三氟甲烷
三氟甲烷是一种廉价且对环境无害的试剂。常见的碱如叔丁醇钾可使三氟甲烷脱质子化生成三氟甲基负离子1。在该反应中DMF具有溶剂和负离子稳定剂的双重功能。形成的中间体22是一修饰化的相当稳定的三氟甲基负离子的形式，其功能相当与三氟甲基的“存储器”。真正的三氟甲基化试剂是CF3-/DMF加成物，该试剂适用于非烯醇化的醛时比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.
三氟乙酰胺以及三氟甲磺酰胺衍生物
三氟乙醛与胺反应生成的加成物经叔丁醇钠脱质子化产生三氟甲基负离子的等价物CF3CH(O-)NMe2,其与醛反应能生成相应的三氟甲基化产物但是产率较使用三氟甲烷偏低。现代研究发现稳定的三氟乙醛半缩醛胺23和它们的硅醚衍生物24在对非烯醇化的羰基化合物的三氟甲基化反应中也是非常高效的三氟甲基化试剂。该反应需要化学计量的强碱或催化量的氟负离子如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.
【参考文献】
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.
