Asymmetric Michael addition reaction of 3-substituted oxindoles to nitroolefins catalyzed by a chiral alkyl-substituted thiourea catalyst

Article abstract of DOI:10.1002/adsc.200900630

A simple alkylthiourea was found to be an effective catalyst for the Michael addition reaction of 3-substituted oxindole to nitroolefins. A number of 3,3′-substituted oxindole derivatives, which have two vicinal quaternary-tertiary chiral centers were syn

Full text of DOI:10.1002/adsc.200900630

FULL PAPERS
DOI: 10.1002/adsc.200900630
Asymmetric Michael Addition Reaction of 3-Substituted
Oxindoles to Nitroolefins Catalyzed by a Chiral Alkyl-
Substituted Thiourea Catalyst
Xin Li,a Bo Zhang,b Zhi-Guo Xi,b Sanzhong Luo,a,* and Jin-Pei Chenga,b,*
a
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and
Function , Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, Peopleꢀs Republic of China
Fax : (+86)-10-6255-4449; e-mail: luosz@iccas.ac.cn
Department of Chemistry and State Key Laboratory of Elementoorganic Chemistry, Nankai University, Tianjin 300071,
b
Peopleꢀs Republic of China
Received: September 11, 2009; Revised: November 15, 2009; Published online: January 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900630.
Abstract: A simple alkylthiourea was found to be an vicinal quaternary-tertiary chiral centers were syn-
effective catalyst for the Michael addition reaction of thesized with up to 99% yield, 19:1 dr and 98% ee.
3-substituted oxindole to nitroolefins. A number of
3,3’-substituted oxindole derivatives, which have two Keywords: bifunctional thioureas; Michael addition
reaction; nitroolefins; organocatalysis; oxindoles
Introduction
merous impressive catalytic applications, however, the
detailed mechanism of thiourea catalysis remains to
With its origin deeply rooted in enzymatic catalysis, be disclosed. In addition, the development of simple
small molecular hydrogen bonding catalysis has been and new thiourea catalysts is still highly desirable in
evolved as a powerful catalytic motif in asymmetric order to further extend the synthetic applications and
catalysis over the last ten years.[1] Chiral thiourea rep- to overcome the limitations of current catalysts with
resents one such prominent type of asymmetric H- respect to both catalytic efficiency and scope. Recent-
bonding catalyst. In particular, tertiary amine-thiour- ly, we have initialized a program for elucidating a sys-
eas, for example, Takemotoꢀs catalyst and Jacobsonꢀs temic electronic activity-stereoselectivity relationship
À
catalyst, have enabled a number of chiral C C bond (EASR) of urea/thiourea catalysis, which eventually
forming transformations featuring distinctive bifunc- would be helpful in guiding the design of new cata-
tional activations of substrates. In the context of nu- lysts and in understanding the catalytic mechanism.[2]
Scheme 1. The identification of a novel alkyl-substituted thiourea catalyst 1b.
416
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 416 – 424

Asymmetric Michael Addition Reaction of 3-Substituted Oxindoles to Nitroolefins
During this study, we noticed that thioureas with alkyl tion[8] etc., have been developed towards the con-
side chains such as 1a, although less acidic than aro- struction of oxindoles bearing quaternary centers at
matic thioureas such as Takemotoꢀs catalyst, turned the 3-positions.[9] However, most of these catalytic
out to be favorable, but as yet largely overlooked cat- methods for the synthesis of oxindoles require the use
alysts for the typical asymmetric bifunctional catalysis of transition metals, organocatalytic methods to these
(Scheme 1). An optimal and simple catalyst 1b was valuable structural motifs, especially for the synthesis
then reached via simply electronic tuning of the alkyl of 3,3’-substituted oxindoles with two vicinal quater-
side chain, demonstrating comparable performance nary-tertiary chiral centers, has been less developed
compared with the well-recognized aromatic thiour- until very recently.[7a] Barbas reported a Takemoto-
eas (Scheme 1).
type aromatic thiourea catalyst for this class of reac-
Due to their promising biological profiles and inter- tions with excellent yields and stereoselectivity.[7a] In
esting structural features, oxindole alkaloids[3] such as this context, it was pleasing to find out that the alkyl-
physostigmine, horsfiline, coerulescine, alstonisine chi- substituted thiourea 1b, identified from our physical
tosenine and strychnofoline have been interesting tar- organic studies, was also an optimal catalyst for this
À
gets for asymmetric total synthesis and a great deal of challenging quaternary-tertiary C C bond forming
asymmetric catalytic reactions, including allylic alkyla- Michael addition reaction, leading to a highly efficient
tion,[4] aldol reactions of oxindoles,[5] Heck reaction,[6] and stereoselective protocol for the synthesis of 3,3’-
Michael addition reaction[7] and cyanoamidation reac-
Table 1. Screening of different thiourea catalysts.[a]
Entry
Catalyst
Time [h]
Yield[b] [%]
dr[c]
ee[d] [%]
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
1g
1h
12
12
12
12
12
72
72
96
93
95
98
92
nr[e]
nr
4:1
3:1
3:1
3:1
5:1
nd[f]
nd
85
69
67
81
À76
nd
nd
[a]
The reaction was carried out on a 0.1-mmol scale in 200 mL dry toluene at 48C, and the molar ratio of oxindole/nitrostyr-
ene is 1/2.
Isolated yield.
Determined by H NMR.
Determined by HPLC.
No reaction.
[b]
[c]
[d]
[e]
[f]
1
Not determined.
Adv. Synth. Catal. 2010, 352, 416 – 424
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
417

Xin Li et al.
FULL PAPERS
oxindole compounds.[11,12] The detailed results from DMSO, DMF and methanol were not applicable lead-
this study are presented herein.
ing to totally depleted activity (Table 2, entries 1 and
2) or low enantioselectivity (Table 2, entry 3). The re-
actions generally proceeded smoothly in less polar
solvent such as CH2Cl2, CHCl3, ClCH2CH2Cl, C6H6
and PhCH3. Among a number of solvents examined,
Results and Discussion
The Michael addition reaction of oxindole 2a, a com- CH2Cl2 was the optimal one, furnishing the best enan-
mercially available compound, to nitrostyrene was se- tioselectivity (Table 2, entry 7, 98% yield, dr=4:1,
lected as our initial test reaction. A variety of bifunc- 91% ee). When the reaction was conducted with cata-
tional tertiary amine-thiourea catalysts 1c–1f, which lyst 1b in CH2Cl2 at À408C, the yield and dr value
have been widely applied in a broad range of asym- were retained, and the ee value could be further im-
metric Michael reactions,[13–16] together with catalyst proved to 93% (Table 2, entry 13).
1b, were then tested in the model reaction and the re-
With the optimal conditions in hand, the substrate
sults are summarized in Table 1. As shown, all cata- scope was next explored with different nitroolefins,
lysts 1b–1f exhibited high catalytic activity affording including twelve substituted nitrostyrenes and two
cleanly the desired product 4a (Table 1, entries 1–5, alkyl nitroolefins. As shown in Table 3, the reactions
92–98% yield). Quite surprisingly, the simply alkyl- worked well with nitrostyrenes bearing either elec-
ACHTUNGTRENNUNGthiourea 1b gave the best (85%) ee among these tron-withdrawing or electron-donating groups to give
tested catalysts, suggesting a favorable feature of the the desired adducts with high yield (90–99%), moder-
alkyl side chain on catalytic performance over that of ate diastereoselectivities and excellent enantioselec-
typical 3,5-bistrifluorophenyl groups usually present tivities (92–96% ee) (Table 3, entries 1–10). Slightly
in catalysts 1c–1f. For comparison, monofunctional lower enantioselectivities were observed with 4-nitro-
thiourea catalysts such as 1g and 1h have also been nitrostyrene (entry 11, 92% yield and 78% ee) and 3-
examined and no reactions were observed in these nitronitrostyrene (entry 12, 94% yield and 80% ee),
cases, proving that the tertiary amine group is indis- probably due to the interference of additional nitro
pensable for the present Michael addition reaction.
groups on the stereocontrolling H-bonding interac-
With alkylthiourea 1b as the optimal catalyst, the tions. Alkyl nitroolefins were also good substrates for
reaction was further optimized by screening different the catalysis of 1b. In these cases, the desired products
solvents (Table 2). Highly polar solvents such as were obtained with excellent yields (95–96%) and
Table 2. Screening of solvents.[a]
Entry
Solvent
Time [h]
Yield[b] [%]
dr[c]
ee[d] [%]
1
2
3
4
5
6
7
8
DMSO
DMF
CH3OH
Et2O
CH3CN
Ethyl acetate
CH2Cl2
CHCl3
ClCH2CH2Cl
THF
12
12
12
12
12
12
12
12
12
12
12
12
48
trace
trace
81
20
85
79
98
97
96
94
95
96
96
nd[e]
nd
nd
nd
45
88
79
80
91
77
90
89
75
85
93[f]
4:1
4:1
5:1
4:1
4:1
3:1
4:1
5:1
3:1
4:1
4:1
9
10
11
12
13
C6H6
PhCH3
CH2Cl2
[a]
The reaction was carried out on a 0.1-mmol scale in 200 mL different solvent at 48C, and the molar ratio of oxindole/ni-
trostyrene is 1/2.
Isolated yield.
Determined by H NMR.
Determined by HPLC.
Not determined.
[b]
[c]
[d]
[e]
[f]
1
Conducted at À408C.
418
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 416 – 424

Asymmetric Michael Addition Reaction of 3-Substituted Oxindoles to Nitroolefins
Table 3. Asymmetric Michael addition reaction of 3-methyl-N-phenyloxindole to different nitroolefins.[a]
Entry
1
Nitroolefin
Time [h]
72
Product: Yield[b] [%]
dr[c]
ee[d] [%]
6: 93
3:1
96
2
72
7: 92
4:1
95
3
4
5
6
7
48
48
48
48
48
8: 99
5:1
4:1
3:1
3:1
2:1
95
93
92
95
96
9: 96
10: 95
11: 95
12: 98
8
60
48
60
13: 90
14: 97
15: 91
4:1
4:1
5:1
94
94
95
9
10
11
72
72
16: 92
17: 94
2:1
3:1
78
80
12
13
54
48
18: 95
19: 96
3:1
3:1
98
98
14
[a]
The reaction was carried out on a 0.1-mmol scale in 200 mL dry CH2Cl2 at À408C, and the molar ratio of oxindole/nitro-
olefin is 1/2.
ACHTUNGTRENNUNG
[b]
[c]
[d]
Isolated yield.
1
Determined by H NMR or weight.
Determined by HPLC.
enantioselectivities (98% ee) (Table 3, entries 13 and been examined in the reaction (Table 4). Not quite
14). unexpectedly, the reaction with 3-phenyl-substituted
To further illustrate the synthetic utility of the cur- oxindole 2b proceeded very fast, but without any
rent reactions, other oxindoles derivatives have also chiral induction (Table 4, entry 1) at 48C. Improved
Adv. Synth. Catal. 2010, 352, 416 – 424
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
419

Xin Li et al.
FULL PAPERS
Table 4. Screening of different oxindole compounds.[a]
Entry
R1
R2
Time [h]
Product: Yield[b] [%]
dr[c]
ee[d] [%]
1
Ph
Ph
CH3
CH3
CH3
CH3
Boc
Boc
Boc
Boc
CH3
CH3
2
8
12
72
12
96
20: 99
20: 94
21: 94
21: 96
22: 93
22: 65
1:1
rac
53
74
89
54
68
2[e]
3
3:1
9:1
19:1
3:1
3:1
4[e]
5
6[e]
[a]
The reaction was carried out on a 0.1-mmol scale in 200 mL dry toluene at 48C, and the molar ratio of oxindole/nitrostyr-
ene is 1/2.
Isolated yield.
Determined by H NMR.
Determined by HPLC.
[b]
[c]
[d]
[e]
1
Reaction in CH2Cl2 at À408C.
stereoselectivity could be obtained when the reaction diastereoselectivity (19:1 dr) and good enantioselec-
was conducted at À408C (Table 4, entry 2). Under the tivity (89% ee), results comparable with those of
optimized conditions, the reactions with other N-sub- Barbasꢀ aromatic thiourea catalyst[17] (Table 4,
stituted oxindoles such as 2c and 2d worked very well entry 4).
(Table 4, entries 3–6). Inspired by the work of Bar-
ACHTUNGTRENNUNG
The X-ray crystal structure of product 12 was deter-
bas,[7a] we examined the reaction N-Boc protected ox- mined (Figure 1), which proved the (1S,2S) relative
indole 2c. To our delight, the reaction furnished the and absolute configurations of the major product. The
desired product in high yield with much improved
Figure 1. X-ray crystal structure of 12.
420
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 416 – 424

Asymmetric Michael Addition Reaction of 3-Substituted Oxindoles to Nitroolefins
(s, 1H), 3.78 (s, 3H), 3.54 (s, 3H), 1.50 (s, 3H); 13C NMR
configurations of other syn-Michael products can
(CDCl3, 75 MHz): d=178.06, 160.57, 159.16, 143.18, 134.18,
131.99, 129.56, 128.30, 128.13, 126.59, 123.95, 122.75, 116.03,
109.29, 104.18, 98.78, 75.64, 55.45, 55.33, 50.27, 20.32; HR-
MS (EI+): m/z=432.1689, calcd. for [C25H24N2O5]: 432.1685.
The enantiomeric excess was determined by HPLC with an
AD-H column at 210 nm (2-propanol:hexane=1:4),
1.0 mLminÀ1; tR =11.7 min (minor), 16.5 min (major).
therefore be deduced.
Conclusions
We have presented a highly enantioselective Michael
addition reaction of 3-methyl-N-phenyloxindole to ni-
troolefins by a simple alkyl-substituted bifunctional
tertiary amine-thiourea organocatalyst. The reaction
scope is substantial and a number of aryl- or alkyl-ni-
troolefins could be successfully applied to give multi-
functional chiral oxindole compounds bearing an ad-
jacent all carbon-substituted quaternary stereocenter
and a tertiary stereocenter with good to excellent
enantioselectivities. And our current work is actively
under way to expand the use of this alkyl-substituted
bifunctional thiourea catalyt 1b to other valuable
transformations.
Compound 7: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 92%. [a]D25: À41.08 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.35–7.24 (m, 3H), 7.19–7.13 (m,
2H), 7.10–7.05 (m, 1H), 6.78–6.68 (m, 4H), 6.59 (d, J=
8.78 Hz, 2H), 6.52 (d, J=7.47 Hz, 1H), 5.09–5.03 (m, 1H),
4.87 (t, J=11.56 Hz, 1H), 3.97 (dd, J=4.67, 11.53 Hz, 1H),
3.65 (s, 3H), 1.56 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=
177.55, 159.51, 143.82, 133.82, 130.16, 129.88, 129.51, 128.85,
128.23, 126.66, 126.52, 123.72, 122.92, 113.54, 109.69, 76.27,
55.25, 51.10, 49.96, 20.60; HR-MS (EI+): m/z=402.1583,
calcd. for [C24H22N2O4]: 402.1580. The enantiomeric excess
was determined by HPLC with an AD-H column at 210 nm
(2-propanol:hexane=1:4),
1.0 mLminÀ1
;
tR =16.1 min
(minor), 31.8 min (major).
Experimental Section
Compound 8: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 99%. [a]D25: À11.08 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.33–7.22 (m, 3H), 7.18–7.12 (m,
2H), 7.08–7.03 (m, 1H), 6.85 (d, J=7.96 Hz, 2H), 6.71 (d,
J=7.14 Hz, 2H), 6.65 (d, J=7.96 Hz, 2H), 6.5 (d, J=
7.68 Hz, 1H), 5.08–5.03 (m, 1H), 4.87 (t, J=11.25 Hz, 1H),
3.96 (dd, J=4.67, 11.25 Hz, 1H), 2.18 (s, 3H), 1.55 (s, 3H);
13C NMR (CDCl3, 75 MHz): d=177.50, 143.86, 137.98,
133.84, 131.64, 130.17, 129.48, 128.82, 128.77, 128.67, 128.22,
126.54, 123.73, 122.89, 109.65, 76.22, 50.99, 50.31, 20.98,
General Remarks
Commercial reagents were used as received, unless other-
wise stated. Chemical shifts are reported in ppm from tetra-
methylsilane with the solvent resonance as the internal stan-
dard. The following abbreviations were used to designate
chemical shift multiplicities: s=singlet, d=doublet, t=trip-
let, q=quartet, h=heptet, m=multiplet, br=broad. All
first-order splitting patterns were assigned on the basis of
the appearance of the multiplet. Splitting patterns that
could not be easily interpreted are designated as multiplet
(m) or broad (br). Mass spectra were obtained using elec-
tron ionization (EI) mass spectrometer. The Michael prod-
uct 21 is a known compound.[7a,b]
20.59;
HR-MS
(EI+):
m/z=386.1634,
calcd.
for
[C24H22N2O3]: 386.1630. The enantiomeric excess was deter-
mined by HPLC with an AD-H column at 210 nm (2-propa-
nol:hexane=1:4), 1.0 mLminÀ1
;
tR =9.5 min (minor),
20.0 min (major).
Catalyst 1b was synthesized by a literature method.[18] 1b:
[a]2D5: À64.88 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.00 (br, 1H), 4.32 (d, J=4.67 Hz, 2H), 3.84 (br, 1H),
2.53 (s, 1H), 2.37 (s, 6H), 2.27 (s, 1H), 1.96–1.72 (m, 3H),
1.36–1.18 (m, 5H); 13C NMR (75 MHz, CDCl3): d=183.50,
128.60, 124.91, 121.21, 66.28, 54.91, 44.83, 38.91, 31.74, 23.17,
23.08, 21.17; HR-MS (EI+): m/z=283.1328, calcd. for
[C11H20F3N3S]: 283.1330.
Compound 9: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 96%. [a]D25: +10.08 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.50–7.45 (m, 2H), 7.41 À7.36 (m,
1H), 7.33–7.30 (m, 1H), 7.13–7.07 (m, 7H), 7.03–7.00 (m,
2H), 6.51–6.48 (m, 1H), 5.34–5.26 (m, 1H), 5.17–5.11 (m,
1H), 4.06 (dd, J=4.67, 10.70 Hz, 1H), 1.66 (s, 3H);
13C NMR (CDCl3, 75 MHz): d=177.81, 142.65, 134.99,
133.90, 131.91, 129.59, 128.61, 128.27, 128.04, 127.92, 126.34,
123.42, 123.07, 109.44, 75.23, 50.89, 21.92; HR-MS (EI+):
m/z=372.1478, calcd. for [C23H20N2O3]: 372.1474 The enan-
tiomeric excess was determined by HPLC with an AD-H
General Experimental Michael Reaction Procedure
To
a
stirred solution of 3-methyl-N-phenyloxindole
column at 210 nm (2-propanol:hexane=1:4), 1.0 mLminÀ1
tR =9.4 min (minor), 23.5 min (major).
;
(0.1 mmol) and nitroolefin (2.0 equiv.) in dry CH2Cl2
(200 mL) was added thiourea catalyst (0.1 equiv.) at À40 8C.
After the reaction was completed, the reaction solution was
concentrated under vacuum and the crude material was pu-
rified by flash chromatography to afford the product.
Compound 6: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 93%. [a]D25: +52.08 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.48 (t, J=7.68 Hz, 2H), 7.38 (t, J=
7.68 Hz, 1H), 7.22–7.14 (m, 3H), 7.08–6.98 (m, 3H), 6.72 (d,
J=7.96 Hz, 1H), 6.41–6.35 (m, 2H), 5.09–4.94 (m, 2H), 4.54
Compound 10: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 95%. [a]D25: +19.08 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.36–7.24 (m, 3H), 7.19–7.14 (m,
2H), 7.10–7.01 (m, 3H), 6.74–6.70 (m, 4H), 6.53 (d, J=
7.14 Hz, 1H), 5.07–5.01 (m, 1H), 4.85 (t, J=12.35 Hz, 1H),
1.55 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=177.17, 143.74,
134.32, 133.62, 133.27, 130.16, 129.63, 129.12, 128.37, 128.31,
126.34, 123.64, 123.14, 109.89, 75.89, 50.88, 50.04, 20.72; HR-
Adv. Synth. Catal. 2010, 352, 416 – 424
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
421

Xin Li et al.
FULL PAPERS
MS (EI+): m/z=406.1088, calcd. for [C23H19N2O3Cl]:
406.1084. The enantiomeric excess was determined by
HPLC with an AD-H column at 210 nm (2-propanol:hex-
at 210 nm (2-propanol:hexane=1:4), 1.0 mLminÀ1
; tR =
8.7 min (minor), 9.8 min (major).
Compound 15: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 91%. [a]D25: À15.08 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.45–7.33 (m, 3H), 7.27–7.12 (m,
3H), 6.95 (d, J=7.68 Hz, 2H), 6.67–6.58 (m, 2H), 6.41–6.34
(m, 2H), 5.86 (d, J=5.69 Hz, 2H), 5.11–5.06 (m, 1H), 4.89
(t, J=12.60 Hz, 1H), 4.00 (dd, J=4.39, 11.25 Hz, 1H), 1.61
(s, 3H); 13C NMR (CDCl3, 75 MHz): d=177.47, 147.47,
147.31, 143.72, 133.85, 130.18, 129.59, 128.95, 128.34, 128.27,
126.41, 123.65, 123.04, 122.71, 109.76, 108.95, 107.91, 101.06,
76.31, 50.90, 50.35, 20.81; HR-MS (EI+): m/z=416.1375,
calcd. for [C24H20N2O5]: 416.1372. The enantiomeric excess
was determined by HPLC with an AD-H column at 210 nm
ane=1:4), 1.0 mLminÀ1
; tR =13.2 min (minor), 27.9 min
(major).
Compound 11: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 95%. [a]D25: +72.08 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.46–7.41 (m, 2H), 7.36–7.30 (m,
3H), 7.21–7.13 (m, 5H), 7.05–6.97 (m, 2H), 6.71 (d, J=
7.68 Hz, 1H), 4.84–4.79 (m, 3H), 1.41 (s, 3H); 13C NMR
(CDCl3, 75 MHz): d=177.50, 143.13, 136.42, 133.94, 133.37,
131.44, 130.05, 129.71, 129.33, 128.89, 128.36, 126.82, 126.51,
126.24, 123.59, 123.50, 109.69, 75.76, 49.57, 44.32, 20.87; HR-
MS (EI+): m/z=406.1087, calcd. for [C23H19N2O3Cl]:
406.1084. The enantiomeric excess was determined by
HPLC with an AD-H column at 210 nm (2-propanol:hex-
(2-propanol:hexane=1:4),
1.0 mLminÀ1
;
tR =13.9 min
(minor), 36.2 min (major).
Compound 16: The Michael product was synthesized ac-
ane=1:4), 1.0 mLminÀ1
;
tR =7.3 min (minor), 8.0 min
(major).
cording to the general procedure as a white solid; overall
1
Compound 12: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 98%. [a]D25: +92.38 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.60–7.40 (m, 5H), 7.32–7.23 (m,
4H), 7.20–7.03 (m, 3H), 6.80 (d, J=7.96 Hz, 1H), 4.92–4.82
(m, 3H), 1.48 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=
177.62, 143.13, 135.10, 133.99, 133.45, 131.61, 129.74, 129.65,
129.07, 128.89, 128.40, 128.40, 127.91, 127.56, 126.55, 123.74,
123.57, 109.70, 75.86, 49.56, 47.10, 20.93; HR-MS (EI+):
m/z=450.0584 and 452.0561, calcd. for [C23H19BrN2O3]:
450.0579 and 452.0559. The enantiomeric excess was deter-
mined by HPLC with an OD-H column at 210 nm (2-propa-
yield: 92%. [a]2D5: À8.08 (c 1.0, CHCl3); H NMR (300 MHz,
CDCl3): d=8.01 (d, J=8.51 Hz, 2H), 7.43–7.34 (m, 3H),
7.30–7.26 (m, 2H), 7.23–7.18 (m, 1H), 7.10 (d, J=8.51 Hz,
2H), 6.82 (d, J=7.14 Hz, 2H), 6.65 (d, J=7.68 Hz, 1H),
5.17–5.11 (m, 1H), 5.00 (t, J=12.90 Hz, 1H), 4.22 (dd, J=
4.39, 11.25 Hz, 1H), 1.66 (s, 3H); 13C NMR (CDCl3,
75 MHz): d=176.77, 147.80, 143.46, 142.23, 133.35, 129.93,
129.72, 129.47, 129.21, 128.53, 125.99, 123.59, 123.48, 123.19,
110.16, 75.52, 50.66, 50.23, 21.12. The enantiomeric excess
was determined by HPLC with an AD-H column at 210 nm
(2-propanol:hexane=1:4),
1.0 mLminÀ1
;
tR =24.6 min
(minor), 45.2 min (major).
Compound 17: The Michael product was synthesized ac-
nol:hexane=1:9), 1.0 mLminÀ1
;
tR =12.3 min (minor),
31.9 min (major).
cording to the general procedure as a white solid; overall
1
Compound 13: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 90%. [a]D25: À23.08 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.51–7.48 (m, 2H), 7.44–7.40 (m,
2H), 7.36–7.30 (m, 6H), 7.27–7.22 (m, 2H), 7.20–7.15 (m,
1H,), 6.89 (d, J=7.96 Hz, 2H), 6.76–6.73 (m, 2H), 6.55 (d,
J=7.68 Hz, 1H), 5.22–5.16 (m, 1H), 5.02 (t, J=12.90 Hz,
1H), 4.14 (dd, J=4.67, 11.25 Hz, 1H), 1.69 (s, 3H, s);
13C NMR (CDCl3, 75 MHz): d=177.36, 143.98, 141.25,
140.52, 133.72, 133.67, 129.87, 129.54, 128.17, 128.98, 128.81,
128.28, 127.46, 127.01, 126.81, 126.51, 123.71, 122.99, 109.75,
76.04, 51.18, 50.41, 20.53; HR-MS (EI+): m/z=448.1791,
calcd. for [C29H24N2O3]: The enantiomeric excess was deter-
mined by HPLC with an AD-H column at 210 nm (2-propa-
yield: 94%. [a]25: +448 (c 1.0, CHCl3); H NMR (300 MHz,
CDCl3): d=8.1D1 (td, J=1.92, 7.41 Hz, 1H), 7.65 (s, 1H),
7.44–7.35 (m, 5H), 7.33–7.21 (m, 3H), 6.82 (d, J=7.14 Hz,
2H), 6.65–6.62 (m, 1H), 5.17–5.11 (m, 1H), 5.05–4.97 (m,
1H), 4.23 (dd, J=4.39, 11.25 Hz, 1H), 1.66 (s, 3H);
13C NMR (CDCl3, 75 MHz): d=176.85, 147.76, 143.36,
137.07, 135.94, 133.38, 129.70, 129.57, 129.14, 128.48, 126.06,
123.61, 123.29, 122.98, 110.10, 75.59, 50.63, 50.13, 21.03. The
enantiomeric excess was determined by HPLC with an AD-
H
column
at
210 nm
(2-propanol:hexane=1:4),
1.0 mLminÀ1; tR =13.0 min (minor), 29.5 min (major).
Compound 18: The Michael product was synthesized ac-
cording to the general procedure as colorless oil; overall
yield: 95%. [a]D25: +53.28 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.57–7.52 (m, 2H), 7.46–7.37 (m,
3H), 7.29–7.19 (m, 5H), 7.14–7.10 (m, 2H), 6.85 (d, J=
7.68 Hz, 1H), 4.65–4.59 (m, 1H), 4.49–4.42 (m, 1H), 3.05–
2.97 (m, 1H), 2.71–2.54 (m, 2H), 2.06–1.95 (m, 1H), 1.77–
1.64 (m, 1H), 1.54 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=
178.14, 143.16, 140.95, 134.13, 131.43, 129.71, 128.64, 128.52,
128.32, 126.51, 126.20, 123.42, 109.91, 49.96, 44.04, 33.98,
30.92, 22.19; HR-MS (EI+): m/z=400.1790, calcd. for
[C25H24N2O3]: 400.1787. The enantiomeric excess was deter-
mined by HPLC with an AD-H column at 210 nm (2-propa-
nol:hexane=1:4), 1.0 mLminÀ1
29.3 min (major).
;
tR =14.1 min (minor),
Compound 14: The Michael product was synthesized ac-
cording to the general procedure as a white solid; overall
yield: 97%. [a]D25: À91.68 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.22 (d, J=8.51 Hz, 1H), 7.80–7.71
(m, 2H), 7.53–7.41 (m, 2H), 7.31–7.16 (m, 5H), 7.11–7.00
(m, 2H), 7.88 (d, J=7.14 Hz, 1H), 6.63–6.59 (m, 3H), 5.32–
5.26 (m, 1H), 5.20–5.15 (m, 1H), 5.09–5.01 (m, 1H), 1.65 (s,
3H); 13C NMR (CDCl3, 75 MHz): d=177.45, 143.74, 133.81,
133.72, 132.56, 131.43, 130.72, 129.44, 128.85, 128.45, 128.08,
126.52, 126.29, 125.82, 124.43, 124.31, 123.82, 123.42, 122.95,
109.60, 76.61, 50.40, 42.70, 20.70; HR-MS (EI+): m/z=
422.1635, calcd. for [C27H22N2O3]: 422.1630. The enantiomer-
ic excess was determined by HPLC with an AD-H column
nol:hexane=1:4), 1.0 mLminÀ1
;
tR =10.8 min (minor),
17.6 min (major).
Compound 19: The Michael product was synthesized ac-
cording to the general procedure as colorless oil; overall
yield: 96%. [a]D25: +40.28 (c 1.0, CHCl3); 1H NMR
422
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 416 – 424

Asymmetric Michael Addition Reaction of 3-Substituted Oxindoles to Nitroolefins
(300 MHz, CDCl3): d=7.57–7.52 (m, 2H), 7.45–7.38 (m,
Acknowledgements
3H), 7.28–7.22 (m, 2H), 7.14–7.09 (m, 1H), 6.85 (d, J=
7.68 Hz, 1H), 4.61–4.55 (m, 1H), 4.36–4.30 (m, 1H), 3.05–
2.97 (m, 1H), 1.61–1.50 (m, 4H), 1.44–1.35 (m, 1H), 1.29–
1.19 (m, 1H), 0.89 (q, J=6.31, 11.53 Hz, 6H); 13C NMR
(CDCl3, 75 MHz): d=178.23, 143.21, 134.19, 131.49, 129.71,
128.53, 128.25, 126.48, 123.46, 123.29, 109.79, 50.11, 42.33,
37.92, 25.91, 23.47, 22.01, 21.64; HR-MS (EI+): m/z=
352.1790, calcd. for [C21H24N2O3]: 352.1787. The enantiomer-
ic excess was determined by HPLC with an OD-H column
at 210 nm (2-propanol:hexane=1:19), 1.0 mLminÀ1; tR =
8.9 min (minor), 15.8 min (major).
The project was supported by the Natural Science Foundation
(NSFC 20632060, 20702052 and 20902091) and MOST
(2008CB617501, 2009ZX09501-018).
References
[1] a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713; b) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289;
c) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006,
118, 1550; Angew. Chem. Int. Ed. 2006, 45, 1520;
d) S. J. Connon, Chem. Commun. 2008, 2499.
Compound 20: The Michael product was synthesized as a
white solid; overall yield: 99%. 1H NMR (300 MHz,
CDCl3): d=7.70 (d, J=8.23 Hz, 1H), 7.63–7.60 (m, 2H),
7.45–7.32 (m, 6H), 7.17–7.12 (m, 1H), 7.09–7.03 (m, 3H),
6.78 (d, J=7.41 Hz, 2H), 5.00–4.86 (m, 2H), 4.75 (dd, J=
1.65, 11.25 Hz, 1H), 1.45 (s, 9H); 13C NMR (75 MHz,
CDCl3): d=173.85, 148.30, 141.02, 135.44, 132.85, 129.65,
129.27, 128.89, 128.80, 128.64, 128.40, 128.04, 127.90, 126.60,
125.19, 125.73, 124.22, 115.72, 84.24, 75.83, 60.14, 50.89,
28.10, 27.87; HR-MS (EI+): m/z=458.1845, calcd. for
[C27H26N2O5]: 458.1842. The enantiomeric excess was deter-
mined by HPLC with an AD-H column at 210 nm (2-propa-
[2] X. Li, H. Deng, B. Zhang, J. Y. Li, L. Zhang, S. Z. Luo,
J.-P. Cheng, Chem. Eur. J. 2010, 16, 450–455.
[3] For reviews see: a) A. B. Dounay, L. E. Overman,
Chem. Rev. 2003, 103, 2945; b) H. Lin, S. J. Danishef-
sky, Angew. Chem. 2003, 115, 38; Angew. Chem. Int.
Ed. 2003, 42, 36; c) C. V. Galliford, K. A. Scheidt,
Angew. Chem. 2007, 119, 8902; Angew. Chem. Int. Ed.
2007, 46, 8748. Other selected examples: d) X. Zhang,
C. D. Smith, Mol. Pharmacol. 1996, 49, 228; e) H. C.
Malinakova, L. S. Liebeskind, Org. Lett. 2000, 2, 4083;
f) X. Z. Wearing, J. M. Cook, Org. Lett. 2002, 4, 4237;
g) B. K. Albrecht, R. M. Williams, Org. Lett. 2003, 5,
197; h) A. H. Abadi, S. M. Abou-Seri, D. E. Abdel-
Rahman, C. Klein, O. Lozach, L. Meijer, Eur. J. Med.
Chem. 2006, 41, 296; i) S. E. Reisman, J. M. Ready,
M. M. Weiss, A. Hasuoka, M. Hirata, K. Tamaki, T. V.
Ovaska, C. J. Smith, J. L. Wood, J. Am. Chem. Soc.
2008, 130, 2087.
[4] a) B. M. Trost, Y. Zhang, J. Am. Chem. Soc. 2006, 128,
4590; b) B. M. Trost, N. Cramer, S. M. Silverman, J.
Am. Chem. Soc. 2007, 129, 12396; c) B. M. Trost, Y.
Zhang, J. Am. Chem. Soc. 2007, 129, 14548, and refer-
ences cited therein.
[5] S. Ogawa, N. Shibata, J. Inagaki, S. Nakamura, T. Toru,
M. Shiro, Angew. Chem. 2007, 119, 8820; Angew.
Chem. Int. Ed. 2007, 46, 8666, and references cited
therein.
[6] A. B. Dounay, K. Hatanaka, J. J. Kodanko, M. Oest-
reich, L. E. Overman, L. A. Pfeifer, M. M. Weiss, J.
Am. Chem. Soc. 2003, 125, 6261, and references cited
therein.
[7] a) T. Bui, S. Syed, C. F. III Barbas, J. Am. Chem. Soc.
2009, 131, 8758; b) Y. Kato, M. Furutachi, Z. Chen, H.
Mitsunuma, S. Matsunaga, M. Shibasaki, J. Am. Chem.
Soc. 2009, 131, 9168; c) R. He, C. Ding, K. Maruoka,
Angew. Chem. 2009, 121, 4629; Angew. Chem. Int. Ed.
2009, 48, 4559.
nol:hexane=1:19), 1.0 mLminÀ1
;
tR =7.2 min (minor),
8.2 min (major), racemic.
Compound 22: The Michael product was synthesized as
1
yellow oil; overall yield: 65%. H NMR (300 MHz, CDCl3):
d=7.27–7.14 (m, 3H), 7.11–7.09 (m, 3H), 7.04 (d, J=
7.41 Hz, 1H), 7.00–6.96 (m, 2H), 6.61–6.58 (m, 1H), 5.15–
5.07 (m, 1H), 4.98–4.91 (m, 1H), 3.98 (dd, J=4.67,
10.98 Hz, 1H), 3.05 (s, 3H), 1.47 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=178.49, 142.61, 134.95, 131.71, 128.50,
128.39, 127.89, 127.84, 123.43, 122.59, 108.11, 75.37, 50.60,
26.02, 21.79; HR-MS (EI+): m/z=310.1321, calcd. for
[C18H18N2O3]: 310.1317. The enantiomeric excess was deter-
mined by HPLC with an AD-H column at 210 nm (2-propa-
nol:hexane=3:97), 0.5 mLminÀ1
;
tR =24.5 min (minor),
25.7 min (major).
X-Ray Crystallographic Determination of Compound
12
Single crystals of enantiopure 12 suitable for X-ray analysis
were obtained by recrystallization from i-PrOH/hexane at
room temperature. Crystal data for 12: C23H19BrN2O3
(451.31), orthorhombic, space group: P2(1)2(1)2(1), a=
9.839(2), b=10.575(2), c=19.779(4) ꢂ, U=2057.9(7) ꢂ3,
Z=4, specimen 0.41ꢃ0.39ꢃ0.33 mm3, T=173(2) K, absorp-
tion coefficient: 2.024 mmÀ1, reflections collected: 16670, in-
dependent reflections: 4649 [Rint =0.0421], refinement by
full-matrix least-squares on F2, data/restraints/parameters
4649/0/262, goodness-of-fit on F2 =1.127, final R indices [I>
2s(I)] R1=0.0341, wR2=0.0782, R indices (all data) R1=
0.0365, wR2=0.0795, largest diff. peak and hole 0.295 and
À0.280eꢂÀ3. CCDC 739992 contains the supplementary
crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[8] Y. Yasui, H. Kamisaki, Y. Takemoto, Org. Lett. 2008,
10, 3303.
[9] Other selected examples of catalytic asymmetric syn-
thesis of oxindoles with quaternary carbon stereocen-
ters: a) S. Lee, J. F. Hartwig, J. Org. Chem. 2001, 66,
3402; b) I. D. Hills, G. C. Fu, Angew. Chem. 2003, 115,
4051; Angew. Chem. Int. Ed. 2003, 42, 3921; c) S. A.
Shaw, P. Aleman, E. Vedejs, J. Am. Chem. Soc. 2003,
125, 13368; d) E. P. Kꢄndig, T. M. Seidel, Y.-X. Jia, G.
Bernardinelli, Angew. Chem. 2007, 119, 8636; Angew.
Chem. Int. Ed. 2007, 46, 8484; e) T. B. Poulsen, L. Ber-
Adv. Synth. Catal. 2010, 352, 416 – 424
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
423

Xin Li et al.
FULL PAPERS
nardi, J. Alemꢅn, J. Overgaard, K. A. Jørgensen, J. Am.
Chem. Soc. 2007, 129, 441; f) B. K. Corkey, F. D. Toste,
J. Am. Chem. Soc. 2007, 129, 2764; g) X. Tian, K. Jiang,
J. Peng, W. Du, Y.-C. Chen, Org. Lett. 2008, 10, 3583;
h) E. C. Linton, M. C. Kozlowski, J. Am. Chem. Soc.
2008, 130, 16162; i) T. A. Duffey, S. A. Shaw, E. Vedejs,
J. Am. Chem. Soc. 2009, 131, 14; j) P. Galzerano, G.
Bencivenni, F. Pesciaioli, A. Mazzanti, B. Giannichi, L.
Sambri, G. Bartoli, P. Melchiorre, Chem. Eur. J. 2009,
15, 7846–7849.
9185; f) Y. Hoashi, T. Yabuta, P. Yuan, H. Miyabe, Y.
Takemoto, Tetrahedron 2006, 62, 365.
[14] For leading examples of catalyst 1e: a) B. Vakulya, S.
Varga, A. Csꢅmpai, T. Soꢆs, Org. Lett. 2005, 7, 1967;
b) B. J. Li, L. Jiang, M. Liu, Y. C. Chen, L. S. Ding, Y.
Wu, Synlett 2005, 603; c) S. H. McCooey, S. J. Connon,
Angew. Chem. 2005, 117, 6525; Angew. Chem. Int. Ed.
2005, 44, 6367; d) J. Ye, D. J. Dixon, P. S. Hynes, Chem.
Commun. 2005, 4481; e) Y.-Q. Wang, J. Song, R. Hong,
H. M. Li, L. Deng, J. Am. Chem. Soc. 2006, 128, 8156;
f) J. Song, H.-W. Shi, L. Deng, Org. Lett. 2007, 9, 603;
g) J. Song, Y. Wang, L. Deng, J. Am. Chem. Soc. 2006,
128, 6048; h) J. Wang, H. Li, X. H. H Yu, L. S. Zu, W.
Wang, Org. Lett. 2005, 7, 4293.
[15] For leading examples of catalyst 1f: a) T.-Y. Liu, J.
Long, B.-J. Li, L. Jiang, R. Li, Y. Wu, L.-S. Ding, Y.-C.
Chen, Org. Biomol. Chem. 2006, 4, 2097; b) B. Han, Q.-
P. Liu, R. Li, X. Tian, X.-F. Xiong, J.-G. Deng, Y.-C.
Chen, Chem. Eur. J. 2008, 14, 8094; c) X. Li, S. Z. Luo,
J.-P. Cheng, Org. Biomol. Chem. 2010, 8, 77–82.
[16] For leading example of catalyst 1g: Y. Sohtome, A. Ta-
natani, Y. Hashimoto, K. Nagasawa, Tetrahedron Lett.
2004, 45, 5589.
[10] a) A. Berkessel, F. Cleemann, S. Mukherjee, Angew.
Chem. 2005, 117, 7632; Angew. Chem. Int. Ed. 2005, 44,
7466; b) T.-Y. Liu, H.-L. Cui, J. Long, B.-J. Li, Y. Wu,
L.-S. Ding, Y.-C. Chen, J. Am. Chem. Soc. 2007, 129,
1878.
[11] During preparation of this manuscript, Barbas and Shi-
basaki reported elegant organocatalytic asymmetric
1,4-additions of oxindoles to nitroalkenes, see: refs.[7a,b]
[12] C. J. Douglas, L. E. Overman, Proc. Natl. Acad. Sci.
USA 2004, 101, 5363, and references cited therein.
[13] For leading examples of catalyst 1c: a) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672; b) T. Okino, Y. Hoashi, T. Furukawa, X.-N. Xu,
Y. Takemoto, J. Am. Chem. Soc. 2005, 127, 119; c) T.
Inokuma, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc.
2006, 128, 9413; d) T. Okino, S. Nakamura, T. Furuka-
wa, Y. Takemoto, Org. Lett. 2004, 6, 625; e) Y. Hoashi,
T. Yabuta, Y. Takemoto, Tetrahedron Lett. 2004, 45,
[17] Our catalyst 1b is also better than “Takemotoꢀs cata-
lyst” 1c in the currently studied Michael addition reac-
tion of 2b to nitrostyrene. See Scheme S1 in the Sup-
porting Information.
[18] C.-J. Wang, X.-Q. Dong, Z.-H. X, H.-L. Teng, J. Am.
Chem. Soc. 2008, 130, 8606.
424
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 416 – 424