Regioselective Electrochemical Monofluorination of α-Sulfonyl Sulfides

Hirokatsu Nagura; Toshio Fuchigami

doi:10.1055/s-2008-1078498

LETTER

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;

Abstract

All articles of this category

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

Full Text

References

References and Notes

<A NAME="RU01008ST-1A">1a</A> Biomedicinal Aspects of Fluorine Chemistry Filler R. Kobayashi Y. Kodansha and Elsevier Biomedical; Tokyo: 1982.

<A NAME="RU01008ST-1B">1b</A> Welch JT. Eswarakrishnan S. Fluorine in Bioorganic Chemistry Wiley; New York: 1991.

<A NAME="RU01008ST-2A">2a</A> Furuta S. Hiyama T. Tetrahedron Lett. 1996, 37: 7983

<A NAME="RU01008ST-2B">2b</A> Murakami S. Fuchigami T. Synlett 2006, 1015

<A NAME="RU01008ST-2C">2c</A> Nagura H. Murakami S. Fuchigami T. Tetrahedron 2007, 63: 10237

<A NAME="RU01008ST-3">3</A> Solas D. Hale RL. Patel DV. J. Org. Chem. 1996, 61: 1537

<A NAME="RU01008ST-4">4</A> Banks RE. Lawrence NJ. Popplewell AL. J. Chem. Soc., Chem.Commun. 1994, 343

<A NAME="RU01008ST-5">5</A> Ayuba S. Yoneda N. Fukuhara T. Hara S. Bull. Chem. Soc. Jpn. 2002, 75: 1597

<A NAME="RU01008ST-6A">6a</A> Fuchigami T. Shimojo M. Konno A. J. Org. Chem. 1995, 60: 3459

<A NAME="RU01008ST-6B">6b</A> Cao Y. Hidaka A. Tajima T. Fuchigami T. J. Org. Chem. 2005, 70: 9614

<A NAME="RU01008ST-6C">6c</A> Tajima T. Nakajima A. Fuchigami T. J. Org. Chem. 2006, 71: 1436

<A NAME="RU01008ST-6D">6d</A> Zagipa B. Hidaka A. Cao Y. Fuchigami T. J. Fluorine Chem. 2006, 127: 552

<A NAME="RU01008ST-6E">6e</A> Tajima T. Nakajima A. Doi Y. Fuchigami T. Angew. Chem. Int. Ed. 2007, 46: 3550

<A NAME="RU01008ST-7">7</A> Fuchigami T. Konno A. Nakagawa K. Shimojo M. J. Org. Chem. 1994, 59: 5937

<A NAME="RU01008ST-8A">8a</A> Trost BM. Ghadiri MR. J. Am. Chem. Soc. 1984, 106: 7260

<A NAME="RU01008ST-8B">8b</A> Trost BM. Bull. Chem. Soc. Jpn. 1988, 61: 107

<A NAME="RU01008ST-8C">8c</A> Najera C. Jus M. Tetrahedron 1999, 55: 10547

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.

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

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.

<A NAME="RU01008ST-12A">12a</A> Ogura K. Tsuruda T. Takahashi H. Iida H. Tetrahedron Lett. 1986, 27: 3665

<A NAME="RU01008ST-12B">12b</A> Simpkins NS. Tetrahedron Lett. 1988, 29: 6787

<A NAME="RU01008ST-12C">12c</A> Tsunoda T. Nagaku M. Nagino C. Kawamura Y. Ozaki F. Hioki H. Ito S. Tetrahedron Lett. 1995, 36: 2531

<A NAME="RU01008ST-12D">12d</A> Matsumoto S. Ishii M. Kimura K. Ogura K. Bull. Chem. Soc. Jpn. 2004, 77: 1897

<A NAME="RU01008ST-13">13</A> Konno A. Fuchigami T. J. Org. Chem. 1997, 62: 8579

<A NAME="RU01008ST-14A">14a</A> Hill SE. Feller D. Glemdening ED. J. Phys. Chem. A 1998, 102: 3813

<A NAME="RU01008ST-14B">14b</A> Ishii H. Yamada N. Fuchigami T. Tetrahedron 2001, 57: 9067

<A NAME="RU01008ST-15">15</A> Yoshiyama T. Fuchigami T. Chem. Lett. 1992, 21: 1995

<A NAME="RU01008ST-16">16</A> Fuchigami T. Sano M. J. Electroanal. Chem. 1996, 414: 81

<A NAME="RU01008ST-17A">17a</A> Yoon UC. Mariano PS. Acc. Chem. Res. 1992, 25: 233

<A NAME="RU01008ST-17B">17b</A> Fuchigami T. Ichikawa S. J. Org. Chem. 1994, 59: 607

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.

<A NAME="RU01008ST-19">19</A> Fukuzumi T. Shibata N. Sugiura M. Yasui H. Nakamura S. Toru T. Angew. Chem. Int. Ed. 2006, 45: 4973