A Concise Synthetic Pathway for trans-Metanicotine Analogues

A convenient pathway for synthesis of trans-metanicotine analogues was developed. trans-Metanicotine, a subtype(${\alpha}4{\beta}2$)-selective ligand for neuronal nicotinic acetylcholine receptor, is under clinical phase for Alzheimer's disease. Zn-mediated allylation of allyl bromide and acetaldehyde followed by Heck reaction with 3-bromopyridine gave 5-pyridin-3-yl-pent-4-en-3-ol (2). Tosylation of 5-pyridin-3-yl-pent-4-en-3-ol followed by substitution reaction with methylamine in sealed tube gave methyl-(1-methyl-4-pyridin-3-yl-but-3-enyl)-amine (4) in good yields. Thus, trans-metanicotine analogues modified at the $\alpha$-position of the methylamino group with various functional groups can be obtained in 4 steps.