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Article

Palladium-Catalyzed Synthesis of Novel Quinazolinylphenyl-1,3,4-thiadiazole Conjugates

by
Barbara Wołek
1,
Marcin Świątkowski
2 and
Agnieszka Kudelko
3,*
1
Selvita Services Sp. Z o.o., Bobrzyńskiego 14, PL-30348 Kraków, Poland
2
Institute of General and Ecological Chemistry, Lodz University of Technology, Zeromskiego 116, PL-90924 Lodz, Poland
3
Department of Chemical Organic Technology and Petrochemistry, The Silesian University of Technology, Krzywoustego 4, PL-44100 Gliwice, Poland
*
Author to whom correspondence should be addressed.
Catalysts 2022, 12(12), 1586; https://doi.org/10.3390/catal12121586
Submission received: 10 November 2022 / Revised: 1 December 2022 / Accepted: 5 December 2022 / Published: 6 December 2022
(This article belongs to the Section Catalysis in Organic and Polymer Chemistry)
Browse Figures
Versions Notes

Abstract

:
Two novel series of symmetrical and unsymmetrical conjugates, in which 1,3,4-thiadiazole and 4-N,N-dimethylaminoquinazoline scaffolds were connected via 1,4-phenylene linker, were synthetized in high yields by Suzuki cross-coupling reactions. The elaborated protocol makes use of bromo-substituted quinazolines, boronic acid pinacol ester or diboronic acid bis(pinacol)ester of 2,5-diphenyl-1,3,4-thiadiazole, catalytic amounts of [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2, sodium carbonate, and tetrabutylammonium bromide, which plays the role of a phase-transfer catalyst. The structures of prepared compounds were confirmed by 1H NMR, 13C NMR, UV-VIS, IR and HRMS. For the target compounds, the fluorescence spectra were measured to determine their quantum yields and Stokes shifts. The study revealed that among the tested compounds, two highly-conjugated derivatives (8a, 9a), in which 1,3,4-thiadiazole core is connected to 4-(N,N-dimethylamino)quinazoline via a double 1,4-phenylene linker, exhibit high quantum yields of fluorescence and strong fluorescence emission.

Graphical Abstract

1. Introduction

1,3,4-Thiadiazole is an important five-membered heterocycle bearing two nitrogen and sulfur atoms and fascinates scientists more than other thiadiazole isomers [1]. Compounds having 1,3,4-thiadiazole scaffold play a significant role in pharmacology and medicinal chemistry as antimicrobial [2], antiviral [3], anticancer [4], antidepressant [5], analgesic and anti-inflammatory agents [6,7]. 1,3,4-Thiadiazole is also an interesting core for agrochemistry in the area of insecticidal [8] or antifungal applications [9]. Thiadiazole is also a very attractive moiety in material science due to its electron deficiency, electron-absorbing facility properties and the occurrence of π-electron conjugated rings, especially in the optical, electrochemical and photochemical areas [10,11,12]. Many methods for 1,3,4-thiadiazole ring construction are reported in the literature. The most popular procedures include diacylhydrazines thionation with subsequent cyclization [13,14,15,16]. Other methods report the application of thiosemicarbazides [17], N-tosylhydrazones [18] or the replacement of the oxygen atom by sulfur atom in the 1,3,4-oxadiazole ring [19]. Quinazoline is a chemical compound containing fused pyrimidine and benzene heterocyclic rings, with broad application in life and science. Some of them are reported as potential compounds in medicine with antimicrobial [20,21], antimalarial [22], and anticancer [23,24] properties. Quinazoline derivatives also have applications in agrochemistry [25,26], and due to their fluorescent effects, they are largely used in material science as OLEDs [27,28,29]. Various procedures on quinazoline ring formation can be found in the literature. The most common approaches comprise: amidation and oxidative ring closure of 2-aminobenzoic acid derivatives (e.g., 2-aminobenzonitrile [30], 2-aminobenzamide [31,32] and 2-aminobenzoic acid [33]), condensation of imidates with 2-aminobenzoic acid [34], reacting anthranilate esters with guanidine [35,36,37], as well as cyclization of 2-aminobenzophenones and benzyl amines in the presence of t-BuOOH, and catalytic amounts of I2 or ceric ammonium nitrate (CAN) [38,39].
In our previous reports, the synthesis of novel, symmetrical and unsymmetrical quinazolinylphenyl-1,3,4-oxadiazole derivatives was carried out. The prepared compounds showed strong fluorescence emission and high quantum yields [40,41]. These results motivated us to continue the work and examine the analog series of 1,3,4-thiadiazole and quinazoline hybrids as potential optoelectronic motifs (Scheme 1).
The construction of final compounds is based on the well-known methodology of C-C bond formation by palladium-catalyzed Suzuki cross-coupling reactions, which is widely reported in the literature [42,43]. Generally, such reactions proceed between an organic electrophile R1-X and an organic boronate nucleophile R2-BY2 in the presence of a metal catalyst, usually different palladium complexes LnPd0, and with the aim of organic or inorganic base MA (Scheme 2). The catalytic cycle comprises three individual steps including: (a) oxidative addition of the organic halide or pseudohalide to the palladium complex, (b) transmetalation between the adduct and the boronate R2-BY2 in the presence of base MA, and finally, (c) reductive elimination leading to R1-R2 product containing the new C−C bond and regeneration of the catalyst [44].

2. Results and Discussion

Bromo-substituted quinazolines (2a–e), playing the role of starting reagents, were synthetized in a three-step way with the procedures described in the literature [41,45,46,47]. The appropriate benzamide derivative (1) substituted at the para, meta or ortho position of the benzamide ring (1a–c, Scheme 3) or at the meta or para position of the N-phenyl ring (1d–e, Scheme 3) was heated with PCl5 in anhydrous toluene followed by reaction with N,N-dimethylcyanamide (Me2NCN), and then heating in anhydrous toluene with TiCl4. The crude products 2a–e were purified by column chromatography to obtain the corresponding pure quinazolines in high yields (65–87%, Scheme 3).
The second set of reagents, pinacol boronic esters, needed for the Suzuki cross-coupling reaction was prepared in a three-step synthesis according to the methodology known in the literature (Scheme 4). The key 1,3,4-thiadiazole scaffolds (5a and 5b) were prepared in a one-pot reaction between commercially available reagents: 4-bromobenzaldehyde (3) and benzhydrazide (4a) or 4-bromobenzhydrazide (4b) in refluxed ethanol to obtain N-acylhydrazone, followed by direct thionation and oxidative cyclization in the presence of Lawesson’s reagent and 4-dimethylaminopyridine [16]. The crude products were purified by column chromatography and trituration with diethyl ether to obtain pure 2-(4-bromophenyl)-5-phenyl-1,3,4-thiadiazole (5a) and bis(4-bromophenyl)-1,3,4-thiadiazole (5b) in satisfactory yields (Scheme 4). The resulting compounds were then used in Miyaura borylation reactions with bis(pinacolato)diboron in the presence of potassium acetate and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2. Mono (6) and bis (7) pinacol boronic esters were purified by column chromatography and trituration with n-hexane to afford pure reagents for Suzuki cross-coupling in yields of 89% and 91%, respectively.
In the final step, the bromine-containing quinazoline derivatives 2a–e and boronic esters 6, 7 were subjected to Suzuki cross-coupling reactions. To synthesize target products in high yields and in an effective way, diverse conditions between model substrate: 2-(4-bromophenyl)-N,N-dimethylquinazolin-4-amine (2a) and 2-phenyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,4-thiadiazole (6) were tested (Scheme 5), and the results were summarized in Table 1. Firstly, conditions similar to those used for 1,3,4-oxadiazole analogs were utilized [41] (Table 1, Entry 1). The starting compound 2a was treated with a boronic ester 6 used in excess (1:1.2 equivalent ratio). The reaction mixture was heated in a glass-tube reactor in the presence of the 5 mol % palladium catalyst: [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2), sodium bicarbonate Na2CO3 as a base (5 equivalents) and 5 mol % tetrabutylammonium bromide (NBu4Br) as the phase-transfer catalyst, which allows regents transfer between two immiscible phases (toluene and water). In such conditions, product 8a was afforded in high yield (84%). The same conditions, but without NBu4Br—a PTC catalyst gave similar but slightly lower yields (Table 1, Entry 2). The initial optimization also involved different sources of palladium, including [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2), palladium chloride PdCl2 and palladium acetate Pd(OAc)2 used in combination with different ligands. A ligand-free approach using palladium chloride PdCl2 (Table 1, Entry 3) gave product 8a with moderate yield. Then, the catalytic effect of palladium acetate Pd(OAc)2 in the presence of various electron-rich and spatially bulky ligands was checked. The additive of aryl and mono- (XPhos) or diphosphine (Xanthphos) ligands resulted in similar, high yields (Table 1, Entries 4 and 6), while the alkyl monophosphine ligand (CataCXium A) gave low yield (Table 1, Entry 5). Due to the fact that Pd(dppf)Cl2 gave the most effective outcome, it was used in the next tests of various solvents and bases. During the search for the best conditions, several solvents, polar and non-polar, were investigated. The use of polar aprotic solvents (THF, DMF, Table 1, Entries 7, 9) and non-polar dioxane (Table 1, Entry 8) led to the isolation of product 8a with moderate yields (66–77%), while isopropyl alcohol gave one of the best results of 82% in the tested conditions (Table 1, Entry 10). As a last but not least point, bases including: sodium bicarbonate Na2CO3, sodium tert-butoxide t-BuONa, tripotassium phosphate K3PO4 and sodium hydroxide NaOH were studied in a toluene/water system in the presence of Pd(dppf)Cl2 as a catalyst. The role of the base in the Suzuki cross-coupling reaction is the participation in halogen ion exchange involving the initial halide-containing adduct at the surface of the catalyst and the activation of boronic ester to facilitate transmetalation. Among the various bases tested, the highest yields were obtained for Na2CO3 (Table 1, Entry 2). For t-BuONa and K3PO4 (Table 1, Entries 11, 12), yields were moderate and satisfactory, while using NaOH was not effective in the investigated Suzuki-Miayaura coupling reaction (Table 1, Entry 13).
The most effective conditions were successfully applied for the preparation of unsymmetrical and symmetrical quinazolinylphenyl-1,3,4-thiadiazole derivatives. For this reason, pinacol boronic ester 6 was reacted with quinazolines substituted with bromine (2a–e) in the presence of Pd(dppf)Cl2 and Na2CO3 in a toluene/water system with the use of tetrabutylammonium bromide Bu4NBr as a PTC catalyst (Scheme 6). The reaction was carried out in a sealed tube at 115 °C. All products were purified by extraction and column chromatography followed by trituration with diethyl ether. The results are presented in Table 2. All products were obtained in high yields in the range of 77–90%. For the quinazoline derivatives with bromine atom substituted at the phenyl ring located in position 2 (2a–c), the best results were achieved for meta isomer 8b (Table 2, Entry 2). The product with bromine substituent at the para position 8a was obtained in slightly lower yield (Table 2, Entry 1), while the synthesis making use of ortho-substituted quinazoline derivative 2c was the least effective but still satisfying in giving the product 8c (Table 2, Entry 3). It was concluded that such a situation could be a result of steric hindrance. The Suzuki cross-coupling reaction was run as well with two isomers (2d–e) containing the bromine atom on the quinazoline scaffold, which resulted in very high yields for both isomers (Table 2, Entries 4 and 5).
The elaborated Suzuki cross-coupling conditions were also adopted to another set of reactions, including symmetrical diboronic acid bis(pinacol)ester 7 and quinazoline precursors 2a–e in the presence of Pd(dppf)Cl2 and Na2CO3 in biphasic, toluene and water mixture, and with the addition of phase transfer catalyst, NBu4Br (Scheme 7). The reactions were carried out at 115 °C in a sealed glass reactor and gave a series of products 9a–e.
The products 9b and 9c were purified in a similar manner to unsymmetrical compounds via extraction, column chromatography and trituration with diethyl ether. Due to the very low solubility of other derivatives 9a, 9d–e, the purification method had to be changed. The products were finally purified via filtration from the reaction mixtures, and the crude products were washed with H2O, AcOEt, 2% MeOH in CHCl3 and Et2O. Despite the fact of the low solubility of symmetrical products 9a–e, all of them were obtained in satisfactory, high yields (>80%, Table 3), which proves that applied conditions for Suzuki cross-coupling reactions are very effective not only for unsymmetrical scaffolds but also for symmetrical ones. The results of the syntheses are presented in Table 3. The best result was achieved for 9b, which was synthesized from bis boronic ester 7 and 2-(3-bromophenyl)-N,N-dimethylquinazolin-4-amine (2b). This is in line with the result obtained for unsymmetrical derivative 8b, for which the Suzuki reaction was the most effective.
All of the obtained compounds from unsymmetrical (8a–8e) and symmetrical (9a–e) series of N,N-dimethylquinazolin-4-amine-1,3,4-thiadiazole conjugates are novel and were characterized by spectroscopic methods (1H and 13C NMR, HRMS, see Supplementary Materials). The most distinguishing signals from dimethylamino moiety are detected in the range of 2.93–3.52 ppm on the 1H NMR spectra and in the range from 41.5 to 42.1 ppm on the 13C NMR spectra in both the unsymmetrical and symmetrical set of compounds. The second most characteristic signals on the 13C NMR spectra are the quaternary carbon atoms from 1,3,4-thiadiazole and quinazoline scaffolds. The signals from the thiadiazole group are the most downfield and appear in the range of 167.8–168.4 ppm, while the carbon atoms from the quinazoline core are shifted a bit to the higher field (158.9–164.3 ppm) in comparison to unique, thiadiazole carbon atoms. It is worth mentioning that for two compounds, 9a and 9e, 13C NMR spectrum recording was not possible due to the very low solubility of such compounds in NMR solvents. For those compounds, only four signals were detected, most probably coming from the groups of equivalent carbon atoms, which give the most intensive signals. The signal from 42.0 ppm represents the dimethylamino group, whereas three signals in the range from 127.1 to 128.7 ppm, most probably coming from 3 out of 4 phenyl carbon atoms which build the linker between thiadiazole and quinazoline moieties in 9a and 9e and/or attached to C-2 in the quinazoline group in 9e. Finally, the structure of 9a and 9e was confirmed by 1H NMR and HRMS. The NMR spectra for 9a–e compounds showed a reduced number of signals in comparison to 8a–e because of its symmetrical feature. In some NMR spectra, the signals of target compounds are accompanied by signals coming from residual water, ethyl acetate, dichloromethane, acetone and grease. The spectroscopic characteristics (UV-Vis absorption and 3D fluorescence spectra) were performed for compounds 5a, 5b, 6, 7, 8a–e and 9a–e (Figures S37–S53 in Supplementary Materials). All investigated compounds possess fluorescent properties (Table 4). The main absorption maxima are in the range 308–359 nm and correspond to the π→π* transitions, which are typically the sources of fluorescence in thiadiazole derivatives [48,49]. The range of emission wavelengths is 393–437 nm, which results in violet fluorescence. The simultaneous bathochromic shifts of absorption and emission wavelengths are observed in the following order (Figure S54): non-coupled 2,5-diphenyl-1,3,4-thiadiazoles (5a, 5b, 6, and 7) < unsymmetrically coupled compounds (8a–e series) < symmetrically coupled compounds (9a–e series). In consequence, the Stock shifts are comparable in all groups (Table 4). Generally, most of the investigated thiadiazole derivatives are characterized by a low quantum yield of fluorescence (Φf), not exceeding 0.10 (Table 4). The favorable conjugation is observed only in the case of 8a and 9a, whose Φf achieve 0.26 and close to 1, respectively. They also exhibit the highest fluorescence intensity (Figures S44 and S49). In these compounds, the 1,3,4-thiadiazole core is connected with quinazoline via a double 1,4-phenylene linker, causing their structures the most linear. The linear conjugation simplifies the electron transfer between the above moieties within the molecule, which can be the reason for the exceptional properties of 8a (Table 4, Entry 5) and 9a (Table 4, Entry 10). A similar phenomenon was reported in the previous work on the analogical series of quinazolines coupled with 1,3,4-oxadiazole [41]. Among those compounds, only the 1,3,4-oxadiazole analogs of 8d and 9d were efficient fluorescent materials (Φf = 0.61 and close to 1, respectively). It shows that in both thiadiazole and oxadiazole series, good fluorescence properties appear only for one particular geometry of heterocyclic moieties coupling, and which geometry is favorable depends on the electronic properties of the five-membered ring.

3. Materials and Methods

3.1. General Information

All solvents and reagents were purchased from commercial sources and were used without additional purification. Melting points (mp) were measured using a Stuart SMP3 melting point apparatus and were uncorrected. UV-Vis absorption and 3D fluorescence spectra were recorded in dichloromethane solutions (c = 1 × 10−6 mol/dm3) with Jasco V-660 and Jasco F-6300 spectrophotometers. 1H- and 13C-NMR spectra were recorded in CDCl3 solutions using TMS as an internal standard on an Agilent 400-NMR spectrometer. Thin layer chromatography (TLC) was performed on Merck silica gel 60 F254 TLC plates using benzene-EtOAc (3:1), DCM-AcOEt (9:1), DCM-MeOH (95:5) as mobile phases. FT-IR spectra were recorded between 4000 and 6500 cm−1 on a Nicolet 6700 FT-IR apparatus with a Smart iTR accessory. High-resolution mass spectra (HRMS) were acquired on an Ultra-High Resolution (UHR) mass spectrometer Impact IITM QTOF Bruker instrument equipped with an electrospray ionization (ESI) source, using DCM as a solvent.

3.2. Synthesis and Characterization

3.2.1. General Procedure for Preparing 4-(N,N-dimethylamino)-2-phenylquinazoline Derivatives (2a–g)

The derivative of benzamide (0.010 mol): N-phenyl-4-bromobenzamide (1a), N-phenyl-3-bromobenzamide (1b), N-phenyl-2-bromobenzamide (1c), N-(4-bromophenyl)benzamide (1d) or N-(3-bromophenyl)benzamide (1e), anhydrous toluene (25 mL) and PCl5 (2.26 g; 0.011 mol) were placed in a reaction flask. The mixture was gently heated at about 50 °C until the disappearance of starting benzamide derivative was completed (TLC, 3–6 h). Toluene and POCl3 were removed using a rotary evaporator. Anhydrous toluene (25 mL) and N,N-dimethylcyanamide (0.70 g; 0.8 mL; 0.010 mol) were added to the crude N-phenylbenzimidoyl chloride, and the mixture was left for 24 h at room temperature. Then, TiCl4 (1.0 mL; 0.010 mol) in 10 mL of anhydrous toluene was added dropwise, followed by agitation at 50 °C for 5 h. Toluene was decanted from the resulting gluey solid, and 40 mL of 20% aqueous HCl was added. The mixture was left to hydrolyze, filtered, and the resulting solution was neutralized with 20% aqueous NaOH. The precipitate was extracted with chloroform (2 × 20 mL), dried over MgSO4 and concentrated. The crude 4-(N,N-dimethylamino)-2-phenylquinazoline derivatives (2a–e) were purified by column chromatography (silica gel, eluent: benzene-EtOAc, 3:1).
2-(4-Bromophenyl)-4-(N,N-dimethylamino)quinazoline (2a). The product was obtained as a colorless solid (2.13 g, 65%); mp 104–105 °C (108–110 °C [45]); Rf = 0.54 (benzene-EtOAc, 3:1).
2-(3-Bromophenyl)-4-(N,N-dimethylamino)quinazoline (2b). The product was obtained as a colorless solid (2.79 g, 85%); mp 82–84 °C (82–84 °C [41]); Rf = 0.52 (benzene-EtOAc, 3:1).
2-(2-Bromophenyl)-4-(N,N-dimethylamino)quinazoline (2c). The product was obtained as a colorless solid (2.56 g, 78%); mp 148–149 °C (148–150 °C [41]); Rf = 0.56 (benzene-EtOAc, 3:1).
6-Bromo-4-(N,N-dimethylamino)-2-phenylquinazoline (2d). The product was obtained as a yellowish solid (2.85 g, 87%); mp 101–102 °C (99–100 °C [46]); Rf = 0.56 (benzene-EtOAc, 3:1).
7-Bromo-4-(N,N-dimethylamino)-2-phenylquinazoline (2e). The product was obtained as a colorless solid (2.62 g, 80%); mp 134–136 °C (135–136 °C [41]); Rf = 0.50 (benzene-EtOAc, 3:1).

3.2.2. Preparation of 2-(4-Bromophenyl)-5-phenyl-1,3,4-thiadiazole (5a)

4-Bromobenzaldehyde (3, 2.72 g, 0.015 mol) and benzhydrazide (4a, 2.00 g, 0.015 mol) were added to 40 mL of ethanol at room temperature and then refluxed for 2 h. After cooling to room temperature, ethanol was evaporated. Lawesson’s reagent (4.76 g, 0.012 mol), 4-(N,N-dimethylamino)pyridine (2.15 g, 0.018 mol) and toluene (80 mL) were added to the mixture, and it was refluxed for overnight. After cooling, the toluene was evaporated, and the crude product was purified by column chromatography (SiO2, 0–2% AcOEt in DCM) and trituration with Et2O to obtain 3.15 g of pure 2-(4-bromophenyl)-5-phenyl-1,3,4-thiadiazole (5a). White solid (3.15 g, 68%); mp 190–191 °C (153–154 °C [16]); Rf = 0.67 (5% AcOEt in DCM).

3.2.3. Preparation of 2-Phenyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,4-thiadiazole (6)

Bis(pinacolato)diboron (1.88 g; 0.0062 mol) and AcOK (1.82 g; 0.019 mol) were added to a degassed 1,4-dioxane (20 mL) solution of 2-(4-bromophenyl)-5-phenyl-1,3,4-thiadiazole (5a, 1.95 g; 0.0062 mol) in a glass tube reactor. The mixture was bubbled with Ar for 15 min, followed by Pd(dppf)Cl2 (0.23 g; 0.0003 mol) addition. The glass tube reactor was sealed, and the reaction was stirred at 100 °C overnight. The solvent was evaporated, and the residue was portioned between DCM and H2O. The resulting aqueous layer was washed with DCM twice (2 × 40 mL). The product was purified by column chromatography (SiO2, 0–10% AcOEt in DCM) and trituration with n-hexane to obtain 1.99 g of pure product 6. Salmon/pale orange solid (1.99 g, 89%); mp 183–184 °C; Rf = 0.42 (5% AcOEt in DCM). IR (ATR): 2981, 2931, 2164, 1943, 1608, 1516, 1483, 1455, 1434, 1417, 1387, 1370, 1352, 1323, 1298, 1268, 1208, 1166, 1140, 1089, 1070, 1015, 1002, 987, 964, 914, 858, 838, 820, 782, 758, 742, 686 cm−1. 1H NMR (400 MHz, CDCl3) δ= 8.04–8.00 (m, 4H), 7.96–7.89 (m, 2H), 7.54–7.47 (m, 3H), 1.37 (s, 12H). 13C NMR (101 MHz, CDCl3) δ= 168.5, 168.3, 135.6, 132.6, 131.3, 130.3, 129.3, 128.1, 127.2, 84.3, 25.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C20H22BN2O2S 365.1490; found 365.1452. UV (CH2Cl2) λmax (log ε): 228 (4.204), 311 (4.543) nm.

3.2.4. Preparation of Bis(4-bromophenyl)-1,3,4-thiadiazole (5b)

4-Bromobenzaldehyde (3, 4.30 g, 0.023 mol) and 4-bromobenzhydrazide (4b, 5.00 g, 0.023 mol) were added to 100 mL of ethanol at room temperature and then refluxed for 2 h. After cooling to room temperature, ethanol was evaporated. Lawesson’s reagent (7.53 g, 0.019 mol), 4-(dimethylamino)pyridine (3.41 g, 0.028 mol) and toluene (200 mL) were added to the crude and the mixture was refluxed for overnight. After cooling, the toluene was evaporated and the crude was purified by column chromatography (SiO2, 0–2% AcOEt in DCM) and trituration with Et2O to obtain 4.24 g of pure bis(4-bromophenyl)-1,3,4-thiadiazole (5b). White solid (4.24 g, 46%); mp 248–250 °C (241.2–242.8 °C [53]; 245–247 °C [14]); Rf = 0.75 (5% AcOEt in DCM).

3.2.5. Preparation of Bis[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,4-thiadiazole (7)

Bis(pinacolato)diboron (4.64 g; 0.018 mol) and AcOK (3.74 g; 0.038 mol) were added to a degassed 1,4-dioxane (30 mL) solution of bis(4-bromophenyl)-1,3,4-thiadiazole (5b, 3.00 g; 0.0076 mol) in a glass tube reactor. The mixture was bubbled with Ar for 15 min, followed by Pd(dppf)Cl2 (0.28 g; 0.0004 mol) addition. The glass tube reactor was sealed, and the reaction was stirred at 100 °C overnight. The solvent was evaporated, and the residue was portioned between DCM and H2O. The aqueous phase was extracted with DCM twice (2 × 40 mL). The product was purified by column chromatography (SiO22, 0–10% AcOEt in DCM) and trituration with n-hexane to obtain 3.38 g of bis[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,4-thiadiazole (7). Salmon/pale orange solid (3.38 g, 91%); mp 307–308 °C; Rf = 0.25 (5% AcOEt in DCM). IR (ATR): 2982, 2207, 2166, 1937, 1608, 1563, 1516, 1483, 1424, 1388, 1351, 1321, 1269, 1212, 1167, 1140, 1086, 1017, 989, 963, 858, 839, 824, 779, 743, 701, 667 cm−1. 1H NMR (400 MHz, CDCl3) δ= 8.04–7.99 (m, 2H), 7.97–7.89 (m, 2H), 1.37 (s, 12H). 13C NMR (101 MHz, CDCl3) δ= 168.5, 135.6, 132.5, 127.2, 84.3, 25.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C26H33B2N2O4S 491.2342; found 491.2302. UV (CH2Cl2) λmax (log ε): 228 (4.358), 316 (4.574) nm.

3.2.6. General Procedure for the Preparation of Unsymmetrical Quinazolinylphenyl-1,3,4-thiadiazole Derivatives (8a–e) via Suzuki Cross-Coupling from Boronic Acid Pinacol Ester 6

The appropriate bromo-quinazoline derivative (200 mg, 0.61 mmol): 2-(4-bromophenyl)-4-(N,N-dimethylamino)quinazoline (2a), 2-(3-bromophenyl)-4-(N,N-dimethylamino)quinazoline (2b), 2-(2-bromophenyl)-4-(N,N-dimethylamino)quinazoline (2c), 6-bromo-4-(N,N-dimethylamino)-2-phenylquinazoline (2d), 7-bromo-4-(N,N-dimethylamino)-2-phenylquinazoline (2e), 2-phenyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,4-thiadiazole (6, 267 mg; 0.73 mmol), Na2CO3 (324 mg; 3.1 mmol), and NBu4Br (10 mg; 0.03 mmol) were dissolved in toluene (6.6 mL) and H2O (3.4 mL) in a glass tube reactor, and the mixture was bubbled with Ar followed by addition of Pd(dppf)Cl2 (22 mg; 0.03 mmol). Glass tube reactor was sealed, and the reaction was stirred at 115 °C overnight. The solvent was evaporated, and the residue was portioned between DCM and H2O. The resulting mixture was extracted with DCM (2 × 45 mL). The product was purified by column chromatography (SiO2, 0–10% AcOEt in DCM) followed by trituration with Et2O to yield the appropriate derivatives 8a–e.
N,N-dimethyl-2-[4’-(5-phenyl-1,3,4-thiadiazol-2-yl)-[1,1’-biphenyl]-4-yl]quinazolin-4-amine (8a). The product was obtained as a pale yellow solid (250 mg, 84%), mp 217–218 °C; Rf = 0.29 (DCM:AcOEt, 9:1). IR (ATR): 3064, 2943, 2005, 1953, 1605, 1578, 1562, 1521, 1483, 1441, 1411, 1395, 1373, 1334, 1251, 1216, 1176, 1161, 1136, 1102, 1072, 1018, 1001, 987, 954, 876, 864, 833, 798, 757, 725, 697, 678 cm−1. 1H NMR (400 MHz, CDCl3) δ = 8.72–8.62 (m, 2H), 8.15–8.07 (m, 2H), 8.04 (m, 3H), 7.97 (d, J = 8.4 Hz, 1H), 7.85–7.78 (m, 2H), 7.81–7.74 (m, 2H), 7.71 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.55–7.47 (m, 3H), 7.39 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 3.47 (s, 6H). 13C NMR (101 MHz, CDCl3) δ = 168.2, 168.0, 164.1, 158.9, 153.1, 143.7, 141.3, 138.9, 132.2, 131.2, 130.4, 129.3, 129.3, 129.1, 128.9, 128.5, 128.1, 127.9, 127.1, 125.7, 124.3, 115.2, 42.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C30H24N5S 486.1747; found 486.1699. UV (CH2Cl2) λmax (log ε): 227 (4.407), 250 (4.208), 341 (4.709) nm.
N,N-dimethyl-2-[4’-(5-phenyl-1,3,4-thiadiazol-2-yl)-[1,1’-biphenyl]-3-yl]quinazolin-4-amine (8b). The product was obtained as a white solid (266 mg, 90%), mp 230–231 °C; Rf = 0.37 (DCM:AcOEt, 9:1). IR (ATR): 3031, 2931, 2173, 2020, 1942, 1606, 1561, 1523, 1483, 1455, 1437, 1411, 1397, 1371, 1351, 1331, 1273, 1246, 1229, 1165, 1140, 1100, 1071, 1002, 987, 958, 913, 872, 844, 812, 798, 789, 771, 757, 744, 722, 697 cm−1. 1H NMR (400 MHz, CDCl3) δ = 8.88 (t, J = 1.8 Hz, 1H), 8.60 (dt, J = 7.9, 1.4 Hz, 1H), 8.17–8.10 (m, 2H), 8.10–8.02 (m, 3H), 7.97 (dd, J = 8.5, 1.3 Hz, 1H), 7.91–7.83 (m, 2H), 7.78–7.68 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.54–7.46 (m, 3H), 7.40 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 3.47 (s, 6H). 13C NMR (101 MHz, CDCl3) δ = 168.1, 168.1, 164.1, 159.1, 153.1, 144.3, 134.0, 139.9, 132.2, 131.2, 130.4, 129.3, 129.1, 129.1, 128.9, 128.8, 128.5, 128.3, 128.1, 128.1, 127.3, 125.7, 124.4, 115.2, 42.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C30H24N5S 486.1747; found 486.1698. UV (CH2Cl2) λmax (log ε): 228 (4.569), 291 (4.535), 325 (4.698) nm.
N,N-dimethyl-2-[4’-(5-phenyl-1,3,4-thiadiazol-2-yl)-[1,1’-biphenyl]-2-yl]quinazolin-4-amine (8c). The product was obtained as a white solid (228 mg, 77%); mp 179–180 °C; Rf = 0.17 (DCM:AcOEt, 9:1). IR (ATR): 3820, 3712, 3647, 3056, 2515, 2207, 2166, 1995, 1974, 1737, 1609, 1576, 1563, 1520, 1486, 1455, 1435, 1414, 1380, 1332, 1251, 1218, 1161, 1144, 1095, 1073, 1047, 1002, 988, 954, 917, 875, 841, 822, 759, 737, 731, 690, 683 cm−1. 1H NMR (400 MHz, CDCl3) δ = 8.16–8.08 (m, 1H), 8.04–7.97 (m, 2H), 7.94 (dd, J = 8.5, 1.4 Hz, 1H), 7.89 (dd, J = 8.8, 1.5 Hz, 1H), 7.88–7.85 (m, 2H), 7.69 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.57–7.44 (m, 6H), 7.38 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.36–7.33 (m, 2H), 2.93 (s, 6H). 13C NMR (101 MHz, CDCl3) δ = 168.4, 168.0, 163.0, 162.0, 152.9, 146.6, 140.7, 139.4, 132.2, 131.2, 131.1, 130.6, 130.4, 130.1, 129.3, 129.2, 128.8, 128.2, 128.1, 128.0, 127.4, 125.6, 124.5, 114.4, 41.5. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C30H24N5S 486.1747; found 486.1714. UV (CH2Cl2) λmax (log ε): 228 (4.458), 287 (4.276), 326 (4.405) nm.
N,N-dimethyl-2-phenyl-6-[4-(5-phenyl-1,3,4-thiadiazol-2-yl)phenyl]quinazolin-4-amine (8d). The product was obtained as a yellow solid (244 mg, 82%); mp 270–272 °C; Rf = 0.37 (DCM:AcOEt, 9:1). IR (ATR): 3045, 2925, 2193, 2154, 2020, 1969, 1603, 1586, 1566, 1552, 1514, 1453, 1436, 1420, 1411, 1383, 1350, 1318, 1238, 1194, 1167, 1103, 1092, 1064, 1027, 10001, 990, 956, 923, 890, 857, 836, 810, 784, 775, 761, 728, 703, 685, 672 cm−1. 1H NMR (400 MHz, CDCl3) δ = 8.63–8.56 (m, 2H), 8.27 (d, J = 2.0 Hz, 1H), 8.18–8.10 (m, 2H), 8.09–7.97 (m, 4H), 7.84–7.76 (m, 2H), 7.56–7.45 (m, 6H), 3.51 (s, 6H). 13C NMR (101 MHz, CDCl3) δ = 168.3, 167.8, 164.3, 159.8, 152.8, 143.4, 138.9, 135.7, 131.3, 131.2, 130.3, 130.2, 129.5, 129.4, 129.4, 128.7, 128.6, 128.5, 128.1, 127.9, 124.0, 115.3, 42.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C30H24N5S 486.1747; found 486.1753. UV (CH2Cl2) λmax (log ε): 228 (4.571), 314 (4.665) nm.
N,N-dimethyl-2-phenyl-7-[4-(5-phenyl-1,3,4-thiadiazol-2-yl)phenyl]quinazolin-4-amine (8e). The product was obtained as a white solid (266 mg, 90%); mp 252–253 °C; Rf = 0.41 (DCM:AcOEt, 9:1). IR (ATR): 3769, 3735, 3726, 3055, 2932, 2546, 2192, 2137, 2011, 1956, 1613, 1584, 1553, 1514, 1475, 1456, 1437, 1412, 1398, 1373, 1345, 1315, 1275, 1246, 1203, 1171, 1155, 1138, 1102, 1074, 1063, 1025, 990, 955, 930, 910, 892, 867, 884, 818, 795, 776, 758, 732, 723, 700, 689, 679 cm−1. 1H NMR (400 MHz, CDCl3) δ = 8.59 (dd, J = 7.9, 1.8 Hz, 2H), 8.21 (d, J = 2.0 Hz, 1H), 8.12 (m, 3H), 8.06–7.99 (m, 2H), 7.92–7.84 (m, 2H), 7.64 (dd, J = 8.7, 2.0 Hz, 1H), 7.55–7.45 (m, 5H), 3.47 (s, 6H). 13C NMR (101 MHz, CDCl3) δ = 168.4, 167.8, 163.7, 160.0, 153.6, 143.1, 142.6, 138.9, 131.3, 130.3, 130.3, 123.0, 129.4, 128.6, 128.6, 128.4, 128.2, 128.1, 126.6, 126.5, 123.1, 114.4, 41.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C30H24N5S 486.1747; found 486.1709. UV (CH2Cl2) λmax (log ε): 228 (4.518), 297 (4.602), 344 (4.663) nm.

3.2.7. General Procedure for the Preparation of Symmetrical Quinazolinylphenyl-1,3,4-thiadiazole Derivatives (9a–e) via Suzuki Cross-Coupling Using Diboronic Acid Bis(pinacol) Ester 7

The appropriate bromo-quinazoline derivative (267 mg, 0.82 mmol): 2-(4-bromophenyl)-4-(N,N-dimethylamino)quinazoline (2a), 2-(3-bromophenyl)-4-(N,N-dimethylamino)quinazoline (2b), 2-(2-bromophenyl)-4-(N,N-dimethylamino)quinazoline (2c), 6-bromo-4-(N,N-dimethylamino)-2-phenylquinazoline (2f), 7-bromo-4-(N,N-dimethylamino)-2-phenylquinazoline (2g) and bis[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,4-thiadiazole (7, 240 mg, 0.49 mmol), Na2CO3 (432 mg; 4.08 mmol), and NBu4Br (13 mg; 0.041 mmol) were dissolved in toluene (13.2 mL) and H2O (6.6 mL) in a glass tube reactor, and the mixture was bubbled with Ar followed by addition of Pd(dppf)Cl2 (30 mg; 0.041 mmol). The glass tube reactor was sealed, and the reaction was stirred at 115 °C overnight. Due to solubility issues, two different purification methods were applied. For very low soluble compounds, 9a, 9d–e, solids were filtered directly from the reaction mixture, washed with H2O, AcOEt, 2% MeOH in CHCl3 and Et2O. For 9b–c, the product was extracted with DCM (2 × 45 mL), purified by column chromatography (SiO2, 0–10% AcOEt in DCM, 1–5% MeOH in CHCl3), followed by trituration with Et2O.
2-[4’-(5-{4’-[4-(dimethylamino)quinazolin-2-yl]-[1,1’-biphenyl]-4-yl}-1,3,4-thiadiazol-2-yl)-[1,1’-biphenyl]-4-yl]-N,N-dimethylquinazolin-4-amine (9a). The product was obtained as a brownish solid (238 mg, 81%); mp 328–330 °C; Rf = 0.36 (5% MeOH in DCM). IR (ATR): 2938, 2883, 2187, 2165, 2143, 2018, 1933, 1605, 1578, 1563, 1521, 1486, 1439, 1411, 1395, 1378, 1335, 1250, 1219, 1176, 1135, 1101, 1075, 1032, 1003, 988, 955, 878, 861, 830, 793, 753, 724, 698, 676 cm−1. 1H NMR (400 MHz, CDCl3) δ= 8.68 (d, J = 8.3 Hz, 4H), 8.14 (d, J = 8.4 Hz, 4H), 8.08–8.03 (m, 2H), 7.97 (d, J = 8.2 Hz, 2H), 7.86–7.77 (m, 8H), 7.75–7.69 (m, 2H), 7.43–7.36 (m, 2H), 3.48 (s, 12H). HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C46H37N8S 733.2857; found 733.2923. UV (CH2Cl2) λmax (log ε): 227 (4.542), 279 (4.338), 349 (4.675) nm.
2-[4’-(5-{3’-[4-(dimethylamino)quinazolin-2-yl]-[1,1’-biphenyl]-4-yl}-1,3,4-thiadiazol-2-yl)-[1,1’-biphenyl]-3-yl]-N,N-dimethylquinazolin-4-amine (9b). The product was obtained as a beige solid (269 mg, 92%); mp 310–311 °C; Rf = 0.44 (5% MeOH in DCM). IR (ATR): 2937, 2485, 2205, 2157, 2139, 2029, 1967, 1732, 1605, 1564, 1522, 1486, 1456, 1438, 1422, 1393, 1376, 1350, 1333, 1274, 1234, 1169, 1136, 1103, 1071, 1044, 987, 959, 921, 889, 856, 835, 811, 795, 773, 760, 742, 722, 680 cm−1. 1H NMR (400 MHz, CDCl3) δ = 8.89 (t, J = 1.8 Hz, 2H), 8.61 (dt, J = 7.8, 1.4 Hz, 2H), 8.19–8.12 (m, 4H), 8.06 (dd, J = 8.5, 1.4 Hz, 2H), 7.98 (dd, J = 8.5, 1.3 Hz, 2H), 7.93–7.85 (m, 4H), 7.78–7.70 (m, 4H), 7.61 (t, J = 7.7 Hz, 2H), 7.40 (ddd, J = 8.3, 6.9, 1.3 Hz, 2H), 3.48 (s, 12H). 13C NMR (101 MHz, CDCl3) δ = 168.0, 164.1, 159.1, 153.1, 144.3, 140.0, 139.9, 132.3, 129.2, 129.1, 128.9, 128.8, 128.5, 128.3, 128.1, 127.3, 125.7, 124.4, 115.2, 42.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C46H37N8S 733.2857; found 733.2921. UV (CH2Cl2) λmax (log ε): 227 (4.564), 273 (4.541), 333 (4.680) nm.
2-[4’-(5-{2’-[4-(dimethylamino)quinazolin-2-yl]-[1,1’-biphenyl]-4-yl}-1,3,4-thiadiazol-2-yl)-[1,1’-biphenyl]-2-yl]-N,N-dimethylquinazolin-4-amine (9c). The product was obtained as a beige solid (257 mg, 88%); mp 226–227 °C; Rf = 0.26 (5% MeOH in DCM). IR (ATR): 2932, 2195, 2163, 2021, 1972, 1609, 1578, 1561, 1520, 1484, 1440, 1399, 1377, 1348, 1331, 1252, 1215, 1185, 1160, 1140, 1093, 1073, 1048, 1005, 985, 956, 881, 843, 834, 825, 807, 775, 753, 732, 708, 680 cm−1. 1H NMR (400 MHz, CDCl3) δ = 8.16–8.07 (m, 2H), 7.94 (dd, J = 8.6, 0.8 Hz, 1H), 7.89 (dd, J = 8.6, 0.8 Hz, 1H), 7.88–7.81 (m, 2H), 7.69 (ddd, J = 8.3, 6.9, 1.4 Hz, 2H), 7.55–7.49 (m, 4H), 7.51–7.43 (m, 2H), 7.38 (ddd, J = 8.3, 6.9, 1.4 Hz, 3H), 7.37–7.30 (m, 4H), 2.93 (s, 12H). 13C NMR (101 MHz, CDCl3) δ = 168.1, 163.0, 162.0, 152.9, 146.5, 140.7, 139.4, 132.2, 131.1, 130.6, 130.1, 129.2, 128.8, 128.2, 128.0, 127.4, 125.6, 124.5, 114.4, 41.5. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C46H37N8S 733.2857; found 733.2917. UV (CH2Cl2) λmax (log ε): 229 (4.775), 279 (4.579), 329 (4.690) nm.
6-[4-(5-{4-[4-(dimethylamino)-2-phenylquinazolin-6-yl]phenyl}-1,3,4-thiadiazol-2-yl)phenyl]-N,N-dimethyl-2-phenylquinazolin-4-amine (9d). The product was obtained as a dark green solid (255 mg, 87%); mp 317–319 °C; Rf = 0.36 (5% MeOH in DCM). IR (ATR): 2920, 2156, 1964, 1603, 1585, 1552, 1532, 1515, 1444, 1413, 1385, 1347, 1324, 1239, 1191, 1167, 1104, 1065, 1026, 987, 957, 928, 890, 825, 777, 727, 706, 689, 673 cm−1. 1H NMR (400 MHz, CDCl3) δ= 8.59 (dd, J = 7.9, 1.8 Hz, 4H), 8.28 (d, J = 1.9 Hz, 2H), 8.19–8.12 (m, 4H), 8.07–7.98 (m, 4H), 7.84–7.77 (m, 4H), 7.55–7.45 (m, 6H), 3.52 (s, 12H). 13C NMR (101 MHz, CDCl3) δ = 167.8, 164.3, 159.8, 153.0, 143.4, 138.9, 135.6, 131.2, 130.3, 129.6, 129.4, 128.8, 128.6, 128.5, 127.9, 124.1, 115.3, 42.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C46H37N8S 733.2857; found 733.2911. UV (CH2Cl2) λmax (log ε): 227 (4.596), 298 (4.677), 350 (4.733) nm.
7-[4-(5-{4-[4-(dimethylamino)-2-phenylquinazolin-7-yl]phenyl}-1,3,4-thiadiazol-2-yl)phenyl]-N,N-dimethyl-2-phenylquinazolin-4-amine (9e). The product was obtained as a beige solid (248 mg, 85%); mp 350–352 °C; Rf = 0.38 (5% MeOH in DCM). IR (ATR): 2933, 2539, 2157, 2019, 1965, 1613, 1585, 1552, 1534, 1517, 1479, 1452, 1434, 1414, 1381, 1343, 1253, 1203, 1163, 1098, 1079, 1065, 1026, 988, 955, 930, 911, 885, 864, 844, 819, 795, 774, 755, 732, 722, 704, 689, 675 cm−1. 1H NMR (400 MHz, CDCl3) δ = 8.62–8.57 (m, 4H), 8.24 (d, J = 2.0 Hz, 2H), 8.21–8.13 (m, 6H), 7.93 (d, J = 8.4 Hz, 4H), 7.69 (dd, J = 8.6, 2.0 Hz, 2H), 7.55–7.47 (m, 6H), 3.50 (s, 12H). HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for C46H37N8S 733.2857; found 733.2927. UV (CH2Cl2) λmax (log ε): 224 (4.467), 265 (4.611), 345 (4.702) nm.

4. Conclusions

To summarize, two series of new conjugates, combining 2,5-diphenyl-1,3,4-thiadiazole and 4-(N,N-dimethylamino)-2-phenylquinazoline scaffolds, were synthesized. To efficiently prepare such compounds, Suzuki cross-coupling reactions of the appropriate quinazolinyl bromides and mono or bis boronic 1,3,4-thiadiazole-containing esters were applied, proceeding in the presence of [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst. All transformations were conducted in the biphasic solvent system, with the use of the phase transfer catalyst NBu4Br, and Na2CO3 as the base, and resulted in the formation of highly-conjugated products in excellent yields. Generally, the obtained 1,3,4-thiadiazole derivatives exhibit violet fluorescence in the range of 393–437 nm and are characterized by a rather low quantum yield of fluorescence. However, two among the synthesized compounds 8a, 9a, containing a double 1,4-phenylene linker, displayed strong fluorescence and high quantum yields, which may result in interest from material science.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal12121586/s1, Copies of the 1H NMR, 13C NMR, HRMS, UV-Vis and fluorescent spectra of the compounds are available in the online Supplementary Materials.

Author Contributions

B.W. and A.K. conceived and designed the experiments, performed the experiments and analyzed the data. M.Ś. performed emission measurements. B.W. wrote the manuscript with the help of A.K. and M.Ś. All authors have read and agreed to the published version of the manuscript.

Funding

The project was financially supported by the Silesian University of Technology (Poland), Grant No 04/050/BK-22/0139.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 2a–e, 5a–b, 6, 7, 8a–e, and 9a–e are available from the authors.

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Catalysts 12 01586 sch001 550
Scheme 1. Quinazoline and 1,3,4-thiadiazole precursors for Suzuki cross-coupling reactions.
Scheme 1. Quinazoline and 1,3,4-thiadiazole precursors for Suzuki cross-coupling reactions.
Catalysts 12 01586 sch001
Catalysts 12 01586 sch002 550
Scheme 2. Catalytic cycle of Suzuki cross-coupling reaction.
Scheme 2. Catalytic cycle of Suzuki cross-coupling reaction.
Catalysts 12 01586 sch002
Catalysts 12 01586 sch003 550
Scheme 3. Synthesis of 4-(N,N-dimethylamino)-2-phenylquinazoline derivatives (2a–e). Reagents and conditions: (i) PCl5, toluene, 50 °C; (ii) Me2NCN, toluene, rt, 24 h; (iii) TiCl4, toluene, 70 °C, 5 h.
Scheme 3. Synthesis of 4-(N,N-dimethylamino)-2-phenylquinazoline derivatives (2a–e). Reagents and conditions: (i) PCl5, toluene, 50 °C; (ii) Me2NCN, toluene, rt, 24 h; (iii) TiCl4, toluene, 70 °C, 5 h.
Catalysts 12 01586 sch003
Catalysts 12 01586 sch004 550
Scheme 4. Synthesis of mono and bis boronic esters of 2,5-diphenyl-1,3,4-thiadiazole (6, 7). Reagents and conditions: (i) (a) ethanol, 2 h, reflux; (b) Lawesson’s reagent, DMAP, toluene, reflux, overnight; (ii) bis(pinacolato)diboron, 1,4-dioxane, AcOK, Pd(dppf)Cl2, sealed tube, 100 °C, overnight.
Scheme 4. Synthesis of mono and bis boronic esters of 2,5-diphenyl-1,3,4-thiadiazole (6, 7). Reagents and conditions: (i) (a) ethanol, 2 h, reflux; (b) Lawesson’s reagent, DMAP, toluene, reflux, overnight; (ii) bis(pinacolato)diboron, 1,4-dioxane, AcOK, Pd(dppf)Cl2, sealed tube, 100 °C, overnight.
Catalysts 12 01586 sch004
Catalysts 12 01586 sch005 550
Scheme 5. Synthesis of N,N-dimethyl-2-[4’-(5-phenyl-1,3,4-thiadiazol-2-yl)-[1,1’-biphenyl]-4-yl]quinazolin-4-amine (8a).
Scheme 5. Synthesis of N,N-dimethyl-2-[4’-(5-phenyl-1,3,4-thiadiazol-2-yl)-[1,1’-biphenyl]-4-yl]quinazolin-4-amine (8a).
Catalysts 12 01586 sch005
Catalysts 12 01586 sch006 550
Scheme 6. Suzuki cross-coupling reactions of quinazoline derivatives (2a–e) with boronic ester 6. Reagents and conditions: quinazoline derivative 2a–e (0.61 mmol), boronic acid pinacol ester 6 (0.73 mmol), Pd(dppf)Cl2 (0.03 mmol), NBu4Br (0.03 mmol), Na2CO3 (3.1 mmol), toluene-H2O (6.6:3.4 mL), sealed tube, oil bath 115 °C, overnight.
Scheme 6. Suzuki cross-coupling reactions of quinazoline derivatives (2a–e) with boronic ester 6. Reagents and conditions: quinazoline derivative 2a–e (0.61 mmol), boronic acid pinacol ester 6 (0.73 mmol), Pd(dppf)Cl2 (0.03 mmol), NBu4Br (0.03 mmol), Na2CO3 (3.1 mmol), toluene-H2O (6.6:3.4 mL), sealed tube, oil bath 115 °C, overnight.
Catalysts 12 01586 sch006
Catalysts 12 01586 sch007 550
Scheme 7. Suzuki cross-coupling reactions of quinazoline derivatives (2a–e) with bis boronic ester 7. Reagents and conditions: quinazoline derivative 2a–e (0.82 mmol), boronic acid pinacol ester 7 (0.49 mmol), Pd(dppf)Cl2 (0.04 mmol), NBu4Br (0.04 mmol), Na2CO3 (4.1 mmol), toluene-H2O (13.2:6.6 mL), sealed tube, oil bath 115 °C, overnight.
Scheme 7. Suzuki cross-coupling reactions of quinazoline derivatives (2a–e) with bis boronic ester 7. Reagents and conditions: quinazoline derivative 2a–e (0.82 mmol), boronic acid pinacol ester 7 (0.49 mmol), Pd(dppf)Cl2 (0.04 mmol), NBu4Br (0.04 mmol), Na2CO3 (4.1 mmol), toluene-H2O (13.2:6.6 mL), sealed tube, oil bath 115 °C, overnight.
Catalysts 12 01586 sch007
Table
Table 1. Optimization of the Suzuki cross-coupling reaction to obtain 8a.
Table 1. Optimization of the Suzuki cross-coupling reaction to obtain 8a.
EntryCatalystLigandBaseSolventPTC CatalystYield [%] a
1Pd(dppf)Cl2-Na2CO3Toluene/waterBu4NBr84
2Pd(dppf)Cl2-Na2CO3Toluene/water-82
3PdCl2-Na2CO3Toluene/waterBu4NBr61
4Pd(OAc)2XPhosNa2CO3Toluene/waterBu4NBr75
5Pd(OAc)2cataCXium ANa2CO3Toluene/waterBu4NBr47
6Pd(OAc)2XanthphosNa2CO3Toluene/waterBu4NBr73
7Pd(dppf)Cl2-Na2CO3THF/water-77
8Pd(dppf)Cl2-Na2CO3dioxane/water-66
9Pd(dppf)Cl2-Na2CO3DMF/water-69
10Pd(dppf)Cl2-Na2CO3iPrOH/water-82
11Pd(dppf)Cl2-tBuONaToluene/water-67
12Pd(dppf)Cl2-K3PO4Toluene/water-70
13Pd(dppf)Cl2-NaOHToluene/water-43
a Isolated yield with respect to starting quinazoline 2a. Conditions: quinazoline 2a (1 equiv.), boronic ester 6 (1.2 equiv.), catalyst (0.05 equiv.), ligand (0.1 equiv.), base (5 equiv.), PTC catalyst (0.05 equiv.), sealed tube, oil bath 115 °C, overnight.
Table
Table 2. Unsymmetrical quinazolinylphenyl-1,3,4-thiadiazole derivatives (8a–e) synthesized via Suzuki cross-coupling reactions.
Table 2. Unsymmetrical quinazolinylphenyl-1,3,4-thiadiazole derivatives (8a–e) synthesized via Suzuki cross-coupling reactions.
EntrySubstrateProductYield [%] a
1.2aCatalysts 12 01586 i0018aCatalysts 12 01586 i00284
2.2bCatalysts 12 01586 i0038bCatalysts 12 01586 i00490
3.2cCatalysts 12 01586 i0058cCatalysts 12 01586 i00677
4.2dCatalysts 12 01586 i0078dCatalysts 12 01586 i00882
5.2eCatalysts 12 01586 i0098eCatalysts 12 01586 i01090
a Isolated yields with respect to starting quinazoline derivative 2a–e.
Table
Table 3. Symmetrical quinazolinylphenyl-1,3,4-thiadiazole derivatives (9a–e) synthesized via Suzuki cross-coupling reactions.
Table 3. Symmetrical quinazolinylphenyl-1,3,4-thiadiazole derivatives (9a–e) synthesized via Suzuki cross-coupling reactions.
EntrySubstrateProductYield [%] a
1.2aCatalysts 12 01586 i0119aCatalysts 12 01586 i01281
2.2bCatalysts 12 01586 i0139bCatalysts 12 01586 i01492
3.2cCatalysts 12 01586 i0159cCatalysts 12 01586 i01688
4.2dCatalysts 12 01586 i0179dCatalysts 12 01586 i01887
5.2eCatalysts 12 01586 i0199eCatalysts 12 01586 i02085
a Isolated yields with respect to starting quinazoline derivative 2a–e.
Table
Table 4. Spectroscopic data for the studied compounds 5a, 5b, 6, 7, 8a–e, 9a–e.
Table 4. Spectroscopic data for the studied compounds 5a, 5b, 6, 7, 8a–e, 9a–e.
EntryCompoundλabs
(nm)
(ε∙10−4 m3/(mol.cm))		λex(nm)λem (nm)Stokes Shift aΔ (nm)Quantum Yield b
Φf
15a308 (5.6)316393850.06
25b313 (5.6)324400870.09
36306 (4.7)316396900.07
47314 (5.5)324401870.11
58a340 (8.6)346434940.26
68b325 (5.5)338415900.02
78c325 (5.3)344413880.05
88d311 (6.3)3484151040.06
98e342 (5.9)346413710.04
109a348 (3.9)35343789>0.98 c
119b334 (8.1)342414800.05
129c331 (9.7)345428970.02
139d350 (7.0)353435850.05
149e359 (9.5)360431720.06
UV-Vis absorption and 3D fluorescence spectra were registered in dichloromethane solutions (c = 1 × 10−6 mol/dm3). λabs—Wavelength of absorption maximum; λem—excitation wavelength; λem—emission wavelength at global fluorescence maximum. a Stokes shift was calculated as λem—λabs; b the quantum yields Φf were determined according to the method described by Brouwer [50] by comparison with two standards: quinine sulfate (qn-SO42−) [51] and trans,trans-1,4-diphenyl-1,3-butadiene (dpb) [52]—the mean value is presented; c the exact value of Φf larger than 0.98 cannot be determined due to nonlinearity of standard/sample dependence in the Φf region 0.98–1.00 [50].
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Wołek, B.; Świątkowski, M.; Kudelko, A. Palladium-Catalyzed Synthesis of Novel Quinazolinylphenyl-1,3,4-thiadiazole Conjugates. Catalysts 2022, 12, 1586. https://doi.org/10.3390/catal12121586

AMA Style

Wołek B, Świątkowski M, Kudelko A. Palladium-Catalyzed Synthesis of Novel Quinazolinylphenyl-1,3,4-thiadiazole Conjugates. Catalysts. 2022; 12(12):1586. https://doi.org/10.3390/catal12121586

Chicago/Turabian Style

Wołek, Barbara, Marcin Świątkowski, and Agnieszka Kudelko. 2022. "Palladium-Catalyzed Synthesis of Novel Quinazolinylphenyl-1,3,4-thiadiazole Conjugates" Catalysts 12, no. 12: 1586. https://doi.org/10.3390/catal12121586

APA Style

Wołek, B., Świątkowski, M., & Kudelko, A. (2022). Palladium-Catalyzed Synthesis of Novel Quinazolinylphenyl-1,3,4-thiadiazole Conjugates. Catalysts, 12(12), 1586. https://doi.org/10.3390/catal12121586

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