Kitamura Electrophilic Fluorination Using HF as a Source of Fluorine

This review article focused on the innovative procedure for electrophilic fluorination using HF and in situ generation of the required electrophilic species derived from hypervalent iodine compounds. The areas of synthetic application of this approach include fluorination of 1,3-dicarbonyl compounds, aryl-alkyl ketones, styrene derivatives, α,β-unsaturated ketones and alcohols, homoallyl amine and homoallyl alcohol derivatives, 3-butenoic acids and alkynes.

Molecules 2020, 25, 2116 2 of 21 this field was centered on the development of the corresponding reagents capable of releasing the required "electrophilic fluorine". The most successful results have been achieved utilizing compounds with N-F bonds. For example, as presented in Figure 1, 1-chloromethyl-4-fluoro-1,4diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (1), introduced by Professor E. Banks [72], also known as Selectfluor, is one of the best reagents used as a source of "electrophilic fluorine". Other reagents, developed by Professor N. Shibata [73][74][75][76], are N-fluoro-N-(methylsulfonyl)methanesulfonamide (Me-NFSI) (2), 3,5-di-tert-butyl-N-((3,5-di-tert-butyl-4methoxyphenyl)sulfonyl)-N-fluoro-4-methoxybenzenesulfonamide (NFBSI) (3) and axially chiral NFSIs (4), which can be used for enantioselective fluorination [77]. All these reagents are shelf-stable, easy to handle and operationally convenient to use for various synthetic applications [78][79][80][81]. However, the preparation of N-F reagents usually requires molecular fluorine [72,82], rendering them rather expensive and not practical for large-scale syntheses. From the standpoint of practicality, the application of HF, as a source of fluorine, with the in situ formation of the electrophilic species, would offer an attractive alternative as a general methodology for "electrophilic" formation of a C-F bond. In this review article, we discuss the use of hypervalent iodine compounds, as electrophilic centers, and HF as a source of fluorine, creatively assembled in a one-pot sequence, allowing one to perform "electrophilic fluorination" of various types of organic compounds. The synthetic generality and practicality of these methods is critically discussed.

Iodosylbenzene-Mediated Fluorination
In 2011, Professor T. Kitamura's group has reported that mixing ethyl 3-oxo-3-phenylpropionate (5) with 1.2 equivalents of a hypervalent iodine compound and excess (10-fold) of 55% aqueous HF resulted in formation of the corresponding ethyl 2-fluoro-3-oxo-3-phenylpropionate (6) in up to 98% chemical yield (Scheme 1) [83]. From the standpoint of practicality, the application of HF, as a source of fluorine, with the in situ formation of the electrophilic species, would offer an attractive alternative as a general methodology for "electrophilic" formation of a C-F bond. In this review article, we discuss the use of hypervalent iodine compounds, as electrophilic centers, and HF as a source of fluorine, creatively assembled in a one-pot sequence, allowing one to perform "electrophilic fluorination" of various types of organic compounds. The synthetic generality and practicality of these methods is critically discussed.
The mechanistic rationale for the reaction is presented in Scheme 2. It postulates the in situ formation of (difluoroiodo)benzene 7 from iodosylbenzene and two equivalents of hydrogen fluoride. The reaction of 7 with the enol 8 gives rise to intermediate 9, followed by the nucleophilic substitution of the iodine species to afford fluorinated compound 6 along with iodobenzene 10 as the final reaction products. Scheme 2. Mechanistic rationale of the "electrophilic" fluorination of 3-oxo-3-phenylpropionate 5 to 2-fluoro-3-oxo-3-phenylpropionate 6.
The mechanistic rationale for the reaction is presented in Scheme 2. It postulates the in situ formation of (difluoroiodo)benzene 7 from iodosylbenzene and two equivalents of hydrogen fluoride. The reaction of 7 with the enol 8 gives rise to intermediate 9, followed by the nucleophilic substitution of the iodine species to afford fluorinated compound 6 along with iodobenzene 10 as the final reaction products. Scheme 2. Mechanistic rationale of the "electrophilic" fluorination of 3-oxo-3-phenylpropionate 5 to 2-fluoro-3-oxo-3-phenylpropionate 6.
Some support for the proposed mechanistic pathway can be derived from the reactions of iodonium ylides with HF and HCl [105]. As shown in Scheme 3, iodonium ylide 11 can be prepared in quantitative yield by the reaction of keto ester 5 with (diacetoxyiodo)benzene in the presence of KOH in MeCN [106]. Scheme 2. Mechanistic rationale of the "electrophilic" fluorination of 3-oxo-3-phenylpropionate 5 to 2-fluoro-3-oxo-3-phenylpropionate 6.
Some support for the proposed mechanistic pathway can be derived from the reactions of iodonium ylides with HF and HCl [105]. As shown in Scheme 3, iodonium ylide 11 can be prepared in quantitative yield by the reaction of keto ester 5 with (diacetoxyiodo)benzene in the presence of KOH in MeCN [106]. The reaction of iodonium ylide 11 with concentrated aqueous HCl, conducted in dichloromethane at ambient temperature, gave chlorinated product 12 in 55% yield [105]. Similar yields of fluorination product 6 were also obtained under the same conditions in the reactions of 11 with various HF reagents, such as 55% aqueous HF and TEA·3HF [105]. The noticeably lower chemical yields of 6 obtained in the reactions of iodonium ylide 11 with HF reagents (vs 98%), as compared with the reactions of 5 with HF in the presence of PhIO (Schemes 1,2) can be explained by enolization of intermediate 13 to vinyliodonium salt 14, further reactions of which give complex mixtures of products.
Meticulous investigations of HF/PhIO reactivity revealed that this new approach has a general synthetic application for fluorination of various compounds bearing the acidic CH2 moiety, such as 3-keto-esters, 1,3-diketones and malonic acid derivatives, summarized in Scheme 4. Optimization of the reaction conditions and reagents revealed that besides the original iodosylbenzene, its derivatives, such as p-and o-iodosyltoluene, can also be used successfully, and in some cases, even give better chemical yields as compared with unsubstituted iodosylbenzene [107,108]. For example, fluorination of amide derivatives of 3-keto-esters 15 (R' = CONAlk2) with HF/PhIO affords the corresponding products 16 with relatively low (<50%) yield, while the application of o-iodosyltoluene allows for improved yields of the target products 16 (up to 93%). The source of the HF has also been examined in detail showing that other HF reagents such as complexes with triethylamine and pyridine can be successfully used in place of aqueous HF. Of particular importance is the wide synthetic generality of this approach. Thus, 3-keto esters 15 bearing an aromatic ring with electron-withdrawing or donating substituents can be successfully used as substrates. In the case of derivatives 15 featuring alkyl groups (R and/or R' = Alk) the chemical yields The reaction of iodonium ylide 11 with concentrated aqueous HCl, conducted in dichloromethane at ambient temperature, gave chlorinated product 12 in 55% yield [105]. Similar yields of fluorination product 6 were also obtained under the same conditions in the reactions of 11 with various HF reagents, such as 55% aqueous HF and TEA·3HF [105]. The noticeably lower chemical yields of 6 obtained in the reactions of iodonium ylide 11 with HF reagents (vs 98%), as compared with the reactions of 5 with HF in the presence of PhIO (Schemes 1 and 2) can be explained by enolization of intermediate 13 to vinyliodonium salt 14, further reactions of which give complex mixtures of products.
Meticulous investigations of HF/PhIO reactivity revealed that this new approach has a general synthetic application for fluorination of various compounds bearing the acidic CH 2 moiety, such as 3-keto-esters, 1,3-diketones and malonic acid derivatives, summarized in Scheme 4. The reaction of iodonium ylide 11 with concentrated aqueous HCl, conducted in dichloromethane at ambient temperature, gave chlorinated product 12 in 55% yield [105]. Similar yields of fluorination product 6 were also obtained under the same conditions in the reactions of 11 with various HF reagents, such as 55% aqueous HF and TEA·3HF [105]. The noticeably lower chemical yields of 6 obtained in the reactions of iodonium ylide 11 with HF reagents (vs 98%), as compared with the reactions of 5 with HF in the presence of PhIO (Schemes 1,2) can be explained by enolization of intermediate 13 to vinyliodonium salt 14, further reactions of which give complex mixtures of products.
Meticulous investigations of HF/PhIO reactivity revealed that this new approach has a general synthetic application for fluorination of various compounds bearing the acidic CH2 moiety, such as 3-keto-esters, 1,3-diketones and malonic acid derivatives, summarized in Scheme 4. Optimization of the reaction conditions and reagents revealed that besides the original iodosylbenzene, its derivatives, such as p-and o-iodosyltoluene, can also be used successfully, and in some cases, even give better chemical yields as compared with unsubstituted iodosylbenzene [107,108]. For example, fluorination of amide derivatives of 3-keto-esters 15 (R' = CONAlk2) with HF/PhIO affords the corresponding products 16 with relatively low (<50%) yield, while the application of o-iodosyltoluene allows for improved yields of the target products 16 (up to 93%). The source of the HF has also been examined in detail showing that other HF reagents such as complexes with triethylamine and pyridine can be successfully used in place of aqueous HF. Of particular importance is the wide synthetic generality of this approach. Thus, 3-keto esters 15 bearing an aromatic ring with electron-withdrawing or donating substituents can be successfully used as substrates. In the case of derivatives 15 featuring alkyl groups (R and/or R' = Alk) the chemical yields General synthetic applications of HF/PhIO for "electrophilic" fluorination of 1,3-dicarbonyl compounds.
Optimization of the reaction conditions and reagents revealed that besides the original iodosylbenzene, its derivatives, such as pand o-iodosyltoluene, can also be used successfully, and in some cases, even give better chemical yields as compared with unsubstituted iodosylbenzene [107,108]. For example, fluorination of amide derivatives of 3-keto-esters 15 (R' = CONAlk 2 ) with HF/PhIO affords the corresponding products 16 with relatively low (<50%) yield, while the application of o-iodosyltoluene allows for improved yields of the target products 16 (up to 93%). The source of the HF has also been examined in detail showing that other HF reagents such as complexes with triethylamine and pyridine can be successfully used in place of aqueous HF. Of particular importance is the wide synthetic generality of this approach. Thus, 3-keto esters 15 bearing an aromatic ring with electron-withdrawing or donating substituents can be successfully used as substrates. In the case of derivatives 15 featuring alkyl groups (R and/or R' = Alk) the chemical yields of the corresponding fluorinated products 16 are a bit lower (~50-70%), likely due to possible enolization.

Catalytic Iodoarene-Mediated Fluorination
Considering the postulated reaction mechanism (Scheme 2) involving eventual transformation (reduction) of iodosylbenzene to iodobenzene 10, the final reaction product, the authors posited that providing in situ efficient oxidation of the latter to iodosylbenzene, would allow for a catalytic version of this process. Indeed, a significant breakthrough was made with the application of m-CPBA as a terminal oxidant [109]. As presented in Scheme 5, the Ar-I, used in catalytic amounts, undergoes a three-step transformation: oxidation to Ar-IO, reaction with HF to produce Ar-IF 2 and reaction with the enolate form of 15 giving rise to the target product 16. of the corresponding fluorinated products 16 are a bit lower (~50-70%), likely due to possible enolization.

Catalytic Iodoarene-Mediated Fluorination
Considering the postulated reaction mechanism (Scheme 2) involving eventual transformation (reduction) of iodosylbenzene to iodobenzene 10, the final reaction product, the authors posited that providing in situ efficient oxidation of the latter to iodosylbenzene, would allow for a catalytic version of this process. Indeed, a significant breakthrough was made with the application of m-CPBA as a terminal oxidant [109]. As presented in Scheme 5, the Ar-I, used in catalytic amounts, undergoes a three-step transformation: oxidation to Ar-IO, reaction with HF to produce Ar-IF2 and reaction with the enolate form of 15 giving rise to the target product 16. Scheme 5. Proposed catalytic cycle of the iodoarene-mediated "electrophilic" fluorination.
The optimized conditions for this catalytic "electrophilic" fluorination method are presented in Scheme 6 and included the following: as low as 20 mol% ArI, 55% aq. HF as a source of fluorine, m-CPBA as the oxidizing reagent and 1,2-dichloroethane as a solvent. The reactions are conducted at 49 °C and can be easily scaled up. The overall synthetic generality of this catalytic process is rather similar to the stoichiometric version. Scheme 6. "Electrophilic" fluorination using a catalytic amount of Ar-I.
The catalytic version can be used for fluorination of 3-keto-esters and 1,3-diketones bearing substituted aromatic, aliphatic, ester as well as amide groups. It should be notated, however, that the yields of target products 16 are a bit lower as compared with the results obtained in the reactions using a stoichiometric amount of the corresponding iodoarene. Furthermore, in most of the cases, application of o-Tol-I gave the best conversion of the starting 1,3-dicarbonyl compounds 15 and highest yields of fluorinated products 16.

Fluorination of Aryl-Alkyl Ketones
Synthesis of fluorinated derivatives of monocarbonyl compounds, such as ketones and aldehydes, are of high importance in fluoro-organic chemistry [110][111][112][113][114][115][116][117][118][119][120][121]. These types of fluorinated derivatives are of proven synthetic value as building blocks for the preparation of a variety of polyfunctional fluorine-containing compounds of biological interest [30,[122][123][124][125][126][127][128]. In particular, these derivatives can be easily transformed to the corresponding fluorinated amines and amino acids via The optimized conditions for this catalytic "electrophilic" fluorination method are presented in Scheme 6 and included the following: as low as 20 mol% ArI, 55% aq. HF as a source of fluorine, m-CPBA as the oxidizing reagent and 1,2-dichloroethane as a solvent. The reactions are conducted at 49 • C and can be easily scaled up. The overall synthetic generality of this catalytic process is rather similar to the stoichiometric version. of the corresponding fluorinated products 16 are a bit lower (~50-70%), likely due to possible enolization.

Catalytic Iodoarene-Mediated Fluorination
Considering the postulated reaction mechanism (Scheme 2) involving eventual transformation (reduction) of iodosylbenzene to iodobenzene 10, the final reaction product, the authors posited that providing in situ efficient oxidation of the latter to iodosylbenzene, would allow for a catalytic version of this process. Indeed, a significant breakthrough was made with the application of m-CPBA as a terminal oxidant [109]. As presented in Scheme 5, the Ar-I, used in catalytic amounts, undergoes a three-step transformation: oxidation to Ar-IO, reaction with HF to produce Ar-IF2 and reaction with the enolate form of 15 giving rise to the target product 16. Scheme 5. Proposed catalytic cycle of the iodoarene-mediated "electrophilic" fluorination.
The optimized conditions for this catalytic "electrophilic" fluorination method are presented in Scheme 6 and included the following: as low as 20 mol% ArI, 55% aq. HF as a source of fluorine, m-CPBA as the oxidizing reagent and 1,2-dichloroethane as a solvent. The reactions are conducted at 49 °C and can be easily scaled up. The overall synthetic generality of this catalytic process is rather similar to the stoichiometric version. Scheme 6. "Electrophilic" fluorination using a catalytic amount of Ar-I.
The catalytic version can be used for fluorination of 3-keto-esters and 1,3-diketones bearing substituted aromatic, aliphatic, ester as well as amide groups. It should be notated, however, that the yields of target products 16 are a bit lower as compared with the results obtained in the reactions using a stoichiometric amount of the corresponding iodoarene. Furthermore, in most of the cases, application of o-Tol-I gave the best conversion of the starting 1,3-dicarbonyl compounds 15 and highest yields of fluorinated products 16.
The catalytic version can be used for fluorination of 3-keto-esters and 1,3-diketones bearing substituted aromatic, aliphatic, ester as well as amide groups. It should be notated, however, that the yields of target products 16 are a bit lower as compared with the results obtained in the reactions using a stoichiometric amount of the corresponding iodoarene. Furthermore, in most of the cases, application of o-Tol-I gave the best conversion of the starting 1,3-dicarbonyl compounds 15 and highest yields of fluorinated products 16.
It was found that the direct application of Kitamura's approach, using PhIO/hydrofluoric acid, for fluorination of acetophenone (Scheme 7) gives very low yields of the target product 17.
However, careful examination of various reaction conditions and reagents allowed for the discovery that the presence of water is detrimental for the fluorination process. The most likely reason is a reduction of fluoride's nucleophilicity by coordination with water molecules. Consequently, it was found that the application of a triethylamine/5HF complex as a fluorine source provides for a smooth fluorination process affording α-fluoro-acetophenone 17 in a good yield [140]. Further research revealed that this reaction can be generally applied for various aryl-alkyl ketones (Scheme  However, careful examination of various reaction conditions and reagents allowed for the discovery that the presence of water is detrimental for the fluorination process. The most likely reason is a reduction of fluoride's nucleophilicity by coordination with water molecules. Consequently, it was found that the application of a triethylamine/5HF complex as a fluorine source provides for a smooth fluorination process affording α-fluoro-acetophenone 17 in a good yield [140]. Further research revealed that this reaction can be generally applied for various aryl-alkyl ketones (Scheme 8). Among possible sources of hypervalent iodine, p-iodosyltoluene (4-MeC 6 H 4 IO), p-chloloiodosylbenzene (4-ClC 6 H 4 IO), and p-iodosyl(trifluoromethyl)benzene (4-CF 3  biomimetic transamination [129][130][131]. General approaches for the preparation of α-fluoro-ketones include the following: two-step sequence of halogenation followed by nucleophilic substitution using fluoride [132][133][134][135][136] or a two-step process, involving the generation of the corresponding enolates, followed by fluorination using typical electrophilic fluorination reagents [137][138][139]. It was found that the direct application of Kitamura's approach, using PhIO/hydrofluoric acid, for fluorination of acetophenone (Scheme 7) gives very low yields of the target product 17. Scheme 7. Fluorination of acetophenone.
However, careful examination of various reaction conditions and reagents allowed for the discovery that the presence of water is detrimental for the fluorination process. The most likely reason is a reduction of fluoride's nucleophilicity by coordination with water molecules. Consequently, it was found that the application of a triethylamine/5HF complex as a fluorine source provides for a smooth fluorination process affording α-fluoro-acetophenone 17 in a good yield [140]. Further research revealed that this reaction can be generally applied for various aryl-alkyl ketones (Scheme

Fluorination of Styrene Derivatives
In sharp contrast to a trifluoromethyl group, the CHF2 group is still rather scarcely represented among marketed pharmaceuticals [14][15][16][17][18][19][20][21][22]. Known biological properties of difluoromethylcontaining compounds [141], clearly suggest that the application of this fluorinated motif might be as successful as that already established for the trifluoromethylated compounds. The major reason for the current significantly lesser application of a CHF2 group in drug design is, most definitely, a lack of synthetic methods allowing for convenient installation of this functionality. Thus, most generally used methods include reaction of organozinc reagents with potassium bromodifluoroacetate [142], fluorination of gem-bistriflates and gem-dihalides [143][144][145][146], fluorodecarboxylation of dicarboxylic acids [147,148] and chlorodifluoromethylation followed by the elimination of HCl and migration of the double bond [149].

Stoichiometric Hypervalent Iodine Reagents
The synthesis of difluoromethyl-containing compounds via reaction of styrene derivatives with fluorinated hypervalent iodine reagents or iodine in the presence XeF2 [150][151][152][153][154][155][156] is also a known method. However, the necessity of preparing hypervalent iodine compounds or the use of XeF2 limits its synthetic applications. With this in mind, Kitamura's approach was examined for the fluorination of styrene substrates [157]. As presented in Scheme 10, a series of hypervalent reagents were screened and the trifluoroacetoxy derivatives were identified as the best. It should also be noted that a separate optimization study showed that a complex of HF with pyridine was found to serve as a superior source of nucleophilic fluoride. Thus, under these optimized conditions, the target fluorinated product 28 was prepared in greater than 60% yield [157].
Application of these reaction conditions for fluorination of various substituted styrenes gave rather good results. This approach was applied to substrates 29 (Scheme 11) bearing alkyl, halo and

Fluorination of Styrene Derivatives
In sharp contrast to a trifluoromethyl group, the CHF 2 group is still rather scarcely represented among marketed pharmaceuticals [14][15][16][17][18][19][20][21][22]. Known biological properties of difluoromethyl-containing compounds [141], clearly suggest that the application of this fluorinated motif might be as successful as that already established for the trifluoromethylated compounds. The major reason for the current significantly lesser application of a CHF 2 group in drug design is, most definitely, a lack of synthetic methods allowing for convenient installation of this functionality. Thus, most generally used methods include reaction of organozinc reagents with potassium bromodifluoroacetate [142], fluorination of gem-bistriflates and gem-dihalides [143][144][145][146], fluorodecarboxylation of dicarboxylic acids [147,148] and chlorodifluoromethylation followed by the elimination of HCl and migration of the double bond [149].

Stoichiometric Hypervalent Iodine Reagents
The synthesis of difluoromethyl-containing compounds via reaction of styrene derivatives with fluorinated hypervalent iodine reagents or iodine in the presence XeF 2 [150][151][152][153][154][155][156] is also a known method. However, the necessity of preparing hypervalent iodine compounds or the use of XeF 2 limits its synthetic applications. With this in mind, Kitamura's approach was examined for the fluorination of styrene substrates [157]. As presented in Scheme 10, a series of hypervalent reagents were screened and the trifluoroacetoxy derivatives were identified as the best.

Fluorination of Styrene Derivatives
In sharp contrast to a trifluoromethyl group, the CHF2 group is still rather scarcely represented among marketed pharmaceuticals [14][15][16][17][18][19][20][21][22]. Known biological properties of difluoromethylcontaining compounds [141], clearly suggest that the application of this fluorinated motif might be as successful as that already established for the trifluoromethylated compounds. The major reason for the current significantly lesser application of a CHF2 group in drug design is, most definitely, a lack of synthetic methods allowing for convenient installation of this functionality. Thus, most generally used methods include reaction of organozinc reagents with potassium bromodifluoroacetate [142], fluorination of gem-bistriflates and gem-dihalides [143][144][145][146], fluorodecarboxylation of dicarboxylic acids [147,148] and chlorodifluoromethylation followed by the elimination of HCl and migration of the double bond [149].

Stoichiometric Hypervalent Iodine Reagents
The synthesis of difluoromethyl-containing compounds via reaction of styrene derivatives with fluorinated hypervalent iodine reagents or iodine in the presence XeF2 [150][151][152][153][154][155][156] is also a known method. However, the necessity of preparing hypervalent iodine compounds or the use of XeF2 limits its synthetic applications. With this in mind, Kitamura's approach was examined for the fluorination of styrene substrates [157]. As presented in Scheme 10, a series of hypervalent reagents were screened and the trifluoroacetoxy derivatives were identified as the best. It should also be noted that a separate optimization study showed that a complex of HF with pyridine was found to serve as a superior source of nucleophilic fluoride. Thus, under these optimized conditions, the target fluorinated product 28 was prepared in greater than 60% yield [157].
Application of these reaction conditions for fluorination of various substituted styrenes gave rather good results. This approach was applied to substrates 29 (Scheme 11) bearing alkyl, halo and It should also be noted that a separate optimization study showed that a complex of HF with pyridine was found to serve as a superior source of nucleophilic fluoride. Thus, under these optimized conditions, the target fluorinated product 28 was prepared in greater than 60% yield [157].
Application of these reaction conditions for fluorination of various substituted styrenes gave rather good results. This approach was applied to substrates 29 (Scheme 11) bearing alkyl, halo and OAc-type substituents in the o-, mor p-position on the phenyl ring. The chemical yields of difluorinated products 30 ranged from 50% to 93%.
Molecules 2020, 25 OAc-type substituents in the o-, m-or p-position on the phenyl ring. The chemical yields of difluorinated products 30 ranged from 50% to 93%.
Scheme 11. Generality of styrene fluorination using hypervalent iodine and HF complex with pyridine.
Some structural limitations of this method may arise from a mechanism involving the migration of an aryl group. As presented in Scheme 12, in situ generated electrophilic hyper-iodide reagent 30, reacts with starting styrene 29 to form three-ring intermediate 31 which is opened with fluoride to afford mono-fluorinated compound 32. The latter proceeds to a second spirocyclic three-ring intermediate 33 with the elimination of Ar-I. The final step of the process is the nucleophilic opening of 33 with fluoride to give the difluorinated product 30. One can assume that the stability of intermediate 33 will be strongly influenced by the electronic properties of the substituents on the aromatic ring. Nevertheless, as mentioned above, moderately electron-donating/withdrawing substituents, such as alkyl groups and halogens, can be tolerated giving product 30 with synthetically attractive chemical yields.

Catalytic Hypervalent Iodine Reactions
The catalytic version (Scheme 13) of this process was realized with application of 4-iodotoluene, HF/Py complex and m-CPBA, as the oxidizing reagent [157]. Some structural limitations of this method may arise from a mechanism involving the migration of an aryl group. As presented in Scheme 12, in situ generated electrophilic hyper-iodide reagent 30, reacts with starting styrene 29 to form three-ring intermediate 31 which is opened with fluoride to afford mono-fluorinated compound 32. The latter proceeds to a second spirocyclic three-ring intermediate 33 with the elimination of Ar-I. The final step of the process is the nucleophilic opening of 33 with fluoride to give the difluorinated product 30. One can assume that the stability of intermediate 33 will be strongly influenced by the electronic properties of the substituents on the aromatic ring. Nevertheless, as mentioned above, moderately electron-donating/withdrawing substituents, such as alkyl groups and halogens, can be tolerated giving product 30 with synthetically attractive chemical yields. OAc-type substituents in the o-, m-or p-position on the phenyl ring. The chemical yields of difluorinated products 30 ranged from 50% to 93%. Scheme 11. Generality of styrene fluorination using hypervalent iodine and HF complex with pyridine.
Some structural limitations of this method may arise from a mechanism involving the migration of an aryl group. As presented in Scheme 12, in situ generated electrophilic hyper-iodide reagent 30, reacts with starting styrene 29 to form three-ring intermediate 31 which is opened with fluoride to afford mono-fluorinated compound 32. The latter proceeds to a second spirocyclic three-ring intermediate 33 with the elimination of Ar-I. The final step of the process is the nucleophilic opening of 33 with fluoride to give the difluorinated product 30. One can assume that the stability of intermediate 33 will be strongly influenced by the electronic properties of the substituents on the aromatic ring. Nevertheless, as mentioned above, moderately electron-donating/withdrawing substituents, such as alkyl groups and halogens, can be tolerated giving product 30 with synthetically attractive chemical yields.

Catalytic Hypervalent Iodine Reactions
The catalytic version (Scheme 13) of this process was realized with application of 4-iodotoluene, HF/Py complex and m-CPBA, as the oxidizing reagent [157].

Catalytic Hypervalent Iodine Reactions
The catalytic version (Scheme 13) of this process was realized with application of 4-iodotoluene, HF/Py complex and m-CPBA, as the oxidizing reagent [157]. OAc-type substituents in the o-, m-or p-position on the phenyl ring. The chemical yields of difluorinated products 30 ranged from 50% to 93%. Scheme 11. Generality of styrene fluorination using hypervalent iodine and HF complex with pyridine.
Some structural limitations of this method may arise from a mechanism involving the migration of an aryl group. As presented in Scheme 12, in situ generated electrophilic hyper-iodide reagent 30, reacts with starting styrene 29 to form three-ring intermediate 31 which is opened with fluoride to afford mono-fluorinated compound 32. The latter proceeds to a second spirocyclic three-ring intermediate 33 with the elimination of Ar-I. The final step of the process is the nucleophilic opening of 33 with fluoride to give the difluorinated product 30. One can assume that the stability of intermediate 33 will be strongly influenced by the electronic properties of the substituents on the aromatic ring. Nevertheless, as mentioned above, moderately electron-donating/withdrawing substituents, such as alkyl groups and halogens, can be tolerated giving product 30 with synthetically attractive chemical yields.

Catalytic Hypervalent Iodine Reactions
The catalytic version (Scheme 13) of this process was realized with application of 4-iodotoluene, HF/Py complex and m-CPBA, as the oxidizing reagent [157]. However, the outcome of the catalytic reactions was not entirely successful as difluoro products 30 were generally isolated in relatively low yields of about 50%. The highest yield (66%) in the series was obtained for the electron-rich trimethyl derivative 34. In sharp contrast, mono-methyl substituted compound 35 was prepared in only 31% yield. It is interesting to note that fluorination of 1,1-diphenylethene resulted in rearranged difluoro compound 36 isolated in 50% yield.

Fluorination of α,β-Unsaturated Ketones and Alcohols
One may assume that a chemically similar process can also be realized for fluorination of other types of unsaturated compounds [158]. For example, as presented in Scheme 14, it was found that α,β-unsaturated ketones of general structure 37 can be converted to ketones 38 featuring α-aryl and difluoromethyl groups [159]. However, the outcome of the catalytic reactions was not entirely successful as difluoro products 30 were generally isolated in relatively low yields of about 50%. The highest yield (66%) in the series was obtained for the electron-rich trimethyl derivative 34. In sharp contrast, mono-methyl substituted compound 35 was prepared in only 31% yield. It is interesting to note that fluorination of 1,1diphenylethene resulted in rearranged difluoro compound 36 isolated in 50% yield.

Fluorination of α,β-Unsaturated Ketones and Alcohols
One may assume that a chemically similar process can also be realized for fluorination of other types of unsaturated compounds [158]. For example, as presented in Scheme 14, it was found that α,β-unsaturated ketones of general structure 37 can be converted to ketones 38 featuring α-aryl and difluoromethyl groups [159]. Substrate generality in this reaction is rather broad as the substituent R in starting 37 can be a methyl, long-chain alkyl, tert-butyl, aromatic or heteroaromatic group. Furthermore, the aromatic ring on the carbonyl carbon can bear electron-withdrawing or -donating groups, including NO2, halogens, Alk-O and Ac-NH. The aromatic group on the unsaturated C=C fragment is migrating during the reaction to the α-position, relatively to the carbonyl, and therefore is a bit more sensitive to the nature of substitution. Nevertheless, alkyl and halogen groups on the para position of the Ar moiety seem to be perfectly tolerated [159].
A catalytic version of this process was successfully realized using m-CPBA for the in situ oxidation of p-Tol-I to p-Tol-I=O. Optimized conditions included p-Tol-I (0.2 mol%), HF/Py (40 mol%) and (1.3 mol%). Substrate generality under the catalytic conditions was not compromised, however, the chemical yields were about 5-10% lower when compared with those obtained for the reactions conducted with stoichiometric amounts of the p-Tol-I=O [159].
Of particular interest are the results reported for the fluorination of cinnamyl alcohol derivatives [160]. As presented in Scheme 15, starting compounds 39 were treated with Ph-I=O and HF/Py in dichloromethane to furnish fluorinated products 40.

Scheme 15. Fluorination of cinnamyl alcohol derivatives.
It should be noted that this type of fluorination required low reaction temperature due to the sensitive nature of the cinnamyl alcohol functionality. Similar to the previously discussed Substrate generality in this reaction is rather broad as the substituent R in starting 37 can be a methyl, long-chain alkyl, tert-butyl, aromatic or heteroaromatic group. Furthermore, the aromatic ring on the carbonyl carbon can bear electron-withdrawing or -donating groups, including NO 2 , halogens, Alk-O and Ac-NH. The aromatic group on the unsaturated C=C fragment is migrating during the reaction to the α-position, relatively to the carbonyl, and therefore is a bit more sensitive to the nature of substitution. Nevertheless, alkyl and halogen groups on the para position of the Ar moiety seem to be perfectly tolerated [159].
A catalytic version of this process was successfully realized using m-CPBA for the in situ oxidation of p-Tol-I to p-Tol-I=O. Optimized conditions included p-Tol-I (0.2 mol%), HF/Py (40 mol%) and (1.3 mol%). Substrate generality under the catalytic conditions was not compromised, however, the chemical yields were about 5-10% lower when compared with those obtained for the reactions conducted with stoichiometric amounts of the p-Tol-I=O [159].
Of particular interest are the results reported for the fluorination of cinnamyl alcohol derivatives [160]. As presented in Scheme 15, starting compounds 39 were treated with Ph-I=O and HF/Py in dichloromethane to furnish fluorinated products 40.
Molecules 2020, 25, 2116 9 of 21 However, the outcome of the catalytic reactions was not entirely successful as difluoro products 30 were generally isolated in relatively low yields of about 50%. The highest yield (66%) in the series was obtained for the electron-rich trimethyl derivative 34. In sharp contrast, mono-methyl substituted compound 35 was prepared in only 31% yield. It is interesting to note that fluorination of 1,1diphenylethene resulted in rearranged difluoro compound 36 isolated in 50% yield.

Fluorination of α,β-Unsaturated Ketones and Alcohols
One may assume that a chemically similar process can also be realized for fluorination of other types of unsaturated compounds [158]. For example, as presented in Scheme 14, it was found that α,β-unsaturated ketones of general structure 37 can be converted to ketones 38 featuring α-aryl and difluoromethyl groups [159]. Substrate generality in this reaction is rather broad as the substituent R in starting 37 can be a methyl, long-chain alkyl, tert-butyl, aromatic or heteroaromatic group. Furthermore, the aromatic ring on the carbonyl carbon can bear electron-withdrawing or -donating groups, including NO2, halogens, Alk-O and Ac-NH. The aromatic group on the unsaturated C=C fragment is migrating during the reaction to the α-position, relatively to the carbonyl, and therefore is a bit more sensitive to the nature of substitution. Nevertheless, alkyl and halogen groups on the para position of the Ar moiety seem to be perfectly tolerated [159].
A catalytic version of this process was successfully realized using m-CPBA for the in situ oxidation of p-Tol-I to p-Tol-I=O. Optimized conditions included p-Tol-I (0.2 mol%), HF/Py (40 mol%) and (1.3 mol%). Substrate generality under the catalytic conditions was not compromised, however, the chemical yields were about 5-10% lower when compared with those obtained for the reactions conducted with stoichiometric amounts of the p-Tol-I=O [159].
Of particular interest are the results reported for the fluorination of cinnamyl alcohol derivatives [160]. As presented in Scheme 15, starting compounds 39 were treated with Ph-I=O and HF/Py in dichloromethane to furnish fluorinated products 40.

Scheme 15. Fluorination of cinnamyl alcohol derivatives.
It should be noted that this type of fluorination required low reaction temperature due to the sensitive nature of the cinnamyl alcohol functionality. Similar to the previously discussed It should be noted that this type of fluorination required low reaction temperature due to the sensitive nature of the cinnamyl alcohol functionality. Similar to the previously discussed fluorination of compounds with conjugated C=C bonds, the reactions occurred with migration of the Ar group. Substrate generality study of these reactions was limited to two types of products, featuring difluoromethyl 41 and difluoroethyl groups 42.
Molecules 2020, 25,2116 10 of 21 fluorination of compounds with conjugated C=C bonds, the reactions occurred with migration of the Ar group. Substrate generality study of these reactions was limited to two types of products, featuring difluoromethyl 41 and difluoroethyl groups 42.

Homoallyl Amine Derivatives
Compounds containing the 3-fluoropyrrolidine moiety possessing a wide spectrum of biological properties. Some of them have been developed as dipeptidyl peptidase inhibitors [160][161][162][163], glucokinase activators [164] prolyl oligopeptidase inhibitors [165] and purine nucleoside phosphorylase inhibitors [166]. The most commonly used synthetic approach for preparation of 3fluoropyrrolidines is based on fluorine substitution for hydroxy group in 3-hydroxylpyrrolidines [167][168][169][170][171]. Another approach, based on aminofluorination of alkenes [172][173][174][175][176], is more practical allowing both ring construction and introduction of a fluorine atom in one convenient synthetic sequence. It was found that the aminofluorination version of this approach can be successfully realized using the Kitamura fluorination protocol. As presented in Scheme 16, treatment of homoallyl amines 43 with a hypervalent iodine reagent and HF/Py afforded 3-fluoropyrrolidines 44 with respectable yields ranging from 50% to 87% [177]. Optimization of the reaction conditions in terms of hypervalent iodine reagent and source of HF found that a combination of HF/Py and PhI(OCOCF3)2 or PhI(OAc)2 was superior to other compounds such as PhI(OAc)2 and aqueous 55% HF and PhI(OH)OTs and HF/TEA complex [177]. As for the starting homoallyl amines, protection of the amino group with strong electronwithdrawing groups such as Ts, Ms or Ns, was found to be essential for the successful transformation. From the standpoint of generality, the process was shown to be applicable for a reasonably wide range of compounds with the substituent R bearing hydrogen or alkyl groups and with the R 1 representing hydrogen, alkyl, bulky iso-alkyl and aryl groups. Quite remarkably, the reaction can be used for preparation of six-membered rings, as represented by the transformation of N-tosyl-4pentenylamine 45 to N-tosyl-3-fluoropiperidine 46, in 69% yield [177].
To obtain information about the reaction mechanism for this intramolecular aminofluorination, the authors conducted a competitive reaction between homoallyl amines 47 and 48 (Scheme 17). Optimization of the reaction conditions in terms of hypervalent iodine reagent and source of HF found that a combination of HF/Py and PhI(OCOCF 3 ) 2 or PhI(OAc) 2 was superior to other compounds such as PhI(OAc) 2 and aqueous 55% HF and PhI(OH)OTs and HF/TEA complex [177]. As for the starting homoallyl amines, protection of the amino group with strong electron-withdrawing groups such as Ts, Ms or Ns, was found to be essential for the successful transformation. From the standpoint of generality, the process was shown to be applicable for a reasonably wide range of compounds with the substituent R bearing hydrogen or alkyl groups and with the R 1 representing hydrogen, alkyl, bulky iso-alkyl and aryl groups. Quite remarkably, the reaction can be used for preparation of six-membered rings, as represented by the transformation of N-tosyl-4-pentenylamine 45 to N-tosyl-3-fluoropiperidine 46, in 69% yield [177].
To obtain information about the reaction mechanism for this intramolecular aminofluorination, the authors conducted a competitive reaction between homoallyl amines 47 and 48 (Scheme 17).

Scheme 17. Competitive intramolecular aminofluorination.
To this end, an equimolar mixture of 47 and 48 was subjected to the aminofluorination reaction using Ph-I(OAc)2 and HF/Py. It was found that, almost exclusively, homoallyl amine 48 was transformed to 3-fluoro-3-methylpyrrolidine 50, while product 49, derived from homoallyl amine 47, was detected in the reaction mixture only in trace amounts. This result strongly suggested that the hypervalent iodine reagent preferentially reacts with the more electron-rich olefinic moiety. Based on the outcome of this competitive reaction, the authors proposed the following reaction mechanism, presented in Scheme 18. According to the proposed mechanism, the formed in situ (difluoroiodo)benzene is activated by HF and interacts with the nucleophilic double bond of homoallyl amine 51 resulting in formation of the cyclic iodonium salt 52. The three-membered ring is opened next by the nitrogen, attacking the terminal carbon by the bridged iodonium salts 52 to afford pyrrolidine 53. The formation of intermediate 53 is followed by SN2 substitution by a fluoride ion. The final step is the deprotonation of 54 giving rise to the final 3-fluoropyrrolidine product 55.

Homoallyl Alcohol and 3-butenoic Acid Derivatives
An interesting extension of this reaction cascade was demonstrated for other types of polyfunctional olefins, such as homoallyl alcohols and 3-butenoic acid derivatives [178]. The fluorination-cyclization cascade of homoallyl alcohols 56 (Scheme 19) was performed using the reagent system of PhI(OPiv)2 and HF/Py in dichloromethane. The target fluorinated tetrahydrofuran derivatives 57 were isolated with reasonably good 54−65% yields as a mixture of cis-and transisomers. To this end, an equimolar mixture of 47 and 48 was subjected to the aminofluorination reaction using Ph-I(OAc) 2 and HF/Py. It was found that, almost exclusively, homoallyl amine 48 was transformed to 3-fluoro-3-methylpyrrolidine 50, while product 49, derived from homoallyl amine 47, was detected in the reaction mixture only in trace amounts. This result strongly suggested that the hypervalent iodine reagent preferentially reacts with the more electron-rich olefinic moiety. Based on the outcome of this competitive reaction, the authors proposed the following reaction mechanism, presented in Scheme 18. To this end, an equimolar mixture of 47 and 48 was subjected to the aminofluorination reaction using Ph-I(OAc)2 and HF/Py. It was found that, almost exclusively, homoallyl amine 48 was transformed to 3-fluoro-3-methylpyrrolidine 50, while product 49, derived from homoallyl amine 47, was detected in the reaction mixture only in trace amounts. This result strongly suggested that the hypervalent iodine reagent preferentially reacts with the more electron-rich olefinic moiety. Based on the outcome of this competitive reaction, the authors proposed the following reaction mechanism, presented in Scheme 18. According to the proposed mechanism, the formed in situ (difluoroiodo)benzene is activated by HF and interacts with the nucleophilic double bond of homoallyl amine 51 resulting in formation of the cyclic iodonium salt 52. The three-membered ring is opened next by the nitrogen, attacking the terminal carbon by the bridged iodonium salts 52 to afford pyrrolidine 53. The formation of intermediate 53 is followed by SN2 substitution by a fluoride ion. The final step is the deprotonation of 54 giving rise to the final 3-fluoropyrrolidine product 55.

Homoallyl Alcohol and 3-butenoic Acid Derivatives
An interesting extension of this reaction cascade was demonstrated for other types of polyfunctional olefins, such as homoallyl alcohols and 3-butenoic acid derivatives [178]. The fluorination-cyclization cascade of homoallyl alcohols 56 (Scheme 19) was performed using the reagent system of PhI(OPiv)2 and HF/Py in dichloromethane. The target fluorinated tetrahydrofuran derivatives 57 were isolated with reasonably good 54−65% yields as a mixture of cis-and transisomers. According to the proposed mechanism, the formed in situ (difluoroiodo)benzene is activated by HF and interacts with the nucleophilic double bond of homoallyl amine 51 resulting in formation of the cyclic iodonium salt 52. The three-membered ring is opened next by the nitrogen, attacking the terminal carbon by the bridged iodonium salts 52 to afford pyrrolidine 53. The formation of intermediate 53 is followed by S N 2 substitution by a fluoride ion. The final step is the deprotonation of 54 giving rise to the final 3-fluoropyrrolidine product 55.

Homoallyl Alcohol and 3-butenoic Acid Derivatives
An interesting extension of this reaction cascade was demonstrated for other types of polyfunctional olefins, such as homoallyl alcohols and 3-butenoic acid derivatives [178]. The fluorination-cyclization cascade of homoallyl alcohols 56 (Scheme 19) was performed using the reagent system of PhI(OPiv) 2 and HF/Py in dichloromethane. The target fluorinated tetrahydrofuran derivatives 57 were isolated with reasonably good 54−65% yields as a mixture of cis-and trans-isomers.

Scheme 19. Fluorination of homoallyl alcohols and 3-butenoic acid derivatives.
Under similar conditions, except using Ph-I(OCOCF3)2 as the hypervalent iodine reagent and dichloroethane as a solvent, butenoic acid 58 was transformed to fluorinated butyrolactone 59 in 45% yield. The structure of products 57 and 59 is consistent with the above-discussed mechanism (Scheme 18) for the fluorination-cyclization cascade. Thus, in the cases of homoallyl alcohols 56 and 3-butenoic acid 58 the oxygen of the hydroxy group acts as the nucleophilic element attacking the terminal carbon of the corresponding intermediate bridged iodonium salts of type 52, to complete the cyclization step.

Reactions with Alkynes
One of the most recent developments in this chemistry is the synthesis of β-fluorovinyliodonium salts via the reaction of alkynes with hypervalent iodine reagents in the presence of HF (Scheme 20) [179]. It should be noted that direct application of the conditions developed for the reactions of various C=C unsaturated compounds was found to be ineffective for alkynes. In a series of preliminary experiments, it was determined that Ph-IF2 needed some additional activation by a Lewis acid, such as BF3·OEt2. Indeed, treatment of mono-alkyl substituted alkynes 60 with Ph-I=O and HF/Py, followed by the addition of BF3·OEt2, resulted in the formation of β-fluorovinyliodonium salts 61 with a respectable chemical yield. Compound 61 is quite stable to be isolated and fully characterized. In terms of generality one can mention that the alkyl group could bear in its terminal position some functionalities, such as aromatic or heterocyclic rings, a protected alcohol or ester group. The reactions are highly regio-and stereospecific as the fluorine being added to the most substituted carbon on 60 and products 61 are obtained as trans-isomers only. This set of conditions can also be Under similar conditions, except using Ph-I(OCOCF 3 ) 2 as the hypervalent iodine reagent and dichloroethane as a solvent, butenoic acid 58 was transformed to fluorinated butyrolactone 59 in 45% yield. The structure of products 57 and 59 is consistent with the above-discussed mechanism (Scheme 18) for the fluorination-cyclization cascade. Thus, in the cases of homoallyl alcohols 56 and 3-butenoic acid 58 the oxygen of the hydroxy group acts as the nucleophilic element attacking the terminal carbon of the corresponding intermediate bridged iodonium salts of type 52, to complete the cyclization step.

Reactions with Alkynes
One of the most recent developments in this chemistry is the synthesis of β-fluorovinyliodonium salts via the reaction of alkynes with hypervalent iodine reagents in the presence of HF (Scheme 20) [179]. Under similar conditions, except using Ph-I(OCOCF3)2 as the hypervalent iodine reagent and dichloroethane as a solvent, butenoic acid 58 was transformed to fluorinated butyrolactone 59 in 45% yield. The structure of products 57 and 59 is consistent with the above-discussed mechanism (Scheme 18) for the fluorination-cyclization cascade. Thus, in the cases of homoallyl alcohols 56 and 3-butenoic acid 58 the oxygen of the hydroxy group acts as the nucleophilic element attacking the terminal carbon of the corresponding intermediate bridged iodonium salts of type 52, to complete the cyclization step.

Reactions with Alkynes
One of the most recent developments in this chemistry is the synthesis of β-fluorovinyliodonium salts via the reaction of alkynes with hypervalent iodine reagents in the presence of HF (Scheme 20) [179]. It should be noted that direct application of the conditions developed for the reactions of various C=C unsaturated compounds was found to be ineffective for alkynes. In a series of preliminary experiments, it was determined that Ph-IF2 needed some additional activation by a Lewis acid, such as BF3·OEt2. Indeed, treatment of mono-alkyl substituted alkynes 60 with Ph-I=O and HF/Py, followed by the addition of BF3·OEt2, resulted in the formation of β-fluorovinyliodonium salts 61 with a respectable chemical yield. Compound 61 is quite stable to be isolated and fully characterized. In terms of generality one can mention that the alkyl group could bear in its terminal position some functionalities, such as aromatic or heterocyclic rings, a protected alcohol or ester group. The reactions are highly regio-and stereospecific as the fluorine being added to the most substituted carbon on 60 and products 61 are obtained as trans-isomers only. This set of conditions can also be Scheme 20. Synthesis of β-fluorovinyliodonium salts by the reaction of alkynes with hypervalent iodine/HF reagent.
It should be noted that direct application of the conditions developed for the reactions of various C=C unsaturated compounds was found to be ineffective for alkynes. In a series of preliminary experiments, it was determined that Ph-IF 2 needed some additional activation by a Lewis acid, such as BF 3 ·OEt 2 . Indeed, treatment of mono-alkyl substituted alkynes 60 with Ph-I=O and HF/Py, followed by the addition of BF 3 ·OEt 2 , resulted in the formation of β-fluorovinyliodonium salts 61 with a respectable chemical yield. Compound 61 is quite stable to be isolated and fully characterized. In terms of generality one can mention that the alkyl group could bear in its terminal position some functionalities, such as aromatic or heterocyclic rings, a protected alcohol or ester group. The reactions are highly regioand stereospecific as the fluorine being added to the most substituted carbon on 60 and products 61 are obtained as trans-isomers only. This set of conditions can also be successfully applied to symmetrically disubstitute alkynes 62. The corresponding β-fluorovinyliodonium salts 63 were obtained exclusively as trans-isomers with 60-78% yields. The proposed mechanism for the reactions of Ph-I=O and HF/Py reagents with alkynes is presented in Scheme 21. successfully applied to symmetrically disubstitute alkynes 62. The corresponding βfluorovinyliodonium salts 63 were obtained exclusively as trans-isomers with 60-78% yields. The proposed mechanism for the reactions of Ph-I=O and HF/Py reagents with alkynes is presented in Scheme 21. According to the proposed mechanism, the in situ generated PhIF2 is activated by HBF4 and undertakes the electrophilic addition to alkyne 60 affording bridged three-membered iodonium species 62. Intermediate 62 is subjected to the nucleophilic attack of fluoride ions leading to the formation of (E)-β-vinyliodonium fluorides 63. The final step in this sequence is the ligand exchange with HBF4 yielding final product 61. It should be emphasized that the geometric configuration of 63 is controlled by the ring-opening of iodonium species 62 with fluoride ion.

Conclusions
The chemistry discussed in this review article is based on the original idea of the application of HF as a source of fluorine for subsequent "electrophilic" formation of a C-F bond. The target transformation is achieved via in situ generation of the proper electrophilic species derived from hypervalent iodine compounds. The data reported so far clearly show the great synthetic value of this approach for fluorination of various 1,3-dicarbonyl compounds, aryl-alkyl ketones, styrene derivatives, α,β-unsaturated ketones and alcohols, homoallyl amine and homoallyl alcohol derivatives, 3-butenoic acids and alkynes. The major advantage of this chemistry over alternative approaches is its practicality and very attractive cost-structure, boding well for its application in large-scale synthesis of important drug intermediates or other industrial fluoro-organics. However, there are still some issues that need to be solved, to further increase the synthetic value of this methodology. One critical area of improvement would be the application of more safe and still cheaper sources of HF. Thus, most of the research has been performed using aqueous HF, and its complexes with TEA and Py. One would also suggest HF in complex with THF as an alternative source, which was reported by Professor W. R. Dolbier [179,180]. Finally, further optimization of the reaction conditions, alongside with applications of new sources of HF, leading to increased chemical yield would clearly be in the focus for future research in this exciting area of fundamental fluoroorganic methodology. As a word of caution, we would like to remind the readers that hydrogen fluoride, aqueous or in complexes with pyridine, triethylamine or in any other form, is quite toxic, highly corrosive and can easily penetrate skin and muscles destroying cell membranes and nerves. The reactions should be conducted in a well-ventilated hood using Teflon-lined reactors of tubes.   According to the proposed mechanism, the in situ generated PhIF 2 is activated by HBF 4 and undertakes the electrophilic addition to alkyne 60 affording bridged three-membered iodonium species 62. Intermediate 62 is subjected to the nucleophilic attack of fluoride ions leading to the formation of (E)-β-vinyliodonium fluorides 63. The final step in this sequence is the ligand exchange with HBF 4 yielding final product 61. It should be emphasized that the geometric configuration of 63 is controlled by the ring-opening of iodonium species 62 with fluoride ion.

Conclusions
The chemistry discussed in this review article is based on the original idea of the application of HF as a source of fluorine for subsequent "electrophilic" formation of a C-F bond. The target transformation is achieved via in situ generation of the proper electrophilic species derived from hypervalent iodine compounds. The data reported so far clearly show the great synthetic value of this approach for fluorination of various 1,3-dicarbonyl compounds, aryl-alkyl ketones, styrene derivatives, α,β-unsaturated ketones and alcohols, homoallyl amine and homoallyl alcohol derivatives, 3-butenoic acids and alkynes. The major advantage of this chemistry over alternative approaches is its practicality and very attractive cost-structure, boding well for its application in large-scale synthesis of important drug intermediates or other industrial fluoro-organics. However, there are still some issues that need to be solved, to further increase the synthetic value of this methodology. One critical area of improvement would be the application of more safe and still cheaper sources of HF. Thus, most of the research has been performed using aqueous HF, and its complexes with TEA and Py. One would also suggest HF in complex with THF as an alternative source, which was reported by Professor W. R. Dolbier [179,180]. Finally, further optimization of the reaction conditions, alongside with applications of new sources of HF, leading to increased chemical yield would clearly be in the focus for future research in this exciting area of fundamental fluoro-organic methodology. As a word of caution, we would like to remind the readers that hydrogen fluoride, aqueous or in complexes with pyridine, triethylamine or in any other form, is quite toxic, highly corrosive and can easily penetrate skin and muscles destroying cell membranes and nerves. The reactions should be conducted in a well-ventilated hood using Teflon-lined reactors of tubes.

Conflicts of Interest:
The authors declare no conflict of interest.