Monofluorination of Organic Compounds - ACS Publications

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Monofluorination of Organic Compounds: 10 Years of Innovation Pier Alexandre Champagne,‡ Justine Desroches,‡ Jean-Denys Hamel,‡ Mathilde Vandamme,‡ and Jean-François Paquin* Canada Research Chair in Organic and Medicinal Chemistry, CGCC, PROTEO, Département de Chimie, Université Laval, 1045 Avenue de la Médecine, Québec (QC), Canada G1V 0A6 1. INTRODUCTION The unique properties of the fluorine atom1 make it significant in medicinal,2,3 agrochemical,2,4 and material sciences.2,5 Industry sources estimate that as many as 30−40% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine.6 Fluorine is used to tag biochemical probes for the study of various biological processes, as the NMR activity of the 19F nuclei enables in vivo magnetic resonance imaging.7 In addition, 18F-positron-emitting tomography is used daily for CONTENTS diagnosing, staging, and detecting the recurrence or progression 1. Introduction 9073 of various diseases including cancer.8 Since Nature produces 2. Synthetic Approaches for the Creation of a Single only a limited number of structurally simple fluorine-containing C−F Bond 9073 natural products9,10 that can potentially be used as fluorinated 2.1. Nucleophilic Fluorination 9074 starting materials, further developments in these fields are 2.2. Electrophilic Fluorination 9075 closely related to the development of practical, selective, and 2.3. Radical Fluorination 9075 efficient methodologies for the introduction of C−F bonds 3. Synthetic Methods for the Monofluorination of onto organic molecules. Organic Compounds 9075 Taking into account the vast arrays of fluorinated motifs 3.1. Creation of a C(sp3)−F Bond 9075 known,11 this review will be limited to the monofluorination of 3.1.1. Alkyl Fluorides 9075 organic compounds, i.e., synthetic methods allowing the 3.1.2. Formation of a C−F Bond Next to an introduction of a single C−F bond. This subject has been the Electron-Withdrawing Group 9086 topic of reviews in the past12 and will overlap with some recent 3.1.3. Formation of β-Fluoroalcohols and Dereviews.11c,13 The radioisotope labeling with fluorine-18 has rivatives 9109 been excluded and reviews/perspective on this subject can be 3.1.4. Formation of β-Fluoroamines and Defound elsewhere.8,14 In addition, this review deliberately rivatives 9113 emphasizes developments that occurred within the last 10 3.1.5. Formation of β-Fluorothioether Derivayears. Precisely, literature coverage for this review starts from tives 9119 January 1st, 2005 up to December 10th, 2014. For the more 3.1.6. Benzylic Fluorides 9119 traditional synthetic methods, the readers will be referred to 3.1.7. Allylic Fluorides 9126 various reviews cited in the document. 3.1.8. Propargylic Fluorides 9131 After a brief survey of the approaches for the creation of 3.2. Creation of a C(sp2)−F Bond 9133 single C−F bonds, the recent synthetic methods will be 3.2.1. Aryl Fluorides 9133 classified and reviewed according to the hybridization of the 3.2.2. Vinyl Fluorides 9146 carbon atom bearing the fluorine atom. Within each section, 3.2.3. Allenyl Fluorides 9154 further subclassification according to the targeted fluorinated 3.2.4. Acyl Fluorides 9154 motif has been used.

3.2.5. Imidoyl Fluorides 3.2.6. Thio-, Seleno-, and Telluroacyl Fluorides 3.3. Creation of a C(sp)−F Bond 4. Summary and Outlook Author Information Corresponding Author Author Contributions Author Contributions Notes Biographies Acknowledgments Abbreviations References

© 2015 American Chemical Society

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2. SYNTHETIC APPROACHES FOR THE CREATION OF A SINGLE C−F BOND There are three general strategies for the introduction of a single C−F bond into an organic molecule depending on which form the fluorine atom is delivered: nucleophilic, electrophilic, and radical fluorination. Electrochemical fluorination will not be covered.15 Each method will be briefly introduced with a particular focus on the key features and on the new reagents Special Issue: 2015 Frontiers in Organic Synthesis Received: December 17, 2014 Published: April 9, 2015 9073

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Only five new fluoride sources have appeared since 2005, and two are related to TBAF (Figure 3). DiMagno and co-worker reported the synthesis of anhydrous TBAF21 while in 2008, Kim and co-workers described the preparation of tetrabutylammonium tetra(tert-butyl alcohol) fluoride, TBAF(tBuOH)4.22 In 2012, Hara and co-workers carried out the synthesis of IF5-pyridine-HF from IF5 and HF/pyridine.23 Two years later, the same research group prepared the air-stable fluorination reagent BrF3−KHF2.24 Finally, also in 2014, Hammond and co-workers described the preparation of a complex of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone with HF (DMPU/HF).25 A variant of the nucleophilic fluorination reaction is the deoxofluorination reaction (Scheme 2). In this case, the OH

developed since 2005. For more details, the readers are referred to the review articles cited in each section. 2.1. Nucleophilic Fluorination

In nucleophilic fluorination, the substrate behaves as the electrophile while a fluoride ion acts as the nucleophile. In the simplest case, an alkyl chain or an aryl ring bearing a suitable leaving group reacts with a fluoride source (Scheme 1). For more details on nucleophilic fluorination, see reviews dedicated totally or partially to this topic.11,16,17 Scheme 1. Nucleophilic Fluorination

Scheme 2. Deoxofluorination Reaction

Numerous fluoride sources have been used over the years including alkali−metal fluorides (e.g., KF, CsF), HF-based reagents (e.g., HF/pyridine, Et3N·3HF), fluorinated hypervalent silicates and stannates, and tetraalkylammonium fluorides (tetrabutylammonium fluoride, abbreviated TBAF, being the key example of this class). Selected examples of traditional reagents used for nucleophilic fluorination are shown in Figure 1.

functionality of an alcohol substrate attacks the electrophilic deoxofluorinating agent (with the generic formula [X]−F) producing an activated alcohol along with a fluoride ion. The latter then displaces the leaving group (generally through an SN2 reaction though exceptions have been noted) to produce the corresponding alkyl fluoride. A number of reagents have been developed over the years, and among these, DAST26 and Deoxo-Fluor27 are the most commonly used (Figure 4).28

Figure 1. Examples of traditional reagents, aside from alkali−metal fluorides, used for nucleophilic fluorination.

Hypervalent halogen derivatives have also been employed over the years for fluorination reactions. Bis(pyridine)iodine(I) tetrafluoroborate (IPy2BF4) was first described in 1985 by Barluenga and co-workers18 while the first use of paraiodotoluene difluoride for a fluorination reaction was reported in 1982 by Tsushima and co-workers.19 Seven years later, paratrifluoromethylphenylbromine difluoride (p-CF3−C6H4−BrF2) was synthesized by Frohn and co-worker.20 These reagents are depicted in Figure 2.

Figure 4. Examples of traditional reagents used for the deoxofluorination reaction.

Only a handful of new deoxofluorination agents have been developed since 2005 and are shown in Figure 5. Umemoto and co-workers reported the discovery that Fluolead (4-tertbutyl-2,6-dimethyl phenylsulfur trifluoride)29 or arylsulfur chlorotetrafluorides30 could be used in deoxofluorination reactions. Couturier and co-workers described the XtalFluor reagents (aminodifluorosulfinium tetrafluoroborate salts) as stable and crystalline reagents.31 Finally, Ritter and co-workers reported on PhenoFluor (1,3-bis(2,6-diisopropylphenyl)-2,2difluoro-2,3-dihydro-1H-imidazole) as a thermally stable deoxofluorinating agent for phenols32 and alcohols.33 Aside from the arylsulfur chlorotetrafluorides, these reagents are all commercially available.

Figure 2. Examples of hypervalent halogen-based fluorination reagents.

Figure 3. New fluoride sources developed since 2005. 9074

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Figure 5. New deoxofluorinating agents developed since 2005.

2.2. Electrophilic Fluorination

sterically demanding version of NFSI has been described by Shibata,41 and a fluorinated analog was synthesized by Yang and co-workers.42 Gouverneur and co-workers reported chiral electrophilic fluorine sources based on the core of Selecfluor.43 Finally, in 2013, Shibata and co-workers designed two chiral analogs of NFSI.44 Representative examples of these chiral fluorine sources are shown in Figure 7 along with the other new reagents. Mechanistically, the electrophilic fluorine sources do not generate F+, an unknown species, but will transfer the fluorine atom to the nucleophile either via single-electron transfer (SET) or through a SN2 mechanism. The exact mechanism varies according to the conditions used, the nucleophile and the electrophilic fluorine source employed.

In electrophilic fluorination, the role of each reagent is reversed. Hence, the substrate behaves as the nucleophile while the electrophile is a reagent that will deliver an equivalent of “F+”. The nucleophile can take the form of a carbanion (e.g, Grignard reagents), an electron-rich unsaturation (arene, alkene, or alkyne), or a substrate bearing a nucleophilic and labile bond (e.g., C−Si, C−Sn, and C−B). A few illustrative generic cases are presented in Scheme 3. For more details on electrophilic fluorination, see reviews dedicated totally or partially to this topic.11,34 Scheme 3. Electrophilic Fluorination

2.3. Radical Fluorination

In radical fluorination, the C−F bond is produced by the reaction between a carbon-based radical (generated in situ by various means) and an “atomic fluorine” source (Scheme 4).45 Early examples using this approach employed XeF2, hypofluorite, or molecular fluorine as the fluorine source.46 Recent important contributions in this field were the demonstration that some N−F electrophilic fluorine sources47 as well as fluorinated solvents48 could behave as fluorine transfer agents.

3. SYNTHETIC METHODS FOR THE MONOFLUORINATION OF ORGANIC COMPOUNDS

In terms of electrophilic fluorine source, early work has been performed with reagents bearing a O−F bond (e.g., CF3OF, HOF, and CsSO4F), a Xe−F bond (i.e., XeF2), or a F−F bond (i.e., elemental fluorine). The high reactivity, the low selectivity, the absence of commercial sources for some of these reagents, and the drawbacks associated with their preparation initially limited their applicability and the development of this chemistry. A breakthrough in this field was the discovery of a new class of bench-stable reagents bearing an N−F bond,35 allowing their commercialization. Key representatives of this class of reagents include NFPy (N-fluoropyridinium salts),36 NFSI (N-fluorobenzenesulfonimide), 3 7 Selectfluor (1-chloromethyl-4-fluoro-1,4diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)),38 and its derivative Accufluor (1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate)),39 which are depicted in Figure 6. Five new electrophilic fluorine sources have been developed since 2005. Stuart and co-workers have reported a fluoroiodane, a hypervalent iodine-based electrophilic reagent,40 while a

3.1. Creation of a C(sp3)−F Bond

3.1.1. Alkyl Fluorides. 3.1.1.1. Deoxofluorination of Alcohols. Deoxofluorination of alcohols is one of the most effective methods for the synthesis of alkyl fluorides. Many reagents have been developed over the years, but DAST and Deoxofluor still remain the most commonly used (see Figure 4). Since 2005, some variants using these reagents have been reported. In 2007, Grée and co-workers used ionic liquids as recyclable solvents.49 They selected 1-octyl-3-methylimidazolium hexafluorophosphate, [C8mim][PF6], as solvent medium due to its low viscosity, low density, and low melting point, which allowed the use of low temperatures when required. Various alkyl fluorides were obtained in good yields (Scheme 5). In order to develop a scale-up method of deoxofluorination, some authors used continuous-flow microreactors.50 Various fluorinated products were synthesized by this method (i.e., alkyl, benzyl, allyl, acyl and glycosyl fluorides) and very good yields were generally observed. In 2009, Couturier and co-workers developed two aminodifluorosulfinium salts as new deoxofluorination agents: XtalFluor-E and XtalFluor-M (see Figure 5).31 These reagents are crystalline and so are more easily handled and significantly more stable than DAST and Deoxofluor (see Figure 4). Their method allowed the fluorination of a wide range of substrates: primary, secondary, and tertiary alcohols, but also allylic

Figure 6. Commonly used electrophilic fluorine sources. 9075

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Figure 7. New electrophilic fluorine sources since 2005.

Scheme 4. Radical Fluorination

Scheme 7

Scheme 5

Scheme 8

alcohols, carbohydrates, and carboxylic acids, with 72−99% yield (Scheme 6). secondary aliphatic amines across the double bond of 1,1,3,3,3pentafluoropropene 4.54 This reaction gave a mixture of fluorinated products 5 and 6 which were then used as deoxofluorinating agents. Several compounds including primary, secondary, and tertiary alcohols could be fluorinated in low to excellent yields (Scheme 10). Simpson and co-worker used perfluoro-1-butanesulfonyl fluoride (PBSF) for the asymmetric synthesis of fluorinated alanine derivatives using Et3N·3HF as the fluoride source.55 Zhao, Xue and co-workers revisited the reaction using tetrabutylammonium triphenyldifluorosilicate (TBAT) as the fluoride source instead, which decreased the formation of side products (e.g., elimination products).56 Bandgar and co-workers reported in 2005 the direct conversion of alcohols into alkyl fluorides using triphenylphosphine and KF under mild conditions (Scheme 11).57 This method is applicable to a large variety of alcohols such as primary, secondary, tertiary, benzylic, allylic, and propargylic ones. Very good yields were obtained, and the reaction showed a high tolerance toward other functional groups present elsewhere on the molecule. Fluolead (4-tert-butyl-2,6-dimethylphenylsulfur trifluoride), a new deoxofluorinating agent with a high thermal stability and

Scheme 6

Hara and co-workers reported in 2005 the selective monofluorination of diols using N,N-diethyl-α,α-difluoro-(mmethylbenzyl)amine (DFMBA).51,52 The reaction was first applied on a series of diols (Scheme 7) and on (2S,4S)-2,4pentanediol 1 for the synthesis of the corresponding fluorinated ester 2 (Scheme 8). Afterward, they developed a perfluorinated derivative of DFMBA: N,N-diethyl-α,α-difluoro-[3,5-bis(1H,1H,2H,2Hperfluorodecyl)]benzylamine 3.53 Using this reagent, alcohols (Scheme 9a) and diols (Scheme 9b) were fluorinated in good yields. In both cases, the fluorinated products were isolated in pure form by a simple extraction with a fluorous/organic solvent system. Koroniak and co-workers synthesized 1,1,3,3,3-pentafluoropropene secondary amine adducts by nucleophilic addition of 9076

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Scheme 9. Deoxofluorination of (a) Alcohols and (b) Diols Using DMFBA Derivative 3

Scheme 10

Scheme 12

Scheme 13 Scheme 11

an unusual resistance to aqueous hydrolysis, was reported by Umemoto and co-workers in 2010 (see Figure 5).29 The deoxofluorination reaction of various alcohols was described including alkyl, glycosyl, benzylic, and β-amino alcohols and diols, which all provided the corresponding fluorides in good to excellent yields (Scheme 12). In 2012, Umemoto and co-workers described the use of arylsulfur chlorotetrafluorides (ArSF4Cl) as deoxofluorinating reagents (see Figure 5).30 ArSF4Cl were first reduced using a diaryl disulfide to generate a neat arylsulfur trifluoride, the active deoxofluorinating agent. Addition of the substrate then provided the corresponding fluoride (Scheme 13). Monofluorinated alkyl fluorides and acyl fluorides could be synthesized in good yields using this method. Difluoro- and trifluoromethylated compounds could also be synthesized from ketones, thiocarbonyl compounds, and carboxylic acids using this reagent. Dubé and co-workers reported in 2012 the synthesis of alkyl, benzyl, and allyl fluorides using tetramethylfluoroformamidi-

nium hexafluorophosphate (TFFH) as a mild deoxofluorinating agent (Scheme 14).58 An exogenous fluoride source was shown to be necessary to enhance the reaction yields and the use of ethyl acetate as the solvent was found to avoid the formation of elimination products. Scheme 14

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sources were evaluated and N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (2,4,6-Me3-NFPy·BF4) was identified as the optimal one. 3.1.1.2.2. Halofluorination. Fundamentally, halofluorination is achieved with a nucleophilic fluorinating agent and an electrophilic source of halogen. Since 2005, some variants of this transformation have been reported. Ito and co-workers described the halofluorination of alkenes with a combination of halosuccinimide and an ionic liquid, 3ethyl-1-methyl-imidazolium oligo hydrogen fluoride (EMIMF(HF)2.3, 8), as the fluorinating reagent.62 The latter is moisturestable and not volatile. Good yields were obtained for the iodoand the bromofluorination of alkenes, but lower yields were achieved for the chlorofluorination (Scheme 18). Halofluori-

PhenoFluor (see Figure 5), reported by Ritter and coworkers, was originally designed for the deoxofluorination of phenols (see section 3.2.1.5).32 Nonetheless, the chemoselective deoxofluorination of complex alcohols (i.e., natural products and pharmaceuticals) was also reported using this reagent (Scheme 15).33 Scheme 15

Scheme 18

Recently, Qing and co-workers showed that the trifluoromethylthiolating reagent AgSCF3 could also be used in some cases for the deoxofluorination of alcohols in modest yields.59 3.1.1.2. Fluorination of Alkenes. 3.1.1.2.1. Hydrofluorination. Boger and co-workers reported in 2012 the Fe(III)/ NaBH4-mediated free-radical hydrofluorination of unactivated alkenes using Selectfluor (Scheme 16).60 This powerful method

nation of styrene derivatives allowed the formation of benzylic fluorides. However, this ionic liquid is not commercially available and is prepared using anhydrous hydrogen fluoride, which represents a limitation. In 2006, Tingoli and co-workers developed a mild process for the synthesis of iodofluorinated compounds using molecular iodine and 4-iodotoluene difluoride (see Figure 2).63 This combination generates I−F in situ that adds in a Markovnikov fashion to the alkenes with prevalent anti stereoselectivity. This method was applied to various alkenes and styrene derivatives with good yields (Scheme 19). A loss of stereoselectivity was observed for the iodofluorination of glycal esters.

Scheme 16

showed many advantages, such as broad alkene scope, exclusive Markovnikov-addition regioselectivity, insensitivity to air and moisture, and an excellent functional group tolerance. Similarly, Shigehisa, Hiroya and co-workers developed in 2013 the cobalt-catalyzed hydrofluorination of unactivated olefins (Scheme 17).61 Unlike Boger’s reaction, this method requires only a catalytic amount of metal. Various fluorine

Scheme 19

Scheme 17

Esteves, de Mattos and co-workers developed a variant using trihaloisocyanuric acids (9), easily handled solids, instead of Nhalosuccinimides (Scheme 20).64 Using this protocol, fluorinated cyclohexanes and benzylic fluorides could be synthesized with a Markovnikov regioselectivity and following an antiaddition in the case of cyclohexene derivatives. Based on their results for the deoxofluorination of alcohols with 1,1,3,3,3-pentafluoropropene dialkylamine adducts (see section 3.1.1.1), Walkowiak used the same reagent as a fluoride source for the halofluorination of alkenes and styrene derivatives (Scheme 21).65 DBH (1,3-dibromo-5,5-dimethylhydantoin) and NIS were used as electrophilic source of bromine and iodine, respectively. 3.1.1.2.3. Carbofluorination. Kindt and Heinrich reported in 2014 the first example of an intermolecular Meerwein-type carbofluorination reaction (Scheme 22).66 Selectfluor acted as 9078

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Scheme 20

Scheme 24

Scheme 21 3.1.1.2.4. Phosphonofluorination. In 2013, Li and co-workers reported the first phosphonofluorination of alkenes (Scheme 25).69 In this system, the combination of Ag(I) and Selectfluor Scheme 25

an oxidant to generate aryl radicals and as a fluorine source in the final radical fluorine-transfer step. Low to moderate yields were obtained. Scheme 22

leads to the formation of a Ag(III)−F complex, which allows the catalytic oxidative generation of phosphonyl radicals. Reaction of these radicals with Ag(II)−F gives the fluorinated products and regenerates Ag(I). This phosphonofluorination reaction showed a broad substrate scope and a wide functional group compatibility. 3.1.1.3. Fluorination of Alkyl Halides. Fluorination of alkyl halides is generally achieved by nucleophilic substitution of the halide with a fluoride.12a Usual sources of fluoride for this transformation are AgF, KF, and TBAF. TBAF is commonly prepared in a hydrated state and dried by distillation or by heating under vacuum. However, this anhydrous fluoride salt is unstable and decomposes through Hofmann elimination at room temperature. In order to circumvent this problem, DiMagno and co-workers reported the fluorination of various substrates via the in situ formation of anhydrous TBAF.21a Excellent yields (up to 100%) were obtained. Anhydrous TBAF was generated by treating hexafluorobenzene with tetrabutylammonium cyanide in a polar aprotic solvent. Despite its good reactivity, anhydrous TBAF can cause elimination side-reactions since it can act as a good nucleophile as well as a strong base. In this context, Sohn and co-workers demonstrated the efficiency of the use of TBAF in nonpolar protic t-amyl alcohol reaction medium.70 This protic environment reduced the basicity of TBAF while still maintaining its good nucleophilicity.

In the same year, Li and co-workers described the silvercatalyzed carbofluorination of unactivated alkenes with active methylene compounds (Scheme 23) and with acetone (Scheme 24).67 These reactions are performed under mild conditions and allowed the carbofluorination of a wide range of substrates in good yields. Recently, several authors reported the synthesis of trifluoromethylated compounds via the fluorination of difluoroalkenes, either preformed or prepared in situ.68 This method is very efficient for the formation of perfluorinated molecules but will not be described in details in the context of this review. Scheme 23

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Scheme 26

1-n-Butyl-3-methylimidazolium fluoride ([bmim][F], 15) has been used by Pégot, Magnier and co-workers as a new reagent for the nucleophilic substitution of alkyl halides and sulfonates by a fluoride anion (Scheme 30).75 No organic solvent is needed for the fluorination, and the time of reaction is considerably reduced by the use of microwave irradiation. Kim, Chi and co-workers reported in 2008 the fluorination of alkyl halides using the polymer-supported ionic liquid catalyst PS[hmim][BF4] (polymer-supported 1-n-hexyl-3-methylimidazolium tetrafluoroborate).76 The method is also applicable to alkyl sulfonates (see section 3.1.1.4). Excellent yields were obtained for the three alkyl halides studied (Scheme 31). 3.1.1.4. Fluorination of Alkyl Sulfonates. Fluorination of alkyl sulfonates (R−SO2R1 where R1 is typically Me, CF3, or pTol) is similar to the fluorination of halides, since a nucleophilic source of fluoride, commonly CsF, TBAF, or Et3N·3HF, is needed to perform the nucleophilic substitution.12a Recently, CsF77 and TBAF22 have been used with tert-butyl alcohol as the solvent in order to enhance the reactivity of the fluoride salt. This protic solvent reduces the strength of the ionic bond by hydrogen-bonding to the fluoride, thereby generating a tertiary alcohol-solvated fluoride ion that acts as a strong nucleophile and a weak base. In 2008, the nucleophilic fluorination of triflates by tetrabutylammonium bifluoride was considered by Lee, Shin and co-workers as a good alternative, since this reagent is less basic.78 Their method has been applied to a variety of substrates (essentially alkyl and benzyl) with good yields. Chi and co-workers demonstrated that ionic liquids with a tert-alcohol moiety increased nucleophilicity of the fluoride anion, induced high chemoselectivity and reduced formation of the olefin byproduct.79 Ionic liquid [mim-tOH][OMs] (16) gave the best results and excellent yields were obtained (Scheme 32). A few years later, [dihexaEGim][OMs] (17) was prepared to enhance the reactivity of KF (Scheme 33).80 The oligoether part of the molecule acts as a Lewis base toward the metal cation and therefore increases the nucleophilicity of the fluoride

Bertrand and co-worker demonstrated in 2012 that the para C−F bond of pentafluoropyridine can be activated by an ethynyl dithiocarbamate to form cyclic adduct 10.71 The latter is capable of transferring a fluoride ion to various substrates (Scheme 26). A new copper(I) bifluoride complex featuring a neocuproine ligand (11) was synthesized and characterized by Huang, Weng and co-workers in 2013 (Scheme 27).72 This complex reacts Scheme 27

with primary and secondary alkyl bromides to produce the corresponding alkyl fluorides in modest to good yields. This method showed a great compatibility with various functional groups, such as ethers, thioethers, amides, nitriles, alcohols, ketones, esters, and heterocycles. Sulfonium borane salts have been used by Gabbaı̈ and coworker to capture fluoride anions in aqueous phase in order to form zwitterionic fluoroborates 12 as easily isolable nonhygroscopic solids (Scheme 28).73 These salts can react with phenyl sulfide to form 13, a nucleophilic fluorinating reagent. In 2005, a new nucleophilic fluorinating agent 14, synthesized in situ by reaction between DMAP and pentafluoropyridine, has been developed by Sandford and coworkers.74 This reagent was used for the fluorination of a short series of alkyl bromides and chlorides in moderate yields, mostly due to its low solubility in organic solvents (Scheme 29). Scheme 28

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Scheme 29

Scheme 30

Lee, Chi, Song and co-workers showed that oligoethylene glycols could promote a variety of chemical reactions in which alkali metal salts are used as nucleophilic sources.82 In the case of KF, the two OH groups induce a decrease of the basicity of the fluoride anion and an activation of the electrophile by hydrogen-bonding. In 2012, the method was extended to other substrates, and CsF was used in association with a catalytic amount of pentaethylene glycol (pentaEG; Scheme 34).83

Scheme 31

Scheme 34

Chi, Kim and co-workers extensively reported in the literature the fluorination of mesylate 18 by using various polymer-supported ionic catalysts (Scheme 35).76,84 Scheme 35

Scheme 32

Scheme 33 Similarly, polymer-supported oligoethylene glycols have also been used as catalysts for the fluorination of sulfonates, and the reaction has been extended to diverse substrates in good yields (Scheme 36).85 Lalic and co-workers described the chemoselective catalytic fluorination of alkyl triflates (Scheme 37).86 With 10 mol % of (IPr)CuOTf, full conversion could be obtained in under 10 min at 45 °C. This fluorination reaction is compatible with various functional groups, including alkyl tosylates and alkyl bromides. A preliminary study suggested that the copper catalyst could act as a phase-transfer catalyst.

anion. In 2014, this method was extended to the use of other nucleophiles.81 9081

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conditions when used in conjunction with iodosylbenzene as a stoichiometric oxidant.89 Moderate yields were obtained with variable selectivities (Scheme 39).

Scheme 36

Scheme 39

Scheme 37

3.1.1.5. Fluorination of C(sp3)−H Bonds. 3.1.1.5.1. CopperCatalyzed Reactions. Lectka and co-workers have reported the radical monofluorination of C(sp3)−H bonds.87,88 They developed a method in 2012 that was applied to various substrates, affording the desired products in moderate yields (Scheme 38). Their catalytic system involves the use of

3.1.1.5.3. Vanadium-Catalyzed Reactions. Chen and co-workers described in 2014 the vanadium-catalyzed C(sp3)−H fluorination using commercially available vanadium(III) oxide (Scheme 40).90 This simple method allowed the fluorination of a wide range of substrates in good yields.

Scheme 38

Scheme 40

3.1.1.5.4. Fluorination Using a Radical Precursor. A metal-free fluorination of C(sp3)−H bonds was described in 2013 by Inoue and co-workers (Scheme 41).91 N,N-Dihydroxypyromellitimide (NDHPI) was used as a precursor of N-oxyl radical to perform hydrogen abstraction at the electron-rich position. The reaction is compatible with various functional groups, including benzoyl- and methanesulfonyl-protected alcohols, carboxylic acids, tertiary alcohols, cyanides, and bromides. Another metal-free C(sp 3 )−H fluorination has been developed by Lectka and co-workers in 2014 (Scheme 42).92 Their method uses a substoichiometric amount of triethylbor-

Selectfluor, the radical precursor N-hydroxyphthalimide (NHPI), an anionic phase-transfer catalyst (KB(C6F5)4) and a Cu(I) bisimine complex (19). Spectroscopic and synthetic experiments confirmed a radical-chain mechanism initiated by a SET from Cu(I) to Selectfluor. 3.1.1.5.2. Manganese-Catalyzed Reactions. In 2012, Groves and co-workers discovered that a manganese porphyrin complex (20) catalyzed alkyl fluorination using AgF under mild 9082

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Scheme 41

Scheme 43

Scheme 44 Scheme 42

Scheme 45 ane in the presence of O2 to perform a radical-chain reaction. This provides a mild, cheap, and easy way to carry C−H fluorination, but poor to moderate yields were obtained. 3.1.1.5.5. Photocatalyzed Fluorination. A photocatalyzed aliphatic fluorination, employing ultraviolet light and 1,2,4,5tetracyanobenzene (TCB) as photosensitizer, was developed in 2014 by Lectka and co-workers (Scheme 43).93 A variety of substrates were examined, from simple hydrocarbons to complex natural products. In the same year, Britton and co-workers reported the fluorination of unactivated C−H bonds that exploited the hydrogen-abstracting ability of a decatungstate catalyst (TBADT, tetrabutylammonium salt of decatungstate), in combination with NFSI (Scheme 44).94 A variety of fluorinated compounds were synthesized by this manner such as simple alkyl fluorides, natural products, and fluorinated amino acid derivatives. A photocatalytic fluorination of unactivated C(sp3)−H bonds was also described by Tan and co-workers.95 Their method implies the generation of cationic N-radicals from Selectfluor via an energy transfer with anthraquinone (AQN) as a photocatalyst. (Scheme 45). The reaction is scalable (25 mmol), and a variety of functional groups is tolerated. 3.1.1.5.6. Fluorination of Adamantane Derivatives. Several cases of direct fluorination of adamantanes were reported by Hara and co-workers. Iodine pentafluoride96 and bromine trifluor-

ide97 were used for the selective introduction of one, two, or three fluorine atoms on the tertiary carbons of adamantanes. 3.1.1.6. Decarboxylative Fluorination of Carboxylic Acids and Derivatives. In 2009, Ramsden and co-worker studied the reaction of diverse carboxylic acids with XeF2 in CH2Cl2 in both Pyrex and PTFE reaction vessels (Scheme 46).98 Reactions performed in Pyrex led to rearrangement and cyclization products, while fluorodecarboxylation occurred via 9083

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Scheme 46

Scheme 49

a SET when using PTFE vessel. The latter reaction allowed the formation of alkyl, benzyl, and allyl fluorides. In 2012, Sammis and co-workers developed a decarboxylative radical fluorination (Scheme 47).47a Peresters 21 were used as Scheme 47 Scheme 50

radical precursors as they can homolytically fragment to radicals under heating. NFSI acted as the fluorinating agent. This method worked well with a large variety of alkyl radicals, including tertiary, benzylic, and heteroatom-stabilized radicals, as well as with peresters of cholic acid derivatives. In the same year, Li and co-workers reported the radical decarboxylative fluorination of aliphatic carboxylic acids using Selectfluor as the fluorine source and AgNO3 as the catalyst (Scheme 48).47b The proposed mechanism is a Ag(III)-

3.1.1.9. Cyclizations. 3.1.1.9.1. Prins Cyclization. The Prins cyclization reaction is a well-known method for the highly stereoselective synthesis of tetrahydropyran derivatives. Nucleophilic fluorine sources can be used in order to form fluorinated molecules (Scheme 51). Some examples of such reactions have

Scheme 48

Scheme 51. Generic Prins Cyclization

been reported in the past few years with various fluorinating reagents. For instance, BF3·OEt2 was used by the groups of Nokami101 and O’Hagan.102 Fuchigami and co-workers performed the reaction in the ionic liquid Et4NH·5HF,103 while Saikia and co-workers used titanium tetrafluoride as the fluorinating reagent.104 In 2010, Yadav and co-workers used tetrafluoroboric aciddiethyl ether complex (HBF4·OEt2) for the one-pot HosomiSakurai allylation and Prins cyclization of aldehydes with allyltrimethylsilane, in order to form symmetrical 4-fluorotetrahydropyrans (Scheme 52).105

mediated SET followed by a fluorine atom transfer. Many examples have been examined and the method appeared to be compatible with a wide variety of functional groups. 3.1.1.7. Fluorination of Alkylboronates. In 2014, Li and coworkers described the synthesis of alkyl fluorides from alkylboronates and boronic acids via a silver-catalyzed radical fluorination in aqueous solution (Scheme 49).99 Good yields and a wide functional group compatibility were observed by the authors. 3.1.1.8. Hydrofluorination of Tosylhydrazones. In 2013, a simple synthesis of fluoroalkanes by deoxygenative hydrofluorination of tosylhydrazone derivatives was described by Yadav and co-workers (Scheme 50).100 The reaction can also be achieved in a one-pot procedure directly from carbonyl compounds, using TsNHNH2 to generate the tosylhydrazone intermediate.

Scheme 52

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to form 4-fluoro-1-iodocyclohexenes in the presence of IPy2BF4 and HBF4·Et2O (Scheme 57).110

The same group also developed a synthetic route to 4fluoropiperidines via an aza-Prins cyclization (Scheme 53).106 In this case, the reaction occurred between aldehydes and Ntosyl homoallylamines in the presence of a solution of HBF4· OEt2.

Scheme 57

Scheme 53

In 2013, Gouverneur and co-workers developed an asymmetric electrophilic fluorocarbocyclization to generate various tetracyclic molecules possessing a carbon−fluorine quaternary stereocenter.43 They first focused on the nonenantioselective version since this transformation had never been described (Scheme 58a). Excellent yields were obtained,

3.1.1.9.2. Nicholas Cyclization. The Nicholas reaction can be used to synthesize cyclic molecules with stereocontrolled formation of a chiral center. Fluorinated compounds can be prepared using BF3·OEt2 or HBF4 as the source of fluoride. Within the same year, Tyrrell and co-workers described the synthesis of fluorinated benzopyran derivatives (Scheme 54),107 while Bertrand and co-workers reported the synthesis of functionalized fluorinated cyclohexane and cycloheptane derivatives (Scheme 55).108

Scheme 58. (a) Non-Enantioselective and (b) Enantioselective Fluorocarbocyclizations

Scheme 54

Scheme 55

3.1.1.9.3. Nicholas−Prins Cyclization. In 2007, Bertrand and co-workers developed the Nicholas−Prins cyclization leading to functionalized 2-alkynyl tetrahydropyrans.109 By using HBF4 as a Lewis acid during the reaction, fluorinated products were obtained (Scheme 56). 3.1.1.9.4. Electrophilic Cyclization. Kirsch and co-workers described the electrophilic cyclization reaction of 1,5-enynes Scheme 56

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and the syn diastereoisomers were formed preferentially. Then, they synthesized various chiral Selectfluor derivatives and chose compound 22 to perform the asymmetric reaction which afforded enantioenriched fluorocarbocyclized products (Scheme 58b). Recently, the same research group reviewed the asymmetric fluorocyclizations of alkenes.111 3.1.1.10. Reductive Elimination from Organometallic Complexes. Gagné and co-workers developed a general method for the C−F reductive elimination using Pt complexes 23 and 24 in 2011 (Scheme 59)112 and applied this concept to the cyclization of polyenes in 2013 (Scheme 60).113

Scheme 61

Scheme 59 Scheme 62

Scheme 60 In 2012, the same group reported an approach to chiral βfluoroketones (Scheme 63).118 Compounds with various substituents and oxygen-containing rings of diverse sizes were prepared with moderate to excellent enantioselectivities. Bürgi, Alexakis and co-workers also developed fluorinative semipinacol rearrangements and reported two highly enantioselective methods leading to a ring expansion (Scheme 64).119,120 Other studies showed that these conditions allowed the deracemization of a mixture of enantiomers.121 3.1.1.11.2. Fluorination Using Superacid HF/SbF5. Many rearrangements can be observed when compounds are treated with HF/SbF5. Thibaudeau and co-workers reported rearrangement and fluorination of quinidinone in superacid,122 and cases of cyclization/fluorination reactions of N-dienes.123 However, these reactions showed low yields and selectivity. 3.1.1.11.3. 1,4-Halogen Shift-Fluorination of Alkynes. Ochiai and co-workers reported in 2005 and 2007 the stereoselective synthesis of λ-halogenovinyl(aryl)-λ 3 -bromanes/iodanes through domino λ3-bromanation/iodination-1,4-halogen shiftfluorination of alkynes (Schemes 65 and 66).124 3.1.2. Formation of a C−F Bond Next to an ElectronWithdrawing Group. The introduction of a fluorine atom next to an electron-withdrawing group has been largely studied by a number of research groups with a particular attention to αfluorinated carbonyl compounds.13h,125−128 These past ten years, several new methods using electrophilic or nucleophilic sources of fluorine have been developed. 3.1.2.1. Formation of α-Fluoroketones. 3.1.2.1.1. Electrophilic Fluorination of Arylketones using N−F Reagents. In 2007, Stavber and co-workers reported the solvent-free electrophilic fluorination of a cyclic enolate (Scheme 67).129

This type of reaction using gold was also described by Toste and co-worker in 2012 (Scheme 61).114 In particular, they studied the synthesis of alkyl fluorides from alkylgold(III) complexes, affording the desired products in low to excellent yields. In 2012, Sanford and co-workers studied the mechanism of a C(sp3)−F bond-forming reductive elimination from palladium complexes. Notably, this process is insensitive to the presence of water.115 Two years later, Pd-catalyzed C−F bond formation was reviewed by Li, Wang and co-workers.116 3.1.1.11. Rearrangements. 3.1.1.11.1. Fluorinative Semipinacol Rearrangement. Tu and co-workers reported an example of fluorinative semipinacol rearrangement in 2005 (Scheme 62).117 This procedure allowed the stereoselective synthesis of chiral α-quaternary β-fluoroaldehydes, with ee’s up to 82%, using a quinine/Selectfluor combination. 9086

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Scheme 63

Scheme 64. Ring Expansion of (a) Cycloalkyl Alcohols and (b) Cyclopropyl Sulfonamides

Scheme 66

Scheme 67

Hoff and co-workers reported two electrophilic pathways to produce fluorinated 1-arylethanones (Scheme 68).130 The first one (conditions A) implied the formation of a trimethylsilyl enol ether followed by an electrophilic fluorination with Selectfluor, whereas the second method (conditions B) was the direct electrophilic fluorination of the ketone followed by the cleavage of the corresponding fluorinated dimethyl acetals formed during the reaction. Both conditions gave the monofluorinated acetophenone derivatives in moderate to good yields. In 2009, Hoff and co-workers developed the microwaveassisted fluorination of 1-arylethanones (Scheme 69).131 This method clearly improved the reaction times compared to the thermal-activated fluorination they previously reported (see Scheme 68).130 This Selectfluor-mediated fluorination afforded the desired products in moderate to good yields. The same year, Stavber and co-workers reported the direct electrophilic fluorination of a variety of ketones in an aqueous micellar system yielding α-fluorinated cyclic and acyclic ketones in moderate to excellent yields (Scheme 70).132 Batey and co-workers noticed that the presence of a catalytic amount of sulfuric acid facilitates the electrophilic αfluorination of ketones and leads to a more rapid product formation (Scheme 71).133 The reaction times were lower when employing methanol instead of acetonitrile. However, the use of this alcohol as the solvent sometimes yielded the corresponding fluorinated ketal.

Scheme 65

The use of Selectfluor or NFSI as the fluorinating agent gave the α-fluoroindanone in excellent yields. 9087

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Scheme 68

ethers. Hara and co-workers reported, in 2005, the use of pTol-IF2 for the fluorination of cyclic and acyclic silyl enol ethers in moderate to good yields (Scheme 75).136 3.1.2.1.3. Formation of Selenium-Containing α-Fluoroketones. Wu and co-workers reported the formation of α-fluoroketones from α-cyclopropyl ketones using lithium phenylselenolate and an electrophilic source of fluorine (Scheme 76).137 They obtained the monofluorinated compounds in moderate yields with NFSI as the fluorinating agent. 3.1.2.1.4. Nucleophilic Fluorination of Arylketones. Hoff and co-workers described the nucleophilic substitution of α-bromo ketones (Scheme 77).130 Using tetrabutylammonium hydrogen bifluoride (TBABF) as the source of fluorine, they obtained the desired fluorinated ketones in, at best, moderate yields. Later, Fan and co-workers described a similar reaction (Scheme 78).138 They used an excess of TBAF·3H2O (3 equiv) as the fluorinating agent for the nucleophilic substitution of αbromoketones in aqueous media and reported the formation of the desired compounds in good yields within short reaction times. Zou and co-workers reported the nucleophilic fluorination of α-bromoacetophenones using TBAF and/or KF in acetonitrile (Scheme 79).139 They also reported the direct fluorination of acetophenone derivatives in deep eutectic solvent (DES): 1:1 choline chloride/p-TsOH (Scheme 80). 1,3-Dichloro-5,5dimethylhydantoin (DCDMH) was used in the reaction and was thought to produce the α-chlorinated ketone in situ. In each case, the fluorinated compounds were obtained in moderate to good yield. MacMillan and co-workers applied their asymmetric substitution of α-tosyl ketones to a monofluorination reaction. They obtained α-fluoro cyclohexanone, using CsF as the fluorinating agent, in 62% yield.140 3.1.2.1.5. Fluorination of Allyl Alcohols. Martin-Matute and coworkers developed the iridium-catalyzed formation of αfluoroketones starting from allylic alcohols (Scheme 81).141 They obtained α-fluorinated ketones derivatives in good yields using a low catalytic charge of the iridium complex (1 mol %). Interestingly, these conditions also allowed the regioselective formation of α′-fluoro-β-dicarbonyl compounds. 3.1.2.1.6. Oxyfluorination of Alkenes. In 2014, Yang and coworkers reported the metal-free oxyfluorination of styrene derivatives for the synthesis of α-fluorinated ketones (Scheme

Scheme 69

Scheme 70

Scheme 71

In 2013, Fernández and co-worker described the one-pot sequential C−B and C−F bond formation for the synthesis of α-fluoroketones.134 They reported two different conditions for this transformation. The first method (Scheme 72) involved the in situ formation of a neutral β-boryl ketone intermediate yielding α′-fluoro-β-boryl ketones. In contrast, the second conditions (Scheme 73) employed a copper catalyst and provided the α-fluoro-β-boryl ketones via an anionic intermediate. 3.1.2.1.2. Hypervalent Iodine-Based Fluorination of Ketones and Silyl Enol Ethers. More recently, Kitamura and co-workers reported the direct monofluorination of ketones using iodosylarenes and Et3N·5HF in excess (Scheme 74).135 The desired α-monofluorinated compounds were obtained in good yields. However, the scope of the reaction was limited to acetophenone derivatives. Hypervalent iodine-based reagents can be used for the formation of α-fluorinated ketones starting from silylated enol Scheme 72

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Scheme 73

obtained α-fluorinated enones in high yields and stereoselectivities. 3.1.2.1.8. Gold-Catalyzed Oxyfluorination of Alkynes. Hammond and co-workers described the gold-catalyzed formation of α-fluorinated ketones from alkynes (Scheme 84).144 When performing the reaction on nonsymmetrical alkynes, they obtained a mixture of regioisomers with moderate selectivity (up to 6.7:1). The major isomer depends on the nature of the substituents. Nevado and co-worker reported a similar transformation yielding a mixture of regioisomers of the α-fluorinated ketone and acetal (Scheme 85).145 The transformation of nonsymmetrical alkynes was found to be more regioselective (>10:1) than the previous reaction144 (Scheme 84), and the fluorinated compounds were obtained in high yields. 3.1.2.2. Formation of α-Fluoro-1,2-diketones from Isoxazoline N-Oxides. Yao and co-workers described the Selectfluor-mediated fluorination/cleavage of isoxazoline Noxides (Scheme 86).146 The use of an excess of Selectfluor in acetonitrile at room temperature allowed the formation of αfluorinated 1,2-diketones in high yields within very short reaction times. 3.1.2.3. Formation of α-Fluoroesters. 3.1.2.3.1. Substitution of α-Chloroesters. Wang and co-workers reported the nucleophilic fluorination of α-chloroesters with retention of configuration (Scheme 87).147 Using an excess of KHF2 (3 equiv) as the fluorinating agent, they reported the formation of the fluorinated compounds in high yields. The authors explained the stereoselectivity of the reaction by an elimination-addition pathway. 3.1.2.3.2. Fluorination of Alkynyl Enolates Starting from Allenoates. In 2008, Hammond and co-workers reported the transformation of allenoates for the synthesis of α-fluorinated esters (Scheme 88).148 First using lithium diisopropylamide (LDA), they formed alkynyl enolates in situ. Following up with the addition of NFSI, they obtained the desired fluorinated compounds in moderate to good yields. 3.1.2.3.3. Fluorination of α-Seleno Esters. Wirth and co-worker reported the use of p-Tol-IF2 or the fluorination of α-seleno esters, amides, and nitriles (Scheme 89).149 The reaction gave the monofluorinated compounds in moderate yields and proceeds through a fluoro-Pummerer rearrangement. Moderate yields were obtained when performing the reaction on α-seleno cyano derivatives (26−50%). 3.1.2.4. Formation of α-Fluoroamides. Takeuchi, Fujiwara and co-workers described the formation of fluorinated oxindoles by direct oxyfluorination of tryptamines (Scheme 90).150 The desired 3-fluorooxindoles were obtained in high yields using Selectfluor as the source of fluorine in the presence of aluminum chloride and water.

Scheme 74

Scheme 75

Scheme 76

Scheme 77

Scheme 78

82).142 These metal-free conditions allowed the formation of a variety of α-fluorinated aryl- and heteroaryl ketones in moderate to good yields. 3.1.2.1.7. Gold-Catalyzed Fluorination of Allenyl Carbinol Esters. Xu and co-workers described, in 2012, the formation of α-fluorinated enones from allenyl carbinol esters (Scheme 83).143 Using a gold-based catalyst (27) in low catalytic loading (1 mol %) and Selectfluor as the source of fluorine, they 9089

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Scheme 79

Scheme 80

Scheme 84

Scheme 81

Scheme 85

Scheme 86 Scheme 82

Scheme 87

In 2012, Nie and co-workers reported the one-pot synthesis of fluorinated pyrazolone derivatives using NFSI (Scheme 91).151 They reported the simultaneous formation of a C−F and a C−C bond in moderate to good yields and diastereoselectivities. 3.1.2.5. Formation of α-Fluorinated Imines. De Kimpe and co-workers described the first direct electrophilic α-monofluorination of imines using NFSI (Scheme 92).152 Depending on the solvent system used and the temperature, monofluorinated or difluorinated imines can be obtained. The αfluoroimines are formed in moderate to excellent yields when using a combination of acetonitrile and DMF. 3.1.2.6. Formation of α-Fluoronitriles. Sakthivel and coworker reported the monofluorination of 5-(cyanomethyl)-

Scheme 88

Scheme 83

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compounds were obtained in moderate to excellent yields. A couple of years later, Golding, Sadeghi and co-workers developed a similar fluorination reaction.155 Their conditions (Scheme 94, conditions B) allowed the electrophilic fluorination of primary and secondary nitro compounds in high yields. A similar reaction was described by Loghmani-Khouzani and co-workers.156 They reported the sonochemical monofluorination of secondary nitro compounds. However, their method only gave the fluorinated compounds in low yields (20−25%). Khisamutdinov and co-workers reported the α-fluorination of 4-nitrooxazolines (Scheme 95).157 Using sodium methoxide and FClO3 as the fluorinating agent, they obtained the monofluorinated compounds in high yields.

Scheme 89

Scheme 90

Scheme 95 Scheme 91

3.1.2.8. Formation of α-Fluorophosphonates. Guan, He and co-workers described the electrophilic fluorination of αchloro and α-bromophosphonates (Scheme 96).158 Using NFSI as the fluorinating agent, they obtained the α,α-fluorohalogenophosphonates in moderate to good yields.

Scheme 92

Scheme 96

imidazole-4-carboxylate nucleosides (Scheme 93).153 They performed the deprotonation/electrophilic fluorination of these derivatives to access 3-fluoro-3-deazaguanosine analogs.

More recently, Beier and co-workers reported the electrophilic monofluorination of diethyl nitromethylphosphonate.159 The use of Selectfluor in the presence of KOH in a 2:1 mixture of acetonitrile and water afforded the fluorinated nitrophosphonate in 48% yield. 3.1.2.9. Formation of α-Fluorosulfones. In 2006, Zajc and co-worker reported the α-fluorination of sulfones using LDA and NFSI in high yields (Scheme 97).160 These sulfones were then engaged in Julia-Kocienski olefinations. Similar work was later done by Bräse and co-workers.161

Scheme 93

3.1.2.7. Formation of α-Fluoronitro Compounds. Shreeve and co-worker described, in 2005, the electrophilic fluorination of primary nitro compounds using KOH or tetrabutylammonium hydroxide as a base and Selectfluor as the source of fluorine (Scheme 94, conditions A).154 The fluorinated

Scheme 97

Scheme 94 3.1.2.10. Formation of α-Fluoro-β-dicarbonyl Compounds. 3.1.2.10.1. Electrophilic Source of Fluorine. In 2005, Shreeve and co-worker described the microwave-assisted fluorination of β-dicarbonyl compounds (Scheme 98).162 Using Selectfluor as the fluorinating agent, they obtained the monofluorinated compounds in high yields within short reaction times. 9091

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Scheme 98

Scheme 102

The solvent-free electrophilic fluorination described by Stavber and co-workers in 2007 was also applied to βdicarbonyl compounds (Scheme 99).129 The monofluorinated products were obtained in good yields using Selectfluor as the source of fluorine.

Scheme 103

Scheme 99

Two years later, Kita, Shibata and co-workers performed the fluorination of β-ketoesters catalyzed by in-situ-generated ArIF2 (Scheme 104).166 The fluorinated products were obtained in

In 2013, Stuart and co-workers reported the fluorination of β-ketoesters in moderate yields using fluoroiodane and Et3N· 3HF (Scheme 100).40 They observed a very low selectivity for the monofluorinated product when the reaction was performed on β-diketones.

Scheme 104

Scheme 100

high yields using only catalytic amounts of aryl iodide but a large excess of hydrogen fluoride (10 equiv). Their conditions also provided good yields for the fluorination of β-ketoamides and β-ketosulfones. In 2014, Sloop and co-workers described the monofluorination of 1,3-indanedione, 1,3-cyclopentanedione and 1,3-cyclohexanedione using Selectfluor in moderate to good yields (50− 67%).167 3.1.2.10.2. Nucleophilic Source of Fluorine. In 2009, Chambers, Sandford and co-workers described the direct fluorination of βketoesters using elemental fluorine and a nickel catalyst (Scheme 105).168 These conditions allowed the formation of the monofluorinated compounds in high yields. The authors also adapted this fluorination for microreactors.169

Stavber and co-worker reported the direct electrophilic fluorination of β-dicarbonyl compounds in water or without solvent (Scheme 101).129,163 The monofluorinated products were obtained in moderate to good yields using either Selectfluor or NFSI as the source of fluorine. Scheme 101

Scheme 105

Zhang, Yi and co-workers described a microwave-assisted one-pot fluorination/Michael addition (Scheme 102).164 The desired compounds were obtained in excellent yields but with modest diastereoselectivities. They also reported the fluorination/Robinson annulation of this type of derivatives. In 2012, Zhang, Zhang and co-workers reported the catalystfree and highly selective monofluorination of acetoacetamides (Scheme 103).165 They employed Selectfluor as the fluorinating agent in PEG-400, giving the monofluorinated βketoamides in high yields.

Kitamura and co-workers reported the nucleophilic direct fluorination of 1,3-dicarbonyl compounds (Scheme 106).170 The reaction goes through the in situ formation of a C−I bond, later displaced by a fluoride ion. The monofluorinated compounds were obtained in moderate to excellent yields. 9092

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Scheme 106

Scheme 110

They also described a similar reaction using PhIO which was generated in situ from PhI and mCPBA in dichloroethane.171 3.1.2.10.3. Hydrofluorination of Diazo Derivatives. In 2012, Hayes, Moody and co-workers reported the hydrofluorination of β-ketoester derivatives using HBF4·OEt2 as the source of fluorine (Scheme 107).172 The monofluorinated β-ketoesters were obtained in moderate to good yields.

Selectfluor for the fluorination of β-ketophosphonates.176 They noticed that the use of Selectfluor resulted in a better selectivity for the monofluorinated product. Later, Radwan-Olszewska and co-workers reported the selective monofluorination of β-ketophosphonates using Selectfluor as the source of fluorine (Scheme 111).177 They obtained the desired products in moderate yields.

Scheme 107

Scheme 111

3.1.2.10.4. Tandem Cyclization-Fluorination of Vinyl βKetoesters. In 2010, Itoh, Kawatsura and co-workers reported the iron-catalyzed tandem cyclization-fluorination of divinyl ketones allowing the formation of cyclic fluorinated βketoesters in good to excellent yields (Scheme 108).173

3.1.2.12. Formation of α-Fluoro-β-ketosulfones and Derivatives. Rozen and co-workers reported, in 2013, the αmonofluorination of sulfone derivatives (Scheme 112).178 They Scheme 112

Scheme 108

used acetyl hypofluorite (AcOF) as the fluorinating agent for the synthesis of α-fluorosulfones in high yields. They also applied their conditions to the monofluorination of βketophosphonates but obtained lower yields. One year later, Hu and co-workers developed the selective monofluorination of active methylene compounds.179 αFluorinated sulfones were obtained in high yields (Scheme 113). The addition of zinc chloride was found to inhibit overfluorination of the compounds. The authors also successfully fluorinated malonates, β-ketoesters and cyanoderivatives. 3.1.2.13. Diastereoselective α-Fluorination of Lactones and β-Ketoesters. Sauve and co-worker reported, in 2009, the diastereocontrolled electrophilic fluorination of 2-deoxyribonolactone derivatives in order to access 2′-deoxy-2′-fluoro

3.1.2.10.5. Oxyfluorination of 2,3-Allenoates. Liu and coworkers reported the cyclizing oxyfluorination of estersubstituted allenes (Scheme 109).174 Using a gold catalyst and Selectfluor as the fluorinating agent they obtained the αfluoro ketones in moderate to good yields. Scheme 109

3.1.2.10.6. Deoxofluorination of α-Hydroxy-β-diesters. Ruzziconi and co-workers described the deoxofluorination of αhydroxy-β-diesters using DAST (Scheme 110).175 The reaction worked well on α-methyl malonates but the use of larger substituents gave a mixture of polyfluorinated products. The authors reported that the reaction is very sensitive to steric and electronic effects. 3.1.2.11. Formation of α-Fluoro-β-ketophosphonates. In 2005, McKenna and co-workers compared FClO3 and

Scheme 113

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enantioselective fluorinative dearomatization of phenols using phase-transfer catalysis (Scheme 121).188 Employing Selectfluor as the source of fluorine in the presence of (S)-28 allowed the formation of α-fluorinated enones in moderate to good yields and high enantioselectivities. 3.1.2.14.4. Formation of α-Fluorinated Esters from Aldehydes Using N-Heterocyclic Carbenes. The enantioselective formation of α-fluorinated esters from α,β-unsaturated aldehydes using NFSI catalyzed by a N-heterocyclic carbene (29) was reported by Sun and co-workers in 2012 (Scheme 122).189 Good yields and enantioselectivities were obtained. However, significantly lower results were obtained when using αsubstituted aldehydes. More recently, Wang and co-workers reported the enantioselective synthesis of α-fluorinated esters from aldehydes using an N-heterocyclic carbene (30) as the catalyst (Scheme 123).190 This transformation gave good results even when R2 = Me (78%, 77% ee), but a heavier catalytic charge was required (20 mol %). This reaction was also described by Sun and co-workers using a similar system (see Scheme 122).191 3.1.2.14.5. Formation of α-Fluorinated Esters and Amides from Acyl Chlorides. Lectka and co-workers described the enantioselective formation of α-fluorinated esters or amides from acyl chlorides using benzoylquinidine (BQd) as the chiral ligand (Scheme 124).192 Palladium and nickel were both employed as the catalyst, and good yields and high ee’s were obtained. However, an excess of NuH was used even when employing natural products as nucleophiles.192b Later, a Lewis acid cocatalyst (LiClO4) was added to improve the yields and create a virtually complete enantioselectivity.193 3.1.2.14.6. Formation of α-Fluorinated Imines from Enamides. In 2012, Toste and co-workers used phase-transfer catalysis for the enantioselective electrophilic fluorination of cyclic enamides (Scheme 125).194 Using (S)-C8-TRIP as the catalyst and Selectfluor as the source of fluorine,195 they obtained good yields and high enantioselectivities on a wide range of cyclic substrates. 3.1.2.14.7. Formation of α-Fluoro-N-sulfinyl Aldimines from Aldehydes. Schulte and Lindsley described the formation of αfluoro-N-sulfinyl aldimines through enantioselective organocatalysis (Scheme 126).196 These intermediates are of interest because they can be used to synthesize β-fluoroamines in high diastereoselectivities. The fluorinated compounds were obtained in good yields and diastereoselectivities using an excess of NFSI as the fluorinating agent (5 equiv) in the presence of organocatalyst 31 and sulfinamide 32. 3.1.2.14.8. Enantioselective Fluorination of Aldehydes. 3.1.2.14.8.1. Organocatalysis: Use of Cinchona Alkaloids. Jørgensen and co-workers developed a new class of 6′-hydroxy cinchona alkaloids and used one of them (33) for the asymmetric fluorination of 2-phenylpropanal (Scheme 127).197 They obtained 2-fluoro-2-phenylpropanal with a good enantioselectivity.

nucleosides.180 Employing the combination NFSI/LiHMDS, they obtained the fluorinated compounds in low to good yields. The diastereoselective tandem Nazarov cyclization/electrophilic fluorination of unsaturated β-ketoesters was described by Ma and co-workers (Scheme 114).181 They obtained the monofluorinated compounds in low to high yields and diastereoselectivities. Scheme 114

The same year, Ma and co-workers reported a similar transformation via a AlCl3-catalyzed triple-cascade reaction (Scheme 115).182 Using NFSI as the fluorinating agent, they obtained the fluorinated compounds in low to good yields and usually high diastereoselectivities for the trans isomer. In 2012, Ma and co-workers reported another diastereoselective one-pot multistep transformation (Scheme 116).183 Using NFSI as the fluorine source, they synthesized fluorinated 2,3-dihydroquinolin-4(1H)-ones in good yields and high diastereoselectivities. A similar transformation was described by Zhao, Zhu and coworkers (Scheme 117).184 Using L-proline as the catalyst, they obtained diastereomerically pure trans-monofluorinated flavanones in moderate to good yields. 3.1.2.14. Enantioselective Fluorination. 3.1.2.14.1. Fluorination of Protected Enol Ethers in the Presence of Cinchona Alkaloids. In 2006, Shibata and co-workers used the alkaloid DHQB (Scheme 118) in the presence of Selectfluor for the enantioselective fluorination of cyclic ketones. They reported moderate enantiomeric excesses (up to 54% ee) in very long reaction times (>2 days).185 In 2008, Shibata and co-workers used the cinchona alkaloid (DHQ)2PHAL as a catalyst for the enantioselective fluorination of silyl enolates (Scheme 119).186 The desired cyclic fluorinated ketones were obtained in high yields and good enantioselectivities. They used NFSI as the source of fluorine in the presence of an excess of potassium carbonate (6 equiv). 3.1.2.14.2. Formation of α-Fluorinated Esters from Ketenes. Fu and co-workers reported the enantioselective formation of αfluorinated esters from ketenes (Scheme 120).187 The monofluorinated esters were obtained in high yields and enantioselectivities using an iron-based catalyst and NFSI as the source of fluorine. 3.1.2.14.3. Formation of α-Fluorinated Ketones by Dearomatization of Phenols. Toste and co-worker reported the Scheme 115

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Scheme 116

Scheme 117

Scheme 119

3.1.2.14.8.2. Organocatalysis: Through in Situ Enamine Formation. In 2005, Jørgensen and co-workers reported the enantioselective fluorination of aldehydes using a silylated prolinol derivative as the catalyst (34; Scheme 128).198 This reaction, using NFSI as the source of fluorine, gave the αfluorinated aldehydes in moderate to excellent yields and high enantioselectivities. The same year, Barbas and co-workers also described the direct asymmetric fluorination of aldehydes (Scheme 129).199 Using an imidazolidinone derivative ((S)-31) in stoichiometric amount and NFSI as the fluorinating agent they obtained the αfluoroaldehydes in moderate to good yields and high enantioselectivities. The transformation was achieved on secondary aldehydes using different chiral promoters but only low ee’s were obtained. Also in 2005, a similar reaction using an analogous chiral promoter was described by MacMillan and co-workers.200 They combined the imidazolidinone derivative with dichloroacetic acid in catalytic amounts for the formation of the α-fluorinated aldehydes in moderate to excellent yields and high enantioselectivities (54−96%; 91 to 99% ee). They also reported the enantioselective cascade addition of α,βunsaturated aldehydes using the same conditions thus yielding β-substituted α-fluoroaldehydes (62−81%; anti:syn > 9:1; 99% ee).201 3.1.2.14.8.3. Use of Transition Metal Catalysts: Ruthenium Catalysis. The first ruthenium-catalyzed enantioselective fluorination of aldehydes was reported by Mezzetti and coworkers in 2009.202 They supposed that the mechanism involves the oxidation of the aldehyde to the corresponding α-keto cation species followed by asymmetric fluorination by a fluoride ion. The presence of AgHF2 (2.4 equiv) was necessary

Scheme 120

for the reaction to occur. However, they reported low yields (13−35%) and modest enantioselectivities (18 to 27% ee). 3.1.2.14.9. Enantioselective Fluorination of Ketones. 3.1.2.14.9.1. Organocatalysis: Use of Cinchona Alkaloids. Houk and Lam proposed, in a 2014 article, the first stereoselectivity model for the fluorination of cyclic ketones catalyzed by cinchona alkaloids.203 These compounds have been largely used for the enantioselective monofluorination over the past ten years. 3.1.2.14.9.2. Organocatalysis: Through in Situ Enamine Formation. Enders and Hüttl performed, in 2005, the enantioselective α-fluorination of aldehydes and ketones catalyzed by proline derivatives (Scheme 130).204 They used

Scheme 118

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Scheme 121

Salts. Ma and co-workers described the enantioselective fluorination of benzofuran-2-(3H)-ones using a P-spiro phosphonium salt (36; Scheme 133).207 These conditions allowed the formation of the desired α-fluorinated compounds in excellent yields but modest enantioselectivities at best (up to 56% ee). 3.1.2.14.10.2. Organocatalysis: Use of Thiourea-Based Catalysts. Ma and co-workers performed the asymmetric one-pot sequential conjugate addition/dearomative fluorination of isoxazolones using a thiourea (37; Scheme 134) as the catalyst.208 Their conditions allowed the modification of isoxazolones in excellent yields and diastereoselectivities. Enantioselectivities were generally good except when Ar2 is a heteroaryl group. 3.1.2.14.10.3. Metal Catalysis: Palladium Catalysts. Sodeoka and co-workers largely studied the enantioselective palladiumcatalyzed electrophilic α-fluorination of carbonyl compounds between 2005 and 2007 (Scheme 135).209 They reported this transformation, using NFSI as the fluorinating agent and chiral Pd(II)-bisphosphine complexes, on a variety of substrates. They usually obtained the desired α-fluorinated carbonyl derivatives in high yields and enantioselectivities. 3.1.2.14.11. Enantioselective Fluorination of Amides and Oxindoles. 3.1.2.14.11.1. Use of a Chiral Auxiliary. The electrophilic fluorination of N-acyloxazolidinones promoted by TiCl4 was reported by Zakaria and co-workers (Scheme 136).210 The monofluorinated compounds were obtained in moderate to excellent yields and very high diastereoselectivities for most compounds within 1 h. In 2008, Abell and co-workers described the fluorination of oxazolidinone derivatives 38 and 40 (Scheme 137).211 This reaction was performed using NFSI as the source of fluorine and allowed the formation of the desired compound (39 and 41, respectively) in good diastereoselectivities. Ley and co-workers described a similar transformation using a cryo-flow reactor (Scheme 138).212 Instead of using a Lewis acid, they generated the enolate in situ by adding NaHMDS. The desired monofluorinated derivatives were obtained in moderate yields but similar diastereoselectivities.

Scheme 122

Selectfluor as the source of fluorine and obtained the monofluorinated aldehydes and ketones in moderate to good yields. However, the enantioselectivities obtained were, at best, moderate (86% ee).247 The replacement of the tertbutyl group by an ethyl moiety induced a loss of enantioselectivity (8% ee). Ma and co-workers reported, in 2011, the enantioselective 1,4-addition/fluorination of unsaturated 1,3-dicarbonyl compounds (Scheme 169).248 This copper-catalyzed reaction allowed the formation of α-substituted α-fluoro-β-ketoesters in high yields, diastereoselectivities and enantioselectivities using BINOL-derived chiral ligand 63, NFSI as the source of fluorine and an excess of the organozinc compounds (2 equiv).

Scheme 150

Shibatomi, Isawa and co-workers reported a similar transformation for the enantioselective monofluorination of βketoesters using a hybrid chiral N,N,N-tridentate ligand (45; Scheme 164).240 They formed the desired compounds in high yields and enantioselectivities and studied the influence of the order of addition on the enantioselectivity of the reaction. The enantioselective electrophilic fluorination of α-chloro-βketoesters using a chiral nickel catalyst (60) was described by Kim and co-worker in 2010 (Scheme 165).241 The use of Selectfluor as the fluorinating agent allowed the formation of the desired dihalogenated compounds in good yields and high enantioselectivities. The same research group previously developed a similar transformation using (R)-BINAP as a chiral ligand and palladium as the catalyst.242 The enantioselectivities obtained ranged from 63 to 77% ee. In 2011, SPANamine derivatives (61; see Scheme 166) were used as ligands for the enantioselective electrophilic fluorination of β-ketoesters in the presence of a nickel-based catalyst.243 Scheme 151

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Scheme 153

Scheme 154

Scheme 155

In 2013, Kesavan and co-workers reported the coppercatalyzed enantioselective fluorination of β-ketoesters using (S,S)-Nap-(R,R)-Box as the chiral ligand (Scheme 170).249 These conditions gave the monofluorinated products in high yields, but a wide range of enantioselectivities was obtained. One year later, Du and co-worker described the asymmetric electrophilic fluorination of β-ketoesters and β-ketoamides using Cu(OTf)2 as the catalyst and a tridentate chiral ligand (64; Scheme 171).250 High yields and enantioselectivities were obtained for the cyclic substrates engaged in the reaction. 3.1.2.14.12.13. Metal Catalysis: Zinc Catalysts. In 2008, Shibata, Toru and co-workers described the enantioselective fluorination of malonates using Zn(OAc)2 in the presence of (R,R)DBFOX-Ph (Scheme 172).251 The monofluorinated compounds were obtained in high yields and enantioselectivities using NFSI as the fluorinating agent. A wide variety of

Scheme 156

Scheme 157

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Van Leeuwen and co-workers later described the use of the SPANphos ligand (66; Scheme 174) combined with Pd(OAc)2 for the enantioselective electrophilic fluorination of βcyanoesters.256 The yields obtained were mostly high, but the enantiomeric excesses were substrate dependent. In 2012, Kim and co-workers reported the palladiumcatalyzed enantioselective fluorination of α-cyanosulfones (75− 98%; 87 to 99% ee),257 α-cyanoesters, and α-cyanophosphonates (63−98%; 33 to 91% ee)258 using NFSI as the fluorinating agent and a BINAP-derived catalyst (65, Scheme 173). Comparable conditions were also used for the enantioselective fluorination of α-cyanophosphonates. For these substrates, the counterion of the catalyst was replaced by TfO−.259 3.1.2.14.14. Fluorination of α-Nitroesters. 3.1.2.14.14.1. Organocatalysis: Use of Cinchona Alkaloids. In 2007, Togni and coworkers described the use of cinchona alkaloids for the enantioselective fluorination of α-nitroesters.260 The monofluorinated compounds were obtained in high yields (72−91%), but the enantioselectivity was moderate at best (6 to 31% ee). 3.1.2.14.15. Fluorination of β-Ketophosphonates. 3.1.2.14.15.1. Metal Catalysis: Zinc Catalyst. In 2005, Jørgensen and Bernardi described the zinc-catalyzed enantioselective fluorination of βketophosphonates (Scheme 175).261 The compounds were obtained in a wider range of yields and with high enantioselectivities. However, a high catalyst loading was necessary (20 mol %). 3.1.2.14.15.2. Metal Catalysis: Palladium Catalysts. The palladium-catalyzed enantioselective fluorination of β-ketophosphonates was studied by Sodeoka and co-workers between 2005 and 2007 (Scheme 135).209 In 2013, Kim and co-workers also reported that a BINAPderived palladium catalyst (65, Scheme 173) allowed the highly enantioselective fluorination of unsubstituted β-ketophosphonates (see Scheme 173) and α-chloro-β-ketophosphonates (40−88%; 83 to 95% ee).262 3.1.2.15. Formation of α-Fluoroethers. 3.1.2.15.1. Formation of α-Fluorinated Glycosyls. 3.1.2.15.1.1. Fluorination of n-Pentenyl Glycosides. The IPy2BF4-mediated deoxofluorination of glycosides was studied by López, Fraser-Reid and coworkers (Scheme 176).263 Their conditions allowed the formation of the α-fluorinated glycosides in short reaction times and high yields. In 2009, López and co-workers used HFpyridine for the synthesis of glycosyl fluorides from bicyclic 1,2orthoesters.264 The desired compounds were formed in good to excellent yields, and only one isomer was obtained. 3.1.2.15.1.2. Fluorination of Thioglycosides. In 2007, Winssinger and co-worker formed glycosyl fluorides starting from

Scheme 158

substituents were tolerated including sterically demanding groups. 3.1.2.14.12.14. Metal Catalysis: Ruthenium Catalyst. Mezzetti and co-workers studied the ruthenium-catalyzed enantioselective fluorination of β-ketoesters and β-ketoamides.252 They obtained a wide range of yields and enantioselectivities using salen-derived ligands. 3.1.2.14.12.15. Metal Catalysis: Palladium Catalysts. The palladium-catalyzed enantioselective fluorination of β-dicarbonyl derivatives was reported by Sodeoka and co-workers between 2005 and 2007 (Scheme 135).209 A similar transformation was described by Kim and Kim in 2005.253 They used chiral palladium complexes derived from BINAP for the enantioselective α-fluorination of β-cyanoesters. Good yields (42−88%) and high enantioselectivities (85−99% ee) were obtained. Kim and co-workers reported the palladium-catalyzed enantioselective fluorination of β-ketoesters and β-ketophosphonates (Scheme 173).254 Using NFSI as the fluorinating agent and a BINAP-derived catalyst (65), they obtained high enantioselectivities and good yields. In 2006, Inanaga and co-workers reported the use of phosphonates derived from BINOL for the enantioselective fluorination of β-ketoesters.255 Cyclic derivatives gave higher yields, but only moderate to good enantioselectivities were obtained (47 to 88% ee). 3.1.2.14.13. Fluorination of α-Cyanoesters and Derivatives. 3.1.2.14.13.1. Metal Catalysis: Palladium Catalysts. The palladium-catalyzed enantioselective fluorination of β-cyanoesters was also studied by Sodeoka and co-workers between 2005 and 2007 (Scheme 135).209 Scheme 159

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Scheme 160

Scheme 161

Scheme 164

Scheme 162 The same research group also described, in 2008, the fluorodesulfurization of thioglycosides using a large excess of HF-pyridine (Scheme 178).267 Partially unprotected thioglycosides were successfully fluorinated in moderate to high selectivities toward the α-glycoside. However, a large excess of fluorinating agent was necessary for the reaction to occur. Williams and co-workers reported, in 2012, the desulfurization-fluorination of thioglycosides mediated by XtalFluor-E (Scheme 179).268 These conditions formed the desired glycosyl fluorides in moderate to excellent yields and were also applied to telluro- and selenoglycosides as well as glycosyl sulfoxides. A similar transformation was described by Kanie and coworkers.269 This second method, using DAST instead of XtalFluor-E, allowed the formation of α-fluoro glycosides in high yields. DAST has also been used by Lin and co-workers for the regioselective anomeric group migration yielding glycosyl fluorides (67; Scheme 180).270 The migration was facilitated when Z was an electron-donating group and the C−F bond formation became stereoselective. In their article, they reported the C1 → C4 and C1 → C6 migrations in high yields. For the former to occur, it was found necessary that the anomeric group and the free hydroxyl group have an anti relationship to facilitate SN2 attack by the migratory group.

thioglycosides using IPy2BF4 as the source of fluorine (Scheme 177).265 The same year, López, Gómez and co-workers developed the fluorination of thioglycosides using a combination of IPy2BF4 and HF-pyridine.266 High yields were obtained and selectivities for the α-isomer ranged from moderate to excellent. Scheme 163

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Scheme 165

Scheme 166

Scheme 167

Scheme 169

Scheme 168

Scheme 170

In 2012, Karban and co-workers also reported DASTmediated rearrangements.271 Using this method, they obtained a variety of monofluorinated dianhydro-β-D-hexopyranoses in moderate yields. The same year, Mugunthan and Karta described the fluorination of thioglycosides using in-situ-generated iodine

monofluoride, yielding only one stereoisomer depending on the configuration of the starting material (Scheme 181).272 The reaction proceeds quickly at room temperature but has to be carried out in the dark and an excess of silver fluoride and iodine (2 equiv) is required. 9106

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Scheme 171

(Scheme 182).47c This rapidly proceeding reaction used an excess of Selectfluor (3.5 equiv) as the fluorinating agent under 300 nm irradiation and gave the fluorinated ethers in moderate to good yields. The authors also applied this method to the synthesis of difluoromethyl ethers (R = F), but lower yields were obtained. Two years later, Sammis, Paquin and co-workers reported a similar reaction. The new conditions used a ruthenium-based catalyst and gave, under visible-light irradiation, the fluorinated ethers in good yields (56−92%).273 3.1.2.15.3. Fluorodesulfurization and Deoxofluorination. Fuchigami and co-workers reported, in 2010, the fluorination of benzo- and pyrido-oxazine derivatives (Scheme 183).274 They rapidly performed the fluorodesulfurization reaction in moderate to excellent yields using Et3N·3HF as the fluorine source in the presence of NBS or NIS. A few years later, Kunigami and Hara developed a different fluorodesulfurization reaction (Scheme 184).275 They used IF5pyridine-HF as the fluorinating agent for the synthesis of fluoromethyl ethers and esters from methylthiomethyl ethers and esters, respectively. They obtained the desired products in moderate to good yields. The synthesis of monofluorinated aryl ethers by substitution of a triazolium salt using TBAF was described by Chi and coworkers in 2013.276 They formed the fluorinated compounds in high yields (67−83%) after short reaction times. Bonacorso and co-workers reported a chemoselective DASTinduced deoxofluorination reaction for the synthesis of 2fluoro-3,4,7,8-tetrahydro-2H-chromen-5(6H)-ones (Scheme 185).277 This transformation allowed the formation of the desired compounds in good yields. 3.1.2.15.4. Cyclization of Acylaminoketones. Loiseleur and coworkers developed, in 2011, the fluorinative cyclization of α,αdisubstituted-α-acylaminoketones (Scheme 186).278 This DAST-mediated reaction afforded fluorinated heterocycles in good to excellent yields. The reaction time was substratedependent but could be as low as 10 min. 3.1.2.15.5. Rearrangements. Ochiai and co-workers reported the oxidative rearrangement of benzyl alcohols into fluoromethyl ethers using a difluoro(aryl)-λ3-bromane (Scheme 187).279 This reaction was carried out in chloroform under an argon

Scheme 172

Scheme 173

Two years later, Shishimi and Hara described the fluorination of (phenylthio)glycosides with BrF3 −KHF 2, a recently developed air-stable reagent.24 The reaction times reported were short (15 min to 4 h) and glycosyl fluorides were obtained in high yields. 3.1.2.15.2. Fluorodecarboxylation of Aryloxyacetic Acid Derivatives. The photofluorodecarboxylation of 2-aryloxy carboxylic acids was reported by Sammis and co-workers in 2012 Scheme 174

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Scheme 175

Scheme 176

Scheme 181

Scheme 177

Scheme 182

Scheme 178 Scheme 183

Scheme 179 Scheme 184

Scheme 185 atmosphere at room temperature and afforded the desired products in moderate to good yields. In 2010, de Kimpe and co-workers developed the rearrangement of cyclic α,α-dialkoxy ketones into 1,2-dialkoxy-1,2difluorinated compounds using Morph-DAST (Scheme 188).280 This transformation gave the 1,2-difluorinated compounds in moderate to good yields as a mixture of cis and trans diastereoisomers. 3.1.2.16. Formation of α-Fluorothioethers. 3.1.2.16.1. Nucleophilic Fluorination. In 2006, Saint-Jalmes described the α-monofluorination of chlorinated thioethers using Et3N·3HF

at room temperature (Scheme 189).281 The desired compounds were obtained in high yields and the conditions described were also applied to the formation of fluorinated ethers.

Scheme 180

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Scheme 186

Scheme 191

Scheme 187

conditions (HF/SbF5).285 They obtained a complex mixture of regioisomers, some resulting from rearrangements, including the desired β-fluoroalcohols in low yields. The fluorohydroxylation of alkylidenecyclopropanes using Nfluorosuccinimide (NFS) was described by Huang and coworkers in 2009.286 They reported moderate to good yields in rather long reaction times ranging from 48 to 60 h (Scheme 192).

Scheme 188

Scheme 192 Scheme 189

3.1.2.16.2. Electrophilic Fluorination. Hara and co-workers developed air- and moisture-stable fluorination reagent IF5pyridine-HF and used it for the fluorination of αarylthiocarbonyl compounds (Scheme 190).23 Using these conditions, the monofluorinated compounds were obtained in good yields.

The same year, Stavber and co-workers reported the fluorohydroxylation of 1,1-diphenylethene in ionic liquids.287 The use of Selectfluor in [bmim][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) gave the fluorinated product in 76% yield. Later, Chang and co-workers used Selectfluor for the fluorohydroxylation of olefins in good to excellent yields.288 Most of the substrates were exocyclic olefins and yielded fluorinated heterocycles (Scheme 193).

Scheme 190

Scheme 193

3.1.2.16.3. Fluorodecarboxylation. In 2014, Su and co-workers reported an improved synthesis of Fluticasone propionate.282 In their paper, they describe a late stage silver-catalyzed fluorodecarboxylation in the presence of Selectfluor allowing the formation of the desired product in high yield (Scheme 191). 3.1.3. Formation of β-Fluoroalcohols and Derivatives. The past ten years have been filled with novel synthetic pathways for the formation of β-fluoroalcohols, ethers or esters using either nucleophilic or electrophilic sources of fluorine atoms.283 β-Fluorohydrin derivatives and fluorinated oxygencontaining cycles have been given special interest because of their presence in a variety of biologically active compounds.284 3.1.3.1. Oxyfluorination of Alkenes. 3.1.3.1.1. Intermolecular Reactions. In 2006, Jouannetaud and co-workers studied the hydroxyfluorination of quinidine derivatives under superacidic

The oxyfluorination of allylsilanes was described by Xu and Hammond in 2011.289 Using various nucleophiles, they obtained a variety of monofluorinated silyl ethers in moderate to good yields (Scheme 194). Scheme 194

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Later, Davies and co-workers reported the diastereoselective hydroxyfluorination of unsaturated amines.290 Starting from the Z alkene gave the syn isomer while starting from the E alkene yielded the anti isomer with excellent diastereoselectivities (Scheme 195).

Scheme 198

Scheme 195

Chan and co-workers also reported the formation fluorotetrahydrofurans (Scheme 199).294 However, methodology was different. They produced them cyclopropyl methanols through the in situ formation alkenes under acid catalysis.

of 3their from of Z

The fluoroesterification of styrene derivatives was then described by Liu and co-workers.291 Using palladium chloride as the catalyst with the N,N-bidentate ligand 69, they reported good to excellent yields but low diastereoselectivities (Scheme 196).

Scheme 199

Scheme 196

Two years later, Liu and co-workers developed a similar reaction (Scheme 200).295 They reported the palladiumScheme 200

3.1.3.1.2. Intramolecular Reactions. In 2006, Serguchev and coworkers performed the fluorolactonization of norbornene carboxylic acid derivatives (Scheme 197).292 They obtained

catalyzed intramolecular oxyfluorination of styrenes in good yields with low selectivity for the trans isomer using the same ligand (69) as for their method for the fluoroesterification of styrenes (see Scheme 196).291 The same year, Serguchev, Ponomarenko and co-workers reported the formation of fluorinated tetrahydrofurans and tetrahydropyrans from styrene derivatives in ionic liquids.296 Good yields were obtained and the selectivity for the trans or cis isomer depended on the nature of the ionic liquid. This extended their previous work on the fluorolactonization of unsaturated carboxylic acids using Selectfluor in ionic liquids with yields up to 76%.297 3.1.3.1.2.2. Formation of Fluorinated Polycyclic Ethers. Rueping and co-worker studied the formation of fluorinated isobenzofurans from styrene derivatives (Scheme 201).298 Using only Selectfluor in acetonitrile, they obtained the desired

Scheme 197

the desired β-fluorinated esters in over 70% yield when employing Selectfluor as the fluorinating agent. However, the use of XeF2 generated a mixture of fluorinated compounds. 3.1.3.1.2.1. Formation of Fluorinated Tetrahydrofurans. The oxyfluorination of allyl silanes was described in 2009 by Gouverneur and co-workers (Scheme 198).293 They used either Selectfluor or NFSI as the fluorinating agent depending on the nature of the silane. The authors reported that the temporary activation of the alkene by the silyl group was necessary for a regioselective attack of the alcohol. The stereochemistry of the cyclic product depended on the configuration of the starting material: for example predominantly Z alkenes yielded mainly the cis product.

Scheme 201

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The enantioselective tandem oxyfluorination of enamides using (R,R)-PhDAP as the chiral catalyst was described by Toste and co-workers (Scheme 205).303 They reported good to excellent yields with good enantioselectivities on a large scope of enamides. 3.1.3.2. Enantioselective Fluorination of Allylic Alcohols. Toste and co-workers described the regio- and enantioselective fluorination of allylic alcohols using an in situ generated directing group (Scheme 206).304 The use of a chiral anion phase-transfer catalyst (70) allows the formation of the desired β-fluoroalcohols in good yields and enantioselectivities. 3.1.3.3. Opening of Epoxides. 3.1.3.3.1. Racemic Reactions. Hara and co-workers described the fluorination of carbohydrates by opening of epoxides under neat conditions.305 Either TBABF-KHF2 with thermal activation or Et3N·3HF under microwave irradiation can be used. The former required longer reaction times, but similar yields are obtained in both cases. Also in 2006, Matsubara and co-workers reported the ringopening fluorination of epoxides in ionic liquids (Scheme 207).62a They used EMIMF(HF)2.3 (EMIMF = 1-ethyl-3methylimidazolium fluoride) as a mild fluorine source and obtained the desired fluorohydrins in low to good yields. Later, Davies and co-workers reported the formation of synfluorohydrins by the opening of epoxides using BF3·OEt2 (Scheme 208).306 This syn stereoselectivity is consistent with a SN1 type mechanism. The reaction gave the desired fluorinated compounds in good yields within a very short time (5−10 min). In 2011, the same research group described the SN2-type ring-opening fluorination of epoxyamines (Scheme 209).307 The reactions are complete within 5 min and inversion of configuration at the fluorinated carbon is observed. More recently, Nguyen and co-worker performed the rhodium-catalyzed regioselective ring-opening fluorination of vinyl epoxides (Scheme 210).308 First using Et3N·3HF as the fluorinating agent and then transforming the fluorohydrins into fluorinated esters, they obtained the desired compounds in moderate to good isolated yields. The fluorinative ring opening of epoxides can also be applied to the synthesis of fluorinated oligomers as described by Morinaga and co-workers.309 3.1.3.3.2. Opening of Chiral Alkynyl Epoxides. Qing and coworkers reported, in 2011, the regio- and stereoselective opening of a hydroxypropynyl epoxide using Et3N·3HF as the source of fluorine.310 The desired compound was obtained in 54% yield with complete regio- and stereoselectivity which is consistent with a SN2-type epoxide ring-opening process. 3.1.3.3.3. Metal-Catalyzed Asymmetric Openings. Mezzetti and co-workers applied their conditions for the ruthenium-catalyzed fluorination of aldehydes to the asymmetric opening of mesoepoxides.202 They reported low yields and low enantioselectivities for this transformation. In 2010, Doyle and co-worker described the enantioselective ring opening of epoxides using a combination of a Co(II) complex ((R,R)-Co(salen)) and (−)-tetramisole in a cooperative dual-catalyst system (Scheme 211).311 Their system uses PhCOF and HFIP to generate hydrogen fluoride in situ, thus allowing the opening of meso-epoxides in good yields and high ee’s. Kinetic resolution of terminal epoxides was also achieved in excellent selectivities. 3.1.3.4. Ring-Opening Rearrangements. In 2007, the formation of β-monofluoroethylesters through the fluorination of benzamide ethylene acetals was reported by Hara and co-

products in good to excellent yields. This method is also applicable to the synthesis of isoindolines (see Scheme 236). Fujiwara and co-workers described the fluorocyclization of tryptophol derivatives using Selectfluor, N-fluoro-2,4,6-trimethylpyridinium triflate (2,4,6-Me3-NFPy·OTf), or N-fluoro-2,6dichloropyridinium triflate (2,6-Cl2−NFPy·OTf) as the fluorinating agent.299 The desired fluorinated compounds were obtained in moderate yields (33−60%). 3.1.3.1.2.3. Formation of Fluorinated Isoxazolines. Li and coworkers reported, in 2014, the silver-catalyzed synthesis of 5(fluoromethyl)-4,5-dihydroisoxazoles (Scheme 202).300 This oxyfluorination reaction allowed the formation of various substituted isoxazolines in good yields. Scheme 202

3.1.3.1.3. Asymmetric Oxyfluorination of Alkenes. 3.1.3.1.3.1. Organocatalysis: Use of Cinchona Alkaloids. Gouverneur and co-workers described the organocatalyzed enantioselective intramolecular oxyfluorination of indoles (Scheme 203).301 Scheme 203

Using cinchona alkaloid (DHQ)2PHAL as the catalyst and either NFSI or Selectfluor as the fluorinating agent, they obtained the desired cyclic products in good yields and enantioselectivities. However, the use of Selectfluor required a stoichiometric quantity of (DHQ)2PHAL. They also extended the scope of this reaction to the aminofluorination of indoles (see Scheme 242). 3.1.3.1.3.2. Organocatalysis: Use of Phase-Transfer Catalysts. Rauniyar, Lackner and co-workers reported the electrophilic enantioselective oxyfluorination of cyclic enolates (Scheme 204).302 This method uses the sodium salt of (R)-C8-TRIP as the chiral phase-transfer catalyst and generates heterocyclic products with two stereogenic centers in high yields and high enantioselectivities. They also extended the scope of the reaction to benzothiophene derivatives and noncyclic unactivated alkenes. 9111

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Scheme 204

Scheme 205

Scheme 207

Scheme 208

Scheme 209

workers (Scheme 212).312 At high temperatures, the acetal undergoes the elimination of diethylamine followed by the addition of a fluoride ion. This reaction gave moderate to good yields in only 30 min. Later, Lautens and co-workers described the enantioselective rhodium-catalyzed ring-opening fluorination of oxabicyclic alkenes (Scheme 213).313 Their method uses mild conditions and is highly enantioselective, but the scope is limited to benzofused substrates. 3.1.3.5. One-Pot Fluorination/Reduction of Carbonyl Compounds. Sodeoka and co-workers developed a one-pot

enantioselective fluorination of α-ketoesters followed by the reduction of the carbonyl for the synthesis of fluorohydrins (Scheme 214).314 Good yields and high enantioselectivities

Scheme 206

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Scheme 210

Scheme 214

Scheme 211

Scheme 215

3.1.4. Formation of β-Fluoroamines and Derivatives. β-Fluoroamine is a common motif in drug candidates.317 As such, they often constitute key building-blocks. In the past ten years, several methods, including the aminofluorination of alkenes, have been developed for the formation of βfluoroamines.318 Many improvements have been made in their diastereoselective and enantioselective synthesis. 3.1.4.1. Aminofluorination of Alkenes. 3.1.4.1.1. Intermolecular Reactions. 3.1.4.1.1.1. Noncatalyzed Reactions. In 2011, Howell and co-workers performed the aminofluorination of unsaturated oxetane and tetrahydrofuran derivatives by the addition of a nucleobase and using Selectfluor as the source of fluorine (Scheme 217).319 Similar yields were obtained starting from both oxetane and tetrahydrofuran derivatives and a mixture of regio- and stereoisomers was obtained most of the time. Indeed, both α and β isomers were formed and the substitution reaction occurred on both nitrogen atoms of the imidazole ring. The intermolecular aminofluorination of styrenes was performed by Nevado and co-workers (Scheme 218).320 This regioselective addition using difluoroiodonium salts as the fluorinating agent gave access to β-fluoroamines in good yields. 3.1.4.1.1.2. Metal Catalysis. In 2009, Yadav and co-workers described the indium-catalyzed formation of β-fluoroamides (Scheme 219).321 Their reaction used InF3 as the Lewis acid-

Scheme 212

were obtained when using the dimeric palladium complex 71 as the catalyst. O’Reilly and Lindsley described a similar reaction on aldehydes (Scheme 215).315 Using a modified version of the conditions described by MacMillan and co-workers,200 they reported the enantioselective one-pot formation of βfluoroalcohols from aldehydes. The desired fluorinated compounds were obtained in good yields and high enantioselectivities. One year later, Shibatomi and co-workers reported the organocatalyzed asymmetric fluorination/reduction of αchloroaldehydes (Scheme 216).316 This reaction allowed the formation of β-chloro-β-fluoroalcohols in high yields and good to excellent enantioselectivities. Scheme 213

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Scheme 216

One year later, Liu and co-workers reported the palladiumcatalyzed aminofluorination of styrenes using NFSI (Scheme 220).322 Their conditions allowed the regioselective addition of NFSI on styrene derivatives in moderate to good yields. However, the anti:syn ratios obtained were, at best, moderate (up to 4:1). In 2014, Zhang, Zhang and co-workers described the regioselective copper-catalyzed radical aminofluorination of styrenes and enynes in the presence of NFSI (Scheme 221).323 The reaction generally gave better yields when performed on styrene derivatives. Overall, moderate to good yields were obtained.

Scheme 217

Scheme 218

Scheme 221

Scheme 219

3.1.4.1.2. Intramolecular Reactions. In 2009, Liu and coworkers reported the intramolecular palladium-catalyzed aminofluorination of unactivated alkenes using an excess of silver fluoride (5 equiv) as the fluorinating agent (Scheme 222).324 Their conditions allowed the regioselective formation of β-fluorinated piperidines in good yields. A similar reaction was developed by Thibaudeau and coworkers.123b They report the intramolecular aminofluorination of N-dienes in superacid, generating cyclic β-fluoroamines in

catalyst for the regioselective simultaneous addition of a nitrile and a fluorine atom on styrene derivatives. This fast transformation (97% yield for both substrates if 2.1 equiv were used instead.

that there is still an interest to better the scope and regioselectivity of F2 direct fluorinations. 3.2.1.3.7. With Hypervalent Iodine Reagents. Hypervalent iodine complex 166 can be used in combination with BF3· Et2O for the para-fluorination of some 3-phenylpropyl ethers (Scheme 341).451 Isolated yields are moderate and functionalgroup tolerance is limited to alkyl or alkyloxy substituents. Another hypervalent iodine reagent was combined with HF/ pyridine to afford the para-fluorination of anilines with different protecting groups by Li, Meng and co-workers (Scheme 342).452 In the course of the study, it was observed that a pivaloyl (Piv) moiety was the best protecting group, as it allowed the synthesis of simple fluorinated anilides in modest to good yields. Interestingly, when a substituent was positioned at the para position of the amide, no fluorination occurred at any other regioisomeric positions. 3.2.1.4. Fluorination of Boronic Acids, Boronic Esters and Trifluoroborates. 3.2.1.4.1. Through Stoichiometric Transition Metal Complexes. The use of arylboronic acids as substrates for aromatic fluorination started by involving them in the synthesis of stoichiometric arylpalladium(II) complexes that were subsequently fluorinated. Reductive elimination of Ar−F from Ar−Pd(II)−F had been unsuccessfully attempted for some time prior to 2008,453 prompting many scientists to search for alternatives. Ritter and co-worker first established that C−F bond formation through reductive elimination from Pd(IV) fluorides (generated by oxidative fluorination of a Pd(II) complex with Selectfluor) was possible.454 His group went on and designed a system for the two-step transformation of arylboronic acids into aryl fluorides involving a stoichiometric amount of Pd.455 In this process, boronic acids integrate a palladium complex through ligand exchange to form aryl palladium(II) complexes 167, which were isolated in good yields (Scheme 343). These complexes were then fluorinated using Selectfluor to afford the desired fluoro(hetero)arenes in moderate to good yields. Complete mechanistic understanding, which demonstrated the intermediacy of an aryl palladium(IV) fluoride, was later reported by the same group.456 Similarly, Sanford and co-workers published a study where a Pd(II) fluoride complex 169 produced corresponding aryl fluorides when submitted to oxidative fluorinating conditions with XeF2 (Scheme 344).457 This reactivity was shown to occur by reductive elimination from a Pd(IV) intermediate, which was fully characterized. NFSI and 2,4,6-Me3-NFPy·BF4 were

Scheme 338

2-Acylpyrroles can be fluorinated using Selectfluor under microwave heating to afford 5-fluoropyrroles (Scheme 339).443 Selectfluor is also a potent reagent for the fluorination of substituted pyrazoles under microwave conditions (Scheme 340).444 3.2.1.3.6. With F2. Direct fluorination of substituted aromatics or heteroaromatics using F2/N2 was described a while ago by various researchers and usually represents a nonselective method for the synthesis of (hetero)aryl fluorides.445 Recent contributions from the Sandford group for the fluorination of coumarins,446 benzaldehydes,447 and deactivated aromatics in microreactors,448 from the Satyamurthy group for the synthesis of 8-fluoropurine nucleosides,449 and from the Langlois group for the meta-directed fluorination of anilines450 demonstrate 9137

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Scheme 341

Scheme 342

Scheme 344

also suitable fluorinating oxidants, but the desired fluoroarenes were obtained in lower yields. Ritter and co-workers later described an interesting system where a Pd(IV) fluoride (170, synthesized using KF) could serve as the stoichiometric electrophilic fluorinating agent of the same aryl palladium(II) complexes 167 previously reported (Scheme 345).458 The transformation to aryl fluorides occurs rapidly, tolerates multiple functional groups, and allows the synthesis of fluorinated medicinally relevant molecules; however, two equivalents of palladium are necessary. This Pd(IV) fluoride complex 170 was recently shown to serve as a stoichiometric electrophilic fluorination reagent for aryl silver(I) salts (generated from aryl boronic acids), enamines, silyl enol ethers, and indenes.459 Moving away from palladium, Ritter and co-worker disclosed an efficient silver-mediated fluorination of (hetero)arylboronic acids, using Selectfluor (Scheme 346).460 Multiple equivalents of Ag(I) are necessary, and the reaction is thought to proceed through an active arylsilver(II) fluoride, generated by silvermediated oxidation of the Ag(I) complex. Various substituents were tolerated, and the fluoroarenes or heteroarenes were obtained in good to excellent yields.

Scheme 345

Scheme 346

Scheme 343

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Aryl fluorides are also accessible from aryl potassium trifluoroborates using an extremely similar silver-mediated system (Scheme 347).461 Again, an excess amount of silver

Scheme 350

Scheme 347 substituted (hetero)aryl fluorides were thus obtained in moderate yields. 3.2.1.4.2. Palladium-Catalyzed Reactions. Recently, Ritter and co-workers published a truly catalytic system for the fluorination of aryl potassium trifluoroborates, using a Pd(II)/Pd(III) cycle (Scheme 351).465 This reaction is notable on

was required (3 equiv), and various functional groups were tolerated, affording the desired compounds in moderate to good NMR and/or isolated yields. Isolation of the products in pure form was however often impeded by small amounts (2− 5%) of corresponding protodeboronated side-products. Starting from boronate esters, aryl fluorides can be accessed through a Cu-mediated reaction in the presence of the “F+” source 2,4,6-Me3-NFPy·PF6 (Scheme 348).462 Careful opti-

Scheme 351

Scheme 348

mization of the reaction conditions demonstrated that other “F+” sources were not as effective and that the pinacol ester was the best moiety for the transformation. Several equivalents of copper and silver were required. Intensive mechanistic work showed that a cationic Cu(III) species was responsible for the transformation. Moreover, the authors performed a one-pot boronation followed by fluorination, from aryl bromides or unfunctionalized aromatics. Sanford and co-worker described that aryl potassium trifluoroborates react in a similar fashion under the action of stoichiometric amounts of a Cu(I) species in the presence of 2,4,6-Me3-NFPy·OTf (Scheme 349).463 Various electron-rich,

a number of grounds. First, a low catalyst loading (2 mol %) is used, and the species 171 can be replaced by commercial sources of Pd(II) without any negative influence on the yield, except for Pd(II) halides precatalysts which are unsuitable. Moreover, various substitution patterns and functional groups on the boronate reagent are tolerated, generating a wide array of functionalized aryl fluorides in good to excellent yields. Finally, simple boronic acids can be transformed into reactive trifluoroborates in situ, and MIDA boronates react in the same manner, widening the applicability of the system. 3.2.1.4.3. Direct Electrophilic Fluorination. Arylboronic acids can be quickly transformed into aryl fluorides through a direct fluorination procedure with AcOF, which is generated in situ using F2/N2 and NaOAc (Scheme 352).466 This procedure is only applicable to electron-poor boronic acids or boronate esters. Moreover, for some substrates, a mixture of regioisomeric aryl fluorides was obtained. Simple arylboronic acids or trifluoroborates were fluorinated directly under the action of Selectfluor by Lemaire and coworkers (Scheme 353).467 Yields were moderate to good, and for most substrates a varying percentage of protodeboronated product was obtained along with the desired aryl fluoride.

Scheme 349

electron-deficient and ortho-substituted boronates formed the corresponding aryl fluorides in moderate to good NMR and/or isolated yields. Once again, the “F+” source serves as the fluorinating reagent, but also as the oxidant to access the active Cu(III) intermediate. The group of Sanford then simplified their system and described the nucleophilic fluorination of aryl potassium trifluoroborates under copper-mediated conditions (Scheme 350).464 This transformation requires 4 equiv of both Cu(OTf)2 and KF. While the reagent is a simple Cu(II) species, the authors propose that the excess Cu(II) serves as oxidant for the generation of a Cu(III) intermediate. Various

Scheme 352

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(triflates) have been exploited with great success for the synthesis of aryl fluorides. Surprisingly, since other leaving groups require stoichiometric amounts of precious metals or high-valent metal intermediates, all examples of the conversion of aryl triflates rely on Pd(0)/Pd(II) catalytic systems. Buchwald and co-workers were the first to disclose such a catalytic system, using [(cinnamyl)PdCl]2 as the palladium source and t-BuBrettPhos, an electron-rich sterically demanding phosphine, as the ligand of choice (Scheme 356).470 The reaction has a very broad scope, where triflates derived from electron-rich to electron-poor arenes, indoles, and quinolines all reacted in a similar manner to generate aryl or heteroaryl fluorides in moderate to excellent yields. Interestingly, tolyl and anisyl triflates reacted unexpectedly and generated a mixture of regioisomeric aryl fluorides in modest yields. Over the years, mechanistic investigations by the Buchwald group have shed light on the catalyst modification events471 and regioisomer formation472 that were observed in this transformation. The Buchwald group improved their previously developed catalytic system. They reported in 2013 that a stable Pd(0) dimer bearing AdBrettPhos and cyclooctadiene ligands was a better precatalyst for the fluorination of electron-rich aryl triflates and problematic heteroaryl triflates (Scheme 357).473 Under these modified conditions, 12 examples of triflates derived from biologically active phenols were fluorinated in good to excellent yields, while 8 examples of heteroaryl fluorides were synthesized with modest to good results. In all cases, this catalytic system was shown to generate better yields of the desired complex aryl fluorides than the original procedure. Buchwald’s group then demonstrated that this method is amenable to continuous-flow. Indeed, under slightly different conditions, a similar variety of electron-rich to -poor aryl and heteroaryl fluorides were obtained in 60−88% yields.474 Lahred and co-workers described the microwave-assisted one-pot transformation of phenols to aryl fluorides via aryl nonaflates 173 under palladium catalysis (Scheme 358).475 This procedure uses commercially available Pd2(dba)3. The method tolerates a wide variety of electron-rich to electron-poor monoor polysubstituted phenols. However, the rates for the initial formation of 173 varied greatly, from 1 h to several days. 3.2.1.6.2. Through Aryne Intermediates. Arynes generated from 174 using Kobayashi’s method can be trapped by tributyltin fluoride to obtain ortho-fluoro arylstannanes 175 (Scheme 359).476 Due to the very nature of arynes, the selectivity varied depending on the R substituents, with overall yields being modest to good. 3.2.1.7. Electrophilic Fluorination of Aryl Silanes. Ramsden and co-workers first reported the fluorination of arylsilanes, using XeF2 as the oxidative fluorinating reagent (Scheme 360).477 Perfluorobenzene was the only solvent allowing this transformation, and fluoroarenes were formed in good NMR yields, except for substrates bearing strong electron-withdrawing substituents. Later, the group of Ritter published a more complex, but also more efficient, protocol for the fluorination of arylsilane derivatives, inspired by their own system for arylstannane fluorination (see section 3.2.1.8). Their method, using excess amounts of Ag2O with Selectfluor, did not work with trimethylsilyl-substituted compounds but afforded clean fluorination of aryltriethoxysilanes (Scheme 361).478 Multiple functional groups are tolerated, such as acetals, amides, as

Scheme 353

3.2.1.5. Deoxofluorination of Phenols. Ritter’s group described the sought-after deoxofluorination of phenols, using PhenoFluor (Scheme 354).32a The reaction proceeds efficiently Scheme 354

in the presence of cesium fluoride to afford fluorinated aromatics in good to exquisite NMR and/or isolated yields. Most notably, this system tolerates almost any substituent on the phenol or heteroaryl alcohol, from simple halides to various carbonyl groups or tertiary amines. The same year, the formal nucleophilic fluorination of catechols using DAST or Deoxofluor was also described (Scheme 355).468 This sequence involves one-pot oxidation of Scheme 355

the catechols to ortho-quinones, fluorination and subsequent reduction with NaBH4. The main problem with this pathway is the formation of regioisomeric fluorophenols 172a and 172b, which are not easily separated. This sequence was also applied to naturally occurring catechols, with limited success. It has been shown in a later study that a similar reactivity could be applied to the synthesis of fluorinated bridged biphenyls.469 3.2.1.6. Fluorination of Aryl Sulfonates. 3.2.1.6.1. Palladium-Catalyzed Reactions. Aryl trifluoromethanesulfonates 9140

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Scheme 356

Scheme 357

Scheme 358

derivative (Scheme 362). 479 Operationally simple and

well as nonenolizable ketones and esters, generating the desired aryl fluorides in good to excellent NMR yields. 3.2.1.8. Fluorination of Aryl Stannanes by Transition Metals. In 2009, Ritter and co-workers described the Ag(I)mediated fluorination of aryl stannanes with a Selectfluor

extremely fast, this method tolerates various uncommon functional groups (e.g., phenols and amine oxides), and complex pharmaceutically active molecules were fluorinated 9141

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Scheme 349) could also be applied to arylstannanes, provided a slight modification of reaction conditions (Scheme 364).463 The scope of substituents is however quite narrow and the NMR yields were moderate to good.

Scheme 359

Scheme 364 Scheme 360

3.2.1.9. Fluorination of Aryl Halides. Other than the traditional SNAr reactions of aryl chlorides, aryl halides can be used in various other ways for the synthesis of their fluorinated counterparts. Both electrophilic and nucleophilic fluorination methods can be used. 3.2.1.9.1. Through Aryl Lithium Intermediates. Starting from aryl halides, a simple fluorination protocol involves the lithiumhalide exchange with a strong organolithium reagent (n-BuLi, tBuLi, or PhLi), followed by electrophilic fluorination with NFSI. Owing to the very nature of organolithium compounds, this method is incompatible with electrophilic substituents, for example carbonyl, cyano, and nitro groups. A typical procedure from a recent publication is shown in Scheme 365.481

Scheme 361

Scheme 362

Scheme 365. Typical Halogen-Lithium Exchange Procedure for Electrophilic Fluorination

Aryl lithium compounds generated from aryl halides (Br and I) bearing such electrophilic substituents can however be sufficiently stable to be fluorinated in a flow microreactor.482 Using short residence times, which suppress unwanted sidereactions, multiple sensitive substrates were fluorinated by NFSI or N-fluorosultam in moderate to good yields. The conventional procedure depicted in Scheme 365 is especially popular for the synthesis of fluorinated heterocycles (e.g., thiophenes, thiazoles, and benzodithiophenes).483 The intermediate heteroaryl lithium compounds are also accessible through directed lithiation of activated heteroarenes using strong organolithium bases.483b,484 3.2.1.9.2. Through Aryl Magnesium Intermediates. Independently, both the Knochel and Beller groups were the first to develop an efficient electrophilic fluorination of aryl Grignard reagents. The Knochel method started from various (hetero)aryl bromides, which were magnesiated using Mg0 or isopropyl magnesium chloride in THF. The source of fluorine chosen in that study was NFSI, and a careful solvent optimization identified CH2Cl2/perfluorodecalin (4:1) as the best medium for the reaction. The perfluorinated solvent is important since it nullifies the radical pathway that would normally generate sideproducts. Knochel’s method gave access to a variety of substituted aryl and heteroaryl fluorides, as typical functional groups were all tolerated at various positions (Scheme 366).48a Five-membered heterocycles were also accessible using this method.

using this procedure. Overall, the isolated yields of (hetero)aryl fluorides were good. The group of Ritter improved their own method to a catalytic system involving Ag2O, once again using the PF6− derivative of Selectfluor (Scheme 363).480 Simple and complex arylstannanes were fluorinated in good to excellent yields. Notable examples include ezitimibe, taxol, rifamycin S, and strychnine, all of which had their stannyl derivative efficiently fluorinated using this procedure. Sanford and co-workers then established that their Cu(I)mediated system for the fluorination of trifluoroborates (see Scheme 363

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Scheme 366

Scheme 367

Scheme 368

R groups were limited to either alkyl, alkoxy, or fluoro substituents. 3.2.1.9.3. Copper-Catalyzed or -Mediated Reactions. The transition metal-catalyzed fluorination of aryl halides would be highly desirable, especially with abundant metals like copper. The first example of reductive elimination from copper to generate Ar−F bonds was provided by Ribas and co-workers, who demonstrated that a macrocyclic Cu(III) fluoride complex was capable of performing this reaction.488 The complex, generated under stoichiometric or catalytic action of a Cu(I) species from the corresponding aryl chloride or bromide, was fluorinated using AgF (Scheme 369). A similar macrocyclic Cu(III) complex was later reported to be generated from oxidative addition of stoichiometric Cu(I) onto a C−H bond and then fluorinated using AgF.489 Later, Hartwig and co-worker discovered a copper-mediated fluorination of aryl iodides using a Cu(I) species in superstoichiometic quantities (Scheme 370).490 While this method tolerates various electron-donating or -withdrawing substituents, it requires 3 equiv of the copper salt and 2 equiv of AgF as fluoride source. A copper-catalyzed fluorination of 2-pyridyl-2′-bromophenyls 179 was described by Liu and co-workers (Scheme 371).491

The Beller conditions employ a slightly different path. The Grignard reagents are obtained once again through the reaction of aryl bromides with either Mg0 or isopropyl magnesium chloride in THF. Optimisation of the electrophilic fluorine source identified 2,4,6-trimethylpyridinium fluoride tetrafluoroborate (2,4,6-Me3-NFPy·BF4) as the best reagent for the transformation. Solvent screening revealed that both heptane and CH3OC4F9 were equally good and both these solvents were used for evaluating the scope. Various substituted aryl fluorides were obtained in modest to good yields (Scheme 367).485 The Knochel group then demonstrated the applicability of their methodology in a follow-up article.486 They reported five synthetic procedures that are amenable to the 15−20 mmol scale synthesis of aryl and heteroaryl fluorides. The group of Beller later expanded their own method to the synthesis of 2fluorobiaryls (Scheme 368).487 In this transformation, an aryl, naphthyl, or benzothiophenyl bromide was converted to its Grignard equivalent 176 using solid magnesium. Then, a 1,2dihaloarene 177 was reacted with magnesium to generate an aryne, which yielded intermediate Grignard reagent 178 upon reaction with 176. This nucleophile was then fluorinated by 2,4,6-Me3-NFPy·BF4 to obtain a wide variety of 2-fluorobiaryls. 9143

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(see section 3.2.1.6.1). A more active precatalyst was however necessary for the synthesis of nitrogen-containing heteroaryl fluorides (Scheme 372). Catalyst [L2Pd]2(cod), bearing a slight modification on the phosphine ligand, was identified for the task and provided quick access to fluorinated nitrogencontaining heterocycles. Buchwald’s original catalyst system for aryl triflates ([(cinnamyl)PdCl]2, t-BuBrettPhos and CsF, see Scheme 356) was shown to be applicable, with minor modifications, to the fluorination of some substituted bromophenols, bromonitrobenzenes, and bromoquinolines.493 Addition to the reaction mixture of 60 mmol of sodium dodecyl sulfate (SDS) as a surfactant provided the fluorinated aromatics in 65− 78% isolated yields. 3.2.1.10. Fluorination of Diaryliodonium Salts. Fluorination of diaryliodonium salts is already known and is mostly used with symmetrical iodoniums to limit the formation of sideproducts. Typically, iodonium salts bearing hexafluorophosphate or triflate anions are used for this transformation (Scheme 373). Ligand exchange in solution enables the formation of iodonium fluoride salts 180, which undergo thermal decomposition to form aryl fluorides and, concurrently, aryl iodides. Various problems are associated with this method, notably the fact that the ligand exchange step generates some unwanted fluoride-promoted side-reactions.494 Moreover, the tetramethylammonium hexafluorophosphate (or triflate) salt generated in this step reduces the desired reactivity and the solvent used for ligand exchange, acetonitrile, is not the best for the decomposition. As such, DiMagno and co-workers showed that salt removal and solvent-switching to benzene prior to the decomposition of the aryl iodonium fluorides are keys for optimal reactivity, enabling them to isolate increased yields of the desired aryl fluorides.495 Having a symmetrical diaryliodonium is of course problematic for the fluorination of precious aromatic molecules. Sanford and co-workers solved this problem by introducing an asymmetrical iodonium salt 181 that was efficiently fluorinated through copper catalysis with satisfactory selectivity (Scheme 374).496 During the course of their study, the authors demonstrated that copper catalysis was essential; otherwise, nonselective fluorination was observed and both 182 and 183 were isolated. The selectivity in the presence of copper is explained by the fact that the Cu(I) active catalyst undergoes oxidative addition into the least encumbered C−I bond of iodoniums 181, furnishing the desired aryl Cu(III) fluorides after ligand exchange, thus mainly producing 182 as fluorinated products.497 Moderate to excellent isolated and/or NMR yields

Scheme 369

Scheme 370

Scheme 371

The 2-pyridyl moiety is essential to the reactivity as various other directing groups such as esters or amides were unsuccessful to promote the desired catalytic fluorination. The authors explain its importance with two combining effects: (1) by facilitating the oxidative addition and (2) by stabilizing the copper-based complex to slow down its oxidation by AgF (the main problematic side-reaction in the Hartwig process). Overall, various groups are tolerated on the aryl part of the substrate, while electronic or steric variations of the pyridinyl group are not well tolerated. 3.2.1.9.4. Palladium-Catalyzed Reactions. Aryl fluorides can also be accessed from aryl halides through palladium catalysis. The group of Buchwald effected the fluorination of a variety of aryl bromides and iodides with AgF, KF, and Pd(0) precatalyst [L1Pd]2(cod) (Scheme 372).492 Under these conditions, the desired aryl fluorides were obtained in good to excellent yields, independently of their substituents. This catalyst system had previously been identified for the fluorination of aryl triflates

Scheme 372. Palladium-Based Catalyst Variations for the Fluorination of Aryl and Heteroaryl Fluorides

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Scheme 373. Typical Reaction of Aryl Iodonium Salts for the Synthesis of Aryl Fluorides

Fluorinated pyrazoles are also accessible through the aminofluorination of alkynes with hydrazones in the presence of Selectfluor (Scheme 376).501 This tandem process involves

Scheme 374

Scheme 376

were therefore observed, and the 182:183 ratios obtained were always superior to 83:17 (mostly >95:5). 3.2.1.11. Heterocyclization of Alkynes with Fluorination. Metal-catalyzed aminocyclization of alkynes generates interesting heterocycles that can be fluorinated in situ. For example, cyclization of 2-alkynylanilines is possible through gold498 or silver499 catalysis, furnishing 3-fluoroindoles in a one-pot process by Selectfluor, in moderate yields. A different system was reported by Liu and co-worker, where an efficient Ag(I)catalyzed aminofluorination of alkynes with imines and NFSI generated 4-fluoroisoquinolines 184 (Scheme 375a) or 4fluoropyrrolo[α]isoquinolines 185 (Scheme 375b).500 In that case, it is unclear to the authors if NFSI fluorinates a neutral C−H bond of the completed heterocycle or whether a heteroaryl silver species is involved. For both motifs, multiple substituents are tolerated at various positions, with the exception of bulky t-Bu on the alkyne. Complex fluorinated heterocycles were obtained in mostly good yields.

Au(I)-catalyzed cyclization and the authors are unsure whether fluorination occurs on the neutral pyrazoles or on an intermediate pyrazolyl−gold(I) complex. Various simple substituents are tolerated and the isolated yields are good throughout the substitution patterns. A cascade cyclization-fluorination sequence of alkynes with O-methyloximes in the presence of a Au(I) catalyst and Selectfluor can similarly give access to 4-fluoroisoxazoles (Scheme 377).502 The proposed mechanism involves oxidative fluorination of an isoxazolyl Au(I) complex to Au(III), followed by reductive elimination. The fluorinated heteroarenes were

Scheme 375. Fluorocyclization of Alkynes with Imines for the Synthesis of (a) Fluoroisoquinolines and (b) 4Fluoropyrrolo[α]isoquinolines

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Scheme 377

Scheme 378

obtained in good to excellent yields in all cases, except for R1 = 2-furyl. 3.2.1.12. Nucleophilic Fluorination of Arynes Generated by Hexadehydro Diels−Alder Reaction. Following up on the discovery of the hexadehydro Diels−Alder reaction, Lee and co-workers devised a system to effect the formation of complex fluorinated arenes 188 (Scheme 378).503 Functionalized tetraynes 186 are first cyclized under silver catalysis to generate silver arynes 187, which react with a source of fluoride to generate the desired products. Yields for the full process are very good, with AgBF4 as either a stoichiometric or catalytic reagent. Moreover, selectivity for the ortho-fluorination product is almost perfect, except in the case of an extremely bulky R2 group, for instance t-Bu. This method was also applied to the trifluoromethylation and trifluoromethylthiolation of the same arynes 187. 3.2.2. Vinyl Fluorides. Although fluoroalkenes are of high importance in pharmaceutical, medicinal, agrochemical, and material sciences, their preparation still represents a challenge. Many reviews covering the applications of vinyl fluorides and their synthesis both from fluorinated or nonfluorinated precursors were written recently.3c−g,4a,16,504 In the past 10 years, many advances were made in order to control doublebond bond geometry and regioselectivity more efficiently. Nucleophilic and electrophilic fluorination reactions were both shown to be suitable methodologies for the direct synthesis of vinyl fluorides from nonfluorinated starting material. 3.2.2.1. Fluorination of Alkynes. 3.2.2.1.1. Hydrofluorination. In 2007, Sadighi and co-workers devised a gold-catalyzed system for the trans-hydrofluorination of internal alkynes at room temperature, using Et3N·3HF as the fluoride source (Scheme 379).505 Running this transformation on asymmetrical alkynes resulted in a mixture of regioisomeric vinyl fluorides. In the case of alkynes bearing both an aryl and an alkyl group, the preferential formation of β-fluorostyrene derivatives was observed. In 2009, Miller and co-workers improved the regioselectivity of the hydrofluorination process by means of a carbonyl-

Scheme 379

directed gold-catalyzed hydrofluorination of N-propargyl carbamates 189 (Scheme 380).506 2,2,2-Trichloroethoxycarbonyl was shown to be the best directing group, both in terms of regioselectivity and stability to the reaction conditions. Alternatively, esters could also be used, albeit with lesser selectivity. High to excellent regioselectivity could be achieved in all cases, but regioisomers 190 and 191 generally could not be separated. The use of DMPU/HF combined with a gold catalyst was recently shown by Hammond, Xu and co-workers to be a suitable methodology for the hydrofluorination of alkynes (Scheme 381).25 Under their optimized reaction conditions, terminal alkynes were regioselectively converted into branched vinyl fluorides in good to excellent yield. High yields were also obtained when a symmetrically substituted starting material (R1 = R2) was used. In 2015, Nolan and co-workers reported the hydrofluorination of alkynes catalyzed by N-heterocyclic carbene gold bifluoride complexes. The hydrofluorination of symmetrical diarylalkynes proceeded with complete selectivity to afford exclusively the Z isomer in high yields (Scheme 382a).507 The reaction proved tolerant of electron-withdrawing and electron-donating groups either in meta or para position. This transformation could be extended to the hydrofluorination of unsymmetrical substrates upon a slight modification of the 9146

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Scheme 380

Scheme 381

Scheme 383

of electron-poor alkynes (Scheme 384).508 Good to high yields of monofluoroalkenes were obtained in their system with good to excellent selectivity for the (Z)-alkene. Scheme 384

Scheme 382. Gold Bifluoride-Catalyzed Hydrofluorination of (a) Symmetrical and (b) Unsymmetrical Alkynes

3.2.2.1.2. Halofluorination. Tingoli and co-workers used 4iodotoluene difluoride in combination with iodine to promote the E-selective iodofluorination of alkynes (Scheme 385).63 Scheme 385

While the reaction proceeded smoothly on internal alkynes, running it on phenylacetylene resulted in a poor yield of fluoroiodoalkene 193b. In this specific case, 1-iodo-2-phenylacetylene was the main isolated product (65%). For their part, Jiang and co-workers devised a new procedure for the synthesis of trisubstituted bromofluoroalkenes in good to excellent yields from terminal alkynes (Scheme 386).508 In most cases, a strong preference for the formation of (Z)bromofluoroalkenes was observed (Z:E > 95:5). When running this reaction on aromatic alkynes, both electron-donating and

reaction conditions (Scheme 382b). A lower temperature and increased reaction times were mandatory to avoid the formation of a mixture of regioisomers. A similar reaction allowed the preparation of fluorovinyl thioethers from alkynyl sulfides. Jiang and co-workers accomplished the Z-selective AgFmediated direct fluorination of haloalkynes to form bromofluoroalkenes and chlorofluoroalkenes in high yields (Scheme 383).508 Electron-withdrawing and electron-donating groups on the aryl were all well tolerated. In the course of their study on the fluorination of alkynes using AgF, Jiang and co-workers also reported the fluorination

Scheme 386

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electron-withdrawing groups were shown to be well tolerated, the former leading to slightly higher yields. Moreover, substituents at the ortho position did not adversely affect the reaction. However, this transformation could not be extended to the fluorination of trimethylsilylacetylene or internal alkynes. Substrates bearing multiple triple bonds in their structure underwent clean and exclusive bromofluorination of the terminal alkynes (67−92%, 6 examples). In 2005, Ochiai and co-workers reported the regioselective fluoro-λ3-bromanation of terminal aliphatic alkynes (Scheme 387).124a This transformation led preferentially to (E)-β-

Scheme 389

Scheme 387

ambient temperature to give the desired products in moderate to high yields. Later, Fañanás, Rodrı ́guez and co-workers postulated that nucleophilic fluorocyclization of alkynols 201 would occur upon exposure to fluoroboric acid (Scheme 390).511 Indeed,

fluoroalkenyl-λ3-bromanes 194 in modest to high yields. Interestingly, the formation of β-alkoxybromane side-products was avoided by using BF3·i-Pr2O instead of BF3·Et2O. 3.2.2.1.3. Carbofluorination. In 2011, Liu and co-worker devised a new protocol for the palladium-catalyzed tandem fluorination of alkynes and cyclization of enynes, thus giving access to fluorinated lactams and lactones 196 from 195 in modest to good yields with moderate diastereoselectivities (Scheme 388).509 However, this transformation suffers from

Scheme 390

Scheme 388 endocyclic monofluoroalkenes 202 were obtained in high to excellent yields by this method. Under acidic conditions, 201 is converted into a cationic species that undergoes cyclization. Alternatively, under these reaction conditions, a similar cationic intermediate could be formed from enynes, leading to similar cyclic vinyl fluorides. For example, the biomimetic cyclization of geraniol derivative 203 led to fluorinated monoterpenoid 204 in 90% yield (Scheme 391). Scheme 391 the need of a large excess of NFSI to reach completion. The authors explain the formation of 196 via the in situ generation of a Pd(II)-F species that would first add to the alkyne, followed by Heck-type cyclization and reduction of the newly formed C(sp3)−Pd bond with i-PrOH. cis-Fluoropalladation would account for the preferential formation of the E product. In 2013, Yeh and co-workers disclosed the carbofluorination of TBS-protected N-containing cyclic enynols 197 and 199 for the synthesis of azabicycles featuring an exocyclic fluoromethylene moiety (Scheme 389).510 Interestingly, BF3·Et2O acts as both the fluoride source and a Lewis acid in this reaction. The substitution pattern of the alkene had a strong impact on the structure of the product formed. Indeed, compounds 197 were converted into octahydroisoquinolines 198, while azaspirocycles 200 were obtained from 199. The latter transformation could also be adapted to the preparation of fluorinated carbospirocycles. In all cases reported by the authors, the reaction was complete in less than 13 min at

Ji and co-workers prepared tri- and tetrasubstituted monofluoroalkenes 205 via the direct coupling of alkynes, diphenylmethanol derivatives, and HBF4 as the fluoride donor, a transformation run in 1,2-dibromoethane (Scheme 392).512 The reaction afforded low to moderate yields of 205 with the E isomer being the main product. Internal aromatic alkynes were found to be more reactive that terminal alkynes in this system. For their part, Rudenko and co-workers reported the oxidative coupling of symmetrically substituted diarylacetylenes in HF in the presence of PbO2, leading to the formation of fluorinated dienes 206 in poor yields (Scheme 393).513 9148

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Scheme 392

hydrofluorination of alkynyliodonium tetrafluoroborates using aqueous HF (Scheme 396a).516 Although this reaction works

Scheme 393

Scheme 396. (a) HF- and (b) CsF-Mediated Hydrofluorination of Alkynyliodonium Salts

3.2.2.1.4. Alkoxyfluorination. In 2008, in the course of their study on gold-catalyzed alkoxyhalogenation reactions, Gouverneur and co-workers proceeded to the alkoxyfluorination of α,α-difluoro-β-hydroxyynones 207 (Scheme 394).514 However, only low yields of trifluorodihydropyranones 208 were obtained at best, even after prolonged reaction times. Scheme 394 better on aliphatic alkynes than on aryl alkynes, excellent regioand stereoselectivity were observed, with preferential formation of the (Z)-(2-fluoroalkenyl)iodonium tetrafluoroborate (Z:E > 99:1). Alternatively, a similar transformation was disclosed by Emond and co-workers in 2011, but using CsF as the fluoride source (Scheme 396b).517 Changing the counterion of the iodonium salt for a tosylate resulted in much lower yields. The authors also reported the successful one-pot fluorination and subsequent NaBH4-mediated reduction to directly form monofluoroalkenes. Yoshida and co-workers reported the preparation of (Z)-(2fluoroalkenyl)iodonium tetrafluoroborate 212 from potassium (phenylethynyl)trifluoroborate in high yield and with excellent stereoselectivity (Scheme 397).518 The authors showed that a one-pot procedure resulted in the formation of 212 in an improved yield than a two-step procedure with isolation of the intermediate iodonium salt.

3.2.2.1.5. Aminofluorination. In 2013, Liu and co-workers described the silver-catalyzed cascade aminofluorination of alkynes and nucleophilic trifluoromethylation to prepare 1(trifluoromethyl)-4-fluoro-1,2-dihydroisoquinolines 210 from alkynes 209 (Scheme 395).515 A fluorinated isoquinolinium Scheme 395

Scheme 397

intermediate is formed during the first step and is subsequently trapped with the Ruppert−Prakash reagent to afford the desired product in good yields. While this transformation tolerates a fair amount of functional groups, a high amount of silver catalyst (20 mol %) is required. 3.2.2.2. Fluorination of Alkynyliodonium and -Trifluoroborate Salts. Yoshida, Hara and co-worker carried out the

3.2.2.3. Fluorination of Ynamides. In 2012, Evano, Thibaudeau and co-workers described the fast and regioselective hydrofluorination of ynamides 213 in anhydrous HF at low temperature, leading to α-fluoroenamides 214 in moderate to excellent yields, with high stereoselectivity for the E isomer (Scheme 398).519 While an E:Z ratio above 92:8 was observed in most cases, performing this transformation on a conjugated 9149

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Scheme 398

Scheme 400

vinyl fluoride 216 was obtained in 78% yield. Interestingly, performing this reaction in [bmim][BF4] led to the preferential formation of the corresponding β-fluoroalcohol. In 2011, Chang and co-workers prepared vinyl fluorides 218 from 1,1-diarylalkenes 217 in good yields (Scheme 401a).522

enyne resulted in a lesser selectivity of 77:23. Interestingly, in the latter case, no concurrent double-bond hydrofluorination occurred, but the product was nonetheless only isolated in moderate yield (48%). 3.2.2.4. Fluorination of Propargylic Acetates. Gouverneur and co-workers devised in 2010 a gold/silver cocatalyzed system for the synthesis of α-fluoroenones from propargylic acetates (Scheme 399a).520 The authors suggest that this

Scheme 401. Selectfluor-Mediated Fluorination of (a) 1,1Diarylalkenes and (b) 1,1-Diaryldienes

Scheme 399. Synthesis of α-Fluoroenones from Propargylic Acetates As Disclosed by the Groups of (a) Gouverneur and (b) Nevado

This method turned out to be highly limited since changing the methoxy group of 217a for either a hydrogen atom or a fluorine atom led to the formation of the fluorohydrin instead. However, changing the size of the nonaromatic ring had no influence on the outcome of the reaction. Under similar reaction conditions, diene 219 bearing both an endocyclic and an exocyclic alkene reacted cleanly to afford vinyl fluoride 220 exclusively (Scheme 401b). Alkenylmetal reagents prepared by deprotonation of alkenes with strong bases can react with electrophilic sources of fluorine such as NFSI to afford vinyl fluorides. This strategy was recently applied to the fluorination of phosphono-exo-glycals, the Z isomer being always favored. For example, 221 was converted in good yield into vinyl fluoride 222 as the Z product exclusively (Scheme 402).523 Similar products can be obtained via a Selectfluor-mediated hydroxyfluorination-dehydration sequence, but this transformation results in a mixture of diastereoisomers.524 For their part, Charette and co-workers deprotonated 1,2dihydropyridine 223 with n-BuLi. The 6-lithio-1,2-dihydropyridine thus formed was subsequently reacted with NFSI, leading to fluorinated dihydropyridine derivative 224 in moderate yield (Scheme 403).525 3.2.2.5.2. Hydrofluorination-Dehydrohalogenation. In 2012, Zhang, Yu and co-workers carried out the hydrofluorinationdehydrohalogenation of ethyl α-bromocinnamates with TBAF, forming ethyl β-fluorocinnamates in moderate to excellent yields (Scheme 404).526 This reaction only afforded the Z

transformation involves two steps. First, the gold-catalyst would promote a 3,3-sigmatropic shift to form an allenyl acetate intermediate. Direct Selectfluor-mediated electrophilic fluorination would follow, thus affording the desired compound. This cascade rearrangement-fluorination process proceeds in modest to high yields, in favor of the E product. The same year, Nevado and co-workers reported a similar transformation that relied solely on gold catalysis but required higher temperatures (Scheme 399b).521 Good to high yields were achieved, albeit only in moderate diastereoselectivity. The authors suggested a different mechanism for this transformation, involving Selectfluor-mediated oxidation of the vinyl-Au(I) intermediate generated after 1,3-migration of the acyloxy moiety. Reductive elimination from the newly formed Au(III)-species would form the C(sp2)−F bond. 3.2.2.5. Fluorination of Alkenes. 3.2.2.5.1. C(sp2)−H Bond Fluorination. As part of their study on the outcome of electrophilic fluorination reactions with Selectfluor carried out in an ionic liquid instead of a conventional solvent, Stavber and co-workers effected the fluorination of α-phenylstyrene 215 (Scheme 400).287 When the reaction was run in [bmim][PF6], 9150

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Scheme 402

Scheme 403

Scheme 406

Scheme 404

When a similar Selectfluor-mediated ring-opening reaction was performed on methylenecyclopropanes using a nitrile as the solvent, alkenyl fluorides 227 were formed in good to high yields (Scheme 407).528 Here again, smooth conversion into the desired product was shown to be favored in the presence of electron-donating groups. Scheme 407

product, independently of the E:Z ratio of the starting material. The presence of a substituent in ortho position of the benzene ring was not tolerated and no fluorination occurred. In such cases elimination of HBr happened predominantly to give ethyl 3-phenylpropiolate derivatives. 3.2.2.6. Fluorination of Methylene- and Vinylidenecyclopropanes. Shi and co-worker found in 2009 that highly strained methylenecyclopropanes can undergo ring-opening reactions with NFSI to form vinyl fluorides 225 in good to excellent yields (Scheme 405).527 Similar results were reported

3.2.2.7. Fluorination of Allenes. 3.2.2.7.1. Fluorohydroxylation. In 2008, Fu, Ma and co-workers described the highly regioselective fluorohydroxylation of 3-aryl-1,2-allenes with Selectfluor, forming 2-fluoroalken-3-ols in modest to good yields (Scheme 408).529 However, this reaction failed to afford

Scheme 405

Scheme 408

by Ji and co-workers shortly after.528 Depending on the substituents, the products were formed with low to excellent selectivity for the E product. The presence of electron-rich aryl groups led to higher yields and shorter reaction times than electron-deficient aryls. Performing this reaction on dialkylsubstituted methylenecyclopropanes resulted in a complex mixture instead of the desired monofluoroalkene. Under the same reaction conditions, vinylidenecyclopropanes were converted into polyenes (Scheme 406).527 Indeed, fluorinated trienes 226 were formed in good to excellent yields. Electron-poor aryl substituents were shown to have a detrimental effect on the yield. The product was obtained as a mixture of stereoisomers, in favor of the (E)-monofluoroalkene.

any fluorinated product when 1,1-dialkyl allenes were used. For this reason, the authors suggest that this dramatic difference in reactivity is due to stabilization of the cationic allylic intermediate by the aryl groups. The following year, the same authors disclosed the fluorohydroxylation of 3-aryl-1,2-allenyl phosphine oxides with Selectfluor in wet nitromethane (Scheme 409).530 This transformation proceeded with high regio- and stereoselectivity to afford vinyl fluorides 228 in modest to high yields. The preferential formation of the (E)-alkene was explained by neighboring-group participation of the phosphine oxide moiety. Electron-poor aryl substituents at the 3-position led to lower yields of the desired product and required a high excess of Selectfluor. On the other hand, steric hindrance did not affect the reactivity by much. 9151

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Scheme 409

Scheme 412

3.2.2.7.2. Aminofluorination. Liu and co-workers carried out in 2011 the preparation of 4-fluoro-2,5-dihydropyrroles 230 by means of the intramolecular silver-catalyzed oxidative aminofluorination of allenes 229 with NFSI (Scheme 410).531 Low to

3.2.2.10. Fluorination of Allenoic Acids and Allenoates. Fu, Ma and co-workers undertook in 2008 the synthesis of 4fluoro-2(5H)-furanones by the Selectfluor-mediated electrophilic fluorocyclization of 2,3-allenoic acids, a reaction carried out in wet acetonitrile or in water (Scheme 413).534 Moderate to excellent yields of the desired butenolides were achieved by this method. Interestingly, no reaction was observed in the absence of water.

Scheme 410

Scheme 413

high yields of 230 could be achieved, depending on the nature of the substituents. Substrates for which R2 is an aryl or an electron-withdrawing group were the best substrates for this transformation (46−92%), while alkyl-substituted ones led to lower yields (28−35%). This methodology was also adapted to the preparation of fluorinated tetrahydropyridines (two examples). 3.2.2.8. Fluorination of Allenyl Alcohols. Loh and coworkers achieved the preparation of fluorinated 2,6-trans dihydropyrans 233 by Prins cyclization of complex allenyl alcohols 231 with aldehydes 232, using BF3 both as the promoter for the transformation and as the source of fluorine (Scheme 411).532 The 6-membered heterocycles were obtained

For their part, Zhao, Zhu and co-workers used Selectfluor to perform the electrophilic fluorination of 4,5-allenoic acids (Scheme 414).535 In this case, fluorinated γ-lactones were provided in moderate to high yields. However, the reaction proceeded with low diastereoselectivity when R1 was a methyl group. Scheme 414

Scheme 411

Ma and co-workers later reported that electrophilic fluorination of 2,3-allenoates could lead preferentially to two different products, depending on the reaction conditions.536 Indeed, in the presence of 0.5 equiv of water, trisubstituted allenoates 234 were converted into 3-fluoro-4-oxo-2(E)alkenoates 235 in moderate yields with a selectivity superior to 97:3 for the acyclic product (Scheme 415a). On the contrary, trisubstituted allenoates 236 cyclized to 4-fluoro2(5H)-furanones 237 in the presence of excess water, while the conversion of tetrasubstituted substrates into 237 occurred without the addition of water (Scheme 415b). 3.2.2.11. Fluorination of 4,5-Dienoic Sulfonamides. Zhao, Zhu and co-workers accomplished the electrophilic fluorocyclization of 4,5-dienoic sulfonamides 238 using Selectfluor under mild conditions, leading to monofluorinated pyrrolidine derivatives 239 in moderate to good yields (Scheme 416).535 Only poor diastereoselectivity was achieved with R2 = Me. 3.2.2.12. Fluorodesilylation of Allenylsilanes. In 2005, Gouverneur and co-worker engaged allenyltrimethylsilanes into a Selectfluor-mediated electrophilic fluorodesilylation

in moderate to good yields with excellent diastereoselectivities. Performing this reaction with aliphatic aldehydes resulted in higher yields than when benzaldehyde derivatives were used. Interestingly, the size of the ester group had no impact on the outcome of the reaction. However, the presence of a free carboxylic acid was not tolerated. 3.2.2.9. Fluorination of Allenyl ketones. Fan and co-workers reported in 2013 the nucleophilic fluorination of allenyl ketones using TBAF as the fluoride source, thus allowing the preparation of β-fluoroenones in aqueous media (Scheme 412).533 The products were isolated in good yields as a mixture of stereoisomers, with the E-isomer as the main product. Substrates bearing a methyl substituent on the internal (R2 = CH3) or terminal (R3 = CH3) position of the allenyl moiety were found to react more slowly. 9152

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Scheme 415. Preparation of (a) 3-Fluoro-4-oxo-2(E)-alkenoates and (b) 4-Fluoro-2(5H)-furanones from 2,3-Allenoates

Scheme 416

Scheme 418

(Z)-240 led to the formation of 242 in similar yields and diastereoselectivities. The authors failed to adapt this methodology to control the stereochemistry of the homoallylic alcohol. However, the reaction worked well on a substrate featuring two boronates (R1 = B(pin)), leading to an alkenylboronate that can subsequently be functionalized. 3.2.2.14. Fluorination of Alkenyl Boronic Acids. Ritter and co-worker developed in 2009 a set of conditions for the fluorination of arylboronic acids, using an excess amount of silver triflate (see section 3.2.1.4.1). As an extension to this method, they performed the fluorination of alkenyl boronic acids 243 to yield monofluoroalkenes 244 (Scheme 420).460 In this case, complete stereocontrol was observed. 3.2.2.15. Fluorination of Alkenyliodonium Salts. In 2011, Kita and co-workers treated bis(iodonium) salt 245 with CsF to prepare fluorinated spirocycle 246 in 64% yield (Scheme 421).540 3.2.2.16. Fluorination of 1,3-Dicarbonyl Compounds. Hara and co-workers disclosed in 2009 the use of DMFBA as a deoxofluorination agent for the preparation of β-fluoro-α,βunsaturated ketones in good to excellent yields from βdiketones (Scheme 422).541 Depending on the substrates, opposite stereoselectivities were observed. Interestingly, the reaction proceeded regioselectively on unsymmetrical diketones. 3.2.2.17. Fluorination of Unsaturated Oximes. Recently, Xu, Xu and co-workers devised a set of conditions for the palladium-catalyzed, nitrate-promoted, direct fluorination of C(sp2)−H bonds (Scheme 423). Starting from α,β-unsaturated O-methyl oximes 247, alkenyl fluorides 248 were isolated in good yields. This transformation features a quite broad substrate scope but fails on substrates 247 that do not bear a trisubstituted alkene.433

537

reaction (Scheme 417). This new methodology for the preparation of 2-fluoro-1,3-dienes afforded the desired products Scheme 417

in low to excellent yields but poor stereoselectivity. The success of the reaction strongly depended on the nature of the substituents of the allenyl moiety. Nonetheless, this represents the first preparation of 2-fluoro-1,3-dienes not relying on the use of fluorinated building blocks. 3.2.2.13. Fluorodesilylation of Alkenyl- and Allylsilanes. Fluorodesilylation of alkenylsilanes upon exposure to an electrophilic source of fluorine is a practical method for the formation of monofluoroalkenes. Ranjbar-Karimi reported in 2010 that irradiation with ultrasounds allows milder reaction conditions and much shorter reaction times (Scheme 418).538 Good yields were obtained from di- and trisubstituted alkenylsilanes, but the product was always formed as a mixture of stereoisomers. In 2013, Carboni and co-workers described the tandem fluorodesilylation and allylboration of 1-silyl-3-boryl-2-alkenes 240 with aldehydes 241, giving access to monofluoroalkenes 242 in modest to good yields with high selectivity for the Z isomer (Scheme 419).539 Starting from either pure (E)-240 or 9153

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Scheme 419

424).542 In this system, only NFSI provided the desired monofluoroalkenes. The products thus formed were generally

Scheme 420

Scheme 424

Scheme 421

obtained as a mixture of stereoisomers in modest to good yields. Hydrazones derived from aromatic ketones turned out to be the best substrates for this transformation. Alternatively, the authors succeeded in performing this reaction as one-pot sequence by preparing the hydrazone in situ from the corresponding ketone. 3.2.3. Allenyl Fluorides. No methods for the direct synthesis of allenyl fluorides from nonfluorinated precursors have been reported since 1990, when Just and co-workers noticed the formation of an allenyl fluoride from a bis acetylenic mesylate upon exposure to TBAF.543 Over the past 10 years, the preparation of monofluoroallenes was mainly effected by transformation of propargylic fluorides.544 3.2.4. Acyl Fluorides. 3.2.4.1. Deoxofluorination of Carboxylic Acids and Esters. Among the many deoxofluorinating reagents existing for the fluorination of carboxylic acids, cyanuric fluoride is the most commonly used.545,546 In addition, many of the reagents used for the deoxofluorination of alcohols may also be employed (see section 3.1.1.1). In 2006, Rozen and co-workers reported the synthesis of acyl fluorides in moderate yields, starting from carboxylic acids, acyl chlorides, and t-butyl esters using BrF3 (Scheme 425).547

Scheme 422

Scheme 425

Scheme 423

In 2010, a one-pot procedure involving the in situ preparation of acyl chlorides from carboxylic acids was described by Jang and co-workers (Scheme 426).548 A large variety of carboxylic acids were fluorinated, generating acyl fluorides in good yields. Acid-sensitive substrates were also tolerated and the acyl fluorides were obtained without deprotection or rearrangement.

3.2.2.18. Fluorination of Hydrazones. Altman and coworkers described in 2013 the synthesis of monofluoroalkenes from sulfonyl hydrazones via the Shapiro reaction (Scheme 9154

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Scheme 426

Scheme 429

It is worth noting that aldehydes can also be transformed into acyl fluorides using UF6549 or by photocatalysis94 (see section 3.1.1.5.5). 3.2.4.4. Fluorocarbonylation. The fluorocarbonylation of aryl halides is an original route for the formation of acyl fluorides developed by Manabe and co-workers (Scheme 430).552 Easily accessible N-formylsaccharin was employed as

In 2014, Langlois, Billard and co-workers developed the deoxofluorination of carboxylic acids using UF6 (Scheme 427).549

Scheme 430 Scheme 427

3.2.4.2. Fluorination of Acyl Halides. Some of the methods described in the section 3.1.1.3 are also applicable to acyl halides. For example the use of anhydrous TBAF,21 aqueous fluoride solutions, and Sandford’s reagent74 as well as fluoridetransfer reaction71 or methods using continuous-flow microreactors50a are all viable strategies. This transformation can also be achieved using bromine trifluoride, as described by Rozen and co-workers (see Scheme 425).547 In 2008, Růzǐ čka and co-workers used C,N-chelated di-nbutyltin(IV) fluoride 249 for the synthesis of acyl fluorides, fluoroformates, and fluorophosgene (Scheme 428).550 NMR

an efficient organic CO source. This palladium-catalyzed reaction showed a good tolerance to various functional groups and the acyl fluorides were obtained in modest to high yields. 3.2.5. Imidoyl Fluorides. No new methods for the preparation of imidoyl fluorides have been published recently. As such, they are still generally prepared by the reaction of secondary amides with DAST553 or by the nucleophilic fluorination of imidoyl bromides or chlorides.554 3.2.6. Thio-, Seleno-, and Telluroacyl Fluorides. In the past 10 years, the only preparation of a thioacyl fluoride via a new method was done by Rozen and co-workers, when they observed it as an undesired product during the fluorination of dithiocarbamates with BrF3.555 Prior to that, a few thioacyl fluorides have been synthesized from fluorinated precursors.556 Similarly, no new methods for the preparation of seleno- and telluroaycl fluorides have been reported.

Scheme 428

3.3. Creation of a C(sp)−F Bond

Fluoroalkynes have been described a few times in the last century, but they were always synthesized by elimination reaction of fluorinated alkenes or saturated compounds.557 Most fluoroacetylenes, bearing either a hydrogen, silane, alkyl or phenyl group, are known to be unstable in their pure form (but to some extent stable in solution) at room temperature. Indeed, they can trimerize quickly to form fluorinated Dewar benzenes, which decompose to fluorinated benzenes upon heating. 557e,558 They can also engage in cycloaddition reactions.557e,559 When simply solubilized in THF at −78 °C, they react in a radical pathway, forming fluoroalkenes.560 Finally, they can react as electrophiles with organolithium compounds to generate internal alkynes.557d,e The only report

analysis revealed full conversion for a majority of the substrates. The use of compound 249 is advantageous because of its high stability and good solubility in all organic solvents. 3.2.4.3. Fluorination of Aldehydes. The oxidation of primary aliphatic aldehydes with difluoro(aryl)-λ3-bromane was reported by Ochiai and co-workers in 2011 (Scheme 429).551 They obtained moderate to good isolated yields (up to 73%). This method was applicable to many primary aliphatic aldehydes. However, the use of aromatic aldehydes produced difluoromethyl ethers via a 1,2-aryl shift. 9155

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prior to 2005 of an isolable fluoroalkyne was a conjugated fluoroenyne.561 Lately, however, Nie, Ma and co-workers reported the facile formation of substituted fluoroalkynes and diynes 250 through a deprotonation-fluorination sequence of terminal alkynes (Scheme 431).562 Interestingly, chromatographic purification of the sensitive fluoroalkynes allowed their isolation in good to excellent yields.

Author Contributions

Scheme 431

Notes

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Author Contributions ‡

These authors contributed equally.

The authors declare no competing financial interest. Biographies

4. SUMMARY AND OUTLOOK Fluorinated organic compounds being almost inexistent in Nature yet important for multiple applications in medicinal, agrochemical, materials science, and other spheres of chemistry, methods for their synthesis are essential. While monofluorinated molecules of interest can be accessed through fluoride elimination from polyfluorinated compounds, elaboration of fluorinated building blocks or through coupling with monofluorinated partners (all of which have to be synthesized first), a more general strategy remains the direct formation of a C−F bond. This method, which was thoroughly exemplified in the current review, is particularly powerful since a wide array of functional groups can be modified to access fluorinated motifs of a specific variety. This versatility enables the introduction of the fluorine atom at any step of the synthesis of a complex molecule. The last ten years have been fertile in the field of C−F bond formation. Major advances have been made throughout the field, particularly in the development of stereoselective methodologies and for aryl fluoride synthesis, both areas for which there was almost no examples prior to 2005. From all the methods presented herein, some conclusions can be drawn. First, some moieties remain unfortunately underepresented or would benefit from improvements to their traditional methods. Second, while some methods are exquisitely generalizable, most have important limitations that could be addressed. Third, transition-metal-catalyzed fluorinations, which have been successfully applied to aryl fluorides and to fluorination α to an electron-withdrawing group, have not reached their full potential for C(sp3)−F formation. Finally, stereoselective fluorination reactions are still an important challenge that has not been solved throughout the full range of desirable fluorinated compounds. We hope our contribution will inspire scientists to gather and work together to develop more general, predictable, atom-economical, and safe fluorination procedures that could be applied across all fields of chemistry.

Pier Alexandre Champagne was born in 1989 and raised in the Quebec City area in Quebec, Canada. In 2010, he received a B.Sc. degree in Chemistry from the Université Laval, where he then pursued graduate studies under the supervision of Prof. Jean-François Paquin. As fourthyear Ph.D. student, he is currently completing his thesis about novel C−F activation strategies. His research interests also include the elucidation and quantitative analysis of reaction mechanisms.

Justine Desroches was born in 1991 in Ollioules, France. In 2013, she obtained her Master’s degree in organic synthesis from the Université Claude Bernard in Lyon, France. She then joined the group of Prof. Jean-François Paquin at Université Laval in Québec, Canada, where

AUTHOR INFORMATION

she is currently working as a Ph.D. student. Her research project

Corresponding Author

focuses on the development of novel synthetic methodologies with a

*E-mail: [email protected].

special interest in organofluorine chemistry. 9156

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appointed assistant professor in 2005 at the Université Laval in Quebec City (Canada) as a Tier 2 Canada Research Chair in Organic and Medicinal Chemistry (2005−2010). In 2010, he was promoted to associate professor and his Canada Research Chair in Organic and Medicinal Chemistry was renewed (2010−2015). In June 2014, he was promoted to full professor. His current research interests include the development of novel methodologies for the synthesis of organofluorine compounds and their applications for the preparation of bioactive fluorinated compounds or fluorinated biological probes.

ACKNOWLEDGMENTS We thank the Canada Research Chair Program, the Natural Sciences and Engineering Research Council of Canada, the Fonds de recherché du Québec - Nature et technologies (FRQNT), and the Université Laval.

Jean-Denys Hamel was born in 1990 in Quebec City, Canada. He studied chemistry at the Université Laval where he was awarded a B.Sc. in 2013. Soon after, he undertook graduate studies under the supervision of Prof. Jean-François Paquin at the Université Laval, where he is currently working as a Ph.D. student. His research interests are centered on the elaboration of new transition-metal-catalyzed methodologies with a marked interest for organofluorine compounds.

ABBREVIATIONS Ac acetyl acac acetylacetonato Ad 1-adamantyl BCP bathocuproine bipy 2,2′-bipyridine Bn benzyl Boc tert-butyloxycarbonyl Bs 4-bromobenzenesulfonyl Bz benzoyl CAN cerium(IV) ammonium nitrate Cbz carboxybenzyl cod cycloocta-1,5-diene Cp* pentamethylcyclopentadienyl CPME cyclopentylmethyl ether Cs 4-chlorobenzenesulfonyl Cy cyclohexyl DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBN 1,5-diazabicyclo[4.3.0]non-5-ene DBU 1,8-diazabicycloundec-7-ene DCE 1,2-dichloroethane DMA N,N-dimethylacetamide DMAP N,N-dimethyl-4-aminopyridine DMF N,N-dimethylformamide EDG electron-donating group EWG electron-withdrawing group Fmoc fluorenylmethyloxycarbonyl HFIP 1,1,1,3,3,3-hexafluoroisopropanol HMPA hexamethylphosphoramide IBX 2-iodoxybenzoic acid LDA lithium diisopropylamide LG leaving group LiHMDS lithium bis(trimethylsilyl)amide mCPBA 3-chloroperbenzoic acid Mes 1,3,5-trimethylphenyl MIDA N-methyliminodiacetate Ms methanesulfonyl MS molecular sieves MTBE methyl tert-butyl ether μW microwave irradiation NaHMDS sodium bis(trimethylsilyl)amide NBS N-bromosuccinimide NCS N-chlorosuccinimide NFS N-fluorosuccinimide NIS N-iodosuccinimide

Mathilde Vandamme was born in 1990 in Namur, Belgium. She received a Bachelor’s degree in chemistry from the Université de Namur in 2011 and then followed up with a Master’s degree which was awarded in 2013. In 2014, she joined the group of Prof. JeanFrançois Paquin where she is currently working as a Ph.D. student. Her research interests focus on the development of new synthetic tools for the preparation of fluorinated compounds.

Jean-François Paquin studied chemistry at the Université Laval where he graduated with a B.Sc. degree in 1999. In 2004, he received his Ph.D. degree under the supervision of Professor Mark Lautens at the University of Toronto (Canada). After a postdoctoral stay in Professor Erick M. Carreira’s lab at the ETH Zürich (Switzerland), he was 9157

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Chemical Reviews NMO NMP Ns PEG Phth pin Piv PTFE Py SET TBABF TBABr TBAT TBDPS TBS Tf TFA THF TMAF TMEDA TMS Tol tpy Troc Ts

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F-Labelled and 10B-Enriched p-Boronophenylalanine-Fructose Complex to Optimize Boron Neutron Capture Therapy: Phantom Studies at High Magnetic Fields. Phys. Med. Biol. 2006, 51, 3141−3154. (b) Tirotta, I.; Dichiarante, V.; Pigliacelli, C.; Cavallo, G.; Terraneo, G.; Baldelli Bombelli, F.; Metrangolo, P.; Resnati, G. 19F Magnetic Resonance Imaging (MRI): From Design of Materials to Clinical Applications. Chem. Rev. 2015, 115, 106−1129. (8) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Molecular Imaging with PET. Chem. Rev. 2008, 108, 1501−1516. (9) Chan, K. K. J.; O’Hagan, D. The Rare Fluorinated Natural Products and Biotechnological Prospects for Fluorine Enzymology. Methods Enzymol. 2012, 516, 219−235. (10) For a review on enzymatic fluorination, see: O’Hagan, D.; Deng, H. Enzymatic Fluorination and Biotechnological Developments of the Fluorinase. Chem. Rev. 2015, 115, 634−649. (11) For general reviews on the synthesis of organofluorine compounds, see: (a) Shimizu, M.; Hiyama, T. Modern Synthetic Methods for Fluorine-Substituted Target Molecules. Angew. Chem., Int. Ed. 2005, 44, 214−231. (b) Prakash, G. K. S.; Wang, F.; O’Hagan, D.; Hu, J.; Ding, K.; Dai, L.-X. Flourishing Frontiers in Organofluorine Chemistry. In Organic Chemistry - Breakthroughs and Perspectives; Ding, K., Dai, L.-X., Eds.; Wiley-VCH: Weinheim, Germany, 2012. (c) Liang, T.; Neumann, C.; Ritter, T. Introduction of Fluorine and FluorineContaining Functional Groups. Angew. Chem., Int. Ed. 2013, 52, 8214−8264. (12) (a) Wilkinson, J. A. Recent Advances in the Selective Formation of the Carbone-Fluorine Bond. Chem. Rev. 1992, 92, 505−519. (b) Percy, J. M., Ed.; Science of Synthesis; Thieme: Stuttgart, 2005; Vol. 34, pp 345−378. (c) Furuya, T.; Kuttruff, C. A.; Ritter, T. CarbonFluorine Bond Formation. Curr. Opin. Drug Discovery Dev. 2008, 11, 803−819. (13) For selected examples, see (a) Ma, J.-A.; Cahard, D. Update 1 of: Asymmetric Fluorination, Trifluoromethylation, and Perfluoroalkylation Reactions. Chem. Rev. 2008, 108, PR1−PR43. (b) Lectard, S.; Hamashima, Y.; Sodeoka, M. Recent Advances in Catalytic Enantioselective Fluorination Reactions. Adv. Synth. Catal. 2010, 352, 2708−2732. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Catalysis for Fluorination and Trifluoromethylation. Nature 2011, 473, 470−477. (d) Valero, G.; Companyó, X.; Rios, R. Enantioselective Organocatalytic Synthesis of Fluorinated Molecules. Chem.Eur. J. 2011, 17, 2018−2037. (e) Bizet, V.; Besset, T.; Ma, J.-A.; Cahard, D. Recent Progress in Asymmetric Fluorination and Trifluoromethylation Reactions. Curr. Top. Med. Chem. 2014, 14, 901−940. (f) Ma, J.-A.; Li, S. Catalytic Fluorination of Unactivated C(sp3)−H Bonds. Org. Chem. Front. 2014, 1, 712−715. (g) Campbell, M. G.; Ritter, T. Modern Carbon-Fluorine Bond Forming Reactions for Aryl Fluoride Synthesis. Chem. Rev. 2015, 115, 612−633. (h) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in Catalytic Enantioselective Fluorination, Mono-, Di-, and Trifluoromethylation, and Trifluoromethylthiolation Reactions. Chem. Rev. 2015, 115, 826−870. (14) (a) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Synthesis of 11 C, 18F, 15O and 13N Radiolabels for Positron Emission Tomography. Angew. Chem., Int. Ed. 2008, 47, 8998−9033. (b) Brooks, A. F.; Topczewski, J. J.; Ichiishi, N.; Sandford, M. S.; Scott, P. J. H. LateStage [18F]Fluorination: New Solutions to Old Problems. Chem. Sci. 2014, 5, 4545−4553. (15) (a) Conte, L.; Gambaretto, G. P. Electrochemical Fluorination: State of the Art and Future Tendences. J. Fluorine Chem. 2004, 125, 139−144. (b) Dawood, K. M. Electrolytic Fluorination of Organic Compounds. Tetrahedron 2004, 60, 1435−1451. (c) Fuchigami, T.; Tajima, T. Highly Selective Electrochemical Fluorination of Organic Compounds in Ionic Liquids. J. Fluorine Chem. 2005, 126, 181−187. (d) Ignat’ev, N. V.; Willner, H.; Sartori, P. Electrochemical Fluorination (Simons Process) − A Powerful Tool for the Preparation of New Conducting Salts, Ionic Liquids and Strong Brønsted Acids. J. Fluorine Chem. 2009, 130, 1183−1191. (e) Fuchigami, T.; Inagi, S. Selective Electrochemical Fluorination of Organic Molecules and Macromolecules in Ionic Liquids. Chem. Commun. 2011, 47, 10211− 10223.

N-methylmorpholine-N-oxide N-methyl-2-pyrrolidone 4-nitrobenzenesulfonyl polyethylene glycol phthalate pinacolato pivaloyl polytetrafluoroethylene pyridine single electron transfer tetrabutylammonium bifluoride tetrabutylammonium bromide tetrabutylammonium difluorotriphenylsilicate tert-butyldiphenylsilyl tert-butyldimethylsilyl trifluoromethanesulfonyl trifluoroacetic acid tetrahydrofuran tetramethylammonium fluoride N,N,N′,N′-tetramethylethane-1,2-diamine trimethylsilyl p-tolyl 2,2′:6′,2″-terpyridine 2,2,2-trichlorethoxycarbonyl 4-toluenesulfonyl

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