Electrophilic (Ethoxycarbonyl)difluoromethylthiolation Using Difluoroalkyl Sulfonium Salts

Abstract

We report a simple protocol for (ethoxycarbonyl)difluoromethylthiolation of nucleophilic compounds using a difluoroalkyl sulfonium salt which can be prepared in situ via Tf₂O-triggered electrophilic activation of a benzyl difluoroalkyl sulfoxide. With the protocol, difluoroalkylthiolated arenes, heteroarenes, α-difluoroalkylthiolated carbonyl compounds, etc. were obtained smoothly with good to excellent yields. Merits of the reaction include the readily available difluoroalkylthiolation reagent and substrates, mild conditions, and excellent regioselectivity.

Key words

difluoroalkylthiolation - sulfonium salts - dealkylation - alkylthiolation - Pummerer reaction

Publication History

Received: 26 December 2021

Accepted after revision: 30 January 2022

Accepted Manuscript online:
30 January 2022

Article published online:
21 February 2022

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• 12 Typical Difluoroalkylthiolation Procedure To a solution of indole 1b (39 mg, 0.2 mmol) and sulfoxide 2 (79 mg, 0.3 mmol) in MeCN (2.0 mL) was added trifluoromethanesulfonic anhydride (Tf₂O, 50 μL, 0.3 mmol) at 0 °C. After stirring for 1 h, diethylamine (43 mg, 0.6 mmol) was added. The resulted reaction mixture was then gradually warmed to rt and kept stirring for 12 h. After that, the mixture was passed through a short silica gel column and concentrated under vacuum. The obtained residue was further purified by flash chromatography on silica gel (eluent: PE/EtOAc, 40:1) affording product 3b as light yellow oil (47.5 mg, 68%). Characterization Data for 3b ¹H NMR (600 MHz, CDCl₃): δ = 8.80 (s, 1 H), 7.86 (s, 1 H), 7.42 (d, J = 2.2 Hz, 1 H), 7.32 (d, J = 8.6 Hz, 1 H), 7.21 (d, J = 8.6, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 1.25 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 162.28 (t, J = 32.9 Hz), 134.82, 134.20, 131.55, 126.40, 122.00, 119.61 (t, J = 287.3 Hz), 115.08, 113.38, 95.32, 63.88, 13.85 ppm. ¹⁹F NMR (565 MHz, CDCl₃): δ = –84.25 (s) ppm. IR (neat): 3338, 3111, 2996, 2919, 1747, 1305, 1292, 1121, 1090, 728, 605 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₂H₁₀F₂NO₂SBrNa [M + Na⁺]: 371.9476; found: 371.9460.