Suzuki-Miyaura cross-coupling of 2-aryl-6,8-dibromo-1,2,3,4- tetrahydroquinolin-4-ones and subsequent dehydrogenation and oxidative aromatization of the resulting 2,6,8-triaryl-1,2,3,4-tetrahydroquinolin-4-ones

Article abstract of DOI:10.1016/j.tet.2011.06.085

Dichlorobis(triphenylphosphine)palladium(II)/tricyclohexylphosphine- catalyzed Suzuki-Miyaura cross-coupling of the 2-aryl-6,8-dibromo-1,2,3,4- tetrahydroquinolin-4-ones with arylboronic acids afforded the corresponding 2,6,8-triaryl-1,2,3,4-tetrahydroqui

Full text of DOI:10.1016/j.tet.2011.06.085

Tetrahedron 67 (2011) 6819e6825
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
SuzukieMiyaura cross-coupling of 2-aryl-6,8-dibromo-1,2,3,4-
tetrahydroquinolin-4-ones and subsequent dehydrogenation
and oxidative aromatization of the resulting
2,6,8-triaryl-1,2,3,4-tetrahydroquinolin-4-ones
*
Malose J. Mphahlele , Felix A. Oyeyiola
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, PO Box 392, Pretoria 0003, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2011
Received in revised form 10 June 2011
Accepted 24 June 2011
Available online 30 June 2011
Dichlorobis(triphenylphosphine)palladium(II)/tricyclohexylphosphine-catalyzed SuzukieMiyaura cross-
coupling of the 2-aryl-6,8-dibromo-1,2,3,4-tetrahydroquinolin-4-ones with arylboronic acids afforded
the corresponding 2,6,8-triaryl-1,2,3,4-tetrahydroquinolin-4-ones, exclusively. The latter was subjected
to thallium(III) p-tolylsulfonate (TTS) in dimethoxyethane under reflux or to molecular iodine in
methanol at reflux to afford the 2,6,8-triarylquinolin-4-(1H)-ones and 2,6,8-triaryl-4-methoxyquinoline
derivatives, respectively.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
2-Aryl-6,8-dibromo-1,2,3,4-
tetrahydroquinolin-4-ones
SuzukieMiyaura cross-coupling
2,6,8-Triaryl-1,2,3,4-tetrahydroquinolin-4-
ones
2,6,8-Triarylquinolin-4(1H)-ones
2,6,8-Triaryl-4-methoxyquinolines
1. Introduction
alkyl- or aryl-containing substituents on the fused benzo ring.
Consequently, methods that make use of presynthesized haloge-
With their rich biological activities and excellent pharmaco-
logical properties,1e3 the synthesis of 2-aryl-4-quinolinone-based
compounds has been the target of a great deal of research.4 2-Aryl-
1,2,3,4-tetrahydroquinolin-4-ones bearing substituents on the
fused benzo ring are readily accessible through direct one-pot acid-
catalyzed condensation of substituted aniline derivatives with ethyl
benzoylacetate in refluxing toluene.5 On the other hand, the most
convenient and high yielding method developed to-date for the
synthesis of polysubstituted 2-arylquinolin-4(1H)-ones, involves
the use of 2-aminoacetophenones and substituted benzoyl chlo-
rides as starting materials.2,6 Less traditional syntheses of 2-
arylquinolin-4(1H)-ones, which make use of transition metals
have been developed. Palladium-catalyzed carbonylation of 2-
haloanilines in the presence of terminal acetylenes, for example,
afforded a variety of 2-substituted quinolin-4(1H)-ones in high
yields.7 Although effective, the classical and carbonylation ap-
proaches are not suited for the preparation of derivatives bearing
nated quinolinones and transition metals continue to be developed
to allow for the adequate diversity and substitution on the fused
benzo ring.8ꢀ10 An increasingly wide range of alkyl, alkenyl,
alkynyl, aryl and even heteroatom substituents can be installed on
haloheteroaromatic precursors by taking advantage of the ease of
displacement of the halogen atom/s on the aryl or heteroaryl
moiety by nucleophiles or metal catalysts to provide an avenue
for further structure elaboration. A series of 8-aryl-6-chloro-1,2,3,4-
tetrahydroquinolines, for example, were recently prepared through
cross-coupling of 6,8-dichloro-1,2,3,4-tetrahydroquinoline with
aryl- and heteroarylmagnesium bromides (3 equiv) in the presence
of dichlorobis(tricyclohexylphosphine)palladium(II) PdCl2(PCy3)2
in tetrahydrofuran (THF) at 50e70 ꢁC.11
Although a wide variety of polysubstituted quinolin-4-one de-
rivatives have been reported earlier, a thorough literature search
however revealed that 6,8-diaryl-1,2,3,4-tetrahydroquinolin-4-
ones remain surprisingly unexplored so far. These substituted
tetrahydroquinolin-4-ones could serve as valuable precursors for
the synthesis of other medicinally important compounds, such
as polysubstituted quinolin-4(1H)-ones and 4-alkoxyquinolines,
but cannot be easily prepared through the well known classical
* Corresponding author. Tel.: þ27 12 429 8805; fax: þ27 12 429 8549; e-mail
address: mphahmj@unisa.ac.za (M.J. Mphahlele).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.085

6820
M.J. Mphahlele, F.A. Oyeyiola / Tetrahedron 67 (2011) 6819e6825
methods. With our continued interest in the palladium-catalyzed
cross-coupling reactions of dihalogenoquinolines,12 we decided to
investigate the possibility of synthesizing the 2-aryl-6,8-dibromo-
1,2,3,4-tetrahydroquinolin-4-ones to serve as substrates for the
SuzukieMiyaura cross-coupling with arylboronic acids. We herein
describe the outcome of the SuzukieMiyaura cross-coupling of the
2-aryl-6,8-dibromo-1,2,3,4-tetrahydroquinolin-4-ones with aryl-
boronic acids and transformation of the resulting products through
dehydrogenation and oxidative aromatization to afford poly-
substituted quinolin-4(1H)-ones and quinoline derivatives with
potential biological activity.
Bromination of 1d, however, afforded product 2d in relatively low
yield (45%) along with an inseparable mixture of by-products pre-
sumably resulting from possible halogenation of the 2-(4-
methoxyphenyl) substituent. Product 2d was isolated in 63% yield
when a mixture of carbon tetrachloride/chloroform (3:2, v/v) was
used as solvent. This solvent mixture was also found to work well for
substrates 1aec and to afford comparable yields to those obtained
using CCl4 as solvent. Products 2 are easily distinguished from the
correspondingprecursorsbytwosetsofdoubletsat
ca. 7.94 ppm corresponding to 7-H and 5-H, respectively.
Having developed a reliable method for the synthesis of dibromo-
dca. 7.71ppmand
d
2,3-dihydroquinolin-4-ones 2, wenextfocused ourattentionontheir
reactivity in Pd-catalyzed SuzukieMiyaura cross-coupling reactions
witharylboronicacids. AttemptedSuzukieMiyauracross-couplingof
1 with a mixture of phenylboronic acid (1.0 or 2.5 equiv) and 2M
K2CO3 in DMF in the presence of tetrakis(triphenylphosphine)palla-
dium(0) (Pd(PPh3)4) led to the recovery of the starting material after
48 h. The failure of Pd(PPh3)4 to promote the cross-coupling
is probably due to the inhibiting role of the extra PPh3 generated
in the second equilibrium {SPd(0)(PPh3)3SPd(0)(PPh3)2þPPh3 (K2/
[PPh3]<<1); S¼solvent} to afford thereactive lowligated 14-electron
species (Pd(0)(PPh3)2).17 Conversely, the oxidative addition per-
formed by the palladium(0) complex (Pd(0)(PPh3)2Clꢀ) generated
by the reduction of dichlorobis(triphenylphosphine)palladium(II)
(PdCl2(PPh3)2) is reported to be more than 30 times faster than that
performed from Pd(0)(PPh3)4.17 Likewise, alkylphosphine ligands are
knowntocoordinatewithpalladium andincreaseitselectrondensity
more than arylphosphines and, in turn, accelerate the oxidative ad-
dition and reductive elimination steps in the catalytic cycle.18 Based
on this postulate, we subjected 2a to phenylboronic acid (1 equiv) in
the presence of PdCl2(PPh3)2/tricyclohexylphosphine (PCy3) catalyst
mixture and potassium carbonate as a base in dioxane-water (3:1, v/
v) at 80e90 ꢁC. We isolated by column chromatography on silica gel
2,6,8-triphenyl-2,3-dihydroquinolin-4(1H)-one 3a (40%) along with
a significant amount of the starting material due to incomplete
conversion. Product 3a was isolated in relatively high yield and
as sole product with no traces of the isomeric monosubstituted
derivatives or precursor when an excess of phenylboronic acid
(2.5 equiv) was used (Scheme 2). The reaction conditions were
2. Results and discussion
The first task in this investigation was to synthesize the requisite
2-aryl-6,8-dibromo-1,2,3,4-tetrahydroquinolin-4-ones from read-
ily available 2-aryl-1,2,3,4-tetrahydroquinolin-4-ones to serve as
substrates for the palladium-catalyzed SuzukieMiyaura cross-
coupling with arylboronic acids. Whereas the N-tosyl-13 and N-
methylsulfonyl 2-aryl-2,3-dihydroquinolin-4-ones14 are selectively
brominated or iodinated at the a-carbon relative to the carbonyl
group, halogenation of the 2-aryl-1,2,3,4-tetrahydroquinolin-4-ones
or 1,2,3,4-tetrahydroquinoline is rather complex and depends
on the conditions used.15,16 Bromination of 2-phenyl-1,2,3,4-
tetrahydroquinolin-4-one with 1 equiv of bromine in chloroform at
room temperature previously afforded the 6-bromo derivative in 30%
yield.13 2-Phenyl-1,2,3,4-tetrahydroquinolin-4-one with excess bro-
mine (4 equiv) in chloroform, on the otherhand, afforded a mixture of
three products characterized as 3,6,8-tribromo-2-phenylquinolin-
4(1H)-one, 6,8-dibromo-2-phenylquinolin-4(1H)-one and 6,8-
dibromo-4-ethoxy-2-phenylquinoline.15 Formation of the latter was
attributed to the participation of ethanol present as a stabilizer in
chloroform because the product was not detected or isolated when
alcohol-free chloroform was used as solvent. Although no experi-
mental details or analytical data of the corresponding products
were provided, 2-phenyl-1,2,3,4-tetrahydroquinolin-4-one with one
or 2 equiv of N-bromosuccinimide (NBS) in carbon tetrachloride
at room temperature is reported to afford the 6-bromo- or 6,8-
dibromoquinolone derivatives, respectively.13 To establish the gen-
erality of this observation, we subjected compounds 1 to NBS
(2e2.5 equiv) in carbon tetrachloride at room temperature and we
isolated the corresponding 2-aryl-6,8-dibromo-2,3-dihydroquinolin-
4(1H)-ones 2 by column chromatography on silica gel (Scheme 1).
O
O
Ar
Br
(i)
N
H
C6H4R
N
H
C6H4R
Ar
Br
O
O
2a-d
3a-h
Br
(i)
4-R
Ar
% Yield
72
N
H
C6H4R
N
H
C6H4R
3a 4-H
3b 4-F
3c 4-Cl
-C6H5
-C6H5
-C6H5
Br
61
1a-d
2a-d
71
4-R
2a 4-H
2b 4-F
% Yield
70
3d 4-OMe -C6H5
62
3e 4-H
3f 4-F
3g 4-Cl
4-FC6H4-
61
75
4-FC6H4-
4-FC6H4-
51
52
2c 4-Cl
2d 4-OMe
68
3h 4-OMe 4-FC6H4-
66
63
,
Reagents: (i) ArB(OH)2 (2.5 equiv.), PdCl2(PPh3)2, PCy3, K2CO3
Reagents: (i) NBS (2.5 equiv.), CCl4-CHCl3 (3:2, v/v), rt, 3 h
dioxane-water (3:1, v/v), 80–90 °C, 18 h
Scheme 1. Bromination of 2-aryl-1,2,3,4-tetrahydroquinol-4-ones with NBS.
Scheme 2. One-pot double arylation of 2 with arylboronic acids.

M.J. Mphahlele, F.A. Oyeyiola / Tetrahedron 67 (2011) 6819e6825
6821
extended to other substituted derivatives 2 with phenylboronic
and 4-fluorophenylboronic acids to afford the corresponding 2,6,8-
triarylquinolin-4-ones 3. The observed results are complementary
to the literature observation by Slugovc et al. on the Pd(PPh3)4eca-
talyzed SuzukieMiyaura cross-coupling of 8-benzyloxy-5,7-
dibromoquinoline with arylboronic acids to afford the 5,7-diaryl-8-
benzyloxyquinolines in a single-pot operation.19 In contrast, m- and
p-dibromobenzenes were found to undergo single couplings with
arylboronic acids with high selectivity whereas the m- and p-diio-
dobenzenes with arylboronic acids or esters led to selective double
coupling reactions.20 Lack of selectivity was also observed for the
SuzukieMiyaura cross-coupling of dihaloarenes bearing ortho
directing groups, such as OH, NH2, CH2OH or NHBoc.11
The potentially tautomeric 2-arylquinolin-4(1H)-one frame-
work has been found to undergo deprotonation by base followed by
quenching with the corresponding primary alkyl halide to afford
either the O-alkylquinoline or N-alkylquinolinone derivatives.4 This
classical approach however usually leads to mixtures of the
N-alkylquinolinones and O-alkylquinoline isomers particularly
when iodomethane is used as alkylating reagent.3 An indirect, but
sure-fire approach to the isomeric O-methoxyquinolines, on the
other hand, involves phosphoryl chloride-promoted aromatization
of the quinolin-4(1H)-ones and subsequent dechloromethoxylation
of the resultant 4-chloroquinoline derivatives.4 The most conve-
nient direct synthesis of the 4-methoxy-2-arylquinoline derivatives
developed to-date involves oxidative aromatization of the corre-
sponding 2-aryl-1,2,3,4-tetrahydroquinolin-4-one precursors using
oxidative reagents, such as thallium(III) nitrate25a or [hydrox-
yl(tosyloxy)iodo]benzene25b in trimethyl orthoformate in the
presence of perchloric acid as catalyst, molecular iodine in meth-
anol25c or FeCl3$6H2O in methanol.25d With an intent to synthesize
the 2,6,8-triaryl-4-methoxyquinolines, we opted for the use of
an iodine/alcohol mixture and subjected system 3 to molecular
iodine (2 equiv) in methanol under reflux for 2.5 h. We isolated the
corresponding novel 2,6,8-triaryl-4-methoxyquinolines 5aeh in
high yield and purity without the need for column chromato-
graphic separation (Scheme 4). The analogous 4-alkoxy-3,6-
diarylquinolines are reported to exhibit potent and selective
agonism of the somatostatin receptor subtype 2 (sst2) and to rep-
resent promising agents for the treatment of diabetic retinopathy
and proliferative diseases.26 The 6- or 8-aryl substituted 2,4-
dimethoxyquinolines, on the other hand, were found to exhibit
high activity against the agriculturally important nematode, Hae-
monchus contortus with potency comparable to that of the commer-
cially available levamisole.27 Likewise, the analogous 5,7-diaryl-8-
(benzyloxy/hydroxy)quinolines show promising photoluminescence
quantum yields both in the parent and the protonated states, making
them suitable candidates for the active component in pH sensing
applications.20
With tetrahydroquinolin-4-ones 3 in hand, we decided to in-
vestigate the possibility of introducing a different degree of unsa-
turation into the heterocyclic moiety via dehydrogenation or
oxidative aromatization to afford derivatives with potential anti-
bacterial, antitumour or antimalarial activity. Although variously
substituted 2-aryl-1,2,3,4-tetrahydroquinolin-4-ones have been
prepared before,4 only limited examples of their transformation
into the corresponding 2-arylquinolin-4-(1H)-one derivatives have
been reported.21,22 One approach makes use of iodobenzene diac-
etate under basic conditions in methanol,21 and the other employs
thallium(III) p-tolylsulfonate in dimethoxyethane to afford the 2-
arylquinolin-4-(1H)-ones.22 We opted for the use of the readily
prepared and easy-to-handle thallium(III) p-tolylsulfonate (TTS) in
dimethoxyethane (DME), and subjected compounds 3 to de-
hydrogenation to afford the corresponding potentially tautomeric
2,6,8-triarylquinolin-4(1H)-ones 4 (Scheme 3). Their NH-4-oxo
nature is confirmed by the 13C]O signal at
d ca. 179.0 ppm in
CDCl3 and the C]O and NeH absorption bands in their IR spectra,
which compare favourably with previously reported IR data for 2,8-
diphenylquinolin-4(1H)-one.23 The analogous 8-substituted 2-
morpholin-4-yl-quinolin-4(1H)-ones with aryl and heteroaryl groups
as the substituents have been synthesized via SuzukieMiyaura cross-
coupling of 8-bromo-2-morpholin-4-yl-1H-quinolin-4-one with aryl-
boronic acids and were found to inhibit DNA-dependent protein
kinase.24
O
OCH3
Ar
Ar
(i)
O
O
Ar
Ar
N
H
C6H4R
N
C6H4R
(i)
Ar
Ar
N
H
C6H4R
N
H
C6H4R
Ar
Ar
3a-h
5a-h
3a-h
Ar
4a-h
4-R
Ar
% Yield
82
4-R
4a 4-H
4b 4-F
4c 4-Cl
% Yield
5a 4-H
5b 4-F
-C6H5
-C6H5
-C6H5
-C6H5
66
60
55
55
90
50
71
65
-C6H5
78
5c 4-Cl
5d 4-OMe
5e 4-H
5f 4-F
-C6H5
97
-C6H5
88
4d 4-OMe -C6H5
4-FC6H4-
4-FC6H4-
4-FC6H4-
4-FC6H4-
89
4e 4-H
4f 4-F
4g 4-Cl
4-FC6H4-
68
4-FC6H4-
4-FC6H4-
5g 4-Cl
5h 4-OMe
88
76
4h 4-OMe 4-FC6H4-
Reagents: (i) I2, MeOH, 80 °C, 2 h
Reagents: (i) TTS, DME, 100 °C, 30 minutes
Scheme 4. Iodine/methanol-mediated oxidative aromatization of 3.
Scheme 3. Dehydrogenation of 3 with thallium(III) p-tolysulfonate in dimethoxyethane.

6822
M.J. Mphahlele, F.A. Oyeyiola / Tetrahedron 67 (2011) 6819e6825
The generality and brevity of iodine/methanol-mediated oxidative
aromatization reaction and the accompanying yields make this
methodology a suitable alternative to sequential dehydrogenation,
phosphoryl chloride-promoted aromatization and dechloromethox-
ylation to afford methoxyquinoline derivatives.
147.2, 191.2; m/z (100, MHþ) 380; HRMS (ES): MHþ, found 379.9219.
C15H12NO79Br2þ requires 379.9286.
4.2.2. 6,8-Dibromo-2-(4-fluorophenyl)-2,3-dihydroquinolin-4(1H)-
one 2b. Yield (0.56 g, 75%), mp 126e129 ꢁC (ethanol); Rf (toluene)
0.58; nmax (neat) 833, 1160, 1225, 1480, 1592, 1684, 3363 cmꢀ1
; dH
3. Conclusions
(300 MHz, CDCl3) 2.78 (dd, J 4.5 and 16.8 Hz, 1H), 2.86 (dd, J 13.2
and 16.8 Hz, 1H), 4.76 (dd, J 4.5 and 13.2 Hz, 1H), 5.04 (br s, 1H), 7.12
(t, J 8.4 Hz, 2H), 7.43 (t, J 8.4 Hz, 2H), 7.71 (d, J 2.1 Hz, 1H), 7.94 (d, J
2.1 Hz, 1H); dC (75 MHz, CDCl3) 45.4, 67.1, 110.0, 110.8, 116.1 (d, 2JCF
In summary, we have demonstrated that SuzukieMiyaura cross-
coupling of 2-aryl-6,8-dibromo-1,2,3,4-tetrahydroquinolin-4-ones
with arylboronic acids occurs without selectivity to afford the
corresponding 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones in a
single-pot operation. The heterocyclic moiety of the prepared 2,3-
dihydroquinolin-4(1H)-ones enabled the introduction of a differ-
ent degree of unsaturation in the heterocyclic framework via
dehydrogenation and oxidative aromatization to afford the corre-
sponding NH-4-oxo and 4-methoxyquinoline derivatives with
3
4
21.6 Hz), 120.8, 128.3 (d, JCF 8.0 Hz), 129.6, 135.7 (d, JCF 3.2 Hz),
1
139.9, 147.1, 162.8 (d, JCF 246.5 Hz), 190.9; m/z (100, MHþ)
þ
398; HRMS (ES): MHþ, found 397.9191. C15H11FNO79Br2 requires
397.9200.
4.2.3. 6,8-Dibromo-2-(4-chlorophenyl)-2,3-dihydroquinolin-4-one
2c. Yield (0.72 g, 68%), mp 145e147 ꢁC (ethanol); Rf (toluene) 0.63;
potential biological activity. Moreover, the
a
,b
-unsaturated frame-
nmax (neat) 824, 1089, 1280, 1483, 1592, 1672, 3375 cmꢀ1
; dH
work of the NH-4-oxo derivatives contain several reactive centres
for possible functionalization including aromatization with POCl3
followed by substitution with heteroatom-containing nucleophiles
or cross-coupling to afford novel polysubstituted quinolines, or C-3
halogenation and subsequent cross-coupling to afford poly-
substituted 1H-furo[3,2-c]quinoline derivatives. Studies are cur-
rently underway in our laboratory to investigate the reactivity,
biological and photophysical properties of the synthesized poly-
substituted quinolones and quinoline derivatives.
(300 MHz, CDCl3) 2.78 (dd, J 4.2 and 16.5 Hz, 1H), 2.85 (dd, J 13.2
and 16.5 Hz, 1H), 4.75 (dd, J 4.2 and 13.2 Hz, 1H), 5.05 (br s, 1H), 7.38
(s, 4H), 7.72 (d, J 2.4 Hz,1H), 7.94 (d, J 2.4 Hz,1H); dC (75 MHz, CDCl3)
45.2, 57.1, 110.1, 110.8, 120.7, 127.9, 129.4, 129.6, 134.6, 138.4, 139.9,
147.0, 190.8; m/z (1þ00, MHþ) 414; HRMS (ES): MHþ, found 413.8835.
C15H11NO35Cl79Br2 requires 413.8896.
4.2.4. 6,8-Dibromo-2-(4-methoxyphenyl)- 2,3-dihydroquinolin-4(1H)-
one 2d. Yield (0.66 g, 63%), mp 149e151 ꢁC (ethanol); Rf (toluene)
0.40; nmax (neat) 1026, 1180, 1246, 1503, 1596, 1661, 3317 cmꢀ1
; dH
4. Experimental
4.1. General
(300 MHz, CDCl3) 2.77 (dd, J 4.2 and 16.5 Hz, 1H), 2.88 (dd, J 13.2 and
16.5 Hz, 1H), 3.82 (s, 3H), 4.71 (dd, J 4.2 and 13.2 Hz, 1H), 5.03 (br s,
1H), 6.94 (d, J 8.7 Hz, 2H), 7.36 (d, J 8.7 Hz, 2H), 7.70 (d, J 2.1 Hz, 1H),
7.95 (d, J 2.1 Hz, 1H); dC (75 MHz, CDCl3) 45.4, 55.4, 57.2, 109.7, 110.7,
114.5, 120.8, 127.8, 129.6, 131.9, 139.8, 147.3, 159.9, 191.4; m/z (100,
Melting points were recorded on a Thermocouple digital melt-
ing point apparatus and are uncorrected. IR spectra were recorded
as powders using an FTS 7000 Series Digilab Win-IR Pro ATR
(attenuated total reflectance) spectrometer. For column chroma-
tography, Merck kieselgel 60 (0.063e0.200 mm) was used as sta-
tionary phase. NMR spectra were obtained as CDCl3 solutions using
a Varian Mercury 300 MHz 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 a Micromass Autospec-TOF (double focusing high-
resolution) instrument. The synthesis and characterization of
substrates 1 have been described elsewhere.28 Thallium(III) tol-
ylsulfonate (TTS) was prepared from thallium(III) nitrate trihydrate
and p-toluenesulfonic acid following a literature procedure.22
þ
MHþ) 410; HRMS (ES): MHþ, found 409.9383. C16H14NO279Br2 re-
quires 409.9391.
4.3. One-pot Suzuki cross-coupling of 2 to afford 3.
Typical procedure
4.3.1. 2,6,8-Triphenyl-2,3-dihydroquinolin-4(1H)-one 3a. A mixture
of 2a (0.40 g, 1.05 mmol), phenylboronic acid (0.32 g, 2.62 mmol),
PdCl2(PPh3)2 (0.04 g, 0.05 mmol), PCy3 (0.03 g, 0.10 mmol) and
K2CO3 (0.32 g, 2.31 mmol) in dioxane/water (3:1, v/v, 20 mL) in
a two-necked flask equipped with a stirrer bar, rubber septum and
a condenser was flushed for 20 min with argon gas. A balloon filled
with argon gas was then connected to the top of the condenser and
the mixture was heated with stirring at 80e90 ꢁC under argon at-
mosphere for 18 h. The mixture was allowed to cool to room
temperature and then poured into an ice-cold water. The product
was taken-up into chloroform and the combined organic extracts
were sequentially washed with brine, dried over anhydrous MgSO4,
filtered and then evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel to afford 3a as
a solid (0.62 g, 79%), mp 164e166 ꢁC (ethanol); Rf (30% ethyl ace-
4.2. Bromination of 1 with N-bromosuccinimide (NBS).
Typical procedure
4.2.1. 6,8-Dibromo-2-phenyl-2,3-dihydroquinolin-4(1H)-one 2a. NBS
(1.00 g, 5.61 mmol) was added to a stirred suspension of 1a (0.50 g,
2.24 mmol) in carbon tetrachloride-chloroform (3:2, v/v; 40 mL). The
mixture was stirred at room temperature for 3 h and then quenched
with an ice-cold saturated solution of NaHCO3. The organic layer was
separated and the aqueous phase was extracted twice with chloro-
form. The combined organic phases were washed with water and
dried over MgSO4. The salt was filtered off and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel to afford 2a as a yellow solid
(0.86 g, 70%), mp 131e133 ꢁC (ethanol); Rf (toluene) 0.58; nmax (neat)
tate/hexane) 0.75; nmax (neat) 1234, 1474, 1675, 3380 cmꢀ1
; dH
(300 MHz, CDCl3) 2.84 (ddd, J 1.5, 4.5 and 16.3 Hz, 1H), 2.95 (dd, J
13.1 and 16.3 Hz, 1H), 4.70 (dd, J 4.5 and 13.1 Hz, 1H), 4.84 (br s, 1H),
7.27e7.52 (m, 13H), 7.60e7.63 (m, 3H), 8.20 (d, J 2.8 Hz, 1H); dC
(75 MHz, CDCl3) 46.5, 58.3, 119.4, 125.0, 126.4 (2ꢂ C), 126.9, 128.1,
128.3, 128.8, 129.0, 129.1, 129.3, 129.5, 130.9, 134.8, 137.5, 139.9,
141.0, 147.9, 193.3; m/z (100, MHþ) 376; HRMS (ES): MHþ, found
376.1685. C27H22NOþ requires 376.1701.
757, 882, 1155, 1226, 1482, 1590, 1679, 3375 cmꢀ1
; dH (300 MHz,
CDCl3) 2.80 (ddd, J 1.2, 4.5 and 16.5 Hz, 1H), 2.90 (dd, J 13.2 and
16.5 Hz, 1H), 4.77 (dd, J 4.5 and 13.2 Hz, 1H), 5.10 (br s,1H), 7.35e7.46
(m, 5H), 7.71 (d, J 2.1 Hz,1H), 7.95 (d, J 2.1 Hz,1H); dC (75 MHz, CDCl3)
45.3, 57.7, 109.8, 110.8, 120.8, 126.5, 128.8, 129.2, 129.6, 139.9, 140.0,
4.3.2. 2-(4-Fluorophenyl)-6,8-diphenyl-2,3-dihydroquinolin-4(1H)-
one 3b. Yield (0.24 g, 62%), mp 182e185 ꢁC (ethanol); Rf (30% ethyl
acetate/hexane) 0.75; nmax (neat) 1232, 1481, 1600, 1681,

M.J. Mphahlele, F.A. Oyeyiola / Tetrahedron 67 (2011) 6819e6825
6823
3381 cmꢀ1
;
dH (300 MHz, CDCl3) 2.82 (ddd, J 1.5, 4.5 and 16.3 Hz,
(dd, J 12.6 and 16.3 Hz, 1H), 4.64 (br s, 1H), 4.69 (dd, J 4.8 and 12.6 Hz,
1H), 7.09 (t, J 8.4 Hz, 2H), 7.16 (t, J 8.4 Hz, 2H), 7.33 (s, 4H), 7.45 (t, J
6.9 Hz, 2H), 7.51 (d, J 2.1 Hz, 1H), 7.54 (t, J 6.9 Hz, 2H), 8.20 (d, J 2.8 Hz,
1H); dC (75 MHz, CDCl3) 46.2, 57.6, 115.7 (d, 2JCF 21.3 Hz), 116.4 (d, 2JCF
1H), 2.92 (dd, J 12.9 and 16.3 Hz, 1H), 4.70 (dd, J 4.5 and 12.9 Hz,
1H), 4.78 (br s, 1H), 7.05 (t, J 8.7 Hz, 2H), 7.27e7.51 (m, 10H),
7.59e7.62 (m, 3H), 8.19 (d, J 1.8 Hz, 1H); dC (75 MHz, CDCl3) 46.5,
57.6, 115.9 (d, 2JCF 21.4 Hz), 119.5, 125.0, 126.4, 126.9, 128.0, 128.1 (d,
3JCF 8.3 Hz), 128.2, 128.8, 129.1, 129.3, 129.5, 131.2, 134.9, 136.8 (d,
3
21.3 Hz), 119.5, 125.0, 127.7, 127.9 (d, JCF 8.0 Hz), 128.6, 129.3, 130.4,
130.8 (d, 3JCF 8.0 Hz), 133.1 (d, 4JCF 3.3 Hz), 134.2, 134.7, 135.8 (d, 4JCF
3.2 Hz), 139.3, 147.6, 162.2 (d, 1JCF 244.7 Hz), 162.5 (d, 1JCF 246.9 Hz),
192.7; m/z (100, MHþ) 446; HRMS (ES): MHþ, found 446.1101.
C27H19F2NO35Clþ requires 446.1123.
4JCF 3.2 Hz), 137.4, 139.8, 147.8 (d, JCF 245.9 Hz), 193.1; m/z (100,
1
MHþ) 394; HRMS (ES): MHþ, found 394.1599. C27H21FNOþ re-
quires 394.1607.
4.3.3. 2-(4-Chlorophenyl)-6,8-diphenyl-2,3-dihydroquinolin-4(1H)-
4.3.8. 6,8-Bis(4-fluorophenyl)-2-(4-methoxyphenyl)-2,3-
dihydroquinolin-4(1H)-one 3h. Yield (0.28 g, 66%), mp 182e184 ꢁC
(ethanol); Rf (30% ethyl acetate/hexane) 0.64; nmax (neat) 830, 1220,
one 3c. Yield (0.28 g, 72%), mp 202e204 ꢁC (ethanol); Rf (30% ethyl
acetate/hexane) 0.75; nmax (neat) 1274, 1479, 1666, 3373 cmꢀ1
; dH
(300 MHz, CDCl3) 2.87 (dd, J 4.5 and 16.2 Hz, 1H), 2.91 (dd, J 12.3
and 16.2 Hz, 1H), 4.70 (dd, J 4.5 and 12.3 Hz, 1H), 4.77 (br s, 1H), 7.33
(s, 4H), 7.37e7.50 (m, 8H), 7.59e7.62 (m, 3H), 8.18 (d, J 2.7 Hz, 1H);
dC (75 MHz, CDCl3) 46.3, 57.6, 119.5, 125.0, 126.4, 126.9, 127.6, 128.2,
128.8, 129.1, 129.2, 129.3, 129.6, 131.2, 134.1, 134.9, 137.4, 139.5,
139.8, 147.7, 192.9; m/z (100, MHþ) 410; HRMS (ES): MHþ, found
410.1300. C27H21NO35Clþ requires 410.1312.
1484, 1509, 1676, 3402 cmꢀ1
; dH (300 MHz, CDCl3) 2.80 (dd, J 3.0
and 16.8 Hz, 1H), 2.90 (dd, J 12.6 and 16.8 Hz, 1H), 3.80 (s, 3H), 4.65
(br s, 1H), 4.65 (dd, J 4.5 and 12.6 Hz, 1H), 6.89 (d, J 7.5 Hz, 2H), 7.09
(t, J 7.8 Hz, 1H), 7.13 (d, J 9.0 Hz, 2H), 7.15 (t, J 7.8 Hz, 1H), 7.30 (d, J
9.0 Hz, 2H), 7.42e7.56 (m, 5H), 8.13 (d, J 3.0 Hz, 1H); dC (75 MHz,
2
2
CDCl3) 46.5, 55.3, 57.7, 114.4, 115.6 (d, JCF 21.4 Hz), 116.3 (d, JCF
21.4 Hz), 119.5, 125.0, 127.6, 127.9 (d, 3JCF 8.0 Hz), 128.5, 130.0, 130.8
2
3
4
(d, JCF 8.0 Hz), 132.8, 133.2 (d, JCF 3.4 Hz), 134.6, 135.9 (d, JCF
3.3 Hz), 147.9, 159.6, 162.2 (d, 1JCF 244.5 Hz), 162.5 (d, 1JCF 246.5 Hz),
193.4; m/z (100, MHþ) 442; HRMS (ES): MHþ, found 442.1628.
C28H22F2NO2þ requires 442.1619.
4.3.4. 2-(4-Methoxyphenyl)-6,8-diphenyl-2,3-dihydroquinolin-
4(1H)-one 3d. Yield (0.24 g, 62%), mp 194e196 ꢁC (ethanol); Rf (30%
ethyl acetate/hexane) 0.62; nmax (neat) 1240, 1478, 1607, 1675,
3400 cmꢀ1
; dH (300 MHz, CDCl3) 2.80 (ddd, J 1.5, 3.9 and 16.2 Hz,
1H), 2.93 (dd, J 13.2 and 16.2 Hz, 1H), 3.79 (s, 3H), 4.66 (dd, J 3.9 and
13.2 Hz, 1H), 4.78 (br s, 1H), 6.89 (d, J 8.7 Hz, 2H), 7.31 (d, J 8.7 Hz,
2H), 7.36e7.51 (m, 8H), 7.58e7.63 (m, 3H), 8.19 (d, J 2.4 Hz, 1H); dC
(75 MHz, CDCl3) 46.6, 55.3, 57.7, 114.3, 119.4, 125.0, 126.3, 126.8,
127.6, 128.1, 128.8, 129.1, 129.2, 129.5, 130.8, 133.0, 134.8, 137.5,
139.9, 148.0, 159.5, 193.5; m/z (100, MHþ) 406; HRMS (ES): MHþ,
found 406.1790. C28H24NO2þ requires 406.1807.
4.4. Dehydrogenation of 3 with thallium(III) p-tolysulfonate
(TTS). Typical procedure
4.4.1. 2,6,8-Triphenylquinolin-4(1H)-one 4a. A stirred mixture of 3a
(0.20 g, 0.53 mmol) and TTS (0.43 g, 0.59 mmol) in DME (10 mL)
was heated at 100 ꢁC for 30 min. The cooled reaction mixture was
quenched with water and the resulting precipitate was filtered on
a sintered funnel. The crude product was taken-up into chloroform
and the organic solution was washed with saturated Na2CO3 and
dried over MgSO4. The salt was filtered off and the solvent was
concentrated under reduced pressure to afford 4a as a solid
(0.13 g, 66%), mp 241e243 ꢁC (ethanol); nmax (neat) 695, 759, 1492,
4.3.5. 6,8-Bis(4-fluorophenyl)-2-phenyl-2,3-dihydroquinolin-4(1H)-
one 3e. Yield (0.28 g, 66%), mp 167e169 ꢁC (ethanol); Rf (30% ethyl
acetate/hexane) 0.71; nmax (neat) 835, 1218, 1490, 1603, 1682,
3390 cmꢀ1
; dH (300 MHz, CDCl3) 2.84 (ddd, J 1.5, 4.5 and 16.2 Hz,
1H), 2.94 (dd, J 12.9 and 16.2 Hz, 1H), 4.70 (br s, 1H), 4.71 (dd, J 4.5
and 12.9 Hz, 1H), 7.10 (t, J 8.7 Hz, 2H), 7.16 (t, J 8.7 Hz, 2H), 7.31e7.43
(m, 5H), 7.42e7.57 (m, 5H), 8.13 (d, J 2.4 Hz, 1H); dC (75 MHz, CDCl3)
46.4, 58.2, 115.6 (d, 2JCF 21.4 Hz), 115.8 (d, 2JCF 21.4 Hz), 119.5, 125.0,
1591, 1626, 3398 cmꢀ1
; dH (300 MHz, CDCl3) 6.63 (d, J 1.8 Hz, 1H),
6.80 (d, J 7.8 Hz, 1H), 7.11 (d, J 8.1 Hz, 1H), 7.37 (t, J 7.2 Hz, 1H),
7.44e7.64 (m, 10H), 7.75 (d, J 7.2 Hz, 2H), 7.85 (d, J 2.1 Hz, 1H), 8.49
(br s, 1H), 8.67 (d, J 1.8 Hz, 1H); dC (75 MHz, CDCl3) 108.3, 113.9,
123.4, 126.1, 127.2, 127.6, 127.8, 128.9, 129.0, 129.2, 129.6, 129.8,
130.8, 131.8, 134.5, 136.4, 136.6, 136.5, 139.7, 148.7, 179.0; m/z (100,
MHþ) 374; HRMS (ES): MHþ, found 374.1530. C27H20NOþ requires
374.1545.
3
3
126.3, 127.9 (d, JCF 8.0 Hz), 128.4, 128.6, 129.1, 130.1, 130.8 (d, JCF
8.0 Hz),133.2 (d, 3JCF 3.4 Hz),134.6, 135.9 (d, 4JCF 3.1 Hz),140.8,147.9,
162.2 (d, JCF 244.5 Hz), 162.5 (d, JCF 246.7 Hz), 193.1; m/z (100,
MHþ) 412; HRMS (ES): MHþ, found 412.1492. C27H20F2NOþ requires
412.1513.
1
1
4.4.2. 2-(4-Fluorophenyl)-6,8-diphenylquinolin-4(1H)-one 4b. Yield
(0.12 g, 60%), mp 237e238 ꢁC (ethanol); nmax (neat) 697, 770, 832,
4.3.6. 2,6,8-Tris(4-fluorophenyl)-2,3-dihydroquinolin-4(1H)-one
3f. Yield (0.44 g, 51%), mp 176e179 ꢁC (ethanol); Rf (30% ethyl ac-
etate/hexane) 0.70; nmax (neat) 835, 1218, 1490, 1603, 1682,
1236, 1500, 1507, 1592, 1635, 3415 cmꢀ1
; dH (300 MHz, CDCl3) 6.56
(d, J 1.8 Hz, 1H), 6.79 (d, J 8.4 Hz, 2H), 7.10 (d, J 8.4 Hz, 2H), 7.17 (t, J
8.7 Hz, 2H), 7.36 (t, J 7.2 Hz, 1H), 7.43e7.65 (m, 5H), 7.73 (d, J 7.2 Hz,
2H), 7.85 (d, J 2.1 Hz, 1H), 8.42 (br s, 1H), 8.66 (d, J 2.1 Hz, 1H); dC
3390 cmꢀ1
; dH (300 MHz, CDCl3) 2.81 (ddd, J 1.5, 4.5 and 16.2 Hz,
1H), 2.91 (dd, J 12.9 and 16.2 Hz, 1H), 4.67 (br s, 1H), 4.70 (dd, J 4.5
and 12.9 Hz, 1H), 7.02e7.13 (m, 4H), 7.16 (t, J 7.8 Hz, 2H), 7.37 (t, J
6.9 Hz, 2H), 7.54 (t, J 6.9 Hz, 2H), 7.50 (d, J 2.1 Hz,1H), 7.57 (t, J 6.9 Hz,
2H), 8.13 (d, J 2.4 Hz, 1H); dC (75 MHz, CDCl3) 46.4, 57.6, 115.7 (d, 2JCF
2
(75 MHz, CDCl3) 108.2, 113.9, 116.7 (d, JCF 21.9 Hz), 123.4, 125.8,
3
127.1, 127.6, 127.7, 128.1 (d, JCF 8.6 Hz), 128.9, 129.0, 129.1, 129.8,
130.6 (d, 4JCF 3.2 Hz), 131.4, 131.8, 136.2, 136.6, 139.5, 147.7, 164.1 (d,
1JCF 251.0 Hz), 178.9; m/z (100, MHþ) 392; HRMS (ES): MHþ, found
392.1465. C27H19FNOþ requires 392.1451.
2
2
21.4 Hz), 116.0 (d, JCF 21.6 Hz), 116.3 (d, JCF 21.4 Hz), 119.5, 125.0,
127.8 (d, 3JCF 8.0 Hz), 127.9 (d, 3JCF 8.3 Hz), 128.0, 128.6, 130.2, 130.8
(d, JCF 8.0 Hz), 133.1 (d, JCF 3.5 Hz), 134.7, 135.8 (d, JCF 3.2 Hz),
136.6 (d, JCF 3.5 Hz), 147.7, 162.2 (d, JCF 244.4 Hz), 162.5 (d, JCF
245.0 Hz, 2ꢂ C), 193.0; m/z (100, MHþ) 430; HRMS (ES): MHþ,
found 430.1421. C27H19F3NOþ requires 430.1419.
3
4
4
4
1
1
4.4.3. 2-(4-Chlorophenyl)-6,8-diphenylquinolin-4(1H)-one 4c. Yield
(0.11 g, 55%), mp 209e211 ꢁC (ethanol); nmax (neat) 697, 759, 828,
1093, 1246, 1381, 1489, 1596, 1623, 3401 cmꢀ1
; dH (300 MHz, CDCl3)
6.57 (s,1H), 6.80 (d, J 7.8 Hz,1H), 7.10 (d, J 9.3 Hz,1H), 7.37 (t, J 7.8 Hz,
1H), 7.42e7.64 (m, 10H), 7.74 (d, J 7.5 Hz, 2H), 7.84 (d, J 2.1 Hz, 1H),
8.42 (br s, 1H), 8.65 (d, J 2.1 Hz, 1H); dC (75 MHz, CDCl3) 108.4, 113.9,
123.5, 125.8, 127.2, 127.4, 127.7, 128.9, 129.1, 129.2, 129.8, 129.9,
131.4, 131.9, 132.9, 136.1, 136.2, 136.8, 139.6, 147.5, 179.0; m/z (100,
4.3.7. 2-(4-Chlorophenyl)-6,8-bis(4-fluorophenyl)-2,3-dihydroquinolin-
4(1H)-one 3g. Yield (0.23 g, 52%), mp 190e192 ꢁC (ethanol); Rf (30%
ethyl acetate/hexane) 0.71; nmax (neat) 834, 1014, 1231, 1487, 1678,
3392 cmꢀ1
; dH (300 MHz, CDCl3) 2.62 (dd, J 4.8 and 16.3 Hz, 1H), 2.90

6824
M.J. Mphahlele, F.A. Oyeyiola / Tetrahedron 67 (2011) 6819e6825
MHþ) 408; HRMS (ES): MHþ, found 408.1148. C27H19NO35Clþ re-
quires 408.1147.
4.5. Aromatization of 3 with iodine in methanol. Typical
procedure
4.4.4. 2-(4-Methoxyphenyl)-6,8-diphenylquinolin-4(1H)-one
4.5.1. 4-Methoxy-2,6,8-triphenylquinoline 5a. A stirred mixture of
3a (0.20 g, 0.27 mmol) and iodine (0.14 g, 0.53 mmol) in methanol
(15 mL) was refluxed for 2.5 h. The mixture was quenched with an
ice-cold solution of saturated sodium thiosulfate and the product
was extracted into chloroform. The combined chloroform phases
were dried over MgSO4, filtered and then evaporated under reduced
pressure to afford 6a as a white solid (0.17 g, 82%), mp 220e223 ꢁC
4d. Yield (0.12 g, 55%), mp 210e212 ꢁC (ethanol); nmax (neat) 701,
765, 832, 1220, 1482, 1669, 3376 cmꢀ1
; dH (300 MHz, CDCl3) 3.85 (s,
3H), 6.58 (d, J 1.5 Hz, 1H), 6.99 (d, J 8.7 Hz, 2H), 7.36 (t, J 7.8 Hz, 1H),
7.44 (d, J 7.8 Hz, 2H), 7.45 (d, J 8.7 Hz, 2H), 7.50e7.64 (m, 5H), 7.75 (d,
J 7.2 Hz, 2H), 7.83 (d, J 2.1 Hz, 1H), 8.45 (br s, 1H), 8.66 (d, J 2.1 Hz,
1H); dC (75 MHz, CDCl3) 55.5, 107.5, 115.0, 123.5, 125.9, 126.5, 127.1,
127.5,127.6,128.8,128.9,129.2,129.8, 131.3,131.7,136.1,136.3, 136.4,
139.7, 148.5, 161.6, 179.0; m/z (100, MHþ) 404; HRMS (ES): MHþ,
(ethanol); nmax (neat) 692, 768, 835, 1219, 1486, 1592 cmꢀ1
; dH
(300 MHz, CDCl3)4.16 (s, 3H), 7.30 (s,1H), 7.39e7.55 (m, 9H), 7.80 (d, J
7.5 Hz, 2H), 7.91 (d, J 7.5 Hz, 2H), 8.05 (d, J 1.8 Hz,1H), 8.14 (d, J 8.1 Hz,
2H), 8.43 (d, J 1.8 Hz, 1H); dC (75 MHz, CDCl3) 55.7, 97.2, 119.0, 121.2,
127.1, 127.3, 127.4, 127.5, 127.6, 128.6, 128.9, 129.2, 130.4, 131.2, 137.7,
139.8, 140.0, 140.7 (2ꢂ C), 145.9, 157.1, 163.2; m/z (100, MHþ) 388;
HRMS (ES): MHþ, found 388.1709. C28H22NOþ requires 388.1706.
þ
found 404.1634. C28H22NO2 requires 404.1651.
4.4.5. 6,8-Bis(4-fluorophenyl)-2-phenylquinolin-4(1H)-one 4e. Yield
(0.09 g, 90%), mp 239e242 ꢁC (ethanol); nmax (neat) 834, 1218, 1495,
1584, 1628, 3405 cmꢀ1
; dH (300 MHz, DMSO-d6) 6.61 (d, J 1.8 Hz,
1H), 7.14 (t, J 8.7 Hz, 2H), 7.31 (t, J 8.7 Hz, 2H), 7.50 (s, 5H), 7.57 (t, J
8.7 Hz, 2H), 7.67 (t, J 8.7 Hz, 2H), 7.74 (d, J 2.1 Hz, 1H), 8.34 (br s, 1H),
8.59 (d, J 2.1 Hz,1H); dC (75 MHz, CDCl3) 108.4,115.8 (d, 2JCF 21.4 Hz),
116.9 (d, 2JCF 21.6 Hz), 123.5, 125.9, 126.1, 128.7 (d, 3JCF 8.0 Hz), 129.7,
130.4, 130.8, 131.0 (d, 3JCF 8.0 Hz), 131.7, 132.1 (d, 4JCF 3.4 Hz), 134.3,
4.5.2. 2-(4-Fluorophenyl)-4-methoxy-6,8-diphenylquinoline 5b. Yield
(0.08 g, 78%), mp 210e212 ꢁC (ethanol); nmax (neat) 699, 765, 825,
1219, 1484, 1589 cmꢀ1
; dH (300 MHz, CDCl3) 4.16 (s, 3H), 7.13 (t, J
8.4 Hz, 2H), 7.23 (s, 1H), 7.36e7.55 (m, 6H), 7.79 (d, J 7.5 Hz, 2H), 7.87
(d, J 7.5 Hz, 2H), 8.04 (d, J 2.1 Hz, 1H), 8.12 (t, J 8.4 Hz, 2H), 8.42 (d, J
2.1 Hz, 1H); dC (75 MHz, CDCl3) 55.7, 96.8, 115.5(d, 2JCF 21.6 Hz), 118.7,
121.1,127.2,127.4,127.5,127.7,128.9,129.2 (d, 3JCF 8.3 Hz),130.5,131.1,
136.1 (d, 4JCF 3.2 Hz), 137.7, 139.8, 140.7, 145.8, 156.0, 163.3, 163.7 (d,
1JCF 247.3 Hz); m/z (100, MHþ) 406; HRMS (ES): MHþ, found
406.1606. C28H21NFOþ requires 406.1607.
4
1
135.5, 135.6 (d, JCF 3.4 Hz), 136.2, 148.8, 162.7 (d, JCF 245.6 Hz),
1
163.0 (d, JCF 248.4 Hz), 178.8; m/z (100, MHþ) 410; HRMS (ES):
MHþ, found 410.1343. C27H18NF2Oþ requires 410.1356.
4.4.6. 2,6,8-Tris(4-fluorophenyl)quinolin-4(1H)-one 4f. Yield (0.06 g,
50%), mp 240e242 ꢁC (ethanol); nmax (neat) 832, 839, 1237, 1497,
1591, 1627, 3406 cmꢀ1
; dH (300 MHz, CDCl3) 6.52 (s, 1H), 7.14 (t, J
9.0 Hz, 2H), 7.18 (t, J 9.0 Hz, 2H), 7.31 (t, J 9.0 Hz, 2H), 7.48 (t, J
7.5 Hz, 2H), 7.56 (t, J 7.5 Hz, 2H), 7.66 (t, J 7.5 Hz, 2H), 7.74 (d, J
2.4 Hz, 1H), 8.25 (br s, 1H), 8.57 (d, J 2.4 Hz, 1H); dC (75 MHz, CDCl3)
4.5.3. 2-(4-Chlorophenyl)-4-methoxy-6,8-diphenylquinoline 5c. Yield
(0.20 g, 97%), mp 231e233 ꢁC (ethanol); nmax (neat) 698, 760, 824,
1094,1218,1483,1590 cmꢀ1
; dH (300 MHz, CDCl3) 4.14 (s, 3H), 7.22 (s,
2
2
2
108.3, 115.8 (d, JCF 21.3 Hz), 116.84 (d, JCF 22.2 Hz), 117.0 (d, JCF
1H), 7.40e7.55 (m, 8H), 7.79 (d, J 8.4 Hz, 2H), 7.87 (d, J 8.4 Hz, 2H),
8.06 (d, J 8.4 Hz, 2H), 8.07 (d, J 2.4 Hz, 1H), 8.41 (d, J 2.4 Hz, 1H); dC
(75 MHz, CDCl3) 55.7, 96.8, 119.0, 121.2, 127.2, 127.4, 127.6, 127.7,
128.6, 128.8, 128.9, 130.5, 131.1, 135.3, 137.9, 138.4, 139.7, 140.6, 140.7,
145.8, 155.7, 163.3; m/z (100, MHþ) 422; HRMS (ES): MHþ, found
422.1296. C28H21NO35Clþ requires 422.1312.
3
3
21.6 Hz), 123.4, 125.8, 128.1 (d, JCF 8.4 Hz), 128.7 (d, JCF 8.3 Hz),
130.4, 130.5 (d, 3JCF 3.4 Hz), 131.0 (d, 3JCF 8.0 Hz), 131.7, 132.1 (d, 3JCF
3
1
3.4 Hz), 135.6 (d, JCF 3.4 Hz), 135.7, 136.1, 147.8, 162.7 (d, JCF
246.2 Hz), 163.0 (d, 1JCF 261.9 Hz), 164.2 (d, 1JCF 251.3 Hz), 178.7; m/z
(100, MHþ) 428; HRMS (ES): MHþ, found 428.1252. C27H17NF3Oþ
requires 428.1262.
4.5.4. 4-Methoxy-2-(4-methoxyphenyl)-6,8-diphenylquinoline
4.4.7. 2-(4-Chlorophenyl)-6,8-bis(4-fluorophenyl)quinolin-4(1H)-one
4g. Yield (0.07 g, 71%), mp 225e228 ꢁC (ethanol); nmax (neat) 828,
5d. Yield (0.08 g, 87%), mp 196e198 ꢁC (ethanol); nmax (neat) 697,
758, 825, 1207, 1168, 1217, 1233, 1484, 1591 cmꢀ1
; dH (300 MHz,
1094, 1158, 1224, 1490, 1601, 1624 cmꢀ1
;
dH (300 MHz, CDCl3) 6.56 (d, J
CDCl3) 3.85 (s, 3H), 4.14 (s, 3H), 6.97 (d, J 9.0 Hz, 2H), 7.22 (s, 1H),
7.35e7.59 (m, 6H), 7.89 (d, J 7.7 Hz, 2H), 7.89 (d, J 8.7 Hz, 2H), 8.02 (d,
J 2.1 Hz, 1H), 8.09 (d, J 8.7 Hz, 2H), 8.40 (d, J 2.1 Hz, 1H); dC (75 MHz,
CDCl3) 55.3, 55.6, 96.6, 114.0, 118.9, 120.9, 127.0, 127.3, 127.4, 127.6,
128.7, 128.8, 130.3, 131.2, 132.6, 137.3, 139.9, 140.5, 140.8, 145.9,
156.7, 160.7, 163.0; m/z (100, MHþ) 418; HRMS (ES): MHþ, found
418.1816. C29H24NO2þ requires 418.1807.
1.8 Hz, 1H), 7.15 (t, J 8.7 Hz, 2H), 7.31 (t, J 8.7 Hz, 2H), 7.43 (d, J 9.0 Hz,
2H), 7.48 (d, J 9.0 Hz, 2H), 7.56 (t, J 8.7 Hz, 2H), 7.68 (t, J 8.7 Hz, 2H), 7.75
(d, J 2.1 Hz,1H), 8.24 (br s,1H), 8.59 (d, J 2.1 Hz,1H); dC (75 MHz, CDCl3)
108.5, 115.9 (d, 2JCF 21.4 Hz), 117.0 (d, 2JCF 21.3 Hz), 123.5, 125.9, 127.4,
128.7 (d, 3JCF 8.0 Hz), 130.0, 130.4, 131.0 (d, 3JCF 8.3 Hz), 131.8, 132.0 (d,
4JCF 3.7 Hz), 132.8, 135.6 (d, 4JCF 3.6 Hz), 135.8, 136.1, 137.2, 147.6, 162.7
(d, 1JCF 245.9 Hz), 163.1 (d, 1JCF 248.5 Hz), 178.8; m/z (100, MHþ) 444;
HRMS (ES): MHþ, found 444.0957. C27H17F2NO35Clþ requires
444.0967.
4.5.5. 6,8-Bis(4-fluorophenyl)-4-methoxy-2-phenylquinoline
5e. Yield (0.09 g, 89%), mp 231e233 ꢁC (ethanol); nmax (neat) 772,
832,1159,1219,1486,1509,1593 cmꢀ1
; dH (300 MHz, CDCl3); 4.17 (s,
4.4.8. 6,8-Bis(4-fluorophenyl)-2-(4-methoxyphenyl)quinolin-4(1H)-
one 4h. Yield (0.13 g, 65%), mp 219e220 ꢁC (ethanol); nmax (neat)
3H), 7.17 (d, J 8.4 Hz, 2H), 7.22 (d, J 8.4 Hz, 2H), 7.30 (s,1H), 7.39e7.51
(m, 3H), 7.74 (t, J 8.7 Hz, 2H), 7.85 (t, J 8.7 Hz, 2H), 7.93 (d, J 2.1 Hz,1H),
8.12 (d, J 8.4 Hz, 2H), 8.36 (d, J 2.1 Hz, 1H); dC (75 MHz, CDCl3) 55.8,
97.3,114.5 (d, 2J 21.3 Hz),115.8 (d, 2J 21.4 Hz),118.9,121.2,127.3,128.7,
130.0 (d, 3JCF 8.0 Hz), 129.4, 130.0, 132.7 (d, 3JCF 8.0 Hz), 135.6 (d, 4JCF
3.5 Hz),136.7,136.8 (d, 4JCF 3.5 Hz),139.7,139.8,145.7,157.3,162.4 (d,
1JCF 244.7 Hz), 162.6 (d, 1JCF 245.0 Hz), 163.1; m/z (100, MHþ) 424;
HRMS (ES): MHþ, found 424.1519. C28H20F2NOþ requires 424.1513.
827, 1158, 1223, 1501, 1508, 1582, 1628, 3413 cmꢀ1
; dH (300 MHz,
CDCl3) 3.85 (s, 3H), 6.56 (s, 1H), 7.01 (d, J 9.3 Hz, 2H), 7.14 (t, J
9.3 Hz, 2H), 7.31 (t, J 9.3 Hz, 2H), 7.43 (d, J 9.3 Hz, 2H), 7.57 (t, J
7.8 Hz, 2H), 7.67 (t, J 7.8 Hz, 2H), 7.73 (d, J 1.8 Hz, 1H), 8.28 (br s,
1H), 8.58 (d, J 1.8 Hz, 1H); dC (75 MHz, CDCl3) 55.5, 107.5, 115.0,
2
2
115.9 (d, JCF 21.4 Hz), 116.9 (d, JCF 21.4 Hz), 123.5, 125.8, 126.4,
127.4, 128.7 (d, 3JCF 8.0 Hz), 130.3, 131.1 (d, 3JCF 8.3 Hz), 131.5, 132.2
(d, 4JCF 3.4 Hz), 135.4, 135.7 (d, 4JCF 3.4 Hz), 136.1, 148.5, 161.7, 162.6
4.5.6. 2,6,8-Tris(4-fluorophenyl)-4-methoxyquinoline5f. Yield (0.07 g,
68%), mp 197e199 ꢁC (ethanol); nmax (neat) 819, 1155, 1216, 1509,
1
1
(d, JCF 245.9 Hz), 163.0 (d, JCF 248.1 Hz), 178.8; m/z (100, MHþ)
440; HRMS (ES): MHþ, found440.1300. C28H20F2O2Nþ requires
440.1310.
1586 cmꢀ1
;
dH (300 MHz, CDCl3) 4.16 (s, 3H), 7.15 (t, J 8.7 Hz, 2H), 7.21
(t, J 8.7 Hz, 2H), 7.23 (t, J 8.7 Hz, 2H), 7.24 (s, 1H), 7.73 (t, J 8.7 Hz, 2H),

M.J. Mphahlele, F.A. Oyeyiola / Tetrahedron 67 (2011) 6819e6825
6825
2. Xia, Y.; Yang, Z.; Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J.; Lee, K. J. J. Med.
Chem. 2001, 44, 3932e3936.
3. Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S.-C.; Hamel, E.;
7.81 (t, J 8.7 Hz, 2H), 7.92 (d, J 2.1 Hz, 1H), 8.10 (t, J 8.7 Hz, 2H), 8.35 (d,
J 2.1 Hz, 1H); dC (75 MHz, CDCl3) 55.7, 96.9, 114.6 (d, JCF 21.1 Hz),
2
115.6 (d, 2JCF 21.7 Hz), 115.8 (d, 2JCF 21.1 Hz), 118.9, 121.0, 128.9 (d, 3JCF
8.0 Hz), 129.1 (d, 3JCF 8.0 Hz), 130.1, 132.6 (d, 3JCF 8.0 Hz), 135.6 (d, 4JCF
3.2 Hz), 136.0 (d, 4JCF 3.2 Hz), 136.6 (d, 4JCF 3.2 Hz), 136.7, 139.7, 145.6,
156.1, 162.3 (d, 1JCF 244.7 Hz), 162.6 (d, 1JCF 245.6 Hz), 163.2, 163.7 (d,
1JCF 247.6 Hz); m/z (100, MHþ) 442; HRMS (ES): MHþ, found
442.1408. C28H19F3NOþ requires 442.1419.
Hackl, T.; Lee, K.-H. J. Med. Chem. 1998, 41, 1155e1162.
4. See review by Mphahlele, M. J. J. Heterocycl. Chem. 2010, 47, 1e14.
5. Park, M.-S.; Lee, J.-I. Bull. Korean Chem. Soc. 2004, 25, 1269e1272.
6. (a) Kuo, S.-C.; Lee, H.-Z.; Juang, J.-P.; Lin, H.-T.; Wu, T.-S.; Chang, J.-J.; Lednicer,
D.; Paull, K. D.; Lin, C. M.; Hamel, E.; Lee, K.-H. J. Med. Chem. 1993, 36,
1146e1156; (b) Li, L.; Wang, H.-K.; Kuo, S.-C.; Wu, T.-C.; Lednicer, D.; Lin, C. M.;
Hamel, E.; Lee, K.-H. J. Med. Chem. 1994, 37, 3400e3407.
7. (a) Torii, S.; Okumoyo, H.; Xu, L. H. Tetrahedron Lett. 1991, 32, 237e240; (b)
Kalanin, V. N.; Shostakovsky, M. V.; Ponomaryov, A. B. Tetrahedron Lett. 1992, 33,
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A 2003, 369, 125e132; (d) Genelot, M.; Dufaud, V.; Djakovitch, L. Tetrahedron
2011, 67, 976e981.
4.5.7. 2-Chlorophenyl-6,8-bis(4-fluorophenyl)-4-methoxyquinoline
5g. Yield (0.09 g, 88%), mp 236e238 ꢁC (ethanol); nmax (neat) 819,
1094, 1156, 1212, 1234, 1480, 1512 cmꢀ1
; dH (300 MHz, CDCl3) 4.16 (s,
8. McGlacken, G. P.; McSweeney, C. M.; O’Brein, T.; Lawrence, S. E.; Elcoate, C. J.;
Reen, F. J.; O’Gara, F. Tetrahedron Lett. 2010, 51, 5919e5921.
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7317e7322.
3H), 7.16 (d, J 8.4 Hz, 2H), 7.22 (d, J 8.4 Hz, 2H), 7.24 (s, 1H), 7.43 (d, J
8.4 Hz, 2H), 7.73 (t, J 8.7 Hz, 2H), 7.81 (t, J 8.7 Hz, 2H), 7.93 (d, J 2.1 Hz,
1H), 8.04 (d, J 8.7 Hz, 2H), 8.35 (d, J 2.1 Hz,1H); dC (75 MHz, CDCl3) 55.8,
10. Layek, M.; Reddy, M. A.; Rao, A. V. D.; Alvala, M.; Arunasree, M. K.; Islam, A.;
Mukkanti, K.; Iqbal, J.; Pal, M. Org. Biomol. Chem. 2011, 50, 1004e1007.
11. Konishi, H.; Itoh, T.; Manabe, K. Chem. Pharm. Bull. 2010, 58, 1255e1258.
12. (a) Mphahlele, M. J. Tetrahedron 2010, 66, 8261e8266; (b) Mphahlele, M. J.;
Mphahlele, M. M. Molecules 2010, 15, 7423e7437.
2
96.9, 114.6 (d, 2JCF 21.1 Hz), 115.7 (d, JCF 21.1 Hz), 118.9, 121.2, 128.5,
128.8, 128.9 (d, 3JCF 8.3 Hz),129.0,130.1, 132.6 (d, 3JCF 8.0 Hz),135.4 (d,
4JCF 2.5 Hz),135.5,136.7 (d, 4JCF 3.1 Hz),136.9,138.2,139.8,156.0,162.4
(d, 1JCF 244.7 Hz), 162.7 (d, 1JCF 245.6 Hz), 163.3; m/z (100, MHþ) 458;
HRMS(ES):MHþ, found 458.1135. C28H19F2NO35Clþ requires458.1123.
ꢀ
13. Janzso, G. In Topics in Flavonoid Chemistry and Biochemistry; Farkas, L., Gabor, M.,
ꢀ
Kallay, F., Eds.; Elsevier Scientific Publishing Company: Amsterdam, 1975;
pp 144e148.
14. Mphahlele, M. J.; Hlatshwayo, S. M.; Ndlovu, S. M.; Fernandes, M. A. S. Afr. J.
Chem. 2001, 54, 60e68.
15. Janzso, G.; Philibin, E. M. Tetrahedron Lett. 1971, 3075e3076.
16. Sahin, A.; Cakmak, O.; Demirtas, I.; Okten, S.; Tutar, A. Tetrahedron 2008, 64,
10068e10074.
4.5.8. 6,8-Bis(4-fluorophenyl)-4-methoxy-2-(4-methoxyphenyl)
quinoline 5h. Yield (0.008 g, 76%), mp 171e173 ꢁC (ethanol); nmax
(neat) 826, 1159, 1218, 1486, 1508, 1598 cmꢀ1
; dH (300 MHz, CDCl3)
3.86 (s, 3H), 4.13 (s, 3H), 6.99 (d, J 8.7 Hz, 2H), 7.14e7.24 (m, 5H), 7.72
(t, J 8.7 Hz, 2H), 7.84 (t, J 8.7 Hz, 2H), 7.90 (d, J 1.8 Hz, 1H), 8.06 (d, J
8.7 Hz, 2H), 8.32 (d, J 1.8 Hz, 1H); dC (75 MHz, CDCl3) 55.4, 55.7, 96.7,
114.0, 114.5 (d, 2J 21.1 Hz), 115.7 (d, 2J 21.4 Hz), 118.9, 120.9, 128.6,
128.9 (d, 3JCF 8.0 Hz), 129.9, 132.5, 132.6 (d, 3JCF 8.0 Hz), 135.7 (d, 4JCF
2.5 Hz),136.2,136.8 (d, 4JCF 3.1 Hz),139.5,145.7,156.8,160.8,162.3 (d,
1JCF 244.4 Hz), 162.6 (d, 1JCF 245.3 Hz), 162.9; m/z (100, MHþ) 454;
HRMS (ES): MHþ, found 454.1608. C29H22NF2O2þ requires 454.1619.
17. Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254e278.
18. Haman, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369e7370.
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19. Kappaun, S.; Sovic, T.; Stelzer, F.; Pogantsch, A.; Zojer, E.; Slugovc, C. Org.
Chem. 2006, 4, 1503e1511.
Biomol.
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This work was funded by the University of South Africa and the
National Research Foundation.
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26. Rossiter, S.; Peron, J.-M.; Whitfield, P. J.; Jones, K. Bioorg. Med. Chem. Lett. 2005,
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