A Fluorescence-Based Assay for High-Throughput Screening of Coupling Reactions. Application to Heck Chemistry

A new fluorescence-based assay for high-throughput screening of reactions that couple two organic molecules is described. The assay involves reaction of one substrate containing a tethered fluorophore with a second molecule that is attached to a solid support. A successful coupling process is signaled by fluorescence of the solid support, which can be isolated by either simple centrifugation or filtration. To evaluate this assay in the context of a catalytic process under intense current study, we searched for improved, readily available phosphines for Heck chemistry. An acrylate containing a tethered coumarin was reacted with an aryl halide supported on a cross-linked polystyrene resin. Comparison of the results from our fluorescence-based assay with results from serial GC analysis showed that the fluorescence-based assay accurately selected the most active ligands for the Heck coupling of aryl bromides and chlorides. Two ligands chosen by the assay, tri(tert-butyl)phosphine and di(tert-butylphosphino)ferrocene, were found to be the most active systems to date for the olefination of unactivated aryl bromides, and di(tert-butylphosphino)ferrocene is the most efficient ligand for olefination of unactivated aryl chlorides.