Regiochemical flexibility: the optional functionalization of 2,3,5-trihalopyridines at the 4- or 6-position

A deprotonation study was performed using 2,3,5-trichloropyridine, 3,5-dichloro-2-fluoropyridine, and 5-chloro-2,3-difluoropyridine as the substrates. Upon reaction with lithium diisopropylamide (LDA), deprotonation occurred exclusively at the 4-position. Subsequent carboxylation and iodination led to the acids and 4-iodopyridines. The exposure of the latter compds. to lithium 2,2,6,6-tetramethylpiperidide (LITMP) caused deprotonation and immediately ensuing iodine migration. The intermediates were trapped with dry ice to afford the carboxylic acids. Upon neutralization, the 6-iodopyridines were obtained. These compds. readily exchanged the heavy halogen for metal when treated with isopropylmagnesium chloride. In this way, functional groups could be selectively introduced in the 6-position. Employing carbon dioxide routinely as the model electrophile, trihalopyridinecarboxylic acids were formed which, all unknown so far, should provide valuable new building blocks for pharmaceutical research. Moreover, the selective nucleophilic displacement of the halogen at the 2-position could give rise to an immense variety of new structures. [on SciFinder (R)]