Svenja Warratz

N-Acyl Amino Acid Ligands for Ruthenium(II)-Catalyzed meta-C–H tert-Alkylation with Removable Auxiliaries

Acylated amino acid ligands enabled ruthenium(II)-catalyzed C-H functionalizations with excellent levels of meta-selectivity. The outstanding catalytic activity of the ruthenium(II) complexes derived from monoprotected amino acids (MPAA) set the stage for the first ruthenium-catalyzed meta-functionalizations with removable directing groups. Thereby, meta-alkylated anilines could be accessed, which are difficult to prepare by other means of direct aniline functionalizations. The robust nature of the versatile ruthenium(II)-MPAA was reflected by challenging remote C-H transformations with tertiary alkyl halides on aniline derivatives as well as on pyridyl-, pyrimidyl-, and pyrazolyl-substituted arenes. Detailed mechanistic studies provided strong support for an initial reversible C-H ruthenation, followed by a SET-type C-Hal activation through homolytic bond cleavage. Kinetic analyses confirmed this hypothesis through an unusual second-order dependence of the reaction rate on the ruthenium catalyst concentration. Overall, this report highlights the exceptional catalytic activity of ruthenium complexes derived from acylated amino acids, which should prove instrumental for C-H activation chemistry beyond remote functionalization.

Ruthenium(II)‐Catalyzed CH Activation/Alkyne Annulation by Weak Coordination with O2 as the Sole Oxidant

Aerobic oxidative CH functionalizations of weakly coordinating benzoic acids have been accomplished with versatile ruthenium(II) biscarboxylates under ambient oxygen or air. Mechanistic studies identified the key factors controlling the elementary step of the oxidation of the ruthenium(0) complex.

Ruthenium Oxidase Catalysis for Site‐Selective C–H Alkenylations with Ambient O2 as the Sole Oxidant

Ruthenium(II) oxidase catalysis by direct dioxygen-coupled turnover enabled step-economical oxidative C-H alkenylation reactions at ambient pressure. Versatile ruthenium(II) biscarboxylate catalysts displayed ample substrate scope and proved applicable to weakly coordinating and removable directing groups. The twofold C-H functionalization strategy was characterized by exceedingly mild reaction conditions as well as excellent positional selectivity.

Cobalt-Catalyzed Oxidase C−H/N−H Alkyne Annulation: Mechanistic Insights and Access to Anticancer Agents

Cp*-free cobalt-catalyzed alkyne annulations by C-H/N-H functionalizations were accomplished with molecular O2 as the sole oxidant. The user-friendly oxidase strategy proved viable with various internal and terminal alkynes through kinetically relevant C-H cobaltation, providing among others step-economical access to the anticancer topoisomerase-I inhibitor 21,22-dimethoxyrosettacin. DFT calculations suggest that electronic effects control the regioselectivity of the alkyne insertion step.

Single-Component Phosphinous Acid Ruthenium(II) Catalysts for Versatile C−H Activation by Metal–Ligand Cooperation

Well-defined ruthenium(II) phosphinous acid (PA) complexes enabled chemo-, site-, and diastereoselective C-H functionalization of arenes and alkenes with ample scope. The outstanding catalytic activity was reflected by catalyst loadings as low as 0.75 mol %, and the most step-economical access reported to date to angiotensin II receptor antagonist blockbuster drugs. Mechanistic studies indicated a kinetically relevant C-X cleavage by a single-electron transfer (SET)-type elementary process, and provided evidence for a PA-assisted C-H ruthenation step.

Heterogeneous palladium-catalysed Catellani reaction in biomass-derived γ-valerolactone

Herein, we report the unprecedented use of a heterogeneous palladium catalyst for the step-economical Catellani reaction. The substrate scope with encapsulated Pd(OAc)2 (Pd EnCat™ 30) or Pd/Al2O3 proved to be broad, while the renewable biomass-derived γ-valerolactone (GVL) was identified as an effective reaction medium. Mechanistic studies highlighted the possible heterogeneous nature of the Pd/Al2O3 catalyst, while showing that the reaction performed in the presence of Pd EnCat™ 30 is most likely catalysed by leached homogeneous palladium species. The heterogeneous Pd/Al2O3 catalyst can be easily recovered at the end of the reaction and efficiently reused in consecutive reaction runs.

Ruthenium(II)-catalysed remote C–H alkylations as a versatile platform to meta -decorated arenes

The full control of positional selectivity is of prime importance in C–H activation technology. Chelation assistance served as the stimulus for the development of a plethora of ortho-selective arene functionalizations. In sharp contrast, meta-selective C–H functionalizations continue to be scarce, with all ruthenium-catalysed transformations currently requiring difficult to remove or modify nitrogen-containing heterocycles. Herein, we describe a unifying concept to access a wealth of meta-decorated arenes by a unique arene ligand effect in proximity-induced ruthenium(II) C–H activation catalysis. The transformative nature of our strategy is mirrored by providing a step-economical entry to a range of meta-substituted arenes, including ketones, acids, amines and phenols—key structural motifs in crop protection, material sciences, medicinal chemistry and pharmaceutical industries.

Synergistic Manganese(I) C−H Activation Catalysis in Continuous Flow: Chemoselective Hydroarylation

Chemoselective hydroarylations were accomplished by a novel synergistic Brønsted acid/manganese(I)-catalyzed C-H activation manifold. Thus, alkynes bearing O-leaving groups could, for the first time, be employed for C-H alkenylations without concurrent β-O elimination, thereby setting the stage for versatile late-stage diversifications. Also described is the first manganese-catalyzed C-H activation in continuous flow, thus enabling efficient hydroarylations within only 20 minutes.

Arene‐Ligand‐Free Ruthenium(II/III) Manifold for meta‐C−H Alkylation: Remote Purine Diversification

meta-Selective C-H alkylations of bioactive purine derivatives were accomplished by versatile ruthenium catalysis. Thus, the arene-ligand-free complex [Ru(OAc)2 (PPh3 )2 ] enabled remote C-H functionalizations with ample scope and excellent levels of chemo- and positional selectivities. Detailed experimental and computational mechanistic studies provided strong support for a facile C-H activation within a ruthenium(II/III) manifold.