Cu(II)-Catalyzed Unsymmetrical Di-oxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-Phenoxyketones

Abstract

A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver α,α-difluorinated-α-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of α,α-difluorinated ketone and α,α-difluorinated ether moieties, these compounds have rarely been reported as a synthetic intermediate. Computational predictions and later experimental corroboration suggest that the phenoxy-substituted fluorinated ketone’s sp³-hybridized hydrate form is energetically favoured relative to the respective non-ether variant, and that perturbation of the electronic character of the ketone can further encourage formation of the hydrate. The more facile conversion between ketone and hydrate forms suggest that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.

Graphical Abstract

INTRODUCTION

Fluorinated organic compounds are important in many fields such as medicine, agrochemistry, and material science;^1–10 methods that can rapidly and convergently convert readily accessible fluorinated synthons into useful substructures can greatly accelerate these applied sciences. One such synthon, the gem-difluoroalkene, serves as a valuable and readily-accessible building block for further functionalization;^11–14 though notably, most catalytic reactions of gem-difluoroalkenes involve monofunctionalization, and selective difunctionalization reactions of gem-difluoroalkenes are uncommon.^13,15–23 To complement a recent publication describing difunctionalization of gem-difluoroalkenes to generate C–S/C–O or C–S/C=O bonds,²⁴ we describe a Cu-based aerobic catalyst system to promote sequential C–O/C=O bonds through a distinct process (anionic vs. radical) to deliver an unstudied moiety, the α,α-difluorinated-α-phenoxy-ketone, a hybrid group composed of both difluorinated ketone and difluorinated ether components (Scheme 1A).

Scheme 1. Construction of α,α-Difluorinated-α-Phenoxyketones by Cu-Catalyzed Oxidation of gem-Difluoroalkenes.

Among fluorinated functional groups, α,α-difluoroketones are valuable substructures for medicinal chemistry, as well as synthons for accessing other fluorinated substructures.²⁵ This group readily rehybridizes from an sp²-hybridized keto form to an sp³-hybridzed form, which can interact with aspartyl proteases through noncovalent hydrogen-bonding interactions, with serine proteases through reversible covalent interactions by forming stable tetrahedral adducts,^26–28 and also with non-protease targets.^29,30 Therefore, this substructure has drawn significant attention to synthetic and medicinal chemists.³¹ Separately, α,α-difluoroalkyl ethers display a wide range of applications in pharmaceuticals,³² agrochemicals³³ and material chemistry.^34,35 For example, α,α-difluoroalkyl ethers can enhance metabolic stability³² and control molecular conformation.^36,37 Due to the small rotational barrier around the ArO–CF₂R bond, difluorinated phenyl ethers can access a wide range of conformers versus the parent alkyl-aryl ethers that preferentially reside in the plane of the arene,³⁷ and versus trifluoromethyl-aryl ethers that reside orthogonally to the plane of the arene.³⁸ Interestingly, despite the individual significance of the α,α-difluoroketone and α,α-difluoroalkyl ethers components, the hybrid α,α-difluorinated-α-phenoxy-ketone functional group has rarely been reported, with uses as synthetic intermediates en route to other substructures^39–41 or as a specialized resin.⁴² The lack of synthetic strategies for accessing α,α-difluorinated-α-phenoxy ketones precludes evaluation of the properties of the functional group, and also impedes its use in medicinal chemistry and chemical biology. Herein, we report the synthesis and physicochemical characterization of the α,α-difluorinated-α-phenoxy-ketone functional group, and predict its utility (computationally and experimentally) in biological and medicinal chemistry.

RESULTS AND DISCUSSION

To access α,α-difluorinated-α-phenoxy-ketones, we envisioned exploiting the unique reactivity of readily available gem-difluorinated alkenes,^11,13,43 specifically a sequence involving nucleophilic attack on the electrophilic difluorinated center and subsequent oxidation (Scheme 1B). However, transition metal-catalyzed reactions of gem-difluoroalkenes typically proceed through β-fluoro anionic or β-fluoro metal intermediates that are both prone to undergo β-fluoride elimination and generate monofluoroalkene products; in contrast, “fluorine-retentive” catalytic functionalization reactions of gem-difluorinated alkenes¹² are rare.^14,44,45 To overcome these challenges, we hypothesized that one-electron radical functionalization of the gem-difluorinated alkene would avoid anionic intermediates and subsequent β-fluoride elimination. Applied to the preparation of α,α-difluorinated-α-phenoxy ketones, addition of a phenoxy radical to the gem-difluorinated alkene would provide an α,α-difluorinated-α-phenoxy radical, which might be trapped under oxidative conditions to deliver the unsymmetrically dioxygenated target substructure (Scheme 1C). Considering that cobalt-catalyzed aerobic coupling reactions of phenols with gem-difluorinated alkenes generates β,β-difluorinated-α-phenoxyalcohols in a difunctionalization process that generates C–O and C–O bonds,⁴⁶ we hypothesized that an alternate transition metal might generate the related keto-derived products in a process that forms C–O and C=O bonds (Scheme 1D). Such a strategy that exploits distinct transition metals to selectively generate ketone- or alcohol-derived products would contrast recently published aerobic difunctionalization reactions of thiols with gem-difluorinated alkenes, which exploited distinct solvents to differentiate selectively generate ketone- or alcohol-derived products though formation of C–S and C=O or C–S and C–O bonds, respectively (Scheme 1E).²⁴ However, the addition of phenols to generate α,α-difluorinated-α-phenoxy-ketones remains unexplored.²⁴

Routine synthetic optimization identified an optimal Cu-based catalyst system for reacting gem-difluoroalkenes with phenols to selectively produce α,α-difluorinated-α-phenoxy ketone 3ab, while avoiding formation of a related alcohol-containing side product 4ab. Notably, the combination of 20% CuCl₂ and 10% 2,2’:6’,2”-terpyridine in a mixed solvent system (3:1 ratio) of 1,2-dichlorobenzene (DCB) and DMSO under O₂ at 100 °C afforded the desired ketone product in in 87% yield (Table 1, entry 1; see Supporting Information for more optimization details). Interestingly, these oxidative Cu(II)-catalyzed oxidative conditions delivered the ketone-derived product, as has been previously seen in reactions of non-fluorinated alkenes,^47–49 in contrast to a recently published Co(II/III)-based oxidative system that delivered alcohol-derived products (e.g. 4ab, entry 2).⁴⁶ Further, use of CuCl or other Cu-based catalysts instead of CuCl₂ lowered the conversion of substrates and delivered lower yield of the ketone (entry 3 and Table S1, see supporting information), while the removal of a Cu-catalyst significantly reduced the conversion of product and confirmed that Cu was required (entry 4). Replacement of terpyridine with bipyridine or phenanthroline provided lower yield of the desired product (entries 5 and 6). Reactions run with lower loadings of CuCl₂ (10%) reduced the yield of ketone product, whereas an increase in ligand (20%) decreased formation of the desired ketone product (entries 7 and 8). Use of DCB alone in place of DCB:DMSO delivered low conversion and yield of 3ab (entry 9).^50,51 However, use of DMSO alone provided no yield of anticipated product (entry 10). Elevating or lowering the reaction temperature lowered the yield of desired product (11 and 12), though elevated temperatures were beneficial for certain substrates (see Tables 2–3). Finally, O₂ served as an essential oxidant for this reaction, as no product formed under an atmosphere of N₂ (entry 13), though under an atmosphere of air, a low yield of desired product was obtained along with the undesired secondary alcohol (entry 14).

Table 1.

Optimization of Reaction Conditions for the Synthesis of α,α-Difluorinated-α-Phenoxyketone^a

entry	deviation from the optimized conditions	conversion (%)	yieldb (%)
			3ab	4ab
1	none	100	87	-
2	Co(acac)2 instead of CuCl2	100	3	70
3	CuCl instead of CuCl2	100	73	-
4	No catalyst	11	3	-
5	bipyridine instead of terpyridine	100	78	-
6	1,10-phenanthroline instead of terpyridine	100	68	-
7	10% CuCl2 instead of 20% CuCl2	100	77	-
8	20% terpyridine instead of 10% terpyridine	100	81	-
9	using DCB as only solvent	100	30	-
10	using DMSO as only solvent	33	2	-
11	80 °C instead of 100 °C	31	30	-
12	120 °C instead of 100 °C	100	77	-
13	reaction under N2 atmosphere instead of O2 atmosphere	6	-	-
14	reaction under air instead of O2 atmosphere	71	33	12

^aStandard conditions: 1 (1.0 equiv., 0.10 mmol), 2 (3.0 equiv., 0.30 mmol), DCB (0.30 mL), DMSO (0.10 mL), 24 h under an atmosphere of O₂.

^bDetermined by ¹⁹F NMR analysis of the crude reaction mixture using α,α,α-trifluorotoluene as a standard.

Table 2.

Scope of gem-Difluoroalkenes^a

^aStandard conditions: 1 (1.0 equiv., 1.0 mmol), 2 (3.0 equiv., 3.0 mmol), DCB (3.0 mL), DMSO (1.0 mL), CuCl₂ (20 mol%, 0.20 mmol) and terpyridine (10 mol%, 0.10 mmol) at 100 °C for 24 h under an atmosphere of O₂. Yields of isolated material represent the average of 2 runs.

^bDCB (4.0 mL), 120 °C, 60 h, sealed tube.

^cDCB (4.0 mL), 120 °C, 30 h.

^dDCB (4.0 mL), 140 °C, 60 h, sealed tube.

^eDCB (4.0 mL), 140 °C, 30 h.

^fYield determined by ¹⁹F NMR.

Table 3.

Scope of Phenols^a

^aStandard conditions: 1 (1.0 equiv., 1.0 mmol), 2 (3.0 equiv., 3.0 mmol), DCB (3.0 mL), DMSO (1.0 mL), CuCl₂ (20 mol%, 0.20 mmol) and terpyridine (10 mol%, 0.10 mmol) at 100 °C for 24 h under an atmosphere of O₂. Yields of isolated material represent the average of 2 runs.

^bDCB (4.0 mL), 140 °C, 30 h.

^cDCB (4.0 mL), 140 °C, 60 h, sealed tube.

^dA trace amount of dimerised phenol was observed as an impurity observed.

^eK₂CO₃ (20 mol%, 0.20 mmol) has been used as an additive.

The generality and scope of the developed protocol were explored utilizing a wide range of electron-rich and -deficient gem-difluoroalkenes (1) and phenols (2), which generally afforded the corresponding α,α-difluorinated-α-phenoxyketones 3 in good to high yields (Tables 2–3). Numerous substituents like OR (R = alkyl), SMe, alkyl, and halogen groups on the aryl ring of the gem-difluoroalkene were compatible under standard conditions (Table 2, 3aa–3ap). Remarkably, gem-difluoroalkene containing an ortho substituent on the aryl ring also provided the corresponding α,α-difluorinated-α-phenoxyketone in good yield (Table 2, 3al); whereas gem-difluoroalkene containing two ortho-substituents on the aryl ring only afforded trace amount of product (3ap), possibly due to the steric hindrance exerted by two ortho methyl groups. Importantly, gem-difluoroalkenes (1) bearing heteroaromatic groups, such as 3-pyrazolyl and 3-indolyl were tolerated under optimal conditions, with reactions affording the corresponding products in high yields (Table 2, 3am, 3an). In addition, an extended heteroaromatic, dibenzothiophene also afforded the corresponding α,α-difluorinated-α-phenoxyketone 3ao in 64% yield. Of note, reactions of gem-difluoroalkenes bearing electron-withdrawing substituents required higher temperatures to increase the yield, which might implicate an electron-deficient intermediate (radical or cation) at the benzylic position (Table 2, 3ad-3ag). Finally, gem-difluorinated alkenes bearing aliphatic substituents did not convert to product under the reaction conditions (3aq).

A variety of phenols were successfully coupled to deliver α,α-difluorinated-α-phenoxyketones in good to excellent yields (Table 3). Synthetically useful functional groups, such as halogens, ethers, esters, carboxylic acids, aldehydes, carbamates, and nitro groups, were also well tolerated under the optimized conditions (Table 3, 3ba–3bt). Phenols bearing an electron donating group (–OMe) at the para position required higher temperature (140 °C) to achieve synthetically useful conversion and yield (Table 3, 3bd). Furthermore, phenols bearing a free acid group also yielded the corresponding α,α-difluorinated-α-phenoxyketones (Table 3, 3bm and 3bn) in excellent yield using K₂CO₃ as an additive. Moreover, a phenol bearing a redox-sensitive aldehyde group reacted to deliver product 3bo in excellent yield (Table 3). Of note, phenols bearing free amino groups did not react to yield the corresponding α,α-difluorinated-α-phenoxyketones, presumably because aminophenols can undergo oxidative reactions in the presence of copper under aerobic conditions.^52–54 A number of biologically active phenols, such as vanillin (flavoring agent), triclosan (antimicrobial agent), or a dextromethorphan derivative (cough suppressant), were coupled with a gem-difluoroalkene to yield the corresponding α,α-difluorinated-α-phenoxyketones in moderate to good yields (Table 3, 3br–3bt). Both 1- and 2-naphthol were not compatible with the reaction conditions, as these substrates preferentially underwent oxidative dimerization under the aerobic conditions in the presence of Cu, a process that has been previously studied.^55–58

To gain quantitative insight into the physicochemical differences between the unstudied α,α-difluorinated-α-phenoxyketones versus the already-established α,α-difluorinated-α-benzylketones, we computed the ketone-hydrate equilibria using density functional theory (DFT) at the ωb97XD⁵⁹/def2-TZVP⁶⁰//PBE⁶¹/6–31G*⁶² level of theory and SMD solvation corrections⁶³ in water as implemented in Gaussian 16,⁶⁴ and compared a range of difluorinated vs. nonfluorinated substructures as well as phenyl ether vs. benzyl substitutions (Scheme 2). Conformational searches were performed using the Schrödinger Macromodel software package.³⁸

Scheme 2. Reversible Formation of Geminal Diols from Fluorinated and Nonfluorinated Phenoxyketones. ΔG and ΔH in kcal mol⁻¹ and ΔS in kcal mol⁻¹ K⁻¹.

The ketone is typically favoured over the hydrate by ~5.6–11.8 kcal mol⁻¹. Notably, within this series the novel α,α-difluorinated-α-phenoxy ketone substructure shows the lowest energy barrier to form the hydrate (5.6 kcal mol⁻¹, eq. 1). Four factors appear to govern these equilibria.

1. For the fluorinated and/or ether-containing analogues (eq. 1–3), the hydrate form is enthalpically favoured (−0.9 to −6.8 kcal mol⁻¹), though the magnitude of this driving force is overcome by the entropic penalty of losing water (−3.8 to −4.4 × 10⁻² kcal mol⁻¹ K⁻¹). However, the nonfluorinated benzyl ketone enthalpically slightly favours the ketone state (0.3 kcal/mol, eq. 4). Increasing the temperature pushes the equilibrium towards the ketone. For example, DFT analysis of 3aj and 3bi confirmed that raising the temperature from rt to 100 °C increased the favourability of the ketone by ~3 kcal mol⁻¹ (Tables 2 and 3, respectively; See Supporting Information).

2. The geminal fluorine atoms significantly increase the favourability of the hydrates, as has been previously established experimentally.²⁷ Going from the hydrocarbon analogue to the fluorinated compound (eq. 3 to eq. 1), the preference for the hydrate increased by 4.8 kcal mol⁻¹. Similarly, for the benzyl-derived analogues, going from the hydrocarbon to the analogous fluorinated compound (eq. 4 to eq. 2), the favourability of the hydrate increased by 4.3 kcal mol⁻¹ (Scheme 2).

3. Replacing the methylene linker with the ether oxygen atom decreased the favourability of the ketone. In the fluorocarbon case (eq. 2 to eq. 1), the favourability decreased by 1.9 kcal mol⁻¹, while in the hydrocarbon case (eq. 4 to eq. 3) the favourability decreased by 1.4 kcal mol⁻¹ (Scheme 2).

4. Electron withdrawing groups on the ketone moiety reduced the favourability of the ketone. For example, the addition of NO₂ to the phenone moiety on 3aj reduced the favourability of the ketone by 3.0 kcal mol⁻¹ (See Supporting Information). In contrast, the addition of a methoxy group on the phenone moiety of 3bi increased the favourability of the ketone by 0.9 kcal mol⁻¹ (See Supporting Information).

In general, the ketone possessed fewer conformations than the hydrate, but the hydrate was more rigid with a higher energy barrier for conversion between conformations. For both the ketone and hydrate forms (eq. 1, Scheme 2), the most stable conformation exhibited double anomeric donation of both ether oxygen lone pairs into the adjacent σ*_CF orbitals. The aryl ketone was planar, and the aryl ether typically resided orthogonal to the ketone. The torsional rotational barrier around the carbonyl carbon and the α-CF₂ group was 3.8 kcal mol⁻¹ (See Supporting Information). In contrast, the hydrate tolerated a wider range of conformations. As found in spiroketal natural products,^65,66 both hydrate hydroxyl groups were oriented anti to each other, presumably to maximize the hyperconjugative stabilization of the hydrate oxygen lone pairs. The increase in hybridization from the ketone to the hydrate increased the torsional rotational barrier to 5.2 kcal mol⁻¹ (See Supporting Information). These results suggest that the α,α-difluorinated-α-phenoxyketone can readily adopt several conformations, but upon facile rehybridization to the sp³ form, the substructure should become more rigid in an enzyme’s active site.

In support of these computational findings, ketones bearing electron-deficient moieties experimentally rehybridize to form hydrates (3af → 5) more readily relative to ketones bearing electron-donating moieties (3ab → 5’, Scheme 3). Specifically, when dissolved in MeCN with H₂O (10 equiv.), a difluorinated ketone bearing an electron withdrawing group (3af: ¹⁹F NMR δ −74.0 ppm; ¹³C NMR δ 181.1 ppm; IR 1476 cm⁻¹) readily formed an sp³-hybridized hydrate (5: ¹⁹F NMR δ −87.0 ppm; ¹³C NMR δ 93.8 ppm). This experimental observation matches computational predictions of 3aj, in which the ketone is energetically preferred by 1.7 kcal mol⁻¹ at rt (See Supporting Information). Experimentally, this hydration process was reversible, as extraction of such electron-deficient difluorinated geminal diol (e.g. 5) into organic solvent (DCM or EtOAc), and evaporation regenerated the corresponding α,α-difluorinated-α-phenoxyketone 3aj. Notably, the ¹⁹F NMR spectra of products bearing either neutral or electron-rich ketone moieties did not show the diol form, as supported by the DFT computations.

Scheme 3. Ketone Moieties Bearing Electron-Withdrawing Groups Readily form the Hydrate as Observed by ¹⁹F NMR, While Ketones Bearing Electronically Neutral or Rich Rings do not Readily form Hydrates.

These computational analyses help quantitatively calibrate the new fluorinated phenoxyketone derivatives relative to the known non-ether-containing analogues, and suggest strategies for encouraging formation of the sp³-hybridized form. In the context of drug/probe design, the entropic reluctance to rehybridize to the hydrate form might be readily offset by strong ligand-binding interactions that present a nucleophilic residue (or water) towards the ketone, which promotes the enthalpically favoured rehybridization. Such reversible rehybridization has been exploited to engage biological targets via reversible covalent interactions (e.g. with serine proteases) or by intricate hydrogen-bonding networks (e.g. aspartate proteases).^26–28 Moreover, the computations suggest that increasing the electron-withdrawing character around the ketone, either by introduction of an O-atom at the α-position and/or an electron-withdrawing group off the non-fluorinated side of the ketone, can further push the equilibrium toward the sp³-hybrized form.

In addition to this potential to inhibit enzymes, the α,α-difluorinated-α-phenoxyketone substructure (3) can also serve as a synthetic intermediate for generating various fluorinated substructures (Scheme 4). This group readily participates in Horner-Wadsworth Emmons olefination, reduction, reductive amination, and deoxyfluorination reactions to deliver corresponding difluoroalkyl-substituted acrylates (6), alcohols (7), amines (8), and tetrafluoroethanes (9) in good to excellent yields. Thus, the intermediate α,α-difluorinated-α-phenoxyketone can serve synthetically useful for accessing other important substructures.

Scheme 4. Potential Applications α,α-Difluorinated-α-Phenoxyketones.

Literature reports support a plausible mechanism involving radical intermediates (Scheme 5).^67–69 Initial reaction of phenol and Cu^IICl₂ generates phenoxy radical 10.⁷⁰ Addition of radical 10 to gem-difluoroalkene 1 produces benzylic radical 11. This regioselective attack of the radical to the difluorinated position is consistent with other radical functionalization reactions of alkenes.^{13,43,46,71–73} Trapping of radical 11 with Cu^ICl and molecular oxygen affords peroxo intermediate 12. Concerted elimination of Cu^II peroxide 12 might afford product 3 and Cu^IICl(OH) 13,^67,68,74,75 which could react with HCl to regenerate the active catalyst Cu^IICl₂. Notably, this Cu-catalyzed elimination step (12→13) contrasts the Fenton-like fragmentation of related peroxo intermediates that presumably form in the complementary cobalt-catalyzed process to generate the corresponding alcohols.⁴⁶

Scheme 5. Plausible Mechanism.

In support of a radical process, experiments were run in the presence of three radical traps, 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT), and benzoquinone. All three radical quenchers decreased the yield of product (0–35% yield; (see SI Scheme S1). Further, the fact that many substrates generated oxidized products in the absence of DMSO (Tables 2 footnotes b–e, Table 3 footnotes b–c) suggests that the oxygen atom from DMSO is not transferred to the ketone. In contrast, we speculate that O₂ donates the O-atom of the ketone, as previously substantiated by reports of Cu-catalyzed oxidative functionalization reactions of nonfluorinated alkenes.^67–69 Finally, subjection of the corresponding β,β-difluorinated-α-phenoxyalcohol to the reaction conditions did not oxidize the substrate to the ketone, thus, discounting the corresponding alcohol as a likely intermediate.

Critically, the Cu-catalyst system overcomes multiple issues involving selectivity. First, by invoking radical intermediates, this reaction sequence avoids β-fluoro anionic or β-fluoro metal intermediates that are prone to eliminate fluoride and generate monofluorinated products.^44,45 Second, by invoking a Cu-mediated fragmentation of the peroxide intermediate (12), this reaction avoids formation of alcohol-derived side products (e.g. 4ab), which contrasts solvent-controlled fragmentation of related peroxide intermediates that occur with more modest selectivities.²⁴

CONCLUSION

In summary, we developed a copper-catalyzed difunctionalization reaction of gem-difluoroalkenes by readily available phenols and O₂ to furnish an array of novel α,α-difluorinated-α-phenoxyketones. The mild reaction conditions tolerate many useful functional groups and afforded the products in good yields. In addition, the α,α-difluorinated-α-phenoxyketones can also serve as substrates for further synthetic elaboration in reductive amination, reduction, halogenation, and C–C bond-forming reactions to deliver a broad set of products. Computational studies predict that the unstudied sp²-hybridized α,α-difluorinated-α-phenoxyketone substructure can rehybridize to the tetrahedral hydrate, and more so that the ether oxygen atom pushes the ketone/hydrate equilibrium toward the hydrate form by 1.4 kcal/mol relative to the methylene-based linker. Further, the introduction of additional electron-withdrawing groups on the nearby aryl moiety enables the enthalpic driving forces to counteract the entropic cost of the bimolecular hydration (ketone + H₂O) and encourage this rehybridization. These two strategies for lowering the energy of the hydrate provide opportunities for medicinal chemists and chemical biologists to tune the equilibrium reactivity of these ketone/hydrate forms, thus enabling use of these substructures for future biomedical applications, specifically towards covalent inhibition of proteases or other enzymes with nucleophilic residues at the binding site.

EXPERIMENTAL SECTION

General Considerations.

Unless otherwise noted, reactions were performed under an atmosphere of oxygen using oven-dried glassware. Selective di-oxidation reactions of phenols and gem-difluoroalkenes were performed in 100 mL round-bottom flasks sealed with a glass stopper or 50 mL sealed tube. Reactions were monitored either by ¹⁹F NMR with an internal standard of α,α,α-trifluorotoluene (TFT) or by thin layer chromatography (TLC) on UNIPLATE Silica Gel HLF plates, visualized by quenching of fluorescence. Column chromatography was conducted either using an automated flash chromatography system utilizing gradient elution with a Teledyne ISCO C18 EZ Prep or Teledyne Isco CombiFlash R_f 200 system utilizing gradient elution. Isolated yields reported in the manuscript represent an average of at least 2 independent runs of final compound deemed to be at least 95% pure by NMR. Yields reported in the supporting information refer to a single experiment.

Compound 1a-q were prepared according to a previous report.⁷⁶ Unless otherwise noted, reagents were purchased from commercial sources and used as received. Copper(II) chloride (CuCl₂), DMSO (anhydrous), N-methylpyrrolidine (NMP, anhydrous), and ethanol (EtOH, anhydrous) were purchased from Sigma Aldrich. 1,2–Dichlorobenzene (DCB, anhydrous, 99+%), was purchased from Alfa Aesar. Solvents, including dimethylformamide (DMF), toluene (PhMe), dichloromethane (DCM), methanol (MeOH), acetonitrile (MeCN), and tetrahydrofuran (THF) were used directly from a solvent purification system, in which solvent was dried by passage through two columns of activated alumina under argon. Other chemical abbreviations utilized in this document include: sodium sulfate (Na₂SO₄), magnesium sulfate (MgSO₄), ethyl acetate (EtOAc), diethyl ether (Et₂O), ammonium chloride (NH₄Cl), sodium hydroxide (NaOH), room temperature (rt), and hydrochloric acid (HCl), triethyl amine (NEt₃), melting point (mp).

Proton nuclear magnetic resonance (¹H NMR) and fluorine nuclear magnetic resonance (¹⁹F NMR) were taken on Bruker DRX 500 spectrometer (500 and 470 MHz respectively). Proton and carbon nuclear magnetic resonance (¹³C{1H} NMR) were taken on a Bruker AVIII 500 Avance spectrometer with a BBFO cryoprobe (500 and 126 MHz respectively) or on a Bruker Avance III 800 with a QCI cryoprobe (800 and 201 MHz respectively). Chemical shifts (δ) for protons are reported in parts per million (ppm) downfield from tetramethylsilane, and are calibrated against the residual solvent peak (CHCl₃: δ = 7.26 ppm; DMSO: δ = 2.50 ppm, CH₃CN: δ = 1.96 ppm). Chemical shifts (δ) for carbon are reported in ppm downfield from tetramethylsilane, and are calibrated against residual solvent peak (CDCl₃: δ = 77.2 ppm; DMSO-d₆: δ = 39.5 ppm, CH₃CN: δ = 118.2 and 1.7 ppm). Chemical shifts for fluorine are reported uncorrected in ppm upfield from trichlorofluoromethane (0.0 ppm). NMR data are represented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet), coupling constant in Hertz (Hz), integration. High-resolution mass determination was carried out either by electrospray ionization (ESI) on a Waters LCT Premier mass spectrometer where samples were dissolved in MeOH and MeOH was used as the ionization solvent or by atmospheric-pressure chemical ionization (APCI-hexanes/PhMe) on a Waters Q-Tof Premier, where samples were dissolved in hexanes, and hexanes or PhMe/hexanes were used as the ionization solvent or on an LTQ Orbitrap mass spectrometer (ThermoFisher Scientific, Bremen, Germany) using a high resolution scan setting of 60,000. After tuning and calibrating the instrument in positive mode with a Thermo LTQ positive ion calibration Solution, the samples were analyzed in APCI mode using low capillary temperature (150 °C) and low vaporizer temperature (150 °C) to prevent thermal decomposition of the compounds. Infrared spectra were measured on a Perkin Elmer Spectrum Two Fourier Transform Infrared Spectrometer by drying samples on a diamond ATR Sample base plate. Uncorrected melting points were measured on a Thomas Hoover Capillary Melting Point apparatus or Chemglass Digital Melting Point apparatus.

General Procedure A for the Synthesis of α,α-Difluorinated-α-Phenoxyketones (3).

An oven-dried 100 mL round-bottom flask, equipped with a magnetic stir bar, was charged with difluoroalkene (1.0 mmol, 1.0 equiv.), phenol (3.0 mmol, 3.0 equiv.), CuCl₂ (0.20 mmol, 0.20 equiv.) and terpyridine (0.10 mmol, 0.10 equiv.). Then anhydrous DCB (3.0 mL) and DMSO (1.0 mL) were added, and the system was purged with O₂ gas for 90 seconds. The system was sealed with a glass stopper and stirred for 1 min at rt. Subsequently, the round-bottom flask was placed in a pre-heated oil bath and stirred vigorously at 100 °C for the required time. The round-bottom flask was cooled to rt, and 12.3 μL of TFT was added via microsyringe. The solution was diluted with approximately 1.0 mL of DCM and then stirred at rt for 10 min to allow adequate mixing. After mixing, a 0.3 mL aliquot was removed from the round-bottom flask and passed through a 0.250 g pad of silica gel using DCM as the eluent into an NMR tube to remove CuCl₂, after which the reaction was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis, then returned to the round-bottom flask. The solvents were evaporated by using BioChromato Smart Evaporator, and the residue was again filtered through a small plug of silica using DCM as eluent to remove the metal catalyst. The filtrate was concentrated in vacuo. The residue was loaded onto celite and then purified by flash reverse phase chromatography using a 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN to provide the desired product in >95% purity.

General Procedure B for the Synthesis of α,α-Difluorinated-α-Phenoxyketones (3).

An oven-dried 50 mL sealed tube, equipped with a magnetic stir bar, was charged with difluoroalkene (1.0 mmol, 1.0 equiv.), phenol (3.0 mmol, 3.0 equiv.), CuCl₂ (0.20 mmol, 0.20 equiv.) and terpyridine (0.10 mmol, 0.10 equiv.). Then anhydrous DCB (4.0 mL) was added, and the system was purged with O₂ gas for 90 seconds. The system was sealed with a screw cap and stirred for 1 min at rt. Subsequently, the sealed tube was placed in a pre-heated oil bath and stirred vigorously at 120 °C for the required time. The sealed tube was cooled to rt, and 12.3 μL of TFT was added via microsyringe. The solution was diluted with approximately 1.0 mL of DCM and then stirred at rt for 10 min to allow adequate mixing. After mixing, a 0.3 mL aliquot was removed from the sealed tube and passed through a 0.250 g pad of silica gel using DCM as the eluent into an NMR tube to remove CuCl₂, after which the reaction was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis, then returned to the sealed tube. The solvents were evaporated by using a BioChromato Smart Evaporator, and the residue was again filtered through a small plug of silica using DCM as eluent to remove the metal catalyst. The filtrate was concentrated in vacuo. The residue was loaded onto celite and then purified by flash reverse phase chromatography using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN to provide the desired product in >95% purity.

General Procedure C for the Synthesis of α,α-Difluorinated-α-Phenoxyketones (3).

An oven-dried 100 mL round-bottom flask, equipped with a magnetic stir bar, was charged with difluoroalkene (1.0 mmol, 1.0 equiv.), phenol (3.0 mmol, 3.0 equiv.), CuCl₂ (0.20 mmol, 0.20 equiv.) and terpyridine (0.10 mmol, 0.10 equiv.). Then anhydrous DCB (4.0 mL) was added, and the system was purged with O₂ gas for 90 seconds. The system was sealed with a glass stopper and stirred for 1 min at rt. Subsequently, the round-bottom flask was placed in a pre-heated oil bath and stirred vigorously at 120 °C for the required time. The round-bottom flask was cooled to rt, and 12.3 μL of TFT was added via microsyringe. The solution was diluted with approximately 1.0 mL of DCM and then stirred at rt for 10 min to allow adequate mixing. After mixing, a 0.3 mL aliquot was removed from the round-bottom flask and passed through a 0.250 g pad of silica gel using DCM as the eluent into an NMR tube to remove CuCl₂, after which the reaction was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis, then returned to the round-bottom flask. The solvents were evaporated by using a BioChromato Smart Evaporator, and the residue was again filtered through a small plug of silica using DCM as eluent to remove the metal catalyst. The filtrate was concentrated in vacuo. The residue was loaded onto celite and then purified by flash reverse phase chromatography using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN to provide the desired product in >95% purity.

General Procedure D for the Synthesis of α,α-Difluorinated-α-Phenoxyketones (3).

An oven-dried 50 mL sealed tube, equipped with a magnetic stir bar, was charged with difluoroalkene (1.0 mmol, 1.0 equiv.), phenol (3.0 mmol, 3.0 equiv.), CuCl₂ (0.20 mmol, 0.20 equiv.) and terpyridine (0.10 mmol, 0.10 equiv.). Then anhydrous DCB (4.0 mL) was added, and the system was purged with O₂ gas for 90 seconds. The system was sealed with a screw cap and stirred for 1 min at rt. Subsequently, the sealed tube was placed in a pre-heated oil bath and stirred vigorously at 140 °C for the required time. The sealed tube was cooled to rt, and 12.3 μL of TFT was added via microsyringe. The solution was diluted with approximately 1.0 mL of DCM and then stirred at rt for 10 min to allow adequate mixing. After mixing, a 0.3 mL aliquot was removed from the sealed tube and passed through a 0.250 g pad of silica gel using DCM as the eluent into an NMR tube to remove CuCl₂, after which the reaction was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis, then returned to the sealed tube. The solvents were evaporated by using a BioChromato Smart Evaporator, and the residue was again filtered through a small plug of silica using DCM as eluent to remove the metal catalyst. The filtrate was concentrated in vacuo. The residue was loaded onto celite and then purified by flash reverse phase chromatography using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN to provide the desired product in >95% purity.

General Procedure E for the Synthesis of α,α-Difluorinated-α-Phenoxyketones (3).

An oven-dried 100 mL round-bottom flask, equipped with a magnetic stir bar, was charged with difluoroalkene (1.0 mmol, 1.0 equiv.), phenol (3.0 mmol, 3.0 equiv.), CuCl₂ (0.20 mmol, 0.20 equiv.) and terpyridine (0.10 mmol, 0.10 equiv.). Then anhydrous DCB (4.0 mL) was added, and the system was purged with O₂ gas for 90 seconds. The system was sealed with a glass stopper and stirred for 1 min at rt. Subsequently, the round-bottom flask was placed in a pre-heated oil bath and stirred vigorously at 140 °C for the required time. The round-bottom flask was cooled to rt, and 12.3 μL of TFT was added via microsyringe. The solution was diluted with approximately 1.0 mL of DCM and then stirred at rt for 10 min to allow adequate mixing. After mixing, an aliquot of 0.3 mL was removed from the round-bottom flask and passed through a 0.250 g pad of silica gel into an NMR tube using DCM as eluent to remove CuCl₂, after which the reaction was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis then returned to the round-bottom flask. The solvents were evaporated by using a BioChromato Smart Evaporator and again filtered through a small plug of silica to remove the metal catalyst using DCM as eluent and concentrated in vacuo. The residue was loaded onto celite and then purified by flash reverse phase chromatography using a 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN to provide the desired product in >95% purity.

General Procedure F for the Synthesis of α,α-Difluorinated-α-Phenoxyketones (3).

An oven-dried 100 mL round-bottom flask, equipped with a magnetic stir bar, was charged with difluoroalkene (1.0 mmol, 1.0 equiv.), phenol (3.0 mmol, 3.0 equiv.), CuCl₂ (0.20 mmol, 0.20 equiv.), terpyridine (0.10 mmol, 0.10 equiv.) and K₂CO₃ (0.20 mmol, 0.20 equiv.). Then anhydrous DCB (3.0 mL) and DMSO (1.0 mL) were added, and the system was purged with O₂ gas for 90 seconds. The system was sealed with a glass stopper and stirred for 1 min at rt. Subsequently, the round-bottom flask was placed in a pre-heated oil bath and stirred vigorously at 100 °C for the required time. The round-bottom flask was cooled to rt, and 12.3 μL of TFT was added via microsyringe. The solution was diluted with approximately 1.0 mL of DCM and then stirred a rt for 10 min to allow adequate mixing. After mixing, a 0.3 mL aliquot was removed from the sealed tube and passed through a 0.250 g pad of silica gel using DCM as the eluent into an NMR tube to remove CuCl₂, after which the reaction was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis, then returned to the sealed tube. The solvents were evaporated by using a BioChromato Smart Evaporator, and the residue was again filtered through a small plug of silica using DCM as eluent to remove the metal catalyst. The filtrate was concentrated in vacuo. The residue was loaded onto celite and then purified by flash reverse phase chromatography using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN to provide the desired product in >95% purity.

Preparation and Characterization of Compounds.

2-(2,4-Dichlorophenoxy)-2,2-difluoro-1-(3,4,5-trimethoxyphenyl)ethanone (3aa).

General procedure A was followed using 1a (0.230 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.250 g (62%) of the title compound as yellow semisolid. ¹H NMR (500 MHz, CDCl₃) δ 7.53 (s, 2H), 7.50 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.31 – 7.29 (m, 1H), 4.00 (s, 3H), 3.96 (s, 6H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.1 (t, ²J_C-F2 = 33.4 Hz), 153.0, 144.5 (t, ³J_C-F2 = 1.9 Hz), 132.2, 130.6, 128.0, 127.7, 125.3, 123.8 (t, ³J_C-F2 = 1.9 Hz), 115.9 (t, ¹J_C-F2 = 280.4 Hz), 108.1 (t, ³J_C-F2 = 2.5 Hz), 61.0, 56.4. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.1 (s, 2F). IR (film) 2943, 1708, 1699, 1582, 1505, 1473, 1418, 1345, 1257, 1212, 1127, 995, 868, 749, 564 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₇H₁₄Cl₂F₂O₅ [M]⁺, 406.0186; found 406.0184.

2-(2,4-Dichlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3ab).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.260 g (75%) the title compound as yellow solid (mp = 56–58 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.27 (d, J = 8.6 Hz, 2H), 7.50 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 10.0 Hz, 1H), 7.03 (d, J = 10.0 Hz, 2H), 3.94 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 180.7 (t, ²J_C-F2 = 33.1 Hz), 165.0, 144.6 (t, ³J_C-F2 = 1.9 Hz), 133.1 (t, ³J_C-F2 = 1.9 Hz), 132.5, 132.0, 130.6, 128.0, 127.9, 123.8 (t, ³J_C-F2 = 1.9 Hz), 123.5, 116.0 (t, ¹J_C-F2 = 279.4 Hz), 114.1, 55.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.7 (s, 2F). IR (film) 2936, 1700, 1600, 1512, 1474, 1383, 1267, 1162, 936, 860, 750, 572 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₁₁Cl₂F₂O₃ [M + H]⁺, 347.0053; found 347.0068.

2-(2,4-Dichlorophenoxy)-2,2-difluoro-1-(4-(methylthio)phenyl)ethanone (3ac).

General procedure A was followed using 1c (0.186 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.243 g (67%) of the title compound as yellow solid (mp = 54–56 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 3.2 Hz, 1H), 2.57 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.2 (t, ²J_C-F2 = 33.7 Hz), 149.2, 144.5 (t, ³J_C-F2 = 1.9 Hz), 132.1, 130.8 (t, ³J_C-F2 = 1.9 Hz), 130.6, 128.0, 127.9, 126.6, 124.8, 123.9 (t, ³J_C-F2 = 1.9 Hz), 115.9 (t, ¹J_C-F2 = 278.1 Hz), 14.5. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.9 (s, 2F). IR (film) 2924, 1704, 1588, 1550, 1474, 1332, 1251, 1174, 936, 859, 767, 571 cm⁻¹. HRMS (ESI)⁺ m/z: calcd C₁₅H₁₁Cl₂F₂O₂S [M + H]⁺, 362.9825; found 362.9826.

1-(4-(Tert-butyl)phenyl)-2-(2,4-dichlorophenoxy)-2,2-difluoroethanone (3ad).

General procedure B was followed using 1d (0.196 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 120 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.205 g (55%) of the title compound as yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J = 10.0 Hz, 2H), 7.58 (d, J = 10.0 Hz, 2H), 7.50 (d, J = 2.5 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.31 – 7.28 (m, 1H), 1.39 (s, 9H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.8 (t, ²J_C-F2 = 33.7 Hz), 159.2, 144.5 (t, ³J_C-F2 = 1.9 Hz), 132.1, 130.6 (t, ³J_C-F2 = 1.9 Hz), 130.3, 130.1, 128.1, 128.0, 127.9, 125.8, 125.7, 124.8, 124.0 (t, ³J_C-F2 = 1.9 Hz), 115.9 (t, ¹J_C-F2 = 278.1 Hz), 35.4, 30.9. ¹⁹F NMR (469 MHz, CDCl₃) δ −74.0 (s, 2F). IR (film) 2964, 1711, 1604, 1562, 1474, 1383, 1267, 1174, 938, 863, 743, 574 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₈H₁₇Cl₂F₂O₂ [M + H]⁺, 373.0568; found 373.0571.

1-(4-Bromophenyl)-2-(2,4-dichlorophenoxy)-2,2-difluoroethanone (3ae).

General procedure C was followed using 1c (0.219 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 120 °C for 30 h. Evaporation of the solvent followed reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.198 g (50%) of the title compound as yellow solid (mp = 54–56 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.29 – 7.27 (m, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 170.0 (t, ²J_C-F2 = 30.0 Hz), 136.9, 126.3, 126.2, 125.9, 124.9, 124.8, 123.6, 122.4, 118.8, 111.4 (¹J_C-F2, J = 249.5 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ −74.3 (s, 2F). IR (film) 2918, 1716, 1584, 1474, 1382, 1280, 1169, 1071, 933, 861, 730, 572 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₄H₈BrCl₂F₂O₂ [M + H]⁺, 394.9047; found 394.9043.

4-(2-(2,4-Dichlorophenoxy)-2,2-difluoroacetyl)benzonitrile (3af).

General procedure D was followed using 1d (0.165 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.215 g (63%) of the title compound (keto:dihydrate = 8.55:1) as colorless solid (mp = 89–91 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.35 (d, J = 7.6 Hz, 2H), 7.85 (dd, J = 8.2, 1.3 Hz, 2H), 7.49 (t, J = 2.0 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.33 – 7.28 (m, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.1 (t, ²J_C-F2 = 35.2 Hz), 143.9, 133.5, 132.5, 132.4, 130.7, 130.6, 128.0, 127.9, 123.9, 118.0, 117.3, 115.2 (t, ¹J_C-F2 = 280.9 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ −74.6 (s, 2F, keto) and −87.1 (s, 2F, dihydrate 5, see page S79). IR (film) 2918, 1731, 1583, 1476, 1287, 1218, 1163, 925, 868, 772, 603, 518 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₈Cl₂F₂NO₂ [M + H]⁺, 341.9895; found 341.9893.

1-([1,1’-Biphenyl]-4-yl)-2-(2,4-dichlorophenoxy)-2,2-difluoroethanone (3ag).

General procedure D was followed using 1g (0.216 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.196 g (50%) the title compound as yellow solid (mp = 62–64 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 7.7 Hz, 3H), 7.34 – 7.27 (m, 2H), 7.17 – 7.15 (m, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.8 (t, J = 34.0 Hz), 147.7, 144.5, 139.3, 132.2, 131.2 (t, J = 1.9 Hz), 130.6, 129.3, 129.1, 128.7, 127.9, 127.4, 127.3, 124.0, 115.9 (t, J = 289.8 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ −74.1 (s, 2F). IR (film) 2922, 1710, 1603, 1557, 1474, 1383, 1251, 1171, 937, 864, 750, 571 cm⁻¹. HRMS (APCI)⁺ m/z: calcd, C₂₀H₁₃Cl₂F₂O₂ [M + H]⁺, 393.0255; found 393.0249.

1-(3-(Benzyloxy)phenyl)-2-(2,4-dichlorophenoxy)-2,2-difluoroethanone (3ah).

General procedure B was followed using 1h (0.246 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 120 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.245 g (58%) the title compound as pale-yellow solid (mp = 42–44 °C). ¹H NMR (500 MHz, CDCl₃) δ 7.81 (dt, J = 7.8, 2.2 Hz, 1H), 7.74 (t, J = 2.9 Hz, 1H), 7.40 (dd, J = 2.6, 1.1 Hz, 1H), 7.39 – 7.34 (m, 3H), 7.33 – 7.23 (m, 4H), 7.22 – 7.21 (m, 1H), 7.20 – 7.19 (m, 1H), 5.07 (s, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 182.1 (t, ²J_C-F2 = 34.0 Hz), 158.9, 144.5 (t, ³J_C-F2 = 1.9 Hz), 136.2, 132.2, 131.8, 130.6, 129.9, 128.7, 128.2, 128.1, 127.9, 127.5, 123.9, 123.5 (t, ³J_C-F2 = 1.9 Hz), 122.5, 115.7 (t, ¹J_C-F2 = 280.9 Hz), 115.6, 70.3. ¹⁹F NMR (469 MHz, CDCl₃) δ −74.0 (s, 2F). IR (film) 2930, 1713, 1595, 1473, 1382, 1293, 1140, 959, 867, 750, 653, 572 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₂₁H₁₅Cl₂F₂O₃ [M + H]⁺, 423.0361; found 423.0367.

3-(2-(2,4-Dichlorophenoxy)-2,2-difluoroacetyl)benzonitrile (3ai).

General procedure D was followed using 1i (0.165 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.177 g (52%) the title compound as colorless solid (mp = 94–96 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.56 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.98 – 7.96 (m, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.32 – 7.30 (m, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 180.5 (t, ²J_C-F2 = 34.6 Hz), 143.9, 137.5, 134.1 (d, J = 13.8 Hz), 132.6, 131.3, 130.6, 129.8, 128.0, 127.9, 124.0, 117.2, 115.2 (t, ¹J_C-F2 = 280.9 Hz), 113.5. ¹⁹F NMR (469 MHz, CDCl₃) δ −74.3 (s, 2F). IR (film) 1724, 1475, 1275, 1260, 1223, 1167, 1098, 764, 750 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₈Cl₂F₂NO₂ [M + H]⁺, 341.9895; found 341.9898.

2-(2,4-Dichlorophenoxy)-2,2-difluoro-1-(3-nitrophenyl)ethanone (3aj).

General procedure D was followed using 1j (0.185 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.257 g (71%) the title compound as colorless solid (mp = 73–75 °C). ¹H NMR (500 MHz, CDCl₃) δ 9.15 (s, 1H), 8.58 – 8.55 (m, 2H), 7.80 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.32 – 7.30 (m, 1H). ¹³C{¹H} NMR (201 MHz, CDCl₃) δ 180.5 (t, ²J_C-F2 = 35.1 Hz), 148.3, 143.9, 135.7, 132.7, 131.8, 130.7, 130.1, 129.0, 128.1, 128.0, 125.4, 124.3, 115.3 (t, ¹J_C-F2 = 280.4 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ −74.7 (s, 2F). IR (film) 2920, 1536, 1475, 1350, 1098, 851, 712, 579, 494, 455 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₄H₈Cl₂F₂NO₄ [M + H]⁺, 361.9793; found 361.9788.

Ethyl-3-(3-(2-(2,4-dichlorophenoxy)-2,2-difluoroacetyl)phenyl)acrylate (3ak).

General procedure D was followed using 1k (0.238 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.210 g (51%) the title compound as yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 16.0 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.31 – 7.29 (m, 1H), 6.54 (d, J = 16.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (201 MHz, CDCl₃) δ 181.8 (t, ²J_C-F2 = 35.1 Hz), 166.3, 144.3, 142.6, 135.3, 133.8, 132.3, 131.6, 131.2, 130.6, 129.7, 129.4, 127.9, 123.9, 120.3, 115.3 (t, ¹J_C-F2 = 279.4 Hz), 60.7, 14.2. ¹⁹F NMR (469 MHz, CDCl₃) δ −74.0 (s, 2F). IR (film) 2918, 1717, 1475, 1310, 1091, 868, 712, 629, 494, 474, 454 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₉H₁₅Cl₂F₂O₄ [M + H]⁺, 415.0310; found 415.0313.

1-(4’-(Tert-butyl)-[1,1’-biphenyl]-2-yl)-2-(2,4-dichlorophenoxy)-2,2-difluoroethanone (3al).

General procedure C was followed using 1l (0.272 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 120 °C for 30 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.250 g (56%) the title compound as yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.39 – 8.36 (m, 1H), 8.15 – 8.09 (m, 1H), 7.84 – 7.81 (m, 1H), 7.55 – 7.49 (m, 3H), 7.45 – 7.41 (m, 3H), 7.34 – 7.31 (m, 1H), 7.27 – 7.20 (m, 1H), 1.30 (s, 9H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 182.3 (t, ²J_C-F2 = 34.0 Hz), 164.1, 151.2, 151.1, 146.0, 144.5, 141.9, 141.7, 136.8, 136.7, 133.5, 132.5, 132.2, 131.9, 131.1, 130.6, 130.2, 129.2, 129.1, 129.0, 128.98, 128.91, 128.8, 128.1, 128.05, 128.01, 127.9, 126.8, 126.0, 125.9, 124.7, 124.1, 115.9 (t, ¹J_C-F2 = 280.9 Hz), 34.6, 31.3. ¹⁹F NMR (376 MHz, CDCl₃) δ −74.1 (s, 2F). IR (film) 2962, 1714, 1599, 1474, 1385, 1251, 1163, 1036, 948, 862, 753, 581 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₂₄H₂₁Cl₂F₂O₂ [M + H]⁺, 449.0881; found 449.0876.

2-(2,4-Dichlorophenoxy)-2,2-difluoro-1-(1-phenyl-1H-pyrazol-4-yl)ethanone (3am).

General procedure A was followed using 1m (0.206 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.290 g (76%) of the title compound as yellow solid (mp = 109–111 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.76 (s, 1H), 8.42 (s, 1H), 7.78 – 7.75 (m, 2H), 7.56 – 7.50 (m, 3H), 7.46 – 7.39 (m, 2H), 7.33 – 7.29 (m, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 176.5 (t, ²J_C-F2 = 35.9 Hz), 144.4, 143.1, 138.8, 132.3, 131.8 (t, ³J_C-F2 = 1.9 Hz), 130.6, 129.7, 129.5, 128.3, 128.0, 127.9, 124.0, 119.9, 119.3, 118.3, 115.5 (t, ¹J_C-F2 = 279.7 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ −77.1 (s, 2F). IR (film) 3074, 1698, 1599, 1504, 1474, 1384, 1292, 1165, 950, 852, 757, 569 cm⁻¹. HRMS (ESI)⁺ m/z: calcd C₁₇H₁₀Cl₂F₂N₂O₂Na [M + Na]⁺, 404.9985; found 404.9999.

2-(2,4-dichlorophenoxy)-2,2-difluoro-1-(1-tosyl-1H-indol-3-yl)ethanone (3an).

General procedure A was followed using 1n (0.333 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.411 g (81%) of the title compound as yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.84 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 2.5 Hz, 1H), 7.48 – 7.42 (m, 3H), 7.34 – 7.33 (m, 3H), 2.41 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 177.9 (t, ²J_C-F2 = 35.2 Hz), 146.4, 144.5, 135.9 (t, ³J_C-F2 = 4.4 Hz), 134.4, 134.1, 132.3, 130.6, 130.4, 128.1, 127.9, 127.7, 127.3, 126.3, 125.4, 124.1, 122.8, 115.5 (t, ¹J_C-F2 = 280.3 Hz), 114.0, 113.2, 21.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −75.6 (s, 2F). IR (film) 3151, 1693, 1596, 1532, 1475, 1383, 1266, 1146, 974, 882, 750, 572 cm⁻¹. HRMS (ESI)⁺ m/z: calcd C₂₃H₁₆Cl₂F₂NO₄S [M + H]⁺, 510.0145; found 510.0146.

1-(Dibenzo[b,d]thiophen-4-yl)-2-(2,4-dichlorophenoxy)-2,2-difluoroethanone (3ao).

General procedure B was followed using 1o (0.246 g, 1.00 mmol), 2u (0.489 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run tube at 120 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.269 g (64%) the title compound as yellow solid (mp = 150–152 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.63 (d, J = 7.8 Hz, 1H), 8.50 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.55 – 7.53 (m, 2H), 7.49 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.31 – 7.29 (m, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.2 (t, ²J_C-F2 = 34.0 Hz), 155.4, 144.4, 142.1, 141.3, 137.5, 133.5, 132.1, 131.2, 130.5, 128.0, 127.9, 127.7, 127.5, 124.8, 124.5, 124.0, 123.9, 122.8, 121.3, 115.8 (t, ¹J_C-F2 = 280.3 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ −72.6 (s, 2F). IR (film) 2918, 1693, 1474, 1381, 1224, 1090, 1023, 966, 887, 712, 629, 494 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₂₀H₁₁Cl₂F₂O₂S [M + H]⁺, 422.9819; found 422.9821.

2,2-Difluoro-1-(4-methoxyphenyl)-2-phenoxyethanone (3ba).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2a (0.282 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 36 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.144 g (52%) the title compound as yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 8.8 Hz, 2H), 7.42 – 7.39 (m, 2H), 7.30 – 7.26 (m, 3H), 7.04 – 7.01 (m, 2H), 3.93 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.6 (t, ²J_C-F2 = 34.5 Hz), 164.8, 149.7, 133.0 (t, ³J_C-F2 = 1.9 Hz), 132.2, 129.6, 129.4, 126.0, 123.8, 122.7, 121.8, 121.3, 116.0 (t, ¹J_C-F2 = 277.2 Hz), 114.1, 55.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.7 (s, 2F). IR (film) 2917, 1700, 1699, 1573, 1490, 1337, 1269, 1087, 932, 831, 688, 561 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₁₃F₂O₃ [M + H]⁺, 279.0833; found 279.0836.

2,2-Difluoro-1-(4-methoxyphenyl)-2-(4-nitrophenoxy)ethanone (3bb).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2b (0.417 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.260 g (81%) the title compound as yellow solid (mp = 57–59 °C).

¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 9.1 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 3.95 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 180.5 (t, ²J_C-F2 = 34.0 Hz), 165.2, 154.5 (t, ³J_C-F2 = 1.9 Hz), 145.2, 132.9 (t, ³J_C-F2 = 2.3 Hz), 125.6, 123.3 (d, ³J_C-F2 = 2.5 Hz), 121.4 (t, ³J_C-F2 = 1.9 Hz), 115.9 (t, ¹J_C-F2= 280.49 Hz), 114.3, 55.7. ¹⁹F NMR (469 MHz, CDCl₃) δ −74.1 (s, 2F). IR (film) 1702, 1600, 1526, 1491, 1348, 1274, 1214, 1166, 1026, 936, 848, 749 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₁₂F₂NO₅ [M + H]⁺, 324.0684; found 324.0689.

2-(4-Bromophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3bc).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2c (0.519 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 36 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.268 g (75%) the title compound as yellow solid (mp = 29–31 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.16 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.9 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.01 – 6.98 (m, 2H), 3.91 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.0 (t, ²J_C-F2 = 34.0 Hz), 164.8, 148.8, 132.8, 132.6, 123.4, 123.0, 119.2, 115.8 (t, ¹J_C-F2 = 264.6 Hz), 114.1, 55.4. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.9 (s, 2F). IR (film) 2939, 1693, 1572, 1483, 1320, 1266, 1150, 1061, 931, 848, 799, 555 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₁₂BrF₂O₃ [M + H]⁺, 356.9932; found 356.9929.

2,2-Difluoro-2-(4-methoxyphenoxy)-1-(4-methoxyphenyl)ethanone (3bd).

General procedure E was followed using 1b (0.170 g, 1.00 mmol), 2d (0.373 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 36 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.137 g (42%) the title compound as pale-yellow solid (mp = 36–38 °C). ¹H NMR (500 MHz, CDCl₃) δ 8. 22 (d, J = 9.0 Hz, 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.91 – 6.90 (m, 2H), 3.93 (s, 3H), 3.83 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.7 (t, ²J_C-F2 = 34.5 Hz), 164.7, 157.6, 142.9, 133.0 (t, ³J_C-F2 = 1.9 Hz), 123.9, 122.7, 116.0 (t, ¹J_C-F2 = 239.4 Hz), 114.5, 114.0, 55.63, 55.60. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.9 (s, 2F). IR (film) 2922, 1786, 1275, 899, 764, 749, 548, 520, 497, 483, 454 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₆H₁₄F₂O₄ [M]⁺, 308.0860; found 308.0865.

2,2-Difluoro-1-(4-methoxyphenyl)-2-(4-(methylthio)phenoxy)ethanone (3be).

General procedure D was followed using 1b (0.170 g, 1.00 mmol), 2e (0.421 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.170 g (53%) the title compound as colorless liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J = 9.0 Hz, 2H), 7.26 – 7.24 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.04 – 6.95 (m, 2H), 3.91 (s, 3H), 2.48 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.42 (t, ²J_C-F2 = 34.4 Hz)., 164.7, 147.1, 136.1, 132.9, 127.8, 123.6, 121.8, 115.8 (t, ¹J_C-F2 = 276.6 Hz), 114.0, 55.5, 16.1. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.9 (s, 2F). IR (film) 2925, 1662, 1597, 1490, 1370, 1266, 1171, 1096, 982, 758, 648 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₆H₁₅F₂O₃S [M + H]⁺, 325.0705; found 325.0703.

2-(4-(Tert-butyl)phenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3bf).

General procedure D was followed using 1b (0.170 g, 1.00 mmol), 2f (0.450 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.153 g (46%) the title compound as colorless solid (mp = 57–59 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 3.91 (s, 3H), 1.32 (s, 9H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.6 (t, ²J_C-F2 = 34.5 Hz), 164.7, 148.9, 147.2 132.9, 126.4, 123.7, 120.7, 115.9 (t, ¹J_C-F2 = 277.2 Hz), 113.9, 55.5, 34.3, 31.2. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.7 (s, 2F). IR (film) 2962, 1701, 1599, 1508, 1462, 1364, 1266, 1168, 934, 842, 760, 568 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₉H₂₁F₂O₃ [M + H]⁺, 335.1453; found 335.1448.

2-([1,1’-Biphenyl]-4-yloxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3bg).

General procedure E was followed using 1b (0.170 g, 1.00 mmol), 2g (0.511 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol) and 1,2-DCB (4.0 mL). The reaction was run at 140 °C for 36 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.198 g (56%) the title compound as yellow solid (mp = 68–70 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J = 8.8 Hz, 2H), 7.62 – 7.55 (m, 4H), 7.46 (t, J = 7.6 Hz, 2H), 7.39 – 7.33 (m, 3H), 7.05 – 6.98 (m, 2H), 3.91 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.4 (t, ²J_C-F2 = 34.0 Hz), 164.8, 149.0, 139.9, 139.1, 132.9, 128.7, 128.2, 127.4, 126.9, 123.7, 121.4, 115.9 (t, ¹J_C-F2 = 277.2 Hz), 114.0, 55.5. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.9 (s, 2F). IR (film) 2918, 1701, 1600, 1512, 1427, 1337, 1259, 1150, 1028, 847, 759, 554 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₂₁H₁₇F₂O₃ [M + H]⁺, 355.1140; found 355.1138.

2,2-Difluoro-1-(4-methoxyphenyl)-2-(4-methyl-3-nitrophenoxy)ethanone (3bh).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2h (0.460 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.276 g (82%) the title compound yellow solid (mp = 82–84 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J = 9.0 Hz, 2H), 7.94 (t, J = 1.8 Hz, 1H), 7.47 – 7.45 (m, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.05 – 7.03 (m, 2H), 3.95 (s, 3H), 2.64 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 180.7 (t, ²J_C-F2 = 33.4 Hz), 165.1, 149.2, 147.8 (t, ³J_C-F2 = 2.3 Hz), 133.8, 133.0 (t, ³J_C-F2 = 2.3 Hz), 131.5, 126.0, 123.4, 117.8, 115.9 (t, ¹J_C-F2 = 277.2 Hz), 114.2, 55.7, 20.0. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.8 (s, 2F). IR (film) 3097, 1694, 1599, 1424, 1333, 1215, 1130, 1026, 947, 849, 746, 571 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₆H₁₄F₂NO₅ [M + H]⁺, 338.0840; found 338.0838.

2-(3-Chlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3bi).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2i (0.386 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.268 g (86%) the title compound yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J = 8.9 Hz, 2H), 7.36 – 7.33 (m, 2H), 7.29 – 7.27 (m, 1H), 7.22 – 7.20 (m, 1H), 7.05 – 7.02 (m, 2H), 3.95 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.0 (t, ²J_C-F2 = 34.6 Hz), 164.9, 150.1, 134.9, 133.0 (t, ³J_C-F2 = 1.9 Hz), 130.4, 126.3, 123.6, 121.8, 119.5, 115.8 (t, ¹J_C-F2 = 279.0 Hz), 114.2, 55.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.9 (s, 2F). IR (film) 1700, 1599, 1473, 1314, 1266, 1165, 1027, 937, 841, 765, 676 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₁₂ClF₂O₃ [M + H]⁺, 313.0443; found 313.0438.

2,2-Difluoro-2-(3-iodophenoxy)-1-(4-methoxyphenyl)ethanone (3bj).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2j (0.660 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.322 g (80%) the title compound yellow semisolid. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J = 9.0 Hz, 2H), 7.66 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.29 – 7.27 (m, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.03 – 7.01 (m, 2H), 3.93 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.0 (t, ²J_C-F2 = 34.0 Hz), 164.9, 149.9, 135.2, 133.0 (t, ³J_C-F2 = 2.3 Hz), 130.9, 130.4, 123.6, 120.7, 115.8 (t, ¹J_C-F2 = 278.4 Hz), 114.2, 93.7, 55.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.8 (s, 2F). IR (film) 2934, 1699, 1599, 1467, 1335, 1266, 1165, 1083, 996, 838, 763, 574 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₁₂F₂IO₃ [M + H]⁺, 404.9799; found 404.9781.

2,2-Difluoro-1-(4-methoxyphenyl)-2-(3-(trifluoromethoxy)phenoxy)ethanone (3bk).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2k (0.535 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.293 g (81%) the title compound yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J = 8.5 Hz, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.17 – 7.15 (m, 2H), 7.04 – 7.02 (m, 2H), 3.94 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.0 (t, ²J_C-F2 = 33.3 Hz), 165.0, 150.3 (t, ³J_C-F2 = 1.9 Hz), 149.6 (dd, ³J_C-F3 = 3.8, 1.9 Hz), 133.0 (t, ³J_C-F2 = 1.9 Hz), 130.5, 123.6, 120.3 (q, ¹J_C-F3 = 259.5 Hz), 119.5, 118.3, 115.9 (t, ¹J_C-F2 = 292.3 Hz), 114.5, 114.2, 55.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.9 (s, 2F), −58.2 (s, 3F). IR (film) 2939, 1702, 1600, 1573, 1463, 1336, 1253, 1162, 978, 844, 770, 548 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₆H₁₂F₅O₄ [M + H]⁺, 363.0656; found 363.0648.

2-(3-Chloro-2-fluorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3bl).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2l (0.440 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.277 g (84%) the title compound yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.27 (d, J = 7.0 Hz, 2H), 7.38 – 7.34 (m, 2H), 7.16 – 7.12 (m, 1H), 7.06 – 7.04 (m, 2H), 3.95 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 180.8 (t, ²J_C-F2 = 33.3 Hz), 165.0, 151.3 (d, ¹J_C-F = 253.2 Hz), 137.8 (d, ²J_C-F = 12.6 Hz), 133.1 (t, ³J_C-F2 = 1.9 Hz), 128.4, 124.2 (d, ³J_C-F = 5.0 Hz), 123.5, 123.0, 122.6 (d, ²J_C-F = 16.0 Hz), 115.8 (t, ¹J_C-F2 = 280.3 Hz), 114.2, 55.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −129.3 (s, F), −74.6 (s, 2F). IR (film) 2936, 1701, 1599, 1513, 1460, 1316, 1266, 1163, 942, 843, 766, 573 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₁₁ClF₃O₃ [M + H]⁺, 331.0349; found 331.0342.

3-(3-(1,1-Difluoro-2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)acrylic acid (3bm).

General procedure F was followed using 1b (0.170 g, 1.00 mmol), 2m (0.492 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), K₂CO₃ (0.028 g, 0.20 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 36 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.215 g (56%) the title compound colorless solid (mp = 148–150 °C). ¹H NMR (500 MHz, DMSO-d₆) δ 12.51 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.71 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 16.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 16.0 Hz, 1H), 3.87 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.0 (t, ²J_C-F2 = 33.3 Hz), 167.7, 165.3, 149.5, 142.7, 136.8, 133.3, 130.8, 126.8, 123.4, 122.9, 121.5, 121.3, 115.9 (t, ¹J_C-F2 = 276.0 Hz), 115.1, 56.1. ¹⁹F NMR (469 MHz, DMSO-d₆) δ −72.4 (s, 2F). IR (film) 2918, 1693, 1578, 1414, 1232, 1212, 1139, 1075, 854, 775, 652, 587 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₈H₁₅F₂O₅ [M + H]⁺, 349.0882; found 349.0878.

5-Bromo-2-(1,1-difluoro-2-(4-methoxyphenyl)-2-oxoethoxy)benzoic acid (3bn).

General procedure F was followed using 1b (0.170 g, 1.00 mmol), 2n (0.652 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), K₂CO₃ (0.028 g, 0.20 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 36 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.221 g (55%) the title compound colorless solid (mp = 124–126 °C). ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.11 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 2.6 Hz, 1H), 7.64 – 7.61 (m, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.90 – 6.88 (m, 2H), 3.79 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 180.8 (t, ²J_C-F2 = 34.0 Hz), 168.0, 165.0, 148.1 (t, ³J_C-F2 = 2.2 Hz), 137.1, 135.3, 133.1 (t, ³J_C-F2 = 2.2 Hz), 125.0, 124.5, 123.4, 119.2, 115.9 (t, ¹J_C-F2 = 289.0 Hz), 114.1, 55.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −72.3 (s, 2F). IR (film) 3337, 2965, 2079, 1719, 1632, 1408, 1101, 1018, 748, 626, 548, 469 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₆H₁₂BrF₂O₅ [M + H]⁺, 400.9831; found 400.9825.

4-Bromo-2-(1,1-difluoro-2-(4-methoxyphenyl)-2-oxoethoxy)benzaldehyde (3bo).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2o (0.603 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 36 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.253 g (66%) the title compound pale-yellow (mp = 74–76 °C). ¹H NMR (400 MHz, CDCl₃) δ 10.19 (s, 1H), 8.08 (d, J = 9.1 Hz, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 3.0, 1.5 Hz, 1H), 7.46 (ddd, J = 8.3, 1.7, 0.8 Hz, 1H), 6.96 – 6.92 (m, 2H), 3.85 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 187.2, 180.2 (t, ²J_C-F2 = 33.5 Hz), 165.2, 151.8, 132.9 (t, ³J_C-F2 = 2.2 Hz), 129.9, 129.8, 129.6, 127.2, 124.9 (t, ³J_C-F2 = 2.0 Hz), 123.2, 115.9 (t, ¹J_C-F2 = 280.0 Hz), 114.4, 55.7. ¹⁹F NMR (376 MHz, CDCl₃) δ −73.1 (s, 2F). IR (film) 2924, 1724, 1567, 1474, 1320, 1213, 1100, 100, 870, 764, 662, 548 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₆H₁₂BrF₂O₄ [M + H]⁺, 384.9887; found 384.9872.

2-(2-Chlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3bp).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2p (0.385 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 36 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.218 g (70%) the title compound yellow solid (mp = 36–38 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.27 (d, J = 8.8 Hz, 2H), 7.47 – 7.44 (m, 2H), 7.29 (td, J = 8.1, 1.5 Hz, 1H), 7.20 (td, J = 7.7, 1.2 Hz, 1H), 7.01 – 6.99 (m, 2H), 3.91 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.0 (t, ²J_C-F2 = 33.3 Hz), 164.8, 145.7, 133.1, 130.7, 127.6, 126.89, 126.85, 123.5, 123.0, 115.9 (t, ¹J_C-F2 = 279.7 Hz), 114.0, 55.5. ¹⁹F NMR (469 MHz, CDCl₃) δ −73.6 (s, 2F). IR (film) 2939, 1699, 1599, 1475, 1315, 1265, 1152, 1059, 933, 851, 790, 568 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₁₂ClF₂O₃ [M + H]⁺, 313.0438; found 313.0442.

2,2-Difluoro-1-(4-methoxyphenyl)-2-(perfluorophenoxy)ethanone (3bq).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2q (0.552 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.283 g (77%) the title compound colorless solid (mp = 82–84 °C). ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 179.3 (t, ²J_C-F2 = 31.6 Hz), 165.1, 143.6 – 143.5 (m), 141.6 – 141.1 (m), 139.02 (dt, J = 24.5, 12.9 Hz), 136.9 – 136.6 (m), 123.3 (t, J = 13.5 Hz), 122.9, 115.7 (t, ¹J_C-F2 = 276.0 Hz), 114.1, 55.4. ¹⁹F NMR (469 MHz, CDCl₃) δ −75.4 (t, J = 10.2 Hz, 2F), −150.7 – −150.8 (m, 2F), −156.18 (t, J = 21.3 Hz, 1F), −161.9 – −161.0 (m, 2F). IR (film) 2941, 1703, 1649, 1576, 1467, 1365, 1268, 1163, 993, 845, 750, 547 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₅H₈F₇O₃ [M + H]⁺, 369.0362; found 369.0344.

4-(1,1-Difluoro-2-(4-methoxyphenyl)-2-oxoethoxy)-3-methoxybenzaldehyde (3br).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2r (0.456 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 60 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.170 g (50%) the title compound yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 9.92 (s, 1H), 8.28 (d, J = 8.8 Hz, 2H), 7.49 − 7.43 (m, 3H), 7.01 − 6.91 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 190.8, 181.0 (t, ²J_C-F2 = 33.3 Hz), 164.8, 152.4, 143.3, 134.9, 133.1, 124.4, 123.48, 123.40, 115.9 (t, ¹J_C-F2 = 279.7 Hz), 113.9, 110.8, 55.9, 55.5. ¹⁹F NMR (469 MHz, CDCl₃) δ –74.0 (s, 2F). IR (film) 2917, 1698, 1575, 1465, 1389, 1268, 1117, 1027, 865, 763, 630, 563 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₇H₁₅F₂O₅ [M + H]⁺, 337.0882; found 337.0878.

2-(5-Chloro-2-(2,4-dichlorophenoxy)phenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3bs).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2s (0.869 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.406 g (86%) the title compound yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 1.1 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.22 – 7.16 (m, 2H), 6.92 – 6.89 (m, 2H), 6.86 – 6.81 (m, 2H), 3.88 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 180.7 (t, ²J_C-F2 = 33.3 Hz), 164.9, 150.8, 147.1, 140.3, 133.1, 132.4, 130.5, 129.6, 129.3, 128.1, 127.4, 126.8, 125.9, 124.7, 123.4, 120.2, 120.1, 115.9 (t, ¹J_C-F2 = 280.9 Hz), 114.0, 113.8, 55.6. ¹⁹F NMR (469 MHz, CDCl₃) δ −74.3 (s, 2F). IR (film) 2917, 1701, 1574, 1472, 1315, 1219, 1121, 1027, 937, 841, 738, 586 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₂₁H₁₄Cl₃F₂O₄ [M + H]⁺, 472.9926; found 472.9903.

(4bS,8aS,9S)-Ethyl-3-(1,1-difluoro-2-(4-methoxyphenyl)-2-oxoethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-arboxylate (3bt) (mixture of rotamers).

General procedure A was followed using 1b (0.170 g, 1.00 mmol), 2s (0.869 g, 3.00 mmol), CuCl₂ (0.027 g, 0.20 mmol), terpyridine (0.023 g, 0.10 mmol), 1,2-DCB (3.0 mL) and DMSO (1.0 mL). The reaction was run at 100 °C for 24 h. Evaporation of the solvent followed by reverse phase chromatographic purification using 100 gram HP GOLD C18 column with gradient elution from 98% H₂O (with 0.1% acetic acid) in MeCN to 100% MeCN, provided 0.348 g (70%) the title compound as yellow liquid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.14 (d, J = 8.9 Hz, 2H), 7.22 – 7.08 (m, 5H), 4.08 – 4.05 (m, 2H), 3.90 (s, 3H), 3.78 – 3.75 (m, 1H), 3.16 (s, 1H), 3.07 (dd, J = 18.4, 6.0 Hz, 1H), 2.64 (d, J = 18.5 Hz, 1H), 2.41 (s, 1H), 2.27 (s, 1H), 1.64 – 1.49 (m, 3H), 1.44 (t, J = 13.2 Hz, 2H), 1.35 – 1.23 (m, 3H), 1.19 (t, J = 6.9 Hz, 3H), 1.08 – 1.03 (m, 1H), 0.93 – 0.88 (m, 1H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 181.6 (t, ²J_C-F2 = 34.6 Hz), 165.3, 155.1, 148.4, 141.3, 137.7, 134.9, 133.0, 132.2, 129.8, 129.2, 128.5, 125.6, 123.6, 119.2, 118.5, 116.4 (t, ¹J_C-F2 = 275.3 Hz), 115.0, 114.6, 61.0, 56.2, 49.7, 43.5, 41.2, 38.1, 37.6, 36.1, 31.5, 26.5, 26.1, 22.0, 21.3, 14.9. ¹⁹F NMR (469 MHz, DMSO-d₆) δ −73.3 (s, 2F). IR (film) 2929, 1689, 1599, 1512, 1462, 1375, 1265, 1164, 936, 883, 732, 577 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₂₈H₃₂F₂NO₅ [M + H]⁺, 500.2243; found 500.2249.

4-(2-(2,4-dichlorophenoxy)-2,2-difluoro-1,1-dihydroxyethyl)benzonitrile (5).

4-(2-(2,4-Dichlorophenoxy)-2,2-difluoroacetyl)benzonitrile 3af (0.034 g, 0.10 mmol, 1.0 equiv.), was taken in a NMR tube and dissolved that in acetonitrile-d₃ (0.5 mL) and then water (2.0 μL, 10.0 equiv.) was added. After 12 h NMR was recorded. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J = 8.5 Hz, 2H), 7.79 – 7.72 (m, 2H), 7.47 (d, J = 2.2 Hz, 1H), 7.31 – 7.24 (m, 2H), 5.38 (s, 2H, D₂O Exchangable). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 144.5, 143.1, 131.5, 130.1, 128.6, 127.9, 127.7, 124.2, 121.3 (t, ¹J_C-F2= 279.4 Hz), 118.3, 117.2, 112.6, 93.8 (t, ²J_C-F2 = 30.8 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ −87.0 (s, 2F).

Ethyl-4-(2,4-dichlorophenoxy)-4,4-difluoro-3-(4-methoxyphenyl)but-2-enoate (6).

An oven-dried 25 mL round-bottom flask, equipped with a magnetic stir bar, was charged with NaH (60% dispersion in mineral oil) (0.010 g, 0.40 mmol, 2.0 equiv.) and was then evacuated and back-filled with nitrogen for 3 times. Dry THF (5.0 mL) was added to the round-bottom flask, and the flask was placed in an ice bath. After 10 min, triethylphosphonoacetate (0.040 mL, 0.22 mmol, 1.1 equiv.) was added dropwise, and the reaction was stirred for 1 h in the ice bath. Then, 2-(2,4-dichlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethenone (3ab, 0.105 g, 0.20 mmol, 1.0 equiv.) was dissolved dry THF (5.0 mL) and added dropwise to the reaction, and the mixture was stirred for 4 h at 0 °C. Then, the round-bottom flask was removed from the ice bath and stirred for 12 h. TFT (6.0 μL) was added via microsyringe. The solution was diluted with diethylether (1 mL) and then stirred at rt for 10 min to allow adequate mixing. After mixing, an aliquot was removed from the round-bottom flask and passed through a pad of silica gel using diethylether as eluent into an NMR tube and was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis then returned to the round-bottom flask. A saturated NH₄Cl solution (50 mL) was added, and the layers were separated. The aqueous layer was extracted with diethylether (3 X 20 mL). The combined organic layers were at washed with brine (1 X 20 mL), dried over Na₂SO₄, concentrated in vacuo. The residue was purified by silica gel (60 Å) flash chromatography using EtOAc and hexanes (1:7) to provide 0.079 g (95%) of the title compound as yellow liquid. ¹H NMR (500 MHz, CDCl₃) (mixture of Z (major) and E (minor)) δ 7.41 (d, J = 8.5 Hz, 1H, minor), 7.35 (d, J = 2.5 Hz, 1H, major), 7.31 (d, J = 9.0 Hz, 2H, minor), 7.24 (d, J = 8.5 Hz, 2H, major), 7.20 (s, 1H, minor), 7.18 (s, 1H, major), 7.14 (d, J = 2.5 Hz, 1H, major), 7.12 (d, J = 2.5 Hz, 1H, minor), 6.87 – 6.83 (m, 2H, major + minor), 6.68 (s, 1H, major), 6.22 (s, 1H, minor), 4.21 (q, J = 7.1 Hz, 2H, minor), 4.01 (q, J = 7.1 Hz, 2H, major), 3.76 (s, 3H, major + minor), 1.24 (t, J = 7.2 Hz, 3H, minor), 1.05 (q, J = 7.2 Hz, 3H, major). ¹³C{¹H} NMR (126 MHz, CDCl₃) (mixture of E and Z) δ 165.2, 164.8, 144.7, 144.5 (t, ²J_C-F2 = 29.5 Hz), 139.5 (t, ²J_C-F2 = 30.5 Hz), 131.5, 130.3, 130.2, 129.4, 128.4, 128.2, 127.6, 126.7, 124.5, 124.1, 124.0, 123.5 (t, ³J_C-F2 = 5.0 Hz), 120.8 (t, ¹J_C-F2 = 268.3 Hz), 113.6, 113.3, 61.3, 60.7, 55.2, 55.1, 13.9, 13.8. ¹⁹F NMR (469 MHz, CDCl₃) (mixture of E and Z) δ −64.0 (s, 2F, minor), −74.3 (s, 2F, major). IR (film) 2917, 1731, 1657, 1576, 1474, 1382, 1274, 1175, 1094, 867, 785, 569 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₁₉H₁₆Cl₂F₂O₄ [M + H]⁺, 417.0467; found 417.0461.

2-(2,4-Dichlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanol (7).

An oven-dried 25 mL round-bottom flask, equipped with a magnetic stir bar, was evaluated and back-filled with N₂, and then charged with 2-(2,4-dichlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3ab, 0.105 g, 0.30 mmol, 1.0 equiv.) and dry ethanol (5.0 mL). Then, the round-bottom flask was placed in an ice bath and allowed to cool for 30 min. Then NaBH₄ (0.023 g, 0.60 mmol, 2.0 equiv.) was added in small portions and allowed to stir for more 2 h. The round-bottom flask was taken out from ice bath and allowed to warm to rt, and TFT (6.0 μL) was added via microsyringe. The reaction mixture was diluted with DCM (1 mL), and the mixture was then stirred at rt for 10 min to allow adequate mixing. An aliquot was removed from the round-bottom flask and passed through a pad of silica gel using DCM as eluent into an NMR tube and was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis then returned to the round-bottom flask. The solvents were evaporated by using BioChromato Smart Evaporator. Water (50 mL) was added to the residue, and the aqueous layer was extracted with DCM (3 X 20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel (60 Å) flash chromatography using EtOAc and hexanes (1:30) to provide 0.084 g (80%) of the title compound as colorless liquid. ¹H NMR (500 MHz, CDCl₃) δ 7.49 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 2.4 Hz, 1H), 7.26 – 7.18 (m, 2H), 6.94 – 6.93 (m, 2H), 5.10 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H), 2.94 (s, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 160.0, 144.6, 131.4, 130.1, 129.0, 128.1, 127.6, 126.8, 123.8, 122.6 (t, ¹J_C-F2 = 275.6 Hz), 113.6, 73.8 (t, ²J_C-F2 = 30.8 Hz), 55.1. ¹⁹F NMR (469 MHz, CDCl₃) δ −82.9 (dd, J = 404.0, 139.0 Hz). IR (film) 2918, 1716, 1586, 1475, 1386, 1271, 1177, 1073, 854, 766, 687, 569 cm⁻¹. HRMS (APCI)⁻ m/z: calcd C₁₅H₁₁Cl₂F₂O₃ [M – H]⁻, 347.0048; found 347.0043.

N-(2-(2,4-Dichlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethyl)-4-methoxyaniline (8).

An oven-dried 25 mL round-bottom flask, equipped with a magnetic stir bar, was charged with 2-(2,4-dichlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethanone (3ab, 0.105 g, 0.30 mmol, 1.0 equiv.), p-anisidine (0.045 g, 0.38 mmol, 1.25 equiv.), PTSA (0.0060 g, 0.03 mmol, 0.1 equiv. and then the vessel was attached to reflux condenser and a Schlenk line. The whole system was evacuated and back-filled with N_2(g) three times. Dry EtOH (5.0 mL) was added to the round-bottom flask, and the vessel was placed in a pre-heated oil bath at 80 °C. After 36 h, the round-bottom flask was taken removed from the oil bath and allowed to cool to room temperature. Then, the round-bottom flask was placed in an ice bath. After 15 min, NaBH₄ (0.023 g, 0.60 mmol) was added in eight portions over 15 min and allowed to stir for 2 h. The round-bottom flask was taken out of the ice bath and allowed to warm to rt. TFT (6.0 μL) was added via microsyringe. The solution was diluted with DCM (1.0 mL) and then stirred at rt for 10 min to allow adequate mixing. After mixing, an aliquot was removed from the round-bottom flask and passed through a pad of silica gel using DCM as eluent into an NMR tube and was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis then returned to the round-bottom flask. The solvents were evaporated by using BioChromato Smart Evaporator. Water (50 mL) was added and the mixture was extracted with DCM (3 X 20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by a glass coated silica gel preparative TLC using EtOAc and hexanes (1:20) to yield 0.057 g (42%) of the title compound as pale-yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 7.48 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 2.3 Hz, 1H), 7.25 – 7.19 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.74 – 6.73 (m, 2H), 6.62 – 6.60 (m, 2H), 4.88 (t, J = 6.7 Hz, 1H), 4.48 (s, 1H), 3.81 (s, 3H), 3.71 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.7, 152.2, 144.7, 140.0, 131.5, 130.1, 129.5, 128.1, 127.7, 127.2, 123.9, 123.3 (t, ¹J_C-F2 = 171.9 Hz), 115.3, 114.7, 113.8, 62.3 (t, ²J_C-F2 = 18.2 Hz), 55.6, 55.1. ¹⁹F NMR (469 MHz, CDCl₃) δ −77.4 (dd, J = 286.9, 136.4 Hz). IR (film) 2917, 1701, 1611, 1512, 1475, 1383, 1275, 1178, 1093, 867, 785, 494 cm⁻¹. HRMS (APCI)⁺ m/z: calcd C₂₂H₂₀Cl₂F₂NO₃ [M + H]⁺, 454.0783; found 454.0777.

2,4-Dichloro-1-(1,1,2,2-tetrafluoro-2-(4-methoxyphenyl)ethoxy)benzene (9).

An oven-dried 25 mL round-bottom flask, equipped with a magnetic stir bar, was charged with 2-(2,4-dichlorophenoxy)-2,2-difluoro-1-(4-methoxyphenyl)ethenone (3ab, 0.105 g, 0.30 mmol, 1.0 equiv.), and then the vessel was attached to reflux condenser and a Schlenk line. The whole system was evacuated and back-filled with N_2(g) three times. Dry DCM (5.0 mL) was added to the round-bottom flask, and the reaction vessel was placed in an ice bath. After 10 min, DAST (0.60 mL, 4.5 mmol, 15.0 equiv.) was added dropwise over 5 min. The round-bottom flask was removed from the ice bath and allowed to warm to rt. Then, the round-bottom flask was placed in pre heated oil bath at 30 °C. After 36 h, the round-bottom flask was removed from the oil bath and allowed to cool to room temperature. TFT (6.0 μL) was added via microsyringe. The solution was diluted with DCM (1.0 mL) and then stirred at rt for 10 min to allow adequate mixing. After mixing, an aliquot was removed from the round-bottom flask and passed through a pad of silica gel into an NMR tube using DCM as eluent and was analyzed by ¹⁹F NMR for completion. After ¹⁹F NMR analysis, the aliquot was sampled for TLC analysis then returned to the round-bottom flask. The solvents were evaporated by using BioChromato Smart Evaporator. Water was added (50 mL) and the aqeous layer was extracted with DCM (3 X 20 mL). The combined organic layers were at washed with saturated bicarbonate (2 X 20 mL) followed by water (5 X 20 mL), brine (1 X 20 mL), dil. HCl (2 X 20mL) and water (2 X 20 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel (60 Å) flash chromatography using pure hexanes to provide 0.094 g (85%) of the title compound as pale-yellow liquid. ¹H NMR (800 MHz, CDCl₃) δ 7.65 (d, J = 8.8 Hz, 2H), 7.432 – 7.430 (m, 1H), 7.25 – 7.22 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H). ¹³C{¹H} NMR (201 MHz, CDCl₃) δ 161.8, 144.0, 132.1, 130.4, 128.4 (t, ³J_C-F2 = 5.8 Hz), 127.7, 123.8, 121.9 (t, ²J_C-F2 = 24.7 Hz), 117.9 (tt, ¹J_C-F2 = 279.1, 37.8 Hz), 114.6 (tt, ¹J_C-F2 = 253.5, 35.5 Hz), 113.7, 113.6, 55.3. ¹⁹F NMR (469 MHz, CDCl₃) δ −88.0 (s, 2F), −113.2 (s, 2F). IR (film) 2918, 1616, 1585, 1476, 1384, 1288, 1179, 1088, 935, 869, 786, 567 cm⁻¹. HRMS (APCI)⁻ m/z: calcd C₁₅H₁₀Cl₂F₃O₂ [M – F]⁻, 349.0005; found 349.0002.

General Computational Procedure.

All computations were performed using Density Functional Theory (DFT) as implemented in the Gaussian 16 software package. All structures were optimized using PBE/6–31G*^62,77 method and basis set with SMD solvation corrections⁶³ in water at room temperature. In addition, single point energy refinements were computed using ωb97XD/def2-TZVP^59,60 with the same solvation method. Conformational search was performed using Schrodinger Macromodel software package. All reported energy values are free energies in kcal mol⁻¹, and all distances are in Ångströms (Å). Figures of structures were rendered in CYLview software.