1,4-Oxazepines have been extensively studied in the last decades as a prominent class of heterocycles and still obtain significant attention for their interesting biological and medicinal activities. They are often used as histamine H4 receptor (H4R) agonist, progesterone receptor agonists, calcium antagonist, PGE2 antagonist, PI3Ka selective inhibitor and non-nucleoside inhibitor of HIV-1 reverse transcriptase. 1,4-Oxazepines are also employed as building blocks for pharmaceutical research since they are present in the structures of a variety of drugs, including antidepressants Amoxapine and Sintamil (Nitroxazepine), and antipsychotic Loxapine. For their syntheses, many fruitful methods have been developed and new variants also continue to appear since their biological activity has made them a focus of medicinal chemistry over the years. Notably, half and fully unsaturated monocyclic 1,4-oxazepines are less explored. Recently, N-propargylic β-enaminones have been recognized as valuable substrates in organic synthesis since, upon cyclization with suitable reagents, they provide a variety of five- and six-membered heterocycles, such as pyrroles and pyridines. Recently, we have shown that electrophilic cyclization of N-propargylic β-enaminones with proper zinc Lewis acids produces 2-methylene-2,3-dihydro-1,4-oxazepines. Notably, iodo-substituted derivatives have potential for further functionalization with aryl and alkynyl moieties through coupling reactions. When the same reaction is carried out in the presence of molecular iodine, N-propargylic β-enaminones 1 afford 2-(iodomethylene)-2,3-dihydro-1,4-oxazepines 2 in good yields. The scope, limitations and mechanism of these reactions will be discussed.

Synthesis of 2-(iodomethylene)-2,3-dihydro-1,4-oxazepines

254th National Meeting (2017)

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