Synthesis and further studies of chemical transformation of the 2-aryl-3-halogenoquinolin-4(1H)-one derivatives

Article abstract of DOI:10.1002/jhet.5570430203

The C-3 brominated and iodinated derivatives were prepared from the corresponding 2-arylquinolin-4(1H)-ones and their NMe-4-oxo derivatives using pyridinium tribromide in acetic acid or iodine-Na₂CO₃ mixture in THF. The results of fu

Full text of DOI:10.1002/jhet.5570430203

Mar-Apr 2006
255
Synthesis and Further Studies of Chemical Transformation of the
2-Aryl-3-halogenoquinolin-4(1H)-one Derivatives
Malose J. Mphahlele, * Mutshinyalo S. Nwamadi and Peace Mabeta
a
a
b
a
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa,
P.O. Box 392, Pretoria 0003, South Africa. Tel. +27-12-429-8805; Fax: +27-12-429-8549.
E-mail address: mphahmj@unisa.ac.za
b
Department of Physiology, University of Pretoria, Pretoria 0001.
Received April 25, 2005
The C-3 brominated and iodinated derivatives were prepared from the corresponding 2-arylquinolin-
4(1H)-ones and their NMe-4-oxo derivatives using pyridinium tribromide in acetic acid or iodine-Na CO
2
3
mixture in THF. The results of further studies of chemical transformation of the prepared α-haloenones and
preliminary antitumour activity of the 3-bromo NH-4-oxo and NMe-4-oxo derivatives are also described.
J. Heterocyclic Chem., 43, 255 (2006).
Introduction.
found to undergo C-3 halogenation using various halo-
genating reagents [10-15]. Whereas there is enormous data
on the C-3 halogenation (X = Cl [10], Br [10c-15] or I
[10c,15]) of flavones, thiochromones and thioflavones, to
our knowledge, corresponding data for C-3 halogenation
of the quinolin-4(1H)-one derivatives is considerably less
documented [16]. Herein we report the results of C-3 halo-
genation of the 2-arylquinolin-4(1H)-ones and their NMe-
4-oxo derivatives and further studies of chemical transfor-
mation and antitumour activity of these derivatives.
The 2-arylquinolin-4-ones and their quinoline deriva-
tives continue to receive considerable attention in chem-
istry because of their wide range of pharmacological appli-
cations [1-4]. The 2-arylquinolin-4(1H)-one derivatives,
for example, are known to exhibit antibacterial [1] and
antitumour properties [2]. On the other hand, the N-substi-
tuted 2-arylquinoline derivatives serve as antimalarial
agents, immunostimulants and non-nucleoside HIV-1
inhibitors [3,4]. In the course of our ongoing quinolin-
4(1H)-one studies, we prepared analogues that are modi-
fied by changing the position of heteroatoms and the
degree of unsaturation in the heterocyclic ring [5-8]. We
are currently interested in the synthesis of halogenated
quinolone derivatives because of the profound effect a
halogen atom can have on the physical, chemical and bio-
logical properties of such systems [9]. The 2-arylquinolin-
4(1H)-ones and their N-alkylated derivatives are close ana-
logues of flavones and thioflavones which have been
Results and Discussion.
Although the 2-aryl-3-bromoquinolin-4(1H)-ones and
their NCH -4-oxo as well as O-methylquinoline deriva-
3
tives have been prepared in our laboratory before [5,6], we
sought to develop a new, high yield synthetic route that
avoids those multiple steps. Pyridinium tribromide-pyri-
dine mixture in dichloromethane has been used before for
the C-3 bromination of flavones [11]. However, prolonged
Scheme 1
1 (R' = H); 1NMe (R' = Me) 2 (R' = H); 2NMe (R' = Me)
3
Reagents and conditions: (i) C H NHBr , AcOH, r.t., 2h; (ii) POCl , ∆, 2h;
5
5
3
3
(iii) 4-Chloroaniline, EtOH, heat, 18h.

256
M. J. Mphahlele, M. S. Nwamadi and P. Mabeta
Vol. 43
reaction times (6 – 48 hours), use of excess reagents and
tedious workup presented limitations to these reaction con-
ditions for the current investigation. We therefore explored
the use of acetic acid in place of pyridine and subjected
dine)iodonium(I) tetrafluoroborate (IPy BF ) in
2
4
dichloromethane [15] were employed previously for the C-
3 iodination of thioflavone analogues. We required a simple
method that employs readily available and easy-to-handle
reagents for the iodination of substrates 1. Attempted C-3
iodination of 1 using iodine (2 equiv.) in methanol under
reflux for 3 days led to the recovery of the starting material.
The 3-iodo NH-4-oxo derivatives 4 were obtained in high
yields and purity by subjecting substrates 1 to iodine (2
equiv.) and sodium carbonate (1.5 equiv.) mixture in THF
at room temperature or under reflux (Scheme 2). The 3-
iodo NMe-4-oxo derivatives 4NMe were, in turn, obtained
in high yields (> 60%) and purity without the need for col-
umn chromatography by subjecting the corresponding 3-
iodo NH-4-oxo derivatives 4 to NaH in THF at room tem-
perature followed by quenching with iodomethane.
substrates 1 (R' = H) and 1NMe (R' = CH ) to pyridinium
3
tribromide (2 equiv.) at room temperature. We isolated
analytically pure products directly from the reaction mix-
ture after 2 hours and they were found by NMR spec-
troscopy to correspond to the 3-bromo-4-quinolone 2 (R' =
H) and their NCH -oxo derivatives 2NMe (R' = CH ).
3
3
1
13
Their NMR ( H and C) spectral data are identical to
those of the corresponding NH-4-oxo and NCH -4-oxo
3
systems prepared by a different route described in our pre-
vious communications [5,6]. Due to the operational sim-
plicity as well as easy isolation and purification procedures
for the products, the methodology appears to be useful
alternative to the pyridinium tribromide-pyridine mixture
employed before for the C-3 bromination of flavones [11].
The α-haloenones derived from α,β-unsaturated carbonyl
compounds provide an important functional group that
Scheme 2
4
4NMe
5
Reagents and conditions: (i) I , Na CO , THF, r.t., 12h; (ii) NaH, THF, MeI, r.t., 12h;
2
2
3
(iii) PhB(OH) , Pd(PPh ) , 2M Na CO (aq), DMF, ∆, 18h.
2
3 4
2
3
We have previously described the synthesis of the 4-
amino-2-arylquinolines which were obtained by
NaOEt–promoted Neber rearrangement of O-mesyloximes
derived from the 2-aryl-1-methanesulfonyl-2,3-dihydro-
quinolin-4(1H)-ones [8]. However, the known nonbasic
nature of amino group of the 4-amino-2-arylquinoline
derivatives [17] prevented further derivatization to 4-N-
substituted derivatives. In this investigation, we resorted to
the application of an indirect method for the synthesis of
N-substituted 2-aryl-3-halogenoquinoline derivatives. This
procedure makes use of the known 2-aryl-3-bromo-4-
chloroquinoline derivatives [5,6] and takes advantage of
the easy displacement of the halogen atom at γ-position by
the nucleophile. The previously described 2-aryl-3-bromo-
4-chloroquinoline, which are prepared from the NH-4-oxo
derivatives 2 and phosphoryl chloride under reflux [5,6]
were subjected to 4-chloroaniline in refluxing ethanol to
afford the corresponding hitherto unknown 2-aryl-4-(4'-
chlorophenyl)aminoquinolines 3 (Scheme 1).
could facilitate metal-catalyzed carbon-carbon bond forma-
tion [18-21]. The 3-haloflavones (X = Br, I), for example,
have been found to undergo Suzuki coupling with aromatic
boronic acids to yield 2,3-diarylbenzopyran derivatives with
a pharmacophore for selective cyclooxygenase-2 inhibition
[21]. Consequently, we subjected the 3-iodo derivatives
4NMe to palladium-mediated coupling reaction with
phenylboronic acid in DMF in the presence of 2 M sodium
carbonate (aq) and isolated the corresponding 2,3-diaryl-4-
quinolone derivatives 5 in moderate yields (Scheme 2).
In the last part of this investigation, we assayed varying
concentrations (0.2, 0.4, 0.6, 0.8, 1.0, 1.2 µg/ml) of the
NH-4-oxo 2 and NMe-4-oxo derivatives 2NMe prepared
in DMSO for potential antitumour activity against human
bladder carcinoma cell line, T24. Compound 2c shows
increased activity at concentration of 1.2 µg/ml while 2b
induces proliferation of the tumour cells at doses below
1µg/ml. The NMe-4-oxo derivatives 2NMe, on the other
hand, showed no activity at all concentrations employed in
this investigation. This evaluation of antitumour activity
provides a preliminary screening for medicinal potential
and future development.
So far very limited methods have been reported for the
C-3 iodination of flavone analogues [14,15].
Iodine–cerium(IV) ammonium nitrate [14] and bis(pyri-

Mar-Apr 2006
Chemical Transformation of the 2-Aryl-3-halogenoquinolin-4(1H)-one Derivatives
257
EXPERIMENTAL
rated under reduced pressure. The residue was purified by col-
umn chromatography to afford (3).
Melting points were recorded on a Thermocouple digital melt-
ing point apparatus and are uncorrected. IR spectra were recorded
as powder using FTS 7000 Series Digilab Win-IR Pro spectrom-
3-Bromo-4-(4"-chlorophenyl)amino-2-phenylquinoline (3a).
The reaction of 3-bromo-4-chloro-2-phenylquinoline with 4-
chloroaniline in refluxing ethanol followed by column chro-
matography (4:1 Pet. ether-EtOAc, v/v) afforded (3a) as white
eter. NMR spectra were obtained as CDCl or DMSO-d solu-
3
6
tions using Varian Mercury 300MHz NMR spectrometer and the
chemical shifts are quoted relative to the solvent peaks. Low- and
high-resolution mass spectra were recorded at an ionization
potential of 70eV using Micromass Autospec-TOF (double
focusing high resolution) instrument. Elemental (C, H, N) analy-
sis were performed at the ARC Institute for Soil, Climate and
Water (Pretoria). The synthesis and characterization of substrates
(1) [7], (1NMe) [7] and the 2-aryl-3-bromo-4-chloroquinolines
[5,6] have been described elsewhere.
1
solid (62%) m.p. 190 – 192 °C. H NMR (300MHz, CDCl ) δ
3
6.65 (1H, s), 6.83 (2H, d, J = 9.0 Hz), 7.21 (2H, d, J = 9.0 Hz),
7.33 (1H, dt, J = 0.9 and 7.8 Hz), 7.44 - 7.53 (3H, m), 7.62 - 7.71
13
(4H, m), 8.10 (1H, d, J = 8.1 Hz); C NMR (75MHz, CDCl ) δ
3
110.5, 120.3, 121.4, 124.5, 126.0, 127.8, 128.0, 128.7, 129.1,
129.3, 129.9, 130.1, 140.8, 142.0, 144.8, 147.6, 159.1; FT-IR
(neat) ν
760.3, 809.6, 1394.5, 1487.9, 1573.4, 2924.2, 3379.3
max
-1
35 79
cm . HRMS (EI) calculated for C
Found: 408.0029.
H
N
Cl Br: 408.0029.
21 14
2
35 79
C-3 Bromination of Compounds (1), R' = H.
Anal. Calcd. for C
H
N
Cl Br: C, 61.60; H, 3.44; N,
21 14
2
6.84. Found: C, 61.99; H, 3.46; N, 6.82.
General Procedure.
3-Bromo-4-(4"-chlorophenyl)amino-2-(4'-fluorophenyl)-
quinoline (3b).
A stirred solution of 1 (1 equiv.) in acetic acid (5 ml per mmol
of 1) was treated with pyridinium tribromide (2 equiv.) at room
temperature. The mixture was stirred at room temperature for 3
hours and then quenched with aqueous sodium thiosulphate. The
precipitate was washed with ice-cold ethanol and dried in vacuo
to afford pure (2) [5]. The following 2-aryl-3-bromoquinolin-
4(1H)-one derivatives (2) were prepared: 3-bromo-2-
phenylquinolin-4(1H)-one (2a) (80%); 3-bromo-2-(4'-fluo-
rophenyl)quinolin-4(1H)-one (2b) (95%); 3-bromo-2-(4'-
chlorophenyl)quinolin-4(1H)-one (2c) (87%) and 3-bromo-2-(4'-
methoxyphenyl)quinolin-4(1H)-one (2d) (95%).
The reaction of 3-bromo-4-chloro-2-phenylquinoline with 4-
chloroaniline in refluxing ethanol followed by column chro-
matography (4:1 Pet. ether-EtOAc, v/v) afforded (3b) as white
1
solid (68%) m.p. 181 – 183 °C. H NMR (300MHz, CDCl ) δ
3
6.65 (1H, br s), 6.83 (2H, d, J = 9.0 Hz), 7.14 - 7.25 (4H, m), 7.33
(1H, dt, J = 1.2 and 8.4 Hz), 7.62 - 7.72 (4H, m), 8.08 (1H, d, J =
8.1 Hz); C NMR (75MHz, CDCl ) δ 110.2, 115.1 (d, J
21.6 Hz), 120.3, 121.4, 124.5, 126.1, 127.9, 129.3, 130.0, 130.1,
131.2 (d, J = 8.3 Hz), 136.8 (d, J = 3.5 Hz), 142.0, 144.9,
= 246.5 Hz); FT-IR (neat) ν
767.7, 815.9, 1157.3, 1394.5, 1482.0, 1508.3, 1568.5, 3256.2 cm
13
2
=
3
CF
3
4
CF
CF
1
147.5, 158.0, 163.0 (d,
J
CF
max
C-3 Bromination of the 2-Aryl-1-methylquinolin-4(1H)-ones
(1NMe), R' = Me.
-
1
35 79
. HRMS (EI) calculated for C
H N F Cl Br: 425.9935
21 13
2
General Procedure.
Found: 425.9935.
Anal. Calcd. for C
6.55. Found: C, 59.15; H, 3.13; N, 6.50.
35 79
H N F Cl Br: C, 58.97; H, 3.06; N,
21 13 2
A similar procedure applied to (1) was employed for the C-3
bromination of (1NMe), however, the mixture was quenched
with ice-cold water and the precipitate was collected by filtration
and taken-up into chloroform. The organic solution was washed
sequentially with saturated sodium bicarbonate, aqueous sodium
3-Bromo-2-(4'-chlorophenyl)-4-(4"-chlorophenyl)amino-
quinoline (3c).
The reaction of 3-bromo-4-chloro-2-phenylquinoline with 4-
chloroaniline in refluxing ethanol followed by column chro-
matography (4:1 Pet. ether-EtOAc, v/v) afforded (3c) as white
solid (53%) m.p. 188 – 190 °C. H NMR (300MHz, CDCl ) δ
6.65 (1H, br s), 6.82 (2H, d, J = 9.0 Hz), 7.21 (2H, d, J = 9.0 Hz),
7.34 (1H, t, J = 7.5 Hz), 7.47 (2H, J = 8.4 Hz), 7.61 - 7.69 (4H,
m), 8.07 (1H, d, J = 8.1 Hz); C NMR (75MHz, CDCl ) δ 109.9,
120.4, 121.4, 124.5, 126.1, 128.0, 128.3, 129.3, 130.0, 130.1,
130.7, 134.9, 139.1, 141.9, 145.0, 147.6, 157.8; FT-IR (neat)
thiosulphate and brine. The organic solution was dried (Na SO ),
filtered and the solvent was evaporated under reduced pressure to
2
4
1
13
afford analytically ( H NMR and C NMR data) pure products
(2NMe) [5,6]. The following 2-aryl-3-bromo-1-methylquinolin-
4(1H)-one derivatives were prepared: 3-bromo-1-methyl-2-
phenylquinolin-4(1H)-one (2aNMe) (85%); 3-bromo-2-(4'-fluo-
rophenyl)-1-methylquinolin-4(1H)-one (2bNMe) (90%); 3-
bromo-2-(4'-chlorophenyl)-1-methylquinolin-4(1H)-one
(2cNMe) (93%) and 3-bromo-2-(4'-methoxyphenyl)-1-
methylquinolin-4(1H)-one (2dNMe) (70%).
1
3
13
3
-1
ν
762.6, 825.5, 1084.7, 1394.5, 1486.6, 1574.1, 3369.6 cm .
HRMS (EI) calculated for C
441.9935.
max
35
79
H
N
Cl Br: 441.9935 Found:
21 13
2 2
Preparation of 2-Aryl-3-bromo-4-(4"-chlorophenyl)aminoquino-
lines (3).
35
79
Anal. Calcd. for C
6.31. Found: C, 56.97; H, 3.28; N, 5.94.
H
N
Cl Br: C, 56.79; H, 2.95; N,
21 13
2
2
General Procedure.
3-Bromo-4-(4"-chlorophenyl)amino-2-(4'-methoxyphenyl)-
quinoline (3d).
A stirred mixture of 2-aryl-3-bromo-4-chloroquinoline (1
equiv.) and 4-chloroaniline (5 equiv.) in ethanol (5 ml per mmol
of quinoline) was boiled under reflux for 18 h. The mixture was
allowed to cool to room temperature and then quenched with ice-
cold water. The mixture was extracted with chloroform and the
combined organic phases were washed with brine and then dried
The reaction of 3-bromo-4-chloro-2-phenylquinoline with 4-
chloroaniline in refluxing ethanol followed by column chro-
matography (4:1 Pet. ether-EtOAc, v/v) afforded (3d) as white
1
solid (52%) m.p. 192 – 194 °C. H NMR (300MHz, CDCl ) δ
3
3.87 (3H, s), 6.62 (1H, br s), 6.81 (2H, d, J = 8.4 Hz), 7.01 (2H, d,
(MgSO ). The salt was filtered off and the solvent was evapo-
4

258
M. J. Mphahlele, M. S. Nwamadi and P. Mabeta
Vol. 43
J = 8.4 Hz), 7.20 (2H, d, J = 9.0 Hz), 7.31 (1H, dt, J = 0.9 and 8.9
Hz), 7.61 - 7.69 (4H, m), 8.08 (1H, d, J = 8.7 Hz); C NMR
3-Iodo-2-(4'-methoxyphenyl)quinolin-4(1H)-one (4d).
13
The crude product was recrystallised to afford (4d) as white
(75MHz, CDCl ) δ 55.3, 110.8, 113.4, 120.1, 121.4, 124.5,
3
1
solid (80%) m.p. 262 – 264 °C (EtOH). H NMR (300MHz,
125.8, 127.7, 129.3, 129.8, 130.1, 130.8, 133.2, 142.1, 144.7,
DMSO-d ) δ 3.84 (3H, s), 7.10 (2H, d, J = 8.7 Hz), 7.37 (1H, t, J
6
147.6, 158.7, 160.0; FT-IR (neat) ν
767.7, 824.2, 1178.5,
max
= 7.2 Hz), 7.51 (2H, d, J = 8.4 Hz), 7.63 - 7.68 (2H, m), 8.12 (1H,
-1
1240.2, 1394.2, 1486.5, 1573.0, 1600.1, 2928.8, 3378.0 cm .
13
d, J = 8.4 Hz), 12.30 (1H, s); C NMR (75MHz, DMSO-d ) δ
6
35 79
HRMS (EI) calculated for C
Found: 438.0135.
H N O Cl Br: 438.0135.
22 16
2
55.4, 86.2, 113.6, 118.3, 120.8, 124.1, 125.5, 130.2, 130.6, 132.1,
139.3, 152.9, 160.3, 173.6; FT-IR (neat) ν
759.8, 1024.2,
max
35 79
Anal. Calcd. for C
H N O Cl Br: C, 60.09; H, 3.67; N,
22 16 2
-1
1253.6, 1544.3, 1608.6, 1624.1, 3390.7 cm ; MS (EI) m/z (%) =
6.37. Found: C, 59.83; H, 6.10; N, 3.30.
C-3 Iodination of the 2-Arylquinolin-4(1H)-ones (1).
General Procedure.
+
377 [M ] (100), 250 (37), 69 (28), 28 (72). HRMS (EI) calcu-
lated for C
H NO I: 376.993. Found: 376.9913.
16 12 2
Anal. Calcd. for C
H NO I: C, 50.95; H, 3.21; N, 3.71.
16 12 2
Found: C, 50.51; H, 3.60; N, 3.39.
A stirred mixture of (1) (1 equiv.), iodine (2 equiv.) and
sodium carbonate (1.5 equiv.) in THF (5 ml per mmol of 1) was
stirred at room temperature for 18 hours. The mixture was
quenched with sodium thiosulphate and the precipitate was col-
lected by filtration and washed with ice-cold water. The follow-
ing products 4 were prepared:
N-Methylation of the 2-Aryl-3-iodoquinolin-4(1H)-ones (4).
General Procedure.
A stirred suspension of 3-iodo derivative (4) (1 equiv.) in dry
THF (5 mL per mmol of 4) was treated with NaH (1.5 equiv.) at
room temperature under nitrogen atmosphere. After 30 minutes,
the mixture was treated with iodomethane (1.5 equiv.) and stir-
ring was continued for 2 hours at room temperature and the mix-
ture was quenched with cold water. The product was extracted
3-Iodo-2-phenylquinolin-4(1H)-one (4a).
The crude product was recrystallised to afford (4a) as white
1
solid (85%) m.p. 284 – 286 °C (EtOH). H NMR (300MHz,
with chloroform, washed with brine and dried (MgSO ). The sol-
4
DMSO-d ) δ 7.40 (1H, t, J = 8.1 Hz), 7.57 (5H, s), 7.84 - 7.73
6
vent was evaporated to afford analytically pure (4NMe).
3-Iodo-1-methyl-2-phenylquinolin-4(1H)-one (4aNMe).
The crude product was recrystallised to afford (4aNMe) as
13
(2H, m), 8.14 (1H, d, J = 8.1 Hz) and 12.30 (1H, s); C NMR
(75MHz, DMSO-d ) δ 85.9, 118.3, 122.9, 124.2, 125.5, 128.4,
6
129.0, 129.8, 132.2, 137.9, 139.3, 153.1, 173.6; FT-IR (neat)
ν
755.6, 869.7, 1468.3, 1539.5, 1566.2, 1624.8, 1673.9,
3361.9 cm ; MS (EI) m/z (%) = 347 [M ] (86), 220 (62), 165
(36), 131 (62), 69 (100), 28 (96). HRMS (EI) calculated for
1
max
white solid (65%) m.p. 227 – 229 °C (EtOH). H NMR
-1
+
(300MHz, CDCl ) δ 3.57 (3H, s), 7.26 (2H, dd, J = 2.0 and 7.7
3
Hz), 7.43 (1H, dt, J = 0.9 and 7.6 Hz), 7.50 -7.56 (4H, m), 7.71
C
H NOI: 346.9807. Found: 346.9807.
15 10
(1H, dt, J = 1.5 and 7.9 Hz), 8.53 (1H, dd, J = 1.5 and 8.1 Hz); δ
C
Anal. Calcd. for C
H NOI: C, 51.89; H, 2.90; N, 4.03.
15 10
(75MHz, CDCl ) 39.2, 89.2, 115.6, 122.9, 124.4, 127.9, 128.2,
3
Found: C, 51.28; H, 3.20; N, 3.85.
129.2, 129.7, 132.6, 139.4, 140.7, 155.2, 174.1; FT-IR (neat)
-1
ν
750.3, 1074.3, 1394.5, 15245.4, 1593.0, 1616.3 cm ; MS
max
2-(4'-Fluorophenyl)-3-iodoquinolin-4(1H)-one (4b).
The crude product was recrystallised to afford (4b) as white
+
(EI) m/z (%) = 361 [M ] (100), 234 (49). HRMS (EI) calculated
for C
H NOI: 360.9964. Found: 360.9964.
16 12
1
solid (83%) m.p. 196 – 198 °C (EtOH). H NMR (300MHz,
Anal. Calcd. for C
H NOI: C, 53.21; H, 3.35; N, 3.89.
16 12
DMSO-d ) δ 7.40 - 7.50 (3H, m), 7.65 - 7.72 (4H, m), 8.14 (1H,
6
Found: C, 53.28; H, 3.59; N, 3.93.
13
d, J = 7.8 Hz), 12.33 (1H, s); C NMR (75MHz, DMSO-d ) δ
86.2, 115.3 (d, J = 21.9 Hz), 118.6, 121.0, 124.2, 125.5, 131.6
6
2-(4'-Fluorophenyl)-3-iodo-1-methylquinolin-4(1H)-one
(4bNMe).
2
CF
3
4
(d, J = 8.6 Hz), 132.1, 134.6 (d, J = 3.2 Hz), 139.6, 152.4,
CF
CF
1
162.7 (d, J = 245.3 Hz), 173.5; FT-IR (neat) ν
754.7, 818.0,
The crude product was recrystallised to afford (4bNMe) as
CF
max
-1
1
1157.8, 1224.8, 1466.3, 1535.3, 1601.8, 1622.1, 3414.4 cm ; MS
white solid (88%) m.p. 211 - 213°C (EtOH). H NMR (300MHz,
+
(EI) m/z (%) = 365 [M ] (89), 238 (42), 69 (88), 28 (100). HRMS
CDCl ) δ 3.56 (3H, s), 7.21 - 7.26 (4H, m), 7.42 (1H, t, J = 7.5
3
(EI) calculated for C H NOFI: 364.9713. Found: 364.9713.
Hz), 7.50 (1H, d, J = 8.2 Hz), 7.69 (1H, dt, J = 1.8 and 7.9 Hz)
15
9
Anal. Calcd. for C H NOFI: C, 49.34; H, 2.48; N, 3.84.
and 8.67 (1H, dd, J = 1.5 and 8.1 Hz); δ (75MHz, CDCl ) 39.2,
15
9
C
3
2
Found: C, 49.30; H, 3.00; N, 3.71.
89.7, 115.7, 116.5 (d, J = 21.9 Hz), 122.9, 124.6, 127.8, 130.4
CF
3
4
(d, J = 8.3 Hz), 132.7, 135.4 (d, J = 3.7 Hz), 140.7, 154.2,
CF
CF
2-(4'-Chlorophenyl)-3-iodoquinolin-4(1H)-one (4c).
The crude product was recrystallised to afford (4c) as white
1
163.1 (d,
J
= 249.3 Hz), 174.0; FT-IR (neat) ν
859.6, 1217.9, 1488.7, 1589.0, 1612.6 cm ; MS (EI) m/z (%) =
379 [M ] (100), 252 (51). HRMS (EI) calculated for
765.7,
CF
max
-1
1
+
solid (92%) m.p. 254 – 256 °C (EtOH). H NMR (300MHz,
DMSO-d ) δ 7.40 (1H, t, J = 7.2 Hz), 7.58 - 7.73 (6H, m), 8.13
C
H NOFI: 378.9870. Found: 378.9869.
6
16 11
13
(1H, d, J = 7.8 Hz), 12.4 (1H, s); C NMR (75MHz, DMSO-d )
Anal. Calcd. for C
H NOFI: C, 50.68; H, 2.92; N, 3.69.
6
16 11
δ 86.0, 118.4, 120.9, 124.4, 125.6, 128.5, 131.1, 132.3, 134.7,
Found: C, 50.68; H, 3.06; N, 3.68.
136.7, 139.3, 152.1, 173.6; FT-IR (neat) ν
758.6, 995.7,
max
2-(4'-Chlorophenyl)-3-iodo-1-methylquinolin-4(1H)-one
(4cNMe).
-1
1090.0, 1539.5, 1626.2, 3401.0 cm ; MS (EI) m/z (%) = 381
+
[M ] (70), 254 (32), 69 (31) and 28 (100). HRMS (EI) calculated
35
for C H NO ClI: 380.9417. Found: 380.9417.
The crude product was recrystallised to afford (4cNMe) as
15
9
35
1
Anal. Calcd. for C H NO ClI: C, 47.21; H, 2.38; N, 3.67.
white solid (75%) m.p. 246 – 248 °C (EtOH). H NMR
15
9
(300MHz, CDCl ) δ 3.56 (3H, s), 7.24 (2H, dd, J = 1.8 and 7.6
Found: C, 47.37; H, 2.31; N, 3.62.
3

Mar-Apr 2006
Chemical Transformation of the 2-Aryl-3-halogenoquinolin-4(1H)-one Derivatives
259
Hz), 7.42 (1H, dt, J = 0.9 and 7.5 Hz), 7.52 (1H, d, J = 8.1 Hz),
7.55 (2H, dd, J = 1.2 and 7.8 Hz), 7.72 (1H, dt, J = 1.8 and 7.8
13
Hz), 8.55 (1H, dd, J = 1.2 and 8.1 Hz); C NMR (75MHz,
2
CDCl ) δ 37.6, 115.4 (d, J = 21.7 Hz), 115.8, 123.6, 124.5,
126.2, 126.6, 127.3, 127.5, 131.0 (d, J = 3.4 Hz), 131.2, 131.5
(d, J = 8.3 Hz), 132.3, 135.6, 141.3, 150.9, 162.4 (d, J
760.0, 1216.6, 1317.4,
1489.4, 1587.4, 1659.7 cm ; MS (EI) m/z (%) = 345 [M ] (100),
328 (43.0), 77 (25). HRMS (EI) calculated for C
329.1216. Found: 329.1216.
3
CF
Hz), 8.53 (1H, dd, J = 1.5 and 8.1 Hz); δ (75MHz, CDCl ) 39.2,
4
C
3
CF
89.3, 115.6, 122.9, 124.7, 127.9, 129.6, 129.8, 132.8, 135.9,
3
1
=
CF
CF
137.6, 140.7, 154.0, 174.0; FT-IR (neat) ν
767.7, 860.2,
max
248.4 Hz), 176.2; FT-IR (neat) ν
max
-1
1153.6, 1396.5, 1482.4, 1590.1, 1613.6 cm ; MS (EI) m/z (%) =
-1
+
+
397 (25), 395 [M ] (91), 268 (43), 28 (100). HRMS (EI) calcu-
H NOF:
22 16
35
lated for C H NO ClI: 394.9574. Found: 394.9574.
16 11
35
Anal. Calcd. for C H NO ClI: C, 48.58; H, 2.88; N, 3.54.
Anal. Calcd. for C
H NOF: C, 80.22; H, 4.89; N, 4.25.
16 11
22 16
Found: C, 49.05; H, 2.98; N, 3.53.
Found: C, 80.30; H, 4.91; N, 4.08.
3-Iodo-2-(4'-methoxyphenyl)-1-methylquinolin-4(1H)-one
(4dNMe).
2-(4'-Chlorophenyl)-1-methyl-3-phenylquinolin-4(1H)-one (5c).
The residue was recrystallised from ethanol to afford (5c) as
1
The crude product was recrystallised to afford (4dNMe) as
white solid (74%) m.p. 267 – 269 °C (EtOH). H NMR
1
white solid (73%) m.p. 192 – 194 °C (EtOH). H NMR
(300MHz, CDCl ) δ 3.53 (3H, s), 7.01 (2H, d, J = 7.2 Hz), 7.05 -
3
(300MHz, CDCl ) δ 3.66 (3H, s), 3.96 (3H, s), 7.13 (2H, d, J =
7.16 (5H, m), 7.26 (2H, d, J = 8.4 Hz), 7.44 (1H, t, J = 7.5 Hz),
7.56 (1H, d, J = 8.7 Hz), 7.73 (1H, dt, J = 1.5 and 7.8 Hz), 8.56
3
8.7 Hz), 7.26 (2H, d, J = 8.7 Hz), 7.50 (1H, dt, J = 0.9 and 7.4
Hz), 7.60 (1H, d, J = 8.7 Hz), 7.78 (1H, dt, J = 1.8 and 7.8 Hz),
8.60 (1H, dd, J = 0.9 and 7.9 Hz); δ (75.0MHz, CDCl ) 39.2,
13
(1H, dd, J = 1.5 and 8.0 Hz); C NMR (75MHz, CDCl ) δ 37.6,
3
115.7, 123.7, 124.4, 126.3, 126.5, 127.3, 127.6, 128.7, 130.9,
131.2, 132.4, 133.4, 134.8, 135.4, 141.4, 150.7, 176.2; FT-IR
C
3
55.4, 90.0, 114.5, 115.7, 122.9, 124.4, 127.9, 129.7, 131.8, 132.6,
140.8, 155.3, 160.4, 174.2; FT-IR (neat) ν
762.3, 1248.2,
(neat) ν
758.4, 1070.4, 1308.9, 1476.0, 1572.0, 1590.5,
max
max
-1
-1
+
+
1502.4, 1590.3, 1614.4 cm ; MS (EI) m/z (%) = 265 [M ] (100),
237 (34), 222 (26), 51 (53), 28 (58). HRMS (EI) calculated for
1615.1 cm ; MS (EI) m/z (%) = 345 [M ] (60.5), 344 (95.5), 28
35
(100). HRMS (EI) calculated for C
H
NO Cl: 345.0920.
22 16
C
H NO I: 391.038. Found: 391.029.
Found: 345.0921.
Anal. Calcd. for C
17 14 2
35
H
NO Cl: C, 76.41; H, 4.66; N, 4.05.
Anal. Calcd. for C
H NO I: C, 52.19; H, 3.61; N, 3.58.
17 14 2
22 16
Found: C, 76.58; H, 4.86; N, 4.08.
Found: C, 52.31; H, 4.00; N, 3.57.
2-(4'-Methoxyphenyl)-2-phenyl-1-methylquinolin-4(1H)-one
(5d).
Palladium Catalyzed Cross-coupling Reactions of (4NMe).
General Procedure.
The residue was recrystallised to afford (5d) as white solid
A stirred mixture of β-haloenone (4NMe) (1 equiv.), phenyl-
1
(63%) m.p. 266 – 268 °C (EtOH). H NMR (300MHz, DMSO-d )
6
boronic acid (2 equiv.) and Pd(PPh ) (5% of β-haloenone) in a
3 4
δ 3.49 (3H, s), 3.69 (3H, s), 6.74 (2H, d, J = 9.0 Hz), 6.91 - 7.06
(7H, m), 7.35 (1H, dt, J = 1.2 and 7.5 Hz), 7.62 (1H, d, J = 7.8 Hz),
7.69 (1H, dt, J = 1.2 and 8.4 Hz), 8.32 (1H, dd, J = 1.2 and 8.0 Hz);
two-necked flask equipped with a stirrer bar, rubber septum and a
condenser was flushed with nitrogen gas. The flask was filled
through a syringe with DMF (5 ml per mmol of β-haloenone) and
aqueous 2 M Na CO (2 ml per mmol of β-haloenone). The mix-
13
C NMR (75MHz, DMSO-d ) δ 37.2, 54.6, 113.2, 116.1, 122.9,
6
2
3
123.3, 125.3, 125.8, 125.9, 126.6, 126.8, 130.5, 130.9, 131.7,
ture was boiled under reflux for 18 hours and then cooled to room
temperature. The mixture was poured into ice-cold water and the
precipitate was taken-up into chloroform, washed with brine,
dried and evaporated to afford 5.
136.0, 140.9, 151.7, 158.9, 175.0; FT-IR (neat) ν
768.1,
max
-1
1244.1, 1320.1, 1489.9, 1566.2, 1587.7, 1603.1 cm ; MS (EI)
+
m/z (%) = 341 [M ] (49.0), 340 (72.5), 28 (100). HRMS (EI) cal-
culated for C H NO : 341.1416. Found: 341.1415.
23 19
2
Anal. Calcd. for C
Found: C, 81.19; H, 5.79; N, 4.33.
H NO : C, 80.92; H, 5.61; N, 6.84.
1-Methyl-2,3-diphenylquinolin-4(1H)-one (5a).
23 19 2
The residue was recrystallised from ethanol to afford (5a) as
white solid (58%) m.p. 241 – 243 °C (EtOH). H NMR
1
Cell Culture.
(300MHz, CDCl ) δ 3.53 (3H, s), 7.00 - 7.26 (10H, m), 7.42 (1H,
3
Human bladder carcinoma cell line, T24 was incubated at a 37
t, J = 7.8 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.71 (1H, dt, J = 1.5 and
°C in a humidified atmosphere containing 5% CO in air. Cells
2
13
7.8 Hz), 8.57 (1, dd, J = 1.2 and 8.0 Hz); C NMR (75MHz,
were maintained in Dubelco's minimum essential medium (Lab
Specialist Services, SA), supplemented with 10% Fetal Bovine
Serum (Highveld Biologicals, SA). No antibiotics were used and
cells from stock flasks were stained with 0.2 % Trypan blue to
determine viable cells.
CDCl ) δ 37.6, 115.7, 123.5, 124.2, 126.0, 126.6, 127.3, 127.4,
3
128.3, 128.7, 129.5, 131.3, 132.2, 135.0, 135.7, 141.3, 152.0,
176.2; FT-IR (neat) ν
700.5, 752.9, 1317.4, 1477.5, 1496.8,
1569.5, 1585.5, 1614.4 cm . MS (EI) m/z (%) = 311 [M ] (92),
310 (100), 294 (53), 262 (43). HRMS (EI) calculated for
max
-1
+
Cell Viability.
C
H NO: 311.1310. Found: 311.1310.
22 17
Anal. Calcd. for C
C, 85.00; H, 5.40; N, 4.44.
H NO: C, 84.86; H, 5.50; N, 4.49. Found:
Cells were seeded in 24-well culture plates at a density of 20
000 cells per well. After 24 hours cells were exposed to varying
concentrations of test compounds (0.2, 0.4, 0.6, 0.8, 1.0, 1.2
µg/ml) prepared in DMSO so that the final concentration of
DMSO in the medium did not exceed 0.67% and the control cells
were exposed to 0.67% DMSO. Growth was terminated after 48
hours by fixation with 1% glutaraldehyde. Crystal violet was
used to stain the nucleus. The chromophore was extracted and
22 17
2-(4'-Fluorophenyl)-1-methyl-3-phenylquinolin-4(1H)-one (5b).
The residue was recrystallised to afford (5b) as white solid
(52%) m.p. 284 – 286 °C (EtOH). H NMR (300MHz, CDCl ) δ
3.53 (3H, s), 7.00 - 7.15 (6H, m), 7.26 (3H, m), 7.42 (1H, t, J =
7.8 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.72 (1H, dt, J = 1.3 and 8.6
1
3

260
M. J. Mphahlele, M. S. Nwamadi and P. Mabeta
Vol. 43
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results were analyzed following literature procedure [22].
Absorbances of the samples were read at 570nm on an ELx 800
Universal Microplate Reader. Three wells were analyzed for each
concentration and the growth studies were repeated for each test
agent.
Acknowledgements.
We are grateful to the National Research Foundation (S.A.)
and the University of South Africa for financial assistance.
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