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In this study high‐valent Cu(III) trifluoromethyl compounds in combination with DMSO is shown to be an efficient and mild oxidizing system for the conversion of alcohols to ketones (aldehydes as well). Trifluoromethoxylated sulfonium species is proposed to be initially formed that engages in crucial steps of alkoxy replacement at sulfonium center and deprotonative collapse of the resulting alkoxysulfonium intermediate in the presence of a base. This reaction is highly selective without over‐oxidation, and can tolerate a broad range of functional groups owing to mild oxidizing ability of the Cu(III)‐CF3/DMSO system and the inert N2 conditions. This method can be applied to the synthesis and functionalization of commercial drug compounds. This study illustrates an unusual reactivity property of high‐valent Cu(III) trifluoromethyl compounds beyond the conventional CF3 group transfer reactivity, and opens up new opportunities for developing novel reactions of Cu(III)‐CF3 compounds. The combined use of high‐valent Cu(III)‐CF3 compound and DMSO is anticipated to find more applications to develop other novel and useful oxidation reactions. [ABSTRACT FROM AUTHOR]

The selective C−F bonds functionalization in available trifluoromethyl compounds is an economic route for obtaining high‐value organic fluorine compounds. However, due to the high C−F bonds dissociation energy in trifluoromethyl group, the strength of the bond decreases continuously during defluorination, posing a challenge in modifying such molecules without over‐conversion. Over the past few years, there has been significant progress in developing efficient methods for constructing difluoromethylene unit, using approaches such as radical chemistry, photochemistry, electrochemistry, and organometallic chemistry. These methods involve difluorocarbon radicals, difluorocarbon cations, difluorocarbon anions, and trifluoromethyl carbenes as intermediates. In this review, we summarized the recent five years of research achievements in this field for selective single C−F bond cleavage in trifluoromethyl aromatic and carbonyl compounds to gain diverse difluoromethylene‐containing organic molecules via different intermediate strategies. [ABSTRACT FROM AUTHOR]

A robust and practical difluoroalkylation synthon, α,α‐difluoroenol species, which generated in situ from trifluoromethyl diazo compounds and water in the presence of dirhodium complex, is disclosed. As compared to the presynthesized difluoroenoxysilane and in situ formed difluoroenolate under basic conditions, this difluoroenol intermediate displayed versatile reactivity, resulting in dramatically improved enantioselectivity under mild conditions. As demonstrated in catalytic asymmetric aldol reaction and Mannich reactions with ketones or imines in the presence of chiral organocatalysts, quinine‐derived urea, and chiral phosphoric acid (CPA), respectively, this relay catalysis strategy provides an effective platform for applying asymmetric fluorination chemistry. Moreover, this method features a novel 1,2‐difunctionalization process via installation of a carbonyl motif and an alkyl group on two vicinal carbons, which is a complementary protocol to the metal carbene gem‐difunctionalization reaction. [ABSTRACT FROM AUTHOR]

The introduction of trifluoromethyl groups into organic molecules is of paramount importance in modern synthetic chemistry and medicinal chemistry. While methods for constructing C(sp2)−CF3 bonds have been well established, the advancement of practical and comprehensive approaches for forming C(sp3)−CF3 bonds remains considerably restricted. In this work, we describe an efficient and site‐specific deaminative trifluoromethylation reaction of aliphatic primary amines to afford the corresponding alkyl trifluoromethyl compounds. The reaction proceeds at room temperature with readily accessible N‐anomeric amide (Levin's reagent) and bench‐stable bpyCu(CF3)3 (Grushin's reagent, bpy=2,2′‐bipyridine) under blue light. The protocol features mild reaction conditions, good functional group tolerance, and moderate to good yields. Remarkably, the method can be applied to the direct, late‐stage trifluoromethylation of natural products and bioactive molecules. Experimental mechanistic studies were conducted, and a radical mechanism is proposed, wherein the dual roles of Grushin's reagent have been elucidated. [ABSTRACT FROM AUTHOR]

The introduction of trifluoromethyl groups into organic molecules is of paramount importance in modern synthetic chemistry and medicinal chemistry. While methods for constructing C(sp2)−CF3 bonds have been well established, the advancement of practical and comprehensive approaches for forming C(sp3)−CF3 bonds remains considerably restricted. In this work, we describe an efficient and site‐specific deaminative trifluoromethylation reaction of aliphatic primary amines to afford the corresponding alkyl trifluoromethyl compounds. The reaction proceeds at room temperature with readily accessible N‐anomeric amide (Levin's reagent) and bench‐stable bpyCu(CF3)3 (Grushin's reagent, bpy=2,2′‐bipyridine) under blue light. The protocol features mild reaction conditions, good functional group tolerance, and moderate to good yields. Remarkably, the method can be applied to the direct, late‐stage trifluoromethylation of natural products and bioactive molecules. Experimental mechanistic studies were conducted, and a radical mechanism is proposed, wherein the dual roles of Grushin's reagent have been elucidated. [ABSTRACT FROM AUTHOR]

We herein describe a protocol to synthesize trifluoromethylated alkyl boronates from alkenes by the mutual activation of the Togni II and the bis(catecholato)diboron reagents in the absence of any catalyst and additives. This reaction enables synthesizing a series of trifluoromethylated alkyl boronates using unactivated alkenes, including natural products and drug derivatives, in a regioselective manner. Moreover, the synthetic utility of the boronic ester present in the product allows access to a range of trifluoromethyl containing compounds. The radical trapping and gas detection experiments reveal that the more Lewis acidic diboron reagent determines the rapid formation of trifluoromethyl and boron centered radicals. [ABSTRACT FROM AUTHOR]

The use of trifluoromethyl containing compounds is well established within medicinal chemistry, with a range of approved drugs containing C−CF3 and O−CF3 moieties. However, the utilisation of the N−CF3 functional group remains relatively unexplored. This may be attributed to the challenging synthesis of this unit, with many current methods employing harsh conditions or less accessible reagents. A robust methodology for the N‐trifluoromethylation of secondary amines has been developed, which employs an umpolung strategy in the form of a copper‐catalysed electrophilic amination. The method is operationally simple, uses mild, inexpensive reagents, and has been used to synthesise a range of novel, structurally complex N−CF3 containing compounds. [ABSTRACT FROM AUTHOR]

Single C−F transformations of aromatic trifluoromethyl compounds are challenging issues due to the strong C−F bond. We have recently developed selective methods for single C−F transformations such as allylation of o‐hydrosilyl‐substituted benzotrifluorides through the hydride abstraction with trityl cations. Single C−F thiolation and azidation of o‐(hydrosilyl)benzotrifluorides were achieved using trityl sulfides and trityl azide catalyzed by Yb(OTf)3. Treatment of o‐(hydrosilyl)benzotrifluorides with trityl chloride resulted in single C−F chlorination. The resulting fluorosilyl group served in further transformations including protonation, halogenation, and Hiyama cross‐coupling with C−Si cleavage. We also synthesized benzyl fluorides by LiAlH4‐reduction of the resulting fluorosilanes and further C−F transformations. These methods enabled us to prepare a broad range of organofluorines from simple benzotrifluorides through C−F and C−Si transformations. [ABSTRACT FROM AUTHOR]

This account summarizes our recent efforts in the enantioselective organocatalytic synthesis of chiral halogenated compounds. The enantioselective α‐halogenation of aldehydes, decarboxylative chlorination of β‐keto acids, and enantioselective C−C bond formation at the trifluoromethylated prochiral carbon to yield the corresponding organohalides with chlorinated, fluorinated, or trifluoromethylated chiral stereogenic centers are discussed. We applied common organocatalysts, such as Jørgensen‐Hayashi catalyst and cinchona alkaloid‐derivatived catalyst, and developed novel chiral amine catalysts for these reactions. This account also discusses stereospecific derivatizations of the resulting chiral halogenated compounds via nucleophilic substitution. Thus, we synthesized many novel chiral compounds that have not been reported, even as racemates. [ABSTRACT FROM AUTHOR]

This study reports reactivity properties of Cu(III)−CF3 compounds with anilines, wherein basicity‐dictated distinct reactivities are achieved, giving rise to formamides or hydrazines. Competing generation of difluorocarbene and N‐centered radical is proposed that is controlled by the basicity of the reaction solution. Specifically, under acidic or neutral conditions, reaction of anilines with Cu(III)−CF3 compounds produces formamides, where difluorocarbene is involved, undergoing aniline formylation. In contrast, in the presence of a base, this same reaction selectively gives hydrazines instead, where Cu(III)−CF3 compounds act as an oxidizing reagent to allow dehydrogenative N−H/N−H coupling of two anilines through an N‐centered radical. The scope of both reactions is studied, and application to medicinally relevant compounds is shown. This study shows the unusual use of high‐valent Cu(III) trifluoromethyl compounds as hydrogen‐abstracting reagents to allow dehydrogenative reactions. [ABSTRACT FROM AUTHOR]

The difunctionalizative trifluoromethylation of unsaturated C−C bonds is a highly useful and efficient method for the synthesis of trifluoromethyl compounds with attractive architectures from simple feedstocks, allowing the introduction of the CF3 group along with a wide variety of substituents either inter‐ or intramolecularly. Given that trifluoromethyl molecules are increasingly used as promising bioactive species in the design of new drugs and agrochemicals, difunctionalizative trifluoromethylation has been extensively studied during the last decade. This review focuses on reactions proceeding via the simultaneous formation of C−heteroatom (O, N, S, Se, B) and C−H bonds, as these reactions provide useful CF3 group‐containing building blocks. To identify the trends and prospects of the evolution of this methodology, we systematically describe the variants of these types of reactions and provide a more general view of reaction conditions, modes, and mechanisms. The presented comprehensive survey enables the categorization of reactions into those that are synthetically mature and those with room for further development. [ABSTRACT FROM AUTHOR]

Comprehensive Summary Trifluoromethyl 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). [ABSTRACT FROM AUTHOR]

A facile way to introduce CF3 groups on a large variety of secondary amines has been developed, avoiding expensive and hazardous reagents. The advantage of the method could be demonstrated by obtaining crystalline tert‐butyl 4‐(trifluoromethyl)piperazine‐1‐carboxylate, a compound that previously only had been obtained as an oil. A major problem is the extreme sensitivity of these compounds towards moisture. [ABSTRACT FROM AUTHOR]

Fluorine‐containing moieties are widely used in the pharmaceutical, agrochemical, and material fields. Thus, these structures are of immense interest in the fields of organic synthesis and medicinal chemistry. Among various fluorinated groups, the difluoromethyl unit has drawn increasing attention due to its unique pharmaceutical properties. In recent years, several methods for the synthesis of difluoromethylated compounds have been rapidly developed. However, most of these methods treat aromatic compounds with excess difluoromethylating reagents, which often contain organometallic compounds, so these transformations are generally less environmentally friendly and atom‐economical. In this review, we summarize the recent development of new methods for the synthesis of difluoromethyl motifs or difluoroalkenes from trifluoromethylated aromatic compounds or trifluoromethyl alkenes via single C(sp3)−F bond cleavage. [ABSTRACT FROM AUTHOR]

Two new iridium(III) complexes were synthesized by introducing two trifluoromethyl groups into an ancillary ligand to develop pure‐red emitters for organic light‐emitting diodes (OLEDs). The electron‐donating ability of the ancillary ligands is suppressed, owing to the electron‐withdrawing nature of trifluoromethyl groups, which can reduce the HOMO energy levels compared with those of compounds without trifluoromethyl groups. However, the introduction of trifluoromethyl groups into the ancillary ligand has little impact on the LUMO energy levels. Therefore, a well‐tuned, pure‐red, excited‐state energy was achieved by regulating the relative energy level between the HOMO and LUMO. OLEDs with these complexes as emitters showed high external quantum efficiencies (EQEs) of 26 % and realized high EQEs of about 25 % and fairly low driving voltages of 3.3–3.6 V for practical luminance of 1000 cd m−2, as well as excellent Commission Internationale de L'Eclairage (CIE) coordinates of (0.66, 0.33) and (0.67, 0.33); thus, this demonstrates the successful molecular design strategy by modifying the electron‐donating ability of ancillary ligand. [ABSTRACT FROM AUTHOR]

This study reports an oxytrifluoromethylation method for construction of oxazoles and furans motif and the concurrent incorporation of a 2,2,2‐trifluoroethyl group at the aromatic C5‐position. High‐valent copper(III) trifluoromethyl compounds are crucial to this reaction that induces oxy‐trifluoromethylation of alkynes with a pendant amide/enol group functioning as the oxygen‐nucleophile. A wide substrate scope is demonstrated with high efficiency and with broad functional group tolerance. Late‐stage functionalization of dehydrocholic acid, a complex drug compound, is accomplished to show the potential of this method for practical drug design. [ABSTRACT FROM AUTHOR]

A general and selective method is developed that allows direct vinylic C−H bond trifluoromethylation of 1,1‐diarylalkenes by a high‐valent copper(III) trifluoromethyl complex, producing biologically active trifluoromethylated alkenes (as well as trifluoromethylated carbocyclic compounds). This fundamental reactivity of Cu(III)−CF3 compounds has thus far been unknown. The presence of a tertiary amine is crucial to this reaction, acting as both a weak base and a single electron transfer (SET) promoter to abstract the vinylic hydrogen. This method starts from bulk olefins under cost‐effective conditions (without the need for external noble metal photocatalyst or stoichiometric amounts of oxidant), and thus is valuable for practical and sustainable applications. [ABSTRACT FROM AUTHOR]

Herein we report an unprecedented, convenient NHC‐catalyzed one‐pot cascade reaction to afford α,ω‐difunctionalized hydroxytrifluoromethyl alkynones and allenones in a single step. The critical fragile aliphatic aldehydes are introduced by a base‐mediated in situ Grob‐type fragmentation of their corresponding latent cyclic vinylogous hemiacetal triflate (VHAT) and γ‐hydroxy vinyl triflate (GHVT) precursors, avoiding typical problems and losses upon isolation. The ′demasked′ aldehydes are subsequently trapped by NHC‐catalyzed umpolung and further metal‐free C−C‐cross‐coupling to access a broad scope of terminally modified alkynyl or allenyl aliphatic, aromatic and heteroaromatic trifluoromethyl ketones as multifunctionalized, high‐value building blocks for advanced synthetic applications. Additional synthetic utility of this approach is demonstrated with the possibility for asymmetric variants using chiral NHC‐catalysts. [ABSTRACT FROM AUTHOR]

We report the development of photoredox‐catalyzed and copper‐promoted trifluoromethoxylation of arenediazonium tetrafluoroborates, with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. This new method takes advantage of visible‐light photoredox catalysis to generate the aryl radical under mild conditions, combined with copper‐promoted selective trifluoromethoxylation. The reaction is scalable, tolerates a wide range of functional groups, and proceeds regioselectively under mild reaction conditions. Furthermore, mechanistic studies suggested that a Cs[Cu(OCF3)2] intermediate might be generated during the reaction. [ABSTRACT FROM AUTHOR]

A novel synthetic method of the 1, 3, 5‐trinitro‐2, 2‐bis(trifluoromethyl)‐1,3,5‐triazinane (2) has been successfully developed. In addition to IR, 1H 13C NMR and elemental analysis, compound 2 was characterized by 15N NMR and X‐ray single crystal diffraction. Due to the introduction of trifluoromethyl, the density of compound 2 is up to 2.04 g⋅cm−3 at 298 K, which is consistent with its crystal density (2.059 g⋅cm−3, 296(2) K). Compound 2 exhibits excellent detonation pressures and velocities (P, 45.6 GPa; vD, 9564 m⋅s−1), as good as exceptional impact and friction sensitivities(IS, 22.5 J; FS, >360 J). Some of these values are better than the current benchmark explosives, such as 1, 3, 5‐trinitrodihydro‐1, 3, 5‐triazine (RDX) and cyclo‐1, 3, 5, 7‐tetramethylenene‐2, 4, 6, 8‐tetranitramine (HMX).It is a potential high energy density material. [ABSTRACT FROM AUTHOR]

A new method for the synthesis of vinyl trifluoromethyl compounds from α, β‐unsaturated carboxylic acids and CF3SO2Na has been developed. This electrochemical decarboxylative trifluoro‐methylation was found to be highly stereoselective and afforded products in good yields with wide substrate scope under metal‐free and external chemical oxidant‐free conditions. [ABSTRACT FROM AUTHOR]

A method for electrophilic sulfenylation by organophosphorus‐catalyzed deoxygenative O‐atom transfer from sulfonyl chlorides is reported. This C−S bond‐forming reaction is catalyzed by a readily available small‐ring phosphine (phosphetane) in conjunction with a hydrosilane terminal reductant to afford a general entry to sulfenyl electrophiles, including valuable trifluoromethyl, perfluoroalkyl, and heteroaryl derivatives that are otherwise difficult to access. Mechanistic investigations indicate that the twofold deoxygenation of the sulfonyl substrate proceeds by the intervention of an off‐cycle resting state thiophosphonium ion. The catalytic method represents an operationally simple protocol using a stable phosphine oxide as a precatalyst and exhibits broad functional‐group tolerance. Oat field: A method for electrophilic sulfenylation by organophosphorus‐catalyzed deoxygenative O‐atom transfer (OAT) from sulfonyl chlorides is reported. This C−S bond‐forming reaction is catalyzed by 1 (phosphetane) in conjunction with a hydrosilane terminal reductant to afford sulfenyl electrophiles, including valuable trifluoromethyl, perfluoroalkyl, and heteroaryl derivatives. [ABSTRACT FROM AUTHOR]

Direct α‐Trifluoromethylation of acetophenone derivatives was achieved by using trifluoroacetic anhydride (TFAA) as the trifluoromethyl source and pyridine‐N‐oxide (Py−O) as activator and oxidant under visible light irradiation and tris‐(2,2′‐bipyridine)ruthenium(II) hexafluorophosphate (Ru(bpy)3(PF6)2) as the photocatalyst. Different acetophenone derivatives could be converted to the corresponding α‐CF3 derivatives with high selectivity. Extensive mechanistic investigation revealed the formation of vinyl trifluoroacetate as the key intermediate for this transformation. [ABSTRACT FROM AUTHOR]

A conceptually novel, high‐yielding, mono‐ or bis‐homologation was realized with lithium halocarbenoids and enables the one‐step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms, enabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process. Mechanistic studies highlighted that the homologation event, carried out with two different carbenoids (LiCH2Cl and LiCH2F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture. [ABSTRACT FROM AUTHOR]

A simple protocol for the UV light irradiated preparation of heteroaryl trifluoromethyl thioethers from disulfides and inexpensive, environmentally sodium triflinate (CF3SO2Na) has been developed. The features of simple and clean reaction conditions, in moderate to good yields, and broad substrate scope render this new approach synthetically attractive for the preparation of potentially pharmaceutically active compounds. A trifluoromethylation of diheteroaryl disulfides with CF3SO2Na to afford the trifluoromethyl thioethers derivatives. The conversion has good functional group compatibility, without external photocatalyst, generating the corresponding products in moderate to good yields under mild conditions, and the disulfide is fully utilized while constructing two S‐CF3 bonds. [ABSTRACT FROM AUTHOR]

In the present investigation, a series of 4‐((3‐(trifluoromethyl)‐5,6‐dihydro‐[1,2,4]triazolo[4,3‐a]pyrazin‐7(8H)‐yl)methyl)benzenamine analogs 6a–o were synthesized and characterized by IR, NMR (1H and 13C), and mass spectra. All newly synthesized compounds 6a–o were prepared under conventional and microwave irradiation methods. These compounds obtained in higher yields and in shorter reaction times in the microwave irradiation method when compared with the conventional method. Synthesized compounds 6a–o were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra using an established XTT reduction menadione assay. Among the screened compounds, 6i (IC50: 1.82 μg/mL), 6j (IC50: 1.02 μg/mL), and 6k (IC50: 1.59 μg/mL) showed excellent activity. Furthermore, compound 6i showed MIC90 value of 16.02 μg/mL. In summary, the results indicate the identification of some novel, selective, and specific inhibitors against M. tuberculosis that can be explored further for the potential antitubercular drug. [ABSTRACT FROM AUTHOR]

Demonstrated herein is the construction of trifluoromethylated quaternary carbon centers by an asymmetric radical transformation. Enantioenriched trifluoromethylated oxindoles were accessed using a hypervalent iodine‐based trifluoromethyl transfer reagent in combination with a magnesium Lewis acid catalyst and PyBOX‐type ligands to achieve up to 99 % ee and excellent chemical yields. Mechanistic studies were performed by experimental and computational methods and suggest a single‐electron transfer induced SN2‐type mechanism. This example is thereby the first report on the construction of enantioenriched trifluoromethylated carbon centers using hypervalent iodine‐based reagents proceeding through such a reaction pathway. Taming the CF3 radical: A unique single‐electron transfer (SET) induced SN2‐type reaction enables the construction of enantioenriched trifluoromethylated oxindoles using a hypervalent iodine‐based trifluoromethyl transfer reagent. A combination of magnesium Lewis acid catalysis and PyBOX‐type ligands successfully tames the highly reactive CF3 radical to achieve excellent enantioselectivities. [ABSTRACT FROM AUTHOR]

A fast, scalable, and safer Csp3−H oxidation of activated and un‐activated aliphatic chains can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platform allows the in situ generation of TFDO gas and its rapid reactivity toward tertiary and benzylic Csp3−H bonds. The process exhibits a broad scope and good functional group compatibility (28 examples, 8–99 %). The scalability of this methodology is demonstrated on 2.5 g scale oxidation of adamantane. Faster, safer, scalable: A continuous flow concept allowed the direct Csp3−H oxidation of activated and un‐activated aliphatic chains via in situ formation of methyl(trifluoromethyl)dioxirane (TFDO). The reported procedure demonstrated a broad scope and good functional‐group compatibility (28 examples, 8–99 %). [ABSTRACT FROM AUTHOR]

We have demonstrated that reactions of aromatic 1,2‐diesters and the Ruppert–Prakash reagent (TMSCF3) afforded hitherto unknown phthalides 1 with both trifluoromethyl (CF3) and alkoxy groups at the 3 position, and their unique transformation was also investigated in detail to attain construction of a variety of very rare types of compounds, such as 1,3‐dihydroisobenzofurans 8 as well as indanones 9 with a CF3 moiety, whose behavior was completely different from the structurally similar compound 2a. A variety of transformation of unprecedented phthalides readily formed by the reaction of TMSCF3 and aromatic 1,2‐diesters resulted in obtaining different types of CF3‐containing compounds, which were almost inaccessible by previously developed methods. [ABSTRACT FROM AUTHOR]

A water‐compatible method for the diastereoselective synthesis of 2‐trifluormethyl‐1,3‐dioxanes is described. The reaction proceeds under mild reaction conditions using simple inorganic bases; it has a very good substrate scope and can be performed with different Michael acceptors. Additionally, the reaction products can be further functionalized, showing an excellent perspective for future applications. A simple and practical method for the diastereoselective synthesis of fluorinated dioxanes using aqueous fluoral and KOH was developed. The products were obtained with high yields and selectivities, besides they proved to be stable enough to resist further functionalization. The reaction is easily performed and well tolerated with a broad range of substrates. [ABSTRACT FROM AUTHOR]

An intermolecular C(sp3)−H amination reaction is reported that is promoted by internal oxidants and occurs via a C=N bond formation step. This intermolecular C(sp3)−H amination reaction of trifluoromethyl ketones and aryldiazonium tetrafluoroborates affords various valuable trifluoroacetylated hydrazones in high yields with excellent E/Z selectivities. The salient features of this reaction type is that it is free of metal, catalyst, directing groups, and azides, and that it can be carried out under mild conditions, is operationally simple and efficient, gram‐scalable, and it tolerates various functional groups. Remarkably, an ectoparasites‐controlling agent was smoothly synthesized on a gram scale using our method. Aryldiazonium tetrafluoroborates served as the aminating reagents as well as an internal oxidant. An inside job: An intermolecular C(sp3)−H amination reaction is reported that is promoted by internal oxidants and is realized under mild conditions. Trifluoroacetylated hydrazones that are generated upon C=N bond formation are further transformed into various useful compounds decorated with a trifluoromethyl group. [ABSTRACT FROM AUTHOR]

A method for the synthesis of β‐trifluoromethyl ketones promoted by a base is described. In the presence of DBU, 1‐aryl‐4,4,4‐trifluoromethylbutanones with various functional groups were obtained through the reaction of 4‐aryl‐1,1,1‐trifluorobut‐2‐en‐2‐yl trifluoromethanesulfonates with water in moderate to excellent yields. The reaction underwent a double‐bond‐migration/hydrolysis/isomerization pathway, and 1‐aryl‐4,4,4‐trifluorobut‐2‐en‐1‐ols were determined as the key intermediates. Both electron‐withdrawing and electron‐donating groups, such as fluoro, chloro, bromo, ester, cyano, trifluoromethyl, alkyl, and alkoxy, were tolerated well in this reaction. A metal‐free synthesis of 1‐aryl‐4,4,4‐trifluoromethylbutanones has been developed. Promoted by DBU, 4‐aryl‐1,1,1‐trifluorobut‐2‐en‐2‐yl trifluoromethanesulfonates were converted into 1‐aryl‐4,4,4‐trifluoromethylbutanones smoothly in moderate to excellent yields. [ABSTRACT FROM AUTHOR]

A clean, transition metal‐ and oxidant‐free photochemical protocol was described for the direct trifluoromethylation of coumarins with Togni reagent. The reaction proceeded smoothly under mild condition to afford regioselective 3‐trifluoromethyl coumarins, moreover novel bis‐trifluoromethylated coumarins were formed. Preliminary bioactivity evaluation on some products showed potential antifungal activities. Free, free, free! A clean, transition metal‐ and oxidant‐free photochemical protocol was described for the direct trifluoromethylation of coumarins with mild reaction conditions and good substrate tolerance. [ABSTRACT FROM AUTHOR]

Disclosed herein is a direct C−H trifluoromethylation of quinoxalin‐2(1H)‐ones with sodium trifluoromethanesulfinate. This protocol affords a series of 3‐trifluoromethylquinoxalin‐2(1H)‐one derivatives in moderate to excellent yields under transition‐metal‐free conditions. The present methodology features utilization of the inexpensive trifluoromethyl source without transition‐metal‐catalysts, mild reaction conditions and high functional group tolerance, which promises a convenient and efficient access to pharmaceutically interesting quinoxalinones. [ABSTRACT FROM AUTHOR]

A simple trifluoromethoxylation method enables non‐directed functionalization of C−H bonds on a range of substrates, providing access to aryl trifluoromethyl ethers. This light‐driven process is distinctly different from conventional procedures and occurs through an OCF3 radical mechanism mediated by a photoredox catalyst, which triggers an N−O bond fragmentation. The pyridinium‐based trifluoromethoxylation reagent is bench‐stable and provides access to synthetic diversity in lead compounds in an operationally simple manner. N‐O problem: A bench‐stable pyridinium reagent transfers the elusive trifluoromethoxyl radical to a variety of arenes, including a selection of biorelevant compounds. By sidestepping limitations of traditional OCF3 sources, this approach enables late‐stage diversification by direct C−H functionalization in a mechanistically unique fashion. [ABSTRACT FROM AUTHOR]

Abstract: The introduction of a trifluoromethyl (CF3) group into an organic molecule can modify its chemical behavior and lead to changes in its physicochemical and pharmacological properties. The CF3 group is often chosen for its chemical inertness and stability, which are related to the strong C−F bonds. In recent years, the potential of gaining straightforward access to difluorinated compounds through selective single C−F activation in CF3 groups has been unveiled. This review describes the latest methodologies for the synthesis of difluoromethylated arenes, difluoroalkenes and difluorinated aldol products of potential synthetic and/or biological interest, employing low‐valent metals, transition metal catalysis, FLP and Lewis acid mediated transformations as well as photoredox catalysis. [ABSTRACT FROM AUTHOR]

A novel palladium‐catalyzed selective hydroxylfluorination of gem‐difluoroalkenes has been developed. By employing easily obtainable gem‐difluoroalkenes and NFSI as the fluorine source, the scope, advantages, and limitations of this reaction were investigated. The reaction presents an efficient synthesis to afford a series of α‐trifluoromethyl alcohols in good to excellent yields. Furthermore, this reaction probably proceeds via oxidation of Pd0 to PdII fluoride complex by NFSI, followed by fluoropalladation of gem‐difluoroalkenes to generate an α‐trifluoromethylbenzyl–Pd intermediate. And this strategy offers more possibilities for the construction of other bonds, such as C–C, C–N and C–S. [ABSTRACT FROM AUTHOR]

Abstract: The homoleptic silver( I) compound [PPh4][CF3AgCF3] (1) provides a convenient entry to the homoleptic silver( III) derivative [PPh4][Ag(CF3)4] (2). Once isolated as pure substances, these compounds exhibit marked thermal stabilities. Their structural and spectroscopic properties have been experimentally established. Moreover, their electronic structures have been calculated by theoretical methods. The electronic structure of the oxidized species [Ag(CF3)4]− provides a new case of ligand‐field inversion caused by the CF3 ligands. [ABSTRACT FROM AUTHOR]

Abstract: Copper‐catalyzed [4+2] cycloaddition of N‐(2‐pyridyl)ketimines and terminal alkynes has been achieved. Ketimines bearing a trifluoromethyl group reacted with various terminal alkynes to produce pyrido[1,2‐a]pyrimidines in good to high yields. This reaction proceeded through a propargylamine intermediate and the corresponding product was obtained via 6‐endo‐dig cyclization. [ABSTRACT FROM AUTHOR]

Abstract: The diastereoselective trifluoromethylation of chiral α,β‐unsaturated N‐tert‐butanesulfinyl ketimines with Ruppert‐Prakash reagent (TMSCF3) has been attained, which provided a convenient and straightforward method for the asymmetric synthesis of structurally diverse α‐tertiary trifluoromethyl allylic amines in high yields and with excellent diastereoselectivities (dr up to > 99:1). The stereochemical outcome of the present diastereoselective trifluoromethylation of the α,β‐unsaturated N‐tert‐butanesulfinyl ketimines suggested that a cyclic six‐membered transition state is involved in the reaction, which is remarkably different from that of the trifluoromethylation of N‐tert‐butanesulfinyl aldimines. [ABSTRACT FROM AUTHOR]

Abstract: Organo halides and their derivatives have received much attention in both the design and development of new synthetic reagents, drugs, and functional materials. In this review, we provide a comprehensive summary of recent advances and strategies in the halo‐functionalization of diazo compounds, including halogenation, dihalogenation, dihaloolefination, trifluoromethylation, trifluoromethylthiolation, and trifluoromethoxylation, using diverse halogenating agents. Special emphasis is placed on the challenges and achievements of these halogenation strategies. For selected examples, mechanisms leading to unusual reactivities and selectivities are discussed in detail to show the impressive and unique properties of these halogenation reactions. Furthermore, we hope to encourage the scientific community to explore the benefits of using diazo compounds as a straightforward and step‐economic alternative approach to the construction of carbon‐halogen bonds. [ABSTRACT FROM AUTHOR]

Abstract: The first visible‐light‐mediated synthesis of trifluoromethylselenolated arenes under metal‐free conditions is reported. The use of an organic photocatalyst enables the trifluoromethylselenolation of arene diazonium salts using the shelf‐stable reagent trifluoromethyl tolueneselenosulfonate at room temperature. The reaction does not require the presence of any additives and shows high functional‐group tolerance, covering a very broad range of starting materials. Mechanistic investigations, including EPR spectroscopy, luminescence investigations, and cyclic voltammetry allow rationalization of the reaction mechanism. [ABSTRACT FROM AUTHOR]

Abstract: The first visible‐light‐mediated synthesis of trifluoromethylselenolated arenes under metal‐free conditions is reported. The use of an organic photocatalyst enables the trifluoromethylselenolation of arene diazonium salts using the shelf‐stable reagent trifluoromethyl tolueneselenosulfonate at room temperature. The reaction does not require the presence of any additives and shows high functional‐group tolerance, covering a very broad range of starting materials. Mechanistic investigations, including EPR spectroscopy, luminescence investigations, and cyclic voltammetry allow rationalization of the reaction mechanism. [ABSTRACT FROM AUTHOR]

Currently, a great deal of research efforts are focused on C–C bond activation for development of novel synthetic methodology. In this paper, a detrifluoroacetylation of trifluoromethyl‐β‐diketones is described, which allows for the synthesis of succinimides and 1,4‐diketones through cascade Michael addition/retro‐Claisen reaction and nucleophilic substitution/retro‐Claisen reaction. The readily available trifluoromethyl‐β‐diketones, wide substrate scope, and mild conditions make this method very practical. [ABSTRACT FROM AUTHOR]

Abstract: A series of quinoxaline‐based conjugated polymers, in which the electron‐donating benzodithiophene (BDT) unit is linked to the electron‐accepting 6,7‐difluorinated quinoxaline (DFQ) derivatives by a thiophene bridge, is synthesized. To investigate their effects on the intrinsic properties of polymers, strong electron‐withdrawing trifluoromethyl (CF3) groups were incorporated into the meta‐position of the phenyl ring at the 2,3‐positions of the DFQ unit of the reference polymer, labelled PEhB‐FQx, to yield the target polymer PEhB‐FQxCF3. In addition, the 2‐ethylhexyloxy substituents on the BDT donor in PEhB‐FQxCF3 are changed to the more planar 2‐ethylhexyl thiophene units to produce another target polymer PThB‐FQxCF3. Owing to the significant contributions of the CF3 moiety, PEhB‐FQxCF3 exhibits quite discernible optical and electrochemical properties along with significant enhancement in photovoltaic performances compared to the reference polymer PEhB‐FQx. Furthermore, the incorporation of the alkylthienyl side chains on the BDT moiety confers on the resultant PThB‐FQxCF3 to possess the maximum power conversion efficiency of 7.26% with an open circuit voltage of 0.88 V, short‐circuit current density of 12.20 mA cm−2, and fill factor of 67.80%. [ABSTRACT FROM AUTHOR]

Abstract: The first transition‐metal‐free, site‐specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp3)–SCF3 coupling under redox‐neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL‐based phosphorothiols can site‐selectively cleave tertiary sp3 C(sp3)–O ether bonds in complex molecules initiated by a polarity‐matching hydrogen‐atom‐transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp3)−H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C−O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site‐selective C−O bond functionalization of unsymmetrical tertiary alkyl ethers. [ABSTRACT FROM AUTHOR]

An efficient temperature‐dependent organocatalyzed asymmetric formal [3+2] cycloaddition reaction of α‐substituted isocyanoacetates to β‐trifluoromethylated enones by cinchona alkaloid‐derived squaramide has been investigated, affording the optically active trifluoromethylated 2‐pyrrolines in excellent yields (up to 98 %) and high stereoselectivities (>20:1 dr, up to >99 % ee) under mild conditions. [ABSTRACT FROM AUTHOR]

We report herein the preparation of ortho‐vinylaryl S‐trifluoromethylated sulfoximines through cross‐coupling reactions. Two efficient palladium‐catalyzed procedures (Stille and Suzuki) were developed, with use of ortho‐iodo aryl sulfoximines as substrates, to give various vinyl derivatives in good yields. The difference in reactivity of the fluorinated derivatives, compared to nonfluorinated counterparts, allowed the use of free NH sulfoximines in the coupling processes, where they proved to be inert to cyclization. Finally, further transformations have been explored, such as metathesis coupling reactions, after post‐functionalization of the nitrogen atom by another vinyl group. [ABSTRACT FROM AUTHOR]

Fluorinated α‐bromoenones have received considerable attention in the last decade. Their ability to react in 1.2‐ and 1.4‐addition modes, together with the presence of bromine, makes them valuable fluorinated building blocks in organic synthesis. This review focuses on the unusual and often unpredictable transformations of these compounds on treatment with nitrogen nucleophiles. [ABSTRACT FROM AUTHOR]