Asymmetric N‐Alkylation of 1H‐Indoles via Carbene Insertion Reaction

• Published in: Angewandte Chemie International Edition 2023-11, Vol.62 (47), p.e202313091-n/a
• Main Authors: Peng, Quanxin, Huang, Meirong, Xu, Guangyang, Zhu, Yan, Shao, Ying, Tang, Shengbiao, Zhang, Xinhao, Sun, Jiangtao
• Format: Article
• Language: English
• Subjects: Alkylation; Asymmetric Catalysis; Asymmetry; Carbene; Catalysts; Enantiomers; Hydrogen bonds; Indole; Indoles; Insertion; N-Alkylation; Nitrogen; N−H Insertion Reaction; Phosphoric acid; Rhodium; Stereoselectivity
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202313091

An intermolecular enantioselective N‐alkylation reaction of 1H‐indoles has been developed by cooperative rhodium and chiral phosphoric acid catalyzed N−H bond insertion reaction. N‐Alkyl indoles with newly formed stereocenter adjacent to the indole nitrogen atom are produced in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee). Importantly, both α‐aryl and α‐alkyl diazoacetates are tolerated, which is extremely rare in asymmetric X−H (X=N, O, S et al.) and C−H insertion reactions. With this method, only 0.1 mol % of rhodium catalyst and 2.5 mol % of chiral phosphoric acid are required to complete the conversion as well as achieve the high enantioselectivity. Computational studies reveal the cooperative relay of rhodium and chiral phosphoric acid, and the origin of the chemo and stereoselectivity. An intermolecular enantioselective N‐alkylation reaction of 1H‐indoles has been developed enabled by cooperative rhodium and chiral phosphoric acid catalyzed N−H bond insertion reaction. The reaction provides the N‐alkyl indoles with a newly formed stereocenter adjacent to the indole nitrogen atom in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee).