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Regiodivergent Intramolecular Nucleophilic Addition of Ketimines for the Diverse Synthesis of Azacycles.

Yu-Hui WangJun-Song TianPeng-Wei TanQiang CaoXue-Xin ZhangZhong-Yan CaoFeng ZhouXin WangJian Zhou
Published in: Angewandte Chemie (International ed. in English) (2019)
Azacycles such as indoles and tetrahydroquinolines are privileged structures in drug development. Reported here is an unprecedented regiodivergent intramolecular nucleophilic addition reaction of imines as a flexible approach to access N-functionalized indoles and tetrahydroquinolines, by the control of reaction at the N-terminus and C-terminus, respectively. Using ketimines derived from 2-(2-nitroethyl)anilines with isatins or α-ketoesters, the regioselective N-attack reaction gives N-functionalized indoles, while the catalytic enantioselective C-attack reaction affords chiral tetrahydroquinolines featuring an α-tetrasubstituted stereocenter. Mechanistic studies reveal that hydrogen-bonding interactions may greatly facilitate such unusual N-attack reactions of imines. The utility of this protocol is highlighted by the catalytic enantioselective formal synthesis of (-)-psychotrimine, and the construction of various fused aza-heterocycles.
Keyphrases
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