Enabling electrochemical, decarboxylative C(sp²)-C(sp³) cross-coupling for parallel medicinal chemistry

Herein we report the development of an automated protocol for coupling aliphatic carboxylic acids and aryl halides under mild, electrochemical conditions. Carboxylic acids are one of the largest pools of commercially available building blocks utilized in parallel medicinal chemistry to expand structure-activity relationships. However, their usage in decarboxylative cross-coupling reactions to forge C(sp²)-C(sp³) bonds is low due to challenges associated with direct decarboxylation. Redox-active esters (RAE) are commonly employed to increase the reactivity of carboxylic acids for decarboxylative cross-coupling reactions. Previously, coupling reagent byproducts from in situ generated RAEs proved detrimental to transition metal catalysis. We have developed a purification-free protocol for activating carboxylic acids as N-hydroxyphthalimide (NHPI) esters, which are employed in electrochemical decarboxylative cross-coupling in a high-throughput, automated fashion. This automated workflow enables the preparation of compound libraries including PROTACs. By enabling the pool of commercial aliphatic carboxylic acids to be rapidly incorporated into drug-like molecules, this protocol can potentially impact how C(sp²)-C(sp³) cross-coupling reactions are performed in drug discovery campaigns.