Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

Article abstract of DOI:10.1016/j.tet.2004.02.001

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.

Full text of DOI:10.1016/j.tet.2004.02.001

Tetrahedron 60 (2004) 2993–2999
Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives
from N-acyl-o-aminobenzophenones
*
Kwanghee Koh Park and Jin Joo Lee
Department of Chemistry, Chungnam National University, Yu-Sung-Ku, Taejon 305-764, South Korea
Received 19 January 2004; revised 1 February 2004; accepted 2 February 2004
This paper is dedicated to Professor Dong H. Kim on the occasion of his retirement from the Department of Chemistry, Postech
Abstract—An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-
aminobenzophenones 1a-c (a: acyl¼acetyl; b: acyl¼propanoyl; c: acyl¼heptanoyl) using NaH as a base. Treatment of 1 with NaH provided
the quinolones 2a-c with 62–83% yields, whereas the reaction in the presence of alkyl iodide (alkyl¼methyl, ethyl, n-octyl) gave the
corresponding N-alkylated quinolones 3a-g in 75–95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide
gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds
with those of 2a-c indicated that 2a-c exist as the lactam form.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
a,6,12 b13 or c7,8,14 and via cyclization/rearrangement15 or
desulfurization reaction16 have also been reported. Most of
these synthetic methods for 2-quinolones have their own
drawbacks such as difficult accessibility of the starting
materials, low yields, and/or harsh reaction conditions.
Here, we wish to report a facile and efficient synthesis of
4-phenylquinolin-2(1H)-one derivatives 2 and 3 by forming
the bond c from N-acyl-o-aminobenzophenones 1 using
NaH as a base. It provides various 4-phenylquinolin-2(1H)-
one derivatives in high yields from readily available starting
materials by one-pot reaction. The tautomeric form of 2 was
also clarified.
Quinolines and their derivatives occur in numerous natural
products and have interesting biological properties.1 Their
wide-ranging applicabilities such as pharmaceuticals, agro-
chemicals and synthetic building blocks have been dis-
covered.2 Thus, development of efficient methods for their
syntheses is still attracting much interest of organic
chemists,3,4 even though the syntheses of quinolines have
been known for more than a century. 4-Phenylquinolin-
2(1H)-ones 2 and 3 are found to be useful intermediates in
organic synthesis5–7 and some of them show interesting
biological profiles.7–10
2. Results and discussions
2.1. Synthesis of 4-phenylquinolin-2(1H)-ones 2 from
N-acyl-o-aminobenzophenones 1 and study on the
alkylation reaction of 2
N-Acyl-o-aminobenzophenones 1a-c were obtained in
quantitative yields by reacting o-aminobenzophenone with
the corresponding acyl chlorides in dichloromethane in the
presence of pyridine. Treatment of 1a-c with 6 equiv. of
NaH in THF at refluxing temperature for 2.5–20 h provided
4-phenylquinolin-2(1H)-ones 2a-c in 62–83% yields with
the deacylated side product, o-aminobenzophenone in
16–23% yields (Scheme 1). There are scattered reports
for the synthesis of 2a7–9,11b,12,13,15,16 and 2b13,14,17 by
various methods, but the yields are low and/or the
methodologies are rather too specific. We believe that the
Quinolin-2(1H)-one skeletons usually have been prepared
by acid-catalyzed cyclization of acylacetoanilides9 – 11
forming bond d in the benzo-fused pyridine ring. The
synthetic methods involving the final ring closure at bond
Keywords: N-Acyl-o-aminobenzophenones; 4-Phenylquinolin-2(1H)-one;
N-Alkyl-4-phenylquinolin-2(1H)-ones; 2-Alkoxy-4-phenylquinolines;
Lactam–lactim tautomeric form.
*
Corresponding author. Tel.: þ82-42-821-5479; fax: þ82-42-823-1360;
e-mail address: khkoh@cnu.ac.kr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.001

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K. K. Park, J. J. Lee / Tetrahedron 60 (2004) 2993–2999
carbon to the carbonyl group needs to be removed.
However, the hydrogen is less acidic than the hydrogen
atom attached to the nitrogen of the amide group. We
envisioned that N-alkylation of 1 prior to the treatment with
the base would increase the yield of the cyclization reaction
and also give the N-alkylated quinolones. Thus, we carried
out the reaction of 1a-c with NaH in the presence of alkyl
iodide to achieve the alkylation and cyclization reactions in
one pot. The product distributions obtained from the
reactions of 1a with NaH and methyl iodide under various
conditions are listed in Table 2.
Scheme 1. Reaction of N-acyl-o-aminobenzophenones 1a-c with NaH.
present method is very simple general route for the synthesis
of 4-phenyl-quinoline-2(1H)-ones.
Table 2 shows that the yield of N-methyl-4-phenylquinolin-
2(1H)-one 3a is as high as 92% when 2.5 equiv. of CH3I and
6 equiv. of NaH are used at the refluxing temperature of
THF. Either lowering the reaction temperature or using less
amount of NaH or CH3I resulted in N-alkylated, but not-
cyclized product, 5a. The yields of N-alkyl-2-quinolone
derivatives obtained from the reactions of N-acyl-o-
aminobenzophenones 1a-c with 6 equiv. of NaH in the
presence of 2.5 equiv. of various alkyl iodides are
summarized in Table 3. It shows that N-alkyl-4-phenyl-
quinolin-2(1H)-ones 3a-g can be efficiently prepared in the
one-pot reaction of N-acyl-o-aminobenzophenones 1a-c
with alkyl iodide and NaH. Unlike the reaction of 2a with
alkyl halides, O-alkylated products 4 were not detected,
suggesting that N-alkylation of 1 precedes the cyclization
reaction.
We studied the alkylation reaction of 4-phenylquinolin-
2(1H)-one 2a with alkyl halide. The reaction of 2a with
alkyl halide in DMF at 70 8C in the presence of various
bases gave mixtures of the corresponding N-alkylated and
O-alkylated products, 3 and 4 (Table 1). The reaction with
methyl iodide in the presence of K2CO3 gave mostly
N-alkylated product 3a. However, with the alkyl halides of
larger alkyl group, the proportion of the O-alkylated product
4 increases (see entries 1–3), presumably due to the steric
interaction between the bulky N-alkyl group and the
adjacent H atom in the 8-position of the quinoline ring.
Using Cs2CO3 or NaH instead of K2CO3 as a base gave
almost the same results. Changing the reaction medium
from DMF to THF resulted in much slower reaction, but the
yield of the N-alkylated product was higher (compare
entries 2 and 4 vs. 5). This is reminiscent of the previous
reports that pyridin-2-ones undergo alkylation at either
nitrogen or oxygen.18
Based on the data in Tables 2 and 3, we propose the
mechanism for the reaction of N-acyl-o-aminobenzo-
phenones 1a-c with alkyl iodide and NaH as Scheme 2.
To support the involvement of 5 as an intermediate, we
prepared N-ethyl-o-benzoylacetanilide (5b: R¼H; R0¼Et)
from the reaction of 1a with ethyl iodide in the presence of
cesium carbonate in acetone, and then it was reacted with
3 equiv. of NaH in refluxing THF. The yield of N-ethyl-4-
phenylquinolin-2(1H)-one 3b was higher in shorter reaction
time (92% yield after 4 h) compared to the reaction of 1a
(85% yield after 7 h: see entry 2 of Table 3). The fact that
the reaction of 2a with alkyl iodide in THF is very slow and
2.2. One-pot synthesis of N-alkyl-4-phenylquinolin-
2(1H)-ones 3 from 1
The unsatisfactory yields of 2 from 1 and the formation of
both N and O-alkylated products 3 and 4 in the alkylation
reaction of 2 made us to search an alternative route for the
synthesis of 3. For the cyclization of the compounds 1 to the
quinoline ring, the hydrogen atom attached to the alpha
Table 1. Alkylation reaction of 2a with alkyl halides
Entry
R0X
Base
Solvent
Temperature
Time (h)
Yields (%)
3
4
1
2
3
CH3I
C2H5I
n-C8H17Br
C2H5I
C2H5I
K2CO3
K2CO3
K2CO3
Cs2CO3
NaH
DMF
DMF
DMF
DMF
THF
70 8C
70 8C
70 8C
70 8C
Reflux
70 8C
0.5
1
1.5
0.5
120
0.5
84
60
42
59
66 (72)b
43
8
34
48
31
13 (14)b
52
4
5a
6
n-C8H17
I
NaH
DMF
a
8% of the starting material was remained unreacted.
The yield in the parenthesis is the yield based on the consumed starting material.
b

K. K. Park, J. J. Lee / Tetrahedron 60 (2004) 2993–2999
Table 2. Reaction of 1a with methyl iodide and NaH in THF
2995
Entry
Equiv. of CH3I
Equiv. of NaH
T (8C)
Time (h)
Yields (%)
3a
nd
16
13
60
67
78
85
92
5a
100
81
77
31
24
18
9
6a
nd
nd
8
8
7
2
nd
6
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
2.5
2.5
1.5
2.5
3
3
6
6
6
3
6
6
0
25
0
25
3
2
2
1
1
2
2
2
40
Reflux
Reflux
Reflux
nd
92 to 99% in the reaction of 5b with NaH when 1.5 equiv. of
ethyl iodide is added to the reaction mixture.
Table 3. The yields of N-alkyl-2-quinolones 3a-g obtained from the
reaction of 1a-c with various alkyl iodide and NaH in THF
2.3. Tautomeric form of 4-phenylquinolin-2(1H)-ones
2a-c
The tautomeric equilibrium of lactam–lactim continues to
attract much attention owing to its chemical, biological, and
theoretical importance.19 Compounds 2a-c can exist in
either lactam or lactim forms. Of the two tautomers, the
lactim form of 2a (R¼H) is reported to be more stable than
the lactam by ca. 1 kJ/mol in the gas phase,20 and the lactam
is slightly more stable in solution, especially in polar solvent
(ca. 20 kJ/mol in water).21 It was also reported that both the
lactam and lactim tautomers of 2a exist in the supersonic jet
expansion.22 On the other hand, a paper suggested that the
compound 2a exists in the lactim form as 2-hydroxyquino-
line, based on a singlet signal for one proton present at d 12
in the 1H NMR spectrum.12b The crystal structure of 2a has
recently been reported, showing that 2a has the lactam
structure.23
Entry Starting material
R
R0
Time Product Yields
(h)
(%)
1
2
3
4
5
6
7
1a
1a
1a
1b
1b
1c
1c
H
H
H
CH3
2
7
3a
3b
3c
3d
3e
3f
92
85
75
85
88
95
84
C2H5
n-C8H17
CH3
40
4
5
CH3
CH3
n-C5H11 CH3
n-C5H11 C2H5
C2H5
4
8
3g
gives appreciable amount of O-alkylated product 4 (see
entry 5 of Table 1) further supports the involvement of the
intermediate 5 in the transformation of 1 to 3 in the presence
of alkyl halide. We propose the involvement of the
intermediate 7 in addition of 8 based on the following two
facts. One is that the yield of 3a becomes lower with less
than 2 equiv. of alkyl iodide (compare entries 7 and 8 of
Table 2). The other is that the yield of 3b is increased from
Scheme 2. Proposed mechanism for the reaction of N-acyl-o-aminobenzophenones 1 with alkyl iodide and NaH.

2996
K. K. Park, J. J. Lee / Tetrahedron 60 (2004) 2993–2999
Since both N-alkylated and O-alkylated compounds 3a-c
and 4a-c, which correspond to the lactam and lactim forms,
respectively, are at our hands, we compare the spectroscopic
characteristics between the N-alkylated compounds 3 and
the O-alkylated ones 4 and deduce the tautomeric structure
of 2. The NMR data of 3 are significantly different from
those of 4 (see Section 4 for data): major differences are 1H
and 13C peaks of CH2 (or CH3) bonded to the heteroatoms
and 1H peaks of the aromatic protons. The chemical shift of
the carbon atom at the 2-position of the quinoline ring is
almost same for both 3a-c and 4a-c as d 161–162. As
expected, 1H and 13C peaks of CH2 (or CH3) bonded to the
oxygen atom in 4a-c have larger d values than those bonded
to the nitrogen atom in 3a-c: the O-alkylated compounds
4. Experimental
4.1. General
1H and 13C NMR spectra were obtained at 400 and
100 MHz, respectively, using tetramethylsilane as an
internal standard in CDCl3. Melting points are uncorrected.
4.2. General procedure for the preparation of N-acyl-o-
aminobenzophenones
To a mixture of 2-aminobenzophenone (5.00 g, 25.4 mmol)
and pyridine (12.3 ml, 152 mmol) in dichloromethane
(150 ml) was added slowly acyl chloride (30.4 mmol).
After stirring at room temp for 0.5 h, the reaction mixture
was concentrated to ca. 50 ml and washed with 10% aqeous
HCl solution. Then the aqueous solution was extracted with
dichloromethane 2–3 times. The combined organic layers
were dried over sodium sulfate, filtered, and evaporated to
afford a residue. Purification of the residue by silica gel
column chromatography (eluents: n-hexane–ethyl acetate,
3:1) provided the corresponding N-acyl-o-aminobenzo-
phenones 1a-c in 99–100% yields.
1
4a-c have the H peaks at d 4.11, 4.57, and 4.50, and the
13C peaks at d 53.39, 61.65, and 66.00, respectively,
1
while 3a-c have the corresponding H peaks at 3.78, 4.43,
and 4.34, and 13C peaks at 29.45, 37.26, and 42.34,
respectively.
1H Peaks of the aromatic protons of 4a-c are more
downfield-shifted than those of 3a-c: the singlet signal of
the hydrogen atom at the 3-position of the quinoline ring
appears at d 6.84–6.85 for 4a-c, but d 6.66–6.68 for 3a-c,
and the protons at the 5-, 6-, 7-, and 8-positions of the
quinoline ring of 4a-c are well resolved as a doublet at d
7.74–7.75, a triplet at d 7.29–7.31, a triplet at d 7.60–7.62,
and a doublet at d 7.89–7.91, respectively, while those of
3a-c appear unresolved at higher field.
4.2.1. Compound 1a. Rf 0.49 (hexane–ethyl acetate, 2:1);
mp 90–91 8C (lit.24 89–90 8C); 1H NMR d 10.82 (broad s,
1H), 8.63 (d, 1H, J¼8 Hz), 7.70 (d, 2H, J¼8 Hz), 7.60–7.46
(m, 5H), 7.08 (t, 1H, J¼8 Hz), 2.23 (s, 3H). IR (KBr): 3161,
1668, 1645, 1603 cm21
.
It is also seen that the characteristic IR peaks of 3a-c and
4a-c exhibit clear differences: N-alkylated compounds
4.2.2. Compound 1b. Rf 0.56 (hexane–ethyl acetate, 2:1);
mp 83–84 8C; 1H NMR d 10.89 (broad s, 1H), 8.67 (d, 1H,
J¼8 Hz), 7.69 (d, 2H, J¼8 Hz), 7.62–7.53 (m, 3H), 7.48 (t,
2H, J¼8 Hz), 7.07 (t, 1H, J¼8 Hz), 2.48 (q, 2H, J¼8 Hz),
1.28 (t, 3H, J¼8 Hz). IR (KBr): 3223, 1667, 1647,
1601 cm21. Anal. Calcd for C16H15NO2: C, 75.87; H,
5.97; N, 5.53. Found: C, 75.49; H, 5.88; N, 5.35.
3a-c have a very strong peak around 1648–1665 cm21
,
while O-alkylated ones 4a-c have a medium peak at
1608–1611 cm21. Comparison of the IR and NMR
spectral data of 2a with those of 3a-c and 4a-c indicates
that the pattern and positions of the NMR peaks of the
aromatic protons and the characteristic IR peak of 2a are
very much similar with those of N-alkylated compounds
3a-c, but not with those of 4a-c. Also, the spectroscopic
characteristics of 2b and 2c are very alike with their
N-alkylated products 3d and 3e, and 3f and 3g,
respectively. Thus, we can conclude unequivocally that
the compound 2a-c exist as the lactam form in our
experimental conditions, either in chloroform solution or
in KBr pellet.
4.2.3. Compound 1c. Rf 0.78 (hexane–ethyl acetate, 2:1);
oil; 1H NMR d 10.87 (s, 1H), 8.67 (d, 1H, J¼8 Hz), 7.69 (d,
2H, J¼7 Hz), 7.62–7.52 (m, 3H), 7.48 (t, 2H, J¼8 Hz), 7.06
(t, 1H, J¼7 Hz), 2.43 (t, 2H, J¼8 Hz), 1.75 (quintet, 2H,
J¼8 Hz), 1.43–1.25 (m, 6H), 0.87 (t, 3H, J¼7 Hz). IR
(KBr): 3309, 1699, 1635, 1603 cm21. Anal. Calcd for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.74; H,
7.74; N, 4.66.
N-Alkylation of N-acyl-o-aminobenzophenone was carried
out using cesium carbonate as a base. To a mixture of 1a
(0.10 g, 0.42 mmol) and cesium carbonate (0.82 g,
2.5 mmol) in acetone (10 ml) was added slowly ethyl iodide
(67 ml, 0.84 mmol). After heating at reflux for 19 h, the
reaction mixture was concentrated. Dichloromethane was
added to the residue and washed with distilled water. The
organic layer was dried over sodium sulfate, filtered,
concentrated, and then purified by silica gel column
chromatography (eluents: n-hexane–ethyl acetate, 1:1) to
provide N-ethyl-o-benzoylacetanilide 5b (0.105 g,
0.393 mmol) in 94% yield: Rf 0.30 (n-hexane–ethyl acetate,
3. Conclusions
We have described an efficient synthesis of 4-phenyl-
quinolin-2(1H)-ones
2 from N-acyl-o-aminobenzo-
phenones 1 using NaH as a base. The alkylation
reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl
halide gave a mixture of N-alkylated and O-alkylated
products 3 and 4. The reaction of 1 with NaH in the
presence of alkyl iodide gave the corresponding N-alkyl-
ated quinolones 3 in 75–95% yields, resulting from
N-alkylation followed by cyclization reaction in one
pot. Comparison of IR and NMR data of 3 and 4 with
those of 2a-c clearly indicates that 2a-c exist as the
lactam form.
1
1:1); mp 87–88 8C; H NMR d 7.80–7.76 (m, 2H), 7.63–
7.42 (m, 6H), 7.28 (d, 1H, J¼8 Hz), 4.05–3.95 (m, 1H),
3.08–2.98 (m, 1H), 1.86 (s, 3H), 1.03 (t, 3H, J¼7 Hz). IR
(KBr): 1659, 1594, 1577 cm21
. Anal. Calcd for

K. K. Park, J. J. Lee / Tetrahedron 60 (2004) 2993–2999
2997
C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.22; H,
6.56; N, 5.14.
161.71, 150.73, 140.12, 136.90, 130.51, 128.76, 128.52,
128.40, 127.55, 121.77, 121.08, 120.32, 114.32, 29.45. IR
(KBr): nCvO 1665 cm21
.
4.3. General procedure for the synthesis of 4-phenyl-
quinolin-2(1H)-ones 2a-c
4.4.2. Compound 3b. Rf 0.46 (hexane–ethyl acetate, 2:1);
mp 99–100 8C (lit.11c 98–99 8C); 1H NMR d 7.59–7.39 (m,
8H), 7.14 (t, 1H, J¼8 Hz), 6.67 (s, 1H), 4.43 (q, 2H,
J¼7 Hz), 1.42 (t, 3H, J¼7 Hz); 13C NMR d 161.27, 150.69,
139.10, 137.02, 130.47, 128.75, 128.49, 128.41, 127.80,
121.56, 121.21, 120.62, 114.21, 37.26, 12.80. IR (KBr):
The mixture of N-acyl-o-aminobenzophenones 1a-c
(0.84 mmol) and sodium hydride (121 mg, 5.04 mmol) in
THF (4 ml) was heated at reflux for 2.5 h for 1a, 9 h for 1b,
and 20 h for 1c. Dichloromethane was added to the
concentrated reaction mixture and washed with distilled
water. The organic layer was dried over sodium sulfate,
filtered, and concentrated. Silica gel column chromato-
graphy of the residue (eluent: hexane–ethyl acetate, 2:1 for
2a; hexane–ethyl acetate, 3:1 for 2b; hexane–ethyl acetate,
5:1 and then 2:1 for 2c) provided the corresponding 2a-c in
83, 62, and 65% yields, together with the deacylated
compound, o-aminobenzophenone with 16, 23, and 22%
yields, respectively.
nCvO 1648 cm21
.
4.4.3. Compound 3c. Rf 0.84 (hexane–ethyl acetate, 2:1);
1
oil; H NMR d 7.59–7.39 (m, 8H), 7.14 (t, 1H, J¼8 Hz),
6.66 (s, 1H), 4.34 (t, 2H, J¼8 Hz), 1.80 (quintet, 2H,
J¼8 Hz), 1.50 (quintet, 2H, J¼7 Hz), 1.43–1.24 (m, 8H),
0.89 (t, 3H, J¼7 Hz); 13C NMR d 161.43, 150.60, 139.32,
137.02, 130.37, 128.74, 128.45, 128.38, 127.73, 121.49,
121.19, 120.57, 114.35, 42.34, 31.79, 29.36, 29.22, 27.54,
27.07, 22.63, 14.10. IR (KBr): nCvO 1652 cm21. Anal.
Calcd for C23H27NO: C, 82.84; H, 8.16; N, 4.20. Found: C,
82.87; H, 8.28; N, 4.32.
4.3.1. Compound 2a. Rf 0.10 (hexane–ethyl acetate, 2:1);
mp 259–261 8C (lit.16a 260 8C; lit.12b 260–262 8C; lit.15
257–259 8C); 1H NMR d 12.87 (s, 1H), 7.58–7.45 (m, 8H),
7.16 (t, 1H, J¼7 Hz), 6.71 (s, 1H); 13C NMR d 164.16,
153.33, 138.87, 137.05, 130.61, 128.78, 128.72, 128.53,
126.64, 122.46, 120.69, 119.52, 116.66. IR (KBr): nCvO
4.4.4. Compound 3d. Rf 0.31 (hexane–ethyl acetate, 2:1);
1
mp 132–133 8C; H NMR d 7.53–7.42 (m, 4H), 7.39 (d,
1H, J¼8 Hz), 7.23–7.19 (m, 2H), 7.12–7.05 (m, 2H), 3.82
(s, 3H), 2.03 (s, 3H); 13C NMR d 162.50, 146.49, 138.47,
136.92, 129.17, 128.77, 128.53, 127.78, 127.54 (two
overlapped C’s), 121.63, 121.56, 113.75, 29.95, 15.33. IR
(KBr): nCvO 1636 cm21. Anal. Calcd for C17H15NO:
C, 81.90; H, 6.06; N, 5.62. Found: C, 81.98; H, 6.05; N,
5.58.
1663 cm21
.
4.3.2. Compound 2b. Rf 0.13 (hexane–ethyl acetate, 2:1);
1
mp 227–228 8C (lit13 227–230 8C); H NMR d 12.61 (s,
1H), 7.55–7.41 (m, 5H), 7.27–7.24 (m, 2H), 7.09–7.03 (m,
2H), 2.10 (s, 3H); 13C NMR d 164.46, 148.68, 137.02,
136.90, 129.17, 128.70, 128.57, 127.86, 127.37, 126.63,
122.07, 121.02, 115.85, 14.38. IR (KBr): nCvO 1652 cm21
.
4.4.5. Compound 3e. Rf 0.44 (hexane–ethyl acetate, 2:1);
1
mp 111 8C (lit. 107–109 8C25); H NMR d 7.53–7.39 (m,
4.3.3. Compound 2c. Rf 0.28 (hexane–ethyl acetate, 2:1);
1
mp 166–168 8C; H NMR d 12.47 (s, 1H), 7.53–7.39 (m,
5H), 7.23–7.19 (m, 2H), 7.11 (dd, 1H, J¼8, 2 Hz), 7.06 (t,
1H, J¼8 Hz), 4.47 (q, 2H, J¼7 Hz), 2.02 (s, 3H), 1.43 (t,
3H, J¼7 Hz); 13C NMR d 161.95, 146.47, 137.42, 137.03,
129.13, 128.74, 128.53, 127.78, 127.73, 127.54, 121.83,
121.39, 113.64, 37.77, 15.20, 12.80. IR (KBr): nCvO
5H), 7.28–7.22 (m, 2H), 7.07–6.98 (m, 2H), 2.49 (t, 2H,
J¼8 Hz), 1.54 (quintet, 2H, J¼7 Hz), 1.28–1.17 (m, 4H),
0.83 (t, 3H, J¼7 Hz); 13C NMR d 164.08, 148.50, 137.06,
136.70, 132.12, 129.11, 128.72, 128.37, 127.77, 126.82,
121.96, 121.27, 115.67, 31.97, 28.83, 28.19, 22.31, 14.00.
IR (KBr): nCvO 1652 cm21. Anal. Calcd for C20H21NO: C,
82.44; H, 7.26; N, 4.81. Found: C, 82.72; H, 7.30; N, 5.04.
1629 cm21
.
4.4.6. Compound 3f. Rf 0.54 (hexane–ethyl acetate, 2:1);
mp 78–79 8C; 1H NMR d 7.52–7.43 (m, 4H), 7.37 (d, 1H,
J¼8 Hz), 7.22 (d, 2H, J¼8 Hz), 7.09–7.01 (m, 2H), 3.81 (s,
3H), 2.41 (t, 2H, J¼8 Hz), 1.46 (quintet, 2H, J¼8 Hz),
1.23–1.12 (m, 4H), 0.79 (t, 3H, J¼7 Hz); 13C NMR d
162.05, 146.42, 138.53, 136.73, 132.16, 129.17, 128.77,
128.35, 127.72 (two overlapped C’s), 121.78, 121.56,
113.69, 32.06, 29.86, 29.18, 28.79, 22.27, 13.98. IR
(KBr): nCvO 1647 cm21. Anal. Calcd for C21H23NO: C,
82.58; H, 7.59; N, 4.59. Found: C, 82.65; H, 7.64; N, 4.69.
4.4. General procedure for the synthesis of N-alkyl-4-
phenylquinolin-2(1H)-one derivatives 3a-g
The mixture of N-acyl-o-aminobenzophenones 1a-c
(0.84 mmol), alkyl iodide (2.10 mmol), and sodium hydride
(121 mg, 5.04 mmol) in THF (4 ml) was heated at reflux.
After the reaction, dichloromethane was added to the
concentrated reaction mixture and washed with distilled
water. The organic layer was dried over sodium sulfate,
filtered, and evaporated to afford a residue. Silica gel
column chromatography (eluent: hexane–ethyl acetate,
5:1 for 3c and n-hexane–ethyl acetate, 2:1 for others)
provided 3a-g. The yields and reaction times are listed in
Table 3.
4.4.7. Compound 3g. Rf 0.66 (hexane–ethyl acetate, 2:1);
1
oil; H NMR d 7.52–7.37 (m, 5H), 7.27–7.17 (m, 2H),
7.08–6.99 (m, 2H), 4.45 (q, 2H, J¼7 Hz), 2.40 (t, 2H,
J¼8 Hz), 1.51–1.37 (m, 5H), 1.23–1.13 (m, 4H), 0.79 (t,
3H, J¼7 Hz); 13C NMR d 161.47, 146.33, 137.49, 136.83,
132.16, 129.10, 128.75, 128.35, 127.95, 127.66, 122.02,
121.30, 113.55, 37.70, 32.08, 29.09, 28.76, 22.23, 13.98,
12.82. IR (KBr): nCvO 1637 cm21. Anal. Calcd for
C22H25NO: C, 82.72; H, 7.89; N, 4.38. Found: C, 82.80;
H, 7.81; N, 4.39.
4.4.1. Compound 3a. Rf 0.37 (hexane–ethyl acetate, 2:1);
1
mp 146 8C (lit.16a 146 8C); H NMR d 7.60–7.40 (m, 8H),
7.16 (t, 1H, J¼8 Hz), 6.68 (s, 1H), 3.78 (s, 3H); 13C NMR d

2998
K. K. Park, J. J. Lee / Tetrahedron 60 (2004) 2993–2999
cyclic chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon: New York, 1996; Vol. 5, pp 245–300.
(b) Yates, F. S. Comprehensive heterocyclic chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York,
1984; Vol. 2, pp 511–524.
4.5. Alkylation reaction of 2a with alkyl halides
To a mixture of 2a (100 mg, 0.47 mmol) and K2CO3
(393 mg, 2.84 mmol) in DMF (5 ml) was added slowly alkyl
halide (0.95 mmol) and the reaction mixture was heated at
70 8C. After the reaction, dichloromethane was added to the
concentrated reaction mixture and washed with distilled
water. The organic layer was dried over sodium sulfate,
filtered, and evaporated to afford a residue. Separation of the
residue by silica gel column chromatography (eluents:
n-hexane–ethyl acetate, 5:1 and then 2:1 or 1:1) provided
the corresponding N-alkylated product (3a-c) and O-alkyl-
ated product (4a-c): O-alkylated product eluted first and
then followed by N-alkylated product. The reactions using
Cs2CO3 or NaH instead of K2CO3 as a base and THF instead
of DMF as a solvent were carried out similarly. The product
distributions and reaction times are listed in Table 1. The
characterization data of 3a-c are given in Section 4.4.
3. (a) Jones, G. Comprehensive heterocyclic chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: New York, 1996; Vol. 5, pp 167–243. (b) Jones, G.
Comprehensive heterocyclic chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon: New York, 1984; Vol. 2, pp 395–510.
(c) Claret, P. A. Comprehensive organic chemistry; Barton,
D., Ollis, W. D., Eds.; Pergamon: New York, 1979; Vol. 4,
pp 157–166.
4. (a) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5,
4257–4259. (b) Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.;
Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem. 2003, 68,
9371–9378. (c) Abbiati, G.; Beccalli, E. M.; Broggini, G.;
Zoni, C. Tetrahedron 2003, 59, 9887–9893. (d) Fan, X.;
Zhang, Y. Tetrahedron Lett. 2002, 43, 7001–7003. (e) Cacchi,
S.; Fabrizi, G.; Goggiamani, A.; Moreno-Man˜as, M.;
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(f) Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das, J.; Iqbal, J.
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4.5.1. Compound 4a. Rf 0.76 (hexane–ethyl acetate, 5:1);
1
mp 79–80 8C (lit.26 78–80 8C); H NMR d 7.91 (d, 1H,
J¼8 Hz), 7.75 (d, 1H, J¼8 Hz), 7.62 (t, 1H, J¼8 Hz), 7.53–
7.44 (m, 5H), 7.31 (t, 1H, J¼8 Hz), 6.85 (s, 1H), 4.11 (s,
3H); 13C NMR d 161.93, 151.03, 147.10, 137.89, 129.33,
129.27, 128.40, 128.26, 127.55, 125.72, 123.97, 123.88,
112.75, 53.39. IR (KBr): nCvN 1611 cm21
.
4.5.2. Compound 4b. Rf 0.79 (hexane–ethyl acetate, 5:1);
oil (lit.27 54–55 8C); 1H NMR d 7.89 (d, 1H, J¼8 Hz), 7.74
(d, 1H, J¼8 Hz), 7.60 (t, 1H, J¼8 Hz), 7.52–7.43 (m, 5H),
7.29 (t, 1H, J¼7 Hz), 6.84 (s, 1H), 4.57 (q, 2H, J¼7 Hz),
1.46 (t, 3H, J¼7 Hz); 13C NMR d 161.64, 150.92, 147.19,
137.95, 129.26 (two overlapped C’s), 128.38, 128.20,
127.55, 125.67, 123.90, 123.75, 112.98, 61.65, 14.72. IR
(KBr): nCvN 1608 cm21. Anal. Calcd for C17H15NO: C,
81.90; H, 6.06; N, 5.62. Found: C, 81.87; H, 6.04; N, 5.68.
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4.5.3. Compound 4c. Rf 0.87 (hexane–ethyl acetate, 5:1);
oil; 1H NMR d 7.89 (d, 1H, J¼8 Hz), 7.74 (d, 1H, J¼8 Hz),
7.60 (t, 1H, J¼8 Hz), 7.52–7.43 (m, 5H), 7.29 (t, 1H,
J¼8 Hz), 6.85 (s, 1H), 4.50 (t, 2H, J¼7 Hz), 1.84 (quintet,
2H, J¼7 Hz), 1.49 (quintet, 2H, J¼7 Hz), 1.43–1.24 (m,
8H), 0.88 (t, 3H, J¼7 Hz); 13C NMR d 161.85, 150.89,
147.20, 137.96, 129.26, 129.23, 128.36, 128.20, 127.53,
125.66, 123.88, 123.72, 113.01, 66.00, 31.89, 29.46, 29.34,
29.12, 26.22, 22.74, 14.19. IR (KBr): nCvN 1608 cm21
Anal. Calcd for C23H27NO: C, 82.84; H, 8.16; N, 4.20.
Found: C, 83.06; H, 8.22; N, 4.00.
8. Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.;
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This work was supported by grant No. R05-2003-000-
10459-0 from the Basic Research Program of the Korea
Science and Engineering Foundation.
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