3-methylcyclohexan-1-one

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

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

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

Procedure: 3-Methylcyclohexanone (0.56 g, 4.99 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (1.00 g, 5.02 mmol) in 1M methanolic ammonia (50 mL, 50 mmol) and heated at reflux overnight. The solvent was evaporated off and the residue was suspended in CHCl3 and flash chromatographed over silica gel (43 g) eluting with EtOAc/hexane (1:10) to afford a white solid (515 mg, 63% yield): mp 55°-56° C. heated at reflux overnight The solvent was evaporated off flash chromatographed over silica gel (43 g) eluting with EtOAc/hexane (1:10)

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

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

Procedure: 3,3'-Dimethyl-1,1'-peroxydicyclohexylamine (10 g.) derived from 3-methylcyclohexanone, hydrogen peroxide and ammonia, and probably a mixture of stereoisomers was added to a solution of sodium methoxide in methanol (2 g. sodium in 40 c.c. methanol) and the mixture heated under reflux for 2 hours; only a small amount of peroxide remained unreacted. The solution was cooled, diluted with water, neutralised with hydrochloric acid and extracted with chloroform. Distillation of the chloroform extract gave 3-methylcyclohexanone (4.7 g.), methylcaprolactam (4.1 g), b.p. 145°-150°/15 mm., and residue (0.5 g.). Examination of the methylcaprolactam fraction by N.M.R. spectroscopy showed it to be a mixture of 3- and 5-methyl-caprolactam; on storage this fraction crystallized and several recrystallisations yielded the 3-methylcaprolactam, m.p. 87°-100°. probably a mixture of stereoisomers the mixture heated under reflux for 2 hours The solution was cooled extracted with chloroform Distillation of the chloroform extract

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

Procedure: 3,3'-Dimethyl-1,1'-peroxydicyclohexylamine (10 g.) derived from 3-methylcyclohexanone, hydrogen peroxide and ammonia, and probably a mixture of stereoisomers was added to a solution of sodium methoxide in methanol (2 g. sodium in 40 c.c. methanol) and the mixture heated under reflux for 2 hours; only a small amount of peroxide remained unreacted. The solution was cooled, diluted with water, neutralised with hydrochloric acid and extracted with chloroform. Distillation of the chloroform extract gave 3-methylcyclohexanone (4.7 g.), methylcaprolactam (4.1 g), b.p. 145°-150°/15 mm., and residue (0.5 g.). Examination of the methylcaprolactam fraction by N.M.R. spectroscopy showed it to be a mixture of 3- and 5-methyl-caprolactam; on storage this fraction crystallized and several recrystallisations yielded the 3-methylcaprolactam, m.p. 87°-100°. probably a mixture of stereoisomers the mixture heated under reflux for 2 hours The solution was cooled extracted with chloroform Distillation of the chloroform extract

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

Procedure: A three neck 500 mL flask was charged with 20 g (0.23 mole) of piperidine, 53 g (0.47 mole) of 3-methylcyclohexanone and 200 mL of anhydrous cyclohexane. To the resulting solution, 84 g (0.70 mole) of anhydrous magnesium sulfate was added and the mixture was mechanically stirred and heated at reflux (the reaction was monitored by NMR) for 192 hours. The reaction mixture was then filtered through a fritted glass funnel. The filtrate (containing the enamine product, excess 3-methylcyclohexanone and cyclohexane) was transferred to a hydrogenation vessel. To this mixture, 3 g of 10% Pd on activated carbon was added and the vessel affixed to a hydrogenation Parr shaker at 65 psi of hydrogen. The mixture was left on the Parr shaker for 6 hours at room temperature. The mixture was then filtered through a bed of Celite® in a fitted glass filtering funnel. The filtrate was transferred to a round bottom flask and concentrated under reduced pressure on a rotary evaporator. The obtained residue, which contained 1-(3-methylcyclohexyl)piperidine and excess 3-methylcyclohexanone, was treated with 120 mL of 3M aqueous HCl solution. The mixture was stirred in an ice-water bath for 20 minutes. Then, the mixture was transferred to a reparatory funnel and extracted with 200 mL of diethyl ether. The ether layer, containing the excess 3-methylcyclohexanone, was separated from aqueous layer containing the amine in the form of its onium hydrochloride salt. The ether layer was dried over MgSO4, filtered and concentrated under reduced pressure on a rotary evaporator to recover 31 g of the excess 3-methylcyclohexanone. The aqueous layer was treated with 50 wt. % aqueous NaOH solution in an ice bath until a pH of about 11 was reached. This solution was then extracted with 300 mL of diethyl ether. The ether layer was dried over MgSO4, filtered and concentrated under reduced pressure on a rotary evaporator to give 32 g of 1-(3-methylcyclohexyl)piperidine as a yellow oil. The product was confirmed by 1H-NMR and 13C-NMR analysis. Some piperidine was also present in the oil as an impurity. heated at reflux (the reaction for 192 hours The reaction mixture was then filtered through a fritted glass funnel The filtrate (containing the enamine product, excess 3-methylcyclohexanone and cyclohexane) was transferred to a hydrogenation vessel To this mixture, 3 g of 10% Pd on activated carbon was added The mixture was then filtered through a bed of Celite® in a fitted glass filtering funnel The filtrate was transferred to a round bottom flask concentrated under reduced pressure on a rotary evaporator was treated with 120 mL of 3M aqueous HCl solution The mixture was stirred in an ice-water bath for 20 minutes Then, the mixture was transferred to a reparatory funnel extracted with 200 mL of diethyl ether The ether layer, containing the excess 3-methylcyclohexanone was separated from aqueous layer containing the amine in the form of its onium hydrochloride salt The ether layer was dried over MgSO4 filtered concentrated under reduced pressure on a rotary evaporator to recover 31 g of the excess 3-methylcyclohexanone The aqueous layer was treated with 50 wt. % aqueous NaOH solution in an ice bath until a pH of about 11 This solution was then extracted with 300 mL of diethyl ether The ether layer was dried over MgSO4 filtered concentrated under reduced pressure on a rotary evaporator

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

Procedure: 3-Methylcyclohexanone, 22.4 grams, contained in 250 ml. of chloroform and 50 ml. of ethyl acetate, is heated to boiling. A mixture of 98.3 grams of cupric bromide and 50 ml. of ethyl acetate is added and heated to maintain elimination of hydrogen bromide. When all of the hydrogen bromide is evolved, the mixture is heated to its reflux temperature for 15 minutes, filtered and the filtrate evaporated to a small volume. The residue is placed upon an alumina column and eluted with methylene chloride. Evaporation of the eluate yields 35.5 grams of crude 2-bromo-3-methylcyclohexanone suitable for condensation with the triazoles of Examples 1 or 2. heated the mixture is heated to its reflux temperature for 15 minutes filtered the filtrate evaporated to a small volume eluted with methylene chloride Evaporation of the

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

Procedure: 3-Methylcyclohexanone, 22.4 grams, contained in 250 ml. of chloroform and 50 ml. of ethyl acetate, is heated to boiling. A mixture of 98.3 grams of cupric bromide and 50 ml. of ethyl acetate is added and heated to maintain elimination of hydrogen bromide. When all of the hydrogen bromide is evolved, the mixture is heated to its reflux temperature for 15 minutes, filtered and the filtrate evaporated to a small volume. The residue is placed upon an alumina column and eluted with methylene chloride. Evaporation of the eluate yields 35.5 grams of crude 2-bromo-3-methylcyclohexanone suitable for condensation with the triazoles of Examples 1 or 2. heated the mixture is heated to its reflux temperature for 15 minutes filtered the filtrate evaporated to a small volume eluted with methylene chloride Evaporation of the

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

Procedure: For example, magnesium turnings (6.4 g, 0.26 mole) were flame-dried, the containing glassware was cooled, and 3-bromochlorobenzene (50 g, 0.26 mole), in 50 ml of diethyl ether was added. As the reaction began, an additional 200 ml of diethyl ether was added, and the reaction mixture was heated under reflux for 0.5 hour. To the refluxing reaction mixture was added dropwise, during a 0.5 hour period, 3-methylcyclohexanone (29.2 g, 0.26 mole) in 100 ml of diethyl ether. Upon complete addition, the reaction mixture was heated under reflux for an additional 0.5 hour, then poured into 500 ml of icewater containing 50 ml of hydrochloric acid. The mixture was extracted with three 200 ml portions of diethyl ether. The combined extract was washed twice with 100 ml portions of an aqueous solution saturated with sodium chloride. After separation, the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to an oil. The oil was purified by distillation using a Kugelrohr distilling system at 85°/0.05 mm for 2.5 hours to give 1-(3-chlorophenyl)-3-methylcyclohexan-1-ol (25 g). the containing glassware was cooled the reaction mixture was heated under reflux for 0.5 hour To the refluxing reaction mixture was added dropwise, during a 0.5 hour period Upon complete addition the reaction mixture was heated under reflux for an additional 0.5 hour poured into 500 ml of icewater The mixture was extracted with three 200 ml portions of diethyl ether The combined extract was washed twice with 100 ml portions of an aqueous solution saturated with sodium chloride After separation the organic layer was dried over sodium sulfate filtered The filtrate was evaporated under reduced pressure to an oil The oil was purified by distillation distilling system at 85°/0.05 mm for 2.5 hours

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product of Example 268D (0.054 g, 0.15 mmol) was reacted with 3-methylcyclohexanone (1.26 g, 11.25 mmol) in N,N-dimethylacetamide (1 mL) in a sealed tube at 135° C. for 45 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound. concentrated under vacuum The resulting residue was triturated with diethyl ether (3 mL) filtered

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

Procedure: For example, magnesium turnings (6.4 g, 0.26 mole) were flame-dried, the containing glassware was cooled, and 3-bromochlorobenzene (50 g, 0.26 mole), in 50 ml of diethyl ether was added. As the reaction began, an additional 200 ml of diethyl ether was added, and the reaction mixture was heated under reflux for 0.5 hour. To the refluxing reaction mixture was added dropwise, during a 0.5 hour period, 3-methylcyclohexanone (29.2 g, 0.26 mole) in 100 ml of diethyl ether. Upon complete addition, the reaction mixture was heated under reflux for an additional 0.5 hour, then poured into 500 ml of ice-water containing 50 ml of hydrochloric acid. The mixture was extracted with three 200 ml portions of diethyl ether. The combined extract was washed twice with 100 ml portions of an aqueous solution saturated with sodium chloride. After separation, the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to an oil. The oil was purified by distillation using a Kugelrohr distilling system at 85°/0.05 mm for 2.5 hours to give 1-(3-chlorophenyl)-3-methylcyclohexan-1-ol (25 g). the containing glassware was cooled the reaction mixture was heated under reflux for 0.5 hour To the refluxing reaction mixture was added dropwise, during a 0.5 hour period Upon complete addition the reaction mixture was heated under reflux for an additional 0.5 hour The mixture was extracted with three 200 ml portions of diethyl ether The combined extract was washed twice with 100 ml portions of an aqueous solution saturated with sodium chloride After separation the organic layer was dried over sodium sulfate filtered The filtrate was evaporated under reduced pressure to an oil The oil was purified by distillation distilling system at 85°/0.05 mm for 2.5 hours