Decarboxylative Fluorination Research Articles

Decarboxylative Fluorination of Pyridin-2-ylacetates

Key words decarboxylation - fluorination - pyridinylacetates - difluorination

Decarboxylative Fluorination of 2‐Pyridylacetates

Syntheses of substituted pyridines and fluorinated compounds, which are often pharmaceutical targets, are important objectives in organic chemistry. Herein, we found that decarboxylative fluorination of lithium 2-pyridylacetates occur under catalyst-free conditions. The phenomenon can be applied to one-pot transformation of substituted methyl 2-pyridylacetate to 2-(fluoroalkyl)pyridine by decarboxylative fluorination of the intermediate lithium 2-pyridylacetate. This method was also applied to the syntheses of 2-(difluoroalkyl)pyridines.

Cover Feature: Decarboxylative Fluorination of 2‐Pyridylacetates (Chem. Eur. J. 31/2019)

Under catalyst-free conditions, decarboxylative fluorination of lithium 2-pyridylacetates easily occurs. An electrophilic fluorinating reagent dramatically accelerates the decarboxylation of lithium 2-pyridylacetates; this phenomenom has led to a one-pot transformation of methyl 2-pyridylacetates to 2-(fluoroalkyl)pyridines via intermediate lithium 2-pyridylacetates. The method has also been applied to the syntheses of 2-(difluoroalkyl)pyridines. More information can be found in the Communication by K. Shibatomi, et al. on page 7453.

Ag-Catalyzed Chemoselective Decarboxylative Mono- and gem-Difluorination of Malonic Acid Derivatives.

Malonic acid derivatives have been successfully applied in a Ag-catalyzed decarboxylative fluorination reaction, providing an unprecedented route to either gem-difluoroalkanes or α-fluorocarboxylic acids by the judicious selection of base and solvent. This reaction features the use of readily available starting materials, tunable chemoselectivity and good functional group compatibility as well as gram-scale synthetic capability. The advantage of using malonic acid derivatives in this radical decarboxylative functionalization is further highlighted by the facile transformations of the α-fluorocarboxylic acid to valuable fluorine-containing compounds. Preliminary mechanistic studies suggest that an α-carboxylic acid radical is involved in this reaction.

Catalyst-Free Decarboxylative Fluorination of Tertiary β-Keto Carboxylic Acids

Decarboxylative fluorination of tertiary β-keto carboxylic ­acids was performed using an electrophilic fluorinating reagent. The reaction proceeded in the absence of a catalyst or base to yield the corresponding α-fluoroketones with tertiary fluorocarbons in good to high yields. Considering that the α-fluorination of asymmetrical ketones ­often causes problems with the regioselectivity between the α- and α′-positions, this method could be a good alternative to the α-fluorination of simple ketones for the synthesis of tertiary fluoroketones.

Catalytic Formation of C(sp3)–F Bonds via Heterogeneous Photocatalysis

Due to their chemical, physical, and biological properties, fluorinated compounds are widely employed throughout society. Yet, despite their critical importance, current methods of introducing fluorine into compounds suffer from severe drawbacks. For example, several methods are noncatalytic and employ stoichiometric equivalents of heavy metals. Existing catalytic methods, on the other hand, exhibit poor activity, generality, selectivity and/or have not been achieved by heterogeneous catalysis, despite the many advantages such an approach would provide. Here, we demonstrate how selective C(sp3)–F bond synthesis can be achieved via heterogeneous photocatalysis. Employing TiO2 as photocatalyst and Selectfluor as mild fluorine donor, effective decarboxylative fluorination of a variety of carboxylic acids can be achieved in very short reaction times. In addition to displaying the highest turnover frequencies of any reported fluorination catalyst to date (up to 1050 h–1), TiO2 also demonstrates excellent level...

Decarboxylative Fluorination of Arylcarboxylic Acids Promoted by ortho‐Hydroxy and Amino Groups

AbstractA novel decarboxylative fluorination process has been developed for the synthesis of ortho‐hydroxy/amino arylfluorides from salicylic acid analogs, in which the ortho‐hydroxy/amino group plays an important role in the transformation. In addition, various arylfluorides are obtained in good to excellent yields under mild conditions.

Decarboxylative fluorination of aliphatic carboxylic acids under heterogeneous delafossite AgFeO2 nanoparticle catalysis: The utilization of bimetallic cooperativity

A crystalline delafossite of silver ferrite AgFeO2 nanoparticles were successfully synthesized by modified method. Physical characterizations of the AgFeO2 catalyst were obtained by several techniques including X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), X-ray Fluorescence (XRF), and nitrogen physisorption measurements. The material was applied as active heterogeneous catalyst for decarboxylative fluorination of carboxylic acids. The optimized conditions utilized the electrophilic Selectfluor reagent in acetone/H2O solvent at room temperature in 3 h. Investigation of structure/activity relationship revealed strong synergistic effect of iron on silver center. Subsequently, AgFeO2 showed remarkable higher activity than homogeneous silver salts, other metal oxides and common Ag-based heterogeneous catalysts. Leaching test indicated the exceptional stability of AgFeO2 structure as compared to other heterogeneous systems and the contribution of leached species is unlikely. Subsequently, AgFeO2 could be reused for at least 7 runs without significant degradation in activity.

Decarboxylative fluorination of β-Ketoacids with N-fluorobenzenesulfonimide (NFSI) for the synthesis of α-fluoroketones: Substrate scope and mechanistic investigation

Cesium carbonate (Cs2CO3)-mediated decarboxylative fluorination of β-ketoacids using NFSI in the MeCN/H2O mixed solvent system affords α-fluoroketones with a broad scope. Both electron-rich and electron-deficient α-non-substituted β-ketoacids are amenable to this protocol. The mechanistic study indicates that the reaction proceeds through electrophilic fluorination followed by decarboxylation, which is different from the decarboxylative fluorination of normal carboxylic acids.

Controlled radical fluorination of poly(meth)acrylic acids in aqueous solution

Fluorinated alkenes exhibit very poor reactivity in copolymerization with non-fluorinated polar monomers such as acrylates. Herein we describe a convenient method for the synthesis of poly(vinyl fluoride-co-acrylic acid) and poly(2-fluoropropene-co-methacrylic acid) copolymers. Thus, the silver-catalyzed decarboxylative radical fluorination of poly(acrylic acid) with Selectfluor in water at room temperature affords poly(vinyl fluoride-co-acrylic acid) copolymers in high yields with well-defined molecular weights and polydispersities. A linear correlation is observed between the extent of fluorination and the amount of Selectfluor, indicating that the copolymer of virtually any monomer ratio can be readily accessed by controlling the amount of Selectfluor. This controlled decarboxylative fluorination is extended to poly(methacrylic acid), leading to well-defined poly(2-fluoropropene-co-methacrylic acid) copolymers.

Decarboxylative Fluorination of Electron-Rich Heteroaromatic Carboxylic Acids with Selectfluor

A transition-metal-free decarboxylative fluorination of electron-rich five-membered heteroaromatics, including furan-, pyrazole-, isoxazole-, thiophene-, indole-, benzofuran- and indazolecarboxylic acids, with Selectfluor is reported. Fluorinated dimer products were observed for nitrogen-containing heteroaromatic carboxylic acids, such as indole and pyrazole. An effective method has been developed to synthesize the monomer of 2- and 3-fluoroindoles with Li2CO3 as base at low temperature.

Catalytic formation of C(sp3)–F bonds via decarboxylative fluorination with mechanochemically-prepared Ag2O/TiO2 heterogeneous catalysts

Mechanochemically-prepared, Ag2O-containing solid materials, are shown to be efficient heterogeneous catalysts for the synthesis of C(sp3)–F bonds via decarboxylative fluorination.

Radical fluorination reactions by thermal and photoinduced methods.

The radical or radical ion-based fluorination reactions of organic compounds will be presented. These methodologies include fluorination processes accomplished through thermal or photoinduced radical/electron transfer methods. In doing so, the fluorination reactions of diverse families of organic compounds such as aliphatic and aromatic substrates will be presented. Recently summarized or reviewed articles will be mentioned but not discussed.

Recent advances in radical-mediated fluorination through C–H and C–C bond cleavage

The C–H and C–C bonds are abundant in organic compounds, yet generally inert in chemical transformations. Therefore, direct functionalization of inert chemical bonds remains challenging. The fluorine-containing compounds are of special interest for their uses in medicinal chemistry. Direct fluorination of C–H and C–C bonds undoubtedly represents one of the most ideal and attractive approaches to incorporate fluorine atom into complex molecules. Herein, we summarize the recent advances in radical-mediated C–H and C–C bond fluorination. Three types of transformations are discussed: (1) direct C–H abstraction/fluorination of alkanes; (2) decarboxylative fluorination of alkyl carboxylic acids; (3) ring-opening fluorination.

Transition metal free decarboxylative fluorination of cinnamic acids with selectfluor®

Herein we report a transition metal free decarboxylative fluorination of cinnamic acids with selectfluor®. A range of functionalized cinnamic acid derivatives reacted with 2equiv. of selectfluor® and 4equiv. of base in hydrophobic solvent and water to afford β-fluorostyrene with good yield and Z-stereoselectivity. Kinetic study was conducted.

Mechanistic study on silver(I)-catalyzed aminofluorination of unactivated alkenes

A study has been performed on the mechanism for the Ag(I)-catalyzed intramolecular aminofluorination of N-arylpent-4-enamides with Selectfluor by means of density functional theory. According to the calculations, the whole catalytic cycle consists of a series of elementary reactions, including formation of the complex (IMC) of the substrate and Ag(H2O)+ (derived from the ligation of H2O to Ag(I)), oxidation of the complex IMC by Selectfluor, deprotonation, homolytic cleavage of the N–Ag(II) bond, intramolecular radical cyclization, and fluorine abstraction. It is suggested that the oxidation of the complex IMC should be the rate-determining step and that the intramolecular radical cyclization determines the regioselectivity of the reaction. Different from that in the decarboxylative fluorination, herein, the deprotonation of the amide is initiated by Ag(II) rather than Ag(I).

Highly Fluorinated Ir(III)-2,2':6',2″-Terpyridine-Phenylpyridine-X Complexes via Selective C-F Activation: Robust Photocatalysts for Solar Fuel Generation and Photoredox Catalysis.

A series of fluorinated Ir(III)-terpyridine-phenylpyridine-X (X = anionic monodentate ligand) complexes were synthesized by selective C-F activation, whereby perfluorinated phenylpyridines were readily complexed. The combination of fluorinated phenylpyridine ligands with an electron-rich tri-tert-butyl terpyridine ligand generates a "push-pull" force on the electrons upon excitation, imparting significant enhancements to the stability, electrochemical, and photophysical properties of the complexes. Application of the complexes as photosensitizers for photocatalytic generation of hydrogen from water and as redox photocatalysts for decarboxylative fluorination of several carboxylic acids showcases the performance of the complexes in highly coordinating solvents, in some cases exceeding that of the leading photosensitizers. Changes in the photophysical properties and the nature of the excited states are observed as the compounds increase in fluorination as well as upon exchange of the ancillary chloride ligand to a cyanide. These changes in the excited states have been corroborated using density functional theory modeling.

O-Trifluoromethylation of Phenols: Access to Aryl Trifluoromethyl Ethers by O-Carboxydifluoromethylation and Decarboxylative Fluorination.

A new strategy for the synthesis of aryl trifluoromethyl ethers (ArOCF3) by combining O-carboxydifluoromethylation of phenols and subsequent decarboxylative fluorination is reported. This protocol allows easy construction of functionalized trifluoromethoxybenzenes and trifluoromethylthiolated arenes (ArSCF3) in moderate to good yields. Moreover, it utilizes accessible and inexpensive reagents sodium bromodifluoroacetate and SelectFluor II and, thus, is practical for O-trifluoromethylation of phenols. The potential application of this method is demonstrated with the preparation of a plant-growth regulator, Flurprimidol.

Insights into the mechanism of silver-catalyzed decarboxylative fluorination

A systematic study has been given to the Ag(I)-catalyzed decarboxylative fluorination of the carboxylic acid with Selectfluor using density functional theory (DFT). It is proposed that the catalytic cycle consists of five steps, namely the formation of the H2O-ligated Ag-carboxylate, oxidation, homolytic cleavage of the O–Ag(II) bond, decarboxylation (loss of CO2) and fluorine abstraction. It is the formation of the H2O-ligated Ag-carboxylate rather than that of Ag(II)–F or Ag(III)–F intermediate that initiates the fluorodecarboxylation. As for the rate-determining step, there exist two possibilities: (i) the formation of the H2O-ligated Ag-carboxylate and its oxidation by Selectfluor; (ii) decarboxylation (loss of CO2), and which one is dominant depends on the structure of the substrate.

ChemInform Abstract: A Practical Synthesis of α‐Fluoroketones in Aqueous Media by Decarboxylative Fluorination of β‐Ketoacids.

ChemInform Abstract: A Practical Synthesis of α‐Fluoroketones in Aqueous Media by Decarboxylative Fluorination of β‐Ketoacids.