新型三氟甲基化反应的研究及进展

介绍了新型三氟甲基化反应的特点、种类、应用及前景;综述了亲电三氟甲基化、亲核三氟甲基化和自由基三氟甲基化反应。     

Direct Trifluoromethylation of the C?H Bond

Trifluoromethylation meets C H activation: after transition metal‐catalyzed trifluoromethylation became more and more popular, trifluoromethylation via C H activation is now emerging as the latest attraction. Several pioneering examples and their mechanisms are discussed in this review.     

Trifluoromethylation by Visible-Light-Driven Photoredox Catalysis

The trifluoromethyl group widely prevails in pharmaceutical and agrochemical compounds, while accompanying by the development of new methodologies for trifluoromethylation. Recently, the radical trifluoromethylation by photoredox catalysis has emerged. This Article describes several pioneering works and their representative mechanisms via generation of the trifluoromethyl radical based on photoredox processes.     

烷基氯代物在光照下铜催化的三氟甲基化反应

在光照、铜(Ⅰ)催化剂和碱作用下,N,N-二甲基乙酰胺(DMAc)中烷基氯代物与三氟甲基三甲基硅烷反应,完成烷基氯代物的三氟甲基化。该合成方法高效,且避免了高温和有毒有害的反应条件。烷基氯代物的三氟甲基化有助于我们构建一种非活化C(sp~3)-CF_3键,具有十分重要的研究价值。     

Trifluoromethylation of 1‐Aryl‐3,3‐diisopropyltriazenes

A new method for the trifluoromethylation of functionalized aromatic diisopropyltriazenes is described. In a facile two‐step, one‐pot synthesis, various functionalized trifluoromethyl‐substituted arenes are accessible in mostly good yields by using methyl iodide as iodination agent and the trifluoromethylation system (trifluoromethyl)trimethylsilane/potassium fluoride/copper iodide. This concept could be expanded to perfluoroethylation as well as ethoxycarbonyldifluoromethylation reactions.     

Efficient Trifluoromethylation of Activated and Non‐Activated Alkenyl Halides by Using (Trifluoromethyl)trimethylsilane

An efficient method for the trifluoromethylation of halogenated double bonds by using in situ generated “trifluoromethyl copper” is described. Herein, the most common trifluoromethyl source, (trifluoromethyl)trimethylsilane, was converted selectively into “trifluoromethyl copper” by using copper iodide as copper source and potassium fluoride as promoter. In 1,3‐dimethyl‐3,4,5,6‐tetrahydro‐2(1H)‐pyrimidinone (DMPU) as chelating solvent the trifluoromethylation of activated and non‐activated alkenyl halides occurred mostly in good to excellent yields in up to a gram scale.     

Copper‐Catalyzed Aromatic Trifluoromethylation via Group Transfer from Fluoral Derivatives

Starting from a readily available fluoral derivative, catalytic aromatic trifluoromethylation has been successfully achieved. A small amount of copper(I) iodide‐phenanthroline complex catalyzed the cross‐coupling reactions of aryl/heteroaryl iodides with the O‐silylated hemiaminal of fluoral (trifluoroacetaldehyde) to provide trifluoromethylated arenes in moderate to high yields.     

三氟甲基苯的研究进展

三氟甲基苯是三氟甲基芳香化合物中最为重要的有机中间体之一,在含氟农药、含氟医药及含氟染料等方面有着重要的应用。选取三氟甲基苯作为对象,总结和阐述了近年来三氟甲基苯制备的研究进展。其制备可以通过苯环或卤代苯化合物与氟化试剂的三氟甲基化反应来实现。     

Nickel‐Catalyzed C–H Trifluoromethylation of Electron‐Rich Heteroarenes

The first example of a nickel‐catalyzed C–H trifluoromethylation of electron‐rich heteroarenes, including imidazopyridines, indoles and thiophenes, has been developed with the commercially available and relatively inexpensive industrial raw material iodotrifluoromethane (CF₃I) as the trifluoromethylating reagent. The synthetic potential of this method is demonstrated by its successful application to the direct trifluoromethylation of the biologically active molecules melatonin and zolmitriptan.

     

Practical Methods for the Synthesis of Trifluoromethylated Alkynes: Oxidative Trifluoromethylation of Copper Acetylides and Alkynes

Two practical and complementary methods are reported for the synthesis of trifluoromethylated alkynes. The first one, a mix‐and‐stir process, is based on the oxidative trifluoromethylation of readily available and bench‐stable copper acetylides while the second one, which displays a broad substrate scope and has several advantages over existing procedures, is based on the oxidative copper‐catalyzed direct trifluoromethylation of terminal alkynes. Both reactions provide user‐friendly processes for the synthesis of trifluoromethylated acetylenes which can be easily obtained from readily available starting materials.

     

Electro-organic reactions—VIII. The methylation and trifluoromethylation of pyridine by anodically generated radicals

A comparison of the anodic methylation and trifluoromethylation reactions of pyridine is drawn from the results of electrolyses of solutions of acetic and trifuoroacetic acids in aqueous pyridine. The anodically generated radicals are trapped inefficiently (3–20%) but the proportions of α, β, and γ-isomers are markedly dependent on the medium. The efficiency and positional selectivity of the nuclear substitution is rationalised in terms of the relative concentrations of pyridine and pyridinium ion and the likely role of the anode.     

Copper‐Catalyzed Divergent Trifluoromethylation/Cyclization of Unactivated Alkenes

Most of the precedent copper‐catalyzed trifluoromethylation reactions of unactivated alkenes concern terminal alkenes, and these processes are terminated in elimination, or nucleophilic addition, or semipinacol rearrangement, or C H bond functionalization steps. In this study, we develop a trifluoromethylation method for both unactivated terminal and internal alkenes to enable divergent late‐stage radical cyclization and achieve high molecular complexity. These cyclizations are well consistent with Baldwin’s rule. Furthermore, a kinetic isotope effect (KIE) study and control reactions were conducted, and a plausible mechanism is proposed.

     

Transition Metal‐Free Direct Trifluoromethylation of 2,3‐Dihydropyridin‐4(1H)‐ones at Room Temperature

A transition metal‐free, regioselective C‐5 trifluoromethylation of 2,3‐dihydropyridin‐4(1H)‐ones (cyclic enaminones) with trimethyl(trifluoromethyl)silane (TMSCF₃) was developed that proceeds under mild conditions at room temperature. This direct transformation was successful with both electron‐rich and electron‐deficient cyclic enaminones. This method bypasses substrate prefunctionalization and transition metal catalysis, and allows the convenient and direct access to a variety of medicinally important 3‐trifluoromethylpiperidine derivatives. This chemistry also represents a rare example of a direct trifluoromethylation of an internal olefinic C H bond. A radical mechanism is proposed for this reaction.

     

Transition Metal‐Free Trifluoromethylation of N‐Allylamides with Sodium Trifluoromethanesulfinate: Synthesis of Trifluoromethyl‐Containing Oxazolines

A transition metal‐free method for the trifluoromethylation of N‐allylamides has been developed, and the corresponding trifluoromethyl‐containing oxazolines were prepared in moderate to good yields. The protocol uses readily available substituted N‐allylamides as the starting materials, inexpensive and easily stored sodium trifluoromethanesulfinate as the trifluoromethyl source, iodobenzene diacetate as the oxidant, and the procedure involves sequential intermolecular trifluoromethylation of alkenes with sodium trifluoromethanesulfinate and intramolecular cyclization. This is the first example to prepare CF₃‐containing oxazolines. Therefore, the present method should afford an efficient and practical strategy for synthesis of other CF₃‐containing cyclic compounds.

     

分子噻蒽化修饰及偶联反应研究进展

噻蒽盐是近几年来研究较为热门的一个偶联模块,其具有制备简单、活性高、选择性好、转化模式多样等特点。该盐可通过多种未活化的芳烃或者烯烃与噻蒽亚砜直接噻蒽化合成,并可兼容多种官能团,尤其适合多种复杂分子的后期噻蒽化修饰,所得到的噻蒽盐结构可通过金属偶联以及光氧化还原偶联等模式引入多种重要官能团。综述了近3年噻蒽盐的发现及发展过程、制备及反应机制,以及利用其作为原料进行芳烃的三氟甲基化、羟基化、氨基化、氟化、硼基化以及硅基化等转化。     

Selective fluoroalkylations with fluorinated sulfones, sulfoxides, and sulfides

Efficient fluoroalkylations have been proven to be a highly useful strategy for the synthesis of bioactive fluorine-containing compounds and other materials. The design and use of a single category of reagents for multiple synthetic goals are much more attractive to preparative organic chemists. In this Account, we show how we have succeeded in the nucleophilic trifluoromethylation, difluoromethylation, difluoromethylenation, (phenylsulfonyl)difluoromethylation, (phenylthio)difluoromethylation, and monofluoromethylation as well as radical (phenylsulfonyl)difluoromethylation and electrophilic difluoromethylation by using fluorinated sulfones, sulfoxides, sulfides, or fluorinated sulfonium salts. The chemistry not only provides practically powerful synthetic methods, but the molecular design concept that we have developed may also be adopted to tackle other related chemical problems.     

不饱和腙类化合物的三氟甲基化反应

氟具有强的吸电子性、亲脂性,将含氟的取代基引入药物中能显著改变药物的药代动力学性质,包括极性、亲脂性、代谢稳定性等,因此向化合物中引入三氟甲基是近期有机合成及医药领域的热点,开发利用经济、高效、绿色的三氟甲基试剂具有重要的意义。以三氟甲烷亚磺酸钠为三氟甲基源,在温和的条件下实现不饱和腙类化合物的三氟甲基化。结果表明,三氟甲烷亚磺酸钠作为三氟甲基源具有良好的反应活性,反应条件温和,符合绿色化学要求,并提供了向不饱和腙类化合物引入三氟甲基的新方法。     

化学计量银促进的偶联反应研究进展

过渡金属银由于其催化反应符合绿色化学的原则,在有机合成中的应用成为近年来研究的热点。但实际上化学计量的银往往被作为助剂以提高金属离子的反应活性,而银化合物本身作为催化剂的应用却十分有限。针对此类问题,近年来的工作集中在利用银配合物的σ-和π-路易斯酸性研究银催化的反应。综述了银促进的偶联反应在C—P(N、S)键的形成和三氟甲基化反应研究中的应用和进展。     

Copper‐Catalyzed Trifluoromethylation of Acrylamides Coupled with Indole Dearomatization: Access to Trifluoromethyl‐Substituted Spiro[indole‐3,3′‐pyrrolidine] Derivatives

A copper‐catalyzed cascade reaction involving trifluoromethylation of acrylamides coupled with ring closure and indole dearomatization is reported. This facile transformation was highly regioselective and proceeded under mild conditions, allowing efficient access to trifluoromethyl‐substituted spiro[indole‐3,3′‐pyrrolidine] derivatives, which are of increasing interest to the pharmaceutical industry.

     

One‐Pot Sandmeyer Trifluoromethylation and Trifluoromethylthiolation

Practical one‐pot procedures were developed for both Sandmeyer‐type trifluoromethylations and trifluoromethylthiolations. Starting from broadly available (hetero)aromatic amines, various benzotrifluorides were synthesized in high yields via in situ diazotization and copper‐mediated trifluoromethylation using the inexpensive Ruppert–Prakash trifluoromethylating reagent. In the presence of sodium thiocyanate as a sulfur source, aryl trifluoromethyl thioethers are exclusively formed.