methyl 2,2-dimethyl-3-oxopropanoate

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 solution of dimethyl (2-oxopropyl)phosphonate (4.09 mL, 30 mmol) in tetrahydrofuran (200 mL) at 0° C. was added potassium tert-butoxide (3.22 g, 28.7 mmol). After 15 minutes, the reaction flask was moved to a 20° C. water bath and then a solution of methyl 2,2-dimethyl-3-oxopropanoate (3.39 g, 26 mmol) in tetrahydrofuran (10 mL) was added. After 20 hours, the opaque reaction mixture was partitioned between diethyl ether (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (1×100 mL, 1×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (0-4% methanol/dichloromethane gradient) to afford methyl (3E)-2,2-dimethyl-5-oxohex-3-enoate (2.21 g, 12.21 mmol, 47% yield) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ 6.95 (d, J=16.3, 1H), 6.09 (d, J=16.3, 1H), 3.71 (s, 3H), 2.29 (s, 3H), 1.37 (d, J=2.3, 614). was moved to a 20° C. After 20 hours the opaque reaction mixture was partitioned between diethyl ether (100 mL) and water (100 mL) The layers were separated the aqueous layer was extracted with diethyl ether (1×100 mL, 1×50 mL) The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine dried over sodium sulfate filtered concentrated The residue was purified by silica gel flash column chromatography (0-4% methanol/dichloromethane gradient)

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

Procedure: To a solution of dimethyl(2-oxopropyl)phosphonate (4.09 mL, 30 mmol) in tetrahydrofuran (200 mL) at 0° C. was added potassium tert-butoxide (3.22 g, 28.7 mmol). After 15 minutes, the reaction flask was moved to a 20° C. water bath and then a solution of methyl 2,2-dimethyl-3-oxopropanoate (3.39 g, 26 mmol) in tetrahydrofuran (10 mL) was added. After 20 hours, the opaque reaction mixture was partitioned between diethyl ether (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (1×100 mL, 1×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (0-4% methanol/dichloromethane gradient) to afford methyl(3E)-2,2-dimethyl-5-oxohex-3-enoate (2.21 g, 12.21 mmol, 47% yield) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ 6.95 (d, J=16.3, 1H), 6.09 (d, J=16.3, 1H), 3.71 (s, 3H), 2.29 (s, 3H), 1.37 (d, J=2.3, 6H). was moved to a 20° C. After 20 hours the opaque reaction mixture was partitioned between diethyl ether (100 mL) and water (100 mL) The layers were separated the aqueous layer was extracted with diethyl ether (1×100 mL, 1×50 mL) The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine dried over sodium sulfate filtered concentrated The residue was purified by silica gel flash column chromatography (0-4% methanol/dichloromethane gradient)

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

Procedure: To a solution of dimethyl (2-oxopropyl)phosphonate (4.09 mL, 30.0 mmol) in tetrahydrofuran (200 mL) at 0° C. was added potassium tert-butoxide (3.22 g, 28.7 mmol). After 15 minutes the reaction mixture was moved to room temperature, and after an additional 15 minutes methyl 2,2-dimethyl-3-oxopropanoate (3.39 g, 26.0 mmol) was added. The opaque reaction mixture was stirred for 21 hours and then partitioned between diethyl ether (100 ml) and water (100 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (100 mL, 50 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-4% methanol/dichloromethane) to yield methyl (3E)-2,2-dimethyl-5-oxohex-3-enoate. 1H NMR (500 MHz, CDCl3) δ 6.95 (d, J=16.4 Hz, 1H), 6.09 (d, J=16.4 Hz, 1H), 3.71 (s, 3H), 2.29 (s, 3H), 1.37 (s, 6H). The opaque reaction mixture partitioned between diethyl ether (100 ml) and water (100 mL) The layers were separated the aqueous layer was extracted with diethyl ether (100 mL, 50 mL) The combined organic layers were washed with aqueous saturated sodium bicarbonate solution and brine dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on silica gel (0-4% methanol/dichloromethane)

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

Procedure: To a solution of 2,2-dimethyl-3-oxo-propionic acid methyl ester (WHSS0374-001) (0.90 g; 5.44 mmol) in 1,2-dichloroethane (20 mL) was added 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.91 g, 2.7 mmol) and NaBH(OAc)3 (1.62 g; 7.62 mmol). The resulting mixture was stirred overnight at RT, and subsequently treated with 5% aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3×30 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionic acid methyl ester (1.12 g) as a clear colourless oil. The required 2,2-dimethyl-3-oxo-propionic acid methyl ester was prepared as follows: To a solution of 2,2-dimethyl-3-hydroxypropionic acid methyl ester (10.00 g; 75.7 mmol) in CH2Cl2 (200 mL) was added pyridinium chloroformate (28.54 g; 132.4 mmol) in small portions, at 0° C. The reaction mixture was allowed to slowly warm to RT and stirred overnight. Subsequently, the mixture was diluted with CH2Cl2, filtered over kieselguhr, and concentrated in vacuo. The remaining oil was purified by column chromatography (SiO2, hexanes/Et2O 7:3) to afford 2,2-dimethyl-3-oxo-propionic acid methyl ester (5.59 g) The required 2,2-dimethyl-3-oxo-propionic acid methyl ester was prepared at 0° C filtered over kieselguhr concentrated in vacuo The remaining oil was purified by column chromatography (SiO2, hexanes/Et2O 7:3)

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

Procedure: To a solution of 2,2-dimethyl-3-oxo-propionic acid methyl ester (WHSS0374-001) (0.90 g; 5.44 mmol) in 1,2-dichloroethane (20 mL) was added 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.91 g, 2.7 mmol) and NaBH(OAc)3 (1.62 g; 7.62 mmol). The resulting mixture was stirred overnight at RT, and subsequently treated with 5% aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3×30 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionic acid methyl ester (1.12 g) as a clear colourless oil. The required 2,2-dimethyl-3-oxo-propionic acid methyl ester was prepared as follows: To a solution of 2,2-dimethyl-3-hydroxypropionic acid methyl ester (10.00 g; 75.7 mmol) in CH2Cl2 (200 mL) was added pyridinium chloroformate (28.54 g; 132.4 mmol) in small portions, at 0° C. The reaction mixture was allowed to slowly warm to RT and stirred overnight. Subsequently, the mixture was diluted with CH2Cl2, filtered over kieselguhr, and concentrated in vacuo. The remaining oil was purified by column chromatography (SiO2, hexanes/Et2O 7:3) to afford 2,2-dimethyl-3-oxo-propionic acid methyl ester (5.59 g) extracted with CH2Cl2 (3×30 ml) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1)

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

Procedure: To a solution of 2,2-dimethyl-3-oxo-propionic acid methyl ester (WHSS0374-001) (0.90 g; 5.44 mmol) in 1,2-dichloroethane (20 mL) was added 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.91 g, 2.7 mmol) and NaBH(OAc)3 (1.62 g; 7.62 mmol). The resulting mixture was stirred overnight at RT, and subsequently treated with 5% aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3×30 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionic acid methyl ester (1.12 g) as a clear colourless oil. The required 2,2-dimethyl-3-oxo-propionic acid methyl ester was prepared as follows: To a solution of 2,2-dimethyl-3-hydroxypropionic acid methyl ester (10.00 g; 75.7 mmol) in CH2Cl2 (200 mL) was added pyridinium chloroformate (28.54 g; 132.4 mmol) in small portions, at 0° C. The reaction mixture was allowed to slowly warm to RT and stirred overnight. Subsequently, the mixture was diluted with CH2Cl2, filtered over kieselguhr, and concentrated in vacuo. The remaining oil was purified by column chromatography (SiO2, hexanes/Et2O 7:3) to afford 2,2-dimethyl-3-oxo-propionic acid methyl ester (5.59 g) extracted with CH2Cl2 (3×30 ml) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1)

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

Procedure: To a stirred solution of 2′-oxo-N-(piperidin-4-ylmethyl)spiro[cyclopentane-1,3′-indole]-1′(2′H)-carboxamide (480 mg, 1.5 mmol, step 2 of Example 2) and methyl 2,2-dimethyl-3-oxopropanoate (248 mg, 1.7 mmol, Kim, Hwa-Ok et al., Synth. Commun., 1997, 27, 2505) in CH2Cl2 (40 mL) was added sodium triacetoxyborohydride (623 mg, 2.9 mmol) in one portion at room temperature. The mixture was stirred for 20 h at ambient temperature. To the mixture was added sat. NaHCO3 aq. (10 mL), extracted with CH2Cl2 (30 mL×2), dried over MgSO4, filtered and concentrated gave yellow oil. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (9:1) to give 150 mg (23%) of the title compound as clear colorless oil. extracted with CH2Cl2 (30 mL×2) dried over MgSO4 filtered concentrated gave yellow oil The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (9:1)

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

Procedure: To a stirred solution of 2′-oxo-N-(piperidin-4-ylmethyl)spiro[cyclopentane-1,3′-indole]-1′(2′H)-carboxamide (480 mg, 1.5 mmol, step 2 of Example 2) and methyl 2,2-dimethyl-3-oxopropanoate (248 mg, 1.7 mmol, Kim, Hwa-Ok et al., Synth. Commun., 1997, 27, 2505) in CH2Cl2 (40 mL) was added sodium triacetoxyborohydride (623 mg, 2.9 mmol) in one portion at room temperature. The mixture was stirred for 20 h at ambient temperature. To the mixture was added sat. NaHCO3 aq. (10 mL), extracted with CH2Cl2 (30 mL×2), dried over MgSO4, filtered and concentrated gave yellow oil. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (9:1) to give 150 mg (23%) of the title compound as clear colorless oil. extracted with CH2Cl2 (30 mL×2) dried over MgSO4 filtered concentrated gave yellow oil The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (9:1)