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Synlett 2008(11): 1714-1718  
DOI: 10.1055/s-2008-1078498
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Electrochemical Monofluorination of α-Sulfonyl Sulfides

Hirokatsu Nagura, Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
Fax: +81(45)9245406; e-Mail: fuchi@echem.titech.ac.jp;
Further Information

Publication History

Received 14 February 2008
Publication Date:
11 June 2008 (online)

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Abstract

Highly regioselective monofluorination of α-sulfonyl sulfides was successfully carried out using anodic oxidation to provide the corresponding α-fluorinated products in moderate yields. The fluorinated products would be versatile fluorine-containing building blocks.

Key words

sulfones - fluorine - electron transfer - oxidation - cations

9

Preparation of α,α-Di(phenylthio)methyl Phenyl Sulfone (1f) A solution of methyl phenyl sulfone (1.58 g, 10.1 mmol) in dry THF (40 mL) was treated with n-BuLi (6.25 mL, 1.6 M hexane solution) at -78 °C under a nitrogen atmosphere. After stirring of the solution for 10 min at -78 °C, a solution of diphenyl disulfide (1.08 g, 5.0 mmol) in dry THF (10 mL) was added slowly at -78 °C. After additional 3 h of stirring, the solution was treated with 1 M aq HCl (50 mL) and extracted with EtOAc (2 × 100 mL). The combined extracts were washed with brine and dried over anhyd Na2SO4. After the removal of the solvent by evaporation, the residue was purified by column chromatography on SiO2 (hexane-EtOAc, 6:1) to yield 0.93 g (50%) of α,α-di(phenyl-thio)methyl phenyl sulfone (1f). 1H NMR (270 MHz, CDCl3): δ = 8.00-7.96 (m, 2 H), 7.69-7.63 (m, 1 H), 7.56-7.50 (m, 2 H), 7.40-7.23 (m, 10 H) 5.12 (s, 1 H). 13C NMR (68 MHz, CDCl3): δ = 136.70, 134.05, 134.02, 131.74, 129.90, 129.16, 129.08, 128.75, 80.78. HRMS (EI): m/z [M+] calcd for C19H16O2S3: 372.0312; found: 372.0314.
Preparation of Phenyl 2-Pyridylthiomethyl Sulfone (1i)
A solution of 0.61 g (5.5 mmol) of 2-mercaptpyridine in dry MeCN (10 mL) under a nitrogen atmosphere and cooled to 0 °C was treated with NaH (0.20 g, 5.0 mmol; 60% in liquid paraffin) in dry MeCN (10 mL). The solution was stirred for 0.5 h at 0 °C, after which time chloromethyl phenyl sulfone (0.87 g, 4.6 mmol) in dry MeCN (10 mL) was added. After additional 5 h under reflux, the solution was treated with H2O (30 mL) and extracted with EtOAc (2 × 30 mL). The combined extracts were washed with brine and dried over anhyd Na2SO4. After removal of the solvent by evaporation, the residue was purified by column chromatography on SiO2 (hexane-EtOAc, 4:1) to yield 0.87 g (71%) of phenyl 2-pyridylthiomethyl sulfone (1i). 1H NMR (270 MHz, CDCl3): δ = 8.20-8.18 (m, 1 H), 7.93-7.90 (m, 2 H), 7.49-7.36 (m, 4 H), 7.09-7.05 (m, 1 H), 6.95-6.91 (m, 1 H), 4.99 (s, 2 H). 13C NMR (68 MHz, CDCl3): δ = 152.78, 148.80, 137.37, 136.22, 133.50, 128.94, 128.31, 122.12, 120.44, 52.39. HRMS-FAB: m/z [M + H+] calcd for C12H12NO2S2: 266.0309; found: 266.0313.

10

Cyclic voltammetry was carried out at a Pt electrode (0.5 × 0.5 cm2) using a Hokutodenko HA-501 Potentiostat/Galvanostat.

11

Anodic Fluorination of Sulfides
Typical anodic fluorination conditions are as follows: Electrolysis was conducted with a platinum anode and cathode [4 cm2 (2 × 2 cm)] in 0.15 M Et4NF-4HF/DME (10 mL) containing 1.0 mmol of sulfides using an undivided cell at ambient temperature. After the starting sulfide was mostly consumed (monitored by SiO2 TLC), the electrolysis solution was passed through a short column of SiO2 (CHCl3). The solvent was then removed by evaporation and residue was purified by column chromatography on SiO2 (hexane-EtOAc, 10:1 to 5:1 or CHCl3) to provide the desired fluorinated product.
α-Fluoro-α-methylthiomethyl p -Tolyl Sulfone (2a) 1H NMR (270 MHz, CDCl3): δ = 7.84 (d, J = 8.2 Hz, 2 H), 7.40 (d, J = 8.2 Hz, 2 H), 5.99 (d, J = 47.6 Hz, 1 H), 2.47 (s, 3 H), 2.43 (d, J = 2.1 Hz, 3 H). 13C NMR (68 MHz, CDCl3): δ = 145.98, 132.23, 129.84, 129.41, 106.12 (d, J = 262.7 Hz), 21.79, 12.45 (d, J = 2.2 Hz). 19F NMR (254 MHz, CDCl3, TFA): δ = -82.0 (d, J = 47.6 Hz). HRMS-FAB: m/z [M + Na+] calcd for C9H11FO2S2Na: 257.0082; found: 257.0086.
α-Fluoro-α-methylthioethyl p -Tolyl Sulfone (2b) 1H NMR (270 MHz, CDCl3): δ = 7.84 (d, J = 8.1 Hz, 2 H), 7.38 (d, J = 8.1 Hz, 2 H), 2.47 (s, 3 H), 2.38 (s, 3 H), 1.80 (d, J = 19.6 Hz, 3 H). 13C NMR (68 MHz, CDCl3): δ = 145.63, 130.94, 130.26 (d, J = 1.1 Hz), 129.59, 112.88 (d, J = 261.0 Hz), 22.51 (d, J = 20.1 Hz), 21.73, 12.87 (d, J = 5.6 Hz). 19F NMR (254 MHz, CDCl3, TFA): δ = -56.9 (q, J = 19.6 Hz). HRMS-FAB: m/z [M + Na+] calcd for C10H13FO2S2Na: 271.0239; found: 271.0247.
α-Chloro-α-Fluoro-α-methylthiomethyl p -Tolyl Sulfone (2c) 1H NMR (270 MHz, CDCl3): δ = 7.91 (d, J = 8.6 Hz, 2 H), 7.41 (d, J = 8.6 Hz, 2 H), 2.57 (d, J = 1.3 Hz, 3 H), 2.49 (s, 3 H). 13C NMR (68 MHz, CDCl3): δ = 146.73, 131.25 (d, J = 1.1 Hz), 129.68, 128.94, 122.31 (d, J = 322.5Hz), 21.94, 15.84 (d, J = 3.4 Hz). 19F NMR (254 MHz, CDCl3, TFA): δ = -15.8 (s). HRMS-FAB: m/z [M + Na+] calcd for C9H10ClFO2S2Na: 290.9692; found: 290.9689.
α-Fluoro-α-( p -tolylthio)methyl Methyl Sulfone (2d) 1H NMR (270 MHz, CDCl3): δ = 7.53 (d, J = 7.9 Hz, 2 H), 7.21 (d, J = 7.9 Hz, 2 H), 6.13 (d, J = 51.1 Hz, 1 H), 2.97 (d, J = 1.5 Hz, 3 H), 2.38 (s, 3 H). 13C NMR (68 MHz, CDCl3): δ = 140.53, 134.54, 134.52, 130.38, 110.26 (d, J = 262.7 Hz), 37.48, 21.37. 19F NMR (254 MHz, CDCl3, TFA):
δ = -71.7 (d, J = 51.1 Hz). HRMS (EI): m/z [M+] calcd for C9H11FO2S2: 234.0184; found: 234.0185.
α-Fluoro-α-phenylthiomethyl Phenyl Sulfone (2e) 1H NMR (270 MHz, CDCl3): δ = 8.01-7.98 (m, 2 H), 7.76-7.71 (m, 1 H), 7.63-7.56 (m, 4 H), 7.41-7.35 (m, 3 H), 6.20 (d, J = 50.9 Hz, 1 H). 13C NMR (68 MHz, CDCl3): δ = 136.74 (d, J = 1.7 Hz), 134.86, 133.94, 133.91, 129.83 (d, J = 1.1 Hz), 129.68, 129.52, 129.20, 110.66 (d, J = 264.9 Hz). 19F NMR (254 MHz, CDCl3, TFA): δ = -69.0 (d, J = 50.9, 7.4 Hz). HRMS (EI): m/z [M+] calcd for C13H11FO2S2: 282.0184; found: 282.0179.
α-Fluoro-α , α-di(phenylthio)methyl Phenyl Sulfone (2f) 1H NMR (270 MHz, CDCl3): δ = 7.96-7.93 (m, 2 H), 7.69-7.64 (m, 1 H), 7.54-7.45 (m, 2 H), 7.42-7.24 (m, 10 H). 13C NMR (68 MHz, CDCl3): δ = 136.70 (d, J = 1.1 Hz), 134.59, 134.49, 130.82 (d, J = 1.1Hz), 130.16, 129.19, 128.69, 127.16, 120.26 (d, J = 314.7 Hz). 19F NMR (254 MHz, CDCl3, TFA): δ = -28.6 (s). HRMS-FAB: m/z [M + Na+] calcd for C19H15FO2S3Na: 413.0116; found: 413.0122.
α-Fluoro-α-( p -tolylthio)methyl Phenyl Sulfone (2g)
1H NMR (270 MHz, CDCl3): δ = 7.99 (m, 2 H), 7.76-7.70 (m, 1 H), 7.60 (m, 2 H), 7.47 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 8.1 Hz, 2 H), 6.15 (d, J = 50.8 Hz, 1 H), 2.36 (s, 3H). 13C NMR (68 MHz, CDCl3): δ = 140.19, 134.82, 134.23, 134.20, 130.27, 129.81 (d, J = 1.1 Hz), 129.19, 125.54 (d, J = 1.1 Hz), 110.79 (d, J = 264.4 Hz), 21.36. 19F NMR (254 MHz, CDCl3, TFA): δ = -69.6 (d, J = 50.8 Hz). HRMS-FAB): m/z [M + Na+] calcd for C14H13FO2S2Na: 319.0239; found: 319.0237.
α-Fluoro-α-( p -tolylthio)ethyl Phenyl Sulfone (2h) 1H NMR (270 MHz, CDCl3): δ = 8.00-7.97 (m, 2 H), 7.71-7.43 (m, 5 H), 7.16-7.12 (m, 2 H), 2.35 (s, 3 H), 1.72 (d, J = 19.3 Hz, 3 H). 13C NMR (68 MHz, CDCl3): δ = 140.62, 136.67 (d, J = 2.2 Hz), 134.48, 130.62, 130.60, 129.91, 129.49, 128.83, 123.37, 115.78 (d, J = 260.5 Hz), 21.22 (d, J = 21.8 Hz). 19F NMR (254 MHz, CDCl3, TFA): δ = -40.52 (q, J = 19.3 Hz). HRMS (EI): m/z [M+] calcd for C15H15FO2S2: 310.0497; found: 310.0490.
α-Fluoro-α-(2-pyridylthio)methyl Phenyl Sulfone (2i) 1H NMR (270 MHz, CDCl3): δ = 8.45-8.43 (m, 1 H), 8.06v8.03 (m, 2 H), 7.77-7.12 (m, 1 H), 7.71 (d, J = 48.1 Hz, 1 H), 7.64-7.56 (m, 3 H), 7.23 (m, 1 H), 7.16-7.12 (m, 1 H). 13C NMR (68 MHz, CDCl3): δ = 151.57 (d, J = 2.2 Hz), 149.58, 137.22, 134.84, 129.59, 129.18, 123.06, 123.02, 121.79, 106.01 (d, J = 259.9 Hz). 19F NMR (254 MHz, CDCl3, TFA): δ = -77.3 (d, J = 48.1 Hz). HRMS-FAB): m/z [M + H+] calcd for C12H11FNO2S2: 284.0215; found: 284.0219.
α, α-Difluoro-α-( p -tolylthio)methyl Methyl Sulfone (3) 1H NMR (270 MHz, CDCl3): δ = 7.59-7.56 (m, 2 H), 7.23-7.21 (m, 2 H), 3.03 (s, 3 H), 2.39 (s, 3 H). 13C NMR (68 MHz, CDCl3): δ = 141.69, 137.21 (t, J = 1.1 Hz), 130.14, 127.81 (t, J = 323.1 Hz), 119.06, 35.72, 21.51. 19 F NMR (254 MHz, CDCl3, TFA): δ = -5.14. HRMS (EI): m/z [M+] calcd for C9H10F2O2S2: 252.0090; found: 252.0083.
α-(Fluoromethylthio)ethyl p -Tolyl Sulfone (4) 1H NMR (270 MHz, CDCl3): δ = 7.80 (d, J = 8.1 Hz, 2 H), 7.38 (d, J = 8.1 Hz, 2 H), 5.84 (dd, J = 54.4, 10.6 Hz, 1 H), 5.59 (dd, J = 54.4, 10.6 Hz, 1 H), 4.20 (qd, J = 7.3, 1.5 Hz, 1 H), 2.47 (s, 3 H), 1.59 (d, J = 7.3 Hz, 3 H). 13C NMR (68 MHz, CDCl3): δ = 145.27, 132.29, 129.68, 129.61, 85.43 (d, J = 216.3 Hz), 61.33 (d, J = 2.2 Hz), 21.75, 16.15. 19F NMR (254 MHz, CDCl3, TFA): δ = -111.6 (t, J = 54.4 Hz). HRMS-FAB: m/z [M + Na+] calcd for C10H13FO2S2Na: 271.0239; found: 271.0241.

18

Typical Procedure for Oxidation of Sulfides 2a,e,g,i m-Chloroperbenzoic acid (2.2 equiv) was added to a solution of sulfide in CH2Cl2 at 0 °C. The solution was stirred over night at r.t., treated with sat. aq NaHCO3 and extracted with two portions of CH2Cl2. The combined extracts were washed with brine and dried over anhyd Na2SO4. After the removal of the solvent by evaporation, the residue was purified by column chromatography on SiO2 (CHCl3) to provide a pure disulfone.
α-Fluoro-α-methylsulfonylmethyl p -Tolyl Sulfone (5a) 1H NMR (270 MHz, CDCl3): δ = 7.90 (d, J = 8.1 Hz, 2 H), 7.45 (d, J = 8.1 Hz, 2 H), 5.59 (d, J = 45.3 Hz, 1 H), 3.24 (d, J = 1.0 Hz, 3 H), 2.51 (s, 3 H). 13C NMR (68 MHz, CDCl3): δ = 147.59, 131.57, 130.30, 130.00 (d, J = 1.1 Hz), 105.07 (d, J = 263.3 Hz), 39.47, 22.02. 19F NMR (254 MHz, CDCl3, TFA): δ = -96.8 (d, J = 45.3 Hz). HRMS (EI): m/z [M+] calcd for C9H11FO4S2: 266.0083; found: 266.0077.
α-Fluoro-α-( p -tolyl sulfonyl)methyl Phenyl Sulfone (5g) 1H NMR (270 MHz, CDCl3): δ = 7.99 (m, 2 H), 7.86 (d, J = 8.1 Hz, 2 H), 7.80-7.74 (m, 1 H), 7.62 (m, 2 H), 7.40 (d, J = 8.1 Hz, 2 H), 5.70 (d, J = 45.7 Hz, 1 H), 2.49 (s, 3 H). 13C NMR (68 MHz, CDCl3): δ = 147.18, 135.56, 135.17, 132.06, 130.10, 130.08, 130.06, 129.36, 105.59 (d, J = 265.5 Hz), 22.0. 19F NMR (254 MHz, CDCl3, TFA): δ = -92.9 (d, J = 45.7 Hz). HRMS (EI): m/z [M+] calcd for C14H13FO4S2: 328.0239; found: 328.0240.
α-Fluoro-α-(2-pyridylsulfonyl)methyl Phenyl Sulfone (5i) 1H NMR (270 MHz, CDCl3): δ = 8.80 (m, 1 H), 8.10-7.62 (m, 8 H), 6.50 (d, J = 45.3 Hz, 1 H). 13C NMR (68 MHz, CDCl3): δ = 154.47, 150.60, 138.50, 135.71, 134.84, 130.29, 129.31, 128.64, 124.14, 103.05 (d, J = 264.9 Hz). 19F NMR (254 MHz, CDCl3, TFA): δ = -96.5 (d, J = 45.3 Hz). HRMS (EI): m/z [M + H+] calcd for C12H11FNO4S2: 316.0114; found: 316.0096.