tributylborane

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

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

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

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

Procedure: A solution of diisopropylamine (559 μL, 3.99 mmol) in dry tetrahydrofuran (1.2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.99 mmol). The resulting reaction mixture was allowed to warm to 0° C. and then was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 3A, 463.1 mg, 1.22 mmol) in small portions. The reaction mixture turned orange in color. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After 30 min at 25° C., the reaction mixture was cooled back down to 0° C. and then treated with a 1M solution of tributylborane in tetrahydrofuran (1.8 mL, 1.84 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h. The reaction mixture was cooled to 0° C. and then treated with water (3 mL) followed by sodium acetate (702.5 mg, 8.56 mmol) and then finally hydroxyamine-O-sulfonic acid (484.2 mg, 4.28 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. where it was stirred for 44 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide (191.8 mg, 72%) as a white solid: mp 179-181° C.; EI-HRMS m/e calcd for C17H21N3O2S2 (M+) 379.1024, found 379.1029. The resulting reaction mixture to warm to 25° C. where it After 30 min at 25° C. the reaction mixture was cooled back down to 0° C. The resulting reaction mixture was stirred at 0° C. for 10 min to warm to 25° C The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h The reaction mixture was cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min to warm to 25° C. where it was stirred for 44 h The reaction mixture was concentrated in vacuo to remove tetrahydrofuran The resulting aqueous residue was diluted with ethyl acetate (150 mL) The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate filtered concentrated in vacuo

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

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

Procedure: A solution of diisopropylamine (559 μL, 3.99 mmol) in dry tetrahydrofuran (1.2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.99 mmol). The resulting reaction mixture was allowed to warm to 0° C. and then was treated with 3-cyclopentyl-2(-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 3A, 463.1 mg, 1.22 mmol) in small portions. The reaction mixture turned orange in color. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After 30 min at 25° C., the reaction mixture was cooled back down to 0° C. and then treated with a 1M solution of tributylborane in tetrahydrofuran (1.8 mL, 1.84 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h. The reaction mixture was cooled to 0° C. and then treated with water (3 mL) followed by sodium acetate (702.5 mg, 8.56 mmol) and then finally hydroxyamine-O-sulfonic acid (484.2 mg, 4.28 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. where it was stirred for 44 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide (191.8 mg, 72%) as a white solid: mp 179-181° C.; EI-HRMS m/e calcd for C17H21N3O2S2 (M+) 379.1024, found 379.1029. The resulting reaction mixture to warm to 25° C. where it After 30 min at 25° C. the reaction mixture was cooled back down to 0° C. The resulting reaction mixture was stirred at 0° C. for 10 min to warm to 25° C The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h The reaction mixture was cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min to warm to 25° C. where it was stirred for 44 h The reaction mixture was concentrated in vacuo to remove tetrahydrofuran The resulting aqueous residue was diluted with ethyl acetate (150 mL) The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: A solution of diisopropylamine (559 μL, 3.99 mmol) in dry tetrahydrofuran (1.2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.99 mmol). The resulting reaction mixture was allowed to warm to 0° C. and then was treated with 3-cyclopentyl-2(-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 3A, 463.1 mg, 1.22 mmol) in small portions. The reaction mixture turned orange in color. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After 30 min at 25° C., the reaction mixture was cooled back down to 0° C. and then treated with a 1M solution of tributylborane in tetrahydrofuran (1.8 mL, 1.84 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h. The reaction mixture was cooled to 0° C. and then treated with water (3 mL) followed by sodium acetate (702.5 mg, 8.56 mmol) and then finally hydroxyamine-O-sulfonic acid (484.2 mg, 4.28 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. where it was stirred for 44 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide (191.8 mg, 72%) as a white solid: mp 179-181° C.; EI-HRMS m/e calcd for C17H21N3O2S2 (M+) 379.1024, found 379.1029. The resulting reaction mixture to warm to 25° C. where it After 30 min at 25° C. the reaction mixture was cooled back down to 0° C. The resulting reaction mixture was stirred at 0° C. for 10 min to warm to 25° C The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h The reaction mixture was cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min to warm to 25° C. where it was stirred for 44 h The reaction mixture was concentrated in vacuo to remove tetrahydrofuran The resulting aqueous residue was diluted with ethyl acetate (150 mL) The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: A solution of diisopropylamine (559 μL, 3.99 mmol) in dry tetrahydrofuran (1.2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.99 mmol). The resulting reaction mixture was allowed to warm to 0° C. and then was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (463.1 mg, 1.22 mmol) in small portions. The reaction mixture turned orange in color. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After 30 min at 25° C., the reaction mixture was cooled back down to 0° C. and then treated with a 1M solution of tributylborane in tetrahydrofuran (1.8 mL, 1.84 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h. The reaction mixture was cooled to 0° C. and then treated with water (3 mL) followed by sodium acetate (702.5 mg, 8.56 mmol) and then finally hydroxyamine-O-sulfonic acid (484.2 mg, 4.28 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. where it was stirred for 44 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide (191.8 mg, 72%) as a white solid: mp 179-181° C.; EI-HRMS m/e calcd for C17H21N3O2S2 (M+) 379.1024, found 379.1029. The resulting reaction mixture to warm to 25° C. where it After 30 min at 25° C. the reaction mixture was cooled back down to 0° C. The resulting reaction mixture was stirred at 0° C. for 10 min to warm to 25° C The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h The reaction mixture was cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min to warm to 25° C. where it was stirred for 44 h The reaction mixture was concentrated in vacuo to remove tetrahydrofuran The resulting aqueous residue was diluted with ethyl acetate (150 mL) The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: A solution of diisopropylamine (559 μL, 3.99 mmol) in dry tetrahydrofuran (1.2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.99 mmol). The resulting reaction mixture was allowed to warm to 0° C. and then was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 3A, 463.1 mg, 1.22 mmol) in small portions. The reaction mixture turned orange in color. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After 30 min at 25° C., the reaction mixture was cooled back down to 0° C. and then treated with a 1M solution of tributylborane in tetrahydrofuran (1.8 mL, 1.84 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h. The reaction mixture was cooled to 0° C. and then treated with water (3 mL) followed by sodium acetate (702.5 mg, 8.56 mmol) and then finally hydroxyamine-O-sulfonic acid (484.2 mg, 4.28 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. where it was stirred for 44 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide (191.8 mg, 72%) as a white solid: mp 179-181° C.; EI-HRMS m/e calcd for C17H21N3O2S2 (M+) 379.1024, found 379.1029. The resulting reaction mixture to warm to 25° C. where it After 30 min at 25° C. the reaction mixture was cooled back down to 0° C. The resulting reaction mixture was stirred at 0° C. for 10 min to warm to 25° C The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h The reaction mixture was cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min to warm to 25° C. where it was stirred for 44 h The reaction mixture was concentrated in vacuo to remove tetrahydrofuran The resulting aqueous residue was diluted with ethyl acetate (150 mL) The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: A solution of diisopropylamine (559 μL, 3.99 mmol) in dry tetrahydrofuran (1.2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.99 mmol). The resulting reaction mixture was allowed to warm to 0° C. and then was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 3A, 463.1 mg, 1.22 mmol) in small portions. The reaction mixture turned orange in color. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After 30 min at 25° C., the reaction mixture was cooled back down to 0° C. and then treated with a 1M solution of tributylborane in tetrahydrofuran (1.8 mL, 1.84 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h. The reaction mixture was cooled to 0° C. and then treated with water (3 mL) followed by sodium acetate (702.5 mg, 8.56 mmol) and then finally hydroxyamine-O-sulfonic acid (484.2 mg, 4.28 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. where it was stirred for 44 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide (191.8 mg, 72%) as a white solid: mp 179-181° C.; EI-HRMS m/e calcd for C17H21N3O2S2 (M+) 379.1024, found 379.1029. The resulting reaction mixture to warm to 25° C. where it After 30 min at 25° C. the reaction mixture was cooled back down to 0° C. The resulting reaction mixture was stirred at 0° C. for 10 min to warm to 25° C The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h The reaction mixture was cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min to warm to 25° C. where it was stirred for 44 h The reaction mixture was concentrated in vacuo to remove tetrahydrofuran The resulting aqueous residue was diluted with ethyl acetate (150 mL) The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: Under nitrogen, a solution of 4.55 g (13.2 mmol) of 1-[2-(4-fluoro phenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene (from Step 10 of Example 1) in 50 mL of THF at -78° C. was treated with 6.3 mL (0.27 mmol) of n-butylllithium (2.5 M in hexane) over a period of 5 minutes. The reaction was stirred at ambient temperature for 25 minutes, cooled to -78° C., and treated with 19.8 mL (19.8 mmol) of tributylborane (1.0 M in THF). The resulting dark brown solution was stirred at ambient temperature for 30 minutes and then at reflux for 14 hours prior to the addition of 8.7 g (106 mmol) of sodium acetate, 37 mL of water, and 5.2 g (46 mmol) of hydroxyamine-O-sulfonic acid. The resulting light orange mixture was stirred at ambient temperature for 6 hours and the aqueous phase extracted with ethyl acetate. The combined extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 2.0 g (40%) of 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1yl)benzenesulfonamide as a colorless solid: mp 117°-118° C.; NMR (CDCl3) §1.24 (s, 6H), 2.70 (s, 4H), 4.72 (s, 2H), 6.92 (t, J=9 Hz, 2H), 7.09 (dd, J=9 and 7 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.74 (d, J=9 Hz, 2H). HRMS. Calc'd for C19H20FNO2S: 345.1199. Found: 345.1194. Anal. Calc'd for [C19H20FNO2S+0.27 H2O]: C, 65.14; H, 5.91; N, 4.00; S, 9.11. Found: C, 65.07; H, 5.94; N, 3.86; S, 9.29. cooled to -78° C. The resulting dark brown solution was stirred at ambient temperature for 30 minutes at reflux for 14 hours The resulting light orange mixture was stirred at ambient temperature for 6 hours the aqueous phase extracted with ethyl acetate The combined extracts were washed with water, brine dried (MgSO4) concentrated in vacuo The residue was chromatographed on silica gel

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