Synthesis of Substituted α-Carboline Derivatives by Base-Mediated Annulation of Azaindoles with Alkylidene Malononitriles

Abstract

A new synthetic method has been established to synthesize α-carbolines through the reaction of electrophilic azaindoles with ambiphilic alkylidene malononitriles. The versatility of this approach was explored by using various alkylidene malononitriles, and also by conducting nitrogen migration on the azaindole. This method enables the simultaneous introduction of diverse functional groups, such as amine, nitrile, and aryl, onto the benzene ring of a carboline scaffold. As the scaffold putatively shows antiproliferative and other biological activities, the method is valuable in the development of new chemical entities for drug discovery.

Key words

azaindoles - azacarbazoles - carbolines - annulation reaction - base-mediated reaction - medicinal chemistry

Publikationsverlauf

Eingereicht: 17. Dezember 2024

Angenommen nach Revision: 07. Februar 2025

Artikel online veröffentlicht:
20. März 2025

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• 18 5-Aminoazacarbazoles 15: General Procedure A round-bottomed flask was charged with the appropriate tosyl nitro azaindole 11 (1.57 mmol, 1 equiv) and alkylidene malononitrile 14 (1.57 mmol, 1 equiv) dissolved in anhyd THF (0.2 M). Et₃N (1.57 mmol, 1 equiv) was added, and the mixture was heated at 50 °C for 5–6 h under N₂ until the reaction was complete (TLC). The excess solvent was then evaporated under vacuum, and the reaction was quenched with H₂O. The mixture was extracted with EtOAc and brine, and the organic layer was dried (Na₂SO₄) and concentrated in a rotatory evaporator. Finally, the crude product was purified by column chromatography [silica gel (100–200 mesh), EtOAc–hexane (1:9)]. 5-Amino-7-phenyl-9-tosyl-9H-pyrido[2,3-b]indole-6-carbonitrile (15a) Brown solid; yield: 60%. ¹H NMR (500 MHz, CDCl₃): δ = 8.55 (dd, J = 4.9, 1.3 Hz, 1 H), 8.11 (dd, J = 7.8, 1.4 Hz, 1 H), 8.08–8.04 (m, 3 H), 7.67 (d, J = 7.0 Hz, 2 H), 7.53 (t, J = 7.3 Hz, 2 H), 7.49 (d, J = 7.2 Hz, 1 H), 7.34 (dd, J = 7.8, 4.9 Hz, 1 H), 7.23 (d, J = 8.2 Hz, 2 H), 5.12 (s, 2 H), 2.34 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 150.31, 146.95, 146.02, 145.82, 145.62, 140.84, 138.96, 135.48, 129.69, 128.99, 128.89, 128.73, 128.20, 127.91, 119.39, 117.36, 116.84, 107.47, 106.38, 91.75, 21.66. HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₅H₁₉N₄O₂S: 439.1229; found: 439.1221.