Rhodium-Catalyzed N-Reverse Prenylation of Nonactivated Indoles

Abstract

The N-reverse prenylated indole motif is an important structure in natural products and biologically active molecules. Nevertheless, the direct N-reverse prenylation of nonactivated indoles is challenging. We report a rhodium-catalyzed regioselective N-reverse prenylation of indoles bearing various functional groups under neutral conditions. The triphenyl phosphite ligand and acetonitrile solvent together play a key role in the reactivity and selectivity.

Key words

indoles - reverse prenylation - rhodium catalysis - allylic substitution - regioselectivity

Publication History

Received: 24 October 2022

Accepted after revision: 09 December 2022

Accepted Manuscript online:
09 December 2022

Article published online:
11 January 2023

• References and Notes

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For reviews see:
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• 13 4-Chloro-1-(1,1-dimethylprop-2-en-1-yl)-1H-indole (3ba); Typical Procedure In a glove box, a pressure tube equipped with a magnetic stirrer bar was charged with [Rh(cod)Cl]₂ (2.5 mol%, 2.4 mg) and MeCN (1 mL). P(OPh)₃ (5 mol%, 2.6 μL) was added, and the solution was stirred for 10 min. Carbonate 2a′ (5.0 equiv, 200 µL) and 4-chloroindole (1b; 1.0 equiv, 30.2 mg) were added to the reaction tube, which was then sealed with a PTFE-lined cap and heated in an oil bath at 100 °C for 48 h. The crude reaction mixture was cooled and concentrated, and the residue was directly purified to flash column chromatography (silica gel) to give a yellow oil; yield: 29.3 mg (67%). ¹H NMR (400 MHz, CDCl₃): δ = 7.44 (d, J = 8.3 Hz, 1 H), 7.35 (d, J = 3.4 Hz, 1 H), 7.12–7.00 (m, 2 H), 6.61 (dd, J = 3.4, 0.5 Hz, 1 H), 6.13 (dd, J = 17.5, 10.7 Hz, 1 H), 5.22 (dd, J = 34.9, 11.4 Hz, 2 H), 1.76 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 143.74, 136.01, 128.65, 125.97, 125.70, 121.19, 118.88, 113.83, 112.47, 99.23, 59.45, 27.96. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₅ClN: 220.0893; found: 220.0888.