Asymmetric Michael addition reaction of 3-substituted-N-Boc oxindoles to activated terminal alkenes catalyzed by a bifunctional tertiary-amine thiourea catalyst

Article abstract of DOI:10.1039/b918644a

The current article reports an organocatalytic strategy for the asymmetric catalysis of chiral oxindoles bearing 3-position all-carbon quaternary stereocenters. Accordingly, highly enantioselective Michael addition reactions of 3-substituted oxindoles to terminal alkenes have been developed by utilizing a bifunctional tertiary-amine thiourea catalyst. The reactions accommodate a number of Michael donor compounds (different substituted 3-aryl or methyl oxindoles), and Michael acceptor compounds (vinyl ketones and vinyl sulfones) to give the desired oxindole products with moderate to excellent yields (up to 99%) and moderate to excellent enantioselectivities (up to 91% ee). The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b918644a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric Michael addition reaction of 3-substituted-N-Boc oxindoles to
activated terminal alkenes catalyzed by a bifunctional tertiary-amine
thiourea catalyst†
Xin Li,a Zhi-Guo Xi,b Sanzhong Luo*a and Jin-Pei Cheng*a,b
Received 9th September 2009, Accepted 7th October 2009
First published as an Advance Article on the web 29th October 2009
DOI: 10.1039/b918644a
The current article reports an organocatalytic strategy for the asymmetric catalysis of chiral oxindoles
bearing 3-position all-carbon quaternary stereocenters. Accordingly, highly enantioselective Michael
addition reactions of 3-substituted oxindoles to terminal alkenes have been developed by utilizing a
bifunctional tertiary-amine thiourea catalyst. The reactions accommodate a number of Michael donor
compounds (different substituted 3-aryl or methyl oxindoles), and Michael acceptor compounds (vinyl
ketones and vinyl sulfones) to give the desired oxindole products with moderate to excellent yields (up
to 99%) and moderate to excellent enantioselectivities (up to 91% ee).
such reactions has not been achieved until recently. Maruoka
Introduction
reported an enantioselective Michael addition reaction of 3-
Asymmetric construction of all-carbon quaternary stereocenters
aryloxindoles to methyl vinyl ketone (MVK) catalyzed by a chiral
quaternary tetraalkylphosphonium salt.9 Herein, we present a
distinctive organocatalytic approach for the Michael addition of
3-substituted oxindoles to activated terminal alkenes by utilizing
the well-proved bifunctional catalytic features of tertiary amine-
thiourea catalysts.10 A number of 3-substituted oxindoles (R2 = Ar
and CH3) and terminal alkenes (vinyl ketones and vinyl sulfones)
are incorporated into this synthetic strategy and the detailed
results are presented here.
has attracted a great deal of effort over recent decades and
remains a challenging synthetic task.1 One particular context
is in the synthesis of biologically and pharmaceutically active
oxindole alkaloids wherein 3-position quaternary centers are a
common structural motif.2 Accordingly, a number of synthetic
transformations such as allylic alkylation, aldol reaction, Heck re-
action, Michael addition reaction and cyanoamidation reaction3–8
have been developed in order to address this synthetic challenge.
A straightforward approach for the construction of oxindoles
bearing a 3-quaternarycenter would be the direct Michaeladdition
of 3-substituted oxindoles to terminal activated alkenes (Fig. 1).
Though easily conceived, an asymmetric catalytic method for
Results and discussion
Bifunctional tertiary-amine thiourea catalyzed Michael addition
reaction of 3-aryl oxindoles to vinyl ketones
The Michael addition reaction of oxindole 1a to MVK was first
selected as our initial testing reaction. And four widely used
bifunctional tertiary-amine thiourea catalysts 4a–4d11–14 (20 mol%)
with different chiral scaffolds were screened in the current model
reaction at room temperature. To our delight, all of the chiral
thioureas 4a–4d exhibited high catalytic activity and the Michael
addition products were cleanly isolated with quantitative yields
(entries 2–5 in Table 1). No reaction was observed in the
absence of catalyst (Table 1, entry 1). Among the four types of
thiourea catalysts tested, catalyst 4d was found to give the optimal
enantioselectivity (99% yield and 61% ee, entry 5 in Table 1). In
addition, the racemic product obtained with a simple diamine
catalyst 4e suggested an obvious bifunctional catalytic mode in
the current reaction (Table 1, entry 6).
Fig. 1 Strategy of bifunctional tertiary-amine thiourea catalyzed Michael
reactions of oxindoles to terminal alkenes.
With 4d as the optimal catalyst, we next examined different
solvents. As illustrated in Table 1, the initial selected toluene gave
the best result among a range of screened solvents (Table 1, entries
5 and 7–11). The best result was achieved when the reaction was
aBeijing National Laboratory for Molecular Sciences (BNLMS), CAS Key
Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing, 100190, China. E-mail: luosz@
iccas.ac.cn; Fax: (+)86-10-62554449; Tel: (+)86-10-62554446
bDepartment of Chemistry and State Key Laboratory of Elemento-organic
Chemistry, Nankai University, Tianjin, 300071, China
◦
˚
carried out at -60 C in toluene in the presence of 4 A molecular
sieves (Table 1, entry 14). Under this condition, the yield was
almost the same while the ee value was improved to 82%.
† Electronic supplementary information (ESI) available: NMR and HPLC
spectra for all the new compounds. See DOI: 10.1039/b918644a
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 77–82 | 77
©

View Article Online
Table 1 Catalyst screeninga
Table 2 Asymmetric Michael addition reaction of 3-aryl oxindoles to
different vinyl ketonesa
Terminal
Entry alkene
Oxindole
Time/h Yield b(%) ee c(%)
1
2
3
4
5
6
7
8
9
2a
G = 4-CH3O (1a)
4-CH3 (1b)
3,5-(Me)2 (1c)
H (1d)
48
36
36
36
72
36
36
36
60
48
48
48
3a: 92
3b: 99
3c: 98
3d: 98
3e: 93
3f: 99
3g: 99
3h: 99
3i: 96
3j: 99
3k: 99
3l: 99
65
81
88
82(S)d
46
2b
G = 4-CH3O (1a)
4-CH3 (1b)
63
76
61
85
72
60
76
3,5-(Me)2 (1c)
H (1d)
Entry Catalysts
Solvent
Time/h
Yield b(%)
ee c(%)
2c G = 4-CH3O (1a)
ndd
40
45
37
61
rac
56
55
58
58
47
67
79
82
10
11
12
4-CH3 (1b)
3,5-(Me)2 (1c)
H (1d)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
no catalyst
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CHCl3
ClCH2CH2Cl
Benzene
THF
Toluene
Toluene
Toluene
24
2
2
2
2
2
2
2
2
2
2
2
36
36
trace
98
99
97
99
96
99
99
96
97
78
99
94
98
4a
4b
4c
4d
4e
4d
4d
4d
4d
4d
4de
4df
4dg
a The reaction was carried out on a 0.1 mmol scale in 1 mL toluene with
4 A molecular sieves at -60 ◦C, and the molar ratio of oxindole 1/2 is
˚
1/2. b Isolated yield. c Determined by HPLC. d The absolute configuration
of the Michael adduct 3d was determined to be S by comparison with
literature.9
in the current reaction with the hope that better stereocontrol
might be achieved with double H-bonding interactions. Indeed,
the reactions of vinyl sulfone provided generally good enantio-
selectivity (Table 3, 82–91% ee), albeit with lower reactivity than
those of vinyl ketones. Phenyl vinyl sulfone 5b demonstrated higher
activity than the methyl vinyl sulfone 5a. Various 3-aromatic
substituted oxindoles worked well with vinyl sulfone to give the
desired product with yield ranging from 48% to 80%.
a The reaction was carried out on a 0.1 mmol scale in 200 mL solvent
at 4 ◦C, and the molar ratio of oxindole 1d/2a is 1/2. b Isolated yield.
c Determined by HPLC. d Not determined. e The reaction was carried out
on a 0.1 mmol scale in 1 mL toluene with 4 A molecular sieves at 4 ◦C,
˚
and the molar ratio of oxindole 1d/2a is 1/2. f The reaction was carried
out on a 0.1 mmol scale in 1 mL toluene at -60 ◦C, and the molar ratio of
oxindole 1d/2a is 1/2. g The reaction was carried out on a 0.1 mmol scale
in 1 mL toluene with 4 A molecular sieves at -60 ◦C, and the molar ratio
˚
of oxindole 1d/2a is 1/2.
Table 3 Asymmetric Michael addition reaction of 3-aryl oxindoles to
different vinyl sulfonesa
Under the optimal reaction conditions, the substrate scope was
next explored (Table 2). A series of 3-aryl-N-Boc oxindoles 1a–1d
(Michael donor compounds) and vinyl ketones 2a–2c (Michael
acceptor compounds) were examined. As summarized in Table 2,
vinyl ketones including methyl vinyl ketone (MVK), ethyl vinyl
ketone (EVK) and phenyl vinyl ketone (PVK) demonstrated
equally good activity in reacting with different substituted 3-aryl-
N-Boc oxindoles and the reactions generally furnished the desired
Michael products in quantitative yields. Inspection of the results in
Table 2 suggested similar chiral inductions were normally observed
with all three vinyl ketones with slightly better ees in cases of MVK
and PVK. The best enantioselectivity (88% ee) was obtained in the
reaction of MVK and 1c (Table 1, entry 3).
Entry Terminal alkene Oxindole
Time/d Yield b(%) ee c(%)
1
2
3
4
5
6
7
8
5a
G = 4-CH3O
4-CH3
3,5-2CH3
H
8
8
8
6
6
6
6
6
trace
ndd
86
87
91
88
82
90
87
6a: 48
6b: 55
6c: 51
6d: 60
6e: 75
6f: 72
6g: 80
5b
G = 4-CH3O
4-CH3
3,5-2CH3
H
Bifunctional tertiary-amine thiourea catalyzed Michael addition
reaction of 3-aryl oxindoles to vinyl sulfones
a The reaction was carried out on a 0.1 mmol scale in 200 mL toluene with
◦
˚
4 A molecular sieves at -20 C, and the molar ratio of oxindole 1/5 is 1/3.
=
Vinyl sulfones, which bear two S O moieties that enable double
b Isolated yield. c Determined by HPLC. d Not determined.
H-bonding with the N–Hs of thiourea,15 were next attempted
78 | Org. Biomol. Chem., 2010, 8, 77–82
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 4 Asymmetric Michael addition reaction of 3-methyl-N-Boc oxin-
literature methods. Michael products 3a, 3b, 3d and 3h were known
dole to different terminal alkenesa
compounds.9
General experimental procedure for Michael reaction of 1 and 2
To a stirred solution of 3-aryl-N-Boc oxindole 1 (0.1 mmol) and
vinyl ketones 2 (2.0 equiv.) in dry◦ toluene (1 mL) was added
Entry
Terminal alkene
Time/h
Yield b(%)
ee c(%)
˚
thiourea-catalyst (0.2 equiv.) at -60 C with 4 A molecular sieves.
After the reaction completed, the reaction solution was concen-
trated in vacuo and the crude was purified by flash chromatography
to afford the product.
1
2
3
4
5
2a
2b
2c
5a
5b
72
72
72
168
96
8a: 90
8b: 99
8c: 99
8d: trace
8e: 48
22
17
48
ndd
84
3c. The Michael product was synthesized according to the
a The reaction was carried out on a 0.1 mmol scale in 200 mL toluene with
1
general procedure as white solid in 98% overall yield. H NMR
4 A molecular sieves at 4 ◦C, and the molar ratio of oxindole/terminal
˚
(300 MHz, CDCl3): d 7.94 (1H, d, J = 8.51 Hz), 7.37 (1H, td,
J = 8.51, 1.65 Hz), 7.23–7.15 (2H, m), 6.89 (3H, s), 2.77–2.68 (1H,
m), 2.51–2.25 (8H, m), 2.11–2.01 (4H, m), 1.63 (9H, s) ppm; 13C
NMR (CDCl3, 75 MHz): d 207.12, 176.69, 149.30, 139.77, 139.38,
138.20, 130.82, 129.45, 128.57, 124.74, 124.65, 115.21, 84.56,
55.80, 38.74, 31.63, 29.96, 28.11, 21.43 ppm; HRMS (EI+): calcd.
for [C25H29NO4] 407.2097; found 407.2101. The enantiomeric
excess was determined by HPLC with an AD-H column at 210 nm
(2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 4.3 min (major),
5.3 min (minor).
alkene is 1/2. b Isolated yield. c Determined by HPLC. d Not determined.
Bifunctional tertiary-amine thiourea catalyzed Michael addition
reaction of 3-methyl oxindole to terminal alkenes
In addition to the 3-aromatic substituted oxindoles, 3-alkyl
substituted oxindoles such as oxindole 7 have also been examined
in the reactions and the results were summarized in Table 4.
The reactions with vinyl ketones proceeded smoothly to give the
desired Michael products in excellent yields, however, only low
enantioselectivities were obtained in these cases (Table 4, entries
1–3). In accordance with previous observations, the vinyl sulfones
reacted sluggishly with oxindole 7, but good ee (84%) could still
be achieved in the reaction of phenyl vinyl sulfone 5b and oxindole
(Table 4, entry 5).
3e. The Michael product was synthesized according to the
1
general procedure as white solid in 93% overall yield. H NMR
(300 MHz, CDCl3): d 7.94 (1H, d, J = 8.23 Hz), 7.40–7.34 (1H, m),
7.24–7.16 (4H, m), 6.83 (2H, d, J = 9.06 Hz), 3.76 (3H, s), 2.76–
2.66 (1H, m), 2.52–2.43 (1H, m), 2.37–2.14 (3H, m), 2.07–1.97 (1H,
m), 1.63 (9H, s), 0.95 (3H, t, J = 7.14 Hz) ppm; 13C NMR (CDCl3,
75 MHz): d 209.80, 176.77, 159.08, 149.30, 139.85, 131.53, 130.56,
128.62, 128.13, 124.76, 124.68, 115.27, 114.07, 84.55, 55.39, 55.25,
37.48, 35.94, 31.92, 28.09, 7.63 ppm; HRMS (EI+): calcd. for
[C25H29NO5] 423.2046; found 423.2049. The enantiomeric excess
was determined by HPLC with an AD-H column at 210 nm (2-
propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 7.8 min (major),
11.7 min (minor).
Conclusion
In summary, we have presented highly enantioselective Michael
addition reactions of 3-substituted oxindoles to terminal alkenes
using a bifunctional tertiary-amine thiourea organocatalyst. This
study provided a rather mild procedure for the synthesis of
multifunctional chiral oxindole compounds bearing all carbon-
substituted quaternary stereocenters with moderate to excellent
enantioselectivities. Thereaction scopeis substantialand a number
of 3-aryl or methyl oxindoles could be successfully applied in
current studied Michael addition system.
3f. The Michael product was synthesized according to the
general procedure as colorless oil in 99% overall yield. 1H NMR
(300 MHz, CDCl3): d 7.94 (1H, d, J = 7.96 Hz), 7.39–7.33 (1H, m),
7.24–7.09 (6H, m), 2.78–2.68 (1H, m), 2.55–2.45 (1H, m), 2.38–
2.14 (6H, m), 2.10–1.99 (1H, m), 1.63 (9H, s), 0.95 (3H, t, J =
7.14 Hz) ppm; 13C NMR (CDCl3, 75 MHz): d 209.80, 176.69,
149.29, 139.84, 137.48, 136.57, 130.61, 129.41, 128.61, 126.82,
124.75, 124.70, 115.25, 84.53, 55.75, 37.46, 35.46, 31.77, 28.09,
20.91, 7.64 ppm; HRMS (EI+): calcd. for [C25H29NO4] 407.2097;
found 407.2101. The enantiomeric excess was determined by
HPLC with an AD-H column at 210 nm (2-propanol : hexane =
1 : 9), 1.0 mL min-1; tR = 6.0 min (major), 8.7 min (minor).
Experimental section
General remarks
Commercial reagents were used as received, unless otherwise
stated. Chemical shifts are reported in ppm from tetramethylsilane
with the solvent resonance as the internal standard. The following
abbreviations were used to designate chemical shift multiplici-
ties: s = singlet, d = doublet, t = triplet, 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). Elemental analysis was obtained
from thermoQuest (Flash 1112EA, ITALY). Mass spectra were
obtained using electron ionization (EI) mass spectrometer. Cat-
alysts 4a,11 4b,12 4c,13 4d14 and 4e16 were synthesized from the
3g. The Michael product was synthesized according to the
1
general procedure as white solid in 99% overall yield. H NMR
(300 MHz, CDCl3): d 7.93 (1H, d, J = 7.96 Hz), 7.39–7.33 (1H,
m), 7.23–7.15 (2H, m), 6.89 (3H, m), 2.78–2.68 (1H, m), 2.54–
2.44 (1H, m), 2.37–2.16 (9H, m), 2.08–1.98 (1H, m), 1.64 (9H,
s), 0.95 (3H, t, J = 7.14 Hz) ppm; 13C NMR (CDCl3, 75 MHz):
d 209.89, 176.73, 149.31, 139.78, 139.43, 138.18, 130.81, 129.43,
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 77–82 | 79
©

View Article Online
128.54, 124.74, 124.71, 124.66, 115.19, 84.54, 55.92, 37.43, 35.95,
31.74, 28.11, 21.43, 7.65 ppm; Anal. Calcd. for C26H31NO4: C,
74.08; H, 7.41; N, 3.32. Found: C, 73.83; H, 7.47; N, 3.14. The
enantiomeric excess was determined by HPLC with an AD-H
column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL min-1;
tR = 4.2 min (major), 5.2 min (minor).
General experimental procedure for Michael reaction of 1 and 5
To a stirred solution of 3-aryl-N-Boc oxindole 1 (0.1 mmol)
and vinyl sulfones 5 (3.0 equiv.) in dry toluene (200 mL) was
◦
˚
added thiourea-catalyst (0.2 equiv.) at -20 C with 4 A molecular
sieves. After the reaction completed, the reaction solution was
concentrated in vacuo and the crude was purified by flash
chromatography to afford the product.
3i. The Michael product was synthesized according to the
1
general procedure as white solid in 96% overall yield. H NMR
6a. The Michael product was synthesized according to the
(300 MHz, CDCl3): d 7.95 (1H, d, J = 8.23 Hz), 7.81–7.78 (2H,
m), 7.53–7.19 (10H, m), 6.85–6.82 (2H, m), 3.76 (3H, s), 2.97–2.83
(2H, m), 2.67–2.55 (2H, m), 1.64 (9H, s) ppm; 13C NMR (CDCl3,
75 MHz): d 198.80, 176.81, 159.12, 149.33, 139.84, 136.60, 133.07,
131.50, 130.61, 128.70, 128.51, 128.19, 128.01, 124.74, 115.35,
114.11, 84.56, 55.52, 55.26, 33.86, 32.60, 28.12 ppm; Anal. Calcd.
for C29H29NO5: C, 73.87; H, 6.20; N, 2.97. Found: C, 72.76; H,
6.21; N, 2.87. The enantiomeric excess was determined by HPLC
with an OD-H column at 210 nm (2-propanol : hexane = 1 : 49),
1.0 mL min-1; tR = 16.1 min (minor), 23.9 min (major).
1
general procedure as white solid in 48% overall yield. H NMR
(300 MHz, CDCl3): d 7.92 (1H, d, J = 8.23 Hz), 7.42–7.35 (1H, m),
7.26–7.12 (6H, m), 2.98–2.86 (5H, m), 2.79–2.59 (2H, m), 2.31 (3H,
s), 1.63 (9H, s) ppm; 13C NMR (CDCl3, 75 MHz): d 175.89, 148.94,
139.57, 138.08, 135.10, 129.72, 129.35, 129.23, 126.62, 125.10,
124.50, 115.59, 84.99, 55.02, 50.57, 40.62, 30.49, 28.07, 20.92 ppm;
HRMS (EI+): calcd. for [C23H27NO5S] 429.1610; found 429.1613.
The enantiomeric excess was determined by HPLC with an AD-H
column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR =
13.3 min (minor), 16.1 min (major).
3j. The Michael product was synthesized according to the
general procedure as white solid in 99% overall yield. H NMR
6b. The Michael product was synthesized according to the
general procedure as white solid in 55% overall yield. H NMR
1
1
(300 MHz, CDCl3): d 7.94 (1H, d, J = 8.23 Hz), 7.81–7.78 (2H,
m), 7.50 (1H, t, J = 7.14 Hz), 7.41–7.33 (3H, m), 7.25–7.10 (6H,
m), 2.98–2.84 (2H, m), 2.70–2.57 (2H, m), 2.30 (3H, s), 1.63 (9H,
s) ppm; 13C NMR (CDCl3, 75 MHz): d 198.81, 176.72, 149.33,
139.83, 137.52, 136.61, 136.54, 133.07, 130.66, 129.46, 128.68,
128.51, 128.01, 126.87, 124.76, 124.72, 115.32, 84.55, 55.88, 33.84,
32.44, 28.12, 20.94 ppm; Anal. Calcd. for C29H29NO4: C, 76.46; H,
6.42; N, 3.07. Found: C, 76.58; H, 6.49; N, 2.93. The enantiomeric
excess was determined by HPLC with an AD-H column at 210 nm
(2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 7.6 min (minor),
8.7 min (major).
(300 MHz, CDCl3): d 7.92 (1H, d, J = 7.96 Hz), 7.42–7.36 (1H,
m), 7.26–7.24 (2H, m), 6.92–6.90 (3H, m), 2.97–2.87 (5H, m),
2.79–2.58 (2H, m), 2.27 (6H, s), 1.64 (9H, s) ppm; 13C NMR
(CDCl3, 75 MHz):d 175.95, 148.94, 139.52, 138.60, 138.03, 129.88,
129.49, 129.18, 125.12, 124.51, 124.42, 115.54, 85.00, 55.20, 50.56,
40.61, 30.46, 28.09, 21.44 ppm; Anal. Calcd. for C23H27NO5S: C,
64.31; H, 6.34; N, 3.26. Found: C, 64.67; H, 6.62; N, 3.10. The
enantiomeric excess was determined by HPLC with an OD-H
column at 210 nm (2-propanol : hexane = 1 : 9), 1.0 mL min-1;
tR = 7.4 min (minor), 8.1 min (major).
6c. The Michael product was synthesized according to the
1
general procedure as white solid in 51% overall yield. H NMR
3k. The Michael product was synthesized according to the
1
(300 MHz, CDCl3): d 7.93 (1H, d, J = 8.23 Hz), 7.43–7.26 (8H, m),
2.99–2.62 (7H, m), 1.64 (9H, s) ppm; 13C NMR (CDCl3, 75 MHz):
d 175.77, 148.89, 139.60, 138.08, 129.32, 129.14, 129.05, 128.20,
126.76, 125.14, 124.56, 115.63, 82.08, 55.31, 50.55, 40.64, 30.53,
28.07 ppm; HRMS (EI+): calcd. for [C22H25NO5S] 415.1453; found
415.1457. The enantiomeric excess was determined by HPLC
with an AD-H column at 210 nm (2-propanol : hexane = 1 : 19),
1.0 mL min-1; tR = 26.4 min (minor), 36.3 min (major).
6d. The Michael product was synthesized according to the
general procedure as colorless oil in 60% overall yield. 1H NMR
(300 MHz, CDCl3): d 7.91–7.82 (3H, m), 7.69–7.53 (3H, m), 7.37
(1H, td, J = 7.96, 1.37 Hz), 7.23–7.09 (4H, m), 6.80 (2H, d, J =
8.78 Hz), 3.76 (3H, s), 3.12–3.02 (1H, m), 2.88–2.67 (2H, m),
2.55–2.45 (1H, m), 1.60 (9H, s) ppm; 13C NMR (CDCl3, 75 MHz):
d 175.72, 159.33, 148.95, 139.60, 138.60, 133.88, 129.90, 129.39,
129.30, 129.14, 128.11, 128.04, 124.93, 124.47, 115.58, 114.30,
84.88, 55.28, 54.59, 51.87, 30.93, 28.05 ppm; HRMS (EI+): calcd.
for [C28H29NO6S] 507.1716; found 507.1720. The enantiomeric
excess was determined by HPLC with an AD-H column at 210 nm
(2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 19.4 min (minor),
21.3 min (major).
general procedure as white solid in 99% overall yield. H NMR
(300 MHz, CDCl3): d 7.94 (1H, d, J = 8.23 Hz), 7.81–7.78 (2H,
m), 7.50 (1H, t, J = 7.14 Hz), 7.41–7.33 (3H, m), 7.25–7.18 (2H,
m), 6.94–6.89 (3H, m), 2.97–2.84 (2H, m), 2.68–2.56 (2H, m),
2.26 (6H, s), 1.64 (9H, m) ppm; 13C NMR (CDCl3, 75 MHz):
d 198.91, 176.77, 149.35, 139.76, 139.39, 138.24, 136.61, 133.08,
130.86, 129.48, 128.61, 128.52, 128.03, 124.77, 124.72, 115.27,
84.56, 56.06, 33.81, 32.44, 28.14, 21.46 ppm; Anal. Calcd. for
C30H31NO4: C, 76.73; H, 6.65; N, 2.98. Found: C, 74.61; H,
6.64; N, 2.93. The enantiomeric excess was determined by HPLC
with an OD-H column at 210 nm (2-propanol : hexane = 1 : 49),
1.0 mL min-1; tR = 7.9 min (minor), 8.8 min (major).
3l. The Michael product was synthesized according to the
1
general procedure as white solid in 99% overall yield. H NMR
(300 MHz, CDCl3): d 7.95 (1H, d, J = 8.23 Hz), 7.81–7.78 (2H,
m), 7.51 (1H, t, J = 7.14 Hz), 7.41–7.20 (10H, m), 2.99–2.85
(2H, m), 2.72–2.58 (2H, m), 1.64 (9H, s) ppm; 13C NMR (CDCl3,
75 MHz): d 198.75, 176.60, 149.28, 139.84, 139.49, 136.59, 133.09,
130.46, 128.77, 128.52, 128.01, 127.75, 127.01, 124.79, 115.35,
84.64, 56.17, 33.81, 32.51, 28.12 ppm; HRMS (EI+): calcd. for
[C28H27NO4] 441.1940; found 441.1944. The enantiomeric excess
was determined by HPLC with an AD-H column at 210 nm (2-
propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 7.4 min (minor),
8.1 min (major).
6e. The Michael product was synthesized according to the
1
general procedure as white solid in 75% overall yield. H NMR
(300 MHz, CDCl3): d 7.91–7.82 (3H, m), 7.69–7.53 (3H, m), 7.37
80 | Org. Biomol. Chem., 2010, 8, 77–82
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
(1H, td, J = 7.96, 1.37 Hz), 7.22–7.08 (6H, m), 3.12–3.02 (1H,
m), 2.90–2.69 (2H, m), 2.55–2.45 (1H, m), 2.29 (3H, s), 1.60 (9H,
s) ppm; 13C NMR (CDCl3, 75 MHz): d 175.63, 148.94, 139.59,
138.60, 137.97, 135.03, 133.87, 129.64, 129.38, 129.11, 128.12,
126.67, 124.93, 124.45, 115.55, 84.87, 54.94, 51.85, 30.79, 28.05,
20.91 ppm; Anal. Calcd. for C28H29NO5S: C, 68.41; H, 5.95; N,
2.85. Found: C, 67.44; H, 5.97; N, 2.66. The enantiomeric excess
was determined by HPLC with an AD-H column at 210 nm (2-
propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 13.3 min (minor),
16.2 min (major).
8b. The Michael product was synthesized according to the
general procedure as colorless oil in 99% overall yield. 1H NMR
(300 MHz, CDCl3): d 7.84 (1H, d, J = 8.23 Hz), 7.33–7.27 (1H, m),
7.17–7.16 (2H, m), 2.33–2.10 (5H, m), 2.02–1.92 (1H, m), 1.66 (9H,
s), 1.43 (3H, s), 0.94 (3H, t, J = 7.41 Hz) ppm; 13C NMR (CDCl3,
75 MHz): d 209.96, 178.79, 149.28, 139.01, 132.18, 128.22, 124.67,
122.65, 115.01, 84.45, 47.83, 37.19, 35.89, 32.54, 28.11, 24.72,
7.62 ppm; HRMS (EI+): calcd. for [C19H25NO4] 331.1784; found
331.1787. The enantiomeric excess was determined by HPLC
with an OD-H column at 210 nm (2-propanol : hexane = 1 : 49),
1.0 mL min-1; tR = 7.9 min (minor), 9.1 min (major).
6f. The Michael product was synthesized according to the
1
8c. The Michael product was synthesized according to the
general procedure as white solid in 72% overall yield. H NMR
1
general procedure as white solid in 99% overall yield. H NMR
(300 MHz, CDCl3): d 7.91–7.82 (3H, m), 7.69–7.53 (3H, m), 7.36
(1H, td, J = 7.96, 1.37 Hz), 7.22–7.07 (2H, m), 6.89 (1H, s), 6.78
(2H, s), 3.13–3.03 (1H, m), 2.91–2.70 (2H, m), 2.54–2.45 (1H, m),
2.22 (6H, s), 1.61 (9H, s) ppm; 13C NMR (CDCl3, 75 MHz): d
175.66, 148.97, 139.53, 138.65, 138.51, 137.85, 133.86, 129.79,
129.56, 129.38, 129.04, 128.10, 124.92, 124.50, 124.47, 115.50,
84.87, 55.10, 51.82, 30.75, 28.07, 21.41 ppm; Anal. Calcd. for
C29H31NO5S: C, 68.89; H, 6.18; N, 2.77. Found: C, 68.04; H,
6.18; N, 2.60. The enantiomeric excess was determined by HPLC
with an OD-H column at 210 nm (2-propanol : hexane = 1 : 19),
1.0 mL min-1; tR = 12.0 min (minor), 16.5 min (major).
(300 MHz, CDCl3): d 7.79–7.70 (3H, m), 7.46–7.41 (1H, m), 7.34–
7.29 (2H, m), 7.25–7.08 (3H, m), 2.85–2.74 (1H, m), 2.53–2.42
(1H, m), 2.35–2.12 (2H, m), 1.59 (9H, m), 1.40 (3H, s) ppm;
13C NMR (CDCl3, 75 MHz): d 198.94, 178.82, 149.33, 139.01,
136.59, 133.05, 132.28, 128.50, 128.30, 127.98, 124.75, 122.60,
115.09, 84.47, 47.93, 33.51, 33.08, 28.14, 24.85 ppm; Anal. Calcd.
for C23H25NO4: C, 72.80; H, 6.64; N, 3.69. Found: C, 72.47; H,
6.67; N, 3.54. The enantiomeric excess was determined by HPLC
with an OD-H column at 210 nm (2-propanol : hexane = 1 : 49),
1.0 mL min-1; tR = 9.6 min (minor), 10.5 min (major).
8e. The Michael product was synthesized according to the
general procedure as yellow oil in 48% overall yield. H NMR
6g. The Michael product was synthesized according to the
general procedure as white solid in 80% overall yield. H NMR
1
1
(300 MHz, CDCl3): d 7.85–7.80 (3H, m), 7.69–7.53 (3H, m),
7.34–7.29 (1H, m), 7.21–7.10 (2H, m), 2.98 (1H, td, J = 13.45,
4.94 Hz), 2.76 (1H, td, J = 13.45, 4.94 Hz), 2.34–2.10 (2H, m),
1.64 (9H, s), 1.41 (3H, s) ppm; 13C NMR (CDCl3, 75 MHz): d
177.61, 148.93, 138.85, 138.67, 133.86, 130.93, 129.36, 128.79,
128.05, 125.03, 122.40, 125.30, 84.82, 51.64, 47.17, 31.16, 28.08,
24.45 ppm; HRMS (EI+): calcd. for [C22H25NO5S] 415.1453;
found 415.1457. The enantiomeric excess was determined by
HPLC with an AD-H column at 210 nm (2-propanol : hexane =
(300 MHz, CDCl3): d 7.84–7.75 (3H, s), 7.60 (1H, t, J = 7.14 Hz),
7.49 (2H, t, J = 7.41 Hz), 7.31 (1H, td, J = 7.96, 1.37 Hz), 7.22–
7.12 (6H, m), 7.05–7.03 (1H, d, J = 7.41 Hz), 3.06–2.93 (1H,
m), 2.82–2.65 (2H, m), 2.54–2.42 (1H, m), 1.54 (9H, s) ppm; 13C
NMR (CDCl3, 75 MHz): d 175.52, 148.89, 139.60, 138.54, 137.99,
133.93, 129.41, 129.22, 129.13, 128.97, 128.12, 126.82, 125.00,
124.52, 115.61, 84.97, 55.22, 51.82, 30.84, 28.06 ppm; Anal. Calcd.
for C27H27NO5S: C, 67.90; H, 5.70; N, 2.93. Found: C, 67.82; H,
5.71; N, 2.73. The enantiomeric excess was determined by HPLC
with an AD-H column at 210 nm (2-propanol : hexane = 1 : 9),
1.0 mL min-1; tR = 11.3 min (minor), 13.8 min (major).
1 : 9), 1.0 mL min-1; tR
=
11.0 min (minor), 12.6 min
(major).
General experimental procedure for Michael reaction of
7 and 2 (or 5)
Acknowledgements
We would likely to thank the Natural Science Foundation (NSFC
20702052 and 20902091), MOST (2008CB617501, 2009ZX09501-
018) and the Chinese Academy of Sciences for their support.
To a stirred solution of 3-methyl-N-Boc oxindole 5 (0.1 mmol)
and terminal alkene (2.0 equiv.) in dry◦toluene (200 mL) was
˚
added thiourea-catalyst (0.2 equiv.) at 4 C with 4 A molecular
sieves. After the reaction completed, the reaction solution was
concentrated in vacuo and the crude was purified by flash
chromatography to afford the product.
Notes and references
1 Reviews on the catalytic enantioselective construction of quaternary
chiral centers: (a) J. Christoffers and A. Baro, Angew. Chem., Int. Ed.,
2003, 42, 1688–1690; (b) D. J. Ramon and M. Yus, Curr. Org. Chem.,
2004, 8, 149–183; (c) E. A. Peterson and L. E. Overman, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 11943–11948; (d) J. Christoffers and A.
Baro, Adv. Synth. Catal., 2005, 347, 1473–1482.
2 For reviews see: (a) A. B. Dounay and L. E. Overman, Chem. Rev.,
2003, 103, 2945–2963; (b) H. Lin and S. J. Danishefsky, Angew. Chem.,
Int. Ed., 2003, 42, 36–51; (c) C. V. Galliford and K. A. Scheidt, Angew.
Chem., Int. Ed., 2007, 46, 8748–8758. Other examples: (d) X. Zhang and
C. D. Smith, Mol. Pharmacol., 1996, 49, 288–294; (e) H. C. Malinakova
and L. S. Liebeskind, Org. Lett., 2000, 2, 4083–4086; (f) X. Z. Wearing
and J. M. Cook, Org. Lett., 2002, 4, 4237–4240; (g) B. K. Albrecht and
R. M. Williams, Org. Lett., 2003, 5, 197–200; (h) A. H. Abadi, S. M.
Abou-Seri, D. E. Abdel-Rahman, C. Klein, O. Lozach and L. Meijer,
8a. The Michael product was synthesized according to the
general procedure as white solid in 90% overall yield.1H NMR
(300 MHz, CDCl3): d 7.85 (1H, d, J = 8.23 Hz), 7.33–7.27 (1H,
m), 7.18–7.16 (2H, m), 2.35–1.95 (7H, m), 1.66 (9H, s), 1.43
(3H, s) ppm; 13C NMR (CDCl3, 75 MHz): d 207.25, 178.75,
149.28, 139.01, 132.16, 128.26, 124.71, 122.57, 115.04, 84.48,
47.72, 38.48, 32.47, 29.89, 28.11, 24.70 ppm; HRMS (EI+): calcd.
for [C18H23NO4] 317.1627; found 317.1630. The enantiomeric
excess was determined by HPLC with an OD-H column at 210 nm
(2-propanol : hexane = 1 : 9), 1.0 mL min-1; tR = 5.3 min (minor),
5.7 min (major).
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 77–82 | 81
©

View Article Online
Eur. J. Med. Chem., 2006, 41, 296–305; (i) S. E. Reisman, J. M. Ready,
M. M. Weiss, A. Hasuoka, M. Hirata, K. Tamaki, T. V. Ovaska, C. J.
Smith and J. L. Wood, J. Am. Chem. Soc., 2008, 130, 2087–2100.
3 (a) B. M. Trost and Y. Zhang, J. Am. Chem. Soc., 2006, 128, 4590–4591;
(b) B. M. Trost, N. Cramer and S. M. Silverman, J. Am. Chem. Soc.,
2007, 129, 12396–12397; (c) B. M. Trost and Y. Zhang, J. Am. Chem.
Soc., 2007, 129, 14548–14549 and references therein.
4 S. Ogawa, N. Shibata, J. Inagaki, S. Nakamura, T. Toru and M. Shiro,
Angew. Chem., Int. Ed., 2007, 46, 8666–8669 and references therein.
5 A. B. Dounay, K. Hatanaka, J. J. Kodanko, M. Oestreich, L. E.
Overman, L. A. Pfeifer and M. M. Weiss, J. Am. Chem. Soc., 2003,
125, 6261–6271 and references therein.
6 (a) T. Bui, S. Syed and C. F. III Barbas, J. Am. Chem. Soc., 2009,
131, 8758–8759; (b) Y. Kato, M. Furutachi, Z. Chen, H. Mitsunuma,
S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 9168–
9169.
7 Y. Yasui, H. Kamisaki and Y. Takemoto, Org. Lett., 2008, 10, 3303–
3306.
8 Other selected examples of catalytic asymmetric synthesis of oxindoles
with quaternary carbon stereocenters: (a) S. Lee and J. F. Hartwig,
J. Org. Chem., 2001, 66, 3402–3415; (b) I. D. Hills and G. C. Fu,
Angew. Chem., Int. Ed., 2003, 42, 3921–3924; (c) S. A. Shaw, P. Aleman
and E. Vedejs, J. Am. Chem. Soc., 2003, 125, 13368–13369; (d) E. P.
Ku¨ndig, T. M. Seidel, Y.-X. Jia and G. Bernardinelli, Angew. Chem.,
Int. Ed., 2007, 46, 8484–8487; (e) T. B. Poulsen, L. Bernardi, J. Alema´n,
J. Overgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2007, 129, 441–
449; (f) B. K. Corkey and F. D. Toste, J. Am. Chem. Soc., 2007, 129,
2764–2765; (g) X. Tian, K. Jiang, J. Peng, W. Du and Y.-C. Chen, Org.
Lett., 2008, 10, 3583–3586; (h) E. C. Linton and M. C. Kozlowski,
J. Am. Chem. Soc., 2008, 130, 16162–16163; (i) T. A. Duffey, S. A.
Shaw and E. Vedejs, J. Am. Chem. Soc., 2009, 131, 14–15; (j) P.
Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti, B. Giannichi, L.
Sambri, G. Bartoli and P. Melchiorre, Chem.–Eur. J., 2009, 15, 7846–
7849.
10 Reviews on bifunctional thiourea catalysis: (a) M. S. Taylor and E. N.
Jacobsen, Angew. Chem., Int. Ed., 2006, 45, 1520–1543; (b) A. G. Doyle
and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713–5743; (c) S. J. Connon,
Chem. Commun., 2008, 2499–2510.
11 X. Li, H. Deng, B. Zhang, S. Z. Luo and J.-P. Cheng, Chem.–Eur. J.,
DOI: 10.1002/chem.200902430.
12 For leading examples of catalyst 4b: (a) T. Okino, Y. Hoashi and Y.
Takemoto, J. Am. Chem. Soc., 2003, 125, 12672–12673; (b) T. Okino,
Y. Hoashi, T. Furukawa, X.-N. Xu and Y. Takemoto, J. Am. Chem.
Soc., 2005, 127, 119–125; (c) T. Inokuma, Y. Hoashi and Y. Takemoto,
J. Am. Chem. Soc., 2006, 128, 9413–9419; (d) T. Okino, S. Nakamura,
T. Furukawa and Y. Takemoto, Org. Lett., 2004, 6, 625–627; (e) Y.
Hoashi, T. Yabuta and Y. Takemoto, Tetrahedron Lett., 2004, 45, 9185–
9188; (f) Y. Hoashi, T. Yabuta, P. Yuan, H. Miyabe and Y. Takemoto,
Tetrahedron, 2006, 62, 365–374.
13 For leading examples of catalyst 4c: (a) B. Vakulya, S. Varga, A.
Csa´mpai and T. Soo´s, Org. Lett., 2005, 7, 1967–1969; (b) B. J. Li,
L. Jiang, M. Liu, Y. C. Chen, L. S. Ding and Y. Wu, Synlett, 2005,
603–606; (c) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed.,
2005, 44, 6367–6370; (d) J. Ye, D. J. Dixon and P. S. Hynes, Chem.
Commun., 2005, 4481–4483; (e) Y.-Q. Wang, J. Song, R. Hong, H. M.
Li and L. Deng, J. Am. Chem. Soc., 2006, 128, 8156–8159; (f) J. Song,
H.-W. Shi and L. Deng, Org. Lett., 2007, 9, 603–606; (g) J. Song, Y.
Wang and L. Deng, J. Am. Chem. Soc., 2006, 128, 6048–6049; (h) J.
Wang, H. Li, X. H. H. Yu, L. S. Zu and W. Wang, Org. Lett., 2005, 7,
4293–4296.
14 For leading examples of catalyst 4d: B. Han, Q.-P. Liu, R. Li, X. Tian,
X.-F. Xiong, J.-G. Deng and Y.-C. Chen, Chem.–Eur. J., 2008, 14, 8094–
8097; Also see ref. 8g and 15c.
15 For organocatalyzed asymmetric Michael addition to vinyl sulfones,
see: (a) H. Li, J. Song, X. Liu and L. Deng, J. Am. Chem. Soc., 2005,
127, 8948–8949; (b) S. Moss´e and A. Alexakis, Org. Lett., 2005, 7,
4361–4364; (c) T.-Y. Liu, J. Long, B.-J. Li, L. Jiang, R. Li, Y. Wu, L.-S.
Ding and Y.-C. Chen, Org. Biomol. Chem., 2006, 4, 2097–2099.
16 S. Z. Luo, H. Xu, J. Y. Li, L. Zhang and J.-P. Cheng, J. Am. Chem. Soc.,
2007, 129, 3074–3075.
9 R. He, C. Ding and K. Maruoka, Angew. Chem., Int. Ed., 2009, 48,
4559–4561.
82 | Org. Biomol. Chem., 2010, 8, 77–82
This journal is
The Royal Society of Chemistry 2010
©