2-Aryl-4-azido-3-(bromo/iodo)quinolines as substrates for the synthesis of primary 4-amino-2,3-disubstituted quinoline derivatives

Article abstract of DOI:10.1002/jhet.5570450515

(Chemical Equation Presented) Staudinger reaction of the 2-aryl-4-azido-3-bromoquinolines and 2-aryl-4-azido-3-iodoquinolines with triphenyl phosphine in refluxing tetrahydrofuran afforded series of 2-aryl-3-halogeno-4-(triphenylphosphoranylideneamino)quinolines. The latter were, in tum, hydrolyzed to the corresponding primary 4-amino-2-aryl-3-(bromo/ iodo)quinolines using 80% acetic acid under reflux. Tetrakis(triphenylphosphine) palladium(0)-catalyzed Suzuki reaction of the 2-aryl-3-iodo-4- (triphenylphosphoranylideneamino)quinolines with phenylboronic acid in dimethyl formamide in the presence of 2 M K₂CO₃ followed by hydrolysis of the incipient 2,3-diaryl-4-(triphenylphosphoranylideneamino) quinolines with 80% acetic acid afforded the 4-amino-2,3-diarylquinolines.

Full text of DOI:10.1002/jhet.5570450515

Sep-Oct 2008
1343
2-Aryl-4-azido-3-(bromo/iodo)quinolines as Substrates for the
Synthesis of Primary 4-Amino-2,3-disubstituted Quinoline
Derivatives
Malose J. Mphahlele* and Vathiswa Mtshemla
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
Received October 23, 2007
NH2
Br, I
PPh 3
X
N3
(ii)
N
N
C6H4R
X
(i)
3
N
C6H4R
N
C6H4R
(iii)
(iv)
NH2
1
2
C6H5
X = Br, I; R = H, F, Cl, OMe
N
C6H4R
4
Reagents and conditions: (i) PPh3, THF, heat, 12h; (ii) 80% acetic acid, heat, 5h;
(iii) PhB(OH)2, Pd(PPh3)4, K2CO3 (aq), DMF, heat, 48h (X = I); (iv) 80% acetic acid, heat, 5h
Staudinger reaction of the 2-aryl-4-azido-3-bromoquinolines and 2-aryl-4-azido-3-iodoquinolines with
triphenyl phosphine in refluxing tetrahydrofuran afforded series of 2-aryl-3-halogeno-4-(triphenylphos-
phoranylideneamino)quinolines. The latter were, in turn, hydrolyzed to the corresponding primary 4-
amino-2-aryl-3-(bromo/iodo)quinolines using 80% acetic acid under reflux. Tetrakis(triphenylphosphine)-
palladium(0)–catalyzed Suzuki reaction of the 2-aryl-3-iodo-4-(triphenylphosphoranylideneamino)-
quinolines with phenylboronic acid in dimethyl formamide in the presence of 2 M K2CO3 followed by
hydrolysis of the incipient 2,3-diaryl-4-(triphenylphosphoranylideneamino)quinolines with 80% acetic acid
afforded the 4-amino-2,3-diarylquinolines.
J. Heterocyclic Chem., 45, 1343 (2008).
INTRODUCTION
benzylamino-2-arylquinolines [5] or N,N-bis(trimethyl-
silyl)-2-phenylquinolin-4-amine [6] using cerium(IV)
ammonium nitrate in acetonitrile, boron tribromide in
dichloromethane or tetrabutylammonium fluoride,
respectively. Several derivatives have also been
prepared through reduction of 4-azidoquinolines
derived from quinoline derivatives bearing a leaving
group such as tosyloxy or halogen using sodium azide
[7] or from the 4-oxo precursors using diphenylphos-
phorylazide [8]. We have also synthesized 4-amino-2-
arylquinolines via sodium ethoxide-promoted Neber
rearrangement of O-mesyloximes derived from the 2-
aryl-1-methylsulfonyl-2,3-dihydroquinolin-4(1H)-ones
[9]. Although several methods have been developed
before for the synthesis of 4-amino-2-arylquinolines
corresponding data for the synthesis of 2,3-disubstituted
primary 4-aminoquinolines is considerably less
documented [5,8].
4-Aminoquinolines represent an important class of
compounds and have attracted a great deal of attention
in recent years because of their pharmacological
properties [1-3]. They are known to serve as
antimalarial, anti-inflammatory, antibacterial, and
antihypertensive agents [1] as well as immuno-
stimulants [2a] and non-nucleoside HIV-1 inhibitors
[2b]. It is reported that over-activation of N-methyl-D-
aspartate (NMDA) subtype of central excitatory amino
acid receptors play
degenerative disorders, for example, it delays neuronal
loss following cerebral ischaemia, epilepsy,
a role in numerous neuro-
Alzheimer’s diseases and AIDS related dementia [3a].
4-Amino-2-arylquinolines have been found to represent
a novel class of NR1/2B subtype selective NMDA
receptor antagonists [3b]. Several methods continue to
appear in literature describing the synthesis of primary
4-amino-2-arylquinolines and most involve depro-
tection of 4-(p-methoxyphenyl)aminoquinolines [4], 4-
In our continuing efforts to introduce exhaustive
substitution into the 2-arylquinoline moiety, we
required an efficient method for the synthesis of 4-

1344
M. J. Mphahlele and V. Mtshemla
Vol 45
amino-2-arylquinolines bearing a halogen at the 3-
position of the heterocyclic framework because of the
profound effect a halogen atom can have on the
physical, chemical and biological properties of such
systems. We now report that Staudinger reaction of 2-
aryl-4-azido-3-(bromo/iodo)quinolines with triphenyl
phosphine in refluxing THF followed by acetic acid–
promoted hydrolysis of the incipient 2-aryl-3-halogeno-
4-(triphenylphosphoranylideneamino)quinolines may
provide a versatile, new approach to primary 4-amino-
2-aryl-3-halogenoquinolines. Moreover, palladium–
catalyzed Suzuki–Miyaura coupling of the 2-aryl-3-
iodo-4-(triphenylphosphoranylideneamino)quinolines
with phenylboronic acid followed by hydrolysis
afforded 4-amino-2,3-diarylquinolines.
reasonable yields (Scheme 1). The presence of the azido
group in systems (3) is confirmed by strong ir
absorption bands in the regions ꢁmax 2116.3 – 2119.0
cm-1 (asymmetric) and ꢁmax 1226.7 – 1258.0 cm-1
(symmetric) in agreement with the literature values for
organic azides [13].
There are several reagents and conditions described
in literature for the reduction of azides to primary
amines and these include the use of lithium aluminum
hydride, sodium borohydride, sodium borohydride/
phase-transfer catalyst, catalytic hydrogenation, triethyl
phosphite and electrolysis [7,14]. Staudinger reaction
involving reaction of azides with triphenyl phosphine
followed by acid hydrolysis has been shown to reduce
azides to primary amines in the presence of cyano,
halogen or carbonyl groups [7]. We required a method
that would reduce the azido group to amino
functionality without promoting possible reductive
removal of 3-halogen atoms that could be observed
with most of the reducing agents or conditions
described above [7,15]. Consequently, in this
investigation we opted for the use of Staudinger
reaction conditions and subjected the azido derivatives
(3a-h) to triphenyl phosphine in tetrahydrofuran under
reflux and isolated the corresponding 2-aryl-3-
halogeno-4-(triphenylphosphoranylideneamino)quino-
lines (4) (Scheme 2). Aryliminophosphoranes
(RN=PPh3, R = aryl) are known to be generally stable
in air and often in water, but to hydrolyze readily in
dilute acid or base [16]. We observed no hydrolysis
products when we conducted Staudinger reaction in
aqueous THF and attempted hydrolysis of the
iminophosphorane using dilute sodium hydroxide in
THF-methanol mixture led to the recovery of starting
RESULTS AND DISCUSSION
In the first part of this investigation, we subjected the
previously described 2-aryl-3-halogenoquinolin-4(1H)-
ones 1 (X = Br, I) [10] to phosphoryl chloride under
reflux to afford series of the known 2-aryl-3-bromo-4-
chloroquinolines (2a-d) [10b] and the previously
undescribed 2-aryl-4-chloro-3-iodoquinoline deriv-
atives (2e-h) (Scheme 1). Attempted nucleophilic
displacement of 4-chloro substituent from the 2-aryl-3-
halogenoquinolines with benzylamine in phenol under
reflux in analogy with literature procedure for the
synthesis of 4-(benzylamino)-7-methoxy-2-phenyl-
quinoline from 4-chloro-7-methoxyquinoline [11] led in
all cases to complete decomposition of the substrate.
We then resorted to literature method that involves
displacement of chlorine at the ꢀ-position of the
quinoline nucleus by azide ion to form azidoquinoline
derivatives under very mild conditions [7,12]. The 2-
Scheme 1
O
Cl
N3
Br, I
Br, I
(i)
Br, I
(ii)
N
H
C6H4R
N
C6H4R
N
C6H4R
(1) (R = H, F, Cl, OCH3)
(2)
(3)
Reagents and conditions: (i) POCl3, heat, 3h; (ii) NaN3, DMF, r.t., 48h
1 - 3
a
b
c
d
e
f
g
h
X
R
Br
H
Br
Br
Br
I
I
I
I
4-F
4-Cl
4-OCH3
H
4-F
4-Cl
4-OCH3
aryl-4-chloro-3-halogenoquinolines
(2a-h)
were
material. We then resorted to the use of dilute acetic
acid under reflux and converted the iminophosphoranes
(4) to the corresponding previously undescribed
subjected to NaN3 in DMF at room temperature to
afford the corresponding hitherto unknown 2-aryl-4-
azido-3-halogenoquinoline derivatives (3a-h) in
primary
4-amino-2-aryl-3-halogenoquinolines
(5)

Sep-Oct 2008
2-Aryl-4-azido-3-(bromo/iodo)quinolines as Substrates
1345
1
(Scheme 2). The H nmr spectra of systems (5) are
characterized by a broad singlet in the region ꢀ 5.40 –
5.50 ppm corresponding to the amino group and a set of
signals in the aromatic region. The presence of the
amino group in these compounds is further confirmed
by the ir absorption bands in the region ꢁmax 3060 –
3430 cm-1.
4-amino-2,3-diarylquinolines (7) using 80% acetic acid
under reflux (Scheme 3).
In summary, the observed results of Staudinger
reaction of the 2-aryl-4-azido-3-halogenoquinolines and
subsequent hydrolysis of the resulting 2-aryl-3-halo-
geno-4-(triphenylphosphoranylideneamino)quinolines
represents convenient synthetic strategy for the
Scheme 2
N3
N=PPh3
Br, I
NH2
N
Br, I
(i)
Br, I
(ii)
N
C6H4R
N
C6H4R
C6H4R
(3)
(4)
(5)
Reagents and conditions: (i) PPh3, THF, heat, 12h; (ii) AcOH (aq), heat, 7h
4 - 5
a
b
c
d
e
f
g
h
X
R
Br
H
Br
Br
Br
I
I
I
I
4-F
4-Cl
4-OCH3
H
4-F
4-Cl
4-OCH3
construction of 3-halogenated 4-amino-2-arylquinolines
of potential biological interest that can be obtainable
only with difficulty otherwise. The 3-iodoquinoline
moiety also provides an important functional group that
could facilitate other transition metal-mediated carbon–
carbon bond formation. Further studies of chemical
transformation and biological activity of the products
prepared in this investigation are currently under way in
our laboratory.
Among all C-C bond forming cross-coupling
processes, Suzuki–Miyaura reaction which involves
palladium–catalyzed cross-coupling of aryl halides with
organoboronic acids in the presence of a base is one of
the versatile procedures for the synthesis of
unsymmetrical biaryl derivatives [17]. In our
continuing efforts to introduce exhaustive substitution
into 2-arylquinoline moiety, we subjected the 3-
iodoquinoline derivatives (4e–h) to cross-coupling
reaction with phenylboronic acid in the presence of
Pd(PPh3)4 and 2 M K2CO3 in refluxing DMF. The 2,3-
diaryl-4-(triphenylphosphoranylideneamino)quinolines
6 were isolated as sole products and in high yields with
or without any need for column chromatography.
Systems (6) were, in turn, hydrolyzed to the
EXPERIMENTAL
Melting points were recorded on a Thermocouple digital
melting point apparatus and are uncorrected. Nmr spectra were
obtained as CDCl3 or DMSO-d6 solutions using Varian Mercury
300 MHz NMR spectrometer and the chemical shifts are quoted
relative to the solvent peaks. The ir spectra were recorded as
corresponding
previously
undescribed
primary
Scheme 3
PPh3
N
PPh3
NH2
N
N
C6H5
C6H5
I
(i)
(ii)
N
C6H4R
C6H4R
N
C6H4R
(4)
6)
(7)
Reagents and conditions: (i) PhB(OH)2, Pd(PPh3)4, K2CO3(aq), DMF, heat, 48h; (ii) 80% AcOH, heat, 7h.
(6), (7)
a
b
c
d
R
H
4-F
4-Cl
4-OCH3

1346
M. J. Mphahlele and V. Mtshemla
Vol 45
powder using FTS 7000 Series Digilab Win-IR Pro
spectrometer. Low-resolution and high-resolution (EI) mass
J = 7.8 Hz), 8.24 (1H, d, J = 8.3 Hz); 13C nmr (75 MHz, DMSO-
d6): ꢀ 55.4, 98.2, 113.3, 125.1, 125.7, 128.2, 129.7, 130.6, 130.9,
136.0, 147.3, 147.7, 160.1, 162.2; ir (neat): ꢁmax/cm-1 760, 824,
1030, 1177, 1246, 1511, 1606; ms (EI) m/z 395 (M+, 6), 269
(100), 254 (69), 191 (24), 162 (27), 127 (32). Hrms (EI)
calculated for C16H11NO35ClI: 394.9568. Found: 394.9574. Anal.
calc. for C16H11NO35ClI: C, 48.66; H, 2.81; N, 3.55. Found: C,
48.41; H, 2.69; N, 3.40.
General procedure for the Reaction of (2a-h) with sodium
azide in DMF. A stirred mixture of (2) (1 equiv.) and sodium
azide (1.5 equiv.) in DMF (5mL per mmol of (2)) was stirred at
room temperature for 48 hours with the exclusion of moisture.
The mixture was poured into ice-cold water and the resulting
precipitate was collected by filtration and recrystallized to afford
2-aryl-4-azido-3-halogenoquinoline (3).
4-Azido-3-bromo-2-phenylquinoline (3a). This compound
was obtained as solid (65%) m.p. 124 – 126˚C (ethanol); 1H nmr
(300 MHz, CDCl3): ꢀ 7.46 – 7.53 (3H, m), 7.59 (1H, dt, J = 1.2
and 7.8 Hz), 7.63 – 7.68 (2H, m), 7.76 (1H, dt, J = 1.2 and 8.7
Hz), 8.09 (1H, d, J = 8.4 Hz), 8.21 (1H, d, J = 8.7 Hz); 13C nmr
(75 MHz, CDCl3): ꢀ 111.5, 122.5, 123.0, 127.4, 128.0, 128.9,
129.2, 129.5, 130.6, 140.1, 142.7, 146.9, 159.6; ir (neat):
ꢁmax/cm-1 765, 1380, 1481, 1566, 2114; ms (EI) m/z 324 (M+,
5%), 298 (40), 296 (28), 219 (46), 217 (100), 190 (32), 89 (36).
Hmrs (EI) calculated for C15H9N479Br: 324.0016. Found:
324.0005. Anal. calc. for C15H9N479Br: C, 55.61; H, 2.80; N,
17.29. Found: C, 55.33; H, 2.76; N, 17.07.
spectra were recorded on
a VG70-SEQ double-focusing
magnetic sector spectrometer (University of Northwest,
Potchefstroom campus). Elemental analysis was performed at
the Department of Chemistry of the University of Cape Town.
The synthesis and characterization of substrates (1a-d) [10a] and
(2a-d) [10b] have been described elsewhere. Substrates (2e-h)
which are new were prepared as follows:
General Procedure for the Reactions of 2-Aryl-3-
iodoquinolin-4(1H)-ones (1) with POCl3. A stirred mixture of
2-aryl-3-iodoquinolin-4-(1H)-one (1) (1 equiv.) and phosphoryl
chloride (5 mL per mmol of (1)) was heated under reflux for 3
hours. The cooled mixture was transferred to a volumetric flask
and then quenched slowly with ice-cold water. After 30 minutes,
the mixture was neutralized with ammonia solution and stirred
vigorously at room temperature. The resulting precipitate was
filtered and recrystallized to afford the corresponding 2-aryl-4-
chloro-3-iodoquinoline (2).
4-Chloro-3-iodo-2-phenylquinoline (2e). This compound
was obtained as white solid (55%) m.p. 150 – 153˚C (ethyl
1
acetate); H nmr (300 MHz, DMSO-d6): ꢀ 7.47 – 7.58 (5H, m),
7.77 (1H, dt, J = 1.5 and 7.8 Hz), 7.91 (1H, dt, J = 1.2 and 7.8
Hz), 8.07 (1H, d, J = 8.4 Hz), 8.26 (1H, dd, J = 0.9 and 8.4 Hz);
13C nmr (75 MHz, DMSO-d6): ꢀ 99.2, 124.7, 125.0, 127.8,
128.7, 129.0, 129.1, 129.4, 131.3, 143.2, 146.5, 146.6, 162.5; ir
(neat): ꢁmax/cm-1 762, 845, 1026, 1088, 1339, 1555; ms (EI) m/z
365 (M+, 83), 238 (100), 220 (69), 203 (58). Hrms (EI)
calculated for C15H9N35ClI: 364.9477. Found: 364.9468. Anal.
calc. for C15H9N35ClI: C, 49.37; H, 2.49; N, 3.84. Found: C,
49.08; H, 2.48; N, 3.47.
4-Azido-3-bromo-2-(4-fluorophenyl)quinoline (3b). This
compound was obtained as solid (70%) m.p. 177 – 179˚C
1
(ethanol); H nmr (300 MHz, CDCl3): ꢀ 7.18 (2H, t, J = 8.7
Hz), 7.60 (1H, dt, J = 1.2 and 7.8 Hz)), 7.66 (2H, t, J = 7.8
Hz), 7.76 (1H, dt, J = 1.5 and 7.8 Hz), 8.07 (1H, d, J = 8.4
Hz), 8.21 (1H, dd, J = 0.9 and 8.2 Hz); 13C nmr (75 MHz,
4-Chloro-2-(4-fluorophenyl)-3-iodoquinoline (2f). This
compound was obtained as white solid (62%) m.p. 176 – 178˚C
1
2
(ethyl acetate); H nmr (300 MHz, DMSO-d6): ꢀ 7.35 (2H, J =
CDCl3): ꢀ 111.4, 115.2 (d, JCF = 21.6 Hz), 122.6, 123.1,
3
4
9.0 Hz), 7.64 (2H, dd, J = 5.7 and 9.0 Hz), 7.78 (1H, dt, J = 1.2
and 7.8 Hz), 7.92 (1H, dt, J = 1.5 and 7.8 Hz), 8.08 (1H, d, J =
9.0 Hz), 8.27 (1H, dd, J = 0.6 and 8.7 Hz); 13C nmr (75 MHz,
127.7, 129.6, 130.8, 131.3 (d, JCF = 8.3 Hz), 136.1 (d, JCF
=
1
3.4 Hz), 143.0, 146.9, 158.6, 163.2 (d, JCF = 247.3 Hz); ir
(neat): ꢁmax/cm-1 752, 826, 1160, 1222, 1377, 1580, 1600,
2115; ms (EI) m/z 343 (M+, 10), 342 (45), 316 (65), 256 (30),
236 (48), 235 (100), 208 (52), 107 (71). Hmrs (EI) calculated
for C15H8N4F79Br: 343.9895. Found: 343.9859. Anal. calc. for
C15H8N4F79Br: C, 52.37; H, 2.34; N, 16.28. Found: C, 51.48;
H, 2.18; N, 16.35.
2
DMSO-d6): ꢀ 99.3, 114.7 (d, JCF = 21.6 Hz), 124.7, 125.0,
3
4
129.1, 131.3, 131.4 (d, JCF = 8.3 Hz), 139.6 (d, JCF = 3.6 Hz),
1
146.6, 146.7, 161.5, 162.2 (d, JCF = 244.8 Hz); ir (neat):
ꢁmax/cm-1 758, 828, 1219, 1343, 1508, 1597; ms (EI) m/z 383
(M+, 94), 256 (100), 221 (73). Hrms (EI) calculated for
C15H8NF35ClI: 382.9374. Found 382.9368. Anal. calc. for
C15H8NF35ClI: C, 47.05; H, 2.11; N, 3.67. Found: C, 47.15; H,
2.05; N, 3.65.
4-Azido-3-bromo-2-(4-chlorophenyl)quinoline (3c). This
compound was obtained as solid (73%) m.p. 170 – 172˚C
(ethanol); 1H nmr (30 MHz, CDCl3): ꢀ 7.47 (2H, d, J = 8.7 Hz),
7.58 – 7.64 (3H, m), 7.77 (1H, t, J = 7.8 Hz), 8.07 (1H, d, J =
8.4 Hz), 8.21 (1H, d, J = 8.3 Hz); 13C nmr (75 MHz, CDCl3):
111.2, 122.6, 123.1, 127.8, 128.4, 129.6, 130.8, 130.9, 135.1,
138.5, 143.0, 146.9, 158.5; ir (neat): ꢁmax/cm-1 757, 824, 1096,
1222, 1380, 1479, 1508, 2114; ms (EI) m/z 360 (M+, 4), 316
(42), 271 (37), 237 (41), 235 (100). Hmrs (EI) calculated for
C15H8N435Cl79Br: 359.9970. Found: 359.9978. Anal. calc. for
C15H8N435Cl79Br: C, 50.05; H, 2.24; N, 15.56. Found: C, 49.48;
H, 2.03; N, 15.74.
4-Chloro-2-(4-chlorophenyl)-3-iodoquinoline (2g). This
compound was obtained as white solid (65%) m.p. 218 – 220˚C
(ethyl acetate); 1H nmr (300 MHz, DMSO-d6): ꢀ 7.59 (2H, d, J =
8.4 Hz), 7.70 (2H, d, J = 8.4 Hz), 7.83 (1H, dt, J = 1.5 and 7.5
Hz), 7.94 (1H, dt, J = 1.2 and 7.5 Hz), 8.11 (1H, d, J = 8.4 Hz),
8.26 (1H, dd, J = 0.9 and 8.4 Hz); 13C nmr (75 MHz, DMSO-d6):
ꢀ 99.2, 124.7, 125.0, 127.9, 129.2, 129.4, 131.1, 131.4, 133.5,
142.0, 146.5, 146.8, 161.3; ir (neat): ꢁmax/cm-1 756, 822, 1092,
1247, 1342, 1473, 1605; ms (EI) m/z 399 (M+, 62), 273 (100),
238 (70), 220 (54). Hrms (EI) calculated for C15H8N35Cl2I:
398.9079. Found: 398.9078. Anal. calc. for C15H8N35Cl2I: C,
45.16; H, 2.02; N, 3.51. Found: C, 44.83; H, 2.02; N, 3.44.
4-Chloro-3-iodo-2-(4-methoxyphenyl)quinoline (2h). This
compound was obtained as white solid (56%) m.p. 185 – 187˚C
4-Azido-3-bromo-2-(4-methoxyphenyl)quinoline (3d). This
compound was obtained as solid (80%) m.p. 169 – 171˚C
1
(ethanol); H nmr (300 MHz, CDCl3): ꢀ 3.87 (3H, s), 7.02 (2H,
d, J = 8.2 Hz), 7.57 (1H, t, J = 7.7 Hz), 7.65 (2H, d, J = 8.4 Hz),
7.74 (1H, t, J = 7.2 Hz), 8.07 (1H, d, J = 8.1 Hz), 8.19 (1H, d, J
= 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 55.3, 111.8, 113.4,
122.5, 122.9, 127.3, 129.5, 130.6, 130.8, 132.5, 142.8, 146.9,
159.2, 160.1; ir (neat): ꢁmax/cm-1 745, 818, 1026, 1173, 1246,
1
(ethyl acetate); H nmr (300 MHz, DMSO-d6): ꢀ 3.84 (3H, s),
7.05 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 9.0 Hz), 7.75 (1H, tt, J
= 1.5 and 8.0 Hz), 7.89 (1H, tt, J = 1.5 and 7.5 Hz), 8.05 (1H, d,

Sep-Oct 2008
2-Aryl-4-azido-3-(bromo/iodo)quinolines as Substrates
1347
1373, 1512, 1558, 1610, 2111; ms (EI) m/z 354 (M+, 15), 328
(21), 249 (43), 247 (57), 86 (60), 84 (100). Hmrs (EI) calculated
for C16H11N4O79Br: 354.0120. Found: 354.0109. Anal. calc. for
C16H11N4O79Br: C, 54.28; H, 3.13; N, 15.83. Found: C, 53.97; H,
2.87; N, 15.67.
elution of the product with ethyl acetate. The following products
were prepared:
3-Bromo-2-phenyl-4-(triphenylphosphoranylideneamino)-
quinoline (4a). This compound was obtained as solid (75%)
1
m.p. 170 – 172˚C; H nmr (300 MHz, CDCl3): ꢀ 7.17 (1H, dt, J
= 1.2 and 8.1 Hz), 7.33 – 7.56 (15H, m), 7.70 – 7.78 (6H, m),
4-Azido-3-iodo-2-phenylquinoline (3e). This compound was
1
obtained as solid (60%) m.p. 137 – 140˚C (ethanol); H nmr
7.97 (1H, d, J = 8.1 Hz), 8.10 (1H, d, J = 7.8 Hz); 13C nmr (75
4
(300 MHz, CDCl3): ꢀ 7.46 – 7.51 (3H, m), 7.55 – 7.59 (2H, m),
7.62 (1H, dt, J = 1.2 and 7.7 Hz), 7.63 (1H, dt, J = 1.2 and 8.4
Hz), 7.78 (1H, dt, J = 1.5 and 7.7 Hz), 8.23 (1H, td, J = 0.6 and
8.5 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 88.4, 121.8, 122.9, 127.6,
128.0, 128.9, 129.1, 129.9, 130.9, 142.8, 146.8, 147.8, 162.8; ir
(neat): ꢁmax/cm-1 698, 764, 1258, 1374, 1479, 2111; ms (EI) m/z
372 (M+, 32), 344 (63), 317 (100), 190 (33), 89 (37). Hmrs (EI)
calculated for C15H9N4I: 371.9869. Found: 371.9872. Anal. calc.
for C15H9N4I: C, 48.43; H, 2.44; N, 15.06. Found: C, 48.22; H,
2.36; N, 14.59.
MHz, CDCl3): ꢀ 112.5 (d, JCP = 10.8 Hz), 124.6, 125.6, 125.9,
3
126.0, 127.6, 127.8, 128.5 (d, JCP = 12.5 Hz), 128.8, 129.0,
1
4
131.7 (d, JCP = 104.7 Hz), 131.4 (d, JCP = 2.9 Hz), 132.5 (d,
2JCP = 10.0 Hz), 142.6, 147.4, 154.3, 159.8; 31p nmr: ꢀ 2.78; ir
(neat): ꢁmax/cm-1 749, 990, 1113, 1217, 1359, 1419, 1479, 1526,
1557; ms (EI) m/z 559 (70), 558 (M+, 71), 557 (33), 480 (37),
479 (100), 262 (36), 183 (81). Hmrs (EI) calculated for
C33H24N279BrP: 558.0860. Found: 558.0860. Anal. calc. for
C33H24N279BrP: C, 71.02; H, 4.33; N, 5.02. Found: C, 70.78; H,
3.83; N, 4.67.
4-Azido-2-(4-fluorophenyl)-3-iodoquinoline (3f). This
compound was obtained as solid (75%) m.p. 169 – 170˚C
(ethanol); H nmr (300 MHz, CDCl3) ꢀ 7.14 (2H, m), 7.53 –
3-Bromo-2-(4-fluorophenyl)-4-(triphenylphosphoranyl-
ideneamino)quinoline (4b). This compound was obtained as
solid (80%) m.p. 184 – 186˚C. H nmr (300 MHz, CDCl3): ꢀ
1
1
7.63 (3H, m), 7.76 (1H, dt, J = 1.5 and 7.1 Hz), 8.08 (1H, d, J =
8.4 Hz), 8.19 (1H, dd, J 1.2 and 8.4 Hz); 13C nmr (75 MHz,
7.06 (2H, t, J = 8.4 Hz), 7.17 (1H, dt, J = 1.5 and 7.7 Hz), 7.41 –
7.58 (12H, m), 7.69 – 7.77 (6H, m), 7.96 (1H, d, J = 8.4 Hz),
8.09 (1H, dd, J = 1.2 and 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ
112.5 (d, 4JCP = 8.0 Hz), 114.5 (d, 2JCF = 21.4 Hz), 124.7, 125.7,
2
CDCl3): ꢀ 88.2, 115.5 (d, JCF 21.6 Hz), 121.8, 122.8, 127.7,
3
4
129.7, 131.0, 131.1 (d, JCF = 8.6 Hz), 138.6 (d, JCF = 3.4 Hz),
1
3
146.9, 147.7, 161.7, 163.0 (d, JCF = 247.1 Hz); ir (neat):
127.8, 127.9, 128.6 (d, JCP = 12.5 Hz), 128.9, 129.0, 131.0 (d,
ꢁmax/cm-1 761, 834, 1227, 1369, 1477, 1510, 1600, 2116; ms (EI)
m/z 390 (M+, 23), 362 (51), 235 (100), 208 (27), 107 (41). Hmrs
(EI) calculated for C15H8N4FI: 389.9783. Found: 389.9778.
Anal. calc. for C15H8N4FI: C, 46.20; H, 2.07; N, 14.27. Found:
C, 46.23; H, 2.08; N, 14.66.
1
4
3JCF = 8.3 Hz), 131.6 (d, JCP = 104.8 Hz), 131.8 (d, JCp = 2.9
2
4
Hz), 132.4 (d, JCP = 10.0 Hz), 138.7 (d, JCF = 3.1 Hz), 147.4,
158.7 (d, JCP = 1.7 Hz), 162.5 (d, JCF = 245.0 Hz); 31p nmr: ꢀ
3.01; ir (neat): ꢁmax/cm-1 750, 826, 990, 1108, 1202, 1360, 1395,
1431, 1474, 1506, 1555; ms (EI) m/z 578 (M+, 64), 498 (40),
497 (100), 262 (43), 183 (86). Hmrs (EI) calculated for
C33H23N2F79BrP: 576.0773. Found: 576.0770. Anal. calc. for
C33H23N2F79BrP: C, 68.80; H, 4.02; N, 4.86. Found: C, 68.43; H,
3.98; N, 4.67.
5
1
4-Azido-2-(4-chlorophenyl)-3-iodoquinoline (3g). This
compound was obtained as solid (78%) m.p. 173 – 175˚C
(ethanol); 1H nmr (300 MHz, CDCl3) ꢀ 7.46 (2H, d, J = 8.4 Hz),
7.55 (2H, d, J = 8.4 Hz), 7.63 (1H, dt, J = 1.2 and 8.4 Hz), 7.79
(1H, dt, J = 1.2 and 7.4 Hz), 8.10 (1H, td, J = 0.6 and 8.4 Hz),
8.30 (1H, td, J = 0.6 and 8.5 Hz); 13C nmr (75 MHz, CDCl3): ꢀ
87.8, 121.9, 122.9, 127.8, 128.3, 129.9, 130.7, 131.0, 135.0,
141.1, 147.0, 147.8, 161.6; ir (neat): ꢁmax/cm-1 761, 827, 1092,
1233, 1369, 1480, 2118; ms (EI) m/z 406 (M+, 24), 378 (49),
251 (100), 216 (29), 123 (35). Hmrs (EI) calculated for
C15H8N435ClI: 405.9482. Found: 405.9482. Anal. calc. for
C15H8N435ClI: C, 44.38; H, 1.98; N, 13.80. Found: C, 44.60; H,
1.81; N, 14.19.
3-Bromo-2-(4-chlorophenyl)-4-(triphenylphosphoranyl-
ideneamino)quinoline (4c). This compound was obtained as
1
solid (85%) m.p. 220 – 222˚C; H nmr (300 MHz, CDCl3): ꢀ
7.17 (1H, dt, J = 1.2 and 7.8 Hz), 7.34 (1H, J = 8.4 Hz), 7.42 –
7.59 (12H, m), 7.69 – 7.77 (7H, m), 7.95 (1H, d, J = 8.4Hz),
8.09 (1H, dd, J = 0.9 and 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ
4
112.2 (d, JCP = 8.0 Hz), 124.8, 125.7, 127.8, 128.0, 128.2,
1
3
128.6 (d, JCP = 12.5 Hz), 129.0, 130.6, 131.6 (d, JCP = 105.0
4
2
Hz), 131.8 (d, JCP = 2.9 Hz), 132.3, 132.5 (d, JCP = 10.2 Hz),
133.8, 141.0, 147.4, 154.5, 158.5; 31p nmr: ꢀ 3.09; IR (neat):
ꢁmax/cm-1 742, 990, 1109, 1200, 1395, 1431, 1477; ms (EI) m/z
594 (M+, 74), 592 (51), 515 (42), 514 (57), 513 (100), 277
(58), 262 (46), 183 (97). Hmrs (EI) calculated for
C33H23N235Cl79BrP: 592.0462. Found: 592.0455. Anal. calc. for
C33H23N235Cl79BrP: C, 66.95; H, 3.92; N, 4.73. Found: C,
66.38; H, 3.95; N, 4.34.
4-Azido-3-iodo-2-(4-methoxyphenyl)quinoline (3h). This
compound was obtained as solid (67%) m.p. 137 – 140˚C
1
(ethanol); H nmr (300 MHz, CDCl3): ꢀ 3.88 (3H, s), 7.01 (2H,
d, J = 9.0 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.60 – 7.80 (1H, m),
7.77 (1H, dt, J = 1.5 and 7.6 Hz), 8.11 (1H, d, J = 8.6 Hz), 8.16
(1H, dd, J = 0.9 and 8.6 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 55.4,
88.8, 113.4, 121.9, 122.8, 127.4, 129.8, 130.7, 130.8, 135.3,
146.8, 147.9, 160.1, 162.4; ir (neat): ꢁmax/cm-1 760, 826, 1034,
1176, 1247, 1369, 1513, 1605, 2115; ms (EI) m/z 402 (M+, 59),
374 (17), 247 (100), 204 (22), 119 (25). Hmrs (EI) calculated for
C16H11N4OI: 401.9835. Found: 401.9834. Anal. calc. for
C16H11N4OI: C, 47.80; H, 2.77; N, 13.94. Found: C, 47.40; H,
3.05; N, 13.46.
General Procedure for the Reactions of (3) with PPh3 in
THF. A stirred mixture of (3) (1 equiv.) and PPh3 (3 equiv.) in
THF (5mL per mmol of (3)) was refluxed for 5 hours. The
mixture was evaporated under reduced pressure and the residue
was purified by column chromatography, first with benzene or
toluene to remove excess triphenyl phosphine followed by
3-Bromo-2-(4-methoxyphenyl)-4-(triphenylphosphoranyl-
ideneamino)quinoline (4d). This compound was obtained as
1
solid (76%) m.p. 208 – 210˚C; H nmr (300 MHz, CDCl3): ꢀ
3.82 (3H, s), 6.91 (2H, d, J = 9.0 Hz), 7.15 (1H, dt, J = 1.2 and
7.8 Hz), 7.43 – 7.50 (6H, m), 7.51 – 7.58 (6H, m), 7.69 – 7.78
(6H, m), 7.98 (1H, d, J = 8.1Hz), 8.07 (1H, dd, J = 1.5 and 8.6
Hz); 13C nmr (75 MHz, CDCl3): ꢀ 55.3, 113.0 (2 x C), 127.7,
3
127.8, 128.5 (d, JCP = 12.5 Hz), 128.7, 128.9, 130.5, 131.0,
4
1
131.8 (d, JCP = 2.9 Hz), 131.7 (d, JCP = 104.4 Hz), 132.4,
132.5 (d, 2JCP = 10.0 Hz), 135.3, 147.4, 159.3; 31P nmr: ꢀ 2.70; ir
(neat): ꢁmax/cm-1 747, 827, 991, 1107, 1248, 1356, 1433, 1479,
1510, 1557, 1606; ms (EI) m/z 588 (M+, 83), 587 (40), 510 (43),

1348
M. J. Mphahlele and V. Mtshemla
Vol 45
277 (58), 262 (66), 249 (45), 183 (100). Hmrs (EI) calculated for
C34H26N2O79BrP: 588.1066. Found: 588.1066. Anal. calc. for
C34H26N2O79BrP: C, 69.44; H, 4.45; N, 4.76. Found: C, 69.49; H,
4.42; N, 4.46.
C34H26N2OIP: C, 64.20; H, 4.12; N, 4.40. Found: C, 64.28; H,
4.18; N, 4.00.
General procedure for the Hydrolysis of (4) with aqueous
acetic acid. A stirred solution of (4) (1 equiv.) in 80% acetic
acid (5 mL per mmol of (4)) was boiled under reflux for 7 hours.
The mixture was evaporated under reduced pressure and the
residue was purified by column chromatography (3:2 hexane-
ethyl acetate, v/v) to afford 4-amino-2-aryl-3-halogenoquinoline
5. Whenever necessary, traces of triphenyl phosphonium oxide
were removed by washing the solid product with ice-cold
methanol. The following products were prepared:
3-Iodo-2-phenyl-4-(triphenylphosphoranylideneamino)-
quinoline (4e). This compound was obtained as solid (84%)
m.p. 215 – 217˚C; 1H nmr (300 MHz, CDCl3): ꢀ 6.96 (1H, t, J =
7.8 Hz), 7.34 – 7.58 (15H, m), 7.70 – 7.78 (7H, m), 7.96 (1H, d,
4
J = 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 95.1 (d, JCP = 10.8
3
Hz), 124.3, 125.8, 125.9, 126.0, 127.6, 127.7, 128.5 (d, JCP
=
12.5 Hz), 128.8, 128.9, 130.9 (d, 1JCP = 104.2 Hz), 131.4 (d, 4JCP
= 2.9 Hz), 132.7 (d, 2JCP = 10.0 Hz), 145.4, 148.2, 158.1 (d, 4JCP
= 2.6 Hz), 163.1; 31P nmr: ꢀ 1.60; ir (neat): ꢁmax/cm-1 748, 984,
1112, 1213, 1348, 1406, 1476, 1516, 1555; ms (EI) m/z 606
(M+, 47), 479 (100), 262 (28), 183 (49). Hmrs (EI) calculated for
C33H24N2IP: 606.1013. Found: 606.0710. Anal. calc. for
C33H24N2IP: C, 65.40; H, 3.99; N, 4.62. Found: C, 65.39; H,
4.33; N, 4.37.
4-Amino-3-bromo-2-phenylquinoline (5a). This compound
1
was obtained as solid (65%) m.p. 160 – 162˚C; H nmr (300
MHz, CDCl3): ꢀ 5.45 (2H, br s), 7.42 – 7.52 (4H, m), 7.62 –
7.73 (3H, m), 7.79 (1H, d, J = 8.1 Hz), 8.06 (1H, dd, J = 0.2 and
8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 100.4, 117.6, 120.2,
125.7, 127.9, 128.5, 129.1, 129.8, 130.0, 141.0, 146.4, 147.3,
158.6; ir (neat): ꢁmax/cm-1 752, 924, 1070, 1383, 1430, 1495,
1573, 1620, 3190, 3319, 3412; ms (EI) m/z 298 (M+, 25), 219
(100). Hmrs (EI) calculated for C15H11N279Br: 299.1698. Found:
299.1750. Anal. calc. for C15H11N279Br: C, 60.22; H, 3.71; N,
9.36. Found: C, 59.87; H, 3.77; N, 9.36.
2-(4-Fluorophenyl)-3-iodo-4-(triphenylphosphoranylidene-
amino)quinoline (4f). This compound was obtained as solid
1
(79%) m.p. 215 – 217˚C; H nmr (300 MHz, CDCl3): ꢀ 6.97
(1H, dt, 1.5 and, J = 8.1 Hz), 7.07 (2H, t, 8.7 Hz), 7.41 – 7.50
(9H, m), 7.52 – 7.59 (3H, m), 7.69 – 7.79 (7H, m), 7.92 (1H, d, J
= 8.1 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 94.9 (d, 4JCP = 10.8 Hz),
4-Amino-3-bromo-2-(4-fluorophenyl)quinoline (5b). This
1
compound was obtained as solid (73%) m.p. 196 – 198˚C; H
2
114.5 (d, JCF = 21.3 Hz), 124.4, 125.8, 125.9. 126.0, 128.6 (d,
nmr (300 MHz, CDCl3): ꢀ 5.43 (2H, br s), 7.14 (2H, t, J = 8.7
Hz), 7.48 (1H, dt, J = 0.9 and 7.7 Hz), 7.61 – 7.65 (2H, m), 7.68
(1H, dt, J = 1.2 and 7.8 Hz), 7.75 (1H, d, J = 8.4 Hz), 8,02 (1H,
3JCp = 12.5), 128.9, 129.0, 130.8 (d, 3JCF = 8.3 Hz), 130.9 (d, 1JCP
2
= 104.4 Hz), 131.9 (d, 4JCP = 2.8 Hz), 132.8 (d, JCP = 10.2 Hz),
4
4
d, J = 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 100.3, 114.9 (d, 2JCF
141.4 (d, JCF = 3.2 Hz), 158.3 (d, JCP = 2.8 Hz), 162.0, 162.4
(d, JCF = 244.7 Hz); 31P nmr: ꢀ 1.63; ir (neat): ꢁmax/cm-1 744,
1
3
= 21.3 Hz), 117.6, 120.2, 125.8, 129.9, 130.0, 131.1 (d, JCF
=
4
834, 987, 1111, 1217, 1352, 1410, 1475, 1504, 1555; ms (EI)
m/z 624 (M+, 48), 498 (38), 497 (100), 183 (46) . Hmrs (EI)
calculated for C33H23N2FIP: 624.0624. Found: 624.0625. Anal.
calc. for C33H23N2FIP: C, 63.51; H, 3.72; N, 4.49. Found: C,
63.20; H, 3.76; N, 4.07.
8.3 Hz), 137.1 (d, JCF = 3.4 Hz), 146.4, 147.4, 157.6, 162.9 (d,
1JCF = 246.2 Hz); ir (neat): ꢁmax/cm-1 756, 830, 926, 1155, 1227,
1494, 1573, 1643, 3018, 3280, 3412; ms (EI) m/z 316 (M+, 17),
237 (50), 219 (72), 149 (86), 57 (100). Hmrs (EI) calculated for
C15H10N2F79Br: 317.1603. Found: 317.1570. Anal. calc. for
C15H10N2F79Br: C, 56.81; H, 3.18; N, 8.83. Found: C, 56.31; H,
3.17; N, 8.72.
2-(4-Chlorophenyl)-3-iodo-4-(triphenylphosphoranyl-
ideneamino)quinoline (4g). This compound was obtained as
1
solid (95%) m.p. 212 – 213˚C; H nmr (300 MHz, CDCl3): ꢀ
6.97 (1H, t, J = 7.8 Hz), 7.08 (2H, t, J = 8.1 Hz), 7.41 – 7.50
4-Amino-3-bromo-2-(4-chlorophenyl)quinoline (5c). This
1
compound was obtained as solid (75%) m.p. 166 – 169˚C; H
(9H, m), 7.55 – 7.59 (3H, m), 7.69 – 7.782 (7H, m), 7.94 (1H, d,
4
nmr (300 MHz, CDCl3): ꢀ 5.41 (2H, br s), 7.44 (2H, d, J = 8.4
Hz), 7.50 (1H, t, J = 7.8 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.68 (1H,
t, J = 7.8 Hz), 7.75 (1H, d, J = 8.1 Hz), 8.01 (1H, d, J = 8.4 Hz);
13C nmr (75 MHz, CDCl3): ꢀ 100.1, 117.6, 120.2, 125.9, 128.2,
129.9, 130.1, 130.6, 134.6, 139.5, 146.5, 147.4, 157.4; ir (neat):
ꢁmax/cm-1 750, 828, 1090, 1398, 1489, 1596, 3372, 3460; ms (EI)
m/z 334 (27), 278 (31), 277 (100), 253 (62). Hmrs (EI)
calculated for C15H10N235Cl79Br: 333.6146. Found: 333.6081.
Anal. calc. for C15H10N235Cl79Br: C, 54.00; H, 3.02; N, 8.40.
Found: C, 54.29; H, 3.01; N, 8.64.
4-Amino-3-bromo-2-(4-methoxyphenyl)quinoline (5d).
This compound was obtained as solid (80%) m.p. 192 – 194˚C;
1H nmr (300 MHz, CDCl3): ꢀ 3.85 (3H, s), 5.37 (2H, br s), 6.99
(2H, d, J = 8.7 Hz), 7.47 (1H, dt, J = 1.2 and 7.8 Hz), 7.63 (2H,
d, J = 7.8 Hz), 7.66 (1H, dt, J = 1.5 and 7.8 Hz), 7.73 (1H, dd, J
= 0.3 and 8.7 Hz), 8.02 (1H, dd, J = 0.5 and 8.7 Hz); 13C nmr (75
MHz, CDCl3): ꢀ 55.3, 100.7, 113.3, 117.5, 120.1, 125.5, 129.7,
130.0, 130.6, 133.7, 146.5, 147.2, 158.2, 159.8; ir (neat):
ꢁmax/cm-1 829, 922, 1026, 1171, 1246, 1429, 1497, 1508, 1574,
1608, 3314, 3422; ms (EI) m/z 330 (M+, 35), 328 (33), 249
(100), 149 (32), 111 (44), 97 (62), 83 (64), 69 (75). Hmrs (EI)
calculated for C16H13N2O79Br: 329.1961. Found: 329.1954.
Anal. calc. for C16H13N2O79Br: C, 58.37; H, 3.98; N, 8.51.
Found: C, 58.35; H, 4.07; N, 8.30.
J = 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 94.5 (d, JCP = 10.8
Hz), 124.5, 125.8, 125.9, 126.0, 127.8, 128.6 (d, 3JCP = 12.5 Hz),
128.9, 129.0, 130.5, 130.9 (d, 1JCP = 104.4 Hz), 132.0 (d, 4JCP
=
2
2.6 Hz), 132.8 (d, JCP = 10.2 Hz), 133.7, 143.7, 148.2, 158.4,
161.8; 31P nmr: ꢀ 1.82; ir (neat): ꢁmax/cm-1 751, 822, 986, 1106,
1194, 1385, 1431, 1476, 1553; ms (EI) m/z 642 (46), 640 (M+,
91), 513 (100), 262 (48), 183 (85. Hmrs (EI) calculated for
C33H23N235ClIP: 640.0325. Found: 640.0330. Anal. calc. for
C33H23N235ClIP: C, 61.93; H, 3.62; N, 4.38. Found: C, 62.09; H,
3.88; N, 4.17.
3-Iodo-2-(4-methoxyphenyl)-4-(triphenylphosphoranyl-
ideneamino)quinoline (4h). This compound was obtained as
1
solid (90%) m.p. 204 – 206 ˚C; H nmr (300 MHz, CDCl3): ꢀ
3.83 (3H, s), 6.89 – 6.98 (3H, m), 7.41 – 7.48 (9H, m), 7.52 –
7.58 (3H, m), 7.69 – 7.78 (7H, m), 7.93 (1H, d, J = 8.1 Hz); 13
C
nmr (75 MHz, CDCl3): ꢀ 55.3, 95.5 (d, 4JCP = 10.8 Hz), 113.0 (2
3
x C), 124.2, 125.9, 128.6 (d, JCP = 12.2 Hz), 128.7, 128.9,
1
4
130.5, 131.0 (d, JCP = 104.4 Hz), 131.9 (d, JCP = 2.6 Hz),
132.8 (d, JCP = 10.2 Hz), 137.9, 148.1, 158.3, 159.3, 162.6 ;31P
2
nmr: ꢀ 1.47; ir (neat): ꢁmax/cm-1 757, 826, 989, 1026, 1176, 1244,
1354, 1430, 1477, 1510, 1558, 1609; ms (EI) m/z 636 (M+, 100),
509 (87), 262 (42), 183 (64). Hmrs (EI) calculated for
C34H26N2OIP: 636.0828. Found: 636.0829. Anal. calc. for

Sep-Oct 2008
2-Aryl-4-azido-3-(bromo/iodo)quinolines as Substrates
1349
4-Amino-3-iodo-2-phenylquinoline (5e). This compound
was obtained as solid (68%) m.p. 183 – 185˚C; H nmr (300
and a balloon filled with argon gas was connected to the top of
the condenser. The stirred mixture was heated with stirring at 90
– 100˚C under argon atmosphere for 48 hours and then allowed
to cool to room temperature. The cooled mixture was poured
into ice-cold water and the precipitate was collected by filtration
and then recrystallized from ethanol to afford 2,3-diaryl-4-
(triphenylphosphoranylideneamino)quinoline (6).
1
MHz, CDCl3): ꢀ 5.50 (2H, br s), 7.41 – 7.56 (6H, m), 7.69 (1H,
dt, J = 1.5 and 7.8 Hz), 7.78 (1H, dd, J = 0.9 and 8.5 Hz), 8.03
(1H, dd, J = 0.9 and 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 78.2,
116.7, 120.3, 125.8, 127.9, 128.4, 128.9, 129.9, 130.1, 143.9,
147.1, 150.3, 162.0; ir (neat): ꢁmax/cm-1 755, 913, 1119, 1279,
1368, 1423, 1492, 1570, 1632, 3061, 3393; ms (EI) m/z 347
(M+, 14), 346 (75), 219 (100), 57 (56). Hmrs (EI) calculated for
C15H11N2I: 346.1703. Found: 346.1706. Anal. calc. for
C15H11N2I: C, 52.04; H, 3.20; N, 8.09. Found: C, 52.48; H, 3.27;
N, 8.24.
2,3-Diphenyl-4-(triphenylphosphoranylideneamino)quino-
line (6a). The compound was isolated as solid (75%) mp. 239 –
1
240˚C (ethanol); H nmr (300 MHz, CDCl3): ꢀ 6.75 (2H, d, J =
1.5 and 7.8 Hz), 6.95 – 7.12 (7H, m,), 7.18 – 7.34 (14H, m), 7.43
– 7.51 (4H, m), 7.81 (1H, d, J = 8.1 Hz), 8.03 (1H, d, J = 8.2
Hz); 13C nmr (75 MHz, CDCl3) ꢀ: 123.8, 125.7, 125.8, 126.7,
4-Amino-2-(4-fluorophenyl)-3-iodoquinoline (5f). This
1
compound was obtained as solid (70%) m.p. 190 – 192˚C; H
3
126.8, 126.9, 127.2, 127.5, 128.3, 128.4 (d, JCP = 12.2 Hz),
nmr (300 MHz, CDCl3): ꢀ 5.50 (2H, br s), 7.13 (2H, t, J = 8.7
Hz), 7.45 – 7.56 (3H, m), 7.69 (1H, dt, J = 1.5 and 7.5 Hz), 7.77
(1H, dd, J = 0.6 and 8.4 Hz), 8.01 (1H, dd, J = 0.6 and 8.4 Hz);
129.3, 129.5, 131.5 (d, 4JCP = 2.9 Hz), 131.6 (d, 1JCP = 108.3 Hz),
2
132.0, 132.4 (d, JCP = 10.0 Hz), 140.5, 142.3, 148.5, 154.2,
159.8; 31P nmr: ꢀ 0,39; ir (neat): ꢁmax/cm-1 748, 996, 1105, 1225,
1356, 1431, 1479, 1540, 3058; ms (EI) m/z 556 (M+, 100), 295
(38), 262 (42), 183 (44); Hmrs (EI) calculated for C39H29N2P:
556.2068. Found: 556.2051. Anal. calc. for C39H29N2P: C, 84.22;
H, 5.25; N, 5.04. Found: C, 83.97; H, 5.79; N, 5.44.
2
13C nmr (75 MHz, CDCl3): ꢀ 80.0, 114.9 (d, JCF = 21.7 Hz),
116.6, 120.2, 125.9, 129.9, 130.2, 130.9 (d, 3JCF = 8.3 Hz), 140.0
4
1
(d, JCF = 3.4 Hz), 147.1, 150.3, 161.1, 162.7 (d, JCF = 258.1
Hz); ir (neat): ꢁmax/cm-1 754, 827, 923, 1117, 1185, 1225, 1364,
1489, 1510, 1568, 1634, 3056, 3280, 3391; ms (EI) m/z 365
(M+, 5), 364 (36), 278 (64), 277 (100), 237 (40) 199 (32). Hmrs
(EI) calculated for C15H10N2FI: 364.1608. Found: 364.1611.
Anal. calc. for C15H10N2FI: C, 49.47; H, 2.77; N, 7.69. Found: C,
49.32; H, 2.37; N, 7.49.
2-(4-Fluorophenyl)-3-phenyl-4-(triphenylphosphoranyl-
ideneamino)quinoline (6b). This compound was isolated as
solid (85%) mp. 204 – 206˚C (ethanol); 1H nmr (300 MHz,
CDCl3): ꢀ 6.72 – 6.81 (4H, m), 6.95 – 7.12 (5H, m), 7.17 – 7.34
(13H, m), 7.43 – 7.51 (4H, m), 7.79 (1H, d, J = 7.8 Hz), 8.01
4-Amino-2-(4-chlorophenyl)-3-iodoquinoline (5g). This
1
compound was obtained as solid (65%) m.p. 175 – 177˚C; H
(1H, d, J = 7.8 Hz); 13C nmr (75 MHz, CDCl3) ꢀ: 114.1 (d, 2JCF
=
4
21.1 Hz), 123.9, 125.7, 125.8, 126.7 (d, JCP = 2.9 Hz), 127.7,
128.4 (d, 3JCP = 12.5 Hz), 128.5, 129.1, 131.3 (d, 2JCF = 8.3 Hz),
NMR (300 MHz, CDCl3): ꢀ 5.52 (2H, br s), 7.42 – 7.53 (5H, m),
7.70 (1H, dt, J = 1.2 and 7.8 Hz), 7.77 (1H, dd, J = 1.2 and 8.7
Hz), 8.02 (1H, d, J = 8.7 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 77.6,
116.7, 120.3, 125.9, 128.2, 129.8, 130.2, 130.5, 134.4, 142.3,
147.1, 150.4, 160.8; ir (neat): ꢁmax/cm-1 757, 826, 921, 1015,
1088, 1162, 1364, 1431, 1489, 1568, 1610, 3061, 3181, 3305,
3416; ms (EI) m/z 382 (M+, 30), 380 (86), 278 (33), 277 (82),
252 (100), 218 (55), 97 (51), 71 (59), 57 (81). Hmrs (EI)
calculated for C15H10N235ClI: 380.6151. Found: 380.6163. Anal.
calc. for C15H10N235ClI: C, 47.33; H, 2.65; N, 7.36. Found: C,
47.78; H, 2.85; N, 7.85.
1
4
131.4 (d, JCP = 103.9 Hz), 131.5 (d, JCP = 2.9 Hz), 131.9 (d,
2JCP = 10.2 Hz), 132.1, 132.4 (d, JCP = 9.9 Hz), 138.3 (d, JCF
=
2
1
1
3.4 Hz), 140.3, 148.3, 154.5, 158.6, 161.8 (d, JCF = 244.1 Hz);
31P nmr: ꢀ 0.49; ir (neat): ꢁmax/cm-1 714, 753, 994, 1108, 1223,
1434, 1481, 3056; ms (EI) m/z 574 (M+, 100), 313 (72), 277
(40), 262 (51), 183 (57); Hmrs (EI) calculated for C39H28N2FP:
574.1974. Found: 574.1986. Anal. calc. for C39H28N2FP: C,
81.58; H, 4.91; N, 4.88. Found: C, 80.86; H, 4.98; N, 4.65.
2-(4-Chlorophenyl)-3-phenyl-4-(triphenylphosphoranyl-
ideneamino)quinoline (6c). This compound was isolated as
solid (90%) mp. 235 – 236˚C (ethanol); 1H nmr (300 MHz,
CDCl3): ꢀ 6.73 – 6.77 8 (2H, m), 6.96 – 7.13 (8H, m), 7.16 –
7.23 (6H, m), 7.27 – 7.34 (6H, m), 7.44 – 7.51 (4H, m), 7.79
(1H, dd, J = 0.6 and 8.1 Hz), 8.00 (1H, d, J = 7.8 Hz); 13C nmr
4-Amino-3-iodo-2-(4-methoxyphenyl)quinoline (5h). This
1
compound was obtained as solid (60%) m.p. 184 – 186˚C; H
nmr (300 MHz, CDCl3): ꢀ 3.86 (3H, s), 5.50 (2H, br s), 6.98
(2H, J = 8.7 Hz), 7.46 (1H, dt, J = 1.2 and 7.8 Hz), 7.52 (2H, d,
J = 8.7 Hz), 7.67 (1H, dt, J = 1.2 and 7.8 Hz), 7.76 (1H, d, J =
7.8 Hz), 8.02 (1H, d, J = 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ
55.3, 78.6, 113.3, 116.7, 120.2, 125.6, 129.8, 130.0, 130.4,
136.5, 147.1, 150.3, 159.7, 161.6; ir (neat): ꢁmax/cm-1 721, 764,
1117, 1175, 1240, 1433, 1636, 3186, 3301, 3429; ms (EI) m/z
377 (M+, 17), 376 (100), 250 (27), 249 (92), 234 (36), 206 (38),
97 (47), 83 (42), 71 (51), 57 (71). Hmrs (EI) calculated for
C16H13N2OI: 376.1966. Found: 376.1958. Anal. calc. for
C16H13N2OI: C, 51.08; H, 3.48; N, 7.45. Found: C, 51.31; H,
3.62; N, 7.00.
2
(75 MHz, CDCl3) ꢀ: 124.0, 125.8, 125.9, 126.8 (d, JCP = 2.9
Hz), 126.9, 127.4, 127.7, 128.4 (d, 3JCP = 12.5 Hz), 129.1, 129.2,
131.0, 131.4 (d, 1JCP = 103.8 Hz), 131.5 (d, 4JCP = 2.9 Hz), 131.9,
2
132.4 (d, JCP = 12.5 Hz), 132.7, 140.2, 140.7, 148.4, 154.5,
158.4, 162.5; 31P nmr ꢀ 0.50; ir (neat): ꢁmax/cm-1 713, 756, 996,
1107, 1217, 1357, 1416, 1477, 1537, 3059; ms (EI) m/z 592
(58), 590 (M+, 100), 262 (59), 183 (56); Hmrs (EI) calculated for
C39H28N235ClP: 590.1679. Found: 590.1694. Anal. calc. for
C39H28N235ClP: C, 79.37; H, 4.78; N, 4.75. Found: C, 78.98; H,
4.83; N, 4.59.
General procedure for Pd(PPh3)4 catalyzed cross-coupling
reactions of (4) in DMF. 2-Aryl-3-iodo-4-(triphenylphos-
phoranylideneamino)quinolines (4) (1 equiv.), phenylboronic
acid (1.2 equiv.), Pd(PPh3)4 (5% of (4)) and DMF (5 mL per
mmol of 4) were added to a two-necked flask equipped with a
stirrer bar, rubber septum and a condenser. The mixture was
flushed for 10 minutes with argon gas and then aqueous 2 M
K2CO3 (2 mL per mmol of (4)) was added through a syringe.
The mixture was degassed with argon for additional 10 minutes
2-(4-Methoxyphenyl)-3-phenyl-4-(triphenylphosphoranyl-
ideneamino)quinoline (6d). This compound was isolated as
solid (89%) mp. 242 – 244˚C (ethanol); 1H nmr (300 MHz,
CDCl3): ꢀ 3.70 (3H, s), 6.34 (2H, d, J = 8.4 Hz), 6.77 (2H, d, J =
6.6 Hz), 6.96 (1H, t, J = 7.8 Hz), 7.01 – 7.09 (3H, m), 7.17 – 7.33
(14H, m), 7.43 – 7.49 (4H, m), 7.89 (1H, d, J = 8.4 Hz), 8.01 (1H,
d, J 8.4 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 55.1, 112.7, 123.6,
125.6, 125.7, 126.7, 126.8, 127.6, 128.3, 128.4 (d, 3JCP = 12.5 Hz),
129.3, 130.9, 131.5 (d, 4JCP = 2.9 Hz), 131.6 (d, 1JCP = 102.2 Hz),

1350
M. J. Mphahlele and V. Mtshemla
Vol 45
132.4 (d, 2JCP = 9.9 Hz), 135.0, 140.8, 148.5, 154.1, 158.9 (2 x C),
159.3; 31P nmr: ꢀ 0.15; ir (neat): ꢁmax/cm-1 718, 1107, 1248, 1429,
1479, 3059; ms (EI) m/z 586 (M+, 100), 368 (57), 325 (84), 236
(47), 97 (54), 69 (85); Hmrs (EI) calculated for C40H31N2OP:
586.2174. Found: 586.2132. Anal. calc. for C40H31N2OP: C, 81.95;
H, 5.33; N, 4.78. Found: C, 81.85; H, 5.38; N, 4.26.
General Procedure for the Hydrolysis of (3) with Aqueous
Acetic acid. A stirred solution of (6) (1 equiv.) in 80% acetic
acid (5 mL per mmol of (6)) was boiled under reflux for 7 hours.
Acetic acid was evaporated under reduced pressure and the
residue was purified by column chromatography using ethyl
acetate as eluent. The solvent was evaporated under reduced
pressure and the solid residue washed with ice-cold methanol to
remove excess triphenyl phosphine oxide to afford pure 4-
amino-2,3-diarylquinoline (7).
nmr (300 MHz, CDCl3): ꢀ 3.73 (3H, s), 4.71 (2H, br s), 6.69
(2H, d, J = 8.7 Hz), 7.19 – 7.38 (7H, m), 7.44 (1H, dt, J = 0.6
and 7.5 Hz), 7.66 (1H, dt, J = 0.9 and 7.6 Hz), 7.75 (1H, d, J =
8.4 Hz), 8.08 (1H, d, J = 8.7 Hz); 13C nmr (75 MHz, CDCl3): ꢀ
55.1, 113.0, 115.9, 117.4, 120.4, 124.8, 127.4, 129.0, 129.3,
130.0, 131.1, 133.8, 136.8, 147.1, 147.6, 158.2, 158.9; ir (neat):
ꢁmax/cm-1 759, 829, 934, 1016, 1091, 1365, 1420, 1491, 1567,
1624, 3125, 3307, 3429; ms (EI) m/z 326 (M+, 62), 325 (100),
282 (20); Hmrs (EI) calculated for C22H18N2O: 326.1381. Found:
326.1381. Anal. calc. for C22H18N2O: C, 81.02; H, 5.56; N, 8.59.
Found: C, 80.91; H, 5.85; N, 8.57.
Acknowledgement. We are grateful to the University of
South Africa (UNISA) and the National Research Foundation
(NRF) for financial assistance.
4-Amino-2,3-diphenylquinoline (7a). This compound was
isolated as solid (80%) mp. 239 – 241˚C; H NMR (300 MHz,
1
REFERENCES
CDCl3): ꢀ 4.75 (2H, br s), 7.14 – 7.22 (5H, m), 7.26 – 7.37 (5H,
m), 7.48 (1H, dt, J 0.9 and 7.6 Hz), 7.68 (1H, dt, J = 1.2 and 7.8
Hz), 7.79 (1H, dd, J = 0.6 and 8.4 Hz), 8.08 (1H, dd, J = 0.6 and
8.4 Hz); 13C NMR (75 MHz, CDCl3): ꢀ 116.0, 117.4, 120.4,
125.0, 127.3, 127.4, 127.5, 129.0, 129.4, 129.7, 130.1, 131.1,
136.5, 141.2, 147.2, 147.5, 158.8; ir (neat): ꢁmax/cm-1 760, 919,
940, 1305, 1362, 1423, 1493, 1562, 1635, 3087, 3298, 3437; ms
(EI) m/z 296 (M+, 81), 295 (100); Hmrs (EI) calculated for
C22H16N2: 296.1313. Found: 296.1313. Anal. calc. for C22H16N2:
C, 85.17; H, 5.33; N, 9.46. Found: C, 84.67; H, 5.33; N, 9.08.
4-Amino-2-(4-fluorophenyl)-3-phenylquinoline (7b). This
*
Author for correspondence
[1a] Wang, M.; Liu, Y.; Huang, Z. Tetrahedron Lett., 2001, 42,
2553; [b] Hadjeri, M.; Mariotte, A.; Boumendjel, A. Chem. Pharm. Bull.
2001, 49, 1352; [c] Xia, Y.; Yang, Z.; Xia, P.; Hackl, T.; Hamel, E.;
Mauger, A.; Wu, J.; Lee, K. J. J. Med. Chem., 2001, 44, 3932; [d] De, S.
K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 1647.
[2a] Moyer, M. P.; Weber, F. H.; Gross, J. L. J. Med. Chem. 1992,
35, 4595; [b] Kireev, D. B.; Hhretien, J. R.; Raevsky, D. A. Eur. J. Med.
Chem. 1995, 30, 395.
[3a] Rowley, M.; Leeson, P.; Grimwood, S.; Marshall, G.;
Saywell, K. Biorg. Med. Chem. Lett. 1995, 5, 2089 and references cited
therein; [b] Pinard, E.; Alanine, A.; Bourson, A.; Büttelmann, B.; Heitz,
M-P.; Mutel, V.; Gill, R.; Trube, G.; Wyler, R. Bioorg. Med. Chem. Lett.
2002, 12, 2615.
[4] Palacios, F.; de Retana, A.M.O.; Oyarzabal, J. Tetrahedron
1999, 55, 5947.
[5] Paliakov, E.; Strekowski, L. Tetrahedron Lett. 2004, 45,
4093.
[6] Strekowski, L.; Janda, L.; Lee, H. J. Org. Chem. 1997, 62,
4193.
[7] Mekheimer, R. A.; Elgemeie, G. H.; Kappe, T. J. Chem. Res.
2005, 82 and references cited therein.
[8] Aizikovich, A.; Kuznetsov, V.; Gorohovsky, S.; Levy, A.;
Meir, S.; Byk, G.; G. Gellerman, Tetrahedron Lett. 2004, 45, 4241.
[9] Mphahlele, M. J.; Gheevargheese, O; Makhubela, N. F. H.
Phosphorus, Sulfur and Silicon 2000, 166, 303.
[10a] Mphahlele, M.J. J. Chem. Res. (S) 2002, 196; [b] Mphahlele,
M. J.; Nwamadi, M. S.; Mabeta, P. J. Heterocyclic Chem. 2006, 43, 255.
[11] Giardina, G. A. M.; Sarau, H. M.; Farina, C.; Medhurst, A.
D.; Grugni, M.; Raveglia, L. F.; Schmidt, D. B.; Rigolio, R.; Luttmann,
M.; Vechhietti, V.; Hay, D. W. P. J. Med. Chem. 1997, 40, 1794.
[12a] Stadlbauer, W. Monatsh. Chem. 1996, 117, 1305; [b]
Stadlbauer, W.; Hojas, G. J. Chem. Soc. Perkin Trans. 1 2000, 3085.
[13] Lieber, E. Anal. Chem. 1957, 29, 916.
[14] Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 298.
[15] Shinkai, H.; Ito, T.; Iida, T.; Kitao, Y.; Yamada, H.; Uchida,
I. J. Med. Chem. 2000, 43, 4667.
[16] Johnson, A. W. in Ylides and Imines of Phosphorus, John
Wiley and Sons, Inc., New York (USA) 1993, 435.
1
compound was isolated as solid (75%), mp. 215 - 217˚C; H
NMR (300 MHz, CDCl3): ꢀ 4.74 (2H, br s), 6.85 (2H, t, J = 8.7
Hz), 7.17 – 7.20 (2H, m), 7.26 – 7.38 (5H, m), 7.48 (1H, dt, J =
0.9 and 7.6 Hz), 7.68 (1H, dt, J = 1.2 and 7.8 Hz), 7.78 (1H, td, J
= 0.6 and 8.1 Hz), 8.08 (1H, td, J = 1.2 and 7.8 Hz); 13C NMR
2
(75 MHz, CDCl3): ꢀ 114.5 (d, JCF = 21.4 Hz), 115.8, 117.4,
120.3, 125.1, 127.6, 129.1, 129.5, 130.1, 131.1, 131.4 (d, 3JCF
=
4
8.3 Hz), 136.4, 137.3 (d, JCF = 3.5 Hz), 147.3, 147.5, 157.7,
1
162.2 (d, JCF = 245.0 Hz); ir (neat): ꢁmax/cm-1 758, 838, 1221,
1397, 1494, 1569, 1603, 3058, 3429; ms (EI) m/z 314 (M+, 61),
313 (100); Hmrs (EI) calculated for C21H15N2F: 313.1201.
Found: 313.1204. Anal. calc. for C21H15N2F: C, 80.55; H, 4.83;
N, 8.95. Found: C, 80.13; H, 4.68; N, 8.80.
4-Amino-2-(4-chlorophenyl)-3-phenylquinoline (7c). This
1
compound was isolated as solid (65%), mp. 237 – 239˚C; H
nmr (300 MHz, CDCl3): ꢀ 4.76 (2H, br s), 7.12 – 7.24 (4H, m),
7.24 – 7.38 (5H, m), 7.48 (1H, dt, J = 0.9 and 7.6 Hz), 7.69 (1H,
dt, J = 1.2 and 7.8 Hz), 7.77 (1H, d, J = 8.1 Hz), 8.07 (1H, d, J =
8.7 Hz); 13C nmr (75 MHz, CDCl3): ꢀ 115.7, 117.4, 120.4,
125.2, 127.6, 127.8, 129.2, 129.5, 130.1, 131.0, 131.1, 133.4,
136.2, 139.8, 147.4, 147.5, 157.4; ir (neat): ꢁmax/cm-1 759, 829,
934, 1016, 1091, 1365, 1420, 1491, 1567, 1624, 3125, 3307,
3429; ms (EI) m/z 332 (50), 331 (65), 330 (M+, 80), 329 (100);
Hmrs (EI) calculated for C21H15N235Cl: 330.0904. Found:
330.0903. Anal. calc. for C22H14N235Cl: C, 76.41; H, 4.58; N,
8.49. Found: C, 76.17; H, 4.38; N, 8.40.
[17a] Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513; [b] Miyaura, N.; Suzuki, A. J. Organomet. Chem. 1999, 576,
147; [c] Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
4-Amino-2-(4-methoxyphenyl)-3-phenylquinoline (7d).
This compound was isolated as solid (90%) mp. 165 – 167˚C; 1H