Synlett 2005(6): 0991-0993  
DOI: 10.1055/s-2005-864813
LETTER
© Georg Thieme Verlag Stuttgart · New York

Direct Organocatalytic α-Fluorination of Aldehydes and Ketones

Dieter Enders*, Matthias R. M. Hüttl
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule Aachen, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: Enders@RWTH-aachen.de;
Further Information

Publication History

Received 25 January 2005
Publication Date:
23 March 2005 (online)

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%).

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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.

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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.

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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 aHbOH), 3.74 (ddd, J = 25.47, 12.61, 2.97 Hz, 1 H, CHa 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]

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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]