2-bromo-4-chloro-5-methoxybenzaldehyde

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

Procedure: To a degassed solution of 2-bromo-4-chloro-5-methoxybenzaldehyde (1.46 g, 5.9 mmol) and trimethylboroxine (0.82 mL, 5.9 mmol) in 1,4-dioxane (80 mL) was added potassium carbonate (2.43 g, 17.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.68 g, 0.6 mmol). The mixture was heated under reflux for about 23 h, then more tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) and trimethylboroxine (0.2 mL, 1.4 mmol) were added and the mixture was heated under reflux for about another 8 h. After cooling to rt the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:6) to give 4-chloro-5-methoxy-2-methylbenzaldehyde (0.87 g, 4.7 mmol, 81%) as a pale yellow solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.60 (3 H, s); 3.95 (3 H, s); 7.29 (1 H, s); 7.37 (1 H, s); 10.3 (1 H, s). The mixture was heated under reflux for about 23 h the mixture was heated under reflux for about another 8 h was filtered over diatomaceous earth concentrated in vacuo The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:6)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of oxalyl chloride (0.58 mL, 6.9 mmol) in DCM (20 mL) was added dropwise a solution of dimethylsulfoxide (1.11 mL, 15.6 mmol) in DCM (10 mL), at temperature lower than −65° C. The resulting mixture was stirred for about 20 min at about −70° C. Then a solution of (2-bromo-4-chloro-5-methoxy-phenyl)methanol (1.56 g, 6.2 mmol) in DCM (20 mL) was added dropwise at temperatures lower than −65° C., and the resulting mixture was stirred for about another 20 min. Subsequently, TEA (3.52 mL, 25.2 mmol) was added dropwise at temperatures lower than −70° C., and the mixture was stirred for about 10 min at about −70° C. The mixture was allowed to warm to rt and stirred for about 16 h, treated with 1 M aqueous HCl (100 mL) and DCM (50 mL). The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with water (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 5:95) to give 2-bromo-4-chloro-5-methoxybenzaldehyde (1.48 g, 5.9 mmol, 95%) as a white solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 3.96 (3 H, s), 7.46 (1 H, s), 7.68 (1 H, s), 10.3 (1 H, s). lower than −65° C the resulting mixture was stirred for about another 20 min the mixture was stirred for about 10 min at about −70° C to warm to rt stirred for about 16 h The layers were separated the aqueous layer was extracted with DCM (100 mL) The combined organic layers were washed with water (50 mL) dried (MgSO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 5:95)