Visible-light-induced aerobic epoxidation in cyclic ether: Synthesis of spiroepoxyoxindole derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151578

A visible-light-induced aerobic epoxidation of 3-benzylideneindolin-2-ones with a meso-Tetraphenylporphyrin (TPP) photosensitizer in cyclic ether has been established for the efficient synthesis of spiroepoxyoxindole derivatives. This reaction leads to ex

Full text of DOI:10.1016/j.tetlet.2019.151578

Journal Pre-proofs
Visible-Light-Induced Aerobic Epoxidation in Cyclic Ether: Synthesis of Spiro-
epoxyoxindole derivatives
Kaixiu Luo, Xianglin Yu, Peng Chen, Kun He, Jun Lin, Yi Jin
PII:
S0040-4039(19)31377-2
DOI:
https://doi.org/10.1016/j.tetlet.2019.151578
TETL 151578
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
27 November 2019
21 December 2019
27 December 2019
Please cite this article as: Luo, K., Yu, X., Chen, P., He, K., Lin, J., Jin, Y., Visible-Light-Induced Aerobic
Epoxidation in Cyclic Ether: Synthesis of Spiro-epoxyoxindole derivatives, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.151578
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Visible-Light-Induced Aerobic Epoxidation
in Cyclic Ether: Synthesis of Spiro-
epoxyoxindole derivatives
Leave this area blank for abstract info.
Kaixiu Luo, Xianglin Yu, Peng Chen, Kun He, Jun
Lin* and Yi Jin*
TPP, Air, tBuOK
R2
O
3O
2
R2
O
THF, rt, 24h
18 W blue LEDs
R1
O
R1
TPP
N
N
H
H
1O2
1
2
Visible Light
Metal-free
25 examples
O2 as oxidant
Mild conditions
up to 97% yields
trans:cis > 20:1

Tetrahedron Letters
journal homepage: www.elsevier.com
Visible-Light-Induced Aerobic Epoxidation in Cyclic Ether: Synthesis of Spiro-
epoxyoxindole derivatives
Kaixiu Luo, Xianglin Yu, Peng Chen, Kun He, Jun Lin* and Yi Jin*
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan
University, Kunming, 650091, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A visible-light-induced aerobic epoxidation of 3-benzylideneindolin-2-ones with a meso-
Tetraphenylporphyrin (TPP) photosensitizer in cyclic ether has been established for the efficient
synthesis of spiro-epoxyoxindole derivatives. This reaction leads to excellent intermolecular
trans- stereoselective epoxide ring formation. This strategy also proceeds effectively with a
good functional group tolerance under mild reaction conditions. Mechanistic investigations
indicate that light is required for reaction initiation.
Available online
Keywords:
Visible-light-induced; Epoxidation; Spiro-
epoxyoxindole derivatives; Initiation
2
009 Elsevier Ltd. All rights reserved.

3
1
. Introduction
Heterocyclic spirooxindoles bearing a spirocyclic system are well-recognized scaffolds that are widely found in
1-6
natural alkaloids, synthetic bioactive molecules and clinical pharmaceuticals . In particular, spiro-
epoxyoxindoles (Fig. 1) that feature a spiro-carbon and oxirane ring have been identified not only as privileged
frameworks with significant biological activities (e.g., antifungal, antitubercular, anti-Fusarium oxysporum and
anticancer activities) , but also as important precursors for the synthesis of complex drug molecules and natural
products1 . For example, Wang’s group carried out a total synthesis of (+)-gliocladin C by using spiro-
7-9
0-12
13
epoxyoxindoles as the starting substrates .
O
O
A R1 = Me, R2 = H
B R1 = H, R2 = 4-F
C R1 = H, R2 = 4-Cl
D R1 = H, R2 = H
R1
O
N
H
R2
Figure 1. Selected biological spiro-epoxyoxindoles derivatives
Spiro-epoxyoxindoles have attracted tremendous research interest in the synthetic community due to their
potency (synthetic potential) and wide range of bioactivities. Thus, various powerful strategies have been
1
4-16
developed to access these skeletons
(Schemes a and b). However, these methods depend on the use of a
transition metal or a stoichiometric amount of chemical oxidants such as organic and inorganic peroxides, giving
rise to safety, environmental and economic concerns. Recently, visible-light-induced photocatalysis has emerging
17-22
as an attractive, green and powerful method for the realization of challenging chemical transformations . In
1
particular, the generation of singlet oxygen ( O
2
) under mild photocatalytic conditions for oxygenation reactions
has been developed as an alternative synthetic strategy23-28. For example, Luo’s group reported that the
epoxidation of α, β-unsaturated ketones was mediated by amidines via visible light . Therefore, development of
29
2
efficient epoxidations by using O instead of an additive for the synthesis of spiro-epoxyoxindoles is highly
desirable.
Scheme 1. Preparation methods of spiro-epoxyoxindole derivatives
a Inorgano- and organocatalytic synthesis of spiro-epoxyoxindole derivatives
(OEt)2P(O)
O
(O)P(EtO)2
O
Loreto
H2O2, EtOH
NaOH(2M)
R1
O
R1
N
N
R2
R2
EtO2C
O
2
CO Et
TBHP
R1
O
O
Gasperi
Hexane, rt
R1
N
N
b Metal-catalyzed synthesis of spiro-epoxyoxindole derivatives
N2
R'
O
Rh
R
O
R
O
N
R'CHO
N
R''
R''
This work
Ar2
O
O
Ar2
TPP, Air, Base,
Cyclic Ether
O
R1
R1
N
N
H
H
trans:cis > 20:1
Visible Light
3
0
In this context, continuing our previous research on epoxidation , here we describe a visible-light-induced aerobic
epoxidation for the effective production of spiro-epoxyoxindole derivatives in cyclic ether without either an additive or
metal catalysts. This new general approach allows the formation of epoxy via air atmosphere and gives products in
excellent yield in a single step. Our novel protocol offers an efficient pathway for constructing spiro-epoxyoxindole
derivatives under mild conditions.

4
2
. Results and Discussion
Table 1. Optimized conditions for the synthesis of 2a[a]
Ph
H
Ph
O
O
Ps, Air, Base
H
Ph
O
O
O
+
Solvent,
N
N
N
18 W blue LEDs,
H
H
H
Temperature, 24h
2'a
1a
2a trans
cis
Yield
%)
Entry
Ps
Solvent
Base
T/°C 2a:2′a[c]
[
b], [c]
(
1
2
3
4
5
6
7
8
9
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
TPP
Pc
EtOH
DCM
K
K
K
K
K
K
K
K
K
3
3
3
3
3
3
3
3
3
PO
PO
PO
PO
PO
PO
PO
PO
PO
4
4
4
4
4
4
4
4
4
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
60
90
rt
rt
rt
rt
rt
rt
nd
nr
nr
nd
Acetone
Toluene
Ethyl ether
THP
nd
nr
nd
nr
nd
nr
>20:1
>20:1
>20:1
nd
74
82
66
nr
THF
1,4-dioxane
TBME
THF
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Et
3
N
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
72
93
86
73
56
45
nr
THF
tBuOK
NaOH
THF
THF
K
2
CO
DBU
NaH PO
3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
2
4
none
nd
>20:1
>20:1
>20:1
24
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
88
79
59
80
85
68
61
nr
H
2
TPP
24
Eosin B
Eosin Y
Et
3
N
24
tBuOK
tBuOK
tBuOK
24
TPP/N
TPP/O
2
24
2
24
97
[
a] Reaction conditions: 1a (0.5 mmol), TPP (1 × 10−2 mmol), base (0.6 mmol), and solvent (2 mL) were stirred for 24 h
at room temperature under air atmosphere. [b] Isolated yield based on 1a. [c] nr = no reaction, nd = no detected.
In our initial studies, the model reaction of 3-benzylideneindolin-2-one 1a was investigated by using TPP as the
photosensitizer and 18 W blue LEDs as the light source at room temperature under air atmosphere in order to screen
different solvents (Table 1, entries 1−9). To our delight, the desired product 2a was obtained in good yield in cyclic ethers,
and especially in THF (82%), while we could not obtain spiro-epoxyoxindole 1a using aliphatic ethers and other solvents.
Encouraged by this result, we sought to enhance the yield of this reaction and carried out a screening of the bases such as
3 2 3 2 4
Et N, tBuOK, NaOH, K CO , DBU and NaH PO (Table 1, entries 10−15). We found that all of these reactions proceeded
smoothly while t-BuOK delivered the best results (93%). By contrast, the reactions cannot be carried out in the absence of
the bases (Table 1, entries 16). Different photosensitizers were investigated, and it was found that TPP provided the
highest yield (Table 1, entries 11, 20−23). Additionally, room temperature was determined to be the best temperature for
the reaction (Table 1, entries 11, 17-19). The target compound 2a was formed in excellent yield under an O
2
atmosphere
(
Table 1, entries 25). By contrast, spiro-epoxyoxindole 2a was not detected under an N atmosphere (Table 1, entries 24),
2
demonstrating that oxygen plays a key role of a green oxidant in this reaction. Notably, this reaction leads to excellent
intermolecular trans- stereoselective epoxide ring formation. The trans- configuration of compound 2a was confirmed by
NOE spectra (Figure S2, SI file).
Table 2. Preparation of spiro-epoxyoxindoles 2

5
R2 TPP, Air, tBuOK
THF
O
R2
O
O
R1
R1
18 W blue LEDs
N
N
H
rt, 24h
H
1
2, yield%, trans:cis
Cl
F
O
O
O
O
HO
O
O
O
O
Cl
N
N
N
N
H
H
H
H
2
b, 95%, >20:1
2c, 83%, >20:1
2d, 79%, >20:1
2e, 86%, >20:1
NO2
Cl
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
H
2
f, 84%, >20:1
2g, 88%, >20:1 Cl
2h, 89%, >20:1
2i, 94%, >20:1 OCH3
Cl
Cl
OCH3
OCH3
O
O
O
O
O
F
O
O
N
H
N
N
N
O
H
H
H
Cl
2
j, 96%, >20:1
2k, 75%, >20:1
2m, 97%, >20:1
2
l, 70%, >20:1
Cl
O
O
O
O
O
O
O
F
Cl
Cl
N
H
Cl
N
H
N
H
Cl
N
O
Cl
2
n, 90%, >20:1
2o, 91%, >20:1
2p, 88%, >20:1
H
2
q, 68%, >20:1
Cl
Cl
H3CO
Cl
CH3
O
O
O
O
N
OCH3
Cl
O
O
O
O
Cl
N
H
Cl
Cl
N
H
N
N
H
H
2
r, 71%, >20:1
2s, 75%, >20:1
2t, 89%, >20:1
2u, 83%, >20:1
Cl
O
O
O
N
O
O
O
O
O
N
H
N
H
N
H
O
2v, 80%, >20:1
2w, 77%, >20:1
2x, 84%, >20:1
2y, 88%, >20:1
[
a] Reaction conditions: 1 (0.5 mmol), TPP (1 × 10−2 mmol), base (0.6 mmol), and solvent (2 mL) were stirred for 24 h at
room temperature under air atmosphere. [b] Isolated yield based on 1a. [c] nr = no reaction.
With the optimal reaction conditions established, the feasibility of this epoxidation was explored by changing various R
1
and R
chlorine or hydroxyl groups on R
performance of the R substituents at the para, meta, and ortho positions on the aromatic ring. Gratifyingly, all of the
2
substituents in 3-benzylideneindolin-2-ones (Table 2). First, we found that the 3-benzylideneindolin-2-ones bearing
1
were well-tolerated in a good yield (2b 95%, 2c 83%). Next, we examined the
2
reactions proceeded smoothly to generate the target compounds 2d-w in moderate-to-excellent yields. It was found that the
electron-donating groups (Me, Et or OMe) gave higher product yields (2h-j, 2m) than the electron-withdrawing groups (F,
Cl or NO 2e-g). The position of the substituents had a significant influence on the yield with the substituents on the meta
2
or para positions more suitable than those at the ortho position (2b-m). Nevertheless, all of the reactions had high yields.
By contrast, low yields were observed with multiple substituted substrates 1 due to the steric hindrance effects (2k-l, 2q-s).
Reactions of heterocyclic substrates produced the desired products 2u and 2v with moderated yields. Finally, alkyl
substituted substrates can also give desired products (2x, 2y) under standard condition in good yield. Interestingly, both
aryl and alkyl substrate gave the corresponding epoxides in excellent trans- steroselectivity (dr, trans:cis > 20:1).
Figure 2. ORTEP diagram of 2a
The chemical structures of the spiro-epoxyoxindole derivatives were examined by H NMR, 13C NMR, and HRMS
1
analyses. The structure of 2a was unambiguously confirmed by single-crystal X-ray analysis, as shown in Fig. 2 (CCDC
9
66890).
Scheme 2. Control Experiments

6
Ph
Ph
O
O
H
TPP, tBuOK
THF, rt, 24h
O
N
N
H
H
1a
2a
,
trans
N2
O2
O2
no reaction
97%
no reaction
trace
O
1
1
8 W blue LEDs
8 W blue LEDs
OOH
Checked by NMR
In the dark
1
8 W blue LEDs/No TPP O2
In the dark
THF-OOH 95%
Several control experiments were carefully conducted in order to obtain an in-depth understanding of the reaction
mechanism (Scheme 2). When the reaction of 3-benzylideneindolin-2-ones 1a was investigated with the standard
conditions under N
2
atmosphere, the desired product 2a was not detected, suggesting that O
2
from air is needed in this
reaction. By contrast, under O
2
atmosphere, the reaction provided 2a with the highest yield of 97% and the peroxide
intermediate THF-OOH was detected by NMR. The reaction cannot be carried out in the dark and also did not proceed
effectively in the absence of TPP. Meanwhile, a control experiment by using isolated THF-OOH in the absence of TPP
was performed, and the reaction can proceed smoothly. These results indicate that molecular oxygen and light are
necessary for this epoxidation.
Scheme 3. Proposed mechanism for the construction of spiro-epoxyoxindole derivatives 2
O
O
OOH
O
OO
R1
1O2
Base
Ar2
O
TPP
3O2
N
Visible Light
H
O
OH
1
H
Substrate
O
O
Ar2
O
O
Ar2
H
O
O
O
R1
O
O
R1
N
N
H
H
2
, trans
Product
I
O
O
H
H
O
H
O
O
O-
H
O-
N
NH
H
cis-I
trans-I
Based on the above experimental results, a plausible mechanism was proposed as shown in Scheme 3. Initially,
3
1
molecular oxygen is activated from the triplet state ( O
2
) to the singlet state ( O
2
) by TPP through energy transfer under
31
visible light. Next, the α-THF C–H bond was peroxided by singlet O
2
to produce the hydroperoxide THF-OOH . After the
deprotonation, peroxide oxygen anion was added to substrate 1 to provide intermediate I, and then the oxygen anion was
eliminated to produce a spiro-epoxyoxindole 2. Among this transformation, the nucleophilic addition of THF-OO-
anion makes the two possible trans/cis transition states of the intermediate I (Scheme 3). In the trans transition state,
due to the presence of hydrogen bonding cyclization of the (furan oxygen atom)‒(H+ ion)‒(indole oxygen negative
atom), this configuration is more favorable, which results in the product mainly as the trans selectivity. Lastly,
Tetrahydrofuran-2-ol was obtained via abstracting a proton.
Scheme 4. Gram-Scale Reaction
Ph
Ph
O
O
H
O
TPP, Air, tBuOK
THF
N
N
H
H
18 W blue LEDs
1a
2a,
trans
rt, 24h
10.0 mmol, 2.21 g
91% yield, 2.16 g
To demonstrate the potential synthetic application of this strategy, a gram-scale reaction of 1a was carried out (Scheme
). The visible-light-induced aerobic epoxidation of 1a on a 10.0 mmol scale gave 2.16 g of the desired product 2a in 91%
4
yield under the standard reaction conditions.

7
3
. Conclusions
In conclusion, a visible-light-induced aerobic epoxidation was developed for the preparation of spiro-epoxyoxindole
derivatives. This highly effective process proceeds well to afford spiro-epoxyoxindole derivatives without any additive
under mild conditions and shows good functional group tolerance. Our mechanistic study suggests that light irradiation is
critical for the reaction initiation. The reaction can be performed on the gram scale and proceeds smoothly under these
reaction conditions, suggesting the high likelihood of the rapid transition of this novel protocol to use in heterocyclic
chemistry applications.
4
. Acknowledgements
This work was supported by the Program for Changjiang Scholars and Innovative Research Team in University
(
IRT17R94); the National Natural Science Foundation of China (Nos. 21662044, 81560601, 21262043, 81760621, and
U1202221); Training Program for Young and Middle-aged Academic and Technical Leaders in Yunnan Province
2015HB004); the Foundation of “Yunling Scholar” Program of Yunnan Province (C6183005); Program for Excellent
(
Young Talents，Yunnan University; and thank the High Performance Computing Center at Yunnan University for use of
the high performance computing platform.
5
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8
Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Highlights
►
►
►
A novel epoxidation was developed to synthesize spiro-epoxyoxindole derivatives.
Good functional group tolerance was found in our protocol.
Light irradiation is critical for the reaction initiation.