氟化方法前沿預(yù)覽
1. 脫羧氟化
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. 烯烴三氟甲基化 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. 芳雜環(huán)碳?xì)滏I三氟甲基化
之前我們介紹過(guò)芳雜環(huán)直接氟化法，主要為單氟取代，詳情請(qǐng)點(diǎn)擊：
芳雜環(huán)間接氟化法
接下來(lái)我們將介紹一下芳雜環(huán)碳?xì)滏I的三氟甲基化方法，并對(duì)常見(jiàn)的幾類方法進(jìn)行簡(jiǎn)單的匯總。
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(lái)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(gè)重要的課題。經(jīng)過(guò)多年的研究，已經(jīng)發(fā)展了許多引入三氟甲基的方法，近年來(lái)通過(guò)C-H鍵活化實(shí)現(xiàn)C-CF3的構(gòu)建成為研究的熱門方向。
示例1
2011年，Baran課題組報(bào)道了經(jīng)由三氟甲基自由基的含氮雜環(huán)碳?xì)滏I的直接三氟甲基化方法。該反應(yīng)在室溫下進(jìn)行，條件溫和，官能團(tuán)耐受性好，包括吡啶、吲哚、吡咯、吡嗪、嘧啶、咖啡因在內(nèi)的雜環(huán)都是合適的底物。該反應(yīng)使用Langlois試劑CF3SO2Na在氧化劑過(guò)氧叔丁醇存在下失去一分子二氧化硫產(chǎn)生三氟甲基自由基，再對(duì)雜環(huán)發(fā)生原子轉(zhuǎn)移/自由基加成形成中間體[ArHCF3]·以及被氧化劑過(guò)氧叔丁醇單電子氧化，失去質(zhì)子得到最終三氟甲基化的產(chǎn)物。該反應(yīng)使用的三氟甲基試劑和氧化劑都需要很大當(dāng)量，但由于這些試劑本身廉價(jià)易得，且反應(yīng)即使放大至克級(jí)，也能以較高的產(chǎn)率進(jìn)行，充分證明了該方法的實(shí)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，余金權(quán)課題組報(bào)道了鈀催化導(dǎo)向鄰位碳?xì)滏I活化構(gòu)筑C-CF3鍵。該反應(yīng)從二價(jià)鈀啟動(dòng)，在導(dǎo)向基團(tuán)吡啶的作用下形成二價(jià)環(huán)鈀物種，在親電型三氟甲基化試劑Umemoto試劑的作用氧化到高價(jià)鈀（三價(jià)鈀或四價(jià)鈀），并且形成Pd-CF3鍵，再還原消除得到鄰位三氟甲基化的產(chǎn)物。該反應(yīng)利用了高價(jià)鈀有利于芳基和三氟甲基之間的還原消除，但需要鄰位導(dǎo)向基團(tuán)極大地限制了這一反應(yīng)的應(yīng)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%).
芳雜環(huán)碳?xì)滏I三氟甲基化方法匯總
除了上述方式外，本文匯總了一些其他芳雜環(huán)碳?xì)滏I三氟甲基化方法供大家學(xué)習(xí)使用：
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