N-methoxy-N-methylcyclohexanecarboxamide

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

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

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

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

Procedure: To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added a solution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70% yield as oil. The organic layer was separated dried filtered concentrated Purification of the residue by flash chromatography

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

Procedure: To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added a solution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70% yield as oil. The organic layer was separated dried filtered concentrated Purification of the residue by flash chromatography

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

Procedure: To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added a solution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70% yield as oil. The organic layer was separated dried filtered concentrated Purification of the residue by flash chromatography

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

Procedure: To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added a solution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70% yield as oil. The organic layer was separated dried filtered concentrated Purification of the residue by flash chromatography

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

Procedure: To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added a solution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70% yield as oil. The organic layer was separated dried filtered concentrated Purification of the residue by flash chromatography

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

Procedure: To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added a solution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70% yield as oil. The organic layer was separated dried filtered concentrated Purification of the residue by flash chromatography

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

Procedure: To the stirring solution of N-methyl-N-methoxy-cyclohexanecarboxamide (0.05 mol, 8.5 g) in 150 ml anhydrous THF at −10-0° C. (ice-NaCl bath) the solution of vinyl magnesium bromide (1M in THF, 0.1 mol, 100 ml) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h (white solid formed), then at rt for 4 h (the solid dissolved). The resulting solution was added slowly by cannula into a well-cooled Erlenmeyer flask equipped with magnetic stirrer and thermometer, containing 0.5 L saturated aqueous NH4Cl, with such speed that the temperature stays between 0° C. and +10° C., at vigorous stirring. At higher temperatures oligomerization of the product occurs. The phases were separated; the aqueous one extracted with EtOAc (3×100 ml), and the combined organic extracts were washed with sat. aq. NH4Cl until pH<7 (5×50 ml, carefully removing all the N,O-dimethylhydroxylamine product), then washed with brine (100 ml), dried with Na2SO4, and concentrated under vacuum >80 mbar (taking care not to evaporate the volatile product). Yield 11.8 g of yellow oil containing pure vinylcyclohexylketone. Used in the next reaction without purification as 0.05 mol. 1H NMR (400 MHz, CDCl3) δ 6.41 (dd, 1H, 17.5 Hz, 10.3 Hz, Z—H—CH═C), 6.25 (dd, 1H, 17.5 Hz, 1.4 Hz, E-H—CH═C), 5.74 (dd, 1H, 10.3 Hz, 1.4 Hz, CO—CH═C), 2.60 (m, 1H, cyclohexyl CH—CO), 1.9-1.7 (m, 3H, cyclohexyl), 1.7-1.5 (m, 2H, cyclohexyl), 1.4-1.2 (m, 5H, cyclohexyl). (white solid formed) at rt for 4 h (the solid dissolved) The resulting solution was added slowly by cannula into a well-cooled Erlenmeyer flask equipped with magnetic stirrer stays between 0° C. and +10° C., at vigorous stirring The phases were separated the aqueous one extracted with EtOAc (3×100 ml) the combined organic extracts were washed with sat. aq. NH4Cl until pH<7 (5×50 ml carefully removing all the N,O-dimethylhydroxylamine product), then washed with brine (100 ml) dried with Na2SO4 concentrated under vacuum >80 mbar ( to evaporate the volatile product) Yield 11.8 g of yellow oil containing pure vinylcyclohexylketone Used in the next reaction without purification as 0.05 mol

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

Procedure: To the stirring solution of N-methyl-N-methoxy-cyclohexanecarboxamide (0.05 mol, 8.5 g) in 150 ml anhydrous THF at −10-0° C. (ice-NaCl bath) the solution of vinyl magnesium bromide (1M in THF, 0.1 mol, 100 ml) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h (white solid formed), then at rt for 4 h (the solid dissolved). The resulting solution was added slowly by cannula into a well-cooled Erlenmeyer flask equipped with magnetic stirrer and thermometer, containing 0.5 L saturated aqueous NH4Cl, with such speed that the temperature stays between 0° C. and +10° C., at vigorous stirring. At higher temperatures oligomerization of the product occurs. The phases were separated; the aqueous one extracted with EtOAc (3×100 ml), and the combined organic extracts were washed with sat. aq. NH4Cl until pH<7 (5×50 ml, carefully removing all the N,O-dimethylhydroxylamine product), then washed with brine (100 ml), dried with Na2SO4, and concentrated under vacuum >80 mbar (taking care not to evaporate the volatile product). Yield 11.8 g of yellow oil containing pure vinylcyclohexylketone. Used in the next reaction without purification as 0.05 mol. 1H NMR (400 MHz, CDCl3) δ 6.41 (dd, 1H, 17.5 Hz, 10.3 Hz, Z—H—CH═C), 6.25 (dd, 1H, 17.5 Hz, 1.4 Hz, E-H—CH═C), 5.74 (dd, 1H, 10.3 Hz, 1.4 Hz, CO—CH═C), 2.60 (m, 1H, cyclohexyl CH—CO), 1.9-1.7 (m, 3H, cyclohexyl), 1.7-1.5 (m, 2H, cyclohexyl), 1.4-1.2 (m, 5H, cyclohexyl). (white solid formed) at rt for 4 h (the solid dissolved) The resulting solution was added slowly by cannula into a well-cooled Erlenmeyer flask equipped with magnetic stirrer stays between 0° C. and +10° C., at vigorous stirring The phases were separated the aqueous one extracted with EtOAc (3×100 ml) the combined organic extracts were washed with sat. aq. NH4Cl until pH<7 (5×50 ml carefully removing all the N,O-dimethylhydroxylamine product), then washed with brine (100 ml) dried with Na2SO4 concentrated under vacuum >80 mbar ( to evaporate the volatile product) Yield 11.8 g of yellow oil containing pure vinylcyclohexylketone Used in the next reaction without purification as 0.05 mol

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

Procedure: In a dried, flushed with nitrogen round bottom flask, N,O-dimethyl hydroxylamine hydrochloride (0.1 mol, 13.3 ml) was suspended in 200 ml anhydrous dichloromethane. To the resulting mixture triethylamine (0.22 mol, 30 ml) was added dropwise in ˜5 min while cooling by water (stirring became difficult because of salts formation). To the resulting mixture, while stirring under nitrogen and cooling by ice water, cyclohexanecarbonyl chloride was added dropwise in ˜15 min. The mixture was stirred overnight, washed with water (50 ml), saturated aqueous NH4Cl (50 ml), then brine (50 ml), dried over Na2SO4, and concentrated to give 17.8 g of crude product. Purification on 150 g silica gel, eluent hexanes-ethyl acetate, from 100:0 to 50:50, afforded 13.6 g (80%) of N-methyl-N-methoxy-cyclohexanecarboxamide as clear oil, Rf 0.44 (hexanes-EtOAc 1:1), 1H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H, OCH3), 3.15 (s, 3H, NCH3), 2.65 (m, 1H, CH—CO), 1.8-1.6 (m, 5H, cyclohexyl), 1.5-1.4 (qm, 2H, cyclohexyl), 1.3-1.2 (m, 3H, cyclohexyl). In a dried, flushed with nitrogen round bottom flask was added dropwise in ˜15 min The mixture was stirred overnight washed with water (50 ml), saturated aqueous NH4Cl (50 ml) brine (50 ml), dried over Na2SO4 concentrated to give 17.8 g of crude product Purification on 150 g silica gel, eluent hexanes-ethyl acetate