Revisiting the Coupling Reaction Between 4-Aminoantipyrine and Phenols: A Potential One-Pot Reaction Pathway to 4,11- and 5,12-Naphthoxazepine Isomers

This journal (Canadian Journal of Chemistry) published a while ago a set of seminal studies revealing the underlying mechanisms supporting the then widely used analytical technique for detecting phenols at low levels in domestic water supply using 4-aminoantipyrine (4-AAP). The current paper revisits these studies with a primary focus on the dimension of this reaction that synthesizes 6- and 7-membered heterocyclic rings containing both N and O in a single step. Here we report a rather unusual outcome of the reaction in which, while the oxidative coupling of 4-AAP to 1-naphthol in aqueous solution at high pH (or condensation with 1,4-naphthoquinone in chloroform) leads to the same naphthoquinonimide product, a similar set of reactions with 2-naphthol and 1,2-naphthoquinone produces two isomeric forms of an oxazepine instead. In one isomer, the 4-AAP/naphthol C-N and the C-O linkages are at positions 1 and 2 of naphthyl ring, respectively and in the other form, these linkages are at positions 2 and 1, respectively. This unexpected difference in a one-pot reaction at ambient temperature is potentially the flexibility needed to synthesize families of pharmaceutically relevant oxazepines. Spectroscopic features useful for identifying 12 heterocyclic compounds, nine of which are new, are also provided.