Facile Synthesis of 4-Perfluoroalkylated 2H-Pyran-2-ones Bearing Indole Skeleton via a Base-Promoted Cascade Process

Abstract

A protocol for the synthesis of 4-perfluoroalkylated 2H-pyran-2-ones bearing indole skeleton is reported. This efficient synthesis involves a Et₃N-promoted Michael addition/enolization/cyclization cascade process at 40 °C in air, using 3-(1-methyl-1H-indol-3-yl)-3-oxopropanenitriles and methyl perfluoroalk-2-ynoates as the easily available starting materials. Various functionalized 6-(1-methyl-1H-indol-3-yl)-2-oxo-4-(perfluoroalkyl)-2H-pyran-5-carbonitrile derivatives were obtained in 44–99% yield.

Key words

2H-pyran-2-one - indole - perfluoroalkylated - heterocyclic synthesis - Michael addition

Publikationsverlauf

Eingereicht: 08. Juni 2021

Angenommen nach Revision: 09. Juni 2021

Accepted Manuscript online:
09. Juni 2021

Artikel online veröffentlicht:
25. Juni 2021

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• 12 General Procedure for the Preparation of Perfluoroalkylated Indolylpyranone Derivatives 3 Under air in a sealed tube, a mixture of 3-(1-methyl-1H-indol-3-yl)-3-oxopropanenitriles 1 (1.0 mmol) and methyl perfluoroalk-2-ynoates 2 (2.0 mmol) in the presence of Et₃N (1.0 mmol) in THF (5 mL) was stirred at 40 °C for 24 h; then after cooled to room temperature, THF was removed under vacuum, and the residue was purified by column chromatography on silica gel by eluting with petroleum ether/ethyl acetate (20:1) to give the purified product 3. 6-(1-Methyl-1H-indol-3-yl)-2-oxo-4-(trifluoromethyl)-2H-pyran-5-carbonitrile (3a) Light yellow solid; yield 97%; mp 239.8–240.9 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.95 (s, 1 H), 6.40 (s, 1 H), 7.39–7.44 (m, 3 H), 8.38–8.40 (m, 1 H), 8.65 (s, 1 H) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 34.4, 78.9, 106.5, 106.9 (q, ³ J_C–F = 5.3 Hz), 110.6, 115.1, 120.6 (q, ¹ J_C–F = 274.2 Hz), 123.1, 124.1, 124.8, 125.7, 136.5, 137.2, 144.5 (q, ² J_C–F = 33.2 Hz), 157.5, 168.9 ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –66.8 ppm. IR (KBr): ν = 3127, 2217, 1737, 1515, 1276, 1173, 1141, 882, 753, 670 cm^–1. MS (ESI): m/z (%) = 319.0 [M + H]⁺. HRMS (ESI): m/z calcd for C₁₆H₉F₃N₂O₂ [M + H]⁺: 319.0687; found: 319.0686.