methyl cyclohexene-1-carboxylate

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (0° C.) solution of freshly distilled N-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) under argon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol). After 15 min the solution was cooled to 78° C. and dry HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred for 30 min at 78° C. and methyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was then added. After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol) was added. The solution was then allowed to warm to 5° C. over 2 h. An aqueous saturated solution of NH4Cl was poured into the orange mixture. After dilution with hexanes and washing with brine, the organic layer was dried over Na2SO4 and carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification. After stirring an additional 10 min to warm to 5° C. over 2 h After dilution with hexanes and washing with brine the organic layer was dried over Na2SO4 carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (0° C.) solution of freshly distilled N-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) under argon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol). After 15 min the solution was cooled to 78° C. and dry HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred for 30 min at 78° C. and methyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was then added. After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol) was added. The solution was then allowed to warm to 5° C. over 2 h. An aqueous saturated solution of NH4Cl was poured into the orange mixture. After dilution with hexanes and washing with brine, the organic layer was dried over Na2SO4 and carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification. After stirring an additional 10 min to warm to 5° C. over 2 h After dilution with hexanes and washing with brine the organic layer was dried over Na2SO4 carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification

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

Procedure: A solution of cyclohex-1-enecarboxylic acid methyl ester 1 (5.15 g; 36.7 mmol), tetrabutyl ammonium fluoride (55.10 mL; 1 M in THF; 55.1 mmol) and nitromethane (3.97 mL; 73.5 mmol) in tetrahydrofuran (60 mL) was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (500 mL), washed with 2N HCl (2×100 mL) and then with brine (2×100 mL). The phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid. to reflux for 4 hours washed with 2N HCl (2×100 mL) The phases were separated The organic phase was dried over MgSO4 concentrated in vacuo The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid

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

Procedure: A catalytic amount of trifluoroacetic acid was added to a solution of 1-cyclohexene-1-carboxylic acid methyl ester (25.0 g, 178 mmol) and N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (46.6 g, 196 mmol) in 1,2-dichloroethane (178 mL) at room temperature, and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution (200 mL) was added to the reaction solution, followed by extraction with chloroform (150 mL×1, 100 mL×1). The organic layer was washed with brine (450 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→85:15→75:25) to give 21.3 g of the title compound. followed by extraction with chloroform (150 mL×1, 100 mL×1) The organic layer was washed with brine (450 ml) dried over anhydrous sodium sulfate After filtration the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→85:15→75:25)

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

Procedure: Following the procedure as described in Example 342 Step 1 and making non-critical variations to replace methyl cyclohex-1-enecarboxylate with 7,7-difluorobicyclo[4.1.0]-heptane-3-carboxylate, the title compound was obtained as a colorless liquid (0.30 g, 70%): 1H NMR (300 MHz, CDCl3) δ 3.50-3.23 (m, 2H), 2.50-2.25 (m, 1H), 2.15-1.76 (m, 2H), 1.74-0.96 (m, 5H), 0.96-0.54 (m, 1H).

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (0° C.) solution of freshly distilled N-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) under argon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol). After 15 min the solution was cooled to 78° C. and dry HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred for 30 min at 78° C. and methyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was then added. After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol) was added. The solution was then allowed to warm to 5° C. over 2 h. An aqueous saturated solution of NH4Cl was poured into the orange mixture. After dilution with hexanes and washing with brine, the organic layer was dried over Na2SO4 and carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification. After stirring an additional 10 min to warm to 5° C. over 2 h After dilution with hexanes and washing with brine the organic layer was dried over Na2SO4 carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification

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

Procedure: A solution of cyclohex-1-enecarboxylic acid methyl ester 1 (5.15 g; 36.7 mmol), tetrabutyl ammonium fluoride (55.10 mL; 1 M in THF; 55.1 mmol) and nitromethane (3.97 mL; 73.5 mmol) in tetrahydrofuran (60 mL) was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (500 mL), washed with 2N HCl (2×100 mL) and then with brine (2×100 mL). The phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid. to reflux for 4 hours washed with 2N HCl (2×100 mL) The phases were separated The organic phase was dried over MgSO4 concentrated in vacuo The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid

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

Procedure: A solution of cyclohex-1-enecarboxylic acid methyl ester 1 (5.15 g; 36.7 mmol), tetrabutyl ammonium fluoride (55.10 mL; 1 M in THF; 55.1 mmol) and nitromethane (3.97 mL; 73.5 mmol) in tetrahydrofuran (60 mL) was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (500 mL), washed with 2N HCl (2×100 mL) and then with brine (2×100 mL). The phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid. to reflux for 4 hours washed with 2N HCl (2×100 mL) The phases were separated The organic phase was dried over MgSO4 concentrated in vacuo The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (0° C.) solution of freshly distilled N-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) under argon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol). After 15 min the solution was cooled to −78° C. and dry HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred for 30 min at −78° C. and methyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was then added. After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol) was added. The solution was then allowed to warm to −5° C. over 2 h. An aqueous saturated solution of NH4Cl was poured into the orange mixture. After dilution with hexanes and washing with brine, the organic layer was dried over Na2SO4 and carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification. After stirring an additional 10 min to warm to −5° C. over 2 h After dilution with hexanes and washing with brine the organic layer was dried over Na2SO4 carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification

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

Procedure: 3,5-Dihydrobenzoic acid methyl ester (20.2 g) was dissolved in acetone (400 mL) and then potassium carbonate (16.6 g) and benzyl bromide (20.5 g) were added. The resulting mixture was refluxed for 3 h. Then the insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using chloroform and methanol to yield 12.4 g (40% yield) of the title compound. The resulting mixture was refluxed for 3 h Then the insoluble material was filtered off the filtrate was concentrated under reduced pressure The residue was purified on a silica gel column

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

Procedure: Methyl 2-cyclohexene-1-carboxylate (4.0 g; 28.5 m. moles) was added to a solution of sodium (0.73 g; 31.7 m. moles) in methanol (20 ml) and the mixture was allowed to stand at room temperature for a period of 21/2 hours. The mixture was poured into dilute hydrochloric acid, extracted with ether (4×25 ml) and the combined extracts washed with dilute aqueous sodium carbonate and then water. The dried (MgSO4) extract was evaporated and the residue distilled to give methyl 1-cyclohexene-1-carboxylate (3.5 g; yield 87.5%), b.p. 84° C./15 mm. extracted with ether (4×25 ml) the combined extracts washed with dilute aqueous sodium carbonate The dried (MgSO4) extract was evaporated the residue distilled

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

Procedure: 1-(2-Cyclohexen-1-yl)-2,2,2-trichloroethanol (20 g; 87.3 m. moles) was added to a solution of cupric chloride dihydrate (0.25 g; 1.47 m. moles) and a 1,10-phenanthroline hydrate (0.75 g; 3.8 m. moles) in methanol (150 ml). A rapid stream of oxygen was passed through the vigorously stirred solution and a solution of sodium (2.5 g; 108.5 m. moles) in methanol (50 ml) was added over a period of 41/4 hours. A solution of cupric chloride dihydrate (0.125 g; 0.733 m. moles) and 1,10-phenanthroline hydrate (0.375 g; 1.9 m. moles) in methanol (10 ml) was then added and the reaction allowed to proceed for a further 11/4 hours at a temperature of 20°-25° C. The reaction mixture was poured into ice-cold dilute hydrochloric acid, extracted with ether (4×100 ml) and the combined extracts washed twice with dilute aqueous sodium carbonate. The dried (MgSO4) extract was evaporated and the residue distilled to give a mixture of methyl 2-cyclohexene-1-carboxylate and methyl 1-cyclohexene-1-carboxylate (7.2 g; yield 59%), b.p. 80°-85° C./12 mm, containing about 90% of the former as indicated by G.L.C. 4 hours at a temperature of 20°-25° C The reaction mixture was poured into ice-cold dilute hydrochloric acid extracted with ether (4×100 ml) the combined extracts washed twice with dilute aqueous sodium carbonate The dried (MgSO4) extract was evaporated the residue distilled to give