Revisiting the coupling reaction between 4-aminoantipyrine and phenols: a potential one-pot reaction pathway to 4,11-and 5,12-naphthoxazepine isomers

A while ago, this journal (Canadian Journal of Chemistry) published a set of seminal studies that revealed the underlying mech- anism supporting the widely used 4-aminoantipyrine (4-AAP)-based analytical technique for detecting phenols at low levels in domestic water supplies. The current paper revisits these studies, but with a primary focus on an aspect of the mechanism that synthesizes a 6- and a 7-membered heterocyclic ring containing both N and O in a single step. Here we report a rather unusual outcome of this aspect in which, while the same naphthoquinonimide product is produced in the oxidative coupling of 4-AAP to 1-naphthol in aqueous solution and in the condensation of 4-AAP with 1,4-naphthoquinone in chloroform, a sim- ilar pair of reactions with 2-naphthol and 1,2-naphthoquinone produces two oxazepine isomers instead. In one isomer, the 4-AAP/naphthol C-N and C-O linkages are at positions 1 and 2 of the naphthyl ring, respectively; in the other isomer, these linkages are at positions 2 and 1, respectively. This unexpected difference in a one-pot reaction at ambient temperature is po- tentially the flexibility needed to synthesize families of pharmaceutically relevant oxazepines. Spectroscopic features useful for identifying 12 heterocyclic compounds synthesized here, nine of which are new, are also provided.