Zooming in on the hydrated imidazoline ring expansion: Factors influencing the rate of N → N′ aroyl migration in N-aroyl-N-(hetero)aryl ethylenediamines

An Attempt to Achieve Hydrated Imidazoline Ring Expansion (HIRE) of Diarene-Fused [1,4]Diazepinones Delivers Selective Dopamine D2 Receptor Ligands

“…The inability of products 17 to undergo the HIRE-type ring expansion is likely due to the electron-donating character of the [1,4]diazepinone nitrogen atom and insufficiently electron-poor carboaromatic rings. The generalized mechanistic picture for the HIRE process depicted in Scheme 1 implies that the 'hydrated imidazoline' (HI) intermediate is in equilibrium with the open side-chain product 17.…”

“…Furthermore, the formation of the ring-expanded product 18 from the putative HI intermediate involves the elimination of aromatic amine leaving group (Figure 1b). This process is likely more facile for the pyridine-3amine moiety (in the nevirapine-derived HI) than for the carboaromatic counterparts (for the HI derived from dibenzo[b,e] [1,4]diazepin-11-ones 17). Compounds 14a-m are apparent analogues of tricyclic antidepressant and antipsychotic pharmacological space (Figure 2).…”

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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 D 2 ligands with elements of structure-activity relationships.

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“…3a The propensity of the HI intermediate to undergo either ring expansion (HI→3) or side-chain expulsion (HI→4) as well as the likelihood of the process 4→3 is influenced by the electron-withdrawing character of the 'left-hand side' (hetero)aromatic group and, to an even larger extent, by the electron-withdrawing character of the 'right-hand side' (i.e., nitrogen-bound) (hetero)aromatic ring. 4 That is why sulfones (4, X = SO 2 ) were extremely fast to rearrange to the ring-expanded products 3, while certain [1,4]oxazepinones 4 (X = O) were completely reluctant to do so (Scheme 1a). 3b This is also the likely reason why, to our delight, antiviral drug nevirapine (5), when converted into imidazolinium derivative 6, also underwent a facile HIRE process to give ring-expanded products 7, despite the strong donating influence of the central nitrogen atom, and, most likely, due to electronpoor character of the both pyridine rings (Scheme 1b).…”

“…The Buchwald-Hartwig coupling of 2-aminoaromatic esters 10a-c with 2bromonitrobenzenes 11a-e gave high to excellent yields of diarene amines 12a-f. The latter were N-methylated (to avoid complications at the later stages of the HIRE sequence), which was achieved with methyl iodide and sodium hydride in DMF, also in good to excellent yields of N- Scheme 2 Synthesis of diarene-fused [1,4]…”