Organocatalytic and electrophilic approach to oxindoles with C3-quaternary stereocenters

Article abstract of DOI:10.1021/ol101668z

Figure Presented. A Lewis base-catalyzed asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates derived from isatins has been investigated, which provides an electrophilic pathway to access oxindoles bearing C3-quaternary stereocenters. Excellent diastereoselectivity and high enantioselectivity have been obtained in the vinylogous functionalization of α,α-dicyanoolefin nucleophiles, giving multifunctional products with vicinal quaternary and tertiary chiral carbon centers.

Full text of DOI:10.1021/ol101668z

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4260-4263
Organocatalytic and Electrophilic
Approach to Oxindoles with
C3-Quaternary Stereocenters
Jing Peng,† Xin Huang,† Hai-Lei Cui,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug DeliVery System of Education Ministry,
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan
UniVersity, Chengdu 610041, China, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan UniVersity, Chengdu, China
ycchenhuaxi@yahoo.com.cn
Received July 19, 2010
ABSTRACT
A Lewis base-catalyzed asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates derived from isatins has been investigated, which
provides an electrophilic pathway to access oxindoles bearing C3-quaternary stereocenters. Excellent diastereoselectivity and high
enantioselectivity have been obtained in the vinylogous functionalization of r,r-dicyanoolefin nucleophiles, giving multifunctional products
with vicinal quaternary and tertiary chiral carbon centers.
The development of synthetic protocols that can access
quaternary chiral carbon centers remains as one of the most
challenging subjects in asymmetric catalysis.1 The construction
of oxindole architectures with a 3,3-disubstituted pattern is of
particular importance and attracts continuing interest because
such motifs exist in a great amount of natural products and
pharmaceutically relevant compounds.2 Undoubtedly, the ap-
plication of nucleophilic 3-substituted oxindoles provides the
most straightforward and convenient pathway to synthesize the
target oxindoles, and a variety of asymmetric reactions have
been well presented in the past years.3 On the other hand,
recently Stoltz and co-workers reported an elegant and unusual
copper-catalyzed enantioselective synthesis of C3-quaternary
oxindoles, in which a highly electrophilic o-azaxylylene was
involved from C3-halooxindoles in the presence of excess base.4
Nevertheless, the discovery of an alternative catalytic asym-
metric process that employs the oxindole moiety as the
electrophilic partner is still in demand.
(3) For selected examples, see: (a) Hamashima, Y.; Suzuki, T.; Takano,
H.; Shimura, Y.; Sedeoka, M. J. Am. Chem. Soc. 2005, 127, 10164. (b)
Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru,
T.; Shiro, M. Angew. Chem., Ed. Int. 2008, 47, 4157. (c) Ishimaru, T.;
Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem.
Soc. 2006, 128, 16488. (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.,
Ed. Int. 2007, 46, 8666. (f) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc.
2007, 129, 14548. (g) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C.
Org. Lett. 2008, 10, 3583. (h) Jiang, K.; Peng, J.; Cui, H.-L.; Chen, Y.-C.
Chem. Commun. 2009, 3955. (i) Galzerano, P.; Bencivenni, G.; Pesciaioli,
F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem.sEur. J. 2009, 15, 7846. (j) Kato, Y.; Furutachi, M.; Chen, Z.;
Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 9168. (k) Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J. Org. Lett. 2009,
11, 3874. (l) He, R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc.
2009, 131, 16620. (m) Bui, T.; Candeias, N. R.; Barbas, C. F., III. J. Am.
Chem. Soc. 2010, 132, 5574.
† West China School of Pharmacy.
‡ West China Hospital.
(1) For reviews on the construction of quaternary carbon center, see:
(a) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473. (b) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969. (c)
Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(2) For a comprehensive review, see: Zhou, F.; Liu, Y.-L.; Zhou, J. AdV.
Synth. Catal. 2010, 352, 1381.
(4) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2009, 48, 8037.
10.1021/ol101668z  2010 American Chemical Society
Published on Web 09/02/2010

Recently, we5 and others6 have developed a number of
highly stereoselective allylic alkylation reactions of Morita-
Baylis-Hillman (MBH) carbonates or acetates derived from
aldehydes by the catalysis of metal-free Lewis basic tertiary
amines or phosphines. However, to the best of our knowl-
edge, the utilization of MBH products of ketone substrates, from
which a quaternary carbon stereocenter would be generated,
has not been reported yet. We wonder whether the MBH
carbonates of isatins could be successfully applied in the Lewis
base-catalyzed allylic alkylation reaction, and thus an electro-
philic approach to afford 3,3-disubstituted oxindoles would be
realized.7 Moreover, the substitution diversity and molecular
complexity could be well generated since an array of nucleo-
philes might be selected (Scheme 1).
the γ-regioselective allylic alkylation product 4a was isolated
in quantitative yield in less than 10 min (Table 1, entry 1),
Table 1. Screening Studies of Asymmetric Allylic Alkylation of
MBH Carbonates from Isatina
entry cat. temp (°C)
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CCl4
THF
toluene
m-xylene
mesitylene 11
PhCF3
m-xylene
m-xylene
m-xylene
t (h) yieldb (%) eec (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
rt
50
50
50
50
0.1
24
99
/
/
/
24
24
24
24
17
24
10
10
14
11
/
/
/
/
/
/
/
/
Scheme 1
.
Electrophilic Approach to 3,3-Disubstituted
Oxindoles
50
7
8
9
1g
1h
1g
1g
1g
1g
1g
1g
1g
1g
1g
50
50
50
50
50
50
50
50
74
54
99
46
74
76
75
86
78
88
25
50
<5d
75
69
79
80
80
75
82
83
/
10
11
12
13
14
15
16
17
35
36
36
96
rt
-10
-20
Inspired by these considerations, we initially investi-
gated the possible C-C bond formation reaction of MBH
carbonate 2a, which was readily prepared from isatin,8
and a vinylogous nucleophile 3a,9 by the catalysis of 1,4-
diaza-bicyclo[2.2.2]octane 1a (DABCO, 10 mol %, Figure 1) at
a Unless otherwise noted, reactions were performed with 0.1 mmol of
2a, 0.12 mmol of 3a, and 10 mol % of 1 in 0.5 mL of solvent. b Isolated
yield. c Based on chiral HPLC analysis; in general, dr >99:1. d dr ) 1.6:1.
also with excellent diastereoselectivity (dr >99:1). Subse-
quently, we intended to develop an enantioselective variant.
Unfortunately, a number of modified cinchona alkaloids
1b-1f, which have afforded good results in the asymmetric
allylic alkylation of MBH carbonates from aldehydes,5
exhibited no catalytic activity in the model reaction even at
higher temperature, probably because they could not initiate
the catalytic cycle for the steric reasons (entries 2-6). To
our gratification, another known chiral tertiary amine derived
from quinidine, ꢀ-ICD 1g,6b,e demonstrated high catalytic
efficacy and delivered moderate enantiocontrol (entry 7). A
sulfide compound 1h could promote the allylic alkylation
reaction, but poor diastereo- and enantioselectivity were
observed (entry 8).10 Then, more reaction conditions were
screened with 1g to improve the enantioselectivity. It was
found that solvent had dramatic effects on the outcomes
(entries 9-14), and higher ee values could be obtained in
arene materials (entries 11-13). The reaction could be
Figure 1. Structures of tested organocatalysts.
ambient temperature. It was pleasing that the reaction
proceeded very efficiently in 1,2-dichloroethane (DCE), and
(5) (a) Cui, H.-L.; Peng, J.; Feng, X.; Du, W.; Jiang, K.; Chen, Y.-C.
Chem.sEur. J. 2009, 15, 1574. (b) Cui, H.-L.; Feng, X.; Peng, J.; Jiang,
K.; Chen, Y.-C. Angew.Chem., Int. Ed. 2009, 48, 5737. (c) Feng, X.; Yuan,
Y.-Q.; Cui, H.-L.; Jiang, K.; Chen, Y.-C. Org. Biomol. Chem. 2009, 7,
3660. (d) Zhang, S.-J.; Cui, H.-L.; Jiang, K.; Li, R.; Ding, Z.-Y.; Chen,
Y.-C. Eur. J. Org. Chem. 2009, 5804. (e) Cui, H.-L.; Huang, J.-R.; Lei, J.;
Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 720.
(6) (a) Kim, J. N.; Lee, H. J.; Gong, J. H. Tetrahedron Lett. 2002, 43,
9141. (b) Du, Y.; Han, X.; Lu, X. Tetrahedron Lett. 2004, 45, 4967. (c)
Cho, C.-W.; Krische, M. J. Angew. Chem., Int. Ed. 2004, 43, 6689. (d)
Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L. Tetrahedron: Asymmetry 2007, 18,
1990. (e) van Steenis, D. J. V. C.; Marcelli, T.; Lutz, M.; Spek, A. L.; van
Maarseveen, J. H.; Hiemstra, H. AdV. Synth. Catal. 2007, 349, 281. (f) Jiang,
Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202.
(7) For reactions with MBH products from isatins in a racemic form,
see: (a) Shanmugam, P.; Viswambharan, B.; Madhavan, S. Org. Lett. 2007,
9, 4095. (b) Selvakumar, K.; Vaithiyanathan, V.; Shanmugam, P. Chem.
Commun. 2010, 46, 2826. (c) Viswambharan, B.; Selvakumar, K.;
Madhavan, S.; Shanmugam, P. Org. Lett. 2010, 12, 2108.
(8) Chung, Y. M.; Im, Y. J.; Kim, J. N. Bull. Korean Chem. Soc. 2002,
23, 1651.
(9) Cui, H.-L.; Chen, Y.-C. Chem. Commun. 2009, 4479.
(10) Sun, X.-L.; Tang, Y. Acc. Chem. Res. 2008, 41, 937.
Org. Lett., Vol. 12, No. 19, 2010
4261

smoothly conducted at room temperature in m-xylene (entry
15), and more satisfactory results were attained at -10 °C
(entry 16). Nevertheless, further decreasing the reaction
temperature resulted in very sluggish conversion (entry 17).
Some additives were further explored, but the superior results
have not been obtained.11
Consequently, the substrate scope and limitations were
explored under the optimal conditions. The results were
summarized in Table 2. At first, a spectrum of R,R-
Table 2. Substrate Scope and Limitationsa
Figure 2. Structures of vinylogous nucleophiles.
methyl ketone due to steric hindrance (entry 12). In addition,
poor regioselectivity was given when 3m from unsym-
metrical ethyl methyl ketone was applied, while both adducts
could be easily separated (entry 13). We also investigated
the substitution effect on the aryl ring of the oxindole moiety.
Satisfying data were provided for substrates 2b and 2c
bearing electron-withdrawing groups (entries 14 and 15).
Nevertheless, slightly lower reactivity was observed for 2d
with the electron-donating group, while the similar ee value
was gained (entry 16). It was noteworthy that almost all
products were solid, thus the enantiomerically pure material
could be easily obtained by recrystallization (see entry 8,
data in parentheses).
entry
2
3
t (h)
yieldb (%)
4a, 88
4b, 50
4c, 89
4d, 84
4e, 96
4f, 81
eec (%)
1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3a
3a
3a
36
46
47
60
60
24
35
60
69
45
60
96
43
40
65
50
83
80
78
80
79
87
2d
3
4
5
6
7
4g, 98
82e
80 (98)f
85h
88
8
4h, 82 (69)f
4i, 64
9g
10
11i
12i
13d
14
15
16
4j, 88
4k,70
4l, 38
85
77
4m, 50 (4m′, 38)j
4n,83
81 (75)j
85
4o, 82
4p, 60
85
82
a Unless otherwise noted, reactions were performed with 0.1 mmol of
2, 0.12 mmol of 3, and 10 mol % of 1g in m-xylene (0.5 mL) at -10 °C.
b Isolated yield. c Based on chiral HPLC analysis; in general, dr >99:1 (if
involved). d 0.2 mmol of 3b was used. e The absolute configuration of 4g
was determined by X-ray analysis (see Figure 3). The other products were
assigned by analogy. f Data in parentheses referred to recrystallization. g At
rt. h dr ) 83:17. i At 0 °C. j Data in parentheses referred to the regioselective
product.
dicyanoolefins derived from ketones (Figure 2) was inves-
tigated.12 In general, excellent diastereoselectivity was
attained in the tested reactions. The vinylogous nucleophiles
3a-3g derived from cyclic aliphatic or aromatic ketones
could be well tolerated, affording products with high yields
and good enantioselectivity (Table 1, entries 1-7), except
for substrate 3b from cyclopentone, which delivered moder-
ate yield due to the double allylic alkylation (entry 2). On
the other hand, good results were normally obtained from
R,R-dicyanoolefins 3h-3m derived from acyclic ketones
(entries 8-13). It should be pointed out that incomplete
conversion was observed for substrate 3l from tert-butyl
Figure 3. X-ray structure of enantiopure 4g.
The multifunctional allylic-allylic products could be
efficiently converted to spirocyclic oxindoles with high
molecular complexity.13 As illustrated in Scheme 2, in the
presence of DBU, an intramolecular Michael addition of 4a
efficiently proceeded to give tetracyclic oxindole 5a without
loss of enantiopurity. Importantly, the annulation reaction
exhibited remarkable diastereoselectivity, and the iso-
merization of the double bond also showed exclusive
(11) (S)-BINOL (50%, 85% ee), (R)-BINOL (55%, 84% ee), 1,3-bis(3,5-
bis(trifluoromethyl)phenyl)thiourea(61%, 85% ee), LiClO4 (<20% yield).
(12) R,R-Dicyanoolefins derived from aldehydes failed to give the
desired products.
4262
Org. Lett., Vol. 12, No. 19, 2010

an interesting spirocyclic compound 5b bearing an exo-
methylene group was cleanly and quantitatively isolated.
In conclusion, we have developed the first Lewis base-
catalyzed allylic alkylation reaction of Morita-Baylis-Hillman
carbonates from isatins and nucleophilic R,R-dicyanoolefins,
which provides an electrophilic process to oxindoles with
C3-quaternary stereocenters. ꢀ-ICD demonstrated to be a
good chiral inducer for the asymmetric transformations, and
excellent diastereoselectivity (up to >99:1 dr) and good
enantioselectivity (up to 88% ee) have been obtained for an
array of products with high molecular complexity. We
believe that the synthetic strategy presented herein might be
expanded to construct valuable oxindoles with more struc-
tural diversity.14 The results will be reported in due course.
Scheme 2. Synthesis of Spirocyclic Oxindoles
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
China (20772084), PCSIRTC (IRT0846), and National Basic
Research Program of China (973 Program) (2010CB833300).
regioselectivity.5a The same diastereocontrol was also ob-
served for product 4m derived from acyclic substrate, and
Supporting Information Available: Experimental pro-
cedures, structural proofs, NMR spectra, and HPLC chro-
matograms of the products and cif file of enantiopure 4g.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For catalytic asymmetric reactions to construct chiral spirocyclic
oxindoles, see: (a) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem.
Soc. 2007, 129, 12396. (b) Hojo, D.; Noguchi, K.; Hirano, M.; Tanaka, K.
Angew. Chem., Int. Ed. 2008, 47, 5820. (c) Shintani, R.; Hayashi, S.-y.;
Murakami, M.; Takeda, M.; Hayashi, T. Org. Lett. 2009, 11, 3754. (d) Chen,
X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009,
131, 13819. (e) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.;
Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int.
Ed. 2009, 48, 7200. (f) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C.
Chem.sEur.J. 2010, 16, 2852. (g) Wei, Q.; Gong, L.-Z. Org. Lett. 2010,
12, 1008. (h) Jiang, K.; Jia, Z.-J.; Yin, X.; Wu, L.; Chen, Y.-C. Org. Lett.
2010, 12, 2766. (i) Chen, W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang,
X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 3132.
OL101668Z
(14) Currently, moderate enantioselectivity has been obtained when other
nucleophiles, such as malononitrile, were applied by the catalysis of ꢀ-ICD
(71% yield, 59% ee); see the Supporting Information.
Org. Lett., Vol. 12, No. 19, 2010
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