One-Pot Copper-Catalyzed Three-Component Synthesis of Quinoxalines by Condensation and C−N Bond Formation

Abstract

A novel way of synthesizing quinoxalines has been developed that involves condensation and C−N bond formation in a copper-catalyzed, one-pot, three-component reaction. The reaction was optimized when 2-iodoanilines (1.0 equiv), arylacetaldehydes (2.0 equiv), sodium azide (1.2 equiv), CuI (10 mol%), DMEDA (10 mol%), and K₂CO₃ (1.0 equiv) were reacted in DMSO at 80 °C for 20 hours. This approach was used to directly synthesize a variety of quinoxalines in moderate to good yields.

Key words

quinoxalines - arylacetaldehydes - sodium azide - three-component reaction

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• 11 Synthesis of 2-Phenylquinoxaline (4aa); Typical Procedure: 2-Iodoaniline (1a; 54.8 mg, 0.25 mmol), sodium azide (3; 19.5 mg, 0.3 mmol), CuI (4.8 mg, 0.025 mmol), K₂CO₃ (34.5 mg, 0.25 mmol), phenylacetaldehyde (2a; 58 μL, 0.5 mmol), DMEDA (3 μL, 0.025 mmol), and DMSO (1.0 mL) were added to a round-bottom flask equipped with stirrer, and the reaction mixture was heated to 80 °C for 20 h. After cooling to room temperature, the reaction mixture was added to water (2 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (2 × 5 mL), dried over anhydrous MgSO₄, and concentrated in vacuo. The residue was subjected to flash column chromatography (petroleum ether–EtOAc, 20:1) to afford the final product 4aa (75% yield) as a light-yellow solid (mp 63–65 °C). ¹H NMR (300 MHz, CDCl₃): δ = 9.33 (s, 1 H), 8.11–8.22 (m, 4 H), 7.74–7.88 (m, 2 H), 7.57–7.72 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.0, 143.5, 142.5, 141.7, 136.9, 130.4, 130.3, 129.8, 129.7, 129.3, 129.3, 127.7. MS (ESI): m/z = 207 [M + H]⁺ .