methyl 4-bromo-2-methoxybenzoate

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

Procedure: A flask was charged with methyl 4-bromo-2-methoxybenzoate (250 mg, 1.020 mmol), vinyl butyl ether (131 μl, 1.020 mmol), potassium carbonate (169 mg, 1.224 mmol), 1,3-(bis(diphenylohpsophine)propane (25.2 mg, 0.061 mmol) and palladium (II) acetate (6.87 mg, 0.031 mmol). The flask was sealed and 3 evacuation/argon purges were performed. DMF (4554 μl) and Water (546 μl) were added and the reaction was heated in a microwave at 122° C. for 75 minutes. Additional vinyl butyl ether (131 μl, 1.020 mmol) was added and the reaction was heated an additional 30 minutes in a MW at 122° C. Once complete the reaction was stirred overnight at 100° C. with conventional heating. The reaction was then cooled. HCl (5%, 8 mL) was added and the mixture was stirred for 30 minutes and then diluted with ethyl acetate and transferred to a separatory funnel. The organic layer was washed with aqueous saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-acetyl-2-methoxybenzoate (54.4 mg, 0.261 mmol, 25.6% yield). MS ESI: [M+H]+ m/z 200.1. 1H NMR (600 MHz, DMSO-d6) δ 7.70 (d, J=7.9, 1H), 7.57 (dd, J=1.1, 7.9, 1H), 7.53 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 2.49-2.44 (m, 3H). The flask was sealed the reaction was heated an additional 30 minutes in a MW at 122° C The reaction was then cooled the mixture was stirred for 30 minutes transferred to a separatory funnel The organic layer was washed with aqueous saturated NaHCO3, brine dried over Na2SO4 filtered concentrated

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

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

Conditions: temp:122.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with methyl 4-bromo-2-methoxybenzoate (250 mg, 1.020 mmol), vinyl butyl ether (131 μl, 1.020 mmol), potassium carbonate (169 mg, 1.224 mmol), 1,3-(bis(diphenylphosophine)propane (25.2 mg, 0.061 mmol) and palladium (II) acetate (6.87 mg, 0.031 mmol). The flask was sealed and 3 evacuation/argon purges were performed. DMF (4554 μl) and Water (546 μl) were added and the reaction was heated in a microwave at 122° C. for 75 minutes. Additional vinyl butyl ether (131 μl, 1.020 mmol) was added and the reaction was heated an additional 30 minutes in a MW at 122° C. Once complete the reaction was stirred overnight at 100° C. with conventional heating. The reaction was then cooled. HCl (5%, 8 mL) was added and the mixture was stirred for 30 minutes and then diluted with ethyl acetate and transferred to a separatory funnel. The organic layer was washed with aqueous saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-acetyl-2-methoxybenzoate (54.4 mg, 0.261 mmol, 25.6% yield). MS ESI: [M+H]+ m/z 200.1. 1H NMR (600 MHz, DMSO-d6) δ 7.70 (d, J=7.9, 1H), 7.57 (dd, J=1.1, 7.9, 1H), 7.53 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 2.49-2.44 (m, 3H). The flask was sealed the reaction was heated an additional 30 minutes in a MW at 122° C The reaction was then cooled the mixture was stirred for 30 minutes transferred to a separatory funnel The organic layer was washed with aqueous saturated NaHCO3, brine dried over Na2SO4 filtered concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of methyl 4-bromo-2-methoxybenzoate (0.70 g, 2.86 mmol) in 1,4-dioxane (10 mL) and MeOH (2.5 mL) is added 4-chlorophenyl boronic acid (0.536 g, 3.43 mmol), Pd(dppf)Cl2 (0.233 g, 0.286 mmol) and K3PO4 (0.728 g, 3.43 mmol). The resulting suspension is heated to 80° C. and stirred for 3 hours. After this time, the reaction is cooled to room temperature and filtered through Celite™. The solids that form are collected and washed with additional MeOH before the filtrate is concentrated under reduced pressure. The crude material is purified over silica (hexanes:EtOAc; 6:1 to 4:1) to provide 0.615 g (78% yield) of the desired compound as orange crystals. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (1H, d, J=8.0 Hz), 7.52-7.56 (2H, m), 7.44 (2H, d, J=8.7 Hz), 7.17 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=1.6 Hz), 3.99 (3H, s), 3.92 (3H, s). HPLC-MS: m/z 277 [M+H]+. After this time, the reaction is cooled to room temperature filtered through Celite™ The solids that form are collected washed with additional MeOH before the filtrate is concentrated under reduced pressure The crude material is purified over silica (hexanes:EtOAc; 6:1 to 4:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of methyl 4-bromo-2-methoxybenzoate (0.70 g, 2.86 mmol) in 1,4-dioxane (10 mL) and MeOH (2.5 mL) at room temperature under nitrogen blanketing is added 4-chlorophenyl boronic acid (0.536 g, 3.43 mmol), Pd(dppf)Cl2 (0.233 g, 0.286 mmol) and K3PO4 (0.728 g, 3.43 mmol). The resulting suspension is heated to 80° C. and stirred for 3 hours after which the reaction is cooled to room temperature and filtered through Celite™. The collected solids are washed with additional MeOH and the filtrate concentrated under reduced pressure. The crude material is purified over silica (hexanes:EtOAc gradient 6:1 to 4:1) to afford 0.614 g (78% yield) of the desired product as orange crystals. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (1H, d, J=8.0 Hz), 7.52-7.56 (2H, m), 7.44 (2H, d, J=8.7 Hz), 7.17 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=1.6 Hz), 3.99 (3H, s), 3.92 (3H, s). HPLC-MS: m/z 277 [M+H]+. is cooled to room temperature filtered through Celite™ The collected solids are washed with additional MeOH the filtrate concentrated under reduced pressure The crude material is purified over silica (hexanes:EtOAc gradient 6:1 to 4:1)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of methyl 4-bromo-2-methoxybenzoate (4.9 g), (2-cyanophenyl)boronic acid (5.9 g), Pd(dppf)2Cl2 (0.49 g) and 2M aqueous cesium carbonate solution (20 mL) in tetrahydrofuran (60 mL) was stirred under an argon atmosphere at 70° C. for 3 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.9 g, 35%). to cool the mixture was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated The residue was purified by silica gel column chromatography

Conditions: temp:122.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with methyl 4-bromo-2-methoxybenzoate (250 mg, 1.020 mmol), vinyl butyl ether (131 μl, 1.020 mmol), potassium carbonate (169 mg, 1.224 mmol), 1,3-(bis(diphenylohpsophine)propane (25.2 mg, 0.061 mmol) and palladium (II) acetate (6.87 mg, 0.031 mmol). The flask was sealed and 3 evacuation/argon purges were performed. DMF (4554 μl) and Water (546 μl) were added and the reaction was heated in a microwave at 122° C. for 75 minutes. Additional vinyl butyl ether (131 μl, 1.020 mmol) was added and the reaction was heated an additional 30 minutes in a MW at 122° C. Once complete the reaction was stirred overnight at 100° C. with conventional heating. The reaction was then cooled. HCl (5%, 8 mL) was added and the mixture was stirred for 30 minutes and then diluted with ethyl acetate and transferred to a separatory funnel. The organic layer was washed with aqueous saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-acetyl-2-methoxybenzoate (54.4 mg, 0.261 mmol, 25.6% yield). MS ESI: [M+H]+ m/z 200.1. 1H NMR (600 MHz, DMSO-d6) δ 7.70 (d, J=7.9, 1H), 7.57 (dd, J=1.1, 7.9, 1H), 7.53 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 2.49-2.44 (m, 3H). The flask was sealed the reaction was heated an additional 30 minutes in a MW at 122° C The reaction was then cooled the mixture was stirred for 30 minutes transferred to a separatory funnel The organic layer was washed with aqueous saturated NaHCO3, brine dried over Na2SO4 filtered concentrated

Conditions: temp:122.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with methyl 4-bromo-2-methoxybenzoate (250 mg, 1.020 mmol), vinyl butyl ether (131 μl, 1.020 mmol), potassium carbonate (169 mg, 1.224 mmol), 1,3-(bis(diphenylohpsophine)propane (25.2 mg, 0.061 mmol) and palladium (II) acetate (6.87 mg, 0.031 mmol). The flask was sealed and 3 evacuation/argon purges were performed. DMF (4554 μl) and Water (546 μl) were added and the reaction was heated in a microwave at 122° C. for 75 minutes. Additional vinyl butyl ether (131 μl, 1.020 mmol) was added and the reaction was heated an additional 30 minutes in a MW at 122° C. Once complete the reaction was stirred overnight at 100° C. with conventional heating. The reaction was then cooled. HCl (5%, 8 mL) was added and the mixture was stirred for 30 minutes and then diluted with ethyl acetate and transferred to a separatory funnel. The organic layer was washed with aqueous saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-acetyl-2-methoxybenzoate (54.4 mg, 0.261 mmol, 25.6% yield). MS ESI: [M+H]+ m/z 200.1. 1H NMR (600 MHz, DMSO-d6) δ 7.70 (d, J=7.9, 1H), 7.57 (dd, J=1.1, 7.9, 1H), 7.53 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 2.49-2.44 (m, 3H). The flask was sealed the reaction was heated an additional 30 minutes in a MW at 122° C The reaction was then cooled the mixture was stirred for 30 minutes transferred to a separatory funnel The organic layer was washed with aqueous saturated NaHCO3, brine dried over Na2SO4 filtered concentrated