molecules Review Asymmetric Preparation of α-Quaternary Fluorinated β-keto Esters. Review Albert Granados * and Adelina Vallribera * Department of Chemistry and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Carrer dels Til.lers, UAB Campus, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain * Correspondence: albert.granados@uab.es (A.G.); adelina.vallribera@uab.es (A.V.); Tel.: +34-93-5813045 (A.V.) Academic Editor: Mohamed Abarbri   Received: 11 June 2020; Accepted: 15 July 2020; Published: 17 July 2020 Abstract: In this review, recent advances over the past decade in the preparation of fluorinated stereogenic quaternary centers on β-keto esters compounds are analyzed. Since the incorporation of fluorine and fluorinated groups is of special interest in pharmaceutical chemistry, a range of metal-catalyzed and organocatalyzed methods have been developed. Herein, we review the enantioselective fluorination, trifluoromethylation and trifluoromethylthiolation of 3-oxo esters. The scope, the induction of enantioselectivity and mechanistic investigations are presented. Keywords: fluorination; trifluoromethylation; trifluoromethylthiolation; β-keto esters; asymmetric 1. Introduction The field of organofluorine chemistry has been of increasing interest to academia and industry during recent decades [1–3]. Fluorine now occupies a prestigious position, especially in the design of biologically active compounds, and indeed, nearly 30% of human medicines and 35% of agrochemicals on the market contain one or more fluorine atoms [4–6]. The incorporation of fluorine atoms into the drug discovery process has emerged as a common strategy [7]. The physicochemical effects imparted by fluorine explain its utility and impact in a wide range of drugs, including antidepressant, antipsychotic, antitumor, antiviral, anaesthetic, anti-inflammatory agents, etc. [8–10]. The inclusion of a fluorine atom in a drug molecule can have a profound effect on the molecule’s pharmacodynamic, pharmacokinetic, distribution and extent of drug metabolism [11,12]. For example, the addition of functional groups to therapeutic molecules can greatly enhance the lipophilicity of the drug, which in turn can enhance bioavailability, tissue distribution and cell permeability. Also, it can affect the interaction of the drug with the pharmacological target for example, through effects on the inter and intramolecular forces present in the binding [13,14]. In addition, the use of radioactive 18 F nucleus in positron emission topography (PET) labelling broadened the applicability in medicine, serving as a privileged diagnostic tool for cancer and other diseases [15]. The use of [18 F]fluorodeoxyglucose (FDG) and other [18 F]labelled radiotracers in oncology, brain diseases and cardiology has established the value of 18 F as a positron emitter for PET and encouraged new developments for late stage fluorination. Furthermore, to enable early monitoring of various diseases with non-invasive diagnostic tools 19 F magnetic resonance imaging (MRI) has been exploited with great success. Applications can be found in targeted imaging of selected relevant physiological techniques, in targeted drug delivery and cell tracking. 19 F MRI agents have been classified in molecular tracers, polymers and branched derivatives [16]. Fluorinated materials have found applications in materials sciences and their importance in modern industry and technology is expected to grow even more in the near future [17]. Fluorinated materials have been widely used in liquid crystals [18,19], smartphone displays, photovoltaic solar cells, Molecules 2020, 25, 3264; doi:10.3390/molecules25143264 www.mdpi.com/journal/molecules Molecules 2020, 25, 3264 2 of 24 surface modification chemistry [20], stabilization of metal nanoparticles [21,22] and crystal/metal-organic frameworks (MOFs) engineering. Introduction of fluorous tags onto materials can favour ordering, self-organization, hydrophobicity [23] and chemical stability. Fluorinated polymers exhibit outstanding chemical resistance, thermal stability, low friction coefficients and electrical properties [24]. In particular some fluorinated polymers have been intensively investigated and applied due to their electroactive properties in biomedical applications including controlled drug delivery systems and tissue engineering. Thus, due to its importance, the development of new methodologies that give access to fluorinated compounds is in demand [25–27]. In particular, the stereoselective introduction of fluorine or fluoroalkylated groups to generate stereogenic centres has been of growing interest. Specifically, as we will see throughout this manuscript, the selective fluorination at specified positions of an organic compound forming C-F, C-CF3 and C-SCF3 bonds from C-H is especially important and a challenging task. There are plenty of papers published in the past two decades in reference to the asymmetric introduction of these groups into organic molecules and therefore is impossible to include all of them. However, there are excellent reviews that should not be omitted [28–31]. Since 2000, a practical enantioselective methodology leading to construction of a C−F quaternary stereocenter has been developed using chiral N−F reagents derived from N-fluoroammonium salts by the combination of cinchona alkaloids and Selectfluor® . A great diversity of silyl enol ethers, allylsilanes, 1,3-dicarbonyl compounds, oxindoles, dipeptide, and enolates can be used as substrates. Other methods include primary and secondary amine catalysts via enamine intermediates, cationic and anionic phase-transfer catalyst, etc. [28]. At the same time, in 2010 an important breakthrough in this chemistry related to a metal catalytic protocol was the pioneering research by using Ti/TADDOL catalyst with Selectfluor® [28,32]. These protocols are based on electrophilic fluorinating processes. The comprehensive discussion of the catalytic asymmetric scenario for C-F formation, including organocatalytic methods and transition-metal catalyzed transformations, has been previously reviewed [28–30]. Moreover, the development of approaches for the straightforward asymmetric introduction of trifluoromethyl groups into small molecules, including nucleophilic, electrophilic, or free radical processes, has received much recent attention [29,30]. In contrast to their nucleophilic counterparts (generally based on the use of Ruppert–Prakash reagent TMSCF3 ), enantioselective and radical electrophilic trifluoromethylation reactions remain far less developed. In particular, MacMillan and co-workers described a conceptually novel approach to the asymmetric α-trifluoromethylation of aldehydes via the merger of enamine catalysis, CF3 I and photoredox catalysis [33]. Allen and MacMillan also reported in 2010 the highly asymmetric α-trifluoromethylation of aldehydes using Togni’s reagent utilizing both enamine organocatalysis and transition metal catalysis [34]. For a historical background on the most important useful methods for trifluoromethylthiolation please see an excellent review of Billard [31]. While this group has been utilized for some time, it is only very recently that methods for its direct asymmetric introduction have come into the mainstream and will be revised herein. In this review, evolution and advances over the last ten years in the preparation of fluorinated quiral quaternary centres on β-keto esters compounds are analysed. Simple β-keto esters have been selected and studied by many groups and are well established as substrates in synthesis. Possessing an active methylene and two functional groups make them really versatile molecules in organic synthesis [35–37]. They are useful synthetic precursors, as for example the ketone is easily converted to other functional groups (i.e., alcohols and imines) and the ester can be transformed to different amides through the carboxylic acid. The utility of the enantioselective fluorinated β-keto esters has been highlighted by highly diastereoselective transformations of the trifluoromethylated products carried out by Gade’s group [38]. The scope, the induction of enantioselectivity and mechanistic investigations of Cα -F, Cα -CF3 and Cα -SCF3 bonds formation in β-keto esters are presented. Molecules 2020, 25, 3264 3 of 24 2. Asymmetric Preparation of Quaternary C-F Stereocentres on β-keto Esters At first glance, to fluorinate the α-intercarbonylic position of a β-keto ester an electrophilic Molecules 2020, 25, x FOR PEER REVIEW 3 of 28 reagent will be necessary. The development Molecules 2020, 25, x FOR PEER REVIEW of stable sources of electrophilic fluorinating agents 3 of 28 (Figure 1), 2. Asymmetric Preparation of Quaternary C-F Stereocentres on β-keto® Esters such as N-fluorobenzensulfonimide [39] (NFSI) and Selectfluor [40] has had a great impact and At first glance, 2. Asymmetric to fluorinate Preparation the α-intercarbonylic of Quaternary position C-F Stereocentres of a β-keto on β-keto Estersester an electrophilic witnessed encouraging reagent will progress be necessary.on Thethe catalytic development of enantioselective electrophilic stable sources of electrophilic fluorinatingfluorination. agents On the At first glance, to fluorinate the α-intercarbonylic position of a β-keto ester an electrophilic contrary, an enantioselective (Figure 1), such asnucleophilic fluorination N-fluorobenzensulfonimide [39] of β-keto (NFSI) and esters will Selectfluor be an umpolung ® [40] has had a great reagent will be necessary. The development of stable sources of electrophilic fluorinating agents reaction and impact and witnessed encouraging progress on the catalytic enantioselective electrophilic is still in its beginnings (Figure 1), because of the low reactivity of such as N-fluorobenzensulfonimide [39]the fluoride (NFSI) anion. Recently and Selectfluor® [40] has hadnucleophilic fluorination. On the contrary, an enantioselective nucleophilic fluorination of β-keto esters will be an a great fluoride impact and witnessed encouraging progress on the catalytic enantioselective electrophilic sources as Et3 N·3HFumpolung and Et reaction fluorination. On the N·5HF and is have still in its been used beginnings for because the of theenantioselective low reactivity of the oxidative fluoride anion. 3 contrary, an enantioselective nucleophilic fluorination of β-keto esters will be an fluorination of β-keto esters [41,42]. Recently nucleophilic fluoride sources as Et3N·3HF and Et3N·5HF have been used for the umpolung reaction and is still in its beginnings because of the low reactivity of the fluoride anion. enantioselective oxidative fluorination of β-keto esters [41,42]. Recently nucleophilic fluoride sources as Et3N·3HF and Et3N·5HF have been used for the enantioselective oxidative fluorination of β-keto esters [41,42]. Figure 1. Figure 1. Mostly Mostly common common electrophilic and electrophilic andnucleophilic nucleophilicfluorinating reagents. fluorinating reagents. Figure 1. Mostly common electrophilic and nucleophilic fluorinating reagents. 2.1. Metal-Catalyzed Methods 2.1. Metal-Catalyzed Methods An important breakthrough 2.1. Metal-Catalyzed Methods in this chemistry occurred when Togni and Hintermann described the catalytic An important α-fluorination breakthrough reactions in this of α-substituted chemistry occurred acyclic whenβ-ketoTogni esters using a Ti/TADDOL described the and Hintermann An important breakthrough in this chemistry occurred when Togni and Hintermann described complexes (1, Figure 2) and Selectfluor® (Figure 1), yielding the fluorinated compounds in 62–90% ee catalytic α-fluorination the [32]. catalytic α-fluorination reactions of reactions of α-substituted α-substituted acyclic β-keto acyclic β-keto esters esters using using a Ti/TADDOL a Ti/TADDOL complexes complexes (1, Figure 2) and Selectfluor® (Figure 1), yielding the fluorinated compounds in 62–90% ee Selectfluor® (Figure 1), yielding the fluorinated compounds in 62–90% ee [32]. (1, Figure 2) and[32]. Figure 2. Chiral ligands and metals combinations for the catalytic enantioselective fluorination of β-keto esters. Although there was only one substrate which gave an excellent 90% ee, they demonstrated that chiral metal complexes could promote the stereoselective fluorination. Ti/TADDOL complexes acted as Lewis acid activating the β-keto ester. From this report until 2010 a range of metal catalysed fluorination reactions have been developed and previously reviewed [43]. Some years later, in 2012, Togni’s group in a remarkable paper mainly dedicated to acyclic 1,3-dicarbonyl compounds, reported that using the same Ti/TADDOL complex the cyclic tetralone 16 (Scheme 1), gave the α-fluorinated product in 20% ee (entry 20, Table 1) [44]. We will comment on these results on acyclic 1,3-dicarbonyl later on. keto esters. Although there was only one substrate which gave an excellent 90% ee, they demonstrated that chiral metal complexes could promote the stereoselective fluorination. Ti/TADDOL complexes acted as Lewis acid activating the β-keto ester. From this report until 2010 a range of metal catalysed fluorination reactions have been developed and previously reviewed [43]. Some years later, in 2012, Togni’s group in a remarkable paper mainly dedicated to acyclic 1,3-dicarbonyl compounds, reported Molecules 2020, 25, that 3264using the same Ti/TADDOL complex the cyclic tetralone 16 (Scheme 1), gave the α-fluorinated 4 of 24 product in 20% ee (entry 20, Table 1) [44]. We will comment on these results on acyclic 1,3-dicarbonyl later on. Scheme Scheme 1. Cyclic β-keto 1. Cyclic β-keto esters 11–20.11–20. esters In addition to titanium, copper complexes have been also used as Lewis acids. The group of In addition to titanium, Kesavan studied thecoppercombinationcomplexes have been also(2, used of Cu(II)/(S,S)-Nap-(R,R)-Box Figure as2) Lewis with NFSI acids. as a The group of Kesavan studied fluorinating reagent, achieving the combination a 34% ee in the α-fluorination of ethyl of Cu(II)/(S,S)-Nap-(R,R)-Box 1-indanone-2-carboxylate (2, Figure 2) with NFSI13as a fluorinating Upon enlarging the ring size to the cyclohexanone derivative (compound16) the ee decreased to 16% reagent, achieving (entries 11 andee21, a 34% inTable α-fluorination the 1). On the contrary, of ethyl some alkyl1-indanone-2-carboxylate 2-oxocyclopentane-1-carboxylates 17–19 13 Upon enlarging the ring size to (Scheme the cyclohexanone derivative values 1) gave higher enantioselective (compound (72–86% ee)16) the [45]. ee decreased A notable advantageto is 16% (entries 11 and 21, that ester bulkiness is not needed to achieve high ee. Hexafluoro-2-propanol (HFIP) was used as additive to Table 1). On theincrease contrary, the enantioselectivities, promoting the release of the fluorinated product from the catalyst 1) gave higher some alkyl 2-oxocyclopentane-1-carboxylates 17–19 (Scheme enantioselective as values others have (72–86% ee) [45]. reported before [46]. A notable advantage is that ester bulkiness is not needed to If we keep talking about copper, asymmetric fluorination of methyl 1-indanone-2-carboxylate achieve high ee.(12)Hexafluoro-2-propanol (HFIP) was used as additive to increase the enantioselectivities, catalyzed by the Cu(II)/Ar-BINMOL-derived salan system (Ar-BINMOL = 1,1′-binaphthalene-2- promoting the release of the fluorinated α-arylmethanol-2′-ol) (3, Figure 2) gave product 82% ee from and 99% the catalyst yield (entry 10,as others Table have 1) [47]. Only reported β-keto before [46]. ester 12 (Scheme 1) was tested, however, these conditions were applied If we keep talking about copper, asymmetric fluorination of methyl 1-indanone-2-carboxylate with great success to a series of β-keto amides. In addition to this work, efficient enantioselective fluorination of β-keto esters and (4, Figure = (12) catalyzed amides, by thecatalysed Cu(II)/Ar-BINMOL-derived 0 by Cu(II)/diphenylamine-linkedsalan systemcomplexes bis(thiazoline) (Ar-BINMOL 2), 1,1 was -binaphthalene achieved -2-α-arylmethanol-2 0 -ol) [48].(3, These conditions Figure work nicely 2) gave 82%with ee five and(11,99% 13, Scheme yield1)(entry and six membered 10, Table rings [47]. Only β-keto 1) (15, 16, Scheme 1) and with different esters (entries 5, 15, 18 and 22, Table 1). Unfortunately, racemic ester 12 (Scheme 1) was tested, however, these conditions were applied with product (46% yield) was obtained with 19 as substrate, and compound 20 did not react under these great success to a series of β-keto amides. In addition conditions to this (entries 29 andwork, efficient 32, Table enantioselective 1). In 2017, Xu and collaboratorsfluorination reported a offastβ-keto and highlyesters and amides, enantioselective fluorination method for different alkyl 1-indanone-2-carboxylates catalysed by a catalysed by Cu(II)/diphenylamine-linked bis(thiazoline) complexes (4, Figure 2), was achieved [48]. chiral non-commercial diphenylamine Box and Cu(OTf)2 (5, Figure 2) [49]. The reactions were These conditions work nicely conducted with using a ball five mill (11, 13, apparatus Scheme (Fritsch 1) and Planetary Microsix Millmembered rings7”) model “Pulverisette (15, 16, Scheme 1) and in the absence(entries with different esters of solvent,5, yielding 15, 18the andfluorinated 22, Table compounds with enantioselectivities 1). Unfortunately, racemic up to 99% ee (15(46% yield) was product examples, 74–99% ee). Ester functionalities with different steric hindrance were well tolerated (entries obtained with 19 3, 8asandsubstrate, 17, Table 1).and compound Halogen substitutions 20ondid not react the aromatic ringunder theseinduction, gave excellent conditions (entries 29 and 32, whereas Table 1). In 2017,electron-donating Xu and collaborators substituents dropped reported the ee a (21 fastandand 22, Figure highly 3). With a six-member ringfluorination enantioselective substrate method for (compound 15) the ee dropped to 56% (entry 17 of Table 1). In addition, compounds 19 and 20 different alkyl 1-indanone-2-carboxylates (Scheme 1) gave excellent results in terms catalysed by aand of reactivity chiral ee undernon-commercial diphenylamine these conditions (entries 30 and Box and Cu(OTf)2 (5, Figure 33, Table2) 1).[49]. The reactions were conducted using a ball mill apparatus (Fritsch Planetary Micro Mill model “Pulverisette 7”) in the absence of solvent, yielding the fluorinated compounds with enantioselectivities up to 99% ee (15 examples, 74–99% ee). Ester functionalities with different steric hindrance were well tolerated (entries 3, 8 and 17, Table 1). Halogen substitutions on the aromatic ring gave excellent induction, whereas electron-donating substituents dropped the ee (21 and 22, Figure 3). With a six-member ring substrate (compound 15) the ee dropped to 56% (entry 17 of Table 1). In addition, compounds 19 and 20 (Scheme 1) gave excellent results in terms of reactivity and ee under these conditions (entries 30 and 33, Table 1). Chiral Fe(III)-salan complexes (6, Figure 2) with AgClO4 (2 mol.%) as additives and NFSI, catalysed the reaction of t-butyl 1-indanone-2-carboxylates with different substituents in the aromatic ring (11 examples, 94–97% ee). The bulkiness of the ester group played an important role, as less hindered esters gave lower ee (46–79% ee) (compare entries 1, 6 and 12, Table 1). The influence of different substituents in the aromatic position does not have much influence on the ee (23 and 24, Figure 3). With six membered ring substrate (14) the ee dropped to 69% (entry 16, Table 1). Remarkably, acyclic t-butyl keto esters gave excellent ee (87–94%), as did t-butyl 2-oxocyclopentane-1-carboxylate, 17 (95% ee, entry 24, Table 1). Addition of silver salt accelerated the reaction [50]. In 2015, Pd µ-hydroxo dimeric complexes containing (R)-DTBM-SEGPHOS (Ar = 3,5-(t-Bu)2 -4 -MeOC8 H2 ) (7, Figure 2) with NFSI in iPrOH gave 90% ee in the fluorination of t-butyl 2-oxocyclopentane -1-carboxylate (17) as substrate (only one example, entry 25, Table 1). The method was extensively applied to β-keto amides [51]. In the same year chiral mono-oxazoline ligands ((S)-diphenyl(6-(4-phenyl-4,5 -dihydrooxazol-2-yl)pyridine-2-yl)methanol) and Ni(ClO4 )2 ·6H2 O (8, Figure 2) in DCM using NFSI, catalysed the reaction of different alkyl 1-indanone-2-carboxylates (10 examples, 71–78% ee). Different methyl and halogens substituents on the aromatic ring were tested, showing low influence Molecules 2020, 25, 3264 5 of 24 on the results. Curiously enough the t-butyl ester 11 (Scheme 1) gave a racemic fluorination reaction (entry 2 of Table 1), as did methyl 2-oxocyclopentane-1-carboxylate (18, entry 26 of Table 1). Moreover, ethyl 1-oxo-1,2,3,4-tetrahydronaphtalene-2-carboxylate Molecules 2020, 25, x FOR PEER REVIEW (15) gave a low 13% ee (entry 519 of 28of Table 1) [52]. O O O O F F OMe MeO F OMe 21 22 Cu(II)/diphenylamine-bis(oxazoline) (5), Ball mill Cu(II)/diphenylamine-bis(oxazoline) (5), Ball mill [49]: 93% ee [49]: 74% ee O O O CF3 O MeO O F O F O F O F O 23 25 24 Eu(III)/(R,S)-ind-pybox (9) [53]: 81% ee Fe(III)/salan (6) [50]: 95% ee Fe(III)/salan (6) [50]: 95% ee Eu(III)/(R,S)-ind-pybox (9) [53]: 90% ee Eu(III)/(R,S)-ind-pybox (9) [53]: 93% ee O O O MeO O O O MeO F O Br F O F F O 26 27 28 Eu(III)/(R,S)-ind-pybox (9) [53]: 91% ee Ni(II)/Boxmi (10) [54]; 89 % ee Ni(II)/Boxmi (10) [54]: 93% ee Ni(II)/Boxmi (10) [54]: 94% ee Figure 3. Results Figure forforsubstituted 3. Results derivatives substituted derivatives 21–28. 21–28. Chiral Fe(III)-salan complexes (6, Figure 2) with AgClO4 (2 mol.%) as additives and NFSI, Based on our previous catalysed experience the reaction [35–37], we have established of t-butyl 1-indanone-2-carboxylates a catalytic with different substituents in themethod aromatic for the highly enantioselectiveringα-fluorination (11 examples, 94–97% of aee). series of t-butyl The bulkiness of the1-indanone-2-carboxylates, ester group played an important role,using as less europium (III) hindered esters gave lower ee (46–79% ee) (compare entries 1, 6 and 12, Table 1). The influence of triflate and (S,R)-ind-pybox as pre-catalyst (9, Figure 2), and NFSI as electrophilic different substituents in the aromatic position does not have much influence on the ee (23 and 24, fluorinating agent in acetonitrile at −30 ◦ C (6 examples, 81–96% ee). Results revealed a dependence of the enantiocontrol on Figure 3). With six membered ring substrate (14) the ee dropped to 69% (entry 16, Table 1). Remarkably, acyclic t-butyl keto esters gave excellent ee (87–94%), as did t-butyl 2-oxocyclopentane- the steric hindrance of the ester groups in substrates. In general, comparing substituent’s with similar 1-carboxylate, 17 (95% ee, entry 24, Table 1). Addition of silver salt accelerated the reaction [50]. steric hindrance, the In presence of electron 2015, Pd μ-hydroxo dimericwithdrawing complexes containing groups in the benzene (R)-DTBM-SEGPHOS (Ar =harmed the ee (23 and 25, 3,5-(t-Bu)2-4- Figure 3). Access to both enantiomers of the α-fluorinated oxo ester is guaranteed by the commercial MeOC 8H2) (7, Figure 2) with NFSI in iPrOH gave 90% ee in the fluorination of t-butyl 2- oxocyclopentane-1-carboxylate (17) as substrate (only one example, entry 25, Table 1). The method availability of both (R,S) and was extensively (S,R) applied ind-pybox to β-keto C2-symmetric amides [51]. In the same year ligands [53]. chiral mono-oxazoline ligands ((S)- Very recently, Gade’s group reported a remarkable contributionand diphenyl(6-(4-phenyl-4,5-dihydrooxazol-2-yl)pyridine-2-yl)methanol) using Ni(ClOBoxmi 4)2·6H2Oligands (8, Figure in combination 2) in DCM using NFSI, catalysed the reaction of different alkyl 1-indanone-2-carboxylates (10 with Ni(II) andexamples, Zinc (II) complexes (10, Figure 2) with NFSI reagent. They screened four t-butyl 71–78% ee). Different methyl and halogens substituents on the aromatic ring were tested, indanone-2-carboxylates substituted showing low influence in the on the results. aromatic Curiously enough thering with t-butyl esterNi(II)/Boxmi 11 (Scheme 1) gaveobtaining a racemic excellent ee values (89–94%fluorination ee). Methyl reaction (entry 2 of Table 1), as did methyl 2-oxocyclopentane-1-carboxylate (18, entry ester gave worse results (64% ee). Electron-rich substituents, such as 26 of Table 1). Moreover, ethyl 1-oxo-1,2,3,4-tetrahydronaphtalene-2-carboxylate (15) gave a low 13% the methoxy groupee (entryin the 19 of aromatic Table 1) [52]. ring of 1-indanone-2-carboxylate, caused slight increased the ee (Figure 3). Three new examples with other substituents in the aromatic ring were tested with Table 1. Conditions and results for enantioselective fluorination reactions of compounds of Scheme 1 Zn(II)/Boxmi and t-butyl(from 2010ester to 2020).giving also high levels of induction (84–92%) [54]. All these differentSubstratreportedFluorinating methodologies are summarized in Table 1. Indanone 11 possessing a Pre-Catalyst Entry Yield (%) ee (%) Ref e Reagent (see Figure 2) t-butyl ester nicely reacted (78–99 yield and 94–99 ee) under four different pre-catalysts combination Fe(III)/salan (6) 1 11 NFSI (entries 1,3-5). Lower inductions are obtained 0 °C,with MeCN,lessAgClO bulky methyl 96 (2 mol.%) 4 and ethyl 94 [50] esters (compounds 12 2 11 NFSI Ni(II)-monooxazoline (8) 89 0 [52] and 13, Scheme 1). The best general conditionsCu(II)/diphenylamine- are the ones described by Xu and collaborators which 3 11 NFSI 99 95 [49] consist in using the Cu(II)/diphenylamine-bis(oxazoline) bis(oxazoline) (5), Ballcombination mill in a ball mill apparatus [49]. 4 11 NFSI Eu(III)/(R,S)-ind-pybox (9) 78 96 (S) [53] We also recommend the Cu(II)/diphenylamine-linked bis(thiazoline) combination [48]. Generally, alkyl 1-oxo-1,2,3,4-tetrahydronaphtalene-2-carboxylates 14–16 gave lower ee than their indanyl analogues 11–13 (Scheme 1) (compare entries 1 and 16, and entries 8 and 17, Table 1), except in the case of Cu(II)/diphenylamine-linked bis(thiazoline) combination [48]. Alkyl 2-oxocyclopentane-1-carboxylates 17 and 18 normally gave the fluorinated products in lower ee. However, with Fe(III)/salan an excellent 95% ee was reported for substrate 17 having a t-butyl ester [50]. From Table 1 the combination of Cu(II)/diphenylamine-bis(oxazoline) in a ball mill system is recommended for 19 and 20 (Scheme 1), affording 92 and 99% ee, respectively. In general, for all the methodologies (Figure 3) electron-rich substituents such as the methoxy group in the aromatic ring of 1-indanone-2-carboxylate caused increases in ee. case of Cu(II)/diphenylamine-linked bis(thiazoline) combination [48]. Alkyl 2-oxocyclopentane-1- carboxylates 17 and 18 normally gave the fluorinated products in lower ee. However, with Fe(III)/salan an excellent 95% ee was reported for substrate 17 having a t-butyl ester [50]. From Table 1 the combination of Cu(II)/diphenylamine-bis(oxazoline) in a ball mill system is recommended for 19 and 20 (Scheme 1), affording 92 and 99% ee, respectively. In general, for all the methodologies Molecules 2020, 25, 3264 6 of 24 (Figure 3) electron-rich substituents such as the methoxy group in the aromatic ring of 1-indanone-2- carboxylate caused increases in ee. Acyclicβ-keto Acyclic β-ketoesters estersare are difficult difficult substrates substrates in this in this reaction reaction even even in terms in terms of reactivity. of reactivity. Regarding Regarding the the enantioinduction they are not so rigid and have more degrees of conformational enantioinduction they are not so rigid and have more degrees of conformational freedom in comparison freedom in comparison with withesters. cyclic 3-oxo cyclic 3-oxo esters. In 2012, In 2012, Togni’s groupTogni’s group reported [44]reported that using[44]thethat using the Ti/TADDOL Ti/TADDOL complexes complexes (1, Figure 2) and® Selectfluor ® (Figure 1) a series of alkyl α-methyl 3-oxobutanoates were (1, Figure 2) and Selectfluor (Figure 1) a series of alkyl α-methyl 3-oxobutanoates were fluorinated fluorinated giving giving excellent excellent yields (44–96%)yields and (44–96%) moderate and ee (10moderate examples,ee45–81% (10 examples, 45–81% ee). ee). In addition, Inα-methyl alkyl addition, alkyl α-methyl 3-oxopentanoates could be fluorinated with moderate 3-oxopentanoates could be fluorinated with moderate to high selectivities (7 examples, 30–90% ee).to high selectivities (7 examples, 30–90% ee). Alkyl 2-methyl 2-benzoylpropanoate compounds were Alkyl 2-methyl 2-benzoylpropanoate compounds were also examined, giving good results (12 examples, also examined, giving good results 55–82% (12results ee). Best examples, were 55–82% obtainedee). Best with results bulky esterwere obtained groups (29–31,with Figure bulky ester groupsof(29–31, 4). Fluorination ethyl Figure 4). Fluorination of ethyl ester 33 gave a moderate 62% ee (Figure ester 33 gave a moderate 62% ee (Figure 5). The scope of this method is the most extensive 5). The scope of thisreported method is thenow. until most extensive reported until now. Molecules 2020, 25, x FOR PEER REVIEW 8 of 28 fluorinated products were obtained [48]. In addition, Xu’s group reported that using Cu/diphenylamine-linked bis (oxazoline) (5, Figure 2) in a ball mill system [49] fluorination of ethyl 2-benzyl-3-oxobutanoate 35 afforded a moderate yield (60%) and ee (61%); compound 33 also produced the fluorinated compound in 56% yield and 75% ee (Figure 5). Using the Fe(III)-salan combination [50] (6, Figure 2), compound 34 reacted nicely, giving 87% yield and 94% ee. β-Keto ester 36 gave 96% yield and 87% ee of the fluorinated derivative (Figure 5). Low yield (41%) and ee (25%) was obtained using 33 and the Ni(II)-monooxazoline ligand [52]. Figure 4. Fluorinated acyclic β-keto esters prepared by Togni’s research group [44]. Figure 4. Fluorinated acyclic β-keto esters prepared by Togni’s research group [44]. Kesavan’s group reported that ethyl 2-methyl-3-oxobutanoate (32, Figure 5) underwent fluorination in 84% yield and 70% ee (only one example) using the Cu(II)/(S,S)-Nap-(R,R)-Box (2, Figure 2) combination [45]. Du et al. using Cu/diphenylamine-linked bis(thiazoline) (4, Figure 2) evaluated the fluorination of some acyclic α-alkyl β-keto esters, such as ethyl 2-methyl-3-oxo-3- phenylpropanoate (33) and ethyl and t-butyl 2-benzyl-3-oxobutanoates 35, 36. Unfortunately, no Figure 5. Examples Figure of acyclicofβ-keto 5. Examples esters acyclic β-keto used esters usedfor validation for validation of methodologies. of methodologies. Reaction conditions Reaction conditions are summarized in Table 1 and Figure 2; all the results correspond to optimized are summarized in Table 1 and Figure 2; all the results correspond to optimized conditions. conditions. The reactions described above may all proceed through a similar catalytic cycle regardless of the Kesavan’s group reported metal complex used.that First,ethyl 2-methyl-3-oxobutanoate coordination (32,theFigure to the metal centre increases acidity 5) of underwent the α-proton, fluorination in allowing the metal enolate to be easily generated. The chiral 84% yield and 70% ee (only one example) using the Cu(II)/(S,S)-Nap-(R,R)-Box (2, Figureligand normally acts as a base. 2) combination [45]. Subsequent reaction affords the formation of a stereogenic C-F bond through a SN2 mechanism. The Du et al. using Cu/diphenylamine-linked bis(thiazoline) (4, Figure 2) evaluated the enantioselectivity of the reaction stems from the efficient blockage of one of the faces. See as an fluorination of some acyclic α-alkyl β-keto esters, such as ethyl 2-methyl-3-oxo-3-phenylpropanoate (33) and ethyl and t-butyl example the catalytic cycle proposed for the asymmetric fluorination using europium (III) triflate and (S,R)-ind-pybox combination [53] (Scheme 2). 2-benzyl-3-oxobutanoates 35, 36. Unfortunately, no fluorinated products were obtained [48]. In addition, Xu’s group reported that using Cu/diphenylamine-linked bis (oxazoline) (5, Figure 2) in a ball mill system [49] fluorination of ethyl 2-benzyl-3-oxobutanoate 35 afforded a moderate yield (60%) and ee (61%); compound 33 also produced the fluorinated compound in 56% yield and 75% ee (Figure 5). Using the Fe(III)-salan combination [50] (6, Figure 2), compound 34 reacted nicely, giving 87% yield and 94% ee. β-Keto ester 36 gave 96% yield and 87% ee of the fluorinated derivative (Figure 5). Low yield (41%) and ee (25%) was obtained using 33 and the Ni(II)-monooxazoline ligand [52]. The reactions described above may all proceed through a similar catalytic cycle regardless of the metal complex used. First, coordination to the metal centre increases the acidity of the α-proton, allowing the metal enolate to be easily generated. The chiral ligand normally acts as a base. Subsequent reaction affords the formation of a stereogenic C-F bond through a SN 2 mechanism. The enantioselectivity of the reaction stems from the efficient blockage of one of the faces. See as an example the catalytic cycle proposed for the asymmetric fluorination using europium (III) triflate and (S,R)-ind-pybox combination [53] (Scheme 2). Molecules 2020, 25, 3264 7 of 24 Molecules 2020, 25, x FOR PEER REVIEW 9 of 28 Scheme 2. Proposed Scheme catalytic 2. Proposed catalytic cycle cycle [53]. [53]. Table 1. Conditions and results 2.2. Organocatalytic Methods for enantioselective fluorination reactions of compounds of Scheme 1 (from 2010 to Phase-transfer 2020). catalysis (PTC) has been applied to the enantioselective fluorination of β-keto esters. The first example was reported by Kim and Park in 2002 using quaternary ammonium salts from cinchonine (10% Pre-Catalyst mol, Figure 5), NFSI and K2CO 3 [55]. Some years later chiral bifunctional Entry Substrate Fluorinating Reagent Yield (%) phase ee (%) Ref (see Figure 2) transfer catalysts using binaphtyl derivatives 37 (2% mol, Figure 6) were used by Maruoka and Fe(III)/salan (6) 1 collaborators inNFSI 11 the fluorination of different ◦t-butyl 1-indanone-2-carboxylates affording the 96 products94 [50] 0 C, MeCN, AgClO4 (2 mol.%) 2 in 11 excellent yields NFSI and ee (4 examples 94–98% ee) using NFSI Ni(II)-monooxazoline (8) and K 2CO3 [56]. Substrates 14 and 17 89 0 [52] 3 gave 90 and 98% 11 ee, respectively. Only NFSI bulky t-butyl esters were reported Cu(II)/diphenylamine-bis(oxazoline) (5), Ball [56]. mill 99 95 [49] 4 11 In addition,NFSI a designing study of fluorinatedEu(III)/(R,S)-ind-pybox cinchone alkaloids (9) was carried out by the 78 group of96 (S) [53] 5 11 NFSI optimized Gilmour [57]. Using Cu(II)/diphenylamine-linked PTC 38 (10% mol,◦ Figure bis(thiazoline) 6), t-butyl (4), andCHCl 3 , rt adamantyl 93 1-indanone-2-99 (S) [48] 6 12 NFSI Fe(III)/salan (6)0 C, MeCN, AgClO4 (2 mol.%) 99 46 [50] 7 carboxylates gave 12 NFSI moderate ee (78 and 78% eeNi(II)-monooxazoline respectively) with(8) NFSI and Cs2CO3. Some90studies on75 [52] 8 the 12 use of multifunctional NFSI catalyst 41 (Figure 6) combining cinchona alkaloid-derived Cu(II)/diphenylamine-bis(oxazoline), (5), Ball mill primary 97 amines 92 [49] 9 (10% mol) withNFSI 12 L-leucine (20% mol) gave good reactivity using (9) La(III)/(R,S)-ind-pybox Selecfluor®, although low 80 ee in the 62 (S) [53] fluorination of several Cu/Ar-BINMOL-derived salan (3) 39–55% ee) [58]. 10 12 NFSI alkyl 1-indanone-2-carboxylates (four examples, 99 82 (S) [47] 0 ◦C In 2012, bifunctional chiral thioureas 39 (10% Xylene, mol, Figure 6) with NFSI, DMAP as a base at −60 Cu(II)/(S,S)-Nap-(R,R)-Box (2) 11 13 oC were used as NFSI organocatalysts in the enantioselective fluorination 98 of different alkyl 1-indanone-2- 34 [45] 0 ◦ C, toluene, HFIP carboxylates (11 examples, up to 99% ee) [59]. Fe(III)/salanMethyl, ethyl, (6) isopropyl and benzyl ethers gave 12 13 NFSI 99 59 [50] excellent results, whereas surprisingly t-butyl 0 ◦ C, afforded MeCN, AgClO 4 (2 mol.%) racemic fluorination. Some alkyl 2-oxocyclo- 13 13 NFSI Ni(II)-monooxazoline (8) 85 77 [52] pentane-1-carboxylates were assayed with success. Benzyl 1-oxo-1,2,3,4-tetrahydronaphtalene-2- Cu(II)/diphenylamine-bis(oxazoline) 14 carboxylate andNFSI 13 several acyclic β-keto esters gave(5), low ee, except in the case of compound99 35 that91 [49] Ball mill 15 afforded a niceNFSI 13 81% ee. A possible reactive intermediate Cu(II)/diphenylamine-linked has been (4), bis(thiazoline) proposed CHCl3 , rt by the authors 100 that99 [48] illustrates this kind Fe(III)/salan (6) 7). The authors envisioned that the 16 14 NFSI of organocatalysis using thioureas (Figure 96 69 [50] 0 ◦ C, MeCN, AgClO4 (2 mol.%) thiourea group was attached to NFSI via hydrogen bonds; and the β-keto ester was coordinated with Cu(II)/diphenylamine-bis(oxazoline) 17 15 the tertiary amineNFSIthrough a hydrogen bond of its (5), enolBall form 93 56 [49] mill[59]. In addition, the Waser group used 18 urea-containingNFSI 15 chiral ammonium salts 40 (2% mol, Figure Cu(II)/diphenylamine-linked 6) with NFSI bis(thiazoline) and K (4), CHCl 3 , rt 3 PO 4 as a base 100 at −1093 [48] 19 15 °C affording the NFSI fluorination of a small series Ni(II)-monooxazoline (8) of alkyl 1-indanone-2-carboxylates 86 (11 examples, 70–13 [52] 20 16 Selectfluor® Ti/TADDOL (1), rt, MeCN 93 20 [44] 86% ee). β-Keto esters 14 and 17 gave 74 and 78% ee, respectively) [60]. Cu(II)/(S,S)-Nap-(R,R)-Box (2) 21 16 NFSI 90 16 [45] 0 ◦ C, toluene, HFIP 22 16 NFSI Cu(II)/diphenylamine-linked bis(thiazoline) (4), CHCl3 , rt 99 93 [48] Cu(II)/(S,S)-Nap-(R,R)-Box (2) 23 17 NFSI 97 83 [45] 0 ◦ C, toluene, HFIP Fe(III)/salan (6) 24 17 NFSI 88 95 [50] O ◦ C, MeCN, AgClO4 (2 mol.%) Pd(II)/(R)-DTBM-SEGPHOS (7) 25 17 NFSI 93 90 [51] iPrOH, rt 26 18 NFSI Ni(II)-monooxazoline (8) 30 0 [52] Cu(II)/(S,S)-Nap-(R,R)-Box (2) 27 18 NFSI 96 72 [45] 0 ◦ C, toluene, HFIP Cu(II)/(S,S)-Nap-(R,R)-Box (2) 28 19 NFSI 93 86 [45] 0 ◦ C, toluene, HFIP 29 19 NFSI Cu(II)/diphenylamine-linked bis(thiazoline) (4), CHCl3 , rt 46 0 [48] Cu(II)/diphenylamine-bis(oxazoline) 30 19 NFSI 96 92 [49] (8), Ball mill Cu(II)/(S,S)-Nap-(R,R)-Box (2) 31 20 NFSI 90 52 [45] 0 ◦ C, toluene, HFIP 32 20 NFSI Cu(II)/diphenylamine-linked bis(thiazoline) (4), CHCl3 , rt n. r. - [48] Cu(II)/diphenylamine-bis(oxazoline) 33 20 NFSI 95 99 [49] (5), Ball mill Molecules 2020, 25, 3264 8 of 24 Molecules 2020, 25, x FOR PEER REVIEW 10 of 28 2.2. Organocatalytic Methods Akiyama reported in 2014 [61] an interesting work based on the in situ generation of a chiral Phase-transfer catalysis (PTC) has been applied to the enantioselective fluorination of β-keto sodium phosphate derived from a chiral phosphoric acid [42, Figure 6]. Two active species (sodium esters. The first example was reported by Kim and Park in 2002 using quaternary ammonium salts enolate and sodium phosphate) were generated under Na2CO3 basic conditions. The corresponding from cinchonine (10% mol, Figure 5), NFSI and K2 CO3 [55]. Some years later chiral bifunctional α-fluoro β-keto esters including methyl, ethyl and benzyl esters were obtained in excellent yields with phase transfer catalysts using binaphtyl derivatives 37 (2% mol, Figure 6) were used by Maruoka and good to excellent ee. With Akiyama’s group conditions, the enantioselective fluorination of indanones collaborators in the fluorination of different t-butyl 1-indanone-2-carboxylates affording the products 12 and 13 was afforded in a 99% and 87% ee, respectively. For the t-butyl ester only a 20% ee was in excellent yields and ee (4 examples 94–98% ee) using NFSI and K2 CO3 [56]. Substrates 14 and 17 achieved. The method is not useful for tetralone 16. gave 90 and 98% ee, respectively. Only bulky t-butyl esters were reported [56]. Figure 6. Structure of different organocatalysts. Figure 6. Structure of different organocatalysts. In addition, a designing study of fluorinated cinchone alkaloids was carried out by the group of Gilmour [57]. Using optimized PTC 38 (10% mol, Figure 6), t-butyl and adamantyl 1-indanone-2 -carboxylates gave moderate ee (78 and 78% ee respectively) with NFSI and Cs2 CO3 . Some studies on the use of multifunctional catalyst 41 (Figure 6) combining cinchona alkaloid-derived primary amines (10% mol) with l-leucine (20% mol) gave good reactivity using Selecfluor® , although low ee in the fluorination of several alkyl 1-indanone-2-carboxylates (four examples, 39–55% ee) [58]. In 2012, bifunctional chiral thioureas 39 (10% mol, Figure 6) with NFSI, DMAP as a base at −60 ◦ C were used as organocatalysts in the enantioselective fluorination of different alkyl 1-indanone-2 -carboxylates (11 examples,Figure up to 7. 99% ee) [59]. Plausible Methyl, ethyl, intermediate isopropyl proposed by Huand [59].benzyl ethers gave excellent results, whereas surprisingly t-butyl afforded racemic fluorination. Some alkyl 2-oxocyclo-pentane -1-carboxylates were assayed In 2018, Zheng’s groupwith success. Benzyl developed a highly 1-oxo-1,2,3,4-tetrahydronaphtalene-2-carboxylate enantioselective oxidative method for the and several acyclic fluorination β-keto of β-keto esters esters usinggave low ee, as Et3N·3HF except in the casefluoride a nucleophilic of compound source35 that afforded mediated a nice by a chiral 81% ee. iodo arene organocatalyst 43 and mCPBA as oxidant. The yields were low in all the studied cases kind A possible reactive intermediate has been proposed by the authors that illustrates this [41]. of organocatalysis Some months afterusing thioureas Rueping (Figure 7). et al. reported The authors a similar envisioned strategy that iodoarene using chiral the thiourea 44group was obtaining attached higher to NFSI yields via hydrogen bonds; and enantioselectivities and [42] the β-keto (Scheme 3). Aester was coordinated plausible mechanism with the tertiary (Scheme 3) is the amine in situ through a hydrogen bond of its enol form [59]. In addition, the Waser group formation of Ar*-I-F2 by oxidation of the hypervalent iodine reactive with HF and the m-CPBA used urea-containing chiral ammonium followed salts 40 (2%with by the coordination mol,β-keto Figureester 6) with NFSI Then, (INT1). and K3the POnext 4 as astep at −10 ◦ C baseinvolves theaffording reactiontheof fluorination of a small series of alkyl 1-indanone-2-carboxylates (11 examples, 70–86% the enol form of substrate with [Ar-I-F] /[HF2] to abstract the H atom with formation of an O-bonded + − ee). β-Keto esters 14 and 17 gave hypervalent 74 andThis iodine. ee, respectively) 78%underwent [60]. a 1,3-migration to afford intermediate INT3 and posterior Akiyama reductive reported in 2014 [61] an interesting work based on the in situ generation of a chiral sodium elimination. phosphate derived from a chiral phosphoric acid [42, Figure 6]. Two active species (sodium enolate and sodium phosphate) were generated under Na2 CO3 basic conditions. The corresponding α-fluoro β-keto esters including methyl, ethyl and benzyl esters were obtained in excellent yields with good to excellent ee. With Akiyama’s group conditions, the enantioselective fluorination of indanones 12 and Molecules 2020, 25, 3264 9 of 24 13 was afforded in a 99% and 87% ee, respectively. For the t-butyl ester only a 20% ee was achieved. The method is not useful for tetralone Figure 16. 6. Structure of different organocatalysts. Figure Figure 7. Plausible 7. Plausible intermediate proposed intermediate proposedby Hu by[59]. Hu [59]. In 2018, Zheng’s group developed a highly enantioselective oxidative method for the In 2018, Zheng’s group developed a highly enantioselective oxidative method for the fluorination fluorination of β-keto esters using Et3N·3HF as a nucleophilic fluoride source mediated by a chiral of β-keto esters using Et3 N·3HF iodo arene organocatalyst as amCPBA 43 and nucleophilic as oxidant.fluoride The yieldssource were lowmediated by a cases in all the studied chiral [41].iodo arene organocatalyst 43 and mCPBA as oxidant. The yields were low in all the studied Some months after Rueping et al. reported a similar strategy using chiral iodoarene 44 obtaining cases [41]. Some months higher yields and enantioselectivities [42] (Scheme 3). A plausible mechanism after Rueping et al. reported a similar strategy using chiral iodoarene 44 obtaining higher (Scheme 3) is the in situyields and formation of Ar*-I-F2 by oxidation of the hypervalent iodine reactive with HF and the m-CPBA enantioselectivities [42] (Scheme 3). A plausible mechanism (Scheme 3) is the in situ formation of followed by the coordination with β-keto ester (INT1). Then, the next step involves the reaction of Ar*-I-F2 by theoxidation enol form ofof the hypervalent substrate with [Ar-I-F]+iodine /[HF2]− toreactive with abstract the HFwith H atom andformation the m-CPBA followed by the of an O-bonded coordination with β-keto hypervalent iodine.ester This (INT1). underwentThen, the next to a 1,3-migration step involves afford the reaction intermediate INT3 andofposterior the enol form of reductive substrate with + /[HF ]− to abstract the H atom with formation of an O-bonded hypervalent elimination. [Ar-I-F] 2 iodine. This underwent a 1,3-migration Molecules 2020, 25, x FOR PEER REVIEW to afford intermediate INT3 and posterior reductive 11 of 28 elimination. O O O Chiral Iodoarene O R2 OR1 R2 OR1 Et3N·3HF, mCPBA F I I (Dmenthyl)OOC O O COO(Dmenthyl) O OMe 43 44 R1 = Et OMe 12 examples OMe CF3 CF3 18-68% yield up to 90% ee R1 = tBu 9 examples 35-45% yield up to 89% ee Proposed Reaction Mechanism HF2 F + F F + I Ar* I Ar* I Ar* O O O O O -2 HF O OEt OEt OEt INT1 INT2 F O I Ar O O O OEt EtO - Ar*-I F INT3 Scheme 3. Combination Scheme 3. Combination of hydrogen of hydrogen fluorideand fluoride and an anoxidant mediated oxidant by an hypervalent mediated by an iodine hypervalent iodine compound. Plausible mechanism. compound. Plausible mechanism. 3. Asymmetric Preparation of Quaternary C-CF3 Stereocentres on β-keto Esters 3. Asymmetric Preparation of Quaternary C-CF3 Stereocentres Nowadays the importance of the trifluoromethyl on β-keto Esters group is well known and appreciated. In pharmaceutical research, molecules bearing the CF3 group are of high interest because it generally Nowadaysencourages the importance of the trifluoromethyl group is well known and appreciated. remarkable and unusual changes in the properties of the original drug (better metabolic In pharmaceutical research, stability, enhancedmolecules biodisponibilitybearing the CF and modulated 3 group[1]. lipophilicity) are ofLehmann Since high interest because reported in 1928 it generally the first biologically active trifluoromethylated molecule [62], the trifluoromethyl group has gained encourages remarkable and unusual changes in the properties of the original drug (better metabolic more and more prominence. stability, enhancedα-Trifluoromethyl biodisponibility β-ketoand modulated esters are intriguing lipophilicity) [1].to Since target molecules due Lehmann the presence reported in 1928 of a chiral quaternary the first biologically centre active and the derivatizable carbonyl trifluoromethylated molecule group. Thus, [62], theits trifluoromethyl enantiopure asymmetricgroup has gained preparation has been a thrilling challenge for the scientific community. more and more prominence. In the 80s [63] the first electrophilic trifluoromethylating reagents developed by Yagupol’skii appeared and later on in the 90s [64], Umemoto presented the second generation based on (trifluoromethyl)dibenzoheterocycle salts, being the S-(trifluoromethyl)dibenzthiophenium tetrafluoroborate, 44, (Umemoto’s reagent, Scheme 4) the best known, but it was not until 2003 that Cahard and co-workers [65] applied these reagents in the preparation of non-asymmetric α-trifluoro- methyl β-keto esters. 3.1. Metal-Catalyzed Methods Gade and co-workers [38] described in 2012 the enantioselective copper-catalysed trifluoromethylation of β-keto esters using commercially available trifluoromethylating reagents. The Molecules 2020, 25, 3264 10 of 24 α-Trifluoromethyl β-keto esters are intriguing target molecules due to the presence of a chiral quaternary centre and the derivatizable carbonyl group. Thus, its enantiopure asymmetric preparation has been a thrilling Moleculeschallenge for REVIEW 2020, 25, x FOR PEER the scientific community. 12 of 28 In the 80s(Scheme [63] the 4). first electrophilic The method tolerated atrifluoromethylating reagents developed great range alkyl 1-indanones-2-carboxylates, either withby Yagupol’skii appeared andelectron-withdrawing later on in the or electron-donating 90s [64], Umemoto groups in aromatic position, presented providing the second excellent generation based enantioselectivities and yields. Primary esters also yielded the corresponding trifluoromethylated on (trifluoromethyl)dibenzoheterocycle products with excellent enantioselectivities salts, being (up to 96% ee). the S-(trifluoromethyl)dibenzthiophenium The method was applied with success to tetrafluoroborate, t-butyl44, (Umemoto’s reagent,and 2-oxocyclopentene-1-carboxylates Scheme 4) the best known, butDespite benzyl 2-oxocyclopentane-1-carboxylates. it was the not until 2003 fact Togni’s reagent 46 was the best choice in the five-membered ring substrates, in order to achieve that Cahard and co-workers [65] applied these reagents in the preparation of non-asymmetric high enantiocontrol in the more enolizable six-membered ring β-keto esters, Umemoto’s reagent 45 α-trifluoro-methyl β-ketoinesters. was selected presence of the non-nucleophilic base iPr2NEt (Scheme 4). Unfortunately, acyclic β- keto esters were found to be unreactive under these reaction conditions. Five-membered enantioselective trifluoromethylation. Conditions and scope O Cu(OTf)2 (10 mol %) O CF3 I O O O boxmi (12 mol %) + OtBu OtBu 46 CH2Cl2, rt, 4Å MS CF3 Up to 94% yield and 99% ee O O R2 = H, i R3 = H, i 92%, 95% ee OR R2 = OCH2, R3 = O, 92%, 99% ee MeO CF3 O O R2 = SMe, R3 = H, 94%, 98% ee R2 R2 = Cl, R3 = H, 94%, 92% ee R = Me, 91%, 92% ee OtBu R2 = OMe R3 = OMe, 93%, 95% ee R3 CF3 R = Bn, 90%, 96% ee R2 = OMe, R3 = H, 92%, 94% ee R = tBu, 91%, 98% eei R2 = H, R3 = Br, 93%, 92% ee R2 = H, R3 = F, 93%, 95% ee O R2 = H, R3 = Me, 92%, 97% eeIi O O R5 O OtBu OBn CF3 R4 CF3 R5 = H, i R4 = OMe, i86%, 98% ee 85%, 92% ee R = Me, R4 = 5 Molecules 2020, 25,H,x FOR88%, PEER97% ee REVIEW 13 of 28 R5 = Me, R4 = Me, 86%, 97% eeI Scheme 4. Cont. Scheme 4. Reaction conditions and scope for the enantioselective electrophilic trifluoromethylation of five- Scheme 4. Reaction conditions and six-membered and cyclic scope β-keto for the enantioselective electrophilic trifluoromethylation of esters. five- and six-membered cyclic β-keto esters. Later, in 2019 Cossío and Vallribera [66] reported a highly enantioselective catalytic method for the synthesis of quaternary α-trifluoromethyl derivatives cyclic β-keto esters under lanthanide 3.1. Metal-Catalyzed Methods catalysis. The methodology implemented by these authors required the use of the Togni reagent 46 and the combination of La(OTf)3 and Nishiyama-type indanyl-pybox ligand, which are commercially Gade andavailable co-workers [38] reagents. With described the optimized in combination pre-catalyst 2012 theand enantioselective copper-catalysed reaction conditions in hand, a trifluoromethylation of β-keto broad range esters of β-keto esters wereusing commercially examined. Best results wereavailable obtained withtrifluoromethylating methyl 1-indanone-2- reagents. carboxylates, which was remarkable since it showed that this method could be applied to simple β- The trifluoromethylation of 1-indanone derivatives proceeded best under Cu(OTf) catalysis in keto esters. In the presence of either electron-donating or electron-withdrawing groups excellent 2 presence of bisoxazoline boxmi enantioselectivities wereas a stereo-directing obtained. ligand six-membered Finally, the more enolizable and with the ringsTogni hypervalent substrates such iodine as alkyl4). 1-oxo-1,2,3,4-tetrahydronaphtalene-2-carboxylates reagent 46 (Scheme The method tolerated a great range and alkyl alkyl2-oxocyclopentanone 1-indanones-2-carboxylates, carboxylates gave lower ee. The mechanism was explored both by experimental and computational either with electron-withdrawing or electron-donating techniques. ESI-MS experiments groupstheinformation and NMR studies determined aromatic position, of INT1 (Scheme providing 5) and excellent the coordination of Togni’s reagent to the lanthanum. Reactions in presence of scavengers determined that the presence of trifluoromethyl radicals in the alkylation process could not be discarded. Afterwards, computational studies at the B3LYP-D3/6-31G*&LanL2DZ level of theory were carried out, and the coordination pattern of the cationic intermediate INT2 in Scheme 5 revealed an efficient blockage of the prochiral Si face of the LaIII enolate. The hindrance of the Si face of the substrate resulted in an efficient SN2-like saddle point TS, which consisted of a Re attack of the Cα atom of the enolate moiety on the CF3 group of the Togni reagent, forming INT3. Unfortunately, this catalytic Molecules 2020, 25, 3264 11 of 24 enantioselectivities and yields. Primary esters also yielded the corresponding trifluoromethylated products with excellent enantioselectivities (up to 96% ee). The method was applied with success to t-butyl 2-oxocyclopentene-1-carboxylates and benzyl 2-oxocyclopentane-1-carboxylates. Despite the fact Togni’s reagent 46 was the best choice in the five-membered ring substrates, in order to achieve high enantiocontrol in the more enolizable six-membered ring β-keto esters, Umemoto’s reagent 45 was selected in presence of the non-nucleophilic base i Pr2 NEt (Scheme 4). Unfortunately, acyclic β-keto esters were found to be unreactive under these reaction conditions. Later, in 2019 Cossío and Vallribera [66] reported a highly enantioselective catalytic method for the synthesis of quaternary α-trifluoromethyl derivatives cyclic β-keto esters under lanthanide catalysis. The methodology implemented by these authors required the use of the Togni reagent 46 and the combination of La(OTf)3 and Nishiyama-type indanyl-pybox ligand, which are commercially available reagents. With the optimized pre-catalyst combination and reaction conditions in hand, a broad range of β-keto esters were examined. Best results were obtained with methyl 1-indanone-2-carboxylates, which was remarkable since it showed that this method could be applied to simple β-keto esters. In the presence of either electron-donating or electron-withdrawing groups excellent enantioselectivities were obtained. Finally, the more enolizable six-membered rings substrates such as alkyl 1-oxo-1,2,3,4 -tetrahydronaphtalene-2-carboxylates and alkyl 2-oxocyclopentanone carboxylates gave lower ee. The mechanism was explored both by experimental and computational techniques. ESI-MS experiments and NMR studies determined the formation of INT1 (Scheme 5) and the coordination of Togni’s reagent to the lanthanum. Reactions in presence of scavengers determined that the presence of trifluoromethyl radicals in the alkylation process could not be discarded. Afterwards, computational studies at the B3LYP-D3/6-31G*&LanL2DZ level of theory were carried out, and the coordination pattern of the cationic intermediate INT2 in Scheme 5 revealed an efficient blockage of the prochiral Si face of the LaIII enolate. The hindrance of the Si face of the substrate resulted in an efficient SN 2-like saddle point TS, which consisted of a Re attack of the Cα atom of the enolate moiety on the CF3 group of the Togni reagent, forming INT3. Unfortunately, this catalytic method could not be applied to open-chain β-keto esters successfully. 3.2. Organocatalytic Methods In 2007, Cahard’s group reported the very first asymmetric preparation of α-trifluoromethylated cyclic β-keto esters under an organocatalyzed based methodology (Scheme 6) which required the use of S-(trifluoromethyl)dibenzthiophenium tetrafluoroborate 45 as electrophilic reagent and a cinchona alkaloid based chiral phase-transfer catalysts (PTC) [67]. They noticed that using a quaternary ammonium PTC and potassium carbonate, the ee were not higher than 20%. The formation of potassium β-keto ester enolate was responsible of the low ee. Thus, to banish the presence of achiral enolates the use of the tertiary PTC hydroquinine was the solution giving the expected α-trifluoromethylated β-keto ester in 53% yield with 71% ee. A few years later, Shibata [68] deeply investigated the use of chiral guanidines with S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate 45. These guanidines act as Brønsted bases to generate chiral guanidinium enolates of β-keto esters, which attack the electrophilic trifluoromethylating reagent in a stereospecific manner. The optimization of the reaction included solvents, temperature, electrophilic CF3 source and six different guanidines (Scheme 7). Mixtures of chlorinated solvents were the best option to achieve high enantioselectivities and yields at very low temperature. The electrophilic power of Umemoto’s reagents strongly influenced the reaction. Thus, the selenophenium analogous was not appropriate and even the dinitro derivative of Umemoto’s reagent gave lower results. Finally, the most sterically encumbered guanidines did not provide higher ee, and the suppression of one H-bonding from the imidazolidine ring system dramatically affects the ee, yielding a racemic compound. Thus, this supports the transition state structure where the guanidinium enolates of β-keto esters coordinates the substrate through H-bonding for an excellent stereochemical CF3 transfer (Scheme 7). The scope of the reaction was investigated. The use of bulkier 1-indanone derivatives did not secure better enantioselectivities; the primary methyl ester provided the best results (63% yield and Molecules 2020, 25, 3264 12 of 24 70% ee). The presence of substituent’s in the aromatic ring with different electronic natures were also tolerated. The 1-tetralone series and benzyl cyclopentanone-2-carboxylate were in the same range of ee values but2020, Molecules lower 25, xyield (Scheme FOR PEER 7). REVIEW 14 of 28 Scheme5. 5. Electrophilic Scheme Electrophilic enantioselective α-trifluoromethylationof ofcyclic enantioselective α-trifluoromethylation β-keto cyclicβ-keto esters esters under under La(III)/(R,S)-ind-pybox La(III)/(R,S)-ind-pybox catalysis. Scopeand catalysis. Scope andproposed proposedmechanism mechanismbasedbasedononexperimental experimentalandand computationaltechniques. computational techniques. 3.2.InOrganocatalytic 2015, Melchiorre’s research group [69] developed an interesting enantioselective perfluoroalkylation Methods and trifluoromethylation of alkyl 1-indanone-2-carboxylates (Scheme 8) combining both visible-light and In 2007, Cahard’s group reported the very first asymmetric preparation of α-trifluoromethylated phase-transfer-catalysts (PTC). cyclic β-keto esters under The methodologybased an organocatalyzed was based on the in(Scheme methodology situ formation 6) whichofrequired the photochemical the use active of S-(trifluoromethyl)dibenzthiophenium tetrafluoroborate 45 as electrophilic reagent andperfluoroalkyl electron donor–acceptor (EDA) complexes from chiral ammonium enolates and a cinchona iodides. alkaloidThe catalyst based optimization chiral revealed phase-transfer that stereocontrol catalysts (PTC) [67]. was Theysensitive noticedtothat structural using amodifications quaternary at ammonium PTC and potassium carbonate, the ee were not higher than 20%. The formation of potassium β-keto ester enolate was responsible of the low ee. Thus, to banish the presence of achiral enolates the use of the tertiary PTC hydroquinine was the solution giving the expected α- trifluoromethylated β-keto ester in 53% yield with 71% ee. Molecules 2020, 25, 3264 13 of 24 the 20 position of the quinoline ring, being the organocatalyst PTC+ Br− (Scheme 8) the one which provided the best results in terms of ee. The synthetic application of this method was tested, assaying different Molecules substituted indanone-derived β-keto esters with methyl iodide. Notably, trifluoromethyl-containing 2020, 25, x FOR PEER REVIEW 15 of 28 quaternary stereocentres could be easily prepared reacting β-keto esters with methyl iodide under the enolates the use of the tertiary PTC hydroquinine was the solution giving the expected α- same conditions, achieving trifluoromethylated ee up β-keto to in ester 96%. 53% yield with 71% ee. Scheme 6. Asymmetric trifluoromethylation of methyl 1-indanone-2-carboxylate using the Umemoto’s reagent and hydroquinine. A few years later, Shibata [68] deeply investigated the use of chiral guanidines with S- (trifluoromethyl)dibenzothiophenium tetrafluoroborate 45. These guanidines act as Brønsted bases to generate chiral guanidinium enolates of β-keto esters, which attack the electrophilic trifluoromethylating reagent in a stereospecific manner. The optimization of the reaction included solvents, temperature, electrophilic CF3 source and six different guanidines (Scheme 7). Mixtures of chlorinated solvents were the best option to achieve high enantioselectivities and yields at very low temperature. The electrophilic power of Umemoto’s reagents strongly influenced the reaction. Thus, the selenophenium analogous was not appropriate and even the dinitro derivative of Umemoto’s reagent gave lower results. Finally, the most sterically encumbered guanidines did not provide higher ee, and the suppression of one H-bonding from the imidazolidine ring system dramatically affects Scheme Schemethe 6. ee, yielding 6. Asymmetric a racemic compound. trifluoromethylation Asymmetric ofThus, trifluoromethylation of this methyl supports the transition stateusing 1-indanone-2-carboxylate methyl 1-indanone-2-carboxylate structure where the Umemoto’s using the the guanidinium enolates of β-keto esters coordinates the substrate through H-bonding for an reagentUmemoto’s reagent and hydroquinine. and hydroquinine. excellent stereochemical CF3 transfer (Scheme 7). A few years later, Shibata [68] deeply investigated Ph H the use of chiral guanidines with S- N (trifluoromethyl)dibenzothiophenium tetrafluoroborate 45. These N guanidines act as Brønsted bases to generate chiral O guanidinium enolates of β-keto Nesters, which attack O the electrophilic Ph H Ph O O trifluoromethylating reagent+in a stereospecific manner. The optimization of the reaction included solvents, temperature, ORelectrophilic CF3Ssource and six CHCl 3/CH2Cl2guanidines (Scheme different OR n CF3 7). Mixtures of 45 CF3to BF4 n chlorinated solvents were the best option achieve high enantioselectivities and yields at very low n = 1 or 2 temperature. The electrophilic power of Umemoto’s reagents strongly influenced the reaction. Thus, Scope the selenophenium analogous was not appropriate Oand O even the dinitro derivative of Umemoto’s R2 O O reagent gave lower O O results. Finally, the most sterically encumbered guanidines did not provide OMe higher ee, and the suppression of one H-bondingR3 from CFthe imidazolidine ring system OBn dramatically OR 3 affects the ee, yielding CF3 structure where CF3a racemic compound. Thus, this supports the transition state R = MeO, i R3 = MeO, i 67%, 58% ee the guanidinium enolates of β-keto2 esters coordinates 22%, 62%H-bonding the substrate through ee for an R = Me, 63%, 70% ee R2 = H, R3 = Br, 64%, 58% eei excellent stereochemical CF3 transfer (Scheme 7). R = Molecules Et, 59%,25,67% 2020, ee PEER REVIEW x FOR O 16 of 28 O O O R = Bn, 56%, 63% ee Ph H NOMe O CF3 R = tBu, 57%, 55% ee N Scheme 7. Cont. R = CHO2CF3, 49%, 66% eeI CF Ph N3 O CF3 O H Ph O + OR S CHCl3/CH2Cl2 OR n CF3 45 CF3 BF4 n n = 1 or 2 Scope O O R2 O O O O OMe R3 CF3 OBn OR CF3 CF3 i i R2 = MeO, R3 = MeO, 67%, 58% ee 22%, 62% ee R = Me, 63%, 70% ee R2 = H, R3 = Br, 64%, 58% eei R = Et, 59%, 67% ee O O O O R = Bn, 56%, 63% Scheme ee 7. Asymmetric organocatalytic trifluoromethylation developed by Shibata and OMe CF the proposed Scheme t Asymmetric R =7.Bu, 57%, 55%organocatalytic transition ee (TS). state trifluoromethylation developed by Shibata O and the3 proposed R = CH I CF3 transition 2CF(TS). state 3, 49%, 66% ee CF3 The scope of the reaction was investigated. The use of bulkier 1-indanone derivatives did not Based on somesecure better enantioselectivities; diagnostic mechanisticthe primary methyl experiments, a ester provided radical chainthepropagation best results (63% yield andwas pathway 70% ee). The presence of substituent’s in the aromatic ring with different electronic natures were also proposed. The trifluorometil radical could be generated upon irradiation of the chiral EDA complex. tolerated. The 1-tetralone series and benzyl cyclopentanone-2-carboxylate were in the same range of Then, the electrophilic CF • reacted with the chiral enolate of the β-keto ester (II in the scheme below) ee values 3 lower but yield (Scheme 7). giving place to the C-CIn bond 2015, formation Melchiorre’sthrough research a group stereo-controlled [69] developedmanner. The resulting an interesting species (III, enantioselective in Scheme 8, videperfluoroalkylation infra) abstractedand trifluoromethylation an iodine atom form the of perfluorinated alkyl 1-indanone-2-carboxylates iodine compound, (Scheme 8) a giving combining both visible-light and phase-transfer-catalysts (PTC). The methodology was based on the new CF3 and the α-trifluoromethyl β-keto ester final product after the elimination of the iodide anion. • in situ formation of the photochemical active electron donor–acceptor (EDA) complexes from chiral ammonium enolates and perfluoroalkyl iodides. The catalyst optimization revealed that stereocontrol was sensitive to structural modifications at the 2′ position of the quinoline ring, being the organocatalyst PTC+Br− (Scheme 8) the one which provided the best results in terms of ee. The synthetic application of this method was tested, assaying different substituted indanone-derived β- keto esters with methyl iodide. Notably, trifluoromethyl-containing quaternary stereocentres could be easily prepared reacting β-keto esters with methyl iodide under the same conditions, achieving ee Molecules 2020, 25, 3264 14 of 24 Years later, Li and collaborators [70] found that EDA complex were responsible for the visible light absorption and the PTC catalyst interacted by electrostatic interactions with the β-keto ester enolate by Molecules 2020, 25, x FOR PEER REVIEW 17 of 28 DFT calculations. Reaction conditions HO N Br F N F F O (20 mol%) O CF3 (PTC Br ) O O + CF3 I white LEDs OtBu OtBu CF3 R Cs2CO3 (2 equiv) R PhCl:C8F18 (2:1) Up to 96% ee 25 ºC Proposed mechanism CF3 I O PTC O O h + II O CF3 + I O But SET OtBu I PTC CF3 O O CsHCO3 + CsBr OtBu II O O OtBu PTC O Cs2CO3 O PTC Br OtBu CF3 III CF3 I O O PTC OtBu O O CF3 I CF3 OtBu CF3 IV Scheme 8. Conditions and mechanism for the visible-light-driven PTC catalyzed enantioselective Scheme 8. Conditions and mechanism for the visible-light-driven PTC catalyzed enantioselective perfluoroalkylation and trifluoromethylation of cyclic β-keto esters assembled by Melchiorre. perfluoroalkylation and trifluoromethylation of cyclic β-keto esters assembled by Melchiorre. 4. Asymmetric Preparation of Quaternary C-SCF3 Stereocentres on β-keto Esters 4.1. Metal-Catalyzed Methods In recent years, considerable attention has been focused on the trifluoromethylthio group (-SCF3 ) due toThe work of properties its unique Gade’s group of [72] is the only remarkable example found in thebehaviour, electron-withdrawing literature, asexcellent far as wemetabolic know, regarding the metal-catalyzed trifluoromethylthiolation of β-keto esters. The methodology consists stability and high lipophilicity [71]. In fact, all these properties allow the trifluoromethylthiolated on the use of chiral copper–boxmi complex (Scheme 9). They applied their broad experience in the therapeutic molecules across lipidic membranes easily, which is crucial for the biodisponibility of use of this chiral pincer ligand in other reactions such as the asymmetric Fe-boxmi catalysed azidation the drug. Because of the high interest in SCF3 containing molecules, well-built methods for their of β-keto esters [73] and the asymmetric Cu-boxmi catalysed trifluoromethylation of β-keto esters [38] insertion into organic molecules have been widely investigated. Specifically, both the racemic and the among others. With their optimized reaction conditions, consisting in using one equivalent of Lu and enantioselective trifluoromethylthiolation reaction on β-keto esters have been widely explored. Shen’s hypervalent iodine reagent 47 [74] to transfer a –SCF3 group. A wide range of substrates possessing indanone, tetralone, cyclopentenone and cyclohexenone (one example, 99% ee) cores were well tolerated, obtaining in all cases excellent enantiomeric excess values (Scheme 9). In general, the Molecules 2020, 25, 3264 15 of 24 4.1. Metal-Catalyzed Methods The work of Gade’s group [72] is the only example found in the literature, as far as we know, regarding the metal-catalyzed trifluoromethylthiolation of β-keto esters. The methodology consists on the use of chiral copper–boxmi complex (Scheme 9). They applied their broad experience in the use of this chiral pincer ligand in other reactions such as the asymmetric Fe-boxmi catalysed azidation of β-keto esters [73] and the asymmetric Cu-boxmi catalysed trifluoromethylation of β-keto esters [38] among others. With their optimized reaction conditions, consisting in using one equivalent of Lu and Shen’s hypervalent iodine reagent 47 [74] to transfer a –SCF3 group. A wide range of substrates possessing indanone, tetralone, cyclopentenone and cyclohexenone (one example, 99% ee) cores were well tolerated, obtaining in all cases excellent enantiomeric excess values (Scheme 9). In general, the size of theMolecules ester2020, group it PEER 25, x FOR is not crucial for achieving high enantioselectivity. Several REVIEW 18 of 28 mechanistic experiments, size including 19 EPR spectroscopy and F-NMR led the authors to propose a catalytic cycle of the ester group it is not crucial for achieving high enantioselectivity. Several mechanistic (Scheme 9). The combination experiments, including ofEPR copper (II) with spectroscopy and boxmi 19F-NMR ligand coordinates led the authors to proposetoa the β-keto catalytic cycleester substrate, (Scheme 9). by which is deprotonated The acombination of copper (II) with boxmi ligand coordinates to the β-keto ester triflate anion. substrate, which is deprotonated by a triflate anion. Scheme 9. Copper-boxmi electrophilic trifluoromethylthiolation of several β-keto esters and the Scheme 9. Copper-boxmi electrophilic trifluoromethylthiolation of several β-keto esters and the proposed catalytic cycle. proposed catalytic cycle. Molecules 2020, 25, 3264 16 of 24 The triflic Molecules 2020,acid in situ 25, x FOR PEER acts as an activator of the hypervalent trifluoromethylthiolated REVIEW iodine 19 of 28 reagent 24, generated which is attacked by the β-keto ester enolate through the more accessible Re face The (the Si face triflic acid blocked is efficiently in situ acts by as an activator boxmi). of the hypervalent The product is evacuatedtrifluoromethylthiolated iodine of the catalytic cycle generating reagent 24, generated which again the chiral catalyst (Scheme 9). is attacked by the β-keto ester enolate through the more accessible Re face (the Si face is efficiently blocked by boxmi). The product is evacuated of the catalytic cycle generating againMethods 4.2. Organocatalytic the chiral catalyst (Scheme 9). The first organocatalyzed 4.2. Organocatalytic Methods enantioselective methodology reported for the introduction of -SCF3 onto the α-position of a β-keto esters was developed independently in 2013 by Shen and Rueping. The first organocatalyzed enantioselective methodology reported for the introduction of -SCF3 Shen’s group [75] reported the use of trifluoromethylthiolated hypervalent iodine 47 and a catalytic onto the α-position of a β-keto esters was developed independently in 2013 by Shen and Rueping. amount of quinine in toluene ◦ C in the reaction of a series of adamantyl 1-indanone-2-carboxylates Shen’s group [75] reportedatthe40 use of trifluoromethylthiolated hypervalent iodine 47 and a catalytic (Scheme 10). The amount reactions of quinine in of substrates toluene at 40with °C inelectron-withdrawing the reaction of a seriesgroups at the aromatic of adamantyl ring occurred 1-indanone-2- with similar enantioselectivity carboxylates (Scheme 10). to those The of substrates reactions with electron-donating of substrates groups, whereas with electron-withdrawing thethe groups at size of aromatic the ester groupring hadoccurred with similar a high impact on theenantioselectivity enantioselectivityto those of substrates (Scheme with electron-donating 10). Interestingly, the methodology couldgroups, whereas the be successfully size oftothe applied theester group had adamantyl cyclopentanone β-keto a high impact on the enantioselectivity ester (95% yield,(Scheme 94% ee),10). but was Interestingly, the methodology could be successfully not useful with larger ring size, such as tetralone derivatives. applied to the adamantyl cyclopentanone β- keto ester (95% yield, 94% ee), but was not useful with larger ring size, such as tetralone derivatives. Scheme Organocatalyzed 10. 10. Scheme Organocatalyzedtrifluoromethylthiolation trifluoromethylthiolation ofofadamantyl adamantyl 1-indanone-2-carboxylates. 1-indanone-2-carboxylates. Reaction conditions Reaction andand conditions scope. scope. In order to to In order understand understand the differencesin in the differences termsterms of enantioselectivity of enantioselectivity on theseon these substrates, substrates, Shen Shen proposed proposed that that thethe mechanism mechanism couldcould proceed proceed throughthrough twopathways two different different(Scheme pathways 11). (Scheme The first 11). pathway The first (A) is(A) pathway based on theon is based transfer of the SCF the transfer of the3 group SCF3fromgroupthefrom hypervalent iodine reagent the hypervalent iodineto the reagent quinine, allowing the formation of a new SCF to the quinine, allowing the formation of a new SCF3 -substituted quinine electrophile, which be 3 -substituted quinine electrophile, which would would attackedby be attacked bythe the nucleophilic nucleophilic enolized enolizedβ-ketoβ-keto ester. TheThe ester. stochiometric mixture stochiometric of Shen’s mixture reagentreagent of Shen’s 47 and quinine in toluene monitored by 19F-NMR ruled out this pathway, because the formation of new 47 and quinine in toluene monitored by 19 F-NMR ruled out this pathway, because the formation of SCF3-substituted quinine electrophile was not evidenced. This experimental feature made the new SCF3 -substituted quinine electrophile was not evidenced. This experimental feature made the pathway B gain prominence, which consisted on a dual activation through simultaneous hydrogen pathway B gain bonding prominence, of the substrate andwhich47 consisted to quinine on a dual11). (Scheme activation through is This mechanism simultaneous steady since hydrogen other bonding of the substrate and 47 to quinine (Scheme 11). cinchona alkaloids without the free OH group showed low reactivity. Moreover, This mechanism is this steady sinceisother proposal cinchona alkaloids sterically without congested the free and justifies theOH lackgroup showed of reactivity low reactivity. of tetralone Moreover, this proposal and 1-benzosuberone-derived β- is sterically keto congested esters. Theseand justifies more the lack enolizable of reactivity substrates of tetralone form nonplanar and 1-benzosuberone-derived enolates that are not able to generate β-keto theThese esters. dual-activated intermediate, more enolizable while the substrates 1-indanone form nonplanar enolates are planar enolates andnot that are fit able very well in this the to generate model. dual-activated intermediate, while the 1-indanone enolates are planar and fit very well in this model. Then, Then, to expandthe to expand the scope scope totothethemore enolizable more 1-tetralone enolizable or 1-benzosuberone-derived 1-tetralone β-keto or 1-benzosuberone-derived esters, they assayed cinchona alkaloids based chiral phase-transfer catalysts, yielding the β-keto esters, they assayed cinchona alkaloids based chiral phase-transfer catalysts, yielding the trifluoromethylthiolated quaternary β-keto esters in great yields and enantioselectivities (Scheme 12). trifluoromethylthiolated quaternary β-keto esters in great yields and enantioselectivities (Scheme 12). Interestingly enough, the reaction of the indanone derivatives through the use of PTC occurred with Interestingly enough, the reaction low enantioselectivity, of the in contrast to theindanone derivatives through high enantioselectivity obtainedthewhen use ofusing PTCquinine occurred as with low enantioselectivity, in contrast to the high enantioselectivity obtained when using quinine as catalyst. Molecules Molecules 2020, 2020, 25, x FOR PEER REVIEW 25, 3264 20 of 28 17 of 24 Molecules 2020, 25, x FOR PEER REVIEW 20 of 28 catalyst. Despite the huge efforts done by Shen’s group, the methodology could not be applied to acyclic β-keto esters. Despite the hugeDespite catalyst. effortsthedone huge by Shen’s efforts done group, by Shen’sthe methodology group, could the methodology not could notbe be applied applied to to acyclic β-keto esters. acyclic β-keto esters. Scheme 11. Proposed mechanisms for the quinine-catalyzed asymmetric trifluoromethylthiolation Scheme 11. Proposed mechanisms for the quinine-catalyzed asymmetric trifluoromethylthiolation reaction. reaction. Scheme 11. Proposed mechanisms for the quinine-catalyzed asymmetric trifluoromethylthiolation reaction. Scheme 12. Scope of asymmetric trifluoromethylthiolation of β-keto esters mediated by PTCs. Scheme 12. Scope of asymmetric trifluoromethylthiolation of β-keto esters mediated by PTCs. Scheme 12. Scope of asymmetric trifluoromethylthiolation of β-keto esters mediated by PTCs. At the same time as this previous work, Rueping’s group [76] reported an organocatalytic scenario using quinidine as catalyst in dichloromethane and N-trifluoromethylthiophtalimide 48 as electrophilic -SCF3 source, an air and moisture stable reagent. The reaction gave excellent yields and enantioselectivities (Scheme 13). In general, the reactions of cyclic 1-indanone derivatives bearing various electron-donating and electron-withdrawing substituents in different positions of the aromatic ring proceeded successfully to provide the corresponding products in high yields and excellent enantioselectivities (88–99% ee; Scheme 13). Furthermore, cyclopentenone β-keto esters underwent Molecules 2020, 25, x FOR PEER REVIEW 21 of 28 At the same time as this previous work, Rueping’s group [76] reported an organocatalytic scenario using quinidine as catalyst in dichloromethane and N-trifluoromethylthiophtalimide 48 as electrophilic -SCF3 source, an air and moisture stable reagent. The reaction gave excellent yields and Molecules 2020, 25,enantioselectivities 3264 (Scheme 13). In general, the reactions of cyclic 1-indanone derivatives bearing 18 of 24 various electron-donating and electron-withdrawing substituents in different positions of the aromatic ring proceeded successfully to provide the corresponding products in high yields and excellent enantioselectivities (88–99% ee; Scheme 13). Furthermore, cyclopentenone β-keto esters trifluoromethylthiolation under these conditions in moderate yields but excellent enantioselectivites. underwent trifluoromethylthiolation under these conditions in moderate yields but excellent Additionally, this methodology accepted enantioselectivites. Additionally, this 1-tetralone β-keto ester based1-tetralone methodology accepted in a ester based β-keto a 46% and 95% ee. 46%inyield yield and 95% ee. Scheme 13. Scope Scheme of the 13. Scope enantioselective of the trifluoromethylthiolation. enantioselective trifluoromethylthiolation. Four years later, in 2017 Xue [77] wanted to cast some light into the mechanism of Rueping’s Four years later, inelectrophilic asymmetric 2017 Xue [77] wanted to cast trifluoromethylthiolation some reaction using light density into the theory functional mechanism studies. of Rueping’s asymmetric electrophilic The Houk-Grayon trifluoromethylthiolation is the commonly preferred modelreaction using [78] for cinchona density functional alkaloid-catalysed reactions, theory studies. however after the evaluation of three different mechanistic scenarios (pathways A, B and C, Scheme The Houk-Grayon is the commonly preferred model [78] for cinchona alkaloid-catalysed reactions, 14), the calculations showed that the most preferred model was the Wynberg ion pair-hydrogen however after the evaluation bonding of three model [79] (pathwaydifferent mechanistic B in Scheme 14) in scenarios which the SCF (pathways 3 transfer A,fromB and N- C, Scheme 14), the calculationstrifluoromethylthiophtalimide showed that the most 25 to β-keto ester proceeds preferred model via was an Sthe N2-like saddle point transition state. Wynberg ion pair-hydrogen bonding model [79] (pathway B in Scheme 14) in which the SCF3 transfer from N-trifluoromethylthiophtalimide 25 to β-keto ester2020, Molecules proceeds via REVIEW 25, x FOR PEER an SN 2-like saddle point transition state. 22 of 28 Scheme 14. Possible Scheme models 14. Possible for the models Rueping’s for the Rueping’s asymmetric electrophilic asymmetric electrophilic trifluoromethylthiolation. trifluoromethylthiolation. Molecules 2020, 25, 3264 19 of 24 Du and collaborators, [80] reported in 2017 the asymmetric electrophilic trifluoro-methylthiolation of (E)-alkyl 3-benzylidene-2-oxocyclopentane carboxylates cyclopentanone using a bifunctional squaramide as organocatalyst and N-trifluoromethylthiosuccinimide (49) as an electrophilic reagent (Scheme 15a). After some experimentation, the squaramide derived from hydroquinine and D-glucopyranose (Scheme 15) afforded the most efficient catalyst. The same conditions were extended to ethyl 4-ethoxy-2-oxocyclohex-3-ene-1-carboxylate in high yield and excellent ee (Scheme 15b). Additionally, the reaction of (E)-alkyl 3-benzylidene-2-oxocyclopentane carboxylates with 49 in presence of 2-mercapto-5-substituted benzaldehydes allowed the formation of a series of chiral spiro-cyclopentanone thiochromanes bearing an SCF3 group through a one pot electrophilic Scheme 14. Possible models for the Rueping’scascade trifluoromethylthiolation−sulfur−Michael/aldol asymmetric electrophilic reaction trifluoromethylthiolation. (16 examples, 92–99% ee, Scheme 15c). Scheme Scheme 15.Enantioselective 15. (a,b) (a) and (b) Enantioselective trifluoromethylthiolation trifluoromethylthiolation of cycloalkenones of cycloalkenones driven by driven by squaramide catalyst. squaramide catalyst. (c) Bifunctional squaramide-catalyzed electrophilic trifluoromethyl- (c) Bifunctional squaramide-catalyzed electrophilic trifluoromethyl-thiolation−sulfur−Michael/aldol cascade thiolation−sulfur−Michael/aldol cascade reaction for the construction of -SCF3 containing spiro- reaction for the construction of -SCF3 containing spiro-cyclopentanone−thiochromanes. cyclopentanone−thiochromanes. 4.3. Methods Involving Chiral -SCF3 Reagents The benefits of transferring a group from a chiral reagent to a prochiral substrate to give the enantiomerically pure product are indubitable, mainly because it offers a simple and straightforward strategy. For this reason, Shen and co-workers [81] put their efforts on designing new optically pure electrophilic -SCF3 containing reagents that could allow reliable methods for the synthesis of enantiomerically pure organic compounds. This field complements all the previous trifluoromethylthiolation strategies explained up to this point. A new family of optically pure (1S)-(−)-N-trifluoromethylthio-2,10-camphorsultam, and derivatives were synthesized and tested. The dimethoxycamphorsultam derivative 50 in THF, at −40 ◦ C and in the presence of K2 CO3 proved excellent for the asymmetric introduction of SCF3 into 1-indanone and 1-tetralone β-keto esters (Scheme 16). These conditions tolerated the presence of electron-donating groups in the aromatic ring, nevertheless for achieving high ee in the cases of less nucleophilic substrates (presence of electron-withdrawing groups in the aromatic ring) the reaction requires a higher temperature. Moreover, the effect of the steric hindrance of the ester group was significant for achieving high ee values. (−)-N-trifluoromethylthio-2,10-camphorsultam, and derivatives were synthesized and tested. The dimethoxycamphorsultam derivative 50 in THF, at −40 °C and in the presence of K2CO3 proved excellent for the asymmetric introduction of SCF3 into 1-indanone and 1-tetralone β-keto esters (Scheme 16). These conditions tolerated the presence of electron-donating groups in the aromatic ring, nevertheless for achieving high ee in the cases of less nucleophilic substrates (presence of electron-withdrawing Molecules 2020, 25, 3264 groups in the aromatic ring) the reaction requires a higher temperature. 20 of 24 Moreover, the effect of the steric hindrance of the ester group was significant for achieving high ee values. Scheme 16. Asymmetric Scheme trifluoromethylthiolation 16. Asymmetric of1-indanone trifluoromethylthiolation of 1-indanoneand and 1-tetralone 1-tetralone β-keto β-keto esters esters using using the chiral the chiral SCF SCF3 reagent reagent 50. 50. 3 5. Conclusions During the past decade, both metal-catalyzed and organocatalyzed asymmetric processes have been devised, making asymmetric fluorination, trifluoromethylayion and trifluorothiomethylation a useful tool. Asymmetric fluorination of β-keto esters has been successfully achieved by different research groups in alkyl 1-indanone 2-carboxylates and alkyl 1-oxo-1,2,3,4-tetrahydronaphtalene-2-carboxylate substrates, independently of the bulkiness of the ester group. In the case of alkyl 2-oxocyclopentane -1-carboxylates and the corresponding cyclohexanes fluorinated products are generally obtained in lower ee. Moreover, acyclic β-keto esters are the most difficult β-keto esters substrates in this reaction in terms of reactivity. Notably, Ti/TADDOL complexes of Togni’s group was useful for a larger number of acyclic compounds. Several different excellent organocatalysts systems have been developed for 1-indanone derivatives; however new organocatalytic systems are still needed for 1-tetralone and acyclic β-keto esters derivatives. Generally NFSI is the selected reagent for asymmetric fluorinations. In the case of nucleophilic reagents, remarkable results have been obtained for 1-indanone derivatives. However, new approaches that permit increase more the scope of substrates are still needed. Organocatalyzed fluorination of β-keto esters has proved to be highly efficient, bifunctional chiral thioureas derived from cinchona alkaloids giving really interesting results. Different successful asymmetric metal-catalyzed trifluoromethylation approaches have been described by Gade’s and Vallribera’s groups. The results are excellent for 1-indanone derivatives. However, poor results have been obtained in the enantioselective fluorination of alkyl 2-oxo-cyclopentane and 2-oxocyclohexane-1-carboxylates. New metal-catalyzed methods also need to be developed for acyclic β-keto esters. In the trifluoromethylation cases, metal-catalyzed are superior to organocatalyzed described methods. However, combining both visible-light and phase-transfer-catalysts seems a good choice. Moreover, the design of new efficient chiral trifluoromethylating reagents is still needed. Remarkable results have been obtained by Gade’s group in the asymmetric metal-catalyzed trifluoromethylthiolation. Competitive results were achieved with cinchone and squarimide derivatives as organocatalyts. Notably, the design and use of (1S)-(−)-N-trifluoromethylthio-2,10-camphorsultam chiral reagent in enantioselective trifluoromethylthiolation reactions resulted an excellent option. Generally, in terms of reagents, organocatalytic methods are more affordable than metal catalyzed methods mainly due to the cost of the chiral ligands. Finally, the creation of new fluorinated compounds Molecules 2020, 25, 3264 21 of 24 is expected to remain a major focus of interest next years and therefore still more new fluorinating, trifluoromethylating and trifluoromethylthiolating processes will be required. Funding: This research was funded by Spanish Ministerio de Economía, Industria y Competitividad (MINECO) CTQ2016-81797-REDC, RED2018-102387-T, Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) RTI2018-097853-B-I00) and DURSI-Generalitat de Catalunya (SGR2017-0465). Acknowledgments: Ministerio de Economía, Industria y Competitividad (MINECO) of Spain (CTQ2016-81797-REDC and RED2018-102387-T). Ministerio de Ciencia, Innovación y Universidades (MCIU) of Spain (RTI2018-097853-B-I00). DURSI-Generalitat de Catalunya (SGR2017-0465). UAB is acknowledged by A.G. for his postdoctoral contract. Conflicts of Interest: The authors declare no conflict of interest. References 1. Kirsch, P. 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