A Green, One-Pot Synthesis of Substituted 2,3-Dihydroquinazoline-4(1H)-ones in the Presence of N-Sulfonic Acid Pyridinium Chloride

Abstract

We present a one-pot method for the synthesis of 2,3-dihydroquinazoline-4(1H)-ones. The three-component reaction between isatoic anhydride, primary amines, and dialkyl acetylenedicarboxylates in the presence of N-sulfonic acid pyridinium chloride under solvent-free conditions affords the corresponding alkyl 2-[(alkoxycarbonyl)methyl]-1,2,3,4-tetrahydro-3-alkyl-4-oxo-quinazoline-2-carboxylates in excellent yields.

Key words

three-component reaction - N-sulfonic acid pyridinium chloride - 2,3-dihydro-4(1H)-quinazolinones - solvent-free - green synthesis

• References and Notes

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• 23 Typical Procedure for the Preparation of Compound 5a A mixture of isatoic anhydride (0.163 g, 1 mmol) and aniline (0.093 g, 1 mmol) was stirred under solvent-free conditions at 70 °C for 40 min. After nearly complete conversion into anthranilamide, as indicated by TLC monitoring, dimethyl acetylenedicarboxylate (0.142 g, 1 mmol) was added over 3 min and stirring was continued under same reaction conditions for 20 min. Next, the reaction mixture was cooled to room temperature, H₂O (2 mL) was added, and the mixture was allowed to stir for 30 min. The pale yellow precipitate was filtered and and recrystallized from of H₂O–EtOH (1:1) to give 5a as pale yellow crystals. Dimethyl 2-[2-(Phenylcarbamoyl)phenylamino]but-2-enedioate (5a) Pale yellow powder, mp 149 °C, yield 0.337 g (95%). IR (KBr): 3312 and 3260 (NH), 1746, 1641 and 1615 (C=O), 1503, 1488, 1434, 1382, 1327, 1248, 1201, 1164, 1129, 1064, 1028, 994, 866, 765, 702, 665, 564 cm^–1. ¹H NMR (500.13 MHz, acetone-d ₆): δ = 3.71 and 3.72 (2 s, 6 H, 2 OCH₃), 5.45 (s, 1 H, C=CH), 6.80 (d, J = 8.1 Hz, 1 H, CH), 7.12 (t, J = 7.9 Hz, 1 H, CH), 7.13 (t, J = 8.1 Hz, 1 H, CH), 7.37 (t, J = 7.9 Hz, 2 H, CH), 7.43 (dt, J = 8.1, 1.1 Hz, 1 H, CH), 7.76 (d, J = 8.1 Hz, 1 H, CH), 7.86 (d, J = 7.9 Hz, 2 H, CH), 9.69 (br s, 1 H, NH), 11.05 (br s, 1 H, NH). ¹³C NMR (125.8 MHz, acetone-d ₆): δ = 51.41 and 53.16 (2 OCH₃), 97.75 (C=CH), 120.93, 120.97, 123.26 and 124.79 (4 CH), 126.26 (C=CH), 129.20, 129.51 and 132.18 (3 CH), 139.97, 141.36 and 146.73 (3 C), 165.66 (NC=O), 167.26 and 168.72 (2 OC=O).
• 24 Typical Procedure for the Preparation of Compounds 4a–l, Exemplified with 4a A mixture of isatoic anhydride (0.163 g, 1 mmol) and aniline (0.093 g, 1 mmol) was stirred under solvent-free conditions at 70 °C for 40 min. After nearly complete conversion into anthranilamide, as indicated by TLC monitoring, dimethyl acetylenedicarboxylate (0.142 g, 1 mmol) and N-sulfonic acid pyridinium chloride (0.04 g, 20 mol%) were added over 3 min and stirring was continued for 50 min. Next, the reaction mixture was cooled to room temperature and was allowed to stir for 30 min in H₂O. The white precipitate was filtered, washed with H₂O (3 × 2 mL), dried, and then recrystallized from of H₂O–EtOH (1:1) to give 4a as white crystals. Methyl 2-[(Methoxycarbonyl)methyl]-1,2,3,4-tetrahydro-4-oxo-3-phenylquinazoline-2-carboxylate (4a) White crystals, mp 156 °C, yield 0.332 g (94%). IR (KBr): 3368 (NH), 1729, 1668 and 1655 (C=O), 1594, 1531, 1508, 1438, 1370, 1324, 1283, 1207, 1154, 1031, 971, 887, 799, 755, 689, 627, 512, 472 cm^–1. ¹H NMR (500.13 MHz, CDCl₃): δ = 2.91 and 2.95 (2 d, ΑΒ system, ² J = 16.0 Hz, 2 H, CH _A H _BCO₂CH₃), 3.63 and 3.68 (2 s, 6 H, 2 OCH₃), 6.22 (s, 1 H, NH), 6.75 (d, J = 8.1 Hz, 1 H, CH), 6.90 (t, J = 8.1 Hz, 1 H, CH), 7.26 (d, J = 7.1 Hz, 2 H, 2 CH), 7.36 (t, J = 7.1 Hz, 1 H, CH), 7.41 (t, J = 8.1 Hz, 1 H, CH), 7.44 (t, J = 7.1 Hz, 2 H, 2 CH), 7.93 (d, J = 8.1 Hz, 1 H, CH). ¹³C (125.8 MHz, CDCl₃): δ = 41.50 (CH₂), 52.24 and 53.22 (2 OCH₃), 76.11 (NCN), 114.61 (CH), 115.69 (C), 119.90, 128.75, 128.90, 129.47, 130.21 and 134.07 (6 CH), 137.34 and 144.72 (2 C), 163.34 (NC=O), 170.34 and 170.61 (2 OC=O). Analytical Data for Novel Products Ethyl 2-[(Ethoxycarbonyl)methyl]-3-(4-chlorophenyl)1,2,3,4-tetrahydro-4-oxoquinazoline-2-carboxylate (4j) White crystals, mp 143 °C, yield 0.371 g (89%). IR (KBr): 3312 (NH), 1744, 1640 and 1622 (C=O), 1511, 1487, 1450, 1412, 1370, 1360, 1331, 1232, 1183, 1112, 1025, 974, 738, 688, 630, 512 cm^–1. ¹H NMR (300.13 MHz, CDCl₃): δ = 1.09 and 1.21 (2 t, J = 7.1 Hz, 6 H, 2 OCH₂CH ₃), 2.82 and 2.90 (2 d, ² J = 15.8 Hz, 2 H, CH ₂CO₂C₂H₅), 4.04–4.15 (m, 4 H, OCH ₂CH₃), 6.24 (s, 1 H, NH), 6.75 (d, J = 8.0 Hz, 1 H, CH), 6.89 (dt, J = 8.0, 1.0 Hz, 1 H, CH), 7.24 (d, J = 8.0 Hz, 2 H, 2 CH), 7.35 (dt, J = 8.0, 1.0 Hz, 1 H, CH), 7.39 (d, J = 8.0 Hz, 2 H, 2 CH), 7.89 (d, J = 8.0 Hz, 1 H, CH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.81 and 13.92 (2 OCH₂ CH₃), 41.46 (CH₂CO₂C₂H₅), 61.54 and 62.61 (2 OCH₂CH₃), 75.92 (NCN), 114.68 (CH), 115.67 (C), 119.95, 128.76, 129.59, 131.75 and 134.13 (5 CH), 134.63, 135.84 and 144.93 (3C), 163.51 (NC=O), 169.56 and 170.04 (OC=O). Ethyl 2-[(Ethoxycarbonyl)methyl]-3-benzyl-1,2,3,4-tetrahydro-4-oxoquinazoline-2-carboxylate (4k) White crystals, mp 136–138 °C, yield 0.361 g (91%). IR (KBr): 3306 (NH), 1736, 1640 and 1617 (C=O), 1523, 1491, 1444, 1392, 1371, 1365, 1328, 1237, 1201, 1120, 1030, 981, 743, 699, 631, 515 cm^–1. ¹H NMR (500.13 MHz, CDCl₃): δ = 1.05 and 1.25 (2 t, J = 7.1 Hz, 6 H, 2 OCH₂CH ₃), 2.88 and 3.26 (2 d, ² J = 16.2 Hz, 2 H, CH ₂CO₂C₂H₅), 3.96 and 4.01 (2 dq, ABX₃ system, ² J = 11.6 Hz, ³ J = 7.1 Hz, 2 H, OCH _A H _BCH₃), 4.09–4.18 (m, 2 H, OCH ₂CH₃), 4.64 and 5.13 (2 d, ² J = 16.5 Hz, 2 H, NCH₂), 6.08 (s, 1 H, NH), 6.70 (d, J = 8.0 Hz, 1 H, CH), 6.89 (t, J = 8.0 Hz, 1 H, CH), 7.22 (t, J = 7.0 Hz, 1 H, CH), 7.27 (d, J = 7.0 Hz, 2 H, 2 CH), 7.31 (t, J = 7.1 Hz, 2 H, 2 CH), 7.35 (dt, J = 8.0, 1.5 Hz, 1 H, CH), 7.94 (d, J = 8.0 Hz, 2 H, CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 13.74 and 14.02 (2 OCH₂ CH₃), 40.52 (CH₂CO₂C₂H₅), 45.58 (NCH₂), 61.50 and 62.54 (2 OCH₂CH₃), 75.54 (NCN), 114.44 (CH), 114.79 (C), 119.58, 126.86, 127.09, 128.58, 128.72 and 133.99 (6 CH), 138.11 and 144.76 (2 C), 163.60 (NC=O), 169.55 and 170.47 (OC=O). Ethyl 2-[(Ethoxycarbonyl)methyl]-3-(4-methylbenzyl)-1,2,3,4-tetrahydro-4-oxoquinazoline-2-carboxylate (4l) White crystals, mp 137 °C, yield 0.370 g (90%). IR (KBr): 3308 (NH), 1740, 1641 and 1619 (C=O), 1521, 1495, 1452, 1399, 1374, 1359, 1332, 1239, 1192, 1118, 1033, 983, 747, 698, 632, 514 cm^–1. ¹H NMR (300.13 MHz, CDCl₃): δ = 1.06 and 1.25 (2 t, J = 7.1 Hz, 6 H, 2 OCH₂CH ₃), 2.32 (s, 3 H, CH₃), 2.88 and 3.27 (2 d, ² J = 16.2 Hz, 2 H, CH ₂CO₂C₂H₅), 3.94 and 4.01 (2 dq, ABX₃ system, ² J = 11.5 Hz, ³ J = 7.1 Hz, 2 H, OCH _A H _BCH₃), 4.08–4.20 (m, 2 H, OCH ₂CH₃), 4.57 and 5.11 (2 d, ² J = 16.4 Hz, 2 H, NCH₂), 6.08 (s, 1 H, NH), 6.69 (d, J = 8.0 Hz, 1 H, CH), 6.88 (dt, J = 8.0, 1.0 Hz, 1 H, CH), 7.10 (d, J = 8.0 Hz, 2 H, 2 CH), 7.16 (d, J = 8.0 Hz, 2 H, 2 CH), 7.33 (dt, J = 8.0, 1.5 Hz, 1 H, CH), 7.94 (dd, J = 8.0, 1.4 Hz, 2 H, CH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.70 and 13.99 (2 OCH₂ CH₃), 40.50 (CH₂CO₂C₂H₅), 45.34 (NCH₂), 61.45 and 62.49 (2 OCH₂CH₃), 75.56 (NCN), 114.33 (CH), 114.79 (C), 119.50, 126.80, 128.67 and 129.19 (4 CH), 133.90 (C), 135.01 (CH), 136.63 and 144.69 (2 C), 163.54 (NC=O), 169.56 and 170.51 (OC=O).