Straightforward Access to Thiocyanates via Dealkylative Cyanation of Sulfoxides

Thiocyanates, versatile building blocks in organic synthesis, are shown to be easily accessible via an interrupted Pummerer reaction of sulfoxides. This facile dealkylative functionalization proceeds under mild conditions through electrophilic activation of the sulfoxide partner. The resulting thiocyanate itself can serve as a handle for diversification in a straightforward one-pot procedure.


General Information
Unless otherwise stated, all glassware was flame-dried before use and all reactions were performed under an atmosphere of argon. All solvents were distilled from appropriate drying agents prior to use. All reagents were used as received from commercial suppliers unless otherwise stated. Trifluoromethanesulfonic anhydride (Tf2O) was distilled over P4O10 prior to use and stored under inert atmosphere in the fridge for a maximum of roughly 3 weeks. 1 Reaction progress was monitored by thin layer chromatography (TLC) performed on aluminum plates coated with silica gel F254 with 0.2 mm thickness. Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining using potassium permanganate.
Neat infrared spectra were recorded using a Perkin-Elmer Spectrum 100 FT-IR spectrometer.
Wavenumbers (νmax) are reported in cm -1 . Mass spectra were obtained using a Bruker maXis UHR-TOF spectrometer with electrospray ionization (ESI) and a Qq-TOF mass analyzer. In several cases, the exact mass was not detected with ESI ionization. These were measured using an Agilent 7200B GC/Q-TOF Spectrometer with electron impact (EI) ionization method and a Q-TOF mass analyzer. The fragmentation pattern for the most significant fragmentations is reported with the relative intensity of the detected mass in percent denoted in parenthesis. Melting points were determined on a capillary apparatus and are uncorrected.
All 1 H NMR and 13 C NMR spectra were recorded using a Bruker AV-400, AV-500 or AV-600 spectrometer at 300K. Chemical shifts are given in parts per million (ppm, δ), referenced to the solvent peak of CDCl3, defined at δ = 7.26 ppm ( 1 H-NMR) and δ = 77.16 ( 13 C-NMR). Coupling constants are quoted in Hz (J). 1 H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q) as they appeared in the spectrum. If the appearance of a signal differs from the expected splitting pattern, the observed pattern is designated as apparent (app).
Splitting patterns that could not be interpreted or easily visualized are designated as multiplet (m) or broad (br).
Sulfoxide 1k 12 was obtained from 3-nitroaniline via a two-step literature procedure. 13
Water was added (20 mL) and the reaction mixture was extracted with CH2Cl2 (2 × 10 ml). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography (SiO2, heptane/ethyl acetate) affording methyl sulfide S2 as a mixture with the starting material in a ratio of 1.15:1 (317.2 mg, 53% purity).
The crude residue was purified by flash column chromatography (SiO2, heptane/ethyl acetate) affording the title compound (114.5 mg, 26% over 2 steps) as a yellow crystalline solid.
Trifluoromethanesulfonic anhydride (Tf2O, 1.0 equiv.) was added and the mixture was stirred for 5 or 15 minutes at this temperature (5 minutes for substrates: 1a-1e, 1h-1j, 1l-1p and 15 minutes for substrates: 1f, 1g, 1k). After this time, trimethylsilyl cyanide (TMSCN, 1.0 equiv.) was added and the resulting mixture was allowed to warm to ambient temperature (23 °C) over the course of 2 h. The reaction was diluted to two times its volume with CH2Cl2 and solid sodium bicarbonate (NaHCO3, 3.0 equiv.) was added. The suspension was stirred for 5 minutes, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography (SiO2, heptane/ethyl acetate) affording the products 2.

One-pot transformations hex-1-yn-1-yl(naphthalen-2-yl)sulfane (3)
A solution of 2-(methylsulfinyl)naphthalene 1h (28.5 mg, 0.15 mmol, 1.0 equiv.) in CH2Cl2 (1.5 mL, 0.1 M) was cooled -78 °C. Trifluoromethanesulfonic anhydride (25 µL, 0.15 mmol, 1.0 equiv.) was added and the mixture was stirred for 5 minutes at this temperature. After this time, trimethylsilyl cyanide (19 µL, 0.15 mmol, 1.0 equiv.) was added and the resulting mixture was S15 allowed to warm to ambient temperature (23 °C) over the course of 2 h. In a separate flamedried Schlenk tube, a solution of 1-hexyne (103 µL, 0.90 mmol, 6.0 equiv.) in THF (4.5 mL) was cooled to -78 °C and n-BuLi (1.6 M in hexane, 0.56 mL, 0.90 mmol, 6.0 equiv.) was added dropwise. This solution was stirred for 30 minutes at -78 °C then warmed to 0 °C. The volatiles of the reaction mixture containing the crude thiocyanate were removed in vacuo and the flask containing the crude material was placed under argon in an ice bath. The solution of lithium alkynylide in THF was transferred using a syringe and the reaction was allowed to warm to ambient temperature (23 °C) and stirred for 15 h. A saturated aqueous solution of ammonium chloride (4 mL) was added and the reaction mixture was extracted with ethyl acetate (2 × 5 mL).
The combined organic phases were dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography (SiO2, heptane/ethyl acetate) affording the product (28.9 mg, 80%) as a yellowish oil.

hex-1-yn-1-yl(naphthalen-2-yl)sulfane (4)
A solution of 2-(methylsulfinyl)naphthalene 1h (28. was added and the mixture was stirred for 5 minutes at this temperature. After this time, trimethylsilyl cyanide (31 µL, 0.25 mmol, 1.0 equiv.) was added and the resulting mixture was allowed to warm to ambient temperature (23 °C) over the course of 2 h. In a separate round bottom flask, a solution of trifluoroacetic anhydride (TFAA, 0.35 mL, 2.5 mmol, 10 equiv.) in CH2Cl2 (2.5 mL) was cooled to 0 °C and treated dropwise with hydrogen peroxide (30 wt.% in H2O, 0.25 mL, 2.5 mmol, 10 equiv.). 24 The mixture was stirred for 45 minutes at 0 °C then, the crude thiocyanate solution in DCM was transferred from the other flask using a syringe. The round bottom flask was closed with a glass lid and placed in a sand bath (40 °C). The reaction mixture was stirred at this temperature for 16 h, when water (5 mL) was added. The reaction was extracted with DCM (2 x 5 mL) and the combined organic phases were dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent removed under reduced pressure afforded a crude residue which was purified by flash column chromatography (SiO2, heptane/ethyl acetate) affording the product (32.9 mg, 61%) as colourless crystals.