Synthesis of sulfonated oxindoles by potassium iodide catalyzed arylsulfonylation of activated alkenes with sulfonylhydrazides in water

Article abstract of DOI:10.1021/jo401069d

A catalytic system consisting of KI, 18-crown-6, and TBHP for arylsulfonylation of activated alkenes with sulfonylhydrazides as sulfonyl precursor is described. This protocol provides a practical and environmentally benign method for the construction of sulfonated oxindoles in water.

Full text of DOI:10.1021/jo401069d

Note
pubs.acs.org/joc
Synthesis of Sulfonated Oxindoles by Potassium Iodide Catalyzed
Arylsulfonylation of Activated Alkenes with Sulfonylhydrazides in
Water
Xiaoqing Li,*,† Xiangsheng Xu,*,† Peizhu Hu,† Xuqiong Xiao,‡ and Can Zhou†
†College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, P. R. China
‡Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University,
Hangzhou 310012, P. R. China
S
* Supporting Information
ABSTRACT: A catalytic system consisting of KI, 18-crown-6,
and TBHP for arylsulfonylation of activated alkenes with
sulfonylhydrazides as sulfonyl precursor is described. This
protocol provides a practical and environmentally benign
method for the construction of sulfonated oxindoles in water.
ulfone-containing molecules are an omnipresent compo-
nent of many classes of biologically active compounds and
iodide catalyzed intramolecular oxidative arylsulfonylation of N-
arylacrylamides with sulfonylhydrazides in water to afford
sulfonated oxindoles.
S
marketed drugs.1 The sulfone moiety also serves as a versatile
building block, especially as a carbon nucleophile as a
consequence of its electron-withdrawing character.2 The
addition of sulfonyl radicals to carbon−carbon multiple
bonds represents a particularly useful contribution to sulfone
synthesis.3 In a recent report, Taniguchi demonstrated iron-
catalyzed synthesis of β-hydroxysulfone by mild oxidative
additions of sulfonyl radicals to alkenes using readily accessible
sulfonylhydrazides as a sulfonyl precursor.4 Investigations by
our group found that the generation of sulfonyl radicals from
sulfonyl hydrazide could also be achieved by using TBAI as
catalyst and TBHP as oxidant.5 These processes are
distinguished by using readily available reagents, environ-
mentally benign byproducts, and an easy experimental
operation. Thus, there still exists a great demand to develop
new approaches toward sulfone-containing molecules using
sulfonylhydrazides as sulfonyl precursor.
We commenced our reaction with N-arylacrylamide 1a and
p-toluenesulfonylhydrazide (TsNHNH2) 2a as model sub-
strates (Table 1). As expected, sulfonated oxindole 3 was
formed when the standard conditions established in our
recently work were applied (TBAI as catalyst, TBHP as
oxidant and water as solvent),5b albeit in a modest yield of 45%
(Table 1, entry 1). The use of KI and NaI as the catalyst
improved the yield of 3 to 55% and 52% (Table 1, entries 2 and
a
Table 1. Optimization of Reaction Conditions
Recently, Pd-catalyzed oxidative difunctionalization of
alkenes in N-arylacrylamides involving the direct aryl C(sp2)-
H functionalization has attracted considerable attention.6
Various functionalized oxindoles could be constructed by this
efficient protocol. Alternative palladium-free methods using
more practical catalysts are also investigated.7−9 Yang and co-
workers reported AgNO3-catalyzed carbon phosphorylation to
form phosphorylated oxindoles.8 The Li group described FeCl3-
catalyzed oxidative coupling of C(sp3)-H bond adjacent to a
heteroatom to form oxindoles using TBHP as oxidant.9a Very
recently, they developed a method for the oxidative coupling of
aldehyde C(sp2)-H bond under metal-free conditions using
TBHP.9b Mechanism studies demonstrated that both Yang and
Li’s works proceed by a radical pathway. We envisaged that the
sulfonyl radicals generated from sulfonylhydrazides using our
recently reported method5 might be utilized to allow similar
aryl C(sp2)-H functionalization/cyclization reactions of N-
arylacrylamides. Herein, we report readily accessible potassium
b
entry
cat. (mol %)
TBAI (20)
solvent
yield (%)
1
2
H2O
H2O
H2O
H2O
MeCN
H2O
H2O
H2O
H2O
H2O
45
55
52
60
KI (20)
3
NaI (20)
4
KI (50)
c
5
KI (20)
51
6
KI (20) + 18-crown-6 (20)
CuBr (20)
CuCl2 (20)
Cu(OAc)2·H2O (20)
d
81
39
41
45
39
7
8
9
10
a
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), catalyst, and
TBHP (70% aqueous solution) (3 equiv) in 2.0 mL of solvent at 80
b
c
d
°C for 2 h. isolated yield. 5 h. Without catalyst.
Received: May 15, 2013
Published: June 27, 2013
© 2013 American Chemical Society
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Note
Table 2. Synthesis of Sulfonated Oxindoles
a
Reaction conditions: N-arylacrylamides 1 (0.25 mmol), sulfonylhydrazides 2 (0.5 mmol), KI (20 mol %), 18-crown-6 (20 mol %), TBHP (70%
b
c
d
aqueous solution) (3 equiv) in H2O (2.0 mL) at 80 °C for 2 h. Isolated yield. KI (50 mol %), 18-crown-6 (50 mol %). Yield of 17 after
recrystallization.
3). The yield was slightly improved to 60% when the loading of
KI was increased from 20 mol % to 50 mol % (Table 1, entry
4). However, the use of MeCN as solvent reduced the reaction
efficiency, and only 51% of 3 was obtained after 5 h (Table 1,
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Note
entry 5). To our delight, the addition of 18-crown-6 as a phase
transfer catalyst significantly improved the yield of 3 to 81%
(Table 1, entry 6). Copper salts, which were reported to assist
the decomposition of TBHP,10 exhibited much lower activity
(Table 1, entries 7−9). Notably, the reaction could occur
smoothly under catalyst-free condition, albeit in lower yield
(Table 1, entry 10).
According to the above experimental results and previous
reports,5,8,9,12 a plausible mechanism is proposed (Scheme 3).
Initially, the tert-butoxyl and tert-butylperoxy radicals were
generated in iodine anion-TBHP catalytic system.12 The
addition of 18-crown-6 as phase-transfer catalyst might
accelerate the rate of transfer of water-soluble KI across the
interface to the organic phase and thus enhance the efficiency
of iodine anion catalyzed TBHP decomposion.12c Then, the
resultant radicals abstract hydrogen atoms from sulfonylhy-
drazides to generate sulfonyl radicals with the release of
molecular nitrogen.5 The addition of sulfonyl radicals to N-
arylacrylamides and subsequent intramolecular radical sub-
stitution reaction of alkyl radical I gives intermediate II. Finally,
radical intermediate II undergoes hydrogen abstraction by
TBHP to give sulfonated oxindoles.9b
In summary, we have developed a novel protocol for the
synthesis of sulfonated oxindoles by transition-metal-free
intramolecular oxidative arylsulfonylation of activated alkenes
through direct aryl C(sp2)-H functionalization. The reaction is
environmentally benign in adoption of readily available
sulfonylhydrazides as sulfonyl precursor, nontoxic KI as
catalyst, and water as solvent.
With the optimized conditions in hand, we then explored the
scope and limitations of the above reaction, and the results are
summarized in Table 2. The effect of N-protecting groups was
first examined. The reaction underwent only for methyl and
benzyl group (products 3 and 4), whereas acetyl and N-free N-
arylacrylamides does not work at all (products 5 and 6). Next,
substrates with various substitution patterns at the N-aryl
moiety were screened. The reaction proceeded smoothly not
only for the N-arylacrylamides bearing an electron-donating
group (products 7 and 8) but also for those substrates having
halides (products 9−12) or strong electron-withdrawing
substituents such as CF3, CO2Et, or CN (products 13−15)
on the para-position, although 50 mol % of the catalyst loading
was required for some substrates to furnish the products. As
expected, meta-substituted substrates gave a mixture of two
regioselective products (products 16/16′ and 17/17′). We
were pleased to discover that pure 17 could be isolated by
recrystallization from DCM/petroleum in 41% yield, thereby
facilitating possible modifications at the meta-positions. Ortho-
substituted substrate failed in the reaction to give the desired
oxindole 18 due to the steric effect. In addition, naphthalene
and tetrahydroquinoline derivative were also viable substrates
to provide the corresponding oxindoles 19 and 20. Next, the
substituent effect at R2 position was evaluated. Both CH2OH
and CH2OAc substituents were compatible with the optimal
conditions (products 21 and 22), whereas monosubstituented
olefin (R2 = H) did not undergo the cyclization (product 23).
Finally, readily accessible phenylsulfonylhydrazide was also
utilized as a sulfonyl precursor to afford the corresponding
oxindole 24.
EXPERIMENTAL SECTION
■
General Procedures. All reagents and solvents were purchased
from commercial suppliers and used without purification. Melting
1
points are uncorrected. The H NMR and 13C NMR spectra were
recorded at 25 °C in CDCl3 at 500 or 400 and 125 or 100 MHz,
respectively, with TMS as the internal standard. Chemical shifts (δ)
are expressed in ppm, and coupling constants J are given in hertz.
High-resolution mass spectra (HRMS) were obtained on a TOF MS
instrument with ESI source. The N-arylacrylamides were synthesized
according to the literature method.13
Typical Procedure for the Synthesis of Sulfonated
Oxindoles. To a suspension of N-arylacrylamides (0.25 mmol),
sulfonylhydrazides (0.50 mol), KI (0.05 mol), and 18-crown-6 (0.05
mmol) in water (2 mL) was added TBHP (0.75 mmol) at room
temperature, and the mixture was heated at 80 °C for 2 h. After the
mixture was cooled to room temperature, the crude product changed
from an oil to a viscous solid. The residue was separated by
decantation and purified by silica gel chromatography (petroleum/
ethyl acetate = 3:2) to give sulfonated oxindoles.
The synthetic utility of the sulfonated oxindoles was
exemplified by the alkylation of oxindole 3 to oxindole 25
(Scheme 1). Treatment of 3 with 1.1 equiv of n-butyllithium at
1,3-Dimethyl-3-(tosylmethyl)indolin-2-one (3): white solid (66.6
mg, 81%); mp 135−137 °C; 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J
= 8.3 Hz, 2H), 7.31−7.26 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.07 (d, J
= 7.0 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.85
(d, J = 14.6 Hz, 1H), 3.67 (d, J = 14.6 Hz, 1H), 3.16 (s, 3H), 2.39 (s,
3H), 1.38 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.6, 144.3,
143.2, 137.1, 129.6, 129.5, 128.5, 127.8, 124.1, 122.4, 108.3, 61.9, 45.6,
26.5, 25.4, 21.5; HRMS (ESI) calcd for C18H20NO3S (M + H)+
330.1164, found 330.1160.
Scheme 1. Alkylation of Oxindole 3
1-Benzyl-3-methyl-3-(tosylmethyl)indolin-2-one (4): colorless oil
1
(51.6 mg, 51%); H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 8.3 Hz,
2H), 7.39−7.23 (m, 5H), 7.18−7.10 (m, 3H), 7.05 (dd, J = 7.4, 0.6
Hz, 1H), 6.85 (td, J = 7.6, 0.8 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 4.99
(d, J = 15.8 Hz, 1H), 4.78 (d, J = 15.8 Hz, 1H), 3.90 (d, J = 14.5 Hz,
1H), 3.71 (d, J = 14.5 Hz, 1H), 2.39 (s, 3H), 1.45 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 177.9, 144.3, 142.4, 137.3, 135.8, 129.8, 129.6,
128.8, 128.4, 127.8, 127.6, 127.3, 124.1, 122.5, 109.5, 61.7, 45.8, 44.2,
26.0, 21.6; HRMS (ESI) calcd for C24H24NO3S (M + H)+ 406.1477,
found 406.1472.
−78 °C led to smooth deprotonation, and the corresponding
carbanion reacted with benzyl bromide to give oxindole 25 in
64% yield.
Several control experiments were conducted to elucidate the
mechanism of this C(sp2)-H functionalization/cyclization
reaction (Scheme 2). First, the inter- and intramolecular kinetic
isotope experiments were performed, and no kinetic isotope
effect (kH/kD = 1.0) was observed. Then, a stoichiometric
amount of TEMPO (2.5 equiv), a well-known radical inhibitor,
was introduced to the reaction mixture and the formation of the
desired oxindole was completely suppressed. All this results
indicated that the reaction underwent by a radical pathway.8,9,11
1,3,5-Trimethyl-3-(tosylmethyl)indolin-2-one (7): colorless oil
1
(59.5 mg, 69%); H NMR (500 MHz, CDCl3) δ 7.31−7.24 (d, J =
8.3 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.03 (dd, J = 7.9, 0.7 Hz, 1H),
6.73 (d, J = 7.9 Hz, 1H), 6.63 (s, 1H), 3.88 (d, J = 14.7 Hz, 1H), 3.66
(d, J = 14.7 Hz, 1H), 3.17 (s, 3H), 2.38 (s, 3H), 2.12 (s, 3H), 1.34 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 177.5, 144.0, 141.0, 137.0,
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Note
Scheme 2. Control Experiments
131.8, 129.3, 128.7, 127.7, 124.7, 108.0, 61.9, 45.5, 26.5, 25.4, 21.4,
20.8; HRMS (ESI) calcd for C19H22NO3S (M + H)+ 344.1320, found
344.1314.
142.5, 136.7, 131.3, 131.3, 129.6, 127.4, 127.0, 115.2, 109.8, 61.7, 45.6,
26.7, 25.2, 21.7; HRMS (ESI) calcd for C18H19BrNO3S (M + H)+
408.0269, found 408.0265.
5-Methoxy-1,3-dimethyl-3-(tosylmethyl)indolin-2-one (8): color-
less oil (57.8 mg, 64%); 1H NMR (500 MHz, CDCl3) δ 7.33−7.29 (m,
2H), 7.13 (d, J = 8.0 Hz, 2H), 6.77 (m,, 2H), 6.47 (d, J = 2.3 Hz, 1H),
3.86 (d, J = 14.7 Hz, 1H), 3.70−3.60 (m, 4H), 3.16 (s, 3H), 2.38 (s,
3H), 1.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.3, 155.7,
144.2, 137.0, 136.7, 130.5, 129.3, 127.7, 113.1, 110.8, 108.6, 61.8, 55.3,
46.0, 26.6, 25.3, 21.4; HRMS (ESI) calcd for C19H22NO4S (M + H)+
360.1270, found 360.1264.
5-Fluoro-1,3-dimethyl-3-(tosylmethyl)indolin-2-one (9): white
solid (56.3 mg, 65%); mp 145−147 °C; 1H NMR (500 MHz,
CDCl3) δ 7.38 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.97 (td, J
= 8.9, 2.6 Hz, 1H), 6.77 (dd, J = 8.5, 4.1 Hz, 1H), 6.70 (dd, J = 7.9, 2.6
Hz, 1H), 3.85 (d, J = 14.7 Hz, 1H), 3.65 (d, J = 14.7 Hz, 1H), 3.18 (s,
3H), 2.40 (s, 3H), 1.37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
177.3, 159.0 (d, J = 239.5 Hz), 144.6, 139.2 (d, J = 1.7 Hz), 136.9,
131.1 (d, J = 8.1 Hz), 129.5, 127.7, 114.8 (d, J = 23.8 Hz), 112.2 (d, J
= 24.9 Hz), 108.8 (d, J = 8.1 Hz), 61.7, 46.0 (d, J = 1.6 Hz), 26.7, 25.2,
21.5; HRMS (ESI) calcd for C18H19FNO3S (M + H)+ 348.1070, found
348.1065.
5-Iodo-1,3-dimethyl-3-(tosylmethyl)indolin-2-one (12): white
solid (88.2 mg, 77%); mp 195−197 °C; 1H NMR (500 MHz,
CDCl3) δ 7.53 (dd, J = 8.2, 1.7 Hz, 1H), 7.27−7.24 (m, 2H), 7.16 (d, J
= 8.0 Hz, 2H), 6.94 (d, J = 1.7 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 3.88
(d, J = 14.9 Hz, 1H), 3.66 (d, J = 14.9 Hz, 1H), 3.22 (s, 3H), 2.46 (s,
3H), 1.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 176.9, 144.7,
143.3, 137.3, 136.8, 132.6, 131.8, 129.8, 127.5, 110.4, 85.1, 61.8, 45.5,
26.7, 25.2, 21.9; HRMS (ESI) calcd for C18H19INO3S (M + H)+
456.0130, found 456.0125.
1,3-Dimethyl-3-(tosylmethyl)-5-(trifluoromethyl)indolin-2-one
1
(13): white solid (40.0 mg, 40%); mp 132−134 °C; H NMR (500
MHz, CDCl3) δ 7.53 (dd, J = 8.2, 0.9 Hz, 1H), 7.28 (d, J = 8.3 Hz,
2H), 7.13 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 0.9 Hz, 1H), 6.95 (d, J = 8.2
Hz, 1H), 3.92 (d, J = 14.8 Hz, 1H), 3.73 (d, J = 14.8 Hz, 1H), 3.28 (s,
3H), 2.37 (s, 3H), 1.39 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
177.7, 146.5, 144.8, 136.9, 130.0, 129.6, 127.4, 126.4 (q, J = 3.5 Hz),
124.5 (q, J = 32.6 Hz), 124.0 (q, J = 269.8), 120.8(q, J = 3.7 Hz),
108.2, 61.9, 45.5, 26.8, 25.2, 21.4; HRMS (ESI) calcd for
C19H19F3NO3S (M + H)+ 398.1038, found 398.1034.
5-Chloro-1,3-dimethyl-3-(tosylmethyl)indolin-2-one (10): white
solid (56.3 mg, 62%); mp 186−188 °C; 1H NMR (500 MHz,
CDCl3) δ 7.31 (d, J = 8.3 Hz, 2H), 7.21 (dd, J = 8.3, 2.1 Hz, 1H), 7.16
(d, J = 8.0 Hz, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H),
3.88 (d, J = 14.8 Hz, 1H), 3.65 (d, J = 14.8 Hz, 1H), 3.21 (s, 3H), 2.41
(s, 3H), 1.35 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.2, 144.7,
142.0, 136.8, 131.0, 129.6, 128.4, 127.9, 127.5, 124.4, 109.3, 61.7, 45.7,
26.7, 25.2, 21.6; HRMS (ESI) calcd for C18H19ClNO3S (M + H)+
364.0774, found 364.0770.
5-Bromo-1,3-dimethyl-3-(tosylmethyl)indolin-2-one (11): white
solid (53.2 mg, 52%); mp 175−177 °C; 1H NMR (500 MHz,
CDCl3) δ 7.35 (dd, J = 8.3, 2.0 Hz, 1H), 7.30−7.26 (m, 2H), 7.16 (d, J
= 7.9 Hz, 2H), 6.80 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 3.88
(d, J = 14.8 Hz, 1H), 3.67 (d, J = 14.8 Hz, 1H), 3.22 (s, 3H), 2.43 (s,
3H), 1.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.1, 144.7,
Ethyl 1,3-dimethyl-2-oxo-3-(tosylmethyl)indoline-5-carboxylate
1
(14): white solid (61.4 mg, 61%); mp 174−176 °C; H NMR (500
MHz, CDCl3) δ 8.00 (dd, J = 8.2, 1.7 Hz, 1H), 7.40 (d, J = 1.5 Hz,
1H), 7.30−7.24 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.2 Hz,
1H), 4.32 (qd, J = 7.1, 1.7 Hz, 2H), 3.93 (d, J = 14.8 Hz, 1H), 3.74 (d,
J = 14.8 Hz, 1H), 3.27 (s, 3H), 2.34 (s, 3H), 1.38 (m, 6H). 13C NMR
(125 MHz, CDCl3) δ 178.0, 165.8, 147.5, 144.3, 136.9, 131.1, 129.5,
129.2, 127.5, 124.9, 124.7, 107.9, 61.9, 60.8, 45.3, 26.8, 25.3, 21.4, 14.4;
HRMS (ESI) calcd for C21H24NO5S (M + H)+ 402.1375, found
402.1371.
1,3-Dimethyl-2-oxo-3-(tosylmethyl)indoline-5-carbonitrile (15):
1
white solid (67.5 mg, 76%); mp 207−209 °C; H NMR (500 MHz,
CDCl3) δ 7.58 (dd, J = 8.2, 1.6 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.21
(d, J = 8.1 Hz, 2H), 7.02 (d, J = 1.5 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H),
3.90 (d, J = 14.8 Hz, 1H), 3.72 (d, J = 14.8 Hz, 1H), 3.28 (s, 3H), 2.46
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Note
4-Bromo-1,3-dimethyl-3-(tosylmethyl)indolin-2-one (17): white
solid (41.8 mg, 41%); mp 175−177 °C; 1H NMR (500 MHz,
CDCl3) δ 7.38−7.33 (m, 2H), 7.16 (m, 3H), 6.96 (dd, J = 8.2, 0.7 Hz,
1H), 6.84 (dd, J = 7.8, 0.6 Hz, 1H), 4.25 (d, J = 14.6 Hz, 1H), 3.78 (d,
J = 14.6 Hz, 1H), 3.23 (s, 3H), 2.40 (s, 3H), 1.48 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 177.1, 145.7, 144.4, 136.7, 130.1, 129.4, 128.0,
127.8, 126.4, 120.2, 107.5, 59.6, 47.2, 26.8, 22.0, 21.6; HRMS (ESI)
calcd for C18H19BrNO3S (M + H)+ 408.0269, found 408.0264.
1-Methyl-1-(tosylmethyl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]-
Scheme 3. Proposed Preliminary Mechanisms
1
quinolin-2(4H)-one (19): yellow oil (46.2 mg, 52%); H NMR (500
MHz, CDCl3) δ 7.41 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H),
7.03 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.82 (t, J = 7.6 Hz,
1H), 3.82 (d, J = 14.5 Hz, 1H), 3.73−3.57 (m, 3H), 2.78 (t, J = 7.6 Hz,
2H), 2.39 (s, 3H), 2.03−1.95 (m, 2H), 1.40 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 176.5, 144.2, 139.0, 137.2, 129.4, 128.2, 127.8, 127.2,
122.0, 121.9, 120.3, 61.8, 46.8, 39.0, 25.0, 24.5, 21.5, 20.9; HRMS
(ESI) calcd for C20H22NO3S (M + H)+ 356.1320, found 356.1315.
1,3-Dimethyl-3-(tosylmethyl)-1H-benzo[g]indol-2(3H)-one (20):
1
white solid (48.4 mg, 51%); mp 207−208 °C; H NMR (400 MHz,
CDCl3) δ 7.67 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.44 (t, J
= 7.9 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.23 (q, J = 6.7 Hz, 3H), 7.02
(d, J = 8.0 Hz, 2H), 6.96 (d, J = 7.3 Hz, 1H), 4.60 (d, J = 14.4 Hz,
1H), 3.88 (d, J = 14.4 Hz, 1H), 3.50 (s, 3H), 2.33 (s, 3H), 1.63 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 143.9, 137.6, 136.4,
133.7, 133.4, 129.2, 127.8, 126.7, 126.6, 123.5, 123.7, 122.7, 119.3,
108.9, 66.0, 45.6, 33.8, 30.0, 21.5; HRMS (ESI) calcd for C22H22NO3S
(M + H)+ 380.1320, found 380.1316.
3-(Hydroxymethyl)-1-methyl-3-(tosylmethyl)indolin-2-one (21):
1
white solid (44.0 mg, 51%); mp 147−148 °C; H NMR (400 MHz,
CDCl3) δ 7.45−7.36 (m, 2H), 7.32 (dd, J = 10.9, 4.5 Hz, 1H), 7.17 (d,
J = 7.4 Hz, 2H), 7.10 (d, J = 7.2 Hz, 1H), 7.00−6.90 (m, 1H), 6.86 (d,
J = 7.8 Hz, 1H), 4.01 (d, J = 14.7 Hz, 1H), 3.84 (d, J = 14.7 Hz, 1H),
3.74−3.58 (m, 2H), 3.16 (d, J = 1.0 Hz, 3H), 2.73 (dd, J = 9.0, 4.3 Hz,
1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.3, 144.5,
143.9, 137.1, 129.6, 129.2, 127.8, 125.8, 124.8, 122.7, 108.6, 67.5, 58.3,
51.0, 26.5, 21.6; HRMS (ESI) calcd for C18H20NO4S (M + H)+
346.1113, found 346.1109.
(1-Methyl-2-oxo-3-(tosylmethyl)indolin-3-yl)methyl acetate (22):
colorless oil (52.3 mg, 54%); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J
= 8.0 Hz, 2H), 7.33 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.13
(d, J = 7.4 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H),
4.31 (d, J = 10.9 Hz, 1H), 4.02 (d, J = 10.9 Hz, 1H), 3.88 (q, J = 14.5
Hz, 2H), 3.16 (s, 3H), 2.40 (s, 3H), 1.97 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 174.4, 169.9, 144.6, 144.0, 136.9, 129.6, 129.4, 127.9,
125.4, 122.5, 108.5, 67.2, 58.2, 49.3, 26.7, 21.6, 20.5; HRMS (ESI)
calcd for C20H22NO5S (M + H)+ 388.1219, found 388.1214.
1,3-Dimethyl-3-((phenylsulfonyl)methyl)indolin-2-one (24): white
solid (42.1 mg, 53%); mp 158−160 °C; 1H NMR (500 MHz, CDCl3)
δ 7.56−7.46 (m, 3H), 7.40−7.35 (m, 2H), 7.27 (m, 1H), 7.03 (dd, J =
7.4, 0.6 Hz, 1H), 6.88 (m, 2H), 3.88 (d, J = 14.6 Hz, 1H), 3.70 (d, J =
14.6 Hz, 1H), 3.17 (s, 3H), 1.39 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 177.6, 143.2, 139.9, 133.3, 129.4, 128.9, 128.6, 127.7, 124.0,
122.5, 108.4, 61.8, 45.6, 26.5, 25.4; HRMS (ESI) calcd for
C17H18NO3S (M + H)+ 316.1007, found 316.1002.
Synthesis of 1,3-Dimethyl-3-((R)-2-phenyl-1-tosylethyl)-
indolin-2-one (25). Oxindole 3 (200 mg, 0.607 mmol) in THF
(10 mL) was cooled to −78 °C and treated with 1.6 M n-butyllithium
in hexanes (1.05 equiv). After the mixture was stirred for 15 min at
−78 °C, benzyl bromide (1.05 equiv) was added dropwise. The
mixture was stirred for 5 min at −78 °C, warmed to room
temperature, and stirred for another 12 h. Saturated aqueous
ammonium chloride (3 mL) was added, and the THF was removed
in vacuo. The residue was dissolved in dichloromethane (20 mL) and
washed with water (50 mL). The aqueous phase was extracted with
dichloromethane (2 × 10 mL). The combined organic portions were
dried over sodium sulfate and concentrated in vacuo. The crude
product was purified by flash chromatography (petroleum/ethyl
acetate = 3:1) to afford the desired product 25 as white solid (163
mg, 64%): mp 213−215 °C; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J
= 7.3 Hz, 1H), 7.35 (m, 3H), 7.09 (m, 8H), 6.92 (d, J = 7.8 Hz, 1H),
(s, 3H), 1.38 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.5, 147.3,
145.1, 136.8, 133.7, 130.4, 129.8, 127.4, 127.1, 118.7, 108.9, 105.6,
61.6, 45.3, 26.9, 25.0, 21.6; HRMS (ESI) calcd for C19H19N2O3S (M +
H)+ 355.1116, found 355.1112.
1,3,4-Trimethyl-3-(tosylmethyl)indolin-2-one (16) and 1,3,6-
trimethyl-3-(tosylmethyl)indolin-2-one (16′): colorless oil (70.5 mg,
82%); 1H NMR (500 MHz, CDCl3) δ 7.44−7.40 (m, 1H), 7.36−7.31
(m, 2H), 7.25−7.14 (m, 4H), 7.01 (d, J = 7.6 Hz, 0.5H), 6.78−6.65
(m, 3H), 3.98 (d, J = 14.7 Hz, 1H), 3.84−3.80 (m, 1.5H), 3.64 (d, J =
14.5 Hz, 0.5H), 3.16 (s, 1.5H), 3.13 (s, 3H), 2.41 (s + s, 6H), 2.14 (s,
3H), 1.41 (s, 3H), 1.38 (s, 1.5H); 13C NMR (125 MHz, CDCl3) δ
178.0, 177.7, 144.4, 144.3, 143.7, 143.3, 138.8, 137.2, 136.6, 135.5,
129.4, 129.4, 128.6, 128.2, 127.9, 126.8, 125.0, 123.9, 123.0, 109.3,
106.1, 62.1, 61.0, 45.9, 45.5, 26.6, 26.5, 25.5, 23.3, 21.9, 21.6, 18.3;
HRMS (ESI) calcd for C19H22NO3S (M + H)+ 344.1320, found
344.1313.
4-Bromo-1,3-dimethyl-3-(tosylmethyl)indolin-2-one (17) and 6-
bromo-1,3-dimethyl-3-(tosylmethyl)indolin-2-one (17′): colorless oil
(73.3 mg, 72%); 1H NMR (400 MHz, CDCl3) δ 7.47−6.83 (m,
8.75H), 4.25 (d, J = 14.5 Hz, 1H), 3.80 (t, J = 14.5 Hz, 1.33H), 3.64
(d, J = 14.5 Hz, 0.33H), 3.23 (s, 3H), 3.16 (s, 1H), 2.41 (s + s, 4H),
1.48 (s, 3H), 1.37 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 177.2,
145.7, 144.4, 136.7, 130.2, 129.6, 129.5, 128.0, 127.7, 126.4, 125.3,
120.2, 107.5, 61.8, 59.6, 47.3, 45.4, 26.8, 25.2, 22.0, 21.6; HRMS (ESI)
calcd for C18H19BrNO3S (M + H)+ 408.0269, found 408.0264.
7347
dx.doi.org/10.1021/jo401069d | J. Org. Chem. 2013, 78, 7343−7348

The Journal of Organic Chemistry
Note
4.36 (dd, J = 7.4, 5.6 Hz, 1H), 3.56 (m, 2H), 3.27 (s, 3H), 2.31 (s,
3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 179.6, 143.7,
143.7, 137.5, 137.2, 129.2, 128.8, 128.7, 128.4, 128.2, 126.6, 124.1,
122.3, 108.8, 71.0, 49.0, 32.4, 26.8, 25.7, 21.5; HRMS (ESI) calcd for
C25H26NO3S (M + H)+ 420.1633, found 420.1628.
W. D.; Feher, F. J. J. Am. Chem. Soc. 1986, 108, 4814. (d) Chen, X.;
Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
6790.
(12) (a) Liu, Z. J.; Zhang, J.; Chen, S. L.; Shi, E.; Xu, Y.; Wan, X. B.
Angew. Chem., Int. Ed. 2012, 51, 3231. (b) Uyanik, M.; Ishihara, K.
ChemCatChem 2012, 4, 177. (c) Wei, W.; Zhang, C.; Xu, Y.; Wan, X.
Chem. Commun. 2011, 47, 10827.
ASSOCIATED CONTENT
■
(13) Fabry, D. C.; Stodulski, M.; Hoerner, S.; Gulder, T. Chem.
S
* Supporting Information
Eur. J. 2012, 18, 10834.
Kinetic isotopic effect (KIE) studies and copies of H and 13C
1
NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xqli@zjut.edu.cn, future@zjut.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21102130) and the Key Innovation Team of Science &
Technology in Zhejiang Province (2010R50018 and
2011R50017) for financial support.
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