2-phenylcyclohexan-1-one

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

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

Procedure: To a cooled solution of 2.78 ml (40 mmol) of cyclopropylamine and 2.87 ml (50 mmol) of acetic acid, together with 5 g of 3 Å molecular sieves, in 50 ml of methanol, are added 3.5 g (20 mmol) of 2-phenylcyclohexanone. The reaction mixture is stirred for 3.5 hrs at reflux. The reaction mixture is then cooled to 0° C. and 3 g (50 mmol) of sodium cyanoborohydride are slowly added and the reaction mixture is further stirred for 2 hrs at reflux. The cooled reaction mixture is then filtered over a cake of diatomaceous earth. The cake is washed twice by 80 ml of methanol and the combined methanolic extracts are concentrated under vacuum. 100 ml of water are then added to the residue and the pH is ajusted to 12 with a 1 N solution of sodium hydroxyde. The watery layer is extracted with 100 ml of ethyl acetate. The organic layer is washed twice by brine and dried over magnesium sulfate to yield after concentration 3.52 g of a yellow oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 1.0 g (23% yield) of cis-N-cyclopropyl-2-phenylcyclo-hexanamine as a yellow oil (M+H=216) and 1.9 g (44% yield) of trans-N-cyclopropyl-2-phenylcyclohexanamine as a colorless oil (M+H=216). at reflux the reaction mixture is further stirred for 2 hrs at reflux The cooled reaction mixture is then filtered over a cake of diatomaceous earth The cake is washed twice by 80 ml of methanol the combined methanolic extracts are concentrated under vacuum 100 ml of water are then added to the residue The watery layer is extracted with 100 ml of ethyl acetate The organic layer is washed twice by brine dried over magnesium sulfate to yield after concentration 3.52 g of a yellow oil

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

Procedure: Preparation of (+/−)-cis-1-(2-Phenyl-cyclohexyl)-piperidin-4-one. To a solution of 2-phenyl-cyclohexanone (46.0 g, 264 mmol) and 1,4-dioxa-8-aza-spiro[4,5]decane (31.5 g, 220 mmol) in toluene (380 ml), p-toluenesulphonic acid monohydrate (4.18 g, 22.0 mmol) was added and the mixture was heated to reflux in an apparatus equipped with a Dean-Stark trap for 24 h. The reaction mixture was then evaporated and the resulting crude enamine dissolved in 1,2-dichloroethane (900 ml) and acetic acid (8.00 ml). To this solution, sodium triacetoxyborohydride (69.0 g, 308 mmol) was added in portion. After a total reaction time of 2.5 h, the reaction mixture was treated with 2N NaOH (250 ml) and extracted with dichloromethane. The pooled organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. Purification of the crude product over a silica gel plug (10:1) with n-heptane/ethyl acetate 10:1 then n-heptane/ethyl acetate 9:1 and finally ethyl acetate as eluent provided (+/−)-8-(cis-2-phenyl-cyclohexyl)-1,4-dioxa-8-aza-spiro[4,5]decane (44.8 g, 68%) as a yellow oil, MS (ISP): m/e=302.4 (M+H+). the mixture was heated to reflux in an apparatus equipped with a Dean-Stark trap for 24 h The reaction mixture was then evaporated the resulting crude enamine dissolved in 1,2-dichloroethane (900 ml) extracted with dichloromethane The pooled organic extracts were washed with brine dried over magnesium sulphate filtered evaporated Purification of the crude product over a silica gel plug (10:1) with n-heptane/ethyl acetate 10:1

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

Procedure: A solution of 15 g (86 mmole) of 2-phenylcyclohexanone in 60 mL of carbon tetrachloride at -5° C. was treated via rapid dropwise addition with a solution of 14.4 g (90 mmole) of bromine in 70 mL of carbon tetrachloride so as to maintain the reaction temperature below 5° C. The color disappeared rapidly. The mixture was concentrated in vacuo to a brown solid and the solid triturated with methanol. The resulting white solid was collected by filtration to provide 9.55 g of product. After cooling the mother liquor at -25° C., an additional 5.2 g of solid was obtained, for a total yield of 68%, a portion of which was carried on directly in Step B below. to maintain the reaction temperature below 5° C The mixture was concentrated in vacuo to a brown solid the solid triturated with methanol The resulting white solid was collected by filtration

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

Procedure: A solution of 15 g (86 mmole) of 2-phenylcyclohexanone in 60 mL of carbon tetrachloride at -5° C. was treated via rapid dropwise addition with a solution of 14.4 g (90 mmole) of bromine in 70 mL of carbon tetrachloride so as to maintain the reaction temperature below 5° C. The color disappeared rapidly. The mixture was concentrated in vacuo to a brown solid and the solid triturated with methanol. The resulting white solid was collected by filtration to provide 9.55 g of product. After cooling the mother liquor at -25° C., an additional 5.2 g of solid was obtained, for a total yield of 68%, a portion of which was carried on directly in Step B below. to maintain the reaction temperature below 5° C The mixture was concentrated in vacuo to a brown solid the solid triturated with methanol The resulting white solid was collected by filtration

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

Procedure: Prepared according to the method of Example 14, Stage A, by thermal condensation in diphenyl ether of 2-phenyl-cyclohexanone and ethyl phenyl malonate. M.P. 185° C. (Dipropyl ether/ethanol). Prepared

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

Procedure: Prepared according to the method of Example 14, Stage A, by thermal condensation in diphenyl ether of 2-phenyl-cyclohexanone and ethyl phenyl malonate. M.P. 185° C. (Dipropyl ether/ethanol). Prepared

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

Procedure: To a mixture of 5 phenoxy pentyl bromide (122.0 g, 0.5 mol) and 2-phenylcyclohexanone (104.4 g, 0.6 mol) in 1.5 L THF, NaH (0.55 mol, 24.0 g) was added portionwise, keeping the temperature between 25° to 30° C. After most of the H2 evolution had ceased, the reaction mixture was heated to reflux for 16 hours under a N2 atmosphere. After cooling to room temperature, 50 mL isopropanol was added and the mixture was concentrated in vacuo to half its volume. This residue was diluted with 2 L ether and 1 L H2O. The layers were separated and the aqueous layer was washed one time with 500 mL ether. The combined organic layers were washed two times each with 500 mL H2O, dried (MgSO4), and concentrated in vacuo to give a solid. Recrystallization from petroleum ether yielded 27.5 g (16.4%), mp 69°-72° C., of the desired product. was added portionwise between 25° to 30° C the reaction mixture was heated to reflux for 16 hours under a N2 atmosphere the mixture was concentrated in vacuo to half its volume This residue was diluted with 2 L ether and 1 L H2O The layers were separated the aqueous layer was washed one time with 500 mL ether The combined organic layers were washed two times each with 500 mL H2O dried (MgSO4) concentrated in vacuo to give a solid Recrystallization from petroleum ether yielded 27.5 g (16.4%), mp 69°-72° C.

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

Procedure: To a mixture of 5 phenoxy pentyl bromide (122.0 g, 0.5 mol) and 2-phenylcyclohexanone (104.4 g, 0.6 mol) in 1.5 L THF, NaH (0.55 mol, 24.0 g) was added portionwise, keeping the temperature between 25° to 30° C. After most of the H2 evolution had ceased, the reaction mixture was heated to reflux for 16 hours under a N2 atmosphere. After cooling to room temperature, 50 mL isopropanol was added and the mixture was concentrated in vacuo to half its volume. This residue was diluted with 2 L ether and 1 L H2O. The layers were separated and the aqueous layer was washed one time with 500 mL ether. The combined organic layers were washed two times each with 500 mL H2O, dried (MgSO4), and concentrated in vacuo to give a solid. Recrystallization from petroleum ether yielded 27.5 g (16.4%), mp 69°-72° C., of the desired product. was added portionwise between 25° to 30° C the reaction mixture was heated to reflux for 16 hours under a N2 atmosphere the mixture was concentrated in vacuo to half its volume This residue was diluted with 2 L ether and 1 L H2O The layers were separated the aqueous layer was washed one time with 500 mL ether The combined organic layers were washed two times each with 500 mL H2O dried (MgSO4) concentrated in vacuo to give a solid Recrystallization from petroleum ether yielded 27.5 g (16.4%), mp 69°-72° C.

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

Procedure: The title compound was prepared from 2-phenyl-2-(2-pyridyl)-cyclohexanone (4.50 g, 0.017 mol, prepared from the alkylation of 2-phenylcyclohexanone with 2-chloropyridine and sodium hydride), 2,6-diisopropyl-phenyl isocyanate (3.60 g, 0.017 mol), and lithium diisopropylamide (0.017 mol) using the procedure described in Example 1.

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

Procedure: To a solution of 2-phenylcyclohexanone (2 g, 11.48 mmol) in 50 ml of anhydrous DME in an ice bath was added 1M sodium bis(trimethylsilyl)amide (12.63 mL, 12.63 mmol) dropwise and the solution was stirred at the same temp for 20 minutes. In a separated flask allylpalladium chloride dimer (0.104 g, 0.287 mmol) was dissolved in 10 ml of anhydrous DME, and triphenylphosphine (0.151 g, 0.574 mmol) was added to the solution. It was stirred for 20 minutes at room temp and then allyl acetate (1.300 mL, 12.05 mmol) was added. This solution was added to the anion solution dropwise and the mixture was stirred at room temp for 2 hrs. The reaction was quenched with saturated NH4Cl and extracted with hexane. The organic layer was washed with brine. The combine aqueous layers were back-extracted with hexane once and combined. Dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with hexane followed by 1:9 EtOAc-hexane to give 2.24 g of 2-allyl-2-phenylcyclohexanone. 1H NMR (400 MHz, CDCl3) δ ppm 7.35 (2 H, t, J=7.58 Hz), 7.21-7.27 (1 H, m), 7.12-7.18 (2 H, m), 5.35-5.52 (1 H, m), 4.82-4.97 (2 H, m), 2.61-2.72 (1 H, m), 2.39-2.55 (2 H, m), 2.24-2.38 (2 H, m), 1.89-1.99 (1 H, m, J=9.39, 6.15, 2.88, 2.88 Hz), 1.62-1.81 (4 H, m). It was stirred for 20 minutes at room temp This solution was added to the anion solution dropwise the mixture was stirred at room temp for 2 hrs The reaction was quenched with saturated NH4Cl extracted with hexane The organic layer was washed with brine The combine aqueous layers were back-extracted with hexane once Dried over Na2SO4 evaporated to give an oily residue It was purified by Combiflash (120 g silica gel) eluting with hexane

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

Procedure: Triton B surfactant (500 μL) was added to a stirred solution of 2-phenylcyclohexanone (5 g, 28.7 mmol) in dioxane (40 mL). A solution of acrylonitrile (1.8 g, 33.9 mmol) in dioxane (5 mL) was added dropwise. A slight exotherm was observed. The solution was stirred at room temperature for 3 h and concentrated. The residue was diluted with EtOAc (50 mL) and washed with water (20 mL, 2×). The EtOAc extract was dried (MgSO4), filtered, and concentrated. The residual oil was chromatographed on a silica gel column. Elution with 2% EtOAc in heptane, followed by 5% EtOAc in heptane afforded 3-(2-oxo-1-phenylcyclohexyl)propanenitrile (Int. 2-A, 5.05 g, 77% yield) as a colorless oil. HPLC: tR=2.73 min, YMC Combi S5 ODS 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.2% H3PO4; Final solvent: 90% aq. MeOH-0.2% H3PO4. LC/MS: m/e 228.26 (M+H)+, 250.14 (M+Na)+. concentrated The residue was diluted with EtOAc (50 mL) washed with water (20 mL, 2×) The EtOAc extract was dried (MgSO4) filtered concentrated The residual oil was chromatographed on a silica gel column Elution with 2% EtOAc in heptane