New sulfuryl fluoride-derived alkylating reagents for the 1,1-dihydrofluoroalkylation of thiols† †Electronic supplementary information (ESI) available: Experimental procedures, methods, and optimization data; NMR, IR, and MS data including 1H, 13C, and 19F NMR spectra. See DOI: 10.1039/c9sc03570b

Herein, we report a new method for the one-pot synthesis of 1,1-dihydrofluoroalkyl sulfides by bubbling sulfuryl fluoride (SO2F2) through a solution of the corresponding alcohol and thiol.


Optimization of one-pot conditions for the trifluoroethylation of benzyl mercaptan (9a)
The reactions were run on 0.3 mmol scale of benzyl mercaptan in 4 mL vials following the general procedure for the one-pot trifluoroethylation of thiols. The yield was determined by 19 F NMR spectroscopy using PhCF3 as an internal standard.
Comments on the amount of trifluoroethanol utilized: While the reaction gives comparable results using 1:1, 1:2, and 1:4 TFE:DMF (v/v) ratios, we selected 1:1 for studies investigating the scope primarily for two reasons. First, when exploring the scope, we wanted to increase the rate of bis(trifluoroethyl) sulfate (6a) formation relative to competing thiol addition to sulfuryl fluoride. Thus, a high concentration of trifluoroethanol was utilized. Second, even though it is less atom economical, trifluoroethanol is commercially available, relatively inexpensive, easily removed from the reaction, and often used as solvent. Therefore, a 1:1 ratio was selected.

Procedure
Two 20 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (2.57 mmol, 0.78 equiv) and anhydrous KF (7.05 mmol, 2.1 equiv), then the system was placed under N2 atmosphere. To vial B was added DCM (2.3 mL), DBU (4.7 mmol, 1.4 equiv), and 1 (3.3 mmol, 1 equiv). The polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (1.6 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 2-3 minutes. When the bubbling subsided, vial B was vented via a needle for approximately 1 minute (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at room temperature for 20 min.
The reaction mixture was poured into a separatory funnel, diluted with DCM (10 mL) and then washed with aqueous HCl (1M, 3 x 10 mL), and then brine (10 mL). The organic layer was dried over anhydrous Na2SO4, decanted, and then concentrated in vacuo to a clear oil. The oil was then passed through a Pasteur pipette silica gel plug and eluted with DCM (~6 mL). The collected liquid was concentrated in vacuo to a clear colorless oil.
For studies with trifluoroethyl fluorosulfate (5a) and DIPEA: Two 4 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (1.35 mmol) and anhydrous KF (3.58 mmol), then the system was placed under N2 atmosphere. To vial B was added dry DMF (0.84 mL), 2,2,2-trifluoroethanol (0.45 mmol) and DIPEA (0.16 mL, 0.92 mmol). The polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (0.75 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 1-2 minutes and when the bubbling subsided, vial B was vented via a needle (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at ambient temperature for 5 minutes. The reaction mixture was degassed with N2 and the amount of reagent was quantified by 19 F NMR spectroscopy using PhCF3 as an internal standard. To the reaction was added a solution of benzyl mercaptan (0.66 equiv) in DMF (0.15 mL). The reaction was stirred at ambient temperature for 60 min and the amount of trifluoroethylated product was 52%, as determined by 19 F NMR spectroscopy. The calculated percentage of trifluoroethanol (1a) was based on the total amount of benzyl mercaptan used.
For studies with trifluoroethyl fluorosulfate (5a) and DBU, the procedure for trifluoroethyl fluorosulfate and DIPEA was followed, however, DBU (0) was added to the reaction before benzyl mercaptan (0.89 equiv) was added. After the addition of benzyl mercaptan, the reaction was stirred at ambient temperature for 20 min and the amount of trifluoroethylated product was 78%, as determined by 19 F NMR spectroscopy. The calculated percentage of trifluoroethanol (1a) was based on the total amount of benzyl mercaptan used.
For studies with bis(trifluoroethyl) sulfate (6a) and DBU: Two 4 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (0.87 mmol) and anhydrous KF (2.3 mmol), then the system was placed under N2 atmosphere. To vial B was added dry DMF (0.80 mL), 2,2,2-trifluoroethanol (1.12 mmol) and DBU (1.60 mmol). The polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (0.50 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 1-2 minutes and when the bubbling subsided, vial B was vented via a needle (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at ambient temperature for 5 minutes. The reaction mixture was degassed with N2 and the amount of reagent was quantified by 19 F NMR spectroscopy, using PhCF3 as an internal standard. To the reaction was added a solution of benzyl mercaptan (0.66 equiv) in DMF (0.15 mL). The reaction was stirred at ambient temperature for 20 min and the amount of trifluoroethylated product was >99%, as determined by 19 F NMR spectroscopy.
For studies with trifluoroethyl triflate (S1, 1.5 equiv): A 4 mL vial was charged with benzyl mercaptan (0.30 mmol), piperidine (0.30 mmol), and DMF (0.84 mL). To the mixture was added DBU (0.24 mL, 5.3 mmol) and then a solution of trifluoroethyl triflate (S1, 0.45 mmol) in DMF (0.15 mL). The reaction was stirred at ambient temperature and the amount of products formed was determined by 19 F NMR spectroscopy using PhCF3 as an internal standard.
For studies with trifluoroethyl fluorosulfate (5a, 1.5 equiv): Two 4 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (1.35 mmol) and anhydrous KF (3.58 mmol), then the system was placed under N2 atmosphere. To vial B was added dry DMF (0.84 mL), 2,2,2-trifluoroethanol (0.45 mmol) and DIPEA (0.16 mL). The polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (0.65 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 1-2 minutes and when the bubbling subsided, vial B was vented via a needle (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at ambient temperature for 5 minutes. The reaction mixture was degassed with N2 and the amount of reagent was quantified by 19 F NMR spectroscopy. To the reaction was added DBU (0.93 mmol), and then a solution of benzyl mercaptan (0.66 equiv) and piperidine (0.66 equiv) in DMF (0.15 mL). The reaction was stirred at ambient temperature and the amount of products formed was determined by 19 F NMR spectroscopy using PhCF3 as an internal standard. The calculated percentage of trifluoroethanol (1a) was based on the total amount of benzyl mercaptan used.
For studies with bis(trifluoroethyl) sulfate (6a, 1.5 equiv): Two 4 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (0.87 mmol) and anhydrous KF (2.3 mmol), then the system was placed under N2 atmosphere. To vial B was added dry DMF (0.84 mL), 2,2,2-trifluoroethanol (1.0 mmol) and DBU (0.30 mL, 2.0 mmol). The polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (0.50 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 1-2 minutes and when the bubbling subsided, vial B was vented via a needle (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at ambient temperature for 5 minutes. The reaction mixture was degassed with N2 and the amount of reagent was quantified by 19 F NMR spectroscopy. To the reaction was added a solution of benzyl mercaptan (0.66 equiv) and piperidine (0.66 equiv) in DMF (0.15 mL). The reaction was stirred at ambient temperature and the amount of products formed was determined by 19 F NMR spectroscopy using PhCF3 as an internal standard. The calculated percentage of trifluoroethanol (1a) was based on the total amount of benzyl mercaptan used.
For studies with trifluoroethyl fluorosulfate (5a, 1.0 equiv): Two 4 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (1.35 mmol) and anhydrous KF (3.58 mmol), then the system was placed under N2 atmosphere. To vial B was added dry DMF (0.84 mL), 2,2,2-trifluoroethanol (0.45 mmol) and DIPEA (0.40 mL, 5.1 equiv). The polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (0.65 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 1-2 minutes and when the bubbling subsided, vial B was vented via a needle (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at ambient temperature for 5 minutes. The reaction mixture was degassed with N2 and the amount of reagent was quantified by 19 F NMR spectroscopy. To the reaction was added a solution of benzyl mercaptan (1 equiv) and piperidine (1 equiv) in DMF (0.15 mL). The reaction was stirred at ambient temperature and the amount of products formed was determined by 19 F NMR spectroscopy using PhCF3 as an internal standard. The calculated percentage of trifluoroethanol (1a) was based on the total amount of benzyl mercaptan used.
For studies with bis(trifluoroethyl) sulfate (6a, 1.0 equiv): Two 4 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (0.87 mmol) and anhydrous KF (2.34 mmol), then the system was placed under N2 atmosphere. To vial B was added dry DMF (0.80 mL), 2,2,2-trifluoroethanol (1.1 mmol) and DBU (0.26 mL). The polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (0.48 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 1-2 minutes and when the bubbling subsided, vial B was vented via a needle (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at ambient temperature for 10 minutes. The amount of reagent was quantified by 19 F NMR spectroscopy. To the reaction was added a solution of benzyl mercaptan (1.0 equiv) and pyrrolidine (1.0 equiv) in DMF (0.10 mL). The reaction was stirred at ambient temperature and the amount of products formed was determined by 19 F NMR spectroscopy using PhCF3 as an internal standard.

Comments on the reactivity of 5a and 6a
It is important to note that 5a is much more reactive to amines than 6a, and both 5a and 6a react with thiolates. This suggests that the electrophilic carbon in 5a is more reactive than the analogous carbon in 6a.

S11
General procedure for the one-pot trifluoroethylation of thiols Scheme S9 -One-pot trifluoroethylation of thiols using sulfuryl fluoride.
Two 20 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (2.89 mmol, 2.89 equiv) and anhydrous KF (7.8 mmol, 7.8 equiv), then the system was placed under N2 atmosphere. To vial B was added dry DMF (1.47 mL), DBU (5.90 mmol, 5.90 equiv), 2,2,2-trifluoroethanol (TFE; 1.47 mL), and thiol (1.0 mmol, 1 equiv). The reaction vial (B) was heated to 40 °C, the polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (1.6 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 2-3 minutes and when the bubbling subsided, vial B was vented via a needle for approximately 1 minute (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at 40 °C for 20 min.

Workup and purification:
To the reaction mixture was added aqueous HCl (3M, 10 mL) and the product was extracted with hexanes or pentanes (3 x 10 mL). The combined organic layer was washed sequentially with H2O (10 mL), NaOH (1M, 10 mL) and then brine (10 mL). The organic layer was dried over anhydrous Na2SO4, decanted, and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography. Fractions containing the desired product were combined and concentrated in vacuo.

General procedure for the trifluoroethylation of thiols by sequential addition
Shreeve et al. have reported that the attack of methanethiol at the sulfur center can presumably form bis(methanethio) sulfate, which can provide the disulfide species by elimination of SO2. 1 The generation of the bis(trifluoroethyl) sulfate reagent followed by addition of the nucleophile can decrease the amount of disulfide byproduct formed by limiting the interaction of the thiol with more reactive species, such as sulfuryl fluoride.
Two 20 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (2.89 mmol, 2.89 equiv) and anhydrous KF (7.80 mmol, 7.8 equiv), then the system was placed under N2 atmosphere. To vial B was added dry DMF (1.47 mL), DBU (5.9 mmol, 5.9 equiv), and 2,2,2-trifluoroethanol (TFE; 1.47 mL). The reaction vial (B) was heated to 40°C, the polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (1.6 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 2-3 minutes and when the bubbling subsided, vial B was vented via a needle for approximately 1 minute (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at 40 °C for 5 min. To vial B was added thiol (1.0 mmol, 1 equiv) and the reaction was stirred at 40 °C for 20 min.
Two 20 mL vials, equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Vial A was charged with SDI (2.89 mmol, 2.89 equiv) and anhydrous KF (7.8 mmol, 7.8 equiv), then the system was placed under N2 atmosphere. To vial B was added dry DMF (1.90 mL), DBU (5.90 mmol, 5.90 equiv), and 2,2,3,3,3pentafluoropropanol (PFP; 1.00 mL). The reaction vial (B) was heated to 40°C, the polyethylene tube in vial B was immersed into the solution and then to vial A was added TFA (1.6 mL) in one portion. Vigorous bubbling of SO2F2 and fuming were observed in vial B for 2-3 minutes and when the bubbling subsided, vial B was vented via a needle for approximately 1 minute (this triggered more bubbling of SO2F2 through the solution). The tube and needle were then removed and the mixture in vial B was allowed to stir at 40 °C for 5 min. To vial B was added thiol (1.0 mmol, 1 equiv) and the reaction was stirred at 40 °C for 30 min.

benzyl(2,2,2-trifluoroethyl)sulfane (10a)
Compound 10a was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The general workup procedure followed by silica gel column chromatography with pentanes as eluent afforded the product as a colorless oil (120 mg, 58% yield). The characterization data is consistent with literature values.

2-(((2,2,2-trifluoroethyl)thio)methyl)furan (10b)
Compound 10b was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. To the reaction mixture was added aqueous HCl (1M, 5 mL), and the product was extracted with diethyl ether (5 x 7 mL). The combined organics were washed with aqueous NaOH (1M, 3 x 5 mL), dried over anhydrous Na2SO4, decanted and concentrated in vacuo. The residue was purified by silica gel column chromatography with 3% diethyl ether in pentanes as eluent to afford the product as an oil (128 mg, 60% yield). The product yield has been corrected for 5% disulfide impurities.

decyl(2,2,2-trifluoroethyl)sulfane (10c)
Compound 10c was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The general workup procedure followed by flash column chromatography with pentanes as eluent afforded the product as a colorless oil (173 mg, 67% yield).

phenethyl(2,2,2-trifluoroethyl)sulfane (10d)
Compound 10d was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The general workup procedure followed by silica gel column chromatography with pentanes as eluent afforded the product as a colorless oil (146 mg, 66% yield). Compound 10e was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. To the reaction mixture was added aqueous HCl (1M, 10 mL), and the product was extracted with diethyl ether (3 x 10 mL). The combined organics were washed with aqueous HCl (1M, 2 x 10 mL), aqueous saturated NaHCO3 (2 x 10 mL), water (3 x 10 mL), brine (2 x 10 mL), and dried over anhydrous Na2SO4, decanted and concentrated in vacuo. The residue was purified by silica gel column chromatography with 0 -5% diethyl ether in pentanes as eluent to afford the product as a colorless oil (116 mg, 62% yield). The product yield has been corrected for 3% solvent impurities.

1,9-bis((2,2,2-trifluoroethyl)thio)nonane (10f)
Compound 10f was prepared on 0.5 mmol scale using the general procedure for one-pot trifluoroethylation of thiols, with 6.90 mmol of DBU. The reaction mixture was added into hexanes and washed with aqueous HCl (1M, 2 x 10 mL). The aqueous layer was back extracted with hexanes (2 x 10 mL). The combined organic layer was washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL) and then dried over anhydrous Na2SO4. The solution was decanted and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using 0-10% diethyl ether in pentanes. Fractions containing the desired product were combined and concentrated in vacuo to afford the product as a colorless oil (130 mg, 73% yield).

(2,2,2-trifluoroethyl)(trityl)sulfane (10h)
Compound 10h was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The reaction was diluted with H2O (12 mL) and then extracted with diethyl ether (3 x 10 mL). The ether layer was washed with saturated aqueous NaHCO3 (10 mL), dried over anhydrous Na2SO4, decanted, and then concentrated in vacuo. The crude solid was purified by silica gel column chromatography with toluene in hexanes (10-100% gradient) as eluent. Fractions containing the desired product were combined and concentrated to dryness in vacuo to afford the product as a white solid (258 mg, 72% yield).

phenyl(2,2,2-trifluoroethyl)sulfane (10i)
Compound 10i was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The general workup procedure followed by flash column chromatography with pentanes as eluent afforded the product as a colorless oil (152 mg, 79% yield). Product 1 H NMR data is consistent with literature data.

thio)phenyl)acetamide (10k)
Compound 10k was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The general workup procedure, using ethyl acetate instead of hexanes/pentanes, followed by silica gel column chromatography with 50% ethyl acetate in hexanes as the eluent afforded the product as a white solid (150 mg, 60% yield).

(2,2,2-trifluoroethyl)(4-(trifluoromethyl)phenyl)sulfane (10m)
Compound 10m was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The reaction mixture was diluted with H2O (10 mL) and the product was extracted with diethyl ether (3 x 10 mL). The combined organic layer was washed sequentially with aqueous HCl (3M, 10 mL), H2O (10 mL), aqueous NaOH (1M, 10 mL), and then brine (10 mL). The organic layer was dried over anhydrous Na2SO4, decanted, and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with pentanes. Fractions containing product were combined and concentrated in vacuo to afford the product as a colorless oil (217 mg, 80% yield). The product's NMR spectra matches literature spectra.

(3-fluorophenyl)(2,2,2-trifluoroethyl)sulfane (10n)
Compound 10n was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The general workup procedure followed by silica gel column chromatography with pentanes as eluent afforded the product as a colorless oil (128 mg, 61% yield). The product's NMR spectra matches literature spectra.

(3-chlorophenyl)(2,2,2-trifluoroethyl)sulfane (10o)
Compound 10o was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. To the reaction mixture was added aqueous HCl (1M, 10 mL) over ice, and the product was extracted with diethyl ether (3 x 10 mL). The combined organics were washed with aqueous HCl (1M, 2 x 10 mL), aqueous NaOH (1M, 2 x 10 mL), water (3 x 10 mL), brine (2 x 10 mL), and dried over anhydrous Na2SO4, decanted and concentrated in vacuo. The residue was purified by silica gel column chromatography with pentanes as eluent to afford the product as a colorless oil (109 mg, 48% yield). Compound 10p was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The general workup procedure followed by silica gel column chromatography with pentanes as eluent afforded the product as a colorless oil (168 mg, 80% yield).

o-tolyl(2,2,2-trifluoroethyl)sulfane (10q)
Compound 10q was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The general workup procedure followed by silica gel column chromatography with pentanes as eluent afforded the product as a colorless oil (180 mg, 83% yield). The yield has been corrected for 4% disulfide impurities.

6-((2,2,2-trifluoroethyl)thio)hexan-1-ol (10r)
Compound 10r was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The reaction mixture was added to aqueous HCl (3M, 10 mL) in a separatory funnel and the product was extracted with diethyl ether (3 x 10 mL). The combined organic layer was washed sequentially with H2O (5 mL), aqueous NaOH (1M, 10 mL), and the brine (10 mL). The organic layer was dried over anhydrous Na2SO4, decanted, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with diethyl ether in pentanes (60-80% gradient). Fractions containing the desired product were combined and concentrated in vacuo to afford the desired product as colorless oil (170 mg, 76%).

2-((2,2,2-trifluoroethyl)thio)acetic acid (10s)
Compound 10s was prepared on 1.0 mmol scale using the general procedure for trifluoroethylation of thiols by sequential addition, with 6.70 mmol of DBU. The reaction mixture was diluted with H2O (10 mL) and washed with diethyl ether:hexanes (1:1 v/v, 2 x 10 mL). The aqueous layer was acidified with aqueous HCl (1M) to a pH ~1 and the product was extracted with ethyl acetate (3 x 10 mL). The organic later was dried over anhydrous Na2SO4, decanted, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using 5% methanol in dichloromethane with 0.1% formic acid as eluent. Fractions containing the desired product were concentrated in vacuo. To remove some of the residual solvent present, the product was taken up in ethyl acetate and washed with aqueous HCl (0.1M, 10 mL), H2O (2 x 10 mL), and then 50% brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo to afford the product as a clear, slightly yellow oil (131 mg, 75% yield).

4-((2,2,2-trifluoroethyl)thio)aniline (10t)
Compound 10t was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols. The reaction mixture was then acidified with aqueous HCl (3M, 10 mL) and washed with hexanes (2 x 5 mL). The aqueous layer was basified with saturated aqueous NaHCO3, and extracted with Et2O (3 x 10 mL). The combined organic layer was washed with H2O (10 mL), brine (10 mL), and then dried over anhydrous Na2SO4, decanted, and concentrated in vacuo to a brown oil. The crude residue was purified by silica gel column chromatography using ethyl acetate in hexanes with triethylamine (2.1:7:0.9). Fractions containing the desired product were combined and concentrated in vacuo to afford the product as a yellow-brown oil (152 mg, 73% yield).

4-((2,2,2-trifluoroethyl)thio)pyridine (10u)
Compound 10u was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols stirring for 2 hours instead of 20 minutes. The reaction mixture was diluted with DCM (5 mL) and the product was extracted with aqueous HCl (3M, 3 x 5 mL). The aqueous layer was basified with aqueous NaOH (1M) until pH ~8. The product was extracted with ethyl acetate (5 x 5 mL). The combined organic layer was washed with brine (3 x 10 mL) and then concentrated in vacuo. The residue was purified by silica gel column chromatography using 50% ethyl acetate in pentanes with 1% triethylamine. Fractions containing the product were combined and concentrated in vacuo to afford the product as a yellow oil (121 mg, 60% yield).

ethyl (S)-2-amino-2-((2,2,2-trifluoroethyl)thio)acetate (10v)
Compound 10v was prepared on 1.0 mmol scale using the general procedure for trifluoroethylation of thiols by sequential addition, starting from the L-cysteine ethyl ester hydrochloride salt. The reaction mixture was diluted in H2O (20 mL), and then extracted with ethyl acetate (5 x10 mL). The combined organic layers were washed with H2O (5 x 10 mL), brine (10 mL), and then dried over anhydrous MgSO4, decanted, and concentrated in vacuo. The crude residue was taken up in diethyl ether (1 mL), and then acidified using HCl in diethyl ether (2 M, 2.0 mL). The solution was sparged with argon gas, concentrated in vacuo, and the resulting solid was filtered and washed with cold diethyl ether. The salt was then free-based by using K2CO3 in ethanol, and then stirred for 10 minutes at ambient temperature. The neutralized product was flushed through a pad of basic alumina using ethyl acetate, and then concentrated in vacuo to afford the product as a slight yellow oil (152 mg, 63% yield).  Compound 10w was prepared on 1.0 mmol scale using the general procedure for one-pot trifluoroethylation of thiols by sequential addition. Two extra equivalents of DBU (0.30 mL) were added to the reaction mixture before the commercially available glutathione (reduced) was added. The reaction was stirred at 40 °C for 20 minutes and then diluted in H2O (15 mL) and washed with diethyl ether (2 x 10 mL). The aqueous layer was acidified to pH 2-3 using aqueous HCl (3M) and then aqueous NaOH (1M) was added until a pH ~6. The aqueous layer was concentrated in vacuo to a white residue and placed under high vacuum for 12 hours. The crude residue was triturated in acetonitrile (40 mL) and then the solid was collected and triturated in 2-propanol (40 mL). The sticky solid was collected and placed under high vacuum for 1 hour. The solid was taken up in ethanol (30 mL) and then acidified to pH ~1 using aqueous HCl (3M). The solvent was removed in vacuo and the residue was taken up in ethanol (70 mL) and then filtered. The filtrate was concentrated in vacuo to give the product as a white sticky solid (252 mg, 59% yield). The product yield has been corrected for 12% ethanol impurities.  benzyl(2,2,3,3,3
Thiobenzoic acid was subjected to the general procedure for one-pot trifluoroethylation of thiols on a 1 mmol scale. The reaction was monitored by quantitative 19 F NMR, using PhCF3 (100 µL, 0.815 mmol) as an internal standard. The 19 F NMR showed that sulfur was alkylated in high yields. The reaction mixture was worked up by diluting in water (15 mL), and then extracted with diethyl ether (5 x 5 mL). The combined organics were washed with water (5 x 5 mL) and brine (2 x 5 mL), and then dried over anhydrous Na2SO4, decanted and concentrated in vacuo. Fractional distillation has been attempted to purify the residue, however, it was unsuccessful in obtaining the desired product. It is presumed that the trifluoroethyl thioester hydrolyzed or underwent a trans-esterification type reaction with the excess trifluoroethanol and DBU in the reaction mixture.