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Citric Acid-Catalyzed Three-Component Synthesis of (E)-3-Aryl-2-Styryl-2,3-Dihydroquinazolin-4-(1H)-Ones and Their Mild Oxidation with I2/DMSO System into (E)-3-Aryl-2-Styrylquinazolin-4(3H)-Ones

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05 February 2025

Posted:

06 February 2025

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Abstract

We hereby report a simple and efficient method for the preparation of (E)-3-aryl-2-styryl-2,3-dihydroquinazolin-4-(1H)-ones, from isatoic anhydride, anilines and cin-namaldehydes in the presence of 20 mol% citric acid in methanol at 60 °C for 2 h. The styryl-dihydroquinazolin-4-(1H)-one products were obtained in moderate and good yields (30-80 %) through the three-component condensation reaction, under an environment-friendly protocol. The latter were easily transformed into styrylquinazolin-4-(3H)-one derivatives with 57-91 % yields using a mild oxidation with I2/DMSO system for less than 60 min.

Keywords: 
three-component condensation reaction
;  
2
;  
3-dihydroquinazolin-4-(1H)-ones
;  
quinazolin-4-(3H)-ones
;  
styryl derivatives
;  
organocatalysis
;  
citric acid
;  
catalytic iodine/DMSO system
Subject: 
Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

The quinazolinone skeletons (dihydroquinazolin-4-(1H)-ones and quinazolin-4-(3H)-ones are the main structural parts for numerous secondary metabolites and privileged scaffolds in medicinal chemistry [1,2,3,4,5], especially in cancer drug research [6,7] and epilepsy treatment [8]. The chemical characteristics of the quinazolinone core (aromatic ring, two not equivalent nitrogen atoms in the pyrimidine ring, group C=O, π-conjugated lactam-aryl motif, and polarized endocyclic imine C=N function) make simple functionalized quinazolinones attractive, proper, and versatile models or/and precursors for diverse biological, pharmacological and agrochemical and fluorescent properties (Figure 1) [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23].
Subsequently, there is a huge review literature on their synthesis [24,25,26,27,28,29,30,31]. Among them, environmentally benign approaches, i.e., solid acid catalyzed, nanocatalyzed or organocatalyzed syntheses stand out as promising green alternative methods for constructing quinazolinone skeletons [29,30,31]. Generally, the quinazolinones are easily prepared using different principal starting materials, 2-substituted aryl amines, such as anthranilic acid (2-aminobenzoic acid), its close derivatives, or 2-aminobenzaldehydes and 2-aminoaryl ketones. Direct synthesis of quinazolinone derivatives through cyclocondensation of 2-aminobenzamide derivatives and aldehydes in the presence of various metal catalysts remains the most popular method [27] although several new methods have been developed for the synthesis of the quinazolinones derivatives [32,33,34,35].
Another equally popular starting material in synthesizing 2,3-dihydroquinazolinones, valuable intermediates in organic synthesis, are isatoic anhydrides. Several methods for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones have been reported, which are usually based on the condensation of isatoic anhydride, aldehydes, and ammonium salts or primary amines in the presence of numerous different catalysts [36], including organocatalysts such as p-TsOH [37], ethylene diamine diacetate [38], dodecylbenzenesulfonic acid [39], L-proline [40], β-cyclodextrin [41], room temperature ionic liquids [42], acetic [43], glutamic [44] or citric [45] acids, etc.
In light of the aforementioned facts and our ongoing commitment to exploring the synthesis of novel bioactive small heterocyclic molecules under environmentally friendly reaction conditions [46,47,48], we established a simple green procedure for the synthesis (E)-3-aryl-2-styryl-2,3-dihydroquinazolin-4-(1H)-ones and corresponding quinazoline-4(3H)-one derivatives.
Although 2-styrylquinazolinones, which combine the medicinally significant stilbene and quinazolinone frameworks, are of great interest to synthetic and medicinal chemists, their reported synthetic protocols often have notable limitations. Methods employing starting materials such as 2-aminobenzamide, 2-methyl-3,1-benzoxazin-4-one, or 2-methylquinazolin-4(3H)-one derivatives typically involve multi-step reactions, harsh conditions, extended reaction times, and reliance on toxic or expensive catalysts [49,50,51,52,53,54]. Notably, even the few reports describing one-pot procedures for synthesizing 2-styrylquinazolin-4(3H)-ones from readily available isatoic anhydride suffer similar drawbacks [55,56].
Therefore, this study presents practical, direct syntheses of novel styryl-quinazolinone derivatives via a three-component condensation reaction involving isatoic anhydride, anilines, and cinnamaldehydes. The reaction, conducted in methanol with 20 mol% citric acid, yields (E)-3-aryl-2-styryl-2,3-dihydroquinazolin-4(1H)-ones. These intermediates are subsequently oxidized using an I₂/DMSO system to produce the corresponding 2-styryl-4(3H)-quinazolinones. A key highlight of our research is the development of two simple, cost-effective procedures under sustainable reaction conditions, enabling the preparation of a diverse series of styryl-quinazolinones. These compounds represent privileged scaffolds and valuable medicinal chemistry and organic synthesis building blocks.

2. Materials and Methods

2.1. Materials and Instruments

The solvents and reagents used for synthesizing both the intermediate and final compounds were of synthesis-grade purity. All chemicals were sourced from Merck, J.T. Baker, Sigma, and Aldrich Chemical Co. and were utilized without additional purification. Reaction progress and product purity were monitored using thin-layer chromatography (TLC) on Silufol UV254 plates (0.25 mm thickness). Visualization was done under UV light at 254 nm or using an ethanolic solution of phosphomolybdic-sulfuric acids. Melting points were determined with a Fisher-Johns apparatus and are reported as uncorrected values.
Nuclear magnetic resonance (NMR) spectra for 1H and 13C were acquired using a Bruker Avance–400 spectrometer (400 MHz for 1H and 101 MHz for 13C). Chemical shifts (δ) are reported in parts per million (ppm), referenced to solvent signals (DMSO-d6: δ 2.50 ppm). Coupling constants (J) are provided in Hz, and signal multiplicity is denoted as follows: (s) singlet, (d) doublet, (dd) doublet of doublets, (ddd) doublet of doublet of doublets, and (m) multiplet. The coupling constants J are expressed in Hz. The aromatic protons of the N3-aryl fragment are designated as HPh and those of 2-styryl moiety shown as HAr.
Infrared spectra were recorded using a Bruker Tensor 27 FTIR spectrophotometer equipped with a platinum ATR cell, operating at 31 scans with a resolution of 2 cm-1. Elemental analyses were performed on a Thermo Scientific CHNS-O analyzer (Model. Flash 2000), with results within ± 0.4 of theoretical values.

2.2. General Procedure for the Synthesis of (E)-3-aryl-2-styryl-2,3-dihydroquinazolin-4(1H)-one derivatives 4a−e

To a solution of isatoic anhydride 1 (1.4 mmol) in 1 mL of methanol, 20 mol% of citric acid monohydrate (CAM) was added, and the mixture was stirred for 20 minutes. Subsequently, the respective aniline derivatives 2a–e, (1.6 mmol) and cinnamaldehydes 3a–b, (1.3 mmol) were added sequentially. The resulting mixture was heated at 60°C for 2 hours, with progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. Methanol was distilled off, and the crude solids were washed with a cold solution of 85% ethanol and filtered to yield products 4a–e. In some cases, purification by column chromatography was required, using alumina as the stationary phase and a petroleum ether: ethyl acetate (1:2) mixture as the eluent. Characterization data for the new compounds 4a−e are provided below:

2.2.1 3-Phenyl-2-styryl-2,3-dihydroquinazolin-4(1H)-one (4a)

was synthesized following the general procedure using isatoic anhydride 1 (0.25 g, 1.53 mmol), aniline 2a (0.14 mL, 1.52 mmol), cinnamaldehyde 3a (0.19 mL, 1.52 mmol), and 20 mol% CAM (69 mg, 0.33 mmol). After reaction, isolation, and recrystallization, a pale yellow solid (0.27 g, 0.83 mmol, 54% yield) was obtained. Rf = 0.23 (1:2, petroleum ether: ethyl acetate); Mp = 192−194 °C. IR (ATR, νmax): 3310 (N−H), 3058 (ArC−H), 1631 (C=O), 1488 (ArC=C), 1395 (C-N) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.76 (1H, dd, J = 7.8, 1.6 Hz, 5-H), 7.43−7.38 (4H, m, HPh), 7.36−7.32 (5H, m, HAr), 7.28−7.21 (3H, m, 6-H, 7-H, and HPh), 6.85 (1H, d, J = 15.0 Hz, =HαCAr), 6.76 (1H, m, J = 15.0 Hz, =HβCQuin), 6.49 (2H, d, J = 4.7 Hz, 8-H and N-H), 5.73−5.66 (1H, m, 2-H). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 161.7, 146.7, 140.6, 135.4, 133.6, 131.9, 128.7 (2), 128.6 (2), 128.1, 128.0, 127.0 (2), 126.7, 126.6 (2), 126.4, 117.5, 115.1, 114.8, 72.5. Anal. calcd. for C22H18N2O (326.40): C, 80.96; H, 5.56; N, 8.58 %. Found: C, 80.84; H, 5.71; N, 8.40 %.

2.2.2 3-(4-Methoxyphenyl)-2-styryl-2,3-dihydroquinazolin-4(1H)-one (4b)

was synthesized following the general procedure using isatoic anhydride 1 (0.23 g, 1.32 mmol), 4-methoxyaniline 2c (0.20 g, 1.62 mmol)), cinnamaldehyde 3a (0.17 mL, 1.27 mmol), and 20 mol% CAM (65 mg, 0.31 mmol). After reaction, isolation, and recrystallization, a white solid (0.40 g, 1.12 mmol, 80 %) was obtained. Rf = 0.27 (1:2, petroleum ether: ethyl acetate); Mp = 234−236 °C. IR (ATR, νmax): 3311 (N−H), 2810 (OCH3), 1630 (C=O), 1507 (ArC=C), 1389 (C−N) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.72 (1H, d, J = 7.7 Hz, 5-H), 7.37−7.34 (2H, m, HAr), 7.34−7.31 (1H, m, 7-H), 7.27 (5H, m, HPh and HAr), 7.23 (1H, m, 6-H), 6.98−6.91 (2H, m, HPh), 6.82 (1H, d, J = 15.1 Hz, =HαCAr), 6.75 (1H, m, J = 15.0 Hz, =HβCQuin), 6.47 (2H, d, J = 3.1 Hz, 8-H and N−H), 5.61−5.57 (1H, m, 2-H), 3.74 (3H, s, OCH3). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 161.8, 157.6, 146.8, 135.4, 133.5, 133.3, 131.9, 128.7 (2), 128.6 (2), 128.1, 127.9, 126.7, 126.6 (2), 117.4, 115.0, 114.7, 113.9 (2), 73.0, 55.2. Anal. calcd. for C23H20N2O2 (356.43): C, 77.51; H, 5.66; N, 7.86 %. Found: C, 77.76; H, 5.53; N, 7.61 %.

2.2.3 3-(3,4-Dimethoxyphenyl)-2-styryl-2,3-dihydroquinazolin-4(1H)-one (4c)

was synthesized following the general procedure using isatoic anhydride 1 (0.21 g, 1.30 mmol), 3,4-dimethoxyaniline 2c (0.22 g, 1.44 mmol), cinnamaldehyde 3a (0.16 mL, 1.30 mmol), and 20 mol% CAM (58 mg, 0.28 mmol). After reaction, isolation, and recrystallization, a white solid (0.35 g, 0.90 mmol, 70 %) was obtained. Rf = 0.10 (1:2, petroleum ether: ethyl acetate); Mp = 227−228 °C. IR (ATR, νmax): 3306 (N−H), 2919 (OCH3), 1630 (C=O), 1608 (C=C), 1507 (ArC=C), 1389 (C−N) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.73 (1H, d, J = 7.8 Hz, 5-H), 7.39−7.35 (2H, m, HAr), 7.34−7.31 (1H, m, 7-H), 7.29 (3H, d, J = 3.7 Hz, HAr), 7.27−7.22 (1H, m, HPh), 6.98−6.95 (1H, m, 6-H), 6.94 (1H, s, HPh), 6.87 (1H, dd, J = 8.5, 2.3 Hz, HPh), 6.83 (1H, d, J = 15.0 Hz, =HαCAr), 6.75 (1H, m, J = 15.0 Hz, =HβCQuin), 6.50 (2H, d, J = 3.2 Hz, 8-H and N−H), 5.64−5.57 (1H, m, 2-H), 3.74 (3H, s, OCH3), 3.70 (3H, s, OCH3). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 161.8, 148.5, 147.4, 146.8, 135.5, 133.5 (2), 132.0, 128.6 (2), 128.1, 128.0, 126.8, 126.6 (2), 119.6, 117.4, 115.0, 114.7, 111.8, 111.4, 73.0, 55.5 (2). Anal. calcd. for C24H22N2O3 (386.45): C, 74.59; H, 5.74; N, 7.25 %. Found: C, 74.40; H, 5.89; N, 7.13 %.

2.2.4 3-(4-Methoxyphenyl)-2-(2-methoxystyryl)-2,3-dihydroquinazolin-4(1H)-one (4d)

was synthesized following the general procedure using isatoic anhydride 1 (0.21g, 1.30 mmol), 4-methoxyaniline 2b (0.17 g, 1.43 mmol), 3-(2-methoxyphenyl)acrylaldehyde 3b (0.21 g, 1.29 mmol), and 20 mol% CAM (59 mg, 0.28 mmol). After reaction, isolation, and recrystallization, a brown solid (0.31 g, 0.80 mmol, 61 %) was obtained. Rf = 0.16 (1:2, petroleum ether: ethyl acetate); Mp = 162−164 °C. IR (ATR, νmax): 3306 (N−H), 2832 (OCH3), 1628 (C=O), 1508 (C=C), 1391 (C−N), 1242 (ArC−H) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.72 (1H, dd, J = 7.8, 1.4 Hz, 5-H), 7.37 (1H, dd, J = 7.7, 1.6 Hz, HAr), 7.33−7.30 (1H, m, 7-H), 7.29−7.26 (3H, m, HAr), 7.25−7.20 (1H, m, 6-H), 6.97−6.92 (3H, m, 8-H and HPh), 6.88−6.80 (3H, m, HPh and N−H), 6.76−6.69 (1H, m, J = 15.0, =HαCAr ), 6.43 (1H, m, J = 15.1, =HβCQuin), 5.60 (1H, m, 2-H), 3.74 (3H, s, OCH3), 3.72 (3H, s, OCH3). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 161.9, 157.5, 156.4, 146.9, 133.4, 133.3, 129.4, 128.7 (2), 127.9, 127.0, 126.7, 126.5, 123.9, 120.5, 117.3, 115.0, 114.7, 113.9 (2), 111.4, 73.3, 55.4, 55. Anal. calcd. for C24H22N2O (386.45): C, 74.59; H, 5.74; N, 7.25 %. Found: C, 74.68; H, 5.61; N, 7.33 %.

2.2.5 3-(4-Bromophenyl)-2-styryl-2,3-dihydroquinazolin-4(1H)-one (4e)

was synthesized following the general procedure using isatoic anhydride 1 (0.20 g, 1.30 mmol), 4-bromoaniline 2d (0.23 g, 1.35 mmol), cinnamaldehyde 3a (0.15 mL, 1.23 mmol), and 20 mol% CAM (63 mg, 0.30 mmol). After reaction, isolation, and recrystallization, a white solid (0.14 g, 1.12 mmol, 30 %) was obtained. Rf = 0.46 (1:2, petroleum ether: ethyl acetate); Mp = 183−185 °C. IR (ATR, νmax): 3306 (N−H), 3067 (ArC−H), 1726 (C=O), 1613 (C=C), 1485 (ArC=C), 1010 (C−N), 751 (C−Br) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92 (1H, dd, J = 7.9, 1.1 Hz, 5-H), 7.60−7.57 (2H, m, HPh), 7.38−7.34 (5H, m, HAr), 7.27−7.24 (2H, m, HPh), 7.16 (2H, d, J = 8.2 Hz, 6-H and 7-H), 6.84 (1H, d, J = 15.2 Hz, =HαCAr), 6.74−6.69 (1H, m,J = 15.0 Hz, =HβCQuin), 6.51−6.46 (2H, m, 8-H and N−H), 5.71 (1H, m, 2-H). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 161.8, 159.8, 147.0, 146.8, 141.3, 132.5, 132.1, 131.6 (2), 128.6 (2), 128.4, 128.2, 126.6 (2), 126.5, 123.4, 117.5, 115.32 (2), 114.9, 72.3. Anal. calcd. for C22H17BrN2O (405.30): C, 65.20; H, 4.23; N, 6.91 %. Found: C, 65.37; H, 4.11; N, 6.82 %.

2.3. General Procedure for the Synthesis of (E)-3-aryl-2-styrylquinazolin-4(3H)-one derivatives 5a−d

The oxidation of 2,3-dihydroquinazolin-4(3H)-ones (4a−d) was conducted as follows: 0.20 g (0.56 mmol) of the corresponding substrate, dissolved in 2 mL of DMSO was introduced into a vial under constant stirring. Subsequently, 20 mol% of I₂ was added, and the reaction was maintained at 100 °C, with progress monitored via TLC for 1 hour. The reaction mixture was then extracted with ethyl acetate and washed with brine (3 × 30 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Final purification was achieved through column chromatography (CC) using petroleum ether: ethyl acetate mixtures (10:1). Characterization data for the newly synthesized compounds 5a−d are provided below:

2.3.1 3-Phenyl-2-styrylquinazolin-4(3H)-one (5a)

was synthesized following the general procedure using 2,3-dihydroquinazolinone 4a (0.20 g, 0.61 mmol) and 20 mol% of I₂ (31 mg, 0.12 mmol), dissolved in 2 mL of DMSO. The reaction mixture was heated at 100 °C. After reaction, isolation, and recrystallization, a pale yellow (0.11 g, 0.35 mmol, 57 %) was obtained. Rf = 0.50 (1:2, petroleum ether: ethyl acetate); Mp = 195−197 °C (lit. 196−197 °C [55]). IR (ATR, νmax): 3055 (ArC−H), 1665 (C=O), 1550 (ArC=C), 1352 (C−N) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31 (1H, d, J = 7.7 Hz, 5-H), 7.98 (1H, d, J = 15.5 Hz, =HαCAr), 7.81−7.78 (2H, m, 6-H and 7-H), 7.63−7.55 (3H, m, HPh), 7.47 (1H, d, J = 8.2 Hz, 8-H), 7.35−7.32 (2H, m, HPh), 7.32−7.29 (5H, m, HAr), 6.40 (1H, d, J = 15.5 Hz, =HβCQuin). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 162.4, 151.8, 147.9, 140.0, 137.1, 135.4, 134.7, 130.0 (2), 129.7, 129.4, 128.9 (2), 128.8 (2), 127.8 (2), 127.4, 127.2, 126.7, 121.0, 120.0. Anal. calcd. for C22H16N2O (324.38): C, 81.46; H, 4.97; N, 8.64 %. Found: C, 81.21; H, 4.82; N, 8.53 %.

2.3.2 3-(4-Methoxyphenyl)-2-styrylquinazolin-4(3H)-one (5b)

was synthesized following the general procedure using 2,3-dihydroquinazolinone 4b (0.20 g, 56 mmol) and 20 mol% of I₂ (28 mg, 0.11 mmol), dissolved in 2 mL of DMSO. The reaction mixture was heated at 100 °C. After reaction, isolation, and recrystallization, a pale yellow solid (0.18 g, 0.52 mmol, 91 %) was obtained. Rf = 0.53 (1:2, petroleum ether: ethyl acetate); Mp = 166−168 °C. IR (ATR, νmax): 2922 (ArC−H), 2838 (OCH3), 1671 (C=O), 1548 (C−N) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30 (1H, d, J = 7.9 Hz, 5-H), 7.97 (1H, d, J = 15.5 Hz, =HαCAr), 7.80−7.76 (2H, m, 6-H and 7-H), 7.46 (1H, d, J = 8.2 8-H), 7.38−7.29 (5H, m, HAr), 7.25−7.19 (2H, m, HPh), 7.11−7.05 (2H, m, HPh), 6.47 (1H, d, J = 15.5 Hz, =HβCQuin), 3.91 (3H, s, 4’-OCH3). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 162.7, 160.0, 152.2, 147.9, 139.9, 135.4, 134.6, 129.8 (2), 129.7, 129.5, 128.9 (2), 127.9 (2), 127.4, 127.3, 126.6, 121.0, 120.1, 115.2 (2), 55.7. Anal. calcd. for C23H18N2O2 (354.41): C, 77.95; H, 5.12; N, 7.90 %. Found: C, 77.82; H, 5.37; N, 7.76 %.

2.3.3 3-(3,4-Dimethoxyphenyl)-2-styrylquinazolin-4(3H)-one (5c)

was synthesized following the general procedure using 2,3-dihydroquinazolinone 4c (0.20 g, 52 mmol) and 20 mol% of I₂ (26 mg, 0.10 mmol), dissolved in 2 mL of DMSO. The reaction mixture was heated at 100 °C. After reaction, isolation, and recrystallization, a pale yellow solid (0.17 g, 0.47 mmol, 87 %) was obtained. Rf = 0.30 (1:2, petroleum ether: ethyl acetate); Mp = 232−233 °C. IR (ATR, νmax): 3005 (ArC−H), 2915 (OCH3), 1673 (C=O), 1551 (C−N) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30 (1H, d, J= 7.9 Hz, 5-H), 7.98 (1H, d, J = 15.5 Hz, =HαCAr), 7.82−7.75 (2H, m, 6-H and 7-H), 7.50−7.43 (1H, m, 8-H), 7.37−7.30 (5H, m, HAr), 7.03 (1H, d, J = 8.4 Hz, HPh), 6.87 (1H, dd, J = 8.4, 2.3 Hz, HPh), 6.82 (1H, d, J = 2.4 Hz, HPh), 6.48 (1H, d, J = 15.5 Hz, =HβCQuin), 3.98 (3H, s, OCH3), 3.88 (3H, s, OCH3). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 162.7, 152.1, 150.0, 149.6, 147.9, 140.0, 135.4, 134.7, 129.8, 129.7, 128.9 (2), 127.9 (2), 127.4, 127.2, 126.7, 121.0 (2), 120.0, 111.7, 111.6, 56.2 (2). Anal. calcd. for C24H20N2O3 (384.44): C, 74.98; H, 5.24; N, 7.29 %. Found: C, 74.71; H, 5.37; N, 7.40 %.

2.3.4 3-(4-Methoxyphenyl)-2-(2-methoxystyryl)-quinazolin-4(3H)-one (5d)

was synthesized following the general procedure using 2,3-dihydroquinazolinone 4c (0.20 g, 52 mmol) and 20 mol% of I₂ (26 mg, 0.10 mmol), dissolved in 2 mL of DMSO. The reaction mixture was heated at 100 °C. After reaction, isolation, and recrystallization, a pale yellow solid (0.17 g, 0.45 mmol, 86%) was obtained. Rf = 0.43 (1:2, petroleum ether: ethyl acetate); Mp = 189−190 °C. IR (ATR, νmax): 3057 (ArC−H), 2935 (OCH3), 1671 (C=O), 1550 (C−N) cm-1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29 (1H, ddd, J = 8.0, 1.4, 0.6 Hz, 5-H), 8.19 (1H, d, J = 15.6 Hz, =HαCAr), 7.82−7.74 (2H, m, 6-H and 7-H), 7.44 (1H, d, J = 8.2, 6.6, 1.7 Hz, 8-H), 7.29−7.25 (2H, m, HAr), 7.23 (2H, d, J = 9.0 Hz, HPh), 7.08 (2H, d, J = 9.0 Hz, HPh), 6.92−6.84 (2H, m, HAr), 6.67 (1H, d, J = 15.6 Hz, =HβCQuin), 3.90 (3H, s, OCH3), 3.76 (3H, s, 4OCH3). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 162.8, 159.9, 158.3, 152.9, 148.0, 135.6, 134.5, 130.8, 129.9, 129.8 (2), 129.5, 127.5, 127.2, 126.4, 124.5, 121.3, 120.9, 120.7, 115.1 (2), 111.1, 55.7, 55.3. Anal. calcd. for C24H20N2O3 (384.44): C, 74.98; H, 5.24; N, 7.29 %. Found: C, 74.83; H, 5.41; N, 7.11 %.

3. Results and Discussion

Drawing on previous reports of 3-aryl-2,3-dihydroquinazolione synthesis catalyzed by organocatalyst [37−45], we selected citric acid as the catalyst. This naturally occurring Brønsted acid is inexpensive, readily available, and has demonstrated good performance in preparing such heterocycles [45]. To explore its efficacy, we investigated the reaction of isatoic anhydride 1, 4-methoxyaniline 2c, and trans-cinnamaldehyde 3a to synthesize 3-(4-methoxyphenyl)-2-styryl-2,3-dihydroquinazolin-4(1H)-one 4b using citric acid under varying reaction conditions (Scheme 1, Table 1).
Based on prior literature on the construction of similar systems, the formation of the target compound 4b was initially investigated using 40 mol% citric acid as a catalyst, yielding 76% (Entry 1, Table 1). Despite this promising result, our goal was to develop a more user-friendly and efficient protocol to accelerate the reaction rate and improve the selective synthesis of dihydroquinazolinones. To this end, microwave radiation (MW) was employed as a heating source under various time and temperature conditions. While MW-assisted synthesis of 2,3-diaryl-2,3-dihydroquinazolinones has been documented [57,58,59], no reports exist for synthesizing 2-styryl derivatives. Experiments using MW revealed a significant decrease in yield (40% and 20%, respectively) as the temperature and reaction time increased (Entries 2–3, Table 1), indicating that these conditions adversely affected the reaction's progress toward the desired quinazoline systems. Subsequently, the citric acid catalyst loading was reduced to 20 mol% under conventional heating. The reaction, monitored via TLC and completed in two hours, successfully yielded 4b with an improved 80% yield (Entry 4, Table 1). Finally, a urea/zinc chloride eutectic solvent system (3.5:1molar ratio) was tested, inspired by recent reports on synthesizing 2,3-diaryl-dihydroquinazolinones in deep eutectic solvents [60]. However, under these conditions, the efficient formation of 4b could not be achieved (Entry 5, Table 1).
Following the optimization of reaction conditions, a small series of 2-styryl-dihydroquinazolinones 4a–e was successfully synthesized (Scheme 2, Table 2). The reaction employed isatoic anhydride (1), selected anilines 2a–d, and cinnamaldehydes 3a–b in the presence of 20 mol% citric acid as a catalyst using methanol as the solvent at 60 °C for 2 hours. The resulting 2,3-dihydroquinazolin-4(1H)-ones 4a–e were obtained in yields ranging from 30% to 80%. The lowest yield (30%) was observed for molecule 4e, likely due to the diminished nucleophilicity of 4-bromoaniline 2d, which impeded its interaction with isatoic anhydride during the initial condensation step. Moreover, no product was formed with 4-nitroaniline (not shown in the scheme), underscoring the essential role of aniline nucleophilicity in successfully forming the target compounds.
In contrast, 2,3-dihydroquinazolin-4(1H)-one 4a and those bearing electron-donating substituents 4b–c were obtained in moderate to excellent yields. As noted in previous studies [36], the synthesis of the 2,3-dihydroquinazolin-4(1H)-one series depends mainly on the balance between the acidity of the reaction medium and the nucleophilicity of the starting anilines. In the initial step, the carbonyl group at the C-4 position of isatoic anhydride 1 undergoes protonation by citric acid, which enhances its electrophilicity and promotes a nucleophilic attack by the amino group of aniline (2a). This reaction produces the intermediate 2-amino-N-phenylbenzamide (AFB), which then progresses to form the desired product. Under the same conditions, the second step proceeds as the carbonyl group of cinnamaldehyde 3a, activated by citric acid, reacts with the amino group at the C-2 position of the intermediate AFB. This nucleophilic attack is followed by dehydration and subsequent protonation facilitated by citric acid in the reaction medium. These steps culminate in cyclization, yielding 2,3-dihydroquinazolin-4(1H)-one 4a (Scheme 3).
The 2-styryl-2,3-dihydroquinazolin-4(1H)-ones 4a–e were obtained as stable solids (Table 2). Their structures were elucidated using a combination of spectroscopic and analytical techniques, including IR, 1H NMR, 13C NMR, and elemental analysis. The 1H NMR spectra provided clear evidence for the molecular structure, with all proton signals and their couplings consistent with the spatial arrangement of the molecule. Key features confirming the skeleton construction included the C-2 proton and the olefinic protons of the styryl fragment, =HαCAr and =HβCQuin, which were observed in the regions of 5.57−5.73 ppm, 6.67−6.85 ppm, and 6.43−6.76 ppm, respectively. The olefinic protons were confirmed to have a trans-configuration, as indicated by the Hα signals appearing as doublets with coupling constants J = 15.0−15.2 Hz. Meanwhile, the Hβ protons were deshielded and appeared as multiplets due to interactions with the two quinazolinone nitrogen atoms and the adjacent C-2 proton.
The products obtained hold significant value not only for medicinal applications but also for their synthetic potential. Typically, 2,3-diaryl-dihydroquinazolinones can be converted into their corresponding 4(3H)-quinazolinone derivatives through oxidation. Established methods include potassium tert-butoxide and tetrabutylammonium bromide in dry THF [61] or KMnO4 in acetone [62]. Additionally, a catalyzed cyclization–oxidation coupling of isatoic anhydride with benzaldehydes and amines in the presence of iodine (1 equiv.) and acetic acid (10 mol%) in a MeCN-H2O mixture was reported in 2010, yielding 2,3-diaryl-4(3H)-quinazolinones [63]. Seeking an efficient method for the oxidation of 2-styryl-2,3-dihydro-4(1H)-quinazolinones 4 to their respective 2-styrylquinazolinones 5, we explored the I2/DMSO catalytic system. This system has gained considerable attention due to its green chemistry attributes, high efficiency, atom economy, low cost, and mild reaction conditions [64,65]. Drawing on these advantages and our prior experience with the system [66], we subjected compounds 4 to oxidation using 20 mol% iodine in DMSO at 100°C for 1 hour. This approach successfully produced the corresponding 4(3H)-quinazolinone derivatives 5 in good to excellent yields, demonstrating that this oxidative catalytic system is also reproducible for this type of quinazoline system (Scheme 4).
The obtained 4(3H)-quinazolinones 5a-d were isolated as stable solids, facilitating the determination of their physical properties and characterization through infrared spectroscopy and nuclear magnetic resonance analysis. A clear comparison of the IR spectra of the dehydro-product 4d and oxidized counterpart 5d reveals the absence of the characteristic peak at 3306 cm-1, corresponding to the NH group. This confirms the successful and complete oxidation of dihydroquinazolinone 4d (Figure S10). Additionally, the NMR spectra of the oxidized products display well-defined signals for the olefinic protons. The olefinic Hβ protons (=HβCQuin) appear as doublets at 6.40−6.67 ppm (J = 15.5−15.6 Hz), while the Hα protons (=HαCAr) are observed as doublets at 7.97−8.19 ppm, exhibiting identical coupling constants.

4. Conclusions

In summary, we have developed an organocatalytic approach for synthesizing 3-aryl-quinazolinones incorporating a trans-stilbene unit. This method, executed in a straightforward and eco-friendly one-pot process, represents a novel contribution to the field. Citric acid, serving as the catalyst, exhibited remarkable efficiency in facilitating these dehydro-products. These intermediates were then efficiently transformed into 2-styryl-quinazolinones through a metal-free catalytic system using iodine/DMSO under mild oxidative conditions. The synthetic strategies introduced here enable the construction of two diverse series of saturated and aromatic N3-aryl-quinazolinone frameworks featuring a styryl group at the C-2 position. Moreover, the workup procedures are simple, cost-effective, and rely on readily available commercial reagents. Both structural series hold significant potential in medicinal chemistry, particularly in cancer drug discovery. This study provides an accessible and practical route for generating novel libraries of styryl-quinazolinones from various amines and cinnamaldehydes.

Supplementary Materials

The following supporting information can be downloaded at: www.mdpi.com/xxx/s1, synthetic procedures FT-IR and NMR.

Author Contributions

Conceptualization, V.V.K.; methodology, A.P.G.; formal analysis, A.P.G., C.E.P.G. and V.V.K.; writing—original draft preparation, V.V.K; writing—review and editing, C.E.P.G. and V.V.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Synthetic procedures and FT-IR and NMR are reported in Supplementary Materials.

Acknowledgments

We thank Escuela de Química of the Universidad Industrial de Santander for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Structures of selected quinazolinone skeletons as pharmaceuticals and fluorophores. Methaqualone (“Quaaludes”) is a sedative-hypnotic medication with effects resembling barbiturates. Today, it has no accepted medical use due to its addictive nature [13]. Piriqualone is an anticonvulsant agent for treating neurodegenerative and CNS-trauma-related conditions. It can be prepared from methaqualone and pyridine-2-carboxaldehyde condensation with acetic anhydride and anhydrous zinc chloride in refluxing dioxane [14]. Quinethazone and Fenquizone are diuretics used to treat hypertension [15]. 2-Styrylquinazolin-4(3H)-one-2 compound A inhibited tubulin polymerization and the growth of L12102 murine leukemia cells [16], while fluorinated 2-styryl quinazolinone DKD-NIPERA derivative is a promising hit for oral cancer, showing cytotoxicity in CAL-27 cancer cells (squamous cell carcinoma tumor) [17]. N'-(4–Arylidene)-2-((4-oxo-3-dihydroquinazolin-2-yl)thio)acetohydrazide derivative B displayed superior sub-micromolar antiproliferative activity towards NSC lung cancer cell line NCI-H460, being a potent EGFR inhibitor [18]. The alkaloid series (Bogorin, Penipanoid C, and Pegamine) also showed high cytotoxic activity [19,20,21]. Fluorophores HPQ and ELFTM 97 are insoluble in aqueous media but strongly fluorescent in the solid state [22,23].
Figure 1. Structures of selected quinazolinone skeletons as pharmaceuticals and fluorophores. Methaqualone (“Quaaludes”) is a sedative-hypnotic medication with effects resembling barbiturates. Today, it has no accepted medical use due to its addictive nature [13]. Piriqualone is an anticonvulsant agent for treating neurodegenerative and CNS-trauma-related conditions. It can be prepared from methaqualone and pyridine-2-carboxaldehyde condensation with acetic anhydride and anhydrous zinc chloride in refluxing dioxane [14]. Quinethazone and Fenquizone are diuretics used to treat hypertension [15]. 2-Styrylquinazolin-4(3H)-one-2 compound A inhibited tubulin polymerization and the growth of L12102 murine leukemia cells [16], while fluorinated 2-styryl quinazolinone DKD-NIPERA derivative is a promising hit for oral cancer, showing cytotoxicity in CAL-27 cancer cells (squamous cell carcinoma tumor) [17]. N'-(4–Arylidene)-2-((4-oxo-3-dihydroquinazolin-2-yl)thio)acetohydrazide derivative B displayed superior sub-micromolar antiproliferative activity towards NSC lung cancer cell line NCI-H460, being a potent EGFR inhibitor [18]. The alkaloid series (Bogorin, Penipanoid C, and Pegamine) also showed high cytotoxic activity [19,20,21]. Fluorophores HPQ and ELFTM 97 are insoluble in aqueous media but strongly fluorescent in the solid state [22,23].
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Scheme 1. The model reaction of isatoic anhydride 1, 4-methoxyaniline 2c, and trans-cinnamaldehyde 3a to afford 2-styryl-2,3-dihydroquinazolin-4(1H)-one 4b evaluating reaction parameters.
Scheme 1. The model reaction of isatoic anhydride 1, 4-methoxyaniline 2c, and trans-cinnamaldehyde 3a to afford 2-styryl-2,3-dihydroquinazolin-4(1H)-one 4b evaluating reaction parameters.
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Scheme 2. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones 4a−e using citric acid as catalyst.
Scheme 2. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones 4a−e using citric acid as catalyst.
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Scheme 3. Proposed mechanism of 2,3-dihydroquinazolin-4(1H)-ones via multicomponent reaction.
Scheme 3. Proposed mechanism of 2,3-dihydroquinazolin-4(1H)-ones via multicomponent reaction.
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Scheme 4. Preparation of 3-aryl-2-styryl-4(3H)-quinazolinones 5 promoted by the I2/DMSO catalytic system.
Scheme 4. Preparation of 3-aryl-2-styryl-4(3H)-quinazolinones 5 promoted by the I2/DMSO catalytic system.
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Table 1. Study of the optimal reaction conditions for the preparation of 2-styryl-2,3-dihydroquinazolin-4(1H)-one (4b)a.
Table 1. Study of the optimal reaction conditions for the preparation of 2-styryl-2,3-dihydroquinazolin-4(1H)-one (4b)a.
Entry Citric acid (mol %) Dissolvent t, °C T (h) Yield, %
1 40 Methanol 60 2 76
2 40 Methanol 100b 10 min 40
3 40 Methanol 160b 15 min 20
4 20 Methanol 60 2 80
5 -- Urea/ZnCl2 110 1 20c
a Reaction conditions: 4-methoxyaniline 2c (1.62 mmol, 1.1 equiv), isatoic anhydride 1 (1.39 mmol, 1 equiv), trans-cinnamaldehyde 3a (1.27 mmol, 1 equiv), mol % of citric acid monohydrate, 1 mL of methanol (MeOH), time and temperature. b Microwave heating (min). c Catalytic system with eutectic solvent Urea/ZnCl2 (3.5:1).
Table 2. 2-Styryl-dihydroquinazolinone derivatives obtained via a citric acid-catalyzed three-component condensation reaction.
Table 2. 2-Styryl-dihydroquinazolinone derivatives obtained via a citric acid-catalyzed three-component condensation reaction.
Comp. R1 R2 R3 Mp., °C Yield, %
4a H H H 192−194 54
4b OMe H H 234−236 80
4c OMe OMe H 227−228 70
4d OMe H OMe 162−164 61
4e Br H H 183−185 30
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