Direct Arylation of Thiophenes in Continuous Flow

Abstract Synthetic methodologies involving direct C−H functionalization are promising to improve sustainability in organic synthesis. However, these newly developed strategies may have a scarce appeal for larger scale applications due to the high catalyst loading, harsh conditions or their typically long reaction times that affect severely the process productivity. Flow chemistry technology is a recognized tool to improve both the efficiency and scalability in organic synthesis that can overcome these issues. In the present paper we studied an “in flow” method for the direct arylation of thiophene derivatives with aromatic bromides to promptly afford heteroaromatic biaryls, which are recurrent motifs both in biologically active molecules and in functional materials. By using a packed‐bed reactor containing potassium carbonate as the solid base and an automated system, we could develop a reliable methodology for thiophene arylation in flow with yields up to 90 % within a residence time of 30–60 minutes. This strategy is suitable for a wide variety of substrates and allowed the reaction to be carried out at gram‐scale reaching a productivity value of 1.1 g h −1 .