Regio- and diastereoselective construction of spirocyclopenteneoxindoles through phosphine-catalyzed [3 + 2] annulation of methyleneindolinone with alkynoate derivatives

Article abstract of DOI:10.1021/acs.joc.7b01582

A phosphine-catalyzed [3 + 2] annulation of isatin-derived α,β-unsaturated ketones with alkynoates for the synthesis of cyclopentene spiro-oxindole skeletons has been developed. This reaction afforded the desired products in high to excellent yields (up to 99%) with high regioselectivity and moderate to high diastereoselectivities (up to 20:1). This strategy allows facile diastereoselective preparation of biologically important spiro-(cyclopentene) oxindoles containing three contiguous stereocenters, including the quaternary stereogenic center joining the two rings.

Full text of DOI:10.1021/acs.joc.7b01582

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Article
Regio- and Diastereoselective Construction of
Spirocyclopenteneoxindoles through Phosphine-catalyzed [3+2]
Annulation of Methyleneindolinone with Alkynoate Derivatives
Jiayong Zhang, Cheng Cheng, Dian Wang, and Zhiwei Miao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01582 • Publication Date (Web): 12 Sep 2017
Downloaded from http://pubs.acs.org on September 12, 2017
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Regio-
and
Diastereoselective
Construction
of
Spirocyclopenteneoxindoles through Phosphine-catalyzed
[3+2] Annulation of Methyleneindolinone with Alkynoate
Derivatives
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†
†
†
,†,‡
Jiayong Zhang , Cheng Cheng , Dian Wang , Zhiwei Miao*
†
State Key Laboratory and Institute of ElementoꢀOrganic Chemistry, College of
Chemistry, Nankai University, Weijin Road 94, Tianjin 300071, China
‡
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, China
Regio- and Diastereoselective Construction of Spirocyclopenteneoxindoles through
Phosphine-catalyzed [3+2] Annulation of Methyleneindolinone with Alkynoate Derivatives
Jiayong Zhang, Cheng Cheng, Dian Wang, and Zhiwei Miao*
R1 = Me, Et, Bn
R1
2
CO
CO R3
2
R2 = H, Me, Bn
t
R2
CO
2
R3 R3 = Me, Et, Bu
CO
2
R1
R4
PBu
3
(20 mol%)
R4
R4 = H, 5-Br, 5-Cl, 5-Me,
O
O
R2
+
toluene, rt, 24h
N
N
R5
5
-NO , 6-OMe, 7-Me
2
R5
R5 = Me, Bn
dr > 20:1
Yield: 76-99%
Abstract:
A phosphineꢀcatalyzed [3+2] annulation of isatin derived α,βꢀunsaturated ketones
with alkynoates for the synthesis of cyclopentene spiroꢀoxindole skeletons has been
developed. This reaction afforded the desired products in high to excellent yields (up
to 99%) with high regioselectivity and moderate to high diastereoselectivities (up to
20:1). This strategy allows facile diastereoselective preparation of biologically
important spiroꢀ(cyclopentene) oxindoles containing three contiguous stereocenters,
including the quaternary stereogenic center joining the two rings.
Keywords:
Phosphineꢀcatalyzed annulation; Spirocyclopenteneoxindoles; Asymmetric synthesis;
Regioselectivity; Diastereoselectivity
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Introduction
The regioselective and stereoselective preparation of biologically relevant
spirooxindoles, which contain a tetrasubstituted carbon stereocenter at the Cꢀ3
position, is challenging and has led to a demand for efficient methods for their
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synthesis. Among the family of spirooxindoles, the spirooxindoles with carbocyclic
fiveꢀmembered rings behave a key pharmacophore in many bioactive natural products,
2
3
4
such as citrinadins, cycloplamines, versicolamides, and notoamides as well as in
5
synthetic bioactive compounds. Consequently, much effort aimed toward identifying
general methods for the synthesis of these spirocyclopentene oxindole scaffolds has
6
been made. The challenging point is that biologically relevant spirooxindoles often
display a stereogenic allꢀcarbon quaternary center at the C3ꢀposition, the
7
stereochemistry of which must be controlled through appropriate synthetic strategies.
Considering the intriguing molecular architecture and potent biological activities,
various protocols have been developed to synthesize this class of molecules. However,
the diastereoselective synthesis of fiveꢀmembered spirooxindole, especially
functionalized allꢀcarbon spirocyclopentene oxindole containing three contiguous
8
stereocenters still remains a challenging task.
In 2013, Marinetti and Voituriez developed the phosphineꢀpromoted synthesis of
3,3ꢀspirocyclo penteneoxindoles by [3+2] annulations between γꢀsubstituted
9
allenoates and arylideneoxindoles (Scheme 1, a). Huang and coꢀworkers described a
phosphineꢀcatalyzed RauhutꢀCurrier domino reaction of conjugated diene with
1
0
methyleneindolinones for the synthesis of carbocyclic spirooxindoles (Scheme 1, b).
Even though a lot of phosphineꢀparticipated reactions have been discovered, few
efforts so far have been focused on the strategy for spiroꢀfused penteneoxindole
11
framworks employing alkynoate derivatives as substrates.
Recently,
a
nucleophilicꢀphosphineꢀcatalyzed annulation of electron deficient alkynes has
emerged as a powerful tool for the construction of various biologically active
1
2
13
carbocycles and heterocycles containing spiroꢀoxindole skeletons. We have
recently reported the regioꢀ and stereocontrolled synthesis of cyclopenteneꢀfused
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spiroꢀrhodanines through phosphineꢀcatalyzed [3+2] cycloaddition of alkynoate
1
4
derivatives with 5ꢀarylideneꢀ3ꢀ(tertꢀbutyl)ꢀ2ꢀthioxothiazolidinꢀ4ꢀones (Scheme 1, c).
Inspired by our previous studies on the use of alkynoate derivatives in [3+2]
cycloaddition reaction, in this report we describe phosphineꢀcatalyzed highly
diastereoselective [3+2] cycloaddition between 5ꢀarylpentꢀ2ꢀynoates and
methyleneindolinones in the synthesis of cyclopenteneꢀfused spiroꢀoxindole skeletons.
This methodology led to molecules containing three contiguous stereocenters,
including one spiro quaternary carbon center in good to excellent yields and
stereoselectivities with up to >20:1 diastereomeric ratio (dr).
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Previous work:
1
R O C
2
Ar
Ar
1
CO R
2
PPh (20 mol%)
R
O
3
(a)
O +
R
toluene, rt
N
N
Ac
Ac
trans-trans
R1
R1
O
O
O
R1
R1
R3
R3
O
O
O
PBu (20 mol%)
R4
R4
3
+
R1
R1
o
R3
CHCl
, 60 C
(b)
(c)
3
O
O
+
N
N
R4
R2
cis
R2
trans
O
N
R2
2
R O
tBu
O
EtO C
N
CO Et
2
2
R2
PBu (20 mol%)
tBu
3
R1
+
N
S
toluene, rt
S
S
S
R1
This work:
1
CO R
2
3
CO R
2
R2
3
CO R
2
1
PBu
(20 mol%)
3
CO R
R4
R4
2
O
O
(d)
R2
+
N
R5
toluene, rt, 24h
N
R5
Scheme 1. Previous and proposed work.
Result and Discussion
We initiated our investigation by evaluating the reaction of ethyl
5
ꢀphenylpentꢀ2ꢀynoate 1a and (Z)ꢀmethyleneindolinone 2a with toluene as the solvent
3
in the presence of 20 mol% of triphenylphosphine (PPh ) at room temperature (Table
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, entry 1). Unexpectedly, triphenylphosphine failed to catalyze the reaction. No
product was obtained after 24h, and 1a was completely recovered. We assumed that
the lack of reaction was due to the weak nucleophilic ability of the phosphine.
Therefore, we turned our attention to more active phosphine catalysts (Table 1, entries
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2ꢀ6). With sterically bulky methylꢀdiphenylphosphine (Ph PMe) as the catalyst, the
2
desired cycloadditon product 3a was obtained in 43% yield with moderate
diastereoselectivity (8:1 dr) (Table 1, entry 2). The result inspired us and
demonstrated that our design is feasible. In the screening of phosphine catalysts,
3
tributylphosphine (Bu P) emerged as the preferred catalyst in terms of the yield and
diastereoselectivity (Table 1, entries 3ꢀ6). This result, in line with the nucleophilicity
of the phosphines, showed that the efficiency of formation of these skeletons is highly
catalystꢀdependent.
a
Table 1. Optimization of conditions of the [3+2] cycloaddition of 1a and 2a.
CO Et
2
CO Et
CO Et
2
2
Bn
CO Et
2
Cat. (20 mol%)
Solvent, rt, Time
+
O
O
N
N
1
a
2a
3a
b
c
Entry
1
Catalyst
PPh3
Solvent
toluene
Time (h)
d.r.
Yield (%)
24
24
24
24
24
24
24
24
24
24
12
24
－
－
2
3
4
5
6
7
8
9
Ph PMe
toluene
toluene
toluene
toluene
toluene
THF
8:1
7:1
9:1
6:1
6:1
6:1
5:1
5:1
6:1
8:1
8:1
43
57
93
52
61
73
51
59
37
82
53
2
Ph PEt
2
PBu3
d
DPPP
e
DPPB
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
DCM
MeCN
f
1
0
1
MTBE
1
toluene
toluene
g
1
2
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h
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PBu3
toluene
24
9:1
42
a
Unless otherwise specified, all reactions were carried out using ethyl 5ꢀphenylpentꢀ2ꢀynoate 1a
(
0.15 mmol) and (Z)ꢀmethyleneindolinone 2a (0.10 mmol) in 1 mL solvent with 20 mol% of
b
1
catalyst at room temperature. Diastereomeric ratio (dr) values were determined by H NMR of crude
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c
d
products.
Yield of isolated product of 3a after column chromatography.
DPPP =
e
f
1
,3ꢀbis(diphenylphosphino)propane.
DPPB = 1,3ꢀbis(diphenylphosphino)butane. MTBE =
g
h
methyl tertꢀbutyl ether. 10% PBu
3
was used. The temperature of the reaction was reduced to
0
ºC.
Subsequently, solvent effects were investigated for this reaction. Various solvents,
such as THF, DCM, MeCN, and methyl tertꢀbutyl ether (MTBE) were scanned, but no
better results could be obtained (Table 1, entries 7ꢀ10), nor did toluene lead to a
satisfactory yield and diastereoselectivity. Further studies suggested that reduce
reaction time disfavoured this reaction, when the reaction time shorted to 12h, the
reaction yield decreased to 82% with 8:1 dr (Table 1, entry 11). Decreasing the
loading of catalyst and the reaction temperature lead to the decrease of the
diastereoselectivities and yields (Table 1, entries 12ꢀ13). Finally, we confirmed the
optimal reaction conditions for this transformation as 0.15 mmol ethyl
5
ꢀphenylpentꢀ2ꢀynoate 1a, 0.10 mmol (Z)ꢀmethyleneindolinone 2a, and 20 mol% of
PBu as a catalyst in 1 mL toluene as a solvent at room temperature. The
3
1
diastereomeric ratio of product was determined by H NMR spectroscopy of the crude
product. In order to determine the relative configuration of the major diastereomer 3a,
a single crystal Xꢀray diffraction study of 3a was performed (see the details in
15
Supporting Information). The molecular structure of 3a showed that the relative
configuration of the main product was assigned as threo.
We then examine the scope and limitations of this reaction between alkynoate
derivatives 1 and diversified (Z)ꢀmethyleneindolinones 2. In the case of compound 2,
either bearing a neutral, electronꢀwithdrawing or electronꢀdonating group at 5ꢀ, 6ꢀ or
7
ꢀ position of the benzene ring of Nꢀmethyl isatins, the reactions proceeded smoothly
to give cyclopentene 4ꢀspiroꢀoxindoles 3 in good to excellent yields with moderate to
excellent diastereoselectivities (Table 2). However, when the substituent at the
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ꢀposition with electronꢀwithdrawing group of the benzene ring of Nꢀmethyl isatin 2k
and 2l, the spiro compounds 3p and 3q were obtained in somewhat lower yields with
lower diastereoselectivities (Table 2, entries 16 and 17). Furthermore, it was observed
that the steric hindrance of the ester substituent of (Z)ꢀmethyleneindolinones 2 has no
effect on the result (Table 2, entries 6ꢀ8). Exchanging the Nꢀprotecting group with Bn
also gave the cyclic adducts in good yields with moderate diastereoselectivities (Table
0
1
2
3
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5
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8
9
0
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
2
, entries 19ꢀ20).
Finally, selected alkynoates 1 were further examined in the cycloaddition
reaction with representative (Z)ꢀmethyleneindolinones 2. The substituents in the
alkynoates 1 were well tolerated, leading to formation of desired products in good
yields and moderate diastereoselectivities (Table 2, entries 12ꢀ20). We were delighted
to find that the aliphatic substitute alkynoate derivative, ethyl butꢀ2ꢀynoate (1d),
underwent smooth sequential annulations with 2h and 2a, respectively, to give the
corresponding products (i.e., 3i and 3u) in good yields with excellent
diastereoselectivities (Table 2, entries 9 and 21).
a
Table 2. Substrate scope of the reaction
CO R1
2
CO R3
2
2
4
R
5
CO
R3
2
O
PBu (20 mol%)
CO R1
3
3
R4
R4
2
O
R2
toluene, rt, 24h
2
N
R5
6
1N
7
R5
1
2
3
1
2
3
4
5
b
Entry Product
R
R
R
R
R
dr
Yield
c
(%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
Et
Et
Bn (1a)
Bn (1a)
Me (1b)
Bn (1a)
Bn (1c)
Bn (1c)
Bn (1a)
Bn (1c)
H (1d)
Et
H
Me (2a)
Me (2b)
Me (2c)
Me (2d)
Me (2e)
Me (2f)
Me (2g)
Me (2g)
Me (2h)
Me (2f)
Me (2h)
Me (2f)
9:1
93
87
76
91
86
99
97
87
91
93
83
95
Me
5ꢀBr
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
16:1
t
Et
Bu
5ꢀCl
Et
Et
Et
Et
5ꢀMe
Bn
Bn
Et
5ꢀBr
6ꢀOMe
6ꢀOMe
6ꢀOMe
6ꢀOMe
6ꢀOMe
6ꢀOMe
6ꢀOMe
t
3g
3h
3i
Bu
t
Bn
Et
Bu
Me
Et
10
3j
Me
Me
Et
Bn (1e)
Bn (1e)
Me (1b)
11
3k
3l
Me
Et
10:1
12
8:1
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3m
3n
3o
3p
3q
3r
3s
Bn
Me
Et
Bn (1c)
Bn (1e)
Me (1b)
Me (1b)
Bn (1a)
Bn (1c)
Bn (1a)
Bn (1c)
H (1d)
Me
Et
Et
Et
Et
Et
7ꢀMe
7ꢀMe
5ꢀMe
Me (2i)
Me (2j)
Me (2d)
Me (2k)
Me (2l)
Me (2a)
Bn (2m)
Bn (2m)
Me (2a)
8:1
6:1
96
87
82
69
79
86
91
85
86
1
4
5
1
6:1
16
Et
5ꢀNO
5ꢀCl
H
2
4:1
17
18
19
Et
2:1
Bn
Et
8:1
10
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t
Bu
H
8:1
t
20
3t
Bn
Et
Bu
H
12:1
>20:1
21
3u
Et
H
a
Reaction conditions: alkynoate 1 (0.15 mmol), methyleneindolinones 2 (0.10 mmol) in 1 mL of
b
toluene at room temperature in the presence of 20 mol% of PBu
3
. Diastereomeric ratio (dr) values
1
c
were determined by H NMR of crude products. Isolated yield after silica gel chromatography of 3.
The regiochemical outcome of this reaction may be rationalized as depicted in
Scheme 2. Based on steric considerations, this [3+2] cycloaddition reaction can take
place via the transition state TS I, which would be expected to be favoured over the
more sterically demanding transition state TS II. Thus, we obtained regioisomer A as
our product.
PBu3
PBu3
EtO C
2
CO Et
2
CO Et
CO Et
2
2
O
O
N
N
TS I
TS II
favored
disfavored
Bn
CO Et
2
Bn
EtO C
2
CO Et
CO Et
2
2
O
O
N
N
regioisomer A
regioisomer B
Scheme 2. Targeted approach to regioselectivitive synthesis of cyclopentene 5ꢀspiroꢀoxindole 3a.
In order to gain insight into the influences the product stereochemical outcome of
this reaction, we carried out one control experiment (Scheme 3). Under the identified
conditions,
treatment
of
ethyl
5ꢀphenylpentꢀ2ꢀynoate
1a
with
(
E)ꢀmethylideneꢀoxindole 2a’ in the presence of 20 mol% of PBu
3
furnished the
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3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
cyclopentane 4ꢀspiroꢀoxindole 3a’ in 86% yield with 8:1 dr. This result suggested that
the starting material alkyleneindolinone 2 cannot determine the product 3
stereochemical outcome.
CO Et
EtO C
2
2
CO Et
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
Bn
CO Et
2
PBu (20 mol%)
3
+
O
O
toluene, rt, 24h
N
N
1
a
2a'
3a'
6% yield
8:1 dr
8
Scheme 3. Control experiment for the synthesis of cyclopentene 5ꢀspiroꢀoxindole 3a’.
Preliminary studies on the asymmetric variant of this phosphineꢀcatalyzed [3+2]
annulation between methyleneindolinone and alkynoate derivatives were also
investigated by employing several chiral phosphines as catalyst. The [3+2] annulation
of
ethyl
5ꢀphenylpentꢀ2ꢀynoate
1a
with
ethyl
(Z)ꢀ2ꢀ(1ꢀmethylꢀ2ꢀmethyleneindolinꢀ3ꢀylidene) acetate 2a was selected as a model
reaction (Table 3). The chiral bifunctional catalyst P1 demonstrate good
diastereoselective but poor enantioselective catalytic capability (Table 3, entry 1).
Subsequent examination of several chiral bisphosphines (P2ꢀP5) showed that the
desired [3+2] annulation products could not be obtained and only starting materials
were recovered (Table 2, entries 2ꢀ5).
In particular, the commercially available tartaric acid based phosphine (ꢀ)ꢀDIOP
(P6) gave an encouraging result (73% yield, 98:2 dr and 59% ee) (the absolute
configuraton of the product 3a has not been determined) (Table 3, entry 6). However,
with P6 as chiral catalyst, the attempt to improve the enantioselectivity by decreasing
the reaction temperature to 0 ºC failed, only affording the cycloaddition product in
49% yield and 53% ee (Table 3, entry 7). Increasing the reaction temperature to 60 ºC
leads to a higher yield with excellent diastereoselectivity and 58% ee (Table 3, entry
8
).
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a
Table 3. Screening of the reaction conditions for an asymmetric variant
CO Et
2
CO Et
∗
Bn
CO Et
2
2
∗
CO Et
2
∗
cat. (20 mol%)
toluene, 24h
+
O
O
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
a
2a
3a
Pri
P
P
iPr
iPr
PPh2
Ph P
2
S
O
PPh2
N
N
H
H
Pri
NHBoc
(R)-BINAP
(R,R)-iPr-DuPhos
P1
P2
P3
Ph
Ph
PPh2
O
O
PPh2
P
P
Fe
PPh
2
Ph2P
Ph
Ph
(-)-DIOP
(
R,R)-Ph-BPE
DPPF
P4
P5
P6
b
c
d
Entry
Catalyst
P1
T (℃ )
rt
Yield (%)
dr (%)
ee (%)
5
1
2
3
4
5
6
7
8
43




73
49
92
11:1

P2
rt

P3
rt


P4
rt


P5
rt


59
P6
rt
98:2
95:5
>99:1
P6
0
53
P6
60
58
a
Unless otherwise specified, all reactions were carried out with 1a (0.15 mmol), 2a (0.10 mmol)
b
in the presence of 20 mol% of chiral catalyst in 1.0 mL toluene at room temperature. Yield of
c
isolated product of 3a after column chromatography. Diastereomeric ratio (dr) values were
1
d
determined by H NMR of crude products. Determined by chiral HPLC analysis.
The mechanism of this [3+2] annulation reaction is proposed on the basis of
16
previous literatures as shown in Scheme 4. The catalyst phosphine as a nucleophile
reacts with ethyl 5ꢀphenylpentꢀ2ꢀynoate 1a to produce the zwitterionic intermediate A,
which can isomerize to intermediate B. Intermediate B subsequently undergoes a
Michael addition to generate the intermediate C, which further undergoes an
intramolecular cyclization to furnish the phosphorene D. Intermediate D can be
converted to intermediate E via a Hꢀshift. Releasing the phosphine, the products 3 are
finally furnished. The reaction rate and diastereoselective product distribution of 3 is
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2
2
2
2
2
2
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3
3
3
3
3
3
3
3
3
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attributed to the steric hindrance effects and electronic repulsions between benzyl
group of alkynoate and tributylꢀphosphonium.
CO
2
R1
PBu3
PBu3
CO R1
2
CO R1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1a
A
B
CO
R3
2
PBu
3
R4
O
CO
2
R1
N
R5
Bn
2
CO
2
R3
R4
O
Bu3P
Bn
Bu3P
PBu3
O
R1
R3 H-shift
CO R1
2
CO
2
N
R5
CO R1
2
Bn
CO R3
3
CO
O
2
CO R3
2
O
2
R4
R4
N
N
R4
N
R5
R5
R5
E
D
C
Scheme 4. Proposed reaction mechanism.
Conclusion
In conclusion, we have developed an efficient phosphineꢀcatalyzed
diastereoselective [3+2] cycloaddition of alkynoate derivatives with
(Z)ꢀmethyleneindolinone, affording the functionalized 5ꢀspiroꢀcyclopenteneoxindole
derivatives in good to excellent yields, with high regioselectivities and
diastereoselectivities. Two new CꢀC bonds together with three contiguous
stereocenters, including one spiro quaternary chiral center were formed. Further
studies on the reactions of activated alkynoate derivatives to complex molecular
synthesis are currently underway in our laboratory and will be reported in due course.
Experimental
General section
2
All reactions were performed under N atmosphere in ovenꢀdried glassware with magnetic stirring.
Solvents were dried and distilled prior to use according to the standard methods. Unless otherwise
indicated, all materials were obtained from commercial sources, and used as purchased without
dehydration. Flash column chromatography was performed on silica gel (particle size 10ꢀ40 µm,
Ocean Chemical Factory of Qingdao, China). Nitrogen gas (99.999%) was purchased from Boc
1
13
3
Gas Inc. H NMR and C NMR spectra were recorded in CDCl at Bruker 400 MHz
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13
spectrometers, TMS served as internal standard (δ = 0 ppm) for H NMR and C NMR. The
crystal structure was determined on a Bruker SMART 1000 CCD diffractometer. Mass spectra were
obtained using an electrospray ionization (ESIꢀTOF) mass spectrometer. Optical rotations were
taken on a digital polarimeter. Enantiomeric excesses were determined using an HPLC instrument
with Chiralpak columns as noted.
10
11
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49
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53
54
55
56
57
58
59
60
Experimental section
General procedure for formal [3+2] cycloaddition reaction for products 3:
Under a nitrogen atmosphere, to a mixture of (Z)ꢀmethyleneindolinones 2 (0.1 mmol, 1.0 equiv),
3
and Bu P (4.1 mg, 0.02 mmol, 20 mmol%) was added toluene (1 mL) via a syringe and allowed to
stir for 5 min at room temperature. Alkynoates 1 (0.15 mmol, 1.5 equiv.) was added and the
reaction was allowed to stir for 24 h at room temperature. The reaction was monitored by TLC.
After the reaction was completed, the reaction mixture was directly purified by flash column
chromatograph (eluted with 20:1 petroleum ether/EtOAc) to afford the product 3.
Diethyl 5-benzyl-1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate (3a).
2
5
1
Yellow oil (40.3 mg, 93% yield); [α]D = +15 (c = 1.0, CH Cl ). H NMR (400 MHz, CDCl ): δ
2
2
3
7
.29 (d, J = 2.9 Hz, 1H), 7.24 (s, 1H), 7.06 (dd, J = 4.9, 1.6 Hz, 3H), 7.01 (t, J = 7.5 Hz, 1H), 6.77
(
t, J = 2.2 Hz, 1H), 6.66ꢀ6.54 (m, 3H), 4.48ꢀ4.38 (m, 1H), 4.27ꢀ4.19 (m, 2H), 3.85 (ddd, J = 10.3,
6
.4, 2.4 Hz, 1H), 3.57 (q, J = 7.1 Hz, 2H), 2.86 (dd, J = 14.0, 6.7 Hz, 1H), 2.80 (s, 3H), 2.36 (dd, J
13
=
14.0, 10.7 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.66 (t, J = 7.1 Hz, 3H); C NMR (101 MHz,
3
CDCl ): δ 177.1, 167.7, 163.2, 143.9, 143.4, 136.2, 132.4, 127.9, 127.7, 126.9, 125.2, 125.1, 124.6,
120.7, 106.9, 59.7, 59.3, 58.5, 57.9, 52.9, 34.5, 25.0, 13.2, 12.5; HRMS (ESIꢀTOF): m/z calcd for
+
C H NO [M+H] : 434.1962, found 434.1956. The enantiomeric excess was determined by
2
6
28
5
HPLC (Chiralpak ADꢀH column: nꢀhexane/iꢀPrOH, 90:10 v/v, flow rate = 1.0 mL/min, λ = 254
nm): t (major) = 52.82 min, t (minor) = 61.19 min.
R
R
3-Ethyl
2-methyl
5-benzyl-5'-bromo-1'-methyl-2'-oxospiro[cyclopentane-1,3'-indoline]-3-ene-2,3-dicarboxylate
1
(3b). Yellow oil (43.2mg, 87% yield); H NMR (400 MHz, CDCl
3
): δ 7.40 (dd, J = 6.9, 1.9 Hz,
2H), 7.07 (dd, J = 4.9, 1.8 Hz, 3H), 6.80 (t, J = 2.2 Hz, 1H), 6.64 (dd, J = 6.5, 2.7 Hz, 2H), 6.44 (d,
J = 8.9 Hz, 1H), 4.46ꢀ4.36 (m, 1H), 4.31ꢀ4.19 (m, 2H), 3.92ꢀ3.82 (m, 1H), 3.19 (s, 3H), 2.93 (dd, J
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
5
5
5
5
5
5
6
13
=
14.1, 6.5 Hz, 1H), 2.76 (s, 3H), 2.39 (dd, J = 14.1, 11.0 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H); C
3
NMR (101 MHz, CDCl ): δ 174.1, 168.4, 162.3, 147.2, 141.5, 135.8, 131.8, 130.7, 127.8, 127.7,
1
26.9, 125.4, 124.9, 113.8, 108.8, 59.9, 58.6, 58.3, 53.2, 51.4, 33.9, 25.0, 13.1; HRMS (ESIꢀTOF):
+
m/z calcd for C25
H
25BrNO
5
[M+H] : 498.0911, found 498.0906.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2-(tert-Butyl)
3-ethyl
5
'-chloro-1',5-dimethyl-2'-oxospiro[cyclopentane-1,3'-indoline]-3-ene-2,3-dicarboxylate (3c).
1
Yellow oil (31.9 mg, 76% yield); H NMR (400 MHz, CDCl
3
): δ 7.29ꢀ7.26 (m, 1H), 7.16 (d, J =
2
3
.0 Hz, 1H), 6.96ꢀ6.89 (m, 1H), 6.77 (d, J = 8.3 Hz, 1H), 4.29ꢀ4.17 (m, 2H), 3.79 (s, 1H),
.71ꢀ3.60 (m, 1H), 3.22 (s, 3H), 1.42 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H), 0.82 (d, J = 7.5 Hz, 3H);
13
3
C NMR (101 MHz, CDCl ): δ 174.7, 166.8, 162.7, 148.0, 146.3, 140.7, 132.1, 127.5, 126.7,
1
22.7, 108.0, 80.6, 59.7, 59.4, 59.3, 47.1, 26.9, 25.4, 13.2, 12.7; HRMS (ESIꢀTOF): m/z calcd for
+
C
22
H
27ClNO
5
[M+H] : 420.1572, found 420.1571.
Diethyl 5-benzyl-1',5'-dimethyl-2'-oxospiro[cyclopentane-1,3'-indoline]-3-ene-2,3-dicarboxylate
1
(3d). Yellow oil (40.7 mg, 91% yield); H NMR (400 MHz, CDCl
3
): δ 7.07 (dt, J = 6.4, 5.9 Hz,
5
1
3
H), 6.77 (t, J = 2.2 Hz, 1H), 6.63 (dd, J = 7.0, 2.3 Hz, 2H), 6.47 (d, J = 7.9 Hz, 1H), 4.48ꢀ4.38 (m,
H), 4.31ꢀ4.17 (m, 2H), 3.88ꢀ3.73 (m, 1H), 3.58 (q, J = 7.1 Hz, 2H), 2.89ꢀ2.81 (m, 1H), 2.80 (s,
H), 2.39ꢀ2.35 (m, 1H), 2.33 (d, J = 6.5 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 0.67 (t, J = 7.1 Hz, 3H);
13
C NMR (101 MHz, CDCl ): δ 177.1, 167.7, 163.4, 144.1, 141.1, 136.4, 132.4, 130.2, 128.2,
3
1
27.8, 127.0, 125.4, 125.3, 125.2, 106.7, 59.7, 59.3, 58.7, 57.9, 53.1, 34.5, 25.1, 20.2, 13.2, 12.5;
+
HRMS (ESIꢀTOF): m/z calcd for C27
H
30NO
5
[M+H] : 448.2118, found 448.2116.
3-Benzyl
2-ethyl
5-benzyl-5'-bromo-1'-methyl-2'-oxospiro[cyclopentane-1,3'-indoline]-3-ene-2,3-dicarboxylate
1
(3e). Yellow oil (50.5 mg, 88% yield); H NMR (400 MHz, CDCl
3
): δ 7.36 (ddd, J = 15.1, 9.1, 6.6
Hz, 7H), 7.10ꢀ7.02 (m, 3H), 6.84 (t, J = 2.1 Hz, 1H), 6.65ꢀ6.57 (m, 2H), 6.41 (d, J = 8.1 Hz, 1H),
5
3
1
1
5
.27 (d, J = 12.4 Hz, 1H), 5.18 (d, J = 12.3 Hz, 1H), 4.42 (t, J = 2.8 Hz, 1H), 3.92ꢀ3.81 (m, 1H),
.59 (q, J = 7.1 Hz, 2H), 2.93 (dd, J = 14.1, 6.3 Hz, 1H), 2.74 (s, 3H), 2.38 (dd, J = 14.1, 11.2 Hz,
13
H), 0.71 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl
3
): δ 176.5, 167.3, 162.8, 144.5, 142.5,
35.7, 134.7, 132.0, 130.8, 127.7, 127.6, 127.5, 127.3, 127.2, 127.0, 125.3, 113.1, 108.3, 65.5,
+
9.6, 58.5, 57.9, 52.8, 34.4, 25.1, 12.5; HRMS (ESIꢀTOF): m/z calcd for C31
H
29BrNO
5
[M+H] :
574.1224, found 574.1217.
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-Benzyl
2-ethyl
5-benzyl-6'-methoxy-1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate
1
(3f). Yellow oil (51.9 mg, 99% yield); H NMR (400 MHz, CDCl
3
): δ 7.34 (t, J = 5.8 Hz, 5H),
7.16 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 6.1 Hz, 3H), 6.81 (s, 1H), 6.64 (d, J = 7.0 Hz, 2H), 6.50 (d, J
= 8.1 Hz, 1H), 6.15 (s, 1H), 5.21 (dd, J = 28.7, 12.4 Hz, 2H), 4.40 (s, 1H), 3.82 (s, 4H), 3.57 (q, J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
=
7.1 Hz, 2H), 2.84 (dd, J = 13.9, 6.6 Hz, 1H), 2.77 (s, 3H), 2.35 (dd, J = 13.7, 10.9 Hz, 1H), 0.68
13
(
t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl
3
): δ 177.6, 167.7, 163.0, 159.9, 144.8, 144.7,
136.3, 134.8, 131.9, 127.7, 127.5, 127.2, 126.9, 125.3, 125.2, 117.1, 104.3, 94.9, 65.4, 59.3, 58.2,
+
57.9, 54.6, 53.1, 34.5, 25.0, 12.6; HRMS (ESIꢀTOF): m/z calcd for C32
H32NO
6
[M+H] : 526.2224,
found 526.2227.
2-(tert-Butyl)
3-ethyl
5-benzyl-6'-methoxy-1'-methyl-2'-oxospiro[cyclopentane-1,3'-indoline]-3-ene-2,3-dicarboxylate
1
(3g). Yellow oil (47.6 mg, 97% yield); H NMR (400 MHz, CDCl
3
): δ 7.18 (d, J = 8.2 Hz, 1H),
7.07 (t, J = 6.0 Hz, 3H), 6.71 (t, J = 2.2 Hz, 1H), 6.65 (dd, J = 7.4, 1.8 Hz, 2H), 6.51 (dd, J = 8.3,
.3 Hz, 1H), 6.17 (d, J = 2.3 Hz, 1H), 4.33 (dt, J = 10.7, 5.4 Hz, 1H), 4.30ꢀ4.11 (m, 2H), 3.84ꢀ3.80
m, 3H), 3.80ꢀ3.71 (m, 1H), 2.83 (dd, J = 14.0, 6.6 Hz, 1H), 2.76 (s, 3H), 2.34 (dd, J = 13.9, 10.6
2
(
13
Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.94 (s, 9H); C NMR (101 MHz, CDCl
3
): δ 177.9, 166.7,
1
5
4
63.7, 160.0, 145.0, 143.5, 136.5, 132.9, 127.8, 127.0, 125.5, 125.2, 117.7, 104.3, 95.1, 79.6, 59.6,
+
6
8.7, 58.4, 54.7, 53.1, 34.5, 26.3, 25.0, 13.2; HRMS (ESIꢀTOF): m/z calcd for C29H34NO [M+H] :
92.2381, found 492.2373.
3-Benzyl
2-tert-butyl
5-benzyl-6'-methoxy-1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate
1
(3h). Yellow oil (49.7 mg, 90% yield); H NMR (400 MHz, CDCl
3
): δ 7.37ꢀ7.28 (m, 5H), 7.18 (d,
J = 8.2 Hz, 1H), 7.07 (d, J = 7.0 Hz, 3H), 6.77 (t, J = 2.2 Hz, 1H), 6.63 (dd, J = 7.3, 1.8 Hz, 2H),
.52 (s, 1H), 6.17 (d, J = 2.3 Hz, 1H), 5.20 (dd, J = 54.2, 12.4 Hz, 2H), 4.40ꢀ4.27 (m, 1H), 3.81 (d,
6
J = 9.7 Hz, 4H), 2.83 (dd, J = 14.0, 6.5 Hz, 1H), 2.74 (d, J = 6.3 Hz, 3H), 2.33 (dd, J = 13.9, 10.8
13
Hz, 1H), 0.88 (s, 9H); C NMR (101 MHz, CDCl
3
): δ 177.7, 166.6, 163.4, 159.9, 144.9, 144.2,
136.3, 134.7, 132.4, 127.7, 127.4, 127.2, 127.1, 126.9, 125.4, 125.1, 117.6, 104.2, 95.0, 79.6, 65.5,
+
6
58.5, 58.3, 54.7, 53.0, 34.3, 26.2, 24.9; HRMS (ESIꢀTOF): m/z calcd for C34H36NO [M+H] :
554.2537, found 554.2527.
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-Ethyl
2-methyl
(3i).
6
'-methoxy-1'-methyl-2'-oxospiro[cyclopentane-1,3'-indoline]-3-ene-2,3-dicarboxylate
1
Yellow oil (32.7 mg, 91% yield); H NMR (400 MHz, CDCl
3
): δ 7.07 (d, J = 8.3 Hz, 1H), 6.97 (d,
J = 2.1 Hz, 1H), 6.49 (dd, J = 8.3, 2.1 Hz, 1H), 6.41 (d, J = 2.0 Hz, 1H), 4.27 (d, J = 2.0 Hz, 1H),
4.21 (ddd, J = 10.8, 9.0, 3.7 Hz, 2H), 3.81 (s, 3H), 3.27 (s, 3H), 3.23 (s, 3H), 3.10 (dd, J = 18.5,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
2
.0 Hz, 1H), 2.78 (dd, J = 18.5, 2.1 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); C NMR (101 MHz,
CDCl
3
): δ 179.1, 169.5, 163.0, 159.9, 144.0, 142.3, 133.3, 123.8, 121.9, 105.5, 95.4, 59.9, 58.2,
+
54.8, 53.5, 50.9, 43.5, 25.9, 13.5; HRMS (ESIꢀTOF): m/z calcd for C H NO [M+H] : 360.1442,
1
9
22
6
found 360.1439.
2-Ethyl
3-methyl
5-benzyl-6'-methoxy-1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate (3j).
1
Yellow oil (42.6 mg, 95% yield); H NMR (400 MHz, CDCl
3
): δ 7.15 (d, J = 8.2 Hz, 1H), 7.08 (t,
J = 6.0 Hz, 3H), 6.77 (t, J = 2.2 Hz, 1H), 6.69ꢀ6.62 (m, 2H), 6.51 (dd, J = 8.3, 2.3 Hz, 1H), 6.16 (d,
J = 2.3 Hz, 1H), 4.39 (t, J = 2.8 Hz, 1H), 3.82 (s, 3H), 3.81ꢀ3.78 (m, 1H), 3.77 (s, 3H), 3.61 (qd, J
=
7.1, 2.0 Hz, 2H), 2.84 (dd, J = 13.9, 6.7 Hz, 1H), 2.78 (s, 3H), 2.35 (dd, J = 13.9, 10.5 Hz, 1H),
1
3
0
3
.72 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl ): δ 177.6, 167.7, 163.7, 159.8, 144.7, 144.4,
136.3, 131.9, 127.7, 126.9, 125.2, 117.1, 104.3, 94.9, 59.3, 58.2, 57.8, 54.6, 53.1, 50.8, 34.5, 25.1,
+
12.6; HRMS (ESIꢀTOF): m/z calcd for C H NO [M+H] : 450.1911, found 450.1910.
2
6
28
6
Dimethyl
5-benzyl-6'-methoxy-1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate
1
(3k). Yellow oil (36.1 mg, 83% yield); H NMR (400 MHz, CDCl ): δ 7.14 (d, J = 8.2 Hz, 1H),
3
7.09 (q, J = 5.1 Hz, 3H), 6.79 (t, J = 2.1 Hz, 1H), 6.70ꢀ6.62 (m, 2H), 6.51 (dd, J = 8.3, 2.3 Hz, 1H),
6.18 (d, J = 2.2 Hz, 1H), 4.40 (t, J = 2.7 Hz, 1H), 3.83 (s, 3H), 3.80 (d, J = 2.1 Hz, 1H), 3.77 (s,
3H), 3.14 (s, 3H), 2.85 (dd, J = 14.0, 7.0 Hz, 1H), 2.79 (s, 3H), 2.36 (dd, J = 13.8, 10.4 Hz, 1H);
13
3
C NMR (101 MHz, CDCl ): δ 177.6, 168.3, 163.6, 159.8, 144.7, 144.6, 136.3, 131.7, 127.7,
126.9, 125.2, 125.1, 117.1, 104.3, 94.9, 58.1, 57.9, 54.5, 53.1, 50.8, 50.4, 34.5, 25.1; HRMS
+
(
ESIꢀTOF): m/z calcd for C25
H
26NO
6
[M+H] : 436.1755, found 436.1754.
Diethyl
6
'-methoxy-1',5-dimethyl-2'-oxospiro[cyclopentane-1,3'-indolin]-3-ene-2,3-dicarboxylate (3l).
1
3
Yellow oil (36.8 mg, 95% yield); H NMR (400 MHz, CDCl ): δ 7.07 (d, J = 8.2 Hz, 1H), 6.72 (t,
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J = 2.0 Hz, 1H), 6.46 (dd, J = 8.3, 2.2 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 4.38 (t, J = 2.5 Hz, 1H),
4
1
.22 (dd, J = 14.0, 7.0 Hz, 2H), 3.80 (s, 3H), 3.68 (q, J = 7.1 Hz, 2H), 3.43 (qd, J = 7.3, 4.9 Hz,
1
3
3
H), 3.24 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 0.95ꢀ0.76 (m, 6H); C NMR (101 MHz, CDCl ): δ
178.1, 168.1, 163.3, 159.6, 146.1, 144.2, 131.9, 125.5, 117.4, 104.4, 95.0, 59.6, 59.3, 59.0, 57.6,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
54.5, 46.9, 25.6, 13.4, 13.2, 12.7; HRMS (ESIꢀTOF): m/z calcd for C21
H
26NO
6
[M+H] : 388.1755,
found 388.1749.
3-Benzyl
2-methyl
5
-benzyl-1',7'-dimethyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate
(3m).
1
Yellow oil (47.5mg, 96% yield); H NMR (400 MHz, CDCl
3
) : δ 7.44ꢀ7.27 (m, 5H), 7.08 (dd, J =
6
1
2
.9, 3.8 Hz, 4H), 6.88 (ddd, J = 18.1, 13.8, 4.8 Hz, 3H), 6.69ꢀ6.42 (m, 2H), 5.22 (dd, J = 44.1,
2.4 Hz, 2H), 4.54ꢀ3.97 (m, 1H), 3.85 (ddt, J = 8.3, 6.0, 3.1 Hz, 1H), 3.06 (s, 3H), 3.02 (s, 3H),
13
3
.88 (dd, J = 14.0, 6.3 Hz, 1H), 2.45ꢀ2.30 (m, 4H); C NMR (101 MHz, CDCl ): δ 177.9, 168.2,
163.0, 145.1, 141.0, 136.0, 134.7, 131.8, 131.6, 127.7, 127.5, 127.2, 126.9, 126.7, 125.5, 125.1,
122.3, 120.5, 118.5, 65.4, 58.1, 57.7, 53.3, 50.3, 34.3, 28.5, 18.0; HRMS (ESIꢀTOF): m/z calcd for
+
C
31
H
30NO
5
[M+H] : 496.2118, found 496.2123.
2-Ethyl
3-methyl
(3n).
5
-benzyl-1',7'-dimethyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate
1
Yellow oil (37.7 mg, 87% yield); H NMR (400 MHz, CDCl ): δ 7.16ꢀ7.02 (m, 4H), 6.97 (d, J =
3
7
3
.6 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.76 (s, 1H), 6.69ꢀ6.45 (m, 2H), 4.43 (t, J = 2.7 Hz, 1H),
.89ꢀ3.80 (m, 1H), 3.77 (d, J = 4.2 Hz, 3H), 3.72ꢀ3.43 (m, 2H), 3.00 (d, J = 24.9 Hz, 3H), 2.87 (dd,
1
3
J = 13.9, 6.4 Hz, 1H), 2.46ꢀ2.27 (m, 4H), 0.66 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl ): δ
3
178.0, 167.6, 163.8, 144.3, 141.2, 136.1, 132.0, 131.5, 127.8, 126.7, 125.6, 125.1, 122.4, 120.6,
118.4, 59.2, 58.0, 57.8, 53.2, 50.8, 34.3, 28.4, 17.9, 12.4; HRMS (ESIꢀTOF): m/z calcd for
+
C
26
H
28NO
5
[M+H] : 434.1962, found 434.1961.
Diethyl 1',5,5'-trimethyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate (3o).
1
Yellow oil (30.4 mg, 82% yield); H NMR (400 MHz, CDCl
3
): δ 7.06 (d, J = 7.9 Hz, 1H), 6.99 (s,
1
3
0
H), 6.74 (t, J = 2.2 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 4.42 (t, J = 2.7 Hz, 1H), 4.29ꢀ4.20 (m, 2H),
.64 (q, J = 7.1 Hz, 2H), 3.51ꢀ3.40 (m, 1H), 3.24 (s, 3H), 2.28 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H),
13
3
.80 (d, J = 7.4 Hz, 3H), 0.72 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl ): δ 177.4, 168.0,
163.4, 146.1, 140.5, 131.9, 130.4, 128.0, 125.6, 125.5, 106.6, 59.6, 59.4, 59.3, 57.5, 46.8, 25.6,
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
2
0.0, 13.4, 13.2, 12.5; HRMS (ESIꢀTOF): m/z calcd for C H NO [M+H] : 372.1805, found
21 26 5
372.1802.
Diethyl 1',5-dimethyl-5'-nitro-2'-oxospiro[cyclopentane-1,3'-indolin]-3-ene-2,3-dicarboxylate
1
(3p). Yellow oil (27.7 mg, 69% yield); H NMR (400 MHz, CDCl
3
): δ 7.22ꢀ7.15 (m, 1H), 6.97 (t,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 7.5 Hz, 1H), 6.88ꢀ6.79 (m, 1H), 6.73 (t, J = 2.2 Hz, 1H), 4.40 (dd, J = 26.9, 24.2 Hz, 1H), 4.23
(
ddt, J = 10.7, 6.9, 3.5 Hz, 2H), 3.63 (q, J = 7.1 Hz, 2H), 3.47 (ddd, J = 9.8, 7.4, 4.9 Hz, 1H), 3.25
(
d, J = 16.7 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.80 (d, J = 7.3 Hz, 3H), 0.73 (dd, J = 19.4, 12.2 Hz,
13
3
H); C NMR (101 MHz, CDCl ): δ 177.4, 168.2, 163.0, 145.9, 142.8, 131.8, 127.7, 126.7, 124.6,
3
1
20.9, 106.8, 59.6, 59.3, 59.2, 57.7, 46.8, 25.6, 13.4, 13.2, 12.6; HRMS (ESIꢀTOF): m/z calcd for
+
C
H
20 23
N
O
2 7
[M+H] : 403.1500, found 403.1506.
Diethyl
5
-benzyl-5'-chloro-1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate (3q).
1
Yellow oil (35.5 mg, 76% yield); H NMR (400 MHz, CDCl
3
): δ 7.37ꢀ7.26 (m, 2H), 7.07 (t, J =
5.7 Hz, 3H), 6.78 (s, 1H), 6.64 (d, J = 7.1 Hz, 2H), 6.51 (dd, J = 31.8, 8.3 Hz, 1H), 4.47ꢀ4.27 (m,
1
7
7
1
1
5
H), 4.23 (ddd, J = 10.5, 6.9, 3.4 Hz, 2H), 4.10ꢀ3.86 (m, 1H), 3.85ꢀ3.36 (m, 2H), 2.91 (dt, J = 14.3,
.3 Hz, 1H), 2.77 (s, 3H), 2.37 (ddd, J = 14.0, 11.0, 6.0 Hz, 1H), 1.32ꢀ1.26 (m, 3H), 0.76 (t, J =
13
3
.1 Hz, 3H); C NMR (101 MHz, CDCl ): δ 176.6, 174.2, 167.9, 167.4, 163.1, 162.4, 147.1,
43.7, 142.0, 141.0, 135.8, 135.7, 132.3, 131.8, 131.5, 127.8, 127.7, 127.0, 127.7, 127.0, 126.9,
26.8, 126.6, 126.0, 125.4, 125.3, 124.8, 122.3, 108.3, 107.8, 60.3, 59.9, 59.8, 59.5, 58.6, 58.5,
8.3, 57.9, 53.1, 52.8, 34.4, 33.9, 25.1, 24.9, 13.2, 13.1, 13.0, 12.5; HRMS (ESIꢀTOF): m/z calcd
+
for C H ClNO [M+H] : 468.1572, found 468.1573.
2
6
27
5
3-Benzyl
2-ethyl
5-benzyl-1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate (3r). Yellow oil
1
(42.1 mg, 85% yield); H NMR (400 MHz, CDCl
3
): δ 7.42ꢀ7.27 (m, 6H), 7.24 (s, 1H), 7.09ꢀ6.97
(
m, 4H), 6.83 (t, J = 2.1 Hz, 1H), 6.70ꢀ6.46 (m, 3H), 5.22 (dd, J = 28.8, 12.4 Hz, 2H), 4.44 (t, J =
2
2
.8 Hz, 1H), 3.86 (dd, J = 10.9, 5.6 Hz, 1H), 3.65ꢀ3.44 (m, 2H), 2.86 (dd, J = 14.0, 6.5 Hz, 1H),
13
.79 (s, 3H), 2.36 (dd, J = 14.0, 10.9 Hz, 1H), 0.61 (t, J = 7.1 Hz, 3H); C NMR (101 MHz,
CDCl ): δ 177.1, 167.6, 163.0, 144.8, 143.4, 136.1, 134.8, 132.0, 128.0, 127.8, 127.7, 127.5, 127.2,
3
1
26.9, 125.2, 125.1, 124.6, 120.7, 106.9, 65.5, 59.3, 58.5, 57.9, 53.0, 34.4, 25.0, 12.4; HRMS
+
(ESIꢀTOF): m/z calcd for C31
H30NO
5
[M+H] : 496.2118, found 496.2115.
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2
-tert-Butyl 3-ethyl 1',5-dibenzyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate
1
(3s). Yellow oil (47.8 mg, 89% yield); H NMR (400 MHz, CDCl
3
): δ 7.36ꢀ7.28 (m, 3H),
7
.26ꢀ6.90 (m, 8H), 6.73 (dd, J = 8.5, 5.2 Hz, 3H), 6.56 (d, J = 7.8 Hz, 1H), 4.71 (d, J = 15.6 Hz,
1H), 4.45 (d, J = 2.4 Hz, 1H), 4.30ꢀ4.24 (m, 1H), 4.18 (ddd, J = 26.7, 17.9, 10.6 Hz, 2H), 3.85 (t, J
= 8.3 Hz, 1H), 2.74 (dd, J = 13.9, 7.6 Hz, 1H), 2.32 (dd, J = 13.9, 9.4 Hz, 1H), 1.27 (t, J = 7.1 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
3
3
H), 0.86 (s, 9H); C NMR (101 MHz, CDCl ): δ 177.7, 166.9, 163.4, 143.2, 142.6, 136.7, 134.8,
1
33.0, 127.7, 127.6, 127.1, 127.0, 126.6, 126.5, 125.9, 125.5, 125.3, 120.8, 107.9, 79.9, 59.6, 58.6,
+
5
8.5, 53.8, 43.2, 34.5, 26.2, 13.2; HRMS (ESIꢀTOF): m/z calcd for C H NO [M+H] : 538.2588,
3
4
3 6
5
found 538.2588.
3
-Benzyl 2-tert-butyl 1',5-dibenzyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate
1
(
3t). Yellow oil (50.9 mg, 85% yield); H NMR (400 MHz, CDCl ): δ 7.40ꢀ7.26 (m, 9H),
3
7
.25ꢀ7.14 (m, 3H), 7.14ꢀ7.08 (m, 3H), 6.98 (t, J = 7.5 Hz, 1H), 6.79 (t, J = 2.1 Hz, 1H), 6.70 (dd, J
= 6.4, 2.7 Hz, 2H), 6.56 (d, J = 7.8 Hz, 1H), 5.20 (dd, J = 31.2, 12.4 Hz, 2H), 4.69 (d, J = 15.6 Hz,
1H), 4.46 (t, J = 2.8 Hz, 1H), 4.23 (d, J = 15.6 Hz, 1H), 3.85 (dd, J = 11.2, 5.4 Hz, 1H), 2.73 (dd, J
13
=
3
14.0, 7.6 Hz, 1H), 2.32 (dd, J = 14.0, 9.4 Hz, 1H), 0.79 (s, 9H); C NMR (101 MHz, CDCl ): δ
1
77.6, 166.8, 163.3, 144.0, 142.7, 136.6, 134.8, 134.7, 132.7, 127.8, 127.7, 127.5, 127.3, 127.1,
1
27.1, 126.6, 126.5, 125.6, 125.3, 125.2, 120.8, 107.9, 80.0, 65.5, 58.7, 58.5, 53.8, 43.3, 34.5, 26.2;
+
HRMS (ESIꢀTOF): m/z calcd for C H NO [M+H] : 600.2744, found 600.2738.
39
38
5
Diethyl 1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate (3u). Yellow oil
1
(
29.5 mg, 86% yield); H NMR (400 MHz, CDCl
3
): δ 7.28 (dd, J = 7.8, 1.1 Hz, 1H), 7.19 (d, J =
6.9 Hz, 1H), 6.99 (td, J = 7.6, 0.8 Hz, 1H), 6.95 (dd, J = 4.7, 2.4 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H),
4.34 (dd, J = 4.4, 2.2 Hz, 1H), 4.28ꢀ4.15 (m, 2H), 3.74ꢀ3.58 (m, 2H), 3.26 (s, 3H), 3.13 (dt, J =
18.4, 2.4 Hz, 1H), 2.78 (dt, J = 18.4, 2.4 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.75 (t, J = 7.1 Hz, 3H);
13
3
C NMR (101 MHz, CDCl ): δ 178.1, 168.3, 162.7, 142.3, 141.4, 133.2, 130.0, 127.8, 122.8,
1
21.7, 106.8, 59.6, 59.4, 58.0, 53.7, 43.1, 25.6, 13.2, 12.6; HRMS (ESIꢀTOF): m/z calcd for
+
C
19
H
22NO
5
[M+H] : 344.1492, found 344.1494.
Diethyl 5-benzyl-1'-methyl-2'-oxospiro[cyclopent[3]ene-1,3'-indoline]-2,3-dicarboxylate (3a’).
1
Yellow oil (37.3 mg, 86% yield); H NMR (400 MHz, CDCl
3
): δ 7.29 (d, J = 2.7 Hz, 1H), 7.26 (d,
J = 8.8 Hz, 1H), 7.08ꢀ7.05 (m, 3H), 7.01 (t, J = 7.5 Hz, 1H), 6.78 (t, J = 2.0 Hz, 1H), 6.60 (dt, J =
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2
2
2
2
2
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2
3
3
3
3
3
3
3
3
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3
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5
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5
5
5
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6
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6.1, 7.2 Hz, 3H), 4.43 (t, J = 2.7 Hz, 1H), 4.28ꢀ4.19 (m, 2H), 3.89ꢀ3.81 (m, 1H), 3.57 (q, J = 7.1
Hz, 2H), 2.86 (dd, J = 14.0, 6.6 Hz, 1H), 2.80 (s, 3H), 2.36 (dd, J = 13.9, 10.7 Hz, 1H), 1.28 (t, J =
7
1
5
3
.1 Hz, 3H), 0.65 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl ): δ 177.1, 167.7, 163.3, 143.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
43.4, 136.2, 132.4, 127.9, 127.7, 126.9, 125.2, 125.1, 124.6, 120.7, 106.9, 59.7, 59.3, 58.5, 57.9,
2.9, 34.5, 25.0, 13.2, 12.5.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: miaozhiwei@nankai.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (21072102), the Committee of
Science and Technology of Tianjin (15JCYBJC20700) and State Key Laboratory of
ElementoꢀOrganic Chemistry in Nankai University for financial support. We also thank the
anonymous reviewer’s helpful suggestions improving our manuscript.
ASSOCIATED CONTENT
*Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
13
H and C NMR spectra for all products (PDF)
Xꢀray data for compound 3a (CIF)
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15] Crystallographic data for the structural analysis of compound 3a has been deposited at the
Cambridge Crystallographic Data Centre as No. CCDC 1540158. These data can be obtained
free of charge by contacting The Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033; Eꢀmail: deposit@ccdc.cam.ac.uk.
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