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Synlett 2011(6): 834-836  
DOI: 10.1055/s-0030-1259909
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solvent-Free Reaction between Anthranilic Acids and Isocyanides: A Novel Approach for the Synthesis of 2-Unsubstituted 4(3H)-Quinazolinones

Mehdi Adib*a, Morteza Karimzadeha, Mohammad Mahdavia, Ehsan Sheikhia, Peiman Mirzaeib
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
Fax: +98(21)66495291; e-Mail: madib@khayam.ut.ac.ir;
b Department of Chemistry, Shahid Beheshti University, Tehran, Iran
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Publication History

Received 5 October 2010
Publication Date:
15 March 2011 (online)

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Abstract

A novel synthesis of 2-unsubstituted 4(3H)-quinazolinones is described. Heating a mixture of an anthranilic acid and an isocyanide under solvent-free conditions afforded the title compounds in good to excellent yields.

Key words

anthranilic acids - isocyanides - 2-unsubstituted 4(3H)-quinazolinones - solvent-free synthesis - cyclizations - heterocycles

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General Procedure for the Preparation of Compounds 3a-l
A mixture of the appropriate anthranilic acid (2 mmol) and isocyanide (2.2 mmol) was stirred at 150 ˚C for 2 h. Progress of the reaction was indicated by TLC monitoring. Next, the reaction mixture was cooled to r.t. and acetone (2 mL) was added, and stirring was continued for 10 min at ambient temperature. The precipitate was filtered and washed with cold acetone (2 mL), and the product was recrystallized from n-hexane-EtOAc (1:1). Compounds 3a-i were purified by this procedure, and compounds 3j-l were purified by column chromatography using n-hexane-EtOAc (3:1) as eluent.
3-Cyclohexyl-4(3 H )-quinazolinone (3a)
Yield 0.41g (90%); colorless crystals; mp 126-127 ˚C. IR (KBr): 1659 (C=O), 1596, 1564, 1468, 1399, 1334, 1240, 1172, 1132, 1024, 956, 894, 805, 766, 695 cm-¹. ¹H NMR (300.1 MHz, CDCl3): δ = 1.20-2.04 [m, 10 H, CH(CH 2)5], 4.77-4.86 [m, 1 H, CH(CH2)5], 7.49 (dd, J = 7.2, 7.4 Hz, 1 H, CH), 7.68 (d, J = 7.6 Hz, 1 H, CH), 7.74 (dd, J = 7.0, 7.9 Hz, 1 H, CH), 8.12 (s, 1 H, CH), 8.31 (d, J = 8.0 Hz, 1 H, CH). ¹³C NMR (75.5 MHz, CDCl3): δ = 25.27, 25.89 and 32.60 (3 × CH2), 53.54 (NCH), 121.93 (C), 126.95, 127.10, 127.24, 134.10 and 143.91 (5 × CH), 147.50 (C), 160.70 (C=O). MS (EI): m/z (%) = 228 (24) [M+], 192 (7), 181 (5), 171 (4), 160 (7), 147 (100), 129 (8), 118 (10), 102 (5), 90 (7), 77 (9), 67 (14), 55 (16), 41 (22). Anal. Calcd for C14H16N2O (228.29): C, 73.66; H, 7.06; N, 12.27. Found: C, 73.6; H, 7.2; N, 12.1.
6-Chloro-3-cyclohexyl-4(3 H )-quinazolinone (3j)
Yield 0.43 g (82%); colorless crystals; mp 137-138 ˚C.
IR (KBr): 1668 (C=O), 1597, 1552, 1465, 1388, 1358, 1320, 1240, 1137, 1072, 1022, 947, 895, 822, 775 cm-¹. ¹H NMR (300.1 MHz, CDCl3): δ = 1.25-1.97 [m, 10 H, CH(CH 2)5], 4.76-4.84 [m, 1 H, CH(CH2)5], 7.60 (d, J = 8.8 Hz, 1 H, CH), 7.63 (dd, J = 2.1, 8.8 Hz, 1 H, CH), 8.11 (d, J = 2.1 Hz, 1 H, CH), 8.26 (s, 1 H, CH). ¹³C NMR (75.5 MHz, CDCl3): δ = 25.22, 25.28, and 32.56 (3 × CH2), 53.59 (NCH), 122.97 (C), 126.30 and 128.95 (2 × CH), 132.88 (C), 134.52 and 144.08 (2 × CH), 146.02 (C), 159.68 (C=O). MS (EI): m/z (%) = 264 (8) [M+ ³7Cl], 262 (22) [M+ ³5Cl], 228 (5), 205 (3), 181 (100), 163 (4), 147 (18), 136 (7), 124 (5), 110 (5), 97 (4), 82 (9), 67 (20), 55 (18), 41 (23). Anal. Calcd for C14H15ClN2O (262.74): C, 64.00; H, 5.75; N, 10.66. Found: C, 63.9; H, 5.7; N, 10.6.
6-Chloro-3-(1,1,3,3-tetramethylbutyl)-4(3 H )-quinazolinone (3l)
Yield 0.44 g (76%); colorless crystals; mp 118-119 ˚C.
IR (KBr): 1662 (C=O), 1592, 1560, 1467, 1362, 1324, 1285, 1219, 1128, 1075, 918, 835, 805, 754, 712 cm-¹. ¹H NMR (500.1 MHz, CDCl3): δ = 0.81 [s, 9 H, C(CH3)3], 1.75 [s, 6 H, C(CH3)2], 2.22 (s, 2 H, CH2), 7.56 (d, J = 8.9 Hz, 1 H, CH), 7.60 (dd, J = 2.2, 8.9 Hz, 1 H, CH), 8.20 (d, J = 2.2 Hz, 1 H, CH), 8.26 (s, 1 H, CH). ¹³C NMR (125.8 MHz, CDCl3): δ = 30.00 [C(CH3)2], 31.24 [C(CH3)3], 31.93 [C(CH3)3], 48.88 (CH2), 64.76 [C(CH3)2], 124.13 (C), 126.23 and 128.55 (2 × CH), 132.66 (C), 134.34 and 144.84 (2 × CH), 145.85 (C), 161.41 (C=O). MS (EI): m/z (%) = 294 (1) [M+ ³7Cl], 292 (3) [M+ ³5Cl], 235 (8), 180 (100), 163 (9), 153 (8), 138 (7), 124 (6), 112 (26), 97 (68), 69 (10), 57 (54), 41 (31). Anal. Calcd for C16H21ClN2O (292.81): C, 65.63; H, 7.23; N, 9.57. Found: C, 65.7; H, 7.4; N, 9.4.