A metal-free strategy to construct fluoroalkyl–olefin linkages using fluoroalkanes

Abstract

We present a metal-free strategy to access fluoroalkyl–olefin linkages from fluoroalkane precursors and vinyl-pinacol boronic ester (BPin) reagents. This reaction sequence is templated by the boron reagent, which induces C–C bond formation upon oxidation. We developed this strategy into a one-pot synthetic protocol using RCF₂H precursors directly with vinyl-BPin reagents in the presence of a Brønsted base, which tolerated oxygen- and nitrogen-containing heterocycles, and aryl halogens. We also found that HCF₃ (HCF-23; a byproduct of the Teflon industry) and CH₂F₂ (HCF-32; a low-cost refrigerant) are amenable to this protocol, representing distinct strategies to generate RCF₂H and RCF₃ molecules. Finally, we demonstrate that the vinyldifluoromethylene products can be readily derivatized, representing an avenue for late-stage modification after installing the fluoroalkyl unit.

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Introduction

Fluorine-containing functional groups are often incorporated within medicinally-relevant compounds to modulate molecular properties, including metabolic stability, lipophilicity, stereoelectronics, and affinity to biological targets.^1,2 In addition to these general features, difluoromethylene units (–CF₂–) are considered as bioisosteres of oxygen atoms in ether, carbonyl, and sulfonyl groups.³ For example, within a series of ledipasvir (GS-5885) variants that feature an Ar–X–Ar linkage, highest activity was found when X = CF₂, compared to –O– or –CH₂– analogues.⁴ Despite their potential advantages, molecules containing Ar–CF₂–R and Ar–CF₂–Ar linkages are not common in commercial pharmaceuticals, likely due to limited synthetic pathways for direct –CF₂–R incorporation.

Metal-free routes to prepare Ar–CF₂–alkyl and Ar–CF₂–Ar linkages include radical difluorination of C–H bonds using fluorine atom transfer reagents (e.g. Selectfluor),^5,6 or fluorodeoxygenation of ketones using trifluorosulfuranes (e.g. DAST; Et₂NSF₃)^7,8 and defluorinative functionalization.^9–13 Many of these strategies require reagents that are toxic, explosive,¹⁴ and of limited scope, which lessen their synthetic utility.¹⁵ Metal-catalyzed routes include reactions of aryl/alkyl boronic acids with ArCF₂X; (X = halide, amides),^16–19 and recently, reactions of ArCF₂SiMe₃ with aryl halides.²⁰ However, limitations of these approaches include: (a) low availability of ArCF₂X electrophiles and pronucleophiles, and (b) low compatibility of procedures needed to prepare the requisite reagents.^9,21–24

Difluoromethanes (RCF₂H; R = H, R = Ar) are widely available pronucleophiles²⁵ that can be unmasked by deprotonation,²⁶ and represent an attractive entry point to access R–CF₂–R′ molecules. A key challenge to broad use of RCF₂H compounds as synthons is that upon deprotonation, RCF₂⁻ anions decompose to fluorocarbenes via fluoride elimination, even at ambient temperatures.²⁷ To overcome this deleterious pathway, our group developed a strategy to use Lewis acids (e.g. hexamethylborazine; B₃N₃Me₆) to stabilize RCF₂⁻ anions against defluorination.^28–33

One class of fluorinated compounds that is underdeveloped is aryl/alkyl difluoromethylene containing internal olefins.³⁴ These moieties are an attractive functionality in medicinal chemistry, and are present within marketed drugs such as tafluprost and glecaprevir (Fig. 1a).^35,36 Such motifs are particularly desirable not only because fluorine atoms may improve metabolic stability and/or binding affinity with the target of interest,³⁷ but also because they are amenable to late-stage functionalization.^38,39 This latter feature exploits an olefin as a functional handle to build molecular complexity and/or as a branch point for structure–activity relationship studies in drug discovery. Unfortunately, there are limited synthetic strategies to access vinyldifluoromethylene linkages and most proceed by coupling RCF₂Br (R = aryl, alkyl, ester) electrophiles with either alkane, alkyne, or aryl nucleophiles (Fig. 1b).^40–49 Alternatively, RCF₂-internal olefins have been prepared photochemically via either Ru or Ni based catalytic systems.^50,51 Although promising, all these strategies require electrophilic RCF₂Br as RCF₂– sources, whose preparation by radical bromination is incompatible with many substrate classes.^21,22 Defluoroalkylation of trifluoromethyl alkenes is an alternative approach to access vinyldifluormethylene linkages.^52–56

Fig. 1 (a) Vinyldifluoromethylene containing drugs. (b) Prior strategies to construct vinyldifluoromethylene motifs. (c) Our approach: Zweifel olefination using fluoroalkanes.

Zweifel olefination represents an attractive metal-free route to construct a vinylic C–C bond.^57–59 This reaction sequence proceeds through an anionic vinyl borate intermediate. Oxidation induces 1,2-rearrangement, and addition of an alkoxide base leads to a product containing a new C–C bond. We hypothesized that if the key anionic vinyl borate intermediate could be accessed by deprotonating RCF₂H molecules, subsequent oxidation would provide α,α-difluoroalkylated vinyl compounds. Our group previously established that fluoroalkyl B₃N₃Me₆ adducts [RCF₂B₃N₃Me₆]⁻ can transfer the RCF₂⁻ group to stronger Lewis acids such as B(OMe)₃.^26,29,30,33 Given the similar Lewis acidity of R-BPin to B(OMe)₃,^60,61 we hypothesized that [(R)(ArCF₂)BPin]⁻ could be formed analogously,⁶² and if R = vinyl, the borate intermediate would be uniquely situated for a net Zweifel olefination reaction to form α,α-difluoroalkylated olefin products (Fig. 1c).

Results and discussion

To establish feasibility of fluoroalkyl transfer to R-BPin, we allowed an equimolar mixture of [K(18-crown-6)(B₃N₃Me₆-CF₂Ph)] (1) and Ph-BPin (2a) to react in tetrahydrofuran solvent for 1.5 h at 50 °C. The reaction furnished [K(18-c-6)(Ph-BPin-CF₂Ph)] (2b) quantitatively (Fig. 2) as assessed by ¹H, ¹³C, ¹⁹F, ¹¹B NMR and ESI-MS analyses (¹¹B: 3.95 ppm and ¹⁹F: −104.21 ppm). The clean transfer of PhCF₂⁻ from B₃N₃Me₆ to Ph-BPin demonstrates feasibility of the approach. To evaluate the Zweifel olefination sequence, we introduced 1 to vinyl-BPin 2c. The reaction afforded adduct 2d with 98% conversion, as assessed by ¹⁹F and ¹¹B NMR spectroscopy (¹¹B: 3.67 ppm and ¹⁹F: −105.66 ppm), and was isolated as a white powder in 88% yield.

Fig. 2 PhCF₂⁻ transfer reactions to aryl and vinyl-BPin (top) and Zweifel olefination (bottom).

After achieving clean conversion to 2d above, we evaluated a one-pot Zweifel olefination sequence to form α,α-difluoroalkylated olefin (2e). Initial conditions using 1 equiv. I₂ and NaOMe at room temperature afforded 2e in 26% yield (ESI, Table S1,† entry 1). The identity of 2e was established by ¹H and ¹⁹F NMR spectroscopy (¹H NMR: vinyl hydrogen at 5.79–5.82 ppm (m) and ¹⁹F NMR: −95.41 ppm). The yield was increased to 40% by lowering the temperature to −78 °C prior to adding I₂ and NaOMe (ESI, Table S1,† entry 2). Importantly, increasing the stoichiometry of I₂ and NaOMe to 2 equiv. further improved the conversion to 94% (Fig. 2).

We assessed the reaction scope by varying the vinyl-BPin derivatives (Fig. 3, entries 3a–3i). Aliphatic vinyl-BPin reagents generally responded well, with good yields (73–81%; Fig. 3, entries 3a–3c). Dihydronaphthalene and 2H-chromene derivatives furnished 89 and 84% isolated yields for 3e and 3g, respectively. The latter substrate is of particular interest because chromene derivatives are an important class of heterocycles used in cosmetic agents, food additives, and biodegradable agrochemicals.^63,64 Acyclic vinyl-BPin reagents were also tolerated, affording 3d (77%), 3f (89%) and 3i (94%) in good yields.

Fig. 3 Zweifel olefination scope by varying the vinyl-BPin reagents. R-BPin (0.1 mmol), [K(18-c-6)(B₃N₃Me₆-CF₂Ph)] (0.1 mmol), I₂ (0.2 mmol), NaOMe (0.2 mmol), THF (1.8 mL). ¹⁹F NMR yields (isolated yields in parentheses).*Only ¹⁹F NMR yield acquired due to product volatility.

Although the reaction sequence provides high yields of PhCF₂–olefin products, one limitation to broad scope adoption is the requirement of B₃N₃Me₆. To overcome this requirement, we evaluated whether the use of B₃N₃Me₆ could be eliminated in the Zweifel olefination sequence. Importantly, because 2c is more Lewis acidic than B₃N₃Me₆, we hypothesized that it could effect the direct capture/olefination of PhCF₂⁻ following deprotonation of PhCF₂H. To examine the feasibility of the one-pot Zweifel olefination strategy, we evaluated a series of bases to deprotonate ArCF₂H in the presence of 2c. We optimized the formation of 2d in a single step starting from 2c, PhCF₂H and base. In the absence of 18-crown-6, deprotonation of PhCF₂H with 1.5 equiv. KN(ⁱPr)₂ gave 95% conversion to 2d, but for the tandem Zweifel reaction, only 27% yield of 2e (Fig. 4, ESI Table S2†). However, adding 18-crown-6 after deprotonation enabled subsequent conversion to 2e in 64% yield over two steps.

Fig. 4 Strategy for the one-pot Zweifel olefination reaction by in situ deprotonation of PhCF₂H with KN(ⁱPr)₂. 2c (0.06 mmol), KN(ⁱPr)₂ (0.09 mmol), 18-c-6 (0.06 mmol), I₂ (0.12 mmol), NaOMe (0.12 mmol), THF (1 mL). ¹⁹F NMR yields (PhOCF₃ used as internal standard).

After demonstrating feasibility of the one-pot methodology, we assessed scope in both the vinyl-BPin, and fluoroalkyl component (Fig. 5). Although most of the previous scope in vinyl-BPin (Fig. 3) translated to the one-pot method, two substrates were incompatible (3f and 3a), which we attribute to deleterious reactivity with KN(ⁱPr)₂. Dihydronaphthalene and the 2H-chromene derivative responded well, providing isolated yields of 71% (3e) and 51% (3g). Vinyl-BPin reagents containing aliphatic functionality afforded moderate isolated yields (2e (56%) and 3b (40%)). Styrenyl-BPin similarly afforded 3i in 72% isolated yield.

Fig. 5 Scope of one-pot Zweifel olefination reaction. BPin derivatives (0.26 mmol), KN(ⁱPr)₂ (0.39 mmol), 18-c-6 (0.26 mmol) I₂ (0.52 mmol), NaOMe (0.52 mmol), THF (3 mL). ¹⁹F NMR yields (PhOCF₃ used as internal standard). Isolated yields are in parentheses. *5–8% hydrodebromination also observed.

Next, we explored the scope in pronucleophile by investigating difluoromethyl pyridine and difluoromethyl aryl bromide substrates. Pyridine units are an important structural motif in pharmaceutical and medicinal chemistry.^65,66 We evaluated the reactivity of 3-(difluoromethyl)pyridine and 4-(difluoromethyl)pyridine with four representative vinyl-BPin substrates: (dihydronaphthalene, 2H-chromene, cyclohexenyl and styrenyl) (Fig. 5). They all furnished the Py–CF₂–olefin products in 44–61% isolated yields (5a–5e). Finally, although aryl bromides generally have low compatibility with electrochemical and photoredox fluorination reactions,^67,68 they were compatible with the one-pot Zweifel protocol. For example, 1-bromo-4-(difluoromethyl)benzene and 1-bromo-3-(difluoromethyl)benzene substrates provided their respective products in 34–48% (5f–5h) isolated yield.

Our group previously demonstrated that hydrofluorocarbons (HFCs) can be used as low cost –CF₃, and –CF₂H sources,^28–30 representing a strategy to repurpose refrigerants or fluorinated waste products that are produced on a >15 kt scale.^69,70 Importantly, the use of CH₂F₂ (HCF-32) as a fluoroalkyl precursor affords products that are also pro-nucleophiles, primed for subsequent functionalization. We evaluated the feasibility of a one-pot difluoromethylation reaction using [K(18-c-6)(B₃N₃Me₆-CF₂H)] (6a) and vinyl-BPin derivatives. Although higher temperature (80 °C) was required for –CF₂H transfer, the previously optimized conditions for Zweifel olefination afforded 6b in 76% yield (Fig. 6, ESI Table S3†). We also evaluated the protocol using dihydronaphthalene and styrenyl BPin derivatives, which provided conversions of 72% and 68% for 6c and 6d, respectively (Fig. 6). We directly compared this approach to Me₃Si-CF₂H, a common –CF₂H pronucleophile that requires activation by F⁻ or OH⁻.^71–73 Addition of vinyl-BPin (2c) to a solution of Me₃Si-CF₂H activated with either [Me₄N][OH] or [ⁿBu₄N][F] did not afford ¹⁹F NMR resonances consistent with the –CF₂H analogue of 2d (see ESI, S75†), under similar conditions used with 6a (see ESI, Fig. S114 and S115†). These results highlight the challenge of selective nucleophilic fluoroalkyl transfer from R-SiMe₃ reagents that contain more than one nucleophilic sites, and demonstrate a clear advantage for using –CF₂R transfer reagents that do not need an activator.

Fig. 6 (a) Zweifel olefination for the synthesis of vinyldifluoromethane molecules from CH₂F₂. (b) Scope of vinyldifluoromethanes, conditions: R-BPin (0.2 mmol), [K(18-c-6)(B₃N₃Me₆-CF₂H)] (0.2 mmol), I₂ (0.4 mmol), NaOMe (0.4 mmol), THF (4.0 mL). (c) Scope in fluoroalkanes. *Only ¹⁹F NMR yield acquired due to product volatility. ¹⁹F NMR yields (isolated yields are in parentheses).

Next, we examined the feasibility of the Zweifel olefination using other fluoroalkanes (HCF₃, CH₃CF₂H, CF₃CFH₂ and CF₃CH₃). We found that the HCF₃-derived reagent, [(B₃N₃Me₆-CF₃)(K(18-c-6))], was readily adapted, affording the trifluoromethyl containing product, 6e, in 65% isolated yield (Fig. 6c). When translating these conditions to fluoroethanes, we found that although CH₃CF₂H and CF₃CH₃ did not afford the olefination products, CF₃CFH₂ furnished 6f and 6g with 17% and 14% yield as assessed by ¹⁹F NMR spectroscopy. In these cases, β-fluoride elimination occurred at the first step (generating [(B₃N₃Me₆-CF=CF₂)(K(18-c-6))]), a species competent for the net Zweifel olefination (Fig. 6c, ESI S78–S80†). Finally, we attempted the direct capture/olefination of HCF₂⁻ following deprotonation of CF₂H₂. Deprotonation of CF₂H₂ with 5 equiv. KN(ⁱPr)₂ gave 32% conversion to the vinyl boronate intermediate, that when subjected to NaOMe/I₂, afforded 9% yield of 6d over two steps (ESI S77†).

Given previous data showing rapid transfer of the RCF₂⁻ unit to carbonyl electrophiles,²⁶ we examined whether transfer to vinyl BPin may occur in the presence of another, competitive electrophile. We performed a series of competition experiments to examine reaction tolerance to carbonyl electrophiles as additives. The addition of esters and a ketone (benzyl benzoate, phenyl benzoate and benzophenone) provided low conversion to the final product (Fig. 7, 8%, 5% and 10%, respectively). However, the reaction tolerated an amide electrophile, N,N-dimethylbenzamide, and we observed only 3% reduction in product formation (92% yield of 3e) (Fig. 7, ESI S78†). These results demonstrate the feasibility of the reaction sequence with select competitive electrophiles.

Fig. 7 Tolerance to ester, ketone and amide additives.

We next investigated the feasibility of late-stage modifications of three representative Ar–CF₂–olefins formed from the Zweifel olefination sequence (Fig. 8). Hydrogenation of 3e using Pd/C at 25 psi H₂ furnished 8a in 84% isolated yield. A net dehydrogenation reaction was effected by treating 3e with AIBN/NBS at room temperature, affording 8b in 72% isolated yield. An epoxidation reaction of 3i with m-CPBA in CH₂Cl₂ at 60 °C provided 8c in 74% isolated yield. Reduction of 3fvia BH₃ hydroboration followed by oxidation furnished 8d in 56% isolated yield. Finally, a defluorinative S_N2′ reaction with ⁿBuLi yielded the E isomer 8e with 73% isolated yield (9 : 1 selectivity of E/Z alkenes).

Fig. 8 Further transformation of vinyldifluoromethylene products spanning oxidative, reductive and substitution chemistry. *10% Z isomer also formed.

Conclusion

In summary, we have developed a metal-free strategy to access vinyldifluoromethylene molecules from fluoroalkane precursors and vinyl-BPin reagents. Lewis acidic boranes stabilize and template α,α-difluoroalkyl- and vinylic-moieties, ultimately enabling C–C bond formation. This strategy was extended to a straightforward one-pot synthesis using RCF₂H precursors and vinyl-BPin reagents. We showed that this reaction sequence can be used to generate RCF₂H precursors directly from inexpensive CH₂F₂ (HCF-32), which represents a new strategy to repurpose this underutilized synthon. Importantly, we demonstrated that this CF₂H⁻ reactivity is a unique application of the deprotonation approach, and not possible using the most common –CF₂H transfer reagent: Me₃Si-CF₂H. Finally, we established that the vinyldifluoromethylene products can be readily derivatized, representing an avenue for late-stage modification of fluoroalkylated compounds.

Data availability

All relevant experimental data and characterization details are provided in the ESI.† Crystallographic data for compound 3e has been deposited at the Cambridge Crystallographic Data Centre (CCDC) under access number 2299679.

Author contributions

The manuscript was written through contributions of all authors. The project was designed by K. Chakrabarti, M. M. Wade Wolfe, S. Guo, and N. K. Szymczak. All optimizations, syntheses and characterizations were performed by K. Chakrabarti. J. W. Tucker and J. Lee provided insights related to project development. All authors have given approval to the final version of the manuscript.

Conflicts of interest

NKS holds a patent relating to fluoroalkyl transfer reagents.

Acknowledgements

This work was supported by the NSF (CHE 1955284). We thank Dr Fengrui Qu for acquiring data for X-ray crystallography and Dr Russell Bornschein for Mass Spectrometry assistance. We thank Dr Daniel Beagan for assistance solving the crystal structure.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2299679. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc05616c

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