Synthesis of sterically shielded piperidine nitroxides via acid catalyst heterocyclization of β-aminoketone derivatives with ketones

The capabilities of modern methods for the synthesis of sterically shielded piperidine nitroxides with acyclic substituents are largely limited to symmetrical tetraethyl structures and do not allow the introduction of functional groups into position 2. We propose an alternative approach that allows for variation of substituents adjacent to the nitroxyl group, which significantly expands the potential of sterically hindered nitroxides for promising applications in materials science and structural biology. The new heterocyclization strategy implies construction of 2,2,6-trisubstituted piperidine scaffold from β-aminoketone acetals and dialkyl ketones under acid catalysis. The resulting amines were oxidized to corresponding ketonitrones and subsequent reaction with moderately basic organometallic reagents, such as 2-alkynyl and 2-allyl magnesium halides, enable facile introduction of diverse substituents, including those with functional groups. If necessary, the multiple carbon-carbon bonds in the side chain can be subjected to hydrogenation to give saturated alkyl or functionalized alkyl groups. The study of reduction kinetics for alkyl and allyl substituted piperidine nitroxides in ascorbate/glutathione media (30% EtOH, pH 7.5) yielded second-order rate constants of ~10 -2 M -1 s -1 , which is close to that earlier reported for TEEPONE.