Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification

Electrochemistry has emerged as an increasingly viable tool in molecular synthesis. Here the authors realize electrocatalyzed C-H activations, with the aid of data science and artificial intelligence, towards selective alkenylations for late-stage drug diversifications. Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C-H activations, these arene functionalizations generally require directing groups to enable the C-H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C-H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C-H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C-H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C-H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.

Automated summary

Electrochemistry, with the aid of data science and artificial intelligence, is increasingly being used for molecular synthesis. The authors have successfully utilized electrocatalyzed C-H activations for selective alkenylation in late-stage drug diversification. This approach eliminates the need for directing groups, which simplifies the synthesis process and reduces waste.