Intramolecular amidation - An efficient synthesis of 3-aryl-2-quinolinones

Article abstract of DOI:10.1139/V06-163

To reveal the scope of the syntheses of 3-aryl-2-quinolinones from 2-nitro-α-phenylcinnamic acids, the isomerization of (E)-2-amino-α- phenylcinnamic acids was studied. The results showed that (E)-2-amino-α- phenylcinnamic acids were isomerized to its (Z)

Full text of DOI:10.1139/V06-163

1620
Intramolecular amidation — An efficient synthesis
of 3-aryl-2-quinolinones
Yinggang Luo, Feiyan Tao, Yan Liu, Bogang Li, and Guolin Zhang
Abstract: To reveal the scope of the syntheses of 3-aryl-2-quinolinones from 2-nitro-α-phenylcinnamic acids, the
isomerization of (E)-2-amino-α-phenylcinnamic acids was studied. The results showed that (E)-2-amino-α-
phenylcinnamic acids were isomerized to its (Z)-forms under sunlight in organic solvents. The reaction temperature and
the functional groups at both phenyl rings have no effect on the isomerization of (E)-2-amino-α-phenylcinnamic acids
and the following intramolecular spontaneous amidation of (Z)-2-amino-α-phenylcinnamic acids. Various 3-aryl-2-
quinolinones prepared in high total yields indicated that the syntheses of 3-aryl-2-quinolinones from Perkin condensa-
tion products 2-nitro-α-phenylcinnamic acids via reduction, sunlight-induced isomerization of (E)-2-amino-α-
phenylcinnamic acids, and the following intramolecular amidation is an efficient procedure.
Key words: 3-aryl-2-quinolinones, isomerization, amidation.
Résumé : Afin d’évaluer la portée des synthèses de 3-aryl-2-quinoléinones à partir d’acides 2-nitro–phénylcinnamiques,
on a étudié l’isomérisation des acides (E)-2-amino-α-phénylcinnamiques. Les résultats montrent que les acides (E)-2-
amino-α-phénylcinnamiques en solution dans des solvants organiques s’isomérisent en formes (Z) sous l’influence de la
lumière du jour, que la température de la réaction et les groupes fonctionnels sur l’un ou l’autre des groupes phényles
n’ont aucune influence sur l’isomérisation des acides (E)-2-amino-α-phénylcinnamiques et sur l’amidation spontanée in-
tramoléculaire des acides (Z)-2-amino-α-phénylcinnamiqued. Les synthèses de 3-aryl-2-quinoléinones à partir des acides
2-nitro-α-phénylcinnamiques qui ont été obtenus comme produits de condensation de Perkin, puis soumis à une réduc-
tion, une isomérisation induite par la lumière des acides (E)-2-amino-α-phénylcinnamiques et une amidation intramolé-
culaire s’avèrent efficaces.
Mots clés : 3-aryl-2-quinoléinones, isomérisation, amidation.
[Traduit par la Rédaction] Luo et al. 1625
Introduction
To date, the condensation of anilines with arylmalonate or
its analogues (1, 2a) and the palladium-catalyzed annulation
of o-iodoaniline derivatives with aryl substituted terminal al-
kynes or 2-phenylacrylic acid were introduced into the syn-
theses of 3-aryl-2-quinolinones (5, 6). The total yields
ranged from 9.10 to 40.85% for the former strategy (1, 2)
and from 20 to 42% for the latter one (5, 6). Recently, palla-
dium-catalyzed amidation of o-carbonyl-substituted aryl
halides for quinolinones (7a) and a rapid assembly of 4-
fluoroquinolinones were reported (7b).
3-Aryl-2-quinolinones, a small-amount by-product in
Pschorr’s phenanthrene synthesis, were obtained from the re-
duction of (Z)-2-nitro-α-phenylcinnamic acids originally formed
in Perkin condensation (8). (E)-2-Amino-α-phenylcinnamic
acids could be converted to 3-aryl-2-quinolinones by treat-
ment with acetic anhydride and concentrated sulfuric acid or
zinc chloride (8a, 9) or by exposure to ultraviolet (8a) or
sunlight (10). The methyl esters of (E)-2-amino-α-phenyl-
cinnamic acids were converted to 3-aryl-2-quinolinones by
heating or by standing at room temperature (10).
3-Aryl-2-quinolinones could inhibit the migration of tu-
mor cells with no cytotoxicity in vitro or in vivo. The com-
bination of 3-aryl-2-quinolinones and doxorubicin (or
etoposide), two drugs routinely used in clinic, led to additive
in vivo benefits compared with individual administration of
the drugs (1). 3-Aryl-2-quinolinones were also efficient tools
in the treatment of osteoporosis (2). They were selective
non-competitive antagonists of N-methyl-D-aspartate recep-
tors and (or) antagonists of 2-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptors (3). They could serve as
precursors of a new class for nonpeptide gonadotropin re-
leasing hormone receptor antagonists (4).
Received 30 March 2006. Accepted 20 October 2006.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 7 December 2006.
Y. Luo, Y. Liu, B. Li, and G. Zhang.1 Chengdu Institute of
Biology, The Chinese Academy of Sciences, Chengdu
610041, People’s Republic of China.
F. Tao. Chengdu Institute of Biology, The Chinese Academy
of Sciences, Chengdu 610041, People’s Republic of China;
Graduate School of the Chinese Academy of Sciences,
Beijing 10049, People’s Republic of China.
However, the scope of the preparation of 3-aryl-2-quino-
linones from 2-amino-α-phenylcinnamic acids including the
detailed process of the isomerization of the (E)-2-amino-α-
phenylcinnamic acids, the effect of the functional groups at
aryl moieties on the isomerization, and the following sponta-
neous intramolecular amidation has not been reported.
1Corresponding author (e-mail: zhanggl@cib.ac.cn).
Can. J. Chem. 84: 1620–1625 (2006)
doi:10.1139/V06-163
© 2006 NRC Canada

Luo et al.
1621
1
Fig. 1. H NMR spectra of the isomers of compound 3d in CDCl3: (a) (E)-3d; (b) (Z)-3d.
1
Taken as an example, Fig. 1 shows the H NMR spectra of
(E)-3d and (Z)-3d, which could be separated by silica gel
column chromatography or fractional crystallization.
Scheme 1.
R4
R1
CHO
COOH
R3
R1
R2
R3
R5
R6
1
R2
R4
NO2
R1
R2
Reduction of the mixture of (E)-3 and (Z)-3 by ferrous
sulfate in aq. ammonia led to the formation of (E)-4 and 3-
aryl-2-quinolinones (5); thus, indicating that (Z)-4 spontane-
ously cyclized to give the intramolecular amidation products
5. Roy and Bhaduri (8c) suggested that only (Z)-3d could be
converted to 3-aryl-2-quinolinone by reduction. To confirm
their conclusion, the (E)-3d and (Z)-3d were isolated and
characterized on the basis of NMR, IR, UV, and mass spec-
tral data. The stereochemistry of (E)-3d was confirmed by
X-ray crystallographic analysis (Fig. S1, the ORTEP draw-
ing of CCDC 264443, see supplementary data).2 Reduction
of (Z)-3d by ferrous sulfate in aqueous ammonia with or
without exposure to sunlight led to 3-aryl-2-quinolinone
(5d), whereas the reduction of (E)-3d under the same condi-
tions afforded only (E)-4d.
NO2
R6
Ac2O, NEt3
R3
COOH
NO2
Argon, reflux
+
R4
(E)-3
COOH
(Z)-3
R5
FeSO4.7H2O
FeSO4.7H2O
NH3.H2O
2
R5
NH3.H2
O
R6
R4
C
R4
R5
4'
R3
COOH
R1
R3
R5
sunlight
5
B
8
4
6
3
R1
R
R3
R4
R6
R1
1'
O
R2
NH2
R6
A
N
H
2
Intramolecular
amidation
COOH
27
1
R6
R2
NH2
R5
5
-4
(E)
-4
(Z)
Herein, we report our investigations concerning these prob-
lems.
Results and discussion
Perkin condensation of 2-nitro-benzaldehydes (1) and
phenylacetic acids (2) gave a mixture of the (E)- and (Z)-iso-
mers of 2-nitro-α-phenylcinnamic acids (3) (Scheme 1). The
ratio of (E)- and (Z)-isomers could be determined by proton
However, 3-aryl-2-quinolinone (5d) was obtained when
(E)-4d was dissolved in acetone and was left standing under
sunlight at room temperature. Initially, only (E)-4d was ob-
served in the H NMR spectrum, and it was stable without
exposure to sunlight. When the acetone solution of (E)-4d
1
1
integration in the H NMR spectra without separation (8c).
2 Supplementary data for this article are available on the journal Web site or may be purchased from the Depository of Unpublished Data,
Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0S2, Canada. DUD 5108. For more information on ob-
taining material refer to http://cisti-icist.nrc.cnrc.gc.ca/irm/unpub_e.shtml. CCDC 264442 and 264443 contain the crystallographic data for
this manuscript. These data can be obtained, free of charge, via ww.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
© 2006 NRC Canada

1622
Can. J. Chem. Vol. 84, 2006
1
Fig. 2. Conversion of (E)-4d to 5d in acetone-d6 monitored by H NMR spectra: (a) 10 min, (b) 30 min, (c) 60 min, (d) 90 min,
(e) 10 h, and ( f ) 16 h.
1
was left standing under sunlight, the ratio of (E)-4d, (Z)-4d,
and 5d changed from 100:0:0 to 0:0:100 in 16 h (Fig. 2),
suggesting that the isomerization of (E)-4d to (Z)-4d is a
sunlight-induced process and the formation of 5d from (Z)-
4d is an intramolecular spontaneous amidation.
All 3-aryl-2-quinolinones were identified by H and 13C
NMR, UV, IR, ESIMS, and HR-ESIMS data. The basic skel-
eton of 3-aryl-2-quinolinone, compound 5i, was confirmed
by X-ray crystallographic analysis (Fig. S2, the ORTEP
drawing of CCDC 264442).2
In conclusion, it is an efficient procedure to prepare
3-aryl-2-quinolinones from Perkin condensation products
(Z)- and (E)-2-nitro-α-phenylcinnamic acids via reduction,
sunlight-induced isomerization of (E)-2-amino-α-phenyl-
cinnamic acids to its (Z)-forms, and the spontaneous
intramolecular amidation of the latter.
(E)-4d kept unchanged in H2O, 5% HCl (aq.), 5% NaOH
(aq.), or 25% aq. ammonia under sunlight, indicating that
sunlight could not induce the isomerization of (E)-4d to its
(Z)-isomer in acidic, basic, or neutral aqueous media. The
conversion of (E)-4d to 5d in protic and polar aprotic sol-
vents was very easy and fast (10–18 h), but it was difficult in
nonpolar aprotic solvents (>48 h).2
To investigate the scope of this method, 26 3-aryl-2-
quinolinones with electron-withdrawing and electron-
donating groups on the rings B and C were synthesized
(Scheme 1 and Table 1). The functional groups have no ef-
fect on the isomerization of (E)-4 to (Z)-4 or on the subse-
quent intramolecular amidation of (Z)-4 to 3-aryl-2-
quinolinones in view of the total yields of the title com-
pounds (Table 1). The same conversion rate of (E)-4d to 5d
was observed when the acetone solution of (E)-4d was ex-
posed to sunlight with stirring under reflux at room tempera-
ture or at 0 °C, indicating that the temperature has no effect
on this process.
Experimental
General
All reagents were commercial and were used without pu-
rification. The 2-nitrobenzaldehydes with electron-
withdrawing groups such as 4-bromo (11), 5-bromo (12), 5-
chloro (12), and 4-acetyl (13) were prepared according to
the literature. 2-Benzyloxyphenylacetic acid was prepared
according to the reported procedure (14). Acetic anhydride
was obtained by fractional distillation. Triethylamine was
refluxed for 6 h with the freshly distilled acetic anhydride,
then distilled, refluxed with CaH2, and distilled again.
Melting points were recorded on an X-6 apparatus and were
uncorrected. IR spectra were recorded on a PerkinElmer
Spectrum One spectrometer using KBr discs, and νmax is
given in cm–1. UV spectra were recorded in MeOH (1 mg in
In the case of 3f–3h and 3n–3p, the hydroxyl groups were
acetylated during Perkin reaction. The acetyl groups were
removed during reduction, which was concluded from their
1H NMR spectral data (Table 1, entries 6–8 and 14–16).
© 2006 NRC Canada

Luo et al.
1623
Table 1. The prepared 3-aryl-2-quinolinones bearing different functional groups.
Entry
Compound
R1
R2
R3
R4
R5
R6
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
Cl
Cl
Br
H
Br
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
OMe
H
H
H
OH
H
H
H
OMe
H
H
H
OH
H
H
H
H
H
H
H
H
OMe
H
OMe
H
OH
H
H
H
OMe
H
OMe
H
OH
H
H
Cl
H
H
Cl
H
H
H
H
OMe
H
H
H
OH
H
H
H
OMe
H
H
H
OH
OMe
H
OMe
OMe
H
H
H
H
H
OMe
H
H
H
H
H
H
H
OMe
H
H
H
H
H
88.9
88.4
86.8
88.4
88.0
85.9
87.5
89.2
88.2
85.7
89.6
87.6
89.0
86.5
88.6
88.6
89.3
83.6
89.4
88.0
87.0
95.6
H
H
H
H
5t
5u
5v
H
H
H
CH3CO
OMe
23
5w
H
CH3CO
H
H
F
H
82.7
24
25
26
5x
5y
5z
OMe
OMe
OMe
OMe
OMe
OMe
H
H
OBn
Cl
H
H
H
F
H
H
H
H
84.0
86.0
84.7
aIsolated total yield starting from compound 1.
50 mL) on a PerkinElmer Lambda 35 spectrometer. NMR
spectra were recorded on a Bruker Avance 600 spectrometer
(1H NMR: 600 MHz; 13C NMR: 150 MHz) at room temper-
ature in DMSO-d6, when not mentioned. The chemical shifts
(δ) are reported in ppm relative to tetramethylsilane as an in-
ternal standard, and the coupling constants (J) are given
in Hz. HR-ESIMS spectra were obtained on a Bio TOF IIIQ
mass spectrometer. Column chromatography (CC) was per-
formed on self-packed open column with silica gel (200–
300 mesh) from Qingdao Ocean Chemical Engineering
Company (QOCEC, Qingdao, P.R. China). TLC analyses
were carried out on plates precoated with 10–40 µ of silica
gel GF254 from QOCEC and were visualized under an ultra-
violet lamp.
and ethyl acetate. The organic layers were combined,
washed with brine, dried over anhyd. Na2SO4, and concen-
trated to give a residue. The residue and the precipitate were
pure enough for the next step. For compound 3d, the two
isomers can be separated by column chromatography over
silica gel and eluted with petroleum ether (bp 60–90 °C) :
acetone : acetic acid (5:1:0.025) (the value of Rf-(E)-3d > the
value of Rf-(Z)-3d) or by fractional crystallization from etha-
nol, in which (E)-3d crystallized from ethanol and (Z)-3d
was left in the mother liquor.
General procedure for preparation of substituted 2-
amino-␣-phenylcinnamic acids 4
Compounds 4 were prepared according to Bradsher et al.
(15b) with some modifications. A solution of 3 in 10% aq.
ammonia was added dropwise in the course of 3 to 6 min to
a solution of 440 mg of FeSO4·7H2O in 1.3 mL of H2O and
0.03 mL of 25% aq. ammonia (several drops of n-butanol
was added to the solution before heating to prevent foaming)
under reflux. A total of 0.5 mL of concd. aq. ammonia was
added slowly to the mixture within 85 min. When the reac-
tion was completed, the reaction solution was cooled to 40–
50 °C and filtered. The dark residue was washed six times
with 10% aq. ammonia solution at about 50 °C, then washed
10 times with ethyl acetate. The combined basic solution
was acidified carefully with acetic acid to pH = 6.0 and then
extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over anhyd. Na2SO4, and con-
General procedure for preparation of substituted 2-
nitro-α-phenylcinnamic acids 3.
Compounds 3 were prepared according to Lebrun et al.
(15a) with some modifications. A solution of 2-nitro-
benzaldehyde (1, 0.2 mmol), NEt3 (0.5 mL), substituted
phenylacetic acid (2, 0.22 mmol), and Ac2O (0.5 mL) was
refluxed under argon for 30 min (TLC analysis). When the
reaction was completed, water (10 mL) was added to the re-
action mixture. During the addition, the temperature of the
mixture should be maintained at 100–110 °C. Then, the re-
action mixture was cooled to room temperature and then to
0 °C. The precipitate from the cold solution was collected by
filtration. The mother liquor was partitioned between water
© 2006 NRC Canada

1624
Can. J. Chem. Vol. 84, 2006
centrated to give a residue. For compound (E)-4d, the resi-
due was subjected to column chromatography over silica gel
and eluted with petroleum ether (bp 60–90 °C) : acetone : ace-
tic acid (2:1:0.025) to give (E)-4d and 5d.
3-(2-Hydroxyphenyl)-quinolin-2(1H)-one (5n)
White solid (41 mg); mp 272–274 °C. UV λmax (log ε):
239 (4.34), 269 (3.97), 292 (3.99), 342 nm (4.18). IR νmax
:
3436, 1641, 1603, 1573, 1553, 1490, 1476, 1424, 1379,
1292, 1256, 1233, 1196, 1161, 1109, 1048, 995, 952, 943,
1
927, 911, 847, 807, 750, 718, 676 cm–1. H NMR: δ 12.23
General procedure for the preparation of 3-aryl-2-
quinolinones 5
(1H, s, NH), 9.73 (1H, s, OH), 8.08 (1H, s), 7.76 (1H, d, J =
7.86 Hz), 7.55 (1H, t, J = 8.1 Hz), 7.40 (1H, d, J = 8.22 Hz),
7.35 (1H, d, J = 7.44), 7.25 (1H, t, J = 7.32 Hz), 7.24 (1H, t,
J = 7.74 Hz), 6.91 (1H, d, J = 8.1 Hz), 6.88 (1H, t, J =
7.32 Hz). 13C NMR: δ 162.5, 155.9, 140.5, 138.4, 131.6,
131.1, 130.8, 129.8, 128.5, 124.5, 122.7, 120.2, 119.6,
117.3, 115.5. ESIMS (positive ion mode) m/z: 238 ([M +
H]+, 100). ESIMS (negative ion mode) m/z: 236 ([M – H]–,
100). HR-ESIMS (positive ion mode) m/z: 260.0682 ([M +
Na]+ calcd. for C15H11NO2Na, 260.0682; error 0.10 ppm).
The previously obtained residue was dissolved in acetone
and was left standing under sunlight at room temperature un-
til (E)-4 was converted to 3-aryl-2-quinolinones (5, TLC
analysis). Most of the 3-aryl-2-quinolones were crystallized
or precipitated from the solution. The mother liquor was
subjected to silica gel column chromatography and eluted
with petroleum ether (bp 60–90 °C) : acetone (5:2) to give
another portion of 3-aryl-2-quinolinones.
6,7-Dimethoxy-3-(4-methoxyphenyl)-quinolin-2(1H)-one (5d)
White solid (55 mg); mp 259–260 °C (lit. 247–249 °C
(16)). UV λmax (log ε): 239 (4.40), 299 (3.88), 360 nm
(4.23). IR νmax: 3436, 1650, 1628, 1571, 1509, 1448, 1421,
1395, 1264, 1245, 1212, 1178, 1153, 1037, 1005, 929, 843,
7-Bromo-3-(4-methoxyphenyl)-quinolin-2(1H)-one (5t)
White solid (58 mg); mp 222–225 °C. UV λmax (log ε):
237 (4.38), 299 (3.95), 316 (4.01), 346 nm (4.22). IR νmax
:
3436, 2924, 2853, 1657, 1607, 1564, 1512, 1462, 1393,
1
1255, 1179, 1071, 1033, 988, 945, 826, 617, 555 cm–1. H
1
830, 795, 755, 605 cm–1. H NMR: δ 11.72 (1H, s, NH),
NMR: δ 11.98 (1H, s, NH), 8.07 (1H, s), 7.74 (2H, d, J =
8.6 Hz), 7.67 (1H, d, J = 8.2 Hz), 7.49 (1H, s), 7.35 (1H, dd,
J = 8.2, 1.3 Hz), 7.00 (2H, d, J = 8.6 Hz), 3.80 (3H, s, H-4′-
OMe). 13C NMR: δ 161.5, 160.0, 139.5, 136.2, 131.9, 130.4,
128.6, 125.2, 123.2, 119.2, 117.3, 113.9, 55.6. ESIMS (posi-
tive ion mode) m/z: 352 ([M + Na]+, 100). HR-ESIMS (posi-
tive ion mode) m/z: 351.9936 ([M + Na]+calcd. for
C16H1279BrNNaO2, 351.9944; error 2.17 ppm).
7.95 (1H, s), 7.72 (2H, d, J = 8.8 Hz), 7.25 (1H, s), 6.98
(2H, d, J = 8.8 Hz), 6.87 (1H, s), 3.83, 3.80 and 3.79 (each
3H, s, H-6, 7, 4′-OMe). 13C NMR: δ 161.4, 159.2, 152.1,
145.4, 136.5, 134.2, 130.1, 129.5, 128.4, 113.8, 113.4,
109.3, 97.7, 56.2, 56.0, 55.6. ESIMS (positive ion mode)
m/z: 312 ([M + H]+, 100). HR-ESIMS (positive ion mode)
m/z: 312.1221 ([M + H]+ calcd. for C18H18NO4, 312.1230;
error 3.12 ppm).
6-Bromo-3-(3-chlorophenyl)-quinolin-2(1H)-one (5u)
White solid (58 mg); mp 258–261 °C. UV λmax (log ε):
242 (4.65), 291 (4.18), 350 nm (4.10). IR νmax: 3435, 2972,
2924, 1727, 1663, 1567, 1477, 1426, 1282, 1227, 1103, 924,
6,7-Dimethoxy-3-(2-hydroxyphenyl)-quinolin-2(1H)-one (5f)
Off-yellow solid (51 mg); mp 204.5–205.5 °C. UV λmax
(log ε): 240 (4.51), 298 (3.96), 361 nm (4.42). IR νmax: 3434,
1644, 1625, 1611, 1568, 1516, 1490, 1474, 1443, 1414,
1394, 1352, 1293, 1277, 1252, 1215, 1160, 1039, 1012, 932,
916, 857, 832, 817, 761, 741, 724, 688, 608 cm–1. 1H NMR: δ
12.33 (1H, s, NH), 10.1 (1H, s, OH), 8.10 (1H, s), 7.38 (1H,
dd, J = 7.6, 1.4 Hz), 7.35 (1H, s), 7.24 (1H, td, J = 7.9,
1.4 Hz), 6.97 (1H, s), 6.92 (1H, dd, J = 7.3, 1.4 Hz), 6.90
(1H, td, J = 7.9, 1.4 Hz), 3.87 and 3.82 (each 3H, s, H-6, 7-
OMe). 13C NMR: δ 162.6, 156.2, 152.9, 146.1, 140.7, 134.0,
131.3, 129.7, 127.8, 125.1, 120.0, 118.1, 114.0, 109.2, 97.8,
56.3, 56.2. ESIMS (negative ion mode) m/z: 296 ([M – H]–,
25). HR-ESIMS (positive ion mode) m/z: 320.0881 ([M +
Na]+ calcd. for C17H15NO4Na, 320.0893; error 3.74 ppm).
1
867, 813, 791, 763, 687, 605, 567, 516, 468 cm–1. H NMR:
δ 12.20 (1H, s, NH), 8.20 (1H, s), 7.99 (1H, d, J = 1.8 Hz),
7.85 (1H, s), 7.71 (1H, d, J = 7.0 Hz), 7.68 (1H, dd, J = 8.7,
2.0 Hz), 7.46–7.50 (2H, m), 7.29 (1H, d, J = 8.7 Hz). 13C
NMR: δ 161.0, 138.3, 138.0, 137.7, 133.5, 133.1, 131.4,
130.6, 130.4, 128.9, 128.4, 127.8, 121.6, 117.4, 114.02. HR-
ESIMS (positive ion mode) m/z: 355.9449 ([M + Na]+calcd.
for C15H979Br35ClNNaO, 355.9448; error –0.32 ppm).
7-Acetyl-3-(4-methoxyphenyl)-quinolin-2(1H)-one (5v)
Off-yellow solid (56 mg); mp 243–245 °C. UV λmax
(log ε): 238 (4.31), 274 (3.83), 339 (4.04), 366 nm (4.11). IR
ν
max: 3435, 2930, 1689, 1663, 1607, 1564, 1518, 1500, 1396,
3-Phenyl-quinolin-2(1H)-one (5i)
1369, 1302, 1251, 1222, 1180, 1112, 1033, 913, 872, 820,
638, 621, 591 cm–1. H NMR: δ 12.11 (1H, s, NH), 8.14
1
Granule crystals (39 mg); mp 226.2–227 °C (lit. white
solid; mp 230–231 °C (5)). UV λmax (log ε): 239 (4.24), 290
(3.97), and 339 nm (3.96). IR νmax: 3436, 1656, 1599, 1567,
1497, 1444, 1429, 1368, 1310, 1227, 1126, 1073, 1029, 985,
(1H, s), 7.88 (1H, s), 7.85 (1H, d, J = 7.6 Hz), 7.77 (2H, d, J
= 8.3 Hz), 7.76 (1H, d, J = 7.6 Hz), 7.01 (2H, d, J = 7.5 Hz),
3.81 (3H, s, H-4′-OMe), 2.62 (3H, s, 7-CH3CO–). 13C NMR:
δ 198.0, 161.7, 159.9, 138.2, 137.4, 135.9, 133.8, 130.5,
128.7, 128.5, 123.5, 121.8, 114.9, 113.9, 55.7, 27.3. HR-
ESIMS (positive ion mode) m/z: 316.0939 ([M + Na]+calcd.
for C18H15NNaO3, 316.0944; error –1.48 ppm).
1
946, 909, 880, 788, 752, 730, 698 cm–1. H NMR: δ 11.94
(1H, s, NH), 8.09 (1H, s), 7.73 (3H, m), 7.38 (5H, m), 7.19
(1H, br s). 13C NMR: δ 161.5, 138.8, 138.1, 136.7, 132.0,
130.7, 129.1, 128.6, 128.4, 128.3, 122.4, 120.0, 115.1.
ESIMS (positive ion mode) m/z: 222 ([M + H]+, 100).
ESIMS (negative ion mode) m/z: 220 ([M – H]–, 100). HR-
ESIMS (positive ion mode) m/z: 244.0739 ([M + Na]+ calcd.
for C15H11NONa, 244.0733; error –2.43 ppm).
7-Acetyl-3-(4-fluorophenyl)-quinolin-2(1H)-one (5w)
White solid (46 mg); mp 293–296 °C. UV λmax (log ε):
238 (4.34), 312 (4.15), 360 nm (4.03). IR νmax: 3435, 2930,
© 2006 NRC Canada

Luo et al.
1625
3. (a) P.D. Lesson, R. Baker, R.W. Carling, J.J. Kulagowski, I.M.
Mawer, M.P. Ridgill, M. Rowley, J.D. Smith, and I.
Standsfield. Bioorg. Med. Chem. Lett. 3, 299 (1993); (b) R.W.
Carling, P.D. Leeson, K.W. Moore, and M. Rowley. WO
9311115, 1993.
2844, 1664, 1603, 1564, 1501, 1398, 1371, 1301, 1222,
1163, 1114, 877, 826, 806, 635, 593, 549, 522, 468 cm–1.
1H NMR: δ 12.17 (1H, s, NH), 8.20 (1H, s), 7.88 (1H, s),
7.83–7.86 (3H, m), 7.76 (1H, d, J = 8.1 Hz), 7.28 (2H, t, J =
8.8 Hz), 2.62 (3H, s, 7-CH3CO–). 13C NMR: δ 197.9, 163.4,
161.7, 138.5, 137.8, 137.2, 133.1, 132.6, 131.4, 131.3,
129.0, 123.2, 121.8, 115.4, 115.3, 115.0, 27.4. HR-ESIMS
(positive ion mode) m/z: 304.0740 ([M + Na]+calcd. for
C17H12FNNaO2, 304.0744; error 1.53 ppm).
4. (a) J.L. Jiang, R.J. DeVita, M.T. Goulet, M.J. Wyvratt, J.L. Lo,
N. Ren, J.B. Yudkovitz, J.S. Cui, Y.T. Yang, K. Cheng, and
S.P. Rohrer. Bioorg. Med. Chem. Lett. 14, 1795 (2004);
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Ujjainwalla, R.B. Toupence, M. Parikh, S.X. Huang, J.A. Fair,
M.T. Goulet, M.J. Wyvratt, J.L. Lo, N. Ren, J.B. Yudkovitz,
Y.T. Yang, K. Cheng, J.S. Cui, G. Mount, S.P. Rohrer, J.M.
Schaeffer, L. Rhodes, J.E. Drisko, E. McGowan, D.E. MacIn-
tyre, S. Vincent, J.R. Carlin, J. Cameron, and R.G. Smith. J.
Med. Chem. 44, 917 (2001); (c) J.R. Young, S.X. Huang, I.
Chen, T.F. Walsh, R.J. DeVita, M.J. Wyvratt, M.T. Goulet, N.
Ren, J.L. Lo, Y.T. Yang, J.B. Yudkovitz, K. Cheng, and R.G.
Smith. Bioorg. Med. Chem. Lett. 10, 1723 (2000); (d) T.F.
Walsh, R.B. Toupence, J.R. Young, S.X. Huang, F.
Ujjainwalla, R.J. DeVita, M.T. Goulet, M.J. Wyvratt, M.H.
Fisher, J.L. Lo, N. Ren, J.B. Yudkovitz, Y.T. Yang, K. Cheng,
and R.G. Smith. Bioorg. Med. Chem. Lett. 10, 443 (2000);
(e) R.J. DeVita, M.T. Goulet, M.J. Wyvratt, M.H. Fisher, J.L.
Lo, Y.T. Yang, K. Cheng, and R.G. Smith. Bioorg. Med.
Chem. Lett. 9, 2621 (1999); ( f ) R.J. DeVita, D.D. Hollings,
M.T. Goulet, M.J. Wyvratt, M.H. Fisher, J.L. Lo, Y.T. Yang, K.
Cheng, and R.G. Smith. Bioorg. Med. Chem. Lett. 9, 2615
(1999).
5. D.V. Kadnikov and R.C. Larock. J. Organomet. Chem. 687,
425 (2003).
6. M.O. Terpko and R.F. Heck. J. Am. Chem. Soc. 101, 5281
(1979).
7. (a) P.J. Manley and M.T. Bilodeau. Org. Lett. 6, 2433 (2004);
(b) A.S. Kiselyov, E.L. Piatnitski, and J. Doody. Org. Lett. 6,
4061 (2004).
8. (a) J.W. Gulland and C.J. Virden. J. Chem. Soc. 1478 (1928);
(b) G.L. Buchanan, J.W. Cook, and J.D. Loudon. J. Chem.
Soc. 325 (1944); (c) J. Roy and A.P. Bhaduri. Indian J. Chem.
16B, 744 (1978).
3-(3-Chlorophenyl)-6,7-dimethoxy-quinolin-2(1H)-one (5x)
White needle crystal (53 mg); mp 247–248 °C. UV λmax
(log ε): 238 (4.32), 298 (3.79), 362 nm (4.06). IR νmax: 3436,
2925, 1664, 1630, 1594, 1572, 1508, 1491, 1470, 1421,
1389, 1276, 1263, 1243, 1211, 1158, 1021, 928, 834, 785,
754, 701, 674, 606, 575, 542 cm–1. 1H NMR: δ 11.87 (1H, s,
NH), 8.12 (1H, s), 7.88 (1H, s), 7.72 (1H, d, J = 7.6 Hz),
7.45 (1H, t, J = 7.6 Hz), 7.40 (1H, d, J = 7.6 Hz), 7.28
(1H, s), 6.88 (1H, s), 3.80 and 3.83 (each 3H, s, H-6, 7-
OMe). 13C NMR: δ 161.0, 152.8, 145.5, 139.2, 138.4, 134.8,
133.0, 130.3, 128.6, 127.6, 127.3, 126.8, 113.2, 109.4, 56.2,
56.1. HR-ESIMS (positive ion mode) m/z: 338.0556, ([M +
Na]+calcd. for C17H1435ClNNaO3, 338.0554 ; error –0.40 ppm).
3-(2-Benzyloxyphenyl)-6,7-Dimethoxy-quinolin-2(1H)-one
(5z)
White solid (66 mg); mp 160–162 °C. UV λmax (log ε):
238 (3.83), 291 (3.24), 350 nm (3.56). IR νmax: 3435, 2910,
2826, 1668, 1650, 1576, 1510, 1464, 1448, 1398, 1266,
1245, 1153, 1124, 1043, 1018, 918, 838, 783, 758, 731, 691,
1
677, 605, 574, 462 cm–1. H NMR (CDCl3): δ 12.12 (1H, s,
NH), 7.84 (1H, s), 7.51 (1H, dd, J = 7.0, 1.5Hz), 7.33–7.35
(3H, m), 7.19–7.21 (2H, m), 7.16 (1H, m), 7.05–7.07
(2H, m), 6.88 (1H, s), 6.81 (1H, s), 5.12 (2H, s, CH2), 3.90
and 3.91 (each 3H, s, H-6, 7-OMe). 13C NMR (CDCl3): δ
162.8, 156.6, 152.3, 145.8, 140.0, 137.2, 134.0, 131.5,
129.3, 128.3, 127.5, 127.2, 126.9, 126.3, 120.9, 113.5,
113.2, 107.9, 70.7, 56.2. HR-ESIMS (positive ion mode)
m/z: 388.1558 ([M + H]+calcd. for C24H22NO4, 388.1543;
error –3.79 ppm).
9. (a) D.H. Hey and J.M. Osbond. J. Chem. Soc. 3164 (1949);
(b) D.H. Hey and J.M. Osbond. J. Chem. Soc. 3172 (1949);
(c) K. Hino, Y. Nagai, and H. Uno. Chem. Pharm. Bull. 35,
2819 (1987).
10. (a) M. Pailer, A. Schleppnik, and M. Meller. Monatsh. Chem.
96, 1695 (1965); (b) M. Pailer and G. Willvonseder. Monatsh.
Chem. 109, 511 (1978).
For the physicochemical data of 3-aryl-2-quinolinones
(5a–5c, 5e, 5g–5h, 5j–5m, 5o–5s, and 5y), see supplemen-
tary data.2
11. A.T. Hewson, K. Hughes, S.K. Richardson, D.A. Sharpe and
A.H. Wadsworth. J. Chem. Soc., Perkin Trans. 1, 6, 1565
(1991).
Acknowledgement
12. (a) J.S. Buck and W.S. Ide. Org. Syn. Coll. 2, 130 (1943);
(b) E.J. Alford and K. Schofield. J. Chem. Soc. 2102 (1952).
13. (a) C.R. Noller and R. Adams. J. Am. Chem. Soc. 46, 1889
(1924); (b) O.L. Brady and J.N.E. Day. J. Chem. Soc., 114
(1934); (c) A. Kalir. Org. Syn. Coll. 5, 825 (1973).
14. D. Rakowitz, A. Gmeiner, N. Schröer, and B. Matuszczak. Eur.
J. Pharm. Sci. 27, 188 (2006).
15. (a) S. Lebrun, A. Couture, E. Deniau, and P. Grandclaudon.
Tetrahedron, 55, 2659 (1999); (b) C.K. Bradsher and H.
Berger. J. Am. Chem. Soc. 80, 930 (1958).
This work was supported by National Natural Science
Foundation of China (20442006).
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© 2006 NRC Canada