Synthesis and photophysical properties of polycarbo-substituted quinazolines derived from the 2-Aryl-4-chloro-6-iodoquinazolines

Article abstract of DOI:10.3390/molecules200814656

The reactivity of the 2-aryl-4-chloro-6-iodoquinazolines towards palladium catalyzed sequential (Sonogashira/Suzuki-Miyaura) and one-pot two-step cross-coupling (bis-Sonogashira, and successive Sonogashira/Stille) reactions to afford novel unsymmetrical polycarbo-substituted quinazolines has been evaluated. In contrast to the chloro-bromo substituted quinazolines in which selectivity has been previously found to generally favor substitution at the more activated C(4)-Cl bond over the weaker Csp2-Br bond, substitution in the case of the chloro-iodo derivatives favors cross-coupling through the intrinsically more reactive Csp2-I bond. The electronic absorption and emission properties of the prepared 2,3-diaryl-6-(phenylethynyl)quinazolines were studied in solvents of different polarity (dichloromethane, toluene, DMF, methanol) and CH2Cl2-TFA mixture using UV-Vis and emission spectroscopic techniques complemented with density functional theory method to establish the effect of substituents on intramolecular charge transfer properties.

Full text of DOI:10.3390/molecules200814656

Molecules 2015, 20, 14656-14683; doi:10.3390/molecules200814656
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Photophysical Properties of
Polycarbo-Substituted Quinazolines Derived from the
2-Aryl-4-chloro-6-iodoquinazolines
Malose Jack Mphahlele 1,*, Hugues Kamdem Paumo 1, Lydia Rhyman 2
and Ponnadurai Ramasami 2
1
Department of Chemistry, College of Science, Engineering and Technology,
University of South Africa, P.O. Box 392, Pretoria 0003, South Africa;
E-Mail: tkademph@unisa.ac.za
2
Computational Chemistry Group, Department of Chemistry, Faculty of Science,
University of Mauritius, Réduit 80837, Mauritius; E-Mails: lyd.rhyman@gmail.com (L.R.);
ramchemi@intnet.mu (P.R.)
* Author to whom correspondence should be addressed; E-Mail: mphahmj@unisa.ac.za;
Tel.: +27-11-670-9301; Fax: +27-12-429-8549.
Academic Editor: Philippe Belmont
Received: 3 July 2015 / Accepted: 7 August 2015 / Published: 13 August 2015
Abstract: The reactivity of the 2-aryl-4-chloro-6-iodoquinazolines towards palladium
catalyzed sequential (Sonogashira/Suzuki-Miyaura) and one-pot two-step cross-coupling
(bis-Sonogashira, and successive Sonogashira/Stille) reactions to afford novel unsymmetrical
polycarbo-substituted quinazolines has been evaluated. In contrast to the chloro-bromo
substituted quinazolines in which selectivity has been previously found to generally favor
substitution at the more activated C(4)-Cl bond over the weaker Csp2-Br bond, substitution in
the case of the chloro-iodo derivatives favors cross-coupling through the intrinsically more
reactive Csp2-I bond. The electronic absorption and emission properties of the prepared
2,3-diaryl-6-(phenylethynyl)quinazolines were studied in solvents of different polarity
(dichloromethane, toluene, DMF, methanol) and CH2Cl2-TFA mixture using UV-Vis and
emission spectroscopic techniques complemented with density functional theory method to
establish the effect of substituents on intramolecular charge transfer properties.

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Keywords: 2-aryl-4-chloro-8-iodoquinazolines; cross-coupling reactions; polycarbo-substituted
quinazolines; photophysical properties
1. Introduction
The design and synthesis of polycarbo-substituted quinazolines continue to attract considerable
attention in research because of their rich biological activities and interesting photophysical (electronic
absorption and emission) properties [1–8]. Halogenated quinazoline moiety has to this end established
itself as an important scaffold for transition metal-mediated Csp2-Csp2, Csp2-Csp or Csp2-heteroatom
bond formation to afford diversely carbo-(aryl, alkenyl or alkynyl) or heteroatom-substituted quinazolines
with potential application in medicinal chemistry [6] and materials [7–9]. The versatility of halogenated
quinazolines as substrates in these transformations stems from the reactivity of the Csp2-X bonds,
which readily undergo metal exchange or metal-catalyzed cross-coupling to afford novel polysubstituted
derivatives [10]. For multihalogenated heterocycles bearing different halogen atoms, selectivity in
transition metal-mediated cross-coupling has been established to generally relate to the relative Csp2-X
bond strengths (trend: C-I < C–Br < C-Cl < C-F), which make it possible to effect selective cross-coupling
with iodides or bromides in the presence of chlorides [11–13]. However, the C(4)-Cl bond of 6-bromo-
2,4-dichloroquinazoline [3] and the analogous 2-aryl-6,8-dibromo-4-chloroquinazolines [7] has been
found to be more reactive in metal-catalyzed cross-coupling than the weaker Csp2-Br bond, which in turn
undergoes cross-coupling more readily than the C(2)-Cl bond [1–5]. Theoretical calculations at B3LYP
level, on the other hand, revealed that the bond dissociation energy of the C(4)-Cl bond (84.8 kcal/mol)
for 6-bromo-2,4-dichloroquinazoline is larger than that of the weaker Csp2-Br bond (83 kcal/mol at
B3LYP) [1]. The increased reactivity of the C(4)-Cl bond for quinazolines is attributed to the α-nitrogen
effect, which makes this position more electrophilic than the other chlorinated or brominated positions
on the heterocyclic scaffold [1,2,4]. Additional activation of the C(4)-Cl position, which also relates to
selectivity of cross-coupling in the case of bromo-substituted 4-chloroquinazolines is the consequence
of strong PdL2 dxy HOMO-heterocycle π* LUMO interaction in the oxidative-addition step which
favors C(4)-Cl cross-coupling instead of the weaker Csp2-Br bond [1,13].
Although there have been numerous reports on the site-selective sequential cross-couplings of the
di- and trihalogenated quinazolines, these studies focused mainly on derivatives bearing a combination
of chloro-chloro or chloro-bromo as substituents [2,3,7]. The need to access structurally diverse
polycarbo-substituted quinazolines prompted us to investigate the relative reactivity of the C(4)-Cl and
Csp2-I bonds of the analogous 2-aryl-4-chloro-6-iodoquinazolines in palladium catalyzed cross-coupling
reactions to afford novel polycarbo-substituted quinazolines. Successful discernment of the reactivity
of the two Csp2-halogen bonds led to the first one-pot double cross-coupling (bis-Sonogashira and
successive Sonogashira/Stille) approach towards the synthesis of unsymmetrical polycarbo-substituted
quinazoline derivatives. Electronic absorption and emission properties of selected examples of the prepared
polycarbo-substituted quinazolines were probed in solvents of different polarity (dichloromethane, toluene,
DMF, methanol, CH2Cl2-TFA) using UV-Vis and emission spectroscopic techniques in conjunction with

Molecules 2015, 20
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density functional theory (DFT) method to establish the effect of substituents and protonation on
intramolecular charge transfer (ICT) properties.
2. Results and Discussion
The 2-aryl-6-iodoquinazolin-4(3H)-ones employed as precursors for the synthesis of the requisite
2-aryl-4-chloro-6-iodoquinazolines were, in turn, prepared via cyclocondensation of 2-amino-5-
iodobenzamide and benzaldehyde derivatives. 2-Amino-5-iodobenzamide 1 and benzaldehyde derivatives
were subjected to molecular iodine in ethanol under reflux for 7 h to afford the corresponding 2-aryl-6-
iodoquinazolin-4(3H)-ones 2a–d (Scheme 1). The latter were, in turn, subjected to POCl3–promoted
aromatization in the presence of triethylamine under reflux for 6 h to afford the corresponding 2-aryl-
4-chloro-6-iodoquinazolines 3a–d.
1
2a–d
3a–d
Compound
R
4-H
%Yield of 2 %Yield of 3
a
b
c
83
93
89
98
86
78
74
82
4-F
4-Cl
4-OMe
d
Scheme 1. Synthesis and aromatization of the 2-aryl-6-iodoqinazolin-4(3H)-ones. Reagents
and conditions: (i) ArCHO, I2 (2 equiv.), ethanol, reflux, 7 h; (ii) POCl3, NEt3, reflux, 6 h.
We explored the reactivity of the dihalogenoquinazolines 3a–d in palladium-copper iodide
catalyzed Sonogashira cross-coupling with terminal alkynes as coupling partners. Hitherto, the analogous
2-aryl-6,8-dibromo-4-chloroquinazolines were found to undergo Sonogashira cross-coupling with
terminal alkynes at room temperature through C(4)-Cl bond substitution with ease [7]. This literature
precedent made it difficult for us at the outset to predict how different the reactivity of the highly
activated Csp2-Cl bond and the intrinsically reactive Csp2-I bond in 3 would be during Pd-catalyzed
Csp2-Csp bond formation. We nevertheless subjected compound 3a to phenylacetylene (1.2 equiv.)
in the presence of dichlorobis(triphenylphosphine)palladium(II) pre-catalyst as a source of active
Pd(0) species, CuI as co-catalyst and Cs2CO3 in THF at r.t. for 18 h in analogy with the literature
precedent [7] (Scheme 2). Thin layer chromatography (TLC) analysis of the reaction mixture and the
crude product revealed the presence of only two spots, which were purified by column chromatography
on silica gel to afford in sequence traces of the undesired dimer and the cross-coupled product
characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques as the
13
4-chloro-2-phenyl-6-(2-phenylethynyl)quinazoline 4a. Its C-NMR spectrum revealed the absence of
the Csp2-I signal, which resonates at δ ca. 93.0 ppm in the spectrum of 3a and the presence of
two carbon signals at δ 88.2, and 92.3 ppm corresponding to the acetylene moiety. The molecular ion

Molecules 2015, 20
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region of the mass spectrum of this compound, on the other hand, revealed the presence of the M+ and
M+2 peaks in the ratio 3:1 typical for compounds containing the 35Cl and 37Cl isotopes, thus confirming
its 6-alkynyl-4-chloroquinazoline nature. The reaction conditions were then extended to other derivatives 3
using phenylacetylene or 3-butyn-1-ol as coupling partners to afford compounds 4a–h. These results
reveal an opposite trend to that observed for the chloro-chloro or chloro-bromo substituted quinazolines
in which case, reactivity and selectivity are governed by the electronic position of the Csp2-X bond
(trend: C(4)-Cl > Csp2-Br > C(2)-Cl > Csp2-Cl). In order to rationalize the observed selectivity, we
probed the relative Csp2-X bond dissociation energies of 3a by DFT method [B3LYP/6-311G(d)], which
revealed that the Csp2-I bond is weaker (66.45 kcal/mol) than the C(4)-Cl bond (83.14 kcal/mol). The
observed selectivity and reactivity through Csp2-I bond is thus attributed to the relative Csp2-X bond
strengths, which make it possible to substitute the intrinsically more reactive Csp2-I bond in the presence
of the highly activated C(4)-Cl bond.
3a–d
4a–h
Compound
R
4-H
4-F
4-Cl
4-OMe
4-H
4-F
4-Cl
4-OMe
R′
-C6H5
-C6H5
-C6H5
% Yield of 4
4a
4b
4c
4d
4e
4f
93
89
78
75
90
90
85
82
-C6H5
-CH2CH2OH
-CH2CH2OH
-CH2CH2OH
-CH2CH2OH
4g
4h
Scheme 2. Regioselective C-6 alkynylation of the 2-aryl-4-chloro-6-iodoquinazolines
3a–d. Reagents and conditions: (i) R′C≡CH (1.2 equiv.), PdCl2(PPh3)2, CuI, Cs2CO3, THF,
r.t., 18 h.
The Suzuki-Miyaura cross-coupling of compounds 4a–f with either 4-fluorophenylboronic acid or
4-methoxyphenylboronic acid in the presence of PdCl2(PPh3)2-PCy3 catalyst complex and K2CO3 as a
base in DMF under reflux for 2 h afforded the corresponding novel 2,4-diaryl-6-alkynylquinazolines
5a–h (Scheme 3).
4a–e
5a–h
Scheme 3. Cont.

Molecules 2015, 20
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Compound
R
4-H
4-F
4-Cl
4-OMe
4-F
4-Cl
4-OMe
4-H
R′
-C6H5
-C6H5
-C6H5
-C6H5
-C6H5
-C6H5
-C6H5
Ar
4-FC6H4-
4-FC6H4-
4-FC6H4-
%Yield of 5
5a
5b
5c
5d
5e
5f
76
85
83
78
79
70
79
90
4-FC6H4-
4-MeOC6H4-
4-MeOC6H4-
4-MeOC6H4-
4-MeOC6H4-
5g
5h
-CH2CH2OH
Scheme 3. Suzuki-Miyaura cross-coupling of 4a–e with arylboronic acids. Reagents and
conditions: (i) ArB(OH)2, PdCl2(PPh3)2, PCy3, K2CO3, dioxane-water (3:1, v/v), reflux, 2 h.
Despite the successes in site-selective metal-catalyzed cross-coupling reactions of the di- or
trihalogenated quinazolines bearing different halogen atoms [10], so far there is no literature
precedence for their involvement in one-pot sequential multi-step reactions to afford unsymmetrical
polycarbo-substituted quinazolines. Since both C(4)-Cl bond [7] and Csp2-I bond (this investigation)
undergo Sonogashira cross-coupling under the same conditions, we opted for the use of a single
catalyst mixture on 3a–d and only varied the reaction time and temperature for the subsequent step.
The 1st cross-coupling step was carried out with either phenylacetylene or 3-butyn-1-ol (1 equiv.) at
r.t. for 18 h as for the synthesis of compounds 4a–h above to avoid double coupling. After 18 h at r.t.
(TLC monitoring), the reaction mixtures were each treated with a different alkyne (1.2 equiv.) in THF
and then heated at 60 °C to ensure complete conversion of the incipient monoalkynylated product.
To our delight, we isolated on silica gel the corresponding unsymmetrically substituted dialkynylated
quinazolines 6a–h exclusively after 2 h by column chromatography (Scheme 4).
3a–d
6a–f
Compound
R
R′
R′′
%Yield of 6
6a
6b
6c
6d
6e
6f
4-H
4-F
4-Cl
4-OMe
4-H
4-F
-C6H5
-C6H5
-C6H5
-C6H5
-CH2CH2OH
-CH2CH2OH
-CH2CH2OH
-CH2CH2OH
-C6H5
78
55
65
65
61
52
75
59
-CH2CH2OH
-CH2CH2OH
-CH2CH2OH
-CH2CH2OH
-C6H5
-C6H5
-C6H5
6g
6h
4-Cl
4-OMe
Scheme 4. One-pot sequential Sonogashira cross-coupling of 3a–d with terminal alkynes.
Reagents and conditions: (i) R′C≡CH (1 equiv.), PdCl2(PPh3)2, CuI, Cs2CO3, THF, r.t.,
18 h; (ii) R′′C≡CH (1.2 equiv.), THF, 60 °C, 2 h.

Molecules 2015, 20
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The success of the above single-pot bis-Sonogashira cross-coupling prompted us to further investigate
the possibility of effecting one-pot successive cross-coupling reactions using different coupling carbon
sources. Here we opted for the one-pot sequential Sonogashira and Stille cross-coupling of compounds
3a–d with phenylacetylene and 2-(tributylstannyl)furan. Initial cross-coupling of 3a–d with phenyl
acetylene (1 equiv.) in the presence of PdCl2(PPh3)2, CuI, Cs2CO3, THF at r.t. for 18 h followed by
Stille cross-coupling of the incipient 2-aryl-4-chloro-6-(phenylethynyl)quinazoline (tlc monitoring) with
2-(tributylstannyl)furan (1.1 equiv.) in THF and heating at 60 °C afforded albeit in moderate yields
products 7a–d, exclusively (Scheme 5).
3a–d
7a–d
Compound
R
4-H
%Yield of 7
7a
7b
7c
7d
56
62
69
59
4-F
4-Cl
4-OMe
Scheme 5. One-pot sequential Sonogashira and Stille cross-coupling of 3a–d. Reagents
and conditions: (i) R′C≡CH (1 equiv.), PdCl2(PPh3)2, CuI, Cs2CO3, THF, r.t., 18 h; (ii)
2-(tributylstannyl)furan, THF, 60 °C, 2 h.
The molecular backbone of the compounds prepared in this investigation is interesting because it
comprises an electron-deficient quinazoline framework as an electron-acceptor linked to the aryl or
heteroaryl ring directly and through a π-conjugated spacer to comprise donor-π-acceptor systems with
potential intramolecular charge transfer properties. Moreover, the presence of π-conjugated spacers
between the central chromophore and the π-electron donors has been found to extend the conjugated
framework to broaden the absorption window and enlarge the Stokes shift characteristics of light
emission of a donor-π-acceptor system [14]. As a prelude to compounds with potential photophysical
properties, in the last part of this investigation we probed the electronic absorption and emission
properties of selected compounds in solution using UV-Vis and fluorescence spectrometry in
conjunction with density functional theory (DFT) method. The aim was to establish the effect of aryl
and (alkyl/aryl)alkynyl substituents on intramolecular charge transfer (ICT) properties. The UV-Vis
spectra of compounds 5a–g, 6d and 7d in dichloromethane (CH2Cl2) reveal the presence of three
absorption bands of different intensity (Figure 1). The first two bands in the region λ 283–300 nm and
λ 305–330 nm are due to π→π* transition of the conjugated quinazoline ring and the intramolecular
donor-acceptor charge transfer absorption, respectively [14]. The less intense broad band in the region
λ 358–400 nm presumably corresponds to the weakly allowed π→π* transitions or relatively strong
pyrimidine-based n→π* transitions [15]. Both the absorption maxima and the wavelength of these
compounds are influenced by the variation of substituents on the heterocyclic framework. The
2-(4-halogenophenyl) substituted derivatives 5b and 5c, which bear the moderately resonance-donating

Molecules 2015, 20
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4-(4-fluorophenyl) group exhibit increased intensity of the absorption maxima and slight red shift as
compared to 5a bearing the 2- and 4-phenyl groups. The 2-(4-fluoro/chlorophenyl) groups in compounds
5b and 5c presumably withdraw electrons away from the quinazoline moiety causing the moderately
resonance-donating 4-fluorophenyl group at the 6-position to increase the π→π* transition, hence the
observed increased absorption intensities for these compounds. The absorption maxima for compounds
5d–g bearing the strong resonance donating 4-methoxyphenyl group are located around λ 310–330 nm.
Increased peak broadening and reduced intensity for these compounds indicate that the strong electron
donating methoxy groups interfere with the conjugation of the π electrons presumably restricting the
transition from bonding orbital to the antibonding orbital. Increased broadening and slight red shift are
observed for 6d and 7d bearing but-3-yn-1-ol or 2-furanyl group at the 4-position.
3
2.5
2
5a
5b
5c
5d
5e
1.5
5f
5g
6d
7d
1
0.5
0
250
300
350
400
450
Wavelength (nm)
Figure 1. Absorption spectra of 5a–g, 6d and 7d in CH2Cl2 (r.t.) at 2.25 × 10−5 mol/L.
The fluorescence excitation spectra of compounds 5a–g, 6d and 7d at room temperature in CH2Cl2
are characterized by several bands which are located at wavelengths close to those of the absorption
spectra. Their emission spectra in CH2Cl2 at the excitation wavelength, λex = 355 nm, reveal similar
patterns and are characterized by a single emission band in the region, λem = 480–495 nm except for 5a
which also showed a shoulder at λ ca. 404 nm (Figure 2). These bands are attributed to the π→π*
transition resulting from direct π-electron delocalization by 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 are also influenced by the variation of substituents on the
heterocycle (Table 1). The presence of 4-methoxyphenyl group at the 2- and/ or 4-position enhances the
emission and the trend in intensity is as follows: 5d > 5g > 5f > 5e. A combination of the moderately
resonance-donating 4-(4-fluorophenyl)- and strongly donating 2-(4-methoxyphenyl)-substituents in 5d
resulted in the highest emission intensity and slight redshift than for 5g bearing the strongly donating
4-methoxyphenyl groups at the 2- and 4-positions. Compounds 5a, 5b and 5c bearing 4-fluorophenyl
ring at the 4-position exhibit relatively reduced emission intensities with peak broadening and the trend
in intensity is as follows: 5c > 5b > 5a. Reduced emission intensity and increased broadening are
observed for compounds 6d and 7d bearing the but-3-yn-1-ol and 2-furanyl groups at the 4-position,
respectively. The large Stokes shift values for these compounds are an indication of the high
polarizability of the π-conjugated framework.

Molecules 2015, 20
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1200
1000
800
600
400
200
0
5a
5b
5c
5d
5e
5f
5g
6d
7d
380
430
480
530
580
Wavelength (nm)
Figure 2. Emission spectra of 5a–g, 6d and 7d in CH2Cl2 (r.t.) at 7.5 × 10−6 mol/L
(λex = 355 nm).
Table 1. The absorption and emission data for compounds 5a–g, 6d and 7d.
Compound λmax abs (nm) (ε) × 103 mol−1·cm−1 λem (nm) (a) Quantum Yields (Φ) Stokes Shifts
5a
5b
5c
5d
5e
5f
326
328
329
329
309
311
321
318
323
49.28
88.47
81.55
80.50
68.86
86.24
109.32
86.19
108.98
429
436
435
444
437
436
437
454
461
0.027
0.019
0.025
0.051
0.047
0.043
0.037
0.013
0.003
7364
7552
7406
7872
9479
9218
8269
9420
9268
5g
6d
7d
(a) The relative quantum yields in CH2Cl2 were calculated according to the equation indicated under Experimental
section using quantum yield value of quinine sulfate as the standard (Φst = 0.55) in 0.50 M H2SO4.
Achelle et al., previously observed dramatic color change of the analogous arylvinyl-, aryl-, and
arylethynyl-substituted quinazoline derivatives upon protonation with trifluoroacetic acid, which became
reversible by neutralization with a base (NEt3 or t-BuOK) [8]. These authors projected that nitrogen at
position 3 is the most basic centre for the quinazoline nucleus, however, they were not certain about
the exact nitrogen atom (N-1 vs. N-2) which is most likely to be protonated or both. Hitherto, Liu et al.
had also reported a novel approach involving controlled acid protonation of the blue emissive
2,4-diarylquinazoline derivatives, which resulted in white photoluminescence and electroluminescence
properties [9]. These authors argued on the basis of X-ray crystal structure that the free space around
the N-2 atom is greatly limited by a peripheral phenyl ring to hinder possible protonation by the acid
molecules. Acidification of these compounds had maximum impact on the proton NMR chemical shift
of H-8 indicating that N-1 is the one that is protonated by trifluoroacetic acid (TFA). [9] Intrigued by
these two literature precedents, we decided to probe the optical behavior of compound 5g in acidic
medium. First we acquired the 1H-NMR (see Figures S1–S3 in Supplementary Data) and heteronuclear
multiple bond correlation (HMBC) 1H-15N NMR pectra (Figure 3) of 5g in CDCl3 and CDCl3+TFA to

Molecules 2015, 20
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establish the exact site of protonation. Protonation in CDCl3+TFA (3 drops) is confirmed by the presence
of a singlet at δH ca. 11.5 ppm (see Figure S3 in Supplementary data) and significant downfield shift of
the resonance corresponding to H-8 with less effect on the chemical shift of H-7 (Figure 3, AAA).
Both the 1H-15N NMR spectra of 5g in CDCl3 and CDCl3+TFA (Figure 3) obtained by irradiation of H-8
revealed the presence of a single intense N-15 signal at δ 261.95 ppm before addition of an acid (baa)
and at δ 155.59 ppm after addition of an acid (AAA). The resonance for N-2, on the other hand, was
not observed in CDCl3 or CDCl3+TFA because it is furthest away (five bond distance) from the
irradiated H-8 than N-1. The observed significant changes in chemical shifts for H-8 and the nitrogen
1
signal in the H-15N NMR spectrum upon acidification in our view confirm protonation to take place
on N-1 in analogy with the previous literature observation by Liu et al. [9]. With the exact protonation
site for these compounds established, we then probed the electronic absorption and emission properties of
5g in dichloromethane at different concentrations of trifluoroacetic acid. Addition of TFA is accompanied
by color change from green to yellow and an increase in concentration of TFA leads to bathochromic
shift of the absorption maxima compared to a neutral solution ([TFA] = 0) of 5g (Figure 4). The less
intense shoulder at λ ca. 370 nm in the spectrum of this compound in CH2Cl2 becomes more intense
and broader with increasing acidity due to increased charge transfer from the donors to the protonated
quinazoline moiety. Since the π→π* state is much more polarizable than the ground state, a change in
polarity of the solvent has been previously found to cause measurable displacements of the π→π*
transition towards the red bands [16]. Based on this literature precedent we rationalize the observed
increased intensity and bathochromic shift of the absorption maxima and emission maxima (see Figure 4)
to be the result of the increased polarity of the medium (CH2Cl2+TFA) on the highly polar protonated
compound. Additional interaction of trifluoroacetic acid with the methoxy groups is expected to occur
at lower pH and therefore reduce their propensity for π-electron pair delocalization into the quinazolium
moiety. This interaction in turn, would lead to reduced π→π* transition and therefore less pronounced
ICT, hence reduced absorption and emission intensities for 5g at high concentration of trifluoacetic acid
(>10−3 M). Fluorescence enhancement and absorption changes indicate that this compound is sensitive
to pH changes and has potential in pH sensing.
baa
AAA
1
Figure 3. H-15N NMR spectra of 5g in CDCl3 (baa) and in CDCl3+TFA (AAA) using
nitromethane as an external standard.

Molecules 2015, 20
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0.8
0.6
0.4
0.2
0
OCH3
N
N
OCH3
= 7.60×10-1 M
= 7.60×10-2 M
= 7.60×10-3 M
= 7.60×10-4 M
= 7.60×10-5 M
= 7.60×10-6 M
= 0
[TFA]
[TFA]
[TFA]
[TFA]
[TFA]
[TFA]
[TFA]
270
320
370
420
470
Wavelength (nm)
700
600
500
400
300
200
100
0
OCH3
N
N
OCH3
= 7.60×10-1
= 7.60×10-2
= 7.60×10-3
= 7.60×10-4
= 7.60×10-5
= 7.60×10-6
= 0
M
M
M
M
M
M
[TFA]
[TFA]
[TFA]
[TFA]
[TFA]
[TFA]
[TFA]
380
430
480
530
580
Wavelength (nm)
Figure 4. UV-Vis (upper) and PL spectra of 5g in CH2Cl2 (conc. = 1.46 × 10−5 M) at
different concentrations of TFA (10−6 to 10−1).
We also studied the emission properties of compounds 5g (solid lines) and 5f (broken lines) in
solvents of different polarity and hydrogen bonding ability as a means of extending investigation of
electronic interactions of these polycarbo-substituted quinazoline scaffold in the excited state (Figure 5).
A change in polarity of the medium has been previously found to cause measurable displacements of
the π→π* transition towards the red bands [16]. The fluorescence emission spectra of compounds 5g
and 5f are slightly red-shifted upon increasing the polarity of the solvent, which indicates an increase in
dipole moment of excited state compared to ground state. The 2,4-bis(4-methoxyphenyl)–substituted
derivative 5g emits at λem = 438 nm in non-polar toluene and the emission maxima is red-shift in polar
aprotic DMF (λem = 455 nm) and polar protic methanol (λem = 453 nm). A slight red-shift is observed
in both DMF and methanol for the 2-(4-methoxyphenyl)-substituted derivative 5f with reduced intensity
in DMF. Slight fluorescence quenching in polar protic methanol is observed for 5g compared to 5f. This
is presumably the consequence of hydrogen bonding with oxygen of the 4-(4-methoxyphenyl) group
leading to reduced π→π* transition into the electron poor quinazoline moiety. No appreciable difference
in fluorescence intensity was observed for compound 5f in toluene and methanol.
The solvent polarity dependent electronic transitions may result from dipolar interaction with DMF
and methanol thus suggesting the intramolecular charge transfer (ICT) of the emission state in which
the HOMOs and LUMOs are presumably localized on the aryl rings and the quinazoline-based moiety,

Molecules 2015, 20
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respectively. To prove this hypothesis, we employed computational methods to determine the HOMO
and LUMO orbital energies of compounds 5a–h. The HOMO and LUMO surfaces of compounds
5a–h in CH2Cl2 are illustrated in Figure 6 and the HOMO-LUMO gap for all the compounds is about
6 eV. In general, for the compounds, there are no significant changes observed on the electron density
distributions. The HOMO is localized over the entire molecule while the LUMO tends to be localized
over the quinazoline moiety representing the π and π* orbitals, respectively.
1200
1000
5g in toluene
800
5g in DMF
5g in methanol
5f in toluene
600
5f in DMF
5f in methanol
400
200
0
380
430
480
530
Wavelength (nm)
Compound
λem (nm) CH2Cl2
λem (nm) Toluene
λem (nm) DMF
λem (nm) CH3OH
5f
436
437
436
438
440
455
442
453
5g
Figure 5. Emission of compounds 5g and 5f in solvent of different polarity.
HOMO-LUMO gap = 6.00 eV
5a-HOMO
5a-LUMO
HOMO-LUMO gap = 5.98 eV
5b-HOMO
5b-LUMO
Figure 6. Cont.

Molecules 2015, 20
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HOMO-LUMO gap = 5.96 eV
HOMO-LUMO gap = 5.86 eV
HOMO-LUMO gap = 5.98 eV
5c-HOMO
5d-HOMO
5e-HOMO
5f-HOMO
5c-LUMO
5d-LUMO
5e-LUMO
5f-LUMO
HOMO-LUMO gap = 5.96 eV
Figure 6. Cont.

Molecules 2015, 20
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HOMO-LUMO gap = 5.88 eV
5g-HOMO
5g-LUMO
HOMO-LUMO gap = 6.27 eV
5h-HOMO
5h-LUMO
Figure 6. HOMO and LUMO surfaces of compounds 5a–h in CH2Cl2 [CAM-B3LYP/6-
31G(d,p), isovalue = 0.02 and density = 0.0004].
3. Experimental Section
3.1. General
Melting points were recorded on a Thermocouple digital melting point apparatus and are uncorrected.
IR spectra were recorded as powders using a Bruker VERTEX 70 FT-IR Spectrometer (Bruker Optics,
Billerica, MA, USA) with a diamond ATR (attenuated total reflectance) accessory by using the thin-film
method. For column chromatography, Merck kieselgel 60 (0.063–0.200 mm) (Merck KGaA, Frankfurt,
Germany) was used as stationary phase. NMR spectra were obtained as CDCl3 or DMSO-d6 solutions
using Agilent 500 MHz NMR spectrometer (Agilent Technologies, Oxford, UK) and the chemical
shifts are quoted relative to the TMS peak. Low- and high-resolution mass spectra were recorded at an
ionization potential of 70 eV using Synapt G2 Quadrupole Time-of-flight mass spectrometer (Waters
Corp., Milford, MA, USA) at the University of Stellenbosch Mass Spectrometry Unit. The UV-Vis
spectra were recorded on a Cecil (Cecil Instruments, Cambridge, UK) CE 9500 (9000 Series) UV-Vis
spectrometer while emission spectra were taken using a Perkin Elmer LS45 fluorescence spectrometer
(Perkin Elmer, Llantrisant, UK). The quantum efficiencies of fluorescence (Φfl) were obtained with the
following equation:
2
2
Φx = Φst × (Fx/Fst) × (Ast/Ax) × (nx /nst )
(1)
F denotes the area under the fluorescence band (F = aIfl(λ), where Ifl(λ) is the fluorescence intensity at each
emission wavelength), A denotes the absorbance at the excitation wavelength, and n is the refractive index
of the solvent [17].

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3.2. Synthesis of 2-Amino-5-iodobenzamide (1)
A stirred suspension of anthranilamide (1.00 g, 7.34 mmol) in acetonitrile (20 mL) was treated with
N-iodosuccinimide (1.65 g, 7.34 mmol) at room temperature. The mixture was stirred at this temperature
for 30 min. and then quenched with an ice-cold saturated aqueous solution of sodium thiosulphate. The
resultant precipitate was filtered and washed thoroughly with cold water and then recrystallized from
ethanol to afford 1 as a white solid (1.69 g, 88%); mp. 198–200 °C (Lit. [18] 197–198 °C); νmax (ATR)
502, 531, 664, 817, 1062, 1228, 1384, 1600, 3162, 3278, 3343 cm−1; δH (500 MHz, DMSO-d6) 6.53 (d,
J = 8.5 Hz, 1H), 6.69 (s, 2H), 7.12 (br s, 1H), 7.36 (dd, J = 2.0 and 8.5 Hz, 1H), 7.80 (d, J = 2.0 Hz,
1H), 7.81 (br s, 1H); δC (150 MHz, DMSO-d6) 74.8, 116.5, 119.4, 136.9, 140.2, 150.1, 170.3.
3.3. Typical Procedure for the Synthesis of the 2-Aryl-6-iodoquinazolin-4(3H)-ones 2a–2d
3.3.1. 6-Iodo-2-phenylquinazolin-4(3H)-one (2a)
A stirred mixture of 1 (1.00 g, 3.81 mmol), benzaldehyde (0.48 g, 4.57 mmol) and iodine (1.93 g,
7.62 mmol) in ethanol (100 mL) was heated under reflux for 8 h and then allowed to cool to room
temperature. An ice-cold saturated aqueous solution of sodium thiosulphate was added to the mixture
and the resultant precipitate was filtered and washed thoroughly with cold water. The product was
recrystallized to afford 2a as a white solid (1.11 g, 83%), mp. >345 °C (acetonitrile); νmax (ATR) 542,
624, 698, 777, 834, 1284, 1460, 1562, 1595, 1667, 2853, 2955 cm−1; δH (500 MHz, DMSO-d6) 7.52 (d,
J = 8.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H), 7.59 (d, J = Hz, 1H), 8.11 (dd, J = 2.0 and 8.5 Hz, 1H), 8.17
(d, J = 7.0 Hz, 2H), 8.41 (d, J = 2.0 Hz, 1H), 12.69 (brs, 1H); δC (125 MHz, DMSO-d6) 91.3, 123.4,
128.3, 128.9, 130.0, 131.8, 133.8, 134.7, 142.9, 148.8, 154.4, 162.5; m/z 349 (100, MH+); HRMS (ES):
MH+, found 348.9833. C14H10IN2O+ requires 348.9760.
3.3.2. 2-(4-Fluorophenyl)-6-iodoquinazolin-4(3H)-one (2b)
A mixture of 1 (1.00 g, 3.81 mmol), 4-fluorobenzaldehyde (0.57 g, 4.57 mmol) and iodine (1.93 g,
7.62 mmol) in ethanol (100 mL) afforded 2b as a white solid (1.30 g, 93%), mp. 337–339 °C (acetonitrile);
νmax (ATR) 538, 648, 737, 830, 840, 942, 1154, 1460, 1514, 1572, 1667, 2867, 2926 cm−1; δH (500 MHz,
DMSO-d6) 7.39 (t, J = 9.0 Hz, 2H), 7.51 (d, J = 9.0 Hz, 1H), 8.11 (dd, J = 2.0 and 8.5 Hz, 1H), 8.24
(t, J = 9.0 Hz. 2H), 8.40 (d, J = 2.0 Hz, 1H), 12.72 (s, 1H); δC (125 MHz, DMSO-d6) 91.9, 116.1 (d,
2
3
2JCF = 21.8 Hz), 123.1, 129.5, 130.0 (d, JCF = 3.7 Hz), 130.9 (d, JCF = 8.5 Hz) 134.6, 143.3, 148.3,
152.5, 161.4, 164.6 (d, JCF = 250.5 Hz); m/z 367 (100, MH+); HRMS (ES): MH+, found 366.9744.
1
C14H9FIN2O+ requires 366.9747.
3.3.3. 2-(4-Chlorophenyl)-6-iodoquinazolin-4(3H)-one (2c)
A mixture of 1 (1.00 g, 3.81 mmol), 4-chlorobenzaldehyde (0.64 g, 4.57 mmol) and iodine (1.93 g,
7.62 mmol) in ethanol (100 mL) afforded 2c as a white solid (1.31 g, 89%), mp. >345 °C (acetonitrile);
ν
max (ATR) 541, 622, 644, 730, 830, 841, 940, 1091, 1459, 1473, 1556, 1595, 1667, 2922, 3038 cm−1;
δH (500 MHz, DMSO-d6) 7.51 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 8.10 (dd, J = 2.0 and
8.5 Hz, 1H), 8.19 (d, J = 8.5 Hz, 2H), 8.40 (d, J = 2.0 Hz, 1H), 12.74 (br s, 1H); δC (125 MHz,

Molecules 2015, 20
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DMSO-d6) 92.0, 123.3, 129.1, 130.0, 130.2, 132.1, 134.7, 136.8, 143.3, 148.4, 152.8, 161.0; m/z 383
35
(100, MH+); HRMS (ES): MH+, found 382.9448. C14H9 ClIN2O + requires 382.9370.
3.3.4. 6-Iodo-2-(4-methoxyphenyl)quinazolin-4(3H)-one (2d)
A mixture of 1 (1.00 g, 3.81 mmol), 4-methoxybenzaldehyde (0.62 g, 4.57 mmol) and iodine
(1.93 g, 7.62 mmol) in ethanol (20 mL) afforded 2d as a white solid (1.42 g, 98%), mp. 321–323 °C
(acetonitrile); νmax (ATR) 541, 649, 742, 831, 841, 939, 1027, 1250, 1459, 1517, 1594, 1662, 2852,
2922 cm−1; δH (500 MHz, DMSO-d6) 3.84 (s, 3H), 7.07 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 9.0 Hz, 1H),
8.06 (dd, J = 2.0 and 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 2H), 8.37 (d, J = 2.0 Hz, 1H), 12.50 (br s, 1H); δC
(125 MHz, DMSO-d6) 55.9, 91.1, 114.5, 123.0, 125.3, 129.8, 130.0, 134.6, 143.1, 148.7, 153.3, 161.8,
+
162.4; m/z 379 (100, MH+); HRMS (ES): MH+, found 378.9943. C15H12IN2O2 requires 378.9865.
3.4. Typical Procedure for the Synthesis of the 2-Aryl-4-chloro-6-iodoquinazolines 3a–d
3.4.1. 4-Chloro-6-iodo-2-phenylquinazoline (3a)
A stirred mixture of 2a (1.00 g, 2.87 mmol) and phosphoryl chloride (10 mL) was treated dropwise
with triethylamine (4 mL) at room temperature. The mixture was then heated under reflux for 6 h and
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 over anhydrous MgSO4, filtered and evaporated under reduced pressure to afford 3a as a brown
solid (0.91 g, 86%), mp. 148–150 °C (ethanol); νmax (ATR) 532, 663, 685, 703, 830, 866, 985, 1295,
1410, 1469, 1535, 1555 cm−1; δH (500 MHz, CDCl3) 7.52–7.55 (m, 3H), 7.81 (d, J = 8.5 Hz, 1H), 8.17
(dd, J = 1.5 and 8.5 Hz, 1H), 8.57–8.59 (m, 2H), 8.63 (d, J = 1.5 Hz, 1H); δC (125 MHz, CDCl3) 93.3,
123.8, 128.7, 128.8, 130.3, 131.4, 134.6, 136.2, 143.6, 150.8, 160.4, 160.9; m/z 367 (100, MH+);
35
+
HRMS (ES): MH+, found 366.9498. C14H9 ClIN2 requires 366.9499.
3.4.2. 4-Chloro-2-(4-fluorophenyl)-6-iodoquinazoline (3b)
A mixture of 2b (1.00 g, 2.60 mmol), phosphoryl chloride (10 mL) and NEt3 (4 mL) afforded 3b as
a white solid (1.00 g, 78%), mp. 192–193 °C (ethanol); νmax (ATR) 548, 648, 687, 736, 826, 845, 986,
1156, 1214, 1298, 1343, 1410, 1553, 1595 cm−1; δH (500 MHz, CDCl3) 7.21 (t, J = 9.0 Hz, 2H), 7.83
(d, J = 9.0 Hz, 1H), 8.17 (dd, J = 2.0 and 8.5 Hz, 1H), 8.59 (t, J = 9.0 Hz, 2H), 8.63 (d, J = 2.0 Hz,
2
3
1H); δC (125 MHz, CDCl3) 93.3, 115.7 (d, JCF = 21.8 Hz), 123.7, 130.2, 131.0 (d, JCF = 8.5 Hz),
4
1
132.5 (d, JCF = 3.7 Hz), 134.6, 143.7, 150.8, 159.4, 160.9, 165.1 (d, JCF = 250.2 Hz); m/z 385 (100,
MH+); HRMS (ES): MH+, found 384.9398. C14H8 ClFIN2 requires 384.9405.
35
+
3.4.3. 4-Chloro-2-(4-chlorophenyl)-6-iodoquinazoline (3c)
A mixture of 2c (1.00 g, 2.61 mmol), phosphoryl chloride (10 mL) and NEt3 (4 mL) afforded 3c as
a white solid (0.78 g, 74.5%), mp. 207–209 °C (ethanol); νmax (ATR) 533, 732, 829, 878, 1088, 1295,
1343, 1411, 1534, 1552, 1592 cm−1; δH (500 MHz, CDCl3) 7.50 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 9.0 Hz,
1H), 8.18 (dd, J = 2.0 and 8.5 Hz, 1H), 8.53 (d, J = 9.0 Hz, 2H), 8.63 (d, J = 2.0 Hz, 1H); δC (125 MHz,

Molecules 2015, 20
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CDCl3) 93.6, 123.8, 128.9, 130.1, 130.3, 134.6, 134.7, 137.7, 143.8, 150.8, 159.4, 161.0; m/z 401 (100,
35
+
MH+); HRMS (ES): MH+, found 400.9106. C14H8 Cl2IN2 requires 400.9109.
3.4.4. 4-Chloro-6-iodo-2-(4-methoxyphenyl)quinazoline (3d)
A mixture of 2d (1.00 g, 2.64 mmol), phosphoryl chloride (10 mL) and NEt3 (4 mL) afforded 3d as
a yellow solid (0.87 g, 82%), mp. 165–167 °C (ethanol); νmax (ATR) 523, 562, 647, 736, 783, 828, 844,
870, 984, 1026, 1166, 1295, 1411, 1466, 1553, 1595 cm−1; δH (500 MHz, CDCl3) 3.91 (s, 3H), 7.03 (d,
J = 9.0 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H), 8.13 (dd, J = 2.0 and 8.5 Hz, 1H), 8.53 (d, J = 9.0 Hz, 2H),
8.59 (d, J = 2.0 Hz, 1H); δC (125 MHz, CDCl3) 55.4, 92.5, 114.0, 123.4, 128.9, 130.1, 130.5,
134.5, 143.4, 151.0, 160.2, 160.7, 162.4; m/z 397 (100, MH+); HRMS (ES): MH+, found 396.9691.
C15H1135ClIN2O+ requires 396.9605.
3.5. Typical Procedure for Site-Selective Sonogashira Cross-Coupling of 3a–d with Terminal Alkynes
3.5.1. 4-Chloro-2-phenyl-6-(phenylethynyl)quinazoline (4a)
A stirred mixture of 3a (0.30 g, 0.82 mmol), PdCl2(PPh3)2 (0.057 g, 0.082 mmol), CuI (0.008 g,
0.041 mmol) and Cs2CO3 (0.40 g, 1.23 mmol) in THF (15 mL) was purged with argon gas for 30 min.
Phenylacetylene (0.10 g, 0.98 mmol) was added to the mixture using a syringe. The reaction mixture
was stirred at room temperature for 24 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
Na2SO4, filtered and evaporated under reduced pressure. The residue was recrystallized to afford 4a as
a yellow solid (0.26 g, 93%), Rf (2:1 hexane/toluene) 0.36, mp. 164–165 °C; νmax (ATR) 526, 649,
686, 706, 754, 848, 1327, 1361, 1413, 1556, 2208 cm−1; δH (500 MHz, CDCl3) 7.40–7.41 (m, 3H),
7.53–7.54 (m, 3H), 7.60–7.65 (m, 2H), 8.01 (dd, J = 1.5 and 9.0 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H),
8.41 (d, J = 1.5 Hz, 1H), 8.59–7.70 (m, 2H); δC (125 MHz, CDCl3) 88.2, 92.3, 122.4, 122.5, 123.5,
128.5, 128.6, 128.7, 128.8, 128.9, 129.0, 131.4, 131.8, 136.5, 137.4, 151.2, 160.5, 162.0; m/z 341 (100,
+
MH+); HRMS (ES): MH+, found 341.0838. C22H1435ClN2 requires 341.0846.
3.5.2. 4-Chloro-2-(4-fluorophenyl)-6-(phenylethynyl)quinazoline (4b)
A mixture of 3b (0.30 g, 0.78 mmol), PdCl2(PPh3)2 (0.054 g, 0.078 mmol), CuI (0.007 g, 0.039 mmol),
Cs2CO3 (0.38 g, 1.17 mmol) and phenylacetylene (0.096 g, 0.94 mmol) in THF (15 mL) afforded 4b as
a yellow solid (0.25 g, 89%), Rf (2:1 hexane/toluene) 0.47, mp. 189–191 °C; νmax (ATR) 524, 600, 682,
751, 841, 995, 1160, 1222, 1366, 1414, 1564, 2214 cm−1; δH (500 MHz, CDCl3) 7.21 (t, J = 8.5 Hz, 2H),
7.39–7.41 (m, 3H), 7.60–7.62 (m, 2H), 8.01 (dd, J = 1.5 and 8.5 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H),
8.40 (d, J = 1.5 Hz, 1H), 8.61 (t, J = 8.5 Hz, 2H); δC (125 MHz, CDCl3) 88.2, 92.4, 115.7 (d,
2JCF = 21.7 Hz), 122.3, 122.4, 123.5, 128.5, 128.8, 128.9, 129.0, 131.0 (d, 3JCF = 8.5 Hz), 131.8, 132.6
(d, 4JCF = 3.8 Hz), 137.6, 151.2, 159.5, 162.1, 165.1 (d, 1JCF = 250.2 Hz); m/z 359 (100, MH+); HRMS
+
(ES): MH+, found 359.0751. C22H1335ClFN2 requires 359.0751.

Molecules 2015, 20
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3.5.3. 4-Chloro-2-(4-chlorophenyl)-6-(phenylethynyl)quinazoline (4c)
A mixture of 3c (0.30 g, 0.75 mmol), PdCl2(PPh3)2 (0.052 g, 0.074 mmol), CuI (0.007 g, 0.037 mmol),
Cs2CO3 (0.36 g, 1.12 mmol) and phenylacetylene (0.091 g, 0.90 mmol) in THF (15 mL) afforded 4c as
a yellow solid (0.22 g, 78%), Rf (2:1 hexane/toluene) 0.56, mp. 214–215 °C; νmax (ATR) 523, 680,
747, 836, 1088, 1364, 1404, 1417, 1538, 1552, 2211; cm−1; δH (500 MHz, CDCl3) 7.41–7.42 (m, 3H),
7.51 (d, J = 9.0 Hz, 2H), 7.60–7.62 (m, 2H), 8.03 (dd, J = 1.5 and 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz,
1H), 8.42 (d, J = 1.5 Hz, 1H), 8.56 (d, J = 9.0 Hz, 2H); δC (125 MHz, CDCl3) 88.1, 92.5, 122.4, 122.4,
123.7, 128.5, 128.7, 128.9, 129.0, 129.1, 130.1, 131.8, 134.9, 137.6, 137.7, 151.1, 159.4, 162.1; m/z
+
375 (100, MH+); HRMS (ES): MH+, found 375.0468. C22H1335Cl2N2 requires 375.0456.
3.5.4. 4-Chloro-2-(4-methoxyphenyl)-6-(phenylethynyl)quinazoline (4d)
A mixture of 3d (0.30 g, 0.75 mmol), PdCl2(PPh3)2 (0.053 g, 0.075 mmol), CuI (0.007 g, 0.037 mmol),
Cs2CO3 (0.36 g, 1.12 mmol) and phenylacetylene (0.091 g, 0.90 mmol) in THF (15 mL) afforded 4d as
a yellow solid (0.21 g, 75%), Rf (1:1 hexane/toluene) 0.50, mp. 170–172 °C; νmax (ATR) 526, 564,
606, 747, 789, 831, 849, 995, 1028, 1173, 1246, 1364, 1413, 1553, 2209 cm−1; δH (500 MHz, CDCl3)
3.90 (s, 3H), 7.03 (d, J = 8.5 Hz, 2H), 7.40–7.41 (m, 3H), 7.60 (d, J = 3.5 Hz, 2H), 7.96 (dd, J = 1.5
and 8.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 8.36 (d, J = 1.5 Hz, 1H), 8.54 (d, J = 8.5 Hz, 2H); δC
(125 MHz, CDCl3) 55.4, 88.3, 92.0, 114.0, 122.0, 122.6, 122.8, 128.5, 128.7, 128.8, 128.9, 129.1,
130.6, 131.8, 137.3, 151.4, 160.3, 161.8, 162.4; m/z 371 (100, MH+); HRMS (ES): MH+, found
371.0943. C23H1635ClN2O+ requires 341.0951.
3.5.5. 4-(4-Chloro-2-phenylquinazolin-6-yl)but-3-yn-1-ol (4e)
A mixture of 3a (0.30 g, 0.82 mmol), PdCl2(PPh3)2 (0.057g, 0.082 mmol), CuI (0.008 g, 0.041 mmol),
Cs2CO3 (0.40 g, 1.23 mmol) and 3-butyn-1-ol (0.068 g, 0.98 mmol) in THF (20 mL) afforded 4e as a
yellow solid (0.23 g, 90%), Rf (2:1 hexane/ethyl acetate) 0.37, mp. 139–141 °C; νmax (ATR) 554, 687,
705, 767, 836, 991, 1062, 1211, 1306, 1361, 1417, 1557, 2235, 3218 cm−1; δH (500 MHz, CDCl3) 1.91
(s, 1H), 2.78 (t, J = 6.5 Hz, 2H), 3.90 (dt, J = 6.5 and 8.5 Hz, 2H), 7.52–7.54 (m, 3H), 7.88 (dd, J = 1.5
and 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H), 8.57–8.59 (m, 2H); δC (125 MHz,
CDCl3) 23.9, 61.0, 81.3, 89.9, 122.3, 123.6, 128.6, 128.7, 128.8, 128.9, 131.3, 136.5, 137.6, 151.1, 160.4,
161.9; m/z 309 (100, MH+); HRMS (ES): MH+, found 309.0789. C18H1435ClN2O+ requires 309.0795.
3.5.6. 4-(4-Chloro-2-(4-fluorophenyl)quinazolin-6-yl)but-3-yn-1-ol (4f)
A mixture of 3b (0.30 g, 0.78 mmol), PdCl2(PPh3)2 (0.054 g, 0.078 mmol), CuI (0.007 g, 0.039 mmol),
Cs2CO3 (0.38 g, 1.17 mmol) and 3-butyn-1-ol (0.066 g, 0.94 mmol) in THF (15 mL) afforded 4f as a
yellow solid (0.23 g, 90%), Rf (2:1 hexane/ethyl acetate) 0.39, mp. 180–181 °C; νmax (ATR) 557, 647,
740, 748, 840, 986, 1064, 1150, 1221, 1307, 1361, 1410, 1557, 2235, 3196 cm−1; δH (500 MHz,
CDCl3) 1.84 (br s, 1H), 2.79 (t, J = 6.5 Hz, 2H), 3.90 (t, J = 6.5 Hz, 2H), 7.20 (t, J = 9.0 Hz, 2H), 7.90
(dd, J = 1.5 and 8.5 Hz, 1H), 7.98 (J = 8.5 Hz, 1H), 8.29 (d, J = 1.5 Hz, 1H), 8.60 (t, J = 9.0 Hz, 2H);
2
δC (125 MHz, CDCl3) 23.9, 61.0, 81.2, 89.9, 115.7 (d, JCF = 20.8 Hz), 122.1, 123.5, 128.8, 128.9,

Molecules 2015, 20
14673
130.9 (d, 3JCF = 8.5 Hz), 132.6 (d, 4JCF = 3.7 Hz), 137.7, 151.0, 159.3, 161.9, 165.0 (d, 1JCF = 250.3 Hz);
m/z 327 (100, MH+); HRMS (ES): MH+, found 327.0694. C18H1335ClFN2O+ requires 327.0700.
3.5.7. 4-(4-Chloro-2-(4-chlorophenyl)quinazolin-6-yl)but-3-yn-1-ol (4g)
A mixture of 3c (0.30 g, 0.75 mmol), PdCl2(PPh3)2 (0.052 g, 0.075 mmol), CuI (0.007 g, 0.037 mmol),
Cs2CO3 (0.36 g, 1.12 mmol) and 3-butyn-1-ol (0.062 g, 0.89 mmol) in THF (15 mL) afforded 4g as a
yellow solid (0.22 g, 85%), Rf (2:1 hexane/ethyl acetate) 0.40, mp. 199–201 °C; νmax (ATR) 556, 647,
701, 735, 840, 991, 1011, 1064, 1091, 1360, 1403, 1418, 1539, 2233, 3213 cm−1; δH (500 MHz,
CDCl3) 1.84 (t, J = 6.0 Hz, 1H), 2.79 (t, J = 6.5 Hz, 2H), 3.90 (q, J = 6.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H),
7.90 (dd, J = 1.5 and 8.5 Hz, 1H), 7.99 (J = 8.5 Hz, 1H), 8.30 (d, J = 1.5 Hz, 1H), 8.53 (d, J = 8.5 Hz, 2H);
δC (125 MHz, CDCl3) 23.9, 61.0, 81.3, 90.0, 115.6, 115.8, 122.2, 123.6, 128.8, 130.9, 131.0, 132.6,
137.7, 151.0, 159.4, 162.0; m/z 343 (100, MH+); HRMS (ES): MH+, found 343.0402. C18H1335Cl2N2O+
requires 343.0405.
3.5.8. 4-(4-Chloro-2-(4-methoxyphenyl)quinazolin-6-yl)but-3-yn-1-ol (4h)
A mixture of 3d (0.30 g, 0.75 mmol), PdCl2(PPh3)2 (0.053 g, 0.075 mmol), CuI (0.007 g, 0.037 mmol),
Cs2CO3 (0.36 g, 1.12 mmol) and 3-butyn-1-ol (0.063 g, 0.90 mmol) in THF (15 mL) afforded 4h as a
yellow solid (0.21 g, 82%), Rf (2:1 hexane/ethyl acetate) 0.37, mp. 159–160 °C; νmax (ATR) 596, 744,
789, 836, 850, 988, 1033, 1061, 1163, 1173, 1247, 1311, 1361, 1416, 1551, 2230, 3285 cm−1; δH
(500 MHz, CDCl3) 1.85 (t, J = 6.0 Hz, 1H), 2.78 (t, J = 6.5, 2H), 3.89 (t, J = 6.5 Hz, 2H), 3.91 (s, 3H),
7.03 (d, J = 9.5 Hz, 2H), 7.86 (dd, J = 1.5 and 8.5 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 1.5 Hz,
1H), 8.54 (d, J = 9.0 Hz, 2H); δC (125 MHz, CDCl3) 23.9, 55.4, 61.1, 81.4, 89.5, 114.1, 121.9, 122.9,
128.7, 128.8, 129.1, 130.5, 137.6, 151.2, 160.2, 161.8, 162.4; m/z 339 (100, MH+); HRMS (ES): MH+,
+
found 339.0894. C19H1635ClN2O2 requires 339.0900.
3.6. Typical Procedure for the Suzuki-Miyaura-Miyaura Cross-Coupling of 4a–h
3.6.1. 4-(4-Fluorophenyl)-2-phenyl-6-(phenylethynyl)quinazoline (5a)
A stirred mixture of 4a (0.10 g, 0.29 mmol), PdCl2(PPh3)2 (0.009 g, 0.014 mmol), PCy3 (0.008 g,
0.029 mmol) and K2CO3 (0.060 g, 0.43 mmol) in 3:1 dioxane/water (v/v; 10 mL) was purged with
argon gas for 30 min. 4-Fluorophenylboronic acid (0.048 g, 0.35 mmol) was added to the mixture
using a syringe. The reaction 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 Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel to afford 5a as a yellow solid (0.089 g, 76%), Rf (2:1
hexane/toluene) 0.40, mp. 177–180 °C; νmax (ATR) cm−1 520, 570, 595, 685, 708, 752, 846, 1157,
1230, 1400, 1538, 1607, 2204; δH (500 MHz, DMSO-d6) 7.33 (t, J = 8.5 Hz, 2H), 7.38–7.39 (m, 3H),
7.52–7.57 (m, 5H), 7.93 (dd, J = 6.5 and 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz,
1H), 8.24 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 6.5 Hz, 2H); δC (125 MHz, DMSO-d6) 88.7, 91.4, 115.8 (d,
2JCF = 21.7 Hz), 121.4, 122.2, 122.5, 128.4, 128.6, 128.7, 128.8, 129.4, 129.7, 130.8, 131.7, 132.2 (d,

Molecules 2015, 20
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3JCF = 8.6 Hz), 133.3 (d, 4JCF = 2.7 Hz), 136.3, 137.8, 151.5, 160.5, 164.0 (d, 1JCF = 249.3 Hz), 166.8;
+
m/z 401 (100, MH+); HRMS (ES): MH+, found 401.1448. C28H18FN2 requires 401.1454.
3.6.2. 2,4-Bis(4-fluorophenyl)-6-(phenylethynyl)quinazoline (5b)
A mixture of 4b (0.10 g, 0.28 mmol), PdCl2(PPh3)2 (0.009 g, 0.014 mmol), PCy3 (0.008 g,
0.028 mmol), 4-fluorophenylboronic acid (0.046 g, 0.33 mmol) and K2CO3 (0.060 g, 0.43 mmol) in
aqueous dioxane (10 mL) afforded 5b as a yellow solid (0.10 g, 85%), Rf (2:1 hexane/toluene) 0.50,
mp. 220–222 °C; νmax (ATR) 523, 560, 588, 685, 750, 802, 840, 1027, 1156, 1220, 1244, 1300, 1400,
1509, 1536, 1600, 2211 cm−1; δH (500 MHz, CDCl3) 7.21 (t, J = 8.5 Hz, 2H), 7.34 (t, J = 8.5 Hz, 2H),
7.37–7.39 (m, 3H), 7.56–7.58 (m, 2H), 7.92 (dd, J = 5.5 and 8.5 Hz, 2H), 7.99 (dd, J = 2.0 and 8.5 Hz,
1H), 8.10 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.71 (t, J = 8.5 Hz, 2H); δC (125 MHz, CDCl3)
2
2
88.6, 91.5, 115.5 (d, JCF = 21.8 Hz), 115.9 (d, JCF = 21.8 Hz), 121.3, 122.3, 122.5, 128.4, 128.8,
129.3, 129.7, 130.8 (d, 3JCF = 8.6 Hz), 131.7, 132.2 (d, 3JCF = 8.6 Hz), 133.3 (d, 4JCF = 3.7 Hz), 134.0 (d,
4JCF = 3.1 Hz), 136.4, 151.4, 159.6, 164.1 (d, 1JCF = 249.3 Hz), 164.8 (d, 1JCF = 249.3 Hz), 166.8; m/z
+
419 (100, MH+); HRMS (ES): MH+, found 419.1362. C28H17F2N2 requires 419.1360.
3.6.3. 4-(4-Fluorophenyl)-2-(4-chlorophenyl)-6-(phenylethynyl)quinazoline (5c)
A mixture of 4c (0.10 g, 0.26 mmol), PdCl2(PPh3)2 (0.009 g, 0.013 mmol), PCy3 (0.007 g, 0.026 mmol),
4-fluorophenylboronic acid (0.044 g, 0.32 mmol) and K2CO3 (0.053 g, 0.39 mmol) in aqueous dioxane
(10 mL) afforded 5c as a yellow solid (0.094 g, 83%), Rf (2:1 hexane/toluene) 0.50, mp. 206–207 °C;
νmax (ATR) 499, 525, 571, 588, 689, 750, 802, 836, 1013, 1089, 1160, 1228, 1314, 1416, 1509, 1536,
1602, 2207 cm−1; δH (500 MHz, CDCl3) 7.34 (t, J = 9.0 Hz, 2H), 7.38–7.39 (m, 3H), 7.50 (d, J = 8.5 Hz,
2H), 7.56–7.57 (m, 2H), 7.91 (t, J = 8.5 Hz, 2H), 7.98 (dd, J = 1.5 and 8.5 Hz, 1H), 8.09 (d, J = 8.5 Hz,
1H), 8.23 (d, J = 1.5 Hz, 1H), 8.63 (d, J = 8.5 Hz, 2H); δC (125 MHz, CDCl3) 88.7, 91.7, 115.9 (d,
2JCF = 21.7 Hz), 121.4, 122.5, 122.6, 128.5, 128.7, 128.8, 129.4, 129.7, 130.0, 131.7, 132.2 (d,
3JCF = 8.5 Hz), 133.3 (d, 4JCF = 3.7 Hz), 136.3, 136.4, 137.1, 151.4, 159.5, 164.1 (d, 1JCF = 249.4 Hz),
166.8; m/z 435 (100, MH+); HRMS (ES): MH+, found 435.1057. C28H17N2F35Cl+ requires 435.1064.
3.6.4. 4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-6-(phenylethynyl)quinazoline (5d)
A mixture of 4d (0.10 g, 0.27 mmol), PdCl2(PPh3)2 (0.009 g, 0.013 mmol), PCy3 (0.007 g, 0.027 mmol),
4-fluorophenylboronic acid (0.044 g, 0.32 mmol) and K2CO3 (0.056 g, 0.40 mmol) in aqueous dioxane
(10 mL) afforded 5d as a yellow solid (0.091 g, 78%), Rf (2:1 hexane/toluene) 0.25, mp. 198–200 °C;
νmax (ATR) 525, 571, 588, 685, 750, 802, 842, 1027, 1161, 1245, 1300, 1401, 1510, 1536, 1601,
2211 cm−1; δH (500 MHz, CDCl3) 3.91 (s, 3H), 7.05 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 9.0 Hz, 2H),
7.37–7.39 (m, 3H), 7.56 (dd, J = 2.5 and 6.0 Hz, 2H), 7.92 (dd, J = 5.5 and 8.5 Hz, 2H), 7.96 (dd,
J = 1.5 and 9.0 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 8.65 (d, J = 9.0 Hz, 2H); δC
2
(125 MHz, CDCl3) 55.4, 88.8, 91.2, 113.9, 115.8 (d, JCF = 21.8 Hz), 121.1, 121.7, 122.6, 128.4,
3
4
128.6, 128.7, 129.1, 129.8, 130.3, 131.7, 132.1 (d, JCF = 8.5 Hz), 133.5 (d, JCF = 3.7 Hz), 136.2,
151.6, 160.3, 162.0, 164.0 (d, 1JCF = 249.4 Hz), 166.6; m/z 431 (100, MH+); HRMS (ES): MH+, found
431.1556. C29H20FN2O+ requires 431.1560.

Molecules 2015, 20
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3.6.5. 2-(4-Fluorophenyl)-4-(4-methoxyphenyl)-6-(phenylethynyl)quinazoline (5e)
A mixture of 4b (0.10 g, 0.28 mmol), PdCl2(PPh3)2 (0.009 g, 0.014 mmol), PCy3 (0.008 g,
0.028 mmol), 4-methoxyphenylboronic acid (0.050 g, 0.33 mmol) and K2CO3 (0.058 g, 0.42 mmol) in
aqueous dioxane (10 mL) afforded 5e as a yellow solid (0.096 g, 79%), Rf (2:1 hexane/toluene) 0.30,
mp. 197–200 °C; νmax (ATR) 591, 687, 754, 841, 1145, 1174, 1223, 1255, 1397, 1508, 1534, 1610,
2196 cm−1; δH (500 MHz, CDCl3) 3.96 (s, 3H), 7.16 (d, J = 9.0 Hz, 2H), 7.21 (t, J = 8.5 Hz, 2H),
7.37–7.39 (m, 3H), 7.56–7.58 (m, 2H), 7.91 (d, J = 9.0 Hz, 2H), 7.98 (dd, J = 2.0 and 9.0 Hz, 1H),
8.08 (d, J = 8.5 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.71 (dt, J = 3.5 and 8.5 Hz, 2H); δC (125 MHz,
2
CDCl3) 55.5, 88.9, 91.2, 114.2, 115.5 (d, JCF = 21.8 Hz), 121.4, 121.9, 122.7, 128.5, 128.7, 129.2,
3
4
129.8, 130.3, 130.8 (d, JCF = 8.6 Hz), 131.7, 131.9, 134.2 (d, JCF = 2.8 Hz), 136.1, 151.5, 159.6,
161.5, 164. (d, JCF = 248.3 Hz), 167.5; m/z 431 (100, MH+); HRMS (ES): MH+, found 431.1554.
1
C29H20FN2O+ requires 431.1560.
3.6.6. 2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-6-(2-phenylethynyl)quinazoline (5f)
A mixture of 4c (0.10 g, 0.26 mmol), PdCl2(PPh3)2 (0.009 g, 0.013 mmol), PCy3 (0.007 g, 0.026 mmol),
4-methoxyphenylboronic acid (0.048 g, 0.32 mmol) and K2CO3 (0.053 g, 0.39 mmol) in aqueous
dioxane (10 mL) afforded 5f as a yellow solid (0.082 g, 70%), Rf (2:1 hexane/toluene) 0.37, mp.
186–187 °C; νmax (ATR) 524, 539, 581, 685, 751, 803, 841, 1012, 1090, 1256, 1395, 1531, 1609,
2204 cm−1; δH (500 MHz, CDCl3) 3.96 (s, 3H), 7.17 (d, J = 9.0 Hz, 2H), 7.38–7.39 (m, 3H), 7.50 (d,
J = 8.5 Hz, 2H), 7.56–7.58 (m, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.5 Hz, 1H), 8.08 (d,
J = 7.0 Hz, 1H), 8.33 (s, 1H), 8.65 (d, J = 8.0 Hz, 2H); δC (125 MHz, CDCl3) 55.5, 88.8, 91.3, 114.2,
121.5, 122.1, 122.6, 128.6, 128.4, 128.7, 129.0, 129.2, 130.0, 130.2, 131.7, 131.8, 136.2, 136.5, 136.8,
151.4, 159.5, 161.4, 167.4; m/z 447 (100, MH+); HRMS (ES): MH+, found 447.1249. C29H2035ClN2O+
requires 447.1264.
3.6.7. 2,4-Bis(4-methoxyphenyl)-6-(phenylethynyl)quinazoline (5g)
A mixture of 4d (0.10 g, 0.27 mmol), PdCl2(PPh3)2 (0.009 g, 0.013 mmol), PCy3 (0.007 g, 0.027 mmol),
4-methoxyphenylboronic acid (0.049 g, 0.32 mmol) and K2CO3 (0.056 g, 0.40 mmol) in aqueous
dioxane (10 mL) afforded 5g as a yellow solid (0.095 g, 79%), Rf (2:1 hexane/toluene) 0.14, mp.
170–172 °C; νmax (ATR) 525, 574, 685, 749, 801, 840, 1024, 1159, 1246, 1299, 1399, 1511, 1532,
1604, 2202 cm−1; δH (500 MHz, CDCl3) 3.91 (d, J = 2.0 Hz, 3H), 3.95 (d, J = 2.5 Hz, 3H), 7.05 (dd,
J = 2.5 and 8.5 Hz, 2H), 7.16 (dd, J = 2.5 and 9.0 Hz, 2H), 7.37–7.38 (m, 3H), 7.55–7.57 (m, 2H), 7.91
(dd, J = 2.5 and 8.5 Hz, 2H), 7.94 (dd, J = 2.0 and 8.5 Hz, 1H), 8.05 (dd, J = 2.5 and 9.0 Hz, 1H), 8.31
(s, 1H), 8.66 (dd, J = 2.5 and 8.5 Hz, 2H); δC (125 MHz, CDCl3) 55.4, 55.5, 89.0, 90.9, 13.9, 114.2,
121.2, 121.3, 122.8, 128.4, 128.6, 129.0, 129.9, 130.3, 130.4, 130.7, 131.7, 131.8, 136.0, 151.7, 160.4,
+
161.4, 161.9, 167.3; m/z 443 (100, MH+); HRMS (ES): MH+, found 443.1750. C30H23N2O2
requires 443.1760.

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3.6.8. 4-(4-(4-Methoxyphenyl)-2-phenylquinazolin-6-yl)but-3-yn-1-ol (5h)
A mixture of 4e (0.10 g, 0.32 mmol), PdCl2(PPh3)2 (0.011 g, 0.016 mmol), PCy3 (0.009 g, 0.032 mmol),
4-fluorophenylboronic acid (0.058 g, 0.38 mmol) and K2CO3 (0.066 g, 0.48 mmol) in aqueous dioxane
(10 mL) afforded 5h as a yellow solid (0.110 g, 90%), Rf (2:1 hexane/ethyl acetate) 0.26, mp. 181–183 °C;
νmax (ATR) 528, 568, 687, 751, 800, 848, 1026, 1167, 1242, 1408, 1511, 1532, 2210, 3032, 3060 cm−1;
δH (500 MHz, CDCl3) 1.81 (s, 1H), 2.75 (t, J = 6.5 Hz, 2H), 3.86 (t, J 5.5 Hz, 2H), 3.95 (s, 3H), 7.15
(d, J = 8.0 Hz, 2H), 7.51–7.55 (m, 3H), 7.85 (dd, J = 1.5 and 8.5 Hz, 1H), 7.89 (d, J = 9.0 Hz, 2H),
8.06 (d, J = 9.0 Hz, 1H), 8.22 (s, 1H), 8.69 (dd, J = 1.5 and 8.5 Hz, 2H); δC (125 MHz, CDCl3) 23.9,
55.4, 61.0, 81.9, 88.5, 114.1, 121.3, 121.9, 128.5, 128.6, 129.1, 129.8, 130.2, 130.6, 131.8, 136.2,
138.0, 151.4, 160.4, 161.3, 167.3; m/z 381 (100, MH+); HRMS (ES): MH+, found 381.1597.
+
C25H21N2O2 requires 381.1603.
3.7. Typical Procedure for the One-Pot Sequential Sonogashira cross-Coupling of 2a–d with
Terminal Alkynes
3.7.1. 4-(2-Phenyl-6-(phenylethynyl)quinazolin-4-yl)but-3-yn-1-ol (6a)
A stirred mixture of 3a (0.30 g, 0.82 mmol), PdCl2(PPh3)2 (0.057 g, 0.082 mmol), CuI (0.008 g;
0.041 mmol) and Cs2CO3 (0.40 g, 1.23 mmol) in THF (20 mL) was purged with argon gas for 30 min.
Phenylacetylene (0.084 g, 0.82 mmol) was added to the mixture using a syringe. The reaction mixture
was stirred at room temperature for 18 h until the starting material was consumed (tlc monitoring). A
solution of 3-butyn-1-ol (0.069 g, 0.98 mmol) in THF (5 mL) was added by means of a syringe and the
mixture was heated at 80 °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 Na2SO4,
filtered and evaporated under reduced pressure. The residue was purified by column chromatography
on silica gel to afford 6a as a yellow solid (0.24 g, 78%), Rf (1:1 hexane/ethyl acetate) 0.65, mp.
163–164 °C; νmax (ATR) 522, 527, 690, 709, 748, 837, 1059, 1402, 1531, 1737, 2229, 3059, 3256 cm−1;
δH (500 MHz, CDCl3) 2.74 (br s, 1H), 2.95 (t, J = 6.5 Hz, 2H), 4.02 (t, J = 6.5 Hz, 2H), 7.39–7.42 (m,
3H), 7.51–7.55 (m, 3H), 7.61–7.63 (m, 2H), 7.95 (dd, J = 2.0 and 8.5 Hz, 1H), 8.00 (d, J = 9.0 Hz,
1H), 8.35 (d, J = 2.0 Hz, 1H), 8.56–8.58 (m, 2H); δC (125 MHz, CDCl3) 24.3, 60.6, 78.8, 88.7, 91.9,
97.8, 122.6, 122.7, 123.7, 128.5, 128.6, 128.7, 128.8, 129.0, 129.5, 130.7, 131.8, 136.9, 137.4, 150.3,
152.3, 161.1; m/z 375 (100, MH+); HRMS (ES): MH+, found 375.1487. C26H19N2O+ requires 375.1497.
3.7.2. 4-(2-(4-Fluorophenyl)-6-(phenylethynyl)quinazolin-4-yl)but-3-yn-1-ol (6b)
A mixture of 3b (0.30 g, 0.78 mmol), PdCl2(PPh3)2 (0.054 g, 0.078 mmol), CuI (0.007 g, 0.039 mmol),
Cs2CO3 (0.38 g, 1.17 mmol) and phenylacetylene (0.079 g, 0.78 mmol) in THF (20 mL), followed by
the addition of 3-butyn-1-ol (0.065 g, 0.93 mmol) in THF (5 mL) was treated as described for 6a to
afford 6b as a yellow solid (0.17 g, 55%), Rf (1:1 hexane/ethyl acetate) 0.60, mp. 174–175 °C; νmax
(ATR) 528, 570, 691, 744, 758, 839, 1060, 1154, 1224, 1295, 1404, 1532, 2230, 3050, 3271 cm−1; δH
(500 MHz, CDCl3) 2.25 (br s, 1H), 2.98 (t, J = 6.0 Hz, 2H), 4.04 (d, J = 6.0 Hz, 2H), 7.20 (t, J = 8.5 Hz,
2H), 7.40–7.41 (m, 3H), 7.61–7.63 (m, 2H), 7.96 (dd, J = 2.0 and 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz,

Molecules 2015, 20
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1H), 8.39 (d, J = 2.0 Hz, 1H), 8.61 (t, J = 8.5 Hz, 2H); δC (125 MHz, CDCl3) 24.3, 60.6, 78.6, 88.6,
91.9, 98.1, 115.6 (d, 2JCF = 21.8 Hz), 122.6, 122.7, 123.5, 128.5, 128.9, 129.4, 130.8 (d, 3JCF = 8.5 Hz),
131.8, 133.7 (d, 4JCF = 3.0 Hz), 137.0, 146.1, 150.2, 152.3, 160.1, 164.8 (d, 1JCF = 248.3 Hz); m/z 393
(100, MH+); HRMS (ES): MH+, found 393.1412. C26H18FN2O+ requires 393.1403.
3.7.3. 4-(2-(4-Chlorophenyl)-6-(phenylethynyl)quinazolin-4-yl)but-3-yn-1-ol (6c)
A mixture of 3c (0.30 g, 0.75 mmol), PdCl2(PPh3)2 (0.052 g, 0.074 mmol), CuI (0.007 g, 0.037 mmol),
Cs2CO3 (0.36 g, 1.12 mmol) and phenylacetylene (0.076 g, 0.75 mmol) in THF (20 mL), followed by
the addition of 3-butyn-1-ol (0.062 g, 0.89 mmol) in THF (5 mL) was treated as described for 6a to
afford 6c as a yellow solid (0.20 g, 65%), Rf (1:1 hexane/ethyl acetate) 0.70, mp. 202–204 °C; νmax
(ATR) 525, 567, 684, 737, 749, 837, 1039, 1087, 1296, 1402, 1532, 2233, 3048, 3252 cm−1; δH
(500 MHz, CDCl3) 2.40 (br s, 1H), 2.97 (t, J = 6.5 Hz, 2H), 4.03 (t, J = 6.5 Hz, 2H), 7.40–7.41 (m, 3H),
7.48 (d, J = 8.5 Hz, 2H) 7.60–7.62 (m, 2H), 7.94 (d, J = 8.5 Hz, 2H), 8.31 (s, 1H), 8.50 (d,
J = 8.5 Hz, 2H); δC (125 MHz, CDCl3) 24.3, 60.6, 78.6, 88.6, 92.1, 98.1 122.6, 122.9, 123.6, 128.5,
128.8, 128.9, 129.0, 129.4, 130.0, 131.8, 135.9, 137.0, 137.1, 150.3, 152.3, 160.0; m/z 409 (100,
MH+); HRMS (ES): MH+, found 409.1104. C26H18N2O35Cl+ requires 409.1108.
3.7.4. 4-(2-(4-Methoxyphenyl)-6-(phenylethynyl)quinazolin-4-yl)but-3-yn-1-ol (6d)
A mixture of 3d (0.30 g, 0.75 mmol), PdCl2(PPh3)2 (0.053 g, 0.075 mmol), CuI (0.007 g, 0.037 mmol),
Cs2CO3 (0.36 g, 1.12 mmol) and phenylacetylene (0.076 g, 0.75 mmol) in THF (20 mL), followed by
the addition of 3-butyn-1-ol (0.063 g, 0.90 mmol) in THF (5 mL) was treated as described for 6a to
afford 6d as a yellow solid (0.20 g, 66%), Rf (1:1 hexane/ethyl acetate) 0.50, mp. 141–142 °C; νmax
(ATR) 527, 569, 690, 748, 837, 1027, 1059, 1217, 1402, 1531, 1737, 2229, 3040, 3256 cm−1;
δH (500 MHz, CDCl3) 2.74 (br s, 1H), 2.95 (t, J = 6.5 Hz, 2H), 3.89 (s, 3H), 4.02 (t, J = 6.5 Hz, 2H),
7.02 (d, J = 9.0 Hz, 2H), 7.39–7.41 (m, 3H), 7.60–7.62 (m, 2H), 7.76 (dd, J = 2.0 and 8.5 Hz, 1H),
7.94 (d, J = 8.5 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 8.5 Hz, 2H); δC (125 MHz, CDCl3) 24.4,
55.4, 60.6, 78.7, 88.8, 91.6, 97.7, 113.9, 122.1, 122.7, 123.3, 128.5, 128.7, 128.8, 129.5, 130.0, 130.4,
131.8, 136.8, 150.3, 152.2, 160.8, 162.1; m/z 405 (100, MH+); HRMS (ES): MH+, found 405.1600.
+
C27H21N2O2 requires 405.1603.
3.7.5. 4-(2-Phenyl-4-(phenylethynyl)quinazolin-6-yl)but-3-yn-1-ol (6e)
A mixture of 3a (0.30 g, 0.82 mmol), PdCl2(PPh3)2 (0.057 g, 0.082 mmol), CuI (0.008 g, 0.041 mmol),
Cs2CO3 (0.40 g, 1.23 mmol) and 3-butyn-1-ol (0.057 g, 0.82 mmol) in THF (20 mL), followed by the
addition of phenylacetylene (0.10 g, 0.98 mmol) in THF (5 mL) was treated as described for 6a to
afford 6e as a yellow solid (0.19 g, 61%), Rf (1:1 hexane/ethyl acetate) 0.67, mp. 126–127 °C; νmax
(ATR) 546, 687, 708, 755, 838, 1037, 1309, 1409, 1527, 2208, 2922, 3058, 3358 cm−1; δH (500 MHz,
CDCl3) 1.89 (s, 1H), 2.80 (t, J = 5.5 Hz, 2H), 3.90 (t, J = 5.5 Hz, 2H), 7.48–7.55 (m, 6H), 7.81 (d,
J = 6.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 8.41 (s, 1H), 8.64 (d, J = 6.5 Hz,
2H); δC (125 MHz, CDCl3) 23.9, 61.0, 81.8, 85.4, 89.4, 982, 121.2, 122.8, 123.6, 128.6, 128.7, 128.8,

Molecules 2015, 20
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129.0, 129.4, 130.2, 130.8, 132.6, 137.1, 137.5, 150.3, 152.3 161.2; m/z 375 (100, MH+); HRMS (ES):
MH+, found 375.1495. C26H19N2O+ requires 375.1497.
3.7.6. 4-(2-(4-Fluorophenyl)-4-(phenylethynyl)quinazolin-6-yl)but-3-yn-1-ol (6f)
A mixture of 3b (0.30 g, 0.78 mmol), PdCl2(PPh3)2 (0.054 g, 0.078 mmol), CuI (0.007 g, 0.039 mmol),
Cs2CO3 (0.38 g, 1.17 mmol) and 3-butyn-1-ol (0.054 g, 0.78 mmol) in THF (20 mL), followed by the
addition of phenylacetylene (0.095 g, 0.93 mmol) in THF (5 mL) was treated as described for 6a to
afford 6f as a yellow solid (0.16 g, 52%), Rf (1:1 hexane/ethyl acetate) 0.50, mp. 150–152 °C; νmax
(ATR) 566, 690, 742, 760, 835, 1037, 1148, 1221, 1308, 1404, 1509, 1527, 2209, 2922, 3316 cm−1; δH
(500 MHz, CDCl3) 2.02 (br s, 1H), 2.79 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 6.0 Hz, 2H), 7.20 (t, J = 9.0 Hz,
2H), 7.46–7.51 (m, 3H), 7.79 (d, J = 7.5 Hz, 2H), 7.85 (dd, J = 2.0 and 8.5 Hz, 1H), 7.97 (d, J = 9.0 Hz,
1H), 8.36 (d, J = 2.0 Hz, 1H), 8.64 (t, J = 7.5 Hz, 2H); δC (125 MHz, CDCl3) 25.0, 61.1, 81.7, 85.3, 89.5,
98.4, 115.6 (d, 2JCF = 21.8 Hz), 121.2, 122.9, 123.5, 128.7, 128.9, 129.4, 130.3, 130.9 (d, 3JCF = 8.6 Hz),
131.7, 133.5 (d, 4JCF = 3.5 Hz), 136.9, 137.2, 150.2, 152.3, 160.2, 164.8 (d, 1JCF = 249.3 Hz); m/z 393
(100, MH+); HRMS (ES): MH+, found 393.1396. C26H18FN2O+ requires 393.1403.
3.7.7. 4-(2-(4-Chlorophenyl)-4-(phenylethynyl)quinazolin-6-yl)but-3-yn-1-ol (6g)
A mixture of 3c (0.30 g, 0.75 mmol), PdCl2(PPh3)2 (0.052 g, 0.074 mmol), CuI (0.007 g, 0.037 mmol),
Cs2CO3 (0.36 g, 1.12 mmol) and 3-butyn-1-ol (0.052 g, 0.75 mmol) in THF (20 mL), followed by the
addition of phenylacetylene (0.091 g, 0.89 mmol) in THF (5 mL) was treated as described for 6a to
afford 6g as a yellow solid (0.23 g, 75%), Rf (1:1 hexane/ethyl acetate) 0.40, mp. 181–182 °C; νmax
(ATR) 569, 683, 736, 748, 838, 1012, 1089, 1167, 1308, 1401, 1530, 2213, 2921, 3256 cm−1; δH
(500 MHz, CDCl3) 1.86 (br s, 1H), 2.80 (t, J = 6.0 Hz, 2H), 3.91 (t, J = 6.5 Hz, 2H), 7.47–7.51 (m,
5H), 7.80 (d, J = 8.5 Hz, 2H), 7.88 (dd, J = 2.0 and 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 8.40 (d,
J = 2.0 Hz, 1H), 8.60 (d, J = 8.5 Hz, 2H); δC (125 MHz, CDCl3) 24.0, 61.1, 81.7, 85.3, 89.7, 98.5,
121.2, 123.1, 123.6, 128.7, 128.8, 128.9, 129.4, 130.0, 130.3, 132.6, 136.0, 137.1, 137.3, 150.2, 152.3,
160.1; m/z 409 (100, MH+); HRMS (ES): MH+, found 409.1101. C26H18N2O35Cl+ requires 409.1108.
3.7.8. 4-(2-(4-Methoxyphenyl)-4-(phenylethynyl)quinazolin-6-yl)but-3-yn-1-ol (6h)
A mixture of 3d (0.30 g, 0.75 mmol), PdCl2(PPh3)2 (0.053 g, 0.075 mmol), CuI (0.007 g, 0.037 mmol),
Cs2CO3 (0.36 g, 1.12 mmol) and 3-butyn-1-ol (0.052 g, 0.75 mmol) in THF (20 mL), followed by the
addition of phenylacetylene (0.091 g, 0.90 mmol) in THF (5 mL) was treated as described for 6a to
afford 6h as a yellow solid (0.18 g, 59%), Rf (1:1 hexane/ethyl acetate) 0.51, mp. 175–177 °C; νmax
(ATR) 560, 687, 746, 756, 836, 1025, 1166, 1246, 1306, 1409, 1514, 1528, 2211, 2926, 3418 cm−1; δH
(500 MHz, CDCl3) 1.91 (br s, 1H), 2.79 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 6.0 Hz, 2H), 3.91 (s, 3H), 7.04
(d, J = 9.0 Hz, 2H), 7.46–7.50 (m, 3H), 7.80 (dd, J = 2.0 and 8.0 Hz, 2H), 7.84 (dd, J = 1.5 and 9.0 Hz,
1H), 7.96 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.60 (d, J = 9.0 Hz, 2H); δC (125 MHz, CDCl3)
24.0, 55.4, 61.1, 81.8, 85.5, 89.2, 97.9, 113.9, 121.3, 122.3, 123.3, 128.4, 128.6, 128.8, 129.5, 130.1,
130.2, 130.4, 132.6, 137.1, 150.4, 161.0, 162.1; m/z 405 (100, MH+); HRMS (ES): MH+, found
+
405.1602. C27H21N2O2 requires 405.1603.

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3.8. Typical Procedure for the One-Pot Sequential Sonogashira and Stille Cross-Coupling of 2a–d
3.8.1. 4-(Furan-2-yl)-2-phenyl-6-(phenylethynyl)quinazoline (7a)
A stirred mixture of 3a (0.10 g, 0.27 mmol), PdCl2(PPh3)2 (0.019 g, 0.027 mmol), CuI (0.002 g,
0.013 mmol) and Cs2CO3 (0.13 g, 0.40 mmol) in THF (10 mL) was purged with argon gas for 30 min.
Phenylacetylene (0.027 g, 0.27 mmol) was added to the mixture using a syringe. The reaction mixture
was stirred at room temperature for 18 h until the starting material was consumed (tlc monitoring).
A solution of 2-(tributylstannyl)furan (0.11 g, 0.32 mmol) in THF (5 mL) was added by means of a
syringe and the mixture was heated at 80 °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 MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel to afford 7a as a yellow solid (0.056 g, 56%), Rf (2:1 hexane/toluene)
0.25, mp. 184–186 °C; νmax (ATR) 525, 592, 686, 703, 752, 918, 996, 1314, 1474, 1532, 2202 cm−1; δH
(500 MHz, CDCl3) 6.72 (dd, J = 1.5 and 3.0 Hz, 1H), 7.39–7.40 (m, 3H), 7.51–7.56 (m, 3H) , 7.61–7.63
(m, 2H), 7.75 (d, J = 3.5 Hz, 1H), 7.86 (s, 1H), 7.95 (dd, J = 1.5 and 8.5 Hz, 1H), 8.04 (d, J = 8.5 Hz,
1H), 8.66 (d, J = 7.0 Hz, 2H), 9.10 (d, J = 1.5 Hz, 1H); δC (125 MHz, CDCl3) 89.2, 91.1, 112.4, 116.3,
119.3, 122.2, 122.8, 128.4, 128.5, 128.6, 128.7, 129.3, 130.0, 130.6, 131.7, 136.1, 137.8, 146.1, 152.2,
153.9, 154.7, 160.4; m/z 373 (100, MH+); HRMS (ES): MH+, found 373.1332. requires 373.1341.
3.8.2. 2-(4-Fluorophenyl)-4-(furan-2-yl)-6-(phenylethynyl)quinazoline (7b)
A mixture of 3b (0.10 g, 0.26 mmol), PdCl2(PPh3)2 (0.018 g, 0.026 mmol), CuI (0.002 g, 0.013 mmol),
Cs2CO3 (0.13 g, 0.39 mmol) and phenylacetylene (0.026 g, 0.26 mmol) in THF (10 mL), followed by
the addition of 2-(tributylstannyl)furan (0.11 g, 0.31 mmol) in THF (5 mL) was treated as for 7a to
afford 7b as a yellow solid (0.062 g, 62%), Rf (2:1 hexane/toluene) 0.30, mp. 195–196 °C; νmax (ATR)
524, 574, 684, 742, 840, 1015, 1220, 1398, 1511, 1534, 2203 cm−1; δH (500 MHz, CDCl3) 6.72 (dd,
J = 1.5 and 3.5 Hz, 1H), 7.39–7.41 (m, 3H), 7.50 (d, J = 8.0 Hz, 2H), 7.61–7.62 (m, 2H), 7.73 (d,
J = 3.5 Hz, 1H), 7.87 (s, 1H), 7.95 (dd, J = 2.0 and 8.5 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 8.66 (d,
J = 8.5 Hz, 2H) 9.09 (d, J = 1.5 Hz, 1H); δC (125 MHz, CDCl3) 89.1, 91.2, 112.4, 115.4 (d,
2JCF = 21.7 Hz), 116.3, 119.2, 122.3, 122.8, 128.4, 128.7, 129.1, 130.0, 130.6 (d, 3JCF = 8.5 Hz), 131.7,
134.0 (d, 4JCF = 2.7 Hz), 136.2, 146.2, 152.1, 153.8, 154.7, 159.5, 164.7 (d, 1JCF = 249.3 Hz); m/z 391
(100, MH+); HRMS (ES): MH+, found 391.1238. C26H16N2OF+ requires 391.1247.
3.8.3. 2-(4-Chlorophenyl)-4-(furan-2-yl)-6-(phenylethynyl)quinazoline (7c)
A mixture of 3c (0.10 g, 0.25 mmol), PdCl2(PPh3)2 (0.018 g, 0.025 mmol), CuI (0.002 g, 0.012 mmol),
Cs2CO3 (0.12 g, 0.37 mmol) and phenylacetylene (0.026 g, 0.25 mmol) in THF (10 mL), followed by
the addition of 2-(tributylstannyl)furan (0.11 g, 0.30 mmol) in THF (5 mL) was treated as for 7a to
afford 7c as a yellow solid (0.070 g, 69%), Rf (2:1 hexane/toluene) 0.36, mp. 164–166 °C; νmax (ATR)
524, 539, 682, 736, 745, 849, 1013, 1089, 1400, 1532, 1580, 2207 cm−1; δH (500 MHz, CDCl3) 6.72
(dd, J = 1.5 and 3.5 Hz, 1H), 7.39–7.40 (m, 3H), 7.49 (d, J = 8.5 Hz, 2H), 7.61–7.62 (m, 2H), 7.72 (d,
J = 3.5 Hz, 1H), 7.87 (s, 1H), 7.94 (dd, J = 1.5 and 8.5 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 8.60 (t,

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J = 9.0 Hz, 2H) 9.09 (d, J = 1.5 Hz, 1H); δC (125 MHz, CDCl3) 89.1, 91.3, 112.5, 116.4, 119.3, 122.5,
122.7, 128.4, 128.6, 128.7, 129.2, 129.8, 130.0, 131.7, 132.6, 136.3, 136.8, 146.2, 152.1, 153.8, 154.7,
159.4; m/z 407 (100, MH+); HRMS (ES): MH+, found 407.0939. C26H16N2O35Cl+ requires 407.0951.
3.8.4. 4-(Furan-2-yl)-2-(4-methoxyphenyl)-6-(phenylethynyl)quinazoline (7d)
A mixture of 3d (0.10 g, 0.25 mmol), PdCl2(PPh3)2 (0.018 g, 0.025 mmol), CuI (0.002 g, 0.012 mmol),
Cs2CO3 (0.12 g, 0.37 mmol) and phenylacetylene (0.026 g, 0.25 mmol) in THF (10 mL), followed by
the addition of 2-(tributylstannyl)furan (0.11 g, 0.30 mmol) in THF (5 mL) was treated as for 7a to
afford 7d as a yellow solid (0.059 g, 59%), Rf (toluene) 0.50, mp. 148–150 °C; νmax (ATR) 529, 574,
574, 690, 744, 836, 1010, 1163, 1246, 1407, 1514, 2217 cm−1; δH (500 MHz, CDCl3) 3.91 (s, 3H), 6.71
(dd, J = 1.5 and 3.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.38–741 (m, 3H), 7.60–7.62 (m, 2H), 7.72 (d,
J = 3.5 Hz, 1H), 7.86 (s, 1H), 7.93 (dd, J = 1.5 and 8.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 8.62 (d,
J = 8.5 Hz, 2H) 9.07 (d, J = 1.5 Hz, 1H); δC (125 MHz, CDCl3) 55.3, 89.3, 90.9, 112.4, 113.8, 116.1,
119.1, 121.7, 122.9, 128.4, 128.6, 129.0, 130.0, 130.2, 130.5, 131.7, 136.0, 146.0, 152.2, 153.9, 154.6,
+
160.3, 161.9; m/z 403 (100, MH+); HRMS (ES): MH+, found 403.1439. C27H19N2O2 requires 403.1447.
3.9. Computational Method
Compounds 5a–h were fully optimized in the gas phase using density functional theory (DFT)
method. [19] The functional used was CAM-B3LYP [20] and the basis sets for all atoms were
6-31G(d,p). The compounds were also fully optimized using the same functional and basis set
in CH2Cl2 as the solvent based on the Polarizable Continuum Model (PCM) as developed by
Tomasi et al. [21,22] Frequency computations were performed to identify the nature of the stationary
points. All computations were carried out using Gaussian09 [23] running on Gridchem [24,25].
4. Conclusions
In summary, we have demonstrated that the 2-aryl-4-chloro-6-iodoquinazolines undergo palladium
catalyzed sequential and chemoselective Sonogashira and Suzuki-Miyaura reactions to afford novel
unsymmetrical polycarbo-substituted quinazolines with potential photophysical properties. Successful
discernment of the relative reactivity of the two Csp2-halogen bonds (trend: Csp2-I > C(4)-Cl) of the
2-aryl-4-chloro-6-iodoquinazolines facilitated single-pot bis-Sonogashira and successive Sonogashira/
Stille cross-coupling reactions co-catalyzed by PdCl2(PPh3)2 and CuI to afford novel unsymmetrical
polycarbo-substituted quinazolines. The one-pot double bifunctionalization approach employed in this
investigation is in our opinion cost effective from an economic and environmental point of view
because it makes use of a single catalyst mixture and avoids several workup and separation stages
involving large quantities of solvents. From a synthesis point of view, it would be interesting to extend
this approach towards 4-chloroquinazoline scaffold decorated with two different halogen atoms, e.g.,
Br and I on the fused benzo ring to establish a general trend in the reactivity of Csp2-X bond for the
polyhalogenated quinazoline series. Preliminary results on the photophysical properties of compounds
5a–g, 6d and 7d reveal that the 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

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of the 2- and 4-aryl groups. These photophysical property results serve as a pre-requisite to further
detailed studies of photophysics and photochemistry as a prelude to compounds with nonlinear optical
properties. Likewise, the prevalence of alkynyl and aryl/heteroaryl substituents in biologically relevant
polycarbo-substituted quinazolines such as potent epidermal growth factor receptor (EGFR), tyrosine
kinase inhibitors [26], and liver X-receptor modulators [27]. Thus polycarbo-substituted quinazolines
prepared in this investigation represent suitable candidates for studies of biological activity.
Supplementary Materials
1
1H-NMR spectra for 5g in CDCl3 and CDCl3-TFA mixture (S1–S3) as well as copies of H- and
13C-NMR spectra of all the new compounds (Figure S4). All the Cartesian coordinates are also listed in
the supplementary materials (S5). Supplementary materials can be accessed at: http://www.mdpi.com/
1420-3049/20/08/14656/s1.
Acknowledgments
The authors are grateful to the University of South Africa and the National Research Foundation for
financial assistance. We also thank R.M. Mampa of the University of Limpopo for NMR spectral data.
The computational work used the Extreme Science and Engineering Discovery Environment
(XSEDE), which is supported by National Science Foundation grant number OCI-1053575.
Author Contributions
The results of this investigation form part of H.K.P.’s PhD project at UNISA under the supervision
of M.J.M. who is the lead author. L.R. and P.R. performed the quantum chemical calculations and
contributed in the discussion of the corresponding results.
Conflicts of Interest
The authors declare no conflict of interest.
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© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).