tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate

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

Procedure: To a solution of potassium tert-butoxide, 1M in tetrahydrofuran (3694 μl, 3.69 mmol) at 0° C. was added dropwise by syringe a solution of diethyl cyanomethylphosphonate (570 μl, 3.52 mmol) in 5 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and then cooled to 0° C. again. This solution was treated with tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (701 mg, 3.52 mmol) in 2 ml tetrahydrofuran dropwise by syringe and then allowed to warm to room temperature. After stirring overnight the gelatinous mixture was quenched with water (20 ml) and extracted with ethyl acetate (2×20 ml); the organic layers were washed with brine (20 ml), dried with magnesium sulfate, filtered and concentrated. The liquid residue was flash chromatographed to give the title compound as a 1:1 mixture of E/Z isomers. cooled to 0° C. again to warm to room temperature was quenched with water (20 ml) extracted with ethyl acetate (2×20 ml) the organic layers were washed with brine (20 ml) dried with magnesium sulfate filtered concentrated chromatographed

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

Procedure: To a solution of oxalyl chloride (488 μl, 5.58 mmol) in 40 ml dichloromethane at −78° C. was added dimethyl sulfoxide (792 μl, 11.16 mmol) dropwise by syringe. The mixture was stirred for 15 minutes at −78° C. when a solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (936 mg, 4.65 mmol) in 10 ml dichloromethane was added dropwise by syringe. After 1 hour at −78° C., triethylamine (3241 μl, 23.25 mmol) was added and the suspension was warmed to room temperature and stirred for an additional hour. The mixture was quenched with water (25 ml) and saturated aqueous potassium carbonate (10 ml), stirred vigorously and separated. The aqueous layer was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The crude material was flash chromatographed to give the title compound. was added dropwise by syringe The mixture was quenched with water (25 ml) and saturated aqueous potassium carbonate (10 ml) stirred vigorously separated The aqueous layer was extracted with dichloromethane (2×20 ml) the combined organic layers were dried with magnesium sulfate filtered concentrated chromatographed

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

Procedure: To a solution of oxalyl chloride (488 μl, 5.58 mmol) in 40 ml dichloromethane at −78° C. was added dimethyl sulfoxide (792 μl, 11.16 mmol) dropwise by syringe. The mixture was stirred for 15 minutes at −78° C. when a solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (936 mg, 4.65 mmol) in 10 ml dichloromethane was added dropwise by syringe. After 1 hour at −78° C., triethylamine (3241 μl, 23.25 mmol) was added and the suspension was warmed to room temperature and stirred for an additional hour. The mixture was quenched with water (25 ml) and saturated aqueous potassium carbonate (10 ml), stirred vigorously and separated. The aqueous layer was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The crude material was flash chromatographed to give the title compound. was added dropwise by syringe The mixture was quenched with water (25 ml) and saturated aqueous potassium carbonate (10 ml) stirred vigorously separated The aqueous layer was extracted with dichloromethane (2×20 ml) the combined organic layers were dried with magnesium sulfate filtered concentrated chromatographed

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

Procedure: N-tert-Butyloxycarbonyl-3-formylmethylazetidine (0.4 g, 2.01 mmol) was added to a solution of 4-(1,2,4-triazol-1-yl)phenylhydrazine (0.35 g, 2.01 mmol) in 4% H2SO4 (50 ml) and the mixture refiuxed for 16h. The mixture was then cooled to room temperature, basified (K2CO3) and extracted with n-butanol (5 x). The crude product obtained was chromatographed on silica-gel eluting with CH2Cl2 /MeOH/NH3 (20:8:1) to give the title-azetidinylindole (0.186 g, 39%); δ (360 MHz, CD3OD) 3.80-3.88 (4H, m, 2 of CH2 of azetidine), 4.12-4.23 (1H, m, CH), 7.23 (1H, s, Ar--H), 7.39 (2H, s, Ar--H), 7.65 (1H, d, J=2.5 Hz, Ar--H), 8.04 (1H, s, Ar--H), 8.89 (1H, s, Ar--H). extracted with n-butanol (5 x) The crude product obtained was chromatographed on silica-gel eluting with CH2Cl2 /MeOH/NH3 (20:8:1)

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

Procedure: N-tert-Butyloxycarbonyl-3-formylmethylazetidine (0.3 g, 1.51 mmol) was added to a solution of 4-(2-methylimidazol-1-ylmethyl)phenylhydrazine (0.36 g, 1.51 mmol) in 4% H2SO4 (25 ml) and the resulting solution refluxed for 3h. The mixture was then cooled to room temperature, basified with K2CO3 and extracted with n-butanol (2×100 ml). The combined extracts were dried (MgSO4), evaporated, and the residue chromatographed through silica-gel eluting with CH2Cl2 /MeOH/NH3 (20:8:1) to give the title-indole (0.186 g, 46%), mp 88°-90° C.; δ (250 MHz, CD3OD) 2.02 (3H, s, CH3), 3.76-3.86 (4H, m, 2 of CH2), 4.04-4.20 (1H, m, CH of azetidine), 5.06 (2H, s, CH2), 6.70 (1H, d, J=1.4 Hz, Ar--H), 6.82 (1H, dd, J=1.5 and 8.4 Hz, Ar--H), 6.90 (1H, d, J=1.4 Hz, Ar--H), 7.12 (1H, s, Ar--H), 7.23 (1H, d, J =8.4Hz, At-H), 7.26 (1H, d, J =1.5Hz, Ar--H). the resulting solution refluxed for 3h extracted with n-butanol (2×100 ml) The combined extracts were dried (MgSO4) evaporated the residue chromatographed through silica-gel eluting with CH2Cl2 /MeOH/NH3 (20:8:1)

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

Procedure: To a solution of potassium tert-butoxide, 1M in tetrahydrofuran (3694 μl, 3.69 mmol) at 0° C. was added dropwise by syringe a solution of diethyl cyanomethylphosphonate (570 μl, 3.52 mmol) in 5 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and then cooled to 0° C. again. This solution was treated with tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (701 mg, 3.52 mmol) in 2 ml tetrahydrofuran dropwise by syringe and then allowed to warm to room temperature. After stirring overnight the gelatinous mixture was quenched with water (20 ml) and extracted with ethyl acetate (2×20 ml); the organic layers were washed with brine (20 ml), dried with magnesium sulfate, filtered and concentrated. The liquid residue was flash chromatographed to give the title compound as a 1:1 mixture of E/Z isomers. cooled to 0° C. again to warm to room temperature was quenched with water (20 ml) extracted with ethyl acetate (2×20 ml) the organic layers were washed with brine (20 ml) dried with magnesium sulfate filtered concentrated chromatographed

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

Procedure: To a solution of oxalyl chloride (488 μl, 5.58 mmol) in 40 ml dichloromethane at −78° C. was added dimethyl sulfoxide (792 μl, 11.16 mmol) dropwise by syringe. The mixture was stirred for 15 minutes at −78° C. when a solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (936 mg, 4.65 mmol) in 10 ml dichloromethane was added dropwise by syringe. After 1 hour at −78° C., triethylamine (3241 μl, 23.25 mmol) was added and the suspension was warmed to room temperature and stirred for an additional hour. The mixture was quenched with water (25 ml) and saturated aqueous potassium carbonate (10 ml), stirred vigorously and separated. The aqueous layer was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The crude material was flash chromatographed to give the title compound. was added dropwise by syringe The mixture was quenched with water (25 ml) and saturated aqueous potassium carbonate (10 ml) stirred vigorously separated The aqueous layer was extracted with dichloromethane (2×20 ml) the combined organic layers were dried with magnesium sulfate filtered concentrated chromatographed