Oxidative ring-opening of isatins for the synthesis of 2-aminobenzamides and 2-aminobenzoates

Article abstract of DOI:10.1016/j.tet.2019.01.067

An efficient and practical isatin-based oxidative domino protocol has been developed for the facile synthesis of 2-aminobenzamides and 2-aminobenzoates. The robust nature of this reaction system is reflected by accessible starting materials, room temperature and high-yield gram-scale synthesis.

Full text of DOI:10.1016/j.tet.2019.01.067

Accepted Manuscript
Oxidative ring-opening of isatins for the synthesis of 2-aminobenzamides and 2-
aminobenzoates
Yu-Wei Wang, Lei Zheng, Feng-Cheng Jia, Yun-Feng Chen, An-Xin Wu
PII:
S0040-4020(19)30121-8
https://doi.org/10.1016/j.tet.2019.01.067
TET 30119
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 December 2018
Revised Date: 26 January 2019
Accepted Date: 29 January 2019
Please cite this article as: Wang Y-W, Zheng L, Jia F-C, Chen Y-F, Wu A-X, Oxidative ring-opening of
isatins for the synthesis of 2-aminobenzamides and 2-aminobenzoates, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.01.067.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Oxidative ring-opening of isatins for the
synthesis of 2-aminobenzamides and 2-
aminobenzoates
Leave this area blank for abstract info.
a
a
a
a
b
Yu-Wei Wang, Lei Zheng, Feng-Cheng Jia,* Yun-Feng Chen,* An-Xin Wu
a.
School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430073, China.
E-mail: fengcheng-jia@wit.edu.cn; yfchen@wit.edu.cn.
b.
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal
University, Wuhan 430079, P. R. China.
.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Oxidative ring-opening of isatins for the synthesis of 2-aminobenzamides and 2-
aminobenzoates
a
a
a
a
b
Yu-Wei Wang, Lei Zheng, Feng-Cheng Jia,* Yun-Feng Chen, * An-Xin Wu
a.
School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430073, China. E-mail: fengcheng-jia@wit.edu.cn；
yfchen@wit.edu.cn
b.
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and practical isatin-based oxidative domino protocol has been developed for the
facile synthesis of 2-aminobenzamides and 2-aminobenzoates. The robust nature of this reaction
system is reflected by accessible starting materials, room temperature and high-yield gram-scale
synthesis.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
oxidative domino protocol
2
2
-aminobenzamides
-aminobenzoates
1
. Introduction
based oxidative domino methodologies for the preparation of
valuable compounds, Herein we report an efficient transition-
metal-free domino strategy for the facile synthesis of 2-
aminobenzamide derivatives from commercially available isatins
and ammonium hydroxide. To our delight, this proposal is also
appropriate for the synthesis of 2-aminobenzoate derivatives
Anthranilic acid derivatives represent a kind of important and
fundamental organic compounds which have been widely applied
in many fields such as pharmacochemistry, biochemistry and
synthetic chemistry.
acid derivatives, 2-aminobenzamide is exemplified as
privileged structure that exists in many pharmaceutical molecules
[
1-6]
In particular, as one of the anthranilic
a
(Scheme 1c).
[
1]
and biologically active compounds such as anticancer drug,
anti-inflammatory analgesic
[
2]
[3]
and hypolipidemic drug.
In
addition, 2-aminobenzamide derivatives are often used as
synthetic intermediates for the direct synthesis of biologically
[
6]
active molecules. Accordingly, extensive synthetic methods
[
7-
have been developed to access 2-aminobenzamide derivatives.
1
0]
Among them, nucleophilic substitution reaction of organic
amine with anthranilic acid derivatives were regarded as the
prevalent methods. Besides, some groups develop transition-
2
metal-catalyzed sp C-H amination to afford 2-aminobenzamide
[
10]
derivatives from benzoyl amide and appropriate amine source.
Despite these advances, the development of new methodologies
for constructing diverse 2-aminobenzamides is still in demand.
Isatin is a unique structure possessing a γ-lactam and a ketone.
On account of its distinct potential to serve as both an
electrophile and a nucleophile, various reactions involving isatins
have been established for the construction of useful
Scheme 1. isatin-based oxidative domino strategy for the
synthesis valuable compounds.
[
11]
compounds. Recently, we have reported two robust synthetic
methods of quinazolines and 4-quinolones via an innovative
[12]
isatin-based oxidative cyclization strategy (Scheme 1a and 1b).
In conjunction with our ongoing research into developing isatin-

2
Tetrahedron
ACCEPTED MANUSCRIPT
2
. Results and discussion
Our study commenced with the reaction of isatin 1a (1.0
mmol) and ammonia hydrate 2a (3.0 mmol) in the presence of
K PO and TBHP in DMSO at room temperature (25–30 °C) in a
3
4
sealed vessel under air for 4 h (Table 1, entry 1). Gratifyingly,
the desired 2-aminobenzamide (3a) identified by NMR spectra
was obtained in 56% yield. However, we found that in the
absence of K PO , the reaction can reach a higher yield of 78%
3
4
[
12]
(
Table 1, entry 2). In light of the importance of the oxidant,
series of oxidants was subsequently inspected (Table 1, entries 4–
), and H O showed the highest efficiency (Table 1, entry 3).
a
8
2
2
Next, several solvents were tested (Table 1, entries 9–12), and
DMSO was proved to be the most effective solvent (Table 1,
compare entries 3 and 9–12). Overall, the optimized reaction
conditions were identified as 1a (1.0 mmol), 3.0 equiv of 2, 2.0
equiv of H O in 4 mL of DMSO at room temperature in a sealed
2
2
vessel under air ( Table 1, entry 3).
a
Table 1. Optimization of the reaction conditions .
b
Scheme 2. Substrates scope of 2-aminobenzamide
entry base
oxidant
TBHP
TBHP
H O
solvent
DMSO
DMSO
DMSO
DMSO
yield
56%
78%
89%
trace
trace
trace
trace
82%
51%
trace
1
2
3
4
5
6
7
8
9
1
1
1
K PO4
none
In consideration of the importance of 2-aminobenzoate
3
[
14]
derivatives, we also attempted to apply this oxidative domino
strategy to synthesize 2-aminobenzoates. After investigating
various reaction parameters including bases and oxidants, the
optimized reaction conditions were eventually identified as 1a
none
none
none
none
none
none
none
none
none
none
2
2
K S O
8
2
2
(1.0 mmol), 2.0 equiv of TBHP, and 2 equiv of Cs CO in 4 mL
2 3
t-BuONO DMSO
m-CPBA DMSO
of CH OH or CH CH OH at room temperature for 4 h (SI, Table
3
3
2
1). Several representative isatins were selected to construct 2-
aminobenzoate derivatives. Isatins containing electron-neutral (5-
Me), electron-rich (5-OMe), and halogenated substituents (5-F,
DTBP
BPO
H O
DMSO
DMSO
DMF
5
-Cl, 6-Cl, 7-F) were converted to the corresponding products in
2
2
2
2
2
moderate to good yields (Scheme 3, 4a–e, 54%–93%; 4i, 48%;
4
l, 59%; 4a′, 72%).
0
1
2
H O
CH CN
2
3
H O
CH CH OH trace
2
3
2
H O
2
H O
2
trace
a
Reaction conditions: 1a (1.0 mmol), 2 (3.0 mmol), and oxidant (2.0
mmol) were added at room temperature (25–30 °C) in 4 mL of
b
solvent in a sealed vessel under air for 4 h. Isolated yield.
After identifying the optimized conditions, we further
evaluated the substrate generality for this reaction (Scheme 2).
To our delight, the reaction demonstrated good compatibility and
proved to be
aminobenzamides. Reactions with isatins bearing electron-neutral
H, 5-Me, 7-Me) and electron-donating (5-OMe, 6-OMe) groups
a general method to build diverse 2-
(
all underwent the desired transformation to deliver the
corresponding products in moderate to good yields (3a–3c, 85%–
8
9%; 3k, 68%; 3h, 72%). An array of halogen-substituted isatins
a
Reaction conditions: 1 (1.0 mmol), TBHP (70%, 2.0 mmol), and
(5-F, 5-Cl, 5-Br, 5-I, 6-Cl, 6-Br, 7-F, 7-Cl, 7-Br) were all found
Cs CO (2.0 mmol) in CH OH or CH CH OH (4 mL) at room
temperature (25-30 °C) in a sealed vessel under air for 4 h. Isolated
yields.
to be compatible with the reaction (3d–3g, 65%–87%, 3i–3j,
1%–82%, 3l–3n, 74%–90%), which provided opportunities for
further synthetic elaboration.
2
3
3
3
2
b
8
Scheme 3. Direct synthesis of 2-aminobenzoates from isatins,
a,b
methanol and ethanol.
To shed light on the mechanism of this oxidative domino
reaction, a series of control experiments were performed (Scheme
4
). Only a trace of the oxidative product isatoic anhydride (5)

3
was detected by mass spectroscopy whenAisCatCinE(P1aT) EwDas MAafNforUd SthCe dResIiPreTd product 3a. Similarly, the target product 4a
conducted under the optimized conditions (Scheme 4a). Next,
reaction of isatoic anhydride (5) with ammonia (2) or methanol
under standard conditions yielded the desired product 3a or 4a in
could be obtained through an analogous nucleophilic attack.
Scheme 5. Possible mechanism.
8
6% and 87% yield, respectively. These results indicated that the
To show the generality of this isatin-based oxidative domino
protocol for the synthesis of anthranilic acid derivatives,
butylamine and piperidine were selected to construct 2-
aminobenzamide derivatives, which gave the desired products in
good yields under standard conditions ( Scheme 6a and 6b). To
further indicate the synthetic practicality of the reaction, gram-
scale syntheses of 2-aminobenzamide (3a) and methyl 2-
aminobenzoate (4a) were performed, and the desired products 3a
and 4a were obtained in 72% and 90% yield respectively
isatoic anhydride might act as the key intermediate involved in
these processes (Scheme 4b and 4c). In the absence of H O ,
these reactions still reacted smoothly to give the target products,
indicating that H O or TBHP is mainly responsible for the
transformation of isatin to isatoic anhydride (Scheme 4b and 4c).
Moreover, we attempted to react isatin (1a) with methanol for
this oxidative domino protocol without Cs CO . Unfortunately,
2
2
2
2
2
3
the desired product 4a was not detected (Scheme 4d).
(Scheme 6c and 6d).
Scheme 6. Gram-Scale experiments
3
. Conclusions
Scheme4. Control experiments
In summary, we have developed an efficient transition-metal-
On the basis of the above observations and precedent
free oxidative domino reaction for the facile synthesis of 2-
aminobenzamide and 2-aminobenzoates from commercially
available isatins, ammonium hydroxide, methanol and ethanol.
The easily accessible starting materials, mild reaction conditions,
and simple manipulation render this methodology attractive.
Further applications of this isatin-based oxidative domino
strategy for the synthesis of other valuable compounds are
currently underway in our laboratory.
[
12-13]
literature
was proposed. Initially, intermolecular nucleophilic attack of
H O or TBHP to isatin (1a) affords intermediate B with the
, a tentative reaction mechanism shown in Scheme
5
2
2
assistance of base, and intramolecular cyclization followed by
rearrangement leads to the formation of the intermediate isatoic
anhydride (5). Finally, ammonia (2) underwent a further
nucleophilic attack to the intermediate isatoic anhydride (5) to
4
. Experimental
General Synthesis Information: All isatins (1a-1n), ammonia and
other reagents were obtained from commercial suppliers and used
without further purification. TLC analysis was performed using
pre-coated glass plates. Column chromatography was performed
1
using silica gel (200–300 mesh). H spectra were recorded in
1
3
CDCl on a Varian Mercury 600 MHz spectrometers. C spectra
3
were recorded in CDCl3 or DMSO-d6 on 150 MHz NMR
spectrometers. Chemical shifts are reported in ppm, relative to
the internal standard of tetramethylsilane (TMS). The high
resolution mass spectra (HRMS) were measured on a Bruker
Apex IV FTMS spectrometer by ESI. MS equipped with an
electrospray source. Trace MS spectrometer (EI, 70 eV).
Representative procedure for the synthesis of 3 (A): A sealed
tube was charged with isatin 1 (1a 147 mg, 1.0 mmol), ammonia
hydrate 2 (25%, 421mg, 3.0mmol) and H O (30%, 227mg, 2.0
2
2
mmol) at room temperature, and then solvent DMSO (4 mL) was

4
Tetrahedron
added. The resulting mixture was stirred at A30C°CCEinPaTseEalDed MA(1N50UMSHCz,RDMIPSTO-d ): δ (ppm) 170.4, 153.4, 151.9, 147.1, 119.6,
6
+
vessel under air after 4 hours, then added 50mL water to the
mixture, extracted with CH COOC H 3 times (3 × 50 mL). The
117.8, 114.2, 113.5; HRMS (ESI): m/z [M+H] calcd for
C H ON F: 155.0615; found: 155.0610. the overall spectroscopic
3
2
5
7
8
2
extract was washed with 30% NaCl solution (V/V), dried over
anhydrous Na SO and concentrated under reduced pressure. The
data are in complete agreement with assigned structures and
18
consistent with literature
-amino-5-chlorobenzamide (3e): Following general procedure
2
4
residue was purified by column chromatography on silica gel
Petroleum ether /Ethyl acetate = 3:1) to yield the desired product
a as a yellow solid (89% yield).
2
(
3
A using 5-chloroindoline-2,3-dione (1e, 181 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
Representative procedure for the synthesis of 4 (B): A sealed
tube was charged with isatin 1 (1a 147 mg, 1.0 mmol), TBHP
1
yellow solid (148 mg, Yield 87%); H NMR (600 MHz, DMSO-
(
70%, 257mg, 2.0 mmol), and Cs CO (652mg, 2.0 mmol) at
d ): δ (ppm) 7.85 (s, 1H), 7.59 (s, 1H), 7.17 (m, 2H), 6.70 (d, J =
2
3
6
1
3
room temperature, and then solvent CH OH (4 mL) was added.
8.4 Hz, 3H); C NMR (150 MHz, DMSO-d ): δ (ppm) 170.1,
3
6
The resulting mixture was stirred at 30 °C in a sealed vessel
under air after 4 hours, then added 50mL water to the mixture,
extracted with CH COOC H 3 times (3 × 50 mL). The extract
149.1, 131.7, 128.0, 118.1, 117.5, 114.5; HRMS (ESI): m/z
+
[M+H] calcd for C H ON Cl: 171.0321; found: 171.0318. the
7
8
2
overall spectroscopic data are in complete agreement with
3
2
5
1
9
was washed with 30% NaCl solution (V/V), dried over
anhydrous Na SO and concentrated under reduced pressure. The
assigned structures and consistent with literature
2
4
2
-amino-5-bromobenzamide (3f): Following general procedure A
residue was purified by column chromatography on silica gel
Petroleum ether /Ethyl acetate = 10:1) to yield the desired
product 4a as a yellow liquid (93% yield).
using 5-bromoindoline-2,3-dione (1f, 226 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
(
1
2
-aminobenzamide (3a): Following general procedure A using
indoline-2,3-dione (1a, 147 mg, 1.0 mmol), ammonia hydrate (2,
21 mg, 3.0 mmol) and purified by silicagel column
white solid ( 183 mg, Yield 85%); H NMR (600 MHz, DMSO-
d ): δ (ppm) 7.87 (s, 1H), 7.69 (s, 1H), 7.24 (m, 2H), 6.72 (d, J =
6
1
3
4
9.6 Hz, 2H), 6.65 (d, J = 9.0 Hz, 1H); C NMR (150 MHz,
chromatography, afforded the compound as yellow solid (121.1
DMSO-d ): δ (ppm) 170.0, 149.5, 134.4, 130.8, 118.6, 115.1,
104.8; MS (EI): m/z 213.95 the overall spectroscopic data are in
6
1
mg, Yield 89%); H NMR (600 MHz, DMSO-d ): δ (ppm) 7.74
6
(
7
s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.11-7.14 (m, 2H), 6.68 (d, J =
.8 Hz, 1H), 6.56 (br, 2H), 6.48 (d, J = 7.2 Hz, 1H); C NMR
complete agreement with assigned structures and consistent with
literature
1
3
19
(
1
1
150 MHz, DMSO-d ): δ (ppm) 171.4, 150.2, 132.0, 128.8, 116.5,
6
+
2-amino-5-iodobenzamide (3g): Following general procedure A
using 5-iodoindoline-2,3-dione (1g, 273 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
14.5, 113.7; HRMS (ESI): m/z [M+H] calcd for C H ON :
7 9 2
37.0709; found: 137.0709. the overall spectroscopic data are in
complete agreement with assigned structures and consistent with
literature
1
5
1
yellow solid ( 170 mg, Yield 65%); H NMR (600 MHz, DMSO-
2
-amino-5-methylbenzamide (3b): Following general procedure
d ): δ (ppm) 7.88 (s, 1H), 7.82 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H),
7.18 (s, 1H), 6.71 (s, 2H), 6.55 (d, J = 8.4 Hz, 1H); C NMR
6
1
3
A using 5-methylindoline-2,3-dione (1b, 161 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
yellow solid (127.6 mg, yield 85%); H NMR (600 MHz,
DMSO-d ): δ (ppm) 7.68 (s, 1H), 7.35 (s, 1H), 6.95-7.01 (m, 2H),
(150 MHz, DMSO-d ): δ (ppm) 170.1, 149.8, 140.0, 136.6, 119.1,
6
+
116.1, 74.6; HRMS (ESI): m/z [M+H] calcd for C H ON I:
7
8
2
1
262.9676; found: 262.9666. the overall spectroscopic data are in
complete agreement with assigned structures and consistent with
6
1
6
6
.59 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 12.6 Hz, 2H), 2.14 (s, 3H);
literature
1
3
C NMR (150 MHz, DMSO-d ): δ (ppm) 171.4, 147.9, 132.8,
6
+
2-amino-4-methoxybenzamide (3h): Following general procedure
A using 6-methoxyindoline-2,3-dione (1h, 177 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
1
28.7, 122.7, 116.6, 113.7, 20.1; HRMS (ESI): m/z [M+H]
calcd for C H ON : 151.0866; found: 151.0861. the overall
spectroscopic data are in complete agreement with assigned
structures and consistent with literature
8
11
2
1
6
1
yellow solid (119 mg, Yield 72%); H NMR (600MHz, DMSO-
2
-amino-5-methoxybenzamide (3c): Following general procedure
d6): δ (ppm) 7.58 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 6.87 (s, 1H),
6.75 (s, 2H), 6.19 (s, 1H), 6.07 (d, J = 9.0 Hz, 1H), 3.68 (s, 3H);
A using 5-methoxyindoline-2,3-dione (1c, 177 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
1
3
C NMR (150 MHz, DMSO-d ): δ (ppm) 171.2, 162.3, 152.5,
6
+
130.6, 106.9, 102.3, 99.3, 54.9; HRMS (ESI): m/z [M+H] calcd
1
yellow solid (146 mg, Yield 88%); H NMR (600 MHz, DMSO-
for C H O N : 167.0815; found: 167.0808 the overall
8
11
2
2
d6): δ (ppm) 7.57 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H),
spectroscopic data are in complete agreement with assigned
structures and consistent with literature
20
6
.75 (s, 2H), 6.19 (s, 1H), 6.06 (d, J = 8.4 Hz, 1H), 3.68 (s, 3H);
1
3
C NMR (150 MHz, DMSO-d ): δ (ppm) 171.2, 162.3, 152.5,
6
+
2-amino-4-chlorobenzamide (3i): Following general procedure A
using 6-chloroindoline-2,3-dione (1i, 181 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
1
30.6, 106.9, 102.3, 99.3, 54.9; HRMS (ESI): m/z [M+H] calcd
for C H O N : 167.0815; found: 167.0813. the overall
8
11
2
2
spectroscopic data are in complete agreement with assigned
1
7
structures and consistent with literature
1
white solid ( 140 mg, Yield 82%); H NMR (600 MHz, DMSO-
2
-amino-5-fluorobenzamide (3d): Following general procedure A
d ): δ (ppm) 7.80 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H),
6.83 (s, 2H), 6.73 (s, 1H), 6.48 (d, J = 7.8 Hz, 1H); C NMR
6
1
3
using 5-fluoroindoline-2,3-dione (1d, 165 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
white solid; (128 mg, Yield 83%); H NMR (600 MHz, DMSO-
d ): δ (ppm) 7.81 (s, 1H), 7.39 (d, J = 10.2 Hz, 1H), 7.22 (s, 1H),
(150 MHz, DMSO-d ): δ (ppm) 170.5, 151.6, 136.4, 130.7, 115.2,
6
+
114.1, 112.4; HRMS (ESI): m/z [M+H] calcd for C H ON Cl:
7
8
2
1
171.0320; found: 171.0312 the overall spectroscopic data are in
complete agreement with assigned structures and consistent with
6
1
3
19
7
.04 (s, 1H), 6.69 (d, J = 4.8 Hz, 1H), 6.45 (s, 2H); C NMR
literature

5
2
-amino-4-bromobenzamide (3j): Following geAneCralCpErocPeTduEreDA MA7.N8 HUz,S1CH)R, 6I.P47T(t, J = 7.2 Hz, 2H), 5.60 (s, 2H), 3.68 (s, 3H).
1
3
using 6-bromoindoline-2,3-dione (1j, 226 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
C NMR (150 MHz, CDCl ): δ (ppm) 168.4, 150.3, 133.9, 131.0,
116.5, 116.0, 110.4, 51.3; MS (EI): m/z 151.10 the overall
spectroscopic data are in complete agreement with assigned
3
1
23
white solid ( 174 mg, Yield 81%); H NMR (600 MHz, DMSO-
structures and consistent with literature
d ): δ (ppm) 7.84 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H),
6
1
3
methyl 2-amino-5-methylbenzoate (4b): Following general
procedure A using 5-methylindoline-2,3-dione (1b, 161 mg, 1.0
mmol), methanol (4ml) and purified by silicagel column
6
.92 (s, 1H), 6.80 (s, 2H), 6.62 (d, J = 8.4 Hz, 1H). C NMR
(
1
2
150 MHz, DMSO-d ): δ (ppm) 170.9, 151.7, 130.8, 125.7, 118.4,
17.1, 112.8.; HRMS (ESI): m/z [M+H] calcd for C H ON Br:
7 8 2
14.9815; found: 214.9806. the overall spectroscopic data are in
6
+
chromatography, afforded the compound as yellow solid (143.7
1
mg, Yield 87%); H NMR (600 MHz, CDCl ): δ (ppm) 7.66 (s,
3
complete agreement with assigned structures and consistent with
2
0
1H), 7.09 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 5.53 (s,
literature
13
2
H), 3.86 (d, J = 72.0 Hz, 3H), 2.23 (d, J = 61.8 Hz, 3H);
C
2
-amino-3-methylbenzamide (3k): Following general procedure
NMR (150 MHz, CDCl ): δ (ppm) 168.5, 148.2, 135.2, 130.7,
3
A using 7-methylindoline-2,3-dione (1k, 161 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
125.3, 116.8, 110.5, 51.4, 20.2; MS (EI): m/z 165.10 the overall
spectroscopic data are in complete agreement with assigned
2
4
structures and consistent with literature
1
yellow solid (102 mg, Yield 68%); H NMR (600 MHz, DMSO-
methyl 2-amino-5-methoxybenzoate (4c): Following general
procedure A using 5-methoxyindoline-2,3-dione (1c, 177 mg, 1.0
mmol), methanol (4ml) and purified by silicagel column
d ): δ (ppm) 7.74 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.06 (d, J =
6
1
3
7
.2 Hz, 2H), 6.37–6.45 (m, 3H), 2.06 (s, 3H); C NMR (150
MHz, DMSO-d ): δ (ppm) 171.9, 148.3, 132.9, 126.8, 123.2,
6
chromatography, afforded the compound as yellow solid (101.4
1
14.4, 113.6, 17.8; MS (EI): m/z 150.10 the overall spectroscopic
1
mg, Yield 56%); H NMR (600 MHz, CDCl ): δ (ppm) 7.30 (s,
3
data are in complete agreement with assigned structures and
1
9
1H), 6.89-6.90 (m, 1H), 6.57 (d, J = 9.0 Hz, 1H), 5.47 (s, 2H),
consistent with literature
13
3
.81 (s, 3H). 3.70 (s, 3H); C NMR (150 MHz, CDCl ): δ (ppm)
3
2
-amino-3-fluorobenzamide (3l): Following general procedure A
168.0, 150.1, 145.0, 123.0, 118.0, 112.6, 110.1, 55.4, 51.3; MS
(EI): m/z 181.10 the overall spectroscopic data are in complete
agreement with assigned structures and consistent with
using 7-fluoroindoline-2,3-dione (1l, 165 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
white solid (114 mg, Yield 74%); H NMR (600 MHz, DMSO-
d ): δ (ppm) 7.91 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H),
2
5
literature
1
methyl 2-amino-5-fluorobenzoate (4d): Following general
procedure A using 5-fluoroindoline-2,3-dione (1d, 165 mg, 1.0
mmol), methanol (4ml) and purified by silicagel column
6
1
3
7
.12–7.15 (m, 1H), 6.50 (s, 3H); C NMR (150 MHz, DMSO-d6):
δ (ppm) 170.7, 152.1, 150.5, 138.9, 124.4, 117.1, 116.2, 113.8;
HRMS (ESI): m/z [M+H] calcd for C H ON F: 155.0615; found:
1
agreement with assigned structures and consistent with
literature
+
chromatography, afforded the compound as yellow oil (140.4 mg,
7
8
2
1
Yield 83%); H NMR (600 MHz, CDCl ): δ (ppm) 7.53 (d, J =
3
55.0609. the overall spectroscopic data are in complete
9
.6 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.61–6.62 (m, 1H), 5.59 (s,
13
2
1
2H), 3.88 (d, J = 21.6 Hz, 3H); C NMR (150 MHz, CDCl
): δ
3
(ppm) 167.8, 154.8, 153.2, 147.1, 122.2, 117.9, 116.2, 110.7,
2
-amino-3-chlorobenzamide (3m): Following general procedure
51.9; MS (EI): m/z 169.05 the overall spectroscopic data are in
A using 7-chloroindoline-2,3-dione (1m, 181.5 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
complete agreement with assigned structures and consistent with
literature
2
6
1
methyl 2-amino-5-chlorobenzoate (4e): Following general
procedure A using 5-chloroindoline-2,3-dione (1e, 181.5 mg, 1.0
mmol), methanol (4ml) and purified by silicagel column
yellow solid (153.5 mg, Yield 90%); H NMR (600 MHz,
DMSO-d ): δ (ppm) 7.95 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37
6
(
1
1
d, J = 7.2 Hz, 2H), 6.71 (d, J = 18.0 Hz, 2H), 6.55 (t, J = 7.8 Hz,
1
3
chromatography, afforded the compound as white solid (100.2
H); C NMR (150 MHz, DMSO-d ): δ (ppm) 170.6, 145.7,
1
6
+
mg, Yield 54%); H NMR (600 MHz, CDCl
3
): δ (ppm) 7.81 (s,
32.0, 127.9, 119.1, 115.7, 115.0; HRMS (ESI): m/z [M+H]
1
2
H), 7.19 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.74 (s,
calcd for C H ON Cl: 171.0320; found: 171.0311. the overall
13
7
8
2
H), 3.86 (s, 3H).; C NMR (150 MHz, CDCl ): δ (ppm) 167.6,
3
spectroscopic data are in complete agreement with assigned
2
2
148.9, 134.0, 130.3, 120.5, 118.0, 111.3, 51.8; MS (EI): m/z
structures and consistent with literature
1
85.00 the overall spectroscopic data are in complete agreement
27
2
-amino-3-bromobenzamide (3n): Following general procedure
with assigned structures and consistent with literature
A using 7-bromoindoline-2,3-dione (1n, 226 mg, 1.0 mmol),
ammonia hydrate (2, 421 mg, 3.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
white solid (163 mg, Yield 76%); H NMR (400 MHz, DMSO-
d6): δ (ppm) 7.95 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 (d, J =
methyl 2-amino-4-chlorobenzoate (4i): Following general
procedure A using 6-chloroindoline-2,3-dione (1i, 181.5 mg, 1.0
mmol), methanol (4ml) and purified by silicagel column
1
chromatography, afforded the compound as light yellow solid (89
1
mg, Yield 48%); H NMR (600 MHz, CDCl ): δ (ppm) 7.53 (d, J
3
7
7
1
.8 Hz, 1H), 7.38 (s, 1H), 6.67 (d, J = 21.6 Hz, 2H), 6.50 (t, J =
1
3
= 8.4 Hz, 1H), 6.42 (s, 1H), 6.36–6.37 (m, 1H), 5.64 (s, 2H), 3.63
.8 Hz, 1H); C NMR (100 MHz, DMSO-d ): δ (ppm) 170.6,
13
6
(
s, 3H); C NMR (150 MHz, CDCl ): δ (ppm) 167.8, 151.1,
3
51.6, 136.5, 130.7, 115.2, 114.1, 112.4; MS (EI): m/z 213.95
+
139.8, 132.4, 116.4, 115.7, 108.9, 51.5; MS (EI): m/z 185.05 the
[
M] the overall spectroscopic data are in complete agreement
2
0
overall spectroscopic data are in complete agreement with
with assigned structures and consistent with literature
28
assigned structures and consistent with literature
methyl 2-aminobenzoate (4a): Following general procedure B
using indoline-2,3-dione (1a, 147 mg, 1.0 mmol), methanol (4ml)
and purified by silicagel column chromatography, afforded the
methyl 2-amino-3-fluorobenzoate (4l): Following general
procedure A using 7-fluoroindoline-2,3-dione (1l, 165 mg, 1.0
mmol), methanol (4ml) and purified by silicagel column
1
compound as light yellow oil (140.5 mg, Yield 93%); H NMR
chromatography, afforded the compound as yellow solid (99.8
(
600 MHz, CDCl ): δ (ppm) 7.69 (d, J = 8.1 Hz, 1H), 7.08 (t, J =
1
3
mg, Yield 59%); H NMR (600 MHz, CDCl ): δ (ppm) 7.63 (d, J
3

6
Tetrahedron
=
7.8 Hz, 1H), 7.09–7.12 (m, 1H), 6.55 (d,AJ C= C6.6EPHzT, E1HD), MA2 N(a)UShSoCji,RNI.;PUTmeyama, A.; Iuchi, A.; Saito, N.; Takemoto, T.;
1
3
5
1
.80 (s, 2H), 3.88 (s, 3H); C NMR (150 MHz, CDCl ): δ (ppm)
67.9, 152.2, 150.6, 139.6, 126.2, 118.4, 114.6, 112.5, 51.7; MS
Nomoto, K.; Ohizumi, Y. J. Nat. Prod. 1988, 51, 791-792; (b)
Kukar, T.; Murphy, M. P.; Eriksen, J. L.; Sagi, S. A.; Weggen, S.;
Smith, T. E.; Ladd, T.; Khan, M. A.; Kache, R.; Beard, J.;
Dodson, M.; Merit, S.; Ozols, V. V.; Anastasiadis, P. Z.; Das, P.;
Fauq, A.; Koo, E. H.; Golde, T. E. Nat. Med. 2005, 11, 545-550;
3
(EI): m/z 169.10 the overall spectroscopic data are in complete
agreement with assigned structures and consistent with
literature
2
9
(
2
c) Narsinghani, T.; Chaturvedi, S. C. Bioorg. Med. Chem. Lett.
006, 16, 461-468.
ethyl 2-aminobenzoate (4a′): Following general procedure B
using indoline-2,3-dione (1a, 147 mg, 1.0 mmol), ethanol (4ml)
and purified by silicagel column chromatography, afforded the
3 Roy, K.; De, A. U.; Sengupta, C. Drug Des. Discovery. 2002,
18, 23-31.
1
compound as red oil (118.9 mg, Yield 72 %); H NMR (600
MHz, CDCl ): δ (ppm) 8.01 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.2
3
4
Zhang, X. L.; Liu, A. L.; Zhao, Y.; Xiong, L. X.; Li, Z. M.
Hz, 1H), 6.78 (t, J = 8.1 Hz, 2H), 5.87 (s, 2H), 4.46 (dd, J = 13.2,
1
3
Chem. Res. Chin. Univ. 2013, 29, 1134-1139.
6
.6 Hz, 2H), 1.52 (t, J = 6.6 Hz, 3H). C NMR (150 MHz,
CDCl ): δ (ppm) 168.1, 150.4, 133.9, 131.1, 116.6, 116.1, 110.9,
5 (a) Xu, Z. H.; Zhang, Y. P.; Fu, H. C.; Zhong, H. M.; Hong, K.;
Zhu, W. M. Bioorg. Med. Chem. Lett. 2011, 21, 4005-4007; (b)
Bilokin, Y. V.; Kovalenko, S. M. Heterocycl. Commun. 2000, 6,
409-414.
3
6
0.2, 14.3; MS (EI): m/z 165.10 the overall spectroscopic data
are in complete agreement with assigned structures and
3
0
consistent with literature
2
-amino-N-butylbenzamide (6a): Following general procedure A
6 For selected papers, see: (a) Mohammed, S.; Vishwakarma, R.
A.; Bharate, S. B. J. Org. Chem. 2015, 80, 6915-6921; (b) Jiang,
X.; Tang, T.; Wang, J. M.; Chen, Z.; Zhu, Y. M.; Ji, S. J. J. Org.
Chem. 2014, 79, 5082-5087; (c) Li, Z. W.; Dong, J. Y.; Chen, X.
L.; Li, Q.; Zhou, Y. B.; Yin, S. F. J. Org. Chem. 2015, 80, 9392-
9400; (d) Yang, X.; Chen, G.; Shen, J.; Kuai, C.; Cui, X. Org.
Chem. Front. 2015, 2, 366-368.
using indoline-2,3-dione (1a, 147 mg, 1.0 mmol), butylamine
219 mg, 3.0 mmol) and purified by silicagel column
(
chromatography, afforded the compound as white solid (160 mg,
Yield 83%); H NMR (400 MHz, CDCl ): δ (ppm) 7.29 (dd, J =
7
1
3
.9, 1.2 Hz, 1H), 7.18 – 7.12 (m, 1H), 6.72 – 6.54 (m, 2H), 6.27
(
(
(
s, 1H), 5.33 (s, 2H), 3.35 (dd, J = 13.0, 7.1 Hz, 2H), 1.60 – 1.47
m, 2H), 1.41-1.32 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). C NMR
100 MHz, CDCl ): δ (ppm) 169.2, 148.3, 131.9, 127.0, 117.1,
1
3
7
Mahiwal, K.; Kumar, P.; Narasimhan, B. Med. Chem. Res.
012, 21, 293-307.
3
2
1
16.5, 116.4, 39.3, 31.6, 20.0, 13.7. the overall spectroscopic
data are in complete agreement with assigned structures and
consistent with literature
8
(a) Wang, Z. W.; Wang, M. X.; Yao, X.; Li, Y.; Tan, J.; Wang,
3
1
L. Z.; Qiao, W. T.; Geng, Y. Q.; Liu, Y. X.; Wang, Q. M. Eur. J.
Med. Chem. 2012, 53, 275-282; (b) Duan, H. L.; Zheng, J.; Lai,
Q. L.; Liu, Z.; Tian, G. H.; Wang, Z.; Li, J. F.; Shen, J. S. Bioorg.
Med. Chem. Lett. 2009, 19, 2777-2779; (c) Shao, M. F.; He, L.
H.; Zheng, L.; Huang, L. X.; Zhou, Y. Y.; Wang, T. J.; Chen, Y.;
Shen, M. S.; Wang, F.; Yang, Z.; Chen, L. J. Bioorg. Med. Chem.
Lett. 2017, 27, 4051-4055.
(2-aminophenyl)(piperidin-1-yl)methanone (7a): Following
general procedure A using indoline-2,3-dione (1a, 147 mg, 1.0
mmol), piperidine (255 mg, 3.0 mmol) and purified by silicagel
column chromatography, afforded the compound as white solid
1
(
161 mg, Yield 79%); H NMR (600 MHz, CDCl ): δ (ppm) 7.14
3
(t, J = 8.4 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.77 – 6.66 (m, 2H),
4
.21 (s, 2H), 3.55 (s, 4H), 1.67 (d, J = 4.2 Hz, 2H), 1.59 (s, 4H).
9
Correa, A.; Tellitu, I.; Dominguez, E.; Sanmartin, R. J. Org.
1
3
C NMR (150 MHz, CDCl ): δ (ppm) 169.3, 145.1, 130.0, 127.4,
3
Chem. 2006, 71, 3501-3505.
1
20.2, 117.2, 116.4, 29.7, 26.3, 24.7. the overall spectroscopic
1
0 For selected papers, see: (a) Lee, D.; Kim, Y.; Chang, S. J.
data are in complete agreement with assigned structures and
consistent with literature
3
2
Org. Chem. 2013, 78, 11102-11109; (b) Zhang, T.; Hu, X.; Wang,
Z.; Yang, T.; Sun, H.; Li, G.; Lu, H. Chem. Eur. J. 2016, 22,
2
2
920-2924; (c) Kim, H.; Shin, K.; Chang, S. J. Am. Chem. Soc.
014, 136, 5904-5907; (d) Zhang, L. B.; Zhang, S. K.; Wei, D.;
Acknowledgements
Zhu, X.; Hao, X. Q.; Su, J. H.; Niu, J. L.; Song, M. P. Org. Lett.
2016, 18, 1318-1321; (e) Yan, Q.; Chen, Z.; Yu, W.; Yin, H.; Liu,
Z.; Zhang, Y. Org. Lett. 2015, 17, 2482-2485.
We are grateful for financial support from the Natural Science
Foundation of Hubei Association for Science and Technology
(
2018CFB149), foundation from Young and middle-aged talent
program of Hubei Provincial Department of Education
Q20181509), foundation from Science foundation project of
1
1 For selected papers, see: (a) Singh, G. S.; Desta, Z. Y. Chem.
Rev. 2012, 112, 6104-6155; (b) Liu, Y. Y.; Wang, H.; Wan, J. P.
Asian J. Org. Chem. 2013, 2, 374-386; (c) Liu, Y. C.; Zhang, R.;
Wu, Q. Y.; Chen, Q.; Yang, G. F. Org. Prep. Proced. Int. 2014,
(
Wuhan Institute of Technology(K201834), and foundation from
the 10th Graduate's Innovation of Wuhan Institute of
Techonology(CX2018139).
4
6, 317-362; (d) Borad, M. A.; Bhoi, M. N.; Prajapati, N. P.;
Patel, H. D. Synth. Commun. 2014, 44, 1043-1057; (e) Liu, Y. L.;
Wang, B. L.; Cao, J. J.; Chen, L.; Zhang, Y. X.; Wang, C.; Zhou,
J. J. Am. Chem. Soc. 2010, 132, 15176-15178; (f) Liu, Y. L.;
Wang, X.; Zhao, Y. L.; Zhu, F.; Zeng, X. P.; Chen, L.; Wang, C.
H.; Zhao, X. L.; Zhou, J. Angew. Chem., Int. Ed. 2013, 52,
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