4-methylidenecyclohexan-1-one

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

Procedure: To a flask charged with dry, freshly ground magnesium turnings (1.1 g, 45 mmol) and iodine (25 mg, 0.1 mmol) in THF (50 mL) was added a solution of 1,4-dibromobenzene (10.6 g, 45.0 mmol) in THF (30 mL) slowly by dropping funnel over 30 min. The resulting mixture was stirred at rt for 1 hr. The resultant grey Grignard solution was cooled to −78° C. and to it was added a solution of 4-methylenecyclohexanone (3.3 g, 30 mmol) in THF (20 mL) slowly dropwise over 20 min. The reaction was stirred at −78° C. for 30 min before being allowed to stir and warm to rt for 3 h. The resulting reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography (80 g silica gel, 0-50% EtOAc:Hept, monitor for 225 nm) afforded 2.94 g of a colorless oil that was used without further purification. ESI-MS m/z: not ionized [M+H]+, retention time 1.50 min (condition E). To a flask charged with dry over 30 min The resultant grey Grignard solution was cooled to −78° C. and to it The reaction was stirred at −78° C. for 30 min to stir warm to rt for 3 h The resulting reaction mixture was quenched with a saturated aqueous NH4Cl solution extracted with methyl tert-butyl ether The combined organic phases were washed with a saturated aqueous NaCl solution dried over MgSO4 filtered concentrated by rotary evaporation in vacuo to afford a crude yellow oil Purification of the crude material by column chromatography (80 g silica gel, 0-50% EtOAc:Hept, monitor for 225 nm)

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

Procedure: N-(para-Toluenesulfonyl)dimethylsulfoximine (1.49 g, 6.01 mmol) and anhydrous DMSO (5 mL) were added to NaH 60% oil dispersion (0.22 g, 5.46 mmol) kept under stirring under anhydrous inert gas atmosphere in a flamed 3 necks flask. The mixture became greenish, and then changed to yellow. After stirring at 35° C. for 10 h, a solution of 4-methylidenecylohexanone (0.2 g, 1.82 mmol) in 5 mL of DMSO was added and the reaction mixture was stirred at 50° C. for 20 h. Afterwards, the reaction mixture was diluted with a saturated solution of NaCl and extracted with Et2O (3 times). After drying on Na2SO4 and evaporation to dryness, the residue from evaporation was purified by means of automated flash chromatography (Isolera®TM-Biotage; isocratic Petroleum Ether-EtOAc 9:1) to give 0.252 g of the title compound as a colorless oil. Yield: 27.8%. a flamed 3 necks flask After stirring at 35° C. for 10 h the reaction mixture was stirred at 50° C. for 20 h extracted with Et2O (3 times) After drying on Na2SO4 and evaporation to dryness the residue from evaporation was purified by means of automated flash chromatography (Isolera®TM-Biotage; isocratic Petroleum Ether-EtOAc 9:1)

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

Procedure: To a mixture of ethyl 4-(piperazinyl)benzoate (2.00 g) and 4-methylenecyclohexan-1-one (0.98 g) in a mixture of methanol (40 ml) and acetic acid (1.47 ml) was portionwise added sodium cyanoborohydride (644 mg) with stirring under ice-cooling and the mixture was stirred at ambient temperature overnight. To the reaction mixture was added water (200 ml) and the mixture was adjusted to pH 8-9 with saturated aqueous sodium hydrogen carbonate. The resulting precipitates were collected and chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give ethyl 4-[4-(4-methylenecyclohexyl)-1-piperazinyl]benzoate (1.39 g). cooling the mixture was stirred at ambient temperature overnight The resulting precipitates were collected chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v) The fractions containing the desired compound were collected evaporated under reduced pressure

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

Procedure: To a flask charged with dry, freshly ground magnesium turnings (1.1 g, 45 mmol) and iodine (25 mg, 0.1 mmol) in THF (50 mL) was added a solution of 1,4-dibromobenzene (10.6 g, 45.0 mmol) in THF (30 mL) slowly by dropping funnel over 30 min. The resulting mixture was stirred at rt for 1 hr. The resultant grey Grignard solution was cooled to −78° C. and to it was added a solution of 4-methylenecyclohexanone (3.3 g, 30 mmol) in THF (20 mL) slowly dropwise over 20 min. The reaction was stirred at −78° C. for 30 min before being allowed to stir and warm to rt for 3 h. The resulting reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography (80 g silica gel, 0-50% EtOAc:Hept, monitor for 225 nm) afforded 2.94 g of a colorless oil that was used without further purification. ESI-MS m/z: not ionized [M+H]+, retention time 1.50 min (condition E). To a flask charged with dry over 30 min The resultant grey Grignard solution was cooled to −78° C. and to it The reaction was stirred at −78° C. for 30 min to stir warm to rt for 3 h The resulting reaction mixture was quenched with a saturated aqueous NH4Cl solution extracted with methyl tert-butyl ether The combined organic phases were washed with a saturated aqueous NaCl solution dried over MgSO4 filtered concentrated by rotary evaporation in vacuo to afford a crude yellow oil Purification of the crude material by column chromatography (80 g silica gel, 0-50% EtOAc:Hept, monitor for 225 nm)