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

Abstract

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.

Fig. 1. The disulfide moiety in natural products and drugs.

Unsymmetrical disulfides in natural products and drugs.

Fig. 2. State of art methods for the preparation of unsymmetrical disulfides.

Reported methods for preparation of unsymmetrical disulfides and this work.

Fig. 3. Reaction design.

The suggested mechanism for direct C-H disulfuration via decatungstate photocatalysis.

Fig. 4. Reaction scope.

Isolated yields are provided. Selectivity determined by gas chromatography is reported as the percentage of the major regioisomer. GC yields with alkanes as the limiting reagent in parentheses: substrate 2 (0.3 mmol) and tetrasulfide 3 (0.45 mmol). ^aMethod A: tetrasulfide 3 (0.3 mmol, 1.0 equiv.), 2 (3 mmol, 10 equiv.), TBADT 2 mol%, Na₂S₂O₈ (0.45 mmol, 1.5 equiv.), solvent 3 mL (CH₃CN/H₂O, v/v, 2/1), 390 nm, Ar, 60 °C, and 12 h. ^bMethod B: tetrasulfide 3 (0.3 mmol, 1.0 equiv.), 2 (3 mmol, 10 equiv.), TBADT 2 mol%, solvent 3 mL [CH₃CN/(HCl aq. 1.0 M), v/v, 2/1], 390 nm, Ar, 60 °C, and 12 h. ^cUsing CH₃CN/H₂O (v/v, 2/1) as solvent. ^d2 (0.3 mmol, 1.0 equiv.), tetrasulfide 3 (0.45 mmol, 1.5 equiv.), TBADT 2 mol%, solvent 3 mL [CH₃CN/(HCl aq. 1.0 M), v/v, 2/1], 390 nm, Ar, 60 °C, and 12 h. ^eTetrasulfide 3 (0.3 mmol, 1.0 equiv.), substrate 2 (1.5 mmol, 5.0 equiv.), TBADT 2 mol%, Na₂S₂O₈ (0.45 mmol, 1.5 equiv.), solvent 3 mL (CH₃CN/H₂O, v/v, 2/1), 390 nm, Ar, 60 °C, and 12 h. ^fDetermined by ¹H NMR spectroscopy. ^gTetrasulfide 3 (0.45 mmol, 1.5 equiv.), substrate 2 (0.3 mmol, 1.0 equiv.), TBADT 2 mol%, Na₂S₂O₈ (0.45 mmol, 1.5 equiv.), solvent 3 mL (CH₃CN/H₂O, v/v, 2/1), 390 nm, Ar, room temperature, and 12 h.

Fig. 5. Products obtained by disulfuration of aldehydes and functionalization of natural compounds.

Isolated yields are provided. Reaction conditions: substrate 5 (0.3 mmol, 1.0 equiv.), tetrasulfide 3a (0.45 mmol, 1.5 equiv.), TBADT 2 mol%, Na₂S₂O₈ (0.45 mmol, 1.5 equiv.), solvent 3 mL (CH₃CN/H₂O, v/v, 2/1), 390 nm, Ar, 60 °C, and 12 h. ^aReaction time: 4 h. If the reaction time is extended to 12 h, some of the products will decompose into aroylmonosulfides (see SI for details). ^bReaction conducted at room temperature. ^cWith tetrasulfide 3b (1.5 equiv.). ^dDetermined by ¹H NMR spectroscopy. ^eReaction run in the absence of Na₂S₂O₈ in 3 mL [CH₃CN/(HCl aq. 1.0 M), v/v, 2/1]. ^fReaction conditions: substrate 5m (0.2 mmol, 1.0 equiv.), 5 h. ^gReaction conditions: substrate 5n (0.1 mmol, 1.0 equiv.), room temperature, 12 h.

Fig. 6. Gram-scale experiments and mechanistic studies.

a Gram-scale preparation of disulfides 4a and 6 g. b Disulfuration in the presence of TEMPO and methyl acrylate.