A microfluidic approach for flexible and efficient operation of a cross-coupling reactive flow

Abstract

In this work, a flexible and efficient flow microreactor has been developed for the synthesis of an aromatic amine via a Buchwald–Hartwig reaction, a key bond-forming reaction in the synthesis of a wide range of naturally-occurring and pharmaceutically active targets. The microreactor, coupled with a highly active palladium N-heterocyclic carbene (NHC) catalyst, enabled the full conversion of the reagents within twenty minutes, even at very low catalyst concentrations. In addition to the classical two-feed design, a novel, more flexible four-feed flow system was developed with a configuration optimised to avoid clogging, which is one of the main problems in microreactors and in continuous flow reactive systems in general. We report the effect of flow rate, temperature and catalyst loading on conversion degree. In particular, a slight increase in temperature allowed faster conversion even at low catalyst loadings, likely due to the highly efficient heat transfer provided by the confined microreactor geometry.