A. Synthesis of 3-chloro-N-(4-chlorophenyl)pyridine-4-carboxamide. At -78 °C, 3-chloropyridine (1.00 mL, 10.5 mmol) was dissolved in THF and a freshly prepared lithium diisopropylammonium THF solution [prepared by the reaction of butyl lithium (7.21 mL, 11.5 mmol) with diisopropylamine (11.5 mmol)] was slowly added. After 0.25 h of reaction, carbon dioxide gas was passed into the mixture and slowly warmed to room temperature. After completion of the reaction, the mixture was concentrated and subsequently partitioned between EtOAc and water. The aqueous layer was washed twice with EtOAc. The pH of the aqueous layer was adjusted to about 3 by adding 1N HCl and extracted three more times with EtOAc. The organic phases were combined, dried with magnesium sulfate and concentrated. The residue was recrystallized by EtOAc to give 200 mg (12% yield) of 3-chloroisonicotinic acid.
