Trifluoromethanesulfinamide from Ephedrine: A More Efficient Trifluoro-methylating Reagent

Abstract

Nucleophilic trifluoromethylation of non-enolizable and enolizable carbonyl compounds was achieved with the trifluoromethanesulfinamide derived from O-silylated ephedrine. In contrast to the trifluoroacetamide analog, previously described, this reagent is able to trifluoromethylate more acidic enolizable compounds.

amino alcohols - nucleophilic additions - fluorine - nucleophilic trifluoromethylation - trifluoromethanesulfinamides

References

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<A NAME="RG26004ST-11">11</A>

Synthesis of 2:
[CF₃SO⁺] Solution : A flame-dried three-necked vessel was successively charged, under nitrogen, with potassium triflinate (3.5g, 20.0 mmol), CH₂Cl₂ (60 mL) and POCl₃ (935 µL, 10.0 mmol). The reaction medium was stirred at r.t. for 40 min. In another flame-dried three-necked vessel was successively charged, under nitrogen, ephedrine (1.65 g, 10.0 mmol) and CH₂Cl₂ (47 mL). The resulting mixture was cooled to 0 °C before addition of N-(trimethylsilyl)imidazole (1.5 mL, 10.2 mmol). The reaction medium was stirred at 0 °C for 20 min then warmed to r.t. and kept under stirring for 2 h. After this period, diisopropylethylamine (3.5 mL, 20.0 mmol) was added and the mixture was cooled again to 0 °C. Then, the [CF₃SO⁺] solution was dropped within 1 h. After addition, the temperature was kept at 0 °C for 10 min then raised to r.t. After stirring for 24 h, the reaction medium was washed with 6% aq NaHCO₃. The organic phase was dried over Na₂SO₄ and evaporated in vacuo. The crude residue was purified by chromatography over silica gel.
Compound 2: ¹H NMR (300 MHz, CDCl₃): δ = 7.23-7.35 (massif, 5 H), 4.85 (d, 0.6 H, J = 3.9 Hz), 4.68 (d, 0.4 H, J = 5.7 Hz), 3.70 (dq, 0.4 H, J = 5.7 Hz, J = 7.0 Hz), 3.58 (dq, 0.6 H, J = 3.9 Hz, J = 7.0 Hz), 2.84 (q, 1.8 H, J = 1.4 Hz), 2.70 (q, 1.2 H, J = 1.8 Hz), 1.32 (d, 1.2 H, J = 7.0 Hz), 1.22 (d, 1.8 H, J = 7.0 Hz), 0.06 (s, 5.4 H), 0.04 (s, 3.6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 141.8, 141.4, 128.7, 128.6, 128.4, 128.1, 127.0, 126.8, 124.5 (q, J = 343.1 Hz), 124.5 (q, J = 341.6 Hz), 77.9, 77.0, 64.5 (br s), 62.8, 29.1, 26.6, 13.9, 13.2, 0.34, 0.32. ¹⁹F NMR (282 MHz, CDCl₃): δ = -75.03 (s, 0.6 F), -75.27 (s, 0.4 H). Anal. Calcd for C₁₄H₂₂F₃NO₂SSi: C, 47.57; H, 6.27; N, 3.96; S, 9.07; Si, 7.95. Found: C, 47.69; H, 6.56; N, 3.91; S, 9.40; Si, 8.20.

<A NAME="RG26004ST-12">12</A>

Trifluoromethylation with 2 and CsF:
To a solution of 2 (1 mmol) and the electrophile (1 mmol) in DME (1 mL) was added 15 mg of dried CsF (0.1 equiv). After 24 h, the crude product was desilylated with 1 M TBAF in THF (1 mL) for 1 h and extracted with pentane and brine. The organic phase was dried over Na₂SO₄ and the solvent evaporated in vacuo. The crude products were purified by chromatography over silica gel.
Trifluoromethylation with 2 and TBAT:
A solution of tetrabutylammonium triphenyldifluorosilicate (TBAT, 54 mg, 0.1 equiv) in THF (0.5 mL) was dropped (in 15 min) to a stirred solution of 2 (1 mmol) and the electrophile (1 mmol) in THF (1 mL). After 6 h, the crude mixture was desilylated with 1 M TBAF in THF (1 mL) for 1 h, then extracted with pentane and brine. The organic phase was dried over Na₂SO₄ and the solvent evaporated in vacuo. The crude products were purified by flash chromatography over silica gel.

For other syntheses see:

<A NAME="RG26004ST-13A">13a</A>

Ref.⁷

<A NAME="RG26004ST-13B">13b</A> Large S. Roques N. Langlois BR. J. Org. Chem.  2000,  65:  8848 

<A NAME="RG26004ST-14">14</A> Iseki K. Nagai T. Kobayashi V. Tetrahedron Lett.  1994,  35:  3137