Highly diastereo- and enantioselective michael additions of 3-substituted oxindoles to maleimides catalyzed by chiral bifunctional thiourea-tertiary amine

Article abstract of DOI:10.1021/ol100822k

A highly diastereo- and enantioselective Michael addition reaction with respect to prochiral 3-substituted oxindoles and maleimides by a chiral bifunctional thiourea-tertiary amine catalyst was investigated for the first time. The corresponding adducts, containing a quaternary center at the C3-position of the oxindole as well as a vicinal tertiary center, were generally obtained in good to high yields (up to 92%) with high to excellent diastereo- (up to 99:1 dr) and enantioselectivities (up to 99% ee).

Full text of DOI:10.1021/ol100822k

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2896-2899
Highly Diastereo- and Enantioselective
Michael Additions of 3-Substituted
Oxindoles to Maleimides Catalyzed by
Chiral Bifunctional Thiourea-Tertiary
Amine
Yu-Hua Liao,†,‡ Xiong-Li Liu,†,‡ Zhi-Jun Wu,‡,§ Lin-Feng Cun,† Xiao-Mei Zhang,†
and Wei-Cheng Yuan*,†
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu
610041, China, Graduate School of Chinese Academy of Sciences, Beijing, China, and
Chengdu Institute of Biological, Chinese Academy of Sciences, Chengdu, China
yuanwc@cioc.ac.cn
Received January 31, 2010
ABSTRACT
A highly diastereo- and enantioselective Michael addition reaction with respect to prochiral 3-substituted oxindoles and maleimides by a chiral
bifunctional thiourea-tertiary amine catalyst was investigated for the first time. The corresponding adducts, containing a quaternary center
at the C3-position of the oxindole as well as a vicinal tertiary center, were generally obtained in good to high yields (up to 92%) with high to
excellent diastereo- (up to 99:1 dr) and enantioselectivities (up to 99% ee).
Stereoselective construction of vicinal quaternary-tertiary
carbon centers not only is one of the most difficult challenges
in asymmetric catalysis, but also belongs to one of the key
issues that is encountered during the synthesis of complex
molecules.1 Significant effort has been directed toward to
this area over the past decades.1,2 The addition of 3-substi-
tuted oxindoles to appropriate electrophiles provides a very
straightforward approach to access oxindole derivatives
bearing a C3-quaternary center. In addition, chiral 3,3-
disubstituted oxindoles are ubiquitous in nature and have
(2) For selected examples of related stereoselective construction of
vicinal quaternary-tertiary carbon centers, see: (a) Taylor, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 2003, 125, 11204. (b) Austin, J. F.; Kim, S.-G.;
Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5482. (c) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.;
Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105. (d) Poulsen,
T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2005, 44, 2896. (e) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 6366. (f) van Steenis, D. J. V. C.; Marcelli,
T.; Lutz, M.; Spek, A. L.; van Maarseveen, J. H.; Hiemstra, H. AdV. Synth.
† Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences.
‡ Graduate School of Chinese Academy of Sciences.
§ Chengdu Institute of Biological, Chinese Academy of Sciences.
(1) For reviews of related stereoselective construction of contiguous
quaternary-tertiary carbon centers, see: (a) Christoffers, J.; Baro, A. Angew.
Chem., Int. Ed. 2003, 42, 1688. (b) Ramon, D. J.; Yus, M. Curr. Org. Chem.
2004, 8, 149. (c) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11943. (d) Christoffers, J.; Baro, A. AdV. Synth. Catal.
2005, 347, 1473. (e) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (f) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969.
Catal. 2007, 349, 281
.
10.1021/ol100822k  2010 American Chemical Society
Published on Web 06/08/2010

been utilized as building blocks for alkaloid synthesis.3,4
Therefore, several methods for the synthesis of chiral 3,3-
disubstituted oxindoles have been developed.5,6 Discovering
diverse electrophiles to react with 3-substituted oxindoles
for the synthesis of diversely structured 3,3-disubstituted
oxindoles is still strongly desired. To the best of our
knowledge, some progress has been made in organic
synthesis using maleimides as electrophiles reacting with
various donors,7 but the asymmetric reaction between
3-substituted oxindoles and maleimides has never been
investigated. Thus, searching for a highly effective method
to realize the reaction of 3-substituted oxindoles with
maleimides is still challenging and interesting, as more
challenging molecular complexity with vicinal quaternary-
tertiary carbon centers must be created concurrently.
The past few years have witnessed a flourish of organo-
catalyzed reactions targeting the asymmetric formation of
quaternary stereocenters.8 Meanwhile, numerous reports on
thiourea-catalyzed asymmetric C-C bond-forming reactions
also have been widely published.9 In this context, as a
continuation of our studies on organocatalysis,10 we envi-
sioned that the asymmetric Michael reaction11 of 3-substi-
tuted oxindoles and maleimides should be realized with some
organocatalysts, giving a new range of oxindole derivatives
bearing vicinal quaternary-tertiary carbon centers, Herein,
we wish to describe our preliminary results.
Initially, we focused on the reaction between 2a and
N-phenylmaleimide (3a) in dichloromethane (DCM) for
obtaining a set of optimal reaction conditions. As summarized
in Table 1, in the presence of 5 mol % bifunctional
(3) For selected reviews, see: (a) Hibino, S.; Choshi, T. Nat. Prod. Rep.
2001, 18, 66. (b) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003,
42, 36. (c) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945.
(d) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (e) Galliford,
C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748
.
(4) For selected examples, see: (a) Wearing, X. Z.; Cook, J. M. Org.
Lett. 2002, 4, 4237. (b) Albrecht, B. K.; Williams, R. M. Org. Lett. 2003,
5, 197. (c) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc.
2004, 126, 14043. (d) Abadi, A. H.; Abou-Seri, S. M.; Abdel-Rahman, D. E.;
Klein, C.; Lozach, O.; Meijer, L. Eur. J. Med. Chem. 2006, 41, 296. (e)
Reisman, S. E.; Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.;
Tamaki, K.; Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc.
2008, 130, 2087. (f) Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin,
Table 1. Screening Studies of the Optimal Reaction Conditionsa
M.; Kandur, W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4711
.
(5) For transition-metal-catalyzed asymmetric reactions, see: (a) Ha-
mashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am.
Chem. Soc. 2005, 127, 10164. (b) Trost, B. M.; Brennan, M. K. Org. Lett.
2006, 8, 2027. (c) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.; Feringa,
B. L.; Minnaard, A. J. Org. Lett. 2006, 8, 2715. (d) Shintani, R.; Inoue,
M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353. (e) Ishimaru, T.;
Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem.
Soc. 2006, 128, 16488. (f) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.;
Marsden, S. P.; Ku¨ndig, E. P. Chem. Commun. 2008, 4040. (g) Tomita,
D.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 6946. (h) Hanhan, N. V.; Sahin, A. H.; Chang, W.; Fettinger, J. C.;
entry
1(x)
solvent
temp (°C) yieldb (%) drc eed (%)
1
2
3
4
5
6
7
8
9
1a (5) DCM
1b (5) DCM
1c (5) DCM
1d (5) DCM
1e (5) DCM
1f (5)
1g (5) DCM
1h (5) DCM
rt
rt
62
31
52
58
59
66
57
21
42
80
52
51
52
52
47
47
39
16
74
67
62
68
73
91
70:30 78
71:29
8
rt
rt
rt
rt
70:30 89
90:10 96
63:37 96
58:42 95
65:35 (-) 93
Franz, A. K. Angew. Chem., Int. Ed. 2010, 49, 744
.
(6) For organocatalytic asymmetric reactions, see: (a) Hills, I. D.; Fu,
G. C. Angew. Chem., Int. Ed. 2003, 42, 3921. (b) Luppi, G.; Cozzi, P. G.;
Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J. Org. Chem.
2005, 70, 7418. (c) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 3670. (d) Shaw, S. A.; Aleman, P.; Christy, J.;
Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925. (e)
Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M.
Angew. Chem., Int. Ed. 2007, 46, 8666. (f) Nakamura, S.; Hara, N.;
Nakashima, H.; Kubo, K.; Shibata, N.; Toru, T. Chem.sEur. J. 2008, 14,
8079. (g) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura,
S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 4157. (h) Tian,
X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583. (i)
Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593. (j) Duffey, T. A.;
Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14. (k) Jiang, K.;
Peng, J.; Cui, H.-L.; Chen, Y.-C. Chem. Commun. 2009, 3955. (l) Cheng,
L.; Liu, L.; Jia, H.; Wang, D.; Chen, Y.-J. Org. Lett. 2009, 11, 3874. (m)
Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.; Zhao, X.-L.; Zhou,
J. Chem. Commun. 2009, 6753. (n) Cheng, L.; Liu, L.; Jia, H.; Wang, D.;
Chen, Y.-J. J. Org. Chem. 2009, 74, 4650. (o) Galzerano, P.; Bencivenni,
G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.;
Melchiorre, P. Chem.sEur. J. 2009, 15, 7846. (p) He, R.; Ding, C.;
Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 4559. (q) Chen, X.-H.; Wei,
Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819.
(r) Li, X.; Xi, Z.-G.; Luo, S.; Cheng, J.-P. Org. Biomol. Chem. 2010, 8, 77.
(s) Li, X.; Zhang, B.; Xi, Z.-G.; Luo, S. Z.; Cheng, J.-P. AdV. Synth. Catal.
DCM
rt
rt
85:15 5
1i (5)
DCM
DCM
rt
rt
45:55 5/13
44:56 5/18
10 1j (5)
11 1d (5) CHCl3
12 1d (5) DCE
13 1d (5) p-xylene
14 1d (5) mesitylene
15 1d (5) THF
16 1d (5) CH3CN
17 1d (5) Et2O
18 1d (5) DMF
19 1d (5) DCM
20 1d (5) DCM
21 1d (5) DCM
22 1d (5) CHCl3
23 1d (10) DCM
24 1d (20) DCM
rt
92:8
96
rt
rt
rt
rt
rt
rt
rt
0
-20
-40
45
rt
90:10 96
81:19 94
87:13 95
85:15 11
80:20 47
87:13 83
80:20 10
93:7
92:8
95:5
93e
94f
95g
88:12 94h
92:8
95:5
96i
97i
rt
a Unless otherwise noted, reactions were carried out with 2a (0.2 mmol),
3a (0.24 mmol), and appropriate catalyst 1 in 1.0 mL of solvent for 10 h.
b Isolated yields. c Determined by 1H NMR. d Determined by chiral-HPLC
analysis. e Run for 18 h. f Run for 20 h. g Run for 24 h. h Run for 6 h. i 1.5
equiv of 3a was used.
2010, 352, 416
.
(7) For recently selected examples of maleimides used in organic
synthesis, see: (a) Hilt, G.; Lu¨ers, S.; Smolko, K. I. Org. Lett. 2005, 7,
251. (b) Cabrera, S.; Arraya´s, R. G.; Carretero, J. C. J. Am. Chem. Soc.
2005, 127, 16394. (c) Shen, J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu, X.;
Xu, J.; Tan, C.-H. J. Am. Chem. Soc. 2006, 128, 13692. (d) Zu, L.; Xie,
H.; Li, H.; Wang, J.; Jiang, W.; Wang, W. AdV. Synth. Catal. 2007, 349,
1882. (e) Ye, W.; Jiang, Z.; Zhao, Y.; Goh, S. L. M.; Leow, D.; Soh, Y.-
T.; Tan, C.-H. AdV. Synth. Catal. 2007, 349, 2454. (f) Na´jera, C.; Retamosa,
M. G.; Sansano, J. M. Org. Lett. 2007, 9, 4025. (g) Lu, J.; Zhou, W.-J.;
Liu, F.; Loh, T.-P. AdV. Synth. Catal. 2008, 350, 1796. (h) Soh, J. Y.-T.;
Tan, C.-H. J. Am. Chem. Soc. 2009, 131, 6904.
thiourea-tertiary amines 1a-g (Figure 1), respectively, it
was only found that 1b was inefficient for this model reaction
(entry 2) and the other analogous organocatalysts afforded
Org. Lett., Vol. 12, No. 13, 2010
2897

ature caused slightly decreased ee values and prolonged
reaction times (entries 4 vs 19-21). In contrast, when the
reaction was carried out in CH3Cl at 45 °C, it was found
that the reaction was complete in 6 h and gave 94% ee for
the major isomer, but the dr value decreased to 88:12 (entry
22). To our delight, further optimization of catalyst loading
revealed that 20 mol % of 1d was able to afford the best
yield (entries 23 and 24). On the basis of these results, a set
of optimal reaction conditions were screened out: 0.2 mmol
2a and 1.5 equiv of 3a in 1.0 mL of DCM with 20 mol %
of 1d as catalyst at room temperature.
With the optimal reaction conditions in hand, the
generality of the Michael reaction with respect to N-Boc-
3-phenyloxindole (2a) and various maleimides 3 was first
investigated. As shown in Table 2, a wide range of
Figure 1. Chiral organocatalysts screened in this work.
moderate yields and high diastereo- and enantioselectivities
at room temperature (entries 1 and 3-7). In addition, we
also investigated organocatalysts 1h-j but achieved very
poor enantioselectives (entries 8-10). Consequently, the
survey of organocatalysts 1a-j (Figure 1) revealed that the
dual functionality of chiral thiourea tertiary-amine bearing
thiourea and tertiary amine was crucial to the diastereo- and
enantioselectivity of this Michael addition. By all accounts,
1d turned out to be the most effective catalyst for this
transformation (entry 4).12 Then, screening of solvents
reveled that slight variations in diastereoselectivity and
significant solvent-dependent in enantioselectivity were
observed (entries 4 and 11-18). Despite a similar level of
dr values for these solvent, very high ee values in chlorinated
solvents (entries 4, 11, and 12), xylene (entry 13), and
mesitylene (entry 14) were obtained. At the same time, a
good ee value in diethyl ether (entry 17) and poor ee values
in THF (entry 15), CH3CN (entry 16), and DMF (entry 18)
were also observed. Thus, in an overall consideration of
reactivity, yield, dr, and ee, DCM was chosen as the optimal
solvent (entry 4). Afterward, lowering the reaction temper-
Table 2. Asymmetric Michael Reaction of
N-Boc-3-phenyloxindole (2a) and Different N-Substituted
Maleimidesa
entry
3
R1
4
yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
9
3b 4-BrC6H4
3c 4-ClC6H4
3d 4-CH3C6H4
4b
4c
4d
4e
4f
89
74
92
82
68
92
50
65
45
64
91:9
94:6
96:4
92:8
82:18
95:5
87:13
89:11
94:6
98
96
97
94
92e
96
94
86
85
91
3e
3f
3-ClC6H4
3-BrC6H4
3g
3-MeOC6H4 4g
3h 3,4-Cl2C6H3 4h
3i
3j
c-hexyl
i-propyl
4i
4j
4k
10
3k allyl
89:11
a Reaction conditions: 2a (0.2 mmol), 3 (0.3 mmol), 1d (0.04 mmol
%), and CH2Cl2 (1.0 mL) at rt for 10 h. b Isolated yields. c Determined by
1H NMR. d Determined by chiral-HPLC analysis. e The absolute configu-
ration of 4f was determined by X-ray analysis; it contains a (C7R, C20S)
configuration (see the Supporting Information). The other products of this
paper were assigned by analogy.
(8) For a recent review of organocatalytic formation of quaternary
stereocenters, see: (a) Marco, B.; Tecla, G. Synthesis 2009, 1583, and
references cited therein.
(9) For selected reviews of bifunctional urea and thiourea catalysts, see:
(a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (b) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (c) Connon, S. J.
Chem.sEur. J. 2006, 12, 5418. (d) Doyle, A. G.; Jacobsen, E. N. Chem.
ReV. 2007, 107, 5713. (e) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc. Jpn.
2008, 81, 785. (f) Connon, S. J. Synlett 2009, 354.
N-aromatic and N-aliphatic maleimides worked well with
2a, and the reaction tolerated a number of functional
groups on the electrophile. For maleimide derivatives
3b-h with either electron-donating or electron-withdraw-
ing substituents on the phenyl ring, the reaction smoothly
gave the desired products in high diastereoselectivity and
high to excellent enantioselectivity (92-98% ee) for the
major isomer (entries 1-7). For the N-linear and N-
branched aliphatic substrates 3i-k, the reaction also
provided the corresponding products with high dr and ee
values but moderate yields (entries 8-10).
(10) (a) Zheng, H.-J.; Chen, W.-B.; Wu, Z.-J.; Deng, J.-G.; Lin, W.-Q.;
Yuan, W.-C.; Zhang, X.-M. Chem.sEur. J. 2008, 14, 9864. (b) Liao, Y.-
H.; Zhang, H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Tetrahedron: Asymmetry 2009, 20, 2397. (c) Xue, Z.-Y.; Jiang, Y.; Yuan,
W.-C.; Zhang, X.-M. Eur. J. Org. Chem. 2010, 616. (d) Chen, W.-B.; Du,
X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010, 66, 1441.
(e) Liao, Y.-H.; Chen, W.-B.; Wu, Z.-J.; Du, L.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. AdV. Synth. Catal 2010, 352, 827. (f) Zhang, H.; Cun, L.-F.;
Zhang, X.-M.; Yuan, W.-C. Lett. Org. Chem. 2010, 7, 219.
(11) (a) Ballini, R.; Bosica, G.; Fiorini, D.; Palmeiri, A.; Petrini, M.
Chem. ReV. 2005, 105, 933. (b) Shibasaki, M.; Matsunaga, S. Chem, Soc,
ReV. 2006, 35, 269. (c) Ting, A.; Schaus, S. E. Eur, J. Org. Chem. 2007,
5797.
(12) For selected examples using catalysts that closely resemble 1d, see:
(a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem.
Soc. 2007, 127, 119. (b) Li, B.-J.; Lin, J.; Liu, M.; Chen, Y.-C.; Ding,
L.-S.; Wu, Y. Synlett 2005, 603. (c) Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang,
L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2006, 4,
2097. (d) Marini, F.; Sternativo, S.; Del Verme, F.; Testaferri, L.; Tiecco,
M. AdV. Synth. Catal. 2009, 351, 103.
Subsequently, the scope of the Michael reaction with
respect to various N-Boc-3-substituted oxindoles 2b-k and
N-phenyl maleimide (3a) or N-p-chlorophenyl maleimide
(3c) was also examined (Table 3). Generally, the desired
2898
Org. Lett., Vol. 12, No. 13, 2010

Table 3. Asymmetric Michael Reaction of Different
3-Substituted Oxindoles to Maleimides 3a or 3ca
Table 4. Examination of the Effects of N-Protection Group of
Oxindolea
entry
R
4
yield (%)
dr
ee (%)
96
1
2
3
4
5
6
Boc (2a)
H (2l)
Me (2m)
Bn (2n)
EtOCO (2o)
Ac (2p)
4a
4v
4w
4x
4y
4z
58
90:10
trace
nrb
nrb
60
entry
2
3
4
yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
2g
2h
2i
3a
3a
3a
3a
3a
3a
3c
3c
3c
3c
4l
86
87
80
81
90
67
75
87
73
65
92:8
94:6
94:6
92:8
92:8
99:1
90:10
63:37
90:10
95:5
95
97
95
99
96
94e
94
94
96
97f
63:37
53:47
16/4
1/1
4m
4n
4o
4p
4q
4r
4s
4t
36
a The same reaction conditions as in Table 1, entry 4. b nr ) no reaction.
2j
2k
10
4u
a Reaction conditions: 2a (0.2 mmol), 3 (0.3 mmol), 1d (0.04 mmol
%), and CH2Cl2 (1.0 mL) at room temperature for 10 h. b Isolated yields.
c
Determined by H NMR. d Determined by chiral-HPLC analysis. e Run
1
for 36 h. f Run for 24 h.
oxindole products bearing various substituents at C3-position
were obtained in moderate to good yields with good to
excellent dr and ee. In most cases, more than 90:10 dr values
were observed (entries 1-7, 9, and 10). In the only one
exceptional case, moderate dr (63:37) was provided in the
addition of 2i to 3c (entry 8). It should be noted that, for the
above-surveyed cases, all of the major isomeric products
4l-u exhibited greatly satisfied ee values (94-99%).
Additionally, we also examined the effects of N-protection
group of oxindole. As shown in Table 4, under the same
reaction conditions, N-unprotected (entry 2), N-methyl (entry
3), and N-benzyl (entry 4) decreased the reaction rate. At
the same time, N-carbethoxy (entry 5) and N-acetyl (entry
6) protected substrates provided poor results. However, in
sharp contrast, N-Boc-oxindole 2a gave the desired product
with acceptable results (entry 1). This indicates the N-Boc
group is crucial for the reactivity and stereocontrol.
Notably, another electrophile, maleic anhydride, was also
attempted in this study with 1a as catalyst (Figure 2). To
our delight, the addition reactions of oxindoles 2d and 2b
to maleic anhydride using 1a proceeded smoothly (see the
Supporting Information) and provided the desired products
in good yields with good diastereo- and enantioselectivites
(5a: 71% yield, 94:6 dr and 85% ee; 5b: 76% yield, 95:5 dr
and 85% ee).
Figure 2. Experimental results with maleic anhydride as electro-
phile.
prochiral 3-substituted oxindoles and maleimides by a chiral
bifunctional thiourea-tertiary amine catalyst. The high
stereoselectivity and very broad substrate scope of this
reaction make it potentially useful in the synthesis of a new
range of oxindole derivatives. The desired products of this
reaction, containing a quaternary center at the C3-position
of the oxindole as well as a vicinal tertiary center that are
readily obtained via this viable approach, are difficult to
access through other methods. Investigations are ongoing in
our laboratory to utilize versatile oxindoles as nucleophiles
with chiral organocatalysts for asymmetric catalysis.
Acknowledgment. We are grateful for financial support
from the NSFC (No. 20802074) and the National Basic
Research Program of China (973 Program) (2010CB833300).
Supporting Information Available: Experimental pro-
cedures, spectral data, X-ray crystal structure, and a CIF.
This information is available free of charge via the Internet
at http://pubs.acs.org.
In summary, we have developed a highly diastereo- and
enantioselective Michael addition reaction with respect to
OL100822K
Org. Lett., Vol. 12, No. 13, 2010
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