由于三氟甲基的强电负性，高稳定性和良好的脂溶性，三氟甲基的引入，往往使化合物的性质，特别是其生理活性发生显著的改变，其在新药开发中越来越被关注。所以如何将三氟甲基引入目标分子，成为氟化学中的一个重要的课题。经过多年的研究，已经发展了许多引入三氟甲基的方法，按照反应机理，脂肪族化合物中三氟甲基的引入主要分为三大类：脂肪族化合物的自由基三氟甲基化，亲电三氟甲基化和亲核三氟甲基化1。
脂肪族化合物的自由基三氟甲基化
三氟甲基自由基能通过多种途径得到，如在氧化，还原，光，热以及电化学等条件下。多种分子已被用来作为三氟甲基自由基的前体。一般亲电的三氟甲基自由基与富电子的芳环或芳杂环的反应研究的更多一些2。在这部分，我们仅讨论脂肪族化合物的自由基三氟甲基化。
三氟碘甲烷
最近报道了1, 3-二羰基化合物和三氟碘甲烷在连二亚硫酸钠的存在下发生的烯醇铵盐的自由基三氟甲基化3。
可能的反应机理如下。首先亚磺酸自由基负离子与三氟碘甲烷反生单电子转移生成亲电性很强的三氟甲基自由基，该自由基与在含氮碱如三乙胺，二异丙胺以及DBU作用下生成的烯醇铵盐反应。
反应实例：
Representative procedure of trifluoromethylation of-ketoester b. To a two-neck flask equipped with septum and magnetic stirrer were added 1b(0.53 mmol, 108.2 mg), DBU(1.06 mmol, 161.4 mg) and CH3CN(3 mL). The solution was stirred for 15 min at room temperature and then was cooled to -30 oC and CF3I(3 equiv, 588 mg) was added under vacuum via a syringe. A solution of sodium dithionite(0.53mmol, 92.3mg) in 2 mL of H2O was added and the mixture was warmed to room temperature and stirred for 1h. The end of reaction was monitored by TLC(hexane/ethylacetate = 8/1). The reaction mixture was diluted with 10 mL water and extracted with CH2Cl2(3×10 mL). The organic layer was dried over MgSO4 and evaporated under vacuum. The residue was purified by column chromatography to give compound 2b in 86% yield.
最近，Mikami报道了在三氟碘甲烷和三乙基硼烷作用下羰基化合物的α位自由基三氟甲基化。羰基化合物的烯醇钛盐由羰基化合物和LDA作用下或羰基化合物相对应的烯醇硅醚和正丁基锂的作用下生成。强碱性的烯醇锂盐也可应用于自由基三氟甲基化反应4。
反应实例：
Typical Experimental Procedurefor Radical trifluoromethylation of Lithium Enolate.
To a solution of iPr2NH(28.0μL, 0.20 mmol) in THF (2.0mL) was added nBuLi (126.3 μL of 1.58 M solution in hexane, 0.20 mmol) at -78 oC. The reaction mixture was stirred at 0 oC for 30 min and then cooled to -78 oC. To the solution was added cyclohexanone(20.7 μL, 0.2 mmol), and the mixture was stirred for 60min at the temperature. Then, gaseous CF3I (ca. 200 mg, ca.1.0 mmol) was added with a cannula. Next, a syringe, which was filled with 0.12 mL of 5 M solution of aceticacid in THF, was set to the reaction vessel and kept untouching till quenching the reaction. Then Et3B (0.2 mL of 1.0 M solution inhexane, 0.2 mmol) was added in 15 s to start the radical addition reaction. The reaction mixture was immediately quenched (in ~1 s) by acetic acid solution, which was set before hand, at -78 oC. After warming to room temperature, BTF (10 μL, 0.082 mmol) was added as an internal standard. The yield was determined by 19F NMR of the crude mixture (81%).
【参考文献】
1. (a) Trifluoromethylationsand Related Reactions in Organic Chemistry, McClinton, D. A. Tetrahedron. 1992, 48,6555-6666.
(b) Ma, J. A.; Cahard, D. J. Fluo. Chem.2007, 128, 975-996.
2. McClinton, M.A.; McClinton,D.A.Tetrahedron1992, 48, 6555-6666.
3. Petrik, V.; Cahard, D.Tetrahedron Lett. 2007, 48, 3327-3330.
4. (a) Itoh,Y.; Mikami,K.Org. Lett. 2005, 7, 4883-4885.
(b) Mikami, K.; Itoh,Y.Chem. Rec. 2006,6, 1-11.
(c) Itoh,Y.;Houk,K.N.; Mikami,K.J. Org. Chem. 2006, 71, 8918-8925.
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