Convenient Synthesis of Furo[3,2-b]quinolin-4(1H)-ones

Abstract

In this work, we report the simple synthesis of furo[3,2-b]quinolin-4(1H)-ones from readily available 4-ethynyl-[1,3]dioxolo[4,5-c]quinolone as the key starting material. After Sonogashira (hetero)arylation, formation of the furoquinoline scaffold was accomplished using methanesulfonic acid and metal-free conditions. Although the cyclization was affected by the substitution of reaction intermediates, the method allowed the preparation of derivatives varying at the C3-position.

Keywords

furoquinolines - quinolines - cyclization - Sonogashira coupling

• References and Notes

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• 27 To a solution of alkyne 1 (200 mg, 0.54 mmol) in DMAC/H₂O (9.5/0.5; 950 μL/50 μL), 10% Pd/C (0.05 equiv, 0.027 mmol, 29 mg), PPh₃ (0.1 equiv, 0.054 mmol, 14 mg), CuI (0.1 equiv, 0.054 mmol, 10 mg), and DIPEA (3 equiv, 210 μL) were added. The reaction mixture was flushed with nitrogen, followed by addition of aryl or heteroaryl iodide (1 equiv). The reaction was heated to 70–75 °C and was monitored by TLC (hexane/EtOAc, 4:1). Upon completion (2–4 h), the reaction mixture was diluted with DCM and filtered through glass filter. Dark brown solution was evaporated, and the product was purified by column chromatography (hexane/EtOAc, 4:1 → EtOAc).Representative Product: 4-(Phenylethynyl)-[1,3]dioxolo[4,5-c]quinoline (2)Yield: 46%; mp 120–121 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.96 (d, J = 8.7 Hz, 1 H), 7.83 (d, J = 8.2 Hz, 1 H), 7.67 (td, J = 7.7, 1.7 Hz, 3 H), 7.56–7.60 (m, 1 H), 7.49–7.53 (m, 3 H), 6.48 (s, 2 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 149.1, 145.3, 142.1, 131.8, 129.9, 129.0, 128.9, 128.7, 127.3, 126.1, 120.9, 119.8, 115.1, 104.0, 93.4, 84.1. HRMS: m/z calcd for C₁₈H₁₁NO₂ [M + H]: 274.0863; found: 274.0863.
• 28 To a solution of alkyne 1 (1 equiv, 200 mg, 0.54 mmol) in acetonitrile (HPLC quality, 2 mL), PdCl₂(PPh₃)₂ (0.02 equiv, 0.01 mmol, 7.6 mg), CuI (0.01 equiv, 0.005 mmol, 1 mg), and Et₃N (3 equiv, 225 μL) were added. The reaction mixture was flushed with nitrogen, followed by addition of aryl or heteroaryl bromide/iodide (1 equiv). The reaction was heated to 50–55 °C and was monitored by TLC (hexane/EtOAc, 4:1). Upon completion (2–4 h), the reaction mixture was diluted with DCM and filtered through the glass filter. The dark brown solution was evaporated, and the product was purified by column chromatography (hexane/EtOAc, 4:1 → EtOAc).
• 29 To a solution of quinoline 1 (50 mg, 1 equiv) in dioxane (0.5 mL), methanesulfonic acid (5 equiv) and water in volume ratio 1:2 were added. The reaction mixture was heated to 85–90 °C in the pressurized tube until the disappearance of starting material (monitored by LC–MS). After that, the reaction mixture was quenched by water (4 mL), and pH was adjusted on 6–7 by 10% NaOH. The precipitated solid was filtered off, washed with water, and dried. The crude product was purified by stirring in chloroform.Furo[3,2-b]quinolin-9(4H)-one (21)Yield 60%, mp 180–183 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.12 (s, 1 H), 8.24 (d, J = 8.2 Hz, 1 H), 8.14 (s, 1 H), 7.55–7.65 (m, 2 H), 7.26 (t, J = 7.3 Hz, 1 H), 6.86 (s, 1 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 164.0, 149.9, 139.6, 137.9, 137.5, 131.3, 125.4, 124.5, 121.4, 117.9, 102.3. HRMS: m/z calcd for C₁₁H₇NO₂ [M + H]: 186.0550; found: 186.0551.
• 30 Alabugin VI, Gonzalez-Rodriguez E, Kawade KR, Stepanov AA, Vasilevsky FS. Molecules 2019; 24: 1036