Iodide/H2O2 catalyzed intramolecular oxidative amination for the synthesis of 3,20-pyrrolidinyl spirooxindoles

Article abstract of DOI:10.3390/molecules23092265

An ammonium iodide/hydrogen peroxide-mediated intramolecular oxidative amination of 3-aminoalkyl-2-oxindoles was achieved, affording the corresponding 3,2⁰-pyrrolidinyl spirooxindoles and their 6- or 7-membered analogous in moderate to high yields. This metal-free procedure features very mild reaction conditions, non-toxicity and easily handled hydrogen peroxide as a clean oxidant.

Full text of DOI:10.3390/molecules23092265

molecules
Article
Iodide/H2O2 Catalyzed Intramolecular Oxidative
Amination for the Synthesis of
3,20-Pyrrolidinyl Spirooxindoles
Yu-Ting Gao 1,2, Xiao-Yang Jin 1,2, Qi Liu 1,2, An-Di Liu 1,2, Liang Cheng 1,2, ID , Dong Wang 1
*
and Li Liu 1,2,
*
1
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular
Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China; gaoyuting@iccas.ac.cn (Y.-T.G.);
jinxy123@iccas.ac.cn (X.-Y.J.); liuqir@iccas.ac.cn (Q.L.); liuandi@iccas.ac.cn (A.-D.L.);
dwang210@iccas.ac.cn (D.W.)
2
University of Chinese Academy of Sciences, Beijing 100049, China
*
Correspondence: chengl@iccas.ac.cn (L.C.); lliu@iccas.ac.cn (L.L.); Tel.: +86-10-6255-4614 (L.L.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 27 July 2018; Accepted: 24 August 2018; Published: 5 September 2018
Abstract: An ammonium iodide/hydrogen peroxide-mediated intramolecular oxidative amination of
0
3-aminoalkyl-2-oxindoles was achieved, affording the corresponding 3,2 -pyrrolidinyl spirooxindoles
and their 6- or 7-membered analogous in moderate to high yields. This metal-free procedure features
very mild reaction conditions, non-toxicity and easily handled hydrogen peroxide as a clean oxidant.
Keywords: spirooxindoles; iodine/H2O2; oxidative amination
1. Introduction
The 3,20-pyrrolidinyl spirooxindoles and their 6- or 7- membered analogous are among one
of the most important privileged structural units, whicH-Not only frequently appear in a plethora
of biologically active oxindole alkaloids, but also in several pharmaceuticals [
most common such skeletons, 3,20-pyrrolidinyl spirooxindoles shown a wide spectrum of notable
bioactivities [14 17], such as local anesthetic and antimycobacterial effects, and binding to the MDM2
1–13]. As one of the
–
protein to interrupt its protein-protein interaction with TP53 (Figure 1).
Ar
Cl
F
HN
O2N
NH
O
N
N
N
O
O
O
N
N
N
N
H
Cl
H
H
H
3,2'-pyrrolidinyl
spirooxindoles
local anesthetic
agent
antimycobacterial
candidate
MDM2-p53 inhibitor
0
Figure 1. Biologically active 3,2 -pyrrolidinyl spirooxindole derivatives
Considering their potential pharmaceutical value, decades of research have introduced
several synthetic methods to assemble this type of spirooxindole compounds. However, almost
all published approaches are based on the powerful (3 + 2) cyclization to construct the
five-membered pyrrolidinyl ring [18
–26] (Scheme 1). For example, metal-catalyzed and organocatalytic
cycloadditions of azomethine imines derived from isatins with a variety of dipolarophiles have
Molecules 2018, 23, 2265; doi:10.3390/molecules23092265
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2265
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been successfully developed (a,b-bond construction, pathway (1)). Alternatively, a nucleophilic
attack of 1,3-ylides on isatin-3-imine derivatives also led to the formation of corresponding
spirooxindoles (a,c-bond construction, pathway (2)). Despite the fact that these elegant one-step
assemblies are capable of producing various spirooxindoles with molecular complexity and
diversity, efficient and accessible methodologies towards these synthetic targets are still in high
demand. The first intramolecular nucleophilic substitution of 3-halo-2-oxindoles providing a
3,20-pyrrolidinyl-spirooxindole intermediate was reported by Cohen et al. almost 30 years ago
(d-bond construction, pathway (3)) [27]. Unfortunately, almost no further development has been
reported in the field of intramolecular amination. Very recently, Chen et al. described an annulation
reaction of 3-bromo-2-oxindoles generating spirocyclic oxindoles, in which a cinchona alkaloid
catalyzed amination was involved [27]. Thus, the potential application of simpler 3-H-2-oxindole
precursors, which would provide the spirooxindole derivatives via a challenging intramolecular
oxidative amination approach (pathway (4)), has not succeeded [28,29].
0
Scheme 1. Strategies for the 3,2 -pyrrolidinyl spirooxindole synthesis.
On the other hand, oxidative C–H/N–H coupling is a direct approach for the effective
construction of C-N bonds [30
use of transition metals, which has hindered their practical application [30
development of new C-N bond formation reactions under metal-free conditions is also in high
demand [36
41]. Recently, the catalytic system with I− or I2 and a terminal oxidant has emerged as
an environmentally benign oxidative system for a range of transformations, such as etherification,
lactonization, and others [42 51]. Based on our continuing interest in the synthesis of 2-oxindole
derivatives and the application of iodine/iodide catalysis [52 57], we herein report our progress in
–
35]. However, most of the existing methods typically require the
–
35]. Therefore, the
–
–
–
the TBAI/H2O2 catalyzed intramolecular oxidative amination of 3-aminoalkyl 2-oxindoles to give
3,20-pyrrolidinyl-spirooxindoles and their 6/7-membered analogs [58–62].
2. Results and Discussion
To explore the possibility of the proposed intramolecular C-N bond formation process, our
investigation began with a screening of several iodides to evaluate their catalytic activity under different
reaction conditions (Table 1). The model reaction of (3-(benzylamino)propyl)-2-oxindole (1a) was

Molecules 2018, 23, 2265
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firstly performed with the commonly used oxidant TBHP (entries 1–3). While the desired cyclization
product 10-benzylspiro[indoline-3,20-pyrrolidin]-2-one (2a) could be obtained, only moderate yields
were observed. To our delight, when H2O2 was used as the terminal oxidant, a slightly better result
(62% yield) was obtained with TBAI as the optimal iodide source in CH3CN (entries 4–5). Subsequently,
a survey of other solvents was carried out (entries 6–9). The results indicated that changing the solvent
has a significant effect on the reaction. Among the solvents screened, toluene emerged as the most
suitable medium in terms of high chemical yield (79%) and short reaction time (30 min) (entry 9).
Table 1. Studies and optimization of the reaction paramaters1.
◦
Entry
[I]
Oxidant
Solvent
Temp. ( C)
Yield (%) 2
1 2,3
2 2,3
3
4
5
41 4
33 5
56 4
58 4
62 4
33 4
56 6
64 6
79
TBAI
I2
NaI
TBHP
TBHP
TBHP
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O
H2O
H2O
CH3CN
CH3CN
H2O
MeOH
THF
60
60
RT
RT
RT
RT
RT
RT
RT
NaI
TBAI
TBAI
TBAI
TBAI
TBAI
6
7
8
9 2,7
Toluene
1
Unless noted otherwise, all the reactions were conducted with 3-(3-(benzylamino)-propyl)-2-oxindole (1a
,
0.1 mmol), catalyst (0.01 mmol), oxidant (6.0 equiv.) in the indicated solvent (1 mL) for 30 min. Isolated yields
2
3
4
5
are given. Catalyst loading: 20 mol
·
%. Oxidant amount: 2.0 equiv. Reaction time: 5 h. Reaction time: 4 h.
6
7
Reaction time: 3.5 h. Solvent volume: 0.5 mL.
The results with different substrates under the optimized conditions that probed the scope of this
transformation are summarized in Scheme 2. A variety of substituted 3-aminopropanyl- 2-oxindoles
1b
substituents on the oxindole ring were examined. Gratifyingly, all of these substrates afforded the
desired cyclization products 2b in good to high yields. It is noteworthy that the substituents on the
–n, including those bearing electron-withdrawing (F, Cl, Br, CF3) and electron-donating (CH3)
–n
amino group did not much influence the yield of the reaction and a good yield of 2n was obtained when
an N-Ph substrate was used. However, for 2-oxindoles with longer aminoalkyl chains (compounds
2o–p), diminished yields were observed for the 6-membered and 7-membered spirooxindoles,
respectively. The configuration of products was also confirmed by the X-ray crystallographic analysis
of product 2k.

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R'
NH
n
TBAI (20 mol%)
H2O2 (6 equiv.)
n
N
R'
O
R
O
R
Toluene, RT, 30 min
N
N
H
H
1a-n
2a-n
Br
N
N
N
N
N
Cl
Bn
O
Bn
O
Bn
O
Bn
O
Bn
O
N
H
N
H
N
N
N
Cl
F
H
H
H
2e, 61%
2a, 79%
2b, 49%
2c, 46%
2d, 52%
F
O
N
N
N
Bn
O
N
O
O
O
N
H
N
N
N
H
H
H
2f, 70%b
2g, 79%
2i, 37%
2h, 56%
CF3
Br
Cl
N
O
N
N
O
O
N
H
N
F
N
H
H
2l, 56%
2k, 79%
2j, 74%
CF3
N
N
N
N
Bn
O
Bn
O
Ph
O
O
N
N
H
N
Cl
N
H
H
H
2m, 52%
2n, 72%
2o, 34%
2p, 15%
Scheme 2. Investigations on the substrate scope.
In order to demonstrate the synthetic utility of this methodology, we next performed the selective
reduction of the amide by using borane. Spiro[indoline-3,20-pyrrolidine]
, a core structure found in
3
several natural products and pharmaceutical agents [63], was obtained in 53% yield (Scheme 3).
Scheme 3. Selective reduction of the cyclization product.
Some control experiments were conducted in order to elucidate the mechanism. Previous
reports [58–62] have suggested that a radical process was involved in iodide/oxidant catalyzed
C-N bond formation. However, when a stoichiometric amount of radical inhibitors, like TEMPO,
BHT and hydroquinone, was used, the cyclization of 1a proceeded smoothly and afforded the desired
product 2a in comparable yields (Scheme 4), indicating a complete different pathway.

Molecules 2018, 23, 2265
5 of 16
Scheme 4. Control experiments.
On the basis of the experimental results and recent studies [64
–
66], a possible stepwise mechanism
is proposed (Scheme 5). First, two hypervalent iodine species, i.e., IO– and IO2 were likely generated
by the oxidation of iodide with H2O2. Those hypervalent iodines then reacted with aminoalkyl
−
2-oxindoles
1
to form an iodoamino intermediate
A
, which was in equilibrium with its enolate
B.
The latter readily underwent an intramolecular substitution to afford the cyclization product
2, while
releasing the iodide, which further underwent oxidation to regenerate the reactive hypervalent
iodine species.
Scheme 5. The proposed mechanism.
We had an initial predisposition toward using chiral iodide salts because of their easy
preparation from enantiopure amines and well-known role as phase-transfer catalysts in asymmetric
transformations [67
–
69]. Other catalytic use, particularly for asymmetric C-N bond formations, has
as chiral
been quite limited. Thus we prepared several cinchona alkaloid-based iodide salts 4a
–
c
quaternary ammonium iodide salts, and tested their stereocontrol in this reaction with hydrogen
peroxide as an environmentally benign oxidant (Scheme 6).
Scheme 6. Preliminary experiments applying chiral iodide catalysts.

Molecules 2018, 23, 2265
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All those tested catalysts gave good results, with an average yield of 60%, however, no
enantioselectivity was observed. Thus, a more detailed screening of other quaternary ammonium
iodide salts may be needed for this transformation.
3. Materials and Methods
3.1. Chemicals and Instruments
Unless otherwise noted, all reagents were obtained from commercially suppliers and were used
without further purification. All reactions were carried out under argon atmosphere using Schlenk
techniques. Oxindoles
1 were obtained from commercially suppliers or prepared according to the
literature procedures. TBAI were obtained from commercially suppliers. TLC analysis was performed
on glass-baked silica plates and visualized with UV light. Column chromatography was performed on
1
silica gel (200–300 mesh) using petroleum ether/ethyl acetate/ dichloromethane/methanol. H-, and
13C-NMR spectra were obtained on Bruker 300 MHz, 400 MHz or 500 MHz NMR spectrometer in the
deuterated solvents indicated (Bruker, Billerica, MA, USA). Chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard. The following abbreviations
were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
h = heptet, m = multiplet. All first-order splitting patterns were assigned on the basis of the appearance
of the multiplet. Splitting patterns that could not be easily interpreted are designated as multiplet (m)
or (br). Melting points were measured without correction on a Beijing Tech X-4 apparatus (Beijing Tech
Instrument Co., Ltd., Beijing, China). IR spectra were recorded on a Nicolet 6700 FT-IR spectrometer
(Thermo Fisher Scientific, Waltham, MA, USA). HRMS were obtained using electrospray ionization
(ESI) mass spectrometer (Exactive, Thermo Fisher Scientific, Waltham, MA, USA).
3.2. Synthetic Procedures
3.2.1. General Procedure for Synthesis of 1
To a mixture of indolyl propionic acid [64] (10.0 mmol, 1.9 g) and triethylamine (20.0 mmol,
2.8 mL) in dichloromethane (70 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo
[4,5-b]pyridinium 3-oxid hexafluorophosphate (12.0 mmol, 4.6 g) and benzylamine (12.0 mmol,
1.3 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane
(200 mL). The organic layer was washed by water (200 mL
×
2), dried over anhydrous sodium
sulfate and evaporated to afford the intermediate N-benzyl-3-(1H-indol-3-yl)propanamide without
further purification. N-Benzyl-3-(1H-indol-3-yl)propanamide (8.0 mmol, 2.3 g) was dissolved in
dry tetrahydrofuran (40 mL) under argon, and then a solution of lithium aluminum hydride
(32.0 mmol, 12.8 mL, 2.5 M in THF) was added dropwise. The mixture was heated to reflux
overnight and then cooled to room temperature. To the vigorously stirring mixture were
added H2O (4 mL), 15% NaOH (4 mL), H2O (4 mL
×
3) at 0 ◦C. After being stirred at 0 ◦C
for another 10 min, the mixture was filtered through celite, the white filter cake was washed
with methanol and the filtrate was concentrated in vacuum. The crude was purified by silica
column chromatography (elute: dichloromethane /methanol 10/1, with 1% NH4OH) to afford
the intermediate N-benzyl-3-(1H-indol-3-yl)- propan-1-amine[70] as a yellow oil. To the solution
of N-benzyl-3-(1H-indol-3-yl)propan-1-amine (6.9 mmol,1.8 g) in dimethyl sulfoxide (20.7 mmol,
1.5 mL) and methanol (0.3 mL) was added concentrated hydrochloric acid (20.7 mmol, 1.7 mL) slowly
◦
◦
at 0 C. The resulting mixture was stirred at 50 C for 5 h. After cooling to room temperature,
the mixture was diluted with ethyl acetate (50 mL) and washed with H2O (50 mL). Aqueous
phase was adjust to pH = 7 by ammonium hydroxide and extracted with ethyl acetate (50 mL
×
2). The organic was dried over anhydrous sodium sulfate, evaporated and purified by silica
column chromatography (elute: dichloromethane /methanol 10/1, with 1% NH4OH) to afford the

Molecules 2018, 23, 2265
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desired product 3-(3-(benzylamino)propyl)indolin-2-one (1a) [71]. See the Supplementary Materials
for the details.
3.2.2. General Procedure for the Synthesis of Compounds 2
To the mixture of oxindole
1 (0.10 mmol) and TBAI (20 mol%) in toluene (0.5 mL) was added 35%
H2O2 (6 equiv.), the reaction mixture was stirred at room temperature until completion the reaction.
After that time, the mixture was quenched by saturated sodium thiosulfate solution (1 mL) and diluted
with dichloromethane (10 mL). The organic layer was washed by water (10 mL
×
2), dried over
anhydrous sodium sulfate and evaporated to afford the crude product. The crude was purified by
silica column chromatography (elute: petroleum ether/ethyl acetate 2/1) to give the pure desired
products 2.
3.3. Characterization Data
3-(3-(Benzylamino)propyl)indolin-2-one (1a): Yellow oil. 1H-NMR (300 MHz, CDCl3)
δ 8.47 (br, 1H),
7.31–7.30 (m, 4H), 7.24–7.16 (m, 3H), 7.03–6.98 (t, J = 7.5, 1H), 6.86–6.84 (d, J = 7.5 Hz, 1H), 3.78 (s, 2H),
3.49–3.45 (t, J = 6.0 Hz, 1H), 2.68–2.63 (m, 2H), 2.49 (br, 1H), 2.05–1.98 (dd, J = 14.1, 8.1 Hz, 2H), 1.66–1.53
(m, 2H). 13C-NMR (126 MHz, DMSO-d6)
121.2, 109.2, 51.3, 47.3, 44.7, 27.2, 23.6. IR
δ
178.7, 142.7, 136.2, 129.4, 129.0, 128.3, 127.7, 127.6, 124.0,
ν
(KBr, film, cm−1): 3203, 3061, 2929, 2856, 1683, 1471, 751.
max
HRMS (ESI): calcd for C18H21ON2+ [M + H]+: 281.1648, found: 281.1647.
◦
1
3-(3-(benzylamino)propyl)-4-bromoindolin-2-one (1b): Pink solid, m.p. 83–85 C. H-NMR (300 MHz,
DMSO-d6) 10.70 (s, 1H), 8.56 (br, 1H), 7.43–7.38 (m, 5H), 7.16–7.14 (d, J = 5.4 Hz, 2H), 6.86–6.84
δ
(d, J = 3.9 Hz, 1H), 4.01 (s, 2H), 3.60 (s, 1H), 2.84–2.79 (t, J = 7.8 Hz, 2H), 2.21–2.18 (m, 1H), 2.02–1.98
(m, 1H), 1.42–1.37 (m, 2H). 13C-NMR (126 MHz, DMSO-d6)
128.49, 127.8, 124.6, 118.4, 108.7, 50.2, 46.5, 46.2, 24.6, 21.4. IR
1698, 1458, 1019, 699. HRMS (ESI): calcd for C18H20ON2Br+ [M + H]+: 359.0754, found: 359.0750.
δ
177.3, 144.8, 133.0, 130.0, 129.8, 128.54,
ν
max (KBr, film, cm−1): 3360, 2920, 2848,
3-(3-(benzylamino)propyl)-5-chloroindolin-2-one (1c): Orange solid, m.p. 89–91 ◦C. 1H-NMR (500 MHz,
DMSO-d6)
1H), 6.85–6.82 (m,1H), 4.02 (s, 2H), 3.53–3.51 (t, J = 5.5 Hz, 1H), 2.83–2.80 (m, 2H), 1.89–1.85 (m, 2H),
1.60–1.58 (m, 2H). 13C-NMR (126 MHz, DMSO-d6)
178.2, 141.7, 133.0, 131.5, 129.8, 128.6, 128.5, 127.5,
125.4, 124.3, 110.6, 50.3, 46.5, 44.8, 26.6, 22.2. IR
max (KBr, film, cm−1): 3446, 2920, 2849, 1702, 1478, 699.
HRMS (ESI): calcd for C18H20ON2Cl+ [M + H]+: 315.1259, found: 315.1257.
δ 10.59 (s, 1H), 8.81 (br, 1H), 7.51–7.48 (m, 2H), 7.39–7.36 (m, 4H), 7.24–7.21 (t, J = 8.0 Hz,
δ
ν
◦
1
3-(3-(Benzylamino)propyl)-6-fluoroindolin-2-one (1d): Pink solid, m.p. 81–83 C. H-NMR (500 MHz,
DMSO-d6) 10.62 (s, 1H), 9.05 (br, 1H), 7.52–7.51 (m, 2H), 7.40 (m, 1H), 7.39–7.38 (m, 2H), 7.30–7.26
(m, 1H), 6.77–6.74 (m, 1H), 6.66–6.64 (m, 1H), 4.04 (s, 2H), 3.47–3.45 (t, J = 5.5 Hz, 1H), 2.85–2.82
(t, J = 6.5 Hz, 2H), 1.91–1.82 (m, 2H), 1.64–1.63 (m, 2H). 13C-NMR (126 MHz, DMSO-d6)
178.9, 163.0,
161.0, 144.3, 144.2, 132.5, 129.9, 128.7, 128.5, 125.33, 125.26, 125.02, 125.00, 107.3, 107.1, 97.5, 97.3, 50.1,
δ
δ
46.4, 44.0, 26.9, 22.0. 19F NMR (377 MHz, DMSO-d6)
−
113.9(s). IR ν
max (KBr, film, cm−1): 3359, 3195,
2920, 2849, 1702, 1469, 1340. HRMS (ESI): calcd for C18H20ON2F+ [M + H]+: 299.1554, found: 299.1554.
3-(3-(Benzylamino)propyl)-6-chloroindolin-2-one (1e): Orange solid, m.p. 89–91 ◦C. 1H-NMR (300 MHz,
DMSO-d6)
(dd, J = 7.8, 1.5 Hz, 1H), 6.87–6.86 (d, J = 1.5 Hz, 1H), 4.04 (s, 2H), 3.50–3.47 (t, J = 5.7 Hz, 1H), 2.85–2.80
(t, J = 7.8 Hz, 2H), 1.91–1.81 (m, 2H), 1.65–1.63 (m, 2H). 13C-NMR (75 MHz, DMSO)
178.4, 144.3, 132.5,
max (KBr, film, cm−1):
δ 10.64 (s, 1H), 9.07 (br, 1H), 7.53–7.50 (m, 2H), 7.43–7.38 (m, 3H), 7.30–7.27 (m, 1H), 7.01–6.87
δ
131.9, 129.8, 128.6, 128.5, 128.1, 125.5, 120.8, 109.3, 50.0, 46.3, 44.1, 26.7, 21.9. IR
ν
3360, 3188, 2920, 2848, 1703, 1486, 749. HRMS (ESI): calcd for C18H20ON2Cl+ [M + H]+: 315.1259,
found: 315.1258.
3-(3-(Benzylamino)propyl)-7-methylindolin-2-one (1f): White solid, m.p. 202–204 ◦C. 1H-NMR (300 MHz,
DMSO-d6)
δ 10.45 (s, 1H), 9.00 (br, 1H), 7.51–7.48 (m, 2H), 7.45–7.40(m, 3H), 7.10–7.07 (d, J = 7.2 Hz,
1H), 7.01–6.98 (d, J = 7.8 Hz, 1H), 6.90–6.85 (t, J = 7.5 Hz, 1H), 4.07 (s, 2H), 3.49–3.48 (t, J = 5.4 Hz, 1H),

Molecules 2018, 23, 2265
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2.90–2.85 (m, 2H), 2.19 (s, 3H), 1.91–1.82 (m, 2H), 1.68–1.61 (m, 2H). 13C-NMR (126 MHz, DMSO-d6)
δ
179.0, 141.3, 132.2, 129.9, 129.0, 128.81, 128.78, 128.6, 121.3, 118.5, 50.1, 46.5, 44.8, 26.8, 22.0, 16.5. IR
+
ν
(KBr, film, cm−1): 3392, 2946, 2838, 1702, 1458, 694. HRMS (ESI): calcd for C19H23ON2 [M + H]+:
max
295.1805, found: 295.1804.
1
3-(3-((4-Methylbenzyl)amino)propyl)indolin-2-one (1g): Yellow oil. H-NMR (300 MHz, CDCl3)
δ
8.04
(br, 1H), 7.22–7.10 (m, 6H), 7.03–6.98 (t, J = 7.2 Hz, 1H), 6.85–6.83 (m, 1H), 3.71 (s, 2H), 3.49–3.46
(t, J = 6.0 Hz, 1H), 2.65–2.60 (t, J = 7.2 Hz, 2H), 2.32 (s, 3H), 2.02–1.97 (m, 2H), 1.72 (br, 1H), 1.64–1.52
(m, 2H). 13C-NMR (126 MHz, CDCl3)
109.6, 53.5, 48.9, 45.7, 28.1, 26.0, 21.1. IR
751. HRMS (ESI): calcd for C19H23ON2+ [M + H]+: 295.1805, found: 295.1804.
δ 180.2, 141.6, 136.9, 136.5, 129.5, 129.1, 128.1, 127.8, 124.1, 122.2,
ν
(KBr, film, cm−1): 3204, 3022, 2923, 2857, 1706, 1620, 1486,
max
1
3-(3-((4-Methoxybenzyl)amino)propyl)indolin-2-one (1h): Yellow oil. H-NMR (300 MHz, DMSO-d6)
δ
10.34 (br, 1H), 7.23–7.13 (m, 4H), 6.96–6.91 (t, J = 7.5 Hz, 1H), 6.85–6.81 (m, 3H), 3.71 (s, 3H), 3.56 (s, 2H),
3.42–3.38 (t, J = 5.7 Hz, 1H), 2.97 (br, 1H), 2.46–2.41(t, J = 7.2 Hz, 2H), 1.89–1.79 (m, 2H), 1.43–1.37
(m, 2H). 13C-NMR (126 MHz, DMSO-d6)
δ 178.9, 158.0, 142.8, 132.6, 129.7, 129.1, 127.5, 123.9, 121.2,
113.4, 109.1, 54.9, 52.2, 48.3, 45.0, 27.7, 25.5. IR ν
max (KBr, film, cm−1): 3197, 2933, 2835, 1698, 1471, 1177,
751. HRMS (ESI): calcd for C19H23O2N2+ [M + H]+: 311.1765, found: 311.1747.
3-(3-((4-Fluorobenzyl)amino)propyl)indolin-2-one (1i): Yellow solid, m.p. 101–103 ◦C 1H-NMR (300 MHz,
DMSO-d6)
1H), 6.84–6.82 (d, J = 7.8 Hz, 1H), 4.05 (s, 2H), 3.50–3.48 (t, J = 5.7 Hz, 1H), 2.87–2.82 (t, J = 7.8 Hz, 2H),
1.89–1.82 (m, 2H), 1.67–1.59 (m, 2H). 13C-NMR (101 MHz, DMSO-d6)
178.5, 163.4, 161.0, 142.7, 132.3,
132.3, 129.2, 128.6, 127.6, 124.0, 121.2, 115.4, 115.2, 109.2, 49.1, 46.2, 44.5, 26.9, 22.0. 19F NMR (377 MHz,
DMSO-d6) δ −113.9(s). IR
(KBr, film, cm−1): 3361, 2920, 2849, 1703, 1471, 1226, 751. HRMS (ESI):
δ 10.42 (s, 1H), 8.86 (br, 1H), 7.57–7.52 (m, 2H), 7.28–7.15 (m, 4H), 6.98–6.93 (t, J = 7.5 Hz,
δ
ν
max
calcd for C18H20ON2F+ [M + H]+: 299.1554, found: 299.1553.
1
3-(3-((4-Chlorobenzyl)amino)propyl)indolin-2-one (1j): Yellow oil. H-NMR (300 MHz, CDCl3)
δ
8.76 (br,
1H), 7.31–7.28 (m, 1H), 7.25–7.17(m, 5H), 7.03–6.98 (t, J = 7.5 Hz, 1H), 6.87–6.84 (d, J = 7.8 Hz, 1H),
3.72 (s, 2H), 3.49–3.45 (t, J = 5.7 Hz, 1H), 2.64–2.59 (t, J = 7.2 Hz, 2H), 2.24–2.19 (m, 1H), 2.04–1.97 (dd,
J = 14.1, 7.8 Hz, 2H), 1.62–1.51 (m, 2H). 13C-NMR (126 MHz, CDCl3) δ 180.2, 141.6, 138.3, 132.7, 129.5,
129.4, 128.5, 127.9, 124.1, 122.3, 109.7, 53.0, 48.7, 45.7, 28.0, 25.9. IR
ν
max (KBr, film, cm−1): 3200, 2932,
1714, 1471, 1015, 751. HRMS (ESI): calcd for C18H20ON2Cl+ [M + H]+: 315.1259, found: 315.1256.
◦
1
3-(3-((4-Bromobenzyl)amino)propyl)indolin-2-one (1k): Yellow solid, m.p. 102–104 C. H-NMR (300
MHz, DMSO-d6) 10.41 (s, 1H), 8.33 (br, 1H), 7.60–7.58 (d, J = 8.1 Hz, 2H), 7.44–7.41 (d, J = 8.1 Hz,
δ
2H), 7.27–7.24 (d, J = 7.2 Hz, 1H), 7.20–7.15 (t, J = 7.8 Hz, 1H), 6.97–6.92 (t, J = 7.5 Hz, 1H), 6.84–6.81
(d, J = 7.8 Hz, 1H), 3.96 (s, 2H), 3.48–3.44 (t, J = 5.7 Hz, 1H), 2.80–2.74 (t, J = 7.5 Hz, 2H), 1.91–1.80
(m, 2H), 1.64–1.55 (m, 2H). 13C-NMR (75 MHz, DMSO-d6)
δ 178.6, 142.7, 131.8, 131.3, 129.3, 127.7, 124.0,
121.6, 121.2, 109.2, 49.8, 46.8, 44.7, 26.9, 22.7. IR
ν
(KBr, film, cm−1): 3366, 3197, 2922, 2850, 1702,
max
1622, 1471, 753. HRMS (ESI): calcd for C18H20ON2Br+ [M + H]+: 359.0754, found: 359.0740.
1
6-Fluoro-3-(3-((4-(trifluoromethyl)benzyl)amino)propyl)indolin-2-one (1l): Orange oil. H-NMR (300 MHz,
DMSO-d6)
6.81–6.67 (m, 2H), 3.77 (s, 2H), 3.48–3.44 (t, J = 6.3Hz, 1H), 2.56 (s, 1H), 1.95–1.87 (m, 3H), 1.49–1.41
(m, 3H). 13C-NMR (126 MHz, DMSO-d6)
179.8, 163.3, 161.4, 146.5, 144.8, 144.7, 128.9, 125.9, 125.6,
125.5, 125.30, 125.27, 107.7, 107.5, 97.9, 97.7, 52.8, 49.0, 45.0, 28.1, 26.0. 19F NMR (377 MHz, DMSO-d6)
δ −60.86(s), 113.93 (s). IR
max (KBr, film, cm−1): 3633, 2952, 2855, 1717, 1558, 1329, 1020, 849, 737.
HRMS (ESI): calcd for C19H19ON2F4+ [M + H]+: 367.1428, found: 367.1422.
δ 10.56 (br, 1H), 7.69–7.66 (d, J = 7.8 Hz, 2H), 7.58–7.55 (d, J = 7.8 Hz, 2H), 7.30–7.25 (m, 1H),
δ
−
ν
1
6-Chloro-3-(3-((4-(trifluoromethyl)benzyl)amino)propyl)indolin-2-one (1m): Orange oil. H-NMR (300 MHz,
DMSO-d6) 10.57 (br, 1H), 7.71–7.68 (d, J = 7.8 Hz, 2H), 7.58–7.56 (d, J = 7.8 Hz, 2H), 7.30–7.28 (m, 1H),
7.05–7.02 (m, 1H), 6.89 (s, 1H), 3.77 (s, 2H), 3.52–3.48 (t, J = 5.7 Hz, 1H), 2.57 (s, 1H), 1.97–1.86 (m, 3H),
1.50–1.38 (m, 3H). 13C-NMR (126 MHz, DMSO-d6)
178.9, 146.1, 144.3, 131.8, 128.6, 128.4, 125.3, 124.83,
δ
δ

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124.80, 120.8, 109.2, 52.3, 48.5, 44.6, 27.5, 25.5. 19F NMR (377 MHz, DMSO-d6) δ −60.79 (s). IR
ν
max
(KBr, film, cm−1): 3419, 3181, 2952, 2800, 1704, 1619, 1326, 1127, 1068, 737. HRMS (ESI): calcd for
C19H19ON2ClF3+ [M + H]+: 382.1133, found: 383.1126.
3-(3-(Phenylamino)propyl)indolin-2-one (1n): Pale yellow solid, m.p. 105–107 ◦C. 1H-NMR (500 MHz,
CDCl3)
δ 8.87 (s, 1H), 7.24–7.22 (m, 2H), 7.17–7.14 (t, J = 7.5 Hz, 2H), 7.06–7.03 (t, J = 7.5 Hz, 1H),
6.93–6.91 (d, J = 8.5 Hz, 1H), 6.70–6.67 (m, 1H), 6.57–6.56 (d, J = 8.5 Hz, 2H), 3.67 (br, 1H), 3.56–3.54
(t, J = 5.5 Hz, 2H), 3.14–3.11 (t, J = 7.0 Hz, 2H), 2.13–2.09 (m, 2H), 1.77–1.66 (m, 2H). 13C-NMR (126 MHz,
CDCl3)
ν
δ
180.4, 148.2, 141.6, 129.3, 129.2, 128.0, 124.0, 122.4, 117.2, 112.7, 109.8, 45.7, 43.7, 27.9, 25.7. IR
max (KBr, film, cm−1): 3368, 3210, 2925, 2855, 1707, 1602, 1471, 749. HRMS (ESI): calcd for C17H19ON2
+
[M + H]+: 267.1492, found: 267.1494.
3-(4-(Benzylamino)butyl)indolin-2-one (1o): Pale yellow solid, m.p. 172–173 C. 1H-NMR (300 MHz,
DMSO-d6) 10.41 (s, 1H), 8.66 (br, 1H), 7.52–7.50 (m, 2H), 7.38–7.36 (m, 3H), 7.26–7.24 (d, J = 7.5 Hz,
◦
δ
1H),7.19–7.14 (t, J = 7.5 Hz, 1H), 6.96–6.91 (t, J = 7.2 Hz, 1H), 6.84–6.82 (d, J = 7.5 Hz, 1H), 3.99 (s, 2H),
3.43–3.39 (m, 1H), 2.77–2.71 (t, J = 7.5 Hz, 2H), 1.85–1.76 (m, 2H), 1.65–1.60 (m, 2H), 1.32–1.24 (m, 2H).
13C-NMR (101 MHz, DMSO-d6)
δ 178.7, 142.7, 133.3, 129.7, 129.5, 128.42, 128.38, 127.5, 123.9, 121.1,
109.1, 50.2, 46.4, 44.9, 29.5, 25.8, 22.6. IR ν
max (KBr, film, cm−1): 3359, 2920, 2849, 1702, 1472, 751. HRMS
(ESI): calcd for C19H23ON2+ [M + H]+: 295.1805, found: 295.1802.
3-(5-(Benzylamino)pentyl)indolin-2-one (1p): Yellow oil. 1H-NMR (300 MHz, CDCl3)
δ 8.47 (br, 1H),
7.34–7.28 (m, 5H), 7.24–7.20 (m, 2H), 7.05–7.00 (m, 1H), 6.90–6.88 (d, J = 8.1 Hz, 1H), 3.80 (s, 2H),
3.49–3.45 (t, J = 6.0 Hz, 1H), 2.65–2.60 (t, J = 6.9 Hz, 2H), 2.22 (br, 1H), 2.00–1.95 (m, 2H), 1.55–1.48
(m, 2H), 1.45–1.36 (m, 4H). 13C-NMR (126 MHz, CDCl3)
δ
180.2, 141.5, 139.7, 129.7, 128.4, 128.2, 127.8,
127.0, 124.1, 122.2, 109.6, 53.8, 49.0, 45.9, 30.4, 29.5, 27.2, 25.5. IR
max (KBr, film, cm−1): 3197, 3061, 2830,
2856, 1683, 1506, 1471, 749. HRMS (ESI): calcd for C20H25ON2+ [M + H]+: 309.1961, found: 309.1959.
ν
0
0
1 -Benzylspiro[indoline-3,2 -pyrrolidin]-2-one (2a): White solid, 21.9 mg (from 0.10 mmol), 79% yield, m.p.
154–156 C. 1H-NMR (500 MHz, DMSO-d6)
(m, 2H), 7.20–7.18 (m, 4H), 7.03–7.00 (t, J = 7.5 Hz, 1H), 6.80–6.79 (d, J = 7.5 Hz, 1H), 3.31–3.25 (m, 2H),
2.98–2.91 (m, 2H), 2.14–2.06 (m, 2H), 2.04–1.98 (m, 2H). 13C-NMR (126 MHz, DMSO-d6)
179.7, 142.4,
(KBr,
δ 10.28 (s, 1H), 7.35–7.33 (d, J = 7.5 Hz, 1H), 7.26–7.22
◦
δ
139.3, 130.7, 128.7, 128.1, 127.9, 126.8, 123.8, 121.9, 109.4, 70.8, 53.1, 50.4, 35.8, 21.7. IR
ν
max
−
film, cm−1): 3207, 3061, 3028, 2925, 2852, 1706, 1620, 1470, 749. HRMS (ESI): calcd for C18H17ON2
[M − H]−: 277.1364, found: 277.1364.
10-Benzyl-4-bromospiro[indoline-3,20-pyrrolidin]-2-one (2b): White solid, 17.6 mg (from 0.10 mmol), 49%
◦
1
yield, m.p. 169–171 C. H-NMR (500 MHz, CDCl3)
δ 8.74 (s, 1H), 7.32–7.31 (d, J = 7.5 Hz, 2H),
7.26–7.15 (m, 4H), 7.08–7.05 (m, 1H), 6.81–6.80 (dd, J = 7.5, 1.0 Hz, 1H), 3.59–3.49 (m, 2H), 3.17–3.10
(m, 2H), 2.68–2.63 (m, 1H), 2.25–2.18 (m, 3H). 13C-NMR (126 MHz, CDCl3) δ 181.3, 143.2, 139.5, 130.1,
128.7, 128.5, 128.0, 127.4, 126.8, 119.9, 108.9, 72.5, 53.4, 51.1, 32.8, 23.1. IR ν
max (KBr, film, cm−1): 3213,
3086, 3027, 2964, 2831, 1717, 1613, 1447, 736. HRMS (ESI): calcd for C18H18ON2Br+ [M + H]+: 357.0597,
found: 354.0594.
10-Benzyl-5-chlorospiro[indoline-3,20-pyrrolidin]-2-one (2c): White solid, 14.3 mg (from 0.10 mmol), 46%
◦
1
yield, m.p. 149–151 C. H-NMR (500 MHz, CDCl3)
6.79–6.78 (d, J = 8.0 Hz, 1H), 3.52–3.45 (m, 2H), 3.18–3.13 (m, 1H), 3.10–3.07 (m, 1H), 2.35–2.31 (m, 1H),
2.24–2.21 (m, 1H), 2.17–2.08 (m, 2H). 13C-NMR (126 MHz, CDCl3)
181.2, 139.5, 138.9, 133.4, 128.6,
max (KBr, film, cm−1): 3213, 3063,
δ 8.47 (s, 1H), 7.34 (s, 1H), 7.25–7.19 (m, 6H),
δ
128.5, 128.2, 128.1, 127.0, 124.6, 110.8, 71.7, 53.9, 51.4, 37.0, 22.3. IR
3029, 2963, 2840, 1717, 1619, 1475, 733. HRMS (ESI): calcd for C18H18ON2Br+ [M + H]+: 313.1102,
ν
found: 313.1102.
10-Benzyl-6-fluorospi◦ro[indoline-3,20-pyrrolidin]-2-one (2d): White solid, 15.3 mg (from 0.10 mmol), 52%
δ 8.88 (s, 1H), 7.33–7.29 (m, 1H), 7.23–7.15 (m, 5H),
yield, m.p. 141–143 C. 1H-NMR (300 MHz, CDCl3)
6.81–6.74 (m, 1H), 6.65–6.62 (dd, J = 14.5, 2.1 Hz, 1H), 3.52–3.41 (m, 2H), 3.22–3.06 (m, 2H), 2.35–2.04

Molecules 2018, 23, 2265
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(m, 4H). 13C-NMR (126 MHz, CDCl3)
δ
182.1, 164.1, 162.2, 142.5, 142.4, 139.0, 128.5, 128.1, 126.9, 126.7,
126.6, 125.3, 125.2, 109.2, 109.0, 98.7, 98.4, 71.2, 53.8, 51.2, 36.7, 22.1. 19F NMR (377 MHz, CDCl3)
δ
−
111.7 (s). IR
ν
max (KBr, film, cm−1): 3226, 3063, 3029, 2965, 2836, 1717, 1622, 1456, 733. HRMS (ESI):
calcd for C18H18ON2F+ [M + H]+: 297.1398, found: 297.1400.
10-Benzyl-6-chlorospiro[indoline-3,20-pyrrolidin]-2-one (2e): White solid, 19.0 mg (from 0.10 mmol), 61%
yield, m.p. 170–172 ◦C. 1H-NMR (500 MHz, CDCl3)
8.67 (s, 1H), 7.30–7.28 (m, 1H), 7.25–7.21 (m,
2H), 7.20–7.18 (m, 3H), 7.08–7.05 (m, 1H), 6.89 (s, 1H), 3.50–3.42 (m, 2H), 3.19–3.14 (m, 1H), 3.10–3.06
(m, 1H), 2.35–2.29 (m, 1H), 2.27–2.22 (m, 1H), 2.17–2.07 (m, 2H). 13C-NMR (126 MHz, CDCl3)
181.6,
max (KBr,
δ
δ
142.2, 139.0, 134.3, 129.8, 128.5, 128.1, 127.0, 125.2, 122.8, 110.5, 71.3, 53.9, 51.2, 36.7, 22.2. IR
ν
film, cm−1): 3232, 3064, 3029, 2965, 2834, 1717, 1615, 1455, 732. HRMS (ESI): calcd for C18H18ON2Cl +
[M + H]+: 313.1102, found: 313.1101.
10-Benzyl-7-methylspiro[indoline-3,20-pyrrolidin]-2-one (2f): White solid, 20.5 mg (from 0.10 mmol), 70%
◦
yield, m.p. 148–150 C. 1H-NMR (500 MHz, CDCl3)
δ
8.83 (s, 1H), 7.23–7.16 (m, 6H), 7.07–7.05 (m, 1H),
7.03–7.00 (m, 1H), 3.51–3.42 (m, 2H), 3.20–3.15 (m, 1H), 3.10–3.06 (m, 1H), 2.35–2.31 (m, 1H), 2.29 (s, 3H),
2.27–2.21 (m, 1H), 2.19–2.14 (m, 1H), 2.11–2.08 (m, 1H). 13C-NMR (126 MHz, CDCl3)
182.0, 139.9,
δ
139.4, 130.9, 130.0, 128.5, 128.0, 126.8, 122.7, 121.5, 119.0, 72.0, 54.0, 51.2, 36.7, 22.2, 16.2. IR
ν
max (KBr,
+
film, cm−1): 3280, 3061, 3028, 2964, 2837, 1704, 1627, 1458, 732. HRMS (ESI): calcd for C19H21ON2
[M + H]+: 293.1648, found: 293.1648.
10-(4-Methylbenzyl◦)spiro[indoline-3,20-pyrrolidin]-2-one (2g): White solid, 22.7 mg (from 0.10 mmol), 79%
yield, m.p. 96–98 C. 1H-NMR (500 MHz, CDCl3)
δ 9.03 (s, 1H), 7.37–7.36 (d, J = 7.0 Hz, 1H), 7.23–7.20
(t, J = 8.0 Hz, 1H), 7.09–7.06 (m, 3H), 7.03–7.01 (m, 2H), 6.89–6.87 (d, J = 8.0 Hz, 1H), 3.45–3.38 (m, 2H),
3.20–3.15 (m, 1H), 3.09–3.05 (m, 1H), 2.35–2.30 (m, 1H), 2.26 (s, 3H), 2.22–2.04 (m, 3H). 13C-NMR
(126 MHz, CDCl3) δ 182.0, 141.3, 136.3, 136.2, 131.4, 128.7, 128.6, 128.4, 124.1, 122.7, 109.9, 71.7, 53.5,
51.1, 36.6, 22.2, 21.0. IR
ν
(KBr, film, cm−1): 3215, 3025, 2971, 2830, 1706, 1620, 1471, 750. HRMS
max
(ESI): calcd for C19H21ON2+ [M + H]+: 293.1648, found: 293.1647.
10-(4-Methoxybenzyl)spiro[indoline-3,20-pyrrolidin]-2-one (2h): White solid, 17.1 mg (from 0.10 mmol),
56% yield, m.p. 135–137 ◦C. 1H-NMR (500 MHz, CDCl3)
δ 8.52 (s, 1H), 7.37–7.36 (d, J = 7.0 Hz, 1H),
7.24–7.21 (t, J = 7.5 Hz, 1H), 7.10–7.07 (m, 3H), 6.87–6.85 (d, J = 8.0 Hz, 1H), 6.77–6.75 (d, J = 8.0 Hz,
2H), 3.73 (s, 3H), 3.44–3.36 (m, 2H), 3.20–3.15 (m, 1H), 3.09–3.05 (m, 1H), 2.35–2.30 (m, 1H), 2.24–2.21
(m, 1H), 2.18–2.07 (m, 2H). 13C-NMR (126 MHz, CDCl3)
δ
181.6, 158.5, 141.2, 131.5, 131.4, 129.7, 128.6,
(KBr, film, cm−1): 3251, 2962, 2834,
124.2, 122.7, 113.4, 109.8, 71.5, 55.1, 53.3, 51.2, 36.7, 22.2.−IR
ν
max
1700, 1622, 1471, 751. HRMS (ESI): calcd for C19H19ON2 [M − H]−: 307.1452, found: 307.1454.
10-(4-Fluorobenzyl)spiro[indoline-3,20-pyrrolidin]-2-one (2i): White solid, 10.9 mg (from 0.10 mmol), 37%
◦
yield, m.p. 126–127 C. 1H-NMR (500 MHz, CDCl3)
δ 7.89 (s, 1H), 7.36–7.35 (d, J = 7.0 Hz, 1H), 7.24–7.21
(td, J = 7.5, 1.0 Hz, 1H), 7.16–7.13 (m, 2H), 7.10–7.07 (t, J = 7.5 Hz, 1H), 6.92–6.88 (m, 2H), 6.84–6.82
(d, J = 7.5 Hz, 1H), 3.46–3.39 (m, 2H), 3.17–3.13 (m, 1H), 3.07–3.03 (m, 1H), 2.35–2.30 (m, 1H), 2.28–2.20
(m, 1H), 2.18–2.13 (m, 1H), 2.11–2.06 (m, 1H). 13C-NMR (126 MHz, CDCl3) δ 181.6, 162.8, 160.9, 141.1,
134.9, 131.3, 130.1, 130.0, 128.7, 124.1, 122.8, 114.8, 114.7, 109.9, 71.5, 53.2, 51.3, 36.7, 22.2. 19F NMR
(377 MHz, CDCl3) δ −116.1 (s). IR
ν
(KBr, film, cm−1): 3213, 3086, 2964, 2836, 1717, 1622, 1471, 750.
max
HRMS (ESI): calcd for C18H18ON2F+ [M + H]+: 297.1398, found: 297.1395.
10-(4-Chlorobenzyl)spiro[indoline-3,20-pyrrolidin]-2-one (2j): White solid, 23.3 mg (from 0.10 mmol), 74%
◦
yield, m.p. 140–142 C. 1H-NMR (500 MHz, CDCl3)
δ 8.54 (s, 1H), 7.36–7.34 (d, J = 7.5 Hz, 1H), 7.25–7.21
(m, 1H), 7.19–7.18 (m, 2H), 7.13–7.12 (m, 2H), 7.10–7.07 (td, J = 7.5, 0.5 Hz, 1H), 6.88–6.86 (d, J = 7.5 Hz,
1H), 3.46–3.39 (m, 2H), 3.17–3.13 (m, 1H), 3.07–3.04 (m, 1H), 2.36–2.31 (m, 1H), 2.28–2.21 (m, 1H),
2.19–2.13 (m, 1H), 2.12–2.04 (m, 1H). 13C-NMR (126 MHz, CDCl3)
δ
181.5, 141.1, 137.8, 132.5, 131.2,
max (KBr, film, cm−1): 3212, 2925,
2849, 1705, 1622, 1471, 750. HRMS (ESI): calcd for C18H18ON2Cl+ [M + H]+: 313.1102, found: 313.1099.
129.8, 128.7, 128.1, 124.1, 122.7, 109.9, 71.5, 53.2, 51.3, 36.7, 22.2. IR
ν

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10-(4-Bromobenzyl)spiro[indoline-3,20-pyrrolidin]-2-one (2k): White solid, 19.6 mg (from 0.10 mmol), 55%
◦
1
yield, m.p. 140–142 C. H-NMR (500 MHz, CDCl3)
δ 8.36 (s, 1H), 7.35–7.33 (m, 3H), 7.24–7.21
(t, J = 7.5 Hz, 1H), 7.09–7.07 (m, 3H), 6.86–6.85 (d, J = 8.0 Hz, 1H), 3.43–3.38 (m, 2H), 3.17–3.12
(q, J = 7.5 Hz, 1H), 3.07–3.03 (m, 1H), 2.35–2.30 (m, 1H), 2.28–2.20 (m, 1H), 2.19–2.13 (m, 1H), 2.12–2.08
(m, 1H). 13C-NMR (126 MHz, CDCl3)
δ
181.3, 141.1, 138.3, 131.2, 131.1, 130.2, 128.7, 124.2, 122.9, 120.6,
109.8, 71.5, 53.3, 51.3, 36.7, 22.3. IR
ν
max
(KBr, film, cm−1): 3216, 3090, 2925, 2851, 1706, 1621, 1470, 750.
HRMS (ESI): calcd for C18H18ON2Br+ [M + H]+: 357.0597, found: 357.0594.
6-Fluoro-10-(4-(trifluoromethyl)benzyl)spiro[indoline-3,20-pyrrolidin]-2-one (2l): Syrup, 20.5 mg (from 0.10
1
mmol), 56% yield. H-NMR (300 MHz, CDCl3)
δ
8.84 (br, 1H), 7.50–7.47 (d, J = 7.8 Hz, 2H), 7.33–7.27 (m,
3H), 6.79–6.74 (m, 1H), 6.65–6.62 (mz, 1H), 3.51 (s, 2H), 3.19–3.04 (m, 2H), 2.35–2.10 (m, 4H). 13C-NMR
(126 MHz, CDCl3) 181.9, 164.2, 162.23, 143.2, 142.5, 142.4, 129.4, 129.1, 128.8, 128.6, 126.38, 126.36,
δ
125.5, 125.3, 125.2, 125.1, 125.03, 125.00, 124.97, 109.4, 109.2, 98.7, 98.5, 713, 53.4, 51.3, 36.7, 22.2. 19F
NMR (377 MHz, CDCl3) δ −62.4 (s),
−
111.3 (s). IR
ν
(KBr, film, cm−1): 3235, 2964, 2842, 1717, 1619,
max
1458, 1326, 1125, 1067, 1019, 810. HRMS (ESI): calcd for C19H17ON2F4 [M + H]+: 365.1272, found:
+
365.1266.
0
0
6-Chloro-1 -(4-(trifluoromethyl)benzyl)spiro[indoline-3,2 -pyrrolidin]-2-one (2m): Syrup, 19.7 mg (from 0.10
1
mmol), 52% yield. H-NMR (300 MHz, CDCl3)
7.09–7.06 (m, 1H), 6.91–6.90 (m, 1H), 3.51 (s, 2H), 3.17–3.07 (m, 2H), 2.33–2.13 (m, 4H). 13C-NMR (126
δ
8.75 (br, 1H), 7.51–7.47 (m, 2H), 7.33–7.27 (m, 3H),
MHz, CDCl3)
δ 181.5, 143.2, 142.2, 134.5, 129.5, 128.6, 125.09, 125.05, 125.0, 123.0, 110.6, 71.3, 53.5, 51.3,
36.7, 22.3. 19F NMR (377 MHz, CDCl3) δ −62.4 (s). IR
ν
(KBr, film, cm−1):3232, 2963, 2938, 1713,
max
1616, 1486, 1325, 1124, 1066, 812. HRMS (ESI): calcd for C19H17ON2ClF3+ [M + H]+: 381.0976, found:
381.0971.
10-Phenylspiro◦[indoline-3,20-pyrrolidin]-2-one (2n): White solid, 19.0 mg (from 0.10 mmol), 72% yield,
m.p. 140–142 C. 1H-NMR (400 MHz, CDCl3)
δ 9.03 (s, 1H), 7.22–7.18 (td, J = 7.6, 0.8 Hz, 1H), 7.13–7.11
(d, J = 7.6 Hz, 1H), 7.05–7.01 (m, 2H), 7.00–6.96 (m, 1H), 6.89–6.86 (d, J = 8.0 Hz, 1H), 6.63–6.59
(t, J = 7.2 Hz, 1H), 6.28–6.26 (d, J = 8.0 Hz, 2H), 3.85–3.82 (m, 2H), 2.57–2.52 (m, 1H), 2.46–2.37 (m, 1H),
2.33–2.18 (m, 2H). 13C-NMR (126 MHz, CDCl3)
δ 181.5, 145.3, 139.2, 132.1, 129.0, 128.6, 123.02, 122.99,
117.0, 112.7, 110.8, 69.7, 50.5, 41.8, 23.0. IR
ν
max (K−Br, film, cm−1): 3202, 3092, 3059, 2922, 2851, 1717,
1505, 1469, 746. HRMS (ESI): calcd for C17H15ON2 [M − H]−: 263.1190, found: 263.1191.
10-Benzylspiro[indoline-3,20-piperidin]-2-one (2o): White solid, 9.8 mg (from 0.10 mmol), 34% yield, m.p.
◦
167–169 C. 1H-NMR (500 MHz, CDCl3)
δ 7.50 (br, 1H), 7.48–7.46 (d, J = 7.5 Hz, 1H), 7.26–7.25 (m, 4H),
7.23–7.18 (m, 2H), 7.09–7.06 (t, J = 7.5 Hz, 1H), 6.83–6.82 (d, J = 7.5 Hz, 1H), 3.38–3.36 (d, J = 13.0 Hz,
1H), 3.20–3.19 (d, J = 13.0 Hz, 1H), 3.16–3.11 (m, 1H), 2.71–2.67 (m, 1H), 2.11–2.04 (m, 1H), 1.96–1.88
(m, 2H), 1.76–1.72 (m, 1H), 1.69–1.62 (m, 2H). 13C-NMR (101 MHz, CDCl3) δ 180.7, 140.2, 139.4, 133.1,
128.5, 128.4, 128.0, 126.8, 124.1, 122.7, 109.7, 66.3, 56.3, 46.1, 35.3, 25.6, 19.1. IR
3210, 3061, 3028, 2929, 2851, 1702, 1619, 1472, 754. HRMS (ESI): calcd for C19H19ON2 [M
291.1503, found: 291.1504.
ν
max (KBr, film, cm−1):
−
−
H]−:
1-Benzylspiro[azepane-2,30-indolin]-20-one (2p): White solid, 4.7 mg (from 0.10 mmol), 15% yield, m.p.
177–179 ◦C. 1H-NMR (500 MHz, CDCl3)
7.67 (s, 1H), 7.62–7.61 (d, J = 7.5 Hz, 1H), 7.32–7.30 (m, 2H),
δ
7.27 (s, 1H), 7.25 (s, 1H), 7.24–7.17 (m, 2H), 7.08–7.05 (t, J = 7.5 Hz, 1H), 6.85–6.83 (d, J = 7.5 Hz, 1H),
3.55–3.50 (dd, J = 15.0, 10.5 Hz, 1H), 3.44–3.42 (d, J = 13.5 Hz, 1H), 3.24–3.21 (d, J = 13.0 Hz, 1H),
2.68–2.64 (dd, J = 15.0, 6.0 Hz, 1H), 2.19–2.05 (m, 2H), 1.92–1.84 (m, 3H), 1.60 (m, 1H) 1.47–1.40 (m, 2H).
13C-NMR (126 MHz, CDCl3)
69.6, 56.5, 47.2, 38.3, 32.4, 30.1, 22.7. IR
δ
182.4, 140.3, 139.8, 134.8, 128.5, 128.2, 128.0, 126.8, 124.0, 122.7, 109.7,
ν
(KBr, film, cm−1): 3207, 3028, 2925, 2853, 1704, 1651, 1469,
max
747. HRMS (ESI): calcd for C20H23ON2+ [M + H]+: 307.1805, found: 307.1808.

Molecules 2018, 23, 2265
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3.4. Further Functionalization
0
0
1 -Benzylspiro[indoline-3,2 -pyrrolidin]-2-one (2a, 0.5 mmol, 139.0 mg) was dissolved in dry THF
(10 mL), B2H6 (2.5 mmol, 2.5 mL, 1 M in THF) was added slowly under the Ar. The mixture was heated
◦
to reflux for 5 h. And then to the vigorously stirring mixture were added methanol (5 ml) at 0 C. After
being stirred at 0 ◦C. 10 min, the mixture was warmed to room temperature and reflux for another
30 min. After this time, the solvent was removed under vacuum and residue was purified by silica
column chromatography (elute: dichloromethane /methanol 10/1, with 1% NH4OH) to afford the
desired product 10-benzylspiro[indoline-3,20-pyrrolidine] (3) as an orange solid.
10-Benzylspiro[indoline-3,20-pyrrolidine] (
79–81 ◦C. 1H-NMR (500 MHz, CDCl3)
3
δ
): Orange solid, 70.0 mg (from 0.50 mmol), 53% yield, m.p.
8.14 (s, 1H), 7.59–7.58 (d, J = 7.5 Hz, 1H), 7.31–7.30 (m, 4H),
7.25–7.23 (m, 1H), 7.18–7.15 (t, J = 7.5 Hz, 1H), 7.11–7.09 (t, J = 7.5 Hz, 1H), 6.89 (s, 1H), 3.77 (s, 2H),
2.81–2.78 (t, J = 7.5 Hz, 2H), 2.73 (m, 2H), 2.06 (s, 1H), 1.95–1.92 (t, J = 7.5 Hz, 2H). 13C-NMR (126 MHz,
CDCl3)
30.2, 30.0, 22.8. IR
(ESI): calcd for C18H21N2+ [M + H]+: 265.1699, found: 265.1695.
δ 140.2, 136.3, 128.4, 128.2, 127.4, 126.9, 121.8, 121.2, 119.0, 118.8, 116.1, 111.0, 62.5, 53.9, 49.1,
ν
(KBr, film, cm−1): 3414, 3241, 3057, 2926, 2849, 1456, 1098, 741, 697. HRMS
max
3.5. Control Experiment
3-(3-(Benzylamino)propyl)indolin-2-one (1a, 0.10 mmol, 28.0 mg), TBAI (0.02 mmol, 7.4 mg) and
additive (0.1 mmol) was dissolved in toluene (0.5 mL). 35% of H2O2 (0.6 mmol, 52.0 µL) was added
and the reaction mixture was stirred at room temperature for 0.5 h. After that time, the mixture
was quenched by saturated sodium thiosulfate solution (1 mL) and diluted with dichloromethane
(10 mL). The organic layer was washed by water (10 mL
and evaporated to afford the crude product. The crude was purified by silica column chromatography
×
2), dried over anhydrous sodium sulfate
(elute: petroleum ether/ethyl acetate 2/1) to give the pure product 2a.
4. Conclusions
In summary, we have disclosed a new strategy for the construction of spirooxindoles via an
intramolecular cyclization through an oxidative C-H/N-H bond coupling process under the catalysis
of an iodide/H2O2 system. The representative synthetic examples demonstrate the inherent potential
0
of this metal-free catalytic approach for the preparation of various 3,2 -pyrrolidinyl-spirooxindoles and
their 6-/7-membered analogs. Further application of this method for the efficient synthesis of complex
chiral 3,20-pyrrolidinyl-spirooxindole products and other larger fused oxindoles are underway in our
laboratory and will be reported in due course.
Supplementary Materials: The following supplementary information are available online: Experimental details,
1H and 13C NMR spectra of starting materials and products, X-Ray structural data for product 2k.
Author Contributions: Conceptualization, L.C. and L.L.; Methodology, D.W.; Investigation, Y.-T.G., X.-Y.J., Q.L.
and A.-D.L. Supervision, L.C. and L.L.; Funding Acquisition, L.C. and L.L.
Funding: This work was supported by the National Key R&D Program of China (2016YFA0602900), National
Natural Science Foundation of China (21778057, 21502201 and 21420102003), Young Elite Scientist Sponsorship
Program by CAST (2015QNRC001) and Chinese Academy of Sciences.
Conflicts of Interest: The authors declare no conflict of interest.
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