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Attempts to extend the hydrated imidazoline ring expansion (HIRE) strategy to a series of diarene-fused [1,4]diazepinones (earlier applied successfully to bis-pyrido substrate nevirapine) did not result in ring expansion but, rather, led to 2-aminoethyl side chain expulsion. This seeming setback (setting the limitations to the HIRE methodology substrate scope) led to the discovery of selective dopamine D2 ligands with elements of structure–activity relationships.

The tricyclic ring system of the antiviral drug nevirapine has been employed to test the workability of the hydrated imidazoline ring expansion (HIRE) reaction which was previously exemplified for [1.4]oxazepine and [1.4]thiazepine counterparts. The imidazoline nucleus was grafted onto the lactam moiety of nevirapine in two high-yielding steps. Subsequent N-alkylation and the HIRE reaction proceeded as envisioned and delivered rare ring-expanded diarene-fused 1,4,7-triazecines with a diversity of alkyl substituents at the lactam nitrogen atom. These findings extend the scope of the HIRE reaction to the medicinally prominent [1.4]diazepine chemical space.

The influence of electronic factors on the rates of N → N′ aroyl migration in N-aroyl-N-(hetero)aryl ethylenediamines has been examined. Electron-withdrawing substituents on the aroyl group were found to weakly accelerate the reaction (in linear correlation with the Hammett σp constants). Much stronger influence came from the nitrogen-bound aromatic group which gave a strong linear correlation with the Hammett σp− constants. For electron-deficient heteroaromatics and nitroaromatics, the migration was nearly instantaneous in basic medium. These findings will significantly impact the planning of mechanistically related transformations of N-(2-aminoethyl) lactams through the hydrated imidazoline ring expansion (HIRE) process.