Trifluoromethyl Radicals Research Articles

Theoretical Study for Evaluating and Discovering Organic Hydride Compounds as Potential Novel Methylation Reagents.

Methylation reaction is a fundamental chemical reaction that plays an important role in the modification of drug molecules, DNA, as well as proteins. This work focuses on seeking potential novel methylation reagents through a systematic investigation of the thermodynamics and reactivity of methyl-substituted organic hydride radical cations (XH•+s). In this work, 45 classical and important XH•+s were designed to investigate the relationship between their structure and reactivity, to find excellent or potential methylation reagents. The Gibbs free energy and activation free energy of XH•+ to release the methyl radical in MeCN at 298.15 and 355 K are calculated with the density functional theory (DFT) method to quantitatively measure the reactivity of XH•+ as a methylation reagent in this work. The relationships between structures and reactivities on XH•+s as methylation reagents are well examined. Since we have calculated the Gibbs free energy and activation free energy of trifluoromethyl-substituted organic hydride compound radical cations (X′H•+) releasing trifluoromethyl radicals in MeCN with the DFT method in our previous work, accordingly, the relationship of thermodynamics and reactivity between X′H•+ releasing trifluoromethyl radical and XH•+ releasing methyl radical is discussed in detail. Excitingly, 4 XH•+s (1H•+, 3H•+∼4H•+, and 44H•+) are found to be excellent methyl radical reagents, while 9 XH•+s (5H•+, 6H•+, 9H•+, 10H•+, 12H•+, 13H•+, 15H•+, 43H•+, and 45H•+) are found to be potential methyl radical reagents in chemical synthesis. The molecular library and reactivity database of novel methylation reagents could be established for synthetic chemists to query and use. Our work may offer a theoretical basis and reference experience for screening different substituted organic hydride compounds (YRHs) as alkylation reagents.

Multifunctional Mn(II) Metal-Organic framework for photocatalytic aerobic oxidation and C[sbnd]H direct trifluoromethylation

The design and synthesis of multifunctional metal–organic frameworks (MOFs) has been widely attentions and certain challenges. In this work, we successfully synthesized and designed a 3D Mn-MOF ([Mn4(L)4(DMF)3]n (Mn-MOF), L = 4,4′-(anthracene-9,10-diyl)dibenzoic acid). Structural analysis suggests that the Mn(II) ions in each one-dimensional (1D) arrangement are evenly distributed on both sides of the central pseudoatomic column, and each two Mn(II) ion centers are coordinated with five or four oxygen atoms from five or four L ligands to form a 1D chain structure. The 1D chains are linked one to another via ligands to form a 3D framework that generates 3D channels of rhombic aperture. In this work, the anthracene group with conjugated structure was successfully inserted into the highly porous stable Mn-MOF, which showed obvious photoactivity. In photocatalytic studies, Mn-MOF not only shows high catalytic activity on the aerobic oxidation of benzyl alcohol via the generation of O2− under 420 nm light irradiation but also exhibits well efficiency in the trifluoromethylation of different arenes by the formation of the trifluoromethyl radical (CF3) as an intermediate. Mn-MOF has high recoverability and applicability to various substrates, which makes it a potential photocatalyst.

Visible-Light-Enabled Ph3P/LiI-Promoted Tandem Radical Trifluoromethylation/Cyclization/Iodination of 1,6-Enynes with Togni's Reagent.

We report the visible-light-induced Ph3P/LiI-promoted intermolecular cascade trifluoromethyl radical addition/5-exo-dig cyclization/iodination of 1,6-enynes with Togni's reagent using LiI as the iodine source without the need of the transition metal, oxidant, and base. This reaction promises to be a useful method for the preparation of trifluoromethyl-substituted and vinyl C-I bond-containing pyrrolidines and benzofuran products with good regioselectivity and functional-group tolerance under ambient conditions.

Metal-Free Photochemical Imino-Alkylation of Alkenes with Bifunctional Oxime Esters.

The concurrent installation of C-C and C-N bonds across alkene frameworks represents a powerful tool to prepare motifs that are ubiquitous in pharmaceuticals and bioactive compounds. To construct such prevalent bonds, most alkene difunctionalization methods demand the use of precious metals or activated alkenes. We report a metal-free, photochemically mediated imino-alkylation of electronically diverse alkenes to install both alkyl and iminyl groups in a highly efficient manner. The exceptionally mild reaction conditions, broad substrate scope, excellent functional group tolerance, and facile one-pot reaction protocol highlight the utility of this method to prepare privileged motifs from readily available alkene and acid feedstocks. One key and striking feature of this transformation is that an electrophilic trifluoromethyl radical is equally efficient with both electron-deficient and electron-rich alkenes. Additionally, dispersion-corrected density functional theory (DFT) and empirical investigations provide detailed mechanistic insight into this reaction.

Visible-Light-Induced Photocatalyst-Free Radical Trifluoromethylation.

An attractive, versatile, and operationally simple, visible-light-induced, transition-metal-free, photocatalyst-free, and oxidant-free trifluoromethylation has been demonstrated. Triflic anhydride (Tf2O), being inexpensive and readily available, was chosen as the radical trifluoromethyl source. Thianthrene was used as a recyclable Tf2O-activating reagent, and a high-yielding and scalable trifluoromethylation reaction was achieved. Density functional theory and mechanistic studies showed that a free radical homolytic process excited by visible light is involved in this reaction, generating a key trifluoromethyl radical intermediate.

Multiplex Chemical Labeling of Amino Acids for Protein Footprinting Structure Assessment.

Protein footprinting with mass spectrometry is an established structural biology technique for mapping solvent accessibility and assessing molecular-level interactions of proteins. In hydroxyl radical protein footprinting (HRPF), hydroxyl (OH) radicals generated by water radiolysis or other methods covalently label protein side chains. Because of the wide dynamic range of OH reactivity, not all side chains are easily detected in a single experiment. Novel reagent development and the use of radical chain reactions for labeling, including trifluoromethyl radicals, is a potential approach to normalize the labeling across a diverse set of residues. HRPF in the presence of a trifluoromethylation reagent under the right conditions could provide a "one-pot" reaction for multiplex labeling of protein side chains. Toward this goal, we have systematically evaluated amino acid labeling with the recently investigated Langlois' reagent (LR) activated by X-ray-mediated water radiolysis, followed by three different mass spectrometry methods. We compared the reactivity of CF3 and OH radical labeling for all 20 protein side chains in a competition-free environment. We found that all 20 amino acids exhibited CF3 or OH labeling in LR. Our investigations provide the evidence and knowledge set to perfect hydroxyl radical-activated trifluoromethyl chemistry as "one-pot" reaction for multiplex labeling of protein side chains to achieve higher resolution in HRPF.

A novel type of radical-addition-induced β-fragmentation and ensuing remote functionalization

<h2>Summary</h2> Herein, we report a strategically novel synthetic protocol for the efficient construction of α-trifluoromethyl-β-amino ketone and α-sulfonyl-β-amino ketone derivatives. 4-Isoxazoline is introduced, for the first time, as a class of effective nucleophilic SOMOphile (SOMO, single occupied molecular orbital) that readily reacts with electrophilic open-shell species such as trifluoromethyl radical and sulfonyl radical through a cascade of the homolytic addition/β-fragmentation manifold. The underlying polar effect is ascribed as the dominant factor that guarantees the cascade process both in high reaction efficiency and regioselectivity. This protocol is characterized by its mild reaction conditions and broad substrate scope, whereas the ease of acquiring enantiopure α-polyfluoroalkyl-β-amino ketone derivatives with readily accessed chiral 4-isoxazolines adds extra merit to this reaction.

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

Highly Effective Photocatalytic Radical Reactions Triggered by a Photoactive Metal-Organic Framework.

On account of their inherent reactive properties, radical reactions play an important role in organic syntheses. The booming photochemistry provides a feasible approach to trigger the generation of radical intermediates in organic reaction processes. Thus, developing effective photocatalysts becomes the key step in radical reactions. In this work, the triphenylamine moiety with photoactivity is successfully embedded in a highly porous and stable metal-organic framework (MOF), and the obtained MOF, namely, Zr-TCA, naturally displays a photoactive property derived from the triphenylamine-based ligand. In photocatalytic studies, the triphenylamine-based Zr-TCA not only exhibits a high catalytic activity on the aerobic oxidation of sulfides via the generation of the superoxide radical anion (O2•-) under light irradiation but also shows good efficiency in the trifluoromethylation of arenes and heteroarenes by the formation of the trifluoromethyl radical (CF3•) as an intermediate. Moreover, the high performance of Zr-TCA can be well maintained over a wide range of substrates in these radical reactions, and the recycled Zr-TCA still retains its excellent photocatalytic activity. The high recyclability and catalytic efficiency to various substrates make the constructed triphenylamine-based Zr-TCA a promising photocatalyst in diverse radical reactions.

Synthesis, structure, and electrochemical properties of [LNi(Rf)(C4F8)]- and [LNi(Rf)3]- complexes.

The new anionic nickelate complexes [(MeCN)Ni(C4F8)(CF3)]-, [(MeCN)Ni(C4F8)(C2F5)]-, [(IMes)Ni(C4F8)(CF3)]-, [(IMes)Ni(CF3)3]- (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), and [(F-NHC)Ni(Rf)3]- (F-NHC = 1,3-bis(2,4-F2Ph), 2,4,6-F3Ph- or 3,4,5-F3Ph)imidazol-2-ylidene; (Rf = CF3 or C2F5) were synthesized and structurally characterized. The electrochemical properties of all new compounds were revealed by cyclic voltammetry studies and compared to the known CF3 analogue [(MeCN)Ni(CF3)3]-. The IMes-coordinated complexes exhibited initial oxidation events that were well-separated from a second oxidation process in the cyclic voltammograms. The complexes containing F-substituted NHC ligands [(F-NHC)Ni(CF3)3]- are structurally quite similar to the IMes derivative and reveal also two separated oxidation waves in their cyclic voltammograms. The absolute potentials as well as the separation between the two waves vary with the substitution pattern, suggesting that the NHC ligand environment (NHC = N-heterocyclic carbene) is an interesting platform for the development of new redox-triggered reactions that release trifluoromethyl and perfluoroalkyl radicals upon oxidation.

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

Visible-Light-Promoted Radical Cyclization of N-Arylvinylsulfonamides: Synthesis of CF3/CHF2/CH2CF3-Containing 1,3-Dihydrobenzo[c]isothiazole 2,2-Dioxide Derivatives

AbstractA photocatalyzed and highly efficient trifluoromethylation of N-arylvinylsulfonamides using commercially available CF3SO2Cl as the trifluoromethyl radical source under blue LEDs is reported. The reaction proceeds through radical cyclization under mild conditions. An investigation of the substrate scope is performed to establish a general, synthetically useful protocol for the synthesis of novel trifluoromethylated 1,3-dihydrobenzo[c]isothiazole 2,2-dioxides in moderate to high yields. This method is also successfully applied for the synthesis of difluoromethylated and trifluoroethylated 1,3-dihydrobenzo[c]isothiazole 2,2-dioxides in good to excellent yields.

Copper-Catalyzed Direct Cycloaddition of Imidazoles and Alkenes to Trifluoromethylated Tricyclic Imidazoles.

We reported herein a copper-catalyzed trifluoromethylarylated cycloaddition of imidazoles and olefins using CF3SO2Cl as the radical source to synthesize highly functionalized tricyclic imidazoles. This procedure exhibits a wide range of substrate scope with 25%-93% isolated yields (36 examples). Mechanistic studies were carried out to support a free trifluoromethyl radical pathway.

One-Pot Synthesis of CF3-Substituted Vinyl Trifluoromethanesulfonamides from Imines and Trifluoromethanesulfonic Anhydride.

The one-pot triflation/radical trifluoromethylation/triflation of imines leading to CF3-substituted vinyl trifluoromethanesulfonamides is described. The reaction proceeds via the radical trifluoromethylation of vinyl trifluoromethanesulfonamides as the key step. This reaction is suitable for a variety of imines that contain halogen atoms, electron-donating groups, or electron-withdrawing groups, leading to moderate to good yields. Vinyl trifluoromethanesulfonamides can act as bifunctional reagents whereby they serve as both the trifluoromethyl radical source and the radical acceptor.

Recent advances of sodium sulfinates in radical reactions

Decade advances of sodium sulfinates in radical reactions (2010–2021) were summarized via three categories by mechanisms: (1) sulfonyl radicals (2) RS radicals; (3) trifluoromethyl radicals. Their reactions with arenes, quinoline N-oxides, aryl halides, ethers, alkenes and alkynes, enamides, cinnamic acids, propiolic acids, nitrostyrenes, 2-methylquinolines, enamines, ketones, diazoium salts, isocyanides, amines, NH-sulfoximines or Selectfluor will be discussed.

A Readily Available Trifluoromethylation Reagent and Its Difunctionalization of Alkenes.

Trifluoromethyl substitution is notably popular in pharmaceuticals and agrochemicals; however, trifluoromethylated compounds normally rely on the use of cost-prohibitive or gaseous trifluoromethylating reagents, which diminishes the general applicability of these methods. Herein an efficient trifluoromethylation reagent trifluoromethylsulfonyl-pyridinium salt (TFSP) was reported, which can be readily prepared from cheap and easily available bulk industrial feedstocks. TFSP can generate a trifluoromethyl radical under photocatalysis and realize the effective azido- or cyano-trifluoromethylation reactions of alkenes.

Rational Design and Development of Low‐Price, Scalable, Shelf‐Stable and Broadly Applicable Electrophilic Sulfonium Ylide‐Based Trifluoromethylating Reagents

Main observation and conclusionThe development of two highly reactive electrophilic trifluoromethylating reagents (trifluoromethyl)(4‐nitrophenyl)bis(carbomethoxy)methylide (1g) and (trifluoromethyl)(3‐chlorophenyl)bis(carbomethoxy)methylide (1j) through structure‐activity study was described. Under mild conditions, reagent 1g reacted with β‐ketoesters and silyl enol ethers to give α‐trifluoromethylated‐β‐ketoesters or α‐trifluoromethylated ketones in high yields. In addition, reagent 1g could serve as a trifluoromethyl radical for a variety of trifluoromethylative transformations under visible light irradiation, including radical trifluoromethylation of electron‐rich indoles and pyrroles and sodium aryl sulfinates as well as trifluoromethylative difunctionalization with styrene derivatives. On the other hand, as a complimentary, under reductive coupling conditions, reagent 1j reacted with a variety of (hetero)aryl iodides for the formation of trifluoromethylated (hetero)arenes.

Metal‐, Photocatalyst‐, Light‐ and Electrochemical‐Free C‐3 Trifluoromethylation of Quinoxalin‐2(1H)‐ones, Imidazo[1,2‐a]pyridines and 2H‐Indazoles

AbstractWe report an efficient protocol for the synthesis of 3‐trifluoromethylquinoxalin‐2(1H)‐ones, 3‐trifluoromethylimidazo[1,2‐a]pyridines and 3‐(trifluoromethyl)‐2H‐indazoles under metal‐, photocatalyst‐, light‐ and electrochemical‐free conditions. The combination of Langlois’ reagent (sodium triflinate) with the oxidant (NH4)2S2O8 in DMSO: H2O (10 : 1) works as an efficient reagent system to promote this free radical trifluoromethylation reaction. The trifluoromethyl radical generated by the oxidation of sodium triflinate with (NH4)2S2O8 attacks on to the C‐3 position of quinoxalin‐2(1H)‐ones, imidazo[1,2‐a]pyridines and 2H‐indazoles; and the excess SO4•− completes the reaction furnishing their respective 3‐trifluoromethyl derivatives in very good to excellent yields. Radical scavenging experiments with (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO), butylated hydroxy toluene (BHT), and 1,1‐diphenylethylene also prove the participation of radical.

Photocatalyzed Dual-Oxidative Trifluoromethylthio-Trifluoromethylation of Alkenes with CF 3 SO 2 Na

A novel photocatalyzed trifluoromethylthio-trifluoromethylation of alkenes has been developed, using CF3SO2Na as both CF3 and SCF3 source. This photocatalyzed dual-oxidative strategy, which combine...

Direct C(sp3)−H Trifluoromethylation of Unactivated Alkanes Enabled by Multifunctional Trifluoromethyl Copper Complexes

AbstractA mild and operationally simple C(sp3)−H trifluoromethylation method was developed for unactivated alkanes by utilizing a bench‐stable CuIII complex, bpyCu(CF3)3, as the initiator of the visible‐light photoinduced reaction, the source of a trifluoromethyl radical as a hydrogen atom transfer reagent, and the source of a trifluoromethyl anion for functionalization. The reaction was initiated by the generation of reactive electrophilic carbon‐centered CF3 radical through photoinduced homolytic cleavage of bpyCu(CF3)3, followed by hydrogen abstraction from an unactivated C(sp3)−H bond. Comprehensive mechanistic investigations based on a combination of experimental and computational methods suggested that C−CF3 bond formation was enabled by radical–polar crossover and ionic coupling between the resulting carbocation intermediate and the anionic CF3 source. The methylene‐selective reaction can be applied to the direct, late‐stage trifluoromethylation of natural products and bioactive molecules.