Triphosgene/Sodium Organosulfinate System: A General and Efficient Electrophilic Thiolation of Silylenol Ethers and Electron-Rich Heteroaromatics

Abstract

An efficient and practical approach to electrophilic thiolation was developed by using commercially available triphosgene as a reductant and the appropriate alkyl- or arylsulfinates, which were transformed in situ into electrophilic RSCl intermediates in the presence of triphosgene. This procedure represents a general and powerful approach for the synthesis of α-(trifluoromethyl)thio-substituted ketones and thiolated electron-rich heteroaromatic compounds.

Key words

drifluoromethylthiolation - difluoromethylthiolation - triphosgene - silylenol ethers - indoles

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• 11 Electrophilic Trifluoromethylthiolation of Silyl Enol Ethers; General Procedure A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with F₃CSO₂Na (0.4 mmol), the appropriate silyl enol ether (0.2 mmol), and MeCN (1 mL), and the mixture was stirred at –78 °C for the initial time. A solution of triphosgene (0.4 mmol) in MeCN (1 mL) was then added slowly from a syringe. After 1 h at –78 °C, the mixture was warmed to rt over 1 h, then diluted with CH₂Cl₂ (20 mL). The mixture was washed 5% aq NaHCO₃ (10 mL), and the combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel). 1-Phenyl-2-[(trifluoromethyl)sulfanyl]ethanone (2a) Yellow oil; yield: 40.9 mg (93%). ¹H NMR (300 MHz, CDCl₃): δ = 7.96 (d, J = 6.8 Hz, 2 H), 7.65 (t, J = 6.8 Hz, 1 H), 7.54 (t, J = 6.8 Hz, 2 H), 4.53 (s, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 192.1 (s), 134.7 (s), 134.3 (d, J = 1.5 Hz), 130.7 (q, J = 306.4 Hz), 129.0 (s), 128.5 (s), 38.5 (q, J = 1.8 Hz). HRMS (EI-TOF): m/z [M]+ calcd for C₉H₇F₃OS: 220.0170; found: 220.0162. Electrophilic Thiolation of Indoles or N-Methylpyrrole; General Procedure A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with RSO₂Na (0.4 mmol) and the appropriate indole or N-methylpyrrole (0.2 mmol). The tube was then evacuated and backfilled with dry N₂ (this operation was repeated three times), and the mixture was stirred at –78 °C for the initial time. A solution of triphosgene (0.4 mmol) in MeCN (1 mL) was added slowly from a syringe, and the mixture was stirred at –78 °C for 1 h. When the reaction was complete, the mixture was warmed to rt and diluted with CH₂Cl₂ (20 mL). The mixture was then washed with 5% aq NaHCO₃ (10 mL), and the combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel). 3-[(Difluoromethyl)sulfanyl]-1-methyl-1H-indole (4a) Yellow oil; yield: 37.9 mg (89%). ¹H NMR (300 MHz, CDCl₃): δ = 7.80 (d, J = 7.8 Hz, 1 H), 7.42–7.20 (m, 4 H), 6.67 (t, J = 57.7 Hz, 1 H), 3.83 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 137.31, 136.14, 130.50, 122.82, 121.15 (t, J = 275 Hz), 120.98, 119.47, 109.82, 94.28, 33.23. MS (EI): m/z = 213.1 [M]⁺. HRMS (EI-TOF): m/z [M]⁺ calcd for C₁₀H₉F₂NS: 213.0424; found: 213.042.