Facile synthesis of 3-substituted and 1,3-disubstituted quinolin-2(1H)-ones from 2-nitrobenzaldehydes

Article abstract of DOI:10.3987/COM-05-10462

2-Nitrobenzaldehydes were reduced with iron powder to 2-aminobenzaldehydes, which were reacted immediately with acyl chlorides to provide 2-carboxamidobenzaldehydes (1) with overall yields of 71-90 %. Reaction of 1 with base provided 3-substituted quinolin-2(1H)-ones with 63-97 % yields. Treatment of 1 with methyl iodide and base gave 1-methyl-3-substituted quinolin-2(1H)-ones with 82-95 % yields, whereas the treatment with isopropyl iodide gave 1-isopropyl-3-substituted quinolin-2(1H)-ones with 7-42 % yields.

Full text of DOI:10.3987/COM-05-10462

HETEROCYCLES, Vol. 65, No. 9, 2005
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HETEROCYCLES, Vol. 65, No. 9, 2005, pp. 2095 - 2105
Received, 27th May, 2005, Accepted, 20th July, 2005, Published online, 22nd July, 2005
FACILE SYNTHESIS OF 3-SUBSTITUTED AND 1,3-DISUBSTITUTED
QUINOLIN-2(1H)-ONES FROM 2-NITROBENZALDEHYDES
Kwanghee Koh Park* and Jin Young Jung
Department of Chemistry, Chungnam National University, Daejeon 305-764,
South Korea
khkoh@cnu.ac.kr
Abstract – 2-Nitrobenzaldehydes were reduced with iron powder to
2-aminobenzaldehydes, which were reacted immediately with acyl chlorides to
provide 2-carboxamidobenzaldehydes (1) with overall yields of 71-90 %.
Reaction of 1 with base provided 3-substituted quinolin-2(1H)-ones with 63-97 %
yields. Treatment of 1 with methyl iodide and base gave 1-methyl-3-substituted
quinolin-2(1H)-ones with 82-95 % yields, whereas the treatment with isopropyl
iodide gave 1-isopropyl-3-substituted quinolin-2(1H)-ones with 7-42 % yields.
INTRODUCTION
Quinolin-2(1H)-one skeleton is frequently found in many pharmacologically useful compounds,1-6 such
as antitumor,1,2 antiplatelet,3 and antiviral agents,4 and various types of receptor antagonists.5,6 Extensive
efforts have been made for the synthesis of quinolin-2(1H)-one derivatives.1-17 Conventional method for
the synthesis is the cyclization of β-ketoanilides or acrylanilides.7 However, this method has two major
limitations. One is that mixtures of 5- and 7-substituted quinolin-2(1H)-ones are obtained when
meta-substituted anilides are cyclized and the other is that the necessary starting materials are not readily
accessible.7 A wide variety of other synthetic routes for quinolin-2(1H)-one derivatives have also been
reported. These include intramolecular Wittig reaction of 2-pyruvoylaminobenzyltriphenylphosphonium
halide,1,8 palladium-catalyzed carbonylative annulation of alkyne by o-substituted aryl iodide,9
electrocyclizations of o-vinylphenyl isocyanate,10 palladium-catalyzed amidation of o-carbonyl-

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HETEROCYCLES, Vol. 65, No. 9, 2005
substituted aryl halides,11 conversion of Baylis-Hillman adducts of 2-nitrobenzaldehydes,12 cyclization of
3-(2-aminophenyl)acrylic acid derivatives,5,13 reaction of α–substituted acetanilides with Vilsmeier
reagent,2,14 tandem Ugi-Knoevenagel condensation,15 free radical cyclization of alkylsulfonyl substituted
anilides,16 introduction of the desired substituent into the preformed quinoline ring system.17 However,
many of them suffer narrow scope, harsh reaction conditions, and/or low yields. Thus, the development of
efficient and general synthetic methods for quinolin-2(1H)-one derivatives is still highly desired. Recently,
we found that 4-phenylquinolin-2(1H)-ones can be efficiently prepared from N-acyl-o-
aminobenzophenones.18 Here, we wish to report a facile and efficient synthesis of 3-substituted
quinolin-2(1H)-ones (2) and 1,3-disubstituted quinolin-2(1H)-ones (3) starting from 2-nitrobenzaldehydes
via 2-carboxamidobenzaldehyde intermediates (1) (Scheme 1).
Scheme 1
X
Y
R
O
N
H
base
O
O
O
X
Y
H
X
Y
H
X
Y
H
2
3
Fe powder
RCOCl
pyridine
CH2R
NH2
NO2
N
H
R'I
O
X
Y
R
base
1
N
R'
O
RESULTS AND DISCUSSION
Preparation of 2-Carboxamidobenzaldehydes (1) From 2-Nitrobenzaldehydes
There are numerous methods for reduction of nitrobenzenes to anilines. As 2-aminobenzaldehyde is
unstable and easily undergoes self-condensation reaction,19 the reduction of 2-nitrobenzaldehydes to
2-aminobenzaldehydes should be carried out by a method requiring minimal work-up procedure and the
product should be used immediately for the next step. We tested various reducing agents for the synthesis
of 2-acetamidobenzaldehyde (1a) from 2-nitrobenzaldehyde and found that iron powder20 is simple and
facile agent for the reduction. The reduction reaction could be effectively coupled with the acylation
reaction with a minimal work-up.21
Reduction of 2-nitrobenzaldehyde to 2-aminobenzaldehyde with iron powder was accomplished within 15
min, and the crude reduction product was immediately subjected to acylation reaction. The reaction with
acetyl chloride in the presence of pyridine in benzene solvent for 10 min gave 1a with overall yield of
80 %: the reaction in dichloromethane solvent for 6 h gave 1a with only 40 % yield. We believe that this

HETEROCYCLES, Vol. 65, No. 9, 2005
2097
procedure for the synthesis of 1a is much better than the reported methods for 1a. Meanwell et al.
reported the synthesis of 1a from 2-nitrobenzaldehyde by the lengthy sequence via protection of carbonyl
group, reduction (10 % Pd on C), and acetylation (the yields were not mentioned),23 while Dave et al.
reported 58 % overall yield of 1a from 2-nitrobenzaldehyde using FeSO4/acetic anhydride after rather
complicated work-up procedure.19 This reduction/acylation procedure for 1a was successfully applied for
the synthesis of various other 2-carboxamidobenzaldehydes (1) with the overall yields of 71-90 %. The
results are summarized in Table 1.
Table 1. Yields of 2-carboxamidobenzaldehydes (1) from 2-aminobenzaldehydes, and yields of
3-substituted quinolin-2(1H)-ones (2) from 1
yields
entry
X
Y
R
1a
2b,c
1
2
3
4
5
6
7
8
9
H
H
H
H
H
Me
1a (80%)
1b (73%)
1c (71%)
2a (83%)
2b (76%)
2c (72%)
H
H
n-Pr
n-C5H11
Ph
H
H
1d (82%)
1e (72%)
2d (63%)
2e (92%)
H
H
1fd
2f (75%)e
2g (97%)
2h (64%)
2i (95%)
CO2Et
Ph
H
H
Cl
H
1g (90%)
1h (89%)
1i (74%)
OMe
OMe
OMe
OMe
H
Ph
a Isolated yields from the corresponding 2-nitrobenzaldehydes. b Isolated
yields from 1. c Cs2CO3 was used as a base for 2a-d and 2h, and K2CO3
was used for 2e-g and 2i.d Crude product was used for the synthesis of
2f. e The yield is the isolated overall yield from 2-nitrobenzaldehyde.
Synthesis of 3-substituted quinolin-2(1H)-ones (2) from 1
The facile access of 2-carboxamidobenzaldehydes (1) prompted us to try the synthesis of various
3-substituted quinolin-2(1H)-ones (2) via intramolecular Aldol-type condensation of 1. Various bases
such as NaH, K2CO3, and Cs2CO3 were tested for the cyclization reaction. When R is electron-
withdrawing group such as phenyl or ethoxycarbonyl, K2CO3 was strong enough to induce cyclization
and the yields of 2 were better than 90 % (Table 1, entries 5-7 and 9).24 When R is H or alkyl group
(Table 1, entries 1-4 and 8), NaH or Cs2CO3 was necessary for the cyclization reaction. The use of

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HETEROCYCLES, Vol. 65, No. 9, 2005
Cs2CO3 gave 8-17 % better yields than NaH. Longer acyl moiety in 1 (compare entries 1-4 of Table 1)
and electron-donating substituent in the benzene ring (entry 8) lowered the yield. The yields of 2 from 1
are included in Table 1.
Synthesis of 1,3-disubstituted quinolin-2(1H)-ones (3) from 2-carboxamidobenzaldehydes (1)
The alkylation reaction of the preformed quinolin-2(1H)-one ring with alkyl halide gives a mixture of N-
and O-alkylated products.5,18 Thus, to prepare 1,3-disubstituted quinolin-2(1H)-ones (3) from 1,
N-alkylation of 1 and subsequent cyclization of the resulting N-alkyl-2-carboxamidobenzaldehyde would
be a desirable choice. We first tested the reaction of 1a with methyl iodide in DMF in the presence of
various bases. As hoped, N-alkylation to give N-methyl-2-acetamidobenzaldehyde preceded the
cyclization and the one pot reactions provided 1-methyl-quinolin-2(1H)-ones (3a) without any noticeable
amount of O-methylated isomer. N-Methylation reaction went into completion in the presence of either
o
K2CO3 or Cs2CO3 at 40 C, and Cs2CO3 required much less reaction time (2 h) than K2CO3 (18 h). For
the subsequent cyclization reaction of N-methyl-2-acetamidobenzaldehyde, Cs2CO3 or NaH was effective
at the reaction temperature of 60 oC. N-Methylation at 40 oC and then cyclization at 60 oC in the presence
of ten molar excess of Cs2CO3 was found to give the highest yield (86 %) of 3a from 1a.
The similar reaction of 1a with isopropyl iodide in the presence of Cs2CO3 provided
1-isopropylquinolin-2(1H)-one (3b) with 42 % yield (Table 2, entry 2). The yield is far better than the
reported yield (6.5 %) of 1-isopropylated compound obtained from the alkylation reaction of a
quinolin-2(1H)-one derivative with isopropyl iodide.5 The corresponding reactions of 1b with methyl or
isopropyl iodide and the reaction of 1e with methyl iodide gave the corresponding 1,3-disubstituted
quinolin-2(1H)-ones with moderate to excellent yields (Table 2, entries 3-5).
The reaction of 2-phenylacetamidobenzaldehyde (1e) with isopropyl iodide in the presence of base gave a
quite contrasting result (Table 2, entry 6). It gave both the N-isopropylated product, 1-isopropyl-3-
phenylquinolin-2(1H)-one (3f) and the O-isopropylated product, 2-isopropoxy-3-phenylquinoline (4f)
with 7 % and 81 % yields, respectively. We could not increase the yield of 3f by changing the reaction
conditions such as base and/or temperature. The similar yields of the N-alkylated and O-alkylated
products were also obtained from the reaction of 3-phenylquinolin-2(1H)-one (2e) with isopropyl iodide.
The result indicates that in the reaction of 1e with isopropyl iodide in the presence of base, the cyclization
reaction of 1e proceed prior to the N-alkylation reaction of 1e. This can be explained by the fact that the
α-hydrogen atom to the carbonyl group is more acidic in 1e than the one in 1a or 1b, and isopropyl iodide
is much poorer alkylating agent than methyl iodide.
It is noteworthy that the yields of the consecutive reactions of N-methylation and cyclization of 1 to 3 are
higher than the yields of the simple cyclization reactions of the corresponding 1 to 2 (compare the yields
of 2 in entries 1, 2, and 5 of Table 1 with the respective yields of 3 in entries 1, 3, and 5 of Table 2). This

HETEROCYCLES, Vol. 65, No. 9, 2005
2099
is reasonable as the removal of the α-hydrogen atom to the carbonyl group for the cyclization would be
more feasible in N-methyl-2-carboxamidobenzaldehyde than in 2-carboxamidobenzaldehyde without
N-methyl group: the former has only one kind of acidic hydrogens to be removed, while the latter has two
kinds of them and N-H hydrogen is more acidic than the α-hydrogen atom.
Table 2. Yields of 1,3-disubstituted quinolin-2(1H)-ones (3) obtained from alkylation/cyclization reaction
of 1
O
R
H
base
CH2R
N
O
R'I
N
H
R'
O
3a-f
1a,b,e
starting
material
yield of 3a
entry
base
product
R
R'
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
1
2
3
4
5
6
H
H
Me
i -Pr
Me
86%
42%
82%
40%
95%
7%b
1a
3a
3b
3c
3d
3e
3f
1a
1b
1b
1e
1e
CH3
CH3
Ph
i -Pr
Me
Ph
i -Pr
a Isolated yields. b O -Alkylated product (4f) was obtained in 81 % yield, together
with 3f.
In conclusion, facile synthetic routes for 3-substituted and 1,3-disubstituted quinolin-2(1H)-ones (2 and 3)
from 2-nitrobenzaldehydes via 2-carboxamidobenzaldehydes (1) have been developed. The compounds
(1) are efficiently prepared from 2-nitrobenzaldehydes via reduction with iron powder and then acylation
reaction. Base-catalyzed cyclization of 1 affords various 3-substituted quinolin-2(1H)-ones (2). The
reaction of 1 with alkyl iodide in the presence of base gives the corresponding 1-alkyl-3-substituted
quinolin-2(1H)-ones (3), resulting from N-alkylation followed by cyclization reaction in one pot, except
for the case of the reaction of 2-phenylacetamidobenzaldehyde (1e) with isopropyl iodide. In the reaction
of 1e with isopropyl iodide, N-alkylation occurs after the cyclization reaction, giving mostly O-alkylated
product (4f).
EXPERIMENTAL
13
1H and C NMR spectra were obtained at 400 and 100 MHz, respectively, using tetramethylsilane as an
internal standard in CDCl3 or DMSO-d6. Melting points are uncorrected.

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HETEROCYCLES, Vol. 65, No. 9, 2005
General procedure for the preparation of 2-carboxamidobenzaldehydes (1) from
2-nitrobenzaldehydes
2-Nitrobenzaldehyde (3.31 mmol) and iron powder (1.29 g, 23.2 mmol) were added to a mixture of
ethanol (8 mL), acetic acid (8 mL), and water (4 mL), and the mixture was refluxed for 5 min and then
stirred at rt for 10 min. The reaction mixture was filtered, and the filtrate was diluted with water and
extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 aqueous solution and
water, dried over anhydrous sodium sulfate, and concentrated to give crude 2-aminobenzaldehyde. The
crude 2-aminobenzaldehyde was used for the synthesis of 1 without further purification.
To a mixture of crude 2-aminobenzaldehyde and pyridine (0.393 g, 4.96 mmol) in benzene (20 mL) was
added slowly acyl chloride (4.96 mmol). After stirring at rt for 10 min, the reaction mixture was washed
with 10 % aqueous HCl solution and then water. The organic layer was dried over sodium sulfate,
concentrated, and purified by silica gel column chromatography (eluents: n-hexane-ethyl acetate, 4:1) to
afford the corresponding 2-carboxamidobenzaldehydes (1) in 71-90 % yields (see Table 1). In case of the
reaction of 2-aminobenzaldehyde with ethyl malonyl chloride (Table 1, entry 6), the concentrated organic
layer was used for the synthesis of 2f without purification.
1a: mp 70-71 oC (lit.,19 70 oC); 1H NMR (CDCl3) δ 11.12 (br s, 1H), 9.91 (s, 1H), 8.73 (d, 1H, J = 8 Hz),
7.66 (dd, 1H, J = 8 and 2 Hz), 7.61 (dt, 1H, J = 8 and 2 Hz), 7.22 (dt, 1H, J = 8 and 1 Hz), 2.26 (s, 3H);
13C NMR (CDCl3) δ 195.4, 169.5, 140.8, 136.1, 135.9, 122.8, 121.4, 119.7, 25.4.
1b: oil (lit.,25 mp 46 oC); 1H NMR (CDCl3) δ 11.14 (br s, 1H), 9.92 (s, 1H), 8.76 (d, 1H, J = 8 Hz), 7.66
(dd, 1H, J = 8 and 2 Hz), 7.61 (dt, 1H, J = 8 and 2 Hz), 7.21 (dt, 1H, J = 8 and 1 Hz), 2.50 (q, 2H, J = 8
13
Hz), 1.29 (t, 3H, J = 8 Hz); C NMR (CDCl3) δ 195.4, 173.3, 141.0, 136.1, 135.9, 122.6, 121.5, 119.8,
31.6, 9.5. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.88; H, 6.47; N, 7.76.
1c: oil; 1H NMR (CDCl3) δ 11.13 (br s, 1H), 9.91 (s, 1H), 8.76 (d, 1H, J = 8 Hz), 7.66 (dd, 1H, J = 8 and
2 Hz), 7.58 (dt, 1H, J = 8 and 2 Hz), 7.21 (t, 1H, J = 8 Hz), 2.46 (t, 2H, J = 7.5 Hz), 1.75 (quintet, 2H, J =
7.5 Hz), 1.43 (sextet, 2H, J = 7.5 Hz), 0.96 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3) δ 195.4, 172.7, 140.9,
136.1, 135.9, 122.6, 121.4, 119.7, 38.3, 27.5, 22.3, 13.8. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N,
6.82. Found: C, 70.39; H, 7.27; N, 6.86.
1d: oil; 1H NMR (CDCl3) δ 11.13 (br s, 1H), 9.92 (s, 1H), 8.76 (d, 1H, J = 9 Hz), 7.66 (dd, 1H, J = 8 and
2 Hz), 7.60 (dt, 1H, J = 8 and 2 Hz), 7.21 (dt, 1H, J = 8 and 1 Hz), 2.46 (t, 2H, J = 8 Hz), 1.76 (quintet,
2H, J = 8 Hz), 1.43-1.28 (m, 6H), 0.89 (t, 3H, J = 7 Hz); 13C NMR (CDCl3) δ 195.4, 172.7, 140.9, 136.1,
135.9, 122.6, 121.4, 119.8, 38.6, 31.5, 28.9, 25.4, 22.5, 14.1. Anal. Calcd for C14H19NO2: C, 72.07; H,
8.21; N, 6.00. Found: C, 72.09; H, 8.36; N, 5.99.
1e: mp 42-44 oC; 1H NMR (CDCl3) δ 11.08 (br s, 1H), 9.80 (s, 1H), 8.74 (d, 1H, J = 8 Hz), 7.62-7.55 (m,
13
2H), 7.40-7.30 (m, 5H), 7.19 (dt, 1H, J = 8 and 1 Hz), 3.78 (s, 2H); C NMR (CDCl3) δ 195.1, 170.6,

HETEROCYCLES, Vol. 65, No. 9, 2005
2101
140.67, 136.0, 135.8, 133.9, 129.6, 128.9, 127.4, 122.9, 121.7, 119.8, 45.8. Anal. Calcd for C15H13NO2: C,
75.30; H, 5.48; N, 5.85. Found: C, 75.53; H, 5.65; N, 5.87.
1g: mp 118-119 oC; 1H NMR (CDCl3) δ 10.95 (br s, 1H), 9.73 (s, 1H), 8.73 (d, 1H, J= 9 Hz), 7.56 (s, 1H),
13
7.52 (d, 1H, J = 9 Hz), 7.44-7.30 (m, 5H), 3.78 (s, 2H); C NMR (CDCl3) δ 193.8, 170.5, 139.1, 135.7,
134.8, 133.6, 129.6, 129.10, 128.0, 127.5, 122.7, 121.5, 45.7. Anal. Calcd for C15H12NO2Cl: C, 65.82; H,
4.42; N, 5.12. Found: C, 65.74; H, 4.74; N, 5.00.
o
o
1
1h: mp 181-183 C (lit.,26 178-179 C); H NMR (CDCl3) δ 11.32 (br s, 1H), 9.75 (s, 1H), 8.47 (s, 1H),
13
7.03 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 2.25 (s, 3H); C NMR (CDCl3) δ 193.0, 169.5, 155.4, 144.2,
137.5, 116.3, 114.3, 102.8, 56.4, 56.2, 25.4.
o
1
1i: mp 132-134 C; H NMR (CDCl3) δ 11.33 (br s, 1H), 9.67 (s, 1H), 8.48 (s, 1H), 7.43-7.30 (m, 5H),
13
7.00 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.77 (s, 2H); C NMR (CDCl3) δ 192.9, 170.6, 155.2, 144.3,
137.3, 133.9, 129.5, 128.8, 127.4, 116.1, 114.5, 102.9, 56.4, 56.2, 45.7. Anal. Calcd for C17H17NO4: C,
68.21; H, 5.72; N, 4.68. Found: C, 68.33; H, 5.62; N, 4.65.
General procedure for the synthesis of 3-substituted quinolin-2(1H)-ones 2 from 1
A mixture of 2-carboxamidobenzaldehyde (1) (0.500 mmol) and base (2.50 mmol) in DMF (5 mL) was
o
heated at 60 C for 2-16 h. Dichloromethane was added to the reaction mixture and then washed with
aqueous saturated NH4Cl solution and water. The organic layer was dried over sodium sulfate and
concentrated. Silica gel column chromatography of the residue (eluent: hexane-ethyl acetate, 1:1 or 2:1)
provided the corresponding quinolin-2(1H)-ones (2) in 63-97 % yields (see Table 1).
2a: mp 197-199 oC (lit.,27 198-199 oC); 1H and 13C NMR were identical with those from Aldrich.
o
o
o
1
2b: mp 247-249 C (lit. 250 C28; 237-240 C17d); H NMR (DMSO-d6) δ 11.72 (br s, 1H), 7.73 (s, 1H),
7.54 (dd, 1H, J = 8 and 1 Hz), 7.40 (ddd, 1H, J = 8, 7 and 1 Hz), 7.26 (d, 1H, J = 8 Hz), 7.12 (ddd, 1H, J =
13
8, 7 and 1 Hz), 2.07 (d, 3H, J = 1 Hz); C NMR (DMSO-d6) δ 162.3, 137.8, 136.3, 129.7, 129.0, 126.9,
121.6, 119.4, 114.7, 16.6.
2c: mp 142-143 oC; 1H NMR (CDCl3) δ 12.77 (br s, 1H), 7.57 (s, 1H), 7.49-7.39 (m, 3H), 7.15 (ddd, 1H,
13
J = 8, 6 and 2 Hz), 2.67 (t, 2H, J = 7 Hz), 1.75 (sextet, 2H, J = 7 Hz), 1.04 (t, 3H, J = 7 Hz); C NMR
(CDCl3) δ 164.5, 137.4, 136.4, 133.7, 129.0, 126.7, 122.1, 120.1, 115.7, 32.3, 21.6, 14.0. Anal. Calcd for
C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 76.90; H, 7.12; N, 7.37.
2d: mp 140-142 oC; 1H NMR (CDCl3) δ 12.59 (br s, 1H), 7.59 (s, 1H), 7.49 (d, 1H, J = 8 Hz), 7.45-7.40
(m, 2H), 7.16 (ddd, 1H, J = 8, 5 and 3 Hz), 2.69 (t, 2H, J = 7 Hz), 1.72 (quintet, 2H, J = 7 Hz), 1.46-1.35
13
(m, 4H), 0.93 (t, 3H, J = 7 Hz); C NMR (CDCl3) δ 164.5, 137.4, 136.3, 134.1, 129.1, 126.8, 122.2,
120.2, 115.7, 31.7, 30.2, 28.1, 22.6, 14.1. Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found:
C, 78.11; H, 8.17; N, 6.30.

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HETEROCYCLES, Vol. 65, No. 9, 2005
o
o
1
2e: mp 234-235 C (lit.,9a 230-231 C); H NMR (DMSO-d6) δ 11.95 (br s, 1H), 8.10 (s, 1H), 7.77-7.72
(m, 3H), 7.50 (t, 1H, J = 7 Hz), 7.44 (t, 2H, J = 7 Hz), 7.38 (d, 1H, J = 8 Hz), 7.34 (d, 1H, J = 8 Hz), 7.20
13
(t, 1H, J = 7 Hz); C NMR (DMSO-d6) δ 160.9, 138.2, 137.5, 136.2, 131.4, 130.1, 128.6, 128.0, 127.8,
127.7, 121.8, 119.5, 114.6.
2f: mp 183-184 oC (lit.,5 175-179 oC); 1H NMR (CDCl3) δ 12.74 (br s, 1H), 8.56 (s, 1H), 7.65 (d, 1H, J =
8 Hz), 7.60 (t, 1H, J = 8 Hz), 7.53 (d, 1H, J = 8 Hz), 7.25 (t, 1H, J = 8 Hz), 4.46 (q, 2H, J = 7 Hz), 1.46 (t,
13
3H, J= 7 Hz); C NMR (CDCl3) δ 164.3, 161.3, 145.6, 140.0, 132.9, 129.0, 123.0, 122.0, 118.4, 116.3,
61.4, 14.4.
2g: mp 249-250 oC (lit.,29 234-235 oC); 1H NMR (DMSO-d6) δ 12.06 (br s, 1H), 8.11 (s, 1H), 7.86 (d, 1H,
J = 2 Hz), 7.77 (d, 2H, J = 7 Hz), 7.56 (dd, 1H, J = 9 and 2 Hz), 7.50-7.42 (m, 3H), 7.38 (d, 1H, J = 9 Hz);
13C NMR (DMSO-d6) δ 160.7, 136.9, 136.4, 135.8, 132.7, 129.9, 128.6, 128.0, 127.9, 126.9, 125.6, 120.6,
116.5.
2h: mp 232-234 oC (lit.,13a 231 oC); 1H NMR (DMSO-d6) δ 11.53 (br s, 1H), 7.75 (d, 1H, J = 9 Hz), 7.15
13
(s, 1H), 6.84 (s, 1H), 6.30 (d, 1H, J = 9 Hz), 3.79 (s, 3H), 3.76 (s, 3H); C NMR (DMSO-d6) δ 161.7,
151.7, 144.6, 139.6, 134.4, 118.6, 112.2, 108.7, 97.6, 55.7, 55.5.
o
o
o
1
2i: mp 259-261 C (lit. 260 C;13b 242-244 C17e); H NMR (DMSO-d6) δ 11.73 (br s, 1H), 7.98 (s, 1H),
7.73 (d, 2H, J = 7.5 Hz), 7.39 (t, 2H, J = 7.5 Hz), 7.31 (t, 1H, J = 7.5 Hz), 7.24 (s, 1H), 6.87 (s, 1H), 3.81
(s, 3H), 3.78 (s, 3H); 13C NMR (DMSO-d6) δ 160.6, 151.8, 144.7, 137.1, 136.6, 134.0, 128.3, 128.2,
127.7, 127.2, 112.7, 108.9, 97.1, 55.7, 55.5.
General procedure for the synthesis of 1-alkyl-3-substituted quinolin-2(1H)-ones (3) from 1
To a stirred mixture of 2-carboxamidobenzaldehyde (1a or 1b) (1.00 mmol) and Cs2CO3 (3.26 g, 10.0
mmol) in DMF (5 mL) at 40 oC, alkyl iodide (2.50 mmol) was added slowly and stirring was continued at
o
40 C until TLC showed that 2-carboxamidobenzaldehyde disappeared almost completely. Then
o
o
o
temperature was raised from 40 C to 60 C and the reaction mixture was stirred at 60 C for 1-48 h. In
case of 1e (0.239 g, 1.00 mmol), K2CO3 (0.691 g, 5.00 mmol) was used as a base and the reaction went to
o
completion at 40 C. After the reaction, dichloromethane was added to the reaction mixture and then
washed with aqueous saturated NH4Cl solution and water. The organic layer was dried over sodium
sulfate and concentrated. Silica gel column chromatography of the residue (eluent: hexane-ethyl acetate,
1:1 or 2:1) provided the corresponding 1-alkylquinolin-2(1H)-ones (3a-e) (see Table 2). In case of the
reaction of 1e with isopropyl iodide in the presence of K2CO3, purification by silica gel column
chromatography (eluent: hexane-ethyl acetate, 9:1) afforded N-isopropylated product (3f) and

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2103
O-isopropylated product (4f) with 7 % and 81 % yields, respectively (Table 2, entry 6).
3a: mp 75-76 oC (lit.,16 74-75 oC); 1H NMR (CDCl3) δ 7.66 (d, 1H, J = 9 Hz), 7.56 (t, 1H, J = 8 Hz), 7.55
(d, 1H, J = 8 Hz), 7.36 (d, 1H, J = 8 Hz), 7.23 (t, 1H, J = 8 Hz), 6.71 (d, 1H, J = 9 Hz), 3.72 (s, 3H); 13C
NMR (CDCl3) δ 162.2, 139.9, 138.8, 130.5, 128.6, 122.0, 121.6, 120.6, 114.0, 29.4.
3b: oil; 1H NMR (CDCl3, 70 oC) δ 7.55 (d, 2H, J = 9 Hz), 7.51-7.44 (m, 2H), 7.15 (t, 1H, J = 7 Hz), 6.60
(d, 1H, J = 9 Hz), 5.48 (br s, 1H), 1.64 (d, 6H, J = 7 Hz). Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N,
7.48. Found: C, 76.92; H, 7.20; N, 7.29.
3c: mp 73-74 oC (lit.,30 64-65 oC) 1H NMR (CDCl3) δ 7.54 (s, 1H), 7.52-7.47 (m, 2H), 7.32 (d, 1H, J = 9
Hz), 7.20 (dt, 1H, J = 8 and 1 Hz), 3.74 (s, 3H), 2.26 (d, 3H, J = 1 Hz); 13C NMR (CDCl3) δ 162.7, 138.9,
135.5, 129.9, 129.1, 127.6, 121.8, 120.6, 113.7, 29.7, 17.8.
3d: oil; 1H NMR (CDCl3, 70 oC) δ 7.52 (d, 1H, J = 9 Hz), 7.46-7.38 (m, 3H), 7.12 (t, 1H, J = 7 Hz), 5.47
(br s, 1H), 2.22 (s, 3H), 1.64 (d, 6H, J = 7 Hz). Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.64; H, 7.30; N, 6.88.
3e: mp 140-142 oC (lit.,14 137-138 oC); 1H NMR (CDCl3) δ 7.78 (s, 1H), 7.70 (d, 2H, J = 8 Hz), 7.59 (d,
1H, J = 8 Hz), 7.55 (t, 1H, J = 8 Hz), 7.43 (t, 2H, J = 8 Hz), 7.39-7.34 (m, 2H), 7.24 (t, 1H, J = 8 Hz),
13
3.79 (s, 3H); C NMR (CDCl3) δ 161.4, 139.5, 136.7, 132.4, 130.2, 128.9, 128.7, 128.0, 127.9, 122.1,
120.6, 113.9, 30.0 (one carbon is missing due to overlap).
3f: oil; 1H NMR (CDCl3, 70 oC) δ 7.70 (s, 1H), 7.69 (d, 2H, J = 8 Hz), 7.55 (d, 2H, J = 8 Hz), 7.47 (t, 1H,
J = 8 Hz), 7.39 (t, 2H, J = 7 Hz), 7.32 (t, 1H, J = 7 Hz), 7.16 (t, 1H, J = 7 Hz), 5.47 (br s, 1H), 1.69 (d, 6H,
J = 7 Hz); 13C NMR (CDCl3, 70 oC) δ 161.8,139.1, 137.0, 136.5, 133.3, 129.4, 129.2, 129.1, 128.0, 127.9,
121.7, 121.6, 114.6, 47.4, 19.9. Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C, 82.15;
H, 6.59; N, 5.24.
4f: oil; 1H NMR (CDCl3) δ 7.94 (s, 1H), 7.82 (d, 1H, J = 8 Hz), 7.69 (dd, 1H, J = 8 and 2 Hz), 7.65-7.62
(m, 2H), 7.57 (ddd, 1H, J = 8, 7, and 2 Hz), 7.44-7.39 (m, 2H), 7.37-7.31 (m, 2H), 5.65 (heptet, 1H, J = 6
Hz), 1.39 (d, 6H, J = 6 Hz); 13C NMR (CDCl3) δ 158.8, 145.9, 137.8, 137.0, 129.4, 129.0, 127.9, 127.4,
127.3, 126.7, 126.6, 125.2, 123.8, 68.4, 22.0. Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32.
Found: C, 82.14; H, 6.56; N, 5.16.
ACKNOWLEDGEMENTS
This work was supported by grant No. R05-2003-000-10459-0 from the Basic Research Program of the
Korea Science & Engineering Foundation.
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