Cinchona alkaloid catalyzed enantioselective chlorination of 3-aryloxindoles

Article abstract of DOI:10.1002/ejoc.201100061

O-Benzoylquinidine is an effective organocatalyst for the asymmetric chlorination of 3-aryloxindoles by using easily available N-chlorosuccinimide (NCS as chlorine source to give the corresponding 3-aryl-3-chlorooxindoles in excellent yields and up to 93% enantiomeric excess. We have developed a highly effective asymmetric α-chlorination reaction of oxindoles by using an inexpensive cinchona alkaloid as the organocatalyst and N-chlorosuccinimide (NCS as the chlorination reagent under mild conditions, providing the corresponding 3-aryl-3-chlorooxindoles in excellent yields and up to 93% ee.

Full text of DOI:10.1002/ejoc.201100061

FULL PAPER
DOI: 10.1002/ejoc.201100061
Cinchona Alkaloid Catalyzed Enantioselective Chlorination of 3-Aryloxindoles
Mei-Xin Zhao,*[a,b] Zhi-Wang Zhang,[a] Ming-Xiao Chen,[a] Wen-Hao Tang,[a] and
Min Shi*[a,c]
Keywords: Alkaloids / Chlorination / Enantioselectivity / Organocatalysis / Synthetic methods
O-Benzoylquinidine is an effective organocatalyst for the
asymmetric chlorination of 3-aryloxindoles by using easily
available N-chlorosuccinimide (NCS) as chlorine source to
give the corresponding 3-aryl-3-chlorooxindoles in excellent
yields and up to 93% enantiomeric excess.
a tetrasubstituted stereogenic center. The obtained product
can further undergo substitution with C-[14] or O-nucleo-
philes[15] to produce more complex compounds. Despite in-
tense research efforts on the aforementioned transforma-
tions,[4–9] enantioselective, asymmetric chlorination reac-
tions of oxindoles are rare. To the best of our knowledge,
only one example of a chlorination reaction of 3-aryloxin-
dole has been described in the literature, giving the corre-
sponding product in moderate enantioselectivity using
(dbfox-Ph)Ni complex [dbfox-Ph = 4,6-dibenzofurandiyl-
2,2Ј-bis(4-phenyloxazoline)] as the catalyst,[3e,3f] and no ex-
amples could be found for the enantioselective chlorination
of 3-aryloxindoles using an organocatalyst. Herein, we wish
to report our initial studies on the enantioselective chlorina-
tion of 3-aryloxindoles using N-chlorosuccinimide (NCS)
as chlorine source in the presence of a cinchona alkaloid as
an organocatalyst under mild reaction conditions.
Introduction
Oxindoles are important structural motifs that are found
in a wide array of natural and biologically active mole-
cules.[1] In particular, oxindole compounds bearing a qua-
ternary stereogenic center at the 3-position are extremely
useful.[2] In this context, various synthetic approaches, in-
cluding fluorination,[3] hydroxylation,[4] amination,[5] aldol
and Mannich reactions,[6] allylic alkylation,[7] and conjugate
addition[8] with 3-substituted oxindoles as nucleophiles,
have been developed in recent years for the asymmetric syn-
thesis of 3,3-disubstituted oxindole derivatives.[9] Moreover,
optically active 3-acylated oxindoles bearing a quaternary
stereocenter can be generated through carboxyl migration
of O-acylated oxindoles mediated by a chiral nucleophilic
catalyst.[10]
Recently, the enantioselective construction of a carbon–
halogen stereocenter has become a topical area of current
asymmetric catalysis research by virtue of the fact that
halogen atoms attached to a chiral stereocenter can serve
as a linchpin for further stereospecific manipulations.[11]
Over the past several years, electrophilic chlorination of
carbonyl compounds has drawn significant interest. For ex-
ample, aldehydes, ketones, acyl halides, β-oxo esters, and
their derivatives are often employed as nucleophiles in these
reactions.[12,13] We envisioned that a similar transformation
could be achieved if oxindoles are used as nucleophiles,
forming a C–Cl bond at C-3 along with the generation of
Results and Discussion
Considering that the transformation described above re-
lies on the deprotonation of the C-3 methine proton with a
chiral amine, cinchona alkaloids were therefore used as a
catalyst to effect the stereoselective chlorination. Initially,
the enantioselective catalytic chlorination of N-Boc-3-phen-
yloxindole (2a) with NCS (1.2 equiv.) was carried out in
dichloromethane in the presence of 20 mol-% quinine 1a,
affording the desired product 3a in excellent yield (99%)
with 23% ee (Table 1, Entry 1). Encouraged by this result,
a series of cinchona alkaloids were prepared and used as
catalysts to examine the reaction outcome (Figure 1); the
results are summarized in Table 1. O-Benzylquinine 1b
and -quinidine 1i were not effective catalysts for this reac-
tion (Table 1, Entries 2 and 9), and quinidine 1h also gave
a poor result (Table 1, Entry 8). However, O-acylated cata-
lysts, such as O-benzoyl-, O-acetyl-, and O-naphthoyl-de-
rived quinidine derivatives 1j–l gave better ee values than
those of the corresponding O-acylated quinine catalysts
[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: +86-21-64166128
E-mail: Mshi@mail.sioc.ac.cn
[b] CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, P. R. of China
[c] 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.201100061.
Eur. J. Org. Chem. 2011, 3001–3008
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M.-X. Zhao, M. Shi et al.
FULL PAPER
1c–e (Table 1, Entries 10–12 vs. 3–5), which is consistent
with the previously reported result for the chlorination of
1,3-dicarbonyl compounds in which O-benzoylquinidine is
a more effective catalyst than O-benzoylquinine.[13g] It
should also be noted that O-acylcinchonidine and -cincho-
nine did not give satisfactory enantioselectivities in this re-
action (Table 1, Entries 6–7 and 13–14). O-Benzoylquinid-
ine derivative 1j turned out to be an excellent catalyst, giv-
ing the desired product 3a in 99% yield with 74% ee
(Table 1, Entry 10). An alternative chlorination reagent, tri-
chloroquinolinone, which has shown good enantio-
selectivity in the chlorination of 1,3-dicarbonyl com-
pounds,[13g] did not give good results in our case (Table 1,
Entry 15). The combination of 3-chloroquinolinone and an
inorganic base such as NaHCO3 also gave a poor result
(Table 1, Entry 16).
Figure 1. Catalyst screening.
in 99% yield with low enantioselectivity (Table 2, Entry 1).
In polar solvents, such as acetonitrile and methanol, 3a was
obtained in moderate enantioselectivities (Table 2, Entries 2
and 3). Good enantiomeric excesses were observed in
dichloromethane (CH2Cl2), acetone, tetrahydrofuran
(THF) and 1,2-dichloroethane (DCE) (Table 1, Entry 10
and Table 2, Entries 4–6). THF was found to be the best
solvent for this chlorination reaction, affording 3a in up to
76% ee and good yield (Table 2, Entry 5).
Table 1. Catalysts and chlorine source screening for the enantiose-
lective chlorination of oxindole 2a.[a]
Table 2. Optimization of the reaction conditions for the chlorina-
tion of oxindole 2a mediated by catalyst 1j.[a]
Entry
Solvent
T [°C]
t [h]
Yield [%][b]
ee [%][c]
Entry Catalayst
Chlorine
source
t [h] Yield [%][b] ee [%][c]
1
2
toluene
CH3CN
MeOH
acetone
THF
20
20
20
20
20
2
2
2
2
2
2
2
2
2
2
2
3
99
99
66
99
99
82
99
99
99
99
96
99
37
58
56
72
76
70
82
87
85
93
91
84
3[d]
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1f
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
2
2
2
2
2
2
2
2
2
2
2
2
2
2
24
99
99
99
99
94
97
98
99
99
99
99
99
99
92
50
23
13
51
33
36
8
5
6
7
8
DCE
20
CH2Cl2
CH2Cl2
THF
THF
THF
–20
–30
–20
–30
–35
–30
1g
1h
1i
5
9
15
22
74
66
64
36
23
66
10
11
12[e]
1j
THF
1k
1l
[a] Reagents and conditions: 2a (0.1 mmol), 1j (20 mol-%), NCS
(0.12 mmol), solvent (2.0 mL). [b] Yield of isolated product. [c] De-
termined by HPLC analysis on a chiral stationary phase (Chiralcel
OJ-H column). [d] 3-Methoxy-substituted oxindole was obtained.
[e] 10 mol-% of catalyst 1j was used.
1m
1n
1j
Examination of the effect of temperature revealed that
lowering of the temperature could significantly improve the
enantioselectivity of 3a without sacrificing the yield (99%)
(Table 2, Entries 7–11); the best enantioselectivity for 3a
was obtained in THF at –30 °C. The effect of catalyst load-
ing was also examined, and it was found that the use of
10 mol-% catalyst led to a decrease in enantioselectivity and
required a longer reaction time (Table 2, Entry 12). Thus,
20 mol-% catalyst was employed in subsequent studies.
The substrate scope of the reaction was then examined
under the optimized conditions (Table 3). Generally, all of
16[d]
1j
24
53
58
[a] Reagents and conditions: 2a (0.1 mmol), 1 (20 mol-%), chlori-
nating reagent (0.12 mmol), CH2Cl2 (2.0 mL), 20 °C. [b] Yield of
isolated product. [c] Determined by HPLC analysis on a chiral sta-
tionary phase (Chiralcel OJ-H column). [d] NaHCO3 was used as
an additive.
Solvent effects were then extensively studied. It was the 3-aryloxindoles underwent this chlorination reaction
found that, although chlorination of oxindole 2a with NCS smoothly within short reaction times. Both the electronic
proceeded smoothly in a wide range of solvents, the ee val- and steric nature of the substituents on the oxindoles and
ues obtained under otherwise identical conditions varied the aromatic ring at the C-3 position played important roles
dramatically (Table 2). For instance, in nonpolar solvent in determining the reaction outcome. The N-Boc-3-phenyl-
such as toluene, the reaction proceeded smoothly, giving 3a substituted oxindoles gave the corresponding products 3a–c
3002
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Eur. J. Org. Chem. 2011, 3001–3008

Enantioselective Chlorination of 3-Aryloxindoles
in excellent yields (Ͼ96%) and excellent enantioselectivities, contrast, N-(9H-fluoren-9-yloxycarbonyl)-substituted oxin-
regardless of the electron-withdrawing or -donating nature dole 2r gave the desired product 3r in acceptable yield and
of the substituents on the 5-position of the oxindoles (90– ee, indicating that the presence of a bulky N-protecting
93% ee; Table 3, Entries 1–3). However, N-Boc-3-aryl-sub- group is crucial for a satisfactory stereochemical outcome
stituted oxindoles gave the corresponding products in lower (Scheme 1).
enantioselectivities, and substrates with an electron-donat-
ing group on the aromatic ring at the C-3 position required
longer times to complete the reaction than the correspond-
ing substrates with electron-withdrawing groups (Table 3,
Entries 7–9 vs. 4–6). Substrates 2j and 2k, bearing a bulky
2-naphthyl group at the C-3 position of the oxindole, also
gave the corresponding products 3j and 3k, respectively, in
lower enantioselectivities (Table 3, Entries 10–11). In the
case of 3-(m-tolyl)-substituted oxindole 2l, the desired prod-
Scheme 1. Effect of alternative 3-aryloxindole N-protecting groups.
uct 3l was obtained in 99% yield and 84% ee, which is very
similar to the case of 3-(p-tolyl)-substituted substrate 2h
(Table 3, Entries 12 vs. 8). However, only 7% ee of product
3m was observed for 3-(o-tolyl)-substituted oxindole 2m,
Conclusions
presumably due to steric hindrance (Table 3, Entry 13). It
should be noted that when 3-alkyloxindoles 2n and 2o were
used, the corresponding chlorinated products 3n and 3o
were obtained in high yields, but with lower enantio-
selectivities (Table 3, Entries 14 and 15).
Several oxindoles with different N-protecting groups
were also examined. As shown in Scheme 1, N-benzyl- and
N-phenyl-substituted 3-phenyloxindoles 2p and 2q, respec-
tively, gave the corresponding products 3p and 3q with
A highly effective asymmetric α-chlorination reaction of
oxindoles has been developed by using an inexpensive cin-
chona alkaloid as the organocatalyst and NCS as the chlo-
rination reagent under mild conditions, providing an opera-
tionally simple protocol to access enantiomerically highly
enriched chloro-substituted compounds. Investigations
aimed at fully understanding the reaction mechanism and
developing more effective catalysts with broad substrate
lower ee values under the optimized conditions. In sharp
scope are ongoing.
Table 3. Enantioselective chlorination of oxindoles 2 mediated by
catalyst 1j.[a]
Experimental Section
General Remarks: NMR spectra were recorded with a Bruker Av-
ance III 400 MHz or a Varian Mercury vx 300 MHz spectrometer
with solutions in CDCl3 and tetramethylsilane (TMS) as an in-
ternal standard; J values are reported in Hz. IR spectra were re-
corded with a Bio-Rad FTS-185 spectrometer. Chiral HPLC was
performed with a Shimadzu SPD-10A series instrument with chiral
columns. MS and HRMS (EI) were measured with a Finnigan
MA+ instrument. Flash column chromatography was performed
using silica gel (300–400 mesh). Unless otherwise noted, all com-
mercially obtained reagents were used without further purification.
All reactions were carried out under air in a closed system. Cata-
lysts 1b–g and 1i–n were synthesized according to literature meth-
ods.[6c,16] Substrates 2a,[3d] 2b,[7c,8b] 2c,[4a] 2d,[3d] 2f,[4a] 2g,[3d] 2i,[4a]
2j,[8b,8e] 2n,[3d] 2o,[3d] 2p,[17] and 2q,[18] and product 3a[3e] are known
compounds.
Entry Substrate
X
R
Product t [h] Yield [%][b] ee [%]
2
3
1
2
3
4
5
2a
2b
2c
2d
2e
2f
H
F
Me
H
F
Me
H
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
2
2
3
2.5
1
2
3
2
5
2
99
99
96
99
99
98
92
98
81
97
96
99
99
91
85
93[c]
90[d]
91[d]
81[d]
84[d]
65[d]
73[d]
84[e]
70[e]
72[d]
66[c]
84[c]
7[f]
p-FC6H4
p-FC6H4
p-FC6H4
p-MeC6H4
p-MeC6H4
6
7
8
9
2g
2h
2i
F
Me p-MeC6H4
H
F
F
F
10
11
12
13
14
15
2j
2k
2l
2m
2n
2o
2-naphthyl
2-naphthyl
m-MeC6H4
o-MeC6H4
Me
General Procedure for the Synthesis of 3-Aryl-N-Boc-oxindoles
2:[3d,3g] A solution of ArBr (51 mmol) in THF (20 mL) was added
to a mixture of magnesium (1.2 g, 51 mmol) and a trace amount
of iodine under argon. The mixture was stirred at room tempera-
ture until complete consumption of the magnesium was observed.
To a stirred, cold (–40 °C) suspension of isatins (20.4 mmol) in
THF (40 mL) under argon was added dropwise the above solution
of ArMgBr (2.5 equiv.) in THF (20 mL). The reaction mixture was
allowed to warm to room temperature and stirred for 5 h, then the
reaction mixture was quenched with 2 n HCl and extracted with
ethyl acetate. The combined organic layers were washed with satu-
rated aqueous Na2CO3 and brine, and then dried with Na2SO4.
After the solvent was evaporated under reduced pressure, purifica-
2
2
2
5
H
H
22[e]
29[e]
Bn
5
[a] Reagents and conditions: 2 (0.1 mmol), 1j (20 mol-%), NCS
(0.12 mmol), THF (2.0 mL), –30 °C. [b] Yield of isolated product.
[c] Determined by HPLC analysis on a chiral stationary phase
(Chiralcel OJ-H column). [d] Determined by HPLC analysis on a
chiral stationary phase (Chiralpak AS-H column). [e] Determined
by HPLC analysis on a chiral stationary phase (Chiralpak AD-H
column). [f] Determined by HPLC analysis on a chiral stationary
phase (Chiralpak IC column).
Eur. J. Org. Chem. 2011, 3001–3008
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M.-X. Zhao, M. Shi et al.
FULL PAPER
tion by silica gel column chromatography was carried out to give
the 3-aryl-3-hydroxyoxindole.
3-Aryl-N-Boc-oxindole 2l: Yield: 1.7 g (65%; total yield); white so-
lid; m.p. 125.4–125.9 °C. 1H NMR (300 MHz, CDCl3): δ = 7.92
(dd, J = 9.0, 4.5 Hz, 1 H, ArH), 7.23 (t, J = 7.5 Hz, 1 H, ArH),
7.12 (d, J = 7.5 Hz, 1 H, ArH), 7.05 (td, J = 9.0, 2.7 Hz, 1 H,
ArH), 6.97–6.95 (m, 2 H, ArH), 6.87 (ddd, J = 7.5, 2.4, 0.9 Hz, 1
H, ArH), 4.66 (s, 1 H, CH), 2.32 (s, 3 H, CH3), 1.62 (s, 9 H, 3
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.5, 160.0 (d, J =
242.3 Hz), 149.3, 138.8, 136.3 (d, J = 2.3 Hz), 135.5, 129.3 (d, J =
8.5 Hz), 129.1, 128.8, 125.5, 116.3 (d, J = 7.9 Hz), 115.1 (d, J =
22.7 Hz), 112.4 (d, J = 24.3 Hz), 84.5, 52.6 (d, J = 1.7 Hz), 28.0,
21.3 ppm. 19F NMR (376 MHz, CDCl3, non-decoupled): δ =
–117.593, –117.605, –117.614, –117.626, –117.636, –117.648 ppm.
To a solution of 3-aryl-3-hydroxyoxindole (17.8 mmol) in CH2Cl2
(80 mL) was added (Boc)2O (35.5 mmol) and DMAP (0.22 g,
1.8 mmol). The reaction mixture was stirred at room temperature
for 3 h and then quenched with saturated aqueous NH4Cl. The
aqueous layer was extracted with dichloromethane and then dried
with Na2SO4. After removal of the solvent, the crude product was
purified by silica gel column chromatography to give the 3-aryl-N-
Boc-3-[(tert-butoxycarbonyl)oxy]oxindole.
To a solution of 3-aryl-N-Boc-3-[(tert-butoxycarbonyl)oxy]oxin-
dole (7.1 mmol) in MeOH (60 mL), Pd/C (0.3 g) was added, and
the mixture was stirred under hydrogen at room temperature for
4 h. The reaction mixture was filtered through Celite to remove Pd/
C. After removal of the solvent, the crude product was purified by
silica gel column chromatography to give the 3-aryl-N-Boc-oxin-
dole.
IR (film): ν = 1761, 1727, 1479, 1369, 1341, 1293, 1268, 1250, 1141,
˜
1093 cm–1. MS (EI): m/z (%) = 341 (1) [M]+, 241 (100), 212 (28),
198 (32), 183 (4), 57 (6). HRMS: calcd. for C20H20FNO3 [M]+
341.1427; found 341.1429.
3-Aryl-N-Boc-oxindole 2m: Yield: 2.1 g (72%; total yield); white so-
lid; m.p. 104.5–105.5 °C. 1H NMR (400 MHz, CDCl3): δ = 7.92
(dd, J = 8.8, 4.4 Hz, 1 H, ArH), 7.25–7.18 (m, 2 H, ArH), 7.13–
7.09 (m, 1 H, ArH), 7.03 (ddt, J = 8.8, 2.8, 0.8 Hz, 1 H, ArH),
6.85–6.81 (m, 1 H, ArH), 6.78 (dd, J = 7.6, 2.0 Hz, 1 H, ArH),
4.96 (s, 1 H, CH), 2.38 (s, 3 H, CH3), 1.62 (s, 9 H, 3 CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.4, 160.0 (d, J = 242.3 Hz),
149.3, 137.2, 136.3, 134.5, 131.1, 129.7 (d, J = 8.3 Hz), 128.1, 126.4,
125.5, 116.3, 116.2, 114.9 (d, J = 22.6 Hz), 112.0 (d, J = 24.3 Hz),
84.5, 28.0, 19.8 ppm. 19F NMR (376 MHz, CDCl3, non-decou-
pled): δ = –117.577, –117.601, –117.612, –117.647 ppm. IR (film):
3-Aryl-N-Boc-oxindole 2e: Yield: 2.0 g (75%; total yield); white so-
lid; m.p. 106.7–107.5 °C. 1H NMR (400 MHz, CDCl3): δ = 7.93
(dd, J = 8.8, 4.4 Hz, 1 H, ArH), 7.18–7.14 (m, 2 H, ArH), 7.09–
7.02 (m, 3 H, ArH), 6.87 (ddd, J = 7.6, 2.8, 1.2 Hz, 1 H, ArH),
4.69 (s, 1 H, CH), 1.62 (s, 9 H, 3 CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 173.3, 162.5 (d, J = 245.7 Hz), 160.0 (d, J = 242.7 Hz),
149.2, 136.4 (d, J = 2.4 Hz), 131.3 (d, J = 3.2 Hz), 130.2 (d, J =
8.2 Hz), 128.8 (d, J = 8.4 Hz), 116.6 (d, J = 7.8 Hz), 116.0 (d, J =
21.6 Hz), 115.4 (d, J = 22.7 Hz), 112.4 (d, J = 24.3 Hz), 84.7, 51.8
(d, J = 1.5 Hz), 28.0 ppm. 19F NMR (376 MHz, CDCl3): δ =
ν = 1766, 1724, 1481, 1346, 1294, 1268, 1252, 1141, 1086, 848, 813,
˜
736, 629 cm–1. MS (EI): m/z (%) = 341 (2) [M]+, 241 (100), 226 (8),
212 (17), 198 (15), 183 (4), 57 (22). HRMS: calcd. for C20H20FNO3
[M]+ 341.1427; found 341.1432.
–113.9, –117.4 ppm. IR (film): ν = 1759, 1728, 1509, 1485, 1345,
˜
1295, 1270, 1255, 1228, 1146, 1091 cm–1. MS (EI): m/z (%) = 345
(1) [M]+, 245 (82), 216 (100), 201 (5), 169 (6), 57 (10). HRMS:
calcd. for C19H17F2NO3 [M]+ 345.1177; found 345.1179.
Procedure for the Synthesis of the N-(9H-Fluoren-9-yloxycarbonyl)-
3-phenyloxindole (2r):[3d] BF3·OEt2 (1.9 mL, 15 mmol) was added
to a solution of 3-hydroxy-3-phenyloxindole (1.7 g, 7.5 mmol) and
triethylsilane (2.4 mL, 15 mmol) in CH2Cl2 (30 mL) at 0 °C. After
15 min, the reaction mixture was warmed to room temperature and
stirred overnight. The reaction mixture was quenched with satu-
rated aqueous Na2CO3, extracted with CH2Cl2,and the combined
organic layers were dried with Na2SO4. After removal of the sol-
vent, the crude product was purified by silica gel column
chromatography (petroleum ether/ethyl acetate, 2:1) to give 3-phen-
yloxindole (63%, 1.0 g).
3-Aryl-N-Boc-oxindole 2h: Yield: 1.9 g (70%; total yield); white so-
lid; m.p. 120.4–121.0 °C. 1H NMR (400 MHz, CDCl3): δ = 7.91
(dd, J = 8.8, 4.4 Hz, 1 H, ArH), 7.16 (d, J = 8.0 Hz, 2 H, ArH),
7.06 (d, J = 8.0 Hz, 2 H, ArH), 7.09–7.04 (m, 1 H, ArH), 6.87
(ddd, J = 7.6, 2.8, 1.2 Hz, 1 H, ArH), 4.66 (s, 1 H, CH), 2.33 (s, 3
H, CH3), 1.62 (s, 9 H, 3 CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 173.6, 160.0 (d, J = 242.3 Hz), 149.3, 137.9, 136.4 (d, J =
2.2 Hz), 132.6, 129.7, 129.4 (d, J = 8.4 Hz), 128.4, 116.4 (d, J =
7.8 Hz), 115.1 (d, J = 22.7 Hz), 112.4 (d, J = 24.4 Hz), 84.5, 52.3
(d, J = 1.6 Hz), 28.0, 21.1 ppm. 19F NMR (376 MHz, CDCl3): δ =
–117.7 ppm. IR (film): ν = 1769, 1727, 1478, 1294, 1268, 1251,
˜
To a stirred, cold (–40 °C) suspension of 3-phenyloxindole (0.42 g,
2 mmol) in THF (10 mL) under argon, was added dropwise a pre-
pared solution of EtMgBr (2.2 mmol, 1.1 equiv.) in THF (10 mL).
After 10 min, a solution of 9H-fluoren-9-yl 1H-imidazole-1-car-
boxylate[3d] (0.61 g, 2.2 mmol) in THF (3 mL) was added to the
reaction vessel at –40 °C. The reaction mixture was warmed to
room temperature and stirred for 4 h. The reaction was quenched
1143, 1090 cm–1. MS (EI): m/z (%) = 341 (1) [M]+, 241 (100), 226
(11), 212 (47), 198 (43), 183 (6), 170 (4), 57 (6). HRMS: calcd. for
C20H20FNO3 [M]+ 341.1427; found 341.1426.
3-Aryl-N-Boc-oxindole 2k: Yield: 1.8 g (57%; total yield); white so-
lid; m.p. 129.4–129.9 °C. 1H NMR (400 MHz, CDCl3): δ = 7.96
(dd, J = 8.8, 4.4 Hz, 1 H, ArH), 7.84–7.77 (m, 3 H, ArH), 7.66 (d,
J = 1.2 Hz, 1 H, ArH), 7.50–7.45 (m, 2 H, ArH), 7.25 (dd, J = 8.4, with saturated aqueous NH4Cl solution and the mixture extracted
2.0 Hz, 1 H, ArH), 7.09 (tdd, J = 8.8, 2.8, 0.8 Hz, 1 H, ArH), 6.91
(ddd, J = 8.0, 2.8, 0.8 Hz, 1 H, ArH), 4.87 (s, 1 H, CH), 1.62 (s, 9
with ethyl acetate. The combined organic layers were washed with
brine and then dried with Na2SO4. After removal of the solvent,
H, 3 CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.4, 160.0 the crude product was purified by silica gel column chromatog-
(d, J = 242.5 Hz), 149.3, 136.4 (d, J = 2.3 Hz), 133.3, 132.96, raphy (petroleum ether/ethyl acetate, 8:1) to give 2r (52%, 0.44 g) as
132.92, 129.2 (d, J = 8.3 Hz), 129.0, 127.82, 127.79, 127.7, 126.4,
126.3, 125.9, 116.5 (d, J = 7.8 Hz), 115.3 (d, J = 22.7 Hz), 112.5 = 7.89 (d, J = 8.0 Hz, 1 H, ArH), 7.74–7.72 (m, 2 H, ArH), 7.65
a white solid. M.p. 166.9–168.0 °C. 1H NMR (400 MHz, CDCl3): δ
(d, J = 24.4 Hz), 84.6, 52.8 (d, J = 1.6 Hz), 28.0 ppm. 19F NMR
(376 MHz, CDCl3, non-decoupled): –117.443, –117.456,
–117.464, –117.477, –117.486, –117.498 ppm. IR (film): ν = 1764,
(d, J = 7.6 Hz, 2 H, ArH), 7.41 (dt, J = 7.2, 2.4 Hz, 2 H, ArH),
7.34–7.25 (m, 6 H, ArH), 7.17–7.14 (m, 4 H, ArH), 6.90 (s, 1 H,
CH), 4.74 (s, 1 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ =
δ
=
˜
1727, 1483, 1345, 1295, 1271, 1145, 1090 cm–1. MS (EI): m/z (%) 173.5, 151.6, 141.1, 141.1, 140.9, 140.9, 139.8, 135.9, 129.8, 128.9,
= 377 (1) [M]+, 277 (100), 248 (77), 233 (4), 220 (5). HRMS: calcd.
for C23H20FNO3 [M]+ 377.1427; found 377.1426.
128.8, 128.5, 128.0, 127.9, 127.4, 126.3, 126.3, 125.2, 124.9, 120.0,
115.2, 78.0, 52.3 ppm. IR (film): ν = 1766, 1721, 1478, 1452, 1353,
˜
3004
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3001–3008

Enantioselective Chlorination of 3-Aryloxindoles
1285, 1238, 1181, 1151, 1089, 1040, 1000, 935, 753, 742, 696 cm–1. 2-propanol, 95:5; 0.6 mL/min; 254 nm; tmajor = 5.92 min, tminor
=
MS (EI): m/z (%) = 373 (13) [M]+, 208 (41), 180 (8), 165 (100).
6.35 min). 1H NMR (400 MHz, CDCl3): δ = 8.00 (dd, J = 8.8,
HRMS: calcd. for C27H19NO [M]+ 373.1467; found 373.1468.
4.4 Hz, 1 H, ArH), 7.51–7.46 (m, 2 H, ArH), 7.20–7.13 (m, 2 H,
ArH), 7.07 (tt, J = 8.8, 2.0 Hz, 2 H, ArH), 1.62 (s, 9 H, 3 CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.4, 163.2 (d, J =
248.8 Hz), 160.2 (d, J = 244.4 Hz), 148.8, 135.0 (d, J = 2.6 Hz),
131.6 (d, J = 3.2 Hz), 130.1 (d, J = 8.2 Hz), 129.8 (d, J = 8.6 Hz),
117.8 (d, J = 22.9 Hz), 117.4 (d, J = 7.8 Hz), 115.7 (d, J = 21.8 Hz),
113.2 (d, J = 24.8 Hz), 85.5, 65.5 (d, J = 1.5 Hz), 28.0 ppm. 19F
NMR (376 MHz, CDCl3): δ = –111.7 (d, J = 1.5 Hz), –115.6 (d, J
General Procedure for the Chlorination of Oxindoles 2: To a solution
of oxindole 2 (0.1 mmol) in THF (1.5 mL) was added O-benzoyl-
quinidine (8.6 mg, 0.02 mmol) with stirring. The mixture was co-
oled to –30 °C (bath temperature) for 20 min; then a solution of
NCS (16 mg, 0.12 mmol) in THF (0.5 mL) was added dropwise.
The resulting mixture was stirred at –30 °C for 1–5 h (monitored
by TLC until no oxindole remained), concentrated, and purified by
silica gel column chromatography to give compound 3.
= 1.5 Hz) ppm. IR (film): ν = 1776, 1736, 1507, 1484, 1339, 1295,
˜
1262, 1144, 1095 cm–1. MS (EI): m/z (%) = 379 (1) [M]+, 279 (17),
244 (100), 216 (51), 188 (7), 169 (5), 57 (10). HRMS: calcd. for
C19H16ClF2NO3 [M]+ 379.0787; found 379.0790.
3-Aryl-3-chlorooxindole 3a:[3e] Yield: 34.0 mg (99%); pale-yellow
oil; [α]2D5 = +107.2 (c = 1.0, CHCl3); 93% ee (Chiralcel OJ-H; hex-
ane/2-propanol, 90:10; 0.5 mL/min; 254 nm; tmajor = 11.98 min,
3-Aryl-3-chlorooxindole 3f: Yield: 36.8 mg (98%); pale-yellow oil;
[α]2D5 = +101.8 (c = 1.0, CHCl3); 65% ee (Chiralpak AS-H; hexane/
1
tminor = 14.07 min). H NMR (400 MHz, CDCl3): δ = 7.98 (d, J =
8.4 Hz, 1 H, ArH), 7.52–7.50 (m, 2 H, ArH), 7.48–7.42 (m, 2 H,
ArH), 7.38–7.35 (m, 3 H, ArH), 7.30–7.26 (m, 1 H, ArH), 1.62 (s,
9 H, 3 CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9, 148.9,
139.1, 136.3, 130.7, 129.1, 128.9, 128.5, 127.8, 126.1, 125.4, 115.6,
85.2, 66.5, 28.0 ppm.
2-propanol, 99:1; 0.3 mL/min; 254 nm; tmajor = 15.38 min, tminor
=
1
17.43 min). H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.4 Hz,
1 H, ArH), 7.52–7.48 (m, 2 H, ArH), 7.27–7.22 (m, 2 H, ArH),
7.07–7.03 (m, 2 H, ArH), 2.39 (s, 3 H, CH3), 1.62 (s, 9 H, 3 CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9, 163.1 (d, J =
248.1 Hz), 148.9, 136.7, 135.4, 132.3 (d, J = 3.2 Hz), 131.5, 130.0
(d, J = 8.4 Hz), 128.4, 126.3, 115.5 (d, J = 7.0 Hz), 115.4, 85.1, 66.1,
28.0, 21.1 ppm. 19F NMR (376 MHz, CDCl3): δ = –112.4 ppm. IR
3-Aryl-3-chlorooxindole 3b: Yield: 35.8 mg (99%); pale-yellow oil;
[α]2D5 = +129.5 (c = 1.0, CHCl3); 90% ee (Chiralpak AS-H; hexane/
2-propanol, 98:2; 0.6 mL/min; 214 nm; tmajor = 9.28 min, tminor
=
9.88 min). 1H NMR (400 MHz, CDCl3): δ = 7.99 (dd, J = 8.8,
4.4 Hz, 1 H, ArH), 7.50–7.48 (m, 2 H, ArH), 7.39–7.36 (m, 3 H,
ArH), 7.18–7.12 (m, 2 H, ArH), 1.62 (s, 9 H, 3 CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.5, 160.1 (d, J = 244.1 Hz), 148.9,
135.8, 135.0 (d, J = 2.5 Hz), 130.6 (d, J = 8.3 Hz), 129.3, 128.7,
127.6, 117.6 (d, J = 22.8 Hz), 117.2 (d, J = 7.7 Hz), 113.3 (d, J =
(film): ν = 1774, 1735, 1506, 1491, 1332, 1300, 1277, 1248, 1149,
˜
1113 cm–1. MS (EI): m/z = 375 (1) [M]+, 275 (13), 240 (100), 225
(11), 212 (28), 183 (7), 57 (7). HRMS: calcd. for C20H19ClFNO3
[M]+ 375.1037; found 375.1039.
3-Aryl-3-chlorooxindole 3g: Yield: 32.9 mg (92%); pale-yellow oil;
[α]2D5 = +87.6 (c = 0.9, CHCl3); 73% ee (Chiralpak AS-H; hexane/
24.8 Hz), 85.3, 66.1 (d,
J =
1.6 Hz), 28.0 ppm. 19F NMR
2-propanol, 95:5; 0.6 mL/min; 214 nm; tmajor = 7.63 min, tminor
=
(376 MHz, CDCl ): δ = –115.8 ppm. IR (film): ν = 1778, 1734,
˜
3
8.18 min). 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 1
H, ArH), 7.47–7.38 (m, 4 H, ArH), 7.30–7.26 (m, 1 H, ArH), 7.17
(d, J = 8.4 Hz, 2 H, ArH), 2.34 (s, 3 H, CH3), 1.62 (s, 9 H, 3 CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 171.0, 149.0, 139.2, 139.1,
133.3, 130.6, 129.2, 129.0, 127.8, 126.1, 125.3, 115.6, 85.0, 66.5,
1483, 1339, 1293, 1262, 1144, 1098 cm–1. MS (EI): m/z (%) = 361
(1) [M]+, 261 (26), 226 (100), 198 (16), 170 (7), 57 (69), 41 (10).
HRMS: calcd. for C19H17ClFNO3 [M]+ 361.0881; found 361.0886.
3-Aryl-3-chlorooxindole 3c: Yield: 34.4 mg (96%); pale-yellow oil;
[α]2D5 = +119.6 (c = 1.0, CHCl3); 91% ee (Chiralpak AS-H; hexane/
28.0, 21.1 ppm. IR (film): ν = 1777, 1734, 1478, 1467, 1341, 1288,
˜
1249, 1145, 1093 cm–1. MS (EI): m/z (%) = 357 (1) [M]+, 257 (17),
222 (100), 194 (9), 57 (12). HRMS: calcd. for C20H20ClNO3 [M]+
357.1132; found 357.1139.
2-propanol, 99:1; 0.3 mL/min; 254 nm; tmajor = 17.13 min, tminor
=
1
18.33 min). H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.4 Hz,
1 H, ArH), 7.52–7.50 (m, 2 H, ArH), 7.37–7.35 (m, 3 H, ArH),
7.26–7.22 (m, 2 H, ArH), 2.38 (s, 3 H, CH3), 1.62 (s, 9 H, 3 CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 171.1, 149.0, 136.7, 136.5,
135.2, 131.3, 129.1, 128.8, 128.5, 127.8, 126.4, 115.4, 84.9, 66.8,
3-Aryl-3-chlorooxindole 3h: Yield: 36.8 mg (98%); pale-yellow oil;
[α]2D5 = +83.9 (c = 0.95, CHCl3); 84% ee (Chiralpak AD-H; hexane/
2-propanol, 95:5; 0.6 mL/min; 250 nm; tmajor = 6.29 min, tminor
=
28.0, 21.0 ppm. IR (film): ν = 1777, 1733, 1489, 1332, 1299, 1276,
˜
6.82 min). 1H NMR (400 MHz, CDCl3): δ = 7.98 (dd, J = 8.8,
4.0 Hz, 1 H, ArH), 7.37 (dt, J = 8.4, 1.6 Hz, 2 H, ArH), 7.19–7.17
(m, 2 H, ArH), 7.14 (dt, J = 8.4, 1.6 Hz, 2 H, ArH), 2.35 (s, 3 H,
CH3), 1.61 (s, 9 H, 3 CH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 170.6, 160.1 (d, J = 243.8 Hz), 148.9, 139.5, 135.0 (d, J = 2.5 Hz),
132.8, 130.7 (d, J = 8.3 Hz), 129.4, 127.6, 117.5 (d, J = 22.8 Hz),
117.2 (d, J = 7.7 Hz), 113.2 (d, J = 24.7 Hz), 85.3, 66.1 (d, J =
1.5 Hz), 28.0, 21.1 ppm. 19F NMR (376 MHz, CDCl3): δ =
1248, 1149, 1113 cm–1. MS (EI): m/z (%) = 357 (1) [M]+, 257 (20),
222 (100), 207 (13), 194 (18), 165 (7), 57 (18). HRMS: calcd. for
C20H20ClNO3 [M]+ 357.1132; found 357.1136.
3-Aryl-3-chlorooxindole 3d: Yield: 35.8 mg (99%); pale-yellow oil;
[α]2D5 = +175.7 (c = 1.0, CHCl3); 81% ee (Chiralpak AS-H; hexane/
2-propanol, 200:1; 0.2 mL/min; 230 nm; tmajor = 26.38 min, tminor
= 27.78 min). 1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 8.4 Hz,
1 H, ArH), 7.53–7.42 (m, 4 H, ArH), 7.32–7.28 (m, 1 H, ArH),
7.07–7.02 (m, 2 H, ArH), 1.62 (s, 9 H, 3 CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.7, 163.1 (d, J = 248.2 Hz), 148.8, 139.1,
132.2 (d, J = 3.2 Hz), 130.9, 130.0 (d, J = 8.6 Hz), 128.5, 125.7 (d,
J = 57.6 Hz), 115.7, 115.6, 115.4, 85.3, 65.8, 28.0 ppm. 19F NMR
–116.0 ppm. IR (film): ν = 1780, 1734, 1483, 1340, 1294, 1262,
˜
1144, 1096 cm–1. MS (EI): m/z (%) = 375 (1) [M]+, 275 (17), 240
(100), 212 (13), 57 (15). HRMS: calcd. for C20H19ClFNO3 [M]+
375.1037; found 375.1039.
3-Aryl-3-chlorooxindole 3i: Yield: 30.1 mg(81%); pale-yellow oil;
[α]2D5 = +86.8 (c = 0.91, CHCl3); 70% ee (Chiralpak AD-H; hexane/
(376 MHz, CDCl ): δ = –112.2 ppm. IR (film): ν = 1775, 1735,
˜
3
1507, 1467, 1340, 1287, 1249, 1144, 1093 cm–1. MS (EI) m/z (%) =
361 (1) [M]+, 261 (18), 226 (100), 198 (9), 170 (4), 57 (11). HRMS:
calcd. for C19H17ClFNO3 [M]+ 361.0881; found 361.0889.
2-propanol, 99:1; 0.5 mL/min; 230 nm; tmajor = 12.79 min, tminor
=
1
13.82 min). H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.4 Hz,
1 H, ArH), 7.39 (d, J = 8.4 Hz, 2 H, ArH), 7.25–7.22 (m, 2 H,
ArH), 7.17 (d, J = 8.4 Hz, 2 H, ArH), 2.37 (s, 3 H, CH3), 2.34 (s,
3 H, CH3), 1.61 (s, 9 H, 3 CH3) ppm. 13C NMR (100 MHz,
3-Aryl-3-chlorooxindole 3e: Yield: 37.6 mg (99%); pale-yellow oil;
[α]2D5 = +128.0 (c = 0.96, CHCl3); 84% ee (Chiralpak AS-H; hexane/
Eur. J. Org. Chem. 2011, 3001–3008
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3005

M.-X. Zhao, M. Shi et al.
FULL PAPER
CDCl3): δ = 171.2, 149.0, 139.2, 136.7, 135.2, 133.5, 131.2, 129.2,
128.9, 127.8, 126.4, 115.3, 84.9, 66.8, 28.0, 21.1, 21.0 ppm. IR
117.4, 117.1, 117.1, 117.0, 111.9 (d, J = 24.8 Hz), 85.4, 28.0,
20.0 ppm. 19F NMR (376 MHz, CDCl3, non-decoupled): δ =
–115.831, –115.843, –115.853, –115.864, –115.873, –115.885 ppm.
(film): ν = 1778, 1733, 1491, 1333, 1298, 1277, 1248, 1150,
˜
1108 cm–1. MS (EI): m/z (%) = 371 (1) [M]+, 271 (17), 236 (100), IR (film): ν = 1778, 1735, 1484, 1339, 1294, 1263, 1250, 1142, 1094,
˜
208 (16), 194 (11), 57 (11). HRMS: calcd. for C21H22ClNO3 [M]+
371.1288; found 371.1292.
851, 731 cm–1. MS (EI): m/z (%) = 375 (1) [M]+, 275 (70), 240
(100), 211 (17), 197 (16), 183 (8), 57 (62), 41 (8). HRMS: calcd. for
C20H19ClFNO3 [M]+ 375.1037; found 375.1038.
3-Aryl-3-chlorooxindole 3j: Yield: 38.2 mg (97%); pale-yellow solid;
m.p. 146.1–147.0 °C; [α]2D5 = +64.9 (c = 0.96, CHCl3); 72% ee (Chi-
ralpak AS-H; hexane/2-propanol, 95:5; 0.7 mL/min; 230 nm; tmajor
3-Chloro-3-methyloxindole 3n: Yield: 25.6 mg (91%); colorless oil;
[α]2D5 = +12.5 (c = 0.9, CHCl3); 22% ee (Chiralpak AD-H; hexane/
1
2-propanol, 98:2; 0.5 mL/min; 230 nm; tmajor = 9.54 min, tminor
=
= 7.33 min, tminor = 7.93 min). H NMR (400 MHz, CDCl3): δ =
1
11.21 min). H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.4 Hz,
1 H, ArH), 7.46 (dd, J = 7.6, 0.8 Hz, 1 H, ArH), 7.38 (td, J = 7.6,
1.6 Hz, 1 H, ArH), 7.23 (td, J = 7.6, 1.2 Hz, 1 H, ArH), 1.95 (s, 3
H, CH3), 1.65 (s, 9 H, 3 CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 172.2, 148.9, 138.2, 130.5, 129.7, 125.2, 123.8, 115.5, 85.0, 61.9,
8.03 (dd, J = 0.8, 8.4 Hz, 1 H, ArH), 7.87 (d, J = 8.8 Hz, 1 H,
ArH), 7.83–7.81 (m, 2 H, ArH), 7.78–7.74 (m, 2 H, ArH), 7.52–
7.46 (m, 4 H, ArH), 7.33–7.29 (m, 1 H, ArH), 1.62 (s, 9 H, 3 CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.8, 148.9, 139.1, 133.5,
133.2, 132.4, 130.8, 128.8, 128.7, 128.4, 127.5, 127.3, 127.1, 126.6,
28.0, 26.4 ppm. IR (film): ν = 1781, 1736, 1609, 1468, 1344, 1290,
˜
126.1, 125.4, 125.1, 115.6, 85.1, 66.7, 27.9 ppm. IR (film): ν = 1771,
˜
1250, 1151 cm–1. MS (EI): m/z (%) = 281 (4) [M]+, 181 (71), 146
(100), 128 (11), 57 (31). HRMS: calcd. for C14H16ClNO3 [M]+
281.0819; found 281.0821.
1732, 1606, 1479, 1465, 1339, 1290, 1253, 1163, 1148, 1090 cm–1.
MS (EI): m/z (%) = 393 (1) [M]+, 316 (4), 293 (8), 259 (100), 230
(63), 215 (7), 202 (7), 57 (6). HRMS: calcd. for C23H20ClNO3
[M]+ 393.1132; found 393.1139.
3-Chloro-3-benzyloxindole 3o: Yield: 30.4 mg (85%); pale-yellow
oil; [α]2D5 = +4.1 (c = 0.91, CHCl3); 29% ee (Chiralpak AD-H; hex-
ane/2-propanol, 90:10; 0.7 mL/min; 214 nm; tmajor = 5.99 min,
3-Aryl-3-chlorooxindole 3k: Yield: 39.5 mg (96%); pale-yellow so-
lid; m.p. 138.6–139.1 °C; [α]2D5 = +40.1 (c = 0.9, CHCl3); 66% ee
(Chiralcel OJ-H; hexane/2-propanol, 90:10; 0.7 mL/min; 230 nm;
tmajor = 12.13 min, tminor = 8.38 min). 1H NMR (400 MHz, CDCl3):
δ = 8.04 (dd, J = 9.6, 4.4 Hz, 1 H, ArH), 7.88 (d, J = 8.8 Hz, 1 H,
ArH), 7.84–7.79 (m, 3 H, ArH), 7.72 (dd, J = 8.8, 2.0 Hz, 1 H,
ArH), 7.54–7.48 (m, 2 H, ArH), 7.22–7.17 (m, 2 H, ArH), 1.61 (s,
9 H, 3 CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 160.2
(d, J = 244.1 Hz), 148.9, 135.1 (d, J = 2.6 Hz), 133.3, 132.9, 132.4,
130.5 (d, J = 8.3 Hz), 128.9, 128.5, 127.6, 127.3, 127.1, 126.8, 124.8,
117.7 (d, J = 22.9 Hz), 117.3 (d, J = 7.7 Hz), 113.4 (d, J = 24.8 Hz),
85.4, 66.4 (d, J = 1.6 Hz), 28.0 ppm. 19F NMR (376 MHz, CDCl3,
non-decoupled): δ = –115.673, –115.685, –115.695, –115.707,
1
tminor = 6.68 min). H NMR (400 MHz, CDCl3): δ = 7.65 (d, J =
8.0 Hz, 1 H, ArH), 7.34–7.27 (m, 2 H, ArH), 7.21–7.10 (m, 4 H,
ArH), 6.94 (d, J = 7.2 Hz, 2 H, ArH), 3.61 (d, J = 13.2 Hz, 1 H,
CH), 3.54 (d, J = 13.2 Hz, 1 H, CH), 1.58 (s, 9 H, 3 CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 171.8, 148.5, 138.9, 133.0, 130.5,
130.4, 128.1, 127.5, 124.9, 124.7, 115.2, 84.8, 65.4, 46.1, 28.0 ppm.
IR (film): ν = 1780, 1738, 1607, 1467, 1370, 1348, 1290, 1252,
˜
1150 cm–1. MS (EI): m/z (%) = 357 (4) [M]+, 257 (100), 222 (10),
204 (8), 165 (8), 91 (89), 57 (31). HRMS: calcd. for C20H20ClNO3
[M]+ 357.1132; found 357.1134.
3-Aryl-3-chlorooxindole 3p: Yield: 30.0 mg (90%); pale-yellow oil;
[α]2D5 = +76.4 (c = 0.7, CHCl3); 31% ee (Chiralpak AS-H; hexane/
2-propanol, 90:10; 0.7 mL/min; 214 nm; tmajor = 14.23 min, tminor
= 15.23 min). 1H NMR (400 MHz, CDCl3): δ = 7.58–7.56 (m, 2
H, ArH), 7.41–7.24 (m, 10 H, ArH), 7.11 (dt, J = 7.6, 0.4 Hz, 1 H,
–115.715, –115.727 ppm. IR (film): ν = 1776, 1733, 1484, 1339,
˜
1295, 1261, 1144, 1124, 1095, 1020 cm–1. MS (EI): m/z (%) = 411
(2) [M]+, 311 (17), 276 (100), 248 (40), 233 (4), 220 (6), 57 (8).
HRMS: calcd. for C23H19ClFNO3 [M]+ 411.1037; found 411.1042.
ArH), 6.77 (d, J = 8.0 Hz, 1 H, ArH), 4.94 (s, 2 H, CH2) ppm. 13
C
3-Aryl-3-chlorooxindole 3l: Yield: 37.2 mg (99%); pale-yellow oil;
[α]2D5 = +86.5 (c = 0.97, CHCl3); 84% ee (Chiralcel OJ-H; hexane/
2-propanol, 90:10; 0.5 mL/min; 230 nm; tmajor = 10.38 min, tminor
= 9.21 min). 1H NMR (400 MHz, CDCl3): δ = 7.99 (q, J = 8.8,
4.4 Hz, 1 H, ArH), 7.32 (s, 1 H, ArH), 7.28–7.21 (m, 2 H, ArH),
7.19–7.11 (m, 3 H, ArH), 2.36 (s, 3 H, CH3), 1.62 (s, 9 H,
3ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.6, 160.1 (d,
J = 244.0 Hz), 148.9, 138.6, 135.6, 135.0 (d, J = 2.3 Hz), 130.8 (d,
J = 8.3 Hz), 130.2, 128.5, 128.2, 124.6, 117.5 (d, J = 22.9 Hz), 117.1
(d, J = 7.8 Hz), 113.2 (d, J = 24.8 Hz), 85.3, 66.2 (d, J = 1.5 Hz),
28.0, 21.5 ppm. 19F NMR (376 MHz, CDCl3, non-decoupled): δ =
–115.887, –115.900, –115.908, –115.919, –115.929, –115.942 ppm.
NMR (100 MHz, CDCl3): δ = 173.6, 141.9, 136.6, 135.1, 130.4,
130.3, 128.9, 128.6, 127.8, 127.5, 127.1, 126.0, 123.6, 109.9, 66.3,
44.2 ppm. IR (film): ν = 1726, 1610, 1486, 1468, 1344, 1187, 1164,
˜
928, 878, 750, 692 cm–1. MS (EI): m/z (%) = 333 (16) [M]+, 298
(100), 270 (10), 242 (12), 208 (9), 179 (13), 165 (12), 152 (5), 91
(71), 65 (6). HRMS: calcd. for C21H16ClNO [M]+ 333.0920; found
333.0927.
3-Aryl-3-chlorooxindole 3q: Yield: 29.4 mg (92%); white solid; m.p.
127.6–129.4 °C; [α]2D5 = +13.4 (c = 1.0, CHCl3); 11% ee (Chiralpak
AS-H; hexane/2-propanol, 90:10; 1.0 mL/min; 230 nm; tmajor
=
7.18 min, tminor = 10.08 min). 1H NMR (400 MHz, CDCl3): δ =
7.63 (dd, J = 8.0, 2.0 Hz, 2 H, ArH), 7.54–7.30 (m, 10 H, ArH),
7.21–7.17 (m, 1 H, ArH), 6.89 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.6, 142.8, 136.7, 133.8, 130.3,
130.1, 129.7, 129.0, 128.6, 128.4, 127.6, 126.5, 126.3, 124.0, 110.2,
IR (film): ν = 1779, 1735, 1483, 1370, 1339, 1294, 1263, 1251, 1145,
˜
1101 cm–1. MS (EI): m/z (%) = 375 (1) [M]+, 275 (24), 240 (100),
225 (4), 212 (8), 197 (5), 57 (12). HRMS: calcd. for C20H19ClFNO3
[M]+ 375.1037; found 375.1042.
66.4 ppm. IR (film): ν = 1728, 1593, 1496, 1468, 1361, 1200, 1167,
˜
3-Aryl-3-chlorooxindole 3m: Yield: 37.2 mg (99%); pale-yellow oil;
[α]2D5 = +4.7 (c = 0.99, CHCl3); 7% ee (Chiralpak IC; hexane/2-
877, 758, 732, 695 cm–1. MS (EI): m/z (%) = 319 (11) [M]+, 284
(100), 256 (31), 178 (7), 152 (7), 128 (6), 77 (7). HRMS: calcd. for
C20H14ClNO [M]+ 319.0764; found 319.0771.
propanol, 70:30; 0.5 mL/min; 214 nm; tmajor = 9.71 min, tminor
=
10.38 min). 1H NMR (400 MHz, CDCl3): δ = 8.13 (dd, J = 7.6,
1.2 Hz, 1 H, ArH), 7.95 (dd, J = 8.8, 4.4 Hz, 1 H, ArH), 7.38–7.29 3-Aryl-3-chlorooxindole 3r: Yield: 42.9 mg (95%); white solid; m.p.
(m, 2 H, ArH), 7.12–7.07 (m, 2 H, ArH), 6.75 (dd, J = 7.6, 2.8 Hz, 167.8–169.1 °C; [α]2D5 = +58.8 (c = 1.01, CHCl3); 83% ee (Chiralpak
1 H, ArH), 1.80 (s, 3 H, CH3), 1.66 (s, 9 H, 3 CH3) ppm. 13C NMR IC; hexane/2-propanol, 90:10; 0.7 mL/min; 214 nm; tmajor
=
1
(100 MHz, CDCl3): δ = 170.6, 160.2 (d, J = 244.2 Hz), 149.0, 134.9,
134.7, 132.5, 131.8, 131.3, 131.2, 129.3 (d, J = 31.8 Hz), 126.4,
13.58 min, tminor = 14.78 min). H NMR (400 MHz, CDCl3): δ =
7.94 (d, J = 8.4 Hz, 1 H, ArH), 7.74–7.71 (m, 2 H, ArH), 7.67 (d,
3006
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3001–3008

Enantioselective Chlorination of 3-Aryloxindoles
[6]
J = 7.2 Hz, 2 H, ArH), 7.50–7.47 (m, 2 H, ArH), 7.44–7.40 (m, 4
H, ArH), 7.37–7.27 (m, 6 H, ArH), 6.89 (s, 1 H, CH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.6, 151.3, 141.2, 141.1, 140.6,
140.6, 138.4, 136.0, 130.9, 130.0, 129.2, 129.0, 128.6, 128.1, 128.0,
127.8, 126.4, 126.3, 126.2, 125.8, 120.1, 115.7, 78.5, 66.3 ppm. IR
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(film): ν = 1783, 1733, 1469, 1348, 1280, 1234, 1152, 1094, 1039,
˜
1002, 952, 757, 742, 724, 698 cm–1. MS (EI): m/z (%) = 407 (1)
[M]+, 373 (6), 298 (10), 208 (19), 180 (5), 165 (100), 91 (7). HRMS:
calcd. for C27H18ClNO [M]+ 407.1077; found 407.1084.
[7]
[8]
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of new compounds and HPLC traces for the
determination of the enantiomeric excess for compounds 3.
Acknowledgments
We are grateful for the financial support from the National Natural
Science Foundation of China (20772030, 21072056) and the Fun-
damental Research Funds for the Central Universities, Scientific
Research Foundation for the Returned Overseas Chinese Scholars,
State Education Ministry.
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Published Online: April 19, 2011
3008
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3001–3008