Enantioselective organocatalytic anti-Mannich-type reaction of N-unprotected 3-substituted 2-oxindoles with aromatic N-Ts-aldimines

Article abstract of DOI:10.1021/jo9006688

(Chemical Equation Presented) The modified cinchona alkaloid-catalyzed direct Mannich-type reaction of N-unprotected 2-oxindoles with N-Ts-imine was developed to afford anti-3,3-disubstituted 2-oxindoles with vicinal chiral quaternary and tertiary carbon

Full text of DOI:10.1021/jo9006688

intermediates of bioactive molecules.2 Numerous oxindole
alkaloids with strong bioactive profiles and interesting structural
properties, such as salacin (1),3a uncarine E (2),3b,c and
spirotryprostatin A (3),3e,f contain a 3,3-disubstituted 2-oxindole
subunit in their backbones and an anti-diastereomeric structure
(Figure 1). Though a handful of synthetic methods are available
for creating the single quaternary carbon centers at the C-3
position with complete control, the challenge still lies primarily
in the efficient construction of a vicinal chiral tertiary carbon
center.4
Enantioselective Organocatalytic
anti-Mannich-Type Reaction of N-Unprotected
3-Substituted 2-Oxindoles with Aromatic
N-Ts-aldimines
Liang Cheng,†,‡ Li Liu,*,† Han Jia,† Dong Wang,† and
Yong-Jun Chen*,†
Beijing National Laboratory for Molecular Sciences
(BNLMS), CAS Key Laboratory of Molecular Recognition
and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China, and Graduate School of
Chinese Academy of Sciences, Beijing 100049, China
lliu@iccas.ac.cn; yjchen@iccas.ac.cn
ReceiVed April 2, 2009
FIGURE 1. Biologically active 2-oxindoles bearing 3,3-disubstituted
centers.
Direct Mannich-type reaction is one of the most powerful
methods for carbon-carbon bond formation, and the versatility
of this process has been widely exploited in the development
of asymmetric methods for the synthesis of chiral ꢀ-aminocar-
bonyl compounds.5 Inspired by the success in asymmetric
reactions of imine derivatives,6 we were encouraged to ascertain
whether the daunting problem that the formation of chiral
quaternary carbon center and an adjacent tertiary center could
be processed concurrently by employing an appropriate 3-mono-
substituted oxindole. While direct organocatalytic asymmetric
Mannich-type reaction giving syn-adducts has been well estab-
lished, the development of an anti-Mannich-type reaction is
considerably sluggish.7 The exploitation of a highly efficient
(1) For reviews, see: (a) Quaternary Stereocenters: Challenges and Solutions
for Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
2005. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591–
4597. (c) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688–
1690, and references cited therein.
(2) For an excellent review on biologically active spirooxindoles, see:
Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–8758.
(3) (a) Ponglux, D.; Wongseripipatana, S.; Aimi, N.; Nishimura, M.; Ishikawa,
M.; Sada, H.; Haginiwa, J.; Sakai, S.-I. Chem. Pharm. Bull. 1990, 38, 573–575.
(b) Lee, K. K.; Zhou, B.-N.; Kingston, D. G. I.; Vaisberg, A. J.; Hammond,
G. B. Planta Med. 1999, 65, 759–760. (c) Mohamed, A.-F. A.-F.; Matsumoto,
K.; Tabata, K.; Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H. J. Pharm.
Pharmacol. 2000, 52, 1553–1561. (d) Muhammad, I.; Dunbar, D. C.; Khan,
R. A.; Ganzera, M.; Khan, I. A. Phytochemistry 2001, 57, 781–786. (e) Cui,
C.-B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651–12666. (f) Edmond-
son, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc.
1999, 121, 2147–2155.
(4) For some recent excellent examples, see: (a) Trost, B. M.; Zhang, Y.
J. Am. Chem. Soc. 2007, 129, 14548–14549. (b) Ishimaru, T.; Shibata, N.;
Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem.,
Int. Ed. 2008, 47, 4157–4161.
(5) For recent reviews, see: (a) Kobayashi, S.; Ueno, M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 2003; Suppl. 1, Chapter 29.5. (b) Ueno, M.; Kobayashi, S. In
EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok,
V. A., Eds.; Wiley: New York, 2005; pp 139-157. (c) Marques, M. M. B. Angew.
Chem., Int. Ed. 2006, 45, 348–352.
The modified cinchona alkaloid-catalyzed direct Mannich-
type reaction of N-unprotected 2-oxindoles with N-Ts-imine
was developed to afford anti-3,3-disubstituted 2-oxindoles
with vicinal chiral quaternary and tertiary carbon centers in
yields up to 90% with excellent diastereoselectivities (anti/
syn up to 95:5) and good enantioselectivies (up to 89% ee).
A transition model for the anti-diastereo- and enantioselec-
tivity of the reaction was proposed.
Stereoselective (diastereo- and enantioselective) formation of
quaternary centers is one of the key issues that are encountered
during the synthesis of the center of complex molecules.
Consequently, the installation of a specific fully substituted chiral
center has been a challenging task for synthetic organic chemists
for decades.1 Due to the unique biological and pharmacological
proprieties, the framework of 2-oxindole is extensively incor-
porated in substructures of natural products and synthetic
† Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key
Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China.
(6) (a) Chen, Y.-J.; Lei, F.; Liu, L.; Wang, D. Tetrahedron 2003, 59, 7609–
7614. (b) Zhao, C.-H.; Liu, L.; Wang, D.; Chen, Y.-J. Eur. J. Org. Chem. 2006,
2977–2986. (c) Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J. Tetrahedron:
Asymmetry 2007, 18, 1833–1843.
‡ Graduate School of Chinese Academy of Sciences, Beijing 100049, China.
4650 J. Org. Chem. 2009, 74, 4650–4653
10.1021/jo9006688 CCC: $40.75 2009 American Chemical Society
Published on Web 05/18/2009

TABLE 1. Optimization of Mannich-Type Reaction of 2-Oxindole
5 with Imine 6 Catalyzed by Cinchona Alkaloids 4a
SCHEME 1. Asymmetric Addition of 2-Oxindoles 5 with
Imines 6
entry
5
6
4
solvent T (°C) yield (%) anti/synb eec (%)
1d
2d
3d
4d
5d
6d
7d
8f
5a 6a 4i CH2Cl2 rt
5a 6a 4a CH2Cl2 rt
5a 6a 4b CH2Cl2 rt
5a 6a 4e CH2Cl2 rt
5a 6a 4f CH2Cl2 rt
5a 6a 4c CH2Cl2 rt
5a 6a 4h CH2Cl2 rt
5a 6a 4d CH2Cl2 rt
5a 6a 4g CH2Cl2 rt
74
65
86
70
70
<5
<10
90
83
99
83
15
99
41
77
68
40
75:25
49:51
42:58
46:54
54:46
23:77
84:16
92:8
93:7
94:6
93:7
92:8
94:6
90:10
95:5
94:6
94:6
-20
-6
8
25
-11
nde
nde
82
-80
84
9
anti-diastereoselective Mannich-type reaction is still a challenge
in contemporary asymmetric synthesis. Recently, Chen and co-
worker disclosed a novel transformation between N-Boc-
oxindoles and N-Boc-imines catalyzed by thiourea-tertiary
amine to generate the syn-diastereoisomers with high enanti-
oselectivities.8 Herein, we describe the asymmetric anti-Man-
nich-type reaction of N-unprotected 2-oxindole with aromatic
N-tosylimine in the presence of modified cinchona alkaloids as
the catalysts.9 The highly functionalized chiral oxindole deriva-
tives obtained from this reaction will surely provide versatile
building blocks for the preparation of oxindole alkaloids with
biological activities.
In light of the thiourea-tertiary amine-catalyzed asymmetric
Mannich-type reaction of N-Boc-2-oxindole 5c,8 at first the
reaction of 3-methyl-2-oxindole (5a, R ) H) with N-Ts-imine
6a was carried out in CH2Cl2 at room temperature in the
presence of quinine-thiourea catalyst 4i (Scheme 1, Figure 2).
Unfortunately, 4i exhibited relatively lower reactivity and
provided the product 7a with poor diastereo- and enantioselec-
tivity (Table 1, entry 1).
Subsequently, the asymmetric additions of 5a with 6a under
the catalysis of chiral natural cinchona alkaloids (4a,b,e,f)
proceeded smoothly to give the desired adduct 7a in moderate
yields but with poor diastereo- and enantioselectivities (Table
1, entries 2-5). It was found that QN-1-naphthoate 4c was
totally inactive in the reaction of 5a with 6a (entry 6) in spite
of its highly catalytic ability in enantioselective aldol-type
reaction of 2-oxindoles with ethyl trifluoropyruvate.10 As to the
limited conformational flexibility, ꢀ-ICD 4h was another catalyst
with increased basicity, nucleophilicity, and reduced steric
hindrance of the quinuclidine nitrogen center.11 However, it
10
11
12
13
14
15
16
17
18
19
20
21
5a 6a 4d CHCl3
5a 6a 4d DCE
5a 6a 4g THF
5a 6a 4g Et2O
5a 6a 4g PhMe
5a 6a 4d CHCl3
5a 6a 4d CHCl3
5a 6a 4d CHCl3
5b 6a 4d CHCl3
rt
rt
rt
rt
rt
0
-10
-30
rt
80
-79
-79
nde
86
86
81
trace
NRg
trace
NRg
5c 6a 4d CH2Cl2 rt
5a 6b 4d CHCl3
5a 6c 4d CHCl3
rt
rt
a Oxindole 5 (0.2 mmol), imine 6 (0.2 mmol), catalyst 4 (0.02 mmol),
solvent (200 µL), 48 h. b dr (anti/syn) determined by 1H NMR or chiral
HPLC of the reaction mixture. c Determined by chiral HPLC and refer
to the major diastereoisomers. d Solvent (2 mL). e nd: not determined.
f Reaction time: 60 h. g NR: no reaction.
could barely catalyze the addition (entry 7), which indicates
the crucial transition-state structure of the substrate-catalyst
complex (vide infra).
On the basis of these results, it was found that both of natural
cinchona alkaloid catalysts (4a,b,e,f) disfavored for highly
stereoselective reaction of 5 with 6 and appropriate bulky group
on C9 should be introduced. To our delight, when the catalyst
4d bearing a 6′-hydroxyquinoline ring with a bulky phenan-
threne group on C9 position (R2 ) 9-PHN) was employed, the
desired product 7a was isolated with an excellent yield of 90%
and high diastereoselectivity (8:92) (entry 8). The enantiomeric
excess of the major diastereoisomer could reach 82%. To the
best of our knowledge, this is the first example of asymmetric
direct Mannich-type reactions catalyzed by 6′-OH cinchona
alkaloid catalysts bearing 9-OR groups, which have been widely
applied in organocatalytic asymmetric reactions.12 The pseu-
doenantiomeric quinidine derivative 4g gave results similar to
those for 4d, but with opposite configuration (entry 9) as
determined by chiral HPLC analysis.
To examine the effect of solvents, various solvents were
employed in the reaction of 5a with 6a. Compared with that in
(7) For recent organocatalytic anti-selective direct asymmetric Mannich-type
reactions, see: (a) Zhang, H.; Mitsumori, S.; Utsumi, N.; Imai, M.; Garcia-
Delgado, N.; Mifsud, M.; Albertshofer, K.; Cheong, P. H.-Y.; Houk, K. N.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2008, 130, 875–886, and
references cited therein.
(8) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10,
3583–3586.
(9) For examples of using natural cinchona alkaloids catalyst in asymmetric
Mannich reactions, see: (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am.
Chem. Soc. 2005, 127, 11256–11257. (b) Ting, A.; Lou, S.; Schaus, S. E. Org.
Lett. 2006, 8, 2003–2006. For utilization of (DHQD)2PYR, see: (c) Poulsen,
T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A. Angew. Chem,, Int.
Ed. 2005, 44, 2896–2899.
(10) Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M.
Angew. Chem., Int. Ed. 2007, 46, 8666–8669.
(11) For recent application of ꢀ-ICD in enantioselective synthesis, see: (a)
Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507–4510. (b) Saaby, S.;
Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120–8121. (c) Nakano,
A.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357–5360,
and references cited therein.
FIGURE 2. Catalyst library for screening.
J. Org. Chem. Vol. 74, No. 12, 2009 4651

FIGURE 3. Key NOESY correlations (double-headed arrows) observed
for adduct 7a established the relative stereochemistry as the anti-
configuration.
FIGURE 4. Proposed transition state of the anti-Mannich-type reaction
of N-unprotected oxindole with N-Ts-imine catalyzed by cinchona
alkaloid 4d.
SCHEME 2. Asymmetric Addition of 2-Oxindoles 5 to
N-Ts-imines 6 under the Catalysis of 4d
mine 6b exhibited comparable activity in many kinds of
reactions, it was totally inactive in the reaction system employed
here. Less reactive N-methoxyphenyl (N-PMP) benzaldimine
6c gave the same results (entries 20 and 21).
Employing the optimal conditions, a wide range of aldimines
(6a,d-j) derived from aryl, heteroaryl, and vinyl aldehydes were
treated with 3-substituted 2-oxindoles (5a,d,e) in CHCl3 at 0
°C or room temperature in the presence of catalyst 4d to give
the products 7a-j (Scheme 2, Table 2). Good to excellent
diastereo- and enantioselectivities of the products were obtained.
The substituents with either multifarious electronic properties
or steric effect in aldimines were found to be well tolerated in
this transformation (entries 2-7), while the aldimine derived
from piperonal 6h gave the best results (dr anti/syn 95:5, ee
89%) (entry 6). Interestingly, R,ꢀ-unsaturated imine 6j was a
good substrate for the Mannich-type reaction with 5a and
exclusively afforded 1,2-addition product 7h in moderate yield
with good anti-diastereo- and enantioselectivity (entry 8). Other
3-substituted-2-oxindoles were also found to be effective for
the asymmetric Mannich-type reaction catalyzed by cinchona
alkaloid. 3-(4-Bromobenzyl)-2-oxindole 5d was facilely con-
verted to the product 7i with an 88% yield, of which the ee
could reach 97% after recrystallization. Substitution in the
phenyl ring of 2-oxindole has less effect on the yield of the
product, albeit with moderate enantioselctivity of the anti-
diastereoisomer (entry 10).
CH2Cl2 (entry 8) or DCE (entry 11), the reaction performed in
CHCl3 gave better results (entry 10). For polar oxygen-
containing solvents (such as THF, Et2O), the ee values of the
product decreased slightly (entries 12 and 13).
The use of a nonpolar solvent (e.g., toluene) would make
the yield of 7a decrease to only 41% (entry 14). The reaction
temperature also influenced the yield and selectivity notably.
The reaction performed at 0 or -10 °C afforded 7a with better
diastereo- and enantioselectivities than that at room temperature,
albeit with inferior yields (entries 15 and 16). By lowering the
temperature to -30 °C, the reaction was evidently impeded
(entry 17).
The assignment of relative configuration of the product 7a
was achieved by NMR experiments. Key NOESY correlations
were observed from H-23 to H-1 and H-8, but not to the protons
in the phenyl ring (Figure 3), which confirmed the anti-
relationship (see the Supporting Information for details).
We further examined the effect of N-substitution of 2-oxin-
dole in the reaction process. For N-methyl-2-oxindole 5b and
N-Boc-2-oxindole 5c, no addition products were detected in the
reaction with 6a (entries 18 and 19), which indicates that
the N-H subunit of oxindole is necessary for this reaction. On
the other hand, N-substitution in the aldimines also influenced
the Mannich-type reaction strongly. Although N-Boc-benzaldi-
As indicated above, although N-Boc-protected 2-oxindoles
provided syn-Mannich products under the catalysis of thiourea,8
an excess of anti-diastereomeric isomers were detected in the
Mannich-type reaction of N-unprotected 2-oxindole with N-Ts-
aldimines in the presence of cinchona alkaloid catalyst. Mean-
while, the X-ray single-crystal structure analysis of the adduct
7i13 also demonstrated that the major Mannich product had an
TABLE 2. Catalytic Enantioselective Addition of 2-Oxindoles 5 to N-Ts-imines 6a
entry
X
R1
R2
yield (%)
anti/synb
eec (%)
1
H
H
H
H
H
H
H
H
H
Br
5a, Me
5a
5a
5a
5a
5a
5a
5a
6a, Ph
7a, 77
7b, 65
7c, 90
7d, 88
7e, 79
7f, 90
7g, 71
7h, 57
7i, 88
7j, 70
95:5
86
81
80
85
85
89
83
80
2
6d, 2-Cl-C6H4
6e, 3-Cl-C6H4
6f, 4-Br-C6H4
6g, 2-OMe-C6H4
6h, 3,4-OCH2O-C6H3
6i, 2-furyl
6j, Ph-CHdCH
6a
6a
79:21
83:17
84:16
80:20
95:5
89:11
90:10
80:20
88:12
3d
4
5
6
7
8d
9
5d, 4-Br-C6H4-CH2
5e, Me
71 (97)e
70
10
b
a Oxindole 5/imine 6 ) 1:1; catalyst 4d loading ) 10 mol %; reaction performed at 0 °C unless otherwise noted. Determined by H NMR or chiral
HPLC of the reaction mixture. c Determined by chiral HPLC and refer to the anti diastereoisomers. d Reaction performed at room temperature. e After
recrystallization from petroleum ether/CH2Cl2.
1
4652 J. Org. Chem. Vol. 74, No. 12, 2009

254 nm; T ) 25 °C; tR ) 36.1 min for the S,S- and 86.5 min for
the R,R-enantiomer): 1H NMR (300 MHz, CDCl3) δ 1.62 (s, 3H),
2.27 (s, 3H), 4.42-4.53 (d, 1H, J ) 9.0 Hz), 5.39 (br, 1H),
6.44-6.46 (d, 2H, J ) 7.2 Hz), 6.65-6.68 (d, 1H, J ) 7.8 Hz),
6.84-6.89 (t, 2H, J ) 7.6 Hz), 6.98-7.10 (m, 5H), 7.20-7.23 (d,
1H, J ) 7.5 Hz), 7.29-7.31 (m, 1H), 7.41-7.44 (d, 2H, J ) 8.4
Hz); 13C NMR (75 MHz, CDCl3) δ 20.4, 21.4, 53.1, 62.8, 109.7,
122.7, 124.5, 127.3, 127.4, 127.6, 127.7, 128.8, 129.2, 130.7, 136.1,
136.6, 140.4, 143.2, 179.5; HRMS (EI) m/z calcd for C23H22N2O3S
406.1351 (M+), found 406.1348.
anti-diastereomeric structure, while the configurations of the two
newly formed chiral carbon centers were deduced as (C8S,
C15S).
Based on experimental results, we proposed a model of the
transition state to rationalize the observed anti-diastereoselection
and asymmetric induction (Figure 4). The bulky 9-phenanthryl
ether substituent at C9 position as well as the utilization of polar
solvent (chloroform) facilitated the catalyst 4d to adapt its
conformation12d to simultaneously close and activate the depro-
tonated enolated oxindole and N-Ts-imine in favoring the re-
face attack of the imine. Remarkably, the unprotected N-H of
oxindole was found to be essential for the transition state and
hence the catalytic process.14 The use of N-substituted 2-oxin-
doles (N-Me, N-Boc) gave nothing or trace addition product.
The network of hydrogen bonding forced the substituents of
the two bond-forming carbons in a staggered arrangement to
afford the anti-diastereoisomers. Deduced from the X-ray
analysis of the 7i, the re-face of the imine was preferably
attacked by the re-face of enolated oxindole, which is consistent
with the observed anti-diastereoselection in this transformation
(see the Supporting Information for details).
Acknowledgment. We thank the National Natural Science
Foundation of China and the Chinese Academy of Sciences for
financial support. L.C. gratefully acknowledges Ms. Juan Lv
(Bruker BioSpin AG Ltd.) for the operation of some NMR
experiments.
Supporting Information Available: Experimental proce-
dures, characterization data, chiral chromatographic analysis for
all new compounds, and single-crystal structure data for 7i (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed a highly anti-diastereose-
lective and enantioselective direct Mannich-type reaction of
N-unprotected 2-oxindoles with N-Ts-aldimines catalyzed by a
modified cinchona alkaloid to give versatile chiral 2-oxindole
derivatives bearing chiral amino functional moiety and a chiral
quaternary carbon center, and a transition model was proposed
for the anti-diastereoselectivity.
JO9006688
(12) For leading review on cupreines and cupreidines, see: (a) Marcelli, T.;
van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496–
7504. For examples of 6′-OH cinchona alkaloid catalysts, see: (b) Li, H.; Wang,
Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906–9907. (c) Li, H.;
Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732–733. (d) Li, H.; Song, J.;
Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948–8949. (e) Li, H.; Wang,
Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem.,
Int. Ed. 2005, 44, 105–108. (f) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc.
2006, 128, 3928–3930. (g) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am.
Chem. Soc. 2007, 129, 768–769. (h) Zhao, J.-L.; Liu, L.; Gu, C.-L.; Wang, D.;
Chen, Y.-J. Tetrahedron Lett. 2008, 49, 1476–1479. (i) Rigby, C. L.; Dixon,
D. J. Chem. Commun. 2008, 3798–3800.
(13) Crystal data for compound 7i: C29H25BrN2O3S, MW ) 561.48, tetrago-
nal, space group P4(3)2(1)2, final R indices [I > 2σ(I)], R1 ) 0.0357, wR2 )
0.0785, R indices (all data) R1 ) 0.0854, wR2 ) 0.0855, a ) 13.4440(19) Å,
b ) 13.4440(19) Å, c ) 32.156(6) Å, R ) 90°, ꢀ ) 90°, γ ) 90°, V ) 5811.9(16)
Å3, T ) 173(2) K, Z ) 8. Supplementary crystallographic data have been
deposited at the Cambridge Crystallographic Data Centre, CCDC 712210.
(14) For recent examples in which the N-H of indole plays a crucial role,
see: (a) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int.
Ed. 2005, 44, 6576–6579. (b) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.;
Zhou, Q.-L. Angew. Chem., Int. Ed. 2007, 46, 5565–5567.
Experimental Section
Representative Procedure for the Synthesis of 3,3-Disubsti-
tuted 2-Oxindoles. To the mixture of 2-oxindole 5a (30 mg, 0.2
mmol) and N-Ts-aldimine 6a (52 mg, 0.2 mmol) in CHCl3 (200
µL) at 0 °C was added the catalyst 4d (10 mg, 0.02 mmol). The
resulting mixture was continuously stirred until TLC showed
consumption of starting materials and was then directly purified
by column chromatography on silica gel (elute: petroleum ether/
ethyl acetate) to obtain the product 7a as a white solid (63 mg,
yield 77%). The ee was determined by HPLC analysis (Chiralcel
AD-H column, 5% 2-propanol in n-hexane at 1 mL ·min-1; λ )
J. Org. Chem. Vol. 74, No. 12, 2009 4653