A Catalyst‐Free Amination of Functional Organolithium Reagents by Flow Chemistry

• Published in: Angewandte Chemie International Edition Vol. 57; no. 15; pp. 4063 - 4066
• Main Authors: Kim, Heejin, Yonekura, Yuya, Yoshida, Jun‐ichi
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 03.04.2018; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Amination; Catalysis; Catalysts; Chemical reactions; Chemistry; Chemistry, Multidisciplinary; flow chemistry; Intermediates; Microreactors; NMR; NMR spectroscopy; Nuclear magnetic resonance; organolithiums; Physical Sciences; Reaction time; Reagents; Science & Technology; ORGANIC-SYNTHESIS; FLASH CHEMISTRY; organolithiums; REACTION-TIME CONTROL; ELECTROPHILIC AMINATION; DIORGANOZINC REAGENTS; CROSS-COUPLING REACTIONS; microreactors; SERIAL MICROREACTIONS; ALKOXYCARBONYL GROUPS; amination; CHEMICAL-SYNTHESIS; NMR spectroscopy; C-H AMINATION; flow chemistry
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201713031

Reported is the electrophilic amination of functional organolithium intermediates with well‐designed aminating reagents under mild reaction conditions using flow microreactors. The aminating reagents were optimized to achieve efficient C−N bond formation without using any catalyst. The electrophilic amination reactions of functionalized aryllithiums were successfully conducted under mild reaction conditions, within 1 minute, by using flow microreactors. The aminating reagent was also prepared by the flow method. Based on stopped‐flow NMR analysis, the reaction time for the preparation of the aminating reagent was quickly optimized without the necessity of work‐up. Integrated one‐flow synthesis consisting of the generation of an aryllithium, the preparation of an aminating reagent, and their combined reaction was successfully achieved to give the desired amine within 5 minutes of total reaction time. Go with the flow: Reported is the electrophilic amination of organolithium intermediates using optimized amine reagents under mild reaction conditions within flow microreactors. Flow reactions are suitable for fast and mild amination using unstable organolithium compounds. Also notable is the fact that additional reagents and catalysts were not necessary. FG=functional group, R1 and R2=alkyl groups.