Trifluoromethyl Research Articles

Enantioselective Desymmetrization of Trifluoromethylated Tertiary Benzhydrols via Hydrogen-Acceptor-Free Ir-Catalyzed Dehydrogenative C-H Silylation: Decisive Role of the Trifluoromethyl Group.

Although the trifluoromethyl (CF3) group is one of the most important fluorinated groups owing to its significant ability to modulate pharmacological properties, constructing trifluoromethylated stereogenic centers in an enantioselective manner has been a formidable challenge. Herein, we report the development of the enantioselective desymmetrization of trifluoromethylated benzhydrols via intramolecular dehydrogenative silylation using Ir catalysts with chiral pyridine-oxazoline (PyOX) ligands. The produced benzoxasilol was transformed into several unsymmetrical benzhydrols via iododesilylation and subsequent transition-metal-catalyzed cross-coupling reactions. Moreover, the same Ir catalyst system was used for the kinetic resolution of unsymmetrical trifluoromethylated benzhydrols.

Electrocatalytic hydrogen evolution by cobalt(Ⅲ) triphenyl corrole bearing different number of trifluoromethyl groups

Hydrogen production from electrolyzing water is known as the most promising hydrogen production method. To further understand the effect of steric hindrance and electron-withdrawing groups on catalysts, four cobalt triphenyl corroles bearing different number of ortho-trifluoromethyls (1, 2, 3, 4) had been synthesized and used as hydrogen evolution electrocatalysts. These cobalt corroles showed effective electrocatalytic hydrogen evolution activity in organic medium and neutral aqueous medium, with turnover frequency ranging from 100 s−1 to 220 s−1 using 32 equivalents of trifluoroacetic acid proton source in DMF. The electrocatalytic HER goes via competitive ECEC or EECC pathway depending on the used proton source. The electrocatalytic HER activity varies obviously with the number of the peripheral ortho- groups. This work is helpful for the design of new metal corrole HER electrocatalyst.

Preparation and properties of high-temperature resistant bisphthalonitrile resins containing trifluoromethyl groups reinforced by poly (aryl ether nitrile) capped by phthalonitrile and their composites

A new series of high-temperature resistant bisphthalonitrile resins containing trifluoromethyl groups were prepared based on 4,4’-(hexafluoroisopropylidene) bisphthalonitrile (BFPh), which was toughened by hexafluoroisopropylidene-containing poly (aryl ether nitrile) oligomer capped by phthalonitrile (FPEN-Ph) in the different content. In addition, glass fiber reinforced composites were prepared by hot pressing process. The structure of the oligomer was characterized by FTIR and 1HNMR. The curing behavior of the blends was studied by DSC. Thermal stability and mechanical properties were also studied. The results showed that the introduction of appropriate content of FPEN-Ph could improve the reactivity of the curing reaction. TGA and DMA results showed that the cured polymers and composites had excellent thermal properties. The residual mass of FPEN-Ph content of 10% at 800°C was 72.4%, and the 5% thermal degradation temperature (T5%) under inert atmosphere was 530°C. The flexural strength of glass fiber reinforced composites was about 592.7 MPa, and the shear strength was about 61.6 MPa, showing excellent mechanical properties. The high-tech thermosetting resin was toughened and enhanced at the same time without reducing heat resistance.

Recent Advance in the C−F Bond Functionalization of Trifluoromethyl Aromatic and Carbonyl Compounds

AbstractThe 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.

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles.

A visible-light-promoted research protocol for constructing dihydropyrido[1,2-a]indolone skeletons is herein described proceeding through a cascade cyclization mediated by trifluoromethyl radicals. This method allows the efficient synthesis of various indole derivatives without the need of photocatalysts or transition-metal catalysts. Mechanism experiments indicate that the process involves a radical chain process initiated by the homolysis of Umemoto's reagent. This straightforward method enables a rapid access to heterocycles containing a trifluoromethyl group.

Site‐Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines**

AbstractThe 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.

Site-Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines.

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.

Copper Dispersed Covalent Organic Framework for Azide-Alkyne Cycloaddition and Fast Synthesis of Rufinamide in Water.

A crystalline porous bipyridine-based Bpy-COF with a high BET surface area (1864m2g-1) and uniform mesopore (4.0nm) is successfully synthesized from 1,3,5-tris-(4'-formyl-biphenyl-4-yl)triazine and 5,5'-diamino-2,2'-bipyridine via a solvothermal method. After Cu(I)-loading, the resultant Cu(I)-Bpy-COF remained the ordered porous structure with evenly distributed Cu(I) ions at a single-atom level. Using Cu(I)-Bpy-COF as a heterogeneous catalyst, high conversions for cycloaddition reactions are achieved within a short time (40min) at 25°C in water medium. Moreover, Cu(I)-Bpy-COF proves to be applicable for aromatic and aliphatic azides and alkynes bearing various substituents such as ester, hydroxyl, amido, pyridyl, thienyl, bulky triphenylamine, fluorine, and trifluoromethyl groups. The high conversions remain almost constant after five cycles. Additionally, the antiepileptic drug (rufinamide) is successfully prepared by a simple one-step reaction using Cu(I)-Bpy-COF, proving its practical feasibility for pharmaceutical synthesis.

Decaging-to-labeling: Development and investigation of quinone methide warhead for protein labeling

Biomolecule labeling in living systems is crucial for understanding biological processes and discovering therapeutic targets. A variety of labeling warheads have been developed for multiple biological applications, including proteomics, bioimaging, sequencing, and drug development. Quinone methides (QMs), a class of highly reactive Michael receptors, have recently emerged as prominent warheads for on-demand biomolecule labeling. Their highly flexible functionality and tunability allow for diverse biological applications, but remain poorly explored at present. In this regard, we designed, synthesized, and evaluated a series of new QM probes with a trifluoromethyl group at the benzyl position and substituents on the aromatic ring to manipulate their chemical properties for biomolecule labeling. The engineered QM warhead efficiently labeled proteins both in vitro and under living cell conditions, with significantly enhanced activity compared to previous QM warheads. We further analyzed the labeling efficacy with the assistance of density functional theory (DFT) calculations, which revealed that the QM generation process, rather than the reactivity of QM, contributes more predominantly to the labeling efficacy. Noteworthy, twelve nucleophilic residues on the BSA were labeled by the probe, including Cys, Asp, Glu, His, Lys, Asn, Gln, Arg, Ser, Thr, Trp and Tyr. Given their high efficiency and tunability, these new QM warheads may hold great promise for a broad range of applications, especially spatiotemporal proteomic profiling for in-depth biological studies.

Modified aryldifluorophenylsilicates with improved activity and selectivity in nucleophilic fluorination of secondary substrates.

Nucleophilic fluorination of secondary aliphatic substrates, especially of halides, still remains a challenge. Among the available reagents, TBAT belongs to one of the best choices due to its stability, affordable price and low toxicity. With the aim to improve its selectivity, we synthesized three analogues modified in the aryl part of the TBAT reagent with one or two electron donating methoxy groups or with one electron withdrawing trifluoromethyl group. All three reagents are air-stable compounds and their structure was confirmed by a single crystal X-ray analysis. In testing the reactivity and selectivity of the reagents with a library of secondary bromides, as well as of other selected primary and secondary substrates, we found that substitution with methoxy groups mostly improves both reactivity and selectivity compared to TBAT, while the substitution with trifluoromethyl group leads to inferior results. Difluorosilicates modified by more than two electron donating methoxy groups proved to be unstable and decomposed spontaneously to the HF2 - anion. DFT calculations of tetramethylammonium analogues of the studied reagents disclosed that the substitution of the phenyl group with the methoxy substituent lowers the transitions state energy of the decomposition to a fluorosilane-fluoride complex, while the substitution with the trifluoromethyl group has an opposite effect.

Rigidochromism of tetranuclear Cu(I)-pyrazolate macrocycles: steric crowding with trifluoromethyl groups.

Macrocyclic Cu(I)-pyrazolate tetramers (Cu4pz4) can fold into compact structures with luminescent Cu4 cores whose emission wavelengths are sensitive to steric effects along the periphery of the macrocycle. Introducing CF3 at the C4 position of 3,5-di-tBu-pyrazolate increases steric crowding that modifies the conformational behavior of the Cu4pz4 complex, highlighted by a low-temperature martensitic transition. Variable-temperature analysis of solid-state luminescence reveal an unexpected blueshifting of emission with rising temperature.

Electrochemical oxidative cyclization of N-allylamides for the synthesis of CF3-containing benzoxazines and oxazolines.

The introduction of trifluoromethyl (-CF3) groups into compounds is a common synthetic strategy in organic chemistry. Commonly used methods for introducing trifluoromethyl groups are limited by harsh reaction conditions, low regioselectivity, or the need for excess reagents. In this study, a facile electrochemical oxidative and radical cascade cyclization of N-(2-vinylphenyl)amides for the synthesis of CF3-containing benzoxazines and oxazolines was obtained. This sustainable protocol features inexpensive and durable electrodes, a wide range of substrates, diverse functional group compatibility under transition-metal-free, external-oxidant-free, and additive-free conditions, and can be applied in an open environment.

Preparation of fluorinated polyimides with low dielectric constants and low dielectric losses by combining ester groups and triphenyl pyridine structures

By superimposing triphenylpyridine structure, trifluoromethyl group, and ester group, we have obtained PIs with excellent overall performance such as low dielectric and low loss.

Chiral π-Cu(ii)-catalyzed site-, exo/endo-, and enantioselective dearomative (3 + 2) cycloadditions of isoquinolinium ylides with enamides, dienamides, and a trienamide.

Here, we report a highly effective dearomative (3 + 2) cycloaddition reaction between isoquinolinium ylides and α,β-enamides, α,β-γ,δ-dienamides, or an α,β-γ,δ-ε,ζ-trienamide, which is catalyzed by a chiral π-Cu(ii) complex (1-10 mol%) and proceeds in a site-selective, exo/endo-selective, and enantioselective manner. The (3 + 2) cycloaddition involving the α,β-enamides proceeds with high exo-selectivity and enantioselectivity. This method is applicable to various substrates including α-substituted, α,β-disubstituted, or β,β-disubstituted α,β-enamides, which are compounds with an intrinsically low reactivity. This method provides synthetic access to pyrroloisoquinoline derivatives with up to three chiral carbon centers, including those featuring fluorine and trifluoromethyl groups, as well as quaternary carbon centers. The (3 + 2) cycloaddition involving α,β-γ,δ-dienamides proceeds with high γ,δ-site-selectivity and enantioselectivity, whereby the exo/endo-selectivity depends on the substrates and ligands. Remarkably, the (3 + 2) cycloaddition of δ-phenyl-α,β-γ,δ-dienamide proceeds with high α,β-site-selectivity, exo-selectivity, and enantioselectivity. In a manner similar to the reaction with the α,β-γ,δ-dienamides, α,β-γ,δ-ε,ζ-trienamide furnishes a (3 + 2) cycloadduct with good ε,ζ-site-selectivity, endo-selectivity, and enantioselectivity.

Synthesis of Nucleotides Bearing the 2'-O-Trifluoromethyl Group and Their Application in RNA Analogs Preparation.

The integration of fluorine atoms into biologically active organic compounds has proved to be a vital technique in small molecule drugs. This technique can substantially enhance crucial properties, including metabolic stability, lipophilicity, and bioavailability, often with a mere addition of a single fluorine atom or a trifluoromethyl group. Over the past few decades, this concept has also been applied in nucleic acid chemistry. A commonly employed 2'-OH substitution is the introduction of a 2'-deoxy-2'-fluoro (2'-F) group. The strong electronegativity of fluorine prompts the modified siRNA to readily adopt a C3'-endo conformation, resulting in significant advantages in terms of binding affinity. To enrich the toolbox of chemical modification of oligonucleotides, the replacement of the 2'-OH with the 2'-O-trifluoromethyl group has been developed in RNA analog synthesis. Oligodeoxynucleotides containing the 2'-O-trifluoromethyl group can greatly increase the thermal stability of DNA/RNA duplexes depending on the position and amount of the modification. Moreover, 2'-O-trifluoromethylated oligodeoxynucleotide also exhibited a slightly higher resistance to snake venom phosphodiesterase than the unmodified oligodeoxynucleotide. The 2'-O-trifluoromethylated oligonucleotides can emerge as a label to study RNA structure and function as well, or to develop DNA/RNA-based diagnostics. Hence, it is necessary to report an effective method for the synthesis, deprotection, purification, and characterization of oligonucleotides bearing a 2'-O-trifluoromethyl group. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Preparation of 6-N-benzoyl-5'-O-dimethoxytrityl-2'-O-trifluoromethyl adenosine 3'-(2-cyanoethyl N,N-diisopropyl)phosphoramidite Basic Protocol 2: Preparation of 4-N-acetyl-5'-O-dimethoxytrityl-2'-O-trifluoromethyl cytidine 3'-(2-cyanoethyl N,N-diisopropyl)phosphoramidite Basic Protocol 3: Preparation of 2-N-isobutyryl-5'-O-dimethoxytrityl-2'-O-trifluoromethyl guanine 3'-(2-cyanoethyl N,N-diisopropyl)phosphoramidite Basic Protocol 4: Preparation of 5'-O-dimethoxytrityl-2'-O-2-trifluoromethyl uridine 3'-(2-cyanoethyl N,N-diisopropyl) phosphoramidite Basic Protocol 5: Solid-phase synthesis of 2'-O-trifluoromethylated RNA analogs Basic Protocol 6: Deprotection and purification of 2'-O-trifluoromethyl-RNAs.

Effects of solvatomorphism, the nature of a chelating ligand synthon and a counterion on the single crystal XRD structure and SMM properties of paramagnetic monocapped cobalt(II) tris-pyrazoloximates.

A series of monocapped cobalt(II) tris-pyrazoloximates was obtained through the template condensation of the corresponding pyrazoloxime, phenylboronic acid and a suitable cobalt(II) halogenide. Comparing 3-acetylpyrazoloxime versus its methine-containing homolog, the former produced cobalt(II) clathrochelates in substantially higher yields due to the electron donating effect of the methyl substituent, increasing the N-donor ability of its oxime group. Their less N-donor analog with the electron acceptor trifluoromethyl group did not form cobalt(II) complexes of this type. In all their solvent-free and solvent-containing crystals, the encapsulated cobalt(II) ion adopted a high-spin state, as gauged by the Co-N bond lengths of 2.112(4)-2.188(9) Å, and was located almost in the center of its CoN6-coordination polyhedron. Their CoN6-polyhedra had an almost ideal trigonal-prismatic (TP) geometry with distortion angles φ below 4°. This TP-like geometry was assisted by hydrogen bonding between their NH groups and the apical counterion. The absence of methyl groups makes them close to an ideal TP. In contrast, stronger N-H⋯Cl hydrogen bonds occurred in the methyl-containing complex, while the Co-N bond lengths stayed the same at 2.144(2) Å on average. In its solvates with benzene, chloroform and acetone, there is a clear tendency for φ to decrease from 2.7(3)° to 0.47(13)°. The comparable effects of the ribbed methyl substituents, the cross-linking counterion and the lattice solvent on their molecular geometry were observed; the larger the distortions from an ideal TP geometry, the stronger the hydrogen bonds to the corresponding apical halogenide anion. The analysis of the experimental AC- and DC-magnetometry data for their fine-crystalline samples suggests that the passing from the derivative of the methyl-substituted synthon to that of its methine-containing homolog caused a substantial decrease in the magnetic susceptibility value χT and an increase in the QTM contribution to the magnetic relaxation. The effect of a cross-linking halogenide counteranion on the Orbach remagnetization barrier is greater than that of the solvatomorphism of their crystals.

Fluorescence quenching of deprotonated phenylurea through twisting motion induced by an electron-donating substituent group.

The excited-state proton transfer (ESPT) reaction between anthracen-2-yl-3-phenylurea (PUA) derivatives and tetrabutylammonium acetate (TBAAc) in dimethyl sulfoxide (DMSO) solvent was theoretically investigated using time-dependent density functional theory. The electron-donating methoxy group (OMe) and electron-withdrawing trifluoromethyl group (CF3) were bonded to 2PUA to form OMe-2PUA and CF3-2PUA, respectively. Two hydrogen bonds formed in the 1 : 1 hydrogen-bonded complexes between the 2PUA derivative and acetate ion (AcO-), namely N1-H1⋯O1 and N2-H2⋯O2. Strong charge transfer (CT) due to the electron-donating OMe group led to H1 transfer in the S1 state for the OMe-2PUA:AcO- hydrogen-bonded complex. On the contrary, weak CT due to the electron-withdrawing CF3 group led to H2 transfer in the S1 state for CF3-2PUA. After the ESPT reaction, the binding energies of the hydrogen-bonded complexes strongly decreased in both cases, and this promoted the separation of contact-ion pairs (CIPs*) and formed different types of anionic species. CF3-2PUA- could keep its nearly planar structure in the S1 state and emit "abnormal" fluorescence. On the other hand, the anionic OMe-2PUA- underwent a twisting motion to form a twisted structure in the S1 state with very low energy, and this led to a rapid internal conversion (IC) to quench long-wave fluorescence in the emission spectra.

Synthesis of C-C bonded trifluoromethyl-based high-energy density materials via the ANRORC mechanism.

A trifluoromethyl group substituted C-C bonded nitrogen rich energetic material 3-(3-nitro-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (4), its hydroxyl amine (5) and 3,6,7-triamino-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-2-ium (6) salts and hydrazinium 5-(3-nitro-1H-pyrazol-4-yl)-3-(trifluoromethyl)-1,2,4-triazol-1-ide (7) were synthesized and fully characterized using infrared spectroscopy (IR), multinuclear magnetic resonance (NMR) spectroscopy (1H, 13C, and 19F), high-resolution mass spectrometry (HRMS), elemental analysis (EA) and differential scanning calorimetry (DSC) studies. Furthermore, compounds 4 and 7 were confirmed using single-crystal X-ray diffraction studies (SC-XRD). All compounds possess good density (1.70-1.80 g cm-3), detonation velocity (6432-7144 m s-1), pressure (16.38-20.31 GPa), and thermal stability (>170 °C). They are insensitive towards mechanical stimuli, impact (IS > 35 J) and friction (FS > 288 N). Overall, due to their balanced performance, these compounds can be a better replacement for presently used explosives such as trinitrotoluene (TNT).

Visible Light-Mediated Selective C—F Bond Cleavage of Trifluoromethyl Groups and Its Application in Synthesizing gem-Difluoro-Containing Compounds

Visible Light-Mediated Selective C—F Bond Cleavage of Trifluoromethyl Groups and Its Application in Synthesizing <i>gem</i>-Difluoro-Containing Compounds

Synthesis of fluorescent 5-heteroarylpyrimidine-containing oligonucleotides via post-synthetic trifluoromethyl conversion.

Post-synthetic conversion of the trifluoromethyl group to a heteroaryl group at the C5 position of the pyrimidine base in DNA oligonucleotides was achieved. Specifically, the oligonucleotides containing 5-trifluoromethylpyrimidine bases were treated with o-phenylenediamines and o-aminothiophenols as nucleophiles to afford the corresponding 5-(benzimidazol-2-yl)- and 5-(benzothiazol-2-yl)-pyrimidine-modified bases. Furthermore, evaluation of the fluorescence properties of the obtained oligonucleotides revealed that among them the oligonucleotide containing 5-(5-methylbenzimidazol-2-yl)cytosine exhibited the highest fluorescence intensity. These results indicated that post-synthetic trifluoromethyl conversion, which is practical and operationally simple, is a powerful tool for exploring functional oligonucleotides.