Sodium Triflinate Research Articles

Redox-Neutral Decarboxylative and Desulfonylative C(sp3) Trifluoromethylation: Method Development and Mechanistic Inquiry.

Sodium triflinate (CF3SO2Na) is an inexpensive bench-stable radical CF3 source that is often activated by external oxidants such as peroxides. However, despite the commercial accessibility of CF3SO2Na, the salt has never been applied to decarboxylative trifluoromethylation due to challenges in controlled cross-radical coupling. We report a redox-neutral approach to decarboxylative C(sp3) trifluoromethylation of carboxylic acid derivatives. Mechanistic inquiry is performed to address the limitations in scope.

Proflavine-catalysed trifluoromethylation of α,β-unsaturated carbonyls

Radical trifluoromethylation of α,β-unsaturated carbonyl compounds has been achieved using proflavine hemisulfate as a metal-free photoredox catalyst under visible light irradiation. With sodium triflinate (CF3SO2Na) and trifluoroacetic acid as the CF3 and H-atom sources in oxygen-free acetonitrile, hydrotrifluoromethylation addition takes place across the double bond of substrates such as maleimide, enone and acrylamide. In contrast, CF3-substitution at the double bond is preferred for coumarin, uracil and (hetero)arenes while both addition and substitution are observed for thymine. A mechanism has been proposed where the excited-state proflavine hemisulfate performs a dual role as an electron acceptor to generate the CF3 radical and as a H-atom abstraction agent for the CF3-substitution reaction. A proflavine-H radical species is suggested to be the H-atom donor for hydrotrifluoromethylation.

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.

Visible-Light Photocatalysis of Eosin Y: HAT and Complementing MS-CPET Strategy to Trifluoromethylation of β-Ketodithioesters with Langlois' Reagent.

A metal- and oxidant-free photoinduced strategy for thioxo sulfur-selective trifluoromethylation of β-ketodithioesters at room temperature is reported. Excellent Z/E-stereoselectivity has been achieved with cheap and viable Langlois' reagent (CF3SO2Na, sodium triflinate) in the presence of eosin Y, which acts as a hydrogen atom transfer (HAT) catalyst. The reaction proceeds via disulfide intermediate disulfanediylbis(3-(alkylthio)-1-phenylprop-2-en-1-one) (a dimer of β-ketodithioester) followed by complementing proton-coupled electron transfer-mediated reverse HAT cycle of eosin Y. This operationally simple and efficient protocol allows direct access to triflinated α-oxoketene dithioacetals in good to excellent yields bearing diverse synthetically useful functional groups of different electronic and steric nature.

B lymphocytes contribute to indirect pathway T cell sensitization via acquisition of extracellular vesicles.

B cells have been implicated in transplant rejection via antibody-mediated mechanisms and more recently by presenting donor antigens to T cells. We have shown in patients with chronic antibody-mediated rejection that B cells control the indirect T cell alloresponses. To understand more about the role of B cells as antigen-presenting cells for CD4+ T cell with indirect allospecificity, B cells were depleted in C57BL/6 mice, using an anti-CD20 antibody, prior to receiving MHC class I-mismatched (Kd ) skin. The absence of B cells at the time of transplantation prolonged skin graft survival. To study the mechanisms behind this observation, T cells with indirect allospecificity were transferred in mice receiving a Kd skin transplant. T cell proliferation was markedly inhibited in the absence of recipient B cells, suggesting that B cells contribute to indirect pathway sensitization. Furthermore, we have shown that a possible way in which B cells present alloantigens is via acquisition of MHC-peptide complexes. Finally, we demonstrate that the addition of B cell depletion to the transfer of regulatory T cells (Tregs) with indirect alloresponse further prolonged skin graft survival. This study supports an important role for B cells in indirect T cell priming and further emphasizes the advantage of combination therapies in prolonging transplant survival.

Fast Protein Footprinting by X-ray Mediated Radical Trifluoromethylation.

Synchrotron radiolysis generates hydroxyl radicals (•OH) that are successful footprinting reagents. Here, we describe a new reagent for the synchrotron platform, the trifluoromethyl radical (•CF3). The radical is produced by •OH displacement of •CF3 from sodium triflinate (Langlois reagent). Upon X-ray beam exposure, the reagent labels proteins extensively without any additional chemicals on a millisecond or shorter time scale. The •CF3 is comparably reactive to •OH and produces footprinting information that complements that of •OH alone. This reagent in combination with •OH should enable novel chemistry for protein footprinting on the synchrotron platform.

The Photoinduced Metal‐Free Hydrotrifluoromethylation of Vinyl Phosphonates or Phosphine Oxides

We describe a simple and metal‐free photochemical strategy for the direct hydrotrifluoromethylation of vinyl phosphonates or phosphine oxides by sodium triflinate under ultraviolet or visible light irradiation. Acetone and diacetyl were used as radical initiators to generate CF3 radicals that were efficiently added to vinyl phosphonates or phosphine oxide to yield β‐trifluoromethylated phosphorus compounds without the use of any catalyst. A broad scope of substrates scope is demonstrated in moderate to excellent yields. Mechanistic experiments were performed to study the source of hydrogen; the results indicate that H2O in the solvent or additive is the primary hydrogen source.

UV‐Light‐Irradiated Trifluoromethylation of Diheteroaryl Disulfides with CF3SO2Na

A simple protocol for the UV light irradiated preparation of heteroaryl trifluoromethyl thioethers from disulfides and inexpensive, environmentally sodium triflinate (CF3SO2Na) has been developed. The features of simple and clean reaction conditions, in moderate to good yields, and broad substrate scope render this new approach synthetically attractive for the preparation of potentially pharmaceutically active compounds.

On the reactivity of anodically generated trifluoromethyl radicals toward aryl alkynes in organic/aqueous media.

An in-depth study of the reaction of electrochemically generated trifluoromethyl radicals with aryl alkynes in the presence of water is presented. The radicals are readily generated by anodic oxidation of sodium triflinate, an inexpensive and readily available CF3 source, with concomitant reduction of water. Two competitive pathways, i.e. aryl trifluoromethylation vs. oxytrifluoromethylation of the alkyne, which ultimately lead to the generation of α-trifluoromethyl ketones, have been observed. The influence of several reaction parameters on the reaction selectivity, including solvent effects, electrode materials and substitution patterns on the aromatic ring of the substrate, has been investigated. A mechanistic rationale for the generation α-trifluoromethyl ketones based on cyclic voltammetry data and radical trapping experiments is also presented. DFT calculations carried out at the M06-2X/6-311+G(d,p) level on the two competing pathways account for the observed selectivity.

Metal- and Oxidant-Free Photoinduced Aromatic Trifluoromethylation Performed in Aerated Gel Media: Determining the Effects on Yield and Selectivity.

In this work we have investigated the potential benefits of using supramolecular gel networks as reaction media to carry out air-sensitive metal-free light-induced trifluoromethylation of six-membered (hetero)arenes under aerobic conditions. This reaction was performed at room temperature (RT) using sodium triflinate (CF3SO2Na, Langlois’ reagent) as a source of radicals and diacetyl as electron donor. The effects of confinement in gel media, concentration of reactants, and type of light source on yield and product distribution were evaluated and compared to the results obtained in homogeneous solution. Four different low molecular weight (LMW) gelators were employed in this study. The results confirmed the blocking effect of the gel medium against reaction quenching by external oxygen, as well as a certain control on the kinetics and selectivity.

Catalyst-Free Oxytrifluoromethylation of Alkenes through Paired Electrolysis in Organic-Aqueous Media.

A mild, catalyst-free electrochemical oxytrifluoromethylation of alkenes has been developed. The procedure is based on the paired electrolysis of sodium triflinate and water in an undivided cell. Anodic oxidation of the triflinate anion generates trifluoromethyl radicals that react with the alkene. Water plays a dual role as oxidant for the cathode and nucleophile. The method has been utilized to prepare a diverse set of 1-hydroxy-2-trifluoromethyl compounds in moderate to excellent yields (27-94 %). Alcohols have also been tested as nucleophiles for this versatile method with moderate yields. Facile recycling of the electrolyte has been demonstrated, and application of electricity avoids the use of stoichiometric amounts of oxidizers in a safe and environmentally benign reaction.

Carbotrifluoromethylation of Allylic Alcohols via 1,2‐Aryl Migration Promoted by Visible‐Light‐Induced Photoredox Catalysis

AbstractVisible‐light‐enabled photocatalytic carbotrifluoro‐methylations of allylic alcohols and sodium triflinate were explored through 1,2‐migration of an aryl group, affording an efficient method for synthesis of β‐trifluoromethyl‐α‐substituted carbonyl compounds under mild reaction conditions. This catalyst system is well tolerant of various synthetically useful functional groups.magnified image

A green and transition-metal-free light-mediated trifluoromethylation reaction of coumarins

A simple, metal- and oxidant-free photo catalysis strategy for the direct trifluoromethylation of coumarins with inexpensive sodium triflinate (Langlois reagent, CF3SO2Na) as the CF3 source under xenon lamp irradiation is described. The reaction proceeds under ambient conditions and affords the corresponding products in moderate yields. The acetone can be used as low-cost radical initiator to generate CF3 radicals from sodium triflinate efficiently.

Synthesis of 6‐Trifluoromethylphenanthridines through Radical Trifluoromethylation of Isocyanides with Sodium Triflinate under Visible Light

Trifluoromethylation enabled by photochemistry enriched the toolbox of synthetic chemists, to allow the simple and efficient installation of CF3 groups in organic molecules. Herein, we report a cascade addition/annulation reaction of 2‐isocyanobiphenyls towards the synthesis of 6‐trifluoromethylphenanthridines. It is proposed that this reaction is triggered by the CF3 radical generated from photoexcited 2,3‐butanedione (diacetyl) and sodium triflinate. In contrast to classical aromatic trifluoromethylations, this work does not require any additives and features formation of a C–CF3 bond with concomitant construction of an aromatic scaffold.

N-Trifluoromethylation of Nitrosoarenes with Sodium Triflinate.

A highly efficient N-trifluoromethylation of nitrosoarenes is reported. The inexpensive and convenient Langlois reagent (sodium triflinate) is employed as a CF3-radical source in combination with a copper catalyst and an oxidant. N-Trifluoromethylated hydroxylamines are obtained in high yields within 1 h at room temperature. The addition of hydroquinone was found to be instrumental to prevent the formation of side products. The method is high-yielding, is scalable, and displays a high functional group tolerance.

Two-step conversion of carboxylic esters into distally fluorinated ketones via ring cleavage of cyclopropanol intermediates: application of sulfinate salts as fluoroalkylating reagents.

Tertiary cyclopropanols easily available from carboxylic esters have been used in the synthesis of distally fluorinated ketones. Cyclopropane ring cleavage reactions in methanol with aqueous tert-butyl hydroperoxide in the presence of a copper(ii) acetate catalyst and sodium triflinate (Langlois reagent) afford β-trifluoromethyl ketones in 16-74% isolated yields. Sodium triflinate serves as a precursor of reactive trifluoromethyl copper species, enabling ring-opening trifluoromethylation, as evidenced by mechanistic studies. We also demonstrate here that other sulfinate salts, such as sodium 1,1-difluoroethanesulfinate, sodium 2-(4-bromophenyl)-1,1-difluoroethanesulfinate and sodium 1-(trifluoromethyl)cyclopropanesulfinate, can be used as fluoroalkylation reagents, resulting in the corresponding fluorinated ketones.

Visible-light-induced thiotrifluoromethylation of terminal alkenes with sodium triflinate and benzenesulfonothioates.

An unconventional reductive quenching cycle was developed to realize the visible-light-induced thiotrifluoromethylation of terminal alkenes. CF3SO2Na was used as an easy to handle CF3 radical source to afford the desired products in moderate to good yields. Mild reaction conditions and a broad substrate scope feature in this transformation.

Photoredox-catalysed chloro-, bromo- and trifluoromethylthio-trifluoromethylation of unactivated alkenes with sodium triflinate.

A mild and transition-metal-free protocol is herein presented for chloro-, bromo- and trifluoromethylthiotrifluoromethylation of unactivated alkenes. The easy-handling Langlois reagent, as well as N-halophthalimide and N-trifluoromethylthiosaccharin, is used in this method. In the presence of an organic photoredox catalyst N-methyl-9-mesityl acridinium, a broad range of desired products were afforded in satisfactory yields upon visible-light irradiation via a radical process.

ChemInform Abstract: Iodine‐Mediated Regioselective Synthesis of Vinyl Triflones from Styrenes with CF3SO2Na.

AbstractThe unexpected direct C—H triflylation of styrenes (I) with sodium triflinate (II) affording title compounds (III) is reported.

Toward Sustainable Trifluoromethylation Reactions: Sodium Triflinate under the Spotlight

Direct trifluoromethylation of organic molecules is of upmost importance in medicinal chemistry and agrochemical research. However, finding sustainable reaction conditions should be a priority for chemists to improve the applicability of their research. Herein, we highlight recent advances in transition-metal-free and photochemical activation of sodium triflinate, a commercially available and easy-to-handle source of CF₃ radical. 1. Introduction 2. Transition-Metal-Free Activation of Sodium Triflinate 3. Photochemical Activation of Sodium Triflinate 4. Conclusions and Outlook