New tetracyclic 1,4-oxazepines constructed via practically simple tandem condensation strategy from readily available synthons

Atom-economical construction of tetracyclic [1,4]oxazepines involving intramolecular arylation of a 2-imidazoline moiety

“…15,16 This result could be rationalized by the generally lower activation barrier for intramolecular reactions which, in turn, lowers the selectivity. Finally, the regiochemical outcome of [1,4]oxazepine formation described herein was confirmed by through-space interactions observed in the NOESY spectra of several representative compounds (4d, 4g, 4l as well as in the mixture of 6a and 7a, Fig. 2).…”

“…The regiochemical outcome of these condensations was dependent of two factors: (i) which nucleophilic center of 2a would initially interact with bis-electrophilic substrate 3 and (ii) whether the initial aromatic nucleophilic substitution was followed by the Smiles rearrangement. In our previous Letters, we have shown that, without exception, the phenoxide anion is the first to react and the Smiles rearrangement is the second step, followed by [1,4]oxazepine ring closure via halide displacement or denitrocyclization. [1][2][3][4] Based on the regiochemistry of compounds 4 obtained in this work (vide infra), we could conclude that the reactions leading to them follow the same mechanistic course as shown for compound 4i in Scheme 2.…”

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a b s t r a c tNovel [1,4]oxazepines containing a fused imidazoline moiety were synthesized from 2-hydroxyphenyl imidazolines and bis-electrophilic aromatic substrates in a reaction involving sequential nucleophilic aromatic substitution steps and a Smiles rearrangement. A notable step was the remarkably facile, metal-free intramolecular N-arylation of the imidazoline moiety with a fluoro-, nitro-or chloroaromatic or heteroaromatic ring.

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“…The base-promoted condensation of phenols containing potentially nucleophilic functional groups (such as pyrazole 1 or a secondary amide 2 ), which can be activated by deprotonation, with 1,2-halonitro 3 or 1,2-dihalo 4 aromatic synthons has been recently reported by our research group as an efficient, atom-economical strategy to construct medicinally relevant polycyclic [1,4] oxazepine scaffolds from readily available precursors (Scheme 1).…”

“…Our current efforts in this area have been focused on identifying new N-H-acidic heterocyclic motifs that could be incorporated, as substituents, on the structure of the phenolic synthon, thus enabling new types of heterocycles to be fused to the [1,4] oxazepine core. In light of its privileged character 5 and also the similarity of the resultant compounds to classical tricyclic antidepressants such as nitroxazepine, trianeptine, or imipramine, 6 particular emphasis was given to the 2-imidazoline moiety.…”