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NHC/Copper-Cocatalyzed [4 + 3] Annulations of Salicylaldehydes with Aziridines for the Synthesis of 1,4-Benzoxazepinones

You-Feng Han, Zhong-Hua Gao, Chun-Lin Zhang* and Song Ye*

*Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China, Email: zhangchunliniccas.ac.cn, songyeiccas.ac.cn

Y.-F. Han, Z.-H. Gao, C.-L. Zhang, S. Ye, Org. Lett., 2020, 22, 8396-8400.

DOI: 10.1021/acs.orglett.0c03026



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Abstract

N-heterocyclic carbene/copper-cocatalyzed [4 + 3] annulations of salicylaldehydes with aziridines provide the corresponding 1,4-benzoxazepinones in good yields with exclusive regioselectivity.

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proposed mechanism



Details

The document details the development of an N-heterocyclic carbene (NHC)/copper-cocatalyzed [4 + 3] annulation of salicylaldehydes with aziridines to synthesize 1,4-benzoxazepinones. This method achieves good yields with exclusive regioselectivity, where copper acts as a Lewis acid to activate aziridines, and the NHC-salicylaldehyde adduct enhances regioselectivity. The study highlights the biological significance of 1,4-benzoxazepines, such as rocastine, ICBP112, and SUN 8399, which exhibit antihistaminic, bromodomain inhibition, and serotonin agonist activities, respectively. Optimization of reaction conditions revealed that DMSO is the best solvent, and a triazolium with an N-2,4,6-tribromophenyl substituent is the most effective NHC precatalyst. The reaction tolerates various substituents on salicylaldehydes and aziridines, producing the desired products in good yields. The mechanism involves the formation of a Breslow intermediate, which is oxidized to an acyl azolium intermediate, facilitating aziridine ring opening and subsequent lactamization. The reaction can be scaled up without yield loss, and further transformations of the products are possible. The study concludes that the NHC/copper cocatalysis method is effective for synthesizing 1,4-benzoxazepinones, with ongoing research to explore more NHC-catalyzed annulation reactions.


Key Words

benzo-fused O-heterocycles, benzo-fused N-heterocycles, 3,3',5,5'-tetra-tert-butyldiphenoquinone, DPQ


ID: J54-Y2020