Decatungstate-catalyzed radical disulfuration through direct C-H functionalization for the preparation of unsymmetrical disulfides

Unsymmetrical disulfides are widely found in the areas of food chemistry, pharmaceutical industry, chemical biology and polymer science. Due the importance of such disulfides in various fields, general methods for the nondirected intermolecular disulfuration of C-H bonds are highly desirable. In this work, the conversion of aliphatic C(sp3)-H bonds and aldehydic C(sp2)-H bonds into the corresponding C-SS bonds with tetrasulfides (RSSSSR) as radical disulfuration reagents is reported. The decatungstate anion ([W10O32]4−) as photocatalyst is used for C-radical generation via intermolecular hydrogen atom transfer in combination with cheap sodium persulfate (Na2S2O8) as oxidant. Herein a series of valuable acyl alkyl disulfides, important precursors for the generation of RSS-anions, and unsymmetrical dialkyl disulfides are synthesized using this direct approach. To demonstrate the potential of the method for late-stage functionalization, approved drugs and natural products were successfully C-H functionalized.

Tetrasulfides were synthesized by the following general method: Thiol (10 mmol) and Et3N (10 mmol) were added dropwise as a solution in dry ether (30 mL) to a solution of freshly distilled S2Cl2 (5 mmol) in dry ether (30 mL) cooled to -78°C in a dry ice/acetone bath. After the addition is complete, the solution was stirred at -78°C for an additional 30 minutes, after which it was diluted with ether (100 mL) and washed with water, Na2CO3 (sat.) and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude oil was purified by column chromatography using 5% EtOAc in hexane to obtain the corresponding tetrasulfides.

The SS-(tert-butyl) 4-methylbenzenesulfono(dithioperoxoate) was synthesized by the following method:
To a solution of t BuSS t Bu (10 mmol) in Et2O (40 mL) was added SO2Cl2 (10 mmol) slowly at 0 o C and then the mixture was stirred at the same temperature for 1 hour. Then a solution of TsSK (20 mmol) in acetone (50 mL) was added slowly at 0 o C and continue stirred at room temperature for 2 hours. The precipitate was filtered and evaporated under reduced pressure and purified by column chromatography.
5n was synthesized by the following method: To a stirred solution of commercially available indomethacin (1 mmol, 1 equiv.) in DCM (5 mL) were added p-hydroxybenzaldehyde (1.2 mmol, 1.2 equiv.) and DCC (1.5 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature for 16 h. Then, the crude reaction mixture was filtered over a pad of Celite eluting with EtOAc. This yellow solution was concentrated by rotary evaporation and the residue was purified by column chromatography using hexane: DCM mixtures as eluent to afford the desired compound.

Optimization of conditions with cyclohexane as the substrate and 3a as the disulfuration reagent
Supplementary Table 1 Reaction conditions: To an oven dried Schlenk tube with a magnetic stirring bar, the tetrasulfide 3a (0.3 mmol, 1.0 equiv.), the cyclohexane 2a (3 mmol, 10 mmol), photocatalyst TBADT (2 mol%), Na2S2O8 (0.45 mmol, 1.5 equiv.) and 3.0 mL mixed solvent (CH3CN/H2O, v/v, 2/1) were added under argon atmosphere using standard Schlenk techniques at ambient temperature. After backfilling with nitrogen, the tube was placed in a photoreactor, stirred and irradiated with a Kessil 40 W 390 nm lamp for 12 h at 60 o C. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography with hexane as the eluent to afford the desired product.

General synthetic procedure for the synthesis of disulfides 4 and 6
General procedure A: To an oven dried Schlenk tube with a magnetic stirring bar, the tetrasulfides 3 (0.3 mmol, 1.0 equiv.), the substrates (3 mmol, 10 equiv.), Na2S2O8 (0.45 mmol, 1.5 equiv.), photocatalyst TBADT (  The resulting mixture was analyzed by HRMS (ESI), and the TEMPO-trapping product 7 was detected. Then, the solvent was removed under reduced pressure and the crude residue was purified by column chromatography with hexane as the eluent to afford the desired product 6f (0.147 mmol, 38.5 mg, 49% yield). The NMR spectra were in agreement with those reported in the literature. 10 The resulting mixture was analyzed by HRMS (EI), and the product 9, generated by the radical cascade reaction could be detected. Then, the solvent was removed under reduced pressure and the crude residue was purified by column chromatography with hexane as the eluent to afford the desired product 4a (0.288 mmol, 58.7 mg, 48% yield).

Stern-Volmer quenching experiments
Stern-Volmer luminescence quenching analysis was conducted using a Jasco FP8300 spectrofluorometer at 25 °C. The following parameters were employed: Excitation bandwidth = 5 nm, data interval = 0. Comment: Stern-Volmer quenching experiments showed that the tetrasulfide 3a could indeed also be oxidized with the photoexcited TBADT. As shown above, the Stern-Volmer constant is around 1.5 × 10 2 M -1 , and we could calculate the quenching rate constant kq ( ̴ 3 × 10 9 M -1 s -1 ) based on the lifetime of the emissive excited state of TBADT (4.75 × 10 -8 s). 11 Moreover, referring to the literature, 12 the reaction of alkanes with the photoexcited TBADT has a comparable quenching rate constant (1 × 10 8 M -1 s -1 ). Although it seems reasonable that the tetrasulfide can also quench the excited photocatalyst, we are not able to draw a possible pathway how we can convert the tetrasulfide radical cation to the disulfuration product. We definitely need a CH abstraction to generate the C-radical and the following trapping with the tetrasulfide is established and fast. Moreover, for the less activated substrates such as cyclohexane the substrate is used in excess further supporting the C-H abstraction path. For the activated substrates the H-abstraction will be faster. We therefore assume, that even if reductive quenching will happen, it is likely not a productive pathway. Moreover, we have shown the TEMPOtrapping product is formed. The NMR spectra were in agreement with those reported in the literature. 13 1,4-Bis(4-chlorobenzyl)tetrasulfane (3f): The NMR spectra were in agreement with those reported in the literature. The NMR spectra were in agreement with those reported in the literature. 9 1-(Tert-butyl)-2-cyclohexyldisulfane (4a):

Characterization data
Following the General Procedure A and purification via column chromatography on silica gel (pentane), 4a was obtained as a colorless oil (105.2 mg, 86% yield). The NMR spectra were in agreement with those reported in the literature. 16 2-((Cyclohexyldisulfaneyl)methyl)furan (4h): Following the General Procedure A and purification via column chromatography on silica gel (pentane/EtOAc The NMR spectra were in agreement with those reported in the literature. 19 Methyl N-acetyl-S-(cyclohexylthio)-L-cysteinate (4k): Following the General Procedure A and purification via column chromatography on silica gel (pentane/EtOAc 3-(Tert-butyldisulfaneyl)adamantan-1-ol (4q): Following the General Procedure C and purification via column chromatography on silica gel (pentane/EtOAc = 5/1, v/v) and preparative RP-MPLC (acetonitrile/water, gradient), 4q was obtained as a colorless oil (53.8 mg, 66% yield).