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Synlett 2021; 32(07): 738-742
DOI: 10.1055/a-1327-6933
letter

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

Xuan Sha‡
,
Jie Ren‡
,
Yi-ran Hu
,
Yun-yi Zhao
,
Shi-ying Wu
,
Rui Yang
,
Yao Chen
,
Fei Ji  ∗
This work was supported by the National Natural Science Foundation of China (No. 81903498) and the Innovation and Entrepreneurship Training Program for Undergraduates (No. 202010316248).
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1327-6933.
  • Supporting Information


Publication History

Received: 27 October 2020

Accepted after revision: 02 December 2020

Accepted Manuscript online:
02 December 2020

Article published online:
05 January 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.