Trifluoroacetic anhydride → (4-Bromo-3-methylpyridin-2-YL)methanol

Participants

Reaction Steps

To a stirred solution of 4-bromo-1-hydroxy-2,3-dimethyl-pyridin-1-ium acetate (which may be prepared as described in Description 5) (18120 mg, 69.13 mmol) in DCM (100 mL) was added trifluoroacetic anhydride (23.89 mL, 171.9 mmol) dropwise and the reaction was stirred at room temperature for 8 hours, then additional trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was introduced. After 1 day, the reaction mixture was concentrated in vacuo to remove excess TFAA & DCM. The residue was then diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution [exotherms]. The resultant suspension was stirred for 3 hours and then concentrated in vacuo. The residue was then partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue, diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution, and the resulting suspension was stirred for 3 hours. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was purified over silica (100 g SNAP), using the Isolera instrument, eluting with EtOAc: isohexane 0%-50%. Fractions containing desired product were combined and concentrated in vacuo to give (4-bromo-3-methyl-2-pyridyl)methanol (D6) (7055 mg, 34.917 mmol, 50.5% yield) as a yellow solid;

Provenance & Evidence