Asymmetric synthesis of spiro[isoxazolin-3,3'-oxindoles] via the catalytic 1,3-dipolar cycloaddition reaction of nitrile oxides

Article abstract of DOI:10.1021/jo5012625

A highly enantioselective 1,3-dipolar cycloaddition of nitrile oxides with 3-arylidene-oxindoles was realized by a chiral N,N'-dioxide-nickel(II) complex catalyst under mild reaction conditions. A series of spiro-isoxazoline-oxindole derivatives were obtained in moderate yields (up to 65%) with good regioselectivities (up to 99:1), excellent enantioselectivities (up to 99% ee), and exclusive diastereoselectivity as well.

Full text of DOI:10.1021/jo5012625

Note
pubs.acs.org/joc
Asymmetric Synthesis of Spiro[isoxazolin-3,3′-oxindoles] via the
Catalytic 1,3-Dipolar Cycloaddition Reaction of Nitrile Oxides
Xiangjin Lian, Songsong Guo, Gang Wang, Lili Lin, Xiaohua Liu, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, People’s Republic of China
S
* Supporting Information
ABSTRACT: A highly enantioselective 1,3-dipolar cycloaddition of nitrile oxides with 3-arylidene-oxindoles was realized by a
chiral N,N′-dioxide−nickel(II) complex catalyst under mild reaction conditions. A series of spiro-isoxazoline-oxindole derivatives
were obtained in moderate yields (up to 65%) with good regioselectivities (up to 99:1), excellent enantioselectivities (up to 99%
ee), and exclusive diastereoselectivity as well.
Scheme 1. 1,3-DCR between Nitrile Oxides and 3-Arylidene-
Oxindoles and the Chiral Ligands Evaluated in the Reaction
pirooxindoles are an important subset of oxindole-based
1
Smolecules, which represent an attractive synthetic target
due to the biological activity and as the intermediates for
generating further molecular complexity.2 The asymmetric 1,3-
dipolar cycloaddition reaction (1,3-DCR) provides a useful
route to synthesize a variety of spirooxindoles when 3-
arylidene-oxindole derivatives are employed as the dipolar-
ophiles.3 The extraordinary advancement in this area focused
on the employment of the dipoles, such as nitrones,4
azomethine imines,5 azomethine ylides,6 and nitrile imines.7
From a synthetic point of view, the asymmetric 1,3-DCR
between nitrile oxides and 3-arylidene-oxindoles can efficiently
construct isoxazoline-based spirooxindoles with two stereo-
centers. Nevertheless, catalytic asymmetric 1,3-DCR of nitrile
oxides is underdeveloped.8 Owing to the instability of nitrile
oxides, they are generally prepared in situ from the hydroximoyl
chloride by treatment with a basic reagent. High electron-donor
ability of an oxygen atom of the dipole,9 as well as the
propensity of the dipole to dimerize, enhances the complexity
of achieving high efficiency in a Lewis acid mediated process.10
Additionally, several challenges related to selectivity are also
associated with the construction of such spirooxindole
structures. The reaction potentially yields regioselectively either
the favored C-adduct or the disfavored O-adduct (Scheme 1).
Moreover, vicinal stereogenic centers bearing a unique spiro
quaternary carbon and a tertiary carbon are created in the
counter-competitive background reaction mediated by a base.
Otherwise, the acid generated from hydroximoyl chloride may
dull the chiral Lewis acids and deteriorate the enantioselectivity.
The pioneering work of chiral Lewis acids catalyzed 1,3-DCR
of nitrile oxides was reported by Inomata and co-workers using
Received: June 6, 2014
Published: July 23, 2014
© 2014 American Chemical Society
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Note
Table 1. Evaluation of the Reaction Conditions
a
b
c
d
entry
ligand
metal salt
solvent
CH2Cl2
yield (%)
3a:4a
ee (%)
1
2
L1
L1
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
Mg(ClO4)2
50
54
47
58
52
44
43
35
33
30
32
43
76
94:6
97:3
98:2
96:4
96:4
95:5
97:3
99:1
93:7
93:7
5
Zn(OTf)2
CH2Cl2
trace
11
30
42
51
44
33
87
89
92
99
11
3
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
CH2Cl2
4
CH2Cl2
5
CH2Cl2
6
CH2Cl2
7
CH2Cl2
8
CH2Cl2
9
CHCl3
10
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
e
11
ef
,
90:10
97:3
97:3
12
13
efg
, ,
a
Unless otherwise noted, the reactions were performed with 1a (0.10 mmol), 2a (0.10 mmol), L (0.01 mmol), metal (0.01 mmol), and 4 Å MS (40
b
c
mg) in 1.0 mL of the solvent at 35 °C for 24 h. Isolated yield of the mixture of 3a and 4a. Regioselectivity (3a:4a) determined by chiral HPLC
analysis (Chiralpak IA). Determined by chiral HPLC for the major regioisomer 3a. In 0.3 mL of ClCH2CH2Cl. H2O (3 μL) was added. 1.0 equiv
d
e
f
g
of K2CO3 was added.
allylic alcohols as the dipolarophiles and a chiral diisopropyl
tartrate−zinc complex as the catalyst.11 Sibi and co-workers
reported the successful reaction between the preformed nitrile
oxides and oxazolidinone crotonates by a chiral bisoxazoline−
magnesium catalyst.8a,b Afterward, Suga et al. demonstrated a
chiral BINIM−Ni(II) complex catalyzed asymmetric cyclo-
addition of several nitrile oxides with good yields and
enantioselectivities.8c However, the search for new dipolar-
ophiles and chiral Lewis acid catalysts is still a promising
strategy for the development of highly enantioselective 1,3-
DCR of nitrile oxides. In the past several years, our research has
been focused on developing chiral N,N′-dioxide−metal
complexes catalysts. This undertaking has enabled efficient
and selective catalysis of a range of asymmetric reactions.12 We
are inspired by the excellent performance and tolerance toward
acids, bases, and moisture of these catalysts in asymmetric
cyclization reactions12 and expect these chiral Lewis acids also
work in the construction of the new spirooxindole structures.
Herein, we report a highly stereoselective cycloaddition
between 3-arylidene-oxindoles and nitrile oxides using an
N,N′-dioxide−nickel(II) complex as the catalyst (Scheme 1).
Excellent enantioselectivities (85−99% ee’s) and good
regioselectivities were achieved in the presence of 4 Å
molecular sieves, albeit the yields were moderated.
Initially, 3-benzylidene-oxindole derivative 1a was chosen as
the model substrate to react with the nitrile oxide precursor 2a.
Various chiral Lewis acid catalysts that generated in situ from
metal salts and the N,N′-dioxide L1 (Scheme 1) were first
evaluated. Four Å molecular sieves (4 Å MS) instead of a base
were used to convert hydroximoyl chloride 2a into the
corresponding nitrile oxide.8c The representative results are
summarized in Table 1. The C-adduct 3a was obtained as the
major product, and a trace amount of the regioisomer of the O-
adduct 4a was detected. Both the L1−Mg(ClO4)2 and L1−
Zn(OTf)2 complexes could promote the reaction in moderate
yields, while the enantiomeric excess (ee) were poor (Table 1,
entries 1, 2). The combination of Ni(ClO4)2·6H2O with L1
afforded the products in 47% yield, 98:2 rs, and 11% ee for 3a
(Table 1, entry 3). To our delight, increasing the steric
hindrance of the amide subunits of the ligand benefited the
enantioselectivity of the reaction, and the N,N′-dioxide L2
bearing 2,6-dimethyl-substituted anilines raised the ee to 30%,
though the yield did not change too much (Table 1, entry 4).
When the ligands donated with more steric hindered amide
moieties, such as when 2,6-diethyl or 2,6-diisopropyl anilines
were used, the yields decreased slightly with maintained
regioselectivities, while the ee improved to 42% and 51% for
ligands L3 and L4, respectively (Table 1, entries 5, 6). The
N,N′-dioxide L5 derived from L-proline and L6 derived from L-
ramipril exhibited inferior results in terms of yield and
enantioselectivity (Table 1, entries 7 and 8 vs 6).
With the optimized catalyst in hand, we next tested the effect
of the solvent on the reaction. The use of CHCl3 led to the ee
increased to 87% (Table 1, entry 9). When the reaction was
performed in CH2ClCH2Cl, the yield was 30% and the ee
increased to 89% (Table 1, entry 10). Decreasing the amount of
CH2ClCH2Cl resulted in an improved enantioselectivity (92%
ee), a decreased regioselectivity (90:10), and a yield of 32%
(Table 1, entry 11). Fortunately we found that the addition of
water had a positive effect on both the enantioselectivity and
the yield (Table 1, entry 12). It may be for the reason that the
water can absorb hydrochloride that was generated in the
formation of nitrile oxide from the precursor 2a in the presence
of 4 Å molecular sieves, and then the adverse effect of acid to
the chiral metal complex catalyst was minimized to a certain
degree. It was also noteworthy that hydrochloride can remove
the Boc group on the nitrogen of 1a. Therefore, the low yield
partly attributed to the deprotection of the N-Boc group by
HCl, leading to the less effective N−H free 3-benzylideneindo-
linone which was detected in the reaction mixture. Although
high yield could be obtained by the addition of K2CO3, the
enantioselectivity dropped sharply as a result of the strong
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Table 2. Substrate Scope of 3-Arylidene-Oxindoles in the Asymmetric 1,3-Dipolar Cycloaddition Reaction
a
b
c
d
entry
R1, R2 (1)
Ph, H (1a)
3
yield (%)
3:4
ee (%)
1
2
3a
3b
3c
3d
3e
3f
43
30
45
48
44
31
53
48
65
42
40
35
32
40
41
40
35
44
38
97:3
98:2
>99
>99
>99
96
3-FC6H4, H (1b)
4-FC6H4, H (1c)
2-ClC6H4, H (1d)
3-ClC6H4, H (1e)
4-ClC6H4, H (1f)
2,6-Cl2C6H3, H (1g)
2-BrC6H4, H (1h)
3-BrC6H4, H (1i)
4-BrC6H4, H (1j)
3-MeC6H4, H (1k)
4-MeC6H4, H (1l)
4-F3CC6H4, H (1m)
3-MeOC6H4, H (1n)
3-PhOC6H4, H (1o)
2-naphthyl, H (1p)
Ph, 5-F (1q)
3
98:2
4
>99:1
96:4
5
99
6
94:6
99
7
3g
3h
3i
>99:1
>99:1
68:32
92:8
99
8
97
9
99
10
11
12
13
14
15
16
17
18
19
3j
>99
>99
97
3k
3l
98:2
>99:1
99:1
3m
3n
3o
3p
3q
3r
3s
>99
>99
97
90:10
>99:1
71:29
98:2
93
>99
96
Ph, 5-Br (1r)
96:4
Ph, 5-MeO (1s)
94:6
97
a
Unless otherwise noted, the reactions were performed with L4 (0.01 mmol), Ni(ClO4)2·6H2O (0.01 mmol), 1 (0.10 mmol), 2a (0.10 mmol), H2O
b
c
(3 μL), and 4 Å MS (40 mg) in 0.3 mL of ClCH2CH2Cl at 35 °C for 24 h. Isolated yield of the mixture of 3 and 4. Regioselectivity (3:4)
determined by chiral HPLC analysis (Chiralpak IA or ID). Determined by chiral HPLC for the major regioisomer.
d
Table 3. Substrate Scope of the Nitrile Oxide Precursors
a
b
c
d
entry
R3 (2)
3
yield (%)
3:4
ee (%)
1
2
3
4
5
6
7
8
4-FC6H5 (2t)
3t
60
44
52
46
49
40
53
43
96:4
>99:1
>99:1
95:5
97
87
92
99
93
99
92
95
3-ClC6H5 (2u)
4-ClC6H5 (2v)
3-BrC6H5 (2w)
4-BrC6H5 (2x)
4-MeC6H5 (2y)
4-F3CC6H5 (2z)
4-MeOC6H5 (2aa)
3u
3v
3w
3x
>99:1
96:4
3y
3z
99:1
3aa
90:10
a
Unless otherwise noted, the reactions were performed with L4 (0.01 mmol), Ni(ClO4)2·6H2O (0.01 mmol), 1a (0.10 mmol), 2 (0.10 mmol), H2O
b
c
(3 μL), and 4 Å MS (40 mg) in 0.3 mL of ClCH2CH2Cl at 35 °C for 24 h. Isolated yield of the mixture of 3 and 4. Regioselectivity (3:4)
determined by chiral HPLC analysis (Chiralpak IA). Determined by chiral HPLC for the major regioisomer.
d
background reaction (Table 1, entry 13). Therefore, the
optimal reaction conditions were 10 mol % of L4−Ni(ClO4)2·
6H2O (1:1) with 4 Å molecular sieves and a small amount of
H2O in CH2ClCH2Cl at 35 °C for 24 h, which afforded the
product with 43% yield, 97:3 regioselectivity, and 99% ee. The
C-adduct and O-adduct regioisomers could not be isolated by
column chromatography.
Table 2. The enantiocontrol of the reaction was sensitive to
neither the electronic property nor the steric hindrance of
substituents on the phenyl ring. 3-Arylidene-oxindoles with
either electron-withdrawing or electron-donating substituents
on the aromatic ring provided the corresponding products in
excellent enantioselectivities (96−99% ee’s; Table 2, entries 1−
15). High regioselectivities were achieved in most cases.
Especially, ortho-halo-substituted dipolarophiles, such as 1d,
1g, and 1h, afforded the spirooxindoles 3 in up to 99:1
Under the optimized conditions, the scope of 3-arylidene-
oxindoles was examined, and the results are summarized in
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Note
regioselectivity (Table 2, entries 4, 7, 8). One exception was 3-
bromo-substituted substrate 1i, which performed the asym-
metric 1,3-DCR with moderate rs, generating 5-substituted
adduct 3i and 4-substituted adduct 4i in a 68:32 ratio and 65%
yield (Table 2, entry 9). As well, the fused-ring substrate 1p was
also tolerable to afford the desired product with 71:29
regioselectivity and 93% ee (Table 2, entry 16). The reduced
regioselectivity might mainly be influenced by steric factors due
to important differences in terminal nitriloxide atoms involved
in bond formation. Moreover, the 5-substituted oxindole
derivatives could also afford the corresponding products in
good results (Table 2, entries 17−19). Unfortunately,
alkylideneoxindoles do not react under the optimized
conditions. The absolute configuration of the product 3h was
determined to be (3S,4′R) by X-ray crystallography analysis
(see details in the Supporting Information).14
Next, the performance of other nitrile oxide precursors 2 was
investigated. As shown in Table 3, cycloaddition of aryl-
substituted nitrile oxides gave the corresponding products in
good to excellent regioselectivities and enantioselectivities
depending on the position and electronic nature of the
substituents. The enantioselectivities were lower with 3-
chloro-substituted hydroximoyl chloride (Table 3, entry 2).
Electron-donating substituted dipoles yielded relatively lower
regioselectivity in comparison with most of the electron-
withdrawing ones (Table 3, entries 6 and 8). The 4-methoxyl-
substituted nitrile oxide produced the product with 90:10 rs,
and good ee (Table 3, entry 8).
To demonstrate the practicality of the present approach, the
reaction was scaled up to a gram scale. Under the optimized
reaction conditions, upon treatment of 3 mmol of the starting
materials, the corresponding product 3g was produced without
any loss of the reactivity and enantioselectivity (48% yield, 99:1
rs, and 98% ee). It was noted that there was no self-
disproportionation of enantiomers observed in the purification
process via achiral chromatography.15
An asymmetric catalytic model was proposed as a hexa-
coordinated octahedral structure on the basis of the X-ray
structural analysis of the N,N′-dioxide−Ni(II) complex as
reported in the previous reports.13d,g As shown in Scheme 2,
nitrile oxide was generated from N-hydroximoyl chloride 2
assisted with 4 Å molecular sieves. The Re face of oxindole
derivative 1 is effectively shielded by the amide moiety and
piperidine ring underneath of the ligand. In contrast, the Si face
is located in a relatively open space. The highly selective
approach of the nitrile oxide toward the Si face of bidentate-
coordinated 3-arylidene-oxindole gives the (3S,4′R)-adduct 3,
which is consistent with the observed absolute configuration of
the cyclic product.
In summary, we have developed a highly enantioselective
N,N′-dioxide−nickel(II) complex catalytic system for the
asymmetric 1,3-dipolar cycloaddition of nitrile oxides with 3-
arylidene-oxindoles. The corresponding spiro-isoxazoline-oxin-
dole derivatives were afforded in moderate yields and high
regio-, diastereo-, and enantioselectivities under mild reaction
conditions.
EXPERIMENTAL SECTION
■
General Remarks. Reactions were carried out using commercially
available reagents in a dry apparatus. ClCH2CH2Cl was directly
distilled before use. Enantiomeric excesses (ee’s) were determined by
HPLC analysis using the corresponding commercial chiral column as
stated in the experimental procedures at 23 °C with a UV detector at
254 nm. Optical rotations were reported as follows: [α]2D5 (c g/100
mL, solvent). 1H NMR spectra were recorded on commercial
instruments (400 MHz). 13C NMR spectra was collected on
commercial instruments (100 MHz) with complete proton decou-
pling.
General Procedure for the Catalytic Asymmetric 1,3-Dipolar
Cycloaddition Reaction. To a dry reaction tube were added L4
(0.01 mmol, 6.5 mg), Ni(ClO4)2·6H2O (0.01 mmol, 3.7 mg), 4 Å MS
(40 mg), and ClCH2CH2Cl (0.3 mL). After stirring at 35 °C for 1 h, 1
(0.1 mmol), 2 (0.1 mmol), and H2O (3 μL) were added. The reaction
mixture continued stirring at 35 °C for 24 h. The crude mixture was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 10/1 to 5/1) to afford the desired product as a white solid. The
enantiomeric excess (ee) was determined by high-performance liquid
chromatography (HPLC), and the regioselectivity was determined by
1H NMR.
tert-Butyl-2-oxo-3′,4′-diphenyl-4′H-spiro[indoline-3,5′-isoxa-
zole]-1-carboxylate (3a). Purified by flash chromatography (petro-
leum ether:EtOAc = 10:1) to afford a white solid, 18.9 mg, 43% yield,
97:3 rs, and 99% ee, mp 168−170 °C; [α]1D8 = −218.8 (c = 0.35 in
CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH = 80:20, flow rate 1.0
mL/min, λ = 254 nm) retention time: 4.94 min (minor), 5.92 min
(minor regioisomer), 6.22 min (major), 7.43 min (minor
1
regioisomer). H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz,
1H), 7.65 (d, J = 6.8 Hz, 2H), 7.32- 7.26 (m, 3H), 7.23 (m, 4H), 7.06
(d, J = 3.2 Hz, 2H), 6.75 (t, J = 7.6 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H),
5.08 (s, 1H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 172.3,
157.9, 148.0, 139.8, 132.2, 129.8, 129.4, 128.0, 127.7, 127.6, 127.3,
126.8, 125.7, 123.2, 120.2, 113.9, 87.2, 83.9, 59.8, 27.0. HRMS (ESI-
TOF) calcd for C27H25N2O4 ([M + H+]) = 441.1814, Found
441.1819.
tert-Butyl-4′-(3-fluorophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3b). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 13.7 mg, 30% yield, 98:2 rs, and 99% ee, mp 165−166 °C; [α]D17
= −283.6 (c = 0.28 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.24 min
(minor), 5.91 min (minor regioisomer), 6.85 min (major), 8.85 min
(minor regioisomer).1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4
Hz, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.38−7.30 (m, 3H), 7.26−7.23 (m,
2H), 6.97 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.80−6.77 (m,
2H), 6.35 (d, J = 7.6 Hz, 1H), 5.06 (s, 1H), 1.64 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ = 172.0, 157.6, 147.9, 139.8, 134.7, 130.0, 129.7,
129.7, 129.6, 127.8, 127.0, 126.7, 125.5, 123.8, 123.3, 119.9, 115.2,
115.0, 114.8, 114.6, 114.1, 87.1, 84.0, 59.3, 27.0. HRMS (ESI-TOF)
calcd for C27H24FN2O4 ([M + H+]) = 459.1720, Found 459.1713.
tert-Butyl-4′-(4-fluorophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3c). Purified by flash chro-
matography (petroleum ether:EtOAc = 10:1) to afford a white solid,
Scheme 2. Proposed Catalytic Model for the Asymmetric
1,3-DCR
20.7 mg, 45% yield, 98:2 rs, and 99% ee, mp 161−162 °C; [α]D16
=
−240.1 (c = 0.33 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.47 min
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Note
(minor), 6.29 min (minor regioisomer), 7.54 min (minor
regioisomer), 8.39 min (major).1H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.39−7.27 (m, 4H),
7.06−6.99 (m, 2H), 6.96 (t, J = 8.4 Hz, 2H), 6.81 (t, J = 7.6 Hz, 1H),
6.30 (d, J = 7.6 Hz, 1H), 5.07 (s, 1H), 1.64 (s, 9H). 13C NMR (100
MHz, CDCl3) δ = 172.1, 157.8, 147.9, 139.8, 129.9, 129.8, 129.7,
129.5, 127.7, 127.0, 126.7, 125.6, 123.3, 120.1, 115.3, 115.0, 114.0,
84.0, 59.0, 27.0. HRMS (ESI-TOF) calcd for C27H24FN2O4 ([M +
H+]) = 459.1720, Found 459.1712.
tert-Butyl-4′-(2-chlorophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3d). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 22.7 mg, 48% yield, >99:1 rs, and 96% ee, mp 149−150 °C; [α]D18
= −196.5 (c = 0.41 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.21 min
(minor), 7.92 min (major).1H NMR (400 MHz, CDCl3) δ 7.88 (d, J =
8.4 Hz, 1H), 7.62 (d, J = 7.2 Hz, 2H), 7.38−7.27 (m, 4H), 7.22 (s,
4H), 6.75 (t, J = 7.6 Hz, 1H), 6.19 (d, J = 7.2 Hz, 1H), 5.61 (s, 1H),
1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 172.1, 157.2, 148.0,
140.3, 133.6, 130.5, 129.9, 129.6, 129.4, 128.9, 128.8, 127.8, 127.0,
126.7, 126.2, 124.9, 123.0, 120.3, 114.0, 86.9, 83.8, 56.2, 27.0. HRMS
(ESI-TOF) calcd for C27H2434.9689ClN2O4 ([M + H+]) = 475.1425,
Found 475.1425; HRMS (ESI-TOF) calcd for C27H2436.9659ClN2O4
([M + H+]) = 477.1395, Found 477.1422.
57.0, 27.0. HRMS (ESI-TOF) calcd for C27H2334.9689Cl2N2O4 ([M +
H+]) = 509.1035, Found 509.1032; HRMS (ESI-TOF) calcd for
C27H2336.9659Cl2N2O4 ([M + H+]) = 513.0975, Found 513.0982.
tert-Butyl-4′-(2-bromophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3h). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 25.0 mg, 48% yield, >99:1 rs, and 97% ee, mp 166−167 °C; [α]D16
= −178.3 (c = 0.55 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 6.91 min
(minor) 13.33 min (major).1H NMR (400 MHz, CDCl3) δ 7.88 (d, J
= 8.0 Hz, 1H), 7.62 (d, J = 6.8 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H),
7.37−7.30 (m, 3H), 7.30−7.25 (m, 2H), 7.22 (d, J = 6.4 Hz, 1H), 7.14
(t, J = 7.2 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 6.18 (d, J = 7.6 Hz, 1H),
5.61 (s, 1H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 172.0,
157.3, 148.0, 140.4, 132.2, 132.2, 129.9, 129.6, 129.6, 129.0, 127.8,
126.9, 126.8, 126.7, 125.0, 124.6, 123.0, 120.3, 114.0, 86.9, 83.8, 58.7,
27.0. HRMS (ESI-TOF) calcd for C27H2478.9183BrN2O4 ([M + H+]) =
519.0919, Found 519.0913; HRMS (ESI-TOF) calcd for
C27H2480.9163BrN2O4 ([M + H+]) = 521.0899, Found 521.0898.
tert-Butyl-4′-(3-bromophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3i). Purified by flash chro-
matography (petroleum ether:EtOAc = 10:1) to afford a white solid,
33.7 mg, 65% yield, 68:32 rs, and 99% ee, mp 148−150 °C. HPLC
(Chiralpak IA, hexane/i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254
nm) retention time: 4.93 min (minor), 6.01 min (minor regioisomer),
6.57 min (major), 8.40 min (minor regioisomer).1H NMR (400 MHz,
CDCl3) δ 7.89 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.59−7.47
(m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.15−7.12
(m, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.32 (d, J =
7.6 Hz, 1H), 5.01 (s, 1H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ = 171.9, 157.6, 147.9, 139.8, 134.5, 130.9, 130.8, 130.1, 129.6, 129.6,
127.8, 127.0, 126.7, 126.5, 125.6, 123.3, 122.2, 119.8, 114.1, 87.1, 84.1,
59.2, 27.0. HRMS (ESI-TOF) calcd for C27H2478.9183BrN2O4 ([M +
H+]) = 519.0919, Found 519.0912; HRMS (ESI-TOF) calcd for
C27H2480.9163BrN2O4 ([M + H+]) = 521.0899, Found 521.0914.
tert-Butyl-4′-(4-bromophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3j). Purified by flash chro-
matography (petroleum ether:EtOAc = 10:1) to afford a white solid,
tert-Butyl-4′-(3-chlorophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3e). Purified by flash chro-
matography (petroleum ether:EtOAc = 10:1) to afford a white solid,
21.0 mg, 44% yield, 96:4 rs, and 99% ee, mp 162−164 °C; [α]D11
=
−279.4 (c = 0.25 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 9.15 min
(minor), 10.20 min (minor regioisomer), 10.92 min (major), 13.14
min (minor regioisomer).1H NMR (400 MHz, CDCl3) δ 7.82 (d, J =
8.2 Hz, 1H), 7.59−7.54 (m, 2H), 7.31−7.21 (m, 4H), 7.19 (s, 1H),
7.14 (t, J = 7.7 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.75 (t,
J = 7.6 Hz, 1H), 6.25 (d, J = 7.6 Hz, 1H), 4.96 (s, 1H), 1.57 (s, 9H).
13C NMR (100 MHz, CDCl3) δ = 172.0, 157.6, 147.9, 139.8, 134.2,
134.1, 130.1, 129.6, 129.3, 128.1, 127.9, 127.8, 126.8, 126.7, 126.2,
125.6, 123.3, 119.7, 114.1, 87.1, 84.1, 59.2, 27.0. HRMS (ESI-TOF)
calcd for C27H2334.9689ClN2NaO4 ([M + Na+]) = 497.1244, Found
497.1243; HRMS (ESI-TOF) calcd for C27H2336.9659ClN2NaO4 ([M +
Na+]) = 499.1214, Found 499.1130.
21.8 mg, 42% yield, 92:8 rs, and >99% ee, mp 166−168 °C; [α]D17
=
−270.6 (c = 0.33 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.66 min
(minor), 6.79 min (minor regioisomer), 7.68 min (minor
regioisomer), 8.94 min (major).1H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H),
7.37−7.28 (m, 4H), 6.93 (d, J = 8.0 Hz, 2H), 6.84 (t, J = 7.6 Hz, 1H),
6.33 (d, J = 7.6 Hz, 1H), 5.04 (s, 1H), 1.64 (s, 9H). 13C NMR (100
MHz, CDCl3) δ = 172.0, 157.6, 147.9, 139.8, 131.3, 130.0, 129.7,
129.6, 127.8, 126.9, 126.7, 125.6, 123.4, 121.7, 119.9, 114.1, 87.0, 84.0,
59.1, 27.0. HRMS (ESI-TOF) calcd for C27H2478.9183BrN2O4 ([M +
H+]) = 519.0919, Found 519.0926; HRMS (ESI-TOF) calcd for
C27H2480.9163BrN2O4 ([M + H+]) = 521.0899, Found 521.0923.
tert-Butyl-2-oxo-3′-phenyl-4′-(m-tolyl)-4′H-spiro[indoline-3,5′-
isoxazole]-1-carboxylate (3k). Purified by flash chromatography
(petroleum ether:EtOAc = 10:1) to afford a white solid, 17.7 mg,
40% yield, 98:2 rs, and >99% ee, mp 148−150 °C; [α]1D7 = −249.5 (c =
0.39 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH = 80:20, flow
rate 1.0 mL/min, λ = 254 nm) retention time: 4.65 min (minor), 5.24
min (minor regioisomer), 5.48 min (minor regioisomer), 5.10 min
(major).1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 1H),
7.70−7.61 (m, 2H), 7.35−7.23 (m, 4H), 7.14 (t, J = 7.8 Hz, 1H), 7.07
(d, J = 7.2 Hz, 1H), 6.86 (s, 2H), 6.76 (t, J = 7.6 Hz, 1H), 6.28 (d, J =
7.6 Hz, 1H), 5.01 (s, 1H), 2.24 (s, 3H), 1.64 (s, 9H). 13C NMR (100
MHz, CDCl3) δ = 172.3, 158.2, 148.0, 139.8, 137.8, 132.0, 129.8,
129.3, 128.6, 128.3, 127.9, 127.6, 127.4, 126.8, 125.8, 125.2, 123.1,
120.2, 113.8, 87.2, 83.9, 59.7, 27.0, 20.3. HRMS (ESI-TOF) calcd for
C28H27N2O4 ([M + H+]) = 455.1971, Found 455.1970.
tert-Butyl-4′-(4-chlorophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3f). Purified by flash chro-
matography (petroleum ether:EtOAc = 10:1) to afford a white solid,
15.0 mg, 31% yield, 94:6 rs, and 99% ee, mp 164−165 °C; [α]D18
=
−256.2 (c = 0.29 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.44 min
(minor), 6.45 min (minor regioisomer), 7.40 min (minor
regioisomer), 8.62 min (major).1H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.40−7.27 (m, 4H), 7.25
(d, J = 10.8 Hz, 3H), 6.99 (d, J = 8.0 Hz, 2H), 6.83 (t, J = 7.6 Hz, 1H),
6.33 (d, J = 7.6 Hz, 1H), 5.05 (s, 1H), 1.64 (s, 9H). 13C NMR (100
MHz, CDCl3) δ = 172.0, 157.7, 147.9, 139.8, 133.6, 130.8, 130.0,
129.6, 129.4, 128.3, 127.8, 127.0, 126.7, 125.6, 123.4, 120.0, 114.1,
87.01, 84.0, 59.1, 27.0. HRMS (ESI-TOF) calcd for
C27H2434.9689ClN2O4 ([M + H+]) = 475.1425, Found 475.1417;
HRMS (ESI-TOF) calcd for C27H2436.9659ClN2O4 ([M + H+]) =
477.1395, Found 477.1453.
tert-Butyl-4′-(2,6-dichlorophenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3g). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 27.1 mg, 53% yield, >99:1 rs, and 99% ee, mp 178−180 °C; [α]D18
= −386.6 (c = 0.37 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 7.55 min
(minor), 9.49 min (major).1H NMR (400 MHz, CDCl3) δ 7.86 (d, J =
8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.36−
7.19 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 7.11−7.04 (m, 1H), 6.91 (t, J =
7.6 Hz, 1H), 5.95 (s, 1H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ = 172.6, 156.6, 147.9, 140.0, 135.4, 135.3, 130.1, 129.7, 129.5, 129.1,
129.1, 128.0, 127.7, 127.5, 125.8, 125.2, 123.5, 121.0, 114.2, 87.4, 83.8,
tert-Butyl-2-oxo-3′-phenyl-4′-(p-tolyl)-4′H-spiro[indoline-3,5′-iso-
xazole]-1-carboxylate (3l). Purified by flash chromatography
(petroleum ether:EtOAc = 10:1) to afford a white solid, 15.7 mg,
35% yield, >99:1 rs, and 97% ee, mp 180−181 °C; [α]1D8 = −288.8 (c =
7707
dx.doi.org/10.1021/jo5012625 | J. Org. Chem. 2014, 79, 7703−7710

The Journal of Organic Chemistry
Note
0.24 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH = 90:10, flow
rate 1.0 mL/min, λ = 254 nm) retention time: 6.10 min (minor), 9.29
min (major),.1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 1H),
7.65 (d, J = 6.8 Hz, 2H), 7.26−7.30 (m, 3H), 7.23−7.26 (m, 2H), 7.06
(d, J = 7.6 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 6.77 (t, J = 7.6 Hz, 1H),
6.33 (d, J = 7.6 Hz, 1H), 5.04 (s, 1H), 2.29 (s, 3H), 1.63 (s, 9H). 13C
NMR (100 MHz, CDCl3) δ = 172.3, 158.1, 148.0, 139.8, 137.4, 129.7,
129.3, 129.0, 128.7, 128.0, 127.6, 127.4, 126.8, 125.9, 123.2, 120.3,
113.8, 87.1, 83.9, 59.5, 27.0, 20.1. HRMS (ESI-TOF) calcd for
C28H27N2O4 ([M + H+]) = 455.1971, Found 455.1965.
121.1, 114.9, 88.2, 85.0, 61.0, 28.1. HRMS (ESI-TOF) calcd for
C31H27N2O4 ([M + H+]) = 491.1971, Found 491.1975.
tert-Butyl-5-fluoro-2-oxo-3′,4′-diphenyl-4′H-spiro[indoline-3,5′-
isoxazole]-1-carboxylate (3q). Purified by flash chromatography
(petroleum ether:EtOAc = 10:1) to afford a white solid, 11.2 mg,
35% yield, 98:2 rs, and >99% ee, mp 164−165 °C; [α]1D6 = −286.2 (c =
0.21 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH = 80:20, flow
rate 1.0 mL/min, λ = 254 nm) retention time: 4.67 min (minor), 5.55
min (minor regioisomer), 6.17 min (major).1H NMR (400 MHz,
CDCl3) δ 7.79 (dd, J = 9.0, 4.5 Hz, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.28
(dd, J = 8.8, 4.3 Hz, 2H), 7.24−7.22 (m, 3H), 7.19 (s, 1H), 7.03−6.95
(m, 2H), 6.88 (td, J = 8.8, 2.7 Hz, 1H), 5.91 (dd, J = 8.2, 2.7 Hz, 1H),
5.03 (s, 1H), 1.56 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 171.9,
159.5, 157.9, 147.9, 131.7, 129.5, 128.3, 127.9, 127.7, 127.0, 126.8,
122.1, 116.5, 116.3, 115.3, 115.2, 113.2, 113.0, 86.8, 84.1, 60.0, 27.0.
HRMS (ESI-TOF) calcd for C27H24FN2O4 ([M + H+]) = 459.1720,
Found 459.1715.
tert-Butyl-2-oxo-3′-phenyl-4′-(4-(trifluoromethyl)phenyl)-4′H-
spiro[indoline-3,5′-isoxazole]-1-carboxylate (3m). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 16.2 mg, 32% yield, 99:1 rs, and >99% ee, mp 175−176 °C; [α]D17
= −269.9 (c = 0.31 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 4.87 min
1
(minor), 5.54 min (minor regioisomer), 7.06 min (major). H NMR
(400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.4 Hz,
2H), 7.53 (d, J = 8.0 Hz, 2H), 7.39−7.29 (m, 3H), 7.27 (d, J = 6.8 Hz,
1H), 7.18 (d, J = 7.8 Hz, 2H), 6.78 (t, J = 7.6 Hz, 1H), 6.24 (d, J = 7.6
Hz, 1H), 5.14 (s, 1H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ =
171.9, 157.4, 147.9, 139.8, 136.4, 130.1, 129.7, 128.5, 127.8, 126.8,
126.7, 125.4, 125.0, 125.0, 123.3, 119.7, 114.1, 87.2, 84.1, 59.3, 27.0.
HRMS (ESI-TOF) calcd for C28H24F3N2O4 ([M + H+]) = 509.1688,
Found 509.1681.
tert-Butyl-4′-(3-methoxyphenyl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3n). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 18.5 mg, 40% yield, 90:10 rs, and >99% ee, mp 146−148 °C;
[α]1D7 = −259.4 (c = 0.39 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-
PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time:
5.54 min (minor), 6.25 min (minor regioisomer), 6.98 min (major),
8.58 min (minor regioisomer).1H NMR (400 MHz, CDCl3) δ 7.85 (t,
J = 10.0 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.36−7.28 (m, 3H), 7.25
(d, J = 7.2 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.79 (t, J = 7.4 Hz, 2H),
6.66 (d, J = 7.4 Hz, 1H), 6.57 (s, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.03
(s, 1H), 3.68 (s, 3H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ =
172.3, 159.0, 157.9, 148.0, 139.8, 133.6, 129.8, 129.4, 129.1, 127.7,
127.3, 126.7, 125.7, 123.3, 120.4, 120.2, 113.9, 113.7, 112.9, 87.1, 83.9,
59.7, 54.3, 27.0. HRMS (ESI-TOF) calcd for C28H27N2O5 ([M + H+])
= 471.1920, Found 471.1924.
tert-Butyl-2-oxo-4′-(3-phenoxyphenyl)-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3o). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 21.6 mg, 41% yield, >99:1 rs, and 97% ee, mp 165−167 °C; [α]D17
= −307.0 (c = 0.36 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.48 min
(minor), 5.94 min (major).1H NMR (400 MHz, CDCl3) δ 7.90 (d, J =
8.2 Hz, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.41−7.30 (m, 4H), 7.25 (d, J =
3.6 Hz, 1H), 7.23−7.18 (m, 2H), 7.05 (t, J = 7.3 Hz, 1H), 6.99−6.87
(m, 2H), 6.87−6.82 (m, 1H), 6.67 (d, J = 7.9 Hz, 2H), 6.62 (s, 1H),
6.45 (d, J = 7.5 Hz, 1H), 5.05 (s, 1H), 1.63 (s, 9H). 13C NMR (100
MHz, CDCl3) δ = 172.2, 157.4, 156.5, 155.7, 147.9, 139.8, 134.1,
129.9, 129.5, 129.4, 128.7, 127.7, 127.1, 126.8, 125.7, 123.2, 122.8,
122.3, 120.4, 118.6, 118.3, 117.4, 114.0, 87.2, 84.0, 59.7, 27.0. HRMS
(ESI-TOF) calcd for C33H29N2O5 ([M + H+]) = 533.2076, Found
533.2079.
tert-Butyl-5-bromo-2-oxo-3′,4′-diphenyl-4′H-spiro[indoline-3,5′-
isoxazole]-1-carboxylate (3r). Purified by flash chromatography
(petroleum ether:EtOAc = 10:1) to afford a white solid, 15.5 mg,
44% yield, 96:4 rs, and 96% ee, mp 164−166 °C; [α]1D6 = −118.7 (c =
0.29 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH = 80:20, flow
rate 1.0 mL/min, λ = 254 nm) retention time: 4.89 min (minor), 5.52
min (minor regioisomer), 5.88 min (minor regioisomer), 6.69 min
(major).1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.6 Hz, 1H), 7.65
(d, J = 7.4 Hz, 2H), 7.39−7.34 (m, 2H), 7.32 (d, J = 2.7 Hz, 4H), 7.26
(s, 1H), 7.04 (d, J = 4.1 Hz, 2H), 6.32 (s, 1H), 5.08 (s, 1H), 1.63 (s,
9H). 13C NMR (100 MHz, CDCl3) δ = 171.5, 157.8, 147.8, 138.7,
132.6, 131.7, 129.5, 128.9, 128.3, 127.9, 127.7, 127.0, 126.8, 122.3,
116.2, 115.5, 86.8, 84.3, 60.0, 27.0. HRMS (ESI-TOF) calcd for
C27H2478.9183BrN2O4 ([M + H+]) = 519.0919, Found 519.0922;
HRMS (ESI-TOF) calcd for C27H2480.9163BrN2O4 ([M + H+]) =
521.0899, Found 521.0956.
tert-Butyl-5-methoxy-2-oxo-3′,4′-diphenyl-4′H-spiro[indoline-
3,5′-isoxazole]-1-carboxylate (3s). Purified by flash chromatography
(petroleum ether:EtOAc = 10:1) to afford a white solid, 18.0 mg, 38%
yield, 94:6 rs, and 97% ee, mp 168−170 °C; [α]1D6 = −199.2 (c = 0.37
in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH = 80:20, flow rate
1.0 mL/min, λ = 254 nm) retention time: 5.60 min (minor), 7.33 min
(minor regioisomer), 8.39 min (major).1H NMR (400 MHz, CDCl3)
δ 7.78 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.35 (dd, J = 12.8,
6.0 Hz, 2H), 7.30 (d, J = 7.0 Hz, 4H), 7.08 (s, 2H), 6.79 (dd, J = 9.0,
2.6 Hz, 1H), 5.79 (d, J = 2.4 Hz, 1H), 5.08 (s, 1H), 3.34 (s, 3H), 1.63
(s, 9H). 13C NMR (100 MHz, CDCl3) δ = 172.3, 158.0, 155.2, 148.1,
133.1, 132.3, 129.4, 128.2, 128.1, 127.7, 127.6, 127.2, 126.8, 121.0,
116.7, 115.0, 110.0, 87.1, 83.7, 59.7, 54.3, 27.0. HRMS (ESI-TOF)
calcd for C28H27N2O5 ([M + H+]) = 471.1920, Found 471.1920.
tert-Butyl-3′-(4-fluorophenyl)-2-oxo-4′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3t). Purified by flash chro-
matography (petroleum ether:EtOAc = 10:1) to afford a white solid,
27.4 mg, 60% yield, 96:4 rs, and 97% ee, mp 94−95 °C; [α]1D1 = −209.8
(c = 0.54 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH = 80:20,
flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.61 min (minor),
6.69 min (minor regioisomer), 7.01 min (major), 7.91 min (minor
regioisomer).1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 1H),
7.64 (dd, J = 8.6, 5.3 Hz, 2H), 7.26 (dd, J = 10.0, 6.8 Hz, 4H), 7.15−
7.01 (m, 3H), 6.99 (d, J = 8.6 Hz, 2H), 6.75 (t, J = 7.4 Hz, 1H), 6.27
(d, J = 7.6 Hz, 1H), 5.04 (s, 1H), 1.64 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ = 172.3, 157.0, 147.9, 139.8, 131.9, 129.9, 128.8, 128.7,
128.1, 128.0, 127.7, 125.7, 123.2, 120.0, 115.0, 114.8, 113.9, 87.2, 84.0,
59.7, 27.0. HRMS (ESI-TOF) calcd for C27H23FKN2O4 ([M + K+]) =
497.1279, Found 497.1273.
tert-Butyl-4′-(naphthalen-2-yl)-2-oxo-3′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3p). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 19.5 mg, 40% yield, 71:29 rs, and 93% ee, mp 165−166 °C.
HPLC (Chiralpak ID, hexane/i-PrOH = 80:20, flow rate 1.0 mL/min,
λ = 254 nm) retention time: 11.73 min (minor), 13.13 min (major),
tert-Butyl-3′-(3-chlorophenyl)-2-oxo-4′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3u). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 20.8 mg, 44% yield, >99:1 rs, and 87% ee, mp 136−138 °C; [α]D11
= −243.8 (c = 0.40 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 4.86 min
(minor), 6.07 min (major).1H NMR (400 MHz, CDCl3) δ 7.87 (d, J =
8.0 Hz, 1H), 7.72 (t, J = 1.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.38−
1
15.77 min (minor regioisomer), 20.11 min (minor regioisomer). H
NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 1H), 7.73−7.71 (m,
1H), 7.67−7.64 (m, 2H), 7.62−7.59 (m, 2H), 7.55−7.51 (m, 2H),
7.42−7.39 (m, 2H), 7.25−7.23 (m, 2H), 7.13−7.10 (m, 1H), 7.07−
7.02 (m, 1H), 6.52 (t, J = 7.6 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 5.15
(s, 1H), 1.58 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 173.3, 159.2,
149.1, 140.9, 133.2, 133.0, 130.8, 130.4, 129.0, 128.7, 127.8, 126.7,
7708
dx.doi.org/10.1021/jo5012625 | J. Org. Chem. 2014, 79, 7703−7710

The Journal of Organic Chemistry
Note
7.30 (m, 2H), 7.30−7.28 (m, 2H), 7.26−7.19 (m, 2H), 7.08−7.00 (m,
2H), 6.76 (t, J = 7.6 Hz, 1H), 6.26 (d, J = 7.6 Hz, 1H), 5.03 (s, 1H),
1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 172.1, 157.0, 147.9,
139.8, 133.7, 131.6, 129.9, 129.4, 129.0, 128.9, 128.2, 128.0, 127.8,
126.6, 125.7, 124.9, 123.2, 119.8, 113.9, 87.4, 84.0, 59.4, 27.0. HRMS
(ESI-TOF) calcd for C27H2334.9689ClN2NaO4 ([M + Na+]) = 497.1244,
Found 497.1239; HRMS (ESI-TOF) calcd for C27H2336.9659ClN2NaO4
([M + Na+]) = 499.1214, Found 499.1093.
tert-Butyl-2-oxo-4′-phenyl-3′-(4-(trifluoromethyl)phenyl)-4′H-
spiro[indoline-3,5′-isoxazole]-1-carboxylate (3z). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 26.0 mg, 53% yield, 99:1 rs, and 92% ee, mp 108−110 °C; [α]D16
= −197.2 (c = 0.46 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.45 min
(minor), 6.57 min (major), 7.27 min (minor regioisomer), 8.12 min
(minor regioisomer).1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.0
Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.29−7.28
(m, 2H), 7.27−7.25 (m, 2H), 7.08−7.00 (m, 2H), 6.77 (t, J = 7.6 Hz,
1H), 6.29 (d, J = 7.6 Hz, 1H), 5.08 (s, 1H), 1.64 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ = 172.1, 156.9, 147.9, 139.9, 131.6, 130.0, 128.2,
128.0, 127.9, 126.9, 125.7, 124.7, 124.6, 123.3, 119.8, 114.0, 87.6, 84.1,
59.4, 27.0. HRMS (ESI-TOF) calcd for C28H23F3KN2O4 ([M + K+]) =
547.1242, Found 547.1233.
tert-Butyl-3′-(4-methoxyphenyl)-2-oxo-4′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3aa). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 20.4 mg, 43% yield, 90:10 rs, and 95% ee, mp 131−132 °C; [α]D13
= −238.1 (c = 0.40 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 6.406 min
(minor), 7.64 min (minor regioisomer), 8.77 min (major), 9.942 min
(minor regioisomer).1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.2
Hz, 1H), 7.63−7.55 (m, 2H), 7.27−7.24 (m, 4H), 7.05 (m, 2H),
6.85−6.79 (m, 2H), 6.75 (m, 1H), 6.27 (dd, J = 7.6, 0.8 Hz, 1H), 5.05
(s, 1H), 3.78 (s, 3H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ =
172.4, 160.2, 157.5, 148.0, 139.8, 132.3, 129.7, 128.4, 128.1, 128.0,
127.5, 125.7, 123.1, 120.4, 119.7, 113.8, 113.1, 86.9, 83.9, 60.0, 54.3,
27.0. HRMS (ESI-TOF) calcd for C28H26N2NaO5 ([M + Na+]) =
493.1739, Found 493.1740.
tert-Butyl-3′-(4-chlorophenyl)-2-oxo-4′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3v). Purified by flash chro-
matography (petroleum ether:EtOAc = 10:1) to afford a white solid,
24.5 mg, 52% yield, >99:1 rs, and 92% ee, mp 89−90 °C; [α]D16
=
−217.2 (c = 0.41 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.48 min
(minor), 7.32 min (major).1H NMR (400 MHz, CDCl3) δ 7.87 (d, J =
8.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.33−7.24 (m, 7H), 7.03 (d, J =
3.6 Hz, 2H), 6.76 (t, J = 7.6 Hz, 1H), 6.28 (d, J = 7.6 Hz, 1H), 5.04 (s,
1H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 172.2, 157.0,
147.9, 139.8, 135.4, 131.8, 129.9, 128.2, 128.0, 128.0, 128.0, 127.7,
125.8, 125.7, 123.2, 120.0, 113.9, 87.4, 84.0, 59.6, 27.0. HRMS (ESI-
TOF) calcd for C27H2334.9689ClN2NaO4 ([M + Na+]) = 497.1244,
F o u n d 4 9 7 . 1 2 4 4 ; H R M S ( E S I - T O F ) c a l c d f o r
C27H2336.9659ClN2NaO4 ([M + Na+]) = 499.1214, Found 499.1126.
tert-Butyl-3′-(3-bromophenyl)-2-oxo-4′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3w). Purified by flash
chromatography (petroleum ether:EtOAc = 10:1) to afford a white
solid, 23.7 mg, 46% yield, 95:5 rs, and 99% ee, mp 170−172 °C; [α]D14
= −180.6 (c = 0.32 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH
= 95:5, flow rate 1.0 mL/min, λ = 254 nm) retention time: 7.97 min
(minor), 10.56 min (minor regioisomer), 11.62 min (major).1H NMR
(400 MHz, CDCl3) δ 7.90 (t, J = 1.6 Hz, 1H), 7.87 (d, J = 8.4 Hz,
1H), 7.48 (dd, J = 8.0, 1.5 Hz, 2H), 7.28 (m, 4H), 7.17 (t, J = 8.0 Hz,
1H), 7.09−6.97 (m, 2H), 6.81−6.71 (m, 1H), 6.33−6.21 (m, 1H),
5.02 (s, 1H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 172.1,
156.91, 147.9, 139.8, 132.3, 131.6, 129.9, 129.5, 129.3, 129.2, 128.2,
128.0, 127.8, 125.7, 125.3, 123.2, 121.8, 119.8, 113.9, 87.4, 84.0, 59.4,
27.0. HRMS (ESI-TOF) calcd for C27H2378.9183BrN2NaO4 ([M +
Na+]) = 541.0739, Found 541.0742; HRMS (ESI-TOF) calcd for
C27H2380.9163BrN2NaO4 ([M + Na+]) = 543.0719, Found 543.0709.
tert-Butyl-3′-(4-bromophenyl)-2-oxo-4′-phenyl-4′H-spiro-
[indoline-3,5′-isoxazole]-1-carboxylate (3x). Purified by flash chro-
matography (petroleum ether:EtOAc = 10:1) to afford a white solid,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Full optimization details, H and 13C NMR spectra, HPLC
analyses for all the products, and X-ray crystal data of
compound 3h (CIF) are available. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xmfeng@scu.edu.cn
■
25.3 mg, 49% yield, >99:1 rs, and 93% ee, mp 140−142 °C; [α]D16
=
Notes
−201.6 (c = 0.43 in CH2Cl2). HPLC (Chiralpak IA, hexane/i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm) retention time: 5.73 min
(minor), 7.81 min (major).1H NMR (400 MHz, CDCl3) δ 7.86 (d, J =
8.4 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.27−
7.26 (m, 2H), 7.24 (m, 2H), 7.03−7.02 (m, 2H), 6.75 (t, J = 7.6 Hz,
1H), 6.27 (d, J = 7.6 Hz, 1H), 5.04 (s, 1H), 1.64 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ = 172.2, 157.1, 147.9, 139.8, 131.8, 130.9, 129.9,
128.2, 128.1, 128.0, 127.7, 126.2, 125.7, 123.8, 123.2, 120.0, 113.9,
87.4, 84.0, 59.5, 27.0. HRMS (ESI-TOF) calcd for C27H2378.9183BrN2-
NaO4 ([M + Na+]) = 541.0739, Found 541.0743; HRMS (ESI-TOF)
calcd for C27H2380.9163BrN2NaO4 ([M + Na+]) = 543.0719, Found
543.0611.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate the National Natural Science Foundation of
China (Nos. 21290182, 21172151), the Ministry of Education
(No. 20110181130014), and the National Basic Research
Program of China (2011CB808600) for financial support.
REFERENCES
■
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