An Efficient Synthesis of 2-Substituted Quinazolin-4(3H)-ones Catalyzed by Iron(III) Chloride

Abstract

A simple and highly efficient synthesis of 2-substituted quinazolin-4(3H)-ones by the iron(III) chloride catalyzed reaction of isatoic anhydride with various amidoxime derivatives was developed. Several aryl and alkyl amidoximes were screened to demonstrate the scope of the methodology.

Key words

heterocycles - polycycles - ketones - catalysis - iron - quinazolinones

• References and Notes

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• 12 2-Substituted Quinazolin-4(3H)-ones 8a–m; General Procedure The appropriate amidoxime 7 (1.1 mmol) and FeCl₃ (10 mol%) were added sequentially to a solution of isatoic anhydride (6; 1 mmol.) in 1,4-dioxane (10 mL), and the mixture was stirred at 80 °C for 2–9 h until the reaction was complete (TLC). The mixture was then diluted with EtOAc (10 mL) and washed with H₂O (2 × 5 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give a crude product that was purified by column chromatography (silica gel, 30% EtOAc–hexanes). All new compounds gave satisfactory analytical and spectroscopic results. 2-(4-Aminophenyl)quinazolin-4(3H)-one (8e) Yellow solid; yield: 284 mg (78%); mp 250–254 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 5.83 (s, 2 H, NH₂), 6.62 (d, J = 8.8 Hz, 2 H, ArH), 7.40 (t, J = 6.9 Hz, 1 H, ArH), 7.61 (d, J = 8.3 Hz, 1 H, ArH), 7.76 (t, J = 6.8 Hz, 1 H, ArH), 7.95 (d, J = 8.8 Hz, 2 H, ArH), 8.08 (dd, J = 6.9, 1 Hz, 1 H, ArH), 12.06 (br s, 1 H, NH); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 113.0, 121.5, 125.3, 125.8, 126.9, 128.7, 129.1, 134.4, 149.6, 152.2, 152.4, 162.4; MS: m/z = 238.1 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₄H₁₂ N₃O: 238.0980; found: 238.0969. 2-[4-(Methylsulfanyl)phenyl]quinazolin-4(3H)-one (8g) White solid; yield: 383 mg (93%); mp 237–239 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.55 (s, 3 H, SCH₃), 7.40 (d, J = 8.4 Hz, 2 H, ArH), 7.50 (t, J = 7.2 Hz, 1 H, ArH), 7.72 (d, J = 7.6 Hz, 1 H, ArH), 7.83 (t, J = 7.6 Hz, 1 H, ArH), 8.13–8.16 (m, 3 H, ArH), 12.48 (br s, 1 H, NH); ¹³C NMR (400 MHz, DMSO-d ₆): δ = 14.1, 120.8, 125.1, 125.8, 126.4, 127.4, 128.0, 128.6, 134.6, 143.0, 148.7, 151.78, 162.2; MS: m/z = 269.0 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₅H₁₃N₂OS: 269.07486; found: 269.07446. 2-(5-Fluoropyridin-2-yl)quinazolin-4(3H)-one (8j) Brown solid; yield: 296 mg (80%); mp 180–183 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.56 (m, 1 H, ArH), 7.61–7.65 (m, 1 H, ArH), 7.77–7.80 (m, 2 H, ArH), 8.35 (d, J = 7.4 Hz, 1 H, ArH), 8.51 (d, J = 2.9 Hz, 1 H, ArH), 8.63 (dd, J = 8.8, 4.8 Hz, 1 H, ArH), 10.76 (br s, 1 H, NH); ¹³C NMR (100 MHz, CDCl₃): δ = 122.2, 123.7 (d, J = 5.4 Hz), 124.4 (d, J = 18.4 Hz), 126.7, 127.4, 127.9, 134.6, 137.2 (d, J = 25.2 Hz), 144.7, 147.9, 148.9, 161.1 (d, J = 260.0 Hz), 161.3; MS: m/z = 242.1 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₃H₉N₃OF: 242.0730; found: 242.0722. 2-(Cyclopropylmethyl)quinazolin-4(3H)-one (8k) White solid; yield: 279 mg (91%); mp 210–213 °C; ¹H NMR (400 MHz,, CDCl₃): δ = 0.38–0.42 (m, 2 H, CH₂), 0.70–0.73 (m, 2 H, CH₂), 1.14–1.21 (m, 1 H, CH), 2.70 (d, J = 7.6 Hz, 2 H, CH₂), 7.26–7.49 (m, 1 H, ArH), 7.68 (d, J = 7.6 Hz, 1 H, ArH), 7.74–7.79 (m, 1 H, ArH), 8.28 (dd, J = 6.8, 1.2 Hz, 1 H, ArH), 10.20 (br s, 1 H, NH); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 4.2, 9.2, 39.2, 120.8, 125.7, 126.0, 126.8, 134.3, 149.0, 157.2, 161.8; MS: m/z = 201.1 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₂H₁₃ N₂O: 201.1028; found: 201.1037. 2-(4-Nitrobenzyl)quinazolin-4(3H)-one (8m) Light-brown solid; yield: 383 mg (89%); mp >300 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 4.11 (s, 2 H, PhCH₂), 7.48 (t, J = 7.4 Hz, 1 H, ArH), 7.58 (d, J = 8.4 Hz, 1 H, ArH), 7.65 (d, J = 8.4 Hz, 2 H, ArH), 7.75–7.79 (m, 1 H, ArH), 8.08 (d, J = 6.9 Hz, 1 H, ArH), 8.20 (d, J = 8.8 Hz, 2 H, ArH), 12.49 (br s, 1 H, NH); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 40.7, 121.3, 123.6, 125.7, 126.4, 126.9, 128.3, 128.6, 130.4, 134.4, 144.4, 154.9, 161.7; MS: m/z = 282.0 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₅H₁₂ N₃O₃: 282.0879; found: 282.0877.