5-bromo-7-fluoro-3H-2-benzofuran-1-one

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

Procedure: To a flask charged with 5-bromo-7-fluoro-2-benzofuran-1 (3H)-one (300 mg, 1.3 mmol) and a stir bar was added allyl tri-n-butyltin (0.6 mL, 2.0 mmol), palladium tetrakis triphenylphosphine (230 mg, 0.19 mmol), lithium chloride (170 mg, 3.9 mmol), and toluene (5 mL). The mixture was purged three times with nitrogen, and heated to reflux for 4 hours. LC showed formation of the desired product, which was purified by silica gel chromatography to deliver 5-allyl-7-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 193 [M+1]+; The mixture was purged three times with nitrogen heated to reflux for 4 hours was purified by silica gel chromatography

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

Procedure: To a flask charged with (3-bromo-5-fluorophenyl)methanol (360 mg, 1.8 mmol) and a stir bar was added added thallium trifluoroacetate (1.0 g, 1.8 mmol) and TFA (3.0 mL) at 0° C. The mixture was allowed to stir for 16 hours. LC showed no SM left at that point. The volatiles were removed under reduced pressure, and the residue was dissolved in DCM and concentrated twice to affect azeotropic removal of all TFA. After pumping the residue under high vacuum for 20 minutes, palladium chloride (31 mg, 0.18 mmol), lithium chloride (150 mg, 3.5 mmol), magnesium oxide (140 mg, 3.5 mmol), and MeOH (15 mL) were added to the flask. The mixture was treated under an atmosphere of CO for 2 hours. To this mixtue was added DCM and EtOAc to precipitate all the inorganic solids. The crude solution was filtered through a Celite® pad, and the filtrate was collected, adsorbed onto silica gel, and purified by silica gel chromatography. Removal of solvents gave rise to 5-bromo-7-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 231 [M+1]+; was added left at that point The volatiles were removed under reduced pressure the residue was dissolved in DCM concentrated twice removal of all TFA for 20 minutes The mixture was treated under an atmosphere of CO for 2 hours to precipitate all the inorganic solids The crude solution was filtered through a Celite® pad the filtrate was collected purified by silica gel chromatography Removal of solvents

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

Procedure: A mixture of 5-bromo-7-fluoro-2-benzofuran-1(3H)-one (4.6 g, 20.0 mmol), potassium vinyltrifluoroborate (2.9 g, 22 mmol) and Pd(dppf)2Cl2 (0.5 g) in 40 mL of EtOH and 40 mL of TEA was refluxed under Ar for 4 hours. After concentration, the residue was purified by column chromatography (PE:EtOAc=20:1) to afford 7-fluoro-5-vinyl-2-benzofuran-1(3H)-one. was refluxed under Ar for 4 hours After concentration the residue was purified by column chromatography (PE:EtOAc=20:1)

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

Procedure: A solution of n-BuLi (36.7 mL, 91.6 mmol) was added dropwise to a solution of 2,4-dibromo-6-fluorobenzoic acid (13.0 g, 43.6 mmol, in 200 mL of THF) at −70° C. The resulting solution was stirred for 15 minutes before CH2O gas (generated by heating 5.1 g of Para formaldehyde to 200° C.) was bubbled into the mixture at −70° C. The suspension was stirred for 1 hour then warmed to room temperature and stirred for another 2 hours. HCl gas was bubbled into the suspension for 15 minutes to give a clear solution. The mixture was diluted with 1 L of EtOAc and washed subsequently with water, saturated Na2CO3 and brine, then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EtOAc=5:1) to give 5-bromo-7-fluoro-2-benzofuran-1(3H)-one as white solid. was bubbled into the mixture at −70° C stirred for another 2 hours HCl gas was bubbled into the suspension for 15 minutes to give a clear solution washed subsequently with water, saturated Na2CO3 and brine dried over anhydrous Na2SO4 concentrated The residue was purified by column chromatography (PE:EtOAc=5:1)

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

Procedure: A mixture of 5-bromo-7-fluoro-2-benzofuran-1(3H)-one (4.6 g, 20.0 mmol), potassium vinyltrifluoroborate (2.9 g, 22 mmol) and Pd (dppf)2Cl2 (0.5 g) in 40 mL of EtOH and 40 mL of TEA was refluxed under Ar for 4 hours. After concentration, the residue was purified by column chromatography (PE:EtOAc=20:1) to afford 7-fluoro-5-vinyl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.23 (s, 1H), 7.17 (d, J=10.0 Hz, 1H), 6.70-6.77 (m, 1H), 5.89 (d, J=17.2 Hz, 1H), 5.51 (d, J=11.2 Hz, 1H), 5.28 (s, 2H). was refluxed under Ar for 4 hours After concentration the residue was purified by column chromatography (PE:EtOAc=20:1)

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

Procedure: A solution of n-BuLi (36.7 mL, 91.6 mmol) was added dropwise to a solution of 2,4-dibromo-6-fluorobenzoic acid (13.0 g, 43.6 mmol, in 200 mL of THF) at −70° C. The resulting solution was stirred for 15 minutes before CH2O gas (generated by heating 5.1 g of Para formaldehyde to 200° C.) was bubbled into the mixture at −70° C. The suspension was stirred for 1 hour then warmed to room temperature and stirred for another 2 hours. HCl gas was bubbled into the suspension for 15 minutes to give a clear solution. The mixture was diluted with 1 L of EtOAc and washed subsequently with water, saturated Na2CO3 and brine, then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EtOAc=5:1) to give 5-bromo-7-fluoro-2-benzofuran-1(3H)-one as white solid. was bubbled into the mixture at −70° C stirred for another 2 hours HCl gas was bubbled into the suspension for 15 minutes to give a clear solution washed subsequently with water, saturated Na2CO3 and brine dried over anhydrous Na2SO4 concentrated The residue was purified by column chromatography (PE:EtOAc=5:1)