1,2-dihydropyridines: from transient intermediates to isolable compounds

Dihydropyridines are important molecules to study due to their diverse roles in pharmacology (for example as L-type calcium channel blockers used to treat hypertension), biochemistry (for example as reducing agents in the coenzyme NADPH, a biological reducing agent in photosynthesis) and synthetic chemistry (for example as intermediates to substituted pyridines).1 Since simple dihydropyridines are not potent hydride donors themselves, the acceptors often need pre-activation by a metal cation. However, metallo-dihydropyridines can exhibit enhanced hydride transfer capability due to the extra negative charge transferred to the heterocycle, but generally these only exist as transient intermediates in pyridine functionalization reactions and thus have been rarely studied in their own right.

Rather than focusing on the functionalized pyridine product, our interest lies in the metal-hydride moiety. The key to opening up this area was to subject lithium alkyls to a stoichiometric amount of pyridine in the absence or presence of donor solvents.2 This produced 1-lithio-2-alkyl-1,2-dihydropyridines, the structures of which (and hence their organo-solubility) depend on the nature of the alkyl (for example, n-Bu, t-Bu).
Here, I will discuss the synthetic approach to isolating and characterizing these reactive intermediates, extension to other metallo species and their uses as metal hydride sources for functional group transformation and in catalysis.

(1) D L Comins, K. Higuchi, D. W. Young in Advances in Heterocyclic Chemistry vol.10, ed. A. R. Katritzky, Academic Press, 2013, chapter 6, 175.

(2) S. D. Robertson, A. R. Kennedy, J. J. Liggat, R. E. Mulvey, Chem. Commun. 2015, 51, 5452.