A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

Abstract

Open AccessCCS ChemistryMINI REVIEW5 Aug 2022A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions Feng-Ling Qing, Xin-Yuan Liu, Jun-An Ma, Qilong Shen, Qiuling Song and Pingping Tang Feng-Ling Qing *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 Google Scholar More articles by this author , Xin-Yuan Liu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Shenzhen Grubbs Institute, Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Jun-An Ma *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Tianjin University, Tianjin 300072 Google Scholar More articles by this author , Qilong Shen *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 Google Scholar More articles by this author , Qiuling Song *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Institute of Next Generation Matter Transformation, College of Chemical Engineering, Huaqiao University, Fujian 361021 Google Scholar More articles by this author and Pingping Tang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory, Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202201935 SectionsAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The development of synthetic methods for the introduction of the fluorine atom and fluoroalklyl groups into organic molecules has gained increased attention. Synthetic organic chemists have recently jumped into the field of organofluorine chemistry and have thus made significant contributions. Furthermore, these newly developed methods are typically safer and more effective than the traditional methods. In this review, we will summarize the representative contributions of new reagents and reactions developed in the past decade. Download figure Download PowerPoint Introduction The fluorine atom is very small, and fluorine is the most electronegative element in the periodic table. Consequently, with a short bond length and high bond dissociation energy, the C–F bond is one of the strongest covalent single bonds.1 The incorporation of a fluorine atom into a compound has a significant electronic consequence and can greatly change the physicochemical properties, such as metabolic stability, lipophilicity, and permeability. Owing to this unique property, fluorinated compounds have found widespread application in the preparation of pharmaceuticals, agrochemicals, and materials. It has been estimated that approximately 20% of pharmaceuticals and 50% of agrochemicals contain one or more fluorine atoms.2 In addition, 18F-labeled molecules are frequently used as imaging probes in positron emission tomography for diagnosis,3 an important tool to track many diseases at an early stage of development. Although fluorine is abundant on Earth, it exists mainly in the form of inorganic calcium fluoride (CaF2), known as fluorite or fluorspar. Due to the inert reactivity of CaF2, Nature has hardly evolved a biosynthesis of fluorinated compounds. Therefore, natural products containing at least one fluorine atom are virtually nonexistent, albeit with occasional occurrence.4 And almost all organofluorine compounds used in academia and industry have been synthesized by chemists, thanks to the successful reaction of CaF2 with a strong acid, which provides hydrofluoric acid (HF) as a viable fluorine source. Accordingly, many fluorination reagents have been developed, ranging from those corrosive reagents that were developed in early times to the recently developed bench-stable reagents. At the same time, synthetic methods based on nucleophilic, electrophilic, or radical strategies for selective fluorination and fluoroalkylation on many functionalities have also been disclosed. In particular, the advance of transition metal catalysis, photoredox catalysis, and electrochemical catalysis have driven the burgeoning development of fluorination reagents and reactions in the past decade. This review is organized into two parts: new reagents and new reactions. We will focus on the most recent and representative contributions of reagents and synthetic methods for fluorination, monofluoroalkylation, difluoroalkylation, trifluoromethylation, trifluoromethylthiolation, trifluoromethoxylation, defluorofunctionalization, and so on. We regret that many excellent works were not included because of space limitation. New Fluorinating and Fluoroalkylating Reagents Fluorinating reagents Nucleophilic fluorinating reagents The commonly used nucleophilic fluorinating reagents include metal fluoride salts (KF, CsF, and AgF), HF-based reagents (Et3N•3HF and pyridine•9HF), tetraalkylammonium fluorides, and fluorinated hypervalent silicates. Over the past decade, several types of new nucleophilic fluorinating reagents have been developed (Figure 1). Hammond et al. reported two novel HF-based reagents, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)•(HF)x and KHSO4•(HF)x.5,6 Figure 1 | New nucleophilic fluorinating reagents. Download figure Download PowerPoint Deoxyfluorinating reagents The deoxyfluorination reactions typically proceed through in situ activation of the hydroxyl group followed by nucleophilic substitution with a fluoride. Classic deoxyfluorinating reagents include SF4 and its derivatives (e.g., diethylaminosulphur trifluoride (DAST), Deoxo-Fluor, and XtalFluor). In 2010, Umemoto et al. discovered 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead) as a deoxyfluorinating agent with high thermal stability and unusual resistance to aqueous hydrolysis (Figure 2).7 2-Pyridinesulfonyl fluoride (PyFluor) was developed by Doyle et al. as an inexpensive and thermally stable deoxyfluorinating reagent.8 In 2011, Ritter et al. reported a new deoxyfluorinating reagent PhenoFluor.9 In 2017, Hu et al. reported the use of 3,3-difluoro-1,2-diarylcyclopropenes (CpFluors) as a class of novel deoxyfluorinating reagents with an all-carbon scaffold.10 Figure 2 | New deoxyfluorinating reagents. Download figure Download PowerPoint Electrophilic fluorinating reagents The appearance of commercially available and easy-to-handle electrophilic fluorinating reagents including N-fluorobenzenesulfonimide (NFSI), Selectfluor, N-fluoropyridinium salts (NFPY), and ArIF2 has brought a breakthrough in synthetic fluorine chemistry. Over the past decade, a series of new electrophilic fluorinating reagents have been developed (Figure 3). Shibata et al. and Yang et al. independently reported the synthesis of substituted N-fluorobenzenesulfonimide (NFSI) derivatives ( EF-I).11,12 The chiral analogs of NFSI ( EF-II) based on the C2-symmetric chiral binaphthyl bis(sulfonimide) topology as a privileged motif were initially reported by Cahard et al.13 Gouverneur et al. prepared a new class of chiral electrophilic fluorinating reagents EF-III, based on the dicationic structural core of Selectfluor.14 In 2013, Stuart et al. reported an air- and moisture-stable cyclic hypervalent iodine-based electrophilic fluorinating reagents EF-IV.15 Nevado et al. synthesized chiral iodine(III) reagents EF-V.16 Figure 3 | New electrophilic fluorinating reagents. Download figure Download PowerPoint Trifluoromethylating reagents Electrophilic trifluoromethylating reagents (Trifluoromethyl)dibenzothiophenium salts ( Umemoto reagents) and 1-trifluoromethyl-3,3-dimethyl-1,2-benziodoxole or 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one ( Togni reagents I and II) are widely used as the electrophilic trifluoromethylating reagents. In 2015, Shen et al. reported trifluoromethyl-substituted sulfonium ylide as the electrophilic trifluoromethylating reagents ( ETF-I) (Figure 4).17 In 2017, Umemoto et al. reported powerful, thermally stable, one-pot-preparable and recyclable second-generation Umemoto’s reagents ( Umemoto reagents II).18 In 2021, Ritter et al. described the Umemoto type reagent trifluoromethyl thianthrenium triflate (TT-CF3+OTf−, ETF-III). TT-CF3+OTf− that could serve not only as a competent electrophilic or a radical trifluoromethylating reagent but also as a nucleophilic trifluoromethylating reagent.19 Figure 4 | Electrophilic trifluoromethylating reagents. Download figure Download PowerPoint Nucleophilic trifluoromethylating reagents The most studied nucleophilic trifluoromethylating reagent was TMSCF3 (Figure 5), the so-called Ruppert-Prakash reagent. PhSO2CF3 and PhSOCF3 can also serve as nucleophilic trifluoromethylating reagents in the presence of an alkoxide. Fluoroform (CF3H) can also serve as a nucleophilic trifluoromethylating reagent. In 2011, Grushin et al. reported the reaction of CF3H with CuCl/KOtBu in dimethylformamide (DMF) to give stable CuCF3 after treatment with Et3N•3HF or Py•nHF.20 Figure 5 | Nucleophilic trifluoromethylating reagents. Download figure Download PowerPoint Radical trifluoromethylating reagents Even though electrophilic trifluoromethylating reagents can serve as a trifluoromethyl radical precursor under certain conditions, several types of radical trifluoromethylating reagents have been developed (Figure 6). The gaseous nature of trifluoroiodomethane makes it difficult to be used efficiently. Ritter et al. found that 1∶1 adduct of CF3I and tetramethylguanidine (TMG) forms a stable liquid TMG•CF3I, which acted as a radical trifluoromethyl reagent.21 Derivative of triflic acid or trifluoroacetic acid can also serve as trifluoromethyl radical precursor. One of the most studied radical trifluoromethyl reagents is CF3SO2Na (Langlois’ reagent). Trifluoromethanesulfonyl chloride (CF3SO2Cl) can also be used as a radical trifluoromethyl reagent22 while trifluoromethane anhydride (CF3SO2)2O) has also been reported to be used as trifluoromethyl radical precursor by merging photoredox catalysis and pyridine activation.23 Baran et al. described that (CF3SO2)2Zn was a more efficient radical trifluoromethylating reagent.24 Trifluoroacetic anhydride can serve as a trifluoromethyl radical reagent in the presence of pyridine N-oxide under irradiation of blue light in combination with a photoredox catalyst.25 Figure 6 | Radical trifluoromethylating reagents. Download figure Download PowerPoint Difluoromethylating reagents Among all nucleophilic difluoromethylating reagents, Me3SiCF2H (Figure 7) is currently the most used nucleophilic difluoromethylating source. Difluoromethyl aryl sulfone (ArSO2CF2H) is a good alternative choice. In 2015, Shen et al. reported a thermally stable and well-defined NHC-ligated difluoromethylated silver complex [(SIPr)Ag(CF2H)] which could be used in transition metal-mediated or -catalyzed difluoromethylating reactions.26 An isolable and user-friendly zinc difluoromethyl reagent (DMPU)2Zn(CF2H)2 was developed by Xu and Vicic.27 In 2012, Baran et al. reported the invention of a novel radical reagent Zn(SO2CF2H)2 that was an air-stable and free-flowing white powder.28 Qing et al. disclosed that (difluoromethyl)triphenylphosphonium bromide ([Ph3PCF2H]+Br–) might be the most readily available and easily handled radical difluoromethylating reagent under visible-light photoredox conditions.29 Hu et al. found that 2-[(difluoromethyl)sulfonyl]benzo[d]thiozole ( 2-BTSO2CF2H) was used as the precursor of the difluoromethyl radical by visible-light photoredox catalysis.30 Figure 7 | Difluoromethylating reagents. Download figure Download PowerPoint Monofluoromethylating reagents In 2008, Prakash et al. reported the first shelf-stable yet highly reactive electrophilic monofluoromethylating reagent S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate ( MEF-I) (Figure 8).31 Shen et al. reported the electrophilic monofluoromethylating reagents based on sulfonium ylide skeleton ( MEF-II).32 In addition, two radical monofluoromethylating reagents CH2FSO2Na and (CH2FSO2)2Zn have been reported by Hu et al.33 and Baran et al.24 respectively. Figure 8 | Monofluoromethylating reagents. Download figure Download PowerPoint Trifluoromethylthiolating reagents Electrophilic trifluoromethylthiolating reagents Before 2010, the electrophilic trifluoromethylthiolating reagent N-(trifluoromethythio)phthalimide ( ESF-I, Munavalli reagent) was developed (Figure 9).34 In early 2013, Shibata et al. reported a hypervalent iodonium ylide skeleton-based electrophilic trifluoromethylthiolating reagent ( ESF-II).35 In 2013, Shen et al. also reported a new electrophilic trifluoromethylthiolating reagent ( ESF-III, Lu-Shen reagent).36 Later N-trifluoromethylthiosaccharin ( ESF-IV, Shen reagent)37 showcased unparalleled high electrophilicity. Furthermore, N-trifluoromethylthio bis(phenylsulfonyl)imide ( ESF-V, Shen reagent II) remarkably showed much higher electrophilicity.38 Figure 9 | Electrophilic trifluoromethylthiolating reagents. Download figure Download PowerPoint Nucleophilic trifluoromethylthiolating reagents AgSCF3 and CuSCF3 as well as Me4NSCF3 were widely used as the nucleophilic trifluoormethylthio sources (Figure 10). In 2012, Weng et al. reported the two stable nucleophilic trifluoromethylthiolating reagents (L)CuSCF3 (L = 2,2-bipyridine (bpy) and 1,10-phenanthroline (phen)).39 Likewise, in 2015, Vicic et al. also prepared two stable trifluoromethylthiolated copper(I) complexes (Ph3P)2CuSCF3 and (dppf)CuSCF3 as nucleophilic reagents.40 Figure 10 | Nucleophilic trifluoromethylthiolating reagents. Download figure Download PowerPoint Trifluoromethoxylating reagents Nucleophilic trifluoromethoxylating reagents In 2007, Kolomeitsev et al. discovered that trifluoromethyl trifluoromethanesulfonate ( TFMT, Figure 11) could generate CF3O− anion when treated with hard nucleophilic fluoride. In 2010, Langlois et al. found that 2,4-dinitro(trifluoromethoxy)benzene ( DNTFB) could be used as a new precursor of trifluoromethoxide anion. Jiang and Tang discovered that trifluormethyl sulfonates ( TFMS) could be activated to release CF3O− in the presence of fluoride anions.41 Hu et al. developed a new and practical trifluoromethoxylation reagent trifluoromethyl benzoate ( TFBz).42 In 2019, Tang et al. reported a new nucleophilic trifluoromethoylating reagent (E)-O-trifluoromethyl-benzaldoximes ( TFBO).43 Umemoto et al. discovered that trifluoromethyl nonafluorobutanesulfonate ( TFNf) was a reactive trifluoromethoxylating reagent with a high boiling point.44 Figure 11 | Nucleophilic trifluoromethoxylating reagents. Download figure Download PowerPoint Radical trifluoromethoxylating reagents In 2018, Ngai et al. identified a benzimidazole bearing the N–OCF3 moiety as a novel radical trifluoromethoxylating reagent under irradiation of blue LED ( N-OCF3-I, Figure 12).45 Togni et al. also discovered that trifluoromethoxypyridinium salt ( N-OCF3-II) was also a radical trifluoromethoxylating reagent under the irradiation of blue light.46 Furthermore, Ngai et al. found that N-trifluoromethoxy triazolium salt ( N-OCF3-III) favors the selective generation of a single OCF3 radical species after the single electron transfer (SET) reduction.47 Figure 12 | Radical trifluoromethoxylating reagents. Download figure Download PowerPoint Fluorinated carbene (difluorocarbene) reagents Fluoromethyl diazo and hydrazone reagents Di- and trifluorodiazoethane (XCF2CHN2, X = F, H) is an attractive precursor of XCF2CH: carbene (Figure 13). In 2010, Morandi and Carreira disclosed the in situ generation of 2,2,2-Trifluorodiazoethane (CF3CHN2) in a mixture of water and organic solvents.48 In 2012, Ma et al. developed a flow setup for the continuous gaseous CF3CHN2 generation/transformation sequence.49 Subsequently, Mykhailiuk50 and Ma et al.51 described the preparation of difluoromethyldiazo reagents. Zhang et al. took advantage of trifluoroacetaldehyde toluenesulfonylhydrazone for the insitu formation of CF3CHN2.52 Bi et al. established trifluoroacetaldehyde N-triftoylhydrazones as bench-stable crystalline precursor to CF3CHN2.53 Figure 13 | Fluoroalkyl diazo and hydrazone reagents. Download figure Download PowerPoint Difluorocarbene reagents Difluorocarbene can be generated from many available and stable precursors. The earlier studies in this area focused on the use of environmentally unfriendly or toxic reagents [such as CHXF2, CX2F2 (X = Cl, Br), Me3SnCF3, or PhHgCF3]. To overcome this problem, recent research has paid more attention to new surrogate molecules. Hu et al. has centered on the development of (halodifluoromethyl)trimethylsilanes and difluoromethyltri(n-butyl)ammonium chloride (Figure 14) for the generation of difluorocarbene.54–56 Lin and Xiao demonstrated that the reaction of BrCF2CO2K and Ph3P could smoothly afford the difluorocarbene precursor Ph3P+CF2CO2− ((triphenylphosphonio)difluoroacetate, PDFA).57 Chen et al. found that difluoromethanesulfonyl fluoride (HCF2SO2F) and difluoromethanesulfonic acid (HCF2SO3H) could serve as difluorocarbene precursors. Subsequently, the corresponding fluorosulfonyldifluoroacetic acid (FSO2CF2CO2H) and its derivatives (FSO2CF2CO2Me and FSO2CF2CO2TMS) were directly used as difluorocarbene precursors.58 Figure 14 | Difluorocarbene reagents. Download figure Download PowerPoint New Fluorination and Fluoroalkylation Reactions Electrophilic fluorination and fluoroalkylation reactions Fluorination Aryl fluoride represents one of the most important structural motifs that is frequently found in many drug molecules. Classic methods for the preparation of aryl fluorides typically rely on the Balz-Schiemann reaction of aryl diazonium salts. An alternative and straightforward approach for the preparation of aryl fluorides is direct fluorination of aryl metal species with an electrophilic reagent. In 2010, Knochel et al.59 and Beller et al.60 independently reported reactions of (hetero)aryl magnesium reagents with NFSI or N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (F-TMP-BF4) to give the corresponding (hetero)aryl fluorides in high yields (Scheme 1). Scheme 1 | Aryl fluoride formation from Grignard reagents. Download figure Download PowerPoint In 2013, Hartwig et al. described the first copper-mediated fluorination of arylboronate esters using F-TMP-BF4 as the electrophilic fluorine source (Scheme 2a).61 Shortly afterward, Ye and Sanford reported a similar process using N-fluoro-2,4,6-trimethylpyridinium triflate as the electrophilic fluorine source for direct fluorination of aryl trifluoroborates (Scheme 2b).62 In 2020, Cornella et al. reported a bismuth-catalyzed direct fluorination of aryl boronic acids as well as aryl boronic esters using N-fluoro-2,6-dichloropyridinium tetrafluoroborate as the electrophilic fluorine source (Scheme 2c).63 Scheme 2 | Aryl fluoride formation from aryl boronic acids and derivatives. Download figure Download PowerPoint Aggarwal et al. reported that “ate”-type lithium aryl alkyl boronate complexes reacted efficiently with Selectfluor in the presence of styrene to give stereospecific alkyl fluorides with inversed configuration (Scheme 3).64 It was proposed that the reaction proceeds via a polar SE2inv pathway, and the role of styrene is to act as a radical scavenger to prohibit the SET pathway. Scheme 3 | Preparation of alkyl fluorides. Download figure Download PowerPoint An alternative approach to using an electrophilic fluorinating reagent is transition metal-catalyzed C–H fluorination. The first palladium-catalyzed directed arene ortho C–H bond fluorination was reported by Sanford et al. in 2006 (Scheme 4a).65 In 2015, Shi et al. (Scheme 4b)66 and Yu et al. (Scheme 4c)67 independently reported a Pd-catalyzed substrate-controlled methods for diastereoselective C(sp3)-H fluorination. Scheme 4 | Pd-catalyzed directed C–H fluorination. Download figure Download PowerPoint Trifluoromethylation Trifluoromethylated (hetero)arenes are important structural motifs in drug molecules. Transition metal-catalyzed coupling of a nucleophilic aryl reagent with an electrophilic trifluoromethylating reagent represents a general approach for the preparation of such compounds. In 2011, Shen, Liu and Xiao independently reported three copper-mediated trifluoromethylation of aryl boronic acids with an electrophilic trifluoromethylating reagent (Scheme 5).68 Scheme 5 | Copper-mediated trifluoromethylation of aryl boronic acids. Download figure Download PowerPoint In 2010, Yu et al. reported the first Pd(OAc)2/Cu(OAc)2 catalyzed ortho-C–H trifluoromethylation of arenes using pyridyl, pyrimidinyl, or thiazole as the directing group and (trifluoromethyl)dibenzothiophenium tetrafluoroborate salt as the electrophilic trifluoromethylating reagent (Scheme 6a).69 Not only aromatic C–H bonds but olefinic C–H bonds can be trifluoromethylated by an electrophilic trifluoromethylating reagent. In 2012, Feng and Loh found initially that reactions of N-(1-phenylvinyl)acetamide with Togni’s reagent II in the presence of 10 mol % Cu(MeCN)4PF6 occurred smoothly to give the trans-trifluoromethylated alkenes in good yields (Scheme 6b).70 Scheme 6 | C–H trifluoromethylation. Download figure Download PowerPoint The allylic C–H bond also underwent C–H activation/trifluoromethylation, as the groups of Liu and Wang reported simultaneously in 2011. In Liu et al.’s protocol, terminal alkenes reacted with Umemoto’s reagent to give the trifluoromethylated products in high yields (Scheme 7a).71 Mechanistically, it was proposed that the reaction proceeds via a Heck-like four-membered-ring transition state. Likewise, Wang et al. reported the similar allylic trifluoromethylation with Togni’ reagent in good to excellent yields (Scheme 7b).72 Scheme 7 | Cu-catalyzed allyllic C–H trifluoromethylation. Download figure Download PowerPoint Difluoromethylation The direct introduction of the difluoromethyl group into organic molecules has been realized using the in situ-generated electrophilic difluorocarbene. The highly selective C-difluoromethylation of β-ketoesters was first reported in 2018 by Shen et al.73 using an isolated shelf-stable difluoromethyl-substituted ylide as difluoromethylating source and using Li2CO3 or LiOtBu as the base (Scheme 8). Mechanistic studies showed that the reaction occurred via a difluorocarbene intermediate, and the lithium cation played an important role in alleviation of the nucleophilicity of the oxygen in the enolate. Likewise, in 2019, Liu et al. and Hu et al. reported that using S-(difluoromethyl)-S-phenyl-S-(2,4,6-trialkoxyphenyl) sulfonium salt74 and TMSCF2Br,75 respectively, as the difluorocarbene precursor could also achieve highly C-selective difluoromethylation of various soft carbon nucleophiles (Scheme 8). Scheme 8 | C-selective difluoromethylation of soft carbon nucleophiles. Download figure Download PowerPoint Transition metal catalysis could also mediate the coupling of a nucleophile such as boronic acid with the in situ-generated difluorocarbene. Zhang et al. reported in 2016 that palladium-catalyzed coupling of aryl boronic acids with BrCF2CO2Et, a difluorocarbene precursor, reacted smoothly to give difluoromethylated arenes in good yields (Scheme 9).76 Shortly thereafter, Xiao et al. reported a similar reaction, in which Ph3P+CF2CO2− (PDFA) was used as the difluorocarbene precursor.77 In 2017, Zhang et al. improved such reaction by using HCF2Cl as the difluorocarbene precursor.78 Scheme 9 | Pd-catalyzed difluoromethylation of aryl boronic acids. Download figure Download PowerPoint Monofluoromethylation The monofluoromethyl group is a hard electrophile, and the direct reaction of soft carbon nucleophiles with an electrophilic monofluoromethyl reagent often gives o-monofluoromethylated products. In 2017, Shen et al. discovered that a monofluoromethyl sulfonium ylide was able to react with soft carbon nucleophile malonates to give C-monofluoromethylated products in excellent yields (Scheme 10).32 Likewise, Liu et al. found that S-(monofluoromethyl)-S-phenyl-S-(2,4,6-trimethyoxyphenyl) sulfonium salt is also a highly reactive electrophilic monofluoromethylating reagent which reacts with malonates, tetrahydroquinolinone carboxylate, and pyrrolidinone carboxylate to give C-monofluoromethylated products in excellent yields.79 Scheme 10 | C-selective monofluoromethylation of soft carbon nucleophiles. Download figure Download PowerPoint Trifluoromethylthiolation The first copper-catalyzed coupling of aryl boronic acids with an electrophilic trifluoromethylthiolating reagent was reported by Shen et al. in 2013 (Scheme 11).36 In 2014, Rueping et al.80 and Shen et al.81 simultaneously reported a copper-catalyzed trifluoromethylthiolation of aryl boronic acids with N-trifluoromethylthiophthalimide (Manuvalli’s reagent). In 2015, Billard et al. reported the copper-catalyzed trifluoromethylthiolation of aryl boronic acids with the second-generation Billard’s reagent TsN(Me)SCF3.82 Scheme 11 | Cu-catalyzed trifluoromethylthiolation of aryl boronic acids. Download figure Download PowerPoint The first transition metal-catalyzed directed C–H trifluoromethylthiolation was reported by Daugulis using CF3S-SCF3 as the electrophilic trifluoromethylathiolating reagent (Scheme 12).83 In 2015, Xu and Shen reported a palladium-catalyzed C–H trifluoromethylthiolation with N-trifluoromethylthiosuccimide.84 Similarly, Li and Yoshino/Matsunaga reported [Cp*RhCl2]2 and [Cp*Co(CH3CN)3](SbF6)2 catalyzed directly C–H trifluoromethylthiolation, using Shen’s N-trifluoromethylthiosaccharin and (PhSO2)2NSCF3 as the electrophilic trifluoromethylthiolating source respectively.85 Scheme 12 | Transition metal-catalyzed C–H trifluoromethylthiolation. Download figure Download PowerPoint Nucleophilic fluorination and fluoroalkylation reactions Fluorination Daugulis et al. reported the first Cu-catalyzed directed C–H fluorination of arenes with AgF in combination with the terminal oxidant N-methylmorpholine N-oxide (Scheme 13a).86 This C–H fluorination was proposed to possibly proceed through C–F reductive elimination from a high-oxidation-state CuIII fluoride complex. Direct sp3 C–H fluorination is an efficient synthesis method for introducing fluorine atoms into alkanes. In 2012, Groves et al. reported manganese-catalyzed oxidative C–H bond fluorination using AgF (Scheme 13b).87 This was the first catalytic method for selective and direct incorporation of fluoride ion into the unreactive sp3 C–H bond. Scheme 13 | C–H fluorination. Download figure Download PowerPoint Deoxyfluorination of alcohols has found widespread applications due to the abundance and accessibility of alcohol-containing precursors. However, the traditional use of DAST for deoxyfluorination is limited by the functional group tolerance and formation of the elimination side products. In 2015, Doyle et al. reported a low-cost and highly thermal stable deoxyfluorination reagent PyFluor for deoxyfluorination of alcohols (Scheme 14a).8 Phenols are also an ideal starting material for fluorination reactions. In 2011, Ritter et al. developed a new deoxyfluorination reagent PhenoFluor for ipso-fluorination of phenols to deliver aryl fluorides in one-step (Scheme 14b).9 Scheme 14 | Deoxyfluorination of hydroxy group. Download figure Download PowerPoint Aryl boron reagents are particularly attractive starting materials for C–F bond-forming reactions. In 2013, Sanford et a