A Reliable Multikilogram-Scale Synthesis of 2-Acetamido-5-Vinylpyridine Using Catalytic BINAP in a Modified Heck Reaction

An optimized Heck ethylenation of 2-acetamido-5-bromopyridine using a unique catalytic combination of phosphine ligands, tri- o -tolylphosphine and BINAP ( S -(−)- or racemic) as an additive/promoter is described. The best conditions for ethylenation were determined to be 1 mol % of palladium acetate, 3.3 mol % of tri- o -tolylphosphine, 0.25 mol % of BINAP and 180 mol % of triethylamine in acetonitrile at 90 °C. In optimizing the reaction, the purity of the tri- o -tolylphosphine was critical. The reaction time was extended by 3-fold when lower purity phosphine was used. The final process was carried out on 46.5 mol of 2-acetamido-5-bromopyridine, providing 71.6% of the corresponding vinyl-substituted pyridine adduct.