A novel three-component reaction between isocyanides, alcohols or thiols and elemental sulfur: a mild, catalyst-free approach towards O-thiocarbamates and dithiocarbamates

A new multicomponent reaction has been developed between isocyanides, sulfur and alcohols or thiols under mild reaction conditions to afford O-thiocarbamates and dithiocarbamates in moderate to good yields. The one-pot reaction cascade involves the formation of an isothiocyanate intermediate, thus a catalyst-free synthesis of isothiocyanates, as valuable building blocks from isocyanides and sulfur is proposed, as well. The synthetic procedure suits the demand of a modern organic chemist, as it tolerates a wide range of functional groups, it is atom economic and easily scalable.

S1 Table of

Experimental General information
All melting points were determined on a Jasco SRS OptiMelt apparatus and are uncorrected. 1 H and 13 C NMR spectra were recorded in  or CDCl3 solution at room temperature, on a Varian Unity Inova 500 spectrometer (500 and 125 MHz for 1 H and APT NMR spectra, respectively), with the residual solvent signal as the lock and TMS as the internal standard. Chemical shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively. HPLC-MS measurements were performed using a Shimadzu LCMS-2020 device equipped with a Reprospher 100 C18 (5 µm; 100 × 3 mm) column and positive-negative double ion source (DUIS±) with a quadrupole MS analyzer in a range of 50-1000 m/z. The samples were eluted with gradient elution using eluent A (0.1% formic acid in water) and eluent B (0.1% formic acid in acetonitrile). Flow rate was set to 1.5 mL/min. The initial condition was 5% B eluent, followed by a linear gradient to 100% B eluent by 1.5 min, from 1.5 to 4.0 min 100% B eluent was retained; and from 4.0 to 4.5 min back to initial condition with 5% B eluent and retained to 5 min. The column temperature was kept at room temperature, and the injection volume was 1-10 µL. The purity of the compounds was assessed by HPLC with UV detection at 215 and 254 nm; all starting compounds are known, purchased or synthetically feasible and >95% pure.
The rotation around the N-CS bond of the O-thiocarbamates and dithiocarbamates is hindered and slow at room temperature compared to the time of the NMR measurement, therefore both S-cis and S-trans isomers were observed [1]. By the integration of characteristic signals of the 1 H NMR spectra, the ratio of the isomers is calculated and presented in (Table S1). In the experimental data, the mean of the rotamer signals and when possible, the individual chemical shifts are presented.

S3
General procedure for the synthesis of thiocarbamates 3a-v: Isocyanide (1, 1.0 mmol) was added to a mixture of sulfur (64 mg, 2.0 mmol), alcohol (2, 2.0 mmol) and sodium hydride (60% in paraffin oil, 80 mg, 2.0 mmol) in tetrahydrofuran (3 mL) under argon atmosphere, and the resulting mixture was stirred at 40 °C for 2 hours. Afterwards, the reaction mixture was diluted with ethyl acetate (30 mL), filtered through celite, and washed with brine (2 × 30 mL). Evaporation of the solvent, followed by the purification by flash column chromatography on silica gel provided the thiocarbamates 3a-v in 30-94% yield.

Scaled-up procedure for the synthesis of thiocarbamate 3a:
The solution of 2,6-dimethylphenylisocyanide (1a, 2.62 g, 20.0 mmol) and 2a (1.62 mL, 40.0 mmol) in tetrahydrofuran (30 mL) was added dropwise to a mixture of sulfur (1.28 g, 40.0 mmol), sodium hydride (60% in paraffin oil, 1.60 g, 40.0 mmol) in tetrahydrofuran (30 mL) under argon atmosphere at 0 °C and the resulting mixture was stirred at 40 °C for 2 hours. Afterwards, the reaction mixture was diluted with ethyl acetate (60 mL), filtered through celite, and washed with brine (2 × 60 mL), then the aqueous phase was extracted with ethyl acetate (60 mL). The organic phases were combined and after the evaporation of the solvent the crude product was recrystallized from ethyl acetate/hexane. Two additional crops were obtained from the recycled mother liquor. The combined fractions provided the thiocarbamate 3a in 74% yield. through celite, and washed with brine (2 × 30 mL). Evaporation of the solvent, followed by purification by flash column chromatography on silica gel provided the isothiocyanate 8 in 85% yield.