cycloheptylmethanol

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:0.00; pressure:0.00; stir:

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

Procedure: The subtitle compound was prepared by the method of Preparation 9 from cycloheptylmethanol and carbon tetrabromide. The crude product was purified by fractional distillation, b.pt. 115° C.-120° C. @ 30mmHg to afford 1-(bromomethyl)cycloheptane as an oil. The crude product was purified by fractional distillation, b.pt. 115° C.-120° C.

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

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

Procedure: To a stirred solution of triphenylphosphine (24.59 g; 92.8 mmol) and imidazole (6.40 g; 93.1 mmol) in methylene chloride (100 mL) cooled to 0° C. and Iodine (23.52 g; 92.7 mmol) was added portionwise over a 10 minute period. A solution of cycloheptane methanol (9.14 g; 71.3 mmol) dissolved in methylene chloride (50 mL) was then added over a 5 minute period. The cooling bath was removed and the mixture allowed to warm to room temperature and stirred overnight. The mixture was diluted with methylene chloride, washed with water and the organic layer dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed (eluent:hexanes) to give 15.35 g (93%) of cycloheptylmethyl iodide as an oil. was then added over a 5 minute period The cooling bath was removed The mixture was diluted with methylene chloride washed with water the organic layer dried (magnesium sulfate) filtered concentrated in vacuo The crude product was chromatographed (eluent:hexanes)

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

Procedure: To a stirred solution of borane tetrahydrofuran complex (95 mL of 1.5 M solution in tetrahydrofuran/ether) under argon at 0° C. was added cycloheptanecarboxylic acid (10.05 g; 69.3 mmol) in 30 mL tetrahydrofuran. After 2 h, the mixture was quenched by careful addition of methanol and the mixture concentrated in vacuo. The residue was taken up into ethyl acetate and washed with successively with 1N HCl, saturated sodium bicarbonate and brine solutions. The organic layer was dried (sodium sulfate) filtered and concentrated in vacuo to give 9.19 g (100%) of cycloheptane methanol as a colorless oil. the mixture was quenched by careful addition of methanol the mixture concentrated in vacuo washed with successively with 1N HCl, saturated sodium bicarbonate and brine solutions The organic layer was dried (sodium sulfate) filtered concentrated in vacuo

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

Procedure: To an ice-cold solution of cycloheptylmethanol (5.244 g, 40.9 mmol), triphenylphosphine (10.73 g, 40.9 mmol) and 3-hydroxybenzaldehyde (11) (5.0 g, 40.9 mmol) in THF (50 mL) was added diethyl azodicarboxylate (9.097 g, 44.99 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the residue was suspended in 20% diethyl ether-hexanes. Solids were removed by filtration then the mixture was concentrated under reduced pressure. Purification by flash chromatography (5% EtOAc-hexanes) gave 3-(cycloheptylmethoxy)benzaldehyde as a colorless oil. Yield (3.9 g, 41%): 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.46-7.51 (m, 2H), 7.39-7.40 (m, 1H), 7.25, (dt, J=6.8, 2.6 Hz, 1H), 3.81 (d, J=6.8 Hz, 2H), 1.88-1.93 (m, 1H), 1.76-1.82 (m, 2H), 1.22-1.68 (m, 10H). The mixture was concentrated under reduced pressure Solids were removed by filtration the mixture was concentrated under reduced pressure Purification by flash chromatography (5% EtOAc-hexanes)

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

Procedure: Cycloheptylmethanol was coupled with 3-bromophenol following the method used in Example 10. After concentration under reduced pressure, hexanes was added. The mixture was stirred and sonicated then the precipitate was removed by filtration and the solids washed with hexanes. The combined filtrates were concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave ((3-bromophenoxy)methyl)cycloheptane. (Yield 1.0697 g, 56%): 1H NMR (400 MHz, CDCl3) δ 7.12 (t, J=8.4, 1H), 7.06-7.04 (m, 2H), 6.82 (dq, J=8.0, 1.2, 1H), 3.70 (d, J=6.4, 2H), 1.91-1.98 (m, 1H), 1.81-1.88 (m, 2H), 1.42-1.72 (m, 8H), 1.24-1.34 (m, 2H). After concentration under reduced pressure, hexanes was added sonicated the precipitate was removed by filtration the solids washed with hexanes The combined filtrates were concentrated under reduced pressure Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)

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

Procedure: Cycloheptylmethanol was coupled with 3-bromophenol following the method used in Example 10. After concentration under reduced pressure, hexanes was added. The mixture was stirred and sonicated then the precipitate was removed by filtration and the solids washed with hexanes. The combined filtrates were concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave ((3-bromophenoxy)methyl)cycloheptane. (Yield 1.0697 g, 56%): 1H NMR (400 MHz, CDCl3) δ 7.12 (t, J=8.4, 1H), 7.06-7.04 (m, 2H), 6.82 (dq, J=8.0, 1.2, 1H), 3.70 (d, J=6.4, 2H), 1.91-1.98 (m, 1H), 1.81-1.88 (m, 2H), 1.42-1.72 (m, 8H), 1.24-1.34 (m, 2H). After concentration under reduced pressure, hexanes was added sonicated the precipitate was removed by filtration the solids washed with hexanes The combined filtrates were concentrated under reduced pressure Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)

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

Procedure: To an ice-cold solution of cycloheptane carboxylic acid (83 g, 0.58 mol) in THF (350 mL) was added BH3-THF (700 mL of a 1M solution in THF, 0.70 mol) dropwise. The reaction mixture was stirred at 0° C. for 30 min. After warming to room temperature, the reaction was quenched with the addition of MeOH (300 mL) initially dropwise then more quickly. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and aqueous NaHCO3, washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification by distillation (96° C. at 19 Torr) gave pure cycloheptylmethanol. Yield (58.3 g, 78%). 1H NMR (DMSO-d6) δ 4.36 (dt, J=3.5, 1.9 Hz, 1H), 3.13 (t, J=6.0 Hz, 2H), 1.34-1.69 (m, 11H), 1.02-1.10 (m, 2H). After warming to room temperature the reaction was quenched with the addition of MeOH (300 mL) initially dropwise The mixture was concentrated under reduced pressure The residue was partitioned between EtOAc and aqueous NaHCO3 washed with brine dried over MgSO4 concentrated under reduced pressure Purification by distillation (96° C. at 19 Torr)