Preparation of 3-sulfonylated 3,3-disubstituted oxindoles by the addition of sulfinate salts to 3-halooxindoles

Article abstract of DOI:10.1021/jo502270a

An efficient method for the preparation of 3-sulfonylated 3,3-disubstituted oxindole derivatives has been developed. The protocol involves a base-catalyzed addition of sulfinate salts to 3-halooxindoles, affording a wide range of 3-sulfonylated 3,3-disubstituted oxindoles in good to excellent yields under mild conditions. A preliminary trial of asymmetric catalytic version was conducted and gave promising enantioselectivity. The mechanism for the reaction was tentatively explored with the help of mass spectrometric analysis.

Full text of DOI:10.1021/jo502270a

Note
pubs.acs.org/joc
Preparation of 3‑Sulfonylated 3,3-Disubstituted Oxindoles by the
Addition of Sulfinate Salts to 3‑Halooxindoles
Jian Zuo,†,§ Zhi-Jun Wu,‡ Jian-Qiang Zhao,†,§ Ming-Qiang Zhou,†,§ Xiao-Ying Xu, Xiao-Mei Zhang,†
and Wei-Cheng Yuan*,†
†National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, China
‡Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
§University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: An efficient method for the preparation of 3-
sulfonylated 3,3-disubstituted oxindole derivatives has been
developed. The protocol involves a base-catalyzed addition of
sulfinate salts to 3-halooxindoles, affording a wide range of 3-
sulfonylated 3,3-disubstituted oxindoles in good to excellent
yields under mild conditions. A preliminary trial of asymmetric
catalytic version was conducted and gave promising enantioselectivity. The mechanism for the reaction was tentatively explored
with the help of mass spectrometric analysis.
3,3-disubstituted oxindole core is present as a character-
istic structural motif in numerous alkaloids that exhibit
envisioned that it would be possible to develop a direct
sulfonylation of 3-halooxindoles with sulfinate salts as
nucleophiles, giving a new class of 3,3-disubstituted oxindoles
containing a sulfonyl group. Herein, we report our progress on
this subject. Notably, this represents the first example regarding
the synthesis of 3-arylsulfonyl-3,3-disubstituted oxindole
compounds.
A
diverse biological and pharmaceutical activities.1 In particular,
3,3-disubstituted oxindoles bearing a heteroatom at the C-3
position have received considerable attention owing to their
potential applications in medicinal chemistry.1,2 Consequently,
a variety of synthetic strategies have been reported to access
various 3-heteroatom-containing 3,3-disubstituted oxindoles,1
including 3-aminooxindoles,2h 3-hydroxyoxindoles,2f,g 3-chlor-
ooxindoles,2d 3-fluorooxindoles,2e etc.2a−c Notably, it has been
found that many 3,3-disubstituted oxindoles bearing a sulfur
atom at the C-3 position possess some antitubercular,
antifungal, or anticancer activities.3 In this context, the synthesis
of 3-sulfur-containing 3,3-disubstituted oxindoles has been
widely explored and many approaches have been developed.4
Despite all this, we noticed that a method for the direct
construction of 3-sulfonylated 3,3-disubstituted oxindoles
remained elusive.
We began our studies on the sulfonylation of 3-halooxindoles
by investigating the reaction of 3-benzyl-3-bromooxindole (1a)
and sodium p-toluenesulfinate (2a) (Table 1). First, the
background reaction provided the sulfonated product 3a in
less than 10% yield after 36 h in CH2Cl2 at room temperature
(entry 1). Afterward, a screening for various bases was
performed with 200 mol % loading in CH2Cl2 (entries 2−7);
K3PO4 appeared to be the most active catalyst for the reaction,
furnishing 3a in 85% yield (entry 3). To our delight, the
subsequent catalyst loading screening (entries 8−10) revealed
that 3a could be obtained in almost quantitative yield with only
20 mol % K3PO4 (entry 10). Ultimately, the effect of solvent
was examined in the presence of 20 mol % K3PO4 (entries 11−
15). CH3CN turned out to be the best choice for the reaction
in light of the reactivity and yield (entry 13). In particular, the
reaction could proceed to completion at room temperature in
CH3CN within only 8 h with K3PO4 (entry 13). Under similar
conditions, 3a could be obtained in 97% yield after 13 h with
Na3PO4 (entry 16). The structure of 3a has been confirmed by
X-ray crystal structure analysis.11
Among the remarkable advancements in the construction of
3,3-disubstituted oxindoles,1 to the best of our knowledge, the
corresponding progress in the functionalization of 3-haloox-
indoles to access 3,3-disubstituted oxindoles is limited. Inspired
by pioneering work of Hinman and Bauman5 as well as Stoltz6
employing 3-halooxindoles as electrophiles in substitution
chemistry, we reported the related enantioselective stereo-
ablative reactions of 3-halooxindoles.7 In the intervening time,
some strategies taking advantage of the electrophilicity of 3-
halooxindoles for the synthesis of oxindole derivatives have also
been reported.8 Additionally, sulfinate salts are well-known to
serve as a class of nucleophilic reagents in some addition
reactions.9 Based on these concerns, as part of our ongoing
efforts in the application of 3-halooxindoles as electrophiles
precursor for the synthesis of 3,3-disubstituted oxindoles,7,10 we
Table 2 summarizes the scope of the reaction conducted
under the optimized conditions. First, we employed different 3-
Received: October 3, 2014
© XXXX American Chemical Society
A
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Note
Table 1. Optimization Studies for the Sulfonylation of 3-
Halooxindoles
Table 2. Substrate Scope of the Sulfonylation of 3-
Halooxindoles
a
a
b
entry
solvent
base
x
t (h)
yield (%)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
−
−
36
16
16
10
8
<10
74
85
38
35
25
52
86
90
98
82
95
98
87
94
97
2
K2CO3
K3PO4
NaOH
DBU
200
200
200
200
200
200
100
50
3
4
5
6
NEt3
8
7
Na2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Na3PO4
48
16
16
16
16
16
8
8
9
10
11
12
13
14
15
16
20
20
CHCl3
CH3CN
toluene
THF
20
20
20
16
16
13
20
CH3CN
20
a
Reactions were performed with 1a (0.1 mmol), 2a (0.12 mmol), and
base (x mol %) in solvent (2.0 mL) at room temperature for the
b
specified time. Isolated yield. DCE = 1,2-dichloroethane, DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene.
benzyl-3-bromooxindoles 1b−i, containing electron-donating
or -withdrawing groups at different positions on the aryl
moiety, reacting with 2a. It was observed that the reactions
were completed within 8 h at room temperature under the
catalysis of 20 mol % K3PO4, furnishing 3-sulfonylated 3,3-
disubstituted oxindoles 3b−i in good to excellent yields (entries
1−8). The naphthyl moiety incorporated to 3-bromooxindole
was tolerated in the sulfonylation reaction and resulted in 3j in
66% yield (entry 9). Nevertheless, two heteroaromatic 3-
bromooxindoles were successfully employed for generating 3k
and 3l in good yields, thereby broadening the scope of the
reaction (entries 10 and 11). Installing an aliphatic group on
the 3-bromooxindole as substrate 1m could deliver the product
in good yield (entry 12). By employing a substrate bearing
other functional groups, for example, a carbamate group, the
same level of yield was obtained (entry 13). The presence of Cl
or Br at the indolinone moiety had no influence on the
reactivity, affording the products in excellent yields (entries 14
and 15). Meanwhile, we treated 1a with several sodium
aromatic sulfinates 2b−d under the standard conditions, and
the products 3q−s could be obtained in moderate to excellent
yields (entries 16−18). Disappointingly, when 1-naphthalene
substituted sodium sulfinate 2e was reacted with 1a, the
reaction gave 3t only at trace levels, which might be caused by
the steric hindrance (entry 19). Gratifyingly, the current
reaction system was also effective for 3-benzyl-3-chlorooxindole
(1q) and 3-phenyl-3-chlorooxindole (1r), affording the
corresponding products in excellent yield (entries 20 and 21).
Notably, installing a methyl group to the nitrogen of 1s or 1t
was significantly detrimental to the reaction (entries 22 and
23). The steric size of the N-protecting group did not seem to
be important, as methyl (1u) and benzyl (1v) gave similar
results (entries 24 and 25). Our attempt to employ N-Boc-
a
Unless noted, reactions were run with 1 (0.1 mmol), 2 (0.12 mmol),
and K3PO4 (20 mol %) in CH3CN (2.0 mL) at room temperature for
8 h. Isolated yields. Using 100 mol % K3PO4. Run for 12 h. Run
for 24 h. Run for 15 h. Run for 36 h. Run for 48 h.
b
c
d
e
f
g
h
protected 3-chlorooxindole 1w as a substrate showed that the
reaction system became very messy under the developed
conditions (entry 26).
An asymmetric version of this methodology was attempted
by using cinchonidine-derived squaramide Cat as a catalyst for
B
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Note
enantioselective synthesis of 3-sulfonylated 3,3-disubstituted
oxindoles (Scheme 1).12 The enantioselective reaction of 1a
Scheme 1. Asymmetric Sulfonylation of 3-Halooxindoles
Catalyzed by Chiral Organocatalyst and the Transformation
of 4 into N-Boc-Protected Oxindole 5
and 2a proceeded well with 20 mol % of Cat in CH2Cl2 at −20
°C, furnishing (+)-3a in 81% yield with 64% ee. We also
conducted the asymmetric sulfonylation reaction of 1a with 2b
at room temperature with 20 mol % Cat; chiral product 4 could
be obtained after 48 h in 96% yield with 52% ee. After
treatment of 4 with Boc-anhydride and dimethylaminopyridine
(DMAP) in CH2Cl2, N-Boc-protected oxindole 5 was readily
obtained in 93% yield without loss in the enantiomeric excess.
The absolute configuration of product 5 was determined by
comparison of the specific rotation of the compound with
literature data.4e Chiral products (+)-3a and 4 were assumed to
have the same configuration as 5.
On the basis of our experimental results and previous related
studies,6−8 we performed some experiments to obtain insight
into the reaction mechanism. First, the examination of the
background reaction of 1a and 2a (Table 1, entry 1) revealed
that the base catalyst was essential for the reactivity of the
sulfonylation of 3-halooxindoles. Further studies were carried
out with the help of MS spectroscopy. When a 5:1 mixture of
1a and Na3PO4 was analyzed by ESI-MS, a base peak at m/z
244.0745 was detected and assigned as o-azaxylylene inter-
mediate A, while a peak at m/z 324.0013 was assigned as 1a
(Figure 1, (1); Table 3, entry 1). This observation led us to
propose a base-mediated dehydrohalogenation process for the
generation of o-azaxylylene intermediate A from 3-haloox-
indoles 1. Adding sodium p-toluenesulfinate 2a into the
mixture, the peaks of A and 1a almost completely disappeared,
but the mass of 3a characterized by a base peak at m/z
400.0998 was clearly observed (Figure 1, (2); Table 3, entry 2).
Meanwhile for the N-substituted 3-halooxindoles, when 1u was
mixed with K3PO4, a new species characterized by a base at m/z
222.0934 was detected and assigned to be 1-methyl-o-
azaxylylene-1-ium intermediate B, while a peak at m/z
280.0526 was assigned as 1u (Figure 1, (3); Table 3, entry
3). After the conduct of program 4, only the species was
obviously detected by a base peak at m/z 400.1008 and
assigned to be 3w (Figure 1, (4); Table 3, entry 4). Notably,
these studies here represent the first spectral evidence for the
intermediates A and B in situ generated from 3-halooxindoles
and base.
Figure 1. New species detected by ESI-MS analysis in different
experimental program.
intermediate A is readily generated under the action of
base,5,6 while for the N-substituted substrates 1, due to the
function of the added base, it probably promotes the
elimination of the halide of the 3-halooxindoles 1, thus leading
to the generation of intermediate B.12 Afterward, the addition
of sulfinate salts to the intermediate A or B leads to the
formation of 3-sulfonylated 3,3-disubstituted oxindoles.
In summary, we have developed an efficient method for the
sulfonylation of 3-halooxindoles to produce 3-sulfonylated 3,3-
disubstituted oxindoles. The protocol involves the addition of
sulfinate salts to 3-halooxindoles with K3PO4 as the catalyst
under mild conditions, affording a range of 3-sulfonylated 3,3-
disubstituted oxindoles in good to excellent yields. This new
methodology was also extended to asymmetric catalysis with a
chiral organocatalyst, giving the chiral 3-sulfonated oxindoles
with promising enantioselectivity. Furthermore, the mechanism
for the transformation was tentatively explored with the help of
mass spectrometric analysis. The studies provide the first
spectral evidence for the two classes of intermediates A and B
in situ generated from 3-halooxindoles and a base.
In light of the above-mentioned clues, we propose the
following reaction pathways for the reaction of 3-halooxindoles
with sulfinate salts (Scheme 2). 3-Halooxindoles 1 are
subjected to K3PO4 or Na3PO4, thus readily generating an o-
azaxylylene intermediate A or 1-alkyl-o-azaxylylene-1-ium B.
For the N-unsubstituted substrates 1, the o-azaxylylene
C
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Note
1H), 7.22 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1
Hz, 2H), 7.61 (d, J = 7.5 Hz, 1H), 10.54 (s, 1H); 13C NMR (DMSO-
d6, 75 MHz), δ (ppm): 19.7, 21.1, 30.5, 75.6, 109.6, 121.8, 122.0,
125.4, 127.0, 129.1, 129.2, 130.0, 130.3, 130.6, 131.8, 132.3, 136.9,
143.1, 145.3, 170.7. HRMS (ESI-TOF) calcd for C23H21NNaO3S [M
+ Na]+: 414.1134; found: 414.1133.
Table 3. ESI-MS Analysis for the Insight into the Reaction
Mechanism
a
program
1
m/z
C15H11NNaO
C15H12BrNNaO
[A + Na]+
[1a + Na]+
3-(3-Methylbenzyl)-3-tosylindolin-2-one (3c). White solid, 37.6
mg, 96% yield; mp 254.1−255.8 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.06 (s, 3H), 2.36 (s, 3H), 3.53 (d, J = 12.9 Hz, 1H), 3.62 (d,
J = 12.9 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H),
6.74−6.92 (m, 3H), 7.07−7.18 (m, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.41
(d, J = 8.1 Hz, 2H), 7.65 (d, J = 7.2 Hz, 1H), 10.49 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz), δ (ppm): 20.9, 21.1, 34.4, 75.7, 109.6, 121.6,
121.7, 127.0, 127.1, 127.6, 127.8, 129.3, 130.0, 130.4, 130.7, 132.0,
133.3, 136.9, 142.9, 145.3, 170.4. HRMS (ESI-TOF) calcd for
C23H21NNaO3S [M + Na]+: 414.1134; found: 414.1127.
3-(4-Methylbenzyl)-3-tosylindolin-2-one (3d). White solid, 38.7
mg, 99% yield; mp 267.0−268.4 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.10 (s, 3H), 2.35 (s, 3H), 3.53 (d, J = 12.9 Hz, 1H), 3.61 (d,
J = 12.9 Hz, 1H), 6.47 (d, J = 7.5 Hz, 1H), 6.78−6.86 (m, 4H), 7.06 (t,
J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.40
(d, J = 8.1 Hz, 2H), 7.65 (d, J = 7.5 Hz, 1H), 10.47 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz), δ (ppm): 20.5, 21.1, 34.0, 75.8, 109.6, 121.6,
121.7, 127.1, 128.6, 129.3, 129.9, 130.0, 130.3, 130.4, 132.0, 136.0,
142.9, 145.3, 170.4. HRMS (ESI-TOF) calcd for C23H21NNaO3S [M
+ Na]+: 414.1134; found: 414.1130.
C.:244.0733;
F.:244.0745
C.:323.9994;
F.:324.0013
b
2
dis.
dis.
C22H19NNaO3S
[3a + Na]+
C.:400.0978;
F.:400.0998
3
C15H12NO [B]
C15H12ClNNaO
[1u + Na]+
C.:222.0913;
F.:222.0934
C.:280.0500;
F.:280.0526
b
4
dis.
dis.
C22H19NNaO3S
[3w + Na]+
C.:400.0978;
F.:400.1008
a
b
Reactions were run with CH3CN as solvent. 2a (1.2 equiv to 1a or
1u) was added to the corresponding mixture. dis. = disappeared. C. =
calcd. F. = found.
Scheme 2. Proposed Reaction Pathways
3-(2-Chlorobenzyl)-3-tosylindolin-2-one (3e). White solid, 32.9
mg, 80% yield; mp 265.3−266.9 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.35 (s, 3H), 3.66 (d, J = 13.8 Hz, 1H), 4.06 (d, J = 13.8 Hz,
1H), 6.52 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.08−7.27 (m,
4H), 7.32 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 7.5
Hz, 1H), 10.73 (s, 1H); 13C NMR (DMSO-d6, 75 MHz), δ (ppm):
21.2, 30.7, 75.3, 109.6, 121.0, 121.6, 127.1, 127.4, 129.0, 129.3, 129.6,
130.1, 130.6, 130.7, 131.6, 131.9, 133.7, 142.9, 145.5, 170.7. HRMS
(ESI-TOF) calcd for C22H18ClNNaO3S [M + Na]+: 434.0588; found:
434.0592.
3-(3-Chlorobenzyl)-3-tosylindolin-2-one (3f). White solid, 37.9
mg, 92% yield; mp 260.9−262.6 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.35 (s, 3H), 3.57 (d, J = 12.9 Hz, 1H), 3.72 (d, J = 12.9 Hz,
1H), 6.50 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 6.9 Hz, 1H), 6.96−7.14 (m,
4H), 7.20 (t, J = 6.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.4
Hz, 2H), 7.69 (d, J = 7.2 Hz, 1H), 10.59 (s, 1H); 13C NMR (DMSO-
d6, 75 MHz), δ (ppm): 21.5, 34.2, 76.0, 110.1, 121.6, 122.3, 127.5,
127.6, 129.1, 129.7, 130.2, 130.3, 131.0, 132.1, 132.8, 136.4, 143.2,
145.8, 170.7. HRMS (ESI-TOF) calcd for C22H18ClNNaO3S [M +
Na]+: 434.0588; found: 434.0595.
3-(4-Chlorobenzyl)-3-tosylindolin-2-one (3g). White solid, 35.0
mg, 85% yield; mp 270.2−271.9 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.35 (s, 3H), 3.55 (d, J = 12.9 Hz, 1H), 3.69 (d, J = 12.9 Hz,
1H), 6.49 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 7.05−7.22 (m,
4H), 7.30−7.40 (m, 4H), 7.67 (d, J = 7.2 Hz, 1H), 10.54 (s, 1H); 13C
NMR (DMSO-d6, 75 MHz), δ (ppm): 21.5, 34.1, 76.0, 110.0, 121.7,
122.3, 127.5, 128.3, 129.7, 130.3, 131.0, 132.2, 132.9, 143.2, 145.8,
170.7. HRMS (ESI-TOF) calcd for C22H18ClNNaO3S [M + Na]+:
434.0588; found: 434.0599.
3-(2-Bromobenzyl)-3-tosylindolin-2-one (3h). White solid, 36.9
mg, 81% yield; mp 267.4−269.1 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.36 (s, 3H), 3.70 (d, J = 13.8 Hz, 1H), 4.08 (d, J = 13.8 Hz,
1H), 6.53 (d, J = 7.8 Hz, 1H), 6.96−7.04 (m, 3H), 7.10−7.18 (m,
2H), 7.31−7.45 (m, 5H), 7.59 (d, J = 7.5 Hz, 1H), 10.75 (s, 1H); 13C
NMR (DMSO-d6, 75 MHz), δ (ppm): 21.1, 33.3, 75.4, 109.6, 121.0,
121.6, 125.0, 127.5, 127.7, 129.2, 129.3, 130.0, 130.2, 130.7, 131.5,
132.9, 133.7, 142.9, 145.5, 170.7. HRMS (ESI-TOF) calcd for
C22H18BrNNaO3S [M + Na]+: 478.0083; found: 478.0086.
EXPERIMENTAL SECTION
General Methods. Reagents were purchased from commercial
■
sources and were used as received unless mentioned otherwise.
1
Reactions were monitored by TLC. H NMR and 13C NMR spectra
1
were recorded in CDCl3 and DMSO-d6. H NMR chemical shifts are
reported in ppm relative to tetramethylsilane (TMS) with the solvent
resonance employed as the internal standard (CDCl3 at 7.26 ppm,
DMSO-d6 at 2.50 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q
= quartet, m = multiplet), coupling constants (Hz), and integration.
13C NMR chemical shifts are reported in ppm from tetramethylsilane
(TMS) with the solvent resonance as the internal standard (CDCl3 at
77.20 ppm, DMSO-d6 at 39.51 ppm). Melting points were recorded on
a melting point apparatus.
General Procedure for the Synthesis of Compounds 3. A
solution of 3-halooxindole 1 (0.1 mmol), sulfinate salts 2 (0.12 mmol),
and K3PO4 (0.02 or 0.1 mmol) in CH3CN (2 mL) was stirred at room
temperature for the indicated time. Solvent was removed in vacuo. The
products 3 were isolated by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 3/1).
3-Benzyl-3-tosylindolin-2-one (3a). White solid, 37.0 mg, 98%
yield; mp 268.4−270.1 °C. 1H NMR (DMSO-d6, 300 MHz), δ (ppm):
2.35 (s, 3H), 3.59 (d, J = 12.9 Hz, 1H), 3.67 (d, J = 12.9 Hz, 1H), 6.47
(d, J = 7.5 Hz, 1H), 6.93−7.10 (m, 6H), 7.17 (t, J = 7.5 Hz, 1H), 7.32
(d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 7.2 Hz, 1H),
10.48 (s, 1H); 13C NMR (DMSO-d6, 75 MHz), δ (ppm): 21.1, 34.4,
75.8, 109.5, 121.6, 121.7, 127.0, 127.1, 128.0, 129.3, 130.0, 130.4,
131.9, 133.4, 142.9, 145.3, 170.4. HRMS (ESI-TOF) calcd for
C22H19NNaO3S [M + Na]+: 400.0978; found: 400.0974.
3-(3-Bromobenzyl)-3-tosylindolin-2-one (3i). White solid, 44.3 mg,
1
97% yield; mp 256.6−258.3 °C. H NMR (DMSO-d6, 300 MHz), δ
(ppm): 2.35 (s, 3H), 3.56 (d, J = 12.9 Hz, 1H), 3.71 (d, J = 12.9 Hz,
1H), 6.50 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 7.8
Hz, 1H), 7.09 (d, J = 5.4 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.25 (d, J
= 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.68
3-(2-Methylbenzyl)-3-tosylindolin-2-one (3b). White solid, 38.3
mg, 98% yield; mp 255.6−257.4 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.23 (s, 3H), 2.35 (s, 3H), 3.70 (s, 2H), 6.53 (d, J = 7.8 Hz,
1H), 6.65 (d, J = 7.8 Hz, 1H), 6.82−6.99 (m, 3H), 7.07 (t, J = 7.5 Hz,
D
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The Journal of Organic Chemistry
Note
(d, J = 7.5 Hz, 1H), 10.59 (s, 1H); 13C NMR (DMSO-d6, 75 MHz), δ
(ppm): 21.5, 34.2, 76.0, 110.1, 121.4, 121.6, 122.3, 127.6, 129.5, 129.7,
130.3, 130.4, 131.0, 132.1, 133.0, 136.6, 143.2, 145.8, 170.7. HRMS
(ESI-TOF) calcd for C22H18BrNNaO3S [M + Na]+: 478.0083; found:
478.0094.
3-Benzyl-3-(phenylsulfonyl)indolin-2-one (3q). White solid, 34.5
mg, 95% yield; mp 255.0−256.8 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 3.60 (d, J = 12.9 Hz, 1H), 3.70 (d, J = 12.9 Hz, 1H), 6.45 (d,
J = 7.5 Hz, 1H), 6.94−7.10 (m, 6H), 7.17 (t, J = 7.2 Hz, 1H), 7.53−
7.70 (m, 6H), 10.50 (s, 1H); 13C NMR (DMSO-d6, 75 MHz), δ
(ppm): 34.3, 75.8, 109.6, 121.4, 121.8, 127.0, 127.2, 128.0, 128.8,
129.9, 130.0, 130.5, 133.4, 134.6, 134.7, 142.9, 170.3. HRMS (ESI-
TOF) calcd for C21H17NNaO3S [M + Na]+: 386.0821; found:
386.0821.
3-(Naphthalen-1-ylmethyl)-3-tosylindolin-2-one (3j). White solid,
1
28.2 mg, 66% yield; mp 267.1−268.8 °C. H NMR (DMSO-d6, 300
MHz), δ (ppm): 2.36 (s, 3H), 4.09 (d, J = 13.8 Hz, 1H), 4.23 (d, J =
13.8 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 6.92−7.20 (m, 4H), 7.33 (d, J
= 8.1 Hz, 2H), 7.44−7.51 (m, 4H), 7.65 (t, J = 6.9 Hz, 2H), 7.77 (d, J
= 7.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 10.52 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz), δ (ppm): 21.2, 29.9, 75.7, 109.5, 121.5, 124.2,
124.9, 125.7, 125.9, 127.5, 127.8, 127.9, 128.4, 129.3, 130.0, 130.1,
130.5, 131.7, 131.9, 133.2, 143.0, 145.4, 170.7. HRMS (ESI-TOF)
calcd for C26H21NNaO3S [M + Na]+: 450.1134; found: 450.1144.
3-(Thiophen-2-ylmethyl)-3-tosylindolin-2-one (3k). White solid,
3-Benzyl-3-((4-bromophenyl)sulfonyl)indolin-2-one (3r). White
1
solid, 42.9 mg, 97% yield; mp 257.3−259.2 °C. H NMR (DMSO-
d6, 300 MHz), δ (ppm): 3.57 (d, J = 12.9 Hz, 1H), 3.69 (d, J = 12.9
Hz, 1H), 6.50 (d, J = 7.5 Hz, 1H), 6.91−6.94 (m, 2H), 7.04−7.20 (m,
5H), 7.44 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 8.7
Hz, 2H), 10.56 (s, 1H); 13C NMR (DMSO-d6, 75 MHz), δ (ppm):
34.2, 75.9, 109.6, 121.1, 121.9, 127.0, 127.1, 127.9, 129.0, 129.9, 130.6,
131.8, 131.9, 133.1, 133.9, 142.8, 170.1. HRMS (ESI-TOF) calcd for
C21H16BrNNaO3S [M + Na]+: 463.9926; found: 463.9952.
1
34.1 mg, 89% yield; mp 264.2−265.8 °C. H NMR (DMSO-d6, 300
MHz), δ (ppm): 2.34 (s, 3H), 3.77 (d, J = 14.1 Hz, 1H), 3.90 (d, J =
14.1 Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H), 6.64 (d, J = 2.7 Hz, 1H), 6.71−
6.73 (m, 1H), 7.07−7.22 (m, 3H), 7.31 (d, J = 8.1 Hz, 2H), 7.39 (d, J
= 8.1 Hz, 2H), 7.58 (d, J = 7.2 Hz, 1H), 10.56 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz), δ (ppm): 21.1, 29.4, 75.2, 109.7, 121.6, 122.0,
125.8, 126.5, 126.8, 128.0, 129.3, 130.0, 130.8, 131.8, 134.5, 143.4,
145.5, 170.3. HRMS (ESI-TOF) calcd for C20H17NNaO3S2 [M +
Na]+: 406.0542; found: 406.0526.
3-Benzyl-3-(thiophen-2-ylsulfonyl)indolin-2-one (3s). White solid,
1
18.8 mg, 51% yield; mp 261.8−263.6 °C. H NMR (DMSO-d6, 300
MHz), δ (ppm): 3.62 (d, J = 12.9 Hz, 1H), 3.68 (d, J = 12.9 Hz, 1H),
6.52 (d, J = 7.8 Hz, 1H), 6.92−6.95 (m, 2H), 7.05−7.07 (m, 4H),
7.17−7.20 (m, 2H), 7.41−7.63 (m, 2H), 8.11−8.12 (m, 1H), 10.54 (s,
1H); 13C NMR (DMSO-d6, 75 MHz), δ (ppm): 34.5, 76.3, 109.6,
121.5, 121.8, 127.0, 127.2, 127.9, 128.0, 130.0, 130.6, 133.3, 134.7,
136.9, 137.6, 143.1, 170.1. HRMS (ESI-TOF) calcd for
C19H15NNaO3S2 [M + Na]+: 392.0386; found: 392.0409.
3-(Furan-2-ylmethyl)-3-tosylindolin-2-one (3l). White solid, 30.1
mg, 82% yield; mp 239.6−241.4 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.35 (s, 3H), 3.55 (d, J = 14.4 Hz, 1H), 3.77 (d, J = 14.4 Hz,
1H), 5.82 (d, J = 2.7 Hz, 1H), 6.11 (d, J = 0.9 Hz, 1H), 6.58 (d, J = 7.8
Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.27−7.32
(m, 3H), 7.38 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 10.59 (s,
1H); 13C NMR (DMSO-d6, 75 MHz), δ (ppm): 21.1, 28.0, 73.6,
108.3, 109.6, 110.4, 121.6, 121.8, 126.8, 129.3, 130.0, 130.6, 131.5,
142.5, 143.1, 145.5, 147.8, 170.4. HRMS (ESI-TOF) calcd for
C20H17NNaO4S [M + Na]+: 390.0770; found: 390.0775.
3-Phenyl-3-tosylindolin-2-one (3u). White solid, 34.9 mg, 96%
yield; mp 220.5−222.4 °C. 1H NMR (DMSO-d6, 300 MHz), δ (ppm):
2.32 (s, 3H), 6.76 (d, J = 7.8 Hz, 1H), 7.19−7.29 (m, 5H), 7.35 (t, J =
6.9 Hz, 1H), 7.43−7.45 (m, 3H), 7.84 (d, J = 7.5 Hz, 1H), 7.92−7.95
(m, 2H), 10.96 (s, 1H); 13C NMR (DMSO-d6, 75 MHz), δ (ppm):
21.1, 76.4, 110.3, 122.1, 122.3, 128.4, 128.6, 129.0, 129.1, 129.2, 130.1,
130.8, 132.2, 142.6, 145.2, 169.7. HRMS (ESI-TOF) calcd for
C21H17NNaO3S [M + Na]+: 386.0821; found: 386.0838.
3-Allyl-3-tosylindolin-2-one (3m). White solid, 24.5 mg, 75% yield;
mp 201.4−203.2 °C. 1H NMR (DMSO-d6, 300 MHz), δ (ppm): 2.36
(s, 3H), 2.91−2.96 (m, 1H), 3.08−3.15 (m, 1H), 4.91−5.20 (m, 3H),
6.70 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.26−7.39 (m, 5H),
7.47 (d, J = 7.5 Hz, 1H), 10.69 (s, 1H); 13C NMR (DMSO-d6, 75
MHz), δ (ppm): 21.1, 33.6, 74.0, 109.8, 120.7, 121.7, 122.0, 126.6,
129.2, 129.4, 129.8, 129.9, 130.5, 131.8, 143.0, 145.3, 170.4. HRMS
(ESI-TOF) calcd for C18H17NNaO3S [M + Na]+: 350.0821; found:
350.0831.
3-Benzyl-1-methyl-3-tosylindolin-2-one (3v). White solid, 12.1
mg, 31% yield; mp 202.7−204.4 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.34 (s, 3H), 2.69 (s, 3H), 3.63 (d, J = 12.9 Hz, 1H), 3.71 (d,
J = 12.9 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 6.89−7.04 (m, 5H), 7.13 (t,
J = 7.5 Hz, 1H), 7.23−7.34 (m, 5H), 7.71 (d, J = 7.2 Hz, 1H); 13C
NMR (DMSO-d6, 75 MHz), δ (ppm): 21.1, 26.1, 33.9, 75.6, 108.6,
120.8, 122.5, 126.9, 127.0, 128.0, 129.2, 129.7, 129.8, 130.6, 131.5,
133.3, 144.1, 145.5, 169.0. HRMS (ESI-TOF) calcd for
C23H21NNaO3S [M + Na]+: 414.1134; found: 414.1159.
Methyl (2-(2-Oxo-3-tosylindolin-3-yl)ethyl)carbamate (3n). White
1-Methyl-3-phenyl-3-tosylindolin-2-one (3w). White solid, 23.8
1
1
solid, 29.1 mg, 75% yield; mp 206.7−208.4 °C. H NMR (DMSO-d6,
mg, 63% yield; mp 173.5−174.9 °C. H NMR (CDCl3, 300 MHz), δ
300 MHz), δ (ppm): 2.33 (s, 3H), 2.36−2.50 (m, 2H), 2.56−2.66 (m,
2H), 3.35 (s, 3H), 6.73 (d, J = 7.8 Hz, 1H), 7.04−7.13 (m, 2H), 7.29−
7.42 (m, 6H), 10.75 (s, 1H); 13C NMR (DMSO-d6, 75 MHz), δ
(ppm): 21.1, 29.5, 36.0, 51.3, 73.3, 110.0, 121.4, 122.1, 126.3, 129.2,
130.0, 130.6, 131.6, 143.2, 145.3, 156.3, 170.5. HRMS (ESI-TOF)
calcd for C19H20N2NaO5S [M + Na]+: 411.0985; found: 411.1000.
3-Benzyl-4-chloro-3-tosylindolin-2-one (3o). White solid, 39.9 mg,
(ppm): 2.34 (s, 3H), 3.00 (s, 3H), 6.67 (d, J = 7.8 Hz, 1H), 7.08 (d, J
= 8.1 Hz, 2H), 7.21−7.40 (m, 7H), 8.00−8.04 (m, 3H); 13C NMR
(CDCl3, 75 MHz), δ (ppm): 21.6, 26.5, 76.9, 108.3, 108.5, 122.3,
122.8, 126.8, 128.3, 128.6, 128.9, 129.2, 129.4, 130.5, 130.6, 132.2,
144.2, 145.0, 169.0. HRMS (ESI-TOF) calcd for C22H19NNaO3S [M
+ Na]+: 400.0978; found: 400.1005.
1-Benzyl-3-phenyl-3-tosylindolin-2-one (3x). White solid, 25.9 mg,
57% yield; mp 185.7−187.4 °C. 1H NMR (CDCl3, 300 MHz), δ
(ppm): 2.36 (s, 3H), 4.70 (d, J = 15.9 Hz, 1H), 4.84 (d, J = 15.9 Hz,
1H), 6.61 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 7.8 Hz, 4H), 7.19−7.30 (m,
5H), 7.37−7.40 (m, 5H), 8.02−8.08 (m, 3H); 13C NMR (DMSO-d6,
75 MHz), δ (ppm): 21.7, 44.2, 76.8, 109.6, 122.4, 122.8, 127.1, 127.6,
128.4, 128.7, 128.8, 128.9, 129.2, 129.3, 129.4, 130.4, 130.8, 132.4,
134.7, 143.4, 145.0, 169.3. HRMS (ESI-TOF) calcd for
C28H23NNaO3S [M + Na]+: 476.1291; found: 476.1313.
1
97% yield; mp 249.4−251.3 °C. H NMR (DMSO-d6, 300 MHz), δ
(ppm): 2.37 (s, 3H), 3.61 (d, J = 13.2 Hz, 1H), 4.08 (d, J = 13.2 Hz,
1H), 6.48 (d, J = 7.8 Hz, 1H), 7.04−7.12 (m, 6H), 7.19 (t, J = 7.9 Hz,
1H), 7.34 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 10.83 (s, 1H);
13C NMR (DMSO-d6, 75 MHz), δ (ppm): 21.2, 31.6, 78.3, 108.8,
118.5, 124.0, 127.2, 128.3, 129.3, 129.4, 129.8, 132.0, 132.1, 132.2,
133.7, 145.3, 145.6, 169.6. HRMS (ESI-TOF) calcd for
C22H18ClNNaO3S [M + Na]+: 434.0588; found: 434.0601.
3-Benzyl-5-bromo-3-tosylindolin-2-one (3p). White solid, 43.3
mg, 95% yield; mp 273.4−275.1 °C. 1H NMR (DMSO-d6, 300 MHz),
δ (ppm): 2.37 (s, 3H), 3.53 (d, J = 12.9 Hz, 1H), 3.72 (d, J = 12.9 Hz,
1H), 6.46 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 3.6 Hz, 2H), 7.07−7.08 (m,
3H), 7.37 (d, J = 8.4 Hz, 3H), 7.45 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 1.5
Hz, 1H), 10.67 (s, 1H); 13C NMR (DMSO-d6, 75 MHz), δ (ppm):
21.2, 34.4, 76.0, 111.5, 113.3, 124.0, 127.1, 128.1, 129.5, 129.8, 129.9,
130.0, 131.6, 133.2, 142.2, 145.7, 170.2. HRMS (ESI-TOF) calcd for
C22H18BrNNaO3S [M + Na]+: 478.0083; found: 478.0084.
General Procedure for the Asymmetric Sulfonylation of 3-
Halooxindoles Catalyzed by Chiral Organocatalyst and the
Transformation of 4 into N-Boc-protected Oxindole 5. A
solution of 1a (0.1 mmol), 2a (0.12 mmol), and Cat (0.02 mmol) in
DCM (2 mL) was stirred at −20 °C for 58 h. The residue was purified
by column chromatography using EtOAc/petroleum ether (1:3) as the
20
eluent to afford (+)-3a as a white solid in 81% yield, 64% ee, [α]D
=
+21.8 (c 1.18, CHCl3). The H and 13C data were in agreement with
1
those of the racemic compound (3a). Chiral HPLC condition: Daicel
E
dx.doi.org/10.1021/jo502270a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Chiralpak OD-H, hexanes/i-PrOH = 85/15, Flow rate = 1.0 mL/min,
UV = 230 nm, tmajor = 8.67 min, and tminor = 16.54 min.
(3) (a) Mehta, R. G.; Liu, J.; Constantinou, A.; Hawthorne, M.;
Pezzuto, J. M.; Moon, R. C.; Moriarty, R. M. Anticancer Res. 1994, 14,
1209. (b) Dandia, A.; Sati, M.; Arya, K.; Sharma, R.; Loupy, A. Chem.
Pharm. Bull. 2003, 51, 1137. (c) Pedras, M. S. C.; Hossain, M. Org.
Biomol. Chem. 2006, 4, 2581. (d) Vintonyak, V. V.; Warburg, K.;
A solution of 1a (0.1 mmol), 2b (0.12 mmol), and Cat (0.02 mmol)
in DCM (2 mL) was stirred at room temperature for 48 h. The residue
was purified by column chromatography using EtOAc/petroleum
ether (1:3) as the eluent to afford 4 as a white solid in 96% yield, 52%
Kruse, H.; Grimme, S.; Hubel, K.; Rauh, D.; Waldmann, H. Angew.
̈
1
ee. The mass and H, 13C data were in agreement with those for the
Chem., Int. Ed. 2010, 49, 5902. (e) Gomez-Monterrey, I.; Bertamino,
A.; Porta, A.; Carotenuto, A.; Musella, S.; Aquino, C.; Granata, I.; Sala,
M.; Brancaccio, D.; Picone, D.; Ercole, C.; Stiuso, P.; Campiglia, P.;
Grieco, P.; Ianelli, P.; Maresca, B.; Novellino, E. J. Med. Chem. 2010,
53, 8319.
racemic compound (3q). HPLC analysis: Chiralcel OD-H column,
hexanes/i-PrOH = 90/10, Flow rate = 1 mL/min, λ = 230 nm, tmajor
7.9 min, tminor = 17.2 min.
=
To a solution of 4 (0.09 mmol) and DMAP (0.018 mmol) in
CH2Cl2 (4 mL) was added (Boc)2O (0.27 mmol). The resulting
mixture was stirred at room temperature for 20 min. The mixture was
directly purified by column chromatography using EtOAc/petroleum
ether (1:5) as the eluent to afford analytically pure 5 as a white solid in
(4) For selected examples, see: (a) Li, Y.; Shi, Y.; Huang, Z.; Wu, X.;
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Yuan, W.-C. Org. Lett. 2011, 13, 2472. (e) Liu, X.-L.; Wu, Z.-J.; Du, X.-
L.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2011, 76, 4008. (f) Han,
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(h) Han, Y.-Y.; Han, W.-Y.; Hou, X.; Zhang, X.-M.; Yuan, W.-C. Org.
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Org. Chem. 2013, 78, 8833. (l) Cui, B.-D.; Zuo, J.; Zhao, J.-Q.; Zhou,
20
93% yield (41.3 mg), 51% ee, [α]D = +19.9 (c 2.00, CHCl3); The
4e
1
mp, mass, and H, 13C data were in agreement with the literature.
HPLC analysis: Chiralcel OD-H column, hexanes/i-PrOH = 90/10,
Flow rate = 0.8 mL/min, λ = 230 nm, tmajor = 10.4 min, tminor = 12.4
min.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of the NMR spectra for products 3; HPLC spectra for
products (+)-3a, 4, and 5; X-ray structures for product 3a. This
materials is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yuanwc@cioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (No. 21372217), the National
Basic Research Program of China (973 Program)
(2010CB833300), and Sichuan Youth Science and Technology
Foundation (2013JQ0021).
REFERENCES
■
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Org. Chem. 2003, 2209. (b) Galliford, C. V.; Scheidt, K. A. Angew.
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