HTE-enabled discovery of palladium-catalysed (hetero)arylation of barbituric and meldrum's acid

Abstract

This study demonstrates the potential of high-throughput experimentation (HTE) to discover favorable conditions for the direct palladium-catalysed arylation of unprotected barbituric acid and Meldrum's acid—conditions that are not easily attainable through traditional one-factor-at-a-time screenings. We present a method that allows for the rapid synthesis of 5-aryl barbiturates and 5-aryl Meldrum's acids from a wide range of aryl halides, utilizing commercially available palladium precatalysts. Harnessing our open-source HTE OS platform, we efficiently conducted and analysed the reactions required. Our optimised conditions led to satisfactory yields typically in the range between 50–90% and good reproducibility when scaled up in a traditional bench chemistry setting. We observe interference of steric hindrance on the aryl halide, observed also for other 1,3-dicarbonyl nucleophiles as well as poor performance of some heterocyclic substrates.