that with the 1,2-dibenzyl linker (entry 8 vs entry 6). Not
surprisingly, C-6 quinidine dimer IX (5 mol %) was most
effective among the catalysts examined. These results mirrored
those obtained from previously reported catalytic, enantiose-
lective aminooxygenations of alkyl oxindoles.2
Having established the optimal reaction conditions, we began
to investigate the scope of the R-amination reaction with respect
to oxindole substrates (Table 2). The reaction was general in
The moderate enantioselectivity obtained with catalyst IX
warranted further investigation. We discovered that Boc-
protected aryl oxindole 1a was highly reactive, and a competing
nonselective reaction occurred (due to the inherent reactivity
of aryl oxindoles vida supra), thereby compromising the
enantioselectivity. This problem was solved by performing the
R-amination reaction at low temperature (entry 9 vs entry 10).
However, the ee increased only marginally when the temper-
ature was lowered from -50 to -70 °C (entry 10 vs entry 11).
A survey of solvents resulted in conditions that provided
excellent yield and ee: the optimal results were obtained when
the R-amination was performed in toluene at -70 °C for 48 h
(entry 15). The long reaction time was required to ensure good
yield and ee of the desired product (24 h, entry 14 vs 48 h,
entry 15). As previously observed, the free hydroxyl groups in
catalyst IX were important for high yield and enantioselectivity
(entry 15 vs entry 17). These results suggest that these hydroxyl
groups might direct or orient the incoming azadicarboxylate
electrophile via weak hydrogen bonding before C-N bond
formation takes place.2,9
Table 2. Enantioselective R-Aminations of Aryl Oxindoles
entry
X
Y
product
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
H
OMe
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
93
96
71
95
76
87
94
92
91
93
87
98
95
96
97
96
96
98
97
73
93
87
4′-Me
3′-OMe
4′-tBu
4′-F
4′-Me
3′-OMe
4′-F
H
OMe
OMe
OMe
OCF3
F
9
10
11
3′-OMe
3′-OMe
3j
3k
a Isolated yields. b Determined by chiral HPLC analysis.
(8) For selected related C-C bond-forming reactions involving oxindoles
in organocatalysis :(a) Bui, T.; Syed, S.; Barbas, C. F., III J. Am. Chem.
Soc. 2009, 131, 8756. (b) He, R.; Ding, C.; Maruoka, K. Angew. Chem.,
Int. Ed. 2009, 48, 4559. (c) Galzerano, P.; Bencivenni, G.; Pesciaioli, F.;
Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem.sEur. J. 2009, 15, 7846. (d) Duffey, T. A.; Shaw, S. A.; Vedejs, E.
J. Am. Chem. Soc. 2009, 131, 14. (e) Shaw, S. A.; Aleman, P.; Christy, J.;
Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925. (f)
Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M.
Angew. Chem., Int. Ed. 2007, 46, 8666. (g) Tian, X.; Jiang, K.; Peng, J.;
Du, W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583. (h) Chen, X.-H.; Wei, Q.;
Luo, S.-W.; Xao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (i)
Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 12, 1008. (j) Bencivenni, G.; Wu,
L.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200. (k) Cucinotta, C. S.;
Kosa, M.; Melchiorre, P.; Cavalli, A.; Gervasio, F. L. Chem.sEur. J. 2009,
15, 7913. (l) Deng, J.; Zhang, S.; Ding, P.; Jiang, H.; Wang, W.; Li, J.
AdV. Syn. Catal. 2010, 352, 833. (m) Zhu, Q.; Lu, Y. Angew. Chem., Int.
Ed. 2010, DOI: 10.1002/anie.201003837. Selected references for C-C bond-
forming reactions of oxindoles involving transition metal catalysis: (n) Kato,
Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 9168. (o) Doumay, A. B.; Hatanaka, K.;
Kodanko, J. J.; Oestreich, M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M.
J. Am. Chem. Soc. 2003, 125, 6261. (p) Trost, B. M.; Zhang, Y. J. Am.
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to isatins: (u) Luppi, G.; Monari, M.; Correa, R. J.; Violante, F. A.; Pinto,
A. C.; Kaptein, B.; Broxterman, Q. B.; Garden, S. J.; Tomasini, C.
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scope, tolerating aryl oxindoles of different electronic natures
and with different aromatic substitution patterns. For example,
oxindoles bearing electron-neutral and electron-rich substituents
at C5 afforded the desired products in excellent yields and ee’s
(entries 1-2). Moreover, reactions with substrates with various
aryl groups at the C3 position also provided products in moderate
to good yields with excellent ee’s (entries 3-6). It is noteworthy
that oxindole 3f, which contains a fluorine atom, was obtained
in good yield and high ee (entry 6). Enantiomerically enriched
syntheses of fluorine-containing molecules are of importance
in drug discovery and development.10 Under our optimized
conditions, oxindoles with various substituents at C5 and
different substitution patterns on the C3-substituted aryl ring
were all viable substrates (entries 7-11). The yields and ee’s
of the desired products were high for most of these substrates.
The absolute configuration at the newly created center was
determined to be R by comparison with a known oxindole
derivative of 3a.11 Finally, we demonstrated that product 3a
could be converted into the corresponding, free amino aryl
oxindole in good yield with excellent optical purity.11
To determine the role of the dimeric structure and the quinidine
units in catalysis by IX, analogues were synthesized and examined
in the enantioselective R-amination of 1a (Table 3). Catalysts XI
and XII had only one quinuclidine moiety within the catalyst
(9) Hydroxy-directing effects of cinchona alkaloid catalysts: (a) Hiem-
stra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417. (b) Li, H.; Wang,
Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906.
(10) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry:
Principles and Commercial Applications; Plenum Press: NewYork, 1994.
(11) See Supporting Information.
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