methyl 3-bromo-4-iodobenzoate

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

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

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Stir a solution of 4.84 g (14.2 mmol) of methyl 3-bromo-4-iodobenzoate (J. Med. Chem., 1999, 42, 4088) and 3.88 g (21.29 mmol) of 2,6-dimethoxyphenyl boronic acid in 120 mL of DMF and 14.2 mL of a 2M aqueous solution of caesium carbonate for 15 minutes under argon, then add 984 mg (0.85 mmol) of Pd(PPh3)4 and heat for 2.5 h at 85° C. After concentration under reduced pressure, distribute the residue obtained in 600 mL of a 1:1 DCM/water mixture. Wash the organic phase with 100 mL of water, dry over MgSO4 and concentrate at reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 10% of EtOAc. After concentration under reduced pressure, we obtain 2.79 g of methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate in the form of oil. After concentration under reduced pressure obtained in 600 mL of a 1:1 DCM/water mixture Wash the organic phase with 100 mL of water dry over MgSO4 concentrate at reduced pressure Purify the residue obtained by silica gel column chromatography eluting with a heptane/EtOAc gradient from 0 to 10% of EtOAc After concentration under reduced pressure, we

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Stir a solution of 4.84 g (14.2 mmol) of methyl 3-bromo-4-iodobenzoate (J. Med. Chem., 1999, 42, 4088) and 3.88 g (21.29 mmol) of 2,6-dimethoxyphenyl boronic acid in 120 mL of DMF and 14.2 mL of a 2M aqueous solution of caesium carbonate for 15 minutes under argon, then add 984 mg (0.85 mmol) of Pd(PPh3)4 and heat for 2.5 h at 85° C. After concentration under reduced pressure, distribute the residue obtained in 600 mL of a 1:1 DCM/water mixture. Wash the organic phase with 100 mL of water, dry over MgSO4 and concentrate at reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 10% of EtOAc. After concentration under reduced pressure, we obtain 2.79 g of methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate in the form of oil. After concentration under reduced pressure obtained in 600 mL of a 1:1 DCM/water mixture Wash the organic phase with 100 mL of water dry over MgSO4 concentrate at reduced pressure Purify the residue obtained by silica gel column chromatography eluting with a heptane/EtOAc gradient from 0 to 10% of EtOAc After concentration under reduced pressure, we

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

Procedure: To a solution of methyl 3-bromo-4-iodobenzoate (110.0 mg, 0.322 mmol) in tetrahydrofuran (2 mL) was added 2 M lithium tetrahydroborate in tetrahydrofuran (0.161 mL) at room temperature. After stirring for 36 h, the reaction was quenched with sat. ammonium chloride solution, diluted with diethyl ether. The aqueous phase was extract with diethyl ether once. The combined organic solutions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified with silica gel chromatography (5% to 20% ethyl acetate/hexane) to give a white solid (66 mg, 65%). 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J=8.2 Hz, 1H), 7.63 (m, 1H), 6.98 (m, 1H), 4.63 (s, 2H). LCMS found for C7H5BrI (M+H−H2O)+: m/z=295, 297. the reaction was quenched with sat. ammonium chloride solution diluted with diethyl ether The aqueous phase was extract with diethyl ether once The combined organic solutions were dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified with silica gel chromatography (5% to 20% ethyl acetate/hexane)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-bromo-4-iodobenzoate (5.9 g, 17 mmol), methyl acrylate (2.01 mL, 22.3 mmol), tetra-N-butylammonium chloride (4.8 g, 17 mmol), palladium acetate (80 mg, 0.3 mmol) and finely ground potassium carbonate (5.98 g, 43.3 mmol) in N,N-dimethylformamide (21 mL) was stirred at 50° C. for 20 h. The reaction mixture was cooled to room temperature. Ethyl acetate (200 mL) and brine (50 mL) were added, and the mixture was filtered under suction. The filtrate was collected, and aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over NaSO4, filtered, and concentrated. The product was crashed out after concentration, filtered and washed with ethyl acetate to give product. The remained residue was purified with silica gel chromatography (10% ethyl acetate/hexanes) to provide white solid (3.5 g, 67%). 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J=1.7 Hz, 1H), 8.04 (d, J=16.0 Hz, 1H), 7.98 (m, 1H), 7.65 (d, J=8.2 Hz, 1H), 6.46 (d, J=15.8 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H). LCMS found for C12H12BrO4 (M+H)+: m/z=299, 301. The reaction mixture was cooled to room temperature the mixture was filtered under suction The filtrate was collected aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried over NaSO4 filtered concentrated after concentration filtered washed with ethyl acetate to give product The remained residue was purified with silica gel chromatography (10% ethyl acetate/hexanes)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-bromo-4-iodobenzoate (5.9 g, 17 mmol), methyl acrylate (2.01 mL, 22.3 mmol), tetra-N-butylammonium chloride (4.8 g, 17 mmol), palladium acetate (80 mg, 0.3 mmol) and finely ground potassium carbonate (5.98 g, 43.3 mmol) in N,N-dimethylformamide (21 mL) was stirred at 50° C. for 20 h. The reaction mixture was cooled to room temperature. Ethyl acetate (200 mL) and brine (50 mL) were added, and the mixture was filtered under suction. The filtrate was collected, and aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over NaSO4, filtered, and concentrated. The product was crashed out after concentration, filtered and washed with ethyl acetate to give product. The remained residue was purified with silica gel chromatography (10% ethyl acetate/hexanes) to provide white solid (3.5 g, 67%). 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J=1.7 Hz, 1H), 8.04 (d, J=16.0 Hz, 1H), 7.98 (m, 1H), 7.65 (d, J=8.2 Hz, 1H), 6.46 (d, J=15.8 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H). LCMS found for C12H12BrO4 (M+H)+: m/z=299, 301. The reaction mixture was cooled to room temperature the mixture was filtered under suction The filtrate was collected aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried over NaSO4 filtered concentrated after concentration filtered washed with ethyl acetate to give product The remained residue was purified with silica gel chromatography (10% ethyl acetate/hexanes)

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

Conditions: temp:110.01; pressure:0.00; stir:

Procedure: To a solution of methyl 3-bromo-4-iodobenzoate (1.981 g, 5.81 mmol) in DME (10 mL) were morpholine (0.559 mL, 6.39 mmol), rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (0.362 g, 0.58 mmol), Palladium acetate (0.130 g, 0.58 mmol) and CESIUM CARBONATE (3.79 g, 11.62 mmol) added. The mixture was heated in the microwave oven for 12h at 110°C. The solids were filtered off through celite, the solvent was evaporated and the crude product was added to a silica gel column, 0-30% EtOAc in heptane yielding methyl 3-bromo-4-morpholinobenzoate (0.566 g, 32.5 %)

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

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

Procedure: To a solution of methyl 3-bromo-4-iodobenzoate (409 mg, 1.2 mmol) in dioxane/H2O (4:1, 10 mL) was added K2CO3 (497 mg, 3.6 mmol), tetrakistriphenylphosphine Pd(0) (69 mg, 0.06 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (349 mg, 3.6 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (307 mg, 87%): LC-MS (ES) m/z=296 (M+H)+. was then partitioned between 6N NaOH and DCM washed several times with DCM The combined organic fractions were dried (Na2SO4) concentrated under vacuum used directly without further purification (307 mg, 87%)

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

Procedure: To a solution of methyl 3-bromo-4-iodobenzoate (409 mg, 1.2 mmol) in dioxane/H2O (4:1, 10 mL) was added K2CO3 (497 mg, 3.6 mmol), tetrakistriphenylphosphine Pd(0) (69 mg, 0.06 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (349 mg, 3.6 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (307 mg, 87%): LC-MS (ES) m/z=296 (M+H)+. was then partitioned between 6N NaOH and DCM washed several times with DCM The combined organic fractions were dried (Na2SO4) concentrated under vacuum used directly without further purification (307 mg, 87%)