2-(4-fluorophenyl)cyclohexan-1-one

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

Procedure: bii) Alternatively, to a solution of rac-2-(4-fluoro-phenyl)-cyclohexanol (7.5 g, 39 mmol) in dry DMSO (67 mL) was added triethylamine (27 mL, 190 mmol) under argon and the resulting mixture cooled to 0° C. and then a solution of sulfur trioxide pyridine complex (18.4 g, 116 mmol) in dry DMSO (98 mL) was added dropwise over 15 min. After 1 h, the mixture was diluted with water (200 mL) and the product extracted with DCM (2×100 mL). The combined organic extracts were then dried over sodium sulfate, followed by filtration and evaporation. Purification by filtration through silica gel, eluting with ethyl acetate:hexane (1:4) afforded the title compound (7.1 g, 95%) as white crystals. MS: m/e=192.1 (M). the product extracted with DCM (2×100 mL) The combined organic extracts were then dried over sodium sulfate followed by filtration and evaporation Purification by filtration through silica gel eluting with ethyl acetate:hexane (1:4)

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

Procedure: bi) To a solution of rac-2-(4-fluoro-phenyl)-cyclohexanol (3.8 g, 20 mmol) in DCM (320 mL) was added Dess-Martin periodinane [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one](10 g, 24 mmol) at room temperature and after 2 h the reaction mixture was washed with sodium hydrogen carbonate (10%, 150 mL). The organic phase was then separated and washed with sodium thiosulfite (10%, 150 mL) and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography through silica gel, eluting with ethyl acetate:hexane (1:4) afforded the title compound (3.4 g, 89%) as white crystals. MS: m/e=192.1 (M). after 2 h the reaction mixture was washed with sodium hydrogen carbonate (10%, 150 mL) The organic phase was then separated washed with sodium thiosulfite (10%, 150 mL) dried over sodium sulfate filtered evaporated Purification by chromatography through silica gel eluting with ethyl acetate:hexane (1:4)

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-4-fluorobenzene (12.5 mL, 114 mmol) in diethylether (250 mL) at −78° C. was added BuLi (1.6 M, 68 mL, 109 mmol) under argon. After 5 min at this temperature, cyclohexenoxide (11.0 mL, 109 mmol) was added followed by the addition of borontrifluoride-diethyletherate (13.8 mL, 109 mmol) whereby the temperature increased to approx. −50° C. After 4 h at this temperature the reaction was quenched by the addition of ammonium chloride (saturated, 200 mL) and diluted with water (50 mL). The product was then extracted with diethylether (3×100 mL) and the combined organic extracts dried over sodium sulfate. Filtration and evaporation afforded the tide compound (11.9 g, 56%) as white crystals after trituration from hexane. MS: m/e=194.1 (M). After 4 h at this temperature the reaction was quenched by the addition of ammonium chloride (saturated, 200 mL) diluted with water (50 mL) The product was then extracted with diethylether (3×100 mL) the combined organic extracts dried over sodium sulfate Filtration and evaporation

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

Procedure: To a solution of oxalyl chloride (0.45 mL, 5.2 mmol) in dry dichloromethane (15 mL) at −78° C. is added a solution of DMSO (0.73 mL, 10.3 mmol) in dichloromethane (10 mL) dropwise, and the resulting mixture is allowed to stir at −78° C. for 30 minutes. Then a solution of 2-(4-Fluoro-phenyl)-cyclohexanol (500 mg, 2.57 mmol) in dichloromethane (5 mL) is added and stirred for 15 minutes. Then triethylamine (2.87 mL, 15.4 mmol) is added and the reaction is allowed to slowly warm up to 20° C. and stirred for 16 hours. The mixture is poured into ice-water (30 mL) and organic layer is washed with water (10 mL×5), then brine (10 mL×1) and dried over anhdrous sodium sulfate. After concentration, the crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 30%) to give 342 mg of the desired product. stirred for 15 minutes to slowly warm up to 20° C. stirred for 16 hours is washed with water (10 mL×5) brine (10 mL×1) and dried over anhdrous sodium sulfate After concentration the crude is purified by silica flash column chromatography

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

Procedure: 2-(4-fluorophenyl)cyclohexanone and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was reacted as in Intermediate AC(1) to provide 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-(4-fluorophenyl)-4-a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid.

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

Procedure: 2-(4-fluorophenyl)cyclohexanone and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was reacted as in Intermediate AC(1) to provide 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-(4-fluorophenyl)-4a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid. 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione. LC-MS (M+H)+=262.1. 1H NMR (500 MHz, CDCl3) δ ppm 9.61 (1H, br s), 7.10 (2H, dd, J=5.0, 8.5 Hz), 6.98 (2H, app t, J=8.5 Hz), 3.77 (1H, t, J=4.9 Hz), 2.38-2.53 (2H, m), 2.16-2.07 (1H, m), 1.87-1.62 (3H, m).

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

Procedure: bii) Alternatively, to a solution of rac-2-(4-fluoro-phenyl)-cyclohexanol (7.5 g, 39 mmol) in dry DMSO (67 mL) was added triethylamine (27 mL, 190 mmol) under argon and the resulting mixture cooled to 0° C. and then a solution of sulfur trioxide pyridine complex (18.4 g, 116 mmol) in dry DMSO (98 mL) was added dropwise over 15 min. After 1 h, the mixture was diluted with water (200 mL) and the product extracted with DCM (2×100 mL). The combined organic extracts were then dried over sodium sulfate, followed by filtration and evaporation. Purification by filtration through silica gel, eluting with ethyl acetate:hexane (1:4) afforded the title compound (7.1 g, 95%) as white crystals. MS: m/e=192.1 (M). the product extracted with DCM (2×100 mL) The combined organic extracts were then dried over sodium sulfate followed by filtration and evaporation Purification by filtration through silica gel eluting with ethyl acetate:hexane (1:4)

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

Procedure: bi) To a solution of rac-2-(4-fluoro-phenyl)-cyclohexanol (3.8 g, 20 mmol) in DCM (320 mL) was added Dess-Martin periodinane [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one](10 g, 24 mmol) at room temperature and after 2 h the reaction mixture was washed with sodium hydrogen carbonate (10%, 150 mL). The organic phase was then separated and washed with sodium thiosulfite (10%, 150 mL) and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography through silica gel, eluting with ethyl acetate:hexane (1:4) afforded the title compound (3.4 g, 89%) as white crystals. MS: m/e=192.1 (M). after 2 h the reaction mixture was washed with sodium hydrogen carbonate (10%, 150 mL) The organic phase was then separated washed with sodium thiosulfite (10%, 150 mL) dried over sodium sulfate filtered evaporated Purification by chromatography through silica gel eluting with ethyl acetate:hexane (1:4)

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-4-fluorobenzene (12.5 mL, 114 mmol) in diethylether (250 mL) at −78° C. was added BuLi (1.6 M, 68 mL, 109 mmol) under argon. After 5 min at this temperature, cyclohexenoxide (11.0 mL, 109 mmol) was added followed by the addition of borontrifluoride-diethyletherate (13.8 mL, 109 mmol) whereby the temperature increased to approx. −50° C. After 4 h at this temperature the reaction was quenched by the addition of ammonium chloride (saturated, 200 mL) and diluted with water (50 mL). The product was then extracted with diethylether (3×100 mL) and the combined organic extracts dried over sodium sulfate. Filtration and evaporation afforded the tide compound (11.9 g, 56%) as white crystals after trituration from hexane. MS: m/e=194.1 (M). After 4 h at this temperature the reaction was quenched by the addition of ammonium chloride (saturated, 200 mL) diluted with water (50 mL) The product was then extracted with diethylether (3×100 mL) the combined organic extracts dried over sodium sulfate Filtration and evaporation

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

Procedure: The Grignard reagent prepared by adding 210 g of p-fluorobromobenzene in 800 ml. of anhydrous ether to 29.1 g of magnesium turnings in 50 ml. of ether was added, with cooling to keep the temperature of the reaction less than 15° C., to a solution of 158.4 g of 2-chlorocyclohexanone in 800 ml. of anhydrous benzene. The reaction was stirred at 25° for 18 hrs. then the ether was distilled off and the resulting benzene solution refluxed for 24 hrs. It was then poured into a mixture of 1 liter water and 200 ml. hydrochloric acid and extracted with ether. After evaporation of the ether the residue was distilled to yield 117 g (51%), b.p. 115 (0.2 mm). The material solidified on standing and was recrystallized from hexane, m.p. 56°-59° C. with cooling the temperature of the reaction less than 15° C. then the ether was distilled off the resulting benzene solution refluxed for 24 hrs It was then poured into a mixture of 1 liter water and 200 ml hydrochloric acid and extracted with ether After evaporation of the ether the residue was distilled to yield 117 g (51%) was recrystallized from hexane, m.p. 56°-59° C.

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

Procedure: The Grignard reagent prepared by adding 210 g of p-fluorobromobenzene in 800 ml. of anhydrous ether to 29.1 g of magnesium turnings in 50 ml. of ether was added, with cooling to keep the temperature of the reaction less than 15° C., to a solution of 158.4 g of 2-chlorocyclohexanone in 800 ml. of anhydrous benzene. The reaction was stirred at 25° for 18 hrs. then the ether was distilled off and the resulting benzene solution refluxed for 24 hrs. It was then poured into a mixture of 1 liter water and 200 ml. hydrochloric acid and extracted with ether. After evaporation of the ether the residue was distilled to yield 117 g (51%), b.p. 115 (0.2 mm). The material solidified on standing and was recrystallized from hexane, m.p. 56°-59° C. with cooling the temperature of the reaction less than 15° C. then the ether was distilled off the resulting benzene solution refluxed for 24 hrs It was then poured into a mixture of 1 liter water and 200 ml hydrochloric acid and extracted with ether After evaporation of the ether the residue was distilled to yield 117 g (51%) was recrystallized from hexane, m.p. 56°-59° C.

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

Procedure: 2-(4-fluorophenyl)cyclohexanone and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was reacted as in Intermediate AC(1) to provide 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-(4-fluorophenyl)-4a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid. 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione. LC-MS (M+H)+=262.1. 1H NMR (500 MHz, CDCl3) δ ppm 9.61 (1H, br s), 7.10 (2H, dd, J=5.0, 8.5 Hz), 6.98 (2H, app t, J=8.5 Hz), 3.77 (1H, t, J=4.9 Hz), 2.38-2.53 (2H, m), 2.16-2.07 (1H, m), 1.87-1.62 (3H, m).