Synthesis of ¹⁵ N-labelled 3,5-dimethylpyridine

¹⁵ N-labelled pyridines are liquid- and solid-state nuclear magnetic resonance (NMR) probes for chemical and biological environments because their ¹⁵ N chemical shifts are sensitive to hydrogen-bond and protonation states. By variation of the type and number of substituents, different target pyridines can be synthesized exhibiting different pK_a values and molecular volumes. Various synthetic routes have been described in the literature, starting from different precursors or modification of other ¹⁵ N-labelled pyridines. In this work, we have explored the synthesis of ¹⁵ N ¹⁵ N-labelled pyridines using a two-step process via the synthesis of alkoxy-3,4-dihydro-2H-pyran as precursor exhibiting already the desired pyridine substitution pattern. As an example, we have synthesized 3,5-dimethylpyridine-¹⁵ N (lutidine-¹⁵ N) as demonstrated by ¹⁵ N-NMR spectroscopy. That synthesis starts from methacrolein, propenyl ether, and ¹⁵ N-labelled NH₄ Cl as nitrogen source.