Pyridine N-Alkylation by Lithium, Magnesium, and Zinc Alkyl Reagents: Synthetic, Structural, and Mechanistic Studies on the Bis(imino)pyridine System

The 2,6-bis(α-iminoalkyl)pyridines 2,6-[ArNC(CR3)]2C5H3N [R = H, D; Ar = 2,6-i-Pr2C6H3 (DIPP),
2,6-Me2C6H3 (DMP)] react with MeLi in Et2O to give a binary mixture of products:  the pyridine N-methylated
species 2,6-[ArNC(CR3)]2C5H3N(Me)Li(OEt2) and the deprotonated/dedeuterated species 2-[ArNC(CR3)],6-[ArNC(CR2)]C5H3NLi(OEt2). For R = D, the product ratio is 2:1 in favor of the N-methylated product,
while, for R = H, the deprotonated product is favored by 5:1, increasing to 8:1 in toluene solvent. Warming
solutions of the N-methylated species leads to clean conversion to the thermodynamically preferred
deprotonated species. Crossover experiments show that MeLi is re-formed and dissociates from the
terdentate ligand before deprotonating the ketimine methyl unit. For MgR2 (R = Et, i-Pr) and ZnR2 (R = Et)
reagents, N-alkylation products are formed exclusively, but derivatives containing bulky aryl substituents
are found to undergo further rearrangement to 2-alkylated species, arising by migration of the alkyl group
of the N-alkyl moiety to the adjacent ring carbon atom. The reversibility of the N-alkylation process has
been probed using deuterio-labeled Mg alkyl reagents and mixed alkyl zinc species. A cationic zinc derivative
is shown to undergo “reverse” alkyl migration, from the heterocycle nitrogen atom to the zinc center. EPR
spectroscopy reveals a paramagnetic intermediate in which the unpaired electron is delocalized over the
heterocycle and di-imine moieties of the ligand, indicating that the N-alkylation reactions proceed via single
electron-transfer processes.