3-(2-tert-butylphenoxy)azetidine

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:0.00; pressure:0.00; stir:

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

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

Procedure: To a stirred solution of 3-(2-tert-Butylphenoxy)azetidine (0.21 g, 1.02 mmol) in pyridine (10 ml) was added ethyl isocyanate (0.078 g, 1.10 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water and saturated sodium chloride, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was triturated with heptane/ethyl acetate to provide 3-(2-tert-Butylphenoxy)-N-ethylazetidine-1-carboxamide (0.15 g, 53%) as a white powder. The reaction mixture was concentrated under reduced pressure the resulting residue was partitioned between ethyl acetate and 1N hydrochloric acid The organic layer was washed with water and saturated sodium chloride dried (MgSO4) filtered concentrated under reduced pressure The resulting residue was triturated with heptane/ethyl acetate

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

Procedure: To a stirred solution of sodium imidazo[1,2-a]pyridine-2-carboxylate (0.19 g, 1.0 mmol), 3-(2-tert-butylphenoxy)azetidine (0.21 g, 0.53 mmol) and DIPEA (0.39 g, 3.0 mmol) in DMF (5.0 mL) was added HBTU (0.76 g, 2.0 mmol) at room temperature. After 1 h the reaction mixture was diluted with ethyl acetate (50 mL) and washed with a 10% K2CO3 solution (3×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, ethyl acetate to 95:5 methanol/ethyl acetate) to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(imidazo[1,2-a]pyridin-2-yl)methanone (0.18 g, 51%) as a white solid. washed with a 10% K2CO3 solution (3×20 mL) dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by flash column chromatography (silica gel, ethyl acetate to 95:5 methanol/ethyl acetate)

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

Procedure: To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.18 g, 0.80 mmol) and triethylamine (0.24 g, 2.4 mmol) in methylene chloride (4.0 mL) was added 5-methylisoxazole-3-carbonyl chloride (0.12 g, 0.80 mmol) at room temperature. After 2 h the reaction mixture was directly purified by flash column chromatography (silica gel, 80:20 heptane/ethyl acetate) to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(5-methylisoxazol-3-yl)methanone (0.21 g, 83%) as a white solid. After 2 h the reaction mixture was directly purified by flash column chromatography (silica gel, 80:20 heptane/ethyl acetate)

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

Procedure: To an ice-cold stirred solution of 4-ethoxy-4-oxobutanoic acid (0.42 g, 2.56 mmol) and DMF (0.03 ml) in THF (15 mL) was added oxalyl chloride (0.35 g, 2.72 mmol). After 1 h the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (5.0 mL) and the solution was added to an ice-cold solution of 3-(2-tert-butylphenoxy)azetidine (0.35 g, 1.70 mmol) and triethylamine (0.31 g, 3.06 mmol) in THF (30.0 ml) and the resulting reaction mixture was warmed to room temperature. After 16 h the reaction mixture was filtered, the filtrate was partitioned between ethyl acetate and water and separated. The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide ethyl 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutanoate (0.51 g, 90%) as a colorless oil. After 1 h the reaction mixture was concentrated under reduced pressure The resulting residue was dissolved in THF (5.0 mL) the resulting reaction mixture After 16 h the reaction mixture was filtered the filtrate was partitioned between ethyl acetate and water separated The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate)

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

Procedure: To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.35 g, 1.70 mmol), ethyl hydrogen malonate (0.25 g, 1.87 mmol) in methylene chloride (20.0 mL) was added EDCI (0.36 g, 1.87 mmol) and HOBt (0.25 g, 1.87 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure, the resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide ethyl 3-(3-(2-tert-butylphenoxy)azetidin-1-yl)-3-oxopropanoate (0.29 g, 53%) as a colorless oil. After 16 h the reaction mixture was concentrated under reduced pressure the resulting residue was partitioned between ethyl acetate and water separated The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate)

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

Procedure: To an ice-cold stirred solution of 3-(2-tert-butylphenoxy)azetidine (2.00 g, 9.74 mmol) in pyridine (20.0 ml) was added picolinoyl chloride hydrochloride (2.08 g, 11.7 mmol). After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3 and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered by a pad of silica gel and concentrated under reduced pressure. The residue was purified with flash column chromatography (silica gel, 90:10 to 50:50 heptane/ethyl acetate) to provide a yellow solid. The solid was recrystallized from heptane/ethyl acetate to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(pyridin-2-yl)methanone (0.94 g, 31%) as a off-white solid. the reaction mixture was concentrated under reduced pressure The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3 separated The organic layer was washed with saturated sodium chloride dried (Na2SO4) filtered by a pad of silica gel concentrated under reduced pressure The residue was purified with flash column chromatography (silica gel, 90:10 to 50:50 heptane/ethyl acetate) to provide a yellow solid The solid was recrystallized from heptane/ethyl acetate

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

Procedure: To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.30 g, 1.46 mmol) in pyridine (5.0 mL) was added benzenesulfonyl chloride (0.28 g, 1.61 mmol). After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1.0 N hydrochloric acid, water, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting yellow solid was recrystallized from heptane/ethyl acetate to provide 3-(2-tert-butylphenoxy)-1-(phenylsulfonyl)azetidine (0.29 g, 57%) as a pale brown powder. the reaction mixture was concentrated under reduced pressure the residue was dissolved in ethyl acetate The organic layer was washed with 1.0 N hydrochloric acid, water, saturated sodium chloride dried (Na2SO4) filtered concentrated under reduced pressure The resulting yellow solid was recrystallized from heptane/ethyl acetate