4-Bromo-6-fluoro-2,3-dihydro-1H-inden-1-one

Under argon 3-(2-bromo-4-fluorophenyl)propanoic acid (1 .2 g) is added in small portions to trifluoromethanesulfonic acid (15 mL) at room temperature. The mixture is stirred for 2 hours at 60°C and for 16 hours at 80°C. After cooling to room temperature the mixture is poured slowly in ice-water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous NaTo a solution of 3-(2-bromo-4-fluoro-phenyl)-propionic acid (5.6 g, 22.67 mmol) in 0H2012 (56 mL) was added oxalyl chloride (4.13 mL, 48.18 mmol) at 0 00 and allowed to stir atRT for 1 8h. Excess oxalyl chloride was removed in vacuo to give the acid chloride as a semi-solid. The acid chloride was dissolved in 0H2012 (30 mL) and added to a suspension of anhydrous AId3 (3.77 g, 28.340 mmol) in 0H2012 (60 mL) at 0 00 and the reaction mixture was heated under reflux for 2h. The reaction mixture was cooled to RT, poured into ice-water and extracted with 0H2012 (1 x 150 mL). The combined organiclayers were washed with 0.1 M sodium hydroxide solution and water. The organic layer was dried (Na2SO4) and concentrated in vacuo to afford 4-bromo-6-fluoro-indan-1-one as an off-white solid (4.1 g, 78%).Rt:0.5 (10% EtOAc/pet-ether).1H NMR (400MHz, 0D013): O 7.55-7.52 (m, 1H), 7.39-7.37 (m, 1H), 3.06-3.03 (m, 2H), 2.79-2.76 (m, 2H).A stirred solution of According to Scheme 2, step 1: To a solution of 4-Bromo-6-fluoro-indan-1 -one (10.0 g, 43.7 mmol) in ethanol (183 ml) at 0C NaBH4 (3.67 g, 97.0 mmol) was added in portions and then the mixture was stirred at room temperature for 18 h. After evaporation of solvents in vacuo, water was added to the residue, the solution was extracted 3 times with ethyl acetate, then 2N aqueous HCI was added and the combined organic layers were washed with saturated aq. NaHCO3 and water. After drying over Na2SO4 and filtration, solvents were evaporated in vacuo to give 10.0 g of 4-Bromo-6-fluoro-indan-1 -ol (4a) which was used immediately in the next step without purification. Rt = 1 .19 min (LC method 4). 1H-NMR (d6-DMSO): ' (ppm) = 1 .7-1 .9 (m, 1 H); 2.38-2.45 (m, 1 H); 2.66-2.70 (m, 1 H); 2.8-2.9 (m, 1 H); 5.1 (d, 1 H); 5.5 (d, 1 H); 7.15 (dd, 1 H); 7.4 (dd, 1 H).4-Bromo-6-fluoro-indan-1 -ol (4a): According to Scheme 2, step 1 : To a solution of 4-Bromo-6-fluoro-indan-1 -one (10.0 g, 43.7 mmol) in ethanol (183 ml) at 0C NaBH4 (3.67 g, 97.0 mmol) was added in portions and then the mixture was stirred at room temperature for 18 h. After evaporation of solvents in vacuo, water was added to the residue, the solution was extracted 3 times with ethyl acetate, then 2N aqueous HCI was added and the combined organic layers were washed with saturated aq. NaHCO3 and water. After drying over Na2SO4 and filtration, solvents were evaporated in vacuo to give 10.0 g of 4-Bromo-6-fluoro-indan-1 -ol (4a) which was used immediately in the next step without purification.Rt = 1.19 min (LC method 4).1H-NMR (d6-DMSO): ' (ppm) = 1 .7-1 .9 (m, 1 H); 2.38-2.45 (m, 1 H); 2.66-2.70 (m, 1 H); 2.8-2.9 (m, 1 H); 5.1 (d, 1 H); 5.5 (d, 1 H); 7.15 (dd, 1 H); 7.4 (dd, 1 H).According to Scheme 2, step 1: To a solution of 4-Bromo-6-fluoro-indan-1-one (10.0 g, 43.7 mmol) in ethanol (183 ml) at 0 C. NaBH4 (3.67 g, 97.0 mmol) was added in portions and then the mixture was stirred at room temperature for 18 h. After evaporation of solvents in vacuo, water was added to the residue, the solution was extracted 3 times with ethyl acetate, then 2N aqueous HCl was added and the combined organic layers were washed with saturated aq. NaHCO3 and water. After drying over Na2SO4 and filtration, solvents were evaporated in vacuo to give 10.0 g of 4-Bromo-6-fluoro-indan-1-ol (4a) which was used immediately in the next step without purification. Rt=1.19 min (LC method 4). 1H-NMR (d6-DMSO): delta (ppm)=1.7-1.9 (m, 1H); 2.38-2.45 (m, 1H); 2.66-2.70 (m, 1H); 2.8-2.9 (m, 1H); 5.1 (d, 1H); 5.5 (d, 1H); 7.15 (dd, 1H); 7.4 (dd, 1H).(i) 4-Bromo-6-Fluoro-1-indanone. Recrystallization of an 0.8 g sample from hexanes gave 0.54 g of General procedure: Step 2 (0504) To a mixture of 3-(2-bromo-3-methylphenyl)propionic acid (3. 5g), dichloromethane (15 mL) and oxalyl dichloride (4.0 g) was added N, N-dimethylformamide (0.05 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. To a mixture of the residue and dichloromethane (30 mL) was added aluminium. chloride (2.64 g), and the mixture was stirred at an external temperature of 50 C. for 12 hours. The mixture was cooled to room temperature. The mixture was poured into ice water, and the resulting mixture was diluted with dichloromethane. The insoluble material was removed by filtration with Celite pad, and the dichloromethane layer of the filtrate was separated. The dichloromethane layer was washed with 0.1 mol/L sodium hydroxide aqueous solution and brine successively, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 0%-20% ethyl acetate/hexane, gradient elution) to give the title compound (2.59 The structural formula was illustrated in Table 6.

Molecular Weight:229.05
XLogP3:2.5
Hydrogen Bond Acceptor Count:2
Exact Mass:227.95861
Monoisotopic Mass:227.95861
Topological Polar Surface Area:17.1
Heavy Atom Count:12
Complexity:207
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes