Highly enantioselective michael addition of 3-aryloxindoles to phenyl vinyl sulfone catalyzed by cinchona alkaloid-derived bifunctional amine-thiourea catalysts bearing sulfonamide as multiple hydrogen-bonding donors

Article abstract of DOI:10.1002/ejoc.201100791

A highly enantioselective Michael addition of 3-aryloxindole to phenyl vinyl sulfone catalyzed by a quinine-derived bifunctional amine-thiourea-bearing sulfonamide as multiple hydrogen-bonding donor catalyst has been investigated. The corresponding adduct

Full text of DOI:10.1002/ejoc.201100791

FULL PAPER
DOI: 10.1002/ejoc.201100791
Highly Enantioselective Michael Addition of 3-Aryloxindoles to Phenyl Vinyl
Sulfone Catalyzed by Cinchona Alkaloid-Derived Bifunctional Amine–Thiourea
Catalysts Bearing Sulfonamide as Multiple Hydrogen-Bonding Donors
Mei-Xin Zhao,*[a] Wen-Hao Tang,[a] Ming-Xiao Chen,[a] Deng-Ke Wei,[a] Tong-Lei Dai,[a]
and Min Shi*[a,b]
Keywords: Organocatalysis / Synthetic methods / Michael addition / Enantioselectivity / Heterocycles
A highly enantioselective Michael addition of 3-aryloxindole
to phenyl vinyl sulfone catalyzed by a quinine-derived bi-
functional amine–thiourea-bearing sulfonamide as multiple
hydrogen-bonding donor catalyst has been investigated. The
corresponding adducts, which contain a chiral quaternary
carbon center at the 3-position of the oxindole, were ob-
tained in moderate-to-good yields (52–86%) with high-to-ex-
cellent enantioselectivities (83–98% ee).
thiourea organocatalysts that rely on multiple hydrogen-
bonding donors and show excellent activity, diastereoselec-
tivity, enantioselectivity, and structural scope in asymmetric
Michael addition to nitroolefins.[7] Inspired by all of this
work, we attempted to design novel bifunctional catalysts
by incorporating different hydrogen-bonding donors into a
cinchona alkaloid-derived alkylthiourea, and thus a series
of bifunctional amine–thiourea-bearing multiple hydrogen-
bonding donor catalysts 3 were synthesized.
Introduction
During the last decade, asymmetric organocatalysis has
emerged as a powerful and environmentally friendly meth-
odology for the enantioselective construction of valuable
synthetic building blocks and has been adopted as a major
research area on a global scale.[1] Moreover, this burgeoning
field has grown from a small collection of chemically
unique reactions to a thriving area of general catalysis con-
cepts, atypical reactivity, and widely applicable reactions. In
the light of these facts, the design and application of
organocatalysts have received much attention. Of the devel-
oped organocatalysts, chiral thiourea represents a promi-
nent type of asymmetric hydrogen-bonding catalyst. In par-
ticular, bifunctional tertiary amine–thioureas have been
proven to be powerful catalysts and have enabled a diverse
range of reactions with high enantioselectivities featuring
distinctive bifunctional activation of substrates.[2–5] During
the investigation of a systematic electronic activity–stereo-
selectivity relationship, Luo and Cheng and co-workers
found that thioureas with alkyl side-chains, especially the tri-
fluoroethyl-substituted thiourea in which the electronic ef-
fect has been simply tuned, demonstrated superior perform-
ance in Michael addition reactions compared with well-rec-
ognized aromatic thioureas.[6] Wang and co-workers have
also designed elaborate fine-tunable bifunctional amine–
Recently, the enantioselective synthesis of oxindoles
bearing a tetrasubstituted carbon stereocenter at the 3-posi-
tion has become an important area of research in asymmet-
ric catalysis by virtue of the fact that oxindoles are impor-
tant structural motifs and widely presented in a wide array
of natural and biologically active molecules.[8] Among the
various synthetic approaches to 3,3-disubstituted oxindole
derivatives,[9] the catalytic asymmetric direct functionaliza-
tion of 3-substituted oxindoles has attracted significant
interest, including their fluorination,[10] hydroxylation,[11]
amination,[12] aldol and Mannich reactions,[13] allylic alkyl-
ation,[14] and conjugate addition.[6a–6d,15] As part of our
interest in the enantioselective synthesis of chiral 3,3-disub-
stituted oxindoles, we have developed a highly enantioselec-
tive chlorination of 3-aryl-N-Boc-oxindoles 4 by using an
inexpensive cinchona alkaloid as organocatalyst and NCS
as the chlorination reagent.[16] Vinyl sulfones are valuable
and unique acceptors in conjugate addition[17] and have
been employed in a wide range of asymmetric organocata-
lytic conjugate addition reactions,[6b,15h,18] and therefore we
envisioned that cinchona alkaloid-derived amine–thioureas
bearing multiple hydrogen-bonding donors, as shown in
Scheme 1, could facilitate the formation of more hydrogen
bonds in addition to the double hydrogen-bonding interac-
tions between the thiourea moiety and the sulfone group
and thereby significantly enhance their catalytic activity for
[a] School of Chemistry & Molecular Engineering, East China
University of Science and Technology, Laboratory for
Advanced Materials and Institute of Fine Chemicals,
130 Mei Long Road, Shanghai 200237, P. R. of China
Fax: +86-21-34201699
E-mail: mxzhao@ecust.edu.cn
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. of China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100791.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6078–6084

Michael Addition of 3-Aryloxindoles to Phenyl Vinyl Sulfone
the Michael addition of 3-aryl-N-Boc-oxindole derivatives amide-protected diamines (Scheme 1), together with known
4 to vinyl sulfone. To the best of our knowledge, only two catalysts 3d and 3e, were then tested in the model reaction
examples[6b,15h] of the catalytic asymmetric Michael ad- and the results of these experiments are summarized in
dition of vinyl sulfone to 3-aryl-N-Boc-oxindoles have been Table 1. Quinine-derived catalyst 3a exhibited high catalytic
reported despite the fact that the desired adducts bearing a activity. The reaction proceeded smoothly at room tempera-
tetrasubstituted carbon stereocenter can be readily con- ture in toluene to afford the desired adduct 5a in high yield
verted into optically enriched 3-alkyl-3-aryl-substituted ox- along with good enantioselectivity (91%, 84% ee, Table 1,
indoles, which are of great importance and synthetic poten- entry 1). Replacing the Ms group of 3a with the sterically
tial in organic synthesis. Herein we wish to report our stud- more bulky Ts group reduced the yield and enantio-
ies on this subject.
selectivity of 5a, presumably due to the steric hindrance of
the hydrogen-bonding donor site of the catalyst 3b (Table 1,
entry 2). Quinidine-derived catalyst 3c also promoted the
reaction, but gave 5a in moderate yield and with a lower
enantioselectivity than the quinine-derived catalyst 3a
(53%, 30% ee, Table 1, entry 3). Replacing the bulky sulfon-
amide NHSO2R with OH in the corresponding organocata-
lyst 3, known catalysts 3d and 3e produced the correspond-
ing adduct 5a in moderate yields and with low enantio-
selectivities (Table 1, entries 4 and 5). These results suggest
that the strength and steric hindrance of the hydrogen-
bonding donor may play important roles in the catalytic
Table 1. Screening studies of the enantioselective Michael addition
of 3-phenyloxindole 4a to phenyl vinyl sulfone.[a]
Entry Cat. Solvent
T
t
Yield
[%][b]
ee
[°C] [h]
[%][c]
1
2
3
4
5
6
7
8
3a toluene
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
0
75
51
48
77
75
32
28
57
144
52
76
66
95
71
78
95
95
50
96
144
91
45
53
68
50
90
92
40
45
59
20
72
51
63
55
84
85
74
53
77
68
86
50
84
71
30
–27
20
–49
77
81
84
77
87
70
30
47
84
88
87
80
90
92
95
94
94
3b toluene
3c toluene
3d toluene
3e toluene
Scheme 1. Synthesis of cinchona alkaloid-derived bifunctional
amine–thiourea catalysts 3 bearing multiple hydrogen-bonding do-
nors.
3f toluene
3g toluene
3a xylene
9
3a DCE
10
11
12
13
14
15
16
17
18[d]
19[e]
20
21
22[f]
23[g]
3a DCM
3a CHCl3
3a acetone
Results and Discussion
3a CH3OH
3a THF
The synthesis of cinchona alkaloid-derived amine–thio-
ureas bearing multiple hydrogen-bonding donors 3 is out-
lined in Scheme 1. Azides 1, prepared from quinine or
quinidine in a one-pot reaction with triphenylphosphane,
diisopropyl azodicarboxylate (DIAD), and diphenylphos-
phoryl azide (DPPA), was treated with triphenylphosphane
and carbon disulfide to form isothiocyanate 2, which was
then converted into catalysts 3 after reaction with various
different amines (Scheme 1).
The Michael addition reaction of oxindole 4a with
phenyl vinyl sulfone was selected as our initial test reaction.
A variety of bifunctional tertiary amine–thiourea catalysts
3a–3c, which were synthesized by the reaction of cinchona
3a toluene/CHCl3 (2:1)
3a toluene/CHCl3 (1:1)
3a toluene/CHCl3 (1:2)
3a toluene/CHCl3 (1:1)
3a toluene/CHCl3 (1:1)
3a toluene/CHCl3 (1:1)
3a toluene/CHCl3 (1:1) –20 144
3a toluene/CHCl3 (1:1) –20 120
3a toluene/CHCl3 (1:1) –20 120
[a] Unless otherwise noted, reactions were carried out with
0.2 mmol of oxindole 4a, 0.1 mmol of phenyl vinyl sulfone, and
0.02 mmol of catalyst 3 in 1.0 mL of solvent. [b] Yield of the iso-
lated product. [c] Determined by HPLC analysis on a chiral sta-
tionary phase. [d] Molecular sieves (4 Å) were added. [e] 2.0 mL of
solvent were used. [f] 0.5 mL of solvent was used. [g] 10 mol-% of
alkaloid-derived isothiocyanate 2 with mono-N-sulfon- catalyst 3a was used.
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M.-X. Zhao, M. Shi et al.
FULL PAPER
activity and the level of enantioselectivity achieved. To im- corresponding products 5n and 5o in reasonable yields and
prove the catalytic efficiency of these organocatalysts, we with excellent enantioselectivities (Table 2, entries 14 and
also introduced a trifluoroethyl group into the cinchona al- 15).
kaloid-derived thiourea catalysts by the reaction of isothio-
cyanate 2 with trifluoroethylamine. Not quite unexpectedly,
catalysts 3f and 3g exhibited higher catalytic activities than
Table 2. Enantioselective Michael addition of various oxindoles 4
to phenyl vinyl sulfone.[a]
the thiourea catalysts 3a–e, affording the corresponding ad-
duct 5a in high yields in shorter times (Table 1, entries 6
and 7). Note that quinidine-derived thiourea catalyst 3g
gave 5a with a much higher ee value than the corresponding
quinine-derived trifluoroethyl thiourea catalyst 3f, but
slightly lower than that of quinine-derived catalyst 3a. Thus,
quinine-derived catalyst 3a is an excellent catalyst for this
reaction.
Entry Substrate
X
R
Product
t
Yield
ee
[d] [%][b]
[%][c]
In view of the high enantioselectivity, efforts were made
to further optimize the reaction conditions by examining
other parameters such as solvent, temperature, and reactant
concentrations (Table 1). It was found that 5a was obtained
with higher enantioselectivity in less polar solvents such as
toluene, xylene, dichloroethane (DCE), dichloromethane
(DCM), and chloroform (Table 1, entries 1 and 8–11). Polar
solvents such as THF, acetone, and methanol were not suit-
able for this reaction, giving 5a with low enantioselectivity
(Table 1, entries 12–14). Of the various solvents screened,
toluene and chloroform gave the best yield and enantio-
selectivity, respectively (Table 1, entries 1 and 11). Further
examination of solvent effects revealed that the mixed sol-
vent toluene/CHCl3 (1:1) was the solvent of choice for this
reaction, affording 5a in up to 88% ee and 84% yield
(Table 1, entry 16). Lowering the reaction temperature and
increasing the reactant concentration significantly improved
the enantioselectivity of 5a (Ͼ90% ee) without sacrificing
the yield (86%; Table 1, entries 19–22). However, reducing
catalyst loading to 10 mol-% led to a decrease in yield of
5a although with a comparable enantioselectivity (Table 1,
entry 23). Thus, the best enantioselectivity for 5a was ob-
tained in toluene/CHCl3 (1:1, 0.2 m) at –20 °C by using
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
F
Me
OMe
H
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
86
57
56
52
60
63
64
71
55
62
63
58
78
55
61
61
75
60
15
36
94
93
96
93
95
98
97
95
87
90
92
90
92
95
91
93
93
83
13
30
p-FC6H4
p-FC6H4
p-FC6H4
p-FC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeOC6H4
2-naphthyl
2-naphthyl
m-MeC6H4
3,5-Me2C6H3
o-MeC6H4
Me
F
Me
OMe
H
9
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
F
5j
5k
5l
Me
OMe
H
H
F
F
H
F
H
4m
4n
4o
4p
4q
4r
4s
4t
5m
5n
5o
5p
5q
5r
5s
5t
H
Bn
[a] All of reactions were carried out with oxindoles 4 (0.2 mmol),
phenyl vinyl sulfone (0.1 mmol), and catalyst 3a (20 mol-%) in tolu-
ene/CHCl3 (1:1, 0.5 mL) at –20 °C. [b] Yield of the isolated prod-
uct. [c] Determined by HPLC analysis on a chiral stationary phase.
In the case of the 3-(m-tolyl)- and 3-(3,5-dimeth-
20 mol-% of catalyst and the results are comparable to ylphenyl)-substituted oxindoles 4p and 4q, the correspond-
those of the alkylthiourea catalyst of Cheng and Luo (80%, ing products 5p and 5q were obtained in good yields and
87% ee)[6b] and the quinidine-derived arylthiourea catalyst with excellent enantioselectivities, and are even better than
in the Michael addition of 3-aryl-N-Boc-oxindoles to 1,1- the results obtained with the corresponding 3-(p-tolyl)-sub-
bis(phenylsulfonyl)ethylene (–20 °C, 95%, 81% ee).[15h,19]
stituted oxindoles 4i and 4j (Table 2, entries 16 and 17 vs. 9
The substrate scope was then examined under the opti- and 10). However, with 3-(o-tolyl)-substituted oxindole 4r,
mized reaction conditions and the results of these experi- the desired product 5r was formed in only 83% ee, presum-
ments are summarized in Table 2. In general, all of the 3- ably due to steric hindrance (Table 2, entry 18). The 3-alkyl-
aryloxindoles readily undergo this Michael addition reac- oxindoles 4s and 4t are not suitable for this Michael ad-
tion to afford the desired adducts in moderate-to-good dition reaction,[9–15] affording the corresponding adducts 5s
yields (52–86%) and with good-to-excellent enantio- and 5t in very low yields and with low enantioselectivities
selectivities (83–98%). The electronic and steric properties (Table 2, entries 19 and 20).
of the substituents on the oxindole and the aromatic ring
Several 3-phenyloxindoles with different N-protecting
at the 3-position both played important roles in determin- groups were also examined under the standard conditions
ing the reaction outcome. Substrates with an electron-do- and the results are summarized in Table 3. In contrast to
nating group on the aromatic ring at the 3-position gave the N-Boc-oxindole 4a (Table 3, entry 1), the reactions became
desired products in slightly lower enantioselectivities than sluggish with N-unprotected oxindole 4u and N-benzyl-sub-
those of the corresponding substrates without substituents stituted oxindole 4v as the substrates (Table 3, entries 2 and
or with electron-withdrawing groups (Table 2, entries 9–13 3). N-Phenyl- and N-(9H-fluoren-9-yloxycarbonyl)-pro-
vs. 1–8). Substrates 4n and 4o, which bear a bulky 2-naphth- tected oxindoles 4w and 4x gave the corresponding prod-
yl group at the 3-position of the oxindoles, also gave the ucts 5w and 5x in low yields and with low ee values, which
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Michael Addition of 3-Aryloxindoles to Phenyl Vinyl Sulfone
indicates that the presence of the N-Boc-protecting group is π stacking interactions between the aryl group at the 3-posi-
crucial for a satisfactory yield and stereochemical outcome tion in the oxindole and the phenyl group in the sulfone
(Table 3, entries 4 and 5).
may be involved when the phenyl vinyl sulfone reagent ap-
proaches the oxindole substrate.
Table 3. Effects of N-protecting groups of 3-aryloxindole.[a]
Conclusions
A highly enantioselective Michael addition reaction of
3-aryl-N-Boc-oxindoles with phenyl vinyl sulfone has been
developed by using a simple quinine-derived bifunctional
tertiary amine–thiourea-bearing sulfonamide as multiple
hydrogen-bonding donor organocatalyst. The reaction
scope is substantial and a number of oxindoles have been
successfully used to give the corresponding multifunctional
chiral oxindole compounds bearing an all-carbon-substi-
tuted quaternary stereocenter in moderate-to-good yields
and with good-to-excellent enantioselectivities. Investi-
gations aimed at fully understanding the reaction mecha-
nism and expanding the use of this kind of bifunctional
amine–thiourea-bearing multiple hydrogen-bonding donor
organocatalyst to other valuable transformations are ongo-
ing.
Entry
Substrate
R
Product
t
Yield
ee
[d] [%][b] [%][c]
1
2
3
4
5
4a
4u
4v
4w
4x
Boc
H
Bn
Ph
5a
5u
5v
5w
5x
5
6
86
n.r.
94
–
–
rac
15
15 trace
6
6
10
8
fluoren-9-yl-O-C(O)-
[a] All of the reactions were carried out with oxindoles 4
(0.2 mmol), phenyl vinyl sulfone (0.1 mmol), and catalyst 3a
(20 mol-%) in toluene/CHCl3 (1:1, 0.5 mL) at –20 °C. [b] Yield of
the isolated product. [c] Determined by chiral HPLC analysis on a
chiral stationary phase.
The absolute configuration of 5 was confirmed to be R
by chemical correlation with (R)-3-ethyl-3-phenylindolin-2-
one (7; Scheme 2). Deprotection of the N-Boc group of 5a
with TFA in dichloromethane followed by magnesium/
methanol reduction gave the desired desulfonated product
7 in 80% yield.[15h] The absolute configuration of 7 at the
3-position was assigned as R by comparing the specific ro-
Experimental Section
General: NMR spectra were recorded with a Bruker AVANCE III
400 MHz spectrometer or a Varian Mercury vx 300 MHz spec-
trometer in solutions of CDCl3 or CD3OD and with tetramethylsil-
ane (TMS) as an internal standard; J values are reported in Hz.
tation of 7 with the reported one [for (S)-7,[20] [α]D20 = –99.4 IR spectra were recorded with a Bio-Rad FTS-185 spectrometer.
Chiral HPLC was performed with a SHIMADZU SPD-10A series
instrument using chiral columns. MS and HRMS (EI, ESI) were
measured with
(c = 0.89, CHCl3, 81% ee)]. Therefore the absolute configu-
rations of the other products were also assigned as R.
a
Finnigan MA+ instrument. Flash column
chromatography was performed on silica gel (300–400 mesh). Un-
less otherwise noted, all commercially obtained reagents were used
without further purification. All reactions were carried out in air
in a closed system. Catalysts 3d[18h] and 3e[21] and substrates 4a,[10d]
4b,[14c,15b] 4c,d,[11a] 4e,[10d] 4f,[16] 4g,h,[11a] 4i,[10d] 4j,[16] 4k,[11a] 4l,[10g]
4m,n,[15b] 4o,p,[16] 4q,[15f] 4r,[16] 4s,t,[10d] 4u,[12b] 4v,[22] 4w,[23] and
4x,[16] and products 5a,[6b] 5i,[6b] 5m,[6b] 5q,[6b] 6,[15h] and 7[15h] were
known compounds.
Scheme 2. Determination of the absolute configuration of 5a.
Although the mechanism of the reactions reported herein Representative Procedure for the Synthesis of Catalyst 3a: Quinine
(0.648 g, 2.0 mmol) and triphenylphosphane (0.63 g, 2.4 mmol)
were dissolved in THF (10 mL) and the solution was cooled to
0 °C. Diisopropyl azodicarboxylate (3.07 g, 12 mmol) was added
all at once under argon. After stirring for another 10 min, a solu-
tion of diphenylphosphoryl azide (0.66 g, 2.4 mmol) in dry THF
(5 mL) was added dropwise at 0 °C. The reaction mixture was
warmed to room temperature. After being stirred for 18 h, solvents
were removed in vacuo and the residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate/trieth-
ylamine, 2:1:0.03) to afford the azide 1 as a white solid (0.454 g,
65%).[24]
remain to be clarified, a plausible transition-state model is
proposed in Scheme 3. For N-Boc-substituted 3-aryloxind-
oles, the tertiary amine–thiourea 3a catalyzes the reaction
in a multifunctional mode and it appears that aromatic π–
Triphenylphosphane (1.94 g, 7.39 mmol) was added to a solution
of the azide 1 (2.35 g, 6.72 mmol) in THF (9 mL) and CS2 (8.5 mL,
141 mmol) in a 50 mL round-bottomed flask fitted with a con-
denser. After evolution of nitrogen, the solution gently self-refluxed
and was left overnight. After concentration under reduced pressure,
the residue was purified by flash chromatography (ethyl acetate/
Scheme 3. Proposed transition-state model.
Eur. J. Org. Chem. 2011, 6078–6084
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M.-X. Zhao, M. Shi et al.
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methanol, 25:1) to yield isothiocyanate 2 as a yellow solid (1.22 g,
Activated magnesium metal (48 mg, 2.0 mmol) was added to a
50%).[25] 1H NMR (CDCl3, TMS, 400 MHz): δ = 8.74 (d, J = stirred solution of 6 (19 mg, 0.05 mmol) in anhydrous methanol
4.4 Hz, 1 H, ArH), 8.03 (d, J = 9.2 Hz, 1 H, ArH), 7.38 (s, 2 H,
ArH), 7.31 (d, J = 2.4 Hz, 1 H, ArH), 5.64–5.76 (m, 1 H, =CH),
5.36 (d, J = 10 Hz, 1 H, CH), 5.03–5.14 (m, 2 H, =CH2), 3.95 (s,
3 H, OCH3), 3.68–3.76 (m, 1 H, CH), 3.35–3.53 (m, 2 H, CH),
(2 mL). After 30 min, the reaction mixture was heated at reflux for
2 h. Then the reaction mixture was poured into aq. 2 n HCl (3 mL)
and extracted with diethyl ether (3ϫ5 mL). The combined organic
extracts were dried with Na2SO4 and filtered. The solvent was re-
3.25–3.35 (m, 1 H, CH), 3.08–3.16 (m, 1 H, CH), 2.56–2.67 (br. s, moved in vacuo and the residue was purified by column
1 H, CH), 2.03–2.11 (br. s, 1 H, CH), 1.79–1.95 (m, 3 H, CH),
1.44–1.54 (m, 1 H, CH), 0.81–0.92 (m, 1 H, CH) ppm.
chromatography (petroleum ether/ethyl acetate, 4:1) to afford 7 as
a colorless oil (9.5 mg, 80%). [α]2D5 = +52.3 (c = 1.0, CHCl3); 93%
ee (Chiralpak AD-H; hexane/2-propanol, 90:10; 1.0 mL/min;
254 nm; tmajor = 8.96 min, tminor = 11.74 min). 1H NMR (400 MHz,
CDCl3): δ = 8.00 (s, 1 H, NH), 7.38–7.36 (m, 2 H, ArH), 7.32–7.29
(m, 2 H, ArH), 7.26–7.23 (m, 2 H, ArH), 7.18 (d, J = 7.2 Hz, 1 H,
ArH), 7.11–7.08 (m, 1 H, ArH), 6.95 (d, J = 8.0 Hz, 1 H, ArH),
2.51–2.42 (m, 1 H, CH), 2.29–2.20 (m, 1 H, CH), 0.76 (t, J =
7.2 Hz, 3 H, CH3) ppm.
(1S,2S)-N-Methylsulfonyl-1,2-diphenylethanediamine[7a]
(0.29 g,
1.0 mmol) was added to a solution of isothiocyanate 2 (0.37 g,
1.0 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at
room temperature for 8 h (monitored by TLC until no starting ma-
terial remained), concentrated, and purified by column chromatog-
raphy on silica gel (ethyl acetate/triethylamine, 100:1) to give the
catalyst 3a as a white solid (0.524 g, 80%); m.p. 124.6–127.5 °C.
[α]2D5 = –36.1 (c = 1.0, CHCl3). 1H NMR (400 MHz, CD3OD): δ =
8.60 (s, 1 H, ArH), 7.98 (s, 1 H, ArH), 7.91 (d, J = 8.8 Hz, 1 H,
ArH), 7.52–7.41 (m, 2 H, ArH), 7.08–7.01 (m, 10 H, ArH), 6.15 (s,
1 H, NH), 5.83–5.74 (m, 1 H, =CH), 5.66 (s, 1 H, NH), 5.00–4.92
(m, 2 H, =CH2), 4.64 (s, 1 H, NH), 4.01 (s, 3 H, OCH3), 3.45 (s, 1
H, CH), 3.32 (s, 3 H, CH3), 3.23–3.17 (m, 2 H, CH), 2.72–2.70 (m,
2 H, CH), 2.36–2.32 (m, 4 H, CH), 1.64–1.59 (m, 3 H, CH), 1.38–
1.32 (m, 1 H, CH), 0.87 (s, 1 H, CH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 182.0, 158.2, 147.8, 144.5, 141.0, 138.5, 137.0, 131.9,
128.4, 128.3, 127.8, 127.7, 127.4, 126.8, 122.5, 119.6, 114.6, 101.6,
64.1, 63.2, 61.9, 55.7, 55.4, 50.2, 42.1, 40.5, 39.2, 27.8, 27.2,
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data and chiral HPLC traces of the compounds
shown in Tables 1–3 and Scheme 2, and detailed descriptions of the
experimental procedures.
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC) (grant numbers 20772030
and 21072056), the Fundamental Research Funds for the Central
Universities, the Scientific Research Foundation for Returned
Overseas Chinese Scholars, and the Ministry for State Education
25.2 ppm. IR (film): ν = 3305, 2947, 1509, 1318, 1447, 1147,
˜
1028 cm–1. HRMS (ESI): calcd. for C36H42N5O3S2 [M + H]+
656.2729; found 656.2736.
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General Procedure for the Michael Addition of Oxindoles 4 to
Phenyl Vinyl Sulfone: The catalyst 3a (13.1 mg, 0.02 mmol) was
added to a stirred solution of oxindole 4 (0.2 mmol) and phenyl
vinyl sulfone (16.8 mg, 0.1 mmol) in toluene/CHCl3 (1:1, 0.5 mL)
at –20 °C. The resulting mixture was stirred at –20 °C for 5–6 d
(monitored by TLC), concentrated, and purified by flash silica gel
column chromatography to afford the product 5.
Compound 5b: Yield 28.2 mg (57%). White solid; m.p. 127.9–
130.0 °C. [α]2D5 = +21.1 (c = 1.0, CHCl3); 93% ee (Chiralpak AD-
H; hexane/2-propanol, 90:10; 0.7 mL/min; 230 nm; tminor
=
1
15.33 min, tmajor = 18.49 min). H NMR (400 MHz, CDCl3): δ =
7.91 (dd, J = 8.8, 4.4 Hz, 1 H, ArH), 7.85–7.83 (m, 2 H, ArH),
7.70–7.66 (m, 1 H, ArH), 7.57 (t, J = 7.6 Hz, 2 H, ArH), 7.33–7.28
(m, 3 H, ArH), 7.20–7.18 (m, 2 H, ArH), 7.10–7.05 (td, J = 8.8,
2.8 Hz, 1 H, ArH), 6.79 (dd, J = 7.6, 2.8 Hz, 1 H, ArH), 3.11–3.05
(m, 1 H, CH), 2.89–2.76 (m, 2 H, CH2), 2.52–2.46 (m, 1 H, CH),
1.61 (s, 9 H, 3 CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.1,
161.2, 158.8, 148.8, 138.4, 137.4, 135.49, 135.48, 134.0, 131.12,
131.05, 129.4, 129.1, 128.3, 128.1, 126.6, 117.1, 117.0, 116.0, 115.8,
112.0, 111.7, 85.2, 55.4, 51.6, 30.6, 28.0 ppm. 19F NMR (376 MHz,
CDCl ): δ = –116.1 ppm. IR (film): ν = 1793, 1760, 1742, 1480,
˜
3
1449, 1290, 1267, 1249, 1142, 1084, 965 cm–1. MS (EI): m/z (%) =
495 (1) [M]+, 395 (90), 226 (100), 198 (10). HRMS (ESI): calcd. for
C27H26FNO5S [M]+ 495.1516; found 495.1512.
Determination of the Absolute Configuration of 5a:[15h] TFA
(0.4 mL) was added to a stirred solution of 5a (52.5 mg, 0.11 mmol)
in CH2Cl2 (4.0 mL) at room temperature. After stirring for 2.5 h,
aqueous NaHCO3 (10 mL) was added. The resulting mixture was
extracted with CH2Cl2 (3ϫ10 mL). The combined organic extracts
were dried with Na2SO4 and concentrated in vacuo, and the residue
was purified by column chromatography (petroleum ether/ethyl
acetate, 1:1) to afford 6 as a white solid (39.4 mg, 95% yield).
6082
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6078–6084

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6083

M.-X. Zhao, M. Shi et al.
FULL PAPER
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Owing to the higher reactivity of 1,1-bis(phenylsulfonyl)ethyl-
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can be accomplished in higher yields and excellent enantio-
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Received: June 3, 2011
Published Online: August 18, 2011
6084
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Eur. J. Org. Chem. 2011, 6078–6084