Synthesis and Photophysical Property Studies of the 2,6,8-Triaryl-4-(phenylethynyl)quinazolines

The 2-aryl-6,8-dibromo-4-chloroquinazolines derived from the 2-aryl-6,8-dibromoquinazolin-4(3H)-ones were subjected to the Sonogashira cross-coupling with terminal acetylenes at room temperature to afford novel 2-aryl-6,8-dibromo-4-(alkynyl)quinazoline derivatives. Further transformation of the 2-aryl-6,8-dibromo-4-(phenylethynyl)quinazolines via Suzuki-Miyaura cross-coupling with arylboronic acids occurred without selectivity to afford the corresponding 2,6,8-triaryl-4-(phenylethynyl)quinazolines. The absorption and emission properties of these polysubstituted quinazolines were also determined.


Introduction
Halogenated quinazolines constitute important substrates for structural elaboration via metalcatalyzed carbon-carbon bond formation to afford novel polysubstituted quinazoline derivatives. It has been established that the order of reactivity of carbon-halogen bonds, C-I > C-Br >> C-Cl, in transition metal-mediated cross-coupling of aryl/heteroaryl halides allows selective coupling with iodides or bromides in the presence of chlorides [1,2]. Although the bond dissociation energy (BDE) of the C-Cl bond at the 4-position (84.8 kcal/mol at B3LYP) of 6-bromo-2,4-dichloroquinazoline is larger than that of the weaker C-Br bond (83 kcal/mol at B3LYP) [3], the selectivity of Pd-catalyzed cross-coupling favours C-4 substitution due to α-nitrogen effect [4,5]. For cross-coupling reactions employing 2,4-dichloroquinazoline, for example, exclusive selectivity for the most electrophilic C-4 position is favoured [3,4,6]. Likewise, regioselective Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of 2,4,7-trichloroquinazoline with aryl-and heteroarylboronic acids favours coupling at C-4 position albeit in low yield due to competitive hydrolysis at this site [7]. Attempts to achieve monosubstitution via the Stille cross-coupling with 6-bromo-2,4-dichloroquinazoline, on the other hand, resulted in mixtures of the C-4 (major) and C-6 (minor) cross-coupled products [4]. However, Sonogashira cross-coupling of 6-bromo-2,4-dichloroquinazoline with stoichiometric amount of terminal alkynes led to exclusive replacement of the 4-chloro atom [5]. During our research on the development of novel polysubstituted heterocycles [8,9], we became interested in the synthesis of polysubstituted quinazolines in which the electron-deficient quinazoline framework is linked to the 4-phenyl ring via π-conjugated spacer and to the 6-and 8-aryl rings directly to comprise donor-π-acceptor systems. We envisioned that the 2-aryl-6,8-dibromo-4-chloroquinazolines represent suitable candidates for sequential Pd-catalyzed Sonogashira and Suzuki cross-coupling to afford the requisite polysubstituted quinazolines with potential photophysical properties.

Sonogashira Cross-Coupling of the 2-Aryl-6,8-dibromo-4-chloroquinazolines
Sonogashira cross-coupling of 4a with phenylacetylene (1.5 equiv.) in the presence of tetrakis(triphenylphosphine)palladium(0), CuI and Cs 2 CO 3 in THF at room temperature for 24 h afforded product 5a, exclusively. The reaction conditions were extended to other substrates using phenylacetylene, 2-ethynylpyridine and 3-butyn-2-ol to afford products 5b-h (Scheme 3). The analogous 2-substituted quinazolines bearing alkynyl substituent on the C-4 or C-6 position exhibit excellent EGFR or Aurora A kinase inhibition activity [23]. The presence of the two bromine atoms in compounds 5 makes them suitable candidates for further transformation through transition metal-catalyzed cross-coupling or metal exchange reactions to enable adequate diversity on the heterocycle. This prompted us to explore the reactivity of compounds 5 in palladium catalyzed Suzuki-Miyaura cross-coupling with arylboronic acids as models for Csp 2 -Csp 2 bond formation.

Suzuki-Miyaura Cross-Coupling of the 2-Aryl-6,8-dibromo-4-(phenylethynyl)quinazolines
We first subjected compounds 5a-d to 1-1.5 equiv. of the arylboronic acid using PdCl 2 (PPh 3 ) 2 /PCy 3 as catalyst complex, K 2 CO 3 as a base in dioxane (aq) under reflux. We isolated after 4 h the dicoupled product in low to moderate yields (30-50%) along with the starting material without any traces of the mono cross-coupled derivative. This observation was found to compare with previous literature results for the Suzuki-Miyaura cross-coupling reactions of the analogous 2-arylquinolines bearing two bromine atoms on the fused benzo ring [9] and 3,6,8-tribromoquinoline which occur without selectivity [24]. Computed bond dissociation energies at B3LYP and G3B3 levels reveal that all of the positions on the fused benzo ring of various heterocycles bearing identical halogen atoms have comparable C-X bond dissociation energies [3]. This presumably accounts for the observed lack of selectivity. In analogy with the literature precedents on the analogous di/tribromoquinolines, we opted for the use of an excess arylboronic acid (2.5 equiv.) on compounds 5a-d and we isolated the corresponding tetrasubstituted quinazolines 6a-h in more than 50% yields (Scheme 4).  The molecular backbone of compounds 6a-l comprises of the electron-deficient quinazoline framework as an electron-acceptor linked to the 4-phenyl ring via π-conjugated spacer and to the 6-and 8-aryl rings directly to comprise donor-π-acceptor systems.

Photophysical Property Studies of Compounds 6
To understand the influence of substituents on intramolecular charge transfer (ICT), absorption and emission spectra were measured in solution for compounds 6a-l. Electronic properties of compounds 6a-l were studied by UV/Vis and fluorescence spectroscopy in conjunction with quantum chemical calculations to establish the effect of substituents on the absorption and emission properties of these polysubstituted quinazoline derivatives. The electronic absorption spectra of compounds 6a-l (Figures 1-3) were acquired in CHCl 3 and are characterized by intense broad bands in the ultraviolet region λ 270-295 nm. These bands are attributed to the π-π* transition and the intramolecular donor-acceptor charge transfer absorption, respectively [25]. Both the absorption maxima and wavelength within each series are influenced by the variation of substituents on the para position of the aryl groups on the fused benzo ring and the 2-aryl substituents. In the case of the 2-phenyl derivatives 6a, 6e and 6i, intensity of the absorption bands decreases with increasing conjugative effect of the substituent on the 2-aryl ring, 6a > 6e > 6i, and is accompanied by the reverse trend in peak broadening (6a < 6e < 6i). Moreover, the absorption wavelengths for 6e and 6i bearing the moderately and strongly donating 4-fluorophenyl-and 4-methoxyphenyl substituents are blue shifted relative to 6a. Increased intensity of the absorption maxima is observed in the spectra of all the 2-(4-fluorophenyl) substituted derivatives 6b, 6f and 6j. The trend in molar extinction coefficients, 6j > 6f > 6b, reflects the electron donating effect of the 6-and 8-aryl rings. The presence of a strong electron withdrawing 2-(4-chlorophenyl) group in compounds 6g and 6k causes the moderately resonance donating 4-fluorophenyl and strongly donating 4-methoxyphenyl groups to increase the π-π* transition resulting in increased absorption intensities for these compounds. Reduced intensity of the absorption maxima due to reduced π-π* transition accompanied by increased broadening are observed for 6c bearing the 6-and 8-phenyl groups. A combination of the 2-(4-methoxyphenyl) substituent with phenyl groups in 6d or with the 4-methoxyphenyl groups at the 6-and 8-positions in compounds 6h and 6l resulted in reduced intensity of the absorption maxima and increased broadening. Increased peak broadening and reduced intensity indicate that the strong electron donating methoxy groups interfere with the conjugation of the π electrons presumably restricting the transition from bonding orbital to antibonding orbital. The additional low intensity band observed for compound 6l at μ ca. 320 nm is probably the consequence of poor through-space charge transfer by the strongly electron donating 4-methoxyphenyl groups at the 6-and 8-positions.

Emission properties of the 2,6,8-triaryl-4-(phenylethynyl)quinazolines 6a-l
The emission properties of compounds 6a-l have also been studied at room temperature in the moderately polar chloroform (Figures 4-6) and strongly polar DMF (Figures 7-9) at the excitation wavelengths, λ ex = 380 nm and 400 nm, respectively. Their emission spectra in both solvents are characterized by intense single emission bands attributed to increased π-π* transition resulting from direct π-electron delocalization by the aryl groups and through the conjugate bridge towards the electron-deficient quinazoline ring. Moreover, within each series the emission wavelengths, Stokes shift and the fluorescence quantum yields are influenced by the variation of substituents on either the para position of the 2-aryl or the 6-and 8-aryl groups (Table 1). Compounds 6a and 6e, for example, exhibit relatively reduced emission intensities in CHCl 3 than 6i bearing the 4-methoxyphenyl groups at 6-and 8-positions. Moreover, the following trends in Stokes shift and quantum yields: 6i > 6e > 6a are consistent with the conjugative effects of the 6-and 8-aryl substituents. Likewise, compound 6j exhibits larger Stokes shift than 6b and 6f, but with lower quantum yield.   Since the π,π* state is much more polarizable than the ground state, a change in polarity of the medium has been previously found to cause measurable displacements of the π-π* transition towards the red bands [26]. The emission spectra of compounds 6a-l in DMF are also characterized by intense single emission bands (Figures 7-9). For the 4-phenylethynylquinazolines 6a, 6f and 6l bearing similar aryl groups at the 2-, 6-and 8-positions, the presence of strongly electron donating 4-methoxyphenyl groups in compound 6l leads to reduced emission intensity, which is accompanied by higher emission wavelength. A similar trend in intensity is observed for compounds 6c, 6g and 6k bearing a strong electron withdrawing chloro group on the 2-phenyl ring. However, a combination of the 2-(4-chlorophenyl) and 6-and 8-(4-fluorophenyl) groups leads to decreased emission wavelength. For the 2-(4-methoxyphenyl) derivatives 6d, 6h and 6l the emission intensity seems to be influenced by the electron donating effect of the 6-and 8-(4-ethoxyphenyl) rings. Additional interaction of DMF with the methoxy group of 6d would reduce the propensity of the 2-(4-methoxyphenyl) substituent for π-electron pair delocalization into the quinazoline ring. Such interaction would probably result in relatively less pronounced ICT and therefore reduced maxima for 6d ( Figure 7). Relatively increased emission maxima observed in the spectra of compounds 6h ( Figure 8) and 6l ( Figure 9) in DMF are presumably due to increased π-electron delocalization into the quinazoline ring by the moderately and strongly donating 4-fluorophenyl and 4-methoxyphenyl groups, respectively. A combination of the 2-(4-methoxyphenyl) group and the 4-fluorophenyl groups at the 6-and 8-positions in 6h, on the other hand, leads to red shift of the emission maxima ( Figure 8). An additional undesired red-shifted emission band of reduced intensity exhibited by 6h in DMF is presumably due to the re-absorption of light emitted and/ or molecular excited state interaction with a ground state molecule leading to a partial transfer of charge in the molecule [27]. The emission spectra of compounds 6i-l showed pronounced red shifts with increasing solvent polarity and the intensities of their emission maxima in DMF seem to be influenced by the electronic effect of the substituent on the para position of the 2-phenyl group: MeO>H>F>Cl ( Figure 9). The solvent-dependent emission characteristics may result from the dipolar interaction with DMF thus suggesting the ICT character of the emission state [28].

Quantum Chemical Calculations
To further establish the structural features and molecular orbitals of compounds 6, we carried out a theoretical approach using density functional theory at the B3LYP/6-31G* level. The geometries were optimized using CAM-B3LYP/6-31G(d,p) [29] as implemented in Gaussian 09 suite [30] to obtain reasonable structures for the subsequent electronic structure computations. Based upon the CAM-B3LYP geometries, single-point ZINDO/S calculations were preformed in chloroform as inexpensive, rapid and relatively accurate computations [31]. Compound 6a was chosen as a representative model to assign the absorption bands in the electronic spectra. The lowest energy band at 373 nm which represents S 1 state has moderate oscillator strength of ca. 0.5. This band is assigned mainly to the electronic transition between the frontier orbitals, where the HOMO→LUMO transition is the main contribution to the first excited state (S 1 ). The HOMO is delocalized over the entire molecule whereas the LUMO shrinks toward the quinazoline core ( Figure 10) and these represent π and π* orbitals, respectively. The band located at 328 nm with oscillator strength of 0.3 is based on S 4 singlet state. This state consists of HOMO→LUMO (55%), HOMO-1→LUMO (15%) and HOMO→LUMO+1 (15%). The HOMO-1 is mainly localized over the 6-and 8-aryl groups, while the LUMO-1 is mainly localized on the quinazoline framework, 2-and 8-aryl moieties. The most intense band at 298 nm, on the other hand, arises from the electronic excitation to S 7 singlet state, which consists predominantly of HOMO-1→LUMO (47%) and HOMO→LUMO+1 (25%) transitions. Similar results were observed for the other compounds. Figure 10 shows the HOMO and LUMO of 6a, 6f and 6k and no great changes were observed on the electron density distributions. The computed spectral profiles of 6a, 6f and 6k were chosen and are presented in Figure 11 in order to reveal the effect of substitution on the para position of the 2-, 6-and 8-phenyl groups on the electronic spectra. The presence of electron donating group on the para positions of the phenyl ring causes a blue shift (ca. 15 nm) in compounds 6a to 6l. The calculated spectral data compares favourably with the experimental ones. The 4-methoxy groups in compound 6l, on the other hand, enhance the intramolecular charge transfer from the aryl groups into the quinazoline core more than the 4-fluoro substituents in 6f and the parent compound 6a. This could explain the appearance of CT-band in 6l compared to 6f. In the case of 6a, the CT-band at the longer wavelength is merged with the most intense band presumably due to the relatively poor resonance donation by the phenyl groups that are not able to make charge separation with the acceptor core.

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 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) was used as stationary phase. The UV-vis spectra were recorded on a Cecil CE 9500 (9000 Series) UV-Vis spectrometer while emission spectra were taken using a Perkin Elmer LS 55 fluorescence spectrometer. The quantum efficiencies of fluorescence (Φ fl ) were obtained with the following equation: F denotes the area under the fluorescence band (F = a I fl (λ), where I fl (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 [32]. NMR spectra were obtained as DMSO-d 6 or CDCl 3 solutions using Varian Mercury 300 MHz NMR spectrometer and the chemical shifts are quoted relative to the solvent peaks. Low-and high-resolution mass spectra were recorded at the University of Stellenbosch Mass Spectrometry Unit using Synapt G2 Quadrupole Time-of-flight mass spectrometer.

I 2 -Promoted Cyclocondensation of 3,5-Dibromoanthranilamide and Arylaldehydes
Typical Procedure A stirred mixture of 2-amino-3,5-dibromobenzamide 1 (1 equiv.), benzaldehyde derivative 2 (1.4 equiv.) and iodine (2 equiv.) in ethanol (20 mL per mmol of 1) was refluxed for 7 h. The mixture was allowed to cool to room temperature and then quenched with an ice-cold saturated sodium thiosulfate solution. The resulting precipitate was filtered on a sintered funnel and then washed with an ice-cold water. The solid product was recrystallized from acetonitrile to afford the corresponding quinazolin-4(3H)-one 3. The following products were prepared in this fashion:

Sonogashira Cross-Coupling of 4a-d with Terminal Acetylynes
Typical Procedure A mixture of 4 (1 equiv.), Pd(PPh 3 ) 4 (5% of 4), CuI (5% of 4) and Cs 2 CO 3 (1.5 equiv.) in THF (ca. 5 mL/mmol of 4) in a two-necked flask equipped with a stirrer bar, rubber septum and a condenser equipped with a balloon was flushed for 20 min with argon gas. Terminal acetylene (1.2 equiv.) was added to the flask via a syringe and the mixture was flushed for additional 10 min. The mixture was stirred for 24 h at room temperature under argon atmosphere and then quenched with an cold water. The precipitate was filtered on a sintered funnel and then taken-up into chloroform. The solution was dried with MgSO 4 , filtered and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the 2-aryl-6,8-dibromo-4-(aryl/alkylethynyl)quinazoline 5. The following products were prepared in this fashion:

Conclusions
Elaboration of the 6,8-dibromo-4-chloroquinazoline scaffold via sequential Sonogashira and Suzuki-Miyaura cross-coupling reactions with terminal alkynes and arylboronic acids afforded novel polysubstituted quinazoline derivatives that would not be readily accessible otherwise. Exclusive replacement of 4-chloro atom of the 6,8-dibromo-4-chloroquinazolines via Sonogashira cross-coupling with stoichiometric amount of terminal alkynes is attributed to the α-nitrogen effect, which makes the 4-position highly activated than other positions. Lack of selectivity during Suzuki cross-coupling of the 2-aryl-4-alkynyl-6,8-dibromoquinazolines with arylboronic acids, on the other hand, is presumably the consequence of comparable C(6)-Br and C(8)-Br bond dissociation energies. The polyaryl substituted heterocycles 6 comprise an electron-deficient quinazoline framework as an electron-acceptor linked to the aryl rings directly or through a π-conjugated bridge to comprise donor-π-acceptor systems. Preliminary photophysical (absorption and emission) properties of these compounds showed a strong correlation with the substituents on the 2-, 6-and 8-phenyl groups. Based on the orbital diagrams, the electronic transitions of compounds 6 can be attributed to ICT from the aryl substituents to the quinazoline ring. Due to its electron deficiency, the quinazoline moiety may provide a site for reduction in this D-π-A system. This makes quinazolines 6a-l suitable candidates for further studies using cyclic voltametry to probe oxidation and reduction potentials and the stability of the oxidized and reduced forms. Compounds 6a-l, on the other hand, can be used as substrates for the synthesis of metal complexes with iridium, palladium or platinum, for example, as a prelude to compounds with potential application as organic light-emitting diode in materials. Moreover, the analogous 2substituted quinazolines bearing alkynyl substituent on the C-4 or C-6 position exhibit excellent EGFR or Aurora A kinase inhibition activity [23].