Synthesis of Indolo[1,2-a]quinoxalinones through Palladium/Copper-Cocatalyzed Oxidative Isocyanide-Insertion Cyclization of Indoles and Hydrolysis of Enamines

Abstract

A novel Pd/Cu-cocatalyzed isocyanide-insertion cyclization of indoles and hydrolysis of enamines has been developed for the construction of indolo[1,2-a]quinoxalinones. A secondary amine group on the N-phenylindole skeleton acts as an important directing groups that participates in activation of the C(2)-position of the indole and the subsequent isocyanide-insertion cyclization. The fragile generated enamine bond is easily hydrolyzed by the acid medium to give the corresponding quinoxalinone skeleton. This regioselective and high-yielding transformation, which avoids the use of hazardous CO gas, might be extendable to syntheses of natural polycyclic products.

Key words

isocyanide insertion - C–H bond activation - enamines - hydrolysis - indoloquinoxalinones

Publikationsverlauf

Eingereicht: 27. Oktober 2020

Angenommen nach Revision: 02. Dezember 2020

Accepted Manuscript online:
02. Dezember 2020

Artikel online veröffentlicht:
05. Januar 2021

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• 10 5-Methylindolo[1,2-a]quinoxalin-6(5H)-one (3a): Typical Procedure A 10 mL oven-dried Schlenk round-bottomed flask was charged with amine 1a (0.5 mmol), Pd(TFA)₂ (10 mol%), Cu(OAc)₂·xH₂O (2.0 equiv), t-BuN≡C (2a; 0.75 mmol), toluene (2.5 mL), and HOAc (0.5 mmol). The mixture was flushed three times with O₂ from a balloon, then stirred at 80 °C for 12 h under O₂. When the reaction was complete, the mixture was cooled to rt and filtered through diatomite. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:10)] to give a white solid; yield: 93 mg (75%); mp 163.3–165.3 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.77 (s, 3 H), 7.31–7.46 (m, 4 H), 7.57 (t, J = 8.4 Hz, 1 H), 7.65 (s, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 8.34 (d, J = 8.7 Hz, 1 H), 8.41–8.44 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 29.0, 106.8, 114.2, 115.4, 115.6, 122.4, 123.2, 123.3, 124.2, 125.3, 126.7, 128.1, 129.2, 129.8, 134.2, 156.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₃N₂O: 249.1028; found: 249.1026.