Multi-component reactions (MCRs) are a promising and important field of chemistry because the synthesis of complex molecules can be achieved in a fast, efficient, and time-saving manner without the isolation of any intermediates. Organic chemists have therefore become interested in developing novel MCRs or improving known MCRs ^{[1, 2, 3]}. One such reaction is the synthesis of 2,3-dihydroquinazolin-4(1H)-ones.

2,3-Dihydroquinazolin-4(1H)-ones are an important class of fused heterocycles with a wide range of pharmacological and biological activities, which include antifertility, antibacterial, antitumor, and antifungal applications ^{[4, 5]}. Therefore, considerable efforts have been made to explore new simple and direct approaches towards the construction of 2,3-dihydroquinazolin- 4(1H)-one skeletons. Several methods for the synthesis of these compounds have been reported in the literature. One method involves the condensation of aldehydes with anthranilamide using various promoting agents ^{[6, 7, 8, 9]}, but this is only suitable for the synthesis of 2-substituted-2,3-dihydroquinazolin- 4(1H)-ones. Other methods include reduction of quinazolin- 4(3H)-ones using sodium borohydride or sodium cyanoborohydride in acetic acid ^[10], condensation of anthranilamide with benzyl followed by base-catalyzed hydrolysis ^[11], and a two-step synthesis starting from the reaction of isatoic anhydride and amines, then ring-closing with ketones ^[12]. The most straightforward procedure for the preparation of 2-substituted- and 2,3-disubstituted-2,3-dihydroquinazolin- 4(1H)-ones involves the one-pot three-component reaction of isatoic anhydride, aromatic aldehydes, and a nitrogen source such as ammonium acetate or primary amines in the presence of various catalysts. These catalysts include [bmim]HSO₄ ^[13], silica sulfuric acid ^[14], p-toluenesulfonic acid- paraformaldehyde copolymer (copolymer-PTSA) ^[15], trifluoroethanol ^[16], thiamine hydrochloride ^[17], Cu-CNTs nanocomposite under microwave irradiation ^[18], aluminum methanesulfonate ^[19], montmorillonite K-10 ^[20], silica-bonded S-sulfonic acid ^[21], acetic acid ^[22], KAl(SO₄)₂·12H₂O ^[23], silica-bonded N- propylsulfamic acid ^[24], and magnetic Fe₃O₄ nanoparticles ^[25]. However, some of these methods have disadvantages such as long reaction time, expensive catalysts, and using microwave irradiation for accelerated synthesis. Therefore, the discovery of a new and efficient catalyst with high activity, short reaction time, and simple work-up for the synthesis of 2,3- dihydroquinazolin-4(1H)-ones is of prime interest.

Recently cerium (IV) salts have been used for many organic transformations such as the synthesis of carboxylic esters from alkenes ^[26], synthesis of acetamido phenols ^[27], conversion of oximes into aldehydes and ketones ^[28], and one-pot synthesis of 3-acylisoxazoles or polyhydroquinolines ^{[29, 30]}. The cerium (IV) salts act as Lewis acids in all of these reactions. To the best of our knowledge there are no examples of the use of Ce(SO₄)₂·4H₂O as catalyst for the synthesis of 2,3- dihydroquinazolin-4(1H)-ones.

As part of our research program directed towards the development of expedient methods using reusable catalysts for the synthesis of organic compounds ^{[31, 32, 33, 34, 35, 36, 37, 38]}, we have recently successfully applied Ce(SO₄)₂·4H₂O to the synthesis of tetrahydrobenzo[a]xanthene-11-ones ^[39] and in the protection of aldehydes as 1,1-diacetates ^[40] under solvent-free conditions. This reusable heterogeneous solid acidic catalyst performs well and shows high catalytic activity. These results encouraged us to investigate the use of Ce(SO₄)₂·4H₂O in the synthesis of 2,3- dihydroquinazolin-4(1H)-ones in a one-pot three- component reaction of isatoic anhydride 1, aromatic aldehydes 2, and a nitrogen source 3 (ammonium acetate, ammonium carbonate, ammonium chloride, or methylamine) under solvent-free conditions.

Table 1 Optimization of reaction conditions for the synthesis of compound 4a catalyzed by Ce(SO4)2·4H2O. Entry Catalyst (mol%) Solvent T (°C) Time (min) Isolated yield (%) 1 — — 120 120 — 2 1 — 100 120 59 3 1 — 120 90 72 4 3 — 90 90 58 5 3 — 100 60 71 6 3 — 110 60 83 7 3 — 120 45 95 8 3 — 140 50 94 9 5 — 100 60 72 10 5 — 110 60 82 11 5 — 120 45 93 12 7 — 120 50 92 13 3 EtOH Reflux 120 58 14 3 H2O Reflux 120 41 15 3 CH2Cl2 Reflux 120 30 16 3 CH3CN Reflux 120 45 Reaction conditions: isatoic anhydride 1 mmol, benzaldehyde 1 mmol, ammonium acetate 1.2 mmol.

Table 1 Optimization of reaction conditions for the synthesis of compound 4a catalyzed by Ce(SO4)2·4H2O.

A general procedure for the synthesis of 2,3- dihydroquinazolin-4(1H)-ones 4a−4k is as follows. A mixture of isatoic anhydride 1 (1 mmol), an aromatic aldehyde 2 (1 mmol), a nitrogen source (ammonium acetate 1.2 mmol, ammonium carbonate 0.6 mmol, ammonium chloride 1.2 mmol, or methylamine 1.2 mmol), and Ce(SO₄)₂·4H₂O (0.03 mmol, 3 mol% based on isatoic anhydride) was heated in an oil bath at 120 °C for 30-50 min and monitored by TLC. Upon completion of the transformation, the reaction mixture was cooled to room temperature, and hot ethanol was added. The precipitated catalyst was collected by filtration, and the filtrate was cooled to room temperature. The crude product was collected and recrystallized from ethanol to give compounds 4a−4k (Scheme 1).

Scheme 1. Ce(SO4)2·4H2O catalyzed synthesis of 2,3-dihydroquinazolin- 4(1H)-ones.

The melting points were recorded using a Stuart SMP3 melting point apparatus. The IR spectra of the products were obtained with KBr disks using a Tensor 27 Bruker spectrophotometer. The ¹H NMR spectra were recorded using Bruker 400 MHz and 500 MHz spectrometers.

We first examined the reaction by using isatoic anhydride (1 mmol), benzaldehyde (1 mmol), and ammonium acetate (1.2 mmol) as model substrates for the synthesis of compound 4a. We decided to investigate the efficiency of Ce(SO₄)₂·4H₂O in the synthesis of 2,3-dihydroquinazolin-4(1H)-ones under solvent- free conditions, which offers several advantages such as being environmentally friendly, simpler work-ups, cleaner products, enhanced selectivity, reduction of by-products, and faster reactions. To find the optimum reaction conditions, different parameters were studied for the formation of compound 4a. The results are summarized in Table 1. First, the model reaction was carried out without any catalyst at high temperature under solvent-free conditions. No product was observed even after prolonged reaction time (entry 1). Varying the percentage of the catalyst showed that 3 mol% of Ce(SO₄)₂·4H₂O is sufficient to push the reaction to completion within 45 min (entry 7). The effect of reaction temperature on the output was also investigated, and the optimum temperature was found to be 120 °C (entry 7). Next, the reaction was performed in the presence of 3 mol% of Ce(SO₄)₂·4H₂O in different solvents including EtOH, H₂O, CH₂Cl₂, and CH₃CN. As shown, low to moderate yields were obtained in the tested solvents. Therefore, our optimized conditions are 3 mol% of Ce(SO₄)₂·4H₂O at 120 °C under solvent-free conditions. All subsequent reactions were carried out using these conditions.

To determine the scope of the novel protocol, a range of 2,3-dihydroquinazolin-4(1H)-ones were prepared by the reaction of isatoic anhydride, aromatic aldehydes, and ammonium acetate or methylamine in the presence of Ce(SO₄)₂·4H₂O under the optimized reaction conditions. The results are summarized in Table 2. As shown, all reactions proceed very cleanly to give the corresponding 2,3-dihydroquinazolin-4(1H)-one products 4a−4k in high yields over short reaction times, and no undesirable side-products were observed.

Table 2 Synthesis of 2,3-dihydroquinazolin-4(1H)-ones 4a−4k using Ce(SO4)2·4H2O catalyst. Product * R Ar X Time (min) Isolated yield (%) Melting point (°C) Found Reported 4a H C6H5 OAc 45 95 218-219 219-221 [15] Cl 50 95 CO3 35 97 4b H 4-ClC6H4 OAc 50 90 205-206 198-200 [15] Cl 50 92 CO3 30 93 4c H 2-ClC6H4 OAc 50 88 215-217 203-205 [19] Cl 50 85 CO3 40 91 4d H 4-BrC6H4 OAc 35 90 200-202 201-203 [21] Cl 35 90 CO3 30 93 4e H 4-MeC6H4 OAc 45 86 233-234 234-236 [15] Cl 50 85 CO3 30 92 4f H 4-MeOC6H4 OAc 45 87 190-192 182-184 [19] Cl 50 89 CO3 30 91 4g H 2-thienyl OAc 35 90 218-220 216-219 [21] Cl 40 86 CO3 30 90 4h CH3 C6H5 — 45 85 169-171 164-166 [15] 4i CH3 4-ClC6H4 — 45 85 205-207 201-203 [16] 4j CH3 4-MeOC6H4 — 40 90 146-148 145-147 [15] 4k CH3 4-NO2C6H4 — 40 86 198-200 200-202 [19] Reaction conditions: isatoic anhydride 1 (1 mmol), aromatic aldehyde 2 (1 mmol), a nitrogen source 3 (ammonium acetate 1.2 mmol, ammonium carbonate 0.6 mmol, ammonium chloride 1.2 mmol, or methyl amine 1.2 mmol), Ce(SO4)2·4H2O (0.03 mmol, 3 mol% based on isatoic anhydride), 120 °C, solvent-free. * All the products were characterized by their IR spectral data and a comparison of their melting points with those of authentic samples. The structures of some products were also confirmed by 1H NMR analysis.

Table 2 Synthesis of 2,3-dihydroquinazolin-4(1H)-ones 4a−4k using Ce(SO4)2·4H2O catalyst.

Table 3 Comparison of the efficiencies of different catalysts for the one-pot three-component synthesis of 2,3-dihydroquinazolin-4(1H)-ones. Catalyst Conditions Time (min) Yield (%) Ref. Solvent T/°C Other [bmim]HSO4 H2O reflux — 150-240 70-91 [13] Silica sulfuric acid H2O 80 — 180-330 75-89 [14] Silica sulfuric acid — 80 — 240-360 70-83 [14] Copolymer-PTSA EtOH reflux — 200-420 70-94 [15] Trifluoroethanol CF3CH2OH reflux — 180 80-97 [16] Thiamine hydrochloride EtOH reflux — 120-360 75-94 [17] Cu-CNTs nanocomposite — — MW 5-23 87-99 [18] Aluminum methanesulfonate EtOH/H2O reflux — 30-420 33-96 [19] Montmorillonite K-10 EtOH reflux — 180-420 70-95 [20] Silica-bonded S-sulfonic acid EtOH reflux — 35-240 75-90 [21] Acetic acid AcOH reflux — 60-150 79-92 [22] KAl(SO4)2·12H2O EtOH reflux — 180-360 69-92 [23] Silica-bonded N-propylsulfamic acid EtOH reflux — 150-180 81-88 [24] Magnetic Fe3O4 nanoparticles H2O reflux — 90-360 51-88 [25] Ce(SO4)2·4H2O — 120 — 30-50 85-97 this work MW: microwave.

Table 3 Comparison of the efficiencies of different catalysts for the one-pot three-component synthesis of 2,3-dihydroquinazolin-4(1H)-ones.

To compare the efficiency of ammonium salts in the synthesis of 2,3-dihydroquinazolin- 4(1H)-ones, the reactions were also carried out using ammonium carbonate and ammonium chloride under the same reaction conditions. In all cases, the corresponding 2,3- dihydroquinazolin-4(1H)-one was produced in high yield over short reaction time (Table 2).

To show the merit of this methodology, the results were compared with those using other catalysts reported for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones. As shown in Table 3, our reaction conditions gave a shorter reaction time than all the other conditions (except catalysis by Cu-CNTs nanocomposite with microwave irradiation) and gave high yields of the desired products.

The recyclability of the catalyst was also investigated using the same model reaction. The catalyst was readily recovered from the reaction mixture using the procedure outlined in the experimental section. The separated catalyst was washed with hot ethanol and subsequently dried at 60 °C under vacuum for 2 h before being reused in a similar reaction. The recovered yields of the catalyst were 99%, 98%, 98%, 99%, and 98% in runs 1 to 5, respectively. The recycled catalyst in each run (1 to 4) was just used for the next run. The results show that the catalyst can be used at least five times without substantial reduction in its catalytic activity (Fig. 1). Furthermore, retention of the structure of the catalyst was confirmed by comparing the FT-IR spectra of the recovered catalyst after the fifth run with that of the fresh catalyst for the model reaction (Fig. 2). As shown, these spectra are almost identical.

We have demonstrated the efficiency of Ce(SO₄)₂·4H₂O as a novel inorganic solid acidic catalyst for the preparation of 2,3-dihydroquinazolin-4(1H)-ones via the one-pot three- component reaction of isatoic anhydride, aromatic aldehydes, and a nitrogen source (ammonium acetate, ammonium carbonate, ammonium chloride, or methylamine) under solvent-free conditions. A variety of aromatic aldehydes participated well in the reaction affording the expected products in high yields with short reaction times and simple work-up. Furthermore, the catalyst could be easily recycled and reused at least five times without significant reduction in its catalytic activity. The procedure is also advantageous because it is a solvent-free reaction and therefore operates under environmentally friendly conditions.