Copper-Catalyzed Carbene Insertion into the Sulfur–Sulfur Bond of RS–SCF₂H/SCF₃ under Mild Conditions

Abstract

A copper-catalyzed carbene insertion into the sulfur–sulfur bond of trifluoromethyl/difluoromethyl/diphenyldisulfides under mild conditions has been developed. Diverse dithioketal derivatives were synthesized in moderate to good yields in an atom-economic process.

Key words

copper - carbene - difluoromethylthio - dithioketal

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• 17 General procedure for copper-catalyzed carbene insertion of disulfides (3a–e, 3g–o, 3r–z). In a flame-dried glass tube, under an argon atmosphere, a mixture of disulfide (0.3 mmol) and Cu(OTf)₂ (2.7 mg, 0.0075 mmol, 2.5 mol%) was added to DCE (0.6 mL) at room temperature. Diazo compound (0.3 mmol) was then added in one portion. The mixture was stirred for 1 h and then additional diazo compound (0.3 mmol) was added. The mixture was stirred for another 1 h and subsequently filtered through a short plug of Celite and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc/PE) to give the product. Ethyl 2-((Difluoromethyl)thio)-2-((4-fluorophenyl)thio)-2-phenylacetate (3a). R_f = 0.5 (EtOAc/PE, 1:20); yield: 76 mg (68%); yellow oil. ¹H NMR (400 MHz, CDCl₃, 293 K, TMS): δ = 7.33–7.20 (m, 5 H), 7.17–7.13 (m, 2 H), 6.93 (dd, J = 56.2, 54.1 Hz, 1 H), 6.89 (t, J = 8.6 Hz, 2 H), 4.35–4.23 (m, 2 H), 1.27 (t, J = 7.1 Hz, 3 H). ¹⁹F NMR (375 MHz, CDCl₃): δ = –92.72 (dd, J = 252.6, 56.2 Hz, 1 F), –95.60 (dd, J = 252.7, 54.3 Hz, 1 F), –109.87 (s, 1 F). ¹³C NMR (100.7 MHz, CDCl₃): δ = 169.4, 164.2 (d, J = 251.6 Hz), 139.6 (d, J = 8.8 Hz), 136.3, 128.8, 128.3, 127.6, 124.4 (d, J = 3.2 Hz), 122.7 (t, J = 269.9 Hz), 115.7 (d, J = 21.9 Hz), 70.6, 63.5, 13.7. IR (KBr): ν_max = 2984, 1728, 1589, 1489, 1446, 1232, 1067, 1041, 864 cm^–1. MS (ESI): m/z = 390.0 [M + NH₄ ⁺]. HRMS (ESI): m/z calcd for C₁₇H₁₉NF₃O₂S₂ [M + NH₄ ⁺]: 390.0809; found: 390.0803. Ethyl 2-((4-Cchlorophenyl)thio)-2-((difluoromethyl)thio)-2-phenylacetate (3b). R_f = 0.5 (EtOAc/PE, 1:20); yield: 100 mg (86%); yellow oil. ¹H NMR (400 MHz, CDCl₃, 293 K, TMS): δ = 7.30–7.22 (m, 5 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.08 (d, J = 8.6 Hz, 2 H), 6.92 (dd, J = 56.2, 54.1 Hz, 1 H), 4.34–4.22 (m, 2 H), 1.25 (t, J = 7.1 Hz, 3 H). ¹⁹F NMR (375 MHz, CDCl₃): δ = 92.65 (dd, J = 252.7, 56.2 Hz, 1 F), –95.65 (dd, J = 252.7, 54.1 Hz, 1 F). ¹³C NMR (100.7 MHz, CDCl₃): δ = 169.3, 138.6, 136.8, 136.3, 128.9, 128.8, 128.4, 127.6, 122.6 (t, J = 269.9 Hz), 70.6, 63.5, 13.7. IR (KBr): ν_max = 2983, 1728, 1573, 1475, 1301, 1233, 1067, 1042, 796 cm^–1. MS (ESI): m/z = 406.0 [M + NH₄ ⁺]. HRMS (ESI): m/z calcd for C₁₇H₁₉NF₂ClO₂S₂ [M + NH₄ ⁺]: 406.0514; found: 406.0508. Ethyl 2-((4-Bromophenyl)thio)-2-((difluoromethyl)thio)-2-phenylacetate 3c. R_f = 0.5 (EtOAc/PE, 1:20); yield: 107 mg (82%); yellow oil. ¹H NMR (400 MHz, CDCl₃, 293 K, TMS): δ = 7.25 (d, J = 8.4 Hz, 2 H), 7.23–7.16 (m, 5 H), 6.95 (d, J = 8.4 Hz, 2 H), 6.85 (dd, J = 56.2, 54.1 Hz, 1 H), 4.28–4.16 (m, 2 H), 1.19 (t, J = 7.1 Hz, 3 H). ¹⁹F NMR (375 MHz, CDCl₃): δ = –92.64 (dd, J = 252.7, 56.3 Hz, 1 F), –95.67 (dd, J = 252.7, 54.1 Hz, 1 F). ¹³C NMR (100.7 MHz, CDCl₃): δ = 169.3, 138.8, 136.2, 131.7, 128.8, 128.4, 128.1, 127.5, 125.2, 122.6 (t, J = 270.1 Hz), 70.5, 65.8, 63.5. IR (KBr): ν_max = 2982, 1727, 1473, 1446, 1232, 1068, 1041, 815, 769 cm^–1. MS (ESI): m/z = 449.9 [M + NH₄ ⁺]. HRMS (ESI): m/z calcd for C₁₇H₁₉NF₂BrO₂S₂ [M + NH₄ ⁺]: 450.0009; found: 450.0003