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 and good reproducibility when scaled up in a traditional bench chemistry setting.