Environmentally Friendly Protocol for 2,3-Difunctionlization of Indole Derivatives

Article abstract of DOI:10.1021/acs.joc.0c01484

Environmentally friendly and highly regioselective C-3 dichlorination and C-2 oxidation of N-substituted indoles have been established using NaCl as a chlorine source and H2O as an oxygen source. A series of 3,3-dichloro-2-oxindoles were obtained in moderate to excellent yields. The gram-scale synthesis and derivatization reaction were explored. The possible mechanism for this reaction was elucidated.

Full text of DOI:10.1021/acs.joc.0c01484

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Article
An environmentally friendly protocol for
,3-difunctionlization of indole derivatives
2
Wen-Wu Sun, Na Chen, Ting-Ting Wei, Guo-Jing You, Hao Yang, JiKai Liu, and Bin Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01484 • Publication Date (Web): 13 Jul 2020
Downloaded from pubs.acs.org on July 13, 2020
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An environmentally friendly protocol for 2,3-difunctionlization of indole
derivatives
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Wen-Wu Sun,* Na Chen, Ting-Ting Wei, Guo-Jing You, Hao Yang, Ji-Kai Liu,* Bin Wu*
School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China
E-mail:
2016027@mail.scuec.edu.cn
(Wen-Wu
Sun);
jkliu@mail.kib.ac.cn
(Ji-Kai
Liu)
2
015084@mail.scuec.edu.cn (Bin Wu)
Cl
Cl
p-MeC H I (10 mol%)
6
4
Oxone (3.0 equiv)
R1
R1
O
NaCl (5.0 equiv)
H O/DCM, rt, 4 h
2
N
R2
N
R2
room temperature
high step efficiency
H O as oxygen source
2
broad substrate scope
NaCl as chlorine source
high regio- and chemoselectivity
ABSTRACT: An environmentally friendly and highly regioselective C-3 dichlorination and C-2
oxidation of N-substituted indoles has been established by using NaCl as a chlorine source and H O
2
as an oxygen source. A series of 3,3-dichloro-2-oxindoles were obtained in moderate to excellent
yields. The gram-scale synthesis and derivatization reaction were explored. The possible mechanism
for this reaction was elucidated.
INTRODUCTION
3
,3-Dihalo-2-oxindoles have been widely used in medicine and agriculture industry, and they are also
1
important intermediates in organic synthesis. Given the pharmaceutical relevance of this structure unit,
the development of novel methodologies for the synthesis of 3,3-dichloro-2-oxindoles has attracted
2
considerable attention from organic chemists in the past few years. In 2005, Padwa reported a
nucleophilic addition-[3,3]-sigmatropic rearrangement-cyclization reaction of vinyl sulfilimines with
3
dichloroketene, producing diverse γ-lactam derivatives. Murphy described (dichloroiodo)benzene
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(PhICl
2
)-mediated a,a-dichlorination of isatin-3-p-tosylhydrazones or isatin-3-hydrazones leading to the
formation of 3,3-dichloroindolin-2-ones.4 Phosphorus pentachloride (PCl
),1e,
5
sulfonylchloride
5
2 2 3 6
SO Cl H) and tungsten(VI) chloride (WCl
),6 chlorosulfonic acid (ClSO )8 were used as chlorine
7
(
0
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sources for chlorination of isatins. The halogenation–decarboxylation of indolecarboxylic acids with 1,3-
dichloro-5,5-dimethylhydantoin (DCDMH) and phenyliodine diacetate (PIDA) was also achieved.9
However, these transformations inherently required prefunctional substrates or highly toxic reagents. To
address these issues, it is highly desirable to develop superior procedures for the construction of 3,3-
dichloro-2-oxindoles from simple and readily available indoles.
In 2015, Finn reported only one example of the synthesis of 3,3-dichloro-2-oxindole from indole with
NaN
, NaClO, and AcOH.10 Yu’s group described a hypervalent iodine-mediated chlorooxidation of
3
indoles.11 We recently demonstrated an efficient route to 3,3-dichloro-2-oxindoles from N-substituted
1
2
2
indoles using PhICl as oxidation reagent and chlorine source. In 2017, our group employed aryliodide,
.
13
x 2
selectfluor and amine (HF) to generate PhIF in situ to synthesize 3,3-difluoro-2-oxindoles. With our
continuous interest in the synthesis of 3,3-dihalo-2-oxindoles, we herein report a 4-iodotoluene promoted
water-phase C-3 dichlorination and C-2 oxidation of N-substituted indoles at room temperature.
Compared with the previous reports, this method has several advantages: (1) water is acted as an oxygen
source and solvent; (2) NaCl, an environmentally friendly reagent, is used as a chlorine source; (3) Oxone,
a nontoxic, cheap and stable reagent, is used as an oxidant; (4) the reaction conditions are mild and easy
to operate.
RESULTS AND DISCUSSION
2
Our original idea was to develop a transition-metal catalyzed C(sp )−H bonds activation at C3 position
of indoles with 2-aminopyrimidine as directing group, but in the end, a metal-free synthetic strategy to
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oxindoles has been developed via the PhICl
2
-mediated C-2 oxidation and C-3 dichlorination of N-
substituted indoles.12 In this project, we plan to further develop an easily-handled aryliodide-catalyzed
procedure for oxindole synthesis (Table 1). The desired product 2a was obtained in 6% yield, along with
1
1
1
1
1
1
1
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1
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6 4
% of 3a in the presence of p-MeC H I (10 mol%) and Oxone (1.1 equiv) (entry 1). Next, a series of
3 2
cosolvents (DCM, DCE, MeCN, EtOAc, THF, MeOH, EtOH, CF CH OH and AcOH) were screened
(entry 2-10), giving rise to a slightly higher yield (15%) of 2a when DCM was used. Increasing the
loading of Oxone led to a significant improvement of the product 2a in 85% yield (entry 11-13). The
6 4
desired product 2a was obtained in 83% when p-MeC H I was replaced by PhI (entry 14). Compound
3
a was the major product when the amount of NaCl decreased to 2.0 equivalents. A slightly lower yield
was obtained when KCl was used as the chlorine source (entry 17). Further attempts of other oxidants
4 2 2 8
revealed that the performance of m-CPBA, NaIO and K S O was limited (entries 18-20). The 3,3-
6 4
dichloro-2-oxindole 2a was formed in 54% yield in the absence of p-MeC H I (entry 21). These results
6 4 2
indicated that aryliodide could effectively promote the reaction via in-situ generation of p-MeC H ICl
since it has better stability than chlorine cation (Cl+).
Table 1. Optimization of the reaction conditions.a, b
Cl
Cl
Cl
p-MeC H I (10 mol%)
6
4
O
Cl
oxidant (x equiv)
NaCl (y equiv)
N
N
+
N
N
H O/cosolvent
N
N
N
2
N
N
4 h, rt
1a
2a
3a
Entry
ArI
Oxidant
Chlorine
source
Cosolvent
Yield [%] of
(x equiv)
2a/3a
(y equiv)
1
2
3
4
p-MeC
p-MeC
p-MeC
p-MeC
6
6
6
6
H
H
H
H
4
4
4
4
I
I
I
I
Oxone (1.1)
Oxone (1.1)
Oxone (1.1)
Oxone (1.1)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
-
6/6
15/20
11/ 9
8/7
DCM
DCE
MeCN
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5
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5
6
p-MeC
p-MeC
p-MeC
p-MeC
p-MeC
p-MeC
p-MeC
p-MeC
p-MeC
6
6
6
6
6
6
6
6
6
H
H
H
H
H
H
H
H
H
4
4
4
4
4
4
4
4
4
I
I
I
I
I
I
I
I
I
Oxone (1.1)
Oxone (1.1)
Oxone (1.1)
Oxone (1.1)
Oxone (1.1)
Oxone (1.1)
Oxone (1.5)
Oxone (2.5)
Oxone (3.0)
Oxone (3.0)
Oxone (3.0)
Oxone (3.0)
Oxone (3.0)
m-CPBA (3.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (2.0)
NaCl (3.0)
KCl (5.0)
EtOAc
THF
-/-
7/trace
11/7
trace/6
9/trace
-/-
7
MeOH
EtOH
8
9
3 2
CF CH OH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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9
0
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0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
10
AcOH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
1
1
1
2
30/43
65/10
85/-
13
1
1
1
4
5
6
PhI
83/-
p-MeC
p-MeC
p-MeC
p-MeC
p-MeC
p-MeC
-
6
H
H
H
H
H
H
4
4
4
4
4
4
I
I
I
I
I
I
11/61
26/53
69/8
-/-
6
6
6
6
6
17
1
1
8
9
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaCl (5.0)
NaIO
4
(3.0)
(3.0)
-/-
20
K
2
S
2
O
8
-/-
2
1
Oxone (3.0)
54/-
a
Reaction conditions: 1a (0.1 mmol), ArI (10 mol%), oxidant (x equiv), chlorine source (y equiv) and
b
cosolvent (0.2 mL) in H
2
O (1.0 mL), 4 h, room temperature. Isolated yield.
With the optimized reaction conditions in hand, the substrate scope and limitation of this protocol were
explored. As depicted in Table 2, the indole substrates bearing different groups on the phenyl ring
afforded the desired products 2a-2o in moderate to excellent yields. The substrates with methyl group on
the phenyl ring gave the corresponding products 2b-2d up to 87% yield under the standard reaction
conditions. These results showed that the position of the methyl group has a less effect on the reaction.
However, the strong electron-donating group, OMe moiety, on the indole ring led to the polyhalogeno-
substituted products 3e in 32% yield. A strong electron-donating group may increase the electron cloud
density in the ortho-position of phenyl ring, which is beneficial to the electrophilic substitution reaction
on the phenyl ring. The F, Cl and Br substituted groups on the indole backbone were tolerated to afford
the products 2f-2n in moderate to good yields. 2o was obtained in 92% yield by using 3-methyl-1-
(
pyrimidin-2-yl)-1H-indole 1o as the substrate under our standard reaction conditions.
Table 2. Substrate scope.a, b
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Cl
Cl
p-MeC H I (10 mol%)
R
6
4
R
O
N
Oxone (3.0 equiv)
N
NaCl (5.0 equiv)
H O/DCM, rt, 4 h
2
N
N
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
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9
0
1
2
3
4
5
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9
0
1
2
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Me
O
O
O
O
N
Me
N
N
N
N
N
N
N
N
N
N
N
2
d, 81%
2c, 87%
2
a, 85%
2b, 87%
Cl
Cl
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
MeO
O
O
O
O
N
N
F
N
N
N
N
N
N
N
N
N
N
2
g, 71%
2h, 84%
2e, 32%
2f, 77%
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O
O
O
N
N
N
N
N
Cl
N
N
N
N
N
N
N
2
i, 46%
2j, 66%
2k, 85%
2l, 59%
Cl
Me
Cl
Cl
Cl
Cl
Br
F
F
O
O
O
N
N
N
N
N
N
N
N
N
2m, 46%
2n, 82%
2o,
92%
a
Reaction conditions: 1 (0.1 mmol), p-MeC
6
H
4
I (10 mol%), Oxone (3.0 equiv), NaCl (5.0 equiv) and
b
DCM (0.2 mL) in H
2
O (1.0 mL), 4 h, room temperature. Isolated yield.
Next, the effect of the N-substituent group on indole was investigated on this reaction (Table 3). There
was less effect on the reaction with methoxy group substituted on the pyrimidine ring. The yields of the
products were up to 89%. Generally, substrates with electron-donating or electron-withdrawing group
substituted on the pyrimidine ring gave the corresponding products 2p-2w in good yields. Under the
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
standard reaction conditions, 1-phenyl-1H-indole afforded the product 2x in 71% yield. 1-Methylindole
was reacted to provide 2y in 53% yield. The polyhalogeno-substituted products 2z was obtained in 57%
yield. The indole was converted to a nearly 2:1 mixture of 3,3-dichloroindolin-2-one (2aa) and 3,3,5-
trichloroindolin-2-one (2aa’).
0
1
2
3
4
5
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7
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9
0
1
2
3
4
5
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7
8
9
0
1
2
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4
5
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9
0
1
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3
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9
0
1
2
3
4
5
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8
9
0
Table 3. Substrate scope. a, b
Cl
p-MeC H I (10 mol%)
Cl
6
4
Oxone (3.0 equiv)
R1
O
R1
N
NaCl (5.0 equiv)
N
R2
H O/DCM, rt, 4 h
2
R2
1
2
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Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Me
Cl
O
O
O
O
N
N
N
F
N
N
N
N
N
N
N
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
OMe
OMe
OMe
OMe
2
p, 82%
2q, 65%
2r, 72%
2s, 73%
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
N
O
O
O
N
N
N
N
N
N
N
N
N
N
N
Me
Me
F
OMe
2v, 78%
2w, 80%
2t, 89%
2u, 73%
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
N
O
O
HO
N
Me
N
Me
2y, 53%
2
x, 71%
2z, 57%
Cl
Cl
Cl
Cl
Cl
O
O
N
H
N
H
2aa
2aa'
2aa/2aa' = 2/1, 39%
a
Reaction conditions: 1 (0.1 mmol), p-MeC
6 4
H I (10 mol%), Oxone (3.0 equiv), NaCl (5.0 equiv) and
b
DCM (0.2 mL) in H O (1.0 mL), 4 h, room temperature. Isolated yield.
2
In order to illustrate the practicality of this method, the gram-scale reaction was carried out with 1a as
the substrate under our standard reaction conditions to afford the product 2a in 75% yield. When 2a was
treated with 3.0 equivalents of zinc powder in AcOH, 2a was reduced to the corresponding product 4 in
9
7% yield (Scheme 1).
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5
6
Cl
p-MeC H I (10 mol%)
Cl
6
4
Oxone (3.0 equiv)
NaCl (5.0 equiv)
O
O
N
Zn (3.0 equiv)
AcOH, rt, 1 h
N
N
N
N
H O/DCM, rt, 4 h
2
N
N
N
N
97%
0
1
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a
1.171 g, 6.0 mmol
4
75% yield of 2a, 1.265 g
Scheme 1. Gram-scale synthesis and reduction of 3,3-dichloro-2-oxindole
1
8
To further investigate the mechanism, a H
2
O -labeling experiment was carried out with 10 mol% of p-
O18 and DCM at
6 4 2
MeC H I, 3.0 equivalents of Oxone and 5.0 equivalents of NaCl in a co-solvent of H
room temperature for 4 h. The desired product 2a was obtained in 76% yield (Scheme 2a). The high
resolution mass spectrometry (HRMS) indicated that the oxygen at the C-2 position of 2a largely
18
2
stemmed from H O (see supporting information). With 3a as substrate, in the presence or absence of p-
6 4
MeC H I, the reaction produced 2a in 88% and 76% yield, respectively (Scheme 2b and 2c). These
results showed that 3a was the intermediate compound and p-MeC
6
H
4
I could promote this reaction. The
’
production of the polyhalogeno-substituted 3,3-dichloro-2-oxindoles 2e, 2aa and 2z indicated that the
+
electrophilic chlorine cation (Cl ) was generated in situ.
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Cl
Cl
p-MeC H I (10 mol%)
6
4
O18
Oxone (3.0 equiv)
NaCl (5.0 equiv)
18
N
N
a)
N
N
N
H O /DCM, rt, 4 h
2
N
76%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
1a
2a
Cl
Cl
Cl
p-MeC H I (10 mol%)
6
4
Oxone (2.0 equiv)
NaCl (2.0 equiv)
O
Cl
N
N
b)
N
N
H O/DCM, rt, 4 h
2
N
N
88%
3
a
2a
Cl
Cl
Cl
Oxone (2.0 equiv)
NaCl (2.0 equiv)
O
Cl
N
N
c)
N
N
H O/DCM, rt, 4 h
2
N
N
72%
3
a
2a
Scheme 2. Mechanistic studies.
Based on the mechanistic studies and previous results, 12, 14 two possible mechanisms can be proposed,
as shown in Scheme 3. In pathway A, as we stated early,12 the electrophilic addition of 1a towards the
2
in-situ generated ArICl forms C, which is then converted to D after the loss of one molecule of ArI via
2
intramolecular nucleophilic substitution reaction. ArI is further oxidized to produce ArICl , which
participates in the next electrophilic addition reaction to form H. The rearomatization of H affords 3a by
2
the loss of one molecule of ArI. Compound 3a reacts with a third PhICl to afford K and K losses one
2
molecule of ArI to afford L. L reacts with H O to yield the final product 2a. The other possibility is that
2
the in situ generated ArICl reacts with the electron-rich double bond of indole 1a to form D, which is
further converted to the intermediate E. E could be transformed to N via electrophilic addition with
+
another chlorine cation (Cl ), followed by the attack of a chlorine anion at the C-2 of indole ring to
produce O. The rearomatization of O affords 3a by the loss of one proton. Compound 3a reacts with a
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
+
2
third chlorine cation (Cl ) to afford L. Subsequently, L is attacked by H O, followed by the removal of
one hydrochloride (HCl), affording 3,3-dichloro-2-oxindoles 2a ( Scheme 3, pathway B).
Pathway A
Oxone + ArI + NaCl
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
Cl
Cl
Cl
Ar
I
Ar
N
I
Ar
Cl
Cl
Cl
Ar
I
I
N
-ArI
Cl
N
N
N
N
N
N
N
N
N
N
1a
B
C
A
Ar
Cl
Cl
Ar
H
Cl
Ar
I
Cl
I
Cl
I
Cl
Cl
Cl
N
N
N
N
Cl
N
N
N
N
N
N
N
N
D
G
E
F
Ar
Ar
Cl
Ar
Cl
Ar
Cl
Cl
Cl
I
Cl
Cl
I
Cl
Cl
I
Cl
Cl
I
-ArI
Cl
H
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
N
H
J
3a
I
Cl
Cl
Cl Ar
Cl
Cl
Cl
Cl
H O
2
Cl
OH
I
-ArI
Cl
Cl
O
Cl
N
N
Cl
N
N
N
HCl
N
N
N
N
N
N
N
K
L
M
2a
Pathway B
Oxone + NaCl
Cl
Cl
+
Oxone + NaCl
Cl
Cl
Cl
H
-H+
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
N
1a
D
E
N
Cl
Cl
Cl
Oxone + NaCl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OH
Cl
Cl
H
O
Cl H O
2
-HCl
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
2a
3a
L
M
O
Scheme 3. Plausible mechanism.
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CONCLUSION
In summary, an efficient route to the synthesis of 3,3-disubstituted 2-oxindoles has been established via
+
2
2
,3-difunctionlization of indoles by using the ArICl and/or chlorine cation (Cl ) generated in situ.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
Moreover, this method provides an environmentally friendly synthesis of 2-oxindole derivatives in
moderate to excellent yield with a wide range of functional group tolerance. The gram-scale synthesis
and derivatization reaction have been studied. Further investigation of the anti-inflammatory activity of
these 3,3-disubstituted 2-oxindoles is underway.
EXPERIMENTAL SECTION
Materials and Methods. Unless otherwise specified, all reactions were carried out under an air
atmosphere. All chemicals and solvents that are commercially available were used without further
purification. Analytical thin-layer chromatography (TLC) was performed on silica gel plates (GF254)
using UV light (254 and 365 nm). Flash chromatography was conducted on silica gel (300−400 mesh).
1H NMR spectra were recorded at 500 MHz and 600 MHz in CDCl
and dimethyl sulfoxide (DMSO)-
3
1
3
6 3 6
d . C NMR spectra were recorded at 150 MHz in CDCl and DMSO-d using tetramethylsilane (TMS)
or residual solvent signals as internal standard. J values are given in hertz. All melting points are
uncorrected. IR spectra were measured for samples as KBr pellets. High-resolution mass spectra
(HRMS) were obtained using electrospray ionization (ESI) [quantitative time-of-flight (Q-TOF)]
ionization sources. All substrates were prepared according to the literature procedures.12
General procedure for the synthesis of 3,3-dichloro-2-oxindoles:
To a 10 mL of round-bottom flask equipped with a stirrer was charged with substrate 1 (0.1 mmol), p-
MeC
6
H
4
2
I (2.2 mg, 0.1 mmol), Oxone (182.2 mg, 0.3 mmol) and NaCl (29.2 mg, 0.5 mmol). Then, H O
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
(1.0 mL) and DCM (0.2 mL) were added to the reaction flask. The reaction mixture was stirred at room
2 2
temperature for 4 h and monitored by TLC. Next, the reaction mixture was extracted with CH Cl (3 ×
1
2 4
0 mL). The combined organic phase was dried over anhydrous Na SO , and concentrated under vacuum.
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
The residue was purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate =
1
0:1) to afford the product 2.
1
2
3
,3-Dichloro-1-(pyrimidin-2-yl)indolin-2-one (2a) : The general procedure described above was
6 4
followed using substrate 1a (19.5 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2 mg,
0
2
.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified by
flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product 2a
1
(23.5 mg, 85% yield). Yellow oil, H NMR (600 MHz, CDCl
3
) δ 8.91 (d, J = 4.8 Hz, 2H), 7.74 (d, J =
5
.7 Hz, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 4.8 Hz, 1H), 7.29 (t, J = 7.6
Hz, 1H).
3
,3-Dichloro-4-methyl-1-(pyrimidin-2-yl)indolin-2-one (2b): The general procedure described above
6 4
was followed using substrate 1b (20.8 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
o
1
2
3
b (25.6 mg, 87% yield). Yellow soild; mp:105-107 C; H NMR (600 MHz, CDCl ) δ 8.91 (d, J = 4.8
Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.36 (t, J = 4.9 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.05 (d, J = 7.7 Hz,
1H), 2.68 (s, 3H). 13C{1H}NMR (150 MHz, CDCl
3
) δ 167.3, 158.8, 155.1, 138.5, 137.4, 131.3, 127.4,
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+
125.2, 119.7, 110.7, 75.2, 17.6. HRMS(ESI) m/z: [M+H] Calcd for C13
H
10Cl
2
N
3
O 294.0201; Found
-1
2
94.0195; IR(KBr) v(cm ):1757, 1566, 1404, 1356, 1198, 787, 673.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
2
3
,3-Dichloro-5-methyl-1-(pyrimidin-2-yl)indolin-2-one (2c) : The general procedure described above
6 4
was followed using substrate 1c (20.9 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2 mg,
2
0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified by
flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product 2c
1
(
3
25.5 mg, 87% yield). Yellow oil, H NMR (600 MHz, CDCl ) δ 8.89 (d, J = 4.8 Hz, 2H), 7.65 (d, J =
8
3
.3 Hz, 1H), 7.56 – 7.50 (m, 1H), 7.33 (t, J = 4.8 Hz, 1H), 7.21 (dd, J = 8.3 and 0.96 Hz, 1H), 2.41 (s,
H).
1
2
3
,3-Dichloro-6-methyl-1-(pyrimidin-2-yl)indolin-2-one (2d) : The general procedure described
6 4
above was followed using substrate 1d (20.9 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone
(
2
182.2 mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was
purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the
1
product 2d (23.7 mg, 81% yield). Yellow oil, H NMR (600 MHz, CDCl
3
) δ 8.92 (d, J = 4.8 Hz, 2H),
7
.61 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.36 (t, J = 4.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 2.41 (s, 3H).
3
,3,6-Trichloro-5-methoxy-1-(pyrimidin-2-yl)indolin-2-one (2e): The general procedure described
6 4
above was followed using substrate 1e (22.9 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone
2
(182.2 mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was
purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
o
1
3
product 2e (11.0 mg, 32% yield). White solid; mp:109-110 C; H NMR (600 MHz, CDCl ) δ 8.90 (d, J
=
4.8 Hz, 2H), 7.71 (d, J = 8.9 Hz, 1H), 7.35 (t, J = 4.8 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 3.94 (s, 3H).
13C{1H}NMR (150 MHz, CDCl
) δ 166.6, 158.8, 155.2, 153.2, 132.5, 125.9, 122.0, 119.6, 114.0, 112.4,
3
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
+
343.9760; Found 343.9755; IR(KBr) v(cm-
7
4.1, 56.8. HRMS(ESI) m/z: [M+H] Calcd for C13
H
9
Cl
3
N
3
O
2
1)
: 2924, 1757, 1460, 1263, 748.
3
,3-Dichloro-4-fluoro-1-(pyrimidin-2-yl)indolin-2-one (2f): The general procedure described above
6 4
was followed using substrate 1f (21.3 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2 mg,
0
2
.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified by
flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product 2f
o
1
3
(22.9 mg, 77% yield). White solid; mp: 106-107 C; H NMR (600 MHz, CDCl ) δ 8.92 (d, J = 4.8 Hz,
2
1
H), 7.58 – 7.53 (m, 1H), 7.43 (td, J = 8.3 and 5.5 Hz, 1H), 7.38 (t, J = 4.8 Hz, 1H), 6.98 (t, J = 8.7 Hz,
13
3
H). C{1H}NMR (150 MHz, CDCl ) δ 166.7, 159.0 (d, J = 257.3 Hz), 158.9, 155.0, 139.6 (d, J = 5.9
Hz), 133.4 (d, J = 8.9 Hz), 119.9, 115.5 (d, J = 17.6 Hz), 112.7 (d, J = 18.8 Hz), 109.5 (d, J = 3.5 Hz),
+
7
1.5. 19F NMR (470 MHz, CDCl
3
) δ -114.5. HRMS (ESI) m/z: [M+H] Calcd for C12
H
7
Cl
2
FN
3
O
-1
297.9950; Found 297.9944; IR(KBr) v(cm ):1771, 1466, 1402, 1200, 781.
3
,3-Dichloro-5-fluoro-1-(pyrimidin-2-yl)indolin-2-one (2g): The general procedure described above
6 4
was followed using substrate 1g (21.3 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
o
1
2
3
g (21.1 mg, 71% yield). Yellow solid; mp:104-105 C; H NMR (600 MHz, CDCl ) δ 8.90 (d, J = 4.8
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Hz, 2H), 7.82 (dd, J = 8.9 and 4.2 Hz, 1H), 7.45 (dd, J = 7.1 and 2.8 Hz, 1H), 7.36 (t, J = 4.8 Hz, 1H),
7
1
.14 (td, J = 8.8 and 2.8 Hz, 1H). 13C{1H}NMR (150 MHz, CDCl
) δ 167.0, 160.1 (d, J = 246.3 Hz),
3
58.8, 155.2, 134.0 (d, J = 2.7 Hz), 123.0 (d, J = 8.6 Hz), 119.6, 118.6 (d, J = 23.2 Hz), 115.6 (d, J = 7.7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
9
+
3
Hz), 112.4 (d, J = 25.5 Hz), 73.8. F NMR (470 MHz, CDCl ) δ -115.5. HRMS(ESI) m/z: [M+H] Calcd
-1
for C12
831.
7 2 3
H Cl FN O 297.9950; Found 297.9944; IR(KBr) v(cm ):1767, 1568, 1483, 1402, 1352, 1167,
12
3
,3-Dichloro-6-fluoro-1-(pyrimidin-2-yl)indolin-2-one (2h) : The general procedure described above
6 4
was followed using substrate 1h (21.3 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
1
2
h (25.1 mg, 84% yield). Yellow oil, H NMR (600 MHz, CDCl
3
) δ 8.91 (d, J = 4.9 Hz, 2H), 7.71 (dd,
J = 8.5 and 5.4 Hz, 1H), 7.59 (dd, J = 9.6 and 2.4 Hz, 1H), 7.37 (t, J = 4.8 Hz, 1H), 6.99 (td, J = 8.6 and
2
.4 Hz, 1H).
1
2
3,3,4-Trichloro-1-(pyrimidin-2-yl)indolin-2-one (2i) : The general procedure described above was
6 4
followed using substrate 1i (23.3 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2 mg, 0.3
2
mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified by flash
chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product 2i (14.6
1
mg, 46% yield). White solid, mp 167-169 °C; H NMR (600 MHz, CDCl
3
) δ 8.92 (d, J = 4.8 Hz, 2H),
7.65 (d, J = 8.2 Hz, 1H), 7.42-7.33 (m, 2H), 7.25 (d, J = 8.6 Hz, 1H).
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3,3,5-Trichloro-1-(pyrimidin-2-yl)indolin-2-one (2j) : The general procedure described above was
6 4
followed using substrate 1j (21.1 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2 mg, 0.3
2
mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified by flash
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
chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product 2j (20.8
1
mg, 66% yield). Yellow oil, H NMR (600 MHz, CDCl
3
) δ 8.89 (d, J = 4.8 Hz, 2H), 7.76 (d, J = 8.7 Hz,
1H), 7.69 (d, J = 2.2 Hz, 1H), 7.38 (dd, J = 8.8 and 2.3 Hz, 1H), 7.36 (t, J = 5.0 Hz, 1H).
12
3
,3,6-Trichloro-1-(pyrimidin-2-yl)indolin-2-one (2k) : The general procedure described above was
6 4
followed using substrate 1k (21.3 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2 mg, 0.3
2
mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified by flash
chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product 2k (26.7
1
mg, 85% yield). Yellow solid; mp 160-162 °C; H NMR (600 MHz, CDCl
3
) δ 8.92 (d, J = 4.9 Hz, 2H),
7
1
.84 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 4.8 Hz, 1H), 7.28 (dd, J = 8.2 and 1.8 Hz,
H).
4-bromo-3,3-Dichloro-1-(pyrimidin-2-yl)indolin-2-one (2l): The general procedure described above
6 4
was followed using substrate 1l (27.4 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2 mg,
0
2
.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified by
flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product 2l
o
1
(
3
21.0 mg, 59% yield). Yellowish solid; mp:110-111 C; H NMR (600 MHz, CDCl ) δ 8.92 (d, J = 4.8
Hz, 2H), 7.68 (dd, J = 8.2 and 0.9 Hz, 1H), 7.44 (dd, J = 8.2 and 0.9 Hz, 1H), 7.38 (t, J = 4.8 Hz, 1H),
.29 (t, J = 8.2 Hz, 1H). 13C{1H}NMR (150 MHz, CDCl
7
3
) δ 166.6, 158.9, 154.7, 140.2, 132.5, 129.7,
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9
+
125.8, 120.9, 120.0, 112.3, 74.9. HRMS(ESI) m/z: [M+H] Calcd for C12
H
7
BrCl
2
N
3
O 357.9150; Found
-1
3
57.9149; IR(KBr) v(cm ):1759, 1599, 1445, 1404, 1161, 785, 673.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
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
5
-bromo-3,3-Dichloro-1-(pyrimidin-2-yl)indolin-2-one (2m): The general procedure described above
6 4
was followed using substrate 1m (27.3 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
1
2
3
m (16.5 mg, 46% yield). Yellow oil, H NMR (600 MHz, CDCl ) δ 8.90 (d, J = 4.9 Hz, 2H), 7.85 (d, J
=
2.1 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 8.7 and 2.1 Hz, 1H), 7.36 (t, J = 4.9 Hz, 1H).
13C{1H}NMR (150 MHz, CDCl
) δ 166.6, 158.8, 155.1, 137.1, 134.6, 130.3, 128.0, 119.7, 118.0, 115.7,
3
+
7 2 3
H BrCl N
O 357.9150; Found 357.9146; IR(KBr) v(cm-
73.5. HRMS(ESI) m/z: [M+H] Calcd for C12
1)
:2924, 1773, 1472, 1404, 816.
1
2
3
,3-Dichloro-5,6-difluoro-1-(pyrimidin-2-yl)indolin-2-one (2n) : The general procedure described
6 4
above was followed using substrate 1n (23.3 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone
2
(182.2 mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The combined
2 4
organic phase was dried over anhydrous Na SO , and concentrated under vacuum. The residue was
purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the
1
product 2n (26.0 mg, 82% yield). Yellow oil, H NMR (600 MHz, DMSO-d
6
) δ 9.02 (d, J = 4.9 Hz, 2H),
8
.22 (dd, J = 9.3 and 7.7 Hz, 1H), 7.81 (dd, J = 11.1 and 6.7 Hz, 1H), 7.65 (t, J = 4.9 Hz, 1H).
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1
2
3-Chloro-3-methyl-1-(pyrimidin-2-yl)indolin-2-one (2o) : The general procedure described above
6 4
was followed using substrate 1o (20.9 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
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
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
1
2
o (23.9 mg, 92% yield). Yellow oil, H NMR (600 MHz, CDCl
3
) δ 8.90 (d, J = 4.8 Hz, 2H), 7.72 (d, J
= 8.1 Hz, 1H), 7.52 (dd, J = 7.5 and 1.3 Hz, 1H), 7.36 (td, J = 7.9 and 1.4 Hz, 1H), 7.31 (t, J = 4.9 Hz,
1
H), 7.23 (td, J = 7.6 and 1.0 Hz, 1H), 2.04 (s, 3H).
3
,3-Dichloro-1-(5-methoxypyrimidin-2-yl)indolin-2-one (2p): The general procedure described above
6 4
was followed using substrate 1p (22.8 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
o
1
2
3
p (25.3 mg, 82% yield). Yellow soild; mp: 91-92 C; H NMR (600 MHz, CDCl ) δ 8.54 (s, 2H), 7.71
(
dd, J = 7.7 and 1.3 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.39 (td, J = 7.9 and 1.4 Hz, 1H), 7.29 – 7.24 (m,
1
H), 3.99 (s, 3H). 13C{1H}NMR (150 MHz, CDCl
3
) δ 167.4, 152.2, 147.7, 144.7, 138.6, 131.7, 128.5,
+
125.1, 124.9, 112.7, 74.5, 56.4. HRMS(ESI) m/z: [M+H] Calcd for C13
H
10Cl
2
N
3
O
2
310.0150; Found
-1
3
10.0143; IR(KBr) v(cm ):1757, 1609, 1452, 1427, 1290, 1177, 754.
3
,3-Dichloro-1-(5-methoxypyrimidin-2-yl)-5-methylindolin-2-one (2q): The general procedure
6 4
described above was followed using substrate 1q (23.9 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol),
2
Oxone (182.2 mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue
was purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford
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9
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the product 2q (21.2 mg, 65% yield). Yellow oil, H NMR (600 MHz, CDCl
3
) δ 8.53 (s, 2H), 7.52 (s,
1
H), 7.39 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 3.99 (s, 3H), 2.40 (s, 3H). 13C{1H}NMR (150
3
MHz, CDCl ) δ 167.5, 152.0, 148.0, 144.7, 136.2, 135.1, 132.2, 128.5, 125.3, 112.6, 74.7, 56.4, 21.0.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
2 3 2
HRMS(ESI) m/z: [M+H] Calcd for C14H12Cl N O 324.0307; Found 324.0300; IR(KBr) v(cm ): 2926,
1
763, 1422, 1277, 748.
3
,3-Dichloro-6-fluoro-1-(5-methoxypyrimidin-2-yl)indolin-2-one (2r): The general procedure
6 4
described above was followed using substrate 1r (24.3 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol),
2
Oxone (182.2 mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue
was purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford
1
the product 2r (23.6 mg, 72% yield). Orange solid; mp:99-100 °C; H NMR (600 MHz, CDCl
3
) δ 8.54
(
s, 2H), 7.69 (dd, J = 8.5 and 5.3 Hz, 1H), 7.31 (dd, J = 9.4 and 2.3 Hz, 1H), 6.96 (td, J = 8.7 and 2.3 Hz,
13
1
3
H), 4.00 (s, 3H). C{1H}NMR (150 MHz, CDCl ) δ 167.3, 164.3 (d, J = 250.9 Hz), 152.2, 146.6 (d, J
=
276.5 Hz), 144.7, 140.1 (d, J = 12.6 Hz), 126.6 (d, J = 10.3 Hz), 124.3 (d, J = 3.3 Hz), 112.0 (d, J =
2
3.4 Hz), 101.8 (d, J = 29.5 Hz), 73.8, 56.4. 19F NMR (470 MHz, CDCl
3
) δ -114.6. HRMS(ESI) m/z:
+
-1
[M+H] Calcd for C13
H
9
Cl
2
FN
3
O
2
328.0056; Found 328.0049; IR(KBr) v(cm ):1765, 1605, 1497, 1422,
1
281, 1099.
3
,3,4-Trichloro-1-(5-methoxypyrimidin-2-yl)indolin-2-one (2s): The general procedure described
6 4
above was followed using substrate 1s (25.9 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone
2
(182.2 mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was
purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
product 2s (25.0 mg, 73% yield). Yellow oil. H NMR (600 MHz, CDCl
3
) δ 8.53 (s, 2H), 7.37 (d, J = 8.0
1
3
3
Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 4.00 (s, 3H). C{1H}NMR (150 MHz, CDCl )
δ 166.7, 152.5, 147.4, 144.8, 140.5, 132.8, 132.4, 126.1, 124.5, 111.0, 73.7, 56.5. HRMS(ESI) m/z:
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
[
9 3 3 2
M+H] Calcd for C13H Cl N O 343.9760; Found 343.9785; IR(KBr) v(cm ):1757, 1603, 1452, 1421,
1
358, 1281.
3
,3,5-Trichloro-1-(5-methoxypyrimidin-2-yl)indolin-2-one (2t): The general procedure described
6 4
above was followed using substrate 1t (26.0 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone
(
2
182.2 mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was
purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the
1
product 2t (30.5 mg, 89% yield). Yellow oil. H NMR (600 MHz, CDCl
3
) δ 8.53 (s, 2H), 7.68 (d, J = 2.2
Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 8.7 and 2.2 Hz, 1H), 3.99 (s, 3H). 13C{1H}NMR (150
3
MHz, CDCl ) δ 166.8, 152.2, 147.6, 144.7, 137.1, 131.7, 130.5, 130.0, 125.1, 114.3, 73.6, 56.4.
+
-1
9 3 3 2
HRMS(ESI) m/z: [M+H] Calcd for C13H Cl N O 343.9760; Found 342.9763. IR(KBr) v(cm ):1773,
1
474, 1452, 1422, 1356, 1277.
3
,3-Dichloro-1-(5-methylpyrimidin-2-yl)indolin-2-one (2u): The general procedure described above
6 4
was followed using substrate 1u (20.9 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
1
2u (21.3 mg, 73% yield). Lavender solid; mp:109-111 °C; H NMR (600 MHz, CDCl
3
) δ 8.73 (s, 2H),
7
.73 (dd, J = 7.6 and 1.3 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.41 (td, J = 7.9 and 1.4 Hz, 1H), 7.30 – 7.27
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8
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1
3
(m, 1H), 2.42 (s, 3H). C{1H}NMR (150 MHz, CDCl
3
) δ 167.3, 158.7, 153.0, 138.3, 131.7, 129.5, 128.6,
+
1
2
25.2, 124.9, 113.2, 74.5, 15.4. HRMS (ESI) m/z: [M+H] Calcd for C13
H
10Cl
2
N
3
O 294.0201; Found
-1
94.0193; IR(KBr) v(cm ):1755, 1422, 1364, 1177, 752.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
2
3
,3-Dichloro-1-(4-methylpyrimidin-2-yl)indolin-2-one (2v) : The general procedure described above
6 4
was followed using substrate 1v (20.9 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
1
2
v (23.0 mg, 78% yield). Yellow oil. H NMR (600 MHz, CDCl
3
) δ 8.73 (d, J = 5.1 Hz, 1H), 7.71 (d, J
=
7.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H),
2.64 (s, 3H).
3
,3-Dichloro-1-(5-fluoropyrimidin-2-yl)indolin-2-one (2w): The general procedure described above
6 4
was followed using substrate 1w (21.4 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2
2
mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified
by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product
1
2
w (23.8 mg, 80% yield). Yellow oil. H NMR (600 MHz, CDCl
3
) δ 8.77 (s, 2H), 7.74 (d, J = 8.5 Hz,
13
1
H), 7.64 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 8.6 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H). C{1H}NMR (150 MHz,
CDCl
3
) δ 167.3, 156.7, 155.4 (d, J = 132.6 Hz), 150.8 (d, J = 3.6 Hz), 146.6 (d, J = 22.1 Hz), 138.0,
1
31.8, 128.5, 125.3 (d, J = 75.1 Hz), 113.2, 74.3. 19F NMR (470 MHz, CDCl
3
) δ -138.0. HRMS(ESI)
+
-1
m/z: [M+H] Calcd for C12
H
7
Cl
2
FN
3
O 297.9950; Found 297.9943; IR(KBr) v(cm ):1773, 1420, 1261,
7
50.
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1
1
2
2
2
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
6
9
a
3
,3-dichloro-1-phenylindolin-2-one (2x) : The general procedure described above was followed using
6 4
substrate 1x (38.6 mg, 0.2 mmol), p-MeC H I (4.5 mg, 0.2 mmol), Oxone (364.4 mg, 0.6 mmol), NaCl
0
1
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0
(
2
58.4 mg, 1.0 mmol), H O (2.0 mL) and DCM (0.4 mL). The residue was purified by flash
chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the product 2x (39.6
1
mg, 71% yield). Orange solid. H NMR (500 MHz, CDCl
3
) δ 7.71 (dd, J = 7.6 and 0.9 Hz, 1H), 7.56 (t,
J = 7.7 Hz, 2H), 7.50 – 7.42 (m, 3H), 7.34 (td, J = 7.8 and 1.3 Hz, 1H), 7.23 (td, J = 7.6 and 0.9 Hz, 1H),
6
.83 (d, J = 8.0 Hz, 1H).
4
a
3
,3-Dichloro-1-methylindolin-2-one (2y) : The general procedure described above was followed using
6 4
substrate 1y (13.1 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone (182.2 mg, 0.3 mmol), NaCl
(
2
29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was purified by flash
chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 20:1) to afford the product 2y (11.5
1
mg, 53% yield). Orange oil. H NMR (600 MHz, CDCl
3
) δ 7.63 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.7 Hz,
1
H), 7.19 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 3.27 (s, 3H).
3
,3,5-Trichloro-6-(hydroxymethyl)-1-methylindolin-2-one (2z): The general procedure described
6 4
above was followed using substrate 1z (16.2 mg, 0.1 mmol), p-MeC H I (2.2 mg, 0.1 mmol), Oxone
(
2
182.2 mg, 0.3 mmol), NaCl (29.2 mg, 0.5 mmol), H O (1.0 mL) and DCM (0.2 mL). The residue was
purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 10:1) to afford the
1
product 2z (16.0 mg, 57% yield). Yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.59 (s, 1H), 7.15 (s, 1H),
4
.83 (d, J = 0.9 Hz, 2H), 3.28 (s, 3H). 13C{1H}NMR (150 MHz, CDCl
) δ 168.7, 142.9, 139.6, 128.9,
3
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+
126.9, 125.5, 108.6, 73.4, 62.2, 27.3. HRMS(ESI) m/z: [M+H] Calcd for C10
H
9
Cl
3
NO
2
279.9699; Found
-1
2
79.9699; IR(KBr) v(cm ): 3472, 1763, 1730, 1614, 1460, 827, 669.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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
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
’
9a
3
,3-dichloroindolin-2-one (2aa) and 3,3,5-trichloroindolin-2-one (2aa ) : The general procedure
6 4
described above was followed using substrate 1aa (23.4 mg, 0.2 mmol), p-MeC H I (4.5 mg, 0.2 mmol),
2
Oxone (364.4 mg, 0.6 mmol), NaCl (58.4 mg, 1.0 mmol), H O (2.0 mL) and DCM (0.4 mL). The residue
was purified by flash chromatography (Silica gel, eluent: petroleum ether: ethyl acetate = 5:1) to afford
’
’
1
a mixture of 2aa and 2aa (2aa/2aa = 2/1, 16.8 mg, 39% yield). Orange solid. H NMR (500 MHz,
3
CDCl ) δ 9.13 (s, 0.5H), 8.95 (s, 1.0H), 7.62 (dd, J = 7.6 and 1.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 0.5H),
7
.37 (td, J = 7.7 and 1.0 Hz, 1H), 7.34 (dd, J = 8.5 and 2.0 Hz, 0.5H), 7.18 (td, J = 7.7 and 0.8 Hz, 1H),
6.98 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 8.4 Hz, 0.5H).
Gram-scale synthesis and derivation of 3,3-dichloro-2-oxindole:
To a 100 mL of round-bottom flask equipped with a stirrer was charged with substrate 1a (1.171 g, 6.0
6 4
mmol), p-MeC H I (0.131 g, 0.6 mmol), Oxone (11.069 g, 18.0 mmol) and NaCl (1.752 g, 30.0 mmol).
2
Then, H O (30.0 mL) and DCM (6.0 mL) were added to the reaction flask. The reaction mixture was
stirred at room temperature for 4 h and monitored by TLC. Then, the reaction mixture was extracted with
2 2 2 4
CH Cl (3 × 50 mL). The combined organic phase was dried over anhydrous Na SO , and concentrated
under vacuum. The residue was purified by flash chromatography (Silica gel, eluent: petroleum ether:
ethyl acetate = 10:1) to afford the product 2a (1.265 g, 75% yield).
In a 10 mL of round-bottom flask was placed substrate 2a (28.0 mg, 0.1 mmol), Zn (19.6 mg, 0.3 mmol)
and AcOH (1.0 mL). The reaction mixture was stirred at room temperature for 1 h. Then the reaction
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2
2
2
2
2
2
2
2
2
3
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5
5
5
5
6
2 2
mixture was neutralized by addition of aqueous saturated sodium bicarbonate and extracted with CH Cl .
2 4
The combined extracts were dried over Na SO and concentrated. Purification by flash chromatography
(Silica gel, eluent: petroleum ether: ethyl acetate = 4 : 1) afforded the product 4 (20.5 mg, 97% yield).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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6
7
8
9
0
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6
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9
0
1
2
3
4
5
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7
8
9
0
o
1
White solid; mp:108-110 C. H NMR (600 MHz, CDCl
H), 7.27 – 7.18 (m, 3H), 7.06 (t, J = 7.7 Hz, 1H), 3.71 (s, 2H). 13C{1H}NMR (150 MHz, CDCl
) δ
3
3
) δ 8.82 (d, J = 4.8 Hz, 2H), 7.52 (d, J = 8.1 Hz,
1
173.9, 158.6, 155.9, 142.3, 127.7, 124.4, 123.8, 123.7, 118.9, 112.4, 36.4. HRMS (ESI) m/z:
+
-1
[
10 3
M+H] Calcd for C12H N O 212.0824; Found 212.0819; IR(KBr) v(cm ): 1740, 1566, 1483, 1412,
1
368, 1088, 750.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:,
18
1
13
2
including H O -labeling experiments, H NMR and C NMR spectra for new compounds.
AUTHOR INFORMATION
Corresponding Author
*E-mail: 2016027@mail.scuec.edu.cn.
*
*
E-mail: jkliu@mail.kib.ac.cn.
E-mail: 2015084@mail.scuec.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (no. 21772236).
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Motabar, O.; Lea, W. A.; Hu, X.; Velayati, A.; Zheng, W.; Southall, N.; Gustafson, A. M.; Goldin, E.;
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(
(
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(
oxindoles from 2-substituted indoles via halogenation-decarboxylation/desulfonamidation-oxidation
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Cl
p-MeC H I (10 mol%)
6
4
Cl
Oxone (3.0 equiv)
R1
R1
O
NaCl (5.0 equiv)
H O/DCM, rt, 4 h
2
N
R2
N
R2
room temperature
high step efficiency
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H O as oxygen source
2
broad substrate scope
NaCl as chlorine source
high regio- and chemoselectivity
Table of Contents
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