由于三氟甲基的強(qiáng)電負(fù)性，高穩(wěn)定性和良好的脂溶性，三氟甲基的引入，往往使化合物的性質(zhì)，特別是其生理活性發(fā)生顯著的改變，其在新藥開發(fā)中越來越被關(guān)注。所以如何將三氟甲基引入目標(biāo)分子，成為氟化學(xué)中的一個重要的課題。經(jīng)過多年的研究，已經(jīng)發(fā)展了許多引入三氟甲基的方法，按照反應(yīng)機(jī)理，脂肪族化合物中三氟甲基的引入主要分為三大類：脂肪族化合物的自由基三氟甲基化，親電三氟甲基化和親核三氟甲基化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過多種途徑得到，如在氧化，還原，光，熱以及電化學(xué)等條件下。多種分子已被用來作為三氟甲基自由基的前體。一般親電的三氟甲基自由基與富電子的芳環(huán)或芳雜環(huán)的反應(yīng)研究的更多一些2。在這部分，我們僅討論脂肪族化合物的自由基三氟甲基化。
三氟碘甲烷
最近報(bào)道了1, 3-二羰基化合物和三氟碘甲烷在連二亞硫酸鈉的存在下發(fā)生的烯醇銨鹽的自由基三氟甲基化3。
可能的反應(yīng)機(jī)理如下。首先亞磺酸自由基負(fù)離子與三氟碘甲烷反生單電子轉(zhuǎn)移生成親電性很強(qiáng)的三氟甲基自由基，該自由基與在含氮堿如三乙胺，二異丙胺以及DBU作用下生成的烯醇銨鹽反應(yīng)。
反應(yīng)實(shí)例：
Representative procedure of tri?uoromethylation of-ketoester b. To a two-neck ?ask 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 puri?ed by column chromatography to give compound 2b in 86% yield.
最近，Mikami報(bào)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。羰基化合物的烯醇鈦鹽由羰基化合物和LDA作用下或羰基化合物相對應(yīng)的烯醇硅醚和正丁基鋰的作用下生成。強(qiáng)堿性的烯醇鋰鹽也可應(yīng)用于自由基三氟甲基化反應(yīng)4。
反應(yīng)實(shí)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%).
【參考文獻(xiàn)】
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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