Nucleophilic 5-endo-trig Cyclization of 3,3-Difluoroallylic Ketone Enolates: Synthesis of 5-Fluorinated 2-Alkylidene-2,3-dihydrofurans

Abstract

3,3-Difluoroallylic ketones readily undergo nucleophilic 5-endo-trig cyclization through their metal enolates to afford 5-fluor­inated 2-alkylidene-2,3-dihydrofurans. O-Cyclization exclusively occurred via intramolecular substitution of the vinylic fluorines.

Key words

cyclization - fluorine - alkenes - furans - 5-endo-trig - ­ketone enolates - vinylic substitution

• References and Notes


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• 15 (Z)-5-Fluoro-3,3-dimethyl-2-(2-phenylethylidene)-2,3-dihydrofuran (5b) To a suspension of KH (oil free, 46 mg, 1.2 mmol) in THF (11 mL) was added 6,6-difluoro-4,4-dimethyl-1-phenylhex-5-en-3-one (2b, 138 mg, 0.58 mmol), and the mixture was heated to reflux for 2 h. After cooling to r.t., the reaction was quenched with phosphate buffer (pH 7). Organic materials were extracted with Et₂O three times. The combined extracts were washed with brine and dried over MgSO₄. After removal of the solvent under reduced pressure, the residue was purified by TLC on silica gel (EtOAc–hexane, 1:5) to give 5b (122 mg, 97%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (d, J _HF = 1.1 Hz, 6 H), 3.45 (d, J = 7.5 Hz, 2 H), 4.20 (d, J _HF = 5.4 Hz, 1 H), 4.73 (td, J = 7.5 Hz, J _HF = 3.4 Hz, 1 H), 7.18–7.22 (m, 3 H), 7.27–7.30 (m, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 30.1 (d, J _CF = 2 Hz), 30.9, 44.2 (d, J _CF = 2 Hz), 79.7 (d, J _CF = 8 Hz), 99.4, 125.9, 128.2, 128.4, 141.0, 157.5 (d, J _CF = 276 Hz), 160.6 (d, J _CF = 3 Hz). ¹⁹F NMR (470 MHz, CDCl₃): δ = 46.2 (s). IR (neat): 3028, 2970, 2931, 1801, 1726, 1703, 1454, 1279, 1219, 1126, 1088, 993, 976, 748, 698 cm^–1. Anal. Calcd for C₁₄H₁₅FO: C, 77.04; H, 6.93. Found: C, 76.80; H, 7.16%.
• 16 3,3-Disubstituted 5-fluoro-2-alkylidene-2,3-dihydrofurans 5 are air- and heat-stable.
• 17 In the NOESY experiment of dihydrofuran 5b, substantial correlation between the methyl protons and the vinylic proton H^a was observed. No NOE correlation was detected between the methyl protons and the allylic protons H^b (Figure 1).
• 18 For a review on bioactivities of fluorinated compounds, see: Müller K, Faeh C, Diederich F. Science 2007; 317: 1881