Regioselective alkynylation of 2-aryl-4-chloro-3-iodoquinolines and subsequent arylation or amination of the 2-aryl-3-(alkynyl)-4-chloroquinolines

Article abstract of DOI:10.1016/j.tet.2010.08.043

Palladium-CuI catalyzed Sonogashira coupling of 2-aryl-4-chloro-3- iodoquinolines with terminal acetylenes (1 equiv) in triethylamine afforded the 2-aryl-3-(alkynyl)-4-chloroquinolines as sole products. The 2-aryl-4-chloro-3- iodoquinolines coupled with excess terminal acetylenes (2.5 equiv) in dioxane/water to yield the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-pot operation. The 2-aryl-3-(alkynyl)-4-chloroquinolines were, in turn, subjected to arylation via Suzuki cross-coupling with arylboronic acid derivatives or amination with methylamine, respectively. The structures of the products of successive Sonogashira and Suzuki cross-couplings were also confirmed by X-ray crystallography.

Full text of DOI:10.1016/j.tet.2010.08.043

Tetrahedron 66 (2010) 8261e8266
Contents lists available at ScienceDirect
Tetrahedron
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Regioselective alkynylation of 2-aryl-4-chloro-3-iodoquinolines and subsequent
arylation or amination of the 2-aryl-3-(alkynyl)-4-chloroquinolines
*
Malose J. Mphahlele
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 17 June 2010
Received in revised form 29 July 2010
Accepted 16 August 2010
Available online 21 August 2010
PalladiumeCuI catalyzed Sonogashira coupling of 2-aryl-4-chloro-3-iodoquinolines with terminal acet-
ylenes (1 equiv) in triethylamine afforded the 2-aryl-3-(alkynyl)-4-chloroquinolines as sole products. The
2-aryl-4-chloro-3-iodoquinolines coupled with excess terminal acetylenes (2.5 equiv) in dioxane/water
to yield the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-pot operation. The 2-aryl-3-(alkynyl)-4-
chloroquinolines were, in turn, subjected to arylation via Suzuki cross-coupling with arylboronic acid
derivatives or amination with methylamine, respectively. The structures of the products of successive
Sonogashira and Suzuki cross-couplings were also confirmed by X-ray crystallography.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2-Aryl-4-chloro-3-iodoquinolines
Sonogashira reaction
Suzuki reaction
Amination
2,3,4-Trisubstituted quinolines
1. Introduction
yield.8 Reisch and Gunaherath coupled 2,4-dibromoquinoline with
various terminal acetylenes to afford monosubstituted compounds
In recent years, the elaboration of strategies to efficiently
functionalize presynthesized halogenated quinolines into poly-
substituted quinoline derivatives with potential application in
natural products, pharmaceuticals, and materials has attracted
considerable attention. During our research on the development of
novel 2,3,4-trisubstituted quinoline derivatives with potential
biological activity,1 we became interested in the synthesis of alky-
nylated and alkenylated quinolines based on the 2-aryl-4-chloro-3-
iodoquinoline framework. The aryl and alkynyl or alkenyl moieties
are widely distributed in quinoline derivatives that serve as potent
inhibitors of tyrosine kinase PDGF-RTK,2 anti-retroviral agents3 or
LTD4 receptor antagonists,4 respectively. 2-Arylquinolines bearing
a vinyl, alkynyl or phenyl substituent on the C-4 position were also
found to display high affinity (3e5 nM) and significant selectivity
believed to be the 4-alkynylated quinoline derivatives.9 This re-
action was however reinvestigated by Nolan and Comins who, on
the basis of heteronuclear multiple bond correlation (HMBC) and
some chemical transformations, established the structure of the
resulting products to be that of the 2-substituted derivatives.10
A
similar regioselectivity was also observed for the Pd/
CeCuIePPh3 catalyzed Sonogashira coupling of 2,4-dichloro-
quinoline with terminal alkynes in water.11 In contrast to the re-
activity of 2,4-dibromoquinoline, the analogous 2-bromo-
4-iodoquinoline afforded the 4-alkynylated 2-bromoquinoline
derivative, exclusively.12 Stille, Suzuki, and Heck reactions of
2-bromo-4-iodoquinoline were also found to proceed with similar
regioselectivity.12 The observed trend relates to the AreX bond
strength, which increases as follows: I<Br<Cl<F (DPheX values 65,
81, 96, and 126 Kcal/mol, respectively) and makes the oxidative
addition step increasingly difficult.13e16
Although the known order of reactivity in transition metal-
mediated cross-coupling of aryl halides (I>Br>>Cl)15,16 allows se-
lective couplingwith iodides or bromidesinthepresenceof chlorides,
several activated heteroaryl chlorides, such as 4-chloropyridine and
4-chloroquinoline derivatives have since been found to undergo
Sonogashira coupling with ease.13,14 The reaction of 4-chloro-6-
iodoquinoline with a stoichiometric amount of arylacetylenes in THF
or dioxane in the presence of 2 equiv of triethylamine and a Pd
(PPh3)4eCuI catalyst mixture also led to exclusive replacement of
iodine.17 However, the use of an excess of phenylacetylene (2.2 equiv)
(up to 83-fold) for estrogen receptor
b (ERb
).5 The Sonogashira
reaction, which involves palladium-catalyzed coupling of terminal
acetylenes with aryl or heteroaryl halides has become an important
tool for the construction of carbon(sp2)ecarbon(sp) bonds to afford
alkynylated systems.6,7 This reaction was employed before on 2-(4-
chlorophenyl)-4-iodoquinoline with phenylacetylene in triethyl-
amine at reflux in the presence of a Pd(PPh3)4eCuI catalyst mixture
to afford 2-(4-chlorophenyl)-4-(phenylethynyl)quinoline in 72%
* Corresponding author. Tel.: þ27 12 429 8805; fax: þ27 12 429 8549;
e-mail address: mphahmj@unisa.ac.za.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.043

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M.J. Mphahlele / Tetrahedron 66 (2010) 8261e8266
led to a mixture of the monoalkynylated derivative (15%) and dia-
lkynylated quinoline (83%). Our continued interest in the chemistryof
2-aryl-4-chloro-3-iodoquinolines prompted us to investigate their
reactivity in Sonogashira cross-coupling using terminal alkynes as
model systems for CeC bond formation to compare the reactivity of
Csp2eI and activated Csp2eCl bond. Moreover, the reactivity of the
resulting monoalkynylated derivatives toward Suzuki cross-coupling
with boronic acid derivatives and nucleophilic displacement of
chlorine by methylamine have also been investigated.
In the second part of this investigation, we optimized conditions
for the one-pot dialkynylation of substrates 1. The corresponding
2-aryl-3,4-bis(alkynyl)quinolines 3 were isolated as sole products
when systems 1 were treated with excess terminal acetylenes
(2.5 equiv), PdCl2(PPh3)4eCuI catalyst mixture, and triethylamine
in dioxaneeH2O (3:1, v/v) at 80 ꢀC (Scheme 2). The 2,3,4-tri-
substituted derivatives 3 are analogues of 2-, 3-, and 4-(p-
substituted phenyl)ethynylquinolines and 1- and 4-(p-substituted
phenyl)ethynylisoquinolines with photophysical and electro-
generated chemiluminescence (ECL) properties.18
2. Results and discussion
The ability to efficiently functionalize presynthesized dihalo-
quinolines into polysubstituted derivatives via metal-catalyzed
cross-coupling reactions remains an important issue in synthetic
organic chemistry. The ease of activated chloroquinoline derivatives
toundergometal-catalyzed CeC bond formation makes it difficult to
easily predict how different the reactivity of the two Csp2ehalogen
bonds in 2-aryl-4-chloro-3-iodoquinolines would be during Pd-
catalyzed alkynylation reactions. We nevertheless took advantage of
the known order of reactivity in transition metal-mediated cross-
couplingof aryl halides (I>Br>>Cl)9,10,12,15,16 and subjected system 1
to dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2)e
copper iodide (CuI) catalyzed reaction with phenylacetylene
(1.2 equiv) in the presence of triethylamine in dioxane at 80 ꢀC as
a reference starting point for exploration based on literature pre-
cedence. Although the reaction was found to be selective for the
monosubstituted product 2, we were however concerned about the
low yields (<50%) and prolonged reaction times (18 h). When DMF
was used as solvent at 80 ꢀC we isolated a mixture of the mono-
substituted derivatives and the dialkynylated derivatives in com-
parable amounts, albeit in low yields. After some experimentation
we found the use of triethylamine as solvent at 80 ꢀC to afford
products 2 as sole products and in reasonable yields within 2 h
(Scheme 1). The reaction was extended to 3-butyn-1-ol to afford
products 2eeh as sole products. The observed selectivity is com-
plementary to our previously reported results of Suzuki coupling of
2-aryl-3-iodo-4-(chloro/methoxy)quinolines with phenylboronic
acid, which proceeded with C-3 regioselectivity.1 We attribute the
selectivity in both cases to the greater reactivity of the aryleiodide
bond toward oxidative addition with palladium relative to the
activated Csp2eCl bond.
Scheme 2. One-pot Pd(0)eCuI catalyzed dialkynylation of 2-aryl-4-chloro-3-
iodoquinolines.
Successive substitution of halogen atoms using electron-
deficient heterocycles containing two or more halogens located in
positions activated toward metal-catalyzed cross-coupling or nu-
cleophilic attack is of particular interest in organic synthesis.19 The
potential of the 4-chloro atom on the quinoline ring to promote
metal-catalyzed CeC bond formation20e22 prompted us to in-
vestigate the reactivity of 2 in the SuzukieMiyaura cross-coupling
reaction. Whereas the analogous 4-chloro-6-iodoquinoline21 and
4-chloro-8-tosyloxyquinoline22 were found to undergo successive
cross-coupling with various arylboronic acids using Pd(PPh3)4 as
catalyst and K2CO3 as base in DMF, under similar conditions we
recovered the starting material 2 after 48 h. The 18-electron, Pd(0)
(PPh3)4, is known to dissociate in solution to form a stable 16-
electron SPd(0)(PPh3)3 {Pd(0)(PPh3)4#SPd(0)(PPh3)2þPPh3, (K1/
[PPh3]>>1)}; where S¼solvent}.23 However, the actual reactive
species in oxidative addition with aryl iodides has been established
on the basis of kinetic studies to be the low ligated 14-electron Pd
(0)(PPh3)2 generated by the dissociation of SPd(0)(PPh3)3 {SPd(0)
(PPh3)3#SPd(0)(PPh3)2þPPh3 (K2/[PPh3]<<1)}. It is this extra PPh3
that has been found to inhibit the oxidative addition step particu-
larly when the palladium(0) complex is generated from Pd(0)
(PPh3)4.23 Alkylphosphine ligands, on the other hand, are known to
coordinate with palladium and increase its electron density more
so than arylphosphines and, in turn, accelerate the oxidative ad-
dition and reductive elimination steps in the catalytic cycle.23e27
We envisioned the use of an alkylphosphine ligand to counteract
the inhibitory effect of the extra PPh3 to speed up the oxidative
addition step in analogy with literature observation for Pd(OAc)2 or
PdCl2(PPh3)2.23 Based on this postulate, we subjected systems 2 to
Pd(PPh3)4 catalyzed Suzuki cross-coupling with trans-phenyl-
vinylboronic acid in the presence of K2CO3 and tricyclohex-
ylphosphine (PCy3) as ligand in aqueous dioxane at 80 ꢀC and we
isolated products 4aed in reasonable yields (Scheme 3). The re-
action conditions involving the Pd(PPh3)4ePCy3 mixture were also
Scheme 1. Regioselective Sonogashira cross-coupling on 2-aryl-4-chloro-3-
iodoquinolines.

M.J. Mphahlele / Tetrahedron 66 (2010) 8261e8266
8263
extended to 4-fluorophenylboronic acid to afford the 2-aryl-4-
(4-fluorophenyl)-3-(phenylethynyl)quinolines 4e and f, which are
analogues of NK-104 {calcium salt of 7-[2-cyclopropyl-4-(4-fluo-
rophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid}, a highly
potent HMG-CoA reductase inhibitor.28 Notably, this conversion is
the first example involving the use of Pd(0)(PPh3)4 as palladium
source and alkylphosphine ligand to promote Suzuki cross-coupling
reaction. We strongly believe PCy3 counteracts the inhibitory effect
of PPh3 by coordinating to palladium of either the 16- or 14-electron
species thereby increasing the electron density of the metal and
speed up the oxidative addition step.
ring as evidenced by the large torsion angles 44.6ꢀ [C(60)eC(10)eC
(2)eN(1)] and ꢁ45.6ꢀ [C(4A)eC(4)eC(17)eC(18)], respectively. This
deviation from co-planarity is presumably the consequence of steric
interaction with the alkynyl moiety.
To further demonstrate the versatility of the 4-chloroquinoline
derivatives in synthesis, we took advantage of the ease of dis-
placement of the 4-chloro atom on the quinoline ring by nucleo-
philes,1,30 and subjected selected systems 2 to methylamine in
ethanol under reflux for 18 h (Scheme 4). We isolated the corre-
sponding primary 4-aminoquinoline derivatives 5aed, which are
analogues of 4-phenylamino-3-vinylquinolines prepared before via
palladium-catalyzed intermolecular Heck reaction of 3-iodo-2-
methyl-4-(phenylamino)quinoline with terminal alkenes and were
found to exhibit gastric Hþ/Kþ-ATPase inhibitory activity.31 The
analogous 4-amino-2-arylquinolines have also been found to rep-
resent a novel class of NR1/2B subtype selective N-methyl-D-as-
partate (NMDA) receptor antagonists.32
NHCH3 R'
Cl
R'
NH2CH3, EtOH, heat, 18h
N
C6H4R
N
C6H4R
2
5a - d
R
R'
% Yield
5a
H
-C6H5
-C6H5
68
61
58
5b Cl
5c OMe -C6H5
5d Cl
Scheme 3. Palladium-catalyzed Suzuki cross-coupling of 2 with boronic acid derivatives.
-CH(OH)Me 61
Crystals of quality suitable for X-ray diffractionwere obtained for
4a and the molecular structure of this compound was independently
confirmed by X-ray diffraction (Fig. 1).29 The 2-aryl and 4-phenyl-
ethenyl moiety are strongly deformed out of plane of the quinoline
Scheme 4. Nucleophilic displacement of the 4-chloro atom from 2-aryl-4-chloro-3-
iodoquinolines.
3. Conclusions
The results described in this investigation demonstrate the
application of 2-aryl-4-chloro-3-iodoquinolines as valuable in-
termediates for metal-catalyzed Csp2eCsp and Csp2eCsp2 bond
formation to afford novel 2,3,4-trisubstituted quinoline derivatives.
These systems cannot be easily achieved through the well known
classical methods such as Skraup, DoebnereVon Miller, and
Friedlander reactions for the synthesis of polysubstituted quino-
lines. The 2-aryl-4-(phenylethenyl)-3-(phenylethynyl)quinolines
and the 3,4-bis(alkynyl)-2-arylquinolines have the potential to
serve as molecular organic materials in nanomaterials or building
blocks for polyquinolines or quinoline-based copolymers with en-
hanced photonic and electronic properties.33 Moreover, the 2-aryl-
3-(alkynyl)-4-(methylamino)quinolines are suitable candidates for
further transformation involving metal-catalyzed cyclization or
iodocyclization to afford biologically relevant annulated derivatives
with potential to undergo further transformation into biologically
important compounds.
4. Experimental
4.1. General
Melting points were recorded on a Thermocouple digital melt-
ing point apparatus. IR spectra were recorded as powders using the
FTS 7000 Series Digilab Win-IR Pro ATR (attenuated total re-
flectance) spectrometer. For column chromatography, Merck Kie-
selgel 60 (0.063e0.200 mm) was used as stationary phase. NMR
Figure 1. (a) ORTEP diagram (50% probability level) of 2-phenyl-4-(2-phenylethenyl)-
3-(phenylethynyl)quinoline 4a showing crystallographic numbering. For clarity, hy-
drogen atoms are not labeled.

8264
M.J. Mphahlele / Tetrahedron 66 (2010) 8261e8266
spectra were obtained as CDCl3 solutions using a Varian Mercury
300 MHz NMR spectrometer and the chemical shifts are measured
relative to the solvent peaks. Low and high-resolution mass spectra
were recorded at an ionisation potential of 70 eV using a Micromass
Autospec-TOF (double focusing high-resolution) instrument. The
synthesis and characterization of substrates 1 have been described
elsewhere.1
130.7, 131.1, 131.5, 132.0, 145.2, 146.8, 159.0, 160.5; m/z (100, MHþ)
370; HRMS (ES): MHþ, found 370.1012. C24H17N35ClOþ requires
370.0999.
4.2.5. 4-Chloro-3-(3-hydroxybutyn-1-yl)-2-phenylquinoline
(2e). Yield (0.22 g; 64%), mp 106e108 ꢀC; Rf (30% ethyl acetate/
hexane) 0.53; nmax (neat) 1067, 1476, 1562, 3225 cmꢁ1
; dH
(300 MHz, CDCl3) 1.47 (d, J 6.6 Hz, 3H),1.90 (d, J 5.4 Hz,1H), 4.72 (q, J
6.6 Hz, 1H), 7.45e7.51 (m, 3H), 7.64 (dt, J 1.2 and 7.8 Hz,1H), 7.76 (dt,
J 1.5 and 7.7 Hz, 1H), 7.90 (dt, J 1.8 and 7.8 Hz, 2H), 8.14 (td, J 0.9 and
7.5 Hz, 1H), 8.22 (td, J 0.9 and 7.5 Hz, 1H); dC (75 MHz, CDCl3) 23.7,
59.9, 79.7, 102.2, 115.6, 124.4, 124.7, 127.9, 128.2, 129.3, 129.5, 130.0,
131.0, 139.4, 145.6, 146.9, 159.8; m/z (100, MHþ) 308; HRMS (ES):
MHþ, found 308.0852. C19H15NO35Clþ requires 308.0842.
4.2. Synthesis of 2-aryl-4-chloro-3-(alkynyl)quinolines 2.
Typical procedure
4.2.1. 4-Chloro-2-phenyl-3-(phenylethynyl)quinoline (2a). A mix-
ture of 1a (1.00 g, 2.74 mmol), PdCl2(PPh3)2 (0.10 g, 0.14 mmol),
and CuI (0.03 g, 0.14 mmol) in a three-necked flask equipped
with a stirrer, condenser, and rubber septum was flushed with
nitrogen gas for 20 min. Phenylacetylene (0.36 g, 3.30 mmol) and
triethylamine (8.0 mL) were added sequentially to the flask via
a syringe. The mixture was flushed for additional 10 min and
then heated at reflux for 2 h under a nitrogen atmosphere. The
cooled mixture was added to a beaker containing ice-cold water
and extracted with ethyl acetate. The combined organic solution
was dried over Mg2SO4, filtered, and then evaporated. The resi-
due was purified by column chromatography to afford 2a as
a white solid (0.69 g; 74%), mp 145e148 ꢀC; Rf (10% ethyl acetate/
hexane) 0.44; nmax (neat) 834, 955, 1067, 1343, 1496, 1476, 1562,
4.2.6. 4-Chloro-2-(4-fluorophenyl)-3-(3-hydroxybutyn-1-yl)quino-
line (2f). Yield (0.15 g; 59%), mp 152e155 ꢀC; Rf (30% ethyl acetate/
hexane) 0.59; nmax (neat) 837, 1160, 1230, 1346, 1477, 1514, 1604,
3298 cmꢁ1
; dH (300 MHz, CDCl3) 1.50 (d, J 6.6 Hz, 3H), 1.96 (d, J
5.4 Hz,1H), 4.74 (q, J 6.6 Hz, 1H), 7.17 (t, J 8.4 Hz, 2H), 7.64 (t, J 7.5 Hz,
1H), 7.67 (t, J 7.5 Hz, 1H), 7.93 (t, J 8.4 Hz, 2H), 8.11 (d, J 8.4 Hz, 1H),
8.23 (d, J 8.4 Hz, 1H); dC (75 MHz, CDCl3) 23.8, 58.9, 79.7, 102.4, 114.9
3
(d, 2JCF 21.6 Hz), 115.4, 124.3, 124.6, 128.0, 129.8, 131.1, 131.5 (d, JCF
4
4
8.6 Hz), 135.3 (d, JCF 3.4 Hz), 145.8, 146.8, 158.5, 163.5 (d, JCF
247.9 Hz); m/z (100, MHþ) 326; HRMS (ES): MHþ, found 326.0763.
C19H14FNO35Clþ requires 326.0748.
3225 cmꢁ1
; dH (300 MHz, CDCl3) 7.31e7.36 (m, 3H), 7.39e7.44 (m,
2H), 7.49e7.56 (m, 3H), 7.65 (dt, J 1.2 and 7.5 Hz, 1H), 7.77 (dt, J
1.5 and 7.7 Hz, 1H), 8.00e8.04 (m, 2H), 8.15 (dd, J 0.9 and 7.7 Hz,
1H), 8.27 (dd, J 0.9 and 8.6 Hz, 1H); dC (75 MHz, CDCl3) 85.5,
100.6, 116.4, 122.7, 124.4, 124.8, 127.8, 127.9, 128.4, 129.0, 129.2,
129.6, 130.0, 130.7, 131.5, 139.5, 145.1, 146.9, 159.8; m/z (100,
MHþ) 340; HRMS (ES): MHþ, found 340.0888. C23H15N35Clþ
requires 340.0893.
4.2.7. 4-Chloro-2-(4-chlorophenyl)-3-(3-hydroxybutyn-1-yl)quino-
line (2g). Yield (0.12 g; 66%), mp 167e169 ꢀC; Rf (30% ethyl acetate/
hexane) 0.65; nmax (neat) 824, 1019, 1087, 1340, 1473, 3302 cmꢁ1
; dH
(300 MHz, CDCl3) 1.51 (d, J 6.6 Hz, 3H),1.93 (d, J 5.4 Hz,1H), 4.75 (q, J
6.6 Hz, 1H), 7.46 (d, J 8.7 Hz, 2H), 7.65 (dt, J 1.5 and 7.8 Hz, 1H), 7.77
(dt, J 1.5 and 7.8 Hz, 1H), 7.90 (d, J 8.4 Hz, 2H), 8.11 (td, J 0.6 and
7.8 Hz, 1H), 8.22 (td, J 0.3 and 8.6 Hz, 1H); dC (75 MHz, CDCl3) 23.8,
59.0, 79.7, 102.4, 115.3, 124.4, 124.7, 128.1 (2ꢂC), 129.9, 130.9, 131.1,
135.5, 137.7, 145.9, 146.9, 158.4; m/z (100, MHþ) 342; HRMS (ES):
MHþ, found 342.0454. C19H14NO35Clþ2 requires 342.0452.
4.2.2. 4-Chloro-2-(4-fluorophenyl)-3-(phenylethynyl)quinoline
(2b). Yield (0.30 g; 64%), mp 175e178 ꢀC; Rf (10% ethyl acetate/
hexane) 0.42; nmax (neat) 827, 1156, 1228, 1344, 1474, 1496, 1598,
2214 cmꢁ1
; dH (300 MHz, CDCl3) 7.22 (t, J 8.1 Hz, 2H), 7.36 (s, 3H),
7.44 (m, 2H), 7.65 (t, J 8.1 Hz, 1H), 7.77 (t, J 8.4 Hz, 1H), 8.05 (t, J
7.5 Hz, 2H), 8.13 (d, J 8.4 Hz, 1H), 8.27 (d, J 8.4 Hz, 1H); dC (75 MHz,
4.2.8. 4-Chloro-3-(3-hydroxybutyn-1-yl)-2-(4-methoxyphenyl)quin-
oline (2h). Yield (0.22 g; 65%), mp 120e124 ꢀC; Rf (30% ethyl ace-
tate/hexane) 0.42; nmax (neat) 824, 1174, 1253, 1343, 1516, 1607,
2
CDCl3) 85.3, 100.6, 114.9 (d, JCF 21.3 Hz), 116.1, 122.5, 124.3, 124.7,
127.9, 128.4, 129.1, 129.9, 130.9, 131.5, 131.6 (d, 3JCF 8.6 Hz), 135.5 (d,
3176 cmꢁ1
; dH (300 MHz, CDCl3) 1.50 (d, J 6.6 Hz, 3H), 2.16 (d, J
1
4JCF 3.5 Hz), 145.3, 146.7, 158.4, 163.5 (d, JCF 247.6 Hz); m/z (100,
5.7 Hz, 1H), 3.86 (s, 3H), 4.73 (q, J 6.6 Hz, 1H), 6.99 (d, J 8.7 Hz, 2H),
7.59 (dt, J 1.2 and 7.8 Hz, 1H), 7.72 (dt, J 1.5 and 7.8 Hz, 1H), 7.92 (d, J
8.7 Hz, 2H), 8.09 (dd, J 0.6 and 7.8 Hz, 1H), 8.18 (td, J 0.9 and 8.7 Hz,
1H); dC (300 MHz, CDCl3) 23.7, 55.3, 58.8, 80.0, 102.2, 113.2, 115.3,
124.2, 124.3, 127.5, 129.7, 130.8, 131.0, 131.7, 145.6, 146.8, 159.1,
160.5; m/z (100, MHþ) 338; HRMS (ES): MHþ, found 338.0953.
C20H17NO235Clþ requires 338.0948.
MHþ) 358; HRMS (ES): MHþ, found 358.0786. C23H14FN35Clþ
requires 358.0799.
4.2.3. 4-Chloro-2-(4-chlorophenyl)-3-(phenylethynyl)quinoline
(2c). Yield (0.25 g; 67%), mp 180e183 ꢀC; Rf (10% ethyl acetate/
hexane) 0.69; nmax (neat) 823, 1087, 1343, 1343, 1403, 1472, 1491,
1559, 1596, 2216 cmꢁ1
; dH (300 MHz, CDCl3) 7.34e7.39 (m, 3H),
7.42e7.47 (m, 2H), 7.50 (d, J 8.7 Hz, 2H), 7.66 (dt, J 1.5 and 7.7 Hz,
1H), 7.77 (dt, J 1.5 and 7.5 Hz, 1H), 8.01 (d, J 8.4 Hz, 2H), 8.13 (d, J
8.7 Hz, 1H), 8.25 (dd, J 0.9 and 8.4 Hz, 1H); dC (75 MHz, CDCl3) 85.2,
100.8, 116.1, 122.4, 124.4, 124.9, 128.1, 128.2, 128.5, 129.1, 129.9,
130.9, 131.0, 131.5, 135.4, 137.9, 145.4, 146.8, 158.3; m/z (100, MHþ)
374; HRMS (ES): MHþ, found 374.0500. C23H1435Cl2Nþ requires
374.0503.
4.3. One-pot synthesis of 2-aryl-3,4-bis(alkynyl)quinoline 4.
Typical procedure
4.3.1. 2-Phenyl-3,4-bis(phenylethynyl)quinoline (3a). A mixture of
1a (0.14 g, 0.39 mmol), PdCl2(PPh3)2 (0.02 g, 0.01 mmol), CuI
(0.004 g, 0.01 mmol) in dioxane/water (3:1, v/v; 10 mL) in a three-
necked flask equipped with a stirrer, condenser, and rubber septum
was flushed with nitrogen gas for 20 min. Phenylacetylene (0.11 g,
0.47 mmol) and triethylamine (0.2 mL, 1.17 mmol) were added
sequentially to the flask via a syringe. The mixture was flushed for
additional 10 min and then heated at reflux for 18 h under nitrogen
atmosphere. The cooled mixture was added to a beaker containing
ice-cold water and the product was extracted into ethyl acetate. The
combined organic layers were dried over anhydrous MgSO4, fil-
tered, and evaporated under reduced pressure. The residue was
purified by column chromatography to afford 3a as a white solid
4.2.4. 4-Chloro-2-(4-methoxyphenyl)-3-(phenylethynyl)quinoline
(2d). Yield (0.34 g; 70%), mp 120e123 ꢀC; Rf (10% ethyl acetate/
hexane) 0.31; nmax (neat) 822, 1029, 1175, 1253, 1345, 1400, 1515,
1608, 2213 cmꢁ1
; dH (300 MHz, CDCl3) 3.90 (s, 3H), 7.05 (d, J 8.7 Hz,
2H), 7.32e7.37 (m, 3H), 7.44e7.50 (m, 2H), 7.62 (dt, J 1.2 and 7.5 Hz,
1H), 7.74 (dt, J 1.2 and 7.5 Hz, 1H), 8.05 (d, J 8.7 Hz, 2H), 8.12 (d, J
8.7 Hz, 1H), 8.25 (dd, J 0.9 and 8.1 Hz, 1H); dC (75 MHz, CDCl3) 55.4,
85.8, 100.3, 113.3, 116.0, 122.7, 124.3, 124.5, 127.5, 128.4, 128.9, 129.8,

M.J. Mphahlele / Tetrahedron 66 (2010) 8261e8266
8265
(0.11 g; 72%), mp 184e186 ꢀC; Rf (10% ethyl acetate/hexane) 0.47;
nmax (neat) 1070, 1442, 1493, 1560, 2205, 3059 cmꢁ1
dH (300 MHz,
(0.01 g, 0.03 mmol) was taken in 3:1 dioxane/water (20 mL) in
a two-necked flask equipped with a stirrer bar, rubber septum, and
condenser. After degassing with argon for 10 min, K2CO3 (0.08 g,
0.59 mmol) was added and the mixture was degassed further with
argon for 10 min. The mixture was heated at 80e90 ꢀC under argon
atmosphere for 18 h and then allowed to cool to room temperature.
The cooled mixture was quenched with ice-cold water and the
product was extracted into chloroform. The combined organic
phases were washed with brine, dried over anhydrous Mg2SO4, and
then evaporated under reduced pressure. The residue was purified
by column chromatography to afford 4a as a white solid (0.11 g;
92%), mp 183e184 ꢀC (EtOH); Rf (30% ethyl acetate/hexane) 0.63;
;
CDCl3) 7.30e7.33 (m, 3H), 7.39e7.45 (m, 5H), 7.49e7.58 (m, 3H),
7.64 (t, J 8.4 Hz, 1H), 7.72e7.78 (m, 3H), 8.06 (dd, J 5.4 and 8.7 Hz,
2H), 8.15 (d, J 8.4 Hz, 1H), 8.37 (d, J 8.4 Hz, 1H); dC (300 MHz, CDCl3)
85.3, 87.8, 99.4, 103.0, 118.3, 122.5, 123.1, 125.9 (2ꢂC), 127.5, 127.9,
128.4, 128.6, 128.7, 129.0, 129.5, 129.6, 129.9, 130.4, 131.4, 132.0,
133.1, 139.8, 146.3, 159.3; m/z (100, MHþ) 406; HRMS (ES): MHþ,
found 406.1590. C31H20Nþ requires 406.1596.
4.3.2. 2-(4-Fluorophenyl)-3,4-bis(phenylethynyl)quinoline
(3b). Yield (0.11 g; 67%), mp 153e157 ꢀC; Rf (10% ethyl acetate/
hexane) 0.49; nmax (neat) 827, 1157, 1227, 1343, 1472, 1511, 1599,
nmax (neat) 971, 1446, 1488, 3056 cmꢁ1
; dH (300 MHz, CDCl3)
2214 cmꢁ1
;
dH (300 MHz, CDCl3) 7.23 (t, J 8.7 Hz, 2H), 7.31e7.38 (m,
7.26e7.30 (m, 5H), 7.42 (t, J 8.1 Hz, 1H), 7.46e7.61 (m, 7H),
7.68e7.75 (m, 3H), 7.79 (d, J 16.5 Hz, 1H), 8.03 (dd, J 1.5 and 7.8 Hz,
2H), 8.19 (dd, J 0.9 and 8.4 Hz, 1H), 8.27 (td, J 0.9 and 8.1 Hz, 1H); dC
(75 MHz, CDCl3) 77.2, 87.9, 99.9, 114.1, 123.1, 123.4, 124.8, 125.0,
126.9 (2ꢂC), 127.8, 128.4, 128.5, 128.8, 129.0, 129.7, 130.0, 130.3,
131.2, 136.7, 138.8, 140.3, 146.7, 146.9, 160.0; m/z (100, MHþ) 408;
HRMS (ES): MHþ, found 408.1735. C31H22Nþ requires 408.1735.
5H), 7.44e7.47 (m, 2H), 7.52e7.56 (m, 3H), 7.66 (dt, J 0.9 and 7.7 Hz,
1H), 7.78 (dt, J 1.5 and 7.7 Hz,1H), 8.06 (dd, J 5.4 and 8.7 Hz, 2H), 8.14
(d, J 8.4 Hz, 1H), 8.27 (dd, J 0.9 and 8.4 Hz, 1H); dC (300 MHz, CDCl3)
2
73.9, 81.5, 85.3, 100.7, 114.9 (d, JCF 21.3 Hz), 116.2, 121.8, 122.5,
124.4, 124.8, 128.0, 128.4, 128.5, 129.1, 129.2, 129.9, 130.9, 131.5,
131.6 (d, 3JCF 8.6 Hz), 132.5, 135.6 (d, 4JCF 3.5 Hz), 145.3, 146.8, 158.5,
1
163.5 (d, JCF 246.9 Hz); m/z (100, MHþ) 424; HRMS (ES): MHþ,
found 424.1553. C31H19FNþ requires 424.1553.
4.4.2. 2-(4-Fluorophenyl)-4-(2-phenylethenyl)-3-(phenylethynyl)-
quinoline (4b). Yield (0.07 g; 90%), mp 156e158 ꢀC (EtOH); Rf (30%
ethyl acetate/hexane); nmax (neat) 833, 1158, 1224, 1510, 1599,
4.3.3. 2-(4-Chlorophenyl)-3,4-bis(phenylethynyl)quinoline
(3c). Yield (0.14 g; 84%), mp 165e677 ꢀC; Rf (10% ethyl acetate/
hexane) 0.46; nmax (neat) 827, 1015, 1087, 1404, 1492, 1596,
2927 cmꢁ1
; dH (300 MHz, CDCl3) 7.18e7.30 (m, 7H), 7.37e7.48 (m,
4H), 7.58 (t, J 8.4 Hz, 1H), 7.66e7.76 (m, 3H), 7.77 (d, J 16.8 Hz, 1H),
8.03 (t, J 8.4 Hz, 2H), 8.14 (d, J 8.4 Hz, 1H), 8.25 (d, J 8.4 Hz, 1H); dC
(75 MHz, CDCl3) 87.7, 99.9, 113.9, 114.7 (d, 2JCF 21.6 Hz), 122.9, 123.3,
125.1,126.9, 127.0, 128.5, 128.7, 128.8, 129.0, 130.1,103.2, 131.2, 131.5,
131.7 (d, 3JCF 8.1 Hz), 136.3 (d, 4JCF 3.5 Hz), 136.6, 138.9, 146.8, 146.9,
2204 cmꢁ1
; dH (300 MHz, CDCl3) 7.34e7.37 (m, 3H), 7.42e7.45
(m, 4H), 7.50 (d, J 8.1 Hz, 3H), 7.65 (dt, J 0.9 and 7.7 Hz, 1H),
7.71e7.79 (m, 3H), 8.04 (d, J 8.4 Hz, 2H), 8.13 (d, J 8.1 Hz, 1H), 8.37
(d, J 8.1 Hz, 1H); dC (75 MHz, CDCl3) 85.2, 97.5, 99.6, 103.3, 117.9,
122.4, 122.9, 125.9, 126.0, 127.7, 128.1, 128.5, 128.7, 128.9, 129.6,
129.9, 130.6, 131.1, 131.4, 132.0, 133.4, 35.2, 138.2, 146.3, 157.8; m/z
(100, MHþ) 440; HRMS (ES): MHþ, found 440.1227. C31H19N35Clþ
requires 440.1206.
1
158.7, 163.3 (d, JCF 246.4 Hz); m/z (100, MHþ) 426; HRMS (ES):
MHþ, found 426.1629. C31H21FNþ requires 426.1638.
4.4.3. 2-(4-Methoxyphenyl)-3-(phenylethynyl)-4-(2-phenylethenyl)-
quinoline (4c). Yield (0.05 g; 55%), mp 128e129 ꢀC (EtOH); Rf (30%
ethyl acetate/hexane) 0.46; nmax (neat) 836, 1033, 1176, 1251, 1489,
4.3.4. 2-(4-Methoxyphenyl)-3,4-bis(phenylethynyl)quinoline
(3d). Yield (0.13 g; 79%), mp 134e137 ꢀC; Rf (10% ethyl acetate/
hexane) 0.20; nmax (neat) 823, 1033, 1178, 1246, 1491, 1515, 1608,
1514, 1578, 3060 cmꢁ1
; dH (300 MHz, CDCl3) 3.91 (s, 3H), 7.06 (d, J
9.0 Hz, 2H), 7.26e7.33 (m, 5H), 7.33e7.48 (m, 4H), 7.54 (dt, J 1.5 and
7.6 Hz, 1H), 7.66e7.72 (m, 3H), 7.77 (d, J 16.8 Hz, 1H), 8.05 (d, J
8.7 Hz, 2H), 8.15 (dd, J 0.9 and 8.7 Hz, 1H), 8.23 (dd, J 0.9 and 8.4 Hz,
1H); dC (75 MHz, CDCl3) 55.4, 88.1, 99.7, 113.2, 113.8, 123.1, 123.5,
124.5, 125.0, 126.6, 126.9, 128.4, 128.5, 128.7, 128.9, 129.9, 130.1,
131.2 (2ꢂC), 132.8, 136.7, 138.6, 146.8, 147.0, 159.2, 160.2; m/z (100,
MHþ) 438; HRMS (ES): MHþ, found 438.1847. C32H24NOþ requires
438.1844.
2204 cmꢁ1
; dH (300 MHz, CDCl3) 3.90 (s, 3H), 7.06 (d, J 8.7 Hz, 2H),
7.31e7.35 (m, 3H), 7.41e7.49 (m, 5H), 7.62 (dt, J 1.2 and 7.5 Hz, 1H),
7.71e7.77 (dt, J 1.5 and 8.5 Hz, 3H), 8.09 (d, J 8.7 Hz, 2H), 8.12 (dd, J
0.9 and 8.7 Hz, 1H), 8.36 (dd, J 0.9 and 7.5 Hz, 1H); dC (75 MHz,
CDCl3) 55.4, 85.4, 88.1, 99.2, 102.9, 113.3, 118.0, 122.5, 123.1, 125.7,
125.8,127.2,128.4,128.6,128.7,129.4,129.7,130.3,131.1,131.4,132.0,
132.3, 133.1, 146.3, 158.5, 160.4; m/z (100, MHþ) 436; HRMS (ES):
MHþ, found 436.1700. C32H22NOþ requires 436.1701.
4.4.4. 2-(4-Fluorophenyl)-3-(3-hydroxybutyn-1-yl)-4-(2-phenyl-
ethenyl)quinoline (4d). Yield (0.07 g; 50%), mp 105e108 ꢀC (EtOH);
Rf (30% ethyl acetate/hexane) 0.46; nmax (neat) 841, 1158, 1230, 1510,
4.3.5. 2-(4-Chlorophenyl)-3,4-bis(3-hydroxybutyn-1-yl)quinoline
(3e). Yield (0.60 g; 97%), mp 162e164 ꢀC; Rf (30% ethyl acetate/
hexane) 0.59; nmax (neat) 824, 1087, 1341, 1473, 1560, 3350 cmꢁ1
;
dH
1601, 3180 cmꢁ1
; dH (300 MHz, CDCl3) 1.38 (d, J 6.6 Hz, 3H), 2.07 (br
(300 MHz, CDCl3) 1.47 (d, J 6.6 Hz, 3H),1.51 (d, J 6.6 Hz, 3H), 1.84 (d, J
5.4 Hz, 1H), 1.86 (d, J 5.4 Hz, 1H), 4.57 (q, J 6.6 Hz, 1H), 4.75 (q, J
6.6 Hz, 1H), 7.46 (d, J 8.7 Hz, 2H), 7.65 (dt, J 1.2 and 7.8 Hz, 1H), 7.77
(dt, J 7.5 Hz, 1H), 7.90 (d, J 8.8 Hz, 2H), 8.11 (td, J 0.6 and 7.5 Hz, 1H),
8.24 (td, J 0.6 and 8.8 Hz, 1H); dC (75 MHz, CDCl3) 23.8, 23.9, 58.6,
58.9, 68.0, 79.6, 81.2, 102.5, 115.3, 124.4, 124.7, 128.1 (2ꢂC), 129.9,
130.9, 131.2, 135.5, 137.6, 146.0, 146.8, 158.3; m/z (100, MHþ) 376;
HRMS (ES): MHþ, found 376.1207. C23H19NO235Clþ requires
376.1211.
s, 1H), 4.61 (q, J 6.6 Hz, 1H), 7.14 (t, J 8.7 Hz, 2H), 7.26 (d, J 16.5 Hz,
1H), 7.32e7.45 (m, 3H), 7.53 (dt, J 1.2 and 7.5 Hz, 1H), 7.56e7.63
(3H), 7.71 (dt, J 1.5 and 7.5 Hz, 1H), 7.88e7.94 (m, 2H), 8.12 (dd, J 0.6
and 8.4 Hz, 1H), 8.19 (dd, J 0.6 and 8.4 Hz, 1H); dC (75 MHz, CDCl3)
23.9, 58.8, 81.8, 101.7, 113.1, 114.7 (d, 2JCF 21.6 Hz), 123.1, 124.6, 125.0,
126.9, 127.0, 128.8, 128.9, 130.5 (d, 3JCF 8.3 Hz), 131.5, 131.6, 136.1 (d,
4JCF 3.2 Hz), 136.5, 138.8, 146.9, 147.5, 158.6, 163.2 (d, 1JCF 247.0 Hz);
m/z (100, MHþ) 394; HRMS (ES): MHþ, found 394.1596.
C27H21FONþ requires 394.1594.
4.4. SuzukieMiyaura cross-coupling of 2 to afford 4. Typical
procedure
4.4.5. 4-(4-Fluorophenyl)-2-phenyl-3-(phenylethynyl)quinoline
(4e). Yield (0.13 g; 74%), mp 147e149 ꢀC (EtOH); Rf (30% ethyl ac-
etate/hexane) 0.79; nmax (neat) 844, 1223, 1486, 1512, 1603,
4.4.1. 2-Phenyl-4-(2-phenylethenyl)-3-(phenylethynyl)quinoline
(4a). A mixture of 1a (0.10 g, 0.29 mmol), trans-phenylboronic acid
(0.05 g, 0.35 mmol), Pd(PPh3)4 (0.02 g, 0.02 mmol), and PdCy3
3059 cmꢁ1
; dH (300 MHz, CDCl3) 6.98 (dd, J 1.5 and 7.5 Hz, 2H),
7.18e7.32 (m, 5H), 7.44e7.57 (m, 6H), 761 (d, J 8.4 Hz, 1H), 7.72 (dt, J
1.5 and 7.5 Hz, 1H), 8.01 (dd, J 1.5 and 7.5 Hz, 2H), 8.20 (d, J 8.1 Hz,

8266
M.J. Mphahlele / Tetrahedron 66 (2010) 8261e8266
2
1H); dC (75 MHz, CDCl3) 87.6, 98.5, 115.2 (d, JCF 21.6 Hz), 115.7,
122.9, 125.7, 126.0, 127.0, 127.9, 128.3, 128.5, 129.0, 129.7, 129.9,
130.1, 131.1, 131.9 (d, 3JCF 8.3 Hz), 132.9 (d, 4JCF 3.2 Hz), 140.1, 146.8,
6.6 Hz, 3H), 1.60 (br s, 1H), 3.50 (s, 3H), 4.69 (q, J 6.6 Hz, 1H), 5.62 (br
s, 1H), 7.40 (d, J 8.4 Hz, 2H), 7.62 (dt, J 1.5 and 7.7 Hz, 1H), 7.80 (d, J
8.4 Hz, 2H), 8.00 (dd, J 0.6 and 8.6 Hz, 1H), 8.12 (dd, J 0.6 and 8.6 Hz,
1H); dC (75 MHz, CDCl3) 24.2, 35.7, 59.1, 80.3, 97.6,101.5,117.5,123.0,
124.6, 127.9, 130.0, 130.2, 130.8, 134.6, 139.1, 148.2, 155.3, 159.0; m/z
(100, MHþ) 337; HRMS (ES): MHþ, found 337.1122. C20H18N2O35Clþ
requires 337.1108.
150.7, 159.6, 162.8 (d, JCF 246.2 Hz); m/z (100, MHþ) 400; HRMS
1
(ES): MHþ, found 400.1516. C29H19FNþ requires 400.1502.
4.4.6. 4-(4-Fluorophenyl)-2-(methoxyphenyl)-3-(phenylethynyl)-
quinoline (4f). Yield (0.05 g; 62%), mp 166e167 ꢀC (EtOH); Rf (30%
ethyl acetate/hexane) 0.73; nmax (neat) 830, 1028, 1227, 1250, 1486,
Acknowledgements
1513, 1603, 3054, 3074 cmꢁ1
; dH (300 MHz, CDCl3) 3.91 (s, 3H),
7.00e7.08 (m, 4H), 7.22e7.31(m, 5H), 7.45 (t, J 7.5 Hz, 1H), 7.51 (t, J
8.1 Hz, 2H), 7.58 (d, J 8.4 Hz, 1H), 7.71 (t, J 7.8 Hz, 1H), 8.08 (d, J
8.4 Hz, 2H), 8.17 (d, J 8.7 Hz, 1H); dC (75 MHz, CDCl3) 55.4, 87.9, 98.4,
113.3, 115.2 (d, 2JCF 21.6 Hz), 122.9, 125.5, 125.9, 126.8, 128.3, 128.5,
129.8, 130.0, 131.1, 131.3, 131.8 (d, JCF 8.0 Hz), 132.7, 133.0 (d, JCF
3.5 Hz), 133.1, 146.9, 150.8, 158.9, 160.4, 162.7 (d, 1JCF 246.2 Hz); m/z
(100, MHþ) 430; HRMS (ES): MHþ, found 430.1602. C30H21FNOþ
requires 430.1607.
This work was funded by the University of South Africa and the
National Research Foundation (NRF). The author is grateful to the
following persons: Dr. M. Stander of Stellenbosch University; Dr.
M.A. Fernandes of University of the Witwatersrand, and Ms. H.R.
Makelane for mass spectrometric data, X-ray data and technical
assistance, respectively.
3
4
Supplementary data
4.5. Reaction of 2 with methylamine to afford (5). Typical
procedure
Detailed information on the crystal structure determination and
refinement of 4a. Supplementary data associated with this article
can be found in the online version at doi:10.1016/j.tet.2010.08.043.
4.5.1. 4-Methylamino-2-phenyl-3-(phenylethynyl)quinoline (5a). A
mixture of 2a (0.13 g, 0.382 mmol) and methylamine (0.02 g,
0.765 mmol) in ethanol (40 mL) was heated at 80 ꢀC for 18 h and
then evaporated under reduced pressure. The residue was taken up
into chloroform and the organic solution was washed with water,
dried (MgSO4), and filtered. The organic solution was evaporated
under reduced pressure and the residue was purified by column
chromatography to afford (5a) as a white solid (0.08 g, 68%), mp
158e160 ꢀC (EtOH); Rf (30% ethyl acetate/hexane) 0.29; nmax (neat)
References and notes
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1352, 1390, 1527, 1561, 2200, 3356 cmꢁ1
; dH (300 MHz, CDCl3) 3.57
(d, J 3.6 Hz, 3H), 5.67 (br s, 1H), 7.29 (s, 5H), 7.38e7.50 (m, 4H), 7.63
(dt, J 1.2 and 7.2 Hz, 1H), 7.93 (dd, J 1.8 and 8.0 Hz, 2H), 8.04 (d, J
8.7 Hz, 1H), 8.12 (d, J 8.4 Hz, 1H); dC (75 MHz, CDCl3) 35.7, 86.2, 98.7,
99.4, 117.7, 122.7, 123.3, 124.5, 127.7, 128.1, 128.4, 128.5, 129.4, 129.8,
130.4, 130.7, 140.8, 148.1, 154.7, 160.5; m/z (100, MHþ) 335; HRMS
(ES): MHþ, found 335.1545. C24H19Nþ2 requires 335.1548.
4.5.2. 2-(4-Chlorophenyl)-4-methylamino-3-(phenylethynyl)quino-
line (5b). Yield (0.09 g; 61%), mp 176e179 ꢀC (EtOH); Rf (30% ethyl
acetate/hexane) 0.46; nmax (neat) 1093, 1261, 1523, 1571, 2201,
3446 cmꢁ1
; dH (300 MHz, CDCl3) 3.57 (d, J 4.5 Hz, 3H), 5.71 (d, J
15. Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047e1062.
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189e193.
4.8 Hz, 1H), 7.33 (s, 5H), 7.42 (t, J 7.5 Hz, 1H), 7.45 (d, J 7.5 Hz, 2H),
7.64 (t, J 7.5 Hz, 1H), 7.91 (d, J 9.3 Hz, 2H), 8.01 (d, J 7.5 Hz, 1H), 8.11
(d, J 9.0 Hz, 1H); dC (75 MHz, CDCl3) 35.7, 85.8, 98.3, 99.6, 117.6,
122.7, 123.1, 124.6, 127.9, 128.3, 128.5, 129.9, 130.3, 130.7, 130.9,
134.5, 139.2, 148.0, 154.8, 159.0; m/z (100, MHþ) 369; HRMS (ES):
MHþ, found 369.1154. C24H18N235Clþ requires 369.1154.
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4.5.3. 2-(4-Methoxyphenyl)-4-methylamino-3-(phenylethynyl)quin-
oline (5c). Yield (0.08 g; 58%), mp 131e134 ꢀC (EtOH); Rf (30% ethyl
acetate/hexane) 0.20; nmax (neat) 1028, 1170, 1247, 1515, 1568, 2198,
3388 cmꢁ1
; dH (300 MHz, CDCl3) 3.55 (s, 3H), 3.87 (s, 3H), 5.73 (br s,
1H), 7.00 (d, J 8.7 Hz, 2H), 7.29e7.42 (m, 6H), 7.62 (dt, J 1.5 and
7.7 Hz, 1H), 7.95 (d, J 9.0 Hz, 2H), 8.02 (dd, J 0.6 and 8.6 Hz, 1H), 8.11
(dd, J 0.6 and 8.6 Hz, 1H); dC (75 MHz, CDCl3) 35.7, 55.4, 86.3, 98.5,
99.3, 113.1, 117.5, 122.8, 123.4, 124.3, 128.1, 128.4, 129.8, 130.0, 130.8,
130.9, 133.2, 148.0, 154.9, 159.7, 160.0; m/z (100, MHþ) 365; HRMS
(ES): MHþ, found 365.1644. C25H21N2Oþ requires 365.1654.
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29. CCDC779927 contains the cif file for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
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4.5.4. 2-(4-Chlorophenyl)-3-(3-hydroxybutyn-1-yl)-4-(methyl-
amino)quinoline (5d). Yield (0.03 g; 61%), mp 183e184 ꢀC (EtOH); Rf
(30% ethyl acetate/hexane) 0.67; nmax (neat) 829, 1013, 1085, 1310,
1413, 1522, 1568, 3145, 3289 cmꢁ1
; dH (300 MHz, CDCl3) 1.44 (d, J