Ru(III)-mediated intramolecular ortho-C(sp2)-H activation/oxidative acylation: One-pot synthesis of isatins from α-hydroxy amides

Article abstract of DOI:10.1016/j.tet.2016.04.041

A novel and efficient synthesis of isatins from α-hydroxy amides via ruthenium-mediated aromatic C-H activation is described. The reactions proceeded smoothly under mild conditions and generated the corresponding products in good to excellent yields. This methodology has a broad substrate scope and opens up an interesting and attractive avenue for the application of intramolecular ortho-C-H activation.

Full text of DOI:10.1016/j.tet.2016.04.041

Accepted Manuscript
2
Ru(III)-mediated intramolecular ortho-C(sp )-H activation/oxidative acylation: one-pot
synthesis of isatins from α-hydroxy amides
Yaoling Wang, Weijian Li, Xu Cheng, Zhen Zhan, Xiaojun Ma, Li Guo, Hui Jin, Yong
Wu
PII:
S0040-4020(16)30310-6
10.1016/j.tet.2016.04.041
TET 27684
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 January 2016
Revised Date: 7 April 2016
Accepted Date: 15 April 2016
Please cite this article as: Wang Y, Li W, Cheng X, Zhan Z, Ma X, Guo L, Jin H, Wu Y, Ru(III)-mediated
2
intramolecular ortho-C(sp )-H activation/oxidative acylation: one-pot synthesis of isatins from α-hydroxy
amides, Tetrahedron (2016), doi: 10.1016/j.tet.2016.04.041.
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Ru( )-mediated intramolecular ortho-
C(sp2)-H activation/oxidative acylation: One-
pot synthesis of isatins from α-hydroxy
amides
Leave this area blank for abstract info.
Yaoling Wang, Weijian Li, Xu Cheng, Zhen Zhan, Xiaojun Ma, Hui Jin* and Yong Wu*
Key Laboratory of Drug Targeting and Drug Delivery System of Education Ministry, Department of Medicinal
Chemistry, West China School of Pharmacy, Sichuan University, No. 17, 3th Section, South Renmin Road,
Chengdu 610041 (P. R. China)

1
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Tetrahedron
journal homepage: www.elsevier.com
Ru( )-mediated intramolecular ortho-C(sp2)-H activation/oxidative acylation: One-
pot synthesis of isatins from α-hydroxy amides
Yaoling Wang, Weijian Li, Xu Cheng, Zhen Zhan, Xiaojun Ma, Li Guo, Hui Jin* and Yong Wu
Key Laboratory of Drug Targeting and Drug Delivery System of Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, No. 17, 3th Section, South Renmin Road, Chengdu 610041 (P. R. China)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and efficient synthesis of isatins from α-hydroxy amides via ruthenium-mediated
aromatic C-H activation is described. The reactions proceeded smoothly under mild conditions
and generated the corresponding products in good to excellent yields. This methodology has a
broad substrate scope and opens up an interesting and attractive avenue for the application of
intramolecular ortho-C-H activation.
Available online
Keywords:
C-H activation
ruthenium-mediated
intramolecular reaction
isatins
2009 Elsevier Ltd. All rights reserved
.
α-hydroxy amides
1. Introduction
Isatins and their derivatives are a group of important structural
units and have been found in many bioactive molecules. For
example, they have been used as DNA gyrase inhibitors,[1]
caspase
glucosidase inhibitors,[4] apoptosis inducers[5] and diacylglycerol
acyltransferase type
inhibitors.[6] Besides, isatins are
3
inhibitors,[2] antiparkinsonian drugs,[3] alpha-
2
synthetically versatile building blocks for the synthesis of various
heterocyclic compounds,[7] such as isatoic anhydrides, indoles,
quinolines, and spiro-fused frameworks.[8] Consequently, much
attention has been paid to their preparation. Among the
traditional ways of synthesizing isatins, three methods stood out
from the rest. They are the Sandmeyer procedure,[9] the Stollé
procedure[10] and the Martinet procedure.[11] Later, several
improved protocols have also been reported, such as the aryne-
based methods,[12] Sandmeyer modifications,[13] metal catalyzed
oxidations,[14] sulfur ylide mediated carbonyl homologation,[15]
and C-H amination.[16] Recently, Ilangovan and co-workers
reported a molecular iodine-promoted domino synthesis of isatins
Scheme 1. Our previous reports on the synthesis of isatins.
Recently, we have reported the synthesis of isatins from α-
formyl amides via the palladium-catalyzed intramolecular ortho-
C-H activation/oxidative acylation[18] or the ferric-catalyzed
intramolecular Friedel-Crafts acylation (Scheme 1a).[19] As we all
know, α-formyl amide is the oxidation product of α-hydroxy
amide. So we are very interested in realizing the transformation
from α-hydroxy amides to isatins in one pot. However, no
product could be found when the reaction was mediated by PdCl2
from
easily accessible
2’-aminophenylacetylenes,
2’-
aminostyrenes, and 2’-amino-β-ketoesters.[17] Nevertheless, all
these reported methods suffer from some drawbacks, such as the
use of expensive or toxic catalyst, long reaction time, tedious
synthetic procedures, and low yield of product. Therefore, the
development of a more milder, convenient, and environmentally
benign process to access isatins is still highly necessary.
Corresponding author. e-mail: jinhui_1974@126.com; wyong@scu.edu.cn

2
Tetrahedron
or FeCl3 (Scheme 1b). Therefore, we have made detailed
(Table 1, entries 9 and 13-17). Among various solvents examined,
ACCEPTED MANUSCRIPT
studies on this transformation.
DMSO turned out to be the best choice, while others such as
DMF, dioxane, CH3CN and PhMe were less effective (Table 1,
entries 14-17). Further investigation indicated that temperature
was important for this transformation. An excellent yield has
In this paper, we described a novel and efficient one-pot
synthesis of isatins from α-hydroxy amides in the presence of
ruthenium trichloride (Scheme 1c). To the best of our knowledge,
using α-hydroxy amide as the raw material of isatin hasn’t been
reported before.
o
been obtained when the reaction carried out at 100 C (Table 1,
entry 9). However, when the temperature was increased to 120 oC,
the yield of desired product dropped to 59% (Table 1, entry 18).
And the decrease of reaction temperature also reduced the yield
of isatin (Table 1, entries 19-20). Therefore, as observed in this
study, the optimized conditions for the synthesis of isatins tend to
be: α-hydroxy amides (1.0 mmol) and RuCl3 (1.0 mmol) in
DMSO at 100 oC in air for 5h.
2. Results and discussion
Table 1. Optimization of Reaction Conditions.a
R2
R2
N
N
RuCl3, air
OH
R1
O
R1
O
DMSO, 100 o
C
H
O
Entry
Transition-metal
Solvent
Temp (oC)
Yield b
(%)
1
2
OMe
1
PdCl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
50
0
11
0
N
N
N
N
N
O
N
O
O
O
N
O
O
MeO
2
Pd(TFA)2
CoCl2
O
O
O
O
O
O
3
2b, 93%
2c, 91%
2d, 78%
2e, 91%
2f, 94%
2g, 93%
N
N
N
4
TiCl4
0
N
N
O
O
O
O
O
O
O
Cl
Cl
Br
O2N
5
FeCl3
0
O
O
O
O
O
O
2i, 82%
2j, 71%
2m, 91%
2h, 80%
2k, 95%
2l, 93%
6
Fe(TFA)3
IrCl3
40
0
N
N
N
Br
N
N
N
O
O
7
+
+
+
O
O
O
O
O
O
Cl
Br
2o'
O
O
O
8
Ni(OAc)2
RuCl3
0
2n
2n'
2o
2p
2p'
total yield 81% (2n/2n' = 1.2:1.0)
total yield 80% (2o/2o' = 1.3:1.0)
total yield 89% (2p/2p' = 1.0:1.0)
9
91
37
65
88
83
81
79
80
33
59
63
81
N.R.f
N
O
N
N
O
N
10
11 c
12 d
13 e
14
15
16
17
18
19
20
21
[RuCl2(p-Cymene)]2
RuCl3
O
O
O
O
O
O
F
Cl
2q, 90%
2r, 86%
2s, 88%
2t, 85%
Cl
O
N
RuCl3
N
N
O
Cl
O
NC
S
RuCl3
O
O
O
2u, 84%
Cl
2v, 82%
2w, 74%
RuCl3
RuCl3
Dioxane
CH3CN
PhMe
Scheme 2. Transformation of α-hydroxy amides (1) to isatins (2). Reaction
conditions: α-hydroxy amides (1, 1.0 mmol) and RuCl3 (1.0 mmol) in DMSO
(2 mL) at 100 oC for 5h, air.
RuCl3
RuCl3
To further determine the scope of this new method, a wide
range of α-hydroxy amides were reacted under the optimized
conditions. And the results were summarized in Scheme 2. A
host of α-hydroxy amides bearing either the electron-donating
groups such as methyl and methoxy, or electron-withdrawing
groups such as nitro and halogen, were well tolerated during the
course of the reaction providing the desired compounds 2b-2m in
good to excellent yields. And the results showed that electron-
donating groups could improve the reaction yields. Notably, the
substrates with meta-methyl or halogens on N-substituted
aromatic ring provided a mixture of 4-substituted and 6-
substituted isatins, and 2n-2p were major products from the
transformation, which indicated that steric hindrance had obvious
effect on this reaction. Besides, synthetically useful biphenyl,
thienyl and allyl were tolerated in this transformation, giving 2d
and 2o-2w in good yields. Furthermore, a variety of functional
groups such as ether, nitryl, halogen, cyano and vinyl were well-
suited for this reaction.
RuCl3
DMSO
DMSO
DMSO
DMSO
RuCl3
RuCl3
80
/
100
a
Reaction conditions: 1a (1 mmol) and transition-metal (1 mmol) in solvent
(2 mL) under the corresponding temperature in air for 5h.
b Isolated yield.
c RuCl3 (0.5 mmol).
d RuCl3 (2.0 mmol).
e In Ar.
f No reaction.
At the beginning of our investigation, experiments were
carried out using 2-hydroxy-N-methyl-N-phenylacetamide (1a)
as a model substrate. After extensive screenings, RuCl3 turned
out to be the best choice for the reaction (Table 1, entries 1-10).
For the optimization of the amount of RuCl3 used in the model
reaction, one equivalent was found to be adequate, as neither
larger nor smaller amount showed better yields (Table 1, entries
11-12). Notably, molecular oxygen and dimethylsulfoxide, as
dual oxidants, are very important for the present reaction system
Scheme 3. Large-scale reaction.

3
Finally, considering the general application of this
transformation, we demonstrated the gram-scale progress, and an
example of large-scale reaction with excellent yield of the
product is shown in Scheme 3.
into α-formyl amide 3a in the presence of RuCl3. Secondly,
ACCEPTED MANUSCRIPT
coordination of the carbonyl group of 3a to ruthenium center
followed by ligand exchange with the concomitant generation of
HCl gave ruthenium complex 6, which was then transferred into
the Ru species 7 and Ru species 8. The subsequent reductive
elimination of intermediate 7 and 8 delivered the final cyclization
product 2a.
O
a)
N
RuCl3, DMSO, air
100 oC, 20 min
N
N
OH
O
(71% 1a recoverd)
H
+
O
O
O
O
2a, 17%
3a, 4%
1a
O
O
b)
3. Conclusion
N
N
N
RuCl3, dioxane, Ar
100 oC
N
O
H
OH
H
+
+
O
O
In summary, we demonstrated a novel and efficient synthesis
of isatins from α-hydroxy amides. Many functional groups were
compatible with this procedure, and a diverse array of isatins
were obtained in good to excellent yields. Besides, the present
protocol was suitable for gram scale and retained its high yield.
Further studies for the utilization of these products are ongoing in
our laboratory.
O
2a, 0%
1a
3a, 0%
3a, 0%
O
O
O
O
c)
d)
e)
f)
N
O
N
RuCl3, DMSO, air
100 oC, 1 h
H
H
H
H
O
O
O
3a
2a, 95%
O
N
N
RuCl3, DMSO, Ar
O
O
O
100 o
C
3a
2a, 87%
O
O
N
N
RuCl3, dioxane, air
100 o
4. Experimental section
C
3a
2a, 80%
2a, 43%
2a, 0%
4.1. General chemical methods and materials
N
N
N
RuCl3, dioxane, Ar
100 o
O
+
All the reactions were monitored by thin-layer
chromatography (TLC) and were visualized using UV light. The
product purification was done using silica gel column
O
O
C
OH
O
4, 0%
3a
g)
N
N
N
RuCl3, dioxane
100 oC, Ar
O
+
OH
O
chromatography.
Thin
layer
chromatography
(TLC)
O
5, 0%
1a
characterization was performed with precoated silica gel GF254
(0.2mm), while column chromatography characterization was
performed with silica gel (100-200mesh). 1H and 13C NMR
spectra were recorded with tetramethylsilane as the internal
Scheme 4. Control experiments for the reaction mechanism.
A series of control experiments have also been performed to
explore the mechanism of this transformation (Scheme 4). When
1a was conducted under the optimized conditions for twenty
minutes, 4% yield of 3a was detected (Scheme 4a). And isatin 2a
could be synthesized from 3a under the optimized conditions in
excellent yield (Scheme 4c). These results suggested that α-
formyl amide 3 should be an important intermediate in the
synthesis of isatin. Besides, RuCl3 plays two roles in this reaction.
Firstly, RuCl3 act as an catalyst in the transformation of α-
hydroxy amide to α-formyl amide. Secondly, it act as an oxidant
in the formation of isatin from α-formyl amide (Scheme 4f).
DMSO and air also play the role of oxidant in the whole
transformation (Scheme 4a-e). Notably, When 3a was treated
1
standard. H NMR spectra were recorded at 400 or 600 MHz
(Varian) and 13C NMR spectra were recorded 150 MHz (Varian).
Chemical shifts are reported in ppm downfield from CDCl3 (δ =
7.26 ppm) for 1H NMR and relative to the central CDCl3
resonance (δ = 77.0 ppm) for 13C NMR spectroscopy. Coupling
constants are given in Hz. Melting points were measured with
YRT-3 melting point apparatus (Shantou Keyi Instrument &
Equipment Co., Ltd., Shantou, China). High resolution mass
spectroscopy data of the products were collected on a Waters
Micromass GCT or a Bruker Apex IV FTMS instrument. All the
α-hydroxy amides 1 were prepared according to the reported
procedures.[21]
o
with RuCl3 in 1,4-dioxane under Ar at 100 C, no product of the
4.2. General reaction procedure for the synthesis of isatins
Friedel-Crafts reaction (4) was obtained (Scheme 4f). Similarly,
when 3a was replaced by 1a, no compound 5 was formed
(Scheme 4g). These suggested that the reaction is not compatible
with the Friedel-Crafts mechanism.
A mixture of α-hydroxy amides 1 (1 mmol) and RuCl3 (1
mmol) were added in 2 mL DMSO and then stirred under air at
100 oC for 5h. After the completion of the reaction (monitored by
TLC), the mixture was cooled to room temperature, diluted with
water and extracted with ethyl acetate (10 mL x 3). The organic
layer was washed with saturated brine, dried over anhydrous
sodium sulfate and the solvent was evaporated to dryness. The
crude residue was purified by flash chromatography on silica
(petroleum ether/ethyl acetate) to afford pure isatins 2 as a red
solid.
N
OH
O
H
1a
RuCl3
[O]
N
N
O
O
O
N
H
2a
O
2a
O
H
O
RuCl2
(
4.2.1. 1-methylindoline-2,3-dione (2a): Yield 91%; red solid; mp.
RuCl
o
1
3a
(
)
130-133 C; H NMR (400 MHz, CDCl3): δ 7.64-7.58 (m, 2H),
7.15-7.11 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.26 (s, 3H); 13C
NMR (CDCl3, 150 MHz): δ 183.3, 158.1, 151.4, 138.4, 125.1,
123.8, 117.3, 109.9, 26.2; HRMS (ESI): m/z [M + Na+] calcd for
C9H7NO2+Na+ 184.0374, found 184.0370.
reductive
elimination
reductive
elimination
RuCl3
C-H activation
Cl
H
Ru
O
N
Cl
O
Ru Cl
Cl
O
Ru
(
)
(
)
(
)
Cl
N
O
O
N
[O]
O
4.2.2. 1-ethylindoline-2,3-dione (2b): Yield 93%; red solid; mp.
8
6
7
o
1
92-94 C; H NMR (400 MHz, CDCl3): δ 7.62-7.58 (m, 2H),
7.14-7.10 (m, 1H), 6.93-6.91 (m, 1H), 3.80 (q, J = 7.6 Hz, 2H),
1.32 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz): δ 182.3,
158.3, 151.4, 138.2, 125.2, 123.9, 117.0, 109.6, 36.0, 14.4;
Scheme 5. Proposed reaction mechanism.
Based on the preliminary mechanistic investigations and some
relevant publications,[20] a plausible mechanism is proposed as
shown in Scheme 5. Firstly, α-hydroxy amide 1a was oxidized

4
Tetrahedron
HRMS (ESI): m/z [M + Na+] calcd for C1 H9NO2+Na+
HRMS (ESI): m/z [M + Na+] calcd for C10H9NO2+Na+ 198.0531,
ACCEPTED MANUSCRIPT
0
198.0531, found 198.0534.
found 198.0527.
4.2.3. 1-butylindoline-2,3-dione (2c): Yield 91%; red solid; mp.
4.2.12. 1-ethyl-7-methylindoline-2,3-dione (2l): Yield 93%; red
solid; mp. 188-190 oC; 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J
= 7.6 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.02-6.98 (m, 1H), 4.01
(q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 150 MHz): δ 184.1, 159.1, 148.4, 142.3, 123.7,
123.5, 121.4, 118.8, 36.9, 18.7, 14.5; HRMS (ESI): m/z [M +
Na+] calcd for C11H11NO2+Na+ 212.0687, found 212.0683.
o
1
35-36 C; H NMR (400 MHz, CDCl3): δ 7.61-7.57 (m, 2H),
7.13-7.09 (m, 1H), 6.91-6.88 (m, 1H), 3.76-3.71 (m, 2H), 1.73-
1.64 (m, 2H), 1.61-1.55 (m, 1H), 1.44-1.39 (m, 1H), 0.99 (t, J =
6.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): δ 183.4, 158.5, 151.3,
138.5, 125.1, 123.5, 116.9, 109.8, 43.1, 31.0, 20.7, 13.8; HRMS
(ESI): m/z [M + Na+] calcd for C12H13NO2+Na+ 226.0844, found
226.0842.
4.2.13. 1-ethyl-5-methylindoline-2,3-dione (2m): Yield 91%; red
o
1
4.2.4. 1-allylindoline-2,3-dione (2d): Yield 78%; red solid; mp.
solid; mp. 74-76 C; H NMR (400 MHz, CDCl3): δ 7.42-7.38
(m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 3.77 (q, J = 7.2 Hz, 2H), 2.39
(s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz): δ
184.0, 159.2, 148.3, 142.5, 123.2, 123.1, 121.7, 118.2, 36.9, 18.7,
14.5; HRMS (ESI): m/z [M + Na+] calcd for C11H11NO2+Na+
212.0687, found 212.0685.
o
1
89-90 C; H NMR (600 MHz, CDCl3): δ 7.62 (d, J = 7.2 Hz,
1H), 7.58-7.56 (m, 1H), 7.14-7.11 (m, 1H), 6.90 (d, J = 7.8 Hz,
1H), 5.88-5.82 (m, 1H), 5.31-5.29 (m, 2H), 4.37 (d, J = 5.4 Hz,
2H); 13C NMR (CDCl3, 150 MHz): δ 183.2, 157.8, 150.8, 138.3,
130.3, 125.4, 123.8, 118.6, 117.5, 110.8, 42.5; HRMS (ESI): m/z
[M + Na+] calcd for C11H9NO2+Na+ 210.0531, found 210.0531.
4.2.14. 6-chloro-1-methylindoline-2,3-dione (2n): Yield 44.1%;
o
1
4.2.5. 1-(4-methoxybenzyl)indoline-2,3-dione (2e): Yield 91%;
red solid; mp. 177-178 C; H NMR (400 MHz, CDCl3): δ 7.55
(d, J = 8.0 Hz, 1H), 7.12 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H), 6.91
(d, J = 1.6 Hz, 1H), 3.27 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ
181.7, 158.1, 152.4, 144.8, 126.3, 124.0, 115.7, 110.8, 26.4;
HRMS (ESI): m/z [M + Na+] calcd for C9H6ClNO2+Na+
217.9985, found 217.9983.
o
1
red solid; mp. 169-171 C; H NMR (400 MHz, CDCl3): δ 7.59
(d, J = 6.8 Hz, 1H), 7.51-7.46 (m, 1H), 7.27 (d, J = 8.8 Hz, 2H),
7.10-7.06 (m, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.0 Hz,
1H), 4.86 (s, 2H), 3.78 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ
183.3, 159.4, 158.2, 150.7, 138.2, 128.9, 126.4, 125.3, 123.7,
117.6, 114.3, 111.0, 55.2, 43.5; HRMS (ESI): m/z [M + Na+]
calcd for C16H13NO3+Na+ 290.0793, found 290.0790.
4.2.15. 4-chloro-1-methylindoline-2,3-dione (2n') Yield 36.8%;
Red solid; mp. 192-195 oC; 1H NMR (400 MHz, CDCl3): δ 7.53-
7.49 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H),
3.27 (s, 3H), 3.23 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 181.1,
158.3, 152.3, 144.5, 126.2, 124.0, 115.7, 110.5, 26.4; HRMS
(ESI): m/z [M + Na+] calcd for C9H6ClNO2+Na+ 217.9985, found
217.9981.
4.2.6. 1,5-dimethylindoline-2,3-dione (2f): Yield 94%; red solid;
o
1
mp. 149-150 C; H NMR (400 MHz, CDCl3): δ 7.42-7.28 (m,
2H), 6.79 (d, J = 8.0 Hz, 1H), 3.23 (s, 3H), 2.34 (s, 3H); 13C
NMR (CDCl3, 150 MHz): δ 182.2, 158.7, 151.5, 150.7, 125.3,
124.4, 115.2, 110.8, 26.2, 22.9; HRMS (ESI): m/z [M + Na+]
calcd for C10H9NO2+Na+ 198.0531, found 198.0535.
4.2.16. 6-bromo-1-methylindoline-2,3-dione (2o): Yield 45.2%;
o
1
4.2.7. 5-methoxy-1-methylindoline-2,3-dione (2g): Yield 93%;
red solid; mp. 118-119 C; H NMR (400 MHz, CDCl3): δ 7.47
(d, J = 7.6 Hz, 1H), 7.30 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H), 7.08
(d, J = 1.6 Hz, 1H), 3.25 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ
182.3, 157.4, 150.2, 140.6, 128.1, 118.6, 116.5, 111.7,
26.3;HRMS (ESI): m/z [M + Na+] calcd for C9H6BrNO2+Na+
261.9480, found 261.9484.
o
1
red solid; mp. 175-176 C; H NMR (400 MHz, CDCl3): δ 7.17-
7.15 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 3.23 (s, 3H);
13C NMR (CDCl3, 150 MHz): δ 183.8, 158.2, 156.6, 145.7,
124.0, 117.8, 110.9, 109.8, 55.5, 26.1; HRMS (ESI): m/z [M +
Na+] calcd for C10H9NO3+Na+ 214.0480, found 214.0482.
4.2.8. 5-chloro-1-methylindoline-2,3-dione (2h): Yield 80%; red
4.2.17. 4-bromo-1-methylindoline-2,3-dione (2o'): Yield 34.7%;
Red solid; mp. 199-200 oC; 1H NMR (600 MHz, CDCl3): δ 7.44-
7.41 (m, 1H), 7.26 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H),
3.26 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 182.0, 157.2, 150.3,
140.3, 128.1, 118.5, 116.6, 111.2, 26.3; HRMS (ESI): m/z [M +
Na+] calcd for C9H6BrNO2+Na+ 261.9480, found 261.9483.
o
solid; mp. 171-173 C; 1H NMR (400 MHz, CDCl3): δ 7.59-7.56
(m, 2H), 6.86 (d, J = 9.2 Hz, 1H), 3.26 (s, 3H); 13C NMR (CDCl3,
150 MHz): δ 181.5, 158.2, 152.2, 144.3, 126.4, 124.0, 115.2,
110.5, 26.5; HRMS (ESI): m/z [M
+
Na+] calcd for
C9H6ClNO2+Na+ 217.9985, found 217.9982.
4.2.9. 5-bromo-1-methylindoline-2,3-dione (2i): Yield 82%; red
4.2.18. 1,6-dimethylindoline-2,3-dione (2p): Yield 44.5%; red
solid; mp. 150-151 oC; 1H NMR (400 MHz, CDCl3): δ 7.49 (d, J
= 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 3.32 (s,
3H), 2.40 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 182.6, 158.9,
151.8, 150.7, 125.3, 124.4, 115.3, 110.7, 26.1, 22.9; HRMS
(ESI): m/z [M + Na+] calcd for C10H9NO2+Na+ 198.0531, found
198.0533.
o
solid; mp. 163-164 C; 1H NMR (400 MHz, CDCl3): δ 7.74-7.70
(m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 3.26 (s, 3H); 13C NMR (CDCl3,
150 MHz): δ 182.1, 157.4, 150.1, 140.6, 128.0, 118.5, 116.6,
111.6, 26.3; HRMS (ESI): m/z [M
+
Na+] calcd for
C9H6BrNO2+Na+ 261.9480, found 261.9478.
4.2.10. 1-methyl-5-nitroindoline-2,3-dione (2j): Yield 71%; red
o
solid; mp. 201-202 C; 1H NMR (400 MHz, CDCl3): δ 7.74-7.71
4.2.19. 1,4-dimethylindoline-2,3-dione (2p'): Yield 44.5%; Red
(m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 3.26 (s, 3H); 13C NMR (CDCl3,
150 MHz): δ 182.1, 157.5, 150.1, 140.6, 128.0, 118.5, 116.6,
solid; mp. 164-165 C; 1H NMR (400 MHz, CDCl3): δ 7.46-7.42
o
(m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 3.24
(s, 3H), 2.57 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 182.8,
158.8, 151.8, 150.7, 125.4, 124.4, 115.5, 110.8, 26.1, 22.9;
HRMS (ESI): m/z [M + Na+] calcd for C10H9NO2+Na+ 198.0531,
found 198.0528.
111.6, 29.6; HRMS (ESI): m/z [M
+
Na+] calcd for
C9H6N2O4+Na+ 229.0225, found 229.0228.
4.2.11. 1,7-dimethylindoline-2,3-dione (2k): Yield 95%; red
solid; mp. 162-164 oC; 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J
= 7.2 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.02-6.98 (m, 1H), 3.53
(s, 3H), 2.57 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 182.7,
158.0, 151.8, 150.5, 125.5, 124.5, 115.5, 110.9, 26.1, 22.9;
4.2.20. 1-methyl-5-phenylindoline-2,3-dione (2q): Yield 90%; red
o
solid; mp. 182-184 C; 1H NMR (400 MHz, CDCl3): δ 7.85-7.82
(m, 2H), 7.54-7.51 (m, 2H), 7.47-7.44 (m, 2H), 7.40-7.37 (m,
1H), 6.98 (d, J = 8.0 Hz, 1H), 3.29 (s, 3H); 13C NMR (CDCl3,

5
3. Gentry, P. R.; Bridges, T. M.; Lamsal, A. Bioorg. Med. Chem.
150 MHz): δ 183.3, 160.1, 150.5, 139.3, 137.2, 136.5, 129.2,
127.9, 126.6, 123.5, 117.8, 110.5, 26.4; HRMS (ESI): m/z [M +
Na+] calcd for C15H11NO2+Na+ 260.0687, found 260.0689.
ACCEPTED MANUSCRIPT
Lett. 2013, 23, 2996.
4. Han, K.; Li, Y.; Zhang, Y. Bioorg. Med. Chem. Lett. 2015, 25,
1471.
5. Han, K.; Zhou, Y.; Liu, F. Bioorg. Med. Chem. Lett. 2014, 24, 591.
6. Kim, M. O.; Lee, S. U.; Lee, H. J. Biol. Pharm. Bull. 2013, 36,
1167.
7. (a) Garden, S. J.; da Silva, R. D.; Pinto, A. C. Tetrahedron. 2002,
58, 8399; (b) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.; Feringa,
B. L.; Minnaard, A. J. Org. Lett. 2006, 8, 2715; (c) Shintani, R.;
Inoue, M.; Hayashi, T. Angew. Chem. Int. Ed. 2006, 45, 3353; (d)
Mohammadi, S.; Heiran, R.; Herrera, R. P.; Marqués-López, E.
ChemCatChem. 2013, 5, 2131.
8. (a) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104; (b)
Hong, L.; Wang, R. Adv. Synth. Catal. 2013, 355, 1023.
9. (a) Sandmeyer, T.; Helv. Chim. Acta, 1919, 2, 234; (b) Pinto, A.
C.; Lapis, A. A. M.; da Silva, B. V.; Bastos, R. S.; Dupont, J.;
Neto, B. A. D. Tetrahedron Lett., 2008, 49, 5639.
10. (a) Stollé, R. Ber. Bunsenges. Dtsch. Chem., 1913, 46, 3915; (b)
Stollé, R. J. Prakt. Chem., 1922, 106, 137.
11. (a) Martinet, J. Compt. Rend., 1918, 166, 851; (b) Bonnefoy J.;
Martinet, J. Compt. Rend., 1921, 172, 220.
12. Rogness, D. C.; Larock, R. C. J. Org. Chem. 2011, 76, 4980.
13. (a) Klein, L. L.; Tufano, M. D. Tetrahedron Lett. 2013, 54, 1008.
(b) Chouhan, M.; Senwar, K. R.; Sharma, R.; Grover, V.; Nair, V.
A. Green Chem. 2011, 13, 2553.
14. (a) Sun, J.; Liu, B.; Xu, B. RSC Adv. 2013, 3, 5824. (b) Liu, T.;
Yang, H.; Jiang, Y.; Fu, H. Adv. Synth. Catal. 2013, 355, 1169.
15. Lollar, C. T.; Krenek, K. M.; Bruemmer, K. J.; Lippert, A. R. Org.
Biomol. Chem. 2014, 12, 406.
16. Huang, P. C.; Gandeepan, P.; Cheng, C. H. Chem. Commun. 2013,
49, 8540.
17. Satish, G.; Polu, A.; Ramar, T.; Ilangovan, A. J. Org. Chem. 2015,
80, 5167.
18. Li, J.; Zheng, Y.; Yu, X. L.; Lv, S. Y.; Wang, Q. T.; Hai, L.; Wu,
Y. RSC Adv. 2015, 5, 103280.
19. Zheng, Y.; Li, J.; Yu, X. L.; Lv, S. Y.; Hai, L.; Wu, Y.
Tetrahedron Lett. 2016, 57, 39.
20. (a) Aihara, Y.; Chatani, N. Chem. Sci. 2013, 4, 664; (b)
Manikandan, R.; Jeganmohan, M. Org. Lett. 2014, 16, 3568; (c)
Manikandan, R.; Jeganmohan, M. Org. Lett. 2014, 16, 912; (d)
Allu, S.; Kumara Swamy, K. C. J. Org. 6Chem. 2014, 79, 3963.
21. Miller, M.; Vogel, J. C.; Tsang, W.; Merrit, A.; Procter, D. J. Org.
Biomol. Chem, 2009, 7, 589.
4.2.21. 5-(4-fluorophenyl)-1-methylindoline-2,3-dione (2r): Yield
o
1
86%; red solid; mp. 136-139 C; H NMR (400 MHz, CDCl3): δ
7.79-7.75 (m, 2H), 7.50-7.46 (m, 2H), 7.16-7.11 (m, 2H), 6.98 (d,
J = 8.0 Hz, 1H), 3.29 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ
183.3, 162.1 (d, JC-F = 246.8 Hz), 158.2, 150.4, 136.6, 136.3,
135.1, 128.2 (d, JC-F = 7.6 Hz), 123.5, 117.8, 115.9 (d, JC-F = 21.4
Hz), 110.3, 26.3; HRMS (ESI): m/z [M + Na+] calcd for
C15H10FNO2+Na+ 278.0593, found 278.0597.
4.2.22. 5-(4-chlorophenyl)-1-methylindoline-2,3-dione (2s):
1
Yield 88%; red solid; mp. 180-182 oC; H NMR (400 MHz,
CDCl3): δ 7.80 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H), 7.60 (d, J = 1.6
Hz, 1H), 7.46-7.40 (m, 4H), 6.98 (d, J = 8.0 Hz, 1H), 3.29 (s,
3H); 13C NMR (CDCl3, 150 MHz): δ 183.2, 158.2, 150.6, 137.4,
136.6, 136.0, 134.0, 129.2, 127.8, 123.5, 117.8, 110.4, 26.4;
HRMS (ESI): m/z [M + Na+] calcd for C15H10ClNO2+Na+
294.0298, found 294.0298.
4.2.23. 5-(3-chlorophenyl)-1-methylindoline-2,3-dione (2t): Yield
85%; red solid; mp. 188-189 oC;; 1H NMR (400 MHz, CDCl3): δ
7.81-7.78 (m, 2H), 7.49 (s, 1H), 7.39-7.35 (m, 3H), 6.98 (d, J =
8.0 Hz, 1H), 3.29 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ 183.2,
158.2, 150.8, 140.7, 136.7, 135.9, 135.0, 130.3, 127.9, 126.7,
124.7, 123.7, 117.9, 110.4, 26.4; HRMS (ESI): m/z [M + Na+]
calcd for C15H10ClNO2+Na+ 294.0298, found 294.0294.
4.2.24. 5-(3,5-dichlorophenyl)-1-methylindoline-2,3-dione (2u):
1
Yield 84%; red solid; mp. 228-230 oC; H NMR (400 MHz,
CDCl3): δ 8.08 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 7.94 (d, J = 1.6
Hz, 1H), 7.79 (d, J = 1.2 Hz, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.24
(d, J = 8.4 Hz, 1H), 3.18 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ
183.3, 158.6, 151.6, 142.3, 136.8, 134.9, 132.4, 127.0, 125.2,
122.9, 118.2, 111.3, 26.4; HRMS (ESI): m/z [M + Na+] calcd for
C15H9Cl2NO2+Na+ 327.9908, found 327.9911.
4.2.25. 3-(1-methyl-2,3-dioxoindolin-5-yl)benzonitrile (2v): Yield
o
1
82%; red solid; mp. 236-237 C; H NMR (400 MHz, CDCl3): δ
8.22 (s, 1H), 8.10-8.04 (m, 2H), 7.94 (d, J = 1.6 Hz, 1H), 7.81 (d,
J = 8.0 Hz, 1H), 7.67-7.63 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 3.20
(s, 3H); 13C NMR (DMSO-d6, 150 MHz): δ 183.4, 158.5, 151.4,
139.8, 136.6, 133.2, 131.2, 130.3, 130.1, 122.7, 118.9, 118.3,
112.3, 111.3, 26.4; HRMS (ESI): m/z [M + Na+] calcd for
C16H10N2O2+Na+ 285.0640, found 285.0638.
4.2.26. 1-methyl-5-(thiophen-2-yl)indoline-2,3-dione (2w): Yield
o
1
74%; red solid; mp. 206-208 C; H NMR (400 MHz, CDCl3): δ
7.84 (d, J = 1.6 Hz, 1H), 7.82 (s, 1H), 7.30 (dd, J1 = 0.8 Hz, J2 =
4.0 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.10-7.08 (m, 1H), 6.92 (d,
J = 8.8 Hz, 1H), 3.28 (s, 3H); 13C NMR (CDCl3, 150 MHz): δ
183.1, 158.1, 150.3, 142.3, 135.2, 130.9, 128.2, 125.3, 123.1,
122.4, 117.8, 103.1, 26.4; HRMS (ESI): m/z [M + Na+] calcd for
C13H9NO2S+Na+ 266.0252, found 266.0250.
Acknowledgments
We are grateful for financial support from the National
Natural Science Foundation of China (NSFC) (grant number
81373259 & 81573286 & 21472130).
References and notes
1. Jeankumar, V. U.; Renuka, J.; Pulla, V. K. Int. J. Antimicrob.
Agents. 2014, 43, 269.
2. Limpachayaporn, P.; Wagner, S.; Kopka, K.; Schober, O.;
Schaefers, M.; Haufe, G. J. Med. Chem. 2014, 57, 9383.