Synthesis of 15N-labelled 3,5-dimethylpyridine

Abstract

N-labelled pyridines are liquid- and solid-state nuclear magnetic resonance (NMR) probes for chemical and biological environments because their 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 values and molecular volumes. Various synthetic routes have been described in the literature, starting from different precursors or modification of other N-labelled pyridines. In this work, we have explored the synthesis of N 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-N (lutidine-N) as demonstrated by N-NMR spectroscopy. That synthesis starts from methacrolein, propenyl ether, and N-labelled NHCl as nitrogen source.