A Facile and Mild Approach for Stereoselective Synthesis of α-Fluoro-α,β-unsaturated Esters from α-Fluoro-β-keto Esters via Deacylation

Abstract

The highly stereoselective olefination reaction of α-fluoro-β-keto esters for the synthesis of α-fluoro-α,β-unsaturated esters has been developed. The olefination combines nucleophilic addition, intramolecular nucleophilic addition, and elimination in one step, as well as provides a facile synthetic approach to α-fluoro-α,β-unsaturated esters which are important units in many biologically active compounds and useful precursors in a variety of functional-group transformations.

Key words

olefination - highly stereoselective - deacylation - fluoro­olefins - carbon–carbon bond cleavage

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• 14 Typical Experimental Procedure for the FluoroolefinsThe reaction mixture of fluorinated substrates (0.55 mmol), aldehyde (0.5 mmol), Cs₂CO₃ (1 mmol) and MeCN (1.5 mL) was stirred at 40 °C for the indicated time until complete consumption of the starting material, which was monitored by TLC analysis (6–12 h). The solvents were removed by rotary evaporation to provide raw products. The residue was then chromatographed on silica gel (eluent: hexane–EtOAc), affording the desired fluoroolefins.Ethyl (Z)-2-Fluoro-3-phenylacrylate (3aa)Colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 7.64 (d, J = 6.8 Hz, 2 H), 7.43–7.35 (m, 3 H), 6.92 (d, J = 35.2 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H). ¹⁹F NMR (470 MHz, CDCl₃): δ = –125.31 (s). ¹³C NMR (126 MHz, CDCl₃): δ = 160.45 (d, J = 34.3 Hz), 146.07 (d, J = 267.5 Hz), 130.20 (s), 129.30 (d, J = 7.2 Hz), 128.68 (s), 127.82 (s), 116.48 (s), 60.89 (s), 13.23 (s). MS (EI): m/z = 194.12 [M⁺].(Z)-2-Fluoro-1-phenyl-3-[2-(trifluoromethyl)phenyl]prop-2-en-1-one (5ar)Colorless solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.03 (d, J = 7.9 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 2 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.63 (t, J = 7.5 Hz, 2 H), 7.56–7.47 (m, 3 H), 7.19 (d, J = 33.6 Hz, 1 H). ¹⁹F NMR (470 MHz, CDCl₃): δ = –59.57 (s), –118.61 (s). ¹³C NMR (126 MHz, CDCl₃): δ = 187.69 (d, J = 28.3 Hz), 154.69 (d, J = 276.2 Hz), 135.67 (s), 133.32 (s), 132.07 (s), 131.51 (d, J = 12.1 Hz), 129.47 (d, J = 3.6 Hz), 129.32 (s), 129.11 (s), 128.59 (s), 126.22 (q, J = 5.5 Hz), 124.96 (s), 122.79 (s), 115.25 (s). MS (EI): m/z = 294.15 [M⁺].(Z)-2-Fluoro-N-phenyl-3-[4-(trifluoromethyl)phenyl]acrylamide (5bg)Colorless solid. ¹H NMR (500 MHz, DMSO): δ = 10.47 (s, 1 H), 7.90 (d, J = 8.2 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.74 (d, J = 7.7 Hz, 2 H), 7.35 (t, J = 7.9 Hz, 2 H), 7.20–7.07 (m, 2 H). ¹⁹F NMR (470 MHz, DMSO): δ = –61.30 (s), –121.52 (s). ¹³C NMR (126 MHz, DMSO): δ = 157.26 (d, J = 29.8 Hz), 50.89 (d, J = 281.5 Hz), 137.26 (s), 134.70 (s), 129.89 (d, J = 6.0 Hz), 128.52 (d, J = 32.1 Hz), 128.18 (s), 125.22 (s), 24.04 (s), 120.38 (s), 111.49 (s). MS (EI): m/z = 309.10 [M⁺].