tert-butyl 4-bromo-2-methylbenzoate

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

Procedure: A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example I1) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of butyl lithium (“BuLi”) (1.6 M in hexane) (163 ml) was added dropwise at −100° C. N,N-Dimethylformamide (1.14 ml) was added at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured on a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H). was cooled to −100° C The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C The mixture was stirred for 10 minutes at −90° C. warmed to 0° C. poured on a mixture of ice and water to warm to ambient temperature extracted twice with ethyl acetate The combined organic phases were washed with water dried over sodium sulfate concentrated

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

Procedure: A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example I1) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of butyl lithium (“BuLi”) (1.6 M in hexane) (163 ml) was added dropwise at −100° C. N,N-Dimethylformamide (1.14 ml) was added at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured on a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H). was cooled to −100° C The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C The mixture was stirred for 10 minutes at −90° C. warmed to 0° C. poured on a mixture of ice and water to warm to ambient temperature extracted twice with ethyl acetate The combined organic phases were washed with water dried over sodium sulfate concentrated

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

Procedure: A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example I16) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of n-butyl lithium (1.6 M in hexane) (163 ml) was added dropwise at −100° C. The reaction mixture was stirred at −95° C. for 20 minutes. N,N-Dimethylformamide (43 ml) was added dropwise. The reaction mixture was stirred at −95° C. for 45 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° and poured on a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H). was cooled to −100° C The reaction mixture was stirred at −95° C. for 45 minutes The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C The mixture was stirred for 10 minutes at −90° C. warmed to 0° poured on a mixture of ice and water to warm to ambient temperature extracted twice with ethyl acetate The combined organic phases were washed with water dried over sodium sulfate concentrated

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

Procedure: tert.-butyl 4-bromo-2-methyl-benzoate (12 g; 43.4 mmol), caesium carbonate (21.2 g, 65 mmol), palladium(II)-acetate (1 g, 4.45 mmol) and BINAP (2.37 g, 4.40 mmol) are suspended in 150 ml of toluene under a nitrogen atmosphere and stirred for 10 minutes at ambient temperature. Then benzylamine (5.7 ml, 52.1 mmol) is added dropwise and the mixture is heated to 100° C. for two days. The mixture is then cooled, filtered to remove undissolved matter and evaporated to dryness. The oily residue is purified by chromatography (silica gel, petroleum ether/ethyl acetate 98:2). White crystals are obtained. the mixture is heated to 100° C. for two days The mixture is then cooled filtered to remove undissolved matter evaporated to dryness The oily residue is purified by chromatography (silica gel, petroleum ether/ethyl acetate 98:2) White crystals are obtained

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

Procedure: tert.-butyl 4-bromo-2-methyl-benzoate (12 g; 43.4 mmol), caesium carbonate (21.2 g, 65 mmol), palladium(II)-acetate (1 g, 4.45 mmol) and BINAP (2.37 g, 4.40 mmol) are suspended in 150 ml of toluene under a nitrogen atmosphere and stirred for 10 minutes at ambient temperature. Then benzylamine (5.7 ml, 52.1 mmol) is added dropwise and the mixture is heated to 100° C. for two days. The mixture is then cooled, filtered to remove undissolved matter and evaporated to dryness. The oily residue is purified by chromatography (silica gel, petroleum ether/ethyl acetate 98:2). White crystals are obtained. the mixture is heated to 100° C. for two days The mixture is then cooled filtered to remove undissolved matter evaporated to dryness The oily residue is purified by chromatography (silica gel, petroleum ether/ethyl acetate 98:2) White crystals are obtained

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

Procedure: tert.-butyl 4-bromo-2-methyl-benzoate (12 g; 43.4 mmol), caesium carbonate (21.2 g, 65 mmol), palladium(II)-acetate (1 g, 4.45 mmol) and BINAP (2.37 g, 4.40 mmol) are suspended in 150 ml of toluene under a nitrogen atmosphere and stirred for 10 minutes at ambient temperature. Then benzylamine (5.7 ml, 52.1 mmol) is added dropwise and the mixture is heated to 100° C. for two days. The mixture is then cooled, filtered to remove undissolved matter and evaporated to dryness. The oily residue is purified by chromatography (silica gel, petroleum ether/ethyl acetate 98:2). White crystals are obtained. the mixture is heated to 100° C. for two days The mixture is then cooled filtered to remove undissolved matter evaporated to dryness The oily residue is purified by chromatography (silica gel, petroleum ether/ethyl acetate 98:2) White crystals are obtained

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

Procedure: To a solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (500 g, 1.8 mol) in tetrahydrofuran (5 L) was added n-butyl lithium (1.6 M solution, 1.4 L, 2.2 mol) at such a rate that the reaction temperature is between −95° C. to −100° C. After completion of the addition, the reaction mixture was stirred for 30 min at −100° C. and monitored by quenching the reaction mixture with water and following the product by TLC. After complete conversion, DMF (170 ml, 2.2 mol) was added to the reaction mixture and after 15 min the reaction mixture was quenched with ammonium chloride (sat. solution, 5 L). The organic layers were separated at room temperature and the aqueous layer was extracted with ethyl acetate (3×2 L). The combined organic layer was washed with water (3×5 L), dried over sodium sulphate and concentrated to yield tert-butyl 4-formyl-2-methyl-benzoate (390 g, 96% isolated yield, 75-78% HPLC purity). The crude product was used as such without any further purification for the next step. 1H-NMR (CDCl3, 400 MHz): δ in ppm=1.59 (s, 9 H), 2.61 (s, 3 H), 7.71 (d, 2 H), 7.92 (d, 1 H), 10.01 (s, 1 H). is between −95° C. to −100° C After completion of the addition by quenching the reaction mixture with water was quenched with ammonium chloride (sat. solution, 5 L) The organic layers were separated at room temperature the aqueous layer was extracted with ethyl acetate (3×2 L) The combined organic layer was washed with water (3×5 L) dried over sodium sulphate concentrated

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

Procedure: A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example 4.1) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of butyl lithium (1.6M in hexane) (163 ml) was added dropwise at −100° C. Dimethylformamide (“DMF”) (1.14 ml) was added at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured onto a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H). The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C The mixture was stirred for 10 minutes at −90° C. warmed to 0° C. poured onto a mixture of ice and water to warm to ambient temperature extracted twice with ethyl acetate The combined organic phases were washed with water dried over sodium sulfate concentrated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-bromo-2-methylbenzoate (2 g, 7 mmol) in dioxane/water (50 mL, 4:1) was added styrylboronic acid pinacol ester (1.64 g, 7 mmol), tetrakis(triphenylphosphine)palladium (0.7 mmol, 0.904 g), sodium carbonate (21 mmol, 2.3 g). The mixture was stirred at 90° C. under nitrogen gas atmosphere for 18 hours. LC-MS showed the start material has been consumed. Then evaporated the solvent and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 2-methyl-4-(1-phenylvinyl)benzoate (1.8 g, 91%). has been consumed Then evaporated the solvent purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-bromo-2-methylbenzoate (2 g, 7 mmol) in dioxane/water (50 mL, 4:1) was added styrylboronic acid pinacol ester (1.64 g, 7 mmol), tetrakis(triphenylphosphine)palladium (0.7 mmol, 0.904 g), sodium carbonate (21 mmol, 2.3 g). The mixture was stirred at 90° C. under nitrogen gas atmosphere for 18 hours. LC-MS showed the start material has been consumed. Then evaporated the solvent and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 2-methyl-4-(1-phenylvinyl)benzoate (1.8 g, 91%). has been consumed Then evaporated the solvent purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1)

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

Procedure: A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example I1) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of butyl lithium (“BuLi”) (1.6 M in hexane) (163 ml) was added dropwise at −100° C. N,N-Dimethylformamide (1.14 ml) was added at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured on a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H). was cooled to −100° C The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C The mixture was stirred for 10 minutes at −90° C. warmed to 0° C. poured on a mixture of ice and water to warm to ambient temperature extracted twice with ethyl acetate The combined organic phases were washed with water dried over sodium sulfate concentrated

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

Procedure: A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example I16) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of n-butyl lithium (1.6 M in hexane) (163 ml) was added dropwise at −100° C. The reaction mixture was stirred at −95° C. for 20 minutes. N,N-Dimethylformamide (43 ml) was added dropwise. The reaction mixture was stirred at −95° C. for 45 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° and poured on a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H). was cooled to −100° C The reaction mixture was stirred at −95° C. for 45 minutes The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C The mixture was stirred for 10 minutes at −90° C. warmed to 0° poured on a mixture of ice and water to warm to ambient temperature extracted twice with ethyl acetate The combined organic phases were washed with water dried over sodium sulfate concentrated