5,6-difluoro-2,3-dihydroinden-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:

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

Procedure: A solution of 10.6 g of 5,6-difluoro-1-indanone, 13.1 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 2:1). In addition to 3.6 g of educt there were obtained 5.32 g (38%) of (RS)-2-(2-buten-1-yl)-5,6-difluoro-1-indanone as a brown oil. separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped) The reaction mixture was subsequently concentrated in a vacuum purified by column chromatography on silica gel (hexane/diethyl ether 2:1) In addition to 3.6 g of educt

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

Procedure: A solution of 10.6 g of 5,6-difluoro-1-indanone, 13.1 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 2:1). In addition to 3.6 g of educt there were obtained 5.32 g (38%) of (RS)-2-(2-buten-1-yl)-5,6-difluoro-1-indanone as a brown oil. separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped) The reaction mixture was subsequently concentrated in a vacuum purified by column chromatography on silica gel (hexane/diethyl ether 2:1) In addition to 3.6 g of educt

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

Procedure: 5,6-Difluoroindan-1-one (59.3 g, 0.353 mol) was dissolved in 1 L of ethanol and sodium borohydride (6.68 g, 0.176 mol) was added. The mixture was stirred for 48 hours and the ethanol was removed by evaporation under reduced pressure. The residue was partitioned between diethyl ether and water and the mixture was acidified with 1N hydrochloric acid. The mixture was dried over magnesium sulfate and filtered. The solvents were evaporated giving 5,6-difluoro-1-hydroxyindane (59.8 g) as an oil. the ethanol was removed by evaporation under reduced pressure The residue was partitioned between diethyl ether and water The mixture was dried over magnesium sulfate filtered The solvents were evaporated

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

Procedure: 5,6-difluoro-indan-1-one (2.49 g, 14.8 mmol) and piperidine (4.4 ml, 3.78 g, 44.4 mmol) were dissolved in pyridine (10 ml) and heated to reflux for 16 hours. The reaction was cooled, and the solvent removed under vacuum. The residue was taken in ethyl ether, washed with 1N aqueous sodium hydroxide and water, dried with magnesium sulfate, and the solvent removed under vacuum to give the desired product as 2.97 g of a black solid that was used without further purification. 1H NMR (300 MHz, CDCl3) 7.32 (d, 1H), 6.88 (d, 1H), 3.19 (m, 4H), 3.03 (m, 2H), 2.66 (m, 2H), 1.73 (m, 4H), 1.62 (m, 2H). MS (CSI) m/e 234 (M+H)+ heated to reflux for 16 hours The reaction was cooled the solvent removed under vacuum washed with 1N aqueous sodium hydroxide and water dried with magnesium sulfate the solvent removed under vacuum

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

Procedure: To a carbon disulfide solution (300 mL) containing AlCl3 (76.4 g, 572.6 mmol) at 0° C. was added a carbon disulfide solution (120 mL) of 3-(3,4-difluorophenyl)propanoyl chloride (33.4 g, 163.6 mmol) over 10 min. The solution was stirred for 30 min at 0° C. and heated to reflux for 4 hours. Upon cooling to room temperature the solution was carefully poured onto crushed ice. The carbon disulfide layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residual solid was purified by silica gel column chromatography (5-10% ethyl acetate/hexanes) yielding 19.3 g (114.9 mmol, 70% yield) of 5,6-difluoro-2,3-dihydro-1H-inden-1-one as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.50 (t, 1H, J=8.0 Hz), 7.24 (t, 1H, J=6.6 Hz), 3.09 (t, 2H, J=5.5 Hz), 2.72-2.69 (m, 2H). heated to reflux for 4 hours Upon cooling to room temperature the solution was carefully poured onto crushed ice The carbon disulfide layer was separated the aqueous layer extracted with ethyl acetate The combined organic layers were dried over MgSO4 the solvent removed in vacuo The residual solid was purified by silica gel column chromatography (5-10% ethyl acetate/hexanes)

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

Procedure: To a carbon disulfide solution (300 mL) containing AlCl3 (76.4 g, 572.6 mmol) at 0° C. was added a carbon disulfide solution (120 mL) of 3-(3,4-difluorophenyl)propanoyl chloride (33.4 g, 163.6 mmol) over 10 min. The solution was stirred for 30 min at 0° C. and heated to reflux for 4 hours. Upon cooling to room temperature the solution was carefully poured onto crushed ice. The carbon disulfide layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residual solid was purified by silica gel column chromatography (5-10% ethyl acetate/hexanes) yielding 19.3 g (114.9 mmol, 70% yield) of 5,6-difluoro-2,3-dihydro-1H-inden-1-one as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.50 (t, 1H, J=8.0 Hz), 7.24 (t, 1H, J=6.6 Hz), 3.09 (t, 2H, J=5.5 Hz), 2.72-2.69 (m, 2H). heated to reflux for 4 hours Upon cooling to room temperature the solution was carefully poured onto crushed ice The carbon disulfide layer was separated the aqueous layer extracted with ethyl acetate The combined organic layers were dried over MgSO4 the solvent removed in vacuo The residual solid was purified by silica gel column chromatography (5-10% ethyl acetate/hexanes)

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

Procedure: To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6 mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min the solution was cooled to room temperature and water was added. Precipitated solid was collected by filtration and rinsed thoroughly with water affording 3.97 g of a light orange solid. The solid was dissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10% Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H2 for 24 hr using a Parr hydrogenation apparatus, and filtered through a bed of Celite (CHCl3 wash). The filtrate was concentrated in vacuo and the residue was dissolved in water. The aqueous solution was basified with solid K2CO3, extracted with CHCl3 (3×), combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2) affording the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H) 170, 0.68 min (LC/MS method A). Upon heating for 45 min the solution Precipitated solid was collected by filtration rinsed thoroughly with water affording 3.97 g of a light orange solid The solid was dissolved in HOAc (100 mL) conc HCl (8 mL) was added filtered through a bed of Celite (CHCl3 wash) The filtrate was concentrated in vacuo the residue was dissolved in water extracted with CHCl3 (3×) were dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (MeOH/CH2Cl2)

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

Procedure: To a solution of 3,4-difluorophenyl propionic acid (30.45 g; 163.6 mmol) and 2 drops of DMF in CH2Cl2 (200 mL) was added oxalyl chloride (41.4 g, 327 mmol) over 20 min. The resulting solution was stirred for 24 hr and concentrated in vacuo (chased 1×PhMe, ca. 100 mL). The residue was dissolved in CS2 (300 mL), cooled to 0° C. and AlCl3 (76.4 g, 573 mmol) was added over 10 min. The mixture was stirred 30 min at 0° C., then heated under reflux for 4 hr. Upon cooling to room temperature the solution was carefully poured onto crushed ice, the carbon disulfide layer was separated and the aqueous layer extracted with EtOAc. Combined organics were dried over MgSO4 and the concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.50 (t, 1H, J=8.0 Hz), 7.24 (t, 1H, J=6.6 Hz), 3.09 (t, 2H, J=5.5 Hz), 2.72-2.69 (m, 2H). concentrated in vacuo (chased 1×PhMe, ca. 100 mL) The residue was dissolved in CS2 (300 mL) The mixture was stirred 30 min at 0° C. heated under reflux for 4 hr Upon cooling to room temperature the solution was carefully poured onto crushed ice the carbon disulfide layer was separated the aqueous layer extracted with EtOAc Combined organics were dried over MgSO4 the concentrated in vacuo The residue was purified by flash chromatography (EtOAc/hexanes)

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

Procedure: 5,6-difluoro-indan-1-one (2.49 g, 14.8 mmol) and piperidine (4.4 ml, 3.78 g, 44.4 mmol) were dissolved in pyridine (10 ml) and heated to reflux for 16 hours. The reaction was cooled, and the solvent removed under vacuum. The residue was taken in ethyl ether, washed with 1N aqueous sodium hydroxide and water, dried with magnesium sulfate, and the solvent removed under vacuum to give the desired product as 2.97 g of a black solid that was used without further purification. 1H NMR (300 MHz, CDCl3) 7.32 (d, 1H), 6.88 (d, 1H), 3.19 (m, 4H), 3.03 (m, 2H), 2.66 (m, 2H), 1.73 (m, 4H), 1.62 (m, 2H). MS (CSI) m/e 234 (M+H)+ heated to reflux for 16 hours The reaction was cooled the solvent removed under vacuum washed with 1N aqueous sodium hydroxide and water dried with magnesium sulfate the solvent removed under vacuum