Regioselective Synthesis of Fluorohydrines via S_N2-Type Ring-Opening of Epoxides with TBABF-KHF₂

Abstract

We found that the ring-opening fluorination of terminal epoxides using TBABF-KHF₂ proceeds with high selectivity through the S_N2 mechanism. As TBABF-KHF₂ is easily obtainable, is stable, and can be used in glassware, it can be a useful reagent for 1-fluoro-2-alkanol synthesis from the terminal epoxides.

epoxides - fluorohydrine - regioselectivity - ring-opening - tetrabutylammonium bifluoride (TBABF)-KHF₂

References

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TBABF was previously used for the halogen exchange fluorination reaction in polar solvents, see:

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8

The generated TBAF must be converted to the stable TBABF again by KHF₂ before the decomposition to Bu₃N. [9] As KHF₂ is slightly soluble in the reaction mixture, further addition of KHF₂ was not effective.

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11

Enantiomeric excess values of (S)-2b and (R)-3b were determined from ¹⁹F NMR after conversion to MTPA esters.

12

The representative procedure for 2a is as follows: To a 1 M THF solution of TBAF (30 mL, 30 mmol) in a glass vessel was added 46% aq HF (1.3 g, 30 mmol) and the volatile part was removed by evaporator to give a crude TBABF. The crude TBABF, containing a little water, is storable in a glass bottle. [15] The crude TBABF (845 mg, 3 mmol) and KHF₂ (24 mg, 0.3 mmol) were put in a glass vessel and water was completely removed (for 15 min at 100 °C and 0.55 mmHg). After cooling to room temperature, heptane (0.1 mL) [16] and 1a (1 mmol) were added. The mixture was kept at 120 °C for 4 h and then cooled to room temperature again. To the reaction mixture, 2 mL of water was added and the mixture was extracted with ether (2 mL × 3). NMR yield and the product ratio were determined from ¹⁹F NMR using FCH₂CH₂OH as an internal standard. Isolation was carried out by column chromatography (silica gel/hexane-ether) after concentration. 2a: IR (film) 3390, 2930, 1460 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 4.50-4.20 (m, 2 H), 3.89-3.86 (m, 1 H), 2.00 (s, 1 H), 1.48-1.43 (m, 3 H), 1.33-1.28 (m, 7 H), 0.89 (t, 3 H, J = 7.0 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ -228.81 (dt, J = 18.3 Hz, 47.7 Hz, 1 F); 3a: IR (film) 3365, 2930, 1466 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 4.58 (dm, J = 50.3 Hz, 1 H), 3.79-3.61 (m, 2 H), 1.88 (t, J = 6.3 Hz, 1 H), 1.75-1.30 (m, 12 H), 0.89 (t, 3 H, J = 6.8 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ -190.03 to -190.42 (m, 1 F).

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15

Complete removal of water gave pure TBABF as a highly viscous liquid, [17] which is difficult to handle. Therefore, it is better to store the crude TBABF and to remove the water completely just before use. [18] TBABF is commercially available and TBABF obtained from Tokyo Kasei Kogyo Co., Ltd. showed the same reactivity.

16

Heptane was used to wash the substrates attached on the wall of the vessel during the reaction, and in a larger-scale experiment, the solvent is not necessary.

17

Spectra data of TBABF thus prepared coincided with the reported ones; ¹⁹F NMR (CD₂Cl₂, -80 °C) δ -151.5 (d, J _HF = 123.0 Hz), lit. [19] (CD₂Cl₂, -80 °C) δ -147.5 (d, J _HF = 123.3 Hz).

18 Camps F. Chamorro E. Casol V. Guerrero A. J. Org. Chem.  1989,  54:  4294 

19 Sharma RK. Fry JL. J. Org. Chem.  1983,  48:  2112