Waste-minimized continuous flow copper-catalyzed azide-alkyne cycloaddition with low metal contamination

Metal contamination is a waste-generating and serious issue in the synthesis of chemicals, in particular in the case of products with biological activity. The appropriate selection of operating conditions plays a crucial role in the abatement of metal leaching in solution and associated wastes. Herein we report a waste-minimized continuous flow process for the synthesis of 1,4-disubstituted β-keto 1,2,3-triazoles exploiting the use of a copper tube flow reactor (CTFR). The selection of the proper azeotropic mixture allowed an almost quantitative recovery of the reaction medium greatly influencing the E-factor of the protocol. A thorough understanding of the main parameters affecting the waste generation was given by calculation of the E-factor distribution for different work-up tested under batch and flow conditions. Furthermore, the measurement of different green metrics (AE: Atom Economy, SF: Stoichiometric Factor, RME: Reaction Mass Efficiency, and MRP: Mass Recover Parameter) clearly demonstrated the benefits of the flow scale-up that allowed to perform a low environmental footprint CuAAC reaction.