Identification of N‐ or O‐Alkylation of Aromatic Nitrogen Heterocycles and N‐Oxides Using 1H–15N HMBC NMR Spectroscopy

A series of representative diazines and pyridine N ‐oxides were subjected to alkylation using several different alkylating agents. The 15 N NMR chemical shifts (δ N values) of the diazines, pyridine N ‐oxides and derived alkylation products were determined using 1 H‐ 15 N HMBC NMR spectroscopy at natural 15 N abundance. The changes in the 15 N NMR chemical shifts (Δ(δ N ) values) that occurred on going from starting materials to products in these reactions were analyzed. N‐alkylation of diazines resulted in large upfield shifts of the δ N values of the alkylated nitrogen (of the order of 100 ppm or greater). While O‐alkylation of pyridine N ‐oxides resulted in upfield shifts of the δ N values of the N ‐(alkoxy)pyridinium nitrogen, the Δ(δ N ) values were of a much smaller magnitude ( ca . –42 ppm) than those observed for N‐alkylations of diazines. Nitrogen NMR spectroscopic data from the literature of relevance to alkylation of azines, diazines, azine N ‐oxides and diazine N ‐oxides was gathered together, and using this in tandem with our 15 N NMR spectroscopic data, we have been able to corroborate our observations on the trends observed in the Δ(δ N ) values associated with N‐ and O‐alkylation reactions of aromatic N‐heterocycles and N ‐oxides. An analysis protocol that relies on synergistic evaluation of 1 H‐ 15 N HMBC and 1 H‐ 13 C HMBC NMR spectra has been developed that enables unambiguous diagnosis of the occurrence of N‐alkylation of aromatic N‐heterocycles and O‐alkylation of aromatic N ‐oxides.