Exploring Homogeneous Conditions for Mild Buchwald-Hartwig Amination in Batch and Flow

Cross-couplings are among the most frequently used reac-tions in complex molecule synthesis. However, the require-ment of stoichiometric base can cause challenges. Harsh, insoluble inorganic bases can lead to poor tolerance of sen-sitive functional groups, scale-up issues, and difficult adap-tation to continuous flow platforms. Herein, we describe the use of high throughput experimentation to identify a num-ber of conditions that enable Buchwald-Hartwig reactions to be carried out using readily available ligands (e.g. XantPhos) with DBU as a soluble, functional group tolerant, homogeneous base. Application of this system to diverse aminations in batch and flow are demonstrated, as is the translation of this technique to performing continuous Mi-zoroki-Heck and Sonogashira coupling reactions.