Direct Organocatalytic α-Fluorination of Aldehydes and Ketones

Abstract

The first organocatalytic direct α-fluorination of aldehydes and ketones employing Selectfluor {1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)} as the fluorine source is reported. (S)-Proline and related derivatives act as organocatalysts to give the corresponding α-fluoroaldehydes and a-fluoroketones in moderate to good yields (47-78%). The asymmetric ­inductions are still low (ee ≤ 36%).

Key words

organocatalysis - Selectfluor - electrophilic fluorination - aldehydes - ketones

References

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11

General Procedure for the Preparation of α-Fluoro-aldehydes and a-Fluoroketones.
To a stirred mixture of carbonyl compound 1 (1.0 mmol) and (S)-proline 3a (0.3 mmol) in MeCN (2 mL) was added Selectfluor (1.5 mmol) in one portion at 0 °C. Afterwards trifluoro acetic acid (0.3 mmol) was added and the reaction mixture was stirred at r.t. (0 °C in case of the aldehydes) until the reaction was complete (monitored by GC). Purification by flash chromatography or filtration through a short silica plug, respectively, afforded the pure product 2.

13

Reduction of the α-Fluoroaldehydes 2a-d with NaBH ₄ .
To the crude reaction mixture of α-fluoroaldehyde 2 MeOH (1 mL) and NaBH₄ (2.0 mmol) were subsequently added. The mixture was stirred until complete conversion (monitored by TLC), followed by evaporation of the solvents. Purification of the crude product by flash chromatography afforded the pure β-fluoroalcohols.

14

Representative Spectroscopic Data. 2-Fluoro-3-phenyl-propan-1-ol (reduced 2d): ¹H NMR (300 MHz, CDCl₃): δ = 2.20 (br s, 1 H, OH), 2.97 (m, 2 H, CH ₂Ph), 3.65 (ddd, J = 23.25, 12.62, 5.94 Hz, 1 H, CH _aH_bOH), 3.74 (ddd, J = 25.47, 12.61, 2.97 Hz, 1 H, CH_a H _bOH), 4.76 (dm, J = 48.72 Hz, 1 H, CHF), 7.28 (m, 5 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 37.45 (d, J _C,F = 20.9 Hz, CH₂), 64.09 (CH₂), 94.65 (d, J _C,F = 171.8 Hz, CHF), 126.77 (Ar-CH), 128.59 (2 C, Ar-CH), 129.31 (2 C, Ar-CH), 205.71 (d, J _C,F = 5.4 Hz, Ar-C) ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = -187.35 (m, CHF) ppm. The spectroscopic data were in accordance with those reported in the literature. [15]

16

Representative Spectroscopic Data.
2-Fluorocyclohexan-1-one (2e): ¹H NMR (400 MHz, CDCl₃): δ = 1.70 (m, 2 H, CH ₂), 1.88 (m, 1 H, CH ₂), 2.02 (m, 2 H, CH ₂), 2.34 (m, 1 H, CH ₂), 2.56 (m, 1 H, CH ₂), 4.90 (dddd, J = 48.90, 11.26, 6.32, 1.22 Hz, 1 H, CHF) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 22.75 (d, J _C,F = 9.9 Hz, CH₂), 26.91 (CH₂), 34.18 (d, J _C,F = 18.9 Hz, CH₂), 40.21 (CH₂), 92.58 (d, J _C,F = 188.9 Hz, CHF), 205.71 (d, J _C,F = 188.9 Hz, C=O) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = -188.23 (d, J = 50,5 Hz, CHF) ppm. The spectroscopic data were in accordance with those reported in the literature. [17]