2,4-dibromophenol

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

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 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: Employing 3-bromo-2-cyanopyridine (5.88 g) in place of 2-cyanopyridine in the production of Compound 75 in Example 9, substantially the same reaction as in Example 9 was conducted to give (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-bromopyridine O-t-butyloxime (3.74 g) (Compound 81) from 2,4-dibromophenol (8.01 g).

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

Procedure: Employing 3-bromo-2-cyanopyridine (5.88 g) in place of 2-cyanopyridine in the production of Compound 75 in Example 9, substantially the same reaction as in Example 9 was conducted to give (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-bromopyridine O-t-butyloxime (3.74 g) (Compound 81) from 2,4-dibromophenol (8.01 g).

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

Procedure: A mixture of 2,4-dibromophenol (5.0 g) and 2-methoxypropene (4 ml) was stirred for one hour at room temperature, to which was added diethyl ether (50 ml). The mixture was cooled to -78° C. under argon atmosphere, to which was added dropwise a 1.6M n-butyl lithium hexane solution (14 ml), followed by stirring for one hour at the same temperature. To the reaction mixture was then added dropwise 2-cyanopyridine (2.1 ml). The cooling bath was removed, and the reaction mixture was stirred for 3 hours while warming up to room temperature. To the reaction mixture was added ethanol (10 ml), followed by stirring for several minutes. Then, the solvent was distilled off under reduced pressure. To the residue were added triethylamine (20 ml), O-t-butylhydroxylamine hydrochloride (2.5 g) and ethanol (50 ml). The mixture was heated for 5 hours under reflux, then the solvent was distilled off. To the residue were added chloroform and water for extraction. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by subjecting to a silica gel column chromatography, eluting with ethyl acetate/hexane to give (Z)-2-(5-bromo-2-hydroxybenzoyl)pyridine O-t-butyloxime (4.24 g) (Compound 75). The mixture was cooled to -78° C. under argon atmosphere, to which by stirring for one hour at the same temperature The cooling bath was removed the reaction mixture was stirred for 3 hours while warming up to room temperature To the reaction mixture was added ethanol (10 ml) by stirring for several minutes Then, the solvent was distilled off under reduced pressure To the residue were added triethylamine (20 ml), O-t-butylhydroxylamine hydrochloride (2.5 g) and ethanol (50 ml) The mixture was heated for 5 hours under reflux the solvent was distilled off To the residue were added chloroform and water for extraction The organic layer was dried (anhydrous magnesium sulfate) the solvent was distilled off under reduced pressure The residue was purified eluting with ethyl acetate/hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-Dibromophenol (25.7 g) and 2-methoxypropene (10 ml) were stirred for one hour at room temperature. To the mixture was added diethyl ether (300 ml). The mixture was cooled at -78° C. under atmosphere of argon. Then, to the resultant mixture, a 1.6M solution of n-butyl lithium haxane solution (70 ml) was added dropwise. The mixture was stirred for one hour while maintaining the temperature. Then, 2-cyano-3-trimethylsilyloxy pyridine (19.1 g) was added dropwise to the reaction mixture. The cooling bath was then removed, and the reaction mixture was stirred for 3 hours while warming the reaction system to room temperature. Then, methanol (10 ml) was added to the reaction system, and the mixture was stirred for several minutes, followed by distilling off the solvent under reduced pressure. To the residue were added methanol (50 ml), THF (tetrahydrofuran) (15 ml) and 2N HCl (60 ml), and the mixture was stirred for 2 hours at room temperature. The resultant mixture was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with ethyl acetate/hexane, followed by purification to give 2-(5-bromo-2-hydroxybenzoyl)-3-hydroxypyridine (19.9 g) (Compound A-1). Physical properties and spectrum data of the compound are shown in Table 1 and Table 3. while maintaining the temperature The cooling bath was then removed the reaction mixture was stirred for 3 hours while warming the reaction system to room temperature Then, methanol (10 ml) was added to the reaction system the mixture was stirred for several minutes by distilling off the solvent under reduced pressure To the residue were added methanol (50 ml), THF (tetrahydrofuran) (15 ml) and 2N HCl (60 ml) the mixture was stirred for 2 hours at room temperature followed by extraction with ethyl acetate The organic layer was dried (anhydrous magnesium sulfate) the solvent was distilled off under reduced pressure eluting with ethyl acetate/hexane followed by purification

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

Procedure: 2,4-Dibromophenol (7.45 g, 29.6 mmol) was added as a solution in THF and dimethylaniline to a mixture of triphosgene (2.849 g, 9.6 mmol) in THF according to general procedure 3. Yield=6.09 g, 68%. m/z MH+=402.22. HPLC rt=12.49 min. HPLC rt=12.49 min.

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

Procedure: Two hundred and eighty-four grams of crude tris-(2,4-dibromophenyl)phosphate were mixed with 808 grams of a solution of 85% n-heptane and 15% toluene as above. The liquid portion weighed 733 grams and contained 0.047% 2,4-dibromophenol, 1.45% ester product and 0.06% chloridates.