Facile Synthesis of 11H-Indolo[3,2-c]quinolines Through Pictet–Spengler Cyclization and Aromatization by Oxygen

Abstract

An operationally simple and facile synthesis of 11H-indolo[3,2-c] quinolines through p-TSA-mediated Pictet–Spengler reaction followed by aerobic oxidation using oxygen is reported. The reaction is robust, efficient, metal-free, and versatile with broad functional group tolerance.

Keywords

Alkaloids - Indoloquinolines - Cyclization - Aerobic oxidation - Pictet–Spengler reaction - p-TSA - O₂ atmosphere

Publikationsverlauf

Eingereicht: 23. Juli 2025

Angenommen nach Revision: 17. September 2025

Accepted Manuscript online:
17. September 2025

Artikel online veröffentlicht:
22. Oktober 2025

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• 13 Typical experimental procedure: 11H-indolo[3,2-c]quinoline: An oven dried Schlenk tube, equipped with a magnetic stir bar, charged with 2-(1H-indol-2-yl)aniline (100 mg) in 2 mL of xylene, formaldehyde (1.5 equiv) and p-TSA (1.2 equiv) were added and continued stirring at room temperature. This Schlenk tube was shifted to pre-heated oil bath maintained at 120°C with stirring. Reaction continued in the same temperature for 3 days in open air. Upon completion, reaction mixture was cooled to room temperature and poured into ice-cold water and neutralized using saturated Na₂CO₃ solution until pH reaches 7. Then extracted with DCM (15 mL × 3), washed with brine and dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude product was purified by using column chromatography with hexane and EtOAc mixture. White solid; yield: 30%; m p: - >200 °C; R_f = 0.42 (EtOAc: Hexane, 3:7); IR (neat): 3394, 2923, 2853, 1650, 1275, 824, 761, 569 cm⁻¹. 1H NMR (500 MHz, DMSO-d ₆ ): δ 12.74 (br s, 1H), 9.60 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.76–7.768 (m, 3H), 7.51 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H). ¹³C (100 MHz, DMSO-d ₆ ): δ 145.9, 145.3, 140.2, 139.2, 130.0, 128.5, 126.2, 126.0, 122.6, 122.3, 121.0, 120.6, 117.6, 114.8, 112.4; HRMS (ESI); m/z [M+H]⁺ calcd for C₁₅H₁₀N₂: 219.0922; found: 219.0941. Synthesis of Isocryptolepine (1): From 11H-indolo[3,2-c]quinoline (3), natural product Isocryptolepine (1) can be synthesized using the reported procedure.¹²