Copper-Catalyzed Sequential N-Arylation and Aerobic Oxidation: Synthesis of Quinazoline Derivatives

Abstract

A novel and efficient copper-catalyzed cascade method for the synthesis of quinazoline derivatives has been developed. The protocol uses readily available substituted (2-bromophenyl)methylamines and amidine hydrochlorides as the starting materials, inexpensive CuBr as the catalyst, and economical and environment friendly air as the oxidant, and the corresponding quinazoline derivatives were obtained in moderate to good yields. The procedure underwent sequential intermolecular N-arylation, intramolecular nucleophilic substitution and aerobic oxidation.

Key words

copper - N-arylation - aerobic oxidative - cascade reaction - quinazolines

• References and Notes

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• 11 General Procedure for the Synthesis of Compounds 3a–v: A 25-mL Schlenk tube was charged with a magnetic stirrer and DMSO (2.0 mL). Substituted (2-bromophenyl)methylamine 1 (0.5 mmol), amidine hydrochloride 2 (1.0 mmol), CuBr (0.1 mmol, 14.2 mg), and K₂CO₃ (1.5 mmol, 207 mg) were added to the tube. The mixture was stirred at 80–120 °C under nitrogen atmosphere for 24 h, and then under air for 0.5 h. The resulting mixture was cooled to r.t. and filtered, and the solid was washed with EtOAc three times (3 × 3 mL). The combined filtrate was concentrated by the rotary evaporator, and the residue was purified by column chromatography on silica gel using petroleum ether–EtOAc as eluent to give the desired target product. Three representative examples are shown as follows: Quinazolin-2-amine (3j); (Ref. 12): Eluent: petroleum ether–EtOAc (1:3). Yield: 49.3 mg (68%); yellow solid. ¹H NMR (300 MHz, DMSO-d ₆): δ = 9.10 (s, 1 H), 7.77 (d, J = 8.1 Hz, 1 H), 7.66 (t, J = 7.2 Hz, 1 H), 7.43 (d, J = 8.1 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 1 H), 6.91 (s, 2 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 162.8, 161.4, 152.3, 134.5, 128.3, 125.0, 122.4, 120.0. ESI–MS: m/z = 146.3 [M + H]⁺. 2-(4-Chlorophenyl)-6-methoxyquinazoline (3q); (Ref. 13): Eluent: petroleum ether–EtOAc (10:1 → 5:1). Yield: 90.5 mg (67%); white solid. ¹H NMR (300 MHz, CDCl₃): δ = 9.31 (s, 1 H), 8.50 (d, J = 9.0 Hz, 2 H), 7.95 (d, J = 9.3 Hz, 1 H), 7.54 (dd, J = 9.3, 2.7 Hz, 1 H), 7.47 (d, J = 6.9 Hz, 2 H), 7.11 (d, J = 2.7 Hz, 1 H), 3.95 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 158.9, 158.5, 147.0, 136.8, 136.4, 130.2, 129.6, 128.9, 127.4, 124.6, 104.0, 55.8. ESI–MS: m/z = 271.2 [M + H]⁺. 7-Fluoro-2-phenylquinazoline (3u); (Ref. 14): Eluent: petroleum ether–EtOAc (10:1). Yield: 56.0 mg (50%); white solid. ¹H NMR (300 MHz, CDCl₃): δ = 9.40 (s, 1 H), 8.59–8.62 (m, 2 H), 7.88–7.91 (m, 1 H), 7.70–7.77 (m, 1 H), 7.51–7.55 (m, 3 H), 7.36–7.40 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.0 (J = 255.8 Hz), 161.9, 160.0, 152.5 (d, ³ J = 13.6 Hz), 137.8, 131.1, 129.8 (d, J = 10.8 Hz), 128.8, 121.0, 118.0 (d, J = 25.1 Hz), 112.6 (d, J = 20.8 Hz). ESI–MS: m/z = 225.2 [M + H]⁺.
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