Strategies for the Selective Functionalization of Dichloropyridines at Various Sites

Whereas 2,3-dichloropyridine and 2,5-dichloro-4-(lithiooxy)pyridine undergo deprotonation exclusively at the 4- and 2-positions, respectively, optional site selectivity can be implemented with 2,5- and 3,4-dichloropyridine (which are attacked, depending on the choice of the reagents, at either the 4- or 6- and either the 2- and 5-positions, respectively). Upon treatment with lithium diisopropylamide, 2,4-dichloro-3-iodopyridine, 3,5-dichloro-4-bromopyridine and 2,6-dichloro-3-iodopyridine afford 5-, 2- and 4-lithiated intermediates, but the latter isomerize instantaneously to species in which lithium and iodine have swapped places, the driving force being the low basicity of C−Li bonds when flanked by two neighboring halogens.