Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of “super-trifluoromethyl” arene chemistry and its industry

Various arylsulfur pentafluorides, ArSF5, have long been desired in both academic and industrial areas, and ArSF5 compounds have attracted considerable interest in many areas such as medicines, agrochemicals, and other new materials, since the highly stable SF5 group is considered a “super-trifluoromethyl group” due to its significantly higher electronegativity and lipophilicity. This article describes the first practical method for the production of various arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides), from the corresponding diaryl disulfides or aryl thiols. The method consists of two steps: (Step 1) treatment of a diaryl disulfide or an aryl thiol with chlorine in the presence of an alkali metal fluoride, and (step 2) treatment of the resulting arylsulfur chlorotetrafluoride with a fluoride source, such as ZnF2, HF, and Sb(III/V) fluorides. The intermediate arylsulfur chlorotetrafluorides were isolated by distillation or recrystallization and characterized. The aspects of these new reactions are revealed and reaction mechanisms are discussed. As the method offers considerable improvement over previous methods in cost, yield, practicality, applicability, and large-scale production, the new processes described here can be employed as the first practical methods for the economical production of various arylsulfur pentafluorides and their higher homologues, which could then open up a new era of “super-trifluoromethyl” arene chemistry and its applications in many areas.


Cl 2
CsF A typical procedure [S3]: Chlorine (Cl 2 ; 10.1 L, 451 mmol) was passed with a flow rate of 35 mL/min into a stirred mixture of 10.1 g (60.2 mmol) of p-tert-butylthiophenol and 91.6 g (602 mmol) of dry cesium fluoride in 150 mL of dry acetonitrile at 6-10 °C. The reaction mixture turned yellow and then colorless. After chlorine was passed, the reaction mixture was stirred at room temperature for 24 h.
The reaction mixture was filtered and washed with 100 mL of dry acetonitrile in dry air or nitrogen.
After complete removal of the solvent in vacuum at room temperature, the obtained solid was mixed with 100 mL of dry hexane and filtered under nitrogen. The filtrate (hexane) was concentrated and p-(tert-butyl)phenylsulfur chlorotetrafluoride (2c) (14 g, 84%) was obtained by crystallization. The product was a trans isomer.
The reaction conditions and results for thiophenol are shown in Table 1 (Text).
Chlorine (Cl 2 ) was passed with a flow rate of 37 mL/min into a stirred mixture of 5.00 g (26.4 mmol) of p-nitrobenzenesulfenyl chloride and 15.3 g (264 mmol) of spray-dried KF in 40 mL of dry S8 acetonitrile at 5-11 °C. The total amount of chlorine passed was 2.54 L (113 mmol). The reaction mixture was filtered in dry air or nitrogen. After removal of the solvent in vacuum, 4.69 g (76%) of trans-p-nitrophenylsulfur chlorotetrafluoride (2i) as a solid was obtained.

KF
PhSF 4 Cl (2a) Chlorine (Cl 2 ) was passed with a flow rate of 34 mL/min into a stirred mixture of 5.00 g (30.1 mmol) of phenylsulfur trifluoride and 8.74 g (150 mmol) of spray-dried KF in 20 mL of dry acetonitrile at 6-9 °C. Chlorine was passed for 43 min and the total amount of chlorine passed was 1.47 L (65.5 mmol). The reaction mixture was filtered in dry air or nitrogen. After removal of the solvent in vacuum, 5.62 g (84%) of trans-phenylsulfur chlorotetrafluoride was obtained as a colorless liquid.

Preparation of aryl bis-and tris(sulfur chlorotetrafluorides), Ar(SF 4 Cl) n (n = 2 and 3)
A typical procedure [S5]: A 500 mL fluoropolymer (PFA) reactor was set up with a magnetic stirrer, a gas (N 2 , Cl 2 ) inlet tube, and a gas outlet tube protected by a CaCl 2 tube. Gas flow was controlled by a digital controller and measured by a digital integrator. The vessel was charged with dry KF (100 g, 1.72 mol), and set up for reaction under nitrogen flow. Anhydrous acetonitrile (300 mL) was added, followed by 1,3-benzenedithiol (9.78 g, 68.7 mmol). After cooling in the ice bath with stirring under N 2 flow for 1 hour, N 2 was stopped and then chlorine gas was introduced below the surface at 60-80 mL/min with vigorous stirring. Over approximately 6 h, a total of 27.1 L (1.21 mol) of Cl 2 was added. The reaction was then allowed to come to room temperature with stirring. After being stirred for two days at room temperature, the reaction mixture was filtered and washed through with dry acetonitrile (200 mL). The solvent was then removed at room temperature under vacuum, leaving the crude product (23.2 g, crude yield 93%) as a white solid, which was recrystallized from pentane in a freezer to give white crystals of 1,3-bis(chlorotetrafluorosulfanyl)benzene (2p') (14.1 g, yield 56%). To obtain a sample for analysis, some of the crystals were further recrystallized. The reaction conditions and results for each of the Ar(SF 4 Cl) n are shown in Table 2 (Text). The physical and spectral data of the products are shown below.

4-1. Examination on the reactivity of PhSF 4 Cl to different fluorides
Phenylsulfur chlorotetrafluoride (2a) was treated with a different fluoride as shown in Table 3 in the text. For BF 3 (gas) (Runs 1-2), the reaction was carried out in the following way [S3].
Run 1: A steel reactor (25-30 mL) was charged with 1.0 g (4.5 mmol) of trans-2a and cooled in a dry ice-acetone bath. The reactor was then evacuated by a vacuum pump and BF 3 gas was introduced into the reactor until the pressure reached 18 psi. The reaction mixture (reactor) was warmed to room temperature and stood for three days. After that, the reactor was opened and the reaction mixture was analyzed. All of the starting material became a solid residue.
Run 2: A steel reactor (25-30 mL) was charged with 1.42 g (6.4 mmol) of trans-2a and 6.4 mL of dry dichloromethane and cooled to around −100 °C with a liquid N 2 bath. The reactor was evacuated by a vacuum pump and BF 3 gas was introduced into the reactor until the pressure reached 80 psi. The reaction mixture (reactor) was warmed to room temperature and stood for 5 h. In the meantime, additional BF 3 was added until the pressure reached 100 psi. After the reaction, the reactor was opened and the reaction mixture was analyzed. 19 F NMR showed that the yield of 3a was 28%.
For Runs 3-11, the reaction was carried out as shown in the following typical procedure [S3].
A typical procedure: In a dry box, a reaction vessel made of fluoropolymer was charged with 1.0 g (4.54 mmol) of trans-2a and 0.26 g (1.4 mmol) of dry SnF 4 . The reaction vessel was brought out from the dry box and equipped with a rubber balloon filled with N 2. The mixture was stirred at 80 °C for 2 h.
The analysis of the reaction mixture by 19 F-NMR showed that product 3a was produced in 34% yield.

S11
The results with other different fluorides are shown together with reaction conditions in Table 3 in the text.

4-2. Preparation of various ArSF 5 from ArSF 4 Cl with ZnF 2
ArSF 4 Cl ZnF 2 ArSF 5 under a N 2 balloon A typical procedure [S3]: A 100 mL fluoropolymer (TEFLON ® ·PFA) vessel was charged with PhSF 4 Cl (2a) (44 g, 0.2 mol) and dry ZnF 2 (12.3 g, 0.12 mol) in a dry box filled with N 2 . The vessel was brought out from the dry box and equipped with a condenser made of fluoropolymer and a balloon filled with N 2 . The reaction mixture was slowly heated to 120 °C over a period of one hour. The reaction mixture changed from colorless to yellow, pink, and then eventually green. The reaction mixture was stirred at 120 °C for 20 h. After being cooled to room temperature, about 50 mL of pentane was added to the reaction mixture. The mixture was filtered to remove all insoluble solid to give a yellow solution, which was concentrated. The resulting residue was distilled at reduced pressure to give  1616,1593,1568,1295,1241,1222,1112,1054,1010,876,843,790,756,720,684,608,588,554,542,516

4-3. Effect of the atmosphere on the reaction of PhSF 4 Cl with ZnF 2
Reactions of phenylsulfur chlorotetrafluoride with ZnF 2 were conducted under no flow of N 2 gas (Run 1), a slow flow (Run 2) and a fast flow (Run 3) of N 2 gas, and a flow of Cl 2 gas (Run 4).
[Run 1] In a dry box, a reaction vessel made of fluoropolymer was charged with 1.0 g (4.54 mmol) of trans-phenylsulfur chlorotetrafluoride (2a) and 0.28 g (2.7 mmol) of anhydrous ZnF 2 . The reaction vessel was removed from the dry box and equipped with a rubber ballon filled with N 2 gas. The reaction mixture was stirred at 120 °C for 4 h. After being cooled to room temperature, the reaction mixture was analyzed by 19 F NMR. The reaction was completed. The results are shown in Table S device. The reaction mixture was slowly heated to 120 °C with N 2 flowing at a rate of 5.4 mL/min. The reaction mixture was stirred at 120 °C with the N 2 flowing for 5 h. After being cooled to room temperature, the reaction mixture was analyzed with 19 F NMR. The reaction was not completed. The results are shown in Table S-1.
[Run 3] In a dry box, a 50 mL reaction vessel made of fluoropolymer was charged with 10.0 g (45.4 mmol) of trans-2a and 2.8 g (27 mmol) of anhydrous ZnF 2 . The reaction vessel was removed from the dry box, and equipped with a condenser made of fluoropolymer and connected to a N 2 gas flowing device. The reaction mixture was slowly heated to 120 °C with N 2 flowing at the rate of 26.9 mL/min. The reaction mixture was stirred at 120 °C with the N 2 flowing for 5 h. After being cooled to room temperature, the reaction mixture was analyzed with 19 F NMR. The reaction was not completed. The results are shown in Table S-1.

[Run 4]
In a dry box, a 50 mL reaction vessel made of fluoropolymer was charged with 10.0 g (45.4 mmol) of trans-2a and 2.8 g (27 mmol) of anhydrous ZnF 2 . The reaction vessel was removed from the dry box, and equipped with a condenser made of fluoropolymer and connected to a Cl 2 gas flowing device. The reaction mixture was slowly heated to 120 °C with Cl 2 flowing at a rate of 4.6 mL/min. The reaction mixture was stirred at 120 °C with the Cl 2 flowing for 1.7 h. After being cooled to room temperature, the reaction mixture was analyzed with 19 F NMR. The reaction was completed. The results are shown in Table S-1.

S13
The results showed that the reaction of 2a with ZnF 2 became slow as the flow rate of N 2 gas increased and that the reaction was fast and its yield was high under the Cl 2 atmosphere.

4-4. Large-scale preparation of PhSF 5 from PhSF 4 Cl with ZnF 2 in Cl 2 atmosphere
PhSF 5 (3a) was prepared in a large scale according to the following procedure. under stirring with a magnetic stirrer. trans-Phenylsulfur chlorotetrafluoride (2a) [662 g, 2.85 mol, S14 purity 95%: Note; impurity (5%) was phenylsulfur trifluoride] was dropwise added to the stirred mixture through the dropping funnel for 72 min. During the addition, the reaction temperature (inside) was mostly 105-101 °C. After the additon, the reaction mixture was stirred for 30 min at 110 °C (oil bath temperature) and then for 3 h at 115 °C (oil bath temperature). After the reaction, the Cl 2 flow was stopped and N 2 flow was started, and the oil bath was removed and the reactor was left at room temperature to cool. 19 F NMR analysis at this moment showed that the reaction was completed. The cooled reaction mixture was filtered with 600 mL of dichloromethane and the filtrate was mixed with 300 mL of a cooled aq. 10% KOH solution. The mixture was stirred for 1 hour and the organic layer was separated, washed with an aq. NaCl solution (300 mL × 2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure (30 °C, 100 mmHg) and the resulting residue was distilled under reduced pressure to give 658 g of phenylsulfur pentafluoride (3a), bp 67-71 °C/26-29 mmHg). The real yield was (658 g −180 g =) 478 g (yield 82%). Its purity was >99% (by GC).
A 125 mL fluoropolymer reactor with a magnetic stir bar was charged with anhydrous ZnF 2 (10.9 g, 105 mmol), anhydrous ZnCl 2 (1.4 g, 10 mmol), and AlCl 3 (0.7 g, 5 mmol) in a dry box filled with N 2 and then the reactor was taken from the dry box. Dry dichloromethane (5 mL) was added to the reactor and the mixture was stirred for 1 hour under N 2 . Dichloromethane was removed by a vacuum pump and then the reactor was equipped with a condenser made of fluoropolymer connected to a Tshaped N 2 gas inlet. The reactor was purged with N 2 and p-chlorophenylsulfur chlorotetrafluoride (2f (3a). The purity of the product was determined to be 100 % by GC analysis.
The product was identified by spectral comparison with an authentic sample.
The reaction conditions and results for the fluorinations with anhydrous hydrogen fluoride are shown in Table 5 (Text).

Preparation of PhSF 5 from PhSF 4 Cl with 70 wt % HF-pyridine
Under nitrogen, phenylsulfur chlorotetrafluoride (2a) (32.4 g, 141 mmol) [purity 96 wt %; the impurity (4 wt %) was phenylsulfur trifluoride] was added over 1 hour by syringe pump into a stirred liquid (38.2 mL) of 70 wt % HF-pyridine (available from Sigma-Aldrich) in a fluoropolymer vessel heated in an oil bath at 55 °C. After the addition, the reaction mixture was stirred for an additional 2 h at that temperature (55 °C) and cooled to room temperature. 19 F NMR of the reaction mixture showed that the starting material 2a was consumed. The reaction mixture was slowly poured into a stirred, cooled 25% aq. KOH solution (KOH, 104 g). The resulting alkaline solution was extracted with S16 dichloromethane and the organic layer was separated, washed with water, 2 M aq. HCl, and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated at atmospheric pressure and then distilled at reduced pressure to give 18.1 g (63%) of phenylsulfur pentafluoride (3a); bp 62 °C/44 mmHg. Its purity was determined to be 100% by GC.
As another experiment, 32.4 g (141 mmol) (purity 96 wt %) of 2a was mixted with 38.2 mL of 70 wt % HF-pyridine in a fluoropolymer vessel at room temperature under nitrogen, and the stirred mixture was heated at 50 °C (oil bath temperature) for 6 h. The mixture was then cooled to room temperature. The reaction mixture was treated in a similar way as above and 16.4 g (57%) of product 3a was obtained after the distillation.
The reaction conditions and results for products 3l-n are shown in Table 6 (Text). The boiling points and spectral data of products 3l-o and spectral data of a byproduct, 3-chloro-2,4,6trifluorophenylsulfur pentafluoride (see Text), are shown below. The byproduct was obtained as a mixture with product 3m when 2m was treated with SbF 5 alone. (m), 101.9 (m); IR (neat) 3111,1640,1606,1451,1178,1135,1098,1048,1011,870,690,625,584,556  of phenyl-1,3-bis(sulfur chlorotetrafluoride) (2p') in 10 mL of dry dichloromethane was then added by syringe. Over 2.5 h the temperature of the stirred solution was allowed to rise to -25 °C, at which time the reaction was carefully quenched by adding KF (total 4 g) in portions. Cooling was removed, 2 g of celite was added to the mixture, and the mixture was stirred while being warmed to room temperature.
After suction filtration, solvents were removed by evaporator and the residue was column chromatographed on silica gel (20 g) using pentane as an eluent to give 2.02 g (57%) of phenyl-1,3-S18 bis(sulfur pentafluoride) (3p") as white crystals. The reaction conditions and results for others are shown in Table 7 (Text). The physical and spectral data of new compounds are shown below.

8-2. Preparation of phenyl-1,3,5-tris(sulfur pentafluoride) (3u")
1,3,5-Ph(SF 4 Cl) 3 SbF 5 1,3,5-Ph(SF 5 ) 3 2u' 3u" Procedure: A 500 mL fluoropolymer (PFA) jar (reactor) with septum, magnetic stirrer, nitrogen blanket, and cooling bath was set up and charged with 160 mL of dry dichloromethane. The reactor was cooled to -25 to -30 °C, and 67.5 mL (SbF 5 , 99 mmol) of a solution of 17.4% (w/w) of SbF 5 in FC-72 S19 was introduced by syringe over 8 min. After holding at this temperature for approximately 7 min, the reaction mixture was cooled to -95 °C over 15 min. A solution of 16.0 g (32 mmol) of phenyl-1,3,5tris(sulfur chlorotetrafluoride) (2u') in 50 mL of dry dichloromethane was introduced by syringe over 8 min as the temperature rose to -86 °C. The reaction mixture was allowed to warm to +7 °C over 6 h, at which time the reaction was quenched with the addition of KF (10 g) in portions over 20 min. Celite (5 g) was added, and the mixture was suction filtered. Solvents were removed by atmospheric fractional distillation to 70 °C leaving the crude residue as a yellow slush. The crude product was triturated with a minimum volume of ether and filtered to give a solid, which was then dried at room temperature in vacuum to give 8.03 g (55%) of product 3u". The physical and spectral data of 3u" are shown below.

DSC measurement of arylsulfur chlorotetrafluorides
For DSC analysis, three types of cells were used as shown below.
Cell 1, a cell made of gold-coated stainless steel Cell 2, a cell made of stainless steel Cell 3, a cell made of stainless steel with a cap made of gold-coated copper The analysis using Cells 1 and 2 was conducted by Kayaku Japan Ltd. with Rigaku DSC8230 instrument. We conducted the analysis using Cell 3 with Perkin Elmer Pyris 1. Samples were heated at 5 or 10 °C/min. The results are shown in Table S-2.

S21
As seen from Table S-2, the decomposition onset temperature by DSC varied depending on the material of the cell. For example, DSC showed that 2a started to decompose at 190 °C in Cell 2 made of stainless steel (SS), but at 131 °C in Cell 1 made of gold-coated SS. It was a surprise that 2a decomposed at a temperature (131 °C), with much less reactive gold, which was much lower than that (190 °C) with reactive SS. This means that 2a reacted with both gold and SS metals of the cells. The observed higher decompostion temperature of SS than gold could probably be a matter of solid surface.
The real thermal decomposition temperature of 2a should be higher than at least 190 °C, which was measured with the SS cell, rather than 131 °C measured with the gold-coated SS. This is in accordance with the fact that 2a was stable for 48 h at 150 °C in a Teflon tube that is inactive (see the Text). Thus, it has been concluded that any data (Table S-2) obtained by the DSC measurement did not provide the real thermal decomposition data of arylsulfur chlorotetrafluorides.

t-BuSNa
AlCl 3 toluene SO 2 CH 3 HS Br 2 SO 2 CH 3 S 2 1j Step 1 Step 2 Step 3 Step 1: A 50 mL single-neck flask with magnetic stirrer and septum was flushed with nitrogen, and charged with sodium tert-butylthiolate (6.95 g, 62 mmol), dry N-methylpyrrolidinone (12 mL), and 4-chlorophenyl methyl sulfone (9.53 g, 50 mmol). The mixture was heated to 50 °C. An exothermic reaction occurred. GC/MS analysis verified complete conversion to the product in 2 h. The reaction mixture was quenched into dilute aq. HCl solution and a mixture of hexane and dichloromethane was added to the mixture. The organic layer was separated and stripped to yield an oil. This residue was then slurried in hexane plus water, and the precipitated solids were filtered and washed through water followed by hexane. The solids were then taken up in dichloromethane and the solution was dried over anhydrous magnesium sulfate, filtered and stripped to yield 10.5 g (93%) of 4-(tert-butylthio)phenyl methyl sulfone as white crystals: 1 H NMR (CDCl 3 )  7. 86-7.89 (d, 2H), 7.69-7.72 (d, 2H). 3.07 (s, 3H), 1.33 (s, 9H); GC-Mass m/z 244 (M + ). Note: 4-(tert-butylthio)phenyl methyl sulfone is poorly soluble in hexane.

S22
Step 2: A 500 mL single-neck flask was flushed with nitrogen, then charged with 4-(tertbutylthio)phenyl methyl sulfone (29.6 g, 0.12 mol) obtained by step 1, followed by dry, deoxygenated toluene (200 mL), and finally aluminium chloride (21.7 g, 0.16 mol). The reaction mixture was stirred at room temperature for 4 h under nitrogen. The reaction was quenched with aq. dilute HCl solution and a small amount of ether. The organic layer was separated and the aq. layer was extracted with hexane. The combined organic layer was washed with water and dried over anhydrous sodium sulfate, and filtered.
Step 2: A 1 liter flask was charged with 1,3-bis(tert-butylthio)-5-bromobenzene (98.5 g, 0.295 mol) and dry deoxygenated toluene (700 mL). AlCl 3 (7.02 g, 0.0526 mol) was then quickly added into the mixture keeping a nitrogen blanket. After stirring at room temperature for 65 h, the reaction was quenched and agitated with 1N aq. HCl, aq. NaCl and pentane. The organic layer was separated, washed once with aq. NaCl, dried over MgSO 4 , and filtered. Evaporation of the solvent from the filtrate under reduced pressure by heating gave a residue, which solidified into a white solid mass (66.9 g) on cooling.
The solid was triturated in pentane, filtered, and dried in vacuum to give 57.8 g (88%) of 5-

iso-PrSNa
AlCl 3 toluene 1t Step 1 Step 2 Step 1: A 250 mL flask was charged with hexafluorobenzene (9.38 g, 0.05 mol) and diethyl ether (120 mL). Sodium isopropylthiolate (9.95 g, 0.10 mol) was added and the white slurry was stirred at room temperature for 2 days. A small amount of pentane was added and the reaction quenched with dilute aq. HCl to a pH of 5-6. The separated aqueous phase was extracted twice with diethyl ether, and the combined ether phases washed once with aq. sodium bicarbonate, dried over Na 2 SO 4 , filtered and evaporated to give a residue (12.7 g), which was dissolved in 20 mL pentane, and the solution was placed in a freezer overnight. The thick crop of resulting crystals was separated by efficient decantation, and then dried at room temperature in vacuum to give 10.7 g (71% yield) of 1,4-bis(isopropylthio)-2,3,5,6-tetrafluorobenzene [S14] as large needles. 1 H NMR (CDCl 3 )  3.54 (septet, 2H), 1.28 (d, 12H); Step 2: A 1 liter flask was charged with 1,4-bis(isopropylthio)-2,3,5,6-tetrafluorobenzene (55.9 g., 0.187 mol) and flushed with nitrogen. Dry, deoxygenated toluene (375 mL) was then added, maintaining nitrogen atmosphere. AlCl 3 (5.0 g, 0.037 mol) was added into the reaction mixture under nitrogen. An immediate red color developed along with a small white crystalline precipitate. The reaction was stirred at room temperature for 3 days. The reaction was quenched with dilute aq. HCl, aq.

S26
NaCl, and ether, and the phases separated. The aqueous layer was extracted once with ether, and the combined organic phases washed once with dilute aq. NaCl, dried over Na 2 SO 4 , and filtered. After the removal of most volatiles on a rotovap, the residue solution was subjected to atmospheric distillation, raising the pot to a maximum of 230 °C until no more distillate came over. Upon cooling, crystals of the product appeared from the residue. The crystals were collected by suction filtration, washing through with a little pentane. An additional product was obtained by placing the filtrate in a freezer (−10 °C) overnight. The collected crystalline product was dried at 50 °C in vacuum (~1 mm Hg) for several hours, giving 29.9 g (74% yield) of 2,3,5,6-tetrafluorobenzene-1,4-dithiol (1t) [S15] as an off-white to

10-4. Preparation of aryl trithiol 1u t-BuSNa
AlCl 3 toluene 1u Step 1 Step 2 Cl S NMP SH Cl S HS Cl S SH Step 1: A 1 liter flask was charged with sodium tert-butylthiolate (81 g, 0.72 mol) and dry Nmethylpyrrolidinone (200 mL). While the mixture was stirred, 1,3,5-trichlorobenzene (36.3 g, 0.20 mol) was added. The reaction mixture was then heated to 120 °C and stirred for 17 h at that temperature. The reaction was cooled and the solvent was removed by evaporation under reduced pressure on heating.