tert-butyl cyclohexanecarboxylate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of dicyclohexylamine (13.19 g, 72.72 mmol) in THF (90 mL) 1.6 M n-BuLi in hexane (40.7 mL, 65.12 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this suspension a solution of cyclohexanecarboxylic acid t-butyl ester (10.0 g, 54.3 mmol) in THF (30 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C., then 1-bromo-2-ethylbutane (12.54 g, 76.0 mmol) in THF (37.5 mL) was added at the same temperature over 15 min. Stirring was continued 5 h at 0° C. and overnight at room temperature. At 5° C. cold water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and toluene. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with toluene. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (12.9 g) was distilled at 60° C. (0.05 mbar) to give 7.6 g (52%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid t-butyl ester as a colorless oil, purity 96% (GC area). 1H-NMR (CDCl3, 400 MHz): ppm 0.81 (t, 6H), 1.12-1.60 (m, 15H), 1.48 (s, 9H), 1.95-2.05 (m, 2H). The orange suspension was stirred 10 min at −20° C. The resulting solution was stirred 30 min at 0° C. Stirring was continued 5 h at 0° C. and overnight at room temperature The white suspension was filtered the filter cake was washed with water and toluene The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl The aqueous phases were extracted with toluene dried over sodium sulfate concentrated The crude product (12.9 g) was distilled at 60° C. (0.05 mbar)

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

Procedure: To a solution of cyclohexanecarboxylic acid (10.0 g, 78 mmol) in DCM (75 mL) concentrated sulfuric acid (765 mg, 7.8 mmol) was added. At a temperature between −15° C. and −10° C. isobutylene (10.94 g, 195 mmol) was introduced over 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature for 72 h. Then a second portion of isobutylene (10.94 g, 195 mmol) was introduced over 1 h at −10° C. The reaction mixture was stirred at room temperature for an additional 20 h, then NaHCO3 (7.864 g, 93.6 mmol) was added before the mixture was stirred at room temperature for another 1 h. Water (50 mL) was added under stirring. After 45 min the reaction mixture was worked up and washed until neutral. The organic phases were combined, dried over sodium sulfate and concentrated on a rotary evaporator. The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar) to afford 10.9 g (76%) cyclohexanecarboxylic acid tert-butyl ester as a colorless oil. 1H-NMR (CDCl3, 400 MHz): ppm 1.12-1.54 (m, 14H), 1.55-1.99 (m, 5H), 2.12-2.22 (m, 1H). The cooling bath was removed The reaction mixture was stirred at room temperature for an additional 20 h was stirred at room temperature for another 1 h under stirring After 45 min the reaction mixture was worked up washed until neutral dried over sodium sulfate concentrated on a rotary evaporator The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar)

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

Procedure: To a solution of cyclohexanecarboxylic acid (10.0 g, 78 mmol) in DCM (75 mL) concentrated sulfuric acid (765 mg, 7.8 mmol) was added. At a temperature between −15° C. and −10° C. isobutylene (10.94 g, 195 mmol) was introduced over 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature for 72 h. Then a second portion of isobutylene (10.94 g, 195 mmol) was introduced over 1 h at −10° C. The reaction mixture was stirred at room temperature for an additional 20 h, then NaHCO3 (7.864 g, 93.6 mmol) was added before the mixture was stirred at room temperature for another 1 h. Water (50 mL) was added under stirring. After 45 min the reaction mixture was worked up and washed until neutral. The organic phases were combined, dried over sodium sulfate and concentrated on a rotary evaporator. The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar) to afford 10.9 g (76%) cyclohexanecarboxylic acid tert-butyl ester as a colorless oil. 1H-NMR (CDCl3, 400 MHz): ppm 1.12-1.54 (m, 14H), 1.55-1.99 (m, 5H), 2.12-2.22 (m, 1H). The cooling bath was removed The reaction mixture was stirred at room temperature for an additional 20 h was stirred at room temperature for another 1 h under stirring After 45 min the reaction mixture was worked up washed until neutral dried over sodium sulfate concentrated on a rotary evaporator The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar)

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

Procedure: A solution of 48.2 g of dicyclohexylcarbodiimide in 100 ml of methylene chloride is added dropwise at room temperature with stirring to a solution of 27.7 g (0.2 mol) of 4-cyclohexanecarboxylic acid, 28.9 g of tert-butanol and 24 g of 4-dimethylaminopyrimidine in 200 ml of methylene chloride. The mixture is stirred for 24 hours at room temperature, dicyclohexylurea is removed by filtration, and the product is extracted twice by stirring with water. The organic phase is dried and concentrated. The crude product is purified by distillation on a thin-film evaporator (150°/0.4 mm). This gives 20 g (51.8% of theory) of a colorless oil. dicyclohexylurea is removed by filtration the product is extracted twice by stirring with water The organic phase is dried concentrated The crude product is purified by distillation on a thin-film evaporator (150°/0.4 mm)

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

Procedure: A solution of 48.2 g of dicyclohexylcarbodiimide in 100 ml of methylene chloride is added dropwise at room temperature with stirring to a solution of 27.7 g (0.2 mol) of 4-cyclohexanecarboxylic acid, 28.9 g of tert-butanol and 24 g of 4-dimethylaminopyrimidine in 200 ml of methylene chloride. The mixture is stirred for 24 hours at room temperature, dicyclohexylurea is removed by filtration, and the product is extracted twice by stirring with water. The organic phase is dried and concentrated. The crude product is purified by distillation on a thin-film evaporator (150°/0.4 mm). This gives 20 g (51.8% of theory) of a colorless oil. dicyclohexylurea is removed by filtration the product is extracted twice by stirring with water The organic phase is dried concentrated The crude product is purified by distillation on a thin-film evaporator (150°/0.4 mm)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of dicyclohexylamine (13.19 g, 72.72 mmol) in THF (90 mL) 1.6 M n-BuLi in hexane (40.7 mL, 65.12 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this suspension a solution of cyclohexanecarboxylic acid t-butyl ester (10.0 g, 54.3 mmol) in THF (30 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C., then 1-bromo-2-ethylbutane (12.54 g, 76.0 mmol) in THF (37.5 mL) was added at the same temperature over 15 min. Stirring was continued 5 h at 0° C. and overnight at room temperature. At 5° C. cold water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and toluene. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with toluene. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (12.9 g) was distilled at 60° C. (0.05 mbar) to give 7.6 g (52%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid t-butyl ester as a colorless oil, purity 96% (GC area). 1H-NMR (CDCl3, 400 MHz): ppm 0.81 (t, 6H), 1.12-1.60 (m, 15H), 1.48 (s, 9H), 1.95-2.05 (m, 2H). The orange suspension was stirred 10 min at −20° C. The resulting solution was stirred 30 min at 0° C. Stirring was continued 5 h at 0° C. and overnight at room temperature The white suspension was filtered the filter cake was washed with water and toluene The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl The aqueous phases were extracted with toluene dried over sodium sulfate concentrated The crude product (12.9 g) was distilled at 60° C. (0.05 mbar)

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

Procedure: To a solution of cyclohexanecarboxylic acid (10.0 g, 78 mmol) in DCM (75 mL) concentrated sulfuric acid (765 mg, 7.8 mmol) was added. At a temperature between −15° C. and −10° C. isobutylene (10.94 g, 195 mmol) was introduced over 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature for 72 h. Then a second portion of isobutylene (10.94 g, 195 mmol) was introduced over 1 h at −10° C. The reaction mixture was stirred at room temperature for an additional 20 h, then NaHCO3 (7.864 g, 93.6 mmol) was added before the mixture was stirred at room temperature for another 1 h. Water (50 mL) was added under stirring. After 45 min the reaction mixture was worked up and washed until neutral. The organic phases were combined, dried over sodium sulfate and concentrated on a rotary evaporator. The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar) to afford 10.9 g (76%) cyclohexanecarboxylic acid tert-butyl ester as a colorless oil. 1H-NMR (CDCl3, 400 MHz): ppm 1.12-1.54 (m, 14H), 1.55-1.99 (m, 5H), 2.12-2.22 (m, 1H). The cooling bath was removed The reaction mixture was stirred at room temperature for an additional 20 h was stirred at room temperature for another 1 h under stirring After 45 min the reaction mixture was worked up washed until neutral dried over sodium sulfate concentrated on a rotary evaporator The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar)