Iodine-Mediated Oxidative [3+2] Annulation of Quinoxalinones with Oxime Esters: An Approach toward Imidazo[1,2-a]quinoxalin-4(5H)-ones

Abstract

We describe an efficient and operationally simple method for the synthesis of imidazo[1,2-a]quinoxalin-4(5H)-ones by a molecular-iodine-mediated annulation of quinoxalin-2(1H)-ones and oxime acetates in a [3+2] fashion. This reaction offers a novel and straightforward method for constructing functionalized imidazo[1,2-a]quinoxalin-4(5H)-ones in a highly regioselective manner.

Key words

imidazoquinoxalinones - quinoxalinones - imidazoles - iodine-mediated reaction - [3+2] annulation

Publication History

Received: 31 December 2024

Accepted after revision: 21 January 2025

Accepted Manuscript online:
21 January 2025

Article published online:
06 March 2025

• References and Notes

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• 16 Imidazo[1,2-a]quinoxalinones (3): General Procedure An oven-dried 10 mL round-bottomed flask was charged with the appropriate quinoxalin-2(1H)-one derivative 1 (1.0 equiv) and oxime acetate 2 (2.0 equiv) in DMSO (2 mL). I₂ (3.0 equiv) was added and the mixture was stirred at 100 °C in a paraffin-oil bath for 4–6 h until the reaction was complete (TLC). The mixture was then cooled to r.t. and ice-cold sat. aq Na₂S₂O₃ was added. The organic layer was washed with sat. aq NaHCO₃ and brine, then extracted with EtOAc (3 × 20 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give a residue that was purified by column chromatography (silica gel). 2-Phenylimidazo[1,2-a]quinoxalin-4(5H)-one (3a) Prepared according to the general from quinoxalin-2(1H)-one (1a; 100 mg, 0.684 mmol), 1-phenylethan-1-one O-acetyl oxime (2a; 243 mg, 1.37 mmol), and I₂ (521 mg, 2.05 mmol) as a yellow solid; yield: 125 mg (70%); mp 238–242 °C; R_f = 0.2 (50% EtOAc–hexane). ¹H NMR (400 MHz, DMSO-d₆ ): δ = 11.88 (s, 1 H), 9.07 (s, 1 H), 8.12–8.10 (m, 1 H), 8.01–7.99 (m, 2 H), 7.51–7.47 (m, 2 H), 7.43–7.39 (m, 2 H), 7.37–7.32 (m, 2 H). ¹³C NMR (100 MHz, DMSO-d₆ ): δ = 152.6, 144.1, 136.6, 133.0, 128.8, 128.8, 127.9, 127.0, 125.2, 122.9, 121.6, 116.6, 116.0, 112.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₂N₃O: 262.0980; found: 262.0968. 4-Chloroimidazo[1,2-a]quinoxalines 4: General Procedure An oven-dried 25 mL round-bottomed flask was charged with the appropriate imidazo[1,2-a]quinoxalin-4(5H)-one 3, and POCl₃ (20 equiv) was added at 0 °C. The mixture was refluxed at 130 °C for 30 min until the reaction was complete (TLC). The mixture was then diluted with EtOAc and slowly added to sat. aq Na₂CO₃ (~100 mL) with constant stirring until effervescence stopped. The organic layer was extracted with EtOAc (3 × 20 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give a residue that was purified by column chromatography (silica gel). 4-Chloro-2-phenylimidazo[1,2-a]quinoxaline (4a) Prepared according to the general procedure from 2-phenylimidazo[1,2-a]quinoxalin-4(5H)-one (3a; 100 mg, 0.382 mmol) and POCl₃ (0.715 mL, 7.65 mmol) as a white solid; yield: 75 mg (70%); mp 155–160 °C; R_f = 0.6 (20% EtOAc–hexane). ¹H NMR (400 MHz, CDCl₃): δ = 8.39 (s, 1 H), 8.05–8.02 (m, 3 H), 7.90 (dd, J = 8.2, 1.1 Hz, 1 H), 7.68 (td, J = 8.3, 7.8, 1.4 Hz, 1 H), 7.60 (td, J = 7.8, 7.3, 1.3 Hz, 1 H), 7.46 (td, J = 6.9, 1.5 Hz, 2 H), 7.40–7.36 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.4, 143.1, 136.3, 135.1, 132.5, 130.2, 129.3, 129.0, 129.0, 127.3, 126.9, 126.5, 114.9, 109.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₁ClN₃: 280.0642; found: 280.0634. 4-Amino Derivatives of Imidazo[1,2-a]quinoxaline 5a–j; General Procedure A 10 mL pressure vial was charged with the appropriate 4-chloroimidazo[1,2-a]quinoxaline 4, amine derivative (1.2 equiv), K₃PO₄ (1.5 equiv), and H₂O (2.0 mL). The vial was then sealed and the mixture was stirred at 100 °C for 4 h until the reaction was complete (TLC). EtOAc and H₂O were added and the organic layer was extracted with EtOAc (3 × 10 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give a residue that was purified by column chromatography (silica gel). 2-Phenyl-4-(4-phenylpiperazin-1-yl)imidazo[1,2-a]quinoxaline (5a) Prepared according to the general procedure from 4a (100 mg, 0.358 mmol), 1-phenylpiperazine (70 mg, 0.429 mmol), and K₃PO₄ (114 mg, 0.536 mmol), as an off-white solid; yield: 112 mg (77%); mp 207–212 °C; R_f = 0.6 (20% EtOAc–hexane). ¹H NMR (400 MHz, CDCl₃): δ = 8.24 (s, 1 H), 8.01–7.99 (m, 2 H), 7.74–7.71 (m, 2 H), 7.49–7.45 (m, 2 H), 7.45–7.40 (m, 1 H), 7.39–7.34 (m, 1 H), 7.33–7.28 (m, 3 H), 7.04–7.02 (m, 2 H), 6.92–6.88 (m, 1 H), 4.64 (t, J = 5.2 Hz, 4 H), 3.43 (t, J = 5.2 Hz, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 151.6, 147.8, 144.0, 136.7, 133.9, 133.5, 129.4, 128.9, 128.2, 127.3, 126.6, 126.0, 124.8, 123.6, 120.2, 116.5, 114.3, 108.0, 49.8, 46.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₄N₅: 406.2032; found: 406.2024.