methyl 6-hydroxy-1-benzofuran-2-carboxylate

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:

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 267 (650 mg, 3.39 mmol) in a 1:1 mixture of DMF-acetone (20 mL) was added 4-(2-chloroethyl)morpholine (630 mg, 3.39 mmol) and potassium carbonate (937 mg, 6.78 mmol). The reaction mixture was stirred at 60° C. for 72 hours. The solvents were removed under reduced pressure and water (50 mL) was added to the residue. 2M Sodium carbonate solution (20 mL) was added and the resultant solution was extracted with ethyl acetate (2×40 mL). The organic phase was separated, dried with sodium sulfate and the solvents removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 1:1 ethyl acetate-hexanes, then ethyl acetate, then 9:1 ethyl acetate-methanol. This afforded 268 as a clear oil (760 mg, 73% yield). 1H NMR: (DMSO) δ 7.67-7.63 (m, 2H), 7.32 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.14-4.16 (m, 2H), 3.85 (s, 3H), 3.57-3.55 (m, 4H), 2.88-2.86 (m, 2H), 2.72-2.70 (m, 4H). The solvents were removed under reduced pressure and water (50 mL) was added to the residue 2M Sodium carbonate solution (20 mL) was added the resultant solution was extracted with ethyl acetate (2×40 mL) The organic phase was separated dried with sodium sulfate the solvents removed under reduced pressure The residue was purified by flash chromatography on silica gel eluting with a gradient of 1:1 ethyl acetate-hexanes

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 267 (650 mg, 3.39 mmol) in a 1:1 mixture of DMF-acetone (20 mL) was added 4-(2-chloroethyl)morpholine (630 mg, 3.39 mmol) and potassium carbonate (937 mg, 6.78 mmol). The reaction mixture was stirred at 60° C. for 72 hours. The solvents were removed under reduced pressure and water (50 mL) was added to the residue. 2M Sodium carbonate solution (20 mL) was added and the resultant solution was extracted with ethyl acetate (2×40 mL). The organic phase was separated, dried with sodium sulfate and the solvents removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 1:1 ethyl acetate-hexanes, then ethyl acetate, then 9:1 ethyl acetate-methanol. This afforded 268 as a clear oil (760 mg, 73% yield). 1H NMR: (DMSO) δ 7.67-7.63 (m, 2H), 7.32 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.14-4.16 (m, 2H), 3.85 (s, 3H), 3.57-3.55 (m, 4H), 2.88-2.86 (m, 2H), 2.72-2.70 (m, 4H). The solvents were removed under reduced pressure and water (50 mL) was added to the residue 2M Sodium carbonate solution (20 mL) was added the resultant solution was extracted with ethyl acetate (2×40 mL) The organic phase was separated dried with sodium sulfate the solvents removed under reduced pressure The residue was purified by flash chromatography on silica gel eluting with a gradient of 1:1 ethyl acetate-hexanes

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

Procedure: To a stirred solution of 266 (1.2 g, 4.26 mmol) in methanol (20 mL) was added 10% palladium on charcoal (250 mg). The flask was purged with hydrogen gas for 1 minute and then the reaction was stirred under a hydrogen atmosphere for 15 hours. The palladium was filtered through a celite pad, the filtrate was evaporated under reduced pressure, and the resulting solid dried under vacuum to afford 267 as a white solid (700 mg, 86%). 1H NMR: (DMSO) δ 10.07 (s, 1H), 7.63 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 6.98 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 3.84 (s, 3H). The flask was purged with hydrogen gas for 1 minute The palladium was filtered through a celite pad the filtrate was evaporated under reduced pressure the resulting solid dried under vacuum

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

Procedure: To a stirred solution of 266 (1.2 g, 4.26 mmol) in methanol (20 mL) was added 10% palladium on charcoal (250 mg). The flask was purged with hydrogen gas for 1 minute and then the reaction was stirred under a hydrogen atmosphere for 15 hours. The palladium was filtered through a celite pad, the filtrate was evaporated under reduced pressure, and the resulting solid dried under vacuum to afford 267 as a white solid (700 mg, 86%). 1H NMR: (DMSO) δ 10.07 (s, 1H), 7.63 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 6.98 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 3.84 (s, 3H). The flask was purged with hydrogen gas for 1 minute The palladium was filtered through a celite pad the filtrate was evaporated under reduced pressure the resulting solid dried under vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 267 (650 mg, 3.39 mmol) in a 1:1 mixture of DMF-acetone (20 mL) was added 4-(2-chloroethyl)morpholine (630 mg, 3.39 mmol) and potassium carbonate (937 mg, 6.78 mmol). The reaction mixture was stirred at 60° C. for 72 hours. The solvents were removed under reduced pressure and water (50 mL) was added to the residue. 2M Sodium carbonate solution (20 mL) was added and the resultant solution was extracted with ethyl acetate (2×40 mL). The organic phase was separated, dried with sodium sulfate and the solvents removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 1:1 ethyl acetate-hexanes, then ethyl acetate, then 9:1 ethyl acetate-methanol. This afforded 268 as a clear oil (760 mg, 73% yield). 1H NMR: (DMSO) δ 7.67-7.63 (m, 2H), 7.32 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.14-4.16 (m, 2H), 3.85 (s, 3H), 3.57-3.55 (m, 4H), 2.88-2.86 (m, 2H), 2.72-2.70 (m, 4H). The solvents were removed under reduced pressure and water (50 mL) was added to the residue 2M Sodium carbonate solution (20 mL) was added the resultant solution was extracted with ethyl acetate (2×40 mL) The organic phase was separated dried with sodium sulfate the solvents removed under reduced pressure The residue was purified by flash chromatography on silica gel eluting with a gradient of 1:1 ethyl acetate-hexanes

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

Procedure: To a stirred solution of 266 (1.2 g, 4.26 mmol) in methanol (20 mL) was added 10% palladium on charcoal (250 mg). The flask was purged with hydrogen gas for 1 minute and then the reaction was stirred under a hydrogen atmosphere for 15 hours. The palladium was filtered through a celite pad, the filtrate was evaporated under reduced pressure, and the resulting solid dried under vacuum to afford 267 as a white solid (700 mg, 86%). 1H NMR: (DMSO) δ 10.07 (s, 1H), 7.63 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 6.98 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 3.84 (s, 3H). The flask was purged with hydrogen gas for 1 minute The palladium was filtered through a celite pad the filtrate was evaporated under reduced pressure the resulting solid dried under vacuum

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

Procedure: Boron tribromide (24.9 g) was added dropwise to a solution of methyl 6-methoxybenzofuran-2-carboxylate (18.6 g) in dichloromethane (200 ml) at 0° C., followed by stirring at room temperature for 1 day. The reaction mixture was poured over ice water; ethyl acetate (300 ml) was added. After the organic layer was washed with water and dried (MgSO4), the solvent was distilled off; 10% hydrochloric acid-methanol (60 ml) was added to the residue, followed by heating at 70° to 80° C. for 5 hours. The reaction mixture was concentrated under reduced pressure; the resulting crystals of methyl 6-hydroxybenzofuran-2-carboxylate (10.75 g) were collected by filtration using diethyl ether-isopropyl ether (2:1, v/v). The filtrate was concentrated; the residue was subjected to silica gel column chromatography. From the fraction eluted with diethyl ether-hexane (1:2, v/v), methyl 6-hydroxybenzofuran-2-carboxylate (1.75 g) was obtained (total yield 73%), which was then recrystallized from diethyl ether-isopropyl ether to yield colorless prisms having a melting point of 176° to 177° C. After the organic layer was washed with water dried (MgSO4) the solvent was distilled off 10% hydrochloric acid-methanol (60 ml) was added to the residue by heating at 70° to 80° C. for 5 hours The reaction mixture was concentrated under reduced pressure the resulting crystals of methyl 6-hydroxybenzofuran-2-carboxylate (10.75 g) were collected by filtration The filtrate was concentrated From the fraction eluted with diethyl ether-hexane (1:2