Catalytic asymmetric synthesis of 3-hydroxyl-2-oxindoles via enantioselective Morita-Baylis-Hillman reaction of isatins

Article abstract of DOI:10.1016/j.tet.2011.02.045

The enantioselective Morita-Baylis-Hillman reaction of acrylates to isatins was investigated for the first time, employing bifunctional phosphinothiourea organocatalysts based on chiral cyclohexane scaffold. The 3-hydroxyl-2-oxindole derivatives were obta

Full text of DOI:10.1016/j.tet.2011.02.045

Tetrahedron 67 (2011) 2974e2978
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic asymmetric synthesis of 3-hydroxyl-2-oxindoles via enantioselective
MoritaeBayliseHillman reaction of isatins
*
Ci-Ci Wang, Xin-Yan Wu
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2010
Received in revised form 24 January 2011
Accepted 15 February 2011
Available online 22 February 2011
The enantioselective MoritaeBayliseHillman reaction of acrylates to isatins was investigated for the first
time, employing bifunctional phosphinothiourea organocatalysts based on chiral cyclohexane scaffold.
The 3-hydroxyl-2-oxindole derivatives were obtained in excellent yields with moderate enantiose-
lectivity (up to 69% ee) in the presence of 10 mol % catalyst 1b.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective organocatalysis
MoritaeBayliseHillman reaction
Bifunctional phosphinothiourea
Isatin
3-Hydroxyl-2-oxindole
1. Introduction
The oxindole motifs bearing C3-quaternary structures are widely
distributed in many natural products and pharmaceutical mole-
cules.1 Forexample, the 3-substituted 3-hydroxyl-oxindole units are
existed in various alkaloids, such as convolutamydines, dioxi-
brassinine and donaxaridine (Fig. 1).1d,e Over the past several years,
the enantioselective synthesis of 3,3-disubstituted oxindoles has
received considerable attention.2 The nucleophilic addition to pro-
chiral isatins is a very simple and straightforward approach for the
preparation of opticallyactive 3-substituted-3-hydroxyl-2-oxindole
derivatives.2b Since Hayashi’s pioneering work,3a several organo-
metallic catalytic systems were developed for the asymmetric
conjugate additions to isatins.3 With the development of enantio-
selective organocatalysis,4 the aldol reaction of isatins was also used
to construct the chiral 3-hydroxyl-2-oxindole derivatives.5
The MoritaeBayliseHillman (MBH) reaction is known to be
a powerful tool for the construction of densely functionalized al-
cohols.6 And isatin derivatives could serve as electrophiles in the
MBH reaction.7,8 To the best of our knowledge, enantioselective
synthesis of 3-hydroxyl-2-oxindole derivatives is not known by
MBH reaction. Herein we report the first enantioselective MBH
reaction of isatins to provide chiral 3-hydroxyl-2-oxindole
derivatives.9
Fig. 1. Examples of natural products bearing 3-hydroxyl-2-oxindole moiety.
2. Result and discussion
In our previous work, we found the chiral bifunctional phos-
phinothioureas were highly efficient for the MBH reaction due to
the nucleophilic activation by tertiary phosphine and the electro-
philic activation by hydrogen-bonding.10 Initially, we chose the
MBH reaction of N-methyl isatin with methyl acrylate as a model
reaction to evaluate the cyclohexane-based bifunctional catalysts
(Fig. 2). The results are summarized in Table 1. In general, the ar-
omatic thioureas provided better enantioselectivities but lower
yields than the aliphatic thioureas (entries 2e4 vs 6e9). However,
catalyst 1e bearing strongly electron-withdrawing group resulted
in racemic MBH adduct (entry 5). Comparable results were
obtained when the urea derivative 1a was used as catalyst, al-
though it was ineffective in the MBH reaction of MVK with alde-
hyde (entry 1 vs 2).10a In term of both chemical yield and
enantioselectivity, 1b was selected for further study to optimize the
reaction conditions.
* Corresponding author. Tel.: þ86 21 64252011; fax: þ86 21 64252758; e-mail
address: xinyanwu@ecust.edu.cn (X.-Y. Wu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.045

C.-C. Wang, X.-Y. Wu / Tetrahedron 67 (2011) 2974e2978
2975
more suitable solvent, and the trace amount of water in the solvent
had no effect on the MBH reaction (entry 4 vs 5).
To improve the enantioselectivity of the MBH reaction, other
aspects of this reaction, such as the reaction temperature, the sub-
strate concentration, the loading of the catalyst and the additives
wereinvestigated (Table 3). The results indicated the higher reaction
temperature resulted in shorter reaction time and lower enantio-
selectivity (entries 1e5). In the ranger from ꢀ15 to 40 ꢁC, the suitable
reaction temperature is 0 ꢁC (entry 4, 99% yield with 52% ee). The
substrate concentration has no effect on the chemical yield, and the
influence on enantioselectivity is negligible (entries 6 and 7 vs 4).
Similarly, the increase of methyl acrylate loading could not improve
the enantioselectivity (entries 8 and 9 vs 4). The same enantiose-
lectivity and yield was also observed as decreasing the catalyst
loading, certainly longer reaction time was demanded (entries 10
and 11). In addition, different additives were examined.11 The ter-
tiary amines, such as imidazole, triethylamine and DABCO would
decelerate the reactionwith a slight decrement of enantioselectivity
(entries 12e14 vs 4), probably due to the background reaction pro-
moted by the tertiary amines. While benzoic acid was added, the
reaction was quenched and no product was observed.
Fig. 2. Structures of the screened phosphinothiourea catalysts.
Table 1
Screening of catalysts for MBH reaction of N-methyl isatin with methyl acrylatea
b
Entry
Catalyst
Time (d)
Yield (%)
ee (%) c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
3
3
3
3
3
3
3
3
3
65
75
75
62
73
84
87
89
83
42
43
35
44
0
23
21
17
1
Table 3
Further optimization of reaction conditionsa
a
The reactions were performed with 10 mol % of organocatalyst, 0.2 mmol
N-methyl isatin and 2 equiv of methyl acrylate in 1 mL CH2Cl2 at 25 ꢁC.
Entry
Temp
(ꢁC)
Concn
(M)
Additive
1b (mol %)
Time
(h)
Yield
(%) b
ee
b
Isolated yield after column chromatography.
Determined by HPLC analysis using chiralcel OD-H column.
(%)c
c
1
2
3
4
5
6
7
40
25
10
0
0.2
0.2
0.2
0.2
0.2
0.1
0.3
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
None
None
None
None
None
None
None
None
None
None
None
Imidazole
Et3N
10
10
10
10
10
10
10
10
10
5
4
5
5
90
99
99
99
99
99
99
99
99
99
99
99
99
99
0
33
45
50
52
52
52
50
52
52
52
52
50
50
50
n.d.f
Next, the effect of reaction solvent was investigated using 10 mol %
of 1b as catalyst. As illustrated in Table 2, in ethyl acetate and various
ethers, the MBH reaction was accomplished in a short time (3e5 h)
and provided nearly quantitative yields, while the enantioselectivity
was different (entries 4e9). In other solvents examined, the MBH
reaction was relatively slower and a longer reaction time (at least one
day) was required (entries 1e3, 10 and 11). On the whole, the enan-
tioselectivitywasmoderate. ThesolventsurveyindicatedTHFwasthe
8
ꢀ15
48
12
8
8
8
48
216
24
24
24
48
0
0
0
0
0
0
0
0
0
8d
9e
10
11
12
13
14
15
1
10
10
10
10
Table 2
DABCO
PhCO2H
The survey of solvents for the MBH reaction of N-methyl isatin with methyl acrylatea
0
a
Unless stated otherwise, the reactions were performed with organocatalyst 1b,
0.2 mmol N-methyl isatin and 2 equiv of methyl acrylate in 1 mL THF.
b
Isolated yield after column chromatography.
Determined by HPLC using chiralcel OD-H column.
3 equiv of methyl acrylate was used.
5 equiv of methyl acrylate was used.
c
d
e
f
Not determined.
Entry
Solvent
Time (h)
Yield (%) b
ee (%) c
1
2
3
CH2Cl2
CHCl3
PhMe
THF
THF
Ether
1,4-Dioxane
Dimethoxyethane
Ethyl acetate
CH3CN
72
48
24
5
5
3
5
5
5
48
24
75
84
99
99
99
99
95
98
99
86
98
43
41
24
45
45
31
40
42
33
48
40
Under the optimized reaction conditions (10 mol % of 1b as
catalyst, 2 equiv of acrylate, THF as solvent, 0 ꢁC), the scope of
substrates was probed. Firstly, various acrylates were applied as
Michael donor to react with N-methyl isatin. The results summa-
rized in Table 4 showed that the structure of acrylate had obvious
effect on the reactivity (entries 1e6). Generally, the larger the alkyl
group of acrylate, the longer the reaction time was required to
achieve excellent yields. And the reaction with tert-butyl and
phenyl acrylate afforded poor enantioselectivity probably due to
steric hindrance. Therefore, methyl acrylate was selected to react
with different isatin derivatives. As shown in Table 4, the N-sub-
stituents of isatins had a limited influence on both yields and
enantioselectivity, and comparable results were obtained (entries
7e11 vs 1). The best enantioselectivity was achieved using N-benzyl
4d
5e
6
7
8
9
10
11
DMSO
a
The reactions were performed with 10 mol % of organocatalyst 1b, 0.2 mmol
N-methyl isatin and 2 equiv of methyl acrylate in 1 mL solvent at 25 ꢁC.
b
Isolated yield after column chromatography.
Determined by HPLC analysis using chiralcel OD-H column.
Dry THF was used.
Commercial available THF was used directly.
c
d
e

2976
C.-C. Wang, X.-Y. Wu / Tetrahedron 67 (2011) 2974e2978
Table 4
3. Conclusion
The MBH reaction of isatins with different acrylatesa
In summary, we have explored the first example of enantiose-
lective MoritaeBayliseHillman reaction using isatin derivatives as
electrophiles catalyzed by chiral phosphinothioureas. In the presence
of 10 mol % of phosphinothiourea 1b, the MoritaeBayliseHillman
reaction of acrylates to isatins could proceed smoothly to afford 3-
substituted-3-hydroxyl-oxindole derivatives in excellent yields
(82e99%) and up to 69% ee.
c
Entry
R1
R2
R3
Time (h)
Yield (%) b
ee (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Cl
Cl
H
Me
Me
Me
Me
Me
Me
Et
n-Bu
Bn
n-C12H25
H
Me
H
Me
H
Bn
Bn
Me
Et
n-Bu
t-Bu
Bn
8
18
15
103
48
48
12
12
8
12
120
24
120
24
120
20
36
99
99
99
99
99
99
99
99
98
99
87
99
85
99
82
89
15
99
52
49
41
10
53
14
53
50
69
49
49
56
56
8
4. Experimental
4.1. General methods
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Melting points are taken without correction. Optical rotations
were measured on a WZZ-2A digital polarimeter at the wavelength
of the sodium D-line (589 nm) at 20 ꢁC. 1H and 13C spectra were
recorded on Bruker 400 spectrometer. 1H NMR spectra were ref-
9
10
11
12
13
14
15
16
17
18
erenced to tetramethylsilane (d 0.00 ppm) using CDCl3 or DMSO-d6
as solvent. 13C NMR spectra were referenced to the solvent carbon
(77.0 ppm for CDCl3). IR spectra were recorded on Nicolet Magna-I
550 spectrometer. High Resolution Mass spectra (HRMS) were
recorded on Micromass GCT spectrometer with Electron Ionization
(ESI) resource. HPLC analysis was performed on Waters equipment
using Daicel Chiralcel OD-H, Chiralpak AD-H or AS-H column.
THF was directly used without further purification. And other
solvents were purified and dried according to standard methods
prior to use.
16
9
38
35
H
H
CH(CF3)2
Bn
Bn
24
a
The reactions were performed with 10 mol % of organocatalyst 1b, 0.2 mmol
N-methyl isatin and 2 equiv of acrylate in 1 mL THF at 0 ꢁC.
b
Isolated yield after column chromatography.
Determined by HPLC using chiral column.
c
isatin as an electrophile (entry 9, 69% ee with 98% yield). In addi-
tion, it appeared that the electronic property of the substituent on
the phenyl moiety of isatin derivatives had an obvious effect on the
enantioselectivity. The electron-rich substituent for the phenyl ring
of isatins gave higher enantioselectivity than electron-deficient one
(entries 11e15 and 1). It’s notably that the N-protected group free
isatin derivatives could provide the desired products in good
chemical yields and comparative enantioselectivity (entry 11 vs 1,
entry 13 vs 12, entry 15 vs 14). The absolute configuration of the
BMH adducts were assigned as R- by comparing the optical rotation
and the retention time of products 4p and 4q (entries 16 and 17)
with those reported in the literature.9b
4.2. General procedure for the MoritaeBayliseHillman
reaction
To a solution of phosphinothiourea 1b (0.02 mmol) in THF
(1.0 mL) was added acrylate (0.4 mmol) at 0 ꢁC. After 10 min stirring
at this temperature, isatin (0.2 mmol) was added. The reaction
mixture was stirred at 0 ꢁC (monitoring by TLC). Then the resulting
solution was concentrated under reduced pressure and the residue
was purified by a flash column chromatography on silica gel to
afford the desired adducts and the ee values were determined by
HPLC analysis with chiral column.
In addition, other nucleophiles were examined (Scheme 1).
Acrolein is so reactive that the MBH reaction was completed in half
an hour.9a And the MBH reaction between methyl vinyl ketone
(MVK) and N-methyl isatin was accomplished in 12 h. The mod-
erate yields resulted from side-reaction. However, cyclohex-2-one
is inert under the typical reaction conditions.
4.2.1. Compound 4a (Table 4, entry 1)12a. Yield 99%, 52%ee, [
(c 0.49, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
7.37e7.33 (m, 1H), 7.20
a
]D þ7.1
d
(d, J¼6.4 Hz, 1H), 7.05 (t, J¼7.2 Hz, 1H), 6.88 (d, J¼7.6 Hz, 1H), 6.57
(s,1H), 6.42 (s,1H), 3.65 (s, 3H), 3.59 (s,1H), 3.26 (s, 3H). HPLC analysis
(OD-H column,
rate: 1.0 mL/min): tR¼21.43 min (major), 12.75 min (minor).
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow
4.2.2. Compound 4b (Table 4, entry 2)7a. Yield 99%, 49% ee, [
a
]
D
þ15.4 (c 0.52, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d 7.37e7.33 (m,
1H), 7.20 (d, J¼6.8 Hz, 1H), 7.05 (t, J¼7.2 Hz, 1H),6.87 (d, J¼8.0 Hz,
1H), 6.59 (s, 1H), 6.40 (s, 1H), 4.10e4.01 (m, 2H), 3.55 (s, 1H), 3.26 (s,
3H), 1.14 (t, J¼7.2 Hz, 3H). HPLC analysis (OD-H column, ¼254 nm,
l
eluent: hexane/2-propanol¼90/10, flow rate: 1.0 mL/min):
tR¼26.23 min (major), 16.35 min (minor).
4.2.3. Compound 4c (Table 4, entry 3). Yield 99%, 41% ee, [
(c 0.58, CH2Cl2); IR (KBr, cmꢀ1):
3334, 2958, 1715, 1701, 1615, 1471,
1060, 750; 1H NMR (CDCl3, 400 MHz):
7.35e7.30 (m, 1H), 7.17 (d,
a]
D þ5.2
n
d
J¼6.4 Hz, 1H), 7.03 (t, J¼8.0 Hz, 1H), 6.85 (d, J¼7.6 Hz, 1H), 6.58
(s, 1H), 6.44 (s, 1H), 4.22 (s, 1H), 4.04e3.91 (m, 2H), 3.23(s, 3H),
1.50e1.43 (m, 2H), 1.24e1.18 (m, 2H), 0.853 (t, J¼7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz):
d 176.4, 164.7, 144.5, 139.3, 130.1, 129.6,
127.9, 123.8, 123.0, 108.6, 64.9, 30.4, 26.4, 19.0, 13.7; HRMS (ESI)
Scheme 1. The MBH reactions of acrolein and MVK to isatin.
calcd for C16H19NO4([M]þ) 312.1212, obsd 312.1211. HPLC analysis

C.-C. Wang, X.-Y. Wu / Tetrahedron 67 (2011) 2974e2978
2977
(OD-H column,
rate: 1.0 mL/min): tR¼12.68 min (major), 10.31 min (minor).
l
¼254 nm, eluent: hexane/2-propanol¼96/4, flow
propanol¼90/10, flow rate: 1.0 mL/min): tR¼19.17 min (major),
11.45 min (minor).
4.2.4. Compound 4d (Table 4, entry 4). Yield 99%, 10% ee, [
(c 0.58, CH2Cl2); IR (KBr, cmꢀ1):
3333, 2967, 1716, 1614, 1495,
1058, 772; 1H NMR (CDCl3, 400 MHz):
7.35e7.30 (m, 1H), 7.18
a
]
þ6.0
4.2.10. Compound 4j (Table 4, entry 10). Yield 99%, 49% ee, [a]
D
D
n
þ4.4 (c 0.80, CH2Cl2); IR (KBr, cmꢀ1):
n
3327, 2953, 1716, 1467,
7.31 (t, J¼8.0 Hz, 1H),
d
1063, 767; 1H NMR (CDCl3, 400 MHz):
d
(d J¼6.8 Hz, 1H), 7.03 (t, J¼7.2 Hz, 1H), 6.83 (d, J¼8.0 Hz,
7.17 (d, J¼7.2 Hz, 1H), 7.01 (t, J¼7.6 Hz, 1H), 6.87 (d, J¼8.0 Hz,
1H), 6.56 (s, 1H), 6.45 (s, 1H), 4.22 (s, 1H), 3.69 (m, 2H), 3.60
(s, 3H), 1.72 (m, 2H),1.26 (m, 18H), 0.89 (t, J¼6.4 Hz, 3H); 13C NMR
1H),6.50 (s, 1H), 6.30 (s, 1H), 4.16 (s, 1H), 3.20 (s, 3H), 1.22
(s, 9H); 13C NMR (CDCl3, 100 MHz):
d 176.2, 163.9, 144.3, 140.3,
129.9, 129.8, 127.3, 123.7, 122.9, 108.4, 81.7, 76.1, 27.6, 26.3;
(CDCl3, 100 MHz): d 176.3, 165.0, 144.0, 139.2, 130.1, 129.7, 127.8,
HRMS (ESI) calcd for C16H19NO4([M]þ) 328.0951, obsd 328.0953.
123.9, 122.7, 108.9, 76.2, 51.9, 40.4, 31.9, 29.7, 29.6, 29.4, 27.2,
HPLC analysis (AS-H column,
l
¼254 nm, eluent: hexane/2-
27.0, 22.7, 14.1; HRMS (EI) calcd for C24H35NO4([M]þ) 424.2464,
propanol¼90/10, flow rate: 1.0 mL/min): tR¼7.34 min (major),
obsd 424.2465. HPLC analysis (OD-H column,
l
¼254 nm, eluent:
11.29 min (minor).
hexane/2-propanol¼90/10, flow rate: 0.9 mL/min): tR¼12.04 min
(major), 6.16 min (minor).
4.2.5. Compound 4e (Table 4, entry 5). Yield 99%, 53% ee, [
(c 0.64, CH2Cl2); IR (KBr, cmꢀ1):
3319, 1713, 1699, 1614, 1470,
1058, 767; 1H NMR (CDCl3, 400 MHz):
7.36e7.31 (m, 4H), 7.20
a
]
þ8.6
D
n
4.2.11. Compound 4k (Table 4, entry 11)8a. Yield 87%, 49% ee, [
a]
D
d
þ8.5 (c 0.41, CH2Cl2); 1H NMR (DMSO-d6, 400 MHz):
d 10.24 (s, 1H),
(d, J¼6.8 Hz, 1H), 7.13e7.10 (m, 2H), 7.05 (t, J¼7.6 Hz, 1H), 6.73
(d, J¼8.0 Hz, 1H), 6.67 (s, 1H), 6.46 (s, 1H), 5.00 (d, J¼12.4 Hz,
1H), 4.96 (d, J¼12.4 Hz, 1H), 3.43 (s, 1H), 2.98 (s, 3H); 13C NMR
7.14e7.10 (m, 1H), 6.89 (d, J¼6.8 Hz, 1H), 6.80 (t, J¼7.2 Hz, 1H), 6.74
(d, J¼7.6 Hz, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 6.37 (s, 1H), 3.43 (s, 3H).
HPLC analysis (AD-H column,
l
¼254 nm, eluent: hexane/2-prop-
(CDCl3, 100 MHz):
d
176.3, 164.4, 144.4, 139.1, 134.9, 130.1, 129.5,
anol¼90/10, flow rate: 1.0 mL/min): tR¼38.67 min (major),
128.6, 128.5, 128.4, 123.8, 123.0, 108.8, 76.1, 67.0, 26.1; HRMS
28.17 min (minor).
(ESI) calcd for C19H17NO4([M]þ) 324.1236, obsd 324.1231. HPLC
analysis (AD-H column,
l
¼254 nm, eluent: hexane/2-prop-
4.2.12. Compound 4l (Table 4, entry 12)12c. Yield 99%, 56% ee, [
a]
D
anol¼90/10, flow rate: 1.0 mL/min): tR¼29.96 min (major),
þ13.5 (c 0.52, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d 7.13
27.30 min (minor).
(d, J¼7.6 Hz, 1H), 7.00 (s, 1H), 6.75 (d, J¼8.0 Hz, 1H), 6.56 (s, 1H), 6.44
(s, 1H), 3.92 (s, 1H), 3.63 (s, 3H), 3.22 (s, 3H), 2.30 (s, 3H). HPLC
4.2.6. Compound 4f (Table 4, entry 6). Yield 99%, 14% ee, [
(c 0.62, CH2Cl2); IR (KBr, cmꢀ1):
3551, 3082, 1700, 1609, 1468,
1047, 770; 1H NMR (CDCl3, 400 MHz):
7.38e7.27 (m, 4H), 7.19
a
]
þ5.6
analysis (AD-H column,
10, flow rate: 1.0 mL/min): tR¼19.46 min (major), 30.18 min (minor).
l
¼254 nm, eluent: hexane/2-propanol¼90/
D
n
d
(t, J¼7.6 Hz, 1H), 7.11e7.07 (m, 1H), 6.93e6.90 (m, 2H),
4.2.13. Compound 4m (Table 4, entry 13)12c. Yield 85%, 56% ee, [
a]
D
6.86e6.84 (m, 2H), 6.66 (s, 1H), 3.47 (s, 1H), 3.22 (s, 3H); 13C
þ8.3 (c 0.42, CH2Cl2); 1H NMR (DMSO-d6, 400 MHz):
d 10.15 (s, 1H),
NMR (CDCl3, 100 MHz):
d
176.3, 163.1, 150.1, 144.6, 139.2, 130.3,
6.93 (d, J¼8.0 Hz, 1H), 6.72 (s, 1H), 6.64 (d, J¼8.0 Hz, 1H), 6.40
129.5, 129.4, 126.0, 123.8, 123.1, 121.4, 108.8, 76.2, 26.5; HRMS
(s, 2H), 6.36 (s, 1H), 3.45 (s, 3H), 2.14 (s, 3H). HPLC analysis (AD-H
(ESI) calcd for C18H15NO4([M]þ) 310.1079, obsd 310.1084. HPLC
column,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow rate:
analysis (OD-H column,
l
¼254 nm, eluent: hexane/2-prop-
1.0 mL/min): tR¼49.36 min (major), 30.13 min (minor).
anol¼90/10, flow rate: 1.0 mL/min): tR¼33.49 min (major),
22.34 min (minor).
4.2.14. Compound 4n (Table 4, entry 14)8a. Yield 99%, 8% ee, [
a]
D
þ10.7 (c 0.56, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d 7.30e7.28
4.2.7. Compound 4g (Table 4, entry 7)12b. Yield 99%, 53% ee, [
a
]
(m, 1H), 7.13 (s, 1H), 6.78 (d, J¼8.4 Hz, 1H), 6.58 (s, 1H), 6.49 (s, 1H),
D
þ6.7 (c 0.52, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d
7.35e7.31 (m,
4.50 (s, 1H), 3.62 (s, 3H), 3.21 (s, 3H). HPLC analysis (AD-H column,
1H), 7.19 (d, J¼6.4 Hz, 1H), 7.03 (t, J¼7.6 Hz, 1H), 6.89 (d, J¼8.0 Hz,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow rate: 1.0 mL/
1H), 6.57 (s, 1H), 6.43 (s, 1H), 3.90e3.69 (m, 3H), 3.62 (s, 3H), 1.32
min): tR¼16.90 min (major), 26.59 min (minor).
(t, J¼8.0 Hz, 3H). HPLC analysis (AD-H column, ¼254 nm, eluent:
l
hexane/2-propanol¼90/10, flow rate: 1.0 mL/min): tR¼29.39 min
4.2.15. Compound 4o (Table 4, entry 15)8a. Yield 82%, 16% ee, [
a]
D
(major), 54.48 min (minor).
þ10.5 (c 0.43, CH2Cl2); 1H NMR (DMSO-d6, 400 MHz):
d 10.40
(s, 1H), 7.19e7.16 (m, 1H),
d
6.89(s, 1H), 6.76 (d, J¼8.4 Hz, 1H), 6.62
4.2.8. Compound 4h (Table 4, entry 8). Yield 99%, 50% ee, [
(c 0.58, CH2Cl2); IR (KBr, cmꢀ1):
3327, 2954, 1716, 1467, 1063, 767;
1H NMR (CDCl3, 400 MHz):
a
]D þ6.0
(s, 1H), 6.43 (s, 1H), 6.38 (s, 1H), 3.46 (s, 3H); HPLC analysis (AD-H
column,
n
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow rate:
d
7.34e7.30 (m, 1H), 7.18 (d, J¼6.4 Hz,
1.0 mL/min): tR¼44.06 min (major),23.19 min (minor).
1H), 7.02 (t, J¼7.6 Hz, 1H), 6.88 (d, J¼8.0 Hz, 1H), 6.57 (s, 1H), 6.43
(s, 1H), 3.94 (s, 1H), 3.72 (m, 2H), 3.62 (s, 3H), 1.71 (m, 2H), 1.44 (m,
4.2.16. Compound 4p (Table 4, entry 16)9b. Yield 89%, 9% ee, [
a]
D
2H), 0.97 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d
176.2, 165.1,
þ5.8 (c 0.69, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d 7.35e7.28
144.0, 139.2, 130.1, 129.6, 127.8, 124.0, 122.8, 108.9, 76.2, 52.0, 40.1,
(m, 5H), 7.23e7.18 (m, 5H), 7.05 (d, J¼7.6 Hz, 1H), 6.92 (s, 1H),
6.87 (d, J¼7.2 Hz, 2H), 6.76 (s, 1H), 6.70 (d, J¼8.0 Hz, 1H), 4.94
(d, J¼15.6 Hz, 1H), 4.88 (d, J¼15.6 Hz, 1H), 4.15 (s, 1H). HPLC
29.2, 20.2, 13.8; HRMS (ESI) calcd for C16H19NO4([M]þ) 290.1392,
obsd 290.1395. HPLC analysis (AD-H column,
l
¼254 nm, eluent:
hexane/2-propanol¼90/10, flow rate: 1.0 mL/min): tR¼19.62min
analysis (OD-H column,
l¼254 nm, eluent: hexane/2-prop-
(major), 23.87min (minor).
anol¼80/20, flow rate: 1.0 mL/min): tR¼11.46 min (major),
8.93 min (minor).
4.2.9. Compound 4i (Table 4, entry 9)8a. Yield 98%, 69% ee, [
(c 0.64, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
a
]
D þ8.6
d
7.39 (d, J¼7.2 Hz, 2H),
4.2.17. Compound 4q (Table 4, entry 17)9b. Yield 15%, 38% ee, [
a]
D
7.33 (t, J¼6.8 Hz, 2H), 7.28 (d, J¼7.2 Hz, 1H), 7.23e7.18 (m, 2H), 7.00
(t, J¼7.2 Hz, 1H), 6.72 (d, J¼7.2 Hz, 1H), 6.60 (s, 1H), 6.43 (s, 1H), 4.98
(d, J¼15.6 Hz, 1H), 4.90 (d, J¼15.6 Hz, 1H), 3.60 (s, 3H), 3.57 (s, 1H).
þ39.3 (c 0.14, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d 7.35e7.20
(m, 7H), 7.05 (t, J¼7.6 Hz, 1H), 6.85 (s, 1H), 6.83 (s, 1H), 6.75 (d,
J¼7.2 Hz, 1H), 5.60 (s, 1H), 5.05 (d, J¼15.6 Hz, 1H), 4.86 (d, J¼15.6 Hz,
HPLC analysis (OD-H column,
l¼254 nm, eluent: hexane/2-
1H), 4.02 (s, 1H). HPLC analysis (OD-H column,
l¼254 nm, eluent:

2978
C.-C. Wang, X.-Y. Wu / Tetrahedron 67 (2011) 2974e2978
Tetrahedron Lett. 2006, 47, 3199e3202; (c) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J.
G.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2006, 8, 2715e2718; (d) Tomita, D.;
Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946e6948;
(e) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 6313e6316;
(f) Lai, H.; Huang, Z.; Wu, Q.; Qin, Y. J. Org. Chem. 2009, 74, 283e288; (g) Qiao,
X.-C.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron: Asymmetry 2009, 20, 1254e1261; (h)
Hanhan, V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz, A. K. Angew. Chem.,
Int. Ed. 2010, 49, 744e747.
4. For recent reviews on asymmetric organocatalysis, see: (a) Dalko, P. I. Enan-
tioselective Organocatalysis: Reactions and Experimental Procedures; Wiley-VCH:
Weinheim, 2007; (b) List, B. Asymmetric Organocatalysis; Springer: Heidelberg,
2010; (c) Pellissier, H. Tetrahedron 2007, 63, 9267e9331; (d) Gaunt, M. J.; Jo-
hansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today 2007, 12, 8e27; (e)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638e4660; (f) Mac-
Millan, D. W. C. Nature 2008, 455, 304e308; (g) Bertelsen, S.; Jøgensen, K. A.
Chem. Soc. Rev. 2009, 38, 2178e2189.
hexane/2-propanol¼90/10, flow rate: 1.0 mL/min): tR¼17.76 min
(major), 15.72 min (minor).
4.2.18. Compound 4r (Table 4, entry 18)9c. Yield 99%, 35% ee, [
a]
D
þ13.8 (c 0.80, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d 7.39e7.28
(m, 7H), 7.25 (d, J¼7.6 Hz, 1H), 7.23e7.18 (m, 2H), 7.15e7.13 (m, 2H),
7.00 (t, J¼7.2 Hz, 1H), 6.68 (s, 1H), 6.62 (d, J¼7.2 Hz, 1H), 6.50 (s, 1H),
5.07 (d, J¼12.4 Hz, 1H), 4.93 (d, J¼12.4 Hz, 1H), 4.86 (d, J¼15.6 Hz,
1H), 4.53 (d, J¼15.6 Hz, 1H), 3.59 (s, 1H). HPLC analysis (AD-H col-
umn,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow rate:
1.0 mL/min): tR¼62.12min (major), 57.02min (minor).
4.2.19. Compound 5 (Scheme 1)9a. Yield 82%, 13% ee, [
a
]
ꢀ28.6
5. (a) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tom-
asini, C. J. Org. Chem. 2005, 70, 7418e7421; (b) Chen, J.-R.; Liu, X.-P.; Zhu, X.-
Y.; Li, L.; Qian, T.-F.; Zhang, J.-M.; Xiao, W.-J. Tetrahedron 2007, 63,
10437e10444; (c) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata,
N.; Toru, T. Chem.dEur. J. 2008, 14, 8079e8081; (d) Luppi, G.; Monari, M.;
CorrTa, R. J.; Violante, F. A.; Pinto, A. C.; Kaptein, B.; Broxterman, Q. B.;
Garden, S. J.; Tomasini, C. Tetrahedron 2006, 62, 12017e12024; (e) Malkov, V.;
D
(c 0.35, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d 9.46 (s,1H), 7.36e7.32
(m, 1H), 7.14 (d, J¼7.2 Hz, 1H), 7.03(t, J¼7.2 Hz, 1H), 6.97(s, 1H), 6.88
(d, J¼8.0Hz, 1H), 6.37(s, 1H), 3.99(s, 1H), 3.25 (s, 3H). HPLC analysis
(AD-H column,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow
rate: 1.0 mL/min): tR¼18.23 min (major), 16.57 min (minor).
ꢀˇ
Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev, D. A.; Pluhckov, K.;
ꢀ
ꢁ
Kocovsky, P. Org. Lett. 2007, 9, 5473e5476; (f) Angelici, G.; Correa, R. J.;
Garden, S. J.; Tomasini, C. Tetrahedron Lett. 2009, 50, 814e817; (g) Hara, N.;
Nakamura, S.; Shibata, N.; Toru, T. Chem.dEur. J. 2009, 15, 6790e6793; (h)
Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854e3857; (i) Xue, F.;
Zhang, S.; Liu, L.; Duan, W.; Wang, W. Chem.dAsian J. 2009, 4, 1664e1667; (j)
Deng, J.; Zhang, S.; Ding, P.; Jiang, H.; Wang, W.; Li, J. Adv. Synth. Catal. 2010,
352, 833e838; (k) Raj, M.; Veerasamy, N.; Singh, V. K. Tetrahedron Lett. 2010,
51, 2157e2159.
4.2.20. Compound 6 (Scheme 1)8b. Yield 42%, 20% ee, [
a]
þ31.4
D
(c 0.43, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d
7.32 (t, J¼8.0 Hz, 1H),
7.12 (d, J¼7.2 Hz,1H), 7.01 (t, J¼7.6 Hz,1H), 6.87 (d, J¼7.6 Hz,1H), 6.66
(s,1H), 6.43 (s,1H), 3.53(s,1H), 3.26(s, 3H), 2.30(s, 3H). HPLC analysis
(AD-H column,
l
¼254 nm, eluent: hexane/2-propanol¼90/10, flow
rate: 1.0 mL/min): tR¼20.02 min (major), 24.78 min (minor).
6. For reviews on the asymmetric MBH reactions, see: (a) Masson, G.; Housseman,
C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614e4628; (b) Basavaiah, D.; Rao, K.
V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581e1588; (c) Krishna, P. R.; Sachwani,
R.; Reddy, P. S. Synlett 2008, 2897e2912; (d) Carrasco-Sanchez, V.; Simirgiotis,
M. J.; Santos, L. S. Molecules 2009, 14, 3989e4021; (e) Wei, Y.; Shi, M. Acc. Chem.
Res. 2010, 43, 1005e1018.
7. (a) Garden, S. J.; Skakle, J. M. S. Tetrahedron Lett. 2002, 43, 1969e1972; (b)
Chung, Y. M.; Im, Y. J.; Kim, J. N. Bull. Korean Chem. Soc. 2002, 23, 1651e1655; (c)
Luo, S. Z.; Mi, X. L.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 8413e8422;
(d) Basavaiah, D.; Roy, S.; Das, U. Tetrahedron 2010, 66, 5612e5622.
8. Selected papers for the application of MBH adducts of isatins in the synthesis of
oxindole derivatives: (a) Kim, S. C.; Gowrisankar, S.; Kim, J. N. Tetrahedron Lett.
2006, 47, 3463e3466; (b) Shanmugam, P.; Viswambharan, B.; Madhavan, S. Org.
Lett. 2007, 9, 4095e4098.
Acknowledgements
We are grateful for the financial support from National Natural
Science Foundation of China (20772029), the Program for New
Century Excellent Talents in University (NCET-07-0286), and the
Fundamental Research Funds for the Central Universities.
Supplementary data
9. After the submission of this manuscript, the enantioselective MBH reaction of
isatin was reported. (a) Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.;
Wang, C.; Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176e15178; (b) Guan, X.-Y.; Wei,
Y.; Shi, M. Chem.dEur. J. 2010, 16, 13617e13621; (c) Zhong, F.; Chen, G.-Y.; Lu, Y.
Org. Lett. 2011, 13, 82e85.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.02.045.
References and notes
10. (a) Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron Lett. 2008, 49,
6262e6264; (b) Yuan, K.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron 2009, 65,
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2117e2120; (d) Gong, J.-J.; Yuan, K.; Song, H.-L.; Wu, X.-Y. Tetrahedron 2010, 66,
2439e2443; (e) Yuan, K.; Song, H.-L.; Hu, Y.; Fang, J.-F.; Wu, X.-Y. Tetrahedron:
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64, 3322e3330; (c) Shanmugam, P.; Vaithiyanathan, V.; Selvakumar, K. Tetra-
hedron Lett. 2008, 49, 2119e2123.
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1381e1407.
3. (a) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45,
3353e3356; (b) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama, H.