Development of a High-Throughput Kinetics Protocol and Application to an Aza-Michael Reaction

High-throughput experimentation (HTE) has become integral to the pharmaceutical industry with most major pharmaceutical companies investing in automation and high-throughput screening technologies. Testing hundreds of reactions in parallel has distinct advantages; however, one clear disadvantage is that performing a reaction on micromolar scale is not always indicative of the reaction's performance on multikilogram scale. Additionally, a great deal of information is lost by looking at a single time point. Valuable data around intermediates, over-reaction, catalyst induction periods, and so forth are invisible to a typical HTE workflow, which involves analyzing reactions at a single time point (e.g., 18 h). We envisioned a workflow in which time courses for each well of a high-throughput screen were collected. With this change in strategy, it could then become possible to complete high-throughput screening, select reaction conditions, gather kinetic information, and successfully build a kinetic model in less than 1 week. A kinetic model consisting of scale-independent parameters allows for virtual reaction optimization where the input concentrations, catalyst loading, and temperature can all be simulated and adjusted to understand their impact on yield or quality in a matter of seconds. A case study is presented with a transition metal salt/TMSCl-catalyzed aza-Michael reaction to showcase the performance and robustness of the high-throughput kinetic platform. A reaction progress kinetic analysis approach is utilized to quickly screen the rates of 48 catalyst/solvent combinations and create a mechanistic model. The first-principles kinetic model provides support for a proposed mechanism of dual activation by TMSCl.