甲基 1,4-二恶烷-2-羧酸乙酯

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-diisopropylamine (1.67 g, 2.3 mL, 16.5 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. under nitrogen. n-Butyllithium (6.6 mL, 16.5 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. A solution of [1,4]dioxane-2-carboxylic acid methyl ester (1.61 g, 11 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was stirred at −78° C. for 30 minutes. Acetaldehyde (1.45 g, 1.8 mL, 33 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 5° C. and ice-cold 1 M hydrochloric acid was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the solution and the mixture was extracted with diethyl ether (4×). The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 1:1 to 0:1 to afford the title compound (1.49 g, 71%), as an oil, and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 213.2 [M+H], Tr=0.62 min. the reaction mixture was stirred at −78° C. for 30 minutes The cooling bath was removed the reaction mixture was stirred at room temperature for 30 minutes The reaction mixture was cooled to 5° C. ice-cold 1 M hydrochloric acid was added Sodium chloride was added to saturate the solution the mixture was extracted with diethyl ether (4×) washed with brine The organic solution was filtered through a hydrophobic frit the filtrate was evaporated The residue was purified by silica gel chromatography

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of [1,4]dioxane-2-carboxylic acid (supplied by Enamine Ltd.), (2.90 g, 22.0 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature. Potassium carbonate (6.07 g, 44.0 mmol) was added and the suspension was stirred at 5° C. Iodomethane (6.25 g, 2.75 mL, 44.0 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Water and brine were added and the mixture was extracted with diethyl ether. The aqueous layer was saturated with sodium chloride and the mixture was extracted with ethyl acetate (3×). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 4:1 to 1:1 to afford the title compound (3.06 g, 95%) as a volatile, pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 3.68-3.78 (m, 4H), 3.81 (s, 3H), 3.97-4.05 (m, 2H), 4.29 (dd, J=8.5, 3.1 Hz, 1H). LCMS (m/z) 169.2 [M+Na], Tr=0.69 min. the reaction mixture was stirred at room temperature for 24 h the mixture was extracted with diethyl ether the mixture was extracted with ethyl acetate (3×) dried over anhydrous magnesium sulfate filtered evaporated The residue was purified by silica gel chromatography