High-Throughput Work-Up and Purification Strategies for Suzuki–Miyaura Library Synthesis

Since its introduction, the Suzuki–Miyaura coupling has become one of the most widely applied carbon–carbon bond-forming reactions in medicinal chemistry and discovery-oriented synthesis. While substantial efforts have focused on catalyst development, substrate scope, and reaction miniaturization, considerably less attention has been devoted to downstream processing, which can represent a major bottleneck in high-throughput (HT) library synthesis. This review surveys post-2000 developments, with particular emphasis on the last decade, in the automated work-up and purification of Suzuki–Miyaura reaction mixtures for small-scale parallel discovery chemistry. The characteristic features of these mixtures are first examined from a downstream perspective, including solvent systems, catalyst types, substrate classes, phase behavior, by-products, and product profiles, and their impact on automation compatibility. Current strategies are then critically evaluated in two major areas: automated work-up and automated purification. Approaches include filtration and precipitation, liquid–liquid extraction, scavenger-assisted cleanup, solid-supported and plate-based methods, miniaturized solid-phase extraction (SPE), membrane-assisted processing, mass-triggered purification, and integrated robotic platforms. Their advantages and limitations are assessed in terms of throughput, robustness, chemical compatibility, scalability, environmental impact, and economic feasibility. Finally, emerging opportunities for integrated, chromatography-minimized downstream processing are discussed, including chemically functionalized and covalently modified plate-based systems for automated Suzuki library purification. By focusing specifically on downstream bottlenecks, this review provides a framework for developing more efficient, sustainable, and automation-compatible Suzuki workflows for modern discovery chemistry.