Article

Cite This: J. Org. Chem. 2018, 83, 9278−9290 pubs.acs.org/joc

Asymmetric Construction of Bispiro[oxindole-pyrrolidine-

rhodanine]s via Squaramide-Catalyzed Domino Michael/Mannich [3
+ 2] Cycloaddition of Rhodanine Derivatives with N‑(2,2,2-
Trifluoroethyl)isatin Ketimines
Yong-Xing Song and Da-Ming Du*
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
*
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ABSTRACT: Squaramide-catalyzed asymmetric domino Mi-

chael/Mannich [3 + 2] cycloaddition reaction between
rhodanine derivatives and N-(2,2,2-trifluoroethyl)isatin keti-
mines has been developed to synthesize various bispiro-
[oxindole-pyrrolidine-rhodanine]s with good to excellent
yields (up to 99%) and excellent stereoselectivities (up to
>99% ee and >99:1 dr). The biologically active rhodanine,
oxindole, and pyrrolidine moieties were embedded in these
novel bispirocyclic products, which will provide some support
for the enrichment of chiral heterocyclic compound databases
with potential medical value.

■ INTRODUCTION
Chiral pyrrolidines have long been considered as the “parent
nuclear structure” in many natural bioactive products and
pharmaceuticals.1 As an important branch of the pyrrolidine
molecule, spiropyrrolidine2 has many special biological
activities, so it is always an extremely attractive synthetic
target as the intermediate for the further synthesis of complex
molecules.3 Chiral spirocyclic compounds, characterized by an
interesting connection of two rings through a quaternary
carbon atom, are usually found in many natural products and
bioactive compounds.4 Due to its unique structural properties,
spirocycles have demonstrated a wide range of therapeutic
potentials, which present great challenges for chemists to
prepare such compounds using mild conditions from simple
and easy-to-get raw materials.5 Meanwhile, owing to the fact
that the fluorine atom has a small atomic radius and high
electronegativity,6 organofluorine compounds always play a
very important role in pharmaceuticals and pesticides.7 Among
the fluorinated compounds, the trifluoromethyl group occupies
a special position, especially when the trifluoromethyl is in the
α-position of the nitrogen atom; meanwhile the N atom is
considered as a low basic amide, which is considered to be one
of the key factors affecting the affinity of the drug receptor.8
However, the methodological choice of introducing the
trifluoromethyl group to the desired location is still limited
compared to the monofluorination process.9 Therefore, the
development of diverse synthetic strategies and methods to
synthesize trifluoromethyl-containing compounds has been
pursued by chemists in recent decades.10
On the other hand, 2-thioxo-1,3-thiazolidin-4-one, com-
monly named as rhodanine, has long been sought after by
pharmacologists as an important compound in medicinal
chemistry.11 As a peculiar structure with pharmacological
activity (Figure 1), the modification of rhodanine attracted the
attention of chemists.12 Up to now, only a few cases of
asymmetric synthetic methods have been reported for the
preparation of chiral thiazolidinone derivatives (Scheme 1).13
In 2012, Ye and co-workers first disclosed the synthesis of
various spirocyclic compounds via a diamine-catalyzed
asymmetric tandem reaction between α,β-unsaturated ketones
and rhodanine derivatives.13a Then, in 2013, Ye and co-
workers reported the synthesis of various spirocyclic
compounds via trienamine-catalyzed asymmetric Diels−Alder
reaction between 2,4-dienals and rhodanine/hydantoin de-
rivatives.13b In 2015, Peng and co-workers developed an
efficient and convenient one-pot, three-component tandem
reaction for the asymmetric synthesis of diverse spirocyclic
druglike skeletons.13c In the same year, Deng and co-workers
reported a highly efficient asymmetric 1,3-dipolar cyclo-
addition of azomethine ylides to 5-alkylidenethia(oxa)-
zolidine-2,4-diones catalyzed by a chiral N,O-ligand/Cu-
(CH3CN)4BF4 system.13d From a comprehensive point of
view, the corresponding asymmetric studies on thiazolidinone
derivatives were based on the monospirocyclic structures.
Therefore, combining the three classes of key heterocyclic
motifs (oxindole, pyrrolidine, rhodanine) and the CF3 group
through two unique spiro-quaternary stereogenic carbons
would rebuild structurally novel bispiro[oxindole-pyrrolidine-
rhodanine]s containing the trifluoromethyl group. The
Received: May 17, 2018
Published: June 29, 2018

© 2018 American Chemical Society 9278 DOI: 10.1021/acs.joc.8b01245

J. Org. Chem. 2018, 83, 9278−9290
The Journal of Organic Chemistry
Figure 1. Biologically active thiazolidinones and spirooxindole.
Scheme 1. Asymmetric Study of Thiazolidinone Derivatives
resulting novel bispirocyclic heterocycles may provide some
unprecedented benefits to medicinal chemistry, with the hope
of finding valuable applications in drug discovery.
Recently, N-(2,2,2-trifluoroethyl)isatin ketimines serving as
efficient azomethine ylide precursors have been used to
generate structurally diverse CF 3 -containing spiro-
[pyrrolidine-oxindole] derivatives.14 Meanwhile, on the basis
of our continuing interest in the construction of diverse
complex and novel spirocyclic oxindole skeletons with
organocatalysis,15 we envisioned that CF3-containing bispiro-
[oxindole-pyrrolidine-rhodanine]s 3 with multiple stereo-
centers, including two spiro-quaternary centers, could be
constructed by the domino Michael/Mannich [3 + 2]
cycloaddition reactions between the rationally designed
isatin-derived CF3-containing azomethine ylides 2 with
rhodanine derivatives 1.
■
RESULTS AND DISCUSSION
The initial investigation commenced with the reaction of ethyl
2-(4-oxo-3-phenyl-2-thioxothiazolidin-5-ylidene)acetate (1a)
and N-(2,2,2-trifluoroethyl)isatin ketimine 2a in dichloro-
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methane at room temperature. Using quinine-derived squar-
amide C1 as the catalyst, the reaction could give the
bispirocyclic compound 3aa in 97% yield with 88% ee and
>99:1 dr after 12 h (Table 1, entry 1). Inspired by this good
result, a series of bifunctional organocatalysts, C2−C12
(Figure 2), were evaluated for this cascade reaction under
the same experimental conditions. It was found that a cinchona
alkaloid skeleton was essential for achieving high asymmetric
induction (Table 1, entries 1−9 and 12 vs entries 10 and 11).
Although catalyst C3 is superior to catalyst C1 in terms of
yield and enantioselectivity, it is significantly reduced in
diastereoselectivity (Table 1, entry 3). The catalyst C4 has
better enantioselectivity than the catalyst C1, but the yield and
the diastereoselectivity decrease (Table 1, entry 4). The
catalyst C5 and catalyst C9 showed similar effects, but the
enantioselectivity decreased, especially the catalyst C9 (Table
1, entries 5 and 9). Catalyst C12 decreased slightly in the
aspect of stereoselectivity (Table 1, entry 12). The
experimental results show that the catalysts C2, C6, C7, and
C8 are superior to the catalyst C1, in particular, the catalytic
effect of the catalyst C2 (Table 1, entries 2, 6, 7, and 8).
DOI: 10.1021/acs.joc.8b01245
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The Journal of Organic Chemistry Article

Table 1. Optimization of the Reaction Conditionsa rhodanine derivatives 1 was examined (Table 2). As illustrated
in Table 2, the reaction showed good functional group
tolerance, and a variety of bispiro[oxindole-pyrrolidine-
rhodanine]s, 3aa−3na, were obtained in high yields (65−
99%) with excellent enantio- and diastereoselectivities (92:8 to
>99:1 dr and 57% to >99% ee). The effect of the substituents
R1 on the rhodanine derivatives was first investigated. When R1
= Boc, the reaction can still proceed with very high yield and
entry solvent catalyst yieldb (%) drc eed (%) stereoselectivity, and when R1 = CN, the enantioselectivity and
1 CH2Cl2 C1 97 >99:1 88 diastereoselectivity of the reaction are reduced. However, when
2 CH2Cl2 C2 99 99:1 94 R1 = Ph, the reaction cannot occur. We tried to synthesize
3 CH2Cl2 C3 98 86:14 95 alkyl-substituted rhodanine derivatives, but unfortunately, we
4 CH2Cl2 C4 92 97:3 −90 failed to obtain the corresponding substrates. Then we studied
5 CH2Cl2 C5 98 >99:1 86 the effect of substituent R2 on the nitrogen atom of rhodanine.
6 CH2Cl2 C6 98 99:1 92 The experimental results show that, regardless of the R2
7 CH2Cl2 C7 99 >99:1 90 substituent (aliphatic or aromatic), the reaction proceeds
8 CH2Cl2 C8 99 99:1 93 smoothly with high yield and stereoselectivity (Table 2, 3ea−
9 CH2Cl2 C9 98 >99:1 76 3ha). However, when R2 = H, the reaction time becomes
10 CH2Cl2 C10 94 95:5 14 longer and the yield and enantioselectivity decrease. We
11 CH2Cl2 C11 96 99:1 32 believe that this substrate may bind to the catalyst and reduce
12 CH2Cl2 C12 99 96:4 84 the catalytic activity of the catalyst. It was found that either
13 CHCl3 C2 94 99:1 95 electron-donating (1j and 1k) or electron-withdrawing (1l−
14 toluene C2 79 94:6 95 1n) substituents on the benzene ring were tolerated and
15 THF C2 99 81:19 55 delivered the desired bispiro[oxindole-pyrrolidine-rhodanine]s
16 Et2O C2 84 90:10 90 3ja−3na in excellent yields (90−99%) with excellent
17 dioxane C2 39 82:18 37 diastereoselectivities (98:2 to 99:1 dr) and enantioselectivities
18 CH3CN C2 96 5:95 0, 2 (90−91% ee) (Table 2, 3ja−3na).
19 DCE C2 85 98:2 94 Further exploration of the substrate scope was focused on
20 xylene C2 79 96:4 96 the N-(2,2,2-trifluoroethyl)isatin ketimines 2b−2m bearing
21e CH2Cl2 C2 99 98:2 96 various substituents (Table 3). As shown in Table 3, a series of
22f CH2Cl2 C2 97 99:1 95 ketamines, 2b−2m, tolerated the reaction and furnished the
23g CH2Cl2 C2 95 98:2 95 corresponding products 3ab−3am in high to excellent yields
24h CH2Cl2 C2 98 99:1 95 (80−99%) with high to excellent stereoselectivity (86:14 to
a
Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), and catalyst >99:1 dr and 80% to >99% ee). For example, the ketimines
(10 mol %) in solvent (1.0 mL) were stirred at room temperature for bearing electron-donating groups (MeO− and Me−) or
12 h. bIsolated yield after column chromatography purification. cThe electron-withdrawing groups (Cl− and Br−) at the 5-position
diastereomeric ratio (dr) was determined by HPLC analysis. dThe
of the indolinone ring led to similar enantioselectivities of 93%
enantiomeric excess (ee) was determined by HPLC analysis. eThe
reaction was performed with 5 mol % catalyst for 12 h. fThe reaction to >99% ee and 93:7 to 99:1 dr (Table 3, 3ab, 3ac, 3af, and
was performed with 2.5 mol % catalyst for 24 h. gThe reaction was 3ah). However, when the substrate 2d with a 5,7-dimethyl
performed at 0 °C for 16 h. hThe reaction was performed at −10 °C group was used, the yield and diastereoselectivity of the
for 24 h. corresponding product were decreased (Table 3, 3ad). When
R3 was 5-F, the stereoselectivity of the reaction was decreased
With optimal catalyst C2 identified, the screening of a (Table 3, 3ae). When Cl was in the 6-position of the ketimine,
variety of solvents, including chloroform, toluene, THF, diethyl the yield and stereoselectivity of the reaction were also
ether, dioxane, acetonitrile, 1,2-dichloroethane (DCE), and decreased (Table 3, 3ag). Moreover, we also evaluated the
xylene, was performed (Table 1, entries 13−20). Dichloro- substitution at the 1-position of ketamines. As summarized in
methane was the best solvent for this reaction under the same Table 3, with or without the substituent at the 1-position, N-
experimental conditions. When the catalyst loading was (2,2,2-trifluoroethyl) ketimine showed good reactivity, and the
lowered from 10 to 5 mol %, there was no effect on the [3 + 2] cycloaddition reaction gave the products in high to
reactivity and stereoselectivity (Table 1, entry 21). With a excellent yields with high to excellent stereoselectivities (Table
further decrease of the catalyst loading to 2.5 mol %, an 3, 3ai−3am).
excellent yield and diastereo- and enantiocontrol could still be To demonstrate the practical utility and robustness of this
achieved but with a prolonged reaction time (Table 1, entry asymmetric domino Michael/Mannich [3 + 2] cycloaddition,
22). When the reaction temperature decreased, there was no the reaction between 1a and 2a was conducted on a gram scale
significant difference in the results of the reaction except for (3.0 mmol) using our standard conditions, and the
the prolonged reaction time (entries 23 and 24). As the bispirocyclic product 3aa could be obtained in 95% yield
conditions of choice, we utilized rhodanine derivatives and N- with >99:1 dr and 91% ee (Scheme 2). In addition,
(2,2,2-trifluoroethyl)isatin ketimines at a molar ratio of 1:1.2 in regioselective N-methylation of 3ai (88% ee) was achieved at
dichloromethane with 5 mol % catalyst C2 at room the N1 position of indolinone, and product 3aj was obtained in
temperature for 12 h. 96% yield with 99:1 dr and 88% ee (Scheme 3a). Finally, we
Having identified the optimal reaction conditions (Table 1, also tried to demonstrate the synthetic transformation of these
entry 21), we then explored the generality of this Michael/ products. The rhodanine moiety could be easily oxidized to
Mannich cycloaddition reaction. First, the scope of the thiazolidine-2,4-dione using chromium trioxide as the oxidant,
9280 DOI: 10.1021/acs.joc.8b01245
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The Journal of Organic Chemistry
Figure 2. Structures of screened organocatalysts.
and the corresponding new type of bispirocyclic heterocycle 4
was obtained in 87% yield (Scheme 3b).
To determine the absolute configurations of the target
products, a single crystal of compound 3na was obtained by
recrystallization from petroleum ether/ethyl acetate. As shown
in Figure 3, the absolute configuration of 3na was determined
to be (3S,3′R,4′S,5′S). The absolute configurations of the
other products were assigned by analogy with 3na.16
As shown in Figure 4, on the basis of our experiments and
previously reported17 dual activation model, we proposed a
plausible mechanism for this domino Michae/Mannich [3 + 2]
cycloaddition reaction. In the first Michael addition step,
catalyst C2 initially promotes the formation of transition state
A through deprotonation of the N-(2,2,2-trifluoroethyl)isatin
ketimine 2a. Then both 1a and 2a are simultaneously activated
via hydrogen-bonding interactions with catalyst C2. Afterward,
the rhodanine is attacked by the deprotonated N-(2,2,2-
trifluoroethyl)isatin ketimine from the Si-face via transition
state B, which undergoes an intermolecular Michael addition.
Subsequently, the resulting nucleophilic rhodanine anion
attacks the CN double bond of the imine in a Mannich
cyclization reaction via intermediate C, which delivers the
observed bispirocyclic product 3aa and regenerates the
bifunctional catalyst C2 after a protonation process.
■
CONCLUSIONS
In conclusion, we have developed a highly diastereo- and
enantioselective domino Michael/Mannich [3 + 2] cyclo-
addition reaction of N-(2,2,2-trifluoroethyl)isatin ketimines
with rhodanine derivatives. In the presence of a squaramide
tertiary amine catalyst, a wide range of CF3-containing
bispiro[oxindole-pyrrolidine-rhodanine]s bearing four consec-
utive stereocenters, including two vicinal spiro-quaternary
chiral centers, were efficiently obtained with excellent results
(up to 99% yield, >99:1 dr, and >99% ee). A large-scale
experiment and further transformation of the products were
also successfully performed to demonstrate the promising
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applicability of the methodology. We expect that the
availability of these CF3-containing bispiro[oxindole-pyrroli-
dine-rhodanine]s will provide promising drug candidates for
chemical biology and drug discovery.
■
EXPERIMENTAL SECTION
General Information. All commercial reagents were used without
further purification. Solvents were distilled according to the
purification procedures. Column chromatography was performed
with silica gel (200−300 mesh). Melting points were determined with
an XT-4 melting-point apparatus and are uncorrected. 1H NMR
spectra were measured with a 400 MHz spectrometer, and chemical
shifts are reported in δ (ppm) units relative to tetramethylsilane
(TMS) as the internal standard. 13C NMR spectra were measured at
176 MHz with a 700 MHz spectrometer, and chemical shifts are
reported in δ (ppm) units relative to tetramethylsilane and referenced
to the solvent peak (CDCl3, δ(C) = 77.00 ppm). 19F NMR spectra
were measured at 376 MHz. Proton coupling patterns are described as
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and
broad (br). High-resolution mass spectra were recorded with an
Agilent 6520 accurate-mass-Q-TOF MS system equipped with an
electrospray ionization (ESI) source. Enantiomeric excesses were
determined by chiral HPLC analysis using an Agilent 1200 LC
instrument with Daicel Chiralpak IA, IB, IC, and AD-H columns.
Optical rotations were measured with a polarimeter at the indicated
concentration with the units of grams per 100 mL.
1a−1n were prepared according to the literature.18 2a−2m were
prepared according to literature reported by Wang and co-workers
and slightly modified.14a The squaramide organocatalysts were
prepared by following the reported procedures.19
General Procedure for Asymmetric Domino Michael/
Mannich [3 + 2] Cycloaddition Reaction. Rhodanine derivatives
1 (0.10 mmol), N-(2,2,2-trifluoroethyl)isatin ketimines 2 (0.12
mmol), and catalyst C2 (5 mol %) in CH2Cl2 (1.0 mL) were stirred
at room temperature for 12 h. After completion of the reaction
(monitored by TLC analysis), the crude product was purified by flash
column chromatography on silica gel (PE/EtOAc, 8:1) to afford the
pure product 3. The chiral catalyst was replaced by Et3N, and the
other conditions remained unchanged to obtain racemates of 3.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-2,4″-dioxo-3″-phenyl-2″-thioxo-
5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
DOI: 10.1021/acs.joc.8b01245
J. Org. Chem. 2018, 83, 9278−9290
The Journal of Organic Chemistry
Table 2. Substrate Scope of Rhodanine Derivatives 1a
a
Unless noted otherwise, the reaction was carried out with 1 (0.10 mmol), 2a (0.12 mmol), and catalyst C2 (0.005 mmol) in CH2Cl2 (1.0 mL) at
rt for 12 h. The yields were isolated after column chromatography. The dr and ee values were determined by chiral HPLC analysis. bThe reaction
time is 60 h.
dine]-4′-carboxylate (3aa). 3aa was obtained as a light yellow solid
(60.5 mg, 99% yield), mp 94−96 °C. HPLC (Daicel Chiralpak IB, n-
hexane:2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254
nm): major diastereoisomer, tR = 14.0 min (minor), tR = 8.8 min
(major); minor diastereoisomer, tR = 32.7 min (minor), tR = 6.9 min
(major); 99:1 dr, 96% ee for the major diastereoisomer. [α]20 D =
−189.7 (c 4.01, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J =
7.6 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.27 (t,
J = 8.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 3H), 7.11 (t, J = 7.2 Hz, 2H),
7.04 (t, J = 7.6 Hz, 1H), 6.70−6.66 (m, 3H), 5.25 (d, J = 10.8 Hz,
1H), 5.22 (d, J = 16.8 Hz, 1H), 4.65−4.55 (m, 1H), 4.41−4.33 (m,
2H), 4.27−4.19 (m, 1H), 2.93 (d, J = 8.0 Hz, 1H), 1.29 (t, J = 7.2 Hz,
3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.0, 173.3, 170.8,
167.1, 143.6, 134.8, 134.5, 131.3, 129.6, 129.4, 128.7, 127.9, 127.6,
127.3, 126.6, 124.6 (q, 1JC−F = −280.4 Hz), 123.6, 122.7, 109.5, 73.8,
73.2, 62.5, 60.3 (q, 2JC−F = 32.8 Hz), 51.4, 44.6, 14.2 ppm. 19F NMR
(376 MHz, CDCl3): δ −71.60 ppm. HRMS (ESI): m/z calcd for
C30H25F3N3O4S2 [M + H]+ 612.1233, found 612.1243.
(3S,3′R,4′S,5′S)-tert-Butyl 1-Benzyl-2,4″-dioxo-3″-phenyl-2″-thi-
oxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thia-
zolidine]-4′-carboxylate (3ba). 3ba was obtained as a light yellow
solid (61.4 mg, 96% yield), mp 164−167 °C. HPLC (Daicel
Chiralpak IC, n-hexane:2-propanol = 80:20, flow rate 1.0 mL/min,
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detection at 254 nm): major diastereoisomer, tR = 7.3 min (minor), tR
= 6.2 min (major); minor diastereoisomer, tR = 25.9 min (minor), tR
= 5.5 min (major); 99:1 dr, 93% ee for the major diastereoisomer.
D = −187.5 (c 2.75, CH2Cl2). H NMR (400 MHz, CDCl3): δ
[α]20 1
7.74 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.35−7.25 (m, 3H),
7.18 (t, J = 7.2 Hz, 3H), 7.12−7.03 (m, 3H), 6.67 (d, J = 8.0 Hz, 3H),
5.23 (d, J = 15.6 Hz, 1H), 5.19 (d, J = 10.0 Hz, 1H), 4.58−4.52 (m,
1H), 4.37 (d, J = 15.6 Hz, 1H), 2.88 (d, J = 7.2 Hz, 1H), 1.49 (s, 9H)
ppm. 13C NMR (176 MHz, CDCl3): δ 195.3, 173.4, 170.7, 166.0,
143.6, 134.8, 134.6, 131.3, 129.6, 129.4, 128.7, 127.9, 127.6, 127.4,
126.6, 124.7 (q, 1JC−F = −280.4 Hz), 123.6, 122.7, 109.5, 83.9, 73.9,
73.5, 60.3 (q, 2JC−F = 32.6 Hz), 51.7, 44.6, 27.9 ppm. 19F NMR (376
MHz, CDCl3): δ −71.53 ppm. HRMS (ESI): m/z calcd for
C32H29F3N3O4S2 [M + H]+ 640.1546, found 640.1562.
(3S,3′R,4′S,5′S)-1-Benzyl-2,4″-dioxo-3″-phenyl-2″-thioxo-5′-
(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5′’-thiazoli-
dine]-4′-carbonitrile (3ca). 3ca was obtained as a light yellow solid
(53.4 mg, 95% yield), mp 110−113 °C. HPLC (Daicel Chiralpak IA,
n-hexane:2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254
nm): major diastereoisomer, tR = 7.6 min (minor), tR = 18.1 min
(major); minor diastereoisomer, tR = 14.8 min (minor), tR = 9.5 min
D = −28.8
(major); 92:8 dr, 83% ee for the major diastereoisomer. [α]20
(c 1.83, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.6 Hz,
DOI: 10.1021/acs.joc.8b01245
J. Org. Chem. 2018, 83, 9278−9290
The Journal of Organic Chemistry Article

Table 3. Substrate Scope of Ketimines 2a

a
Unless noted otherwise, the reaction was carried out with 1a (0.10 mmol), 2 (0.12 mmol), and catalyst C2 (0.005 mmol) in CH2Cl2 (1.0 mL) at
rt for 12 h. The yields were isolated after column chromatography. The dr and ee values were determined by chiral HPLC analysis.

Scheme 2. Gram-Scale Experiment Scheme 3. Synthetic Transformations of the

Bispiro[oxindole-pyrrolidine-rhodanine]s

1H), 7.48−7.33 (m, 5H), 7.18 (s, 4H), 7.13 (t, J = 7.8 Hz, 1H), 6.89
(d, J = 5.2 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 5.21 (d, J = 15.6 Hz,
1H), 5.05 (d, J = 9.2 Hz, 1H), 4.54−4.45 (m, 2H), 3.27 (d, J = 9.6
Hz, 1H) ppm. 13C NMR (176 MHz, CDCl3): δ 193.0, 171.7, 171.2,
143.3, 134.2, 134.1, 131.8, 130.0, 129.6, 129.0, 128.0, 127.9, 127.3,
127.1, 125.5, 124.1, 123.6, 123.5 (q, 1JC−F = −280.2 Hz), 114.8, 110.2,
74.1, 70.9, 63.1 (q, 2JC−F = 33.1 Hz), 44.7, 38.3 ppm. 19F NMR (376
MHz, CDCl3): δ −72.68 ppm. HRMS (ESI): m/z calcd for
C28H20F3N4O2S2 [M + H]+ 565.0974, found 565.0969.
(3S,3′R,4′S,5′S)-Ethyl 1,3″-Dibenzyl-2,4″-dioxo-2″-thioxo-5′- −331.3 (c 2.12, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J =
(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli- 7.6 Hz, 1H), 7.25−7.18 (m, 6H), 7.11 (t, J = 7.4 Hz, 1H), 7.04−6.97
dine]-4′-carboxylate (3ea). 3ea was obtained as a light yellow solid (m, 3H), 6.84 (d, J = 7.6 Hz, 2H), 6.56 (d, J = 8.0 Hz, 1H), 5.35 (d, J
(53.2 mg, 85% yield), mp 90−93 °C. HPLC (Daicel Chiralpak IB, n- = 9.6 Hz, 1H), 5.04−4.93 (m, 3H), 4.52−4.46 (m, 2H), 4.15−4.07
hexane:2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 (m, 1H), 3.97−3.89 (m, 1H), 2.76 (d, J = 7.2 Hz, 1H), 1.01 (t, J = 7.2
nm): major diastereoisomer, tR = 13.3 min (minor), tR = 11.5 min Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.8, 173.8, 170.9,
(major); minor diastereoisomer, tR = 8.0 min (minor), tR = 8.9 min 166.6, 143.6, 134.9, 133.7, 131.2, 128.6, 128.4, 127.7, 127.64, 127.57,
(major); 99:1 dr, 97% ee for the major diastereoisomer. [α]20 D = 126.8, 124.6 (q, 1JC−F = −280.6 Hz), 122.9, 122.5, 109.7, 72.93, 72.88,

9283 DOI: 10.1021/acs.joc.8b01245

J. Org. Chem. 2018, 83, 9278−9290
The Journal of Organic Chemistry
Figure 3. X-ray crystal structure of compound 3na (displacement ellipsoids are drawn at the 50% probability level).
Figure 4. Proposed mechanism for the domino Michael/Mannich [3 + 2] cycloaddition reaction.
62.2, 59.7 (q, 2JC−F = 32.9 Hz), 51.5, 47.6, 44.5, 13.8 ppm. 19F NMR
(376 MHz, CDCl3): δ −71.38 ppm. HRMS (ESI): m/z calcd for
C31H27F3N3O4S2 [M + H]+ 626.1390, found 626.1402.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-3″-cyclohexyl-2,4″-dioxo-2″-thio-
xo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thia-
zolidine]-4′-carboxylate (3fa). 3fa was obtained as a light yellow
solid (58.3 mg, 94% yield), mp 190−193 °C. HPLC (Daicel
Chiralpak ADH, n-hexane:2-propanol = 85:15, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 15.4 min (minor),
tR = 58.9 min (major); minor diastereoisomer, tR = 7.3 min (minor),
tR = 6.0 min (major); 99:1 dr, >99% ee for the major diastereoisomer.
D = −207.0 (c 1.58, CH2Cl2). H NMR (400 MHz, CDCl3): δ
[α]20 1
7.63 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz,
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2H), 7.29 (d, J = 6.8 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 7.4
Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.23−5.19 (m, 2H), 4.53−4.46 (m,
2H), 4.41 (d, J = 15.6 Hz, 1H), 4.30−4.22 (m, 1H), 4.16−4.08 (m,
1H), 2.76 (d, J = 7.2 Hz, 1H), 2.14 (q, J = 12.0 Hz, 1H), 1.76 (d, J =
12.8 Hz, 1H), 1.66 (d, J = 10.8 Hz, 1H), 1.55−1.45 (m, 3H), 1.30−
1.23 (m, 1H), 1.18 (t, J = 7.0 Hz, 3H), 1.09−1.07 (m, 2H), 0.71−
0.68 (d, J = 10.4 Hz, 1H) ppm. 13C NMR (176 MHz, CDCl3): δ
196.0, 173.7, 170.9, 167.0, 143.6, 135.1, 131.2, 128.7, 128.2, 127.8,
126.6, 124.7 (q, 1JC−F = −280.4 Hz), 123.3, 122.5, 109.1, 73.2, 70.3,
62.2, 60.0 (q, 2JC−F = 32.7 Hz), 58.5, 51.0, 44.7, 27.2, 26.6, 25.77,
25.75, 24.7, 14.1 ppm. 19F NMR (376 MHz, CDCl3): δ −71.48 ppm.
HRMS (ESI): m/z calcd for C30H31F3N3O4S2 [M + H]+ 618.1703,
found 618.1695.
DOI: 10.1021/acs.joc.8b01245
J. Org. Chem. 2018, 83, 9278−9290
The Journal of Organic Chemistry
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-3″-methyl-2,4″-dioxo-2″-thioxo-
5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
dine]-4′-carboxylate (3ga). 3ga was obtained as a light yellow solid
(51.2 mg, 93% yield), mp 79−82 °C. HPLC (Daicel Chiralpak IC, n-
hexane:2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254
nm): major diastereoisomer, tR = 8.1 min (minor), tR = 16.3 min
(major); minor diastereoisomer, tR = 5.6 min (minor), tR = 6.5 min
(major); 98:2 dr, 95% ee for the major diastereoisomer. [α]20 D =
−239.6 (c 2.56, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J =
7.6 Hz, 1H), 7.32−7.26 (m, 5H), 7.22 (t, J = 8.0 Hz, 1H), 7.00 (t, J =
7.6 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.22−5.18 (m, 2H), 4.58−4.47
(m, 2H), 4.26−4.20 (m, 1H), 4.15−4.08 (m, 1H), 3.21 (s, 3H), 2.83
(d, J = 7.6 Hz, 1H), 1.55 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176
MHz, CDCl3): δ 195.2, 173.4, 171.4, 166.8, 143.5, 135.0, 134.5,
131.2, 128.7, 127.8, 127.6, 126.7, 124.6 (q, 1JC−F = −280.4 Hz), 123.7,
122.6, 109.5, 73.0, 72.6, 62.3, 60.0 (q, 2JC−F = 32.7 Hz), 52.3, 44.4,
31.6, 14.0 ppm. 19F NMR (376 MHz, CDCl3): δ −71.71 ppm. HRMS
(ESI): m/z calcd for C25H23F3N3O4S2 [M + H]+ 550.1077, found
550.1073.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-2,4″-dioxo-3″-propyl-2″-thioxo-
5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
dine]-4′-carboxylate (3ha). 3ha was obtained as a light yellow solid
(56.3 mg, 97% yield), mp 152−155 °C. HPLC (Daicel Chiralpak IC,
n-hexane:2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254
nm): major diastereoisomer, tR = 15.0 min (minor), tR = 27.8 min
(major); minor diastereoisomer, tR = 9.1 min (minor), tR = 12.9 min
(major); 99:1 dr, >99% ee for the major diastereoisomer. [α]20 D =
−274.6 (c 2.44, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J =
7.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.27
(d, J = 8.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H),
6.66 (d, J = 7.6 Hz, 1H), 5.25 (d, J = 9.6 Hz, 1H), 5.20 (d, J = 15.6
Hz, 1H), 4.55−4.43 (m, 2H), 4.28−4.20 (m, 1H), 4.14−4.06 (m,
1H), 3.82−3.66 (m, 2H), 2.80 (d, J = 7.2 Hz, 1H), 1.22 (t, J = 7.4 Hz,
2H), 1.15 (t, J = 7.2 Hz, 3H), 0.50 (t, J = 7.2 Hz, 3H) ppm. 13C NMR
(176 MHz, CDCl3): δ 195.2, 173.6, 171.0, 166.8, 143.6, 135.1, 131.2,
128.7, 127.9, 127.8, 126.7, 124.6 (q, 1JC−F = −280.5 Hz), 123.3, 122.5,
109.4, 73.1, 72.5, 62.2, 60.0 (q, 2JC−F = 32.7 Hz), 51.6, 46.2, 44.5,
19.7, 13.9, 10.5 ppm. 19F NMR (376 MHz, CDCl3): δ −71.56 ppm.
HRMS (ESI): m/z calcd for C27H27F3N3O4S2 [M + H]+ 578.1390,
found 578.1373.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-2,4″-dioxo-2″-thioxo-5′-
(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
dine]-4′-carboxylate (3ia). 3ia was obtained as a white solid (34.8
mg, 65% yield), mp 104−107 °C. HPLC (Daicel Chiralpak IA, n-
hexane:2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254
nm): major diastereoisomer, tR = 12.2 min (minor), tR = 29.0 min
(major); minor diastereoisomer, tR = 9.0 min (major); >99:1 dr, 57%
ee for the major diastereoisomer. [α]20 D = −124.5 (c 1.59, CH2Cl2).
1
H NMR (400 MHz, CDCl3): δ 9.16 (br s, 1H), 7.64 (d, J = 7.6 Hz,
1H), 7.31−7.23 (m, 7H), 7.03 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 7.6 Hz,
1H), 5.20 (d, J = 9.6 Hz, 1H), 5.14 (d, J = 15.6 Hz, 1H), 4.57−4.48
(m, 2H), 4.35−4.27 (m, 1H), 4.21−4.13 (m, 1H), 2.79 (d, J = 6.8 Hz,
1H), 1.23 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ
194.2, 173.4, 171.5, 166.9, 143.6, 134.9, 131.4, 128.8, 127.8, 127.5,
126.8, 124.6 (q, 1JC−F = −280.4 Hz), 123.6, 122.7, 109.8, 76.0, 73.0,
62.6, 60.6 (q, 2JC−F = 32.7 Hz), 52.2, 44.5, 13.9 ppm. 19F NMR (376
MHz, CDCl3): δ −71.60 ppm. HRMS (ESI): m/z calcd for
C24H21F3N3O4S2 [M + H]+ 536.0920, found 536.0914.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-2,4″-dioxo-2″-thioxo-3″-(p-tolyl)-
5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
dine]-4′-carboxylate (3ja). 3ja was obtained as a light yellow solid
(61.0 mg, 97% yield), mp 175−177 °C. HPLC (Daicel Chiralpak
ADH, n-hexane:2-propanol = 75:25, flow rate 1.0 mL/min, detection
at 254 nm): major diastereoisomer, tR = 11.2 min (minor), tR = 26.2
min (major); minor diastereoisomer, tR = 9.1 min (minor), tR = 6.5
min (major); 99:1 dr, 90% ee for the major diastereoisomer. [α]20 D =
−115.8 (c 2.81, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J =
7.6 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.21−7.11 (m, 7H), 7.03 (t, J =
7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.59 (br s, 2H), 5.24 (d, J = 9.6
Hz, 1H), 5.19 (d, J = 15.6 Hz, 1H), 4.64−4.55 (m, 1H), 4.42 (d, J =
15.6 Hz, 1H), 4.38−4.32 (m, 1H), 4.27−4.19 (m, 1H), 2.92 (d, J =
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7.6 Hz, 1H), 2.37 (s, 3H), 1.28 (t, J = 6.8 Hz, 3H) ppm. 13C NMR
(176 MHz, CDCl3): δ 195.2, 173.3, 170.9, 167.1, 143.6, 139.8, 134.8,
131.8, 131.3, 130.1, 128.7, 127.6, 127.5, 127.4, 126.6, 124.6 (q, 1JC−F
= −280.4 Hz), 123.7, 122.7, 109.5, 73.8, 73.1, 62.4, 60.4 (q, 2JC−F =
32.6 Hz), 51.4, 44.6, 22.3, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ
−71.62 ppm. HRMS (ESI): m/z calcd for C31H27F3N3O4S2 [M + H]+
626.1390, found 626.1381.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-3″-(4-methoxyphenyl)-2,4″-
dioxo-2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrroli-
dine-3′,5″-thiazolidine]-4′-carboxylate (3ka). 3ka was obtained as a
light yellow solid (62.5 mg, 97% yield), mp 141−143 °C. HPLC
(Daicel Chiralpak ADH, n-hexane:2-propanol = 85:15, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, tR = 25.6 min
(minor), tR = 43.5 min (major); minor diastereoisomer, tR = 15.6 min
(minor), tR = 20.2 min (major); 99:1 dr, 90% ee for the major
diastereoisomer. [α]20D = −168.9 (c 2.80, CH2Cl2). H NMR (400
1
MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H), 7.28−7.12 (m, 6H), 7.03
(t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.0 Hz, 1H),
6.62 (br s, 2H), 5.24−5.19 (m, 2H), 4.63−4.57 (m, 1H), 4.40 (d, J =
16.0 Hz, 1H), 4.38−4.31 (m, 1H), 4.27−4.19 (m, 1H), 3.80 (s, 3H),
2.93 (d, J = 8.0 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H) ppm. 13C NMR
(176 MHz, CDCl3): δ 195.4, 173.3, 171.0, 167.1, 160.1, 143.5, 134.8,
131.3, 129.0, 128.8, 127.6, 127.4, 126.9, 126.6, 124.6 (q, 1JC−F =
−280.4 Hz), 123.7, 114.7, 109.5, 73.8, 72.9, 62.4, 60.3 (q, 2JC−F = 32.6
Hz), 55.4, 51.4, 44.6, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ
−71.63 ppm. HRMS (ESI): m/z calcd for C31H27F3N3O5S2 [M + H]+
642.1339, found 642.1331.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-3″-(4-fluorophenyl)-2,4″-dioxo-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3la). 3la was obtained as a light
yellow solid (56.7 mg, 90% yield), mp 85−88 °C. HPLC (Daicel
Chiralpak ADH, n-hexane:2-propanol = 80:20, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 13.6 min (minor),
tR = 25.9 min (major); minor diastereoisomer, tR = 12.0 min (minor),
tR = 7.8 min (major); 98:2 dr, 91% ee for the major diastereoisomer.
[α]20D = −180.6 (c 2.55, CH2Cl2). H NMR (400 MHz, CDCl3): δ
1
7.74 (d, J = 7.6 Hz, 1H), 7.30−7.19 (m, 4H), 7.14 (t, J = 7.0 Hz, 2H),
7.07−7.00 (m, 3H), 6.70 (d, J = 7.6 Hz, 3H), 5.25−5.20 (m, 2H),
4.65−4.56 (m, 1H), 4.41−4.32 (m, 2H), 4.28−4.20 (m, 1H), 2.94 (d,
J = 8.0 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz,
CDCl3): δ 194.9, 173.2, 170.9, 167.2, 162.8 (d, 1JC−F = −250.8 Hz),
143.5, 134.8, 131.4, 130.2 (d, 4JC−F = 2.8 Hz), 129.9 (d, 3JC−F = 9.0
Hz), 128.8, 127.7, 127.4, 126.6, 124.6 (q, 1JC−F = −280.4 Hz), 122.9,
116.5 (d, 2JC−F = 22.9 Hz), 109.5, 73.8, 72.9, 62.5, 60.4 (q, 2JC−F =
32.6 Hz), 51.5, 44.6, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ
−71.67, −110.32 ppm. HRMS (ESI): m/z calcd for C30H24F4N3O4S2
[M + H]+ 630.1139, found 630.1132.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-3″-(4-chlorophenyl)-2,4″-dioxo-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3ma). 3ma was obtained as a
light yellow solid (63.4 mg, 98% yield), mp 94−96 °C. HPLC (Daicel
Chiralpak ADH, n-hexane:2-propanol = 85:15, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 23.1 min (minor),
tR = 35.1 min (major); minor diastereoisomer, tR = 20.7 min (minor),
tR = 11.9 min (major); 99:1 dr, 90% ee for the major diastereoisomer.
[α]20D = −155.3 (c 2.91, CH2Cl2). H NMR (400 MHz, CDCl3): δ
1
7.73 (d, J = 7.6 Hz, 1H), 7.31−7.19 (m, 6H), 7.13 (t, J = 7.2 Hz, 2H),
7.05 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 6.0 Hz,
2H), 5.24−5.20 (m, 2H), 4.65−4.56 (m, 1H), 4.39 (d, J = 15.2 Hz,
1H), 4.37−4.31 (m, 1H), 4.28−4.20 (m, 1H), 2.93 (d, J = 8.0 Hz,
1H), 1.28 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ
194.6, 173.1, 170.8, 167.1, 143.5, 135.7, 134.7, 132.8, 131.4, 129.7,
129.3, 128.7, 127.7, 127.5, 126.6, 124.6 (q, 1JC−F = −280.4 Hz), 123.7,
122.9, 109.5, 73.9, 73.0, 62.5, 60.4 (q, 2JC−F = 32.7 Hz), 51.4, 44.6,
14.2 ppm. 19F NMR (376 MHz, CDCl3): δ −71.69 ppm. HRMS
(ESI): m/z calcd for C30H24ClF3N3O4S2 [M + H]+ 646.0843, found
646.0835.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-3″-(4-bromophenyl)-2,4″-dioxo-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3na). 3na was obtained as a light
yellow solid (68.5 mg, 99% yield), mp 106−108 °C. HPLC (Daicel
DOI: 10.1021/acs.joc.8b01245
J. Org. Chem. 2018, 83, 9278−9290
The Journal of Organic Chemistry
Chiralpak IA, n-hexane:2-propanol = 90:10, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 14.8 min (minor),
tR = 42.2 min (major); minor diastereoisomer, tR = 18.2 min (minor),
tR = 11.7 min (major); 98:2 dr, 91% ee for the major diastereoisomer.
D = −145.6 (c 3.23, CH2Cl2). H NMR (400 MHz, CDCl3): δ
[α]20 1 thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-
7.73 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.30−7.18 (m,
4H), 7.13 (t, J = 7.2 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 8.0
Hz, 1H), 6.56 (d, J = 6.0 Hz, 2H), 5.23−5.19 (m, 2H), 4.63−4.57 (m,
1H), 4.40−4.31 (m, 2H), 4.27−4.19 (m, 1H), 2.93 (d, J = 7.6 Hz,
1H), 1.28 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ
194.5, 173.1, 170.7, 167.1, 143.5, 134.7, 133.3, 132.7, 131.4, 129.6,
128.7, 127.7, 127.5, 126.6, 124.5 (q, 1JC−F = −280.4 Hz), 123.9, 123.7,
122.8, 109.5, 73.9, 73.1, 62.5, 60.4 (q, 2JC−F = 32.8 Hz), 51.4, 44.6,
14.2 ppm. 19F NMR (376 MHz, CDCl3): δ −71.69 ppm. HRMS
(ESI): m/z calcd for C30H24BrF3N3O4S2 [M + H]+ 690.0338, found
690.0328.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-5-methoxy-2,4″-dioxo-3″-phenyl-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3ab). 3ab was obtained as a light
yellow solid (63.7 mg, 99% yield), mp 185−188 °C. HPLC (Daicel
Chiralpak IC, n-hexane:2-propanol = 95:5, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 32.0 min (major);
minor diastereoisomer, tR = 13.9 min (minor), tR = 17.7 min (major);
98:2 dr, >99% ee for the major diastereoisomer. [α]20 D = −89.9 (c
1.50, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.45−7.35 (m, 4H),
7.19−7.11 (m, 5H), 6.82−6.77 (m, 3H), 6.58 (d, J = 8.8 Hz, 1H),
5.22 (d, J = 15.6 Hz, 1H), 5.15 (d, J = 9.6 Hz, 1H), 4.65−4.59 (m,
1H), 4.42−4.33 (m, 2H), 4.28−4.24 (m, 1H), 3.77 (s, 3H), 2.96 (d, J
= 7.2 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz,
CDCl3): δ 195.0, 172.8, 171.3, 167.4, 155.8, 136.6, 134.8, 134.5,
129.7, 129.5, 128.8, 128.0, 127.6, 127.3, 125.3, 124.5 (q, 1JC−F =
−280.4 Hz), 116.3, 113.5, 110.2, 74.3, 72.7, 62.5, 60.8 (q, 2JC−F = 32.6
Hz), 56.0, 51.6, 44.7, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ
−71.64 ppm. HRMS (ESI): m/z calcd for C31H27F3N3O5S2 [M + H]+
642.1339, found 642.1333.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-5-methyl-2,4″-dioxo-3″-phenyl-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3ac). 3ac was obtained as a light
yellow solid (61.8 mg, 99% yield), mp 170−172 °C. HPLC (Daicel
Chiralpak IC, n-hexane:2-propanol = 90:10, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 10.1 min (minor),
tR = 13.2 min (major); minor diastereoisomer, tR = 6.9 min (minor),
tR = 8.8 min (major); 99:1 dr, 93% ee for the major diastereoisomer.
D = −116.7 (c 1.42, CH2Cl2). H NMR (400 MHz, CDCl3): δ
[α]20 1
7.56 (s, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.4 Hz, 2H), 7.18 (t,
J = 7.0 Hz, 3H), 7.13−7.06 (m, 3H), 6.71 (br s, 2H), 6.57 (d, J = 8.0
Hz, 1H), 5.23−5.19 (m, 2H), 4.63−4.57 (m, 1H, CH), 4.41−4.33
(m, 2H), 4.29−4.22 (m, 1H), 2.90 (d, J = 7.6 Hz, 1H), 2.30 (s, 3H),
1.29 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.2,
173.2, 171.0, 167.2, 141.1, 134.9, 134.5, 132.5, 131.5, 129.4, 129.6,
129.4, 128.7, 128.0, 127.6, 127.4, 124.6 (q, 1JC−F = −280.4 Hz), 123.8,
109.3, 74.0, 73.1, 62.4, 60.5 (q, 2JC−F = 32.7 Hz), 51.4, 44.6, 21.2, 14.2
ppm. 19F NMR (376 MHz, CDCl3): δ −71.70 ppm. HRMS (ESI):
m/z calcd for C31H27F3N3O4S2 [M + H]+ 626.1390, found 626.1393.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-5,7-dimethyl-2,4″-dioxo-3″-phe-
nyl-2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3ad). 3ad was obtained as a light
yellow solid (51.2 mg, 80% yield), mp 145−148 °C. HPLC (Daicel
Chiralpak IC, n-hexane:2-propanol = 90:10, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 10.9 min (minor),
tR = 13.5 min (major); minor diastereoisomer, tR = 7.4 min (minor),
tR = 11.9 min (major); 97:3 dr, 98% ee for the major diastereoisomer.
D = −139.4 (c 1.62, CH2Cl2). H NMR (400 MHz, CDCl3): δ
[α]20 1
7.47 (s, 1H), 7.43−7.38 (m, 3H), 7.15−7.04 (m, 5H), 6.90 (s, 1H),
6.85 (d, J = 5.6 Hz, 2H), 5.23 (d, J = 16.8 Hz, 1H), 5.03 (d, J = 9.2
Hz, 1H), 4.94 (d, J = 16.8 Hz, 1H), 4.68−4.62 (m, 1H), 4.38−4.24
(m, 2H), 2.99 (d, J = 8.8 Hz, 1H), 2.30 (s, 3H), 2.18 (s, 3H), 1.30 (t,
J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.3, 173.8,
171.9, 167.5, 138.9, 136.7, 135.6, 134.6, 132.6, 129.7, 129.4, 128.8,
128.0, 127.1, 125.7, 125.5, 124.9, 124.5 (q, 1JC−F = −280.2 Hz), 120.0,
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73.9, 72.7, 62.5, 61.1 (q, 2JC−F = 32.3 Hz), 52.1, 45.8, 20.9, 18.7, 14.2
ppm. 19F NMR (376 MHz, CDCl3): δ −71.92 ppm. HRMS (ESI):
m/z calcd for C32H29F3N3O4S2 [M + H]+ 640.1546, found 640.1563.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-5-fluoro-2,4″-dioxo-3″-phenyl-2″-
thiazolidine]-4′-carboxylate (3ae). 3ae was obtained as a light
yellow solid (61.8 mg, 98% yield), mp 91−94 °C. HPLC (Daicel
Chiralpak ADH, n-hexane:2-propanol = 85:15, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 14.4 min (minor),
tR = 12.1 min (major); minor diastereoisomer, tR = 10.4 min (minor),
tR = 8.4 min (major); 95:5 dr, 80% ee for the major diastereoisomer.
[α]20D = −204.2 (c 0.63, CH2Cl2). H NMR (400 MHz, CDCl3): δ
1
7.56 (d, J = 8.0 Hz, 1H), 7.47−7.37 (m, 3H), 7.22−7.12 (m, 5H),
6.99 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 4.4 Hz, 2H), 6.61 (q, J = 4.2 Hz,
1H), 5.23 (d, J = 16.0 Hz, 1H), 5.15 (d, J = 9.2 Hz, 1H), 4.64−4.55
(m, 1H), 4.43−4.25 (m, 3H), 2.92 (d, J = 7.2 Hz, 1H), 1.31 (t, J = 7.0
Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.5, 173.1, 171.1,
167.2, 158.7 (d, 1JC−F = −243.1 Hz), 139.5, 134.5 (d, 4JC−F = 4.4 Hz),
129.8, 129.5, 128.9, 128.0, 127.8, 127.3, 125.7 (d, 3JC−F = 7.9 Hz),
124.5 (q, 1JC−F = −280.7 Hz), 117.7 (d, 2JC−F = 19.4 Hz), 115.1 (d,
2
JC−F = 22.5 Hz), 110.2 (d, 3JC−F = 7.7 Hz), 73.9, 72.5, 62.7, 60.7 (q,
2
JC−F = 33.1 Hz), 51.8, 44.8, 14.2 ppm. 19F NMR (376 MHz, CDCl3):
δ −71.56, −118.12 ppm. HRMS (ESI): m/z calcd for
C30H24F4N3O4S2 [M + H]+ 630.1139, found 630.1147.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-5-chloro-2,4″-dioxo-3″-phenyl-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3af). 3af was obtained as a light
yellow solid (61.3 mg, 95% yield), mp 200−203 °C. HPLC (Daicel
Chiralpak IC, n-hexane:2-propanol = 90:10, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 5.3 min (minor), tR
= 9.4 min (major); minor diastereoisomer, tR = 6.0 min (minor), tR =
7.5 min (major); 93:7 dr, >99% ee for the major diastereoisomer.
[α]20D = −52.2 (c 1.37, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.76
1
(s, 1H), 7.46−7.37 (m, 3H), 7.25−7.12 (m, 6H), 6.79 (br s, 2H),
6.60 (d, J = 8.4 Hz, 1H), 5.21 (d, J = 16.0 Hz, 1H), 5.16 (d, J = 9.6
Hz, 1H), 4.64−4.56 (m, 1H), 4.43−4.23 (m, 3H), 2.91 (d, J = 6.8 Hz,
1H), 1.31 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ
194.4, 173.0, 171.0, 167.0, 142.0, 134.4, 134.3, 131.2, 129.8, 129.5,
128.9, 128.3, 127.9, 127.8, 127.3, 127.2, 125.7, 124.5 (q, 1JC−F =
−280.6 Hz), 110.5, 73.7, 72.6, 62.7, 60.5 (q, 2JC−F = 32.7 Hz), 51.7,
44.7, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ −71.59 ppm. HRMS
(ESI): m/z calcd for C30H24ClF3N3O4S2 [M + H]+ 646.0843, found
646.0832.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-6-chloro-2,4″-dioxo-3″-phenyl-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3ag). 3ag was obtained as a light
yellow solid (58.9 mg, 91% yield), mp 181−183 °C. HPLC (Daicel
Chiralpak IB, n-hexane:2-propanol = 85:15, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 12.4 min (minor),
tR = 8.6 min (major); minor diastereoisomer, tR = 20.0 min (minor),
tR = 6.7 min (major); 86:14 dr, 91% ee for the major diastereoisomer.
[α]20D = −40.5 (c 2.25, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.67
1
(d, J = 8.4 Hz, 1H), 7.47−7.35 (m, 4H), 7.22−7.15 (m, 4H), 7.04 (d,
J = 8.4 Hz, 1H), 6.78 (br s, 2H), 6.67 (s, 1H), 5.24−5.18 (m, 2H),
4.62−4.55 (m, 1H), 4.40−4.23 (m, 3H), 2.86 (d, J = 7.6 Hz, 1H),
1.30 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.6,
173.3, 170.9, 167.1, 144.8, 137.4, 134.4, 129.8, 129.5, 129.2, 129.0,
127.94, 127.90, 127.7, 127.3, 124.5 (q, 1JC−F = −280.5 Hz), 123.3,
122.8, 122.2, 110.1, 73.4, 72.7, 62.6, 60.3 (q, 2JC−F= 32.7 Hz), 51.7,
44.7, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ −71.60 ppm. HRMS
(ESI): m/z calcd for C30H24ClF3N3O4S2 [M + H]+ 646.0843, found
646.0848.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-5-bromo-2,4″-dioxo-3″-phenyl-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3ah). 3ah was obtained as a light
yellow solid (66.3 mg, 96% yield), mp 205−208 °C. HPLC (Daicel
Chiralpak IC, n-hexane:2-propanol = 95:5, flow rate 1.0 mL/min,
detection at 254 nm): major diastereoisomer, tR = 16.8 min (minor),
tR = 18.3 min (major); minor diastereoisomer, tR = 9.5 min (minor),
tR = 13.1 min (major); 95:5 dr, 95% ee for the major diastereoisomer.
DOI: 10.1021/acs.joc.8b01245
J. Org. Chem. 2018, 83, 9278−9290
The Journal of Organic Chemistry
D = −10.6 (c 2.08, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.88
[α]20 1
(s, 1H), 7.46−7.36 (m, 4H), 7.21−7.11 (m, 5H), 6.78 (br s, 2H),
6.55 (d, J = 8.4 Hz, 1H), 5.22−5.15 (m, 2H), 4.60−4.55 (m, 1H),
4.41−4.23 (m, 3H), 2.91 (d, J = 7.2 Hz, 1H), 1.30 (t, J = 7.0 Hz, 3H)
ppm. 13C NMR (176 MHz, CDCl3): δ 194.4, 172.9, 170.9, 167.0,
142.5, 134.4, 134.3, 134.1, 129.9, 129.7, 129.5, 128.9, 127.9, 127.8,
127.3, 125.9, 124.5 (q, 1JC−F = −280.7 Hz), 115.4, 111.0, 73.7, 72.6,
62.6, 60.4 (q, 2JC−F = 32.9 Hz), 51.7, 44.7, 14.2 ppm. 19F NMR (376
MHz, CDCl3): δ −71.69 ppm. HRMS (ESI): m/z calcd for
C30H24BrF3N3O4S2 [M + H]+ 690.0338, found 690.0346.
(3S,3′R,4′S,5′S)-Ethyl 2,4″-Dioxo-3″-phenyl-2″-thioxo-5′-
(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
dine]-4′-carboxylate (3ai). 3ai was obtained as a light yellow solid
(44.3 mg, 85% yield), mp 95−98 °C. HPLC (Daicel Chiralpak IC, n-
hexane:2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254
nm): major diastereoisomer, tR = 9.4 min (minor), tR = 19.1 min
(major); minor diastereoisomer, tR = 7.3 min (minor), tR = 6.4 min
(major); 97:3 dr, 89% ee for the major diastereoisomer. [α]20 D =
−133.8 (c 0.55, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.07 (s,
1H), 7.69 (d, J = 7.6 Hz, 1H), 7.40 (s, 3H), 7.33 (t, J = 7.8 Hz, 1H),
7.07 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 8.0 Hz, 3H), 5.24 (d, J = 9.6 Hz,
1H), 4.57−4.52 (m, 1H), 4.40−4.30 (m, 1H), 4.28−4.20 (m, 1H),
2.79 (d, J = 6.8 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H) ppm. 13C NMR
(176 MHz, CDCl3): δ 195.0, 175.3, 170.8, 167.0, 141.4, 134.6, 131.5,
129.8, 129.5, 127.9, 127.2, 124.6 (q, 1JC−F = −280.7 Hz), 123.6, 122.7,
110.2, 73.8, 73.4, 62.5, 60.0 (q, 1JC−F = 32.5 Hz), 51.3, 14.2 ppm. 19F
NMR (376 MHz, CDCl3): δ −71.41 ppm. HRMS (ESI): m/z calcd
for C23H19F3N3O4S2 [M + H]+ 522.0764, found 522.0759.
(3S,3′R,4′S,5′S)-Ethyl 1-Methyl-2,4″-dioxo-3″-phenyl-2″-thioxo-
5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
dine]-4′-carboxylate (3aj). 3aj was obtained as a light yellow solid
(49.3 mg, 92% yield), mp 160−162 °C. HPLC (Daicel Chiralpak
ADH, n-hexane:2-propanol = 70:30, flow rate 1.0 mL/min, detection
at 254 nm): major diastereoisomer, tR = 9.0 min (minor), tR = 36.1
min (major); minor diastereoisomer, tR = 5.2 min (minor), tR = 7.0
min (major); 99:1 dr, 89% ee for the major diastereoisomer. [α]20 D =
−181.9 (c 2.11, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J =
7.6 Hz, 1H), 7.42 (s, 4H), 7.10 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.2
Hz, 3H), 5.26 (d, J = 9.6 Hz, 1H), 4.56 (br s, 1H), 4.39−4.31 (m,
1H), 4.27−4.19 (m, 1H), 3.11 (s, 3H), 2.86 (s, 1H), 1.28 (t, J = 7.2
Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.1, 173.4, 170.8,
167.0, 144.2, 134.6, 131.4, 129.8, 129.5, 127.8, 126.7, 124.6 (q, 1JC−F
= −280.6 Hz), 123.3, 122.6, 108.3, 73.5, 73.4, 62.5, 60.1 (q, 2JC−F =
32.8 Hz), 51.4, 20.5, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ
−71.33 ppm. HRMS (ESI): m/z calcd for C24H21F3N3O4S2 [M + H]+
536.0920, found 536.0904.
(3S,3′R,4′S,5′S)-Ethyl 1-Allyl-2,4″-dioxo-3″-phenyl-2″-thioxo-5′-
(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
dine]-4′-carboxylate (3ak). 3ak was obtained as a light yellow solid
(55.0 mg, 98% yield), mp 83−86 °C. HPLC (Daicel Chiralpak IC, n-
hexane:2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254
nm): major diastereoisomer, tR = 8.2 min (minor), tR = 9.9 min
(major); minor diastereoisomer, tR = 5.2 min (minor), tR = 6.8 min
(major); 98:2 dr, 89% ee for the major diastereoisomer. [α]20 D =
−180.3 (c 1.95, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J =
7.6 Hz, 1H), 7.42−7.36 (m, 4H), 7.09 (t, J = 7.4 Hz, 1H), 6.84−6.80
(m, 3H), 5.69−5.60 (m, 1H), 5.19 (s, 1H), 5.15 (d, J = 9.2 Hz, 1H),
5.10 (d, J = 9.6 Hz, 1H), 4.61−4.55 (m, 1H), 4.49 (dd, J1 = 16.4 Hz,
J2 = 3.6 Hz, 1H), 4.39−4.31 (m, 1H), 4.27−4.19 (m, 1H), 4.00 (dd,
J1 = 16.0 Hz, J2 = 6.0 Hz, 1H), 2.87 (d, J = 7.2 Hz, 1H), 1.28 (t, J =
7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.0, 172.9,
170.8, 167.1, 143.4, 134.6, 131.3, 130.8, 129.8, 129.4, 127.9, 126.6,
124.6 (q, 1JC−F = −280.5 Hz), 123.6, 122.7, 118.2, 109.2, 73.8, 73.4,
62.5, 60.4 (q, 2JC−F = 32.6 Hz), 51.2, 42.8, 14.2 ppm. 19F NMR (376
MHz, CDCl3): δ −71.59 ppm. HRMS (ESI): m/z calcd for
C26H23F3N3O4S2 [M + H]+ 562.1077, found 562.1053.
(3S,3′R,4′S,5′S)-Ethyl 1-(4-Nitrobenzyl)-2,4″-dioxo-3″-phenyl-2″-
thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-
thiazolidine]-4′-carboxylate (3al). 3al was obtained as a light yellow
solid (53.9 mg, 82% yield), mp 110−113 °C. HPLC (Daicel
Chiralpak IB, n-hexane:2-propanol = 70:30, flow rate 1.0 mL/min,
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detection at 254 nm): major diastereoisomer, tR = 11.1 min (minor),
tR = 9.3 min (major); minor diastereoisomer, tR = 8.4 min (major);
>99:1 dr, 90% ee for the major diastereoisomer. [α]20 D = −241.3 (c
2.36, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.0 Hz,
1H), 7.77 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.35−7.30 (m,
5H), 7.09 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 3H), 5.38−5.30 (m,
2H), 4.62−4.56 (m, 1H), 4.43−4.35 (m, 2H), 4.27−4.19 (m, 1H),
2.92 (d, J = 7.2 Hz, 1H), 1.29 (t, J = 7.0 Hz, 3H) ppm. 13C NMR
(176 MHz, CDCl3): δ 194.5, 173.7, 170.4, 166.7, 147.3, 143.0, 142.2,
134.3, 131.6, 129.9, 129.5, 128.5, 127.7, 127.2, 124.6 (q, 1JC−F =
−280.7 Hz), 123.9, 123.1, 123.0, 108.8, 73.7, 73.6, 62.5, 59.9 (q, 2JC−F
= 33.0 Hz), 50.8, 43.8, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ
−71.66 ppm. HRMS (ESI): m/z calcd for C30H24F3N4O6S2 [M + H]+
657.1084, found 657.1100.
(3S,3′R,4′S,5′S)-Ethyl 1-(4-Bromobenzyl)-2,4″-dioxo-3″-phenyl-
2″-thioxo-5′-(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-
3′,5″-thiazolidine]-4′-carboxylate (3am). 3am was obtained as a
light yellow solid (60.1 mg, 87% yield), mp 109−112 °C. HPLC
(Daicel Chiralpak ADH, n-hexane:2-propanol = 80:20, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, tR = 13.2 min
(minor), tR = 37.2 min (major); minor diastereoisomer, tR = 9.2 min
(minor), tR = 11.3 min (major); 98:2 dr, 92% ee for the major
diastereoisomer. [α]20D = −199.3 (c 2.06, CH2Cl2). H NMR (400
1
MHz, CDCl3): δ 7.74 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H),
7.36 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 7.6 Hz,
2H), 7.07 (t, J = 8.4 Hz, 2H), 6.66−6.61 (m, 3H), 5.29 (d, J = 9.6 Hz,
1H), 5.22 (d, J = 15.6 Hz, 1H), 4.61−4.57 (m, 1H), 4.42−4.34 (m,
1H), 4.27−4.19 (m, 2H), 2.88 (br s, 1H), 1.29 (t, J = 7.2 Hz, 3H)
ppm. 13C NMR (176 MHz, CDCl3): δ 194.7, 173.5, 170.5, 166.9,
143.3, 134.4, 133.8, 131.8, 131.5, 129.8, 129.5, 129.4, 127.8, 126.9,
124.6 (q, 1JC−F = −280.6 Hz), 123.3, 122.9, 121.6, 109.2, 73.7, 73.4,
62.5, 60.1 (q, 2JC−F = 32.9 Hz), 51.0, 44.0, 14.2 ppm. 19F NMR (376
MHz, CDCl3): δ −71.68 ppm. HRMS (ESI): m/z calcd for
C30H24BrF3N3O4S2 [M + H]+ 690.0338, found 690.0337.
Synthetic Transformation of 3aa. To a solution of compound
3aa (61.2 mg, 0.10 mmol) in acetic acid (1.0 mL) was added
chromium trioxide (30.0 mg, 0.30 mmol) in three portions over 30
min at room temperature. The solution was stirred at 50 °C for 12 h.
The mixture was treated with H2O (10 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed
with brine and dried over Na2SO4, and the solvent was removed
under vacuum. The residue was purified by silica gel chromatography
to yield the desired product 4.
(3S,3′R,4′S,5′S)-Ethyl 1-Benzyl-2,2″,4″-trioxo-3″-phenyl-5′-
(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,5″-thiazoli-
dine]-4′-carboxylate (4). 4 was obtained as a light yellow solid (51.8
mg, 87% yield), mp 88−91 °C. [α]20 D = −95.8 (c 1.14, CH2Cl2). H
1
NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H), 7.39−7.32 (m,
3H), 7.30−7.22 (m, 3H), 7.19 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 7.2 Hz,
2H), 7.06 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 2H), 6.69 (d, J = 8.0
Hz, 1H), 5.32 (d, J = 9.6 Hz, 1H), 5.21 (d, J = 15.6 Hz, 1H), 4.63−
4.54 (m, 1H), 4.42 (d, J = 15.6 Hz, 1H), 4.38−4.32 (m, 1H), 4.30−
4.23 (m, 1H), 2.87 (d, J = 7.6 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H) ppm.
13
C NMR (176 MHz, CDCl3): δ 173.7, 169.1, 167.1, 166.7, 143.7,
134.9, 132.2, 131.4, 129.4, 129.3, 128.7, 127.7, 127.5, 127.0, 126.9,
124.7 (q, 1JC−F = −280.4 Hz), 123.7, 122.6, 109.5, 73.7, 71.9, 62.4,
60.2 (q, 2JC−F = 32.7 Hz), 51.6, 44.6, 14.2 ppm. 19F NMR (376 MHz,
CDCl3): δ −71.54 ppm. HRMS (ESI): m/z calcd for C30H25F3N3O5S
[M + H]+ 596.1462, found 596.1462.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01245.
1
H, 13C, and 19F NMR spectra, HPLC chromatograms of
the products, and X-ray crystallographic data of 3na
(PDF)
X-ray crystallographic data of 3na (CIF)
DOI: 10.1021/acs.joc.8b01245
J. Org. Chem. 2018, 83, 9278−9290
The Journal of Organic Chemistry
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: dudm@bit.edu.cn.
ORCID
Da-Ming Du: 0000-0002-9924-5117
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21272024). We also
thank the Analysis & Testing Center of the Beijing Institute of
Technology for the measurement of NMR and mass
spectrometry.
■ REFERENCES
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9290 DOI: 10.1021/acs.joc.8b01245

J. Org. Chem. 2018, 83, 9278−9290