A three-minute gram-scale synthesis of amines via ultrafast “on-water” in continuo organolithium addition to imines

Although "on-water" organic reactions, including organometallics, are a sustainable alternative to traditional strategies, serious concerns related to the safety and feasibility of large-scale application exist. Here, the on-water continuous-flow addition of organolithium reagents to imines is studied in a continuous stirred tank reactor. Fast reaction times (10–20 s) lead to a more productive (gram scale in a 2.5 mL continuous stirred tank reactor) and safer methodology compared to the in-batch reaction. A calorimetric study is performed to understand the thermal behavior and the critical parameters that affect the safety of the process. The methodology is applied to the synthesis of an enantiopure amine. A telescoped process, comprising 3 units of operation (synthesis-inline extraction-separation) that resembles an industrial operation line, is developed, demonstrating the feasibility of the scaleup. Functionalized secondary amines can be synthesized on water, in continuo, with high yields and very short reaction times.