Ultra-fast Cu-based A3-coupling catalysts: faceted Cu2O microcrystals as efficient catalyst-delivery systems in batch and flow conditions

Abstract

Cu(I) catalysts were studied for the synthesis of a propargylamine via A3-coupling of aldehyde, amine, and alkyne, under solvent-free and low loading conditions, using batch microwave or flow thermal heating. We explored ultra-low loading conditions with Cu(I) salts as fast and active catalysts featuring turnover frequencies (TOFs) above 105 h−1. Well-defined octahedral and cubic Cu2O microcrystals were also successfully applied and compared with this reaction. Both types of microcrystals exhibited excellent catalytic activities within minutes, via in situ generation of low dose of Cu(I) ions within the reaction medium, to achieve TON beyond 2000 and recycling up to 10 times in a flow reactor. The study of the catalytic system demonstrated that the activity was surface-structure dependent and allowed for the design of low Cu contamination A3-coupling systems, affording a product at the decigram scale, with Cu contamination below FDA recommendations for drug synthesis, without the need for a purification procedure.