react well with aryl halides in
the presence of phebox–Pd catalyst resulting in high
yields (Scheme 4). Aryl boronic esters 11 were reacted
with aryl iodides in the presence of catalyst 3 (S/C =
10,000) to give the corresponding aryl coupling products
in high yields. With ester group substituted aryl boronic
ester in methanol or ethanol, methyl or ethyl ester was
observed as a side product (entry 4) (Table 2).
recovered after simple column chromatography on silica
gel and the structure was determined as phebox–PdI by
elemental analysis and NMR, which could be reused for
Suzuki–Miyaura coupling reaction and gave same level
of catalytic activity.
We screened several solvents and catalytic activity for
the reaction of aryl boronic acid with iodobenzene
(
the Suzuki–Miyaura coupling reaction worked well in
many different type of organic solvents. Interestingly,
even in water phase, biphasic and no solvent reaction
condition, the reaction was efficiently proceeded (entries
Table 1). Phebox–Pd(II) complexes as catalysts for
3
, 6, and 8). Furthermore, the catalyst can be recovered
in high yields for every cases (entries 1–10). As these
results, we choose i-PrOH as a solvent for further opti-
mization because of its cost merit, easy handling, and
low toxicity. Catalytic activity in i-PrOH was briefly
examined and attained more than 900,000 of TON
and 45,000 of TOF (entries 11–15).
On the other hand, Jones, et al., and Eberhard, et al.,
reported independently that the true catalyst related
pincer transition metal complexes were metallic form
derived from the decomposition of the complex based
Standard reaction condition was as follows: a mixture of
aryl boronic acid 5 (0.22 mmol), aryl halide (0.23 mmol)
and catalytic amount of i-Pr–phebox–Pd(II) (3)
6
on their observations. The pincer catalysts such as
(
0.011 mmol, S/C = 20) in i-PrOH (1.0 mL) was heated
PCP, SCS or SCN–Pd(II) complexes merely act as only
precatalysts. In order to find out mechanistic informa-
tion on phebox–Pd(II) catalyzed reaction, this coupling
to 90 °C under N atmosphere for 14 h. Restricted N
atmosphere was unnecessary during the reaction. At
the end of this period, the reaction mixture was cooled
2
2
1
reaction was monitored by H NMR resulting in no

T. Takemoto et al. / Tetrahedron Letters 48 (2007) 3397–3401
3399
Table 1. Solvent effect and catalytic activities for phebox–Pd(II) catalyzed Suzuki–Miyaura coupling reactions of iodobenzene 4 and phenyl boronic
acid 5
cat., 3
(S/C = 20–1,000,000)
K CO (5 equiv.)
2
3
I
(HO)2B
solvent, 90 ˚C, Time
4
5
6
a
b
c
d
e
Entry
Solvent
S/C
T (h)
6 Yield (%)
Recovery of catalyst (%)
TON
TOF
1
2
3
4
5
6
7
8
9
DMF
DMA
H O
2
Toluene
i-PrOH
DMF/H
20
20
20
20
20
20
20
20
20
20
14
14
14
14
14
14
14
14
14
14
95
97
94
74
97
95
90
86
69
75
>99
>99
>99
>99
>99
86
>99
>99
>99
95
2
O (1/4 = v/v)
3
CH CN
Neat
1,4-Dioxane
DMSO
1
0
11
12
13
14
15
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
100
1000
10,000
100,000
16
20
19
19
20
94
99
97
91
90
—
—
—
—
—
94
990
9700
6
50
511
91,000
900,000
4790
45,000
1,000,000
a
b
c
S/C = substrate (mol)/catalyst (mol).
Isolated yield.
i-Pr–phebox–Pd(I) (7).
TON (turnover number) = product (mol)/catalyst (mol).
TOF (turnover frequency) = TON/reaction time (h).
d
e
cat.,3
(S/C = 100–100,000)
K CO (5 equiv.)
R1
I
(HO)2B
9 (1 equiv.)
2
3
R1
R2
i-PrOH, 90 °C, 18 h
R2
8
10
O N
R2
R1
2
R2
(S/C = 100,000) yield (%)
(S/C = 10,000) yield (%)
(S/C = 100) yield (%)
2
2
10k; R1 = CH3
1
0a; R =
p
-OCH3 87
10g; R = H
95
98
2
2
1
1
1
1
1
1
0b; R =
p
-CH3
-NO2
-Cl
-Cl
-Br
94
95
93
86
75
10h; R = OCH 93
10l; R = OCH
3 98
3
2
2
0c; R =
m
10i; R = CH
94
95
3
2
2
0d; R =
p
10j; R = Cl
2
0e; R =
o
2
0f; R =
p
Scheme 3. Phebox–Pd(II) catalyzed Suzuki–Miyaura coupling reactions of various arylhalides 8 and boronic acids 9.
cat.; 3
S/C = 10,000)
K CO (5 equiv.)
(
O
O
2
3
I
B
R
R
i-PrOH, 90 °C, 24 h
4
11
12
Scheme 4. Phebox–Pd(II) catalyzed Suzuki–Miyaura coupling reactions with various boronic esters 11.

3400
T. Takemoto et al. / Tetrahedron Letters 48 (2007) 3397–3401
Table 2.
of aryl coupling reaction include Pd(II)–Pd(IV) catalytic
cycle, which is different from another pincer type precat-
alysts such as PCP, SCS and SCN systems. In axial chi-
ral induction reactions of the aryl halides and aryl
boronic acids or their derivatives, chiral phebox ligands
can serve as effective controllers of enantioselectivity for
axis symmetry. Further research is underway to demon-
strate Heck–Mizoroki reaction and Sonogashira cou-
pling reaction.
a
b
c
Entry
11 (R)
12 Yield (%)
TON
TOF
1
2
3
11a (H)
11a (CH
11a (CI)
11a (CO
11a (NO )
12a (66)
12b (66)
12c (84)
12d (84)
12e (87)
6600
6600
8400
8400
8700
275
275
350
350
363
3
)
d
4
2
Me)
5
2
a
Isolated yield.
b
c
TON (turnover number) = product (mol)/catalyst (mol).
TOF (turnover frequency) = TON/reaction time (h).
i-Pr ester was obtained.
d
Acknowledgement
S.I. and H.N. thank the Ministry of Education, Culture,
Sports, Science and Technology for partial financial
support.
Table 3.
Entry 15
1
2
a
b
R
R
Temperature Yield
ee
(°C)
(%)
(%)
1
2
3
4
5
6
15a
H
CH
H
H
H
H
3
80
80
50
50
50
50
34
78
61
71
55
62
45 (S)
46 (S)
49 (S)
40 (R)
39 (R)
43 (R)
15b CH
15b CH
15c OCH
15d Oi-Pr
15e OBn
3
References and notes
3
3
1
. (a) Motoyama, Y.; Makihara, N.; Mikami, Y.; Aoki, K.;
Nishiyama, H. Chem. Lett. 1997, 951; (b) Motoyama, Y.;
Mikami, Y.; Kawakami, H.; Aoki, K.; Nishiyama, H.
Organometallics 1999, 18, 3584; (c) Motoyama, Y.; Naru-
sawa, H.; Nishiyama, H. Chem. Commun. 1999, 131; (d)
Motoyama, Y.; Kurihara, O.; Murata, K.; Aoki, K.;
Nishiyama, H. Organometallics 2000, 19, 1025; (e) Moto-
yama, Y.; Koga, Y.; Nishiyama, H. Tetrahedron 2001, 57,
53; (f) Motoyama, Y.; Okano, M.; Narusawa, H.; Maki-
hara, N.; Aoki, K.; Nishiyama, H. Organometallics 2001,
0, 1580; (g) Motoyama, Y.; Kawakami, H.; Shimozono,
K.; Aoki, K.; Nishiyama, H. Organometallics 2002, 21,
408; (h) Motoyama, Y.; Koga, Y.; Kobayashi, K.; Aoki,
H
a
Isolated yields.
Determined by chiral HPLC.
b
induction period. Furthermore, chiral inductions using
phebox–Pd(II) catalyst in asymmetric Suzuki–Miyaura
aryl coupling reactions were briefly examined and
moderate chiral induction was observed in the case of
-naphto boronic acid and 2-alkyl or methoxy-1-iodo-
napthalene using chiral phebox–Pd(II) catalyst 16
Table 3). The absolute configuration of this product
8
2
1
3
K.; Nishiyama, H. Chem. Eur. J. 2002, 8, 2968; (i)
Motoyama, Y.; Shimozono, K.; Aoki, K.; Nishiyama, H.
Organoletallics 2002, 21, 1684; (j) Motoyama, Y.; Nishi-
yama, H. Synlett 2003, 1883.
(
was determined as R by comparison with the known
levorotatory R-enantiomer. Although there were not
7
very high enantioselectivities for this reaction, phebox–
Pd(II) catalyzed Suzuki–Miyaura coupling reaction
may not include Pd(0)–Pd(II) catalytic cycle compare
to the recent reports (Scheme 5).
2. Reviews for phebox, see: (a) Nishiyama, H. In Advances in
Catalytic Processes; Doyle, M. P., Ed.; JAI Press: New
York, 1997; Vol. 2, p 153; (b) Nishiyama, H.; Itoh, K. In
Catalytic Asymmetric Synthesis, 2nd ed.; Iwao, O., Ed.;
Wiley-VCH: New York, 2000; Chapter 2; (c) Motoyama,
Y.; Nishiyama, H. In Latest Frontiers of Organic Synthesis;
Kobayashi, Y., Ed.; Research Signpost: India, 2002; 1.
In conclusion, phebox–Pd(II) complexes were found to
be efficient catalysts for the synthesis of biaryl com-
pounds without induction periods and palladium metal
aggregations along with complete recovery of the cata-
lyst. In addition, our results suggest that the mechanism
3
. Review for pincer and their catalytic applications: (a)
Albrecht, M.; van Kotene, G. Angew. Chem., Int. Ed. 2001,
40, 3751; (b) Singleton, J. T. Tetrahedron 2003, 59, 1837; (c)
Bedford, R. B. Chem. Commun. 2003, 1787.
cat.,16
S/C = 20)
K PO ·3H O (5 equiv.)
I
B(OH)2
R2
(
R1
R1
R2
3
4
2
ClCH CH Cl, 24 h
2
2
13
14 (1 equiv.)
15
O
O
N
S
N
Pd
Br
S
S
S
cat.:16 (SS,SS)-(s-Bu-phebox)PdBr
Scheme 5. Phebox–PdCl catalyzed asymmetric Suzuki–Miyaura coupling reactions.

T. Takemoto et al. / Tetrahedron Letters 48 (2007) 3397–3401
3401
4
5
. (a) Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.;
Edwards, J. P. J. Org. Chem. 1997, 62, 3375; (b) Stark, M.
A.; Richards, C. J. Tetrahedron Lett. 1997, 38, 5881.
. Reviews for Suzuki–Miyaura coupling reactions, see: (a)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b)
Br a¨ se, S.; de Meijere, A. In Metal-Catalyzed Cross-Cou-
pling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998; Chapters 2, 3, and 5; (c) Chemler, S.
R.; Trauner, D.; Danishefsky, S. Angew. Chem., Int. Ed.
2001, 40, 4545; (d) Miyaura, M. Angew. Chem., Int. Ed.
2004, 43, 2201.
6. (a) Yu, K.; Sommer, W.; Richardson, J. M.; Weck, M.;
Jones, C. W. Adv. Synth. Catal. 2005, 347, 161; (b)
Eberhard, M. R. Org. Lett. 2004, 6, 2125.
7. (a) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am.
Chem. Soc. 1998, 110, 8153; (b) Mikami, K.; Miyamoto, T.;
Hatano, M. Chem. Commun. 2004, 2082, and references
cited therein.