methyl 2-(2-bromo-5-chlorophenyl)acetate

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

Procedure: A solution of n-butyllithium (1.67 mL of a 2.5 M solution in hexanes, 4.17 mmol) was added dropwise via syringe to a stirred solution of diisopropylamine (0.61 mL, 4.36 mmol) in tetrahydrofuran (10 mL) at −78° C. After approximately 10 min, the reaction mixture was warmed to 0° C. and aged for another 10 min. After re-cooling to −78° C., a solution of methyl (2-bromo-5-chlorophenyl)acetate (1-2) (1.00 g, 3.79 mmol) in tetrahydrofuran (10 mL) was added dropwise via syringe and the resulting yellow mixture was stirred at −78° C. for approximately 30 min. Iodomethane (0.35 mL, 5.69 mmol) was added and after 1 h, the reaction mixture was warmed to ambient temperature and quenched with saturated aqueous ammonium chloride. The resulting mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent) furnished 2-1 as a colorless oil (1.00 g). aged for another 10 min After re-cooling to −78° C. the reaction mixture was warmed to ambient temperature quenched with saturated aqueous ammonium chloride The resulting mixture was poured into water extracted three times with ethyl acetate The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent)

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

Procedure: A solution of n-butyllithium (1.67 mL of a 2.5 M solution in hexanes, 4.17 mmol) was added dropwise via syringe to a stirred solution of diisopropylamine (0.61 mL, 4.36 mmol) in tetrahydrofuran (10 mL) at −78° C. After approximately 10 min, the reaction mixture was warmed to 0° C. and aged for another 10 min. After re-cooling to −78° C., a solution of methyl (2-bromo-5-chlorophenyl)acetate (1-2) (1.00 g, 3.79 mmol) in tetrahydrofuran (10 mL) was added dropwise via syringe and the resulting yellow mixture was stirred at −78° C. for approximately 30 min. Iodomethane (0.35 mL, 5.69 mmol) was added and after 1 h, the reaction mixture was warmed to ambient temperature and quenched with saturated aqueous ammonium chloride. The resulting mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent) furnished 2-1 as a colorless oil (1.00 g). aged for another 10 min After re-cooling to −78° C. the reaction mixture was warmed to ambient temperature quenched with saturated aqueous ammonium chloride The resulting mixture was poured into water extracted three times with ethyl acetate The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent)

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

Procedure: A solution of n-butyllithium (1.67 mL of a 2.5 M solution in hexanes, 4.17 mmol) was added dropwise via syringe to a stirred solution of diisopropylamine (0.61 mL, 4.36 mmol) in tetrahydrofuran (10 mL) at −78° C. After approximately 10 min, the reaction mixture was warmed to 0° C. and aged for another 10 min. After re-cooling to −78° C., a solution of methyl (2-bromo-5-chlorophenyl)acetate (1-2) (1.00 g, 3.79 mmol) in tetrahydrofuran (10 mL) was added dropwise via syringe and the resulting yellow mixture was stirred at −78° C. for approximately 30 min. Iodomethane (0.35 mL, 5.69 mmol) was added and after 1 h, the reaction mixture was warmed to ambient temperature and quenched with saturated aqueous ammonium chloride. The resulting mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent) furnished 2-1 as a colorless oil (1.00 g). aged for another 10 min After re-cooling to −78° C. the reaction mixture was warmed to ambient temperature quenched with saturated aqueous ammonium chloride The resulting mixture was poured into water extracted three times with ethyl acetate The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A vigorously stirred mixture of the tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-4) (1.40 g, 4.53 mmol), methyl(2-bromo-5-chlorophenyl)acetate (1-2) (1.31 g, 4.98 mmol), potassium phosphate tribasic (2.85 g, 13.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.262 g, 0.227 mmol) in N,N-dimethylformamide (22 mL) was degassed via three vacuum/nitrogen ingress cycles and then heated at 100° C. for approximately 18 h. After cooling to room temperature, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-25% ethyl acetate/hexanes as eluent) afforded 1-5 (0.967 g) as a colorless oil. was degassed via three vacuum/nitrogen ingress cycles After cooling to room temperature the reaction mixture was poured into water extracted three times with ethyl acetate The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-25% ethyl acetate/hexanes as eluent)

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

Procedure: A solution of (2-bromo-5-chlorophenyl)acetic acid (1-1) (15.0 g, 60.1 mmol) and concentrated sulfuric acid (0.150 mL of a 36N solution) in methanol (120 mL) was heated at reflux for approximately 15 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous phase re-extracted twice with methylene chloride. The combined organic extracts were washed with water, brine, dried (MgSO4) and the volatiles evaporated. The residual colorless liquid (15.9 g) was used without further purification in the Step C below. at reflux for approximately 15 h the reaction mixture was concentrated in vacuo the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate The organic layer was separated the aqueous phase re-extracted twice with methylene chloride The combined organic extracts were washed with water, brine dried (MgSO4) the volatiles evaporated The residual colorless liquid (15.9 g) was used without further purification in the Step C below

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

Procedure: A solution of (2-bromo-5-chlorophenyl)acetic acid (1-1) (15.0 g, 60.1 mmol) and concentrated sulfuric acid (0.150 mL of a 36N solution) in methanol (120 mL) was heated at reflux for approximately 15 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous phase re-extracted twice with methylene chloride. The combined organic extracts were washed with water, brine, dried (MgSO4) and the volatiles evaporated. The residual colorless liquid (15.9 g) was used without further purification in the Step C below. at reflux for approximately 15 h the reaction mixture was concentrated in vacuo the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate The organic layer was separated the aqueous phase re-extracted twice with methylene chloride The combined organic extracts were washed with water, brine dried (MgSO4) the volatiles evaporated The residual colorless liquid (15.9 g) was used without further purification in the Step C below