2-tert-butylbenzenethiol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 2-t-butyl-thiophenol (0.216 g, 1.3 mmol), Nat-BuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-heptane: ethyl acetate 8:2) to give 440 mg of the title compound as colorless oil (yield 71%). 1H NMR (CDCl3) δ 8.00-8.10 (m, 2H), 7.15-7.65 (m, 7H), 3.60-3.70 (m, 1H), 3.30-3.45 (m, 4H), 3.05-3.20 (m, 3H), 1.55 (s, 9H), 1.50 (s, 9H). The reaction mixture was filtered The filtrate was concentrated the residue was dissolved in ethyl acetate The organic phase was washed with water (50 mL×3) separated dried (MgSO4) filtered The volatiles were evaporated the residue was purified by flash column chromatography (SiO2, n-heptane: ethyl acetate 8:2)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 2-t-butyl-thiophenol (0.216 g, 1.3 mmol), Nat-BuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-heptane: ethyl acetate 8:2) to give 440 mg of the title compound as colorless oil (yield 71%). 1H NMR (CDCl3) δ 8.00-8.10 (m, 2H), 7.15-7.65 (m, 7H), 3.60-3.70 (m, 1H), 3.30-3.45 (m, 4H), 3.05-3.20 (m, 3H), 1.55 (s, 9H), 1.50 (s, 9H). The reaction mixture was filtered The filtrate was concentrated the residue was dissolved in ethyl acetate The organic phase was washed with water (50 mL×3) separated dried (MgSO4) filtered The volatiles were evaporated the residue was purified by flash column chromatography (SiO2, n-heptane: ethyl acetate 8:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-tert-butyl-benzenethiol (5.0 g, 24.09 mmol) in acetone (25 mL) is reacted with 2,3-dichloro-propene (2.2 mL, 24.09 mmol) and K2CO3 (4.3 g, 31.32 mmol) at reflux overnight. It is cooled to rt and filtered and washed with EtOAc, and concentrated. The crude material is purified by chromatography gives the title compound (5.66 g, 23.58 mmol, 98%). 1H NMR (CDCl3): δ 1.52 (s, 9H), 3.77 (s, 2H), 5.27 (bs, 1H), 5.31 (bs, 1H), 7.11-7.20 (m, 2H), 7.36-7.43 (m, 1H) ppm. ES-MS (m/z): calcd for C13H17CIS M+: 240.8. found: 240.9. at reflux overnight filtered washed with EtOAc concentrated The crude material is purified by chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-tert-butyl-benzenethiol (5.0 g, 24.09 mmol) in acetone (25 mL) is reacted with 2,3-dichloro-propene (2.2 mL, 24.09 mmol) and K2CO3 (4.3 g, 31.32 mmol) at reflux overnight. It is cooled to rt and filtered and washed with EtOAc, and concentrated. The crude material is purified by chromatography gives the title compound (5.66 g, 23.58 mmol, 98%). 1H NMR (CDCl3): δ 1.52 (s, 9H), 3.77 (s, 2H), 5.27 (bs, 1H), 5.31 (bs, 1H), 7.11-7.20 (m, 2H), 7.36-7.43 (m, 1H) ppm. ES-MS (m/z): calcd for C13H17CIS M+: 240.8. found: 240.9. at reflux overnight filtered washed with EtOAc concentrated The crude material is purified by chromatography

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tetramethylethylenediamine (198.4 mmol, 30 mL) in cyclohexane (140 mL) is slowly added n-BuLi (198.4 mmol, 99.2 mL; 2M solution in cyclohexane) at 23° C. The resulting solution is cooled to 0° C. A solution of 2-tert-butylthiophenol (15.0 g, 90.2 mmol) in cyclohexane (40 mL) is then added at a rate such that the temperature stays below 10° C. The reaction is then stirred at 0° C. for 5 h and is then allowed to warm to 23° C. overnight. To the resulting yellow solution at 23° C. is added sec-BuLi (90.2 mmol, 69.4 mL of 1.3M solution in cyclohexane) over 0.5 h. The resulting solution gradually turns orange. After 1.5 h, the orange, cloudy reaction mixture is cannulated into a stirring solution of 1,2-dibromotetrafluoroethane (180.4 mmol, 21.5 mL) in THF (50 mL) over 1 h. After addition is complete, the resulting reaction mixture is quenched with 1N HCl (80 mL), and extracted with hexanes (3×100 mL). The hexanes are dried (MgSO4) and evaporated to a dark oil (29.48 g). This oil is taken up in 1N NaOH (100 mL), and extracted with CH2 Cl2 (3×50 mL). The organic phase is discarded, and the aqueous phase is acidified with 12N HCl, and extracted with CH2Cl2 (3×100 mL). The organic phase is dried (MgSO4) and evaporated to provide the title compound as a yellow oil. at 23° C stays below 10° C to warm to 23° C. overnight After 1.5 h the orange, cloudy reaction mixture After addition the resulting reaction mixture is quenched with 1N HCl (80 mL) extracted with hexanes (3×100 mL) The hexanes are dried (MgSO4) evaporated to a dark oil (29.48 g) extracted with CH2 Cl2 (3×50 mL) extracted with CH2Cl2 (3×100 mL) The organic phase is dried (MgSO4) evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tetramethylethylenediamine (198.4 mmol, 30 mL) in cyclohexane (140 mL) is slowly added n-BuLi (198.4 mmol, 99.2 mL; 2M solution in cyclohexane) at 23° C. The resulting solution is cooled to 0° C. A solution of 2-tert-butylthiophenol (15.0 g, 90.2 mmol) in cyclohexane (40 mL) is then added at a rate such that the temperature stays below 10° C. The reaction is then stirred at 0° C. for 5 h and is then allowed to warm to 23° C. overnight. To the resulting yellow solution at 23° C. is added sec-BuLi (90.2 mmol, 69.4 mL of 1.3M solution in cyclohexane) over 0.5 h. The resulting solution gradually turns orange. After 1.5 h, the orange, cloudy reaction mixture is cannulated into a stirring solution of 1,2-dibromotetrafluoroethane (180.4 mmol, 21.5 mL) in THF (50 mL) over 1 h. After addition is complete, the resulting reaction mixture is quenched with 1N HCl (80 mL), and extracted with hexanes (3×100 mL). The hexanes are dried (MgSO4) and evaporated to a dark oil (29.48 g). This oil is taken up in 1N NaOH (100 mL), and extracted with CH2 Cl2 (3×50 mL). The organic phase is discarded, and the aqueous phase is acidified with 12N HCl, and extracted with CH2Cl2 (3×100 mL). The organic phase is dried (MgSO4) and evaporated to provide the title compound as a yellow oil. at 23° C stays below 10° C to warm to 23° C. overnight After 1.5 h the orange, cloudy reaction mixture After addition the resulting reaction mixture is quenched with 1N HCl (80 mL) extracted with hexanes (3×100 mL) The hexanes are dried (MgSO4) evaporated to a dark oil (29.48 g) extracted with CH2 Cl2 (3×50 mL) extracted with CH2Cl2 (3×100 mL) The organic phase is dried (MgSO4) evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of freshly distilled tetramethylethylenediamine (7.5 mL, 50 mmol) in dry cyclohexane (35 mL) is added dropwise at 24° C. a solution of n-butyl lithium in hexanes (31 mL, 50 mmol). After addition is complete, the reaction mixture is cooled to 0° C. A solution of 2-tert-butylthiophenol (3.77 g, 22.7 mmol) in dry cyclohexane (10 mL) is added at a rate such that the reaction temperature stays below 10° C. The reaction is allowed to stir at 24° C. for 14 h. A solution of sec-butyl lithium in hexanes (17.5 mL, 22.7 mmol) is added at this temperature, and the color of the reaction changes from yellow to orange. After 1 h, the reaction mixture is added at -78° C. to a solution of 1,2-dibromotetrafluoroethane (5.4 mL, 45.4 mmol) in dry tetrahydrofuran (100 mL). The mixture is allowed to warm to 24° C., and is partitioned against 0.1N HCl (100 mL). The organic phase is dried (MgSO4), filtered and evaporated to give 2-bromo-6-tert-butylthiophenol as a yellow oil. After addition stays below 10° C the color of the reaction changes from yellow to orange After 1 h to warm to 24° C. is partitioned against 0.1N HCl (100 mL) The organic phase is dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cold stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.20 g, 12.7 mmol) and triethylamine (1.54 g, 15.2 mmol) in THF (60.0 mL) was added methanesulfonyl chloride (1.60 g, 14.0 mmol) and the resulting reaction mixture was warmed to room temperature. After 2 h the reaction mixture was filtered and filtrate concentrated under reduced pressure. The residue was dissolved in toluene (30.0 mL), added to a stirred solution of 80% 2-tert-butylthiophenol (2.12 g, 10.2 mmol), tetrabutylammonium bromide (0.41 g, 1.27 mmol) and sodium hydroxide (4.80 ml of 8.0 M solution in water, 38.4 mmol) in toluene (30.0 mL) and the resulting reaction mixture was heated at 100° C. for 3 h. Then, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and separated. The organic layer was washed with water, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95:5 to 80:20 heptane/ethyl acetate) provided tert-butyl 3-(2-tert-butylphenylthio)azetidine-1-carboxylate (1.80 g, 55%) as a pale yellow oil. the resulting reaction mixture After 2 h the reaction mixture was filtered filtrate concentrated under reduced pressure The residue was dissolved in toluene (30.0 mL) the resulting reaction mixture was heated at 100° C. for 3 h Then, the reaction mixture was cooled to room temperature separated The organic layer was washed with water, saturated sodium chloride dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by flash column chromatography (silica gel, 95:5 to 80:20 heptane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-4-nitrobenzene and 4.9 grams of 2-t-butylbenzenethiol, there was obtained 1.46 grams of 1,2-dicyano-3-(2-t-butylphenylthio)benzene (yield of 50%). Next, as in Synthesis Example 1 but using 1.46 grams of this benzene compound and 0.42 gram of BBr3 l there was obtained 0.73 gram of the end product (yield 45%, mp 160°-161° C.). As in Synthesis Example 1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a well stirred solution of the carbamate (30.0 g, 0.127 mol) dissolved in 500 ml of methanol was added a solution of sodium hydroxide (15.2 g, 0.38 mol) in methanol (100 ml). The resulting mixture was stirred at room temperature for 30 min followed by gentle reflux (1.5 h) to completion (TLC). Usual work-up followed by flash chromatography yielded 2-tert-butylbenzenethiol (18.0 g, 86% yield) as a pale yellow liquid. by gentle reflux (1.5 h) to completion (TLC)