Acetic Acid → 5-Bromopyridine-2-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

To a solution of 5-bromopyridine-2-carbonitrile (commercially available from Sigma-Aldrich, St. Louis, Mo.) in ethanol (1.4 M) was added 3 equivalents of sodium hydroxide as a 1.5 M aqueous solution and the resulting solution was allowed to reflux at a temperature of about 85° C. until no further evolution of ammonia gas was detected. The resulting solution was then concentrated under reduced pressure to provide a residue. The residue was dissolved in water, acidified with acetic acid, and allowed to stir for about 16 h at a temperature of about 25° C. to provide a solid precipitate. The solid was collected by vacuum filtration and washed with acetone to provide 5-bromopyridine-2-carboxylic acid (Compound B) as a solid. 5-bromopyridine-2-carboxylic acid (Compound B), 0.5 equivalents of HOBT, and 1 equivalent of EDCI were dissolved in DMF and combined with about 1.1 equivalents of 4-tert-butylaniline (Compound C; commercially available from Sigma-Aldrich) dissolved in DMF (0.8 M) and the resulting mixture was allowed to stir for about 2 h at about 25° C. The reaction mixture was then diluted with about 80 mL of 2N aqueous sodium hydroxide and extracted with ethyl acetate (3 extractions, 80 mL/extraction). The ethyl acetate layers were combined and the ethyl acetate was removed under reduced pressure to provide a solid. The resulting solid was suspended in water and filtered using vacuum filtration to provide Compound D as a solid. Compound D was dissolved in DMF (0.04M) and about 3 equivalents of the zinc bromide Compound F (commercially available from Sigma-Aldrich) and about 0.05 equivalents of Pd(PPh3)4 (commercially available from Sigma-Aldrich) were added to the solution under a nitrogen atmosphere, and the resulting reaction mixture was allowed to stir for about 2 h at a temperature of about 100° C. The solvent was then removed under reduced pressure to provide Pyridylene Compound E35(a). Pyridylene Compound E35(a) was purified using preparative thin-layer chromatography with a 1:1 ethyl acetate:hexane mobile phase to provide purified Pyridylene Compound E35(a) as an off-white solid (yield 47%).

Provenance & Evidence