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A divergent and enantioselective procedure for synthesis of 2,3-disubstituted indolines was developed through Brønsted acid/palladium-complex promoted condensation/reductive alkylation/ hydrogenation cascade reactions from simple amino ketones and aldehydes in one operation. Five Brønsted acid-promoted steps and two Pdcatalyzed hydrogenation steps were involved in this process. This strategy provides facile synthesis of structurally diverse multi-substituted chiral indolines. Chiral 2,3-disubstituted indolines are significant building blocks in natural products and pharmaceutically compounds. Previous syntheses of chiral 2,3-disubstituted indolines mainly focused on multiple step reactions or metal catalyzed tandem reactions, et al., which caused tremendous low atom economy and environmental problems. To satisfy the demand for optically pure indolines, the development of efficient methods for their synthesis has attracted increasing attention. One of the straightforward and efficient ways to access chiral indolines may be the asymmetric reduction of substituted indole derivatives. Thus, a few of metal or organic catalyst systems have been successfully developed. Despite these contributions, the tedious procedure for the preparation of indoles limits its synthetic applications. Tandem reactions have become a powerful tool due to their ability to construct multiple stereogenic centers in a single operation. These processes represent a new entry for the preparation of complex molecules in a more cost-efficient and environmentally friendly manner. Given the importance of chiral indolines, the development of facile tandem reactions to prepare chiral 2,3-disubstituted indoline derivatives remains indispensable. In 2011, our group reported a tandem reaction for the synthesis of chiral 2,3-disubstituted indolines from 2substituted indoles and aldehydes (or N-sulfonylimines) in the presence of Brønsted acid/palladium complex. Recently, we reported a one-pot synthesis of chiral 2-substituted indolines through palladium-catalyzed asymmetric hydrogenation of indoles generated in situ (Scheme 1). We envisioned that 2,3disubstituted indolines should be also synthesized through 3component reaction from the readily available aminoketones, aldehydes and hydrogen gas through 2-substituted indole synthesis, 2,3-disubstituted indole synthesis and asymmetric hydrogenation cascade. The detailed reaction pathway was shown in Scheme 1. First, the Brønsted acid could promote aminoketone to 2substituted indole and following Friedel-Crafts reaction with aldehyde to afford the intermediate 3-(a-hydroxyalkyl)indole. Then, this intermediate proceeds Brønsted acid-catalyzed dehydration and palladium-catalyzed hydrogenation to give the 2,3-disubstituted indole, followed by palladium-catalyzed asymmetric hydrogenation to give the chiral 2,3-disubstituted indoline in the presence of Brønsted acid. For the above process, several issues should be addressed. Firstly, aldehyde and 2substituted indole might be directly hydrogenated (Scheme 2a and b). Secondly, the rate of the condensation to 2-substituted indole and reductive alkylation (Friedel-Crafts/dehydration/ reduction) of 2-substituted indoles and aldehydes should be fast (Scheme 2c and d). In our previous work, we found that indole synthesis and the Friedel-Crafts reaction between 2methylindole and benzaldehyde were very fast. To verify the hypothesis of this process, we began the reaction with aminoketone 1a and p-tolualdehyde 2a as model substrates, EtSO3H and chiral palladium/SegPhos complex [12] [a] Dr. C.-B. Yu, X. Li, Dr. Y.-G. Zhou State Key Laboratory of Catalysis Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023, P. R. China E-mail: [email protected] [email protected] Homepage: http://www.lac.dicp.ac.cn/ [b] Dr. Y.-G. Zhou Collaborative Innovation Centre of Chemical Science and Engineering Tianjin 300071, P. R. China Supporting information for this article is available on the WWW under https://doi.org/10.1002/ajoc.201900289 This manuscript is part of a special issue on Heterocyclic Chemistry. For the joint special collection with the European Journal of Organic Chemistry on the same topic, please click here. Scheme 1. Strategies for Synthesis of Chiral 2,3-Disubstituted Indolines. Communication DOI: 10.1002/ajoc.201900289 1118 Asian J. Org. Chem. 2019, 8, 1118–1121 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley VCH Freitag, 19.07.2019 1907 / 139086 [S. 1118/1121] 1