Reagents for Selective Fluoromethylation: A Challenge in Organofluorine Chemistry

Abstract The introduction of a monofluoromethyl moiety has undoubtedly become a very important area of research in recent years. Owing to the beneficial properties of organofluorine compounds, such as their metabolic stability, the incorporation of the CH2F group as a bioisosteric substitute for various functional groups is an attractive strategy for the discovery of new pharmaceuticals. Furthermore, the monofluoromethyl unit is also widely used in agrochemistry, in pharmaceutical chemistry, and in fine chemicals. The problems associated with climate change and the growing need for environmentally friendly industrial processes mean that alternatives to the frequently used CFC and HFBC fluoromethylating agents (CH2FCl and CH2FBr) are urgently needed and also required by the Montreal Protocol. This has recently prompted many researchers to develop alternative fluoromethylation agents. This Minireview summarizes both the classical and new generation of fluoromethylating agents. Reagents that act via electrophilic, nucleophilic, and radical pathways are discussed, in addition to their precursors.


Introduction 1.General Overview
Fluorine occurs abundantly in nature as fluorspar and fluoroapatite. [1]Despite these widespread natural resources, only one enzyme exists that has been confirmed to be able to perform fluorination:f luorinase.H owever,c urrent research suggests that there might be at least one more enzyme capable of fluorination. [2]Perhaps surprisingly,a mong an estimated number of 130 000 natural products,t here are only five naturally occurring organofluorine compounds present in plants,bacteria, or animals (Figure 1). [1,2] uoroacetate is the most common of the naturally occurring organofluorine compounds and occurs in about 40, mostly poisonous plants in the southern and tropical regions of Africa, Australia, and Brazil. [2,3] onsidering that organofluorine compounds are almost absent in nature,i ti s remarkable that 20 %o fa ll pharmaceuticals and 30-40 %o f all agrochemicals contain fluorine. [4]Ther eason for this is simple and can be clearly illustrated by considering the toxicity of Dichapetalum cymosum.3b] Their metabolic stability and other unique physical, chemical, and biological properties of organofluorine compounds make them particularly interesting for the pharmaceutical and agricultural industries. [5]hese features make the monofluoromethyl group highly versatile as abioisosteric unit for as eries of functional groups found in biological systems (Figure 2). [6]his bioisosterism, combined with the enhanced metabolic stability,b ioavailability,l ipophilicity,a nd membrane permeability imparted by the fluorine substituent, allows for efficient drug design. [7]As aresult, avariety of monofluoromethylated drugs and inhibitors have been developed (Figure 3).6a, 9] Compound 9,i sa ni nhibitor for the tumor suppressor protein menin.The b-fluorinated amino acid 10 acts as socalled "suicide substrate", which can deactivate decarboxylase enzymes and can be used against Parkinsonsd isease.6a, 9] Thec ompounds CH 2 FBr (HFBKW-31) and CH 2 FCl (HFCKW-31) are frequently used on alarge scale in industry for synthesis [10] even though these compounds have high ozone-depleting potentials. [11]As these substances are going to be subject to successive banning under the Montreal Protocol, and the handling of these chemicals will have to The introduction of amonofluoromethyl moiety has undoubtedly become avery important area of researchinrecent years.Owing to the beneficial properties of organofluorine compounds,such as their metabolic stability,t he incorporation of the CH 2 Fgroup as abioisosteric substitute for various functional groups is an attractive strategy for the discovery of new pharmaceuticals.Furthermore,t he monofluoromethyl unit is also widely used in agrochemistry,i np harmaceutical chemistry,and in fine chemicals.The problems associated with climate change and the growing need for environmentally friendly industrial processes mean that alternatives to the frequently used CFC and HFBC fluoromethylating agents (CH 2 FCl and CH 2 FBr) are urgently needed and also required by the Montreal Protocol.This has recently prompted many researchers to develop alternative fluoromethylation agents.This Minireview summarizes both the classical and new generation of fluoromethylating agents.Reagents that act via electrophilic, nucleophilic, and radical pathways are discussed, in addition to their precursors.follow increasingly stricter rules, [11b] alternative fluoromethylating agents are urgently needed.Although af luoromethyl group can be generated by introducing fluorine in place of as uitable functional group [12] or by direct monofluorination, [13] the majority of synthetic procedures use af luoromethylating agent instead, which can directly transfer aC H 2 F group. [14]7a] In addition, Review articles focusing on fluorine-containing functional groups, [5b] difluoro-and fluoromethylation, [14] transition-metal-mediated di-and monofluoroalkylations, [15] sulfur-based fluorination and fluoroalkylation reagents, [16] and on shelf-stable reagents for fluorofunctionalization reactions [17] have been published.This Minireview provides an overview over the reagents used for the specific introduction of the CH 2 Fg roup into organic compounds.C lassical monofluoromethylating agents as well as newly developed reagents have been considered (Figure 4).Thel iterature has been covered until the end of 2019.The reagents were classified by considering their ability to either directly transfer the CH 2 Fgroup in electrophilic,nucleophilic, or radical fluoromethylation reactions,o rt oact as suitable precursors generating CH 2 Fafter proper workup.T he introduction of CH 2 Fmoieties by transition-metal-mediated crosscoupling reactions is discussed in the Section covering the corresponding reagent.

AHistorical Overview of Monofluoromethylating Reagents
Then umber of monofluoromethylating reagents has almost doubled over the last ten years (Figure 4), reflecting adramatic development in this field.Particularly active in this area has been the group of Hu, providing eight of these reagents.S tarting with simple compounds such as fluoromethanol and the fluoromethyl halides CH 2 FX (X = Cl, Br, I), more sophisticated and efficient reagents applicable to ab road range of substrates have been developed with time.Efforts were focused on the introduction of better leaving Marco Reichel received his M. Sc. degree in chemistry from Ludwig-Maximilian University.H ei sc urrently completing his PhD thesis under the supervision of Prof. K. Karaghiosoff.H is research is focused on the development of new selective fluoromethylating agents and on studying and understanding the effect of the monofluoromethyl unit on energetic materials.Konstantin Karaghiosoff is professor for inorganic chemistry at Ludwig-Maximilian University and subgroup leader at the chair of Prof. T. M. Klapçtke.He is am ember of the GDCh and European Editor of "Phosphorus, Sulfur,S ilicon and Related Elements".His research interests,i na ddition to multinuclear NMR spectroscopy and the analysis of high-order NMR spectra, are focused on phosphorusc ompounds for possible application in OLEDs, as well as phosphonates and organofluorine compounds for pharmaceutical or energetic use.groups as compared to the halides and on fluoromethylating reagents acting as nucleophiles-the generation of CH 2 FLi being certainly ah ighlight-or reacting through ar adical pathway.O ver the last ten years,i np articular reagents and synthetic protocols for radical fluoromethylation as well as for CH 2 Fi ntroduction through transition-metal-mediated crosscoupling-mainly,but not exclusively,based on fluoromethyl halides-have been developed.

Electrophilic Monofluoromethylation
Fluoromethanol was the first reagent to be used for the electrophilic introduction of CH 2 F. Olah and Pavlath reported in 1953 the formation of fluoromethyl-substituted arenes upon reaction with FCH 2 OH in the presence of aLewis acid (ZnCl 2 ). [18]Recently,i th as been used for the fluoromethylation of special alcohols. [19]1.1.Fluoromethyl Halides Thef luoromethyl halides CH 2 FX (X = Cl, Br,I )a re all volatile,w hich represents ac hallenge when using these compounds.N onetheless,t his property is also an advantage as this volatility allows for an excess of the reagent to be readily separated from the product.In general, CH 2 FX halides are weak fluoromethylating agents.F luoromethylation through an S N 2reaction mechanism is more difficult than the analogous methylation with am ethyl halide.[5b, 20] The a-fluorine effect is responsible for this behavior (Figure 5).[21] Af luorine atom in the a-position stabilizes ap ositive charge by p-donation.This effect is so strong that the destabilizing inductive effect can effectively be ignored, and an S N 2reaction can only take place if agood leaving group is present at the CH 2 Fm oiety.[21b,c] Thus,t he reactivity of the CH 2 FX halides increases in the order Cl < Br < I.However, some reactions such as the electrophilic fluoromethylation of carbon nucleophiles,a sw ell as CH 2 Ft ransfer to weak nucleophiles,a re problematic.[22] Thef luoromethylating strength of CH 2 FX can be increased considerably through the presence of silver cations to bind the halide, [21b,23] making the fluoromethylation of weak nucleophiles such as NO 3 À [23]   and ClO 4 À [21b] possible.I nitially,C H 2 FI (Orr, [24] 1963) and later CH 2 FBr (Lesuisse, [25] 1992) and CH 2 FCl (Sundermeyer, [26] 1985) was used for the fluoromethylation of al arge number of substrates.[25][26][27] Thea lkylation of as eries of oxygen, sulfur,n itrogen, and carbon nucleophiles by fluoromethyl halides has been described.[7a] Moreover,fluoromethyl halides have often been used as starting materials for more efficient fluoromethylating agents (Figure 6).[28] Thef irst fluoromethylated compounds acting as aromatase inhibitors, or compounds with anabolic properties,were prepared using CH 2 FI and CH 2 FBr.[24,25] Aseries of 18 F-labeled fluoromethylcontaining compounds that are frequently used for positron emission tomography (PET) imaging have been prepared by employing CH 2 18 FBr.[29] One of the most important applications of CH 2 FBr is its use in the last step of the synthesis of Fluticasone TM , [30] which involves the fluoromethylation of at hiocarboxylate precursor at the sulfur atom (Scheme 1).Fluoroiodomethane [27c-e,31]] and the monosubstituted derivatives CHRFI [27f,g] and CHRFBr [27f-h] have been used in several cases to introduce aC H 2 Fo rC HRF group.T he first systematic studies on the fluoromethylation of phenols, thiophenols,imidazoles,and indoles with CH 2 FCl (Scheme 2) were reported in 2007 by Hu and co-workers.[5b, 22] Over the last ten years,several transition-metal-mediated fluoromethylation reactions starting from fluoromethyl halides CH 2 FX (X = Br,I )o rc arbon-monosubstituted derivatives thereof have been developed (Scheme 3).All of these syntheses involve C À Cb ond formation.Thus aryl boronic esters or aryl boronic acids can be converted into the corresponding fluoromethyl derivatives by coupling with CH 2 FI, CH 2 FBr, or CHRFBr (R = CO 2 Et, SO 2 Ph) in Pd 0 (Suzuki, [27i] Hu, [27c] Qing [32] )Cu I (Qing [27e] ), or Ni II (Zhang, [27b] X.-S.W ang [27f] )c atalyzed reactions,r espectively.N i II in combination with Mn has been used to promote the introduction of CH 2 F(X.-S.W ang [27a] )and CHRF (R = alkyl; X.-S.W ang [27g] )i nto heteroarenes and arenes starting from  TheC H(CO 2 Et)F group has been introduced in the para (Zhao [33] )o rmeta position (G.-W.W ang, [27l] Ackermann [27m] ) by Ru II -catalyzed reactions of CH 2 F(CO 2 Et) with the corresponding methoxyphenyl ketoximes or monosubstituted arene derivatives,r espectively.I th as been shown by Wu and co-workers [27m] that 8-aminoquinolines react with CHF-(CO 2 Et)Br in the presence of Cu II and HP(O)(OMe) 2 to give the corresponding CHF(CO 2 Et)-substituted derivatives.

Fluoromethyl Sulfonates
7a] Them ain and most important application of these reagents is in the synthesis of 18 F-labeled fluoromethyl compounds to enable PET imaging. [39]Thef luoromethyl sulfonates 12 a and 12 b have been prepared starting from bis(mesyloxy) and bis(tosyloxy) methane and by introducing fluorine by reaction with KF. [40] Thesynthesis of 12 b has been considerably improved [41] and is almost quantitative when CsF in tert-amyl alcohol is used to introduce fluorine. [12]28h,42]

S-Monofluoromethyl Diarylsulfonium Tetrafluoroborate
In 2008, Prakash and Olah developed ap owerful fluoromethylating agent that has been successfully applied in the fluoromethylation of numerous nucleophiles (Scheme 5).5b] The sulfonium salt 13 is amoisture-insensitive solid;itis stable for several months in the solid state and is also stable in acetonitrile solution.28b] Substrates that possess heteroatoms as nucleophilic centers are readily fluoromethylated upon reaction with 13.In particular,fluoromethyl sulfonates can be prepared under mild conditions by using the sulfonium salt 13.H owever,i ts application to carbon nucleophiles has thus far remained limited to only afew compounds.Avery effective fluoromethylating reagent was developed in 2011 by Shibata and co-workers. [43]It shows ap ronounced preference for fluoroalkylation at oxygen atoms,w hich provides as ynthetic approach for the preparation of monofluoromethyl ethers.This method was applied to anumber of 1,3-dicarbonyl compounds.I ti saregioselective reagent for b-keto esters and was successful also in the fluoromethylation of carboxylic and sulfonic acids,o xindole derivatives,a nd phenols,aswell as naphthols (Scheme 6). [17,43] 28b,43] Ther eagent 14 is as olid that is easy to handle and can be stored. [43]Although O-alkylation can also be performed well with other reagents,the E/Z stereoselectivity of 14 is particularly noteworthy.T he O-regiospecificity of 14 was explained by ar adical-like mechanism involving aS ET process. [45]28d] 2.1.5.Monofluoromethyl-Substituted Sulfonium Ylides Completing the series of difluoromethyl-and trifluoromethyl-substituted sulfonium ylides,Shen and Lu reported in 2017 the missing monofluoromethyl sulfonium ylide 15,which was structurally characterized by single-crystal X-ray diffraction.28d] It was shown that 15 is as trong alkylating agent.28d]

Nucleophilic Monofluoromethylation
7a] In 2017, Pace and Luisi achieved ag reat breakthrough in this field.They reported the generation and use of fluoromethyllithium, which was the first and still remains the only direct nucleophilic monofluoromethylation reagent (Scheme 8). [46]n order to perform reactions with this unstable species,i ti s important to stick strictly to the reaction conditions reported, [46] as the generation of 16 only succeeds upon adding MeLi•LiBr in am olar ratio of 2:1.5 to the substrate.Furthermore,the reaction has to be quenched, and as olvent mixture of THF/Et 2 O( 1:1) has to be used. [46]Unfortunately, unlike MeLi, reagent 16 cannot be isolated at room temperature as decomposition occurs very quickly,most probably by elimination of LiF.

Radical Monofluoromethylation 2.3.1. N-Tosyl-S-fluoromethyl-S-phenylsulfoximine
13a] Despite the time-consuming (3 days) synthesis of 17 and the only moderate yield, an important advantage of this reagent is its stability.Atroom temperature, 17 is ac rystalline solid, which has been characterized by single-crystal X-ray diffraction and does not decompose even upon storage in air for one year. [47]

FluoromethylsulfonylChloride
28j] Sulfonyl chloride 18 (colorless oil) is readily obtained from 4-chlorobenzyl thiol in three steps in excellent yield (90 %).In the cases of N-phenyl acrylamide and electrondeficient alkenes,i nstead of cyclization, af ormal addition of chlorine and CH 2 Ft ot he C = Cd ouble bond takes place to yield saturated derivatives with at erminal fluoromethyl group (Scheme 10).Ther eaction is catalyzed by copper and is induced by visible light.Both reactions also occur with CHF 2 or CF 3 substituents in place of CH 2 F. [28c] However, although the yields of the fluoroalkylated products are good, applications of this reagent still remain limited at the present time.
In 2015, Hu and co-workers developed al arge-scale synthesis for sodium sulfinate 19 b and used it for radical monofluoromethylation reactions. [49]Later, in 2017, Liu and co-workers demonstrated that sodium sulfinate 19 b is asuitable reagent for the transition-metal-free radical fluoroalkylation of isocyanides to form phenanthridines. [50] Coumarin derivatives with aC H 2 Fg roup have been prepared very recently by Li and co-workers starting from alkoxynates by as ilver-catalyzed cascade monofluoromethylation with 19 b. [51] Thez inc sulfinate 19 a has also been widely used for the synthesis of bioactive compounds, [48] and is remarkable because of its simple and straightforward synthesis.C ompound 19 a has been isolated as acolorless solid and is stable at room temperature.H owever,t he synthesis of the sodium salt, starting from ah eteroaryl sulfone,i smuch simpler. [49]

Monofluoromethyl Sulfones
In 2016, Hu and co-workers reported av isible-lightinduced photoredox synthesis of fluoromethyl-substituted phenanthridines based on the reaction of suitable isocyanides with fluoromethyl sulfone 20. [52]Theh igh redox potential of the fluoromethyl sulfone is essential for successful fluoromethylation, and an irradiation time of 48 hw as required (Scheme 12). [12-15, 17, 53]hef luoromethylating reagent 20 is isolated in the last step in moderate yield as ac olorless,a ir-stable solid, which makes it easy to handle.I ts overall synthesis,h owever, includes several steps and requires the use of CH 2 FCl as the source of the fluoromethyl group. [12-15, 17,53]

Indirect Monofluoromethylation
Because of the instability of organometallic fluoromethyl reagents such as fluoromethyllithium, it is sometimes necessary to use precursor compounds containing afunctionalized fluoromethyl group.A fter the transfer of the functionalized group to the substrate,the desired -CH 2 Fmoiety is generated during workup.

Fluoromalonates
In the 1980s,t he monofluoromethylation of organic compounds attracted increasing interest.7a, 54] Thek ey step involves the nucleophilic attack of an intermediately generated fluoromethyl carbanion to the imidazolide of the carboxylic acid.Thus,r eagent 21 may be viewed as as ynthon of the unstable CH 2 F À anion.The resulting b-keto a-fluoro esters give the corresponding fluoromethyl ketones upon hydrogenation in good yields.Thestarting fluoromalonate ester is readily prepared [54,55] and is nowadays commercially available.F luoromalonate methyl [55a] and ethyl [55b] ester have also been directly used in fluoromethylation reactions.T he formation of 21 (colorless solid) is straightforward, although it comprises three steps.7a]

Fluoromethyl Phenyl Sulfone and Related Compounds
Fluoromethyl phenyl sulfone (22)i sacolorless solid that was reported as far back as 1985 to form the corresponding fluoromethylidene ylide,a nd it has been used to prepare fluoroolefins in aW ittig-analogous reaction. [56]In 2006, Hu and co-workers extended this methodology to formally transfer the CH 2 Fm oiety,w hich is formed after cleavage of the sulfonyl group (Scheme 14). [57]Thus starting from (R)-(tert-butylsulfinyl)imines,primary a-fluoromethyl amines and cyclic secondary a-fluoromethyl amines become readily accessible with high stereoselectivity using this reagent.The method was further extended by Fustero and co-workers to include the synthesis of chiral fluoromethyl isoindolines [58] and isoquinolines. [59]Hu and co-workers further successfully utilized 22 for the stereoselective synthesis of av icinal fluoromethyl ethylene diamine. [60]Monofluoromethyl-containing amides can also be prepared using 22 in aR itter reaction. [61]7a, 58, 59, 62] Ac arbanion with af luorine atom directly bonded to the negatively charged carbon atom can also be stabilized by as ulfoxide group.D eprotonation of fluoromethyl phenyl sulfoxide at the methylene group with LDAatÀ78 8 8Cresults in the formation of acarbanion, which is moderately stable at low temperatures.R eaction with aldehydes followed by pyrolysis generates the corresponding fluoromethyl ketones in moderate yields (Scheme 15). [63]An aromatic fluoromethylation with an a-fluoro-b-keto phenyl sulfone,a cting as as oft nucleophile,h as been reported by Hu and co-workers. [62]Thet hree-step synthesis involves the addition to ab enzyne generated in situ, followed by the reduction of the keto group and the reductive cleavage (Na/Hg) of the sulfonyl moiety. [62]27f, 64a,b] Finch and co-workers described in 1988 the use of sulfoximine 26 as an ucleophilic source for the fluoromethyl group.Its reaction with aldehydes and ketones in the presence of abase proceeds with addition to the C=Obond yielding the corresponding b-fluorosulfonyl alcohols.T he reductive cleavage of the sulfonyl substituent with aluminum amalgam produces the respective fluorinesubstituted olefins together with the fluoromethyl alcohols.In the case of R 1 = Ha nd R 2 = 4-MeOC 6 H 4 ,t he fluoromethyl alcohol is obtained in 57 %y ield when sodium amalgam is used (Scheme 15). [65]1.3.Fluorobis(phenylsulfonyl)methane 28i,66] Thesynthesis of 23 has also been improved.5c] Hu and Prakash reported that FBSM acts as anucleophilic fluoromethylating reagent and undergoes addition reactions with epoxides, [66a] aziridines, [62] a,b-unsaturated ketones, [62,67] alkynyl ketones, [62] and benzynes. [62]7a,67b] Using an in situ formed iminium compound as the catalyst, Wang et al. reported an enantioselective addition of 23 to enals. [68]In the last ten years,some research groups have described the reaction of FBMS with aliphatic aldehydes resulting in enantioselective fluoromethylation in the bposition, [69] as well as the addition of FBMS to MBH carbonates or acetates yielding the products of an enantioselective asymmetric allylic alkylation (Scheme 16). [70]Gouverneur and co-workers showed that the palladium-catalyzed allylic alkylation reaction of 23 with Morita-Baylis-Hillmann (MBH) carbonates (allyl carbonates) proceeds with high regioselectivity. [71]Thea ddition to alkyl and benzyl halides also proceeds with high yields,a ss hown by Olah and coworkers. [72]Thef luoromethyl group is finally formed after reductive cleavage of the sulfonyl substituents with Mg in MeOH (Scheme 16). [70c, [71][72][73] Instead of the palladium catalyst, the combination of ac inchona alkaloid and FeCl 2 or ac inchona-catalyzed Mannich-type reaction can be used for enantioselective monofluoromethylation (Shibata and coworkers). [74]Furthermore,t he addition of 23 to carbonyl compounds, [69a] a,b-unsaturated carbonyl compounds, [75] and functionalized alkynes [76] as well as the enantioselective synthesis of tertiary allylic fluorides by iridium-catalyzed allylic fluoromethylation with 23 have been described by the groups of Hu, Vesely,a nd Hartwig. [77]Reductive cleavage of the sulfonyl substituents to yield the corresponding fluoromethyl derivatives,asinthe other examples discussed above, was not reported.
Thereaction of 23 with MBH carbonates (Toru and Tan) proceeds with high enantio-and diastereoselectivity and yields alcohols with afluoromethyl group in g-position to the OH group after workup. [74,78] hei ntroduction of af luoro- in Ibuprofen by using 23 in place of the methyl group results in an increase in its inhibitory activity. [79]The reaction of secondary amines with formaldehyde in the presence of FBSM (Prakash et al.,2 013) opens up ag eneral and straightforward synthetic route to b-fluoro ethylamines. [80]77b] In 2014, Ramos and Yang extended the addition reaction of FBSM to enals,providing an enantioselective synthesis for fluoroindane and fluorochromanol derivates (Scheme 18). [81]ibata and co-workers reported an efficient method for preparing C2-aryl indoles with af luoromethyl group at the alkyl side chain starting from the corresponding aryl sulfonyl derivatives and replacing the SO 2 Ar substituent by CH 2 F, by utilizing 23 in the presence of ac hiral phase transfer catalyst. [82]Furthermore,the acetate group of allenyl acetates can be replaced with aCH 2 Fgroup by employing 23 (Ma and Lu), yielding the corresponding fluoromethyl allenes (Scheme 19). [83]FBSM is also the key reagent of ah ighly selective two-step synthesis of functionalized monofluoromethylated allenes,reported by Shibata and co-workers. [84]In the first step,2 -bromo-1,3-dienes react with FBSM in ap alladium-catalyzed nucleophilic substitution that selectively introduces the fluorobis(phenylsulfonyl)methyl group directly bonded to the allene skeleton.Thef ollowing reductive desulfonation (Mg,M eOH) gives the fluoromethyl allenes in excellent (81-83 %) yields. [84]n efficient synthesis of a-fluoromethyl alcohols has been reported by Prakash and Olah in 2012, using the related trimethylsilyl derivative 24.T his reagent contains aS iMe 3 group in place of the hydrogen atom of FBSM and is readily prepared from 23 by deprotonation with NaH and subsequent silylation with Me 3 SiCl (Scheme 20). [85]1.4.2-Fluoro-1,3-benzothiole-1,1,3,3-tetraoxide Thec yclic version (FBDT) 25 of FBSM was reported in 2010 by Shibata and co-workers.[86] Reagent 25 is prepared starting from the corresponding methylene-bridged derivative by fluorination with Selectfluor and formed as acolorless solid.FBDT adds efficiently to the C=Ogroup of avariety of aldehydes yielding the corresponding a-fluoromethyl alcohols after workup.The addition is complete within 24 h.In the case of a,b-unsaturated aldehydes,1 ,2-addition competes with 1,4-addition, and the selectivity is strongly dependent on the base used (DABCO or pyrrolidone).[86] In the presence of bifunctional cinchona alkaloid derived thiourea titanium complexes,t he reaction of 25 with aldehydes becomes enantioselective (32-96 % ee)a nd yields the fluoromethyl alcohols in 73-91 %y ield (Scheme 21).[87] Thes tructure of FBDT (25)h as been determined in the solid state by singlecrystal X-ray diffraction.[86]

Phosphorus-Containing Fluoromethyl Precursors
9c, 88] Thes tructure of the fluoromethyl triphenylphosphonium cation salt in the solid state as its iodide salt has been determined by single-crystal X-ray diffraction. [8]e a-fluoromethyl phosphonate 28 displays increased acidity for the proton in a-position, supported by the electron-withdrawing sulfonyl group.I ts reaction with formaldehyde (Takeuchi and co-workers,1 987) results in the formation of the corresponding sulfonyl-substituted fluoroalkene,w hich can be converted with the anion of diethyl acetamido malonate into the corresponding fluoromethyl derivative after reductive elimination of the sulfonyl group (Scheme 22). [89]

Conclusion
Theu nique properties of organic molecules containing afluoromethyl (CH 2 F) group and their use in various fields of pharmacya nd medicine has resulted in ah igh demand for reagents that are capable of selectively introducing aC H 2 F group.Inrecent decades,great efforts have been made in the development of fluoromethylating reagents and several new reagents have been prepared and used.Most of the reagents are based on fluorohalomethanes and, more specifically, fluorochloromethane,o rd erivatives thereof.T he main synthetic strategies are the introduction of as uitable leaving group in place of the halogen (Cl, Br, I), or the introduction of electron-withdrawing substituents at the carbon atom bonded to fluorine.Inthe former case,the CH 2 Fgroup is transferred as the electrophile.T he alkylation strengths of the reagents differ and can be fine-tuned by the nature of the respective leaving group.I nt he latter case,e lectron-withdrawing substituents (SO 2 Ar, PhCH 2 OC(O), PhS(O)NTBS) stabilize anegative charge at the carbon atom bonded to fluorine,and CH 2 Fisintroduced as anucleophile;the reagent can thus be considered as ar eplacement for the unstable and very sensitive FCH 2 Li.Over the last decade,p articular attention has been paid to reagents that are able to transfer the CH 2 F group by aradical pathway.The strategy behind this approach was again the introduction of suitable substituents at the carbon atom bonded to fluorine that favor radical formation.Despite the great progress that has been made,m ost of the reagents are effective in transferring CH 2 Fo nly to heteroatoms (nitrogen, oxygen, sulfur).Thet ransfer of CH 2 Fw ith concurrent C À Cb ond formation is less effective,a nd the development of readily available fluoromethylating reagents capable of achieving this goal still remains ac hallenge for organofluorine chemists.

Figure 4 .
Figure 4. Historical overview of monofluoromethylating reagents and year of their first use as aC H 2 Ftransfer reagent.

Figure 6 .
Figure 6.Selected strong fluoromethylating agents derived from fluoromethyl halides and year of their first application as aCH 2 Ftransfer reagent.