A Mild and Direct C(sp3)-S Cross-Coupling of Oxindoles with Thiols: Synthesis of Unsymmetrical 3-Thiooxindoles

Article abstract of DOI:10.1021/acs.joc.9b02205

Herein, an operationally simple and mild strategy to construct sulfenation of oxindoles with a series of thiols in the absence of transition metals was developed. This methodology provides an efficient way to directly form a C-S bond at the C-3 position of oxindoles under mild reaction conditions with a cheap and common solvent and base in moderate to good yields.

Full text of DOI:10.1021/acs.joc.9b02205

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Note
A Mild and Direct C(sp3)-S Cross-Coupling of Oxindoles
with Thiols: Synthesis of Unsymmetrical 3-Thiooxindoles
Hui Qin, Qi Li, Jian Xu, Jie Zhang, Wei Qu, Wenyuan Liu, Feng Feng, and Haopeng Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02205 • Publication Date (Web): 03 Oct 2019
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The Journal of Organic Chemistry
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A Mild and Direct C(sp3)-S Cross-Coupling of Oxindoles with Thiols:
Synthesis of Unsymmetrical 3-Thiooxindoles
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Hui Qin,Δ Qi Li,Ω Jian Xu,Δ Jie Zhang,Δ Wei Qu,Δ,Φ Wenyuan Liu,Λ Feng Feng *,Δ,Φ,Σ and Haopeng Sun *,Ω
ΔDepartment of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China
ΦKey Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 211198, China
ΛDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
ΣJiangsu Food and Pharmaceutical Science College, Huai’an 223003, China
ΩDepartment of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People’s Republic of China
Supporting Information
ABSTRACT: Herein, an operationally simple and mild strategy to construct sulfenation of oxindoles with a series of thiols in
the absence of transition metals was developed. This methodology provides an efficient way to directly form C-S bond at C-3
position of oxindoles under mild reaction conditions with a cheap and common solvent and base in moderate to good yields.
Oxindoles are prevalent and significant structural cores in
a wide range of naturally occurring products as well as a
series of marketed pharmaceuticals,1 which exhibit diverse
biological activities.2 Furthermore, oxindoles owning a
hetero atom at the C-3 position are even more in demand
because of the increased bioactivities.3 Among them, 3-
thiooxindoles are valuable architectures in drug
development and have been found to display a broad
spectrum of biological activities, for example, as an
anticancer agent,4 antitubercular activities,5 antirheumatic
agent,6 and antifungal agent.7 Hence, attention has been
temperature;8e Zhou’s group and Peddinti’s research team
has separately disclosed an analogous Lewis acids
catalyzed sulfenylation reaction of 3-hydroxy oxindoles
with thiols.8f, 10 Additionally, Zhang et al. has described a
new strategy for the preparation of 3-arylthio-1,3-
disubstituted-oxindoles in good yields by the reaction of α-
diazocarbonyl compounds and sulfenamides, which
involves
a
Rh-catalyzed thia-Sommelet-Hauser-type
rearrangement in 20118a (Scheme 1a). Although great
improvements in thiolation of oxindoles have been made,
the development of simple, green and general
methodologies with inexpensive and less hazardous
reagent under environmentally benign and mild conditions
remain important and valuable.
paid to the development of oxindoles bearing sulfur at the
C-3 position in organic chemistry.8,9
During the past decade, the most dominant methods for
the synthesis of 3-thiooxindoles directly from oxindoles or
3-hydroxy oxindole are as follows: Feng’s group has
reported a catalytic asymmetric sulfenylation of 3-
substituted oxindoles with N-(phenylthio)phthalimide as
sulfur source via cooperative catalysis of a chiral N,N’-
dioxide-Sc(OTf)3 complex and a Brønsted base;8b In 2015, a
new methodology for the synthesis of structurally diverse
chiral dithioketals with 3-thiooxindoles and N-
Thus, based on our interest and effort, we envisaged
that oxindoles, which undergo deprotonation in the
presence of base to form enolates that can reversibly exist,
react with thiols, which can form disulphide intermediates
via oxidation in the present of air, to generate 3-
thiooxindoles through the C-S cross-coupling reaction. To
our delight, a concise and efficient approach for the
synthesis of C-3 3-thiooxindoles by employing a series of
oxindoles and a range of thiols under mild conditions has
been depicted by our groups (Scheme 1b).
(phenylthio)pyrrolidine-2,5-dione
through
cinchona
alkaloid derivative at -70 ℃ has been developed by Zhou et
al;8c In 2017, Lu and co-workers have described an
thiolation of oxindoles using sulfonyl chlorides as
sulfenylation reagent at high temperature;8d Meanwhile,
Kumar et al has introduced the sulfenylation reaction of
oxindole with phenyl disulfide as sulfur source at room
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a)
Previous reports:
phenyl disulfide, tBuOK or
R1
the standard reaction conditions for the synthesis of 3-
OH
1
2
3
4
5
6
7
8
sulfonyl chlorides, PPh3, 80 °C
O
thiols, lewis acid, 70 °C
or room temperature
thiooxindoles were obtained as follow: p-toluenethiol 2a
(1.2 equiv.), NaOH (1.0 equiv.) under air in DMF (0.5 M) at
0 ℃.
O
R1
N
R1
SR2
O
N
H
O
N2
N
SPh
N
MeO2
C
R1
H
R3
O
SR2
L-Sc(OTf)3, 35 °C or
dihydroquinine, -70 °C
Rh2(OAc)4, 0 °C
Table 1. Optimization of the reaction conditions for
sulfenylation with 1a a
N
R3
b)
This work:
R2
SH
n
R2
S
Y
R
NaOH, air
0°C, DMF
n
SH
R1
O
+
air
R1
O
N
R3
S
N
R3
X
temp.
base, solvent
O
R
+
N
O
H
X, Y= C, N
n= 0, 1
N
9
TM-, catalyst-free
Broad substrate scope
Moderate to good yields
H
1a
2a
3a
10
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Mild reaction condition
Entry
2a
Base
Solvent
Temp.
Time
(h)
Yield
(%) b
Scheme 1. Strategies for the synthesis of 3-
thiooxindoles
(equiv.)
(equiv.)
(℃)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
2.0
1.2
tBuOK (1)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
0
10
16
15
9
41
39
43
56
53
54
54
13
69
nr c
nr
1
2
With this hypothesis, our initial investigations focused on
the screening of a suitable base to acquire a desired
product with simple and readily available 1H-oxindole 1a
and p-toluenethiol 2a as model substrate in dimethyl
sulfoxide (DMSO) under air at room temperature (Table 1).
To our delight, when using potassium t-Butoxide (tBuOK)
as the base, the sulfenylation product 3a was obtained in
41% yield (Table 1, entry 1). It was found that the type of
the base had a significant effect on the yield. For example,
3a was obtained in only 13% yield under organic base
triethylamine (Et3N) after reacting for 64h (Table 1, entry
8). The commonly used inorganic bases such as NaOH,
KOH, LiOH gave moderate results (Table 1, entries 4-6) in
9, 8 and 10 hours, respectively. Additionally, Cs2CO3 and
K2CO3 individually afforded 39% and 43% yield (Table 1,
entries 2-3) after 15 or 16 hours of reaction. Considering
the cost and availability, NaOH was chosen as alkali source
for further research. In order to improve the yield of the
target product, we next investigated the effect of the
solvent on the sulfenylation reaction. We discovered that
solvent played an important role to proceed the reaction.
No product was detected when using polar aprotic
solvents such as dioxane, Tetrahydrofuran (THF) and
Acetonitrile (ACN), or polar protic solvents such as ethanol
and water (Table 1, entries 10-11, 13-15). Meanwhile,
when non-polar solvent dichloromethane (DCM) was used,
the reaction was not observed (Table 1, entry 12).
Interestingly, a relatively higher yield 69% was obtained
when the reaction was performed in N, N-
dimethylformamide (DMF) as opposed to DMSO (Table 1,
entries 4 and 9).
Cs2CO3 (1)
K2CO3 (1)
NaOH (1)
KOH (1)
3
4
8
5
LiOH (1)
DBU (1)
10
13
64
7
6
7
Et3N (1)
8
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (0.5)
NaOH (2)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
9
dioxane
THF
14
14
14
13
13
14
4
10
11
12
13
14
15
16
17
18
19
20
21
22
DCM
ACN
nr
nr
EtOH
H2O
nr
nr
DMF
16
38
28
79
59
71
41 d
DMF
12
1.5
9
DMF
DMF
DMF
0
6
DMF
0
12
1.5
DMF
0
a
Reaction conditions: oxindole 1a (0.5 mmol), indicated
amount of p-toluenethiol 2a, base and 1ml solvent, under an
air atmosphere for the indicated time. Yield of isolated
products. nr: no reaction occurred. Reaction was carried
out in 3ml DMF.
b
c
d
With the optimized conditions established in hand, we
then examined the application of this method by using
multiple substrates. First, we utilized the standard
conditions to the coupling of a series of substituted free
(NH) oxindoles 1 with p-toluenethiol 2a (Table 2).
Fortunately, the protocol was well tolerated for different
kinds of substituted oxindoles such as electron-donating
substituents (Me and OMe) and electron-withdrawing
groups (F, Cl and Br) at para, meta, ortho position of
aromatic rings to afford 3-thiooxindoles in moderate to
good yields (3a-3f, 3h-3o and 3r), demonstrating that the
weak electronic properties of the substituents on the
phenyl ring slightly influenced the reactivity of the
reaction. However, the 5-NO2 oxindole 1g and a boronic
ester group on C-6 position of oxindole ring 1s provided
the corresponding products 3g and 3s in relatively low
yields, indicating that strong electron-withdrawing
substituents and steric hindrance had a great influence on
the reaction. In addition, disubstituted oxindoles could be
Further improvement of the reaction conditions was
focused on the concentration of NaOH. Unexpectedly, both
0.5 equivalent NaOH for 4 h of reaction and 2.0 equivalent
NaOH for 12 h of reaction remarkably decreased the yield
of 3a (Table 1, entries 17-18). Furthermore, using 3ml
DMF led to a decreased yield of 3a in 41% yield at 0 ℃
(Table 1, entry 22). These results indicated that the
reaction was very sensitive to the concentration of alkali.
Finally, entries with varied reaction temperature
proved that low temperature was preferred for this
reaction, for example, entry 19 provided the highest yield
(79%, Table 1) in all the tested conditions, much higher
than entries with 40 ℃ reaction temperature (Table 1,
entries 18-19). Based on such condition, when the
amounts of 2a were reduced or increased, the yield of 3a
was slightly decreased (Table 1, entries 20 and21). Hence,
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also employed as the reaction substrates, supplying the benzyldisulfide, which was generated from benzyl
1
2
3
4
5
6
7
8
thiolation products 3p and 3q with good yields. Meanwhile,
3-methyloxindole 1t successfully reacted with p-
toluenethiol 2a, providing 69% yield. Gratifyingly, the
yield of corresponding compound 3u was significantly
enhanced to 97%. Additionally, we found that N-
heteroaryl-bearing oxindole 1v exhibited the general
reaction activity to give the desired product 3v in 59%
yield.
mercaptan.
Table 3. Substrate scope of thiols a
SH
Y
S
n
R
NaOH, air
O
n
+
0°C, DMF
N
H
O
R
N
H
Y= C, N; n= 0, 1
1a
3
2
OMe
OH
NH2
F
Cl
Table 2. Substrate scope of substituted oxindoles a
S
S
S
S
S
9
O
O
O
O
O
N
N
N
H
N
N
10
11
12
13
14
15
16
17
18
H
H
H
H
R2
SH
3ab
60%, 9h
3ac
0%, 24h
3ad
61%, 12h
3ae
69%, 3h
3af
47%, 3h
R2
S
NaOH, air
+
R1
O
Br
R1
O
0°C, DMF
S
S
S
S
S
N
R3
X
N
R3
Me
O
F
Cl
O
O
O
O
O
N
N
H
N
H
N
H
N
H
X= C, N
H
2a
3
1
3ag
3ah
3ai
3aj
3ak
61%, 5h
61%, 7h
80%, 4h
33%, 4h
30%, 4h
S
S
S
S
S
Me
O
F
Cl
S
S
S
N
S
S
O
O
O
O
O
O
Br
N
N
N
H
N
N
O
O
O
O
O
H
H
H
H
N
H
N
H
N
H
N
H
N
H
3a
3b
62%, 8h
3c
3d
3e
79%, 9h
S
78%, 20h
74%, 9h
S
53%, 9h
S
3al
28%, 4h
3am
79%, 3h
3an
30%, 4h
3ao
54%, 18h
3ap
26%, 5h
S
S
a
Br
O2
N
All the reactions were carried out using 1a (0.5 mmol), 2
(1.2 equiv., 0.6 mmol), and NaOH (1.0 equiv., 0.5 mmol) in
DMF (1ml), at 0 ℃ under an air atmosphere.
19
20
21
22
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32
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53
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59
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O
O
O
O
N
H
N
H
N
H
N
N
F
Cl
Br
H
H
3f
3g
37%, 6h
3h
3i
3j
61%, 11h
60%, 11h
68%, 10h
83%, 10h
F
Cl
Br
Me
S
S
S
S
S
Additionally, to further demonstrate the efficiency and
practicality of this transformation, we next performed a
gram scale experiment of 2-oxindole 1a (5.0 mmol) with p-
toluenethiol 2a (6.0 mmol) under the standard conditions.
As shown in Scheme 2, the scale synthesis of compound 3a
was afforded in 80% yield, illustrating that the present
method should be a good potential tool in the practical
synthesis.
O
O
O
O
O
N
H
N
H
N
H
N
H
N
H
Cl
3k
69%, 12h
3l
3m
80%, 9h
3n
91%, 10h
3o
64%, 7h
66%, 9h
S
S
S
S
S
Cl
Cl
F
F
O
O
O
O
O
O
O
N
H
N
H
N
H
N
N
H
B
H
O
O
3p
87%, 9h
3q
62%, 9h
3r
3s
39%, 6h
3t
79%, 10h
69%, 6h
S
S
SH
O
N
O
N
H
N
S
Ph
3u
97%, 6h
O
DMF, air
+
3v
N
NaOH, 0°C
59%, 7h
O
H
N
a
All the reactions were carried out using 1 (0.5 mmol), 2a
H
(1.2 equiv., 0.6 mmol), and NaOH (1.0 equiv., 0.5 mmol) in
1a
2a
3a
(80%, 1.02 g)
(5.0 mmol)
(6.0 mmol)
DMF (1ml), at 0 ℃ under an air atmosphere.
Scheme 2. The gram scale synthesis of the product 3a
To develop the further generality of the protocol, we
next focused on the sulfenation of 1H-oxindole 1a with a
variety of thiols 2 under the standard reaction conditions.
As shown in Table 3, different substrates with electron-
rich or electron-poor substituents positioned para to the
sulfhydryl group proceeded smoothly in modest yield
(3ab-3ag) except 4-mercaptophenol 2c. Exploration
showed that thiols with electron enriched groups such as
alkoxyl and amino or electron deficient groups such as
halide (F, Cl and Br), which were at para-position, had no
marked electronic effect to the reaction. Mercaptans with
meta-electron-donating substituents (3h and 3i) were also
applicable substrates to give good results in 61% and 80%
yield, respectively. However, halogen at meta-position of
the mercaptans resulted in remarkedly reduced yields,
ranging from 28% - 33% (3aj-3al). In addition, the cases of
3ag and 3al were synthetically worth, since the presence
of bromide provided a platform for elaboration of the
products to other complex compounds by cross-coupling
reactions. Surprisingly, bicyclic-thiol like bulky 2-
naphthalenethiol provided the desired compound 3ao in
modest yield of 54%. Unfortunately, alkyl thiols
phenylmethanethiol (2p) only afforded relatively low yield
about 26%, probably due to the poor electrophilicity of the
In the procedure of optimizing the reaction conditions,
we found that reaction system could supply a common side
product p-tolyldisulfide 4a. To gain further insight into the
reaction mechanism, several control experiments were
conducted under the standard conditions, as show in
Scheme 3. Firstly, we found that p-toluenethiol 2a under
the standard conditions could be converted into p-
tolyldisulfide 4a in excellent yield of 89% via aerobic
oxidation11 (Scheme 3a). Whereafter, the reaction of 1H-
oxindole 1a with p-tolyldisulfide 4a was performed and
produced the desired product in high yield with 77%,
which exemplified that p-tolyldisulfide 4a might be an
intermediate in this reaction (Scheme 3b). In addition,
when 1a reacted with 2a or 4a under a nitrogen
atmosphere, the yield of desired product 3a significantly
decreased to 0% and trace separately after the reaction
maintained for 24 h, indicating that the aerial dioxygen
was essential to activate 2a or 4a reacting with 1a
(Scheme 3c and 3d). Finally, the addition of radical
inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
hampered the output of the desired product 3a, resulting
in a reduction to 32% yield of 3a. Meanwhile, TEMPO-
trapped compound 5 was obtained in 29% yield by
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reaction of 1a and 2a in the presence of TEMPO under the
General Information. Unless stated otherwise, all
1
standard conditions and further identified by H and 13C
reactions for preparing compound 3a-ap were carried out
under an air atmosphere. All reagents and solvents were of
commercial quality and were used without further
purification. Purification was carried out according to
standard laboratory methods14. All reactions were
monitored by TLC analysis with silica gel-coated plates
1
2
3
4
5
6
7
8
NMR, indicating that the sulfur radical (RS•) should be
involved as a reactive intermediate in the reaction process.
(Scheme 3e).
1
S
with fluorescent indicator UV254. H and 13C NMR spectra
S
standard conditions
2a
(a)
were obtained on either a Bruker AV 300 at 300 MHz and
75 MHz, respectively. Chemical shifts are reported in ppm
and coupling constants are reported in Hz with TMS at 0.0
ppm (1H and 13C) or CDCl3 referenced at 7.26 (1H) and
77.0 ppm (13C) and DMSO-d6 referenced at 2.50 (1H) and
39.5 (13C). Mass spectra were measured with an Agilent Q-
TOF 6520 mass spectrometer using ESI ionization.
6 hour
4a
89%
9
3a
77%
standard conditions
5 hour
10
11
12
13
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1a
1a
1a
+
+
4a
2a
4a
(b)
(c)
(d)
3a
0%
1.0 eq. NaOH, N2
0°C, DMF, 24 hour
3a
trace
1.0 eq. NaOH, N2
0°C, DMF, 24 hour
+
+
General procedure for the synthesis of 3a-ap. In a 25
mL round bottomed flask different substituted oxindole
1a-v (0.5 mmol, 1.0 equiv.) and various thiols 2a-p (0.6
mmol, 1.2 equiv.) was dissolved with 1 ml DMF and was
treated with NaOH (0.5 mmol, 1.0 equiv.) at 0 °C under air
atmosphere. Then mixture was stirred until the reaction
completed. The progress of the reaction was monitored by
TLC. After that, reaction system was quenched with
saturated ammonium chloride solution (5 mL), and was
extracted with EtOAc (3 x 10 mL). The combined organic
layer was washed with aqueous brine solution (10 mL)
and water (2 x 10 mL). Then, the organic layer was dried
with anhydrous sodium sulfate. After concentration,
product was purified using column chromatography on
silica gel with petroleum ether / ethyl acetate (10:1 to 2:1)
or dichloromethane / methanol (100:1 to 40:1).
N
S
3a
32%
1.0 eq. NaOH, TEMPO
0°C, DMF, 6.5 hour
O
1a
2a
(e)
+
5,
29%
Scheme 3. Control experiments
On the basis of the above experimental results and
previous reports,12, 8e, 13 a plausible reaction mechanism is
proposed and depicted in Scheme 4. Firstly, p-toluenethiol
2a was autoxidized to generate sulfur radical I, which
underwent homocoupling to form the disulfide 4a, which
also converted to the sulfur radical I ether via direct
radical cracking or the aerial dioxygen. Meanwhile, the
nucleophilic addition of enolate II was generated from
substrate 1H-oxindole 1a under NaOH. Then, enolate I
combined with the sulfur radical I to generate the
corresponding intermediate III resonating with oxygen
centered radical IV by the single electron transfer (SET).
Finally, oxygen centered radical IV was transformed into
desired compound 3a by the single electron transfer,
simultaneously, disulfide 4a regenerated sulfur radical I
which could also form compound 2a via trapped proton
and the single electron transfer.
Procedure for the Gram-Scale Synthesis. 2-oxindole
1a (676 mg, 5.0 mmol) and p-toluenethiol 2a (781 mg, 6.0
mmol, 1.2 equiv.) was dissolved with 10 ml DMF in a 25
mL round bottomed flask and was treated with NaOH (210
mg, 5.0 mmol, 1.0 equiv.) at 0 °C under air atmosphere.
Then mixture was stirred until the reaction completed. The
progress of the reaction was monitored by TLC. After that,
reaction system was quenched with saturated ammonium
chloride solution (20 mL), and was extracted with EtOAc
(3 x 30 mL). The combined organic layer was washed with
aqueous brine solution (20 mL) and water (2 x 20 mL).
Then, the organic layer was dried with anhydrous sodium
sulfate. After concentration, the crude material was
purified using column chromatography on silica gel with
petroleum ether / ethyl acetate (10:1 to 2:1) to afford the
desired product 3a in 80% yield (1.02 g).
O2
SH
S
S
S
Ⅰ
or O2
OOH
Ⅰ
2a
4a
O-
O
base
N
N
N
S
H
H
O
TEMPO
Ⅱ
1a
5
S
S
S
Ⅰ
SET
O-
O
O
3-(p-Tolylthio)-indolin-2-one (3a).8e Pale yellow solid,
N
H
N
H
N
H
H
2a
4a
1
(101 mg, 79% yield). mp 152-154 °C. H NMR (400 MHz,
Ⅲ
Ⅳ
3a
CDCl3): δ 8.63 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.30 (d, J =
7.8 Hz, 2H), 7.20 (t, J = 7.7 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H),
7.00 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 4.54 (s, 1H),
2.28 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 176.9,
141.1, 138.9, 134.4, 129.5, 128.9, 127.0, 126.9, 125.5,
122.7, 110.0, 49.9, 21.2. HRMS (ESI-TOF) calcd for
C15H14NOS [M+H] +: 256.0791; found: 256.0797.
Scheme 4. Proposed mechanism for the reaction
In summary, we have successfully developed an efficient
and green economical synthetic strategy to form 3-
thiooxindoles under mild conditions without a metal
catalyst. A wide range of oxindoles and mercaptans have
been converted to structurally diverse products in
moderate to good yields. This novel approach may provide
a complementary and simple operation approach to
synthesize 3-thiooxindole derivatives.
5-Methyl-3-(p-tolylthio)-indolin-2-one
(3b).
white
1
crystalline, (84 mg, 62% yield). mp 177-180 °C. H NMR
(300 MHz, CDCl3): δ 8.29 (s, 1H), 7.21 (d, J = 8.1 Hz, 2H),
7.12 (s, 1H), 6.92 (d, J = 8.0 Hz, 3H), 6.58 (d, J = 7.9 Hz, 1H),
4.41 (s, 1H), 2.26 (s, 3H), 2.19 (s, 3H). 13C {1H} NMR (75
EXPERIMENTAL SECTION
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The Journal of Organic Chemistry
MHz, CDCl3): δ 176.7, 138.8, 138.6, 134.2, 132.2, 129.5,
6-Chloro-3-(p-tolylthio)-indolin-2-one (3i). pale brown
solid, (98 mg, 68% yield). mp 159-162 °C. H NMR (300
1
1
2
3
4
5
6
7
8
129.3, 127.3, 126.9, 126.1, 109.6, 49.9, 21.2, 21.1. HRMS
+
(ESI-TOF) calcd for C16H16NOS [M+H] : 270.0947; found:
MHz, DMSO-d6): δ 10.56 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H),
7.21 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.00 (dd, J =
2.0, 8.0 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 4.94 (s, 1H), 2.23
(s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 175.5, 144.2,
138.6, 133.6, 133.2, 130.0, 127.8, 126.8, 126.5, 121.8,
109.9, 48.7, 21.1. HRMS (ESI-TOF) calcd for C15H12ClNNaOS
[M+Na] +: 312.0220; found: 312.0224.
270.0951.
5-Methoxy-3-(p-tolylthio)-indolin-2-one (3c). pale yellow
1
solid, (114 mg, 78% yield). mp 108-110 °C. H NMR (300
MHz, CDCl3): δ 8.65 (br s, 1H), 7.21-7.18 (m, 2H), 6.91 (d, J
= 8.2 Hz, 3H), 6.67-6.57 (m, 2H), 4.42 (s, 1H), 3.71 (s, 3H),
2.18 (s, 3H). 13C {1H} NMR (75 MHz, CDCl3): δ 176.8, 155.9,
138.9, 134.6, 134.4, 129.6, 128.2, 127.0, 114.1, 111.9,
110.5, 55.8, 50.4, 21.2. HRMS (ESI-TOF) calcd for
C16H16NO2S [M+H] +: 286.0896; found: 286.0901.
6-Bromo-3-(p-tolylthio)-indolin-2-one (3j). pale brown
9
1
powder, (139 mg, 83% yield). mp 152-154 °C. H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(300 MHz, DMSO-d6): δ 10.55 (s, 1H), 7.21-7.15 (m, 4H),
7.07 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 1.7 Hz, 1H), 4.92 (s, 1H),
2.23 (s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 175.4,
144.4, 138.6, 133.6, 130.0, 127.8, 127.1, 126.9, 124.7,
121.5, 112.6, 48.7, 21.1. HRMS (ESI-TOF) calcd for
C15H12BrNNaOS [M+Na] +: 357.9695; found: 357.9701.
5-Fluoro-3-(p-tolylthio)-indolin-2-one (3d). pale grey
1
solid, (101 mg, 74% yield). mp 191-193 °C. H NMR (300
MHz, DMSO-d6): δ 10.42 (s, 1H), 7.22-7.19 (m, 2H), 7.10-
7.04 (m, 3H), 7.02-6.95 (m, 1H), 6.69 (dd, J = 4.4 8.5 Hz,
1H), 4.95 (s, 1H), 2.23 (s, 3H). 13C {1H} NMR (75 MHz,
DMSO-d6): δ 175.4, 159.8-156.7 (d, JC-F = 227.9 Hz), 139.04-
7-Chloro-3-(p-tolylthio)-indolin-2-one (3k). pale yellow
1
139.02 (d, JC-F = 1.9 Hz), 138.6, 130.0, 129.4-129.3 (d, JC-F
=
powder, (100 mg, 69% yield). mp 179-181 °C. H NMR
8.5 Hz), 127.7, 115.6-115.3 (d, JC-F = 23.2 Hz), 113.1-112.7
(d, JC-F = 33.1 Hz), 110.6-110.5 (d, JC-F = 8.1 Hz), 49.4, 21.1.
HRMS (ESI-TOF) calcd for C15H13FNOS [M+H] +: 274.0696;
found: 274.0699.
(300 MHz, DMSO-d6): δ 10.86 (brs, 1H), 7.23-7.18 (m, 4H),
7.07-7.04 (m, 2H), 6.98-6.96 (m, 1H), 5.06 (s, 1H), 2.23 (s,
3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 175.5, 140.4,
138.6, 133.5, 129.4, 129.0, 127.8, 124.0, 123.3, 114.0, 49.7,
+
21.0. HRMS (ESI-TOF) calcd for C15H12ClNNaOS [M+Na] :
5-Chloro-3-(p-tolylthio)-indolin-2-one (3e). grey solid,
1
312.0220; found: 312.0224.
(97 mg, 53% yield). mp 199-190 °C. H NMR (300 MHz,
DMSO-d6): δ 10.54 (s, 1H), 7.25-7.19 (m, 4H), 7.08 (d, J =
8.0 Hz, 2H), 6.72 (d, J = 8.3 Hz, 1H), 4.96 (s, 1H), 2.23 (s,
3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 175.2, 141.7,
138.6, 133.6, 130.0, 129.7, 129.0, 127.8, 126.0, 125.3,
111.3, 49.1, 21.1. HRMS (ESI-TOF) calcd for C15H13ClNOS
[M+H] +: 290.0401; found: 290.0399.
4-Fluoro-3-(p-tolylthio)-indolin-2-one (3l). pale yellow
1
crystalline, (89 mg, 66% yield). mp 149-151 °C. H NMR
(300 MHz, DMSO-d6): δ 10.55 (s, 1H), 7.23-7.20 (m, 1H),
7.18-7.14 (m, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.77 (t, J = 8.9
Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 4.99 (s, 1H), 2.21 (s, 3H).
13C {1H} NMR (75 MHz, DMSO-d6): δ 175.1, 160.3-157.0 (d,
JC-F = 246.4 Hz), 144.9-144.8 (d, JC-F = 8.6 Hz), 138.9, 134.3,
131.4-131.3 (d, JC-F = 8.8 Hz), 129.9, 127.2, 113.2-112.9 (d,
JC-F = 18.4 Hz), 109.4-109.1 (d, JC-F = 20.1 Hz), 106.3-106.2
(d, JC-F = 3.1 Hz), 47.25-47.22 (d, JC-F = 2.2 Hz), 21.1. HRMS
5-Bromo-3-(p-tolylthio)-indolin-2-one (3f). pale brown
1
solid, (101 mg, 61% yield). mp 180-182 °C. H NMR (400
MHz, DMSO-d6): δ 10.55 (s, 1H), 7.36-7.32 (m, 2H), 5.76 (s,
1H),7.22-7.19 (m, 2H) ,7.09-7.06 (m, 2H), 6.68 (d, J = 8.1
Hz, 1H), 4.9 (s, 1H), 2.24 (s, 3H). 13C {1H} NMR (100 MHz,
DMSO-d6): δ 175.1, 142.1, 138.6, 133.6, 131.8, 130.1, 130.0,
128.0, 127.8, 113.6, 111.8, 49.0, 21.1. HRMS (ESI-TOF)
calcd for C15H12BrNNaOS [M+Na] +: 357.9695; found:
357.9697.
+
(ESI-TOF) calcd for C15H12FNNaOS [M+Na] : 296.0516;
found: 296.0521.
4-Chloro-3-(p-tolylthio)-indolin-2-one (3m). pale yellow
1
powder, (118 mg, 80% yield). mp 183-185 °C. H NMR
(300 MHz, DMSO-d6): δ 10.49 (s, 1H), 7.19-7.11 (m, 3H),
7.03-6.98 (m, 3H), 6.61 (d, J = 7.7 Hz, 1H), 4.82 (s, 1H), 2.21
(s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 174.8, 144.7,
139.0, 134.6, 130.9, 130.7, 129.8, 127.0, 124.2, 122.4,
108.5, 49.5, 21.1. 13C NMR (75 MHz, DMSO-d6): δ 174.8,
144.7, 139.0, 134.6, 130.9, 130.7, 129.8, 127.0, 124.2,
122.4, 108.5, 49.5, 21.1. HRMS (ESI-TOF) calcd for
C15H12ClNNaOS [M+Na] +: 312.0220; found: 312.0221.
5-Nitro-3-(p-tolylthio)-indolin-2-one (3g). red solid, (56
mg, 37% yield). mp 158-161 °C. 1H NMR (400 MHz, DMSO-
d6): δ 11.09 (s, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.0 (s, 1H), 7.21
(d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.5
Hz, 1H), 5.0 (s, 1H), 2.23 (s, 3H). 13C {1H} NMR (100 MHz,
DMSO-d6): δ 175.8, 149.2, 142.5, 139.1, 134.3, 130.1, 128.9,
127.0, 126.3, 120.8, 110.0, 48.9, 21.1. HRMS (ESI-TOF)
calcd for C15H13N2O3S [M+H] +: 301.0641; found: 301.0631.
4-Bromo-3-(p-tolylthio)-indolin-2-one
(3n).
yellow
1
crystalline, (152 mg, 91% yield). mp 168-170 °C. H NMR
(300 MHz, DMSO-d6): δ 10.49 (s, 1H), 7.17-7.08 (m, 4H),
7.06-7.01 (m, 2H), 6.64 (d, J = 7.4 Hz, 1H), 4.71 (s, 1H), 2.21
(s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 174.7, 144.8,
139.0, 134.6, 131.1, 129.8, 127.0, 126.1, 125.4, 119.9,
109.0, 50.9, 21.1. HRMS (ESI-TOF) calcd for
C15H12BrNNaOS [M+Na] +: 357.9695; found: 357.9694.
6-Fluoro-3-(p-tolylthio)-indolin-2-one (3h). pale brown
1
solid, (82 mg, 60% yield). mp 164-166 °C. H NMR (300
MHz, DMSO-d6): δ 10.56 (s, 1H), 7.25 (dd, J = 5.7, 8.1 Hz,
1H), 7.21 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.77
(ddd, J = 2.4, 8.3, 10.3 Hz, 1H), 6.54 (dd, J = 2.4, 9.2 Hz, 1H),
4.9 (s, 1H), 2.23 (s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6):
δ 175.9, 164.3-161.1 (d, JC-F = 241.2 Hz), 144.4-144.2 (d, JC-F
= 12.4 Hz), 138.5, 133.6, 129.9, 127.9, 126.9-126.7 (d, JC-F
=
4-Methyl-3-(p-tolylthio)-indolin-2-one (3o). pale yellow
1
9.9 Hz), 123.36-123.33 (d, JC-F = 2.7 Hz), 108.4-108.1 (d, JC-F
= 22.3 Hz), 98.2-97.9 (d, JC-F = 27.0 Hz), 48.5, 21.1. HRMS
solid, (87 mg, 64% yield). mp 155-156 °C. H NMR (300
MHz, DMSO-d6): δ 10.27 (s, 1H), 7.17 (d, J = 8.1 Hz, 2H),
7.07-7.00 (m, 3H), 6.78 (d, J = 7.7 Hz, 1H), 6.50 (d, J = 7.7
Hz, 1H), 4.80 (s, 1H), 2.43 (s, 3H), 2.22 (s, 3H). 13C {1H}
+
(ESI-TOF) calcd for C15H12FNNaOS [M+Na] : 296.0516;
found: 296.0515.
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NMR (75 MHz, DMSO-d6): δ 175.8, 142.8, 138.4, 135.6,
Page 6 of 8
δ 11.03 (s, 1H), 8.02 (d, J = 4.7 Hz, 1H), 7.58 (d, J = 7.3 Hz,
1H), 7.21 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.96
(dd, J = 6.3, 7.4 Hz, 1H), 5.02 (s, 1H), 2.23 (s, 3H). 13C {1H}
NMR (75 MHz, DMSO-d6): δ 175.1, 157.3, 147.7, 138.8,
134.0, 132.9, 130.0, 127.4, 122.0, 118.3, 48.6, 21.1. HRMS
1
2
3
4
5
6
7
8
133.9, 129.8, 129.1, 128.0, 124.6, 123.7, 107.3, 48.9, 21.1,
+
18.5. HRMS (ESI-TOF) calcd for C16H15NNaOS [M+Na] :
292.0767; found: 292.0762.
5,6-Dichloro-3-(p-tolylthio)-indolin-2-one (3p). pale
brown solid, (142 mg, 87% yield). mp 158-159 °C. 1H NMR
(300 MHz, DMSO-d6): δ 10.67 (s, 1H), 7.43 (s, 1H), 7.22 (d, J
= 8.2 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 6.89 (s, 1H), 4.97 (s,
1H), 2.24 (s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ
175.1, 142.9, 138.9, 133.9, 131.2, 130.1, 128.7, 127.4,
127.0, 123.9, 111.5, 48.8, 21.1. HRMS (ESI-TOF) calcd for
C15H12Cl2NOS [M+H] +: 324.0011; found: 324.0014.
+
(ESI-TOF) calcd for C14H13N2OS [M+H] : 257.0743; found:
257.0742.
3-((p-Methoxyphenyl) thio)-indolin-2-one (3ab). pale red
solid, (81 mg, 60% yield). mp 140-143 °C. H NMR (300
1
MHz, DMSO-d6): δ 10.34 (s, 1H), 7.26-7.20 (m, 3H), 7.14 (tt,
J = 0.3, 7.6 Hz, 1H), 6.96 (dt, J = 1.1, 7.5 Hz, 1H), 6.80 (d, J =
8.9 Hz, 2H), 6.69 (d, J = 7.7 Hz, 1H), 4.80 (s, 1H), 3.69 (s,
3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 175.5, 160.2,
142.8, 136.2, 129.0, 127.5, 125.4, 122.0, 121.6, 114.7,
109.8, 55.6, 49.6. HRMS (ESI-TOF) calcd for C15H13NNaO2S
[M+Na] +: 294.0559; found: 294.0562.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5,6-Difluoro-3-(p-tolylthio)-indolin-2-one (3q). pale grey
powder, (92 mg, 62% yield). mp 197-199 °C. 1H NMR (300
MHz, DMSO-d6): δ 10.52 (s, 1H), 7.34 (t, JH-F = 8.9 Hz, 1H),
7.21 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 6.74 (dd JH-F
= 6.7, 10.5 Hz, 1H), 4.91 (s, 1H), 2.23 (s, 3H). 13C {1H} NMR
(75 MHz, DMSO-d6): δ 175.6, 139.48-139.45 (d, JC-F = 2.2
Hz), 139.34-139.31 (d, JC-F = 1.9 Hz), 138.8, 134.0, 130.0,
127.3, 123.7, 115.0-114.7 (d, JC-F = 20.1 Hz), 99.8-99.5 (d, JC-
3-((p-Aminophenyl) thio)-indolin-2-one (3ad). red solid,
1
(77 mg, 61% yield). mp 99-102 °C. H NMR (300 MHz,
DMSO-d6): δ 10.23 (s, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.11 (tt, J
=1.1, 7.6 Hz, 1H), 6.97-6.91 (m, 3H), 6.66 (d, J = 7.7 Hz, 1H),
6.36 (d, J = 8.5 Hz, 2H), 5.31 (br s, 2H), 4.59 (s, 1H). 13C {1H}
NMR (75 MHz, DMSO-d6): δ 175.7, 150.1, 142.9, 136.8,
128.8, 127.9, 125.4, 121.8, 114.2, 109.6, 50.2. HRMS (ESI-
TOF) calcd for C14H13N2OS [M+H] +: 257.0743; found:
257.0745.
= 22.3 Hz), 49.0, 21.0. HRMS (ESI-TOF) calcd for
F
C15H11F2NNaOS [M+Na] +: 314.0422; found: 314.0420.
Methyl-3-(p-tolylthio)-2-oxoindoline-6-carboxylate (3r).
1
red solid, (125 mg, 79% yield). mp 139-142 °C. H NMR
(300 MHz, DMSO-d6): δ 10.60 (s, 1H), 7.62 (dd, J = 1.6, 7.7
Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.20-7.16 (m, 2H), 7.05 (d, J
= 7.8 Hz, 2H), 6.93-6.88 (m, 1H), 5.04 (s, 1H), 3.82 (s, 3H),
2.21 (s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 175.2,
166.3, 143.2, 138.7, 133.7, 133.2, 130.2, 130.0, 127.6,
125.6,123.4, 109.7, 52.7, 49.1, 21.0. HRMS (ESI-TOF) calcd
for C17H16NO3S [M+H] +: 314.0845; found: 314.0855.
3-((p-Florophenyl) thio)-indolin-2-one (3ae)8e. pale white
1
solid, (90 mg, 69% yield). mp 116-118 °C. H NMR (300
MHz, DMSO-d6): δ 10.44 (s, 1H), 7.39-7.34 (m, 2H), 7.28 (d,
J = 7.4 Hz, 1H), 7.19-7.07 (m, 3H), 6.97 (t, J = 7.3 Hz, 1H),
6.73 (d, J = 7.7 Hz, 1H), 4.96 (s, 1H). 13C {1H} NMR (75 MHz,
DMSO-d6): δ 175.5, 164.3-161.0 (d, JC-F = 244.5 Hz), 142.8,
135.9-135.8 (d, JC-F = 8.5 Hz), 129.3, 127.44-127.40 (d, JC-F
=
6-(4’,4’,5’,5’-Tetramethyl-1’,3’,2’-dioxaborolan-2’-yl)-3-(p-
3.3 Hz), 127.0, 125.4, 122.1, 116.4-116.1 (d, JC-F = 21.8 Hz),
109.9, 49.0. HRMS (ESI-TOF) calcd for C14H10FNNaOS
[M+Na] +: 282.0359; found: 282.0364.
tolylthio)-indolin-2-one (3s). red solid, (37 mg, 39% yield).
1
mp 164-166 °C. H NMR (300 MHz, DMSO-d6): δ 10.47 (s,
1H), 7.25-7.31 (m, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.06 (d, J =
8.0 Hz, 2H), 6.96 (s, 1H), 4.98 (s, 1H), 2.22 (s, 3H), 1.27 (s,
12H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 175.3, 142.4,
138.3, 133.3, 131.0, 129.9, 128.5, 128.3, 114.9, 84.2, 49.1,
25.1, 21.0. HRMS (ESI-TOF) calcd for C21H25BNO3S [M+H] +:
382.1647; found: 382.1650.
3-((p-Chlorophenyl) thio)-indolin-2-one (3af)8e. pale red
1
crystalline, (66 mg, 47% yield). mp 141-143 °C. H NMR
(300 MHz, DMSO-d6): δ 10.51 (s, 1H), 7.38-7.32 (m, 4H),
7.31-7.26 (m, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.98 (dt, J = 1.1,
7.6 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H). 13C {1H} NMR (75 MHz,
DMSO-d6): δ 175.6, 142.8, 134.2, 133.2, 131.5, 129.4, 129.2,
126.8, 125.4, 122.2, 110.0, 48.4. HRMS (ESI-TOF) calcd for
C14H10ClNNaOS [M+Na] +: 298.0064; found: 298.0067.
3-Methyl-3-(p-tolylthio)-indolin-2-one (3t)8d. white solid,
1
(94 mg, 69% yield). mp 141-143 °C. H NMR (300 MHz,
DMSO-d6): δ 10.28 (s, 1H), 7.31 (dd, J = 1.3, 7.4 Hz, 1H),
7.13 (dt, J = 1.3, 7.7 Hz, 1H), 7.07-6.96 (m, 5H), 6.66 (d, J =
7.7 Hz, 1H), 2.23 (s, 3H), 1.53 (s, 3H). 13C {1H} NMR (75
MHz, DMSO-d6): δ 177.9, 141.5, 139.6, 136.2, 132.0, 129.6,
129.1, 126.9, 124.4, 122.1, 109.8, 54.7, 22.0, 21.2. HRMS
(ESI-TOF) calcd for C16H15NNaOS [M+Na] +: 292.0767;
found: 292.0768.
3-((p-Bromophenyl) thio)-indolin-2-one (3ag). pale red
1
solid, (98 mg, 61% yield). mp 155-158 °C. H NMR (300
MHz, DMSO-d6): δ 10.52 (s, 1H),7.47 (d, J = 8.3 Hz, 2H),
7.31-7.28 (m, 3H), 7.19 (t, J = 7.8 Hz, 1H), 6.98 (t, J = 7.5 Hz,
1H), 6.77 (d, J = 7.7 Hz, 1H), 5.09 (s, 1H). 13C {1H} NMR (75
MHz, DMSO-d6): δ 175.5, 142.8, 134.3, 132.1, 129.4, 126.8,
125.4, 122.2, 121.7, 110.0, 48.3. HRMS (ESI-TOF) calcd for
C14H10BrNNaOS [M+Na] +: 343.9538; found: 343.9540.
1-Phenyl-3-(p-tolylthio)-indolin-2-one (3u). pale white
1
solid, (161 mg, 97% yield). mp 124-127 °C. H NMR (300
MHz, DMSO-d6): δ 7.53-7.39 (m, 4H), 7.21-7.12 (m, 4H),
7.07-7.03 (m, 4H). 6.52 (d, J = 7.4 Hz, 1H), 5.15 (s, 1H), 2.23
(s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ 173.3, 144.0,
139.0, 134.4, 134.3, 130.0, 129.8, 129.2, 128.6, 127.1,
126.9, 126.7, 125.7, 123.4, 109.2, 48.9, 21.2. HRMS (ESI-
TOF) calcd for C21H18NOS [M+H] +: 332.1104; found:
332.1103.
3-((3’-Methylphenyl) thio)-indolin-2-one (3ah). pale red
solid, (79 mg, 61% yield). mp 68-71 °C. (300 MHz, DMSO-
d6): δ 10.49 (s, 1H), 7.25 (d, J = 7.4 Hz, 1H), 7.18-7.13 (m,
4H), 7.07-7.04 (m, 1H),6.96 (t, J = 6.9 Hz, 1H), 6.77 (d, J =
7.7 Hz, 1H), 5.01 (s, 1H), 2.20 (s, 3H). 13C {1H} NMR (75
MHz, DMSO-d6): δ 175.7, 142.8, 138.5, 132.6, 132.4, 129.25,
129.22, 129.1, 128.8, 127.3, 125.5, 122.1, 109.9, 48.4, 21.1.
+
HRMS (ESI-TOF) calcd for C15H13NNaOS [M+Na]
278.0610; found: 2780610.
:
3-(p-tolylthio)-7-azaoxindole (3v). red solid, (77 mg,
1
59% yield). mp 157-159 °C. H NMR (300 MHz, DMSO-d6):
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3-((3’-Methoxy phenyl) thio)-indolin-2-one (3ai). brick
red solid, (110 mg, 80% yield). mp 81-84 °C. H NMR (300
7.45 (dd, J = 1.9, 8.6 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.17 (t,
1
1
2
3
4
5
6
7
8
J = 7.7 Hz, 1H), 6.97 (dt, J = 1.1, 7.6 Hz, 1H), 6.75 (d, J = 7.7
Hz, 1H), 5.17 (s, 1H). 13C {1H} NMR (75 MHz, DMSO-d6): δ
175.6, 142.8, 133.4, 132.4, 131.1, 130.2, 129.5, 129.3,
128.6, 128.0, 127.7, 127.2, 127.1, 126.9, 125.4, 122.2,
110.0, 48.3. HRMS (ESI-TOF) calcd for C18H13NNaOS
[M+Na] +: 314.0610; found: 314.0616.
MHz, DMSO-d6): δ 10.52 (s, 1H), 7.27 (d, J = 7.4 Hz, 1H),
7.21-7.14 (m, 2H), 6.97 (dt, J = 0.8, 7.6 Hz, 1H), 6.92 (d, J =
7.7 Hz, 1H), 6.86-6.85 (m, 1H), 6.82-6.75 (m, 2H), 5.08 (s,
1H), 3.63 (s, 3H). 13C {1H} NMR (75 MHz, DMSO-d6): δ
175.6, 159.6, 142.8, 134.0, 130.1, 129.3, 127.3, 125.3,
123.9, 122.2, 116.7, 114.1, 110.0, 55.4, 48.3. HRMS (ESI-
3-(Benzylthio)-indolin-2-one (3ap). yellow solid, (33 mg,
+
TOF) calcd for C15H13NNaO2S [M+Na] : 294.0559; found:
1
26% yield). mp 69-71 °C. H NMR (300 MHz, DMSO-d6): δ
294.0560.
10.56 (s, 1H), 7.32-7.18 (m, 7H), 6.96 (dt, J = 1.1, 7.5 Hz,
1H), 6.85 (d, J = 7.7 Hz, 1H), 4.43 (s, 1H), 4.05 (d, J = 12.5
Hz, 1H), 3.82 (d, J = 12.6 Hz, 1H). 13C {1H} NMR (75 MHz,
DMSO-d6): δ 176.9, 142.9, 137.8, 129.4, 129.2, 128.9, 127.5,
126.9, 125.2, 122.2, 110.0, 44.2, 33.8. HRMS (ESI-TOF)
calcd for C15H14NOS [M+H] +: 256.0791; found: 256.0799.
9
3-((3’-Florophenyl) thio)-indolin-2-one (3aj). brick red
solid, (43 mg, 33% yield). mp 88-90 °C. 1H NMR (300 MHz,
DMSO-d6): δ 10.60 (s, 1H), 7.35-7.18 (m, 5H), 7.09 (dt, J =
1.5, 8.9 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 7.7 Hz,
1H), 5.19 (s, 1H). 13C {1H} NMR (75 MHz, DMSO-d6): δ
175.7, 163.8-162.7 (d, JC-F = 82.9 Hz), 142.8, 131.0-130.9 (d,
JC-F = 8.5 Hz), 129.5, 127.3, 126.6, 125.4, 122.3, 118.0-117.7
(d, JC-F = 22.7 Hz), 114.9-114.6 (d, JC-F = 20.4 Hz), 110.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
p-tolyldisulfide (4a)11c. white solid, (67 mg, 89% yield).
1
mp 41-43 °C. H NMR (300 MHz, CDCl3): δ 7.31 (d, J = 8.2
Hz, 4H), 7.03 (d, J = 8.0 Hz, 4H), 2.23 (s, 6H). 13C {1H} NMR
(75 MHz, CDCl3): δ 137.4, 133.9, 129.8, 128.5, 21.0.
+
47.9. HRMS (ESI-TOF) calcd for C14H10FNNaOS [M+Na] :
282.0359; found: 282.0365.
2,2,6,6-tetramethyl-1-((p-tolylthio) oxy) piperidine (7)15.
3-((3’-Chlorophenyl) thio)-indolin-2-one (3ak). brick red
solid, (42 mg, 30% yield). mp 86-87 °C. 1H NMR (300 MHz,
DMSO-d6): δ 10.58 (s, 1H), 7.45-7.43 (m, 1H), 7.32-7.27 (m,
4H), 7.21 (tt, J = 1.1, 7.6 Hz, 1H), 6.99 (dt, J = 1.1, 7.6 Hz,
1H), 6.80 (dd, J = 1.1, 7.7 Hz, 1H), 5.17 (s, 1H). 13C {1H} NMR
(75 MHz, DMSO-d6): δ 175.7, 142.8, 135.4, 133.6, 130.9,
1
pale yellow oil, (41 mg, 29% yield). H NMR (300 MHz,
CDCl3): δ 7.58-7.55 (m, 2H), 7.27-7.24 (m, 2H), 2.40 (s, 3H),
1.67-1.51 (m, 15H), 0.93 (s, 3H). 13C {1H} NMR (75 MHz,
CDCl3): δ 147.0, 139.4, 129.2, 125.9, 61.1, 58.6, 43.5, 41.3,
35.3, 32.5, 28.7, 27.9, 21.2, 17.3.
130.8, 130.1, 129.5, 127.9, 126.6, 125.4, 122.3, 110.1, 48.0.
ASSOCIATED CONTENT
Supporting Information
+
HRMS (ESI-TOF) calcd for C14H10ClNNaOS [M+Na]
298.0064; found: 298.0064.
:
The Supporting Information is available free of charge on the
ACS Publications website.
NMR spectra and HRMS chromatographs of compound 3a-
3ap; NMR spectra chromatographs of compound 4a and 5
(PDF)
3-((3’-Bromophenyl) thio)-indolin-2-one (3al). pale red
solid, (34 mg, 28% yield). mp 95-98 °C. 1H NMR (300 MHz,
DMSO-d6): δ 10.59 (s, 1H), 7.44-7.43 (m, 1H), 7.33-7.27 (m,
4H), 7.21 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.80 (d, J
= 7.7 Hz, 1H), 5.18 (s, 1H). 13C {1H} NMR (75 MHz, DMSO-
d6): δ 175.6, 142.8, 135.6, 133.6, 131.1, 130.8, 130.6, 129.5,
126.6, 1245.4, 122.3, 122.1, 110.1, 48.0. HRMS (ESI-TOF)
calcd for C14H10BrNNaOS [M+Na] +: 343.9538; found:
343.9537.
AUTHOR INFORMATION
Corresponding Author
* E-mail: fengfeng@cpu.edu.cn (F. Feng),
sunhaopeng@163.com (H. p. Sun)
3-((2’-Methylphenyl) thio)-indolin-2-one (3am). pale red
1
solid, (103 mg, 79% yield). mp 58-61 °C. H NMR (300
MHz, DMSO-d6): δ 10.56 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H),
7.22-7.16 (m, 4H), 7.14-7.05 (m, 1H), 6.95 (t, J = 7.5 Hz,
1H), 6.80 (d, J = 7.7 Hz, 1H), 5.05 (s, 1H), 2.33 (s, 3H). 13C
{1H} NMR (75 MHz, DMSO-d6): δ 175.8, 142.8, 139.4, 132.4,
132.3, 130.6, 129.3, 128.0, 127.2, 126.7, 125.3, 122.1,
110.0, 47.7, 20.8. HRMS (ESI-TOF) calcd for C15H13NNaOS
[M+Na] +: 278.0610; found: 278.0608.
Notes
There are no conflicts to declare.
ACKNOWLEDGMENT
We gratefully appreciate the support from the grants (Nos.
81573281 and 81830105) of National Natural Science
Foundation of China; “Double First-Class” initiative innovation
team project of China Pharmaceutical University (Nos.
CPU2018GF11 and CPU2018GY34). We also appreciated for
the support from the Joint Laboratory of China
Pharmaceutical University and Taian City Central Hospital.
3-(Pyridin-2-ylthio)-indolin-2-one (3an)8e. brick red
1
solid, (37 mg, 30% yield). mp 99-100 °C. H NMR (300
MHz, DMSO-d6): δ 10.66 (s, 1H), 8.34 (m, 1H), 7.68 (dt, J =
1.9, 7.9 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.23-7.12 (m, 3H),
6.94-6.85 (m. 2H), 5.56 (s, 1H). 13C {1H} NMR (75 MHz,
DMSO-d6): δ 175.7, 156.5, 149.6, 143.2, 137.4, 129.1, 127.8,
124.7, 122.3, 122.1, 120.9, 109.9, 44.8. HRMS (ESI-TOF)
calcd for C13H10N2NaOS [M+Na] +: 265.0406; found:
265.0399.
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