Me-BIPAM for the synthesis of optically active 3-aryl-3-hydroxy-2-oxindoles by ruthenium-catalyzed addition of arylboronic acids to isatins

Article abstract of DOI:10.1002/asia.201200481

A chiral O-linked C₂-symmetric bidentate phosphoramidite (Me-BIPAM) was found to be efficient for the ruthenium-catalyzed addition of arylboronic acids to isatins. Asymmetric synthesis of 3-aryl-3-hydroxy-2- oxindoles by 1,2-addition of arylboronic acids to isatins was carried out in the presence of [RuCl₂(PPh₃)₃]/(R,R)-Me-BIPAM and KF, resulting in an enantioselectivity as high as 90 % ee. It was found that the reaction with N-protected isatins proceeds with high yields and good enantioselectivities. The best protective groups on the nitrogen atom were different depending on the substituents on the aromatic ring. The use of a N-benzyl group resulted in excellent enantioselectivities in many substrates compared with other groups. Add it up: A chiral O-linked C₂-symmetric bidentate phosphoramidite (Me-BIPAM) was found to be efficient for the ruthenium-catalyzed addition of arylboronic acids to isatins. Asymmetric synthesis of 3-aryl-3-hydroxy-2-oxindoles by 1,2-addition of arylboronic acids to isatins was carried out in the presence of [RuCl₂(PPh ₃)₃]/(R,R)-Me-BIPAM and KF, resulting in an enantioselectivity as high as 90 % ee. Copyright

Full text of DOI:10.1002/asia.201200481

DOI: 10.1002/asia.201200481
Me-BIPAM for the Synthesis of Optically Active 3-Aryl-3-hydroxy-2-
oxindoles by Ruthenium-catalyzed Addition of Arylboronic Acids to Isatins
Yasunori Yamamoto,*[a] Masaaki Yohda,[b] Tomohiko Shirai,[b] Hajime Ito,[b] and
Norio Miyaura[a]
Abstract: A chiral O-linked C2-sym-
metric bidentate phosphoramidite (Me-
BIPAM) was found to be efficient for
the ruthenium-catalyzed addition of ar-
ylboronic acids to isatins. Asymmetric
synthesis of 3-aryl-3-hydroxy-2-oxin-
doles by 1,2-addition of arylboronic
acids to isatins was carried out in the
BIPAM and KF, resulting in an enan-
tioselectivity as high as 90% ee. It was
found that the reaction with N-protect-
ed isatins proceeds with high yields and
good enantioselectivities. The best pro-
tective groups on the nitrogen atom
were different depending on the sub-
stituents on the aromatic ring. The use
of a N-benzyl group resulted in excel-
lent enantioselectivities in many sub-
strates compared with other groups.
Keywords: 1,2-addition · 3-substi-
tuted-3-hydroxy-2-oxindole · boron ·
isatin · ruthenium
presence of [RuCl2ACTHUNTRGENNUG(PPh3)3]/AHCTUNGTRENN(UGN R,R)-Me-
Introduction
copper catalyst.[13] In 2010, Hayashi et al. reported a copper-
catalyzed asymmetric addition reaction.[14] In this field, we
have already reported enantioselective addition reactions
using organoboron compounds under rhodium, palladium,
and ruthenium catalysis.[15] We previously developed biden-
tate chiral phosphoramidites (Me-BIPAM and N-Me-
BIPAM), derived from linked BINOL (BINOL=1,1’-bi-
naphthalene-2,2’-diol) units, for the enantioselective 1,4-ad-
dition of arylboronic acids to enones,[16] arylation of aldi-
mines,[17] and hydrogenation of alkenes.[18] These ligands
were also found to be highly efficient for ruthenium-cata-
lyzed enantioselective arylation of aldehydes, ketoesters,
and glyoxylate.[19] In the course of our study on bisphosphor-
oamidites as a chiral auxiliary for enantioselective bond-
forming reactions, we report here on the asymmetric addi-
tion of aryl boronic acids to isatins catalyzed by a Ru/Me-
BIPAM complex (Scheme 1).
Optically active 3-substituted 3-hydroxy-2-oxindoles are not
only important structures in biologically active compounds
but also serve as fundamental building blocks in organic
synthesis.[1,2] Over the past decade, various methods for the
synthesis of these chiral compounds have been developed.
Enantioselective Morita–Baylis–Hillman reactions,[3] aldol
reactions,[4] asymmetric allylation of isatins,[5] Friedel–Crafts
reactions,[6] direct hydroxylation,[7] and metal-catalyzed in-
tramolecular coupling reactions have been reported.[8,9] In
recent years, the use of stable, commercially available aryl
boronic acids in transition metal-catalyzed carbon–carbon
bond-forming reactions has attracted considerable attention.
Transition metal-catalyzed asymmetric nucleophilic addition
of organoboronic compounds to isatins is a particularly pow-
erful and straightforward approach. In 2006, the groups of
Hayashi and Minnaard independently reported the addition
of arylboronic acids to isatins by a rhodium-catalyzed reac-
tion.[10,11] Since then, palladium-catalyzed addition reactions
have been developed.[12] In 2009, Shibasaki and co-workers
reported the arylation of isatins in the presence of a chiral
[a] Prof. Dr. Y. Yamamoto, Prof. Dr. N. Miyaura
Frontier Chemistry Center, Faculty of Engineering
Hokkaido University
Kita 13, Nishi 8, Kita-ku, Sapporo, 060-8628 (Japan)
Fax : (+81)11-706-6560
E-mail: yasuyama@eng.hokudai.ac.jp
[b] M. Yohda, T. Shirai, Prof. Dr. H. Ito
Division of Chemical Process Engineering
Faculty of Engineering, Hokkaido University
Kita 13, Nishi 8, Kita-ku, Sapporo, 060-8628 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200481.
Scheme 1. Enantioselective addition of arylboronic acids to isatins.
Chem. Asian J. 2012, 00, 0 – 0
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Results and Discussion
The best result was achieved when the reaction of N-p-me-
thoxybenzyl isatin was controlled at 508C in toluene in the
Initially, we utilized the reaction of 5-chloroisatin with
phenyl boronic acid in the presence of KF (2 equiv) and
ruthenium/ACHTUNGTRENNUNG(R,R)-Me-BIPAM complex (Table 1). Since the
presence of KF and [RuCl2ACHTGUNTRENU(NG PPh3)3]/ACTHGNUTREN(NUNG R,R)-Me-BIPAM
(Table 1, entry 11 (97% yield, 88% ee)). Encouraged by
these results, we then studied the reactions of 5-phenyl
isatin bearing methyl, benzyl, and PMB groups on the nitro-
gen atom with phenyl boronic acid (Table 1, en-
tries 14–19). N-Methyl- and N-PMB-5-phenyl isatin
can be reacted effectively at 508C in 96% yield
with 90% ee and 87% yield with 90% ee, respec-
tively (entries 16 and 19).
rhodium complex was inefficient, the use of ruthenium as
Table 1. Reaction conditions.[a]
Next, we investigated the substrate scope focus-
ing on isatins bearing substituents on the aromatic
ring. The arylation of isatins proceeded efficiently
to give the corresponding products in yields of 92–
99% with 86–90% ee. As shown in Table 2, the
best protective groups on the nitrogen atom were
different depending on the substituents on the aro-
matic ring. In addition to 5-bromo-, 5-methyl-, and
non-substituted isatin, the p-methoxybenzyl group
was the most effective (entries 3, 5, and 9). The N-
benzyl group resulted in the best enantioselectivi-
ties for 5-fluoro- and 6-chloro isatins (entries 2 and
8).
We then studied the scope and limitations for
various arylboronic acids. Again, a difference in
enantioselectivity was observed depending on the
protecting group on the nitrogen atom (Table 3).
The addition of 4-methoxyphenylboronic acid to N-
Bn-5-chloroisatin resulted in better enantioselectivi-
ty than the use of other protective groups. When p-
tolyl- and p-fluorophenylboronic acid were used, N-
Me isatin yielded better selectivities as compared to
N-Bn isatin. On the other hand, the addition of p-
trifluoromethylphenyl boronic acid to N-p-fluoro-
benzyl isatin resulted in enantioselectivities higher
than N-Bn- and N-p-CF3-Bn isatins. The results of
the arylation of 5-chloroisatin with other arylboron-
ic acids are summarized in Table 4. Para- and meta-
Entry Catalyst
R
PG
3
T [8C] Yield[b] [%] ee[c] [%]
1
2
3
4
5
6
7
8
[Rh
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
G
N
Cl
Bn
Bn
3ba 50
3ba 80
3aa 80
3aa 80
3ba 50
3aa 80
3ba 80
3ca 80
3aa 50
3ba 50
3ca 50
>99
72
94
78
94
58[d]
17 (R)
49 (R)
24[e]
1
E
C
E
N
Me
Me
Bn
Me
Bn
PMB
Me
Bn
N
N
E
R
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
T
G
>99
99
95
>99
99
97
85 (R)
85 (R)
84 (R)
81 (R)
87 (R)
88 (R)
83
G
CHTUNGTRENNUNG
G
N
9
R
G
10
11
12
13
14
15
16
17
18
19
R
CHTUNGTRENNUNG
N
U
PMB
p-F-Bn 3da 50
Tr 3ea 50
G
G
>99
71
N
G
77
N
(p-cymene)]2 Ph Me
U
3 fa
3 fa
3 fa
3 fa
3ga 50
3ha 50
80
80
50
30
71
94
96
88
58
88
90
90
G
Ph Me
Ph Me
Ph Me
Ph Bn
Ph PMB
E
E
G
N
T
G
90
86
A
T
87
90
[a] Reaction conditions:
A mixture of isatin (0.5 mmol), phenylboronic acid
(1.0 mmol), KF (1.0 mmol), Ru catalyst (2 mol%), and (R,R)-Me-BIPAM (2.2 mol%)
in toluene (3 mL) and H2O (0.3 mL) was stirred for 24 h. [b] Isolated yields. [c] Deter-
mined by HPLC. [d] A mixture of isatin (0.5 mmol), phenylboronic acid (0.75 mmol),
RhACHTUNGTRENNUNG(acac)ACHTUNGTRENNUNG(C2H4)2 (3 mol%), and (R,R)-N-Me-BIPAM (3.3 mol%) in toluene/H2O
(20:1) was stirred at 508C for 16 h. [e] (R,R)-N-Me-BIPAM was used as ligand.
Table 2. Ruthenium-catalyzed asymmetric addition of phenylboronic
acids to isatins.
the central metal was critical for achieving high enantiose-
lectivities (entry 1). [RuCl2ACTHNUGTRENN(GU p-cymene)]2 and [RuClCAHUTNGTRENN(UGN C6H6)]2
led to adducts in 72% yield with 17% ee (N-Bn isatin),
94% yield with 49% ee (N-Me isatin), and 94% yield with
1% ee (N-Bn isatin) (Table 1, entries 2, 3, and 5). The use of
N-Me-BIPAM as a ligand resulted in lower selectivity than
that when Me-BIPAM was used (entries 3 and 4). We al-
Entry
1
R
PG
3
Yield[a] [%]
ee[b] [%]
1
2
3
4
5
6
7
8
9
1i
1j
1k
1l
1m
1n
1o
1p
1q
5-F
5-F
PMB
Bn
PMB
Bn
PMB
Bn
PMB
Bn
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
>99
95
97
96
97
92
97
>99
>99
87
90 (R)
90
ready reported [RuCl
catalyzed highly enantioselective arylation of glyoxylate.[19c]
When [RuCl2A(PPh3)3] was used as the precursor, the product
2ACHUTNGTREN(NGU PPh3)3]/ACHTUTGNREN(NUGN R,R)-Me-BIPAM complex-
5-Br
5-Br
5-Me
5-Me
6-Cl
6-Cl
H
86
CHTUNGTRENNUNG
90 (R)
87 (R)
88
89
89 (R)
was obtained in 99% yield and 85% ee (Table 1, entry 6).
The use of benzyl, p-fluorobenzyl (p-F-Bn), p-methoxyben-
zyl (PMB), and trityl (Tr) groups as protective groups on
the nitrogen atom also resulted in similar yield and enantio-
selectivity under these conditions (Table 1, entries 6–13).
PMB
[a] Isolated yields. [b] Determined by HPLC.
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Me-BIPAM for the Synthesis of Optically Active 3-Aryl-3-hydroxy-2-oxindoles
Table 3. Arylation of 5-chloroisatins.[a]
Ar
PG=
Me (1a)
Bn (1b)
PMB (1c)
p-F-Bn (1d)
p-CF3-Bn (1r)
4-MeOC6H4 (2b)
4-MeC6H4 (2c)
4-FC6H4 (2d)
>99%, 61% ee (3ab) 87%, 78% ee (R), (3bb)
>99%, 83% ee (3ac)
78%, 52% ee (R), (3cb) 75%, 64% ee (3db)
>99%, 81% ee (R), (3bc) 93%, 79% ee (R), (3cc) >99%, 52% ee (3dc)
90%, 60% ee (3rb)
>99%, 76% ee (3rc)
>99%, 75% ee (3rd)
51%, 69% ee[b] (3re)
>99%, 83% ee (3ad) 97%, 74% ee (R), (3bd)
91%, 77% ee (R), (3cd) 99%, 77% ee (3dd)
4-CF3C6H4 (2e)
–
57%, 74% ee[b] (3be)
–
74%, 82% ee[b] (3de)
[a] Reaction conditions: A mixture of isatin (0.5 mmol), phenylboronic acid (1.0 mmol), KF (1.0 mmol), Ru catalyst (2 mol%), and (R,R)-Me-BIPAM
(2.2 mol%) in toluene (3 mL) and H2O (0.3 mL) was stirred for 24 h. [b] The reaction was carried out at 808C.
Table 4. Arylation of N-benzyl 5-chloroisatin.
Entry
Ar
3
Yield[a] [%]
ee[b] [%]
1
2
3
4
5
6
7
4-PhC6H4 (2 f)
3-MeC6H4 (2g)
3-ClC6H4 (2h)
3-CF3C6H4 (2i)
2-naphthyl (2j)
2-MeOC6H4 (2k)
2-FC6H4 (2l)
3bf
3bg
3bh
3bi
3bj
3bk
3bl
>99
>99
>99
99
99
97
88
87 (R)
72[c]
68[c]
82
46
>99
51[c]
[a] Isolated yields. [b] Determined by HPLC. [c] The reaction was carried
out at 808C.
Figure 1. Proposed catalytic cycle.
substituted arylboronic acids bearing electron-donating or
electron-withdrawing substituents afforded 3-aryl-3-hy-
droxy-2-oxindole derivatives in good yields with good enan-
tioselectivities in the range of 68–88% ee (entries 1–5).
However, since the steric hindrance was increased, the cata-
lyst was less effective for ortho-substituted arylboronic acids.
The addition of o-methoxyphenyl- and o-fluorophenyl bor-
onic acids resulted in 97% yield with 46% ee and >99%
yield with 51% ee, respectively (entries 6 and 7).
The catalytic cycle involves 1) transmetalation of an aryl-
Figure 2. Proposed coordination modes.
À
boronic acid to a Ru/Me-BIPAM complex giving an Ar
[Ru] species, 2) insertion of the C=O bond of isatin into the
À
Ar Ru bond, and finally 3) formation of a 3-aryl-3-hydroxy-
À
2-oxindole through hydrolysis of the Ru O intermediate
Conclusions
with water (Figure 1). The absolute configuration and enan-
tioselectivity are determined at the insertion step of the C=
O bond into an arylruthenium intermediate (Figure 2).
Thus, the R configuration in Tables 1–3 caused by (R,R)-
Me-BIPAM is rationalized by the coordination of an isatin
with its si-face. The si-coordination of the substrate is pre-
ferred without significant steric interaction to give the ex-
perimentally observed R enantiomer by parallel coordina-
In conclusion, we have developed asymmetric arylation of
N-protected isatins with arylboronic acids using an [RuCl2
ACHUTNGRENU(NG PPh3)3]/ACHUTGNTREN(NGUN R,R)-Me-BIPAM catalyst system. High perfor-
mance of Me-BIPAM for enantioselective 1,2-addition to N-
protected isatins was demonstrated. A variety of chiral 3-
aryl-3-hydroxy-2-oxindoles were obtained with good enan-
tioselectivities for para- and meta-substituted arylboronic
acids (68-90% ee). The mechanisms underlying enantiose-
lection will be reported elsewhere.
À
tion of the C=O bond to the Ar Ru bond for the subse-
quent insertion step.
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FULL PAPER
[5] a) X.-C. Qiao, S.-F. Zhu, Q.-L. Zhou, Tetrahedron: Asymmetry 2009,
20, 1254–1261; b) J. Itoh, S. B. Han, M. J. Krische, Angew. Chem.
2009, 121, 6431–6434; Angew. Chem. Int. Ed. 2009, 48, 6313–6316.
[6] a) D. B. Ramachary, G. B. Reddy, R. Mondel, Tetrahedron Lett.
2007, 48, 7618–7623; b) N. V. Hanhan, A. H. Sahin, T. W. Chang,
J. C. Fettinger, A. K. Franz, Angew. Chem. 2010, 122, 756–759;
Angew. Chem. Int. Ed. 2010, 49, 744–747; c) J. Deng, S. Zhang, P.
Ding, H. Jiang, W. Wang, J. Li, Adv. Synth. Catal. 2010, 352, 833–
838; d) P. Chauhan, S. S. Chimni, Chem. Eur. J. 2010, 16, 7709–7713;
e) E. G. Gutierrez, C. J. Wong, A. H. Sahin, A. K. Franz, Org. Lett.
2011, 13, 5754–5757.
[7] a) T. Ishimaru, N. Shibata, J. Nagai, S. Nakamura, T. Toru, S. Kane-
masa, J. Am. Chem. Soc. 2006, 128, 16488–16489; b) D. Sano, K.
Nagata, T. Itoh, Org. Lett. 2008, 10, 1593–1595; c) T. Bui, N. R. Can-
deias, C. F. Barbas, III, J. Am. Chem. Soc. 2010, 132, 5574–5575;
d) Z. Zhang, W. Zheng, J. C. Antilla, Angew. Chem. 2011, 123,
1167–1170; Angew. Chem. Int. Ed. 2011, 50, 1135–1138.
[8] a) E. P. Kꢃndig, T. M. Seidel, Y.-x. Jia, G. Bernardinelli, Angew.
Chem. 2007, 119, 8636–8639; Angew. Chem. Int. Ed. 2007, 46, 8484–
8487; b) Y.-X. Jia, J. M. Hillgren, E. L. Watson, S. P. Marsden, E. P.
Kꢃndig, Chem. Commun. 2008, 4040–4042; c) J. M. Hillgren, S. P.
Marsden, J. Org. Chem. 2008, 73, 6459–6461; d) Y.-X. Jia, D. Ka-
tayev, E. P. Kꢃndig, Chem. Commun. 2010, 46, 130–132.
[9] a) J.-X. Hu, H. Wu, C.-Y. Li, W.-J. Sheng, Y.-X. Jia, J.-R. Gao,
Chem. Eur. J. 2011, 17, 5234–5237; b) L. Yin, M. Kanai, M. Shibasa-
ki, Angew. Chem. 2011, 123, 7762–7765; Angew. Chem. Int. Ed.
2011, 50, 7620–7623.
[10] a) R. Shintani, M. Inoue, T. Hayashi, Angew. Chem. 2006, 118,
3431–3434; Angew. Chem. Int. Ed. 2006, 45, 3353–3356; b) P. Y.
Toullec, R. B. C. Jagt, J. G. de Vries, B. L. Feringa, A. J. Minnaard,
Org. Lett. 2006, 8, 2715–2718.
[11] a) X. Feng, Y. Nie, J. Yang, H. Du, Org. Lett. 2012, 14, 624–627;
b) J. Gui, G. Chen, P. Gao, J. Liao, Tetrahedron: Asymmetry 2012,
23, 554–563.
[12] a) H. Lai, Z. Huang, Q. Wu, Y. Qin, J. Org. Chem. 2009, 74, 283–
288; b) Z. Liu, P. Gu, M. Shi, P. McDowell, G. Li, Org. Lett. 2011,
13, 2314–2317.
[13] D. Tomita, K. Yamatsugu, M. Kanai, M. Shibasaki, J. Am. Chem.
Soc. 2009, 131, 6946–6948.
Experimental Section
Typical procedure for ruthenium-catalyzed asymmetric additions of aryl-
boronic acids to isatins: flask was charged with [RuCl2A(PPh3)2]
A
CHTUNGTRENNUNG
(0.01 mmol, 2 mol%) and (R,R)-Me-BIPAM (0.011 mmol, 2.2 mol%)
under a nitrogen atmosphere. Subsequently, toluene (3.0 mL) was added
to the flask and the mixture was stirred at room temperature for 30 min
to prepare the catalyst. Isatin (0.5 mmol), arylboronic acid (1.0 mmol),
KF (1.0 mmol), and H2O (0.3 mL) were then added to the catalyst solu-
tion. The reaction mixture was stirred at 508C for 24 h, at which time the
crude reaction mixture was extracted using ethyl acetate, washed with sa-
turated NH4Cl and brine, dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash column chromatography on
silica gel (EtOAc/CHCl3) to give 3-aryl-3-hydroxy-2-oxindole.
Acknowledgements
This work was supported by the Global COE Program (Project No. B01:
Catalysis as the Basis for Innovation in Materials Science) from the Min-
istry of Education, Culture, Sports, Science and Technology, Japan.
[1] a) S. Peddibhotla, Curr. Bioact. Compd. 2009, 5, 20–38; b) F. Zhou,
Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352, 1381–1407;
c) J. E. M. N. Klein, R. J. K. Taylor, Eur. J. Org. Chem. 2011, 6821–
6841.
[2] a) J. E. Thomson, A. F. Kyle, K. A. Gallagher, P. Lenden, C. Concel-
lꢁn, L. C. Morrill, A. J. Miller, C. Joannesse, A. M. Z. Slawin, A. D.
Smith, Synthesis 2008, 2805–2818; b) C. D. Grant, M. J. Krische,
Org. Lett. 2009, 11, 4485–4487; c) S. Urgaonkar, J. F. Cortese, R. H.
Barker, M. Cromwell, A. E. Serrano, D. F. Wirth, J. Clardy, R. Ma-
zitschek, Org. Lett. 2010, 12, 3998–4001; d) M. K. Christensen, K. D.
Erichsen, C. Trojel-Hansen, J. Tjørnelund, S. J. Nielsen, K. Fryden-
vang, T. N. Johansen, B. Nielsen, M. Sehested, P. B. Jensen, M. Ikau-
nieks, A. Zaichenko, E. Loza, I. Kalvinsh, F. Bjçrkling, J. Med.
Chem. 2010, 53, 7140–7145; e) S. Chowdhury, M. Chafeev, S. Liu, J.
Sun, V. Raina, R. Chui, W. Young, R. Kwan, J. Fu, J. A. Cadieux,
Bioorg. Med. Chem. Lett. 2011, 21, 3676–3681; f) F. Zhou, Z.-Y.
Cao, J. Zhang, H.-B. Yang, J. Zhou, Chem. Asian J. 2012, 7, 233–
241; g) C. Guo, J. Song, J.-Z. Huang, P.-H. Chen, S.-W. Luo, L.-Z.
Gong, Angew. Chem. 2012, 124, 1070–1074; Angew. Chem. Int. Ed.
2012, 51, 1046–1050; h) L. Song, Q.-X. Guo, X.-C. Li, J. Tian, Y.-G.
Peng, Angew. Chem. 2012, 124, 1935–1938; Angew. Chem. Int. Ed.
2012, 51, 1899–1902.
[14] R. Shintani, K. Takatsu, T. Hayashi, Chem. Commun. 2010, 46,
6822–6824.
[15] a) Y. Yamamoto, T. Nishikata, N. Miyaura, J. Synth. Org. Chem.
Jpn. 2006, 64, 1112–1121; b) Y. Yamamoto, T. Nishikata, N.
Miyaura, Pure Appl. Chem. 2008, 80, 807–817; c) N. Miyaura, Syn-
lett 2009, 2039–2050.
[16] a) Y. Yamamoto, K. Kurihara, N. Sugishita, K. Oshita, D. Piao, N.
Miyaura, Chem. Lett. 2005, 34, 1224–1225; b) K. Kurihara, N. Su-
gishita, K. Oshita, D.-G. Piao, Y. Yamamoto, N. Miyaura, J. Organo-
met. Chem. 2007, 692, 428–435.
[17] a) K. Kurihara, Y. Yamamoto, N. Miyaura, Adv. Synth. Catal. 2009,
351, 260–270; b) Y. Yamamoto, Y. Takahashi, K. Kurihara, N.
Miyaura, Aust. J. Chem. 2011, 64, 1447–1453.
[3] a) X.-Y. Guan, Y. Wei, M. Shi, Chem. Eur. J. 2010, 16, 13617–13621;
b) Y.-L. Liu, B.-L. Wang, J.-J. Cao, L. Chen, Y.-X. Zhang, C. Wang,
J. Zhou, J. Am. Chem. Soc. 2010, 132, 15176–15178; c) F. Zhong, G.-
Y. Chen, Y. Lu, Org. Lett. 2011, 13, 82–85.
[4] a) A. V. Malkov, M. A. Kabeshov, M. Bella, O. Kysilka, D. A. Maly-
ˇ
ˇ
´
shev, K. Pluhꢂckovꢂ, P. Kocovsky, Org. Lett. 2007, 9, 5473–5476;
b) S. Nakamura, N. Hara, H. Nakashima, K. Kubo, N. Shibata, T.
Toru, Chem. Eur. J. 2008, 14, 8079–8081; c) N. Hara, S. Nakamura,
N. Shibata, T. Toru, Chem. Eur. J. 2009, 15, 6790–6793; d) F. Xue, S.
Zhang, L. Liu, W. Duan, W. Wang, Chem. Asian J. 2009, 4, 1664–
1667; e) Q. Guo, M. Bhanushali, C.-G. Zhao, Angew. Chem. 2010,
122, 9650–9654; Angew. Chem. Int. Ed. 2010, 49, 9460–9464; f) K.
Aikawa, S. Mimura, Y. Numata, K. Mikami, Eur. J. Org. Chem.
2011, 62–65.
[18] K. Kurihara, Y. Yamamoto, N. Miyaura, Tetrahedron Lett. 2009, 50,
3158–3160.
[19] a) Y. Yamamoto, K. Kurihara, N. Miyaura, Angew. Chem. 2009, 121,
4478–4480; Angew. Chem. Int. Ed. 2009, 48, 4414–4416; b) Y. Ya-
mamoto, T. Shirai, M. Watanabe, K. Kurihara, N. Miyaura, Mole-
cules 2011, 16, 5020–5034; c) Y. Yamamoto, T. Shirai, N. Miyaura,
Chem. Commun. 2012, 48, 2803–2805.
Received: May 31, 2012
Published online: && &&, 0000
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www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

FULL PAPER
Asymmetric Synthesis
Yasunori Yamamoto,* Masaaki Yohda,
Tomohiko Shirai, Hajime Ito,
Norio Miyaura
&&&& — &&&&
Me-BIPAM for the Synthesis of Opti-
cally Active 3-Aryl-3-hydroxy-2-oxin-
doles by Ruthenium-catalyzed Addi-
tion of Arylboronic Acids to Isatins
Add it up: A chiral O-linked C2-sym-
metric bidentate phosphoramidite
(Me-BIPAM) was found to be efficient
for the ruthenium-catalyzed addition
of arylboronic acids to isatins. Asym-
metric synthesis of 3-aryl-3-hydroxy-2-
oxindoles by 1,2-addition of arylbor-
onic acids to isatins was carried out in
the presence of [RuCl2ACHTNUTRGENN(GU PPh3)3]/ACHTUGNTREN(NUGN R,R)-
Me-BIPAM and KF, resulting in an
enantioselectivity as high as 90% ee.
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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These are not the final page numbers! ÞÞ