Recent Progress in Synthesis of Alkyl Fluorinated Compounds with Multiple Contiguous Stereogenic Centers

Abstract

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.

1. Introduction

The fluorine atom has the properties of strong electronegativity and a small atomic radius. The introduction of fluorine atoms into organic molecules can regulate the physicochemical and biological properties of the compounds, including the dipole moment, lipophilicity, metabolic stability, and bioavailability [1,2,3]. Notably, approximately 45% and 41% of small-molecule fluoro-pharmaceuticals were approved by the Food and Drug Administration (FDA) in 2018 and 2019, respectively [4,5,6]. Fluorinated compounds also play a crucial role in positron emission tomography (PET) [7,8,9,10] and materials science [11,12,13,14]. Especially, with the development of chiral fluorine chemistry and chiral drugs, fluorinated stereocenters have gradually become an important class of structural motifs widely used in medicinal chemistry and health sciences. For example, the glucocorticoid drugs fluticasone propionate (1, Figure 1), fludrocortisone acetate (2, Figure 1), and dexamethasone (3, Figure 1); the antichildhood leukaemia drug clofarabine (4, Figure 1); the antiviral drug sofosbuvir (5, Figure 1) against hepatitis C virus; the antiviral drug clevudine (6, Figure 1) against hepatitis B virus; and the antibacterial drugs lascufloxacin (7, Figure 1) and sitafloxacin (8, Figure 1) all contain C(sp³)–F stereocenters in their structures [3,5,6]. Therefore, it is of great significance to develop efficient synthetic methods for the preparation of chiral alkyl fluorides.

In recent years, the flourishing development of fluorine chemistry has promoted remarkable advancements in the synthesis of chiral fluorinated compounds [15,16,17,18,19,20]. Innovative asymmetric catalytic methods for the synthesis of chiral alkyl fluorides continue to emerge, such as transition metal-catalyzed [21], organocatalyzed [22], high-valent iodine-catalyzed [23,24], and phase-transfer-catalyzed [25]. It is worth noting that the enantioselective construction of C(sp³)–F quaternary stereocenters is quite challenging. In 2018, Toste et al. provided a comprehensive review of modern methods for asymmetrically constructing C(sp³)–F quaternary stereocenters [26]. In 2019, Han et al. summarized cyclic fluorinated enolates generated in situ via detrifluoroacetylative for the preparation of compounds with quaternary C–F stereogenic carbon [27]. In 2020, Granado and Vallribera published a review on the preparation of α-quaternary fluorinated β-keto esters via asymmetric fluorination of β-keto esters [28]. In 2021, Hartwig et al. reported an elegant review on transition metal-catalyzed monofluoroalkylation: the synthesis of alkyl fluorides via C–C bond formation [29]. However, the synthesis of chiral alkyl fluorides bearing multiple contiguous stereogenic centers in a highly enantio- and diastereoselective manner remains a remarkably challenging task, and methods supporting this goal are rare, mainly due to the inherent difficulties of constructing the C(sp³)–F bond and controlling enantio- and diastereoselectivities simultaneously. Notably, intense efforts toward this goal have been seen in recent years. It was found that a variety of chiral ligands (L1–L16, Figure 2), including bisphosphine ligands (L1, L5, L6, L15); phosphoramidite ligands (L2, L3); phosphine-oxazoline ligand (L4); ferrocenyl ligands (L7, L8, L12); prophenol ligands (L9, L10), diamine ligand (L11); bisoxazoline ligand (L13, L14); aminophenol (L16); and metal complexes and chiral catalysts (C1–C27, Figure 3), for example, cinchona alkaloid catalyst (C1), anion phase-transfer catalysts (C2–C4), quinine squaramide catalysts (C5, C6, C11), aryl iodide organocatalyst (C8), quinine-derived sulfonamide (C13), amine phosphoramide (C15), etc., could effectively promote the asymmetric synthesis of those compounds. Herein, the recent advances in the highly enantio- and diastereoselective synthesis of alkyl fluorides bearing multiple consecutive stereocenters are summarized, including asymmetric electrophilic fluorination and asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions). The synthetic methodologies, substrate scopes, and reaction mechanisms are mainly discussed.

2. Asymmetric Electrophilic Fluorination

The development of readily available and efficient sources of electrophilic fluorinating reagents, such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) (9, Figure 4) [30] and N-fluorobenzenesulfonimide (NFSI) (10, Figure 4) [31], has had a significant impact on catalytic asymmetric electrophilic fluorination, and encouraging progress has been made. In contrast, the synthesis of chiral alkyl fluorides with multiple contiguous stereogenic centers using nucleophilic fluorinating reagents is more difficult due to the poor reactivity of the fluorine anion. Asymmetric electrophilic fluorination catalyzed by transition metal catalysts or chiral organocatalysts is one of the typical methods used for the synthesis of chiral alkyl fluorinated compounds with multiple contiguous stereogenic centers containing a C–F quaternary carbon. The diastereo- and enantioselective electrophilic fluorination mainly includes asymmetric fluorinative dearomatization, sequential asymmetric addition/fluorination, and asymmetric cyclization/fluorination.

Catalytic asymmetric dearomatization (CADA) [32,33,34,35,36,37,38,39] reactions via fluorination represent a powerful strategy for constructing chiral fluorine-containing compounds from readily available aromatic derivatives. In 2011, Gouverneur et al. reported the first organocatalyzed asymmetric dearomatization of indole derivatives 13 via cascade fluorocyclization utilizing a cinchona alkaloid C1 as a catalyst and NFSI or Selectfluor as an electrophilic reagent (Scheme 1) [40]. Enantioenriched fluorinated heterocycles 14 were obtained with moderate to high enantioselectivities. Almost at the same time, Toste et al. developed asymmetric electrophilic fluorination using a chiral anion phase-transfer catalyst C2. Interestingly, benzothiophenes substrates 15 were converted to desired fluorocyclization products 16 in high optical purity and good yield through CADA reactions via fluorination (Scheme 2) [25]. The proposed catalytic mechanism is shown in Scheme 2. Phosphate (2 equiv.) undergoes salt substitution with Selectfluor to produce the chiral ion pair, which is soluble in nonpolar solvents, and then the chiral ion pair can mediate the fluorocyclization of the substrate 17. In 2017, You et al. developed asymmetric fluorinative dearomatization of tryptamine derivatives 19 under anion phase-transfer catalysis, which entailed the use of Selectfluor as an electrophilic fluoride source and a chiral phosphate anion derived from BINOL backbone C3 as a catalyst (Scheme 3) [41]. They noticed that a proton sponge (PS) can effectively improve the reaction yield. A variety of fluorinated pyrroloindolines 20 bearing two contiguous quaternary stereogenic centers were obtained with excellent enantioselectivities (up to 97% ee) and high yields (up to 92% yield). Regarding the exploration of the substrates’ scope, tryptamines with electron-withdrawing protecting groups (Boc, CO₂Me, Cbz, and Fmoc) were well tolerated. N-Boc protected tryptamines with different electron-withdrawing (5-CO₂Et, 5-CF₃, 5-Cl, 5-Br, and 5-F) and electron-donating (5-MeO, 5-CH₃, and 5-^tBu) substituents at the C5 position, which proceeded with excellent enantioselectivity. 4,6-dihalo-substituted substrates and 2- or 6-substituent of the indole moiety were also well tolerated to provide target products with high enantioselectivity. Substrates bearing higher steric hindrance substituents or simple H and methyl at the C7 position resulted in moderate enantioselectivity. Control experiments suggested that the reaction proceeded via bifunctional activation using a chiral BINOL-derived phosphate anion C3. Recently, the asymmetric dearomatizing fluoroamidation of indole acetamide derivatives 21 using a dicarboxylate phase-transfer catalyst C4 under mild conditions was developed by Hamashima et al. (Scheme 4) [42]. Indoles with various substitution patterns were suitable substrates, providing easy access to chiral fluoropyrroloindoline derivatives 22 in 50–90% yields and 74–97% ee. It is worth mentioning that the addition of an appropriate amount of water to the reaction system was essential to facilitate the reaction and ensure reproducibility.

In 2015, Wang et al. reported a one-pot reaction sequence of the organocatalytic asymmetric Friedel–Crafts addition of 4-nonsubstituted pyrazolones 24 to isatin-derived N-Boc ketimine 23 followed by diastereoselective electrophilic fluorination (Scheme 5) [43]. By using 0.5 mol% quinine squaramide C5 as a catalyst, CH₂Cl₂ as a solvent in the first step, NFSI as an electrophilic reagent, and K₂CO₃ as a base in the second step, a variety of fluorinated oxindole–pyrazolone adducts 25 bearing vicinal tetrasubstituted stereocenters containing a C–F quaternary carbon were obtained with 88–96% yields, 95–99% ee, and >20:1 dr. In 2020, Šebesta and co-workers reported the squaramide C6-catalyzed asymmetric Mannich reaction of oxindole imines 23 with pyrazolones 24, followed by electrophilic diastereoselective fluorination (Scheme 6) [44]. The reaction proceeded under liquid-assisted grinding conditions to provide oxindolyl fluoropyrazolone derivatives 25 with enantiomer purities up to a 99:1 enantiomeric ratio. The organocatalytic Domino Mannich reaction was also suitable for isoxazole, but the yield was slightly lower, with up to 52% ee. However, thiazolones and oxazolones were ineffective substrates. Notably, the ball-milling reaction was more efficient than that of the solution reaction. The ball milling reaction time could be greatly shortened to a few minutes, and the amount of solvent required for the reaction could be minimized.

In 2018, Lu et al. reported an enantioselective sequential Nazarov cyclization/electrophilic fluorination of divinyl ketone derivatives 26 catalyzed by the thiazoline iminopyridine (TIP)-Co complex C7, yielding various substituted chiral α-fluorinated cyclopentenones 27 with 48–96% yields, 44–97% ee, and >20:1 dr (Scheme 7) [45]. Further derivatization of the α-fluorinated cyclopentenones allowed the construction of chiral cyclopentenols with three contiguous stereocenters and the synthesis of chiral α-single fluorine substituted cyclopentenones. Additionally, the gram-scale experiment proceeded well with little loss of ee values for the target compounds.

We also note two particular examples of the synthesis of chiral alkyl fluorides with two adjacent chiral centers by using nucleophilic fluorinating reagents. In 2019, Jacobsen et al. reported a diastereo- and enantioselective 1,2-difluorination of cinnamamides utilizing pyr·9HF (11) as a fluoride source mediated by chiral aryl iodide organocatalyst C8 and m-CPBA as a stoichiometric oxidant (Scheme 8) [46]. This method afforded 1,2-difluoride-containing compounds with 1,2-/1,1-difluorination selectivity of 2.2:1–>100:1, in yields of 40–84%, ee of 77–98%, and dr generally > 20:1. Selectivity for 1,2-difluorination versus 1,1-difluorination resulting from phenonium rearrangement was enforced through anchimeric assistance by a proximal N-tert-butyl amide substituent. In 2020, Marek and co-workers reported that optically pure cyclopropyl carbinol derivatives 31 undergo a stereo- and regioselective nucleophilic substitution at the quaternary carbon center with a pure conformational inversion, yielding tertiary alkyl fluoride and ester derivatives 32 as a single diastereomer (Scheme 9) [47].

3. Asymmetric Elaboration of Fluorine-Containing Substrates

Asymmetric allylic alkylation reactions, Mannich addition reactions, Michael addition reactions, aldol reactions, and cross-coupling reactions of fluorine-containing substrates represent another classical approach for constructing multiple contiguous stereocenters containing C-F stereocenters.

3.1. Allylic Alkylation Reactions

Transition metal-catalyzed asymmetric allylic substitution reactions [48,49,50,51,52,53,54,55,56,57,58,59] are one of the most powerful methods for building up stereocenters. Asymmetric allylic alkylation reactions of prochiral fluorine-containing nucleophiles provide an efficient and reliable strategy for the synthesis of chiral alkyl fluorinated molecules bearing two or more vicinal stereogenic centers.

α-Pyridine-α-fluoro esters are important synthons for the synthesis of chiral molecules containing both a fluorine atom and a pyridine ring. However, α-pyridine-α-fluoro esters are less nucleophilic, and the potential inactivation or poisoning of catalysts through the coordination of heteroaromatics will result in poor control of reactivity and stereoselectivities. In 2019, Hartwig, He and co-workers reported the stereodivergent allylic alkylation of α-fluorinated azaaryl acetates 33 with cinnamyl methyl carbonates 34 utilizing the combination of a chiral cyclometalated iridium catalyst C9 and a Cu complex ligated to (R,R)-BPE (L1) (Scheme 10) [60]. In the presence of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) as a base, the allylic substitution reaction gave fluorinated products within vicinal quaternary and tertiary stereogenic centers in yields generally >90%, >20:1 dr, and 97–99% ee. A variety of alkyl- and aryl-substituted allylic esters, α-fluorinated azaaryl acetates, ketones, and amides were amenable to this Cu/Ir catalytic system, giving the desired products with satisfactory results. Notably, the copper catalyst and iridium catalyst could, respectively, control the configuration of the nucleophilic carbon of an unstabilized enolate and the electrophilic carbon of allylic carbonates in this reaction system.

In 2022, Wang and co-workers described a dual Cu/Ir catalytic system for the asymmetric [3+2] annulation of α-fluoro-α-azaaryl acetates 33 with vinylethylene carbonates 36 via a cascade allylic alkylation/lactonization reaction (Scheme 11) [61]. In the presence of Cu(CH₃CN)₄PF₆ and C10 as a catalyst, (S,S)-L1 as ligand, Et₃N as a base, α-fluoro-γ-butyrolactones 37 containing vicinal stereogenic centers were obtained with 34–98% yields, 16:1–>20:1 dr, and 97–99% ee. It is worth noting that all four possible stereoisomers of these valuable products could be readily accessed individually via simple permutations of two chiral catalysts. The proposed mechanism for this [3+2] annulation reaction is shown in Scheme 11. Under basic conditions, chiral Cu(I)-(S,S)-L1 could coordinates with the nitrogen atom of the azaarene ring and carbonyl oxygen in α-fluoro-α-azaryl acetate to generate the chiral metalated intermediate A. Simultaneously, the coordination of [(S,S,S)-Ir(I)] C10 with racemic vinylethylene carbonate(±) generated the corresponding complexes [Ir(I)∗]·(R)-B and [Ir(I)∗]·(S)-B. (R)-vinylethylene carbonate (R)-36 could be recovered from the less reactive former species through kinetic resolution, while the latter more reactive species was prioritized to undergo decarboxylative oxidation addition and generate the zwitterionic Ir(III)-π-allyl species C with the configuration inversion. The chiral metalated intermediate A then nucleophilically attacked the Ir(III)-π-allyl species C in a highly Re-Re stereoselective manner to form the allylic alkylation intermediate (2S,3S)-D-Int and regenerate the chiral Cu/Ir catalysts. Finally, the intermediate (2S,3S)-D-Int underwent intramolecular esterification to access target products.

In 2019, You et al. reported iridium-catalyzed asymmetric allylic alkylation/fluorination of acyclic ketones 38 (Scheme 12) [62]. α-pyridyl-α-fluoroketones 41 bearing vicinal tertiary and fluorine-containing quaternary stereocenters were obtained in 59–97% yields, 4.1:1–>19:1 dr, and 93–98% ee by utilizing Me-THQphos (R,R)-L2 as a chiral ligand in the presence of ^tBuOLi and 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD) in THF at room temperature. Distinct from the above-mentioned stereodivergent synthesis strategies reported by Hartwig [60] and Wang [61], which generally required the use of two different chiral catalysts (Cu/Ir), only one single chiral iridium catalyst was required in You’s work, providing an elegant pathway for the stereodivergent synthesis of molecules bearing multiple consecutive stereocenters. All four possible stereoisomers of the desired products were prepared from the same pyridone derivatives as substrates by simply adjusting the sequence of fluorination and allylic alkylation and changing the absolute configuration of the iridium catalyst.

In 2023, Gong and co-workers developed a branch- and asymmetric allylic C–H alkylation reaction of allylarenes 43 and α-fluorinated α-benzothiazylacetates 42 catalyzed by chiral phosphoramidite (L3)-palladium catalysis in the presence of Li₂CO₃ and 2,5-diphenylquinone (2,5-DPBQ) in 1,4-dioxane at 60 °C (Scheme 13) [63]. Under the optimized reaction conditions, varieties of α-quaternary fluorinated ester products 44 were obtained in yields of 79–99%, dr of 3:1–20:1, and ee of 70–95%. A catalytic cycle was proposed in Scheme 13. In the presence of a Pd-L3 catalyst and 2,5-DPBQ, allylbenzene underwent allylic C–H bond cleavage via a concerted proton and two-electron-transfer process to form the π-allylpalladium intermediate A. Then, deprotonation of α-fluorinated α-benzothiazylacetate and π-σ isomerization of the allyl skeleton generated the ion pair complex B, wherein 2,5-DPBQ might be adjacent to the enolate anion via hydrogen-bonding interaction. Finally, the intermediate B underwent an inner-sphere allylation to yield the desired product and regenerate the Pd-L3 catalyst.

We also noted that Wolf et al. reported asymmetric fluoroenolate alkylation with allyl acetate/carbonate 47 under palladium catalysis using (S)-t-Bu-PHOX (L4) as a chiral ligand (Scheme 14) [64]. Versatile 3, 3-disubstituted fluorooxindoles 48 bearing vicinal chirality centers were synthesized in 86–98% yields, 88:12–>99:1 dr, and ≥99% ee. In addition, the regioselective asymmetric alkylation of nonsymmetrically substituted allylic acetates was studied, and the corresponding products were obtained with excellent regioselectivities. The stereochemical outcome of this reaction can be rationalized by a preferential attack occurring from the Si face of the fluoroenolate at the allylic position that is trans to the P atom of the L4 in a favored exo-η³-allyl Pd complex. This pathway provides the (R,R,E) isomer 48f as the major product, whereas an attack originating from the Re face of the fluoroenolate results in the formation of the minor (S,R,E) diastereomer 48e (Scheme 14).

The preparation of arylfluoroacetonitrile derivatives bearing two or more vicinal stereogenic centers via enantioselective C–C bond formation using arylfluoroacetonitrile as a starting material is challenging due to the relatively low C–H acidity of arylfluoroacetonitriles, the possibility of decomposition or HF elimination the side reaction of fluoroacetonitrile under basic conditions, and the difficulty in controlling the stereoselectivity of α-fluoronitrile carbanions [65,66,67,68,69]. To tackle the aforementioned challenges, Wolf and co-workers developed a palladium-catalyzed asymmetric allylic alkylation with α-aryl-α-fluoroacetonitriles 49 in the presence of phosphinoxazoline ligand L4 and DBU at −20 °C in acetonitrile (Scheme 15) [70]. This reaction afforded the target product 50 featuring two contiguous chirality centers in 60–78% yields, 5:1–>15:1 dr, and ≥98% ee. The gram-scale synthesis of this method was also carried out, and good yield and stereochemical outcomes (>99% ee) were obtained. Additionally, asymmetric allylic alkylation products can be further derivatized via Stille cross-coupling reaction without obvious HF elimination.

3.2. Hydrofunctionalization Reactions

Transition metal-catalyzed enantioselective hydrofunctionalization of alkenes, 1,3-dienes, allenes, and conjugated alkynes were discovered as efficient routes for the construction of a stereogenic center or axis [71,72,73,74,75,76,77,78,79,80,81,82,83,84,85]. In 2021, Lin, He and co-workers reported a novel Cu/Pd synergistic catalysis strategy for diastereoselective hydrocarbonation of conjugated alkynes (Scheme 16) [86]. The coupling of α-fluorinated azaaryl esters 33 with conjugated enynes 51, in the presence of Cu(CH₃CN)₄PF₆, (S,S)-BPE [(S,S)-L1], [Pd(allyl)Cl]₂, L5, NaBArF₄, Et₃N, and DBU, provided tertiary fluoride-tethered allenes 52 containing a stereogenic center and axis with up to 99% yield, >20:1 dr, and >99% ee. This reaction has been shown to have a broad substrate scope. A variety of electron-withdrawing and electron-donating groups at different positions on the aryl units in conjugated enynes; a series of α-fluoro nucleophiles bearing quinolinyl, pyrazinyl, pyridinyl, benzothiazolyl and pyrimidinyl groups; and diverse natural and biologically active compounds were well tolerated. The proposed mechanism cycle is shown in Scheme 16. The enyne would initially insert regioselectively into the Pd-H generated in situ, yielding an allylpalladium species. Concurrently, the Cu-coordinated fluorinated enolate would act as an outer-sphere nucleophile. All four possible stereoisomers of the tertiary fluoride-tethered allenes were precisely synthesized with good diastereoselectivities and excellent enantioselectivities by simply permutating the absolute configuration of the ligand of Cu/Pd catalysts.

Recently, the same group employed a similar strategy to realize an asymmetric hydromonofluoroalkylation reaction of 1,3-diene 53 (Scheme 17a) [87]. A series of alkyl fluorine derivatives 54, bearing a quaternary F-stereogenic center and vicinal tertiary stereogenic carbon center, were synthesized in yields up to 99%, >20:1 dr, and >99% ee. Intriguingly, all four stereoisomers of corresponding products can also be stereodivergently synthesized through Cu/Pd co-catalysis by using L1, L5, or L6 as chiral ligands. The Pd/L7 or Pd/L8-catalyzed asymmetric hydromonofluoroalkylation reaction of monosubstituted and internal dienes 56 was also developed to access alkyl fluorides in up to 99% yield, >20:1 rr, and 95% ee (Scheme 17b). In addition, asymmetric migratory monofluoroalkylation of skipping dienes 58 was established to realize the straightforward allylic C–H fluoroalkylation (Scheme 17c). Pleasantly, a variety of enantioenriched fluorinated rings can be obtained by diverse transformations.

3.3. Mannich Addition Reactions

The catalytic asymmetric Mannich reaction of fluorinated nucleophiles provides an efficient route for the synthesis of pharmaceutically important fluorinated amino compounds [88,89]. The efficient organocatalytic asymmetric Mannich reaction of α-fluorinated β-ketoesters, α-fluorinated β-keto acyloxazolidinone, and α-fluorinated aromatic ketones for the synthesis of corresponding products featuring fluorinated tetrasubstituted carbon centers have been reported by Huang, Lu [90] and Jiang, Tan et al. [91,92]. In 2016, Wennemers and co-workers reported asymmetric addition reactions of α-fluorinated monothiomalonates 60 to protected imines 61, providing various acyclic α-fluorinated β-amino thioesters 62 in 80–99% yields, 4:1–>20:1 dr, and 91–99.9% ee (Scheme 18) [93]. The reaction was carried out under mild conditions, and only 1 mol% of epi-quininederived squaramide catalyst (C11) was used. Later, Yan, Song et al. reported an asymmetric organocatalytic Mannich reaction for the synthesis of β-fluoroamine derivatives 65 bearing quaternary C–F centers (Scheme 19) [94]. In the presence of Song’s chiral oligoEG (C12) as a cation binding catalyst and KF as a base, α-fluoro cyclic ketones 63 were used as nucleophiles to react with α-aminosulfones 64 (as the imine surrogates) to give corresponding products in high yields (36–99%) with good enantioselectivities (88–99% ee) and diastereoselectivities (1:2–1:20 syn:anti). The proposed reaction mechanism is shown in Scheme 19. Firstly, KF was complexed with catalyst C12 to form Int I, which then complexed with amidinosulfone 64 to generate the Int II. Subsequently, the sulfite group on the 64 was removed to obtain the imine-activated Int III. The subsequent coordination of potassium enolate (generated in situ from 63 with KF) to the catalyst was followed by its addition to the imine to provide the products 65. It is noteworthy that the binding of the cation (K⁺) to the catalyst was instrumental in instigating both high reactivity and excellent enantioselectivity during the enantio-determining step by the formation of the chiral cage. Later, a similar catalytic system was applied to the asymmetric Mannich reaction of 3-fluoro-oxindoles 66 with α-amidosulfones 64 by the same research group (Scheme 20) [95]. α-amidosulfones bearing different aryl and heteroaryl substituents were compatible with generating chiral α-fluoro-β-amino-oxindole derivatives 67 possessing two contiguous stereogenic centers in 63–97% yields, 1:1–>20:1 dr, and 81–99% ee (syn). Unfortunately, alkyl α-amidosulfone was unsuitable for this reaction.

In 2018, Du et al. described a bifunctional chiral squaramide (C11) catalyzed asymmetric Mannich reactions of 3-fluorooxindoles 66 to isatin-derived imines 68, which provided fluorinated 3,3’-bisoxindoles 69 bearing two vicinal stereocenters in 41–99% yields, 81:19–>99:1 dr, and 38–99% ee under mild conditions (Scheme 21) [96]. It should be mentioned that the yield, dr, and ee values of the products featuring free N–H were significantly lower. Substituents on N atoms of both substrates were mainly limited to simple methyl substitutions. Additionally, a gram-scale reaction proceeded without the obvious erosion in yield and stereoselectivity.

In 2011, Kim et al. reported a Pd-catalyzed asymmetric Mannich reaction of α-fluoro-β-ketoesters with N-Boc aldimines, which afforded β-aminated-α-fluoro-β-ketoesters bearing two contiguous stereogenic centers with excellent enantioselectivities (up to 99% ee) and good yields (up to 89% yield) [97]. However, the main limitation of this approach was that poor diastereoselectivities were obtained in most cases. In 2015, the Trost group reported a ZnEt₂/(R,R)-prophenol (L9)-catalyzed highly enantio- and anti-diastereoselective Mannich reaction by using α-fluorinated aromatic ketones 70 and Boc-protected aldimines 61 as starting materials (Scheme 22) [98]. A series of chiral β-fluoroamine 71 were synthesized with 69–99% yields, 94–99% ee, and generally >20:1 dr. In addition, gram-scale studies were also performed at low catalyst loadings (2 mol% L9, 4 mol% ZnEt₂) to obtain the desired product in 98% yield, >20:1 dr, and 99% ee. The proposed binding mode suggests that the Boc-protected imines are coordinated between the two zinc centers in a two-point binding manner (Scheme 22). In 2019, the same group realized the asymmetric Mannich reaction between branched acyclic vinyl α-fluoro ketones 72 and alkynyl α-fluoro ketones 74 and aldimines 61 using similar catalytic systems (Scheme 23) [99]. This was the first example of an asymmetric Mannich reaction involving acyclic α-branched α-fluoroketones, affording the corresponding acyclic β-fluoro amines featuring two contiguous stereogenic centers in high yields (52–99%), excellent enantioselectivities (90–99% ee), and diastereoselectivities (5:1–>20:1 dr). A variety of vinyl-, cyclopropyl-, aryl-, and heteroaryl-substituted aldimines and various heavily substituted fluoroketones were well worked in this catalytic system.

In 2015, Wang et al. reported a Cu-catalyzed enantioselective detrifluoroacetylative Mannich reaction of 2-fluoro-1,3-diketones/hydrates 76 and isatin-derived ketimines 77 using chiral diamine (L11) as ligand (Scheme 24) [100]. Diverse 3-substituted 3-amino-2-oxindoles 78 featuring vicinal tetrasubstituted stereocenters with a quaternary C–F stereogenic carbon were obtained with excellent yields (up to 99%) and good stereochemical results (up to >20:1 dr, 94% ee).

In 2018, Kumagai and Shibasaki et al. reported a Cu-catalyzed asymmetric Mannich reaction of α-fluoronitrile 79 with N-diphenylphosphinoyl (N-Dpp) imines 80 (Scheme 25) [101]. A series of β-amino-α-fluoronitriles 82 bearing two adjacent chiral centers were synthesized in 71–97% yields, 4.7:1–>20:1 dr, and 71–99% ee using (R)-Segphos (L6) as the ligand, achiral thiourea (TU1, 81) as the secondary ligand, and 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG/Barton’s base) as the base. Further derivatization of the products gave rapid access to α-fluorinated-β-amino acid derivatives. A gram-scale experiment was carried out without any detrimental effects. Kinetic studies revealed that achiral trisubstituted thioureas enhance the stereoselectivity by binding to the CuI complex. They proposed a plausible reaction mechanism shown in Scheme 25. Firstly, α-fluoronitrile coordinates with the preformed CuI/L6/TU2 complex to form complex A. Deprotonation of complex A promoted by Barton’s base generates CuI- ketenimine complex B. The resulting CuI-ketenimine complex B reacts with CuI-imine complex C to generate CuI amide complex D by forming C–C bonds. Finally, CuI amide complex D undergoes proton exchange with the protonated Barton’s base to generate the desired product and regenerate the CuI/L6/TU2 complex.

Subsequently, Wolf and co-workers used a similar strategy to realize a Cu-catalyzed asymmetric Mannich reaction of α-fluorinated arylacetonitrile 49 with isatin-derived N-Boc ketimines 83 (Scheme 26) [102]. Anti-diastereomers of multifunctionalized 3-aminooxindoles 84 bearing two adjacent tetrasubstituted stereocenters were obtained in 81–99% yields, 8.5:1–>50:1 dr, and 84–97% ee when L6 was used as a chiral ligand and the N-protecting group of isatin was triphenylmethyl. When L12 was used as a chiral ligand and the N-protecting group of isatin was phenyl, syn-diastereomers of 3-aminooxindoles 85 possessing a quaternary carbon–fluorine stereocenter were synthesized in 84–99% yields, 3:1–7:1 dr, and 83–97% ee. The Mannich products can be converted to other useful molecules via selective transformations of oxindole ring opening and nitrile functionality. Additionally, a gram scale experiment was also carried out to probe the utility of this reaction, and the desired anti-α-fluoro-β-aminonitrile was prepared in excellent yield (0.94 g, 99% yield) with 12.7:1 dr and 90% major ee. They proposed a plausible catalytic cycle, shown in Scheme 26. Firstly, α-fluorinated arylacetonitrile was coordinated to the (L6) Cu(I) complex to form complex A, which then underwent reversible deprotonation in the presence of BTMG to form the cuprous keteniminate complex B. Subsequently, the isatin ketimine was attacked from the Si face of complex B to form complex C through irreversible C–C bond formation. Finally, complex C underwent proton transfer and dissociation to yield the desired product and regenerate the free CuI complex and BTMG.

3.4. Michael Addition Reactions

The asymmetric Michael addition reaction is the other effective method used to construct continuous stereocenters containing fluorine atoms. In 2014, Lu and co-workers reported that quinine-derived sulfonamide C13 catalyzed asymmetric Michael addition reactions with nitroalkenes 87 as acceptors to react with 2-fluoro-1,3 diketones 86 (Scheme 27) [103]. Several aryl methyl diketones reacted very well with aryl nitroolefins, and the corresponding Michael adducts 88 were obtained in good chemical yields (70–95%), excellent enantioselectivities (89–>99% ee), but moderate diastereoselectivties (2:1–8:1 dr). However, the isopropyl-substituted nitroalkenes substrate showed moderate reactivity and low stereoselectivity with almost no stereoselectivity. The proposed transition-state model is shown in Scheme 27. They believe that the hydrogen-bonding interaction between the nitro group of nitroalkenes and the NH group of sulfonamides is crucial for the observed stereoselectivity. In the same year, an enantioselective Michael addition of α-fluoro-α-nitroalkanes 89 to nitroolefins 87 was developed by the same group (Scheme 28) [104]. They used amino acid-incorporating multifunctional quinine-derived compound C14 as the organocatalyst for this reaction, which provided the desired products 90 in 71–95% yields, 5:1–8:1 dr, and 82–96% ee. Different α-aryl-α-fluoronitromethanes, as well as various aromatic and aliphatic nitroolefins, were suitable substrates for this Michael reaction. However, simple alkyl-substituted α-fluoro-α-nitroalkanes were unsuitable substrates. Intriguingly, different diastereomers of the Michael addition products could be isolated by a regular flash silica gel chromatographic column. The proposed stereochemical model is shown in Scheme 28. They believed that bifunctional activation of the substrates was important for the observed stereoselectivity.

In 2015, Zhou et al. developed asymmetric Michael addition of monofluorinated enol silyl ethers 91 to isatylidene malononitriles 92 (Scheme 29) [105]. They used chiral secondary amine phosphoramide C15 as the organocatalyst for this reaction, which afforded the corresponding monofluorinated oxindole derivatives 93 bearing adjacent and tetrasubstituted carbon stereocenters in excellent chemical yields (95–99%) and high enantioselectivities (84–94% ee) and diastereoselectivities (4:1–>20:1 dr). The product could be transformed into the polycyclic compound in the presence of NaBH₄ without loss of enantioselectivity.

In 2016, Wennemers et al. reported an organocatalytic asymmetric Michael addition reaction for the synthesis of α-fluoro-γ-nitro thioesters 95 bearing adjacent tetrasubstituted and tertiary stereogenic carbon centers (Scheme 30) [106]. They employed fluorinated monothiomalonates (F-MTMs, 94) as fluoroacetate–enolate equivalents to react with nitroolefins 87 in the presence of 1 mol% of epi-cinchonine–urea C16. A range of aromatic, heteroaromatic, and even aliphatic nitroolefins were well tolerated and provided the Michael addition products in high chemical yields (61–98%) and excellent stereochemical outcomes (13:1–>20:1 dr, 93–99% ee). Interestingly, the product could be elaborated into fluorinated lactams. In the same year, Kim et al. reported a catalytic asymmetric conjugate addition reaction of α-fluoro-β-ketophosphonates 96 to nitroalkenes 87 (Scheme 31) [107]. They used 1,2-cyclohexanediamine-coordinated dicationic nickel C17 as the best chiral catalyst for this reaction, which afforded the corresponding γ-nitro α-fluorophosphonates derivatives 97 in 66–98% yields, 10:1–50:1 dr, and 93–99% ee. The gram-scale reaction was also conducted to provide the Michael adduct with a high chemical yield (91%) and stereochemical result (12:1 dr, 96% ee).

Recently, Singh et al. reported a Cu-catalyzed enantioselective Michael addition reaction between alkyl azaarenes 33 and α,β-unsaturated 2-acyl imidazoles 98 (Scheme 32) [108]. A range of 2-alkyl azaarene derivatives bearing vicinal quaternary–tertiary stereocenters were synthesized with a high level of chemical yields (up to 97%), diastereoselectivities (>20:1), and enantioselectivities (up to 99%) in the presence of 5.5 mol% (S,S)-L1 and 5 mol% DBU. The substrates scope was investigated, and α,β-unsaturated 2-acyl imidazoles with different ortho-, meta-, and para-substitution patterns and heteroaromatic rings substrates were well tolerated, affording excellent yields and enantioselectivities. Surprisingly, under optimized reaction conditions, the yields and selectivity decreased significantly when R² = Me, OMe, Ph. In addition, benzothiazolyl fluoroacetate substrates with electron-donating, electron-withdrawing, halogenated, and heteroaryl substituents proceeded well. 1,6-Michael receptor substrates also reacted smoothly, with the addition reaction occurring only at the 1,4-position. The proposed transition-state model, illustrated in Scheme 32, postulated that the high stereoselectivity was primarily attributed to the binding of chiral Cu(I)-bisphosphines to both the nitrogen of the azaarene ring and the ester carbonyl oxygen of 33. This binding configuration effectively obstructed one face of the azaarene 33 with the ligand substituent, thereby directing the reaction toward high stereoselectivity.

In 2023, Lee et al. reported a stereodivergent conjugate addition reaction for the preparation of tertiary alkyl fluorides in adjacent stereogenic pairs (Scheme 33) [109]. They used α-fluoro azaaryl acetamides as the α-fluoroenolate precursor to react with in situ-generated chiral iminium electrophiles from α,β-unsaturated aldehydes 100. The products, 4-fluorinated 1,5-aldehyde amides 101, were obtained in generally good yields with high stereocontrol. Most of the adducts were isolated after the reduction of aldehyde to alcohol 102, during which the diastereomeric ratio did not change. All four stereoisomers of the desired products with vicinal stereocenters were synthesized by variation of the combinations of the enantiomers of phosphine ligand L1 and amine C18. It is worth mentioning that this stereodivergent conjugate addition strategy, combined with aminocatalytic asymmetric α-fluorination, enabled the rapid synthesis of all eight stereoisomers of molecules bearing three contiguous stereocenters containing two fluorinated stereocenters.

3.5. Aldol Addition Reactions

In 2014, Zhou et al. reported an organocatalytic asymmetric aldol addition reaction for the synthesis of optically active 3-hydroxyoxindole derivatives 104 with two adjacent tetrasubstituted carbon stereocenters featuring a C–F bond (Scheme 34) [110]. They used prochiral monofluorinated enol ethers 91 to react with isatins 103 in the presence of cinchona alkaloid-derived bifunctional (thio)urea catalysts C19 or urea-tertiary amine catalyst C20. The solvent had a significant effect on the reaction results, and MeCN was considered the best reaction medium. In the cases of isatins without electron-withdrawing substituents, the reactions were carried out using organocatalyst C19, providing the desired products 104 in high chemical yields (37–98% yield), excellent enantioselectivities (70–94% ee), and good diastereoselectivities (5:1–15:1 dr). However, when 5-halo groups substituted isatins were used as substrates, the corresponding products were obtained in 5:1 dr and 81–86% ee in the presence of urea-tertiary amine catalyst C20. It should be noted that acyclic monofluorinated silyl enol ether was able to react with isatin under the same conditions, affording the expected product with a moderate yield (46%) and stereochemical outcome (2:1 dr, 81% ee).

In 2011, Colby et al. discovered that 1,1,1,3,3-pentafluoro-2,4-diones could release trifluoroacetic acid to generate α,α-difluoroenolates via C–C bond cleavage under mild reaction conditions [111,112]. Subsequently, Wolf [113,114], Wu [115], and others [27] used this novel detrifluoroacetylative strategies in an asymmetric aldol addition reaction. In 2015, Han and co-workers developed a Cu-catalyzed enantioselective detrifluoroacetylative aldol addition reaction for the preparation of α-fluoro-β-hydroxy ketone derivatives 106 with two consecutive stereogenic centers featuring a fluorine atom (Scheme 35) [116]. Under mild conditions, varieties of 2-fluoro-1,3-diketones/hydrates generated from cyclic ketones via two steps could react smoothly with aldehydes in the presence of chiral bidentate ligand L13 and N,N-diisopropylethylamine (DIPEA). Various hydrates, arylaldehydes, heteroarylaldehydes, α,β-unsaturated aldehydes, and phenylacetaldehyde were well tolerated to afford the expected addition products 106 with high yields (75–96% yields) and excellent enantio- and diastereoselectivities (70:30–99:1 dr, 67–98% ee). They proposed a chair-like transition state model (Scheme 35) to explain the observed stereochemical preferences. In 2016, Han, Soloshonok et al. employed a similar strategy to achieve asymmetric detrifluoroacetylative aldol reactions of aliphatic aldehydes 107 (Scheme 36) [117]. Various α-fluoro-β-hydroxy ketones 108 bearing two contiguous stereogenic centers were obtained with up to 98:2 dr and 98% ee at ambient temperature. They also found that a by-product was generated due to the low reactivity of aliphatic aldehydes. It should be noted that aldehydes containing β-branched alkyl groups, such as ^tBu, ⁱPr, and ^chexyl, were not suitable substrates. In the same year, Han et al. developed the first example of the Cu-catalyzed enantioselective cascade aldol-cyclization reaction between detrifluoroacetylatively in situ-generated enolate precursors and ester-aldehydes 109 (Scheme 37) [118]. Various bicyclic ketoesters 110 featuring fluorinated quaternary stereogenic were obtained in 49–94% yields, 80:20 dr, and 59–96% ee. However, seven-membered rings containing 1,3-di-keto-hydrate and linear alkyl groups substituted-acyclic 1,3-di-keto-hydrates were ineffective substrates for this catalytic system. Recently, Han, Soloshonok et al. reported a Cu/bisoxazoline ligand L14-catalyzed asymmetric detrifluoroacetylative aldol reaction for the synthesis of a range of α-fluoro-β-hydroxy-indolin-2-ones 112 bearing adjacent tetrasubstituted and tertiary stereogenic centers (Scheme 38) [119]. They used in situ-generated unprotected tertiary enolates derived from 3-(1,1-dihydroxy-2,2,2-trifluoroethyl)-substituted derivatives of 3-fluoro-2-oxindoles 111 as starting materials to react with aldehydes 105, resulting in the desired products 112 with good yields and satisfactory enantio- and diastereoselectivities. Both benzaldehydes and starting enolate precursors bearing electron-donating and electron-withdrawing groups at almost all positions on the aromatic ring were suitable substrates. Intriguingly, hetero-aromatic, aliphatic aldehydes and enolate precursors containing an unprotected N–H group were well tolerated in this catalytic system.

In 2016, Wennemers and Saadi used fluoromalonic acid halfthioesters (F-MAHTs, 113) as fluoroacetate surrogates for the asymmetric aldol addition reaction (Scheme 39) [120]. The quinidine–urea catalyst C21 was chosen as the best organocatalyst for this aldol reaction, which could catalyze this reaction smoothly to give the corresponding fluorinated thioesters 114 with up to 87% yields, 17:1 dr, and 99% ee. Both the more-reactive aromatic aldehydes and the less-reactive aliphatic aldehydes were well tolerated to react with electron-rich 4-methoxythiophenol-derived F-MAHT or 2-fluorothiophenol-derived F-MAHT. They also utilized the pseudo-enantiomer quinine-derived catalyst C22 for this reaction and provided the mirror image product with high yields and stereoselectivities, similar to the corresponding enantiomers. Gladly, the anti- and syn-diastereoisomers could be easily separated by column chromatography, and the minor syn-isomers were obtained in high enantioselectivities equal to the corresponding major anti-isomers.

In 2020, Kumagai, Shibasaki et al. developed a Cu-catalyzed asymmetric aldol addition reaction between α-fluoronitriles 49 and aldehydes 105/107 (Scheme 40) [121]. The reaction used L6 as the chiral ligand and conducted the reaction at −80 °C in the presence of asymmetrical achiral thioureas TU2 as a secondary ligand and Barton’s base. Nitriles with electron-donating and electron-withdrawing substituents and aliphatic and aromatic aldehydes were well tolerated to give the desired α-fluoro-β-hydroxynitriles 115 featuring two vicinal stereogenic centers with 70–89% yields, 1:1–16:1 dr, and 70–99% ee. The stereoselectivity of this chiral CuI/Barton’s base catalytic system could be significantly enhanced by the combined use of trimethylthiourea TU2.

3.6. Miscellaneous Reactions

In 2016, Wang, Xia et al. reported an organocatalytic asymmetric tandem Michael addition/cycloketalization/hemiacetalization and acylation transformations for the preparation of optically pure fluorinated O,O-acetal fused tricyclic derivatives with multiple adjacent stereogenic centers using α,β-unsaturated aldehydes 100 and 2-fluoro-1-(2-hydroxyaryl)-1,3-dione 116 as starting materials (Scheme 41) [122]. The chiral amine C23 was chosen as the best catalyst, which efficiently catalyzed the reaction to give the desired products 117 with excellent stereochemical outcome (>19:1 dr, 90–>99% ee). A plausible mechanism for this asymmetric tandem reaction is shown in Scheme 41. Firstly, with the assistance of salicylic acid 118, the chiral amine C23 and cinnamaldehyde generated the chiral iminium ion A. Then, 2-fluoro-1-(2-hydroxyaryl)-1,3-dione 116 attacked the Si face of chiral iminium A and underwent a Michael addition reaction to generate the intermediate B. After the hydrolysis of intermediate B, the catalyst C23 was recovered. Subsequently, the intermediate B underwent cyclic ketonization/hemiacetalization and acylation reactions to give the target products 117.

In 2021, Huang, Fan et al. reported a Cu^II-catalyzed enantioselective 1,3-dipole cycloaddition of glycine imines 120 with α-fluoro-β-aryl-α,β-unsaturated arylketones 119 (Scheme 42) [123]. Diverse chiral exo-pyrrolidine derivatives 121 with four contiguous stereogenic centers containing a fluorinated quaternary stereogenic center at the C4 position could be prepared in high yields (up to 98%) with excellent enantio- and diastereoselectivity (up to 99:1 dr and 99% ee) in the presence of a Cu(OAc)₂·H₂O/(S)-tol-BINAP L15 catalyst, DBU, and 4 Å molecular sieves in DCM/EtOH at −20 °C. These exo-products could be further converted to the unusual exo’ adducts 122 in good yields (56–84%) with excellent stereochemical outcomes (>99:1 dr, 96–99% ee) at 5.0 equivalents of DBU and 90 °C.

In 2022, Córdova and Himo et al. reported a solvent dependency in the stereoselective intramolecular amidation reaction of chiral 5-inofunctionalized-2-fluoromalonate ester derivatives in the presence of a chiral catalyst C24 (Scheme 43) [124]. In solvents with dielectric constants (ε) less than 10 (e.g., CH₂Cl₂), δ-lactams 123/125 with a syn-configuration between adjacent tertiary carbon and fluorine-containing quaternary stereocenters were generally generated. In solvents with ε > 15 (e.g., MeOH), the corresponding δ-lactams 124/126 with anti-configuration were formed. This catalytic asymmetric cascade reaction combined with solvent-directed stereoselective reactions provided a novel strategy for the stereodivergent synthesis of all possible stereoisomers of heterocyclic compounds with two vicinal stereogenic centers featuring C–F quaternary stereocenters.

In 2022, Hoveyda, Liu et al. developed an in situ-generated Zn(O^tBu)Et/aminophenol (L16) complex catalyzed highly regio-, diastereo-, and enantioselective reactions between fluoro-substituted allylboronates 128 and aldehydes (Scheme 44) [125]. Diverse aryl-, heteroaryl-, alkenyl-, and alkyl-substituted aldehydes were well tolerated in this catalytic system to give homoallylic alcohols 129 with adjacent stereogenic carbon centers containing a trifluoromethyl- and a fluoro-substituted stereogenic center. It is worth noting that the electrophilicity of aldehydes affected γ selectivity, and the more electron-rich aldehydes provided higher γ selectivity. In contrast, γ:α selectivity was lower for the more electron-deficient aldehydes.

In 2023, Szabó et al. developed a catalytic asymmetric one-pot homologation-allylboration sequence for the preparation of β-fluorohydrins 135 with adjacent C–F and C–O stereocenters in 45–75% yields, >20:1 dr, and 85–99% ee (Scheme 45) [126]. The target products were obtained via the homologation of trisubstituted fluoroalkenes 131 by using (R)-iodo-BINOL C25 as a catalyst, followed by the allylboration of ketone, aldehyde, and imine.

We also noted that Hartwig et al. reported an iridium-catalyzed enantioselective allylic substitution reaction between 3-fluoro allylic electrophiles and soft carbon nucleophiles. Encouragingly, diastereoselective fluoroalkylation of ethyl 2-oxocyclohexanecarboxylate 137 with 3-fluoroallyl phosphate 136 in the presence of the ent-C26 catalyst processed smoothly to give desired diastereomers with two consecutive stereogenic centers in suitable yields with moderate diastereo- and enantioselectivity (Scheme 46) [127]. In 2020, Hartwig et al. developed the iridium-catalyzed desymmetrization of allylic difluoromethylene groups to afford optically pure tertiary allylic fluorides 143 with high yield, regioselectivity, and enantioselectivity via the activation of a single C–F bond. The participation of a prochiral β-keto ester in the reaction gave allyl fluorides with two contiguous, fully substituted stereocenters containing one fluorine atom with good diastereoselectivity (6:1 dr) and excellent enantioselectivity (96% ee) (Scheme 47) [128].

4. Conclusions

Fluorinated compounds are important molecules that are widely used in material sciences, pharmaceuticals, agrochemicals, and other fields. Particularly, fluorine-containing compounds with complex and variable structures and multiple continuous stereocenters have attracted much attention. This review summarizes the important research progress in the synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers in recent years, including the asymmetric electrophilic fluorination and asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, Aldol addition reactions, and miscellaneous reactions), and with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms. The success of these methods is attributed to the ingenious design of catalysts/substrates/reaction modes. We hope that this review will provide new ideas for the discovery of more common and efficient new catalysts/methods/reagents for the synthesis of high-value fluorinated compounds and their derivatives.