methyl 4-bromo-2-fluoro-6-hydroxybenzoate

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:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1.7 g, 5.6 mmol), sodium methanesulfinate (95%) (0.91 g, 8.5 mmol), CuI (0.64 g, 3.4 mmol), L-proline (0.78 g, 6.8 mmol) and K2CO3 (0.47 g, 3.4 mmol) was dissolved in DMSO (dry) (10 ml). Nitrogen was bubbled through the solution for 15 min. The mixture was stirred and heated at 95° C. for 6 h under nitrogen. After cooling to RT, the mixture was filtered on a plug of silica and eluted with ETOAc. The filtrate was washed with 1M citric acid. The waterlayer was extracted once with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Purification on flash column chromatography (isooctane/EtOAc) gave the crude title compound (0.14 g). MS m/z (rel. intensity, 70 eV) 248 (M+, 36), 216 (bp), 173 (19), 125 (20), 81 (24). Nitrogen was bubbled through the solution for 15 min After cooling to RT the mixture was filtered on a plug of silica eluted with ETOAc The filtrate was washed with 1M citric acid The waterlayer was extracted once with EtOAc The combined organic phases were washed with brine dried (Na2SO4) filtered concentrated Purification on flash column chromatography (isooctane/EtOAc)

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

Procedure: Methyl 4-bromo-2-fluoro-6-hydroxybenzoate (0.34 g, 1.4 mmol) was dissolved in dry THF (20 ml) under a blanket of nitrogen. The solution was cooled down to 0° C. and borane tetrahydrofuran complex (5.0 ml, 5.0 mmol) was slowly added. The mixture was stirred at 0° C. for 30 min and at ambient temperature for 15 min. Then it was cooled once more to 0° C. and carefully quenched with water, acidified with aqueous HCl (5%) and finally extracted several times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness (0.33/g) to afford the title compound. No further purification was done on this intermediate. ESIMS: m/z 223 (M+H)+, 221 (M+H)+. borane tetrahydrofuran complex (5.0 ml, 5.0 mmol) was slowly added Then it was cooled once more to 0° C. carefully quenched with water The combined organic phases were dried (Na2SO4) filtered evaporated to dryness (0.33/g)

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

Procedure: Methyl 4-bromo-2,6-difluorobenzoate (0.5 g, 2.0 mmol), 2-butyn-1-ol (0.16 ml, 2.1 mmol), potassium tertbutoxide (0.47 g, 4.2 mmol) in dry DMSO (5 ml) was heated in a microwave oven at 125° C. for 2.5 min. The reaction mixture was cooled to ambient temperature and quenched with water. The mixture was acidified with aqueous HCl (1 M) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated to dryness to afford an oil. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (0.19 g, 35%). MS m/z (rel. intensity, 70 eV) 250 (M+, 43), 248 (M+, 44), 218 (96), 216 (bp), 190 (44),188 (45). quenched with water extracted with EtOAc dried (Na2SO4) filtered evaporated to dryness to afford an oil Purification by flash column chromatography (isooctane/EtOAc 10:1)

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

Procedure: Methyl 4-bromo-2,6-difluorobenzoate (0.5 g, 2.0 mmol), 2-butyn-1-ol (0.16 ml, 2.1 mmol), potassium tertbutoxide (0.47 g, 4.2 mmol) in dry DMSO (5 ml) was heated in a microwave oven at 125° C. for 2.5 min. The reaction mixture was cooled to ambient temperature and quenched with water. The mixture was acidified with aqueous HCl (1 M) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated to dryness to afford an oil. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (0.19 g, 35%). MS m/z (rel. intensity, 70 eV) 250 (M+, 43), 248 (M+, 44), 218 (96), 216 (bp), 190 (44),188 (45). quenched with water extracted with EtOAc dried (Na2SO4) filtered evaporated to dryness to afford an oil Purification by flash column chromatography (isooctane/EtOAc 10:1)

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

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1.7 g, 5.6 mmol), sodium methanesulfinate (95%) (0.91 g, 8.5 mmol), CuI (0.64 g, 3.4 mmol), L-proline (0.78 g, 6.8 mmol) and K2CO3 (0.47 g, 3.4 mmol) was dissolved in DMSO (dry) (10 ml). Nitrogen was bubbled through the solution for 15 min. The mixture was stirred and heated at 95° C. for 6 h under nitrogen. After cooling to RT, the mixture was filtered on a plug of silica and eluted with ETOAc. The filtrate was washed with 1M citric acid. The waterlayer was extracted once with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Purification on flash column chromatography (isooctane/EtOAc) gave the crude title compound (0.14 g). MS m/z (rel. intensity, 70 eV) 248 (M+, 36), 216 (bp), 173 (19), 125 (20), 81 (24). Nitrogen was bubbled through the solution for 15 min After cooling to RT the mixture was filtered on a plug of silica eluted with ETOAc The filtrate was washed with 1M citric acid The waterlayer was extracted once with EtOAc The combined organic phases were washed with brine dried (Na2SO4) filtered concentrated Purification on flash column chromatography (isooctane/EtOAc)

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

Procedure: Methyl 4-bromo-2-fluoro-6-hydroxybenzoate (0.34 g, 1.4 mmol) was dissolved in dry THF (20 ml) under a blanket of nitrogen. The solution was cooled down to 0° C. and borane tetrahydrofuran complex (5.0 ml, 5.0 mmol) was slowly added. The mixture was stirred at 0° C. for 30 min and at ambient temperature for 15 min. Then it was cooled once more to 0° C. and carefully quenched with water, acidified with aqueous HCl (5%) and finally extracted several times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness (0.33/g) to afford the title compound. No further purification was done on this intermediate. ESIMS: m/z 223 (M+H)+, 221 (M+H)+. borane tetrahydrofuran complex (5.0 ml, 5.0 mmol) was slowly added Then it was cooled once more to 0° C. carefully quenched with water The combined organic phases were dried (Na2SO4) filtered evaporated to dryness (0.33/g)

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

Procedure: Methyl 4-bromo-2,6-difluorobenzoate (0.5 g, 2.0 mmol), 2-butyn-1-ol (0.16 ml, 2.1 mmol), potassium tertbutoxide (0.47 g, 4.2 mmol) in dry DMSO (5 ml) was heated in a microwave oven at 125° C. for 2.5 min. The reaction mixture was cooled to ambient temperature and quenched with water. The mixture was acidified with aqueous HCl (1 M) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated to dryness to afford an oil. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (0.19 g, 35%). MS m/z (rel. intensity, 70 eV) 250 (M+, 43), 248 (M+, 44), 218 (96), 216 (bp), 190 (44),188 (45). quenched with water extracted with EtOAc dried (Na2SO4) filtered evaporated to dryness to afford an oil Purification by flash column chromatography (isooctane/EtOAc 10:1)