1,4-Oxazepines occupied a unique position in the design and synthesis of novel biologically active agents that exhibit noteworthy medicinal activities. In fact, properly substituted derivatives display a wide range of biological properties, including analgesic, anticonvulsant, antidepressant, antihistaminic, antiinflammatory, antipsychotic, anxiolytic, antiulcer and antitumor activities. 1,4-Oxazepine derivatives have also proven to be useful for the treatment of various diseases, such as allergic bronchitis, bronchial asthma, breast cancer, epilepsy and trigeminal neuralgia, and psychotic disorders. Although many methods have been developed for their syntheses and new approaches still continue to appear stimulated by the broad spectrum of biological activity of these compounds, half and fully unsaturated monocyclic 1,4-oxazepines are less known. In particular, fully unsaturated monocyclic derivatives are very rare. Recently, N-propargylic β-enaminones have emerged as valuable intermediates in organic synthesis since, when treated with proper reagents, they afford a variety of heterocycles, including pyrroles and pyridines. Our continued interest in the synthesis of new heterocyclic compounds as potential pharmaceuticals and scaffolds has prompted us to investigate new reactivity patterns of N-propargylic β-enaminones. We have uncovered that when treated with proper zinc Lewis acids, N-propargylic β-enaminones 1, prepared readily by conjugate addition of propargylamine to α,β-alkynic ketones, undergo electrophilic cyclization to afford 2-methylene-2,3-dihydro-1,4-oxazepines 2 in good to high yields with a broad range of functional group tolerability. The scope, limitations and mechanism of these reactions will be discussed.

Development of a new methodology for synthesis of 1,4-oxazepines

254th National Meeting (2017)

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