ethyl 4-hydroxy-4-methylcyclohexane-1-carboxylate

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

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-oxocyclohexanecarboxylate (4.00 g, 23.5 mmol) in diethyl ether (80 mL) was added MeLi (37.6 mL, 1M in diethyl ether) at −60° C. under nitrogen atmosphere. The reaction mixture was stirred at −60° C. for 30 min. Saturated aqueous NH4Cl (50 mL) was added and the resulting mixture was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (150 mL) and water (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1) to afford ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (1.8 g, 41% yield) as an oil. the resulting mixture was extracted with EtOAc (100 mL×2) The combined organic layers were washed with brine (150 mL) and water (150 mL) dried over anhydrous sodium sulfate concentrated The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-oxocyclohexanecarboxylate (4.00 g, 23.5 mmol) in diethyl ether (80 mL) was added MeLi (37.6 mL, 1M in diethyl ether) at −60° C. under nitrogen atmosphere. The reaction mixture was stirred at −60° C. for 30 min. Saturated aqueous NH4Cl (50 mL) was added and the resulting mixture was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (150 mL) and water (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1) to afford ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (1.8 g, 41% yield) as an oil. the resulting mixture was extracted with EtOAc (100 mL×2) The combined organic layers were washed with brine (150 mL) and water (150 mL) dried over anhydrous sodium sulfate concentrated The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1)

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

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

Procedure: A solution of ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (2.50 g, 13.42 mmol) in dichloromethane (35 mL) at 0° C. was added with diethylaminosulfur trifluoride (14.2 mL, 107.40 mmol) slowly under nitrogen. The resulting mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and poured into ice (200 g). The organic layer was washed with saturated sodium bicarbonate (3×100 mL) and brine (100 mL); dried with anhydrous sodium sulfate; filtered and concentrated in vacuo to provide the crude product as an oil; which was dissolved in anhydrous tetrahydrofuran (60 mL) and anhydrous methanol (1.10 mL, 26.8 mmol). To the mixture was added lithium borohydride (4 M solution in tetrahydrofuran, 6.70 mL, 26.8 mmol) dropwise and the resulting mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature and quenched with water and then 3 M aqueous hydrochloric acid solution. The mixture was diluted with ethyl acetate (150 mL) and the organic layer was washed with saturated sodium bicarbonate (2×100 mL) and brine (100 mL); dried with anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate) to provide the title compound as a colorless oil (0.66 g, 34%): 1H NMR (300 MHz, CDCl3) δ 3.50-3.43 (m, 2H), 1.97-1.86 (m, 1H), 1.85-1.71 (m, 2H), 1.69-1.52 (m, 4H), 1.49-1.24 (m, 5H), 1.20-1.03 (m, 1H). The organic layer was washed with saturated sodium bicarbonate (3×100 mL) and brine (100 mL) dried with anhydrous sodium sulfate filtered concentrated in vacuo to provide the crude product as an oil the resulting mixture was refluxed under nitrogen for 4 hours quenched with water The mixture was diluted with ethyl acetate (150 mL) the organic layer was washed with saturated sodium bicarbonate (2×100 mL) and brine (100 mL) dried with anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 25.0 g of ethyl 4-oxocyclohexanecarboxylate in 500 ml of diethyl ether, 150 ml of 1.6N methyl lithium-ether solution was added at −60° C. in nitrogen atmosphere, followed by 30 minutes' stirring at −60° C. Water was added to the reaction liquid which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (ethyl acetate/hexane=1/4) to provide 22.7 g of the title compound. then was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried on anhydrous magnesium sulfate the solvent was distilled off The residue was separated purified on silica gel column chromatography (ethyl acetate/hexane=1/4)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-oxocyclohexanecarboxylate (4.00 g, 23.5 mmol) in diethyl ether (80 mL) was added MeLi (37.6 mL, 1M in diethyl ether) at −60° C. under nitrogen atmosphere. The reaction mixture was stirred at −60° C. for 30 min. Saturated aqueous NH4Cl (50 mL) was added and the resulting mixture was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (150 mL) and water (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1) to afford ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (1.8 g, 41% yield) as an oil. the resulting mixture was extracted with EtOAc (100 mL×2) The combined organic layers were washed with brine (150 mL) and water (150 mL) dried over anhydrous sodium sulfate concentrated The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1)