Regioselective Anodic Fluorination of α-(Arylthio)benzylphosphonate Esters, α-(Arylthio)methylphosphonate Esters and Their Analogues

Abstract

Regioselective anodic α-fluorination of α-(arylthio)benzylphosphonate esters and [(arylthio)methyl]- and [(heteroaryl­thio)methyl]phosphonate esters was successfully carried out at a glassy carbon anode or platinum anode in dimethoxyethane and ­nitromethane to provide the corresponding α-fluorophosphonate ­esters in excellent to moderate yields.

electrochemical fluorination - α-fluorophosphonate ester - Emmons-Wittig reagent - anodic substitution - electrosynthesis

References and Notes

1 Romanenko VD. Kukhar VP. Chem. Rev.  2006,  106:  3868 

2 Berkowitz DB. Bose M. Pfannenstied TJ. Doukov T. J. Org. Chem.  2000,  65:  4498 

3 Wnuk SF. Robins MJ. J. Am. Chem. Soc.  1996,  118:  2519 

4a Fuchigami T. Tajima T. In Fluorine-Containing Synthons, ACS Symposium Series 911   Soloshonok VA. American Chemical Society; Washington DC: 2005.  p.276 

4b Fuchigami T. Organic Electrochemistry   4th ed.:  Lund H. Hammerich O. Marcel Dekker; New York: 2001.  Chap. 25.

5 Zagipa B. Hidaka A. Cao Y. Fuchigami T. J. Fluorine Chem.  2006,  127:  552 

6 Cao Y. Hidaka A. Tajima T. Fuchigami T. J. Org. Chem.  2005,  70:  9614 

7 Wnuk SF. Bergolla LA. Garcia PI. J. Org. Chem.  2002,  67:  3065 

8a Trost BM. Salzmann TN. Hiroi K. J. Am. Chem. Soc.  1976,  98:  4887 

8b Trost BM. Acc. Chem. Res.  1978,  11:  453 

9a McCarthy JR. Huber EW. Matthews LD. Tetrahedron  1996,  52:  45 

9b Shen Y. Wang G. Org. Lett.  2002,  2083 

9c Berkowitz DB. Bose M. Nathan G. Org. Lett.  2001,  2009 

10a Fuchigami T. Shimojo M. Konno A. Nakagawa K. J. Org. Chem.  1990,  55:  6074 

10b Dawood KM. Higashiya S. Hou Y. Fuchigami T. J. Org. Chem.  1999,  64:  7935 

10c Cao Y. Fuchigami T. J. Electroanal. Chem.  2006,  587:  25 

11 Fuchigami T. Shimojo M. Konno A. Nakagawa K. J. Org. Chem.  1994,  59:  5937 

12

Typical procedure for anodic fluorination: Anodic oxidation of 1 (0.5 mmol) was carried out in an undivided cell equipped with a GC plate anode (2 × 2 cm²) and platinum plate cathode (2 × 2 cm²) in Et₄NF·3HF-DME (1 M, 5 mL) at r.t. Constant current (2.5 mA/cm²) was passed until the starting material 1 was almost consumed (monitored by TLC). After electrolysis, the electrolytic solution was passed through a short column filled with silica gel using EtOAc as an eluent to remove fluoride salts. The eluent was evaporated under reduced pressure, and the residue was further purified by column chromatography on silica gel using EtOAc to give pure fluorinated products. The products were identified by spectroscopic data.

13

Diethyl α-Fluoro-α-(phenylthio)benzylphosphonate (2a): ¹H NMR (CDCl₃): δ = 1.11 (t, J = 7.09 Hz, 3 H), 1.31 (t, J = 7.09 Hz, 3 H), 3.69-3.79 (m, 1 H), 3.91-4.02 (m, 1 H), 4.05-4.22 (m, 2 H), 7.13-7.55 (m, 10 H); ¹³C NMR (CDCl₃): δ = 16.3 (d, J _PC = 11.7 Hz), 16.4 (d, J _PC = 11.7 Hz), 64.4 (dd, J _FC = 0.02 Hz, J _PC = 7.27 Hz), 64.6 (dd, J _FC = 0.02 Hz, J _PC = 7.27 Hz), 106.2 (dd, J _PC = 175.7 Hz, J _FC = 234.3 Hz), 126.3 (t, J = 3.91 Hz), 126.4 (t, J = 3.91 Hz), 127.7 (t, J _PC = J _FC = 1.68 Hz), 128.3, 128.7 (d, J = 1.68 Hz), 129.0, 134.8 (d, J = 22.4 Hz), 135.9 (d, J = 2.24 Hz); ¹⁹F NMR (CDCl₃): δ = -67.3 (d, J _PF = 90.4 Hz); HRMS: m/z calcd for C₁₇H₂₀FO₃PS: 354.0855; found: 354.0843.

14

Diethyl α-Fluoro-α-(phenylthio)-4-methoxybenzylphos-phonate (6): ¹H NMR (CDCl₃): δ = 1.14 (t, J = 6.75 Hz, 3 H), 1.32 (t, J = 6.75 Hz, 3 H), 3.80 (s, 3 H), 3.91-3.97 (m, 1 H), 4.07-4.19 (m, 1 H), 4.29-4.33 (m, 2 H), 6.83 (d, J = 8.64 Hz, 2 H), 7.36-7.58 (m, 5 H), 7.63 (d, J = 7.83 Hz, 2 H); ¹³C NMR (CDCl₃): δ = 16.1 (d, J _PC = 5.56 Hz), 16.3 (d, J _PC = 5.56 Hz), 64.6 (dd, J _FC = 1.68 Hz, J _PC = 7.25 Hz), 65.2 (d, J _PC = 6.70 Hz), 106.4 (dd, J _PC = 162.3 Hz, J _FC = 229.2 Hz), 113.4 (t, J _PC = J _FC = 1.68 Hz), 113.6 (t, J _PC = J _FC = 1.68 Hz), 127.7 (d, J _PC = 3.35 Hz), 127.8 (d, J _PC = 3.35 Hz), 130.4, 134.1, 134.5 (d, J = 2.80 Hz), 160.6; ¹⁹F NMR (CDCl₃): δ = -89.0 (d, J _PF = 68.3 Hz); HRMS: m/z calcd for C₁₈H₂₂FO₆PS: 416.0859; found: 416.0862.

15

Diethyl α-Fluoro-α-(phenylthio)-4-iodebenzylphos-phonate (7): ¹H NMR (CDCl₃): δ = 1.09 (t, J = 7.09 Hz, 3 H), 1.29 (t, J = 7.09 Hz, 3 H), 3.69-3.78 (m, 1 H), 3.93-4.01 (m, 1 H), 4.09-4.22 (m, 2 H), 7.13-7.25 (m, 5 H), 7.40 (d, J = 7.03 Hz, 2 H), 7.54 (d, J = 7.03 Hz, 2 H); ¹³C NMR (CDCl₃): δ = 16.2 (d, J _FC = 11.7 Hz), 16.4 (d, J _PC = 11.7 Hz), 64.3 (dd, J _FC = 1.68 Hz, J _PC = 7.27 Hz), 64.6 (dd, J _FC = 1.68 Hz, J _PC = 7.27 Hz), 106.0 (dd, J _PC = 174.6 Hz, J _FC = 233.7 Hz), 126.3 (t, J _PC = J _FC = 7.83 Hz), 126.4 (t, J _PC = J _FC = 7.83 Hz), 127.7 (t, J _PC = J _FC = 1.68 Hz), 128.3, 128.6 (d, J = 7.83 Hz), 129.0, 134.9 (d, J = 22.9 Hz), 135.8 (d, J = 1.68 Hz); ¹⁹F NMR (CDCl₃): δ = -67.3 (d, J _PF = 64.5 Hz); HRMS: m/z calcd for C₁₇H₁₉FIO₃PS: 479.9821; found: 479.9809.

16

Diethyl [Fluoro(2-naphthyl)(phenylthio)methyl]phos-phonate (8): ¹H NMR (CDCl₃): δ = 1.07 (t, J = 7.02 Hz, 3 H), 1.28 (t, J = 7.02 Hz, 3 H), 3.65-3.78 (m, 1 H), 3.91-4.04 (m, 1 H), 4.12-4.25 (m, 2 H), 7.07-7.16 (m, 3 H), 7.41-7.47 (m, 4 H), 7.47-7.79 (m, 4 H), 7.94 (m, 1 H); ¹³C NMR (CDCl₃): δ = 16.3 (d, J _PC = 5.56 Hz), 16.4 (d, J _PC = 5.56 Hz), 64.5 (d, J _PC = 7.26 Hz), 65.2 (d, J _PC = 7.26 Hz), 106.2 (dd, J _PC = 176.8 Hz, J _FC = 234.3 Hz), 124.0 (dd, J _PC = 2.80 Hz, J _FC = 5.59 Hz), 125.8 (dd, J _PC = 5.59 Hz, J _FC = 9.50 Hz), 126.1, 126.5, 127.4, (d, J _FC = 6.10 Hz), 128.4, 128.5, 128.8, 132.4 (t, J _FC = 11.1 Hz), 132.8, 135.8; ¹⁹F NMR (CDCl₃): δ = -65.9 (d, J _PF = 92.5 Hz); HRMS: m/z calcd for C₂₁H₂₂FO₃PS: 404.1011; found: 404.1007.

17

Diethyl α-Fluoro-α-(2-pyridylthio)benzylphosphonate (11): ¹H NMR (CDCl₃): δ = 1.14 (t, J = 7.02 Hz, 3 H), 1.26 (t, J = 7.02 Hz, 3 H), 3.89 (q, J = 7.29 Hz, 1 H), 4.14 (q, J = 6.48 Hz, 1 H), 4.34 (q, J = 6.9 Hz, 2 H), 6.90-7.56 (m, 8 H), 8.34 (d, J = 4.86 Hz, 1 H); ¹³C NMR (CDCl₃): δ = 16.33 (d, J _PC = 10.62 Hz), 16.39 (d, J _PC = 10.65 Hz), 64.7 (dd, J _PC = 7.29 Hz, J _FC = 31.02 Hz), 65.1 (dd, J _PC = 6.78 Hz, J _FC = 22.87 Hz), 106.21 (dd, J _PC = 170.11 Hz, J _FC = 230.11 Hz), 126,3 (t, J _PC = 3.91 Hz), 126.6 (t, J _PC = 3.91 Hz), 127.9 (s), 128.2 (t, J = 1.69 Hz), 129.1 (t, J = 1.68 Hz), 134.5 (d, J = 22.42 Hz), 149.19 (s); ¹⁹F NMR (CDCl₃): δ = -66.28 (d, J _PF = 92.2 Hz); HRMS: m/z calcd for C₁₆H₁₉FNO₃PS: 355.0807; found: 355.0800.

18

Diethyl α-Fluoro-α-(4-pyridylthio)benzylphosphonate (12): ¹H NMR (CDCl₃): δ = 1.13 (t, J = 7.02 Hz, 3 H), 1.29 (t, J = 7.02 Hz, 3 H), 3.86 (q, J = 7.29 Hz, 1 H), 4.01 (q, J = 7.02 Hz, 1 H), 4.15 (q, J = 6.95 Hz, 2 H), 7.16-7.53 (m, 5 H), 7.57 (d, J = 6.92 Hz, 2 H), 8.34 (d, J = 5.21 Hz, 2 H); ¹³C NMR (CDCl₃): δ = 16.30 (d, J _PC = 10.62 Hz), 16.38 (d, J _PC = 10.62 Hz), 64.76 (dd, J _PC = 7.25 Hz, J _FC = 22.85 Hz), 65.1 (dd, J _PC = 6.71 Hz, J _FC = 22.31 Hz), 106.1 (dd, J _PC = 169.52 Hz, J _FC = 229.8 Hz), 126,3 (t, J _PC = 3.91 Hz), 126.6 (t, J _PC = 3.91 Hz), 127.6 (s), 128.1 (t, J = 1.68 Hz), 128.9 (t, J = 1.68 Hz), 134.1 (d, J = 22.36 Hz), 149.17 (s); ¹⁹F NMR (CDCl₃): δ = -66.67 (d, J _PF = 86.9 Hz); HRMS: m/z calcd for C₁₆H₁₉FNO₃PS: 355.0807; found: 355.0789.

19 Erian AW. Konno A. Fuchigami T. J. Org. Chem.  1995,  60:  7654 

20 Hou Y. Fuchigami T. J. Electrochem. Soc.  2000,  147:  4567 

21 Shaaban MR. Ishii H. Fuchigami T. J. Org. Chem.  2000,  65:  8685 

22

Diethyl [Fluoro(4-pyridylthio)methyl]phosphonate (19): ¹H NMR (CDCl₃): δ = 1.37 (t, J = 7.09 Hz, 6 H), 4.24-4.36 (m, 4 H), 6.19 (dd, J _HF = 53.6 Hz, J _HP = 7.56 Hz, 1 H, CHF), 7.34 (d, J = 1.48 Hz, 1 H), 7.36 (d, J = 1.48 Hz, 1 H), 8.53 (d, J = 1.48 Hz, 1 H), 8.55 (d, J = 1.48 Hz, 1 H); ¹³C NMR (CDCl₃): δ = 16.65 (d, J _PC = 6.15 Hz), 64.5 (dd, J _PC = 6.70 Hz, J _FC = 11.7 Hz), 93.7 (dd, J _PC = 177.2 Hz, J _FC = 232.5 Hz, CHF), 122.9 (d, J _FC = 1.68 Hz), 144.5 (d, J _PC = 2.80 Hz), 144.7 (d, J _PC = 2.80 Hz), 149.9 (s); ¹⁹F NMR (CDCl₃): δ = -93.6 (dd, J _PF = 83.3 Hz, J _HF = 53.6 Hz); HRMS: m/z calcd for C₁₀H₁₅FNO₃PS: 279.0494; found: 279.0489.

23 Mikolajczyk M. Balczewski P. Gazejszczak S. Synthesis  1980,  127