Enantioselective Construction of Tetrahydroquinolin-5-one-Based Spirooxindole Scaffold via an Organocatalytic Asymmetric Multicomponent [3 + 3] Cyclization

Article abstract of DOI:10.1021/acs.joc.6b01598

The first catalytic enantioselective construction of biologically important tetrahydroquinolin-5-one-based spirooxindole has been developed via a chiral cinchona alkaloid catalyzed asymmetric three-component [3 + 3] cyclization of cyclic enaminone, isatin

Full text of DOI:10.1021/acs.joc.6b01598

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Article
Enantioselective Construction of Tetrahydroquinolin-5-
one-based Spirooxindole Scaffold via An Organocatalytic
Asymmetric Multicomponent [3+3] Cyclization
Qiu-Ning Zhu, Yu-Chen Zhang, Meng-Meng Xu, Xiao-Xue Sun, Xue Yang, and Feng Shi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01598 • Publication Date (Web): 15 Aug 2016
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Enantioselective Construction of Tetrahydroquinolin-5-one-based
Spirooxindole Scaffold via An Organocatalytic Asymmetric
Multicomponent [3+3] Cyclization
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Qiu-Ning Zhu,‡ Yu-Chen Zhang,‡ Meng-Meng Xu, Xiao-Xue Sun, Xue Yang and Feng Shi*
School of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, 221116, China
E-mail: fshi@jsnu.edu.cn
‡These authors contributed equally to the work.
Abstract: The first catalytic enantioselective construction of biologically important
tetrahydroquinolin-5-one-based spirooxindole has been developed via chiral cinchona
alkaloid-catalyzed asymmetric three-component [3+3] cyclization of cyclic enaminone, isatin, and
malononitrile, which afforded a series of tetrahydroquinolin-5-one-based spirooxindoles in high
yields and with excellent enantioselectivities (up to 99% yield, 97:3 er). This reaction could be
applicable to large-scale synthesis of enantioenriched tetrahydroquinolin-5-one-based
spirooxindoles. This synthetic methodology will not only provide a unique approach for the
construction of chiral tetrahydroquinolin-5-one-based spirooxindole scaffolds but also increase
our understanding of catalytic enantioselective multicomponent reactions.
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Introduction
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Spirooxindole represents one of the most important heterocyclic frameworks, which
constitutes the core structures of many natural alkaloids and pharmaceuticals.1-2 Among the large
family of spirooxindoles, tetrahydroquinolin-5-one-based spirooxindoles exhibit a wide spectrum
of bioactivities such as antimicrobial,3a cytotoxic to MCF-7,3a lifespan-altering,3b antioxidant4a,
and inhibiting alanyl aminopeptidase4b (Figure 1). Consequently, the construction of such
spiro-frameworks has received much attention from chemists. However, all established methods
focus on the synthesis of racemic tetrahydroquinolin-5-one-based spirooxindoles.5 In sharp
contrast, no catalytic asymmetric approaches are available for synthesizing such biologically
important chiral spirooxindoles. Nevertheless, the enantioselective construction of bioactive
molecules is important because the enantiomers may have different or better bioactivities
compared with the racemates.6 Thus, it is important to develop catalytic enantioselective
approaches for the construction of chiral tetrahydroquinolin-5-one-based spirooxindole scaffolds.
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HN
O
O
Me
O
HN
O
N
N
O
O
O
CN
N
N
O
CN
H
NH2
N
Antioxidant
NH2
N
HN
O
CO2Et
NH2
R = H, Cl
R
Cl
Antimicrobial,
N
Lifespan-altering
H
cytotoxic to MCF-7
Inhibiting alanyl
aminopeptidase
Figure 1. Selected bioactive tetrahydroquinolin-5-one-based spirooxindoles.
In recent years, due to the significance of chiral spirooxindoles in medicinal chemistry,
numerous catalytic asymmetric reactions have been developed rapidly for the enantioselective
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construction of a wide range of structurally diversified spirooxindole skeletons (Scheme 1, eq.
1).7-8 Despite these recent advances in this research field, the catalytic enantioselective
construction of tetrahydroquinolin-5-one-based spirooxindole scaffold remains underdeveloped
(eq. 2). This may be associated with challenges in enantioselectively constructing this framework,
such as the design of the enantioselective reaction, the selection of chiral catalysts based on the
reaction mechanism, and the activation mode. Therefore, it is important to design catalytic
enantioselective reactions and identify suitable catalytic systems to construct a spirooxindole
framework.
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Scheme 1. Profile of catalytic enantioselective construction of spirooxindole skeletons.
Organocatalytic asymmetric transformations,9-10 especially multicomponent reactions, are
considered robust methods for the enantioselective construction of frameworks with medicinal
relevance, which can avoid transition-metal contamination of the products.11 In addition, catalytic
enantioselective [3+3] cyclizations, especially organocatalytic enantioselective multicomponent
[3+3] cyclizations, have proven to be efficient strategies for constructing chiral six-membered
rings in a single step.12 To construct a tetrahydroquinolin-5-one-based spirooxindole scaffold in an
enantioselective fashion, and due to our continuous interest in organocatalytic enantioselective
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transformations,13 we designed an organocatalytic enantioselective multicomponent [3+3]
cyclization (Scheme 2). In this design, we envisioned the three-component reaction of cyclic
enaminone 1, isatin 2, and malononitrile 3 could be catalyzed by a tertiary amine-based
bifunctional catalyst, which could form multiple hydrogen bonds with enaminone 1 and
intermediate A to facilitate an enantioselective Michael addition and subsequent intramolecular
nucleophilic addition of the intermediate B, thus constructing the desired
tetrahydroquinolin-5-one-based spirooxindole scaffold in an enantioselective fashion.
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This work: the first catalytic asymmetric construction of
tetrahydroquinolin-5-one-based spirooxindole scaffold
R2
R3
O
N
O
O
O
CN
CN
3
Organo-Cat.*
*
R3
CN
+
+
O
R1
R1
[3+3] cyclization
N
R2
NH
R1
R1
N
NH2
R
R
4
2
1
R3
R2
N
R2
R3
R2
N
N
R3
O
O
O
A
O
O
*
O
N
isomerize
*
R4
N
R1
R1
H
R1
R1
X
N
N
N
N
H
R1
N
R4
N
H
H
X
R1
R
H
R6
R
1
N
H
X
*
N
R
X
B
*
R6
N
R5
intramolecular
nucleophilic addition
*
X = O, N
X = O, N
R5
Michael addition
Scheme 2. Design of the catalytic asymmetric reaction for the construction of an enantioenriched
tetrahydroquinolin-5-one-based spirooxindole scaffold.
Herein, we report the first catalytic asymmetric construction of
a
chiral
tetrahydroquinolin-5-one-based spirooxindole scaffold (up to 99% yield, 97:3 er) that takes
advantage of the three-component [3+3] cyclization of enaminone, isatin, and malononitrile in the
presence of a chiral bifunctional organocatalyst. This reaction also represents the first catalytic
enantioselective version of this type of three-component [3+3] cyclization.
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Results and Discussion
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To test the feasibility of our hypothesis, the reaction of dimedone-derived enaminone 1a,
N-benzyl substituted isatin 2a, and malononitrile 3 was used as a model reaction in the presence of
chiral cinchona alkaloid catalyst 5a, which smoothly afforded the desired
tetrahydroquinolin-5-one-based spirooxindole 4aa, but in a moderate yield and with low
enantioselectivity (Table 1, entry 1). A series of bifunctional catalysts, 5b–5i, derived from
various cinchona alkaloids14 were screened (entries 2–9). Although the yields were still
unsatisfactory, cinchona alkaloid derivatives 5b and 5d bearing two hydroxyl groups were
superior to others in controlling the enantioselectivity (entries 2 and 4 vs. entries 1, 3 and 5–9),
which may be attributed to the action of the two hydroxyl groups in forming multiple hydrogen
bonds with enaminone 1 and intermediate A. In particular, catalyst 5d afforded the product with
the highest level of enantioselectivity (entry 4 vs. entry 2). Subsequently, screening the solvents
showed that chloroform remained the best solvent, which delivered the reaction with the highest
enantioselectivity of 79:21 er with a moderate yield of 46% (entry 4 vs. entries 10–14). Under this
condition, the replacement of catalyst 5d by 5j resulted in further improved enantioselectivity of
88:12 er, but with no obvious enhancement in yield (entry 15 vs. entry 4). Besides, several chiral
thiourea−tertiary amine and squaramide−tertiary amine catalysts 5k–5u were applied to the model
reaction, but all showed lower catalytic activity than 5j in terms of the enantioselective control
(see Supporting Information for details). Thus, catalyst 5j was selected as the optimal catalyst. To
further improve the enantioselectivity and yield, different additives were evaluated in the presence
of catalyst 5j (entries 15−18), which revealed that MgSO4 was inferior to other additives with
regard to the enantioselective control and yield (entry 18 vs. entries 15–17). Among these
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additives, 4 Å molecular sieves (MS) were the most suitable, which could improve the yield to
81% with a retained enantioselectivity of 88:12 er (entry 17 vs. entries 15–16 and 18). When we
increased the volume of the solvent from 0.5 to 2 mL, the enantioselectivity increased to 94:6 er
albeit with a decreased yield (entry 20 vs. entries 18–19). Fortunately, when the molar ratio of
reagents was changed to 1:1.5:1.5, the yield could be increased to 75% with a retained
enantioselectivity (entry 21 vs. entry 20). However, when we further increased the volume of the
solvent or lowered the reaction temperature, the yields decreased sharply with no improvement in
enantioselectivity (entry 21 vs. entries 22–23). Finally, the best enantioselectivity of 96:4 er and
the highest yield of 91% were obtained by modulating the molar ratio to 1:4:4 with a prolonged
reaction time (entry 24).
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Table 1. Screening of catalysts and optimization of reaction conditionsa.
Entry
5
Solvent
Additives
Yield (%)b
erc
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
22
69
39
46
61
54
99
17
53:47
70:30
52:48
79:21
44:56
57:43
52:48
50:50
5g
5h
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5i
5d
5d
5d
5d
5d
5j
5j
5j
5j
5j
5j
5j
5j
5j
5j
5j
CHCl3
toluene
THF
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
3 Å MS
4 Å MS
MgSO4
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
20
22
49:51
77:23
-
11
Trace
38
12
CH3CN
EtOAc
acetone
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
52:48
-
13
Trace
Trace
50
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14
-
15
88:12
82:18
88:12
81:19
90:10
94:6
94:6
95:5
94:6
94:6
96:4
16
62
17
81
18
47
19d
20e
21e,f
22g,f
23e,f,h
24e,f,i
25e,i,j
80
54
75
45
43
80
91
aUnless otherwise indicated, the reaction was performed at the 0.05 mmol scale and catalyzed by
10 mol% 5 in a solvent (0.5 mL) with additives (100 mg) at 10°C for 2 days, and the molar ratio
b
c
of 1a:2a:3 was 1.2:1:1. Isolated yield. The er value was determined by high-performance liquid
d
e
chromatography (HPLC). The volume of solvent was 1 mL. The volume of solvent was 2 mL.
g
h
fThe molar ratio of 1a:2a:3 was 1:1.5:1.5. The volume of solvent was 3 mL. Performed at 0°C.
iThe reaction time was 4 days. jThe molar ratio of 1a:2a:3 was 1:4:4.
After establishing the optimal reaction conditions, we investigated the substrate scope of this
organocatalytic enantioselectivity multicomponent reaction. First, we examined the generality of
enaminones 1 by the reaction with N-benzyl substituted isatin 2a and malononitrile 3. As shown in
Table 2, this approach was applicable to a wide range of substrates 1 bearing different R1/R2
groups, which afforded structurally diverse tetrahydroquinolin-5-one-based spirooxindoles 4 at
generally high yields and excellent enantioselectivities (90:10 to 96:4 er). In detail, the electronic
nature of the aniline moieties had no obvious effect on the enantioselectivity (entries 1–6). For
example, in the cases of meta-substituted aniline-derived enaminones, both electron-donating
groups such as methoxy (OMe) and electron-withdrawing groups such as fluorine (F) proved to be
suitable substituents for enaminone substrates, which delivered the reaction in nearly identical
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enantioselectivities (entries 5–6). However, the position of the substituents in the aniline moieties
seemed to have effects on both the reactivity and enantioselectivity because para-substituted
aniline-derived enaminones 1a–1d showed higher reactivity and capability in enantioselective
control than their meta-substituted counterparts 1e–1f (entries 1–4 vs. entries 5–6). Substrate 1h
bearing a 2-naphthyl group could be utilized in this reaction at a high yield of 85% and a good
enantioselectivity of 92:8 er (entry 8). Alkylamine-derived enaminones 1i and 1j successfully
participated in this reaction to generate the corresponding [3+3] cyclization products with good
enantioselectivities (entries 9–10). These results increase the applicability of this reaction. Apart
from dimedone-derived enaminones, cyclohexanedione-derived enaminone 1k could play a role in
the reaction with a good enantioselectivity of 93:7 er (entry 11).
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Table 2. Substrate scope of enaminones 1a.
Bn
O
O
N
O
10 mol% 5j, 10 o
C
O
CN
CN
CN
R2
R2
O
+
+
CHCl3,4 Å MS
N
NH
R1
R2
R2
Bn
NH2
N
R1
1
3
2a
4
entry
1
4
R1/R2
yield (%)b
erc
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
4-OMeC6H4/Me (1a)
4-MeC6H4/Me (1b)
4-FC6H4/Me (1c)
4-ClC6H4/Me (1d)
3-OMeC6H4/Me (1e)
3-FC6H4/Me (1f)
C6H5/Me (1g)
91
99
99
99
78
85
79
85
43
71
45
96:4
93:7
93:7
94:6
90:10
91:9
92:8
92:8
93:7
90:10
93:7
2
3
4
5d
6
7
8
2-naphthyl/Me (1h)
Bn/Me (1i)
9e
10e
11f
4ja
4ka
n-C3H7/Me (1j)
4-OMeC6H4/H (1k)
aUnless otherwise indicated, the reaction was performed at the 0.1 mmol scale and catalyzed by 10
mol% 5j in chloroform (4 mL) at 10°C for 4 days, and the molar ratio of 1:2a:3 was 1:4:4.
c
d
bIsolated yields. The er value was determined by HPLC. Performed at 0°C for 4 days.
ePerformed at 70°C for 7 days. fPerformed at 50°C for 4 days.
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Furthermore, in place of cyclic enaminones, ethyl acetoacetate-derived enaminone 1l
was tentatively used as a substrate for this [3+3] cyclization under optimal conditions (eq 3);
however, no desired spirooxindole 4la was generated. Instead, pyran-based spirooxindole 6
was obtained in an acceptable enantioselectivity of 87:13 er, albeit with a low yield of 36%.
The generation of product 6 may be ascribed to the instability of enaminone 1l, which easily
decomposed into ethyl acetoacetate to undergo [3+3] cyclization.
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Next, the substrate scope of isatins 2 was studied based on the reaction with enaminone 1a
and malononitrile 3. As summarized in Table 3, this protocol was amenable to a series of isatins 2,
which generated structurally diversified spirooxindoles 4 at overall high yields (60% to 91%) and
with excellent enantioselectivities (90:10 to 96:4 er). We first investigated the effect of
N-substituents of isatins 2 in the reaction (entries 1–5). Generally, N-benzyl-substituted isatins
2a–2c showed similar capability in enantioselective control with N-alkyl-substituted and
N-allyl-substituted isatins 2d and 2e (entries 1–3 vs. entries 4–5). N-unprotected isatin 2f could
play a role in this [3+3] reaction with a good enantioselectivity of 90:10 er and a high yield of
86% (entry 6). Next, a wide scope of isatins 2 bearing electronically different substituents at
various positions of the phenyl moiety were applied to the [3+3] reactions (entries 7–12), which
revealed that the position of the substituents influenced the enantioselectivity. For example,
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C5-substituted isatins were inferior to C7-substituted isatins in terms of enantioselective control
(entries 10–11 vs. entries 7–9). Moreover, apart from mono-substituted substrates, disubstituted
isatin 2l could smoothly undergo the [3+3] cyclization in the highest enantioselectivity of 97:3 er
(entry 12).
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Table 3. Substrate scope of isatins 2a.
Entry
1
4
R1/R2
Bn/H (2a)
Yield (%)b
erc
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
91
87
63
60
72
86
84
74
82
77
72
66
96:4
93:7
90:10
93:7
96:4
90:10
90:10
94:6
90:10
96:4
95:5
97:3
2
3d
o-FC6H4CH2/H (2b)
C6F5CH2/H (2c)
Allyl/H (2d)
Me/H (2e)
4
5d
6
H/H (2f)
7
Bn/5-OMe (2g)
Bn/5-Me (2h)
Bn/5-Br (2i)
8
9d
10
11
12
4aj
4ak
4al
Bn/7-OMe (2j)
Bn/7-Me (2k)
Bn/5,7-Me2 (2l)
aUnless indicated otherwise, the reaction was performed at the 0.1 mmol scale and catalyzed by 10
mol% 5j in chloroform (4 mL) at 10oC for 4 days, and the molar ratio of 1a:2:3 was 1:4:4.
bIsolated yields. cThe er value was determined by HPLC. dPerformed at 0°C for 4 days.
The absolute configuration of product 4aa (>99:1 er after recrystallization) was determined to
be (R) based on single crystal X-ray diffraction analysis (see the Supporting Information for
details).15 Thus, the absolute configurations of other tetrahydroquinolin-5-one-based
spirooxindoles 4 were assigned by analogy.
Based on the experimental results, we suggested a possible reaction pathway and activation
mode to explain the stereochemistry of this three-component reaction. As exemplified by the
formation of product 4aa (Scheme 3), the Knoevenagel condensation of isatin 2a with
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malononitrile 3 in the presence of catalyst 5j afforded an intermediate A.16 The intermediate A and
dimedone-derived enaminone 1a were simultaneously activated by chiral cinchona alkaloid 5j
through multiple hydrogen-bonding activation mode. This activation mode and the fixed
orientation between the substrates and catalyst 5j promoted an enantioselective Michael addition
of dimedone-derived enaminone 1a to the intermediate A, leading to the generation of another
intermediate B with a fixed configuration. Subsequently, activated again by multiple hydrogen
bonds between the catalyst 5j and the intermediate B, this intermediate immediately underwent an
intramolecular nucleophilic addition of the amino group to the cyano group, which resulted in the
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formation of the final product 4aa with (R)-configuration.
Bn
O
N
O
O
CN
+
O
CN
N
CN
Bn
NH2
N
2a
3
PMP
4aa
5j
Knoevenagel
condensation
H2O
5j
isomerize
H
O
A
BnN
O
C
C
N
N
O
N
C
H
H
BnN
O
N
N
O
C
N
BnN
N
C
N
H
O
O
C
isomerize
O
O
O
H
N
N
H
N
N
B
PMP
N
1a
PMP
PMP
intramolecular
nucleophilic addition
5j
Michael addition
Scheme 3. Suggested transition state and activation mode.
To verify our suggested reaction pathway, we performed a control experiment (Scheme 4).
We monitored the reaction mixture, which revealed that the intermediate A (isatylidene
malononitrile A) was rapidly generated within a short reaction time of 5 min. We then used
isatylidene malononitrile A as starting material to perform [3+3] cyclization with enaminone 1a
under standard conditions. As expected, this two-component reaction gave rise to the desired
product 4aa in the same enantioselectivity of 96:4 er with that of the three-component reaction.
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This outcome demonstrated that the Knoevenagel condensation of isatins 2 with malononitrile 3
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was indeed the first step of this one-pot three-component reaction.
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Bn
NC
N
O
CN
O
O
O
10 mol% 5j, 10 o
C
CN
+
CHCl3, 4 Å MS
NH
N
N
NH2
PMP
Bn
PMP
4aa
76%, 96:4 er
1a
A
Scheme 4. Control experiment.
Finally, to explore the potential of this approach, the model reaction was performed at a
1-mmol scale under standard conditions. As shown in eq. 4, compared with the small-scale
reaction (Table 2, entry 1), the desired product 4aa was obtained at a high yield of 91% and an
excellent enantioselectivity of 96:4 er. This outcome indicated that this approach could be
applicable for a large-scale synthesis of enantioenriched tetrahydroquinolin-5-one-based
spirooxindoles. In addition, product 4aa could be easily acylated by benzoyl chloride to generate
compound 7 at a good yield of 92% and an almost retained enantioselectivity of 95:5 er (eq. 5).
Bn
N
O
O
O
O
10 mol% 5j, 10 o
C
CN
CN
CN
+
+
(4)
O
CHCl3, 4 Å MS
N
NH
PMP
N
NH2
Bn
PMP
3
4aa
91% (482 mg), 96:4 er
1a
1 mmol
2a
4 mmol
4 mmol
Bn
Bn
N
N
O
O
O
O
CN
CN
PhCOCl, DAMP, NEt3
DCM, r.t., 2 days
(5)
NH2
N
N
NHCOPh
PMP
4aa
96:4 er
PMP
6
70%, 95:5 er
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Conclusions
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Overall, we established the first catalytic enantioselective construction of a biologically
important tetrahydroquinolin-5-one-based spirooxindole scaffold in high yields and with excellent
enantioselectivities (up to 99% yield, 97:3 er) that takes advantage of chiral cinchona
alkaloid-catalyzed enantioselective three-component reactions. Moreover, this reaction combined
the merits of the multicomponent reaction and asymmetric organocatalysis, which realized the
first catalytic enantioselective three-component [3+3] cyclization of cyclic enaminone, isatin, and
malononitrile. Additionally, this reaction can be applied to large-scale synthesis of
tetrahydroquinolin-5-one-based spirooxindoles in an enantioselective fashion. This synthetic
methodology will not only provide an efficient approach for the construction of chiral
tetrahydroquinolin-5-one-based spirooxindole scaffolds with biological importance but also
increase our understanding of catalytic enantioselective three-component [3+3] cyclizations.
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Experimental Section
1H and 13C NMR spectra were measured at 400 and 100 MHz, respectively. The solvents used
for NMR spectroscopy were CDCl3, acetone-d6, and DMSO-d6, using tetramethylsilane as the
internal reference. HRMS (ESI) was determined by a HRMS/MS instrument. Enantiomeric ratios
(er) were determined by chiral high-performance liquid chromatography (chiral HPLC). The
chiral columns used for the determination of enantiomeric ratios by chiral HPLC were Chiralpak
AS-H, OD-H, AD-H and IA columns. Optical rotation values were measured with instruments
operating at λ = 589 nm, corresponding to the sodium D line at the temperatures indicated. The
X-ray source used for the single crystal X-ray diffraction analysis of compound 4aa was CuKα (λ
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= 1.54178). Analytical grade solvents for the column chromatography were used after distillation.
All starting materials commercially available were used directly.
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Typical experimental procedure for the synthesis of products 4 and 6:
To the mixture of enaminones 1 (0.1 mmol), isatins 2 (0.4 mmol), malononitrile 3 (0.4 mmol),
chiral catalyst 5j (0.01 mmol) and 4 Å MS (100 mg) was added chloroform (4 mL). After being
o
stirred at 10 C for 4 days, the reaction mixture was filtered to remove the molecular sieves and
the solid powder was washed with ethyl acetate. The resultant solution was concentrated under the
reduced pressure to give the residue, which was purified through flash column chromatography on
silica gel to afford pure products 4 or 6.
(R)-2'-amino-1-benzyl-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetrahydr
o-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4aa): Flash column chromatography
eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 91% (48.4 mg); white
o
20
1
solid; m.p. 189–190 C; [α]D = +14.1 (c 0.7, Acetone); H NMR (400 MHz, CDCl3) δ (ppm):
7.53 (d, J = 7.6 Hz, 2H), 7.38 – 7.30 (m, 2H), 7.30 – 7.27 (m, 1H), 7.25 – 7.19 (m, 2H), 7.13 (d, J
= 7.2 Hz, 1H), 7.10 – 6.93 (m, 4H), 6.58 (d, J = 7.6 Hz, 1H), 5.11 (d, J = 16.0 Hz, 1H), 4.95 (d, J
= 16.0 Hz, 1H), 4.29 (s, 2H), 3.85 (s, 3H), 2.20 (d, J = 16.0 Hz, 1H), 2.15 – 2.03 (m, 2H), 1.91 (d,
J = 17.2 Hz, 1H), 0.97 (s, 3H), 0.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.7, 178.7,
160.7, 152.2, 151.1, 142.2, 136.1, 135.4, 131.0, 130.6, 128.7, 128.4, 127.8, 127.3, 127.2, 122.8,
122.7, 118.7, 116.0, 115.5, 111.1, 109.4, 62.7, 55.7, 49.7, 48.6, 44.5, 42.1, 32.5, 29.3, 27.0; IR
(KBr): 3468, 2959, 2929, 2184, 1716, 1649, 1509, 1362, 1253, 758, 696; ESI FTMS exact mass
calcd for (C33H30N4O3+H)+ requires m/z 531.2396, found m/z 531.2405; The enantiomeric ratio
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(er) value: 96:4, determined by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 70/ 30,
flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 5.860 (major), tR = 8.613 (minor).
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(R)-2'-amino-1-benzyl-7',7'-dimethyl-2,5'-dioxo-1'-(p-tolyl)-5',6',7',8'-tetrahydro-1'H-spiro
[indoline-3,4'-quinoline]-3'-carbonitrile (4ba): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 99% (51.0 mg); white solid; m.p.
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209–211 C; [α]D = +12.6 (c 0.8, Acetone); H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.2 Hz,
2H), 7.45 – 7.33 (m, 4H), 7.33 – 7.29 (m, 1H), 7.28 – 7.20 (m, 2H), 7.20 – 7.07 (m, 2H), 7.05 –
6.95 (m, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.14 (d, J = 16.0 Hz, 1H), 5.00 (d, J = 16.0 Hz, 1H), 4.19
(s, 2H), 2.49 (s, 3H), 2.29 – 2.18 (m, 1H), 2.18 – 2.07 (m, 2H), 1.93 (d, J = 17.2 Hz, 1H), 1.00 (s,
3H), 0.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.6, 178.6, 151.8, 150.7, 142.3, 141.0,
136.0, 135.3, 133.0, 131.4, 131.3, 129.5, 129.2, 128.7, 128.4, 127.3, 127.2, 122.8, 122.7, 118.5,
111.2, 109.4, 63.2, 49.8, 48.6, 44.6, 42.1, 32.5, 29.2, 27.0, 21.3; IR (KBr): 3445, 2958, 2355, 2335,
2182, 1716, 1645, 1362, 1185, 1152, 750, 694; ESI FTMS exact mass calcd for (C33H30N4O2+H)+
requires m/z 515.2447, found m/z 515.2439; The enantiomeric ratio (er) value: 93:7, determined
by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 oC,
254 nm): tR = 7.330 (major), tR = 11.077 (minor).
(R)-2'-amino-1-benzyl-1'-(4-fluorophenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetrahydro-1
'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4ca): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 99% (51.2 mg); white solid; m.p.
320–321 oC; [α]D20 = +9.0 (c 0.8, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.52 (d, J = 7.6
Hz, 2H), 7.44 – 7.29 (m, 5H), 7.26 – 7.18 (m, 2H), 7.15 – 7.05 (m, 2H), 7.03 – 6.93 (m, 1H), 6.60
(d, J = 8.0 Hz, 1H), 5.10 (d, J = 16.0 Hz, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.21 (s, 2H), 2.25 – 2.16
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(m, 1H), 2.14 – 2.04 (m, 2H), 1.86 (d, J = 17.2 Hz, 1H), 0.97 (s, 3H), 0.92 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm): 194.6, 178.5, 163.2 (J = 251.2 Hz), 151.5, 150.7, 142.3, 135.9, 135.2,
132.0 (J = 8.6 Hz), 131.6, 131.6, 131.5, 128.7, 128.5, 127.3, 127.2, 122.8, 118.4, 117.9 (J = 26.8
Hz), 111.5, 109.5, 63.4, 49.7, 48.6, 44.6, 42.2, 32.5, 29.2, 27.0; IR (KBr): 3447, 3365, 2960, 2359,
2181, 1701, 1650, 1364, 1154, 1252, 758, 694; ESI FTMS exact mass calcd for
(C32H27FN4O2+H)+ requires m/z 519.2196, found m/z 519.2208; The enantiomeric ratio (er) value:
93:7, determined by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0
mL/min, T = 30 oC, 254 nm): tR = 8.363 (major), tR = 16.387 (minor).
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(R)-2'-amino-1-benzyl-1'-(4-chlorophenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetrahydro-
1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4da): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 99% (53.2 mg); white solid; m.p.
278–280 oC; [α]D20 = +19.3 (c 0.7, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.58 – 7.48 (m,
4H), 7.39 – 7.31 (m, 3H), 7.26 – 7.21 (m, 1H), 7.15 – 7.05 (m, 3H), 7.01 – 6.95 (m, 1H), 6.61 (d, J
= 7.6 Hz, 1H), 5.10 (d, J = 16.0 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.20 (s, 2H), 2.21 (d, J = 16.0
Hz, 1H), 2.14 – 2.05 (m, 2H), 1.87 (d, J = 17.2 Hz, 1H), 0.98 (s, 3H), 0.93 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm): 194.6, 178.5, 151.2, 150.4, 142.3, 136.8, 135.9, 135.1, 134.2, 128.7, 128.5,
128.3, 127.3, 127.2, 127.0, 122.8, 122.8, 120.7, 118.3, 111.6, 109.5, 63.7, 49.7, 48.6, 44.6, 42.2,
32.6, 29.2, 27.0; IR (KBr): 3056, 2957, 2358, 2185, 1716, 1649, 1360, 1091, 1015, 754, 696; ESI
FTMS exact mass calcd for (C32H27ClN4O2+H)+ requires m/z 535.1901, found m/z 535.1923; The
enantiomeric ratio (er) value: 94:6, determined by HPLC (Daicel Chiralpak AS-H, hexane/
o
isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR = 5.510 (major), tR = 8.027
(minor).
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(R)-2'-amino-1-benzyl-1'-(3-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetrahydr
o-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4ea): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 78% (41.3 mg); white solid; m.p.
158–160 oC; [α]D20 = +11.1 (c 0.6, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.59 – 7.43 (m,
3H), 7.39 – 7.29 (m, 2H), 7.25 – 7.20 (m, 1H), 7.17 – 7.05 (m, 3H), 7.02 – 6.76 (m, 3H), 6.60 (d, J
= 7.6 Hz, 1H), 5.11 (d, J = 16.0 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.23 (s, 2H), 3.87 (d, J = 9.6
Hz, 3H), 2.28 – 2.12 (m, 2H), 2.09 (d, J = 16.4 Hz, 1H), 1.96 (d, J = 17.2 Hz, 1H), 0.98 (s, 3H),
0.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.6, 178.6, 161.2, 151.5, 150.5, 142.3,
136.7, 136.0, 135.3, 131.5, 131.3, 128.7, 128.4, 127.2, 122.8, 121.8, 121.4, 118.5, 116.5, 115.7,
115.5, 115.2, 109.4, 63.1, 55.8, 49.8, 48.6, 44.6, 41.9, 32.6, 29.2, 27.0, 26.9; IR (KBr): 3441, 2961,
2186, 1716, 1645, 1362, 1259, 1021, 734; ESI FTMS exact mass calcd for (C33H30N4O3+H)+
requires m/z 531.2396, found m/z 531.2401; The enantiomeric ratio (er) value: 90:10, determined
by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 oC,
254 nm): tR = 10.333 (major), tR = 16.723 (minor).
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(R)-2'-amino-1-benzyl-1'-(3-fluorophenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetrahydro-1
'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4fa): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 85% (44.2 mg); white solid; m.p.
178–180 oC; [α]D20 = +10.9 (c 0.7, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.60 – 7.49 (m,
3H), 7.39 – 7.27 (m, 3H), 7.26 – 7.17 (m, 2H), 7.16 – 7.02 (m, 3H), 7.01 – 6.94 (m, 1H), 6.60 (d, J
= 7.6 Hz, 1H), 5.10 (d, J = 16.0 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.22 (s, 2H), 2.25 – 2.11 (m,
2H), 2.07 (s, 1H), 1.89 (d, J = 17.2 Hz, 1H), 0.98 (s, 3H), 0.93 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 194.5, 178.4, 163.2 (J = 251.4 Hz), 151.2, 151.1, 150.3, 142.3, 137.1 (J = 9.3
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Hz), 135.9, 135.1, 132.0, 128.7, 128.5, 127.3, 122.8, 118.3, 118.1 (J = 20.6 Hz), 111.6, 109.5, 63.7,
49.8, 48.6, 44.6, 42.0, 32.6, 29.1, 27.0; IR (KBr): 3648, 3586, 3326, 2957, 2359, 2189, 1705, 1652,
1362, 1175, 797, 660; ESI FTMS exact mass calcd for (C32H27FN4O2+H)+ requires m/z 519.2196,
found m/z 519.2194; The enantiomeric ratio (er) value: 91:9, determined by HPLC (Daicel
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Chiralpak AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR =
8.177 (major), tR = 13.227 (minor).
(R)-2'-amino-1-benzyl-7',7'-dimethyl-2,5'-dioxo-1'-phenyl-5',6',7',8'-tetrahydro-1'H-spiro[
indoline-3,4'-quinoline]-3'-carbonitrile (4ga): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 79% (39.5 mg); white solid; m.p.
279–280 oC; [α]D20 = +10.8 (c 0.6, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.62 – 7.51 (m,
5H), 7.40 – 7.30 (m, 4H), 7.24 (d, J = 7.2 Hz, 1H), 7.17 – 7.13 (m, 1H), 7.12 – 7.06 (m, 1H), 7.03
– 6.94 (m, 1H), 6.60 (d, J = 7.6 Hz, 1H), 5.12 (d, J = 16.0 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.18
(s, 2H), 2.27 – 2.10 (m, 2H), 2.09 – 2.03 (m, 1H), 1.94 – 1.81 (m, 1H), 0.96 (s, 3H), 0.92 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm): 194.6, 178.6, 151.6, 150.6, 142.3, 136.0, 135.8, 135.3,
130.8, 130.6, 129.9, 129.6, 128.7, 128.5, 128.4, 127.3, 127.2, 122.8, 118.5, 111.3, 109.5, 63.3,
49.8, 48.6, 44.6, 42.1, 32.5, 29.2, 27.0; IR (KBr): 3471, 3310, 2958, 2360, 2196, 1640, 1363, 1153,
1048, 745, 699; ESI FTMS exact mass calcd for (C32H28N4O2+H)+requires m/z 501.2290, found
m/z 501.2308; The enantiomeric ratio (er) value: 92:8, determined by HPLC (Daicel Chiralpak
o
AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR = 9.740
(major), tR = 16.327 (minor).
(R)-2'-amino-1-benzyl-7',7'-dimethyl-1'-(naphthalen-1-yl)-2,5'-dioxo-5',6',7',8'-tetrahydro-
1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4ha): Flash column chromatography eluent,
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dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 85% (46.5 mg); white solid; m.p.
264–265 oC; [α]D20 = +12.9 (c 0.7, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 8.13 – 8.03 (m,
1H), 8.03 – 7.83 (m, 3H), 7.75 – 7.60 (m, 2H), 7.53 (d, J = 7.6 Hz, 2H), 7.48 – 7.37 (m, 1H), 7.37
– 7.30 (m, 2H), 7.25 – 7.17 (m, 2H), 7.14 – 7.06 (m, 1H), 7.05 – 6.97 (m, 1H), 6.60 (d, J = 7.6 Hz,
1H), 5.15 – 5.05 (m, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.23 (d, J = 7.2 Hz, 2H), 2.28 – 2.06 (m, 3H),
2.03 – 1.86 (m, 1H), 0.98 – 0.86 (m, 6H); 13C NMR (100 MHz, Acetone-d6) δ (ppm): 193.8, 178.2,
142.8, 136.9, 136.3, 133.7, 133.6, 130.6, 129.9, 128.4, 128.0, 127.7, 127.3, 127.3, 126.9, 123.2,
122.1, 118.5, 108.6, 68.8, 62.2, 54.6, 49.6, 48.8, 43.8, 41.8, 32.2, 31.1; IR (KBr): 3648, 3310,
2958, 2359, 2183, 1716, 1646, 1361, 1260, 1173, 1101; ESI FTMS exact mass calcd for
(C36H30N4O2+H)+ requires m/z 551.2447, found m/z 551.2462; The enantiomeric ratio (er) value:
92:8, determined by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 90/ 10, flow rate 1.0
mL/min, T = 30 oC, 254 nm): tR = 30.020 (major), tR = 47.763 (minor).
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(R)-2'-amino-1,1'-dibenzyl-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetrahydro-1'H-spiro[indoli
ne-3,4'-quinoline]-3'-carbonitrile
(4ia):
Flash
column
chromatography
eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 7 d; yield: 43% (22.1 mg); white solid; m.p.
269–271 oC; [α]D20 = +13.3 (c 0.4, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.56 – 7.45 (m,
4H), 7.41 – 7.33 (m, 3H), 7.30 – 7.27 (m, 3H), 7.13 – 7.04 (m, 2H), 7.02 – 6.96 (m, 1H), 6.62 (d, J
= 7.6 Hz, 1H), 5.11 (d, J = 16.0 Hz, 1H), 5.05 – 4.82 (m, 3H), 4.48 (s, 2H), 2.59 – 2.36 (m, 2H),
2.26 – 2.02 (m, 2H), 1.07 (s, 3H), 0.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.4,
178.8, 152.4, 151.9, 142.2, 135.9, 135.6, 135.2, 129.7, 128.7, 127.2, 125.2, 122.9, 118.6, 112.4,
109.5, 65.9, 49.4, 49.0, 48.3, 44.6, 40.7, 32.6, 28.7, 27.4; IR (KBr): 3438, 2963, 2360, 2184, 1652,
1363, 1261, 800, 668; ESI FTMS exact mass calcd for (C33H30N4O2+H)+ requires m/z 515.2447,
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found m/z 515.2455; The enantiomeric ratio (er) value: 93:7, determined by HPLC (Daicel
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Chiralpak IA, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR =
8
9
16.653 (minor), tR = 19.590 (major).
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(R)-2'-amino-1-benzyl-7',7'-dimethyl-2,5'-dioxo-1'-propyl-5',6',7',8'-tetrahydro-1'H-spiro[i
ndoline-3,4'-quinoline]-3'-carbonitrile (4ja): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 7 d; yield: 71% (32.9 mg); white solid; m.p.
250–251 oC; [α]D20 = +28.0 (c 0.6, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.64 – 7.49 (m,
2H), 7.45 – 7.35 (m, 2H), 7.33 – 7.26 (m, 1H), 7.16 – 7.05 (m, 1H), 7.04 – 6.94 (m, 2H), 6.62 (d, J
= 7.6 Hz, 1H), 5.12 (d, J = 16.4 Hz, 1H), 4.98 (d, J = 16.4 Hz, 1H), 4.92 (s, 2H), 3.82 – 3.50 (m,
2H), 2.76 – 2.39 (m, 2H), 2.28 – 2.10 (m, 2H), 1.89 – 1.62 (m, 2H), 1.17 (s, 3H), 1.08 (s, 3H),
1.05 – 0.96 (m, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.5, 179.3, 152.4, 152.1, 142.0,
135.9, 135.2, 128.8, 128.7, 128.4, 127.3, 127.2, 122.9, 122.8, 119.3, 112.3, 109.4, 64.9, 49.5, 48.9,
46.5, 44.6, 40.7, 32.5, 28.9, 27.7, 23.1, 11.0; IR (KBr): 3189, 2961, 2359, 2181, 1651, 1380, 1029,
734, 693; ESI FTMS exact mass calcd for (C29H30N4O2+H)+ requires m/z 467.2447, found m/z
467.2457; The enantiomeric ratio (er) value: 90:10, determined by HPLC (Daicel Chiralpak OD-H,
hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 9.727 (minor), tR =
34.767 (major).
(R)-2'-amino-1-benzyl-1'-(4-methoxyphenyl)-2,5'-dioxo-5',6',7',8'-tetrahydro-1'H-spiro[in
doline-3,4'-quinoline]-3'-carbonitrile (4ka): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 45% (22.8 mg); white solid; m.p.
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181–182 C; [α]D = +34.5 (c 0.2, Acetone); H NMR (400 MHz, CDCl3) δ (ppm): 7.53 (d, J =
7.2 Hz, 2H), 7.40 – 7.31 (m, 3H), 7.30 – 7.27 (m, 1H), 7.26 – 7.21 (m, 1H), 7.17 – 7.12 (m, 1H),
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7.12 – 7.03 (m, 3H), 7.02 – 6.95 (m, 1H), 6.59 (d, J = 7.6 Hz, 1H), 5.12 (d, J = 16.0 Hz, 1H), 4.99
(d, J = 16.0 Hz, 1H), 4.17 (s, 2H), 3.88 (s, 3H), 2.42 – 2.25 (m, 2H), 2.24 – 2.09 (m, 2H), 2.00 –
1.88 (m, 1H), 1.88 – 1.77 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.6, 178.7, 160.8,
153.9, 150.7, 142.3, 136.0, 135.4, 130.9, 130.6, 128.7, 128.4, 127.8, 127.2, 127.2, 122.9, 122.7,
118.5, 115.9, 115.5, 112.5, 109.4, 63.2, 55.7, 48.7, 44.6, 36.3, 28.6, 21.2; IR (KBr): 3361, 2963,
2359, 2178, 1705, 1635, 1261, 1022, 801, 694; ESI FTMS exact mass calcd for (C31H26N4O3+H)+
requires m/z 503.2083, found m/z 503.2098; The enantiomeric ratio (er) value: 93:7, determined
by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 oC,
254 nm): tR = 15.467 (major), tR = 23.407 (minor).
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(R)-2'-amino-1-(2-fluorobenzyl)-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-
tetrahydro-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile
(4ab):
Flash
column
chromatography eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 87%
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(47.8 mg); white solid; m.p. 256–258 C; [α]D = +18.5 (c 0.8, Acetone); H NMR (400 MHz,
CDCl3) δ (ppm): 7.71 – 7.58 (m, 1H), 7.35 – 7.26 (m, 1H), 7.25 – 7.18 (m, 2H), 7.16 – 6.95 (m,
7H), 6.65 (d, J = 7.6 Hz, 1H), 5.17 – 4.95 (m, 2H), 4.24 (s, 2H), 3.87 (s, 3H), 2.27 – 2.09 (m, 2H),
2.09 – 2.03 (m, 1H), 1.97 – 1.87 (m, 1H), 0.97 (s, 3H), 0.92 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm): 194.7, 178.8, 160.7, 160.5 (J = 243.6 Hz), 152.2, 151.0, 142.0, 135.3, 130.9, 130.6, 129.6
(J = 3.6 Hz), 128.8 (J = 8 Hz), 128.5, 127.8, 124.6, 123.1, 122.9, 118.6, 115.8 (J = 47.2 Hz), 115.0,
114.8, 111.1, 108.9, 62.8, 55.7, 49.7, 48.7, 42.1, 37.7, 32.5, 29.2, 27.0; IR (KBr): 3472, 2957,
2328, 2148, 1716, 1649, 1609, 1511, 1362, 1252, 1028, 909, 758, 690; ESI FTMS exact mass
calcd for (C33H29FN4O3+H)+ requires m/z 549.2302, found m/z 549.2307; The enantiomeric ratio
(er) value: 93:7, determined by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 80/ 20,
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flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 8.940 (major), tR = 14.810 (minor).
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(R)-2'-amino-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-1-((perfluorophenyl)methyl)-
5',6',7',8'-tetrahydro-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4ac): Flash column
chromatography eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 63%
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(39.0 mg); white solid; m.p. 220–221 C; [α]D = +11.0 (c 0.6, Acetone); H NMR (400 MHz,
CDCl3) δ (ppm): 7.28 – 7.18 (m, 3H), 7.15 – 7.09 (m, 1H), 7.08 – 6.98 (m, 3H), 6.93 (d, J = 7.6
Hz, 1H), 5.23 (d, J = 15.2 Hz, 1H), 4.83 (d, J = 15.2 Hz, 1H), 4.20 (s, 2H), 3.89 (s, 3H), 2.22 –
2.04 (m, 2H), 2.04 – 1.97 (m, 1H), 1.90 (d, J = 17.2 Hz, 1H), 0.96 (s, 3H), 0.91 (s, 3H);13C NMR
(100 MHz, CDCl3) δ (ppm): 194.5, 177.9, 160.7, 151.5 (J = 130.9 Hz), 138.4, 130.8 (J = 30.4 Hz),
128.6, 127.7, 123.1, 123.1, 117.9, 115.7 (J = 34.4 Hz), 110.9, 107.9, 62.5, 55.7, 49.6, 48.2, 42.0,
32.5, 32.0, 28.9, 27.1; IR (KBr): 3475, 3333, 2959, 2187, 1724, 1645, 1363, 1254, 1047, 954, 606;
ESI FTMS exact mass calcd for (C33H25F5N4O3+H)+ requires m/z 621.1925, found m/z 621.1952;
The enantiomeric ratio (er) value: 90:10, determined by HPLC (Daicel Chiralpak IA, hexane/
isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 14.587 (minor), tR = 17.857
(major).
(R)-1-allyl-2'-amino-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetrahydro-
1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4ad): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 60% (28.8 mg); white solid; m.p.
197–198 oC; [α]D20 = +7.7 (c 0.6, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.33 – 7.27 (m,
1H), 7.25 – 7.17 (m, 2H), 7.14 – 7.09 (m, 1H), 7.09 – 7.04 (m, 2H), 7.03 – 6.97 (m, 1H), 6.83 (d, J
= 7.6 Hz, 1H), 6.03 – 5.84 (m, 1H), 5.56 – 5.41 (m, 1H), 5.32 – 5.15 (m, 1H), 4.50 – 4.35 (m, 2H),
4.17 (s, 2H), 3.90 (s, 3H), 2.24 – 1.99 (m, 3H), 1.96 – 1.83 (m, 1H), 0.95 (s, 3H), 0.91 (s, 3H); 13C
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NMR (100 MHz, CDCl3) δ (ppm): 194.6, 178.1, 160.7, 152.0, 150.9, 142.3, 135.3, 131.7, 130.9,
130.6, 128.4, 127.8, 122.8, 122.6, 118.4, 117.5, 116.0, 115.5, 111.2, 109.2, 63.0, 55.7, 49.7, 48.5,
42.9, 42.1, 32.5, 29.2, 27.0; IR (KBr): 3315, 3213, 2958, 2924, 2185, 1719, 1650, 1509, 1363,
1252, 848, 605; ESI FTMS exact mass calcd for (C29H28N4O3+H)+ requires m/z 481.2239, found
m/z 481.2254; The enantiomeric ratio (er) value: 93:7, determined by HPLC (Daicel Chiralpak
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AS-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR = 5.773
(major), tR = 8.960 (minor).
(R)-2'-amino-1'-(4-methoxyphenyl)-1,7',7'-trimethyl-2,5'-dioxo-5',6',7',8'-tetrahydro-1'H-s
piro[indoline-3,4'-quinoline]-3'-carbonitrile (4ae): Flash column chromatography eluent,
dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 72% (32.7 mg); white solid; m.p.
144–145 oC; [α]D20 = +1.6 (c 0.6, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.33 – 7.27 (m,
1H), 7.27 – 7.18 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H), 7.09 – 7.03 (m, 2H), 7.04 – 6.97 (m, 1H), 6.84
(d, J = 7.6 Hz, 1H), 4.16 (s, 2H), 3.90 (s, 3H), 3.30 (s, 3H), 2.15 (d, J = 16.0 Hz, 1H), 2.10 – 2.00
(m, 2H), 1.89 (d, J = 17.2 Hz, 1H), 0.95 (s, 3H), 0.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm): 194.6, 178.5, 160.7, 151.9, 150.9, 143.2, 135.3, 130.9, 130.6, 128.6, 127.8, 122.7, 122.6,
118.4, 116.0, 115.5, 111.3, 108.1, 62.9, 55.7, 49.7, 48.5, 42.1, 32.5, 29.1, 27.0, 26.7; IR (KBr):
3674, 3445, 2962, 2923, 2359, 2184, 1715, 1645, 1260, 801, 668; ESI FTMS exact mass calcd for
(C27H26N4O3+H)+requires m/z 455.2083, found m/z 455.2096; The enantiomeric ratio (er) value:
96:4, determined by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 70/ 30, flow rate 1.0
mL/min, T = 30 oC, 254 nm): tR = 7.297 (major), tR = 12.977 (minor).
(R)-2'-amino-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetrahydro-1'H-spi
ro[indoline-3,4'-quinoline]-3'-carbonitrile (4af): Flash column chromatography eluent,
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dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 86% (38.0 mg); white solid; m.p.
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269–271 C; [α]D = +6.6 (c 0.2, Acetone); H NMR (400 MHz, DMSO-d6) δ (ppm): 10.21 (s,
1H), 7.43 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.24 – 7.07 (m, 4H), 7.00 – 6.86 (m, 1H),
6.76 (d, J = 7.6 Hz, 1H), 5.37 (s, 2H), 3.85 (s, 3H), 2.19 – 2.06 (m, 2H), 1.97 – 1.81 (m, 2H), 0.89
(s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 194.3, 180.0, 160.3, 152.8, 151.9,
141.9, 137.2, 131.7, 131.4, 128.6, 128.1, 123.6, 121.8, 119.5, 116.0, 115.6, 110.7, 109.3, 61.0,
56.0, 49.8, 48.9, 41.8, 32.5, 28.8, 27.1; IR (KBr): 3675, 3385, 2971, 2900, 2359, 1647, 1508, 1260,
1048, 880, 669; ESI FTMS exact mass calcd for (C26H24N4O3+Na)+ requires m/z 463.1746, found
m/z 463.1731; The enantiomeric ratio (er) value: 90:10, determined by HPLC (Daicel Chiralpak
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AD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR = 21.313
(minor), tR = 28.627 (major).
(R)-2'-amino-1-benzyl-5-methoxy-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8
'-tetrahydro-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile
(4ag):
Flash
column
chromatography eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 84%
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(46.8 mg); white solid; m.p. 199–200 C; [α]D = -13.4 (c 0.9, Acetone); H NMR (400 MHz,
CDCl3) δ (ppm): 7.52 (d, J = 7.2 Hz, 2H), 7.37 – 7.27 (m, 3H), 7.25 – 7.17 (m, 2H), 7.08 – 6.94
(m, 2H), 6.78 – 6.67 (m, 1H), 6.63 – 6.54 (m, 1H), 6.47 (d, J = 8.4 Hz, 1H), 5.13 – 4.83 (m, 2H),
4.25 (s, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 2.21 (d, J = 16.4 Hz, 1H), 2.15 – 2.02 (m, 2H), 1.95 – 1.85
(m, 1H), 0.97 (s, 3H), 0.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.7, 178.3, 160.7,
156.0, 152.2, 151.0, 136.9, 136.1, 135.9, 130.9, 130.6, 128.6, 127.8, 127.3, 127.2, 118.6, 116.0,
115.5, 111.6, 111.3, 111.1, 109.6, 63.0, 55.7, 55.6, 49.7, 49.0, 44.6, 42.1, 32.5, 29.2, 27.1; IR
(KBr): 3462, 3336, 2956, 2836, 2360, 1713, 1648, 1510, 1252, 804, 606, 563; ESI FTMS exact
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mass calcd for (C34H32N4O4+H)+ requires m/z 561.2502, found m/z 561.2515; The enantiomeric
ratio (er) value: 90:10, determined by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 80/
20, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 13.013 (major), tR = 25.820 (minor).
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(R)-2'-amino-1-benzyl-1'-(4-methoxyphenyl)-5,7',7'-trimethyl-2,5'-dioxo-5',6',7',8'-tetrahy
dro-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4ah): Flash column chromatography
eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 74% (40.0 mg); white
solid; m.p. 279–280 oC; [α]D20 = +3.1 (c 0.7, Acetone); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.51
(d, J = 7.2 Hz, 2H), 7.38 – 7.28 (m, 3H), 7.25 – 7.19 (m, 2H), 7.11 – 7.00 (m, 2H), 6.95 – 6.77 (m,
2H), 6.47 (d, J = 8.0 Hz, 1H), 5.16 – 4.85 (m, 2H), 4.21 (s, 2H), 3.88 (s, 3H), 2.26 (s, 3H), 2.23 –
2.11 (m, 2H), 2.07 (s, 1H), 1.93 (d, J = 17.2 Hz, 1H), 0.98 (s, 3H), 0.94 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm):194.7, 178.6, 160.7, 152.0, 150.9, 139.9, 136.1, 135.4, 132.0, 131.0, 130.7,
128.8, 128.6, 127.9, 127.2, 127.1, 123.6, 118.7, 116.0, 115.5, 111.3, 109.1, 63.2, 55.7, 49.8, 48.7,
44.5, 42.1, 32.5, 29.1, 27.2, 21.3; IR (KBr): 3445, 2956, 2358, 2180, 1715, 1644, 1362, 1256,
1148, 1029, 806, 701; ESI FTMS exact mass calcd for (C34H32N4O3+H)+ requires m/z 545.2552,
found m/z 545.2581; The enantiomeric ratio (er) value: 94:6, determined by HPLC (Daicel
o
Chiralpak AS-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR =
4.960 (major), tR = 7.477 (minor).
(R)-2'-amino-1-benzyl-5-bromo-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-t
etrahydro-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile
(4ai):
Flash
column
chromatography eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 82%
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(49.6 mg); white solid; m.p. 280–282 C; [α]D = -17.3 (c 1.0, Acetone); H NMR (400 MHz,
CDCl3) δ (ppm): 7.50 (d, J = 7.2 Hz, 2H), 7.39 – 7.27 (m, 4H), 7.26 – 7.23 (m, 1H), 7.23 – 7.14
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(m, 2H), 7.14 – 7.00 (m, 2H), 6.52 – 6.41 (m, 1H), 5.12 – 4.92 (m, 2H), 4.23 (s, 2H), 3.90 (s, 3H),
2.28 – 2.10 (m, 2H), 2.10 – 2.02 (m, 1H), 1.95 (d, J = 17.2 Hz, 1H), 0.99 (s, 3H), 0.95 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm): 194.7, 178.1, 160.8, 152.4, 151.0, 141.5, 137.3, 135.5, 131.2,
130.9, 130.6, 128.8, 127.5, 127.4, 127.2, 126.1, 118.3, 116.0, 115.7, 115.4, 110.9, 110.7, 62.5, 55.8,
49.7, 48.8, 44.6, 42.1, 32.5, 28.9, 27.4; IR (KBr): 3451, 3312, 3211, 2956, 2603, 2359, 2186, 1720,
1640, 1362, 1028, 808, 698; ESI FTMS exact mass calcd for (C33H29BrN4O3+H)+ requires m/z
609.1501, found m/z 609.1511; The enantiomeric ratio (er) value: 90:10, determined by HPLC
(Daicel Chiralpak AS-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm):
tR = 5.853 (major), tR = 11.587 (minor).
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(R)-2'-amino-1-benzyl-7-methoxy-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8
'-tetrahydro-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile
(4aj):
Flash
column
chromatography eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 77%
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(42.9 mg); white solid; m.p. 209–211 C; [α]D = +24.9 (c 0.8, Acetone); H NMR (400 MHz,
CDCl3) δ (ppm): 7.50 (d, J = 7.2 Hz, 2H), 7.35 – 7.27 (m, 3H), 7.24 – 7.14 (m, 2H), 7.10 – 6.99
(m, 2H), 6.98 – 6.90 (m, 1H), 6.82 – 6.69 (m, 2H), 5.31 – 5.14 (m, 2H), 4.18 (s, 2H), 3.87 (s, 3H),
3.53 (s, 3H), 2.26 – 2.09 (m, 2H), 2.06 (d, J = 6.4 Hz, 1H), 1.96 – 1.85 (m, 1H), 0.97 (s, 3H), 0.92
(s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.5, 178.9, 160.7, 152.0, 150.9, 144.9, 139.0,
136.9, 131.0, 130.6, 130.5, 128.1, 128.0, 127.0, 126.3, 123.3, 118.6, 116.0, 115.7, 115.5, 112.9,
111.3, 63.3, 55.8, 55.7, 49.8, 48.7, 46.4, 42.1, 32.5, 29.2, 27.0; IR (KBr): 3442, 3273, 2955, 2836,
2359, 2183, 1655, 1254, 1029, 736, 633; ESI FTMS exact mass calcd for (C34H32N4O4+H)+
requires m/z 561.2502, found m/z 561.2510; The enantiomeric ratio (er) value: 96:4, determined
by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 oC,
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254 nm): tR = 9.143 (major), tR = 16.177 (minor).
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(R)-2'-amino-1-benzyl-1'-(4-methoxyphenyl)-7,7',7'-trimethyl-2,5'-dioxo-5',6',7',8'-tetrahy
dro-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4ak): Flash column chromatography
eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 72% (39.0 mg); white
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solid; m.p. 270–271 C; [α]D = +31.7 (c 0.4, Acetone); H NMR (400 MHz, CDCl3) δ (ppm):
7.53 (d, J = 7.6 Hz, 2H), 7.43 – 7.35 (m, 2H), 7.34 – 7.30 (m, 1H), 7.28 – 7.17 (m, 2H), 7.13 –
7.00 (m, 3H), 6.99 – 6.86 (m, 2H), 5.42 – 5.20 (m, 2H), 4.19 (s, 2H), 3.91 (s, 3H), 2.32 – 2.18 (m,
4H), 2.17 – 2.06 (m, 2H), 1.94 (d, J = 17.2 Hz, 1H), 1.00 (s, 3H), 0.96 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm): 194.6, 179.6, 160.7, 151.9, 150.8, 140.5, 138.5, 136.3, 132.5, 130.9, 130.6,
128.7, 127.9, 126.7, 126.1, 122.8, 121.0, 119.7, 118.7, 116.0, 115.5, 111.6, 63.7, 55.7, 49.8, 48.1,
45.9, 42.1, 32.5, 29.3, 26.9, 18.7; IR (KBr): 3565, 2931, 2327, 2180, 1690, 1641, 1512, 1363,
1256, 849, 736; ESI FTMS exact mass calcd for (C34H32N4O3+H)+ requires m/z 545.2552, found
m/z 545.2559; The enantiomeric ratio (er) value: 95:5, determined by HPLC (Daicel Chiralpak
o
AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR = 7.850
(major), tR = 13.960 (minor).
(R)-2'-amino-1-benzyl-1'-(4-methoxyphenyl)-5,7,7',7'-tetramethyl-2,5'-dioxo-5',6',7',8'-tetr
ahydro-1'H-spiro[indoline-3,4'-quinoline]-3'-carbonitrile (4al): Flash column chromatography
eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d; yield: 66% (36.7 mg); white
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solid; m.p. 272–273 C; [α]D = +26.9 (c 0.7, Acetone); H NMR (400 MHz, CDCl3) δ (ppm):
7.50 (d, J = 7.6 Hz, 2H), 7.37 – 7.27 (m, 3H), 7.25 – 7.17 (m, 2H), 7.11 – 6.97 (m, 2H), 6.78 (s,
1H), 6.71 (s, 1H), 5.23 (s, 2H), 4.18 (s, 2H), 3.88 (s, 3H), 2.24 (s, 3H), 2.21 – 2.16 (m, 3H), 2.15 –
2.10 (m, 2H), 2.09 – 2.04 (m, 1H), 1.93 (d, J = 17.2 Hz, 1H), 0.97 (s, 3H), 0.94 (s, 3H); 13C NMR
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(100 MHz, CDCl3) δ (ppm): 194.7, 179.6, 160.7, 151.9, 150.7, 138.5, 138.0, 136.5, 133.1, 132.0,
131.0, 130.7, 128.7, 127.9, 126.7, 126.1, 121.8, 119.3, 118.8, 116.0, 115.5, 111.6, 63.8, 55.7, 49.8,
48.2, 45.9, 42.1, 32.5, 29.1, 27.1, 21.0, 18.6; IR (KBr): 3627, 2954, 2359, 2181, 1699, 1643, 1557,
1363, 1253, 1029, 930, 752, 668; ESI FTMS exact mass calcd for (C35H34N4O3+H)+ requires m/z
559.2709, found m/z 559.2720; The enantiomeric ratio (er) value: 97:3, determined by HPLC
(Daicel Chiralpak AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 oC, 254 nm):
tR = 6.527 (major), tR = 11.353 (minor).
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(R)-ethyl
2'-amino-1-benzyl-3'-cyano-6'-methyl-2-oxospiro[indoline-3,4'-pyran]-5'-carboxylate
(6):
Flash column chromatography eluent, dichloromethane/ethyl acetate = 4/1; Reaction time = 4 d;
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yield: 36% (14.9 mg); white solid; m.p. 209–211 C; [α]D = +14.9 (c 0.4, Acetone); H NMR
(400 MHz, CDCl3) δ (ppm): 7.48 (d, J = 7.2 Hz, 2H), 7.40 – 7.33 (m, 2H), 7.31 (s, 1H), 7.24 –
7.11 (m, 2H), 7.08 – 6.99 (m, 1H), 6.77 – 6.71 (m, 1H), 5.12 (d, J = 15.6 Hz, 1H), 4.85 (d, J =
14.8 Hz, 1H), 4.79 (s, 2H), 3.98 – 3.85 (m, 1H), 3.68 – 3.53 (m, 1H), 2.43 (s, 3H), 0.77 – 0.57 (m,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 177.5, 164.6, 159.5, 158.5, 142.8, 135.5, 133.2, 129.1,
128.7, 127.7, 123.6, 123.2, 116.7, 109.3, 105.2, 61.0, 60.7, 44.6, 19.1, 13.3; IR (KBr): 3391, 2922,
2359, 2192, 1715, 1362, 1082, 794, 668; ESI FTMS exact mass calcd for (C24H21N3O4+H)+
requires m/z 416.1610, found m/z 416.1600; The enantiomeric ratio (er) value: 87:13, determined
by HPLC (Daicel Chiralpak AS-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 oC,
254 nm): tR = 8.320 (major), tR = 10.080 (minor).
Procedure for the synthesis of intermediate A: To the mixture of N-benzyl substituted isatin
2a (3 mmol), malononitrile 3 (3 mmol), MgSO4 (1 g) was added dichloromethane (20 mL). After
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being stirred at r.t. for 1 h, the reaction mixture was filtered to remove the MgSO4. The resultant
solution was concentrated under the reduced pressure to give the residue, which was purified
through flash column chromatography on silica gel to afford pure product A.
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2-(1-benzyl-2-oxoindolin-3-ylidene)malononitrile (intermediate A): Flash column
chromatography eluent, petroleum ether/ethyl acetate = 4/1; Reaction time = 1 h; yield: 86%
(735.2 mg); purple solid; m.p. 200–202 oC; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.13 (d, J = 7.8
Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.41 – 7.28 (m, 5H), 7.11 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz,
1H), 4.91 (s, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm): 162.6, 149.2, 146.2, 137.6, 134.2, 129.1,
128.4, 127.5, 126.9, 123.9, 118.3, 112.3, 110.6, 82.9, 44.2; IR (KBr): 3492, 2228, 1719, 1612,
1593, 1470, 1348, 1110, 1084, 789, 629; ESI FTMS exact mass calcd for (C18H11N3O+H)+
requires m/z 286.0980, found m/z 286.0982.
Procedure for the synthesis of compound 7: A newly distilled dichloromethane (1 mL) was
added to the mixture of compound 4aa (0.2 mmol) and DMAP (0.05 mol) in a dried reaction
bottle. After Et3N (0.8 mmol) was added, the reaction mixture was stirred at room temperature for
15 min. Then, benzoyl chloride (0.3 mmol) and distilled dichloromethane (1 mL) were added to
the reaction mixture, which was stirred at room temperature for 2 days. After the completion of the
reaction as indicated by TLC, 1 M HCl was added to the reaction mixture, which was further
extracted by dichloromethane and dried by anhydrous Na2SO4. The resultant organic layer was
concentrated under the reduced pressure to give the residue, which was purified through flash
column chromatography on silica gel to afford pure product 7.
(R)-N-(1-benzyl-3'-isocyano-1'-(4-methoxyphenyl)-7',7'-dimethyl-2,5'-dioxo-5',6',7',8'-tetr
ahydro-1'H-spiro[indoline-3,4'-quinolin]-2'-yl)benzamide (7): Flash column chromatography
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