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Diphenyl disulfide is an endogenous metabolite.
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Garosi, Benedetta ; Arathala, Parandaman ; Musah, Rabi A ;
Abstract: Direct analysis in real time–high-resolution mass spectrometry (DART-HRMS) has proven useful for the detection and faithful representation of labile organosulfur compounds (OSCs). Nevertheless, it has been found that when exposed to the metastable helium (He*) of the DART gas stream under soft ionization conditions, some classes of OSCs such as disulfides, undergo several reactions to produce new organosulfur species, which complicate interpretation of their spectra. In this work, these new entities were characterized and the mechanisms of their formation explored. DART-HRMS analysis of diphenyl disulfide (PhSSPh) exhibited peaks consistent with [PhSSPh]+•, [PhSSPh + H]+, [PhSPh]+•, and [PhSOSPh + H]+ and various fragments and adducts including [PhSS]+ and [Ph3S3]+. Ab initio/DFT calculations coupled with variational transition state theory revealed that several of these peaks are artifacts of reactions occurring with He* and •OH. Branching ratio analysis showed the dominant decomposition pathway of [PhSSPh]+• to be [PhSSPh]+• → PhS• + PhS:, rather than [PhSSPh]+• → PhS+=S + Ph•. The PhS•, Ph•, and •OH formed serve as key intermediates in subsequent reactions that lead to the m/z values observed. From the results, a systematic approach for the interpretation of the DART mass spectra of organic disulfides was developed and successfully applied to various disulfide compound classes (e.g., aryl, alkyl, benzyl, and phenyl). Organic solvents were also observed to influence the ability to detect the compounds. Benzene; dichloromethane; hexane; and with some exceptions, ethyl acetate and tetrahydrofuran were found to be suitable, while disulfide signals in dimethylformamide were totally absent.
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Keywords: DART-HRMS ; disulfides ; density functional theory ; rate coefficient ; variational transition state theory
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| CAS No. : | 882-33-7 |
| Formula : | C12H10S2 |
| M.W : | 218.34 |
| SMILES Code : | C1(SSC2=CC=CC=C2)=CC=CC=C1 |
| English Name : | 1,2-Diphenyldisulfane |
| MDL No. : | MFCD00003065 |
| InChI Key : | GUUVPOWQJOLRAS-UHFFFAOYSA-N |
| Pubchem ID : | 13436 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 96% | With sodium hydroxide; sodium tris(acetoxy)borohydride In tetrahydrofuran for 2.5h; Heating; | |
| 95% | With borohydride exchange resin In methanol for 3h; Ambient temperature; | |
| 95% | With zinc In acetonitrile for 12h; Ambient temperature; |
| 92% | With hydrogenchloride; zinc In water at 20℃; for 0.25h; Ionic liquid; Inert atmosphere; | General procedure for the synthesis of diorganyl selenides and sulfides: commercially available Zn dust (33 mg, 0.5 mmol) and PhSeSePh/PhSSPh (0.5 mmol) and 15 μL of HCl 1N were added to BMIM-BF4 (0.5 mL) at room temperature under nitrogen. The mixture was allowed to stir for 2-3 min. Then corresponding organic halides (1 mmol) was slowly added. The reaction mixture was allowed to stir until the color change (monitored by TLC and assisted by visual observation). The mixture was then extracted with ether (3×15 mL), and the combined ether extract was washed with brine, dried (MgSO4), and evaporated to leave the crude product. Purification by column chromatography over silica gel (hexane/ethyl acetate 98:2) furnished the corresponding products. |
| 85% | With tin(ll) chloride; copper(ll) bromide at 20℃; for 0.5h; Inert atmosphere; Ionic liquid; | General Procedure for the synthesis of diorganyl selenide and sulfides General procedure: In a schlenk tube, under argon atmosphere, diaryl dichalcogenide (0.5 mmol) SnCl2 (1.2 mmol) and CuBr2 (0.1 mmol) were added to BMIM-BF4 (0.5 mL) at room temperature. Then organic halide (1.1 mmol) was slowly added. The reaction mixture was stirred 60 min to afford the corresponding diorganyl selenide whereas 30 minute reaction time was used for the synthesis of diorganyl sulfide. After completion of the reaction, (monitored by TLC) the mixture was then extracted with diethylether (5x 10 mL), and the combined ether extract was washed with brine, dried (MgSO4) and evaporated to leave the crude products which were purified by column chromatography. |
| 80% | Stage #1: diphenyldisulfane With zirconium(IV) chloride; zinc In tetrahydrofuran at 40℃; for 5h; Stage #2: benzyl chloride In tetrahydrofuran | |
| 80% | With triphenylphosphine; 1-pentyl-3-methylimidazolium bromide at 75℃; for 2.5h; | Representative procedure for the synthesis of benzyl phenyl sulfide (Table 2, entry 2a). General procedure: A mixture of benzyl bromide (171 mg, 1 mmol), diphenyl disulfide (131 mg, 0.6 mmol), PPh3 (184 mg, 0.7 mmol), and [pmIm]Br21 (94 mg, 0.4 mmol) was stirred at 75 °C for 1.5 h (TLC). The reaction mixture was extracted with Et2O, and the organic layer was washed with brine (2 × 5 mL) and dried (Na2SO4). Evaporation of solvent left the crude product which was purified by column chromatography over silica gel (hexane) to afford the pure product, benzyl phenyl sulfide (168 mg, 84%) as a colorless liquid; IR (neat) 3058, 3028, 2923, 1581, 1495, 1479, 1452, 1438, 1238, 1090, 1068, 1024 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.21 (s, 2H), 7.32-7.41 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 39.5, 127.6, 128.0, 129.0 (2C), 129.3 (2C), 129.5 (2C), 130.3 (2C), 136.9, 137.9. The spectroscopic (FT-IR, 1H NMR and 13C NMR) data are in good agreement with the reported values.9b The remaining ionic liquid was washed with ether, dried under vacuum, and reused five times without appreciable loss of catalytic activity. |
| 75% | With indium iodide In dichloromethane at 20℃; for 3h; | |
| With sodium hydroxide | ||
| 80 %Chromat. | With indium In dichloromethane for 3h; Reflux; Inert atmosphere; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | With Fe(tetrabenzoporphyrin); diisopropylamine In tetrahydrofuran at 60℃; for 24h; | |
| 91% | With copper(l) iodide; dimethyl sulfoxide; diethylamine at 30℃; for 20h; air atmosphere; | |
| 78% | With dihydrogen peroxide; iodine In water at 80℃; for 12h; | General Experimental Procedure General procedure: Diaryl disulfide (0.5 mmol), H-phosphonate (2.5 mmol), I2 (0.1 mmol) and 30% H2O2 (0.5 mmol) were taken in a 25 mL two-neck flask under air. The reaction mixture was stirred at 80 °C for 12 h. Water (20 mL) was added and then the mixture was extracted with EtOAc (4×10 mL). The extracts were combined and washed by brine (3×10 mL), dried over MgSO4, filtered, and evaporated, and purified by chromatography on silica gel to obtain the desired products with ethyl acetate/hexane (v/v=1:31:10). The products were characterized by their spectral and analytical data and compared with those of the known compounds. O,O-Diethyl S-phenyl phosphorothioate (3a) Colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.59-7.55(m, 2H), 7.37-7.34 (m, 3H), 4.26-4.13 (m, 4H), 1.31 (t, J=7.0Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 134.5 (d, J=5.2 Hz),129.2 (d, J=2.2 Hz), 128.9 (d, J=2.7 Hz), 126.7 (d, J=7.1Hz), 64.0 (d, J=6.3 Hz), 16.0 (d, J=7.0 Hz); GC-MS (EI,m/z): 246 [M+]. |
| 76% | With di-tert-butyl peroxide In dimethyl sulfoxide at 80℃; for 20h; Inert atmosphere; | 1 General procedure of the coupling between disulfides and diethyl phosphite (3a, 3e, 3p, 3r, 3u, 3v) General procedure: A Schlenk tube was charged with disulfide 4 (0.5mmol), dialkyl phosphite 2 (2.0mmol), and DTBP (2.0mmol), then 1.5mL DMSO was added as solvent. This reaction was performed under N2 atmosphere at 80°C for 20h. After completion of the reaction, the mixture was quenched with 20mL Na2S2O4 solution (5%) then extracted with ethyl acetate (15mL×3). The organic layer was combined and dried with anhydrous Na2SO4. After the evaporation in a vacuum, the crude product was purified by a gel column chromatography using petroleum ether/ ethyl acetate as eluent to afford the desired product 3. |
| 68% | With zinc In ethanol at 20℃; for 0.5h; Green chemistry; | Synthesis of Selenophosphoric acid O,O'-diethyl ester Se-phenyl ester (3a, Table 2): General procedure: In a oven dried 10 mL round bottom flask, diphenyl diselenide (156 mg, 0.5 mmol), diethyl phosphite (128 µL, 1 mmol), zinc dust (33 mg, 0.5 mmol), dry EtOH (2 mL) were added and stirred for 30 mins. at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction the excess EtOH was evaporated and the crude reaction mixture was diluted with water (3 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography (hexane/ethyl acetate as eluent) to afford the pure product (235 mg, 80%). |
| 63% | at 100℃; for 48h; | 28 Synthesize (3z3) using diphenyl disulfide (1a) and diethyl phosphite (2z3) as raw materials : 0.3 mmol of diphenyl disulfide (1a) and 0.3 mmol of diethyl phosphite (2z3) were added to the reaction flask and reacted at 100° C. until the raw materials disappeared completely. Dichloromethane and saturated sodium carbonate aqueous solution were added for extraction three times, and the organic phases were combined and dried to obtain a colorless transparent liquid with a yield of 63%. |
| 63% | In neat (no solvent) at 100℃; for 48h; Sealed tube; Green chemistry; | Experimental Procedure. General procedure: Disulfide 1 (0.3 mmol, 1.0 equiv.) and P(O)H compound 2 (0.3 mmol, 1.0 equiv.) were added to a 4 mL sealed tube and the mixture was then stirred at the corresponding temperature in air for several hours. The reaction was monitored by TLC. After completion of the reaction, DCM (10 mL) was added and the mixture was washed with saturated Na2CO3 solution (3 × 10 mL). During this weak alkali wash process, mercaptan was removed and recovered efficiently. The combined organic layer was dried over anhydrous Na2SO4 and concentrated by vacuum. In most cases, the products were obtained without any further purification. In some cases, the residues were purified by flash column chromatography on silica gel to provide the corresponding product with good to excellent yields. |
| 61% | With iodine; caesium carbonate In tetrahydrofuran; methanol at 20℃; for 0.0833333h; | 11 4.1 typical procedure for the preparation of chalcogenophosphates General procedure: Dialkyl phosphite 1 (0.24mmol), dichalcogenide 2 (0.10mmol), I2 (0.2mmol) and Cs2CO3 (0.3mmol) were added successively to a mixed solvent MeOH/THF (v/v, 3/1) (4mL). The mixture was vigorously stirred at r.t. for several minutes (monitored by TLC). Upon completion, the reaction was quenched by addition of sat. aq. Na2S2O3 (2mL) and H2O (5mL), respectively. Then the water phase was extracted with CH2Cl2 (3×5mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was finally purified on a silica gel plate (petroleum ether/ethyl acetate, 3/1) to furnish chalcogenophosphate 3. |
| 57% | With tetraethylammonium chloride In acetonitrile at 25℃; Flow reactor; Electrochemical reaction; Green chemistry; | 1.5 General procedure for electrochemical selenenylations of phosphonates (GP) General procedure: The electrolysis was performed in an undivided cell using a Vapourtec Ion Electrochemical FlowReactor (reactor volume = 0.6 mL, spacer 0.5 mm) using a Graphite (Gr) electrode as the anodeand a platinum (Pt) electrode as the cathode (surface area: A = 12 cm2). A solution of phosphonates(0.2 M in CH3CN) placed in vial A and mixture of diphenyl diselenide (0.05M) and Et4NCl(0.01M) in CH3CN was placed in vail B. Each solution was injected to 8 mL sample loop. Afterthat, the reactor temperature was set at 25 °C with the flow rate 1.2 mL min-1 and the current wasset at 96 mA turn on automatically. Then, both solutions were pumped into a PTFE coil (1 mminternal diameter) and mix via a T-piece connected to 30 cm PTFE coil before the inlet of theelectrochemical rector. After reaching a steady state, the solution (12 mL) was collectedautomatically into a collection glass vial. The solvent was removed under vacuum. The crudeproduct was purified by column chromatography (EtOAc/ Cyclohexane). |
| 41% | With 2,2'-azobis(isobutyronitrile) In benzene at 60 - 65℃; for 192h; | |
| With tetraethylammonium perchlorate; sodium bromide In acetonitrile | ||
| >95 % | With copper acetylacetonate; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In toluene; acetonitrile at 70℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | at 20℃; for 3h; | 3 Synthesis (3c) from diphenyl disulfide (1a) and bis(4-chlorophenyl)phosphine oxide (2c): 0.3 mmol of diphenyl disulfide (1a) and 0.3 mmol of bis(4-chlorophenyl)phosphine oxide (2c) were added to a reaction flask and reacted at room temperature until the raw materials disappeared completely. Dichloromethane and saturated sodium carbonate aqueous solution were added for extraction three times, and the organic phases were combined and dried to obtain an oily liquid with a yield of 88%. |
| 88% | In neat (no solvent) at 25℃; for 3h; Sealed tube; Green chemistry; | Experimental Procedure. General procedure: Disulfide 1 (0.3 mmol, 1.0 equiv.) and P(O)H compound 2 (0.3 mmol, 1.0 equiv.) were added to a 4 mL sealed tube and the mixture was then stirred at the corresponding temperature in air for several hours. The reaction was monitored by TLC. After completion of the reaction, DCM (10 mL) was added and the mixture was washed with saturated Na2CO3 solution (3 × 10 mL). During this weak alkali wash process, mercaptan was removed and recovered efficiently. The combined organic layer was dried over anhydrous Na2SO4 and concentrated by vacuum. In most cases, the products were obtained without any further purification. In some cases, the residues were purified by flash column chromatography on silica gel to provide the corresponding product with good to excellent yields. |
| With hydroquinone In <i>tert</i>-butyl alcohol |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99% | With silica gel In neat (no solvent) at 20℃; for 6h; Green chemistry; | |
| 75% | at 20℃; for 3h; | 11 Synthesis (3k) using diphenyl disulfide (1a) and bis(p-methylphenyl)phosphine oxide (2k) as raw materials: 0.3 mmol of diphenyl disulfide (1a) and 0.3 mmol of bis(p-methylphenyl)phosphine oxide (2k) were added to a reaction flask and reacted at room temperature until the raw materials disappeared completely. Dichloromethane and saturated sodium carbonate aqueous solution were added for extraction three times, and the organic phases were combined and dried to obtain white needle-like crystals with a yield of 75%. |
| 75% | In neat (no solvent) at 25℃; for 3h; Sealed tube; Green chemistry; | Experimental Procedure. General procedure: Disulfide 1 (0.3 mmol, 1.0 equiv.) and P(O)H compound 2 (0.3 mmol, 1.0 equiv.) were added to a 4 mL sealed tube and the mixture was then stirred at the corresponding temperature in air for several hours. The reaction was monitored by TLC. After completion of the reaction, DCM (10 mL) was added and the mixture was washed with saturated Na2CO3 solution (3 × 10 mL). During this weak alkali wash process, mercaptan was removed and recovered efficiently. The combined organic layer was dried over anhydrous Na2SO4 and concentrated by vacuum. In most cases, the products were obtained without any further purification. In some cases, the residues were purified by flash column chromatography on silica gel to provide the corresponding product with good to excellent yields. |
| With hydroquinone In <i>tert</i>-butyl alcohol |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | at 70℃; for 1h; | 4 Synthesis (3d) from diphenyl disulfide (1a) and bis(4-bromophenyl)phosphine oxide (2d): 0.3 mmol of diphenyl disulfide (1a) and 0.3 mmol of bis(4-bromophenyl)phosphine oxide (2d) were added to a reaction flask and reacted at 70°C until the raw materials disappeared completely. Dichloromethane and saturated sodium carbonate aqueous solution were added for extraction three times, and the organic phases were combined and dried to obtain a white powder with a yield of 90%. |
| 90% | In neat (no solvent) at 70℃; for 1h; Sealed tube; Green chemistry; | Experimental Procedure. General procedure: Disulfide 1 (0.3 mmol, 1.0 equiv.) and P(O)H compound 2 (0.3 mmol, 1.0 equiv.) were added to a 4 mL sealed tube and the mixture was then stirred at the corresponding temperature in air for several hours. The reaction was monitored by TLC. After completion of the reaction, DCM (10 mL) was added and the mixture was washed with saturated Na2CO3 solution (3 × 10 mL). During this weak alkali wash process, mercaptan was removed and recovered efficiently. The combined organic layer was dried over anhydrous Na2SO4 and concentrated by vacuum. In most cases, the products were obtained without any further purification. In some cases, the residues were purified by flash column chromatography on silica gel to provide the corresponding product with good to excellent yields. |
| With hydroquinone In <i>tert</i>-butyl alcohol |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | at 70℃; for 3h; | 5 Synthesis (3e) using diphenyl disulfide (1a) and bis(4-trifluoromethylphenyl)phosphine oxide (2e) as raw materials: 0.3 mmol of diphenyl disulfide (1a) and 0.36 mmol of bis(4-trifluoromethylphenyl)phosphine oxide (2e) were added to a reaction flask and reacted at 70°C until the raw materials disappeared completely. Dichloromethane and saturated sodium carbonate aqueous solution were added for extraction three times, and the organic phases were combined and dried to obtain yellow-white needle-shaped crystals with a yield of 95%. |
| 95% | In neat (no solvent) at 70℃; for 3h; Sealed tube; Green chemistry; | Experimental Procedure. General procedure: Disulfide 1 (0.3 mmol, 1.0 equiv.) and P(O)H compound 2 (0.3 mmol, 1.0 equiv.) were added to a 4 mL sealed tube and the mixture was then stirred at the corresponding temperature in air for several hours. The reaction was monitored by TLC. After completion of the reaction, DCM (10 mL) was added and the mixture was washed with saturated Na2CO3 solution (3 × 10 mL). During this weak alkali wash process, mercaptan was removed and recovered efficiently. The combined organic layer was dried over anhydrous Na2SO4 and concentrated by vacuum. In most cases, the products were obtained without any further purification. In some cases, the residues were purified by flash column chromatography on silica gel to provide the corresponding product with good to excellent yields. |
| With hydroquinone In <i>tert</i>-butyl alcohol |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With n-butyllithium In tetrahydrofuran at 0℃; for 12h; | |
| 75% | Stage #1: 2-(furan-3-yl)ethan-1-ol With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; for 1h; Inert atmosphere; Stage #2: diphenyldisulfane In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99% | With potassium carbonate In dimethyl sulfoxide at 100℃; for 9h; Green chemistry; | |
| 99% | With iodine; toluene-4-sulfonic acid In 1,2-dichloro-ethane at 80℃; for 12h; regioselective reaction; | |
| 98% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 25℃; for 1h; | 1; 2; 3 Example 1 Add 4mL of reaction bottles separatelyIndole(0.2mmol),1,2-diphenyldisulfide (0.3 mmol),Potassium tert-butoxide(0.4 mmol) and DMF (2.0 mL),Stir at room temperature.TLC tracks the detection reaction.After 1 hour, the starting material was completely converted.Water and dichloromethane were added to the reaction system, and the organic layer was separated.Wash the aqueous layer twice with dichloromethane and combine all the organic layers.Wash twice with water.The organic layer was dried over anhydrous sodium sulfate and concentrated.Separation by column chromatography (9% ethyl acetate petroleum ether solution),Get product(CAS number: 54491-43-9) 43.6mg,The yield was 98% and the reaction process was as follows: |
| 98% | With iron(III) chloride; potassium iodide In dimethyl sulfoxide at 60℃; for 8h; | General procedure for preparation FeCl3/KI mediated chalcogenylation of indoles derivatives General procedure: A mixture of indole 1a-f (1.0 mmol), dichalcogenide 2a-i or 4a-f (0.5 mmol), FeCl3 (10 mol%) and KI (10 mol%) in DMSO (2 mL) was stirred at 60 °C for 3 h until complete consumption of the starting material, as monitored by TLC. After the reaction was finished, the mixture was poured into EtOAc (15 mL) and washed with sat. NaCl soln (3 × 10 mL), followed by extraction of the aqueous layer with EtOAc (5 × 3 mL). The combined organic layer was dried (anhyd Mg2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane-EtOAc) to afford the 3-chalcogenyl indole product. |
| 98% | With selenium(IV) oxide; potassium iodide In acetonitrile at 60℃; for 1.5h; | |
| 98% | With iron(III) chloride; potassium iodide In dimethyl sulfoxide at 60℃; for 3h; | 3.2 Preparation of selenylindoles and thiophenylindoles General procedure: In a dried test tube (25 mL) or a round-bottom flask (15 mL) equipped with amagnetic stir bar, the indole derivative (1.0 mmol), diorganoyl dichalcogenide (0.5 mmol),FeCl3 (10 mol%) and KI (10 mol%) were dissolved in DMSO (2 mL). The reaction wasstirred at 60 °C for 3 h until complete consumption of the starting materials, as monitoredby TLC. After the reaction was finished, 15 mL of EtOAc was added to the reaction flask,and the organic phase was washed with aqueous saturated solution of NaCl (3 × 10 mL).Then, the organic layer was dried over anhydrous MgSO4, filtered and concentratedunder reduced pressure. The residue was further purified by column chromatography onsilica gel (hexane/EtOAc gradient) to afford the selanylindole or sulfanylindole EQ-30 toEQ-44. |
| 96% | With iodine; dimethyl sulfoxide In carbonic acid dimethyl ester at 40℃; for 6h; | |
| 95% | With dipotassium peroxodisulfate; iodine In water; acetonitrile at 60℃; for 8h; Green chemistry; | Procedure (e) A mixture of indole 1a (0.5 mmol), diphenyl disulfide 2a (0.25 mmol), I (10 mol%,0.05 mmol), and KSO (0.75 mmol) was placed in a glass tube. MeCN/HO (5:1, 2 mL) wasadded, and the reaction mixture was vigorously stirred at 60 °C for 8 h. The mixture was filteredthrough a pad of silica gel, which was diluted with water (10 mL) and extracted three timeswith ethyl acetate (10 mL each). The combined organic layers were dried over anhydrousNaSO and concentrated under reduced pressure. The crude residue was purified by silica-gelcolumn chromatography using hexane/ethyl acetate as the eluent to afford the corresponding3-sulfenylindole 3a in 95% yield. |
| 94% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 2h; | |
| 93% | With N-Bromosuccinimide In N,N-dimethyl-formamide at -15℃; for 2h; regioselective reaction; | |
| 93% | With cesiumhydroxide monohydrate In water at 70℃; for 5h; Schlenk technique; regiospecific reaction; | 3. Experimental procedure and characterization data of 3a-3y, 3ya, 3yb General procedure: Indole (0.5 mmol), diaryl disulfides (0.25 mmol), CsOH·H2O (0.75 mmol) and H2O (0.2mL) were added to a 10 ml Schlenk tube. Then the mixture was stirred at 70 °C, under air for 5 hours. After the reaction finished, the mixture was extracted with ethyl acetate (3 mL × 3). The upper layer of organic solvent is slowly drawn out with a syringe. The remaining trace water phase is used for the next cycle. The organic phase was dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to afford corresponding product 3. |
| 93% | With cesiumhydroxide monohydrate In water at 70℃; for 5h; Schlenk technique; regiospecific reaction; | 3. Experimental procedure and characterization data of 3a-3y, 3ya, 3yb General procedure: Indole (0.5 mmol), diaryl disulfides (0.25 mmol), CsOH·H2O (0.75 mmol) and H2O (0.2mL) were added to a 10 ml Schlenk tube. Then the mixture was stirred at 70 °C, under air for 5 hours. After the reaction finished, the mixture was extracted with ethyl acetate (3 mL × 3). The upper layer of organic solvent is slowly drawn out with a syringe. The remaining trace water phase is used for the next cycle. The organic phase was dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to afford corresponding product 3. |
| 92% | With iodine; dimethyl sulfoxide In neat (no solvent) at 80℃; for 0.0833333h; Microwave irradiation; Sealed tube; Green chemistry; | |
| 91% | With caesium carbonate In 1,4-dioxane at 130℃; for 32h; Sealed tube; Inert atmosphere; | |
| 90% | With iron(III) trifluoride; iodine In acetonitrile at 80℃; for 36h; regioselective reaction; | |
| 90% | With iodine In ethanol at 20℃; for 12h; | Typical experimental procedure for the iodine-promoteddirect 3-selanyl- and 3-sulfenylation of indoles withdichalcogenides General procedure: indole (0.5 mmol), disulfide (0.28 mmol), I2 (0.25 mmol), and EtOH (3 mL) were added to a Schlenk tube or round-bottomed flask and stirred at room temperature for 12 h. After the reaction was finished, the reaction mixture was washed with sodium thiosulfate. Then the mixture was extracted with ethyl acetate.The combined organic extracts were dried over Na2SO4, concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography to afford the desired product. Complete characterization of the products and selected 1Hand 13C NMR spectra for 3, 4, and 5 are presented in the Supplemental Materials (Figures S1-S6) |
| 88% | With 1-benzyl-3-butyl-2-ethylimidazolium tetrafluoroborate; caesium carbonate at 80℃; for 15h; Green chemistry; | |
| 87% | With (Dichloroiodo)benzene In N,N-dimethyl-formamide at 20℃; for 0.5h; Darkness; | |
| 86% | With sodium tetrafluoroborate; potassium iodide In acetonitrile at 60℃; for 12h; Electrolysis; | Electrosynthesis of 3-sulfenylindoles General procedure: The electrochemical experiment was performed on 263A Potentiostat/Galvanostat (PrincetonApplied Research, USA) in a 25 mL undivided cell. Two graphite rods(6mmin diameter, 1 cm in length) were employed as the working electrode and the counter electrode respectively. The reference electrode was Ag/Ag+ electrode (0.1 mol/L AgNO3 in CH3CN). 2-Methylindole(1a, 1.0 mmol), diphenyl disulfide (2a, 0.5 mmol) and KI (0.05 mmol) were added into 0.1 mol/L of NaBF4/CH3CN solution (15 mL)with stirring at 60°C. The electrolysis reactions were operated at 0.4V. After completion of the reaction (monitored by GC or TLC), the resulting mixture was concentrated under reduced pressure and purified by column chromatography on silica gel using hexanes/EtOAc(100:1) as eluent to afford 2-methyl-3-(phenylthio)-indole (3aa) as a white solid in 94% yield. |
| 86% | With sodium tetrafluoroborate; potassium iodide In acetonitrile at 60℃; for 12h; Electrochemical reaction; | 35 Example 35: Preparation of 3-phenylthio-1H-indole (Formula 20) Add in a 30ml beaker 0.1 mol/L sodium tetrafluoroborate in acetonitrile solution (15 mL),1H-indole (1 mmol), diphenyl disulfide (0.5 mmol) and potassium iodide (0.05 mmol). Constant potential electrolysis at 60 ° C, 0.4 V, and the reaction was completed after 12 h. The solvent is distilled off under reduced pressure, and then subjected to column chromatography. The mixture is eluted with ethyl acetate / n-hexane in a ratio of 1:100 as an eluent, and the eluent containing the target compound is collected, and the solvent is distilled off to obtain the product 3- Phenylthio-1H-indole. The isolated yield was 86%. |
| 83% | With oxygen; acetic acid; potassium iodide; sodium nitrite In acetonitrile at 60℃; for 2h; Sealed tube; Green chemistry; regioselective reaction; | 3-[(3-Methoxyphenyl)thio]-1H-indole (3aa):Typical Procedure General procedure: A 15 mL tube equipped with a magnetic stirring bar wascharged with 1H-indole (0.5 mmol), sodium S-(3-methoxyphenyl)thiosulfate (0.6 mmol), KI (20 mol%), and NaNO2 (10 mol%).The tube was then sealed with a rubber plug, and MeCN (3 mL)and HOAc (0.5 mL) were injected into the tube. The air in thetube was replaced by charging with oxygen, and the mixturewas stirred under an oxygen atmosphere (balloon) at 80 °Cuntil the reaction was complete (GC). The mixture was cooledto r.t. and the solvent was removed under vacuum. The residuewas washed with 10% aq Na2S2O3 (30 mL) and extracted withCH2Cl2 (4 × 20 mL). The organic layer was then dried (Na2SO4)and concentrated under vacuum. The residue was further purifiedby flash column chromatography (silica gel, PE-Et2O) togive a light-yellow solid; yield: 92 mg (72%); mp 87.6-88.4 °C. |
| 82% | With silver nitrate In ethanol; N,N-dimethyl-formamide at 110℃; for 13h; | |
| 82% | With potassium iodate; glycerol In neat (no solvent) at 100℃; for 6h; Inert atmosphere; Schlenk technique; | |
| 78% | With silver nitrate In ethanol; N,N-dimethyl-formamide at 70℃; for 8h; Sealed tube; | Typical Procedure for the Preparation of Products 3. General procedure: Disulfides 1 (0.2 mmol), indoles 2 (0.3 mmol),AgNO3 (1 equiv, 0.2 mmol), and EtOH/DMF (v:v = 1:1) was added respectively to the an oven-driedsealed tube with a magnetic stirrer bar. The vial was sealed with a cap. The mixture was stirred at 70 °Cfor 8 h. And reaction progress was monitored by TLC. When the reaction time was over, the reactionmixture was cooled to room temperature. The precipitated silver mercaptide was filtered and the solventremoved at reduced pressure. The product was extracted with EtOAc (3×10 mL). The EtOAc layer wasdried with anhydrous MgSO4, and the solvent was then removed under vacuum. The residue was purifiedby column chromatography (silica gel, 200-300 mesh) using EtOAc/petroleum ether (V:V = 1:10) aseluent to afford the product 3. |
| 76% | With ammonium iodide; water; acetic acid; dimethyl sulfoxide at 110℃; for 6h; Green chemistry; regioselective reaction; | 30 4.2.1. General procedure for synthesis General procedure: N-heteroarene (0.25 mmol), diorganyl dichalcogenide (0.125 mmol) NH4I (0.025 mmol, 10 mol%, 3.6 mg), acetic acid (1 eq.) and the mixture of DMSO/H2O (2.5:2.5 eq.) were placed into a round-bottom flask. The reaction was stirred at 110 °C in an oil bath for appropriate time (Tables 3-6). After the completion of the reaction, the mixture was cooled to room temperature, quenched with water and the aqueous layer was extracted with EtOAc. The organic phase was dried over MgSO4, filtered, and the volatiles were completely removed under vacuum to give the crude product. Purification by flash chromatography on silica with a mixture of Hexane/EtOAc as eluent furnished the desired chalcogenated product. |
| 75% | Stage #1: diphenyldisulfane With trichloroisocyanuric acid In ethyl acetate at 20℃; Stage #2: indole With magnesium oxide In ethyl acetate at 20℃; for 0.0833333h; | 4.2. General synthesis procedure General procedure: TCCA (0.4 mmol, 1.2 equiv) was added to a solution of the diaryl dichalcogenide (0.6 mmol) in EtOAc (5 mL), and the solution was stirred at room temperature until colorless. Then, a mixture of indole (1.0 mmol) and MgO (1.0 mmol) in EtOAc was added and the reaction mixture was stirred at room temperature for the specified time. Then, a saturated solution of NH4Cl (20 mL) and EtOAc (310 mL) were added and the organic phase was separated and successively washed with water (20 mL) and brine (20 mL). The extract was dried over anhydrous MgSO4, concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (hexanes/EtOAc 95:5) to afford the pure products (5ao). |
| 70% | With sodium iodide In acetonitrile at 20℃; for 18h; Irradiation; | Preparation of the benzothiazole 3a General procedure: To a 20 mL glass tube with a stir bar was charged 2-methyl-1H-indole 1a (39.35 mg, 0.3 mmol), diphenyldisulfide 2a (65.50 mg, 0.3 mmol), NaI (0.06 mmol, 9 mg) and MeCN (2 mL). The solution was stirred at room temperature with the irradiation of a 12 W blue LED for 18 h. The solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether/ethyl acetate = 15/1) to give the product 3a (60 mg, 83%). |
| 68% | Stage #1: diphenyldisulfane With ammonium peroxydisulfate In methanol at 70℃; for 3h; Stage #2: indole In methanol at 20 - 70℃; | |
| 67% | With copper(l) iodide; oxygen In dimethyl sulfoxide at 110℃; regioselective reaction; | 4.2. General procedure for chalcogenylation of azaheterocycles with dichalcogenides General procedure: A mixture of azaheterocycles 1 or 4 (0.20 mmol), dichalcogenides 2 (0.10 mmol), and CuI (0.020 mmol, 10 mol %) in DMSO (2.0 mL) was stirred at 110 °C under air atmosphere for 10-18 h until complete consumption of staring material as monitored by TLC. The solution was then cooled to room temperature, diluted with ethyl acetate (10 mL), washed with H2O (3×10 mL), dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (eluting with PE/EA=25/1 to 4/1) to afford the desired products 3 or 5. |
| 44% | With ferric(III) bromide In N,N-dimethyl-formamide at 145℃; for 48h; | |
| 37% | With copper dichloride; palladium dichloride In dimethyl sulfoxide at 120℃; for 12h; Sealed tube; | |
| 25% | With ammonium iodide; 1,10-Phenanthroline; acetic acid In 1,4-dioxane at 100℃; for 6h; Sealed tube; | |
| With n-butyllithium 1.) 0 deg C; Multistep reaction; | ||
| With sodium hydride 1.) DMF, room temp., 2.) room temp., 18 h; Yield given. Multistep reaction; | ||
| With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; | ||
| With iodine at 70℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry; | ||
| 97 %Chromat. | With iodine; dimethyl sulfoxide In 1,2-dichloro-ethane at 60℃; for 3h; regioselective reaction; | |
| 95 % | With bismuth vanadate In acetonitrile at 20℃; Irradiation; | Vulcanized/selenated (hetero)aromatics 13. General procedure: Substrates 8(0.2 mmol, 1 equiv.), 12 (0.4 mmol, 1 equiv.), BiVO4-180 (5mol%, 3.2 mg), and MeCN (2 mL) were sequentially added to a25-mL reaction tube. The reaction mixture was then exposed tolight from a 10-W blue LED at room temperature in open air togive 13ab, 13g, and 13j (after 15 h), 13cf (after 18 h), 13h(after 22 h), and 13i (after 5 h). The solvent was evaporatedunder vacuum, and each crude product was purified by silica-gel column chromatography using 20:1 (v/v) PE/EA as theeluent to give desired products 13. |
| 84% | With iodine; urea hydrogen peroxide adduct In acetonitrile at 20℃; | 2.2. Procedure for the synthesis of 3-Sulfenylindoles General procedure: Indoles (0.5 mmol), disulfides (0.25 mmol), molecular iodine (10 mol%), urea-hydrogen peroxide (1 equiv., 0.5 mmol) and acetonitrile (1 mL) were added in a 10 mL round-bottomed flask and the reactions were carried out at room temperature. The mixture was monitored by thin layer chromatography (TLC) until completion of the reaction. When the reaction was complete, the product was extracted with ethyl acetate. The organic layer was concentrated under vacuum. The pure product was purified by column chromatography over silica gel with mixture of hexane and ethyl acetate as eluent. 2.2.1. 3-(phenylsulfenyl)-1H-indole (6n). 0.0945g; Yield: 84%; white solid; m.p.: 149-151 °C (lit. m.p.: 150-151 °C). 13C NMR (100 MHz, CDCl3) δ = 139.28, 136.56, 130.68, 129.17, 128.73, 125.98, 124.84, 123.09, 120.95, 119.71, 111.61, 102.99. 1H NMR (400 MHz, CDCl3) δ = 8.38 (s, 1H), 7.66 (s, 1H), 7.47 (d, J = 18.3 Hz, 2H), 7.30 (d, J = 10.0 Hz, 1H), 7.24 - 7.07 (m, 6H). |
| 92 % | With iodine In acetonitrile at 20℃; Green chemistry; regioselective reaction; | |
| 36 % | With dipotassium peroxodisulfate; 2,3,4,5,6-pentahydroxy-hexanal In water at 20℃; Green chemistry; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 65% | With iodine In ethanol at 20℃; for 12h; | Typical experimental procedure for the iodine-promoteddirect 3-selanyl- and 3-sulfenylation of indoles withdichalcogenides General procedure: indole (0.5 mmol), disulfide (0.28 mmol), I2 (0.25 mmol), and EtOH (3 mL) were added to a Schlenk tube or round-bottomed flask and stirred at room temperature for 12 h. After the reaction was finished, the reaction mixture was washed with sodium thiosulfate. Then the mixture was extracted with ethyl acetate.The combined organic extracts were dried over Na2SO4, concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography to afford the desired product. Complete characterization of the products and selected 1Hand 13C NMR spectra for 3, 4, and 5 are presented in the Supplemental Materials (Figures S1-S6) |
| 20% | With iron(III) trifluoride; iodine In acetonitrile at 80℃; for 36h; regioselective reaction; | |
| With sodium hydride 1.) DMF, room temp., 2.) 80 deg C, 18 h; Yield given. Multistep reaction; |