Trifluoromethyl Complexes Research Articles

The Role of Electron Transfer in Copper-Mediated C(sp2)-H Trifluoromethylation.

We report copper(II) and copper(III) trifluoromethyl complexes supported by pyridinedicarboxamide ligand (L) as a platform for investigating the role of electron transfer in C(sp2)-H trifluoromethylation. While the copper(II) trifluoromethyl complex is unreactive towards (hetero)arenes, the formal copper(III) trifluoromethyl complex performs C(sp2)-H trifluoromethylation of a wide range of (hetero)arenes. Mechanistic studies using the copper(III) trifluoromethyl complex suggest that the mechanism of arene trifluoromethylation is substrate-dependent. When the thermodynamic driving force for electron transfer is high, the reaction proceeds through a previously unidentified single electron transfer (SET) mechanism, where an initial electron transfer occurs between the substrate and oxidant prior to CF3 group transfer. Otherwise, a CF3 radical release/electrophilic aromatic substitution (SEAr) mechanism is followed. These studies provide valuable insights into the role of strong oxidants and potential mechanistic dichotomy in Cu-mediated C(sp2)-H trifluoromethylation.

Gold Trifluoromethyl Complexes as Efficient Regioselective Catalysts in Alkyne Hydration.

Gold(III) complexes containing trifluoromethyl ligands are efficient catalysts in the hydration of alkynes, operating at low catalyst loadings, without additives, using environmentally friendly solvents and at mild conditions (60 °C). Hydration of terminal and internal alkynes provides the corresponding ketones in quantitative yields without special precautions as dry solvents or inert atmospheres. Remarkably, hydration of asymmetric internal alkynes proceeds with moderate to notable regioselectivities, providing mixtures of the two possible isomers with ratios up to 90 : 10.

Cu(III) Trifluoromethyl Complexes with 1,3‐Diketonate Ligands and Their Versatile Reactivity in C−H Trifluoromethylation

AbstractHigh‐valent Cu(III) trifluoromethyl complexes with 1,3‐diketonates as bidentate oxygen donor ligands LCu(III)(CF3)2 were prepared for the first time and fully characterized, including by X‐ray crystallography. These complexes are bench stable and soluble in most organic solvents. Promising reactivity of Cu(III) trifluoromethyl diketonates in radical and radical‐polar crossover trifluoromethylation reactions was demonstrated. Direct C−H trifluoromethylation of electron‐rich arenes and indoles using Cu(III) trifluoromethyl diketonates under blue light irradiation is described. Azolo‐ and oxy‐trifluoromethylation of terminal alkynes and S‐trifluoromethylation of aromatic thiol can be achieved using LCu(III)(CF3)2 in mild conditions.

Stabilizing Effect of Pre-equilibria: A Trifluoromethyl Complex as a CF2 Reservoir in Catalytic Olefin Difluorocarbenation

Stabilizing Effect of Pre-equilibria: A Trifluoromethyl Complex as a CF₂ Reservoir in Catalytic Olefin Difluorocarbenation

Synthesis of Gold(I)-Trifluoromethyl Complexes and their Role in Generating Spectroscopic Evidence for a Gold(I)-Difluorocarbene Species.

Readily prepared and bench-stable [Au(CF3 )(NHC)] compounds were synthesized by using new methods, starting from [Au(OH)(NHC)], [Au(Cl)(NHC)] or [Au(L)(NHC)]HF2 precursors (NHC=N-heterocyclic carbene). The mechanism of formation of these species was investigated. Consequently, a new and straightforward strategy for the mild and selective cleavage of a single carbon/fluorine bond from [Au(CF3 )(NHC)] complexes was attempted and found to be reversible in the presence of an additional nucleophilic fluoride source. This straightforward technique has led to the unprecedented spectroscopic observation of a gold(I)-NHC difluorocarbene species.

(MeCN)Ni(CF3)3]- and [Ni(CF3)4]2-: Foundations toward the Development of Trifluoromethylations at Unsupported Nickel.

Nickel anions [(MeCN)Ni(CF3)3]- and [Ni(CF3)4]2- were prepared by the formal addition of 3 and 4 equiv, respectively, of AgCF3 to [(dme)NiBr2] in the presence of the [PPh4]+ counterion. Detailed insights into the electronic properties of these new compounds were obtained through the use of density functional theory (DFT) calculations, spectroscopy-oriented configuration interaction (SORCI) calculations, X-ray absorption spectroscopy, and cyclic voltammetry. The data collectively show that trifluoromethyl complexes of nickel, even in the most common oxidation state of nickel(II), are highly covalent systems whereby a hole is distributed on the trifluoromethyl ligands, surprisingly rendering the metal to a physically more reduced state. In the cases of [(MeCN)Ni(CF3)3]- and [Ni(CF3)4]2-, these complexes are better physically described as d9 metal complexes. [(MeCN)Ni(CF3)3]- is electrophilic and reacts with other nucleophiles such as phenoxide to yield the unsupported [(PhO)Ni(CF3)3]2- salt, revealing the broader potential of [(MeCN)Ni(CF3)3]- in the development of "ligandless" trifluoromethylations at nickel. Proof-in-principle experiments show that the reaction of [(MeCN)Ni(CF3)3]- with an aryl iodonium salt yields trifluoromethylated arene, presumably via a high-valent, unsupported, and formal organonickel(IV) intermediate. Evidence of the feasibility of such intermediates is provided with the structurally characterized [PPh4]2[Ni(CF3)4(SO4)], which was derived through the two-electron oxidation of [Ni(CF3)4]2-.

Radical C−H Bond Trifluoromethylation of Alkenes by High‐Valent Copper(III) Trifluoromethyl Compounds

AbstractA 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.magnified image

Synthesis of (MeCN)2Pd(CF3)OTs, a General Precursor to Palladium(II) Trifluoromethyl Complexes LPd(CF3)X

In palladium-catalyzed aryl–trifluoromethyl cross-coupling reactions, reductive elimination is often the rate-limiting step. Stoichiometric studies of reductive elimination have proved effective in evaluating the ability of various ligands to facilitate this challenging elementary step. However, the difficulty of synthesizing palladium trifluoromethyl complexes has hindered the use of this strategy. To address this deficiency, we herein report the synthesis of (MeCN)2Pd(CF3)OTs, an air- and moisture-stable solid that can be used as a common precursor to access various LPd(CF3)X complexes. From this complex we were able to prepare palladium trifluoromethyl complexes bearing many monophosphine, bisphosphine, and diamine ligands that are known to help facilitate Ar–CF3 and vinyl–CF3 reductive elimination. Further, we found that the anionic ligand (X) could be readily changed by modifying the NaX or AgX salt used.

Synthesis and Reactivity of Mn–CF3 Complexes

The synthesis, characterization and reactivity of several bi- and tridentate, N-ligated manganese carbonyl trifluoromethyl complexes are presented. These complexes exhibit elongated Mn–CCF3 bonds (versus Mn(CF3)(CO)5), suggesting a lability that could be utilized for the transfer or insertion of the CF3 functional group into organic substrates. Unlike their Mn–X congeners (X = Cl, Br), these Mn–CF3 complexes exhibit a preference for hard donor ancillary ligands, thus enabling the synthesis of 4 N-ligated Mn–CF3 complexes including a mixed-donor tridentate complex using an NNS Schiff base ([2-(methylthio)-N-(1-(pyridin-2-yl)ethylidene)aniline]). Although we have not yet identified efficient CF3 transfer reactions, fluoride abstraction from the Mn–CF3 complexes using trimethylsilyl triflate affords the first stable Mn fluorocarbenes as evidenced by 19F NMR spectroscopy.

Isolation of OH-bridged Ag(i)/Cu(iii) and ion-pair Cu(i)/Cu(iii) trifluoromethyl complexes with monophosphines.

Cu(iii)-CF3 complexes are important intermediates of both synthetic and mechanistic interest. This study describes the isolation, and spectroscopic and X-ray crystallographic characterization of CuIII-CF3 complexes 2-4 with typical monophosphine ligands PPh3 and Buchwald-type biarylmonophosphines. Distinct from the ion-pair [P2Cu(i)]+[Cu(iii)(CF3)4]- structures of 2 and 4 (P: PPh3 or SPhos), complex 3 exhibits a novel OH-bridged Ag(i)-Cu(iii) dinuclear structure with XPhos-coordinated linear Ag(i) and square planar Cu(iii) components. This is the first heterobimetallic Cu(iii)-CF3 complex confirmed by both solution-phase NMR spectroscopy and solid state X-ray crystal structure analysis. Complex 3 is found to have the LUMO orbital of major σ*(Cu-CF3) nature and electrophilic CF3 ligands. Accordingly, complex 3 is able to trifluoromethylate 2 equivalents of aryl boronic acids in up to quantitative yields, regardless of the inert or oxidative conditions. In contrast, the ion-pair complexes 2 and 4 show low reactivity. This study enriches the coordination and reactivity chemistry of Cu(iii)-CF3 compounds and shows the feasibility of modulation of structures and reactivity by ligand design, which may inspire future efforts on Cu(iii)-CF3 chemistry.

Diverse copper(iii) trifluoromethyl complexes with mono-, bi- and tridentate ligands and their versatile reactivity.

Cu(iii) trifluoromethyl complexes are proposed as essential intermediates for many copper-promoted trifluoromethylation reactions, but remain elusive and scarcely explored. We report herein the isolation and spectroscopic and X-ray crystallographic characterization of diverse CuIII-CF3 complexes (6-10) with varied coordinating motifs (mono-, bi- or tridentate) and formal charges (neutral or monoanionic) for the ligand L (L is pyridine, 2,4,6-trimethylpyridine, quinol-8-yloxide or 2,6-bis(2'-pyridyl)pyridine). Square planar complexes 6, 7 and 9 show rapid dynamic behavior in solution possibly due to the weak Cu-CF3 bonds that can quickly dissociate and recombine with the CF3 radical. In contrast, 10, with octahedral geometry, is more rigid. Reactivity studies show that except for ion-pair complex 8, they are highly reactive for the trifluoromethylation of arylboronic acids and the C-H bond of terminal alkynes. Furthermore, syn-fluoro- and -oxy-trifluoromethylation across the triple bond of alkynes can be achieved using 6 and CsF or NaOPh. These results greatly expand the scope of isolated and well-characterized Cu(iii)-CF3 complexes, and establish their versatile reactivity that may be widely involved in copper-mediated trifluoromethylation reactions, thus substantiating the essential yet undeveloped aspects of trifluoromethylation chemistry.

Synthesis, Characterization, and Reactivity of Palladium Fluoroenolate Complexes.

Cross-coupling reactions of aryl groups with α-fluoro carbonyl compounds catalyzed by palladium complexes have been reported, but palladium fluoroenolate intermediates relevant to such reactions have not been isolated or even detected previously. We report the synthesis, structural characterization, and reactivity of a series of C-bound arylpalladium fluoroenolate complexes ligated by monophosphines and bisphosphines. DPPF-ligated arylpalladium fluoroenolate complexes (DPPF = 1,1-bis(diphenylphosphino)-ferrocene) derived from a monofluoroester, a difluoroester, difluoroamides, and difluoroacetonitrile underwent reductive elimination in high yields. Reductive elimination was faster from complexes containing less electron-withdrawing fluoroenolate groups and longer Pd-C(enolate) bonds than from complexes containing more electron-withdrawing fluoroenolate groups and shorter Pd-C(enolate) bonds. The rates of reductive elimination from these C-bound fluoroenolate complexes were significantly faster than those of the analogous trifluoromethyl complexes.

CF3 Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues were synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes. Addition of CF3 groups also provided a spectroscopic handle for (19)F NMR studies of ligand exchange processes and protein interactions. The lipophilicities of the CF3-functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient D at pH 7.4 (log D7.4). The solution behavior of the CF3-functionalized complexes was characterized in phosphate-buffered saline (PBS) using (19)F NMR, electron paramagnetic resonance (EPR), and UV-vis spectroscopies. These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA). From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA. These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species. EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation. (19)F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA. In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity. Addition of CF3 groups enhances the activity of the indazole complex against A549 nonsmall cell lung carcinoma cells. Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line but showed strong cytotoxicity with CF3 functionalization. Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes.

Isolation and characterization of copper(iii) trifluoromethyl complexes and reactivity studies of aerobic trifluoromethylation of arylboronic acids

Novel phenCuIII–CF3 complexes, isolated purely and fully characterized, are highly reactive for aerobic trifluoromethylation of arylboronic acids.

Synthesis and reductive elimination of arylPd(ii) trifluoromethyl complexes: a remarkable concentration effect on chemoselectivity.

Reductive elimination from Pd(ii) aryl trifluoromethyl complexes is a challenging and elusive step which is accompanied by a number of kinetically more favorable side reactions giving rising to a complex mixture. We report herein the synthesis and isolation of several arylPd(ii) trifluoromethyl complexes (2a-c) and study their electronic structures, photophysical properties and reductive elimination reactivities. A remarkable concentration effect on chemoselectivity is observed for thermal decomposition of (Xantphos)Pd(ii)(Ar)(CF3) (2c) that favors the formation of Ar-CF3 at lower concentrations, but gives increasingly more Ar-Ar homocoupling product to a dominant extent as the concentration of 2c increases. This is solid evidence for the involvement of an intermolecular Ar/CF3 ligand exchange/Ar-Ar reductive elimination mechanism that has been proposed based on DFT computational studies. The interplay between theory and experiment provides valuable insights into the mechanism and kinetics of the key elementary reaction of reductive elimination at Pd(ii), and may thus prompt the design of more efficient Pd-mediated nucleophilic trifluoromethylation reactions.

Ligand-dependent formation of ion-pair CuI/CuIII trifluoromethyl complexes containing bisphosphines.

We report novel ion-pair bisphosphine CuI/CuIII trifluoromethyl complexes [(P2)2CuI]+[CuIII(CF3)4]- (P2 = DPPE, BINAP or Xantphos) featuring tetrahedral CuI and square planar CuIII units that are prepared via oxidative trifluoromethylation of CuI with CF3SiMe3 in the presence of AgF. The bisphosphine CuI/CuIII CF3 complexes are highly reactive for aerobic trifluoromethylation of arylboronic acids to produce trifluoromethylated arenes in good to quantitative yields, which is in sharp contrast to the CuI/CuIII complex with phen/PPh3 ligands (1'). These results not only provide strong evidence that both the neutral and ion-pair CuIII CF3 complexes are competent catalytic species for Cu-mediated oxidative trifluoromethylation reactions, but also have important mechanistic implications that the active catalyst and reaction mechanism should be distinct and ligand-dependent for trifluoromethylation reactions with different types of ancillary ligands.

ChemInform Abstract: Gold Trifluoromethyl Complexes

AbstractReview: synthesis, reactivity and applications of gold trifluoromethyl complexes; 128 efs.

The mechanism, electronic and ligand effects for reductive elimination from arylPd(II) trifluoromethyl complexes: a systematic DFT study.

A systematic theoretical study is reported on the mechanisms of reductive elimination from arylPd(II) trifluoromethyl complexes, an important elementary reaction for Pd-catalyzed trifluoromethylation reactions. Various mechanisms leading to the formation of trifluoromethylated products and also competing side pathways have been evaluated. Furthermore, ligand effects are systematically evaluated which provide valuable information about the favourable properties of the ancillary ligands for promoting reductive elimination of trifluoromethylated products from Pd(II) centers.

Fluoride, bifluoride and trifluoromethyl complexes of iridium(i) and rhodium(i)

Herein we report robust methods for the preparation and full characterisation of a range of Ir(I) and Rh(I) fluoride and bifluoride complexes using N-heterocyclic carbenes (NHCs) as ancillary ligands. The processes that link the fluoride and the bifluoride species are investigated and reports of the first Ir-bifluoride and Ir(I)-NHC and Rh(I)-NHC trifluoromethyl complexes are revealed.

Gold trifluoromethyl complexes

This article reviews the synthesis, reactivity and applications of gold trifluoromethyl complexes, which are the only isolated perfluoroalkyl complexes of gold. The most reported examples are neutral Au(i) complexes of the type [Au(CF3)L], whereas only two Au(ii) trifluoromethyl complexes have been reported, both being diamagnetic and containing a strong Au-Au bond. A number of Au(iii) trifluoromethyl complexes have been prepared by oxidative addition of halogens or iodotrifluoromethane to Au(i) complexes or, in a few cases, by transmetallation reactions. Owing to the limitations of the available synthetic methods, a lower number of examples is known, particularly for the oxidation states (ii) and (iii). Gold trifluoromethyl complexes present singular characteristics, such as thermal stability, strong Au-C bonds and, in some cases, reactive α-C-F bonds. Some of the Au(iii) complexes reported, show unusually easy reductive elimination reactions of trifluoromethylated products which could be applied in the development of gold-catalyzed processes for the trifluoromethylation of organic compounds.