A Metal-Free TBHP-Triggered Cascade Cyclization of 2-Arylindoles with Alcohols: Synthesis of Hydroxyalkylated Indolo[2,1-a]isoquinoline Derivatives

Abstract

A practical method for the synthesis of hydroxyalkylated indolo[2,1-a]isoquinoline derivatives through the metal-free cascade cyclization of 2-arylindoles with alcohols in the presence of tert-butyl hydroperoxide (TBHP) is disclosed. The present method features transition-metal-free conditions and exceptional functional group tolerance. A series of valuable hydroxyalkylated indolo[2,1-a]isoquinoline derivatives bearing various functional groups is synthesized in moderate to excellent yields.

Key words

2-arylindoles - alcohols - addition/cyclization - hydroxyalkylation - indolo[2,1-a]isoquinolines

Publication History

Received: 04 September 2022

Accepted after revision: 27 September 2022

Accepted Manuscript online:
27 September 2022

Article published online:
28 October 2022

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• 18 Hydroxyalkylated Indolo[2,1-a]isoquinolines; General Procedure TBHP (70% aqueous solution, 0.8 mmol) was added to a solution of 2-arylindole 1 (0.2 mmol) in alcohol 2 (2 mL). The reaction mixture was then heated to 100 °C and stirred for 10 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 6:1 to 9:1) to afford the desired product 3. (R)-5-(2-Hydroxy-2-methylpropyl)-5-methyl-12-phenylindolo[2,1-a]isoquinolin-6(5H)-one (3aa) Colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.67 (d, J = 8.2 Hz, 1 H), 7.58–7.34 (m, 8 H), 7.28–7.18 (m, 3 H), 6.99 (t, J = 7.7 Hz, 1 H), 2.87 (d, J = 14.5 Hz, 1 H), 2.35 (d, J = 14.6 Hz, 1 H), 1.70 (s, 3 H), 1.07 (s, 3 H), 0.75 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.27, 138.78, 134.35, 134.32, 132.47, 130.33, 129.54, 129.28, 128.09, 127.99, 127.29, 126.69, 125.82, 125.43, 125.11, 124.53, 120.30, 119.41, 116.94, 71.07, 54.08, 46.26, 32.46, 32.25, 29.70. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₆NO₂: 396.1964; found: 396.1969.