Convenient Synthesis of Functionalized Unsymmetrical Vinyl Disulfides and Their Inverse Electron-Demand Hetero-Diels-Alder Reaction

The simple, convenient, and efficient methods for the preparation of unsymmetrical vinyl disulfides with additional functional groups under mild conditions with moderate to high yields were designed. The developed methods include the reaction of S-vinyl phosphorodithioate with thiotosylates or S-vinyl thiotosylate with thiols. The designed methods allow for the synthesis of unsymmetrical vinyl disulfides with additional functionalities such as hydroxy, carboxy, protected amino, or ester groups. Vinyl disulfides reacted with the generated transient o-iminothioquinones in an inverse electron-demand [4+2] cycloaddition to produce benzo[b][1,4]thiazine derivatives.


General information.
Preparation of thiotosylates 1a-1e; 1k; 1m-1n; 1r was described in previous works. 1 All bromides were purchased from ProChimia, preparation of sodium 4-methylbenzenesulfonothioate from sodium 4-methylbenzenesulfonate purchased from Merck, was described previously. 1 Vinyl magnesium bromide solution (1M) in THF and tetrabutylammonium fluoride (TBAF) solution (1M) in THF were purchased from Merck. Tetrahydrofuran was pre-dried over KOH pellets and distilled. Then it was dried by heating under reflux over potassium in the presence of benzophenone as an indicator. Chloroform, acetonitrile and dichloromethane were dried according to literature procedure. TLC was performed with silica gel Polygram SIL G/UV254. Column chromatography was performed using silica gel 60 (230-400 mesh, Merck). NMR spectra were recorded on Brucker 400 MHz spectrometers. The residual solvent peak was used as the internal reference (CDCl3: δ=7.26 ppm for 1 H, δ=77.0 ppm for 13 C). IR spectra were recorded on Nicolet Is50 Ft-IR spectrometer by ATR method. Melting points were measured with a Gallenkamp 7936B apparatus and were not standardized.

Experimental Procedures
General procedure for the preparation of thiotosylates derivatives 1f-j;1l;1p.
From alkyl halides 1 To the solution of alkyl halide (1 eq, 14.7 mmol) in dry acetonitrile (50 mL) under reflux condenser sodium 4methylbenzenesulfonotioate (1 eq, 14.7 mmol) was added, reaction was refluxed 3 h, then was stirred overnight at rt. After this time solvent was evaporated, residue was washed with water (30 mL), and extracted 3 times with diethyl ether (50 mL). Combined organic layers were dried over MgSO4, filtered and evaporated to constant volume. Crude product was purified by column chromatography (SiO2). Pure compounds were identified by 1 H NMR and 13 C NMR spectra. Results are summarized in Table S1.

Synthesis of N-Boc cysteamine thiotosylate 1f
A solution of 564 mg of tosyl bromide (2.4 mmol) and triethylamine (2.4 mmol, 334 µL) in dry THF (20 mL) was cooled to 0°C under nitrogen. Then a solution of 354 mg N-Boc cysteamine (2.0 mmol) in dry THF (5 mL) was added for 30 minutes. Mixture was stirred at 0°C for 1 h after complete addition. Then solvent was removed in vacuo and the residue was purified by column chromatography (SiO2) using DCM as eluent to provide 464 mg of S- (2-((tert-butoxycarbonyl)amino)ethyl) 4-methylbenzenesulfonothioate as a white solid with 70% yield.

b. General procedure for synthesis of vinyl disulfide 2 form S-vinyl
[a] Isolated yield

RT
Ditosylsulfide was prepared using modified literature procedure 2 : To a suspension of 13.54 g (76 mmol) sodium p-toluenesulifnate in dry CHCl3 (150 mL) under N2, sulfur dichloride (40 mmol, 2.54 mL) was added dropwise. Mixture was stirred for 2 h at rt, then the insoluble material was filtered off. Solvent was removed in vacuo, obtained yellowish solid was recrystallized from boiling glacial acetic acid to provide 9.24g (68%) of bis (p-toluenesulfonyl)sulfide as white needles (mp. 136-137°C, lit. 137°C), spectra were identical as reported in literature 2 .

b. Synthesis of S-vinyl thiotosylate
Vinylmagnesium bromide (10 mmol, 1M solution in THF, 10 mL) was added dropwise to a stirred solution of bis-(p-toluenesulfonyl)sulfide 5.47 g (16 mmol) in dry THF (200 mL) at -78°C under nitrogen . After the complete addition, mixture was stirred for 2 h at this temperature, then cooling bath was removed, and mixture was warmed to rt. Solvent was removed in vacuo, and the residue was purified by column chromatography (Hexene : DCM 2:1) to provide 1.29 g (60%) of S-vinyl thiotosylate as a yellow oil.

c. General procedure for synthesis of vinyl disulfides 2 form S-vinyl thiotosylate
To stirred, ice cooled solution of S-vinyl thiotosylate 428 mg (2.0 mmol) and thiol 4 (1.0 mmol) in dry DCM (10 mL) under nitrogen, NEt3 (1.0 mmol, 140µL) was added in one portion. The mixture was stirred at rt for 15 min. Then solvent was evaporated and the reside was purified by column chromatography (SiO2) to provide disulfide 2. Results are summarized in Table S3.