Fluoroalkyl Compounds Research Articles

Ligand‐Controlled Copper‐Catalyzed Halo‐Halodifluoromethylation of Alkenes and Alkynes Using Fluorinated Carboxylic Anhydrides

AbstractPolyhalogenated molecules are often found as bioactive compounds in nature and are used as synthetic building blocks. Fluoroalkyl compounds hold promise for the development of novel pharmaceuticals and agrochemicals, as the introduction of fluoroalkyl groups is known to improve lipophilicity, membrane permeability, and metabolic stability. Three‐component 1,2‐halo‐halodifluoromethylation reactions of alkenes are useful for their synthesis. However, general methods enabling the introduction of halodifluoromethyl (CF2X) and halogen (X’) groups in the desired combination of X and X’ are lacking. To address this gap, for the first time, we report a three‐component halo‐halodifluoromethylation of alkenes and alkynes using combinations of commercially available fluorinated carboxylic anhydrides ((CF2XCO)2O, X=Cl and Br) and alkali metal halides (X’=Cl and Br). In situ prepared fluorinated diacyl peroxides were identified as important intermediates, and the use of appropriate bipyridyl‐based ligands and a copper catalyst was essential for achieving high product selectivity. The synthetic utility of the polyhalogenated products was demonstrated by exploiting differences in the reactivities of their C−X and C−X’ bonds to achieve selective derivatization. Finally, the reaction mechanism and ligand effect were investigated using experimental and theoretical methods to provide important insights for the further development of catalytic reactions.

Ligand-Controlled Copper-Catalyzed Halo-Halodifluoromethylation of Alkenes and Alkynes Using Fluorinated Carboxylic Anhydrides.

Polyhalogenated molecules are often found as bioactive compounds in nature and are used as synthetic building blocks. Fluoroalkyl compounds hold promise for the development of novel pharmaceuticals and agrochemicals, as the introduction of fluoroalkyl groups is known to improve lipophilicity, membrane permeability, and metabolic stability. Three-component 1,2-halo-halodifluoromethylation reactions of alkenes are useful for their synthesis. However, general methods enabling the introduction of halodifluoromethyl (CF2X) and halogen (X') groups in the desired combination of X and X' are lacking. To address this gap, for the first time, we report a three-component halo-halodifluoromethylation of alkenes and alkynes using combinations of commercially available fluorinated carboxylic anhydrides ((CF2XCO)2O, X=Cl and Br) and alkali metal halides (X'=Cl and Br). In situ prepared fluorinated diacyl peroxides were identified as important intermediates, and the use of appropriate bipyridyl-based ligands and a copper catalyst was essential for achieving high product selectivity. The synthetic utility of the polyhalogenated products was demonstrated by exploiting differences in the reactivities of their C-X and C-X' bonds to achieve selective derivatization. Finally, the reaction mechanism and ligand effect were investigated using experimental and theoretical methods to provide important insights for the further development of catalytic reactions.

Dual-mode electrochemical and SERS detection of PFAS using functional porous substrate

Human activity is the cause of the continuous and gradual grooving of environmental contaminants, where some released toxic and dangerous compounds cannot be degraded under natural conditions, resulting in a serious safety issue. Among them are the widely occurring water-soluble perfluoroalkyl and polyfluoroalkyl substances (PFAS), sometimes called “forever chemicals” because of the impossibility of their natural degradation. Hence, a reliable, expressive, and simple method should be developed to monitor and eliminate the risks associated with these compounds. In this study, we propose a simple, express, and portable detection method for water-soluble fluoro-alkyl compounds (PFOA and GenX) using mutually complementary methods: electrochemical impedance spectroscopy (EIS) and surface-enhanced Raman spectroscopy (SERS). To implement our method, we developed special substrates based on porous silicon with a top-deposited plasmon-active Au layer by subsequently grafting –C6H4-NH2 chemical moieties to provide surface affinity toward negatively charged water-soluble PFAS. Subsequent EIS utilization allows us to perform semiquantitative detection of PFOA and GenX up to 10−10 M concentration because surface entrapping of PFAS leads to a significant increase in the electrode–electrolyte charge-transfer resistance. However, distinguishing by EIS whether even PFAS were entrapped was impossible, and thus the substrates were subsequently subjected to SERS measurements (allowed by surface plasmon activity due to the presence of a porous Au layer), clearly indicating the appearance of characteristic C–F vibration bands.

Hydroxy- and Hydro-Perfluoroalkylation of Styrenes by Controlling the Quenching Cycle of Eosin Y.

Fluoroalkyl compounds are widely used, underscoring a pressing need for the development of methods for their synthesis. However, reports on perfluoroalkylation to styrenes have been sparse. In this study, both hydroxy- and hydro-perfluoroalkylation of styrene were achieved using visible light reactions, catalyzed by eosin Y, by selecting appropriate additives and controlling the eosin Y quenching cycle. These reactions are heavy-metal free, use water as the hydroxyl or hydrogen source, and employ inexpensive and readily available reagents.

Photoredox Catalytic Trifluoromethylation and Perfluoroalkylation of Arenes Using Trifluoroacetic and Related Carboxylic Acids

Summary Trifluoroacetic acid (TFA) is among the most attractive trifluoromethylation reagents with respect to its low prices, ease of handling, and availability in large quantities. However, because of its exceedingly high oxidation potential, harsh conditions are required for the direct oxidation of TFA to the trifluoroacetate radical, which after prompt CO2 extrusion, affords the desired CF3 radical. Therefore, mild and efficient protocols for the direct conversion of TFA to the CF3 radical are still in high demand. Here, we report a mild and practical method that allows for the direct C–H trifluoromethylation, perfluoroalkylation, and chlorodifluoromethylation of (hetero)arenes using TFA and the related carboxylic acids. A diverse array of arenes and heteroarenes were successfully transformed into valued fluoroalkylated compounds. The combination of photoredox catalysis and a diaryl sulfoxide provides a platform for the facile generation of fluoroalkyl radicals from the corresponding fluoroalkyl carboxylic acids under mild conditions.

Photoredox Catalytic Trifluoromethylation and Perfluoroalkylation of (Hetero)Arenes Using Trifluoroacetic and Related Carboxylic Acids

A mild and practical method has been achieved that allows for the direct C–H trifluoromethylation, perfuoroalkylation and chlorodifluoromethylation of (hetero)arenes using inexpensive, abundant trifluoroacetic acid and the related carboxylic acids. A diverse array of arenes and heteroarenes were successfully transformed into valued fluoroalkylated compounds. The combination of photoredox catalysis and a diaryl sulfoxide provides a platform for the facile generation of fluoroalkyl radicals from the corresponding fluoroalkyl carboxylic acids under mild conditions.

Fluoroalkylation Methods for Synthesizing Versatile Building Blocks

Abstract In this account, we provide an overview of synthetic methods for accessing fluoroalkylated compounds via electrophilic fluoroalkylation, especially of alkenes, focusing mainly on our own studies directed towards the discovery of drugs and agrochemicals. First, we describe trifluoromethylations with Togni reagent 1 in the presence of catalysts or electron-donating additives, providing access to a wide range of fluoroalkylated molecules. We then cover fluoroalkylations using fluorinated acid anhydrides. We recently showed that these acid anhydrides enable alkene fluoroalkylation via the in-situ formation of diacyl peroxide, with or without the aid of copper catalysts, affording various fluoroalkyl group-containing molecules in a practical manner. We also present some examples of structural diversification of the products, illustrating their synthetic utility as building blocks, which could be widely applicable, for example, in the construction of fluoroalkylated compound libraries.

Copper-Catalyzed Highly Stereoselective Trifluoromethylation and Difluoroalkylation of Secondary Propargyl Sulfonates.

It is challenging to stereoselectively introduce a trifluoromethyl group (CF3 ) into organic molecules. To date, only limited strategies involving direct asymmetric trifluoromethylation have been reported. Herein, we describe a new strategy for direct asymmetric trifluoromethylation through the copper-catalyzed stereospecific trifluoromethylation of optically active secondary propargyl sulfonates. The reaction enables propargylic trifluoromethylation with high regioselectivity and stereoselectivity. The reaction could also be extended to stereospecific propargylic difluoroalkylation. Transformations of the resulting enantiomerically enriched fluoroalkylated alkynes led to a variety of chiral fluoroalkylated compounds, thus providing a useful protocol for applications in the synthesis of fluorinated complexes.

A Diheteroatom Fluoroalkylation Reagent for Preparation of S- and N-Containing Fluoroalkyl Compounds and Sulfonic Acid Polymer.

The first stable diheteroatom fluoroalkylation reagent, 2-((2-azido-1-chloro-1,2,2-trifluoroethyl)thio)pyrimidine (ACTP), has been prepared by a novel method. By using this reagent, various fluorinated thioethers and sulfones have been successfully prepared. The dearylation and dearylation-oxidation of fluoroalkyl 2-pyrimidyl sulfone in one-pot reaction were investigated systematically, and the results demonstrated that both fluoroalkyl sulfinates and sulfonates could be obtained in high yields. In addition, ACTP proved to be useful for the preparation of a fluorinated sulfonic acid proton-exchange membrane.

Directed Functionalization of Aromatic C-H Bonds in Electrocatalytic Phosphorylation and Fluoroalkylation Reactions with the Participant of Transition Metal Complexes

The formation of carbon-phosphorus and carbon-fluoroalkyl bonds catalyzed by transition metal complexes is considered as an important methodology for producing of various useful compounds. Many of these compounds exhibit a high biological activity and are widely used in organic synthesis, medical chemistry, materials or as versatile ligands in many catalytic reactions.1-2 However, it should be noted that in majority of papers as aromatic substrates are used organic halides, while examples of substituted C-H bonds, where the leaving group is hydrogen, are much smaller. Major reviews of the latest achievements in the field of formation of metal-catalyzed С-P bonds published in recent years almost do not consider examples of phosphorylation of aromatic C-H bonds.3 Known fluoroalkylation reactions also have the drawbacks: the high cost of the reagents, the frequent requirement for forcing reaction conditions, a modest substrate scope.4 That is why the purpose of our work is to develop a more economically and environmentally beneficial method of obtaining phosphorus, fluoroalkyl compounds by electrochemical activation of aromatic C-H bonds under electrocatalysis involving transition metal complexes. The interest in electrochemical fluoroalkylation and phosphorylation reactions is driven by a number of factors: mild conditions (moderate temperature, ambient pressure), the possibility of closed-loop implementation with a small amount of the catalyst reactant that is repeatedly recycled, and the high environmental safety of the synthesis, especially in comparison with the traditional organic chemistry techniques. Electrosynthesis is also useful in transition metal catalysis for generating the active form of the catalyst without the need to add external oxidizing or reducing agents.5-7 Thus in a series of experiments products of phosphorylation and fluoroalkylation of aromatic substrates (benzene, coumarin, caffeine, pyridine, ferrocene) were obtained under mild conditions (room temperature, normal pressure) from good to excellent yields (90%).8-9 Acknowledgements This work was supported by the Russian Science Foundation no. 14-23-00016. References Kirk, K.L. J. Fluorine Chem. 2006, 127, 1013.Demmer, C. S.; Krogsgaard-Larsen, N.; Bunch, L. Chem. Rev. 2011, 111, 7981.Evano, G.; Gaumont, A.-C.; Alayrac, C.; Wrona, I. E.; Giguere, J. R.; Delacroix, O.; Silvanus, A. C. Tetrahedron. 2014, 70, 1529. Loy, R. N.; Sanford, M. S. Org. Lett. 2011, 13, 2548.Khrizanforov, M.; Gryaznova, T.; Sinyashin, O.; Budnikova, Y. J. Organomet. Chem., 2012, 718, 101. Dudkina, Y. B.; Khrizanforov, M. N.; Gryaznova, T. V.; Budnikova, Y. H. J. Organomet. Chem., 2014, 751, 301.Budnikova, Y. H. Russ. Chem. Rev., 2002, 71, 111.Khrizanforov, M.; Strekalova, S.; Khrizanforova, V.; Grinenko, V.; Kholin, K.; Kadirov, M.; Burganov, T.; Gubaidullin, A.; Gryaznova, T.; Sinyashin, O.; Xu, L.; Vicic, D. A.; Budnikova, Y. Dalton Trans. 2015, 44, 19674. Khrizanforov, M. N.; Strekalova, S. O.; Gryaznova, T. V.; Khrizanforova, V. V.; Budnikova, Y. H. Russ. Chem. Bull. 2015, 8, 1926. Figure 1

ChemInform Abstract: Prospects of Synthetic Electrochemistry in the Development of New Methods of Electrocatalytic Fluoroalkylation

AbstractReview: [73 refs.

Synthesis of Chiral Fluoroalkyl Products via Copper-Free Asymmetric Allylic Alkylation

Key words fluoroalkyl compounds - asymmetric allylic alkylation - Grignard reagents - NHC ligands

ChemInform Abstract: Synthesis of Homocyclic Fluoroalkyl Compounds by Diels‐Alder Reaction of 3‐Fluoroalkylpropynoates.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Une evaluation du: Phenyltetrafluorophosphorane comme agent de fluoration des alcools

Resume The fluorination of hydroxylic groups by reacting their silylethers with phenyltetrafluorophosphorane was investigated over a large range of alcohols belonging to the various usual structural classes, for which widely different reactivities, reaction products, and yields were found. The quantitative, immediate formation of the intermediate monoalkoxytrifluorophosphoranes 5 from the stoichiometric amounts of the reactants was established in almost every case. It generally occurs in very mild conditions and appears to be mainly controlled by steric factors. The subsequent decomposition of 5, as well as redistribution reactions giving the dialkoxydifluorophosphorane 6, and hence the reaction products, are strongly dependent on the class of the alcohol and on the electronic effects of the substituents. The yields in the expected fluoroalkyl compounds range from 15 to 95% for the primary and secondary alcohols. They are generally higher and sometimes near quantitative for tertiary alcohols, β-alkyl substituted primary and secondary alcohols, and when the alcohols are substituted by electro-attracting groups. Transposed fluoroalkyl compounds are formed each time that they correspond to more stable carbocations. Other common side products include alcenes, ethers and the phenylfluorophosphonates 7. When the alcohols are substituted by very strongly electroattracting groups, the alkoxyfluorophosphoranes become too stable and do not give the alkyl fluorides anymore upon decomposition, at 200° or more. A mechanism involving a carbocation as intermediate is proposed.

(Fluoroalkyl)cobalt(III) Schiff-base complexes

The (fluoroalkyl)cobalt(III) Schiff-base complexes R fCoChelL (R f=CF 3, C 2F 5, C 3F 7; Chel = Salen, Acacen, Tfacacen, Bzacacen; L = -, H 2O, pyridine) have been synthesised by oxidative addition of R fI to tetrahydrofuran solutions of sodium reduced cobalt Schiff-base chelates. The 1H NMR spectra of the complexes show that less electron density is transmitted via the cobalt atom to the planar chelate groups from the R f group than from the analogous R group. 19F NMR spectra show that the α-CF 2 resonances do not undergo the pronounced low-field shifts experienced by low-valent metal fluoroalkyl compounds.

Electron‐impact studies of organometallic molecules—X. Some simple transition metal fluorocarbon complexes

AbstractThe mass spectra of several fluoroalkyl, fluoroalkenyl and fluoroacyl complexes of manganese, rhenium, iron and ruthenium carbonyls are described. After loss of carbonyl groups, fluoroalkyl compounds eliminate an olefin, with formation of metal halide species. A trifluorovinyl complex shows a novel elimination of a carbon atom to give an ion postulated to be a difluorocarbene‐metal fluoride; the occurrence of difluorocarbene‐metal ions in the spectra of some related complexes is also discussed. The spectra of the acyl complexes show little evidence of elimination of the acyl carbonyl group; the major process is fission of the CORf bond with loss of a fluoroalkyl radical and formation of the cationic metal carbonyl, e.g. π‐C5H5M(CO)3+ (M  Fe or Ru). The relevance of thermal or photochemical model reactions to processes occurring in the mass spectrometer is discussed.