期刊
CHEM
卷 8, 期 1, 页码 210-224出版社
CELL PRESS
DOI: 10.1016/j.chempr.2021.10.022
关键词
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资金
- National Institutes of Health [R35 GM119812]
- Sloan Research Foundation
- Eli Lilly
- National Science Foundation Graduate Research Fellowship
In this study, we developed a remote C-H desaturation of amines by utilizing Ir photocatalytic initiation of 1,5-HAT and Cu-catalyzed interception of the C-centered radical. This method demonstrates high efficiency, selectivity, functional group tolerance, and medicinal utility.
A majority of medicines contain a nitrogen atom within a five- or six-membered ring. To rapidly access both such aza-heterocycles, we sought to develop a remote C-H desaturation of amines. Inspired by the Hofmann-Loffler-Freytag (HLF) synthesis of five-membered pyrrolidines, we tackled the century-old challenge of synthesizing six-membered piperidines by H-atom transfer. Herein, we present a double, vicinal C-H oxidation by dual catalysis, entailing Ir photocatalytic initiation of 1,5-HAT by an N-centered radical and Cu-catalyzed interception of the C-centered radical to facilitate desaturation. By this mechanism, two C-H bonds (delta and epsilon to N) are regioselectively removed from unbiased, remote positions of an alkyl chain. Over 50 examples illustrate the efficiency, selectivity, functional group tolerance, and medicinal utility of the synthesis of both internal and terminal delta vinylic amines and aza-heterocycles. Mechanistic experiments probe the alkylcopper intermediate, as well as the kinetics and regioselectivity of the HAT and elimination steps.
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