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

Abstract

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.

Recent advances in the synthesis of dibenzofurans

“…In most cases, syntheses of dibenzofurans with biological or photovoltaic properties begin with creating the dibenzofuran unit, which is then functionalized. 100 With this in mind, we think simpler to synthesize this heterocycle by first creating the C-O bond or the C-C bond of the central 5-membered ring (sections 2 and 3). Fig.…”

Noncovalent interaction with a spirobipyridine ligand enables efficient iridium-catalyzed C–H activation

“…A notable early example is a report by Noyori on an enantioselective transfer hydrogenation of aryl ketones catalyzed by chiral η 6 -ruthenium complexes, where a CH–π interaction between the C–H bond of the ligand and the aryl substituent of the ketone was proposed by computational studies to stabilize one of the diastereomeric transition states 9 . Several subsequent studies also proposed through computation the stabilization of a transition state by CH–π interaction as a rationale for the observed enantio- 10 – 14 and regioselectivity 15 , 16 , including in transition-metal-catalyzed C–H functionalization (Fig. 1a ).…”

Palladium-Catalyzed Electrooxidative Double C–H Arylation

“…21 Referring to palladaelectrocatalysis, 22 we have extended the scope of oxidative coupling to asymmetric catalysis 23 and undirected C−H olefination. 24 However, to the best of our knowledge, biaryl formation via electrochemical palladium-catalyzed double C−H activation has proven elusive.…”

“…Harnessing the advantages of replacing toxic and undesirable stoichiometric chemical oxidants with electricity, our group has significantly contributed to the progress on electrochemical C–H activation catalyzed by 3d-, 4d-, and 5d-metals . Referring to palladaelectrocatalysis, we have extended the scope of oxidative coupling to asymmetric catalysis and undirected C–H olefination . However, to the best of our knowledge, biaryl formation via electrochemical palladium-catalyzed double C–H activation has proven elusive.…”