Microwave Radiation for Organolithium Chemistry: Mechanistic Studies on the Direct <i>α</i>‐Metalation of a Tertiary Amine

Deprotonation reactions with lithium alkyls exhibit a high temperature dependency. However, the reactivity of lithium alkyls with conventionally used Lewis bases limits their deprotonation capability of more challenging substrates like tertiary amines. Therefore, we have focused on the use of high but exactly set reaction temperatures by usage of microwave radiation in the deprotonation reaction of a tertiary amine in the absence of polar additives. Our study proves the robustness of lithium alkyls, like t-butyllithium and α-metalated tertiary amines under microwave conditions. A solid-state structure of the prelithiation aggregate and quantum chemical calculations offer an insight into the mechanism, revealing that the substrate amine performs as Lewis base for deaggregation itself. By our method, N-methylpiperidine was deprotonated without any intermediate or possibly toxic reaction steps, solvents, or additives, solely with t-butyllithium in the microwave with 56% yield. By using design of experiments we identified the most important factors for a successful deprotonation, revealing the closed reaction conditions under pressure and an excess of amine to be crucial. This investigation proves the high potential of microwave radiation in lithium chemistry, as it provides high but exact energy and introduces new possibilities for deprotonation reactions to overcome high kinetic reaction barriers.