Trifluoromethyl Research Articles

Copper-Catalyzed Synthesis of 4-CF3-1,2,3-Triazoles: An Efficient and Facile Approach via Click Reaction.

Incorporation of a trifluoromethyl group with 1,2,3-triazoles motifs was described. We explored a click reaction approach for regioselective synthesis of 1-susbstituted-4-trifluoromethyl-1,2,3-triazoles in which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) reacts with commercial 2-bromo-3,3,3-trifluoropropene (BTP) to form 3,3,3-trifloropropyne (TFP) in situ. Arising from merits associated with the availability and stability of BTP, and the high efficiencies of CuI/1,10-Phenanthroline (Phen)-catalyzed cycloaddition reactions of azides with alkynes, this readily performed click process takes place to form the target 1,2,3-triazoles in high yields, and with a wide azide substrate scope. The potential value of this protocol was demonstrated by its application to a gram-scale reaction.

Synthesis and evaluation of a rociletinib analog as prospective imaging double mutation L858R/T790M in non-small cell lung cancer

Context: Imaging the mutation status of non-small cell lung cancer (NSCLC) using radiolabeled tyrosine kinase inhibitor (TKI) analogs has garnered interest due to their unique interactions with the target epidermal growth factor receptor (EGFR). Rociletinib is a third-generation TKI that selectively inhibits the activated EGFR L858R/T790M mutations while sparing the wild-type EGFR. Aims: To synthesize a rociletinib analog for radioiodination purposes and evaluate its affinity for EGFR L858R/T790M using molecular docking and in vitro cytotoxicity assay. Methods: The rociletinib analog, N-{3-[(4-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-2-yl)amino] -5-iodophenyl} acrylamide (I-RMFZ), was produced by adding iodine into the diaminophenyl group and changing the position of the trifluoromethyl group. A simulation of molecular docking was conducted using the AutoDock Vina software suite. IC50 of I-RMFZ was determined using a cell cytotoxicity assay. Results: I-RMFZ was successfully synthesized through multistep reactions. Molecular docking revealed that I-RMFZ interacts with the EGFR L858R/T790M mutation. Cytotoxicity assay demonstrated that I-RMFZ had a high selectivity towards EGFR L858R/T779M mutation. Conclusions: I-RMFZ is notable for radioiodination and is anticipated to be comparable with in vivo features of rociletinib. Thus, I-RMFZ can potentially be developed as an imaging agent for NSCLC through preclinical assay.

Density Functional Theory-Based Approach For Dielectric Constant Estimation of Soluble Polyimide Insulators.

Evaluation of the insulating properties of polymers, such as the dielectric constant and dissipation factor, is crucial in electronic devices, including field-effect transistors and wireless communication applications. This study applies density functional theory (DFT) to predict the dielectric constant of soluble polyimides (SPIs). Various SPIs containing trifluoromethyl groups in the backbone with different pendant types, numbers, and symmetries are successfully synthesized, and their dielectric constants are evaluated and compared with the DFT-estimated values. Two types of DFT-optimized SPIs, single-chain and stacked-chain models, are used to describe the local geometries of the SPIs. In addition, to reveal the relationship between the molecular structure and dielectric constant, further investigations are conducted by considering the dielectric constant of composing ionic and electronic components. The DFT-estimated static dielectric constant of the single-chain model accurately reproduces the corresponding experimental value with at least 80% accuracy. Our approach provides a rational and accelerated strategy to evaluate polymer insulators for electronic devices based on cost-effective DFT calculations.

Rigid and crosslinkable polyimide curing epoxy resin with enhanced comprehensive performances

The flammability and hydrophilicity of epoxy resins hinder their applications in the high-tech fields of aerospace and electronics. To break these limitations, a highly rigid and hydrophobic polyimide structure has been designed as the harder for epoxy resins. This diamine monomer polyimide (PI–OH) featured a new spiral fluorene-xanthene core doubly grafted phenolic hydroxyl units, to match the commercial bi-trifluoromethyl dianhydride monomer. The curing performance of the polyimide PI-OH was studied in a concentration gradient fashion with the epoxy resin N, N, N′, N′-tetraglycidyl-4, 4′-diaminodiphenylmethane (TGDDM), and compared to the benchmark curer 4, 4′-diaminodiphenyl sulfone (DDS). Due to the unique structural rigidity of spiral crosslinks and the compatibility of the polyimide, the cured PI-OH/TGDDM exhibited Young's modulus of 6.18 GPa and a hardness of 480 MPa, 27.7% and 42.3% higher than that of DDS/TGDDM, demonstrating excellent comprehensive performance. The introduction of PI-OH also reduced the curing temperature with higher curing activity. Resin with 40% loading of the polyimide reached a residual carbon rate of 49.0% at 700 °C (under nitrogen), presenting flame retardancy superior to DDS/TGDDM. Furthermore, the involvement of trifluoromethyl groups reduced the surface free energy and hydrophilicity, lowering the water absorption rate for the modified epoxy resin. This study opens an avenue for comprehensively improving the performance of epoxy resins at lower curing temperatures, which has broad application prospects in aerospace and motor vehicle fields.

Asymmetric Fluorocyclization of Difluoroalkenes with Concomitant Formation of a Trifluoromethyl Group.

Asymmetric electrophilic fluorination of difluoroalkenes remains undeveloped because of the poor reactivity of difluoroalkenes with electrophiles. However, such reactions, if feasible, are expected to be useful for the synthesis of chiral heterocyclic compounds with a trifluoromethyl group at the stereogenic center. In this Letter, we disclose the first example of asymmetric fluoroamide cyclization of difluoroalkenes using our dianionic phase-transfer catalyst. This reaction provides unique chiral trifluoromethylated oxazoline derivatives at a synthetically useful level.

Stabilization of LiCoO2 Cathodes in High Voltage Lithium Metal Batteries Through 2-(Trifluoromethyl)Benzamide (2-TFMBA) Electrolyte Additives.

Increasing the charging cutoff voltage of LiCoO2 to 4.6V is significant for enhancing battery density. However, the practical application of Li‖LiCoO2 batteries with a 4.6V cutoff voltage faces significant impediments due to the detrimental changes under high voltage. This study presents a novel bifunctional electrolyte additive, 2-(trifluoromethyl)benzamide (2-TFMBA), which is employed to establish a stable and dense cathode-electrolyte interface (CEI). Characterization results reveal that an optimized CEI is achieved through the synergistic effects of the amide groups and trifluoromethyl groups within 2-TFMBA. The resulting CEI not only enhances the structural stability of LiCoO2 but also serves as a high-speed lithium-ion conduction channel, which expedites the insertion and extraction of lithium ions. The Li‖LiCoO2 batteries with 0.5wt% 2-TFMBA achieves an 84.7% capacity retention rate after enduring 300 cycles at a current rate of 1C, under a cut-off voltage of 4.6V. This study provides valuable strategic insights into the stabilization of cathode materials in high-voltage batteries.

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.

Pyrazole Scaffold: Potential PTP1B Inhibitors for Diabetes Treatment.

The overexpression of the Protein Tyrosine Phosphatase 1B (PTP1B), a key role in the development of insulin resistance, diabetes (T2DM) and obesity, seems to have a substantial impact as a negative regulator of the insulin and leptin signaling pathways. Therefore, inhibiting PTP1B is a prospective therapeutic approach for the treatment of diabetes and obesity. However, the pyrazole scaffold is expected to be of significant pharmaceutical interest due to its broad spectrum of pharmacological actions. This study aims to focus on the significance of pyrazole scaffold in medicinal chemistry, the impact of PTP1B in diabetes and the therapeutic approach of pyrazole scaffold to treat T2DM. A comprehensive analysis of the published literature in several pharmaceutical and medical databases, such as the Web of Science (WoS), PubMed, ResearchGate, ScienceDirect etc., were indeed successfully completed and classified accordingly. Results: As reviewed, the various derivatives of the pyrazole scaffold exhibited prominent PTP1B inhibitory activity. The result showed that derivatives of oxadiazole and dibenzyl amine, chloro substituents, 1, 3-diaryl pyrazole derivatives with rhodanine-3-alkanoic acid groups, naphthalene and also 1, 3, 5-triazine-1H-pyrazole-triazolothiadiazole derivatives, octyl and tetradecyl derivative, indole- and N-phenylpyrazole-glycyrrhetinic acid derivatives with trifluoromethyl group, 2,3-pyrazole ring-substituted-4,4-dimethyl lithocholic acid derivatives with 4- fluoro phenyl substituted and additional benzene ring in the pyrazole scaffold significantly inhibits PTP1B. In silico study observed that pyrazole scaffold interacted with amino acid residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. Diabetes is a metabolic disorder that elevates the risk of mortality and severe complications. PTP1B is a crucial component in the management of diabetes and obesity. As a result, PTP1B is a promising therapeutic target for the treatment of T2DM and obesity in humans. We concluded that the pyrazole scaffold has prominent inhibitory potential against PTP1B.

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.