Lewis Acid-Catalyzed Rearrangement of Fluoroalkylated Propargylic Alcohols: An Alternative Approach to β-Fluoroalkyl-α,β-enones

Abstract

A practical Lewis acid-catalyzed Meyer–Schuster rearrangement of fluoroalkylated propargylic alcohols, leading to a series of β-fluoroalkyl-α,β-enones, is developed. The methodology reported herein features moderate to high yields and high stereoselectivity in the synthesis of β-alkyl-β-fluoroalkyl-α,β-enones.

Key words

Lewis acids - Meyer–Schuster rearrangement - β-trifluoromethyl-α,β-enones - metal triflates - fluorinated compounds

• References and Notes

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• 19 General Procedure for the Synthesis of Compounds 2a–r The general procedure is illustrated immediately below with compound 2a as a specific example. A stirred solution of compound 1a (100 mg, 0.50 mmol) and BF₃·OEt₂ (36 mg, 0.25 mmol) in dichloroethane (2 mL) was heated at 70 ^oC under nitrogen for 4 h. Then, water (2 mL) and saturated Na₂CO₃ solution (1 mL) were added to quench the reaction at 0 °C. The aqueous layer was separated and extracted with CH₂Cl₂ (3 x 3 mL). The combined organic extracts were washed with brine, dried with MgSO₄, filtered, and concentrated to give the crude residue, which was purified by flash chromatography on silica gel with EtOAc/n-hexane (1:19) to afford compound 2a (80 mg, 80% yield) as a yellow oil and compound 3a (5 mg, 4% yield) as colorless oil. (E)-4,4,4-Trifluoro-1-phenylbut-2-en-1-one (2a) The spectroscopic data were in good agreement with the literature data.12b Colorless oil; ¹H NMR (CDCl₃, 500 MHz): δ 8.00 (d, J = 8.5 Hz, 2 H), 7.69–7.65 (m, 1 H), 7.58–7.54 (m, 3 H), 6.85 (dq, J = 15.5, 6.5 Hz, 1 H); ¹³C NMR (CDCl₃, 125 MHz): δ 188.0, 136.1, 134.1, 131.0, 130.3 (q, J = 35.0 Hz), 129.0, 128.3, 122.5 (q, J = 268.7 Hz); ¹⁹F NMR (CDCl₃, 470 MHz): δ –65.1; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₈F₃O: 201.0527; found: 201.0525. 4,4,4-Trifluoro-3-hydroxy-1-phenylbutan-1-one (3a) The spectroscopic data were in good agreement with the literature data.20 White solid; mp = 76.0–77.0 °C; ¹H NMR (CDCl₃, 500 MHz): δ 7.95–7.93 (m, 2 H), 7.62–7.58 (m, 1 H), 7.49–7.46 (m, 2 H), 4.69–4.65 (m, 1 H), 3.56–3.55 (m, 1 H), 3.39–3.26 (m, 2 H); ¹³C NMR (CDCl₃, 125 MHz): δ 197.5, 136.0, 134.1, 128.8, 128.4, 124.7 (q, J = 277.0 Hz), 67.0 (q, J = 32.5 Hz), 38.2; ¹⁹F NMR (CDCl₃, 470 MHz): δ –79.2.
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• 21 A similar mechanism in syn-selective Meyer–Schuster rearrangement, mediated by BF₃·OEt₂, was reported. See reference 18.
• 22 As shown below, the BF₃·OEt₂-catalyzed reaction of 1s did not proceed and only the starting substrate was recovered.

For Brønsted acid-promoted Meyer–Schuster reactions, see
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• 24 All of the synthetic β-fluoroalkyl-α,β-enones were characterized according to their ¹H NMR, ¹³C NMR, ¹⁹F NMR, and mass spectra. The stereochemistry of (E)-β-alkyl-β-fluoroalkyl-α,β-enones was unequivocally determined by comparing their NMR spectra to those of structurally identical or similar compounds.