Synthesis, photophysical properties and DFT study of novel polycarbo-substituted quinazolines derived from the 2-aryl-6-bromo-4-chloro-8-iodoquinazolines

Article abstract of DOI:10.1016/j.tet.2015.11.014

A series of novel 2-aryl-6-bromo-4-chloro-8-iodoquinazolines were prepared and subjected to sequential two-step (Sonogashira and subsequent one-pot bis-Suzuki) and one-pot three-step Sonogashira cross-coupling reactions to afford unsymmetrical polycarbo-substituted quinazolines. Selectivity in the cross-coupling for these multihalogenated quinazolines was found to depend on both the intrinsic reactivity of the Csp²-halogen bond, which relates to the bond dissociation energy or bond strength and the electronic position of the halogen atom on the electron deficient scaffold (trend: Csp²-I>C(4)-Cl>Csp²-Br). The electronic absorption and emission properties of the prepared polycarbo-substituted quinazolines were evaluated in solution by means of UV-vis and emission spectroscopy in conjunction with density functional theory (DFT) method.

Full text of DOI:10.1016/j.tet.2015.11.014

Tetrahedron xxx (2015) 1e11
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis, photophysical properties and DFT study of novel
polycarbo-substituted quinazolines derived from the
2-aryl-6-bromo-4-chloro-8-iodoquinazolines
a
a
,
b
b
*
Hugues K. Paumo , Malose J. Mphahlele , Lydia Rhyman , Ponnadurai Ramasami
a
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, PO Box 392, Pretoria 0003, South Africa
Computational Chemistry Group, Department of Chemistry, Faculty of Science, University of Mauritius, R ꢀe duit 80837, Mauritius
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 2-aryl-6-bromo-4-chloro-8-iodoquinazolines were prepared and subjected to se-
quential two-step (Sonogashira and subsequent one-pot bis-Suzuki) and one-pot three-step Sonogashira
cross-coupling reactions to afford unsymmetrical polycarbo-substituted quinazolines. Selectivity in the
cross-coupling for these multihalogenated quinazolines was found to depend on both the intrinsic re-
Received 29 September 2015
Received in revised form 28 October 2015
Accepted 9 November 2015
Available online xxx
2
activity of the Csp ehalogen bond, which relates to the bond dissociation energy or bond strength and
2
the electronic position of the halogen atom on the electron deficient scaffold (trend: Csp eI>C(4)e
Keywords:
2
Cl>Csp eBr). The electronic absorption and emission properties of the prepared polycarbo-substituted
2-Aryl-6-bromo-4-chloro-8-
quinazolines were evaluated in solution by means of UVevis and emission spectroscopy in conjunc-
tion with density functional theory (DFT) method.
iodoquinazolines
Cross-coupling reactions
Polycarbo-substituted quinazolines
Photophysical properties
DFT
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
quinazolines,10,11 we became interested in the synthesis of
polycarbo-substituted derivatives in which the electron-deficient
Polycarbosubstitued quinazolines are sought-after nitrogen-
based heterocycles due to their important biological activities such
as potent epidermal growth factor receptor (EGFR) tyrosine kinase
quinazoline framework is linked directly to the
ing aryl groups at the 2-, 4- and 6-positions and through a
jugated spacer (CeC triple bond) at the 8-position for studies of
photophysical properties. However, such unsymmetrical polycarbo-
substituted quinazolines would not be easily accessible via the use
p
-electron donat-
p
-con-
1
2
inhibition, liver X-receptor modulation and novel aurora A kinase
3
inhibition. Interest in these compounds is not only limited to the
10
synthesis or development of more diverse and complex bioactive
derivatives for structureeactivity relationship evaluations, but has
since been extended to focus on their photophysical properties as
of the known 2-aryl-4-chloro-6,8-dibromoquinazolines and the
analogous 6,8-dibromo-2,4-dichloroquinazoline,
13,14
which have
been found to undergo initial site-selective C(4)-Cl substitution and
subsequent cross-coupling at the 6- and 8-positions without se-
lectivity. It has recently been demonstrated for the first time that
4
e9
potential fluorescence probes.
Fluorescent carbo-substituted
quinazolines such as the medicinally important Lapatinib, for ex-
2
ample, functions as an environmentally responsive ‘turn-on’ fluo-
Csp eCsp bond formation in the case of the chloro-iodo substituted
rophore.8
Its
analogue,
(E)-6-(4-dimethylaminostyryl)-N-
quinazolines favours cross-coupling through the intrinsically more
2
11
phenylquinazolin-4-amine, acts as a turn-on fluorescence kinase
reactive Csp eI bond instead of the highly activated C(4)eCl bond.
9
2
inhibitor in MCF7 cells. An alkynyl substituent at the C-4 or C-6
The observed reactivity of the Csp eX bond for multihalogenated
position of the 2-substituted quinazolines has previously been
found to lead to enhanced EGFR or Aurora A kinase inhibition ac-
quinazolines is in contrast to the generic order of reactivity for other
polyhalogenated compounds, which allows selective coupling with
iodides or bromides in the presence of chlorides. We envisioned
that the bromo-iodo-substituted 4-chloroquinazolines could serve
as suitable substrates for sequential and/or one-pot multi-step
cross-coupling reactions to afford unsymmetrical polycarbo-
substituted quinazolines. Herein, we report the synthesis of the 2-
1
10,11
15
tivity and intramolecular charge transfer properties.
In view of
the biological12 and fluorescence properties of 4/6-alkynylated
*
Corresponding author. Tel.: þ27 12 429 8805; fax: þ27 12 429 8549; e-mail
address: mphahmj@unisa.ac.za (M.J. Mphahlele).
http://dx.doi.org/10.1016/j.tet.2015.11.014
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
aryl-6-bromo-4-chloro-8-iodoquinazolines and their trans-
formation via sequential and one-pot multi-step cross-coupling
reactions involving initial site-selective Sonogashira cross-
coupling to incorporate the alkynyl group at the 8-position. The
electronic absorption and emission properties of the resultant un-
symmetrical polycarbo-substituted 8-alkynylquinazoline de-
rivatives were evaluated in solution by means of Uv-vis and
emission spectroscopy in conjunction with density functional (DFT)
method.
of 2-amino-5-bromo-3-iodobenzamide as a precursor for cyclo-
condensation with benzaldehyde derivatives. Recourse to the lit-
erature revealed that 2-amino-5-bromobenzamide has been
16
prepared in high yield from anthranilamide before, however, it
has not been subjected to further halogenation to afford the cor-
17
responding mixed 3,5-dihalogenated 2-aminobenzamides. The
analogous 2-amino-6,8-dibromobenzamide, on the other hand, has
10
also been prepared in high yield from anthranilamide before. 2-
Aminobenzamide 1 was subjected to N-bromosuccimide in aceto-
nitrile at room temperature to afford 2-amino-5-bromobenzamide
2, which in turn, was reacted with N-iodosuccinimide in acetic
2
2
. Results and discussion
acid at rt to afford 2-amino-5-bromo-3-iodobenzamide
(Scheme 1).
3
.1. Synthesis of 2-aryl-6-bromo-4-chloro-8-iodoquinzolines
1
2 (93%)
3 (88%)
Reagents and conditions: (i) NBS, CH
3
CN, r.t., 0.5 h (2); (ii) NIS, AcOH, r.t., 1 h (3)
Scheme 1. Sequential halogenation of 2-aminobenzamide to afford 2 and 3.
The first task in this investigation was to prepare the 2-aryl-6-
We then exploited the combined electrophilic and oxidative
properties of iodine in ethanol under reflux to effect the direct one-
pot cyclocondensation of 3 with benzaldehyde derivatives and
subsequent dehydrogenation of the incipient 4(1H)-oxo in-
termediates to afford novel potentially tautomeric 2-aryl-6-bromo-
bromo-8-iodoquinazolin-4(3H)-ones required as substrates for
phosphorus oxychloride-promoted aromatization to afford the
requisite 2-aryl-6-bromo-4-chloro-8-iodoquinazolines. Access to
the dihalogenated quinazolin-4(3H)-ones, in turn, required the use
3
4a–d
Compound
R
4-H
%Yield of 4
4a
87
86
91
93
4b
4-F
4c
4-Cl
4-OMe
4d
6 4 2
Reagents and conditions: (i) 4-RC H CHO, I , ethanol, reflux, 7 h
Scheme 2. Iodine-promoted cyclocondensation-dehydrogenation of 3 with aryldehydes.
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H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
3
8
-iodoquinazolin-4(3H)-ones 4aed (Scheme 2). The resultant solid
mol)<Br (78.17 kcal/mol)<Cl (82.70 kcal/mol). Based on DFT cal-
culations and the observed experimental results, it is concluded
that reactivity and selectivity of cross-coupling through C-8 relate
products, which were purified by recrystallization without the need
for column chromatography were characterized through NMR ( H
and C) spectroscopy and their 4-oxo-N-(3H) nature was also con-
firmed by IR spectroscopy. Moreover, their accurate calculated m/z
values represent a closest fit consistent with the assigned structures.
Quinazolin-4(3H)-one framework readily undergoes aromati-
1
13
2
to the Csp eX bond strength, which in this case favours sub-
2
11
stitution of the weakest Csp eI bond in the presence of the highly
activated C(4)eCl bond.
1
8,19
Next we focused our attention on the reactivity of the dihalo-
zation with reagents such as SOCl
2
, POCl
3
, and PCl
5
in the presence
genated derivatives 6 in SuzukieMiyaura cross-coupling with
arylboronic acids as models for Csp eCsp bond formation.
2
2
or absence of an amine base to generate the 4-chloroquinazoline
moiety.1
1,13,18
In this investigation, we subjected compounds 4aed
to phosphoryl chlorideetriethylamine mixture under reflux for 7 h
2.2.2. SuzukieMiyaura cross-coupling of the 2-aryl-8-alkynyl-6-
and isolated by aqueous work-up and recrystallization the corre-
bromo-4-chloroquinzolines. Attempted
site-selective
Suzu-
sponding
aed (Scheme 3). These compounds are easily distinguished from
the corresponding precursors by the absence of the amide signals
novel
2-aryl-6-bromo-4-chloro-8-iodoquinazolines
kieMiyaura cross-coupling of 6a with either 4-fluorophenylboronic
acid or 4-methoxyphenylboronic acid (1.2 equiv) in the presence of
5
2 3 2
PdCl (PPh ) pre-catalyst as a source of active Pd(0) species and
1
13
in their NMR ( H and C) and IR spectra.
K
2
CO
3
in dioxane (aq) under reflux led to complete replacement of
4
a–d
%Yield of 5
5a–d
Compound
R
5
a
4-H
4-F
77
80
5
b
5
c
4-Cl
91
77
5d
4-OMe
Reagents and conditions: (i) POCl
3
3
, NEt , reflux, 6 h
Scheme 3. Phosphoryl chloride promoted aromatization of 4aed.
With the halogenated quinazolines 5aed in hand, we were
ready to investigate their reactivity in palladium catalysed cross-
coupling reactions.
the two halogen atoms after 2 h. We then resorted to the use of the
less reactive Pd(PPh as a source of active Pd(0) catalyst. We
3 4
)
isolated after 3 h by column chromatography on silica gel two
products in sequence in different ratio characterized using a com-
bination of spectroscopic techniques as the 8-arylated 7a (major)
and the symmetrical 6,8-diaryl substituted derivative 8a (minor),
respectively (Scheme 5). These reaction conditions were extended
to other substrates 6bed with arylboronic acids (1.2 equiv) to afford
the mono- 7beh (major) and diaryl-substituted derivatives 8beg
(minor). Traces of the 4-benzaldehyde derivative 8h were detected
by thin layer chromatography on silica gel in the reaction mixture,
but could not be isolated by careful column chromatography. De-
spite the formation of two cross-coupled products, the reactivity of
the C(4)eCl bond (BDE¼82.70 kcal/mol) under SuzukieMiyaura
2
.2. Reactivity of compounds 5aed in palladium catalysed
cross-coupling reactions
2
.2.1. Sonogashira cross-coupling of the 2-aryl-6-bromo-4-chloro-8-
iodoquinazolines. Compounds 5aed were subjected to the Sono-
gashira cross-coupling with phenylacetylene in the presence of
2 3 2 2 3
PdCl (PPh ) -CuI catalyst mixture and Cs CO as a base in THF at rt
for 18 h (Scheme 4). To our delight, we isolated in each case by
column chromatography on silica gel a single mono-alkynylated
1
13
product characterized using a combination of NMR ( H and C)
and IR spectroscopic techniques as well as mass spectrometry as
the 8-alkynylated 2-aryl-6-bromo-4-chloroquinazolines 6aeh. In
order to rationalize the observed selectivity, we explored the rel-
2
conditions was found to be superior to that of the weaker Csp eBr
bond (BDE¼78.17 kcal/mol). We rationalize the preponderance of
the 4-aryl substituted quinazoline to be due to a-nitrogen effect
2
18,19
ative Csp eX bond dissociation energies of these mixed multi-
based on the literature precedents.
halogenated quinazolines by DFT method [B3LYP/6-311G(d)] using
Encouraged by the successful differentiation in reactivity among
the three halogen atoms within these series of substrates (trend:
2
a as a model, which revealed the following trend: I (66.69 kcal/
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4
H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
5a–d
6a–h
Compound
R
4-H
R’
%Yield of 6
6a
-C
6
6
6
6
H
5
5
5
5
2
2
2
2
80
85
79
68
78
65
87
73
6b
4-F
-C
-C
-C
H
H
H
6c
4-Cl
4-OMe
4-H
6d
6e
-CH
2
2
2
2
CH
CH
CH
CH
OH
OH
OH
OH
6f
4-F
-CH
-CH
-CH
6g
4-Cl
4-OMe
6h
Reagents and conditions: (i) R'C≡CH, PdCl
2
(PPh )
3 2
, CuI, Cs
2
CO
3
, THF, r.t., 18 h.
Scheme 4. Site-selective Pd-catalysed Sonogashira cross-coupling of 5aed.
2
2
Csp eI>C(4)eCl>Csp eBr), an investigation to effect one-pot
SuzukieMiyaura cross-coupling of the 8-alkynylated derivatives
6
Although one-pot sequential metal-catalysed cross-coupling
reactions of multihalogenated aromatic and heteroaromatic com-
pounds is a well-established procedure in the literature, to our
knowledge, this strategy has only been applied recently on a single
set of dihalogenated substrates in the quinazoline series. This
prompted us to explore further the reactivity of 5aed in one-pot
three-step Sonogashira cross-coupling reaction with different ter-
minal acetylenes.
aed with different arylboronic acids was pursued. We envisioned
that the requisite mixed 4,6-diaryl-substituted quinazolines de-
rived from the incipient 7 could be separated by conventional
column chromatography from the preformed symmetrical 4,6-
diaryl-substituted products 8. With this assumption in mind, we
subjected compounds 6aed to 1 equiv of an arylboronic acid (4-
fluorophenylboronic or 4-methoxyphenylboronic acid) in aqueous
11
dioxane in the presence of Pd(PPh
3
)
4
catalyst source and K
2
CO
3
as
2.2.3. One-pot Sonogashira cross-coupling of the 2-aryl-6-bromo-4-
ꢀ
10
2
a base at 80 C for 2 h (thin layer chromatography monitoring)
followed by addition of the second arylboronic acid and further
heating at this temperature for additional 3 h (Scheme 6). We
isolated by column chromatography on silica gel the bis-Suzu-
kieMiyaura cross-coupled products 8aeh (minor) resulting from
the first step and the expected mixed 6,8-diaryl-substituted qui-
nazoline derivatives 9aeh. The sequence of elution of 8 and 9 from
the column was found to depend on the nature and polarity of the
substituent on the para position of the 4- and 6-aryl rings. In
general the 4,6-bis(4-methoxyphenyl)-substituted derivatives
eluted slower than derivatives bearing a combination of 4-
fluorophenyl and 4-methoxyphenyl groups at either the 4- or 6-
positions.
chloro-8-iodoquinzolines. Since both C(4)eCl bond and Csp eI
11
bond undergo Sonogashira cross-coupling at room temperature
2
with ease (trend: Csp eI>C(4)eCl), we envisaged the possibility to
effect one-pot three-step alkynylation of compounds 5aed with
different terminal acetylenes. We opted for the use of a single
catalyst mixture and varied the reaction time and temperature as
illustrated in Scheme 5. The first Sonogashira cross-coupling step
was conducted under similar experimental conditions to those
described in Scheme 1 using phenylacetylene as coupling partner
followed after 18 h by addition of the second acetylene derivative
(1.2 equiv) and further stirring at this temperature for additional
18 h to displace the chlorine atom. Then a solution of the third
terminal acetylene in THF was added and the mixture was heated at
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H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
5
6a–d
7a–h
8a–g
Compound
R
Ar
%Yield of 7
%Yield 8
a
b
c
4-H
4-Cl
4-FC
6
6
6
H
4
4
4
-
-
-
66
69
58
16
16
12
4-FC
4-FC
H
H
4-OMe
d
e
f
4-H
4-F
4-MeOC
4-MeOC
4-MeOC
4-MeOC
6
6
6
6
H
H
H
H
4
4
4
4
-
-
-
-
71
64
63
60
10
9
4-Cl
4-OMe
4-F
9
g
h
7
6 4
4-H(O)CC H -
5
1
-
2 3 4 2 3
Reagents and conditions: (i) ArB(OH) , Pd(PPh ) , K CO , dioxane (aq), 80 ºC, 2 h
Scheme 5. Site selective SuzukieMiyaura cross-coupling of 6aed.
ꢀ
6
0 C for 2 h. To our delight, we isolated by column chromatography
2.3. Photophysical property studies of compounds 8aeg,
9aeh and 10aee
on silica gel the corresponding novel unsymmetrical polycarbo-
substituted quinazolines 10aee, exclusively (Scheme 7). The ob-
served selectivity of cross-coupling of 5aed in conjunction with
prior studies on the di- and trihalogenated quinazolines reveal the
following general trend in reactivity of the Csp ehalogen bonds for
multi-halogenated quinazolines: Csp eI>C(4)eCl>Csp eBr>C(2)e
2.3.1. Electronic absorption and emission properties. The UVevis
spectra of compounds 8aeg and 9aeh in chloroform (CHCl ) reveal
the presence of two broad absorption bands of different intensity
and wavelength in the ultraviolet region 289e313 nm and
378e395 nm attributed to the * transition and the intra-
3
2
2
2
l
l
2
Cl>Csp eCl. The 2-position of the pyrimidine ring is generally
pep
known to be less reactive to oxidative addition of Pd than the 4-
position, but to be more reactive than the other chlorinated posi-
tions on the fused benzo ring.
The molecular backbone of the polycarbo-substituted hetero-
cycles 8e10 comprises an electron-deficient quinazoline frame-
work linked to the electron donating aryl rings directly or through
molecular donor-acceptor charge transfer absorption, respectively
(Fig. 1a and b). Within each series, the intensity and wavelength of
the absorption bands are influenced by the variation of substituents
on the para position of the aryl groups. The red shift of the wave-
length corresponding to the longest absorption band for com-
pounds 8g and 9g, for example, indicates that the presence of the
strong electron donating 4-methoxyphenyl groups at positions 2
and 6 enhances the charge transfer character. The UVevis spectra of
compounds 10aee in chloroform, on the other hand, reveal the
presence of three absorption bands of different intensity (Fig. 1c).
13
p-conjugated spacer to comprise donor-p-acceptor systems with
potential intramolecular charge transfer properties. As a prelude to
compounds with potential photoelectronic properties, we evalu-
ated the electronic absorption and emission properties of com-
pounds 8aeg, 9aeh and 10aee in solution by means of UVevis and
fluorescence spectrometry in conjunction with density functional
theory (DFT) method.
The first two bands in the ultraviolet region
303e332 nm are due to * transition of the conjugated qui-
nazoline ring while the less intense broad bands in the visible
l 270e278 and l
p
/p
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6
H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
Scheme 6. Sequential one-pot bis-SuzukieMiyaura cross-coupling of 6aed with arylboronic acids.
region
l
401e413 nm are due to the intramolecular donor-acceptor
fluorophenyl- and strongly donating 4-methoxyphenyl sub-
stituents at the 4- and 6-positions exhibit similar pattern to that
observed for compounds 8aeg. A 4-methoxyphenyl group at the 6-
charge transfer absorption. The bathochromic shift of the absorp-
tion bands observed for compounds 10aee as compared to 8aeg
and 9aeh is due to extended
p-conjugation of the donor-acceptor
position enhances p/p* transition more so than when at the 4-
systems. Both the absorption bands and the wavelength of these
compounds are influenced by the variation of substituents on the
heterocyclic framework. The fluorescence excitation spectra of
compounds 8aeg, 9aeh and 10aee in chloroform at room tem-
perature, on the other hand, are characterised by several bands
located at the wavelength closest to those of their optimal ab-
position of the heterocycle. The trend in emission intensity for
compounds 10aee reflects the resonance donating effect of the
substituent on the 2-aryl ring (H<Cl<F<OMe) and the emission
bands of the 2-(4-methoxyphenyl)-substituted derivatives 10d and
10e are slightly red shifted than the other three compounds
(Fig. 1c). The
state and a change in polarity of the solvent has been previously
found to cause measurable displacements of the * transition
for polycarbo-substituted quinazolines towards the red
p,p* state is much more polarizable than the ground
sorption spectra. Their emission spectra in CHCl
wavelength,
ex¼320 nm (Fig. 1aec), are characterised by single
emission bands in the green region,
em¼450e475 nm, due to
* transition resulting from direct -electron delocalization by
3
at the excitation
l
p/p
l
10,11,20,21
p/p
p
bands.
Based on this literature precedent we decided to
the aryl groups and through the conjugate bridge towards the
electron-deficient quinazoline ring. The intensity of the emission
bands, Stokes shifts, and the fluorescence quantum yields of these
compounds are influenced by the variation of aryl substituents on
the heterocyclic scaffold (Table 1). Compounds 9aeh bearing
evaluate the emission behaviour of compound 9g (solid lines) and
10e (broken lines) as representative models in solvents of different
polarity (toluene and DMF) and their emission spectra are depicted
in Fig. 1d.
The fluorescence emission spectra of compounds 9g and 10e are
slightly red-shifted upon increasing the polarity of the solvent
a
combination of the moderately resonance-donating 4-
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H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
7
Scheme 7. One-pot sequential three-step Sonogashira cross-coupling of 5aed.
(
toluene to DMF), which indicates an increase in dipole moment of
HOMOeLUMO gap for all the compounds at the B3LYP/6-31G(d,p)
level is the range 5e6 eV. However, compounds 10 demonstrated
the lowest band gaps 5.38e5.47 eV due to increased conjugative
excited state compared to ground state. The solvent polarity de-
pendent electronic transitions may result from dipolar interaction
with DMF thus suggesting the intramolecular charge transfer (ICT)
of the emission state in which the HOMOs and LUMOs are pre-
sumably localized on the quinazoline-based moiety and the aryl
rings. To further establish the structural features and molecular
orbitals of compounds 8e10, we carried out a theoretical approach
using DFT method at the B3LYP/6-31G* level to determine the
HOMO and LUMO orbital energies of compounds 8aeg, 9aeh and
effect by the
p-spacer between the electron-deficient quinazoline
framework and the surrounding substituents. Based on the orbital
diagrams, the electronic transitions of all compounds can be at-
tributed to ICT from the aryl substituents to the electron-deficient
quinazoline framework.
The UVevis spectra of compounds 8aeg, 9aeh and 10aee in
chloroform were simulated and these are in agreement with those
obtained experimentally (see Fig. 1). The simulated spectra of 8aeg
are depicted in Fig. 3 (see Supplementary data for simulated spectra
of compounds 9aeh and 10aee). The UV spectrum of 8a was
chosen as a representative model to assign the absorption bands in
the electronic spectra. The lowest energy band at 346.8 nm has an
oscillator strength of about 0.6 and the HOMO/LUMO transition
(91.7%) dominates the electron transition between the frontier or-
bitals for this band. The band at 277.5 nm with the highest oscillator
strength of ca. 1.6, on the other hand, is assigned to HOMO-
1/LUMO (36.5%), HOMO-1/LUMOþ1 (2.8%), HOMO/LUMOþ1
(45.2%) and HOMO/LUMOþ2 (5.5%). The third band at 254.5 nm is
mainly characterized with transitions of HOMO-6/LUMOþ1
(11.2%), HOMO-2/LUMO (25.2%) and HOMO/LUMOþ2 (26.5%).
In conclusion, successful differentiation of the relative reactivity
1
0aee.
2
.3.2. Density functional theory data. The geometries were opti-
2
2
mized in the gas phase using CAM-B3LYP/6-31G(d,p) as imple-
2
3
mented in Gaussian 09 suite to obtain reasonable structures for
the subsequent electronic structure computations. The compounds
were also fully optimized using the same functional and basis set in
CHCl
PCM) as developed by Tomasi et al. The HOMO and LUMO sur-
faces of selected examples (8a, 9a and 10e) in CHCl are illustrated
3
as the solvent based on the Polarizable Continuum Model
2
4
(
3
Fig. 2 (see Supplementary data for other compounds). In general
there are no significant changes observed on the electron density
distributions and the HOMO is delocalized over the entire molecule
but with less contribution from the substituent at the 4-position
whereas the LUMO shrinks toward the quinazoline core and
2
2
2
of the three Csp ehalogen bonds (Csp eI>C(4)eCl>Csp eBr) of the
these represent
p
and
p* orbitals, respectively. The calculated
2-aryl-4-chloro-6-bromo-8-iodoquinazolines facilitated sequential
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8
H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
.2
1
9
9
9
9d
9
9f
9g
9h
a
b
c
1
1
0
0
0
0
0
.2
.0
.8
.6
.4
.2
.0
8
8
8
8d
8
a
b
c
1.0
0
0
0
0
.8
.6
.4
.2
e
e
8f
8
g
0.0
2
50
300
350
400
450
500
550
600
650
300
350
400
450
500
550
600
Wavelength (nm)
Wavelength (nm)
(a)
(b)
1
.0
10a
1
1
1
1
0b
0c
0d
0e
0
0
0
0
0
0
0
0
0
0
.9
.8
.7
.6
.5
.4
.3
.2
.1
.0
9
g in toluene
1
.0
9g in DMF
1
1
0e in toluene
0e in DMF
0.8
0.6
0
0
0
.4
.2
.0
4
00
450
500
550
600
2
50
300
350
400
450
500
550
600
(d)
Wavelength (nm)
Wavelength (nm)
(c)
Fig. 1. Absorption and normalized emission spectra of 8aeg (a), 9aeh (b) and 10aee (c) in CHCl
toluene and DMF (d).
3
(rt) at 1.3ꢁ10ꢂ5 mol/L as well as normalized emission spectra of 9g and 10e in
double cross-coupling (Sonogashira and subsequent single-pot
double SuzukieMiyaura) and single-pot three-step Sonogashira
cross-coupling reactions to afford novel unsymmetrical polycarbo-
substituted quinazolines. The observed results in conjunction with
preceding literature data on the chloroechloro and chloroebromo
substituted quinazolines reveal the following general trend in re-
Table 1
The absorption and emission data for compounds 8aeg, 9aeh & 10aee
3
ꢂ1
ꢂ1
)
aQuantum Stokes
Compound
l
abs, nm (εꢁ10 , mol cm
l
em
(nm) yields (
F
)
shifts
8
8
8
8
8
8
8
9
9
9
9
9
9
9
9
1
1
1
1
1
a
b
c
d
e
f
g
a
b
c
d
e
f
g
h
0a
0b
0c
0d
0e
289 (83.48); 382 (13.32)
298 (46.41); 382 (8.84)
312 (58.29); 387 (13.27)
295 (65.01); 384 (16.11)
293 (91.39); 389 (20.02)
300 (58.14); 388 (13.93)
306 (47.85); 395 (8.94)
296 (98.41); 378 (23.62)
298 (45.00); 382 (12.10)
300 (45.92); 383 (10.85)
313 (85.88); 389 (23.55)
292 (81.20); 384 (19.23)
299 (47.84); 384 (11.61)
310 (66.36); 393 (15.42)
312 (66.25); 380 (19.93)
450
448
457
458
457
456
460
453
455
461
459
459
459
458
456
0.038
0.083
0.179
0.195
0.181
0.255
0.365
0.054
0.089
0.119
0.146
0.167
0.266
0.258
0.110
0.115
0.152
0.148
0.233
0.208
3955
3856
3957
4207
3825
3843
3577
4380
4200
4417
3920
4255
4255
3611
4386
3524
3432
3570
3085
3160
2
activity of the Csp ehalogen bonds for multi-halogenated quina-
2
2
2
zolines: Csp eI>C(4)-Cl>Csp eBr>C(2)eCl>Csp eCl. In contrast,
the 4-chloroquinazoline framework has been found to be more
preferred in cross-coupling reactions over the bromo- and iodo-
substituted bonds. The example relates to the Sonogashira cross-
coupling of 4-bromo- and 4-iodo-2-trichloromethylquinazolines
with cyclopropylacetylene and phenylacetylene, which afforded
the corresponding 4-alkynyl-2-trichloromethylquinazolines in 15%
25
and 9%, respectively. We conclude that selectivity in metal-
mediated cross-coupling for multihalogenated quinazolines de-
2
pends on both the intrinsic reactivity of the Csp ehalogen bond,
which relates to its bond strength and the electronic position of the
270 (65.93); 303 (70.87); 401 (18.35) 467
271 (63.51); 304 (67.93); 401 (17.36) 465
272 (59.91); 307 (67.47); 401 (17.26) 468
278 (64.16); 325 (49.68); 412 (13.06) 472
275 (47.14); 332 (62.87); 413 (15.63) 475
halogen atom on the electron deficient heterocycle. In our view,
2
knowledge of the trend in reactivity of the Csp eX bonds for
multihalogenated quinazolines will facilitate elaboration of the
heterocyclic framework with various substituents to lead to novel
polysubstituted quinazolines with interesting biological and/or
photophysical properties. Preliminary results on the photophysical
property studies of compounds 8aeg, 9aeh and 10aee reveal that
a
3
The relative quantum yields in CHCl were calculated according to the equation
indicated under Experimental section using quinine sulfate as the standard
st¼0.55) in 0.50 M H SO
(F
2
4
.
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H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
9
Fig. 2. Orbital topology of 8a, 9a and 10e in CHCl
3
[CAM-B3LYP/6-31G(d,p), isovalue¼0.02 and density¼0.0004] as representative compounds.
intensity of the absorption and emission bands, Stokes shifts and
the fluorescence quantum yields are influenced by the variation of
substituents on the para position of the 2-, 4- and 6-aryl groups and
this donor-p-acceptor system, which makes the polycarbo-
substituted quinazolines prepared in this investigation suitable
candidates for further studies using cyclic voltammetry to probe
oxidation and reduction potentials and the stability of the oxidized
and reduced forms.
the presence of the
p-conjugated spacer. Due to its electron de-
ficiency, the quinazoline moiety may provide a site for reduction in
3
3
. Experimental
1
00000
90000
80000
70000
60000
50000
40000
30000
20000
10000
0
.1. General
Melting points were recorded on a Thermocouple digital melt-
8
8
8
8
8
a
b
c
d
e
ing point apparatus and are uncorrected. IR spectra were recorded
as powders using a Bruker VERTEX 70 FT-IR Spectrometer with
a diamond ATR (attenuated total reflectance) accessory by using the
thin-film method. For column chromatography, Merck kieselgel 60
(0.063e0.200 mm) was used as stationary phase. NMR spectra
were obtained as CDCl or DMSO-d solutions using Varian Mer-
3
6
cury 300 MHz and Agilent 500 MHz NMR spectrometers, and the
chemical shifts are quoted relative to the TMS peak. Low- and high-
resolution mass spectra were recorded at an ionization potential of
70eV using Micromass Autospec-TOF (double focussing high
1
50
200
250
300
350
400
450
500
λ (nm)
Fig. 3. Simulated electronic spectra of compounds 8aeg.
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1
0
H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
ꢂ1
H 3
; d (500 MHz, CDCl ) 7.51e7.53 (m, 3H), 8.31 (d,
resolution) instrument. The UVevis spectra were recorded on
a Cecil CE 9500 (9000 Series) UVevis spectrometer while emission
spectra were taken using a Perkin Elmer LS45 fluorescence spec-
trometer. The quantum efficiencies of fluorescence (
tained with the following equation:
1582 cm
J¼2.0 Hz,1H), 8.49 (d, J¼2.0 Hz,1H), 8.59 (dd, J¼2.0 and 8.0 Hz, 2H);
d
C
(125 MHz, CDCl
3
) 103.5, 122.1, 123.1, 128.4, 128.7, 129.0, 131.8,
þ
F
fl) were ob-
135.6, 147.3, 149.8, 160.7, 161.6; m/z 445 (100, MH ); HRMS (ES):
MH , found 444.8602. C14H Br ClIN requires 444,8604.
8
þ
79 35
þ
2
ꢀ
.
ꢁ
2
2
F
x
¼
F
st ꢁ ðF
x
=FstÞ ꢁ ðAst=A
x
Þ ꢁ nx
n
(1)
3.5. Typical procedure for the site-selective Sonogashira
cross-coupling of 6aed
st
F denotes the area under the fluorescence band (F¼aIfl(
l), where
Ifl(
l
) is the fluorescence intensity at each emission wavelength), A
3.5.1. 6-Bromo-4-chloro-2-phenyl-8-(phenylethynyl)quinazoline
denotes the absorbance at the excitation wavelength, and n is the
refractive index of the solvent.
(6a). A stirred mixture of 5a (0.30 g, 0.67 mmol), PdCl (PPh )
(0.047 g, 0.06 mmol), CuI (0.006 g, 0.03 mmol) and Cs CO (0.32 g,
2 3
2
3 2
2
6
1.00 mmol) in THF (10 mL) was purged with argon gas for 30 min.
3
.2. Synthesis of 2-amino-5-bromo-3-iodobenzamide (3)
Phenyl acetylene (0.075 g, 0.74 mmol) was added to the mixture
using a syringe. The reaction mixture was stirred at room tem-
perature for 24 h and then quenched with ice-cold water. The
product was extracted into chloroform and the combined organic
layers were washed with water, dried over Na SO , filtered and
A stirred solution of 2-aminobenzamide (1.00 g, 7.34 mmol) in
acetonitrile (20 mL) at room temperature was treated with N-
bromosuccinimide (1.36 g, 7.70 mmol). The mixture was stirred at
room temperature for 0.5 h and then quenched with an ice-cold
water. The resulting precipitate was filtered and the residue was
recrystallized from acetonitrile to afford a pale yellow solid 2-
amino-5-bromobenzamide (2) (1.47 g, 93%), mp 186e187
2
4
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel to afford 6a as a yellow solid
ꢀ
(0.21 g, 80%), R (2:1 hexane/toluene) 0.57, mp 166e168 C;
f
n
max
ꢀ
C
(ATR) 503, 528, 561, 613, 681, 708, 751, 839, 860, 1332, 1413, 1458,
ꢀ
27
ꢂ1
(
185e187 C ). Compound 2 was dissolved in acetic acid (20 mL)
1551, 2213, 3058 cm
H 3
; d (500 MHz, CDCl ) 7.43e7.46 (m, 3H),
followed by addition of N-iodosuccimide at room temperature. The
mixture was stirred at room temperature for 1 h and then
quenched with an ice-cold aqueous sodium thiosulfate solution.
7.53e7.55 (m, 3H), 7.69e7.72 (m, 2H), 8.18 (d, J¼2.0 Hz, 1H), 8.33 (d,
J¼2.0 Hz, 1H), 8.65e8.67 (m, 2H);
d
C
(125 MHz, CDCl ) 84.5, 98.4,
3
121.1, 122.7, 123.4, 125.5, 127.8, 128.5, 128.7, 129.0, 129.1, 131.6, 132.0,
þ
The precipitate was filtered and recrystallized to afford 3 as a white
136.2, 140.9, 150.7, 160.3, 161.6 m/z 419 (100, MH ); HRMS (ES):
ꢀ
þ
79 35
þ
2
solid (2.05 g, 88%), mp 238e240 C;
n
max (ATR) 416, 540, 648, 804,
13
MH , found 418.9944. C22H Br ClN requires 418.9951.
8
3
72, 1239, 1386, 1413, 1535, 1566, 1600, 1640, 3181, 3326,
ꢂ1
368 cm
;
d
H
(500 MHz, CDCl
3
) 6.69 (br s, 2H), 7.41 (br s, 1H), 7.76
(125 MHz,
); 87.6, 106.3, 116.5, 131.7, 143.2, 148.7, 169.7; m/z 341 (100,
3.6. Typical procedure for the Suzuki cross-coupling of 6aed
(
d, J¼2.0 Hz, 1H), 7.85 (d, J¼2.0 Hz, 1H), 8.02 (br s, 1H);
d
C
CDCl
3
3.6.1. 6-Bromo-4-(4-fluorophenyl)-2-phenyl-8-(phenylethynyl)qui-
nazoline (7a) and 4,6-bis(4-fluorophenyl)-2-phenyl-8-(phenyl-
ethynyl)quinazoline (8a). A stirred mixture of 6a (0.20 g,
þ
þ
79
þ
MH ); HRMS (ES): MH , found 340.8786. C
7
H
7
BrIN
2
O requires
3
40.8786.
3 4 2 3
0.48 mmol), Pd(PPh ) (0.027 g, 0.024 mmol) and K CO (0.099 g,
3
.3. Typical procedure for the synthesis of the 2-aryl-6-
0.72 mmol) in 3:1 dioxane-water (v/v, 10 mL) was purged with
argon gas for 30 min. 4-Fluorophenylboronic acid (0.067 g,
bromo-8-iodoquinazolin-4(3H)-ones 4aed
0
.48 mmol) was added to the mixture using a syringe. The reaction
ꢀ
3
.3.1. 6-Bromo-8-iodo-2-phenylquinazolin-4(3H)-one (4a). A stir-
red mixture of 2 (1.00 g, 2.94 mmol), benzaldehyde (0.37 g,
.52 mmol) and iodine (1.49 g, 5.88 mmol) in ethanol (100 mL) was
mixture was heated at 100 C for 2 h and then quenched with an
ice-cold water. The product was extracted into chloroform and the
combined organic layers were washed with water, dried over
3
refluxed for 7 h and then allowed to cool to room temperature. The
2 4
Na SO , filtered and evaporated under reduced pressure. The resi-
mixture was quenched with an ice-cold aqueous sodium thiosul-
due was purified by column chromatography on silica gel to afford
7a and 8a in sequence.
fate solution and the precipitate was filtered and recrystallized to
ꢀ
afford 4a as a white solid (1.10 g, 87%), mp>345 C;
n
max (ATR) 527,
7a: Yellow solid (0.15 g, 66%), R
f
(2:1 hexane/toluene) 0.34, mp
ꢀ
5
52, 636, 688, 698, 848, 946, 1129, 1291, 1384, 1446, 1470, 1563,
191e193 C;
n
max (ATR) 524, 562, 689, 755, 847, 1158, 1225, 1252,
ꢂ1
ꢂ1
1
(
1
1
598, 1658, 3073, 3164 cm
m, 3H), 8.20 (d, J¼2.0 Hz, 1H), 8.25e8.29 (m, 2H), 8.49 (d, J¼2.0 Hz,
H), 12.86 (s, 1H); (125 MHz, DMSO-d ) 103.5, 119.7, 122.9, 128.5,
28.9, 129.2, 132.4, 132.7, 145.9, 148.1, 153.7, 161.7; m/z 427 (100,
;
d
H
(500 MHz, DMSO-d
6
) 7.56e7.62
1372, 1418, 1509, 1536, 1601, 2213, 2922, 3069 cm
CDCl
7.74e7.76 (m, 2H), 7.88 (t, J¼9.0 Hz, 2H), 8.17 (d, J¼2.0 Hz, 1H), 8.19
(d, J¼2.0 Hz, 1H), 8.77e8.80 (m 2H); (125 MHz, CDCl ) 85.1, 97.9,
116.0 (d, JCF¼21.9 Hz), 119.9, 122.5, 123.0, 125.7, 128.5, 128.6, 128.8,
H
; d (500 MHz,
3
) 7.33 (t, J¼9.0 Hz, 2H), 7.44e7.48 (m, 3H), 7.53e7.57 (m, 3H),
d
C
6
d
C
3
þ
þ
79
þ
2
MH ); HRMS (ES): MH , found 426.8937. C14H BrIN O requires
9 2
3
4
26.8943.
128.9, 130.0, 131.1, 132.0, 132.2 (d,
J
CF¼8.6 Hz), 133.1 (d,
4
1
J
CF¼2.9 Hz), 137.6, 139.9, 151.0, 160.4, 164.2 (d,
J
CF¼250.3 Hz),
þ
þ
3
.4. Typical procedure for the synthesis of the 2-aryl-6-
166.7; m/z 479 (100, MH ); HRMS (ES): MH , found 479.0557.
7
9
þ
bromo-4-chloro-8-iodoquinazolines 5aed
C
28
H
17 BrFN requires 479.0559.
2
8
a: Yellow solid (0.04 g, 16%), R
f
(2:1 hexane/toluene) 0.32, mp
ꢀ
3.4.1. 6-Bromo-4-chloro-8-iodo-2-phenylquinazoline (5a). A stirred
196e198 C;
848, 1157, 1226, 1491, 1510, 1602, 2927, 3059 cm
CDCl
n
max (ATR) 518, 556, 567, 693, 716, 754, 783, 802, 834,
ꢂ1
mixture of 4 (2.35 mmol) and phosphoryl chloride (6 equiv) was
treated dropwise with triethylamine (1.5 equiv) at room tempera-
ture. The mixture was heated under reflux for 6 h and then allowed
to cool to room temperature. An ice-cold water was added to the
mixture and the aqueous layer was extracted with chloroform. The
combined organic layers were washed with water and then dried
H
; d (500 MHz,
3
) 7.17 (t, J¼8.5 Hz, 2H), 7.31 (t, J¼8.5 Hz, 2H), 7.43e7.45 (m,
3H), 7.51e7.54 (m, 3H), 7.60 (dd, J¼5.0 and 8.0 Hz, 2H), 7.75 (dd,
J¼2.0 and 8.0 Hz, 2H), 7.93 (dd, J¼5.5 and 8.0 Hz, 2H), 8.13 (d,
J¼2.0 Hz, 1H), 8.31 (d, J¼2.0 Hz, 1H), 8.80 (m, 2H);
C
d (125 MHz,
2
CF¼21.6 Hz), 116.1 (d, 2JCF¼21.7 Hz),
3
CDCl ) 86.3, 96.6, 115.9 (d, J
3
over anhydrous MgSO
pressure to afford 5a as a white solid (0.80 g, 77%), mp 194e195 C;
4
, filtered and evaporated under reduced
21.8, 123.3, 124.1, 128.5, 128.6, 128.7, 128.8, 128.9 (d,
129.0, 130.9, 131.9, 132.2 (d, J
135.4 (d,
J
CF¼8.2 Hz),
ꢀ
3
CF¼8.5 Hz), 133.6 (d, 4JCF¼3.1 Hz),
4
n
max (ATR) 534, 685, 704, 863, 1022, 1212, 1297, 1330, 1455, 1551,
J
CF¼3.1 Hz), 136.5, 137.8, 138.4, 151.3, 160.1, 162.9 (d,
Please cite this article in press as: Paumo, H. K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.11.014

H.K. Paumo et al. / Tetrahedron xxx (2015) 1e11
11
1JCF¼247.1 Hz), 164.0 (d, JCF¼249.4 Hz), 167.6; m/z 495 (100, MH );
1
þ
86.5, 90.1, 97.3, 97.5, 119.8, 122.8, 123.3, 123.9, 124.0, 128.7, 128.9,
129.1,129.2,129.4,130.2,131.4, 132.2,134.1,136.8,137.5,140.7,150.6,
þ
þ
HRMS (ES): MH , found 495.1685. C34
H F
21 2
N
2
requires 495.1673.
þ
þ
1
52.5, 161.4; m/z 509 (100, MH ); HRMS (ES): MH , found
3
5
þ
2
3
.7. Typical procedure for the one-pot sequential Suzu-
509.1426. C34H22ClN O requires 509.1421.
kieMiyaura cross-coupling of 6aed
Acknowledgements
3
.7.1. 4,6-Bis(4-methoxyphenyl)-2-phenyl-8-(phenylethynyl)quina-
zoline (8d) and 6-(4-fluorophenyl)-4-(4-methoxyphenyl)-2-phenyl-
The authors are grateful to the University of South Africa and the
National Research Foundation in South Africa for financial assis-
tance. The computational work used the Extreme Science and En-
gineering Discovery Environment (XSEDE), which is supported by
National Science Foundation grant number OCI-1053575. L.R. and
P.R. acknowledge the facilities from the University of Mauritius.
8
0
2
-(phenylethynyl)quinazoline (9a). A stirred mixture of 6a (0.30 g,
.72 mmol), Pd(PPh (0.041 g, 0.036 mmol) and K CO (0.30 g,
.16 mmol) in 3:1 dioxane-water (v/v, 15 mL) was purged with
3
)
4
2
3
argon gas for 30 min 4-methoxyphenylboronic acid (0.11 g,
0
.72 mmol) was added to the mixture using a syringe. The reaction
ꢀ
mixture was heated at 100 C for 2 h and then a solution of (4-
fluorophenyl)boronic acid (0.12 g, 0.86 mmol) in dioxane (5 mL)
was added via a syringe and heating was continued for additional
Supplementary data
4
h. The mixture was allowed to cool to room temperature and the
quenched with an ice-cold water. The product was extracted into
chloroform and the combined organic layers were washed with
Supplementary data (Experimental procedures for the syn-
thesis of all the new compounds (S1) and the frontier molecular
orbitals of compounds 8aeh, 9aeh and 10aee (S2) as well as
calculated results for the absorption of compounds 8a (S3)) as-
sociated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2015.11.014.
2 4
water, dried over Na SO , filtered and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel to afford 8d (0.03 g, 08%), R
f
(toluene) 0.25, mp
(1:1 hexane/
ꢀ
2
23e224 C and 9a as yellow solid (0.25 g, 68%), R
f
ꢀ
toluene) 054, mp 220e222 C;
nmax (ATR) 512, 557, 691, 758, 782,
ꢂ1
8
18, 833, 1174, 1223, 1253, 1396, 1461, 1534, 1601, 2912, 3052 cm
(500 MHz, CDCl
;
References and notes
d
H
3
) 3.94 (s, 3H), 7.14 (d, J¼8.5 Hz, 2H), 7.18 (t,
J¼8.5 Hz, 2H), 7.43e7.45 (m, 3H), 7.53e7.55 (m, 3H), 7.63 (dd, J¼5.0
and 8.5 Hz, 2H), 7.77 (dd, J¼1.5 and 8.0 Hz, 2H), 7.93 (d, J¼9.0 Hz,
1. Kitano, Y.; Suzuki, T.; Kawahara, E.; Yamazaki, T. Bioorg. Med. Chem. Lett. 2007,
17, 5863e5867.
2. Bernotas, R. C.; Ullrich, J. W.; Travins, J. M.; Wrobel, J. E.; Unwalla, R. J.
2
H), 8.24 (d, J¼3.0 Hz, 1H), 8.32 (d, J¼2.5 Hz, 1H), 8.83 (d, J¼8.5 Hz,
WO2009020683 A2, 12 February 2009.
2
H);
d
C
3
(125 MHz, CDCl ) 55.5, 86.5, 96.3, 114.1, 116.0 (d,
3. Sardon, T.; Cottin, T.; Xu, J.; Giannis, A.; Vernos, I. ChemBioChem 2009, 10,
464e478.
2
J
CF¼20.8 Hz), 121.9, 123.4, 123.9, 124.6, 128.2, 128.4, 128.5, 128.6,
3
4. Kappaun, S.; Sovic, T.; Stelzer, F.; Pogantsch, A.; Zojer, E.; Slugovc, C. Org. Biomol.
Chem. 2006, 4, 1503e1511.
1
J
28.8, 128.9, (d,
J
CF¼8.5 Hz), 129.0, 130.7, 131.9, 135.6 (d,
4
CF¼2.8 Hz), 136.2, 138.0, 138.1, 151.4, 160.1, 161.4, 162.8 (d,
5
. Achelle, S.; Rodríguez-L oꢀ pez, J.; Guen, F. R.-L. J. Org. Chem. 2014, 79, 7564e7571.
6. Kulkarni, A. P.; Tonzola, C. J.; Babel, A.; Jenekhe, S. A. Chem. Mater. 2004, 16,
556e4573.
. Liu, D.; Zhang, Z.; Zhang, H.; Wang, Y. Chem. Commun. 2013, 49, 10001e10003.
1JCF¼246.5 Hz), 168.2; m/z 507 (100, MH ); HRMS (ES): MH , found
þ
þ
þ
4
5
07.1864. C35
H24FN
2
O requires 507.1873.
7
8
. Wilson, J. N.; Liu, W.; Brown, A. S.; Landgraf, R. Org. Biomol. Chem. 2015, 13,
5006e5011.
. Dhuguru, J.; Liu, W.; Gonzalez, W. G.; Babinchak, W. M.; Miksovska, J.; Landgraf,
R.; Wilson, J. N. J. Org. Chem. 2014, 79, 4940e4947.
3
.8. Typical procedure for the one-pot three-step Sonogashira
9
cross-coupling of 5aed
1
0. Mphahlele, M. J.; Paumo, K. H.; El-Nahas, A. M.; El-Hendawy, M. M. Molecules
2014, 19, 795e818.
3.8.1. 4-(4-(4-Chlorophenylethynyl)-2-phenyl-8-(phenylethynyl)qui-
nazolin-6-yl)but-3-yn-1-ol (10a). A stirred mixture of 5a (0.30 g,
11. Paumo, K. H.; Mphahlele, M. J.; Rhyman, L.; Ramasami, P. Molecules 2015, 20,
1
4656e14683.
2. Mphahlele, M. J.; Maluleka, M. M. Molecules 2014, 19, 17435e17463.
3. Kabri, Y.; Crozet, D.; Redon, S.; Vanelle, P. Synthesis 2014, 46, 1613e1620.
14. Kabri, Y.; Crozet, M. D.; Terme, T.; Vanelle, P. Eur. J. Org. Chem. 2015, 17,
806e3817.
5. Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047e1062.
6. Rudolph, J.; Esler, W. P.; O’Connor, S.; Coish, P. D. G.; Wickens, P. L.; Brands, M.;
0
.67 mmol), PdCl
2
(PPh
3
)
2
(0.077 g, 0.067 mmol), CuI (0.006 g;
1
1
0
.033 mmol) and Cs
2
CO
3
(0.87 g, 2.68 mmol) in THF (15 mL) was
purged with argon gas for 30 min. Phenyl acetylene (0.068 g,
.67 mmol) was added to the mixture using a syringe. The reaction
3
0
1
1
mixture was stirred at room temperature for 18 h and then a solu-
tion of 4-chlorophenyl acetylene (0.091 g, 0.67 mmol) in THF (5 mL)
was added via a syringe. The mixture was stirred at room tem-
perature for additional 18 h and a solution of 3-butyn-1-ol (0.056 g,
Bierer, D. E.; Bloomquist, B. T.; Bondar, G.; Chen, L.; Chuang, C. Y.; Claus, T. H.;
Fathi, Z.; Fu, W.; Khire, U. R.; Kristie, J. A.; Liu, X. G.; Lowe, D. B.; McClure, A. C.;
Michels, M.; Ortiz, A. A.; Ramsden, P. D.; Schoenleber, R. W.; Shelekhin, T. E.;
Vakalopoulos, A.; Tang, W.; Wang, L.; Yi, L.; Gardell, S. J.; Livingston, J. N.; Sweet,
L. J.; Bullock, W. H. J. Med. Chem. 2007, 50, 5202e5216.
0
.80 mmol) in THF (5 mL) was added via a syringe under nitrogen
17. Waghmare, A. A.; Bose, P.; Pati, H. N. Der Pharma Chem. 2010, 2, 212e241.
atmosphere. The mixture was heated under reflux for 3 h and then
allowed to cool to room temperature. An ice-cold water was added
to the mixture and the product was extracted into chloroform. The
combined organic layers were washed with water, dried over
18. Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem.
Soc. 2009, 131, 6632e6639.
19. Mangalagiu, I.; Benneche, T.; Undheim, K. Acta Chem. Scand. 1996, 50, 914e917.
20. Aaron, J. J.; Tine, A.; Gaye, M. D.; Parkanyi, C.; Boniface, C.; Bieze, T. W. N.
Spectrochim. Acta 1991, 47A, 419e430.
2 4
Na SO , filtered and evaporated under reduced pressure. The resi-
21. Diaz, A. N. Photochem. Photobiol. A 1990, 53, 141e167.
due was purified by column chromatography on silica gel to afford
22. Yanai, T.; Tew, D.; Handy, N. Chem. Phys. Lett. 2004, 393, 51e57.
23. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A., et al.
Gaussian 09, Revision B.01; Gaussian: Wallingford, CT, USA, 2010.
a yellow solid 10a as a yellow solid (0.23g, 68%), R
f
(2:1 hexane/
ꢀ
ethyl acetate) 0.48, mp. 188e189 C;
n
max (ATR) 524, 613, 683, 715,
7
3
52, 828, 1013, 1043, 1090, 1404, 1490, 1538, 2208, 2923, 3049,
2
4. Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996, 255, 327e335.
25. Achelle, S.; Pl eꢀ , N.; Kreher, D.; Attias, A.-J.; Arfaoui, L.; Charra, F. Tetrahedron Lett.
009, 50, 7055e7058.
6. Sunahara, H.; Urano, Y.; Kojima, H.; Nagano, T. J. Am. Chem. Soc. 2007, 129,
597e5604.
27. Kaniskan, N.; Kokten, S.; Celik, I. Arkivoc 2012, Viii, 198e213.
ꢂ1
287 cm
;
d
H
(500 MHz, CDCl
3
) 1.85 (t, J¼6.0 Hz, 1H), 2.78 (t,
2
J¼6.0 Hz, 2H), 3.89 (q, J¼6.0 Hz, 2H), 7.42e7.45 (m, 6H), 7.53e7.55
m, 3H), 7.70e7.73 (m, 3H), 8.11 (d, J¼2.0 Hz, 1H), 8.29 (d, J¼2.0 Hz,
H), 8.72e8.76 (m, 2H); (125 MHz, CDCl ) 24.2, 61.3, 81.4, 85.5,
2
(
1
5
d
C
3
Please cite this article in press as: Paumo, H. K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.11.014