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Godlewska, Klaudia ; Białk-Bielińska, Anna ; Rostkowski, Pawel ; Paszkiewicz, Monika ;
Abstract: Tire wear particles are generated during driving a vehicle as a result of friction between tires and road surfaces and are released into environment. Knowledge of their environmental occurrence and fate is still limited. In this study, we investigated the presence of 16 tire wear contaminants (TWCs) and their transformation products in the surface waters, tap water and soils in Poland.The developed extraction methods were used with recoveries in the range of 71–100% (except for 2-methylthio-benzothiazole - 51%) for water samples and in the range of 62–97% for soil samples. Ten TWCs were detected in soil samples, with the highest concentration of benzothiazole (BTH)(387 ng/g). Meanwhile, all analytes were detected in water samples, also with the highest concentration of BTH (326 ng/L). N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q), 1,3-diphenylguanidine (DPG) and BTH were detected in all examined surface waters. P-phenylenediamine-quinones(PPD-Qs)were detected in higher concentrations (1.85–297 ng/l) compared to the parent compounds (0.50–58 ng/l) in surface waters. Conversely, for soil samples, PPDs (0.170–116 ng/g) were more prevalent than PPD-Qs (0.167–4.71 ng/g). 6PPD-Q showed high ecological risks at all surface water sites. This is the first report on the TWCs levels in the environment in Poland.
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Keywords: Tire wear contaminants ; Transformation products ; 6PPD-Q ; Environmental analysis ; Environmental risk assessment
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| CAS No. : | 615-22-5 |
| Formula : | C8H7NS2 |
| M.W : | 181.28 |
| SMILES Code : | CSC1=NC2=C(S1)C=CC=C2 |
| English Name : | 2-(Methylthio)benzo[d]thiazole |
| MDL No. : | MFCD00005784 |
| InChI Key : | UTBVIMLZIRIFFR-UHFFFAOYSA-N |
| Pubchem ID : | 11989 |
* 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 |
|---|---|---|
| Reaktion ueber mehrere Stufen; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | at 100℃; for 0.25h; | |
| 92% | In acetonitrile for 12h; Reflux; | |
| 90% | In acetonitrile at 80℃; for 24h; |
| 83.4% | In acetonitrile at 80℃; for 8h; | |
| 83% | In acetonitrile at 80℃; for 12h; | |
| 82% | at 50℃; | |
| 76% | In methanol for 15h; Reflux; | 4.1.2. Synthesis of 3-methyl-2-(methylthio)benzothiazol-3-ium iodide (2) 2-(Methylthio)benzothiazole (1.02 g, 5.6 mmol) was placed in a round-bottom flask, and methyl iodide (1.03 mL, 16.53 mmol) was added at room temperature. The reaction mixture was heated to reflux at 100 C for 15 h. After completion, the product was precipitated by addition of isopropyl ether, and the resulting solid was washed with ethyl acetate to afford a white solid (1.38 g, 4.3 mmol) in 76.0% yield. 1H NMR (600 MHz, DMSO-d6) δ 8.41 (dd, J =8.2, 1.2 Hz, 1H), 8.22-8.18 (m, 1H), 7.85 (ddd, J =8.5, 7.3, 1.2 Hz, 1H), 7.73 (ddd, J =8.2, 7.2, 1.0 Hz, 1H), 4.12 (s, 3H), 3.14 (s, 3H). MS(ESI) m/z: [M]+calculated for C9H10N3S2+196.02; found 195.87. |
| 72.2% | In methanol at 43℃; for 24h; | |
| 65% | at 50 - 60℃; for 12h; | |
| 47% | In acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere; | |
| 40% | In ethanol at 50℃; for 5h; | |
| at 45 - 55℃; for 17.5h; sealed tube; | ||
| In methanol at 80℃; for 8h; Sealed tube; Inert atmosphere; | ||
| In acetonitrile at 90℃; for 8h; | 1 Synthesis of 3-methyl-2-(methylthio)benzo[d]thiazole iodide (V) Weigh 1g (1.103mmol/L) of 2-methylthiobenzothiazole (IX) into an explosion-proof bottle, and 8mL of acetonitrile as a solvent.Ultrasonic vibration makes the two mixed evenly; under the condition of a fume hood, add methyl iodide (2.206mmol/L), put the reaction system in an oil bath at 90 and turn on the magnetic stirring for 8h; after the reaction is over, cool the system to room temperature , Then add 10 mL of ethyl acetate and shake well, let it stand for 15 minutes, and precipitate a solid, which is vacuum filtered.The filter cake was washed with 5 mL of ethyl acetate and dried to obtain 1.07 g of white solid 3-methyl-2-(methylthio)benzo[d]thiazole iodide (V). The reaction equation is as shown in formula (1) As shown, thin plate chromatography showed no by-products, and the crude yield was 60%. | |
| In acetonitrile at 90℃; | 1 Example 1: Synthesis of the compound shown in formula (V). Weigh 1.0g (1.103mM) of 2-methylthiobenzothiazole (IV.) into an explosion-proof bottle, 8mL acetonitrile as solvent, ultrasonic shaking to mix the two evenly; Under the condition of fume hood, twice the molar amount (2.206mM) of methyl iodide was added, the reaction system was placed in the oil bath and the magnetic stirring was turned on, the reaction temperature was 90 °C, and the reaction time was 8h; After the reaction is cooled to room temperature after the end of the reaction, 10mL of ethyl acetate is added to fully shake, standing for 15min, solids are precipitated, vacuum filtered, and the filter cake is rinsed with 5mL of ethyl acetate, and 1.07g of white solid (V.) is obtained by drying, and the thin plate chromatography shows no by-products, and the crude yield is 60%. | |
| 92 % | at 100℃; | |
| 83.4 % | In acetonitrile at 80℃; | |
| In N,N-dimethyl-formamide | ||
| at 50 - 60℃; | 3 Synthesis of 3-methyl-2-(methylthio)benzo[d]thiazole iodide 2-(Methylthio)benzo[d]thiazole (4.30 g, 23.70 mmol) and CH3I (13.39 g, 95.02 mmol) were heated at 50-60° C. for 12 hours. After the reaction was completed, the yellow salt was washed with ether to remove the unreacted thioether. The yellow solid obtained was 3-methyl-2-(methylthio)benzo[d]thiazole iodide. | |
| at 50 - 60℃; | 3 Synthesis of 3-methyl-2-(methylthio)benzo[d]thiazole iodide 2-(Methylthio)benzo[d]thiazole (4.30 g, 23.70 mmol) and CH3I (13.39 g, 95.02 mmol) were heated at 50-60° C. for 12 hours. After the reaction was completed, the yellow salt was washed with ether to remove the unreacted thioether. The yellow solid obtained was 3-methyl-2-(methylthio)benzo[d]thiazole iodide. | |
| 11.5 % | at 50℃; Inert atmosphere; | |
| In acetonitrile Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99.7% | With sodium hypochlorite In water; toluene at 20℃; for 2.5h; | 11 (Example 11) 2-(methylthio)benzothiazole (1.00 g, 5.52 mmol) and cyanuric acid (71 mg, 0.55 mmol) were mixed with toluene (20 mL). 10% aqueous solution of sodium hypochlorite (13.6 g, 18.2 mmol) was added to the mixture at room temperature, and it was stirred for 2.5 hours. After that, sodium sulfite (696 mg, 5.52 mmol) and water (10 mL) were added to the reaction mixture, and it was extracted with ethyl acetate (10 mL). An organic layer was concentrated under reduced pressure, and the residue was subjected to purification by means of a silica gel column to obtain 2-(methylsulfonyl)benzothiazole (1.17 g, yield: 99.7 %). 1H-NMR (300MHz, CDCl3) δ 3.42 (3H, s), 7.57-7.68 (2H, m), 7.99-8.05 (1H, m), 8.19-8.24 (1H, m) |
| 99% | With sodium hypochlorite; water; Cyanuric acid In toluene at 20℃; for 2.5h; Inert atmosphere; | |
| 94% | With chromium(VI) oxide; periodic acid In ethyl acetate; acetonitrile at 0℃; for 1.75h; |
| 94% | With H(Py)H3PMo11VO40; dihydrogen peroxide In water; acetonitrile at 40℃; for 4h; | General procedure: The oxidation of methyl phenyl sulfide to methyl phenyl sulfoxide or methyl phenyl sulfone (Scheme 1) was typically carried out bystirring a solution of 0.7 mmol of the substrate and 0.01 mmol of the catalyst in 5 mL of acetonitrile, at 20 or 40 °C, respectively. Theoxidant used was H2O2 35% in aqueous solution (2 or 20 mmol,respectively). The sample was collected from the reaction mixtureduring the reaction at time intervals. About 20 μL of the reactionmixture was taken for each sample, which was then diluted in amixture of water-dichloromethane (2 mL). The dichloromethanelayer was dried with anhydrous sodium sulfate and filtered. GC/MSanalyses were performed on an HP 5971 mass detector coupled to anHP gas chromatograph fitted with a 30 m×0.25 mm DB5 capillarycolumn. The percentages of each compound in the reaction mixturewere directly estimated from the corresponding chromatographicpeak areas. The yield (%) of pure sulfoxide or sulfone, the turnovernumber (TON: product mol×catalyst mol-1) and turnover frequency(TOF: product mol×catalyst mol-1×h-1) were also calculated. Under these optimum conditions and using M11PV1Py1 ascatalyst, different sulfides were oxidized to sulfoxides (for 30 min)and to sulfones (for 2.5 and 3.5 h) depending on the substrate. |
| 94% | With sodium tungstate (VI) dihydrate; dihydrogen peroxide In ethanol; water at 20℃; | |
| 93% | With dihydrogen peroxide In water; butan-1-ol at 50℃; for 8h; | |
| 89% | With sodium hypochlorite In water; toluene at 20℃; for 2h; | Sulfones 6; General Procedure for Small-Scale Oxidation of Sulfides 4 General procedure: A 13 wt% aq NaOCl solution (12.8 g, 24 mmol), prepared in advancefrom NaOCl·5H2O and H2O, was added in one portion to a solution ofsulfide 4 (10 mmol) in toluene (10 mL or 30 mL) at 20 °C. The mixturewas stirred at the same temperature and monitored using TLC or GC.The reaction was quenched with aq Na2SO3 (10 mL) and the mixturewas extracted with EtOAc (3 × 30 mL). The combined extracts weredried over anhydrous Na2SO4 and concentrated to yield sulfone 6. Ifnecessary, the residue was purified by column chromatography (silicagel) to obtain pure 6. |
| 88% | With Oxone; water at 60℃; for 12h; chemoselective reaction; | |
| 88% | With ammonium molybdate tetrahydrate; dihydrogen peroxide In ethanol at 25℃; Inert atmosphere; | |
| 86% | With hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide In ethanol at 0 - 20℃; Inert atmosphere; | |
| 84% | Stage #1: 2-methylmercaptobenzothiazole With sodium tungstate (VI) dihydrate In ethanol at 0℃; for 0.0833333h; Stage #2: With dihydrogen peroxide In ethanol; water at 0 - 20℃; for 10.5h; | |
| 82% | With dihydrogen peroxide In water; acetonitrile at 50℃; for 3h; chemoselective reaction; | General procedure for the oxidation of sulfide to sulfone General procedure: A solution of sulfide (1 mmol) and catalyst (100 mg), in acetonitrile (9 mL), was added to H2O2 35% (w/v) (10 mmol). The mixture was stirred at 50 °C for a time period (see Tables 1 and 2). The solvent was evaporated and then H2O (5 mL) was added. The substrate was extracted with toluene (2 × mL) and dried with anhydrous Na2SO4; filtration and evaporation afforded the corresponding sulfoxides. The crude solids were purified by recrystallization to affordthe pure sulfones |
| 81% | With potassium permanganate In acetic acid for 0.5h; Ambient temperature; | |
| 73% | With Oxone In water at 60℃; for 14h; | 2-(Methylsulfonyl)benzothiazole (MSBT) Oxone (4.61 g, 7.49 mmol) was added to asolution of 2-(methylthio)benzothiazole (908 mg, 5.01 mmol) in water (25 mL). The mixturewas stirred at 60 °C for 14 h. The mixture was then cooled to room temperature, and theproduct was extracted with EtOAc (25 mL × 4). The mixture was dried over Na2SO4 andconcentrated. Purification by silica gel column chromatography (hexane/EtOAc (2:1))followed by recrystallization from THF/hexane afforded MSBT as a white solid (783 mg,73%). |
| 70% | With dihydrogen peroxide In ethanol; water for 1h; Reflux; | |
| With potassium permanganate; acetic acid | ||
| With potassium permanganate | ||
| With 3-chloro-benzenecarboperoxoic acid | ||
| With potassium permanganate | ||
| With ammonium molybdate tetrahydrate; dihydrogen peroxide In ethanol at 0℃; for 18h; Yield given; | ||
| With potassium permanganate; acetic acid at 25℃; for 2h; Yield given; | ||
| With potassium permanganate In water; acetic acid at 20℃; for 48.5h; | 3.6 To a solution of 2-methylsulfanyl-benzothiazole (1.22, 6.7 mmol) dissolved in 15 mL of acetic acid was added potassium permanganate (1.81 g, 1.7 eq.) in 17 mL of H2O. The resulting mixture was heated for 30 min and stirred at RT for over 48 h. The reaction was quenched with NaHSO3, and the pH of the solution was adjusted to 8 with NH4OH. The reaction was extracted with EtOAc, the EtOAc layer was washed with H2O, dried over Na2SO4 and concentrated to give the desired product, 2-methanesulfonyl-benzothiazole: (M)+: 213. | |
| 12.323 g | With sodium periodate; ruthenium(III) chloride trihydrate In tetrachloromethane; water; acetonitrile at 20℃; for 12h; Inert atmosphere; Schlenk technique; | |
| 96.2 %Chromat. | With sodium hypochlorite pentahydrate In water; toluene at 20 - 21.7℃; for 2.01667h; | 24 As a substrate in a 50 mL three-necked flask1.81 g (10 mmol) of 2- (methylthio) benzothiazole,And 10 mL of toluene,While stirring in a water bath at 20 ° C.,to this,12.86 g (24 mmol, pH 11) of a solution in which the effective chlorine concentration was reduced to 13% by thinning the sodium hypochlorite pentahydrate crystal with water was added at once.The reaction temperature rose to 21.7 ° C after 1 minute and gradually approached 20 ° C.Two hours laterGC analysis revealed that 96.2% of 2- (methylsulfonyl) benzothiazole was formed as a product. |
| With ruthenium trichloride; sodium periodate In tetrachloromethane; water; acetonitrile at 20℃; for 5h; | ||
| With oxone In water at 60℃; | ||
| 10.6 g | With chromium(VI) oxide; periodic acid In acetonitrile at 0 - 20℃; Inert atmosphere; | |
| With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; | ||
| 42 % | With oxygen; sodium 4-dodecylbenzenesulfonate In water at 25℃; Irradiation; Schlenk technique; Green chemistry; | |
| With hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide In ethanol at 0 - 20℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With sulfuric acid; nitric acid at 0℃; for 1h; | |
| With nitric acid | ||
| 5.7 g (25 mmol, 91%) | With nitric acid In sulfuric acid | 1 Preparation of 2-(methylthio)-6-nitrobenzothiazole (7). Preparation of 2-(methylthio)-6-nitrobenzothiazole (7). See FIG. 4A 1.93 g of fuming nitric acid was added dropwise to a solution of 5 g of 2-(methylthio)benzothiazole in 16.8 g concentrated sulfuric acid cooled in an ice bath. After stirring at 5° C. for 3 h, the solution was poured onto ice and filtered to provide 5.7 g (25 mmol, 91%) 7 as a yellow solid. |
| With nitric acid In sulfuric acid | 1 Preparation of 2-(methylthio)-6-nitrobenzothiazole 7 Preparation of 2-(methylthio)-6-nitrobenzothiazole 7 See FIG. 4A. Fuming nitric acid (1.93 g) was added dropwise to a solution of 2-(methylthio)benzothiazole (5 g) in concentrated sulfuric acid (16.8 g) cooled in an ice bath. After stirring at 5° C. for 3 h the solution was poured onto ice and filtered to provide a yellow solid (5.7 g, 25 mmol, 91%). | |
| With nitric acid |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 55% | With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 24h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 24h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 1: 21% 2: 36% 3: 64% |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 48% | In toluene for 72h; Ambient temperature; Yields of byproduct given; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 67% | In toluene for 0.33h; Ambient temperature; Yields of byproduct given; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 1: 91% 2: 17% 3: 83% |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 1: 70.2% 2: 20.4% | at 100℃; for 4h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 50% | With N-chloro-succinimide; Perbenzoic acid In tetrachloromethane at 90℃; for 3h; | |
| Multi-step reaction with 2 steps 1: 70 percent / m-chloroperbenzoic acid / CHCl3 / 16 h / Ambient temperature 2: 28 percent / p-nitrobenzoyl chloride / CH2Cl2 / 1 h / 50 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 84% | Stage #1: 2-methylmercaptobenzothiazole With sodium tungstate (VI) dihydrate In ethanol at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: With dihydrogen peroxide In ethanol; water at 0 - 20℃; for 10.5h; Inert atmosphere; | |
| 1: 78% 2: 17% | With dihydrogen peroxide at 50℃; for 7h; | |
| 1: 78% 2: 17% | With phosphotungstic acid; poly(acrylamide) based ammonium salt; dihydrogen peroxide at 50℃; for 7h; |
| 1: 55% 2: 24% | With urea hydrogen peroxide; 1-butyl-3-methylimidazolium Tetrafluoroborate at 0℃; for 24h; Electrochemical reaction; | |
| 1: 69 %Chromat. 2: 30 %Chromat. | With dihydrogen peroxide In water; acetonitrile at 40℃; for 5h; | 2.3 Catalytic tests The oxidation of 2-(methylthio)-benzothiazole to the corresponding sulfoxide or sulfone (scheme 1) was carried out in a reactor batch at atmospheric pressure by stirring a solution of 1mmol of the substrate and 100mg of the catalyst in 9 mL of acetonitrile, which was immersed in an oil bath with temperature control at the required temperatures (20-60°C). The oxidant used was H2O2 35% (w/v) in aqueous solution (0.1-1mL). Aliquots were withdrawn from the reaction mixture during the reaction at different time intervals. GC/MS analyses were performed on HP 5971 mass detector coupled to HP gas chromatograph fitted with a 30m ×0.5mm DB5 capillary column. The percentages of each compound in the reaction mixture were directly estimated from the corresponding chromatographic peak areas. The conversion was calculated as mol% of consumed substrate and the selectivity as mol% of the product to mol of substrate. Blank experiments without catalyst and using only the support were performed. After reaction, the catalyst was filtered, washed thoroughly with acetonitrile (2 × 3mL), dried under vacuum, and reused in the oxidation reaction, following the procedure described above. 2.4 Product identification 2.4a Mass spectra of 2-(methylthio)-benzothiazolesulfoxide: m/z (I %) 197 (62) M+.; 182 (78); 153 (60);151 (100); 150 (64); 134 (42%); 123 (15); 108 (25); 90(26); 50 (30); 39 (98). 2.4b Mass spectra of 2-(methylthio)-benzothiazolesulfone: m/z (I %): 197 (18) M+.; 150 (100); 134 (42);108 (20); 90 (25); 50 (24); 39 (74). 2.4c Mass spectra of 2-hydroxybenzothiazole: m/z (I%): 151 (100) M+.; 123 (55); 96 (57); 45 (60); 39 (50). |
| With KTi0.2Nb0.8O3; dihydrogen peroxide In water; acetonitrile at 40℃; for 1h; | The catalytic selective oxidation of 2-(methylthio)benzothiazole with H2O2 as the oxidizing agent was carried out in a glass reactor (25cm3) with magnetic stirring, immersed in a thermostated bath and equipped with a reflux condenser. The catalytic tests were performed from room temperature to 60°C evaluating different reaction conditions such as the mass of catalyst and different molar ratios of sulfide/H2O2 (R). Several solvents with different dielectric constants were tested. Prior to analysis, the catalyst was separated out by filtration. Organic compounds were quantitatively analyzed by gas chromatography (Perkin Elmer Clarus 500) with a HP1 capillary column and a FID as well as qualitatively by GC-MS (Shimadzu QP 5050 GC-17 A) using a HP-5 (25m×0.2mm i.d) capillary column. | |
| With dihydrogen peroxide In water; acetonitrile at 40℃; for 5h; | 2.3 Catalytic activity 2-(Methylmercapto)-benzothiazole (2-MMBT) (97%, Aldrich) oxidation reactions were performed employing H2O2 (aqueous solution 30wt%, Cicarelli) as oxidant agent in a glass flask reactor (25cm3) with magnetic stirring immersed in a thermostatized bath, equipped with a reflux condenser. The standard catalytic tests were done at 40°C during 5h, in a 2-MMBT/hydrogen peroxide molar ratio of 0.1, employing acetonitrile (99.5%, Cicarelli) as solvent and 100mg of the selected catalyst. Nevertheless, temperature was varied from 25 to 60°C, solvents of different characteristics (polarity and proticity) were tested and different types of catalysts and concentrations were also evaluated. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94% | Stage #1: 2-methylmercaptobenzothiazole With chlorosulfonic acid at -78 - 60℃; Inert atmosphere; Stage #2: With thionyl chloride for 1h; Reflux; | 2 2-(Methylthio)benzo[d]thiazole-6-sulfonyl chloride (37) Chlorosulfonic acid (5.1 mL, 77.35 mmol) was added to 2- (Methylthio)benzothiazole (36) (2 g, 11 mmol) slowly (very exothermic) at - 78°C under argon atmosphere. The reaction mixture was warmed to 23°C and stirred at 60o C for 90 min. Again, the mixture was cooled to 23°C before adding thionyl chloride (1.2 mL, 16.57 mmol). The reaction mixture was stirred at reflux for 1 h and cool to 23°C. EtOAc and water were added to the cooled mixture slowly until bubbles ceased. Two layers were separated, organic layer was concentrated, dried (Na2SO4) and purified by silica gel column chromatography to give 37 (2.9 g, 94 % yield). (0131) [0094] 1H NMR (500 MHz, CDCl3) δ: 8.46 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 9.0, 2.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 2.85 (s, 3H). (0132) [0095] 13C NMR (125 MHz, CDCl3) δ: 175.9, 157.4, 139.5, 136.0, 125.0, 122.1, 121.1, 16.3. |
| Stage #1: 2-methylmercaptobenzothiazole With chlorosulfonic acid Stage #2: With thionyl chloride |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With potassium hexamethylsilazane In toluene at 60℃; for 24h; Schlenk technique; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | Stage #1: 2-methylmercaptobenzothiazole In acetonitrile at 20℃; for 0.0833333h; Stage #2: 2-(2-iodoethyl)-1,3-dioxolane In acetonitrile for 40h; Reflux; | 1.1 (1) Synthesis of Intermediate 1 and Intermediate 2 PREPARATION EXAMPLES Preparation Example 1. Synthesis of Compound 1 (1) Synthesis of Intermediate 1 and Intermediate 2 2-(methylthio)benzothiazole (11.115 g, 0.0614 mol) and acetonitrile (110 mL) were added to a 250 mL single-neck reactor, and the mixture was stirred at room temperature for 5 minutes. Then, oxolane, i.e., 2-iodoethyl-1,3-dioxolane (21 g, 0.0921 mol) was added to the reactor, and the mixture was stirred under reflux for 40 hours, cooled, concentrated, and then purified by column to obtain Intermediate 1 (14 g, 0.0523 mol, 85%). 1H-NMR (400 MHz, CDCl3) δ 7.45-7.48 (m, 1H), 7.38-7.43 (m, 1H), 7.26-7.32 (m, 2H), 5.00 (t, J=4.0 Hz, 1H), 4.54-4.58 (m, 2H), 3.89-4.02 (m, 4H), 2.18-2.23 (m, 2H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 40% | With tetrakis(triphenylphosphine) palladium(0); copper(I) thiophene-2-carboxylate; zinc diacetate In tetrahydrofuran at 60℃; Inert atmosphere; Schlenk technique; | |
| 42 % | With tetrakis(triphenylphosphine) palladium(0); copper(I) 3-methylsalicylate; lithium tert-butoxide In tetrahydrofuran at 25℃; Inert atmosphere; Schlenk technique; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 64% | With tetrakis(triphenylphosphine) palladium(0); copper(I) thiophene-2-carboxylate; zinc diacetate In tetrahydrofuran at 60℃; for 18h; Inert atmosphere; Schlenk technique; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 84% | With tetrakis(triphenylphosphine) palladium(0); copper(I) thiophene-2-carboxylate; zinc diacetate In tetrahydrofuran at 60℃; Inert atmosphere; Schlenk technique; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With 1,1'-bis(diphenylphosphanyl)ferrocene; Potassium phosphate, dibasic; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II); palladium diacetate; zinc powder In N,N-dimethyl acetamide at 100℃; for 12h; Inert atmosphere; Molecular sieve; | 7 Example 7 Combine 1.0 equiv of benzothiazole methyl sulfide (0.2 mmol, 36.2 mg), 1.0 equiv of 1-bromo-4-methoxybenzene (0.2 mmol, 37.2 mg), Pd(OAc)2 (0.02 mmol, 4.5 mg) ) and Ni(dppe)Cl2 (0.02mmol, 10.6mg), 1-1'-bis(diphenylphosphorus)ferrocene (0.02mmol, 11.1mg), 2.0 equivalents of dipotassium hydrogen phosphate (0.4mmol, 69.7 mg) and 2.5 equivalents of zinc powder (0.5 mmol, 32.5 mg) were placed in the reaction vial. After three nitrogen purges, dry dimethylacetamide (2.0 mL) was added. After stirring at 100°C for 12 hours, saturated sodium chloride solution was added to the reaction system to quench the reaction, then the organic phase was extracted three times with dichloromethane, the organic phase was dewatered by anhydrous sodium sulfate, then the organic solvent was removed under reduced pressure, and the organic phase was removed by rapid Column machine gave a yellow liquid (24.7 mg, 80%). |
| 80% | With 1,1'-bis(diphenylphosphanyl)ferrocene; Potassium phosphate, dibasic; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II); palladium diacetate; zinc powder In N,N-dimethyl acetamide at 100℃; for 12h; Inert atmosphere; Schlenk technique; Molecular sieve; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 78% | With 1,1'-bis(diphenylphosphanyl)ferrocene; Potassium phosphate, dibasic; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II); palladium diacetate; zinc powder In N,N-dimethyl acetamide at 100℃; for 12h; Inert atmosphere; Molecular sieve; | 13 Example 13 Combine 1.0 equiv of benzothiazole methyl sulfide (0.2 mmol, 36.2 mg), 1.0 equiv of methyl 4-bromobenzoate (0.2 mmol, 42.8 mg), Pd(OAc) 2 (0.02 mmol, 4.5 mg) and Ni and 2.5 equivalents of zinc powder (0.5 mmol, 32.5 mg) were placed in the reaction vial. After three nitrogen purges, dry dimethylacetamide (2.0 mL) was added. After stirring at 100°C for 12 hours, saturated sodium chloride solution was added to the reaction system to quench the reaction, then the organic phase was extracted three times with dichloromethane, the organic phase was dewatered by anhydrous sodium sulfate, then the organic solvent was removed under reduced pressure, and the organic phase was removed by rapid Column machine gave a colorless liquid (28.5 mg, 78%). |
| 78% | With 1,1'-bis(diphenylphosphanyl)ferrocene; Potassium phosphate, dibasic; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II); palladium diacetate; zinc powder In N,N-dimethyl acetamide at 100℃; for 12h; Inert atmosphere; Schlenk technique; Molecular sieve; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 61% | With 1,1'-bis(diphenylphosphanyl)ferrocene; Potassium phosphate, dibasic; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II); palladium diacetate; zinc powder In N,N-dimethyl acetamide at 100℃; for 12h; Inert atmosphere; Molecular sieve; | 16 Example 16 Combine 2.0 equiv of benzothiazole methyl sulfide (0.4 mmol, 72.4 mg), 1.0 equiv of 1,4-dibromobenzene (0.2 mmol, 47.2 mg), Pd(OAc) 2 (0.04 mmol, 9.0 mg) and Ni (dppe)Cl2 (0.04mmol, 21.2mg),1-1'-Bis(diphenylphosphonium)ferrocene (0.04 mmol, 22.2 mg), 4.0 equiv of dipotassium hydrogen phosphate (0.8 mmol, 140.0 mg) and 5.0 equiv of zinc powder (1.0 mmol, 65.0 mg) into the reaction flask. After three nitrogen purges, dry dimethylacetamide (4.0 mL) was added. After stirring at 100 °C for 12 hours, saturated sodium chloride solution was added to the reaction system to quench the reaction, then the organic phase was extracted three times with dichloromethane, the organic phase was dewatered by anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure, and the organic phase was removed by rapid Column machine gave a colorless liquid (41.4 mg, 61%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 61% | With 1,1'-bis(diphenylphosphanyl)ferrocene; Potassium phosphate, dibasic; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II); palladium diacetate; zinc powder In N,N-dimethyl acetamide at 100℃; for 12h; Inert atmosphere; Schlenk technique; Molecular sieve; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95 % | With tetrakis(triphenylphosphine) palladium(0); copper(I) 3-methylsalicylate; lithium tert-butoxide In tetrahydrofuran at 25℃; Inert atmosphere; Schlenk technique; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92 % | With tetrakis(triphenylphosphine) palladium(0); copper(I) 3-methylsalicylate; lithium tert-butoxide In tetrahydrofuran at 25℃; Inert atmosphere; Schlenk technique; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 68 % | With tetrakis(triphenylphosphine) palladium(0); copper(I) 3-methylsalicylate; lithium tert-butoxide In tetrahydrofuran at 25℃; Inert atmosphere; Schlenk technique; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 49.7 mg | With tetrakis(triphenylphosphine) palladium(0); copper(I) 3-methylsalicylate; lithium tert-butoxide In tetrahydrofuran at 25℃; Inert atmosphere; Schlenk technique; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81 % | With tetrakis(triphenylphosphine) palladium(0); copper(I) 3-methylsalicylate; lithium tert-butoxide In tetrahydrofuran at 25℃; Inert atmosphere; Schlenk technique; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 71% | With 1,1'-bis-(diphenylphosphino)ferrocene; (1,2-dimethoxyethane)dichloronickel(II); molybdenum hexacarbonyl In 1,4-dioxane at 100℃; for 12h; Schlenk technique; Inert atmosphere; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | With 1,1'-bis-(diphenylphosphino)ferrocene; (1,2-dimethoxyethane)dichloronickel(II); molybdenum hexacarbonyl In 1,4-dioxane at 100℃; for 12h; Schlenk technique; Inert atmosphere; Sealed tube; |