AlCl3-promoted selective michael addition with allenoate and methyleneindolinone: Synthesis of spirocyclic oxindole by using allenoate as a four-carbon component building block

Article abstract of DOI:10.1021/jo502209f

The AlCl₃-promoted cyclization of readily available allenoates with methyleneindolinone is disclosed. The present strategy provides a rapid access to spirocyclic oxindole-cyclohexenones in an efficient manner. Remarkably, the allenoate is implemented as a four-carbon (4C) component to form the ring, which shows high synthetic efficiency. Flexibility of this method allows quick synthesis of spirocyclic oxindole-dihydropyrans by varying one of the components. It is also noteworthy that AlCl₃ serves as the chlorine source as well as an effective catalyst to facilitate this interesting transformation.

Full text of DOI:10.1021/jo502209f

Article
pubs.acs.org/joc
AlCl3‑Promoted Selective Michael Addition with Allenoate and
Methyleneindolinone: Synthesis of Spirocyclic Oxindole by Using
Allenoate as a Four-Carbon Component Building Block
Shibo Xu,† Chunju Li,† Xueshun Jia,*,†,‡ and Jian Li*,†
†Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
‡CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The AlCl3-promoted cyclization of readily available allenoates with methyleneindolinone is disclosed. The present
strategy provides a rapid access to spirocyclic oxindole-cyclohexenones in an efficient manner. Remarkably, the allenoate is
implemented as a four-carbon (4C) component to form the ring, which shows high synthetic efficiency. Flexibility of this method
allows quick synthesis of spirocyclic oxindole-dihydropyrans by varying one of the components. It is also noteworthy that AlCl3
serves as the chlorine source as well as an effective catalyst to facilitate this interesting transformation.
antitumor, and antibacterial properties.2 Enormous efforts have
been dedicated to the efficient and selective construction of this
Spirocyclic oxindole represents a privileged synthetic motif in a
core skeleton. As such, transition metal-catalyzed synthesis
INTRODUCTION
■
large family of clinical pharmaceuticals and natural products
including welwitindolinone A, horsfiline, paraherquamide A,
involving a domino approach, as well as C−H activation, has
been widely documented.3 More recently, organocatalyzed
and citrinadin A (Scheme 1).1 These compounds often showed
reactions and Lewis acid-promoted annulation have emerged as
attractive synthetic strategies.4,5 Although considerable progress
a broad range of biological activities such as insecticidal,
has been described toward their syntheses, developing a novel
method to efficiently synthesize this core structure remains
valuable.
Scheme 1. Natural Products Possessing Spirooxindole as a
Core Structure
In recent decades, allenoate has received significant interests
in organic synthesis due to its facile preparation and versatile
reactivity.6 For instance, nucleophilic addition and electrophilic
addition reactions with a wide range of substances, as well as
rearrangements, have been well-documented.7,8 In particular,
they were proven to be valuable building blocks in many types
of cycloaddition reactions.9 In this field, the phosphine-
catalyzed cycloaddition reaction is of great interest due to
simple reagents and structural diversity of the adduct (Scheme
2a).10 The first example of phosphine-catalyzed [3 + 2]
cycloaddition reaction could be dated back to the work of
Zhang and Lu in 1995.11 Following this pioneering work, Zhu
et al.12 reported another important variant [4 + 2] cyclo-
addition. After that, a large number of asymmetric versions as
Received: September 26, 2014
© XXXX American Chemical Society
A
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Scheme 2. Representative Cyclization Reactions Involving
Allenoate and Electron-Deficient Species with Different
Reagents
Table 1. Optimization for Cyclization of Allenoate 1a with
Methyleneindolinone 2a
a
b
entry
Lewis acid
MXn (equiv)
solvent
temp (°C) yield (%)
1
AlCl3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.5
1.5
1.5
1.5
1.5
1.5
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
toluene
THF
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
80
38
2
FeCl3
CuCl2
SnCl2·2H2O
BiCl3
c
3
d
4
NR
c
5
6
TMSCl
ZnCl2
InCl3
d
7
NR
trace
46
8
9
AlCl3
10
11
12
13
14
15
AlCl3
53
AlCl3
33
AlCl3
rt
trace
trace
35
well as applications in natural product synthesis were fully
investigated.13,14 In 2011, we reported an unprecedented [2 + 2
+ 1] cycloaddition involving allenoate by using isocyanide as
nucleophile instead of phosphine (Scheme 2b).15 In such case,
the allenoate and electron-deficient carbonyl-containing isatin
in the presence of isocyanide gave quick access to
spirooxindole. Replacement of the carbonyl group with reactive
carbon−carbon double bond also worked well,16a,b and thus a
new class of multicomponent [2 + 2+1] cycloaddition reaction
was successfully developed. More recently, we also found a
novel [1,5]-hydride shift when α-substituted allenoate was
used.16c Mechanistically, the above-mentioned cycloaddition
reactions begin with nuclophilic addition toward allenoate,
while isocyanide or phosphine acts as a good nucleophile to
trigger the subsequent annulation. We thus envisioned that
other nucleophiles may also be used to react with allenoate to
bring us structurally novel skeletons.16d,e Herein we report that,
in the presence of AlCl3, an unexpected cyclization of allenoate
and methyleneindolinone takes place to afford spirocyclic
oxindole (Scheme 2c).
AlCl3
reflux
reflux
reflux
AlCl3
AlCl3
NR
a
Reaction conditions: allenoate 1a (0.6 mmol), methyleneindolinone
b
2a (0.5 mmol), and Lewis acid in 5 mL of solvent. Yield of product
c
after silica gel chromatography. Complex mixture was detected.
d
Isomerization of substrate 2a was detected.
With the optimal reaction conditions in hand, we sought to
briefly investigate the feasibility of methyleneindolinone 2
bearing different substitution patterns. As shown in Table 2,
various methyleneindolinones 2 having electron-neutral (Table
2, entry 1), electron-deficient (Table 2, entries 2−4, 7, and 8),
and electron-rich substituents (Table 2, entries 5 and 6) on the
Table 2. AlCl3-Promoted Cyclization of Allenoate 1a with
Substituted Methyleneindolinone 2
a
RESULTS AND DISCUSSION
■
Treatment of ethyl 2,3-butadienoate 1a and methyleneindoli-
none 2a with AlCl3 and dichloroethylene (DCE) afforded a
new cyclization product 3a in 38% yield (Table 1, entry 1).
Following this encouraging result, several chloride-containing
Lewis acids, such as FeCl3, BiCl3, and trimethylsilyl chloride
(TMSCl) as well as ZnCl2, were subsequently evaluated.
However, replacement of AlCl3 with these metal chlorides did
not display any reactivity and no desired product was obtained
(Table 1, entries 2−7). The use of InCl3 resulted in only a trace
amount of 3a (Table 1, entry 8). Further experiments also
demonstrated that the amount of AlCl3 had a significant
influence. The isolated yield was improved to 53% when 1.5
equiv of AlCl3 was used (Table 1, entry 10). Lower temperature
(80 °C or room temperature) dramatically decreased the
efficiency of the annulation. Subsequent solvent screening
revealed that DCE was the most suitable medium for the
reaction while toluene gave lower efficiency; other polar
solvents such as tetrahydrofuran (THF) and CH3CN resulted
in either a trace amount or none of the desired product.
b
entry
R1
R
time (h)
product
yield (%)
1
H
Me
Me
Me
Me
Me
Me
Me
Me
H
20
12
15
12
12
12
12
12
20
20
20
3a
3b
3c
3d
3e
3f
53
56
61
50
46
49
60
68
32
43
NR
2
5-F
3
5-Cl
5-Br
5-CH3
5-CH3O
4-Br
6-Br
H
4
5
6
7
3g
3h
3i
8
9
10
11
H
Bn
Ac
3j
H
a
Reaction conditions: allenoate 1a (0.6 mmol), 0.5 mmol methyl-
eneindolinone 2 (0.5 mmol), and 1.5 equiv of AlCl3in DCE (5 mL)
b
under reflux. Isolated yields.
B
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aryl ring were employed to correlate with the substitution
effect. Gratifyingly, all substrates performed well with allenoate
1a under optimal conditions (see Supporting Information for
details). The structure of 3a (CCDC 1014495) was
unambiguously confirmed by single-crystal X-ray analysis (see
Supporting Information).17 Experiments to examine the
influence of different protecting groups at the nitrogen of
methyleneindolinone 2 were also conducted (Table 2, entries
9−11). Lower yield was obtained when methyleneindolinone 2
was free of a protecting group, while a complex mixture was
found if the nitrogen was masked with an acetyl group (Table
2, entry 11).
Scheme 3. Proposed Mechanism
To further demonstrate the scope and limitations of the
above formal [4 + 2] annulation, we then focused our attention
on the utilization of allenoates bearing different substitution
patterns. As shown in Table 3, a series of structurally varied
Table 3. AlCl3-Promoted Cyclization of
Methyleneindolinone 2a with Substituted Allenoate 1
a
derived from AlCl3. With the aid of aluminum, the ethoxy
group can act as a leaving group to facilitate the key
Dieckmann-type transformation, presented in the proposed
transition state C, which leads to the final cyclization product 3.
To further demonstrate the versatility of the present method,
the structurally varied methyleneindolinones 5 were also tested
under standard reaction conditions. In this case, however, no
corresponding cyclization product was obtained (Table 4). In
b
entry
R2
CH3
time (h)
product
yield (%)
Table 4. AlCl3-Promoted Michael Addition of
a
1
2
24
24
36
24
24
36
36
36
36
24
4a
4b
4c
4d
4e
4f
57
50
75
73
45
55
51
63
43
60
Methyleneindolinone 5 with Allenoate 1
Bn
3
4-NO2Bn
3-NO2Bn
2-NO2Bn
3-FBn
4
5
6
7
3-ClBn
4-BrBn
4-CH3Bn
2-CH3Bn
4g
4h
4i
8
9
10
4j
b
entry
R2
R3
R4
Ph
time (h) product yield (%)
a
Reaction conditions: allenoate 1 (0.6 mmol), methyleneindolinone
1
2
3
4
5
6
7
8
9
H
H
20
15
15
20
20
20
20
24
24
6a
6b
6c
6d
6e
6f
72
73
75
61
79
75
66
61
72
2a (0.5 mmol), and 1.5 equiv of AlCl3 in DCE (5 mL) under reflux.
b
H
H
4-FPh
4-ClPh
4-BrPh
Ph
Isolated yields.
H
H
H
H
allenoates 1 were used under the standard reaction conditions.
To our delight, all reactions proceeded well to produce the
corresponding products 4 (Table 3). When R2 was changed
from Me to CH2Ph (Bn) and other substituents, the yields did
not decreased significantly. For instance, the reaction of 4-
NO2Bn-substituted allenoate and methyleneindolinone 2a
produced 4c in 75% yield (Table 3, entry 3). Moreover, the
structure of 4c (CCDC 1014497) was unambiguously
confirmed by single-crystal X-ray analysis (see Supporting
Information).18
Although the mechanism of the above cyclization reaction
has not been unequivocally established, one reasonable pathway
is outlined in Scheme 3. The beginning of the cyclization
involves Michael addition of allenoate 1 and methyleneindo-
linone 2. From a mechanistic standpoint, both the external and
internal site of allenoate can be approached in the Michael
addition. But the present transformation is obviously high-
lighted by the excellent regioselectivity observed. As shown in
Scheme 3, only the more electron-rich external bond of the
allenic fragment is used to furnish the cyclization. Then the in
situ generated carbocation A is trapped by a chloride anion
H
5-Cl
5-Br
5-Me
H
H
Ph
H
Ph
6g
6h
6i
Me
Bn
Ph
H
Ph
a
Reaction conditions: allenoate 1 (0.6 mmol), methyleneindolinone 5
(0.5 mmol), and 1.5 equiv of AlCl3 in DCE (5 mL) under reflux.
Isolated yields.
b
contrast, a different Michael addition took place to give rise to a
new product 6, thus constituting a novel carbon−carbon bond-
forming method. During this process, the structure of 6e
(CCDC 1014496) was also confirmed by X-ray analysis (see
Supporting Information).19 The substitution patterns of R4
bearing the carbonyl group were first investigated (Table 4,
entries 1−4). Then the possibilities with electron-deficient and
-rich substituents on the aromatic ring of the oxindole skeleton
were subsequently verified (Table 4, entries 5−7). Substituted
allenoates were also included to further establish the scope and
limitations (Table 4, entries 8 and 9).
C
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From the above-mentioned experimental results, we can see
that two kinds of Michael addition patterns exist (Scheme 4).
Scheme 6. Controlled Experiments with Carbonyl
Compounds
Scheme 4. Regioselective Michael (1,4-) Addition of
Allenoate
hexenones from readily available starting materials. Flexibility of
this method also allows the rapid synthesis of spirocyclic
oxindole-dihydropyrans by varying one of the components. The
mechanistic proposal indicates that two kinds of Michael
addition can take place depending on the electron-deficient
degree of methyleneindolinone. Moreover, AlCl3 acts as a
chlorine source as well as catalyst, which is quite interesting.
Another remarkable characteristic of this strategy is that
substituted allenoate is used as four-carbon component (4C)
to form the ring, which is very rare. This method is also
distinguished by its convenient experimental setup and
excellent regioselectivity. As a result, the present protocol has
potential to be applied in medicinal and synthetic chemistry.
When substrate 2 bearing an ester group was used, nuclophilic
addition started from the exocyclic vinyl carbon. In contrast, the
nucleophilic site transferred to the internal position of the
double bond when methyleneindolinone 5, having a more
electron-deficient carbonyl group, was employed. These
experimental results also imply that the reaction behavior is
heavily dependent on the electron-deficient degree of the
carbon−carbon double bond. Remarkably, no cyclization
products were obtained in reactions involving substrates 5,
which may result from the different addition patterns in the first
step.
EXPERIMENTAL SECTION
■
General Information. NMR spectra were recorded on a 500 MHz
1
spectrometer (500 MHz for H NMR and 125 MHz for 13C NMR)
Subsequently, 6 was further converted to other ring systems
for the illustration of its potential applications (Scheme 5).
with CDCl3 as the solvent and tetramethylsilane (TMS) as internal
1
reference. H NMR spectral data are reported as follows: chemical
shift (δ in parts per million, ppm), multiplicity, integration, and
coupling constant (in hertz). 13C NMR spectral data were reported in
terms of the chemical shift. The following abbreviations are used to
indicate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
and m = multiplet. IR spectra were recorded on a Fourier transform
infrared (FT-IR) spectrometer. High-resolution mass spectra (HRMS)
were recorded on a FTMS instrument in electrospray ionization (ESI)
mode and reported as m/z. Melting points were obtained on a digital
melting point apparatus without correction. Unless otherwise stated,
all reagents were commercially purchased and used without further
purification. All allenoates 1 were synthesized according to procedures
reported previously.20,12 Substrate oxindolylidene acetates 2 and
arenacylideneoxindoles 5 were synthesized according to procedures
reported previously.21−24
Scheme 5. Further Application of 6
Typical Procedures for Preparation of Allenoate 1a.
Triphenylphosphine (131.0 g, 500 mmol) was dissolved in benzene
(500 mL), and ethyl bromoacetate (83.5 g, 500 mmol) was added.
The reaction mixture was vigorously stirred at room temperature and
monitored (by thin-layer chromatography, TLC) for disappearance of
the substrate. The resulting white precipitate was filtered off and
washed with benzene to give the phosphonium salt in quantitative
yield. Residual benzene was removed under vacuum, and a mixture of
dichloromethane and n-hexane (2:1, 1.2 L) was subsequently added.
The flask was cooled in an ice bath, followed by the addition of
triethylamine (72.7 mL, 523 mmol). The mixture was stirred for 2 h, at
which point triethylamine (72.7 mL, 523 mmol) was added, and then
acetyl chloride (37.1 mL, 523 mmol) was added dropwise over 2 h.
The reaction mixture was stirred in its ice bath overnight. The copious
precipitate was filtered and rinsed with a mixture of n-hexane and
dichloromethane (3:1). The resulting crude allenoate solution was
concentrated to 300 mL; additional solid precipitate was filtered off
after the addition of hexane (300 mL). The resulting solution was
concentrated at room temperature and the residue was further distilled
under reduced pressure (10 mmHg) to give the desired allenoate 1a.20
Typical Procedure for Preparation of Substituted Allenoate
1. To a stirred solution of (carbethoxymethylene)triphenylphos-
phorane (10.0 g, 27.27 mmol) in chloroform (80 mL) was added 1.27
Treatment of 6 with Et3N as base essentially resulted in the
cyclization product 7. The nucleophilic addition followed by
cyclization enabled rapid access to spirocyclic oxindole-
dihydropyrans, which may require tedious synthetic steps by
traditional methods.
After the successful development of the regioselective
Michael reactions involving methyleneindolinones, we were
also interested in further application of the present strategy. In
this process, however, no reactions occurred when carbonyl-
containing substrates benzaldehyde and isatin were used
(Scheme 6). The reasons are not clear at present, but one
possibility may be insufficient reactivity of the corresponding
carbonyl group. Further experiments are still underway in our
laboratory.
In conclusion, we have disclosed a novel, efficient cyclization
reaction to generate functionalized spirocyclic oxindole-cyclo-
D
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equiv of (bromomethyl)benzene at room temperature. The reaction
mixture was refluxed until (carbethoxymethylene)triphenylphos-
phorane (monitored by TLC) disappeared. The solvent and excess
(bromomethyl)benzene were evaporated under reduced pressure. To
the resulting phosphornium salt were added dichloromethane (100
mL) and 2.2 equiv of triethylamine (8.4 mL). After the mixture was
stirred for about 1 h, 1.0 equiv of acetyl chloride (1.96 mL) was added
dropwise over 30 min. Then the reaction mixture was stirred
overnight. The resulting mixture was poured into a Buchner funnel
that was packed with silica gel and was washed with dichloromethane
for several times. The combined filtrate was carefully concentrated,
and the residue was subjected to flash column chromatography (20:1
petroleum ether/ethyl acetate eluent) to provide allenoate 1c.12
Representative Procedures for Preparation of Methylenein-
dolinone. a. General Procedure for Synthesis of N-methylisatins.
Isatin (3.0 mmol) was dissolved in anhydrous N,N-dimethylformamide
(DMF, 15 mL), and the resultant solution was cooled to 0 °C (ice
bath), whereupon sodium hydride 80% dispersion in oil (105 mg, 3.5
mmol) was added in one portion and stirred for 5 min. Iodomethane
(3.5 mmol) was added and the reaction was stirred at 0 °C for 30 min.
The reaction mixture was then poured into saturated aqueous NH4Cl
and extracted with ethyl acetate. The combined organic portions were
washed with water and brine, dried (MgSO4), filtered, and
concentrated to give the crude product, which was used without
further purification.
b. General Procedure for Synthesis of Methyleneindolinone 2. To
a stirred solution of Wittig reagent (10 mmol) in dichloromethane
(DCM, 5 mL) at 0 °C, was slowly added the solution of the
appropriate isatin crude product (10 mmol) in DCM. The resulting
mixture was stirred at room temperature for 2 h and then concentrated
under reduced vacuum. The residue was purified by column
chromatography (petroleum ether/dichloromethane = 10/1) to give
oxindolylidene acetates 2.
General Procedure for Syntheses of Spirocyclic Oxindoles 3
and 4. Allenoate 1 (0.6 mmol) and methyleneindolinone 2 (0.5
mmol) were placed in 5 mL of DCE in a flask. Then AlCl3 (1.5 equiv)
was added to this solution under nitrogen atmosphere. The mixture
was stirred under reflux for several hours, and the reation progress was
monitored by TLC detection. After completion, the reaction mixture
was concentrated under vacuum. The residue was purified by column
chromatography on silica gel (silica 200−300, eluent petroleum ether/
ethyl acetate) to afford the product 3 or 4.
1H, J = 18.0, 5.5 Hz), 1.03 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz,
CDCl3) δ (ppm) = 188.9, 171.3, 169.0, 158.4, 143.7, 129.4, 129.3,
128.2, 126.4, 123.7, 109.3, 61.7, 59.8, 46.9, 33.7, 26.7, 13.8. HRMS
(ESI) calcd for C17H16Cl2NO4 [M + H]+ 368.0456, found 368.0462.
Ethyl 5′-Bromo-4-chloro-1′-methyl-2,2′-dioxospiro[cyclohex[3]-
ene-1,3′-indoline]-6-carboxylate (3d). 102.8 mg, 50% yield; white
solid, mp 138−139 °C. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.46
(dd, 1H, J = 8.0, 1.5 Hz), 7.16 (d, 1H, J = 2.0 Hz), 6.73 (d, 1H, J = 7.5
Hz), 8.36 (d, 1H, J = 2.0 Hz), 4.01−3.91 (m, 2H), 3.81 (ddd, 1H, J =
18.5, 12.0, 2.5 Hz), 3.69 (dd, 1H, J = 11.5, 5.0 Hz), 3.18 (s, 3H), 3.01
(dd, 1H, J = 18.0, 5.0 Hz), 1.04 (t, 3H, J = 7.0 Hz). 13C NMR (125
MHz, CDCl3) δ (ppm) = 188.9, 171.2, 169.0, 158.4, 144.2, 132.2,
129.8, 126.4, 115.4, 109.8, 61.7, 59.7, 46.9, 33.7, 26.6, 13.8. HRMS
(ESI) calcd for C17H16BrClNO4 [M + H]+ 411.9951, found 411.9962.
Ethyl 4-Chloro-1′,5′-dimethyl-2,2′-dioxospiro[cyclohex[3]ene-
1,3′-indoline]-6-carboxylate (3e). 79.8 mg, 46% yield; white solid,
1
mp 139−142 °C. H NMR (500 MHZ, CDCl3) δ (ppm) = 7.12 (dd,
1H, J = 8.0, 1.0 Hz), 6.87 (s, 1H), 6.74 (d, 1H, J = 8.0 Hz), 6.37 (d,
1H, J = 2.0 Hz), 3.98−3.89 (m, 2H), 3.84 (ddd, 1H, J = 18.0, 11.5, 2.5
Hz), 3.70 (dd, 1H, J = 11.5, 5.0 Hz), 3.17 (s, 3H), 2.98 (dd, 1H, J =
18.0, 5.0 Hz), 2.32 (s, 3H), 0.98 (t, 3H, J = 7.0 Hz). 13C NMR (125
MHz, CDCl3) δ (ppm) = 189.9, 171.6, 169.2, 158.1, 142.5, 132.4,
129.7, 127.5, 126.6, 124.0, 108.2, 61.4, 59.7, 47.2, 33.8, 26.5, 21.2, 13.7.
HRMS (ESI) calcd for C18H19ClNO4 [M + H]+ 348.1003, found
348.0998.
Ethyl 4-Chloro-5′-methoxy-1′-methyl-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (3f). 88.9 mg, 49%
1
yield; white solid, mp 145−147 °C. H NMR (500 MHZ, CDCl3) δ
(ppm) = 6.85 (dd, 1H, J = 8.5, 2.5 Hz), 6.76 (d, 1H, J = 8.5 Hz), 6.66
(d, 1H, J = 2.5 Hz), 6.37 (d, 1H, J = 2.0 Hz), 3.98−3.90 (m, 2H), 3.84
(ddd, 1H, J = 18.0, 11.5, 2.5 Hz), 3.77 (s, 3H), 3.69 (dd, 1H, J = 11.5,
5.0 Hz), 3.17 (s, 3H), 2.99 (dd, 1H, J = 18.5, 5.0 Hz), 1.00 (t, 3H, J =
7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 189.7, 171.3, 169.1,
158.2, 156.1, 138.5, 128.9, 126.6, 113.3, 110.9, 108.7, 61.5, 60.0, 55.8,
47.1, 33.9, 26.6, 13.8. HRMS (ESI) calcd for C18H19ClNO5 [M + H]+
364.0952, found 364.0953.
Ethyl 4′-Bromo-4-chloro-1′-methyl-2,2′-dioxospiro[cyclohex[3]-
ene-1,3′-indoline]-6-carboxylate (3g). 123.3 mg, 60% yield; white
1
solid, mp 127−129 °C. H NMR (500 MHZ, CDCl3) δ (ppm) =
7.23−7.17 (m, 2H), 6.79 (dd, 1H, J = 7.5, 1.5 Hz), 6.40 (d, 1H, J = 2.0
Hz), 4.61−4.58 (m, 1H), 3.99−3.92 (m, 2H), 3.86 (ddd, 1H, J = 18.5,
12.0, 2.5 Hz), 3.18 (s, 3H), 3.02 (dd, 1H, J = 18.5, 5.5 Hz), 1.02 (t,
3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 187.5,
170.9, 169.3, 158.5, 147.0, 130.8, 126.9, 126.6, 126.5, 118.7, 107.4,
61.5, 61.1, 43.8, 33.4, 26.7, 13.8. HRMS (ESI) calcd for
C17H16BrClNO4 [M + H]+ 411.9951, found 411.9960.
Ethyl 4-Chloro-1′-methyl-2,2′-dioxospiro[cyclohex[3]ene-1,3′-in-
doline]-6-carboxylate (3a). 88.2 mg, 53% yield; white solid, mp 158−
160 °C. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.34 (td, 1H, J = 8.0,
1.5 Hz), 7.10−7.05 (m, 2H), 6.85 (d, 1H, J = 8.0 Hz), 6.37 (d, 1H, J =
2.0 Hz), 3.83 (ddd, 1H, J = 18.0, 11.5, 2.5 Hz), 3.72 (dd, 1H, J = 11.5,
5.0 Hz), 3.20 (s, 3H), 2.99 (dd, 1H, J = 18.0, 5.0 Hz), 0.97 (t, 3H, J =
7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 189.7, 171.6, 169.2,
158.1, 144.9, 129.4, 127.5, 126.6, 123.2, 122.9, 108.4, 61.4, 59.6, 47.2,
33.8, 26.5, 13.7. HRMS (ESI) calcd for C17H17ClNO4 [M + H]+
334.0846, found 334.0841.
Ethyl 6′-Bromo-4-chloro-1′-methyl-2,2′-dioxospiro[cyclohex[3]-
ene-1,3′-indoline]-6-carboxylate (3h). 139.7 mg, 68% yield; white
solid, mp 143−144 °C. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.21
(dd, 1H, J = 8.0, 1.5 Hz), 7.00 (d, 1H, J = 1.5 Hz), 6.90 (d, 1H, J = 8.0
Hz), 6.36 (d, 1H, J = 2.0 Hz), 4.01−3.90 (m, 2H), 3.81 (ddd, 1H, J =
18.0, 11.5, 2.5 Hz), 3.70 (dd, 1H, J = 11.5, 5.0 Hz), 3.18 (s, 3H), 2.99
(dd, 1H, J = 18.0, 5.0 Hz), 1.04 (t, 3H, J = 7.0 Hz). 13C NMR (125
MHz, CDCl3) δ (ppm) = 189.0, 171.5, 169.0, 158.3, 146.4, 126.6,
126.4, 125.7, 124.4, 123.1, 112.0, 61.7, 59.4, 46.9, 33.7, 26.7, 13.8.
HRMS (ESI) calcd for C17H16BrClNO4 [M + H]+ 411.9951, found
411.9959.
Ethyl 4-Chloro-2,2′-dioxospiro[cyclohex[3]ene-1,3′-indoline]-6-
carboxylate (3i). 51.0 mg, 32% yield; white solid, mp 136−138 °C.
1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.83 (s, 1H), 7.29−7.25 (m,
1H), 7.08−7.04 (m, 2H), 6.87 (d, 1H, J = 8.0 Hz), 6.39 (d, 1H, J = 2.0
Hz), 4.00−3.93 (m, 2H), 3.83 (ddd, 1H, J = 18.0, 11.5, 2.5 Hz), 3.73
(dd, 1H, J = 11.5, 5.0 Hz), 2.99 (dd, 1H, J = 18.0, 5.0 Hz), 1.00 (t, 3H,
J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 189.4, 173.1,
169.3, 158.1, 141.8, 129.4, 128.1, 126.5, 123.5, 122.9, 110.0, 61.6, 60.0,
47.2, 33.7, 13.7. HRMS (ESI) calcd for C16H15ClNO4 [M + H]+
320.0690, found 320.0683.
Ethyl 4-Chloro-5′-fluoro-1′-methyl-2,2′-dioxospiro[cyclohex[3]-
ene-1,3′-indoline]-6-carboxylate (3b). 98.3 mg, 56% yield; white
solid, mp 137−139 °C. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.04
(td, 1H, J = 8.5, 2.0 Hz), 6.82 (dd, 1H, J = 7.5, 2.5 Hz), 6.78 (dd, 1H, J
= 8.5, 4.0 Hz), 6.37 (d, 1H, J = 2.5 Hz), 4.01−3.90 (m, 2H), 3.84
(ddd, 1H, J = 18.0, 11.5, 2.0 Hz), 3.69 (dd, 1H, J = 12.0, 5.5 Hz), 3.19
(d, 3H, J = 0.5 Hz), 3.00 (dd, 1H, J = 18.5, 5.5 Hz), 1.03 (t, 3H, J = 7.0
Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 189.1, 171.3, 159.2 (d,
4
3
1JC−F = 240.0 Hz), 158.4, 141.0 (d, JC−F = 1.3 Hz), 129.2 (d, JC−F
=
8.8 Hz), 126.4, 115.5 (d, 2JC−F = 22.5 Hz), 111.5 (d, 2JC−F = 25.0 Hz),
108 (d, 3JC−F = 8.8 Hz), 61.6, 60.0, 47.0, 33.7, 27.0, 13.8. HRMS (ESI)
calcd for C17H15ClFNNaO4 [M + Na]+ 374.0571, found 374.0585.
(E)-Ethyl 4,5′-Dichloro-1′-methyl-2,2′-dioxospiro[cyclohex[3]ene-
1,3′-indoline]-6-carboxylate (3c). 111.9 mg, 61% yield; white solid,
1
mp 139−141 °C. H NMR (500 MHZ, CDCl3) δ (ppm) = 7.31 (dd,
1H, J = 8.5, 2.0 Hz), 7.03 (d, 1H, J = 2.0 Hz), 6.78 (d, 1H, J = 8.5 Hz),
6.36 (d, 1H, J = 2.0 Hz), 4.00−3.92 (m, 2H), 3.82 (ddd, 1H, J = 18.5,
12.0, 2.5 Hz), 3.69 (dd, 1H, J = 11.5, 5.5 Hz), 3.18 (s, 3H), 3.01 (dd,
Ethyl 1′-Benzyl-4-chloro-2,2′-dioxospiro[cyclohex[3]ene-1,3′-in-
1
doline]-6-carboxylate (3j). 87.9 mg, 43% yield; white oil. H NMR
(500 MHZ, CDCl3) δ (ppm) = 7.45 (d, 2H, J = 7.5 Hz), 7.34 (t, 2H, J
E
dx.doi.org/10.1021/jo502209f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 7.0 Hz), 7.27 (t, 1H, J = 7.5 Hz), 7.18 (td, 1H, J = 8.0, 1.0 Hz), 7.09
(d, 1H, J = 7.0 Hz), 6.95 (td, 1H, J = 7.5, 0.5 Hz), 6.71 (d, 1H, J = 7.5
Hz), 6.40 (d, 1H, J = 2.0 Hz), 5.23 (d, 1H, J = 15.5 Hz), 4.76 (d, 1H, J
= 15.5 Hz), 4.07−4.04 (m, 1H), 3.99−3.92 (m, 1H), 3.86−3.80 (m,
1H), 3.43 (ddd, 1H, J = 20.0, 11.5, 2.5 Hz), 3.28 (dd, 1H, J = 20.0, 6.5
Hz), 0.90 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm)
= 189.7, 174.9, 168.9, 156.7, 144.1, 135.2, 129.5, 128.8, 127.6, 127.4,
127.0, 125.9, 123.1, 122.6, 110.0, 61.5, 60.2, 44.3, 44.0, 33.3, 13.7.
HRMS (ESI) calcd for C23H21ClNO4 [M + H]+ 410.1159, found
410.1155.
(ppm) = 7.32 (td, 1H, J = 7.5, 1.5 Hz), 7.21−7.17 (m, 1H), 7.06 (td,
1H, J = 7.5, 1.0 Hz), 7.02−7.00 (m, 2H), 6.94 (dd, 1H, J = 10.0, 2.0
Hz), 6.87−6.82 (m, 2H), 3.97−3.89 (m, 3H), 3.85−3.79 (m, 2H),
3.70 (dd, 1H, J = 11.5, 5.5 Hz), 3.18 (s, 3H), 3.08 (dd, 1H, J = 18.0,
5.5 Hz), 0.97 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ
(ppm) = 189.4, 171.4, 169.3, 162.8 (d, 1JC−F = 242.5 Hz), 154.6, 144.7,
3
3
140.6 (d, JC−F = 7.5 Hz), 134.6, 129.7 (d, JC−F = 8.8 Hz), 129.3,
4
2
127.8, 124.2 (d, JC−F = 3.8 Hz), 123.2, 122.9, 115.4 (d, JC−F = 22.5
2
Hz), 113.1 (d, JC−F = 21.3 Hz), 108.4, 61.4, 59.8, 46.5, 34.2, 32.7,
32.7, 30.9, 26.5, 13.7. HRMS (ESI) calcd for C24H22ClFNO4 [M +
Ethyl 4-Chloro-1′,3-dimethyl-2,2′-dioxospiro[cyclohex[3]ene-
H]+ 442.1221, found 442.1224.
1,3′-indoline]-6-carboxylate (4a). 98.9 mg, 57% yield; white solid,
Ethyl 4-Chloro-3-(3-chlorobenzyl)-1′-methyl-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (4g). 116.5 mg, 51%
1
mp 120−122 °C. H NMR (500 MHZ, CDCl3) δ (ppm) = 7.32 (td,
1
yield; white solid, mp 183−185 °C. H NMR (500 MHZ, CDCl3) δ
1H, J = 7.5, 2.0 Hz), 7.09−7.04 (m, 2H), 6.84 (d, 1H, J = 8.0 Hz),
3.96−3.83 (m, 3H), 3.70 (dd, 1H, J = 11.5, 5.0 Hz), 3.19 (s, 3H), 3.02
(ddd, 1H, J = 18.0, 5.5, 1.5 Hz), 1.97−1.96 (m, 3H), 0.98 (t, 3H, J =
7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 189.7, 171.8, 169.4,
152.9, 144.8, 132.1, 129.2, 128.3, 123.0, 122.8, 108.4, 61.3, 59.8, 46.6,
33.9, 26.5, 13.8, 13.2. HRMS (ESI) calcd for C18H19ClNO4 [M + H]+
348.1003, found 348.0998.
(ppm) = 7.32 (td, 1H, J = 7.5, 1.5 Hz), 7.21 (s, 1H), 7.18−7.10 (m,
3H), 7.06 (td, 1H, J = 7.5, 0.5 Hz), 7.02 (dd, 1H, J = 7.5, 1.0 Hz), 6.83
(d, 1H, J = 8.0 Hz), 3.98−3.87 (m, 3H), 3.83−3.77 (m, 2H), 3.70 (dd,
1H, J = 11.5, 5.5 Hz), 3.18 (s, 3H), 3.08 (dd, 1H, J = 18.5, 5.5 Hz),
0.98 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) =
189.4, 171.4, 169.3, 154.6, 144.7, 140.2, 134.6, 134.1, 129.6, 129.3,
128.7, 127.8, 126.7, 126.5, 123.2, 122.9, 108.4, 61.4, 59.9, 46.5, 34.2,
32.7, 26.5, 13.7. HRMS (ESI) calcd for C24H22Cl2NO4 [M + H]+
458.0926, found 458.0934.
Ethyl 3-Benzyl-4-chloro-1′-methyl-2,2′-dioxospiro[cyclohex[3]-
ene-1,3′-indoline]-6-carboxylate (4b). 105.8 mg, 50% yield; white
solid, mp 172−174 °C. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.31
(td, 1H, J = 7.5, 1.5 Hz), 7.25−7.24 (m, 4H), 7.18−7.15 (m, 1H), 7.05
(td, 1H, J = 7.5, 0.5 Hz), 7.01 (dd, 1H, J = 7.0, 1.0 Hz), 6.83 (d, 1H, J
= 8.0 Hz), 3.97−3.89 (m, 3H), 3.84 (s, 2H), 3.70 (dd, 1H, J = 11.5, 5.5
Hz), 3.18 (s, 3H), 3.07 (dd, 1H, J = 18.0, 5.5 Hz), 0.98 (t, 3H, J = 7.0
Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 189.5, 171.5, 169.4,
154.3, 144.8, 138.2, 135.2, 129.3, 128.6, 128.4, 128.1, 126.2, 123.1,
122.8, 108.4, 61.4, 59.9, 46.6, 34.2, 33.0, 26.5, 13.7. HRMS (ESI) calcd
for C24H23ClNO4 [M + H]+ 424.1316, found 424.1330.
Ethyl 3-(4-Bromobenzyl)-4-chloro-1′-methyl-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (4h). 157.8 mg, 63%
1
yield; white solid, mp 181−183 °C. H NMR (500 MHZ, CDCl3) δ
(ppm) = 7.36−7.34 (m, 2H), 7.32 (td, 1H, J = 8.0, 1.5 Hz), 7.11 (d,
2H, J = 8.5 Hz), 7.06 (td, 1H, J = 7.5, 1.0 Hz), 7.01 (dd, 1H, J = 7.5,
1.0 Hz), 6.83 (d, 1H, J = 8.0 Hz), 3.97−3.87 (m, 3H), 3.80−3.74 (m,
2H), 3.69 (dd, 1H, J = 11.5, 5.5 Hz), 3.17 (s, 3H), 3.07 (dd, 1H, J =
18.0, 5.5 Hz), 0.97 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ
(ppm) = 189.4, 171.4, 169.2, 154.5, 144.7, 137.2, 134.7, 131.4, 130.3,
129.3, 127.8, 123.2, 122.9, 120.1, 108.4, 61.4, 59.8, 46.5, 34.2, 32.5,
26.6, 13.7. HRMS (ESI) calcd for C24H22BrClNO4 [M + H]+
502.0421, found 502.0414.
Ethyl 4-Chloro-1′-methyl-3-(4-nitrobenzyl)-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (4c). 175.5 mg, 75%
1
yield; white solid, mp 176−178 °C. H NMR (500 MHZ, CDCl3) δ
(ppm) = 8.08 (d, 2H, J = 9.0 Hz), 7.38 (d, 2H, J = 9.0 Hz), 7.32 (td,
1H, J = 7.5, 1.5 Hz), 7.06 (td, 1H, J = 7.5, 1.0 Hz), 7.02 (dd, 1H, J =
7.5, 1.0 Hz), 6.83 (d, 1H, J = 8.0 Hz), 3.97−3.88 (m, 5H), 3.72 (dd,
1H, J = 11.5, 5.5 Hz), 3.17 (s, 3H), 3.10 (ddd, 1H, J = 18.5, 5.5, 0.5
Hz), 0.96 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm)
= 189.5, 171.2, 169.1, 155.4, 146.6, 145.9, 144.7, 133.9, 129.5, 129.3,
127.5, 123.7, 123.2, 122.9, 108.5, 61.5, 59.8, 46.5, 34.2, 33.0, 26.6, 13.7.
HRMS (ESI) calcd for C24H22ClN2O6 [M + H]+ 469.1166, found
469.1162.
Ethyl 4-Chloro-1′-methyl-3-(4-methylbenzyl)-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (4i). 94.0 mg, 43%
1
yield; white solid, mp 195−196 °C. H NMR (500 MHZ, CDCl3) δ
(ppm) = 7.31 (td, 1H, J = 8.0, 1.0 Hz), 7.13 (d, 2H, J = 8.0 Hz), 7.06−
7.04 (m, 3H), 7.01 (d, 1H, J = 7.0 Hz), 6.82 (d, 1H, J = 8.0 Hz), 3.96−
3.88 (m, 3H), 3.79 (s, 2H), 3.69 (dd, 1H, J = 11.5, 5.5 Hz), 3.18 (s,
3H), 3.05 (dd, 1H, J = 18.0, 5.5 Hz), 2.29 (s, 3H), 0.97 (t, 3H, J = 7.0
Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 189.4, 171.5, 169.4,
154.1, 144.8, 135.6, 135.4, 135.1, 129.2, 129.1, 128.4, 128.1, 123.1,
122.8, 108.3, 61.4, 59.9, 46.6, 34.2, 32.6, 26.5, 21.0, 13.7. HRMS (ESI)
calcd for C25H25ClNO4 [M + H]+ 438.1472, found 438.1463.
Ethyl 4-Chloro-1′-methyl-3-(3-nitrobenzyl)-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (4d). 170.8 mg, 73%
1
yield; white solid, mp 167−169 °C. H NMR (500 MHZ, CDCl3) δ
(ppm) = 8.06 (t, 1H, J = 1.5 Hz), 8.01 (dd, 1H, J = 8.0, 1.5 Hz), 7.55
(d, 1H, J = 7.5 Hz), 7.39 (t, 1H, J = 8.0 Hz), 7.32 (td, 1H, J = 7.5, 1.5
Hz), 7.08−7.02 (m, 2H), 6.83 (d, 1H, J = 7.5 Hz), 3.97−3.88 (m, 5H),
3.72 (dd, 1H, J = 11.5, 5.5 Hz), 3.17 (s, 3H), 3.13−3.08 (m, 1H), 0.97
(t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 189.5,
171.2, 169.2, 155.3, 148.3, 144.7, 140.2, 134.7, 134.0, 129.4, 129.3,
127.5, 123.5, 123.2, 122.9, 121.5, 108.5, 61.5, 59.9, 46.5, 34.2, 32.7,
26.6, 13.7. HRMS (ESI) calcd for C24H22ClN2O6 [M + H]+ 469.1166,
found 469.1159.
Ethyl 4-Chloro-1′-methyl-3-(2-methylbenzyl)-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (4j). 131.1 mg, 60%
1
yield; white solid, mp 139−141 °C. H NMR (500 MHZ, CDCl3) δ
(ppm) = 7.32−7.29 (m, 1H), 7.09−7.02 (m, 6H), 6.81 (d, 1H, J = 8.0
Hz), 4.04−3.90 (m, 3H), 3.84−3.72 (m, 3H), 3.18 (s, 3H), 3.11 (dd,
1H, J = 18.0, 5.5 Hz), 2.33 (s, 3H), 0.99 (t, 3H, J = 7.0 Hz). 13C NMR
(125 MHz, CDCl3) δ (ppm) = 189.2, 171.5, 169.3, 154.9, 144.8, 136.1,
135.9, 134.9, 130.0, 129.2, 128.0, 126.8, 126.1, 126.0, 123.2, 122.8,
108.3, 61.4, 60.0, 46.8, 34.2, 30.0, 26.5, 19.8, 13.8. HRMS (ESI) calcd
for C25H25ClNO4 [M + H]+ 438.1472, found 438.1468.
Ethyl 4-Chloro-1′-methyl-3-(2-nitrobenzyl)-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (4e). 105.3 mg, 45%
General Procedure for Syntheses of Oxindole 6. Allenoate 1
(0.6 mmol) and arenacylideneoxindoles 4 (0.5 mmol) were placed in 5
mL of DCE in a flask. Then AlCl3 (1.5 equiv) was added to this
solution under nitrogen atmosphere. The mixture was stirred under
reflux for several hours, and the reaction progress was monitored by
TLC detection. After completion, the reaction mixture was
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (silica 200−300; eluant petroleum ether/
ethyl acetate) to afford the product 6.
Ethyl 3-Chloro-4-[1-methyl-2-oxo-3-(2-oxo-2-phenylethyl)-
indolin-3-yl]but-2-enoate (6a). 148.0 mg, 72% yield; pale yellow
oil. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.83 (d, 2H, J = 7.0 Hz),
7.51 (t, 1H, J = 7.5 Hz), 7.39 (t, 2H, J = 8.0 Hz), 7.24 (td, 1H, J = 8.0,
1.0 Hz), 7.11 (dd, 1H, J = 7.5, 1.0 Hz), 6.89−6.87 (m, 2H), 5.95 (s,
1
yield; white solid, mp 141−143 °C. H NMR (500 MHZ, CDCl3) δ
(ppm) = 7.89 (dd, 1H, J = 8.0, 1.0 Hz), 7.49 (td, 1H, J = 7.5, 1.0 Hz),
7.33−7.29 (m, 3H), 7.07−7.06 (m, 2H), 6.82 (d, 1H, J = 8.0 Hz), 4.24
(d, 1H, J = 16.5 Hz), 4.12 (d, 1H, J = 16.5 Hz), 4.02−3.90 (m, 3H),
3.76 (dd, 1H, J = 11.5, 5.5 Hz), 3.18 (s, 3H), 3.11 (ddd, 1H, J = 18.5,
5.5, 1.0 Hz), 0.98 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ
(ppm) = 189.1, 171.4, 169.2, 156.2, 149.2, 144.7, 133.5, 133.2, 132.9,
129.6, 129.4, 127.6, 127.1, 124.7, 123.3, 123.0, 108.4, 61.5, 59.8, 46.7,
34.3, 29.7, 26.6, 13.7. HRMS (ESI) calcd for C24H22ClN2O6 [M + H]+
469.1166, found 469.1166.
Ethyl 4-Chloro-3-(3-fluorobenzyl)-1′-methyl-2,2′-dioxospiro-
[cyclohex[3]ene-1,3′-indoline]-6-carboxylate (4f). 121.3 mg, 55%
1
yield; white solid, mp 138−139 °C. H NMR (500 MHZ, CDCl3) δ
F
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1H), 4.21 (d, 1H, J = 13.5 Hz), 4.08 (q, 2H, J = 7.0 Hz), 3.91 (d, 1H, J
= 18.0 Hz), 3.74 (d, 1H, J = 18.0 Hz), 3.30 (s, 3H), 3.20 (d, 1H, J =
13.5 Hz), 1.23 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ
(ppm) = 195.5, 178.8, 164.2, 149.8, 144.6, 136.3, 133.3, 129.7, 128.5,
128.4, 128.0, 123.1, 122.4, 121.7, 108.1, 60.6, 49.2, 45.5, 41.9, 26.6,
14.1. HRMS (ESI) calcd for C23H23ClNO4 [M + H]+ 412.1316, found
412.1311.
7.03 (dd, 1H, J = 8.0, 1.0 Hz), 6.91 (t, 1H, J = 1.0 Hz), 6.76 (d, 1H, J =
8.0 Hz), 5.95 (s, 1H), 4.18 (d, 1H, J = 13.5 Hz), 4.07 (q, 2H, J = 7.0
Hz), 3.88 (d, 1H, J = 18.0 Hz), 3.74 (d, 1H, J = 18.0 Hz), 3.28 (s, 3H),
3.19 (d, 1H, J = 13.5 Hz), 2.20 (s, 3H), 1.23 (t, 3H, J = 7.0 Hz). 13C
NMR (125 MHz, CDCl3) δ (ppm) = 195.4, 178.7, 164.2, 150.0, 142.2,
136.3, 133.2, 131.0, 129.7, 128.6, 128.5, 128.0, 124.0, 122.4, 107.8,
60.5, 49.2, 45.4, 42.0, 26.7, 21.0, 14.1. HRMS (ESI) calcd for
C24H25ClNO4 [M + H]+ 426.1472, found 426.1465.
Ethyl 3-Chloro-2-methyl-4-[1-methyl-2-oxo-3-(2-oxo-2-
phenylethyl)indolin-3-yl]but-2-enoate (6h). 129.6 mg, 61% yield;
pale yellow oil. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.82 (d, 2H, J
= 7.0 Hz), 7.51 (t, 1H, J = 7.5 Hz), 7.39 (t, 2H, J = 8.0 Hz), 7.23 (td,
1H, J = 7.5, 1.0 Hz), 7.06 (dd, 1H, J = 7.0, 0.5 Hz), 6.90−6.85 (m,
2H), 4.05 (q, 2H, J = 7.0 Hz), 3.91 (d, 1H, J = 18.0 Hz), 3.86 (d, 1H, J
= 14.0 Hz), 3.73 (d, 1H, J = 18.0 Hz), 3.32 (dd, 1H, J = 14.0, 1.0 Hz),
3.29 (s, 3H), 1.89 (s, 3H), 1.24 (t, 3H, J = 7.0 Hz). 13C NMR (125
MHz, CDCl3) δ (ppm) = 195.7, 179.2, 166.6, 144.6, 141.5, 136.4,
133.2, 130.2, 129.4, 128.5, 128.2, 128.0, 123.2, 121.7, 107.9, 61.1, 49.3,
45.2, 43.4, 26.6, 17.8, 14.0. HRMS (ESI) calcd for C24H25ClNO4 [M +
H]+ 426.1472, found 426.1464.
Ethyl 3-Chloro-4-{3-[2-(4-fluorophenyl)-2-oxoethyl]-1-methyl-2-
oxoindolin-3-yl}but-2-enoate (6b). 156.6 mg, 73% yield; white
1
solid, mp 159−161 °C. H NMR (500 MHZ, CDCl3) δ (ppm) =
7.86−7.83 (m, 2H), 7.24 (td, 1H, J = 8.0, 1.0 Hz), 7.10 (dd, 1H, J =
8.0, 1.0 Hz), 7.05 (t, 2H, J = 8.5 Hz), 6.88 (t, 2H, J = 7.0 Hz), 5.94 (s,
1H), 4.20 (d, 1H, J = 13.5 Hz), 4.09−4.05 (m, 2H), 3.85 (d, 1H, J =
18.0 Hz), 3.71 (d, 1H, J = 18.0 Hz), 3.29 (s, 3H), 3.19 (d, 1H, J = 13.5
Hz), 1.22 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm)
= 193.9, 178.7, 165.8 (d, 1JC−F = 252.5 Hz), 164.2, 149.7, 144.6, 132.7
4
3
(d, JC−F = 2.5 Hz), 130.6 (d, JC−F = 8.8 Hz), 129.6, 128.5, 123.1,
2
122.5, 121.7, 115.6 (d, JC−F = 22.5 Hz), 108.1, 60.6, 49.1, 45.3, 41.9,
26.6, 14.1. HRMS (ESI) calcd for C23H22ClFNO4 [M + H]+ 430.1221,
found 430.1225.
Ethyl 2-Benzyl-3-chloro-4-[1-methyl-2-oxo-3-(2-oxo-2-
phenylethyl)indolin-3-yl]but-2-enoate (6i). 180.4 mg, 72% yield;
pale yellow oil. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.82 (dd, 2H,
J = 8.0, 1.0 Hz), 7.51 (t, 1H, J = 7.5 Hz), 7.39 (t, 2H, J = 8.0 Hz), 7.29
(td, 1H, J = 7.5, 1.0 Hz), 7.17−7.14 (m, 4H), 6.89−6.86 (m, 2H), 6.78
(dd, 2H, J = 8.0, 2.0 Hz), 4.15 (d, 1H, J = 14.0 Hz), 4.04 (q, 2H, J =
7.0 Hz), 3.88 (d, 1H, J = 17.5 Hz), 3.80 (d, 1H, J = 15.0 Hz), 3.73−
3.66 (m, 2H), 3.27 (s, 3H), 3.22 (d, 1H, J = 18.5 Hz), 1.14 (t, 3H, J =
7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 195.6, 179.3, 166.0,
144.8, 143.0, 137.8, 136.4, 133.2, 132.4, 129.8, 128.5, 128.3, 128.2,
128.1, 128.0, 126.1, 123.7, 121.9, 108.1, 61.1, 49.3, 45.8, 43.7, 37.2,
26.6, 13.9. HRMS (ESI) calcd for C30H29ClNO4 [M + H]+ 502.1785,
found 502.1781.
General Procedure for Syntheses of Spirocyclic Oxindole 7.
To a solution of 6 (0.5 mmol) in 5 mL of DCE was added NEt3 (0.2
mL, 3.0 equiv). The stirred mixture was heated at 70 °C for several
hours, and the reaction progress was monitored by TLC detection.
After completion, the reaction mixture was concentrated under
vacuum. The residue was purified by column chromatography on
silica gel (silica 200−300; eluant petroleum ether/ethyl acetate) to
afford the desired product 7.
Ethyl 3-Chloro-4-{3-[2-(4-chlorophenyl)-2-oxoethyl]-1-methyl-2-
oxoindolin-3-yl}but-2-enoate (6c). 166.9 mg, 75% yield; white
1
solid, mp 144−146 °C. H NMR (500 MHZ, CDCl3) δ (ppm) =
7.75 (d, 2H, J = 8.5 Hz), 7.35 (d, 2H, J = 9.5 Hz), 7.23 (t, 1H, J = 8.0
Hz), 7.10 (d, 1H, J = 7.0 Hz), 6.88 (t, 2H, J = 8.0 Hz), 5.93 (s, 1H),
4.20 (d, 1H, J = 13.5 Hz), 4.09−4.04 (m, 2H), 3.84 (d, 1H, J = 17.5
Hz), 3.70 (d, 1H, J = 18.0 Hz), 3.28 (s, 3H), 3.18 (d, 1H, J = 13.5 Hz),
1.22 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) =
194.3, 178.7, 164.2, 149.7, 144.6, 139.7, 134.6, 129.5, 129.4, 128.8,
128.5, 123.1, 122.5, 121.7, 108.1, 60.6, 49.1, 45.4, 41.9, 26.6, 14.1.
HRMS (ESI) calcd for C23H22Cl2NO4 [M + H]+ 446.0926, found
446.0929.
Ethyl 4-{3-[2-(4-Bromophenyl)-2-oxoethyl]-1-methyl-2-oxoindo-
lin-3-yl}-3-chlorobut-2-enoate (6d). 149.1 mg, 61% yield; white
solid, mp 123−125 °C. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.67
(d, 2H, J = 8.5 Hz), 7.52 (d, 2H, J = 8.5 Hz), 7.24 (td, 1H, J = 8.0, 1.0
Hz), 7.10 (d, 1H, J = 7.0 Hz), 6.88 (t, 2H, J = 8.0 Hz), 5.93 (s, 1H),
4.20 (d, 1H, J = 14.0 Hz), 4.09−4.04 (m, 2H), 3.83 (d, 1H, J = 18.0
Hz), 3.69 (d, 1H, J = 18.0 Hz), 3.28 (s, 3H), 3.18 (d, 1H, J = 13.5 Hz),
1.22 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) =
194.5, 178.6, 164.2, 149.7, 144.6, 135.0, 131.8, 129.5, 128.5, 123.1,
122.5, 121.7, 108.1, 60.6, 49.1, 45.3, 41.9, 26.6, 14.1. HRMS (ESI)
calcd for C23H22BrClNO4 [M + H]+ 490.0421, found 490.0418.
Ethyl 3-Chloro-4-[5-chloro-1-methyl-2-oxo-3-(2-oxo-2-
phenylethyl)indolin-3-yl]but-2-enoate (6e). 175.8 mg, 79% yield;
white solid, mp 148−149 °C. 1H NMR (500 MHZ, CDCl3) δ (ppm) =
7.84 (dd, 2H, J = 8.0, 1.0 Hz), 7.53 (t, 1H, J = 7.5 Hz), 7.41 (t, 2H, J =
7.5 Hz), 7.21 (dd, 1H, J = 8.5, 2.0 Hz), 7.08 (d, 1H, J = 2.0 Hz), 6.80
(d, 1H, J = 8.5 Hz), 5.96 (s, 1H), 4.25 (d, 1H, J = 13.5 Hz), 4.17−4.06
(m, 2H), 3.88 (d, 1H, J = 18.0 Hz), 3.78 (d, 1H, J = 18.0 Hz), 3.28 (s,
3H), 3.15 (d, 1H, J = 14.0 Hz), 1.25 (t, 3H, J = 7.0 Hz). 13C NMR
(125 MHz, CDCl3) δ (ppm) = 195.2, 178.3, 164.3, 149.2, 143.3, 136.0,
133.5, 131.5, 128.6, 128.3, 128.0, 127.0, 123.6, 122.7, 109.0, 60.8, 49.3,
45.5, 41.9, 26.8, 14.1. HRMS (ESI) calcd for C23H22Cl2NO4 [M + H]+
446.0926, found 446.0916.
Ethyl 4-[5-Bromo-1-methyl-2-oxo-3-(2-oxo-2-phenylethyl)-
indolin-3-yl]-3-chlorobut-2-enoate (6f). 183.4 mg, 75% yield; white
solid, mp 160−162 °C. 1H NMR (500 MHZ, CDCl3) δ (ppm) = 7.84
(dd, 2H, J = 8.0, 1.0 Hz), 7.21 (d, 1H, J = 2.0 Hz), 6.76 (d, 1H, J = 8.5
Hz), 5.96 (s, 1H), 4.24 (d, 1H, J = 13.5 Hz), 4.19−4.07 (m, 2H), 3.87
(d, 1H, J = 18.0 Hz), 3.78 (d, 1H, J = 18.0 Hz), 3.28 (s, 3H), 3.14 (d,
1H, J = 13.5 Hz), 1.26 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz,
CDCl3) δ (ppm) = 195.2, 178.3, 164.3, 149.2, 143.8, 136.0, 133.5,
131.9, 131.2, 128.6, 128.0, 126.3, 122.7, 114.3, 109.5, 60.9, 49.3, 45.6,
41.9, 26.7, 14.1. HRMS (ESI) calcd for C23H22BrClNO4 [M + H]+
490.0421, found 490.0407.
Ethyl 2-{1-Methyl-2-oxo-6′-phenylspiro[indoline-3,4′-pyran]-
2′(3′H)-ylidene}acetate (7a). 129.4 mg, 69% yield; yellow oil. 1H
NMR (500 MHZ, CDCl3) δ (ppm) = 7.58−7.56 (m, 2H), 7.33−7.28
(m, 5H), 7.10 (t, 1H, J = 7.5 Hz), 6.84 (d, 1H, J = 7.5 Hz), 5.12 (d,
1H, J = 2.0 Hz), 4.66 (d, 1H, J = 2.5 Hz), 4.22 (q, 2H, J = 7.0 Hz),
3.38 (d, 1H, J = 16.0 Hz), 3.28 (d, 1H, J = 16.0 Hz), 3.24 (s, 3H), 1.30
(t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 178.5,
169.1, 150.8, 147.4, 142.1, 135.7, 133.3, 128.9, 128.8, 128.2, 125.7,
124.8, 123.3, 108.0, 99.5, 96.3, 61.2, 48.7, 39.6, 26.7, 14.2. HRMS
(ESI) calcd for C23H22NO4 [M + H]+ 376.1549, found 376.1555.
Ethyl 2-{5-Chloro-1-methyl-2-oxo-6′-phenylspiro[indoline-3,4′-
pyran]-2′(3′H)-ylidene}acetate (7b). 128.8 mg, 63% yield; pale yellow
1
oil. H NMR (500 MHZ, CDCl3) δ (ppm) = 7.58−7.56 (m, 2H),
7.35−7.33 (m, 3H), 7.29−7.25 (m, 3H), 6.76 (d, 1H, J = 8.0 Hz), 5.09
(d, 1H, J = 2.0 Hz), 4.65 (d, 1H, J = 2.0 Hz), 4.22 (q, 2H, J = 7.0 Hz),
3.38 (d, 1H, J = 16.0 Hz), 3.29 (d, 1H, J = 16.0 Hz), 3.23 (s, 3H), 1.31
(t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 178.1,
168.9, 151.2, 147.8, 140.7, 137.2, 133.1, 129.1, 128.8, 128.7, 128.3,
126.1, 124.9, 109.0, 98.9, 95.6, 61.3, 48.9, 39.5, 26.8, 14.2. HRMS
(ESI) calcd for C23H21ClNO4 [M + H]+ 410.1159, found 410.1159.
Ethyl 2-{5-Bromo-1-methyl-2-oxo-6′-phenylspiro[indoline-3,4′-
pyran]-2′(3′H)-ylidene}acetate (7c). 147.2 mg, 65% yield; white
1
solid, mp 128−130 °C. H NMR (500 MHZ, CDCl3) δ (ppm) =
7.58−7.56 (m, 2H), 7.42 (dd, 1H, J = 8.5, 2.0 Hz), 7.38 (d, 1H, J = 2.0
Hz), 7.34 (dd, 3H, J = 5.0, 2.0 Hz), 6.72 (d, 1H, J = 8.0 Hz), 5.08 (d,
1H, J = 2.0 Hz), 4.65 (d, 1H, J = 2.0 Hz), 4.22 (q, 2H, J = 7.0 Hz),
3.38 (d, 1H, J = 16.0 Hz), 3.29 (d, 1H, J = 16.0 Hz), 3.22 (s, 3H), 1.31
(t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ (ppm) = 177.9,
168.9, 151.2, 147.8, 141.2, 137.5, 133.0, 131.7, 129.1, 128.9, 128.3,
Ethyl 3-Chloro-4-[1,5-dimethyl-2-oxo-3-(2-oxo-2-phenylethyl)-
indolin-3-yl]but-2-enoate (6g). 140.3 mg, 66% yield; white solid,
1
mp 126−127 °C. H NMR (500 MHZ, CDCl3) δ (ppm) = 7.84 (dd,
2H, J = 8.5, 1.0 Hz), 7.52 (t, 1H, J = 7.5 Hz), 7.40 (t, 2H, J = 8.0 Hz),
G
dx.doi.org/10.1021/jo502209f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
124.9, 116.0, 109.5, 98.9, 95.6, 61.3, 48.8, 39.5, 26.7, 14.2. HRMS
(ESI) calcd for C23H21BrNO4 [M + H]+ 454.0654, found 454.0644.
Liang, Y.-M.; Xu, P.-F. Org. Lett. 2014, 16, 1802−1805. (d) Gicquel,
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ASSOCIATED CONTENT
* Supporting Information
■
S
1H NMR and 13C NMR spectra of all compounds; three figures
and six tables with single-crystal X-ray structures, crystal data
and structure refinement, and atomic coordinates and
equivalent isotropic displacement parameters for 3a, 4c, and
6e (PDF). Crystallographic information files for 3a, 4c, and 6e
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
(5) (a) England, D. B.; Merey, G.; Padwa, A. Org. Lett. 2007, 9,
3805−3807. (b) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.;
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail xsjia@mail.shu.edu.cn.
*E-mail lijian@shu.edu.cn.
́
105, 2829−2872. (d) Lopez, F.; Mascarenas, J. L. Chem. Soc. Rev.
̃
2014, 43, 2904−2915. (e) Ma, S. Acc. Chem. Res. 2009, 42, 1679−
1688. (f) Alcaide, B.; Almendros, P.; Martínez del Campo, T. Chem.
Eur. J. 2010, 16, 5836−5842. (g) Aubert, C.; Fensterbank, L.; Garcia,
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Notes
The authors declare no competing financial interest.
(h) Soriano, E.; Fernan
́
dez, I. Chem. Soc. Rev. 2014, 43, 3041−3105.
ACKNOWLEDGMENTS
■
(i) Lop
́
ez, F.; Mascarenas, J. L. Chem.Eur. J. 2011, 17, 418−428.
̃
We thank the National Natural Science Foundation of China
(21272148, 21272147, 21472121) and the Key Laboratory of
Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, Chinese Academy of Science, for
financial support. We thank a reviewer for helpful mechanistic
suggestions that have been incorporated in the manuscript as
they were provided. We also thank Dr. Hongmei Deng and Min
Shao of Laboratory for Microstructures, Shanghai University,
for the NMR and single-crystal X-ray analyses.
(j) Inagaki, F.; Kitagaki, S.; Mukai, C. Synlett 2011, 594−614.
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