三氟甲烷是一種廉價(jià)且對(duì)環(huán)境無(wú)害的試劑。常見(jiàn)的堿如叔丁醇鉀可使三氟甲烷脫質(zhì)子化生成三氟甲基負(fù)離子¹。在該反應(yīng)中DMF具有溶劑和負(fù)離子穩(wěn)定劑的雙重功能。形成的中間體22是一修飾化的相當(dāng)穩(wěn)定的三氟甲基負(fù)離子的形式，其功能相當(dāng)與三氟甲基的“存儲(chǔ)器”。真正的三氟甲基化試劑是CF₃^-/DMF加成物，該試劑適用于非烯醇化的醛時(shí)比Me₃SiCF₃更有效²。

示例：

Fluoroform(200 to 600mg, 1.4 to 8.6 mmol) was bubbled into a solution of 2,6-dimethylcyclohexanone (1mmol) in anhydrous DMF(2mL), maintained at -10 ^oC. Then, t-BuOK(1.1 mL of a 1M solution in THF, 1.1mmol) were successively added at -10 ^oC. The resulting mixture was stirred at -10°C for 1h, warmed to room temperature and stirred at this temperature for 5h. At this stage,¹⁹F NMR analysis was performed on a small sample, in the presence of PhOCF₃ as internal standard. Then, the crude mixture was hydrolyzed with 1N aqueous HCl until neutral. The aqueous phase was extracted with Et₂O. The combined organic phases were washed with brine then water and dried over Na₂SO₄. After filtration and concentration at roomtemperature in vacuo, chromatography on silicagel delivered the  trifluoromethyl carbinol in a 50% yield.

三氟乙醛與胺反應(yīng)生成的加成物經(jīng)叔丁醇鈉脫質(zhì)子化產(chǎn)生三氟甲基負(fù)離子的等價(jià)物CF₃CH(O^-)NMe₂,其與醛反應(yīng)能生成相應(yīng)的三氟甲基化產(chǎn)物但是產(chǎn)率較使用三氟甲烷偏低?，F(xiàn)代研究發(fā)現(xiàn)穩(wěn)定的三氟乙醛半縮醛胺23和它們的硅醚衍生物24在對(duì)非烯醇化的羰基化合物的三氟甲基化反應(yīng)中也是非常高效的三氟甲基化試劑。該反應(yīng)需要化學(xué)計(jì)量的強(qiáng)堿或催化量的氟負(fù)離子如CsF或者TBAT³。

示例：

Synthesis of 1-(4-Benzylpiperazino)-2,2,2-trifluoroethanol (1):

Molecular sieves (4A) and the methyl hemiketal of fluoral (12 g, 92 mmol) were added to a solution of N-benzylpiperazine (14.77 g, 84 mmol) in CH₂Cl₂(80 mL; dried over 4A molecular sieves). The reaction mixture was stirred at room temperature for 48 h then filtered and the solvent sevaporated in vacuo at room temperature. The residue was dissolved in CH₂Cl₂. Compound 1 was precipitated from this solution by addition of pentane to yield 17.56 g of a white solid (76%).

General Procedure for theTrifluoromethylation of 1:

In a two-necked flask 1 (0.548 g, 2 mmol), the carbonyl substrate (1 mmol) and dry THF (1 mL) were successively introduced, under nitrogen. After solubilization, ^tBuOK (2 mL of a 1 M solution in THF, 2 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. After reaction, ClSiMe₃ (0.5 mL) or aqueous 1 M HCl (1 mL) was dropped into the reaction mixture, which was then extracted twice with brine and ether. The combined organic layers were dried over Na₂SO₄ and evaporated in vacuo at room temperature. The crude residue was purified by flash chromatography. Eluents are indicated for each compound.

【參考文獻(xiàn)】

1.(a) Folle′as,B.; Marek, I.; Normant, J.F.; Saint-Jalmes, L. Tetrahedron Lett. 1998,    39, 2973-2976.

  (b) Russell,J.; Roques, N.Tetrahedron1998, 54,13771-13782.

  (c) Folle′as,B.; Marek, I.; Normant, J.F.; Saint-Jalmes,L. Tetrahedron 2000, 56,     275-283.

2. Large,S.; Roques,N.; Langlois, B.R. J. Org. Chem. 2000, 65, 8848-8856.

3.Billard, T.; Langlois, B. R.; Blond, G. Eur. J. Org. Chem. 2001,1467-1471.

來(lái)源：覽博網(wǎng)