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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]

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]

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]

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]

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: A chemoselective cross Rauhut–Currier‐type reaction has been developed involving a tri‐substituted alkene (trifluoromethyl‐containing acrylonitrile derivative) with a di‐ or tri‐substituted alkene to yield tetra‐substituted double bonds in RC‐type products. This approach can support the synthesis of trifluoromethylated tetra‐substituted olefins and synthetically important, structurally complex 3‐allylic‐type oxindole skeletons. The asymmetric version of this RC‐type reaction can be realized by combining a Brønsted acid and Lewis base for bifunctional H‐bonding‐tertiary amine catalysis. Subsequent transformation of multi‐functionalized RC‐type product leads to pharmacologically interesting cyclohexane‐based spiro‐pyrazolones bearing six contiguous chiral centers and two highly congested, vicinal quaternary carbon centers. [ABSTRACT FROM AUTHOR]

Abstract: Two hitherto unreported sulfur‐centered radicals CF3SO. and CF3OS. were generated in the gas phase through high‐vacuum flash pyrolyses of sulfoxide CF3S(O)X (X=CF3, Cl, PhO) precursors. The CF3OS. molecule is the first experimental example that constitutes an oxathiyl radical. It was isolated and characterized by combining matrix‐isolation IR and UV/Vis spectroscopy with quantum chemical computations up to the UCCSD(T)‐F12/cc‐pVTZ‐F12 level of theory. Upon UV light irradiation (254 or 266 nm), sulfinyl radical (CF3SO.) isomerizes to oxathiyl radical (CF3OS.) in cryogenic noble gas matrices (Ar and Ne). Natural population analyses at the BP86/def2‐TZVPP//UCCSD(T)‐F12/cc‐pVTZ‐F12 level suggest that the spin density in CF3OS. is mainly localized on the sulfur atom (0.86), whereas, in CF3SO. the spin density is almost equally distributed on the sulfur (0.55) and oxygen (0.43) atoms. [ABSTRACT FROM AUTHOR]

The direct fluoroalkylselenolation of terminal alkynes is reported herein involving shelf stable electrophilic reagents TsSeRF. The use of these reagents allows for the first time performing the reaction under catalytic conditions (copper/ligand). Moreover, the presence of oxygen directing groups allows the selective addition of the reagents to alkynes, therefore yielding a new family of vinyl sulfones. [ABSTRACT FROM AUTHOR]

Nickel complexes have gained sustained attention as efficient catalysts in cross-coupling reactions and co-catalysts in dual systems due to their ability to react with radical species. Central to this reactivity is nickel's propensity to shuttle through several accessible redox states from Ni0 to NiIV. Here, we report the catalytic generation of trifluoromethyl radicals from a nickel complex bearing redox-active iminosemiquinone ligands. This unprecedented reactivity is enabled through ligand-based oxidation performing electron transfer to an electrophilic CF3+ source while the nickel oxidation state is preserved. Additionally, extension of this reactivity to a copper complex bearing a single redox equivalent is reported, thus providing a unified reactivity scheme. These results open new pathways in radical chemistry with redox-active ligands. [ABSTRACT FROM AUTHOR]

Halogenated analogues of the neurotoxic alkaloid muscimol were prepared with fluorine, iodine or trifluoromethyl at the 4 position of the isoxazole ring system. These compounds were investigated as agonists for GABAA receptors. Only the C-4 fluorine-containing analogue proved to be an active compound in these assays. The fluoro analogue was less active than muscimol, however it showed differential activity between synaptic (α1β2γ2) and extrasynaptic (α4β2γ) GABAA receptors, having a similar potency to the neurotransmitter GABA for the extrasynaptic (α4β2γ) receptor. [ABSTRACT FROM AUTHOR]

The successful perfluoroalkylselenolation of alkynyl copper(I) compounds is described herein. The reaction occurs under oxidant free conditions at room temperature. This convenient one-pot procedure is based on the in situ generation of trifluoromethylselenyl chlorides. The developed system shows high functional group tolerance and also promotes the employment of fluoroalkyl derivatives. [ABSTRACT FROM AUTHOR]

The first example of a magnesium-catalyzed direct trifluoromethylation of 3-substituted oxindoles using an electrophilic hypervalent iodine reagent is reported. The reaction proceeds under unprecedented mild conditions leading to the formation of an all-carbon quaternary center in oxindoles in high chemical yield and demonstrates excellent functional group tolerance. In addition to trifluoromethyl, other perfluoroalkyl groups can be introduced with similar level of efficacy. Mechanistic investigations are consistent with the involvement of a radical pathway. The chemical versatility of the obtained products is further illustrated through their conversion in situ into valuable organofluorine building blocks, making the protocol more widely applicable. [ABSTRACT FROM AUTHOR]

Positron-emission tomography (PET) is an immensely important imaging modality in biomedical research and drug development but must use selective radiotracers to achieve biochemical specificity. Such radiotracers are usually labeled with carbon-11 ( t1/2=20 min) or fluorine-18 ( t1/2=110 min), but these are only available from cyclotrons in a few simple chemical forms. [18F]Fluoroform has emerged for labeling tracers in trifluoromethyl groups but is severely limited in utility by low radioactivity per mass (low molar activity). Here, the synthesis of [11C]fluoroform is described, based on CoF3-mediated fluorination of cyclotron-produced [11C]methane. This process is efficient and repetitively reliable. [11C]Fluoroform shows versatility for labeling small molecules in very high molar activity (>200 GBq μmol−1), far exceeding that possible by using [18F]fluoroform. Therefore, [11C]fluoroform represents a major breakthrough for labeling prospective PET tracers in trifluoromethyl groups at high molar activity. [ABSTRACT FROM AUTHOR]

The homoleptic compound [PPh4][CF3AuCF3] cleanly undergoes photoinduced oxidative addition of CF3I to afford the organogold(III) derivative [PPh4][(CF3)3AuI] in good yield and under mild conditions. This compound provides a convenient entry to the chemistry of the perfluorinated (CF3)3Au fragment, the properties of which were analyzed with the aid of DFT methods and compared with those of the homologous non-fluorinated (CH3)3Au moiety. It was found that reductive elimination of CX3−CX3 in the former (X=F) requires a much higher energy barrier than in the latter (X=H) and is therefore considerably less favored. This can be considered as one of the main features underlying the significantly higher stability associated to the (CF3)3Au fragment and its derivatives. This unsaturated, 14-electron species can be stabilized by coordination of any of the halide ligands, including fluoride. In fact, the whole series of anionic [PPh4][(CF3)3AuX] complexes (X=F, Cl, Br, I, CN) has now been isolated and conveniently characterized. Evidence for intermolecular decomposition pathways upon thermolysis in the condensed phase is presented. [ABSTRACT FROM AUTHOR]

This Minireview describes recent advances toward the synthesis of trifluoromethyl- and difluoromethyl-substituted cyclopropanes. Synthetic methodologies using [2+1] cycloaddition, ring-contraction, and ring-closure cyclopropanations since 2010 are reported. [ABSTRACT FROM AUTHOR]

The anionic trifluoromethylgold(I) derivatives [CF3AuX]−, which have been prepared and isolated as their [PPh4]+ salts in good yield, undergo thermally induced difluorocarbene extrusion in the gas phase, giving rise to the mixed gold(I) fluorohalide complexes [F−Au−X]− (X=Cl, Br, I). These triatomic species have been detected by tandem mass spectrometry (MS2) experiments and their properties have been analyzed by DFT methods. The CF2 extrusion mechanism from the Au−CF3 moiety serves as a model for the CF2 insertion into the Au−F bond, since both reactivity channels are connected by the microreversibility principle. [ABSTRACT FROM AUTHOR]

The introduction of fluorine groups to pharmaceutical compounds can have a dramatic effect on the lipophilicity and metabolic stability of the molecule in vivo. Around 20 % of drugs contain at least one fluorine atom. The trifluoromethyl group is known to have beneficial effects and can dramatically affect the biological activity when substituted for a methyl group, for example. In any case, the direct and late-stage introduction of a trifluoromethyl group is a powerful transformation in the tool box of the medicinal chemist. The use of methyl fluorosulfonyldifluoroacetate (MFSDA) as a relatively inexpensive reagent for trifluoromethylation was first reported in 1989; however, in our opinion it has been somewhat underutilised. Herein, a comprehensive review of trifluoromethylation using MFSDA is reported, which we hope will further expose readers to this useful reagent. [ABSTRACT FROM AUTHOR]

The X-ray crystal structures of cis- and trans-1-(indol-3-yl)-4-methyl cyclohexane and its congeners with stepwise fluorination of the methyl group are reported. The trans-configured compounds adopted diequatorial conformations, whereas the cis analogues adopted regular cyclohexane chair conformations with the methyl group preferentially assuming the axial position, even in the case of the CF3 group. Surprisingly, although the axial CF3 derivative displayed distinct valence deformations in the cyclohexane moiety, the observed structural changes were relatively modest. The cis derivatives with axial mono- and difluorinated methyl groups exhibited conformational disorder in the crystals with significant population levels for the staggered conformations that had one fluorine atom in the endo position; their respective trans counterparts adopted unique conformations, but again with one fluorine atom in the endo position. Theoretical calculations for a series of cis- and trans-1,4-dimethyl cyclohexane model compounds with stepwise fluorination of one equatorial or axial methyl group reproduced the experimentally observed structural response patterns very well, reproduced the experimentally determined nonlinear correlation of the axial-equatorial energy difference with the degree of methyl fluorination in a satisfactory manner, and provided further insights into important conformational aspects of partially fluorinated methyl groups. [ABSTRACT FROM AUTHOR]

A copper-mediated trifluoroacetylation of various arenediazonium salts with ethyl trifluoropyruvate is reported. The reaction proceeded smoothly under mild conditions at room temperature giving trifluoromethyl aryl ketones in moderate to good yields. A variety of functional groups, including methoxy, hydroxy, ester, ketone, trifluoromethyl, and halide groups, were well tolerated. A possible reaction mechanism involving an aryl radical intermediate was proposed and supported by experimental evidence. This reaction provides a new route to trifluoromethyl aryl ketones, notable synthetic targets, from the corresponding anilines. [ABSTRACT FROM AUTHOR]

Photocatalytic radical trifluoromethylation strategies have impacted the synthesis of trifluoromethyl-containing molecules. However, mechanistic aspects concerning such transformations remain poorly understood. Here, we describe in detail the mechanism of the visible-light photocatalytic trifluoromethylation of N-methylpyrrole with gaseous CF3I in flow. The use of continuous-flow microreactor technology allowed for the determination of different important parameters with high precision (e.g., photon flux, quantum yield, reaction rate constants) and for the handling of CF3I in a convenient manner. Our data indicates that the reaction occurs through a reductive quenching mechanism and that there is no radical chain process present. [ABSTRACT FROM AUTHOR]

α-Diazo esters are smoothly converted into the corresponding trifluoromethyl thio- or selenoethers by reaction with Me4NSCF3 or Me4NSeCF3, respectively, in the presence of catalytic amounts of copper thiocyanate. This straightforward method gives high yields under neutral conditions at room temperature and is applicable to a wide range of functionalized molecules, including diverse α-amino acid derivatives. It is well-suited for the late-stage introduction of trifluoromethylthio or -seleno groups into drug-like molecules. [ABSTRACT FROM AUTHOR]

Trifluoromethylation reactions have recently received increased attention because of the beneficial effect of the trifluoromethyl group on the pharmacological properties of numerous substances. A common method to introduce the trifluoromethyl group employs the Ruppert-Prakash reagent, that is, Si(CH3)3CF3, together with a copper(I) halide. We have applied this method to the trifluoromethylation of aromatic alkynes and used electrospray-ionization mass spectrometry to investigate the mechanism of these reactions in tetrahydrofuran, dichloromethane, and acetonitrile as well as with and without added 1,10-phenanthroline. In the absence of the alkyne component, the homoleptic ate complexes [Cu(CF3)2]− and [Cu(CF3)4]− were observed. In the presence of the alkynes RH, the heteroleptic complexes [Cu(CF3)3R]− were detected as well. Upon gas-phase fragmentation, these key intermediates released the cross-coupling products R−CF3 with perfect selectivity. Apparently, the [Cu(CF3)3R]− complexes did not originate from homoleptic cuprate anions, but from unobservable neutral precursors. The present results moreover point to the involvement of oxygen as the oxidizing agent. [ABSTRACT FROM AUTHOR]

β-Trifluoromethyl (CF3) enones were proved to act as good dienophiles in asymmetric normal-electron-demand Diels-Alder cycloadditions with 2,4-dienals under trienamine catalysis with a chiral secondary amine. The sequential reductive amination transformations with benzylamine produced cis- and trans-fused chiral trifluoromethylated octahydroisoquinolines in a diastereodivergent manner by using NaBH(OAc)3 and NaBH3CN as the reductants, respectively. Moreover, other types of activated alkenes that bear a CF3 group have also been successfully utilized to construct a diverse range of chiral cyclic frameworks in high stereoselectivity. [ABSTRACT FROM AUTHOR]

An efficient and easily scalable NHC-copper(I) halide-catalyzed addition of terminal alkynes to 1,1,1-trifluoromethyl ketones, carried out on water for the first time, is reported. A series of addition reactions were performed with as little as 0.1-2.0 mol % of [(NHC)CuX] (X=Cl, Br, I, OAc, OTf) complexes, providing tertiary propargylic trifluoromethyl alcohols in high yields and with excellent chemoselectivity from a broad range of aryl- and more challenging alkyl-substituted trifluoromethyl ketones (TFMKs). DFT calculations were performed to rationalize the correlation between the yield of catalytic alkynylation and the sterics of N-heterocyclic carbenes (NHCs), expressed as buried volume (%VBur), indicating that steric effects dominate the yield of the reaction. Additional DFT calculations shed some light on the differential reactivity of [(NHC)CuX] complexes in the alkynylation of TFMKs. The first enantioselective version of a direct alkynylation in the presence of C1-symmetric NHC-copper(I) complexes is also presented. [ABSTRACT FROM AUTHOR]

This article describes the new economic decarboxylative trifluoromethylating reagent [Cu(phen)(O2CCF3)] ( 1; phen=1,10-phenanthroline) and the efficient difluorocarbene precursor [Cu(phen)2][O2CCF2Cl] ( 2). Treatment of copper tert-butoxide with phen and subsequent addition of trifluoroacetic acid or chlorodifluoroacetic acid afforded air-stable complexes 1 and 2, respectively, which were characterized by X-ray crystallography. The copper(I) ion in 1 is coordinated by a bidentate phen ligand, a monodentate trifluoroacetate group, and a molecule of CH3CN in a distorted tetrahedral coordination geometry. The molecular structure of 2 adopts an ionic form that consists of a [Cu(phen)2]+ cation and a chlorodifluoroacetate anion. Complex 1 reacted with a variety of aryl and heteroaryl halides to form trifluoromethyl (hetero)arenes in good yields. The corresponding Hammett plot exhibited a linear relationship and a reaction parameter ( ρ)=+0.56±0.02, which indicated that the trifluoromethylation reaction proceeded via a nucleophilic reactive species. Complex 2 reacts with phenols to produce aryl difluoromethyl ethers in modest-to-excellent yields. Mechanistic investigations revealed that the difluoromethylation reaction proceeds by initial copper-mediated formation of difluorocarbene and subsequent concerted addition of difluorocarbene to the phenol to form a three-center transition state. [ABSTRACT FROM AUTHOR]

The radical trifluoromethylation of thiophenol in condensed phase applying reagent 1 (3,3-dimethyl-1-(trifluoromethyl)-1 λ3,2-benziodoxol) has been examined by both theoretical and experimental methodologies. On the basis of ab initio molecular dynamics and metadynamics we show that radical reaction mechanisms favourably compete with polar ones involving the S-centred nucleophile thiophenol, their free energies of activation, Δ F≠, lying between 9 and 15 kcal mol−1. We further show that the origin of the proton activating the reagent is important. Hammett plot analysis reveals intramolecular protonation of 1, thus generating negative charge on the sulfur atom in the rate-determining step. The formation of a CF3 radical can be thermally induced by internal dissociative electron transfer, its activation energy, Δ F≠, amounting to as little as 10.8 and 2.8 kcal mol−1 for reagent 1 and its protonated form 2, respectively. The reduction of the iodine atom by thiophenol occurs either subsequently or in a concerted fashion. [ABSTRACT FROM AUTHOR]

A series of new hypervalent iodine reagents based on the 1,3-dihydro-3,3-dimethyl-1,2-benziodoxole and 1,2-benziodoxol-3-(1H)-one scaffolds, which contain a functionalized tetrafluoroethyl group, have been prepared, characterized, and used in synthetic applications. Their corresponding electrophilic fluoroalkylation reactions with various sulfur, oxygen, phosphorus, and carbon-centered nucleophiles afford products that feature a tetrafluoroethylene unit, which connects two functional moieties. A related λ3-iodane that contains a fluorophore was shown to react with a cysteine derivative under mild conditions to give a thiol-tagged product that is stable in the presence of excess thiol. Therefore, these new reagents show a significant potential for applications in chemical biology as tools for fast, irreversible, and selective thiol bioconjugation. [ABSTRACT FROM AUTHOR]

The article presents abstracts on topics related to chemistry which include ring contraction of 3-hydroxy-3-(trifluoromethyl)piperidines, difluoromethylated building blocks, and carbon-hydrogen arylation of (hetero)arenes.

A ring contraction of 3-hydroxy-3-(trifluoromethyl)piperidines was achieved via an aziridinium intermediate. This contraction facilitates the synthesis of a series of 2-substituted 2-(trifluoromethyl)pyrrolidines incorporating a quaternary center at the C2 position. [ABSTRACT FROM AUTHOR]

The reactions of α,β-unsaturated aldehydes with cyclopentadiene in the presence of diarylprolinol silyl ethers as catalyst proceed via iminium cations as intermediates, and can be divided into two types; one involving a Michael-type reaction (type A) and one involving a cycloaddition (type B). Diphenylprolinol silyl ethers and trifluoromethyl-substituted diarylprolinol silyl ethers, which are widely used proline-type organocatalysts, have been investigated in this study. As the LUMO of the iminium ion derived from trifluoromethyl-substituted diarylprolinol silyl ether is lower in energy than that derived from diphenylprolinol silyl ether, as supported by ab initio calculations, the trifluoromethyl-substituted catalyst is more reactive in a type B reaction. The iminium ion from an α,β-unsaturated aldehyde is generated more quickly with diphenylprolinol silyl ether than with the trifluoromethyl-substituted diarylprolinol silyl ether. When the generation of the iminium ion is the rate-determining step, the diphenylprolinol silyl ether catalyst is the more reactive. Because acid accelerates the generation of iminium ions and reduces the generation of anionic nucleophiles in the Michael-type reaction (type A), it is necessary to select the appropriate acid for specific reactions. In general, diphenylprolinol silyl ether is a superior catalyst for type A reactions, whereas the trifluoromethyl-substituted diarylprolinol silyl ether catalyst is preferred for type B reactions. [ABSTRACT FROM AUTHOR]

Enantioselective formal hetero-Diels-Alder reactions of trifluoromethylated enones and 2-amino-1,3-butadienes generated in situ from aliphatic acyclic enones and chiral primary amines are reported. The corresponding tetrahydropyran-4-ones are formed in up to 94 % yield and with up to 94 % ee. The reaction was carried out through a stepwise mechanism, including initial aminocatalytic aldol condensation of 2-amino-1,3-butadiene to the trifluoromethylated carbonyl group followed by an intramolecular oxa-Michael addition. Both NMR investigation and theoretical calculations on the transition state indicate that the protonated tertiary amine could effectively activate the carbonyl group of the trifluoromethyl ketone to promote the addition process through hydrogen-bonding interaction of NH⋅⋅⋅F and NH⋅⋅⋅O simultaneously, and thus provide a chiral environment for the approach of amino-1,3-butadienes to the activated trifluoromethyl ketone, resulting in high enantioselectivity. [ABSTRACT FROM AUTHOR]

The 2'-trifluoromethylthio (2'-SCF3) modification endows ribonucleic acids with exceptional properties and has attracted considerable interest as a reporter group for NMR spectroscopic applications. However, only modified pyrimidine nucleosides have been generated so far. Here, the syntheses of 2'-SCF3 adenosine and guanosine phosphoramidites of which the latter was obtained in highly efficient manner by an unconventional Boc-protecting group strategy, are reported. RNA solid-phase synthesis provided site-specifically 2'-SCF3-modified oligoribonucleotides that were investigated intensively. Their excellent behavior in 19F NMR spectroscopic probing of RNA ligand binding was exemplified for a noncovalent small molecule-RNA interaction. Moreover, comparably to the 2'-SCF3 pyrimidine nucleosides, the purine counterparts were also found to cause a significant thermodynamic destabilization when located in double helical regions. This property was considered beneficial for siRNA design under the aspect to minimize off-target effects and their performance in silencing of the BASP1 gene was demonstrated. [ABSTRACT FROM AUTHOR]

A novel electron-donor-acceptor (EDA) complex-mediated direct CH trifluoromethylation of arenes with Umemoto's reagent has been developed. This transformation has been enabled by an unprecedented EDA complex formed by Umemoto's reagent and an amine, which was supported by experiments and theoretical calculations. The radical-based methodology presented here allows to access highly-functionalized trifluoromethyl arenes in up to 81 % chemical yield. [ABSTRACT FROM AUTHOR]

A general and efficient methodology for the direct transition metal free trifluoromethylthiolation of a broad range of biologically relevant N-heteroarenes is reported employing abundant sodium chloride as the catalyst. This method is operationally simple, exhibits high functional group tolerance, and does not require protecting groups. [ABSTRACT FROM AUTHOR]

An efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni's reagent has been developed. This strategy, accompanied by a double-bond migration, leads to various branched CF3-substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which β-H elimination is prohibited, CF3-containing oxetanes are isolated as the sole product. [ABSTRACT FROM AUTHOR]

The synthesis, characterisation, and crystal structure determination of the closely related compounds 3,3'-bi-(5-trifluoromethyl-1,2,4-oxadiazole) and 5,5'-bi-(2-trifluoromethyl-1,3,4-oxadiazole) are reported. These two compounds are known for their bioactivity; however, in this study they serve as model compounds to evaluate the suitability of the heterocyclic oxadiazole ring system for energetic materials when the fluorine atoms in the exocyclic CF3 groups are substituted successively by nitro groups. Quantum chemical calculations for the bi-1,3,4-oxadiazole derivatives with difluoronitromethyl, fluorodinitromethyl, and trinitromethyl groups have been carried out and predict promising energetic performances for both explosive and propulsive applications. [ABSTRACT FROM AUTHOR]

An efficient organocatalytic stereoselective reduction of β-trifluoromethyl-substituted nitroalkenes, mediated by 3,5-dicarboxylic ester-dihydropyridines (Hantzsch ester type), has been successfully developed. A multifunctional thiourea-based ( S)-valine derivative was found to be the catalyst of choice, promoting the reaction in up to 97 % ee. The methodology has been applied to a wide variety of substrates, leading to the formation of differently substituted precursors of enantiomerically enriched β-trifluoromethyl amines. The mechanism of the reaction and the mode of action of the metal-free catalytic species were computationally investigated; on the basis of DFT transition-state (TS) analysis, a model of stereoselection was also proposed. [ABSTRACT FROM AUTHOR]

The reactivitiy of tetrakis(trifluoromethyl)cyclopentadienone towards different C-based Lewis bases, such as N-heterocyclic carbenes (NHC), ylides and isonitriles, are reported. While sterically not hindered carbenes were found to yield kinetic adducts by regiospecific nucleophilic attack at the position adjacent to the carbonyl group of the ketone, bulkier nucleophiles afforded the thermodynamically more stable O-bridged zwitterions. Interestingly, isonitriles were found to dimerize and trimerize under the same reaction conditions, forming bicyclic products that evolve differently depending on the nature of the substituents. [ABSTRACT FROM AUTHOR]

We describe here a novel procedure for the synthesis of highly substituted 2-quinolinones. By this newly developed approach, 2-quinolinone derivatives were prepared in moderate to good yields by carbonylative cyclization of N-aryl-pyridine-2-amines and internal alkynes by CH activation. Remarkably, [Mo(CO)6] was applied as a solid CO source and the reaction proceeded in an atom economic manner. [ABSTRACT FROM AUTHOR]

A novel copper-catalyzed one-pot cross-coupling of β-ketoacids with in situ generated trifluorodiazoethane has been developed. This reaction provides a direct and efficient method, in which one CC bond and one CO bond were formed in a carbenoid center with concomitant denitrogenation-dehydrogenation-decarboxylation, to afford trifluoromethylated aldol products. In several preliminary experiments, good to high enantioselectivities were also obtained. [ABSTRACT FROM AUTHOR]

Herein, we describe a transition-metal-free protocol for the conversion of simple 2-allyl-3-(trifluoromethyl)phenols into substituted 5-fluoronaphthalen-1-ols. The key events of this reaction include the selective activation of two CF bonds and formation of an intermediate hexatriene system, which undergoes a 6π electrocyclization, followed by rearomatization. This concept enables the rapid conversion (three steps) of various commercially available 3-(trifluoromethyl)phenols into novel fluorine-containing naphthols, which are difficult to prepare by previous methods. The reported sequence was also extended to a one-pot transformation of 3-(trifluoromethyl)phenols into 5-fluoronaphthalen-1-ols. [ABSTRACT FROM AUTHOR]

Poly(trifluoromethyl)fullerene S6-C60(CF3)12 was reduced by sodium fluorenone ketyl in the presence of (PPN)Cl (PPN=bis(triphenylphosphine)iminium) to afford the salt (PPN)[C60(CF3)12] ( 1), which contains C60(CF3)12.− radical anions. In the crystal structure of 1, C60(CF3)12.− layers alternate with the PPN+ cations. There are short F ⋅⋅⋅F contacts between C60(CF3)12.− radical anions within the layers but no C ⋅⋅⋅C contacts. DFT calculations revealed that the negative charge on C60(CF3)12.− is distributed mainly between sp2 carbon and fluorine atoms, whereas spin density is localized mainly on the fullerene-cage sp2 carbon atoms. IR and UV/Vis/NIR spectra in the solid state and solution showed characteristic changes relative to those of neutral S6-C60(CF3)12 due to the formation of radical anions. The solid-state electronic spectrum of 1 exhibits a single broad band at 738 nm attributed to C60(CF3)12.−. Crystals of 1 show a narrow EPR signal with g=2.0025 (Δ H=0.45 mT) at 300 K. The temperature dependence of the integral intensity follows the Curie-Weiss law with a negative Weiss temperature of −11.8 K (30-300 K) indicating antiferromagnetic interaction of spins. This dependence was approximated by the Heisenberg model for one-dimensional chains of antiferromagnetically interacting spins with exchange interaction J/ kB=−9.1 K. It was assumed that magnetic interaction between the C60(CF3)12.− spins in the layers is mediated by short F ⋅⋅⋅F contacts. [ABSTRACT FROM AUTHOR]

A mild, convenient, and step-economical intramolecular aminotrifluoromethylation of unactivated alkenes with a variety of electronically distinct, nitrogen-based nucleophiles in the presence of a simple copper salt catalyst, in the absence of extra ligands, is described. Many different nitrogen- based nucleophiles (e.g., basic primary aliphatic and aromatic amines, sulfonamides, carbamates, and ureas) can be employed in this new aminotrifluoromethylation reaction. The aminotrifluoromethylation process allows straightforward access to diversely substituted CF3-containing pyrrolidines or indolines, in good to excellent yields, through a direct difunctionalization strategy from the respective acyclic starting materials. Mechanistic studies were conducted and a plausible mechanism was proposed. [ABSTRACT FROM AUTHOR]

Pd-catalyzed cross-coupling of halides with CF3-substituted diazo compounds or N-tosylhydrazones has been explored for the synthesis of CF3-substituted alkenes and 1,3-butadienes. Pd-carbene migratory insertion plays the key role in these transformations. [ABSTRACT FROM AUTHOR]

We report three new isomers of C70(CF3)8, structurally related to p7 mp-C70(CF3)10, that are inaccessible by direct trifluoromethylation, but can be easily identified among the products of the transalkylation of higher trifluoromethylfullerenes with C70. The reported compounds are characterized by UV/Vis, 1 D and 2 D COSY 19F NMR spectroscopy, and DFT calculations. A rather unusual addition pattern is observed in p6, i-C70(CF3)8 in which one addend is attached remotely from the others; polarization of the adjacent unsaturated bonds by the addend makes the molecule readily oxidizable. [ABSTRACT FROM AUTHOR]

The development of new strategies for synthesis of trifluoromethylthiolate compounds is of considerable importance in pharmaceuticals, agrochemicals, and advanced materials. Accordingly, currently much attention is being devoted to the development of effective methods and reagents for their synthesis. In contrast, considerably less effort has been afforded to the development of preparing CSeCF3 bonds. Herein we report a concise route to synthesize a family of copper(I) trifluoromethylselenolate reagents by the reaction of CuI with the Ruppert's reagent (Me3SiCF3), KF, and elemental selenium in the presence of dinitrogen ligands in CH3CN at room temperature. The reagent [Cu(bpy)(SeCF3)]2 was proven to be air-stable and highly efficient for nucleophilic trifluoromethylthselenolation of a broad range of (hetero)aryl halides and alkyl halides. This method represents a powerful protocol for the construction trifluoromethylselenolate compounds. [ABSTRACT FROM AUTHOR]

Being economic with fluorine: The direct synthesis of CuCF3 from a cuprate reagent and trifluoromethyl ketones, as one of the most economical and efficient trifluoromethyl sources, was accomplished. The advantages of this method are all of reagents employed are low‐cost, operation is simple, and the yield of CuCF3 is virtually quantitative (see scheme). Furthermore, three types of trifluoromethylations smoothly proceeded to provide the corresponding products in high yields. [ABSTRACT FROM AUTHOR]

A simple and efficient method for the synthesis of 2‐trifluoromethyl quinolines by means of visible‐light‐induced radical cyclization of trifluoroacetimidoyl chlorides with alkynes has been developed. This protocol allows the generation of imidoyl radicals by activation of C(sp2)Cl bonds using a photoredox catalyst under mild and environmentally friendly conditions (see scheme). [ABSTRACT FROM AUTHOR]

Trifluoromethylation of AuCl3 by using the Me3SiCF3/CsF system in THF and in the presence of [PPh4]Br proceeds with partial reduction, yielding a mixture of [PPh4][AuI(CF3)2] ( 1′) and [PPh4][AuIII(CF3)4] ( 2′) that can be adequately separated. An efficient method for the high-yield synthesis of 1′ is also described. The molecular geometries of the homoleptic anions [AuI(CF3)2]− and [AuIII(CF3)4]− in their salts 1′ and [NBu4][AuIII(CF3)4] ( 2) have been established by X-ray diffraction methods. Compound 1′ oxidatively adds halogens, X2, furnishing [PPh4][AuIII(CF3)2X2] (X=Cl ( 3), Br ( 4), I ( 5)), which are assigned a trans stereochemistry. Attempts to activate CF bonds in the gold(III) derivative 2′ by reaction with Lewis acids under different conditions either failed or only gave complex mixtures. On the other hand, treatment of the gold(I) derivative 1′ with BF3⋅OEt2 under mild conditions cleanly afforded the carbonyl derivative [AuI(CF3)(CO)] ( 6), which can be isolated as an extremely moisture-sensitive light yellow crystalline solid. In the solid state, each linear F3C-Au-CO molecule weakly interacts with three symmetry-related neighbors yielding an extended 3D network of aurophilic interactions (Au⋅⋅⋅Au=345.9(1) pm). The high $\tilde \nu $CO value (2194 cm−1 in the solid state and 2180 cm−1 in CH2Cl2 solution) denotes that CO is acting as a mainly σ-donor ligand and confirms the role of the CF3 group as an electron-withdrawing ligand in organometallic chemistry. Compound 6 can be considered as a convenient synthon of the 'AuI(CF3)' fragment, as it reacts with a number of neutral ligands L, giving rise to the corresponding [AuI(CF3)(L)] compounds (L=CN tBu ( 7), NCMe ( 8), py ( 9), tht ( 10)). [ABSTRACT FROM AUTHOR]