Synthesis of Indolo[1,2-a]quinoxalines and 2-Arylquinazolinones by Oxidative Aromatization from Aromatic Aldehydes or Benzyl Alcohols

Abstract

We report a simple protocol for the synthesis of heterocyclic indoloquinoxalines and 2-naphthylquinazolinones by an oxidative aromatization from aromatic aldehydes or benzyl alcohols. For aromatic aldehydes, a diphenyl hydrogen phosphate/Cu(OTf)2/t-BuOOH system delivered the products in high yields (73–93%). From benzyl alcohols, a Fe(NO3)3·9H2O/(2,2,6,6-tetramethylpiperidin-1-yl)oxyl/air system was effective, and the products were obtained in moderate to high yields (51–75%). The indolo[1,2-a]quinoxaline compounds displayed fluorescence emission bands at 501–533 nm. Moreover, intramolecular hydrogen bonding was vital for the free rotation of the aryl–aryl bond in ortho-hydroxyindolo[1,2-a]quinoxalines.

Key words

Brønsted acid catalysis - Pictet–Spengler reaction - aromatization - axial chirality - quinoxalines

• References and Notes

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• 14 Indolo[1,2-a]quinoxalines 3a–e from Aldehydes: General Procedure (Conditions A) A solution of the appropriate aldehyde 1 (0.3 mmol, 1.5 equiv.), aniline 2a (0.2 mmol), and (PhO)₂P(O)OH (5.0 mol%) in toluene (2.0 mL, 0.1 M) was stirred at 80 °C for 4 h. When the reaction was complete, the mixture was cooled to r.t., and Cu(OTf)₂ (5.0 mol%) and t-BuOOH (0.6 mmol, 3.0 equiv) were added, and the resulting mixture was stirred at r.t. for 1 h. The solvent was then removed and the crude product was purified by flash column chromatography [silica gel, PE–EtOAc]. Indolo[1,2-a]quinoxalines 3a–e from Benzylic Alcohols: General Procedure (Conditions B) A solution of alcohol 1′ (0.4 mmol, 2.0 equiv), aniline 2a (0.2 mmol), Fe(NO₃)₃ (10 mol%), TEMPO (10 mol%), and KOH (0.1 mmol, 0.5 equiv) in toluene (2.0 mL, 0.1 M) was stirred at 100 °C for 16 h. The solvent was then removed and the crude product was purified by flash column chromatography [silica gel, PE–EtOAc]. 6-(2-Methoxy-1-naphthyl)-7-methylindolo[1,2-a]quinoxaline (3a) Brown solid, purified by flash chromatography [silica gel, PE–EtOAc (8:1)]; yield: Conditions A; 56.7 mg (73%); Conditions B; 39.6 mg (51%). ¹H NMR (400 MHz, CDCl₃): δ = 8.57–8.46 (m, 2 H), 8.08–7.98 (m, 2 H), 7.88–7.78 (m, 2 H), 7.61 (ddd, J = 8.6, 7.4, 1.6 Hz, 1 H), 7.58–7.51 (m, 1 H), 7.48–7.35 (m, 4 H), 7.35–7.26 (m, 2 H), 3.83 (s, 3 H), 1.68 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 154.7 (2C), 136.0, 133.3, 132.0, 130.9, 130.4 (2C), 130.1, 129.1, 128.4, 128.0, 127.3, 126.8, 124.5, 124.3, 124.0, 123.7, 121.9 (2C), 120.8, 114.6, 114.5, 113.4, 110.5, 56.6, 8.9. HRMS (ESI): m/z [M + H] ⁺ calcd for C₂₇H₂₁N₂O: 389.1654; found: 389.1658.