First Synthesis of 4,4-Difluoro-1,3-oxathiolan-5-one

Abstract

The synthesis of a novel 4,4-difluoro-1,3-oxathiolanone was reported from α,α-difluorosulfoxide. This route involved a fluorination of a symmetrical sulfide, a Pummerer rearrangement, and a ring closure mediated by organic acids.

halogenation - fluorine - sulfoxides - rearrangements - heterocycles

References

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A degradation of the sulfoxide 9b occurred during the purification. It is preferable to use it without purification in the next step.

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Despite a quantitative conversion, a lost of 11 was observed during the distillation.

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19

Experimental:
Methyl 2,2-difluoro-2-(methoxycarbonyl-trifluoro-acetoxymethylsulfanyl) acetate(10): To a solution of difluoroester(8b) [8] [20] (2.00 g, 9.34 mmol) in CH₂Cl₂ (40 mL) was added NaHCO₃ (1.57 g, 18.7 mmol) followed by meta-chloroperoxybenzoic acid (2.42 g, 14.0 mmol). The resulting mixture was stirred at r.t. for 70 min and then poured into a mixture of sat. aq NaHCO₃ (25 mL) and sodium thiosulfate (25 mL). The layers were separated and the aq phase was extracted with CH₂Cl₂ (5 × 40 mL). The combined organic extracts were washed with sat. aq NaHCO₃ (4 × 40 mL) and brine (40 mL), dried over MgSO₄ and concentrated under vacuum to give the crude product(9b) (1.53 g, 6.65 mmol) in 71% yield.(9b): ¹H NMR (CDCl₃): δ = 3.83 (s, 3 H, CH ₃O), 3.95 (s, 2 H, CH₂), 4.00 (s, 3 H, CH ₃O); ¹³C NMR (CDCl₃): δ = 53.1 (t, ³ J _CF = 4.6 Hz, CH₂), 53.4 (CH₃), 54.7 (CH₃), 118.6 (t, ¹ J _CF = 302 Hz, CF₂), 160.2 (t, ² J _CF = 28 Hz, CO-CF₂), 164.7 (CO); ¹⁹F NMR (CFCl₃, CDCl₃): δ = -109.6 (d, ² J _FF = 235 Hz, 1 F), & ndash;110.8 (d, ² J _FF = 235 Hz, 1 F). The crude sulfoxide(9b) (1.53 g, 6.65 mmol) was stirred at r.t. in the presence of trifluoroacetic anhydride (2.82 mL, 0.020 mol). After 48 h, the mixture was concentrated under vacuum, diluted with CH₂Cl₂ (20 mL) and washed with brine. The crude product was distilled under reduced pressure (70 °C/0.07 mm Hg) to afford(10) (1.5 g, 4.60 mmol) in 70% yield.¹H NMR (CDCl₃): δ = 3.87 (s, 3 H, CH ₃O), 3.94 (s, 3 H, CH ₃O), 6.63 (s, 1 H, CH); ¹³C NMR (CDCl₃): δ = 54.4 (CH₃), 54.6 (CH₃), 74.8 (t, ³ J _CF = 3.9 Hz, CH), 114.1 (q, ¹ J _CF = 228 Hz, CF₃), 118.8 (t, ¹ J _CF = 292 Hz, CF₂), 156 (q, ² J _CF = 44.5 Hz, COCF₃), 161.2 (t, ² J _CF = 32 Hz, COCF₂), 164.0 (CO); ¹⁹F NMR (CDCl₃): δ = -75.4 (s, 3 F, CF₃), -81.6 (d, ² J _FF = 224 Hz, 1 F), -83.3 (d, ² J _FF = 224 Hz, 1 F); IR (NaCl): ν = 1802 (CO), 1772 (CO), 1762 (CO) cm^-1; MS (EI, 70 eV): m/z (%) = 326(9) [M⁺], 239(33), 213(70), 179(22), 129(42), 103(100), 69(69), 45(44).
Methyl 4,4-difluoro-5-oxo-[1,3]-oxathiolane-2-carboxyl-ate(11): To a solution of(10) (1.48 g, 4.54 mmol) in CHCl₃ (20 mL) under nitrogen was added triflic acid (0.60 mL, 6.81 mmol). After stirring overnight at r.t. the mixture was diluted wih CH₂Cl₂, washed with NaHCO₃ (20 mL) and brine (20 mL). The organic layer was dried over MgSO₄ and concentrated under vaccum. The crude residue (745 mg, 3.76 mmol) was distilled under reduced pressure (65 °C/1 mbar) to afford(11) (445 mg, 2.45 mmol) in 50% yield. ¹H NMR (CDCl₃): δ = 3.92 (s, 3 H, CH₃), 5.91 (d, 1 H, ⁴ J _HF = 5.8 Hz, CH); ¹³C NMR (CDCl₃): δ = 54.2 (CH₃), 70.3 (d, ³ J _CF = 1.9 Hz, CH), 121.8 (t, ¹ J _CF = 280 Hz, CF₂), 161.7 (t, ² J _CF = 30.5 Hz, CO), 166.3 (CO); ¹⁹F NMR (CDCl₃): δ = -71.8 (dd, ² J _FF = 243 Hz, ⁴ J _HF = 5.8 Hz, 1 F), -80.1 (d, ² J _FF = 243 Hz, 1 F); IR (CHCl₃/NaCl): ν = 1818 (CO), 1762 (CO), 1124, 1084, 1056 cm^-1; MS (EI, 70 eV): m/z (%) = 198(7) [M⁺], 179(16), 139(35), 116(64), 95(18), 83(56), 63(63), 45(100); HMRS (EI) calcd for C₅H₄SO₄F₂ [M⁺]: 197.9798. Found: 197.9780.

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