Enantioselective synthesis of quaternary 3-aminooxindoles via organocatalytic asymmetric michael addition of 3-monosubstituted 3-aminooxindoles to nitroolefins

Article abstract of DOI:10.1021/jo401154b

An enantioselective synthesis of quaternary 3-aminooxindoles with 3-monosubstituted 3-aminooxindoles as nucleophiles is first presented. A Michael addition reaction of 3-monosubstituted 3-aminooxindoles to nitroolefins has been developed with a bifunctional thiourea-tertiary amine as a catalyst to afford a range of 3,3-disubstituted oxindoles bearing adjacent quaternary-tertiary centers in good results (up to 98% yield, >99:1 dr, and 92% ee). We also demonstrate the potential synthetic utility of this methodology by a transformation of the product into a spirocyclic oxindole compound.

Full text of DOI:10.1021/jo401154b

Note
pubs.acs.org/joc
Enantioselective Synthesis of Quaternary 3‑Aminooxindoles via
Organocatalytic Asymmetric Michael Addition of 3‑Monosubstituted
3‑Aminooxindoles to Nitroolefins
Bao-Dong Cui,†,§ Wen-Yong Han,†,§ Zhi-Jun Wu,‡ Xiao-Mei Zhang,† and Wei-Cheng Yuan*,†
†National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, China
‡Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
§University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: An enantioselective synthesis of quaternary 3-
aminooxindoles with 3-monosubstituted 3-aminooxindoles as
nucleophiles is first presented. A Michael addition reaction of
3-monosubstituted 3-aminooxindoles to nitroolefins has been
developed with a bifunctional thiourea-tertiary amine as a
catalyst to afford a range of 3,3-disubstituted oxindoles bearing
adjacent quaternary-tertiary centers in good results (up to 98%
yield, >99:1 dr, and 92% ee). We also demonstrate the
potential synthetic utility of this methodology by a trans-
formation of the product into a spirocyclic oxindole compound.
xindoles are prominent scaffolds in natural products,1 as
oxindoles as nucleophiles with appropriate acceptors would be
Owell as providing valuable pharmaceutical lead com- an alternatively direct approach to access the quaternary 3-
aminooxindole compounds (Scheme 1). As a continuation of
our studies on the construction of structurally diverse 3,3-
disubstituted oxindoles,9 herein, we wish to report an
unprecedented Michael addition reaction of 3-monosubstituted
3-aminooxindoles to nitroolefins with bifunctional thiourea-
tertiary amine organocatalysts (Scheme 2).10 This will
complement a new strategy for the preparation of enantioen-
riched quaternary 3-aminooxindoles bearing adjacent quater-
nary-tertiary centers. Nevertheless, we also strongly believe that
this study will open an opportunity for employing 3-
monosubstituted 3-aminooxindoles as competent nucleophiles
for various catalytic asymmetric transformations.
The studies were initiated by evaluating the reaction between
ethyl 1-methyl-2-oxoindolin-3-ylcarbamate11 2a and β-nitro-
styrene 3a using Takemoto’s catalyst 1a (Figure 2) in toluene
at 0 °C. The reaction proceeded smoothly to afford the desired
Michael adduct 4a in good yield with good diastereoselectivity
and moderate enantioselectivity (Table 1, entry 1). Under the
analogous conditions, 1b or 1c was a little better than 1a for the
reaction, as 4a could be obtained in excellent yield with good
diastereoselectivity and enantioselectivity, respectively (Table 1,
entries 2 and 3). These data suggest that the pyrrolidine
structure of the tertiary amine in the catalyst is superior to the
dimethylamine structure for the reactivity and enantioselectiv-
ity. We then conducted the reaction in the presence of catalyst
pounds. Particularly, 3,3-disubstituted oxindoles ubiquitously
make up the core of many natural products and pharmaceut-
icals.1 Among these, quaternary 3-aminooxindole frameworks
are present in a large number of bioactive, naturally occurring
alkaloids and medicinally relevant compounds (Figure 1).2
Hence numerous stereoselective processes for preparing
various quaternary 3-aminooxindole derivatives have been
developed.3 The known methods for the construction of this
type of fascinating frameworks include asymmetric addition to
isatin imines,4 amination of 3-monosubstituted oxindoles,5
multicomponent reaction,6 hydroxyamination reaction,3a,7 and
other strategies (Scheme 1).8 Despite these achievements,
given the potential bioactive and medicinal significance of the
enantiomerically pure quaternary 3-aminooxindole compounds,
it is still important and desirable to develop more effective and
creative methods to access the compounds containing a
quaternary 3-aminooxindole skeleton.
Indeed the potential clinical significance and the synthetic
application of chiral 3,3-disubstituted oxindoles have led to a
demand for the efficient asymmetric synthetic methods.
Recently, a number of successful examples using various 3-
monosubstituted oxindoles as nucleophiles reacting with
diverse electrophiles to afford 3,3-disubstituted oxindoles have
been reported.1,3 However, to the best of our knowledge, no
examples with 3-monosubstituted 3-aminooxindoles as nucle-
ophiles for catalytic asymmetric transformations were reported
(Scheme 1). In this context, from a synthetic point of view, we
envisioned that the reaction of 3-monosubstituted 3-amino-
Received: May 27, 2013
© XXXX American Chemical Society
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Note
Figure 1. Biologically active compounds based on the quaternary 3-aminooxindole frameworks.
Scheme 1. Catalytic Methods for the Asymmetric Synthesis of Quaternary 3-Aminooxindoles
Scheme 2
1d containing a pyrrolidine structure and chiral DPEN scaffold,
providing 4a in 97% yield with 87:13 dr and up to 81% ee, but
with a prolonged reaction time (Table 1, entry 4). Further
screening of the catalysts 1e−h were carried out under the
analogue conditions as used in entry 1 (Table 1, entries 5−8).
The results revealed that catalysts 1e−h were inferior to 1d in
every respect (Table 1, entries 5−8 vs 4). Then 1d was chosen
for optimization studies. We further explored the effects of the
nitrogen protecting group of the C3-position of oxindole. A
similar yield and diastereoselectivity as in entry 4 could be
achieved for 2b bearing the N-Boc group, but the
corresponding 4b was obtained with only 70% ee (Table 1,
entry 9). Meanwhile, similar results were observed for 2c
bearing the N-Cbz group (Table 1, entry 10, for 4c, 95% yield,
89:11 dr and 71% ee). Screening of the solvent identified
dichloromethane to be the best solvent for the reaction (Table
1, entry 12). Slight improvements in diastereo- and
enantioselectivity accompanied the substrate ratio changes
from 1:1.2 to 1:1.5 regarding 2a:3a (Table 1, entry16 vs 12).
B
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Note
Table 2. Scope of 1d-Catalyzed Asymmetric Michael
Addition of 3-Monosubstituted 3-Aminooxindoles 2 to
a
Nitroolefins 3
Figure 2. Chiral organocatalysts examined in this work.
Table 1. Representative Screening Results for the Michael
Addition of 3-Monosubstituted 3-Aminooxindoles to
a
Nitroolefins
time
(h)
4/yield
b
ee
(%)
c
d
entry
1
2
solvent
(%)
dr
1
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
mesitylene
CH2Cl2
CHCl3
THF
24
24
24
48
30
24
30
24
36
36
96
72
72
96
120
72
40
120
4a/70
4a/97
4a/96
4a/97
4a/85
4a/82
4a/86
4a/80
4b/96
4c/95
4a/98
4a/98
4a/98
4a/72
4a/78
4a/98
4a/97
4a/98
89:11
90:10
79:21
87:13
81:19
86:14
85:15
75:25
85:15
89:11
86:14
90:10
85:15
89:11
90:10
95:5
61
75
71
81
67
66
66
62
70
71
75
86
82
78
78
2
3
a
4
Unless otherwise noted, reactions were carried out with 2 (0.1
5
mmol), 3 (0.15 mmol), and 1d (0.01 mmol) in CH2Cl2 (1.0 mL) at 0
b
c
d
6
°C. Isolated yield. Determined by HPLC analysis. Major
e
7
1g
1h
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
diastereoisomer determined by chiral HPLC analysis. Determined
f
by 1H NMR. The dr and ee values of 4m could be readily improved to
8
>99:1 dr and >99% ee by recrystallizing from ethanol.
9
10
11
12
13
14
15
16
17
18
aromatic groups, heterocyclic analogue 3k was used to acquire
the corresponding quaternary 3-aminooxindole product with
acceptable results (Table 2, entry 11). Under the same
conditions, the aliphatic nitroolefin 3l gave the expected
product 4n only in 30% yield with >99:1 dr and 87% ee (Table
2, entry 12). Afterward, further exploration of the substrate
scope was focused on 3-monosubstituted 3-aminooxindoles.11
It was observed that the oxindole substrates bearing both an
electron-donating (Table 2, entries 13−15) and electron-
withdrawing substituent (Table 2, entry 16) could effectively
react with diversely nitroolefins. Ultimately, replacing the
methyl moiety on the N-1 of 2a with an ethyl group had no
significant detrimental effect on the reaction in every respect,
the corresponding product 4s also could be obtained in 96%
yield, 92:8 dr, and 84% ee (Table 2, entry 17).
In order to illustrate the synthetic utility of this methodology,
we attempted to convert the product 4a into a spiro[tetra-
hydropyrimidin-one-3-oxindole] compound (Scheme 3). First,
the nitro group of 4a was easily reduced to a primary amine by
NaBH4 with NiCl2 as a Lewis acid. And then, the unpurified
compound 5 was directly subjected to a NaOH aqueous
solution with ethanol as solvent, giving the spiro[tetrahydro-
pyrimidin-one-3-oxindole] product 6 in 90% yield for two steps
with 93:7 dr and 91% ee. Notably, the spirocyclic oxindole
compound as 6 was previously not accessible via the
asymmetric catalysis process. Consequently, our approach
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
e
88
86
86
f
90:10
88:12
g
a
Unless otherwise noted, reactions were carried out with 2a (0.1
mmol), 3a (0.12 mmol), and 1 (0.01 mmol) in solvent (1.0 mL) at 0
°C. Isolated yield. Determined by HPLC analysis. Major
diastereoisomer determined by chiral HPLC analysis. The ratio of
b
c
d
e
f
g
2a:3a was 1:1.5. Reaction was conducted at 15 °C. Reaction was
conducted with 20 mol % 1d at −40 °C.
Finally, changes in temperature did not positively effect the
results (Table 1, entries 17−18).
With optimal reaction conditions in hand, the substrate
scope was explored by the reactions of ethyl 1-methyl-2-
oxoindolin-3-ylcarbamate 2a with various nitroolefins 3a−l
(Table 2, entries 1−12). No obvious impact on efficiency as
well as diastereo- and enantioselectivity was observed,
regardless of the electronic nature, bulkiness, or position of
the substituent in the phenyl ring of nitroolefins. Nevertheless,
the sterically demanding nitroolefin 3j was also successfully
employed in the reaction (Table 2, entry 10). In addition to
C
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Note
Scheme 3. Transformation of 4a into
Spiro[tetrahydropyrimidin-one-3-oxindole] Compound
EXPERIMENTAL SECTION
■
Procedure for the Synthesis of Ethyl 1-Methyl-2-oxoindolin-
3-ylcarbamate (2a). To a solution of 3-amino-1-methylindolin-2-one
hydrochloride (1.0 g, 5.0 mmol) in CHCl3 (20 mL) was added Et3N
(1.1 mL, 7.5 mmol) at 0 °C under a N2 atmosphere. The resulting
mixture was vigorously stirred for 15 min, and then ethyl
carbonochloridate (0.55 mL, 5.5 mmol) was added slowly via syringe
to the mixture. The resultant mixture was allowed to stir for 1 h and
concentrated, and the residue was purified by flash chromatography to
furnish product 2a as a white solid in 0.8 g. 68% yield; mp 165.8−
167.2 °C; 1H NMR (300 MHz, CDCl3): δ 1.22 (s, 3H), 3.19 (s, 3H),
4.05−4.16 (m, 2H), 5.05 (d, J = 7.5 Hz, 1H), 5.37 (d, J = 6.9 Hz, 1H),
6.80 (d, J = 7.8 Hz, 1H), 7.02−7.07 (m, 1H), 7.24−7.36 (m, 2H); 13C
NMR (75 MHz, CDCl3): δ 14.4, 26.4, 53.8, 61.5, 108.2, 122.9, 124.3,
126.5, 129.2, 143.6, 156.5, 174.3; HRMS (ESI-TOF): calcd for
C12H14N2NaO3 [M + Na]+, 257.0897; found, 257.0899.
should add a new aspect for the enantioselective synthesis of
quaternary 3-aminooxindoles.
Additionally, we fortunately found that the dr and ee values
of product 4m (Table 2, entry 11) could be readily improved to
>99:1 dr and >99% ee by recrystallizing from ethanol. Based on
this observation, single crystals suitable for X-ray crystallo-
graphic analysis were obtained from the enantiopure 4m.
Consequently, the relative and absolute stereochemistry for the
major diastereoisomer of 4m was unambiguously assigned as
(C4R, C5R) by single crystal X-ray diffraction.12 Other
compounds in a series were assigned analogously.
According to the observed stereochemistry of the product
4m and referring to the related dual activation model reports,13
a transition state involving simultaneous activation by chiral
bifunctional thiourea-tertiary amine catalyst 1d for the Michael
addition process was proposed (Figure 3). It can be assumed
Ethyl 1,5-Dimethyl-2-oxoindolin-3-ylcarbamate (2d). The
method for the synthesis of 2d was similar to that of 2a. Product 2d
could be obtained in 0.45 g as a white solid from 3-amino-1,5-
dimethylindolin-2-one hydrochloride (0.6 g, 2.83 mmol). 64% yield;
1
mp 143.5−144.8 °C; H NMR (300 MHz, CDCl3): δ 1.25 (s, 3H),
2.32 (s, 3H), 3.19 (s, 3H), 4.15 (q, J = 6.9 Hz, 2H), 5.05 (d, J = 6.0
Hz, 1H), 5.35 (d, J = 5.7 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 7.10 (d, J
= 7.8 Hz, 1H), 7.19 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 14.4,
21.0, 26.5, 53.8, 61.6, 108.0, 125.2, 126.5, 129.5, 132.6, 141.3, 156.6,
174.2; HRMS (ESI-TOF): calcd for C13H16N2NaO3 [M + Na]+,
271.1053; found, 271.1060.
Ethyl 5-Fluoro-1-methyl-2-oxoindolin-3-ylcarbamate (2e).
The method for the synthesis of 2e was similar to that of 2a. Product
2e could be obtained in 0.47 g as a white solid from 3-amino-5-fluoro-
1-methylindolin-2-one hydrochloride (0.61 g, 2.83 mmol). 66% yield;
1
mp 170.2−171.6 °C; H NMR (300 MHz, CDCl3): δ 1.25 (s, 3H),
3.21 (s, 3H), 4.11−4.15 (m, 2H), 5.00 (d, J = 6.3 Hz, 1H), 5.49 (s,
1H), 6.73−6.77 (m, 1H), 6.98−7.04 (m, 1H), 7.14 (d, J = 6.9 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ 14.4, 26.6, 54.0, 61.7, 108.8 (d, J
= 8.0 Hz, 1C), 112.7 (d, J = 25.4 Hz, 1C), 115.5 (d, J = 23.5 Hz, 1C),
128.1 (d, J = 8.2 Hz, 1C), 139.6, 156.4, 159.4 (d, J = 240.2 Hz, 1C),
174.0; HRMS (ESI-TOF): calcd for C12H13FN2NaO3 [M + Na]+,
275.0802; found, 275.0804.
Figure 3. Proposed transition state for the Michael addition of 3-
monosubstituted 3-aminooxindoles to nitroolefins.
Ethyl 1-Ethyl-2-oxoindolin-3-ylcarbamate (2f). The method
for the synthesis of 2f was similar to that of 2a. Product 2f could be
obtained in 0.36 g as a white solid from 3-amino-1-ethylindolin-2-one
hydrochloride (0.6 g, 2.83 mmol). 51% yield; mp 122.5−123.8 °C; 1H
NMR (300 MHz, CDCl3): δ 1.26−1.30 (m, 6H), 3.73−3.81 (m, 2H),
4.15 (d, J = 6.6 Hz, 2H), 5.06 (br s, 1H), 5.47 (d, J = 7.2 Hz, 1H), 6.85
(d, J = 7.8 Hz, 1H), 7.04−7.08 (m, 1H), 7.28−7.33 (m, 1H), 7.39 (d, J
= 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 12.4, 14.4, 34.9, 53.8,
61.4, 108.3, 122.6, 124.5, 126.7, 129.1, 142.7, 156.4, 173.9; HRMS
(ESI-TOF): calcd for C13H16N2NaO3 [M + Na]+, 271.1053; found,
271.1052.
General Experimental Procedure for the Asymmetric
Michael Addition Reaction between 3-Amino-3-Monosubsti-
tuted Oxindoles and Nitroolefins Catalyzed by 1d. A solution of
3-amino-3-monosubstituted oxindoles 2 (0.1 mmol), nitroolefins 3
(0.15 mmol, 1.5 equiv) and catalyst 1d (5.4 mg, 10 mol %, 0.01 mmol)
in CH2Cl2 (1.0 mL) was stirred at 0 °C for specified time. After
completion of the reaction, the mixture was directly purified by flash
chromatography to furnish the corresponding products 4.
that nitroolefin was activated by the H-bonding to the thiourea
moiety of the catalyst; meanwhile, deprotonation/enolization of
3-monosubstituted 3-aminooxindole was facilitated by the
tertiary amine moiety of 1d. The si-face attack of enolate to
the si-face of nitroolefin led to the formation of the desired
Michael adduct 4m with an (R,R)-configuration bearing
adjacent quaternary-tertiary centers.
In conclusion, we have developed a new method to
synthesize optically active quaternary 3-aminooxindoles from
3-monosubstituted 3-aminooxindoles and nitroolefins by a
bifunctional thiourea-tertiary amine-catalyzed Michael addition
under mild conditions. A range of quaternary 3-aminooxindoles
bearing adjacent quaternary-tertiary centers could be smoothly
obtained in good yields (up to 98%) with high levels of
diastereoselectivities (up to >99:1 dr) and enantioselectivities
(up to 92% ee). The potential synthetic utility of the optically
active Michael addition product was demonstrated by the
transformation of one product into the spiro-
[tetrahydropyrimidin-one-3-oxindole] compound. A plausible
transition state model was also brought forward. Notably, this
represents the first example about 3-monosubstituted 3-
aminooxindoles serving as nucleophiles for the catalytic
asymmetric transformation.
Ethyl ((R)-1-Methyl-3-((R)-2-nitro-1-phenylethyl)-2-oxo-
indolin-3-yl)carbamate (4a). White solid; 37.6 mg, yield 98%;
20
95:5 dr, 88% ee; [α]D = −6.3 (c 0.35, EtOH); mp 203.4−205.1 °C;
the ee was determined by HPLC analysis (Chiralpak AD-H, i-PrOH/
hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tminor = 6.9 min, tmajor = 8.2 min); 1H NMR (300
MHz, DMSO-d6) for (major diastereomer): δ 1.10 (s, 3H), 2.85 (s,
3H), 3.84 (s, 2H), 4.13 (d, J = 5.1 Hz, 1H), 5.39 (s, 2H), 6.51 (d, J =
7.2 Hz, 1H), 6.79−6.81 (m, 2H), 6.97−7.05 (m, 5H), 7.35 (d, J = 6.6
Hz, 1H), 8.54 (br s, 1H); 13C NMR (75 MHz, DMSO-d6) (for major
diastereomer): δ 14.4, 25.8, 47.9, 60.4, 63.2, 74.2, 107.8, 122.3, 122.5,
127.4, 127.7, 128.6, 128.9, 129.1, 133.2, 142.9, 154.7, 173.8; HRMS
D
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Note
(ESI-TOF): calcd for C20H21N3NaO5 [M + Na]+, 406.1373; found,
406.1384.
3.99−4.06 (m, 2H), 4.40 (s, 1H), 5.13 (dd, J = 9.6 Hz, 14.1 Hz, 1H),
5.31 (dd, J = 4.2 Hz, 14.1 Hz, 1H), 5.90 (br s, 1H), 6.52 (d, J = 7.8 Hz,
1H), 6.86 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.08−7.21 (m,
2H), 7.53 (d, J = 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) for (major
diastereomer): δ 14.2, 26.2, 48.1, 61.7, 63.3, 74.4, 108.2, 122.9, 124.0,
128.2, 129.8, 130.0, 131.5, 134.2, 142.7, 154.9, 173.9; HRMS (ESI-
TOF): calcd for C20H20ClN3NaO5 [M + Na]+, 440.0984; found,
440.0981.
Ethyl ((R)-3-((R)-1-(2-Methoxyphenyl)-2-nitroethyl)-1-meth-
yl-2-oxoindolin-3-yl)carbamate (4d). White solid; 40.5 mg, yield
98%; >99:1 dr (determined by 1H NMR of chiral compound), 82% ee;
20
[α]D = +27.4 (c 0.88, CHCl3); mp 175.2−176.6 °C; the ee was
determined by HPLC analysis (Chiralpak AD-H, i-PrOH/hexane =
30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tminor
=
1
9.1 min, tmajor = 11.1 min); H NMR (300 MHz, CDCl3) for (major
diastereomer): δ 1.13 (s, 3H), 3.17 (s, 3H), 3.79 (s, 3H), 3.94 (d, J =
6.6 Hz, 2H), 4.69 (s, 1H), 5.00−5.04 (m, 2H), 6.45 (s, 1H), 6.64 (d, J
= 7.8 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.83−6.91 (m, 3H), 6.94−
6.96 (br, 1H), 7.17−7.20 (m, 2H); 13C NMR (75 MHz, CDCl3) (for
major diastereomer): δ 14.3, 26.3, 39.4, 55.4, 61.3, 63.7, 74.3, 107.7,
111.0, 120.3, 121.7, 122.0, 124.8, 127.6, 129.5, 129.7, 143.3, 154.6,
156.8, 175.1; HRMS (ESI-TOF): calcd for C21H23N3NaO6 [M + Na]+,
436.1479; found, 436.1491.
Ethyl ((R)-3-((R)-1-(2-Bromophenyl)-2-nitroethyl)-1-methyl-
2-oxoindolin-3-yl)carbamate (4i). White solid; 44.4 mg, 96%
20
yield; 94:6 dr, 69% ee; [α]D = +37.4 (c 1.35, CHCl3); mp 188.7−
190.1 °C; the ee was determined by HPLC analysis (Chiralpak AD-H,
i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
1
diastereomer: tminor = 13.7 min, tmajor = 16.0 min); H NMR (300
MHz, CDCl3) for (major diastereomer): δ 1.06−1.15 (m, 3H), 3.14
(s, 3H), 4.03 (q, J = 6.9 Hz, 2H), 5.01 (dd, J = 9.6 Hz, 14.1 Hz, 1H),
5.18 (dd, J = 3.6 Hz, 9.3 Hz, 1H), 5.42 (dd, J = 3.6 Hz, 14.1 Hz, 1H),
6.00 (br s, 1H), 6.50 (d, J = 7.5 Hz, 1H), 6.95−7.01 (m, 2H), 7.10−
7.17 (m, 3H), 7.30 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3) (for major diastereomer): δ 14.3, 26.3, 46.0,
61.7, 63.5, 75.3, 107.6, 122.6, 124.9, 126.5, 126.8, 127.0, 127.4, 129.7,
129.8, 133.3, 133.4, 142.5, 154.7, 174.3; HRMS (ESI-TOF): calcd for
C20H20BrN3NaO5 [M + Na]+, 484.0479; found: 484.0485.
Ethyl ((R)-3-((R)-1-(3-Methoxyphenyl)-2-nitroethyl)-1-meth-
yl-2-oxoindolin-3-yl)carbamate (4e). White solid; 40.1 mg, yield
20
97%; 85:15 dr, 79% ee; [α]D = −13.9 (c 1.03, CHCl3); mp 129.7−
131.4 °C; the ee was determined by HPLC analysis (Chiralpak AD-H,
ethanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, major
1
diastereomer: tminor = 20.9 min, tmajor = 16.3 min); H NMR (300
MHz, CDCl3) (for major diastereomer): δ 1.07−1.14 (m, 3H), 3.05
(s, 3H), 3.63 (s, 3H), 3.97−4.02 (m, 2H), 4.32 (d, J = 5.7 Hz, 1H),
5.03 (dd, J = 9.6 Hz, 14.1 Hz, 1H), 5.21 (dd, J = 4.2 Hz, 14.1 Hz, 1H),
5.80 (br, 1H), 6.44 (s, 1H), 6.54−6.60 (m, 2H), 6.68 (d, J = 8.1 Hz,
1H), 7.01−7.08 (m, 2H), 7.17−7.22 (m, 1H), 7.47 (d, J = 7.2 Hz,
1H); 13C NMR (75 MHz, CDCl3) for (major diastereomer): δ 14.3,
26.2, 48.7, 55.1, 61.6, 63.2, 74.5, 108.1, 114.2, 114.5, 120.7, 122.8,
124.2, 127.9, 129.1, 129.7, 134.4, 143.0, 159.2, 174.3; HRMS (ESI-
TOF): calcd for C21H23N3NaO6 [M + Na]+, 436.1479; found,
436.1488.
Ethyl ((R)-3-((R)-1-(4-Bromophenyl)-2-nitroethyl)-1-dimeth-
yl-2-oxoindolin-3-yl)carbamate (4j). White solid; 45.3 mg, yield
20
98%; 88:12 dr, 79% ee; [α]D = −32.9 (c 1.13, CHCl3); mp 150.2−
151.3 °C; the ee was determined by HPLC analysis (Chiralpak AD-H,
i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tminor = 5.7 min, tmajor = 6.6 min); 1H NMR (300 MHz,
CDCl3) (for major diastereomer): δ 1.05−1.14 (m, 3H), 3.03 (s, 3H),
4.03 (q, J = 6.9 Hz, 2H), 4.38 (d, J = 5.4 Hz, 1H), 5.12 (dd, J = 9.6 Hz,
14.1 Hz, 1H), 5.31 (dd, J = 4.2 Hz, 14.1 Hz, 1H), 5.85 (br s, 1H), 6.52
(d, J = 7.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 7.03−7.08 (m, 1H),
7.16−7.25 (m, 3H), 7.53 (d, J = 7.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3) for (major diastereomer): δ 14.2, 26.2, 48.2, 61.7, 63.3, 74.4,
108.3, 122.4, 123.1, 124.1, 127.9, 129.8, 130.1, 131.1, 132.1, 142.7,
154.9, 173.9; HRMS (ESI-TOF): calcd for C20H20BrN3NaO5 [M +
Na]+, 484.0479; found, 484.0472.
Ethyl ((R)-3-((R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl)-1-
methyl-2-oxoindolin-3-yl)carbamate (4f). White solid; 39.7 mg,
1
yield 93%; 95:5 dr (determined by H NMR of chiral compound),
84% ee; [α]D20 = −20.8 (c 1.05, CHCl3); mp 187.6−189.1 °C; the ee
was determined by HPLC analysis (Chiralpak AD-H, i-PrOH/hexane
=30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tminor
Ethyl ((R)-3-((R)-1-(4-Fluorophenyl)-2-nitroethyl)-1-di-
1
= 8.8 min, tmajor = 9.8 min); H NMR (300 MHz, CDCl3) for (major
methyl-2-oxoindolin-3-yl)carbamate (4k). White solid; 38.5 mg,
20
diastereomer): δ 1.14 (s, 3H), 3.10 (s, 3H), 3.94−4.01 (m, 2H), 4.26
(d, J = 6.0 Hz, 1H), 4.95 (dd, J = 9.9 Hz, 13.8 Hz, 1H), 5.13 (dd, J =
4.2 Hz, 14.1 Hz, 1H), 5.80 (br, 1H), 5.85−5.87 (m, 2H), 6.45−6.47
(m, 2H), 6.54−6.62 (m, 2H), 7.03−7.08 (m, 1H), 7.19−7.24 (m, 1H),
7.44 (d, J = 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) (for major
diastereomer): δ 14.3, 26.3, 48.5, 61.6, 63.2, 74.8, 101.2, 107.9, 108.2.
108.9, 122.6, 123.0, 124.2, 126.4, 127.8, 129.7, 143.0, 147.4, 147.5,
154.7, 174.4; HRMS (ESI-TOF): calcd for C21H21N3NaO7 [M + Na]+,
450.1272; found, 450.1270.
yield 96%; 91:9 dr, 83% ee; [α]D = −30.8 (c 0.90, CHCl3); mp
168.1−169.3 °C; the ee was determined by HPLC analysis (Chiralpak
AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm,
1
major diastereomer: tminor = 5.2 min, tmajor = 5.9 min); H NMR (300
MHz, CDCl3) (for major diastereomer): δ 1.06−1.15 (m, 3H), 3.02
(s, 3H), 4.03 (q, J = 6.9 Hz, 2H), 4.39 (d, J = 5.1 Hz, 1H), 5.13 (dd, J
= 9.6 Hz, 14.1 Hz, 1H), 5.31 (dd, J = 4.2 Hz, 14.1 Hz, 1H), 5.90 (br s,
1H), 6.50 (d, J = 7.8 Hz, 1H), 6.73−6.78 (m, 2H), 6.87−6.92 (m,
2H), 7.03−7.08 (m, 1H), 7.15−7.20 (m, 1H), 7.53 (d, J = 6.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) for (major diastereomer): δ 14.3,
26.1, 48.1, 61.7, 63.5, 74.6, 108.2, 115.0 (d, J = 21.5 Hz, 1C), 123.1,
124.1, 128.0, 128.8 (d, J = 3.2 Hz, 1C), 129.7, 130.4 (d, J = 8.3 Hz,
1C), 142.7, 154.9, 162.3 (d, J = 246.6 Hz, 1C), 174.0; HRMS (ESI-
TOF): calcd. for C20H20FN3NaO5 [M + Na]+, 424.1279; found,
424.1270.
Ethyl ((R)-3-((R)-1-(2-Chlorophenyl)-2-nitroethyl)-1-methyl-
2-oxoindolin-3-yl)carbamate (4g). White solid; 40.5 mg, yield
20
97%; 87:13 dr, 69% ee; [α]D = +24.8 (c 1.15, CHCl3); mp 156.3−
157.5 °C; the ee was determined by HPLC analysis (Chiralpak AD-H,
i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
1
diastereomer: tminor = 12.9 min, tmajor = 14.1 min); H NMR (300
MHz, CDCl3) for (major diastereomer): δ 1.15 (s, 3H), 3.13 (s, 3H),
3.99−4.06 (m, 2H), 5.04 (dd, J = 9.6 Hz, 13.8 Hz, 1H), 5.19 (dd, J =
3.3 Hz, 9.3 Hz, 1H), 5.42 (dd, J = 3.3 Hz, 14.1 Hz, 1H), 6.00 (br, 1H),
6.49 (d, J = 7.8 Hz, 1H), 6.96−7.16 (m, 6H), 7.59 (d, J = 7.5 Hz, 1H);
13C NMR (75 MHz, CDCl3) (for major diastereomer): δ 14.2, 26.3,
Ethyl ((R)-1-Methyl-3-((R)-1-(naphthalen-1-yl)-2-nitroethyl)-
2-oxoindolin-3-yl)carbamate (4l). White solid; 41.2 mg, yield
20
95%; 79:21 dr, 79% ee; [α]D = +120.5 (c 0.40, EtOH); mp 207.3−
208.6 °C; the ee was determined by HPLC analysis (Chiralpak AD-H,
i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tminor = 8.4 min, tmajor = 10.6 min); 1H NMR (300 MHz,
DMSO-d6) for (major diastereomer): δ 1.12 (br s, 3H), 2.96 (s, 3H),
3.86 (br s, 2H), 5.44−5.60 (m, 3H), 6.37 (d, J = 7.5 Hz, 1H), 6.48−
6.53 (m, 1H), 6.70−6.75 (m, 1H), 7.28−7.37 (m, 4H), 7.47−7.52 (m,
1H), 7.60−7.66 (m, 2H), 8.18 (d, J = 8.7 Hz, 1H), 8.58 (br s, 1H); 13C
NMR (75 MHz, DMSO-d6) (for major diastereomer): δ 14.4, 25.9,
40.1, 60.5, 63.6, 75.8, 107.3, 121.6, 122.9, 123.4, 123.5, 124.2, 125.3,
125.7, 128.2, 128.4, 128.6, 130.5, 132.0, 132.9, 142.6, 154.7, 174.1;
HRMS (ESI-TOF): calcd for C24H23N3NaO5 [M + Na]+, 456.1530;
found, 456.1532.
43.2, 61.7, 63.5, 75.1, 107.5, 122.6, 124.6, 126.3, 127.2, 129.5, 129.7,
129.8, 129.9, 131.7, 135.2, 142.5, 154.7, 174.3; HRMS (ESI-TOF):
calcd for C20H20ClN3NaO5 [M + Na]+, 440.0984; found, 440.0990.
Ethyl ((R)-3-((R)-1-(4-Chlorophenyl)-2-nitroethyl)-1-dimeth-
yl-2-oxoindolin-3-yl)carbamate (4h). White solid; 37.6 mg, yield
20
90%; 90:10 dr, 80% ee; [α]D = −30.9 (c 1.13, CHCl3); mp 148.0−
149.3 °C; the ee was determined by HPLC analysis (Chiralpak AD-H,
i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
1
diastereomer: tminor = 5.4 min, tmajor = 6.2 min); H NMR (300 MHz,
CDCl3) for (major diastereomer): δ 1.05−1.14 (m, 3H), 3.03 (s, 3H),
E
dx.doi.org/10.1021/jo401154b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Ethyl ((R)-1-Methyl-3-((R)-2-nitro-1-(thiophen-2-yl)ethyl)-2-
oxoindolin-3-yl)carbamate (4m). White solid; 38.2 mg, yield
98%; 92:8 dr, 77% ee; [α]D = −18.1 (c 0.51, CHCl3); mp 194.8−
CDCl3) (for major diastereomer): δ 14.2, 21.1, 26.6, 42.7, 61.6, 62.3,
72.9, 108.0, 110.4, 110.6, 125.3, 126.9, 130.2, 132.7, 141.0, 143.2,
147.5, 154.5, 174.2; HRMS (ESI-TOF): calcd for C19H21N3NaO6 [M
+ Na]+, 410.1323; found, 410.1321.
25
196.1 °C; the ee was determined by HPLC analysis (Chiralpak AD-H,
i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tminor = 8.7 min, tmajor = 12.7 min); 1H NMR (300 MHz,
DMSO-d6) (for major diastereomer): δ 1.09 (br s, 3H), 2.90 (s, 3H),
3.84 (d, J = 6.6 Hz, 2H), 4.47 (dd, J = 3.0 Hz, 11.4 Hz, 1H), 5.19−5.27
(m, 1H), 5.42 (dd, J = 3.3 Hz, 14.4 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H),
6.64−6.71 (m, 2H), 6.99−7.04 (m, 1H), 7.12−7.19 (m, 2H), 7.35 (d, J
= 7.2 Hz, 1H), 8.53 (br s, 1H); 13C NMR (75 MHz, DMSO-d6) for
(major diastereomer): δ 14.4, 26.0, 43.4, 60.5, 63.3, 75.6, 108.0, 122.5,
122.6, 126.0, 126.1, 126.7, 129.2, 135.5, 143.4, 154.7, 173.5; HRMS
(ESI-TOF): calcd for C18H19N3NaO5S [M + Na]+, 412.0938; found,
412.0923.
Ethyl ((R)-5-Fluoro-1-methyl-3-((R)-2-nitro-1-phenylethyl)-2-
oxoindolin-3-yl)carbamate (4r). White solid; 38.9 mg, yield 97%;
94:6 dr, 88% ee; [α]D20 = −19.1 (c 0.90, CHCl3); mp 194.6−195.8 °C;
the ee was determined by HPLC analysis (Chiralpak AD-H, i-PrOH/
hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tminor = 5.4 min, tmajor = 4.8 min); 1H NMR (300
MHz, CDCl3) (for major diastereomer): δ 1.17 (br s, 3H), 3.01 (s,
3H), 4.04 (q, J = 6.9 Hz, 2H), 4.34 (d, J = 4.5 Hz, 1H), 5.10 (dd, J =
9.3 Hz, 14.4 Hz, 1H), 5.33 (dd, J = 4.2 Hz, 14.4 Hz, 1H), 5.86 (br,
1H), 6.38−6.42 (m, 1H), 6.83−6.95 (m, 3H), 7.10−7.12 (m, 3H),
7.30 (d, J = 6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) (for major
diastereomer): δ 14.3, 26.3, 48.7, 61.8, 63.6, 74.5, 108.6 (d, J = 8.1 Hz
1C), 112.5 (d, J = 25.0 Hz, 1C), 115.8 (d, J = 23.6 Hz, 1C), 128.2,
128.3, 128.4, 128.7, 132.8, 138.9, 154.8, 159.2 (d, J = 240.6 Hz, 1C),
174.0; HRMS (ESI-TOF): calcd for C20H20FN3NaO5 [M + Na]+,
424.1279; found, 424.1284.
Ethyl ((R)-3-((R)-1-Cyclohexyl-2-nitroethyl)-1-methyl-2-oxo-
indolin-3-yl)carbamate (4n). White solid; 11.7 mg, yield 30%;
1
>99:1 dr (determined by H NMR of chiral compound), 87% ee;
20
[α]D = −2.1 (c 0.38, CHCl3); mp 179.7−181.2 °C; the ee was
determined by HPLC analysis (Chiralpak AD-H, i-PrOH/hexane =
30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tminor
=
Ethyl ((R)-1-Ethyl-3-((R)-2-nitro-1-phenylethyl)-2-oxoindolin-
1
6.7 min, tmajor = 7.2 min); H NMR (300 MHz, CDCl3) for (major
diastereomer): δ 0.75−1.27 (m, 11H), 1.47−1.63 (m, 3H), 2.84 (s,
1H), 3.20 (s, 3H), 3.96 (q, J = 6.9 Hz, 2H), 4.60 (dd, J = 4.2 Hz, 15.3
Hz, 1H), 5.53 (dd, J = 3.0 Hz, 15.3 Hz, 1H), 6.00 (s, 1H), 6.86 (d, J =
7.8 Hz, 1H), 7.10−7.15 (m, 1H), 7.33−7.38 (m, 2H); 13C NMR (75
MHz, CDCl3) (for major diastereomer): δ 14.3, 25.6, 26.1, 26.4, 27.8,
32.9, 37.3, 49.6, 61.4, 72.2, 108.2, 122.8, 123.4, 128.9, 129.7, 143.9,
154.5, 175.2; HRMS (ESI-TOF): calcd for C20H27N3NaO5 [M + Na]+,
412.1843; found, 412.1845.
3-yl)carbamate (4s). White solid; 38.2 mg, yield 96%; 92:8 dr
1
20
(determined by H NMR of chiral compound), 84% ee; [α]D
=
−42.9 (c 0.90, CHCl3); mp 165.1−166.2 °C; the ee was determined
by HPLC analysis (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow
rate 1.0 mL/min, λ = 254 nm, major diastereomer: tminor = 7.5 min,
tmajor = 9.4 min); 1H NMR (300 MHz, CDCl3) (for major
diastereomer): δ 1.08−1.13 (m, 6H), 3.54−3.68 (m, 2H), 3.95−4.03
(m, 2H), 4.38 (d, J = 5.4 Hz, 1H), 5.15 (dd, J = 9.6 Hz, 14.1 Hz, 1H),
5.30 (dd, J = 4.5 Hz, 14.1 Hz, 1H), 5.85 (br s, 1H), 6.54 (d, J = 7.8 Hz,
1H), 6.95−6.98 (m, 2H), 7.03−7.17 (m, 5H), 7.53 (d, J = 7.2 Hz,
1H); 13C NMR (75 MHz, CDCl3) for (major diastereomer): δ 11.9,
14.3, 34.9, 48.6, 61.5, 63.1, 74.6, 108.2, 122.5, 122.7, 124.5, 128.1,
128.2, 129.0, 129.5, 132.8, 142.1, 154.8, 173.8; HRMS (ESI-TOF):
calcd for C21H23N3NaO5 [M + Na]+, 420.1530; found, 420.1535.
(3R,5′R)-1-Methyl-5′-phenyl-5′,6′-dihydro-1′H-spiro[indo-
line-3,4′-pyrimidine]-2,2′(3′H)-dione (6). To the solution of 4a
(100 mg, 0.26 mmol) and NiCl2 (34 mg, 0.26 mmol) in MeOH (10
mL) was added to NaBH4 (12 equiv, 12 mg) at 0 °C. The resulting
mixture was warmed to room temperature and vigorously stirred for 1
h. After the reaction was quenched with a saturated NH4Cl solution,
the mixture was extracted with CH2Cl2, and the combined organic
layers were dried over anhydrous Na2SO4 and concentrated to furnish
the crude product 5 (90 mg). Then the mixture of 5 (90 mg) and a
saturated NaOH solution (4 mL) in EtOH (8 mL) was refluxed for 3.5
h. The mixture was added to water (20 mL) and extracted with
CH2Cl2. After being dried over anhydrous Na2SO4, the mixture was
concentrated, and the residue was purified by flash column
Ethyl ((R)-1,5-Dimethyl-3-((R)-2-nitro-1-phenylethyl)-2-oxo-
indolin-3-yl)carbamate (4o). White solid; 36.2 mg, yield 91%;
20
86:14 dr, 92% ee; [α]D = −38.8 (c 1.00, CHCl3); mp 195.3−196.4
°C; the ee was determined by HPLC analysis (Chiralpak AD-H,
ethanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, major
1
diastereomer: tminor = 15.7 min, tmajor = 12.9 min); H NMR (300
MHz, CDCl3) for (major diastereomer): δ 1.08−1.15 (m, 3H), 2.32
(s, 3H), 3.00 (s, 3H), 3.96−4.05 (m, 2H), 4.32 (d, J = 5.1 Hz, 1H),
5.05 (dd, J = 9.3 Hz, 14.1 Hz, 1H), 5.25 (dd, J = 4.5 Hz, 14.1 Hz, 1H),
5.80 (br, 1H), 6.39 (d, J = 7.8 Hz, 1H), 6.93−6.98 (m, 3H), 7.07−7.14
(m, 3H), 7.27 (s, 1H); 13C NMR (75 MHz, CDCl3) (for major
diastereomer): δ 14.3, 21.2, 26.2, 48.8, 61.6, 63.3, 74.6, 107.8, 124.9,
127.8, 128.0, 128.3, 128.8, 129.8, 132.5, 133.0, 140.5, 154.8, 174.1;
HRMS (ESI-TOF): calcd for C21H23N3NaO5 [M + Na]+, 420.1530;
found, 420.1540.
Ethyl ((R)-3-((R)-1-(3-Bromophenyl)-2-nitroethyl)-1,5-di-
methyl-2-oxoindolin-3-yl)carbamate (4p). Colorless oil; 44.8
20
mg, yield 94%; 85:15 dr, 75% ee; [α]D = −42.8 (c 0.90, CHCl3);
the ee was determined by HPLC analysis (Chiralpak AD-H, ethanol/
hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tminor = 6.4 min, tmajor = 5.4 min); 1H NMR (300
MHz, CDCl3) for (major diastereomer): δ 1.14−1.18 (m, 3H), 2.33
(s, 3H), 3.00 (s, 3H), 4.00−4.08 (m, 2H), 4.37 (d, J = 5.4 Hz, 1H),
5.09 (dd, J = 9.6 Hz, 14.1 Hz, 1H), 5.26 (dd, J = 4.5 Hz, 14.1 Hz, 1H),
5.75 (br, 1H), 6.41 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 6.98
(d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H); 13C NMR
(75 MHz, CDCl3) (for major diastereomer): δ 14.3, 21.2, 26.2, 48.2,
61.7, 63.3, 74.5, 108.0, 122.4, 125.0, 127.8, 130.1, 130.4, 131.1, 131.3,
132.3, 132.8, 140.4, 154.9, 173.8; HRMS (ESI-TOF): calcd for
C21H22BrN3NaO5 [M + Na]+, 498.0635; found, 498.0630.
chromatography (MeOH/ethyl acetate = 1:20) to give the product
20
6 as a white solid in 72 mg. 90% yield; 93:7 dr, 91% ee; [α]D
=
+130.2 (c 0.70, EtOH); mp 236.8−237.9 °C; the ee was determined
by HPLC analysis (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow
rate 1.0 mL/min, λ = 254 nm, major diastereomer: tminor = 12.5 min,
tmajor = 8.4 min); 1H NMR (300 MHz, DMSO-d6) (for major
diastereomer): δ 2.79 (s, 3H), 3.04−3.11 (m, 1H), 3.47 (dd, J = 4.5
Hz, 12.3 Hz, 1H), 4.17 (t, J = 12.0 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H),
6.74 (s, 1H), 6.81 (d, J = 6.0 Hz, 2H), 6.88 (s, 1H), 7.00−7.09 (m,
4H), 7.12−7.18 (m, 1H), 7.49 (d, J = 7.2 Hz, 1H); 13C NMR (75
MHz, DMSO-d6) for (major diastereomer): δ 25.7, 39.8, 45.4, 63.4,
108.1, 122.4, 123.8, 127.4, 127.6, 128.2, 129.1, 129.2, 135.3, 142.8,
155.6, 176.3; HRMS (ESI-TOF): calcd for C18H17N3NaO2 [M + Na]+,
330.1213; found, 330.1218.
Ethyl ((R)-3-((R)-1-(Furan-2-yl)-2-nitroethyl)-1,5-dimethyl-2-
oxoindolin-3-yl)carbamate (4q). Colorless oil; 36.8 mg, yield
20
95%; 93:7 dr, 80% ee; [α]D = −8.6 (c 0.70, CHCl3); the ee was
determined by HPLC analysis (Chiralpak AD-H, i-PrOH/hexane =
ASSOCIATED CONTENT
85/15, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tminor
=
■
12.7 min, tmajor = 15.4 min); 1H NMR (300 MHz, CDCl3) for (major
diastereomer): δ 1.13 (s, 3H), 2.31 (s, 3H), 3.17 (s, 3H), 3.93−4.01
(m, 2H), 4.46 (dd, J = 5.7 Hz, 8.1 Hz, 1H), 4.62−4.73 (m, 2H), 5.81
(br s, 1H), 6.10 (d, J = 3.0 Hz, 1H), 6.25−6.26 (m, 1H), 6.64 (d, J =
7.8 Hz, 1H), 7.05−7.09 (m, 2H), 7.33 (s, 1H); 13C NMR (75 MHz,
S
* Supporting Information
Detailed spectral data for new compounds, X-ray crystal
structure and the CIF files of 4m. This material is available
free of charge via the Internet at http://pubs.acs.org.
F
dx.doi.org/10.1021/jo401154b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Dong, L.; Chen, Y.-C. Beilstein J. Org. Chem. 2012, 8, 1241.
(c) Tolstoy, P.; Lee, S. X. Y.; Sparr, C.; Ley, S. V. Org. Lett. 2012,
14, 4810. (d) Cao, Y. M.; Shen, F. F.; Zhang, F. T.; Wang, R. Chem.
Eur. J. 2013, 19, 1184.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yuanwc@cioc.ac.cn.
■
(9) (a) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.;
Yuan, W.-C. Chem.Eur. J. 2012, 18, 6679. (b) Liao, Y.-H.; Wu, Z.-J.;
Han, W.-Y.; Zhang, X.-M.; Yuan, W.-C. Chem.Eur. J. 2012, 18, 8916.
(c) Liu, X.-L.; Han, W.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2013,
15, 1246. (d) Han, W.-Y.; Li, S.-W.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-
C. Chem.Eur. J. 2013, 19, 5551.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Basic
Research Program of China (973 Program) (2010CB833300),
Western Light Talent Culture Project, and Sichuan Youth
Science and Technology Foundation.
(10) For selected examples about the catalytic asymmetric Michael
addition of 3-substituted oxindoles to nitroolefins, see: (a) Bui, T.;
Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009, 131, 8758. (b) Kato,
Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2009, 131, 9168. (c) He, R.; Shirakawa, S.;
Maruoka, K. J. Am. Chem. Soc. 2009, 131, 16620. (d) Ding, M.; Zhou,
F.; Liu, Y.-L.; Wang, C.-H.; Zhao, X.-L.; Zhou, J. Chem. Sci. 2011, 2,
2035.
REFERENCES
■
(1) For selected reviews, see: (a) Marti, C.; Carreira, E. M. Eur. J.
Org. Chem. 2003, 2209. (b) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (c) Trost, B. M.; Brennan, M. K.
Synthesis 2009, 3003. (d) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth.
Catal. 2010, 352, 1381.
(11) For details about the synthesis of 3-monosubstituted 3-
aminooxindoles, see Experimental Section.
(12) For details, see Supporting Information.
(13) For selected examples, see: (a) Okino, T.; Hoashi, Y.; Furukawa,
T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
(b) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006,
128, 9413. (c) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org.
Lett. 2008, 10, 3583.
(2) For selected examples, see: (a) Takayama, H.; Mori, I.; Kitajima,
M. Org. Lett. 2004, 6, 2945. (b) Ghosh, A. K.; Schiltz, G.; Perali, R. S.;
Leshchenko, S.; Kay, S.; Walters, D. E.; Koh, Y.; Maeda, K.; Mitsuya,
H. Bioorg. Med. Chem. Lett. 2006, 16, 1869. (c) Vintonyak, V. V.;
Warburg, K.; Kruse, H.; Grimme, S.; Hubel, K.; Rauh, D.; Waldmann,
H. Angew. Chem., Int. Ed. 2010, 49, 5902. (d) Czarna, A.; Beck, B.;
̈
Srivastava, S.; Popowicz, G. M.; Wolf, S.; Huang, Y.; Bista, M.; Holak,
T. A.; Domling, A. Angew. Chem., Int. Ed. 2010, 49, 5352.
̈
(3) For a leading review, see: Chauhan, P.; Chimni, S. S. Tetrahedron:
Asymmetry 2013, 24, 343. For selected examples, see: (a) Emura, T.;
Esaki, T.; Tachibana, K.; Shimizu, M. J. Org. Chem. 2006, 71, 8559.
(b) Zhang, T.; Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J. Tetrahedron:
Asymmetry 2010, 21, 2800. (c) Bergonzini, G.; Melchiorre, P. Angew.
Chem., Int. Ed. 2012, 51, 971. (d) Noole, A.; Jarving, I.; Werner, F.;
̈
Lopp, M.; Malkov, A.; Kanger, T. Org. Lett. 2012, 14, 4922. (e) Li, J.;
Du, T.; Zhang, G.; Peng, Y. Chem. Commun. 2013, 49, 1330. (f) Zhou,
F.; Zeng, X.-P.; Wang, C.; Zhao, X.-L.; Zhou, J. Chem. Commun. 2013,
49, 2022.
(4) For selected examples, see: (a) Liu, Y.-L.; Zhou, F.; Cao, J.-J.; Ji,
C.-B.; Ding, M.; Zhou, J. Org. Biomol. Chem. 2010, 8, 3847.
(b) Sacchetti, A.; Silvani, A.; Gatti, F. G.; Lesma, G.; Pilati, T.;
Trucchi, B. Org. Biomol. Chem. 2011, 9, 5512. (c) Yan, W.; Wang, D.;
Feng, J.; Li, P.; Zhao, D.; Wang, R. Org. Lett. 2012, 14, 2512. (d) Guo,
Q.-X.; Liu, Y.-W.; Li, X.-C.; Zhong, L.-Z.; Peng, Y.-G. J. Org. Chem.
2012, 77, 3589. (e) Feng, J.; Yan, W.; Wang, D.; Li, P.; Sun, Q.; Wang,
R. Chem. Commun. 2012, 48, 8003. (f) Hara, N.; Nakamura, S.; Sano,
M.; Tamura, R.; Funahashi, Y.; Shibata, N. Chem.Eur. J. 2012, 18,
9276. (g) Chen, D.; Xu, M.-H. Chem. Commun. 2013, 49, 1327.
(h) Liu, Y.-L.; Zhou, J. Chem. Commun. 2013, 49, 4421.
(5) For selected examples, see: (a) Qian, Z.-Q.; Zhou, F.; Du, T.-P.;
Wang, B.-L.; Ding, M.; Zhao, X.-L.; Zhou, J. Chem. Commun. 2009,
6753. (b) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255.
(c) Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J. Org. Lett. 2010, 11, 3874.
́
(d) Bui, T.; Hernandez-Torres, G.; Milite, C.; Barbas, C. F., III. Org.
Lett. 2010, 12, 5696. (e) Yang, Z.; Wang, Z.; Bai, S.; Shen, K.; Chen,
D.; Liu, X.; Lin, L.; Feng, X. Chem.Eur. J. 2010, 16, 6632. (f) Zhou,
F.; Ding, M.; Liu, Y.-L.; Wang, C.-H.; Ji, C.-B.; Zhang, Y.-Y.; Zhou, J.
Adv. Synth. Catal. 2011, 353, 2945.
(6) For selected examples, see: (a) Shi, F.; Tao, Z.-L.; Luo, S.-W.; Tu,
S.-J.; Gong, L.-Z. Chem.Eur. J. 2012, 18, 6885. (b) Ren, L.; Lian, X.-
L.; Gong, L.-Z. Chem.Eur. J. 2013, 19, 3315.
(7) For selected examples, see: (a) Shen, K.; Liu, X.; Wang, G.; Lin,
L.; Feng, X. Angew. Chem., Int. Ed. 2011, 50, 4684. (b) Jia, L.-N.;
Huang, J.; Peng, L.; Wang, L.-L.; Bai, J.-F.; Tian, F.; He, G.-Y.; Xu, X.-
Y.; Wang, L.-X. Org. Biomol. Chem. 2012, 10, 236.
(8) For selected examples, see: (a) Duce, S.; Pesciaioli, F.; Gramigna,
L.; Bernardi, L.; Mazzanti, A.; Ricci, A.; Bartoli, G.; Bencivenni, G. Adv.
Synth. Catal. 2011, 353, 860. (b) Zhang, H.; Zhang, S.-J.; Zhou, Q.-Q.;
G
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