methyl 2-oxobutanoate

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: A 100 ml flask fitted with a magnetic stirring bar and a Dean-Stark trap was charged with methyl 2-oxobutanoate (7.5 g, 73 mmol), toluene (50 ml, 7 vol) and 2-pyrrolidinone (8.4 ml, 111 mmol, 1.5 equiv) followed by dropwise addition of POCl3 (1.6 ml, 20 mmol, 0.27 equiv). The reaction mixture was stirred under reflux with azeotropic removal of water via the Dean-Star trap for 8 hours. After cooling down the solution was washed with 10% aq KHSO4 (2×3 vol). The aqueous phase was saturated with NaCl and back extracted with toluene (1×6 vol). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford crude material (7.5 g) as an orange mobile oil. The crude oil was distilled (92-94° C., 0.1 mm Hg) and gave pure product (4.7 g, 60%) as a colourless oil. A 100 ml flask fitted with a magnetic stirring bar After cooling down the solution was washed with 10% aq KHSO4 (2×3 vol) back extracted with toluene (1×6 vol) The combined organic phase was dried over MgSO4 filtered concentrated in vacuo to afford crude material (7.5 g) as an orange mobile oil The crude oil was distilled (92-94° C., 0.1 mm Hg)

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

Procedure: A stirred solution of (2-bromo-4-chloro-phenyl)-hydrazine (step A) (1.98 g, 8.94 mmol) in ethanol (6.5 ml) was cooled to 0° C. and a solution of commercially available methyl 2-ketobutyrate (1.08 g, 1.04 ml, 9.3 mmol) in ethanol (2 ml) was added drop wise at 0° C. for 15 min. After the mixture was allowed to stir at room temperature for 3 h it was evaporated. The crude material (3.01 g) was purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield (Z)-2-[(2-bromo-4-chloro-phenyl)-hydrazono]-butyric acid methyl ester (2.67 g, 94%) as a light yellow solid, MS (ISP) m/z=321.3 [(M+H)+], mp 67° C. was evaporated The crude material (3.01 g) was purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%)

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

Procedure: Methyl-2-ketobutyrate (5 g, 43 mmol) was added at ambient temperature to dimethylformamide dimethyl acetal (5.13 g, 43 mmol, 5.72 ml). The solution was stirred overnight under nitrogen and then the volatile components were removed in vacuo at 40° C. The yellow residue was used without further purification. the volatile components were removed in vacuo at 40° C The yellow residue was used without further purification

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

Procedure: 2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), TEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1). The reaction is partitioned between DCM and saturated aqueous NaHCO3 The organic layer is removed dried over anhydrous Na2SO4 concentrated in vacuo The crude residue is used without further purification

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

Procedure: To a solution of methyl 2-oxobutanoate (6.92 g, 59.6 mmol) in DCM (60 mL) at 0° C. was added bromine (3.10 mL, 60.3 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, diluted with EtOAc, washed with saturated NaHCO3 (2×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The product, methyl 3-bromo-2-oxobutanoate, (8.26 g, 42.4 mmol, 71% yield) was used in the next step without further purification. washed with saturated NaHCO3 (2×), water (1×), brine (1×) dried over MgSO4 filtered concentrated

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

Procedure: To a solution of methyl 2-oxobutanoate (6.92 g, 59.6 mmol) in DCM (60 mL) at 0° C. was added bromine (3.10 mL, 60.3 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, diluted with EtOAc, washed with saturated NaHCO3 (2×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The product, methyl 3-bromo-2-oxobutanoate, (8.26 g, 42.4 mmol, 71% yield) was used in the next step without further purification. washed with saturated NaHCO3 (2×), water (1×), brine (1×) dried over MgSO4 filtered concentrated

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

Procedure: 2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), LEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1). The reaction is partitioned between DCM and saturated aqueous NaHCO3 The organic layer is removed dried over anhydrous Na2SO4 concentrated in vacuo The crude residue is used without further purification

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

Procedure: 2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), LEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1). The reaction is partitioned between DCM and saturated aqueous NaHCO3 The organic layer is removed dried over anhydrous Na2SO4 concentrated in vacuo The crude residue is used without further purification

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

Procedure: 2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), LEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1). The reaction is partitioned between DCM and saturated aqueous NaHCO3 The organic layer is removed dried over anhydrous Na2SO4 concentrated in vacuo The crude residue is used without further purification