Acid-Catalyzed Hydrothiolation of gem-Difluorostyrenes to Access α,α–Difluoroalkylthioethers

Abstract

The substitution of hydrogen atoms with fluorine in bioactive molecules can greatly impact physicochemical, pharmacokinetic, and pharmacodynamic properties. However, current synthetic methods cannot readily access many fluorinated motifs, which impedes utilization of these groups. Thus, the development of new methods to introduce fluorinated functional groups is critical for developing the next generation of biological probes and therapeutic agents. The synthesis of one such substructure, the α,α-difluoroalkylthioether, typically requires specialized conditions that necessitate early-stage installation. A late-stage and convergent approach to access α,α-difluoroalkylthioethers could involve nucleophilic addition of thiols across gem-difluorostyrenes. Unfortunately, under basic conditions, nucleophilic addition to gem-difluorostyrenes generates an anionic intermediate that can undergo facile elimination of fluoride to generate α-fluorovinylthioethers. To overcome this decomposition, we herein exploit an acid-based catalyst system to facilitate simultaneous nucleophilic addition and protonation of the unstable intermediate. Ultimately, the optimized mild conditions afford the desired α,α-difluoroalkylthioethers in high selectivity and moderate to excellent yields. These α,α-difluoroalkylthioethers are less nucleophilic and more oxidatively stable relative to non-fluorinated thioethers, suggesting the potential application of this unexplored functional group in biological probes and therapeutic agents.

Graphical Abstract

Introduction

The substitution of hydrogen atoms with fluorine in bioactive molecules can greatly impact physicochemical, pharmacokinetic, and pharmacodynamic properties.^1–5 Thus, the development of new strategies to access fluorinated functional groups is critical for developing the next generation of biological probes and therapeutic agents.^4,6 From a synthetic standpoint, the incorporation of fluorine onto an organic substrate can perturb standard properties, which enables new and specialized reactivities creating opportunities for accessing drug-like substructures.⁵ The synthesis of one such substructure, the α,α-difluoroalkylthioether, currently requires specialized conditions that often necessitate early-stage installation.^7–10 Though a recently published general late-stage strategy generates terminal α,α-difluoroalkylthioethers,¹¹ convergent strategies bringing together two larger fragments remains largely underrepresented.

A late-stage convergent approach to access α,α-difluoroalkylthioethers could involve nucleophilic addition of thiols across gem-difluorostyrenes. Unfortunately, under basic conditions nucleophilic addition to gem-difluorostyrenes generates an anionic intermediate that can undergo facile elimination of fluoride to generate α-fluorovinylthioethers (Scheme 1A, a).^12,13 To avoid this elimination, the β-fluoro anionic intermediate can be trapped intramolecularly with an aldehyde or pronated using a base-catalyzed strategy (Scheme 1A, c–d).¹⁴ Alternately, one electron processes add thiyl radicals to gem-difluorostyrenes (Scheme 1A, b).¹⁵ However, these strategies only function with thiophenol derived nucleophiles. In contrast, the corresponding reactions of gem-difluorostyrenes with alkylthiol derived nucleophiles typically also involve elimination of fluoride (Scheme 1A, e).^12,16–18 Herein, we report conditions for a selective synthesis of α,α-difluoroalkylthioethers that involves acid-catalyzed addition of thiols across gem-difluorostyrenes. Preliminary studies demonstrate that these fluorinated thioethers are less nucleophilic and more oxidatively stable relative to non-fluorinated thioethers.^1,2

Scheme 1:

Strategies for Generating α,α–Difluoroalkylthioethers

Results and Discussion

We initially envisioned that access to alkylthiol derived α,α-difluoroalkylthioethers could be accomplished using a base catalyzed strategy that has successfully added phenols and thiophenols across fluorostyrenes (Scheme 2A).^14,19 Unfortunately, these initial conditions utilizing 1,1,3,3-tetramethylguanidine (TMG) selectively afforded addition/elimination product 3n (Scheme 2A). Upon evaluation of alternate bases, use of catalytic amounts of the corresponding sodium thiolate improved selectivity for the desired α,α-difluoroalkylthioether product 5n (Scheme 2B). However, these conditions did not apply to a variety of gem-difluorostyrene substrates. Borrowing inspiration from Ag-mediated addition of fluoride to gem-difluorostyrenes,²⁰ we envisioned that a Ag-based catalyst system might deliver S-based radicals and prevent the elimination of fluoride. In fact, the use of AgOTf in catalytic amounts provided desired product 5n in excellent selectivity (Scheme 2C). Unfortunately, when scaled to 0.5 mmol, this Ag catalyzed system suffered from poor conversion, and routine optimization (time, temperature, solvent, catalyst loading) did not substantially improve the reaction. Considering the proposed mechanism of nucleophilic addition across the alkene, we explored the use of additives that might protonate the presumed unstable intermediate β,β-difluorosytrenyl anion (Scheme 1A, 2) and deliver the desired product. To this end, the addition of primary alcohols, such as 2-methoxyethanol, improved the selectivity (Scheme 2D). Upon further optimization, the addition of pyridine-derived ligands rendered Ag unnecessary and enabled use of alkali triflate salts (Scheme 2E). Using a system of LiOTf (10 mol%), pyridine (20 mol%), and 2-methoxyethanol (2 equiv.) in o-xylene, the use of an atmosphere of air improved the rate of reaction relative to an atmosphere of N₂ (Scheme 2F). However, when run under a pure O₂ atmosphere this optimized system only generated trace amounts of desired product, presumably from extensive oxidative degradation of the thiol nucleophile (See SI; Figure S1).

Scheme 2:

Optimization Workflow of Selective Hydrofunctionalization of gem-Difluorostyrenes

A range of gem-difluorostyrene substrates reacted with alkylthiols to deliver α,α-difluoroalkylthioethers in high selectivity over α-fluorovinylthioether side products (typically >25:1; Scheme 3). Electron deficient difluorostyrenes containing nitrile, nitro, or trifluoromethyl groups reacted smoothly giving excellent yields (5b–5f; 72–92%). Gem-difluorostyrenes bearing halogens and pseudo-halogens were compatible and afforded products in good yields (5g–5k; 61–82%). Additionally, amides were compatible with this reaction giving the desired product in moderate yield (5u; 63%). Interestingly, a substrate bearing a competing secondary electrophilic site, such as an α,β–unsaturated ester, produced α,α–difluoroalkylthioether product (5t; 76%) in high selectivity. Substrates containing electron-donating groups afforded respectable yields of anticipated products (5l–5q; 62–95%). Unfortunately, a gem-difluorostyrene bearing a free phenol suffered from low overall conversion and poor yields (5v; 22%), though reactions of protected phenols proceeded smoothly under the optimized conditions (5w–5x; 50–87%). Substrates containing dibenzothiophene or pyrazole were also compatible with this system (5y–5z; 53–72%). Though, other heterocycle scaffolds including pyridine, tryptophan, thiazole, and phenothiazines did not couple. Furthermore, a substrate with a fully substituted alkene reacted well under the standard conditions to generate the desired product (5aa; 73%). However, no desired products were obtained when non-styrene derived gem-difluoroalkenes were used.

Scheme 3:

Scope of Gem-Difluorostyrenes^a

^a Unless otherwise stated, all reactions were carried out with 1 (0.5 mmol), 1-octanethiol (0.75 mmol), LiOTf (10 mol%), pyridine (20 mol%), and 2-methoxyethanol (1.0 mmol) in o-xylene heated at 110 °C for 24 hours under an atmosphere of air. ^bReaction was carried out with 1 (1.0 mmol), 1-octanethiol (1.50 mmol), LiOTf (10 mol%), pyridine (20 mol%), and 2-methoxyethanol (2.0 mmol) in o-xylene heated at 110 °C for 24 hours under an atmosphere of air. Isolated yields have >25:1 selectivity, and represent an average of two independent reactions.

Using the optimized conditions, primary aliphatic thiols reacted efficiently in high selectivity (>25:1), though secondary and tertiary thiols reacted sluggishly (Scheme 4A). While cyclohexanethiol reacted smoothly (6f; 81%), increasing steric bulk near sulfur (e.g. tertiary or phenethyl thiols) decreased both conversion and yields (6h–6i; 28–56%) and required more forcing conditions (120 °C, 200 mol% pyridine) to generate product. Unfortunately, further increasing the temperature, equivalents of nucleophile, or reaction times did not improve the reactivity of these hindered substrates. Alkyl thiols bearing carbonyl groups, including esters, were well tolerated (6c; 88%). Free carboxylic acids were compatible, though this reaction required the addition of excess pyridine (6d; 33%). The reaction of substrates bearing an alcohol and a thiol selectively reacted at the thiol (6a–6b; 68–73%). Interestingly, a substrate containing a primary halogen did not undergo intramolecular cyclization but instead generated the linear haloalkane product in moderate yield (6e; 48%). Further, the use of cysteine and its protected equivalents was unsuccessful, which in its current form, discourages application of the method toward peptide and protein bioconjugation reactions. Additionally, initial attempts to adapt the reaction to aqueous biocompatible conditions did not provide appreciable quantities of difluorinated products.

Scheme 4:

Scope of Thiol Nucleophiles^a

^a Unless otherwise stated, all reactions were carried out with 1 (0.5 mmol), thiol (0.75 mmol), LiOTf (10 mol%), pyridine (20 mol%), and 2-methoxyethanol (1.0 mmol) in o-xylene heated at 110 °C for 24 hours under an atmosphere of air. Isolated yields have >25:1 selectivity and represent an average of two independent reactions. ^b Pyridine (200 mol%) was used. ^c Reaction heated to 120 °C. ^d 8 (0.5 mmol), PhSH (1.5 mmol), TMG (5 mol%) in DCE heated to 100 °C for 20 hours under an atmosphere of N₂.

In addition to alkylthiols, the optimized conditions effectively added thiophenol nucleophiles across the gem-difluorostyrenes (Scheme 4B). In fact, the reaction effectively coupled thiophenols with electron-deficient gem-difluorostyrnes (6i–6k; 79–84%), that could not be effectively coupled using our previous base-catalyzed conditions (5 mol% tetramethylguanidine, 1,2-dichlorobenzene, 100 °C).¹⁴

Preliminary mechanistic studies support a general acid catalyzed process involving concurrent nucleophilic attack of the gem-difluorostyrene (1) by the thiol and protonation by pyridinium (9) to generate thionium intermediate 8 (Scheme 5). Thionium 8 is then deprotonated to furnish the desired product (5) and regenerate pyridinium 9. Such concerted hydrothiolation reactions of non-fluorinated alkenes has been previously suggested, though minimal experimental support exists for this mechanistic proposal.^21,22 Notably, this mechanism does not involve a β-F anionic intermediate that would typically decompose to deliver fluorovinylether side products.

Scheme 5:

Plausible Mechanism

Mechanistically, both literature and probing experiments indicate that pyridine might serve as a precursor to an acid-based catalyst system. First, considering pK_as, pyridine (3.4 in DMSO) is insufficiently basic to deprotonate HS–alkyl (17 in DMSO),²³ which disfavors mechanisms that would involve deprotonation of the thiol prior to attacking the difluorostyrene^23,24. This discrepancy in pK_a requires the formation of a more acidic species to protonate pyridine, presumably a sulfinic acid formed via oxidation of the thiol (Scheme 6A).^25–27 This initial oxidation was previously shown to generate an equivalent of superoxide,²⁸ which can further oxidize disulfides to sulfinic and sulfonic acids.²⁶ Supporting this activation sequence, under our reaction conditions, trace quantities of sulfinic and sulfonic acids were observed by LCMS (Figure S2). To probe whether oxidized sulfur-based acids could protonate pyridine and serve as a catalyst, direct use of octanesulfonic acid might eliminate the need to run the reaction in an atmosphere of air. In fact, addition of 1 mol% octanesulfonic acid under N₂ enabled the reaction of 1c with octanethiol to proceeded at the same initial rate as the standard reaction conditions using Pyr under air (2.3 vs 2.2 μmol/min). Further, direct use of a pyridinium surrogate (e.g. Pyr–H⁺OTf⁻) under N₂ proceeded at a similar rate (2.5 μmol/min). Combined, these reactions support the proposed oxidative activation sequence (Scheme 6B).

Scheme 6:

Pyridinium Serves as Active Catalyst

Support for a two-electron process derives from a combination of linear free energy relationship and KIE studies. Specifically, a correlation with σ⁻ (p = −0.41, R² = 0.92) implicated partial anionic character at the benzylic position at the transition state (Scheme 7A). Moreover, poor correlation with σ• (R² = 0.02) and σ⁺ (p = −0.43, R² = 0.74) discounted process that might proceed through benzyl radical or cation intermediates (See SI, Figure S3, S4). During the course of the reaction, homocoupled nucleophile, an intermediate capable of homolytical cleavage to generate •SR, did form (15%, Scheme 7B); however, performing the reaction using pregenerated disulfide 5b did not generate product, thus discounting RSSR serving as an in situ generated substrate (Scheme 7C). Furthermore, both competitive and parallel systems demonstrated a primary KIE, supporting a concerted general acid-catalyzed addition, rather than sequential thiol addition and subsequent proton transfer (Scheme 7D–E).

Scheme 7:

Mechanistic Studies

α,α-Difluorinated thioethers display decreased nucleophilicity and increased oxidative stability relative to non-fluorinated analogs. To assess nucleophilicity, compounds 13 and 5a were subjected to standard alkylation conditions with MeI (DMF, rt). The non-fluorinated analog (13) reacted in 66% conversion over 18 h, while the corresponding α,α-difluorinated analog (5a) remained unreacted (Scheme 8A). This data suggests that fluorination α to S in bioactive compounds might decrease metabolic alkylation by S-methyltransferases and related enzymes.²⁹ Further, upon exposure to common chemical oxidants (NaOCl, KMnO₄, H₂O₂, and m–CPBA) the non-fluorinated analog (13) decomposed substantially within 1 h, while the α,α-difluorinated analog (5a) did not degrade under extended exposure to chemical oxidants (Scheme 8B, See SI, Figure S12). When exposed to m–CPBA, a stronger oxidant, both the fluorinated and non-fluorinated analogs were completely oxidized. These experiments suggest that fluorination α to S might disfavor non-enzymatic oxidation, as experienced in lysosomes and peroxisomes,³⁰ which again highlights the potential utility of this fluorinated motif toward developing biologically active small molecules.

Scheme 8:

α,α–Difluoroalkylthioethers Resist Alkylation and Oxidation

% Remaining is represented by an average of two independent reactions monitored by GC-FID. ^aThioether (0.1 mmol) and MeI (1 equiv.) stirred at rt in DMF (1 mL) for 18 h. ^bThioether (0.1 mmol) and [O] (2 equiv.) heated at 40 °C in EtOH (1 mL) for 1 h.

In conclusion, we developed a new catalytic general acid catalyzed strategy to generate α,α-difluoroalkylthioethers in high selectivity via the addition of thiol- and thiophenol-derived nucleophiles across gem-difluorostyrenes. This reaction circumvents unstable anionic intermediates through a concerted acid-mediated hydrothiolation step. Additionally, these α,α-difluoroalkylthioethers are less nucleophilic and more oxidatively stable than their non-fluorinated counterparts, which should enable the strategic use of this underexplored functional group in biological probes and therapeutic agents.

EXPERIMENTAL SECTION

General Information:

Air- and moisture-sensitive reactions were carried out in oven-dried one-dram vials sealed with a PTFE-lined septum or glassware sealed with a rubber septum under an atmosphere of dry nitrogen. PTFE syringes equipped with stainless-steel needles were used to transfer air- and moisture-sensitive liquid reagents. Reactions were stirred using teflon-coated magnetic stir bars. Elevated temperatures were maintained using thermostat-controlled heating mantles. Organic solutions were concentrated using a rotary evaporator with a diaphragm vacuum pump. Thin-layer chromatography was performed on silica gel UNIPLATE Silica Gel HLF UV254 plates, and spots were visualized by quenching ultraviolet light (λ = 254 nm). Purification of products was accomplished by automated flash column chromatography on silica gel (VWR Common Silica Gel 60 Å, 40–60 μm). Unless otherwise noted, reagents and solvents were purchased from various commercial sources and used as received.

NMR spectra were recorded on a Bruker DRX 500 MHz (¹H at 500 MHz, ¹⁹F at 471 MHz), Bruker AVIIIHD 400 MHz (¹³C at 126 MHz) or AVIII 800 MHz (¹³C at 201 MHz) nuclear magnetic resonance spectrometer. ¹H NMR spectra were calibrated against residual CHCl₃ in the solvent (7.26 ppm). ¹⁹F NMR spectra were calibrated against the internal standard CFCl₃ (0.00 ppm). ¹³C{¹H} NMR spectra were calibrated against the peak of the residual CHCl₃ in the solvent (77.2 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. GC analysis was performed on an Agilent Technologies 7890A instrument equipped with J&W HP-5 GC Column (30 m, 0.32 mm, 0.25 µm and 7-inch cage) and FID detector using helium as the carrier gas. High-resolution mass determinations were obtained either by electrospray ionization (ESI) on a Waters LCT Premier™ mass spectrometer where samples were dissolved in MeOH and MeOH was used as 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 ionization solvent. Infrared spectra were measured on a Perkin Elmer Spectrum Two Fourier Transform Infrared Spectrometer by loading samples on a diamond ATR sample base plate. Uncorrected melting points were measured on a Thomas Hoover Uni-melt Capillary Melting Point apparatus.

General Procedure A for the Preparation of gem-Difluorostyrenes:

An oven-dried 3-neck round-bottomed flask equipped with addition funnel and magnetic stir bar was charged with aryl aldehyde (1.0 equiv.) and PPh₃ (1.5 equiv.). The system was sealed with three rubber septa, and subsequently evacuated and backfilled with dry N₂ three times. Dry DMF was added via syringe, and the system was immersed in an oil bath preheated to 90 °C. A solution of KO₂CCF₂Br (1.8 equiv.) in DMF was added dropwise using an addition funnel over 0.5 h, with the rate of addition controlling the evolution of CO₂ gas. Once all of the KO₂CCF₂Br was added, the solution was allowed to stir for 0.5 h at 90 °C. Upon completion, the reaction was cooled to 0 °C and then quenched with H₂O. Subsequently, Et₂O was added to the mixture, and the organic layer was washed with H₂O (three times) and then an aqueous solution of LiCl (10% in H₂O; one time). Subsequently, MeI (1.5 equiv.) was added to the organic layer, and the mixture stirred at room temperature for 30 min to methylate the residual PPh₃. The organic layer was washed with H₂O (three times) then brine, and then dried over Na₂SO₄. The crude material was eluted through a pad of silica gel with Et₂O:pentane (1:1). The solution was concentrated, and the resulting residue was subjected to normal phase flash chromatography using EtOAc and hexanes.

General Procedure B for the Preparation of gem-Difluorostyrenes.

An oven-dried 3-neck round-bottomed flask equipped magnetic stir bar was charged with aryl aldehyde (1.0 equiv.) and PPh₃ (1.5 equiv.). The system was sealed with three rubber septa, and subsequently evacuated and backfilled with dry N₂ three times. Dry DMF was added via syringe, and the system was immersed in an oil bath preheated to 90 °C. KO₂CCF₂Br (1.8 equiv.) was added portion wise over 0.5 h, with the rate of addition controlling the evolution of CO₂ gas. Once all of the KO₂CCF₂Br was added, the solution was allowed to stir for 0.5 h at 90 °C. Upon completion, the reaction was cooled to 0 °C and then quenched with H₂O. Subsequently, Et₂O was added to the mixture, and the organic layer was washed with H₂O (three times) then an aqueous solution of LiCl (10% in H₂O; one time). Subsequently, H₂O₂ (30% in H₂O) was added to the mother liquor, and the mixture was allowed to react for 30 min to oxidize the residual PPh₃. Solid additions of Na₂S₂O₅ were then added iteratively to quench excess H₂O₂, and the quenching process was monitored for completion using peroxide strips. The organic layer was washed with H₂O (three times) then brine and dried over Na₂SO₄. The crude material was then eluted through a pad of silica gel with Et₂O:pentane (1:1) to remove PPh₃O. The solution was then concentrated, and the resulting residue was subjected to normal phase flash chromatography using EtOAc and hexanes.

(2,2-difluorovinyl)benzene (1a):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of benzaldehyde (2.50 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 2.99 g (85% yield) of desired product 1a as a colorless oil. ¹H NMR spectra matches previous reports.³¹

3-(2,2-difluorovinyl)benzonitrile (1b):

Following general procedure A, a solution of KO₂CCF₂Br (18.6 g, 90 mmol) in 20 mL of DMF was added dropwise to a mixture of 3-formylbenzonitrile (6.56 mL, 50.0 mmol) and PPh₃ (18.6 g, 75 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 3.60 g (44% yield) of desired product 1b as a colorless solid. ¹H NMR spectra matches previous reports.³²

4-(2,2-difluorovinyl)benzonitrile (1c):

Following general procedure A, a solution of KO₂CCF₂Br (19.2 g, 90 mmol) in 20 mL of DMF was added dropwise to a mixture of 4-formylbenzonitrile (6.55 mL, 50.0 mmol) and PPh₃ (19.6 g, 75 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 6.10 g (74% yield) of desired product 1c as a colorless solid. ¹H NMR spectra matches previous reports.³¹

1-(2,2-difluorovinyl)-3-(trifluoromethyl)benzene (1d):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of 3-(trifluoromethyl)benzaldehyde (3.35 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 2.80 g (55% yield) of desired product 1d as a colorless oil. ¹H NMR spectra matches previous reports.³²

1-(2,2-difluorovinyl)-4-(trifluoromethyl)benzene (1e):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of 4-(trifluoromethyl)benzaldehyde (3.4 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 2.5 g (49% yield) of desired product 1e as a colorless oil. ¹H NMR spectra matches previous reports.³¹

1-(2,2-difluorovinyl)-3-nitrobenzene (1f):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of 3-nitrobenzaldehyde (3.78 g, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 0.69 g (15% yield) of desired product 1f as a pale yellow solid. ¹H NMR spectra matches previous reports.³²

4-(2,2-difluorovinyl)phenyl 4-methylbenzenesulfonate (1g):

Following general procedure A, a solution of KO₂CCF₂Br (4.80 g, 22.5 mmol) in 10 mL of DMF was added dropwise to a mixture of 4-formylphenyl 4-methylbenzenesulfonate (3.50 g, 25.0 mmol) and PPh₃ (4.90 g, 18.8 mmol) in 25 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 1.93 g (50% yield) of desired product 1g as a colorless solid. ¹H NMR spectra matches previous reports.³²

1,3-dichloro-5-(2,2-difluorovinyl)benzene (1h):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of 4-chlorobenzaldehyde (5.38 g, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 2.5 g (48% yield) of desired product 1i as a colorless oil. ¹H NMR spectra matches previous reports.³²

1-chloro-4-(2,2-difluorovinyl)benzene (1i):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of 4-chlorobenzaldehyde (3.5 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 2.8 g (65% yield) of desired product 1i as a colorless oil. ¹H NMR spectra matches previous reports.³¹

1-bromo-4-(2,2-difluorovinyl)benzene (1j):

Following general procedure A, a solution of KO₂CCF₂Br (15.4 g, 72 mmol) in 20 mL of DMF was added dropwise to a mixture of 4-bromobenzaldehyde (7.4 g, 40.0 mmol) and PPh₃ (12.6 g, 48.0 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 6.02 g (69% yield) of desired product 1j as a colorless oil. ¹H NMR spectra matches previous reports.³²

1-(2,2-difluorovinyl)-4-methoxybenzene (1l):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of 4-methoxybenzaldehyde (3.05 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 3.63 g (85% yield) of desired product 1l as a colorless oil. ¹H NMR spectra matches previous reports.³²

(4-(2,2-difluorovinyl)phenyl)(methyl)sulfane (1m):

Following general procedure B, KO₂CCF₂Br (28.8 g, 135 mmol) was added portion wise to a mixture of 4-(methylthio)benzaldehyde (10.0 mL, 75.0 mmol) and PPh₃ (29.5 g, 110 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 9.27 g (67% yield) of desired product 1m as a colorless solid. ¹H NMR spectra matches previous reports.³²

5-(2,2-difluorovinyl)-1,2,3-trimethoxybenzene (1n):

Following general procedure B, KO₂CCF₂Br (39.1 g, 180 mmol) was added portion wise to a mixture of 3,4,5-trimethoxybenzaldehyde (20 g, 100.0 mmol) and PPh₃ (40.1 g, 150 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 13.9 g (60% yield) of desired product 1n as a colorless solid. ¹H NMR spectra matches previous reports.³²

1-(tert-butyl)-4-(2,2-difluorovinyl)benzene (1q):

Following general procedure A, a solution of KO₂CCF₂Br (2.3 g, 10.8 mmol) in 5 mL of DMF was added dropwise to a mixture of 4-(tert-butyl)benzaldehyde (1.0 mL, 6.0 mmol) and PPh₃ (2.4 g, 9 mmol) in 10 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 380 mg (32% yield) of desired product 1q as a colorless oil. ¹H NMR spectra matches previous reports.³²

4-(2,2-difluorovinyl)-1,1’-biphenyl (1r):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of [1,1’-biphenyl]-4-carbaldehyde (4.56 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 3.67 g (68% yield) of desired product 1r as a colorless solid. ¹H NMR spectra matches previous reports.³¹

4’-(tert-butyl)-2-(2,2-difluorovinyl)-1,1’-biphenyl (1s):

Following general procedure B, KO₂CCF₂Br (13.2 g, 61.0 mmol) was added portion wise to a mixture of 4’-(tert-butyl)-[1,1’-biphenyl]-2-carbaldehyde (8.01 g, 36.4 mmol) and PPh₃ (13.2g, 50.0 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 4.67 g (80% yield) of desired product 1s as a colorless oil. ¹H NMR spectra matches previous reports.³²

ethyl (E)-3-(3-(2,2-difluorovinyl)phenyl)acrylate (1t):

Following general procedure B, KO₂CCF₂Br (0.9 g, 4.3 mmol) was added portion wise to a mixture of ethyl (E)-3-(3-formylphenyl)acrylate (0.50 g, 2.5 mmol) and PPh₃ ( 0.95 g, 3.6 mmol) in 5 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 499 mg (84% yield) of desired product 1t as a colorless solid. ¹H NMR spectra matches previous reports.³²

4-(2,2-difluorovinyl)-N,N-diethylbenzamide (1u):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of N,N-diethyl-4-formylbenzamide (5.13 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 1.49 g (25% yield) of desired product 1u as a colorless solid. ¹H NMR spectra matches previous reports.³³

1-(2,2-difluorovinyl)-4-(methoxymethoxy)benzene (1w):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of 4-(methoxymethoxy)benzaldehyde (4.15 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 2.8 g (56% yield) of desired product 1w as a colorless oil. ¹H NMR spectra matches previous reports.³³

1-(benzyloxy)-4-(2,2-difluorovinyl)benzene (1x):

Following general procedure A, a solution of KO₂CCF₂Br (9.6 g, 45 mmol) in 20 mL of DMF was added dropwise to a mixture of 4-(benzyloxy)benzaldehyde (5.3 mL, 25.0 mmol) and PPh₃ (9.80 g, 37.5 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 2.56 g (42% yield) of desired product 1x as a colorless solid. ¹H NMR spectra matches previous reports.³³

4-(2,2-difluorovinyl)dibenzo[b,d]thiophene (1y):

Following general procedure B, KO₂CCF₂Br (2.3 g, 11 mmol) was added portion wise to a mixture of dibenzo[b,d]thiophene-4-carbaldehyde (1.3 g, 6.0 mmol) and PPh₃ (2.3 g, 9.0 mmol) in 20 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 0.68 g (46% yield) of desired product 1s as a pale yellow solid. ¹H NMR spectra matches previous reports.³²

4-(2,2-difluorovinyl)-1-phenyl-1H-pyrazole (1z):

Following general procedure B, KO₂CCF₂Br (8.05 g, 38.0 mmol) was added portion wise to a mixture of 1-phenyl-1H-pyrazole-4-carbaldehyde (3.65 g, 21.0 mmol) and PPh₃ (8.33 g, 3.80 mmol) in 50 mL of DMF heated in a 90 °C oil bath and stirred for 1 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:20) to furnish 1.5 g (32% yield) of desired product 1s as a colorless solid. ¹H NMR spectra matches previous reports.³²

1-(2,2-difluorovinyl)-2-iodobenzene (1k):

Compound 1k was prepared according to a previous report.¹⁴

1-(2,2-difluorovinyl)-3,5-dimethylbenzene (1o):

Compound 1o was prepared according to a previous report.³²

2-(2,2-difluorovinyl)-1,3-dimethylbenzene (1p):

Compound 1p was prepared according to a previous report.³²

4-(2,2-difluorovinyl)phenol (1v):

Compound 1v was prepared according to a previous report.³³

Synthesis of Compound 1aa:

An oven-dried round-bottomed flask equipped with magnetic stir bar was charged with aryl 1-(4-methoxyphenyl)ethan-1-one (0.30 g, 2.0 mmol) and 2,2-difluoro-2-(tris(dimethylamino)phosphonio)acetate (1.0 g, 4.0 mmol). The system was sealed with a rubber septa, and subsequently evacuated and backfilled with dry N₂ three times. Dry PhMe (3 mL) and DMA (1 mL) was added via syringe, and the system was immersed in an oil bath preheated to 100 °C for 3 hours. Upon completion, the reaction was cooled to 0 °C and then quenched with H₂O. Subsequently, Et₂O was added to the mixture, and the organic layer was washed with H₂O (three times) then an aqueous solution of LiCl (10% in H₂O; one time). The crude material was then eluted through a pad of silica gel with Et₂O:pentane (1:1). The solution was then concentrated and subjected to normal phase flash chromatography using 0% to 20% EtOAc in hexane furnishing 0.17 g (46% yield) of desired product 1a as a colorless oil. ¹H NMR spectra matches previous reports.³⁴

General Procedure A for the Triflate Catalyzed Addition of Alkylthiols to gem-Difluorostyrenes.

An oven-dried one-dram vial equipped with a magnetic stir bar was charged with gem-difluorostyrene (1.0 equiv.) and LiOTf (1.5 equiv.). Dry o-xylene (0.33 M), pyridine (0.2 equiv.), 2-methoxyethanol (2.0 equiv.), and alkylthiol (1.5 equiv.) were added via syringe and the vial was sealed with a screw-top cap containing a PTFE-lined septum. The vial was then connected to a balloon filled with air using a 16-gauge needle, then stirred in a heating mantle to 110 °C for 24 h. Upon completion, the reaction was cooled to rt, concentrated onto SiO₂ and purified by normal-phase flash chromatography using EtOAc and hexanes to provide the desired product in >95% purity.

General Procedure B for the Triflate Catalyzed Addition of Alkylthiols to gem-Difluorostyrenes.

An oven-dried one-dram vial equipped with a magnetic stir bar was charged with gem-difluorostyrene (1.0 equiv.) and LiOTf (1.5 equiv.). Dry o-xylene (0.33 M), pyridine (1.0 equiv.), 2-methoxyethanol (2.0 equiv.), and alkylthiol (1.5 equiv.) were added via syringe and the vial was sealed with a screw-top cap containing a PTFE-lined septum. The vial was then connected to a balloon filled with air using a 16-gauge needle, then stirred in a heating mantle to 110 °C for 24 h. Upon completion, the reaction was cooled to rt, concentrated onto SiO₂ and purified by normal-phase flash chromatography using EtOAc and hexanes to provide the desired product in >95% purity.

General Procedure C for the Triflate Catalyzed Addition of Alkylthiols to gem-Difluorostyrenes.

An oven-dried one-dram vial equipped with a magnetic stir bar was charged with gem-difluorostyrene (1.0 equiv.) and LiOTf (1.5 equiv.). Dry o-xylene (0.33 M), pyridine (1.0 equiv.), 2-methoxyethanol (2.0 equiv.), and alkylthiol (1.5 equiv.) were added via syringe and the vial was sealed with a screw-top cap containing a PTFE-lined septum. The vial was then connected to a balloon filled with air using a 16-gauge needle, then stirred in a heating mantle to 120 °C for 24 h. Upon completion, the reaction was cooled to rt, concentrated onto SiO₂ and purified by normal-phase flash chromatography using EtOAc and hexanes to provide the desired product in >95% purity.

(1,1-difluoro-2-phenylethyl)(octyl)sulfane (5a):

Following general procedure A, compound 1a (0.070 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.010 mL, 0.100 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.123 g (86% yield) of desired product 5a as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.38 – 7.28 (m, 5H), 3.41 (t, J = 14.6 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 1.63 (p, J = 7.5 Hz, 2H), 1.44 – 1.33 (m, 2H), 1.30 (m, 8H), 0.90 (t, J = 6.7 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 132.3 (t, 3JC-F₂ = 4.0 Hz), 130.5, 130.1(t, 1JC-F₂ = 277.0 Hz), 128.4, 127.7, 46.3 (t, 2JC-F₂ = 42.4 Hz), 31.8, 29.8, 29.1, 29.0, 28.8, 27.9 (t, 3JC-F₂ = 3.6 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.04 (t, J = 14.6 Hz). IR (Film): 3034, 2925, 2855, 1455, 1265, 1153, 1006, 988, 740, 725, 698 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₆H₂₄F₂S [M+H]⁺ 287.1640, found 287.1649.

3-(2,2-difluoro-2-(octylthio)ethyl)benzonitrile (5b):

Following general procedure A, compound 1b (0.082 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.130 g (84% yield) of desired product 5b as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.64 (d, J = 8.3 Hz, 1H), 7.62 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 3.44 (t, J = 14.2 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 1.64 (p, J = 7.4 Hz, 2H), 1.37 (m, 2H), 1.30 (m, 8H), 0.90 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 135.0, 134.0, 133.7 (t, 3JC-F₂ = 3.9 Hz), 131.4, 129.4 (t, 1JC-F₂ = 276.7 Hz), 129.3, 118.56, 112.7, 45.7 (t, 2JC-F₂ = 25.2 Hz), 31.8, 29.7, 29.1, 29.0, 28.8, 28.1 (t, 3JC-F₂ = 3.6 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.3 (t, J = 14.3 Hz). IR (Film) 2926, 2855, 2231, 1353, 1258, 1187, 1151, 1017, 995, 882, 798, 687 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₇H₂₃F₂NS [M+H]⁺ 312.1598, found 312.1587.

4-(2,2-difluoro-2-(octylthio)ethyl)benzonitrile (5c):

Following general procedure A, compound 1c (0.082 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.123 g (79% yield) of desired product 5c as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 7.8 Hz, 2H), 3.48 (t, J = 14.2 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 1.64 (p, J = 7.3 Hz, 2H), 1.36 (m, 2H), 1.29 (m, 8H), 0.90 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 137.8, 132.2, 131.3, 128.3 (t, 1JC-F₂ = 278.0 Hz), 118.6, 111.8, 45.5 (t, 2JC-F₂ = 25.2 Hz), 29.7, 29.1, 29.0, 28.8, 28.1 (t, 3JC-F₂ = 3.7 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −72.9 (t, J = 14.2 Hz). IR (Film) 2927, 2856, 2231, 1509, 1464, 1265, 1013, 993, 740, 705 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₇H₂₄F₂NS [M+H]⁺ 312.1598, found 312.1592.

General Procedure for a 1 mmol Scale reaction to synthesize (5c):

An oven-dried one-dram vial equipped with a magnetic stir bar was charged with 1c (0.165 g, 1.0 mmol) and LiOTf (0.016 g, 0.100 mmol). Dry o-xylene (3 mL, 0.33 M), pyridine (0.02 mL, 0.20 mmol), 2-methoxyethanol (0.160 mL, 2.00 mmol), and 1-octanethiol (0.260 mL, 1.5 mmol) were added via syringe and the vial was sealed with a screw-top cap containing a PTFE-lined septum. The vial was then connected to a balloon filled with air using a 16-gauge needle, then stirred using a heating mantle to 110 °C for 24 h. Upon completion, the reaction was cooled to rt, concentrated onto SiO₂ and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.254 g (82% yield) of desired product 5c as a colorless oil.

(1,1-difluoro-2-(3-(trifluoromethyl)phenyl)ethyl)(octyl)sulfane (5d):

Following general procedure A, compound 1d (0.104 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.164 g (89% yield) of desired product 5d as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.62 – 7.56 (m, 2H), 7.54 – 7.46 (m, 2H), 3.47 (t, J = 14.4 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 1.65 (p, J = 7.4 Hz, 2H), 1.38 (m, 2H), 1.29 (m, 8H), 0.91 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 133.9, 133.6 (t, 3JC-F₂ = 3.7 Hz), 129.6 (t, 1JC-F₂ = 277.6 Hz), 128.9, 127.3 (q, 3JC-F₃ = 4.0 Hz), 125.1, 124.6 (q, 3JC-F₃ = 4.3 Hz), 122.9, 45.4 (t, 2JC-F₂ = 25.2 Hz), 31.8, 29.8, 29.1, 29.0, 28.8, 28.0 (t, 3JC-F₂ = 3.6 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −62.7, −72.8 (t, J = 14.4 Hz). IR (Film) 2927, 2856, 1420, 1323, 1164, 1126, 1112, 1067, 1020, 992, 851, 748 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₇H₂₃F₅S [M+H]⁺ 355.1519, found 355.1509.

(1,1-difluoro-2-(4-(trifluoromethyl)phenyl)ethyl)(octyl)sulfane (5e):

Following general procedure A, compound 1e (0.104 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.161 g (91% yield) of desired product 5e as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.52 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.37 (t, J = 14.3 Hz, 2H), 2.89 (t, J = 7.3 Hz, 2H), 1.54 (p, J = 7.4 Hz, 2H), 1.35 – 1.22 (m, 2H), 1.20 (m, 8H), 0.80 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 136.8 – 136.0 (m), 131.0, 130.2 (q, 2JC-F₂ = 32.4 Hz), 129.9, 129.77 (t, 1JC-F₂ = 276.7 Hz), 125.4 (q, 3JC-F₂ = 4.0 Hz), 45.9 (t, 2JC-F₂ = 25.8 Hz), 31.9, 29.9, 29.2, 29.1, 28.9, 28.1 (t, 3JC-F₂ = 3.6 Hz), 22.7, 14.2. ¹⁹F NMR (471 MHz, Chloroform-d) δ −63.15, −73.06 (t, J = 14.3 Hz). IR (Film) 2927, 2856, 1690, 1621, 1323, 1164, 1126, 1112, 1067, 1020, 992, 851, 748 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₇H₂₃F₅S [M+H]⁺ 355.1519, found 355.1512.

(1,1-difluoro-2-(3-nitrophenyl)ethyl)(octyl)sulfane (5f):

Following general procedure A, compound 1f (0.092 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.114 g (69% yield) of desired product 5f as a yellow oil. ¹H NMR (500 MHz, Chloroform-d) δ 8.21 (d, J = 3.9 Hz, 1H), 8.21 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 9.0, 7.6 Hz, 1H), 3.52 (t, J = 14.1 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 1.65 (p, J = 7.5 Hz, 2H), 1.42 – 1.35 (m, 2H), 1.30 (dd, J = 11.3, 5.5 Hz, 8H), 0.90 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 148.3, 136.6, 134.2 (t, 3JC-F₂ = 3.7 Hz), 129.4 (t, 1JC-F₂ = 278.0 Hz), 129.4, 125.7, 122.9, 45.1 (t, 2JC-F₂ = 25.3 Hz), 31.8, 29.7, 29.1, 29.0, 28.8, 28.1 (t, 3JC-F₂ = 3.5 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.3 (t, J = 14.1 Hz). IR (Film) 3075, 2926, 2855, 1728, 1531, 1349, 1017, 995, 821, 805, 736, 727 cm⁻¹. MS (APCI)⁺ m/z calc’d C₁₆H₂₄F₂NO₂S [M+H]⁺ 332.1496, found 332.1482.

4-(2,2-difluoro-2-(octylthio)ethyl)phenyl 4-methylbenzenesulfane (5g):

Following general procedure A, compound 1g (0.155 g, 0.500 mmol) was reacted 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.167 g (74% yield) of desired product 5g as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.70 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.34 (t, J = 14.4 Hz, 1H), 2.79 (t, J = 7.5 Hz, 1H), 2.45 (s, 2H), 1.61 (p, J = 7.5 Hz, 1H), 1.34 (m, J = 6.9, 4.3 Hz, 1H), 1.31 – 1.22 (m, 4H), 0.87 (t, J = 6.8 Hz, 2H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 149.3, 145.4, 132.5, 131.8, 131.3 (t, 3JC-F₂ = 3.8 Hz), 129.8, 129.8 (t, 1JC-F₂ = 282 Hz), 128.6, 122.4, 45.1 (t, 2JC-F₂ = 24.4 Hz), 31.9, 29.9, 29.2, 29.1, 28.9, 28.1 (t, 3JC-F₂ = 3.6 Hz), 22.7, 21.8, 14.2. ¹⁹F NMR (470 MHz, Chloroform-d) δ −72.79 (t, J = 14.5 Hz). IR (Film) 2926, 2855, 1503, 1375, 1199, 1178, 1152, 1093, 1019, 866, 737, 705 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₂₃H₃₁F₂O₃S₂ [M+H]⁺ 457.1677, found 457.1694.

(2-(3,5-dichlorophenyl)-1,1-difluoroethyl)(octyl)sulfane (5h):

Following general procedure A, compound 1h (0.104 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.130 g (73% yield) of desired product 5h as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.34 (t, J = 1.9 Hz, 1H), 7.21 (d, J = 1.9 Hz, 2H), 3.35 (t, J = 14.2 Hz, 2H), 2.89 – 2.73 (t, J = 7.4, 2H), 1.65 (p, J = 7.4 Hz, 2H), 1.39 (m, 2H), 1.29 (m, 8H), 0.90 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 135.4 (t, 3JC-F₂ = 3.7 Hz), 135.0, 129.4 (t, 1JC-F₂ = 277.9 Hz), 129.1, 128.1, 44.9 (t, 2JC-F₂ = 25.4 Hz), 31.9, 29.8, 29.2, 29.1, 28.9, 28.2 (t, 3JC-F₂ = 3.6 Hz), 22.7, 14.2. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.1 (t, J = 14.2 Hz). IR (Film) 2955, 2925, 2854, 1569, 1434, 1212, 1018, 997, 798, 743 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₆H₂₂Cl₂F₂S [M+H]⁺ 355.0866, found 355.0858

(2-(4-chlorophenyl)-1,1-difluoroethyl)(octyl)sulfane (5i):

Following general procedure A, compound 1i (0.082 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.131 g (82% yield) of desired product 5i as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.22 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 3.27 (t, J = 14.4 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 1.53 (p, J = 7.5 Hz, 2H), 1.31 – 1.24 (m, 2H), 1.20 (m, 8H), 0.80 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 133.8, 131.8, 130.8 (t, 3JC-F₂ = 4.1 Hz), 129.8 (t, 1JC-F₂ = 277.8 Hz), 128.6, 45.6 (t, 2JC-F₂ = 25.0 Hz), 31.7, 29.7, 29.1, 29.0, 28.8, 27.9 (t, 3JC-F₂ = 3.6 Hz), 22.6, 14.0. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.22 (t, J = 14.4 Hz). IR (Film) 3006, 2989, 2839, 1591, 1494, 1275, 1259, 1222, 1097, 1028, 764, 750 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₆H₂₃ClF₂S [M+H]⁺ 321.1250, found 321.1246.

(2-(4-bromophenyl)-1,1-difluoroethyl)(octyl)sulfane (5j):

Following general procedure A, compound 1j (0.110 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.115 g (63% yield) of desired product 5j as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.49 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 3.37 (t, J = 14.4 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 1.64 (p, J = 7.4 Hz, 2H), 1.41 – 1.35 (m, 2H), 1.29 (m, 8H), 0.91 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 132.2, 131.6, 131.2 (t, 3JC-F₂ = 3.8 Hz), 128.6 (t, 1JC-F₂ = 277.5 Hz), 122.0, 45.0 (t, 2JC-F₂ = 25.1 Hz), 31.8, 29.8, 29.1, 29.0, 28.8, 28.0 (t, 3JC-F₂ = 3.6 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.19 (t, J = 14.4 Hz). IR (Film) 2955, 2926, 2854, 1489, 1464, 1264, 1012, 764, 738, 705 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₆H₂₄BrF₂S [M+H]⁺ 365.0750, found 365.0755.

(1,1-difluoro-2-(2-iodophenyl)ethyl)(octyl)sulfane (5k):

Following general procedure A, compound 1k (0.132 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.134 g (65% yield) of desired product 5k as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.88 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.98 (td, J = 7.7, 1.7 Hz, 1H), 3.66 (t, J = 14.5 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 1.64 (p, J = 8.4, 7.6 Hz, 2H), 1.36 (p, J = 6.9 Hz, 2H), 1.31 – 1.19 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 139.9, 135.8 (t, 3JC-F₂ = 3.3 Hz), 131.5, 130.0 (t, 1JC-F₂ = 279.1 Hz), 129.4, 128.2, 102.2, 49.2 (t, 2JC-F₂ = 24.6 Hz), 31.8, 29.8, 29.1, 29.0, 28.9, 28.2 (t, 3JC-F₂ = 3.7 Hz), 22.6, 14.1. ¹⁹F NMR (470 MHz, Chloroform-d) δ −72.1 (t, J = 14.5 Hz). IR (Film) 2955, 2926, 2854, 1464, 1436, 1378, 1264, 1020, 742, 705 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₆H₂₃F₂IS [M+H]⁺ 413.0612, found 413.0624.

(1,1-difluoro-2-(4-methoxyphenyl)ethyl)(octyl)sulfane (5l):

Following general procedure A, compound 1l (0.085 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.144 g (91% yield) of desired product 5l as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.25 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 3.83 (s, 3H), 3.37 (t, J = 14.5 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 1.65 (p, J = 7.5 Hz, 2H), 1.47 – 1.36 (m, 2H), 1.32 – 1.29 (m, 8H), 0.92 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 159.2, 131.5, 129.3 (t, 1JC-F₂ = 277.1 Hz), 124.3 (t, 3JC-F₂ = 3.8 Hz), 113.8, 55.2, 44.8 (t, 2JC-F₂ = 24.8 Hz), 31.8, 29.8, 29.1, 29.1, 28.9, 27.9 (t, 3JC-F₂ = 3.8 Hz), 22.7, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −72.8 (t, J = 14.5 Hz). IR (Film) 2955, 2924, 2854, 1489, 1464, 1264, 1012, 990, 764, 741 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₇H₂₇F₂OS [M+H]⁺ 317.1751, found 317.1741.

General Procedure for a 1 mmol Scale reaction to synthesize (5l):

An oven-dried one-dram vial equipped with a magnetic stir bar was charged with 1l (0.170 g, 1.0 mmol) and LiOTf (0.016 g, 0.100 mmol). Dry o-xylene (3 mL, 0.33 M), pyridine (0.02 mL, 0.20 mmol), 2-methoxyethanol (0.160 mL, 2.00 mmol), and 1-octanethiol (0.260 mL, 1.5 mmol) were added via syringe and the vial was sealed with a screw-top cap containing a PTFE-lined septum. The vial was then connected to a balloon filled with air using a 16-gauge needle, then stirred using a heating mantle to 110 °C for 24 h. Upon completion, the reaction was cooled to rt, concentrated onto SiO₂ and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.228 g (72% yield) of desired product 5c as a colorless oil.

(1,1-difluoro-2-(4-(methylthio)phenyl)ethyl)(octyl)sulfane (5m):

Following general procedure A, compound 1m (0.093 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.108 g (65% yield) of desired product 5m as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.14 (s, 4H), 3.27 (t, J = 14.5 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.40 (s, 3H), 1.54 (p, J = 7.4 Hz, 2H), 1.34 – 1.22 (m, 2H), 1.19 (m, 8H), 0.80 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 138.1, 130.9, 130.1 (t, 1JC-F₂ = 278.4 Hz), 128.9 (t, 3JC-F₂ = 4.0 Hz), 126.5, 45.0 (t, 2JC-F₂ = 24.8 Hz), 31.8, 29.8, 29.1, 29.0, 28.8, 27.9 (t, 3JC-F₂ = 3.6 Hz), 22.6, 15.7, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.13 (t, J = 14.5 Hz). IR (Film) 2923, 2854, 1495, 1437, 1264, 1152, 1009, 989, 870, 766, 740 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₇H₂₆F₂S₂ [M+H]⁺ 333.1517, found 333.1519.

(1,1-difluoro-2-(3,4,5-trimethoxyphenyl)ethyl)(octyl)sulfane (5n):

Following general procedure A, compound 1n (0.115 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:5) to furnish 0.141 g (75% yield) of desired product 5n as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 6.52 (s, 2H), 3.88 (s, 6H), 3.87 (s, 3H), 3.35 (t, J = 14.5, 2H), 2.84 (t, J = 7.3, 2H), 1.66 (p, J = 7.4, 2H), 1.38 (m, 2H), 1.29 (m, 8H), 0.91 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 153.0, 137.6, 130.1 (t, 1JC-F₂ = 276.8 Hz), 127.7 (t, 3JC-F₂ = 3.9 Hz), 107.6, 60.9, 56.1, 31.8, 29.8, 29.1, 29.0, 28.9, 27.9 (t, 3JC-F₂ = 3.8 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.0 (t, J = 14.5 Hz). IR (Film) 2927, 2855, 1730, 1589, 1508, 1459, 1421, 1244, 1127, 1007, 737 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₉H₃₀F₂O₃S [M+H]⁺ 377.1962, found 377.1952.

(2-(3,5-dimethylphenyl)-1,1-difluoroethyl)(octyl)sulfane (5o):

Following general procedure A, compound 1o (0.084 g, 0.500 mmol) was reacted 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.142 g (90% yield) of desired product 5o as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 6.95 (s, 1H), 6.91 (s, 2H), 3.31 (t, J = 14.7 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.31 (s, 6H), 1.62 (p, J = 7.4 Hz, 2H), 1.39 – 1.33 (m, 2H), 1.32 – 1.16 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 137.9, 132.0 (t, 3JC-F₂ = 3.7 Hz), 130.2 (t, 1JC-F₂ = 277.3 Hz), 129.4, 128.3, 45.5 (t, 2JC-F₂ = 25.2 Hz), 31.8, 29.8, 29.12, 29.0, 28.9, 28.0 (t, 3JC-F₂ = 3.7 Hz), 22.6, 21.3, 14.1. ¹⁹F NMR (470 MHz, Chloroform-d) δ −72.9 (t, J = 14.8 Hz). IR (Film) 2955, 2924, 2854, 1463, 1264, 1152, 1022, 742, 714 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₈H₂₉F₂S [M+H]⁺ 315.1958, found 315.1948.

(2-(2,6-dimethylphenyl)-1,1-difluoroethyl)(octyl)sulfane (5p):

Following general procedure A, compound 1p (0.084 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.143 g (91% yield) of desired product 5p as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.10 (dd, J = 8.5, 6.4 Hz, 1H), 7.05 (d, J = 7.4 Hz, 2H), 3.54 (t, J = 15.4 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H), 2.38 (s, 6H), 1.64 (p, J = 7.5 Hz, 2H), 1.37 (p, J = 7.5 Hz, 2H), 1.30 – 1.24 (m, 8H), 0.88 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 138.5, 132.1 (t, 1JC-F₂ = 278.4 Hz), 129.6 (t, 3JC-F₂ = 2.3 Hz), 128.3, 127.5, 39.0 (t, 2JC-F₂ = 24.6 Hz), 31.8, 29.8, 29.1, 29.0, 28.9, 28.1 (t, 3JC-F₂ = 3.6 Hz), 22.6, 20.8 (t, J = 3.1 Hz), 14.1. ¹⁹F NMR (470 MHz, Chloroform-d) δ −70.9 (t, J = 15.5 Hz). IR (Film) 2956, 2926, 2855, 1467, 1264, 986, 766, 743, 708 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₈H₂₉F₂S [M+H]⁺ 315.1958, found 315.1947.

(2-(4-(tert-butyl)phenyl)-1,1-difluoroethyl)(octyl)sulfane (5q):

Following general procedure A, compound 1q (0.098 g, 0.500 mmol) was reacted 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.107 g (62% yield) of desired product 5q as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.27 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 3.28 (t, J = 14.7 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 1.54 (p, J = 7.4 Hz, 2H), 1.27 (s, 9H), 1.26 – 1.23 (m, 2H), 1.18 (m, 8H), 0.80 (t, J = 6.7 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 150.5, 130.2 (t, 1JC-F₂ = 276.6 Hz), 130.1, 129.1 (t, 3JC-F₂ = 3.8 Hz), 125.3, 45.8 (t, 2JC-F₂ = 25.4 Hz), 39.2, 34.5, 31.8, 31.3, 29.8, 29.1, 29.0, 28.8, 27.9 (t, 3JC-F₂ = 3.6 Hz), 22.6, 14.0. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.14 (t, J = 14.7 Hz). IR (Film) 2957, 2925, 2855, 1464, 1153, 1027, 1007, 989, 764, 749 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₂₀H₃₃F₂S [M+H]⁺ 343.2271, found 343.2258.

(2-([1,1’-biphenyl]-4-yl)-1,1-difluoroethyl)(octyl)sulfane (5r):

Following general procedure A, compound 1r (0.108 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.147 g (81% yield) of desired product 5r as a colorless solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.34 (t, J = 7.1 Hz, 1H), 3.43 (t, J = 14.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 1.63 (p, J = 7.4 Hz, 2H), 1.40 – 1.32 (m, 2H), 1.27 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 140.7, 140.6, 131.2, 130.9 (t, 1JC-F₂ = 275.7 Hz), 130.1, 128.7, 127.3, 127.1, 127.1, 45.3 (t, 2JC-F₂ = 24.8 Hz), 31.7, 29.7, 29.1, 29.0, 28.8, 28.0 (t, 3JC-F₂ = 3.7 Hz), 22.3, 14.0. ¹⁹F NMR (471 MHz, Chloroform-d) δ −72.99 (t, J = 14.6 Hz). M.P. 43 – 45 °C. IR (Film) 2955, 2921, 2871, 2851, 1488, 1379, 1275, 1260, 1119, 1075, 989, 764, 749, 724 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₂₂H₂₈F₂S [M+H]⁺ 363.1953, found 363.1953.

(2-(4’-(tert-butyl)-[1,1’-biphenyl]-2-yl)-1,1-difluoroethyl)(octyl)sulfane (5s):

Following general procedure A, compound 1s (0.136 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.144 g (69% yield) of desired product 5s as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.58 – 7.51 (m, 4H), 7.48 (d, J = 8.3 Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 3.46 (t, J = 14.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 1.62 (p, J = 7.4 Hz, 2H), 1.37 (s, 9H), 1.36 (s, 2H), 1.31 – 1.23 (m, 9H), 0.88 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 150.3, 141.1, 132.5, 130.0 (t, 1JC-F₂ = 277.4 Hz), 129.2, 129.0, 126.8, 126.3, 125.6, 45.7 (t, 2JC-F₂ = 24.5 Hz), 31.7, 31.3, 29.7, 29.0, 28.9, 28.7, 27.9, 22.5, 14.0. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.85 (t, J = 14.5 Hz). IR (Film) 2957, 2926, 2855, 1728, 1483, 1267, 1191, 1152, 1008, 835, 766, 750, 703 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₂₆H₃₆F₂S [M+H]⁺ 419.2586, found 419.2586.

ethyl (E)-3-(3-(2,2-difluoro-2-(octylthio)ethyl)phenyl)acrylate (5t):

Following general procedure A, compound 1t (0.119 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.146 g (76% yield) of desired product 5t as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.68 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.40 (t, J = 14.4 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 1.61 (p, J = 14.0, 6.9 Hz, 2H), 1.35 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.27 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 166.9, 144.2, 134.7, 133.0, 132.3, 130.2, 129.9 (t, 1JC-F₂ = 276.8 Hz), 128.9, 127.3, 118.7, 60.5, 46.4 (t, 2JC-F₂ = 24.9 Hz), 31.8, 29.8, 29.1, 29.0, 28.8, 28.0 (t, 3JC-F₂ = 3.5 Hz), 22.6, 14.3, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.03 (t, J = 14.4 Hz). IR (Film) 2925, 2854, 1712, 1639, 1309, 1177, 1161, 1129, 992, 864 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₂₁H₃₀F₂O₂S [M+H]⁺ 385.2007, found 385.1962.

4-(2,2-difluoro-2-(octylthio)ethyl)-N,N-diethylbenzamide (5u):

Following general procedure A, compound 1t (0.120 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:5) to furnish 0.121 g (63% yield) of desired product 5t as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.27 (d, J = 15.0 Hz, 2H), 7.25 (d, J = 15.0 Hz, 2H), 3.48 (s, 2H), 3.33 (t, J = 14.5 Hz, 2H), 3.20 (s, 2H), 2.74 (t, J = 7.5 Hz, 2H), 1.55 (p, J = 7.5 Hz, 2H), 1.31 – 1.25 (m, 2H), 1.19 (s, 8H), 1.05 (s, 6H), 0.80 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR(126 MHz, Chloroform-d) δ 170.9, 136.5, 133.2 (t, 3JC-F₂ = 3.6 Hz), 130.5, 129.8 (t, 1JC-F₂ = 277.3 Hz), 126.4, 45.4 (t, 2JC-F₂ = 25.0 Hz), 43.3, 39.2, 31.7, 29.7, 29.1, 29.0, 28.8, 27.9 (t, 3JC-F₂ = 3.5 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.11 (t, J = 14.5 Hz). IR (Film) 2925, 2854, 1630, 1457, 1425, 1285, 1219, 1094, 1011, 990, 784, 744 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₂₁H₃₃F₂NOSNa [M+Na]⁺ 408.2149, found 408.2137.

4-(2,2-difluoro-2-(octylthio)ethyl)phenol (5v):

Following general procedure A, compound 1v (0.078 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.033 g (22% yield) of desired product 5v as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.16 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 4.89 (s, 1H), 3.32 (t, J = 14.5 Hz, 2H), 2.83 – 2.74 (t, J = 7.5 Hz, 2H), 1.61 (p, J = 7.4 Hz, 2H), 1.42 – 1.18 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 155.1, 131.8, 130.3 (t, 1JC-F₂ = 277.7 Hz), 124.5 (t, 3JC-F₂ = 4.0 Hz), 115.3, 44.7 (t, 2JC-F₂ = 24.8 Hz), 31.8, 29.8, 29.1, 29.0, 28.8, 27.9 (t, 3JC-F₂ = 3.6 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −72.83 (t, J = 14.6 Hz). IR (Film) 3381, 2953, 2920, 2875, 2851, 1516, 1453, 1257, 1153, 998, 785, 766, 749, 707 cm⁻¹. HRMS (ESI)⁻ m/z calc’d C₁₆H₂₃F₂OS [M-H]⁻ 301.1432, found 301.1436.

(1,1-difluoro-2-(4-(methoxymethoxy)phenyl)ethyl)(octyl)sulfane (5w):

Following general procedure A, compound 1w (0.100 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.086 g (50% yield) of desired product 6w as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.24 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 5.20 (s, 2H), 3.51 (s, 3H), 3.36 (t, J = 14.6 Hz, 3H), 2.83 (t, J = 7.5 Hz, 3H), 1.65 (p, J = 14.8, 7.3 Hz, 2H), 1.45 – 1.18 (m, 11H), 0.91 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 156.9, 131.6, 130.2 (t, 1JC-F₂ = 278.5 Hz), 125.5 (t, 3JC-F₂ = 4.3 Hz), 116.1, 94.4, 56.0, 44.8 (t, 2JC-F₂ = 24.8 Hz), 31.8, 29.8, 29.1, 29.1, 28.9, 27.9 (t, 3JC-F₂ = 3.6 Hz), 22.7, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) −72.80 (t, J = 14.6 Hz). IR (Film) 2961, 2926, 2855, 151, 1236, 1151, 1079, 1003, 779, 722, 652 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₈H₂₉F₂O₂S [M+H]⁺ 346.1773, found 346.1780.

(2-(4-(benzyloxy)phenyl)-1,1-difluoroethyl)(octyl)sulfane (5x):

Following general procedure A, compound 1x (0.123 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.171 g (87% yield) of desired product 5x as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.43 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 5.06 (s, 2H), 3.33 (t, J = 14.5 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 1.62 (p, J = 7.4 Hz, 2H), 1.39 – 1.32 (m, 2H), 1.32 – 1.22 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 158.4, 136.9, 131.5, 130.3 (t, 1JC-F₂ = 277.1 Hz), 128.6, 127.9, 127.5, 124.5 (t, 3JC-F₂ = 4.0 Hz), 114.7, 70.0, 45.7 (t, 2JC-F₂ = 24.7 Hz), 31.7, 29.8, 29.1, 29.0, 28.8, 27.9 (t, 3JC-F₂ = 3.6 Hz), 22.6, 14.0. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.31 (t, J = 14.5 Hz). IR (Film) 2925, 2854, 1512, 1245, 1220, 1008, 988, 869, 764, 739, 696 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₂₃H₃₁F₂OS [M+H]⁺ 393.2064, found 393.2059.

4-(2,2-difluoro-2-(octylthio)ethyl)dibenzo[b,d]thiophene (5y):

Following general procedure A, compound 1y (0.123 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.143 g (72% yield) of desired product 5y as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 8.18 – 8.09 (m, 2H), 7.91 – 7.83 (m, 1H), 7.51 – 7.43 (m, 4H), 3.71 (t, J = 14.4 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 1.63 (p, J = 7.4 Hz, 2H), 1.39 – 1.32 (m, 2H), 1.32 – 1.22 (m, 8H), 0.89 (t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 141.0, 139.0, 136.1, 135.9, 131.4 (t, 1JC-F₂ = 278.6 Hz), 129.0, 126.9, 126.8, 124.7, 124.5, 122.7, 121.7, 121.1, 45.8 (t, 2JC-F₂ = 25.8 Hz), 31.7, 29.7, 29.1, 29.0, 28.8, 28.2 (t, 3JC-F₂ = 3.5 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −71.28 (t, J = 14.4 Hz). IR (Film) 2954, 2924, 2853, 1443, 1403, 1053, 1008, 989, 750, 724, 705 cm⁻¹. HRMS (ESI)⁺ m/z calc’d C₂₂H₂₆F₂S₂ [M+H]⁺ 393.1517, found 393.1513.

4-(2,2-difluoro-2-(octylthio)ethyl)-1-phenyl-1H-pyrazole (5z):

Following general procedure A, compound 1z (0.103 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.96 g (53% yield) of desired product 5z as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.65 (s, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 3.35 (t, J = 14.4 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 1.64 (p, J = 7.4 Hz, 2H), 1.41 – 1.34 (m, 2H), 1.34 – 1.20 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 141.9, 140.0, 129.8 (t, 1JC-F₂ = 276.8 Hz), 129.4, 126.9, 126.5, 119.0, 113.8, 35.2 (t, 2JC-F₂ = 26.2 Hz), 31.8, 29.8, 29.1, 29.0, 28.8, 28.0 (t, 3JC-F₂ = 3.5 Hz), 22.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −73.84 (t, J = 14.4 Hz). IR (Film) 2925, 2854, 1601, 1505, 1428, 1400, 1378, 1261, 1073, 1023, 1005, 954, 753, 690 cm⁻¹. HRMS (ESI)⁺ m/z calc’d C₁₉H₂₆F₂N₂S [M+H]⁺ 353.1858, found 353.1859.

(1,1-difluoro-2-(4-methoxyphenyl)propyl)(octyl)sulfane (5aa):

Following general procedure A, compound 1aa (0.097 g, 0.500 mmol) was reacted with 1-octanethiol (0.130 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.110 g (73% yield) of desired product 5aa as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.29 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H), 3.50 – 3.32 (m, 1H), 2.85 (t, J = 7.6 Hz, 2H), 1.64 (p, J = 7.4 Hz, 2H), 1.51 (d, J = 7.3 Hz, 2H), 1.41(m, 2H), 1.32 (m, 8H), 0.93 (t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 159.1, 132.5 (t, 1JC-F₂ = 277.2 Hz), 130.5, 129.9, 113.7, 55.1, 47.9 (t, 2JC-F₂= 21.8 Hz), 31.8, 29.8, 29.1, 29.0, 28.9, 27.8 (t, 3JC-F₂ = 3.9 Hz), 22.6, 15.6, 14.1. ¹⁹F NMR (471 MHz, Chloroform-d) δ −77.68 (dd, J = 202.2, 11.3 Hz), −79.98 (dd, J = 202.3, 14.5 Hz). IR (Film) 2926, 2855, 1514, 1262, 1250, 1180, 1090, 1003, 981, 953, 764, 748, 706 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₈H₂₈F₂OS [M+H]⁺ 331.1902, found 331.1892.

3-(2,2-difluoro-2-((6-hydroxyhexyl)thio)ethyl)benzonitrile (6a):

Following general procedure A, compound 1b (0.084 g, 0.500 mmol) was reacted 6-mercaptohexan-1-ol (0.103 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:5) to furnish 0.105 g (70% yield) of desired product 6a as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.62 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 3.64 (t, J = 6.6 Hz, 2H), 3.42 (t, J = 14.2 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 1.65 (p, J = 7.3 Hz, 2H), 1.56 (p, J = 6.7 Hz, 2H), 1.45 – 1.34 (m, 4H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 135.0, 134.0, 133.7 (t, 3JC-F₂ = 3.9 Hz), 131.5, 129.40 (t, 1JC-F₂ = 278.1 Hz), 129.3, 115.96, 112.7, 62.8, 45.1 (t, 2JC-F₂ = 25.5 Hz), 32.5, 29.7, 28.5, 27.9 (t, 3JC-F₂ = 3.7 Hz), 25.2. ¹⁹F NMR (470 MHz, Chloroform-d) δ −73.2 (t, J = 14.3 Hz). IR (Film) 3353, 2931, 2857, 2231, 1733, 1275, 1260, 1017, 921, 764, 750 cm⁻¹. HRMS (ESI)⁺ m/z calc’d C₁₅H₁₉F₂NOSNa [M+Na]⁺ 322.1053, found 322.1036.

3-(2,2-difluoro-2-((1-hydroxyhexan-3-yl)thio)ethyl)benzonitrile (6b):

Following general procedure A, compound 1b (0.084 g, 0.500 mmol) was reacted 3-mercaptohexan-1-ol (0.105 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:5) to furnish 0.102 g (68% yield) of desired product 6b as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 3.75 (dtt, J = 13.3, 8.0, 4.9 Hz, 2H), 3.43 (t, J = 14.3 Hz, 2H), 1.93 (td, J = 14.0, 5.8 Hz, 1H), 1.74 (ddt, J = 14.5, 9.2, 5.5 Hz, 1H), 1.68 – 1.53 (m, 3H), 1.50 – 1.34 (m, 3H), 0.90 (t, J = 7.3 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 134.9, 134.0, 133.6 (t, 3JC-F₂ = 3.7 Hz), 131.4, 129.7 (t, 1JC-F₂ = 278.4 Hz), 129.2, 118.5, 60.1, 46.5 (t, 2JC-F₂ = 24.7 Hz), 41.1, 38.6, 38.3, 19.7, 13.7. ¹⁹F NMR (471 MHz, Chloroform-d) δ −70.61 (dt, J = 203.5, 14.4 Hz), −71.43 (dt, J = 203.5, 14.2 Hz). IR (Film) 3377, 3006, 2959, 2930, 2872, 2231, 1465, 1275, 1260, 1016, 992, 764, 750 cm⁻¹. HRMS (ESI)⁻ m/z calc’d C₁₅H₁₉F₂NOS [M+Cl]⁻ 334.0843, found 334.0860.

butyl 3-((2-(3-cyanophenyl)-1,1-difluoroethyl)thio)propanoate (6c):

Following general procedure A, compound 1b (0.083 g, 0.500 mmol) was reacted with butyl 3-mercaptopropanoate (0.122 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.134 g (82% yield) of desired product 6c as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.62 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 4.10 (t, J = 6.8 Hz, 2H), 3.42 (t, J = 14.3 Hz, 2H), 3.07 (t, J = 7.1 Hz, 2H), 2.69 (t, J = 7.1 Hz, 3H), 1.70 – 1.57 (m, 2H), 1.37 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 171.6, 135.1, 134.1, 133.6 (d, 3JC-F₂ = 3.9 Hz), 131.7, 129.6 (t, 1JC-F₂ = 278.4 Hz), 129.5, 116.1, 112.9, 64.9, 45.0 (t, 2JC-F₂ = 25.0 Hz), 35.5, 30.7, 23.3 (t, 3JC-F₂ = 4.1 Hz), 19.2, 13.8. ¹⁹F NMR (470 MHz, Chloroform-d) δ −73.39 (t, J = 14.3 Hz). IR (Film) 3005, 2988, 2961, 2873, 2231, 1731, 1275, 1260, 1098, 1018, 764, 750 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₆H₂₀FNO₂S [M-F]⁺ 308.1122, found 308.1129. The found HRMS corresponds to loss of HF, so GCMS was run to confirm the structure: LRMS (EI)⁺ m/z calc’d C₁₆H₂₀FNO₂S 327.1, found 327.0, 307.1, 254.0, 225.0 166.0, 161.0, 116.0, 105.0, 73.0.

3-((2-(3-cyanophenyl)-1,1-difluoroethyl)thio)propanoic acid (6d):

Following general procedure B, compound 1b (0.083 g, 0.500 mmol) was reacted with 3-mercaptopropionic acid (0.065 mL, 0.750 mmol) in the presence of pyridine (0.10 mL, 1.00 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by reverse-phase flash chromatography using Acetonitrile and H2O containing 0.1% acetic acid (5 – 95%) to furnish 0.046 g (34% yield) of desired product 6d as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.62 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 3.43 (t, J = 14.3 Hz, 2H), 3.08 (t, J = 7.1 Hz, 2H), 2.77 (t, J = 7.1 Hz, 2H). ¹³C{¹H} NMR (201 MHz, DMSO) δ 172.9, 136.0, 134.5, 134.4, 131.8, 130.4 (t, 1JC-F₂ = 276.7 Hz), 130.0, 119.0, 111.7, 43.7 (t, 2JC-F₂= 24.1 Hz), 31.1, 15.6. ¹⁹F NMR (471 MHz, Chloroform-d) δ −72.74 (t, J = 14.4 Hz). IR (Film) 3006, 2989, 2925, 2231, 1731, 1705, 1275, 1260, 1027, 919, 754, 750 cm⁻¹. HRMS (ESI)⁻ m/z calc’d C₁₂H₁₁F₂NO₂S [M-H]⁻ 270.0406, found 270.0424.

3-(2-((3-chloropropyl)thio)-2,2-difluoroethyl)benzonitrile (6e):

Following general procedure A, compound 1b (0.083 g, 0.500 mmol) was reacted with 3-chloro-1-propanethiol (0.073 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.066 g (48% yield) of desired product 6e as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.62 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 3.62 (t, J = 6.2 Hz, 2H), 3.43 (t, J = 14.3 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.10 (p, J = 6.6 Hz, 2H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 134.9, 133.9, 133.4 (t, 3JC-F₂ = 3.6 Hz), 131.5, 129.3 (t, 1JC-F₂ = 279.3 Hz), 129.3, 118.4, 44.9 (t, 2JC-F₂ = 25.3 Hz), 43.0, 32.5, 25.2 (t, 3JC-F₂ = 3.7 Hz). ¹⁹F NMR (471 MHz, Chloroform-d) δ −72.94 (t, J = 14.3 Hz). IR (Film) 3006, 2989, 2230, 1260, 1275, 1098, 1017, 994, 764, 749, 725 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₂H₁₃ClF₂NS [M+H]⁺ 276.0420, found 276.0423.

3-(2-(cyclohexylthio)-2,2-difluoroethyl)benzonitrile (6f):

Following general procedure A, compound 1b (0.083 g, 0.500 mmol) was reacted cyclohexanethiol (0.092 mL, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.114 g (81% yield) of desired product 6f as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 9.1 Hz, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 3.40 (t, J = 14.2 Hz, 2H), 3.28 (ddd, J = 14.0, 8.5, 3.8 Hz, 1H), 2.05 – 1.88 (m, 2H), 1.76 – 1.64 (m, 2H), 1.60 – 1.53 (m, 1H), 1.39 (ddt, J = 34.9, 24.1, 11.2 Hz, 4H), 1.28 – 1.19 (m, 1H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 134.0, 133.8 (t, 3JC-F₂ = 3.9 Hz), 131.3, 129.8 (t, 1JC-F₂ = 277.3 Hz), 129.2, 118.6, 45.3 (t, 2JC-F₂ = 25.3 Hz), 42.3 (t, 3JC-F₂ = 2.3 Hz), 34.5, 25.9, 25.4. ¹⁹F NMR (471 MHz, Chloroform-d) δ −71.27 (t, J = 13.6 Hz). IR (Film) 3006, 2989, 2931, 2854, 2231, 1449, 1333, 1275, 1260, 1098, 1016, 764, 750 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₅H₁₈F₂NS [M+H]⁺ 282.1128, found 282.1124.

3-(2,2-difluoro-2-(phenethylthio)ethyl)benzonitrile (6g):

Following general procedure C, compound 1b (0.083 g, 0.500 mmol) was reacted 2-phenylethane-1-thiol (0.100 mL, 0.750 mmol) in the presence of pyridine (0.10 mL, 1.00 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 120 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.077 g (51% yield) of desired product 6g as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.62 (d, J = 7.6 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 6.9 Hz, 2H), 3.43 (t, J = 14.2 Hz, 2H), 3.08 (dd, J = 9.2, 6.5 Hz, 2H), 2.94 (dd, J = 9.1, 6.5 Hz, 2H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 139.6, 134.9, 134.0, 133.6 (t, 3JC-F₂ = 3.7 Hz), 131.4, 129.4 (t, 1JC-F₂ = 277.0 Hz), 129.2, 128.5, 128.4, 126.6, 118.6, 118.4, 44.9 (t, 2JC-F₂ = 25.1 Hz), 36.3, 29.4 (t, 3JC-F₂ = 3.4 Hz). ¹⁹F NMR (470 MHz, Chloroform-d) δ −73.1 (t, J = 14.3 Hz). IR (Film) 2955, 2926, 2854, 2232, 1489, 1264, 1217, 1153, 1012, 990, 764, 738, 764, 705 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₇H₁₆F₂NS [M+H]⁺ 304.0966, found 304.0965.

3-(2,2-difluoro-2-((2-methylundecan-2-yl)thio)ethyl)benzonitrile (6h):

Following general procedure C, compound 1b (0.083 g, 0.500 mmol) was reacted with tert-dodecylmercaptan (0.176 mL, 0.750 mmol) in the presence of pyridine (0.10 mL, 1.00 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 120 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.051 g (28% yield) of desired product 6h as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 5.6 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 3.37 (t, J = 14.3 Hz, 2H), 1.95 – 1.48 (m, 4H), 1.47 – 1.04 (m, 10H), 1.05 – 0.73 (m, 13H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 135.1, 134.1, 131.2 (t, 3JC-F₂ = 4.9 Hz), 130.7 (t, 1JC-F₂= 280.8 Hz), 129.9 – 128.6 (m), 118.6, 112.5 (t, 3JC-F₂ = 4.9 Hz), 48.2 – 43.7 (m), 30.8 – 28.5 (m), 27.2, 26.7 (d, 3JC-F₂ = 3.4 Hz), 25.1, 22.6 (t, 3JC-F₂ = 4.3 Hz), 19.2, 15.0 – 14.2 (m), 14.0, 12.2, 8.7 (d, 3JC-F₂ = 3.5 Hz). ¹⁹F NMR (471 MHz, Chloroform-d) δ −66.38 – −71.38 (m). IR (Film) 3005, 2989, 2872, 2233, 1275, 1260, 1135, 1098, 906, 764, 749 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₂₁H₃₂F₂NS [M+H]⁺ 368.2218, found 368.2223.

3-(2,2-difluoro-2-(phenylthio)ethyl)benzonitrile (6i):

Following general procedure A, compound 1b (0.083 g, 0.500 mmol) was reacted with thiophenol (0.077 g, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.117 g (79% yield) of desired product 6i as a colorless solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.63 (d, J = 6.5, 1H), 7.58 (s, 2H), 7.56 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.45 (q, J = 7.9 Hz, 2H), 7.39 (t, J = 8.0 Hz, 2H), 3.45 (t, J = 14.6 Hz, 1H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 136.8, 135.0, 134.0, 133.5 (t, 3JC-F₂ = 3.6 Hz), 131.5, 130.1, 129.3, 129.2, 128.0 (t, 1JC-F₂ = 279.5 Hz), 126.3 (t, 3JC-F₂ = 2.6 Hz), 118.5, 112.7, 44.6 (t, 2JC-F₂ = 25.1 Hz). ¹⁹F NMR (470 MHz, Chloroform-d) δ −72.6 (t, J = 14.6 Hz). M.P. 33 – 36 °C. IR (Film) 3005, 2989, 2231, 1275, 1260, 1098, 1035, 916, 764, 750, 705 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₅H₁₁F₂NS [M+H]⁺ 276.0653, found 276.0659.

(1,1-difluoro-2-(3-nitrophenyl)ethyl)(phenyl)sulfane (6j):

Following general procedure A, compound 1e (0.093 g, 0.500 mmol) was reacted with thiophenol (0.077 g, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.122 g (83% yield) of desired product 6j as a colorless solid. ¹H NMR matches the previously reported spectra.³⁵

4-(2,2-difluoro-2-(phenylthio)ethyl)benzonitrile (6k):

Following general procedure A, compound 1c (0.083 g, 0.500 mmol) was reacted with thiophenol (0.077 g, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.116 g (84% yield) of desired product 6k as a colorless solid. ¹H NMR matches the previously reported spectra.³⁵

f3-(2,2-difluoro-2-((3-hydroxyphenyl)thio)ethyl)benzonitrile (6l):

Following general procedure A, compound 1b (0.082 g, 0.500 mmol) was reacted with 3-hydroxythiophenol (0.095 g, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:5) to furnish 0.102 g (70% yield) of desired product 6l as a colorless solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.62 (dd, J = 7.6, 1.4 Hz, 1H), 7.57 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 4.5 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.91 (dd, J = 8.2, 2.7 Hz, 1H), 5.11 (s, 1H), 3.45 (t, J = 14.5 Hz, 2H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 155.8, 135.0, 134.1, 133.5 (t, 3JC-F₂ = 3.6 Hz), 131.5, 130.2, 129.3, 128.3, 128.0 (t, 1JC-F₂ = 280.1 Hz), 127.5 (t, 3JC-F₂ = 2.7 Hz), 122.6, 118.5, 117.3, 112.7, 44.6 (t, 2JC-F₂ = 24.7 Hz). ¹⁹F NMR (470 MHz, Chloroform-d) δ −72.4 (t, J = 14.5 Hz). M.P. 94 – 97 °C. IR (Film) 3370, 3005, 2989, 2235, 1583, 1275, 1260, 1035, 1017, 886, 764, 750, 689 cm⁻¹. HRMS (ESI)⁻ m/z calc’d C₁₅H₁₁F₂NOS [M-H]⁻ 290.0457, found 290.0446.

3-(2,2-difluoro-2-((3-(trifluoromethyl)phenyl)thio)ethyl)benzonitrile (6m):

Following general procedure A, compound 1b (0.083 g, 0.500 mmol) was reacted with 3-trifluoromethylthiophenol (0.134 g, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.124 g (72% yield) of desired product 6m as a colorless solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.63 (s, 1H), 7.57 (s, 1H), 7.55 (q, J = 7.9 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 3.52 (t, J = 14.3 Hz, 2H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 139.3, 134.9, 134.0, 133.1 (t, 3JC-F₂ = 3.5 Hz), 132.7 (q, 3JC-F₂ = 4.4 Hz), 131.8, 131.7, 130.0, 129.6, 129.4, 127.8 (t, 1JC-F₂ = 281.7 Hz), 127.5 (t, 3JC-F₂ = 2.4 Hz), 126.8 (q, 3JC-F₂ = 4.0 Hz), 118.4, 112.9, 44.7 (t, 2JC-F₂ = 24.0 Hz). ¹⁹F NMR (470 MHz, Chloroform-d) δ −63.3, −71.9 (t, J = 14.4 Hz). M.P. 46 – 49 °C. IR (Film) 3006, 2989, 2233, 1303, 1275, 1260, 1085, 764, 750 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₆H₁₁F₅NS [M+H]⁺ 344.0527, found 344.0511.

3-(2,2-difluoro-2-((4-methoxyphenyl)thio)ethyl)benzonitrile (6n):

Following general procedure A, compound 1b (0.082 g, 0.500 mmol) was reacted with 4-methoxythiophenol (0.105 g, 0.750 mmol) in the presence of pyridine (0.01 mL, 0.10 mmol), LiOTf (0.008 g, 0.050 mmol), and 2-methoxyethanol (0.080 mL, 1.00 mmol) in 1.5 mL of o-xylene using a heating mantle at 110 °C for 24 h. The material was worked up according to the general procedure and purified by normal-phase flash chromatography using EtOAc and hexanes (1:10) to furnish 0.130 g (85% yield) of desired product 6n as a colorless solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.61 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 (s, 1H), 7.53 (d, J = 7.53, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 7.72, 2H), 3.83 (s, 3H), 3.42 (t, J = 14.5 Hz, 2H). ¹³C{¹H} NMR (126 MHz, Chloroform-d) δ 161.3, 138.1, 135.0, 134.0, 133.7 (t, 3JC-F₂ = 3.1 Hz), 131.4, 129.3, 127.9 (t, 1JC-F₂ = 279.9 Hz), 118.6, 116.7 (t, 3JC-F₂ = 2.7 Hz), 114.8, 55.4, 44.3 (t, 2JC-F₂ = 25.4 Hz). ¹⁹F NMR (470 MHz, Chloroform-d) δ −73.7 (t, J = 14.5 Hz). M.P. 73 – 76 °C. IR (Film) 3006, 2989, 2230, 1591, 1275, 1259, 1097, 1028, 985, 764, 750 cm⁻¹. HRMS (APCI)⁺ m/z calc’d C₁₆H₁₃F₂NOS [M+H]⁺ 306.0759, found 306.0766.

Synthesis of Compound Octane-1-thiol-d:

An oven-dried 50 mL round bottom flask was charged with octanethiol (2.0 mL, 11 mmol). Then methanol-d₄ (10.0 mL, 247 mmol) was added and then removed under reduced pressure. Methanol-d₄ (10.0 mL, 247 mmol) was again added to the material and removed under reduced pressuer to give quantitative yield of the desired product (96% deuteration). ¹H NMR matches the previously reported spectra.³⁶

Synthesis of Compound 2-Methoxyethan-1-ol-d:

2-Methoxyethan-1-ol-d was prepared according to a previous report.³⁷

Synthesis of Compound 13:

An oven-dried 50 mL round bottom flask equipped with a reflux condenser and magnetic stir bar was charged with acetonitrile (20 mL). Then octanethiol (1.5 mL, 8.7 mmol) and styrene (1.0, 8.7 mmol) were added via syringe. The reaction mixture was then heated to 70 °C and stirred for 24 h. The reaction was then cooled to rt, concentrated onto SiO₂ and purified by normal-phase flash chromatography using hexanes to provide 1.15 g (53% yield) of desired product 13 as a colorless oil. ¹H NMR matches the previously reported spectra.³⁸