Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air. Both N−C and C−C axial chiral (hetero)biaryls were successfully constructed, leading to a...
Enantioselective C−H activation has surfaced as a transformative toolbox for the efficient assembly of chiral molecules. However, despite of major advances in rhodium and palladium catalysis, ruthenium(II)‐catalyzed enantioselective C−H activation has thus far largely proven elusive. In contrast, we herein report on a ruthenium(II)‐catalyzed highly regio‐, diastereo‐ and enantioselective C−H alkylation. The key to success was represented by the identification of novel C2‐symmetric chiral imidazolidine carboxylic acids (CICAs), which are easily accessible in a one‐pot fashion, as highly effective chiral ligands. This ruthenium/CICA system enabled the efficient installation of central and axial chirality, and featured excellent branched to linear ratios with generally >20 : 1 dr and up to 98 : 2 er. Mechanistic studies by experiment and computation were carried out to understand the catalyst mode of action.
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.
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.
Die enantioselektive C−H‐Aktivierung hat sich zu einem transformativen Werkzeug für den effizienten Aufbau chiraler Moleküle entwickelt. Trotz großer Fortschritte in der Rhodium‐ und Palladiumkatalyse hat sich die ruthenium(II)‐katalysierte enantioselektive C−H‐Aktivierung bisher jedoch als weitgehend herausfordernd erwiesen. Im Gegensatz dazu berichten wir nun über eine ruthenium(II)‐katalysierte hochregio‐, diastereo‐ und enantioselektive C−H‐Alkylierung. Als Schlüssel zum Erfolg wurden C2‐symmetrischen chiralen Imidazolidincarbonsäuren (CICAs), die leicht in einer Eintopfreaktion hergestellt werden können, als hochwirksame chirale Liganden identifiziert. Dieses Ruthenium/CICA‐System ermöglichte die effiziente Installation der zentralen und axialen Chiralität und verfügte über ausgezeichnete verzweigte bis lineare Verhältnisse mit im Allgemeinen >20 : 1 dr und bis zu 98 : 2 er. Experimentelle und computerchemische mechanistische Studien wurden durchgeführt, um die Wirkungsweise des Katalysators zu entschlüsseln.
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