Cu(I)-catalyzed one-pot reactions of isatins, indoles, and amines toward unsymmetrically substituted 2-carbonylarylureas

Article abstract of DOI:10.1016/j.tet.2018.02.019

A series of unsymmetrical arylureas was obtained by the one-pot method for reacting isatins with indoles incorporating primary amino moieties, a significant heterocyclic skeleton for diverse pharmaceutically active structures. The reaction proceeds through Cu(I)-catalyzed C2–C3 bond of the ring-opening isatins and then expands the substrates in the optimum conditions. Furthermore, selected compounds 4b and 4k exhibit moderate to good anti-schistosomicidal activities.

Full text of DOI:10.1016/j.tet.2018.02.019

Accepted Manuscript
Cu(I)-catalyzed one-pot reactions of isatins, indoles, and amines toward
unsymmetrically substituted 2-carbonylarylureas
Xiangjun Peng, Xianyun Xu, Shuangyang Chen, Zeng Tian, Liangxian Liu, Qian Liu
PII:
S0040-4020(18)30144-3
10.1016/j.tet.2018.02.019
TET 29290
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 September 2017
Revised Date: 9 January 2018
Accepted Date: 5 February 2018
Please cite this article as: Peng X, Xu X, Chen S, Tian Z, Liu L, Liu Q, Cu(I)-catalyzed one-pot reactions
of isatins, indoles, and amines toward unsymmetrically substituted 2-carbonylarylureas, Tetrahedron
(2018), doi: 10.1016/j.tet.2018.02.019.
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ACCEPTED MANUSCRIPT
Cu(I)-Catalyzed One-pot Reactions of Isatins, Indoles, and Amines
toward Unsymmetrically Substituted 2-Carbonylarylureas
b
d
a
b
a
c
Xiangjun Peng, Xianyun Xu, Shuangyang Chen, Zeng Tian, Liangxian Liu,* Qian Liu,*
a
Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal
University, Ganzhou 341000, PR China
b
School of pharmaceutical science, Gannan Medical University, Ganzhou 341000, PR China
Department of pediatric surgery, The first affiliated hospital of Gannan Medical University,
Ganzhou 341000, PR China
c
d
Experimental teaching centre of medical morphology, Basic medical sciences school of
Gannan Medical University, Ganzhou 341000, PR China

ACCEPTED MANUSCRIPT
Cu(I)-Catalyzed One-pot Reactions of Isatins, Indoles, and Amines
toward Unsymmetrically Substituted 2-Carbonylarylureas
b
d
a
b
a
c
Xiangjun Peng, Xianyun Xu, Shuangyang Chen, Zeng Tian, Liangxian Liu,* Qian Liu,*
a
Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal
University, Ganzhou 341000, PR China
b
School of pharmaceutical science, Gannan Medical University, Ganzhou 341000, PR China
Department of pediatric surgery, The first affiliated hospital of Gannan Medical University,
Ganzhou 341000, PR China
c
d
Experimental teaching centre of medical morphology, Basic medical sciences school of
Gannan Medical University, Ganzhou 341000, PR China
E-mail:lxliu@xmu.edu.cn
Abstract: A series of unsymmetrical arylureas was obtained by the one-pot method for
reacting isatins with indoles incorporating primary amino moieties, a significant
heterocyclic skeleton for diverse pharmaceutically active structures. The reaction proceeds
through Cu(I)-catalyzed C2-C3 bond of the ring-opening isatins and then expands the
substrates in the optimum conditions. Furthermore, selected compounds 4b and 4k exhibit
moderate to good anti-schistosomicidal activities.
Introduction
The arylurea moiety, which involved in many useful building blocks because of its versatility,
1
posses diverse biological and pharmaceutical compounds (Figure 1). The distinct annulation
2
pattern demonstrates exceptional properties including anticancer, insecticidal and material
3
reagents. For example, DCC-2036 (Rebastinib) is a conformational control Bcr-Abl kinase
1

ACCEPTED MANUSCRIPT
4
inhabitor. Carbarsone is a drug used to treat the gastrointestinal disease caused by dientamoeba
5
fragilis infections. Hexaflumuron is a pesticide via preventing the formation of chintinous
6
structures in insects. Hydrogelator employs in industrial scale tasks such as waste water treatment
7
and controls drug release especially gene therapy agents such as DNA intercalating drugs.
Therefore, the unique structural features have attracted profound interest from chemists because of
their potential biological activities and industrial applications.
Figure 1. Arylurea structure and representative compounds containing the phenylurea unit.
The conventional methods reported for the arylurea synthesis are essentially based on phosgene or
8
9
10
carbamates, phosgene substitutes, or isocyanates. These approaches have been demonstrated to
be particularly efficient for symmetrical ureas. Although widely used, this methodology suffer
from various limitations: phosgene and isocyanates are toxic, unstable, and expensive to handle.
However, in the case of nonsymmetrical ureas, the synthetic efficiency is limited by the formation
of symmetrical urea side products. In this regard, oxidative sequence for the conversion of indole
2

ACCEPTED MANUSCRIPT
or oxindole derivatives to arylureas represents an attractive strategy toward efficient synthesis of
11
ureas, especially more challenging unsymmetrically substituted arylureas.
1
2
13
14
15
Based on our previous research on the synthesis of trizoles, indoles, pyridines, ect via a
diverse range of homocoupling and cross-coupling, we wish to report that a CuI-catalyzed C2-C3
bond ring-opening of isatins to produce unsymmetrically substituted 2-carbonylarylureas through
one-pot synthetic program with the indole homocoupling.
Results and discussion
At the outset of our studies, the reaction of isatin 1a with indole 2a in the present of K CO was
2
3
attempted under different conditions (Table 1). When without catalysts were used, no desired
product was detected (Table 1, entry 1). Other metal salts, such as LaCl ˑ7H O, PdCl ,
3
2
2
RuCl ˑ3H O, SnCl , CoCl , FeSO , AgNO , and ZrCl , gave lower yields (Table 1, entries 2-9). To
3
2
2
2
4
3
4
our delight, CuI resulted in the formation of 4a in 45% yield (Table 1, entry 10). Other copper
catalysts including CuSO , Cu O, CuBr, CuCl, and CuCN, were found to be less effective than
4
2
CuI (Table 1, entry 11-15). Furthermore, many kinds of acids were tested, and benzoic acid was
found to be the best choice, while other acids gave lower yields or were ineffective (Table 1,
entries 16-18). In additon, it was found that the solvent showed a crucial role in the reaction (Table
1
, entries 19-23). Pyridine proved to be the most suitable solvent and gave the best result with
8
3% yield of the desired product 4a (Table 1, entry 23). Hence, isatin 1a (0.2 mmol), indole 2a
(0.2 mmol), morpholine 3a (0.3 mmol), and benzoic acid (0.1 mmol) involved CuI (0.04 mmol) in
o
pyridine at 80 C for 5 h were chosen as the optimized reaction conditions for the synthesis of 4a.
a
Table 1. Optimization of the reaction conditions
3

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entry
catalyst (mol %)
acid (mmol)
solvent
yield (%)b
0
-
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
HOAc (0.1)
CH CN
1
2
3
4
5
6
7
8
9
3
LaCl3 7H O (20)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
trace
trace
trace
trace
trace
trace
5
8
45
trace
38
32
27
21
20
trace
trace
trace
trace
15
2
PdCl (20)
2
RuCl3 3H O (20)
2
SnCl (20)
2
CoCl (20)
2
FeSO (20)
4
AgNO (20)
3
ZrCl (20)
4
CuI (20)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuSO (20)
4
Cu O (20)
2
CuBr (20)
CuCl (20)
CuCN (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
TsOH (0.1)
CF3CO2H (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
benzoic acid (0.1)
EtOH
THF
toluene
pyridine
36
83
a
Reaction conditions: isatin 1a (0.2 mmol), indole 2a (0.2 mmol), and K CO (0.2 mmol) in
2
3
o
solvent (0.5 mL) at 40 C for 2 h; 3a (0.3 mmol), catalyst (0.04 mmol), and acid (0.1 mmol) were
o
b
added and heated at 80 C for another 5 h. Isolated yield of pure product based on 1a.
With the identification of the optimal conditions in hand, the scope and generality of the substrates
were further explored. We first investigated the reaction between various isatins 1, indoles 2, and
morpholine 3a. The results are shown in Table 2. Pleasingly, the reaction demonstrated wide
2
substrate scope in terms of isatin and indole unit. Indoles bearing an electron-neutral (R = H),
electron-donating (e.g., 5-CH , 5-OCH , 5-OBn), or electron-withdrawing (e.g., 5-F, 5-Br, 5-NO ,
3
3
2
6
-Cl, 6-CO CH ) substituent on their phenyl ring were successfully converted to the
2 3
corresponding products in moderate to good yields (Table 2, entries 1-9). Electron-donating
4

ACCEPTED MANUSCRIPT
groups on the indole ring gave better yields than electron-withdrawing groups in this reaction
(Table 2, entries 5 vs. 7).
a
Table 2. Substrate scope of isatins and indoles
b
entry
isatin
indole
product
4a
yield (%)
83
1
2
1
2
3
4
5
6
7
8
9
R = H
R = H
1
2
R = H
R = 5-F
4b
4c
63
1
2
R = H
R = 5-Br
72
1
2
R = H
R = 5-CH
4d
4e
80
3
1
2
R = H
R = 5-OCH
87
3
1
2
R = H
R = 5-OBn
4f
71
1
2
R = H
R = 5-NO
4g
55
2
1
2
R = H
R = 6-Cl
4h
4i
65
1
2
R = H
R = 6-CO CH
61
2
3
1
2
1
0
1
R = 5-OCH
R = H
4j
78
3
1
2
1
R = 5-OCF
R = H
4k
69
3
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), and K CO (0.2 mmol) in pyridine (0.5 mL) at
2
3
o
4
0 C for 2 h; 3a (0.3 mmol), CuI (0.04 mmol), and benzoic acid (0.1 mmol) were added and
o
b
heated at 80 C for another 5 h. Isolated yield of pure product based on 1.
In addition, we also observed indoles with strong electron-withdrawing substituents at the 5 and 6
positions of indoles, such as NO and CO CH , could provide the corresponding products with
2
2
3
lower yields (Table 2, entries 7 and 9). The structure of 4c was established unambiguously by
X-ray diffraction analysis (see Supporting Information).
Subsequently, the substrate scope of isatins was then investigated. Isatins with a substituent at C-5
could undergo the one-pot synthesis of unsymmetrically substituted arylurea derivatives in good
yields (Table 2, entries 10 and 11). When using the isatin with an electron-donating methoxy
5

ACCEPTED MANUSCRIPT
group at the C-5 position (Table 2, entry 10), the desired product was obtained in 78% yield.
We continued to explore a range of amines examined in the reaction based on the same conditions,
and the results were summarized in Table 3. A wide range of amines, such as primary amines,
secondary amines, aliphatic amines, and arylamines, were found to react with isatin and indoles to
afford the corresponding products 4l-4t in good yields.
a
Table 3. Substrate scope of amines
b
entry
R
amine
dipropylamine
pyrrolidine
product
4l
yield (%)
63
1
2
3
4
5
6
7
8
9
H
5-Br
4m
4n
63
5-Br
aniline
72
5-Br
cyclohexylamine
dicyclohexylamine
piperidine
4o
67
5-CH3
5-CH3
5-CH3
5-OCH3
5-OCH3
4p
66
4q
81
thiomorpholine
pyridin-2-amine
benzyl amine
4r
75
4s
73
4t
78
a
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), and K CO (0.2 mmol) in pyridine (0.5 mL)
2
3
o
at 40 C for 2 h; 3 (0.3 mmol), CuI (0.04 mmol), and benzoic acid (0.1 mmol) were added and
o
b
heated at 80 C for another 5 h. Isolated yield of pure product based on 1a.
To gain some mechanistic insight into the process of this reaction, two control experiments were
conducted (Scheme 1). Under an argon atmosphere, compound 4a was obtained only in 7% yield,
even a long reaction time. The result indicated that O acts as a terminal oxidant. In addition, in
2
the control experiment with CuI but without benzoic acid, only trace amount of the product was
obtained. The result indicated that benzoic acid is essential for the CuI-catalyzed transformation.
6

ACCEPTED MANUSCRIPT
Scheme 1. Control experiments.
In the next step, to obtain more information concerning the reaction pathway, we separated the
intermediates 5, and subjected it to react with morpholine under standard reaction conditions, and
this gave products 4 in good yields (Scheme 2). These results showed that 5 is the intermediate of
the reaction.
Scheme 2. Exploring the mechanistic study.
Although the detailed mechanism remained unclear at the current stage, a plausible reaction
1
3
pathway based on the basis of the results described above and relevant literature is outlined in
Scheme 3. First, the nucleophilic addition of indole on isatin in the presence of K CO affords
2
3
intermediate 5. Then, intermediate 5 involving ring opening and oxidation leads to afford
-carbonylarylurea 4a.
2
7

ACCEPTED MANUSCRIPT
Scheme 3. Plausible reaction pathway.
On the basis of the diverse biological activities of arylurea moiety and as part of our works on
1
1
6
biological activities of indole derivatives, the aim of this work was to evaluate the in vitro
schistosomicidal activity of N-(2-(1H-indole-3-carbonyl)phenyl)morpholine-4-carboxamides 4
against S. japonicum adult worms. Schistosomiasis is a notable neglected tropical disease caused
1
7
by trematodes that infect mainly the intestines, bladder, and liver. Because of the unavailability
of a schistosomiasis vaccine, control of the disease depends mainly on chemotherapy. Praziquantel
(PZQ) has become the exclusive drug because of its low cost and efficacy against the adult form
1
8
of all schistosome species. In view of rapid re-infection following treatment and concern about
the development of tolerance and/or resistance to praziquantel, there is an urgent need for research
1
9
and development of novel drugs for the prevention and treatment of schistosomiasis.
The in vitro schistosomicidal activity of 4a, 4b, 4c, 4g, and 4k (doses ranging from 10 to 100 ꢀM)
was carried out against S. japonicum adult worms (see the Supporting Information for detail). All
pairs or most of coupled adult worms were separated into individual male and female by the action
of 4b, 4k, or 4g at the doses of 100 ꢀM. The compound 4b and 4k exhibit moderate to good
anti-schistosomicidal activities. Especially, the compound 4k exhibits the best in vitro
schistosomicidal activity against S. japonicum adult worms (Table 4). To the best of our
knowledge, the present work represents the first example of arylurea derivatives for
anti-schistosomicidal activity study.
8

ACCEPTED MANUSCRIPT
a
Table 4 In vitro effects of several compounds against 30-day-old adult S. japonicum
b
Samples
Incubation period (h)
1
2
18
-
24
0
48
0
72
0
c
Control
-
1
0% DMSO
-
-
0
0
0
PZQ 10 µM
60
0
100
100
10
10
20
40
0
4
4
4
4
4
a
10 µM
10
2
5
5 µM
0 µM
0
20
40
50
0
100 µM
0
c
10 µM
0
0
2
5
5 µM
0 µM
0
10
20
30
20
30
40
50
30
50
70
90
70
90
100
100
20
30
50
30
40
70
80
50
80
100
100
80
90
100
100
10
20
10
10
20
30
20
40
50
70
50
70
90
100
1
1
1
1
00 µM
g
b
k
10 µM
2
5
5 µM
0 µM
00 µM
10 µM
2
5
5 µM
0 µM
00 µM
10 µM
2
5
5 µM
0 µM
00 µM
a
b
c
Numbers of worms tested were ten in very group.
Data represent the percentage of loss spontaneous movement.
RPMI 1640.
Conclusions
In conclusion, we have developed a convinent, practical and highly efficient one-pot method in the
ring-opening of isatins for the production of unsymmetrically substituted 2-carbonylarylureas. The
advantages of this new method include the broad substrate scope, operational simplicity, high
atom-economy, and the use of inexpensive CuI as the catalyst. Furthermore, a number of
functionalities, such as F, Cl, Br, CH , CH O, BnO, CO CH , and NO , are tolerated under the
3
3
2
3
2
reaction conditions. In addition, the substituted 2-carbonylarylurea derivatives showed promising
9

ACCEPTED MANUSCRIPT
anti-schistosomicidal potency through preliminary biological studies. The current study provides a
clue for the further development of new types anti-schistosomicidal agents.
Experimental Section
General Procedure for the Preparation of 4a: To a solution of isatin (0.2 mmol) and indole (0.2
mmol) in pyridine (0.5 mL) was added K CO (0.2 mmol) under an air atmosphere and the
2
3
o
mixture was stirred at 40 C for 2 h. Then, morpholine (0.3 mmol), CuI (0.04 mmol), and benzoic
o
acid (0.1 mmol) were added to the reaction mixture and the resulting mixture was heated at 80 C
for another 5 h. The reaction mixture was concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:1) to yield the
corresponding product 4a.
N-(2-(1H-Indole-3-carbonyl)phenyl)morpholine-4-carboxamide (4a): Yellow amorphous solid.
1
H NMR (400 MHz, CDCl ): δ 10.97 (s, 1H, NH), 10.17 (s, 1H, NH), 8.32 (dd J = 7.1, 3.0 Hz, 1H,
3
Ar-H), 8.24 (d, J = 7.8 Hz, 1H, Ar-H), 7.62 (dt, J = 1.5, 8.7 Hz, 1H, Ar-H), 7.57 (dd, J = 8.7, 1.5
Hz, 1H, Ar-H), 7.46-7.43 (m, 1H, Ar-H), 7.30 (s, 1H, Ar-H), 7.28 (dd, J = 3.0, 1.5 Hz, 1H, Ar-H),
7
.23 (dt, J = 1.0, 7.8 Hz, 1H, Ar-H), 6.35 (d, J = 3.0 Hz, 1H, Ar-H), 3.76 (t, J = 4.8 Hz, 4H,
1
3
2
XCH ), 3.58 (t, J = 4.8 Hz, 4H, 2XCH ). C NMR (100 MHz, CDCl ): δ 192.1, 155.8, 139.4,
2 2 3
1
37.0, 134.9, 132.0, 131.5, 127.6, 126.4, 123.9, 122.7, 122.2, 122.1, 122.0, 116.8, 112.0, 66.4,
+
4
3.9. MS (ESI): 350 (M+H , 100). Anal calcd for C H N O : C, 68.75; H, 5.48; N, 12.03. Found
2
0
19
3
3
C, 68.57; H, 5.71; N, 11.89.
N-(2-(5-Fluoro-1H-indole-3-carbonyl)phenyl)morpholine-4-carboxamide
(4b):
Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 11.15 (s, 1H, NH), 10.10 (s, 1H, NH), 8.20 (d, J
3
=
8.5 Hz, 1H, Ar-H), 8.00 (dd, J = 9.3, 2.4 Hz, 1H, Ar-H), 7.64 (t, J = 7.5 Hz, 1H, Ar-H), 7.55 (d,
1
0

ACCEPTED MANUSCRIPT
J = 7.5 Hz, 1H, Ar-H), 7.36 (dd, J = 8.5, 4.4 Hz, 1H, Ar-H), 7.25 (t, J = 7.5 Hz, 1H, Ar-H), 7.02
(
dt, J = 9.3, 2.4 Hz, 1H, Ar-H), 6.26 (s, 1H, Ar-H), 3.77 (t, J = 4.8 Hz, 4H, 2XCH ), 3.57 (t, J =
2
1
3
4
.8 Hz, 4H, 2XCH ). C NMR (100 MHz, CDCl ): δ 191.6, 159.8 (d, J = 237.9 Hz), 155.9, 139.3,
2 3
1
35.8, 133.4, 132.1, 131.2, 127.5, 127.2 (d, J = 11.1 Hz), 122.3 (d, J = 3.7 Hz), 116.8 (d, J = 4.4
+
Hz), 112.7 (d, J = 9.8 Hz), 112.5, 112.2, 107.5 (d, J = 25.0 Hz), 66.4, 43.9. MS (ESI): 368 (M+H ,
1
00). Anal calcd for C H FN O : C, 65.39; H, 4.94; N, 11.44. Found C, 65.53; H, 5.27; N, 11.30.
20 18 3 3
N-(2-(5-Bromo-1H-indole-3-carbonyl)phenyl)morpholine-4-carboxamide
(4c):
Yellow
1
amorphous solid. H NMR (400 MHz, DMSO-d ): δ 12.29 (s, 1H, NH), 9.81 (s, 1H, NH), 8.33 (s,
6
1
H, Ar-H), 8.05 (d, J = 7.6 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.72 (d, J = 7.6 Hz, 1H, Ar-H), 7.51
(t, J = 7.6 Hz, 1H, Ar-H), 7.49 (d, J = 8.4 Hz, 1H, Ar-H), 7.38 (d, J = 8.4 Hz, 1H, Ar-H), 7.13 (t, J
1
3
=
7.6 Hz, 1H, Ar-H), 3.53 (s, 4H, 2XCH ), 3.32 (s, 4H, 2XCH ). C NMR (100 MHz, DMSO-d ):
2 2 6
δ 191.9, 154.9, 140.0, 137.6, 135.9, 132.3, 131.4, 128.5, 127.8, 126.2, 124.1, 122.1, 121.8, 115.6,
+
+
1
15.2, 114.8, 66.2, 44.1. MS (ESI): 428 (M+H , 100), 430 (M+H , 100). Anal calcd for
C H BrN O : C, 56.09; H, 4.24; N, 9.81. Found C, 56.35; H, 4.48; N, 9.43.
2
0
18
3
3
N-(2-(5-Methyl-1H-indole-3-carbonyl)phenyl)morpholine-4-carboxamide
(4d):
Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 10.90 (s, 1H, NH), 10.16 (s, 1H, NH), 8.23 (d, J
3
=
8.5 Hz, 1H, Ar-H), 8.13 (s, 1H, Ar-H), 7.60 (dt, J = 1.3, 8.5 Hz, 1H, Ar-H), 7.55 (dd, J = 7.7, 1.3
Hz, 1H, Ar-H), 7.34 (d, J = 8.5 Hz, 1H, Ar-H), 7.21 (t, J = 7.7 Hz, 1H, Ar-H), 7.10 (dd, J = 8.5,
1
2
1
.3 Hz, 1H, Ar-H), 6.33 (s, 1H, Ar-H), 3.76 (t, J = 4.8 Hz, 4H, 2XCH ), 3.58 (t, J = 4.8 Hz, 4H,
2
1
3
XCH ), 2.49 (s, 3H, CH ). C NMR (100 MHz, CDCl ): δ 192.1, 155.8, 139.4, 135.3, 135.1,
2
3
3
32.4, 131.9, 131.4, 127.7, 126.6, 125.5, 122.1, 122.0, 121.7, 116.4, 111.6, 66.4, 43.9, 21.6. MS
+
(
ESI): 364 (M+H , 100). Anal calcd for C H N O : C, 69.41; H, 5.82; N, 11.56. Found C, 69.62;
2
1
21
3
3
11

ACCEPTED MANUSCRIPT
H, 6.03; N, 11.25.
N-(2-(5-Methoxy-1H-indole-3-carbonyl)phenyl)morpholine-4-carboxamide (4e): Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 10.91 (s, 1H, NH), 10.10 (s, 1H, NH), 8.20 (d, J
3
=
8.0 Hz, 1H, Ar-H), 7.83 (d, J = 2.4 Hz, 1H, Ar-H), 7.60 (t, J = 7.3 Hz, 1H, Ar-H), 7.55 (dd, J =
.0, 1.4 Hz, 1H, Ar-H), 7.32 (d, J = 8.7 Hz, 1H, Ar-H), 7.21 (t, J = 7.3 Hz, 1H, Ar-H), 6.92 (dd, J
8.7, 2.4 Hz, 1H, Ar-H), 6.34 (d, J = 2.4 Hz, 1H, Ar-H), 3.89 (s, 3H, OCH ), 3.76 (t, J = 5.0 Hz,
8
=
3
1
3
4
H, 2XCH ), 3.53 (t, J = 5.0 Hz, 4H, 2XCH ). C NMR (100 MHz, CDCl ): δ 192.0, 156.6, 155.8,
2 2 3
1
39.3, 135.1, 131.9, 131.8, 131.3, 127.7, 127.2, 122.1, 122.0, 116.6, 114.2, 112.7, 103.8, 66.4,
+
5
5.9, 44.0. MS (ESI): 380 (M+H , 100). Anal calcd for C H N O : C, 66.48; H, 5.58; N, 11.08.
2
1
21
3
4
Found C, 66.17; H, 5.66; N, 10.90.
N-(2-(5-Benzyloxy-1H-indole-3-carbonyl)phenyl)morpholine-4-carboxamide (4f): Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 10.82 (s, 1H, NH), 10.12 (s, 1H, NH), 8.22 (d, J
3
=
8.5 Hz, 1H, Ar-H), 7.94 (d, J = 2.4 Hz, 1H, Ar-H), 7.60 (dt, J = 1.6, 8.5 Hz, 1H, Ar-H), 7.57 (dd,
J = 7.5, 1.6 Hz, 1H, Ar-H), 7.48 (d, J = 7.5 Hz, 2H, Ar-H), 7.39 (dt, J = 1.6, 7.5 Hz, 2H, Ar-H),
.35 (s, 1H, Ar-H), 7.33 (s, 1H, Ar-H), 7.21 (t, J = 7.5 Hz, 1H, Ar-H), 7.01 (dd, J = 8.5, 2.4 Hz, 1H,
Ar-H), 6.38 (s, 1H, Ar-H), 5.15 (s, 2H, OCH ), 3.77 (t, J = 4.6 Hz, 4H, 2XCH ), 3.58 (t, J = 4.6 Hz,
7
2
2
1
3
4
H, 2XCH2). C NMR (100 MHz, CDCl ): δ 192.0, 155.8, 155.7, 139.4, 137.4, 135.1, 133.4,
3
1
32.0, 131.9, 131.3, 128.5, 127.8, 127.7, 127.6, 127.2, 122.1, 116.7, 114.8, 112.7, 105.3, 70.7,
+
6
6.4, 43.9. MS (ESI): 440 (M+H , 100). Anal calcd for C H N O : C, 73.78; H, 5.73; N, 9.56.
2
7
25
3
3
Found C, 73.46; H, 6.05; N, 9.44.
N-(2-(5-Nitro-1H-indole-3-carbonyl)phenyl)morpholine-4-carboxamide
(4g):
Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 11.74 (s, 1H, NH), 10.62 (s, 1H, NH), 9.34 (d, J
3
1
2

ACCEPTED MANUSCRIPT
=
2.0 Hz, 1H, Ar-H), 8.00 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.53 (d, J = 9.0 Hz, 1H, Ar-H), 7.41 (d,
J = 7.5 Hz, 1H, Ar-H), 7.28 (t, J = 7.5 Hz, 1H, Ar-H), 7.03 (d, J = 7.5 Hz, 1H, Ar-H), 6.98 (s, 1H,
1
3
Ar-H), 6.91 (d, J = 7.5 Hz, 1H, Ar-H), 3.62-3.48 (m, 4H, 2XCH ), 3.58-3.38 (m, 4H, 2XCH ). C
2
2
NMR (100 MHz, CDCl ): δ 191.2, 176.5, 142.3, 141.0, 140.8, 129.5, 128.7, 128.6, 125.8, 125.5,
3
+
1
22.2, 120.1, 117.3, 115.7, 112.6, 110.5, 67.2, 47.7. MS (ESI): 395 (M+H , 100). Anal calcd for
C H N O : C, 60.91; H, 4.60; N, 14.21. Found C, 61.08; H, 4.86; N, 13.95.
2
0
18
4
5
N-(2-(6-Chloro-1H-indole-3-carbonyl)phenyl)morpholine-4-carboxamide
(4h):
Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 11.25 (s, 1H, NH), 10.05 (s, 1H, NH), 8.22 (d, J
3
=
8.5 Hz, 1H, Ar-H), 8.18 (d, J = 7.9 Hz, 1H, Ar-H), 7.63 (dt, J = 1.6, 8.5 Hz, 1H, Ar-H), 7.53 (dd,
J = 7.9, 1.6 Hz, 1H, Ar-H), 7.43 (d, J = 1.6 Hz, 1H, Ar-H), 7.25 (dt, J = 1.6, 8.5 Hz, 2H, Ar-H),
.18 (d, J = 3.0 Hz, 1H, Ar-H), 3.77 (t, J = 4.8 Hz, 4H, 2XCH ), 3.58 (t, J = 4.8 Hz, 4H, 2XCH ).
6
2
2
1
3
C NMR (100 MHz, CDCl ): δ 191.7, 155.8, 139.3, 137.4, 135.2, 132.2, 131.3, 129.7, 127.5,
3
+
1
25.0, 123.3, 123.0, 122.4, 122.3, 116.7, 112.0, 66.4, 43.9. MS (ESI): 384 (M+H , 100), 386
+
(
M+H , 30). Anal calcd for C H ClN O : C, 62.58; H, 4.73; N, 10.95. Found C, 62.93; H, 5.11;
2
0
18
3
3
N, 10.64.
Methyl 3-(2-(morpholine-4-carboxamido)benzoyl)-1H-indole-6-carboxylate (4i): Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 8.90 (s, 2H, NH), 8.47 (d, J = 8.5 Hz, 1H, Ar-H),
3
8
.05 (s, 1H, Ar-H), 7.84 (dd, J = 8.5, 1.1 Hz, 1H, Ar-H), 7.47 (d, J = 8.5 Hz, 1H, Ar-H), 7.19 (t, J
7.6 Hz, 1H, Ar-H), 6.99 (t, J = 7.6 Hz, 1H, Ar-H), 6.86 (s, 1H, Ar-H), 6.85 (d, J = 7.6 Hz, 1H,
=
1
3
Ar-H), 3.92 (s, 3H, OCH ), 3.73-3.63 (m, 4H, 2XCH ), 2.65 (s, 4H, 2XCH ). C NMR (100 MHz,
3
2
2
CDCl ): δ 197.2, 177.9, 168.3, 140.4, 136.5, 129.9, 129.7, 128.9, 127.5, 125.4, 124.0, 122.7, 122.1,
3
+
1
20.7, 113.9, 113.7, 110.4, 67.5, 52.1, 47.5. MS (ESI): 408 (M+H , 100). Anal calcd for
1
3

ACCEPTED MANUSCRIPT
C H N O : C, 64.86; H, 5.20; N, 10.31. Found C, 65.08; H, 4.83; N, 10.25.
2
2
21
3
5
N-(2-(1H-Indole-3-carbonyl)-4-methoxyphenyl)morpholine-4-carboxamide (4j): Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 10.76 (s, 1H, NH), 9.88 (s, 1H, NH), 8.33-8.31
3
(m, 1H, Ar-H), 8.18 (d, J = 8.7 Hz, 1H, Ar-H), 7.47-7.43 (m, 1H, Ar-H), 7.32-7.26 (m, 2H, Ar-H),
7
3
1
.13 (s, 1H, Ar-H), 7.11 (dd, J = 8.7, 3.0 Hz, 1H, Ar-H), 6.79 (s, 1H, Ar-H), 3.77 (s, 3H, OCH3),
1
3
.74 (t, J = 5.0 Hz, 4H, 2XCH ), 3.55 (t, J = 5.0 Hz, 4H, 2XCH ). C NMR (100 MHz, CDCl ): δ
2
2
3
91.9, 156.0, 154.1, 136.9, 134.5, 132.6, 128.3, 126.4, 124.0, 123.4, 122.8, 122.1, 118.2, 116.8,
+
1
15.4, 112.0, 66.4, 55.6, 43.9. MS (ESI): 380 (M+H , 100). Anal calcd for C H N O : C, 66.48;
2
1
21
3
4
H, 5.58; N, 11.08. Found C, 66.23; H, 5.90; N, 10.76.
N-(2-(1H-Indole-3-carbonyl)-4-(trifluoromethoxy)phenyl)morpholine-4-carboxamide (4k):
1
Yellow amorphous solid. H NMR (400 MHz, CDCl ): δ 10.27 (s, 1H, NH), 9.66 (s, 1H, NH),
3
8
.40 (d, J = 9.2 Hz, 1H, Ar-H), 8.33-8.30 (m, 1H, Ar-H), 7.60 (d, J = 2.4 Hz, 1H, Ar-H), 7.49-7.45
(
m, 1H, Ar-H), 7.39-7.33 (m, 4H, Ar-H), 3.77 (t, J = 5.1 Hz, 4H, 2XCH ), 3.57 (t, J = 5.1 Hz, 4H,
2
1
3
2
1
4
4
3
XCH ). C NMR (100 MHz, CDCl ): δ 191.4, 155.0, 142.4 (q, J = 2.0 Hz), 139.2, 136.6, 134.1,
2
3
26.7, 126.3, 125.4, 124.4, 123.9, 123.1, 122.5, 122.2, 121.8, 117.1, 111.8, 66.5, 44.0. MS (ESI):
+
34 (M+H , 100). Anal calcd for C H F N O : C, 58.20; H, 4.19; N, 9.70. Found C, 58.25; H,
2
1
18
3
3
4
.36; N, 9.34.
-(2-(1H-Indole-3-carbonyl)phenyl)-1,1-dipropylurea (4l): Yellow amorphous solid. H NMR
400 MHz, CDCl ): δ 11.33 (s, 1H, NH), 9.98 (s, 1H, NH), 8.36 (dd, J = 6.0, 4.5 Hz, 1H, Ar-H),
1
(
3
8
.27 (d, J = 8.4 Hz, 1H, Ar-H), 7.60 (dt, J = 1.4, 8.4 Hz, 1H, Ar-H), 7.53 (dd, J = 7.5, 1.4 Hz, 1H,
Ar-H), 7.46 (dd, J = 6.0, 4.5 Hz, 1H, Ar-H), 7.30-7.26 (m, 2H, Ar-H), 7.22 (t, J = 7.5 Hz, 1H,
Ar-H), 6.22 (d, J = 3.1 Hz, 1H, Ar-H), 3.32 (t, J = 7.4 Hz, 4H, 2XCH ), 1.70-1.55 (m, 4H, 2XCH ),
2
2
1
4

ACCEPTED MANUSCRIPT
1
3
0
1
.97 (t, J = 7.2 Hz, 6H, 2XCH ). C NMR (100 MHz, CDCl ): δ 191.9, 156.0, 139.5, 137.1, 135.1,
3 3
31.6, 131.1, 127.9, 126.6, 123.6, 122.5, 122.1, 122.0, 121.8, 116.6, 112.1, 49.6, 21.7, 11.3. MS
+
(
ESI): 364 (M+H , 100). Anal calcd for C H N O : C, 72.70; H, 6.93; N, 11.56. Found C, 73.02;
2
2
25
3
2
H, 7.14; N, 11.91.
N-(2-(5-Bromo-1H-indole-3-carbonyl)phenyl)pyrrolidine-1- carboxamide (4m): Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 11.63 (s, 1H, NH), 9.73 (s, 1H, NH), 8.51 (s, 1H,
3
Ar-H), 8.24 (d, J = 8.4 Hz, 1H, Ar-H), 7.62 (dt, J = 1.3, 8.4 Hz, 1H, Ar-H), 7.50 (dd, J = 7.5, 1.3
Hz, 1H, Ar-H), 7.35 (s, 1H, Ar-H), 7.34 (s, 1H, Ar-H), 7.22 (t, J = 7.5 Hz, 1H, Ar-H), 6.10 (t, J =
1
3
3
1
.1 Hz, 1H, Ar-H), 3.52 (s, 4H, 2XCH ), 1.98 (s, 4H, 2XCH ). C NMR (100 MHz, CDCl ): δ
2 2 3
91.3, 154.9, 139.2, 135.8, 135.5, 131.9, 131.0, 128.1, 127.7, 126.7, 124.7, 122.4, 122.1, 116.2,
+
+
1
16.1, 113.6, 45.9, 25.4. MS (ESI): 412 (M+H , 100), 414 (M+H , 100). Anal calcd for
C H BrN O : C, 58.27; H, 4.40; N, 10.19. Found C, 58.60; H, 4.56; N, 9.87.
2
0
18
3
2
1
1
-(2-(5-Bromo-1H-indole-3-carbonyl)phenyl)-3-phenylurea (4n): Yellow amorphous solid. H
NMR (400 MHz, DMSO-d ): δ 11.12 (d, J = 2.4 Hz, 1H, NH), 9.46 (s, 1H, NH), 8.32 (d, J = 8.2
6
Hz, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 8.04 (s, 1H, NH), 7.58 (dt, J = 1.5, 8.7 Hz, 1H, Ar-H), 7.42 (dd,
J = 7.6, 1.5 Hz, 1H, Ar-H), 7.36-7.22 (m, 6H, Ar-H), 7.09 (dt, J = 1.1, 7.1 Hz, 1H, Ar-H), 7.00 (d,
1
3
J = 8.7 Hz, 1H, Ar-H), 6.93 (dd, J = 8.7, 1.5 Hz, 1H, Ar-H). C NMR (100 MHz, CDCl ): δ 191.8,
3
1
1
54.3, 138.1, 137.7, 137.4, 135.4, 131.5, 129.9, 129.6, 129.0, 128.9, 127.3, 126.6, 124.0, 123.8,
+
+
22.8, 122.5, 120.2, 116.2, 113.3. MS (ESI): 434 (M+H , 100), 436 (M+H , 100). Anal calcd for
C H BrN O : C, 60.84; H, 3.71; N, 9.68. Found C, 60.78; H, 4.01; N, 9.31.
2
2
16
3
2
1
-(2-(5-Bromo-1H-indole-3-carbonyl)phenyl)-3-cyclohexylurea (4o): Yellow amorphous solid.
1
H NMR (400 MHz, DMSO-d ): δ 12.28 (s, 1H, NH), 8.76 (s, 1H, NH), 8.42 (d, J = 1.8 Hz, 1H,
6
1
5

ACCEPTED MANUSCRIPT
NH), 8.17 (d, J = 8.6 Hz, 1H, Ar-H), 7.88 (d, J = 1.0 Hz, 1H, Ar-H), 7.59 (dd, J = 7.5, 1.0 Hz, 1H,
Ar-H), 7.49 (d, J = 8.6 Hz, 1H, Ar-H), 7.43 (d, J = 7.5 Hz, 1H, Ar-H), 7.41 (dd, J = 8.6, 1.8 Hz,
1
1
H, Ar-H), 7.10 (d, J = 7.5 Hz, 1H, Ar-H), 7.03 (d, J = 7.5 Hz, 1H, Ar-H), 3.45-3.35 (m, 1H),
.78-1.70 (m, 2H), 1.68-1.58 (m, 2H), 1.55-1.45 (m, 1H), 1.30-1.18 (m, 2H), 1.16-1.05 (m, 3H).
1
3
C NMR (100 MHz, DMSO-d ): δ 191.4, 154.6, 139.7, 137.8, 136.0, 131.6, 130.3, 128.5, 127.8,
6
+
1
4
5
1
26.2, 124.2, 121.3, 120.9, 115.8, 115.2, 114.9, 48.4, 33.3, 25.7, 24.9. MS (ESI): 440 (M+H , 100),
+
42 (M+H , 100). Anal calcd for C H BrN O : C, 60.01; H, 5.04; N, 9.54. Found C, 59.68; H,
2
2
22
3
2
.40; N, 9.32.
,1-Dicyclohexyl-3-(2-(5-methyl-1H-indole-3-carbonyl)phenyl)urea (4p): Yellow amorphous
1
solid. H NMR (400 MHz, CDCl ): δ 11.64 (s, 1H, NH), 9.74 (s, 1H, NH), 8.19 (s, 1H, Ar-H),
3
8
.17 (d, J = 8.3 Hz, 1H, Ar-H), 7.57 (dt, J = 1.5, 8.5 Hz, 1H, Ar-H), 7.48 (dd, J = 7.6, 1.5 Hz, 1H,
Ar-H), 7.37 (d, J = 8.3 Hz, 1H, Ar-H), 7.22 (dt, J = 1.0, 7.6 Hz, 1H, Ar-H), 7.09 (dd, J = 8.5, 1.0
Hz, 1H, Ar-H), 6.08 (d, J = 3.2 Hz, 1H, Ar-H), 3.50 (t, J = 9.9 Hz, 2H), 2.48 (s, 3H, CH3),
1
3
2
1
.00-1.85 (m, 8H), 1.77-1.63 (m, 6H), 1.48-1.25 (m, 6H). C NMR (100 MHz, CDCl ): δ 191.7,
3
55.7, 139.3, 135.5, 135.4, 132.0, 131.2, 130.7, 128.6, 127.0, 125.0, 122.4, 121.9, 121.7, 116.1,
+
1
11.7, 56.3, 31.2, 26.4, 25.5, 21.6. MS (ESI): 458 (M+H , 100). Anal calcd for C H N O : C,
29
35
3
2
7
6.12; H, 7.71; N, 9.18. Found C, 75.83; H, 7.89; N, 8.81.
N-(2-(5-Methyl-1H-indole-3-carbonyl)phenyl)piperidine-1-carboxamide
(4q):
Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 11.34 (s, 1H, NH), 10.05 (s, 1H, NH), 8.20 (dd, J
3
=
8.3, 1.0 Hz, 1H, Ar-H), 8.15 (s, 1H, Ar-H), 7.59 (dt, J = 1.5, 8.3 Hz, 1H, Ar-H), 7.51 (dd, J = 7.7,
.5 Hz, 1H, Ar-H), 7.34 (d, J = 8.3 Hz, 1H, Ar-H), 7.19 (dt, J = 1.0, 7.7 Hz, 1H, Ar-H), 7.08 (dd, J
8.3, 1.5 Hz, 1H, Ar-H), 6.19 (d, J = 3.2 Hz, 1H, Ar-H), 3.55 (s, 4H), 2.48 (s, 3H, CH ), 1.71-1.55
1
=
3
1
6

ACCEPTED MANUSCRIPT
1
3
(
m, 6H). C NMR (100 MHz, CDCl ): δ 192.0, 155.7, 139.6, 135.4, 135.3, 132.2, 131.6, 131.3,
3
1
27.9, 126.7, 125.2, 122.3, 121.8, 121.7, 116.2, 111.8, 45.0, 25.6, 24.3, 21.6. MS (ESI): 362
+
(
M+H , 100). Anal calcd for C H N O : C, 73.11; H, 6.41; N, 11.63. Found C, 73.02; H, 6.75; N,
2
2
23
3
2
11.27.
N-(2-(5-Methyl-1H-indole-3-carbonyl)phenyl)thiomorpholine-4-carboxamide (4r): Yellow
1
amorphous solid. H NMR (400 MHz, CDCl ): δ 10.80 (s, 1H, NH), 10.20 (s, 1H, NH), 8.19 (d, J
3
=
8.3 Hz, 1H, Ar-H), 8.12 (s, 1H, Ar-H), 7.59 (t, J = 7.8 Hz, 1H, Ar-H), 7.56 (d, J = 7.8 Hz, 1H,
Ar-H), 7.32 (d, J = 8.3 Hz, 1H, Ar-H), 7.20 (t, J = 7.8 Hz, 1H, Ar-H), 7.10 (d, J = 8.3 Hz, 1H,
Ar-H), 6.39 (d, J = 3.0 Hz, 1H, Ar-H), 3.89 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 4.8 Hz, 4H), 2.48 (s,
1
3
3
1
1
1
H, CH ). C NMR (100 MHz, CDCl ): δ 192.2, 155.2, 139.6, 135.2, 135.0, 132.4, 131.9, 131.4,
3 3
+
27.6, 126.7, 125.5, 122.1, 122.0, 121.7, 116.5, 111.6, 46.9, 27.1, 21.6. MS (ESI): 380 (M+H ,
00). Anal calcd for C H N O S: C, 66.47; H, 5.58; N, 11.07. Found C, 66.63; H, 5.69; N, 10.81.
2
1
21
3
2
-(2-(5-Methoxy-1H-indole-3-carbonyl)phenyl)-3-(pyridin-2-yl)urea (4s): Yellow amorphous
1
solid. H NMR (400 MHz, DMSO-d ): δ 12.28 (d, J = 2.6 Hz, 1H, NH), 11.63 (s, 1H, NH), 9.79 (s,
6
1
H, NH), 8.27 (d, J = 8.1 Hz, 1H, Ar-H), 7.99 (d, J = 3.6 Hz, 1H, Ar-H), 7.88 (d, J = 8.1 Hz, 1H,
Ar-H), 7.65 (dt, J = 8.5, 1.6 Hz, 1H, Ar-H), 7.54 (d, J = 3.6 Hz, 1H, Ar-H), 7.51 (dd, J = 7.3, 1.6
Hz, 1H, Ar-H), 7.49 (dt, J = 1.0, 8.5 Hz, 1H, Ar-H), 7.20 (t, J = 7.7 Hz, 1H, Ar-H), 7.15 (dt, J =
1
.0, 7.7 Hz, 1H, Ar-H), 7.12 (s, 1H, Ar-H), 6.88 (t, J = 7.3 Hz, 1H, Ar-H), 6.85 (d, J = 8.1 Hz, 1H,
1
3
Ar-H), 3.93 (s, 3H, OCH ). C NMR (100 MHz, DMSO-d ): δ 190.9, 153.2, 152.9, 146.8, 146.4,
3
6
1
39.0, 137.1, 135.9, 131.6, 130.7, 129.0, 127.9, 127.4, 123.5, 122.5, 122.3, 117.5, 117.3, 114.4,
+
1
12.2, 104.5, 55.9. MS (ESI): 387 (M+H , 100). Anal calcd for C H N O : C, 68.38; H, 4.70; N,
2
2
18
4
3
1
4.50. Found C, 68.17; H, 5.02; N, 14.13.
1
7

ACCEPTED MANUSCRIPT
1
1
-Benzyl-3-(2-(7-methoxy-1H-indole-3-carbonyl)phenyl)urea (4t): Yellow amorphous solid. H
NMR (400 MHz, DMSO-d ): δ 12.31 (d, J = 2.2 Hz, 1H, NH), 8.97 (s, 1H, NH), 8.16 (d, J = 8.3
6
Hz, 1H, Ar-H), 7.80 (d, J = 8.0 Hz, 1H, Ar-H), 7.69 (t, J = 5.7 Hz, 1H, NH), 7.60 (d, J = 3.2 Hz,
1
H, Ar-H), 7.58 (dd, J = 7.5, 1.4 Hz, 1H, Ar-H), 7.44 (dt, J = 1.4, 8.5 Hz, 1H, Ar-H), 7.29-7.14 (m,
H, Ar-H), 7.05 (t, J = 7.5 Hz, 1H, Ar-H), 6.85 (d, J = 7.8 Hz, 1H, Ar-H), 4.23 (d, J = 5.7 Hz, 2H),
6
1
3
3
.95 (s, 3H, OCH ). C NMR (100 MHz, DMSO-d ): δ 191.6, 155.5, 146.8, 140.5, 139.4, 135.7,
3 6
1
31.4, 130.5, 128.7, 128.5, 128.2, 127.6, 127.3, 127.1, 123.3, 121.5, 121.2, 117.0, 114.4, 104.4,
+
5
5.9, 43.3. MS (ESI): 400 (M+H , 100). Anal calcd for C H N O : C, 72.17; H, 5.30; N, 10.52.
2
4
21
3
3
Found C, 71.90; H, 5.66; N, 10.37.
1
3
-Hydroxy-3-(1H-indol-3-yl)indolin-2-one (5a): White amorphous solid. H NMR (400 MHz,
DMSO-d ): δ 10.98 (d, J = 2.5 Hz, 1H, NH), 10.34 (s, 1H, NH), 7.36 (d, J = 8.1 Hz, 1H, Ar-H),
6
7
.33 (d, J = 8.1 Hz, 1H, Ar-H), 7.26 (d, J = 8.4 Hz, 1H, Ar-H), 7.24 (d, J = 7.5 Hz, 1H, Ar-H), 7.07
(d, J = 2.5 Hz, 1H, Ar-H), 7.03 (dt, J = 1.0, 8.1 Hz, 1H, Ar-H), 6.95 (dt, J = 1.0, 7.5 Hz, 1H, Ar-H),
1
3
6
.90 (d, J = 7.5 Hz, 1H, Ar-H), 6.87 (dt, J = 1.0, 8.1 Hz, 1H, Ar-H), 6.36 (s, 1H, OH). C NMR
(
100 MHz, DMSO-d ): δ 178.9, 142.1, 137.3, 133.9, 129.5, 125.4, 125.2, 124.0, 122.1, 121.5,
6
+
1
20.8, 118.9, 115.9, 111.9, 110.1, 75.4. MS (ESI): 265 (M+H , 100).
1
3
-Hydroxy-3-(5-methyl-1H-indol-3-yl)indolin-2-one (5b): White amorphous solid. H NMR
(
400 MHz, DMSO-d ): δ 10.84 (d, J = 2.0 Hz, 1H, NH), 10.32 (s, 1H, NH), 7.26-7.21 (m, 4H,
6
Ar-H), 6.98 (d, J = 2.0 Hz, 1H, Ar-H), 6.96 (dt, J = 1.0, 7.6 Hz, 1H, Ar-H), 6.90 (dd, J = 8.3, 1.0
1
3
Hz, 1H, Ar-H), 6.87 (dd, J = 8.3, 1.5 Hz, 1H, Ar-H), 6.32 (s, 1H, OH), 2.28 (s, 3H, CH3).
C
NMR (100 MHz, DMSO-d ): δ 179.0, 142.1, 135.7, 134.0, 129.4, 127.1, 125.7, 125.2, 124.0,
6
+
1
23.1, 122.1, 120.6, 115.4, 111.6, 110.0, 75.4, 21.9. MS (ESI): 279 (M+H , 100).
1
8

ACCEPTED MANUSCRIPT
Acknowledgments
The authors are grateful to the National Natural Science Foundation of China (No: 21462002),
Natural Science Foundation of Jiangxi Province (No: 20161BAB203096) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.
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