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-disubstitutedβ-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.