氟化方法前沿预览
1. 脱羧氟化
Decarboxylative Fluorination of Electron-Rich Heteroaromatic Carboxylic Acids with Selectfluor
Xi Yuan Jian-Fei Yao and Zhen-Yu Tang
Org. Lett. 2017, 19, 1410−1413
DOI: 10.1021/acs.orglett.7b00335
Abstract: A transition-metal-freedecarboxylative fluorination of electron-rich five-membered heteroaromatics,including furan-, pyrazole-, isoxazole-, thiophene-, indole-, benzofuran- and indazole carboxylicacids, with Selectfluor is reported. Fluorinated dimer products were observed fornitrogen-containing heteroaromatic carboxylic acids, such as indole andpyrazole. An effective method has been developed to synthesize the monomer of 2- and 3-fluoroindoles with Li2CO3 as base at low temperature.
Practical Access to Difluoromethyl Ketones via Straightforward Decarboxylative Difluorination of β-Ketoacids Yin-Long Li, Jian Li and Jun Deng Adv. Synth. Catal. 2017，Advance Article DOI: 10.1002/adsc.201601315 Abstract: A facile synthetic approach to aseries of difluoromethyl ketones from β-ketoacids has been described. This transformationis achieved through the straightforward decarboxylative difluorination of β-ketoacids in the absence of any catalyst. Furthermore, the resulted difluoromethyl ketones can be easily converted into corresponding difluoromethylated building blocks for pharmaceuticals and materials. 2. 烯烃三氟甲基化 Metal-free andlight-promoted radical iodotrifluoromethylation of alkenes with Togni reagentas the source of CF3 and iodine Redouane Beniazza, Maxime Douarre, Dominique Lastécouèresand Jean-Marc Vincent Chem. Commun., 2017, Advance Article DOI: 10.1039/C7CC00214A, Communication Abstract: A light-promoted methodology forthe iodotrifluoromethylation of alkenes was developped. For the first time the Togni reagent was exploited as the source of both the CF3 group andiodine atom. Preliminary mechanistic studies suggest that both CF3I and 2- iodobenzoic acid are direct sources of the iodine atom that is transferred to the products. 3. 吲哚烷基化 Cs2CO3-catalyzed alkylation ofindoles with trifluoromethyl ketones Xiao-DongLiu, Yi Wang, Hai-Yan Ma, Chun-Hui Xing, Yu Yuan, Long Lu Tetrahedron 73 (2017) 2283-2289 Doi：10.1016/j.tet.2017.03.012 Abstract: A Cs2CO3-catalyzedalkylation reaction of indoles with trifluoromethyl ketones was presented. Bothalicyclic and aromatic trifluoromethyl ketones as well as various substituted indoles are compatible with the methodology. Good to excellent yields of the corresponding trifluoromethyl substituted tertiary alcohols 2,2,2-tritrifluoro-1-(1H-indol-3-yl)-ethan-1-ols were acquired as the sole products. 芳杂环碳氢键三氟甲基化
之前我们介绍过芳杂环直接氟化法，主要为单氟取代，详情请点击：
芳杂环间接氟化法
接下来我们将介绍一下芳杂环碳氢键的三氟甲基化方法，并对常见的几类方法进行简单的汇总。
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，近年来通过C-H键活化实现C-CF3的构建成为研究的热门方向。
示例1
2011年，Baran课题组报道了经由三氟甲基自由基的含氮杂环碳氢键的直接三氟甲基化方法。该反应在室温下进行，条件温和，官能团耐受性好，包括吡啶、吲哚、吡咯、吡嗪、嘧啶、咖啡因在内的杂环都是合适的底物。该反应使用Langlois试剂CF3SO2Na在氧化剂过氧叔丁醇存在下失去一分子二氧化硫产生三氟甲基自由基，再对杂环发生原子转移/自由基加成形成中间体[ArHCF3]·以及被氧化剂过氧叔丁醇单电子氧化，失去质子得到最终三氟甲基化的产物。该反应使用的三氟甲基试剂和氧化剂都需要很大当量，但由于这些试剂本身廉价易得，且反应即使放大至克级，也能以较高的产率进行，充分证明了该方法的实用性。
Trifluoromethylation of Heterocycles: Standard Procedure.To a solution of heterocycle (0.25 mmol, 1.0 equiv) and sodium trifluoromethylsulfinate (117 mg, 0.75 mmol, 3.0 equiv) in dichloromethane (1.0 mL) and water (0.4 mL) at 0 ºC was slowly added tert-butyl hydroperoxide(70% solution in water, 0.17 mL, 1.25 mmol, 5.0 equiv) with vigorous stirring.The reaction was allowed to warm to room temperature and monitored by thin layer chromatography until completion. For substrates which do not go tocompletion in 24 h, a second addition of sodium trifluoromethylsulfinate (3.0 equiv) and tert-butyl hydroperoxide(5.0 equiv) may be added to drive the reaction towards completion. Upon consumption of starting material, the reaction was partitioned between dichloromethane (2.0 mL) and saturated sodium bicarbonate (2.0 mL). The organiclayer was separated, and the aqueous layer was extracted with dichloromethane (3 X 2.0 mL). The organic layers were dried with sodium sulfate, concentrated,and purified by column chromatography on silica gel.
示例2
2010年，余金权课题组报道了钯催化导向邻位碳氢键活化构筑C-CF3键。该反应从二价钯启动，在导向基团吡啶的作用下形成二价环钯物种，在亲电型三氟甲基化试剂Umemoto试剂的作用氧化到高价钯（三价钯或四价钯），并且形成Pd-CF3键，再还原消除得到邻位三氟甲基化的产物。该反应利用了高价钯有利于芳基和三氟甲基之间的还原消除，但需要邻位导向基团极大地限制了这一反应的应用。
General Procedure for Pd(OAc)2-Catalyzed ortho-trifluoromethylation:
In a 20 mL sealed tube, 2-phenyl pyridine 2a (0.2 mmol, 1.0 equiv.), Pd(OAc)2 (4.5mg, 0.02 mmol, 0.1 equiv.), Cu(OAc)2 (36.3 mg, 0.2 mmol, 1.0 equiv.)and 5-(Trifluoromethyl)-dibenzothiophenium tetrafluoroborate 1b (102.0mg, 0.3 mmol, 1.5equiv.) were dissolved in 1.0 mL dry dichloroethane under air, and then trifluoroacetic acid (148.6 μl, 2.0 mmol, 10 equiv.) was added. The tube was sealed with a Teflon lined cap and the reaction mixture was stirred at 110 °C for 48hours. After cooling to room temperature, the mixture was quenched with aqueous NaOH (2 N, 8 mL) and saturated Na2S solvent (8 mL), and extracted with dichloromethane (15 mL × 3) carefully. The solvent was removed under vacuum and the residue was purified by column chromatography on silicagel with a gradient eluant of hexane and ethyl acetate to afford product 3a(yield 50%).
芳杂环碳氢键三氟甲基化方法汇总
除了上述方式外，本文汇总了一些其他芳杂环碳氢键三氟甲基化方法供大家学习使用：
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