benzyl N-(2-methyl-1-oxopropan-2-yl)carbamate

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

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

Procedure: Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was added dropwise to a stirred solution of 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL, 1.79 mmol) in dry THF (1 mL) at room temperature under N2 and the reaction was stirred for 30 min. The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163.5 mg, 0.739 mmol) in dry THF (1 mL) at −20° C. and the reaction was allowed to warm to room temperature over 3 h. Saturated NH4Cl (10 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1; found=436.0 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H), 1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H), 1.23 (s, 3H). the mixture was extracted with EtOAc (3×20 mL) The combined extracts were dried (Na2SO4) concentrated in vacuo to give the crude product This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisobutylaluminum hydride (1.77 mL, 1M solution in toluene, 0.708 mmol) was added to a stirred solution of benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate (198.5 mg, 0.708 mmol) in dry THF (7.1 mL) at −78° C. under N2. The reaction was stirred at −78° C. for 4 h. MeOH (100 mL) and 1N HCl (250 μL) were added and the reaction was allowed to warm to room temperature. The mixture was diluted with Et2O (50 mL) and washed with 1N HCl (2×50 mL), 50% saturated NaHCO3 (50 mL) and water (50 mL), then dried (MgSO4) and concentrated in vacuo to give benzyl (1,1-dimethyl-2-oxoethyl)carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=244.1; found=244.1 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 9.43 (s, 1H), 7.38-7.30 (m, 5H), 5.34 (s, 1H), 5.09 (s, 2H), 1.37 (s, 6H). to warm to room temperature washed with 1N HCl (2×50 mL), 50% saturated NaHCO3 (50 mL) and water (50 mL) dried (MgSO4) concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-(benzyloxycarbonylamino)-2-methyl-propanoate (which may be prepared as described in Description 33) (4667 mg, 17.59 mmol) in toluene (100 mL) cooled to −78° C. was added diisobutyl aluminium hydride (1 M in toluene) (61.57 mL, 61.57 mmol) as a thin stream over approximately 2 minutes. The mixture was stirred at −78° C. over 30 minutes then allowed to warm to 0° C. and stirred over 1.5 hours. The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt. The quenched mixture was stirred over 1 hour, then extracted into ether (3 times). The combined ethereal extracts were dried over magnesium sulphate, filtered and evaporated to a clear oil. The oil was dissolved in DCM (60 mL) and 4A molecular sieves (4 g) and pyridinium dichromate (16544.34 mg, 43.98 mmol) were added and the mixture stirred at room temperature overnight. The reaction mixture was filtered over kieselguhr and the filtrate evaporated to a dark brown oil. Purification by silica gel column chromatography (20% EtOAc in isohexane) yielded benzyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (D34) (1840 mg, 8.3164 mmol, 47.3% yield) as a clear oil; to warm to 0° C. stirred over 1.5 hours The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt The quenched mixture was stirred over 1 hour extracted into ether (3 times) The combined ethereal extracts were dried over magnesium sulphate filtered evaporated to a clear oil The oil was dissolved in DCM (60 mL) the mixture stirred at room temperature overnight The reaction mixture was filtered over kieselguhr the filtrate evaporated to a dark brown oil Purification by silica gel column chromatography (20% EtOAc in isohexane)

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

Procedure: Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was added dropwise to a stirred solution of 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL, 1.79 mmol) in dry THF (1 mL) at room temperature under N2 and the reaction was stirred for 30 min. The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163.5 mg, 0.739 mmol) in dry THF (1 mL) at −20° C. and reaction was allowed to warn to room temperature over 3 h. Saturated NH4Cl (10 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1; found=436.0 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H), 1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H), 1.23 (s, 3H). reaction to warn to room temperature over 3 h the mixture was extracted with EtOAc (3×20 mL) The combined extracts were dried (Na2SO4) concentrated in vacuo to give the crude product This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient)

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

Procedure: Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was added dropwise to a stirred solution of 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL, 1.79 mmol) in dry THF (1 mL) at room temperature under N2 and the reaction was stirred for 30 min. The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163.5 mg, 0.739 mmol) in dry THF (1 mL) at −20° C. and reaction was allowed to warn to room temperature over 3 h. Saturated NH4Cl (10 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1; found=436.0 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H), 1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H), 1.23 (s, 3H). reaction to warn to room temperature over 3 h the mixture was extracted with EtOAc (3×20 mL) The combined extracts were dried (Na2SO4) concentrated in vacuo to give the crude product This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisobutylaluminum hydride (1.77 mL, 1M solution in toluene, 0.708 mmol) was added to a stirred solution of benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate (198.5 mg, 0.708 mmol) in dry THF (7.1 mL) at −78° C. under N2. The reaction was stirred at −78° C. for 4 h. MeOH (100 μL) and 1N HCl (250 μL) were added and the reaction was allowed to warm to room temperature. The mixture was diluted with Et2O (50 mL) and washed with 1N HCl (2×50 mL), 50% saturated NaHCO3 (50 mL) and water (50 mL), then dried (MgSO4) and concentrated in vacuo to give benzyl (1,1-dimethyl-2-oxoethyl)carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=244.1; found=244.1 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 9.43 (s, 1H), 7.38-7.30 (m, 5H), 5.34 (s, 1H), 5.09 (s, 2H), 1.37 (s, 6H). to warm to room temperature washed with 1N HCl (2×50 mL), 50% saturated NaHCO3 (50 mL) and water (50 mL) dried (MgSO4) concentrated in vacuo

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-(benzyloxycarbonylamino)-2-methyl-propanoate (which may be prepared as described in Description 25) (4667 mg, 17.59 mmol) in toluene (100 mL) cooled to −78° C. was added diisobutyl aluminium hydride (1 M in toluene) (61.57 mL, 61.57 mmol) as a thin stream over approximately 2 minutes. The mixture was stirred at −78° C. over 30 minutes then allowed to warm to 00° C. and stirred over 1.5 hours. The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt. The quenched mixture was stirred over 1 hour, then extracted into ether (3 times). The combined ethereal extracts were dried over magnesium sulphate, filtered and evaporated to a clear oil. The oil was dissolved in DCM (60 mL) and 4 A molecular sieves (4 g) and pyridinium dichromate (16544.34 mg, 43.98 mmol) were added and the mixture stirred at room temperature overnight. The reaction mixture was filtered over kieselguhr and the filtrate evaporated to a dark brown oil. Purification by silica gel column chromatography (20% EtOAc in isohexane) yielded benzyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (D26) (1840 mg, 8.3164 mmol, 47.3% yield) as a clear oil; to warm to 00° C and stirred over 1.5 hours The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt The quenched mixture was stirred over 1 hour extracted into ether (3 times) The combined ethereal extracts were dried over magnesium sulphate filtered evaporated to a clear oil The oil was dissolved in DCM (60 mL) the mixture stirred at room temperature overnight The reaction mixture was filtered over kieselguhr the filtrate evaporated to a dark brown oil Purification by silica gel column chromatography (20% EtOAc in isohexane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-(benzyloxycarbonylamino)-2-methyl-propanoate (which may be prepared as described in Description 25) (4667 mg, 17.59 mmol) in toluene (100 mL) cooled to −78° C. was added diisobutyl aluminium hydride (1 M in toluene) (61.57 mL, 61.57 mmol) as a thin stream over approximately 2 minutes. The mixture was stirred at −78° C. over 30 minutes then allowed to warm to 00° C. and stirred over 1.5 hours. The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt. The quenched mixture was stirred over 1 hour, then extracted into ether (3 times). The combined ethereal extracts were dried over magnesium sulphate, filtered and evaporated to a clear oil. The oil was dissolved in DCM (60 mL) and 4 A molecular sieves (4 g) and pyridinium dichromate (16544.34 mg, 43.98 mmol) were added and the mixture stirred at room temperature overnight. The reaction mixture was filtered over kieselguhr and the filtrate evaporated to a dark brown oil. Purification by silica gel column chromatography (20% EtOAc in isohexane) yielded benzyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (D26) (1840 mg, 8.3164 mmol, 47.3% yield) as a clear oil; to warm to 00° C and stirred over 1.5 hours The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt The quenched mixture was stirred over 1 hour extracted into ether (3 times) The combined ethereal extracts were dried over magnesium sulphate filtered evaporated to a clear oil The oil was dissolved in DCM (60 mL) the mixture stirred at room temperature overnight The reaction mixture was filtered over kieselguhr the filtrate evaporated to a dark brown oil Purification by silica gel column chromatography (20% EtOAc in isohexane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-(benzyloxycarbonylamino)-2-methyl-propanoate (which may be prepared as described in Description 25) (4667 mg, 17.59 mmol) in toluene (100 mL) cooled to −78° C. was added diisobutyl aluminium hydride (1 M in toluene) (61.57 mL, 61.57 mmol) as a thin stream over approximately 2 minutes. The mixture was stirred at −78° C. over 30 minutes then allowed to warm to 00° C. and stirred over 1.5 hours. The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt. The quenched mixture was stirred over 1 hour, then extracted into ether (3 times). The combined ethereal extracts were dried over magnesium sulphate, filtered and evaporated to a clear oil. The oil was dissolved in DCM (60 mL) and 4 A molecular sieves (4 g) and pyridinium dichromate (16544.34 mg, 43.98 mmol) were added and the mixture stirred at room temperature overnight. The reaction mixture was filtered over kieselguhr and the filtrate evaporated to a dark brown oil. Purification by silica gel column chromatography (20% EtOAc in isohexane) yielded benzyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (D26) (1840 mg, 8.3164 mmol, 47.3% yield) as a clear oil; to warm to 00° C and stirred over 1.5 hours The reaction mixture was quenched by addition of a saturated solution of Rochelle's salt The quenched mixture was stirred over 1 hour extracted into ether (3 times) The combined ethereal extracts were dried over magnesium sulphate filtered evaporated to a clear oil The oil was dissolved in DCM (60 mL) the mixture stirred at room temperature overnight The reaction mixture was filtered over kieselguhr the filtrate evaporated to a dark brown oil Purification by silica gel column chromatography (20% EtOAc in isohexane)

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

Procedure: Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was added dropwise to a stirred solution of 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL, 1.79 mmol) in dry THF (1 mL) at room temperature under N2 and the reaction was stirred for 30 min. The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163.5 mg, 0.739 mmol) in dry THF (1 mL) at −20° C. and reaction was allowed to warm to room temperature over 3 h. Saturated NH4Cl (10 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1; found=436.0 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H), 1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H), 1.23 (s, 3H). reaction the mixture was extracted with EtOAc (3×20 mL) The combined extracts were dried (Na2SO4) concentrated in vacuo to give the crude product This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient)