Abstract
A telescoped three-step continuous flow procedure is developed for the synthesis of triazolyl phosphoramidates and phosphinamides in the biomass-derived solvent γ-valerolactone (GVL). The sequence integrates an N-phosphorylation, an azidation and a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), followed by in-line copper removal. The method proceeds under mild and green conditions and delivers a broad range of previously unreported organophosphorus 1,2,3-triazoles in good to high overall yields. A diverse substrate scope was established using aromatic, aliphatic, and sugar-derived azides, and the versatility of the protocol was further demonstrated through the flow synthesis of the triazole-containing drug, rufinamide. The protocol described was evaluated with green metrics calculations, which confirm significant improvements compared with batch approaches and is in accordance with eight of the 12 principles of green chemistry, highlighting the complementary benefits of flow chemistry, telescoped processing, and safer, sustainable reaction media such as GVL.