Trifluoromethylation Reactions Research Articles

CuCF3 mediated deoxyfluorination of redox-active esters

Trifluoromethyl copper (CuCF3), as a diverse fluorination reagent, has been widely used in trifluoromethylation, perfluoroalkylation, and difluorocarbene reactions. However, it has rarely been reported as a single fluorine source involved in nucleophilic fluorination reactions. This work describes a general strategy involving copper-mediated deoxyfluorination of redox-active esters to rapidly access various aliphatic and aromatic acyl fluorides. The highly active CuF species could be generated from either copper fluoride salts or CuCF3. A plausible mechanism of CuCF3 forming an [F-CuCF2F5]- intermediate and NHBC ester forming acyl fluoride has been derived from DFT calculations.

Regioselective C-H Trifluoromethylation and Its Related Reactions of (Hetero)aromatic Compounds.

Fluorinated functional groups, including trifluoromethyl group, play important roles in the development of drugs, agrochemicals, and organic functional materials. Therefore, the development of highly effective and practical reactions to introduce fluorinated functional groups into (hetero)aromatic compounds is highly desirable. We have achieved several regioselective C-H trifluoromethylation and related reactions by electrophilic and nucleophilic activation of six-membered heteroaromatic compounds and steric protection of aromatic compounds. These reactions proceed in good to excellent yields, even on a gram scale, with high functional group tolerance, and are applicable to the regioselective trifluoromethylation of drug molecules. In this personal account, the background of the introduction reactions of fluorinated functional groups, our reaction designs to achieve regioselective C-H trifluoromethylation and the related reactions of (hetero)aromatic compounds are explained.

Recent Advances in the Trifluoromethylation Reactions of Isonitriles To Construct CF3-Substituted N-Heterocycles

AbstractDue to the increasing need for fluorine-containing drugs, the synthesis of organofluorine scaffolds has become a highly researched area of synthetic organic chemistry. The introduction of the trifluoromethyl group into the structure of an organic molecule has considerable potential and several advantages concerning the characteristics of the fluorinated pharmaceuticals. The incorporation of a CF3 group at multiple bonds containing a nitrogen heteroatom is a relatively new field and currently it is an expanding area of synthetic chemistry. This short review summarizes, for the first time, recent developments in trifluoromethylation reactions of isonitriles.1 Introduction2 Trifluoromethylation Reactions of Isonitriles2.1 Synthesis of Trifluoromethylated Phenanthridine Derivatives2.2 Synthesis of Trifluoromethylated Quinoline Derivatives2.3 Synthesis of Trifluoromethylated Isoquinoline Derivatives2.4 Synthesis of Trifluoromethylated Indole Derivatives2.5 Synthesis of Trifluoromethylated Pyridine Derivatives3 Summary and Outlook

Visible-Light-Mediated Deacylated Alkynylation of Unstrained Ketone.

Deconstructive alkynylation of an unstrained ketone catalyzed by an organic photocatalyst under blue light irradiation is reported for the first time. A broad substrate scope with up to 63 examples, excellent functional group tolerance, and gram scale reaction demonstrated the practicality of this novel alkynylation method. The dihydroquinazolinone derivative of trifluoroacetophenone had been proved to have potential as a novel trifluoromethylation reagent after working well for the trifluoromethylation reaction with various alkynyl bromides.

Carbotrifluoromethylations of C-C Multiple Bonds (Excluding Aryl- and Alkynyltrifluoromethylations).

Organofluorine chemistry has become an expanding area of research in organic chemistry and drug design. The synthesis of fluorine-containing molecules has received high significance in synthetic chemistry. Trifluoromethylative difunctionalizations of carbon-carbon multiple bonds with the simultaneous introduction of a CF3 group and another function have considerable relevance. Because of the high importance of carbon-carbon bond-forming reactions in organic synthesis, carbotrifluoromethylations are considered to be a field of synthetic chemistry of increasing importance. Our current goal in this review is to summarize recent developments of various trifluoromethylation reactions (excluding aryl- and alkynyl-trifluoromethylations) taking into consideration several main approaches, such as alkenyltrifluoromethylation, alkyltrifluoromethylation, carbonyltrifluoromethylation, and cyanotrifluoromethylation reactions.

Electron-Deficient Fluoroarene-Mediated Synthesis of Trifluoromethyl Ketones from Carboxylic Acids.

Fluoroarene-mediated trifluoromethylation of carboxylic acids for the synthesis of trifluoromethyl ketones is disclosed. The fluoroarene activates the acid group and generates the fluoride source in situ for the trifluoromethylation reaction. The present protocol is safe and metal-free, operates under mild reaction conditions, and does not require any external additives to generate trifluoromethyl anion. The current transformation provides good functional group tolerance and also delivers 92% and 88% yields of trifluoromethyl ketones in batch and continuous flow, respectively.

Enhanced Energy Transfer in A π‐Conjugated Covalent Organic Framework Facilitates Excited‐State Nickel Catalysis

AbstractCovalent organic frameworks (COFs) have received broad interest owing to their permanent porosity, high stability, and tunable functionalities. COFs with long‐range π‐conjugation and photosensitizing building blocks have been explored for sustainable photocatalysis. Herein, we report the first example of COF‐based energy transfer Ni catalysis. A pyrene‐based COF with sp2 carbon‐conjugation was synthesized and used to coordinate NiII centers through bipyridine moieties. Under light irradiation, enhanced energy transfer in the COF facilitated the excitation of Ni centers to catalyze borylation and trifluoromethylation reactions of aryl halides. The COF showed two orders of magnitude higher efficiency in these reactions than its homogeneous control and could be recovered and reused without significant loss of catalytic activity.

Enhanced Energy Transfer in A π-Conjugated Covalent Organic Framework Facilitates Excited-State Nickel Catalysis.

Covalent organic frameworks (COFs) have received broad interest owing to their permanent porosity, high stability, and tunable functionalities. COFs with long-range π-conjugation and photosensitizing building blocks have been explored for sustainable photocatalysis. Herein, we report the first example of COF-based energy transfer Ni catalysis. A pyrene-based COF with sp2 carbon-conjugation was synthesized and used to coordinate NiII centers through bipyridine moieties. Under light irradiation, enhanced energy transfer in the COF facilitated the excitation of Ni centers to catalyze borylation and trifluoromethylation reactions of aryl halides. The COF showed two orders of magnitude higher efficiency in these reactions than its homogeneous control and could be recovered and reused without significant loss of catalytic activity.

Arene C–H bond trifluoromethylation reactions involving different high valent arylcopper intermediates

在温和的铜盐促进反应条件下，四氮杂杯[1]芳烃[3]吡啶化合物发生高效、高选择性芳香碳氢键三氟甲基化反应，高产率地生成一系列三氟甲基官能化的大环分子。基于结构明确的芳基二价铜和芳基三价铜的三氟甲基化反应的结果，铜促进的芳香碳氢键三氟甲基化反应的途径依据三氟甲基化试剂的性质经历了两条完全不同的途径。当使用亲核性的Ruppert-Prakash试剂时，芳基三价铜与三氟甲基阴离子生成[ArCu(III)CF3]+配合物及发生还原消除是反应的关键步，而当使用亲电性的Umemoto试剂时，反应经历了芳基二价铜与三氟甲基自由基的直接偶联过程。

Using fluoroform in trifluoromethylation reactions

Fluoroform (CF3H), a large-volume industrial by-product and potent greenhouse gas, has emerged as an attractive CF3 source for the development of trifluoromethylation reagents and reactions. This article highlights the recent reports since 2017 on the use of fluoroform in organic synthesis. Topics include direct trifluoromethylation facilitated by organic and inorganic bases, preparation of trifluoromethylation reagents based on transition metals and borazine, and radiolabelled fluoroform.

Reduction of SF5CF3via iridium catalysis: radical trifluoromethylation of aromatics.

The greenhouse gas SF5CF3 acts as CF3 source for the photocatalytic trifluoromethylation of arenes on using [Ir(dtbbpy)(ppy)2]PF6 (4,4'-di-tert-butyl-2,2'-dipyridyl, ppy = 2-phenylpyridine) as catalyst. The trifluoromethylation of C6D6 in the presence of 1-octanol results in the concomitant generation of 1-fluorooctane, presumably by intermediate SF4.

Direct Arene Trifluoromethylation Enabled by a High‐Valent CuIII−CF3Compound

AbstractDirect C−H trifluoromethylation of arenes and heteroarenes poses an important synthetic challenge that is highly desirable. High‐valent CuIII−CF3compounds have often been invoked in copper‐mediated trifluoromethylation reactions, but the fundamental reactivity toward arenes is elusive. Herein, direct C−H trifluoromethylation of arenes/heteroarenes by a high‐valent CuIII−CF3compound is disclosed for the first time. The CuIII−CF3compound serves CF3radical and a CuIIoxidant by homolytic cleavage of a CuIII−CF3bond, which engage synergistically in a SEAr type reaction with arenes. The presence of K2S2O8co‐oxidant can significantly improve the reaction yields. This reaction shows good efficiency, broad functional group tolerance, and the potential in late‐stage functionalization. The reactivity of high‐valent CuIII−CF3compounds disclosed in this study represents an important progress in organofluorine and CuIIIchemistry.

Direct Arene Trifluoromethylation Enabled by a High-Valent CuIII -CF3 Compound.

Direct C-H trifluoromethylation of arenes and heteroarenes poses an important synthetic challenge that is highly desirable. High-valent CuIII -CF3 compounds have often been invoked in copper-mediated trifluoromethylation reactions, but the fundamental reactivity toward arenes is elusive. Herein, direct C-H trifluoromethylation of arenes/heteroarenes by a high-valent CuIII -CF3 compound is disclosed for the first time. The CuIII -CF3 compound serves CF3 radical and a CuII oxidant by homolytic cleavage of a CuIII -CF3 bond, which engage synergistically in a SE Ar type reaction with arenes. The presence of K2 S2 O8 co-oxidant can significantly improve the reaction yields. This reaction shows good efficiency, broad functional group tolerance, and the potential in late-stage functionalization. The reactivity of high-valent CuIII -CF3 compounds disclosed in this study represents an important progress in organofluorine and CuIII chemistry.

Advances in the Transition Metal‐Free C—H Trifluoromethylation

Comprehensive SummaryTrifluoromethyl group is one of the most frequently available and promising functional groups in pharmaceutical, agrochemical as well as material molecules. Developing synthetic methods for the synthesis of trifluoromethyl functionalized compounds by trifluoromethylation reactions occupies significant position in modern organic chemistry. On the other hand, as a typical tool of sustainable synthesis, transition metal‐free synthesis possesses unique advantages in atom economy, easy product purification as well as excellent eco‐tolerance. Consequently, transition metal‐free trifluoromethylation reactions constitute the most important approaches for accessing trifluoromethylated molecules. Herein, the advances in the transition metal‐free C—H trifluoromethylation reactions are reviewed for the first time. According to the updated state‐of‐art, both the catalytic reactions by conventional heating chemistry and the more sustainable photocatalysis are included, covering the trifluoromethylation reactions of C(sp3)–H bond, aromatic C(sp2)–H bond as well as the non‐aromatic C(sp2)–H bond in different substrates over the last five years (2017—2021).

Visible-Light-Induced Photocatalyst-Free Radical Trifluoromethylation.

An attractive, versatile, and operationally simple, visible-light-induced, transition-metal-free, photocatalyst-free, and oxidant-free trifluoromethylation has been demonstrated. Triflic anhydride (Tf2O), being inexpensive and readily available, was chosen as the radical trifluoromethyl source. Thianthrene was used as a recyclable Tf2O-activating reagent, and a high-yielding and scalable trifluoromethylation reaction was achieved. Density functional theory and mechanistic studies showed that a free radical homolytic process excited by visible light is involved in this reaction, generating a key trifluoromethyl radical intermediate.

Photocatalytic fluoroalkylations of (hetero)arenes enabled by the acid-triggered reactivity umpolung of acetoxime esters

The importance of trifluoromethyl (CF 3 ) group-containing compounds in pharmaceuticals, agrochemicals, and materials has spurred tremendous efforts devoted to the development of methods for incorporation of the trifluoromethyl group into molecular frameworks and discoveries of trifluoromethylating reagents. In this paper, we report a general photocatalytic method for regioselective C–H fluoroalkylation of (hetero)arenes and olefines that uses readily available fluoroalkyl carboxylic anhydrides as fluoroalkylating reagents in the presence of simple acetoxime as an activator. The success achieved in the development of such a photocatalytic C–H fluoroalkylation method is attributed to discovery of the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward single-electron reduction-induced cleavage of N–O σ bond. Such a new reactivity mode of oxime esters will stimulate efforts to expand the synthetic applications of readily available oxime esters. • The unprecedented acid-triggered reactivity umpolung of acetoxime ester • Photocatalytic method for C–H fluoroalkylation of (hetero)arenes and olefines • Inexpensive and easily available fluoroalkyl carboxylic anhydrides • Simple acetoxime as an efficient activator to fluoroalkyl carboxylic anhydrides Over the past decades, considerable efforts have been devoted toward exploring readily available trifluoroacetic acid or its anhydride as a CF 3 source for trifluoromethylation reactions. Herein, a general photocatalytic method was developed for fluoroalkylation of arenes and aromatic heterocycles with fluoroalkyl carboxylic anhydrides using simple acetoxime as the activator. The established conditions were also applicable to oxytrifluoromethylation and intramolecular carbotrifluoromethylation of alkenes, and the modification of biologically active molecules and gram-scale synthesis further highlighted its potential utility. Compared with the fact that single-electron transfer (SET) reduction of oxime trifluoroacetate esters generates preferentially iminyl radical and stable trifluoroacetate anions, our work discovered the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward delivering a CF 3 radical. An ongoing challenge in trifluoromethylation reaction is the use of less expensive and more practical trifluoromethyl sources. We describe herein a general photocatalytic method for regioselective C–H fluoroalkylation of (hetero)arenes and olefines that uses readily available fluoroalkyl carboxylic anhydrides as fluoroalkylating reagents in the presence of simple acetoxime as an activator. The success achieved in the development of such a method is attributed to the discovery of the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward single-electron reduction-induced cleavage of N–O σ bond.

Direct Perfluoroalkylation of C-H Bonds in (Hetero)arenes.

Perfluoroalkylated (hetero)arenes represent an extremely important family of molecules commonly utilized in many areas such as medicinal chemistry, agrochemistry and material sciences. Due to their unique properties, they have attracted significant interest from synthetic chemists and various methods have been developed for their synthesis. Among them, the direct perfluoroalkylation of C(sp2 )-H bonds in (hetero)arenes is one of the most attractive and straightforward ones, provided that it proceeds with high levels of regioselectivity. In this review article, a comprehensive overview of advances in this field is presented, with a special focus on the reaction mechanisms involved in these transformations and their regioselectivity. All methods available have been classified according to the nature of the perfluoroalkyl chain introduced, trifluoromethylation reactions being overviewed in a separate section, and to the nature of the reagents/catalysts required.

Acetic acid-promoted photoredox catalyzed trifluoromethylation of aldehyde hydrazones

Radical C(sp2)-H trifluoromethylation of aromatic aldehyde hydrazones is achieved in moderate to high yields under oxidative photoredox catalysis conditions, using inexpensive, bench-stable sodium trifluoromethanesulfinate (Langlois reagent), and Rose Bengal (RB) as the photocatalyst in the presence of acetic acid as the promoter. Acetic acid accelerates the rates of trifluoromethylation reactions and substantially attenuates the formation of the adventitious byproducts.

Synthesis of 5-Trifluoromethyl-Substituted (Z)-N,N-Dimethyl-N′-(pyrazin-2-yl)formimidamides from 2-Aminopyrazines, LiI/Selectfluor, FSO2CF2CO2Me and DMF under Cu Catalysis

AbstractThe synthesis of 5-trifluoromethyl-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides via the iodination of 2-aminopyrazines with Selectfluor/LiI followed by a domino trifluoromethylation with FSO2CF2CO2Me and a condensation with DMF in the presence of CuI is realized under mild conditions. This three-step method offers CF3-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides in yields of 55–70% and with high regioselectivities. LiI serves as an iodine source, whilst DMF functions as both a solvent and a condensation reagent. The regioselectivity of these trifluoromethylation reactions is strongly dependent upon the substituent pattern on the 2-aminopyrazines. A possible mechanism for this method is also discussed.

New Avenues in Copper-Mediated Trifluoromethylation Reactions Using Fluoroform as the CF3 Source

AbstractOrganic molecules containing the trifluoromethyl (CF3) group play a vital role in pharmaceuticals, agrochemicals, and materials. New trifluoromethylation methods should encompass capabilities to address issues in efficiency, selectivity, and CF3 source all at once. Fluoroform (CF3H), an industrial byproduct, has emerged as an attractive CF3 source. The reaction profile of the [CuCF3] reagent derived from fluo­roform has surpassed its original applications in cross-coupling-type trifluoromethylation. We have discovered a host of unique copper-mediated trifluoromethylation reactions using [CuCF3] from fluoroform, especially under oxidative conditions, to deliver efficient and selective synthesis of trifluoromethylated compounds.1 Introduction2 Construction of C–CF3 Bonds for the Synthesis of Trifluoromethylated Building Blocks2.1 C(sp)–CF3 Bond Formation2.2 C(sp2)–CF3 Bond Formation2.3 C(sp3)–CF3 Bond Formation3 Domino Synthesis of Trifluoromethylated Heterocycles3.1 3-(Trifluoromethyl)indoles3.2 3-(Trifluoromethyl)benzofurans3.3 2-(Trifluoromethyl)indoles4 Trifluoromethylative Difunctionalization of Arynes4.1 Trifluoromethylation–Allylation of Arynes4.2 1,2-Bis(trifluoromethylation) of Arynes5 Pentafluoroethylation of Unactivated Alkenes6 Conclusion