Togni Reagent Research Articles

Why do the Togni reagent and some of its derivatives exist in the high-energy hypervalent iodine form? New insight into the origins of their kinetic stability.

In a recent study published in ChemComm, H. F. Schaefer and coworkers showed that the Togni trifluoromethyltation reagent and some of its derivatives appear in a high-energy hypervalent form. The (kinetic) stability of these reagents is granted by the five-membered ring of their benziodoxole-based scaffold, which prevents isomerization to the (inactive) acyclic ether form. Whereas the thermodynamic stability of these reagents can be predicted on the basis of the trans influence of the electrophilic substituent, no such descriptor was found for their kinetic stability. In this study, we explore an array of Togni-type reagents, and show that the barrier to isomerization can be predicted based on the bond length between the iodine atom and the electrophilic substituent. For compounds, where this correlation does not hold, we have a reliable indication that the structure of the transition state is at variance with those in the series.

Mechanistic insight into the thermal activation of Togni's trifluoromethylation reagents.

Herein we investigate the propensity of hypervalent iodine based electrophilic trifluoromethylating agents to undergo thermally induced fragmentation of the F3C-I-O motif. For the first time we are able to observe a dissociative electron transfer mechanism using mass spectroscopy techniques to generate and trap CF3 radicals. Consistent with this mechanism, alkyl radical elimination from these reagents is in full support of an intermediate cyclic iodanyl radical and a reagent-specific temperature of maximum radical production was found to correlate with reported solution phase reactivity.

Tailored Approaches towards the Synthesis of l‐S‐(Trifluoromethyl)cysteine‐ and l‐Trifluoromethionine‐Containing Peptides

Among the fluorinated noncanonical amino acids, l‐trifluoromethionine (TFM) and l‐S‐(trifluoromethyl)cysteine (TfmCys), fluorinated analogues of methionine and cysteine, are of particular interest because of their ability to locally increase the hydrophobicity of peptides. We report herein the synthesis of tert‐butoxycarbonyl/benzyl‐protected TFM and TfmCys by using a cheap and user‐friendly radical trifluoromethylation approach. The benzyl protecting group of these fluorinated amino acids could be conveniently removed by hydrogenolysis, which circumvented troublesome saponification reactions. For the first time, TfmCys was inserted into a peptide sequence by liquid‐ or solid‐phase peptide synthesis. Finally, a late trifluoromethylation strategy with the use of Togni's reagent on disulfide‐bridged peptides was also efficient to incorporate TFM or TfmCys at both N‐terminal and internal positions.

3‐Trifluoromethylated Coumarins and Carbostyrils by Radical Trifluoromethylation of ortho‐Functionalized Cinnamic Esters

A method for the trifluoromethylation of ortho‐hydroxycinnamic esters was developed to achieve the regioselective synthesis of 3‐trifluoromethylated coumarins. The reaction was performed by using the Togni reagent as the CF3 source under mild conditions and showed good functional‐ group tolerance. The scope of this copper‐mediated method was further expanded to the synthesis of 3‐trifluoromethylated carbostyrils starting from ortho‐aminocinnamic derivatives. Interestingly, a sequential one‐pot synthesis of 3‐trifluoromethylated coumarins starting from salicylaldehydes was further developed. The mechanism of this cascade reaction was explored, and a radical pathway was found to be consistent with the obtained results.

ChemInform Abstract: Synthesis of Trifluoromethylated 3,4‐Dihydroquinolin‐2(1H)‐ones via a Photo‐Induced Radical Cyclization of Benzene‐Tethered 1,7‐Enynes with Togni Reagent.

A photoinduced radical cyclization of benzene-tethered 1,7-enynes with Togni reagent in the presence of sodium iodide is developed. Under ultraviolet irradiation, (Z)-4-(iodomethylene)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-2(1H)-ones are generated in moderate to good yields. The transformation works well without any metals or photo-redox catalysts at room temperature. During the reaction process, the reaction proceeds through a trifluoromethyl radical-triggered α,β-conjugated addition/intramolecular 6-exo cyclization/iodination, with the formation of multiple bonds. Good functional group tolerance is observed under the reaction conditions.

ChemInform Abstract: Generation of Benzosultams via Trifluoromethylation of 2‐Ethynylbenzenesulfonamide under Visible Light.

Under visible light irradiation, 2-ethynylbenzenesulfonamides react with Togni's reagent in the presence of a photocatalyst leading to 3-(2,2,2-trifluoroethylidene)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxides in good yields. This transformation proceeds efficiently at room temperature through a photo-initiated trifluoromethylation. The subsequent C–N bond formation produces the corresponding benzosultams.

ChemInform Abstract: Difunctionalization of Alkenes Using 1‐Chloro‐1,2‐benziodoxol‐3‐(1H)‐one.

AbstractOxy‐, di‐ and azidochlorination, chlorothiocyanation and iodoesterification proceed in the presence of Togni reagent Bio‐Cl (XVII) in a site‐selective manner.

ChemInform Abstract: Highly Mono‐Selective ortho‐Trifluoromethylation of Benzamides via 8‐Aminoquinoline Assisted Cu‐Promoted C—H Activations.

AbstractA trifluoromethylation of benzamides with Togni reagent II provides the corresponding aromatic mono(trifluoromethyl) amides by using a quinolinylamino group as directing group.

Fine Design of Photoredox Systems for Catalytic Fluoromethylation of Carbon-Carbon Multiple Bonds.

Trifluoromethyl (CF3) and difluoromethyl (CF2H) groups are versatile structural motifs, especially in the fields of pharmaceuticals and agrochemicals. Thus, the development of new protocols for tri- and difluoromethylation of various skeletons has become a vital subject to be studied in the field of synthetic organic chemistry. For the past decades, a variety of fluoromethylating reagents have been developed. In particular, bench-stable and easy-to-use electrophilic fluoromethylating reagents such as the Umemoto, Yagupolskii-Umemoto, Togni, and Hu reagents serve as excellent fluoromethyl sources for ionic and carbenoid reactions. Importantly, the action of catalysis has become a promising strategy for developing new fluoromethylations. For the past several years, photoredox catalysis has emerged as a useful tool for radical reactions through visible-light-induced single-electron-transfer (SET) processes. Commonly used photocatalysts such as [Ru(bpy)3](2+) and fac-[Ir(ppy)3] (bpy = 2,2'-bipyridine; ppy = 2-pyridylphenyl) have potential as one-electron reductants strong enough to reduce those fluoromethylating reagents, resulting in facile generation of the corresponding fluoromethyl radicals. Therefore, if we can design proper reaction systems, efficient and selective radical fluoromethylation would proceed without any sacrificial redox agents, i.e., via a redox-neutral process under mild reaction conditions: irradiation with visible light, including sunlight, below room temperature. It should be noted that examples of catalytic fluoromethylation of compounds with carbon-carbon multiple bonds have been limited until recent years. In this Account, we will focus on our recent research on photoredox-catalyzed fluoromethylation of carbon-carbon multiple bonds. First, choices of the photocatalyst and the fluoromethylating reagent and the basic concept involving a redox-neutral oxidative quenching cycle are explained. Then photocatalytic trifluoromethylation of olefins is discussed mainly. Trifluoromethylative difunctionalization reactions, i.e., simultaneous introduction of the CF3 group and a different functional group across carbon-carbon double bonds, are in the middle of the discussion. Oxy-, amino-, and ketotrifluoromethylation allow us to synthesize various organofluorine compounds bearing C(sp(3))-CF3 bonds. In addition, the synthesis of valuable trifluoromethylated alkenes is also viable when the olefins have an appropriate leaving group or undergo deprotonation. The present reaction system features high functional group compatibility and high regioselectivity. Furthermore, future prospects, especially trifluoromethylative difunctionalization of alkynes and difluoromethylation of alkenes, are also discussed.

ChemInform Abstract: Radical Perfluoroalkylation — Easy Access to 2‐Perfluoroalkylindol‐3‐imines via Electron Catalysis.

AbstractThe reaction of aryl isonitriles (I) with Togni reagents (II) gives rise to 2‐(perfluoroalkyl)indol‐3‐imines (III), which are converted into oxindoles (VI) and (VIII) with fluorescent properties.

Electron-Catalyzed Fluoroalkylation of Vinyl Azides.

The transition-metal free fluoroalkylation of vinyl azides is herein reported. This operationally simple reaction employs the Togni reagent as a CF3 source, Bu4 NI as an initiator, and occurs under electron catalysis. A range of readily prepared starting materials are functionalized using this approach to produce both phenanthridines and quinoxalin-2-ones.

ChemInform Abstract: Synthesis of α‐Trifluoromethyl‐β‐keto Phosphonates by Electrophilic Trifluoromethylation with Togni Reagent.

AbstractVarious title phosphonates are prepared starting from cyclic and acyclic β‐keto phosphonates.

Hydrotrifluoromethylation of Unactivated Alkenes and Alkynes Enabled by an Electron-Donor-Acceptor Complex of Togni's Reagent with a Tertiary Amine.

An electron-donor-acceptor (EDA) complex between Togni's reagent and a tertiary amine has been introduced. The existence of this EDA complex was supported by NMR titration experiments. The hydrotrifluoromethylation of unactivated aliphatic alkenes and alkynes enabled by this EDA complex has also been developed. This hydrotrifluoromethylation protocol is operationally simple and promoted by a tertiary amine.

ChemInform Abstract: Cyclic Hypervalent Iodine Reagents for Atom‐Transfer Reactions: Beyond Trifluoromethylation

AbstractReview: [87 refs.

ChemInform Abstract: Access to a New Class of Synthetic Building Blocks via Trifluoromethoxylation of Pyridines and Pyrimidines.

AbstractA broad spectrum of differently substituted pyridines and some pyrimidines are treated with Togni reagent I (II) to produce derivatives bearing the important ‐O‐CF3 function.

An Energetic Guide for Estimating Trifluoromethyl Cation Donor Abilities of Electrophilic Trifluoromethylating Reagents: Computations of X-CF3 Bond Heterolytic Dissociation Enthalpies.

This work established an energetic guide for estimating the trifluoromethyl cation-donating abilities (TC(+)DA) of electrophilic trifluoromethylating reagents through computing X-CF3 bond (X = O, S, Se, Te, and I) heterolytic dissociation enthalpies. TC(+)DA values for a wide range of popular reagents were derived on the basis of density functional calculations (M06-2X). A good correspondence has been identified between the computed TC(+)DA values and the experimentally observed relative trifluoromethylating capabilities of the reagents. Substituent effects hold good linear free energy relationships on the TC(+)DAs of the most widely used reagents including Umemoto reagent, Yagupolskii-Umemoto reagent, and Togni reagents, which allow their trifluoromethylating capabilities to be rationally tuned by substituents and thus extend their synthetic utility. All the information disclosed in this work would contribute to future rational exploration of the electrophilic trifluoromethylation chemistry.

Synthesis of α-trifluoromethyl-β-keto phosphonates by electrophilic trifluoromethylation with Togni reagent

ABSTRACTA new synthetic method of trifluoromethylated phosphonates was developed via electrophilic trifluoromethylation with Togni reagent. A variety of β-keto phosphonates were converted into the corresponding α-trifluoromethyl-β-keto phosphonates in moderate to good yields. This protocol could also be extended to other fluoroalkylation reactions, such as pentafluoroethylation.

ChemInform Abstract: Benzylic C—H Trifluoromethylation of Phenol Derivatives.

AbstractPhenol derivatives (I) and (IV) are trifluoromethylated using Togni reagent (II) and a Cu‐catalyst.

ChemInform Abstract: Decarboxylative and Denitrative Trifluoromethylation for the Synthesis of Cvinyl—CF3 Compounds with Togni (II) Reagent.

AbstractBoth processes are successfully carried out with 1 equiv.

Regioselective Synthesis of N‐Heteroaromatic Trifluoromethoxy Compounds by Direct O−CF3 Bond Formation

The first one-step method for the synthesis of ortho-N-heteroaromatic trifluoromethoxy derivatives by site-specific O-CF3 bond formation using hydroxylated N-heterocycles and Togni's reagent is described. The approach enables the unprecedented syntheses of a wide range of six or five-membered N-heteroaromatic trifluoromethoxy compounds containing one or two heteroatoms from most commonly used hydroxylated N-heterocycles. Notable advantages of this method include its simplicity and mild conditions, avoidance of the need for metals or toxic reagents, and compatibility with a variety of functional groups. Furthermore, this method is especially suitable for the larger scale application.