Ideation and Evaluation of Novel Multicomponent Reactions via Mechanistic Network Analysis and Automation

Novel reactivity is paramount to accessing valuable chemical space. Chemists use mechanistic intuition in conjunction with modern reaction screening techniques to discover, invent, or optimise chemical reactions. We have codified this logic in an automated cheminformatic workflow as one approach to systematic reaction invention. Hundreds of expert-encoded elementary reaction templates were used to construct a highly connected mechanistic network. This network can be used to enumerate reaction pathways for a set of given input substrates and reagents, serving as a qualitative “virtual flask”. Our method’s predictive capability is first exemplified through the regeneration of mechanistic pathways to the main and potential side products of seven known multicomponent reactions. Then, we showcase its innovative capability in a multicomponent reaction invention pipeline that rapidly screens three component sets of starting materials for scenarios where two components form an intermediate that is captured by a third reactant. Two novel three component transformations proposed by the model were experimentally validated using robotically dosed parallel reaction plates employing a broad range of reaction conditions. We discuss the potential utility of these novel transformations and interrogate the kinetics of both reaction systems with a robot-operated assay.