Stereoselective construction of Bi-spirooxindole frameworks via a Michael addition/cyclization and an unexpected redox/oxidative coupling/cyclization

Article abstract of DOI:10.1016/j.tet.2016.11.001

A series of polyheterocyclic bi-spirooxindole derivatives with skeletal diversity and molecular complexity were prepared via a cascade synthesis strategy. The key step transfer hydrogenation is smoothly fulfilled by using 3-hydroxyoxindole derivatives as the hydrogen source and the oxidative coupling happened by using simple and green molecular oxygen as the oxidant. The plausible mechanisms for the unexpected redox/oxidative coupling/cyclization were also given.

Full text of DOI:10.1016/j.tet.2016.11.001

Accepted Manuscript
Stereoselective construction of Bi-spirooxindole frameworks via a Michael addition/
cyclization and an unexpected redox/oxidative coupling/cyclization
Xiao-Qian Zhu, Jia-Shou Wu, Jian-Wu Xie
PII:
S0040-4020(16)31133-4
10.1016/j.tet.2016.11.001
TET 28215
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 September 2016
Revised Date: 28 October 2016
Accepted Date: 1 November 2016
Please cite this article as: Zhu X-Q, Wu J-S, Xie J-W, Stereoselective construction of Bi-spirooxindole
frameworks via a Michael addition/cyclization and an unexpected redox/oxidative coupling/cyclization,
Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.001.
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ACCEPTED MANUSCRIPT
Stereoselective Construction of Bi-spirooxindole Frameworks via
a
Michael Addition/Cyclization and an Unexpected
Redox/Oxidative Coupling/Cyclization
Xiao-Qian Zhu, Jia-Shou Wu, Jian-Wu Xie

ACCEPTED MANUSCRIPT
Stereoselective Construction of Bi-spirooxindole Frameworks via a Michael
Addition/Cyclization and an Unexpected Redox/Oxidative Coupling/Cyclization
Xiao-Qian Zhua, Jia-Shou Wub, Jian-Wu Xie a,*
aKey Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry
and Life Science, Zhejiang Normal University, Jinhua 321004, P. R. China; E-mail: xiejw@zjnu.cn
b
School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, Zhejiang, P. R.
of China.
KEYWORDS: Spirooxindoles Michael addition Domino reactions
ABSTRACT: A series of polyheterocyclic bi-spirooxindole derivatives with skeletal diversity and molecular
complexity were prepared via a cascade synthesis strategy. The key step transfer hydrogenation is smoothly
fulfilled by using 3-hydroxyoxindole derivatives as the hydrogen source and the oxidative coupling happened
by using simple and green molecular oxygen as the oxidant. The plausible mechanisms for the unexpected
redox/oxidative coupling/cyclization were also given.
1. Introduction
It is a major challenge to develop novel synthetic methods for the construction of new analogues of
bioactive heterocyclic compounds in synthetic organic and medicinal chemistry. The reactions that generate
new spirocyclic ring units and maximize molecular complexity with a minimum of operations are not only
noteworthy but also fundamental for the construction of spiro heterocyclic molecule frameworks. The
spirooxindole core is a privileged heterocyclic ring system featured in numerous clinical pharmaceuticals and
natural spirooxindole alkaloids with diverse and important biological profiles. Natural products and
pharmaceuticals possessing the spirooxindole skeleton show a wide spectrum of considerable bioactivities,
such as anticonvulsant,1 antimicrobial,2 antitumor,3 antiviral,4 anti-HIV,5 and antitubercular.6 Some additional
biologically active spirocyclic oxindoles have also been described in a broader-context review.7 Moreover,
the unique potential of the C3 position of the oxindole core to be used both as an electrophile and nucleophile
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and their easy availability have made them valuable building blocks for the construction of spiro-fused cyclic
frameworks.8-13 Thus, more and more general and versatile synthetic methodologies to access analogous
compounds possessing the spirocyclic oxindole skeleton have been devoted over the past few decades.7,8
Among various spirocyclic oxindoles, bi-spirooxindole was a very interesting subgroup member, in which
the two oxindole moieties can exist at a new formed cyclic ring. The dispirocyclopentyl-3,3-bisoxindoles
with two oxindoles at 1,3-position of cyclopentyl ring have been reported in several works.9-13 As part of our
heterocyclic chemistry and medicinal chemistry research program,14 we required a robust facile synthesis of
bi-spirooxindole derivatives wherein we could vary the different substitutions. Herein we develop a cascade
synthesis strategy for construction of bi-spirooxindoles with skeletal diversity and molecular complexity.
2. Result and discussion
Scheme 1 Potential strategy for the domino 3-hydroxyoxindoles 1 with α,α-dicyanoolefins 2.
The 3-alkyl- or 3-arylsubstituted oxindoles have recently been identified as versatile synthons to construct
spirocyclic oxindole skeleton at the C3 position of oxindole.15 However, 3-hydroxyoxindole 1a, which
contains a valuable hydroxy moiety at C3, has rarely been used as a nucleophile in analogous reaction
pathways, and remains to be explored.16 In addition, the readily available α,α-dicyanoolefins have been
developed as attractive precursors for the construction of various cyclic compounds by our group17 and
others18. As such, we envisioned that the new domino Michael addition-cyclization reactions would be
possible between 3-hydroxyoxindoles 1 and α,α-dicyanoolefins 2, giving a facile protocol to
2,3-dihydrofuranyl bi-spirooxindole derivatives 4 with multiple substitutions (Scheme 1).
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Table 1 Reaction of N-benzyl-3-hydroxyoxindole 1a and α,α-dicyanoolefin 2a under different
conditions a
Bn
Bn
N
NH2
O
O
O
N
Bn
CN
NH
N
O
NH2
CN
OH
CN
1a
+
OH
NH
O
Cat.
Air, 0 oC, 12 h
+
OH
+
O
CN
O
CN
N
N
O
H
Bn
CN
4aa
N
5aa
A
H
O
2a
Entry
1
Base
K2CO3
KOH
Cs2CO3
TEA
DBU
QN
Solvent
THF
THF
THF
THF
THF
THF
THF
DCM
Yield(4aa/A/5aa)b
30/21/-
Dr(4aa/A/5aa)c
>99:1/>99:1/-
-/-/-
2
-
3
-
-/-/-
4
-/34/-
-/>99:1/-
5
-/45/-
-/>99:1/-
6
34/trace/11
36/trace/17
trace
>99:1/-/>99:1
>99:1/-/>99:1
-/-/-
7
CN
8
CN
9
CN
Toluene
acetone
CH3CN
trace
-/-/-
10
11
12
13d
14e
15f
CN
29/-/10
>99:1/-/>99:1
>99:1/-/>99:1
>99:1/-/>99:1
>99:1/-/>99:1
>99:1/-/>99:1
>99:1/-/>99:1
CN
23/-/14
CN
1,4-dioxane
THF
21/trace/13
71/trace/18
63/trace/23
60/trace/25
CN
CN
THF
CN
THF
a
o
Otherwise noted, reactions performed with 0.10 mmol of 1a, 0.10 mmol of 2a, 20 mol% base in solvent (1.0 mL) at 0 C
under air atmosphere for 12 h; b Isolated yields. c Determined by 1H NMR. d 1.5 eq. of 1a.. e 2.0 eq. of 1a. f 2.5 eq. of 1a.
First, we investigated the reactivity profile of 3-hydroxyoxindole 1a, which was easily derived from isatin,
under different reaction conditions in order to evaluate our reasoning. The oxidative coupling of
N-benzyl-3-hydroxyoxindole 1a easily happened to lead to the isatide A at room temperature under basic
conditions,19 we evaluated the new domino Michael addition-cyclization reaction at a lower temperature. As
such, the model reaction of 3-hydroxyoxindole 1a with electron-deficient α,α-dicyanoolefin 2a was firstly
o
carried out in the presence of K2CO3 in THF at 0 C for 12 h (Table 1, entry 1). Besides oxidative coupling
product A, the desired product 4aa was also obtained in 30% yield with a high diastereoselectivity. Then a
series of bases and organic solvents were screened for this domino reaction. However, when the stronger
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bases, such as KOH, Cs2CO3, were used, the reaction became complicated and no main products were
isolated (entries 2-3). Then the tertiary amines, such as TEA, DBU, were used as catalysts, only the oxidative
coupling product A was isolated (entries 4-5). To our surprise, when the domino reaction was catalyzed by a
milder, less basic organic catalyst quinine (QN), besides the desired product 4aa, an unexpected product
1,5-cyclopent[2]ene bi-spirooxindole 5aa was isolated and trace amount of product A was observed
simultaneously (entry 6). With application of the organic base cinchonine (CN), both the yields of 4aa and
5aa were improved and high diastereoselectivities were also observed (entry 7). Subsequently, we
investigated the effects of commonly used solvents. The domino reaction proceeded smoothly in the polar
solvents (entries 10-12), while the non-polar solvents such as toluene and CH2Cl2, were inert to this reaction
(entries 8 and 9). If the amount of N-benzyl-3-hydroxyoxindole 1a is increased to 1.5 equivalents in the
domino reaction, the yield was significantly improved and the total yields were up to 89% (entry 13).
Continue to increase the amount of N-benzyl-3-hydroxyoxindole 1a, similar results were obtained (entries
14-15). Hence, running the domino reaction in THF at 0 oC with 20 mol% cinchonine as the catalyst and 1.5
equivalents of 1a appeared to be the optimal reaction conditions.
Table 2 Reaction scopes in the domino reaction of 3-hydroxyoxindoles 1 with α,α-dicyanoolefins 2 a
Yield/%b/drc
Entry
1
R1
R2 (1)
H (1a)
R3
H
R4 (2)
H (2a)
4/5
4aa
5aa
4ab
5bb
4ac
5cc
4ba
Bn
71/>99:1
18/>99:1
2
3
4
Bn
H (1a)
H (1a)
H (1b)
C4H9 H (2b)
51/>99:1
15/>99:1
Bn
Bn
H
H (2c)
58/>99:1
13/>99:1
CH3
H (2a)
51/>99:1
4

ACCEPTED MANUSCRI5PaTa
trace
5
6
7
CH3
H (1b)
H (1c)
H (1d)
Bn
Bn
Bn
H (2c)
H (2c)
H (2c)
4bc
5cc
68/>99:1
trace
C4H9
Allyl
4cc
42/>99:1
trace
5cc
4dc
63/>99:1
trace
5cc
-
8
9
C6H5CO H (1e)
Bn
H
H (2c)
4ec/5cc
4fd
Bn
Me (1f)
Me (2d)
75/>99:1
trace
5dd
4ge
10
Bn
Cl (1g)
H
Cl (2e)
63/>99:1
11/>99:1
5ee
a Otherwise noted, reactions performed with 0.15 mmol of 1, 0.10 mmol of 2, 20 mol% cinchonine in THF (1.0 mL) at 0 oC
under air atmosphere for 12 h. b Isolated yields. c Determined by 1H NMR.
With the optimized reaction conditions in hand, we explored the scope of the domino reaction by using
various 3-hydroxyoxindole derivatives 1 and electron-deficient α,α-dicyanoolefin derivatives 2, and the
results are summarized in Table 2. All the products were obtained with excellent diastereoselectivities (>99:1).
α,α-Dicyanoolefin derivatives 2 that bear different substituents at the N-position performed well under the
reaction conditions to give both products 4 and 5 (entries 1-3). It turned out that the substituents on the
N-position of 3-hydroxyoxindole derivatives 1 had a significant influence on the domino reaction with the
optimized reaction conditions (entries 4-10). Only trace amount of products 5 was obtained with other
substituents on the N-position or C5 position of 3-hydroxyoxindole derivatives 1 (entries 4-7, 9), while the
products 4 were obtained in moderate to good yields. Replace benzyl with benzoyl on the N-position of
3-hydroxyoxindole derivatives 1, no products were obtained.
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Having presented the domino reaction to afford the unexpected products 5, more experiments were
conducted to gain some insight into the mechanism of this domino reaction. Under the optimized reaction
conditions, no reaction occurred for the electron-deficient α,α-dicyanoolefin 2a (Eq. 1). To our surprise, the
domino coupling/cyclization of 2-(2-oxoindolin-3-yl)-malononitrile 3a took place smoothly to give
unexpected product 5aa in 86% yield when the reaction was catalyzed by cinchonine at room temperature for
1 hour (Eq. 2). Subsequently, the scope of the unexpected domino reaction was explored. As shown in Table
3, the reactions occurred smoothly to provide the structurally diverse corresponding bi-spirooxindoles 5 in
moderate to excellent diastereoselectivities (>99:1) and good yields (64-86% yields, entries 1-7). The
2-(2-oxoindolin-3-yl)malononitrile derivatives 3 that bear different substituents at the C5 and N positions
have a little effect on the yields. An alkyl at the nitrogen atom slightly improved the reactivity as well as the
electron-donating substituent on the C5 position (entries 2, 4, 6). To our surprise, only trace amount of
product 5aa was observed when the reaction was carried out under argon atmosphere (entry 8).
Table
3
Reaction scopes in the domino redox/oxidative coupling/cyclization of
2-(2-oxoindolin-3-yl)-malononitriles 3a
R3
N
CN
CN
N
CN
O
NH2
CN
Cinchonine
R4
Air, THF, r.t., 1 h
O
R3
CN
N
R4
O
R3
3
R4
5
6

R3
H
R4 (3)
H (3a)
5
Yield/%b
86
drc
ACCEPTED MANUSCRIPT
Entry
1
2
5aa
5bb
5cc
5dd
5ee
5ff
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
-
H
C4H9 (3b)
Bn(3c)
85
3
H
76
4
Me
Cl
H
H (3d)
83
5
H(3e)
71
6
CH3 (3f)
Allyl(3g)
H (3a)
83
7
8d
H
5gg
5aa
64
H
trace
a
Otherwise noted, reactions performed with 0.15 mmol of 3, 20 mol% cinchonine in THF (1.0 mL) at room temperature
under air atmosphere for 1 h. b Isolated yields. c Determined by 1H NMR. d Under argon atmosphere.
Prompted by the above results, we envisioned that the new domino reaction would be possible between
electron-deficient α,α-dicyanoolefins 2 and 2-(2-oxoindolin-3-yl)-malononitriles 3 under the same reaction
conditions, giving a facile protocol to both products 5 and 6 (Table 4). As such, the reaction of
2-(2-oxoindolin-3- yl)-malononitriles 3a with electron-deficient α,α-dicyanoolefin 2c was firstly carried out
at room temperature. To our delight, we found that the reaction generally exhibited high efficiency. Both
products 5aa and 6ca with excellent total yields were obtained in 10 minutes (Entry 1). In all cases, high
yields ranging from 83 to 92% were achieved under the optimized conditions, and the rate of the reactions
was very fast. Of particular interest was that excellent diastereoselectivity (>99:1) could be obtained for most
of the cases except 6fa (Entry 5, 87:13 dr).
Table 4 Reaction scopes in the domino reaction of α,α-dicyanoolefins 2 2-(2-oxoindolin-3-yl)-
malononitriles 3a, b
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a
Otherwise noted, reactions performed with 0.10 mmol of 2, 0.10 mmol of 3, 20 mol% cinchonine in THF (1.0 mL) at room temperature under air
atmosphere for 10 min.. b Isolated yields.
Recently, many organocatalytic asymmetric strategies have been developed for the construction of
bi-spirooxindoles in an enantioselective manner.20 A few organocatalysts have also been screened for the
domino reaction (see Supporting information). However, only a moderate enantioselectivity (46% ee) was
also obtained in the presence of cinchonine (Eq. 3). Asymmetric oganocatalytic the domino reaction catayzed
by other novel catalysts is under way in our laboratory.
On the basis of the experimental observations and the control experiments (see supporting information,
Scheme S1), a possible mechanism was proposed to explain the domino reaction (Scheme 2). On the one
hand, deprotonation of 1a by cinchonine followed by a domino Michael/intramolecular cyclization/proton
transfer to form 2,3-dihydrofuranyl bi-spirooxindole 4aa (a-c). On the other hand, the
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N-benzyl-3-hydroxyoxindole 1a was deprotonated by cinchonine (III) and the hydride transfer to the
electron-deficient α,α-dicyanoolefin 2a to produce N-benzyl isatin 7a and intermediate VI. Subsequently, the
ion VI acquires a proton to form 3a (d-e). After that, the deprotonative activation of compound 3a under
basic conditions followed by a domino Michael/intramolecular cyclization/proton transfer to form compound
6ca (f-g). Simultaneously, an unexpected oxidative coupling (an oxidative dimerization pathway or a radical
process ) happened to form intermediate VII (h-j), following a domino intramolecular cyclization/proton
transfer to produce product 5aa under base conditions (k-l). Nevertheless, the real reaction mechanism still
remains to be explored.
Scheme 2 Proposed mechanisms
Conclusion
In summary, we have developed a facile and mild synthesis of bi-spirooxindole frameworks, including
2,3-dihydrofuranyl bi-spirooxindoles and 1,5-cyclopent[2]ene bi-spirooxindoles, that are potentially relevant
to natural product synthesis via a Michael addition/cyclization, as well as developed an unexpected
9

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redox/oxidative coupling/cyclization to afford 1,5-cyclopent[2]ene bi-spirooxindoles. Both domino reactions
employ very simple and readily available substrates and tolerate a range of functional groups to produce
substituted bi-spirooxindole frameworks in moderate to good yields with excellent diastereoselectivities. The
plausible mechanisms for the Michael addition/cyclization and the unexpected oxidative coupling/cyclization
were given. Further development of this reaction including studies on the reaction mechanism and scopes, is
being pursued and will be reported in due course.
4. Experiment procesure
4.1 General
NMR spectra were recorded with tetramethylsilane as the internal standard. TLC was performed on
glass-backed silica plates. Column chromatography was performed using silica gel (150-200 mesh) eluting
1
13
with ethyl acetate and petroleum ether. H NMR spectra were recorded at 600 MHz, and C NMR spectra
were recorded at 150 MHz. Chemical shifts (δ) are reported in ppm downfield from CDCl3 (δ = 7.26 ppm) or
1
D6-DMSO (δ = 2.50 ppm) for H NMR and relative to the central CDCl3 resonance (δ = 77.0 ppm) or
13
D6-DMSO resonance (δ = 39.5 ppm) for C NMR spectroscopy. Coupling constants (J) are given in Hz.
ESI-HRMS spectrometer was measured with an ion trap mass spectrometer.
4.1 Typical procedure for the synthesis compounds 4 and 5.
(Table 2, entry 1) Catalyst cinchonine (5.88 mg, 20 mol%) was added to the solution of
N-benzyl-3-hydroxyoxindole 1a (36.0 mg, 0.15 mmol) and α,α-dicyanoolefin 2a (20.0 mg, 0.10 mmol) in
o
o
THF (1.0 mL) at 0 C under air atmosphere. The mixture was stirred at 0 C for 12 h. Then the reaction
mixture was concentrated and the residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 4:1) to give 4aa (30.0 mg) and 5aa (7.0 mg).
5'-Amino-1-benzyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile (4aa); (30.0 mg)
Yield 71%; 1H NMR (400 MHz, D6-DMSO) δ 10.44 (s, 1H), 7.99 (s, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.38 (d, J
10

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= 7.6 Hz, 1H), 7.31 – 7.20 (m, 2H), 7.17 (dd, J = 10.8, 7.2 Hz, 3H), 7.05 (s, 1H), 6.94 (s, 1H), 6.80 – 6.70 (m,
3H), 6.60 (d, J = 7.9 Hz, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.49 (d, J = 16.1 Hz, 1H).13C NMR (101 MHz,
D6-DMSO) δ 177.5, 171.7, 171.0, 143.8, 143.5, 135.3, 132.2, 130.4, 129.0, 127.7, 127.5, 127.3, 127.1, 127.0,
126.8, 123.9, 123.4, 122.7, 121.7, 118.1, 110.3, 88.8, 63.2, 53.5, 43.1. IR (KBr) cm-1 3413, 3325, 3290, 2196,
1721, 1567, 1615, 1468, 754, 695；ESI-HRMS: calcd. for C26H18N4O3 + H 435.1452, found 435.1457; ee =
46%; [α]20D = -25.4 (c = 1.10, MeOH) The enantiomeric ratio was determined by HPLC on Chiralpak OJ
column (30% 2-propanol/hexane, 1 mL/min), tmajor = 19.548 min, tminor = 36.789 min.
5'-Amino-1-benzyl-1''-butyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile (4ab);
(25.0 mg) Yield 51%; 1H NMR (600 MHz, D6-DMSO) δ 7.98 (s, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.39 (d, J =
7.5 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.24 (td, J = 7.8, 1.0 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.15 (t, J = 7.3 Hz,
2H), 7.01 (dt, J = 20.9, 7.6 Hz, 2H), 6.95 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 7.3 Hz, 2H), 6.58 (d, J = 7.9 Hz,
1H), 4.88 (d, J = 16.0 Hz, 1H), 4.48 (d, J = 16.1 Hz, 1H), 3.60 (dd, J = 13.8, 7.4 Hz, 1H), 3.37 – 3.29 (m, 2H),
1.27 – 1.10 (m, 4H), 0.67 (t, J = 7.3 Hz, 3H).13C NMR (150 MHz, D6-DMSO) δ 175.6, 171.8, 171.0, 144.5,
143.7, 135.3, 132.1, 130.6, 128.9, 127.7, 127.4, 127.1, 126.7, 123.4, 123.1, 123.2, 121.5, 117.8, 110.2, 109.4,
89.0, 62.8, 53.3, 43.1, 29.4, 19.5, 14.1. IR (KBr) cm-1 3404, 3305, 2971, 2931, 1678, 1640, 1616, 1094, 698,
580; ESI-HRMS: calcd. for C30H26N4O3 + H 491.2078, found 491.2069.
5'-Amino-1,1''-dibenzyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile (4ac); (30.1
mg) Yield 58%; 1H NMR (600 MHz, D6-DMSO) δ 8.05 (s, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.5 Hz,
1H), 7.31 (td, J = 7.8, 1.2 Hz, 1H), 7.22 (td, J = 7.8, 1.2 Hz, 1H), 7.16 – 7.10 (m, 3H), 7.08 (d, J = 7.7 Hz,
1H), 7.07 – 7.03 (m, 2H), 6.98 (ddd, J = 5.7, 4.4, 2.3 Hz, 2H), 6.72 (d, J = 7.5 Hz, 2H), 6.68 (d, J = 7.5 Hz,
2H), 6.65 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 4.94 (d, J = 16.1 Hz, 1H), 4.89 (d, J = 16.1 Hz, 1H),
4.57 (d, J = 16.2 Hz, 1H), 4.52 (d, J = 16.1 Hz, 1H). 13C NMR (150 MHz, D6-DMSO) δ 175.9, 171.9, 171.0,
145.0, 143.8, 135.5, 135.2, 132.2, 130.6, 130.5, 129.6, 128.9, 127.7, 127.5, 127.1, 126.8,125.9, 125.3, 124.8,
11

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124.4, 123.7, 123.3, 121.7, 117.8, 110.4, 110.1, 89.0, 63.1, 53.5, 43.1. .IR (KBr) cm-1 3415, 3325, 3296, 2196,
1720, 1568, 1615, 1470, 756, 699; ESI-HRMS: calcd. for C33H24N4O3 + H 525.1921, found 525.1917.
5'-Amino-1-methyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile (4ba); (18.2 mg)
Yield 51%; 1H NMR (600 MHz, D6-DMSO) δ 10.43 (s, 1H), 7.94 (s, 2H), 7.59 (d, J = 7.5 Hz, 1H), 7.39 (t, J
= 7.7 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz,
1H), 6.90 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 2.92 (s, 3H).13C NMR (150 MHz, D6-DMSO) δ
177.3, 171.7, 171.1, 144.6, 143.3, 132.2, 130.4, 126.9, 126.2, 123.7, 123.2, 122.3, 121.4, 118.1, 110.2, 109.5,
88.7, 63.0, 53.6, 26.2. IR (KBr) cm-1 3334, 3172, 2188, 1720, 1665, 1612, 1470, 1102, 753, 539;
ESI-HRMS: calcd. for C20H14N4O3 +Na 381.0958, found 381.0951.
5'-Amino-1''-benzyl-1-methyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile (4bc);
(30.5 mg) Yield 68%; 1H NMR (600 MHz, D6-DMSO) δ 8.04 (s, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.41 (d, J =
7.3 Hz, 2H), 7.19 – 7.09 (m, 4H), 7.02 (t, J = 7.7 Hz, 2H), 6.89 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 7.4 Hz, 2H),
6.58 (d, J = 7.9 Hz, 1H), 4.95 (d, J = 16.1 Hz, 1H), 4.56 (d, J = 16.1 Hz, 1H), 2.87 (s, 3H).13C NMR (150
MHz, D6-DMSO) δ 175.8, 172.0, 171.2, 144.7, 143.7, 138.6, 135.6, 132.2, 130.5, 128.9, 127.6, 127.1, 127.0,
126.2, 124.7, 123.6, 123.4, 123.3, 123.1, 121.5, 110.9, 109.9, 109.7, 88.9, 62.9, 55.3, 53.8, 43.2, 26.3. IR
(KBr) cm-1 3394, 3298, 2189, 1784, 1640, 1614, 1095, 1007, 597; ESI-HRMS: calcd. for C27H20N4O3+H
449.1608, found 449.1605.
5'-Amino-1''-benzyl-1-butyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile (4cc);
(20.6 mg) Yield 42%; 1H NMR (600 MHz, D6-DMSO) δ 7.98 (s, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.46 – 7.36
(m, 2H), 7.15 (ddd, J = 23.0, 11.3, 4.4 Hz, 5H), 7.06 – 6.91 (m, 3H), 6.70 (d, J = 7.4 Hz, 2H), 6.56 (d, J = 7.8
Hz, 1H), 4.92 (d, J = 16.1 Hz, 1H), 4.54 (d, J = 16.1 Hz, 1H), 3.57 (dd, J = 14.5, 6.9 Hz, 1H), 3.32 – 3.24 (m,
13
1H), 1.61 – 1.11 (m, 4H), 0.68 (t, J = 7.3 Hz, 3H). C NMR (150 MHz, D6-DMSO) δ 175.9, 171.7, 171.1,
144.4, 143.7, 135.6, 132.3, 130.3, 128.9, 127.6, 127.3, 127.0, 126.7, 123.3, 123.2, 123.0, 121.6,117.3, 109.8,
12

ACCEPTED MANUSCRIPT
88.7, 63.0, 53.5, 43.1, 29.3, 19.6, 14.0. IR (KBr) cm-1 3396, 3335, 2188, 1725, 1618, 1613, 1513, 1176, 753,
700; ESI-HRMS: calcd. for C30H26N4O3 + H 491.2078, found 491.2071.
1-Allyl-5'-amino-1''-methyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile (4dc);
(29.9 mg) Yield 63%; 1H NMR (600 MHz, D6-DMSO) δ 7.97 (s, 2H), 7.50 (d, J = 7.2 Hz, 1H), 7.38 – 7.21
(m, 4H), 7.03 (dt, J = 20.9, 7.6 Hz, 2H), 6.86 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 5.49 – 5.40 (m,
1H), 4.88 (dd, J = 10.4, 1.0 Hz, 1H), 4.48 (dd, J = 17.3, 1.0 Hz, 1H), 4.30 – 4.22 (m, 1H), 3.90 (dd, J = 16.7,
5.3 Hz, 1H), 2.91 (s, 3H).13C NMR (150 MHz, D6-DMSO) δ 175.7, 171.7, 171.2, 146.2, 144.6, 143.7, 132.2,
131.0, 130.5, 126.6, 126.2, 123.7, 123.3, 123.1, 122.9, 121.1, 120.7, 119.3, 118.6, 117.9, 117.3, 110.6, 110.2,
109.3, 88.8, 62.9, 52.9, 41.7, 26.4. IR (KBr) cm-1 3397, 3335, 2188, 1727, 1618, 1615, 1513, 1176, 753, 700;
ESI-HRMS: calcd. for C29H22N4O3 + H 475.1765, found 475.1761.
5'-Amino-1-benzyl-5'',6-dimethyl-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile
(4fd); (37.0 mg) Yield 80%; 1H NMR (600 MHz, D6-DMSO) δ 10.36 (s, 1H), 7.90 (s, 2H), 7.42 (s, 1H), 7.18
(dd, J = 15.7, 8.3 Hz, 2H), 7.12 (t, J = 7.5 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 7.5 Hz, 2H), 6.60 (d,
J = 7.8 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 4.97 (d, J = 16.2 Hz, 1H), 4.43 (d, J = 16.2 Hz, 1H), 2.21 (s, 3H),
2.08 (s, 3H).13C NMR (150 MHz, D6-DMSO) δ 177.5, 171.7, 171.0, 141.6, 141.0, 135.5, 134.6, 133.5, 132.3,
131.5, 130.7, 128.9, 127.9, 127.6, 126.8, 125.9, 125.1, 124.0, 121.7, 118.2, 110.0, 109.9, 89.0, 63.2, 53.6,
43.0, 21.1; IR (KBr) cm-1 3416, 3340, 2193, 1719, 1670, 1614, 1468, 1178, 1008, 749, 699, 500; ESI-HRMS:
calcd. for C28H22N4O3 + H 463.1765, found 463.1769.
5'-Amino-1-benzyl-5'',6-dichloro-2,2''-dioxodispiro[indoline-3,2'-furan-3',3''-indoline]-4'-carbonitrile
1
(4ge); (31.6 mg) Yield 63%; H NMR (600 MHz, D6-DMSO) δ 10.80 (s, 1H), 8.12 (s, 2H), 7.55 (d, J = 2.2
Hz, 1H), 7.42 (dd, J = 8.5, 2.2 Hz, 1H), 7.38 (dd, J = 8.3, 2.2 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.23 – 7.16
(m, 3H), 6.78 (dd, J = 12.0, 7.8 Hz, 3H), 6.72 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 16.1 Hz, 1H), 4.49 (d, J = 16.1
Hz, 1H).13C NMR (150 MHz, D6-DMSO) δ 177.1, 171.0, 170.8, 142.8, 142.3, 134.9, 132.3, 130.8, 129.1,
13

ACCEPTED MANUSCRIPT
128.0, 127.7, 127.2, 127.1, 127.0, 126.9, 126.8, 125.6, 123.2, 112.2, 112.1, 88.0, 63.3, 52.9, 43.3.IR (KBr)
cm-1 3381, 3274, 2187, 1718, 1670, 1604, 1424, 1177, 1012, 750, 536; ESI-HRMS: calcd. for
C26H16Cl2N4O3+ H 503.0672, found 503.0679.
1,1'-Dibenzyl-3,3'-dihydroxy-[3,3'-biindoline]-2,2'-dione (A); (21.4 mg) Yield 45%; 1H NMR (600 MHz,
CDCl3) δ 7.69 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.16 – 7.11 (m, 2H), 7.09 (dd, J = 11.4, 7.0 Hz,
2H), 6.98 (dt, J = 10.9, 7.7 Hz, 4H), 6.93 (t, J = 7.7 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.50 (d, J = 7.6 Hz, 4H),
6.40 (d, J = 7.8 Hz, 1H), 6.36 (d, J = 7.9 Hz, 1H), 5.91 (s, 2H), 5.13 (dd, J = 30.6, 16.1 Hz, 2H), 4.32 (d, J =
16.2 Hz, 1H), 4.23 (d, J = 16.1 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 172.1, 170.6, 143.8, 143.8, 134.6,
134.2, 131.5, 130.1, 128.7, 128.6, 127.9, 127.3, 127.1, 126.3, 126.2, 123.7, 123.5, 122.9, 121.6, 109.7, 109.6,
90.3, 43.8; ESI-HRMS: calcd. for C30H24N2O4+ H 477.1809, found 477.1801.
4.2 Typical procedure for the synthesis compounds 5.
(Table 3, entry 1) Catalyst cinchonine (5.88 mg, 20 mol%) was added to the solution of
2-(2-oxoindolin-3-yl)-malononitrile 3a (40.0 mg, 0.20 mmol) in THF (1.0 mL) at room temperature under air
atmosphere. The mixture was stirred for 1 h. Then the reaction mixture was concentrated and the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to give 5aa (33.7 mg).
4'-Amino-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricarbonitrile (5aa);
(33.7 mg) Yield 86%; 1H NMR (600 MHz, D6-DMSO) δ 11.27 (s, 1H), 10.81 (s, 1H), 8.41 (s, 2H), 7.75 (d, J
= 7.8 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.24 (dd, J = 7.7, 1.1 Hz, 1H), 7.16 (dd, J = 7.8, 0.8 Hz, 1H), 7.04 (dd, J
= 7.7, 0.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H). 13C NMR (150 MHz, D6-DMSO) δ
176.7, 173.0, 153.8, 143.3, 143.2, 132.0, 131.0, 127.0, 126.9, 123.4, 123.0, 122.9, 119.8, 115.4, 112.6, 111.8,
110.9, 110.6, 76.3, 62.8, 62.4, 46.8. IR (KBr) cm-1 3416, 3319, 3294, 2193, 1711, 1568, 1616, 1468, 760, 693;
ESI-HRMS: calcd. for C22H12N6O2 + Na 415.0914, found 415.0911.
4'-amino-1,1''-dibutyl-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricarbo
14

ACCEPTED MANUSCRIPT
nitrile (5bb); (42.8 mg) Yield 85%; 1H NMR (600 MHz, D6-DMSO) δ 8.49 (s, 2H), 7.74 (d, J = 7.6 Hz, 1H),
7.42 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.05 (t, J
= 7.9 Hz, 2H), 6.91 (d, J = 7.7 Hz, 1H), 3.64 – 3.54 (m, 3H), 3.50 (dd, J = 13.9, 6.8 Hz, 1H), 1.36 (ddd, J =
22.5, 14.8, 7.5 Hz, 4H), 1.21 – 1.12 (m, 2H), 1.05 (ddd, J = 30.7, 13.9, 7.0 Hz, 2H), 0.81 (dd, J = 13.3, 6.5
Hz, 6H).13C NMR (150 MHz, D6-DMSO) δ 174.9, 171.1, 154.0, 144.2, 144.0, 132.2, 131.2, 126.9, 126.7,
123.5, 123.3, 122.5, 118.9, 115.2, 112.3, 111.8, 110.3, 109.9, 76.1, 62.22, 61.9, 60.2, 46.9, 29.4, 29.2, 19.8,
19.8, 14.0, 113.9. IR (KBr) cm-1 3417, 3322, 3290, 2195, 1720, 1565, 1617, 1464, 758, 697; ESI-HRMS:
calcd. for C30H28N6O2 + Na 527.2166, found 527.2167.
4'-Amino-1,1''-dibutyl-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricarbo
nitrile (5cc); (43.5 mg) Yield 76%; 1H NMR (400 MHz, D6-DMSO) δ 8.59 (s, 2H), 7.74 (d, J = 7.6 Hz, 1H),
7.35 (d, J = 7.2 Hz, 2H), 7.26 – 7.18 (m, 7H), 7.11 – 7.04 (m, 3H), 7.01 (dd, J = 9.2, 5.7 Hz, 3H), 6.84 (d, J =
7.9 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.98 – 4.76 (m, 4H). 13C NMR (150 MHz, D6-DMSO) δ 175.3, 171.4,
154.1, 143.8, 143.5, 135.5, 135.0, 132.1, 131.2, 129.0, 128.2, 128.5, 128.1, 127.6, 127.6, 127.5, 127.4, 126.9,
126.5, 124.1, 123.9, 122.5, 118.9, 115.2, 112.4, 111.8, 111.0, 110.5, 76.1, 62.6, 62.2, 47.1, 43.5 (d, J = 7.4
Hz). IR (KBr) cm-1 3417, 3320, 3296, 2191, 1727, 1565, 1618, 1464, 755, 693; ESI-HRMS: calcd. for
C36H24N6O2 + Na 595.1853, found 595.1844.
4'-Amino-5,5''-dimethyl-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricar
1
bonitrile (5dd) (Table 3, entry 4); (34.9 mg) Yield 83%; H NMR (400 MHz, D6-DMSO) δ 11.18 (s, 1H),
10.72 (s, 1H), 8.35 (s, 2H), 7.54 (s, 1H), 7.18 – 7.09 (m, 2H), 7.00 (d, J = 7.8 Hz, 1H), 6.67 (d, J = 7.9 Hz,
1H), 6.56 (d, J = 7.9 Hz, 1H), 2.26 (s, 3H), 2.21 (s, 3H). 13C NMR (150 MHz, D6-DMSO) δ 176.7, 173.1,
153.8, 140.9, 140.7, 132.3, 131.9, 131.6, 131.3, 127.6, 127.5, 123.64, 120.0, 115.5, 112.69, 111.9, 110.6,
110.3, 76.4, 62.8, 62.4, 55.3, 46.9, 21.3. IR (KBr) cm-1 3416, 33203, 3292, 2194, 1725, 1569, 1619, 1465,
757, 693; ESI-HRMS: calcd. for C24H16N6O2 + Na 443.1227, found 443.1219.
15

ACCEPTED MANUSCRIPT
4'-Amino-5,5''-dichloro-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricarb
onitrile (5ee); (32.7 mg) Yield 71%; 1H NMR (600 MHz, D6-DMSO) δ 10.95 (s, 1H), 10.82 (s, 1H), 8.11 (s,
2H), 7.50 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 7.2 Hz, 2H), 6.84 – 6.73 (m, 2H). 13C NMR (150
MHz, D6-DMSO) δ 177.09, 172.79, 170.98, 142.22 (d, J = 10.9 Hz), 132.31, 130.61, 127.25, 126.76 –
13
126.29 (m), 125.78, 123.55, 117.73, 112.51, 111.97, 88.33, 63.08, 60.24, 52.93. C NMR (150 MHz,
D6-DMSO) δ 177.0, 172.7, 170.9, 142.2, 142.1, 132.3, 130.6, 127.2, 126.7, 126.6, 125.7, 123.5, 117.7, 112.5,
111.9, 88.3, 63.0, 60.2, 52.9; IR (KBr) cm-1 3413, 3327, 3293, 2195, 1727, 1561, 1619, 1461, 755, 696;
ESI-HRMS: calcd. for C22H10Cl2N6O2 + Na 483.0135, found 483.0127.
4'-Amino-1,1''-dimethyl-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricar
1
bonitrile (5ff); (34.9 mg) Yield 83%; H NMR (600 MHz, D6-DMSO) δ 8.60 (s, 2H), 7.47 (td, J = 7.8, 1.0
Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.25 (td, J = 7.8, 1.1 Hz, 2H), 7.19 (dd, J = 7.9, 7.3 Hz, 1H), 7.03 (d, J =
7.9 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 7.5 Hz, 1H), 3.05 (s, 3H), 3.00 (s,
3H).13C NMR (150 MHz, D6-DMSO) δ 173.5, 168.0, 154.5, 144.70, 143.6, 132.1, 131.0, 126.4, 125.4, 123.0,
122.1, 115.2, 111.9, 110.6, 110.2, 109.2, 75.8, 62.7, 62.3, 47.1, 27.1, 27.0; IR (KBr) cm-1 3416, 3321, 3289,
2191, 1720, 1564, 1612, 1469, 755, 690; ESI-HRMS: calcd. for C24H16N6O2+H 421.1408, found 421.1411.
1,1''-Diallyl-4'-amino-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricarbo
nitrile (5gg); (30.2 mg) Yield 64%; 1H NMR (400 MHz, D6-DMSO) δ 8.52 (s, 2H), 7.71 (d, J = 7.4 Hz, 1H),
7.42 (td, J = 7.9, 0.9 Hz, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.93
(d, J = 7.9 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 5.56 (ddd, J = 17.0, 10.7, 5.4 Hz, 2H), 5.01 (ddd, J = 10.4, 5.4,
1.0 Hz, 2H), 4.75 (ddd, J = 27.1, 17.3, 1.0 Hz, 2H), 4.36 – 4.08 (m, 4H). 13C NMR (101 MHz, D6-DMSO) δ
174.7, 171.0, 154.0, 143.7, 143.5, 132.2, 131.1 (d, J = 12.1 Hz), 130.6, 126.9, 126.8, 123.9, 123.6, 122.4,
118.8, 118.1, 117.5, 115.2, 112.3, 111.7, 110.8, 110.4, 75.8, 62.4, 62.2, 46.9, 42.3, 42.2; IR (KBr) cm-1 3413,
3325, 3294, 2198, 1728, 1563, 1613, 1466, 757, 691; ESI-HRMS: calcd. for C28H20N6O2 + Na 495.1540,
16

ACCEPTED MANUSCRIPT
found 495.1539.
4.3 Typical procedure for the synthesis compounds 6.
(Table 4, entry 1) Catalyst cinchonine (5.88 mg, 20 mol%) was added to the solution of
α,α-dicyanoolefin 2c (28.5 mg, 0.10 mmol) and 2-(2-oxoindolin-3-yl)-malononitrile 3a (20 mg, 0.10 mmol)
o
o
in THF (1.0 mL) at 0 C. The mixture was stirred at 0 C under air atmosphere for 12 h. Then the reaction
mixture was concentrated and the residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 4:1) to give 6ca (36.6 mg).
4'-Amino-1-benzyl-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricarbonitr
1
ile (6ca); (36.6 mg) Yield 76%; H NMR (600 MHz, D6-DMSO) δ 10.83 (s, 1H), 8.49 (s, 2H), 7.81 (d, J =
7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.28 – 7.15 (m, 7H), 7.04 (d, J = 6.9 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H),
6.80 (d, J = 7.9 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 4.90 (d, J = 15.9 Hz, 1H), 4.82 (d, J = 15.9 Hz, 1H). 13C
NMR (150 MHz, D6-DMSO) δ 175.2, 171.3, 154.1, 144.3, 143.8, 135.5, 132.2, 131.3, 129.0, 127.95, 127.4,
126.7, 126.4, 124.0, 123.7, 122.6, 118.8, 115.2, 112.4, 111.9, 110.5, 110.3, 62.6, 62.2, 46.8, 43.5; IR (KBr)
cm-1 3417, 3326, 3297, 2198, 1724, 1565, 1619, 1463, 756, 693; ESI-HRMS: calcd for C29H18N6O2 + Na
505.1383, found 505.1379.
4'-Amino-1''-benzyl-1-methyl-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-t
1
ricarbonitrile (6dc); (34.7 mg) Yield 70%; H NMR (600 MHz, D6-DMSO) δ 8.57 (s, 2H), 7.73 (d, J = 7.7
Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.23 (dd, J = 10.5, 7.9 Hz, 4H), 7.09 (dd, J = 14.4,
6.6 Hz, 2H), 7.07 – 7.03 (m, 2H), 7.02 (d, J = 4.1 Hz, 2H), 6.74 (d, J = 7.6 Hz, 1H), 4.84 (q, J = 15.9 Hz, 2H),
3.07 (s, 3H).13C NMR (150 MHz, D6-DMSO) δ 175.2, 171.3, 154.1, 144.3, 143.8, 135.5, 132.2, 131.3, 129.0,
127.9, 127.4, 126.7, 126.4, 124.0, 123.7, 122.6, 118.8, 115.2, 112.4, 111.9, 110.5, 110.3, 62.6, 62.2, 46.8,
43.5, 26.8. IR (KBr) cm-1 3418, 3316, 3288, 2187, 1719, 1558, 1619, 1459, 750, 701; ESI-HRMS: calcd for
C30H20N6O2 + H 497.1721, found 497.1713.
17

ACCEPTED MANUSCRIPT
1''-Allyl-4'-amino-5-chloro-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tri
carbonitrile (6eg); (36.0 mg) Yield 78%; 1H NMR (600 MHz, D6-DMSO) δ 11.54 (s, 1H), 8.60 (s, 2H), 7.65
(s, 1H), 7.47 (dd, J = 20.7, 8.0 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.90 (dd, J = 13.8,
8.1 Hz, 2H), 5.69 (ddd, J = 15.5, 9.7, 4.5 Hz, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.74 (d, J = 17.2 Hz, 1H), 4.49
(d, J = 16.5 Hz, 1H), 4.22 – 4.10 (m, 1H). 13C NMR (150 MHz, D6-DMSO) δ 174.7, 172.6, 153.9, 143.7,
142.1, 132.1, 131.4, 130.9, 127.3, 127.2, 126.7, 123.9, 122.4, 121.4, 117.3, 115.1, 112.6, 112.2, 111.7, 110.4,
75.7, 62.3, 62.1, 46.7, 42.2; IR (KBr) cm-1 3420, 3317, 3285, 2187, 1724, 1560, 1621, 1459, 761, 702;
ESI-HRMS: calcd. for C25H15ClN6O2 + H 467.1018, found 467.1011.
4'-Amino-1''-benzyl-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tricarbonitr
ile (6ac) (34.2 mg) Yield 71%; 1H NMR (600 MHz, D6-DMSO) δ 10.47 (s, 1H), 7.64 (s, 2H), 6.80 (d, J = 7.7
Hz, 1H), 6.58 (dd, J = 7.7, 0.7 Hz, 1H), 6.52 (td, J = 7.8, 1.1 Hz, 1H), 6.43 – 6.31 (m, 5H), 6.23 (td, J = 7.7,
0.8 Hz, 1H), 6.18 – 6.14 (m, 3H), 5.98 (d, J = 7.8 Hz, 1H), 5.88 (d, J = 7.9 Hz, 1H), 1.69 – 1.66 (m, 1H). 13C
NMR (151 MHz, D6-DMSO) δ 175.3, 173.0, 154.1, 143.8, 143.1, 135.4, 132.1, 131.2, 129.0, 127.9, 127.4,
127.1, 126.8, 123.8, 123.3, 122.8, 119.6, 115.2, 112.5, 111.9, 111.1, 110.4, 76.36, 62.4, 55.2, 46.9, 43.5, 40.1.
(KBr) cm-1 3422, 3329, 3288, 2181, 1716, 1617, 1571, 1460, 757, 695; ESI-HRMS: calcd for C29H18N6O2 +
H 483.1564, found 483.1567.
4'-Amino-1-butyl-5''-methyl-2,2''-dioxodispiro[indoline-3,1'-cyclopentane-2',3''-indolin]-3'-ene-3',5',5'-tri
carbonitrile (6fa); (37.0 mg) Yield 80%; 1H NMR (600 MHz, D6-DMSO) δ 10.71 (s, 1H), 8.43 (s, 2H), 7.79
(d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 7.08 (s, 2H), 7.01 (d, J = 7.1 Hz, 1H),
6.59 – 6.53 (m, 1H), 3.70 – 3.51 (m, 2H), 2.22 (s, 3H), 1.36 (s, 2H), 1.21 – 1.06 (m, 2H), 0.89 – 0.75 (m, 3H).
13C NMR (150 MHz, D6-DMSO) δ 176.6, 171.2, 153.8, 144.1, 140.8, 132.2, 131.5, 131.3, 127.5, 126.8,
123.6, 123.2, 119.2, 115.5, 112.4, 111.8, 110.4, 110.3, 76.3, 62.8, 61.9, 46.9, 29.4, 21.2, 19.8, 14.0. IR (KBr)
cm-1 3418, 3324, 3297, 2189, 1725, 1559, 1614, 1458, 760, 701; ESI-HRMS: calcd. for C27H22N6O2 + Na
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485.1696, found 485.1693.
1
1-Benzylindoline-2,3-dione (7a) 18.9 mg, yield 8%; The H NMR spectra agreed well with the
corresponding literature values.[21] 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.4 Hz, 1H), 7.48 (td, J = 7.9,
1.1 Hz, 1H), 7.35 (d, J = 4.6 Hz, 5H), 7.09 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H).
5. Supplementary data
13
Supplementary data (1H NMR, C NMR spectra and X-ray structural data for 4aa and 6ac) associated with
this article can be found in the online version, at XXXX.
6. Acknowledgement
We are grateful for the financial support from the National Natural Science Foundation of P. R. of China (No.
21272214, 21402137).
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