Racemic and enantiopure 4-(piperidine-2′-yl)-pyridazines: novel synthesis of anabasine-analogues with potential nicotinic acetylcholine receptor agonist activity—a new approach via Diels–Alder reaction with inverse electron demand

A novel multistep synthesis of anabasine analogues bearing a bioisosteric pyridazine moiety instead of a pyridine nucleus in 2-position of the piperidine ring of the alkaloid is described. Starting materials are racemic 2-hydroxymethyl-piperidine, racemic pipecolic acid or (S)-(−)-piperidine-1,2-dicarboxylic-acid-1-tert-butyl ester. Key step of this synthetic approach is a Diels–Alder cycloaddition process with inverse electron demand utilizing diverse 1,2,4,5-tetrazines as electron-deficient dienes and the new racemic or enantiopure 2-(2′-methoxyethenyl)-piperidine as electron-rich dienophile. In this [4+2]-cycloadditions 1,2,4,5-tetrazines serve as synthons for introducing the pyridazine ring in the 2-position of the piperidine moiety.