Ynesulfonamide-Based Silica Gel and Alumina-Mediated Diastereoselective Cascade Cyclizations to Spiro[indoline-3,3′-pyrrolidin]-2-ones under Neat Conditions

Article abstract of DOI:10.1002/adsc.201701576

The spiro[indoline-3,3′-pyrrolidin]-2-ones were synthesized via a silica gel and alumina-mediated sequential transformation based on tryptamine-derived ynesulfonamide substrates under neat conditions. The inherent tendency of C?C bond migration through Wagner-Meerwein rearrangement in the synthesis of spirooxindole was prevented by water trapping to the spiroindoleninium intermediate. The functional group tolerances of the methodology were investigated using a variety of substrates. The detailed mechanism of the sequential transformation was probed by the isotope-labeled experiments. This strategy was further applied in the formal syntheses of indole alkaloids coerulescine and horsfiline. (Figure presented.).

Full text of DOI:10.1002/adsc.201701576

Title: Ynesulfonamide-Based Silica Gel and Alumina-Mediated
Diastereoselective Cascade Cyclizations to Spiro[indoline-3,3'-
pyrrolidin]-2-ones under Neat Conditions
Authors: Yanshi Wang, Xiaoyu Wang, Jingsheng Lin, Bo Yao,
Guanghui Wang, Yuandong Zhao, Xinghang Zhang, Bin Lin,
Yang Liu, Maosheng Cheng, and Yongxiang Liu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701576
Link to VoR: http://dx.doi.org/10.1002/adsc.201701576

10.1002/adsc.201701576
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Ynesulfonamide-Based Silica Gel and Alumina-Mediated
Diastereoselective Cascade Cyclizations to Spiro[indoline-3,3'-
pyrrolidin]-2-ones under Neat Conditions
Yanshi Wang,a,b † Xiaoyu Wang,a,b † Jingsheng Lin,a,b,c Bo Yao,a,b Guanghui Wang,a,b,c
Yuandong Zhao,a,b,c Xinhang Zhang,a,b,c Bin Lin,a,b Yang Liu,a Maosheng Cheng,a,b and
Yongxiang Liua,b,c
*
a
Key Laboratory of Structure-Based Drug Design and Discovery Shenyang Pharmaceutical University, Ministry of
Education, Shenyang 110016, P. R. China.
Phone: 86-24-45864056; fax: 86-24-45864056; e-mail: yongxiang.liu@syphu.edu.cn.
Institute of Drug Research in Medicine Capital of China, Benxi, 117000, P. R. China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
These authors contributed equally.
b
c
†
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The spiro[indoline-3,3'-pyrrolidin]-2-ones were methodology were investigated using a variety of substrates.
synthesized via a silica gel and alumina-mediated sequential The detailed mechanism of the sequential transformation
transformation based on tryptamine-derived ynesulfonamide was probed by the isotope-labeled experiments. This strategy
substrates under neat conditions. The inherent tendency of C- was further applied in the formal syntheses of indole
C bond migration through Wagner-Meerwein rearrangement alkaloids coerulescine and horsfiline.
in the synthesis of spirooxindole was prevented by water
trapping to the spiroindoleninium intermediate. The
functional group tolerances of the
Keywords: Alumina; Neat condition; Silica gel; Spiro
compounds; Ynesulfonamide
cyclization method to access this scaffold in a unique
manner (Scheme 2).[4]
Introduction
The spiro[indoline-3,3'-pyrrolidin]-2-one motifs are
significant structural cores of a subfamily of polycyclic
indole alkaloids,[1] which often show diverse bioactivities[2]
such as anticancer,[2b-2d] antimigraine,[2a,2e] antiarrhythmic,[2f]
etc. Therefore, they have attracted much attention from
medicinal chemists and synthetic chemists (Scheme 1). The
complicated structures of these polycyclic indole alkaloids
prompted the development of a myriad of elegant synthetic
strategies towards the tricyclic indoline skeleton,[3] including
oxidative rearrangement sequences,[3a,3b] intramolecular
Mannich reactions,[3c,3f] radical cyclization reactions,[3d,3h]
intramolecular Heck reactions,[3g] MgI2-promoted ring
expansion of cyclopropyloxindolones,[3e,3i] etc. From a
synthetic point of view, the most straightforward strategy to
spiro[indoline-3,3'-pyrrolidine] motif is the cascade
cyclization
of
tryptamine
derivatives
via
a
Scheme 1. Structures of spiro[indoline-3,3'-pyrrolidin]-2-
one-containing indole alkaloids.
spiroindoleninium formation and simultaneous capture to
the iminium ion at C2 position. In this study, we realized this
strategy by developing a tryptamine-based ynamide cascade
Results and Discussion
1
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10.1002/adsc.201701576
Advanced Synthesis & Catalysis
(PCC), pyridinium dichromate (PDC), manganese
dioxide (MnO2), etc. It was found that the
Scheme 2. Proposed cyclization modes of ynesulfonamide
substrates to spiro[indoline-3,3'-pyrrolidin]-2-ones.
Scheme 3. Silica gel/alumina-mediated stereospecific
cyclizations and the identification of the key structures.
The long-standing difficulty for the synthesis of
spiroindolines via the spiroindoleninium intermediate
is the inherent tendency of C-C bond migration
through Wagner-Meerwein rearrangement to generate
tricyclic fused ring system. A number of efforts have
been made to restrict such a high tendency to Wagner-
Meerwein rearrangement[5] such as employing strongly
nucleophilic intramolecular traps,[5a,5c] introducing
electron-deficient groups on the indole and aliphatic
nitrogen,[5b,5d] interrupting the Bischler-Napieralski
reaction,[5e,5f] introducing electron-withdrawing group
to the alkenes,[5g-5l] etc. In our design, we intended to
prevent Wagner-Meerwein rearrangement by utilizing
water as a nucleophile as illustrated in Scheme 2,
which may act in two ways. The first path is that water
can act as a nucleophile to attack directly the
spiroindoleninium intermediate to give the hemiaminal
D via the intermediate C1. The other possible path is
that when the carbonyl group captures the
spiroindoleninium intermediate, water will be induced
to attack the carbonyl group to give the same
hemiaminal D after the tautomerization of hemiacetal
and ketone via the intermediate C2. A following
oxidation of the hemiaminal intermediate D would
result in the formation of spirooxindole product E
(Scheme 2).
ketone 4a was too reactive to be isolated. Therefore,
we dispersed the crude ketone 4a directly in the silica
gel under neat conditions, thus hemiaminal 5a could be
generated in an overall yield of 60% from the
substrates 1a and 2 by the nucleophilic attack of the
water physisorbed in silica gel to the
spiroindoleninium intermediate under the catalysis of
silica gel.[7] The fragile hemiaminal 5a was then
converted into oxindole 6a by a 1,5-hydride migration
mediated by alumina (Al2O3) under neat conditions.[8]
The stereochemistry of the hemiaminal and geometry
of the double bond in the tricyclic indoline 5a were
determined by various 2D NMR spectra. The single
crystal X-ray diffraction of 6a provided unambiguous
support for the stereochemical features of the tricyclic
spirooxindole product (Scheme 3).[9] It is worth
mentioning that the syn-isomers were identified as the
exclusive products in determining the stereoisomers of
both 5a and 6a. As a result, a stereospecific silica
gel/alumina-mediated straightforward approach to the
syntheses of spiro[indoline-3,3'-pyrrolidin]-2-ones
based on tryptamine-derived ynesulfonamides was
developed.
Next, the functional group tolerances of this
transformation were investigated using a variety of
substrates as shown in Scheme 4. The yields of the
substrates with benzyl substitutions on the nitrogen
were better than that of methyl substitutions (Scheme
4, 6a-6c). The electron-rich substitutions both on the
benzene ring and nitrogen of the indole were crucial
for achieving acceptable yields (Scheme 4, 6d-6f). The
substrates with 4-nitrobenzenesulfonyl (Ns) and
methanesulfonyl (Ms) on the nitrogen of
ynesulfonamides provided slightly lower yields
Our studies commenced with the preparation of an
ynesulfonamide substrate 4a by a copper-catalyzed
coupling reaction[6] between tryptamine-derived
sulfonamide 1a and alkynyl bromide 2, and the
subsequent deprotection and oxidation protocols. For
the oxidation, tetrapropylammonium perruthenate
(TPAP)/N-methylmorpholine N-oxide (NMO) system
was employed here since it afforded the best reaction
profile compared with conventional oxidants such as
Dess-Martin periodinane, pyridinium chlorochromate
2
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10.1002/adsc.201701576
Advanced Synthesis & Catalysis
(Scheme 4, 6i-6j). The substrates with substituents on spiroindoleninium intermediate 4a-2, followed by
the α position of ketone gave only moderate yields, isomerization to afford 4a-3, which was then captured
possibly due to the steric hindrance from the bulky
Scheme 4. Substrate scopes for the syntheses of tricyclic
spirooxindoles.
substituents (nPr or Ph) in the vicinity of the lactam
ring (Scheme 4, 6k-6l).
In order to gain an insight into the mechanism of the
1,5-hydride migration, the substrate 3a-D derived from
a 2-deuterio-indole was prepared[10] and subjected to
the oxidation/cyclization/hydride migration conditions.
Scheme 5. Isotope-labeled experiments.
by water to provide hemiaminal 4a-4 after a proton
exchange. The coordination of carbonyl group with
water through a hydrogen bond laid the foundation for
the syn-stereochemistry of the addition, which was
consistent with the original proposal in Scheme 2 (C1
intermediate). According to the deuterated
experiments, the formation of 6a from hemiaminal 5a
1
The H NMR spectroscopy of product 6a-D showed
that the deuterium atom was adjunct to the newly
formed carbon center (Scheme 5, a). To figure out the
detailed trajectory of such a hydride migration, a
crossover experiment was carried out using substrates
3a-D and 3j, which gave 6a-D and 6j as the only
isolated products, indicating that the hydride transfer
occurred only in the intramolecular manner.
To trace the origin of the oxygen in the amide of the
product, an 18O-labeled substrate 3m-18O was
prepared[11] and treated with the standard reaction
conditions. By analyzing the mass spectroscopy, we
found that the heavy atoms existed in both 5m-18O and
6m-18O. To pinpoint the position of 18O, the ozonolysis
of alkene in product 6m-18O was proceeded to provide
the product 7m, containing no 18O, indicated that the
oxygens in the amide of products 5m-18O and 6m-18O
were derived from the water physisorbed in silica gel
(Scheme 5, b), which ruled out the possibility of
trapping of the spiroindoleninium intermediate by
carbonyl group as proposed in Scheme 2 (C2
intermediate).
Based on these experimental results, a plausible
mechanism was proposed in Scheme 6. Under the
catalysis of weak acid media, such as silica gel, the
activation of the carbonyl in 4a-1 by proton promoted
a Michael addition of indole to ynone providing the
Scheme 6. Proposed mechanism on the cascade cyclizations.
3
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10.1002/adsc.201701576
Advanced Synthesis & Catalysis
was proposed to happen via a stereospecific 1,5- Unless otherwise noted, reagents were obtained
hydride migration promoted by Al2O3.[4k,12] The commercially and used without further purification. All
diastereoselectivity of the hydride migration was reactions were carried out in flame-dried glassware.
totally controlled by the stereochemistry of the Anhydrous tetrahydrofuran (THF) was distilled from
hemiaminal in 5a.
sodium-benzophenone. Toluene was distilled from sodium.
A striking application of this strategy to tricyclic 1,2-Dichloroethane (DCE), dichloromethane (DCM) and
spirooxindole was demonstrated by constructing 7m-2, dimethylformamide (DMF) were distilled from calcium
an intermediate in the syntheses of coerulescine and hydride. Acetone was distilled from potassium carbonate.
horsfiline,[13] both are essential components of TLC analysis of reaction mixtures was performed on silica
traditional herbal medicine, isolated from Phalaris gel GF-254 TLC plates. Flash chromatography was carried
coerulescens and Horsfieldia superba, respectively.[14] out on silica gel (200-300 mesh). NMR spectra were
The key intermediate 7m-2 was easily synthesized in recorded with Bruker Avance-III 600 spectrometers and
68% overall yield from 7m, an intermediate in the referenced to CDCl3 and [D6]DMSO. HR-ESI-MS was
mechanism study, after several functional group recorded on a Bruker microTOFQ-Q instrument. IR spectra
manipulations, such as the deprotection of p- were recorded on a Bruker IFS 55 spectrometer. Melting
toluenesulfonyl (Ts) group, N-methylation and acid- point was tested on Thomas Hoover capillary melting point
catalyzed debenzylation of amide (Scheme 7). apparatus.
Compared with Kulkarni’s Wittig olefination–Claisen
rearrangement protocol,[13] this cascade cyclization and
(E)-1-(1-Benzyl-2-hydroxy-1'-tosylspiro[indoline-3,3'-
the following protective group transformations
strategy to the intermediate 7m-2 provided shorter
routes to coerulescine and horsfiline.
pyrrolidin]-2'-ylidene)propan-2-one (5a):
To a solution of the substrate 3a (235 mg, 0.481 mmol) in
DCM (3 mL) were added 4 Å molecular sieves (75 mg) and
NMO (85 mg, 0.73 mmol). The mixture was stirred at 0 °C
for 5 min and TPAP (35 mg, 0.10 mmol) was added. The
reaction was stirred at 0 °C for 30 min before filtered
through a plug of calcined Celite (rinsed with 10% ethyl
acetate/n-hexane). The filtrate was concentrated to give the
crude ketone product 4a. The ketone product 4a was
dissolved in DCM (2 mL) and silica gel (2.35 g, 200-300
mesh) was added. The solvent was removed in vacuo to
afford a yellow powder and it was stirred vigorously at room
temperature for 2 h. TLC monitored the reaction till all the
starting materials disappeared. The powder was filtered,
rinsed with ethyl acetate. The filtrate was concentrated to a
residue, which was recrystallized with n-hexane/ethyl
acetate (5:1) to provide the product 5a (167 mg, 71% yield)
as a yellow solid. m.p. 126.7–127.5 °C; 1H NMR (600 MHz,
CDCl3): δ = 7.76 (d, J = 8.3 Hz, 2H), 7.33 – 7.27 (m, 6H),
7.25 – 7.22 (m, 1H), 7.03 (td, J = 7.7, 1.2 Hz, 1H), 6.89 (s,
1H), 6.79 (dd, J = 7.4, 0.9 Hz, 1H), 6.62 (td, J = 7.4, 0.7 Hz,
1H), 6.36 (d, J = 7.8 Hz, 1H), 6.08 (d, J = 12.2 Hz, 1H), 4.52
(dd, J = 82.2, 16.2 Hz, 2H), 4.43 (d, J = 12.2 Hz, 1H), 4.13
(dd, J = 9.9, 8.0 Hz, 1H), 3.54 (ddd, J = 12.1, 10.0, 5.7 Hz,
1H), 2.43 (s, 3H), 2.16 (dd, J = 13.0, 5.6 Hz, 1H), 2.10 – 2.05
(m, 1H), 2.05 (s, 3H); 13C NMR (150 MHz, CDCl3): δ =
200.2, 155.6, 149.1, 145.3, 138.9, 133.9, 130.0, 129.2, 128.8,
Scheme 7. Formal syntheses of coerulescine and horsfiline
by the modification of tricyclic spirooxindole 7m.
Conclusion
In conclusion, a silica gel and alumina-mediated
tryptamine-derived ynesulfonamide-based robust
approach to synthesize spirooxindole scaffolds has
been developed, which represented a unique and 128.6, 127.7, 127.2, 127.1, 121.3, 118.0, 108.6, 106.3, 92.2,
straightforward strategy to access spiro[indoline-3,3'- 62.7, 48.7, 46.9, 36.2, 30.8, 21.9; IR (thin film, cm−1): 3421,
3027, 2923, 1661, 1582, 1493, 1455, 1383, 1351, 1230, 1166,
1149, 1093, 1058; HRMS (ESI) (m/z) [M+K]+: calcd. for
C28H28KN2O4S 527.1401, found 527.1390.
pyrrolidin]-2-one-containing indole alkaloids from the
ynesulfonamide substrates. The mechanism of the
cascade reaction was studied by isotope-labeled
experiments and a rational explanation to the
stereochemistry of the products was provided as well.
The application of the methodology was demonstrated
by the formal syntheses of two natural products,
coerulescine, and horsfiline
General Procedures and Characteristic Data for
Spiro[indoline-3,3'-pyrrolidin]-2-ones
To a solution of the substrates 3a–3l, 3a-D, 3m-18O (0.20
mmol) in DCM (3 mL) were added 4 Å molecular sieves (30
mg) and NMO (35 mg, 0.30 mmol). The mixture was stirred
at 0 °C for 5 min and TPAP (14 mg, 0.04 mmol) was added.
The reaction was stirred at 0 °C for 30 min before filtered
through a plug of calcined Celite (rinsed with 10% ethyl
acetate/n-hexane). The filtrate was concentrated to give the
crude ketone products 4a–4l, 4a-D, 4m-18O. The ketone
Experimental Section
General Information
4
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10.1002/adsc.201701576
Advanced Synthesis & Catalysis
products were dissolved in DCM (1 mL) and silica gel (m, 1H), 3.83 (dt, J = 10.2, 7.3 Hz, 1H), 3.30 – 3.26 (m, 1H),
(approximate 1.0 g, 200-300 mesh) was added into the 3.12 (s, 3H), 2.47 (s, 3H), 2.16 (dt, J = 12.4, 7.3 Hz, 1H),
solution. The solvent was evaporated in vacuo. The resulting 1.84 – 1.80 (m, 1H), 0.41 (d, J = 6.2 Hz, 3H); 13C NMR (150
powder was stirred vigorously at room temperature for 1 h. MHz, [D6]DMSO): δ = 175.4, 144.6, 142.1, 135.9, 133.4,
TLC monitored the reaction till all the starting materials 131.8, 129.8, 128.5, 127.8, 122.2, 122.1, 117.3, 109.0, 62.6,
disappeared. The powder was filtered, rinsed with ethyl 55.6, 48.8, 35.3, 26.4, 23.8, 21.1; IR (thin film, cm−1): 3463,
acetate. The filtrate was concentrated to a residue, which 3055, 2972, 2924, 2871, 1718, 1611, 1493, 1471, 1344, 1166,
was dissolved in DCM (2 mL) and Al2O3 (224 mg, 2.20 1099, 1031; HRMS (ESI) (m/z) [M+Na]+: calcd. for
mmol) was added into the solution. The solvent was C22H24N2NaO4S 435.1349, found 435.1343.
evaporated in vacuo and the resulted yellow powder was
heated at 50 °C for 3 h with vigorous stirring. The powder
was rinsed with ethyl acetate through a plug of silica gel.
The solvent was removed in vacuo to give a residue, which
was purified by a flash column chromatography on silica gel
to provide the products 6a–6l, 6a-D, 6m-18O.
(E)-1-Benzyl-2'-(2-hydroxypropylidene)-6-methyl-1'-
tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6d):
White solid (68 mg, 68% yield); petroleum ether/ethyl
1
acetate = 4:1; m.p. 134.0–135.2 °C; H NMR (600 MHz,
[D6]DMSO): δ = 7.83 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2
Hz, 2H), 7.35 – 7.28 (m, 4H), 7.26 – 7.24 (m, 1H), 6.72 (s,
1H), 6.48 (d, J = 7.6 Hz, 1H), 5.75 (d, J = 9.3 Hz, 1H), 5.62
(d, J = 7.6 Hz, 1H), 4.90 – 4.82 (m, 2H), 4.39 (d, J = 4.8 Hz,
(E)-1-Benzyl-2'-(2-hydroxypropylidene)-1'-tosylspiro
[indoline-3,3'-pyrrolidin]-2-one (6a):
White solid (62 mg, 64% yield); petroleum ether/ethyl 1H), 3.95 (dt, J = 10.1, 6.9 Hz, 1H), 3.83 (dt, J = 10.1, 7.3
1
acetate = 4:1; m.p. 135.8–136.7 °C; H NMR (600 MHz, Hz, 1H), 3.39 (s, 1H), 2.46 (s, 3H), 2.22 – 2.14 (m, 4H), 1.82
[D6]DMSO): δ = 7.84 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.3 (dt, J = 12.4, 6.2 Hz, 1H), 0.45 (d, J = 6.2 Hz, 3H); 13C NMR
Hz, 2H), 7.33 – 7.28 (m, 4H), 7.27 – 7.22 (m, 1H), 7.11 (td, (150 MHz, [D6]DMSO): δ = 175.9, 144.7, 141.2, 138.0,
J = 7.8, 1.1 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.67 (td, J = 136.2, 135.8, 133.5, 129.8, 129.0, 128.7, 127.8, 127.4, 127.2,
7.5, 1.1 Hz, 1H), 5.75 (t, J = 7.5 Hz, 2H), 4.88 (s, 2H), 4.43 122.7, 122.0, 117.5, 110.2, 62.8, 55.6, 48.7, 43.0, 36.0, 23.9,
(d, J = 4.8 Hz, 1H), 3.99 – 3.95 (m, 1H), 3.85 (dt, J = 10.2, 21.2, 21.1; IR (thin film, cm−1): 3459, 3034, 2975, 2925,
7.2 Hz, 1H), 3.37 – 3.34 (m, 1H), 2.46 (s, 3H), 2.22 (dt, J = 1709, 1663, 1618, 1498, 1453, 1378, 1345, 1169, 1091;
12.5, 7.2 Hz, 1H), 1.89 – 1.85 (m, 1H), 0.41 (d, J = 6.2 Hz, HRMS (ESI) (m/z) [M+Na]+: calcd. for C29H30N2NaO4S
3H); 13C NMR (150 MHz, [D6]DMSO): δ = 175.7, 144.7, 525.1818, found 525.1821.
141.1, 136.1, 135.8, 133.5, 131.9, 129.9, 128.7, 128.4, 127.8,
127.5, 127.4, 122.3, 122.3, 117.5, 109.7, 62.9, 55.8, 48.8,
43.1, 35.8, 23.7, 21.1; IR (thin film, cm−1): 3453, 3063, 2973,
2924, 1692, 1659, 1370, 1347, 1167, 1092; HRMS (ESI)
(m/z) [M+Na]+: calcd. for C28H28N2NaO4S 511.1662, found
511.1660.
(E)-1-Benzyl-2'-(2-hydroxypropylidene)-6-methoxy-1'-
tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6e):
White solid (73 mg, 71% yield); petroleum ether/ethyl
1
acetate = 3:1; m.p. 126.4–127.3 °C; H NMR (600 MHz,
[D6]DMSO): δ = 7.82 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2
Hz, 2H), 7.31 (d, J = 4.4 Hz, 4H), 7.27 – 7.23 (m, 1H), 6.48
(d, J = 2.2 Hz, 1H), 6.20 (dd, J = 8.3, 2.2 Hz, 1H), 5.74 (d, J
= 9.3 Hz, 1H), 5.70 (d, J = 8.3 Hz, 1H), 4.91 – 4.82 (m, 2H),
(E)-2'-(2-Hydroxypropylidene)-1-(4-methoxybenzyl)-1'-
tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6b):
White solid (78 mg, 75% yield); petroleum ether/ethyl 4.40 (d, J = 4.6 Hz, 1H), 3.94 (dt, J = 10.2, 6.9 Hz, 1H), 3.83
1
acetate = 3:1; m.p. 89.0–90.2 °C; H NMR (600 MHz, (dt, J = 10.2, 7.3 Hz, 1H), 3.63 (s, 3H), 3.37 – 3.34 (m, 1H),
[D6]DMSO): δ = 7.83 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 2.46 (s, 3H), 2.17 (dt, J = 12.6, 7.3 Hz, 1H), 1.82 (dt, J =
Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.11 (td, J = 7.8, 1.1 Hz, 12.6, 6.4 Hz, 1H), 0.47 (d, J = 6.4 Hz, 3H); 13C NMR (150
1H), 6.91 – 6.82 (m, 3H), 6.65 (td, J = 7.8, 1.1 Hz, 1H), 5.74 MHz, [D6]DMSO): δ = 176.2, 159.6, 144.7, 142.4, 136.1,
(d, J = 9.4 Hz, 1H), 5.72 (d, J = 7.0 Hz, 1H), 4.84 – 4.77 (m, 135.9, 133.5, 129.9, 128.7, 127.7, 127.5, 127.4, 123.7, 123.0,
2H), 4.41 (d, J = 4.7 Hz, 1H), 3.98 – 3.94 (m, 1H), 3.84 (dt, 117.4, 106.3, 97.4, 62.8, 55.3, 48.7, 43.0, 35.9, 23.9, 21.1;
J = 10.2, 7.5 Hz, 1H), 3.69 (s, 3H), 3.35 – 3.22 (m, 1H), 2.46 IR (thin film, cm−1): 3422, 2967, 2923, 1712, 1613, 1501,
(s, 3H), 2.20 (dt, J = 12.4, 7.5 Hz, 1H), 1.86 – 1.82 (m, 1H), 1382, 1344, 1165, 1095, 1029; HRMS (ESI) (m/z) [M+Na]+:
0.40 (d, J = 6.2 Hz, 3H); 13C NMR (150 MHz, [D6]DMSO): calcd. for C29H30N2NaO5S 541.1768, found 541.1744.
δ = 175.6, 158.6, 144.7, 141.0, 135.8, 133.4, 131.9, 129.9,
128.8, 128.4, 127.9, 127.8, 122.3, 122.2, 117.5, 114.1, 109.8,
62.9, 55.8, 55.1, 48.8, 42.5, 35.8, 23.7, 21.1; IR (thin film,
cm−1): 3428, 2925, 1710, 1611, 1503, 1486, 1441, 1383,
1347, 1164, 1092, 1030; HRMS (ESI) (m/z) [M+Na]+: calcd.
for C29H30N2NaO5S 541.1768, found 541.1768.
(E)-1-Benzyl-2'-(2-hydroxypropylidene)-5-methoxy-1'-
tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6f):
White solid (69 mg, 67% yield); petroleum ether/ethyl
1
acetate = 3:1; m.p. 149.6–151.2 °C; H NMR (600 MHz,
[D6]DMSO): δ = 7.83 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2
Hz, 2H), 7.33 – 7.27 (m, 4H), 7.26 – 7.23 (m, 1H), 6.75 (d,
J = 8.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.5 Hz, 1H), 5.77 (d, J =
9.4 Hz, 1H), 5.37 (d, J = 2.5 Hz, 1H), 4.85 (s, 2H), 4.42 (d,
(E)-2'-(2-Hydroxypropylidene)-1-methyl-1'-tosylspiro
[indoline-3,3'-pyrrolidin]-2-one (6c):
White solid (47 mg, 57% yield); petroleum ether/ethyl J = 4.8 Hz, 1H), 3.96 (dt, J = 10.3, 6.7 Hz, 1H), 3.88 (dt, J =
1
acetate = 2:1; m.p. 126.5–127.6 °C; H NMR (600 MHz, 10.3, 7.1 Hz, 1H), 3.52 (s, 3H), 3.38 (s, 1H), 2.43 (s, 3H),
[D6]DMSO): δ = 7.82 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.3 2.22 (dt, J = 12.6, 7.1 Hz, 1H), 1.86 (dt, J = 12.6, 6.2 Hz,
Hz, 2H), 7.21 (td, J = 7.7, 1.1 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 0.46 (d, J = 6.2 Hz, 3H); 13C NMR (150 MHz,
1H), 6.69 (td, J = 7.3 Hz, 1.1, 1H), 5.74 (d, J = 7.3 Hz, 1H), [D6]DMSO): δ = 175.4, 155.4, 144.9, 136.1, 135.6, 134.3,
5.69 (d, J = 9.2 Hz, 1H), 4.42 (d, J = 4.9 Hz, 1H), 3.96 – 3.92 133.4, 133.1, 129.9, 128.7, 127.7, 127.5, 127.3, 117.7, 112.5,
5
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10.1002/adsc.201701576
Advanced Synthesis & Catalysis
110.1, 109.9, 62.8, 56.2, 55.6, 48.8, 43.1, 36.0, 23.8, 21.1; (E)-1-Benzyl-2'-(2-hydroxypropylidene)-1'-
IR (thin film, cm−1): 3455, 3061, 2970, 2924, 1706, 1660, (methylsulfonyl)spiro[indoline-3,3'-pyrrolidin]-2-one
1600, 1495, 1438, 1383, 1343, 1281, 1244, 1167, 1092, 1035; (6j):
HRMS (ESI) (m/z) [M+Na]+: calcd. for C29H30N2NaO5S White solid (49 mg, 59% yield); petroleum ether/ethyl
1
541.1768, found 541.1765.
acetate = 3:1; m.p. 159.0–160.3 °C; H NMR (600 MHz,
[D6]DMSO): δ = 7.37 – 7.32 (m, 5H), (m, 2H), 7.05 (t, J =
7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.54 (d, J = 9.5 Hz,
1H), 4.94 (s, 2H), 4.43 (d, J = 4.7 Hz, 1H), 3.89 (dt, J = 8.9,
7.0 Hz, 1H), 3.84 –3.80 (m, 1H), 3.35 – 3.29 (m, 1H), 3.14
(s, 3H), 2.33 – 2.20 (m, 2H), 0.57 (d, J = 6.1 Hz, 3H); 13C
NMR (150 MHz, [D6]DMSO): δ = 176.4, 141.7, 137.2,
136.1, 131.1, 128.7, 128.7, 127.5, 127.2, 123.5, 122.9, 115.7,
109.7, 62.3, 55.9, 48.3, 43.0, 35.1, 33.8, 23.5; IR (thin film,
cm−1): 3412, 2926, 2853, 2344, 1690, 1660, 1612, 1467,
1368, 1339, 1169, 1089, 1034; HRMS (ESI) (m/z) [M+Na]+:
calcd. for C22H24N2NaO4S 435.1349, found 435.1347.
(E)-1-Benzyl-5-chloro-2'-(2-hydroxypropylidene)-1'-
tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6g):
White solid (41 mg, 39% yield); petroleum ether/ethyl
1
acetate = 4:1; m.p. 126.2–127.5 °C; H NMR (600 MHz,
[D6]DMSO): δ = 7.85 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1
Hz, 2H), 7.37 – 7.29 (m, 4H), 7.27 – 7.25 (m, 1H), 7.19 (dd,
J = 8.4, 1.9 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.83 (d, J =
9.3 Hz, 1H), 5.51 (d, J = 1.9 Hz, 1H), 4.89 (q, J = 15.7 Hz,
2H), 4.52 (d, J = 4.7 Hz, 1H), 4.04 – 3.93 (m, 1H), 3.93 –
3.83 (m, 1H), 3.34 – 3.30 (m, 1H), 2.45 (s, 3H), 2.26 (dt, J =
12.3, 7.6 Hz, 1H), 1.90 (dt, J = 12.3, 6.2 Hz, 1H), 0.46 (d, J
= 6.2 Hz, 3H); 13C NMR (150 MHz, [D6]DMSO): δ = 175.2, (E)-1-Benzyl-2'-(2-hydroxyhexylidene)-1'-tosylspiro
145.1, 139.9, 135.7, 135.2, 133.8, 133.1, 130.0, 128.7, 128.2, [indoline-3,3'-pyrrolidin]-2-one (6k):
127.8, 127.6, 127.4, 126.6, 122.2, 118.3, 111.1, 62.9, 55.9, White solid (43 mg, 41% yield); petroleum ether/ethyl
1
48.8, 43.2, 35.8, 23.8, 21.3; IR (thin film, cm−1): 3534, 3064, acetate = 6:1; m.p. 119.2–120.8 °C; H NMR (600 MHz,
2962, 2923, 2879, 1716, 1655, 1608, 1479, 1337, 1166, 1091, [D6]DMSO): δ = 7.84 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3
1033; HRMS (ESI) (m/z) [M+Na]+: calcd. for Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H),
C28H27ClN2NaO4S 545.1272, found 545.1268.
7.24 (t, J = 7.3 Hz, 1H), 7.10 (td, J = 7.8, 1.0 Hz, 1H), 6.87
(d, J = 7.8 Hz, 1H), 6.64 (td, J = 7.3, 1.0 Hz, 1H), 5.80 (d, J
= 7.3 Hz, 1H), 5.64 (d, J = 9.7 Hz, 1H), 4.91 (d, J = 15.6 Hz,
1H), 4.84 (d, J = 15.6 Hz, 1H), 4.19 (d, J = 5.2 Hz, 1H), 4.03
– 4.00 (m, 1H), 3.92 – 3.82 (m, 1H), 3.13 – 3.08 (m, 1H),
2.45 (s, 3H), 2.26 (dt, J = 12.4, 7.7 Hz, 1H), 1.91 – 1.83 (m,
1H), 1.01 – 0.90 (m, 1H), 0.70 – 0.62 (m, 1H), 0.61 – 0.51
(m, 2H), 0.45 (t, J = 7.3 Hz, 3H), 0.36 – 0.27 (m, 1H), 0.26
– 0.18 (m, 1H); 13C NMR (150 MHz, [D6]DMSO): δ = 175.6,
144.6, 141.0, 136.5, 136.0, 133.5, 132.1, 129.8, 128.6, 128.2,
127.8, 127.6, 127.5, 122.4, 122.3, 116.0, 109.6, 66.9, 55.8,
48.8, 43.2, 37.5, 35.8, 26.7, 21.6, 21.1, 13.8; IR (thin film,
cm−1): 3447, 3061, 3955, 3925, 2854, 1696, 1610, 1487,
1467, 1346, 1166, 1091; HRMS (ESI) (m/z) [M+Na]+: calcd.
for C31H34N2NaO4S 553.2131, found 553.2134.
(E)-1-Benzyl-5-bromo-2'-(2-hydroxypropylidene)-1'-
tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6h):
White solid (37 mg, 33% yield); petroleum ether/ethyl
1
acetate = 4:1; m.p. 128.7–129.8 °C; H NMR (600 MHz,
[D6]DMSO): δ = 7.85 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2
Hz, 2H), 7.34 – 7.28 (m, 5H), 7.27 – 7.23 (m, 1H), 6.83 (d,
J = 8.4 Hz, 1H), 5.82 (d, J = 9.3 Hz, 1H), 5.72 (d, J = 1.9 Hz,
1H), 4.89 (q, J = 15.8 Hz, 2H), 4.52 (d, J = 4.8 Hz, 1H), 3.99
– 3.95 (m, 1H), 3.90 (dt, J = 10.5, 7.3 Hz, 1H), 3.33 – 3.30
(m, 1H), 2.47 (s, 3H), 2.25 (dt, J = 12.5, 7.4 Hz, 1H), 1.89
(dt, J = 12.5, 6.2 Hz, 1H), 0.46 (d, J = 6.2 Hz, 3H); 13C NMR
(150 MHz, [D6]DMSO): δ = 175.2, 145.0, 140.3, 135.7,
135.2, 134.2, 133.2, 131.1, 130.1, 128.7, 127.7, 127.6, 127.3,
124.9, 118.3, 114.3, 111.6, 62.9, 55.9, 48.9, 43.2, 35.9, 23.7,
21.5; IR (thin film, cm−1): 3545, 3419, 3063, 2977, 2924, (E)-1-benzyl-2'-(2-hydroxy-3-phenylpropylidene)-1'-
1717, 1661, 1603, 1477, 1358, 1340, 1262, 1161, 1091, 1052, tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6l):
1030; HRMS (ESI) (m/z) [M+Na]+: calcd. for White solid (43 mg, 38% yield); petroleum ether/ethyl
1
C28H27BrN2NaO4S 589.0767, found 589.0770.
acetate = 8:1; m.p. 130.1–132 °C; H NMR (600 MHz,
[D6]DMSO): δ = 7.79 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2
Hz, 2H), 7.28 – 7.24 (m, 2H), 7.22 – 7.16 (m, 4H), 7.06 –
7.03 (m, 3H), 6.93 (d, J = 7.9 Hz, 1H), 6.74 (t, J = 7.4 Hz,
1H), 6.40 (d, J = 7.0 Hz, 2H), 5.85 (d, J = 9.6 Hz, 1H), 5.82
(d, J = 7.4 Hz, 1H), 4.88 (d, J = 15.8 Hz, 1H), 4.80 (d, J =
15.8 Hz, 1H), 4.39 (d, J = 6.1 Hz, 1H), 3.97 (dt, J = 10.3, 7.0
Hz, 1H), 3.89 (dt, J = 10.3, 7.0 Hz, 1H), 3.38 (s, 1H), 2.46
(s, 3H), 2.30 (dd, J = 13.6, 9.0 Hz, 1H), 2.22 (dt, J = 13.6,
7.0 Hz, 1H), 1.91 – 1.83 (m, 1H), 1.80 (dd, J = 13.6, 3.8 Hz,
1H); 13C NMR (150 MHz, [D6]DMSO): δ = 175.8, 144.6,
141.4, 138.2, 136.5, 135.9, 133.7, 131.9, 129.9, 129.0, 128.6,
128.4, 127.7, 127.6, 127.4, 127.3, 125.5, 122.6, 122.4, 116.3,
109.8, 67.8, 56.0, 48.7, 43.7, 43.1, 36.3, 21.1; IR (thin film,
cm−1): 3429, 2923, 2854, 1697, 1650, 1610, 1489, 1466,
1383, 1348, 1166, 1108, 1057; HRMS (ESI) (m/z) [M+Na]+:
calcd. for C34H32N2NaO4S 587.1975, found 587.1965.
(E)-1-Benzyl-2'-(2-hydroxypropylidene)-1'-((4-
nitrophenyl)sulfonyl)spiro[indoline-3,3'-pyrrolidin]-2-
one (6i):
Yellow solid (47 mg, 45% yield); petroleum ether/ethyl
1
acetate = 5:1; m.p. 193.7–195.5 °C; H NMR (600 MHz,
[D6]DMSO): δ = 8.46 (d, J = 8.9 Hz, 2H), 8.23 (d, J = 8.9
Hz, 2H), 7.32 – 7.28 (m, 2H), 7.27 – 7.23 (m, 3H), 7.16 (td,
J = 7.8, 1.1 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.82 (td, J =
7.3, 1.1 Hz, 1H), 6.49 (d, J = 7.3 Hz, 1H), 5.77 (d, J = 9.4
Hz, 1H), 4.82 (s, 2H), 4.45 (s, 1H), 4.05 – 3.95 (m, 2H), 3.31
– 3.27 (m, 1H), 2.18 (dt, J = 12.8, 6.5 Hz, 1H), 2.05 (dt, J =
12.8, 7.2 Hz, 1H), 0.48 (d, J = 6.5 Hz, 3H); 13C NMR (150
MHz, [D6]DMSO); δ = 175.5, 150.5, 141.7, 141.4, 136.0,
135.6, 131.1, 129.5, 128.7, 128.6, 127.5, 127.2, 124.5, 122.7,
122.6, 118.1, 109.7, 62.5, 55.6, 48.8, 43.0, 35.4, 23.6; IR
(thin film, cm−1) 3441, 3099, 2961, 2925, 2855, 1718, 1608,
1531, 1349, 1171, 1090, 1031; HRMS (ESI) (m/z) [M+Na]+: (E)-1-Benzyl-2'-(2-d-2-hydroxypropylidene)-1'-
calcd. for C27H25N3NaO6S 542.1356, found 542.1358. tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6a-D):
6
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10.1002/adsc.201701576
Advanced Synthesis & Catalysis
white solid (59 mg, 60% yield); petroleum ether/ethyl To a solution of the spirooxindole 6m-18O (60 mg, 0.109
1
acetate = 4:1; m.p. 132.8–134.0 °C; H NMR (600 MHz, mmol) in DCM (1.0 mL) was added absolute methanol (0.2
[D6]DMSO): δ = 7.84 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 mL). At −78 °C, a stream of ozone was passed through the
Hz, 2H), 7.31 – 7.30 (m, 4H), 7.28 – 7.21 (m, 1H), 7.11 (td, reaction mixture until a grey-blue color appeared. After 30
J = 7.8, 0.9 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.66 (t, J = 7.4 min, the ozone flow was discontinued, and the reaction
Hz, 1H), 5.75 (s, 1H), 5.73 (d, J = 7.4 Hz, 1H), 4.89 (s, 2H), mixture (still at −78 °C) was purged with N2 to remove the
4.42 (s, 1H), 3.99 – 3.95 (m, 1H), 3.85 (dt, J = 10.2, 7.3 Hz, remaining dissolved ozone. Then Me2S was added in one
1H), 2.46 (s, 3H), 2.22 (dt, J = 12.6, 7.3 Hz, 1H), 1.92 – 1.83 portion and the resulting solution was stirred at room
(m, 1H), 0.40 (s, 3H); 13C NMR (150 MHz, [D6]DMSO): δ temperature for 20 min. Concentrated under reduced
= 175.6, 144.7, 141.1, 136.1, 135.7, 133.4, 131.8, 129.9, pressure, the resulting residue was purified by a flash
128.7, 128.4, 127.8, 127.5, 127.4, 122.32, 122.27, 117.5, column chromatography on silica gel (petroleum ether/ethyl
109.7, 55.8, 48.8, 43.1, 35.8, 23.6, 21.1; IR (thin film, cm−1): acetate = 3:1) to provide the product 7m as a white solid (43
3453, 2924, 1693, 1657, 1609, 1488, 1468, 1356, 1165; mg, 88 % yield). m.p. 179.6–180.7 °C; 1H NMR (600 MHz,
HRMS (ESI) (m/z) [M+Na]+: calcd. for C28H27DN2NaO4S CDCl3): δ = 7.95 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz,
512.1715, found 512.1725.
2H), 7.31 – 7.27 (m, 2H), 7.25 – 7.23 (m, 1H), 7.21 – 7.17
(m, 3H), 7.08 (dd, J = 7.5, 0.9 Hz, 1H), 7.00 (td, J = 7.8, 0.9
Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 4.86 (d, J = 15.9 Hz, 1H),
4.77 (d, J = 15.9 Hz, 1H), 4.30 (dt, J = 9.7, 7.7 Hz, 1H), 4.23
– 4.20 (m, 1H), 2.73 – 2.69 (m, 1H), 2.53 – 2.48 (m, 1H),
2.43 (s, 3H); 13C NMR (150 MHz, CDCl3): δ = 173.7, 169.2,
145.7, 143.5, 135.0, 134.5, 129.9, 129.7, 129.0, 128.4, 127.9,
127.7, 127.1, 123.5, 123.3, 109.9, 58.8, 45.2, 44.1, 29.3, 21.9;
IR (thin film, cm−1): 3418, 3061, 3028, 2922, 2187, 2110,
1709, 1610, 1489, 1466, 1360, 1173, 1109; HRMS (ESI)
(m/z) [M+Na]+: calcd. for C25H22N2NaO4S 469.1192, found
469.1182.
(E)-1-benzyl-2'-(-2-O18-hydroxy-2-phenylethylidene)-1'-
tosylspiro[indoline-3,3'-pyrrolidin]-2-one (6m-18O):
white solid (73 mg, 66% yield); petroleum ether/ethyl
1
acetate = 4:1; m.p. 81.0–81.8 °C; H NMR (600 MHz,
[D6]DMSO); δ 7.46 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 7.4 Hz,
2H), 7.29 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.18
– 7.15 (m, 3H), 7.12 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 7.5 Hz,
2H), 6.94 (d, J = 7.9 Hz, 1H), 6.55 (td, J = 7.6, 0.6 Hz, 1H),
6.32 (d, J = 7.3 Hz, 2H), 5.94 (d, J = 10.2 Hz, 1H), 5.38 (d,
J = 7.3 Hz, 1H), 5.20 (s, 1H), 4.95 (s, 2H), 4.22 (d, J = 10.2
Hz, 1H), 4.00 – 3.99 (m, 1H), 3.75 (td, J = 9.7, 6.7 Hz, 1H),
2.40 (s, 3H), 2.35 – 2.30 (m, 1H), 1.93 – 1.90 (m, 1H); 13
C
1-Benzyl-1'-methylspiro[indoline-3,3'-pyrrolidine]-2,2'-
NMR (150 MHz, [D6]DMSO): δ 175.8, 145.0, 145.0, 141.6, dione (7m-1):
137.0, 136.6, 133.2, 132.2, 130.2, 129.2, 128.8, 128.2, 128.1, Preparation of sodium naphthalenide solution: To a solution
128.0, 127.9, 127.1, 125.7, 123.0, 122.7, 116.1, 110.3, 69.7, of naphthalene (256 mg, 2.00 mmol) in anhydrous THF (10
56.2, 49.3, 43.7, 36.1, 21.5 IR (thin film, cm−1): 3423, 2923, mL) was added freshly cut sodium pieces (92 mg, 4.0 mmol).
2853, 2170, 1699, 1657, 1631, 1610, 1465, 1455, 1384, 1346, The mixture was sonicated at room temperature for 20 min
1169, 1109, 1009; HRMS (ESI) (m/z) [M+Na]+: calcd. for with occasional swirling to afford a dark green solution of
C33H30N2NaO3S18O 575.1861, found 575.1861.
sodium naphthalenide (0.2 M) in THF.
To a solution of 7m (100 mg, 0.224 mmol) in anhydrous
THF (10 mL) was added a freshly prepared sodium
naphthalenide solution (4 mL, 0.8 mmol) dropwise at –78 °C
with swirling until the dark green color persisted. After
confirmation of completion by TLC (30 min after dark green
persistence), MeOH (0.5 mL) was added to quench the
reaction and the mixture warmed to room temperature over
30 min. The mixture was concentrated in vacuo to afford the
crude product, which was used without further purification.
The crude product obtained above was dissolved in
anhydrous DMF (10 mL) and cooled to 0 °C with an ice bath.
NaH (10 mg, 0.26 mmol, 60% dispersion in mineral oil) was
added portionwise and the mixture was stirred for 30 min
before MeI (43 mg, 0.30 mmol) was added to the mixture
slowly at 0 °C. Then the mixture was warmed to room
temperature gradually. When finished, the reaction was
quenched with a saturated aqueous solution of NH4Cl (1 mL)
and extracted with EtOAc (10 mL x 3). The combined
organic layers were washed with brine (10 mL) and dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by a flash column chromatography
on silica gel (petroleum ether/ethyl acetate = 2:1) to afford
the product 7m-1 (62 mg, 90% yield) as a white solid. m.p.
The Procedure for Crossover Experiment
The ketone products 4a-D and 4j were prepared from
substrates 3a-D (95 mg, 0.20 mmol) and 3j (79 mg, 0.20
mmol) respectively according to the general procedure
described in the syntheses of tricyclic indolines 6a–6l. The
ketone products 4a-D and 4j were dissolved in DCM (2 mL)
and silica gel (1.74 g, 200-300 mesh) was added. The solvent
was removed in vacuo to afford a yellow powder, then it was
stirred vigorously at room temperature for 1 h. TLC
monitored the reaction till all the starting materials
disappeared. The powder was filtered, rinsed with ethyl
acetate. The filtrate was concentrated. The resulting yellow
residue was dissolved in DCM (2 mL) then Al2O3 (415 mg,
4.07 mmol) was added into the solution. The solvent was
evaporated under reduced pressure and the resulted yellow
powder was heated at 50 °C with vigorous stirring. After 3
h, the resulting powder was rinsed with ethyl acetate through
a plug of silica gel. The solvents were removed in vacuo to
give a white residue, which was purified by a flash column
chromatography on silica gel (petroleum ether/ethyl acetate
= 4:1) providing the products 6a-D (62 mg, 64%) and 6j (49
mg, 60%) as white solids, respectively.
1
165.6–166.9 °C; H NMR (600 MHz, CDCl3): δ = 7.34 –
7.29 (m, 4H), 7.26 – 7.22 (m, 1H), 7.18 – 7.16 (m, 2H), 7.04
– 7.01 (m, 1H), 6.70 – 6.68 (m, 1H), 5.02 (d, J = 15.9, 1H),
4.84 (d, J = 15.9, 1H), 3.81 (ddd, J = 9.4, 8.5, 6.1 Hz, 1H),
1-Benzyl-1'-tosylspiro[indoline-3,3'-pyrrolidine]-2,2'-
dione (7m):
7
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10.1002/adsc.201701576
Advanced Synthesis & Catalysis
3.62 (ddd, J = 9.4, 8.7, 4.7 Hz, 1H), 3.00 (s, 3H), 2.75 (ddd,
J = 13.1, 8.4, 4.7 Hz, 1H), 2.44 (ddd, J = 13.2, 8.6, 6.1 Hz,
1H); 13C NMR (150 MHz, CDCl3): δ = 176.0, 170.5, 143.6,
135.4, 130.1, 129.0, 128.9, 127.6, 127.1, 123.1, 122.9, 109.6,
57.9, 47.3, 44.0, 30.6, 29.5; IR (thin film, cm−1) 3403, 2922,
1707, 1685, 1612, 1493, 1467, 1364, 1345, 1300, 1269, 1172,
1080; HRMS (ESI) (m/z) [M+Na]+: calcd. for
C19H18N2NaO2 329.1260, found 329.1255.
2147–2155; d) T. Kam, Y. Choo in The Alkaloids, Vol.
63 (Ed.: G. A. Cordell), Academic Press, New York,
2006, pp. 181–337; e) C. A. Stump, I. M. Bell, R. A.
Bednar, J. G. Bruno, J. F. Fay, S. N. Gallicchio, V. K.
Johnston, E. L. Moore, S. D. Mosser, A. G. Quigley, C.
A. Salvatore, C. R. Theberge, C. B. Zartman, X. Zhang,
S. A. Kane, S. L. Graham, J. P. Vacca, T. M. Williams,
Bioorg. Med. Chem. Lett. 2009, 19, 214–217; f) C. Chou,
C. Gong, C. Chao, C. Lin, C. Kwan, C. Hsieh, Y. Leung,
J. Nat. Prod. 2009, 72, 830–834; g) A. P. Antonchick, C.
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1'-Methylspiro[indoline-3,3'-pyrrolidine]-2,2'-dione
(7m-2):
To a solution of compound 7m-1 (60 mg, 0.20 mmol) in
toluene (4 mL) was added trifluoromethanesulfonic acid
(0.25 mL, 2.8 mmol) dropwise at room temperature. The
resulting reaction mixture was heated to 80 °C and stirred
for 12 h. The reaction was quenched with a saturated
aqueous solution of NaHCO3 (1 mL) and extracted with
EtOAc (10 mL x 3). The combined organic layers were
washed with brine (10 mL) and dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by a flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 1:1) to afford the product
7m-2 as a white solid (33 mg, 76% yield). m.p. 220.2–
221.9 °C;1H NMR (600 MHz, CDCl3): δ = 8.58 (s, 1H), 7.18
(td, J = 7.7, 0.8 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.01 (t, J
= 7.4 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 3.76 (td, J = 9.0, 6.0
Hz, 1H), 3.59 (td, J = 9.0, 4.8 Hz, 1H), 2.98 (s, 3H), 2.72
(ddd, J = 13.2, 8.4, 4.8 Hz, 1H), 2.42 – 2.36 (m, 1H); 13C
NMR (150 MHz, CDCl3): δ = 176.6, 169.8, 140.9, 129.6,
128.1, 122.1, 121.9, 109.5, 57.4, 46.4, 29.7, 28.5; IR (thin
film, cm−1): 3215, 1802, 1706, 1678, 1634, 1468, 1254;
HRMS (ESI) (m/z) [M+K]+: calcd. for C12H12KN2O2
255.0530, found 255.0527.
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Acknowledgements
We thank the Natural Science Foundation of Liaoning Province of
China for financial support (grant 20170540855). We are grateful
to the program for innovative research team of the Ministry of
Education and the program for Liaoning innovative research team
in university
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FULL PAPER
Ynesulfonamide-Based Silica Gel and Alumina-
Mediated Diastereoselective Cascade Cyclizations
to Spiro[indoline-3,3'-pyrrolidin]-2-ones under
Neat Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Yanshi Wang, Xiaoyu Wang, Jingsheng Lin, Bo
Yao, Guanghui Wang, Yuandong Zhao, Xinhang
Zhang, Bin Lin, Yang Liu, Maosheng Cheng, and
Yongxiang Liu*
10
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