A synthetic methodology for the formation of C–N bond has become an important subject of considerable attentions in organic synthesis. Various transition-metal-catalyzed coupling reactions have been developed as highly reliable means of carrying out the C–N bond formation as a nucleophilic amination. Electrophilic amination of carbanions (typically, organometallic compounds serves as an alternative tool, which is based on the umpolung strategy. Direct amination of organolithiums has also been studied from the beginning of organolithium chemistry, it still remains an ongoing challenge. The direct amination of organolithiums has suffered from low yields, formations of by-products, and limited scopes, due to an instability and low selectivity of organolithiums.
We herein report a design, preparation, and synthetic use of aminating reagents for a rapid amination of functionalized organolithiums in flow microreactors. Various in-situ generated organolithium intermediates could be reacted with optimized aminating reagents in flow for C–N bond formation without using any catalyst under mild conditions in a short time. Based on stopped-flow NMR analysis, the aminating reagent was also prepared by the flow method. The preparation of the aminating reagent was easily optimized without any necessity of work-up. Integrated one-flow synthesis consisting of generation of an aryllithium, the preparation of an aminating reagent, and their reaction was successfully achieved to give desired amine product within 5 min of total reaction time.