Intramolecular Dehydrogenative Coupling Approach to 2-Oxindoles Using Fe(OAc)2/NaI/Na2S2O8

Article abstract of DOI:10.1002/ejoc.202001111

Oxindole units are common structures that are featuring in natural products and drugs. A novel method for synthesizing 2-oxindoles from 1,3-dicarbonyl compounds based on ferrous salt and iodide catalyst was described. Using Fe(OAc)₂/NaI/Na₂S₂O₈, various 2-alkyl-3-phenylamino-3-oxopropanoates, bearing fluoro, chloro, bromo, alkyl, alkoxy, trifluoromethyl, cyano etc. on the benzene ring were converted smoothly into 2-oxindoles.

Full text of DOI:10.1002/ejoc.202001111

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Intramolecular dehydrogenative coupling approach to 2-oxindoles
using Fe(OAc)2/NaI/Na2S2O8
Authors: Junyan Zhao, Xun Song, Dong Li, Jinfeng Zhao, Jingping Qu,
and Yuhan Zhou
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001111
Link to VoR: https://doi.org/10.1002/ejoc.202001111
01/2020

10.1002/ejoc.202001111
European Journal of Organic Chemistry
FULL PAPER
Intramolecular dehydrogenative coupling approach to 2-
oxindoles using Fe(OAc)2/NaI/Na2S2O8
Junyan Zhao,[a] Xun Song,[a] Dong Li,[a] Jinfeng Zhao,[b] Jingping Qu,[b] and Yuhan Zhou*[a]
[a]
J. Zhao, X. Song, D. Li, Prof. Dr. Y. Zhou
State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology,
Dalian 116024, P.R. China.
Email: zhouyh@dlut.edu.cn
http://faculty.dlut.edu.cn/zhouyuhan/zh_CN/index.htm
[b]
Dr. J. Zhao, Prof. Dr. J. Qu
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, P.R. China
Abstract: Oxindole units were common structure features of natural
products and drugs. A novel method for synthesizing 2-oxindoles
from 1,3-dicarbonyl compounds based on ferrous salt and iodide
catalyst was described. Using Fe(OAc)2/NaI/Na2S2O8, various 2-
16] In 2009, Jia and Kündig gave the first report on the synthesis
of 3,3-disubstitued oxindoles by the direct intramolecular
dehydrogenative coupling (IDC) of an aryl Csp2-H and a Csp3-H
center.[17] Soon after, Taylor also successfully prepared oxindoles
alkyl-3-phenylamino-3-oxopropanoates bearing fluoro, chloro, bromo, through IDC of 3-arylamino-3-oxopropanoates.[18] Inspired by
alkyl, alkoxy, trifluoromethyl, cyano etc. on the benzene ring were
these pioneering works, IDC has become one of the most
efficient method for the synthesis of 3,3-disubstitued
oxindoles.[18,35] In general, besides electrochemical activation of
C-H bonds,[20,21] this procedure was promoted by oxidants, such
as Cu2+,[18,19, 22-25,28] di-tert-butyl peroxide (DTBP),[26] DDQ,[27] I2,
converted smoothly to 2-oxindoles.
[29,33,34]
and high-valence iodine.[30-32] Among them, I2 was an
Introduction
efficient oxidant which can promote the reaction at low
temperature.[33] However, the high price of I2 which is consumed
in stoichiometric amounts hindered its application in industry.
In our previous work, we established a new catalytic
oxidative system, FeCl2/NaI/Na2S2O8, which had been
successfully applied in the catalytic ammoxidation of aldehydes
to nitriles.[35] In this reaction, I- was oxidized to I2 with a cheaper
oxidant, FeCl2/Na2S2O8, so that only a catalytic amount of iodine
can be utilized. Thus, this method shows its merit in industry.
Enthused by this work, we envisaged to use the similar method
to synthesize 2-oxindoles from 1,3-dicarbonyl compounds
(Scheme 1).
Indole is an important heterocyclic scaffold, which has unique
biological activity in many bioactive compounds,[1,2] natural
alkaloids[3-5] and pharmaceutically active molecules.[6-8] In the
mid-1950s, Reserpine, an alkaloid, was proposed as the first
choice for the treatment of central nervous system diseases
such as anxiety and neurological disorders.[9] Since then, indole
derivatives had aroused great interests and concerns. In the
1960s, Vincristine, a highly effective anti-tumor drug based on
indole skeleton came out. Subsequently, a large number of
indole alkaloids with physiological activity emerged and were
used for anti-infection, sedation and anti-hypertensio.[10] Among
countless indoles, oxindole skeleton was widely found in
pharmaceuticals, such as the anticancer agent Sunitinib[11] and
the vasopressin V2 receptor antagonist Satavaptan (Figure 1).[12]
Thus, the practical synthesis of oxindoles is of great interest in
synthetic organic chemistry.
Many strategies had been set up to construct oxindole
skeleton, such as the derivatization of isatin and indoles,[13] Heck
reactions,[14] oxidation of indolenines,[15] cyclization of o-
aminophenylacetic acids and α-halo or ahydroxy acetanilides.[13a,
Scheme 1. IDC approach to 2-oxindoles using [Fe]/[I]/Na2S2O8
Results and Discussion
First, to test the feasibility of [Fe]/[I]/Na2S2O8 for the synthesis of
2-oxidoles
ethyl
2-methyl-3-(methyl(phenyl)amino)-3-
oxopropanoate (1a), readily prepared via condensation of N-
methylaniline with monoethyl 2-methylmalonate, was selected
as the model substrate. To our delight, ethyl 1,3-dimethyl-2-
oxoindoline-3-carboxylate (2a) was formed at a desired yield,
after mixing 1a and Fe(OAc)2, Na2S2O8 and NaI in DMSO for 24
h at 110 °C. The results showed that an expected IDC had
occurred following the C(sp2)-C(sp3) bond formation. Later on,
other iron salts, such as Fe(NO3)3, K3[Fe(CN)6], FeCl2, FeCl3,
FeSO4, were put to the test and were also found to be effective
Figure 1. Some biologically and pharmaceutically important oxindole
derivatives
1
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10.1002/ejoc.202001111
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization of the formation of 2a based on various metal catalysts
Table 2. Optimization of the formation of 2a based on various oxidants and
and reaction time.[a]
iodides.[a]
Me
N
Me
N
O
oxidant, [I], Fe(OAc)2
O
Me
1a
COOEt
COOEt
Me
2a
Yield 2a (%)[b]
Entry
1
Cat.
t/h
24
24
24
24
24
24
24
24
24
24
24
18
30
36
Conv. (%)
85
Yield 2a (%)[b]
Entry
Oxidant
Na2S2O8
K2S2O8
[I]
Conv. (%)
Fe(OAc)2
Fe(NO3)3
K3[Fe(CN)6]
FeCl2
81
50
60
53
48
57
38
67
30
10
---
35
79
74
1
NaI
NaI
NaI
NaI
NaI
85
82
90
40
---
---
---
99
85
81
81
79
68
24
---
---
---
46
69
73
2
70
2
3
62
3
H3K5O18S4
(NH4)2S2O8
t-BuOOH
4
78
4
5
FeCl3
69
5
6
FeSO4
76
6
KHSO5·0.5KHSO4·0.5K2SO4
NaI
NaI
LiI
KI
7
Mn(OAc)3·2H2O
Cu(OAc)2·H2O
AlCl3
53
7
O2
8
99
8
Na2S2O8
Na2S2O8
Na2S2O8
9
99
9
10[c]
I2
10
11
12
13
14
ZnCl2
99
SnCl4
99
[a] Standard conditions: 1a (0.4 mmol, 94 mg) was stirred in DMSO (2.5 mL)
at room temperature, then the oxidant (1.5 eq.) and Fe(OAc)2 (30 mol%, 21
mg) and [I] (30 mol%) were added and the mixture was stirred at 110 °C for 24
h. [b] Conversion and yield were determined by 1H NMR spectroscopy with
dimethyl terephthalate as an internal standard. [c] I2 (25 mol%).
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
45
99
99
entry 4). In absence of Fe(OAc)2, the yield of 2a was only 60%
(Table 4, entry 5), and the yield and selectivity of the reaction
were improved with the increasing of Fe(OAc)2 (Table 4, entries
6 and 7). When the amount of NaI was decreased from 30 mol%
to 20 mol%, the yield of 2a was reduced exponentially (Table 4,
entry 8), and there was no expected product was formed without
NaI (Table 4, entry 9). Afterwards, we found that the yield and
[a] Standard conditions: 1a (0.4 mmol, 94 mg) was dissolved in DMSO (2.5
mL) at room temperature, then Na2S2O8 (1.5 eq., 143 mg), catalyst (30 mol%)
and NaI (30 mol%, 18 mg) were added and the mixture was stirred at 110 °C.
[b] Conversion and yield were determined by 1H NMR spectroscopy with
dimethyl terephthalate as an internal standard.
in affording the same product, albeit in slightly lower yields
(Table 1, entries 2-6). Afterwards, other metal catalysts were
also tested, but the results were not as good as expected (Table
1, entries 7-11). Using Fe(OAc)2 as iron catalyst, the time case
was studied. It showed that 24 h gave the best result. Reducing
the reaction time resulted in lower conversion of the starting
materials, while a slight lower selectivity was achieved with
longer reaction time (Table 1, entries 12-14).
Table 3. Optimization of the formation of 2a based on various solvents.[a]
Second, several oxidants and iodides were explored. The
results showed that running the reaction with K2S2O8 or
H3K5O18S4 could lead to a lower yield (Table 2, entries 2 and 3),
and the reaction with (NH4)2S2O8 had a yield of only 24% (Table
2, entry 4). And then, t-BuOOH, KHSO5·0.5KHSO4·0.5K2SO4
and O2 were also tested, but to our disappointment, these three
oxidants gave a relatively poor result (Table 2, entries 5-7).
When LiI, KI or I2 were used, lower yields were given (Table 2,
entries 8-10). Finally, the effect of solvents was studied.
However, except DMSO and sulfolane (Table 3, entries 1 and 2),
other solvents, such as DMF, toluene, 1,4-dioxane and so on,
couldn’t achieve the expected results (Table 3, entries 3-8). It
could be seen that the choice of solvents had a great influence
upon the reaction.
Entry
Solvent
Conv. (%)
Yield 2a (%)[b]
1
2
3
4
5
6
7
8
DMSO
85
97
---
---
---
---
---
---
81
sulfolane
DMF
51
---
toluene
trace
---
xylene
MeCN
trace
trace
---
1,4- dioxane
1,2-dichloroethane
And then, we found there had been a slight decline in
productivity when we tried to reduce the amount of Na2S2O8
(Table 4, entries 2 and 3). Without Na2S2O8, no target product
[a] Reagents and conditions: 1a (0.4 mmol, 94 mg) was dissolved in solvent
(2.5 mL) at room temperature, then Na2S2O8 (1.5 eq., 143 mg) and Fe(OAc)2
(30 mol%, 21 mg) and NaI (30 mol%, 18 mg) were added and the mixture was
stirred at 110 °C for 24 h. [b] Conversion and yield were determined by 1H
NMR spectroscopy with dimethyl terephthalate as an internal standard.
was generated, and
a
small amount of two-molecule
condensation product of 1a was detected by GC/MS (Table 4,
2
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10.1002/ejoc.202001111
European Journal of Organic Chemistry
FULL PAPER
After that, we carried out the reaction at a gram-scale, and the
results showed that the yield remained at 72% (Scheme 2).
Table 4. Optimization of the formation of 2a based on NaI and oxidant
amounts.[a]
Entry
Fe(OAc)2
[I]
Na2S2O8
Conv. (%)
Yield
(%)[b]
2a
1
30 mol%
30 mol%
30 mol%
30 mol%
---
NaI (30 mol%)
NaI (30 mol%)
NaI (30 mol%)
NaI (30 mol%)
NaI (30 mol%)
NaI (30 mol%)
NaI (30 mol%)
NaI (20 mol%)
---
1.5 eq.
1.0 eq.
0.5 eq.
---
85
95
83
99
99
91
87
95
99
99
73
73
81
73
69
---
60
65
72
44
---
56
60
40
Scheme 2. Gram-scale reaction
2
3
Table 5. Synthesis of 2-oxindoles by Fe(OAc)2/NaI/Na2S2O8.[a]
4
R1
N
R1
N
O
Fe(OAc)2, Na2S2O8, NaI
R
O
R
5
1.5 eq.
1.5 eq.
1.5 eq.
1.5 eq.
1.5 eq.
1.5 eq.
---
R2
COOR3
COOR3
R2
2a
1a
6
5 mol%
10 mol%
30 mol%
30 mol%
30 mol%
30 mol%
---
Me
N
Et
n-C4H9
i-Pr
N
O
7
N
O
N
O
O
Me COOEt
COOEt
Me
Me COOEt
Me COOEt
8
2a (74%)[b]
2d (58%)
2b (64%)
2c (75%)
9
Cl
Bn
Me
Ph
N
Me
N
N
O
N
O
10[c]
11
12
NaI (30 mol%)
I2 (1 eq.)
O
O
Cl
Me COOEt
Me COOEt
Me COOEt
Me COOEt
2e (44%)
2f (45%)
2g (77%)
2h (75%)
F
Me
Me
N
Me
Me
I2 (1 eq.)
---
Br
Cl
N
O
N
O
N
O
O
Br
Me COOEt
COOEt
Me COOEt
2l (67%)
Me COOEt
Me
[a] Reagents and conditions: 1a (0.4 mmol, 94 mg) was stirred in DMSO (2.5
mL) at room temperature, then Fe(OAc)2 and Na2S2O8 and NaI were added
and the mixture was stirred at 110 °C for 24 h. [b] Conversion and yield were
determined by 1H NMR spectroscopy with dimethyl terephthalate as an internal
standard. [c] In air.
2j (18%)
2k (64%)
2i (27%)
Me
Me
Me
N
Me
N
O
N
O
N
O
O
F3C
NC
MeO
Me
Me COOEt
Me COOEt
Me COOEt
2o (76%)
Me COOEt
2p (76%)
conversion of the reaction both went down when I2 or
I2/Fe(OAc)2 was used for IDC of 1,3-dicarbonyl compounds
under base-free conditions (Table 4, entries 11 and 12). Finally,
we performed a reaction in air and found the yield had a sharp
fall (Table 4, entry 10).
2m (38%)
2n (26%)
Me
Me
N
Me
Me
N
N
O
N
O
O
O
n-Pr
COOMe
Me COOMe
Me COOi-Pr
2s (69%)
Me
Under the optimal reaction conditions, the scope and
limitations of this method was explored by using differently
substituted anilides (Table 5). As could be seen, different
substituents on nitrogen were compatible with the cyclization
conditions producing oxindoles 2a-2d in good yields. However,
the yield of oxindoles 2e and 2f dropped a bit because the
conversion of substrates 1e and 1f were not high due to steric
effect on nitrogen atom, which were 63% and 65% respectively.
Halogen substitution on 2- or 4-position of the benzene ring
showed little effect on the reaction (2g, 2h, 2k and 2l), while 3-
halogen substituted substrates gave quite low yield (2i and 2j).
And 4-substituted substrates with strong electron withdrawing
groups, such as trifluoromethyl and cyano, also gave low yield
(2m and 2n). In all cases of low yield (2i, 2j, 2m and 2n), the
conversion of the starting materials were also low, even if the
reaction time were prolonged to 36 h. On the other hand, 2o, 2p
and 2q were obtained in good yield, which indicated the electron
donating groups had little effect on the reaction. The results of
different substituted groups indicated that high electronic density
was in favor of the reaction. Then, changing the ester group
from ethyl to methyl or iso-propyl had little effect on the reaction
(2r and 2s). Finally, lower yield of 2t indicated that a bulky group
at the methylene position had negative effect on the reaction.
COOEt
2r (61%)
2t (40%)
2q (65%)
Bn
N
O
F
Me COOEt
2u (59%)
[a] Reagents and conditions: 1 (1 mmol), DMSO (5 mL), Na2S2O8 (1.5 eq., 357
mg), Fe(OAc)2 (30 mol%, 53 mg), NaI (30 mol%, 45 mg), stirred at 110 °C for
24 h. [b] Isolated yield.
Actually, we also tried to other substrates. First of all, when
there were benzyl, fluoro, iso-propyl or allyl substituted on 2-
position of 3-(methyl(phenyl)amino)-3-oxopropanoate, the
intramolecular cyclization reaction didn’t happen. Secondly,
when the ester group of the substrate is tert-butyl, the
intramolecular cyclization reaction didn’t happen because the
tert-butyl ester was unstable, it might be hydrolyzed during the
reaction. Finally, we tried three substrates with only one
substituent on nitrogen, we found that the intramolecular
cyclization reaction did not occur, but ethyl 3-arylamino-2-
methyl-2-methylthio-3-oxopropanoate was found as the major
product.
3
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10.1002/ejoc.202001111
European Journal of Organic Chemistry
FULL PAPER
IR (KBr): 2982, 2935, 1743, 1716, 1610, 1489, 1467, 1376, 1240, 1106,
751 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.7 Hz, 1H), 7.24 (d, J
= 7.4 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 4.08 (q, J
= 7.1 Hz, 2H), 3.78 (q, J = 7.2 Hz, 2H), 1.64 (s, 3H), 1.27 (t, J = 7.2 Hz,
3H), 1.12 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.9, 169.8,
142.7, 130.5, 128.9, 123.1, 122.6, 108.5, 61.8, 55.0, 34.9, 19.8, 13.8,
12.4. HRMS (ESI) m/z: calcd for C14H18NO3 [M + H]+ 248.1287, found:
248.1283.
Ethyl 1-(n-butyl)-3-methyl-2-oxoindoline-3-carboxylate (2c): 2c was
prepared according to the general procedure using 1c as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2c was obtained as an orange yellow liquid. Yield: 75% (208
mg); IR (KBr): 2961, 2934, 1743, 1717, 1609, 1489, 1467, 1375, 1358,
1233, 1107, 751 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.7 Hz,
1H), 7.24 (d, J = 7.4 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.8 Hz,
1H), 4.10 (q, J = 7.4 Hz, 2H), 3.83 (dt, J = 14.2, 7.3 Hz, 1H), 3.65 (dt, J =
14.2, 7.3 Hz, 1H), 1.77 – 1.65 (m, 2H), 1.64 (s, 3H), 1.47 – 1.32 (m, 2H),
1.13 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 175.2, 169.8, 143.1, 130.4, 128.8, 123.0, 122.5, 108.7, 61.8,
55.0, 39.8, 29.3, 19.9, 13.8, 13.7, 1.0. HRMS (ESI) m/z: calcd for
C16H22NO3 [M + H]+ 276.1600, found: 276.1597.
Conclusion
In summary, we had developed an efficient approach for the
synthesis of 2-oxindoles from 1,3-dicarbonyl compounds via
Fe(OAc)2/NaI/Na2S2O8 mediated Csp2-H and Csp3-H bond
formation. Various 2-oxindoles with halogen, alkyl, alkoxy,
trifluoromethyl and cynao groups were obtained in moderate to
good yields. And high electronic density of the benzene ring,
especially the ortho-positon of amide group, was in favor of
reaction. Using NaI and environment-friendly Fe(OAc)2 as
catalyst, this base-free protocol provided a simple approach for
the synthesis of a series of oxyindoles. Futhermore, applications
of this Fe(OAc)2/NaI/Na2S2O8 methodology in the total synthesis
of natural products and bioactive molecules were also under
investigation.
Experimental Section
Ethyl 1-isopropyl -3-methyl-2-oxoindoline-3-carboxylate (2d): 2d was
prepared according to the general procedure using 1d as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2d was obtained as a yellow liquid. Yield: 58% (153 mg); IR
(KBr): 2980, 2927, 1743, 1716, 1608, 1485, 1466, 1351, 1239, 1205,
1106, 749 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.9 Hz, 1H),
7.25 – 7.20 (m, 1H), 7.10 – 7.00 (m, 2H), 4.63 (sep, J = 7.0 Hz, 1H), 4.30
– 4.00 (m, 2H), 1.63 (s, 3H), 1.49 (d, J = 7.0 Hz, 6H), 1.12 (t, J = 7.1 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 174.9, 169.8, 142.4, 130.6, 128.7,
123.1, 122.2, 110.0, 61.7, 54.9, 44.1, 19.7, 19.2, 13.8. HRMS (ESI) m/z:
calcd for C15H20NO3 [M + H]+ 262.1443, found: 262.1441.
Ethyl 1-benzyl-3-methyl-2-oxoindoline-3-carboxylate (2e): 2e was
prepared according to the general procedure using 1e as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2e was obtained as an orange yellow liquid. Yield: 44% (137
mg); IR (KBr): 2987, 2934,1739, 1716, 1610, 1493, 1376, 1364, 1240,
1182, 1108, 1022, 1000, 863, 761, 727, 494 cm-1. 1H NMR (400 MHz,
CDCl3) δ 7.27 – 7.36 (m, 5H), 7.25 (s, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.02
(t, J = 7.5 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 5.18 (d, J = 15.8 Hz, 1H),
4.74 (d, J = 15.8 Hz, 1H), 4.26 – 4.03 (m, 2H), 1.73 (s, 3H), 1.18 (t, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 175.5, 169.8, 142.7, 135.6,
130.2, 128.9, 128.8, 127.6, 127.1, 123.0, 122.9, 109.5, 62.0, 55.1, 43.7,
19.8, 13.9. HRMS (ESI) m/z: calcd for C19H20NO3 [M + H]+ 310.1443,
found: 310.1442.
Ethyl 3-methyl-1-phenyl-2-oxoindoline-3-carboxylate (2f): 2f was
prepared according to the general procedure using 1f as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2f was obtained as an orange yellow liquid. Yield: 45% (134
mg); IR (KBr): 2972, 2921, 1736, 1720, 1609, 1499, 1466, 1373, 1262,
1247, 1105, 1021, 763, 748, 698, 616, 492 cm-1. 1H NMR (400 MHz,
CDCl3) δ 7.57 – 7.49 (m, 2H), 7.47 – 7.38 (m, 3H), 7.32 (d, J = 7.4 Hz,
1H), 7.23 (d, J = 7.7 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.9 Hz,
1H), 4.28 – 4.04 (m, 2H), 1.78 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 174.6, 169.7, 143.7, 134.3, 130.0, 129.7, 128.9,
128.3, 126.6, 123.3, 123.2, 109.7, 62.0, 55.2, 20.1, 13.9. HRMS (ESI)
m/z: calcd for C18H18NO3 [M + H]+ 296.1287, found: 296.1284.
1
General: All H NMR (400 MHz), 13C NMR(101 MHz) were recorded on
Bruker AVANCE II-400 spectrometer with chemical shifts reported as
ppm. IR spectra were recorded on
spectrophotometer. HRMS (ESI) spectra were recorded with Thermo
Scientific LTQ Orbitrap XL. Column chromatography was performed on
silica gel (200~300 mesh).
a Thermo Fisher (6700)
General procedure for 1a: To a stirred solution of 3-ethoxy-2-methyl-3-
oxopropanoic acid (1 g, 6.8 mmol) in CH2Cl2 (30 mL) was added at 0 °C,
N-methylaniline (0.82 mL, 7.5 mmol), 2-chloro-1-methylpyridinium iodide
(2.63 g, 10.3 mmol), and Et3N (4.7 mL, 30.1 mmol). The reaction mixture
was stirred at 0 °C for 30 min and allowed slowly to warm to room
temperature and stirred for a further 2 h. A solution of HCl (10%, 20 mL)
was added and the organic phase was extracted with CH2Cl2 (3×25 mL).
The combined organic portions were washed with water (3×25 mL), dried
(Na2SO4), filtered and concentrated in vacuo. The crude yellow oil was
then purified by column chromatography (SiO2, Hexane/EtOAc, 5:1) to
give the title compound (1.2 g, 66%) as a yellow oil. 1b-1u were all
synthesized according to the method of 1a.[18] 1b,[26] 1e,[33] 1h,[24] 1l,[24]
1m,[22] 1n,[24] 1o,[24] 1r,[34] 1s[22] and 1t[36] had been reported. 1c, 1d, 1f,
1g, 1i, 1j, 1k, 1p, 1q and 1u were new.
General procedure for reaction of 1 to 2: To a 25 mL Schlenk bottle
with branch equipped with a magnetic stirring bar were added 1 (1 mmol),
sodium persulfate (1.5 mmol, 357mg), ferrous acetate (0.3 mmol, 53 mg)
and sodium iodide (0.3 mmol, 45 mg). The mixture was stirred at 110 °C
to give product 2. The reaction progress was monitored by TCL analysis
on silica gel. After 24 h, the suspension was quenched by the addition of
15 mL saturated salt solution and transferred to a 100 mL separating
funnel. The organic layer was separated by extracting with ethyl acetate
six times, dried over aqueous Na2SO4 (1.5 g), filtered into a 50 mL round-
bottomed flask and concentrated by rotary evaporation. The crude
product was purified by column chromatography on silica gel to afford the
product 2.
Ethyl 1,3-dimethyl-2-oxoindoline-3-carboxylate (2a): 2a was prepared
according to the general procedure using 1a as the starting material.
After purification by flash chromatography on silica gel (PE: EA=5/1), 2a
was obtained as an orange yellow liquid. Yield: 74% (174 mg); IR (KBr):
2983, 2920, 1743, 1717, 1611, 1494, 1471, 1376, 1348, 1245, 1105, 752,
543 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.7 Hz, 1H), 7.24 (d, J
= 7.4 Hz, 1H), 7.05 (t, J = 8.1 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.10 (q, J
= 7.1 Hz, 2H), 3.23 (s, 3H), 1.64 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 175.2, 169.7, 143.6, 137.8, 130.2, 129.0,
122.9, 108.5, 61.9, 55.0, 26.5, 20.1, 13.9. HRMS (ESI) m/z: calcd for
C13H16NO3 [M + H]+ 234.1130, found: 234.1127.
Ethyl 7-chloro-1,3-dimethyl-2-oxoindoline-3-carboxylate (2g): 2g was
prepared according to the general procedure using 1g as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2g was obtained as a yellow liquid. Yield: 77% (207 mg); IR
(KBr): 2983, 2929, 1747, 1724, 1606, 1467, 1363, 1333, 1240, 1118,
1
1079, 1060, 743 cm-1. H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.1 Hz,
1H), 7.13 (d, J = 7.1 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 4.22 – 4.00 (m, 2H),
3.61 (s, 3H), 1.64 (s, 3H), 1.16 (t, J = 6.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 174.3, 168.1, 138.5, 131.7, 130.2, 122.6, 120.5, 114.6, 61.1,
53.8, 28.9, 19.4, 13.0. HRMS (ESI) m/z: calcd for C13H15ClNO3 [M + H]+
268.0740, found: 268.0739.
Ethyl 1-ethyl-3-methyl-2-oxoindoline-3-carboxylate (2b): 2b was
prepared according to the general procedure using 1b as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2b was obtained as a pale yellow liquid. Yield: 64% (160 mg);
Ethyl 5-chloro-1,3-dimethyl-2-oxoindoline-3-carboxylate (2h): 2h was
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001111
European Journal of Organic Chemistry
FULL PAPER
prepared according to the general procedure using 1h as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2h was obtained as a yellow liquid. Yield: 75% (202 mg); IR
(KBr): 2980, 2927, 1744, 1720, 1609, 1491, 1340, 1247, 1112, 809, 546
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.2 Hz, 1H), 7.23 (s, 1H),
6.78 (d, J = 8.2 Hz, 1H), 4.14 (q, J = 6.5 Hz, 2H), 3.23 (s, 3H), 1.65 (s,
3H), 1.17 (t, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.6, 169.0,
142.2, 131.6, 128.9, 128.1, 123.5, 109.4, 62.2, 55.1, 26.6, 20.1, 13.9.
HRMS (ESI) m/z: calcd for C13H15ClNO3 [M + H]+ 268.0740, found:
268.0737.
EA=3/1), 2n was obtained as a yellow liquid. Yield: 26% (68 mg); IR
(KBr): 2987, 2934, 2226, 1728, 1614, 1503, 1377, 1369, 1342, 1237,
1111, 1007, 828, 522, 501 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J =
8.2 Hz, 1H), 7.50 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 4.25 – 4.03 (m, 2H),
3.27 (s, 3H), 1.66 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 174.7, 168.4, 147.4, 134.3, 131.0, 126.5, 118.8, 109.0, 106.0,
62.5, 54.7, 26.8, 20.0, 13.9. HRMS (ESI) m/z: calcd for C14H15N2O3 [M +
H]+ 259.1083, found: 259.1078.
Ethyl 1,3-dimethyl-5-methoxy-2-oxoindoline-3-carboxylate (2o): 2o
was prepared according to the general procedure using 1o as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2o was obtained as a yellowish-brown liquid. Yield: 76% (201
mg); IR (KBr): 2980, 2935, 1740, 1716, 1500, 1290, 1233, 1111, 1039,
811, 674,cm-1. 1H NMR (400 MHz, CDCl3) δ 6.92 – 6.80 (m, 2H), 6.76 (d,
J = 8.1 Hz, 1H), 4.12 (q, J = 6.4 Hz, 2H), 3.78 (s, 3H), 3.22 (s, 3H), 1.64
(s, 3H), 1.16 (t, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.8,
169.7, 156.2, 137.0, 131.3, 113.2, 110.3, 108.8, 61.9, 55.8, 55.4, 26.6,
20.2, 13.9. HRMS (ESI) m/z: calcd for C14H18NO4 [M + H]+ 264.1236,
found: 264.1231.
Ethyl 6-chloro-1,3-dimethyl-2-oxoindoline-3-carboxylate (2i): 2i was
prepared according to the general procedure using 1i as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=3/1), 2i was obtained as a yellow liquid. Yield: 27% (72 mg); IR (KBr):
2987, 2935, 1743, 1722, 1608, 1495, 1367, 1244, 1109, 1014, 773, 593
1
cm-1. H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 7.9 Hz, 1H), 7.03 (d, J =
7.9 Hz, 1H), 6.86 (s, 1H), 4.20 – 4.02 (m, 2H), 3.23 (s, 3H), 1.63 (s, 3H),
1.15 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.0, 168.2,
143.8, 133.8, 127.5, 122.9, 121.7, 108.2, 61.1, 53.7, 25.6, 19.0, 12.9.
HRMS (ESI) m/z: calcd for C13H15ClNO3 [M + H]+ 268.0740, found:
268.0735.
Ethyl 6-bromo-1,3-dimethyl-2-oxoindoline-3-carboxylate (2j): 2j was
prepared according to the general procedure using 1j as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=3/1), 2j was obtained as an orange yellow liquid. Yield: 18% (57 mg);
IR (KBr): 2972, 2927, 1739, 1712, 1602, 1493, 1471, 1377, 1364, 1242,
1105, 1007, 927, 859, 820, 768, 588, 462 cm-1. 1H NMR (400 MHz,
CDCl3) δ 7.19 (dd, J = 7.9, 1.7 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.01 (d,
J = 1.6 Hz, 1H), 4.22 – 4.00 (m, 2H), 3.22 (s, 3H), 1.63 (s, 3H), 1.15 (t, J
= 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.9, 169.1, 144.9, 129.0,
125.6, 124.3, 122.6, 112.0, 62.2, 54.8, 26.6, 20.0, 13.9. HRMS (ESI) m/z:
calcd for C13H15BrNO3 [M + H]+ 312.0235, found: 312.0239.
Ethyl 5-bromo-1,3-dimethyl-2-oxoindoline-3-carboxylate (2k): 2k was
prepared according to the general procedure using 1k as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=3/1), 2k was obtained as a yellow liquid. Yield: 64% (199 mg); IR
(KBr): 2980, 2927, 1743, 1722, 1607, 1489, 1363, 1342, 1245, 1111, 811,
533 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.3 Hz, 1H), 7.36 (s,
1H), 6.73 (d, J = 8.3 Hz, 1H), 4.28 – 3.98 (m, 2H), 3.22 (s, 3H), 1.63 (s,
3H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.5, 168.0,
141.7, 130.9, 130.8, 125.2, 114.3, 109.0, 61.2, 54.0, 25.6, 19.1, 12.9.
HRMS (ESI) m/z: calcd for C13H15BrNO3 [M + H]+ 312.0235, found:
312.0233.
Ethyl 1,3,5-trimethyl-2-oxoindoline-3-carboxylate (2p): 2p was
prepared according to the general procedure using 1p as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2p was obtained as a yellowish-brown liquid. Yield: 76% (190
mg); IR (KBr): 2987, 2935, 1736, 1710, 1598, 1501, 1475, 1370, 1348,
1
1236, 1108, 1060, 1011, 810, 689, 554 cm-1. H NMR (400 MHz, CDCl3)
δ 7.20 – 6.98 (m, 2H), 6.74 (d, J = 7.8 Hz, 1H), 4.24 – 3.97 (m, 2H), 3.23
(s, 3H), 2.33 (s, 3H), 1.64 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 174.2, 168.9, 140.2, 131.4, 129.2, 128.2, 122.7, 107.2,
60.8, 54.1, 25.5, 20.0, 19.1, 12.9. HRMS (ESI) m/z: calcd for C14H18NO3
[M + H]+ 248.1287, found: 248.1281.
Ethyl 3,5-dimethyl-1-(4-methylphenyl)-2-oxoindoline-3-carboxylate
(2q): 2q was prepared according to the general procedure using 1q as
the starting material. After purification by flash chromatography on silica
gel (PE: EA=5/1), 2q was obtained as a yellow liquid. Yield: 65% (211
mg); IR (KBr): 2995, 2927, 1743, 1717, 1516, 1491, 1356, 1248, 1202,
1110, 1015, 808, 514 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.28 (m,
4H), 7.12 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.30
– 4.04 (m, 2H), 2.42 (s, 3H), 2.34 (s, 3H), 1.76 (s, 3H), 1.20 (t, J = 7.1 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 174.7, 169.9, 141.5, 138.1, 132.8,
131.9, 130.2, 130.0, 129.2, 126.3, 123.9, 109.5, 62.0, 55.3, 21.2, 21.1,
20.1, 13.9. HRMS (ESI) m/z: calcd for C20H22NO3 [M + H]+ 324.1600,
found: 324.1592.
Methyl 1,3-dimethyl-2-oxoindoline-3-carboxylate (2r): 2r was
prepared according to the general procedure using 1r as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=3/1), 2r was obtained as a yellow liquid. Yield: 61% (135 mg); IR
(KBr): 2987, 2965, 1747, 1716, 1609, 1494, 1471, 1376, 1348, 1241,
1106, 1034, 752, 541, 496 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.33 (t, J =
7.7 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.87 (d, J =
7.8 Hz, 1H), 3.65 (s, 3H), 3.26 (s, 3H), 1.67 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 175.1, 170.3, 143.6, 130.0, 129.1, 123.0, 122.9, 108.5, 54.9,
53.0, 26.5, 20.2. HRMS (ESI) m/z: calcd for C12H14NO3 [M + H]+
220.0974, found: 220.0967.
Ethyl 7-fluoro-1,3-dimethyl-2-oxoindoline-3-carboxylate (2l): 2l was
prepared according to the general procedure using 1l as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2l was obtained as a pale yellow liquid. Yield: 67% (170 mg); IR
(KBr): 2980, 2942, 1747, 1725, 1631, 1483, 1367, 1239, 1102, 1056, 749,
1
724, 565 cm-1. H NMR (400 MHz, CDCl3) δ 7.11 – 6.92 (m, 3H), 4.22 –
4.03 (m, 2H), 3.45 (s, 3H), 1.64 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 173.7, 168.2, 146.6 (d, J = 243.9 Hz), 131.8 (d, J =
3.4 Hz), 129.3 (d, J = 8.6 Hz), 122.4 (d, J = 6.4 Hz), 117.8 (d, J = 3.2 Hz),
115.9 (d, J = 19.3 Hz), 61.0, 54.2, 27.9, 19.2, 12.8. HRMS (ESI) m/z:
calcd for C13H15FNO3 [M + H]+ 252.1036, found: 252.1033.
Isopropyl 1,3-dimethyl-2-oxoindoline-3-carboxylate (2s): 2s was
prepared according to the general procedure using 1s as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=3/1), 2s was obtained as a yellow liquid. Yield: 69% (172 mg); IR
(KBr): 2983, 2935, 1744, 1715, 1611, 1494, 1471, 1375, 1347, 1250,
Ethyl
1,3-dimethyl-5-trifluoromethyl-2-oxoindoline-3-carboxylate
(2m): 2m was prepared according to the general procedure using 1m as
the starting material. After purification by flash chromatography on silica
gel (PE: EA=3/1), 2m was obtained as a yellow liquid. Yield: 38% (115
mg); IR (KBr): 2987, 2935, 1747, 1624, 1376, 1349, 1328, 1294, 1254,
1164, 1117, 1069, 824, 537 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J
= 8.1 Hz, 1H), 7.49 (s, 1H), 6.94 (d, J = 8.1 Hz, 1H), 4.15 (q, J = 7.0 Hz,
2H), 3.28 (s, 3H), 1.68 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 175.0, 168.9, 146.6, 130.6, 126.8 (q, J = 4.0 Hz), 125.1 (q,
J = 32.8 Hz), 124.2 (q, J = 268.7 Hz), 120.1 (q, J = 4.0 Hz), 108.3, 62.2,
54.9, 26.7, 20.0, 13.8. HRMS (ESI) m/z: calcd for C14H15F3NO3 [M + H]+
302.1004, found: 302.0098.
1
1100, 1029, 751, 543 cm-1. H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.7
Hz, 1H), 7.23 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H),
4.97 (sep, J = 6.2 Hz, 1H), 3.24 (s, 3H), 1.64 (s, 3H), 1.18 (d, J = 6.2 Hz,
3H), 1.08 (d, J = 6.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 175.2, 169.1,
143.6, 130.3, 129.2, 128.9, 122.8, 108.4, 69.4, 55.2, 26.4, 21.4, 21.3,
20.0. HRMS (ESI) m/z: calcd for C14H18NO3 [M + H]+ 248.1287, found:
248.1283.
Methyl 1-methyl-3-(n-propyl)-2-oxoindoline-3-carboxylate (2t): 2t was
prepared according to the general procedure using 1t as the starting
material. After purification by flash chromatography on silica gel (PE:
EA=5/1), 2t was obtained as a pale yellow liquid. Yield: 40% (100 mg); IR
Ethyl 5-cyano-1,3-dimethyl-2-oxoindoline-3-carboxylate (2n): 2n was
prepared according to the general procedure using 1n as the starting
material. After purification by flash chromatography on silica gel (PE:
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001111
European Journal of Organic Chemistry
FULL PAPER
(KBr): 2960, 2927, 1747, 1718, 1611, 1493, 1471, 1373, 1348, 1237,
1120, 752, 543, 488 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.3
Hz, 1H), 7.24 (s, 1H), 7.07 (t, J = 6.9 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H),
3.64 (s, 3H), 3.24 (s, 3H), 2.34 – 2.10 (m, 2H), 1.10 – 0.98 (m, 2H), 0.82
(t, J = 6.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.3, 170.0, 144.1,
129.0, 128.1, 123.4, 122.9, 108.3, 59.4, 52.9, 36.4, 26.4, 17.0, 14.0.
HRMS (ESI) m/z: calcd for C14H17NO3 [M + H]+ 248.1287, found:
248.1280.
Ethyl 1-benzyl-5-fluoro-3-methyl-2-oxoindoline-3-carboxylate (2u):
2u was prepared according to the general procedure using 1u as the
starting material. After purification by flash chromatography on silica gel
(PE: EA=5/1), 2u was obtained as a yellow liquid. Yield: 59% (194 mg);
IR (KBr): 3070, 2980, 1740, 1713, 1495, 1380, 1349, 1273, 1239, 1183,
1110, 825, 690, 496 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.25 (m,
5H), 7.01 (d, J = 7.7 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 8.6 Hz,
1H), 5.17 (d, J = 15.8 Hz, 1H), 4.71 (d, J = 15.8 Hz, 1H), 4.27 – 4.07 (m,
2H), 1.72 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
175.0, 169.2, 159.2 (d, J = 241.7 Hz), 138.6 (d, J = 2.0 Hz), 135.3, 131.6
(d, J = 8.3 Hz), 128.8, 127.7, 127.0, 115.2 (d, J = 23.4 Hz), 111.2 (d, J =
25.1 Hz), 110.1 (d, J = 8.1 Hz), 62.2, 55.4, 43.8, 19.8, 13.9. HRMS (ESI)
m/z: calcd for C19H19FNO3 [M + H]+ 328.1349, found: 328.1344.
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Acknowledgements
Financial support for this work was provided by the National
Natural Science Foundation of China (Nos. 21576041 and
21878037). We acknowledge Prof. Baomin Wang, Dr. Yuming
Song and Dr. Ying Peng (Dalian University of Technology, China)
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001111
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
A novel method for synthesizing 2-oxindoles from 1,3-dicarbonyl compounds based on ferrous salt and iodide catalyst was described.
Through a new catalytic oxidation system, the intramolecular dehydrogenation coupling reaction was completed by using catalytic
amount of iodine.
Key Topic: 2-Oxindoles
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This article is protected by copyright. All rights reserved.