Structurally Mapping Sodium-Mediated Synthesis of 1,4-Substituted Dihydropyridines: Nucleophilic Addition vs. Deprotonative Metalation

The advent of organosodium reagents in organic synthesis has provided a more reactive and sustainable alternative to lithium derivatives, uncovering, in some cases, unique reactivities. Here we present the divergent reactivity of in situ generated benzyl sodium (BnNa), obtained by direct toluene sodiation, toward a selection of pyridine derivatives. Emphasizing its capacity as a nucleophile, selective C4-addition into some of these substrates followed by electrophilic interception has unlocked a new method to access 1,4-dihydropyridines. Contrastingly, when using picolines, selective benzylic metalation is observed for 2- and 4-picoline, whereas in the case of 3-picoline, a mixture of C4-addition and benzylic metalation is observed. Attempts to favor the nucleophilic addition using a borane additive revealed the formation of a sodium borate complex, which still shows a basic behavior by partial dissociation in solution. By trapping and characterizing key intermediate sodiated species, new mechanistic insights have been gained that advance the understanding of these sodium-mediated transformations.