2,4-dibromo-1-(methoxymethoxy)benzene

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

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

Procedure: Into a 500-mL round bottom flask equipped with a soxlet and a condensor were placed 2,4-dibromophenol (32.0 g, 0.13 mole), dimethoxymethane (200 mL, 2.26 mole), p-toluenesulfonic acid monohydrate (2.24 g, 12.0 mmol) and CH2Cl2 (200 mL). The soxlet extractor was filled with 3 A and 4 A molecular sieves. The reaction mixture was heated to reflux for 24 h after which time the soxlet extractor was filled with freshly activated sieves. The reaction mixture was heated to reflux for another 24 h. After this period of time, Et3N (10 mL) was added. The reaction mixture was stirred for 5 mn, and concentrated to dryness. The residue was dissolved in CH2Cl2 (400 mL) and the resulting solution was washed with 5% NaOH (400 mL), H2O (400 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc; 6:1) to yield 2,4-Dibromo-1-methoxymethoxybenzene [9](32.9 g, 88%) as a light yellow oil; 1H NMR (CDCl3, 300 MHz) δ7.67 [s, ArH(3)], 7.33 [d, J=8.7 Hz, ArH(5)], 7.02 [d, J=8.7 Hz, ArH(6)], 5.21 [s, OCH2OCH3 ], and 3.49 [s, OCH3 ]; LRMS (EI) m/z 298 (M+, 3), 296 (M+, 5), 294 (M+, 3), and 45 (100) Into a 500-mL round bottom flask equipped with a soxlet The soxlet extractor was filled with 3 A and 4 A molecular sieves The reaction mixture was heated to reflux for 24 h after which time the soxlet extractor was filled with freshly activated sieves The reaction mixture was heated to reflux for another 24 h concentrated to dryness The residue was dissolved in CH2Cl2 (400 mL) the resulting solution was washed with 5% NaOH (400 mL), H2O (400 mL) dried over Na2SO4 concentrated in vacuo The crude product was purified by flash chromatography (hexanes/EtOAc; 6:1)

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

Procedure: Into a 500-mL round bottom flask equipped with a soxlet and a condensor were placed 2,4-dibromophenol (32.0 g, 0.13 mole), dimethoxymethane (200 mL, 2.26 mole), p-toluenesulfonic acid monohydrate (2.24 g, 12.0 mmol) and CH2Cl2 (200 mL). The soxlet extractor was filled with 3 A and 4 A molecular sieves. The reaction mixture was heated to reflux for 24 h after which time the soxlet extractor was filled with freshly activated sieves. The reaction mixture was heated to reflux for another 24 h. After this period of time, Et3N (10 mL) was added. The reaction mixture was stirred for 5 mn, and concentrated to dryness. The residue was dissolved in CH2Cl2 (400 mL) and the resulting solution was washed with 5% NaOH (400 mL), H2O (400 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc; 6:1) to yield 2,4-Dibromo-1-methoxymethoxybenzene [9](32.9 g, 88%) as a light yellow oil; 1H NMR (CDCl3, 300 MHz) δ7.67 [s, ArH(3)], 7.33 [d, J=8.7 Hz, ArH(5)], 7.02 [d, J=8.7 Hz, ArH(6)], 5.21 [s, OCH2OCH3 ], and 3.49 [s, OCH3 ]; LRMS (EI) m/z 298 (M+, 3), 296 (M+, 5), 294 (M+, 3), and 45 (100) Into a 500-mL round bottom flask equipped with a soxlet The soxlet extractor was filled with 3 A and 4 A molecular sieves The reaction mixture was heated to reflux for 24 h after which time the soxlet extractor was filled with freshly activated sieves The reaction mixture was heated to reflux for another 24 h concentrated to dryness The residue was dissolved in CH2Cl2 (400 mL) the resulting solution was washed with 5% NaOH (400 mL), H2O (400 mL) dried over Na2SO4 concentrated in vacuo The crude product was purified by flash chromatography (hexanes/EtOAc; 6:1)

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

Procedure: A solution of 2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O (140 mL) was cooled to −78° C. and treated with n-BuLi (2.5M in hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was added dropwise. The reaction mixture was stirred for 45 minutes at that temperature then quenched cold with saturated ammonium chloride solution. The mixture was partitioned between Et2O and water. The organic phase was separated, washed with water, brine, then dried over MgSO4. The solvent was removed under reduced pressure to afford 49 g of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was used in the next step without further purification. then quenched cold with saturated ammonium chloride solution The mixture was partitioned between Et2O and water The organic phase was separated washed with water, brine dried over MgSO4 The solvent was removed under reduced pressure

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

Procedure: A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. After 3 h at RT the mixture was filtered the filtrate was partitioned between EtOAc and water The organic phase was separated washed with water, aqueous saturated NaHCO3 and brine The organic phase was dried over MgSO4 the solvent was removed under reduced pressure

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

Procedure: A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. After 3 h at RT the mixture was filtered the filtrate was partitioned between EtOAc and water The organic phase was separated washed with water, aqueous saturated NaHCO3 and brine The organic phase was dried over MgSO4 the solvent was removed under reduced pressure

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

Procedure: To a solution of 2,4-dibromo-1-methoxymethoxybenzene (3.50 g) in diethyl ether (50 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (8.1 ml). The mixture was stirred for 20 minutes at the same temperature, to which was added a solution of 3-fluoro-2-formyl-pyridine (1.48 g) in THF (10 ml), followed by stirring for one hour at temperatures ranging from -78° to 60° C. The reaction mixture was poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-bromo-α-hydroxy-2-methoxymethoxybenzyl)-3-fluoropyridine (1.64 g) (Compound D-6). The physical properties and spectrum data are shown in Table 13 and Table 14. by stirring for one hour at temperatures ranging from -78° to 60° C The reaction mixture was poured into a saturated aqueous saline solution followed by extraction with ethyl acetate The extract solution was washed with a saturated aqueous saline solution dried (anhydrous sodium sulfate) concentrated The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane)

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

Procedure: A solution of 2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O (140 mL) was cooled to −78° C. and treated with n-BuLi (2.5M in hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was added dropwise. The reaction mixture was stirred for 45 minutes at that temperature then quenched cold with saturated ammonium chloride solution. The mixture was partitioned between Et2O and water. The organic phase was separated, washed with water, brine, then dried over MgSO4. The solvent was removed under reduced pressure to afford 49 g of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was used in the next step without further purification. then quenched cold with saturated ammonium chloride solution The mixture was partitioned between Et2O and water The organic phase was separated washed with water, brine dried over MgSO4 The solvent was removed under reduced pressure

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

Procedure: A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. After 3 h at RT the mixture was filtered the filtrate was partitioned between EtOAc and water The organic phase was separated washed with water, aqueous saturated NaHCO3 and brine The organic phase was dried over MgSO4 the solvent was removed under reduced pressure

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

Procedure: A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. After 3 h at RT the mixture was filtered the filtrate was partitioned between EtOAc and water The organic phase was separated washed with water, aqueous saturated NaHCO3 and brine The organic phase was dried over MgSO4 the solvent was removed under reduced pressure

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

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

Procedure: A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. Step 2: A solution of 2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O (140 mL) was cooled to −78° C. and treated with n-BuLi (2.5M in hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was added dropwise. The reaction mixture was stirred for 45 minutes at that temperature then quenched cold with saturated ammonium chloride solution. The mixture was partitioned between Et2O and water. The organic phase was separated, washed with water, brine, then dried over MgSO4. The solvent was removed under reduced pressure to afford 49 g of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was used in the next step without further purification. Step 3: A flask was charged with (S)-2-methylpropane-2-sulfinamide (0.764 g, 6.31 mmol) and neopentylzinc(II) iodide (0.5 M in THF, 10.0 mL, 5.00 mmol) was added under nitrogen atmosphere. The mixture was stirred at RT for 15 minutes and ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate (1.00 g, 3.15 mmol) was added in one portion. The reaction mixture was quenched with saturated aqueous ammonium chloride after 8 h. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with NH4Cl, water and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (10-30% EtOAc/hexane) to provide 0.675 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate. was used in the next step without further purification then quenched cold with saturated ammonium chloride solution The mixture was partitioned between Et2O and water The organic phase was separated washed with water, brine dried over MgSO4 The solvent was removed under reduced pressure