Advances in Catalytic Enantioselective Fluorination, Mono-, Di-, and Trifluoromethylation, and Trifluoromethylthiolation Reactions

Abstract

1 Introduction Despite being largely absent from natural products and biological processes, fluorine plays a conspicuous and increasingly important role within pharmaceuticals and agrochemicals, as well as in materials science. 1a−1c Indeed, as many as 35% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine. 1d Fluorine is the most electronegative element in the periodic table, and the introduction of one or more fluorine atoms into a molecule can result in greatly perturbed properties. Fluorine substituents can potentially impact a number of variables, such as the acidity or basicity of neighboring groups, dipole moment, and properties such as lipophilicity, metabolic stability, and bioavailability. The multitude of effects that can arise from the introduction of fluorine in small molecules in the context of medicinal chemistry has been extensively discussed elsewhere. 2 For these reasons, methods to introduce fluorine into small organic molecules have been actively investigated for many years by specialists in the field of fluorine chemistry. However, particularly in the past decade, a combination of the increasing importance of fluorine-containing molecules and the successful development of bench stable, commercially available fluorine sources has brought the expansion of fluorine chemistry into the mainstream organic synthesis community. This has resulted in an acceleration in the development of new fluorination methods and consequently in methods for the asymmetric introduction of fluorine. 3 Catalytic asymmetric fluorination methods have inevitably lagged somewhat behind their nonasymmetric counterparts as understanding of the modes of reactivity of new fluorinating reagents must generally be developed and understood before they can be extended to enantioselective catalysis. 3b Indeed, the last special issue of Chemical Reviews dedicated to fluorine chemistry, in 1996, contained no articles addressing asymmetric fluorine chemistry, and the editor of the issue noted that “although fluorine chemistry is much less abstruse now than when I entered the field a generation ago, it remains a specialized topic and most chemists are unfamiliar, or at least uncomfortable, with the synthesis and behavior of organofluorine compounds.” 4 The field has undoubtedly undergone great change within the last two decades. As with the incorporation of the fluorine atom, the introduction of the trifluoromethyl (CF3) group into organic molecules can substantially alter their properties. As with fluorine, the prevalence of CF3 groups in pharmaceuticals and agrochemicals coupled with the development of new trifluoromethylating reagents also has led to a recent surge in the development of asymmetric trifluoromethylation and perfluoroalkylation. Although the fluorine and trifluoromethyl moieties are often found on the aromatic rings of many pharmaceutical and agrochemicals rather than in aliphatic regions, this may be a result of the lack of efficient methods for the asymmetric introduction of C–F and C–CF3 bonds into molecules; it could be the case that lack of chemical methods is restricting useful exploration of such molecules. However, there are still encouraging examples of drug candidates containing chiral fluorine and trifluoromethyl-bearing carbons (Figure 1). Figure 1 Molecules of medicinal interest bearing C–F and C–CF3 stereocenters. The asymmetric synthesis of fluorine-containing organic compounds using catalytic methods is of particular topical interest and is a vibrant area of chemical research. Since the beginning of the 21st century, much progress has been made in this field with significant advances being made since the preceding Chemical Reviews article in 2008 by Ma and Cahard. 3a In this Review, we aim to comprehensively cover advances in catalytic enantioselective fluorination, trifluoromethylation, and perfluoralkylation reactions up to May 2014. Additionally, we will also include sections covering the introduction of mono- and difluoromethyl groups as well as trifluoromethylthiolation. In contrast to the 2008 review, due to the desire to focus on catalytic asymmetric processes, we will not include diastereoselective processes (with the arguable exception of tandem processes), noncatalytic reactions, or asymmetric functionalization of fluorine-containing compounds, unless these can explicitly lead to a mono- or difluoromethyl group. 2 Catalytic Enantioselective Fluorination 2.1 Electrophilic Fluorination Electrophilic fluorination reactions with highly oxidizing fluorinating reagents such as fluorine gas, hypofluorites, and fluoroxysulfates can be challenging to perform without special equipment and precautions, due to their high reactivity. This largely precluded the development of catalytic asymmetric methods until the development in the 1990s of bench-stable, easily handled electrophilic fluorinating reagents such as N-fluorobenzene-sulfonimide (NFSI), the family of N-fluoropyridinium salts, and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborates) (Selectfluor). It is the development of these “tamed” electrophilic reagents that allowed researchers to develop catalytic enantioselective fluorination of nucleophilic substrates (Figure 2). Figure 2 A selection of commonly used electrophilic fluorinating reagents. 2.1.1 Metal-Catalyzed Fluorination Involving Enolates The earliest advances in catalytic asymmetric fluorination were made by exploiting transition metal enolates, capable of a bidentate mode of coordination to a metal. This approach provided activation of the substrate through enolate formation, together with the ability to impose a rigid chiral environment by virtue of chiral ligands bound to the transition metal. 2.1.1.1 Ti/TADDOL Catalysts The first such reaction was developed by Hintermann and Togni in 2000. 5a The authors reasoned that a catalytic amount of a Lewis acid would accelerate fluorination of β-ketoesters by catalyzing the enolization process. Fluorination of acyclic β-ketoesters 1 with Selectfluor and Ti(TADDOLato) catalyst 2 in MeCN at room temperature afforded the desired products 3 in high yield (>80%) and up to 90% ee (Scheme 1). The authors have recently advanced a steric model explaining the facial selectivity of the fluorination, which was arrived at by combining X-ray data with molecular modeling (Figure 3). 5b,5c While only a few examples in the original disclosure achieved the highest levels of enantioselectivity, this was an extremely influential study and set the stage for much work that followed. Scheme 1 Figure 3 Proposed steric model explaining the facial selectivity in the titanium-TADDOLate-catalyzed fluorination. Reproduced with permission from ref (5b). Copyright 2011 Beilstein-Institut zur Foerderung der Chemischen Wissenschaften. In 2003, Togni and co-workers applied the same catalytic system to the one-pot enantioselective heterodihalogenation of β-ketoesters with Selectfluor and NCS to afford α-chloro-α-fluoro-β-ketoesters (5, 6) in moderate to good yield (Scheme 2). 6 The sequence of addition of the halogenating agents was found to determine the sense of asymmetric induction, although the enantioselectivities were moderate. Scheme 2 In 2006, Togni and co-workers applied the Ti(TADDOLato) catalyst 2 to the asymmetric fluorination of α-acyl lactams 7 (Table 1). 7 They found that using NFSI as fluorinating reagent gave superior enantioselectivity to Selectfluor; however, only one substrate (R1 = Me, R2 = Ph) afforded high enantioselectivity (75% yield, 87% ee). Table 1 Asymmetric Fluorination of α-Acyl Lactams R1 R2 yield, % ee, % Me CH2Ph 75 26 Ph CH2Ph 78 15 Ph Me 75 6 Me Ph 75 87 Cy Me 60 50 Me Cy nd 46 t-Bu Me 40 20 2.1.1.2 Metal/BINAP Catalysts In 2002, Sodeoka and co-workers reported the enantioselective fluorination of β-ketoesters catalyzed by a chiral palladium complex (Scheme 3). 8 The reaction was carried out with NFSI and 2.5 mol % of cationic palladium catalyst (12b and 12c) to afford fluorinated β-ketoesters 10 (both cyclic and acyclic) in high enantioselectivity. In 2003, the same group reported the use of an ionic liquid immobilized palladium complex as catalyst for the same reaction. Similarly high enantioselectivity was achieved, and the immobilized catalyst could be reused up to 10 times with levels of efficiency comparable to those in conventional organic solvents. 9 Scheme 3 The proposed mechanism involves the β-ketoester coordinated in a bidentate manner to the cationic palladium catalyst. This coordination increases the acidity of the α-proton, allowing a nucleophilic metal enolate to be easily generated and to react with the NFSI (Figure 4). The enantioselectivity was rationalized by considering the structure of the square-planar chiral Pd enolate complex, which was proposed to arrange itself to minimize steric interactions between the ligand aryl groups and the ester tert-butyl group. This results in the Si face being shielded by the ester tert-butyl group, requiring the NFSI to approach from the less hindered Re face (Figure 5). 10 Figure 4 Proposed catalytic cycle for enantioselective Pd-catalyzed fluorination of β-ketoesters. Figure 5 Proposed structure of the Pd–enolate complex to account for enantioselectivity. Reproduced with permission from ref (10). Copyright 2006 Elsevier. In 2005, the same group reported the enantioselective fluorination of oxindoles using a similar approach (Table 2). 11 Treatment of 3-substituted oxindoles 13 with NFSI and 2.5 mol % palladium catalyst 12b in 2-propanol gave the fluorinated products 14 in good yield with high to excellent enantioselectivities (75–96% ee). The method was applied to the synthesis of BMS 204352 (MaxiPost), a promising agent for the treatment of stroke. They also demonstrated the asymmetric fluorination of unsubstituted oxindoles; by changing the solvent to ClCH2CH2Cl/MeOH, 16 was obtained with high enantioselectivity. Table 2 Enantioselective Fluorination of Oxindoles Using Palladium Catalysis R1 R2 temp, °C yield, % ee, % Ph H 0 96 90 p-MeC6H4 H rt 97 86 p-MeC6H4 H 0 92 88 p-FC6H4 H rt 94 84 o-MeC6H4 CF3 rt 80 75 Me H rt 86 95 Me H 0 85 96 Et H rt 85 92 CH2COCH3 H rt 85 86 Bn H rt 72 80 i-Bu H rt 85 75 In 2005, Kim and co-workers reported the enantioselective fluorination of α-cyano esters, catalyzed by cationic palladium complex 19a (Scheme 4). 12 Treatment of substrates 17 with NFSI as fluorine source under mild conditions afforded the α-cyano α-fluoro esters 18 in high yields with excellent enantiomeric excesses (85–99% ee). Scheme 4 Soon after, Kim 13a and Sodoeka 10,14 reported the catalytic fluorination of β-ketophosphonates catalyzed by chiral palladium complexes, with high enantioselectivity for both cyclic and acyclic β-ketophosphonate substrates 20 (Scheme 5). Kim and co-workers later reported this reaction in ionic liquids, with the aim of simplified product isolation and catalyst recycling. 13b Scheme 5 Kim and co-workers also developed enantioselective fluorination of α-chloro-β-keto phosphonates 22 catalyzed by chiral palladium complex 19c, which gave the corresponding α-chloro-fluoro-β-keto phosphonates 23 with excellent enantioselectivity (up to 95% ee) (Scheme 6). 15 Scheme 6 In 2007, Kim and co-workers reported employing the chiral Pd(II) complex 19a in the catalytic enantioselective α-fluorination of α-chloro-β-ketoesters 24 with moderate enantioselectivity (Scheme 7). 16 Scheme 7 In 2007, Kim 17 and Sodeoka 18 simultaneously reported the enantioselective fluorination of α-aryl-α-cyano-phosphonates 26 (Scheme 8). Because of the lower reactivity of this substrate class, an organic base was required to accelerate abstraction of the acidic proton. Kim selected 2,6-di-tert-butyl-4-methylpyridine (DTBMP) as base with 81–91% ee; Sodeoka selected 2,6-lutidine as base with 24–78% ee. In both cases, the aryl substituent was required; aliphatic substrates gave no reaction. Scheme 8 In 2007, Sodeoka and co-workers reported an efficient enantioselective fluorination of tert-butoxycarbonyl lactones and lactams 28 with excellent enantioselectivities (94–99% ee) (Scheme 9). 19 In the case of the less acidic lactam substrates, 2,6-lutidine (0.5 equiv) was required to function as a non-nucleophilic, weak base. Scheme 9 In an important advance demonstrating that this strategy could be applied to less acidic substrates, Sodeoka and co-workers in 2007 reported the NiCl2–BINAP-catalyzed direct asymmetric fluorination of α-aryl acetic acid derivatives 30 (Table 3 and Figure 6). 20 Among the acid derivatives tested, thiazolidin-2-one was optimal. In addition, 2,6-lutidine and triethylsilyl triflate were essential for efficient asymmetric fluorination. Triethylsilyl triflate was proposed to play an important role both in generating a dicationic nickel triflate complex and in rendering NSFI more reactive. 2,6-Lutidine was assumed to promote enolization of the substrate. Excellent yields and good enantioselectivities (up to 88% ee) were achieved with α-arylacetic acid derivatives; however, the alkyl derivative gave both poor reactivity and enantioselectivity. Table 3 Asymmetric Fluorination of α-Aryl Acetic Acid Derivatives Using Nickel Phosphine Complex 32 R X cat, mol % yield, % ee, % Ph S 5 99 88 p-FC6H4 S 5 90 83 p-MeOC6H4 S 5 92 81 m-MeOC6H4 S 10 95 82 o-MeOC6H4 S 10 87 78 2-naphthyl S 10 99 83 1-naphthyl S 5 94 87 Ph O 10 95 87 n-propyl S 10 15 11 Figure 6 Proposed model to account for sense of asymmetric induction using catalyst 32. Reproduced with permission from ref (20). Copyright 2007 John Wiley and Sons. In 2012, Sodeoka and co-workers reported the catalytic enantioselective monofluorination of α-ketoesters 33 using a chiral palladium μ-hydroxo complex 12d (Table 4). 21 As the resulting monofluorinated α-ketoesters spontaneously converted into the hydrate during purification, in situ reduction with lithium tri-sec-butylborohydride (L-Selectride) was carried out to give products 34. Aryl-substituted substrates all gave excellent enantioselectivities (up to 95% ee), and substrates with a longer alkyl chain and a benzyloxy-substituted compound gave the desired fluorinated product with reduced but acceptable enantioselectivity (83% ee). A stereochemical model related to that proposed earlier for β-ketoesters was invoked to rationalize the sense of enantioinduction. Table 4 Asymmetric Monofluorination of α-Ketoesters R yield, % ee, % syn:anti Ph 89 94 6.9:1 p-MeC6H4 83 91 4.6:1 p-MeOC6H4 75 94 4.7:1 p-FC6H4 68 95 6.5:1 p-ClC6H4 69 95 7.6:1 PhCH2 65 83 4.2:1 BnOCH2 66 83 1.4:1 2.1.1.3 Metal/Bis(oxazoline) Catalysts In 2004, Ma and Cahard reported the catalytic enantioselective fluorination of both cyclic and acyclic β-ketoesters employing a chiral bis(oxazoline)–copper complex derived from 37 and Cu(OTf)2 (Scheme 10). 22 They found the use of HFIP (1,1,1,3,3,3-hexafluoroisopropanol) as additive was crucial for achieving high enantioselectivity, although only one substrate ultimately gave satisfactory enantiomeric excess (>80% ee). Scheme 10 In the same year, Shibata and co-workers reported fluorination of similar substrates using nickel and copper complexes of 37 (Scheme 11), with the use of MTBE as solvent leading to higher enantioselectivies. 23 An intriguing outcome of this report is that the (S,S)-bis(oxazoline)-Ph-Cu(II) complex provided the fluorination product 10c with opposite configuration to that obtained by the use of (S,S)-bis(oxazoline)-Ph-Ni(II), both with high enantioselectivity. While use of different solvents with the different metal catalysts was required for optimal enantioselectivity, control experiments using the same solvent for both demonstrated that the solvent choice was not responsible for the switch. The authors speculate that this could be a consequence of a change in metal center geometry and provide plausible transition states to support this hypothesis. Scheme 11 In 2005, Shibata and co-workers reported enantioselective chlorination and fluorination of carbonyl compounds capable of two-point binding (Scheme 12). 24 As the previously reported fluorination of β-ketoesters catalyzed by Cu(II) and Ni(II) complexes 37 still left room for improvement, they turned to the DBFOX-Ph ligand (40), which was highly effective in other reactions. A catalyst obtained from DBFOX-Ph and Ni(ClO4)2·6H2O gave fluorinated compounds 39 with extremely high levels of enantioselectivity. The reaction scope was demonstrated on cyclic β-ketoesters (93–99% ee), acyclic β-ketoesters (83% ee), and 3-substituted oxindoles (93–96% ee). The methodology was showcased with a catalytic enantioselective preparation of Maxipost. They proposed an octahedral nickel complex as key intermediate, ligated by both substrate and ligand, and put forward a model to rationalize the absolute stereochemistry observed leading to compound 39a (Figure 7). Scheme 12 Figure 7 Proposed model to account for fluorination leading to 39a. Reproduced with permission from ref (24). Copyright 2005 John Wiley and Sons. In 2008, the same authors reported the enantioselective fluorination of malonates catalyzed by a DBFOX-Ph/Zn(OAc)2 complex (Table 5). 25 In contrast to β-ketoesters, malonates 41 are relatively symmetrical, being differentiated by sterics only. They are also generally less acidic than β-ketoesters; however, reflux of the substrates with NFSI, Zn(OAc)2, and DBFOX-Ph in CH2Cl2 afforded the fluorinated malonates 42 with excellent levels of enantioselectivity. The scope of the reaction was broad, with a wide range of functional groups such as alkyl, aryl, oxygen, sulfur, and amino substitution being tolerated. Ni(ClO4)2·6H2O could be used in place of Zn(OAc)2, but generally the latter gave superior results. Table 5 Enantioselective Fluorination of Malonates entry R yield, % ee, % a CH2Ph 90 98 b Et 94 96 c Me 90 99 d Bu 93 99 e Ph 95 99 f OPh 85 98 g SPh 81 90 h NPht 91 93 i NPht(4-Br) 93 97 In 2008, Shibata and co-workers reported the enantioselective fluorination of 3-(2-arylacetyl)-2-thiazolidinones 43 with NFSI employing DBFOX-Ph/metal complexes as catalysts (Table 6). 26a The best results were obtained using DBFOX-Ph (11 mol %), Ni(ClO4)2·6H2O (10 mol %), and 2,6-lutidine (1.0 equiv) in CH2Cl2 at 0 °C. Later in 2009, they reported modified conditions in which HFIP (0.3 equiv) activated the DBFOX-Ph/Ni(II) catalyst system, permitting lower reaction temperatures. 26b With the help of catalytic HFIP, the reaction proceeded smoothly at −60 °C to afford the desired fluorinated product in high yield with improved enantioselectivity. Table 6 Enantioselective Fluorination of α-Aryl Acetic Acid Derivatives Using a Nickel–DBFOX Complex entry R yield, % ee, % a Ph 91 98 b C6H4-m-OMe 93 96 c C6H4-p-OMe 93 96 d C6H4-m-Me 93 98 e C6H4-p-Me 90 96 f C6H4-p-CF3 94 94 g C6H4-p-F 90 94 h C6H4-p-Br 96 93 i 1-naphthyl 87 92 j 2-naphthyl 94 95 As a further demonstration of the utility of this catalytic system, 3-butenoyl derivatives 45 were tested under these conditions, which gave the desired fluorinated products 46 in high yield and with good enantioselectivity (78–91% ee) (Scheme 13). Scheme 13 In 2007, Iwasa and co-workers reported the design and synthesis of a series of hybrid chiral oxazoline ligands 49, incorporating an axially chiral binaphthyl unit. The Ni(II) complex of this tridentate ligand catalyzed the enantioselective fluorination of β-ketoesters with excellent yields and enantioselectivities (94% ee) (Scheme 14). 27a Later, they found the enantiomeric excess of this reaction could be dramatically improved to 99% ee when a solution of NFSI was slowly added to the mixture of substrate and catalyst. 27b A strong matched–mismatched effect was observed, arising from the two sources of chirality contained within the ligand backbone. Scheme 14 In 2011, Gade and co-workers described the synthesis of a new class of chiral tridentate N-donor pincer ligands, bis(oxazolinyl-methyldiene)isoindolines 52. These ligands were subsequently applied in the Ni(II)-catalyzed enantioselective fluorination of oxindoles 50 and β-ketoesters 47 to afford the corresponding products with enantioselectivities of up to 99% ee (Scheme 15). 28 Scheme 15 In 2013, Kesavan and co-workers reported the enantioselective fluorination of aliphatic cyclic and acyclic β-ketoesters in excellent yield with moderate enantioselectivities using tartrate derived bidentate bisoxazoline–Cu(II) complex 53 (Scheme 16). 29 In this case, the bisoxazoline forms a five-membered chelate with the metal. Scheme 16 In 2011, Shibatomi and co-workers reported the asymmetric α-fluorination of α-chloro-β-ketoesters using Cu(OTf)2 and chiral spiro-oxazoline ligand 54, which was developed into a one-pot tandem chlorination–fluorination transformation, leading to products 6. 30a This could also be extended to asymmetric gem-chlorofluorination of β-ketophosphonates. In both cases, high enantioselectivities could be achieved (Scheme 17). Scheme 17 In 2013, the same authors reported the highly enantioselective fluorination of α-alkyl-β-ketoesters 9 using Cu(OTf)2 and the same catalyst system (Scheme 18). 30b The fluorination proceeded in a highly enantioselective manner both when cyclic and acyclic substrates were applied. Fluorination of α-alkyl-malonate 55 was also performed to afford the corresponding product 56 in good enantioselectivity (83% ee). Scheme 18 2.1.1.4 Miscellaneous Catalysts In 2006, Inanaga and co-workers reported the synthesis of a novel chiral rare earth perfluorinated binaphthyl phosphate, Sc[(R)-F8BNP]3 (57), and its application to the α-fluorination of cyclic and acyclic β-ketoesters with NFPY-OTf (Scheme 19). 31 This report is distinct as being a rare report of successful catalytic asymmetric fluorination using an N-fluoropyridinium salt as an electrophilic fluorine source. Scheme 19 In 2007, Shibata and co-workers reported the enantioselective electrophilic fluorination of β-ketoesters using Selectfluor as fluorine source, and catalyzed by DNA and an achiral copper–bipyridine complex (Scheme 20). 32 DNA is thought to act as a chiral scaffold, and the chirality transfer from DNA (in this case Salmon testis DNA, st-DNA) to the substrate appears to occur through intercalation or groove binding of the substrate–ligand–Cu(II) complex to DNA. The pH of the reaction needed to be carefully controlled, but impressive enantioselectivities were achieved for such a novel and innovative approach to asymmetric catalysis. Scheme 20 In 2007, Togni and co-workers reported the enantioselective electrophilic fluorination of 1,3-dicarbonyl compounds catalyzed by ruthenium(II) complex [RuCl(PNNP)] (58) upon activation with (Et3O)PF6 (2 equiv) (Scheme 21). 33 Oxygen donors, in particular Et2O as cosolvent, increased the activity of the catalyst and, in some case, the enantioselectivity. Scheme 21 In 2009, Frings and Bolm reported the enantioselective fluorination of β-ketoesters catalyzed by Cu(OTf)2 and amino sulfoximine ligands of the general structure 59 (Scheme 22). 34 Starting from both cyclic and acyclic substrates 35, the corresponding products 36 were formed with moderate to good enantioselectivities. Scheme 22 In 2009, Queneau, Billard, and co-workers reported the synthesis of a series of new carbohydrate-substituted bipyridines 60 and their application in the asymmetric fluorination of β-ketoesters (Scheme 23). 35 However, disappointingly low enantioselectivities were obtained with both cyclic and acyclic substrates. Scheme 23 In 2010, Kang and Kim reported the use of chiral nickel–diamine complexes such as 63 to catalyze the electrophilic fluorination of α-chloro-β-ketoesters 61, which allowed access to chiral gem-chlorofluoro products 62 with high enantioselectivities (Scheme 24). 36 Scheme 24 In 2010, Itoh and co-workers reported the enantioselective α-fluorination of β-ketoesters catalyzed by Co(acac)2 and Jacobsen’s salen ligand (R,R)-(64) (Scheme 25). 37 Both cyclic and acyclic substrates 35 gave the corresponding products 36 in high yield with good enantioselectivities. Scheme 25 In 2012, van Leeuwen and co-workers reported the synthesis of a series of new enantiopure wide-bite-angle diphosphanes 67 and their use in the palladium-catalyzed asymmetric fluorination of α-cyanoacetates 65 (Scheme 26). 38 However, the substrate scope was rather limited, with only one substrate (65a) giving greater than 90% ee. Scheme 26 In 2012, Feng and co-workers reported the enantioselective fluorination of 3-substitued oxindoles 68 catalyzed by Sc(III)/N,N′-dioxide complex 70 (Scheme 27). 39 Under mild reaction conditions, a series of 3-aryl and 3-alkyl-3-fluoro-2-oxindoles 69 were obtained with high enantioselectivity. Employing this method, MaxiPost was synthesized with 96% ee. Scheme 27 In 2014, Peng and Du reported an efficient highly enantioselective fluorination of β-keto esters/amides catalyzed by diphenylamine-linked bis(thiazoline) 74–Cu(OTf)2 complex (Scheme 28). 40 Scheme 28 Very recently in 2014, Xu, Che, and co-workers reported the enantioselective fluorination of β-keto esters and N-Boc oxindoles using iron(III)–salen complexes. 41 2.1.2 Metal-Catalyzed Fluorination Not Involving Enolates In 2013, Gagne and co-workers reported the enantioselective cyclization/fluorination of polyenes catalyzed by (Xylyl-phanephos)Pt2+ in combination with XeF2, a rare example of metal-catalyzed asymmetric fluorination not proceeding through an enolate intermediate (Table 7). 42 The authors noted that electrophilic Pt(II) complexes are highly effective for initiating cation-olefin cascades and set out to investigate if the final Pt–C bond of a cascade could be converted to a C–F bond. Accordingly, the isolated complex [(triphos)Pt-alkyl][BF4] (75) reacted rapidly with XeF2 to yield the C–F containing product 76. Under the optimized conditions, a variety of alcohol and phenol terminated dienes and trienes 77 were converted into corresponding C3-fluorinated bicyclic and tricyclic products 76 in moderate to good yield with good enantioselectivities (up to 87% ee). The proposed mechanism is as shown in Figure 8. NMR data studies suggested that 75 is the catalyst resting state and either undergoes β-hydride elimination to give the nonfluorinated byproduct 78 or oxidation (with XeF2) to give the dicationic Pt(IV) complex, which reductively eliminates to give 76. Table 7 Platinum-Catalyzed Enantioselective Cyclization and C3-Fluorination of Polyenes Figure 8 Proposed mechanism for the platinum-catalyzed cyclization/fluorination of polyenes, adapted from ref (42). Recently, Toste and co-workers reported the palladium-catalyzed three-component coupling of Selectfluor, styrenes, and boronic acids, to provide chiral monofluorinated compounds in good yield and in high enantiomeric excess (Scheme 29). 43 They hypothesized that the aromatic amide could act as a directing group to control regioselectivity and to stabilize a high-valent Pd(IV) intermediate in conjunction with the bipyridine ligand. This would disfavor an oxidative Heck-type coupling reaction, with the intention of favoring C–F bond formation. A chiral ligand (pyridyl-oxazolidine ligand, 81) was used for the asymmetric version of this reaction (81% ee); however, with the quinolone-based directing group, the yield was low (15%). Encouragingly, they found the simplified anilide derivatives 79 gave improved yield without significant negative effect on the enantioselectivity. Following these results, a range of boronic acids were tested on the 4-methoxyaniline substrate, and the desired products 80 were obtained in good yield with high enantioselectivities with the exception of the bulky 2,6-dimethylboronic acid (79k). Scheme 29 A proposed mechanism for the reaction is outlined in Figure 9. The catalytic cycle is initiated through formation of N,N-ligated palladium(II) intermediate. Transmetalation with the boronic acid and thereafter coordination and insertion yield a β-arylated Pd(II) species. The coordination of the directing group and N,N-ligand may stabilize this intermediate and retard the competing β-hydride elimination process. Oxidation to the high-valent Pd(IV) intermediate is achieved using Selectfluor, and subsequent reductive elimination yields the desired monofluorinated product and the catalyst complex. Figure 9 Proposed mechanism for the palladium-catalyzed three-component coupling of Selectfluor, a styrene, and a boronic acid. 2.1.3 Organocatalytic Electrophilic Fluorination 2.1.3.1 Tertiary Amine Catalysis Chiral N-fluoro reagents have been investigated for some time in a stoichiometric sense, based on either camphorsultams 44 or other scaffolds, although the preparation of such reagents commonly involves multiple steps and the use of challenging fluorination methods. 45 A significant step forward was made in 2000 when Shibata and co-workers 46a and Cahard and co-workers 46b independently disclosed that combining cinchona alkaloids with Selectfluor results in N-fluoroammonium salts of the cinchona alkaloids, which are stable and isolable. These reagents were demonstrated as being remarkably effective for the enantioselective fluorination of preformed enolates equivalents, such as silyl enol ethers and metal enolates. While they are not catalytic reactions and thus will not be discussed in detail herein, these studies laid important groundwork for subsequent advances. Accordingly, in 2006, Shibata and co-workers reported transition to a catalytic method for the enantioselective fluorination of acyl enol ethers employing a cinchona alkaloid/Selectfluor combination (Scheme 30). 47 The authors found acetyl enol ethers were not significantly reactive toward Selectfluor at room temperature, and this allowed formation of the reactive fluorinated cinchona alkaloid to occur. Addition of NaOAc as base was necessary for enolate activation. While the desired α-fluoroketones 83 were only afforded in moderate enantioselectivities (up to 54% ee), this proved that this approach is viable in a catalytic sense. Scheme 30 By 2008, Shibata and co-workers modified their approach to realize for the first time a highly enantioselective catalytic process (Table 8). 48 They employed NFSI as fluorinating reagent in combination with catalytic amounts of bis-cinchona alkaloids in the presence of excess base. Allyl silanes and silyl enol ethers 85 undergo efficient enantioselective fluorodesilylation to provide the corresponding fluorinated compounds 86 bearing an enantioenriched fluorine-substituted quaternary carbon center, although the requirement for a bulky substituent on the substrate is a limitation on the enantioselectivity of this method. NFSI was chosen as fluorinating reagent because of its low background reaction. The authors advance a mechanistic hypothesis in which excess base would form an N-fluoroammonium KCO3 – salt intermediate, in which the KCO3 – triggers fluorodesilylation of the substrate and would be followed by the enantioselective transfer of fluorine to the substrate. Additionally, they propose a transition state for the reaction, shown below, to account for the observed absolute stereochemistry (Figure 10). Figure 10 Proposed transition state for fluorination of silyl enol ether. Reproduced with permission from ref (48). Copyright 2008 John Wiley and Sons. Table 8 Enantioselective Fluorination of Allyl Silanes and Silyl Enol Ethers Using Bis-cinchona Alkaloid Catalysts X R n catalyst T (°C) yield, % ee, % CH2 C6H5CH2 1 a –40 75 94 CH2 p-Me-C6H4CH2 1 a –20 75 95 CH2 p-Cl-C6H4CH2 1 a –20 81 94 CH2 p-Me-C6H4CH2 1 a –20 65 90 CH2 o-Me-C6H4CH2 1 a –20 58 93 CH2 2-naphthylmethyl 1 a –20 69 91 CH2 Me 1 a –40 73 72 CH2 H 1 a –20 58 51 CH2 C6H5CH2 2 a –20 74 81 CH2 p-Me-C6H4CH2 2 a –20 71 81 O C6H5CH2 2 b –40 82 82 O p-Me-C6H4CH2 2 b –40 79 86 O p-Cl-C6H4CH2 2 b –40 74 86 O p-MeO-C6H4CH2 2 b –40 84 85 O 2-naphthylmethyl 2 b –40 88 84 O Et 2 b –40 95 67 To demonstrate the further synthetic utility of this catalytic approach, they also investigated the catalytic enantioselective fluorination of oxindoles 13a (Scheme 31). An ee value of 85% was able to be obtained when CsOH·H2O was used as a base at −80 °C, although this required use of the modified catalyst (DHQD)2AQN. Scheme 31 In 2011, Gouverneur and co-workers reported the enantioselective fluorocyclization of prochiral indoles 87 catalyzed by cinchona alkaloids (Table 9). 49 The best results were afforded when using a catalytic amount of (DHQ)2PHAL at −78 °C in acetone with NFSI and an excess of K2CO3. The yields and enantiomeric excesses of the catalytic reaction were comparable to the corresponding stoichiometric reactions, which were also reported, although the relatively few results delivering the highest selectivities (>80%) demonstrate the challenging nature of the transformation. The process installs the fluorine substituent on a quaternary benzylic stereogenic carbon center and leads to new fluorinated analogues of natural products featuring the hexahydropyrrolo[2,3-b]indole or the tetrahydro-2H-furo-[2,3-b]indole skeleton 88. Table 9 Enantioselective Fluorocyclization of Prochiral Indoles Catalyzed by Cinchona Alkaloids entry R1 R2 XH yield, % ee, % a H Me OH 72 66 b H Et OH 69 52 c H allyl OH 76 60 d OMe Me OH 65 74 e OBn Me OH 78 74 f OEt Me OH 78 72 g Oallyl Me OH 65 78 h Ph Me OH 61 62 i Mes Me OH 55 84 j H Me NHTs 59 64 k OMe Me NHTs 51 70 l Ph Me NHTs 70 70 m Mes Me NHTs 80 84 n H Me NHCOMe 95 80 o Mes Me NHCOMe 65 92 p H Me NHCO2Me 76 74 q H Me NHCO2BN 47 77 r H Me NHBoc 70 78 Prochiral indole 89 was also subjected to the optimized fluorocyclization conditions, which afforded the difluorinated tricyclic tetrahydrooxazolo[3,2-a] indole 90 in 50% yield, 60% ee (Scheme 32). Scheme 32 In 2012, Tu and co-workers reported the asymmetric fluorination/semipinacol rearrangement of 2-oxa allylic alcohols 91 to afford the corresponding chiral β-fluoroketones 92, catalyzed by cinchona-alkaloid derivatives (Scheme 33). 50 Moderate to good enantioselectivities of the β-fluoroketones 92 were afforded using an NFSI (1.2 equiv)/(DHQD)2PYR (0.2 equiv) combination with K2CO3 as base at −10 °C. Comparable enantioselectivities of the antipodes were afforded when (DHQ)2PYR was used as catalyst. Scheme 33 In 2013, He and co-workers reported using structurally modified N-fluorobenzenesulfonimides (NFSI) in the enantioselective fluorination of oxindoles 93 in the presence of a bis-cinchona alkaloid, (DHQD)2PHAL, as the catalyst (Scheme 34). 51a,51b They investigated a range of NSFI analogues 95 and found that the analogue bearing tert-butyl groups at the para-position of the phenyl rings led to an enhanced enantioselectivity in most cases, although with relatively slow reaction rate and low yield. Scheme 34 2.1.3.2 Enamine Catalysis The rapid advances in enantioselective enamine catalysis seen in the early 2000s were quickly extended to fluorination. In 2005, several groups almost concurrently reported the enantioselective fluorination of aldehydes catalyzed by chiral secondary amines, proceeding via enamine intermediates. Enders and Hüttl reported the organocatalytic direct α-fluorination of aldehydes and ketones employing Selectfluor and proline-related secondary amine 98 as catalyst (Scheme 35). 52 However, only low enantioselectivity (36% ee) was afforded when the best conditions were applied to cyclohexanone (96), and enantioselectivities for the aldehyde substrates were not reported. Scheme 35 Jørgensen and co-workers reported the application of silylated prolinol derivative 101 to tackle the enantioselective α-fluorination of aldehydes. They used NFSI as fluorine source in MTBE, with high enantioselectivities (91–97% ee) (Table 10). 53 Because of their instability, the α-fluorinated aldehydes were reduced in situ to afford the β-fluorinated alcohols 100 for subsequent analysis. Table 10 Scope of Reaction for Enantioselective α-Fluorination of Aldehydes Using Catalyst 101 entry R yield, % ee, % a Pr 95 96 b Bu >90 91 c Hex 55 96 d BnO(CH2)3 64 91 e Bn 74 93 f Cy 69 96 g tBu >90 97 h 1-Ad 75 96 The authors proposed a catalytic cycle for this reaction (Figure 11), and rationalize the stereochemical outcome by invoking formation of the more stable E-configured enamine, with the 3,5-di(trifluoromethyl)phenyl groups blocking the Re face. As a consequence, the electrophilic fluorination occurs from the Si face, with excellent stereocontrol. Figure 11 Proposed catalytic cycle for enantioselective α-fluorination of aldehydes. They also demonstrated preliminary results on the extension of the reaction scope to the formation of quaternary stereocenters (Scheme 36). The sterically encumbered substrate 102 required less bulky catalyst 104 and a higher temperature, allowing product formation with a moderate but encouraging 48% ee. Scheme 36 At a similar time, Barbas and co-workers focused on the enantioselective fluorination of α-branched aldehydes 105 using chiral secondary amine catalysts (Scheme 37). 54 After a catalyst screen in THF at room temperature, moderate enantioselectivities of the fluorinated products were obtained (45% ee for 106a; 66% ee for 106b). The authors found that better results were obtained when applying these conditions to nonbranched aldehydes. While formation of the α,α-difluoro product was initially a problem, a screen of the solvents revealed that DMF could inhibit formation of this byproduct, and the desired product was formed with 88% ee when imidazolidinone catalyst 111 (30 mol %) was employed, although the yield was low (30%). Unfortunately, use of a stoichiometric amount of the catalyst was required to achieve good yield. Scheme 37 MacMillan and co-workers reported the use of imidazolidinone dichloroacetate 112 for the fluorination of linear aldehydes 99 with NFSI to achieve excellent enantioselectivity (up to 99% ee) (Scheme 38). 55 The authors found that addition of 10% i-PrOH as cosolvent generally improved enantiocontrol and efficiency, although the origin of this effect is not clear. A wide range of functional groups, including olefins, esters, amine, carbamates, aryl rings, and sterically demanding substituents, could be readily tolerated on the aldehyde substrates, although α-branched aldehydes were not discussed. They also evaluated the effect of the catalyst loading on reaction efficiency and found that loadings as low as 2.5 mol % could be used without loss of enantiocontrol. Scheme 38 In 2006, Jørgensen and co-workers reported using chiral 8-amino-2-naphthol derivative 114, the product of an asymmetric Friedel–Craft amination, as an organocatalyst in the asymmetric α-fluorination of α-branched aldehydes. 56 This catalyst delivered the products 113 in up to 90% ee (Scheme 39). In general, good enantioselectivities were achieved when R1 was an aromatic substituent, although the yields were low to moderate due to suspected instability of the products upon column chromatography. In the case of substrates bearing two aliphatic substituents, the enantioselectivities of the reaction dropped significantly, highlighting the challenging nature of these substrates. The authors advanced a mechanistic hypothesis for asymmetric induction, inspired by an X-ray structure of an acylated analogue of the catalyst, which suggested that the catalyst naphthol substituents may sit at right angles to the naphthol core and a hydrogen bond may be present between the BOC group and enamine NH (Figure 12). Scheme 39 Figure 12 Proposed structure of enamine intermediate showing one face blocked and an intramolecular hydrogen bond. Reproduced with permission from ref (56). Copyright 2006 John Wiley and Sons. In 2005, MacMillan and co-workers reported a combination of transfer hydrogenation using Hantzsch ester and electrophilic fluorination using NFSI on enal substrates, which would allow the formal asymmetric addition of HF across trisubstituted olefin systems using a cascade-catalysis approach (Scheme 40). 57 The authors assumed that the iminium and enamine steps might be discretely controlled by separate catalysts, although a single catalyst could also enable both activation cycles. Using imidazolidinone catalyst 118 (20 mol %), the product 116 was obtained in 60% yield with 99% ee, albeit with 3:1 anti:syn diastereoselectivity. Implementation of catalyst combination A (118 7.5 mol % and (S)-112 30 mol %) allowed the formal addition of HF to the trisubstituted enal with 16:1 anti:syn selectivity (99% ee). Remarkably, the syn HF addition product 117 could be accessed with 9:1 selectivity and in 99% ee by simply changing the enantiomeric series of 112 employed in this catalyst combination (118 7.5 mol % and (R)-112 30 mol %). Scheme 40 In 2010, Brenner-Moyer and co-workers reported organocatalyzed enantioselective aminofluorination of enals to afford chiral α-fluoro-β-amino aldehydes using the Jørgensen–Hayashi diarylprolinol catalyst 121 (Table 11). 58 The consistently high diastereo- and enantioselectivities are a testament to the power of the enamine/iminium modes of catalysis. The presence of other olefins, ether protecting groups, and remote reactive functional groups, such as cyano groups, was well tolerated. Table 11 Scope of Reaction for Enantioselective Aminofluorination of Enals entry R yield, % dr (syn:anti) ee, % a Et– 73 95:5 99 b n-Pr– 64 94:6 99 c n-Bu– 66 95:5 99 d PhCH2CH2– 51 95:5 98 e (CH3)2CHCH2– 41 90:10 99 f i-Pr– 24 98:2 80 g CH2=CH(CH2)3– 61 93:7 99 h PhCH2OCH2– 57 87:13 99 i N=C(CH2)5– 41 91:9 99 In 2008, Yamamoto and Shibatomi reported enantioselective fluorination of α-chloro-aldehydes 122 to afford α,α-chlorofluoro aldehydes in high enantioselectivity catalyzed by the catalyst (101) developed by Jørgensen et al. (Scheme 41). 59 In situ reduction of the aldehydes with NaBH4 afforded β,β-chlorofluoro alcohols 123 in high enantioselectivity. The products could be further elaborated to the corresponding α,α-chlorofluoro ketones 124. Subsequent mechanistic studies suggest that the reaction mechanism involves a kinetic resolution of the starting α-chloro-aldehyde. 60 Scheme 41 In 2009, Jørgensen and co-workers reported an extension to their earlier published work: a simple, direct one-pot organocatalytic approach to the formation of optically active propargylic fluorides 126 (Table 12). 61 This consists of organocatalytic α-fluorination of aldehydes followed by homologation with the Ohira–Bestman reagent 125, providing optically active propargylic fluorides 126 with enantioselectivities of up to 99% ee. Table 12 One-Pot Organocatalytic Approach to Enantioenriched Propargylic Fluorides entry R yield, % ee, % a –Bn 56 95 b –(CH2)7CH3 67 93 c –(CH2)13CH3 65 99 d –(CH2)7CH=CH2 55 92 e p-OMe-C6H4CH2– 65 91 f p-Br-C6H4CH2– 69 92 g o-Me-C6H4CH2– 58 99 h o-Br-C6H4CH2– 47 94 i –(CH2)3COOMe 45 93 The authors also extended this approach further to the direct synthesis of click adducts 127 from aldehydes in three steps in one pot in 50% yield with 95% ee (Scheme 42). The Wittig reaction is also fully compatible with the organocatalytic asymmetric reaction. The one-pot reaction, organocatalytic formation of α-fluoro aldehydes in combination with the commercially available methyl (triphenylphosphoranylidene) acetate, furnished the corresponding allylic fluorides 128 in moderate yield and high enantioselectivities. Scheme 42 In 2009, Lindsley and co-workers reported the one-pot catalytic enantioselective synthesis of chiral β-fluoramines 129 via organocatalysis, again proving the versatility of the α-fluorination methodology (Scheme 43). 62 This was accomplished using NFSI with imidazolidinone catalyst 112 (20 mol %), at −20 °C in 10% i-PrOH/THF, followed by direct addition of Boc-piperazine and NaBH(OAc)3. The desired β-fluoroamine 129 was isolated in 65% yield and with >96% ee. Scheme 43 In 2011, MacMillan and co-workers reported the first highly enantioselective α-fluorination of cyclic ketones, catalyzed by a cinchona alkaloid-derived primary amine (Scheme 44). 63a This catalyst was identified after a high-throughput evaluation of a library of chiral amine catalysts. Use of the dihydroquinidine catalyst 132 with trichloroacetic acid (TCA) as cocatalyst at −20 °C provided the α-fluoro cyclic ketones 131 in good yield with excellent enantioselectivities (up to 99% ee). The scope of this reaction was well examined; geminal disubstituted cyclohexanones and a wide array of heterocycles were well tolerated. The five-membered and seven-membered cyclic ketones also worked well (88% and 98% ee), albeit with moderate yield. They also successfully applied this methodology to the diastereoselective fluorination of cyclic ketones bearing pre-existing stereocenters. For example, in fluorination of (R)-3-methyl cycylohexanone (130j), the diastereoselectivity of the fluorinated product could be completely controlled by the choice of catalyst. Scheme 44 They also employed the fluorination conditions to more complex substrates, including the hydrogenated Hajos–Parrish ketone 131o, allo-pregnanedione 131p, and cholestanone 131q (Scheme 45). Scheme 45 Very recently, Lam and Houk reported a detailed computational study of MacMillan’s ketone fluorination, to determine the origin of enantioselectivity. 63b They proposed that fluorination of the quinuclidine portion of the catalyst by NFSI is fast and that the enantiodetermining step is intramolecular transfer of fluorine to the enamine, the latter being formed from condensation of the catalyst primary amine and the ketone substrate. They concluded that there are two key determining factors in the enantiocontrol: first the preferred chair conformation of the seven-membered ring in the transition state and second the steric bulk of the C9-quinoline of the catalyst giving it a strong equatorial preference (Figure 13). Figure 13 Two views of calculated lowest energy transition structure for fluorination of cyclohexanone using amine catalyst 132. Reproduced with permission from ref (63b). Copyright 2014 American Chemical Society. Recently, Xu and co-workers reported the enantioselective fluorination of β-ketoesters catalyzed by a combination of chiral primary amine catalysts (Scheme 46). 64 The desired fluorinated product 48 was afforded in moderate enantioselectivities (39–55% ee) only when QN-NH2 and l-leucine were used together catalysts, and the exact function of each catalyst is unclear. Scheme 46 2.1.3.3 Phase-Transfer Catalysis 2.1.3.3.1 Cationic Phase-Transfer Catalysis In 2002, Kim and Park reported the first catalytic enantioselective fluorination of β-ketoesters employing phase-transfer catalysis using chiral quaternary ammonium salts (Table 13). 65 They found that a bulky group at the bridgehead nitrogen of cinchona alkaloids was crucial for high stereoselectivity, as in catalysts 132. Several cyclic β-ketoesters were submitted to fluorination using NFSI and 132a (10 mol %) as catalyst, affording the desired fluorinated products 48 in high yield with moderate enantioselectivities (48–69% ee). The authors found that for different substrates, tailoring of the base was required to obtain the best results. Fluorination of an acylic substrate 133 required NaH as base, and afforded the α-fluoro product 134 in only 40% ee. Table 13 Enantioselective Fluorination of β-Ketoesters by Phase-Transfer Catalysis entry n R base yield, % ee, % a 1 Me K2CO3 92 69 b 1 Et Cs2CO3 91 63 c 2 Me Cs2CO3 88 48 d 2 Et CsOH 78 52 In 2010, Maruoka and co-workers reported the highly enantioselective fluorination of β-ketoesters catalyzed by chiral bifunctional phase-transfer catalysts (Scheme 47). 66 Fluorination of various cyclic β-ketoesters 9 gave the desired α-fluorinated products with excellent enantioselectivities (up to 99% ee) under the catalysis of thiomorpholine-derived catalyst 135. The authors found the presence of hydroxyl groups in 135 is crucially important to obtain high enantioselectivity. They proposed that in the transition state, the Z-enolate would be stabilized by both the ionic interaction of the ammonium enolate and the hydrogen bonding between the enolate oxygen and one hydroxyl group of the catalyst (Figure 14). This would lead to approach of the NFSI from the upper face of the enolate, as depicted. Unfortunately, these conditions were unsuitable for the fluorination of acyclic substrates. Scheme 47 Figure 14 Proposed transition state structure. Reproduced with permission from ref (66). Copyright 2010 The Royal Society of Chemistry. In 2013, Lu and co-workers reported the enantioselective fluorination of indanone-derived β-ketoesters 47 catalyzed by adamantoyl-derivatized cinchona alkaloid phase-transfer catalyst 136, affording the α-fluorinated products 48 in high enantioselectivities (84–94% ee) (Scheme 48). 67 Scheme 48 Ma, Cahard, and co-workers have recently explored the use of P-spiro phosphonium salts for the fluorination of 3-substituted benzofuran-2-(3H)-ones 137, but only moderate enantioselectivities have been obtained thus far (Scheme 49). 68 Scheme 49 2.1.3.3.2 Anionic Phase-Transfer Catalysis The use of chiral cationic salts as phase-transfer catalysts for anionic reagents is well precedented; however, an analogous charge-inverted strategy in which the salt of chiral anion brings an insoluble cationic promoter into solution has been rather less explored. 69 In 2011, Toste and co-workers reported an advance in this field, asymmetric fluorocyclization using an anionic chiral phase-transfer catalyst. 70 Selectfluor is normally insoluble in nonpolar media, but the authors hypothesized that lipophilic, bulky chiral phosphate anions such as the conjugate base of acid 140 may exchange with the tetrafluoroborate anions associated with Selectfluor to bring the reagent into solution. The resulting chiral ion pair could then mediate an asymmetric fluorination of substrate in solution. Given the insolubility of Selectfluor, little background fluorination of the substrate would be anticipated (Figure 15). Figure 15 Proposed catalytic cycle for chiral anion phase-transfer catalysis, leading to fluorocyclization. Employing optimized conditions (5 mol % 140a, 1.25 equiv of Selectfluor, and 1.1 equiv of proton sponge in C6H5F at −20 °C) on electron-rich enol ether substrates 141 gave the desired fluorocyclization product 142 in high yield with excellent enantio- and diastereoselectivities (Scheme 50). Consistent with their hypothesis, the hydrophobic alkyl chains attached to the backbone of the catalyst proved beneficial for the phase-transfer aspect, improving enantioselectivity from 87% with 140b to 92% with 140a. Scheme 50 They also extended the methodology to less electron-rich alkenes 143 (Scheme 51). Accordingly, fluorocyclization of dihydronaphthalene (143a–c) and chromene (143d) substrates also gave excellent enantio- and diastereoselectivities at room temperature. Scheme 51 An unanticipated benefit of the phase-transfer protocol was an improved tolerance toward sensitive functionality. For example, when treated with Selectfluor under homogeneous conditions, benzothiophene substrates 145 were converted to a complex mixture of products. However, when the chiral anion phase-transfer reaction conditions were applied, fluorocyclization products 146 were isolated in good yield and high optical purity (Scheme 52). Scheme 52 In 2012, Toste and co-workers reported the asymmetric fluorination of enamides to access α-fluoroimines using the same chiral anion phase-transfer catalysis strategy (Scheme 53). 71 Applying conditions similar to those previously employed (Selectfluor, chiral phosphoric acid 140a, Na2CO3 in hexane), enamides or ene-carbamates gave the desired α-fluoroimine products, which were stable and isolable. However, only the N-benzoylenamide substrates 147 gave very high enantioselectivities. A number of cyclic indanone and tetralone-derived enamides provided enantioenriched α-(fluoro)benzoylimines 148 bearing a variety of diversely substituted quaternary fluorinated stereocenters. Under the phase-transfer fluorination conditions, chloro- and bromo-substituted enamides also gave the novel β,β-chloro,fluoro and bromo,fluoro compounds with high enantioselectivities. A beneficial effect in enantioselectivity was observed for some substrates when the reaction was run in the presence of 5 equiv of 3-hexanol, although the exact role of this additive is unclear. Scheme 53 Unsubstituted tetralone-derived enamides 149 also delivered stable imine products that did not racemize (Scheme 54). Fluorination of a racemic flavanone-derived enamide 151, which has a pre-existing stereocenter, resulted in approximately equal ratio of separable anti and syn diastereomers (152a, 152b), both with excellent enantioselectivities, illustrating the high selectivity of the catalytic system, regardless of the presence of an existing adjacent stereocenter. Scheme 54 On the basis of the experimentally observed absolute stereochemistry, they advanced a tentative model for interactions with the catalyst (Figure 16). The phosphate anion is thought to form an ion pair with the Selectfluor reagent on the phosphate oxygen, while the phosphoryl oxygen activates the enamide through hydrogen bonding. The absolute stereochemistry can be rationalized by placing the aromatic ring of the tetralone in the “open” quadrant of the catalyst. Figure 16 Proposed model for selectivity in fluorination of enamides using chiral anion phase-transfer catalysis. Reproduced with permission from ref (71). Copyright 2012 American Chemical Society. Subsequently, Toste and co-workers developed an enantioselective tandem oxyfluorination of enamides using a doubly axially chiral phosphoric acid. 72 They proposed that the fluorination of aldehyde-derived enamides 153 would generate, in the first instance, a protonated α-fluoro-N-acyliminium ion. This intermediate should exhibit hydrogen-bonding interactions with the chiral phosphate anion, allowing catalyst-controlled addition of an external oxygen nucleophile, constituting an oxyfluorination of enamides. Optimization of the reaction revealed that only the Z-enamides gave high diastereo- and enantioselectivities when the novel doubly axially chiral catalyst 155 was used. They anticipated this catalyst would generate a more rigid and constrained pocket for the substrate, leading to higher selectivity. Both aromatic and aliphatic substituted enamides 153 were effective in the tandem hydroxyfluorination process (Scheme 55). In accord with the hypothesis that catalyst control is operative in the hydration step, product 154j was produced in high enantioselectivity, in which only the N,O-aminal carbon is chiral. When the reaction was run in the presence of alcohols, alcohol addition was observed rather than hydration, the latter being thought to arise from moisture in the Selectfluor (154k–m). Scheme 55 They also explored substrates that would generate a chiral quaternary fluorine stereocenter (Scheme 56). Fluorination of (E)-156 gave poor diastereoselectivity but extremely high enantioselectivity for the anti-157 and low enantioselectivity for syn-158, which was believed to be a result of double stereodifferentiation. However, this effect was not as pronounced for (Z)-159. Scheme 56 In 2013, Toste and co-workers reported the catalytic asymmetric 1,4-aminofluorination of conjugated dienes using chiral anion phase-transfer catalysis (Table 14). 73 The 6-endo-trig fluorination of diene substrate 160 would produce an allylic fluoride, an important chemical motif. Optimization revealed catalyst 140c to be superior. Although far from the reactive center, substitution on the benzamide arene exerted a strong influence on the selectivity, with tert-butyl substitution at the para position giving the best results. Table 14 Asymmetric 1,4-Aminofluorination of Conjugated Dienes Using Chiral Anion Phase-Transfer Catalysis entry Ar R1 R2 X yield, % ee, % dr a 2-MeC6H4 H H CH2 91 96 >20:1 b 3-MeC6H4 H H CH2 92 92 5.9:1 c C6H5 H H CH2 90 92 6.9:1 d C6H5 H OMe CH2 90 93 6.9:1 e C6H5 H H O 85 91 5.5:1 f 4-CF3C6H4 H H CH2 94 95 10:1 g 4-MeOC6H4 H H CH2 89 93 7.5:1 h C6H5 nBu H CH2 85 94 >20:1 The fluorocyclization of less-reactive dienes 164 was also examined (Scheme 57). When subjected to the optimized reaction conditions using Selectfluor as the fluorine source, dienes 164 (not tetralone-derived, as before) reacted sluggishly, affording only racemic product. The authors hypothesized that the reactivity of the fluorinating reagent may be increased by attaching an electron-deficient aryl group in place of the chlorine atom of Selectfluor. Different derivatives were accessed simply by treating tetrafluoroborate salts 162 with XeF2. The more electron-deficient reagent 163 produced the cyclized product 165c with the highest levels of enantioselectivity (89% ee). Scheme 57 In 2013, Phipps and Toste applied this chiral anion phase-transfer catalysis strategy to the asymmetric fluorinative dearomatization of phenols. 74 They hypothesized that hydrogen bonding of the phenolic hydroxyl group with the phosphoryl oxygen of the catalyst might enable discrimination between the enantiotopic faces of the phenol in a subsequent fluorination reaction. Accordingly, they found that fluorination of 2,3-di- and 2,3,4-trisubstituted phenols under optimized conditions using 5 mol % (S)-140c afforded ortho-fluorinated dearomatized products with high enantioselectivities (Scheme 58). Scheme 58 They also investigated substrates without substitution at the 3-position (Table 15). The isolated products 169 were found to be dimers resulting from [4 + 2] cycloaddition of the chiral 2,4-cyclohexadienones produced after the initial fluorination. They demonstrated the further transformation of the dimeric products in the form of retro-[4 + 2]/[4 + 2] reactions with N-phenylmaleimide and cyclopentadiene dimer to provide rapid access to a diverse fluorinated scaffolds (170, 171) with no loss of enantioenrichment. Table 15 Asymmetric Fluorinative Dearomatization of Phenols – Scope of Phenols Lacking 3-Substitution and Further Transformation of the Products entry R1 R2 yield, % ee, % a Bn H 81 97 b Ph H 55 90 c homoallyl H 65 90 d allyl H 71 87 e iPr H 96 91 f allyl Me 51 92 g Bn Me 67 90 h (CH2)3OTBS H 77 91 A number of para-fluorinated products were also demonstrated to be obtainable with good enantioselectivities by incorporating the geminal 8,8′ disubstitution to increase the steric bulk. Throughout the study, the authors noted that steric bulk on one side of the phenol was required to achieve high selectivities. In the case of the para-fluorination process, yields were moderate due to competitive SEAr arene fluorination at the ortho position (Scheme 59). Scheme 59 In 2013, Toste and co-workers reported the enantioselective fluorination of alkenes using chiral anion phase-transfer catalysis and employing remote directing groups (Scheme 60). 75a On the basis of their previous success with amides as pendant nucleophiles, they posited that allylic amides may be used as remote directing groups to direct alkene fluorination to provide access to allylic fluoride products after elimination. Optimization revealed the catalyst STRIP (176) gave superior enantioselectivity and chemoselectivity to TRIP (140b), which may be caused by its tighter binding pocket. An N-methylated analogue of 174 was unreactive under the same conditions, supporting their hypothesis that a substrate hydrogen-bond donor is required to direct the fluorination. Investigation of the scope of compatible amide directing groups revealed the best enantioselectivities were observed with larger groups on the amide (174a–e). The scope of this reaction was explored; substrates with different ring sizes, benzamide substitution patterns, substitution on the bicyclic core, and heterocyclic substrates were well tolerated. Scheme 60 In addition to amides, 2-hydroxyphenyl was found to be an effective directing group to enable enantioselective fluorination of a number of tethered alkenes under similar conditions (Scheme 61). As compared to related allyl substrates that were previously observed to undergo fluorinative dearomatization under similar conditions (Table 15), increased substitution on the alkene switches the chemoselectivity with fluorination at the alkene being seen exclusively, rather than fluorination at the phenol. Both β-phenolic tertiary and quaternary fluorides 177a–d with alkyl, aryl, or heteroaryl substituents were obtained with good to excellent enantioselectivities. This concept was extended to allylic alcohols using a boronic acid as an in situ directing group. 75b Scheme 61 In 2013, Alexakis and co-workers reported the enantioselective fluorination-induced Wagner–Meerwein rearrangement of strained allylic alcohols using chiral anion phase-transfer catalysis (Scheme 62). 76 Fluorination of substrates 178 with Selectfluor, Na3PO4 in C6H5F/hexane (1:1) at −20 °C with catalyst 180 afforded the ring expanded products 179 with good diastereo- and enantioselectivities. Interestingly, both the enantioselectivity and the diastereoselectivity of the present transformation were controlled by the catalyst. Thus, racemic reaction (using an achiral phosphoric acid) gave low diastereoselectivities. The substrate scope encompasses both allylic cyclobutanols and allylic cyclopropanols based on the tetralone scaffold, as well as the chromanone scaffold. However, allylic alcohol substrates lacking the aromatic ring gave good yields but only moderate stereoselectivities under the optimized conditions. Scheme 62 2.1.3.4 Miscellaneous Catalysts In 2012, Sun and co-workers reported the enantioselective synthesis of β,γ-unsaturated α-fluoroesters catalyzed by N-heterocyclic carbenes (NHCs). 77 NHCs are well-known for their unique capability to reverse the normal polarity of aldehydes. The authors hypothesized that an enal bearing a leaving group in γ-position would provide access to a chiral NHC-bound dienolate that may subsequently react with an electrophilic fluorinating reagent and a nucleophile to afford an enantioenriched fluorinated product (Scheme 63). Scheme 63 Fluorination of γ-methyl-carbonate-substituted α,β-unsaturated enals 181 with NFSI using 183 as catalyst afforded the desired fluorinated products 182 in good yield with high enantioselectivities (Scheme 64). A variety of functional groups on the substrates were well tolerated, including ethers, halides, cyanides, alkenes, aryl aldehydes, ketones, free alcohols esters, and silyl-protected alcohols. The presence of a quaternary carbon atom in γ-position (181q) did not significantly affect the reaction efficiency, and a trisubstituted alkene could be obtained as a single E isomer. In contrast, a substituent at the α-position (181r) significantly retarded the reaction (<10% conversion) and led to moderate enantioselectivity. Alkenes with alkyl substituents at the γ position also participated smoothly in this reaction, albeit with low E/Z ratio. The E/Z ratio could be improved by employing bulkier alkyl groups, such as iPr and tBu. Scheme 64 The authors also proposed a possible transition state to account for the control of enantioselectivity (Figure 17). In the proposed favored dienolate, the chiral backbone of the NHC blocks the Si face, leading to the observed enantiomer. DFT calculations revealed that the less favored rotamer, in which the Re face is blocked, is about 5.3 kca lmol–1 higher in energy than the favored one due to an unfavorable interaction between the enolate oxygen atom and a catalyst methyl group when the system is fully conjugated. Figure 17 Summary of DFT calculations leading to hypothesis to account for absolute stereochemistry. In 2012, Niu and co-workers reported the thiourea-catalyzed enantioselective fluorination of β-ketoesters (Scheme 65). 78 They found that chiral bifunctional thiourea catalyst 184 could efficiently catalyze the fluorination of β-ketoesters 35 with NFSI with the assistance of DMAP in MeOH at −60 °C to afford the desired fluorinated product in high yield with good to excellent enantioselectivities. The alkoxy group of the indanonecarboxylate derivatives had a great influence on enantioselectivity, with Me and Bn being optimal. The tetralone derivatives and acyclic β-ketoesters gave low enantioselectivities in some cases. Scheme 65 The authors also proposed a mechanism proceeding via a dual-activation process wherein the NFSI hydrogen bonds to the catalyst thiourea group and the 1,3-dicarbonyl compound interacts with the basic nitrogen of the catalyst (Figure 18). Figure 18 Proposed intermediate in dual-activation process. Reproduced with permission from ref (78). Copyright 2012 John Wiley and Sons. In 2014, Akiyama and co-workers reported enantioselective fluorination of β-ketoesters catalyzed by a chiral sodium phosphate derived from acid 187 (Scheme 66). 79 The authors supposed that simultaneous formation of the sodium enolate and sodium phosphate under basic conditions is the key to achieving excellent selectivity. Indanone derivatives 185a–c as well as benzofuranone derivatives 185d–f were employed in this reaction to afford the fluorinated products in good yields with good to excellent enantioselectivities. Scheme 66 Very recently, Fu and co-workers reported the asymmetric synthesis of tertiary alkyl fluorides via a nucleophile-catalyzed α-fluorination of ketenes (Scheme 67). 80 In this process, the planar-chiral nucleophilic catalyst 191 reacts with the ketene 189 to form a catalyst-derived chiral enolate. This intermediate undergoes electrophilic fluorination, and the resulting cationic intermediate is attacked by a phenoxide additive (188), which releases the nucleophilic catalyst and forms the product 190. The phenoxide additive needed to be carefully chosen to ensure turnover, and mechanistic studies ruled out an alternative pathway whereby the catalyst itself is directly fluorinated (Figure 19). Using this approach, a range of valuable tertiary α-fluoroesters could be accessed from aryl alkyl ketenes, with very high levels of enantioselectivity. Scheme 67 Figure 19 Proposed mechanism for α-fluorination of ketenes. Reproduced with permission from ref (80). Copyright 2014 American Chemical Society. 2.1.4 Fluorination Using Multiple Catalysts In 2008, Lectka and co-workers reported a catalytic, highly enantioselective α-fluorination of acid chlorides. 81 This reaction exploits a “dual activation” strategy in which a chiral Lewis base catalyst (a cinchona alkaloid derivative) is combined with a transition metal-based Lewis acid cocatalyst (Pd or Ni were particularly effective) to catalytically generate metal-coordinated, chiral ketene enolates. These are fluorinated by NFSI at the α position, followed by attack of the liberated dibenzenesulfonimide anion that can be subsequently quenched with different nucleophiles to afford fluorinated carboxylic acids, amides, esters, and even peptides (Scheme 68). Scheme 68 Treatment of acid chlorides 192 with NFSI, Hünig’s base, 10 mol % BQd catalyst (193), and trans-(Ph3P)2PdCl2 or (dppp)NiCl2, followed by quenching with nucleophiles after 6–15 h afforded the desired α-fluorinated acid derivatives 194 in good yield with excellent enantioselectivities. Acid chlorides containing aromatic as well as heterocyclic substituents proved to be compatible substrates (Table 16). Table 16 Substrate Scope of the Fluorination of Acid Chlorides Using a Dual Catalyst System entry R catalyst [M] NuH yield, % ee/de, % 1 p-MeOPh Ni MeOH 83 99 2 p-MeOPh Pd l-NH2-Ph-OEt 68 >99 3 p-MeOPh Pd PhSH 67 98 4 p-MeOPh Ni N-Boc-l-prolinol 90 >99 5 Ph Ni MeOH 61 99 6 Ph Ni H2O 60 99 7 1-Np Ni MeOH 68 98 8 1-Np Ni N-Coc-l-Cys-OMe 80 >99 9 2-Np Pd MeOH 63 >99 10 2-thiophene Pd MeOH 69 99 11 2-(N-benzoylindolyl) Pd MeOH 58 94 12 2-(3-Ph-(ethylcinnamate) Ni MeOH 71 99 13 phthalimido-CH2 Pd MeOH 72 >99 14 phthalimido-CH2 Pd NH(CH2)5 79 >99 15 indo Pd MeOH 84 95 16 phthalimido-CH2 Pd (+)-emetine 91 >99 In 2010, the same group reported the quenching of the above reaction with nucleophilic natural products to produce biologically relevant α-fluorinated carbonyl derivatives (Scheme 69). 82 They found that the solubility of the nucleophile used to quench the reaction proved critical. Glutathione, morphine, and 6-aminopenicillanic displayed marginal solubility, leading to drastically decreased yields. Some site selectivity was also observed; for example, when p-methoxylphenylacetyl chloride was fluorinated and quenched with taxol, the sole product (195c) resulted from acylation at the hydroxyl shown. Scheme 69 Although the fluorination of aryl and heteroaryl acetyl chlorides (192, R = aromatic) using the above approach proved to be very successful, the related aliphatic substrates (196) worked poorly, delivering low yields of fluorinated products. Following initial mechanistic studies, Lectka and co-workers speculated that addition of a second Lewis acid may coordinate NFSI selectively, thereby increasing its electrophilicity and reactivity (Scheme 70). 83 After optimization, the authors found that addition of 10 mol % LiClO4 combined with the slow addition of Hünig’s base over 12 h could increase the yield of the aliphatic substituted products 197 while still delivering excellent enantioselectivities (>99% ee). Scheme 70 After a subsequent in-depth mechanistic analysis, which took into account the presence of three catalysts, Lewis acid activation of the fluorinating agent by a lithium cation was deduced to be crucial to the efficient reaction (Figure 20). Figure 20 Summary of the key mechanistic aspects involved in enabling the enantioselective fluorination of alkyl-substituted acid chlorides. In 2014, Toste and co-workers reported the asymmetric fluorination of α-branched cyclohexanones enabled by a combination of chiral anion phase-transfer catalysis and enamine catalysis using protected amino acids. 84 While simple ketones did not undergo fluorination under conditions that had previously been successful on other substrate classes, they supposed that inclusion of a catalytic amount of a primary amine may form an enamine that should be reactive to electrophilic fluorination and also act as a hydrogen-bond donor for interaction with the chiral phosphate catalyst (Figure 21, cycle 1). Independently, the lipophilic chiral phosphate would undergo anion exchange with the achiral tetrafluoroborate counteranions of insoluble Selectfluor to catalytically generate a soluble, chiral electrophilic fluorinating reagent (cycle 2). Figure 21 Proposed combination of two catalytic cycles for the enantioselective fluorination of ketones. Reproduced with permission from ref (84). Copyright 2014 American Chemical Society. The authors found that the addition of achiral primary amine catalysts did increase the yield of fluorinated product, but without any significant enantioselective induction (Table 17). Because glycine methyl ester gave reasonable yield, chiral amino acid methyl esters were subsequently evaluated. While l-phenylalanine methyl ester gave −40% ee, the two chiral catalysts were evidently mismatched in this case, as switching to d-phenylalanine methyl ester gave the desired fluorinated product in 88% ee. This was able to be increased to 94% ee by the use of a 1-naphthyl version of d-phenylalanine as increased steric bulk on the amine acid side chain was found to play a key role. In the absence of either catalyst, both yield and ee were found to be <10%, demonstrating the crucial nature of both chiral catalysts to an effective transformation. Table 17 Optimization of the Fluorination of 2-Phenylcyclohexanone Using Two Chiral Catalysts The scope and limitations of this transformation were explored (Scheme 71). A range of para- and meta-substituted aryl groups are well tolerated in the α-position of the cyclohexanone, as well as heteroatom-substituted cyclohexanones (198l, m). They also demonstrated that several 2-alkenyl and 2-alkynyl cyclohexanones (198o–r) are also viable substrates in their fluorination, delivering good to high enantioselectivities (77–86% ee). Complete regioselectivity was observed for fluorination at the α-position and no undesired fluorination of either the alkene or the alkyne was observed, although 2-alkyl-substituted cyclohexanones were not reactive toward fluorination. Scheme 71 2.1.5 One-Pot and Tandem Processes A tandem process can be broadly thought of as one in which the substrate undergoes multiple distinct reactions in a single synthetic operation. If such a process involves the fluorine stereocenter being formed after an initial step, the stereoselectivity of the fluorination step could be either controlled by the first stereocenter or be under catalyst control. While this Review is not intended to cover strictly diastereoselective fluorination reactions, tandem processes will be given an overview in this section due to the potential ambiguities of determining whether or not the fluorination step is under catalyst control. In 2009, Zhao and co-workers reported an organocatalyzed intramolecular oxa-Michael addition/electrophilic fluorination tandem reaction for the synthesis of a series of chiral fluorinated flavanones. 85 They envisioned that by using a bifunctional catalyst, an organocatalytic, asymmetric, intramolecular oxa-Michael addition of 201 would produce enantioenriched enolate, which could be subjected to electrophilic fluorination to provide chiral, fluorinated flavanone derivatives 202. After careful optimization, it was found that catalyst 203 efficiently catalyzed the oxa-Michael addition of the substrate in toluene, after which NFSI and Na2CO3 were added into the mixture to afford the desired fluorinated flavanone product 202 in high enantioselectivities (Scheme 72). The authors found that the rate of fluorination varied with the catalyst used and proposed that the catalyst may be involved in the fluorination step. Scheme 72 In 2011, Ma and co-workers reported the diastereo- and enantioselective tandem 1,4-addition/fluorination catalyzed by chiral monodentate phosphoramidite ligands 206 and copper (Scheme 73). 86 In this reaction, conjugate addition of organometallic reagents to alkylidene β-ketoesters 204 was followed by fluorination with NFSI to afford the fluorinated products 205. In screening of the ligands, the authors developed a superior catalyst 206 bearing bulky substituents at the 3- and 3′-positions of the binaphthol unit, with the aim of narrowing the space around the P-ligated metal center as well as relaying the axial chirality to the reaction site. The scope of this reaction was broad, with aryl substituents on both the ketone and the alkylidene moieties. Alkyl-substituted substrates (204u, v) also provide the tandem products in good yield and enantioselectivities, and various dialkylzinc reagents also participated to give the corresponding products (205m–p). Scheme 73 The authors also demonstrated that if the reaction was conducted in a stepwise manner, the diastereoselectivity of the product was significantly reduced, suggesting that the one-pot operation is important to achieve stereoselectivity (Scheme 74). Scheme 74 In 2012, Ma and co-workers reported an organocatalytic, asymmetric, one-pot sequential 1,4-addition/dearomative-fluorination transformation using pyrazolones (208a, X = NR) as the aromatic partners, thus leading to optically active fluorine-containing products with two adjacent stereogenic centers (Scheme 75). 87 This transformation is catalyzed by a chiral tertiary-amine-thiourea compound 211a in combination with benzoic acid. Other nucleophilic donors were also tested for the sequential reaction, and similarly high levels of reactivity and stereocontrol were observed. Scheme 75 The Michael-addition product 212 could be isolated in almost quantitative yield with excellent levels of enantioselectivity by omission of the fluorination step (Scheme 76). Subjecting this intermediate to triethylamine and NFSI afforded dearomatization-fluorination product 213 in high yield although with slightly lower diastereoselectivity. The authors suggested that the thiourea catalyst also plays some role in stereocontrol for the fluorination step. Scheme 76 A possible mechanism for this transformation was proposed by the authors. In the first cycle, the nitroalkene binds with the thiourea of the catalyst through hydrogen bonding while the pyrazolone in its enol form hydrogen bonds with the ammonium center of the chiral catalyst, providing enantiocontrol in the 1,4 addition. The product then reassociates with the catalyst, again through multiple hydrogen-bond interactions for the subsequent fluorination step (Figure 22). Figure 22 Proposed mechanism for the tandem 1,4-addition/fluorination. Reproduced with permission from ref (87). Copyright 2012 John Wiley and Sons. Ma and co-workers also reported a variation of this reaction using isoxazol-5(4H)-ones (208b, X= O) as substrates (Scheme 75). 88 In this reaction, 1.2 equiv of Na2CO3 as an additive was found to be essential for the high yield of the fluorination step. A variety of different substitutions on the aryl ring of the nitroalkenes were tolerated, although alkyl substituents were unsuitable. The authors observed that the catalyst made some contribution to the control of diastereoselectivity in the fluorination step. 2.2 Nucleophilic Fluorination Nucleophilic sources of fluorine have only been harnessed in the context of asymmetric catalysis much more recently when compared to their electrophilic counterparts. This could be partially attributed to difficulties in dealing with the high basicity of fluoride, relative to its often fairly low nucleophilicity. In an important early report in 2000, Bruns and Haufe described the moderately enantioselective ring opening of meso-epoxides using a stoichiometric amount of Jacobsen’s (S,S)-(+)-salen)chromium chloride complex and KHF2/18-crown-6 as fluoride source. 89a One year later, they reported opening of meso-epoxides 214 with AgF mediated by similar chiral complexes with moderate enantioselectivities (Scheme 77). 89b,89c Scheme 77 In 2010, Kalow and Doyle achieved a catalytic version of the same reaction (Scheme 78). 90 Their strategy involved amine-catalyzed slow generation of HF from benzoyl fluoride and an alcohol, which was hypothesized to permit the mild conditions and efficient catalysis. They envisaged that the use of a chiral amine as catalyst may provide a route into enantioselective catalysis. However, neither achiral nor chiral bases [e.g., (−)-tetramisole (219)] induced measurable reactivity for epoxide opening at room temperature until a Lewis acid was added as a cocatalyst. A combination of (−)-tetramisole (219) and Co(salen) catalyst (R,R)-218 gave excellent enantioselectivities. A pronounced matched/mismatched effect for the combination of the two catalysts was observed in this dual-catalysis approach. Various meso-epoxides were well tolerated in these reactions, including five-, six-, seven-, and eight-membered cyclic epoxides with alkene, ester, and protected amine functionalities, affording fluorohydrins 217 in 85–95% ee. Scheme 78 Kinetic resolution of terminal epoxides 220 was also investigated under these conditions (Scheme 79). Regioselective opening at the terminal position afforded the corresponding fluorohydrins 221 with up to 99% ee. The tolerance of a silyl protecting group in one substrate (220c) under these conditions demonstrated the relative mildness of the catalytically generated fluoride. Scheme 79 In 2011, the same authors described elegant and detailed mechanistic studies of their Co(salen) and amine cocatalyzed reaction. 91 Substituent effects in the opening of para-substituted styrene oxides established that ring opening is the rate-limiting step. The authors deduced that this step proceeds via a bimetallic mechanism, based on a combination of nonlinear effects studies with monomeric catalysts and further experiments using linked, dimeric catalysts and that the active nucleophilic fluorine source is a metal bifluoride (Scheme 80). With these insights, they improved the reaction protocol by developing linked Co(salen) catalyst 222, which afforded significantly elevated rates, expanded substrate scope, and high enantioselectivity for the desymmetrization of meso-epoxides 216 in conjunction with cocatalyst DBN (conditions A, Scheme 81). Notably, an acyclic meso epoxide (216c), which underwent slow ring opening previously (conditions B), provided product 217c in good yield and enantioselectivity. Scheme 80 Scheme 81 Using the dimeric catalyst, rate enhancement was also observed for resolution of terminal epoxides, allowing reactions to be carried out in shorter times with impressively low catalyst loadings (Scheme 82). Scheme 82 In 2013, Kalow and Doyle reported the enantioselective ring opening of aziridines. 92 While Co(salen) complexes proved effective Lewis acids for activation of epoxides, they were unsuitable for protected aziridines, so the authors employed a distinct Lewis acid to achieve this. Ultimately, a combination of two Lewis acids, the chiral Co(salen) (218) and an achiral Ti(IV) cocatalyst, provided optimal reactivity and enantioselectivity to deliver the trans-β-fluoroamine product 224. The use of a chelating protecting group was crucial to reactivity, with picolinamide being optimal. Acyclic and cyclic meso N-picolinamide aziridines 223 underwent fluoride ring opening in up to 84% ee (Scheme 83). Scheme 83 Mechanistic studies supported the proposal that the chiral (salen)Co catalyst delivers the fluoride nucleophile while the Ti(IV) cocatalyst activates the aziridine (Figure 23). Unlike the previous work, dimeric Co(salen) catalysts provided no rate acceleration, consistent with the proposed mechanistic scenario. Figure 23 Proposed mechanistic scenario for ring opening of aziridines. Reproduced with permission from ref (92). Copyright 2013 Elsevier. Doyle and co-workers have very recently applied this methodology in a stoichiometric sense to 18F radiolabeling for PET imaging. 93 In this procedure, the Co(salen)F reagent is readily accessed by anion metathesis from the corresponding tosylate with [18F]fluoride. This can then be reacted with a range of epoxides directly to obtain the “hot” enantioenriched fluorohydrins. In 2010, Katcher and Doyle reported a palladium–bisphosphine complex-catalyzed enantioselective fluorination of allylic chlorides with AgF (Scheme 84). 94 They hypothesized that efficient and mild allylic C–F bond formation proceeded by the nucleophilic attack of fluoride on an electrophilic Pd(II)-allyl intermediate of the type that is well-established for Pd-catalyzed allylic alkylation. Investigations of nucleophilic attack on a stoichiometric Pd(II)–allyl complex showed that more basic alkali metal fluoride sources mostly resulted in elimination; only AgF produced a good yield of the desired substitution. Substrates possessing traditional leaving groups for Pd-catalyzed allylic alkylation were unreactive with the Pd(0) catalyst and AgF; however, the authors discovered that allylic chlorides gave good yields and high enantioselectivities of the desired products. They proposed that precipitation of AgCl provides a strong driving force for C–F bond formation. The commercially available Trost ligand 227 imparted high levels of enantioinduction in the production of the allylic fluoride products 226 (85–96% ee). The scope of the reaction includes six-membered cyclic allylic chlorides with various functional groups. Scheme 84 In 2011, Doyle and co-workers successfully extended their methodology to encompass the regio- and enantioselective fluorination of acyclic allylic halides (Scheme 85). 95 Interestingly, with triphenylphosphine as ligand their reaction exhibited good selectivity for the branched allyl fluoride, rather than the linear. They found that bidentate phosphines with larger bite angles gave higher regioselectivity, with the commercial Trost naphthyl ligand 230 giving >20:1 selectivity for the branched product. They hypothesized that one reason for this preference could be that the small size of fluorine favors attack at the more hindered terminus of the Pd π-allyl complex. They also suggest the possibility of hydrogen bonding of the fluoride with the ligand, effectively directing the nucleophile to give the branched product. Support for this latter hypothesis is provided by the superior regioselectivity in nonpolar solvents. Despite the high regioselectivity, moderate to low enantioselectivities were attained with linear substrates 228a–d. The authors found that substrates possessing allylic substitution performed well, 228e–i bearing α-branching or heteroatom substituents undergo fluorination with 90–97% ee. However, fluorination of cinnamyl chloride (228j) as substrate gave the minor branched isomer with 0% ee, revealing the current limitations of the method. Scheme 85 In 2012, Lautens and co-workers reported the rhodium-catalyzed asymmetric ring opening of oxabicyclic alkenes (Scheme 86). 96 Triethylamine trihydrofluoride (Et3N·3HF) was the optimal source of fluoride; sources such as TBAF, KF, or Doyle’s conditions resulted in no product formation. Use of [Rh(cod)Cl]2 and chiral Josiphos ligand (R,S)-ppf-PtBu2 (233) afforded the ring-opened products with high enantioselectivity. The reaction is suggested to follow a pathway proceeding by SN2′ nucleophilic displacement, giving the 1,2-trans product. Various substituents on the aryl ring were well tolerated. However, with electron-donating groups on the aryl ring (231d, f), the ring-opened products would decompose to 1-naphthol by elimination of HF on silica gel, a problem that was solved by mild hydrogenation after aqueous workup, affording the stable alkyl fluorohydrin products. For unsymmetrical oxabicyclic alkenes (231g, h), both regioisomers were formed with high enantioselectivities, although some isomers proved to be unstable (233g′, h′). Scheme 86 Recently, Shibata and co-workers reported a catalytic fluorination system consisting of catalytic iodoarene together with HF and mCPBA. 97 This system was applicable to two classes of substrates including the fluorination of β-dicarbonyl compounds 47 and the intramolecular aminofluorination of ω-amino-alkenes 234 (Scheme 87). Mechanistically, the catalyst/reagent combination was proposed to generate ArIF2 in situ. In the case of substrates 47, enolate attack onto the active reagent is followed by displacement by fluoride to give 48. In the case of aminoalkenes 234, oxidation of the nitrogen by ArIF2 is thought to lead to aziridinium intermediates, which are subsequently opened by attack of fluoride to give piperidines 235. Preliminary trials of catalytic asymmetric variants were also conducted, and promising enantioselectivities for the desired products were obtained when (R)-binaphthyldiiodide (236) was used as catalyst. Scheme 87 3 Catalytic Enantioselective Trifluoromethylation and Perfluoroalkylation Among perfluoroalkyl groups, the trifluoromethyl group is the most widespread, appearing in numerous pharmaceuticals and agrochemical compounds and being often employed in materials science. The increased lipophilicity and often superior metabolic stability as compared to methyl analogues often accounts for an improved activity profile in a medicinal chemistry context. 2f Hence, the development of approaches for the straightforward introduction of trifluoromethyl groups into small molecules has received much recent attention, including methods for their asymmetric introduction. 3a Methods for their incorporation can be broadly classed as nucleophilic, electrophilic, or free radical processes. However, when compared to nonfluorinated alkyl halides, the reactivity of perfluoroalkyl halides diverges somewhat, due to the strong negative inductive effect of the perfluoroalkyl portion. As result of this strong stabilization of negative charge, perfluoroalkyl iodides in some instances can be used as electrophilic iodination reagents, resulting in the relatively stable perfluoroalkyl anion. In other cases, their behavior can be analogous with that of electrophilic reactivity, although closer analysis often reveals that the mechanism involves a series of single electron transfer steps with radical intermediates. 1c Perhaps due to this element of mechanistic unpredictability, it is only relatively recently that advances in catalytic asymmetric electrophilic trifluoromethylation have been made. 3c,3l,3n 3.1 Asymmetric Nucleophilic Trifluoromethylation 3.1.1 Overview of Nucleophilic Trifluoromethylation Asymmetric nucleophilic trifluoromethylation of carbonyl compounds is an effective and direct strategy to obtain optically active trifluoromethylated alcohols. 98 These fluorine-containing chiral structures have been involved in the design and modification of molecules such as Befloxatone, 99 Efavirenz, 100 and ferroelectric liquid crystals, 101b,101c among other applications. Me3SiCF3 (238) (commonly known as the Ruppert–Prakash reagent) is the most commonly employed synthetic equivalent of the trifluoromethyl anion. 102 The first example of nucleophilic trifluoromethylation of carbonyl compounds using this reagent was reported in 1989 by Prakash (Scheme 88). 103 Commonly, nucleophilic activators such as tetrabutyl ammonium fluoride (TBAF) are used in a catalytic manner to activate the Ruppert–Prakash reagent, initially generating alkoxide 239. The generally accepted mechanism for this transformation is depicted in Scheme 88. The fluoride anion acts as an initiator and reacts at the silicon of 238 to form Me3SiF and tertbutylammonium alkoxide intermediate 239. Following this initiation step, the catalytic cycle can commence as 239 reacts with an equivalent of Me3SiCF3 to form a pentavalent silicate that delivers a trifluoromethyl anion equivalent to an equivalent of ketone. In this step, alkoxide 239 is regenerated to restart the catalytic cycle. Scheme 88 3.1.2 Asymmetric Trifluoromethylation Using Chiral Ammonium Fluorides Given the anionic nature of the species proposed to attack the prochiral carbonyl compound in the generally accepted mechanism for trifluoromethylation using the Ruppert–Prakash reagent, an early approach to induce asymmetry aimed to take advantage of a chiral cation strategy. Iseki, Kobayashi, and co-worker reported the first example of such an approach catalyzed by chiral quaternary ammonium fluorides in 1994. 104 The chiral catalysts 241 derived from cinchona alkaloids were able to convert the carbonyl compounds to corresponding trifluoromethylated alcohols in high yield with moderate but encouraging enantioselectivity (Table 18). It has been described that Prakash showed in unpublished results in 1993 that 9-anthraldehyde was converted to the corresponding trifluoromethylated alcohol with 95% ee. 3a This employed a similar strategy but by using N-benzylquinidinium fluoride 241c; however, further details such as the amount of chiral fluoride employed and the yield of 242 are not readily available, making comparison difficult (Scheme 89). Table 18 Asymmetric Trifluoromethylation of Aldehydes and Ketones Using Chiral Ammonium Fluoride Catalysts 241 entry R1 R2 cat. (mol %) yield (%) ee 1 Ph H 241a (20) >99 46 (R) 2 nC7H15 H 241b (20) >99 15 3 9-anthraldehyde 241b (10) 98 45 (R) 4 Ph Me 241b (20) 91 48 5 Ph iPr 241b (20) 87 51 Scheme 89 In related work not involving ammonium fluorides, Kuroki and Iseki designed and synthesized novel chiral triaminosulfonium salts 243 in an attempt to improve their previous results. Unfortunately, the observed enantioselectivities and substrate scope were not significantly improved, and only the case of benzaldehyde gave improvement, with 52% ee (Table 19). 105 Table 19 Asymmetric Trifluoromethylation of Aldehydes Using Chiral Triaminosulfonium Catalysts 243 entry RCHO yield (%) ee (%) a R = Ph 96 52 (S) b R = 4-MeOC6H4 97 37 c R = 4-CF3C6H4 90 24 d R = 4-ClC6H4 93 30 e R = (E)-PhCH=CH 99 18 f R = C6H11 88 10 Caron and co-workers at Pfizer successfully optimized the trifluoromethylation of a particular aryl ketone of interest to them, to give up to 92% ee after a thorough screening of conditions and chiral ammonium fluorides (Scheme 90). 106 Ammonium fluoride 241d was found to be very effective for the trifluoromethylation of the target substrate; however, the catalyst did not prove to be generally applicable. While demonstrating what is possible, their report suggests that enantioselective induction using this approach may be rather substrate dependent, and extensive catalyst screening may be required to tackle new substrates. Scheme 90 3.1.3 Trifluoromethylation Catalyzed by Chiral Ammonium Bromides Combined with a Fluoride Source In the methodology described in the previous section, the practicalities associated with handling the highly hygroscopic chiral ammonium fluorides somewhat limited their application. Shibata and Toru sought to address this deficiency, and in 2007 developed the highly enantioselective trifluoromethylation of aryl ketones with Me3SiCF3 catalyzed by a combination of the less hygroscopic ammonium bromide of cinchona alkaloids and tetramethylammonium fluoride (TMAF) (Scheme 91). 107 Their approach is especially impressive because of unprecedented high enantoselectivities of up to 94% ee for acyclic and cyclic aryl ketones. However, aryl aldehydes and aliphatic ketones gave much poorer results. They proposed that the obtained high enantioselectivity may result from π-stacking interactions between the aromatic ring in the substrates and those present in the catalysts. Scheme 91 In 2010, Shibata and co-workers extended the scope of this transformation to encompass propargyl ketones, delivering trifluoromethyl-propargyl alcohols with up to 96% ee (Scheme 92). 108 The products were transformed into aryl heteroaryl trifluoromethyl carbinols without any loss of enantiomeric purity of 249a (Scheme 93). Scheme 92 Scheme 93 The same authors also demonstrated the asymmetric synthesis of Efavirenz in five steps from a commercially available precursor through the enantioselective trifluoromethylation of an alkynyl ketone (Scheme 94). 109 Subsequent catalyst modifications have allowed for improvement in selectivity in the key step. 110 Scheme 94 The authors then turned their attention to expanding the substrate of the transformation to aryl aldehydes, which failed under the previous conditions. However, the reaction of 2-naphthaldehyde (261) with Me3SiCF3 gave poor results despite extensive optimization attempts using various chiral ammonium bromides combined with TMAF or KF (Scheme 95). 111 Scheme 95 In 2013, the same authors obtained some improvement for these aryl aldehyde substrates by incorporating sterically bulky groups into the catalyst (Scheme 96). 112 After screening of a range of catalysts, 241i gave enantiomeric excesses of 50–70% for a range of aldehydes. Scheme 96 The authors detailed a mechanistic proposal that involved TMAF first reacting with Me3SiCF3 to provide trifluoromethyl tetramethylammonium 265 and releasing stable Me3SiF (Scheme 97). The ammonium 265 reacts with 241i to generate chiral trifluoromethylammonium 266 and tetramethylammonium bromide (TMAB). This chiral salt 266 then performs the trifluoromethylation of aldehyde 263 in an asymmetric manner. However, achiral ammonium 265 is also reactive to aldehyde 263 furnishing racemic products, perhaps explaining why very high enantioselectivities are still elusive using this approach. Scheme 97 3.1.4 Trifluoromethylation Catalyzed by Chiral Ammonium Phenoxides In 2007, Mukaiyama reported the asymmetric trifluoromethylation of ketones with TMSCF3 catalyzed by cinchonidine-derived quaternary ammonium phenoxides, which proceeded smoothly to afford the trifluoromethylated compounds in high yields with moderate to high enantioselectivities (Table 20). 113 Further studies found that α-ketoesters were also converted to the corresponding trifluoromethylated adducts smoothly under similar conditions, potentially offering a route to Mosher’s acid derivatives (Scheme 98). 114 Table 20 Asymmetric Trifluoromethylation of Ketones Catalyzed by Quaternary Ammonium Phenoxides entry R1 R2 yield (%) ee (%) 1 2-(NO2)C6H4 Me 93 71 2 4-(NO2)C6H4 Me 97 73 3 3-(CN)C6H4 Me 96 71 4 3-BrC6H4 Me 97 61 5 3-(MeO)C6H4 Me 90 59 6 1-naphthyl Me 91 51 7 2-naphthyl Me 95 77 8 3-pyridyl Me 90 46 9 4-pyridyl Me 93 60 10 3-(NO2)C6H4 Et 99 64 Scheme 98 3.1.5 Chiral Ammonium Bromide and (IPr)CuF-Catalyzed Trifluoromethylation A general enantioselective trifluoromethylation of aldehydes was developed by Chen and co-workers in 2012 using (IPr)CuF and quinidine-derived quaternary ammonium salt as the two cooperative catalysts to activate the Ruppert–Prakash reagent. A wide range of aromatic aldehydes participate, giving up to 92% yield and 81% ee at only 2 mol % of catalyst loading (Table 21). 115 To gain insight into the operation of the two catalysts, control experiments were carried out (Table 22). Neither (IPr)CuF nor quaternary ammonium salt 241j alone produced any product, and both yields and ee values decreased to zero by changing the anion of the copper salt from F– to t-BuO– or Cl–. Use of the fluoride salt of the chiral ammonium catalyst (241c) without the copper catalyst still gave good yield but with somewhat reduced ee (57%). This is in contrast to use of the ammonium bromide salt that gave no conversion without the copper fluoride. By use of (IPr)CuCl rather than (IPr)CuF with the latter ammonium salt, the enantioselectivity increased to 67% ee. The authors propose that (IPr)CuF is of key importance for high catalytic performance, and the enhanced activity and enantioselectivity result from the rapid generation of active [(IPr)CuCF3] upon reaction with TMSCF3 (Scheme 99). 116 Table 21 Asymmetric Trifluoromethylation of Aldehydes Using (IPr)CuF and Quinidine-Derived Quaternary Ammonium Salts Ar yield (ee) 2-naphthyl 90%, 75% 1-naphthyl 88%, 60% Ph 80%, 60% 4-BrC6H4 81%, 57% 3-BrC6H4 82%, 51% 4-MeC6H4 88%, 68% 4-PhC6H4 90%, 66% 3-MeOC6H4 89%, 74% 3,4-O(CH2)C6H3 92%, 81% 3,4-O(CH2)2C6H3 92%, 79% 4-EtSC6H4 85%, 74% Table 22 Control Experiments entry ammonium salt (mol %) (IPr)CuX (mol %) yield (%) ee (%) 1 241j (2)   NR   2   (IPr)CuF (2) trace nd 3 241j (2) (IPr)CuF (2) 90 75 4 241j (2) (IPr)CuOt-Bu (2) 57 45 5 241j (2) (IPr)CuCl (2) NR   6 241c (5)   87 57 7 241c (5) (IPr)CuCl (5) 84 67 Scheme 99 3.1.6 Trifluoromethylation Catalyzed by Chiral Ammonium Bromide and Sodium Phenoxide In 2007, Feng and co-workers developed a new dual catalyst system comprising a disodium binaphtholate salt prepared in situ and a chiral quaternary ammonium salt. This allowed enantioselective trifluoromethylation of aromatic aldehydes in up to 71% ee (Table 23). 117 The authors observed that the monosodium binaphtholate salt was not an effective catalyst and speculated that the role of disodium binaphtholate might be as a Lewis base to activate the TMSCF3 and form the hexavalent intermediate 271 (Scheme 100). Table 23 Asymmetric Trifluoromethylation Using a Dual Catalyst Approach Comprising a Disodium Binaphtholate Salt and a Chiral Quaternary Ammonium Salt entry aldehyde yield (%) ee (%) 1 2-naphthaldehyde 85 71 2 benzaldehyde 72 56 3 4-methylbenzaldehyde 87 60 4 3-methylbenzaldehyde 88 58 5 4-chlorobenzaldehyde 72 50 6 3-chlorobenzaldehyde 95 56 7 4-phenylbenzaldehyde 73 56 8 4-methoxybenzaldehyde 87 41 9 piperonal 95 46 10 4-fluorobenzaldehyde 86 57 11 3-thiophenecarboxaldehyde 68 45 Scheme 100 Later, the same authors combined cinchonine-derived quaternary ammonium salt 241f with NaH to establish an effective and fluoride-free system for the catalytic asymmetric trifluoromethylation of methyl ketones in moderate to good ee (up to 82%) and yield (up to 98%) (Table 24). 118 Control experiments showed that when the hydroxyl in 241f was methylated, the reaction still proceeded efficiently, affording the product in 63% ee and 90% yield; however, in the absence of NaH, 274 could not catalyze the reaction. On the basis of these observations, the authors speculated that the hydride ion might serve as the Lewis base to activate TMSCF3 (Scheme 101). Table 24 Asymmetric Trifluoromethylation Using Chiral Quaternary Ammonium Salt 241f with NaH entry R time (h) yield (%) ee (%) 1 2-naphthyl 6 96 81 (R) 2 1-naphthyl 6 98 82 3 2-FC6H4 19 47 68 4 3-ClC6H4 19 96 68 5 4-ClC6H4 19 83 61 6 4-BrC6H4 48 43 60 7 3-NO2C6H4 48 30 68 (R) 8 4-NO2C6H4 24 64 50 9 3-MeOC6H4 96 38 58 10 4-MeC6H4 3 70 67 11 (E)PhCH=CH 22 31 59 Scheme 101 3.1.7 Asymmetric Trifluoromethylation Using Phase-Transfer Catalysis The catalytic asymmetric addition of nucleophilic trifluoromethyl to imines would constitute a concise approach to trifluoromethyl amines. Despite the extensive studies on addition to carbonyl compounds, this was not reported until 2009 when Shibata and co-workers reported the enantioselective trifluoromethylation of azomethine imines 275 with Me3SiCF3 (Scheme 102). 119 The authors found that conventional imines, such as N-tosylimines, were poor in terms of both reactivity and selectivity. They attributed the poor conversion to the poor nucleophilicity of the sulfonamide intermediates that are generated upon CF3 – addition, recalling that this species must be sufficiently nucleophilic to attack Me3SiCF3 in the autocatalytic process previously described (Scheme 88). On this basis, the authors selected azomethine imines 275 as likely being superior, because the resulting anion following addition is delocalized onto the carbonyl oxygen. They also envisaged that the more sterically demanding and rigid nature may increase stereoselectivity of addition. By employing bromide salts of cinchona alkaloids and KOH as catalysts, trifluoromethylated amines 276 were obtained with very high enantiomeric excess. Additionally, it was demonstrated that the trifluoromethylated adduct 276a can be readily transformed to amine 278 (Scheme 103). Scheme 102 Scheme 103 The authors proposed a transition state model for the reaction in which the catalyst hydroxyl group hydrogen bonds with the carbonyl oxygen, the sterically demanding portion of the imine is located in the less sterically congested space, and interactions between the aromatic rings stabilize the transition state (Figure 24). Figure 24 Proposed transition state model to account for observed enantioselectivity. Reproduced with permission from ref (119). Copyright 2009 John Wiley and Sons. Later, the same authors demonstrated that this transformation is viable in the environmental benign solvent-Solkane365mfc with simple cinchona alkaloid ammonium salt 241l. Improved chemical yields and enantioselectivities could be obtained (Scheme 104). 120 Scheme 104 In 2012, Bernardi and co-workers disclosed a racemic protocol for trifluoromethylation of imines employing phase-transfer catalysis using a stoichiometric amount of an insoluble metal phenoxide as promoter. This modification was found to overcome the aforementioned difficulties of standard imines inhibiting the autocatalytic cycle. They disclosed a single example of an enantioselective variant using imine equivalent 279 and cinchona alkaloid derivative 241m as catalyst, that proceeded with moderate yield and enantiomeric excess (Scheme 105). 121 Scheme 105 Shibata and co-workers disclosed a novel and interesting approach using a cation-binding C2-symmetric chiral crown ether 281 for the enantioselective trifluoromethylation of aldehydes and ketones, effectively creating a chiral cation (Scheme 106). 122 Unfortunately, the enantioselectivities induced in the desired trifluoromethylated adducts were low to moderate. Scheme 106 In 2013, Obijalska and co-workers disclosed enantioselective addition of TMSCF3 to α-imino ketones 283 derived from aryl glyoxals 282 using a chiral ammonium bromide catalyst and catalytic K2CO3, to form O-silyated β-imino alcohols 284. These products were reduced to determine the ee values, which ranged from 30% to 71% (Scheme 107). 123 Scheme 107 3.1.8 Allylic Trifluoromethylation of Morita–Baylis–Hillman Adducts In 2010, Shibata and co-workers published a highly enantioselective allylic trifluoromethylation of Morita–Baylis–Hillman adducts 286 using the Ruppert–Prakash reagent and commercially available bis-cinchona alkaloid catalyst, (DHQD)2PHAL. 124 This process takes advantage of the framework of the MBH adducts, which contain an allylic leaving group to enable an SN2′ displacement if the alcohol is suitably derivatized (R1 = Ac or Boc). The authors found initially that if a suitably nucleophilic amine, such as DABCO, was employed, the cationic intermediate generated (287) was liable to a second SN2′ reaction from TMSCF3, the latter reagent presumably activated by acetate (Scheme 108). Scheme 108 Once the reaction was optimized in a racemic sense, they then employed the chiral tertiary amine catalyst (DHQD)2PHAL in place of DABCO and were able to realize excellent enantioselectivities when R1 = Boc, in what they describe as a successive SN2′/SN2′ process (Table 25). Table 25 Enantioselective Allylic Trifluoromethylation of Morita–Baylis–Hillman Adducts entry R1 R2 Ar yield (%) ee (%) a Ac tBu C6H5 trace nd b Boc tBu C6H5 39 92 c Boc tBu 2-BrC6H4 37 88 d Boc tBu 4-BrC6H4 60 90 e Boc Me C6H5 52 94 The authors showed that the β-trifluoromethyl esters 290 obtained can be efficiently converted into potentially interesting carbocyclic and heterocyclic compounds without loss of enantiomeric purity (Scheme 109). Scheme 109 Very shortly after this report, Jiang and co-workers described an almost identical transformation (Scheme 110). 125 They found that they were able to perform the reaction at room temperature using a mixed solvent system and demonstrated a broader scope of aryl and heteroaryl substitution on the starting material, although in some cases enantioselectivity was moderate. Scheme 110 Building on their previous insights, Shibata and co-workers recently disclosed a remarkable transformation involving the kinetic resolution of allyl fluorides 294 by enantioselective allylic trifluoromethylation, relying on enantioselective, silicon-assisted C–F bond cleavage. 126 When the transformation is halted at 50% conversion, enantioenriched starting material 294 and enantioenriched trifluoromethylated compound 290 could both be isolated with extremely high enantiomeric excesses, using (DHQD)2PHAL as catalyst (Table 26). Similarly, excellent results could also be obtained for pentafluorethylation and pentafluorophenylation. Table 26 Kinetic Resolution of Racemic Allyl Fluorides by Enantioselective C–F Bond Cleavage/Allylic Trifluoromethylation entry R1 R2 conv. (%) (S)-290 ee (yield) (%) recovered 294 ee (yield) (%) 1 Me Ph 54 95 (51) 97 (41) 2 Me 4-MeC6H4 53 95 (48) 96 (40) 3 Me 3-MeOC6H4 55 94 (50) 97 (40) 4 tBu Ph 50 94 (48) 93 (42) The proposed mechanism commences with activation of the C–F bond by coordination to the silicon atom of TMSCF3. This is followed by the kinetic resolution step whereby the chiral catalyst selectively participates in SN2′ reaction with only one enantiomer of the activated starting material. Finally, the resulting cationic intermediate is attacked by CF3 – in an enantioselective trifluoromethylation (Scheme 111). This mechanistic picture is supported by the observation that the ee of 290 is consistently high throughout the course of the reaction, while that of 294 increases steadily from 0 to ∼95% as the reaction progresses. Scheme 111 3.1.9 Miscellaneous In 1997, Kobayashi and co-workers investigated the use of nonquaternized cinchona alkaloids as catalysts for the trifluoromethylation of aldehydes. However, only modest yields and low enantioselectivities were observed (Table 27). 127 Table 27 Investigation of Nonquaternized Cinchona Alkaloids To Catalyze Trifluoromethylation of Aldehydes entry silane yield (%) ee (%) 1 Me3Si–CF3 238 49 9 2 PhMe2Si–CF3 296 39 6 3 Ph2MeSi–CF3 297 35 12 4 Et3Si–CF3 298 24 21 5 i-Pr3Si–CF3 299 trace   3.2 Electrophilic Trifluoromethylation In contrast to their nucleophilic counterparts, enantioselective electrophilic trifluoromethylation reactions remain far less developed. A number of electrophilic reagents have been developed for generation of what can be regarded as a “synthetic equivalent” of a trifluoromethyl cation, the development of which has been reviewed elsewhere (Scheme 112). 3s,128 It should be considered that apparent electrophilic reactivity may well proceed via electron-transfer induced radical mechanisms, as perfluoroalkyl radicals tend to be of an electrophilic nature. 1c This behavior is particularly likely with readily oxidizable substrates such as enols and enamines. Scheme 112 Among the first reported investigations of a catalytic enantioselective electrophilic trifluoromethylation reaction was that of Ma and Cahard in 2007. They examined the use of chiral ammonium salts acting as phase-transfer catalysts for trifluoromethylation of β-ketoester 47a, although the highest enantiomeric excess recorded was only 19% (Scheme 113). 129 Scheme 113 Enantioselective trifluoromethylation of this substrate class was not improved until Gade’s disclosure in 2012 of the trifluoromethylation of similar β-ketoesters 309 using commercial electrophilic trifluoromethylating agents 305a and 302a and employing chiral “boxmi” pincer ligands 52b in conjunction with copper catalysts (Scheme 114). 130 Both five- and six-membered ring β-ketoesters were converted to the corresponding products 310 and 311 in high yields with up to 99% ee. To highlight the utility of the enantioselective trifluoromethylation developed in this work, the authors demonstrated highly diastereoselective transformations of the trifluoromethylated products (Scheme 115). Scheme 114 Scheme 115 In a distinct approach utilizing both enamine organocatalysis and transition metal catalysis, Allen and MacMillan in 2010 reported the highly asymmetric α-trifluoromethylation of aldehydes using Togni’s reagent 305a (Scheme 116). 131 Scheme 116 They envisioned that 305a should undergo Lewis acid promoted bond cleavage to generate the highly electrophilic iodonium salt 315. Condensation of the amine catalyst with an aldehyde would generate a chiral enamine that will participate in an enantioselective C–I bond formation via a closed-shell pathway. The resulting λ3-iodane species 316 was envisaged to undergo reductive elimination with stereoretentive alkyl transfer, thus forming the new C–CF3 bond, although a single electron transfer mechanism cannot be completely ruled out for this latter sequence. Hydrolysis would then release the amine catalyst and the desired enantioenriched α-trifluoromethyl aldehyde product 313 (Scheme 117). A range of Lewis acidic metals provided conversion and enantioenrichment, but CuCl proved to be the most effective and a range of substituted aldehydes were demonstrated to be effective. Scheme 117 The authors demonstrated that the α-trifluoromethylated aldehydes 313 were easily converted to a variety of valuable synthons containing the trifluoromethyl group (Scheme 118). Scheme 118 3.3 Radical Trifluoromethylation Trifluoromethyl radicals can be purposely generated by a number of methods and under the right conditions can be long-lived enough to be exploited in useful reactivity. In contrast with alkyl radicals that are generally nucleophilic, trifluoromethyl radicals have electrophilic character. 1c Nevertheless, it is only recently that the first progress has been made to harness these species in the context of catalytic asymmetric synthesis. In 2009, Macmillan and co-workers described a conceptually novel approach to the asymmetric α-trifluoromethylation of aldehydes via the merger of enamine catalysis and photoredox catalysis (Scheme 119). 132 In their proposed cataytic cycle, photoredox catalyst Ir(ppy)2(dtbbpy)+ 321 accepts a photon from a visible spectrum light source to populate the excited-state complex 326 that would then accept a single electron from a sacrificial equivalent of enamine to form a strong reductant Ir(ppy)2(dtbbpy) (327). At this stage, 327 engages in single electron transfer with trifluoromethyl iodide, resulting in an electrophilic trifluoromethyl radical 323, at the same time regenerating the photoredox catalyst 321. In concert with this trifluoromethyl radical formation pathway, the separate organocatalytic cycle would be initiated by condensation of amine catalyst 328 with aldehyde substrate 99 to form the reactive enamine 322. These two cycles would intersect in the trifluoromethylation step via addition of the trifluoromethyl radical 323 to the nucleophilic enamine to form the α-amino radical 324. A second electron transfer event with the excited-state photocatalyst 326 would close the photoredox cycle and deliver the iminium ion 325, prior to hydrolysis. Scheme 119 They demonstrated the effectiveness of this approach to trifluoromethylation of a range of aldehydes, using a 26 W household light bulb as the visible light source (Scheme 120). The authors noted that at room temperature the products racemized rapidly, but this was prevented by running the reactions at −20 °C. Scheme 120 They nicely demonstrated that their strategy could also be extended to perfluoroalkylation of aldehydes using the same conditions (Scheme 121). Scheme 121 4 Catalytic Enantioselective Monofluoromethylation Recognizing that despite the increasing methods for the introduction of the fluorine atom and perfluoroalkyl groups, there was little attention given to reactions resulting in monofluoromethylation, Shibata, Toru, and co-workers introduced 1-fluorobis(phenylsulfonyl)methane (FBSM) as a fluoromethide equivalent (Scheme 122). 133a,134 This reagent was found to participate in Tsuji–Trost allylic substitution reactions on substrates 333 to afford the enantioenriched fluoromethylated products 334 (Scheme 123) using PHOX ligand 335a. A similar process has also been reported using the chiral imidazoline-phosphine ligand 335b. 133b Importantly, it was demonstrated after further transformation of the aldehyde the two sulfone groups could be reductively cleaved using activated magnesium to leave a monofluoromethyl group. Scheme 122 Scheme 123 The versatility of this reagent was demonstrated by the same authors in the catalytic enantioselective Mannich-type monofluoromethylation of imines. 135 The prochiral imine substrates were generated in situ in the presence of a chiral phase-transfer catalyst and CsOH·H2O as base. With regard to the scope of the reaction, both alkyl and aryl imines gave high enantioselectivities, and for all substrates the reductive desulfonylation using magnesium was demonstrated to occur without loss of enantioenrichment (Scheme 124). Scheme 124 The same authors also reported the catalytic, asymmetric conjugate addition of FBSM to α,β-unsaturated ketones 339 (Scheme 125). 136 The ammonium salts of cinchona alkaloids possessing sterically demanding substituents catalyzed the conjugate addition reaction efficiently to give Michael adducts 340 in high yield with excellent enantioselectivity. Scheme 125 In 2009, several groups demonstrated that FBSM is effective as a nucleophile for asymmetric conjugate addition to α,β-unsaturated aldehydes, using established amine catalyst 121 and a catalytic cycle proceeding via iminium activation (Scheme 126). 137−139 Scheme 126 Building on Shibata and Toru’s earlier work, Zhao, You, and co-workers in 2009 demonstrated that [Ir(COD)Cl]2 in combination with phosphoramidite ligand 343 is an efficient catalytic system to allow allylic alkylation of FBSM with 1,3-unsymmetrical allylic substrates, leading to chiral products bearing a terminal alkene with good to excellent regioselectivity (Scheme 127). 140 Scheme 127 In 2011, Shibata and co-workers disclosed another application of FBSM, the enantioselective allylic monofluoromethylation of Morita–Baylis–Hillman carbonates using cooperative catalysis (biscinchona alkaloid and FeCl2). This provided chiral α-methylene β-monofluoromethyl esters with high ee’s of up to 97% (Scheme 128). 141 The transformation is envisaged to proceed by SN2′ attack of the quinuclidine nitrogen atom of the cinchona alkaloid catalyst to afford a cationic intermediate, which is then attacked by the FBSM anion in another SN2′ reaction to give the product (see section 3.1.8 for further discussion of this approach). The authors proposed a transition state model to account for the observed absoute stereochemistry and suggested that the conformation shown may be stabilized by π–π interations in the U-shaped cleft of the (DHQD)2AQN (Figure 25). As the Si face would be blocked by the left half of the catalyst (as depicted), FBSM would attack from the Re face. Supporting this scenario is the observation that low enantioselectivities were observed in nonaromatic substrates. The addition of a metal cocatalyst provided a modest rather than a dramatic increase in efficiency, and the authors speculated that this could be due to bidentate chelation to FBSM increasing its reactivity. Scheme 128 Figure 25 Proposed transition-state model for addition of FBSM to catalyst-bound intermediate. Reproduced with permission from ref (141). Copyright 2011 John Wiley and Sons. Recently, enantioselective addition of FBSM to vinylogous imines generated in situ from 2-aryl-3-(1-arylsulfonylmethyl)indoles 348 was achieved by the same authors using a phase-transfer catalysis strategy (Scheme 129). 142 Reductive desulfonylation gave the monofluoromethyl adduct 350. A one-pot reaction starting from simple indoles 351 was also viable, the first step in the procedure being indium-promoted Friedel–Crafts alkylation with α-amido sulfones 352. Scheme 129 In 2010, Shibata and co-workers introduced a variant of FBSM, 2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT) 353, as a further fluoromethide equivalent. 143 They developed this reagent due to the inability of FBSM to undergo nucleophilic addition to aldehydes. The authors hypothesized that this is due to the instability of the resulting addition product due to steric hindrance of the two phenylsulfonyl groups; hence, the reverse reaction is overwhelmingly favored. FBDT was developed as a less sterically demanding reagent to address this problem. The authors initially demonstrated that this was successful in a racemic sense. In 2013, they reported a catalytic enantioselective variant using a bifunctional cinchona alkaloid-derived thiourea catalyst and stoichiometric titanium complex. While some excellent selectivities were obtained, this was rather dependent on the precise structure of the substrate. The authors showed that samarium diiodide is effective in unmasking the monofluoromethyl motif without loss of enantioenrichment (Scheme 130). 144 Scheme 130 5 Catalytic Enantioselective Difluoromethylation Shibata and co-workers extended their protocol previously employed for enantioselective trifluoromethylation to reagents acting as nucleophilic difluoromethyl equivalents. Using Me3SiCF2SePh3 as nucleophile, enantioselective difluoromethylation of 2-naphthylmethyl ketone (272a) was investigated (Scheme 131). The corresponding difluoromethylated compound 358 was obtained in 41% yield with 44% ee. Some improvements in the enantioselectivity were made by employing the more sterically hindered cinchona alkaloid 241i, although the result was still moderate. 145 Scheme 131 In 2008, Hu and co-workers described the catalytic enantioselective difluoroalkylation of aromatic aldehydes with Me3SiCF2SO2Ph (361) and PhSO2CF2H (362) employing a chiral quaternary ammonium salt as catalyst and KOH as base (Scheme 132). 146 They found that the enantioselectivity was substrate-dependent; for 2-chloro benzaldehyde, ee of up to 64% was obtained. Scheme 132 Shibata and co-workers also attempted catalytic electrophilic or radical enantioselective difluorobromination of β-ketoesters, using CBr2F2 and 360b as catalyst, with excess CsOH as base. The α-bromodifluoromethyl tetralone carboxylate 364 was obtained in 73% yield with 37% ee (Scheme 133). 145 Scheme 133 6 Catalytic Enantioselective Trifluoromethylthiolation The trifluoromethanesulfenyl group (SCF3) is of special interest due to its extremely high lipophilicity, with a Hansch parameter of 1.44 as compared to 0.88 for CF3. 147 This could be particularly beneficial in tuning compound pharmacokinetic properties. While this group has been utilized for some time, it is only very recently that methods for its direct introduction have come into the mainstream. 148 With the development of new reagents such as 365(149) and 366, 150 new possibilities have been realized for catalytic asymmetric introduction of the SCF3 group (Scheme 134). Scheme 134 Very recently, Lu, Shen, and co-workers reported the preparation of trifluoromethylthiolated hypervalent iodine reagent 366. They went on to demonstrate that this could be employed for the asymmetric trifluoromethylsulfenylation of β-ketoesters in the presence of cinchona alkaloid-based phase-transfer catalysts. 151 They found that several of the catalysts in this family were effective and that the hydroxyl group of the cinchona alkaloids was important for the high reactivity of the transformation (Scheme 135). Scheme 135 While these conditions were suitable for indanone-derived substrates, tetralone- or benzosuberone-derived β-ketoesters required phase-transfer catalysts in combination with a base to be used to get conversion, and under these conditions the enantioselectivities were generally not as high (Scheme 136). Scheme 136 The authors considered two plausible pathways. In the first, the catalyst 369a reacts with 366 to give a quaternary ammonium ion 373 that is attacked by the β-ketoester. However, they could not observe formation of this putative species in a stoichiometric reaction (Scheme 137). In the second, quinine deprotonates the β-ketoester and forms a hydrogen-bonded intermediate that is activated to attack 366. The authors favor the latter and propose that the hydroxyl group of the catalyst activates 366; thus, the catalyst acts as a bifunctional catalyst to generate a highly organized transition state that is sensitive to the exact steric nature of the substrate (Scheme 138). They go on to present an argument to explain the difference in reactivity between the tetralone and indanone systems. Scheme 137 Scheme 138 In a back-to-back publication with Shen’s report, Rueping and co-workers reported trifluoromethylsulfenylation of similar substrates using the electrophilic SCF3 source 365 in combination with cinchona alkaloid catalysts (Scheme 139). 152 The majority of their scope was comprised of indanones, although a tetralone-derived substrate also gave high enantioselectivity but with only moderate yield. Scheme 139 The same authors subsequently found that 3-aryl oxindoles 50 also underwent enantioselective trifluoromethylthiolation using (DHQD)2Pyr as organocatalyst (Scheme 140). 153 Scheme 140 Transition metals catalysis has also very recently been utilized for enantioselective SCF3-transfer reactions. In 2014, Gade and co-workers reported the highly enantioselective Cu-catalyzed trifluoromethylthiolation of β-ketoesters by using 366 as SCF3-transfer reagent (Scheme 141). 154 They deployed their copper “boxmi” pincer complexes, which they had previously shown to be effective for trifluoromethylation of β-ketoesters, to great effect. 130 Scheme 141 They propose that the copper(II) catalyst acts as a Lewis acid, to stabilize and orientate the ester-enolate form of the substrate, giving rise to the observed high enantioselectivity according to the model shown (Scheme 142). They propose that in the complexed intermediate, the Si face of the substrate is blocked by the phenyl group of the oxazolinyl unit and the trifluoromethylthiolation reagent 366 therefore preferentially approaches from the Re face of the substrate, consistent with the absolute configuration of product 376a. 155 Scheme 142 7 Summary and Outlook There has been remarkable progress in the past decade toward catalytic asymmetric methods for the introduction of fluorine and a range of fluorine-containing groups into small molecules. No doubt this has been spurred by the demand particularly in the pharmaceutical and agrochemicals sectors, but these advances have necessarily gone hand-in-hand with the development of stable and easily handled reagents. Some of the earlier material included in this comprehensive review has been also covered by previous reviews, but even in the five years since 2009 there have been a remarkable number of advances, which have in some cases arisen as a result of the introduction of new reactivity concepts, for example, photoredox catalysis and chiral anion phase-transfer catalysis. The rapid growth and development of this field makes it a particularly stimulating area of study with new advances being made almost on a daily basis. Yet despite this, there are still limitations; efforts need to be made to expand the substrate classes that can be addressed, so that new methods truly cover new ground. To this end, new fundamental approaches to asymmetric catalysis must be sought as it is in this way that the variety of substrates can be significantly expanded into new and previously unimaginable areas. One certainty is that the introduction of fluorine and fluorine-containing groups is now high on the list of ways to test any new asymmetric method, which makes this an exciting arena in which to witness the latest developments in the field of enantioselective catalysis.