Copper(I) iodide catalyzed synthesis of quinolinones via cascade reactions of 2-halobenzocarbonyls with 2-arylacetamides

Article abstract of DOI:10.1055/s-0030-1259983

An efficient copper-catalyzed method for the synthesis of quinolinones, pyridinones, and heteroannulated pyridinones via cascade reactions of substituted 2-iodo-, 2-bromo-, and 2-chlorobenzocarbonyls with 2-arylacetamides is reported. The protocol works well for the reaction of most of the 2-iodo-, 2-bromo- and 2-chlorobenzocarbonyls with 2-arylacetamides. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259983

PAPER
1547
Copper(I) Iodide Catalyzed Synthesis of Quinolinones via Cascade Reactions
of 2-Halobenzocarbonyls with 2-Arylacetamides
Synthesis of
Q
u
i
inolino
a
nes ngbing Fu,a,b,1 Xiaoli Huang,a,b,1 Deping Wang,a,b Pinghua Zhao,c Ke Ding*a
a
Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences,
No. 190 Kai Yuan Road, Science Park, Guangzhou 510530, P. R. of China
Fax +86(20)32015299; E-mail: ding_ke@gibh.ac.cn
b
c
Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, No. 19 A Yuquan Road, Shijingshan District,
Beijing 100049, P. R. of China
GAC ChangFeng Motor Co. Ltd, YongZhou Branch, No. 68 Liebao North Road, Lengshuitan, Yongzhou, Hunan 425100, P. R. of China
Received 13 February 2011; revised 10 March 2011
indicating that copper catalyst was essential for this cas-
cade reaction. Further investigation revealed that the well-
known supporting ligands such as L-proline, 1,10-phenan-
throline, or diamine compounds such as N,N¢-dimethyl-
Abstract: An efficient copper-catalyzed method for the synthesis
of quinolinones, pyridinones, and heteroannulated pyridinones via
cascade reactions of substituted 2-iodo-, 2-bromo-, and 2-chlo-
robenzocarbonyls with 2-arylacetamides is reported. The protocol
works well for the reaction of most of the 2-iodo-, 2-bromo- and 2- ethylenediamine (DMEDA), cyclohexane-1,2-diamine,
chlorobenzocarbonyls with 2-arylacetamides.
ethylenediamine (EDA), (1R,2R)-1,2-diphenylethane-
1,2-diamine, and benzene-1,2-diamine could significantly
improve the reaction efficiency (Table 1, entries 3–9).
When 10 mol% of ethylenediamine was utilized, about
90% of the desired product was isolated after the reaction
was performed at 110 °C for 24 hours (Table 1, entry 7).
Further screening conditions suggested that other com-
mon inorganic bases such as potassium carbonate or po-
tassium phosphate was also efficient for the cascade
reactions (Table 1, entries 10 and 11). Investigation on the
reaction medium revealed that toluene was the optimal
solvent for this new reaction, while polar solvent N,N-
dimethylformamide was highly detrimental (Table 1, en-
try 13). The combination of 10% copper(I) iodide, 20%
ethylenediamine, and 300% cesium carbonate in toluene
at 110 °C was chosen as the optimal condition for further
investigations.
Key words: copper iodide, diamines, cascade reactions, amidation,
quinolinones
Quinolinones, pyridinones, and heteroannulated pyridi-
nones, represent an important class of motifs in natural
products2 and biologically active compounds3 as well as
valuable intermediates in organic synthesis.4 The synthe-
sis of this class of compounds has attracted huge efforts
and a number of methods have been discovered, such as
Knorr synthesis, cyclization/rearrangement, tandem Ugi–
Knoevenagel condensations, intramolecular Friedel–
Crafts reaction of N-arylamides, and microwave-assisted
methods.5 In recent years, palladium-catalyzed coupling
reactions have been utilized in the construction of these
kinds of compounds with great success.5,6 Copper-cata-
lyzed synthesis of these compounds was also reported
with limited success.5a In continuation of our interest in
copper-catalyzed coupling reactions7 and to meet our
need of quinolinones, pyridinones, and heteroannulated
pyridinones for random biological screening, we report
here an economic and efficient diamine-promoted copper-
catalyzed process for this class of compounds via cascade
amidation/dehydrative cyclization reactions of substituted
2-iodo-, 2-bromo-, and 2-chlorobenzocarbonyls with 2-
arylacetamides.
Under the optimized conditions, the scope of this new pro-
tocol was further explored by using the combinations of 2-
phenylacetamide with a variety of 2-halobenzocarbonyls.
As shown in Table 2, most of the substrates examined af-
forded the desired products in good to excellent yields.
Aryl iodides exhibited superior reactivity than the aryl
bromide substrates (Table 2, entries 1 and 10). When o-
halo aldehydes served as the substrates, the shift of sup-
porting ligand from ethylenediamine to DMEDA is neces-
sary to ensure the efficiency of the catalyst system
(Table 2, entries 9–17). (Z)-4-Bromo-3,4-diphenylbut-3-
en-2-one and (Z)-3-bromo-2,3-diphenylacrylaldehyde
could also react with 2-phenylacetamide to afford the cor-
responding pyridinones (Table 2, entries 8 and 9). It was
noteworthy that the method also worked well for hetero-
aromatic bromide substrates (Table 2, entries 6, 7, 16, and
17). Moreover, the equivalents of carbonyl functional
group were also effective in the cascade reactions
(Table 2, entries 18 and 19).
The investigation was initiated by the coupling of 2-bro-
moacetophenone with 2-phenylacetamide as the model
reaction (Table 1). Although no desired product was de-
tected in the absence of copper salts, we were pleased to
find that the 4-methyl-3-phenylquinolin-2(1H)-one prod-
uct (1) was obtained in 24% yield under the catalysis of 10
mol% copper(I) iodide at 110 °C using cesium carbonate
as the necessary base in toluene (Table 1, entries 1 and 2),
SYNTHESIS 2011, No. 10, pp 1547–1554
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Advanced online publication: 01.04.2011
DOI: 10.1055/s-0030-1259983; Art ID: H19211SS
© Georg Thieme Verlag Stuttgart · New York

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Table 1 Optimization of Copper-Catalyzed Cascade Reactions of 2-Bromoacetophenone with 2-Phenylacetamidea
O
CuI, ligand
O
1
+
base, solvent
110 °C
H2N
N
H
O
Br
NH2
NH2
NH2
NH2
NHMe
NH2
Ph
NH2
NH2
OH
N
H
NHMe
O
N
N
NH2
Ph
A
B
C
D
E
F
G
Entry
Ligand
Base
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
DMF
Yield (%)b
1
2
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
tracec
24d
82
–
3
A
B
C
D
E
F
G
E
E
E
E
E
4
55
5
33
6
63
7
91
8
51
9
42
10
11
12
13
14
42
61
Cs2CO3
Cs2CO3
Cs2CO3
52
35
dimethylglycol
46
a Reaction conditions: 2-bromoacetophenone (1.0 mmol), 2-phenylacetamide (1.2 mmol), CuI (0.1 mmol), ligand (0.2 mmol), base (3.0 mmol),
solvent (1.5 mL), argon atmosphere, 110 °C, 24 h.
b Isolated yield.
c No CuI nor ligand.
d No ligand.
The scope of the amide coupling partner was also ex- well in the reaction (Table 3, entry 8). Unfortunately, this
plored. As shown in Table 3, most of the results were sat- method did not work well for alkylacetamides (Table 3,
isfactory. It was also demonstrated that the electronic entries 9 and 10).
density of the amide might have some impact on the effi-
The protocol also worked for aryl chlorides, the highly
ciency of reaction, since electron-withdrawing group on
challenging substrates in most copper-catalyzed coupling
the aromatic ring of the amide significantly reduced the
reactions. Though the target product was obtained in 21%
yields (Table 3, entries 1–3). In addition, heterocyclic
yield when 2-chloroacetophenone was coupled with 2-
phenylacetamide at 110 °C, the yield increased to 42%
when the reaction was performed at 150 °C (Table 4, en-
acetamides, such as 2-(1-methyl-1H-indol-3-yl)acet-
amide, 3-pyridylacetamide, and 2-pyridylacetamide also
reacted smoothly to offer the desired products (Table 3,
try 1). The reaction also worked well for several other
entries 4–6). Though the secondary amide, N-cyclopro-
substituted 2-chlorobenzocarbonyls to afford the desired
products in moderate yields (Table 4, entries 2–8).
pyl-2-phenylactamide, afforded the product in low yield
(Table 3, entry 7), N-phenyl-2-phenylacetamide worked
Synthesis 2011, No. 10, 1547–1554 © Thieme Stuttgart · New York

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Synthesis of Quinolinones
1549
Table 2 Copper-Catalyzed Synthesis of Quinolinones, Pyridinones, and Heteroannulated Pyridinones: Investigation on the Scope of the
Carbonyl Functional Groupa
R2
O
O
CuI, EDA
Ph
O
R2
+
Ph
R1
R1
H2N
Cs2CO3, toluene
110 °C
N
X
H
Entry Aryl halide
Product
Yield (%)b
93
Entry ArX
Product
Yield (%)b
73c
Ph
O
O
Ph
O
CHO
Br
1
11
N
N
H
H
I
2i
1
Ph
F3C
Ph
O
O
Ph
O
F3C
CHO
Br
2
93
75
77
78
74
34
31
12
62c
51c
58c
51c
61c
67c
46
Ph
N
H
N
H
Br
2j
2a
Cl
Ph
O
Cl
Ph
O
Cl
CHO
Br
Cl
3
4
5
6
7
8
13
N
O
N
H
H
Br
2k
2b
Ph
O
Ph
CHO
14
N
O
MeO
N
O
H
Br
H
MeO
Cl
Br
2l
2c
Ph
MeO
Ph
O
O
Cl
Ph
MeO
CHO
Br
15
Ph
N
N
H
O
H
Br
2m
2d
H
Ph
N
O
S
Br
O
16
S
O
N
O
Ph
CHO
H
O
Br
2n
2e
H
N
O
Ph
O
Br
17
S
N
N
O
Ph
CHO
H
S
N
Br
2o
2f
OH
Me
O
O
Ph
O
Ph
O
Ph
Ph
Ph
18
19
OMe
N
H
N
Ph
2g
Ph
H
Br
Br
2p
2q
NH2
Ph
O
Ph
O
CHO
Br
Ph
Ph
CN
Br
9
50c
81c
76
N
H
Ph
N
H
2h
Ph
CHO
10
N
H
O
I
2i
a Reaction conditions: ArX (1.0 mmol), 2-phenylacetamide (1.2 mmol), CuI (0.1 mmol), EDA (0.2 mmol), Cs2CO3 (3.0 mmol), toluene (1.5
mL), argon, 110 °C, 24 h.
b Isolated yield.
c DMEDA was used as the ligand.
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Table 3 Copper-Catalyzed Synthesis of Quinolinones, Pyridinones, and Heteroannulated Pyridinones: Investigation on the Scope of the
Amide Coupling Partnera
R2
O
R2
CuI, EDA
O
+
Cs2CO3, toluene
110 °C
NH
N
R1
O
Br
R1
Entry Amide
Product
Yield (%)b
Entry Amide
Product
Yield (%)b
F
NH2
N
NH2
N
1
85
80
6
65
O
O
N
O
N
H
O
F
H
3f
3a
H
N
MeO
NH2
OMe
NO2
2
7
8
20
64
N
O
O
O
N
H
O
3b
3g
3h
NH2
NHPh
3
20
O
O
N
O
O2N
N
H
O
Ph
3c
Me
NH2
O
N
O
4
62
71
9
trace
trace
H2N
N
H
O
N
H
O
N
Me
3d
N
NH2
COOEt
O
O
5
10
COOEt
O
H2N
N
H
O
N
N
H
3e
a Reaction conditions: 2-bromoacetophenone (1.0 mmol), amide (1.2 mmol), CuI (0.1 mmol), EDA (0.2 mmol), Cs2CO3 (3.0 mmol), toluene
(1.5 mL), argon, 110 °C, 24 h.
b Isolated yield.
Table 4 Copper-Catalyzed Cascade Reactions of 2-Phenylacetamides with 2-Chlorobenzocarbonyl Compoundsa
R2
O
Ar
CuI, EDA
Ph
O
R2
R1
+
O
Cs2CO3, toluene
150 °C
NH2
Cl
N
H
Entry ArCl
Amide
Product
Yield Entry ArCl
(%)b
Amide
Product
Yield
(%)b
O
O
Ph
O
Ph
O
S
NH2
NH2
42
5
1
41
41
21c
S
O
N
H
O
O
N
H
Cl
O
Cl
1
2e
F
O
F3C
Ph
O
NH2
NH2
F3C
2
40
6
O
N
H
F
N
O
Cl
Cl
H
4a
3a
Synthesis 2011, No. 10, 1547–1554 © Thieme Stuttgart · New York

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Synthesis of Quinolinones
1551
Table 4 Copper-Catalyzed Cascade Reactions of 2-Phenylacetamides with 2-Chlorobenzocarbonyl Compoundsa (continued)
R2
O
Ar
CuI, EDA
Ph
O
R2
R1
+
O
Cs2CO3, toluene
150 °C
NH2
Cl
N
H
Entry ArCl
Amide
Product
Yield Entry ArCl
(%)b
Amide
Product
Yield
(%)b
O
O
Cl
Ph
O
MeO
NH2
NH2
OMe
Cl
3
37
35
7
8
37
O
O
O
N
N
O
H
H
Cl
Cl
2b
3b
2i
Ph
O
O
F
Ph
CHO
Cl
NH2
NH2
40d
F
4
N
H
O
N
O
H
Cl
4b
a Reaction conditions: ArCl (1.0 mmol), amide (1.2 mmol), CuI (0.1 mmol), EDA (0.2 mmol), Cs2CO3 (3.0 mmol), toluene (1.5 mL), argon,
150 °C, 24 h.
b Isolated yield.
c 110 °C.
d DMEDA was used as the ligand.
All reactions were carried out in 10 mL sealed tubes, under a pure
and dry argon atmosphere. Toluene was distilled from Na and was
stored on 4Å activated molecular sieves. Cs2CO3 (Alfa Aesar),
K3PO4 (Alfa Aesar), K2CO3, 2-phenylacetamide, CuI (Aldrich), and
all other solid materials were stored in the presence of P2O5 in a
bench-top desiccator under vacuum at r.t. and weighed in the air. 2-
Halobenzocarbonyls and 2-phenylactamide amides were purchased
from commercial sources (Aldrich, Acros, 3B, Alfa Aesar) and in
most cases used directly without further purification or prepared ac-
cording to literature. Column chromatography was performed with
QDHY 60 A C.C. silica gel (35–70 mm). All products were charac-
terized by NMR, LC/MS, or HRMS. NMR spectra were recorded at
20 °C on a Bruker AC 400 MHz spectrometer working, respective-
ly, at 400 MHz for 1H, at 500 MHz for 13C. Chemical shifts are re-
ported in ppm relative to solvent (CDCl3: 7.27 and 77.0 ppm;
DMSO-d6: 2.50 and 39.51 ppm in 1H and 13C NMR spectra, respec-
tively). The first order peak patterns are indicated as s (singlet), d
(doublet), t (triplet), q (quadruplet). Complex non-first-order sig-
nals are indicated as m (multiplet). Low- and high-resolution ESI-
MS were recorded on an Agilent 1200 HPLC-MSD mass spectrom-
eter and an Applied Biosystems Q-STAR Elite ESI-LC-MS/MS
mass spectrometer, respectively. Melting points were measured on
an OptiMelt MPA 100 melting point apparatus and are uncorrected.
Chemical names were generated using CambridgeSoft ChemDraw
Ultra 10.0.
umn chromatography on silica gel (eluent: CH2Cl2–EtOAc, 4:1)
afforded the desired product.
4-Methyl-3-phenylquinolin-2(1H)-one (1)6a,b
Light yellow solid; mp 264–266 °C.
1H NMR (400 MHz, CDCl3): d = 11.55 (br s, 1 H), 7.74 (d, J = 8.4
Hz, 1 H), 7.39–7.51 (m, 4 H), 7.35 (d, J = 7.6 Hz, 2 H), 7.21–7.27
(m, 2 H), 2.36 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 163.0, 144.7, 137.4, 136.0, 132.3,
130.3, 130.0, 128.2, 127.5, 124.9, 122.3, 120.9, 116.1, 16.9.
ESI-MS: m/z = 236 (M + 1).
3, 4-Diphenylquinolin-2(1H)-one (2a)6a,b
White solid; mp 307–309 °C.
1H NMR (400 MHz, CDCl3): d = 11.87 (br s, 1 H), 7.44 (t, J = 7.6
Hz, 1 H), 7.17–7.35 (m, 10 H), 7.06–7.14 (m, 3 H).
13C NMR (125 MHz, CDCl3): d = 163.2, 149.8, 137.9, 136.3, 135.2,
131.9, 130.9, 130.2, 129.8, 128.0, 127.6, 127.5, 127.5, 127.0, 122.3,
120.9, 115.9.
ESI-MS: m/z = 298 (M + 1).
6-Chloro-4-methyl-3-phenylquinolin-2(1H)-one (2b)
White solid; mp 272–274 °C.
1H NMR (400 MHz, CDCl3): d = 11.89 (br s, 1 H), 7.69 (d, J = 2.0
Hz, 1 H), 7.41–7.51 (m, 3 H), 7.32–7.38 (m, 3 H), 7.17 (d, J = 8.8
Hz, 1 H), 2.32 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 162.9, 143.8, 135.9, 135.6, 133.2,
130.2, 130.2, 128.3, 127.8, 127.7, 124.4, 122.0, 117.6, 16.9.
HRMS: m/z calcd for C16H13ClNO: 270.0680 [M + H]+; found:
270.0681.
Compounds 1–4; General Procedure
A sealed tube was charged with a magnetic stir bar, 2-halobenzocar-
bonyl compound (1.0 mmol, if solid), 2-arylacetamide (1.2 mmol),
CuI (5–10 mmol%), and Cs2CO3 (977.4 mg, 3.0 mmol). The tube
was evacuated and backfilled with argon (this procedure was re-
peated three times). The 2-halobenzocarbonyl compound (1.0
mmol, if liquid), toluene (1.5 mL), and ligand (20 mmol%) were
added by syringe under a counter-flow of argon. The tube was evac-
uated and backfilled with argon (this procedure was repeated three
times) and sealed. Then the reaction mixture was heated to the indi-
cated temperature for 24 h. After cooling to r.t., the mixture was di-
luted with CH2Cl2 (10 mL) and MeOH (5 mL), passed through a
fritted glass filter, and then concentrated under vacuum (this proce-
dure was repeated three times). Purification of the residue by col-
7-Methoxy-4-methyl-3-phenylquinolin-2(1H)-one (2c)
White solid; mp 241–243 °C.
1H NMR (400 MHz, CDCl3): d = 11.26 (br s, 1 H), 7.63 (d, J = 9.2
Hz, 1 H), 7.43–7.47 (m, 2 H), 7.32–7.39 (m, 3 H), 6.83 (dd, J = 8.8,
2.4 Hz, 1 H), 6.71 (d, J = 2.4 Hz, 1 H), 3.83 (s, 3 H), 2.32 (s, 3 H).
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L. Fu et al.
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13C NMR (125 MHz, CDCl3): d = 163.3, 161.3, 144.8, 139.1, 136.2,
130.5, 129.4, 128.1, 127.4, 126.4, 115.0, 111.9, 98.1, 55.5, 16.9.
13C NMR (125 MHz, CDCl3): d = 163.0, 138.4, 138.0, 136.2, 132.5,
130.3, 128.9, 128.3, 128.2, 127.8, 122.7, 120.4, 115.5.
HRMS: m/z calcd for C17H16NO2: 266.1176 [M + H]+; found:
ESI-MS: m/z = 222 (M + 1).
266.1173.
3-Phenyl-6-(trifluoromethyl)quinolin-2(1H)-one (2j)
Yellow solid; mp 238–239 °C.
6-Chloro-3,4-diphenylquinolin-2(1H)-one (2d)8a
White solid; mp 303–305 °C.
1H NMR (400 MHz, CDCl3): d = 11.96 (br s, 1 H), 7.37 (dd, J = 9.2,
2.4 Hz, 1 H), 7.29–7.31 (m, 3 H), 7.10–7.24 (m, 9 H).
1H NMR (400 MHz, CDCl3): d = 12.11 (br s, 1 H), 7.96 (s, 1 H),
7.90 (s, 1 H), 7.80 (d, J = 7.2 Hz, 2 H), 7.70 (d, J = 8.8 Hz, 1 H),
7.44–7.53 (m, 4 H).
13C NMR (125 MHz, CDCl3): d = 163.1, 148.9, 136.4, 135.6, 134.9,
132.9, 130.7, 130.5, 129.7, 128.2, 128.0, 127.7, 127.6, 127.2, 126.6,
121.9, 117.5.
13C NMR (125 MHz, CDCl3): d = 163.5, 139.9, 137.9, 135.4, 133.9,
128.9, 128.7, 128.4, 126.6, 126.6, 125.3, 125.3, 125.2, 125.1, 124.9,
122.9, 119.7, 116.3.
HRMS: m/z calcd for C21H15ClNO: 332.0837 [M + H]+; found:
HRMS: m/z calcd for C16H11F3NO: 290.0787 [M + H]+; found:
332.0840.
290.0789.
7-Methyl-6-phenylthieno[3,2-b]pyridin-5(4H)-one (2e)
White solid; mp 234–236.0 °C.
6-Chloro-3-phenylquinolin-2(1H)-one (2k)8c
Yellow solid; mp 209–210 °C.
1H NMR (400 MHz, CDCl3): d = 13.27 (br s, 1 H), 7.45–7.49 (m, 2
H), 7.34–7.41 (m, 4 H), 6.95 (d, J = 5.6 Hz, 1 H), 2.28 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 163.8, 142.7, 140.2, 135.8, 130.5,
128.5, 128.2, 127.6, 127.4, 121.6, 117.9, 19.1.
1H NMR (400 MHz, CDCl3): d = 11.70 (br s, 1 H), 7.83 (s, 1 H),
7.77–7.79 (m, 2 H), 7.59 (d, J = 2.0 Hz, 1 H), 7.47–7.51 (m, 2 H),
7.42–7.45 (m, 2 H), 7.29 (d, J = 8.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 162.7, 137.2, 136.3, 135.6, 133.7,
130.5, 128.9, 128.5, 128.4, 127.9, 126.9, 121.3, 116.9.
HRMS: m/z calcd for C14H12NOS: 242.0634 [M + H]+; found:
242.0636.
ESI-MS: m/z = 256 (M + 1).
4-Methyl-3-phenyl-1,8-naphthyridin-2(1H)-one (2f)
White solid; mp 296–298 °C.
7-Methyl-3-phenylquinolin-2(1H)-one (2l)
Yellow solid; mp 233–234 °C.
1H NMR (400 MHz, CDCl3): d = 11.82 (br s, 1 H), 8.75 (d, J = 2.8
Hz, 1 H), 8.08 (d, J = 7.6 Hz, 1 H), 7.40–7.48 (m, 3 H), 7.24–7.33
(m, 3 H), 2.35 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 11.03 (br s, 1 H), 7.87 (s, 1 H),
7.79–7.81 (m, 2 H), 7.45–7.50 (m, 3 H), 7.37–7.41 (m, 1 H), 7.12
(s, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 2.46 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 162.6, 149.8, 148.8, 142.8, 135.2,
133.9, 130.0, 128.3, 127.9, 118.4, 116.4, 16.3.
13C NMR (125 MHz, CDCl3): d = 162.9, 141.1, 138.3, 138.0, 136.3,
131.3, 128.8, 128.2, 128.0, 127.7, 124.3, 118.2, 115.2, 21.8.
HRMS: m/z calcd for C15H13N2O: 237.1022 [M + H]+; found:
ESI-MS: m/z = 236 (M + 1).
237.1023.
6-Methoxy-3-phenylquinolin-2(1H)-one (2m)6a
Yellow solid; mp 248–249 °C.
4-Methyl-3,5,6-triphenylpyridin-2(1H)-one (2g)8b
White solid; mp 316–318 °C.
1H NMR (400 MHz, CDCl3): d = 11.37 (br s, 1 H), 7.86 (s, 1 H),
7.81 (d, J = 8.0 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.41 (t, J = 7.2
Hz, 1 H), 7.28 (s, 1 H), 7.14 (dd, J = 8.8, 2.4 Hz, 1 H), 7.04 (d,
J = 2.8 Hz, 1 H), 3.87 (s, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 11.79 (br s, 1 H), 7.42 (t,
J = 7.6 Hz, 2 H), 7.29–7.34 (m, 3 H), 7.19–7.24 (m, 8 H), 7.11 (d,
J = 7.6 Hz, 2 H), 1.71 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 161.0, 146.2, 137.2, 136.7,
131.2, 130.2, 129.5, 128.2, 128.0, 127.9, 127.6, 126.8, 126.7, 19.7.
13C NMR (125 MHz, CDCl3): d = 162.0, 155.2, 137.9, 136.2, 133.0,
132.4, 128.9, 128.3, 128.2, 120.9, 119.8, 116.4, 109.1, 55.7.
ESI-MS: m/z = 338 (M + 1).
ESI-MS: m/z = 252 (M + 1).
3,5,6-Triphenylpyridin-2(1H)-one (2h)
Yellow solid; mp 251–253 °C.
6-Phenylfuro[3,2-b]pyridin-5(4H)-one (2n)
Yellow solid; mp 139–140 °C.
1H NMR (400 MHz, CDCl3): d = 11.48 (br s, 1 H), 7.73–7.75 (m, 3
1H NMR (400 MHz, CDCl3): d = 13.28 (br s, 1 H), 7.84 (s, 1 H),
7.76 (d, J = 7.6 Hz, 2 H), 7.60 (d, J = 1.6 Hz, 1 H), 7.45 (t, J = 7.6
Hz, 2 H), 7.37 (t, J = 7.2 Hz, 1 H), 6.63 (d, J = 1.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 163.3, 147.0, 140.1, 137.1, 132.2,
128.9, 128.2, 127.2, 126.4, 125.5, 102.4.
H), 7.29–7.41 (m, 8 H), 7.22–7.25 (m, 3 H), 7.13–7.15 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 162.5, 142.8, 142.3, 137.9, 135.9,
133.6, 129.6, 129.5, 129.5, 129.2, 128.5, 128.4, 128.4, 128.1, 127.7,
126.9, 119.5.
HRMS: m/z calcd for C23H18NO: 324.1383 [M + H+]; found:
HRMS: m/z calcd for C13H10NO2: 212.0706 [M + H]+; found:
324.1383.
212.0709.
3-Phenylquinolin-2(1H)-one (2i)6a,b
Light yellow solid; mp 232–234 °C.
6-Phenylthieno[3,2-b]pyridin-5(4H)-one (2o)
Yellow solid; mp 217–219 °C.
1H NMR (400 MHz, CDCl3): d = 11.72 (br s, 1 H), 7.92 (s, 1 H),
7.81–7.83 (m, 2 H), 7.61 (dd, J = 8.0, 0.8 Hz, 1 H), 7.47–7.51 (m, 3
H), 7.40–7.44 (m, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.20–7.24 (m, 1
H).
1H NMR (400 MHz, CDCl3): d = 13.19 (br s, 1 H), 7.97 (s, 1 H),
7.78 (d, J = 7.2 Hz, 2 H), 7.53 (d, J = 5.2 Hz, 1 H), 7.46 (t, J = 7.6
Hz, 2 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.11 (d, J = 5.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 163.3, 142.0, 136.7, 133.4, 130.2,
128.8, 128.3, 128.2, 127.8, 119.2, 117.1.
Synthesis 2011, No. 10, 1547–1554 © Thieme Stuttgart · New York

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Synthesis of Quinolinones
1553
HRMS: m/z calcd for C13H10NOS: 228.0478 [M + H]+; found:
HRMS: m/z calcd for C19H17N2O: 289.1335 [M + H]+; found:
228.0481.
289.1340.
4-Hydroxy-3-phenylquinolin-2(1H)-one (2p)6a
White solid; mp 273–275 °C.
4-Methyl-3-(pyridin-3-yl)quinolin-2(1H)-one (3e)
Yellow solid; mp 230–232 °C.
1H NMR (400 MHz, DMSO-d6): d = 11.41 (br s, 1H), 10.01 (br s, 1
H), 7.89 (d, J = 7.6 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.33–7.35 (m,
4 H), 7.23–7.25 (m, 2 H), 7.13 (t, J = 7.2 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 162.6, 157.3, 138.0, 133.3,
131.1, 130.5, 127.6, 126.8, 123.1, 121.0, 115.4, 114.9, 112.6.
1H NMR (400 MHz, DMSO-d6): d = 11.87 (br s, 1 H), 8.56 (dd,
J = 4.8, 1.6 Hz, 1 H), 8.47 (d, J = 1.6 Hz, 1 H), 7.82 (d, J = 7.6 Hz,
1 H), 7.70–7.73 (m, 1 H), 7.52–7.56 (m, 1 H), 7.47 (dd, J = 7.6, 5.2
Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.23–7.26 (m, 1 H), 2.29 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 160.8, 150.7, 148.2, 144.4,
138.0, 137.9, 132.0, 130.3, 128.6, 125.4, 122.9, 121.9, 119.7, 115.2,
16.6.
ESI-MS: m/z = 238 (M + 1).
4-Amino-3-phenylquinolin-2(1H)-one (2q)6a,8d
Yellow solid; mp 325–326 °C.
HRMS: m/z calcd for C15H13N2O: 237.1022 [M + H]+; found:
237.1026.
1H NMR (400 MHz, DMSO-d6): d = 11.00 (br s, 1 H), 7.99 (d,
J = 8.0 Hz, 1 H), 7.42–7.47 (m, 3 H), 7.29–7.33 (m, 3 H), 7.25 (d,
J = 8.0 Hz, 1 H), 7.11 (t, J = 7.2 Hz, 1 H), 5.85 (br s, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 161.6, 148.4, 138.4, 135.1,
131.0, 130.1, 128.4, 126.6, 123.1, 120.5, 115.1, 113.5, 106.0.
4-Methyl-3-(pyridin-2-yl)quinolin-2(1H)-one (3f)
Yellow solid; mp 236–238 °C.
1H NMR (400 MHz, DMSO-d6): d = 11.83 (br s, 1 H), 8.66 (d,
J = 4.8 Hz, 1 H), 7.85 (td, J = 7.6, 1.6 Hz, 1 H), 7.81 (d, J = 7.6 Hz,
1 H), 7.52–7.56 (m, 1 H), 7.35–7.41 (m, 3 H), 7.22–7.26 (m, 1 H),
2.22 (s, 3 H).
ESI-MS: m/z = 237 (M + 1).
13C NMR (125 MHz, DMSO-d6): d = 160.8, 155.3, 148.9, 144.4,
138.0, 135.9, 131.3, 130.3, 125.9, 125.3, 122.3, 121.8, 119.7, 115.2,
16.0.
HRMS: m/z calcd for C15H13N2O: 237.1022 [M + H]+; found:
237.1024.
3-(4-Fluorophenyl)-4-methylquinolin-2(1H)-one (3a)8c
White solid; mp 291–292 °C.
1H NMR (400 MHz, CDCl3): d = 11.09 (br s, 1 H), 7.75 (d, J = 8.0
Hz, 1 H), 7.46–7.50 (m, 1 H), 7.30–7.33 (m, 2 H), 7.24 (d, J = 8.0
Hz, 2 H), 7.17 (t, J = 8.8 Hz, 2 H), 2.36 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 163.3, 162.7, 161.3, 145.0, 137.3,
132.1, 132.0, 131.7, 131.3, 130.2, 125.0, 122.5, 120.8, 115.9, 115.3,
115.2, 16.9.
1-Cyclopropyl-4-methyl-3-phenylquinolin-2(1H)-one (3g)
White solid; mp 159–161 °C.
1H NMR (400 MHz, CDCl3): d = 7.93 (d, J = 8.4 Hz, 1 H), 7.79 (d,
J = 8.0 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.43–7.47 (m, 2 H), 7.35–
7.38 (m, 1 H), 7.29 (d, J = 7.6 Hz, 3 H), 3.00 (m, 1 H), 2.33 (s, 3 H),
1.36 (m, 2 H), 0.95 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 162.9, 142.2, 140.0, 136.4, 132.7,
130.2, 129.4, 128.0, 127.3, 125.3, 121.9, 121.7, 115.4, 26.4, 16.8,
10.5.
ESI-MS: m/z = 254 (M + 1).
3-(3-Methoxyphenyl)-4-methylquinolin-2(1H)-one (3b)
Yellow solid; mp 204–205 °C.
1H NMR (400 MHz, CDCl3): d = 11.86 (br s, 1 H), 7.72–7.74 (m, 1
H), 7.38–7.46 (m, 2 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.20–7.24 (m, 1
H), 6.90–6.98 (m, 3 H), 3.85 (s, 3 H), 2.36 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 163.0, 159.5, 144.8, 137.5, 132.1,
130.1, 129.2, 124.8, 122.7, 122.3, 120.8, 116.3, 115.8, 113.3, 55.2,
16.8.
HRMS: m/z calcd for C19H18NO: 276.1383 [M + H]+; found:
276.1381.
4-Methyl-1,3-diphenylquinolin-2(1H)-one (3h)
Yellow solid; mp 183–184 °C.
HRMS: m/z calcd for C17H16NO2: 266.1176 [M + H]+; found:
1H NMR (400 MHz, CDCl3): d = 7.85 (d, J = 7.6 Hz, 1 H), 7.57 (t,
J = 7.6 Hz, 2 H), 7.47–7.51 (m, 1 H), 7.41–7.45 (m, 2 H), 7.31–7.36
(m, 6 H), 7.24–7.28 (m, 1 H), 6.75 (d, J = 8.4 Hz, 1 H), 2.44 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 161.6, 143.2, 140.1, 138.1, 136.1,
132.7, 130.4, 129.9, 129.6, 129.0, 128.6, 128.0, 127.4, 125.3, 122.2,
121.3, 116.1, 17.1.
266.1178.
4-Methyl-3-(4-nitrophenyl)quinolin-2(1H)-one (3c)
Yellow solid; mp 288–289 °C.
1H NMR (400 MHz, CDCl3): d = 11.02 (br s, 1 H), 8.35 (d, J = 8.4
Hz, 2 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.51–7.55 (m, 3 H), 7.30 (d,
J = 8.0 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 2.38 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 162.0, 147.4, 145.6, 143.0, 137.4,
131.6, 130.9, 130.2, 125.2, 123.5, 122.9, 120.5, 116.0, 17.0.
HRMS: m/z calcd for C22H18NO: 312.1383 [M + H]+; found:
312.1383.
HRMS: m/z calcd for C16H13N2O3: 281.0921 [M + H]+; found:
281.0919.
4-Methyl-3-phenyl-6-(trifluoromethyl)quinolin-2(1H)-one (4a)
White solid; mp 276–277 °C.
1H NMR (400 MHz, CDCl3): d = 11.79 (br s, 1 H), 8.00 (s, 1 H),
7.65 (d, J = 8.8 Hz, 1 H), 7.49–7.53 (m, 2 H), 7.43–7.46 (m, 1 H),
7.29–7.34 (m, 3 H), 2.39 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 163.1, 144.6, 139.5, 135.3, 133.6,
130.1, 128.4, 128.0, 126.4, 126.4, 122.6, 120.5, 116.7, 16.9.
HRMS: m/z calcd for C17H13F3NO: 304.0944 [M + H]+; found:
304.0941.
4-Methyl-3-(1-methyl-1H-indol-3-yl)quinolin-2(1H)-one (3d)
Yellow solid; mp 271–272 °C.
1H NMR (400 MHz, CDCl3): d = 10.58 (br s, 1 H), 7.77 (d, J = 7.6
Hz, 1 H), 7.36–7.46 (m, 3 H), 7.30 (s, 1 H), 7.21–7.28 (m, 3 H), 7.12
(t, J = 7.6 Hz, 1 H), 3.90 (s, 3 H), 2.46 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 163.0, 145.1, 137.0, 136.8, 130.1,
129.6, 128.0, 124.9, 122.3, 121.5, 121.3, 120.5, 119.5, 115.6, 109.5,
108.8, 33.0, 17.6.
6-Fluoro-4-methyl-3-phenylquinolin-2(1H)-one (4b)
White solid; mp 306–307 °C.
Synthesis 2011, No. 10, 1547–1554 © Thieme Stuttgart · New York

1554
L. Fu et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 11.66 (br s, 1 H), 7.49 (t, J = 7.2
Hz, 2 H), 7.38–7.44 (m, 2 H), 7.33 (d, J = 7.2 Hz, 2 H), 7.18–7.21
(m, 2 H), 2.31 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 162.7, 159.1, 157.2, 143.9, 135.7,
133.9, 133.3, 130.2, 128.3, 127.7, 121.8, 121.7, 118.2, 118.0, 117.6,
117.6, 110.3, 110.1, 17.0.
Gonzales, S. S.; Koszalka, G. W.; Hazen, R. J.; Boone, L. R.;
Ferris, R. G.; Creech, K. L.; Roberts, G. B.; Short, S. A.;
Weaver, K.; Reynolds, D. J.; Milton, J.; Ren, J.; Stuart, D. I.;
Stammers, D. K.; Chan, J. H. J. Med. Chem. 2004, 47, 5923.
(4) (a) Sliskovic, D. R.; Picard, J. A.; Roark, W. H.; Roth, B. D.;
Ferguson, E.; Krause, B. R.; Newton, R. S.; Sekerke, C.;
Shaw, M. K. J. Med. Chem. 1991, 34, 367. (b) Suzuki, M.;
Iwasaki, H.; Fujikawa, Y.; Kitahara, M.; Sakashita, M.;
Sakoda, R. Bioorg. Med. Chem. 2001, 9, 2727. (c)Bach, T.;
Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc.
2002, 124, 7982. (d) Kumabea, R.; Nishino, H. Tetrahedron
Lett. 2004, 45, 703.
HRMS: m/z calcd for C16H13FNO: 254.0976 [M + H]+; found:
254.0974.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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Acknowledgment
We thank the Knowledge Innovation Program of the Chinese Aca-
demy of Sciences, the 100-talent program of CAS, National Natural
Science 10 Foundation (Grant # 90813033), and National Basic
Research Program of China (Grant
2009CB940904) for their financial support.
#
2010CB529706,
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Synthesis 2011, No. 10, 1547–1554 © Thieme Stuttgart · New York