Organocatalytic Strategy for Hydrophenolation of Gem-Difluoroalkenes

Abstract

Gem-difluoroalkenes are an easily accessed fluorinated functional group, and a useful intermediate for elaborating into more complex fluorinated compounds. Currently, most functionalization reactions of gem-difluoroalkenes, with or without a transition metal-based catalyst system, involve the addition or removal of a fluorine atom to generate trifluorinated or monofluorinated products, respectively. In contrast, we present a complementary “fluorine-retentive” reaction that exploits an organocatalytic strategy to add phenols across gem-difluoroalkenes to deliver β,β-difluorophenethyl arylethers. The products are produced in good to moderate yields and selectivities, thus providing a range of compounds that are underrepresented in the synthetic and medicinal chemistry literature.

Graphical Abstract

1. Introduction

Fluorine-induced perturbations of an organic molecule’s physicochemical properties can enable new reactivities that contrast the reactivity of the respective non-fluorinated counterpart, as evidenced by the case of gem-difluoroalkenes.^1,2 For these substrates, the σ-withdrawing effects of the fluorine substituents activate the difluorinated position for regioselective attack by a variety of nucleophiles under both metal-catalyzed and non-catalyzed nucleophilic functionalization conditions (Figure 1).¹ However, many of these reactions undergo a net addition/elimination process that defluorinates the substrate. Specifically, these reactions proceed through either unstable β-fluoroanions (Figure 1a)^3–6 or β-fluoroorganometal intermediates (Figure 1b)^7–24 that both undergo β-fluoride elimination and deliver monofluorinated products.¹ This elimination process can be overridden using the nucleophile as a solvent,^25–32 which restricts use to liquid, inexpensive, and readily-available nucleophiles. In a special case, nucleophilic attack of the fluorinated position of a gem-difluoroalkene by a fluoride anion delivers trifluoromethyl-containing products, though these reactions benefit from an in situ equilibrium between the difluoroalkene and the α-trifluormethyl anion that avoids degradation of the organic moiety (Figure 1c).^33–38 A second rare exception involves the addition of 3-hydroxypyridine to gem-difluoroalkenes to selectively provide the hydrophenolated product,³⁹ though this strategy was not applied to other phenolic nucleophiles. In a more general method, the nucleophilic addition of aryl thiols to gem-difluoroalkenes generates β,β-difluorophenethyl arylthioethers using an organocatalytic strategy (1,1,3,3-tetramethylguanidine, TMG, Figure 1e) without β-fluoride elimination,⁴⁰ though additional examples of “fluorine-retentive” nucleophilic hydro-functionalization of gem-difluoroalkenes remain elusive (Figure 1d). To complement this reaction, we herein present a new organocatalytic system for the regioselective nucleophilic addition reactions of phenols to gem-difluoroalkenes that minimizes the loss of fluoride (Figure 1f).

Figure 1: Representative Reactions of Gem-Difluoroalkenes.

2. Results/Discussion

Standard optimization delivered improved conditions for adding phenolic nucleophiles across gem-difluoroalkenes (Table 1). Initially, we explored similar conditions to those used for functionalization with aryl thiols [entry 1: 25% TMG, 1,2-dichloroethane (1,2-DCE), 80 °C]; however, using these conditions, phenolic nucleophiles reacted poorly, giving no yield of desired β,β-difluorophenethylarylether product 3 or α-monofluorovinylether side product 4. Utilizing the same catalyst with a higher boiling solvent and higher temperatures provided low yield and moderate selectivity of 3 (entry 2). Considering the intrinsic differences in acidity and nucleophilicity between phenolic and thiophenolic nucleophiles, we explored the use of stronger bases, such as ^tBuOK (entry 3), 1,8-diazabicylco[5.4,0]undec-7ene (DBU, entry 4), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, entry 5). Use of the stronger nitrogenous bases improved the yields of product 3, but did not greatly increase selectivity, while the inorganic ^tBuOK selectively delivered 4. The use of stronger phosphorazine superbases reduced the selectivity versus α-monofluorovinylether side product 4 (entry 6), presumably due to degredation of desired product 3. The use of aromatic solvents provided improved selectivity versus other solvents (entries 3, 7–10), while increased temperature and loading of TBD improved the yield of desired product (entries 11–14). When performed in the presence of air, the reaction generated a complex mixture of more highly oxidized products, and ongoing work aims to optimize conditions to selectively produce these side products. Finally, we settled on the use of 50% TBD in 1,2-dichlorobenzene (DCB) under N₂ at 140 °C for 24 h as the standard conditions (entry 15). In control reactions, subjection of pure 3 to the optimized conditions generated mixtures of 3:4, indicating that the product is instable to the reaction conditions. Thus for any specific substrate, optimization of the time, temperature, and strength of base might improve the reaction outcome.

Table 1: Optimization of Reaction Conditions.

[a] 1 (1.0 equiv., 0.10 mmol), 2 (5.0 equiv., 0.50 mmol), base (0.25 equiv., 0.025 mmol), solvent (1.0 M, 0.10 mL), 120 °C, for 4 h under an N₂ atmosphere. Conversion of 1 and yields of 3 and 4 were determined by ¹⁹F NMR analysis using α,α,α-trifluorotoluene (TFT) as a standard (10 μL). [b] pKa in THF.^41,42 [c] 80 °C. [d] 100 °C. [e] 0.50 equiv. base. [f] 140 °C. [g] 1 (1.0 equiv., 0.50 mmol), 2 (5.0 equiv., 2.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (1.0 M, 1.0 mL), 140 °C, for 24 h under an N₂ atmosphere.

Entry	Base	pKa[b]	Solv.	Conv.	3	4
1[3]	TMG	16	DCE	40	0	0
2	TMG	16	(NO2)C6H5	40	22	9
3[d]	tBuOK	N/D	(NO2)C6H5	39	7	25
4[d]	DBU	17	(NO2)C6H5	30	15	7
5	TBD	21	(NO2)c6h5	83	46	14
6	P2Et	25	(NO2)C6H5	72	33	19
7	TMG	16	DMF	84	18	30
8	TMG	16	DMSO	98	6	64
9	TMG	16	Anisole	65	16	3
10	TMG	16	DCB	56	18	3
11	TBD	21	DCB	90	53	10
12[e]	TBD	21	DCB	89	61	11
13[d,e]	TBD	21	DCB	63	31	5
14[e,f]	TBD	21	DCB	>99	70	17
15[g]	TBD	21	DCB	>99	60	17

Using these conditions, a range of phenols were successfully added across gem-difluoroalkenes. Reactions of various electron-deficient phenols (Table 2, 6a–f) gave the desired β,β-difluorophenethyl arylethers (6) in good yields (>65%) and high selectivities (>7:1) versus the α-monofluorovinylether side products (7). Using the standard reaction conditions, electron-neutral and ortho-substituted phenols (3, 6g–j) delivered the β,β-difluorophenethyl arylethers in moderate to low yields (30–50%) and selectivities (2:1–4:1). Reactions of electron-rich phenols delivered the anticipated products in low yields and selectivities (6k–l), though reoptimization of the base might improve the reactivity of these less acidic substrates. A range of useful functional groups for further functionalization were tolerated, like halides (6c–f) and nitrogen based functional groups (6a–b), though an aniline-drived phenol (6l) was a poor substrate.

Table 2: Scope of Phenol Nucleophiles.

Standard conditions: 1 (1.0 equiv., 0.50 mmol), 5a–o (5.0 equiv., 2.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.50 M, 1.0 mL), 140 °C, for 24 h under an N₂ atmosphere. The selectivity of 6:7 was determined by ¹⁹F NMR analysis of the crude reaction mixture using TFT (50 μL) as a standard and is reported in parentheses. Yields are reported as the isolated yield of >95% pure material and represent the average of 2 runs. [a] 1.0 equiv. TBD. [b] Contains trifluoroethylbenzene side product.

Many synthetically and biomedically useful functional groups were tolerated on the gem-difluoroalkene substrate. Specifically, reactions tolerated thioethers and ethers (9a–b), morpholine (9c), nitrogen-containing functional groups (9k–l), halides (9m–p) amides (9q), and pseudohalides (9r). Reactions of electron-rich gem-difluoroalkenes generally afforded products in good yields and high selectivities (9a–i), although aniline-based and ^tBu-based gem-difluoroalkenes reacted in lower yields (9e–f). Using electron-deficient substrates, the standard reaction conditions generally delivered products in low yield and <1:1 selectivity (9j–r), though substrates bearing 3-α,β-unsaturated carbonyl and 3-NO₂ groups afforded products in sufficient yield and selectivity (9j, k). To address this limitation, further optimization revealed that a biphasic reaction mixture (9:1 DCB:H₂O) improved both the selectivities and yields (9l–r). Presumably for these eletron-deficient substrates, the water in the biphasic system (1) provided additional protons to quench the reactive β-fluoroanion, and/or (2) minimized degradation of the product by sequestering some of the base in the aqueous phase. Ortho-substituted gem-difluoroalkenes reacted inconsistently, with a 2-(4-^tBu)-Ph-substituted substrate giving high yield (9d), a 2-Me-substituted substrate reacting in low yield and low conversion (9h), and a 2,6–Me₂-substituted substrate not reacting at all (9i).

Heteroaryl-substituted gem-difluoroalkenes reacted similarly to their aryl-derived counterparts. Electron-rich heteroaryl groups, such as indole and pyrazole, gave high selectivity (12a, b), though the yield of pyrazole 12b was moderate. A 2-substituted dibenzothiophene reacted in moderate yield and selectivity (12c). When subjected to the biphasic conditions, a pyridyl substrate gave good yield and selectivity (12d). This series of reactions also highlighted the compatibility of sulfonamide (12a) and acetal (12d) protecting groups.

3. Mechanistic Considerations

The present reaction presumably operates through an addition / protonation sequence, in which the base plays key roles as both a promoter and a quencher of the reaction. Initially, organic base (B) activates the phenol pronucleophile, and subsequently, the phenoxide nucleophile adds to the electrophilic difluorinated carbon of the gem-difluoroalkene. This addition generates an instable β-fluoro anionic intermediate (A) that can react via two pathways. First, intermediate (A) can either accept a proton from the phenol pronucleophile or from the protonated organic base (B) to provide the desired product 3. Second, fluoride elimination from anionic intermediate (A) can provide the undesired monofluoroalkene 4. Alternatively, 4 can form via base-mediated elimination of HF from 3.

Based on this presumed mechanism, the pK_a of the base catalyst must fall within a narrow range to selectively provide 3 over 4. The base catalyst must be sufficiently basic to deprotonate the phenol. In THF, a non-coordinating aprotic solvent, phenol’s pK_a of 18 disfavors deprotonation by weaker bases, such as TMG (pK_a = 16), though stronger bases, such as TBD (pK_a = 21), efficiently deprotonate and activate the phenol. However, bases that are too strong will decompose product 3 to generate 4. Specfically, the strong σ-electron withdrawing effect of the gem-difluoro group and ethereal oxygen activates 3 for elimination. Such deprotonation was observed in control experiments involving the base-mediated decomposition of 3 particularly with strong “superbases,” such as the phosphorazine base P₂Et (pK_a = 25). Therefore in the present studies, TBD provided appropriate reactivity, specifically balancing activation of the phenol with decomposition of product. However, we note that other currently unexplored bases might also work for this reaction. Further, for any specific substate combination with distinct pK_as of the phenol and product, an alternate base might prove optimal.

4. Conclusion

In conclusion, we developed an organocatalytic method to convert gem-difluoroalkenes to β,β-difluorophenethyl arylethers. In contrast to classical syntheses of such products that require harsh conditions^43–45 and/or gaseous reagents⁴⁶ and that many times rely on functional group interconversions^47–56 for generating the fluorine-based substructure, our convergent method utilizes only catalytic quantities of a weak amine base to add phenol nucleophiles across gem-difluoroalkenes and deliver the desired products in moderate to good yields and selectivities. Notably, this reaction contrasts the many reactions of gem-difluoroalkenes that selectively generate monofluoroalkene products.¹ This method delivers a class of products that are underrepresented in synthetic and biomedical literature, and it tolerates many useful functional groups for further functionalization and for medicinal chemistry. Further efforts aim to enable the addition of other nucleophiles, such as alkyl alcohols, to gem-difluoroalkenes, and to expand the scope of such reactions to include aliphatic and secondary gem-difluoroalkenes.

5. Experimental Section

General Considerations:

Unless otherwise noted, reactions were performed under an atmosphere of air using oven-dried glassware. Organocatalytic reactions of phenols and gem-difluoroalkenes were performed in one-dram borosilicate glass scintillation vials sealed with a screw-top cap containing a PTFE-lined septum. Unless otherwise noted all other reactions were performed in round-bottom flasks sealed with rubber septa. PTFE syringes equipped with stainless-steel needles were used to transfer air- and moisture-sensitive liquid reagents. Reactions were monitored by either ¹⁹F NMR with an internal standard of α,α,α-trifluorotoluene or by thin-layer chromatography (TLC) on UNIPLATE Silica Gel HLF plates, visualized by quenching of fluorescence. Normal phase column chromatography was conducted using a automated separations system utilizing gradient elution with VWR Common Silica Gel 60 Å, 40–60 μm. Reverse phase column chromatography was conducted using an automated flash chromatography system utilizing gradient elution with a Teledyne ISCO C18 Redisep Rf Gold 50 g column. 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. Unless otherwise noted, compounds were isolated in >98% purity as determined by ¹H and ¹⁹F NMR.

Unless otherwise noted, reagents were purchased from commercial sources and used as received. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) was purchased form Sigma Aldrich. 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. Chemical abbreviations utilized in this document include: 1,2–Dichlorobenzene (DCB), N-methylpyrrolidine (NMP), α,α,α-trifluorotoluene (TFT), sodium sulfate (Na₂SO₄), magnesium sulfate (MgSO₄), ethyl acetate (EtOAc), diethyl ether (Et₂O), ammonium chloride (NH₄Cl), ⁿbutyl lithium (ⁿBuLi), sodium hydroxide (NaOH), ^tbutyl carbonate anhydride (Boc₂O), potassium carbonate (K₂CO₃), and hydrochloric acid (HCl).

Proton nuclear magnetic resonance (¹H NMR) and fluorine nuclear magnetic resonance (¹⁹F NMR) were taken on a Bruker DRX 500 spectrometer (500 and 376 MHz respectively). Fluorine nuclear magnetic resonance (¹⁹F NMR) was taken on a Bruker AVIII 400 Avance spectrometer (376 MHz). Proton and carbon nuclear magnetic resonance (¹³C NMR) were taken on a Bruker AVIII 500 Avance spectrometer with a CPDUL cryoprobe (500 and 126 MHz respectively). Chemical shifts (δ) for protons are reported in parts per million (ppm) downfield from tetramethylsilane, and are referenced to the proton resonance of residual solvent in the NMR solvent (CHCl₃: δ = 7.26 ppm; DMSO: δ = 2.50 ppm). Chemical shifts (δ) for carbon are reported in ppm downfield from tetramethylsilane, and are referenced to the carbon resonance of the solvent residual peak (CDCl₃: δ = 77.2 ppm; DMSO: δ = 39.52 ppm). Chemical shifts for fluorine are reported in ppm upfield from trichlorofluoromethane (0 ppm), and are referenced to added TFT as a standard (δ = −63.77 ppm) unless otherwise specified. 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 determinations were obtained either by electrospray ionization (ESI) on a Waters LCT Premier™ mass spectrometer or by atmospheric-pressure chemical ionization (APCI-hexanes/PhMe) on a Waters Q-Tof Premier™, for which sample plus near mass internal exact mass standard were dissolved in hexanes, and hexanes or PhMe/hexanes were used as ionization solvent. 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.

General Procedure for the Preparation of Gem-Difluoroalkenes (A):

An oven-dried 3-neck round-bottomed flask equipped with a magnetic stir bar was charged with aryl aldehyde (1.0 equiv.) and triphenylphosphine (1.2 or 1.5 equiv.). The system was sealed with three PFTE septa, and subsequently evacuated and backfilled with N₂ three times. Dry NMP was added via syringe transfer (PTFE syringe with oven-dried stainless-steel needle), and the system was immersed in a preheated 100 °C oil bath. Once no solid reagents remained (approximately 2 min of heating), potassium bromodifluoroacetate (1.5 or 1.8 equiv.) was added portionwise over 0.5 h, with the rate of addition controlling the evolution of CO₂ gas. Once all of the potassium bromodifluoroacetate was added, the solution was allowed to stir for 0.5–1 h. Upon completion, the reaction was cooled to room temperature and then quenched with H₂O. Subsequently, Et₂O was added to the reaction, and the mixture was washed with H₂O (five times), and the aqueous layer was back-extracted with Et₂O (two times). The combined organic layers were dried over Na₂SO₄ and concentrated. The crude material was dry-packed onto silica gel and then eluted through a plug of silica gel with EtOAc:hexanes (1:1) to remove triphenylphosphine oxide. Subsequently, H₂O₂ (30% in H₂O) was added to the mother liquor and allowed to react for 30 min to oxidize the residual triphenylphosphine. The organic layer was washed with H₂O (three times), dried over Na₂SO₄, concentrated, and subjected to normal phase flash chromatography using EtOAc and hexanes.

General Procedure for the Organocatalyzed Addition of Phenols to Gem-Difluoroalkenes (B-1):

An oven-dried one-dram vial equipped with a magnetic stir bar was charged with 1 equivalent of difluoroalkene and 5 equivalents of phenol. The system was brought into a glovebox, and 0.5 equivalents of TBD were added. Dry DCB (1 mL) was added via syringe transfer (PTFE syringe with oven-dried stainless-steel needle), and the vial was sealed with a screw-top cap containing a PTFE-lined septum. The system was removed from the glovebox, and placed within a heating mantle preheated to 140 °C and stirred for 24 h. The reaction was cooled to room temperature, and then standardized by adding 50 μL of TFT. The mixture was diluted with DCM, and then stirred for 5 min. The reaction was analyzed by ¹⁹F NMR, and then washed 3X with 1 N NaOH (aq.). The combined aqueous layer was extracted 2X with DCM, and the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was loaded onto celite and then purified by flash reverse phase chromatography with gradient elution from 98% H₂O in MeCN to 100% MeCN to provide the desired product in >95% purity.

General Procedure for the Organocatalyzed Addition of Phenols to Gem-Difluoroalkenes (B-2):

An oven-dried one-dram vial equipped with a magnetic stir bar was charged with 1 equivalent of difluoroalkene and 3 equivalents of phenol. The system was brought into a glovebox, and 0.5 equivalents of TBD were added. Dry DCB (0.9 mL) was added via syringe transfer (PTFE syringe with oven-dried stainless-steel needle), and the vial was sealed with a screw-top cap containing a PTFE-lined septum. The system was removed from the glovebox, and distilled H₂O (0.1 mL, distilled under N₂ to remove dissolved O₂) was added via syringe transfer (PTFE syringe with oven-dried stainless-steel needle) under N₂. The reaction was placed within a heating mantle preheated to 140 °C and stirred for 24 h. The reaction was cooled to room temperature, and then standardized by adding 50 μL of TFT. The mixture was diluted with DCM, and then stirred for 5 min. The reaction was analyzed by ¹⁹F NMR, and then washed 3X with 1 N NaOH (aq.). The combined aqueous layer was extracted 2X with DCM, and the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was loaded onto celite and then purified by flash reverse phase chromatography with gradient elution from 98% H₂O in MeCN to 100% MeCN to provide the desired product in >95% purity.

Compounds in Table 1:

5-(2,2-difluoro-2-phenoxyethyl)-1,2,3-trimethoxybenzene (3):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.236 g (2.50 mmol) of phenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.080 g (49% yield) of desired product 3 as a colorless solid (MP = 65–66 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.32 (t, J = 7.9 Hz, 2 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 6.60 (s, 2 H), 3.87 (s, 9 H), 3.39 (t, J = 11.0 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.2, 150.5, 137.6 (d, J = 1.4 Hz), 129.4, 127.7 (t, J = 3.3 Hz), 125.6, 123.8, 121.7 (t, J = 267.0 Hz), 107.6, 60.9, 56.2, 42.5 (t, J = 30.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.44 (t, J = 11.0 Hz, 2 F); IR (film) 2940, 2841, 2252, 1699, 1592, 1509, 1492, 1463, 1423, 1361, 1324, 1262, 1238, 1194, 1156, 1128, 1068, 1051, 1026, 1005, 942, 909, 828, 807, 764, 749, 692, 658, 649 cm⁻¹; HRMS (HAPCI+) calc. for C₁₇H₁₈F₂O₄ (M+) 324.1173, found 324.1171.

(E)-5-(2-fluoro-2-phenoxyvinyl)-1,2,3-trimethoxybenzene (4):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.236 g (2.50 mmol) of phenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing desired product 0.024 g (16% yield, 6:1 E:Z) 4 as an orange oil; Characterization represents major E isomer; ¹H NMR (500 MHz, CDCl₃) δ 7.37 (dd, J = 8.7, 7.5 Hz, 2 H), 7.17–7.14 (m, 3 H), 6.66 (s, 2 H), 5.65 (d, J = 5.6 Hz, 1 H), 3.82 (s, 3 H), 3.76 (s, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ 154.7, 154.0 (d, J = 3.5 Hz), 153.3, 130.1, 127.6 (d, J = 8.4 Hz), 124.5, 117.5, 116.3, 105.0 (d, J = 4.1 Hz), 92.7 (d, J = 38.6 Hz), 61.0, 56.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −83.38 (d, J = 5.6 Hz, 1 F). Minor Z isomer characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.24 (d, J = 28.2 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −83.80 (d, J = 28.1 Hz, 1 F).

Compounds in Table 2:

5-(2,2-difluoro-2-(4-nitrophenoxy)ethyl)-1,2,3-trimethoxybenzene (6a):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.348 g (2.50 mmol) of 4-nitrophenol in the presence of 0.066 g (0.5 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.125 g (69% yield, 3% of E-7a) of desired product 6a as a dark yellow solid (MP = 117–120 °C); ¹H NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 9.2 Hz, 2 H), 7.28 (d, J = 8.9 Hz, 2 H), 6.57 (s, 2 H), 3.88 (s, 6 H), 3.86 (s, 3 H), 3.42 (t, J = 11.4 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 155.4, 153.3, 145.0, 138.0, 126.8 (t, J = 3.4 Hz), 125.4, 124.0 (t, J = 269.3 Hz), 121.4 (t, J = 1.9 Hz), 116.6, 107.7, 61.0, 56.3, 42.5 (t, J = 29.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ ; ¹⁹F NMR (376 MHz, CDCl₃) δ −71.41 (t, J = 11.4 Hz, 2 F); IR (film) 2940, 2841, 1614, 1592, 1522, 1509, 1492, 1461, 1424, 1346, 1325, 1301, 1238, 1209, 1157, 1124, 1060, 1009, 943, 930, 911, 853, 801, 764, 750, 723, 692, 649 cm⁻¹; HRMS (HAPCI+) calc. for C₁₇H₁₈F₂NO₆ (M+H) 370.1102, found 370.1099. E-7a characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.79 (d, J = 5.8 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.52 (d, J = 5.9 Hz, 1 F).

4-(1,1-difluoro-2-(3,4,5-trimethoxyphenyl)ethoxy)benzonitrile (6b):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.298 g (2.50 mmol) of 4-hydroxybenzonitrile in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.143 g (82% yield, 5% E-7b, 1% Z-7b) of desired product 6b as a yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 7.62 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.4 Hz, 2 H), 6.56 (s, 2 H), 3.87 (s, 6 H), 3.85 (s, 3 H), 3.40 (t, J = 11.3 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.9, 153.3, 133.8, 126.9 (t, J = 3.4 Hz), 124.0 (t, J = 269.6 Hz), 121.8 (d, J = 1.8 Hz), 118.3, 117.0, 109.2, 107.7, 61.0, 56.3, 42.5 (t, J = 29.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −71.23 (t, J = 11.5 Hz, 2 F); IR (film) 2940, 2842, 2253, 2231, 1596, 1505, 1464, 1424, 1360, 1325, 1296, 1253, 1241, 1210, 1173, 1156, 1129, 1068, 1004, 908, 841, 802, 732, 649 cm⁻¹; HRMS (ESI+) calc. for C₁₈H₁₇F₂NO₄Na (M+Na) 372.1023, found 372.1026. E-7b characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.76 (d, J = 5.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.31 (d, J = 5.5 Hz, 1 F); Z-7b characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.43 (d, J = 27.8 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.81 (d, J = 32.89 Hz, 1 F).

5-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-1,2,3-trimethoxybenzene (6c):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.145 g (72% yield) of desired product 6c as a clear oil; ¹H NMR (500 MHz, CDCl₃) δ 7.40 (d, J = 2.5 Hz, 1 H), 7.27–7.25 (m, 1 H), 7.19 (dd, J = 8.8, 2.5 Hz, 1 H), 6.60 (s, 2 H), 3.87 (s, 6 H), 3.85 (s, 3 H), 3.43 (t, J = 11.0 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.2, 145.3 (t, J = 1.7 Hz), 137.8, 131.3, 130.3, 128.2, 127.8, 127.0 (t, J = 3.5 Hz), 124.07 (t, J = 269.4 Hz), 123.93 (t, J = 2.0 Hz), 107.9, 61.0, 56.3, 42.4 (t, J = 29.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.83 (t, J = 11.0 Hz, 2 F); IR (film) 2940, 2839, 1592, 1508, 1476, 1463, 1423, 1360, 1324, 1258, 1238, 1128, 1061, 1008, 942, 867, 808, 764, 700, 666, 528 cm⁻¹; HRMS (HAPCI+) calc. for C₁₇H₁₆Cl₂F₂O₄ (M+) 392.0394, found 394.0424.

5-(2,2-difluoro-2-(3-iodophenoxy)ethyl)-1,2,3-trimethoxybenzene (6d):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.551 g (2.50 mmol) of 3-iodophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.158 g (71% yield, 2% E-7d) of desired product 6d as a brown oil; ¹H NMR (500 MHz, CDCl₃) δ 7.53–7.50 (m, 2 H), 7.12 (dd, J = 8.25, 2.15 Hz, 1 H), 7.03 (t, J = 8.01 Hz, 1 H), 6.56 (s, 2 H), 3.86 (s, 9 H), 3.36 (t, J = 11.08 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.1, 150.7 (d, J = 2.30 Hz), 137.7 (d, J = 1.69 Hz), 134.7, 130.9, 130.7, 127.3 (t, J = 3.39 Hz), 123.8 (t, J = 267.33 Hz), 121.2, 107.6, 93.5, 60.9, 56.2, 42.4 (t, J = 29.73 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.60 (t, J = 11.13 Hz, 2 F); IR (film) 2938, 2839, 1591, 1583, 1509, 1465, 1422, 1360, 1324, 1260, 1237, 1192, 1156, 1126, 1054, 1008, 945, 910, 865, 832, 765, 750, 735, 686, 665, 649 cm⁻¹; MS (EI+) calc. for C₁₇H₁₇F₂IO₄ (M+) 450.0, found 449.9. E-7d characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.67 (d, J = 5.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.19 (d, J = 5.6 Hz, 1 F).

5-(2-(3-chloro-2-fluorophenoxy)-2,2-difluoroethyl)-1,2,3-trimethoxybenzene (6e):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.26 mL (2.50 mmol) of 2-fluoro-3-chlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.139 g (74% yield, 5% E-7e) of desired product 6e as a clear solid (MP = 50–51 °C); 1H NMR (500 MHz, CDCl₃) δ 7.23 (ddd, J = 8.1, 6.3, 1.6 Hz, 1 H), 7.19 (ddd, J = 8.3, 6.8, 1.4 Hz, 1 H), 7.01 (td, J = 8.3, 1.9 Hz, 1 H), 6.60 (s, 2 H), 3.87 (s, 6 H), 3.86 (s, 3 H), 3.43 (t, J = 11.1 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ ;153.2, 150.4, 137.7 (t, J = 1.5 Hz), 127.5, 127.0 (t, J = 3.5 Hz), 123.97, 123.96 (t J = 269.8 Hz), 123.93, 122.6, 122.3 (d, J = 15.8 Hz), 107.6, 61.0, 56.2, 42.2 (t, J = 29.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −71.19 (td, J = 11.3, 5.3 Hz, 2 F), −131.17 (p, J = 6.2 Hz, 1 F); IR (film) 2941, 2842, 2253, 1705, 1595, 1509, 1483, 1462, 1424, 1360, 1325, 1275, 1260, 1243, 1181, 1156, 1129, 1069, 1027, 1004, 956, 907, 838, 821, 764, 746, 650 cm⁻¹; HRMS (HAPCI+) calc. for C₁₇H₁₆ClF₃O₄ (M+) 376.0689, found 376.0682. E-7e characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.64 (d, J = 6.1 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.26 (d, J = 6.1 Hz, 1 F).

5-(2-(4-bromophenoxy)-2,2-difluoroethyl)-1,2,3-trimethoxybenzene (6f):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.432 g (2.50 mmol) of 4-bromophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.137 g (68% yield, 3% E-7f) of desired product 6f (or 2) as a clear oil; ¹H NMR (500 MHz, CDCl₃) δ 7.42 (d, J = 8.8 Hz, 2 H), 7.01 (d, J = 8.6 Hz, 2 H), 6.57 (s, 2 H), 3.86 (s, 9 H), 3.37 (t, J = 11.1 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.2, 149.4, 137.7 (t, J = 1.6 Hz), 132.4, 127.4, 123.7 (t, J = 267.9 Hz), 123.6, 118.6, 107.6, 60.9, 56.2, 42.4 (t, J = 29.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.87 (t, J = 11.2 Hz, 2 F); IR (film) 2939, 2842, 2252, 1594, 1509, 1486, 1464, 1424, 1361, 1324, 1275, 1260, 1239, 1199, 1156, 1129, 1068, 1012, 908, 827, 797, 764, 744, 698, 649 cm⁻¹; HRMS (HAPCI+) calc. for C₁₇H₁₇BrF₂O₄ (M+) 402.0278, found 402.0267. E-7f characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.66 (d, J = 5.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.44 (d, J = 5.7 Hz, 1 F).

4-(1,1-difluoro-2-(3,4,5-trimethoxyphenyl)ethoxy)-1,1’-biphenyl (6g):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.426 g (2.50 mmol) of 4-phenylphenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by flash normal phase chromatography using a gradient of hexanes to 5% PhMe and 15% EtOAc in hexanes, furnishing 0.107 g of pure compound 6g as colorless solid (MP = 67–70 °C), and 0.053 g of 80% pure compound 6g; ¹H NMR (500 MHz, CDCl₃) δ 7.56–7.54 (m, 4 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.22 (d, J = 8.2 Hz, 2 H), 6.62 (s, 2 H), 3.88 (s, 9 H), 3.42 (t, J = 11.0 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) d 153.2, 149.9 (t, J = 2.1 Hz), 140.4, 138.7, 137.7 (t, J = 1.3 Hz), 128.9, 128.2, 127.7 (t, J = 3.2 Hz), 127.5, 127.2, 123.9 (t, J = 266.4 Hz), 122.0, 107.7, 61.0, 56.3, 42.6 (t, J = 30.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.42 (t, J = 10.9 Hz, 2 F); IR (film) 2253, 1595, 1510, 1486, 1464, 1424, 1325, 1241, 1131, 1009, 905, 729, 650 cm⁻¹; HRMS (HAPCI+) calc. for C₂₃H₂₂F₂O₄ (M+) 400.1486, found 400.1478.

5-(2,2-difluoro-2-(o-tolyloxy)ethyl)-1,2,3-trimethoxybenzene (6h):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.26 mL (2.50 mmol) of o-cresol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by normal-phase flash chromatography using a gradient of 0–10% EtOAc in hexanes with 1% PhMe, followed by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.068 g (40% yield) of desired product 6h as a pale yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 7.21 (dd, J = 8.4, 1.7 Hz, 1 H), 7.15 (t, J = 7.0 Hz, 2 H), 7.08 (dt, J = 7.5, 7.0, 1.4 Hz, 1 H), 6.60 (s, 2 H), 3.87 (s, 6 H), 3.86 (s, 3 H), 3.41 (t, J = 10.6 Hz, 2 H), 2.05 (s, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.1, 148.9, 137.7 (d, J = 1.3 Hz), 131.22, 131.19, 127.8 (t, J = 3.7 Hz), 126.7, 125.5, 124.1 (t, J = 266.8 Hz), 121.9 (d, J = 1.7 Hz), 107.8, 61.0, 56.3, 42.7 (t, J = 30.7 Hz), 16.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −69.81 (t, J = 10.6 Hz, 2 F); IR (film) 2939, 2840, 1591, 1508, 1494, 1460, 1423, 1360, 1324, 1262, 1238, 1177, 1156, 1126, 1091, 1042, 1009, 944, 892, 862, 832, 749, 704, 658, 618 cm⁻¹; HRMS (HAPCI+) calc. for C₁₈H₂₀F₂O₄ (M+) 338.1330, found 338.1320.

5-(2,2-difluoro-2-(2-isopropylphenoxy)ethyl)-1,2,3-trimethoxybenzene (6i):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.336 mL (2.50 mmol) of 2-isoporpylphenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.061 g (34% yield) of desired product 6i as a clear oil; ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.26 (m, 2 H), 7.18 (dt, J = 6.2, 2.5 Hz, 2 H), 6.64 (s, 2 H), 3.90 (s, 9 H), 3.45 (t, J = 10.3 Hz, 2 H), 2.90 (p, J = 6.9 Hz, 1 H), 1.08 (d, J = 6.9 Hz, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.2, 147.6 (t, J = 1.8 Hz), 141.3, 127.9 (t, J = 3.8 Hz), 126.6, 126.5, 125.8, 124.0 (t, J = 266.4 Hz), 121.7 (t, J = 2.0 Hz), 107.8, 61.0, 56.2, 42.8 (t, J = 30.6 Hz), 26.5, 23.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −69.54 (t, J = 10.4 Hz, 2 F); IR (film) 2963, 2840, 1592, 1508, 1489, 1459, 1423, 1362, 1323, 1260, 1238, 1179, 1156, 1127, 1086, 1045, 1009, 944, 892, 860, 829, 809, 752, 722, 705, 659, 603, 545, 529, 472, 455 cm⁻¹; HRMS (HAPCI+) calc. for C₂₀H₂₄F₂O₄ (M+) 366.1643, found 366.1638.

2-(1,1-difluoro-2-(3,4,5-trimethoxyphenyl)ethoxy)-1,1’-biphenyl (6j):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.426 g (2.50 mmol) of 2-phenylphenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.127 g (40 % yield, 23% E-7j, 3% Z-7j) of compound 6j as a pale oil; ¹H NMR (500 MHz, CDCl₃) δ 7.42–7.38 (m, 1 H), 7.34–7.29 (m, 7 H), 7.25 (td, J = 7.4, 1.3 Hz, 1 H), 6.35 (s, 2 H), 3.84 (s, 3 H), 3.75 (s, 6 H), 3.19 (t, J = 10.8 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.0, 147.5, 138.1, 135.3, 131.3, 129.6, 129.4, 128.9, 128.4, 128.0, 127.7, 127.4 (d, J = 3.8 Hz), 127.2, 125.7, 123.9 (t, J = 269.2 Hz), 122.1 (d, J = 2.2 Hz), 107.6, 60.9, 56.1, 42.6 (t, J = 30.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −69.38 (t, J = 10.9 Hz, 2 F); IR (film) 2938, 2839, 1754, 1699, 1591, 1507, 1479, 1460, 1422, 1359, 1324, 1275, 1259, 1235, 1188, 1155, 1125, 1045, 1010, 946, 916, 830, 748, 701, 660, 613, 569, 528 cm⁻¹; HRMS (HAPCI+) calc. for C₂₃H₂₂F₂O₄ (M+) 400.1486, found 400.1486. E-7j characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.61 (d, J = 6.2 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.18 (d, J = 6.2 Hz, 1 F); Z-7j characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.06 (d, J = 28.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.21 (d, J = 28.7 Hz, 1 F).

5-(2,2-difluoro-2-(4-methoxyphenoxy)ethyl)-1,2,3-trimethoxybenzene (6k):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.310 g (2.50 mmol) of 4-methoxyphenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.089 g (51% yield, 5% E-7k) of desired product 6k as a colorless solid (MP = 64–66 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.05 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.59 (s, 2 H), 3.86 (s, 9 H), 3.77 (s, 3 H), 3.36 (t, J = 10.9 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 157.3, 153.1, 143.7, 137.6 (d, J = 1.4 Hz), 127.8 (d, J = 3.2 Hz), 123.8 (t, J = 266.8 Hz), 123.2, 114.4, 107.6, 60.9, 56.2, 55.6, 42.4 (t, J = 30.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.65 (t, J = 11.0 Hz, 2 F); IR (film) 3003, 2939, 2839, 2252, 1702, 1592, 1506, 1463, 1423, 1362, 1324, 1298, 1267, 1241, 1192, 1156, 1128, 1040, 1009, 943, 910, 842, 807, 784, 763, 735, 698, 649 cm⁻¹; HRMS (HAPCI+) calc. for C₁₈H₂₀F₂O₅ (M+) 354.1279, found 354.1269. E-7k characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.57 (d, J = 5.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −83.52 (d, J = 5.8 Hz, 1 F).

3-(1,1-difluoro-2-(3,4,5-trimethoxyphenyl)ethoxy)-N,N-dimethylaniline (6l):

Following General Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted with 0.343 g (2.50 mmol) of 3-dimethylaminophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by normal-phase flash chromatography using a gradient of 0–30% EtOAc in hexanes to remove 3-dimethylaminophenol, followed by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.051 g (28% yield, 3% E-7l) of compound 6l as a yellow semisolid; ¹H NMR (500 MHz, CDCl₃) δ 7.16 (t, J = 8.2 Hz, 1 H), 6.59 (s, 2 H), 6.55 (dd, J = 8.4, 2.5 Hz, 1 H), 6.52 (d, J = 7.5 Hz, 1 H), 6.46 (t, J = 2.4 Hz, 1 H), 3.87 (s, 6 H), 3.86 (s, 3 H), 3.37 (t, J = 11.1 Hz, 2 H), 2.93 (s, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.1, 151.7, 151.6 (t, J = 2.3 Hz), 137.6, 129.6, 127.9 (t, J = 3.2 Hz), 123.9 (t, J = 266.1 Hz), 109.7, 109.5, 107.6, 105.9, 61.0, 56.2, 42.6 (t, J = 30.6 Hz), 40.6; ¹⁹F NMR (376 MHz, CDCl₃) δ −69.93 (t, J = 11.1 Hz, 2 F); IR (film) 2938, 2840, 1699, 1608, 1592, 1505, 1460, 1423, 1358, 1324, 1263, 1236, 1126, 1045, 1003, 941, 876, 838, 812, 765, 750, 687, 668, 612, 528 cm⁻¹; HRMS (ESI+) calc. for C₁₉H₂₄F₂NO₄ (M+H) 368.1673, found 368.1662. E-7l characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.61 (d, J = 5.5 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −82.25 (d, J = 5.7 Hz, 1 F).

Compounds in Table 3:

Table 3: Scope of Gem-difluoroalkene Electrophiles.

[a] Standard conditions: 8a–r (1.0 equiv., 0.50 mmol), 5c (5.0 equiv., 2.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.50 M, 1.0 mL), 140 °C, for 24 h under an N₂ atmosphere. The selectivity of 9:10 was determined by ¹⁹F NMR analysis of the crude reaction mixture using TFT (50 μL) as a standard and is reported in parentheses. Yields are reported as the isolated yield of >95% pure material and represent the average of 2 runs. [b] Standard conditions: 8a–r (1.0 equiv., 0.50 mmol), 5c (3.0 equiv., 1.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.45 M, 0.90 mL), H₂O (0.05 M, 0.10 mL), 140 °C, for 24 h under an N₂ atmosphere. The selectivity of 9:10 was determined by ¹⁹F NMR analysis of the crude reaction mixture using TFT (50 μL) as a standard and is reported in parentheses. Yields are reported as the isolated yield of >95% pure material and represent the average of 2 runs. [c] 4-Bromophenol used as the nucleophile. [d] Yield is reported from ¹⁹F analysis of the crude reaction mixture. [e] Second run used 0.40 mmol of 8q. [f] Second run used 0.30 mmol of 8r.

(4-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)phenyl)(methyl)sulfane (9a):

Following General Procedure B-1, 0.093 g (0.50 mmol) of compound 8a was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.112 g (68% yield, 2% E-10a) of desired product 9a as a tan solid (MP = 69–70 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.40 (d, J = 2.2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.7 Hz, 1 H), 7.18 (ddd, J = 8.8, 2.5, 1.0 Hz, 1 H), 3.45 (t, J = 11.1 Hz, 2 H), 2.49 (d, J = 1.1 Hz, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.3, 138.3, 131.3, 131.2, 130.3, 128.4, 128.3 (t, J = 3.4 Hz), 127.7, 126.6, 124.1 (t, J = 2.0 Hz), 124.0 (t, J = 269.7 Hz), 41.7 (t, J = 29.4 Hz), 15.9; ¹⁹F NMR (376 MHz, CDCl₃) δ −71.10 (t, J = 11.1 Hz, 2 F); IR (film) 2924, 1476, 1433, 1408, 1352, 1324, 1283, 1260, 1217, 1174, 1119, 1095, 1061, 1019, 958, 907, 868, 843, 800, 762, 733, 696, 675, 650 cm⁻¹; HRMS (HAPCI+) calc. for C₁₅H₁₂Cl₂F₂OS (M+) 347.9954, found 347.9944. E-10a characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.69 (d, J = 6.0 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.56 (d, J = 6.1 Hz, 1 F).

1-bromo-4-(1,1-difluoro-2-(4-methoxyphenyl)ethoxy)benzene (9b):

Following General Procedure B-1, 0.086 g (0.50 mmol) of compound 8b was reacted with 0.433 g (2.50 mmol) of 4-bromophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.097 g (56% yield) of desired product 9b as a peach solid (MP = 51–52 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.43 (d, J = 8.9 Hz, 2 H), 7.29 (d, J = 8.3 Hz, 2 H), 7.01 (d, J = 8.5 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 3.82 (s, 3 H), 3.39 (t, J = 11.1 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 159.3, 149.6, 132.4, 131.6, 123.97 (t, J = 3.3 Hz), 123.91 (t, J = 267.2 Hz), 123.6 (d, J = 1.4 Hz), 118.6, 114.0, 55.3, 41.4 (t, J = 29.8 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −71.48 (t, J = 11.2 Hz, 2 F); IR (film) 3005, 2937, 2838, 1614, 1585, 1515, 1486, 1464, 1442, 1352, 1324, 1303, 1248, 1200, 1179, 1127, 1116, 1087, 1067, 1036, 1013, 908, 847, 821, 796, 785, 764, 736, 697, 677, 650 cm⁻¹; HRMS (HAPCI+) calc. for C₁₅H₁₃BrF₂O₂ (M+) 342.0067, found 342.0067.

4-(3-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)phenyl)morpholine (9c):

Following General Procedure B-1, 0.112 g (0.50 mmol) of compound 8c was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.148 g (78% yield, 6% E-10c, 1% Z-10c) of desired product 9c as a yellow solid (MP = 61–64 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.45 (d, J = 2.5 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.30–7.28 (m, 1 H), 7.23 (dd, J = 8.8, 2.5 Hz, 1 H), 7.00 (t, J = 1.9 Hz, 1 H), 6.97 (d, J = 7.5 Hz, 1 H), 6.93 (dd, J = 8.3, 2.4 Hz, 1 H), 3.92–3.90 (m, 4 H), 3.51 (t, J = 11.2 Hz, 2 H), 3.24–3.22 (m, 4 H); ¹³C NMR (126 MHz, CDCl₃) δ 151.4, 145.3, 132.4 (t, J = 3.4 Hz), 131.2, 130.3, 129.2, 128.3, 127.7, 124.1 (t, J = 269.2 Hz), 124.0 (t, J = 1.9 Hz), 122.4, 118.1, 115.1, 67.0, 49.4, 42.4 (t, J = 29.2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.77 (t, J = 11.30 Hz, 2 F); IR (film) 2967, 2860, 2250, 1604, 1585, 1495, 1476, 1449, 1380, 1353, 1325, 1304, 1274, 1259, 1245, 1218, 1175, 1120, 1097, 1068, 998, 976, 908, 869, 837, 812, 763, 745, 697, 650, 618 cm⁻¹; HRMS (ESI+) calc. for C₁₈H₁₈Cl₂F₂NO₂ (M+H) 388.0683, found 388.0669. E-10c characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.73 (d, J = 6.3 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.25 (d, J = 6.7 Hz, 1 F); Z-10c characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.26 (d, J = 28.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.99 (d, J = 28.6 Hz, 1 F).

4’-(tert-butyl)-2-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-1,1’-biphenyl (9d):

Following General Procedure B-1, 0.136 g (0.50 mmol) of compound 8d was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.153 g (70% yield, 3% E-10d) of desired product 9d as a colorless solid (MP = 76–78 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.70 (s, 1 H), 7.64–7.62 (m, 3 H), 7.55 (d, J = 7.9 Hz, 2 H), 7.49 (t, J = 7.7 Hz, 1 H), 7.46 (d, J = 2.1 Hz, 1 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.31 (dd, J = 8.9, 1.3 Hz, 1 H), 7.24 (dt, J = 8.9, 1.8 Hz, 1 H), 3.63 (t, J = 11.1 Hz, 2 H), 1.45 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 150.6, 145.3, 141.4, 138.1, 132.0 (t, J = 3.4 Hz), 131.3, 130.3, 129.6, 129.4, 128.9, 128.5, 127.7, 127.0, 126.6, 125.9, 124.20 (t, J = 2.1 Hz), 124.15 (t, J = 269.3 Hz), 42.3 (t, J = 29.3 Hz), 34.7, 31.5; ¹⁹F NMR (376 MHz, CDCl₃) δ −70.80 (t, J = 11.0 Hz, 2 F); IR (film) 2964, 2250, 1476, 1352, 1324, 1256, 1218, 1174, 1116, 1097, 1062, 1043, 1016, 907, 868, 837, 813, 794, 763, 734, 704, 650, 617 cm⁻¹; HRMS (HAPCI+) calc. for C₂₄H₂₂Cl₂F₂O (M+) 434.1016, found 434.0999. E-10d characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.83 (d, J = 6.2 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.04 (d, J = 6.1 Hz, 1 F).

1-(2-(4-(tert-butyl)phenyl)-1,1-difluoroethoxy)-2,4-dichlorobenzene (9f):

Following General Procedure B-1, 0.098 g (0.50 mmol) of compound 8f was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.074 g (41% yield) of desired product 9f as a clear oil; ¹H NMR (500 MHz, CDCl₃) δ 7.43–7.40 (m, 3 H), 7.35 (d, J = 8.1 Hz, 2 H), 7.28–7.26 (m, 1 H), 7.20 (ddd, J = 8.8, 2.5, 0.8 Hz, 1 H), 3.50 (t, J = 11.3 Hz, 2 H), 1.36 (9 H); ¹³C NMR (126 MHz, CDCl₃) δ 150.8, 145.4, 131.3, 130.4, 130.3, 128.6, 128.4, 127.7, 125.5, 124.2 (t, J = 269.8 Hz), 124.1 (t, J = 2.1 Hz), 41.7 (t, J = 29.2 Hz), 34.7, 31.5; ¹⁹F NMR (376 MHz, CDCl₃) δ −71.02 (t, J = 11.4 Hz, 2 F); IR (film) 2965, 2869, 1477, 1352, 1325, 1274, 1260, 1218, 1175, 1159, 1124, 1097, 1062, 1026, 907, 869, 838, 805, 764, 745, 697, 651 cm⁻¹; HRMS (HAPCI+) calc. for C₁₈H₁₈Cl₂F₂O (M+) 358.0703, found 358.0701.

1-(2,2-difluorovinyl)-3,5-dimethylbenzene (8g):

Following General Procedure A, 3,5-dimethylbenzaldehyde (2.10 mL, 15.0 mmol) was reacted with PPh₃ (6.23 g, 22.5 mmol) and BrCF₂CO₂K (6.05 g, 27.0 mmol). Following workup, the product was purified by flash chromatography using a gradient of 0–10% EtOAc in hexanes, furnishing 1.163 g (44% yield) of desired product 8g as a clear oil; ¹H NMR (400 MHz, CDCl₃) δ 6.97 (bs, 2 H), 6.90 (bs, 1 H), 5.21 (dd, J = 26.4, 4.0 Hz, 1H), 2.32 (s, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ 156.3 (dd, J = 298.2, 287.4 Hz), 138.3, 130.3 (t, J = 6.7 Hz), 128.9 (t, J = 2.2 Hz), 125.6 (dd, J = 6.6, 3.7 Hz), 82.3 (dd, J = 28.9, 13.6 Hz), 21.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −82.39 (dd, J = 32.5, 26.5 Hz, 1 F), −84.62 (dd, J = 32.5, 4.0 Hz, 1F); IR (film) 3019, 2921, 2868, 1726, 1605, 1448, 1379, 1350, 1297, 1198, 1160, 1038, 965, 892, 851, 814, 765, 750, 715, 690, 583, 539, 515 cm⁻¹; HRMS (TAPCI) calc. for C₁₀H₁₀F₂ (M) 168.0751, found 168.0744.

2,4-dichloro-1-(2-(3,5-dimethylphenyl)-1,1-difluoroethoxy)benzene (9g):

Following General Procedure B-1, 0.085 g (0.50 mmol) of compound 8i was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.092 g (55% yield) of desired product 9i as a pale yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 2.5 Hz, 1 H), 7.25 (d, J = 8.6 Hz, 1 H), 7.18 (dd, J = 8.8, 2.5 Hz, 1 H), 7.02 (s, 2 H), 6.97 (s, 1 H), 3.42 (t, J = 11.4 Hz, 2 H), 2.33 (s, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.5, 138.0, 131.3 (t, J = 3.2 Hz), 131.2, 130.3, 129.5, 128.6, 128.4, 127.7, 124.2 (t, J = 269.5 Hz), 124.1 (d, J = 2.2 Hz), 42.1 (t, J = 29.3 Hz), 21.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −70.95 (t, J = 11.4 Hz, 2 F); IR (film) 3010, 2920, 1608, 1584, 1476, 1433, 1382, 1353, 1298, 1276, 1251, 1218, 1168, 1096, 1061, 962, 866, 847, 809, 764, 751, 715, 695, 661 cm⁻¹; HRMS (HAPCI+) calc. for C₁₆H₁₄Cl₂F₂O (M+) 330.0390, found 330.0391.

1-(2,2-difluorovinyl)-2,4-dimethylbenzene (8h):

Following General Procedure A, 2,4-dimethylbenzaldehyde (3.20 mL, 22.0 mmol) was reacted with PPh₃ (8.84 g, 33.0 mmol) and BrCF₂CO₂K (8.76 g, 40.0 mmol). Following workup, the product was purified by flash chromatography using a gradient of 0–10% EtOAc in hexanes, furnishing 1.57 g (41% yield) of desired product 8h as a clear oil; ¹H NMR (400 MHz, CDCl₃) δ 7.31 (dd, J = 8.4, 2.0 Hz, 1 H), 7.02 (dd, J = 4.2, 2.3 Hz, 2 H), 5.34 (dd, J = 25.6, 3.9 Hz, 1 H), 2.32 (s, 3 H), 2.27 (s, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ 156.2 (dd, J = 295.2, 288.1 Hz), 137.2, 135.8 (dd, J = 4.8, 1.7 Hz), 131.1, 128.1 (dd, J = 7.9, 2.0 Hz), 127.0, 126.0 (dd, J = 6.9, 4.9 Hz), 79.3 (dd, J = 28.7, 14.9 Hz), 21.2, 20.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −84.76 (dd, J = 33.1, 4.1 Hz, 1 F), −85.53 (ddd, J = 33.1, 25.5, 1.8 Hz, 1F); IR (film) 2923, 1726, 1616, 1569, 1505, 1453, 1379, 1345, 1281, 1250, 1235, 1180, 1111, 1074, 1037, 948, 917, 876, 836, 818, 765, 750, 721, 615, 581, 549, 534 cm⁻¹; HRMS (HAPCI+) calc. for C₁₀H₁₀F₂ (M+) 168.0751, found 168.0745.

2,4-dichloro-1-(2-(2,4-dimethylphenyl)-1,1-difluoroethoxy)benzene (9h):

Following General Procedure B-1, 0.084 g (0.50 mmol) of compound 8h was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.050 g (27% yield, 8% E-10h) as a pale yellow semisolid; ¹H NMR (500 MHz, CDCl₃) δ 7.40 (d, J = 2.5 Hz, 1 H), 7.25–7.22 (m, 2 H), 7.17 (dd, J = 8.8, 2.4 Hz, 1 H), 7.04 (s, 1 H), 7.01 (d, J = 7.9 Hz, 1 H), 3.50 (t, J = 11.3 Hz, 2 H), 2.40 (s, 3 H), 2.31 (s, 3 H); ¹³C (126 MHz, CDCl₃) δ 145.4 (t, J = 1.6 Hz), 137.74, 137.68, 131.7, 131.4, 131.3, 130.3, 128.5, 127.7, 127.0 (t, J = 3.1 Hz), 126.8, 124.6 (t, J = 271.0 Hz), 124.2 (t, J = 2.0 Hz), 38.6 (t, J = 29.2 Hz), 21.2, 20.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −70.43 (t, J = 11.4 Hz, 2 F); IR (film) 2923, 1702, 1618, 1583, 1508, 1476, 1382, 1347, 1311, 1258, 1217, 1126, 1095, 1060, 963, 942, 866, 810, 792, 762, 694, 673, 626, 566, 465, 455 cm⁻¹; MS (EI+) calc. for C₁₆H₁₄Cl₂F₂O (M+) 330.0, found 330.0. E-10h characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.83 (d, J = 6.4 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −85.72 (d, J = 6.4 Hz, 1 F).

ethyl (E)-3-(3-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)phenyl)acrylate (9j):

Following General Procedure B-1, 0.119 g (0.50 mmol) of compound 8j was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.127 g (64% yield) of desired product 9j as a colorless solid (MP = 70–72 °C); 1H NMR (500 MHz, CDCl₃) d 7.70 (d, J = 16.0 Hz, 1 H), 7.56 (s, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.42–7.36 (m, 3 H), 7.23 (d, J = 8.8 Hz, 1 H), 7.17 (dd, J = 8.8, 2.5 Hz, 1 H), 6.47 (d, J = 16.0 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 3.51 (t, J = 10.9 Hz, 2 H), 1.34 (t, J = 7.1 Hz, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ 167.0, 145.1, 144.2, 134.8, 132.5, 132.3 (t, J = 3.4 Hz), 131.4, 130.4, 130.3, 129.1, 128.4, 127.7, 127.5, 124.1 (d, J = 1.8 Hz), 123.9 (t, J = 269.7 Hz), 118.9, 60.6, 42.0 (t, J = 29.4 Hz), 14.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −70.81 (t, J = 10.9 Hz, 2 F); IR (film) 2983, 2253, 1709, 1640, 1608, 1585, 1476, 1438, 1385, 1367, 1354, 1322, 1274, 1260, 1228, 1179, 1163, 1119, 1097, 1061, 983, 909, 865, 840, 812, 763, 750, 694 cm⁻¹; HRMS (HAPCI+) calc. for C₁₉H₁₆Cl₂F₂O₃ (M+) 400.0445, found 400.0435.

2,4-dichloro-1-(1,1-difluoro-2-(3-nitrophenyl)ethoxy)benzene (9k):

Following General Procedure B-1, 0.093 g (0.50 mmol) of compound 8k was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.083 g (47% yield, 3% E-10k, 1% Z-10k) of desired product 9k as a clear solid (MP = 96–97 °C); ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 2.1 Hz, 1 H), 8.22 (dd, J = 8.3, 2.5 Hz, 1 H), 7.75 (d, J = 7.7 Hz, 1 H), 7.55 (t, J = 7.9 Hz, 1 H), 7.39 (d, J = 2.5 Hz, 1 H), 7.24 (d, J = 9.0 Hz, 1 H), 7.20 (dd, J = 8.8, 2.3 Hz, 1 H), 3.61 (t, J = 10.5 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 144.9 (d, J = 1.9 Hz), 136.9, 133.5, 131.7, 130.4, 129.5, 128.4, 127.9, 125.8, 124.1 (t, J = 2.0 Hz), 123.5 (t, J = 269.6 Hz), 123.1, 41.9 (t, J = 30.2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.75 (t, J = 10.6 Hz, 2 F); IR (film) 2956, 2923, 2870, 1702, 1532, 1475, 1352, 1324, 1300, 1258, 1216, 1173, 1158, 1125, 1097, 1068, 1061, 1027, 970, 908, 866, 802, 765, 34, 697, 677, 657 cm⁻¹; HRMS (HAPCI+) calc. for C₁₄H₉Cl₂F₂NO₃ (M+) 346.9928, found 346.9925. E-10k characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.73 (d, J = 6.0 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −81.93 (d, J = 5.5 Hz, 1 F); Z-10k characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.21 (d, J = 28.0 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −82.18 (d, J = 27.9 Hz, 1 F).

3-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)benzonitrile (9l):

Following General Procedure B-2, 0.083 g (0.50 mmol) of compound 8l was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.080 g (49% yield) of desired compound 9l as a colorless solid (MP = 81–83 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.71 (d, J = 2.3 Hz, 1 H), 7.65–7.63 (m, 2 H), 7.48 (dt, J = 8.5, 4.3 Hz, 1 H), 7.39 (t, J = 2.0 Hz, 1 H), 7.24–7.18 (m, 2 H), 3.53 (t, J = 10.6 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.0, 135.2, 134.3, 133.1, 131.72, 131.66, 130.4, 129.4, 128.4, 127.8, 124.1. 123.5 (t, J = 269.9 Hz), 118.6, 112.9, 41.8 (t, J = 29.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.80 (t, J = 10.6 Hz, 2 F); IR (film) 3082, 2955, 2230, 1704, 1587, 1476, 1434, 1382, 1352, 1303, 1278, 1261, 1242, 1232, 1219, 1179, 1102, 1071, 1056, 1003, 976, 942, 918, 904, 873, 866, 823, 811, 800, 758, 738, 694, 644, 618, 577, 463 cm⁻¹; HRMS (HAPCI+) calc. for C₁₅H₉Cl₂F₂NO (M+) 327.0029, found 327.0031.

2-(2,2-difluorovinyl)-1,3-dimethylbenzene (8l):

Following General Procedure A, 2,6-dimethylbenzaldehyde (2.2 mL, 15.0 mmol) was reacted with PPh₃ (5.91 g, 22.5 mmol) and BrCF₂CO₂K (6.17 g, 27.0 mmol). Following workup, the product was purified by flash chromatography using a gradient of 0–10% EtOAc in hexanes, furnishing 0.763 g (28% yield) of desired product 8l as a clear oil; ¹H NMR (400 MHz, CDCl₃) δ 7.14 (dd, J = 8.6, 6.4 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 2 H), 5.23 (dd, J = 27.5, 2.3 Hz, 1 H), 2.29 (s, 6 H); ¹³C NMR (126 MHz, CDCl₃) 155.0 (q, J = 291.7, 288.4 Hz), 137.5 (dd, J = 2.6, 1.4 Hz), 127.8, 127.6, 78.1 (dd, J = 27.3, 20.6 Hz), 20.5 (d, J = 2.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −83.38 (dd, J = 32.5, 27.0 Hz, 1 F), −87.16 (dd, J = 33.1, 2.4 Hz, 1 F); IR (film) 3024, 2956, 2923, 2330, 1736, 1586, 1468, 1445, 1380, 1329, 1276, 1254, 1222, 1166, 1096, 1032, 932, 850, 802, 768, 746, 698, 599, 537 cm⁻¹; HRMS (TAPCI) calc. for C₁₀H₁₀F₂ (M) 168.0751, found 168.0741.

1-(2-(4-bromophenyl)-1,1-difluoroethoxy)-2,4-dichlorobenzene (9m):

Following General Procedure B-2, 0.110 g (0.50 mmol) of compound 8m was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.113 g (59% yield) of desired compound 9m as a colorless solid (MP = 52–53 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.49 (dd, J = 8.3, 1.7 Hz, 2 H), 7.40 (d, J = 2.3 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 2 H), 7.22 (dd, J = 8.8, 1.5 Hz, 1 H), 7.19 (dd, J = 8.8, 2.3 Hz, 1 H), 3.45 (t, J = 10.9 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.2, 132.4, 131.7, 131.5, 130.6 (t, J = 3.2 Hz), 130.4, 128.5, 127.8, 124.2, 123.8 (t, J = 269.9 Hz), 122.2, 41.7 (t, J = 29.6 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −71.02 (t, J = 10.8 Hz, 2 F); IR (film) 2925, 1701, 1583, 1476, 1433, 1408, 1384, 1350, 1260, 1217, 1099, 1073, 1061, 1014, 897, 868, 843, 799, 762, 672, 623, 565, 489 cm⁻¹; HRMS (HAPCI+) calc. For C₁₄H₉BrCl₂F₂O (M+) 379.9182, found 379.9169.

2,4-dichloro-1-(1,1-difluoro-2-(2-iodophenyl)ethoxy)benzene (9n):

Following General Procedure B-2, 0.133 g (0.50 mmol) of compound 8n was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.105 g (49% yield) of desired compound 9n as a colorless solid (MP = 54–55 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.91 (dd, J = 7.9, 1.3 Hz, 1 H), 7.52 (dd, J = 7.8, 1.6 Hz, 1 H), 7.40 (d, J = 2.5 Hz, 1 H), 7.35 (td, J = 7.6, 1.3 Hz, 1 H), 7.27–7.25 (m, 1 H), 7.19 (dd, J = 8.8, 2.5 Hz, 1 H), 7.01 (td, J = 7.7, 1.7 Hz, 1 H), 3.77 (t, J = 10.9 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.3, 140.0, 135.2 (t, J = 2.8 Hz), 131.8, 131.5, 130.4, 129.6, 128.7, 128.4, 127.8, 124.4, 124.1 (t, J = 270.1 Hz), 102.2, 46.1 (t, J = 29.2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −69.75 (t, J = 10.8 Hz, 2 F); IR (film) 2924, 1698, 1584, 1565, 1475, 1436, 1384, 1349, 1276, 1258, 1216, 1124, 1096, 1061, 1046, 1014, 868, 811, 765, 748, 694, 671, 652, 626, 613, 566, 488, 473, 459 cm⁻¹; HRMS (HAPCI+) calc. for C₁₄H₉Cl₂F₂IO (M+) 427.9043, found 427.9029.

2,4-dichloro-1-(1,1-difluoro-2-(3-(trifluoromethyl)phenyl)ethoxy)benzene (9o):

Following General Procedure B-2, 0.104 g (0.50 mmol) of compound 8o was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.094 g (51% yield) of desired compound 9o as a clear oil; ¹H NMR (500 MHz, CDCl₃) δ 7.69 (s, 1 H), 7.60 (t, J = 7.7 Hz, 2 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.40 (t, J = 2.0 Hz, 1 H), 7.24 (dd, J = 8.8, 1.4 Hz, 1 H), 7.19 (dd, J = 8.8, 2.4 Hz, 1 H), 3.56 (t, J = 10.7 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.2, 134.2, 132.6 (t, J = 3.3 Hz), 131.6, 130.4, 129.0, 128.5, 127.8, 127.6 (q, J = 4.0 Hz), 125.3, 124.9 (q, J = 3.9 Hz), 124.1, 123.8 (t, J = 269.7 Hz), 123.1, 42.1 (t, J = 29.7 Hz); ¹⁹F NMR (376 MHz, CDCl₃, β, β,β-trifluoroethanol as standard with ppm = −79.40) δ −64.86 (s, 3 F), −72.02 (t, J = 11.0 Hz, 2 F); IR (film) 2949, 1584, 1477, 1454, 1435, 1354, 1329, 1257, 1202, 1166, 1126, 1100, 1076, 1062, 870, 800, 764, 751, 703, 664, 617, 564 cm⁻¹; HRMS (HAPCI+) calc. for C₁₅H₉Cl₂F₅O (M+) 369.9951, found 369.9934.

2,4-dichloro-1-(2-(3,5-dichlorophenyl)-1,1-difluoroethoxy)benzene (9p):

Following General Procedure B-2, 0.105 g (0.50 mmol) of compound 8p was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.078 g (42% yield, 1% E-10p, 1% trifluoroethylbenzene side product) of desired compound 9p as a pinkish colorless solid (MP = 46–47 °C); ¹H NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 2.4 Hz, 1 H), 7.35 (t, J = 1.9 Hz, 1 H), 7.31 (d, J = 2.0 Hz, 2 H), 7.24 (d, J = 8.7 Hz, 1 H), 7.20 (dd, J = 8.8, 2.4 Hz, 1 H), 3.45 (t, J = 10.6 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.1, 135.1, 134.7, 131.7, 130.5, 129.3, 128.5, 128.3, 127.8, 124.1, 123.5 (t, J = 269.8 Hz), 41.7 (t, J = 30.1 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ−70.61 (t, J = 10.6 Hz, 2 F); IR (film) 1592, 1570, 1476, 1436, 1385, 1351, 1258, 1062, 867, 800, 763, 702, 643, 565 cm⁻¹; HRMS (HAPCI+) calc. for C₁₄H₈Cl₄F₂O (M+) 369.9297, found 369.9300. E-10p characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.75 (d, J = 5.8 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −81.75 (d, J = 5.8 Hz, 1 F).

4-(2,2-difluorovinyl)-N,N-diisopropylbenzamide (8q):

Following General Procedure A, compound 8q–1 (0.823, 3.60 mmol) was reacted with PPh₃ (1.50 g, 5.30 mmol) and BrCF₂CO₂K (1.42 g, 6.50 mmol) in NMP (2.0 mL, 2 M). Following workup, the product was purified by flash chromatography using a gradient of 0–30% EtOAc in hexanes, furnishing 0.655 g (69% yield) of desired product 8q as a colorless solid (MP = 43–44 °C); ¹H NMR (500 MHz, DMSOD₆, 25 °C) δ 7.41 (d, J = 8.1 Hz, 2 H), 7.29 (d, J = 8.2 Hz, 2 H), 5.85 (dd, J = 28.1, 4.1 Hz, 1 H), 3.61 (bs, 2 H), 1.38–1.15 (m, 12 H); ¹H NMR (500 MHz, DMSO-D₆, 60 °C) δ 7.41 (d, J = 7.9 Hz, 2 H), 7.28 (d, J = 7.9 Hz, 2 H), 5.79 (dd, J = 27.8, 4.0 Hz, 1 H), 3.64 (hept, J = 6.4 Hz, 2 H), 1.28 (bs, 12 H); ¹³C NMR (126 MHz, DMSO-D₆, 60 °C) δ 169.8, 156.1 (dd, J = 297.8, 286.2 Hz), 138.2 (t, J = 2.3 Hz), 130.5 (dd, J = 7.8, 5.8 Hz), 128.1 (dd, J = 6.6, 3.8 Hz), 126.3, 82.3 (dd, J = 29.5, 11.8 Hz), 20.9; ¹⁹F NMR (376 MHz, DMSO-D₆, 25 °C) δ −82.16 (dd, J = 32.1, 28.1 Hz, 1 F), −84.02 (dd, J = 32.2, 4.1 Hz, 1 F); IR (film) 3434, 2252, 2126, 1729, 1660, 1345, 1276, 1052, 1024, 1005, 822, 760, 623 cm⁻¹; HRMS (ESI+) calc. for C₁₅H₂₀F₂NO (M+H) 268.1513, found 268.1500.

4-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-N,N-diisopropylbenzamide (9q):

Following General Procedure B-2, 0.134 g (0.50 mmol) of compound 8q was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.126 g (59% yield, 3% E-10q, 1% Z-10q) of desired compound 9q as a orange solid (MP = 81–83 °C); ¹H NMR (500 MHz, CDCl₃, 25 °C) δ 7.40 (d, J = 7.9 Hz, 2 H), 7.37 (d, J = 2.5 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 8.9 Hz, 1 H), 7.18 (dd, J = 8.8, 2.5 Hz, 1 H), 3.74 (bs, 1 H), 3.49 (t, J = 11.0 Hz, 2 H), 1.46 (bs, 6 H), 1.21 (bs, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ 170.8, 145.2, 138.6, 132.1 (t, J = 3.2 Hz), 131.5, 130.9, 130.3, 128.5, 127.8, 126.2, 125.8, 124.2, 124.0 (t, J = 271.0 Hz), 41.99 (t, J = 29.3 Hz), 20.9; ¹⁹F NMR (376 MHz, CDCl₃) δ −70.73 (t, J = 11.3 Hz, 2 F); IR (film) 2993, 2969, 2933, 1628, 1474, 1440, 1375, 1360, 1339, 1261, 1241, 1226, 1214, 1204, 1112, 1094, 1058, 1028, 902, 876, 856, 842, 811, 800, 771, 753, 676, 578 cm⁻¹; HRMS (ESI+) calc. for C₂₁H₂₃Cl₂F₂NO₂Na (M+Na) 452.0972, found 452.0966. E-10q characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.70 (d, J = 6.1 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.19 (d, J = 5.9 Hz, 1 F); Z-10q characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.24 (d, J = 28.6 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.28 (d, J = 29.0 Hz, 1 F).

4-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)phenyl trifluoromethanesulfonate (9r):

Following General Procedure B-2, 0.144 g (0.50 mmol) of compound 8r was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.110 g (49% yield) of desired compound 9r as a light brown oil; ¹H NMR (500 MHz, CDCl₃) δ 7.49 (d, J = 8.6 Hz, 2 H), 7.39 (d, J = 2.4 Hz, 1 H), 7.30–7.27 (m, 2 H) 7.23 (d, J = 8.8 Hz, 1 H), 7.20 (dd, J = 8.8, 2.4 Hz, 1 H), 3.53 (t, J = 10.6 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 149.4, 145.0 (t, J = 1.7 Hz), 132.7, 132.2 (t, J = 3.5 Hz), 131.7, 130.4, 129.7, 127.8, 124.2 (t, J = 2.1 Hz), 123.6 (t, J = 269.3 Hz), 121.5, 118.9 (q, J = 320.7 Hz), 41.6 (t, J = 29.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃, delay time = 5 s) δ −70.80 (t, J = 10.6 Hz, 2 F), −73.85 (s, 3 F); IR (film) 1704, 1601, 1584, 1504, 1476, 1421, 1353, 1251, 1212, 1183, 1140, 1113, 1100, 1061, 1020, 946, 890, 807, 764, 729, 694, 674, 640, 609, 579, 523, 492 cm⁻¹; HRMS (HAPCI+) calc. for C₁₅H₉Cl₂F₅O₄S (M+) 449.9519, found 449.9516.

Compounds in Table 4:

Table 4: Scope of Heteroaryl Gem-Difluoroalkene Electrophiles.

[a] Standard conditions a: 11a–e (1.0 equiv., 0.50 mmol), 5c (5.0 equiv., 2.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.50 M, 1.0 mL), 140 °C, for 24 h under an N₂ atmosphere. The selectivity of 12:13 was determined by ¹⁹F NMR analysis of the crude reaction mixture using TFT (50 μL) as a standard and is reported in parentheses. Yields are reported as the isolated yield of >95% pure material and represent the average of 2 runs. [b] Standard conditions b: 11a–e (1.0 equiv., 0.50 mmol), 5c (3.0 equiv., 1.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.45 M, 0.90 mL), H₂O (0.050 M, 0.10 mL), 140 °C, for 24 h under an N₂ atmosphere. The selectivity of 12:13 was determined by ¹⁹F NMR analysis of the crude reaction mixture using TFT (50 μL) as a standard and is reported in parentheses. Yields are reported as the isolated yield of >95% pure material and represent the average of 2 runs. [b] Standard conditions b: 11a–e (1.0 equiv., 0.50 mmol), 5c (3.0 equiv., 1.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.45 M, 0.90 mL), H₂O (0.050 M, 0.10 mL), 140 °C, for 24 h under an N2 atmosphere. The selectivity of 12:13 was determined by 19F NMR analysis of the crude reaction mixture using TFT (50 μL) as a standard and is reported in parentheses. Yields are reported as the isolated yield of >95% pure material and represent the average of 2 runs.

3-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-1-tosyl-1H-indole (12a):

Following General Procedure B-1, 0.167 g (0.50 mmol) of compound 11a was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.209 g (84% yield, 3% E-13a, 1% Z-13a) of desired product 12a as an orange solid (MP = 90–93 °C); ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J = 8.3 Hz, 1 H), 7.78 (d, J = 8.2 Hz, 2 H), 7.68 (s, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.38 (d, J = 2.3 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.27 (t, J = 7.3 Hz, 1 H), 7.22–7.16 (m, 5 H), 3.61 (t, J = 10.8 Hz, 2 H), 2.32 (s, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.1, 135.3, 135.0, 131.5, 130.8, 130.3, 130.0, 129.2, 128.5, 128.3, 127.7, 126.9, 126.3, 125.4, 125.0, 124.3 (t, J = 1.9 Hz), 123.9 (t, J = 269.4 Hz), 123.4, 119.8, 113.7, 112.8 (t, J = 3.7 Hz), 32.1 (t, J = 31.5 Hz), 21.6; ¹⁹F NMR (376 MHz, CDCl₃) δ −70.61 (t, J = 10.9 Hz, 2 F); IR (film) 2258, 1598, 1476, 1448, 1369, 1324, 1275, 1259, 1217, 1188, 1175, 1122, 1090, 1061, 1020, 977, 908, 869, 811, 784, 765, 747, 703, 672, 750 cm⁻¹; HRMS (ESI+) calc. for C₂₃H₁₈Cl₂F₂NO₃S (M+H) 496.0353, found 496.0371. E-13a characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.82 (d, J = 3.5 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −86.14 (d, J = 3.0 Hz, 1 F); Z-13a characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.42 (d, J = 29.0 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −80.20 (d, J = 29.1 Hz, 1 F).

4-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-1-phenyl-1H-pyrazole (12b):

Following General Procedure B-1, 0.104 g (0.50 mmol) of compound 11b was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.081 g (44% yield) of desired product 12b as a yellow solid (MP = 44–46 °C); 1H NMR (500 MHz, CDCl₃) δ 7.97 (s, 1 H), 7.74 (s, 1 H), 7.70–7.68 (m, 2 H), 7.45 (dd, J = 8.6, 7.3 Hz, 2 H), 7.42 (d, J = 2.5 Hz, 1 H), 7.30–7.26 (m, 2 H), 7.20 (dd, J = 8.9, 2.5 Hz, 1 H), 3.47 (t, J = 11.0 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.2, 142.1, 140.1, 131.5, 130.4, 129.6, 128.4, 127.8, 127.3, 126.7, 124.2 (t, J = 1.9 Hz), 123.9 (t, J = 268.7 Hz), 119.2, 113.0 (t, J = 3.9 Hz), 31.9 (t, J = 31.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −71.98 (t, J = 11.0 Hz, 2 F); IR (film) 3053, 2927, 1601, 1576, 1505, 1476, 1431, 1403, 1385, 1343, 1258, 1215, 1187, 1120, 1097, 1062, 1042, 1017, 955, 905, 867, 838, 808, 756, 711, 691, 674, 656 cm⁻¹; HRMS (ESI+) calc. for C₁₇H₁₃Cl₂F₂N₂O (M+H) 369.0373, found 369.0347.

4-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)dibenzo[b,d]thiophene (12c):

Following General Procedure B-1, 0.123 g (0.50 mmol) of compound 11c was reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.119 g (58% yield, 1% E-13c, 6% unknown side product) of desired product 12c as a colorless solid (MP = 119–121 °C); ¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, J = 8.0 Hz, 2 H), 7.90–7.88 (m, 1 H), 7.57 (d, J = 7.4 Hz, 1 H), 7.52–7.47 (m, 3 H), 7.40 (s, 1), 7.25 (d, J = 8.8 Hz, 1 H), 7.18 (d, J = 7.9 Hz, 1 H), 3.82 (t, J = 10.9 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 145.2 (d, J = 1.7 Hz), 141.3, 139.1, 136.2, 136.0, 131.5, 130.3, 129.3, 128.7, 127.7, 127.0, 126.3 (t, J = 24.6 Hz), 124.8, 124.6, 124.4 (t, J = 1.9 Hz), 124.3 (t, J = 270.6 Hz), 122.9, 121.9, 121.3, 41.3 (t, J = 30.0 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −69.59 (t, J = 11.0 Hz, 2 F); IR (film) 1476, 1444, 1405, 1385, 1352, 1325, 1265, 1170, 1122, 1099, 1062, 1022, 907, 842, 817, 797, 733, 706, 650, 618 cm⁻¹; HRMS (HAPCI+) calc. for C₂₀H₁₂Cl₂F₂OS (M+) 407.9954, found 407.9940. E-13c characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.97 (d, J = 5.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −82.77 (d, J = 5.8 Hz, 1 F).

2-(3-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)phenyl)-5-(1,3-dioxolan-2-yl)pyridine (12d):

Following General Procedure B-2, 0.1446 g (0.50 mmol) of compound 11d was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at 140 °C for 24 h. After workup with 1 N NaOH (aq.), the product was purified by reverse-phase flash chromatography using a gradient of 2–100% MeCN in H₂O, furnishing 0.137 g (61% yield, 4% E-13d, 1% Z-13d) of desired compound 12d as a yellow solid (MP = 84–86 °C); ¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J = 2.2 Hz, 1 H), 8.05 (s, 1 H), 7.96 (q, J = 2.7, 1.9 Hz, 1 H), 7.86 (dd, J = 8.1, 2.3 Hz, 1 H), 7.76 (d, J = 8.2 Hz, 1 H), 7.47 (d, J = 4.7 Hz, 2 H), 7.38 (d, J = 2.6 Hz, 1 H), 7.24 (d, J = 8.8 Hz, 1 H), 7.17 (dd, J = 8.9, 2.6 Hz, 1 H), 5.91 (s, 1 H), 4.16–4.11 (m, 2 H), 4.10–4.05 (m, 2 H), 3.59 (t, J = 11.1 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 158.0, 148.4, 145.4, 139.4, 135.1, 132.24, 132.17 (t, J = 2.9 Hz), 131.5, 131.4, 130.3, 129.5, 129.0, 128.5, 127.7, 126.6, 124.18, 124.12 (t, J = 269.6 Hz), 120.3, 102.1, 65.6, 42.3 (t, J = 29.2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −70.75 (t, J = 11.0 Hz, 2 F); IR (film) 2887, 1703, 1601, 1569, 1475, 1354, 1256, 1095, 1062, 1025, 982, 942, 864, 839, 799, 757, 698, 564 cm⁻¹; HRMS (ESI+) calc. for C₂₂H₁₈Cl₂F₂NO₃ (M+H) 452.063, found 452.0627. E-13d characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.83 (d, J = 6.0 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.69 (d, J = 5.9 Hz, 1 F); Z-13d characteristic peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.34 (d, J = 28.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.63 (d, J = 28.4 Hz, 1 F).

Figure 2: Plausible Reaction Mechanism.