Diastereo- and enantioselective conjugate addition of 3-substituted oxindoles to nitroolefins catalyzed by a chiral Ni(OAc)2-diamine complex under mild conditions

Article abstract of DOI:10.1021/ol201927c

A simple catalyst system assembled from an enantiomerically pure diamine ligand and Ni(OAc)₂ efficiently generates chiral metal enolates derived from 3-substituted oxindoles bearing an N-1 carbonyl group. The enolates smoothly undergo diastereo

Full text of DOI:10.1021/ol201927c

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5064–5067
Diastereo- and Enantioselective
Conjugate Addition of 3-Substituted
Oxindoles to Nitroolefins Catalyzed
by a Chiral Ni(OAc)2-Diamine Complex
under Mild Conditions
Yan-Yan Han,†, Zhi-Jun Wu,‡ Wen-Bing Chen,†, Xi-Lin Du,§ Xiao-Mei Zhang,†
and Wei-Cheng Yuan*,†
National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu 610041, China, Chengdu Institute of
Biology, Chinese Academy of Sciences, Chengdu 610041, China, Department of General
Surgery, TangDu Hospital, The Fourth Military Medical University, Xi’an 710038,
China, and Graduate School of Chinese Academy of Sciences, Beijing 100049, China
yuanwc@cioc.ac.cn
Received July 16, 2011
ABSTRACT
A simple catalyst system assembled from an enantiomerically pure diamine ligand and Ni(OAc)2 efficiently generates chiral metal enolates derived
from 3-substituted oxindoles bearing an N-1 carbonyl group. The enolates smoothly undergo diastereo- and enantioselective conjugate addition
to a wide range of nitroolefins under mild reaction conditions, furnishing 3,3-disubstituted oxindole products bearing two vicinal quaternary/
tertiary stereocenters in 74ꢀ95% yields and 60:40 to 99:1 dr, 71ꢀ97% ee.
3-Tetrasubstituted oxindoles have attracted significant
attention of some synthetic and medicinal chemistry com-
munities because of the prevalence of them in a wide
variety of structurally complex and biologically active
compounds.1 In particular, 3,30-disubstituted oxindoles
with β-amino functionality are a key structural feature of
several classes of pharmaceuticals and natural products
and are extremely versatile building blocks that can
undergo syntheticallyuseful transformations.1,2 The devel-
opment of efficient synthetic methods for the asymmetric
stereocontrolled construction of 3,30-disubstituted oxi-
ndoles bearing β-amino functionality would be especially
desirable.3,4 Therefore, in view of the high nucleophilicity
(3) For selected examples, see: (a) Chen, X.-H.; Wei, Q.; Luo, S.-W.;
Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (b) Yasui, Y.;
Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303. (c) Trost, B. M.;
Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548. (d) Ogawa, S.;Shibata, N.;
Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2007,
46, 8666. (e) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (f)
Dounay, 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.
(4) Leading examples of asymmetric conjugate additions of 3-sub-
stituted oxindoles to nitroolefins, see: (a) Ding, M.; Zhou, F.; Qian,
Z.-Q.; Zhou, J. Org. Biomol. Chem. 2010, 8, 2912. (b) Li, X.; Zhang, B.;
Xi, Z.-G.; Luo, S. Z.; Cheng, J.-P. Adv. Synth. Catal. 2010, 352, 416. (c)
He, R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 16620.
(d) Kato, Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168. (e) Bui, T.; Syed, S.;
Barbas, C. F., III. J. Am. Chem. Soc. 2009, 131, 8758.
† Chengdu Institute of Organic Chemistry.
Graduate School of Chinese Academy of Sciences.
‡ Chengdu Institute of Biology.
§ TangDu Hospital.
(1) For selected reviews, see: (a) Hibino, S.; Choshi, T. Nat. Prod. Rep.
2001, 18, 66. (b)DaSilva, J. F. M.;Garden, S. J.;Pinto, A. C. J.Braz. Chem.
Soc. 2001, 12, 273. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209. (d) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (e)
Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36. (f) Galliford,
C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
(2) For selected review, see: Trost, B. M.; Brennan, M. K. Synthesis
2009, 3003 and references therein.
r
10.1021/ol201927c
Published on Web 08/31/2011
2011 American Chemical Society

Scheme 1
Scheme 2. Strategy for Metal-Catalyzed Asymmetric Conjugate
Addition of 3-Substituted Oxindoles to Nitroolefins
of the oxindole 3-position5 and the high potential to
rapidly increase molecular complexity as well as the rich
chemistry of the nitro group,6 the catalytic asymmetric
conjugate addition of 3-substituted oxindoles to nitro-
olefins represents one of the most powerful and straightfor-
ward approaches toward optically active 3,30-disubstituted
oxindoles with β-amino functionality and has understand-
ably attracted great synthetic interest.4 However, to the
best of our knowledge, so far, there are only three reports
concerning this conjugate addition reaction with organo-
catalysts described by Barbars,4e Luo,4b and Maruoka,4c
respectively (Scheme 1), and only one approach via an
organometallic pathway was realized by Shibasaki and co-
workers with a homodinuclear Mn(III)2ꢀSchiff base com-
plex as catalyst (Scheme 1).4d Even so, other new and more
general and efficient catalyst systems for this conjugate
addition reaction are still needed. Herein is presented our
recent effort in the development of Ni(OAc)2ꢀdiamine-
catalyzed asymmetric conjugate addition of 3-substituted
oxindoles tonitroolefins, giving a seriesof Michael adducts
in up to 95% yield with up to 95% ee and 99:1 dr.
In addition, our recent endeavor to construct novel 3-tet-
rasubstituted oxindole-containing compounds and utilize the
nucleophilicity of the oxindole 3-position in asymmetric
synthesis led us to further focus on the asymmetric conjugate
addition of 3-substituted oxindoles to nitroolefins with me-
tallic catalysts.7 Importantly, we envisioned that the specified
3-substituted oxindoles, incorporating an carbonyl group at
N-1 position, were prone to coordination with a variety
of chiral Lewis acids via their 1,3-dicarbonyl framework
Figure 1. Chiral diamine ligands evaluated in this study.
(Scheme 2), and then the activation by metal complexes with
an endogenous basic counteranion might deliver a chiral
metal enolate (I) with a specific geometry. Afterward, the
chiral metal enolate (I) assembly with Michael acceptor
nitroolefins via TS would promote the reaction in a stereo-
selective manner for giving the desired chiral adducts
(Scheme 2). Notably, the accomplishment of this research
will represent another successful approach for the conjugate
addition reaction of 3-substituted oxindoles to nitroolefins
via organometallic pathway after Shibasaki’s report.4d
Initially, diamine ligand8 L1 (Figure 1) was selected to
coordinate with various metal salts for promoting the
conjugate addition reaction of oxindole 1a with nitroolefin
2a (Table 1). Delightfully, it was found that the desired
product 3a was obtained with Cu(acac)2ꢀL1 complex as
catalyst in 66% yield in 10 h but with only 3% ee (Table 1,
entry 1). However, some other complexes based on ligand
L1 with various salts, such as Zn(OTf)2, Cu(OTf))2, CrCl2,
(5) For a recent review relating to the application of oxindoles as
nucleophiles, see: Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010,
352, 1381 and references therein.
(6) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
Weinheim, 2001.
NiCl2, Ni(OAc)2 4H2O, and Ni(OAc)2, showed good
3
inductive potential for this reaction (Table 1, entries
2ꢀ7). By comparison, the cheap and air-stable Ni(OAc)2
was especially attractive because product 3a could be
smoothly obtained in 86% yield with 96:4 dr and 85% ee
(Table 1, entry 7).
(7) For reports pertinent to the asymmetric catalysis from our research
group, see: (a) Liao, Y.-H.; Zhang, H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Tetrahedron: Asymmetry 2009, 20, 2397. (b) Liao, Y.-H.;
Chen, W.-B.; Wu, Z.-J.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Adv. Synth. Catal. 2010, 352, 827. (c) Chen, W.-B.; Du, X.-L.; Cun, L.-F.;
Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010, 66, 1441. (d) Liao, Y.-H.;
Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett.
2010, 12, 2896. (e) Chen, W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang,
X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 3132. (f) Liu, X.-L.; Liao, Y.-H.;
Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2010, 75,
4872. (g) Chen, W.-B.; Wu, Z.-J.; Hu, J.; Cun, L.-F.; Zhang, X.-M.; Yuan,
W.-C. Org. Lett. 2011, 13, 2472. (h) Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang,
X.-M.; Yuan, W.-C. J. Org. Chem. 2011, 76, 4008. (i) Sun, H.-W.; Liao,
Y.-H.; Wu, Z.-J.; Wang, H.-Y.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron
2011, 67, 3991. (j) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang,
X.-M.; Yuan, W.-C. Adv. Synth. Catal. 2011, 353, 1720.
(8) For selected examples with chiral diamine ligands for asymmetric
induction, see: (a) Nakamura, A.; Lectard, S.; Hashizume, D.;
Hamashima, Y.; Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4036. (b)
Berthiol, F.; Matsubara, R.; Kawai, N.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2007, 46, 7803. (c) Matsubara, R.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2006, 45, 7993. (d) Matsubara, R.; Kawai, N.; Kobayashi, S.
Angew. Chem., Int. Ed. 2006, 45, 3814. (e) Matsubara, R.; Nakamura,
Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 3257. (f) Matsubara,
R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 1679.
(g) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583.
Org. Lett., Vol. 13, No. 19, 2011
5065

Table 1. Seeking Optimal Metal Saltsa
Table 2. Optimization of the Reaction Conditionsa
entry ligand solvent time (h) yieldb (%)
drc
eed (%)
entry
MX2
time (h) yieldb (%)
drc
eed (%)
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L9
L4
L4
L4
L4
L4
L4
L4
L4
L4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
DMF
10
11
11
5
86
88
93
93
98
91
87
91
96
91
93
89
96
91
92
87
93
91
96/4
85
82
1
2
3
4
5
6
7
Cu(acac)2
Zn(OTf)2
Cu(OTf))2
CrCl2
10
10
17
16
16
10
10
66
72
38
64
86
93
86
89/11
92/8
95/5
92/8
95/5
96/4
96/4
ꢀ3
53
81
66
83
76
85
89/11
90/10
99/1
3
76
4
89
5
6
89/11
90/10
79/21
84/16
94/6
ꢀ81
ꢀ16
ꢀ33
ꢀ10
39
NiCl2
6
9
Ni(OAc)2 4H2O
3
7
9
Ni(OAc)2
8
9
a Unless otherwise noted, the reaction was carried out with 1a (0.15
mmol), 2a (0.225 mmol), MX2 (0.015 mmol), and L1 (0.018 mmol) in
toluene (0.5 mL) under N2 atmosphere at room temperature for the
indicated time. b Isolated yield. c Determined by HPLC analysis. d De-
termined by chiral HPLC.
9
5
10
11
12
13
14
15
16
17
18
5
94/6
87
5
63/37
84/16
85/15
81/19
99/1
0
THF
5
7
CH3CN
toluene
toluene
toluene
toluene
toluene
5
32
10
5
54e
77f
79g
89h
95i
With this promising lead in hand, we next sought to
further optimize reaction conditions. A series of chiral
diamine ligands L1ꢀ9 (Figure 1) were designed, synthe-
sized, and further evaluated in the model reaction (Table 2).
To our delight, high yields and stereoselectivities were
obtained with chiral 1,2-diphenylethane-1,2-diamine-de-
rived ligands L1ꢀ3, respectively (Table 2, entries 1ꢀ3). In
addition, the use of the ligand L4,9 synthesized first by us
for strengthening the asymmetric inductive potential, re-
sulted in better reactivity, diastereoselectivity, and enan-
tioselectivity (Table 2, entry 4).9 We further synthesizedthe
similar ligands L5ꢀ7 and employed them into the same
reaction. It was found that these ligands were not superior
to L4 and led to a longer reaction time and decreased
diastereo- and enantioselectivity, as well as inducted an
opposite configuration (Table 2, entries 5ꢀ7 vs entry 4).
Furthermore, when ligands L8 and L9 were examined, the
enantioselectivities were significantly decreased (Table 2,
entries 8 and 9). These studies indicated that the appropriate
match between the chiral diamine moiety and the axial chiral
binaphthalene moiety in the ligands L4 was crucial for the
enantioselectivity. Afterward, the effect of solvent, reaction
temperature, catalyst loading, and reactant concentration
for this transformation was further investigated with L4 as
the optimal catalyst (Table 2, entries 10ꢀ18). Various
solvents were well tolerated, but toluene was identified as
the most favorable solvent (Table 2, entry 4 vs 10ꢀ13). It is
noteworthy that a racemic product was obtained in DMF as
solvent (Table 2, entry 11), and then the suitable reaction
temperature and catalyst loading were determined as at
room temperature and with 10 mol % Ni(OAc)2ꢀL4 com-
plex (Table 2, entry 4 vs 14ꢀ17). Finally, the transformation
was carried out at lower concentration, giving rise to an
significantly increased ee value (Table 2, entry 18).
9
95/5
4
99/1
20
99/1
a Unless otherwise noted, the reaction was carried out with 1a (0.15
mmol), 2a (0.225 mmol), Ni(OAc)2 (0.015 mmol), and ligand (0.018
mmol) in toluene (0.5 mL) under N2 atmosphere at room temperature
for the indicated time. b Isolated yield. c Determined by HPLC analysis.
d Determined by chiral HPLC. e Run at 0 °C. f Run at 40 °C. g With 5 mol %
Ni complex as catalyst. h With 20 mol % Ni complex as catalyst.
i 3.0 mL of toluene was used, c = 0.05 M based on substrate 1a.
With the optimized reaction conditions in hand, the
substrate scope of this reaction was explored by the reac-
tion of 3-substituted oxindoles with various substituted
nitroolefins. As shown in Table 3, the nitroolefins with
both electron-withdrawing and electron-donating aro-
matic substituents at the β-position reacted smoothly with
oxindole 1a to give the desired adducts in good to high
enantioselectivities (71ꢀ95% ee) and good to excellent
diastereoselectivities (75:25 to 99:1 dr) (Table 3, entries
2ꢀ9). Additionally, the process was also applicable to
heteroaromatic nitroolefins, and the corresponding pro-
duct was obtained in highly stereoselectivity (up to 99:1 dr
and 97% ee) under the mild reaction conditions (Table 3,
entries 10ꢀ11). On the other hand, consistently high
diastereoselectivities (90:10 to 99:1 dr) and enantioselec-
tivities (76% to 90% ee) were observed for oxindoles with
different substituents at the C3 and C5 positions (Table 3,
entries 12ꢀ15). Moreover, similar satisfied results were
also achieved, respectively, with N-Boc-oxindole 1f and N-
Cbz-oxindole 1gasMichael donoraddition to2aunder the
same reaction conditions (Table 3, entries 16ꢀ17). Un-
fortunately, we found that oxindole 1a, which readily
reacted with various aromatic nitroolefins, was not able
to react with aliphatic nitroolefins 2l under the standard
reaction conditions (Table 3, entry 18). After that, we
also found that no reaction proceeded with N-H- or
(9) For the detailed information about the synthesis of L4ꢀ8, see the
Supporting Information.
5066
Org. Lett., Vol. 13, No. 19, 2011

Table 3. Scope of the Reactiona
entry
1
R4
time (h) 3/yieldb (%) drc eed (%)
Figure 2. Proposed transition-state models for the conjugate
addition.
1
2
3
4
5
6
7
8
9
1a Ph (2a)
20
18
18
18
36
36
16
16
36
20
20
48
48
24
24
12
11
24
24
24
3aa/91
3ab/94
3ac/93
3ad/95
3ae/74
3af/76
3ag/91
3ah/91
3ai/74
3aj/90
3ak/91
3ba/81
3ca/79
3da/95
3ea/94
3fa/74
3ga/83
3al/nrf
3ha/nrf
3ia/nrf
99/1
95
95
93
88
89
85
95
95
71
83
97
85
76
90
80
nde
nde
1a 4-Br-C6H4 (2b)
1a 4-Cl-C6H4 (2c)
1a 4-NO2-C6H4 (2d)
1a 4-MeO-C6H4 (2e)
1a 4-Me-C6H4 (2f)
1a 4-F-C6H4 (2g)
1a 2- Br-C6H4 (2h)
1a 2-MeO-C6H4 (2i)
99/1
99/1
that in the transition state the nitronate anion is stabilized
by interaction at the open apical positon on the nickel. In the
disfavored transition state, the aromatic group of the nitroo-
lefins faces steric interactions with the bulky binaphthalene
moiety of chiral ligand L4; thus, the activated metal enolate
attacks the Michael acceptor from the Re face (Figure 2,
TS2). On the other hand, in the favored transition state, the
bulky binaphthalene moiety of chiral ligand L4 is oriented
away form the aromatic group of the nitroolefins, and the
transition state TS1 is more favorably formed than TS2.
Consequently, the activated metal enolate approaches the
Michael acceptor from its Si face accounting for the absolute
configuration of the final products (Figure 2, TS1). Addi-
tionally, the πꢀπstacking interaction between the phenyl ring
of 3-substituted oxindoles and the aromatic groups on the
nitroolefins probably has an important effect on the reactivity
of addition reaction since no reaction was observed when
aliphatic nitroolefin substrate was used (Table 3, entry 18).
In conclusion, a simple catalyst system assembled from
an enantiomerically pure diamine ligand and Ni(OAc)2
efficiently generates chiral metal enolates derived from
3-substituted oxindoles bearing an N-1 carbonyl group.
The enolates smoothly undergo diastereo- and enantiose-
lective conjugate addition to a wide range of nitroolefins
under mild reaction conditions, furnishing the correspond-
ing 3,3-disubstituted oxindole productsbearing two vicinal
quaternary/tertiary stereocenters in 74ꢀ95% yields and
60:40 to 99:1 dr, 71ꢀ97% ee. It is worth noting that
incorporating a carbonyl group on N-1 for the formation
of the 1,3-dicarbonyl framework of oxindoles is crucial to
the formation of chiral metal enolate and then promoting
the conjugate addition reaction in a stereoselective manner.
Studies to explore the addition of similar chiral metal
enolates to alternative electrophiles and to apply these
enolization conditions to alternative nucleophilic compo-
nents are underway and will be reported in due course.
90/10
99/1
99/1
99/1
90/10
75/25
90/10
99/1
10 1a 2-furyl (2j)
11 1a 4-thienyl (2k)
12 1b Ph (2a)
13 1c Ph (2a)
14 1d Ph (2a)
15 1e Ph (2a)
16 1f Ph (2a)
17 1g Ph (2a)
18 1a c-hexyl (2l)
19 1h Ph (2a)
20 1i Ph (2a)
90/10
90/10
99/1
90/10
60/40
99/1
a Unless otherwise noted, the reactions were carried out with 1 (0.15
mmol), 2 (0.225 mmol), Ni(OAc)2 (0.015 mmol), and L4 (0.018 mmol) in
toluene (3.0 mL) under N2 atmosphere at room temperature for the
indicated time. b Isolated yield. c Determined by 1H NMR. d Determined
by chiral HPLC. e Not determined because the method for chiral HPLC
analysis was not yet established. f nr = no reaction.
N-Bn-oxindole (Table 3, entries 19 and 20). Thus, these
substrates scope studies reveal that the carbonyl protecting
group in the N-1 position is essential for the formation of
1,3-dicarbonyl framework of oxindoles and that the 1,3-
dicarbonyl scaffold facilitates the coordination of oxi-
ndoles with the Ni(OAc)2ꢀdiamine complex and further
formation of the metal enolate, thus promoting the occur-
rence of conjugate addition reaction (Scheme 2).
The absolute and relative stereochemistry of 3aa was
determined by transforming the N-ethoxycarbonyl group
of 3aa into the N-Boc group and then comparing the chiral
HPLC analysis with the literature report.10 The absolute
configuration of the two vicinal quaternary/tertiary stereo-
centers was finally assigned as S for C3 and R for the
remaining stereocenter.10 Those of other adducts were
assumed to have similar configurations as 3aa. Moreover,
on the basis of the results as studied above and the relevant
research reported by Evans et al.,8g the observed stereo-
chemistry can be explained rationally by the proposed
transition-state models shown in Figure 2. One can assume
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(No. 20802074) and the National Basic Research Program
of China (973 Program) (2010CB833300).
Supporting Information Available. Experimental details
and characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) For more details about the determination of the configuration of
the products, see the Supporting Information.
Org. Lett., Vol. 13, No. 19, 2011
5067