Electrocatalyzed Direct Arene Alkenylations without Directing Groups: Selective Late-Stage Drug Diversification

Abstract

Electrocatalysis has emerged as an increasingly viable platform for molecular syntheses, that can replace chemical redox agents and enable unprecedented reaction pathways. Despite major progress in electrooxidative C−H activations, these arene transformations generally require directing groups for chelation-induced efficiency and control of position-selectivity in the C−H activation. The installation and removal of these directing groups calls for additional synthesis operations, which jeopardizes the inherent efficacy of the C−H activation approach in terms of undesired waste formation and low resource economy. In sharp contrast, we herein present molecular electrocatalyzed C−H olefinations of simple arenes devoid of exogenous directing groups. The robust palladaelectro-catalysis proved amenable to a wide range of both electronically-diverse arenes under exceedingly mild reaction conditions. The strategy avoids sacrificial chemical oxidants, but operates by the reductive hydrogen evolution reaction (HER). This study points to a remarkable strategy comprising two electrochemical transformations to guarantee unprecedented levels of position-selectivities in direct arene olefinations. Cyclic voltammetry studies and computational analysis identified a direct correlation between the redox potential and catalysis efficacy. The palladaelectro-catalysis strategy avoids protecting and directing group interconversions, the practical importance of which is reflected by direct late-stage functionalizations of structurally complex compounds of relevance to drug discovery and pharmaceutical industries.

Silver‐Free C−H Activation: Strategic Approaches towards Realizing the Full Potential of C−H Activation in Sustainable Organic Synthesis

“…The products 9 a , 9 b , and 9 k were formed under the combination of steric and electronic control exerted by the substituents present in the starting material. In 2022, Ackermann and co‐workers reported an olefination protocol where the authors replaced the silver by using benzoquinone and electrolysis in acetic acid at a graphite felt anode under a constant current of 1 mA (Scheme 10B) [51] . The electrochemical recycling of benzoquinone was performed in a divided cell to avoid the quinone reduction at the cathode.…”

“… A) Non‐directed C−H olefination of arenes with Ag [25] . B) Electrochemical C−H olefination of arenes [51] . C) Electrochemical C−H olefination of arenes [52] …”

“…In 2022, Ackermann and co‐workers reported an olefination protocol where the authors replaced the silver by using benzoquinone and electrolysis in acetic acid at a graphite felt anode under a constant current of 1 mA (Scheme 10 B). [51] The electrochemical recycling of benzoquinone was performed in a divided cell to avoid the quinone reduction at the cathode. The authors employed thiol‐containing carboxylic acid as ligand ( L6 ) and formed products preferentially under electronic control.…”

Silberfreie C−H‐Aktivierung: Strategische Ansätze zur Erschließung des vollen Potenzials von C−H‐Aktivierungen in der nachhaltigen organischen Synthese

“…Die Produkte 9 a , 9 b und 9 k bildeten sich unter einer Kombination von sterischer und elektronischer Kontrolle durch die im Edukt vorhandenen Substituenten. 2022 berichteten Ackermann und Mitarbeiter über ein Olefinierungsprotokoll, bei dem die Autoren das Silber durch Benzochinon ersetzten und eine Elektrolyse in Essigsäure an einer Graphitfilz‐Anode mit einem konstanten Strom von 1 mA durchführten (Schema 10B) [51] . Die elektrochemische Regenerierung von Benzochinon wurde in einer geteilten Zelle durchgeführt, um die Chinonreduktion an der Kathode zu vermeiden.…”

“… A) Nicht‐dirigierte C−H‐Olefinierung von Arenen mit Ag [25] . B) Elektrochemische C−H‐Olefinierung von Arenen [51] . C) Elektrochemische C−H‐Olefinierung von Arenen [52] …”