Catalytic Fluorination with Modern Fluorinating Agents: Recent Developments and Synthetic Scope

Abstract

Fluorinated organic molecules have become indispensable in modern chemistry, owing to the unique properties imparted by fluorine to other compounds, including enhanced metabolic stability, controlled lipophilicity, and improved bioavailability. The site-selective incorporation of fluorine atoms into organic frameworks is essential in pharmaceutical, agrochemical, and material science research. In recent years, catalytic fluorination has become an important methodology for the efficient and selective incorporation of fluorine atoms into complex molecular architectures. This review highlights advances in catalytic fluorination reactions over the past six years and describes the contributions of transition metal catalysts, photocatalysts, organocatalysts, and electrochemical systems that have enabled site-selective fluorination under a variety of conditions. Particular attention is given to the use of well-defined fluorinating agents, including Selectfluor, N-fluorobenzenesulfonimide (NFSI), AlkylFluor, Synfluor, and hypervalent iodine reagents. These reagents have been combined with diverse catalytic systems, such as AgNO₃, Rh(II), Mo-based complexes, Co(II)-salen, and various organocatalysts, including β,β-diaryl serine catalysts, isothiourea catalysts, and chiral phase-transfer catalysts. This review summarizes proposed mechanisms reported in the original studies and discusses examples of electrophilic, nucleophilic, radical, photoredox, and electrochemical fluorination pathways. Recent developments in stereoselective and more sustainable protocols are also examined. By consolidating these strategies, this article provides an up-to-date perspective on catalytic fluorination and its impact on synthetic organic chemistry.

1. Introduction

Fluorine chemistry occupies a central position in synthetic organic chemistry, owing to the unique influence of fluorine on molecular structure and function [1]. A fluorine atom can significantly modify the steric and electronic environment of a compound, owing to its high electronegativity, small atomic size, and the strength of the carbon–fluorine bond [2]. These features contribute to the increased metabolic resistance, greater chemical stability, enhanced membrane permeability, and altered hydrogen bonding characteristics of fluorinated compounds [3]. As a result, fluorine-containing molecules are disproportionately represented in pharmaceuticals, agrochemicals, and diagnostic agents, whose physicochemical properties must be fine-tuned to ensure efficacy and safety [4,5,6].

However, the strategic incorporation of fluorine atoms into organic scaffolds represents a persistent synthetic challenge [7]. Direct fluorination using elemental fluorine or fluorine gas is often impractical in academic or industrial contexts, owing to extreme reactivity, poor selectivity, and safety concerns [8,9]. To address these issues, a wide range of synthetic reagents and catalytic methods have been developed to enable the introduction of fluorine under relatively benign conditions [10].

Electrophilic fluorinating agents such as Selectfluor and N-fluorobenzenesulfonimide (NFSI) are among the most widely used in this area, owing to their operational simplicity and broad applicability [11,12,13]. For example, Selectfluor is a bench-stable, crystalline reagent that enables site-selective fluorination in complex molecules, with minimal byproduct formation [14,15,16]. Its compatibility with various catalysts and functional groups has promoted its application in metal-catalyzed, photocatalytic, and electrochemical fluorination processes [17,18]. NFSI provides similar advantages and is often preferred for its stability and applicability in both mono- and difluorination reactions [19]. More recent developments in Synfluor and related single-electron transfer reagents have expanded the electrophilic fluorination toolkit to include radical mechanisms, offering complementary selectivity and reactivity patterns [20] (Figure 1).

Nucleophilic fluorination, traditionally achieved via using fluoride salts or reagents such as DAST and Deoxofluor, has been significantly improved with the introduction of newer AlkylFluor agents [21]. These reagents are now employed in stereo- and regioselective fluorination of alkyl chains, often in late-stage functionalization [22,23]. Moreover, innovations in hypervalent iodine-based fluorinating agents have further contributed to this area, providing access to highly functionalized fluorinated motifs through oxidative mechanisms [24,25,26,27].

In parallel, the field of catalysis has contributed significantly to advancing fluorination methods. Transition metal catalysts, organocatalysts, photocatalysts, and electrochemical approaches have been applied to achieve site-selective, regioselective, and stereoselective fluorination [28,29,30,31,32]. These catalytic systems often improve reaction efficiency, broaden substrate scope, and facilitate late-stage functionalization of complex molecules.

In recent years, photoredox and electrochemical fluorination have emerged as powerful techniques for constructing C–F bonds. Several comprehensive reviews have been published that specifically focus on these areas. For example, recent articles have provided detailed accounts of photoredox fluorination and electrochemical fluorination [33,34,35,36]. Because of this existing literature, the present review was initially intended to emphasize reagent-based fluorination strategies combined with catalytic methods rather than duplicate these specialized surveys. However, to provide a more complete and balanced perspective, selected examples and brief summaries of photoredox and electrochemical fluorination have been included to reflect the importance of these techniques within modern fluorination chemistry.

While the primary focus of this review is on catalytic fluorination strategies, including metal-catalyzed, organocatalytic, photoredox, and electrochemical methods, a few representative non-catalytic examples relying on reaction promoters or additives are also briefly discussed to ensure a balanced overview of recent advances in the field.

This review aims to provide a comprehensive overview of recent developments in the field because most previous literature surveys have been published before or around 2019 and mainly focused on traditional reagents and methods. For instance, the review by Zhang and co-workers provided a basic overview of fluorination chemistry up to that point in aqueous media [37] but did not cover recent advances in photocatalysis, electrochemical fluorination, and sustainable reagent design. Another review by Zhang and co-workers in 2024 concentrated on synthetic routes to aryl fluorides only [38] but did not include alkyl and modern reagent systems. In particular, this review emphasizes practical applications of well-defined fluorinating agents in combination with catalytic systems, including transition metals and organocatalysts. In addition, many fluorination reactions proceed effectively without a formal catalyst through the use of reaction promoters, bases, oxidants, or other additives. These additive-controlled or promoter-assisted processes provide valuable alternatives in cases where catalyst compatibility is limited or unnecessary.

Over the past six years, significant advances have been made in the development and application of well-defined fluorinating agents in combination with catalytic systems. The topics covered include electrophilic, nucleophilic, and radical fluorination processes, along with recent progress in stereoselective and more sustainable protocols. By consolidating these methods and illustrative examples, this article aims to provide an up-to-date overview of catalytic fluorination strategies and their impact on contemporary organic synthesis.

2. Fluorination by Selectfluor

Selectfluor, chemically known as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis(tetrafluoroborate), is among the most versatile electrophilic fluorinating agents in organic synthesis. Its key advantages include air and moisture stability, broad functional group tolerance, and operational simplicity, making it an essential reagent in both academic and industrial contexts.

The core of the reactivity of Selectfluor lies in its cationic N–F bond, which serves as a potent yet controllable source of electrophilic fluorine. Compared to aggressive reagents such as elemental fluorine or DAST, Selectfluor provides a safer, more selective pathway for fluorination, particularly suited for late-stage functionalization of complex molecules.

One of the main advantages of Selectfluor is its ability to selectively fluorinate electron-rich nucleophilic centers under mild conditions. This compound is also widely applied in C–H fluorination, especially at benzylic, allylic, and heteroatom-adjacent sites. Under transition-metal (e.g., Ag, Cu, Fe) catalysis or photoredox conditions, it is involved in radical or polar fluorination pathways. In photoredox catalysis, Selectfluor serves as both a fluorine source and a terminal oxidant, generating radical intermediates capable of selective fluorination at unactivated C–H sites.

Compared to related reagents such as NFSI or SynFluor, Selectfluor provides higher reactivity and a broader substrate scope. However, this high reactivity can also lead to undesired over-oxidation, especially in electron-rich environments. Unless carefully addressed, the formation of TEDA byproducts upon fluorine transfer may alter catalytic systems. Despite these limitations, the commercial availability, low toxicity, and adaptability of Selectfluor preserve its central role in synthetic fluorine chemistry.

In summary, Selectfluor remains a leading fluorinating reagent, owing to its reliability, versatility, and compatibility with modern synthetic strategies. Its widespread adoption in academic and industrial environments emphasizes its critical role in advancing fluorination chemistry. With the development of new activation modes and synergistic reagent systems, the importance of Selectfluor in site-selective, sustainable fluorination will likely continue to grow.

In 2019, Wang et al. reported the synthesis of gem-difluoroalkanes 3 and α-fluorocarboxylic acids 4 through the silver-catalyzed chemoselective decarboxylative fluorination of the malonic acid derivatives 1, using Selectfluor 2 as fluorine source. This study introduces a novel AgNO₃-catalyzed radical decarboxylative fluorination protocol that enables chemoselective synthesis of either α-fluorocarboxylic acids 4 or gem-difluoroalkanes 3 from the malonic acid derivatives 1 [39].

For gem-difluorination 3, the reaction is performed using AgNO₃ (30 mol%) and PhCO₂Na (3.0 equiv) as the base in a solvent mixture of acetonitrile (CH₃CN), water, and n-hexane (1:1:3 v/v/v) at 55 °C under nitrogen for 12 h, giving the difluorinated products 3 in up to 60% yield. In contrast, for selective monofluorination 4, K₂HPO₄ (4.0 equiv) is used as the base in a biphasic solvent system consisting of cyclopentyl methyl ether (CPME) and water (1:1 v/v) at room temperature, leading to the formation of the α-fluorocarboxylic acids 4 with yields reaching 54%. Selectfluor 2 is employed as a fluorine source in both pathways (Scheme 1 and Scheme 2).

The developed silver-catalyzed decarboxylative fluorination protocol stands out for its high chemoselectivity, functional group tolerance, and synthetic versatility. This method operates under mild conditions and can accommodate a wide range of functional groups, including esters, ketones, nitriles, amides, sulfones, and even sensitive alcohols, making it highly valuable for the synthesis of complex molecules. Moreover, the protocol has been shown to be scalable through Gram-scale reactions, without compromising the yield or selectivity. Its post-synthetic utility is also well established: the α-fluorocarboxylic acids 4 generated via monofluorination can be efficiently transformed into valuable fluorinated building blocks such as gem-chlorofluoroalkanes, propargylic fluorides, and γ-fluoro Michael adducts, enabling further diversification and potential application in pharmaceutical development and late-stage fluorine incorporation. Despite its broad applicability, the study by Wang et al. acknowledges several limitations. Substrates bearing alkynyl and alkenyl groups failed under oxidative fluorination conditions, yielding only undesired oxidative decarboxylation products, indicating sensitivity to radical-promoting environments. Similarly, the monosubstituted malonic acid derivatives proved inefficient for gem-difluorination, leading to low yields and poor selectivity.

The process begins with the formation of a silver(I) salt A from the malonic acid 1 in the presence of a weak base. This salt is oxidized by Selectfluor to produce Ag(II) B and a fluorine radical (path a). Next, the carboxylate moiety B undergoes single-electron oxidation by Ag(II), leading to decarboxylation and the formation of an α-carboxylic acid radical (intermediate C). This radical then abstracts a fluorine atom from Selectfluor to form an α-fluorocarboxylic acid (4). A second decarboxylative step E occurs for gem-difluorination: compound 4 further reacts to give the radical intermediate F that, after fluorine abstraction, forms product 2 (Scheme 3).

In 2019, Tang et al. reported the synthesis of 2-fluoro- and 2,2-difluoro-1,3-dicarbonyl compounds via a chemoselective, catalyst- and base-free fluorination method using Selectfluor in aqueous media. Their study introduces a highly efficient, environmentally friendly, and practical method for achieving chemoselective mono- and difluorination of 1,3-dicarbonyl compounds using Selectfluor as the fluorinating agent. The authors showed that the simple modulation of the reagent stoichiometry (1.1 vs. 2.1 equiv of Selectfluor) in a CH₃CN/H₂O solvent system enables controlled access to either mono- or difluoro-substituted products under ambient, metal-free, and base-free conditions [40].

This transformation involves treating the 1,3-dicarbonyl compounds 5 (e.g., 3-oxo-N-phenylbutanamide) with Selectfluor 2 in a 1:1 mixture of CH₃CN and water. To obtain the monofluorinated product 6, the reaction is carried out with 1.1 equiv of Selectfluor 2, and the mixture is stirred at room temperature for 4 h, producing the 2-fluoro-1,3-dicarbonyl products 6 in yields up to 93%. To prepare the difluorinated compound 7, 2.1 equiv of Selectfluor 2 is used under the same solvent system and temperature conditions, but with an extended reaction time of 16 h, affording the 2,2-difluoro products 7 in yields as high as 99% (Scheme 4).

The protocol tolerates a wide range of β-keto amides, esters, and ketones, affording the fluorinated products 6 and 7 in excellent yields and with high selectivity. This method was also successfully extended to chlorination and bromination using NCS and NBS, and the post-functionalization of fluorinated intermediates was demonstrated through the synthesis of fluorinated pyrazoles. The authors also demonstrated the Gram-scale synthesis of both mono- and difluorinated products, confirming the scalability and practicality of their method. Overall, this study provides a green, scalable fluorination strategy with broad substrate compatibility. Despite its strengths, this method shows limited efficacy with certain substrates; for instance, malononitrile failed to undergo fluorination. This approach is also largely restricted to activated methylene substrates, indicating that less acidic or sterically hindered analogs may not perform as well.

In 2020, Zhang et al. reported the synthesis of tertiary alkyl fluorides 9 via a dehydroxylative fluorination protocol using Selectfluor (2) and a Ph₂PCH₂CH₂PPh₂/ICH₂CH₂I activation system. Their work introduces an efficient and rapid method for the dehydroxylative fluorination of tertiary alcohols (8), a transformation that has long posed challenges due to the steric hindrance and instability of tertiary carbocations. The authors designed a mild and redox-compatible system using Selectfluor (2) as the fluorinating agent and Ph₂PCH₂CH₂PPh₂/ICH₂CH₂I to activate the hydroxyl group, supported by ZnBr₂ serving as halide source [41].

The core transformation involves converting a tertiary alcohol (8) into a tertiary alkyl fluoride (9) via a sequential iodination/bromination and fluorination pathway. In a typical reaction, 0.5 mmol of the tertiary alcohol 8 is combined with 1.5 mmol of Selectfluor 2, 0.3 mmol of Ph₂PCH₂CH₂PPh₂, and 0.6 mmol of ICH₂CH₂I in 5 mL of CH₃CN at room temperature under a nitrogen atmosphere. ZnBr₂ (0.8 mmol) is added to enhance the halogen exchange and fluorination efficiency. The reaction is completed in 15 min, affording the desired fluorinated product 9 in up to 99% yield (Scheme 5).

This protocol provides several advantages, including mild conditions, fast reaction times (15 min), as well as tolerance to a broad range of substrates, including esters, amides, sulfonamides, halides, as well as complex bio-relevant molecules, and has been demonstrated to be scalable. Despite its strengths, the reaction requires careful sequential addition of reagents to prevent redox incompatibility issues between the phosphine system and Selectfluor 2, which may compromise the operational simplicity. The system also depends on ZnBr₂ to support halogen exchange, which implies that the reaction requires a careful choice of additives to work well. Additionally, certain sterically congested or functionally complex substrates (e.g., esters) near the hydroxyl group displayed reduced reactivity, likely due to coordination interference or steric hindrance.

This process starts with the reaction of Ph₂PCH₂CH₂PPh₂ and ICH₂CH₂I to form intermediate A, a diiodophosphonium salt [Ph₂P⁺(I)CH₂CH₂P⁺(I)Ph₂]²I⁻ that activates the hydroxyl group of the tertiary alcohol 8. This leads to in situ halogenation, forming a tertiary iodide or bromide intermediate B or B’. Simultaneously, Selectfluor 2 oxidizes the iodide to produce radical cation D, which abstracts a halogen atom from intermediate C, generating the tertiary alkyl radical E. The latter then reacts with another equivalent of Selectfluor to yield the final fluorinated product 9 (Scheme 6).

In 2022, Poorsadeghi et al. reported the synthesis of enantioenriched α-fluorinated β-diketones 11 using β,β-diaryl serines, serving as primary amine organocatalysts in a highly enantioselective fluorination reaction. Their work demonstrates an efficient organocatalytic method for the enantioselective electrophilic fluorination of α-substituted β-diketones using custom-designed β,β-diaryl serines. The reaction proceeds with high yields (74–99%) and excellent enantioselectivities (up to 94% ee) using Selectfluor under mild conditions [42].

This reaction involves α-substituted β-diketones (10) undergoing electrophilic fluorination with Selectfluor (2) in the presence of a β,β-diaryl serine catalyst. The optimized reaction conditions involve the use of 2.0 equiv of Selectfluor 2 and 10 mol% of cat A catalyst in MeCN at 40 °C for 24 h. This produces the α-fluorinated products (11) in up to 99% isolated yield and 94% ee (Scheme 7).

The key strength of this method lies in its high enantioselectivity and operational simplicity, along with the novel application of β,β-diaryl serines as tunable bifunctional organocatalysts. Substrates bearing electron-donating or electron-withdrawing groups on aromatic rings, as well as sterically hindered and extended alkyl chains, were all compatible. However, this protocol shows limitations when applied to substrates with longer alkyl chains or sterically hindered aromatic groups, which require extended reaction times to reach full conversion.

In 2021, Magre et al. reported the synthesis of aryl sulfonyl fluorides via a redox-neutral Bi(III)-catalyzed process mimicking canonical organometallic steps, while maintaining the oxidation state of bismuth throughout the catalytic cycle. In particular, this study introduces a unique bismuth(III)-catalyzed protocol for the direct one-pot synthesis of (hetero)aryl sulfonyl fluorides from (hetero)aryl boronic acids. The transformation proceeds through transmetalation, SO₂ insertion, and oxidative fluorination steps, while remarkably retaining the Bi(III) oxidation state throughout the process [43].

The key transformation involves the reaction of the aryl boronic acids 12 with sulfur dioxide (1.5 bar) in the presence of the Bi(III) catalyst B (5 mol%), Selectfluor 2 as oxidant, K₃PO₄ as base, and 4 Å molecular sieves in a solvent mixture of CHCl₃/CH₃CN (5:1) at 70 °C for 16 h. Under these conditions, a wide variety of aryl and heteroaryl boronic acids are converted to the corresponding sulfonyl fluorides in moderate to excellent yields. In cases where heterocycles are used, a modified protocol using the Bi catalyst 4 and NFSI as a milder oxidant leads to improved performances (Scheme 8).

This work demonstrates the direct one-pot synthesis of sulfonyl fluorides (13) from simple boronic acids (12), eliminating the need for pre-functionalization. The reaction proceeds under mild and operationally straightforward conditions, showing excellent compatibility with sensitive functional groups and heterocycles. Additionally, the structure of key intermediates, such as the sulfinate complex, was confirmed through X-ray crystallography analysis. The limitations of this method include a reduced efficiency with electron-rich aryl boronic acids, which tend to result in lower yields compared to their electron-deficient counterparts.

The proposed mechanism begins with the Bi(III) catalyst undergoing transmetalation with the aryl boronic acid 12 to give the triarylbismuth species B. Then, the sulfur dioxide insertion into the Bi–C(sp²) bond of B generates the bismuth sulfinate intermediate C, which adopts an O-bound coordination mode due to the oxophilicity of bismuth. Intermediate C is subsequently oxidized at the sulfur (not bismuth) center by Selectfluor 2, yielding the final sulfonyl fluoride product 13 and regenerating the A catalyst (Scheme 9).

In 2021, Niwa et al. reported a structure-dependent enantioselective fluorination and fluorocyclization process of γ-substituted allylamine derivatives, using a dianionic phase-transfer catalyst derived from a chiral dicarboxylic acid. Their study explored a stereodivergent catalytic fluorination platform for acyclic allylamines bearing γ-substituents. Using a chiral dianionic phase-transfer catalyst generated in situ, Niwa et al. achieved highly enantio- and diastereoselective fluorination and fluorocyclization reactions. Their study also explored mechanistic divergence via kinetic analysis, nonlinear effect studies, and isotope labeling, demonstrating that the aggregation state of the catalyst plays a key role in the enantioselectivity [44].

This reaction involves treating γ-substituted allylamine derivatives (14) with Selectfluor 2 (2 equiv) as the electrophilic fluorinating agent in the presence of a chiral dicarboxylic acid precatalyst (5 mol%), converted in situ to a dianionic phase-transfer catalyst using KOH (2 equiv). This reaction is typically conducted in toluene at room temperature for 24 h. Using γ,γ-disubstituted substrates (14), the process yields highly enantioenriched allylic fluorides (15), while γ-monosubstituted substrates (16) undergo cyclization to produce dihydrooxazines (17). The outcome depends on the substitution pattern and influences both the mechanism and the enantioselectivity (Scheme 10 and Scheme 11).

The key aspect of this study lies in the catalyst-controlled stereodivergence, based on substrate substitution. This method provides high enantio-/diastereoselectivity (up to 97% ee and >20:1 dr) and tolerates various functional groups, including heteroaromatics and bulky alkyl substituents. However, substrates bearing electron-withdrawing groups, particularly at meta- or ortho-positions, show lower reaction rates.

In 2022, Madani et al. reported the solvent-dependent benzylic fluorination of the phenylacetic acid derivatives 18 using Selectfluor 2 and 4-(dimethylamino)pyridine (DMAP), mediated by a charge–transfer complex. Their method enables divergent C–F bond formation pathways via radical mechanisms under aqueous or nonaqueous conditions. In particular, their study presents a novel strategy employing a charge–transfer complex between Selectfluor 2 and DMAP to direct the fluorination of the phenylacetic acids 19. In aqueous solvents, the reaction proceeds via decarboxylative fluorination, yielding benzylic fluorides, while α-fluoro-α-arylcarboxylic acids (19) are formed under dry conditions [45].

This involves Selectfluor 2 acting as a fluorine source and DMAP serving as a base and an activator. In the presence of water, the reaction affords decarboxylative benzylic fluorination products, whereas α-fluoro-α-arylcarboxylic acids are formed without water. The reaction is conducted at room temperature, typically in acetonitrile or acetonitrile–water mixtures, and does not require any added catalysts, light, or external energy input. The reactions proceed smoothly over a few hours, with yields of up to 96% (Scheme 12).

Key features of this methodology include its catalyst-free operation, room temperature conditions, and ability to switch the selectivity simply by adjusting the solvent system. This dual-mode pathway provides synthetic flexibility and direct access to both decarboxylated benzylic fluorides and α-fluoro acids. However, the substrate scope is largely confined to phenylacetic acid derivatives, and its applicability to a broader range of structures remains untested, indicating the need for further expansion and mechanistic insights.

The process begins with the formation of a charge–transfer complex between DMAP and Selectfluor, forming a labile and reactive TEDA^2+• chain carrier that is used as a SET or HAT process. In an aqueous medium, this adduct undergoes single-electron transfer (SET) with the phenylacetic acid substrate, generating a benzylic radical A after decarboxylation. Then, this radical undergoes fluorine atom transfer from Selectfluor 2, yielding the benzylic fluorination product 19′. In a dry medium, electrophilic fluorination occurs at the α-position without decarboxylation, likely via direct interaction between the DMAP-activated Selectfluor 2 and the phenylacetic acid derivative 19 (Scheme 13).

In 2022, Komatsuda et al. reported the ring-opening fluorination of isoxazoles using Selectfluor 2, leading to the α-fluorocarbonyl compounds 21 through N–O bond cleavage. The authors developed a ring-opening fluorination protocol for C3-unsubstituted isoxazoles using Selectfluor 2 under thermal conditions; this reaction involves initial electrophilic fluorination followed by N–O bond cleavage and C3 deprotonation, yielding the α-fluorinated carbonyl compounds 21 [46].

This transformation involves the reaction of C3-unsubstituted isoxazoles 20 with 1.0 equiv of Selectfluor 2 in acetonitrile (0.2 M) at 80 °C for 24 h. In most cases, this reaction proceeds without a catalyst or an additive. In the case of substrates bearing electron-withdrawing groups (e.g., formyl, cyano), NaClO₄ (1.0 equiv) is added to improve the yields. This method was further applied to fused-ring isoxazoles and phthalimide derivatives (Scheme 14).

This reaction introduces a new class of ring-opening fluorination processes applicable to aromatic heterocycles, distinct from conventional applications that are limited to small, strained rings. It proceeds under mild, catalyst-free conditions with broad functional group tolerance. Importantly, the resulting α-fluorocyanoketones (21) serve as versatile fluorinated building blocks, enabling transformations into alcohols, olefins, amides, esters, and difluoromethylene groups via standard reduction, Wittig, Ritter, and methanolysis reactions. However, the efficiency of the reaction decreases upon alkyl substitution at the C5 position of the isoxazole, likely due to the lack of stabilization of the benzoyl-type cationic intermediate. Additionally, C4-aryl-substituted isoxazoles show reduced reactivity, possibly due to electron-withdrawing effects that hinder the initial fluorination.

Endo et al. reported a highly enantioselective α-fluorination protocol for both the cyclic and acyclic β-dicarbonyl compounds 23 and 11, including β-diketones, β-ketoesters, and β-ketoamides, using a bulky β,β-diaryl serine primary amine catalyst and Selectfluor 2 as the fluorinating agent. The reaction employs β,β-diaryl serine catalysts and is significantly improved by the addition of alkali metal carbonates, i.e., Li₂CO₃ or Na₂CO₃ [47].

In the case of the cyclic β-dicarbonyl fluorinated compounds 23, including β-diketones and β-ketoamides, the reactions were conducted in anhydrous THF using the β,β-diaryl serine catalyst (20 mol%), Selectfluor 2 (1.1 equiv), and an alkali carbonate base (either Li₂CO₃ or Na₂CO₃, 2.0 equiv) under an argon atmosphere at 40 °C. The reaction times typically ranged from 8 to 24 h, depending on the electronic and steric nature of the substituents (Scheme 15).

In the case of the acyclic β-dicarbonyl compounds 10, the same catalytic system and solvent were used, with the reaction temperatures maintained at 40 °C and similar inert conditions. However, these substrates showed markedly shorter reaction times, with the corresponding processes often completed within 4 to 6 h, while maintaining excellent enantioselectivity. The use of 2.0 equiv of Na₂CO₃ was particularly effective in this series, enhancing the reaction rates and enabling a reduction in the Selectfluor loading to 1.1 equiv, lower than that (2.0 equiv) employed in earlier methods (Scheme 16).

This study introduces a highly efficient and broadly applicable method for the enantioselective α-fluorination of both the cyclic and acyclic β-dicarbonyl compounds 23 and 11. This includes the use of a β,β-diaryl serine catalyst in combination with alkali metal carbonates (Li₂CO₃ or Na₂CO₃), significantly enhancing the activity and enantioselectivity of the catalyst while enabling a reduction in the amount of Selectfluor 2 from 2.0 to 1.1 equiv. This protocol displays excellent functional group tolerance, can accommodate sterically demanding substrates, and provides access to fluorinated building blocks with high stereochemical purity. Additionally, this method enables post-synthetic modifications such as selective protection of unstable fluorinated diketones, thereby extending its synthetic utility. However, the authors reported some limitations: reactions involving cyclic β-ketoesters resulted in nearly racemic products, due to rapid enolate formation, and large-ring cyclic diketones exhibited poor reactivity with incomplete conversion. Furthermore, when scaled up, the high viscosity of reaction mixtures containing inorganic salts reduced the stirring efficiency, requiring longer reaction times and highlighting the need for improved mixing technologies for synthetic applications.

In 2023, Mahmoud et al. introduced a novel elemental sulfur-mediated protocol using Selectfluor, which enabled the direct, efficient, and metal-free transformation of the carboxylic acids 24 into the acyl fluorides 25 with high selectivity and broad functional group compatibility. Their study demonstrates a transition-metal-free, sulfur-mediated method for synthesizing acyl fluorides from carboxylic acids using Selectfluor 2. Unlike previous methods that produced acid anhydrides or required derivatization, this reaction proceeds directly and selectively [48].

In particular, this process involves treating carboxylic acids (24) with Selectfluor 2 (1.5 equiv) and elemental sulfur (S₈, 1.5 equiv) in acetonitrile (MeCN) at 80 °C for 4 h under open-flask conditions. This reaction converts the acids to their corresponding acyl fluorides (25) with no detectable acid anhydride byproducts. The same method was also applied to drugs such as ibuprofen and febuxostat, yielding the corresponding acyl fluorides in good yields (60–74%) (Scheme 17).

This protocol features a transition-metal-free design and the direct use of unmodified carboxylic acids, avoiding the use of harsh reagents such as SF₄ or expensive fluorinating agents. Moreover, it shows broad functional group tolerance, including sensitive groups such as aldehydes and ketones, and enables late-stage functionalization of pharmaceutical molecules. Additionally, the in situ formation and selective reactivity of S₈-derived fluorinating species opens a new avenue in electrophilic fluorination chemistry. However, elemental sulfur is required in stoichiometric (rather than catalytic) amounts, owing to its transformation and degradation during the process.

González-Esguevillas et al. in 2023 reported the synthesis of fluoroalkanes via a visible-light-driven deoxyfluorination of alcohols 26, employing photoredox catalysis to facilitate the reaction of activated alcohol derivatives (alkyl oxalates) with Selectfluor 2^®. This transformation involves the photoredox-catalyzed transformation of alkyl oxalates with Selectfluor 2^® using an iridium photocatalyst such as Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1–2 mol%) in a mixed solvent system (e.g., acetone/H₂O or MeCN/H₂O), under nitrogen, and irradiated with a blue LED (26–34 W) for 1–6 h at room temperature. Under these conditions, secondary and tertiary alcohols are converted into corresponding alkyl fluorides (27) with high efficiency (Scheme 18) [49].

Key features of this methodology include its mild reaction conditions, broad functional group tolerance, and the ability to fluorinate even sterically hindered tertiary alcohols. Importantly, it supports late-stage fluorination of complex molecules and exhibits some diastereoselectivity in specific substrates. However, the authors note certain limitations. For instance, the reaction gives diminished yields with primary alcohols, likely due to the lower stability of the corresponding radical intermediates.

The mechanism for the synthesis of alkyl fluorides (27) is outlined in Scheme 19. Upon irradiation with blue light, the iridium photocatalyst (Ir(III)) (A) is excited to its photoactive state (*Ir(III)) (B), which then undergoes a single electron transfer (SET) with Selectfluor^®2, resulting in the formation of the oxidized species Ir(IV) (C). The generated C subsequently oxidizes the half-ester oxalate derivative D via SET, triggering decarboxylation to expel two molecules of CO₂ and generate the corresponding alkyl radical E. This radical intermediate then engages in a fluorine atom transfer from another equivalent of Selectfluor^®2, forming the desired alkyl fluoride product (27) and producing radical cation F. To close the catalytic cycle, the radical cation F undergoes a SET with the photocatalyst excited state B, regenerating the oxidized photocatalyst C (Scheme 19).

3. Fluorination by NFSI

NFSI is a crystalline, air-stable electrophilic fluorinating reagent that has gained widespread attention for its selective reactivity, operational simplicity, and compatibility with a range of catalytic systems. Its structure features an N–F bond flanked by a sulfonimide group that stabilizes the positive charge via resonance, delivering fluorine in a controlled, electrophilic manner.

Unlike Selectfluor, which often plays a dual role as both fluorinating agent and oxidant, NFSI serves as a pure fluorine donor. This property minimizes the risk of overoxidation and unwanted redox reactions, making NFSI a preferred reagent in transition-metal-catalyzed fluorination protocols where the oxidative balance is critical.

NFSI has been broadly applied in benzylic and allylic C–H fluorination using metal catalysts such as Cu, Fe, Pd, and Co. These reactions are typically regioselective, tolerate a wide range of functionalities, and proceed under mild conditions, making them well-suited for late-stage fluorination of complex molecules. In redox-neutral processes, NFSI often enables C–H activation without altering the metal oxidation states, maintaining the stability of the catalyst.

Overall, NFSI remains a robust and versatile reagent for electrophilic fluorination, especially when selectivity and redox control are essential. Its continued use in photoredox, asymmetric, and sustainable methodologies ensures its place as a central reagent in modern fluorination chemistry.

In 2019, Lovett et al. developed a silyl radical-mediated, open-shell fluorination approach using NFSI (29) as a uniquely effective fluorine donor, enabling highly selective C(sp³)–F bond formation from alkyl bromides under visible light conditions and without metal catalysts. Their study introduces a transition-metal-free, radical-based fluorination of alkyl bromides using visible light, supersilanol [(TMS)₃SiOH], and NFSI 29. Unlike previous methods where Si–F bond formation was the predominant process, in this work, the authors observed unexpected selectivity for C–Br abstraction and fluorination over the thermodynamically favorable N–F cleavage. NFSI 29 was found to be the ideal fluorine source, owing to its lower redox potential and compatibility with radical intermediates. Mechanistic and DFT studies confirmed that this process proceeds through a radical chain mechanism, where polar effects and halogen atom polarizability in the transition state drive the kinetic selectivity [50].

This process involves using alkyl bromides (28) in the presence of NFSI (29, 3.0 equiv) as fluorine source, (TMS)₃SiOH (1.75 equiv) as silyl radical precursor, and K₃PO₄ or Na₂HPO₄ (2.0 equiv) as base. Reactions are performed in 1:1 MeCN/H₂O under blue LED irradiation (40 W) in the presence of benzophenone (2.5–5 mol%) as photosensitizer. Under these mild, metal-free conditions, a wide range of alkyl bromides (28), including secondary, tertiary, and cyclic systems, are converted to alkyl fluorides (30) in good to excellent yields.

This method is characterized by exclusive reliance on radical chemistry, transition-metal-free conditions, and the use of NFSI 29, which combines suitable redox stability with high fluorine-transfer ability. This protocol enables fluorination of substrates incompatible with traditional nucleophilic or ionic conditions, including those bearing alcohols, phenols, aldehydes, and esters. It also tolerates complex molecular scaffolds and enables the selective formation of gem-difluorides. Despite its strengths, this method also exhibits some limitations. For instance, it is selective for alkyl bromides, whereas aryl bromides and alkyl chlorides remain unreactive; primary and benzylic bromides afford modest yields (24–27%), likely due to slower radical formation or alternative side pathways (Scheme 20).

The proposed mechanism begins with benzophenone (A) absorbing visible light to generate its excited triplet state (B), which can engage (TMS)₃SiOH in either a hydrogen atom transfer (HAT) or SET process. This interaction yields the silyl radical (C), a key species capable of abstracting the bromine atom from the alkyl bromide via halogen atom transfer (XAT) to form the corresponding alkyl radical (D). This open-shell intermediate then reacts with NFSI, resulting in fluorine atom transfer (FAT) and formation of the desired alkyl fluoride product, while simultaneously generating a nitrogen-centered radical (E) derived from NFSI 29. This radical can undergo HAT from the O–H bond of the silanol or a radical Brook rearrangement, regenerating the silyl radical C and sustaining the radical chain cycle (Scheme 21).

In 2019, Trost et al. reported the synthesis of the α-fluoro-α′,β′-unsaturated ketones 32 using vanadium-catalyzed coupling of allenyl alcohols with NFSI 29 as electrophilic fluorine source. In their study, the vanadium-catalyzed fluorination of the allenyl alcohols 29 generates the α-fluoro-α′,β′-unsaturated ketones 31 under mild and operationally simple conditions [51].

This process involves allenol 31 undergoing 1,3-rearrangement catalyzed by OV(OSiPh₃)₃ (5 mol%) in the presence of 2 equiv of NFSI 29 and 2 equiv of freshly ground Na₂CO₃ in 1,2-dichloroethane (DCE) at 65 °C for 19 h, affording the α-fluoro-enone 32 in 80–84% yield. This protocol utilizes a mild catalytic system that forms enolates via 1,3-transposition of allenols, enabling monofluorination under basic and non-cryogenic conditions. Unlike traditional approaches, which are adversely affected by overfluorination and harsh conditions, this reaction proceeds selectively to form the monofluorinated products (Scheme 22).

This method enables the highly selective monofluorination of allenyl alcohols 31 without the formation of difluorinated side products, a common issue in conventional enolate fluorination, due to overhalogenation. This reaction exhibits exceptional functional group tolerance, smoothly accommodating substrates bearing terminal alkynes, alkenes, hydroxyls, and even sensitive silyl-protected groups. Although this method can accommodate a broad range of substituents, substrates bearing electron-rich aryl groups showed somewhat reduced reactivities and yields, indicating electronic effects that may influence the generality of the approach.

The reaction begins with the coordination of the allenol hydroxyl group of 31 to the vanadium oxo catalyst A, generating Int-B, which then undergoes a 1,3-sigmatropic rearrangement to form a vanadium-stabilized enolate intermediate (Int-C). This enolate selectively undergoes electrophilic fluorination by NFSI 29 to release the final α-fluoro-α′,β′-unsaturated ketone product 32. Importantly, this mechanism avoids the overfluorination, commonly occurring in enolate chemistry, owing to the mild conditions and selective formation of monoenolate intermediates (Scheme 23).

In 2021, Yuan et al. reported the synthesis of the α-fluoroesters 35 through the highly enantioselective α-fluorination of carboxylic acids using planar chiral [2.2]paracyclophane-based isothiourea catalysts. Their approach utilized NFSI 29 as an electrophilic fluorinating agent, enabling direct and stereoselective fluorination of simple carboxylic acids (33) under mild conditions. This study introduces a new class of planar chiral isothiourea catalysts derived from [2.2]paracyclophane scaffolds, which mediate the direct α-fluorination of carboxylic acids with high yields and excellent enantioselectivities [52].

This process involves the activation of a carboxylic acid (33, e.g., phenylacetic acid) with tosyl chloride in the presence of a planar chiral isothiourea catalyst, followed by fluorination using NFSI 39 and subsequent alcoholysis with benzhydrol to yield the corresponding α-fluoroester 35. The optimized reaction conditions included 20 mol% of the (Sp,R)-2a catalyst, 1.5 equiv of NFSI 29, and 3 equiv of Cs₂CO₃ in DCM at room temperature for 24 h, leading to yields and enantioselectivities of up to 85% and 99% ee, respectively (Scheme 24).

This method presents several unique and valuable features in the context of asymmetric fluorination. A notable feature is the development of a new class of [2.2]paracyclophane-based isothiourea catalysts that exhibit high reactivity and excellent stereocontrol, affording enantioenriched α-fluoroesters with up to 99.5% ee. This protocol employs mild, room-temperature conditions and uses commercially available carboxylic acids as starting materials, an attractive alternative to more activated or unstable carbonyl species such as aldehydes or ketenes. The synthetic potential of the resulting α-fluoroesters is demonstrated through further transformation into fluorinated alcohols without loss of enantiopurity. However, this reaction was found to be ineffective with several non-aryl carboxylic acid substrates, such as aliphatic, alkynic, and α-branched acids, indicating that further catalyst tuning would be needed to broaden the substrate scope.

The proposed catalytic cycle begins with the formation of a mixed anhydride from the carboxylic acid and tosyl chloride. This intermediate undergoes nucleophilic acylation by the isothiourea catalyst, forming an acyl ammonium intermediate (I). Next, base-assisted deprotonation yields a stabilized ammonium enolate (II), which undergoes electrophilic fluorination by NFSI 29 to generate a fluorinated acyl ammonium intermediate (III). Finally, alcoholysis by benzhydrol liberates the α-fluoroester product and regenerates the isothiourea catalyst (Scheme 25).

In 2021, Yuan et al. reported the synthesis of the tertiary α-alkyl fluorides 38 via the enantioselective fluorination of the α-alkynyl-substituted acetic acids 36, catalyzed by a chiral isothiourea catalyst derived from d-phenylglycinol and using NFSI 29 as fluorine source. This work presents a novel organocatalytic method for the enantioselective construction of tertiary α-alkyl fluorides through the fluorination of α-alkynyl-substituted acetic acids [53].

This process involves the activation of the α-alkynyl-substituted acetic acid 36 (0.10 mmol) with pivaloyl chloride (0.15 mmol) and K₂CO₃ (0.30 mmol total) in DCM/toluene (1:1, 1.0 mL) at 0 °C under an inert atmosphere. After 30 min, the isothiourea catalyst A (20 mol%), NFSI 29 (0.15 mmol), and isopropanol (37, 0.30 mmol) are added, and the mixture is stirred at room temperature for 24 h. This one-pot fluorination–esterification affords the tertiary α-fluoroesters 38 in moderate to good yields (60–78%) and with excellent enantioselectivities (up to 97% ee) (Scheme 26).

This protocol enables the enantioselective synthesis of tertiary α-alkyl fluorides from simple carboxylic acid precursors under mild, base-compatible conditions. This method tolerates a wide range of alkyl and aryl substituents and is compatible with sensitive functional groups such as alkenes, alkynes, and heterocycles. This reaction can be performed on a Gram scale without compromising the yield or enantioselectivity. Furthermore, the obtained α-fluoroesters can be transformed into fluorinated alcohols, acids, and ketones, showcasing the versatility of the fluorinated products in synthetic applications. However, this transformation is restricted to α-alkynyl-substituted acetic acids; other types of α-branched carboxylic acids, including aryl–alkyl or alkenyl–alkyl variants, were unreactive under the optimized conditions. Additionally, electron-deficient aromatic groups resulted in slightly reduced yields and enantioselectivity.

The proposed mechanism begins with the activation of the carboxylic acid (36 using pivaloyl chloride to form a mixed anhydride (I), which then reacts with the isothiourea catalyst to generate a reactive acyl ammonium intermediate (B). This intermediate undergoes base-assisted deprotonation (via K₂CO₃) to yield a C1-ammonium enolate (C). The latter is then enantioselectively fluorinated by NFSI 29, forming a diastereomeric intermediate (D). Nucleophilic attack by isopropanol 37 on D gives the final α-fluoroester product 38 and regenerates the catalyst. The stereochemical outcome is controlled by the chiral environment around the enolate and the approach of NFSI 29 during electrophilic fluorination (Scheme 27).

In 2021, Ghosh and Hajra et al. reported a direct, metal-free C3-fluorination of 2H-indazoles (39) using NFSI (29) under aqueous conditions and ambient air. This environmentally benign transformation produces fluorinated indazoles in good to excellent yields, representing the first report of regioselective fluorination of this class of heterocycles in water. This study introduces a simple and scalable method for fluorinating 2H-indazoles using NFSI 29 in water without requiring metal catalysts, additives, or an inert atmosphere [54].

This process involves the reaction of 2-phenyl-2H-indazole (39, 0.2 mmol) with NFSI (29, 1.5 equiv, 0.3 mmol) in 2 mL of water at 80 °C for 30 min under ambient air; no catalyst or additive is required. The product, 3-fluoro-2-phenyl-2H-indazole (40), was isolated in 85% yield after extraction and silica gel purification. This method showed general applicability across electron-rich, electron-poor, and halogenated substrates, with yields ranging from 62% to 87%, depending on substituent effects and reaction time (Scheme 28).

This protocol stands out for its metal-free, additive-free, and environmentally friendly conditions. The use of NFSI 29 as a mild and stable fluorinating agent enables fluorination of a diverse range of indazoles in water, a valuable solvent in synthetic fluorination. This reaction exhibits excellent regioselectivity for C3 substitution, high functional group tolerance, and broad substrate scope, including electron-donating and withdrawing substituents. While this method is efficient, the reaction is specific to 2H-indazoles; other N-heterocycles such as imidazo[1,2-a]pyridine and indole failed to yield fluorinated products under the same conditions.

Based on control experiments with radical scavengers (BHT, TEMPO, and BQ), the reaction likely proceeds via a radical mechanism. Heating induces homolytic cleavage of the N–F bond in NFSI 29, generating an electrophilic fluorine radical. This radical selectively attacks the C3-position of 2H-indazole, generating a carbon-centered radical intermediate (A). The bis(sulfonyl)amidyl radical then abstracts a hydrogen atom from this intermediate, affording the fluorinated indazole product 38 and completing the transformation (Scheme 29).

Huang et al. in 2024 reported a visible-light-promoted, metal- and photocatalyst-free protocol for C–H fluorination of heteroarenes with high regioselectivity, primarily at the C2 position, using NFSI and triethylsilane. This transformation involves the reaction of quinoline (41) with NFSI and Et3SiH in TFA under 405 nm LED irradiation for 8 h at room temperature, using ethyl acetate as a solvent under a nitrogen atmosphere. The product is a C2 and C4-fluorinated quinoline derivative (42 and 43) with high regioselectivity (C2:C4 ratio of up to 20:1, depending on the substrate) [55].

This study offers a significant advancement in the direct and regioselective fluorination of electron-deficient heteroarenes, such as quinolines and pyridines, without the need for metal or photocatalyst mediation. The protocol is suitable for the late-stage fluorination of pharmaceuticals and supports post-synthetic modifications via SNAr and cross-coupling. It is also scalable, with successful Gram-scale and continuous-flow demonstrations. However, this method is ineffective for C2-substituted pyridines and provides low yields with quinoline N-oxides and some 3-substituted pyridines (Scheme 30).

The synthesis of C2-fluorinated quinoline derivatives proceeds through the mechanism discussed in Scheme 30. Under visible light irradiation, NFSI 29 undergoes homolytic cleavage to generate N-centered radical A and fluorine radical B. Radical A abstracts a hydrogen from Et₃SiH to form Et₃Si^• radical C, enhancing the generation of more F^• radicals. Simultaneously, TFA protonates quinoline (41), shifting its absorption to longer wavelengths and enabling excitation to singlet state I* upon light exposure. This excited species engages in single-electron transfer with CF₃COO⁻, generating the quinoline radical intermediate (II) and a CF₃COO^• radical. The quinoline radical (II) can transiently form a triethylsilylated species (III), which is reversible under acidic conditions. The fluorine radical (B) then adds selectively to intermediate II at the C2 position, forming intermediate IV. This is followed by hydrogen atom abstraction by radical A to yield intermediate V, which is subsequently oxidized by CF₃COO^•, restoring aromaticity and delivering the final fluorinated product 43 (Scheme 31).

4. Fluorination by Hypervalent Fluorinating Agents

Hypervalent iodine(III)-based fluorinating agents have emerged as powerful tools in modern fluorination chemistry, owing to their unique ability to transfer electrophilic fluorine under mild and highly selective conditions. These reagents, often derived from aryl iodides and bearing fluorine and/or oxygen ligands, not only enable direct C–F bond formation but also facilitate complex molecular rearrangements and cascade reactions.

Unlike traditional reagents, hypervalent fluoroiodanes can act as both fluorine donors and oxidants. This dual functionality enables the construction of fluorinated motifs along with skeletal rearrangements, heterocycle formation, or ring expansions. These reagents have proven particularly effective in fluorination-triggered semipinacol rearrangements, cyclization reactions, and functionalization of diazonium intermediates, enabling the synthesis of structurally diverse fluorinated building blocks, including aryl fluorides, α-fluoroketones, and fluorinated heterocycles.

Their compatibility with Lewis acids, metal catalysts, and even solvent-free or ball-milling conditions endows them with high versatility. Additionally, their crystalline, bench-stable nature makes them operationally safer and more practical than many conventional electrophilic fluorine sources.

Despite their advantages, some limitations remain, including high cost, occasional need for activating additives, and substrate scope constraints. Nonetheless, hypervalent iodine-based reagents continue to expand the synthetic toolbox for late-stage fluorination and selective C–F bond construction in both small molecules and complex scaffolds.

In 2019, Cortés González et al. reported a rhodium-mediated method for the geminal oxyfluorination of diazoketones (44) using a novel fluorine-18-containing hypervalent iodine reagent, [¹⁸F]fluoro-benziodoxole (45). This strategy enables the synthesis of biologically relevant α-[¹⁸F]fluoroethers under mild conditions, with high radiochemical yield (RCY) and molar activity. This work establishes a practical and high-yield method for the synthesis of α-[¹⁸F]fluoroethers by coupling diazoketones with [¹⁸F]fluoro-benziodoxole 39, a bench-stable electrophilic fluorinating agent derived from [¹⁸F]Bu₄NF [56].

This process involves the reaction of the diazoketone 44 (2 mg, 14 μmol) with [¹⁸F] (39) in neat trimethyl orthoformate 46 (TMOF, 500 μL), using Rh₂(OPiv)₄ (0.5 mg, 0.8 μmol) as catalyst. The mixture is stirred at room temperature for 10 min, yielding the geminal oxyfluorinated product [¹⁸F] 47 in 98% radiochemical yield. The transformation proceeds in the presence of Rh₂(OPiv)₄ and TMOF 46 as nucleophile and solvent. The authors overcame the common challenges associated with ¹⁸F labeling, including low molar activity, side reactions, and instability of ¹⁸F reagents, by replacing conventional alcohol nucleophiles with TMOF, minimizing side reactions and maintaining a high isotopic purity (Scheme 32).

This method presents several notable advantages for fluorine-18 radiochemistry. The use of [¹⁸F]fluoro-benziodoxole as a robust electrophilic fluorinating agent achieves a high molar activity (216 GBq/μmol) and excellent functional group tolerance across a range of diazoketone substrates. This approach eliminates the need for alcohol solvents, which previously reduced the fluorine-18 isotopic purity, and instead, employs trimethyl orthoformate 46 as a mild nucleophile and medium. Despite its advantages, this method has some limitations: substrates with strong electron-withdrawing groups (e.g., nitro) or diazoamides resulted in lower RCYs (as low as 16–26%), and aliphatic diazoketones failed to afford the fluorinated product.

The proposed mechanism starts with the generation of a rhodium carbene intermediate (B) from diazoketone 44 and Rh₂(OPiv)₄. Nucleophilic attack by trimethyl orthoformate (46) forms a rhodium ylide (C), which rearranges into a vinyl ether (E). This intermediate undergoes electrophilic fluorination by [¹⁸F] generating intermediate F, followed by Rh migration and I–F bond isomerization to intermediate G, and eventual displacement of the iodine atom to form the C–F bond in intermediate H. Final dissociation of Rh yields the fluorinated ether [¹⁸F] 47 (Scheme 33).

In 2021, Riley et al. reported a novel and efficient method to synthesize fluorinated tetrahydropyridazines and dihydrooxazines via intramolecular fluorocyclization using a hypervalent iodine(III) fluoroiodane reagent. This method was successfully applied in both conventional solution-phase and mechanochemical (ball-milling) conditions, demonstrating flexibility and minimum solvent use. Their work expands the application of fluoroiodane reagents beyond previously established five-membered rings, providing access to new six-membered fluorinated heterocycles [57].

This process involves the fluorocyclization of β,γ-unsaturated hydrazones (48) using 1.5 equiv of the hypervalent fluoroiodane reagent 45, activated by either AgBF₄ (0.2–1 equiv) or HFIP (1–2 equiv) in CH₂Cl₂ at room temperature, affording the fluorinated tetrahydropyridazines 49 in up to 93% yield within 15–60 min. A greener, mechanochemical approach with minimal solvent use employed the same reagents in a 10 mL stainless steel jar with a 2.5 g ball, milled at 30 Hz for 15 min using only two equivalents of HFIP, and produced comparable yields (Scheme 34).

This work stands out by providing access to new classes of six-membered fluorinated heterocycles, previously unexplored in synthetic chemistry. The development of a mechanochemical protocol with minimal solvent use not only offers advantages in terms of sustainability but also uniquely improves the product selectivity and yield for oximes, where solution-based methods underperformed. Additionally, fluorolactonization under ball-milling conditions was further expanded to fused heterocycles.

In 2023, Hernández-Ruiz et al. reported the direct one-pot synthesis of aryl halides (including fluorinated arenes) from nitroarenes (50) by integrating Mo-catalyzed reduction with Sandmeyer-type halogenation. In particular, the aryl fluorides 51 were accessed via Balz–Schiemann fluorination using a hypervalent iodine (III) reagent (1-fluoro-3,3-dimethylbenziodoxole, 45) under acidic and thermal conditions, providing a rare and practical direct approach to prepare aryl fluorides from nitro compounds [58].

The fluorination reaction involves MoO₂Cl₂(dmf)₂-catalyzed reduction in the nitroarene (50, 1 mmol) to anilines in the presence of pinacol (2.5 equiv) at 150 °C in MeCN. Next, diazotization and fluorination using the hypervalent iodine(III) reagent (45) afford the fluorinated arenes (51) in moderate to good yields (Scheme 35). This reaction shows good chemoselectivity and broad functional group tolerance. However, the fluorination step displayed lower yields and a narrower scope compared to the bromination, chlorination, and iodination sequences.

In 2022, Muta et al. reported the first three-position-selective trifluoromethylation 53 of pyridine and quinoline rings (52) via a nucleophilic activation strategy, marking a significant advancement in the selective C–H functionalization of electron-deficient heterocycles. The authors developed a method that combines hydrosilylation-mediated nucleophilic activation of pyridine rings with subsequent electrophilic trifluoromethylation using Togni reagents (45). The reaction proceeds regioselectively at the C3 position, which is traditionally challenging because of the electron-poor nature of the pyridine and quinoline frameworks [59]. Although trifluoromethylation forms a C–C bond rather than a direct C–F bond, it is included here because it employs a fluorinated reagent that introduces a trifluoromethyl group, which is relevant in the context of synthetic fluorine chemistry.

The pyridine and quinoline derivatives (52) undergo regioselective C3-trifluoromethylation through initial hydrosilylation using a hydrosilane and B(C₆F₅)₃ catalyst, forming an N-silyl enamine intermediate. This intermediate reacts with the Togni reagent 45 as the electrophilic CF₃ source, followed by oxidation with DDQ, to yield the final 3-trifluoromethylated heteroarene 53. This method is compatible with a range of electron-deficient azaarenes and functional groups (Scheme 36).

This method provides unprecedented selectivity for the C3 position in pyridine rings, which had not been achieved by electrophilic or radical trifluoromethylation. This process tolerates a wide range of functional groups, including halides, esters, aryl silanes, and even late-stage modifications of pharmaceutical targets. However, hydrosilylation does not proceed well with sterically hindered or electron-rich pyridines, limiting substrate generality. Some reactions require elevated temperatures (up to 110 °C) and long reaction times, especially for isoquinoline derivatives

The proposed mechanism begins with the hydrosilylation of the nitrogen atom of quinoline or pyridine, forming an N-silyl enamine intermediate (II) via interaction with activated hydrosilane. This intermediate undergoes electrophilic trifluoromethylation at the C3 position using the Togni reagent 45, forming a 3-CF₃-substituted dihydroquinoline intermediate (B). Oxidation with DDQ then leads to aromatization, yielding the final 3-trifluoromethylated product (53). Mechanistic studies using NMR spectroscopy confirmed the presence of both enamine and dihydro intermediates, supporting this stepwise pathway (Scheme 37).

Zhao et al. (2023) reported a novel fluorination strategy using hypervalent fluoro-λ³-iodane reagents (45) to enable a cascade reaction, including semipinacol rearrangement, aryl migration, and fluorination steps, giving access to synthetically challenging α-fluoro ketones. Their paper describes a cascade process involving the treatment of cyclobutanol derivatives (54) with fluoro-λ³-iodane reagents (45) in the presence of AgBF₄ in DCM. This triggers fluorination-induced aryl migration and semipinacol rearrangement, yielding tertiary α-fluoro cyclopentanones (55) [60].

This transformation uses styrene-derived cyclobutanols (54) as substrates. Upon treatment with three equivalents of fluoroiodane 5 and AgBF₄ in DCM at room temperature for 8 h, the reaction proceeds through a cascade mechanism to form α-fluorinated ketones (55). The key fluorinating agent, hypervalent fluoro-λ³-iodane (45), is crucial for initiating the rearrangement. This reaction exhibits excellent functional group tolerance and diastereoselectivity, producing fluorinated products in good to excellent yields (Scheme 38).

This method provides a mild, metal-free, and operationally simple route to access tertiary α-fluoroketones (55) structural motifs, rarely obtained with traditional fluorinating agents such as Selectfluor. The cascade reactivity enables the efficient construction of quaternary carbon centers with fluorine incorporation adjacent to carbonyl groups. While this reaction proceeds efficiently with aryl-substituted cyclobutanols, it is currently limited to compounds bearing aryl substituents. The reaction scope with other ring systems or alkyl-substituted analogs was not explored.

The proposed mechanism involves regioselective addition of the fluoroiodane reagent (45) to the alkene (54) of the cyclobutanol substrate, generating a phenonium ion intermediate (A). The latter undergoes ring expansion via 1,2-aryl migration to afford a fluorinated carbocation (B), which rearranges into the α-fluorinated cyclopentanone (55) (Scheme 39).

5. Fluorination by SynFluor

SynFluor is a bench-stable, crystalline reagent developed for use in iodoarene-catalyzed electrophilic fluorination. Traditionally, these reactions relied on oxidants such as mCPBA to convert aryl iodides to hypervalent iodine(III) difluorides (ArIF₂) in the presence of HF sources. However, mCPBA, while being effective as an oxidant, is not a fluorinating agent and often promotes unwanted side reactions, including epoxidation of alkenes or oxidation of other sensitive functionalities. In contrast, SynFluor acts as both an oxidant and a fluorine donor, enabling the clean, in situ generation of ArIF₂ intermediates under milder and more selective conditions. This dual role simplifies the reaction setup, improves the chemoselectivity, and reduces the need for external oxidants and additional fluorine sources.

Kitamura et al. (2023) reported the use of SynFluor 57 as a new electrophilic fluorinating oxidant for iodoarene-catalyzed fluorination reactions. Their study introduced SynFluor as a superior terminal oxidant in ArI-catalyzed electrophilic fluorination. Unlike mCPBA, which induces undesired side reactions such as epoxidation, SynFluor enables a simplified catalytic cycle with enhanced product selectivity [61].

The fluorination process involves p-iodotoluene as a catalyst and SynFluor (57) as the oxidant and an HF source. Under optimized conditions, typically DCE or DCM at 40 °C, this method enables 1,2-difluorination of terminal alkenes (56), gem-difluorination of conjugated alkenes to form 58, and α-fluorination of 1,3-dicarbonyls 60. Representative products include 1,2-difluorododecane (58) (Scheme 40) and ethyl 2-aryl-3,3-difluoropropanoates (60) (Scheme 41).

This reaction features a broad substrate scope, a high functional group tolerance, and high yields achieved under mild reaction conditions. This method tolerates alkenes bearing hydroxyl, ester, halogen, and aryl substituents. While providing excellent performance for many unsaturated systems, enolizable 1,3-dicarbonyls may undergo fluorination even without catalysis, limiting control in those cases.

6. Fluorination by AlkylFluor

AlkylFluor is a bench-stable monofluoroimidazolium salt developed for the efficient deoxyfluorination of alcohols, especially aliphatic substrates. It addresses limitations associated with previously employed reagents such as DAST and PhenoFluorMix, providing improved air and moisture stability along with high functional group tolerance. AlkylFluor reacts with primary and secondary alcohols in the presence of fluoride sources (e.g., KF or CsF) at elevated temperatures (typically 80 °C in dioxane or toluene), yielding alkyl fluorides in good to excellent yields. For more sterically hindered alcohols, preheating with CsF enhances the reactivity by generating PhenoFluor in situ. This method tolerates a wide array of functional groups, including ketones, amides, and heterocycles, and is particularly effective in cases where other reagents fail.

Goldberg et al. (2016) introduced the AlkylFluor (62) reagent as a novel monofluoroimidazolium salt that is easy to handle, air- and moisture-stable, and capable of promoting the high-yield deoxyfluorination of a broad range of alcohols. Compared to other commercial fluorinating agents, AlkylFluor exhibits improved performance in terms of yield, safety, and substrate scope, especially for secondary and sterically congested alcohols [62].

The general reaction involves a primary or secondary alcohol (61) as the substrate, which reacts with AlkylFluor (62, 1.0 equiv) as the fluorinating agent, in the presence of KF or CsF (used as a base/activator) in 1,4-dioxane or toluene at 80 °C. For challenging substrates, preheating AlkylFluor with CsF at 100 °C before adding the alcohol results in improved yields. This reaction cleanly converts the alcohols to the corresponding alkyl fluorides (63) in good yields (Scheme 42).

This method enables the deoxyfluorination of a wide variety of alcohols, including primary, secondary, and even sterically hindered substrates such as neopentyl alcohols. Functional groups such as alkenes, alkynes, esters, amides, carbamates, unprotected amines, and heterocycles are tolerated without protection or side reactions. However, AlkylFluor is available from limited commercial sources, but often requires international shipping and long lead times, which may preclude its routine use in many laboratories. Additionally, this methodology is optimized for aliphatic alcohols; aryl and benzylic alcohols generally resulted in lower yields or were unreactive.

7. Miscellaneous Methods

Hoogesteger et al. (2023) reported a cobalt-catalyzed approach for the Wagner–Meerwein rearrangement of gem-disubstituted allylarenes, uniquely integrating nucleophilic hydrofluorination and generating fluoroalkane products in high yields. Unlike traditional cationic rearrangements, this method employs a Co(II)-salen catalyst system and N-fluoropyridinium tetrafluoroborate (Me₃NFPY·BF₄) as fluorine source and oxidant, enabling aryl migration through formation of a phenonium ion intermediate under mild, non-acidic conditions [63].

The reaction involves gem-disubstituted allylarene substrates (64 and 65) reacting with Me₃NFPY·BF₄ (66, 2.0 equiv), TMDSO or PhMe₂SiH (4.0 equiv), and a Co(II)-salen catalyst (3–5 mol%) in chlorobenzene (PhCl) at 0 °C for 2 h. The reaction proceeds via hydride abstraction, radical formation, Co(IV) alkyl intermediate formation, and aryl migration, ultimately affording the fluoroalkane products (67 and 68) through trapping of the phenonium ion by BF₄⁻. This study shows that gem-dimethyl allylarenes undergo 1,2-aryl shifts with simultaneous fluorination via a cobalt-catalyzed radical–polar crossover mechanism. The Me₃NFPY·BF₄ reagent plays a dual role: oxidizing the Co catalyst and delivering the nucleophilic fluoride anion (BF₄⁻) that traps the rearranged phenonium intermediate (Scheme 43).

This method is significant for enabling the direct formation of C(sp³)–F bonds adjacent to rearranged carbon skeletons, providing rapid access to fluorinated alkyl arenes. The use of Me₃NFPY·BF₄ as a dual oxidant and fluoride source eliminates the need for harsh fluorinating reagents. Despite its generality, this method has some substrate limitations. Ortho-substituted aryl substrates often lead to lower yields or undesired side products, owing to steric hindrance. Additionally, cyclic alkenes (e.g., cyclobutanes) tend to undergo ring expansion or E1 elimination rather than aryl migration. This method is also ineffective with 1,2-disubstituted or tetrasubstituted alkenes, and substrates bearing Lewis basic heterocycles such as pyridine are incompatible, owing to catalyst deactivation.

The proposed mechanism starts with the Co(II)-salen catalyst reacting with the silane (e.g., TMDSO) to generate a Co–H species (intermediate A). This cobalt hydride undergoes metal hydride atom transfer (MHAT) to the alkene substrate, yielding a benzylic radical (intermediate B) and regenerating the Co(II) species. The radical B is then trapped by Co(II) to form a Co(III)–alkyl complex (intermediate C). Oxidation of C by Me₃NFPY⁺ (the pyridinium oxidant component of Me₃NFPY·BF₄) gives a high-valent Co(IV)–alkyl species (intermediate D). This highly electrophilic intermediate undergoes [1,2]-aryl migration via a non-classical phenonium ion-like transition state (intermediate E), generating a stabilized carbocation. Finally, a nucleophilic fluoride from the BF₄⁻ counterion attacks the intermediate F, resulting in the formation of the rearranged fluoroalkane product 67 and regenerating the Co(II) catalyst (Scheme 44).

Lee et al. (2024) introduced a nickel-catalyzed hydrofluorination process of unactivated alkenes to achieve regio- and enantioselective formation of C–F stereogenic centers using fluoro-trimethylpyridinium tetrafluoroborate as a fluorine source. The authors developed a mild and selective Ni-catalyzed platform for hydrofluorination of both terminal and internal unactivated alkenes using a tailored chiral BOx ligand [64].

This reaction involves the transformation of alkenes, e.g., (E)-N-phenylhex-3-enamide (69) with 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (70, 2.5 equiv) as the fluorinating agent, catalyzed by Ni(BF₄)₂·6H₂O (10 mol%) and ligand L7 (12 mol%), in the presence of (MeO)₂MeSiH (3 equiv) in 1,2-DCE at 24 °C for 18 h under argon. This yields branched β-fluoroamide products (71) with excellent regioselectivity (>20:1) and high enantioselectivity (up to 98:2 er). This method showed broad substrate scope and was successfully applied to the late-stage fluorination of drug derivatives, such as loratadine and paroxetine, with excellent regio- and enantioselectivity (Scheme 45).

This nickel-catalyzed hydrofluorination tolerates a variety of substitution patterns on alkenes. This method enabled late-stage functionalization of pharmaceutical compounds, including loratadine and nortriptyline, without affecting their core structures.

Our group in 2021 reported the synthesis of carbamoyl fluorides via a selective fluorinative Beckmann fragmentation of α-oximinoamides, providing a distinct route to these valuable fluorine-containing motifs with high selectivity and functional group tolerance [65].

This work introduces a novel method for synthesizing carbamoyl fluorides through a fluorinative Beckmann fragmentation of α-oximinoamides, employing DAST as both an activator and a fluoride donor. The synthetic approach involves converting α-oximinoamides (72) into carbamoyl fluorides (74) using DAST (73) in DCM at room temperature for 10 min (Scheme 46). This protocol was also extended to the synthesis of o-Cyanophenyl Carbamoyl Fluorides (76) by employing N-Substituted Isatin-3-oximes (75) under standard conditions (Scheme 47).

This method demonstrates excellent selectivity for C−C bond cleavage over Beckmann rearrangement, enabling broad substrate compatibility across secondary amines, lactams, and isatin derivatives. This reaction operates under simple conditions with high yields and synthetic utility, extending its applicability to the formation of structurally diverse carbamoyl fluorides and further transformations such as annulation to heterocycles and Gram-scale synthesis. However, this transformation exhibited reduced efficiency with substrates containing acid-sensitive Boc groups or highly basic moieties. Furthermore, N-substituted isatin-3-oximes bearing strongly electron-withdrawing groups, such as nitrophenyl or carbomethoxymethyl substituents, did not afford the desired carbamoyl fluorides. Instead, these substrates either decomposed or underwent alternative reaction pathways, yielding undesired products.

Chen et al. (2019) reported the synthesis of fluorinated aromatic compounds via direct arene C–H fluorination using fluorine-18 (¹⁸F) under metal-free conditions through organic photoredox catalysis. This transformation involves a direct fluorination of aromatic substrates (77) using [¹⁸F]-TBAF (tetrabutylammonium fluoride) 78 and an acridinium-based photoredox catalyst with a perchlorate counterion. Under blue-light (450 nm laser) irradiation in acetonitrile at 0 °C, arene substrates (77) are oxidized to radical cations, which are then intercepted by ¹⁸F⁻ to yield fluorinated products (79). TEMPO is used as a redox co-mediator under aerobic conditions (Scheme 48) [66].

This approach addresses the limitations of traditional electrophilic and nucleophilic ¹⁸F-labeling methods, offering a practical and selective route to radiofluorinated arenes for positron emission tomography (PET). This method is broadly applicable to electron-rich arenes, halogenated arenes, and heteroarenes. It also enables labeling bioactive molecules like NSAIDs (e.g., fenoprofen) and amino acids (e.g., tyrosine analogs).

Pulikkottil et al. (2025) reported the synthesis of fluorothioformates via electrochemical fluorination of oxalic acid monothioesters using triethylamine trihydrofluoride (Et₃N·3HF) 80 as both fluorine source and electrolyte. This method involves the electrochemical oxidation of oxalic acid monothioesters (80) in DCM under a current density of 8.9 mA/cm² using a platinum cathode, a carbon anode, and two equivalents of Et₃N·3HF 81. The oxidative process generates a reactive carbonyl sulfide intermediate that is captured by fluoride to form the fluorothioformate product (82) (Scheme 49) [67].

This study presents a practical, mild, and metal-free electrochemical strategy to access fluorothioformates from oxalic acid monothioesters. This method demonstrates broad substrate scope, excellent functional group tolerance, and good yields, including for heterocycles and complex molecules. Despite its advantages, the authors acknowledge several limitations of this method. Aromatic thiol-derived substrates, such as thiophenols, were found to be prone to side reactions under the anodic conditions. Additionally, sterically hindered substrates like adamantane-based monothioesters exhibited reduced yields, suggesting that bulkiness around the reactive center can impede fluoride attack. Electron-deficient substrates, such as those bearing carboxylic acid or amide functionalities, also led to diminished or variable yields and, in some cases, complex mixtures of fluorinated byproducts.

The proposed mechanism begins with the anodic oxidation of the oxalic acid monothioester (80) to yield a carboxyl radical (I), which rapidly undergoes decarboxylation to form an oxythiocarbonyl radical (II). This intermediate loses an electron to become a sulfonium cation (III), a highly electrophilic species that reacts with fluoride from Et₃N·3HF to afford the fluorothioformate product (82) (Scheme 50).

Köpfler et al. (2025) reported the synthesis of bis(5-ethyl-2-methylpyridin-1-ium) hexafluorosilicate (IV), a novel and soluble hexafluorosilicate salt, and demonstrated its use as an efficient nucleophilic fluorine source for electrochemical transformations. This reaction involves the electrochemical decarboxylative fluorination of aliphatic carboxylic acids (83) using (MepH)₂SiF₆ 84 via anodic oxidation in DCM. The optimal conditions included undivided cells with impervious graphite electrodes, a current density of 6.66 mA/cm², and alternating electrode polarity every 2 min at room temperature. The reaction uses 12 F/mol of charge, affording fluorinated product 85 with high selectivity (Scheme 51) [68].

This paper introduces the first application of hexafluorosilicate salts as a soluble and cost-effective fluoride donor in organic synthesis. This method enables selective and high-yielding fluorination of a wide substrate scope, including primary, secondary, and tertiary carboxylic acids. It also demonstrates robustness under batch and scalable flow conditions. Moreover, this salt effectively promotes benzylic C–H fluorination, indicating its potential beyond decarboxylation reactions and its utility in late-stage functionalization

In addition to the widely used electrophilic, nucleophilic, and radical-based fluorinating agents, an increasing number of non-traditional fluorination strategies have emerged since 2019. These approaches employ sulfur-, phosphorus-, and silicon-based reagents, along with transition metal catalysts, offering unique modes of reactivity, milder conditions, and functional group compatibilities that often complement those of conventional methods. Although these reagents may not yet be as widely adopted as Selectfluor or NFSI, their special properties and tunable selectivity are attracting increasing interest in late-stage functionalization, bioconjugation, and complex-molecule assembly.

Future research in fluorination chemistry is expected to focus on several converging themes. One key priority is the development of catalytic, redox-neutral fluorination protocols with minimal reliance on stoichiometric reagents and harsh oxidants. Another goal is the integration of fluorination with green and sustainable technologies, such as flow chemistry, electrochemistry, and photocatalysis, to enable safer and more efficient large-scale synthesis. Moreover, designing fluorinating agents that provide site- and stereocontrol in late-stage functionalization remains critical, especially in the context of drug and agrochemical development. Finally, expanding the availability and cost-efficiency of high-performance reagents such as SynFluor, AlkylFluor, and hypervalent iodine derivatives will be essential for their broader adoption across both academic and industrial settings.

8. Conclusions

In recent years, significant progress has been achieved in the development of catalytic fluorination methods that enable the efficient and selective introduction of fluorine into organic molecules. Transition-metal catalysis, organocatalysis, photocatalysis, and electrochemical approaches have collectively expanded the range of C–F bond-forming reactions, often under mild and sustainable conditions. Reagents such as Selectfluor, N-fluorobenzenesulfonimide, AlkylFluor, and hypervalent iodine compounds have demonstrated broad utility across electrophilic, nucleophilic, and radical fluorination pathways, especially when combined with well-defined catalytic systems.

This review has highlighted key advances in catalytic strategies, including site-selective C–H fluorination, deoxyfluorination of alcohols, decarboxylative fluorination of carboxylic acids, and late-stage functionalization of complex scaffolds. Mechanistic proposals from the original studies illustrate how catalysts and reaction conditions influence reactivity and selectivity, although further investigation will continue to refine our understanding of these processes.

Emerging methods using transition-metal catalysis, organophosphorus and sulfonyl fluorides, as well as electrochemical fluorination, are expanding the field beyond traditional polar pathways, offering new modes of reactivity and improved sustainability.

Future work will likely focus on catalytic, stereoselective, and redox-neutral fluorination strategies, along with improving the integration into flow and green technologies. The ongoing development of accessible and selective fluorination methods is critical for advancing applications in the pharmaceutical, agrochemical, and materials fields.