1-(3-fluoro-2-hydroxyphenyl)ethanone

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 1-(3-fluoro-2-hydroxyphenyl)ethanone (30 g) and diethyl oxalate (31 g) in ethanol (600 mls) was added dropwise to sodium ethoxide (from 9.85 g of sodium) in ethanol (600 mls) and the mixture was stirred and heated at reflux for 2 days. After the mixture had cooled, it was diluted with 60-80 petrol and the solid was collected and dried. A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours. The solid was filtered out, the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum. The aqueous solution was acidified to pH 3, the precipitate was collected, washed with water and recrystallised from acetone/water to give the title compound as yellow needles (18.7 g). M.p. 194°-208°. heated at reflux for 2 days After the mixture had cooled the solid was collected dried A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours The solid was filtered out the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum the precipitate was collected washed with water recrystallised from acetone/water

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

Procedure: A solution of 1-(3-fluoro-2-hydroxyphenyl)ethanone (30 g) and diethyl oxalate (31 g) in ethanol (600 mls) was added dropwise to sodium ethoxide (from 9.85 g of sodium) in ethanol (600 mls) and the mixture was stirred and heated at reflux for 2 days. After the mixture had cooled, it was diluted with 60-80 petrol and the solid was collected and dried. A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours. The solid was filtered out, the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum. The aqueous solution was acidified to pH 3, the precipitate was collected, washed with water and recrystallised from acetone/water to give the title compound as yellow needles (18.7 g). M.p. 194°-208°. heated at reflux for 2 days After the mixture had cooled the solid was collected dried A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours The solid was filtered out the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum the precipitate was collected washed with water recrystallised from acetone/water

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

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

Procedure: Pyrrolidine (4.8 ml, 58 mmol) was added to a stirred solution of 1-(3-fluoro-2-hydroxyphenyl)ethanone (28) (5.9 g, 39 mmol) and tetrahydro-4h-pyran-4-one (4.6 ml, 50 mmol) in toluene (40 mL) at rt. After the exotherm subsided, the reaction mixture was stirred at rt for 1 h. then subjected to Dean-Stark reflux conditions for 6 h. The reaction mixture was cooled, poured into ice and 2 N HCl aqueous solution, and extracted with EtOAc (2×). The combined organics were washed with 2 N HCl aqueous solution (1×), 2 N NaOH aqueous solution (2×), brine (1×), and dried over Na2SO4. Concentration in vacuo gave 8-fluoro-2′,3′,5′,6′-tetrahydrospiro[chromene-2,4′-pyran]-4(3H)-one (29) (4.4 g, 48% yield) which was taken onto the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51-7.60 (2H, m), 7.00-7.07 (1H, m), 3.60-3.73 (4H, m), 2.93 (2H, s), 1.71-1.92 (4H, m). reflux conditions for 6 h The reaction mixture was cooled extracted with EtOAc (2×) The combined organics were washed with 2 N HCl aqueous solution (1×), 2 N NaOH aqueous solution (2×), brine (1×) dried over Na2SO4 Concentration in vacuo

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

Procedure: A solution of 1-(3-fluoro-2-hydroxyphenyl) ethanone (30 g) and diethyl oxalate (31 g) in ethanol (600 mls) was added dropwise to sodium ethoxide (from 9.85 g of sodium) in ethanol (600 mls) and the mixture was stirred and heated at reflux for 2 days. The mixture was cooled, diluted with 60-80 petrol and the solid was collected and dried. A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours. The solid was filtered out, the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum. The aqueous solution was acidified to pH3, the precipitate was collected, washed with water and recrystallised from acetone/water to give the title compound as yellow needles (18.7 g). M.p. 194°-208° (decomp), i.r. λmax (nujol) 1768, 1642 cm-1 (C=O). heated at reflux for 2 days The mixture was cooled the solid was collected dried A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours The solid was filtered out the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum the precipitate was collected washed with water recrystallised from acetone/water

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

Procedure: A solution of 1-(3-fluoro-2-hydroxyphenyl)ethanone (30 g) and diethyl oxalate (31 g) in ethanol (600 mls) was added dropwise to sodium ethoxide (from 9.85 g of sodium) in ethanol (600 mls) and the mixture was stirred and heated at reflux for 2 days. After the mixture had cooled, it was diluted with 60-80 petrol and the solid was collected and dried. A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours. The solid was filtered out, the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum. The aqueous solution was acidified to pH 3, the precipitate was collected, washed with water and recrystallised from acetone/water to give the title compound as yellow needles (18.7 g). M.p. 194°-208°. heated at reflux for 2 days After the mixture had cooled the solid was collected dried A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours The solid was filtered out the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum the precipitate was collected washed with water recrystallised from acetone/water