Bifunctional Squaramide-Catalyzed Asymmetric [3 + 2] Cyclization of 2-(1-Methyl-2-oxoindolin-3-yl)malononitriles with Unsaturated Pyrazolones to Construct Spirooxindole-Fused Spiropyrazolones

Article abstract of DOI:10.1021/acs.joc.9b01268

The present paper reports a highly stereoselective synthesis of spirooxindole-fused spiropyrazolones through the asymmetric [3 + 2] cyclization reaction of 2-(1-methyl-2-oxoindolin-3-yl)malononitriles with unsaturated pyrazolones under mild conditions. Wi

Full text of DOI:10.1021/acs.joc.9b01268

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Article
Bifunctional Squaramide-Catalyzed Asymmetric [3 + 2] Cyclization
of 2-(1-Methyl-2-oxoindolin-3-yl)malononitriles with Unsaturated
Pyrazolones to Construct Spirooxindole-Fused Spiropyrazolones
Ye Lin, Bo-Liang Zhao, and Da-Ming Du
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01268 • Publication Date (Web): 18 Jul 2019
Downloaded from pubs.acs.org on July 18, 2019
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Bifunctional Squaramide-Catalyzed Asymmetric [3 + 2] Cyclization
of 2-(1-Methyl-2-oxoindolin-3-yl)malononitriles with Unsaturated
Pyrazolones to Construct Spirooxindole-Fused Spiropyrazolones
Ye Lin, Bo-Liang Zhao, and Da-Ming Du*
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, 5 South Zhongguancun Street, Beijing
100081, People’s Republic of China
Fax: (+86)-010-68914985; E-mail: dudm@bit.edu.cn
ABSTRACT: The present paper reports a highly stereoselective synthesis of spirooxindole-fused spiropyrazolones through
asymmetric [3 + 2] cyclization reaction of 2-(1-methyl-2-oxoindolin-3-yl)malononitriles with unsaturated pyrazolones under
mild conditions. With only 1 mol% of bifunctional squaramide catalyst, a series of chiral dispirocyclic pyrazolone derivatives
were attained in high yields (85–97%) with excellent stereoselectivities (up to >99% ee and in all case >20:1 dr). Moreover,
gram-scale synthesis and further transformation of the products were also demonstrated.
INTRODUCTION
Over the past decades, spirocyclic compounds have attracted more and more attention from both synthetic
1
and medicinal chemists because of their extensive biological activities. Among the different types of
spirocyclic compounds, the highly functionalized spiropyrazolones, spirooxindoles and spiro-oxindole
pyrazolones have drawn much attention due to their remarkable and varied biological activities (Figure
1
).2-5 As a consequence, significant efforts have been made to construct these highly valuable spirocyclic
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frameworks and a large number of elegant methods have been reported, especially in an asymmetric
manner.6
However, to the best of our knowledge, the reports on the asymmetric synthesis of the dispirocyclic
compounds assembling the oxindole and pyrazolone structures are very limited. For example, in 2013 the
Wang’s group first reported the organocatalytic [3 + 2] cyclization cascade reaction of unsaturated
pyrazolones and isothiocyanato oxindoles to construct spirooxindole-fused spiropyrazolone scaffolds.7
Since then, several organocatalytic cascade reactions using unsaturated pyrazolones or novel pyrazolone
derivatives as synthons for the preparation of spirooxindole-fused spiro-pyrazolones have been
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successfully developed by the groups of Yuan, Wang, Liu, as well as our group (Scheme 1a–d).
Figure 1. Representative examples of biologically active spiropyrazolones, spirooxindoles and spiro-oxindole pyrazolones.
Indeed, in spite of these efforts devoted to the synthesis of dispirocyclic pyrazolone derivatives, the
enantioselective construction of this kind of fused spirocyclic pyrazolones represents still a significant
challenge and there is no report on synthesizing spriooxindole-fused spirocyclopentene-pyrazolones
bearing multiple contiguous stereocenters. Recently, we noticed that the catalytic cycloadditions of 2-(1-
methyl-2-oxoindolin-3-yl)malononitriles used as a kind of highly efficient cascade Michael/cyclization
12
reagent had been reported by Xie. And very recently we have successfuly applied the 2-(1-methyl-2-
oxoindolin-3-yl)malononitriles to the asymmetric organocatalytic cascade Michael/cyclization reaction.13
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Moreover, bifunctional squaramide-catalyzed asymmetric domino/cascade reactions had been well
established.14, 15 In this context, we therefore envisioned that the novel class of spriooxindole-fused
spirocyclopentene-pyrazolone derivatives could be obtained via the asymmetric [3 + 2] cyclization
reaction of unsaturated pyrazolones and 2-(1-methyl-2-oxoindolin-3-yl)malononitriles (Scheme 1e).
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Scheme 1. Previous Strategies on the Asymmetric Construction of Spriooxindole-fused Spiropyra-
zolone Scaffolds
RESULTS AND DISCUSSION
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To test the feasibility, we initially examined the [3 + 2] cyclization reaction with 2-(1-methyl-2-
oxoindolin-3-yl)malononitrile 1a and unsaturated pyrazolone 2a by using 5 mol % quinine-derived
squaramide C1 in dichloromethane (DCM) at room temperature for 4 h. To our delight, under above
conditions, the desired product 3aa was obtained in 97% yield with >99% ee and >20:1 dr (Table 1, entry
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). With the exciting result in hand, we began to screen some other bifunctional squaramide catalysts
C2−C10 (Figure 2) for this [3 + 2] cyclization process (Table 1, entries 2−10). As shown in Table 1, all
catalysts could afford the desired product 3aa in high yields (86−97%) and excellent diastereoselectivity
(>20:1 dr), but no improvements were observed. And then, a quinine-derived thiourea C11 was screen in
comparison with squaramides. Although the yield and diastereoselectivity of the reaction maintained, the
enantioselectivity declined (Table 1, entry 11). Finally, quinine catalyst C12 also promoted the reaction,
but a significant decline in stereoselectivity (3:1 dr, 26% ee) was obtained. The results indicated that the
two hydrogen bonding of the bifunctional catalysts and substituents on the aromatic ring played a pivotal
role in controlling the stereoselectivity. Compared with thioureas, squaramides with longer distance
between the acidic H atoms could better control the enantioselectivity of this [3 + 2] cyclization reaction.16
As a result, the squaramide C1 derived from quinine was proved to be the optimal catalyst for this cascade
reaction, considering the yield, diastereoselectivity and enantioselectivity. Subsequently, a rapid solvent
screening indicated that acetonitrile and tetrahydrofuran (THF) gave significant decline in
diastereoselectivity and reactivity, and the DCM was still the most suitable reaction solvent (Table 1,
entries 13−16). Furthermore, by following these promising results, we tested the cascade reaction with a
lower catalyst loading of 2.5 mol %. Gratifyingly, the yield and stereoselectivity could be maintained in
spite of more reaction time to 8 h (Table 1, entry 17). Moreover, further lowering catalyst loading to 1
mol % led to a set of acceptable results, but a longer reaction time to 12 h was required (Table 1, entry
1
8). At last, we chose to use the 1 mol % catalyst loading. Thus, the optimum reaction conditions for the
3 + 2] cyclization reaction was the use of 1 mol % catalyst loading of squaramide C1 in DCM at room
temperature.
[
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Figure 2. Screened organocatalysts.
With the optimum reaction conditions established, we began to probe the substrate scope of the asym-
metric [3 + 2] cyclization for the synthesis of spirooxindole-fused spirocyclopentane-pyrazolones. As
summarized in Scheme 2, we firstly examined the tolerance of various 2-(1-methyl-2-oxoindolin-3-yl)-
malononitriles 1 under the optimized conditions and the reactions could afford their corresponding prod-
ucts 3ba−3ka in high yields (85−96%) with excellent diastereoselectivities and enantioselectivities (>20:1
dr, 98−>99% ee) in almost all the cases. It was found that regardless of whether the electronic properties
or the positions of substituents the reactivity and stereoselectivity were almost unaffected. Only when the
N-unprotected 2-(1-methyl-2-oxoindolin-3-yl)-malononitrile 1d was examined, the reactivity was lower
and 48 h was needed to complete the reaction but without loss of the yield (96%) and stereoselectivity
(
>20:1 dr, >99% ee). Moreover, the 7-CF and 5,7-dimethyl substituted oxindole ring of substrates were
3
also well-tolerated under the established conditions to afford the corresponding cycloadducts in good
yields and excellent stereoselectivities (Scheme 2, 3ja and 3ka).
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Table 1．Screening of Organocatalysts and Optimization of the Reaction Conditions a
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b
drc
d
entry
solvent
catalyst
C1
time (h)
yield (%)
ee (%)
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8
9
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
4
4
4
4
6
4
6
2
97
93
95
93
96
90
96
91
86
95
97
95
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
3:1
>99
97
C2
C3
>99
96
C4
C5
>99
97
C6
C7
>99
-94
73
C8
C9
1
1
1
0
1
2
C10
C11
C12
88
86
-26
1
1
15
3
4
CHCl
PhMe
3
C1
C1
C1
6
5
6
95
70
81
>20:1
>20:1
4:1
95
97
>99
CH
3
CN
1
6
THF
C1
C1
C1
6
8
85
96
96
8:1
>99
>99
>99
1
7e
18f
CH
CH
2
Cl
2
2
>20:1
>20:1
2
Cl
12
a
Unless otherwise specified, reactions were carried out with 1a (0.1 mmol), 2a (0.12 mmol), and catalyst (5
b
c
1
mol%) in solvent (1.0 mL) at room temperature for 4−12 h. Isolated yield. The dr value was determined by H
NMR analysis of the crude products. The ee value was determined by HPLC analysis. 2.5 mol% catalyst was
used. 1 mol% catalyst was used.
d
e
f
Further exploration of the substrate scope was focused upon structurally diverse unsaturated pyrazolones
3
2
by reacting to 1a. As shown in Scheme 3, various aromatic ring substitutions at the R position were
tolerated, facilely generating the desired products 3ab–3aj in high yields with excellent stereocontrol
3
(
>20:1 dr, >99% ee). Even the R were the heteroaromatic 2-furyl and 2-thienyl substituents, the cascade
process was compatible (Scheme 3, 3ak and 3al). In addition, when the different electronic nature ofaro-
4
matic ring substitutions were introduced on the R position of the unsaturated pyrazolones, facile con
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versions were also observed and the corresponding products (Scheme 3, 3am and 3an) were attained in
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Scheme 2. Substrate Scope of 2-(1-methyl-2-oxoindolin-3-yl)malononitrilesa,b,c,d
Me
N
NC
H N
2
N Ph
O
CN
O
O
0
1
2
3
4
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9
0
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0
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0
NC
Ph
Me
1 mol % C1
R2
+
N Ph
Ph
N
R2
CH Cl , rt
O
N
2
2
R1
N
1
R
1
a-1l
2a
3aa-3ka
Me
H N
Me
H N
Me
H N
Me
H2N
N
N
N
N
2
Ph
2
Ph
N
N
O
Ph
2
N
O
Ph
N
O
NC
NC
NC
NC
O
Ph
Ph
Ph
O
Ph
O
O
O
N
N
N
N
H
Me
aa
2 h, 96% yield
Bn
3ca
12 h, 87% yield
3
3ba
12 h, 88% yield
3da
48 h, 96% yield
1
>
20:1 dr, >99% ee
>20:1 dr, >99% ee
>20:1 dr, >99% ee
>20:1 dr, >99% ee
Me
H2N
Me
N
Me
Me
N
N
N
H N
Ph
H N
Ph
Ph
H N
Ph
2
2
N
2
N
N
N
NC
NC
NC
O
NC
O
O
O
Br
Me
F
Cl
Ph
Ph
Ph
Ph
O
O
O
O
N
N
N
Me
3ha
N
Me
ea
2 h, 95% yield
>20:1 dr, >99% ee
Me
H N
Me
3fa
12 h, 91% yield
>20:1 dr, >99% ee
Me
H N
Me
3ga
12 h, 87% yield
3
1
12 h, 85% yield
>20:1 dr, >99% ee
>20:1 dr, 99% ee
Me
N
N
N
H2N
Ph
2
N Ph
N
2
Ph
N
O
NC
NC
O
NC
O
Me
Ph
O
Ph
O
Ph
O
N
N
N
Cl
Me
Me
Me
ia
2 h, 90% yield
>20:1 dr, >99% ee
CF3
Me
3
3ja
3ka
1
12 h, 89% yield
>20:1 dr, 98% ee
12 h, 93% yield
>20:1 dr, >99% ee
a
Unless otherwise specified, reactions were carried out with 1 (0.1 mmol), 2a (0.12 mmol), and catalyst C1 (1
b
c
mol%) in 1.0 ml CH
2
1
Cl were stirred at room temperature for 12−48 h. Isolated yield. The dr values of products
2
d
were determined by H NMR analysis of the crude products. The ee value was determined by HPLC.
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satisfactory yields (95−97%) with excellent diastereo- and enantioselectivities (>20:1 dr, >99% ee). The
absolute configuration of the product 3af was unambiguously determined by single-crystal X-ray diffrac-
1
7
tion analysis as (2'R,3R,3'S) (Figure 3). The stereochemistry of the other products was tentatively as-
signed by analogy
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Scheme 3. Substrate Scope of Unsaturated Pyrazolonesa,b,c,d
a
Unless otherwise specified, reactions were carried out with 1a (0.1 mmol), 2 (0.12 mmol), and catalyst C1 (1
b
c
mol%) in 1.0 ml CH
2
1
Cl were stirred at room temperature for 7−18 h. Isolated yield. The dr values of products
2
d
were determined by H NMR analysis of the crude products. The ee value was determined by HPLC.
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Figure 3. X-ray crystal structure of 3af. (Displacement ellipsoids are drawn at the 50% probability level, and another
symmetric molecule and two included ethyl acetate molecules were omitted for clarity)
Having investigated the cyclization reaction between a wide range of 2-(1-methyl-2-oxoindolin-3-
yl)malononitriles with unsaturated pyrazolones, we then turned our attention to ethyl 2-cyano-2-(1-me-
thyl-2-oxoindolin-3-yl)acetates. However, under the standard conditions, only trace reaction between
ethyl 2-cyano-2-(1-methyl-2-oxoindolin-3-yl)acetate 1l and unsaturated pyrazolone 2a was detected, in-
dicating the relatively lower reactivity of 1l (Scheme 4).
Scheme 4. Evaluation of Ethyl 2-cyano-2-(1-methyl-2-oxoindolin-3-yl)acetate Substrates
To further illustrate the robustness and practicality of this asymmetric cyclization reaction, the gram-
scale experiment between 1a and 2a was carried out under the optimal reaction conditions (Scheme 5a).
Gratifyingly, the dispirocyclic compound 3aa was obtained in a comparable yield with maintained stere-
oselectivities. In addition, a further structural conversion was conducted by treatment of optically pure
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aa and acetic anhydride with pyridine at 90 ℃ for 24 h. The corresponding product 4aa was attained in
7% yield without sacrifice to the diastereo- and enantioselectivity (Scheme 5b).18
5
Scheme 5. Gram-scale Synthesis and Functional Group Transformation of 3aa
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Finally, for a better understanding of this [3 + 2] cyclization reaction, we proposed a plausible mecha-
12
nism on the basis of previous literature report and our experiment results. As shown in Scheme 6, on the
one hand, the 2-(1-methyl-2-oxoindolin-3-yl)-malononitrile 1a was deprotonated by the tertiary amine
moiety of catalyst C1. On the other hand, unsaturated pyrazolone 2a was activated by two hydrogen
bonding from the amide N−H. Subsequently, the deprotonated activation of 2-(1-methyl-2-oxoindolin-3-
yl)-malononitrile 1a predominantly from the Si face attacked the Re face of the electron-deficient unsatu-
rated pyrazolone 2a which underwent the intramolecular Michael addition. Simultaneously, the Michael
adduct intermediate followed by intramolecular cyclization/isomerization sequence to afford the desired
product 3aa and regenerate the bifunctional squaramide catalyst C1.
Scheme 6. Proposed Mechanism for [3 + 2] Cyclization Reaction
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In conclusion, we have developed a highly stereoselective synthesis of spirooxindole-fused spirocyclo-
pentene-pyrazolones through asymmetric [3 + 2] cyclization reaction of 2-(1-methyl-2-oxoindolin-3-yl)-
malononitriles with unsaturated pyrazolones under mild conditions. With only 1 mol % of bifunctional
squaramide catalyst loading, a series of chiral dispirocyclic pyrazolone derivatives were attained in high
yields (85−97%) with excellent stereoselectivities (up to >99% ee and in all case >20:1 dr). In addition,
gram-scale synthesis and further transformation of the product 3aa were also demonstrated with excellent
stereoselectivities. This elegant strategy provides a novel class of medicinally promising spirooxindole-
fused spiropyrazolone skeletons.
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EXPERIMENTAL SECTION
General Information.
Commercially available compounds were used without further purification. Solvents were dried according
to standard procedures. Column chromatography was performed with silica gel (200-300 mesh). Melting
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points were determined with an melting-point apparatus and are uncorrected. H NMR spectra were meas-
ured with 400 MHz spectrometer in acetone-d6 and CDCl
relative to tetramethylsilane (TMS) as the internal standard. C{ H} NMR spectra were measured at 176
MHz with 700 MHz spectrometer in acetone-d6 and CDCl , chemical shifts were reported in ppm relative
to TMS with the solvent resonance as internal standard (acetone-d6 at 30.83 ppm, CDCl at 77.00 ppm).
F{ H} NMR spectra were measured at 377 MHz with 400 MHz spectrometer. Proton coupling patterns
3
, chemical shifts were reported in δ (ppm) units
13
1
3
3
1
9
1
are described as broad (br) singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). High resolution
mass spectra were measured with an Accurate-Mass-Q-TOF MS system equipped with an electrospray
ionization (ESI) source. Enantiomeric excesses were determined by chiral HPLC analysis using an LC
instrument with a Chiralpak IB and AD-H column.
Materials.
The arylidene azlactones 2a–2n were prepared according to the reported literature procedures.19
Synthesis of 2-(1-methyl-2-oxoindolin-3-yl)-malononitriles 1a–1l.
In a 50 ml flame-dried flask was added isatin (3.0 mmol) in anhydrous EtOH (10 mL), and then malono-
nitrile or ethyl 2-cyanoacetate (3.2 mmol) was added. After that, the mixture was heated 2 h at reflux.
Then, the precipitated solid was collected by filtration and recrystallized from ethanol affording the mal-
onylisatinylidene derivatives or ethyl 2-cyano-2-(1-methyl-2-oxoindolin-3-ylidene)acetates.
Next, the malonylisatinylidene derivatives (1.00 mmol) and Hantzsch ester (1.05 mmol) were combined
in EtOH (15 mL) and left stirring at room temperature for 15–30 min. After the reaction was finished, the
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reaction mixture was isolated by evaporating the solvent, taking up the residue in ethyl acetate, and ex-
tracting with aqueous HCl (1.0 mol/L). The crude product after drying over Na SO , filtration, and evap-
4
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oration of the solvent was filtered through a short column of silica eluting with petroleum ether/ethyl
acetate (2/1 to 1/1 v/v) to give the desired products 1a–1l in the range of 60–80 % yields.
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Reported compounds 2-(1-methyl-2-oxoindolin-3-yl)-malononitriles 1a, 1d were prepared according
20
to the literature. The new substrates 1b, 1c and 1e–1l were obtained according to the literature procedure
with functional group modifications, and the detailed data was listed below.20
2
0
2-(1-Methyl-2-oxoindolin-3-yl)malononitrile (1a). White solid, 147.8 mg, 70% yield, mp 131–133 C.
1
H NMR (400 MHz, DMSO-d6):  7.51 (d, J = 7.6 Hz, 1H), 7.43 (tt, J
td, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 5.69 (d, J = 8.4 Hz, 1H), 4.53 (d, J = 4.8 Hz,
1H), 3.18 (s, 3H) ppm. C{ H} NMR (176 MHz, DMSO-d6):  171.8, 144.4, 129.8, 124.2, 122.7, 112.5,
1
= 7.8 Hz, J = 0.8 Hz, 1H), 7.16
2
(
1
2
1
3
1
1
12.2, 109.2, 43.4, 26.2, 23.8 ppm.
-(1-Allyl-2-oxoindolin-3-yl)malononitrile (1b). White solid, 185.0 mg, 78% yield, mp 108–110 C. H
= 7.6 Hz,
= 0.8 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.88–5.78 (m, 1H), 5.73 (d, J = 4.4 Hz, 1H), 5.22–5.15 (m,
1
2
NMR (400 MHz, DMSO-d6):  7.53 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.16 (td, J
1
J
2
1
3
1
2
H), 4.60 (d, J = 4.4 Hz, 1H), 4.45–4.39 (m, 1H), 4.34–4.27 (m, 1H) ppm. C{ H} NMR (176 MHz,
DMSO-d6):  171.6, 143.4, 131.1, 129.7, 124.3, 122.8, 116.8, 112.6, 112.2, 109.8, 43.5, 41.6, 23.8 ppm.
2
-(1-Benzyl-2-oxoindolin-3-yl)malononitrile (1c). White solid, 229.9 mg, 80% yield, mp 114–116 C.
1
H NMR (400 MHz, DMSO-d6):  7.55 (d, J = 7.6 Hz, 1H), 7.38–7.25 (m, 6H), 7.14 (td, J
1
= 7.6 Hz, J
2
= 0.4 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 8.8 Hz, 1H), 5.04 (d, J = 16.0 Hz, 1H), 4.90 (d, J =
1
3
1
1
1
2
5.6 Hz, 1H), 4.70 (d, J = 4.4 Hz, 1H) ppm. C{ H} NMR (176 MHz, DMSO-d6):  172.1, 143.3, 135.6,
29.7, 128.5, 127.4, 127.1, 124.4, 122.9, 122.8, 112.6, 112.3, 109.8, 43.5, 42.9, 23.8 ppm.
2
0
1
-(2-Oxoindolin-3-yl)malononitrile (1d). White solid, 122.3 mg, 62% yield, mp 161–163 C. H NMR
(
400 MHz, DMSO-d6):  10.90 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.33 (tt, J
1
= 7.4 Hz, J = 1.0 Hz, 1H),
2
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.08 (td, J
Hz, 1H) ppm. C{ H} NMR (176 MHz, DMSO-d6):  173.6, 143.0, 129.7, 124.4, 123.6, 122.1, 112.6,
12.3, 110.1, 43.9, 23.7 ppm.
1
= 7.6 Hz, J
2
= 0.8 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 5.64 (d, J = 4.4 Hz, 1H), 4.44 (d, J = 4.4
1
3
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2-(1,5-Dimethyl-2-oxoindolin-3-yl)malononitrile (1e). White solid, 153.2 mg, 68% yield, mp 125–127
1

C. H NMR (400 MHz, DMSO-d6):  7.32 (s, 1H), 7.24 (dd, J
1
= 8.0 Hz, J = 0.8 Hz, 1H), 7.01 (d, J =
2
1
3
1
8
.0 Hz, 1H), 5.65 (d, J = 4.0 Hz, 1H), 4.47 (d, J = 4.4 Hz, 1H), 3.16 (s, 3H), 2.32 (s, 3H) ppm. C{ H}
NMR (176 MHz, DMSO-d6):  171.6, 142.0, 131.8, 130.0, 124.8, 122.8, 112.6, 112.2, 108.9, 43.5, 26.2,
23.8, 20.6 ppm.
2
-(5-Fluoro-1-methyl-2-oxoindolin-3-yl)malononitrile (1f). White solid, 144.4 mg, 63% yield, mp
1
131–133 C. H NMR (400 MHz, DMSO-d6):  7.39–7.36 (m, 1H), 7.32–7.27 (m, 1H), 7.14 (dd, J
1
= 8.8
1
3
1
Hz, J = 4.4 Hz, 1H), 5.72 (d, J = 4.4 Hz, 1H), 4.57 (d, J = 4.4 Hz, 1H), 3.18 (s, 3H) ppm. C{ H} NMR
2
(
176 MHz, DMSO-d6):  171.7, 158.3 (d, J = 238.1 Hz), 140.7, 124.4 (d, J = 9.0 Hz), 116.1 (d, J = 23.4
Hz), 112.3 (d, J = 25.9 Hz), 112.2, 112.1, 110.2 (d, J = 8.1 Hz), 43.7, 26.4, 23.6 ppm.
2-(5-Chloro-1-methyl-2-oxoindolin-3-yl)malononitrile (1g). White solid, 169.5 mg, 69% yield, mp
1
156–158 C. H NMR (400 MHz, DMSO-d6):  7.55–7.54 (m, 1H), 7.52–7.49 (m, 1H), 7.16 (d, J = 4.4
1
3
1
Hz, 1H), 5.73 (d, J = 4.4 Hz, 1H), 4.57 (d, J = 4.4 Hz, 1H), 3.18 (s, 3H) ppm. C{ H} NMR (176 MHz,
DMSO-d6):  171.6, 143.3, 129.6, 126.6, 124.7, 124.5, 112.2, 112.1, 110.7, 43.5, 26.4, 23.6 ppm.
2
-(5-bromo-1-methyl-2-oxoindolin-3-yl)malononitrile (1h). White solid, 174.1 mg, 60% yield, mp
1
165–167 C. H NMR (400 MHz, DMSO-d6):  7.67–7.66 (m, 1H), 7.65–7.62 (m, 1H), 7.12 (d, J = 8.4
1
3
1
Hz, 1H), 5.73 (d, J = 4.4 Hz, 1H), 4.58 (d, J = 4.4 Hz, 1H), 3.18 (s, 3H) ppm. C{ H} NMR (176 MHz,
DMSO-d6):  171.5, 143.8, 132.5, 127.2, 125.1, 114.2, 112.2, 112.1, 111.2, 43.4, 26.4, 23.5 ppm.
2
-(6-Chloro-1-methyl-2-oxoindolin-3-yl)malononitrile (1i). White solid, 174.5 mg, 71% yield, mp
1
134–136 C. H NMR (400 MHz, DMSO-d6):  7.49 (dd, J
1
= 8.0 Hz, J
2
= 0.8 Hz, 1H), 7.30 (d, J = 2.0
Hz, 1H), 7.23 (dd, J
1
= 8.0 Hz, J
2
= 2.0 Hz, 1H), 5.69 (d, J = 4.4 Hz, 1H), 4.54 (d, J = 4.4 Hz, 1H), 3.18
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(
s, 3H) ppm. C{ H} NMR (176 MHz, DMSO-d6):  171.9, 145.9, 134.4, 125.6, 122.3, 121.6, 112.3,
4
5
6
7
8
9
1
1
1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
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1
12.1, 109.8, 43.1, 26.5, 23.7 ppm.
2
-(1-Methyl-2-oxo-7-(trifluoromethyl)indolin-3-yl)malononitrile (1j). White solid, 215.0 mg, 77%
1
0
1
2
3
4
5
6
7
8
9
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2
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yield, mp 101–103 C. H NMR (400 MHz, DMSO-d6):  7.82 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 8.0 Hz,
1H), 7.36 (t, J = 7.8 Hz, 1H), 5.76 (d, J = 4.8 Hz, 1H), 4.66 (d, J = 4.4 Hz, 1H), 3.33 (q, J = 2.4 Hz, 3H)
1
3
1
ppm. C{ H} NMR (176 MHz, DMSO-d6):  173.1, 142.0, 128.6, 127.3 (q, J = 5.6 Hz), 125.7, 123.3 (q,
J = 271.4 Hz), 122.7, 112.12, 112.06, 111.3 (q, J = 32.6 Hz), 42.2, 28.7 (q, J = 6.0 Hz), 23.9 ppm.
2
-(1,5,7-Trimethyl-2-oxoindolin-3-yl)malononitrile (1k). Brownish yellow solid, 177.1 mg, 74% yield,
1
mp 136–138 C. H NMR (400 MHz, DMSO-d6):  7.15 (s, 1H), 6.98 (s, 1H), 5.62 (d, J = 4.4 Hz, 1H),
1
3
1
4.41 (d, J = 4.4 Hz, 1H), 3.42 (s, 3H), 2.51 (s, 3H), 2.26 (s, 3H) ppm. C{ H} NMR (176 MHz, DMSO-
d6):  172.2, 139.6, 133.6, 131.6, 123.3, 122.5, 120.1, 112.6, 112.3, 43.2, 29.2, 24.0, 20.3, 18.1 ppm.
Ethyl 2-cyano-2-(1-methyl-2-oxoindolin-3-yl)acetate (1l). (Diastereoisomeric mixture, ratio 1.2 : 1.)
1
White solid, 162.7 mg, 63% yield, mp 111–113 C. H NMR (400 MHz, CDCl
3
):  7.51 and 7.23 (d, J =
7
6
3
.6 Hz, 2 × 1H), 7.38–7.33 (m, 2 × 1H), 7.082 and 7.078 (td, J
1
= 7.6 Hz, J
2
= 0.8 Hz, 2 × 1H), 6.90 and
.87 (d, J = 8.0 Hz, 2 × 1H), 4.43 and 4.35 (d, J = 3.2 Hz, 2 × 1H), 4.39 (q, J = 7.2 Hz, 2 × 1H), 4.11 and
.94 (d, J = 3.2 Hz, 2 × 1H), 4.10–4.01 (m, 2 × 1H), 3.23 and 3.22 (s, 2 × 3H), 1.37 and 1.06 (t, J = 7.2
1
3
1
Hz, 2 × 3H) ppm. C{ H} NMR (176 MHz, CDCl
3
):  172.93, 172.91; 164.4, 163.0; 144.5, 144.3; 129.5,
29.3; 124.2, 123.6; 123.5, 123.3; 122.9, 122.7; 115.2, 113.3; 108.6, 108.3; 63.4, 62.8; 44.52, 44.46; 38.7,
7.6; 26.32, 26.26; 13.7, 13.4 ppm.
1
3
General Procedure for the asymmetric [3 + 2] cyclization reaction.
-(1-Methyl-2-oxoindolin-3-yl)malononitriles 1 (0.10 mmol), unsaturated pyrazolinones 2 (0.12 mmol),
and catalyst C1 (0.6 mg, 0.001 mmol) were dissolved in CH Cl (0.5 mL), and the mixture was stirred at
room temperature for 12–48 h. After completion of the reaction, the reaction mixture was concentrated
2
2
2
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and directly purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4/1
to 2/1 v/v) to afford the pure products 3 as solid.
(2'R,3R,3'S)-4'-Amino-1,3''-dimethyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydrodispiro[indoline-
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3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3aa). From 21.1 mg (0.10 mmol) 1a and 31.5
mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh) column chromatog-
raphy using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3aa as a white solid (45.5
mg, 96%), mp 216–218 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 85:15, flow rate 1.0
mL/min, detection at 254 nm): t
R
= 17.1 min (minor), t
R
= 18.9 min (major); >99% ee. [α] 20
= 7.2 Hz, J
= 7.6 Hz, J = 0.8 Hz,
D
= ‒131.0 (c
1
=
2.00, acetone). H NMR (400 MHz, acetone-d6):  7.83–7.81 (m, 2H), 7.54 (dd, J
1
2
= 0.8
Hz, 1H), 7.39–7.34 (m, 2H), 7.32 (td, J
1
= 7.6 Hz, J
2
= 1.2 Hz, 1H), 7.21 (td, J
1
2
1H), 7.18–7.14 (m, 1H), 7.13–7.07 (m, 3H), 7.02–7.00 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.70 (br s, 2H),
1
3
1
4
1
.53 (s, 1H), 3.09 (s, 3H), 2.71 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  178.0, 173.9, 161.6,
60.8, 145.4, 139.9, 134.4, 132.3, 131.3, 130.5, 130.34, 130.33, 130.27, 126.8, 125.1, 125.0, 120.3, 116.8,
110.3, 82.8, 73.4, 66.1, 64.5, 27.6, 18.1 ppm. HRMS (ESI-TOF): m/z calcd. for C29
H
24
N
5
O
[M + H]+
2
474.1925, found 474.1923.
(
2'R,3R,3'S)-1-Allyl-4'-amino-3''-methyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydrodispiro[indo-
line-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ba). From 23.7 mg (0.10 mmol) 1b and
1.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh) column chro-
3
matography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ba as a light yellow
solid (43.9 mg, 88% yield), mp 131–133 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol =
8
5:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 12.7 min (minor), t
= ‒107.9 (c = 2.14, acetone). H NMR (400 MHz, acetone-d6):  7.83–7.80 (m, 2H), 7.57 (dd,
= 1.0 Hz, 1H), 7.39–7.34 (m, 2H), 7.29 (td, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.22 (td, J = 7.4
= 1.2 Hz, 1H), 7.18–7.08 (m, 4H), 7.04–7.01 (m, 2H), 6.82 (d, J = 7.2 Hz, 1H), 6.73 (br s, 2H),
R
= 17.0 min (major); >99%
2
0
1
ee. [α]
D
J
1
= 7.2 Hz, J
2
1
2
1
Hz, J
2
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5
.64–5.55 (m, 1H), 4.94 (dd, J
s, 1H), 4.43–4.36 (m, 1H), 4.22–4.16 (m, 1H), 2.75 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):
177.7, 173.9, 161.6, 160.8, 144.6, 139.9, 134.2, 132.8, 132.2, 131.2, 130.7, 130.5, 130.4, 130.3, 126.8,
1
= 10.4 Hz, J
2
= 1.2 Hz, 1H), 4.74 (dd, J
1
= 17.2 Hz, J
2
= 1.2 Hz, 1H), 4.55
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
(

0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
125.14, 125.10, 120.2, 117.9, 116.9, 111.1, 82.8, 73.4, 66.4, 64.7, 43.6, 18.1 ppm. HRMS (ESI-TOF): m/z
+
calcd. for C31
H
26
N
5
O
2
[M + H] 500.2081, found 500.2084.
(
2'R,3R,3'S)-4'-Amino-1-benzyl-3''-methyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydrodispiro[in-
doline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ca). From 28.7 mg (0.10 mmol) 1c
and 31.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh) column
chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ca as a white
solid (47.6 mg, 87% yield), mp 201–203 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol =
85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 15.3 min (minor), t
= ‒74.7 (c = 1.91, acetone). H NMR (400 MHz, CDCl ):  7.82 (d, J = 7.6 Hz, 2H), 7.58–7.56
m, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.22–7.11 (m, 7H), 7.05 (t, J = 7.8 Hz, 2H), 6.93 (d, J = 7.6 Hz, 2H),
.76 (d, J = 6.8 Hz, 2H), 6.54–6.52 (m, 1H), 5.07 (d, J = 16.0 Hz, 1H), 4.84 (br s, 2H), 4.62 (s, 1H), 4.58
R
= 25.7 min (major); >99%
2
0
1
ee. [α]
D
3
(
6
1
3
1
(d, J = 16.0 Hz, 1H), 2.74 (s, 3H) ppm. C{ H} NMR (176 MHz, CDCl
3
):  175.8, 171.5, 160.6, 157.9,
1
1
42.3, 137.2, 134.7, 131.9, 129.6, 129.5, 129.0, 128.8, 128.6, 128.55, 128.46, 127.3, 126.6, 125.7, 123.8,
23.7, 118.9, 114.7, 109.4, 83.9, 71.4, 63.3, 62.8, 44.0, 17.0 ppm. HRMS (ESI-TOF): m/z calcd. for
+
C
35
H
28
N
5
O
2
[M + H] 550.2238, found 550.2227.
(2'R,3R,3'S)-4'-Amino-3''-methyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydrodispiro[indoline-3,1'-
cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3da). From 19.7 mg (0.10 mmol) 1d and 31.5 mg
0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh) column chromatography
(
using petroleum ether/ethyl acetate (3/1 to 2/1 v/v) as eluent to obtain 3da as a light pink solid (44.1 mg,
96% yield), mp 146–148 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 85:15, flow rate 1.0
20
mL/min, detection at 254 nm): t
R
= 24.1 min (minor), t
R
= 29.0 min (major); >99% ee. [α]
D
= ‒117.9 (c
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
=
1.68, acetone). H NMR (400 MHz, acetone-d6):  9.55 (s, 1H), 7.84–7.81 (m, 2H), 7.52 (d, J = 7.2 Hz,
H), 7.39–7.35 (m, 2H), 7.24 (td, J = 7.6 Hz, J = 1.5 Hz, 1H), 7.19–7.09 (m, 7H), 6.83 (d, J = 7.2 Hz,
1H), 6.68 (br s, 2H), 4.54 (s, 1H), 2.69 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  179.6,
1
1
2
1
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
4
74.0, 161.6, 160.6, 143.6, 139.9, 134.6, 133.0, 131.2, 130.5, 130.4, 130.2, 126.8, 125.4, 124.6, 120.3,
[M + H]+
16.9, 111.6, 83.3, 73.5, 66.0, 64.9, 18.0 ppm. HRMS (ESI-TOF): m/z calcd. for C28
H
22
N
5
O
2
60.1768, found 460.1767.
(2'R,3R,3'S)-4'-Amino-1,3'',5-trimethyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydrodispiro[indo-
line-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ea). From 22.5 mg (0.10 mmol) 1e and
1.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh) column chro-
3
matography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ea as a white solid
(46.4 mg, 95% yield), mp 96–98 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 85:15, flow
20
rate 1.0 mL/min, detection at 254 nm): t
R
= 11.1 min (minor), t
R
= 12.8 min (major); >99% ee. [α]
D
= ‒
1
6
5.9 (c = 2.04, acetone). H NMR (400 MHz, acetone-d6):  7.83 (d, J = 7.6 Hz, 2H), 7.39–7.35 (m, 3H),
7.17 (t, J = 7.6 Hz, 1H), 7.13–7.07 (m, 4H), 7.03–7.02 (m, 2H), 6.77 (d, J = 8.0 Hz, 1H), 6.68 (br s, 2H),
1
3
1
4
1
1
.52 (s, 1H), 3.07 (s, 3H), 2.70 (s, 3H), 2.39 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  177.9,
74.0, 161.7, 160.6, 143.1, 139.9, 134.6, 134.5, 132.3, 131.6, 130.5, 130.3, 130.2, 126.8, 125.6, 120.3,
16.9, 110.1, 83.0, 73.5, 66.0, 64.6, 55.9, 27.6, 22.1, 18.1 ppm. HRMS (ESI-TOF): m/z calcd. for
+
C
30
H
26
N
5
O
2
[M + H] 488.2081, found 488.2078.
(
2'R,3R,3'S)-4'-Amino-5-fluoro-1,3''-dimethyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3fa). From 22.9 mg (0.10
mmol) 1f and 31.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3fa as a
brownish yellow solid (44.7 mg, 91% yield), mp 117–119 C. HPLC (Daicel Chiralpak AD-H, n-hex-
ane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 13.1 min (minor), t = 16.3 min
R
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3
20
1
(
major); >99% ee. [α]
D
= ‒110.6 (c = 2.04, acetone). H NMR (400 MHz, acetone-d6):  7.81 (d, J =
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
.6 Hz, 2H), 7.39–7.32 (m, 3H), 7.19–7.09 (m, 5H), 7.06–7.03 (m, 2H), 6.91 (dd, J
1
= 8.4 Hz, J = 4.0
2
1
3
1
Hz, 1H), 6.80 (br s, 2H), 4.47 (s, 1H), 3.10 (s, 3H), 2.71 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
d6):  177.8, 173.8, 161.44 (d, J = 239.5 Hz), 161.39, 161.1, 151.6, 141.6, 139.9, 134.2 (d, J = 7.2 Hz),
134.1, 130.5, 130.4, 126.9, 125.5, 120.3, 117.6 (d, J = 23.6 Hz), 116.7, 112.9 (d, J = 25.5 Hz), 111.4 (d,
1
9
1
J = 8.4 Hz), 82.1, 73.4, 66.2, 65.0, 27.7, 18.1 ppm. F{ H} NMR (377 MHz, acetone-d6):  –115.9 ppm.
+
HRMS (ESI-TOF): m/z calcd. for C29
H
23FN
5
O
2
[M + H] 492.1830, found 492.1817.
(
2'R,3R,3'S)-4'-Amino-5-chloro-1,3''-dimethyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ga). From 24.6 mg (0.10
mmol) 1g and 31.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ga as a
white solid (44.2 mg, 87% yield), mp 100–102 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol
=
85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 12.4 min (minor), t
R
= 14.8 min (major); 99%
2
0
1
ee. [α]
D
= ‒14.5 (c = 1.81, acetone). H NMR (400 MHz, acetone-d6):  7.83–7.80 (m, 2H), 7.52 (d, J
=
2.0 Hz, 1H), 7.40–7.35 (m, 3H), 7.19–7.11 (m, 4H), 7.05–7.03 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.81
1
3
1
(
br s, 2H), 4.47 (s, 1H), 3.11 (s, 3H), 2.70 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  177.7,
173.7, 161.3, 161.1, 144.3, 139.8, 134.4, 134.0, 131.3, 130.52, 130.46, 130.4, 129.8, 126.9, 125.2, 120.3,
116.7, 111.9, 82.0, 73.4, 66.1, 64.7, 55.9, 27.7, 18.0 ppm. HRMS (ESI-TOF): m/z calcd. for C29
H23ClN
5
O
2
+
[M + H] 508.1535, found 508.1536.
(
2'R,3R,3'S)-4'-Amino-5-bromo-1,3''-dimethyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ha). From 29.0 mg (0.10
mmol) 1h and 31.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ha as a
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
light pink solid (47.0 mg, 85% yield), mp 148–150 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-pro-
panol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t = 12.5 min (minor), t = 15.1 min (major);
= +8.8 (c = 1.22, acetone). H NMR (400 MHz, acetone-d6):  7.83–7.80 (m, 2H), 7.65
d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.40–7.35 (m, 2H), 7.19–7.11 (m, 4H), 7.05–
.02 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.81 (br s, 2H), 4.47 (s, 1H), 3.11 (s, 3H), 2.70 (s, 3H) ppm. C{ H}
R
R
2
0
1
>99% ee. [α]
D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1
2
13
1
7
NMR (176 MHz, acetone-d6):  177.6, 173.7, 161.3, 161.1, 144.8, 139.8, 134.7, 134.3, 134.0, 130.52,
130.47, 130.4, 127.9, 126.9, 120.3, 117.1, 116.7, 112.4, 82.0, 73.4, 66.1, 64.7, 55.9, 27.7, 18.0 ppm.
+
HRMS (ESI-TOF): m/z calcd. for C29
H
23BrN
5
O
2
[M + H] 552.1030, found 552.1032.
(
2'R,3R,3'S)-4'-Amino-6-chloro-1,3''-dimethyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ia). From 24.6 mg (0.10
mmol) 1i and 31.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ia as a
white solid (45.7 mg, 90% yield), mp 102–104 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol
= 88:12, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 28.8 min (minor), t
= ‒93.3 (c = 2.12, acetone). H NMR (400 MHz, acetone-d6):  7.83–7.80 (m, 2H), 7.54 (d, J
8.0 Hz, 1H), 7.39–7.35 (m, 2H), 7.25 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 7.19–7.10 (m, 4H), 7.02–6.99
m, 3H), 6.78 (br s, 2H), 4.48 (s, 1H), 3.13 (s, 3H), 2.71 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-
d6):  178.0, 173.8, 161.4, 161.0, 146.8, 139.9, 136.5, 134.0, 131.0, 130.5, 130.44, 130.43, 130.35, 126.9,
R
= 30.9 min (major); >99%
2
0
1
ee. [α]
D
=
1
2
1
3
1
(
126.4, 124.8, 120.3, 116.7, 111.0, 82.1, 73.3, 66.1, 64.3, 27.8, 18.1 ppm. HRMS (ESI-TOF): m/z calcd.
+
for C29H
23ClN
5
O
2
[M + H] 508.1535, found 508.1537.
(
2'R,3R,3'S)-4'-Amino-1,3''-dimethyl-2,5''-dioxo-1'',2'-diphenyl-7-(trifluoromethyl)-1'',5''-dihy-
drodispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ja). From 33.5 mg
0.10 mmol) 1j and 31.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300
mesh) column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ja
(
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2
3
as a light yellow solid (48.2 mg, 89% yield), mp 113–115 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-
propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t = 7.9 min (minor), t = 9.9 min (major);
= ‒126.0 (c = 1.81, acetone). H NMR (400 MHz, acetone-d6):  7.85 (d, J = 6.8 Hz, 1H),
.83–7.80 (m, 2H), 7.70 (dd, J = 8.2 Hz, J = 1.0 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.40–7.35 (m, 2H),
.20–7.11 (m, 4H), 6.97–6.94 (m, 2H), 6.88 (br s, 2H), 4.47 (s, 1H), 3.25 (q, J = 2.4 Hz, 3H), 2.74 (s, 3H)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R
R
2
0
1
98% ee. [α]
D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
7
1
2
1
3
1
ppm. C{ H} NMR (176 MHz, acetone-d6):  179.1, 173.6, 161.5, 161.3, 143.2, 139.8, 135.2, 133.6,
130.6, 130.54, 130.46, 130.3, 129.3, 129.2 (q, J = 5.9 Hz), 126.9, 125.4 (q, J = 270.9 Hz), 125.1, 120.3,
19
1
1
16.6, 113.6 (q, J = 32.9 Hz), 81.5, 73.2, 67.0, 63.4, 30.3 (q, J = 6.1 Hz), 18.2 ppm. F{ H} NMR (377
+
MHz, acetone-d6):  –53.8 ppm. HRMS (ESI-TOF): m/z calcd. for C30
H
23
3
F N
5
O
2
[M + H] 542.1798,
found 542.1795.
(
2'R,3R,3'S)-4'-Amino-1,3'',5,7-tetramethyl-2,5''-dioxo-1'',2'-diphenyl-1'',5''-dihydrodispiro[in-
doline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ka). From 23.9 mg (0.10 mmol) 1k
and 31.5 mg (0.12 mmol) unsaturated pyrazolinone 2a, purified by silica gel (200-300 mesh) column
chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ka as a white
solid (46.6 mg, 93% yield), mp 134–136 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol =
85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 10.1 min (minor), t
R
= 12.5 min (major); >99%
2
0
1
ee. [α]
D
= ‒80.3 (c = 1.20, acetone). H NMR (400 MHz, acetone-d6):  7.83–7.81 (m, 2H), 7.40–7.35
(m, 2H), 7.19–7.08 (m, 5H), 7.03–7.00 (m, 2H), 6.87 (s, 1H), 6.63 (br s, 2H), 4.47 (s, 1H), 3.36 (s, 3H),
13
1
2
1
.69 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  178.6, 174.1, 161.7,
60.5, 140.8, 139.9, 135.4, 134.6, 134.4, 133.1, 130.5, 130.4, 130.3, 130.2, 126.8, 123.5, 121.6, 120.3,
117.0, 83.6, 73.5, 66.4, 64.0, 21.9, 19.6, 18.1 ppm. HRMS (ESI-TOF): m/z calcd. for C31
H
28
N
5
O [M +
2
+
H] 502.2238, found 502.2241.
(
2'R,3R,3'S)-4'-Amino-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-2'-(p-tolyl)-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ab). From 21.1 mg (0.10
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mmol) 1a and 33.1 mg (0.12 mmol) unsaturated pyrazolinone 2b, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ab as a
light pink solid (46.3 mg, 95% yield), mp 120–122 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-pro-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
panol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 19.8 min (minor), t
= ‒122.7 (c = 2.14, acetone). H NMR (400 MHz, acetone-d6):  7.84–7.82 (m, 2H), 7.53
= 7.6 Hz, J = 0.8 Hz, 1H), 7.39–7.35 (m, 2H), 7.32 (dd, J = 7.8 Hz, J = 1.2 Hz, 1H), 7.21 (dd,
= 7.6 Hz, J = 0.8 Hz, 1H), 7.18–7.14 (m, 1H), 6.92–6.88 (m, 5H), 6.69 (br s, 2H), 4.49 (s, 1H), 3.11
R
= 14.9 min (major);
20
1
>99% ee. [α]
D
(
dd, J
1
2
1
2
J
1
2
13
1
(
s, 3H), 2.71 (s, 3H), 2.10 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  178.1, 174.0, 161.6,
1
60.8, 145.5, 140.0, 139.9, 132.4, 131.3, 131.0, 130.5, 130.3, 126.8, 125.05, 124,99, 120.2, 116.9, 110.3,
[M + H]+
82.9, 73.6, 66.0, 64.6, 27.6, 21.8, 18.1 ppm. HRMS (ESI-TOF): m/z calcd. for C30
H
26
N
5
O
2
488.2081, found 488.2074.
2'R,3R,3'S)-4'-Amino-2'-(4-methoxyphenyl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-dihy-
drodispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ac). From 21.1 mg
0.10 mmol) 1a and 35.1 mg (0.12 mmol) unsaturated pyrazolinone 2c, purified by silica gel (200-300
(
(
mesh) column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ac
as a white solid (48.3 mg, 96% yield), mp 89–91 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propa-
nol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 11.0 min (minor), t
= ‒136.9 (c = 2.98, acetone). H NMR (400 MHz, acetone-d6):  7.84–7.81 (m, 2H), 7.53
= 7.2 Hz, J = 0.8 Hz, 1H), 7.38–7.34 (m, 2H), 7.31 (td, J = 7.8 Hz, J = 1.2 Hz, 1H), 7.21 (td, J
7.4 Hz, J = 0.9 Hz, 1H), 7.18–7.13 (m, 1H), 6.97–6.94 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.68 (br s,
H), 6.64–6.60 (m, 2H), 4.46 (s, 1H), 3.58 (s, 3H), 3.09 (s, 3H), 2.73 (s, 3H) ppm. C{ H} NMR (176
MHz, acetone-d6):  178.1, 174.0, 161.6, 161.5, 160.8, 145.4, 139.9, 132.4, 131.8, 131.3, 130.5, 126.8,
R
= 9.1 min (major);
2
0
1
>99% ee. [α]
dd, J
D
(
1
2
1
2
1
=
2
1
3
1
2
125.8, 125.03, 124.95, 120.2, 116.9, 115.5, 110.3, 82.7, 73.6, 66.0, 64.7, 56.2, 27.6, 18.1 ppm. HRMS
+
(
ESI-TOF): m/z calcd. for C30
H
26
N
5
O
3
[M + H] 504.2030, found 504.2027.
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(
2'R,3R,3'S)-4'-Amino-2'-(4-fluorophenyl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ad). From 21.1 mg (0.10
mmol) 1a and 33.6 mg (0.12 mmol) unsaturated pyrazolinone 2d, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ad as a
light yellow solid (46.2 mg, 94% yield), mp 113–115 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 20.6 min (minor), t = 15.7 min
R
1
(
major); >99% ee. [α] 20
D
= ‒115.7 (c = 1.94, acetone). H NMR (400 MHz, acetone-d6):  7.82–7.80 (m,
2
7
2
H), 7.54 (dd, J
1
= 7.2 Hz, J
2
= 0.8 Hz, 1H), 7.40–7.32 (m, 3H), 7.23 (td, J
1
= 7.6 Hz, J = 0.8 Hz, 1H),
2
.19–7.15 (m, 1H), 7.09–7.05 (m, 2H), 6.92–6.87 (m, 3H), 6.73 (br s, 2H), 4.50, (s, 1H), 3.11 (s, 3H),
1
3
1
.73 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  177.9, 173.8, 164.4 (d, J = 245.7 Hz), 161.4,
160.7, 145.4, 139.8, 132.7 (d, J = 8.4 Hz), 132.1, 131.4, 130.5, 130.4 (d, J = 3.5 Hz), 126.9, 125.2, 125.0,
19
1
1
20.3, 117.1 (d, J = 20.9 Hz), 116.8, 110.4, 82.6, 73.4, 65.7, 64.7, 27.6, 18.0 ppm. F{ H} NMR (377
+
MHz, acetone-d6):  –114.6 ppm. HRMS (ESI-TOF): m/z calcd. for C29
H
23FN
5
O
2
[M + H] 492.1830,
found 492.1822.
(
2'R,3R,3'S)-4'-Amino-2'-(4-chlorophenyl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ae). From 21.1 mg (0.10
mmol) 1a and 35.6 mg (0.12 mmol) unsaturated pyrazolinone 2e, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ae as a
light yellow solid (49.3 mg, 97% yield), mp 102–104 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-
propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 31.1 min (minor), t = 16.6 min
R
1
(
major); >99% ee. [α] 20
2H), 7.54 (dd, J = 7.4 Hz, J
.19–7.14 (m, 3H), 7.05–7.01 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 6.75 (br s, 2H), 4.49 (s, 1H), 3.13 (s, 3H),
D
= ‒102.0 (c = 2.08, acetone). H NMR (400 MHz, acetone-d6):  7.83–7.80 (m,
1
2
= 0.6 Hz, 1H), 7.40–7.32 (m, 3H), 7.31 (td, J
1
= 7.4 Hz, J = 0.9 Hz, 1H),
2
7
2
1
3
1
.72 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  177.8, 173.8, 161.3, 160.6, 145.4, 139.8,
2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
1
6
5
35.8, 133.2, 132.2, 132.0, 131.5, 130.53, 130.46, 126.9, 125.2, 125.0, 120.3, 116.7, 110.5, 82.7, 73.3,
+
5.5, 64.5, 27.6, 18.0 ppm. HRMS (ESI-TOF): m/z calcd. for C29
H
23ClN
5
O
2
[M + H] 508.1535, found
08.1534.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2'R,3R,3'S)-4'-Amino-2'-(4-bromophenyl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3af). From 21.1 mg (0.10
mmol) 1a and 40.9 mg (0.12 mmol) unsaturated pyrazolinone 2f, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3af as a
light yellow solid (49.8 mg, 90% yield), mp 118–120 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-
propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 36.3 min (minor), t = 18.0 min
R
major); >99% ee. [α] 20
2H), 7.54 (dd, J = 7.2 Hz, J
7.20–7.16 (m, 1H), 6.98–6.96 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 6.75 (br s, 2H), 4.48 (s, 1H), 3.13 (s, 3H),
= ‒109.3 (c = 2.09, acetone). H NMR (400 MHz, acetone-d6):  7.83–7.80 (m,
1
(
D
1
2
= 0.8 Hz, 1H), 7.40–7.30 (m, 5H), 7.23 (dd, J
1
= 7.6 Hz, J = 0.8 Hz, 1H),
2
13
1
2
1
.72 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  177.8, 173.8, 161.3, 160.6, 145.4, 139.8,
33.7, 133.5, 132.5, 132.0, 131.5, 130.5, 126.9, 125.2, 125.0, 124.1, 120.3, 116.7, 110.5, 82.7, 73.3, 65.5,
+
64.5, 27.6, 18.0 ppm. HRMS (ESI-TOF): m/z calcd. for C29
52.1031.
2'R,3R,3'S)-4'-Amino-2'-(2-methoxyphenyl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-dihy-
H
23BrN
5
O
2
[M + H] 552.1030, found
5
(
drodispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ag). From 21.1 mg
(0.10 mmol) 1a and 35.1 mg (0.12 mmol) unsaturated pyrazolinone 2g, purified by silica gel (200-300
mesh) column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ag
as a light pink solid (48.9 mg, 97% yield), mp 162–164 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-
propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 25.0 min (minor), t
= ‒109.3 (c = 2.09, acetone). H NMR (400 MHz, acetone-d6):  7.90–7.87 (m,
= 7.6 Hz, J = 0.8 Hz, 1H), 7.46 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 7.41–7.36 (m, 2H),
R
= 31.8 min
2
0
1
(major); >99% ee. [α]
D
2H), 7.53 (dd, J
1
2
1
2
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7
6
1
.29 (td, J
1
= 7.8 Hz, J
2
= 1.2 Hz, 1H), 7.19–7.13 (m, 2H), 7.11–7.07 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H),
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
.78 (td, J
1
= 7.8 Hz, J
2
= 0.9 Hz, 1H), 6.66 (dd, J
1
= 8.4 Hz, J = 0.8 Hz, 1H), 6.56 (br s, 2H), 5.22 (s,
2
1
3
1
H), 3.30 (s, 3H), 3.19 (s, 3H), 2.48 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  178.9, 174.3,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
161.0, 160.9, 159.6, 145.4, 140.4, 132.3, 131.1, 130.5, 130.2, 126.3, 125.5, 124.8, 123.2, 121.9, 119.8,
116.9, 112.6, 110.2, 83.3, 80.2, 72.6, 64.1, 56.8, 55.3, 27.7, 17.9 ppm. HRMS (ESI-TOF): m/z calcd. for
+
C
30
H
26
N
5
O
3
[M + H] 504.2030, found 504.2024.
(
2'R,3R,3'S)-4'-Amino-2'-(3-bromophenyl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ah). From 21.1 mg (0.10
mmol) 1a and 40.9 mg (0.12 mmol) unsaturated pyrazolinone 2h, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ah as a
light yellow solid (50.3 mg, 91% yield), mp 243–245 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-
propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 10.5 min (minor), t = 13.1 min
R
major); >99% ee. [α] 20
H), 7.55 (dd, J = 7.2 Hz, J
1H), 7.01 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.76 (br s, 2H), 4.48 (s, 1H), 3.15 (s, 3H), 2.70 (s,
= ‒102.1 (c = 1.35, acetone). H NMR (400 MHz, acetone-d6):  7.84–7.81 (m,
1
(
D
2
1
2
= 0.8 Hz, 1H), 7.42–7.34 (m, 4H), 7.26–7.17 (m, 3H), 7.10 (t, J = 8.0 Hz,
13
1
3
1
6
H) ppm. C{ H} NMR (176 MHz, acetone-d6):  177.8, 173.7, 161.2, 160.5, 145.3, 139.8, 137.0, 133.4,
33.1, 132.4, 131.9, 131.6, 130.6, 129.4, 127.0, 125.3, 125.1, 123.8, 120.4, 116.7, 110.6, 82.7, 73.2, 65.1,
+
4.4, 27.6, 18.0 ppm. HRMS (ESI-TOF): m/z calcd. for C29
H
23BrN
5
O
2
[M + H] 552.1030, found
552.1033.
2'R,3R,3'S)-4'-Amino-2'-(3-methoxyphenyl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-dihy-
drodispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ai). From 21.1 mg
0.10 mmol) 1a and 35.1 mg (0.12 mmol) unsaturated pyrazolinone 2i, purified by silica gel (200-300
(
(
mesh) column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ai
as a light yellow solid (42.6 mg, 85% yield), mp 140–142 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 16.9 min (minor), t = 14.3 min
R
1
(
major); >99% ee. [α] 20
H), 7.54 (dd, J = 7.6 Hz, J
7.22 (td, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.20–7.15 (m, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 7.6 Hz,
H), 6.70–6.68 (m, 3H), 6.62 (t, J = 2.0 Hz, 1H), 6.54 (dd, J = 7.8 Hz, J = 0.6 Hz, 1H), 4.53 (s, 1H),
.56 (s, 3H), 3.14 (s, 3H), 2.70 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  178.1, 173.9, 161.6,
D
= ‒119.2 (c = 1.84, acetone). H NMR (400 MHz, acetone-d6):  7.86–7.83 (m,
2
1
2
= 0.8 Hz, 1H), 7.41–7.37 (m, 2H), 7.33 (td, J
1
= 7.6 Hz, J = 1.2 Hz, 1H),
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
1
3
1
2
1
3
1
161.4, 160.7, 145.5, 139.9, 135.9, 132.4, 131.4, 130.5, 126.8, 125.1, 125.0, 122.4, 120.3, 116.8, 115.9,
115.3, 110.4, 82.9, 73.4, 65.6, 64.4, 56.3, 27.6, 18.1 ppm. HRMS (ESI-TOF): m/z calcd. for C30
H
26
N
5
O
3
+
[
M + H] 504.2030, found 504.2036.
(
2'R,3R,3'S)-4'-Amino-2'-(3,4-dimethoxyphenyl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-di-
hydrodispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3aj). From 21.1 mg
(0.10 mmol) 1a and 38.7 mg (0.12 mmol) unsaturated pyrazolinone 2j, purified by silica gel (200-300
mesh) column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3aj
as a light yellow solid (46.8 mg, 88% yield), mp 140–142 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-
propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 23.1 min (minor), t
= ‒127.2 (c = 1.81, acetone). H NMR (400 MHz, acetone-d6):  7.84 (d, J =
.6 Hz, 2H), 7.53 (d, J = 7.2 Hz, 1H), 7.40–7.36 (m, 2H), 7.33 (td, J = 7.8 Hz, J = 0.9 Hz, 1H), 7.22 (t,
R
= 25.3 min
20
1
(
major); >99% ee. [α]
D
7
1
2
J = 7.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.71–6.69 (m, 3H), 6.59 (d, J = 8.4 Hz,
1H), 6.46 (dd, J = 8.2 Hz, J = 2.2 Hz, 1H), 4.47 (s, 1H), 3.61 (s, 3H), 3.55 (s, 3H), 3.15 (s, 3H), 2.73 (s,
1
2
13
1
3
H) ppm. C{ H} NMR (176 MHz, acetone-d6):  178.3, 174.1, 161.7, 160.8, 151.2, 150.7, 145.5, 140.0,
132.5, 131.3, 130.5, 126.8, 126.3, 125.1, 125.0, 123.0, 120.2, 116.9, 113.3, 113.0, 110.4, 82.8, 73.6, 66.1,
+
64.6, 56.7, 56.6, 27.6, 18.1 ppm. HRMS (ESI-TOF): m/z calcd. for C31
34.2130.
H
28
N
5
O
4
[M + H] 534.2136, found
5
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The Journal of Organic Chemistry
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3
4
5
(
2'R,3R,3'S)-4'-Amino-2'-(furan-2-yl)-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3ak). From 21.1 mg (0.10
mmol) 1a and 30.3 mg (0.12 mmol) unsaturated pyrazolinone 2k, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3ak as a
light yellow solid (41.8 mg, 90% yield), mp 91–93 C. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
95:5, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 41.1 min (major); >99% ee. [α] 20
= ‒116.5 (c =
D
1
1
.94, acetone). H NMR (400 MHz, acetone-d6):  7.93 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.43
(
t, J = 8.0 Hz, 2H), 7.40–7.36 (m, 1H), 7.25–7.20 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.69 (br s, 2H), 6.20–
13
1
6
.19 (m, 1H), 6.03 (d, J = 3.2 Hz, 1H), 4.59 (s, 1H), 3.24 (s, 3H), 2.48 (s, 3H) ppm. C{ H} NMR (176
MHz, acetone-d6):  177.3, 173.6, 161.5, 160.2, 148.9, 145.7, 144.6, 140.1, 132.2, 131.6, 130.6, 126.8,
125.1, 125.0, 120.3, 116.6, 112.3, 110.4, 109.6, 82.6, 71.6, 62.6, 57.4, 27.7, 17.7 ppm. HRMS (ESI-TOF):
+
m/z calcd. for C27
H
22
N
5
O
3
[M + H] 464.1717, found 464.1712.
(
2'R,3R,3'S)-4'-Amino-1,3''-dimethyl-2,5''-dioxo-1''-phenyl-2'-(thiophen-2-yl)-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3al). From 21.1 mg (0.10
mmol) 1a and 32.2 mg (0.12 mmol) unsaturated pyrazolinone 2l, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3al as a
white solid (40.8 mg, 85% yield), mp 121–123 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol
=
85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 22.2 min (minor), t
= ‒139.0 (c = 1.54, acetone). H NMR (400 MHz, acetone-d6):  7.89–7.87 (m, 2H), 7.51 (dd,
= 0.8 Hz, 1H), 7.43–7.34 (m, 3H), 7.25–7.17 (m, 3H), 6.96 (d, J = 7.6 Hz, 1H), 6.79–6.73
R
= 25.9 min (major); 99%
2
0
1
ee. [α]
D
J
1
= 7.6 Hz, J
m, 4H), 4.77 (s, 1H), 3.16 (s, 3H), 2.67 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  177.6,
173.7, 161.4, 160.4, 145.8, 139.9, 135.5, 132.0, 131.6, 130.6, 128.8, 128.7, 127.8, 126.9, 125.2, 125.0,
2
1
3
1
(
1
20.3, 116.7, 110.5, 82.6, 73.3, 64.6, 60.5, 27.7, 18.2 ppm. HRMS (ESI-TOF): m/z calcd. for
+
C
27
H
22
N
5
O
2
S [M + H] 480.1489, found 480.1481.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
2'R,3R,3'S)-4'-Amino-1,3''-dimethyl-2,5''-dioxo-2'-phenyl-1''-(p-tolyl)-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3am). From 21.1 mg (0.10
mmol) 1a and 33.2 mg (0.12 mmol) unsaturated pyrazolinone 2m, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3am as a
light pink solid (46.5 mg, 95% yield), mp 85–87 C. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
5:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 13.7 min (minor), t
= ‒137.5 (c = 2.03, acetone). H NMR (400 MHz, acetone-d6):  7.70–7.67 (m, 2H), 7.54 (dd,
= 0.8 Hz, 1H), 7.32 (td, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.23–7.17 (m, 3H), 7.13–7.07 (m,
H), 7.01–6.99 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.68 (br s, 2H), 4.52 (s, 1H), 3.10 (s, 3H), 2.69 (s, 3H),
R
= 10.4 min (major); >99%
2
0
1
ee. [α]
D
J
1
= 7.6 Hz, J
2
1
2
3
2
1
3
1
.29 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  178.0, 173.6, 161.4, 160.8, 145.4, 137.5,
136.4, 134.4, 132.3, 131.3, 130.9, 130.34, 130.31, 130.2, 125.1, 125.0, 120.4, 116.9, 110.3, 82.8, 73.4,
+
6
4
6.1, 64.5, 27.6, 21.8, 18.1 ppm. HRMS (ESI-TOF): m/z calcd. for C30
H
26
N
5
O
2
[M + H] 488.2081, found
88.2073.
(
2'R,3R,3'S)-4'-Amino-1''-(4-chlorophenyl)-1,3''-dimethyl-2,5''-dioxo-2'-phenyl-1'',5''-dihydro-
dispiro[indoline-3,1'-cyclopentane-3',4''-pyrazol]-4'-ene-5'-carbonitrile (3an). From 21.1 mg (0.10
mmol) 1a and 35.6 mg (0.12 mmol) unsaturated pyrazolinone 2n, purified by silica gel (200-300 mesh)
column chromatography using petroleum ether/ethyl acetate (4/1 to 2/1 v/v) as eluent to obtain 3an as a
light yellow solid (49.3 mg, 97% yield), mp 79–81 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-pro-
panol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): t
R
= 27.7 min (minor), t
= ‒142.5 (c = 2.25, acetone). H NMR (400 MHz, acetone-d6):  7.85–7.83 (m, 2H), 7.54
d, J = 7.2 Hz, 1H), 7.43–7.40 (m, 2H), 7.32 (td, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.22 (td, J = 7.2 Hz, J
0.7 Hz, 1H), 7.14–7.08 (m, 3H), 7.02–7.00 (m, 2H), 6.89 (d, J = 7.6 Hz, 1H), 6.71(br s, 2H), 4.51 (s, 1H),
R
= 17.4 min (major);
20
1
>
99% ee. [α]
D
(
1
2
1
2
=
13
1
3
1
.10 (s, 3H), 2.72 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6):  177.9, 174.0, 162.1, 160.5, 145.4,
38.6, 134.2, 132.2, 131.39, 131.37, 130.5, 130.4, 130.3, 125.1, 125.0, 121.7, 116.8, 110.4, 82.9, 73.5,
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The Journal of Organic Chemistry
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2
3
+
6
6.2, 64. 5, 27.6, 18.1 ppm. HRMS (ESI-TOF): m/z calcd. for C29
H
23ClN
5
O [M + H] 508.1535, found
2
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
08.1529.
Synthesis of compound 4aa
The compound 4aa were prepared by modified reported procedure. The corresponding chiral com-
pound 3aa (47.4 mg，0.1 mmol) was dissolved in 1.0 mL Ac O and 0.5 mL pyridine, and then stirred for
about 24 h at 90 °C. When the reaction was completed, the solution was concentrated under vacuum. The
residue was then dissolved in dry CH Cl , and washed with water several times. The organic phase was
dried over anhydrous Na SO and concentrated under vacuum. The crude product was purified via flash
chromalography (eluent: petroleum ether/ethyl acetate = 4/1 to 3/1 v/v) to give compound 4aa.
3R,6'R,7'S)-1,2',3''-Trimethyl-1''-phenyl-6'-(p-tolyl)-6'H-dispiro[indoline-3,5'-cyclopenta[d]py-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
2
2
2
2
4
(
rimidine-7',4''-pyrazole]-2,4',5''(1''H,3'H)-trione (4aa). White solid (29.5 mg, 57% yield), mp 154–
156 C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection
20
1
at 254 nm): t
NMR (400 MHz, acetone-d6):  10.02 (s, 1H), 7.64–7.61 (m, 2H), 7.52 (dd, J
1H), 7.36–7.29 (m, 3H), 7.23 (td, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.16–7.06 (m, 6H), 6.89 (d, J = 7.6 Hz,
H), 4.40 (s, 1H), 3.10 (s, 3H), 2.64 (s, 3H), 2.15 (s, 3H) ppm. C{ H} NMR (176 MHz, acetone-d6): 
R
= 34.8 min (minor), t
R
= 10.4 min (major); 99% ee. [α]
D
= ‒248.4 (c = 1.25, acetone). H
1
= 7.2 Hz, J = 0.8 Hz, 1H,
2
1
2
13
1
1
1
1
76.3, 175.0, 170.2, 159.7, 151.9, 145.6, 140.2, 133.2, 131.9, 131.2, 130.8, 130.7, 130.3, 130.1, 126.6,
25.4, 125.0, 120.9, 114.6, 110.7, 99.1, 72.4, 69.0, 64.1, 27.8, 24.5, 18.1 ppm. HRMS (ESI-TOF): m/z
+
calcd. for C31
H
26
N
5
O
3
[M + H] 516.2030, found 516.2018.
ASSOCIATED CONTENT
Supporting Information
2
9
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