Ruthenium-Zeolite Catalyzed Dehydrative N-Benzylation of Amides for the Construction of Macrolactams Under Continuous Flow

Continuous-flow synthesis of acyclic amides and macrolactams has been demonstrated successfully via N-benzylation of amides using a highly reusable heterogeneous Ru-Zeolite as a catalyst, which gives only water as the byproduct. N-Benzylation of acyclic amides furnished 30 N-benzylated amides whereas intramolecular N-benzylation with alcohols was well tolerated with 15 examples of macrolactams bearing 11- to 15-membered rings. Notably, the scalability of this flow process has been demonstrated from milligrams to gram scale using the Ru-Zeolite heterogeneous catalyst. Moreover, the reusability of the catalyst is exemplified by the 16 reaction cycles carried out with one time-packed heterogeneous catalyst in the reactor bed.