Synthesis and Photophysical Properties of Polycarbo-Substituted Quinazolines Derived from the 2-Aryl-4-chloro-6-iodoquinazolines

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.


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][2][3][4][5][6][7][8]. Halogenated quinazoline moiety has to this end established itself as an important scaffold for transition metal-mediated Csp 2 -Csp 2 , Csp 2 -Csp or Csp 2 -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][8][9]. The versatility of halogenated quinazolines as substrates in these transformations stems from the reactivity of the Csp 2 -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 Csp 2 -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][12][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 Csp 2 -Br bond, which in turn undergoes cross-coupling more readily than the C(2)-Cl bond [1][2][3][4][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 Csp 2 -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 Csp 2 -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 Csp 2 -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 Csp 2 -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 density functional theory (DFT) method to establish the effect of substituents and protonation on intramolecular charge transfer (ICT) properties.

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-5iodobenzamide 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-6iodoquinazolin-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. 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 Csp 2 -Cl bond and the intrinsically reactive Csp 2 -I bond in 3 would be during Pd-catalyzed Csp 2 -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 ( 1 H and 13 C) and IR spectroscopic techniques as the 4-chloro-2-phenyl-6-(2-phenylethynyl)quinazoline 4a. Its 13 C-NMR spectrum revealed the absence of the Csp 2 -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 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 35 Cl and 37 Cl 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 Csp 2 -X bond (trend: C(4)-Cl > Csp 2 -Br > C(2)-Cl > Csp 2 -Cl). In order to rationalize the observed selectivity, we probed the relative Csp 2 -X bond dissociation energies of 3a by DFT method [B3LYP/6-311G(d)], which revealed that the Csp 2 -I bond is weaker (66.45 kcal/mol) than the C(4)-Cl bond (83.14 kcal/mol). The observed selectivity and reactivity through Csp 2 -I bond is thus attributed to the relative Csp 2 -X bond strengths, which make it possible to substitute the intrinsically more reactive Csp 2 -I bond in the presence of the highly activated C(4)-Cl bond. 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 Csp 2 -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). 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). 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 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. 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.  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 1  Emission intensity (a.u. )

3a-d 7a-d
Wavelength (nm) 5a 5b 5c 5d 5e 5f 5g 6d 7d 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 1 H-15 N 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 signal in the 1 H-15 N 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.  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, 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.

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: F denotes the area under the fluorescence band (F = a Ifl(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].

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]

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.

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

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].

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 Csp 2 -halogen bonds (trend: Csp 2 -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 Csp 2 -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 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.