1,4-dioxepan-6-one

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

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

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

Procedure: Magnesium (1.27 g, 0.053 mol), dried in an oven for 1 hr at 75° C., was stirred with THF (125 mL) in a 500 mL three-necked flask at reflux. A crystal of iodine was added followed by a solution of 4-methoxybromobenzene in THF (50 mL), added dropwise over 15 min. After the addition of 10 mL of the solution the reaction initiated. After complete addition of the solution, the reaction mixture was heated at reflux for 2 hrs. The resulting grey solution was cooled to 0° C. and a solution of 1,4-dioxepan-6-one (prepared as described in U.S. Pat. No. 4,410,354) (5.08 g, 0.044 mol) in THF (25 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight then evaporated. The residue was acidified to pH=1 with 1N HCl and extracted with ether (2×250 mL). The ether extracts were washed with water, dried (MgSO4), filtered and concentrated to give a sticky brown solid (9.45 g). This was purified by column chromatography on silica gel eluting with ethyl acetate-hexanes. The relevant fractions were concentrated to give the desired product (6.21 g, 63%). at reflux added dropwise over 15 min After complete addition of the solution the reaction mixture was heated at reflux for 2 hrs then evaporated extracted with ether (2×250 mL) The ether extracts were washed with water dried (MgSO4) filtered concentrated

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

Procedure: Magnesium (1.27 g, 0.053 mol), dried in an oven for 1 hr at 75° C., was stirred with THF (125 mL) in a 500 mL three-necked flask at reflux. A crystal of iodine was added followed by a solution of 4-methoxybromobenzene in THF (50 mL), added dropwise over 15 min. After the addition of 10 mL of the solution the reaction initiated. After complete addition of the solution, the reaction mixture was heated at reflux for 2 hrs. The resulting grey solution was cooled to 0° C. and a solution of 1,4-dioxepan-6-one (prepared as described in U.S. Pat. No. 4,410,354) (5.08 g, 0.044 mol) in THF (25 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight then evaporated. The residue was acidified to pH=1 with 1N HCl and extracted with ether (2×250 mL). The ether extracts were washed with water, dried (MgSO4), filtered and concentrated to give a sticky brown solid (9.45 g). This was purified by column chromatography on silica gel eluting with ethyl acetate-hexanes. The relevant fractions were concentrated to give the desired product (6.21 g, 63%). at reflux added dropwise over 15 min After complete addition of the solution the reaction mixture was heated at reflux for 2 hrs then evaporated extracted with ether (2×250 mL) The ether extracts were washed with water dried (MgSO4) filtered concentrated

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

Procedure: 0.47 g (2.1 mmol) 1-(3-fluorophenyl)ethan-1,2-diamine dihydrochloride were placed with 23 mg (0.10 mmol) benzyltriethylammonium chloride in 50 ml dichloromethane and cooled with ice/acetone. Then 0.71 ml (14 mmol) of a 50% sodium hydroxide solution were added. At 0° C. 0.23 g (2 mmol) [1,4]dioxepan-6-one were added dropwise together with 0.24 ml (4.6 mmol) chloroform and 20 ml dichloromethane. The mixture was left overnight to warm up to RT. Then the reaction mixture was cooled to 0° C. and adjusted to pH 1 with a 6N aqueous hydrochloric acid solution. The phases were separated. The aqueous phase was made alkaline with a 4N sodium hydroxide solution and extracted with DCM. The combined organic phases were dried and evaporated to dryness by rotary evaporation. At 0° C Then the reaction mixture was cooled to 0° C. The phases were separated extracted with DCM The combined organic phases were dried evaporated to dryness by rotary evaporation

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

Procedure: 0.68 g (3.0 mmol) 1-(4-fluorophenyl)ethane-1,2-diamine dihydrochloride were placed with 32 mg (0.14 mmol) benzyltriethylammonium chloride in 6 ml dichloromethane and cooled with ice/acetone. Then 1.0 ml (19 mmol) 50% sodium hydroxide solution were added. At 0° C. 0.44 g (3.0 mmol) 80% [1,4]dioxepan-6-one were added dropwise together with 0.37 ml (4.6 mmol) chloroform and 5 ml dichloromethane. The reaction mixture was left overnight to warm up to RT. Then the reaction mixture was acidified with an aqueous 4N hydrochloric acid solution. The phases were separated. The aqueous phase was made alkaline with a 4N sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases were dried and evaporated to dryness by rotary evaporation. Purification was carried out by flash chromatography. At 0° C The phases were separated extracted with ethyl acetate The combined organic phases were dried evaporated to dryness by rotary evaporation Purification

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

Procedure: 3.13 g (15.0 mmol) (R)-1-(3,5-difluorophenyl)ethan-1,2-diamine-hydrochloride were placed with 0.17 g (0.73 mmol) benzyltriethylammonium chloride in 30 ml dichloromethane and cooled with ice/acetone. Then 5.21 ml (102.2 mmol) of a 50% sodium hydroxide solution were added. At 0° C. to 2° C., 1.70 g (14.6 mmol) [1,4]dioxepan-6-one together with 1.83 ml (22.7 mmol) chloroform and 20 ml dichloromethane were added dropwise within 1.5 h. The mixture was left overnight to warm up to RT. Then it was cooled to 0° C. and the reaction mixture was adjusted to pH1 with a 6N aqueous hydrochloric acid solution. The phases were separated. The aqueous phase was made alkaline with a 4N sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases were dried and evaporated to dryness by rotary evaporation. Purification was carried out by flash chromatography. Then it was cooled to 0° C. The phases were separated extracted with ethyl acetate The combined organic phases were dried evaporated to dryness by rotary evaporation Purification