methyl 4-bromo-2-hydroxybutanoate

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

Procedure: To a solution of 5-(2-bromo-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one (synthesized as instructed in Tetrahedron Letters, 1997, 38, 28, 4935) (93 mg, 0.416 mmol) in toluene (0.5 mL) were added p-TsOH.H2O (8 mg, 0.0415 mmol) and methanol (0.5 mL), followed stirring overnight at room temperature. The solution was concentrated in a vacuum, diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic layer thus formed was dried over sodium sulfate and filtered. The filtrate was concentrated to produce 68 mg of the compound as an oil. 1H NMR (300 MHz, CDCl3) δ 1.98 (1H, m), 2.34 (1H, m), 2.96 (1H, d), 3.56 (2H, m), 3.82 (3H, s), 4.37 (1H, pentet). The solution was concentrated in a vacuum diluted with dichloromethane washed with an aqueous saturated sodium bicarbonate solution The organic layer thus formed was dried over sodium sulfate filtered The filtrate was concentrated

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

Procedure: To a solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (2.8 g, 8.5 mmol), 4-bromo-2-hydroxybutyric acid methyl ester (2.5 g, 12.7 mmol) and triphenylphosphine (3.77 g, 14.3 mmol) in dioxane (30 mL) was added DIAD (2.8 ml, 14.3 mmol) and the reaction mixture was stirred at RT for 1 h. Additional amounts of DIAD (1.67 mL) and of triphenylphosphine (2.23 g) were added and stirring was continued for 1 h. The mixture was diluted with EtOAc and washed with aq. NaOH (1N). The aqueous phase was further extracted with EtOAc (×3). The combined organic layers were then washed with brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc followed by Si-PCC, gradient 0-10% MeOH in DCM) affording 4-Bromo-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]butyric acid methyl ester (2.5 g, 58%). 1H NMR (CDCl3, 400 MHz): δ 8.43 (1H, d, J=9.01 Hz), 7.57 (1H, s), 6.74 (1H, d, J=9.15 Hz), 6.55 (1H, d, J=2.56 Hz), 5.95-5.83 (1H, m), 4.92 (1H, dd, J=8.80, 3.97 Hz), 4.51-4.31 (4H, m), 3.79 (3H, s), 3.65-3.53 (2H, m), 2.58-2.36 (5H, m), 1.58-1.51 (6H, m) stirring was continued for 1 h washed with aq. NaOH (1N) The aqueous phase was further extracted with EtOAc (×3) The combined organic layers were then washed with brine dried concentrated in vacuo The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc followed by Si-PCC, gradient 0-10% MeOH in DCM)

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

Procedure: To a solution of 5-(2-bromo-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one (synthesized as instructed in Tetrahedron Letters, 1997, 38, 28, 4935) (93 mg, 0.416 mmol) in toluene (0.5 mL) were added p-TsOH.H2O (8 mg, 0.0415 mmol) and methanol (0.5 mL), followed stirring overnight at room temperature. The solution was concentrated in a vacuum, diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic layer thus formed was dried over sodium sulfate and filtered. The filtrate was concentrated to produce 68 mg of the compound as an oil. 1H NMR (300 MHz, CDCl3) δ 1.98 (1H, m), 2.34 (1H, m), 2.96 (1H, d), 3.56 (2H, m), 3.82 (3H, s), 4.37 (1H, pentet). The solution was concentrated in a vacuum diluted with dichloromethane washed with an aqueous saturated sodium bicarbonate solution The organic layer thus formed was dried over sodium sulfate filtered The filtrate was concentrated