Efficient Synthesis of Novel 1,3,4-Oxadiazoles Bearing a 4-N,N-Dimethylaminoquinazoline Scaffold via Palladium-Catalyzed Suzuki Cross-Coupling Reactions

Two series of novel (symmetrical and unsymmetrical) quinazolinylphenyl-1,3,4-oxadiazole derivatives were synthesized using palladium-catalyzed Suzuki cross-coupling reactions. The presented synthetic methodology is based on the use of bromine-substituted 2-phenyl-4-N,N-dimethylaminoquinazolines and either a boronic acid pinacol ester or a diboronic acid bis(pinacol) ester of 2,5-diphenyl-1,3,4-oxadiazole. The reactions are conducted in a two-phase solvent system in the presence of catalytic amounts of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), sodium carbonate, and tetrabutylammonium bromide, which plays the role of a phase-transfer catalyst. The luminescence properties of the obtained compounds are discussed in the context of applying these compounds in optoelectronics. Specifically, two highly-conjugated final products: N,N-dimethyl-2-phenyl-6-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)quinazolin-4-amine (8f) and 6,6′-(4,4′-(1,3,4-oxadiazole-2,5-diyl)bis(4,1-phenylene))bis(N,N-dimethylquinazolin-4-amine (9f), which contain a 1,3,4-oxadiazole moiety connected to a quinazoline ring by a 1,4-phenylene linker at the 6 position, exhibit strong fluorescence emission and high quantum yields.

The rapidly developing field of material sciences has directed the interest of numerous research groups towards finding new organic arrangements that exhibit interesting luminescent properties. An optimized organic luminophore is typically comprised of an extended π-conjugated chromophore system embodying suitable electron-hole transporting properties, high external quantum efficiency and brightness, as well as chemical and thermal stability [44][45][46]. A comprehensive literature survey revealed the possibility of modifying luminophore electron-transporting properties by direct or indirect (via the appropriate linker) conjugation of the target molecule with other electron-deficient systems, such as tetrazines, pyridines, quinolines, quinazolines, furans, thiophenes, selenophenes, or 1,3,4-oxadiazoles. [47][48][49][50][51][52][53]. Previous work conducted in our laboratory developed the synthesis of novel organic hybrids containing 1,3,4-oxadiazole, 1,3,4-thiadiazole, or 1,2,4-triazole cores conjugated via phenylene linker to different homo-and heteroaromatic arrangements, which resulted in the generation of products with high fluorescence quantum yields [53]. Building upon these results involving novel conjugated diazole-derived monomers for potential optoelectronic applications, herein we describe the combination of two different individual structural motifs (i.e., 1,3,4-oxadiazole and quinazoline) using a phenylene linker via a palladium-catalyzed Suzuki cross-coupling reaction ( Figure 1). It is worth mentioning that Suzuki cross-coupling reactions play an important role in the catalytic construction of C-C bonds, and numerous papers and reviews discussing various catalytic systems, general reaction conditions, and potential applications have been published in recent years [54,55].

Results and Discussion
Quinazoline precursors 2a-g were prepared in a two-step synthesis according to methodologies described in the literature [56][57][58]. The starting material was a benzamide derivative 1 substituted at the ortho, meta, or para position of the N-phenyl ring (X = Br, Scheme 1), or at the meta or para position of the benzamide ring (Y = Cl, Br, Scheme 1). In order to obtain the desired products 2a-g, the
Applying the described optimized conditions, another series of reactions was carried out with symmetrical diboronic acid bis(pinacol)ester, 7, and 4-(N,N-dimethylamine)-2-phenylquinazoline derivatives 2a-c, 2f-g in the presence of 10 mol% palladium catalyst (Pd(dppf)Cl2), Na2CO3, and tetrabutylammonium bromide in the two-phase toluene-water solvent system (Scheme 5). The mixture was heated overnight in a sealed glass reactor, and the products were purified by extraction, followed by column chromatography and trituration. Syntheses of quinazoline regioisomers 2a-2c, substituted with bromine at the 2-phenyl ring position, were successful, and the products, 8a-c, were obtained in high yields (74-86%; Table 2, entries 1-3). However, the yield of product, 8b, which was derived from the meta-substituted arrangement (2b) was slightly lower (74%; Table 2, entry 2) than for products obtained from paraand ortho-substituted derivatives (82-86%; Table 2, entries 1,3). These results can be explained based on the electron-withdrawing nature of the quinazoline scaffold adjacent to the phenyl ring. The same conditions were applied for 4-(N,N-dimethylamino)-2-phenylquinazolines 2d, 2e substituted at positions 6 and 7 with chlorine atoms, where no conversion was observed (Table 2, entries 4,5). For the same substrates 2d, 2e, additional reactions in the microwave reactor were performed, but no positive outcomes were obtained. In contrast, the same coupling reactions conducted for the 6-and 7-bromide variations resulted in the formation of the desired products 8f-g in satisfactory yields (72-75%; Table 2). This observation confirms the general trend in the reactivity of aryl halides in Suzuki cross-coupling reactions, where bromine derivatives are much more reactive than their chloride analogues.
Applying the described optimized conditions, another series of reactions was carried out with symmetrical diboronic acid bis(pinacol)ester, 7, and 4-(N,N-dimethylamine)-2-phenylquinazoline derivatives 2a-c, 2f-g in the presence of 10 mol% palladium catalyst (Pd(dppf)Cl 2 ), Na 2 CO 3 , and tetrabutylammonium bromide in the two-phase toluene-water solvent system (Scheme 5). The mixture was heated overnight in a sealed glass reactor, and the products were purified by extraction, followed by column chromatography and trituration.
Two protons from the phenyl group for 8a-b, 8f-g and 9a-b, 9f-g, substituted at the quinazoline moiety, are shifted to lower field, and appear in the range between 8.50-8.90 ppm. In the remaining derivatives, 8c and 9c, these protons are observed in the range of 8.15-8.18 ppm. Such significant changes in chemical shifts are likely due to the proximity of these protons to the electronegative nitrogen atoms. In the 13 C-NMR spectra, the characteristic signals from the dimethylamino group are observed in the narrow range between 41.4-42.1 ppm. The unsymmetrical quinazolinylphenyl-1,3,4-oxadiazole derivatives (8a-c, 8f-g), have four distinctive signals from the two quaternary quinazoline carbons C-4a and C-8a, as well as carbon atoms C-2 and C-5 of the 1,3,4-oxadiazole ring, which appear in the range of 158.7-164.7 ppm. However, in the symmetrical quinazolinylphenyl-1,3,4-oxadiazole derivatives (9a-c, 9f-g) the signals range from 158.9 to 164.7 ppm. Both the 1 H-and 13 C-NMR spectra of 2,5-bis(4-arylphenyl)-1,3,4-oxadiazoles (9a-c, 9f-g) display a reduced number of peaks due to the symmetrical nature of these compounds' structures.

Entry Compound
Absorption The quantum yields (Φ f ) were determined based on two standards (i.e., 1,4-diphenylbuta-1,3-diene (DPB) and 9,10-diphenylanthracene (DPA) in non-polar solvents [63,64], according to the method described by Brouwer [65]. The analysis of Stokes shifts showed that the quinazolinylphenyl-1,3,4-oxadiazoles 8a-c, 8f-g, representing the series of unsymmetrical arrangements composed of six conjugated and fused aromatic rings, exhibited relatively higher values of Stokes shifts (60-131 nm, Table 4, entries 3-7) in contrast to the corresponding symmetrical derivatives 9a-c, 9f-g, containing the more extended arrangement of nine aromatic rings (58-108 nm, Table 4, entries [8][9][10][11][12]. Moreover, the introduction of the additional aromatic rings of 4-N,N-dimethylamino-2-phenylquinazoline scaffold, and the lenghtening of the conjugation in 9a-c, 9f-g series did not lead to both a significant increase in Stokes shifts and quantum yields, except for the symmetrical derivative 9f (Table 4, entry 11). Generally, the highest quantum yields were achieved for the unsymmetrical 8f and symmetrical 9f compounds (0.61 and 0.98 respectively, Table 4, entries 6, 11), in which the 1,3,4-oxadiazole moiety is connected to the quinazoline by a 1,4-phenylene linker at the 6 position, which allowed effective electron transfer between these two heterocyclic moieties. Noteworthy is the fact that the irradiation of 8f by UV radiation led to violet fluorescence that was visible to the naked eye. It is important to note that the boronic acid pinacol ester and diboronic acid bis(pinacol) ester of 2,5-diphenyl-1,3,4-oxadiazole (6, 7) starting compounds, which play a role in building the scaffolds for the studied conjugated arrangements, also had high quantum yields (0.68 for 6, and 0.91 for 7; Table 4, entries 1,2). However, the other products formed from the conjugation of boronic esters (6, 7) to quinazolines containing a N,N-dimethylamino group did not exhibit increased quantum yields. In fact, they caused fluorescence quenching, such that their quantum yields did not exceed 0.13 (8a-c, 8g, 9a-c, 9g; Table 4, entries [3][4][5]7,[8][9][10]12). A survey of the literature revealed that electron-rich species, including substituted amino groups that can donate electrons to aromatic heterocycles (i.e., fluorophores), can act as potential fluorescence quenchers [66]. They are responsible for the formation of charge transfer complexes, which often return to the ground state without emitting a photon.

General Information
All solvents and reagents were purchased from commercial sources and were used without additional purification. Melting points (mp) were measured using a SMP3 melting point apparatus (Stuart, Staffordshire, UK) and are uncorrected. UV-Vis spectra were recorded on a Jasco V-650 (Jasco Corporation, Tokyo, Japan) or a U-3900H spectrophotometer (Hitachi, Tokyo, Japan). Elemental analysis were performed with a VarioEL analyser (Elementar UK Ltd., Stockport, UK). 1 H-(400 MHz) and 13 C-NMR spectra (101 MHz) were recorded in CDCl 3 solutions using TMS as internal standard on an Agilent 400-NMR spectrometer (Agilent Technologies, Waldbronn, Germany). Thin layer chromatography (TLC) was performed on silica gel 60 F 254 TLC plates (Merck KGaA, Darmstadt, Germany) using benzene-EtOAc (3:1), DCM-EtOAc (9:1), DCM-MeOH (95:5) as the mobile phases. FT-IR spectra were recorded between 4000 and 6500 cm −1 on a Nicolet 6700 FT-IR apparatus (Thermo Fischer Scientific, Wesel, Germany) equipped with a Smart iTR accessory. High-resolution mass spectra (HRMS) were acquired on an Ultra-High Resolution (UHR) mass spectrometer Impact II TM QTOF instrument (Bruker, Bremen, Germany) equipped with an electrospray ionization (ESI) source, using MeOH or DCM as a solvent. Fluorescence spectra were recorded in DCM solution using a Hitachi F-7000 fluorescence spectrophotometer (Hitachi Ltd., Tokyo, Japan) at room temperature. was concentrated on a rotary evaporator to remove toluene and POCl 3 . Anhydrous toluene (50 mL) and N,N-dimethylcyanamide (1.75 g; 2.0 mL; 0.025 mol) were added, and the mixture was left for 24 h at room temperature before dropwise addition of a solution of TiCl 4 (2.5 mL; 0.025 mol) in 10 mL of anhydrous toluene. The mixture was agitated at elevated temperature (70 • C) for 5 h. After cooling, the solvent was decanted from the gluey solid, and 100 mL of 20% aqueous HCl added. The hydrolyzed mixture was filtered, and the resulting solution was neutralized with 20% aqueous NaOH. The precipitate was extracted with chloroform (3 × 20 mL), dried and concentrated. The crude products were purified by column chromatography (silica gel, eluent: benzene-EtOAc, 3:1) to yield the appropriate 4-(N,N-dimethylamino)-2-phenylquinazoline derivatives 2a-g.