Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed regioselective cross-coupling reaction and cyclization

Article abstract of DOI:10.1016/j.tet.2007.12.003

An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 via palladium-catalyzed site-selective cross-coupling reaction and cyclization process was described. Reaction of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with arylboronic acid catalyzed by PdCl₂(PPh₃)₂ afforded 3-bromo-4-aryl-quinolin-2(1H)-one 4, which then reacted with 2-ethynylaniline 5 via Pd-catalyzed Sonogashira coupling and CuI-mediated cyclization leading to the desired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good yields.

Full text of DOI:10.1016/j.tet.2007.12.003

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1736e1742
www.elsevier.com/locate/tet
Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed
regioselective cross-coupling reaction and cyclization
Zhiyong Wang a, Jie Wu a,b,
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 8 October 2007; received in revised form 30 November 2007; accepted 3 December 2007
Available online 8 December 2007
Abstract
An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 via palladium-catalyzed site-selective cross-
coupling reaction and cyclization process was described. Reaction of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with arylboronic acid catalyzed
by PdCl2(PPh3)2 afforded 3-bromo-4-aryl-quinolin-2(1H)-one 4, which then reacted with 2-ethynylaniline 5 via Pd-catalyzed Sonogashira
coupling and CuI-mediated cyclization leading to the desired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: 1H-Indole-2-yl-(4-aryl)-quinolin-2(1H)-one; Palladium; Regioselective cross-coupling; Cyclization
1. Introduction
A number of analogues of this class of heterocyclic structure
have been reported as lead compounds or are currently under-
going clinical trials. In connection with a chemical genetic
approach of analyzing biological systems by using interfacing
libraries of natural product-like molecules with biological as-
says,1 we became interested in developing new approaches for
the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1.
Several different strategies have been utilized for the con-
struction of 1H-indol-2-yl-quinolin-2(1H)-one scaffold 1,
which include Fisher indole reaction, reductive cyclization,
as well as palladium-catalyzed Suzuki-coupling and amination
reactions.3 For example, most recently, Lautens et al.3a utilized
the Pd-catalyzed tandem CeN and CeC coupling reactions
using gem-dibromovinylaniline substrates with boronic acid
for the synthesis of four potent KDR kinase inhibitors
For chemistry to have its maximal effect on biology, effi-
cient methods for discovering natural product-like compounds
are in great demand in the field of chemical genetics.1 Since
KDR (kinase insert domain-containing receptor) is one of
the human tyrosine kinases that has a high affinity for vascular
endothelial growth factor (VEGF) and is believed to be a pri-
mary mediator of tumor-induced angiogenesis,2 compounds,
which inhibit or regulate the KDR kinase have attracted
much attention and are of great interest as potential therapeutic
agents. Recently, Merck reported a class of potent KDR kinase
inhibitors containing the 1H-indol-2-yl-quinolin-2(1H)-one
core structure, such as compound A, which has been utilized
for clinical development for cancer therapy (Fig. 1). There-
fore, synthesis of analogues with 1H-indol-2-yl-quinolin-
2(1H)-one core has received considerable attention in the
last 5 years.3 Meanwhile, in recent years, an increasing interest
in the synthesis of functionalized 4-aryl-quinolin-2(1H)-ones
with promising biological properties has been observed.4
R3
N
R1
N
H
N
H
R2
N
Ms
O
N
H
O
N
H
A
1
KDR IC50 = 5 nM
* Corresponding author. Tel.: þ86 2155664619; fax: þ86 2165102412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
Figure 1.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.003

Z. Wang, J. Wu / Tetrahedron 64 (2008) 1736e1742
1737
OH
R3
R4
R1
O
R3
R1
N
CH3
O
R2
M
N
N
H
N
R4
Cyclization
R2
2
O
6
1
OMe
1. NBS, Mg(ClO4)2
2. Tf2O, Et3N
NH2
92%
[Pd]/[Cu]
B(OH)2
OTf
R1
O
R3
R3
TfO
Br
O
Br
MeO
Br
Br
Pd-catalyzed selective
cross-coupling reaction
+
R2
PdCl2(PPh3)2 (5 mol%)
THF / H2O, Na2CO3
88%
N
N
CH3
O
N
N
R4
R4
NH2
CH3
4a
O
4
5
3
3
Scheme 2.
OH
R3
4-trifloxy group attached to the electron-withdrawing a,b-un-
saturated double bond in compound 3 may increase its
capability to oxidative addition to the transition metals. There-
fore, the regioselective cross-couplings of 3 catalyzed by tran-
sition metal are possible. Due to their easy handling and long
shelf life, arylboronic acid derivatives would be the starting
materials of choice. Therefore, we started to explore the pos-
sibility of using 3 as an electrophile for the SuzukieMiyaura
reaction.7 To our delight, we found that the corresponding
product 4a could be afforded in 88% yield under standard con-
ditions [PdCl2(PPh3)2, THF/H2O, Na2CO3] for the reaction of
3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with 4-methoxyphe-
nylboronic acid (Scheme 2). With this compound in hand,
we started to investigate further the indole formation at 3-
position via transition metal catalyzed cyclization reaction. It
is well-known that the transition metal catalyzed cyclization
of alkynes possessing a nucleophile in proximity to the triple
bond is an important process in organic synthesis, which can
construct various heterocycles in an efficient and atom-
economic way.8e13 Over the past few years, the intramolecular
annulations of amines,8 amides,9 imines,10 carboxylic acids,11
alcohols,12 and phosphonic acid derivatives13 to a triple bond
have been extensively investigated using transition-metal re-
agents as effective catalysts. Compound 5, prepared via Sono-
gashira coupling from the reaction of 2-iodoaniline with
trimethylsilylacetylene, was employed in the reaction of com-
pound 4a in the presence of PdCl2(PPh3)2 (10 mol %), CuI
(10 mol %), and DIPEA in CH3CN at 50 ꢀC. However, no
product was detected under this condition. Further screening
revealed that the reaction proceeded smoothly in the presence
of PdCl2 (5 mol %), CuI (5 mol %), and PPh3 (10 mol %) in
Et3N at 50 ꢀC to afford the desired product 6a in 89% yield.
Subsequently, mediated by CuI in DMF, the final cyclization
was performed to generate the corresponding 1H-indol-2-yl-
(4-aryl)-quinolin-2(1H)-one 1a in 95% yield (Scheme 3).
We also tested the one-pot reaction of 3-bromo-4-(4-
methoxyphenyl)-quinolin-2(1H)-one 4a with acetylene 5.
The operation is simple: after completion of the reaction of
3-bromo-4-(4-methoxyphenyl)-quinolin-2(1H)-one 4a with
acetylene 5 as indicated by TLC, CuI (1.0 equiv) was added
directly in the reaction mixture and the mixture was stirred
N
O
R4
2
Scheme 1.
containing an 1H-indol-2-yl-quinolin-2(1H)-one structure.
Payack et al.3d reported the synthesis of 3-[5-[[4-(methylsul-
fonyl)-1-piperazinyl]methyl]-1H-indol-2-yl]quinolin-2(1H)-one
via a noncryogenic indole boronation and a dicyclohexyl-
amine-mediated Suzuki coupling. Kuethe et al.3c demonstrated
the reductive cyclization approach to be an efficient and high-
yielding method for the construction of the target substrate A
via six steps. All these procedures, however, were not easy to
introduce diversity in the overall synthetic scheme and suf-
fered from multisteps in each case. Especially, the preparation
of analogues, e.g., varying the aryl group at C4 of quinolin-
2(1H)-one, is a cumbersome and lengthy process. In this pa-
per, we describe a novel and flexible synthetic protocol for
the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones
utilizing palladium-catalyzed site-selective cross-coupling re-
actions and cyclization process (Scheme 1).
The key compound in our overall synthetic route was iden-
tified as 3-bromo-4-trifloxy-quinolin-2(1H)-one 3. Prompted
by the recent advances of halogenation of 1,3-dicarbonyl com-
pounds,5 we envisioned that this compound could be generated
by treatment of 4-hydroxyquinolin-2(1H)-one 2 with NBS/
Mg(ClO4)2 and trifluoromethanesulfonic anhydride, subse-
quently. It is well known that 4-hydroxyquinolin-2(1H)-ones
2 are useful intermediates for many industrial products and
several methods for their preparation have been reported.6
To verify the practicability of the projected route as shown
in Scheme 1, an initial model study was performed using the
commercially available 4-hydroxyquinolin-2(1H)-one 2 as
the starting material (Scheme 2).
2. Results and discussion
As described above, 3-bromo-4-trifloxy-quinolin-2(1H)-
one 3 was easily synthesized in high yield (92%) in two steps
from 4-hydroxy-quinolin-2(1H)-one 2. We conceived that the

1738
Z. Wang, J. Wu / Tetrahedron 64 (2008) 1736e1742
1. PdCl2(PPh3)2 (2 mol%)
screening for biological activity of these small molecules are
under investigation in our laboratory.
I
CuI (2 mol%), Et2NH
+
TMS
2. TBAF
90%
NH2
NH2
5
4. Experimental section
OMe
OMe
4.1. General
PdCl2 (5 mol%)
PPh3 (10 mol%)
CuI (5 mol%)
Br
NH2
All the reactions were performed in test tubes under air at-
mosphere at room temperature. Flash column chromatography
was performed as described by Still et al. using silica gel (60-
NH2
+
Et3N, 50 °C
89%
N
O
N
CH3
O
CH3
4a
6a
˚
A pore size, 32e63 mm, standard grade). Analytical thin-layer
5
CuI (1.0 equiv.)
DMF, 160 °C
chromatography was performed using glass plates pre-coated
with 0.25 mm 230e400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatographic
plates were visualized by exposure to ultraviolet light. Organic
95%
one-pot
OMe
79%
1. PdCl2 (5 mol%), PPh3 (10 mol%)
CuI (5 mol%), Et3N, DMF, 50 °C
2. CuI (1.0 equiv.), 160 °C
solutions were concentrated on Buchi R-200 rotary evapora-
¨
tors at w20 Torr (house vacuum) at 25e35 ꢀC. Commercial
reagents and solvents were used as-received. Proton nuclear
magnetic resonance (1H NMR) spectra were recorded in parts
per million from internal tetramethylsilane on the d scale and
are referenced from the residual protium in the NMR solvent
(CHCl3: d 7.27).
N
H
N
CH3
O
1a
Scheme 3.
at 160 ꢀC for another 1 h. Gratifyingly, the reaction also pro-
ceeded well to generate the product 1a in 79% yield. With
this promising result in hand, to demonstrate the generality
of this method, we next investigated the scope of this one-
pot reaction under the conditions shown in Scheme 3 and
the results are summarized in Table 1.
4.2. General procedure for the preparation of compounds 4
through cross-coupling reaction between 3-bromo-4-trifloxy-
quinolin-2(1H)-one and arylboronic acids
Potassium carbonate (2.0 M in water, 0.75 mL) was added
to a solution of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3
(192.5 mg, 0.50 mmol), PdCl2(PPh3)2 (17.5 mg, 0.025 mmol),
and boronic acid (1.1 equiv) in THF (4 mL) under nitrogen at-
mosphere. The reaction mixture was stirred overnight at room
temperature. After completion of the reaction as monitored
by TLC, the reaction mixture was diluted with ethyl acetate
(20 mL) and separated. The solution was dried and filtered,
and the filtrate was concentrated to a residue that was purified
by flash chromatography (silica gel, 2/1 (v/v) petroleum
ether/ethyl acetate) to give the corresponding product 4.
This condition was proved to be useful for one-pot synthe-
sis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 (Table 1).
Starting from 3-bromo-4-triflate-quinolin-2(1H)-one 3, various
aryl groups could be easily introduced at the 4-position of qui-
nolin-2(1H)-one scaffold in good to excellent yields via
SuzukieMiyaura coupling reaction. The subsequent one-pot
cyclization by Sonogashira coupling of vinyl bromide 4 and
CuI-mediated reaction also proceeded well to generate the de-
sired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good
yields. The reaction was found to be tolerable to a range of dif-
ferent aryl groups at 4-position with different electronic de-
mands on aromatic rings involving electron-donating and
electron-withdrawing groups. For instance, 3-bromo-4-(2-me-
thoxyphenyl)-quinolin-2(1H)-one 4b and acetylene 5 reacted
under the conditions leading to the corresponding 1H-indol-
2-yl-(4-(2-methoxyphenyl))-quinolin-2(1H)-one 1b in 65%
yield (entry 2) while the reaction of 3-bromo-4-(4-cyano-
phenyl)-quinolin-2(1H)-one 4f and acetylene 5 afforded prod-
uct 1f in 80% yield (entry 6).
4.2.1. 3-Bromo-4-(4-methoxyphenyl)-1-methylquinolin-
2(1H)-one (4a)14
1
Yield 88%. H NMR (500 MHz, CDCl3): d (ppm) 7.60 (t,
J¼7.5 Hz, 1H), 7.43 (d, J¼8.5 Hz, 1H), 7.20e7.28 (m, 3H),
7.14 (t, J¼7.5 Hz, 1H), 7.07 (d, J¼8.0 Hz, 2H), 3.91 (s, 3H),
3.89 (s, 3H). 13C NMR (125 MHz, CDCl3): d (ppm) 159.9,
158.7, 150.6, 139.1, 131.0, 130.2, 129.8, 128.8, 122.7, 121.9,
119.8, 114.5, 114.3, 55.6, 31.5. MS (ESI): m/z 344.0 (Mþþ1).
4.2.2. 3-Bromo-4-(2-methoxyphenyl)-1-methylquinolin-
2(1H)-one (4b)14
3. Conclusions
Yield 85%. 1H NMR (500 MHz, CDCl3): d (ppm)
7.56e7.61 (m, 1H), 7.48e7.52 (m, 1H), 7.43 (d, J¼8.0 Hz,
1H), 7.07e7.17 (m, 5H), 3.89 (s, 3H), 3.74 (s, 3H). 13C
NMR (125 MHz, CDCl3): d (ppm) 159.6, 156.4, 148.4,
139.1, 131.1, 130.8, 130.6, 130.1, 128.2, 126.5, 122.7,
121.1, 120.2, 114.5, 111.7, 56.0, 31.4. MS (ESI): m/z 344.0
(Mþþ1).
In summary, we have described an efficient and novel route
for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one
1 via palladium catalyzed regioselective cross-coupling reac-
tion and cyclization process, starting from 4-hydroxyquino-
lin-2(1H)-one. Introducing more diversity in the scaffold and

Z. Wang, J. Wu / Tetrahedron 64 (2008) 1736e1742
Table 1 (continued)
1739
Table 1
Synthesis of 1H-indol-2-yl-quinolin-2(1H)-one 1 via Pd-catalyzed selective
cross-coupling reaction and CuI-mediated cyclization
Entry
Product 4
Yielda
(%)
Product 1
Yieldb
(%)
OTf
R
CF3
CF3
Br
O
Br
O
PdCl2(PPh3)2 (5 mol%)
RB(OH)2, THF/H2O
Na2CO3
N
CH3
N
CH3
Br
O
N
3
4
5
85
H
68
N
N
O
CH3
CH3
PdCl2 (5 mol%)
CuI (5 mol%), Et3N
DMF, 50 °C
4e
1e
NH2
R
5
CN
CN
R
CuI (1.0 equiv.)
160 °C
N
H
NH2
Br
N
H
N
CH3
O
6
70
80
N
CH3
O
N
O
O
N
CH3
CH3
1
6
1f
4f
Entry
Product 4
Yielda
(%)
Product 1
Yieldb
(%)
CN
CN
OMe
OMe
Br
O
N
H
7
73
78
N
N
O
CH3
CH3
Br
N
H
1
88
79
4g
1g
N
O
N
O
CH3
CH3
COCH3
COCH3
N
4a
1a
Br
O
8
75
74
MeO
MeO
H
N
CH3
N
CH3
O
Br
O
N
H
4h
2
85
65
1h
N
N
O
CH3
CH3
a
Isolated yield based on compound 3.
Isolated yield based on compound 4.
b
4b
1b
4.2.3. 3-Bromo-1-methyl-4-phenylquinolin-2(1H)-one (4c)14
Yield 87%. 1H NMR (500 MHz, CDCl3): d (ppm)
7.58e7.63 (m, 1H), 7.49e7.58 (m, 3H), 7.44 (d, J¼8.5 Hz,
1H), 7.26e7.30 (m, 2H), 7.10e7.20 (m, 2H), 3.90 (s, 3H).
13C NMR (125 MHz, CDCl3): d (ppm) 158.6, 150.8, 139.1,
137.6, 131.0, 130.1, 128.8, 128.2, 127.7, 122.7, 121.6,
119.4, 114.5, 31.5. MS (ESI): m/z 314.0 (Mþþ1).
Br
O
N
H
3
87
77
N
CH3
O
N
CH3
4c
1c
CF3
CF3
4.2.4. 3-Bromo-1-methyl-4-(4-trifluoromethyl)-
phenyl)quinolin-2(1H)-one (4d)
1
Yield 90%. H NMR (400 MHz, CDCl3): d (ppm) 7.81 (d,
Br
O
J¼8.0 Hz, 2H), 7.62 (t, J¼7.3 Hz, 1H), 7.46e7.41 (m, 3H),
7.15 (t, J¼7.3 Hz, 1H), 7.06 (d, J¼7.8 Hz, 1H), 3.90 (s, 3H).
13C NMR (100 MHz, CDCl3): d (ppm) 158.0, 149.0, 140.8,
138.8, 131.1, 129.1, 127.8, 125.8, 125.7, 122.7, 120.7,
119.1, 114.4, 31.2. MS (ESI): m/z 404.0 (MþþNa). Anal.
Calcd for C17H11BrF3NO: C, 53.43; H, 2.90; N, 3.67. Found:
C, 53.34; H, 2.95; N, 3.62.
N
H
4
90
75
N
CH3
O
N
CH3
4d
1d
(continued)

1740
Z. Wang, J. Wu / Tetrahedron 64 (2008) 1736e1742
4.2.5. 3-Bromo-1-methyl-4-(3-(trifluoromethyl)phenyl)-
dried over MgSO4, and concentrated in vacuo. Purification
by flash column chromatography (silica gel, 2/1 (v/v) petro-
leum ether/ethyl acetate) gave the desired product 1.
quinolin-2(1H)-one (4e)14
1
Yield 85%. H NMR (500 MHz, CDCl3): d (ppm) 7.78 (d,
J¼8.0 Hz, 1H), 7.69 (t, J¼7.5 Hz, 1H), 7.60e7.63 (m, 1H),
7.56 (s, 1H), 7.45e7.50 (m, 2H), 7.16 (t, J¼7.5 Hz, 1H),
7.07 (d, J¼8.5 Hz, 1H), 3.90 (s, 3H). 13C NMR (125 MHz,
CDCl3): d (ppm) 158.4, 149.1, 139.2, 138.3, 132.4, 131.7,
131.4, 129.6, 128.1, 125.8, 125.7, 125.1, 123.0, 121.1, 119.7,
114.8, 31.6. MS (ESI): m/z 382.0 (Mþþ1).
4.3.1. 3-(1H-Indol-2-yl)-4-(4-methoxyphenyl)-1-
methylquinolin-2(1H)-one (1a)
1
Yield 79%. H NMR (400 MHz, CDCl3) d (ppm) 11.49 (s,
1H), 7.54 (t, J¼8.3 Hz, 1H), 7.43 (d, J¼8.3 Hz, 1H), 7.35 (t,
J¼7.8 Hz, 2H), 7.27e7.24 (m, 1H), 7.19e7.076 (m, 6H), 6.97
(t, J¼7.8 Hz, 1H), 5.51 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H). 13
C
4.2.6. 4-(3-Bromo-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)-
benzonitrile (4f)
NMR (125 MHz, CDCl3) d (ppm) 162.3, 159.7, 146.5, 138.2,
135.0, 133.3, 130.3, 130.1, 129.9, 128.6, 127.4, 122.5, 122.3,
122.2, 120.7, 120.5, 119.3, 114.9, 113.9, 111.2, 106.4, 55.3,
30.3. MS (ESI): m/z 403.2 (MþþNa). Anal. Calcd for
C25H20N2O2: C, 78.93; H, 5.30; N, 7.36. Found: C, 78.91;
H, 5.40; N, 7.15.
1
Yield 70%. H NMR (400 MHz, CDCl3): d (ppm) 7.86 (d,
J¼7.8 Hz, 2H), 7.64 (t, J¼7.8 Hz, 1H), 7.46 (d, J¼8.3 Hz,
1H), 7.42 (d, J¼8.2 Hz, 2H), 7.16 (t, J¼8.2 Hz, 1H), 7.02 (d,
J¼8.2 Hz, 1H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3):
d (ppm) 157.9, 148.4, 141.8, 138.9, 132.6, 131.2, 129.6,
127.6, 122.8, 120.4, 119.0, 118.3, 114.6, 112.7, 31.3.
MS (ESI): m/z 361.0 (MþþNa). Anal. Calcd for
C17H11BrN2O: C, 60.20; H, 3.27; N, 8.26. Found: C, 60.04;
H, 3.45; N, 8.01.
4.3.2. 3-(1H-Indol-2-yl)-4-(2-methoxyphenyl)-1-
methylquinolin-2(1H)-one (1b)
1
Yield 65%. H NMR (400 MHz, CDCl3) d (ppm) 11.53 (s,
1H), 7.56e7.51 (m, 2H), 7.44e7.31 (m, 2H), 7.19e6.93 (m,
8H), 7.04e6.96 (m, 2H), 5.55 (s, 1H), 3.89 (s, 3H), 3.60 (s,
3H). 13C NMR (100 MHz, CDCl3) d (ppm) 162.3, 156.7,
143.9, 138.1, 135.0, 133.4, 130.3, 130.2, 130.0, 128.0, 127.5,
126.5, 122.4, 122.1, 121.9, 121.8, 120.9, 120.4, 119.2, 113.9,
111.8, 111.2, 105.1, 55.8, 30.3. MS (ESI): m/z 403.2
(MþþNa). Anal. Calcd for C25H20N2O2: C, 78.93; H, 5.30;
N, 7.36. Found: C, 78.56; H, 5.32; N, 7.04.
4.2.7. 3-(3-Bromo-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)-
benzonitrile (4g)14
1
Yield 73%. H NMR (500 MHz, CDCl3): d (ppm) 7.82 (d,
J¼7.5 Hz, 1H), 7.59e7.71 (m, 3H), 7.53 (d, J¼7.5 Hz, 1H),
7.47 (d, J¼8.5 Hz, 1H), 7.16 (t, J¼7.5 Hz, 1H), 7.03 (d,
J¼8.0 Hz, 1H), 3.90 (s, 3H). 13C NMR (125 MHz, CDCl3):
d (ppm) 158.2, 148.2, 139.2, 138.8, 133.5, 132.6, 132.5,
131.5, 130.1, 127.9, 123.1, 120.9, 119.9, 118.4, 114.9, 113.5,
31.6. MS (ESI): m/z 339.0 (Mþþ1).
4.3.3. 3-(1H-Indol-2-yl)-1-methyl-4-phenylquinolin-2(1H)-
one (1c)
1
Yield 77%. H NMR (400 MHz, CDCl3) d (ppm) 11.50 (s,
4.2.8. 4-(3-Acetylphenyl)-3-bromo-1-methylquinolin-2(1H)-
one (4h)
1H), 7.86e7.83 (m, 1H), 7.55e7.51 (m, 4H), 7.45e7.19 (m,
6H), 7.14e7.08 (m, 2H), 6.95 (t, J¼7.3 Hz, 1H), 5.41 (s,
1H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3) d (ppm)
162.1, 146.5, 138.1, 137.7, 134.9, 133.0, 130.2, 129.4, 129.0,
128.5, 128.4, 127.3, 122.4, 122.3, 122.1, 120.4, 120.3, 119.3,
113.9, 111.2, 106.4, 30.3. MS (ESI): m/z 373.2 (MþþNa).
Anal. Calcd for C24H18N2O: C, 82.26; H, 5.18; N, 7.99.
Found: C, 82.66; H, 4.94; N, 7.80.
Yield 75%. 1H NMR (400 MHz, CDCl3): d (ppm)
8.11e8.09 (m, 1H), 7.89e7.88 (m, 1H), 7.69e7.51 (m, 2H),
7.50e7.45 (m, 2H), 7.14e7.10 (m, 2H), 3.89 (s, 3H), 2.65
(s, 3H). 13C NMR (100 MHz, CDCl3): d (ppm) 197.2, 157.9,
149.2, 138.7, 137.6, 137.3, 133.1, 130.9, 129.0, 128.3, 127.8,
123.1, 120.7, 119.1, 114.3, 31.1, 26.6. MS (ESI): m/z 375.0
(MþþNa). Anal. Calcd for C18H14BrNO2: C, 60.69; H, 3.96;
N, 3.93. Found: C, 60.92; H, 3.99; N, 3.72.
4.3.4. 3-(1H-Indol-2-yl)-1-methyl-4-(4-(trifluoromethyl)-
phenyl)quinolin-2(1H)-one (1d)
1
Yield 75%. H NMR (400 MHz, CDCl3) d (ppm) 11.40 (s,
4.3. General procedure for the synthesis of 1H-indol-2-yl-(4-
aryl)-quinolin-2(1H)-one 1 via Pd-catalyzed Sonogashira
coupling and CuI-mediated cyclization
1H), 7.82 (d, J¼8.2 Hz, 2H), 7.57e7.55 (m, 1H), 7.46e7.28
(m, 5H), 7.17e6.95 (m, 4H), 5.35 (s, 1H), 3.89 (s, 3H). 13C
NMR (100 MHz, CDCl3) d (ppm) 161.9, 144.7, 141.6,
138.2, 135.1, 132.5, 130.8, 130.5, 129.8, 127.9, 127.2, 126.5,
126.4, 122.7, 122.6, 121.5, 120.6, 120.5, 119.5, 114.1, 111.2,
106.6, 30.4. MS (ESI): m/z 441.1 (MþþNa). Anal. Calcd for
C25H17F3N2O: C, 71.76; H, 4.10; N, 6.70. Found: C, 71.30;
H, 4.17; N, 6.46.
2-Ethynylaniline (35.1 mg, 0.3 mmol) was added to a mix-
ture of 4 (0.2 mmol), PdCl2(PPh3)2 (7 mg, 0.01 mmol), CuI
(1.9 mg, 0.01 mmol), and triethylamine (60.6 mg, 0.6 mmol)
in DMF (2 mL) under nitrogen atmosphere. The reaction mix-
ture was stirred at 50 ꢀC overnight. After completion of
the reaction as indicated by TLC, CuI (38.2 mg, 0.2 mmol)
was added to the reaction mixture. After stirring at 160 ꢀC
for additional 1 h, the mixture was poured into water (5 mL)
and extracted with ethyl acetate (3ꢁ5 mL). The organic layer
was washed with water (2ꢁ10 mL) and brine (2ꢁ10 mL),
4.3.5. 3-(1H-Indol-2-yl)-1-methyl-4-(3-(trifluoromethyl)-
phenyl)-quinolin-2(1H)-one (1e)
1
Yield 68%. H NMR (400 MHz, CDCl3) d (ppm) 11.45 (s,
1H), 7.61e7.56 (m, 2H), 7.48e7.11 (m, 9H), 6.97 (t, J¼

Z. Wang, J. Wu / Tetrahedron 64 (2008) 1736e1742
1741
8.0 Hz, 1H), 5.40 (s, 1H), 3.91 (s, 3H). 13C NMR (100 MHz,
CDCl3) d (ppm) 161.9, 150.0, 144.4, 139.7, 138.2, 135.1,
132.5, 131.1, 130.0, 128.0, 127.7, 127.3, 122.7, 122.6, 122.1,
121.6, 120.9, 120.5, 119.5, 114.1, 111.2, 106.6, 30.4. MS
(ESI): m/z 457.1 (MþþK). Anal. Calcd for C25H17F3N2O: C,
71.76; H, 4.10; N, 6.70. Found: C, 71.81; H, 4.28; N, 6.40.
2. (a) Yancopoulos, G. D.; Davis, S.; Gale, N. W.; Rudge, J. S.; Wiegand,
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4.3.6. 4-(3-(1H-Indol-2-yl)-1-methyl-2-oxo-1,2-
dihydroquinolin-4-yl)benzonitrile (1f)
1
Yield 80%. H NMR (400 MHz, CDCl3) d (ppm) 11.35 (s,
1H), 7.83 (d, J¼7.8 Hz, 2H), 7.58 (t, J¼7.7 Hz, 1H), 7.47e
7.6.96 (m, 9H), 5.35 (s, 1H), 3.88 (s, 3H). 13C NMR
(100 MHz, CDCl3) d (ppm) 161.7, 144.1, 142.8, 138.2, 135.1,
133.1, 132.2, 130.6, 130.4, 127.6, 127.1, 122.8, 122.7, 121.0,
120.6, 120.5, 119.7, 118.4, 114.2, 112.4, 111.3, 106.7, 30.4.
MS (ESI): m/z 398.2 (MþþNa). Anal. Calcd for
C25H17N3O: C, 79.88; H, 4.56; N, 11.19. Found: C, 79.47;
H, 4.59; N, 10.95.
4.3.7. 3-(3-(1H-Indol-2-yl)-1-methyl-2-oxo-1,2-
dihydroquinolin-4-yl)benzonitrile (1g)
1
Yield 78%. H NMR (400 MHz, CDCl3) d (ppm) 11.40 (s,
1H), 7.86e7.83 (m, 1H), 7.67e7.45 (m, 5H), 7.37 (d,
J¼8.2 Hz, 1H), 7.30 (d, J¼8.2 Hz, 1H), 7.16e7.11 (m, 2H),
7.04e6.96 (m, 2H), 5.30 (s, 1H), 3.89 (s, 3H). 13C NMR
(100 MHz, CDCl3) d (ppm) 161.7, 143.5, 139.2, 138.2,
135.1, 134.0, 132.9, 132.3, 132.2, 130.6, 130.4, 127.6,
127.2, 122.8, 122.7, 121.3, 120.9, 120.5, 119.7, 118.2,
114.3, 113.7, 111.3, 106.7, 30.4. MS (ESI): m/z 398.2
(MþþNa). Anal. Calcd for C25H17N3O: C, 79.88; H, 4.56;
N, 11.19. Found: C, 79.51; H, 4.24; N, 10.73.
4.3.8. 4-(3-Acetylphenyl)-3-(1H-indol-2-yl)-1-
methylquinolin-2(1H)-one (1h)
1
Yield 74%. H NMR (400 MHz, CDCl3) d (ppm) 11.50 (s,
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1H), 8.15 (d, J¼8.0 Hz, 1H), 7.91 (s, 1H), 7.68e7.24 (m, 6H),
7.14e7.09 (m, 3H), 6.95 (t, J¼8.0 Hz, 1H), 5.34 (s, 1H), 3.91
(s, 3H), 2.60 (s, 3H). 13C NMR (100 MHz, CDCl3) d (ppm)
197.5, 162.0, 145.2, 138.3, 138.2, 138.1, 135.1, 134.0, 132.8,
130.4, 129.9, 129.2, 128.3, 128.1, 127.2, 122.6, 122.5, 121.8,
120.6, 120.4, 119.5, 114.1, 111.2, 106.6, 30.4, 26.7. MS (ESI):
m/z 415.2 (MþþNa). Anal. Calcd for C26H20N2O2: C, 79.57;
H, 5.14; N, 7.14. Found: C, 79.61; H, 4.87; N, 6.85.
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Acknowledgements
We thank Dr. Renhua Fan for his invaluable advice during the
course of this research. Financial support from National Natural
Science Foundation of China (20772018), Program for New
Century Excellent Talents in University (NCET-07-0208), and
Shanghai Pujiang Program is gratefully acknowledged.
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