Efficient Metal-Free Synthesis of Dihydro[1,3]oxazines Assisted by Intramolecular Hydrogen Bonding

摘要

As a class of important heterocyclic compounds,dihydro-[1,3]oxazines exhibit a wide range of bioactivities,including antibacterial,antifungal,antituberculosis,and antitumor.In addition,they showed therapeutic potential against HIV and Parkinson's disease,and could serve as potent nonsteroidal progesterone receptor agonists.Synthetically,they can be used as intermediates in the preparation of ortho-amidoalkylated phenols and bioactive compounds or employed in asymmetric catal-ysis and natural product synthesis.Owing to this versatility,the research to develop efficient synthetic methods for construction of this structure has been extensive.However,the reported methods primarily rely on Mannich-type condensations under high temperatures,which are usually unable to introduce substituents at the C-4 position of the oxazine ring.To overcome these limitations,several alternate approaches have been described,including metal-mediated rearrangements,oxidation,electro-cyclization,ortho-lifhiation,Diels-Alder reaction,and additions to in situ generated iminium ions.Cyclization of N-alkyl aminophenols or similar substrates with formaldehyde has also well studied to give 3,4-substituted oxazines in good yields under mild reaction conditions,However,synthetic methods for N-aryl substituted oxazines have been rarely reported because of the low nucleophilicity of arylamines.Therefore,considering the importance of this heterocyclic system,the development of simple and efficient as well as broad synthetic methods remains a great challenge.